T. K. Gajjar a small factory at parel was started, this firm was ..... extracts of plant drugs used in Ayurveda. Materiamedica ...... Rhubarb powder. Light magnesium ...
A Text Book of Concise Pharmaceutics – I Mr. Sandip B. Ahire M. Pharm. (Quality Assurance) Assistant Professor K.B.H.S.S. Trust's Institute of Pharmacy, Bhaygaon Road, Malegaon Camp, Malegaon Dist: Nashik - 423105.
Dr. Vinod A. Bairagi M.Pharm. PhD ( Pharmacology) Principal K.B.H.S.S. Trust's Institute of Pharmacy, Bhaygaon Road, Malegaon Camp, Malegaon Dist: Nashik - 423105.
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A Text Book of Concise Pharmaceutics – I Authors : Mr. Sandip B. Ahire Dr. Vinod A. Bairagi ISBN :
978 - 81- 938411 - 5 - 0
Publisher :SARA BOOK PUBLICATION 303, Maharana Pratap Complex B/H.V. S. Hospital Paldi, Ahmedabad - 380006. Phone: +91 8866 00 3636, +91 8866 11 3636 First Edition : October 2018 This book is sold subject to the condition that it shall not, by way of trade or otherwise, be lent, resold, hired out, or otherwise circulated without the publisher's prior written consent in any form of binding or cover other than that in which it is published and without a similar condition including this condition being imposed on the subsequent purchaser and without limiting the rights under copyright reserved above, no part of this publication may be reproduced, stored in or introduced into a retrieval system, or transmitted in any form or by any means (electronic, mechanical, photocopying, recording or otherwise), without the prior written permission of both the copyright owner and the abovementioned publisher of this book. Copyright© 2018\ Sara Book Publication, Ahmedabad
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PREFACE
This book offers encouragement and empowers readers to easy learn and understand the basic as well as recent concise information on pharmaceutics. The students of F.Y.B. Pharmacy to who want “easy stepwise study material” for the subject of Pharmaceutics. This book is written in a popular, conversational style. In this book, the author presents his own idea make content easy for reader also provide wide number of examples for every content. The book start with contents, total number of contents cover in this book are 13 for first semester. Every chapter start with separate topic wise new credit based syllabus of Pharmacy Council of India (PCI) for academic year 201819. Total number of FIVE UNITS that is each unit contains TWO or TRHEE CHAPTERS are given in this book. The authors are thankful to who directly or indirectly helped him in publishing this book. We thank our publisher, SARA for timely printing the book. We would like to express our gratitude and thanks to all staff of SARA publication. -Authors
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ACKNOWLEDGEMENT
We would like to express our deepest appreciation to all those who provided us the possibility to complete this book. A special gratitude we give to our chairman Hon. Prasad Bapu Hiray, for his contribution in stimulating suggestions and encouragement. Furthermore we would also like to acknowledge with much appreciation the crucial role of the parents who always support us with their blessing. A special thanks goes to our team mates, Yogesh Ahire, Pratik Patil, Shubhangi Dyandyan, Pramod Deore, Kalyani Deore, Aishwarya Patil, Mangesh Khillare, Ghatul Gokul, who help us to assemble the data and gave suggestion. We have to appreciate the guidance given by SARA publications as well as the panels especially in our book publication.
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BP103T. PHARMACEUTICS- I (Theory)
Course Content: UNIT – I Historical background and development of profession of pharmacy: History of profession of Pharmacy in India in relation to pharmacy education, industry and organization, Pharmacy as a career, Pharmacopoeias: Introduction to IP, BP, USP and Extra Pharmacopoeia. Dosage forms: Introduction to dosage forms, classification and definitions Prescription: Definition, Parts of prescription, handling of Prescription and Errors in prescription. Posology: Definition, Factors affecting posology. Pediatric dose calculations based on age, body weight and body surface area. UNIT – II Pharmaceutical calculations: Weights and measures – Imperial & Metric system, Calculations involving percentage solutions, alligation, proof spirit and isotonic solutions based on freezing point and molecular weight. Powders: Definition, classification, advantages and disadvantages, Simple & compound powders – official preparations, dusting powders, effervescent, efflorescent and hygroscopic powders, eutectic mixtures. Geometric dilutions. Liquid dosage forms: Advantages and disadvantages of liquid dosage forms. Excipients used in formulation of liquid dosage forms. Solubility enhancement techniques UNIT – III Monophasic liquids: Definitions and preparations of Gargles, Mouthwashes, Throat Paint, Eardrops, Nasal drops, Enemas, Syrups, Elixirs, Liniments and Lotions.
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Biphasic liquids: Suspensions: Definition, advantages and disadvantages, classifications, Preparation of suspensions; Flocculated and Deflocculated suspension & stability problems and methods to overcome. Emulsions: Definition, classification, emulsifying agent, test for the identification of type of Emulsion, Methods of preparation & stability problems and methods to overcome. UNIT – IV Suppositories: Definition, types, advantages and disadvantages, types of bases, methods of preparations. Displacement value & its calculations, evaluation of suppositories. Pharmaceutical incompatibilities: Definition, classification, physical, chemical and therapeutic incompatibilities with examples. UNIV – V Semisolid dosage forms: Definitions, classification, mechanisms and factors influencing dermal penetration of drugs. Preparation of ointments, pastes, creams and gels. Excipients used in semi solid dosage forms. Evaluation of semi solid dosages forms.
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INDEX
Chapter
Description
Page No.
Chapter 1
Historical Background and Development of Profession of Pharmacy History of profession of Pharmacy in India in relation to pharmacy education, industry and o rg a n i z a t i o n , P h a r m a c y a s a c a r e e r, Pharmacopoeias: Introduction to IP, BP, USP and Extra Pharmacopoeia.
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Chapter 2
Dosage Forms Introduction to dosage forms, classification and definitions
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Chapter 3
Prescription Definition, Parts of prescription, handling of Prescription and Errors in prescription.
51
Chapter 4
Posology Definition, Factors affecting posology. Pediatric dose calculations based on age, body weight and body surface area.
59
Chapter 5
Pharmaceutical Calculations Weights and measures – Imperial & Metric system, Calculations involving percentage solutions, alligation, proof spirit and isotonic solutions based on freezing point and molecular weight.
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Chapter 6
Powders Definition, classification, advantages and disadvantages, Simple & compound powders – official preparations, dusting powders, effervescent, efflorescent and hygroscopic powders, eutectic mixtures. Geometric dilutions.
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INDEX
Chapter 7
Chapter 8
Chapter 9
Chapter 10
Chapter 11
Chapter 12
Chapter 13
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Liquid Dosage Forms Advantages and disadvantages of liquid dosage forms. Excipients used in formulation of liquid dosage forms. Solubility enhancement techniques. Monophasic Liquids Definitions and preparations of Gargles, Mouthwashes, Throat Paint, Eardrops, Nasal drops, Enemas, Syrups, Elixirs, Liniments and Lotions. Biphasic liquidsSuspensions Definition, advantages and disadvantages, classifications, Preparation of suspensions; Flocculated and Deflocculated suspension & stability problems and methods to overcome.
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103
117
Biphasic liquidsEmulsions Definition, classification, emulsifying agent, test for the identification of type of Emulsion, Methods of preparation & stability problems and methods to overcome.
128
Suppositories Definition, types, advantages and disadvantages, types of bases, methods of preparations. Displacement value & its calculations, evaluation of suppositories.
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Pharmaceutical Incompatibilities Definition, classification, physical, chemical and therapeutic incompatibilities with examples. Semisolid Dosage Forms Definitions, classification, mechanisms and factors influencing dermal penetration of drugs. Preparation of ointments, pastes, creams and gels. Excipients used in semi solid dosage forms. Evaluation of semi solid dosages forms.
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Chapter: 1 Historical Background and Development of Profession of Pharmacy Unit – I Syllabus Historical Background and Development of Profession of Pharmacy: History of profession of Pharmacy in India in relation to pharmacy education, industry and organization, Pharmacy as a career, Pharmacopoeias: Introduction to IP, BP, USP and Extra Pharmacopoeia.
INTRODUCTION The Pharmaceutical sciences are a group of interdisciplinary areas of study involved with the design, action, delivery, disposition and use of drugs. The study and design of drug formulation for optimum delivery, stability, pharmacokinetics and patient acceptance. As new discoveries advance and extend the pharmaceutical sciences, subspecialties continue to be added to this list. Importantly, as knowledge advances, boundaries between these specialty areas of pharmaceutical sciences are beginning to blur. Many fundamental concepts are common to all pharmaceutical sciences. These shared fundamental concepts further the understanding of their applicability to all aspects of pharmaceutical research and drug therapy. Pharmacy has historic roots as the art and science of preparing and dispensing medications. While this traditional role is still a viable role for pharmacists, the preparation of medicines has transitioned in large part to the pharmaceutical industry. Dispensing of medicines has increasingly become more centralized and automated, with many of the tasks formerly per-formed by pharmacists being done using technology or delegated to pharmacy technicians. The provision of drug-related information to other healthcare professionals and the public and disease-state management programs to assure the proper use of medicines has become a more important role for pharmacists. The vast majority of the states have established continuing education requirements for re-licensure. This requirement has been adopted as a way to reassure the public that licensed pharmacists are keeping up-to-date to maintain their professional competence.
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History of Pharmacy Profession and Industry In India. “Bheshaj” is a term used in India since last 4000 years this term is similar to Greek term “pharmacon” (means-drug) from this word “pharmacy” has been derived. At that time the pharmacist is responsible for making the drug into suitable form acceptable to patient. At the same time he was also involved in collecting drug from various sources. Thus the pharmacy is science which requires knowledge to identify, collect, formulate, standardize the drug and provide necessary environment to maintain its therapeutic activity and to dispensed the drug. In ancient days persons involved in this profession was associated with some spiritual power and that drug with its natural effect had some magical involment in curing the disease. Due to this reason these peoples are treated as a different society. This era was followed by the involvement of apothecary in therapeutic activities due to they are near to god and having spiritual power.
Galen who was a physician known for his medical literature containing description of drugs, their formulae and method of preparations. His work is called as “ Galanical Pharmacy” botany as a base of pharmacy was changed to chemistry by Paraselsus, a Swiss Physician. He is responsible for developing the basic thinking of using individual chemical moiety for the treatment of diseases. Then further contribution was made by number of other scientists by developing new drugs from different sources. In India ayurvedic medicines were used as per the ancient books written by Charaka, a Physician, which subsequently replaced by allopathic medicines. after independence the further development in pharmaceutical industries fulfilled the need of our country. HISTORY OF PHARMACEUTICAL INDUSTRY IN INDIA. Over the past 40 years the growth of Indian pharmaceutical industries was so rapid. In 1947 the turnover of Indian pharmaceutical industries was only 10 corer, but in 2004 the sale turnover is about US $ 5.5 billion with as annual growth rate of about 17 %. Ÿ
The history of evolution of Indian pharmaceutical industry has been divided into two phases,
1. Pre-independence 2. Post independence. 12
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Four principalInitial time spans of industry.
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The First timespan is from 1850 to 1945.
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The Second timespan is from 1945 to 1970.
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The Third timespan is from 1980 to 1990.
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The Fourth time span is from 1990 to present time.
evolution of Indian pharmaceutical
1. PRE-INDEPENDENCE PHASE. Ÿ
When India was in British rule, the indigenous medicine like ayurvedic or unani were used in India. The central government of British India first introduce the allopathic medicine in India. Before this there were no any pharmaceutical manufacturing unit engaged in India. The foreign companies exported raw materials from India and converted it into finished products and imported it back to the India. But situation was changed in the era of 18th century.
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In India the first chemist shop was opened in 1811 by Mr. Bathgate in Calcutta, and he was came with east India company. After 100 years that is in the year 1910 this firm started manufacturing of tinctures and spirits.
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After that few scientists like Acharya Praffulla Chandra Ray, AS Kotibhaskar were engaged in manufacturing and was opened manufacturing unit Bengal Chemical and Pharmaceutical Work in 1892 at Calcutta.
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In 1903 under the leadership of Prof. T. K. Gajjar a small factory at parel was started, this firm was shifted to Baroda under name Alembic Chemical Works Ltd.
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These few units were not fulfilling the requirements of medicines to the Indian peoples.
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The drug production in India was low and it was meet only 13 % of the total requirement of the county.
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But after second world war due to fall in supply of drugs from UK, France and Germany.
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So many more companies like Unichem, Chemo Pharma, Zandu Pharmaceuticals Works, Calcutta Chemicals, Standard Chemicals, Chemical Industries and Pharmaceutical Laboratories (now known as CIPLA), East India Pharmaceutical Works and other were established. 13
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With the entry of new firms in the market the production of drug increased rapidly and indigenous firm were able to satisfy about 70 % of the country's medicinal requirements.
2. POST INDEPENDENCE PHASE Ÿ
The time span from 1945 to approximately the mid 1970 a major change known as therapeutic revolution was made beginning of this period and resulted in phenomenal growth of the global pharmaceutical industry located mainly in Germany, Switzerland , UK and also to some extent in the US.
Ÿ
In the post independence era (i.e. post 1947) the Indian pharmaceutical industry was completely dominated by multinational companies (MNCs) and drug price in India was among the highest in the world. In 1970, the Indian parliament passed the Indian Patents Act 1970 with provisions to allow only process patents for pharmaceutical molecules and new chemical entities (NCEs). The Indian Patent Act 1970 was the main reason for the fast and continuous growth of the Indian pharmaceutical industry. The Indian pharmaceutical industry until 2005, engaged in generic product development hence there was no significant activity in patenting in India.
CODE OF ETHICS AS DRAFTED BY PHARMACY COUNCIL OF INDIA (P.C.I.) Ethics is defined as 'code of moral principles'. It emphasizes on the determination of right or wrong while doing one's duty. Code of Pharmaceutical Ethics as formulated by Pharmacy Council of India which are meant to guide the pharmacist as to how he should conduct himself (or herself), in relation to himself (or herself), his / her patrons (owner of the pharmacy), general public, coprofessionals etc. and patients. Profession of Pharmacy is a noble profession as it is indirectly healing the persons to get well with the help of medical practitioners and other coprofessionals. Government has restricted the practice of Pharmacy to only Profession Pharmacists i.e registered Pharmacist under the Pharmacy Act 1948. PCI framed the following ethics for Indian Pharmacists, which may be categorized under the following headings:
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1. Pharmacist in relation to his job. 2. Pharmacist in relation to his trade. 3. Pharmacist in relation to medical profession. 4. Pharmacist in relation to his profession. 1. Pharmacist in relation to his job A pharmacist should keep the following things in relation to his job. (i) Pharmaceutical services: Pharmacy premises (medicine shops) should be registered. Emergency medicines and common medicines should be supplied to the patients without any delay. (ii) Conduct of the Pharmacy : Error of accidental contamination in the preparation, dispensing and supply of medicines should be checked in a pharmacy. (iii) Handling of Prescription : A pharmacist should receive a prescription without any comment on it that may cause anxiety to the patient. No part of the prescription should be changed without the consent of the prescriber. In case of changing the prescription should be referred back to the prescriber. (iv) Handling of drugs : A prescription should always be dispensed correctly and carefully with standard quality drug or excipients. Drugs that have abusive potential should not be supplied to anyone. (v) Apprentice Pharmacist : Experienced pharmacists should provide all the facilities for practical training of the apprentice pharmacists. Until and unless the apprentice proves himself or herself certificate should not be granted to him / her. 2. Pharmacist in relation to his trade Following are the provisions which pharmacist should keep in mind while dealing with his trade: (i) Price structure : The prices charged should be fair keeping with the quality, quantity and labour or skill required. (ii) Fair trade practice : Fair practice should be adopted by a pharmacist in the trade without any attempt to capture other pharmacist's business. If a customer brings a prescription (by mistake) which should be genuinely by some other pharmacy the pharmacist should refuse to accept the prescription. Imitation of copying of the labels, trademarks and other signs or symbols of other pharmacy should not be done. 15
(iii) Purchase of drugs : Pharmacists should buy drugs from genuine and reputable sources. (iv) Advertising and Displays : The sale of medicines or medical appliances or display of materials in undignified style on the premises, in the press or elsewhere are prohibited. 3. Pharmacist in relation to medical profession Following are the code of ethics of a pharmacist in relation to medical profession: (i) Limitation of professional activity : The professional activity of the medical practitioner as well as the pharmacists should be confined to their own field only. Medical practitioners should not possess drugs stores and pharmacists should not diagnose diseases and prescribe remedies. A pharmacist may, however, can deliver first aid to the victim incase of accident or emergency. (ii) Cladenstine arrangement : A pharmacist should not enter into a secret arrangement or contract with a physician by offering him any commission or any advantages. (iii) Liasion with public.: A pharmacist should always maintain proper link between physicians and people. He should advise the physicians on pharmaceutical matters and should educate the people regarding heath and hygiene. The pharmacist should be keep himself / herself up-to-date with pharmaceutical knowledge from various journals or publications. Any information acquired by a pharmacist during his professional activities should not be disclosed to any third party until and unless required to do so by law. 4. Pharmacist in relation to his profession Regarding to the profession the following code of ethics should be fulfilled. (i) Professional vigilance : A pharmacist must abide by the pharmaceutical laws and he/she should see that other pharmacists are abiding it. (ii) Law-abiding citizens : The pharmacists should have a fair knowledge of the laws of the country pertaining to food, drug, pharmacy, health, sanitation etc. (iii) Relationship with Professional Organizations : A pharmacist should be actively involved in professional organization, should advance the cause of such organizations.
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(iv) Decorum and Propriety : A pharmacist should not indulge in doing anything that goes against the decorum and propriety of Pharmacy Profession. (v) Pharmacists Oath : A young prospective pharmacist should feel no hesitation in assuming the following pharmacist's oath: Ÿ
“I promise to do all I can to protect and improve the physical and moral wellbeing of society, holding the health and safety of my community above other considerations. I shall uphold the laws and standards governing my profession, avoiding all forms of misinterpretation, and I shall safeguard the distribution of medical and potent substances.
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Knowledge gained about patients, I shall hold in confidence and never divulge unless compelled to do so by law.
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I shall strive to perfect and enlarge my knowledge to contribute to the advancements of pharmacy and the public health.
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I furthermore promise to maintain my honor in all transactions and by my conduct never bring discredit to myself or to my profession nor to do anything to diminish the trust reposed in my professional brethren.
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May I prosper and live long in flavor as I keep and hold to this, my Oath, but if violated these sacred promises, may the reverse be my lot.”
SCOPE AND POTENTIAL OF PHARMACY For D pharm Business 1. Drug Store2. Whole sale 3. Repacking4. Bulk drug distribution 5. Cosmetic manufacturing 17
Service 1. Hospital Pharmacy 2. Chemist in Drug Store / Whole sale store 3. Medical representative 4. Packaging, store maintenance in Pharmaceutical Industry 5. Secretary / PA to MD in Pharm. Industry FOR B.PHARM. M. PHARM. PhD Business 1. Pharmaceutical industry 2. Bulk Drug Manufacturing 3. Pharmacist job abroad 4. Cultivation of medicinal plants 5. Public testing laboratories6. Consultancy Service 1. FDA job2. Teacher diploma courses 3. Production 4. Marketing 5. Teacher for Graduate level courses6. Research and development ADDITIONAL INFORMATION ON WORLDWIDE PHARMACY PROFESSION THE FUTURE OF PHARMACY In the coming decades, pharmacists are expected to become more integral within the health care system. Rather than simply dispensing medication, pharmacists are increasingly expected to be compensated for their patient care skills. In particular, Medication Therapy Management (MTM) includes the clinical services that pharmacists can provide for their patients. Such services include the thorough analysis of all medication (prescription, non-prescription, and herbals) currently being taken by an individual. The result is a reconciliation of medication and patient education resulting in increased patient health outcomes and decreased costs to the health care system. This shift has already commenced in some countries; for instance, pharmacists in Australia receive remuneration from the Australian Government for conducting comprehensive Home Medicines Reviews. In Canada, pharmacists in certain provinces have limited prescribing rights (as in Alberta and British Columbia) or are remunerated by their provincial government for expanded services such as medications reviews (Medschecks in Ontario). In the United Kingdom, pharmacists who undertake additional training are obtaining prescribing rights and this is because of pharmacy education. They are also being paid for by the government for medicine use reviews. In Scotland the pharmacist can write prescriptions for Scottish registered patients of their regular medications, for the majority of drugs, except for controlled drugs, when the patient is unable to see their doctor, as could happen if they are away from home or the doctor is unavailable. In the United States, pharmaceutical care or clinical pharmacy has 18
had an evolving influence on the practice of pharmacy. Moreover, the Doctor of Pharmacy (Pharm. D.) degree is now required before entering practice and some pharmacists now complete one or two years of residency or fellowship training following graduation. In addition, consultant pharmacists, who traditionally operated primarily in nursing homes are now expanding into direct consultation with patients, under the banner of "senior care pharmacy.” PHARMACOPOEIAS: INTRODUCTION TO IP, BP, USP AND EXTRA PHARMACOPOEIA. Pharmacopoeia the word derives from the ancient Greek (pharmakopoiia), from (pharmako-) ″drug″, followed by the verb-stem (poi-) ″make″ and finally the abstract noun ending (-ia). These three elements together can be rendered as ″drug-mak-ing″ or ″to make a drug″. The word pharmacopoeia can be pronounce in three different ways like pharmacopoeia, pharmacopeia, or pharmacopoea, in its modern sense, is a legally binding collection, prepared by a national or regional authority, of standards and quality specifications for medicines used in that country or region. A quality specification is composed of a set of appropriate tests that will confirm the identity and purity of the product, ascertain the strength (or amount) of the active substance and, when needed, its performance characteristics. The role of a modern pharmacopoeia is to furnish quality specifications for active pharmaceutical ingredients. The texts cover pharmaceutical starting materials, excipients, intermediates and finished pharmaceutical products (FPPs). General requirements may also be given in the pharmacopoeia on important subjects related to medicines quality, such as analytical methods, microbiological purity, dissolution testing, stability, etc. DRUG INFORMATION SOURCES DRUG COMPENDIA
Official Books Indian Pharmacopoeia British Pharmacopoeia United States Pharmacopoeia Ÿ British Pharmaceutical Codex Ÿ European Pharmacopoeia Ÿ Ayurvedic Pharmacopoeia etc. Ÿ Ÿ Ÿ
Non-Official Books Martindale MateriaMedica Merck Index
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Pharmacopoeias and their Importance Q1. What is the need of Pharmacopoeia? Ans: To maintain uniformity and standards of drugs and medical devices which are used in market for this purpose govt. of each country make laws and standard to avoid mixup of standard drugs with substandard drugs or adulterated drugs. Q 2. Who can prepare pharmacopoeia? Ans: Govt. of each country (ministry of health and family welfare) can make pharmacopoeia. Q 3. What is pharmacopoeia and what it includes? Ans: Pharmacopoeia is a book of standards which includes list of drugs with complete monograph, monographs contains description of drug its tests for identification , formulae for their preparations along with this storage condition, uses, dose, assay , all information essential for proper manufacturing and safe use of medicines. All these information given in the book called as pharmacopoeia. Q 4. Why each country has its own book of standards i.e. Pharmacopoeia? Ans: Because the stability and efficacy of drug is affected by geographical climatic environmental conditions in which the drugs are used by people. Development of Indian Pharmacopoeias Editions Indian Pharmacopoeia 1955 - First edition, followed by supplement in 1960. - Dr. B. N. Ghosh, Chairman Indian Pharmacopoeia 1966 - Second edition, followed by supplement in 1975. - Dr. B. Mukherji, Chairman Indian Pharmacopoeia 1985 -Third edition, followed by its addendum in 1989 and 1991. - Dr. Nityanand, Chairman Indian Pharmacopoeia 1996-Fourth edition, followed by its addendum 2000, supplement 2000 for Veterinary Products, addendum 2002 and addendum 2005. - Dr. Nityanand, Chairman Indian Pharmacopoeia 2007 - Fifth edition, followed by addendum 2008. - Dr. Nityanand, Chairman Indian Pharmacopoeia 2010 - Six edition, followed by its addendum 2012. Indian Pharmacopoeia 2014 - Seventh Edition- Addendum/Supplement 2015. - Chairman Mr. KeshavDesiraju. 20
Indian Pharmacopoeia 1955- First edition First edition of Indian pharmacopoeia was published in 1955, but actual process for its preparation was started in 1944. For the preparation of first edition of I.P Govt. of india constituted one board i.e. Drug Technical Advisory Board , (D.T.A.B) this board collected the information about drugs which were used in all over the india and was prepared one list of these drug, this drug list was published by Govt. under the name “The Indian Pharmacopoeial List 1946.” The committee constituted under the chairmanship of Lt. COL. R.N.Chopra and other Nine members. Prepared the list of drugs and classifieds this list of drugs into two parts : 1. Substances which are already included in the British Pharmacopoeia , 48 monographs for crude drugs, chemicals, and its preparations. 2. Substances which are not included in the british pharmacopoeia a) b) c) d) e) f) g) h)
Drugs obtained from plant origin Drugs obtained from animal origin Biological products Insecticides Colouring agents Synthetic drugs Miscellaneous Drugs for veterinary (animal ) use
: 90 :10 : 05 : 07 : 03 : 05 : 15 : 02
The Indian pharmacopeia committee along with other subcommittees like Clinical Sub- Committee, Pharmacology Sub- Committee, Pharmacognosy Sub- Committee, Pharmacy Sub- Committee , Pharmaceutical Subcommittee were important , all these committees helped in compilation and drafting of monograph s of pharmacopoeia. The Dr. B.N.Ghosh appointed as a chairmanof the committee. Under his chairmanship the fist edition of Indian pharmacopoeia was published in1955. Specifications of first editonof I.P 1955. Ÿ Written in English. Ÿ The official titles of the monographs are given in latin. Ÿ It covered total 986 monographs. Ÿ It includes crude drugs, chemicals, biological and several formulas. Ÿ Its cost is Rs. 21. Supplement to first edition of Indian pharmacopoeia 1955 was published in 1960because after publication of first edition many new drugs were introduced in market.
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Indian Pharmacopoeia 1966 - Second edition After the death of Dr. B.N.Ghosh , the Dr. B.Mukharjiwas appointed as a chairman of committee and the under his chairmanship the remaining work of compilation of second edition was done and second edition was published in 1966. Specifications of second edition of I.P 1966 Written in English.
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Titles of monographs are written in English not in latin.
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It covered total 890 monographs.
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Titles contains name of drug at first, category at end, and doses given in metric system .
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Preparations of the drugs are given just after the parent monograph of that drug.
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For tablet and injections “Usual strengths” have been given.
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The non –aqueous titrimetry , column chromatography , complexometry have been given under new analytical techniques.
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Pills and pellets have been deleted from the second edition of I.P 1966.
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274 monographs from I.P 1955 were deleted from the second edition of I.P 1966.
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93 new monographs which are not official in I.P 1955 were added in the second edition of I.P 1966.
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Addition of monographs of vegetable drugs like Jatamansi, Rasna , Vidang.
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Antibiotics like Bacitracin, Neomycin were also added in second edition of I.P 1966.
Pharmacopoeia of India supplement 1975. After the publication of second edition of I.P 1966 , many drugs were introduced in the medical practice due to this it was very essential to provide them official standards. For this the supplement of Indian pharmacopeia was published in 1975. It includes: Ÿ 126 new monographs and also 250 monographs of second edition have been amended. 22
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One monographof cholera vaccine has been deleted.
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Many appendices giving the detailed analytical procedures have been rewritten and some appendices have been added.
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Monographs on eye ointment has been included for first time.
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TLC (Thin Layer Chromatography), GLC (Gas Liquid Chromatography) and IR Spectrophotometry have been added as a new analytical techniques.
Indian Pharmacopoeia 1985 -Third edition The Third edition of Indian Pharmacopoeia was published under the chairmanship of Dr. NityaNand, and the committee consists of 13 members along with member secretary and assistant secretory. The committee assisted by 10 sub-committees. Specifications of Third edition of I.P 1985 Third edition of I.P 1985 was published in TWO volumes.
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Nine appendices.
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261 monographs.
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450 monographs of second edition have been deleted from third edition.
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For organic chemical drugs IUPAC systems of nomenclature has been used.
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Analytical techniques like electrophoresis , flurometry, flame photometry, Photometric have been given the official recognition for the first time.
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Instrumental techniques i.e IR and UV spectrophotometry , gas chromatography, fluorescence and atomic absorption spectrophotometry have been added.
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Dissolution tests has been given for six tablets.
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Limit test for microbial contamination has been given for few frequently used pharmaceutical aids and some oral liquid preparations.
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The appendices for pharmaceutical containers, water for pharmaceutical use, biological assays have been annexed.
a) Addendum (I) to Indian pharmacopoeia 1985 third edition, published in 1989. Ÿ Covers46 new monographs Ÿ Amended 126 monographs of third edition.
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b) Addendum (II) to Indian pharmacopoeia 1985 third edition, published in 1991. Ÿ Covers 62 new drugs monographs Ÿ Amended 110 monographs of third edition. Ÿ Appendix on high performance liquid chromatography (HPLC). Indian Pharmacopoeia1996- Fourth edit It covers 1149 monographs and 123 appendices
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This edition includes 294 new monographs which were not included in third editionof I.P 1985.
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110 monographs have been deleted.
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A good number of monographs like creams, eye drops, gels, nasal preparations, oral liquids, pesseries, suppositories have been included.
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Important new appendices of biological indicators, jelly–strength, osmolarity, particulate matter, content of package dosage forms etc.
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Test for bacterial endotoxins as a substitute test for pyrogens have been added.
Indian Pharmacopoeia1996, Addendum 2000 Compliance with WTO, Indian pharmacopeial committee decided that there is a need for integrating the pharmacopoeial standards in india.
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42 new monographs have been added to IP 1966 by this addendum.
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The carbamazine monograph have some changes while bacterial endotoxin test for pyrogens has been replaced by extensive revised revision to earlier gel clot test.
