Formulation Development and Evaluation of

International Journal of Research in Pharmaceutical and Biomedical Sciences

ISSN: 2229-3701

________________________________________________________________Research Paper

Formulation Development and Evaluation of Divalproex Sodium Extended Release Tablets Vamsy krishna. A3*, K.R. Srinath2, C. Pooja chowdary2, Palanisamy. P3 and G.R.Vijayasankar1 1Caplin 2Pulla

point laboratories Ltd. Unit II, Chennai, Tamil Nadu, India.

Reddy Institute of Pharmacy, Dundigal, Medak, Andha Pradesh, India.

3Vinayaka

Missions College of Pharmacy, Vinayakamission University, Salem, Tamil Nadu, India.

*Address for correspondence: [email protected]

_________________________________________________________________________ ABSTRACT Extended release technology is relatively new field and as a consequence, research in the field has been extremely fertile and has produced many discoveries. Sustained release, Extended action, prolonged action, controlled release, extended action, timed release and depot dosage form are term used to identify drug delivery system that are designed to achieve prolonged therapeutic effect by continuously releasing medication over an extended period of time after administration of a single dose. The matrix system is most often used for a drug-controlled release from a pharmaceutical dosage form. The present study was aim to formulate and evaluate the Extended release oral matrix tablet by using Divalproex Sodium as a model drug and see the effects of different polymers to prolong the release of drug for extended period of time. Various formulations of extended release tablets of Divalproex Sodium were developed using various polymers like HPC-HF, HPMC K4M, HPMC K15M, HPMC K100M in different proportion and combinations by direct compression technique, Bulk density, tapped density, compressibility index, Hausner’s ratio before being punched as tablets. Observations of all formulations for physical characterization had shown that, all of them comply with the specifications of official pharmacopoeias and/or standard references. Results of in vitro release profile indicated that formulation DERT-V was the most promising formulation as the extent of drug release from this formulation was optimum (IHS) when compared to other formulations. It was observed that tablets of batch DERT-V followed the Zero order release profiles. From the above results and discussion it was concluded that formulation of Extended release tablet of Divalproex Sodium containing 19.5% of HPMC K100M and 7% of HPMC K4M, batch DERT-V can be taken as an ideal or optimized formulation of Extended release tablets for 18 hour release as it fulfills all the requirements for Extended release tablet. Key Words: Divalproex Sodium, HPMC K4M, HPMC K15M, HPMC K100M INTRODUCTION One of the least complicated approaches to the manufacture of sustained release dosage forms involves the direct compression of blends of drug, retardant material and additives to form a tablet in which drug is embedded in a matrix of the retardant. Alternatively, retardant drug blends may be granulated prior to compression. The following table identified examples of the three classes or retardant material used to formulate matrix tablets, each class demonstrating a different approach to the matrix concept. The first class consists of retardant that forms insoluble or “Skeleton” matrices, the second class represents water-soluble materials that are potential erodible and the third class consists of polymers that form hydrophilic matrices. Table 1: Materials used as retardants in matrix tablets formulations9 Matrix characteristics 1. Insoluble, Inert 2. Insoluble, Erodible 3. Hydrophilic

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Material Polyethylene, Polyvinyl chloride, Methyl acrylate, Methacrylate co-polymer, Ethyl cellulose. Carnauba wax Stearyl alcohol, Stearic acid PEG. Methyl cellulose,(400cps, 4000cps), Hydroxy ethyl cellulose. HPMC (60HG, 90HG, 25cps, 4000cps, 1500cps). Sodium CMC, Sodium alginate, Carboxyl-poly ethylene.

