formulation and evaluation of orodispersible tablet of ornidazole

International Journal of Pharmaceutical Studies and Research

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Research Article

FORMULATION AND EVALUATION OF ORODISPERSIBLE TABLET OF ORNIDAZOLE Kulkarni Maushumi S*, Zeeshan Ahmed, Bhise Kiran S., Somwanshi shekhar V. Address for Correspondence M.C.E .Society’s Allana College Of Pharmacy, K.B.Hidayatullah Road, Azam Campus, Camp, Pune 411001, India. E Mail: [email protected], [email protected], [email protected], [email protected] ABSTRACT: The objective of this study was to prepare spray dried microspheres of Ornidazole and formulate them into orodispersible tablets. Microspheres were formulated using polymer Poly vinyl pyrrolidone (PVP) and combinations of PVP-Mannitol by spray drying technique at different ratios. The work also describes the preparation of orodispersible tablet of Ornidazole by using superdisintegrant. The tablets were evaluated for properties like hardness, friability, disintegration time and drug content. Dissolution studies using basket method were performed for microspheres of Ornidazole. The effect on release profile in phosphate buffer pH 7.4 was studied and treated with release kinetic model. The combination of PVP-Mannitol masks the taste of Ornidazole at lower concentration as compared to only PVP. It can be concluded that spray dried microspheres depicted taste masking ability, and PVP and mannitol does not affect the release of Ornidazole. The orodispersible tablet (ODT) of Ornidazole shows excellent release and disintegration profile. KEYWORDS: Ornidazole, microspheres, spray drying, orodispersible tablet, taste masking

INTRODUCTION: Taste is one of the most important parameters governing patient compliance. Undesirable taste is one of several important formulation problems that are encountered with certain drugs. Oral administration of bitter drugs with an acceptable degree of palatability is a key issue for health care providers, especially for pediatric patients. The purpose of this research is to mask the intensely bitter taste of ornidazole and to formulate an orodispersible tablet (ODT) of the taste-masked drug. Ornidazole is a 5nitroimidazole derivative which has the antimicrobial action and it is used in the treatment of susceptible protozoan infections and also in the treatment and prophylaxis of anaerobic bacterial infections 1, 2. During treatment or therapy when ornidazole given orally it produces nausea, unpleasant metallic taste and some times vomiting. And in such a condition it is difficult to administer drug with a

IJPSR/Vol. I/ Issue II/October-December,2010/39-47

glass of water1. Hence it is beneficial to administer such a drug as an ODT. Ornidazole is an intensely bitter drug; hence, if it is incorporated directly into an ODT the main objective behind formulation of such a dosage form will definitely get futile. In the present study taste masking of ornidazole was achieved by preparing taste masked microsphere by using PVP and combination of PVP-Mannitol by spray drying technique. These microspheres were then formulated into orodispersible tablet (ODTs) using the technique of super-disintegrant addition3, 4, 5. MATERIALS AND METHODS Ornidazole was procured as a gift sample from Bliss Gus Pharma Limited, Dombivali (India), Poly vinyl pyrrolidone K-30,(PVP) mannitol, microcrystalline cellulose, Croscarmellose and Crospovidone (CP) were purchased from Loba chem. All the other excipients and chemicals used were of AR grade.


The experiment was carried out in the year 2009-2010 in the M.C.E .Society’s Allana College of Pharmacy, K.B.Hidayatullah Road, Azam Campus, Camp, Pune 411001, India. Preparation of microspheres: 6, 7, 8 The microspheres were prepared by spray drying technique. The different drug-polymer ratios used for various microsphere formulations were 1:1, 1:1.5, 1:2, and 1:2.5. The polymer solution was prepared by adding given quantity of polymer to the solvent. For both, that is PVP and combination of PVP-Mannitol, distilled water was used as a solvent. The ratios used in the formulation for Drugs: PVP: Mannitol were 1:1:1, 1:1.5:1, 1:2:1 and 1:2.5:1. The given quantity of Ornidazole was added to the polymer solution and the resulting mixture was spray dried. The spray drying parameters are depicted in Table 1.