Indian Pharmacopoeia1996, Addendum 2002 Ÿ New appendix on residual solvent has been added to monitor the content of organic volatile impurities which are used to produce in the manufacturing of active pharmaceutical substance, excipients. Ÿ
The appendix for HPLC has also been replaced by a revised version of ion chromatography.
Indian Pharmacopoeia 2007- Fifth edition Indian Pharmacopoeia 2010- Six edition Indian Pharmacopoeia 2014 - Seventh Edition The seventh edition of the Indian Pharmacopoeia (IP 2014) is published by the Indian Pharmacopoeia Commission (IPC) on behalf of the Government of India, Ministry of Health & Family Welfare. Chairman Mr. KeshavDesiraju.The Indian Pharmacopoeia (IP) is published in fulfilment of the requirements of the 24
Drugs and Cosmetics Act, 1940 and Rules thereunder. It prescribes the standards for drugs produced and/or marketed in India and thus contributes in the control and assurance of the quality of the medicines. The standards of this pharmacopoeia are authoritative and legally enforceable. It intends to help in the licensing of manufacturing, inspection and distribution of medicines. The Indian Pharmacopoeia 2014 is presented in four volumes. The scope of the Pharmacopoeia has been extended to includes additional anticancer drugs & antiretroviral drugs and formulations, products of biotechnology, indigenous herbs and herbal products, veterinary vaccines. Standards for new drugs and drugs used under National Health Programmes are added and the drugs as well as their formulations not in use now a days are omitted from this edition. The IP 2014 incorporates 2550 monographs of drugs out of which 577 are new monographs consisting of APIs, excipients, dosage forms and herbal products etc.
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A list of 577 New Monographs not included in IP-2010 and its Addendum2012 but added in this edition containing 313 New Monographs on drug substances, Dosage forms& Pharmaceutical aids (A to Z),
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43 New Drugs Substances Monographs,
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10 AntibioticMonographs,
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31 HerbalMonographs,
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05 Vaccines&immunosera for human use,
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06 Insulin Products,
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07 Biotechnology Products etc. alongwith the 19 new General Chapters.
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19 New Radiopharmaceutical Monographs&1 General chapter is first time beingincluded in this edition.
This edition of Indian Pharmacopoeia-2014 is now under printing and will be available to stakeholders probably in Sept.2013, before three months of its effective date, i.e. 1st Jan. 2014. British Pharmacopoeia (BP) The first edition of British Pharmacopoeia 1864 , was published by General Medical Council under the Medical Act 1858. Before that Edinburg, Scotland and Dublin had their pharmacopoeias and all were merged in the first edition of British Pharmacopoeia.
25
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Since after 1948, the British Pharmacopoeia was revised after every five years.
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After the publication of addendum II the responsibility of this publication was handed over to medical commission.
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The commission recommended the health ministers who then appointed a BP st commission on 1 march 1970.
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After 1973, BP was published in 1980 and 1988.
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Addendum were also published in between the regular publications.
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Earlier It included extracts , galanicals, and other crude drugs .
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Latest edition of BP was published in 1993.
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It consists of main four volume and four addendum i.e in 1994, 1995 and 1997.
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Addendum 1997 adds new drugs and preparations to amend the BP 1993.
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Major changes includes the replacement of all the edited texts of the monographs of European Pharmacopoeia entries in the form of cross references to the monographs published in the third edition of the European Pharmacopoeia.
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BP provides authoritative standards for the quality of substances, preparations.
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There are TWO volumes of BP
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First volume contains medicinal and pharmaceutical substances, IR reference spectraneeded for identification of drugs.
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Second Volume contains section on formulated preparation, blood products, immunological products, radio pharmaceutical preparation and surgical materials.
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The 15th edition of BP contains 2040 monographs.
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800 monographs of the second edition of European Pharmacopoeia also has been included in this edition.
British Pharmacopoeia 1980 British Pharmacopoeia 1988 British Pharmacopoeia 1993, 26
British Pharmacopoeia 2011. United States Pharmacopoeia (USP): First planning for creation of National Pharmacopoeia was started in 1817 by Dr. Lyman Speeding in Medical Society of New York . Ÿ
He divided united states into four districts ,Northern, Middle, Southern, Western. The plan includes medical societies and schools in each states to draft a pharmacopoeia.
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All four states with their four draft were invited to general convention held at Washington.
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To compile into a single National Pharmacopoeia.
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First USP was published in 1820.
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Both in English and Latin.
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217 drugs were listed in it.
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The revision of pharmacopoeia was decided after every ten years.
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The committee was consists of only Physicians
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In 1830 and 1840 pharmacists were included to assist new revision.
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In 1850 full membership was given to Pharmacists .
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Presently minimum one third member of revision committee should be from medical profession.
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In 1940 it was decided that revision of pharmacopoeia should be after every five years.
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USP VI published in 1880-90.
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Includes tests and assays to set standards of strength and purity for drugs.
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Two individual compendia published at the end of 1974 were combined to one and included 200 monographs.
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Includes tests for content uniformity, microbial limit and dissolution tests, also standards for container.
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USP XXI-NF XVI published in 1985. 27
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USP XXIII -NF XVIII were the next edition published. Includes 336 monographs and deleted12 monographs.
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First national formulary of united states was published in 1868 by American pharmaceutical association.
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25th revision of USP and 20th revision of NF published in 2002. After this USP-NF will be published annually.
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USP covers 3,400 monographs of drugs.
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NF covers 380 monographs of excipients.
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Eights supplements were published after the publication of main volumes of USP XXIII-NF18 Published in 1995.
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Latest Published Edition of USP 33 –NF 28.
European Pharmacopoeia European Pharmacopoeia commission started compilation of Pharmacopoeia in 1964. Ÿ Ÿ Ÿ Ÿ Ÿ Ÿ Ÿ
European
First volume of EP was published in 1969 and then in 1971. The supplement was published in 1973. USP maintained contact with EP and exchanged information. Third volume of EP was published in 1975. The supplement of third edition was published in 1999. This supplement added 105 new monographs. 124 revised monographs.
Martindale Extra Pharmacopoeia It was published for the purpose of practicing pharmacist and physicians evaluated information on drugs and medicines used through the world.
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The first edition was published in 1883.
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31st edition has been published in 1996. It contains 283 new monographs, 173 have Been deleted.
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It also included description of the diseases which are treated by drugs along with choice of treatment.
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Book has been divided into THREE PARTS.
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Part I contains 4458 monographs.
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Part II contains 784 short monographs of new drugs , toxic substances.
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Part III contains proprietary preparations, as well as official preparations form the current editions of BP,USP, NF and BPC.
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It also includes list of 4800 manufacturers and distributors.
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It also includes information from various pharmacopoeias like Austrian, Belgium, Chinese, Italian, Japanese, etc.
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From last 110 years Extra Pharmacopoeia has developed through 31 editions from William Martindales's small pocket book.
Merck Index The Merck Index is an encyclopedia of chemicals, drugs and biologicals with over 10,000 monographs on single substances or groups of related compounds. It also includes an appendix with monographs on organic name reactions. It was published by the United States pharmaceutical company Merck & Co. from 1889 until 2013, when the title was acquired by the Royal Society of Chemistry. The Merck Index is also available by subscription in an electronic searchable form, commonly carried by research libraries, as well as in a web-accessible form. Ÿ
The current edition is the 15th, published in April 2013.
British Pharmaceutical Codex (BPC) BPC was published for the purpose of providing guidelines to the Physicians and Pharmacists in the British Empire. Ÿ
The Council of Pharmaceutical Society produce a reference book in 1903.
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This reference book was published first time in 1907. Under the title British Pharmaceutical Codex.
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Revised editions were published in 1911, 1923, 1934, 1949, 1959, 1963, 1968 and 1973.
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The BPC used as a supplement for the information of British Pharmacopoeia.
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BPC also provided information of medicaments and formulations which are not included in BP.
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From 1963 BP and BPC was published simultaneously.
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In 1972 medicines commission stated that there should be only one book of standards for all medicines in UK, due to this the provision of codex standards have been discontinued. 29
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th
The 1973 edition of BPC was 10 edition and 1979 edition revised with the desired changes in the 11th edition and is known as “ The Pharmaceutical Codex”.
Ayurvedic Pharmacopoeia The 1st APC was constituted in 1962. Since then it is working continuously. The term of Committee remains for a period of 3 years from the date of its first meeting and the members hold office for that period. The functions of APC are as follows: Ÿ To prepare Ayurvedic Pharmacopoeia of India (API) of single drugs (Part I) and compound formulations (Part II). Ÿ
To prescribe the working standards for raw materials as well as compound formulations including tests for identity, purity, strength and quality so as to ensure uniformity of the finished formulations .
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To develop and standardize method of preparations, dosage forms, toxicity profile etc. of formulations.
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To identify methods and procedures for publication of the standards of all commonly used formulations of AFI in a phased manner.
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To provide all other information on Ayurvedic formulations regarding the distinguishing characteristics, methods of preparation, dosage, method of administration with various anupans or vehicles and their toxicity
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To develop the Quality standards, safety, efficacy profile of different parts of the plants; as well as inclusion of new plants as Ayurvedic drugs
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Any other matter relating to the quality standards, shelf life, identification, new formulations etc.
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To develop Quality standards, safety, efficacy profile of Intermediates like extracts of plant drugs used in Ayurveda
Materiamedica Materiamedica (English: medical material/substance) is a Latin medical term for the body of collected knowledge about the therapeutic properties of any substance used for healing (i.e., medicines). The earliest known writing about medicine was a hundred and ten page Egyptian papyrus. It was supposedly written by the god, Thoth, in about 16 B.C. The Ebers papyrus is an ancient recipe book dated to approximately 1552 B.C. It contains a mixture of magic and medicine with invocations to banish disease and a catalogue of useful plants, minerals, magic amulets and spells. The most famous Egyptian physician was Imhotep, in Memphis about 2500 B.C. Imhotep's materiamedica consisted of 30
procedures for treating head and torso injuries, tending of wounds, and prevention and curing infections and advanced principles of hygiene. National Formulary At its most basic level, a 'formulary' is a list of medicines. Traditionally, a formulary contained a collection of formulas for the compounding and testing of medication (a resource closer to what would be referred to as a pharmacopoeia today). Today, the main function of a prescription formulary is to specify particular medications that are approved to be prescribed under a particular insurance policy. The development of prescription formularies is based on evaluations of efficacy, safety, and cost-effectiveness of drugs. Depending on the individual formulary, it may also contain additional clinical information, such as side effects, contraindications, and doses. By the turn of the millennium, 156 countries had national or provincial essential medicines lists and 135 countries had national treatment guidelines and/or formulary manuals.
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Chapter: 2 Dosage Forms Unit – I Syllabus Introduction to dosage forms, classification and definitions.
INTRODUCTION The proper design and formulation of a dosage form requires consideration of the physical, chemical, and biological characteristics of all of the drug substances and pharmaceutical ingredients (excipients) to be used in fabricating the product. The drug and pharmaceutical materials utilized must be compatible and produce a drug product that is stable, efficacious, palatable, easy to administer, and well tolerated. Pre-formulation factors include physical properties such as particle size, crystalline structure, melting point, solubility, partition coefficient, dissolution, membrane permeability, dissociation constants, and drug stability. There are various types of dosage forms are available in market like solid, liquid, semisolid, gases etc. The dosage form of drug is administered to the patient by convenient manner at proper site for desired therapeutic effect known as routes of administration. Definitions DRUG: According to Drugs and Cosmetics act 1940, drug can be defined as, drug is a chemical substance used to cure, prevention, treatment and mitigation of diseases and disorders in human and animal beings called as Drug. (drug is a substance other than food). NEW-DRUG: According to Drugs and Cosmetics act 1940, drug can be defined as , New drug is a New chemical entity used to cure, prevention, treatment and mitigation of diseases and disorders in human and animal beings called as Drug. 32
SOURCES OF DRUGS
CONCEPT OF DOSAGE FORM: Drugs which are obtained from various sources are rarely administered in their pure chemical form. Drugs are combined with other inert substances (excipients or additives) and converted into suitable form for administration to the patient for their acceptance is called dosage form.
RATIONALE FOR DEVELOPMENT OF DOSAGE FORMThe therapeutic effect of drug will depends on routes of its administration such as orally, parenteraly, topically. Types of dosage form in which it is given such as solid dosage form, liquid dosage form etc. and mechanism used to make the dosage form, physical, chemical nature of drug. Drug given by parenteral route will give response faster than the drug given by oral route. Some times the same drug is available in different dosage forms it known as multiple dosage form. Dosage form is designed by considering various factors which affect the acceptance as well as drug efficacy. Dosage form should have the color, odor, taste and appearance which will not affect the patient acceptance. On the other hand it should be manipulated and presented way which is easily acceptable to 33
patient. The dosage form should be such that patient should not feel any difficulty in the proper use by desired route. Cost of the dosage form should be within limit. All precautions should be taken so that the effectiveness of the drug is maintained throughout the shelf life and when administered it gives the therapeutic effect. The dosage varies with age, sex, severity of the disease. DOSAGE FORMS NON STERILE DOSAGE FORM: Non sterile dosage forms are the dosage forms that are not administered directly to the systemic circulation hence such type of dosage form not requires sterility. A) SOLID DOSAGE FORMS: A substance having definite shape and volume manufactured for the administration of active and /or inert ingredient(s). Solids include tablets, capsules, powders, granules. Solid dosage form are prepared from powders. Unit Dosage forms : Unit dosage form are the dosage form that deliver accurate dose.unit compressed dosage forms such as tablet, unit non- compressed dosage forms such as capsule. Tablets: It may be defined as the solid unit dosage form of medicament or medicaments with or without suitable excipients and prepared either by molding or by compression. It comprises a mixture of active substances and excipients, usually in powder form, pressed or compacted from a powder into a solid dose. Advantages Ÿ Tablets are simple and convenient to use.
34
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They provide an accurately measured dosage of the active ingredient in a convenient portable package, and can be designed to protect unstable medications or disguise unpalatable ingredients.
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Most stable with respect to physical, chemical and microbiological attributes.
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Cheapest oral dosage form, easy to handle, use and carry out with attractive and elegant appearance.
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Cheap, easy to swallow and production does not require and additional processing steps.
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Provide protection of medicaments from atmospheric conditions like air, moisture and light, etc.
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Provide prolonged stability to medicaments.
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Low manufacturing cost as compare to other solid dosage forms and large scale production is possible.
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Administration of minute dose of drug in accurate amount.
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Unpleasant taste can be masked by sugar coating.
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Easy to divide into halves and quarters whenever fraction dose is required.
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Formulate as a special release products such as enteric or delayed release products.
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Packing and production is cheap and does not require more space for storage.
Disadvantages Ÿ Drugs which are amorphous and low density character are difficult to compress into tablet. Ÿ
Hygroscopic drugs are not suitable for compressed tablets.
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Drugs with low or poor water solubility, sloe dissolution, high absorbance in GI tract may be difficult to formulate.
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Sensitive to oxygen drugs may require special coating.
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Cost of production may be increase because of coating and encapsulation to remove bitter and unpleasant taste.
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Some tablet may cause problem in bioavailability.
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Difficult to formulate liquid in tablet and swallowing is difficult especially for children and ill patients.
TYPES OF TABLETS There are many types of tablets according to the intended of use and manufacturing process. [A] ORAL TABLET INTENDED FOR INGESTION Compressed tablets: Tablets can be made by compression of one or more active pharmaceutical ingredient with excipients by basic methods of tablet manufacturing. Multiple compressed tablets: Multiple compressed tablets are prepared by compressing the material more than once. These are known as multiple layered tablets or tablet within tablet. 35
Delayed action or Enteric coated tablets: These types of tablets contain a coating which resist dissolution of tablets in Gastro Intestinal Track (GIT) and disintegrate in intestinal fluids thus rendering delayed release features. Enteric coating is generally apply when drug substance is unstable in gastric fluid and may destroyed or may cause irritation in gastric mucosa or to extent absorption of drug from intestine. Normally coating materials mixed with acid and acid functionality or modified natural polymers. Most commonly used coating polymers are: Cellulose acetate phthalate (CAP), polyvinyl acetate phthalate (PVAP) and hydroxyl propyl methyl cellulose phthalate. Sugar coated tablet: Compressed tablets may be coated with coloured or uncoloured sugar coating and the coater is water soluble and dissolve quickly after swallowing. Sugar coat protects drug from environment, remove bitter taste and odour, enhance the appearance of tablet and permit identifying information. Sugar coating has some disadvantages like increase coat of production, require expertise for coating, increase size and weight. Film coated tablets: Tablets are compressed with a thin layer of polymer which forms a skin like film over tablet. The film is usually coloured, more durable and less bulky. The coating is designed to rupture and expose of tablet at desired location within GIT. Most commonly used polymers are Hydroxy propyl cellulose, Hydroxy ethyl and propyl methyl cellulose. Chewable tablet: These types of tablets have smooth surface, creamy base and usually flavoured and coloured mannitol, rapid disintegration which allow dissolving quickly in mouth. These types mostly useful for administration of large dose to children and adults. [B]TABLET USED FOR ORAL CAVITY Buccal tablets and sublingual tablets: Buccal and sublingual tablets are flat in shape and intended to dissolve drug in buccal cavity or beneath the tongue for mucosa absorption. These techniques useful for drugs which are destroyed by gastric fluid or poor absorption in GIT. Buccal tablets erode slowly and sublingual tablets dissolve quickly and produce rapid effect. Troches and Lozenges: They are intended to slowly dissolution mostly for local effect but sometimes for systemic absorption. Troches and Lozenges are disc shaped which contain active ingredient and flavouring agent in hard candy or sugar base. 36
Dental cones: Dental cones are designed to place in the empty socket for prevention of bacterial growth and sometime bleeding by containing coagulant. Dental cones release slowly for long duration. [C] TABLETS FOR OTHER ROUTES Vaginal tablet: Vaginal tablets are prepared by compression and shaped to fit snugly on plastic inserter devices in uncoated bullet shaped or ovoid tablets which are inserted into vagina for local effects with slow dissolution. They contain anti bacterial effect and also called vaginal inserts. Implantation tablet: Implantation tablets are injected under the skin by giving a small surgical cut into the skin. A special injector a hallow needle and plunger may require for administration. Purpose of these tablets is to prolong drug effect from month to year. These tablets are implanted intramuscularly or subcutaneous so they must be sterile and packed in sterile container. [D] TABLETS FOR SOLUTION Effervescent tablet: Effervescent tablets prepared by compression of granular salts which release in contact with water. Dispensing tablets: These types of tablets are no longer use because they had dangerous potential. They might be termed compounding tablets because it contain highly potent drug and pharmacist use it for compound prescription. Hypodermic tablets: Hypodermic tablets are soft moulded tablets which contain soluble ingredient and used for extemporaneous parenteral preparation by physician. They are no longer in use because it is difficult to achieve sterility and availability of stable liquid. Tablet triturates: Tablet triturates are rarely use now a days because they are obsolete. They are small, cylindrical, molded which contain small amount of potent drug. They must be readily soluble in water and minimum amount pressure require during manufacture. Triturates inserted into capsules or dissolved in liquid to provide accurate potent drug. CAPSULE : Capsule are the non compressed solid unit dosage form in which drug is 37
encapsulated. They are unit solid dosage forms consisting gelatin shell that breaks open after the capsule has been swallowed and releasing the drug. The two main types of capsules are: Hard-shelled capsules, which contain dry, powdered ingredients or miniature pellets made by e.g. processes of extrusion or spheronization. These are made in two halves: a smaller-diameter “body” that is filled and then sealed using a larger-diameter “cap”.
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Soft-shelled capsules, primarily used for oils and for active ingredients that are dissolved or suspended in oil.
PILL S: a small globular or rounded mass of medicinal substance, usually covered with a hard coating, that is to be swallowed whole. BULK DOSAGE FORMS : Solid bulk dosage forms are consist of powder that are directly administered to the patient. POWDER : They are bulk solid dosage forms consisting two or more medicament meant for internal use. The size of particle range from 10,000 microns to 0.1microns. Size of the powder determine the effectiveness of physiological properties. Advantages of powders: i) Powder form is the most versatile and convenient to prescribe, compound and administer. ii) A physician has the option to deviate from the conventional dose of a medicament according to the requirement of the patient. iii) Powders are stable and do not enter into reaction in solid state, lesser difficulties are experienced in compounding them together, iv) It is possible to reduce them in the desired particle size range and thus facilitate rapid absorption. v) Less incompatibility as compared to liquid dosage form. vi) Powders are in the form of small particles; they offer a large surface area and are rapidly dissolved n the gastrointestinal (GI) tract minimizing the problems of local irritation. Drugs that have to be given in bulk can be best administered in powder form by mixing them with foods or drinks.
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vii) Whenever effervescence is desired, accurate quantities of the two reacting powders are mixed with water. viii) It is difficult for children and infants to swallow tablets and capsules and under such circumstances drugs may be administered in powder form making them palatable by mixing with milk, fruit juice or honey. ix) Manufacturing of powder is economic hence product cost is quite economic as compare to other dosage form. Disadvantages of Powder i) As compared to other dosage forms, powders are time consuming to compound. ii) Volatile, hygroscopic, oxidizing and deliquescent drugs create obvious difficulties when dispensed as powders. iii) Dose inaccuracy. GRANULES : It can be defined as the process of enlargement of powder particles to improve flow properties. Need to prepare granules : 1. To avoid powder segregation. 2. To enhance the flow of powder. 3. Granules have higher porosity than powders. 4. To improve the compressibility of powders. 5. Materials, which are slightly hygroscope, may adhere & form a cake if stored as a powder. Effervescent granules: Effervescent granules are uncoated granules generally containing acid substances and carbonates or hydrogen carbonates which react rapidly in the presence of water to release carbon dioxide. They are intended to be dissolved or dispersed in water before administration. SEMISOLID DOSAGE FORMS : Semisolids contain both liquids and solids semi-solid. dosage forms that are too soft in structure to qualify for solids but too thick to be considered liquid. They are meant for topical application. OINTMENT : These are the soft semisolid, greasy preparations meant for external application onto the skin or mucous membrane. They contain medicament in dissolved, suspended or emulsified in the base.
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Advantages : 1. Handling of ointments is easier than bulky liquid dosage forms. 2.
They are chemically more stable than liquid dosage forms.
3.
They facilitate application of the directly to the effected body part and avoid exposure of other parts to the drug.
4.
They are suitable for patients who find it difficult to take the drugs by parenteral and oral routes.
5.
They prolong the contact time between the drug and effected area.
6.
The bioavailability of drugs administered as ointments is more since it prevents passage through liver.
Disadvantages 1. They are bulkier than solid dosage forms. 2.
When applications of an exact quantity of ointment to the affected area are required, it is difficult to ascertain the same.
3.
They are less stable than solid dosage forms.
Ointment bases There are five (5) classes or types of ointment bases which are differentiated on the basis of their physical composition. These are: 1. Oleaginous bases. 2. Absorption bases. 3. Water in oil emulsion bases. 4. Oil in water emulsion bases. 5. Water soluble or water miscible bases. These bases are fats, fixed oils, hydrocarbon or silicones. They are anhydrous, greasy, non-washable does not absorb water and occlusive (form a film on skin so it increases the skin hydration by reducing the rate of loss of surface water. They should not be applied to infected skin. they are used as protectants, emollients , vehicles for hydrolysable drugs. Example: White Petrolatum, White Ointment Oleaginous. Oleaginous base + w/o surfactant. Anhydrous but hydrophilic ointment bases, they can absorb several times their weight of water to form water-in-oil emulsion. They are non-washable, not water soluble They used as protectants, emollients (+/-), vehicles for aqueous solutions, solids, and non-hydrolyzable drugs. 40
Example: Hydrophilic Petrolatum, Anhydrous Lanolin, Aquabase™, Aquaphor®, Polysorb® Absorption . PASTES : Pastes maybe defined as ointments incorporating a high percentage of insoluble particulate solids, sometimes as much as or more than 50%. The use of this high amount of insoluble particulate matter renders a stiffness to the system as a result of direct interactions between the dispersed particulates and by absorption of the liquid hydrocarbons from the vehicles onto the surface of the particles. Because of the stiffness, they remain in place after application and are used effectively to absorb serous secretions. Pastes as such are not suited for application to hairy parts of the body. Examples of insoluble ingredients serving as the dispersed phase include starch, zinc oxide, and calcium carbonate. Pastes make good protective barriers for the following reasons. In addition to forming an unbroken film, pastes also absorb and neutralize certain harmful chemicals before they reach the skin surface. This last feature is attributed to the presence of insoluble particulate matter within the paste formulations. For example, for the treatment of diaper rash, when spread over the baby's bottom, the pastes absorb irritants formed by bacterial action on urine. Advantages : 1. Pastes provide a protective coating over the areas to which they are applied. 2. Due to stiffness pastes provides proactive coating. 3. Pastes are less greasy, less penetrating and macerating. 4. Pastes forms an unbroken film on the skin. Disadvantages : 1. Staining of cloths is problem associated with pastes. 2. Pastes are applied as a thick layer hence they are less acceptable cosmetically. 3. The viscosity of paste create problem for spreading on affected area. GELS : Gels are defined as semisolid preparations consisting of dispersions of small or large molecules in an aqueous liquid vehicle rendered jelly-like through the addition of a gelling agent. Gels are an intermediate state of matter, containing both solid and liquid components. The solid component comprises a threedimensional network of interconnected molecules or aggregates that immobilize the liquid in the continuous phase. Gels may be classified into two primary types: Hydrogels : which have an aqueous continuous phase. Organogels : which have an organic solvent as the liquid continuous medium. 41
Gels may also be classified based on the nature of the bonds involved in the three dimensional solid network: Chemical gels form when strong covalent bonds hold the network together, Physical gels form when hydrogen bonds and electrostatic and van der Waals interactions maintain the gel network. Gelling agents commonly used are synthetic macromolecules (e.g., carbomer 934), cellulose derivatives (e.g., carboxymethylcellulose and hydroxypropylmethylcellulose), and natural gums (e.g., tragacanth). CREAMS : A cream is a preparation usually for application to the skin. Creams for application to mucous membranes such as those of the rectum or vagina are also used. Creams may be considered pharmaceutical products as even cosmetic creams are based on techniques developed by pharmacy and unmedicated creams are highly used in a variety of skin conditions (dermatoses). The use of the finger tip unit concept may be helpful in guiding how much topical cream is required to cover different areas. Creams are semi-solid emulsions of oil and water. They are divided into two types: 1. Oil-in-water (O/W) creams which are composed of small droplets of oil dispersed in a continuous water phase. Oil-in-water creams are more comfortable and cosmetically acceptable as they are less greasy and more easily washed off using water. 2. Water-in-oil (W/O) creams which are composed of small droplets of water dispersed in a continuous oily phase. Water-in-oil creams are more difficult to handle but many drugs which are incorporated into creams are hydrophobic and will be released more readily from a water-in-oil cream than an oil-in-water cream. Water-in-oil creams are also more moisturising as they provide an oily barrier which reduces water loss from the stratum corneum, the outermost layer of the skin. Advantages of creams: 1) They gives prolong contact in their site of application than any other pharmaceutical semi-solid dosage forms. 2) They are not stick in nature, so easily washable 3) Injured area can be dried quickly by creams than other semi-solid preparations. 4) They have three dimensional (3D) thicksotropic properties. Applying pressure cause breakdown of this 3D structure. 42
5) non-irritating when applied to the skin. 6) N Disadvantages of creams: 1) They are less hydrophobic than other semi-solid preparation, so risk of contamination is high than the others. 2) Less viscous then other semi-solid preparation. LIQUID DOSAGE FORMS : Liquid dosage forms consist of solute and solvent, the most commonly used vehicle is water, liquid dosage forms are classified into two types, MONOPHASIC LIQUID DOSAGE FORMS Liquid Dosage forms that consist solute that dissolve in solvent give homogeneous mixture it means consists of only one phase. BIPHASIC LIQUID DOSAGE FORMS Liquid Dosage forms that are heterogeneous systems which consist of two phases one is internal phase and other is external phase, if the internal phase is solid insoluble powder which is dispersed in liquid solvent is known as suspension, if the internal phase is oil or water which is dispersed in liquid vehicle (aqueous / non- aqueous) is considered as emulsion. SOLUTION : It is a homogenous mixture prepared by mixing solute such as solid, liquid, gaseous into the suitable solvent is known as solution. Advantages of Solutions 1. They are easily administered (especially as oral medication for children). 2.
They provide uniform dosage since they are uniform preparations.
3.
They are easy to measure if accurate measuring instruments are used.
4.
They are usually pleasing in appearance to the patient because of their color and clarity.
5.
They have a more rapid onset of action, when administered orally, than tablets or capsules
Disadvantages of Solutions 1. The tastes of medications in solution are more pronounced. Some are almost impossible to overcome.
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2.
There is a possibility of rapid deterioration and chemical reaction in solutions.
3.
Inaccurate measurements may result when using inaccurate measuring instruments such as teaspoons.
GARGLES : Gargling (same root as 'gurgle') is the act of bubbling liquid in the mouth. Vibration caused by the muscles in the throat and back of the mouth cause the liquid to bubble and flurry around inside the mouth cavity. MOUTH WASHES : A medicated liquid used for cleaning the oral cavity and treating mucous membranes of the mouth. may contribute to surface softening and increased wear of dental resins and composite materials. Advantages: 1. Mouthwash promotes oral health and good hygiene. 2. Mouthwash aids in post-surgery treatment. 3. Mouthwash can help heal canker sores. 4. Mouthwash can help avoid complications in pregnancy. Disadvantages: 1. Mouthwash can be dangerous for children when ingested. 2. Mouthwash can damage some parts of the mouth. 3. Mouthwash can stain and darken teeth. 4. Mouthwash can irritate canker sores. THROAT PAINT Throat Paints are solutions or dispersions of one or more active ingredients intended for application to the mucosa of the throat or mouth.” Throat paints are viscous due to a high contact of glycerin, which being sticky, adhere to the affected site and prolong the action of the medicaments. MIXTURES : A mixture is a dosage form consist of two or more different substances which are mixed but are insoluble. A mixture means the physical combination of two or more substances. Mixtures are similar to suspensions. SUSPENSIONS: These are heterogeneous biphasic liquid dosage form in which solid insoluble powder drug which is either diffusible or in-diffusible in nature dispersed into the aqueous vehicle sometimes suitable suspending agent is added to make stable dispersion is known as suspension.