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Insoluble inert polymers such as polyethylene, polyvinylchloride and acrylate Co-polymers have been used as the basic material for many marketed formulations. Tablets prepared from these materials are designed to be suggested instant the not break apart in the GI tract. Tablets may be directly compressed from mixtures of drugs and ground polymer. However if ethyl cellulose is used as the matrix former, a (wet) granulation procedure using ethanol can be employed. The rate limiting step in controlling release from these formulations is liquid penetration into the matrix unless channeling (wetting) agents are included to promote the permeation of the polymer matrix by water, which allows drug dissolution and diffusion from the channels created in the matrix. Formulations should be designed so that pore diffusion becomes rate-controlling, release is defined by equation 1, 2. Drug bioavailability which is critically dependent on the drug: Polymer ratio, may be modified by inclusion of diluents such as lactose in place of polymer in low-milligram potency formulations. Higuchi has provided the theoretic basis for defining drug release from inert matrices. The equation describing drug release form the planner surface of an insoluble matrix is Q = [[DЄCg/T] [2A- Є C s]t]1/2 ……………………..(1) Q is the amount of drug released per unit, surface after time t. Є is porosity of the matrix. D is the diffusion co-efficient of the drug in the elution medium T is the tortuosity of the matrix Cs is the solubility of the drug in the elution medium. A is the initial loading dose of drug in the matrix. Drug release is triggered by penetration of eluting media into the matrix dissolving the drug, there by creating channels through which diffusion takes place. A high tortuosity means that the effective average diffusion path is large. The porosity term takes into account the space available for drug dissolution; an increased porosity results in increased drug release. Both porosity and tortuosity are functions of the amount of dispersed drug, the physico-chemical properties of the matrix, and the dispersion characteristics of the drug in the matrix. If the drug is freely soluble in the elution medium that is Cs > > A, such that the dissolution rate is rapid, then equation (2), which describes the release or drug from a solution entrapped in an insoluble matrix applied; Q = 2A (Dt/ΠT)1/2 ………………………. (2) Release rate is directly proportional to the amount of dispersed drug A; it is proportional to A1/2 for insoluble drugs if 2A = Cs. These expressions predict the plots of Q Vs t1/2 be linear. Release rate is directly proportional to the amount of dispersed drug A; it is proportional to A1/2 for insoluble drugs if 2A = Cs. These expressions predict the plots of Q Vs t1/2 be linear. Release of water soluble drugs, however should be unaffected by the amount of liquid pH value, enzyme content and other physical properties of digestive fluids, unless the drug is in a salt form that precipitates within the matrix pores on dissolution when penetrated by acidic or basic media. The primary objective of sustained release drug delivery is to ensure safety and to improve efficacy or drugs as well as patient compliance. If the drug is given in conventional dosage from, it has to be administered several times a day to produce the desired therapeutic effect. Because of the frequent dosing fluctuation in plasma drug level occurs. If the drug dosing interval is not in accordance with biological half life, larger peaks and valleys are possible with time-drug concentration in blood curve. The pronounced fluctuations resulting from the conventional drug administration are likely to yield period of no therapeutic effect when the drug concentration falls below minimum therapeutic level. Drug concentration can be controlled within a narrow therapeutic range by the use of sustained release systems which will also minimize the severity of side effects. Sustained release formulations may be economical of side effects. Sustained release formulations may be economical also because the average cost of treatment over an extended time may work out to the cheaper. In controlled drug delivery system oral route is the most convenient and common mode of administration which is designed to release the drug over an extend period of time, either in a continuous manner (sustained release) or as a series of pulses (timed release). The main objective of this work is to investigate the possibility of sustained release dosage forms for the drug Divalproex Sodium by using different polymers like Hydroxy Propyl methyl cellulose, Hydroxy Propyl cellulose by the diffusion controlled matrix. For this and to investigate the release characteristics from HPMC and HPC, the formulations from DERT-1 to DERT-5 were made by using drug 250mg. Based on the results of release characteristics of formulations DERT to DERT-5, the final formula is developed. The aim of this study is to evaluate the release pattern of drug from sustained release matrix tablets and compare with the theoretical sustained release profile and that from the marketed sample of sustained and controlled release formulations of Divalproex sodium.

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MATERIALS AND METHODS Divalproex Sodium is procured by Sun Pharma Ltd., Chennai. Hydroxy Propyl Methyl Cellulose K4M, Hydroxy Propyl Methyl Cellulose K15M, Hydroxy Propyl Methyl Cellulose K100M are gifted by Pushkar Pharma Pvt. Ltd. Hydroxy Propyl Cellulose [HF], Lactose DCL-11, Microcrystalline Cellulose (Avicel pH-102) are gifted by Lakshmi Chemicals Pvt. Ltd. Povidone K-30, Colloidal Silicon Dioxide, Purified Talc, Magnesium Stearate, Opadry White, Iron Oxide Yellow, Isopropyl Alcohol, Methylene Chloride are gifted by Colorcon Pvt. Ltd.in Chennai, India. PREFORMULATION STUDIES Preformulation studies are the first step in the rational development of dosage form of a drug substance. The objective of preformulation study is to develop a portfolio of information about the drug substance, so that this information is useful to develop a formulation. Preformulation can be defined as investigation of physical and preformulation of drug substance alone and when combined with excipients. Preformulation investigations are designed to identify those physicochemical properties and excipients that may influence the formulation design, method of manufacture, and pharmacokinetic-biopharmaceutical properties of the resulting product. PROCEDURE Divalproex Sodium was mixed with all excipients in 1:1 ratio the mixture was kept in 2ml glass vials and exposed to 25°C & 60% RH and 400C & 75% RH. The study was performed for 1 month and the observations are given in the Table 2. Table 2: Drug – Excipients Compatibility Studies RT

25°C/60% RH

40°C/75% RH

2nd week

4th week

2nd week

4th week

2nd week

4th week

NC

NC

NC

NC

NC

NC

NC

Hydroxy Propyl Methyl Cellulose K15M

NC

NC

NC

NC

NC

NC

NC

3


NC

NC

NC

NC

NC

NC

NC

4

Hydroxy Propyl Cellulose [HF]

NC

*

5

Lactose DCL-11

NC

NC

NC

NC

NC

NC

NC

6

Microcrystalline Cellulose

NC

NC

NC

NC

NC

NC

NC

S. No.

Excipients

1


2

Initial











(Avicel pH-102) 7

Povidone K-30

NC

NC

NC

NC

NC

NC

NC

8

Colloidal Silicon Dioxide

NC

NC

NC

NC

NC

NC

NC

9

Purified Talc

NC

NC

NC

NC

NC

NC

NC

10

Magnesium Stearate

NC

NC

NC

NC

NC

NC

NC

The Meaning of signs is mentioned below, NC = No change * = Colour change with granule formulation  = Formation of lumps

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IR STUDIES Fig 1: IR Chromatogram for Divalproex Sodium Pure Drug

Fig 2: Divalproex Sodium with Hydroxy Propyl cellulose (HF)

