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FORMULATION AND EVALUATION OF DILTIAZEM HYDROCHLORIDE PRESS-COATED TABLET Kapse Pankaj *1, Mandore Paresh1, Patil Bharat1, Tekade B.W. 1, Thakare V.M1,Dr. Patil V.R. 1
1

Kapse Pankaj

T.V.E.Ss College of Pharmacy; Faizpur (M.S.), India Email : bharat10pharma@gmail.com

ABSTRACT An oral press-coated tablet was developed by means of direct compression to achieve the timecontrolled disintegrating or rupturing function with a distinct predetermined lag time and produce sustained drug delivery. This press-coated tablet containing Diltiazem hydrochloride (DIL) as a model drug in the inner core was formulated with an outer shell by different weight ratios of low viscosity grade hydrophilic polymer of Hydroxypropylmethylcellulose (HPMC) 3-cps, 5-cps, 6-cps powder respectively and weight ratio of that used 1:2.86, 1:3, 1:4, 1:5 for each press-coated polymer to core tablet. The release profile of the press-coated tablet exhibited a time period without drug release (time lag) in pH 1.2 followed by a rapid and complete release phase, the lag phase was markedly dependent on the weight ratios of Core. This ratio of core to press coated polymer press coated tablets displayed acid resistance in the stomach. In vitro dissolution test in pH 6.8 the release of press-coated tablet shows sustained drug release and to avoid gastrointestinal disturbances.1:3 weight ratio shows better sustained release action then other. Key Words: Press-coated tablet, time lag, HPMC, weight ratio, sustained release. INTRODUCTION Direct compression is an accepted pharmaceutical manufacturing technique because of its many advantages such as low equipment costs, short processing time and limited steps, low labor and energy requirements, and use of nonsolvent processes. 1-2 The press-coating technique offers advantages over liquid coating as it does not involve the use of solvents, requires a relatively short manufacturing process, and allows greater weight gain to the core tablet. However, common drawbacks of the press-coating technique are the multi-step processes involved, and the requirement for reliable and reproducible central positioning of the core tablet within press-coated tablet (PCT), a major challenge for large scale industrial manufacturing. Recently, this technique has

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been applied to prepare different solid dosage forms, such as fast-disintegrating tablets or controlled-release preparations.3-4 Timecontrolled release preparations have been extensively developed to achieve time and/or site-specific release.5-7 In order to achieve the chronopharmaceutical design for these timecontrolled release preparations, currently formulation design to control the lag time is prior to the substantial release of drug.8-9 Recently, a TIMERx technology with an erosion mechanism was developed to achieve the chronotherapeutic delivery system.10 Hydroxypropylmethylcellulose (HPMC) is a wellknown water-soluble polymer that has long been used as a rate-controlling membrane in medication dosage forms to regulate drug release. Several reports have directly addressed the use of HPMC as a directly compressible polymer in a controlled-release matrix or in an immediate release tablet.15-17 In our previous studies, HPMC powder with different weight ratios has been directly compressed to form compact HPMC in which Fickian drug transport mechanism of polymeric coating.18 Recently, the unique suitability of HPMC powders to act as an outer shell has also been explored to directly prepare the presscoated tablet with a sustained drug release action. This function can be further and effectively controlled by modifying the compression force applied to the outer shell, the amount of outer shell used, and the excipients added to the inner core tablet. Many studies have reported that the type and amount of excipients used might affect the drug release profile of controlled release tablets to influence the drug bioavailability ; also the type of excipients in the inner core tablet might significantly influence the induction period of the time-controlled disintegration or rupture of a compression-coated tablet. The purpose of this study was to investigate the influence of the type and amount of press coated polymer required to complete coat over a core tablet and