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Advantages 1. It is easy to dispense unstable or degradable drugs in solution form. 2. Suspension is the only choice if the drug is not soluble in water and nonaqueous solvent is not acceptable, e.g., corticosteroids suspension. 3. Suspension is most suitable for drugs having unpleasant taste and odor e.g., Chloramphenicol palmitate (bitter taste). 4. The insoluble solids act as a reservoir and continuously supply the drug into solution, which is absorbed over a long period e.g., Protamine zincInsulin. 5. Drug in suspension exhibits a higher rate of bioavailability compared to the same drug of equivalent dose formulated in tablets or capsules. This is due to larger surface area and high dissolution, e.g., antacid suspension. Disadvantages 1. Sedimentation of solids occasionally gives poor form of product. It may lead to caking (formation of compact mass), which is difficult to dispense. 2. Dose precision cannot be achieved unless suspensions are packed in unit dosage forms. 3. Sometimes microbial contamination takes place if preservation not added in accurate proportion. 4. A suspension being a bulky product, transportation cost is high. EMULSIONS: These are thermodynamically unstable heterogeneous biphasic liquid dosage form in which the minute globules of internal phase are dispersed into the external phase and such types of unstable systems can be stabilized by using suitable emulsifying agent. Advantages Ÿ Unpalatable oils can be administered in palatable form. Ÿ Unpalatable oil-soluble drugs can be administered in palatable form. Ÿ The aqueous phase is easily flavoured. Ÿ The oily sensation is easily removed. Ÿ The rate of absorption is increased. Ÿ It is possible to include two incompatible ingredients, one in each phase of the emulsion.
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Disadvantages Ÿ Preparation needs to be shaken well before use. Ÿ A measuring device is needed for administration Ÿ A degree of technical accuracy is needed to measure a dose. Ÿ Storage conditions may affect stability. Ÿ Bulky, difficult to transport and prone to container breakages. Ÿ Liable to microbial contamination which can lead to cracking. GASEOUS DOSAGE FORMS: Gaseous dosage forms are consist of drug particles are dispersed in propellant (gas) which acts as continuous phase. AEROSOLS : These are dispersed phase system in which very fine solid drug particles or liquid droplets get dispersed in the propellants (gas) which acts as dispersion medium. Advantages : 1. A dose can be removed without contamination of materials. 2.
Stability is enhanced for these substances adversely affected by oxygen and or moisture.
3.
When sterility is an important factor, it can be maintained while a dose is being dispensed.
4.
The medication can be delivered directly to the affected area in a desired form. (localized action)
5.
Irritation produced by the mechanical application of topical medication is reduced or eliminated.
6.
Ease and convenience of application.
7.
Application of medication in thin layer .
8.
Rapid response to the medicament .
9.
Bypasses First pass effect.
Disadvantages : 1. Expensive 2. Chlorofluorocarbon propellants cause Ozone layer depletion. 3. Inflammability 4. Toxicity 5. Explosivity
46
METERED DOSE INHALER A metered-dose inhaler (MDI) is a device that delivers a specific amount of medication to the lungs, in the form of a short burst of aerosolized medicine that is usually self-administered by the patient via inhalation. It is the most commonly used delivery system for treating asthma, chronic obstructive pulmonary disease (COPD) and other respiratory diseases. The medication in a metered dose inhaler is most commonly a bronchodilator, corticosteroid or a combination of both for the treatment of asthma and COPD. Other medications less commonly used but also administered by MDI are mast cell stabilizers, such as cromoglicate or nedocromil. DRY POWDER INHALERS : A dry-powder inhaler (DPI) is a device that delivers medication to the lungs in the form of a dry powder. DPIs are commonly used to treat respiratory diseases such as asthma, bronchitis, emphysema and COPD although DPIs (such as inhalable insulin Afrezza) have also been used in the treatment of diabetes mellitus. STERILE DOSAGE FORMS : These are liquid preparations that are free from pyrogens by using various types of sterilizing methods such as dry heat and moist heat sterilization. PARENTERALS: Parenteral preparations are defined as solutions, suspensions, emulsions for injection or infusion, powders for injection or infusion, gels for injection and implants. They are sterile preparations intended to be administrated directly into the systemic circulation in human or animal body. They are required, like any pharmaceutical dosage forms, to meet the pharmaceutical quality standards as described in pharmacopeias and to be safe for the intended purpose of use. In addition to be sterile parenteral preparations must be pyrogen-free. Sterility can be achieved by different processes of sterilization that should be appropriate to the formulations, while the pyrogen-free aspect will require , if no depyrogenation process is used during the preparation of the sterile drug products, the use of pyrogen-free pharmaceutical ingredients; drug substances or API (Active Pharmaceutical Ingredient) and excipients. TYPES OF PARENTERAL DOSAGE FORMS : Small Volume Parenteral : Small volume parenteral (SVP) solutions are usually 100 ml or less and are packaged in different ways depending on the intended use. If the SVP is a liquid that is used primarily to deliver medications, it is packaged in a small plastic bag called a mini bag of 50 - 100 ml (mini bags look like small plastic LVP bags). SVPs can also be packaged as ampules, vials, and prefilled syringes. Liquid drugs are supplied in prefilled syringes, heat-sealed ampules, or in vials sealed with a rubber closure. Powdered drugs are supplied in vials and must be constituted (dissolved in a suitable liquid) before being added to any solution. SVPs packaged as ampules, vials, 47
Large Volume Parenteral : Parenteral solutions are packaged as large volume parenteral (LVP) solutions and small volume parenteral (SVP) solutions. LVP solutions are typically bags or bottles containing larger volumes of intravenous solutions. Common uses of LVP solutions without additives include: 1) correction of electrolyte and fluid balance disturbances; 2) nutrition; and 3) vehicle for administering other drugs. Large volume parenteral solutions are packaged in containers holding 100 ml or more. There are three types of containers: glass bottle with an air vent tube, glass bottle without an air vent tube, and plastic bags. ROUTES OF ADMINISTRATION : The route by which a dosage form is administered to the patient for desired therapeutic effect is called as route of administration. The drugs are administered by many routes like orally or locally and by injection (pareterally). To produce systemic effects drugs are administered by orally, rectally by parenterally, to produce local effect drugs are applied topically over the skin or mucous membranes. The choice of the route depends on the drug and patient condition. 1. Oral route of administration: The drugs in the form of Tablets, Capsule , solutions, suspensions, emulsion etc. are given by this route for systemic effect.
Advantages : Ÿ Most convenient, easy to administered , Ÿ Pain free, Ÿ No need of skillful person (doctor) . Ÿ Absorption takes place whole length of Gastro intestinal tract ( GI tract). Ÿ Easy to carry, transportation, storage. Disadvantages : Ÿ Degradation of drugs in gastric acid. Ÿ Effect is slow not for preferable in emergencies Ÿ Bitter drugs are not acceptable by patient Ÿ Unable to use in unconscious patients. Parenteral route of admistration: Sterile preparations are injected by this route like Injections, Saline Solution, Dialysis Fluids etc. for fast systemic effect. Various routes are used to inject sterile preparations such as, Intravenous [IV], Intramuscular [IM], Subcutaneous [SC] etc. 48
Advantages : Ÿ For immediate pharmacological action in conditions like cardiac arrest, heart attack. Asthma. Ÿ
When drugs having poor bioavailability.
Ÿ
Drugs which are degraded by GI fluids.
Ÿ
Convent route when patient is unconscious. Patient with nausea , vomiting.
Disadvantages : Ÿ Manufacturing process is complicated requires aseptic condition. Ÿ Skillful person (doctor) is required for administration. Ÿ Painful treatment. 3. TOPICAL ROUTE OF ADMINISTRATION: Liquid preparations such as, Ophthalmic preparations (Eye Drops, Eye Ointment, Eye Lotion), Ear drops, Nasal drops are instilled/ giveninto body cavities like eye, nose, ear. Semi-solid preparations such as suppositories inserted into vaginal and rectum cavities. Other Semi-solid preparations such as, Oinments, Pastes, Creams, Jellies etc. are applied over the skin surface of body. Solid dosage form such as Vaginal Tablets, Pessaries are given by this route for local effect.
ADDITIONAL INFORMATION WORLDWIDE ON DOSAGE FORMS. The pharmaceutical industry as a whole is undergoing certain transformations, such as the move to specialty drugs targeted to specific patient groups and in the longer term, the move to personalized medicines. Although this emphasis is typically oriented toward tailoring an active ingredient to more specific patient 49
groups, personalized/targeted dosing regimes will play an important role in realizing the paradigm of more specialized/personalized medicines.“Masscustomization offers individualized products for everyone to address individual health issues with tailored medication,” observes François Scheffler, vicepresident of global marketing at BASF's Pharma Ingredients & Services business unit. “Today's medication is mostly bound to the indication, not to the individual patient or consumer and his specific needs. In its recent report, Paving the way for Personalized Medicine, FDA's Role in a New Era of Medical Product Development, FDA notes that the term “personalized medicine” is often described as providing “the right patient with the right drug at the right dose at the right time” , but more broadly, “personalized medicine may be thought of as the tailoring of medical treatment to the individual characteristics, needs, and preferences of a patient during all stages of care, including prevention, diagnosis, treatment, and follow-up” . Personalized medicine generally involves the use of two medical products--a diagnostic device and a therapeutic product--to improve patient outcomes. “While considerable attention in personalized medicine is currently being paid to the use of genetic tests to guide therapeutic decisions, a vast variety of medical devices can be used in a personalized approach to improve patient outcomes”. Many medical-device therapies can be tailored to specific patient characteristics, such as patient anatomy (e.g., size), physiology (e.g., nervous and cardiovascular systems, metabolism, and reproduction) and environment (e.g., intensive care unit, home use). Also, physiological sensors may predict treatment responses for individual patients, such as threedimensional (3D) printing, to create personalized medical devices based on imaging of a patient's anatomy. The confluence of traditional therapeutics with devices provides the foundation for the pharmaceutical of the future. Customization is taking root through emerging technologies, such as bioelectronic medicines and 3D printing of pharmaceuticals, through select investment by pharmaceutical companies, venture-capitalists, and academic researchers.
50
Chapter: 3 Prescription Unit – I Syllabus Definition, Parts of prescription, handling of Prescription and Errors in prescription.
INTRODUCTION : A prescription is a health-care program implemented by a physician or other qualified health care practitioner in the form of instructions that govern the plan of care for an individual patient. The term often refers to a health care provider's written authorization for a patient to purchase a prescription drug from a pharmacist. The word "prescription", from "pre-" ("before") and "script" ("writing, written"), refers to the fact that the prescription is an order that must be written down before a compound drug can be prepared. Those within the industry will often call prescriptions simply "scripts". Prescriptions may be entered into an electronic medical record system and transmitted electronically to a pharmacy. Alternatively, a prescription may be handwritten on preprinted prescription forms that have been assembled into pads, or printed onto similar forms using a computer printer or even on plain paper according to the circumstance. In some cases, a prescription may be transmitted from the physician to the pharmacist orally by telephone; this practice may increase the risk of medical error. The content of a prescription includes the name and address of the prescribing provider and any other legal requirement such as a registration number 'R' is a symbol meaning "recipe". It is sometimes transliterated as "Rx" or just "Rx". This symbol originated in medieval manuscripts as an abbreviation of the late Latin verb recipere, specifically the second person singular imperative form recipe meaning "take", thus: "take thou". Originally abbreviated Rx, the x was simplified and finally written as a straight stroke making it look like an x in combination with the right "leg" of R. Medieval prescriptions invariably began with the command to "take" certain materials and compound them in specified ways. 51
DRUGS ARE OF TWO CLASSES 1) OTC (Over the Counter ) drugs : these are non- prescription drugs Examples : analgesics, antipyretics, antacids etc. 2) Prescription drugs : these are schedule H drugs, these drugs are “ to be sold by retail on the prescription of a registered practitioner only.” DEFINITION : PRESCRIPTION : It can be defined as it is order written by physician, doctor, veterinarian and any other registered medical practitioner to the pharmacist to compound and dispense appropriate medication to the patient. TYPES OF PRESCRIPTIONS: Compounding Prescription : In this prescription the generic names of drugs are given or the formulation ingredients as per official compendia are written by the physician to compound and dispense medication. Modern Prescription In this prescription the brand names of prefabricated medicines are written by the physician to dispense appropriate medication to appropriate patient. PARTS OF PRESCRIPTION 1. Date 2. Patient Information, Name , Address, Age , Sex, Body Weight of patient 3. Superscription - Rx 4. Inscription 5. Subscription 6. Signatura 7. Renewal instruction 8. Signature, address and registration number of prescriber. 1. Date : Prescription must be dated to avoid misuse of prescription. Physician must write date before writing the prescription. Dated prescription helps pharmacist while refilling the prescription. 2. Patient Information : Patient information such as name of Patient help to avoid confusion of pharmacist while dispensing medication. Name of patient identify the proper prescription of patient to which it is written. Age and weight of the patient helps in prescribing appropriate dose of drug to avoid danger of administered to wrong member of the family. 52
Address of the patient help recalling the prescription incase of wrong dispensing of medication. It also helps in accessing patient information in the case of emergency. Age of the patient helps in dispensing write dose for children, adult, geriatrics. age also help in calculating dose of drug in posology. Sex of the patient helps in appropriate dispensing of medication to male and female. 3. Superscription : The part of a pharmaceutical prescription which contains or consists of the Latin word recipe or the sign Comments on superscription. This is the Rx symbol on the prescription form that designates the written document to be a prescription. Rx is an abbreviation for a Latin phrase that means "take thou.” In ancient days the Rx symbol was considered as a prayer to Jupiter, the God of healing, for quick recovery. 4. Inscription: An inscription includes the drug name, concentration and type of preparation. Drug names should not be abbreviated and correct spelling is important to assure that the correct medication is dispensed. Maxitrol (neomycin and polymyxin b sulfates and dexamethasone, Alcon) and Tobra Dex (tobramycin and dexamethasone, Alcon) are examples of drugs that are prepared in ointment (ung) or drop (gt) form. Cortisporin (neomycin and polymyxin B sulfates, bacitracin zinc and hydrocortisone, Glaxo Wellcome) comes in ophthalmic and otic (ear drops) preparations. Specify which preparation you wish the patient to use. Drug names can be written using the chemical name, such as ciprofloxacin 0.3% (Ciloxan, Alcon) or the proprietary form that requests a specific brand name drug. This preparation is still under patent, so if you use either name the pharmacy will provide the product manufactured by Alcon. Tobramycin has recently come off patent. If you prescribe "Tobrex" the patient should receive the drug manufactured by Alcon unless you check the box on the prescription stating generics are acceptable. If you write "tobramycin," the patient will likely receive the generic form of the drug. Homatropine and pilocarpine come in different concentrations. It is good practice to always specify the concentration, even if the drug comes in only one concentration. That drug may come in other concentrations in the future. Concentration and preparation form should be written just to the right of the drug name. Use the metric system of weights and measures. 53
To avoid misinterpretation of the preparation strength, follow this standard in writing percentages: If the percent is less than one, always precede the decimal with a zero, such as 0.1% or 0.05%. If the percent is greater than one, with no fraction, do not use a zero after the decimal, such as 1%. Writing 1.0% could easily be misread as 10%. 5. Subscription: Historically, this was an instruction to the pharmacist to compound medications. This could include, for example, instructions regarding the fortification of tobramycin for treating a corneal ulcer. Today, most medications are precompounded preparations. Subscription now indicates the quantity of medication (number of capsules or tablets) or the size of the bottle to be dispensed (5 mL, 10 mL, 15 mL). The doctor's instructions to the pharmacist, Sig, should be as specific as possible to ensure patient compliance and proper use of medication. 6. Signatura (Sig): These are the doctor's instructions to the pharmacist indicating how the patient should use the medication. Latin or English abbreviations are used to provide specific instructions translated by the pharmacist for patient use. Typical instructions on the prescription would follow in this order: Ÿ
2 gtt q2h OD for 3 days These instructions as used on a prescription for Ciloxan would be interpreted as follows: two drops every 2 hours instilled in the right eye for 3 days.
Ÿ
1 tab po BID for 14 days These instructions as used on a prescription for doxycycline would be interpreted as follows: one tablet by mouth two times per day for 14 days.
Ÿ
1 gt QID OU for 7 days, then BID for 14 days, for itchy eyes SHAKE. These instructions as used on a prescription for Livostin (levocabastine HCl, Ciba Vision Ophthalmics) would be interpreted as follows: one drop of Livostin four times per day in each eye for 7 days and then decreased to two times per day for 14 days, for itchy eyes caused by allergies; shake drops before use.
These instructions should be as specific as possible. Poor instructions given in the office and on the prescription lead to poor compliance and often improper use of the medication. It is appropriate to write what the medication is being prescribed for in the signatura to let the patient know the indications for the medication. Phrases such as "for eye pain" or "for itchy eyes" will help ensure that the medication is used appropriately. 7. Refill data: Provide the number of refills the patient should need to complete the cycle of drug treatment. Most antibiotic and steroid prescriptions need no refills or one refill. Glaucoma medications usually have three refills, which allows the patient 54
enough medication for 3 to 6 months, depending on the size of the bottles dispensed. Schedule II controlled substances have no refills. Schedule III through V controlled substances can have five refills or can be refilled for a maximum of 6 months, whichever comes first. In eye care there is seldom a reason to have more than one refill on these controlled drugs. Prescription
RESPONDING TO OR HANDLING OF PRESCRIPTION 1. Receiving the prescription 2. Reading and checking the prescription 3. Compounding 4. Recording the information 5. Pricing the prescription 6. Delivering / Dispending the prescription 1. Receiving the prescription The prescription should be received by the pharmacist himself / herself. Then after receiving prescription from the patient, a pharmacist should not change his facial expression that gives false impression to the patient that the pharmacist is confused after receiving prescription. 2. Reading and checking Prescription should be read by the pharmacist to check date, patient name, age, body weight, sex. refill instructions, sign of prescriber.
55
3. Compounding As given by prescriber a pharmacist should compound the preparation in desired quantity. A pharmacist should compound only one prescription at a time. He must take care while weighing the ingredients. 4. Recording the information A pharmacist should note the name of patient in patient medication record for future reference as well as to maintain the patient medication history. Recorded Patient information also help to keep allergic conditions of patient. 5. Pricing the prescription Pricing the prescription involve cost of ingredients + professional fees + cost of container + other fees. 6. Delivering / Dispending the prescription After completion of compounding and packaging of prescription medicine the compounded medicines delivered i.e. dispense to patient with proper counseling by the pharmacist regarding how to take medication. ERRORS IN PRESCRIPTION. Medication Errors: Medication errors done by doctors, pharmacists, nurses & patients. Medication errors can be categorized as – Prescription errors Dispensing errors Selection errors Bagging errors Administration errors 1. Errors in prescription writing The prescription should be neatly & correctly written by the medical practitioner, otherwise it is major hassle for the pharmacists. a) Spelling mistakes. Illegible handwriting. SALA Medicines(Sound Alike Look Alike): Tab. Dulcolax a laxative tablet & Tab . Duoclox an antibacterial tablet. b) Type of dosage form Same drug can be available in tablet, capsule or liquid oral dosage forms for adults, drops for pediatric patients. Selection of dosage form is based on ability of patients to take that medicines. c) Strength of Medicines Some medicines, especially those whose dosing is critical , are available in 56
different strengths. Eg. Haloperidol , antipsychotic drug available in the form of tablets of various strength viz. 0.25, 2mg, 5mg,10mg, 20 mg. d) Quantity to be dispensed Pharmacists should check the dose & see that the quantity of medicine is sufficient to complete a course. Pharmacists should check the dose, dosage regimen & direction to use. e) Dose & Direction Pharmacists should check the dose, dosage regimen & direction to use. f) Dispensing Errors: 1. Poor handwriting Long prescription Incomplete patient information Deviation in attention of pharmacist Misunderstanding of verbal orders. While removing medicines from shelves pharmacist should be alert. 2. Selection of medicine While removing medicines from shelves pharmacist should be alert. He should remove the correct medicine. SALA medicines should not be kept adjacent to one another. g) Bagging Errors After billing, dosage forms should be packed in appropriate bags or covers & handed over to the right person. h) Errors in administration Breaking the coated or sustained release tablets. Suspension administration without shaking. Taking medicament at wrong time before or after meal. i) Drug interactions 1. Contra – indicated drugs: There are certain drugs which may be contraindicated in a particular disease or a particular patient who is allergic to it. Example: the penicillin & sulpha drugs are contraindicated to the patients who are allergic to it. j) Synergistic & antagonistic drugs Many drugs exhibit Synergism & Antagonism when administered in combination.
57
When the two drugs are prescribed together, they tend to increase the activity of each other, called as synergism. Example: A combination of aspirin & paracetamol increase the analgesic activity. When two drugs having the opposing p'cological effects are called antagonism. Example: Acetyl salicylic acid and probenecid k) Unintentional drug interaction The effect of one drug is altered by the prior or simultaneous administration of another drug. Tetracycline hydrochloride mg Direction –take one capsule with milk Tetracycline inactive by calcium which is present in milk. l) Intentional drug interaction Rx Acetophenetidin mg Acetyl salicylic acid mg Caffeine mg Send 10 capsules. Acetophenetidin & acetyl salicylic acid are analgesic. Acetophenetidin depresses the CNS & this effect is undesirable. Caffeine is CNS stimulant to neutralise the side effect of acetophenetidin.
58
Chapter: 4 Posology Unit – I Syllabus Definition, Factors affecting posology. Pediatric dose calculations based on age, body weight and body surface area.
INTRODUCTION Posology is concern with determination of dose of drug as the dose of drug varies according to patient age, body weight and body surface area. The accurate determination of dose of drug by the pharmacist, nurses etc requires formulae such as youngs formula, dillings formula Clarks formula etc . the appropriate dose administration requires to give therapeutic effect. Dose of drug drug may be defined as “the amount (quantity) of drug administered or taken by a patient for the desired therapeutic effect. Minimum dose is necessary to produce a desired therapeutic effect , but maximum dose is the largest quantity that can be given safely to the patient without any harmful effects. The dose of a drug cannot be fixed because there are so many factors which affect the dose. The posology is implemented by a doctor, nurse, pharmacist, veterinarian or pharmacologist. DEFINITION : Posology is the term which is derived from the Greek word posos meaning “how much” and logos meaning “science”. So posology is the branch of medicine dealing with doses. The optimum dose of a drug varies from patient to patient.
59
The following are some of the factors that influence the dose of a drug. 1. Age 2. Body Weight & Body Surface Area 3. Sex 4. Pathological State (Disease condition) 5. Tolerance 6. Drug-Drug Interactions 7. Time Of administration 8. Route Of Administration 9. Idiosyncrasy 10. Frequency of administration 11. Environmental factors 12. Psychological state & Emotional Factors 13. Accumulation 14. Genetic diseases 15. Pharmaceutical dosage form and drug physical state 1. AGE: Human beings can be categorized into the following age groups: 1. Neonate: From birth up to 30days. 2. Infant: Up to 1 year age 3. Child in between 1 to 4 years 4. Child in between 5 to 12 years. 5. Adult 20-40 6. Geriatric (elderly) patients more than 50 In children the enzyme systems in the liver and renal excretion remain less developed. So all the dose should be less than that of an adult. In elderly patients the renal functions decline. Metabolism rate in the liver also decreases. Drug absorption from the intestine becomes slower in elderly patients. So in geriatric patients the dose is less and should be judiciously administered. 2. BODY WEIGHT & BODY SURFACE AREA It influences the concentration of drug in the body. The average adult dose is calculated for a person with 70kg body weight (BW). For exceptionally obese (fat) or lean (thin) patient the dose may be calculated on body weight basis. Another method of dose calculation is according to the body surface area (BSA). This method is more accurate than the body weight method. The body surface area (BSA) of an individual can be obtained from the following formula: 2
0.425
BSA (m ) = BW(kg)
0.725
x Height (cm)
x 0.007184
3. SEX: Special care should be taken while administering any drug to a women during menstruation, pregnancy and lactation. Strong purgatives should not be 60
given in menstruation and pregnancy. Antimalarials, ergot alkaloids should not be taken during pregnancy to avoid deformation of foetus. Antihistaminic and sedative drugs are not taken during breast feeding because these drugs are secreted in the milk and the child may consume them. 4. PATHOLOGICAL STATE (DISEASE CONDITION) Several diseases may affect the dose of drugs: In gastrointestinal disease like achlorhydria (reduced secretion of HCl acid in the stomach) the absorption of aspirin decreases. In liver disease (like liver cirrhosis) metabolism of some drugs (like morphine, pentobarbitone etc.) decreases. In kidney diseases excretion of drugs (like aminoglycosides, digoxin, phenobarbitone) are reduced, so less dose of the drugs should be administered. 5. TOLERANCE Some time higher dose of a drug is required to produce a given response (previously less dose was required). Natural Tolerance: Some races are inherently less sensitive to some drugs, e.g. rabbits and black race (Africans) are more tolerant to atropine. Acquired Tolerance: By repeated use of a drug in an individual for a long time require larger dose to produce the same effect that was obtained with normal dose previously. Cross tolerance: It is the development of tolerance to pharmacologically related drugs e.g. alcoholics are relatively more tolerant to sedative drugs. Tachyphylaxis: (Tachy = fast, phylaxis = protection) is rapid development of tolerance. When doses of a drug is repeated in quick succession an reduction in response occurs – this is called tachyphylaxis. This is usually seen in ephedrine, nicotine. Drug resistance: It refers to tolerance of microorganisms to inhibitory action of antimicrobials e.g. Staphylococci to penicillin. 6. DRUG INTERACTIONS Simultaneous administration of two drugs may result in same or increased or decrease effects. Drug administration with dose Drug A Drug B
Pharmacological effect Effect A Effect B 61
Drug A + Drug B Effect AB Relationship Name of the effect Examples Effect AB = Effect A + Effect BAdditive effectAspirin + Paracetamol B Effect AB > Effect A + Effect B
Synergistic
(or Sulfamethaxazole +Trimethoprim
potentiation)
Effect AB < Effect A + Effect AntagonismHistamine + Adrenaline 7. TIME OF ADMINISTRATION The drugs are most quickly absorbed from empty stomach. The presence of food in the stomach delays the absorption of drugs. Hence a potent drug is given before meal. An irritant drug is given after meal so that the drug is diluted with food and thus produce less irritation. 8. ROUTE OF ADMINISTRATION In case of intravenous injection the total drugs reaches immediately to the systemic circulation hence the dose is less in i.v. injection than through oral route or any other route. 9. IDIOSYNCRASY This an exceptional response to a drug in few individual patients. For example, in some patients, aspirin may cause asthma, penicillin causes irritating rashes on the skin etc. 10. FREQUENCY OF ADMINISTRATION Frequency of administration means how much time a drug is administered in a day it is depend on the half life of drug the half life of drug means time required for 50% of drug to be eliminated from the body. The drugs having shorter half life get rapidly excreted from the body and hence requires twice and thrice in day dose administration. 11. ENVIRONMENTAL FACTORS Stimulant types of drug are taken at day time and sedative types of drugs are taken at night. So the dose of a sedative required in day time will be much higher than at night. Alcohol is better tolerated in winter than in summer. 12. PSYCHOLOGICAL STATE & EMOTIONAL FACTORS Psychological state of mind can affect the response of a drug, e.g. a nervous and anxious patient requires more general anaesthetics. Placebo is an inert substance that does not contain any drug. Commonly used placebos are lactose tablets and distilled water injections. Some time patients often get some psychological effects from this placebo. Placebos are more often used in clinical trials of drugs. 62
13. ACCUMULATION Any drug will accumulate in the body if the rate of absorption is more than the rate of elimination. Slowly eliminated drugs are often accumulated in the body and often causes toxicity e.g. prolonged use of chloroquin causes damage to retina. Genetic diseases Some patients may have genetic defects. They lack some enzymes. In those cases some drugs are contraindicated. e.g. Patients lacking Glucose-6-phosphate dehydrogenase enzyme should not be given primaquin (an antimalarial drug) because it will cause hemolysis. 15. PHARMACEUTICAL DOSAGE FORM AND DRUG PHYSICAL STATE To increase the surface area of drug requires reduction in particle size of drug hence the it will increases the rate of absorption. The crystalline and amorphous forms of drugs due to changes in their particle size and solubility shows a significant difference in the rate of absorption. Formulae for calculation of dose of drug for Infants and Children A) FORMULAS BASED ON THE AGE I) YOUNG'S FORMULA
Child dos e = Age in Years Age + 12
X adult dose
This formula is used to calculate the dose of a child below 12 years of age PROBLEM : 01. If the average adult dose of aspirin is 500 mg. the child weighs 24 pounds and is 16 months old. How much milligrams of the drug per dose are required. Solution : Given, Average adult dose : 500 mg Age of child : 16 months we need to convert it into years Age of child in years = Age in months 12 Therefore, Age of the child in years = 16 = 1.3 years 12 Using young's formula Child dose = Age in Years X adult dose Age + 12 63
Child dose = 1.3 X 500 15.3 + 12 = 1.3 X 500 = 13.3 Child dose = 48.87 mg The dose of aspirin for 16 months old child weighing 24 pounds is 48.87 mg II) DILLING'S FORMULA
Child dose = Age (Years) X adult dose 20 This formula is used to calculate the dose for a child of age 4-20 years. PROBLEM : 1. If the adult dose of paracetamol is 500 mg what is the dose for a child of 12 years? Solution : Given, Average adult dose = 500 mg Age of the child = 12 years By using dilling's formula, Child dose = Age (Years) X adult dose 20 Child dose = 12 X 500 20 Child dose = 300 mg The dose of paracetamol for a 12 year old child is 300 mg III) COWLINGS FORMULA Child dose = Age (Years) + 1 X adult dose 2
PROBLEM : 1. The maximum daily dose of a drug is 140 mg. how much of it should be given to a child of 12 years? Solution : Given, Average adult dose = 140 mg Age of Child = 12 years Using Cowling's formula, 64
Child dose = Age (months) X adult dose 24 Child dose =
12 + 1 X 140 24
Child dose = 75.83 mg The dose of the drug for 11 year old child is 75.83 mg IV) FRIED'S FORMULA
Child dose = Age (Months) X adult dose 150 This formula is use for calculating the dose for child under 2 years of age PROBLEM: 1. The adult dose of a drug is 60 mg. how much of it can be given to a 6 month old infant ? Solution : Given , Average adult dose = 60 mg Age of the child = 6 months Using fried's formula, Child dose = Age (Months) X adult dose 150 Child dose =
6 X 60 150
Child dose = 2.4 mg The dose of drug for 6 month old infant is 2.4 mg V) BASTEDO'S FORMULA, Child dose = Age (Years) + 3 x adult dose 30 PROBLEM : 1. The adult dose of a drug is 200 mg. how much of it can be given to a 12 year old child? Solution: Given, 65
Average adult dose = 200 mg Age of the child = 12 years Using Bastedo's formula , Child dose = Age (years) +3 x adult dose 30 Child dose = 12 + 3 X 200 30 Child dose = 10 mg The dose of the drug for child of 12 years age is 10 mg B) FORMULA FOR CALCULATION OF DOSE OF DRUG AS PER BODY WEIGHT CLARK'S FORMULA Child dose = Weight in (Pounds) X adult dose 150 Child dose = Weight in (Kg) X adult dose 70 PROBLEM : 1. The parenteral dose of amoxicillin injection is 10 mg/kg/24 hours. Calculate the daily dose of this drug for a 46 pound child. Solution: Given, Here the weight of child is given in pounds while the dose of erythromycin is given per kilogram of body weight. Convert 46 pounds to kilograms Therefore , 46 pounds = 20.90 kg 2.2 Using Clark's formula, Child dose = Weight (Kg) X adult dose 70 Child dose = 20.90 X 10 70 Child dose = 2.98 mg/kg/24 hours 66
The dose of amoxicillin injection for a child weighing 20.90 kg is 20.90 X 2.98 = 62.28 mg/ 24 hours . C) FORMULA FOR CALCULATION OF DOSE OF DRUG AS PER THE BODY SURFACE ARE It is widely use formula for calculation of dose of drug. It is mostly used in two types of patient groups, Ÿ Ÿ
Cancer patient who receive chemotherapy Pediatric patient except premature and full-term newborns
The value for adult body surface is considered as 1.73 m3 Body surface area is calculated from height and weight by means of nomogram. The formula for dose calculation is, Child dose = BSA of a child x adult dose 1.73 PROBLEM: 1. Calculate the dose for child who has a body surface are equal to 0.57 m2 and average adult dose of a drug is 50 mg. Solution : Given, Average adult dose = 50 mg 2 Body surface area of the child = 0.57 m Using formula, Child dose = BSA of a child X adult dose 1.73 Child dose = 0.57 X 50 1.73 Child dose = 16.47 mg The dose of drug for the child is 16.47 mg
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Chapter: 5 Pharmaceutical Calculations Unit – II Syllabus Weights and measures – Imperial & Metric system, Calculations involving percentage solutions, alligation, proof spirit and isotonic solutions based on freezing point and molecular weight.