134.4 130 125 1233.13

%T

1299.40

1555.02

120

1360.94

115

887.57 840.23 1484.02

110

953.84

1423.23

1715.97

2890.99

1734.91 1782.24

778.69

1055.87

1862.72

2769.90

105

1124.26

1646.05

3639.81 3554.50

99.8 4000.0

3000

2000

1500

1000

400.0

cm-1

Fig 3: Divalproex Sodium with Hydroxy Propyl Methyl cellulose K4M

23.9 22 20 2369.66 854.43

18

830.76

553.76 752.30

%T 16

930.17

1381.57 2871.99

14 1216.65 1692.14

2959.40

12

1461.00

1062.72 1257.71

1562.78

1109.96

10.8 4000.0

3000

2000

1500

1000

400.0

cm-1


23.9 22 20 2369.66 854.43

18

830.76

553.76 752.30

%T 16

930.17

1381.57 2871.99

14 1216.65

12

1692.14

2959.40

1461.00

3000

1062.72 1257.71

1562.78

10.8 4000.0

2000

1109.96

1500

1000

400.0

cm-1

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23.9 22 20 2369.66 854.43

18

830.76

553.76 752.30

%T 16

930.17

1381.57 2871.99

14 1216.65

12

1692.14

2959.40

1461.00

10.8 4000.0

3000

1062.72 1257.71

1562.78

2000

1109.96

1500

1000

400.0

cm-1

PRE-COMPRESSION PARAMETERS Loss on Drying Mix and weigh accurately 1 to 2 gm of the substance. If the substance is the form of large crystals, reduce the particle size to about 2mm by quickly crushing. Tare a glass-stoppered shallow weighing bottle that has been dried for 30 minutes under the same conditions to be employed in the determination Put the test specimen in the bottle, replace the cover and accurately weigh the bottle and the contents. Distribute the test specimen as evenly as practicable to a depth of about 5mm generally and not more than 10mm in the case of bulky materials. Place the loaded bottle in the drying chamber (LOD Oven) by removing the stopper and leaving it also in the chamber. Dry the test specimen at the temperature and for the time specified. Note: The temperature specified in the monograph is to be regarded as being within the range of + 20°C of the stated figure. In an oven within a specified temperature range: The drying is carried out in an oven within the temperature range specified in the monograph. Upon opening the chamber close the bottle promptly and allow it to come to room temperature in a dessicator before weighing. Wherever drying to constant weight is mentioned, it means that two consecutive weighing do not differ by more than 0.5 milligram, the second weighing made after an additional period of drying under the specified conditions (1 hour is usually suitable) Calculation W2 - W3 (or) n % Loss on drying = -------------------- x 100 W2 - W1 Where, W1 = Weight of the empty bottle in grams. W2 = Weight of the bottle with sample in grams (Before drying) W3 = Weight of the bottle with sample in grams. (After drying) – As time specified. Bulk density The powder sample (blend) under test was screened through sieve #18 and the sample equivalent to 20g was accurately weighed and filled in a 100ml graduated cylinder and the powder was leveled and the unsettled volume (V0) was noted. The bulk density was calculated in g/cm3 by the formula, Bulk density (ρ0) =

M V0

Where, M = mass of powder taken V0= apparent untapped volume

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Angle of repose Angle of repose of the granules was determined by the height cone method. A funnel was fixed to a desired height and granules were filled in it. They were allowed to flow down on a graph paper fixed on a horizontal surface and angle of repose was calculated using the formula, Tan  =

2h D

Where, h and D are height and diameter of the pile respectively. Table 3: Flow of Powders with Angle of Repose values Angle of repose (degrees)

Type of flow

< 20

Excellent

20-30

Good

30-34

Passable*

> 40

Very poor

*May be improved by glidant

Compressibility Index Percentage compressibility or Carr’s index (CI) Based on the poured density and tapped density, the percentage compressibility of the granules was computed using the Carr’s compressibility index by the formula, Carr’s index (%) = poured density-tapped density/ poured densityX100 Table 4: Flow of Powders with Carr’s Index values Carr’s index (%)

Type of flow

5-15

Excellent

12-16

Good

18-21

Fair to passable*

23-35

Poor

33-38

Very poor

> 40

Extremely poor

*May be improved by glidant

Hausner’s ratio: Hausner’s ratio was calculated using the formula, Hausner’s ratio =

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tapped density poured density


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Table 5: Flow of Powders with Hausner’s Ratio values Values

Comments

Less than 1.25

Good flow

Greater than 1.5

Poor flow

Between 1.25-1.5

Addition normally flow

of glidant improves the

MANUFACTURING PROCEDURE Step: 1 – All ingredients were weighed in specified quantity as given in the formula. Step: 2 - Divalproex sodium was sifted through 20# sieve, Step: 3 -Polymer (HPC-HF, HPMC K100M, HPMC K4M, HPMC K15M) PVP-K30, MCC (Avicel ph102), Lactose DCL-21 was sifted through 40# sieve. Step: 4 - The step 1&2 ingredients were loaded into planetary mixer and mixed for 30 minutes. Step: 5 – Talc, Colloidal Silicon Dioxide and Magnesium Stearate was sifted through 40# sieve. Step: 6 – Then the above sieved materials were transferred to planetary mixer and mixed for 5 minutes with step 3 material. Step: 7 – Finally this dry mixed powder was compressed into tablets and evaluated for all physical and chemical parameters.