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Drug Release Study: 13 The drug release studies were performed by USP Type I dissolution test apparatus. Microspheres equivalent to 8 mg of Ornidazole were filled in hard gelatin capsule shell size '0'. The Phosphate buffer pH 7.4 was used as dissolution medium. The temperature and speed of the apparatus were maintained at 37±0.50C and 50 rpm respectively. The samples were withdrawn at predetermined time interval and analyzed for drug concentration at 320 nm by UV-Visible spectrophotometer after filtration. The readings were taken in triplicate.

In Vitro Evaluation of bitter taste of microspheres: 9, 10 Microspheres (equivalent to 8 mg of Ornidazole) were placed in a volumetric flask with 25 ml of phosphate buffer pH 7.4 and stirred for 5 min. The mixture was filtered and the filtrate was analyzed for Ornidazole concentration at 320 nm by UV-Visible spectrophotometer and that was compared with the threshold value. The microspheres for which the drug concentration was less than the threshold value were selected for the development of Orodispersible tablets.

Optimization of superdisintegrant concentration for formulation of 14, 15 Orodispersible Tablets: Before formulation of orodispersible tablets the concentration of disintegrant in tablet was optimized. Tablets were prepared in various batches as depicted in Table (2) containing blend of microcrystalline cellulose and superdisintegrant in various concentrations. The tablet weight was fixed to 100 mg. All the tablets were prepared by direct compression method using 8 mm flat faced punches. Two different disintegrants namely croscarmellose sodium (CC) and crospovidone (CP) were used. All the other process variables were kept constant in order to determine the optimum superdisintegrant concentration. The tablets were evaluated for in vitro disintegration time.

Drug Loading: 12 The drug loading was determined by UV-Visible spectrophotometer. The microspheres were stirred with 100 ml Phosphate buffer pH 7.4 for 2 hr to ensure complete elution of drug. The drug concentration was determined at 320 nm after suitable dilution. The readings were taken in triplicate.

Formulation of Orodispersible Tablets (ODTs): 16, 17 The tablets were prepared by direct compression method. The optimized superdisintegrant concentration was used for formulation of ODTs. Microcrystalline Cellulose was used as directly compressible vehicle. The ingredient assembly for different batches of ODTs is



depicted in Table 4.The microspheres equivalent to 8 mg of Ornidazole were mixed with given quantity of microcrystalline cellulose and superdisintegrant. The tablets were prepared by using 8 mm flat faced punches. All the other process variables were kept constant.

Dissolution test: This test was carried in USP dissolution test apparatus. The release of the drug from the ODTs was studied using USP Type 2 apparatus. Accelerated Stability Studies: 18 During the stability studies the product was exposed to normal conditions of temperature and humidity as per ICH guidelines. The tablets were sealed in an aluminum packaging coated inside with polyethylene at a temperature of 40°C± 2°C and 75 ± 5 % relative humidity for duration of six months. After an interval of every one month each sample was withdrawn and tested for drug content, hardness and drug release study.

Evaluation of ODTs: Hardness: Tablets were subjected to hardness testing using Pfizer hardness tester. Friability: This test was performed in Roche Friabilator. 20 Tablets were selected at random and the speed was 25 rpm. Disintegration test: Tablets were subjected to test in disintegration test apparatus and time required for disintegration in distilled water was noted. Table 1: Spray drying parameters Polymer Inlet Temperature °C 120 PVP 120 PVP and Mannitol

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Feed pump Speed 35 37

Vacuum (mm Wc) 110 110

Aspirator level (Kg/cm2) 2.2 2.2

Table 2: Optimization of superdisintegrant concentration Batch

Superdisintegrant

Superdisintegrant ( % w/w)

Microcrystalline Cellulose (% w/w)

B0

-

-

100

B1

CP

4

96

B2

CP

5

95

B3

CP

6

94

B4

CP

8

92

B5

CC

5

95

B6

CC

7

93

B7

CC

9

91

B8

CC

11

89

CP– crospovidone; CC– croscarmellose sodium.