INTRODUCTION : WEIGHTS AND MEASURES Weights: Solids and some viscous liquids are weighable in mg/gm/kg etc. Measures : Liquids are measurable in ml/litre etc. IMPERIAL & METRIC SYSTEM The system of imperial units or the imperial system (also known as British Imperial or Exchequer Standards of 1825) is the system of units first defined in the British Weights and Measures Act of 1824, which was later refined and reduced. The Imperial units replaced the Winchester Standards, which were in effect from 1588 to 1825. The system came into official use across the British Empire. By the late 20th century, most nations of the former empire had officially adopted the metric system as their main system of measurement, although some imperial units are still used in the United Kingdom, Canada and other countries formerly part of the British Empire. The imperial system developed from what were first known as English units, as did the related system of United States customary units. The decimal measuring system based on the metre, litre, and gram as units of length, capacity, and weight or mass. The system was first proposed by the French astronomer and mathematician Gabriel Mouton (1618–94) in 1670 and was standardized in Republican France in the 1790s. The metric system is an internationally adopted decimal system of measurement. It is in widespread use, and where it is used, it is the only or most common system 68
of weights and measures. It is now known as the International System of Units (SI). It is used to measure everyday things such as the mass of a sack of flour, the height of a person, the speed of a car, and the volume of fuel in its tank. It is also used in science, industry and trade. The modern metric system consists of four electromechanical base units representing seven fundamental dimensions of measure: length, mass, time, electromagnetism, thermodynamic temperature, luminous intensity, and quantity of substance. The units are: 1. the metre for length 2. kilogram for mass 3. second for time 4. ampere for electromagnetism 5. kelvin for temperature 6. candela for luminous intensity 7. mole for quantity Imperial units of measurement are the units that were in common usage in this country up until about thirty years ago. Even after the introduction of the metric system, Imperial units have continued to be in everyday use in varying degrees. Metric units of measurement are the units originally used in mainland Europe, adopted in this country when we joined the European Economic Community (as it was then called) in the early 1970s. It is based upon a decimal system where each unit is divided into blocks of 10 smaller units. Imperial units of measurement.
1 ounce (oz) 1 pound (lb) 1 stone 1 hundredweight (cwt) 1 ton
= 437.5 grains = 16 ounces =14 pounds =112 pounds =20 hundredweight
Metric units of measurement.
1 gram (g) 1 metric carat 1 kilogram (kg) 1 tonne (t)
=1,000 milligrams = 0.2 grams = 1,000 grams =1,000 kilograms
Converting from Imperial to metric measurements.
1 grain 1 oz 1 grain 1 lb 1 stone 1 cwt 1 ton
= 64.9351 mg = 28.35 g =0.3240 metric carats =0.4536 kg =6.3503 kg =50.802 kg =1.016 t
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Converting from metric to Imperial measurements.
1 mg 1g 1 metric carat 1 kg 1 kg 1 kg 1t
=0.0154 grain =0.0353 oz =3.0865 grains =2.2046 lb =0.1575 stone =0.0197 cwt =0.9842 ton
PERCENTAGE CALCULATIONS As we know percentage means “ for 100”. Solutions can be expressed as % v/v. %w/w and % w/v. I) % v/v : it refers to any dosage form, where solute as well as solvent are both measured as volume. The general formula for 1% v/v solution is, Solute
1 part by volume
(ml/litre)
Solvent to produce
100 parts by volume
(ml/litre)
We can also say that 1ml of solute is dissolved in sufficient amount of solvent to produce 100ml. ii) % w/w : it refers to dosage form, where solute as well as solvent, both are measured on weight basis. The general formula for 1 % w/w solution is Solute Solvent to produce
1 part by weight 100 parts by weight
(mg/g/kg) (mg/g/kg)
iii) % w/v : it refers to dosage form in which solute is measured on weight basis and solvent is measured on volume basis. The general formula % w/v solution is, Solute Solvent to produce
1 part by weight 100 parts by volume
(mg/g/kg) (ml/litre)
PROBLEM: 01. Calculate the quantity of sodium chloride required to produce 250 ml of 0.9 % w/v solution of sodium chloride. Solution : 0.9 % w/v solution means, 0.9 gm of sodium chloride is dissolved in sufficient water to produce 100 ml of sodium chloride solution. Hence, to prepare 250 ml of sodium chloride solution the quantity of sodium chloride is calculated , i.e = 0.9 x 500 = 2.5 gm. 100 70
The 2.5 gm of sodium chloride should be dissolved in sufficient amount of water to produce 500 ml of 0.9 % w/v sodium chloride solution. PROBLEM : 02 Prepare 400 ml of 1 in 2000 solution of potassium chloride. Solution : 1 in 2000 = 100 % = 0.05 % 2000 i.e 1 in 2000 solution of potassium chloride is 0.05 % it means 0.05 gm of potassium chloride is present in 100 ml of potassium chloride solution X gm of potassium chloride will be present in 400 ml of solution X = 0.05 X 400 = 0.2 gm 100 The 0.2 gm of potassium chloride should be dissolved in sufficient water to produce 400 ml of 1 in 2000 solution of potassium chloride. PROBLEM : 03 Prepare 25 ml of 10 % menthol in alcohol. Solution : For preparation of 10 % menthol solution we require 10 gm of menthol which is dissolved in sufficient alcohol to make 100 ml solution of menthol in alcohol. i.e X gm of menthol is required to prepare 25 ml of solution. X = 10 X 25 = 2.5 gm 100 The 2.5 gm of menthol is required to produce 25 ml of 10% solution. ALLIGATIONS METHOD Alligation method is dived into TWO types 1. Alligation alternate method : this method is used to calculate the proporation of two or more products or compositions of different strengths should be mixed to get the product of desired strength. 2. Alligation medial method : this method is used to calculate the resulting strength of the product produced by mixing two or more products or compositions of different concentrations.
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PROBLEM : 01 How will you prepare 250 ml of 60 % solution of isopropyl alcohol from pure isopropyl alcohol. Solution : As we know Pure isopropyl alcohol means 100 % alcohol. To prepare 60 % alcohol from 100% alcohol we must need to dilute pure alcohol with water. By Alligation alternate method 100% IPA
60 -0 = 60 % IPA
60
0 % IPA (Water)
100 -60 = 40 % water
Thus, to make 100 ml of IPA solution; we should mix 60 ml of 100 % IPA and 40 ml of water. But we required to prepare 250 ml. For 100 ml 60 ml IPA is required Then, for 250 ml how much IPA is required 60 x 250 = 150 ml IPA 100 For 100 ml 40 ml water is required Then, for 250 ml how much water is required 40 x 250 = 100 ml Water 100 Thus , 150 ml pure IPA and 100 ml of water should be mixed together to get 250 ml of 60 % of IPA. PROBLEM : 02. Prepare 600 ml of 60 % alcohol using 70% alcohol and 30 % alcohol. Solution : 70%
30% (60-30) = 30 ml of 70% alcohol
60%
30 %
10% (70-60) = 10 ml of 30% alcohol 40 ml of 60 % alcohol
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Thus to prepare 600 ml of 60 % alcohol we require 400 ml of 70% alcohol and 200 ml of 30 % alcohol. PROBLEM : 04. What is the percentage of calamine in an ointment prepared by mixing 20 gm of 10 % ointment, 40 gm of 6 % of ointment and 60 gm of 4 % ointment. Solution : By allegation medial method Multiply the quantity by % of ointment. Quantity 20 40 60 ∑ Qty = 120
% 10 6 4
Quantity X % 200 240 240 ∑ Qty % = 680
Now to get % of calamine ∑ Qty % _ 680 _ 5.66 % ∑Qty 120 Thus, the % of Calamine in an ointment prepared by mixing 20 g of 10% ointment, 40 of 6% ointment and 60 of 4 % ointment is 5.66 %. PROOF SPRIT For Utilization of alcohol excise duty is applicable. For excise purpose or taxation the standard , measure of alcohol is expressed as “proof gallon”. In USA proof gallon is considered as 1 gallon of 50% alcohol. This strength is considered as “proof spirit”. The solution containing less than 50% alcohol is “below proof”. The solution containing more than 50% alcohol is “ above proof”. The proof strength of alcohol solution is exactly double the % strength %v/v. Thus, 50 % alcohol = 100 proof 95 % alcohol = 190 proof 34 % alcohol = 68 proof In India, 1 gallon of 57.1 % v/v alcohol is known as proof spirit and it is considered as 100 proof. The strength of solution above 57.1 % alcohol is considered as “over proof”(o/p). The strength of solution below 57.1 % alcohol is considered as “under proof” (u/p). 73
1 % v/v of alcohol is 1.753 proof spirit. Any proof strength can be converted to % v/v and % v/v of alcohol can be converted to proof strength, by using the following method. Multiply % strength of alcohol by 1.753 and deduct 100 form the product. If the result is positive, it is known as over proof and if the result is negative, then it is known as under proof. PROBLEM :01. Find the proof strength of 80% v/v and 60% v/v ethanol. Solution : 1% v/v alcohol is 1.753 proof spirit Then 80 % v/v alcohol is X proof spirit 80 X 1.753 = 140.24 proof spirit 1 Proof strength = 140.24 – 100 = 40.24 (u/p) Similarly, 1 % v/v of alcohol is 1.753 proof spirit Then 60 % v/v ethanol is X proof spirit 60 X 1.753 = 105.18 proof spirit 1 Proof strength = 105.18 – 100 = 5.18 (u/p) PROBLEM : 02. Calculate the strength of 45.6 O O/p and 76 O u/p Solution : i) 45.6 O O/p = 100 + 46.6 = 146.6 proof spirit 1 % v/v is 1.753 proof spirit Then X % v/v is 146.6 proof spirit X = 146.6 x 1 = 83.62 % v/v 1.753 ii ) 76 O u/p = 100 – 76 = 24 proof spirit 1 % v/v is 1.753 proof spirit Then X % v/v is 24 proof spirit X = 24 X 1 = 13.69 % v/v 1.753
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ISOTONIC SOLUTION BASED ON FREEZING POINT AND MOLECULAR WEIGHT Isotonic means the preparation having same osmotic pressure to that of blood or lachrymal secretions. If the preparation is not isotonic, it cause discomfort and irritation after administration. Two types of effects are, 1) Haemolysis of cells : If a hypotonic solution, i.e the solution with lower osmotic pressure, is used, it cause swelling or bursting of cells, this leads to haemolysis. Means, blood cells are more osmotic and to achieve equilibrium, these take up fluid from hypotonic solution. The damage cause to the cells is irreversible. 2) Shrinkage of cells : When hypertonic solutions having higher osmotic pressure, is administered, it leads to shrinkage of cells. To achieve equilibrium between hypertonic solution and cellular fluids, the cellular fluids comes out of cell membranes. This damage is reversible. When osmotic pressure of body fluid and administered solution is made same, the shrunken of cells regain their original size & shape. Therefore, injections, eye, nasal and rectal preparations must be isotonic. Human blood serum and lachrymal fluid having freezing point of - 520 C. This property can be used to determine isotonicity, and the preparation having same freezing point is isotonic. I) FREEZING POINT METHOD The freezing point of blood and other body fluid is - 52 0 C. the preparation containing drug and additives must have equal freezing point. F.P of body fluid – F.P. of drug solution of particular strength F.P of tonicity adjusting agent PROBLEM : 01. Prepare a potassium chloride injection containing 0.5 % of drug F.P of 1% potassium chloride is 0.439. F.P of 1% NaCl is 0.576 Solution : F.P. of drug solution = 0.5 X 0.439 = 0.2195 Thus, 0.52 – 0.2195 = 0.3005 = 0.52 % NaCl 0.576 0.576 The injection containing 0.5 % potassium chloride and 0.52 % sodium chloride will be isotonic. 75
II ) SODIUM CHLORIDE EQUIVALENT METHOD It is modification of freezing point method. In this ratio of freezing point depression, produce by a solution of medicament and freezing point depressed by a sodium chloride of same strength is calculated as sodium chloride equivalent (ENaCl) of that medicament. Sodium chloride equivalent of 1% potassium chloride is 0.76 0.439 = 0.76 0.576 The formula for calculation of sodium chloride requirement of adjustment of isotonicity is % NaCl = 0.9 – [ % strength of drug solution x E NaCl ] PROBLEM : 01. How much NaCl is required to compound 5 ml drops containing 2 % pilocarpine nitrate. (given By using formula , E NaCl pilocarpine nitrate is 0.22) Solution : By using formula % NaCl = 0.9 – [2 x 0.22 ] = 0.46 % III) MOLECULAR CONCENTRATION METHOD The osmotic pressure is proportional to molar concentration. The molar concentration is the gram per litre. Gram moles = Weight in gram per litre Molecular weight This equation is applicable for non-ionisable substance. Gram Moles = Weight in gram per litre x n Molecular weight This equation is applicable for Ionisable substance. Where “ n” is number of ions formed by dissociation of the substance. Then “n” value is 2 for salt dissociating 2 ions, 3 for salts which dissociate 3 ions etc. As 0.9 % sodium chloride is isotonic, thus on the basis if molar concentration, it can be expressed as, 76
0.9 % NaCl = 9 g/litre of solution Gram mole of NaCl isotonic = 9 x 2 = 0.31 58.5 It means 0.31 gram molar solution of sodium chloride is isotonic. PROBLEM : 01. Prepare 2.5 % dextrose injection. Make it isotonic by sodium chloride. Molecular weight of dextrose is 180. Solution: Calculate gram moles of dextrose, which is non-ionisable 2.5 % dextrose = 25 g /litre Gram moles of dextrose = 25 = 0.139 180 Gram moles of NaCl – Gram moles of active ingredients = Required gram moles 0.31 – 0.139 = 0.179 The required concentration of sodium chloride is Gram moles = X g/ Litre x 2 58.5
0.179 = X g/Litre x 2 58.5
0.179 x 58.5 = 5.235 g/litre 2 Thus required NaCl is = 0.535 %
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Chapter: 6 Powders Unit – II Syllabus Definition, classification, advantages and disadvantages, Simple & compound powders – official preparations, dusting powders, effervescent, efflorescent and hygroscopic powders, eutectic mixtures. Geometric dilutions.
INTRODUCTION Powders are mixtures of dry, finely divided drugs and/or chemicals that may be intended for internal or external use. The term 'Powder' may be used to describe: The physical form of a material, that is, a dry substance composed of finely divided particles. Or, it may be used to describe a type of pharmaceutical preparation, that is, a medicated powder intended for: internal (i.e., oral powder) external (i.e., topical powder) use. Although the use of medicated powders in therapeutics is limited, the use of powdered substances in the preparation of other dosage forms is extensive. For example: 1. Powdered drugs may be blended with powdered fillers and other pharmaceutical ingredients to fabricate solid dosage forms as tablets and capsules 2. They may be dissolved or suspended in solvents or liquid vehicles to make various liquid dosage forms 3. They may be incorporated into semisolid bases in the preparation of medicated ointments and creams. Advantages : It is used both internally and externally. 78
It is more stable than liquid dosage form. It is convenient for the physician to prescribe a specific amount of powder On set of action is faster as compared to tablet, capsules .because it is easily in dissolved in body fluids Easy to carry Easy to administration to the patient orally by dissolving in suitable liquids Disadvantage: Drugs have bitter taste , nausea and unpleasant taste cannot be administered in powder form . Deliquescent and hygroscopic drugs cannot be dispensed in powder form they are packed in double wrapping. Drugs which get affected by atmospheric condition are not suitable for dispense . Quantity less than 100 mg cannot be weighed conveniently . General method of preparation of powders: During powdering , weighing and mixing there is a loss of powder which cannot be avoided . Therefore calculate extra quantity . Dispensing balance are not very sensitive . It is difficult to weigh the quantity less than 100 mg must be triturated with suitable diluents such as lactose . METHODS OF MIXING OF POWDERS : Spatulation Trituration Geometric dilution ' Sifting Tumbling Spatulation : In this method mixing of powder is done by using a spatula through the powders on a sheet of a paper or porcelain tile. It is used for mixing of small quantity of powders It is not suitable for large quantity of powders . Glass tiles Trituration : Trituration It is used to both reduce particle size and mix the powders. If a porcelain dish with rough inner surface is preferred to glass mortar with smooth surface (not stain ) Porcelain Glass Geometric dilution : It is used when potent drugs(less than 60mg ) are mixed with large amount of diluents . The potent drugs is placed equal with diluents in mortar and the substance are slightly mixed by trituration . 100 mg drug + 900 mg lactose =1000 mg powder 100 mg drug + 100 mg lactose = 200 mg of powder mixture 200 mg p. mixture + 200 mg lactose = 400 mg of p. mixture 400 mg powder mixture +400 mg lactose = 800 mg of p. mixture 800 mg p. mixture + 200 mg of lactose = 1000 mg of powder mixture
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Sifting : Sifting The powders are mixed by passing through sifters . This process results in a light fluffy . It is not suitable for potent drugs . Sifter or sieve Tumbling: Tumbling It is the process of mixing of powders in a large container rotated by an electric motor. Powders are subdivided solids which are classified in the BP according to the size of their constituent particles of range from 1.25 (µm to 1.7 mm in diameter. CLASSIFICATION OF POWDERS IS BASED ON THE MANNER OF THEIR DISPENSING. 1. Bulk powders for external use: (a) Dusting powders (b) Snuffs (c) Dental powder (d) Insufflations 2. Bulk powders for internal use. 3. Simple and compound powders for internal use. 4. Effervescent granules 5. Cachets 1. BULK POWDERS FOR EXTERNAL USE External bulk powders contain non-potent substances for external applications. These powders are dispensed in glass, plastic wide mouth bottles and also in cardboard with specific method of application. Bulk powders for external used are of four types. (a) Dusting powders (b) Snuffs (c) Douche powders (d) Dental powder (e) Insufflation (a) Dusting powders These are used externally for local application not intended for systemic action. The desired characteristics of powders include- (a) homogeneity, (b) nonirritability, (c) free flow, (d) good spreadability and covering capability, (e) adsorption and absorption capacity, (f) very fine state of subdivision, and (g) capacity to protect the skin against irritation caused by friction, moisture or chemical irritants. (A) DUSTING POWDERS Dusting powders usually contain substances such as zinc oxide, starch and boric acid or natural mineral substances such as kaolin or talc.
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Talc may be contaminated with pathogenic microorganisms such as Clostridium tetani etc., and hence it should be sterilized by dry heat. Dusting powders should not be applied to broken skin. If desired, powders should be micronised or passed through a sieve # 80 or 100. Dusting powders should preferably be dispensed in sifter-top containers. Such containers provide the protection from air, moisture and contamination as well as convenience of application. Currently some foot powders and talcum powders have been marketed as pressure aerosols. Dusting powders are employed chiefly as lubricants, protectives, absorbents, antiseptics, antipruritics, astringents and antiperspirants. Zinc oxide 20 parts Salicylic acid 2 parts Starch powder 78 parts (B) SNUFFS These are finely divided solid dosage forms of medicaments dispensed in flat metal boxes with hinged lid. These powders are inhaled into nostrils for decongestion, antiseptic, and bronchodilator action. (C) DOUCHE POWDER These powders are intended to be used as antiseptics or cleansing agents for a body cavity; most commonly for vaginal use although they may be formulated for nasal, otic or ophthalmic use also. As douche powder formulation often include aromatic oils, it becomes necessary to pass them through a # 40 or 60 sieve to eliminate agglomeration and to ensure complete mixing. They can be dispensed either in wide mouth glass bottles or in powder boxes but the former are preferred because of protection afforded against air and moisture. Zinc sulphate Magnesium sulphate Boric acid Oil of lemon Water (D) DENTAL POWDERS Dental powders are rarely prescribed. However this class of powders is interesting from the compounding angle. This preparation is a type of dentifrice meant for cleaning the teeth. As such, dental powders contain detergents, abrasives, antiseptics and colouring and flavouring agents incorporated in a suitable base. Generally the base is calcium carbonate. The detergent is in the form of soap and the abrasive action is provided by finely powdered pumice stone. Essential oils are added to provide flavour and freshness to the mouth as well as antiseptic action. Essential oils, if present in smaller quantity, are easily absorbed by calcium carbonate and pumice. This makes the uniform distribution of the oil 81
difficult. Best results are obtained if the oil is triturated in the solids taking considerable care to distribute it uniformly. (E) INSUFFLATION Insufflations are a class of powders meant for application to the body cavities e.g., ear, nose, vagina etc. The powder has to be extremely fine and must find an entry to the cavity deep enough to bring about its action at the site. It is delivered to the affected part in a stream with the help of a device called an insufflator, which blows the powder to the site. Some of the insufflations contain volatile liquid ingredients which may require uniform distribution in the powder. If these liquid ingredients are present in large quantity, the liquid portion may have to be evaporated. Generally evaporation is brought about slowly in a china dish which is heated on a water bath. The resultant product is re-powdered and sifted through a sieve of a suitable size. However, active volatile liquids present in small portions should not be removed by evaporation but only incorporated by trituration in the powder. The pharmaceutical industry packages the insufflations in pressurized form i.e., aerosols. Aerosols contain the medication in a stout container with a suitable valve, the delivery of the powder being accomplished by a liquefied or compressed gas propellant of very low boiling point. On pressing the actuator of the valve the propellant delivers the medication in a stream. 2. BULK POWDERS FOR INTERNAL USE Bulk powders contain many doses in a wide-mouth container that is suitable to remove the powder by a teaspoon. The non-potent substances are used in bulk powder form such as antacid, laxative, purgative, etc. Rhubarb powder Light magnesium carbonate Heavy magnesium carbonate Ginger powder Make a powder. 3. SIMPLE AND COMPOUND POWDERS FOR INTERNAL USE These are unit dose powders normally packed in properly folded papers and dispensed in envelopes, metal foil, small heat-sealed plastic bags or other containers. Usually for the preparation of simple powders, the ingredients are weighed correctly and blended by geometrical mixing in ascending order of weights. The mixture is then either divided into blocks of equal size, numbers of blocks representing the number of powders to be dispensed or each dose is weighed separately and placed on a powder paper. The paper is then folded according to the pharmaceutical art and placed in either an envelope or a powder box. 82
4. EFFERVESCENT GRANULES This class of preparations can be supplied either by compounding the ingredients as granules or dispensed in the form of salts. The ingredients whether in granular form or present as salts, react in presence of water evolving carbon dioxide gas. For evolution of the gas two constituents are essential, a soluble carbonate such as sodium bicarbonate and an organic acid such as citric or tartaric acid. The preparation can be supplied either as a bulk powder or distributed in individual powders. There are three alternative methods of dispensing depending upon the nature of prescription. (i) If the effervescent salts are prescribed to be the dispensed in bulk form, no granulation is necessary. The ingredients are mixed uniformly and directions stated on the label to add the prescribed quantity to water, before use. (ii) If the effervescent salt is prescribed in divided doses, the ingredients which cause effervescence on mixing with water are enclosed separately in papers of different colour. The patient is advised to take one powder of each colour and add to water, before use. Quantities of the sodium bicarbonate and the organic acid, citric or tartaric, are equimolecular in proportion. (iii) In the third case the product contains all the ingredients mixed together in a granular form. Preparation of granular products requires pharmaceutical technique. If sodium bicarbonate and citric acid are taken in equimolecular proportion and mixed to make granules, the quantity of water of crystallization liberated from the citric acid is large enough to make the mass wet and carbon dioxide may be liberated during the preparation itself. If one tries to substitute citric acid by tartaric acid, which contains no water of crystallization; it may not be possible to form a mass necessary for granulation. Therefore both citric and tartaric acids are taken in suitable proportions leaving a little acid in surplus than the quantity required to neutralize sodium bicarbonate. This surplus is necessary to give the final preparation an acidic taste that is more palatable. There is a certain loss in weight of such a preparation due to the loss of water in drying the granules and partial loss of carbon dioxide due to its release during preparation. Heating is done on a water bath keeping all the ingredients thoroughly mixed in a porcelain dish. Gentle application of heat liberates the water of crystallization from citric acid and the mass tends to be coherent. Prolonged heating may result in complete evaporation of the released water leaving the product in the form of a dry lump which can not be rendered into granules. The coherent mass is transferred from the porcelain dish to an inverted sieve of suitable aperture size kept over a glazed paper. 83
The mass is pressed through the sieve taking care to change the position of the sieve over the paper to prevent the formation of a lump of the sieved granules. The granules are dried in an oven taking care to regulate the temperature which should be generally kept below 80°C. The operation requires considerable skill and experience to obtain granules of uniform size and an elegant product. If necessary, the dry granules are passed through a sieve of appropriate size to break larger granules which result due to sticking of the sieved wet granules-. The water of crystallization of the citric acid and the water from the reactions make the material coherent. Loss of weight occurs during granulation due to, (a) evaporation from the damp mixture, and (b) loss of carbon dioxide. The losses constitute approximately one-seventh of the weight of powder used and must be allowed for when calculating the amount to be prepared. Chemical reaction 3 NaHC03 + C6H807.H20 = C6H5Na307 + 3 C02 + 3 H20 (Sodium bicarbonate) (Citric acid) 2 NaHC03 + C4H606 - C4H4Na206 + 2 C02 + 2 H20 (Sodium bicarbonate) (Tartaric acid) 5. CACHETS Cachet as a unit dosage form was very popular sometime back. Presently cachets are seldom used and have been replaced by capsules. Cachets, like capsules, can be easily filled and sealed at the dispensing counter. This dosage form holds larger quantity of the medication as compared to capsules. Since the cachets are made of flour and water they are easily damaged in handling. Further this dosage form offers little protection against light and moisture. Due to its size and shape a cachet is difficult to swallow. The process of filling is similar to that of capsules. The drug is placed in one of the two halves of the cachet, the upper half is then placed over it and pressed with the help of a suitable device. The flange of the upper plate is moistened carefully taking care not to wet it, with the help of a dampener. The sealing takes place due to the moisture between the flanges of the upper and the lower half and the pressure over the flanges. About 15 minutes are allowed for drying of the seal. 84
After this time the middle portion of the cachet is slightly pressed to ensure complete sealing. In absence of a machine a pharmacist can improvise and use two bottles the mouths of which are broad enough so that flanges of the plates upper and lower, when kept over the mouths of the bottles, just rest over them. The drug is transferred to one of the plates resting over the mouth of the bottle kept vertically on the working bench. The flange of the empty half resting over the mouth of another bottle is moistened with the help of a damp camel hair brush. The empty half of the cachet is then placed over the other half in which the medication is kept so that the flanges of the two halves are perfectly superimposed. The second bottle is then inverted and brought over the superimposed cachet and carefully put over the flange and pressed in position without disturbing the resting place of the cachet. This provides a good seal. Cachets can be dry-sealed also. These cachets however are of a different shape where the cap is pressed over the body of the cachet. A protruded stud is also provided to hold the upper and lower halves together. Like capsules, cachets are also expected to remain untouched by hand and one should use gloves while handling them. Since there are inherent losses of the drug in this operation also like that of powders and capsules, the quantities of each ingredient should be weighed for an extra powder over the number to be dispensed. The cachets are dispensed in wide-mouthed bottles of glass or plastic with a perfectly fitting cap. The patient should be instructed to keep the bottle securely closed. (I) SIMPLE POWDER: It consists of only one active ingredient and suitable additive substances. If powder is in crystalline form, then it is reduced to fine. Example : Aspirin Powder, Calcium Gluconate Powder etc. Aspirin powder -300 mg Procedure: Triturate aspirin so as to get fine powder. Weigh the calculated amount of aspirin powder. Wrap each dose in individual powder paper and pack it. (II) COMPOUND POWDER: It consists of mixture of more than one active ingredient and other constituents. Example: 1. Aspirin, Paracetamol and Caffeine Powder Aspirin-300 mg Paracetamol-150 mg Caffeine-50 mg Procedure: Triturate all the ingredients separately so as to get fine powder. Weigh the calculated amount of aspirin powder; paracetamol powder and caffeine powder and mix them in ascending order of their weight. Wrap each dose in individual powder paper. 85
EFFERVESCENT POWDERS: Effervescent powders contain materials which react in presence of water evolving carbon dioxide. This class of preparations can be supplied either by compounding the ingredients as granules or dispensed in the form of salts. For evolution of the gas two constituents are essential, a soluble carbonate such as sodium bicarbonate and an organic acid such as citric or tartaric acid. The preparation can be supplied either as a bulk powder or distributed in individual powders. There are three alternative methods of dispensing effervescent powders based upon the nature of prescription. i) If the effervescent salts are prescribed to be dispensed in bulk form, no granulation is necessary. The ingredients are mixed uniformly and directions stated on the label to add the prescribed quantity to water, before use. (ii) If the effervescent salt is prescribed in divided doses, the ingredients which cause effervescence on mixing with water are enclosed separately in papers of different color. The patient is advised to take one powder of each color and add to water before use. Quantities of the sodium bicarbonate and the organic acid, citric ; tartaric, are equimolecular in proportion. (iii) In the third case, the product contains all the ingredients mixed together in granular form. EFFLORESCENT POWDER When some substances are exposed to air, they lose water to the atmosphere, thereby reducing in weight. Solids that behave in this way are those with water of crystallization. The molecules of water of crystallization are partially or completely lost to the atmosphere, thereby making them lose their crystalline forms. Eg:-such substance include caffeine, citric acid, ferrous sulphate etc. HYGROSCOPY This is when substances absorb water from air, but not enough to form solutions. Examples of such substances include CaO, NaNO3, NaCl, Sucrose and CuO. Also, certain liquid substances absorb water from the air to get diluted - these are also regarded as being hygroscopic. Example, conc. H2SO4 and conc. HCl. lf a hydroscopic substance absorbs so much moisture that an aqueous solution is formed, the substance becomes deliquescent. EUTECTIC MIXTURES A mixture of two or more substances which melts at the lowest freezing point of 86
any mixture of the components. Thistemperature is the eutectic point. The liquid melt has the same composition as the solid. A eutectic mixture is defined as a mixture of two or more components which usually do not interact to form a new chemical compound but, which at certain ratios, inhibit the crystallization process of one another resulting in a system having a lower melting point than either of the components. Eutectic mixtures, can be formed between Active Pharmaceutical Ingredients (APIs), between APIs and excipient or between excipient; thereby providing a vast scope for its applications in pharmaceutical industry. Eutectic mixture formation is usually, governed by following factors: (a) the components must be miscible in liquid state and mostly immiscible in solid state, (b) Intimate contact between eutectic forming materials is necessary for contact induced melting point depression, (c) the components should have chemical groups that can interact to form physical bonds such has intermolecular hydrogen bonding etc., GEOMETRIC DILUTION When a small amount of a potent substance is to be mixed with a large amount of diluent, the geometric dilution method is used to ensure the uniform distribution of the potent drug. This method is especially indicated when the potent substance and other ingredients are the same color and a visible sign of mixing is lacking. By this method, the potent drug is placed with an approximately equal volume of the diluent in a mortar and is mixed thoroughly by trituration. Then, a second portion of diluent equal in volume to the mixture is added and the trituration repeated. This process is continued by adding an equal volume of diluent to the powder mixture and repeating this until all of the diluent is incorporated. Some pharmacists add an inert colored powder to the diluent before mixing to permit visual inspection of the mixing process.
