ISSN 0975 8542

Journal of Global Pharma Technology

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RESEARCH PAPER

FORMULATION DESIGN, DEVELOPMENT AND EVALUATION OF VANCOMYCIN HYDROCHLORIDE TABLETS FOR PSEUDOMEMBRANOUS COLITIS BY DIRECT COMPRESSION METHOD
Gupta M.M. *a, Kedawat Madhulika.b, Srivastava B. c and Saini T.R.d
a b

Jaipur College of Pharmacy, Sitapura, Tonk Road, Jaipur , Rajasthan, India. Dept. of Mathematics and Statistics, Banasthali University, Banasthali , Rajasthan, India, c School of Pharmaceutical Sciences, Jaipur National University, Jaipur,India. d Industrial Pharmacy Lab., Department of Pharmacy, S.G.S.I.T.S., Indore, M.P., India. * For Correspondence: E.Mail- mmingupta@gmail.com Abstract: Conventional dosage form (Tablet) of vancomycin hydrochloride was prepared by direct compression method using Lactose (Direct Compression Lactose-21) as diluent and Avicel 200 as filler disintegrating agent while Kollidon- CL (Crosslinked polyvinyl pyrollidone) was used as superdisintegrant. Tablet prepared by using 10 mm flat punch on single stroke machine. The direct compression method is preferred due to good flow property of powder vancomycin hydrochloride (% Carrs Index 17.5).The drug release profile of tablets was studies in distilled water because drug is freely soluble in water (1 gm in 10 ml). Formula of vancomycin hydrochloride was optimized by varying % of lubricating agent (Magnesium stearate), disintegrating agent (Kollidon CL), hardness of tablets. On increasing the % of magnesium stearate drug release is reduced (delay) as well as increasing in the friability, while as % of disintegrating agent is increases, disintegration time is reduced but again friability was increased that was not desirable. Optimum percentage of magnesium stearate was 1% w/w and 1% w/w kollidon-CL was good regarding drug release and other parameters of tablets. Keywords: Vancomycin hydrochloride, direct compression, Lactose (DCL-21), Avicel-200, Kolidon-CL, Invitro dissolution.

INTRODUCTION Tablets [1] are by far the most popular dosage form for pharmaceutical products for therapeutic use and may be defined as solid pharmaceutical dosage form containing drug substances with or without suitable excipients and prepared by either compression or moulding method.Vancomycin hydrochloride[2] is amphoteric glycopeptide antimicrobial substance produced by the growth of certain strains of Streptomyces orientalis used in the treatment of enterocolitis caused by Staphylococcus aureus, antibiotic associated pseudomembranous colitis caused by C.difficile[3-7]. Drug is poorly absorbed from the gastrointestinal

tract, although absorption may be somewhat greater when the gastrointestinal tract is inflamed. It shows good stability in acidic and alkaline medium and having biological half life between 3-13 hours (average 6 hour). The usual adult daily dose is 500 mg-2 gm administered orally in 3 or 4 divided doses for 7-10 days while for pediatric patients, the usual daily dose is 40 mg/kg in 3 or 4 divided doses for 7 to 10 days [6]. Orally administered vancomycin hydrochloride is only used for enterocolitis and antibiotic associated pseudomembranous colitis and this is not effective for other type of infections [3] .Direct compression method is more suitable for moisture sensitive APIs and less changes in dissolution

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Gupta M. M. et al., Journal of Global Pharma Technology. February 2011; 3(2):1-6