Table 6: PROTOTYPE FORMULATIONS S. No.

Ingredients

Trial-I

Trial-II

Trial-III

Trial-IV

Trial-V

DERT-I

DERT-II

DERT-III

DERT-IV

DERT-V

(mg)

(mg)

(mg)

(mg)

(mg)

1

Divalproex Sodium

269.05

269.05

269.05

269.05

269.05

2

Lactose DCL-11

16.850

13.800

12.800

21.500

21.500

3


14.900

10.900

9.5500

17.300

17.300

-

-

-

-

(Avicel pH-102) 4

Hydroxy [HF]

Propyl

Cellulose 141.00

5

Hydroxy Propyl Cellulose K4M

Methyl

-

-

-

35.250

32.900

6


Methyl

-

-

47.000

-

-

7


Methyl

-

141.00

94.000

89.300

91.650

8

Povidone K-30

14.100

16.450

18.80

18.80

18.80

9


4.7000

4.700

4.700

4.700

4.700

10

Purified Talc

4.7000

7.050

7.050

7.050

7.050

11

Magnesium Stearate

4.7000

7.050

7.050

7.050

7.050

Total

470.00

470.00

470.00

470.00

470.00

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EVALUATION OF PHYSICAL PARAMETERS Hardness: The hardness of ten tablets was measured using Monsanto hardness tester. The mean and standard deviation were computed and reported. It is expressed in kg/cm2. Thickness& Diameter The thickness & Diameter of ten tablets were measured using Vernier Caliper. The mean and standard deviation were computed and reported. It is expressed in mm. Friability The friability of the tablets was determined using Roche friabilator. It is expressed in percentage (%). Ten tablets were initially weighed and transferred into the friabilator. The friabilator was operated at 25rpm for 4min. After 4min the tablets were weighed again. The friability was then calculated using the formula, Friability (%) =

initial weight  final weight x 100 initial weight

Weight variation test Twenty tablets were randomly selected from each batch and individually weighed. The average weight and standard deviation of 20 tablets was calculated. The batch passes the test for weight variation test if not more than two of the individual tablet weights deviate from the average weight by more than the percentage shown in table 9 and none deviate by more than twice the percentage shown. Table 7: Weight variation tolerance for uncoated tablets Average weight of tablets (mg)

Maximum percentage difference allowed

130 or less

10.0

130-324

7.5

More than 324

5.0

EVALUATION OF CHEMICAL PARAMETERS IDENTIFICATION The retention time of Valproic acid peak in the chromatogram obtained with the test solution corresponds to that of the Valproic acid peak in the chromatogram obtained with the reference solution, as obtained in the assay of Valproic acid. DRUG CONTENT Reference solution Weigh accurately about 50 mg of Divalproex sodium WS into a 100ml volumetric flask, and 70ml of methanol, shake and sonicate to dissolve the content, makeup the volume with methanol. Filter the solution through 0.45µm membrane filter. Test solution Weigh 5 tablets and transfer into a 500ml volumetric flask, add 250ml of methanol, shake and sonicate for 30minutes to dissolve the content and make up the volume with methanol. Pipette out 10ml of the above solution into a 50ml volumetric flask, make up the volume with methanol. Filter the solution through 0.45µm membrane filter.

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CHROMATOGRAPHIC SYSTEM Apparatus : HPLC Column : Phenyl 150 x 3.9mm, 5µ (Inertsil Phenyl is suitable) Detector : 210nm Flow rate : 0.9ml/min Mobile phase : Filtered and degassed mixture of citrate buffer solution and acetonitrile in the ratio of 700:300. Adjust pH to 3.0±0.01 with ortho phosphoric acid. Citrate buffer solution Dissolve 0.5gm of citric acid monohydrate and 0.4gm of dibasic sodium phosphate in 1000ml of water. SYSTEM SUITABILITY Chromatograph the reference solution and record the peak responses as directed under procedure. The column efficiency for Valproic acid peak should not be less than 2000 theoretical plates, tailing factor should not be more than 2.0 and relative standard deviation for 5 replicates injections should not be more than 2.0%. PROCEDURE Separately inject 20 µl of filtered portion of the reference solution and test solution into the chromatograph. Record the chromatogram and measure the responses for Valproic acid peak. Calculate the content of Volproic acid in mg per tablet by using the following expression.

AT WS 500 50 P ------- X-------- X-------- X ----- X ---------- X AV X 0.8674 = ___________mg of Valproic acid per tablet. AS 100 WT 10 100 Where ‘AS ‘is average area of Valproic acid peak in reference solution and ‘AT’ is the average area of Valproic acid peak in test solutions, ‘WS’ is the weight of Divalproex sodium WS taken for reference solution in mg, ‘WT’ is the weight of sample taken for test solution in mg, ‘P’ is percent purity of Divalproex sodium WS on as such basis, ‘AV’ is average weight of a tablet. Calculate the content of Valproic acid in % per tablet by using the following expression.

Content of Valproic acid in mg ---------------------------------------- X 100 Label claim

= ___________ % of Valproic acid per tablet.