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Chapter: 7 Liquid dosage forms Unit – II Syllabus Advantages and disadvantages of liquid dosage forms. Excipients used in formulation of liquid dosage forms. Solubility enhancement techniques
INTRODUCTION Dosage Form is a pharmaceutical product, involving a mixture of active drug components and non-drug components (excipients) in the form in which it is marketed for use. Liquid state forms are meant for internal, parental or external use. They are available in monophasic and biphasic forms. Monophasic liquid dosage forms are true or colloidal solution. Water is mainly used as a solvent for majority of monophasic liquid dosage forms. The liquid which consists of two phases are known as biphasic liquids. Liquid form of a dose of a drug used as a drug or medication intended for administration or consumption. There are potential advantages of oral liquid dosage forms, such as no dissolution time and rapid absorption from the stomach/intestine compared to tablets, which may be an important factor for pain-relieving drugs. Inherent in this benefit is the risk of reaching peak plasma levels too fast, which could be harmful. Finally, as the excipient technology advances, a controlled release profile in liquid forms will likely become readily available. Liquid dosage forms Dosage forms are essentially pharmaceutical products in the form which involves a mixture of active drug components and nondrug components (excipients). Liquid form of a dose of a drug used as a drug or medication intended for administration or consumption. Liquid dosage forms are prepared: a. By dissolving the active drug substance in an aqueous or non- aqueous (e.g. alcohol, ether, glycerin) solvent, b. By suspensing the drug in appropriate medium, or 88
c. By incorporating the drug substance into an oil or water phases. Advantages a. Better for patients who have trouble swallowing expiration than other. b. Faster absorption than solids. c. More flexibility in achieving the proper dosage of medication. d. Palatable. e. Best choice for children and old age person. Disadvantages a. Shorter life than other dosage form, b. Harder to measure accuracy, c. Need special storage condition. d. Less stable, e. Easily affected by microorganisms, f. Bulky to carry around. g. Easy to loss by the breakage of the container. h. Measuring dose is required. EXCIPIENTS USED IN FORMULATION OF LIQUID DOSAGE FORMS The word Excipient is derived from the Latin word excipere, meaning is 'to except', which is simply explained as 'other than'. Pharmaceutical excipients are basically everything other than the active pharmaceutical ingredient. Ideally, excipients should be inert. An excipient is generally a pharmacologically inactive substance formulated with the active ingredient ("API") for a medication. Excipients are used to bulk up formulations that contain potent active ingredients (also referred to as "bulking agents," "fillers," or "diluents") to make convenient and accurate dispensing of a drug substance when preparing a dosage form. Excipients can also be useful in the manufacturing process to aid [ helps] in the handling of the active substance. 1. Vehicles (Solvents/ Co- Solvents) : eg. Aqueous vehicle, propylene glycol, glycerol 2. Buffering agents : eg. Citrate, gluconates, lactates 3. Preservatives : eg. Sodium benzoate, methyl paraben, propyl paraben 4. Anti-oxidants : eg. Butylated hydroxyl anisol (BHA), Butylated hydroxyl Toulene (BHT), ascorbic acid 5. Wetting agents : eg. Polysorbate, Sorbitan ester 6. Anti-foaming agents : eg. Simethicone 7. Thickening agents : eg. Methylcellulose 89
8. Sweetening agents : eg. Sorbitol, Saccharin, aspartame 9. Emulsifying agents : eg: Acacia , Tragacanth 10. Flavoring agents : eg. Peppermint, lemon oils. 11. Coloring agents : eg. Amaranth, Scarlet blue. 12. Humectants : eg. Propylene glycol, glycerol, sorbitol. 1. Vehicles (Solvents/ Co- Solvents) Solvents: In solutions, the vehicle is the solvent. The choice of a vehicle depends on: & physicochemical properties of active ingredients. Water as a vehicle Water used as the primary solvent; widely available, relatively inexpensive, palatable and non-toxic for oral use, non-irritant for external use. Water is also a good solvent for many ionizable drugs. Salts of organic compounds are more soluble in water water is the preferred solvent. for solutions to be taken orally, used ophthalmic ally, or injected. Cosolvents: These are substances added to a primary solvent in small amounts to increase the solubility of a poorly-soluble compound. Their use is most prevalent in chemical and biological research relating to pharmaceuticals and food science, where alcohols are frequently used as cosolvents in water (often less than 5% by volume to dissolve hydrophobic molecules during extraction, screening, and formulation. Cosolvents also find applications in environmental chemistry and are known as effective countermeasures against pollutant non-aqueous phase liquids 2. Buffering agents Used to resist change in pH upon dilution or addition of acid or alkali. Examples: Potassium metaphosphate, Potassium phosphate, Monobasic Sodium acetate, Sodium citrate. 3. Preservatives Preservatives are the agents that are used to stabilizes pharmaceutical preparations against chemical and physical degradation due to changed in environmental conditions, most of liquid and semisolid preparations must be preserved from microbial contamination. Some typical preservatives used in pharmaceutical formulations are, Antioxidants like Vitamin A, Vitamin E, Vitamin C, Retinyl Palmitate, and Selenium.
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The amino acids Cysteine and Methionine Citric acid and Sodium Citrate , boric acid. Synthetic preservatives like the Parabens: benzoic acid, alcohol, Methyl Paraben and Propyl Paraben. 4. Antioxidants These are compounds that inhibit oxidation. Oxidation is a chemical reaction that can produce free radicals, thereby leading to chain reactions that may damage the cells of organisms. Antioxidants such as thiols or ascorbic acid (vitamin C) terminate these chain reactions. To balance the oxidative state, plants and animals maintain complex systems of overlapping antioxidants, such as glutathioneand enzymes (e.g., catalase and superoxide dismutase), produced internally, or the dietary antioxidants vitamin C, and vitamin E. 5. Wetting agents Wetting agents are substances that reduce the surface tension of water to allow it to spread drops onto a surface, increasing the spreading abilities of a liquid. Lowering the surface tension lowers the energy required to spread drops onto a film, thus weakening the cohesive properties of the liquid and strengthening its adhesive properties. One example of how wetting agents work is in the formation of micelles. Micelles consist of hydrophilic heads forming an outer layer around lipophilic tails. When in water, the micelles' tails can surround an oil droplet while the heads are attracted to the water.
6. Antifoaming agents : A defoamer or an anti-foaming agent is a chemical additive that reduces and hinders the formation of foam in industrial processliquids. The terms anti-foam agent and defoamer are often used interchangeably. Commonly used agents are insoluble oils, polydimethylsiloxanes and other silicones, certain alcohols, stearates and glycols. The additive is used to prevent formation of foam or is added to break a foam already formed. 7. Thickening agent A thickening agent or thickener is a substance which can increase the viscosity of 91
a liquid without substantially changing its other properties. Edible thickeners are commonly used to thicken sauces, soups, and puddings without altering their taste; thickeners are also used in paints, inks, explosives, and cosmetics. Thickeners may also improve the suspension of other ingredients or emulsions which increases the stability of the product. Thickening agents are often regulated as food additivesand as cosmetics and personal hygiene product ingredients. Some thickening agents are gelling agents (gellants), forming a gel, dissolving in the liquid phase as a colloid mixture that forms a weakly cohesive internal structure. Others act as mechanical thixotropic additives with discrete particles adhering or interlocking to resist strain. 8. Sweetening agents Sweeteners are added to make the ingredients more palatable, especially in chewable tablets such as antacid or liquids like cough syrup. Examples: Sugar can be used to mask unpleasant tastes or smells, Sodium Saccharin, Aspartame. 9. Emulsifying agents Used to stabilize and maintain dispersion of finely subdivided particles of liquid in a vehicle in which it is immiscible. End product may be a liquid emulsion or semisolid emulsion [ e.g. cold cream] Examples: Acacia, Cetyl alcohol, Glyceryl monostearate, Methyl Cellulose, Sodium carboxy methyl cellulose etc. 10. Flavoring agents Flavours can be used to mask unpleasant tasting active ingredients and improve the acceptance that the patient will complete a course of medication. Flavourings may be natural (e.g. fruit extract) or artificial. Flavours are used to improve : a. Bitter product - mint, cherry or anise may be used. b. Salty product - peach, apricot or liquorice may be used. c. Sour product - raspberry or liquorice may be used. d. An excessively sweet product - vanilla may be used. The selection of appropriate flavoring agent depends on taste of the drug substance itself. Fruits or citrous flavors are frequently used to mask sour or acid-tasting drugs. Cinnamon , orange, raspberry flavors are used mask salty drugs. Flavors are consists of oil-soluble or water soluble liquids and dry powders.
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Sometimes degradation of flavors is cause by exposer of light, temperature, water, enzymes, other contaminants. The types of flavoring agent used in the preparation are: 1. Natural Flavors: flavoring constituents derived from spice, fruits, vegetables, herbs, roots, leaf parts of plants. e.g. Aromatic Oils: Like caraway, clove, dill, lemon, orange, pepper – mint. 2. Synthetic flavors: These include synthetic sweeteners, chloroform, vanillin, benzaldehyde etc. and variety of organic compounds like alcohols, aldehydes, esters, ketones, fatty acids and lactones are used alone or combined with essential oils. 11. Colors Colors are added to improve the appearance of a formulation. Consistency of Color is important because it allows easy identification of a medication. Colorants or coloring agents are mainly used to impart a distinctive appearance to the pharmaceutical dosage forms. We can also says that the colorants are the cosmetics for the pharmaceutical preparations. Because the acceptable appearance of dosage form can be enhanced by using suitable colorants. The important categories of dosage form in which coloring agents are used, Tablets ,Capsules, Oral liquids, Topical creams, Toothpastes Pharmaceutical preparations are colored mainly for following reasons: 1. For increasing acceptability of unattractive medication. 2. It is observed that bright colored tonics, powders, ointments are likely used by patient. 3. For identification of a product in its manufacturing and distribution stages. 3. For identification of similar looking product within product line. 4. For eliminating error when different strength of the same drugs are mixed. 5. The elegance and appearance of colored product is valuable specially for children. 6.Coloring agents also help a doctor to recognize a previous treatment. Specific colored products become known to doctors and pharmacists, and this can help in sales of product.
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Ideal properties of coloring agents. 1.Nontoxic and have no physiological activity. 2.Free from harmful impurities. 3.Its coloring power should be high so that only small quantities are required. 12. Humectants A humectant is a hygroscopic substance used to keep things moist; it is the opposite of a desiccant because it is wet. It is often a molecule with several hydrophilicgroups, most often hydroxyl groups; however, amines and carboxyl groups, sometimes esterified, can be encountered as well (its affinity to form hydrogen bonds with molecules of water is the crucial trait). They are used in many products, including food, cosmetics, medicines and pesticides. A humectant attracts and retains the moisture in the air nearby via absorption, drawing the water vapor into or beneath the organism's or object's surface. By contrast, desiccants also attract ambient moisture, but adsorb—not absorb—it, by condensing the water vapor onto the surface, as a layer of film. SOLUBILITY ENHANCEMENT TECHNIQUES Solubility, the phenomenon of dissolution of solute in solvent to give a homogenous system, is one of the important parameters to achieve desired concentration of drug in systemic circulation for desired (anticipated) pharmacological response. Low aqueous solubility is the major problem encountered with formulation development of new chemical entities as well as for the generic development. More than 40% NCEs (new chemical entities) developed in pharmaceutical industry are practically insoluble in water. Solubility is a major challenge for formulation scientist. Any drug to be absorbed must be present in the form of solution at the site of absorption. Various techniques are used for the enhancement of the solubility of poorly soluble drugs which include physical and chemical modifications of drug and other methods like particle size reduction, crystal engineering, salt formation, solid dispersion, use of surfactant, complexation, and so forth. Selection of solubility improving method depends on drug property, site of absorption, and required dosage form characteristics. Solubility is the property of a solid, liquid, or gaseous chemical substance called solute to dissolve in a solid, liquid, or gaseous solvent to form a homogeneous solution of the solute in the solvent. The solubility of a substance fundamentally depends on the solvent used as well as on temperature and pressure. The extent of solubility of a substance in a specific solvent is measured as the saturation concentration where adding more solute does not increase its concentration in the solution Solubility improvement techniques can be categorized in to physical modification, chemical modifications of the drug substance, and other techniques.
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Physical Modifications Particle size reduction like micronization and nanosuspension, modification of the crystal habit like polymorphs, amorphous form and cocrystallization, drug dispersion in carriers like eutectic mixtures, solid dispersions, solid solutions and cryogenic techniques. 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23.
Particle Size Reduction Micronization Solid Dispersion Hot-Melt Method (Fusion Method) Solvent Evaporation Method Hot-Melt Extrusion Nanosuspension Precipitation Technique Media Milling High Pressure Homogenization Combined Precipitation and Homogenization Supercritical Fluid (SCF) Process Cryogenic Techniques Spray Freezing onto Cryogenic Fluids Spray Freezing into Cryogenic Liquids (SFL) Spray Freezing into Vapor over Liquid (SFV/L) Ultra-Rapid Freezing (URF) Inclusion Complex Formation-Based Techniques Kneading Method Lyophilization/Freeze-Drying Technique Microwave Irradiation Method Micellar Solubilization Hydrotrophy
1. Particle Size Reduction The solubility of drug is often intrinsically related to drug particle size; as a particle becomes smaller, the surface area to volume ratio increases. The larger surface area allows greater interaction with the solvent which causes an increase in solubility. Conventional methods of particle size reduction, such as comminution and spray drying, rely upon mechanical stress to disaggregate the active compound. Particle size reduction is thus permitting an efficient, reproducible, and economic means of solubility enhancement. However, the mechanical forces inherent to comminution, such as milling and grinding, often impart significant amounts of physical stress upon the drug product which may induce degradation. The thermal stress which may occur during comminution and spray drying is also a concern when processing thermosensitive or unstable active compounds. Useing traditional approaches for nearly insoluble drugs may not be able to enhance the solubility up to desired level.
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2. Micronization It is another conventional technique for the particle size reduction. Micronization increases the dissolution rate of drugs through increased surface area, it does not increase equilibrium solubility. Decreasing the particle size of these drugs, which cause increase in surface area, improve their rate of dissolution. Micronization of drugs is done by milling techniques using jet mill, rotor stator colloid mills and so forth micronization is not suitable for drugs having a high dose number because it does not change the saturation solubility of the drug. These processes were applied to griseofulvin, progesterone, spironolactone diosmin, and fenofibrate. For each drug, micronization improved their digestive absorption, and consequently their bioavailability and clinical efficacy. Micronized fenofibrate exhibited more than 10-fold (1.3% to 20%) increase in dissolution in at 30 minutes biorelevant media. 3. Solid Dispersion The concept of solid dispersions was originally proposed by Sekiguchi and Obi, who investigated the generation and dissolution performance of eutectic melts of a sulfonamide drug and a water-soluble carrier in the early 1960s. Solid dispersions represent a useful pharmaceutical technique for increasing the dissolution, absorption, and therapeutic efficacy of drugs in dosage forms. The term solid dispersion refers to a group of solid products consisting of at least two different components, generally a hydrophilic matrix and a hydrophobic drug. The most commonly used hydrophilic carriers for solid dispersions include polyvinylpyrrolidone (Povidone, PVP), polyethylene glycols (PEGs), PlasdoneS630. Surfactants like Tween-80, docusate sodium, Myrj-52, Pluronic-F68, and sodium lauryl sulphate (SLS) also find a place in the formulation of solid dispersion. The solubility of celecoxib, halofantrine, and ritonavir can be improved by solid dispersion using suitable hydrophilic carriers like celecoxib with povidone (PVP) and ritonavir with gelucire. Various techniques to prepare the solid dispersion of hydrophobic drugs with an aim to improve their aqueous solubility are listed here. 4. Hot-Melt Method (Fusion Method) The main advantages of this direct melting method is its simplicity and economy. The melting or fusion method was first proposed by Sekiguchi and Obi to prepare fast release solid dispersion dosage forms. In this method, the physical mixture of a drug and a water-soluble carrier are heated directly until the two melts. The melted mixture is then cooled and solidified rapidly in an ice bath with rigorous stirring. The final solid mass is then crushed, pulverized, and sieved, which can be compressed into tablets with the help of tableting agents. The melting point of a binary system is dependent upon its composition, that is, the selection of the carrier and the weight fraction of the drug in the system.
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An important requisite for the formation of solid dispersion by the hot-melt method is the miscibility of the drug and the carrier in the molten form. Another important requisite is the thermostability of both the drug and the carrier. 5. Solvent Evaporation Method Tachibana and Nakamura were the first to dissolve both the drug and the carrier in a common solvent and then evaporate the solvent under vacuum to produce a solid solution. This enabled them to produce a solid solution of the highly lipophilic β-carotene in the highly water soluble carrier povidone. Many investigators studied solid dispersion of meloxicam, naproxen, and nimesulide using solvent evaporation technique. These findings suggest that the abovementioned technique can be employed successfully for improvement and stability of solid dispersions of poorly water soluble drugs. The main advantage of the solvent evaporation method is that thermal decomposition of drugs or carriers can be prevented because of the low temperature required for the evaporation of organic solvents. However, the disadvantages associated with this method are the higher cost of preparation, the difficulty in completely removing the organic solvent (a regulatory perspective), the possible adverse effect of the supposedly negligible amount of the solvent on the chemical stability of the drug, the selection of a common volatile solvent, and the difficulty in reproducing crystal forms. 6. Hot-Melt Extrusion Hot-melt extrusion is essentially the same as the fusion method except that intense mixing of the components is induced by the extruder. Just like in the traditional fusion process, miscibility of the drug and the matrix could be a problem. High-shear forces resulting in high local temperature in the extruder is a problem for heat sensitive materials. However, compared to the traditional fusion method, this technique offers the possibility of continuous production, which makes it suitable for large-scale production. Furthermore, the product is easier to handle because at the outlet of the extruder the shape can be adapted to the next processing step without grinding. 7. Nanosuspension Nanosuspension technology has been developed as a promising candidate for efficient delivery of hydrophobic drugs. This technology is applied to poorly soluble drugs that are insoluble in both water and oils. A pharmaceutical nanosuspension is a biphasic system consisting of nano sized drug particles stabilized by surfactants for either oral and topical use or parenteral and pulmonary administration. The particle size distribution of the solid particles in nanosuspensions is usually less than one micron with an average particle size ranging between 200 and 600 nm. Various methods utilized for preparation of nanosuspensions include precipitation technique, media milling, high-pressure homogenization in water, 97
high pressure homogenization in nonaqueous media, and combination of Precipitation and high-Pressure homogenization. 8. Precipitation Technique In precipitation technique the drug is dissolved in a solvent, which is then added to antisolvent to precipitate the crystals. The basic advantage of precipitation technique is the use of simple and low cost equipments; but the challenge is the addition of the growing drug crystals to avoid formation of microparticles. The limitation of this precipitation technique is that the drug needs to be soluble in at least one solvent and this solvent needs to be miscible with antisolvent. Moreover, precipitation technique is not applicable to drugs, which are simultaneously poorly soluble in aqueous and nonaqueous media. Nanosuspension of Danazol and Naproxen have been prepared by precipitation technique to improve their dissolution rate and oral bioavailability. The size reduction of naproxen was also associated with an apparent increase in the rate of absorption by approximately 4-fold. 9. Media Milling The nanosuspensions are prepared by using high-shear media mills. The milling chamber charged with milling media, water, drug, and stabilizer is rotated at a very high-shear rate under controlled temperatures for several days (at least 2–7 days). The milling medium is composed of glass, Zirconium oxide, or highly cross-linked polystyrene resin. High energy shear forces are generated as a result of the impaction of the milling media with the drug resulting into breaking of microparticulate drug to nanosized particles. 10. High Pressure Homogenization High-pressure homogenization has been used to prepare nanosuspension of many poorly water soluble drugs. In this method, the suspension of a drug and surfactant is forced under pressure through a nanosized aperture valve of a high pressure homogenizer. The principle of this method is based on cavitation in the aqueous phase. The cavitations forces within the particles are sufficiently high to convert the drug microparticles into nanoparticles. The concern with this method is the need for small sample particles before loading and the fact that many cycles of homogenization are required. Dissolution rate and bioavailability of poorly soluble drugs such as spironolactone, budesonide, and omeprazole have been improved by reducing their particle size by high pressure homogenization. 11. Combined Precipitation and Homogenization The precipitated drug nanoparticles have a tendency to continue crystal growth to the size of microcrystals. They need to be processed with high-energy forces (homogenisation). They are in completely amorphous, partially amorphous or completely crystalline forms which create problems in long term stability as well as in bioavailability, so the precipitated particle suspension is subsequently 98
homogenized which preserve the particle size obtained after the precipitation step. 12. Supercritical Fluid (SCF) Process Another novel nanosizing and solubilisation technology whose application has increased in recent years is particle size reduction via supercritical fluid (SCF) processes. Supercritical fluids are fluids whose temperature and pressure are greater than its critical temperature (Tc) and critical pressure (Tp), allowing it to assume the properties of both a liquid and a gas. At near-critical temperatures, SCFs, are highly compressible allowing moderate changes in pressure to greatly alter the density and mass transport characteristics of the fluid that largely determine its solvent power. Once the drug particles are solubilised within the SCF (usually carbon dioxide), they may be recrystallised at greatly reduced particle sizes. The flexibility and precision offered by SCF processes allows micronisation of drug particles within narrow ranges of particle size, often to submicron levels. Current SCF processes have demonstrated the ability to create nanoparticulate suspensions of particles 5–2,000 nm in diameter. Several pharmaceutical companies, such as Nektar Therapeutics and Lavipharm, are specializing in particle engineering via SCF technologies for particle size reduction and solubility enhancement. Several methods of SCF processing have been developed to address individual aspects of these shortcomings, such as precipitation with compressed antisolvent process (PCA), solution enhanced dispersion by SCF (SEDS), supercritical antisolvent processes (SAS), rapid expansion of supercritical solutions (RESS), gas anti solvent recrystallization (GAS), and aerosol supercritical extraction system (ASES). 13. Cryogenic Techniques Cryogenic techniques have been developed to enhance the dissolution rate of drugs by creating nanostructured amorphous drug particles with high degree of porosity at very low-temperature conditions. Cryogenic inventions can be defined by the type of injection device (capillary, rotary, pneumatic, and ultrasonic nozzle), location of nozzle (above or under the liquid level), and the composition of cryogenic liquid (hydrofluoroalkanes, N2, Ar, O2, and organic solvents). After cryogenic processing, dry powder can be obtained by various drying processes like spray freeze drying, atmospheric freeze drying, vacuum freeze drying, and lyophilisation. 14. Spray Freezing onto Cryogenic Fluids Briggs and Maxvell invented the process of spray freezing onto cryogenic fluids. In this technique, the drug and the carrier (mannitol, maltose, lactose, inositol, or dextran) were dissolved in water and atomized above the surface of a boiling agitated fluorocarbon refrigerant. Sonication probe can be placed in the stirred refrigerant to enhance the dispersion of the aqueous solution. 15. Spray Freezing into Cryogenic Liquids (SFL) The SFL particle engineering technology has been used to produce amorphous 99
nanostructured aggregates of drug powder with high surface area and good wettability. It incorporates direct liquid-liquid impingement between the automatized feed solution and cryogenic liquid to provide intense atomization into microdroplets and consequently significantly faster freezing rates. The frozen particles are then lyophilized to obtain dry and free-flowing micronized powders. 16. Spray Freezing into Vapor over Liquid (SFV/L) Freezing of drug solutions in cryogenic fluid vapours and subsequent removal of frozen solvent produces fine drug particles with high wettability. During SFV/L the atomized droplets typically start to freeze in the vapor phase before they contact the cryogenic liquid. As the solvent freezes, the drug becomes supersaturated in the unfrozen regions of the atomized droplet, so fine drug particles may nucleate and grow. 17. Ultra-Rapid Freezing (URF) Ultra-rapid freezing is a novel cryogenic technology that creates nanostructured drug particles with greatly enhanced surface area and desired surface morphology by using solid cryogenic substances. Application of drugs solution to the solid surface of cryogenic substrate leads to instantaneous freezing and subsequent lyophilization (for removal of solvent) forms micronized drug powder with improved solubility. Ultra rapid freezing hinders the phase separation and the crystallization of the pharmaceutical ingredients leading to intimately mixed, amorphous drug-carrier solid dispersions, and solid solutions. 18.Inclusion Complex Formation-Based Techniques Among all the solubility enhancement techniques, inclusion complex formation technique has been employed more precisely to improve the aqueous solubility, dissolution rate, and bioavailability of poorly water soluble drugs. Inclusion complexes are formed by the insertion of the nonpolar molecule or the nonpolar region of one molecule (known as guest) into the cavity of another molecule or group of molecules (known as host). The most commonly used host molecules are cyclodextrins. The enzymatic degradation of starch by cyclodextrin-glycosyltransferase (CGT) produces cyclic oligomers, Cyclodextrins (CDs). These are nonreducing, crystalline, water soluble, and cyclic oligosaccharides consisting of glucose monomers arranged in a donut shaped ring having hydrophobic cavity and hydrophilic outer surface 1. Three naturally occurring CDs are -Cyclodextrin, -Cyclodextrin, and -Cyclodextrin. 19. Kneading Method This method is based on impregnating the CDs with little amount of water or hydroalcoholic solutions to convert into a paste. The drug is then added to the above paste and kneaded for a specified time. The kneaded mixture is then dried and passed through a sieve if required. In laboratory scale, kneading can be achieved by using a mortar and pestle. In large scale, kneading can be done by 100
utilizing the extruders and other machines. This is the most common and simple method used to prepare the inclusion complexes and it presents very low cost of production. 20. Lyophilization/Freeze-Drying Technique In order to get a porous, amorphous powder with high degree of interaction between drug and CD, lyophilization/freeze drying technique is considered suitable. In this technique, the solvent system from the solution is eliminated through a primary freezing and subsequent drying of the solution containing both drug and CD at reduced pressure. Thermolabile substances can be successfully made into complex form by this method. The limitations of this technique is the use of specialized equipment, time consuming process, and yield poor flowing powdered product. Lyophilization/freeze drying technique is considered as an alternative to solvent evaporation and involve molecular mixing of drug and carrier in a common solvent. 21. Microwave Irradiation Method This technique involves the microwave irradiation reaction between drug and complexing agent using a microwave oven. The drug and CD in definite molar ratio are dissolved in a mixture of water and organic solvent in a specified proportion into a round-bottom flask. The mixture is reacted for short time of about one to two minutes at 60°C in the microwave oven. After the reaction completes, adequate amount of solvent mixture is added to the above reaction mixture to remove the residual un complexed free drug and CD. The precipitate so obtained is separated using what man filter paper, and dried in vacuum oven at 40°C. Microwave irradiation method is a novel method for industrial scale preparation due to its major advantage of shorter reaction times and higher yield of the product. 22. Micellar Solubilization The use of surfactants to improve the dissolution performance of poorly soluble drug products is probably the basic, primary, and the oldest method. Surfactants reduce surface tension and improve the dissolution of lipophilic drugs in aqueous medium. They are also used to stabilise drug suspensions. When the concentration of surfactants exceeds their critical micelle concentration (CMC, which is in the range of 0.05–0.10% for most surfactants), micelle formation occurs which entrap the drugs within the micelles. This is known as micellization and generally results in enhanced solubility of poorly soluble drugs. Surfactant also improves wetting of solids and increases the rate of disintegration of solid into finer particles. Commonly used nonionic surfactants include polysorbates, polyoxyethylated castor oil, polyoxyethylated glycerides, lauroyl macroglycerides, and mono- and di-fatty acid esters of low molecular weight polyethylene glycols. Surfactants are also often used to stabilize microemulsions and suspensions into which drugs are dissolved.