profile are likely occur in tablet made from granulation also the drug properties (bulk density, powder flow properties) favours this method In this even primary drug particle is liberated from the tablet mass and is available for dissolution [8,9,10]. As no tablet formulation of vancomycin hydrochloride is manufactured in the world at the time of research we were interested to design and develop such formulation. Our aim was to use less number of readily available raw materials and adopt simple direct compression technique for tablet preparation which avoids many steps result in cost saving, even if used for commercial purpose. Preparation based on direct compression was supposed to fulfill our requirement and therefore, selected for investigation in the present study. MATERIAL AND METHODS Vancomycin hydrochloride USP, lactose (DCL-21), Avicel-200, Kollidon-CL were obtained as a gift samples from Alkem lab Mumbai (India), Aerosil 200 was obtained from Ranbaxy lab. Ltd. Dewas (India) as a gift sample, magnesium stearate was collected from local pharmaceutical industry of pharmaceutical grade. All other chemical were from reagent grade. PREPARATION OF TABLETS Selection of diluents For the formulation of vancomycin hydrochloride tablets lactose (DCL-21) was selected as diluent on the basis of its micromeritic properties, compatibility, inertness, and non-interfering property in the estimation of vancomycin hydrochloride. Avicel-200 [11] was combined with lactose to improve the flow

and compression property of powder blend. Further the bulk density of Avicel200 was 0.45, which is close to the bulk density of vancomycin hydrochloride (bulk density of vancomucin HCl is 0.33) and its presence would therefore minimize the chances of segregation of drug and excipients during tabletting. Selection of disintegrating agent The Kollidon-CL [11] was finally selected as disintegrating agent for vancomycin HCl tablet on the basis of its superior direct compressible and disintegration properties, non-interfering nature in the drug analytical procedure and compatibility with drug. Selection of lubricating agent The magnessium stearate was selected as good lubricating agent [11,12] because its lubricating capacity was found to be the best among all the lubricating studies. Further it did not interfere in the drug analytical procedure and was compatible with drug. Optimization of lubricating agent To optimize the percentage of lubricating agent (Magnesium stearate) different formulation of tablets were prepared according the following composition which shown in table no.1. All the excipients with drug were properly mixed in a polybag and passed through # 30 mesh sieve and reblended in the same polybag. Tablets were compressed using 10 mm flat punch on a single punch machine. The prepared tablets were evaluated employing different evaluation parameters for optimization of excipients (table 2). Theoretical compressed weight per tablet was 350 mg.

Table 1: Formulae of Vancomycin HCl Tablets (Optimization of lubricating agent) Ingredients B.No. L-001 (mg) B.No. L-002 (mg) Vancomycin HCl 128.15* 128.15* Lactose (DCL-21) 128.85 127.10 Avicel-200 86 (24.57%) 86 (24.57%) Kollidon-CL 3.5 (1%) 3.5 (1%)

B.No. L-003 (mg) 128.15* 123.60 86 (24.57%) 3.5 (1%)

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Gupta M. M. et al., Journal of Global Pharma Technology. February 2011; 3(2):1-6

Magnessium Stearate 1.75 (05%) 3.5 (1%) Aerosil -200 1.75 (05%) 1.75 (05%) Total Weight 350 350 * 128.15 mg Vancomycin HCl is equivalent to 125 mg Vancomycin Table 2: Evaluation of Vancomycin HCl Tablets (Hardness 8 1Kg/cm2) Parameters B.No. L-001 B.No. L-002 Thickness (mm) 4.0 4.0 Diameter (mm) 10.0 10.0 Friability (%) 0.013 0.22 Disintegration Time 6.18 7.20 (minute) Assay (%) 101.60 101.30 Table 3: Dissolution Study of Batch L-001, L-002, L-003 S.No. Sampling Time Cumulative Drug (Minute) Release (%) Batch L-001 1 0 0 2 5 67.85 3 10 84.18 4 15 88.18 5 30 91.13 6 45 97.38 7 60 100.50

7 (2%) 1.75 (05%) 350

B.No. L-003 4.0 10.0 0.68 9.45 100.40

Cumulative Release (%) Batch L-002 0 32.65 49.54 61.32 94.25 97.38 100.07

Drug

Cumulative Release (%) Batch L-003 0 31.06 40.87 50.96 63.16 78.50 92.98

Drug

Dissolution study of Batch L-001, L-002, L003 120 100 80 60 40 20 0 0 50 100

Cumulative Drug Relaese (%)

magnesium stearate was considered as optimum lubrication concentration in further studies. Optimization of hardness of vancomycin HCl tablets To optimize the hardness, tablets of vancomycin HCl were prepared according to the formula of L -002, at different compression pressure to get tablet hardness of 61 kg/cm2, 81 kg/ cm2, and 101kg/ cm2,. The tablets were evaluated as earlier for different parameters. The results are recorded in table 4.

