International Journal of Universal Pharmacy and Life Sciences 1(2): September-October 2011

INTERNATIONAL JOURNAL OF UNIVERSAL PHARMACY AND LIFE SCIENCES

Pharmaceutical Sciences Research Article!!! Received: 14-09-2011; Accepted: 16-09-2011; Published Online: 17-09-2011 SYNTHESIS OF HPMC AND ITS APPLICATION AS COATING MATERIAL FOR SUSTAINED RELEASE DILTIAZEM HCL TABLET
Barde L.N.*, Bhutada D.S., Mathur V.B., Shivhare U.D. Sharad Pawar College of Pharmacy, Wanadongri, Hingna Road, Nagpur- 441110

ABSTRACT
Keywords: HPMC, synthesis, coating, sustained release, diltiazem HCl The Polymeric films are finding an ever increasing range of applications in research, development and dosage form design to coat drug particles to produce product with a sustained release, pharmaceutical therapeutic action. For synthesis of HPMC, Raw material used as cellulose synthesized from cotton and wood pulp. A purified form of cellulose is reacted with sodium hydroxide to produced swollen alkali cellulose, which is chemically more reactive. Then it is treated with methyl chloride in which sodium is replaced by hydroxymethyl group, by undergoing nucleophillic substitution reaction to produced intermediate product and sodium chloride as bi-product. Then the intermediate is reacted with propylene oxide then again by undergoing nucleophillic substitution reaction, propylene oxide replaces sodium of alkali cellulose and obtaining hydroxyl propyl methyl cellulose (HPMC) polymer. The manner in which methyl chloride and propylene oxide are added to alkali cellulose is described by two terms, the degree of substitution and the molar substitution. The synthesized HPMC polymer used as coating for sustained release Diltiazem HCl tablet and compared with different grades of polymer HPMC K 100 and HPMC K 15. We found that the synthesized HPMC polymer is superior for sustained release pattern than marketed HPMC K 100 and HPMC K 15 as per drug dissolution study.

For Correspondence:
Barde L.N. Sharad Pawar College of Pharmacy, Wanadongri, Hingna Road, Nagpur441110 E-mail: c_barde@rediffmail.com

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Introduction: The synthesized HPMC polymer used as coating material for sustained release Diltiazem HCl tablet and compared with different grades of polymer HPMC K 100 and HPMC K 15. Film coating of tablets on an industrial scale first occurred in 1954 when Abott lab introduced their film tab. Coating1 involves the deposition of thin but uniform, membranes of pharmaceutically acceptable polymer on to the surface of the substrate (Tablets, granules, capsules etc). Coatings are applied to pharmaceutical dosage forms to protect them against the environment, to improve their appearance, to mask undesirable taste or odor, to impart enteric properties and to modulate the release of medicament.2 Polymeric coating is finding an ever increasing range of application in pharmaceuticals research, development and dosage form design. Polymeric coating has been increasing employed to coat drug particle to produce particle product with a delayed or controlled release pharmaceutical action. For proper tablet coating, it requires proper distribution, continuous mixing, continuous drying and removal of solvent vapor. There are different types of coating film coating, compression coating, electrostatic coating, Dip coating, Vacuum film coating, pan coating, Fluidized coating and Melt coating. Film coating is a process in which the results obtained are attributed to the complex interaction of numerous factors. The properties of film coating are affected by formulation and processing parameters such as film composition, thickness and drying condition. In addition to application to all types of solid dosage form, polymeric film are being employed for such diverse use as the coating of suppositories, encapsulation of liquid, and aerosol bandages. As film theory and technology, continue to advance, both fundamentally and in selected pharmaceutical application increasing and more effective utility of polymeric coating was made by the pharmaceutical industry. Hydroxy propyl methyl cellulose (HPMC) is a non-ionic, water-soluble polymer widely used in pharmaceutical formulations. It is primarily used as a thickening agent in ophthalmic and topical formulations. It is used as a binder and film coating agent for the tablets. It is present in lubricant preparations for dry eye, contact lens care and dry mouth. Hydroxy propyl methyl cellulose is used as an adhesives, agricultural chemicals, ceramic construction products, food leather, paint, plywood, ink, resin, and rubber industries. The swelling properties of HPMC polymer as a sustained release, hydrophilic matrix binder in tablets are well known. HPMC polymer is available in variety of grades with different solution viscosities. Water-soluble