DRUG RELEASE PROFILE DISSOLUTION SYSTEM APPARATUS : Dissolution apparatus II as per BP (Paddle) SPEED : 100 RPM MEDIUM : i) Hydrochloric acid pH 1.2: 900 ml ii) Phosphate buffer pH 6.8: 900 ml TEMPERATURE : 370C ± 0.50CTIME TIME : i) 1 Hour in Hydrochloric acid pH 1.2 ii) 4th,6th,8th,12th,16th & 18th Hour in Phosphate buffer pH 6.8

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Preparation of Hydrochloric Acid pH 1.2 Add 40ml of Hydrochloric acid in 5000ml of water, adjust the pH to 1.2 with 2N Hydrochloric acid, dilute with water to 6.0 liters and mix. Preparation of Phosphate Buffer pH 6.8 Dissolve 40.83 gm of monobasic potassium phosphate and 5.5gm of sodium hydroxide into a 5000ml of water. Adjust the pH to 6.8 with either 1N sodium hydroxide or 1N hydrochloric acid if necessary dilute with water to 6.0 liters and mix. Test solution Acid stage Place one tablet each in 6-dissolution bowl containing hydrochloric acid pH 1.2 and run the apparatus for 1 hour. Withdraw the sample from each bowl and filter the solution through membrane filter. Collect the filtrate after discarding first few ml of the filtrate, and use for acid release. Buffer stage Withdraw all the Hydrochloric acid pH1.2 and add 900ml of pre-adjusted phosphate buffer pH 6.8 and maintained temperature 370c ± 0.50c into the each bowl, run the apparatus for 18 hours. Withdraw 10ml of the solution at above intervals from each bowl, replacing the same amount every time with dissolution medium and collect the filtrate after discarding first few ml of the filtrate and use for buffer release. Reference solution Weigh accurately about 55.0 mg of Divalproex sodium WS into a 200ml volumetric flask add 130ml of phosphate buffer pH 6.8 shake and sonicate to dissolve the content and make up the volume with buffer. Filter the solution through 0.45µm membrane filter. CHROMATOGRAPHIC SYSTEM Apparatus : HPLC Column : Phenyl 150 x 3.9mm, 5µ (Inertsil Phenyl is suitable) Detector : 210nm Flow rate : 0.9ml/min Mobile phase :Filtered and degassed mixture of citrate buffer, Potassium phosphate buffer and acetonitrile in the ratio of 350 : 350 : 300. Adjust pH to 3.0±0.01 with ortho phosphoric acid. Citrate buffer solution Dissolve 0.5gm of citric acid 4gm of dibasic sodium phosphate in 1000ml of water. Potassium phosphate buffer Dissolve 6.0gm of monobasic potassium phosphate and 1.70gm of sodium hydroxide in 1000ml of water, adjust the pH to 7.4ml with ortho phosphoric acid. SYSTEM SUITABILITY Chromatograph the reference solution and record the peak responses as directed under procedure. The column efficiency for Valproic acid peak should not be less than 2000 theoretical plates, tailing factor should not be more than 2.0 and the relative standard deviation for 5 replicate injections should not be more than 2.0%. PROCEDURE Separately inject 20 µl of filtered portion of the reference solution and test solution into the chromatograph. Record the chromatogram and measure the responses for Valproic acid peak. Calculate the release of Valproic acid in percentage with respect to label claim by using the following expression. AT WS 900 P 100 -------- X------- X------- X ------ X -------- X 0.8674 AS 200 1 100 250

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= ___________% Release of Valproic acid


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Where ‘AS’ is the average area of the Valproic acid in reference solution and ‘AT’ is the area of the Valproic acid in test solutions, ‘WS’ is weight of Divalproex sodium WS taken for reference solution in mg. ‘P’ is percent purity of Divalproex sodium WS on as such basis. Table 8: PRE-COMPRESSION PARAMETERS FOR GRANULES Loss on drying

Bulk density

(In %)

(g/ml)

Trial

Angle of repose

Compressibility Index

Hausner’s Ratio

(In %)

(In %)

(In °)

DERT - 1

1.93

0.3796

31.39

20.59

07742

DERT – 2

1.62

0.3836

32.81

20.91

0.7863

DERT – 3

1.61

0.3702

32.73

20.18

0.7588

DERT – 4

1.60

0.3773

32.98

20.57

0.7924

DERT – 5

1.57

0.3802

33.90

20.82

0.7829

Table 9: PHYSICAL AND CHEMICAL PARAMETERS FOR TABLETS Trial DERT - 1

Average weight (mg) 479.4

Hardness (Kg/cm2) 3

Thickness (mm) 4.80

Diameter (mm) 11.11

Friability (%) 0.69

Assay (%) 99.85

DERT – 2

475.2

4

4.75

11.11

0.70

99.20

DERT – 3

470.5

5

4.73

11.11

0.55

99.13

DERT – 4

465.2

5

4.72

11.11

0.45

98.25

DERT – 5

471.2

5

4.80

11.11

0.52

99.65

Table 10: In-vitro Drug Release (Dissolution) Profile of Prototype Formulations In-vitro Drug Release Profile in Percentage (Average of 6 Tablets) st

Time

0 hour

1 hour

4th hour

8th hour

12th hour

16th hour

18th hour

DERT - 1

0

25.50

67.30

-

-

-

-

DERT – 2

0

4.230

14.75

26.35

36.25

49.50

58.15

DERT – 3

0

6.530

19.95

31.25

48.25

52.55

69.65

DERT – 4

0

9.210

26.59

48.53

64.45

83.95

94.55

DERT – 5

0

8.130

23.50

44.75

63.35

76.05

95.45

Limit (in %)

0

NMT 10 %

10-30%

30-50%

50-65%

65-80

NLT 90%

DRUG RELEASE PROFILE COMPARISON OF FINAL FORMULA WITH MARKET SAMPLE: Market Sample Details Brand Name : Dilax - 250 Manufactured By : Sun Pharma Label Claim : Each Film Coated tablet Contains, Divalproex Sodium eqv.to Valproic Acid – 250 mg Shelf Life : 2 years Release Profile : 18 Hrs.