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Table 3: Formulation of Orodispersible Tablets Batch

Microspheres (mg)

Microcrystalline Cellulose (mg)

CP (mg)

CC (mg)

PF1

14.31

79.69

6

–

PF2

14.31

76.69

–

9

PMF3

9.80

84.20

6

–

PMF4

9.80

81.20

–

9

Formula for one tablet is shown in table. Each tablet contains 8 mg of Ornidazole. PF– Tablets made by Polyvinyl pyrrolidone microspheres; PMF– Tablets made by Polyvinyl pyrrolidone and Mannitol microspheres.

RESULT AND DISCUSSION In Vitro Evaluation of bitter taste of microspheres: The drug release in phosphate buffer pH 7.4 was studied to evaluate taste masking. The drug release from PVP microspheres (drug-polymer ratio 1:2) and PVP and Mannitol microspheres (drug-polymer ratio 1:1.5) was less than the threshold bitterness value i.e. 7 µg/ml. The drug release of other ratios was above the threshold value for all the drug-polymer ratio studied. Therefore PVP1:2 and mixture of PVP and Mannitol 1:1.5 microspheres were selected for the development of orodispersible tablets. Drug Loading, Percentage Yield and moisture content from microsheres.: 11 Table (4) summarizes the results of drug loading, percentage yield and moisture content.The drug release results are depicted in Table (5). The PVP and mixture of PVP and Mannitol microspheres passes the bitterness evaluation test therefore selected for drug release study. The PVP microspheres (1:2 drugpolymer ratio) showed 96.85 % release in 15 min. whereas mixture of PVP and Mannitol microspheres (1:1.5 drug-polymer ratio) depicted 90.42 % release in 25 min.


Optimization of superdisintegrant concentration for formulation of orodispersible Tablets: Before formulation of orodispersible tablets of taste masked microspheres the concentration of disintegrant in tablet was optimized. Tablets were prepared in various batches containing blend of Microcrystalline cellulose and superdisintegrant in various concentrations. The disintegration time is depicted in Table (5). The optimum concentration of crospovidone is 6% w/w and croscarmellose sodium is 9% w/w for formulation of orodispersble tablet. Evaluation of ODTs: The ODTs were evaluated for hardness, friability, weight variation and in vitro drug release. The results are depicted in Table (6). The ODT prepared by using croscarmellose sodium exhibited disintegration time of 7 sec. whereas ODT prepared by using crospovidone depicted disintegration time of about 5 sec. Accelerated stability studies: Following tables show results of various tests carried out for accelerated stability studies of optimized formulations.


The final formulation of orodispersible tablets of Ornidazole selected for the evaluation for stability studies were sealed in a aluminum packaging coated inside with polyethylene and kept at 40 o C ± 2o C, 75 ± 5% RH. for a period

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of 6 months. The formuation was evaluated initially and after a period of 3 month. Aim of this study was to check and know, how much stable is the formulation and how much percent of the drug degraded after a span of 3 months.

Table 4: Evaluation of Microspheres Microspheres

PVP Microspheres

PVP & Mannitol Microspheres

DrugPolymer Ratio

% Yield

% Loading*

% Moisture Content

% Drug Release*

1:05

27.73

45.57 ± 0.25

_

95.08 ± 1.63 in 15 min.

1:1

31.99

50.42 ± 0.33

_

97.02 ± 0.68 in 15 min.

1:1.5

33.51

51.83 ± 0.34

_

94.86 ± 2.12 in 15 min.

1:2

35.22

53.57 ± 0.25

_

96.85 ± 1.63 in 15 min.

1:2.5

35.79

40.95 ± 0.41

_

93.61 ± 2.57 in 15 min.

1:3

34.41

29.10 ± 0.57

_

96.35 ± 0.96 in 15 min.

1:0.5

26.15

70.35 ± 0.13

5.45

91.29 ± 2.63 in 25 min.