Series1 Series2 Series3

Sampling Time (minute)

Figure1: Dissolution Study of Batch L-001, L002, L-003

The formulation L -002 containing 1 % w/w magnesium stearate exhibited best properties so therefore 1% w/w

Table 4: Comparative account of properties of Vancomycin HCl tablets of different hardness S.No. Evaluation Parameters B.No. -021 B.No. -022 B.No. -023 ( 6 1 Kg/cm2) ( 8 1 Kg/cm2) ( 10 1 Kg/cm2) 1 Diameter (mm) 10.0 10.0 10.0 2 Thickness (mm) 4.1 4.0 3.9 3 Disintegration Time (Minute) 5.41 7.20 11.20 4 Friability 0.86 0.22 0.04 5 Assay (%) 103.20 99.01 102.40

The formulation HL-022 having hardness 81 kg/ cm2, exhibited best tablet characteristic. Therefore, 81 kg/ cm2,

tablet hardness was selected as optimum hardness for vancomycin HCl tablets in further studies.

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Gupta M. M. et al., Journal of Global Pharma Technology. February 2011; 3(2):1-6

Optimization of % of disintegration agent Vancomycin HCl tablets were prepared according to the formula of HL -022 of varying hardness 81kg/cm2 with percentage of kollidon-CL (disintegrating
Table 5: Formulae for optimization of disintegration agent S.No. Ingredients B.No. DHL-221 (mg) 1 Vancomycin HCl 128.15 2 Lactose DCL-21 128.85 3 Avicel 200 86 (24.57%) 4 Kollidon-CL 1.75 (0.5%) 5 Magnessium Stearate 3.5 (1%) 6 Aerosil 200 1.75 (0.5%) Total Weight 350

agent). The composition of three formulations (DHL -221, DHL -222, DHL -223) thus devised is shown in table 5. The tablets were evaluated as earlier for different parameters. The evaluations are recorded in table 6 &7.
B.No. DHL-222 (mg) 128.15 127.10 86 (24.57%) 3.5 (1%) 3.5 (1%) 1.75 (0.5%) 350 B.No. DHL-223 (mg) 128.15 123.60 86 (24.57%) 7.0 (2%) 3.5 (1%) 1.75 (0.5%) 350

Table 6: Evaluation of vancomycin HCL Tablets (Optimization of disintegration agent) Evaluation Parameters B.No. DHL-221 B.No. DHL-222 Diameter (mm) 10.0 10.0 Thickness (mm) 4.0 4.0 Hardness ( kg/cm2) 8 1 8 1 Friability (%) 0.14 0.24 Disintegration Time (Minute) 8.15 7.05 Assay (%) 102.10 100.40

B.No. DHL-223 10.0 4.0 8 1 0.69 3.02 101.80

Table 7: Dissolution study5,8,9 of third trial batches (B.No. DHL-221, DHL-222, DHL-223)
S.No. Sampling Time (Minute) Cumulative Drug Release (%) B.No. DHL-221 0 36.51 50.39 61.74 86.16 89.85 99.22 Cumulative Drug Release (%) B.No. DHL-222 0 54.79 90.14 93.82 95.25 96.94 99.78 Cumulative Drug Release (%) B.No. DHL-223 0 42.72 57.62 72.82 92.54 97.80 100.63

1 2 3 4 5 6 7

0 5 10 15 30 45 60

Dissolution study of Third Trial Batch DHL-221,DHL222,DHL-223 120

Cumulative Drug Release (%)