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Examples of poorly soluble compounds that use Micellar solubilization are antidiabetic drugs, gliclazide, glyburide, glimepiride, glipizide, repaglinide, pioglitazone, and rosiglitazone. 23. Hydrotrophy Hydrotrophy is a solubilisation process, whereby addition of a large amount of second solute, the hydrotropic agent results in an increase in the aqueous solubility of first solute. Hydrotropic agents are ionic organic salts, consists of alkali metal salts of various organic acids. Additives or salts that increase solubility in given solvent are said to “salt in” the solute and those salts that decrease solubility “salt out” the solute. Several salts with large anions or cations that are themselves very soluble in water result in “salting in” of non electrolytes called “hydrotropic salts”; a phenomenon known as “hydrotropism.” Hydrotrophy designate the increase in solubility in water due to the presence of large amount of additives. The mechanism by which it improves solubility is more closely related to complexation involving a weak interaction between the hydrotrophic agents like sodium benzoate, sodium acetate, sodium alginate, urea, and the poorly soluble drugs. The hydrotropes are known to self-assemble in solution. The classification of hydrotropes on the basis of molecular structure is difficult, since a wide variety of compounds have been reported to exhibit hydrotropic behaviour. Specific examples may include ethanol, aromatic alcohols like resorcinol, pyrogallol, catechol, and -naphthols and salicylates, alkaloids like caffeine and nicotine, ionic surfactants like diacids, SDS (sodium dodecyl sulphate), and dodecylated oxidibenzene. The aromatic hydrotropes with anionic head groups are mostly studied compounds. They are large in number because of isomerism and their effective hydrotrope action may be due to the availability of interactive pi orbital. Hydrotropes with cationic hydrophilic group are rare, for example salts of aromatic amines, such as procaine hydrochloride. Besides enhancing the solubilization of compounds in water, they are known to exhibit influences on surfactant aggregation leading to micelle formation, phase manifestation of multicomponent systems with reference to nanodispersions and conductance percolation, clouding of surfactants and polymers, and so forth.
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Chapter: 8 Monophasic liquids Unit – III Syllabus Definitions and preparations of Gargles, Mouthwashes, Throat Paint, Eardrops, Nasal drops, Enemas, Syrups, Elixirs, Liniments and Lotions.
INTRODUCTION Monophasic dosage form refers to liquid preparation containing two or more components in one phase system, it is represent by true solution. A true solution is a clear homogenous mixture that is prepared by dissolving solute in a suitable solvent. The component of the solution which is present in a large quantity is known as “SOLVENT” where as the component present in small quantity is termed as “SOLUTE”. Advantage 1. It is easier to swallow, therefore easier for children and old age people. 2.
Facilitate absorption of drug faster than solid dosage form as drug is already in solution form. It is homogenous therefore give uniform dose than suspension or emulsion which need shaking.
3.
Simple and fast to formulate
4.
It can be administered by various routes : Oral, Parenteral (injection),enema for rectal use, otic (ear), nasal and ophthalmic preparation.
Disadvantage 1. They are bulky, so difficult to transport and store. 2.
Water is commonly use vehicle, which is prone to microbial growth. So addition of preservative is needed. 103
3.
When expose to direct sunlight it may undergo hydrolysis, so need to store in cool and dark place.
4.
Drug stability reduce by hydrolysis or oxidation. So, they have shorter expire date than solid dosage form.
5.
Other major sign of drug instability are color change, Precipitation, microbial growth etc.
GARGLES Gargling (same root as 'gurgle') is the act of bubbling liquid in the mouth. Vibration caused by the muscles in the throat and back of the mouth cause the liquid to bubble and flurry around inside the mouth cavity. Potassium chlorate & Phenol Gargle B.P.C. Rx Potassium chlorate………… 30 g Patent Blue V ……………… 0.009 g Liquefied phenol ……………. 15 ml Water up to………………….. 1000 ml Prepare mouthwash, send 30 ml Direction: Dilute with warm water before use Gargle Container: White fluted glass bottle with plastic screw cap. Coloured bottle used for preparation which need protection. Labeling: 1. “For external use only” 2. “Diluted with warm water before use” 3. “Not to be swallowed in large amount” Storage: Gargle are supplied in well closed air tight glass container having plastic screw cap. MOUTH WASHES Definition of Mouth wash A medicated liquid used for cleaning the oral cavity and treating mucous membranes of the mouth. may contribute to surface softening and increased wear of dental resins and composite materials. Types of Mouth wash Fluoride mouthwashes : it contain sodium fluoride which helps to strengthen the teeth as well as adding extra protection against tooth decay. Cosmetic mouthwashes : It do not offer the same protection as other types and are used more as a means of disguising bad breath(halitosis).Antiseptic 104
mouthwashes contain chlorhexidine gluconate - a chemical which stops the growth of bacteria and is suitable for people with a mouth infection. Natural mouthwashes: These are alcohol-free (and contain no fluoride) and work in much the same way as conventional mouth washes. They can also treat a mouth infection or injury. Total care mouthwashes contain anti-bacterial ingredients which help to reduce the build up of plaque and prevent gum disease. Advantages of Mouthwash: It can boost your oral health. It may prevent plaque from building up. Rinses with fluoride can help prevent cavities. Fluoride protects against tooth decay(cavities). Mouthwash can help you target plaque. Prevents dry mouth. Disadvantages of Mouthwash: Some mouth rinses contain high levels of alcohol—ranging from 18 to 26 percent. This may produce a burning sensation in the cheeks, teeth, and gums. Preparation and Dispensing of Mouthwashes Detergent Antiseptic agent Fluoride Colorants Sweeteners - sodium saccharine and sucralose. Vehicle – Water Preservative- sodium benzoate. Flavoring - such as eucalyptol or menthol. To prepare mouthwash following ingredients are added: Sodium Bicarbonate…… 10g Sodium Chloride……….. 15g Chloroform……………… 500ml Pepprmintoil……..………. 25ml Water qty to prepare……. 1000ml Procedure : Dissolve Na bicarbonate & Nacl in 10 ml Add chloroform & peppermint oil Makeup the volume Dispense the solution
105
Direction & Storage : Keep out of reach of children Away from sunlight Store at room temperature Storage: Colorless bottles are used unless protection from light is necessary. plastic screw caps fluted Containers Product information Active ingredients Uses Warnings Direction Storage Inactive ingredients Before using a mouth rinse, brush and floss teeth. Measure the proper amount of rinse Dilute it before use Thirty seconds is the suggested rinsing time. Do not rinse, eat, or smoke for thirty minutes after using a mouthwash. NF MOUTHWASH NF Mouthwash is also known as Alkline Aromatic Solution NF II, Liquor Aromaticus Alkalinus, Liquor Antisepticus Alkalinus NF IV, and Alkaline Antiseptic Solution. Formula: Potassium Bicarbonate Sodium Borate Thymol Eucalyptol Methyl salicylate Amaranth Solution Alcohol Glycerin Purified Water, q.s. To make
20 g 20 g 0.5 g 1.0 ml 0.5 ml 14 ml 50 ml 100 ml 1000 ml
Preparation: Dissolve the potassium bicarbonate and sodium borate in 100ml purified water, add the glycerin when effervescence has ceased, add the mixture to 500ml purified water. Dissolve the other ingredients in the alcohol, and add the solution of salts to the alcoholic solution with agitation. Then add sufficient quantity of purified water to make the product measure 1000ml. Allow the mixture to stand, with occasional shaking during 24 hours. Filter using talc, if necessary to produce a clear solution. Possible Uses: Antibacterial mouthwash, nasal douche and throat gargle which is approximately isotonic with body fluids and therefore non-irritant to the mucous membranes. For oral use undiluted; dental spray diluted with 5 volumes of water. THROAT PAINTS Throat Paints are solutions or dispersions of one or more active ingredients intended for application to the mucosa of the throat or mouth. Throat paints are viscous due to a high contact of glycerin, which being sticky, adhere to the affected site and prolong the action of the medicaments. 106
Compound Iodine Paint (Mandl's Paint) – used for pharyngitis or tonsillitis. Iodine throat paint is designed to kill germs. It can be used on sore throats and ulcers to ease them. Crystal Violet Paint – used for thrush. Phenol glycerin (diluted with equal volume of glycerin to reduce its causticity) produces analgesic effect in tonsillitis and ulcerative stomatitis. Tannic acid Glycerin, has astringent action, relieves from sore throat. e.g. Mandls Throat Paint Formula: Glycerol up to 1000ml Peppermint oil 4ml Water 25ml Alcohol 90%v/v 40ml Iodine 12.5g Potassium iodide 25g Procedure: i) Potassium iodide is dissolved in water. (ii) Iodine is added in the concentrated potassium iodide solutions to form KI3 (or higher iodides). (iii) Peppermint oil is dissolved in alcohol 90%v/v and the alcoholic solution is added to the iodine solution. (iv) Volume is made up with glycerin. ROLE OF INGREDIENT Glycerin: Vehicle, Viscous, sticky, adhere to affected site and prolong effect of medicament. Peppermint Oil: Flavoring agent Water: Solvent Alcohol: Preservative Iodine: Antiseptic, Penetrate inn pores and have germicidal effect, treat small abrasion and wounds in Skin. Potassium Iodide: To make soluble iodine in water USES: Tosilitis, Pharyngitis 107
A small quantity of Sodium Citrate or acetate is added as preservative for longer. Since glycerin is hygroscopic solvent, it must be stored in tightly close container. A wax card liner is used for screw caps (because iodine attacks other materials). Dispense in amboured colored bottle. A wide mouthed, fluted, light resistant, screw-capped, glass-jar is used. Food and water before and after application of throat paint, should be avoided for 1 hour Apply with the help of soft brush or a cotton swab. Advice to the patient: Pharmacist should demonstrate the use of throat brush to the patient. Not to be swallowed in large amount. Shake the bottle before use. Store in a cool place. For local application. EAR DROPS These are a form of medicine used to treat or prevent ear infections, especially infections of the outer ear and ear canal (otitis externa). Ear drops are solution or suspension of medicine. They are instilled into the ears to produce a local effect directly inside the ears. Benzocaine Ear Drops Rx Benzocaine (1%v/v) -------- 10ml Phenazone -------------------- 50 gm Glycerol to make ----------- 1000 ml Use : Benzocaine ear drops is a medication for the treatment of ear pain caused by otitis media. NASAL DROPS Nasal drops are the solution of drug that are instilled in to nose with the help of dropper. Nasal drops are isotonic to nasal secretions and buffered to the normal pH range of nasal fluids i.e. pH 5.5 to 6.5, to prevent damage to ciliary transport in the nose. These are usually aqueous and not oily drops because oil can inhibit the movement of cilia in the nasal mucosa and if it reaches to lungs causes lipoid pneumonia. Xylometazoline hydrochloride B.P Xylometazoline hydrochloride -------Benzalkonium chloride ----------------Disodium edetate -------------------------Sodium phosphate dehydrate----------108
0.1 % 0.015 % q.s q.s
Sodium acid phosphate---------------- q.s Sodium chloride --------------------- q.s Water ----------------------------------- qs. *qs : Quantity sufficient Uses : Xylometazoline nasal is a decongestant that shrinks blood vessels in the nasal passages. Dilated blood vessels can cause nasal congestion (stuffy nose). Xylometazoline nasal (for use in the nose) is used to treat stuffy nose caused by allergies, sinus irritation, or the common cold. ENEMAS An enema is the injection of fluid into the lower bowel by way of the rectum. Enemas are rectal injection used to evacuate the bowel, influence the general system by absorption, or to affect locally the seat of disease. They possess anthelmintic, nutritive, sedative, or stimulation properties, or may contain radiopaque substance for roentgenographic examination of the lower bowel. Enemas are usually given at body temperature in quantities of 1 or 2 pints injected slowly with a syringe. They should be used in larger quantities than 6 fluid ounces for an adult if enema is intended to be retained in the intestine. Starch enemas may be used either by itself or as a vehicle for other forms of medication. Sodium Chloride, Sodium Bicarbonate, Sodium Monhydrogen Phosphate and Sodium Dihydrogen Phosphate are used as enemas either alone or in combination with irritants as soap. Types of Enema Enema is classified into Evacuant enema and Retained enema. Evacuant enema is classified into 1. Simple evacuant enema 2. Medicated evacuant enema 3. Cold enema Retained enema is classified into 4. Stimulant enema 5. Sedative enema 6. Anesthetic enema 7. Astringent enema 8. Purgative enema 9. Anti-helminthic enema 10. Carminative enema 1. Simple evacuant enema Simple evacuant enema is used to remove fecal materials and gaseous distension. It is also used to clean the bowel and rectum before investigations, surgeries and child birth. Soap water or normal saline are used usually for simple evacuant 109
enema. The amount of the solution used is variable depending on the age of the patient / client and temperature of the solution. For adults 500 – 1000 ml solution is used, for children 250 – 500 ml and for infants 1 micron) Suspensions having particle sizes of greater than about 1micron in diameter are called as coarse suspensions. 3. Nano suspensions (10 ng) : Suspensions are the biphasic colloidal dispersions of nanosized drug particles stabilized by surfactants. Size of the drug particles is less than 1mm. APPLICATIONS 1. Suspension is usually applicable for drug which is insoluble (or ) poorly soluble. E.g. Prednisolone suspension 2. To prevent degradation of drug or to improve stability of drug. E.g. Oxy tetracycline suspension 3. To mask the taste of bitter of unpleasant drug. E.g. Chloramphenicol palmitate suspension 4. Suspension of drug can be formulated for topical application E.g. Calamine lotion 5. Suspension can be formulated for parentral application in order to control rate of drug absorption. E.g. penicillin procaine 6. Vaccines as a immunizing agent are often formulated as suspension. E.g. Cholera vaccine 119
7. X-ray contrast agent are also formulated as suspension . Eg: Barium sulphate for examination of alimentary tract. FEATURES DESIRED IN PHARMACEUTICAL SUSPENSIONS 1. The suspended particles should not settle rapidly and sediment produced, must be easily re-suspended by the use of moderate amount of shaking. 2.
It should be easy to pour yet not watery and no grittiness.
3.
It should have pleasing odour , colour and palatability.
4.
Good syringeability.
5.
It should be physically,chemically and microbiologically stable.
6.
Parenteral /Ophthalmic suspension should be sterilizable
THE SEDIMENTATION RATE The factors involved in the rate of settling of the particles of a suspension are present in the Stokes law equation:
Where: dx/dt: sedimentation rate. d : diameter of the particles. p_1: density of the particles. p_2: density of the medium. g: gravity constant. η: viscosity of the medium. From the equation it is apparent that the velocity of fall of a suspended particle is greater for larger particles than it is for smaller particles. Reducing the particle size of the dispersed phase produces a slower rate of descent of the particles. Also, the greater the density of the particles, the greater the rate of descent. If the particles were less dense than the vehicle, they would tend to float and floating particles would be quite difficult to distribute uniformly in water. The rate of sedimentation may be reduced by increasing the viscosity of the dispersion medium. However, a product having too high viscosity is not desirable, because it pours with difficulty and it is difficult to redisperse the suspended particles. Therefore, if the viscosity of a suspension is to be increased, it is done only to a moderate extent to avoid these difficulties. The following table shows examples on the sedimentation rate of different particle sizes and vehicles : 120
CONDITION 2.5 m powder in water 0.25 m powder in water 2.5 m powder in glycerin
RATE OF SETTLING(CM/S) 1.02 x 10 -4 1.02 x 10 -6 -8 4.25 x 10
0.25 m powder in glycerin
4.25 x 10-10
The most important consideration in suspensions is the size of the particles. In most good suspensions, the particle diameter is 1-50 µm. Generally, particle size reduction is accomplished by dry milling prior to incorporation of the dispersed phase into the dispersion medium. One of the most rapid, convenient, and inexpensive methods of producing fine drug powders of about 10-50 µm is micropulverization. Micropulverizers are high-speed mills that are efficient in reducing powders to the size acceptable for most suspensions. For still finer particles, under 10 µm, jet milling (also called micronization), is quite effective. Particles of extremely small dimensions may also be produced by spray drying. In spray dryer, a solution of a drug is sprayed and rapidly dried by a current of hot air. The resulting dry powder is very small in size. Although the particle size of a drug may be small when the suspension is first manufactured, there is always a degree of crystal growth that occurs on storage, particularly if temperature fluctuations occur. This is because the solubility of the drug may increase as the temperature rises, but on cooling, the drug will crystallize out. As shown by Stokes' equation, the reduction in the particle size of the suspended material is beneficial to the physical stability of the suspension because the rate of sedimentation of the solid particles is reduced. However, one should avoid reducing the particle size too much, because fine particles have a tendency to form a compact cake upon settling to the bottom of the container. The result may be that the cake resists breakup with shaking and forms rigid aggregates that are larger and less suspendable than the original suspended particles. Advantages of Suspension 1. It is easy to dispense unstable or degradable drugs in solution form. 2.
Suspension is the only choice if the drug is not soluble in water and nonaqueous solvent is not acceptable, e.g., corticosteroids suspension.
3.
Suspension is most suitable for drugs having unpleasant taste and odor e.g., Chloramphenical palmitate (bitter taste).
4.
The insoluble solids act as a reservoir and continuously supply the drug into solution, which is absorbed over a long period e.g., Protamine zincInsulin. 121
5.
Drug in suspension exhibits a higher rate of bioavailability compared to the same drug of equivalent dose formulated in tablets or capsules. This is due to larger surface area and high dissolution, e.g., antacid suspension.
Disadvantages of Suspension 1. Sedimentation of solids occasionally gives poor form of product. It may lead to caking (formation of compact mass), which is difficult to dispense. 2.
Dose precision cannot be achieved unless suspensions are packed in unit dosage forms.
3.
Sometimes microbial contamination takes place if preservation not added in accurate proportion.
4.
A suspension being a bulky product, transportation cost is high.
INGREDIENTS FOR FORMULATION OF SUSPENSION: 1. Suspending agents Also known as hydrophilic colloids which form colloidal dispersion with water and increase the viscosity of continuous phase. Most suspending agents have two functions act as suspending agent and increase viscosity of solution. Preferred suspending agents are those that give thixotropy to the media e.g xanthan gum, NaCMC/MC, Avicel and carrageenan. 2. Wetting agents Used for hydrophobic substances include many types which are: a. Surfactants: decrease the interfacial tension between drug particles and liquid thus, liquid is penetrated in the pores of drug particle displacing air from them and thus ensure wetting e.g polysorbate 80. May be ionic or non ionic, non ionic is preferred because it does not change the pH, no toxicity, safe for internal use. b. Hydrophilic colloids: they coat hydrophobic drug particles so facilitate wetting, they produce deflocculated susp. Because force of attraction is declined e.g acacia, alginate, tragacanth and guar gum. c. Solvents: most commonly used are alcohol, glycerin, polyethyleneglycol and propyleneglycol. The mechanism involve that they are miscible with water and reduce liquid interfacial tension. 3. Buffers All liquid formulations should be formulated to an optimum pH to encounter stability problems, generally pH of suspension between 7.4-8.4 e.g carbonate, phosphate, citrate and gluconate. 122
4. Osmotic agents These are added to produce osmotic pressure comparable to biological fluids when susp. Is intended for ophthalmic or injectable purposes. e.g dextrose, sorbitol, mannitol, sodium chloride and sodium sulfate. 5. Preservatives Naturally occurring agents such as acacia, xanthan gum are susceptible to microbial contamination so we use preservative e.g methylparaben, benzalkonium chloride, disodiumEDTA, benzoic acid. 6. Flavoring and coloring agents This to increase patient acceptance e.g titanium dioxide (white), brilliant blue(blue), tartarzine(yellow), amaranth(red). Sweeting agent like sorbitol, mannitol,mannose. 7. Humectant These absorb moisture and prevent degredation of API by moisture e.g glycerol, propyleneglycol, total quantity should be 0-10% 9. Antioxidants Ascorbic acid, tocopherol, sodium bisulfate, butylated hydroxyl toluene (BHT), butylated hydroxyl anisole (BHA). FORMULATION OF SUSPENSION The formulation depend on whether suspension is flocculated or deflocculated. Three approaches: 1. Use of structured vehicle. 2. Use of controlled flocculation. 3. Combination of both methods. 1. Structured vehicle: It is only applicable to deflocculated suspension e.g methyl cellulose(MC), NaCMC, acacia, gelatin and tragacanth. It also called thickening or suspending agents, they are aqueous solutions of natural and synthetic gums, these are used to increase the viscosity of suspension. Disadvantages is it cause difficulty in pouring and administration. It may affect drug absorption since they may adsorb on particle surface and suppress dissolution. It is Not useful for parenteral suspension Because of problem in syringability due to high viscosity. 2. Controlled flocculation: It is obtained by adding flocculating agents which are: a. Electrolytes. b. Surfactants. c. Polymers. 3. Flocculation in structured vehicles: To retard sedimentation Sometimes suspending agent can be added to flocculated suspension. e.g CMC, carbopol 123
934, veegum and bentonite. PREPARATION OF SUSPENSION We must know the characteristics of dispersed phase and dispersion medium( hydrophilic or hydrophobic). Step 1: Suspensions are prepared by grinding the insoluble materials in the mortar to a smooth paste with a vehicle containing the wetting agent. Step 2: All soluble ingredients are dissolved in same portion of the vehicle and added to the smooth paste to step1 to get slurry. Step 3: The slurry is transformed to a graduated cylinder, the mortar is rinsed with successive portion of the vehicle. Step 4: Decide whether the solids are Suspended in a structured vehicle FlocculatedFlocculated and then suspended Add the vehicle containing the suspending agent (or) flocculating agent Step-5: Make up the dispersion to the final volume, thus suspension is prepared. FLOCCULATED SUSPENSION A flocculated suspension is a suspension in which particles of the suspension has undergone flocculation. Flocculation is the process in which colloids in a suspension can be obtained in an aggregated form. Therefore, a flocculated suspension is composed of large aggregates and this type of suspension will lead to a rapid rate of sedimentation. Sedimentation is the settling down of aggregates or particles of suspension to the bottom of the liquid. Aggregation of particles makes large aggregates that can act as large individual particles. When these aggregates are settling down, a large number of particles are settling down. Then the rate of sedimentation is high. These aggregates are known as floccules. Floccules can sediment faster than smaller particles under the effect of gravity. The sediment formed in a flocculated suspension is larger than expected because the floccules have a loose structure with pores and these pores can entrap liquid. Therefore the volume of the final sediment is larger than expected. DEFLOCCULATED SUSPENSION A deflocculated suspension is a suspension in which no flocculation has taken place. Hence, there are no floccules or other aggregates. Here, single colloid particles act as individual particles. When sedimentation occurs, these single particles settle. In a deflocculated suspension, dispersed particles exist as separated units. The rate of sedimentation is slow since smaller particles are settling rather than large 124
floccules. The slow sedimentation prevents the liquid from being entrapped in the sediment. The final sediment has a small volume than a flocculated suspension. Even after the formation of the sediment, the supernatant of this suspension will still have a cloudiness.
Figure: flocculated and deflocculated suspension. a) deflocculated. b) flocculated. Difference between flocculated and deflocculated suspension Flocculated Suspension
Deflocculated Suspension
Particles forms loose aggregates with network like structure
Particles exist as separate entities
Rate of sedimentation is high
Rate of Sedimentation is slow
Sediment is rapidly formed
Sediment is slowly formed
Sediment is loosely packed and doesn't form a compact cake
Sediment is very closely packed and a compact cake is formed
Sediment is easy to re-disperse
Sediment is difficult to re-disperse
Supernatant liquid is clear
Supernatant liquid is cloudy
EVALUATION OF SUSPENSIONS EVALUATION OF SUSPENSION STABILITY A] Sedimentation method : Two parameters are studied for determination of sedimentation. 1. Sedimentation volume. 2. Degree of flocculation. 125
1. Sedimentation volume Sedimentation volume is the ratio of the ultimate height (Hu) of the sediment to the initial height (H0) of the total suspension. The larger this value, the better is the suspendibility.
At zero time, the Hu=H0 and the sedimentation volume equals to 1. On standing, the suspended solid particles begin to settle and thus sedimentation volume begins to decrease. In general, it is preferred that the suspension retains the same sedimentation volume, as possible. Particle size changes The freeze-thaw cycling technique is useful to stress suspensions for stability testing purposes. This technique promotes particle growth and may indicate the probable future state after prolong storage at room temperature. 2. Degree of flocculation. F = Vu/Vo It is the ratio of the sedimentation volume of the flocculated suspension ,F , to the sedimentation volume of the deflocculated suspension, F∞ ß = F / F∞ The minimum value of ß is 1, when flocculated suspension sedimentation volume is equal to the sedimentation volume of deflocculated suspension. (Vu/Vo) flocculated ß = -------------------- (Vu/Vo) deflocculated Degree of flocculation (β) B] Rheological method It provide information about Settling behaviors. Brookfield viscometer is used to study the viscosity of the suspension . It is mounted on heli path stand and using Tbar spindle. T-bar spindle is made to descend slowly into the suspension and the dial reading on the viscometer is then a measure of the resistance the spindle meets at various level. This technique also indicates at which level of the suspension the structure is greater owing to particle agglomeration. The dial reading is plotted against the number of turns of the spindle. The better suspension show a lesser rate of increase of dial reading with spindle turns, i.e. the curve is horizontal for long period. C] Electro kinetic method. Measurement of Zeta-potential using Micro electrophoresis apparatus & Zeta Plus (Brook haven Instruments Corporation , USA) . It shows the stability of a disperse system. Micro-Electrophoresis Apparatus MkI Zeta Plus. The zeta potential of the formulated suspensions was determined using a Zeta Plus. 126
Approximately 1mL of suspension was transferred into a plastic cuvette using a pipette and diluted with distilled water. The Brookhaven zeta potential software was used for the measurement. Parameters set to a temperature of 250C and refractive index(1.33). The zeta potential of the formulations was determined on day 0, 7, 14,21and day 28 post formulation. Zeta potential. Factors that contribute to appreciable stability of a suspension include: Small particle size- reduce the size of the dispersed particle increases the total surface area of the solid. The greater the degree of subdivision of a given solid the larger the surface area. The increase in surface area means also an increase in interface between the solids and liquids leading to an increase in viscosity of a system. Stability of suspension Viscosity Increasing the viscosity – increasing the viscosity of the continuous phase can lead to the stability of suspensions. This is so because the rate of sedimentation can be reduced by increase in viscosity. Viscosity increase is brought about by addition of thickening agents to the external phase. It is important to note that the rate of release of a drug from a suspension is also dependent on viscosity. Temperature Another factor which negatively affects the stability and usefulness of pharmaceutical suspensions is fluctuation of temperature. Temperature fluctuations can lead to caking and claying.
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Chapter: 10
Biphasic liquids Emulsion Unit – III Syllabus Definition, classification, emulsifying agent, test for the identification of type of Emulsion, Methods of preparation & stability problems and methods to overcome.
INTRODUCTION An emulsion is a mixture of two or more liquids that are normally immiscible (unmixable or unblendable). Emulsions are part of a more general class of twophase systems of matter called colloids. Although the terms colloid and emulsion are sometimes used interchangeably, emulsion should be used when both phases, dispersed and continuous, are liquids. In an emulsion, one liquid (the dispersed phase) is dispersed in the other (the continuous phase). Examples of emulsions include vinaigrettes, homogenized milk, mayonnaise, and some cutting fluids for metal working. Graphene and its modified forms are also a good example of recent unconventional surfactants helping in stabilizing emulsion systems. The word "emulsion" comes from the Latin mulgeo, mulgere "to milk", as milk is an emulsion of fat and water, along with other components. Two liquids can form different types of emulsions. As an example, oil and water can form, first, an oil-in-water emulsion, wherein the oil is the dispersed phase, and water is the dispersion medium. (Lipoproteins, used by all complex living organisms, are one example of this.) Second, they can form a water-in-oil emulsion, wherein water is the dispersed phase and oil is the external phase. Multiple emulsions are also possible, including a "water-in-oil-in-water" emulsion and an "oil-in-water-in-oil" emulsion. Emulsions are important in many fields—e.g., in the dyeing and tanning industries, in the manufacture of synthetic rubber and plastics, in the preparation of cosmetics such as shampoos, and of salves and therapeutic products.