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Table 11: Drug Release Profile Comparison of Final Formula with Market Sample S. No.

Market Sample Drug Release Time in Hours

Final Formula (FDT5) Drug Release (in %)

In-House Specification Limit (in %)

(in %) 1

0

0

0

0

2

1

9.12

8.13

NMT 10

3

4

25.20

23.50

10-30

4

8

41.98

44.75

30-50

5

12

59.33

63.35

50-65

6

16

75.53

79.55

65-80

7

18

89.88

91.84

NLT 85

GRAPHICAL REPRESENTATION OF DRUG RELEASE PROFILES Fig 6

Fig 7

Fig 8

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Fig 9

Fig 10

Fig 11

STABILITY STUDIES Stability studies were used to find out whether the formulation is maintaining its quality during the storage period or not. These studies are used to find out the best formulation. It can be performed by applying a stress to the formulation such as temperature, humidity and light. Here stability study was conducted for DERT-I at 25°C/60%RH and 40°C/75% RH and for long term stability. The product was analysed at the end of the one month by using the same procedure as described previously.

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Table 12: Storage Conditions as per ICH Guidelines Stability

Long term*

Storage Condition

Minimum Time Period Covered by Data at Submission

25°C ± 2°C/60% RH ± 5% RH (or)

12 months

30°C ± 2°C/65% RH ± 5% RH Intermediate**

30°C ± 2°C/65% RH ± 5% RH

6 months

Accelerated

40°C ± 2°C/75% RH ± 5% RH

6 months

* It is up to the applicant to decide whether long term stability studies are performed at 25 ± **If 30°C ± 2°C/65% RH ± 5% RH is the long-term condition, there is no intermediate 2°C/60% RH ± 5% RH or 30°C ± 2°C/65% RH ± 5% RH.

Stability Product Details Name the Product

: Divalproex Sodium Extended release Tablets 250mg

Batch Number

: DERT - V

Date of Mb fg.

: Dec – 2009

Date of Incubation

: 05/01/2009

Label Claim

: Each Film Coated Extended Release Tablet Contains,

Divalproex Sodium USP equivalent to Valproic Acid - 250mg

Table 13: Stability Data for Divalproex Sodium Extended Release Tablets (DERT-V)

30 ° ± 2° C & 65 ± 5% RH

40 ° ± 2 °C & 75 ± 5% RH

(Long Term) Parameters

Limits

(Accelerated)

Initial 1 month

2 month

3

1

2

3

month

month

month

month

Description

-

A pale Yellow coloured circular shaped tablet

complies

complies

Identification

-

The retention time of Sample corresponds to the retention time of Standard

complies

complies

484.1mg

484.0

483.8

± 2.0% Average Weight

Assay (%)

90-110

99.65

99.52

99.43

Dissolution

As per IHS

Complies as per IHS

complies

complies

(As per ICH Guidelines)

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RESULTS AND DISCUSSION The inference of selected excipients with drug (Divalproex Sodium). From those results it was concluded that, those excipients was suitable to formulate the Extended Release Tablet of Divalproex Sodium. Table 14: Trial-I: (Drug Release) In-vitro Drug Release Profile in Percentage (Average of 6 Tablets) st

Time

0 hour

1 hour

4th hour

DERT - 1

0

25.50

67.30

8th hour

12th hour

16th hour

18th hour

30% of HPC (HF) used as a Matrix Polymer in trial-I and the result given in the above table. According to the result the release rate was more, so further trial was taken. And also sticking of granule on punches and dies was occurred during compression. So, glidant and lubricant concentration was increased from 1% to 1.5% in further trials. The hardness of the tablet was also less. So the concentration of Povidone K-30 was increased from 3% to 3.5% in further trials. Table 15: Trial-II: (Drug Release) In-vitro Drug Release Profile in Percentage (Average of 6 Tablets) st

Time

0 hour

1 hour

4th hour

8th hour

12th hour

16th hour

18th hour

DERT – 2

0

4.230

14.75

26.35

36.25

49.50

58.15

In trial-II instead of HPC (HF), HPMC K100M 30% was used as matrix polymer, the result given in above table. According to the above result the release retardness was more so, further trial was conducted with less concentration of HPMC K100M. The sticking problem was optimized with 1.5% of glidants. So this concentration was used in further trials. In this trial also the hardness of the tablet was less. So the the concentration of Povidone K-30 was increased 4% to 4.5% in further trials. Table 16: Trial-III: (Drug Release) In-vitro Drug Release Profile in Percentage (Average of 6 Tablets) Time