100 80 60 40 20 0 0 20 40 60 80 Sampling Time (Minute) Series1 Series2 Series3

The formulation DHL-222 exhibited most satisfactory tablet properties considering the disintegrating time and friability together. Therefore, the composition of this formulation was selected as optimum for final formulation trials. Formulation of Vancomycin Hydrochloride tablets (Final Formulation Trial, Reproducible Batch)

Figure2: Dissolution Study of Third Trial Batch DHL-221, DHL-222, DHL-223

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Gupta M. M. et al., Journal of Global Pharma Technology. February 2011; 3(2):1-6

Table 8: Formula of Final Batch

S.No. 1 2 3 4 5 6 Ingredients Vancomycin HCl Lactose (DCL-21) Avicel 200 Kollidon-CL Magnessium Stearate Aerosil 200 Total Weight Quantity (mg) 128.15 127.10 86 3.5 3.5 1.75 350 % Quantity 36.614 36.314 24.571 1.000 1.000 0.500 100

Table 9: Evaluation of Vancomycin HCl Tablets (Final Formulation)

S. No. 1 2 3 4 5 6 7 8 9 Evaluation Parameters Weight Variation Average tablet weight Appearance Thickness Diameter Hardness Friability Disintegration Time Assay Results Observed is in 5 % acceptable range 347.14 mg White, round shape 4.0 mm 10.0 mm 8 1 kg/cm2 0.24% 7.12 minute 100.4%

Table 10: Dissolution Study of Final Batch S.No. Sampling Time (Minute) 1 2 3 4 5 6 7 8 0 5 10 15 30 45 60 90

Cumulative (mg)

Drug

Release

Cumulative Release

Drug

0 72.92 88.18 96.34 117.89 120.65 125.08 120.47

0 58.34 70.54 77.07 94.31 96.52 100.06 96.38

Dissolution Study of Final Batch 120 100 80 60 40 20 0 0 50 Sampling Time (Minute) 100

Cumulative Drug Release (%)

should be made for oral administration. The developed formula of vancomycin hydrochloride (table 8) can be recommended for the pilot plant and manufacturing scale tablet production after subjecting it to long term stability studies. REFERENCES 1. Ansel H.C., Allen L.V., and Popvich N.G. Pharmaceutical Dosage Forms And Drug Delivery Systems, 7th ed.(1999), Lippincott Williams and wilkins, Philadelphia, USA, 179-228. 2. Rasenack N., and Mullar B.W., Crystal Habit and Tableting Behaviour, International Journal Pharmaceutical, 2002;244: 45-57. 3. www.health.allrefer.com/health/pseudo membranous-colitis-info.html

Figure 3: Dissolution Study of Final Batch

RESULTS AND DISCUSSION The result shows that the properties of tablets of formulation DHL-222 were retained in the bigger size batch. It confirmed the reproducibility of the final formulation (DHL-222) In the light of this research work, it may be concluded that tablets of vancomycin hydrochloride
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4. www.cdc.gov/ncidod/hip/gastro/clostri diumDifficileGen.htm 5. www.lilly.com 6. www.viropharma.com 7. www.ascp.com/public/pubs 8. Liberman H.A., Lachman L. and Schwartz J.B. Pharmaceutical Dosage Forms, Tablets Volume- I, Marcel Dekker, Inc., USA, 1-69,108-121,195245. 9. Khan K.A., and Rhodes C.T. The Production of Tablets by Direct Compression, Can. J. Pharm. Sci.1973l; 8:1-5.

10. Shangraw R.F. Compressed Tablets by Direct Compression Granulation Pharmaceutical Dosage Forms: Tablets, Vol.-1, Marcel Dekkar, USA, 2nd ed., (1989), 195-246. 11. Handbook of Pharmaceutical Excipients, Second Edition (1994), ALPA Pharm. Sc.Great Britain, AphA, Washington DC,89-86. 12. Armstrong N.A., Selection of Excipients for Direct Compression Tablet Formulation, Pharm. Technol. Eur. 1997;9:24-30.

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