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Hydrophobic vs. Hydrophilic Two important terms to know when it comes to emulsions are hydrophobic and hydrophilic. Hydrophobic means a substance that doesn't mix with or dissolve in water. Hydrophilic is a substance that does mix with or dissolve in water. These terms are easier to remember when you know that hydro means 'water,' -phobic means 'fear of', and -philic means 'love of'. So a hydrophobic material is one that is afraid of water and won't mix with it, while a hydrophilic material loves the water and wants to mix with it as much as possible. In the first example, oil is a hydrophobic substance. Something like sugar is a hydrophilic substance, because if you mix sugar into water it will completely dissolve. When hydrophobic and hydrophilic materials are mixed, they will quickly separate because they are not able to associate with each other. But sometimes we need these two materials to mix to make a third material. An emulsifier is a material that can help a hydrophobic and a hydrophilic material mix together. An emulsifier works because it has both hydrophilic and hydrophobic properties. Since it has both hydrophobic and hydrophilic properties, it mixes with both, and by mixing with both, it forces both to mix with each other. EMULSION DEFINITION An emulsion is a colloid of two or more immiscible liquids where one liquid contains a dispersion of the other liquids. In other words, an emulsion is a special type of mixture made by combining two liquids that normally don't mix. The word emulsion comes from the Latin word meaning "to milk" (milk is one example of an emulsion of fat and water). The process of turning a liquid mixture into an emulsion is called emulsification. Properties of Emulsions Emulsion particles unavoidably form dynamic inhomogeneous structures on small length scale.
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Emulsions are highly unstable systems and require an emulsifying agent or emulsifier ( These are usually surface active agents also known as “surfactants”)
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Emulsions are prepared by continuous mixing or agitation of the two phases
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When kept for longer periods of time or in case of absence of an emulsifying agent, the phases in the emulsion tend to separate, resulting in “cracking of emulsion” or ” phase inversion”.
TYPES OF EMULSIONS THERE ARE TWO BASIC TYPE OF EMULSIONS:
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OIL IN WATER AND WATER IN OIL. Emulsions can exist as “oil in water” or ” water in oil” of emulsions. The type of emulsion depends upon the properties of the dispersed phase and continuous phase. Whether an emulsion of oil and water turns into a “water-in-oil” emulsion or an “oil-in-water” emulsion depends on the volume fraction of both phases and the type of emulsifier used to emulsify them. In every emulsion there is a continuous phase(dispersion medium) that suspends the droplets of the other element which is called the dispersed phase.
(I) Oil-in-water emulsions (O/W) : The emulsion in which oil is present as the dispersed phase and water as the dispersion medium (continuous phase) is called an oil-in-water emulsion. If the oil phase is dispersed in a continuous aqueous phase the emulsion is known as “oil in water”. Milk is an example of the oil-in-water type of emulsion. In milk liquid fat globules are dispersed in water. Other examples are, vanishing cream etc. (ii) Water-in-oil emulsion (W/O) : The emulsion in which water forms the dispersed phase, and the oil acts as the dispersion medium is called a water-in-oil emulsion. If the aqueous phase is the dispersed phase and the oil phase is the continuous phase, then its known as “water in oil” . These emulsion are also termed oil emulsions. Butter and cold cream are typical examples of this types of emulsions. Other examples are cod liver oil etc. EMULSIFYING AGENTS These are surface active agents that are added to the emulsions to stabilize the two phases. It acts on the interface and increases the kinetic stability of an emulsion so that the size of the droplets does not change significantly with time, thus stabilizing the emulsion.
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Emulsifiers are compounds that typically have a polar or hydrophilic (i.e. watersoluble) part and a non-polar (i.e. hydrophobic or lipophilic) part. Because of this, emulsifiers tend to have more or less solubility either in water or in oil. According to the Bancroft rule, Emulsifiers and emulsifying particles tend to promote dispersion of the phase in which they do not dissolve very well. For example, proteins dissolve better in water than in oil, and so tend to form oil-inwater emulsions (that is, they promote the dispersion of oil droplets throughout a continuous phase of water). Emulsifiers that are more soluble in water generally form oil-in-water emulsions, while emulsifiers that are more soluble in oil will form water-in-oil emulsions. Examples include egg yolk, sodium phosphates, sodium stearoyl lactylate, etc MECHANISMS OF EMULSIFICATION A number of different chemical and physical processes and mechanisms can be involved in the process of emulsification. Ÿ
Surface tension theory – According to this theory, emulsification takes place by the reduction of interfacial tension between two phases
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Repulsion theory – The theory proposes that the emulsifying agent creates a film over one phase that forms globules, which repel each other. This repulsive force causes them to remain suspended in the dispersion medium
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Viscosity modification – Certain emulgents such as acacia, tragacanth, carboxymethylcellulose, polyethylene glycol, etc increase the viscosity of the medium, which helps create and maintain the suspension of globules of the dispersed phase
TESTS FOR IDENTIFICATION OF EMULSION TYPES Final preparation of both emulsions (o/w or w/o) looks the same in appearance with naked eyes, therefore certain tests are required to differentiate between them. It is also important that at least two tests should be performed to draw a final conclusion. 1. Dilution test: In this test the emulsion is diluted either with oil or water. If the emulsion is o/w type and it is diluted with water, it will remain stable as water is the dispersion medium" but if it is diluted with oil, the emulsion will break as oil and water are not miscible with each other. Oil in water emulsion can easily be diluted with an aqueous solvent whereas water in oil emulsion can be diluted with a oily liquid.
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Fig. Dilution Test 2. Conductivity Test: The basic principle of this test is that water is a good conductor of electricity. Therefore in case of o/w emulsion, this test will be positive as water is the external phase. In this test, an assembly is used in which a pair of electrodes connected to an electric bulb is dipped into an emulsion. If the emulsion is o/w type, the electric bulb glows. (a) o/w type emulsion (b) w/o type emulsion Fig . Conductivity Test
3. Dye Solubility Test: In this test an emulsion is mixed with a water soluble dye (amaranth) and observed under the microscope. If the continuous phase appears red, it means that the emulsion is o/w type as water is in the external phase and the dye will dissolve in it to give color. If the scattered globules appear red and continuous phase colorless, then it is w/o type. Similarly if an oil soluble dye (Scarlet red C or Sudan III) is added to an emulsion and the continuous phase appears red, then it is w/o emulsion.
Fig. Dye solubility test 132
4. Cobalt Chloride Test: When a filter paper soaked in cobalt chloride solution is dipped in to an emulsion and dried, it turns from blue to pink, indicating that the emulsion is o/w type.
Fig. Cobalt Chloride Test 5. Fluorescence Test: If an emulsion on exposure to ultra-violet radiations shows continuous fluorescence under microscope, then it is w/o type and if it shows only spotty fluorescence, then it is o/w type.
Fig. Fluorescence Test METHODS OF EMULSION PREPARATION There are two methods of preparing a primary emulsion: 1-DRY GUM METHOD OR CONTINENTAL (DRY GUM, OR 4:2:1) METHOD Emulsifier (acacia) is mixed with oil before water addition.
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The continental method is used to prepare the initial or primary emulsion from oil, water, and a hydrocolloid or "gum" type emulsifier (usually acacia). The primary emulsion, or emulsion nucleus, is formed from 4 parts oil, 2 parts water, and 1 part emulsifier. The 4 parts oil and 1 part emulsifier represent their total amounts for the final emulsion. The quantities of oil, water and gum for primary emulsion are calculated. The acacia and the oil are placed in a dry porcelain mortar. When the acacia is thoroughly distributed throughout the oil, Water is added, all at once. The mixture is triturated continuously but lightly in one direction until the mixture thickens under the pestle. The primary emulsion is triturated for at least 5 minutes. Finally, the emulsion is transferred to a graduated cylinder and brought to volume with water. The emulsion should be Labeled "Shake well before use. 2-WET GUM METHOD OR ENGLISH (WET GUM) METHOD Emulsifier is added to water to form a mucilage then oil is slowly added to emulsion. In this method, the proportions of oil, water, and emulsifier are the same (4:2:1), but the order and techniques of mixing are different. The 1 part gum is triturated with 2 parts water to form a mucilage; then the 4 parts oil is added slowly, in portions, while triturating. After all the oil is added, the mixture is triturated for several minutes to form the primary emulsion. Then other ingredients may be added as in the continental method. Finally, the emulsion is transferred to graduated cylinder and brought to volume with water. 3. BOTTLE (FORBES) METHOD This method may be used to prepare emulsions of volatile oils, or oleaginous substances of very low viscosities. It is not suitable for very viscous oils since they cannot be sufficiently agitated in a bottle. This method is a variation of the dry gum method. One part powdered acacia (or other gum) is placed in a dry bottle and four parts oil are added. The bottle is capped and thoroughly shaken. To this, the required volume of water is added all at once, and the mixture is shaken thoroughly until the primary emulsion forms. It is important to minimize the initial amount of time the gum and oil are mixed. The gum will tend to imbibe the oil, and will become more waterproof. It is also effective in preparing an olive oil and lime water emulsion, which is selfemulsifying. In the case of lime water and olive oil, equal parts of lime water and olive oil are added to the bottle and shaken. No emulsifying agent is used, but one is formed "in situ" following a chemical interaction between the components. What emulsifying agent is formed?
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4. BEAKER METHOD When synthetic or non-gum emulsifiers are used, the proportions given in the previous methods become meaningless. The most appropriate method for preparing emulsions from surfactants or other non-gum emulsifiers is to begin by dividing components into water soluble and oil soluble components. All oil soluble components are dissolved in the oily phase in one beaker and all water soluble components are dissolved in the water in a separate beaker. Oleaginous components are melted and both phases are heated to approximately 70°C over a water bath. The internal phase is then added to the external phase with stirring until the product reaches room temperature. The mixing of such emulsions can be carried out in a beaker, mortar, or blender; or, in the case of creams and ointments, in the jar in which they will be dispensed. 5. AUXILIARY METHODS Instead of, or in addition to, any of the preceding methods, the pharmacist can usually prepare an excellent emulsion using an electric mixer or blender. An emulsion prepared by other methods can also usually be improved by passing it through a hand homogenizer, which forces the emulsion through a very small orifice, reducing the dispersed droplet size to about 5 microns or less. INSTABILITIES IN EMULSIONS The ability of an emulsion to retain its properties over time is known as the stability of an emulsion.
FOUR TYPES OF INSTABILITIES GENERALLY OCCUR IN AN EMULSION Let us take a look. Ÿ
Flocculation – When the particles or droplets of the dispersed phase aggregate together on account of attractive forces, the phenomenon is known as flocculation and results in an unstable system. Flocculation is mainly observed in case of oil in water type of emulsions.
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Coalescence – When the droplets of discontinuous phase bump into each other to form a larger droplet thus increasing the average particle size over time, it is known as coalescence which is a form of instability.
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Creaming – When the droplets in an emulsion rise to the top of the emulsion under the influence of buoyancy or centripetal force, it results in the creaming of emulsion
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Ostwald Ripening – It describes the change of an inhomogeneous structure over time, i.e., small crystals or sol particles dissolve and redeposit onto larger crystals or sol particles. Ostwald ripening is generally found in water-in-oil emulsions.
USES OF EMULSION
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As Food: Oil-in-water emulsions are common in food products. Examples include butter, margarine, homogenized milk, mayonnaise, etc
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In Healthcare Many cosmetic and pharmaceutical dosage forms are in the form of emulsions. Cosmetics such as lotions, creams, biphasic makeup removers are in fact emulsions. Many oral, as well as topical dosage forms, are emulsions. Microemulsions are used to deliver vaccines and kill microbes. Cod liver oil, cortisol, polysporin are some examples of emulsion formulations.
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In Chemical Synthesis Emulsions are used in the manufacturing of polymer dispersions. These include primary components of glues and paints.
Chapter: 11
Suppositories Unit – IV Syllabus Definition, types, advantages and disadvantages, types of bases, methods of preparations. Displacement value & its calculations, evaluation of suppositories.
INTRODUCTION Suppositories are medicated solid drug delivery systems generally intended for use in the rectum. Several unwanted side effects and disadvantages inherent to oral therapy leads to focused attention on the rectal route of administering drugs, especially, in Europe. Rectal suppositories are much preferred in pediatric and geriatric patients with difficulties in swallowing solid oral dosage forms. Suppositories generally carry medicaments such as emollients, astringent, antiseptic and local anesthetics to exert local action on the rectal mucosa. They are often used as a means of projecting medicaments such as hypnotics, tranquilizers, antispasmodics, non-steroidal anti-inflammatory agents (NSAID) etc for systemic action. The advantages of administration of such medicaments in the form of suppositories is that portal (hepatic) circulation is bypassed and thus preventing or retarding the biotransformation (first pass effect) of drugs in the liver, Similarly pH conditions and activities of gastrointestinal enzymes are bypassed. Drugs such as NSAIDS that cause gastric irritation leading to gastrointestinal ulceration and bleeding can be safely administered by rectal. Sometimes suppositories can give blood levels comparable even to the intravenous injections, except 30 minutes lag period. The ideal suppository base should be nontoxic, nonirritating, inert, compatible with medicaments, and easily formed by compression or molding. It should also dissolve or disintegrate in the presence of mucous secretions or melt at body temperature to allow for the release of the medication. As with the ointment bases, suppository base composition plays an important role in both the rate and extent of release of medications.
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Fig. Suppositories DEFINITION Suppositories are solid dosage forms intended for insertion into body orifices where they melt, soften, or dissolve and exert localized or systemic effects. Advantages of Suppositories Over Oral Drug Administration: Ÿ Avoid first pass metabolism Ÿ Introduce drugs into the body Ÿ Does not cause nausea and vomiting due to gastric irritation in case of oral therapy Ÿ Used before surgery since oral therapy is restricted Ÿ Beneficial for patients suffering from severe vomiting Ÿ Can be administered to unconscious patients Ÿ Can be used as targeted drug delivery system Ÿ Localized action with reduced systemic distribution Ÿ Get to site of action with lower dose reducing systemic toxicity Ÿ Highly beneficial in haemorrhoids or vaginal infections Ÿ Prolonged drug action achieved Over parenteral drug administration: Ÿ Self medication Ÿ No systemic side effects Ÿ No pain or site of action related issues Over Vaginal Tablets: Ÿ Suppositories dissolves faster Ÿ Total bioavailability achieved Ÿ No residue remains like tablet Ÿ No need of applicator Ÿ Non staining Ÿ Non itching 138
Disadvantages of Suppositories/Pessaries: Ÿ Mucosal irritation Ÿ Patient compliance Ÿ Erratic and undesired absorption Ÿ Placement too high into rectum may lead to first pass metabolism Ÿ Installation may trigger defecation reaction Ÿ GI state affects absorption: Ÿ Diarrhea& disease states affect absorption TYPES OF SUPPOSITORIES Suppositories have a base made from substances like gelatin or cocoa butter that surrounds the drug. As the warmth of your body melts the outside, the drug slowly releases. Different types of suppositories go into the rectum, vagina, or the duct that empties your bladder, called the urethra. Sometimes they treat the area where you put them in. Or the medicine absorbs into your blood and travels to other parts of your body. 1. Rectal suppositories Ÿ These are meant for introduction into the rectum for their systemic effect. Ÿ
These are generally made from theobroma oil and are available in various sizes to meet the needs of infants, children and adults.
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Rectal suppositories are usually available in weight about 1-2 g. They are either cone or torpedo shaped.
2. Vaginal suppositories Ÿ These are meant for introduction into the vagina. Ÿ
These suppositories are also known as pessaries and are larger than rectal suppositories.
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The vaginal suppositories may be conical, rod-shaped or wedge shaped and are usually available in weight about 4-8 g.
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Vaginal suppositories are mainly used for their local action on the vagina. Now a days, vaginal tablets and vaginal capsules are also available which has substituted the vaginal suppositories.
3. Nasal suppositories Ÿ These are meant for introduction into the nasal cavity and are also known as nasal bougies. These are similar to urethral suppositories.
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These are thin and cylindrical in shape and are always prepared with glycero-gelatin base.
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Nasal suppositories are about 9-10 cm long and weigh about 1.0 g.
4. Urethral suppositories Ÿ These are meant for introduction into the urethra and are also known as urethral bougies. Ÿ
These are thin, long and cylindrical forms rounded at one end to facilitate insertion.
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Their weight varies from 2 to 4 g. These suppositories are very rarely used.
5. Ear cones Ÿ These are meant for introduction into the ear and are also known as aurinaria. Ÿ
Nowadays ,these are rarely used.
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These suppositories are thin, long and cylindrical in shape and weigh about 1 gram.
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Ear cones are usually prepared with theobroma oil.
METHODS OF PREPARATION Suppositories can be extemporaneously prepared by one of three methods. 1. Hand Rolling is the oldest and simplest method of suppository preparation and may be used when only a few suppositories are to be prepared in a cocoa butter base. It has the advantage of avoiding the necessity of heating the cocoa butter. A plastic-like mass is prepared by triturating grated cocoa butter and active ingredients in a mortar. The mass is formed into a ball in the palm of the hands, then rolled into a uniform cylinder with a large spatula or small flat board on a pill tile. The cylinder is then cut into the appropriate number of pieces which are rolled on one end to produce a conical shape. Effective hand rolling requires considerable practice and skill. The suppository "pipe" or cylinder tends to crack or hollow in the center, especially when the mass is insufficiently kneaded and softened. 2. Compression Molding is a method of preparing suppositories from a mixed mass of grated suppository base and medicaments which is forced into a special compression mold. The method requires that the capacity of the molds first be determined by compressing a small amount of the base into the dies and weighing the finished suppositories. When active ingredients are added, it is necessary to 140
omit a portion of the suppository base, based on the density factors of the active ingredients. 3. Fusion Molding involves first melting the suppository base, and then dispersing or dissolving the drug in the melted base. The mixture is removed from the heat and poured into a suppository mold. When the mixture has congealed, the suppositories are removed from the mold. The fusion method can be used with all types of suppositories and must be used with most of them. Suppositories are generally made from solid ingredients and drugs which are measured by weight. When they are mixed, melted, and poured into suppository mold cavities, they occupy a volume – the volume of the mold cavity. Since the components are measured by weight but compounded by volume, density calculations and mold calibrations are required to provide accurate doses. When a drug is placed in a suppository base, it will displace an amount of base as a function of its density. If the drug has the same density as the base, it will displace an equivalent weight of the base. If the density of the drug is greater than that of the base, it will displace a proportionally smaller weight of the base. Density factors for common drugs in cocoa butter are available in standard reference texts. The density factor is used to determine how much of a base will be displaced by a drug. SUPPOSITORY BASES Suppository bases may be conveniently classified as according to their composition and physical properties: Ÿ Ÿ
Oleaginous (fatty) bases Water soluble or miscible bases
OLEAGINOUS BASES Oleaginous bases include Theobroma Oil and synthetic triglyceride mixtures.
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a) Theobroma Oil or cocoa butter is used as a suppository base because, in large measure, it fulfills the requirements of an ideal base. At ordinary room temperatures of 15° to 25°C (59° to 77°F), it is a hard, amorphous solid, but at 30° to 35°C (86° to 95°F), i.e., at body temperature, it melts to a bland, nonirritating oil. Thus in warm climates, theobroma oil suppositories should be refrigerated. Particular attention must be given to two factors when preparing suppositories with cocoa butter base. First, this base must not be heated above 35°C (95°F) because cocoa butter is a polymorphic compound and if overheated will convert to a metastable structure that melts in the 25° to 30°C (77° to 86°F) range. Thus, the finished suppositories would melt at room temperature and not be usable. The second factor is the change in melting point caused by adding certain drugs to cocoa butter suppositories. For example, chloral hydrate and phenol tend to lower the melting point. It may be necessary to add spermaceti or beeswax to raise the melting point of finished suppositories back to the desired range. b) The newer synthetic triglycerides consist of hydrogenated vegetable oils. Their advantage over cocoa butter is that they do not exhibit polymorphism. They are, however, more expensive. Some of the bases are single entity formulations. Some of the names may denote a series of bases. In a series, the bases are varied to give a range of melting points. For example, Fattibase® is a single entity base that consists of triglycerides from palm, palm kernel, and coconut oils. Wecobee® is a series of bases. Wecobee FS, M, R, and S are all made from triglycerides of coconut oil. But FS has a melting point range of 39.4 to 40.5°C, M has a range of 33.3 to 36.0°C, R has a range of 33.9 to 35.0°C, and S has a range of 38.0 to 40.5°C. Other triglyceride type bases include Dehydag®, Hydrokote®, Suppocire®, and Witepsol®. WATER SOLUBLE/WATER MISCIBLE BASES Water soluble/water miscible bases are those containing glycerinated gelatin or the polyethylene glycol (PEG) polymers.
A. Glycerinated Gelatin is a useful suppository base, particularly for vaginal suppositories. It is suitable for use with a wide range of medicaments including alkaloids, boric acid, and zinc oxide. Glycerinated gelatin suppositories are 142
translucent, resilient, gelatinous solids that tend to dissolve or disperse slowly in mucous secretions to provide prolonged release of active ingredients. Suppositories made with glycerinated gelatin must be kept in well-closed containers in a cool place since they will absorb and dissolve in atmospheric moisture. In addition, those intended for extended shelf-life should have a preservative added, such as methylparaben or propylparaben, or a suitable combination of the two. To facilitate administration, glycerinated gelatin suppositories should be dipped in water just before use.
B. Polyethylene Glycol Polymers have received much attention as suppository bases in recent years because they possess many desirable properties. They are chemically stable, nonirritating, miscible with water and mucous secretions, and can be formulated, either by molding or compression, in a wide range of hardness and melting point. Like glycerinated gelatin, they do not melt at body temperature, but dissolve to provide a more prolonged release than theobroma oil. Certain polyethylene glycol polymers may be used singly as suppository bases but, more commonly, formulas call for compounds of two or more molecular weights mixed in various proportions as needed to yield a finished product of satisfactory hardness and dissolution time. Since the water miscible suppositories dissolve in body fluids and need not be formulated to melt at body temperature, they can be formulated with much higher melting points and thus may be safely stored at room temperature. DISPLACEMENT VALUE It can be defined as the volume of drug that displaces 1 gram of suppository base. The most commonly used suppository base is Coca Butter or Theobroma oil. Traditionally suppositories are prepared using suppositories molds which can generally hold 1 gram or 2 gram of base. i.e. the volume of the mold generally remains constant and cannot change. Whenever we add drug or other excipients to the base the drug occupies some of the space and displaces certain quantity of base.
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To calculate displacement value of drug follow six simple steps: Step I: Theoretical weight of total Base required. Step II: Theoretical weight of total drug required. Step III: Theoretical weight of total suppositories = (Step I +Step II) Theoretical weight of total Base required. + Theoretical weight of total drug required. Step IV: Practical Weight of total suppositories Step V : Difference in weight = (Step III - Step IV) Theoretical weight of total suppositories - Practical Weight of total suppositories Step VI: Displacement value = (Step II/ Step V) Theoretical weight of total drug / Difference in total weight of suppositories. From the above steps we can also define the displacement value as the ratio of theoretical weight of the drug to that of difference in total weight of suppositories. Problem 1: If a prescription requires 400 mg of bismuth subgallate per suppository Weighing two grams, what would be the displacement value? if it is known that six suppositories with required bismuth subgallate weigh 13.6 g? Step I: Theoretical weight of total Base required. = No of suppositories X weight of each suppository. (6 X 2g = 12g ) Step II: Theoretical weight of total drug required. = No of suppositories X weight of drug in each suppository. (6X 400mg ) = 2400mg* or 2.4g (Converting mille grams to gams as weight is given in grams. 2400/1000 = 2.4) Step III: Theoretical weight of total suppositories = (Step I +Step II) Theoretical weight of total Base required. * Theoretical weight of total drug required. (12 g + 2.4 g ) = 14.4g Step IV: Practical Weight of total suppositories i.e. as given in problem = 13.6 g Step V : Difference in weight = (Step III - Step IV) Theoretical weight of total suppositories - Practical Weight of total suppositories (14.4 g – 13.6 g) = 0.8 g
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Step VI: Displacement value = (Step II/ Step V) Theoretical weight of total drug / Difference in total weight of suppositories. (2.4 g / 0.8 g ) = 3 Ans: Displacement value of Bismuth Subgallate is 3 EVALUATION OF SUPPOSITORIES Ÿ Appearance Ÿ Uniformity of weight test Ÿ Melting rang test Ÿ Liquefaction test Ÿ Breaking test Ÿ Dissolution test Appearance Ÿ The suppository when cut longitudinally and examined with the naked eye the internal and external surfaces of the suppository should be uniform in appearance. Ÿ
Compliance with the standard indicates satisfactory subdivision and dispersion of suspended material.
Ÿ
Surface appearance and colour can be verified usually to assess absence of fissuring, absence of fissuring, absence of pitting, absence of exudation, absence of migration of the active ingredients.
Uniformity of weight test Ÿ To perform this 20 suppositories are weighed and average weight is calculated. Ÿ
Then each suppository is weighed individually and weight noted.
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No suppository should deviate from the average weight by more than 5%except that two should not deviate by more than 7.5%.
Ÿ
The weight variation may result if some cavities are under filled and other are overfilled.
Melting Range Test Ÿ This test is also called the macro melting range test and is a measure of the time it takes for the entire suppository to melt when immersed in a o constant-temperature (37 C) water bath. Ÿ
In contrast, the micro melting range test in the melting range measured in capillary tubes for the fat base only. The apparatus commonly used for measuring the melting range of the entire suppository is a USP Tablet Disintegration Apparatus. 145
Ÿ
The suppository is completely immersed in the constant water bath, and the time for the entire suppository to melt or disperse in the surrounding water is measured.
Ÿ
The in vitro drug release pattern is measured by using the same melting range apparatus. If the volume of the water surrounding the suppository is known, then by measuring aliquots of the water for drug content at various intervals within the melting period, a time-versus-drug content curve (in vitro drug release pattern) can be plotted.
Liquefaction or Softening Time Tests of Rectal Suppositories. Ÿ A Modification of the method developed by krowcynski is another useful test of finished suppositories. It consists of a U-tube partially submersed in a constant- temperature water bath. Ÿ
A constriction on one side hold the suppository in place in the tube. A glass rod is placed on top of the suppository, and the time for the rod to pass through to the constriction is recorded as the softening time.
Ÿ
This can be carried out at various temperatures from 35.5 to 37oc, as a quality control chek and can also be studied as a measure of physical stability over time. A water bath with both cooling and heating elements o should be used to assure control with 0.1 c.
Breaking test Ÿ Brittleness of suppositories is a problem for which various solutions have already been described. The breaking test is designed as a method for measuring the fragility or brittleness of suppositories.
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The apparatus used for the test consists of a double-wall chamber in which o the test suppository is placed. Water at 37 c is pumped through the double walls of the chamber, and the suppository contained in the dry inner chamber, supports a disc to which a rod is attached.
Ÿ
The other end of the rod consists of another disc to which weights are applied. The test is conducted by placing 600 g on the platform.
Ÿ
At 1-min intervals, 200-g weights are added, and the weight at which the suppository collapses is the breaking point, or the force that determines the fragility or brittleness characteristics of the suppository.
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Differently shaped suppositories have different breaking points. The desired breaking point of each of these variously shaped suppositories is established as the level that withstands the break forces caused by various types of handling i.e., production, packaging etc.
Dissolution Testing Ÿ Testing for the rate of in vitro release of drug substances from suppositories has always posed a difficult problem, owing to melting deformation, and dispersion in the dissolution medium. Early testing was carried out by simple placement in a beaker containing a medium. Ÿ
In an effort to control the variation in mass or medium interface, various means have been employed, including a wire mesh basket, or a membrane, to separate the sample chamber from the reservoir.
Ÿ
Samples sealed in dialysis tubing or natural membranes have also been studied. Flow cell apparatus have been used, holding the sample in place with cotton, wire screening and most recently with glass beads. Opening A Suppository Mold The suppository mixture is poured into the cavities of a closed mold. When the suppository mixture has congealed, the excess mass is removed from the top surface of the mold and the mold is separated into the two halves. An efficient way to separate the mold is to remove the wing nuts or loosen the centered screw and place the mold so that the posts rest on the table top. Then apply a downward pressure only on the bottom half of the mold.
A knife or spatula should not be used to pry the two halves apart. This will damage the matching mold faces which have been accurately machined to give a tight seal. Suppository shells can be opened by peeling apart the two tabs at the bottom of the shell.
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Chapter: 12
Pharmaceutical Incompatibilities Unit – IV Syllabus Pharmaceutical incompatibilities: Definition, classification, physical, chemical and therapeutic incompatibilities with examples.