0 hour

1st hour

4th hour

8th hour

12th hour

16th hour

18th hour

DERT – 3

0

6.530

19.95

31.25

48.25

52.55

69.65

Trial-III was taken with 20% HPMC K100M and 10% of HPMC K15M, the result of drug release given in above table. According to the release shown in table the further trial planned with reduced concentration of HPMC K100M and Instead of HPMC K15M, HPMC K4M, because the release retard ness was still more. The required hardness was achieved with 4.5% of Povidone K-30. So this concentration was used in further trials. Table 17: Trial-IV: (Drug Release) In-vitro Drug Release Profile in Percentage (Average of 6 Tablets) Time

0 hour

1st hour

4th hour

8th hour

12th hour

16th hour

18th hour

DERT – 4

0

9.210

26.59

48.53

64.45

83.95

94.55

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Based on the trial -III trial-IV was taken with 19% HPMC K100M and 7.5% HPMC K4M, the result of drug release given in above table. The release rate was controlled and satisfactory up to 12th hour, but after 12th hr the release was not match with I.H.S specification, so further trial want to be taken with slight modification of both polymers. Table 18: Trial-V: (Drug Release) In-vitro Drug Release Profile in Percentage (Average of 6 Tablets) Time

0 hour

1st hour

4th hour

8th hour

12th hour

16th hour

18th hour

DERT – 5

0

8.130

23.50

44.75

63.35

76.05

95.45

19.5% of HPMC K100M and 7% of HPMC K4M was used in this trial, the drug release was controlled and match with In-house specifications. The concordant trial was taken with same formula, the same result got, so this trial formula (DERT-V) was considered as Final formula, consequently this batch was planned to go coating. This final formulation was compared with market product for drug release profile. The drug release was match with market product. Stability study was conducted on this formulation as per ICH guidelines. FINAL QUANTITATIVE AND QUALITATIVE FORMULA Name of the Product : Divalproex sodium 250mg ER Tablet Label Claim : Each Film coated ER tablet contains, Divalproex sodium equivalent to Valproic acid –500.0 mg Average Weight : 470.0 mg Punch Size : 14/32 Deep concave (11.113mm)

Table 19: Final Quantitative and Qualitative Formula S. No.

% Composition Name of the Ingredients

Qty. per Tablet

Qty for 1000 Tablets

(In mg) (In gram)

1

Divalproex Sodium

57.245

269.05

269.05

2

Lactose DCL-11

4.5745

21.500

21.500

3


3.6808

17.300

17.300

(Avicel pH-102) 4


7.0000

32.900

32.900

5


19.500

91.650

91.650

6

Povidone K-30

4.0000

18.80

18.80

7


1.0000

4.700

4.700

8

Purified Talc

1.5000

7.050

7.050

9

Magnesium Stearate

1.5000

7.050

7.050

Total

100.00

470.00

470.00

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Conversion factor: Molecular weight of Divalproex sodium = 310.37 Molecular weight of Valproic acid = 144.2 X 2 = 288.4 Equivalent weight factor = 310.37 / 288.4 = 1.0762 Each mg of Valproic acid is equivalent to 1.0762 mg of Divalproex sodium

Table 20: Coating Materials S. No.

Name of Ingredients

Quantity Required for 1000 Tablets

1

Opadry White

14.0 mg

2

Colour Iron Oxide Yellow

0.10 mg

3

Isopropyl Alcohol

50.0 ml

4

Methylene Chloride

50.0 ml

FINISHED PRODUCT SPECIFICATIONS Product Name : Divalproex Sodium 250mg Extended release Tablet Description : Yellow colour, bi-convexed tablet with plain surface. Label Claim : Each Film coated Extended Release Tablet contains, Divalproex Sodium USP is equivalent to Valproic acid – 250mg Punch Dimension : 14/32 (11.11mm) Table 21: Finished Product Specifications Final Formulation S. No.

Compression Parameters

Units

Value

In-process Limits

Parameters

1

Weight of one Tablet

mg

484.1

459.9 – 502.3

485.2

2

Weight of 20 Tablets

g

9.682

9.585 – 9.779

9.783

3

Thickness

mm

4.91

±0.2

4.92

4

Hardness*

Kg/cm2

NLT 3

-

-

5

Friability*

%w/w

NMT 1

-

-

As per IHS

99.65

6

Assay

%

As per IHS

(90 – 110%) Complies

7

Dissolution

As per IHS

As per IHS

as per IHS

Note: * - Not applicable for coated tablets.

SUMMARY AND CONCLUSION The present study was undertaken with an aim to formulate develop and evaluate Divalproex Sodium Extended release tablets using different polymers as release retarding agent. Preformulation study was done initially and results directed for the further course of formulation. Based on Preformulation studies different batches of Divalproex Sodium were prepared using selected excipients. Granules were evaluated for tests Loss on drying, Bulk density, tapped density, Angle of Repose, compressibility index, Hausner’s ratio before being punched as tablets. IR spectra studies revealed that the drug and polymers used were compatible. Various formulations of extended release tablets of Divalproex Sodium were developed using various polymers viz, HPC-HF, HPMC K4M, HPMC K15M and HPMC K100M in different proportions and