avoid drug release in a gastric fluid to avoid a various gastric disturbances produced by drug. And the thickness of coated polymer over a core tablet related with drug release from press coated tablets. The Diltiazem hydrochloride was used as a model drug. MATERIALS AND METHODS Materials Diltiazem hydrochloride (DIL; Divis Lab.LTD. Choutuppal mandal, Dist.Nalgonda, A.P., India) were used as a model drug . Cornstarch (Ipca Lab. LTD.Athal,Silvassa, India), calcium citrate (Loba chemical, India), polyvinylpirrolydone (Loba chemical, India), carboxymethylcellulose-calcium (Loba chemical, India), magnesium stearate (Loba chemical, India) and Ethanol (Qualigens fine chemicals, Mumbai) were used for preparation of the core tablets. Hydroxyl propyl methyl cellulose (HPMC; Ipca Lab. LTD.Athal, Silvassa, India) was used for the hydrophilic polymer outer shell of sustainedrelease press-coated tablets. All other chemicals and solvents were of analytical reagent grade. Preparation of core tablets A wet granulation method was applied to prepare the granules for the core tablets. The powder mixture of DIL and cornstarch was kneaded with 33% (w: v) polyvinylpirrolydone ethanolic solution as the binder. The wet mass was forced through a sieve no.18. The granules were dried at 25-270C for 1hrs. and then sized by passing through a sieve # 22. Calcium citrate, carboxymethylcellulose calcium and magnesium stearate were mixed with the granules for 8-10 min. Tabletting was performed under a compression force of 34 kg/cm2 using a rotary tabletting machine (Jaguar JMD 4-8 Ltd. Mumbai, India). Plain flat faced punches 6 mm in diameter were used for the preparation of the core tablets. The thickness of the core tablets was about 2.0 mm.

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Preparation of Press-coated Tablets HPMC was passed through a sieve # 40 screen and used for the sustained-release outer shells. The press-coating of tablets was performed using a tabletting machine (Jaguar JMD 4-8 Ltd. Mumbai, India). A half amount of the HPMC press-coated polymer powder was filled into the die to make a powder bed, on the center of which was placed the core tablet and remaining equivalent powder of polymer powder was filled in the die, after that press under compression machine. The press coated tablet formed, and the contents were compressed under a compression force of 4-6 kg/cm2, using a concave punch 8 mm and 11 mm in diameter. In Vitro Dissolution Study The release of Diltiazem hydrochloride from the press-coated tablet was accomplished In-vitro release study was carried out (USP dissolution test apparatus Type-II Paddle type) using 900 ml of pH 1.2 solution, for two hours and later on pH 6.8 buffer for further eight hours as a dissolution medium. The paddles are rotated at 100 rpm. The medium was set at 37 0.50 C. Aliquot (10 ml) of the solution was collected from the dissolution apparatus hourly and was replaced with fresh dissolution medium. The withdrawn samples were analyzed by an UV spectrophotometer (Lab India) at 237 nm using pH 1.2 and pH 6.8 buffer as a blank. Aliquots were withdrawn at one hour interval from a zone midway between the surface of dissolution medium and the top of rotating paddle not less than 1 cm apart from the vessel wall. Drug content in dissolution sample was determined by software (PCP disso v2.08) version. RESULTS AND DISCUSSION Table 01 :Composition of press coated tablet (Refer Table No.01) In vitro dissolution profiles of drugs from Press-coated tablets:

After oral administration, PC tablets undergo transit from the stomach to the cecum or colon. Physiological pH in the gastrointestinal tract is highly variable among human subjects and dosage forms are exposed to this variable environmental pH. As the gastric emptying time differs with individual dosage form or physiological conditions, the dissolution pattern after gastric emptying time may be altered due to the time of exposure to gastric pH. In addition, gastrointestinal motility will cause mechanical disruption of administered tablets. The dissolution profile determined in vitro using the USP dissolution test apparatus Type-II Paddle type. Thus, the resistance of drug release in 1.2 pH gastric medium tablets to mechanical impact was evaluated by this method. Fig. shows the dissolution profiles of DIL from PC tablets by USP Type II Paddle type Apparatus used in 1st fluid (pH 1.2). DIL was not released under this condition for 2 h, and this result showed that PC tablets have sufficient resistance against the low pH and impact or frictional force in the stomach. The in vitro dissolution test was then performed in 2nd fluid (pH 6.8) for the tablets after the dissolution test shown in Fig.The results are shown in Fig. The dissolution profiles were not markedly different among non-treated tablets and those pre-treated USP Type II Paddle type Apparatus in 1st fluid (pH 1.2). This result showed that exposure time in the stomach would not affect the dissolution performance during transit in the intestine. Fig. 01: dissolution profiles of DIL from PC tablets by USP Type II Paddle type Apparatus used in 1st fluid (pH 1.2). (Refer Figure No. 01) Fig.02 - Comparative graph of % drug release all formulation containing HPMC-3cp (Refer Figure No. 02)

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Fig. 03 -Comparative graph of % drug release all formulation containing HPMC5cps (Refer Figure No. 03)