INTRODUCTION Pharmaceutical incompatibility occurs as a result of mixing of two or more antagonistic substances and an undesirable product is formed which may affect the safety, efficacy and appearance of pharmaceutical preparation. Pharmaceutical incompatibility may occur not only during compounding and dispensing but also at any stage during compounding and dispensing but also at any stage during formulation, manufacturing, packing or administration of drugs. When two or more than two substances are combined together, physical changes take place and an unacceptable product is formed. These changes which occurs as a result of physical incompatibility are usually visible and can be easily corrected by applying the pharmaceutical skill obtain a product of uniform dosage, substance to help in compounding of the prescription. DEFINITION OF INCOMPATIBILITY: Incompatibility occurs as a result of mixing of two or more “Antagonistic Substances” & an undesirable product is formed which may affect the safety, efficacy & appearance of the pharmaceutical preparation. Types of Incompatibility: Physicochemical Incompatibility A) Physical incompatibility B) Chemical incompatibility C) Therapeutic incompatibility Physicochemical Incompatibilty If mixing two or more drugs or a drug & excipients, by particular method, results 148
in a physicochemical change in the properties of drug or dosage form, or production of a new chemical substance having different pharmacological action, it is called as physicochemical incompatibility. If incompatibility is prevented by addition, substitution or elimination of one or more ingredient is called as adjusted incompatibility. General Methods used to remove incompatibilities. Modify the order of mixing Dispense with labels like Shake well before use recommend storage condition. Add physical stabilizer. (Suspending or emulsifying agent)Add chemical stabilizer. (Antioxidant/Buffer)Add preservative. Select soluble , compatible or stable form of dosage form. A] PHYSICAL INCOMPATIBILITY When two or more than two substances combined together a physical change takes place & unacceptable product is formed. Physical changes involves such as Immiscibility, Insolubility, Precipitation formation or liquefaction of solid materials. The physical incompatibilities may be corrected by using any one or more of the following methods: Change the order of mixing of ingredients of the prescription. Emulsification Addition of suspending agent Change in the form of ingredients By addition, substitution or omission of therapeutically inactive sub. to help in compounding of the prescription. Example of Physical Incompatibility & Their Methods of Correction: Immiscibility: Oils & Water are immiscible with each other. They can be made miscible with water by emulsification. Example: Rx Castor oil ml water upto ml Make an emulsion. To overcome this incompatibility an emulsifying agent is used to make a good emulsion. 2. Insolubility: It means the inability of material to dissolve in a particular solvent system. The liquid preparations containing Indiffusible solids such as chalk, aromatic chalk powder, acetyl salicylic acid, phenacetin, zinc oxide & calamine etc. Suspending agent Ÿ Increase the thickness of the preparation. Ÿ
Uniform distribution of the insoluble substances which facilitating uniform measurement of each dose. E.g. Acacia, Tragacanth, SLS, etc
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Example: Rx Phenacetin g Caffeine g Orange syrup ml Water upto ml Make a mixture. In this prescription phenacetin is an indiffusible substance. Compound powder of tragacanth or mucilage of tragacanth is used as a suspending agent to make a stable suspension. 3. Settling Suspending agent : The drug in mixtures containing insoluble solids(Suspension), during storage settles at the bottom. Insoluble solids are of two types. Diffusible Solids – Kaolin & light magnesium carbonate remains evenly distributed. Indiffusible solids – Chalk , Calamine Has to increase viscosity of vehicles by adding suspending agent like gum tragacanth. 4. Poor Wettability Levigating agent: Some drugs are poorly wetted with given vehicle hence these may float or sink at the bottom of vehicle. Hence levigation of these solids with wetting agent such as glycerine, propylene glycol, or hydrophilic surfactant helps in the uniform distribution of hydrophobic drug in water.Eg. Sulphur lotion. 5. Precipitation: A drug in solution may be precipitated , if the solvent in which it is insoluble is added to the solution e.g. resins are insoluble in water. Volatile oils are soluble in alcohol. When water is added into the alcoholic solution of volatile oil, the non aromatic portion of the oil get precipitated & turbidity appears. Cap – locking Co-solvents : Liquid preparations especially those containing syrups may show crystallization of sugar in the closure , resulting in cap locking. It can be minimized by adding co-solvents like glycerine, propylene glycol or sorbitol
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6. Grainy Semisolids Non uniform cooling : Partial solidification of higher melting point waxes may occur when cool spatula is used for mixing or when a hot product is poured in a cool container. Grains are also developed during preparation of creams, if the aqueous phase & oil phase do not have same temperatures at the time of mixing. This can be prevented by avoiding localized cooling. 7. Liquefaction: Eutectic mixture : If low melting point solids are mixed together, a liquid or soft mass known as 'Eutectic mixture' is produced. This occurs due to the lowering of the melting point of mixture to below the room temp. & liberation of water of hydration. e.g camphor, menthol, thymol. 13. Liquefication can be corrected by Dispensing individual ingredient separately Compounding powder using diluents such as lactose, magnesium oxide or magnesium hydroxide are separately mixed with eutectic substances and such mixtures are mixed to produce final product. This prevents physical contact of liquifiable substances. Allowing completion of liquefaction & absorbing the liquid using adsorbent such as substances like kaolin. B] CHEMICAL INCOMPATIBILITY Definition: It may be as a result of chemical interactions between the ingredients of a prescription & a toxic or inactive product may be formed. It is due to oxidationreduction, acid base hydrolysis or combination reactions. These reactions may be noticed by effervescence, decomposition, color change . Chemical incompatibilities are of following types. 1. Precipitation: Precipitation of the drug takes place due to I. pH change ii. A chemical reaction between drug-drug or drug-additives. When the precipitate product is therapeutically active it is formulated as per the procedure used to prepare mixtures containing diffusible & indiffusible solid. If the resultant ppt is inactive or toxic the formulation should be rejected. 151
2. pH Change: Most of the medicines are often salts of weak acids & weak bases. The unionized forms are insoluble in water & ionisable salts are soluble in water. A pH change, not only changes solubility, but it also changes rate of degradation. If the resultant precipitate has therapeutic value & it is chemical stable, one can tolerate the incompatility. A suitable co-solvent can be used to increase solubility, otherwise a suspension is formulated. Eg. Morphine hydrochloride Eg. Morphine hydrochloride above 2.5 % concentration , is insoluble & results in the formation of diffusible precipitate under alkaline condition. The solubility of precipitated morphine in alcohol is 1 in 100. Thus incompatibility can be treated either by – i) Preparing suspension of diffusible precipitate Ii) Using alcohol as co-solvent to prepare solution.Eg. Caffeine citrate above 2.2 % concentration, under alkaline condition produces indiffusible precipitate but when alcohol is used, it tolerates a higher concentration of caffeine citrate without precipitation. Precipitation by chemical reaction: Drug-drug interactions: Eg. Caffeine Citrate Active ingredients react with other drugs or additives yielding diffusible or indiffusible precipitate. Caffeine citrate is a mixture of equal weight of caffeine & citric acid. The citric acid reacts with sodium salicylate to liberate salicylic acid in the form of precipitate. It causes gastric irritation. Hence only caffeine is used, it forms a soluble complexes with sodium salicylate. Therefore, caffeine citrate should be replaced with half the amount of caffeine to get clear solution. 3. Flavor Liquorice looses its flavour due to precipitation in presence of acid. Acid reacts with glycyrrhizin, a flavouring constituent of liquorice forming glycyrrhizic acid precipitate. 4. Redox reaction Some drugs or their dosage forms undergo oxidation when exposed to air, excessive temperature & due to over dilution of liquids, incorrect pH or presence of catalyst. The common catalyst includes metal ions, enzymes & bacteria. 152
The drug in the liquid state is more sensitive to oxidation than insoluble state . a) Auto oxidation of oils, fats, phenolic substances, aldehydes & vitamins. This can be prevented by addition of primary antioxidants such as alpha tocopherol, or BHT. b) Paraldehyde, tannins, epinephrine, sulphacetamide & related compounds undergo oxidation activated by heat. Hence for such drugs requires against trace metal ions. This can be achieved by adding antioxidants such as ascorbic acid, sodium metabisulfite or complexing agents like EDTA are used to control oxidation. c) Preparations containing riboflavin, folic acid & ascorbic acid show incompatibility. Riboflavin is light sensitive, and easily degraded by heat and light. Hence should be stored at its stable pH 6 to 6.5. d) When dry powders contains both oxidising & reducing agents, the mixture may explode. The inter-particulate friction developed during mixing increases chances of redox reaction. Therefore such reacting substances should be dispensed separately or powders should be mixed lightly by spatulation method. 5. Hydrolysis Hydrolysis can be controlled by avoiding moisture contact or by changing pH. Aspirin is more sensitive to water & gets converted to more irritant acetyl salicylic acid. Hence it is granulared without use of water. Paracetamol is stable between ph 5 & 7 .While ibuprofen shows more solubility above pH 6.Therefore compound suspension of these two drugs in combination pH of solution is 5-6. 6. Racemisation The conversion of an optically active form to an optically inactive form without changing chemical constitution usually results in reduced therapeutic activity. 7. Effervescence : Two or more ingredients of formulation reacts to generate Co2, To overcome such reactions either Mix the reacting ingredients in open container & allow to complete reaction before filling in to container. The rate of reaction can be increased by using hot water. b) Change the one or more reacting ingredients. c) Dispense reacting substances seperately 153
8. Colour change The colour change is visible incompatibility. When the colour reaction is rapid it is allowed to complete before dispensing. The delayed color change in formulation creates confusion in the mind of patient. Eg. Sodium Salicylate mixture BPC During storage the alkaline solution undergoes oxidation by atmospheric oxygen & becomes brownish black. The coloured product is safe and has therapeutic value but it may create confusion in the mind of patient Hence anti-oxidant like sodium metabisulphite is added as antioxidant to control oxidation. 9. Incompatibilty with containers The product filled in a container may react chemically with the container or get absorbed by the container or the closure. Glass containers alkali leaching. Rubber closures may adsorb preservatives. Metal containers catalyse rate of chemical reaction. C) THERAPEUTIC INCOMPATIBILITY It is result of prescribing certain drugs to a patient with the intention to produce a specific degree of p'cological action, but nature or intensity of the action produced is different from that intended by the prescriber. Therapeutic incompatibility is due to : A) Medication errors B) Drug interactions Medication Errors: Medication errors done by doctors, pharmacists, nurses & patients. Medication errors can be categorized as – Prescription errors Dispensing errors Selection errors Bagging errors Administration errors 1. Errors in prescription writing The prescription should be neatly & correctly written by the medical practitioner, otherwise it is major hassle for the pharmacists. a) Spelling mistakes. Illegible handwriting. SALA Medicines(Sound Alike Look Alike): 154
Tab. Dulcolax a laxative tablet & Tab . Duoclox an antibacterial tablet. b) Type of dosage form Same drug can be available in tablet, capsule or liquid oral dosage forms for adults, drops for pediatric patients. Selection of dosage form is based on ability of patients to take that medicines. c) Strength of Medicines Some medicines, especially those whose dosing is critical , are available in different strengths. Eg. Haloperidol , antipsychotic drug available in the form of tablets of various strength viz. 0.25, 2mg, 5mg,10mg, 20 mg. d) Quantity to be dispensed Pharmacists should check the dose & see that the quantity of medicine is sufficient to complete a course.Pharmacists should check the dose, dosage regimen & direction to use. e) Dose & Direction Pharmacists should check the dose, dosage regimen & direction to use. f) Dispensing Errors: 1. Poor handwriting Long prescription Incomplete patient information Deviation in attention of pharmacist Misunderstanding of verbal orders. While removing medicines from shelves pharmacist should be alert. 2. Selection of medicine While removing medicines from shelves pharmacist should be alert. He should remove the correct medicine. SALA medicines should not be kept adjacent to one another. g) Bagging Errors After billing, dosage forms should be packed in appropriate bags or covers & handed over to the right person. h) Errors in administration Breaking the coated or sustained release tablets. Suspension administration without shaking. Taking medicament at wrong time before or after meal. i) Drug interactions 1. Contra – indicated drugs: There are certain drugs which may be contraindicated in a particular disease or a particular patient who is allergic to it. 155
Example: the penicillin & sulpha drugs are contraindicated to the patients who are allergic to it. j) Synergistic & antagonistic drugs Many drugs exhibit Synergism & Antagonism when administered in combination. When the two drugs are prescribed together, they tend to increase the activity of each other, called as synergism. Example: A combination of aspirin & paracetamol increase the analgesic activity. When two drugs having the opposing p'cological effects are called antagonism. Example: Acetyl salicylic acid and probenecid k) Unintentional drug interaction The effect of one drug is altered by the prior or simultaneous administration of another drug. Tetracycline hydrochloride mg Direction –take one capsule with milk Tetracycline inactive by calcium which is present in milk. l) Intentional drug interaction Rx Acetophenetidin mg Acetyl salicylic acid mg Caffeine mg Send 10 capsules. Acetophenetidin & acetyl salicylic acid are analgesic. Acetophenetidin depresses the CNS & this effect is undesirable. Caffeine is CNS stimulant to neutralise the side effect of acetophenetidin.
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Chapter: 13
Semisolid Dosage forms Unit – IV Syllabus Definitions, classification, mechanisms and factors influencing dermal penetration of drugs. Preparation of ointments, pastes, creams and gels. Excipients used in semi solid dosage forms. Evaluation of semi solid dosages forms
INTRODUCTION Semisolids constitute a significant proportion of pharmaceutical dosage forms. They serve as carriers for drugs that are topically delivered by way of the skin, cornea, rectal tissue, nasal mucosa, vagina, buccal tissue, urethral membrane, and external ear lining. A semisolid dosage form is advantageous in terms of its easy application, rapid formulation, and ability to topically deliver a wide variety of drug molecules. Semisolids are available as a wide range of dosage forms, each having unique characteristics. Topical semisolid dosage forms are normally presented in the form of creams, gels, ointments, or pastes. They contain one or more active ingredients dissolved or uniformly dispersed in a suitable base and any suitable excipients such as emulsifiers, viscosity increasing agents, anti microbial agents, antioxidants', or stabilizing agents. The objective of this compiled d ata is to provide a clear and in-depth knowledge of about various tools, strategies, critical process parameters and strategies of the manufacturing and validation processes specific to semisolid dosage forms. Ointments are semisolid preparations for external application to skin or mucous membranes. Their composition softens but does not melt upon application to the skin. Therapeutically, ointments function as skin protectives and emollients, but they are used primarily as vehicles for the topical application of drug substances. Creams are semisolid dosage forms that contain one or more drug substances dissolved or dispersed in a suitable base, usually oil in- water emulsion or aqueous microcrystalline dispersion of long-chain fatty acids or alcohols that are water washable and are cosmetically and aesthetically acceptable. Gels are semisolid systems that consist of either suspensions of small inorganic particles or large organic molecules interpenetrated by a liquid. Pastes are semisolid dosage forms that contain one or more drug substances 157
incorporated in a base with large proportions of finely dispersed solids. A wide range of raw materials is available for the preparation of a semisolid dosage form. Apart from the usual pharmaceutical ingredients such as preservatives, antioxidants, and solubilizers, the basic constituents of a semisolid dosage form are unique to its composition. The choice of suitable raw materials for a formulation development is made on the basis of the drug delivery requirements and the particular need to impart sufficient emolliency or other quasi-medicinal qualities in the formulation. In general, semisolid dosage forms are complex formulations having complex structural elements. Often they are composed of two phases (oil and water), one of which is a continuous (external) phase, and the other of which is a dispersed (internal) phase. The active ingredient is often dissolved in one phase, although occasionally the drug is not fully soluble in the system and is dispersed in one or both phases, thus creating a three-phase system. The physical properties of the dosage form depend upon various factors, including the size of the dispersed particles, the interfacial tension between the phases, the partition coefficient of the active ingredient between the phases, and the product rheology. These factors combine to determine the release characteristics of the drug, as well as other characteristics, such as viscosity. SEMISOLID DOSAGE FORMS : Semisolid dosage forms are dermatological products of semisolid consistency which are applied to skin or mucous membrane for therapeutic or protective action or cosmetic function. IDEAL PROPERTIES OF SEMISOLID DOSAGE FORMS Physical Properties a) Smooth texture b) Elegant in appearance c) Non dehydrating d) Non gritty e) Non greasy and non staining f) Non hygroscopic Physiological Properties g) Non irritating h) Do not alter membrane / skin functioning i) Miscible with skin secretion j) Have low sensitization index Application Properties k) Easily applicable with efficient drug release. l) High aqueous washability. Advantage of semi-solid dosage form: 1. It is used externally 2. Probability of side effect can be reduce 158
3. 4. 5.
Local action First pass gut and hepatic metabolism is avoided. Patient compliance is increased, the drug termination is problematic cases is facilitated as compared with other routes of drug administration.
Disadvantages of semi-solid dosage form: 1. There is no dosage accuracy in this type of dosage form 2. The base which is used in the semi-solid dosage form can be easily oxidized. If we go out after using semi-solid dosage form problems can occur. CLASSIFICATION SEMISOLID DOSAGE FORMS Semisolid Dosage forms
Creams
Poultice
Gels
Pastes
Ointments
Suppositories
CREAMS Viscous semisolid emulsion system with opaque appearance as contrasted with translucent ointments. Consistency depends on weather the cream is w/o or o/w. W/O creams O\W creams Contains lipophilic emulsifying agent. Used as emollient and as cleansing agent. Contains O\ W emulsifying agent. O/W creams are elegant drug delivery system. POULTICES (CATAPLASMS) They are wet masses of solid matter applied to the skin in order to reduce inflammation and in some cases to act as a counterirritant. Poultice must retain heat for a considerable time. After heating the preparation is spread on dressing and applied to the affected area. E.g. Kaolin poultice (B.P.C.) GELS AND JELLIES Gels and jellies are semisolid system in which a liquid phase is constrained within a 3-D polymeric matrix having a high degree of physical or chemical cross-linking. Gels are aqueous colloidal suspensions of the hydrated forms of insoluble medicament. Jellies are transparent or translucent non-greasy semisolid and contains more water than gels. Used for medication, lubrication and carrier for spermicidal agents to be used intra vaginally with diaphragms. PASTES Contains high percentage of insoluble solid (usually 50 % or more) Pastes are usually prepared by incorporating solids directly into a congealed system by levigation with a portion of the base to form a paste like mass. They have good adhesion on skin and less greasy. OINTMENTS : Ointments are semisolid preparations meant for external application to the skin or mucous membrane. They usually contain a medicament or medicaments dissolves, suspended or emulsified in the base. 159
SUPPOSITORIES: It is solid or stiffened semisolid dosage form intended for insertion into body orifices where they melt, soften, or dissolve and exert local or systemic effects. TYPES Rectal suppositories Pessaries Urethral bougies Nasal bougies Ear cones. STRUCTURE OF SKIN Skin is composed of three primary layers: the epidermis, the dermis and the hypodermis. EPIDERMIS Epidermis is the outermost layer of the skin. It forms the waterproof, protective wrap over the body's surface which also serves as a barrier to infection. The epidermis contains no blood vessels, and cells in the deepest layers are nourished almost exclusively by diffused oxygen from the surrounding air. Epidermis is divided into the following 5 sub layers 1. Stratum corneum 2. Stratum lucidum 3. Stratum granulosum 4. Stratum spinosum 5. Stratum basale STRATUM CORNEUM : The stratum corneum is the outermost layer of the epidermis. It consisting of dead cells (corneocytes). The stratum corneum is the rate limiting barrier that restricts the inward & outward movement of chemical substances. These corneocytes are embedded in a lipid. The stratum corneum functions to form a barrier to protect underlying tissue from infection, dehydration, chemicals and mechanical stress. stratum corneum contain a dense network of keratin, a protein that helps keep the skin hydrated by preventing water evaporation. These cells can also absorb water, further aiding in hydration. This layer is responsible for the "spring back" or stretchy properties of skin. The stratum corneum exhibit regional difference in thickness over the body. In the over most of the body it is about 10μm thick. When dry, increasing to about 40μm to 50μm. It is thick on the palm of the hand & soles of the feet in an adult. DERMIS : The dermis is the layer of skin beneath the epidermis that consists of epithelial tissue and cushions the body from stress and strain. The dermis is tightly connected to the epidermis by a basement membrane. It also harbors many nerve endings that provide the sense of touch and heat. It contains the hair follicles, sweat glands, sebaceous glands, apocrine glands, lymphatic vessels and 160
blood vessels. The blood vessels in the dermis provide nourishment and waste removal from its own cells as well as from the Stratum basale of the epidermis. The dermis is structurally divided into two areas: 1. a superficial area adjacent to the epidermis, called the papillary region, and 2. a deep thicker area known as the reticular region. Mechanisms & factors influencing dermal penetration of drug Absorption of substances through the skin depends on a number of factors: 1. 2. 3. 4. 5.
Concentration Molecular Weight of the molecule Duration of contact Solubility of medication Physical condition of the skin
Part of the body exposed including the amount of hair on the skin. Small amounts of chemicals may enter the body rapidly through the glands or hair follicles, they are primarily absorbed through the epidermis. The stratum corneum is the outermost layer of the epidermis and the rate-limiting barrier in absorption of an agent. Once a substance passes through stratum corneum, then its no significant further hindrance to penetration of the remaining epidermal layer & corium. The stratum corneum is primarily composed of lipophilic cholesterol, cholesterol esters and ceramides (fatty acids). Thus lipid-soluble chemicals make it through the layer and into the circulation faster, however nearly all molecules penetrate it to some minimal degree. Also, penetration depending upon effective blood flow, interstitial fluid movement. BIOAVABILITY OF DRUG For bioavailability there are two factors are most important 1. Choice of vehicle (Base). 2. Maximizing movement (partitioning) of drug from vehicle to stratum corneum. CHOICE OF VEHICLE Greases & oils are the most occlusive vehicles those induce the greatest hydration through sweat & accumulation at the skin- vehicle interface. Vehicle such as, humectants, they have high affinity for water. Such vehicle dehydrate the stratum corneum & decrease the penetration. Powders increases the rate of evaporation of water. Paraffin bases suppress transepidermal water diffusion. Skin secretions are more readily miscible with emulsion bases than with greasy bases. Those miscible drugs is more rapidly release to the skin So, that type of the bases required small.
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Maximizing movement (partitioning) of drug from vehicle to stratum corneum. The medicament is favored vehicles which have low soluble. On that reason, they loosely combine with vehicle. Therefore, the rate of release from such drug vehicle combination is fast. Surface active agents appears to increase permeability of the skin to water by altering the physical state of water in the skin. Anionics surfactant have good ability to penetration than cationics & non-ionics. Soaps of different fatty acids have greater penetration for salts of fatty acids having a carbon length of 10 or less. Drugs with molecular weight of 100 to 800 & adequate lipid & aqueous solubility can permeate skin. The ideal molecular weight of drug for transdermal drug delivery is to be 400 or less. Formulation of semisolid dosage forms ingredients used in preparation of semisolids 1. 2. 3. 4. 5. 6. 7. 8. 9.
Active pharmaceutical ingredient (API) Bases Preservative Humectants Antioxidants Emulsifier Gelling agent Permeation enhancer Buffers.
BASES It is one of the most important ingredient used in formulation of semisolid dosage form. Ointment and suppository bases do not merely act as the carriers of the medicaments, but they also control the extent of absorption of medicaments incorporated in them. Ideal properties of a base They should be, Inert, non-irritating and non-sensitizing. Compatible with skin pH and the drug. Good solvent and/or emulsifying agent. Emollient, protective, non-greasy and easily removable. Release medicament readily at the site of application. Pharmaceutically elegant and possess good stability. TYPES OF BASES A. Oleaginous bases. B. Absorption bases. C. Emulsion bases. D. Water soluble bases. A) Oleaginous (hydrocarbon) bases. They consist of a combination of more than one oleaginous material such as 162
water-insoluble hydrophobic oils and fats. They are highly compatible; occlusive; good emollients. They are anhydrous, do not absorb water, readily (hydrophobic) insoluble in water, not washable. Examples: Vaseline, hard paraffin, liquid paraffin, white ointment. Uses: protectants, emollient, and vehicle for solid drugs. B)Absorption (Emulsifiable) Bases They Have capacity to absorb considerable quantities of water or aqueous solution and turn to w/o without marked changes in consistency. They are anhydrous, water insoluble and water unwashable. They have good emollient but poor occlusive property. Uses: protectants, emollient, and vehicle for aqueous solutions and solid drug. C) Emulsion Bases According to the type of emulsion, these bases are classified as either W/O or O/W. Uses: Cleansing creams, emollients and vehicle for solid and liquid drugs. 21 Emulsion Ointment Base (W/O): Hydrous Will absorb water Insoluble in water Not washable Water-Oil-Emulsion Emulsion Ointment Base (O/W): Hydrous Will absorb water Insoluble in water Washable Oil-in-Water Emulsion Hydrophilic Ointment D) Water Soluble Bases These include both anhydrous and hydrous dermatological non-emulsion bases which are water soluble and contain no oil phase. Water soluble, water washable, greaseless. Because they soften with the addition of water, large amounts of aqueous solutions are not effectively incorporated into these bases. Examples . Carbowax compounds such as the polyethylene glycol bases containing pectin, cellulose, Bentonite, and gelatin. 3. Preservative Some base, although, resist microbial attack but because of their high water content, it require an antimicrobial preservative. Commonly used preservatives include Methyl hydroxybenzoate Propyl hydroxybenzoate Chlorocresol Benzoic acid Phenyl mercuric nitrate. 4. Antioxidants Oxygen is a highly reactive atom that is capable of becoming part of potentially damaging molecules commonly called “free radicals.” Free radicals are capable of attacking the healthy cells of the body, causing them to lose their structure and function. To prevent this an antioxidants are added. E.g. Butylated hydroxy anisole, Butylated hydroxy toluene. 5. Gelling agents Gelling agents, forms a gel, dissolving in the liquid phase as a colloid mixture that forms a weakly cohesive internal structure. These are organic hydrocolloids or 163
hydrophilic inorganic substances. E.g. Tragacanth, Sodium Alginate, Pectin, Starch, Gelatin, Cellulose Derivatives, Carbomer, and Poly Vinyl Alcohol Clays. Material % Brookfield viscosity 'CP 0' Carbomer 941resin NF Carbomer 941resin NF Guar gum Methyl cellulose Sodium alginate. 6. Permeation enhancers Skin can act as a barrier. With the introduction of various penetration enhancers, penetration of the drug through the skin can be improved. 7. Emulsifier An emulsifier (emulgent) is a substance that stabilizes an emulsion by increasing its kinetic stability. One class of emulsifiers is known as surface active substances, or surfactants. Ideal properties of emulsifier includes, a) Must reduce surface tension for proper emulsification. b) Prevents coalescence and should quickly absorb around the dispersed phase. c) Ability to increase the viscosity at low concentration. d) Effective at low concentration Anionic Cationic Nonionic Alkyl sulfates Soaps Dodecyl benzene sulfonate Lactylates Sulfosuccinates Monoglyceride sulfonates Phosphate ester Silicones Taurates Quaternary ammonium compounds Alkoxyalkylamines Polyoxyethylene alkyl-aryl ethers Polyoxyethylene sorbitan esters Sorbitan fatty acid esters Glyceryl fatty acid esters Emulsifiers. 8. Humectant A humectant is a hygroscopic substance. It is often a molecule with several hydrophilic groups, most often hydroxyl groups. Since hygroscopic substances absorb water from the air, they are frequently used in desiccation or for humidity buffering. Humectants are used to : increase the solubility of the active ingredient. to elevate its skin penetration. elevate the hydration of the skin. 9. Buffers Buffers are added for various purpose such as : Compatibility with skin. Drug solubility. Drug stability. Influence ionization of drug. Skin, due to its weak acidic nature, tolerates weak acidic preparations. E.g. sodium acetate, sodium citrate, potassium metaphosphate. 10. Vehicle Purified water, Water for injection, Water for injection may be used in ophthalmic semi solid preparations like eye ointment, gels etc. METHODS OF PREPARATION A. TRITURATION This method is also known as levigation, incorporation or mechanical mixing. 164
When base contain soft fats and oils or medicament is solid and insoluble or liquid, then this method is use. B. FUSION This method is used :- When soft fats or waxes are to be incorporated with hard fats or waxes then of this to be melted to get homogenous mixture with stirring. Solid drugs that are readily soluble in melted base. C. CHEMICAL REACTIONS In chemical method a new product is formed by chemical reaction, which involves both fusion and mechanical mixing. Best example of such method is Iodine ointment. E.g. Ointment containing free iodine Iodine is only slightly soluble in most fats and oils. Iodine is readily soluble in concentrated solution of potassium iodide due to the formation of molecular complexes KI.I 2 , KI.2I 2 , KI.3I 2 etc. These solutions may be incorporated in absorption-type ointment bases. EVALUATION OF SEMI SOLID DOSAGE FORM (1) Physical methods Test of rate of absorption Test of non-irritancy Test of rate of penetration Test of rate of drug release Test of rheological properties Test of content uniformity (2) Microbiological methods Test of microbial content Test of preservative efficacy PHYSICAL METHODS Physical methods test of rate of absorption. The ointment should be applied over a definite area of the skin by rubbing. At regular intervals of time, serum and urine samples should be analyzed for the quantity of drug absorbed. TEST OF NON-IRRITANCY Non-irritancy of the preparation is evaluated by patch test. In this test 24 human volunteers are selected. Definite quantity of ointment is applied under occlusion daily on the back or volar forearm for 21 days. Daily the type of pharmacological action observed is noted. No visible reaction or erythema or intense erythema with edema and vesicular erosion should occur. A good ointment base shows no visible reaction. TEST OF RATE OF PENETRATION Flow-through diffusion cell or microdialysis method is used. Animal or human skin of definite area should be collected and tied to the holder present in a diffusion cell. The diffusion cell is placed in a fluid bath. Measured quantity of the preparation is applied over the skin and the amount of drug passed into the fluid is measured at regular intervals by analyzing the aliquots of fluid using a spectrophotometer.
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TEST OF RATE OF DRUG RELEASE A clean test tube is taken and the internal surface is coated with the preparation as a thin layer. Saline or serum is poured into the test tube. After a certain period of time, the saline is analyzed for the quantity of the drug. The amount of drug when divided by the time period gives the rate of drug release. TEST OF RHEOLOGICAL PROPERTIES The viscosity of the preparation should be such that the product can be easily removed from the container and easily applied to the skin. Using cone and plate viscometer the viscosity of the preparation is determined. MICROBIOLOGICAL METHODS 1. TEST OF MICROBIAL CONTENT Solutions of different samples of the preparation are made. Each sample is inoculated into separate volumes of 0.5 ml of rabbit's plasma under aseptic conditions and incubated at 37 0 C for 1-4 hours. No formation of the clot in the incubated mass indicates the absence of the micro-organisms. 2. TEST OF PRESERVATIVE EFFICACY Using pour plate technique the number of micro-organisms initially present in the preparation are determined. Solutions of different samples of the preparation are made and mixed with Tryptone Azolectin (TAT) broth separately. All cultures of the micro-organisms are added into each mixture, under aseptic conditions. All mixtures are incubated. The number of micro-organisms in each sample are counted on 7th, 14th, 21st and 28th days of inoculation.
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