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combinations by direct compression technique. The tablets were evaluated for physical characterization, in vitro release study and stability studies. Observations of all formulations for physical characterization had shown that, all of them comply with the specifications of official pharmacopoeias and/or standard references. Results of in vitro release profile indicated that formulation (DERT-V) was the most promising formulation as the extent of drug release from this formulation was optimum and match with the In-house Specification when compared to other formulations. Stability study was conducted on tablets of Batch DERT-V stored at 30°C ± 2°C/65% RH ± 5% RH (Long term) and 40°C ± 2°C/75% RH ± 5% RH (Accelerated) for one month. Tablets were evaluated for Identification, Weight variation, drug content and in-vitro release profile. After one month no significant changes were observed in any of the studied parameters during the study period, thus it could be concluded that formulation of Batch DERT-V was stable. It was concluded that the tablets of Batch DERT-V had considerable in vitro drug release. It was observed that tablets of Batch DERT-V followed the Zero order release profiles. From the above results and discussion it is concluded that formulation of extended release tablet of Batch DERT-V containing 19.5% of HPMC K100M and 7% of HPMC K4M can be taken as an ideal or optimized formulation of extended release tablets for 18 hour release as it fulfills all the requirements for extended release tablet. REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14.

15.

16. 17. 18. 19. 20. 21. 22.

Remington’s pharmaceutical Sciences,18th edition, 1677 Colombo P, Bettini R, Santi P, Peppas NA. Swellable matrices for controlled drug delivery: Gel layer behavior, mechanisms and optimal performance. Pharm Sci Technol Today 2003; 3:1-12. Theodore JR, Mansdorf SY. Controlled release drug delivery system. New York: Marcel Dekker; 1983, 5th edition. Donald LW. Bioploymeric controlled release system. Vol I USA: CRS Press Inc; 1984. James MA, Sung Wankim. Advances in drug delivery systems. Controlled release series-1. New York: Elsevier; 1980. Theeuwes FG, Higuchi T. Fabrication of sustained release dosage form. U.S. patent No. 3,845,770. Robinson JR. Sustained and controlled release drug delivery system, New York: Marcel Dekker Inc; 1978. Chien YW. Rate controlled drug delivery systems. 2nd ed. New York: Marcel Dekker; 2005. Ballard BE. Prolonged action pharmaceuticals. Pennsylvania: Mack publishing company; 1980. Lippincott Williams, Wilkins. Remington. The science and practice of pharmacy. 20th edition Vol II; 2000. James A. Wilcox Divalproex Sodium as a Treatment for Borderline Personality Disorder Annals of Clinical Psychiatry, Volume 7, Issue 1 March 1995 , 33 – 37. Abbot laboratory, James A. Wilcox Divalproex Sodium as a Treatment for Borderline Personality Disorder Annals of Clinical Psychiatry, Volume 7, Issue 1 March 1995 , 33 – 37 Xu G, Sunada H. Influence of the formulation on the drug release kinetics from hydroxy propyl methyl cellulose matrix tablets. Chem Pharm Bull 1995; 43: 483-487. Maffione a; P. Iamartino a; G. Guglielmini a; A. Gazzaniga High Viscosity HPMC as a FilmCoating Agent Drug Development and Industrial Pharmacy, Volume 19, Issue 16 September 1993 , 2043 – 2053 Yuh-Tyng Huang a; Tong-Rong Tsai a; Chun-Jen Cheng a; Thau-Ming Cham a; Tsun-Fwu Lai Formulation Design of an HPMC-Based Sustained Release Tablet for pyridostigmine Bromide as a Highly Hygroscopic Model Drug and its In Vivo/In Vitro Dissolution Properties Drug Development and Industrial Pharmacy, Volume 33, Issue 11 November 2007 , 1183 – 1191 S. Mahesh Kumar a; M. J. N. Chandrasekhar b; R. Gopinath c; In Vitro and In Vivo Studies on HPMC-K-100 M Matrices Containing Naproxen Sodium Drug Delivery, Volume 14, Issue 3 March 2007 , 163 – 169 Samuel D, uko-nne, Robert W.mendes. Dried ma\molasses as a direct compression matrix for oral control release drug delivery drug development and industrial pharmacy vol-15,april-1989, 719-741 Wikipedia, the free encyclopedia www.drugbank.com Abbot Labraotaroy prescription inserts. Hand book of Pharmaceutical Excipients; Edited by Raymond C.Rowe, Paul J.Sheskery and Paul J.Weller; 3rd ed. 61-63;181-83;297-301;309 - 11;508; 11;641-43 Hand book of Pharmaceutical Excipients; 1985 Edition;138- 41; 131-34; 146-48; 234-40

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23. Hand book of Pharmaceutical Excipients; Edited by Raymond C.Rowe, Paul J.Sheskery and Paul J.Weller; 161-63;181-83;297-301;309 - 11;508;-11;641-44 24. Preformulation testing in Pharmaceutical Dosage forms Tablets; Edited by Herbert A.Lieberman; Leon Lachmann and Joseph. B.Schwartz; 1,2 edition;.57-68. 25. Rockville. The United States Pharmacopoeia. 24th ed. United States: Pharmacopoeial Convention Inc; 2000-2003 26. Lachman L, Lieberman HA, Kanig JL. The theory and practice of industrial pharmacy. Bombay: Varghese Publishing House; 1987, Third Edition, 67 - 71 27. http://www.accessdata.fda.gov/scripts/cder/dissolution/dsp_SearchResults_Dissolutions. cf (July 31, 2008) 28. European Medicines Agency – Note for Guidance on Stability Testing: Stability Testing of New Drug Substances and Products (CPMP/ICH/2736/99), 12 -13 29. http://www.dailymed.com

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