Fig.04 - Comparative graph of % drug release all formulation containing HPMC6cps. (Refer Figure No. 04) TableNo. 02 - Physical parameters of Core tablets P1-P24. (Refer Table No.02) Uniformity of content: Table No. 03 : Uniformity content of core formulations P1 to P24 Stability study Accelerated stability studies (AST) was carried for optimized batch P-16 by exposing it to 40 C/75%RH for 7, 14, 21 and 28 days. The sample was analyzed for physical parameters colour, hardness, uniformity of content, and percentage drug release. ACKNOWLEDGEMENT The authors are thankful to Divis Lab.LTD. Choutuppal mandal, Dist .Nalgonda( A.P.) Ltd.,for their generous donation of Diltiazem hydrochloride. REFERENCES 1) Ding x, Alani AWG, Robinson JR. 2000. Extended release and targeted drug delivery systems. In: Gennaro AR, editor. Remington: The science and practice of industrial pharmacy. 21st edn. Vol 1. Philadelphia: Lippincot Williams and Wilkins, pp 993-940. 2) Collett J, Moreton C. 2002. Modifiedrelease peroral dosage forms. In: Aulton ME, editor. Pharmaceutics: the science of dosage

form design. 2nd edn. London: Churchill Livingstone, pp 289-306. 3) Chang RK, Robinson JR. 2005. Sustained drug release from tablets and particles through coatings. In: Liebermann HA, Lachmann L, Schwartz JB, editors. Pharmaceutical dosage forms: tablets vol. 3. 2nd edn. New York: Marcel Dekker, pp 199287. 4) Brahmankar DM, Jaiswal SB.2007. Biopharmaceutics and pharmacokinetics a treatise. Vallabh prakashan, Delhi, pp 335-357. 5) Welling PG, Dobrinska MR. 1987. Dosing considerations and bioavailabiliy assessments of controlled drug delivery systems. In: Robinson JR, Lee VHL, editors. Controlled drug delivery: fundamentals and applications. 2nd edn. New York: Marcel Dekker, pp 253-292. 6) Chang RK, Robinson JR. 2005. Sustained drug release from tablets and particles through coatings. In: Liebermann HA, Lachmann L, Schwartz JB, editors. Pharmaceutical dosage forms: tablets vol. 3. 2nd edn. New York: Marcel Dekker, pp 205207. 7) Robison JH, Vincent HK. Influence of Drug Properties and routes of drug Administration. Controlled drug delivery fundamental and application, In, Robison JR (ed).Controlled drug delivery and application, 2nd edition New York, Marcel Dekker, 1987; 03-36. 8) Charman SA, Charman WN. Oral modified -release drug delivery system. In, Rathbone MJ (ed). Modified-release drug delivery technology, 3rd edition. New York, Marcel Dekker publisher, 2003; 01-096. 9) Chien Y W. oral drug delivery and delivery system. In, Swarbrick J (ed). Novel drug delivery system, 2nd edition. New York, mercel dekker publisher, vol-50, 1992; 1-38. 10) Indian Pharmacopoeia-2007, Vol-2nd ,Published by The Indian Pharmacopoeia Commission, Ghaziabad, p.1041-43.

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11) Venkatraman S, Davar N, Chester A, Kleiner L. 2005. An overview of controlled release systems. In: Wise DL, editor. Handbook of pharmaceutical controlled release technology. New York: Marcel Dekker, pp 431461. 12) Qiu Y, Zhang G. 2005. Research and development aspects of oral controlled-release dosage forms. In: Wise DL, editor. Handbook of pharmaceutical controlled release technology. New York: Marcel Dekker, pp 465-499. 13) Bodmeier RA. 2002. Waxes. In: Swarbrick J, Boylan JC, editors. Encyclopedia of pharmaceutical technology. Vol 3. 2nd edn. New York: Marcel Dekker, pp 2988-3000. 14) Levina M., Ali R. R-S., The Influence of Excipients on Drug Release from Hydroxypropyl Methylcellulose Matrices. Journal of pharmaceutical sciences, vol. 93, no. 11, (2004) WileyInterScience

(www.interscience.wiley.com) /jps.20181. 274654 15) Bhalekar M. R., Madgulkar A. R., Sheladiya D. D., S. J. Kshirsagar S. J., Wable N. D., S. S. Desale S. S., 16) Halsas M. 2001. Development and biopharmaceutical evaluation of press coated tablets taking account of circadian rhythms of disease. Division of biopharmaceutics and pharmacokinetics department of pharmacy, University of Helsinki. Pp 4-6. 17) Gazzaniga A., Sangalli M. E., Maroni A., Zema L., Busetti C., Giordano F., In vitro and in vivo evaluation of an oral system for time and/or site-specific drug delivery. Jr of C. R. 73 (2001). 103110. 18) Ashford M., Fell J.T., Attwood D., Sharma H., Woodhead P. J., An in vivo investigation into the suitability of pH dependent polymers for colonic targeting. Int. Jr. Pharmaceutics. 95 (1993). 193-199.