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cellulose ethers such as hydroxypropyl methyl cellulose is typically supplied in varying viscosity grades. Material and Methods: Material and Equipments: Diltiazem hydrochloride and polymer Hydroxy Propyl Methyl Cellulose (HPMC) was obtained as gift sample from Zim Laboratories, Kalmeshwar, Nagpur. All other reagents and solvents used were of analytical grade. The following equipment were used for the experiment as dissolution apparatus (Lab India), FTIR Spectrophotometer (Shimadzu Japan), Tablet compression machine (Minipress Rimek Japan). Development Of Hydroxypropyl Methyl Cellulose Polymer: Reaction assembly for synthesis of HPMC polymer :- Reaction kettle consists of 4-necked round bottom flask. It is equipped with glass-paddle stirrer, the thermometer pocket, a nitrogen gas inlet and a reflux condenser. At the bottom of this glass assembly, there is a heating mantle for maintaining temperature of reaction.

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Figure 1: Reaction assembly for synthesis of HPMC polymer Full Text Available On www.ijupls.com (Free)

Synthesis of Cellulose from Cotton and Wood Pulp3 : From raw cotton: Accurately weighed 5 g of raw cotton was treated with 200 ml of 1.25% hydrochloric acid solution for 4-5 hours at a temperature of 60-70C. Then this solution was filtered and particles which were retained on the filter paper were washed with distilled water 34 times and dried it in a hot air oven at 30-35C for 10-15 minutes. After that it was finely crushed in mortar and pestle and weighed. From wood-pulp: Accurately weighed 5 g of wood-pulp was treated with 200 ml of 1.75% hydrochloric acid solution for 4-5 hours at a temperature of 70-80C. Then this solution was filtered and particles which were retained on the filter paper were washed with distilled water 34 times and dried it in a hot air oven at 30-35C for 10-15 minutes. After that it was finely crushed in mortar and pestle and weighed. Synthesis of HPMC polymer4,5: Accurately weighed quantity of cellulose was added with mixture of isopropyl alcohol, water and methyl chloride. Then this solution was kept under nitrogen gas bubbling for 30-45 minutes. A solution consisting of 23% sodium hydroxide was allowed to digest for 45 minutes with continuous vigorous stirring. Then propyl oxide was added drop wise with continuous stirring at a temperature of about 70-800C. The total reaction time was up to 8-12 hours. After the completion of reaction, this solution was allowed to cool and then it was neutralized with glacial acetic acid. After that this solution was filtered and washed with hot water and then dried. Evaluation of HPMC polymer6: The evaluation of HPMC polymer was done by identification test, appearance, solubility, viscosity, loss on drying, determination of pH and film characterization techniques. It was found that synthesized HPMC polymer complies all identification tests. (See Table 1 and 2)

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Table 1:- Various Identification Tests of HPMC Polymer

Sr. No. 1.

Identification test I 10 ml of solution A is heated in water Complies bath with constant cloudy or stirring a at a the test. temperature above 50oC, the solution becomes flocculent precipitate is formed. On cooling, the solution becomes clear or slightly opalescent. II

Observation III Complies the test. IV Complies the test.

Complies the test.

2.

Place 1ml of solution A on glass-plate. Complies After evaporation of the water, a thin the test. film is produced.

Complies the test Complies the test.

Complies the test. Complies the test.

Complies the test. Complies the test.

3.

To 10 ml of solution A, add 0.3 ml of Complies 2M acetic acid and 2.5 ml of 10% w/v the test. solution of tannic acid; a yellowish white flocculent precipitate is produced which dissolves in 6M ammonia

4.

To 10 ml of solution A, add 10 ml of Complies 1M sodium hydroxide or 1M the test. hydrochloric acid. In either case the mixture remains stable.

Complies the test.

Complies the test.

Complies the test.