1:1

28.36

76.01 ± 0.71

6.31

87.38 ± 2.21 in 25 min.

1:1.5

31.71

84.25 ± 0.59

7.01

90.42 ± 2.40 in 25 min.

1:2

33.51

89.29 ± 0.39

8.13

70.89 ± 1.49 in 25 min.

*Data represents n=3, mean ± S.D.

Table 5: Optimization of Disintegration Concentration Batch BO B1 B2 B3 B4 B5 B6 B7 B8 Data represents n=3 mean± S.D

Disintegration Time 59.33 ± 1.24 36 ± 1.63 21.66 ± 2.05 5.23 ± 1.24 5.56 ± 1.24 47.33 ± 1.24 33.66 ± 1.69 12.33 ± 1.24 7.23 ± 1.24

Table 6 : Hardness of tablets kept for stability studies Formulation code PF1 PF2 PMF1 PMF2

Initial 2.5 ± 0.5 2.5 ± 0.5 3 ± 0.5 3 ± 0.5


2 Months 2.4 ± 0.25 2.4 ± 0.20 2.9 ± 0.28 2.9 ± 0.25

3 Months 2.3 ± 0.23 2.3 ± 0.19 2.8 ± 0.15 2.7 ± 16


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Table 7: Drug content of tablets kept for stability study (%) Formulation code PF1 PF2 PMF1 PMF2

Initial 99.75 99.54 99.31 99.46

2 Months 99.54 99.29 99.21 99.32

3 Months 98.49 98.39 98.08 98.21

Table 8: Dissolution profile of tablet kept for stability studies (% drug release after 30 min) Formulation code PF1 PF2 PMF1 PMF2

Initial 96.85 96.87 90.74 90.82

2 Months 96.69 96.71 90.48 90.55

3 Months 94.96 95.01 89.77 89.81

Figure 1: In vitro Drug Release from ODTs of PVP Microspheres Data represents n=3, mean ± S.D.

Figure 2: In vitro Drug Release from ODTs of PVP-Mannitol Microspheres Data represents n=3, mean ± S.D.



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Figure 3: In vitro Drug Release from PVP Microspheres Data represents n=3, mean ± S.D.

Figure 4: In vitro Drug Release from PVP-Mannitol Microspheres Data represents n=3, mean ± S.D. salivary pH. The drug release from all the DISCUSSION batches of PVP microspheres in Phosphate The microspheres were prepared with different buffer pH 7.4 was above 90 % in 15 min. The drug to polymer ratios. The PVP exhibited excellent taste masking at drug-polymer ratio Mannitol is hexahydric alcohol related to mannos and it can be used as taste masking 1:2. Taste masking was also achieved at drugpolymer ratio 1:2.5 and 1:3. All the other ratios agent. The mixture of PVP and Mannitol exhibited taste masking at drug-polymer ratio studied did not show taste masking as the drug 1:1.5 and a drug release of about 90.42% in 25 release at phosphate buffer pH 7.4 was above the min. The slight delay in drug release form PVP threshold bitterness value. This may be because and Mannitol microspheres as compared to PVP of incomplete film formation by the PVP which microspheres was observed. Initially tablets fails to control the release of Ornidazole at



containing blend of superdisintegrant and microcrystalline cellulose were tested for disintegration time. Tablets containing crospovidone showed quick disintegration followed by croscarmellose sodium. The probable reason for delayed disintegration of the tablets with croscarmellose sodium might be due to their tendency to gel more than crospovidone. This result coincides with the findings of Patel et al. wherein they formulated orodispersible tablets of rofecoxib. Crospovidone 6% w/w and croscarmellose sodium 9% w/w was selected as the optimum concentration that showed minimal disintegration time of 5 sec and 7 sec respectively. The ODT prepared by using croscarmellose sodium exhibited disintegration time of 7 sec. whereas ODT prepared by using crospovidone depicted disintegration time of about 5 sec. All the tablets kept for stability studies showed good results.

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