TABLES & FIGURES Fig. 01: dissolution profiles of DIL from PC tablets by USP Type II Paddle type Apparatus used in 1st fluid (pH 1.2).

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Fig.02 - Comparative graph of % drug release all formulation containing HPMC-3cp

Fig. 03 -Comparative graph of % drug release all formulation containing HPMC-5cps

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Fig.04 - Comparative graph of % drug release all formulation containing HPMC-6cps.

Table No. 01 Composition of press coated tablet: Formulation Code P1 P2 P3 P4 P5 P6 P7 P8 P9 P10 P11 P12 P13 Drug (mg) 30 30 30 30 30 30 30 30 30 30 30 30 30 Core tablet (mg) 70 70 70 70 70 70 70 70 70 70 70 70 70 HPMC 3cps (mg) 70 140 160 180 200 HPMC 5cps (mg) 70 140 160 180 HPMC 6cps (mg) 70 140 160 180 -

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P14 P15 P16 P17 P18 P19 P20 P21 P22 P23 P24

30 30 30 30 30 30 30 30 30 30 30

70 70 70 70 70 70 70 70 70 70 70

210 280 350 -

200 210 280 350 -

200 210 280 350

Each formulation contains 30 mg of Diltiazem hydrochloride and the total weight of core tablet is 70 mg.

TableNo. 02 - Physical parameters of Core tablets P1-P24. Parameters Formulations Hardnes s (kg/cm2) ( SD) 3.6 0.095 3.4 0.081 3.6 0.125 3.8 0.115 3.2 0.100 3.3 0.115 3.6 Thickness (mm) ( SD) 2.10 0.020 2.15 0.026 2.05 0.033 1.98 0.050 1.99 0.028 2.00 0.036 2.12 % Friabilit y Weight Uniformity (mg) SD.

P1

0.57

70.252.80

P2

0.65

70.052.50

P3

0.51

69.351.96

P4

0.57

68.351.87

P5 P6 P7

0.51 0.56 0.51

68.501.94 71.352.34 69.402.43

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0.191 P8 P9 P10 P11 P12 P13 P14 P15 P16 P17 P18 P19 P20 P21 P22 P23 P24 (n-6) 4.0 0.115 3.5 0.163 3.6 0.163 3.8 0.115 3.4 0.191 3.5 0.081 3.6 0.125 3.7 0.163 3.3 0.191 3.60.15 7 3.20.18 3 3.40.14 2 3.20.09 8 3.50.12 2 3.80.14 8 3.50.14 0 3.40.18 4

0.011 1.99 0.042 1.98 0.028 1.99 0.028 2.10 0.050 2.00 0.036 1.97 0.011 1.98 0.050 2.10 0.026 2.00 0.028 2.050.017 2.000.022 1.990.040 2.080.043 1.980.032 2.100.018 2.000.024 1.980.036 0.51 0.58 0.65 0.51 0.58 0.58 0.57 0.52 0.59 0.72 0.57 0.65 0.72 0.57 0.79 0.57 0.65 69.251.78 69.252.56 69.452.43 68.802.76 68.401.98 69.352.56 70.301.82 68.102.65 68.452.87 69.662.98 69.902.45 70.102.43 70.002.76 70.201.67 70.251.90 69.802.78 69.902.67

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Uniformity of content: Table No. 03 : Uniformity content of core formulations P1 to P24 Formulatio n P1 P2 P3 P4 P5 P6 P7 P8 P9 P10 P11 P12 (n-3) Uniformity of content( SD) 97.760.58 99.190.56 98.820.48 98.540.5 98.750.53 98.130.51 98.320.52 98.820.34 98.690.57 98.920.44 99.20.58 99.030.55 Formulation P13 P14 P15 P16 P17 P18 P19 P20 P21 P22 P23 P24 Uniformity of content ( SD) 99.020.42 99.150.45 98.620.56 98.940.48 99.390.44 99.220.38 100.150.44 100.720.39 100.520.48 99.410.4 99.390.4 101.580.45

End

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