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Table 2:- Evaluation of HPMC Polymers

Polymer batches Sr. No. Parameters Observation Opalescent, very low viscous colloidal solution Insoluble in hot water, 2. Solubility acetone, ethanol and slowly dissolves in cold water. Viscous solution of 8%w/v polymer was obtained. A clear brittle film forms upon evaporation of water. Complies Complies Complies 27 38 52 Complies Complies Complies HPMC K 15 Complies HPMC K 100 Complies

Synthesized HPMC

1.

Appearance

Complies

3.

Viscosity (cps) Film formation Loss on drying (%) pH

4.

5. 6.

5.6 6.8

7.2 7.5

8.4 8.0

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Infra red spectrum of synthesized and marketed HPMC polymer: The samples were prepared by potassium bromide pellets method by placing one drop of monomer between two potassium bromide pellets and scan for absorbance in the range 4000-400 cm-1.

Figure No.2: I.R. of synthesized HPMC polymer IR KBr cm-1 3450, 2920,2860, 2350, 1745, 1620, 1550, 1500, 1455, 1400, 1150, 1050, 950.

Figure No.3: I.R. Of marketed HPMC polymer IR KBr cm-1 3450, 2920, 2860, 2350, 1745, 1620, 1550, 1500, 1455, 1400, 1150, 1050, 950. Peak at 3450 cm-1 indicate the OH stretching of hydroxyl group and 1050 cm-1 alkane. Peak at 1745 cm-1 indicate the C-O stretching of carbonyl group of ester. indicate the OH bending of hydroxyl group. Another peak at 2920-2860 cm-1 indicates C-H stretching of

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Preparation of Diltiazem HCl granules:The weighed quantity of Diltiazem HCl (12g), lactose (16g), and sodium starch glycolate (2g) were mixed and sufficient quantity of 10%starch paste was added as binder. The damp mass formed was passed through sieve no 16 and was then dried in a hot air ovan at 600C for 2 hours and finally retained through sieve no 40. Evaluation of Diltiazem HCl granules:Evaluation of granules was done by measuring angle of repose7, bulk density8, tapped density9, flow rate10, Carrs index11. Bulk and tapped density were found that 0.864g/cm3, 0.762g/cm3 respectively which are indicative of good packing density. The results of angle of repose, flow rate and Carrs index were found to be 28.40o, 4.8g/sec and 11.80 respectively. These parameters showed good flow property of the granules. (See Table 3) Table 3:- Results Of Evaluation of Diltiazem Hcl Granules Sr.No. 1. 2. 3. 4. 5. Parameter Angle of Repose Flow rate Bulk Density Tapped Density Carrs index Observation 28.40o 4.8g/sec 0.762g/cm3 0.864g/cm3 11.80

Preparation of Diltiazem HCl tablet: The granules were mixed with magnesium stearate (1%) as a lubricant and compressed in multipunch minipress tablet punching machine to form tablets equivalent to 150 mg of Diltiazem HCl. Evaluation of Diltiazem HCl tablet: In-vitro studies of tablet hardness12, friability13, weight variation14, disintegration15 and drug content16 were performed. hardness, friability, disintegration time and drug content the results were found to be 6kg/cm3, 0.7%, 13min. 20sec, 98.50% respectively and the tablet also passes the test for weight variation. (See Table 4)

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Table 4:- Results Of Evaluation Of Diltiazem Hcl Tablets Sr. No. 1. 2. 3. 4. 5. Parameter Hardness Friability Weight variation Disintegration time Drug content Observation 6.0 Kg/cm3 0.7g 0.1% (0.146-0.167g) 7.5% 13 min 20 sec 98.50%

Coating of Diltiazem HCl tablets with synthesized aqueous solution of HPMC polymer17: Diltiazem HCl tablets were coated with developed aqueous solution of hydroxyl propyl methyl cellulose (HPMC) polymer. Preparation of coating Solution:- Polymer is soluble in water, slowly added the polymer to vigorously stirred water by using mechanical stirrer. Continue the agitation until the polymer solubilized; add propylene glycol or polyethylene glycol or both, then adjust volume up to 100 ml with water. Opacifier or coloring agent may be added after milling or dispersion in water. Coating Procedure:- Previously weighed 20 tablets per batch were taken in the coating pan. Tablets were coated by slowly spraying 20 ml of polymer solution on the tablet bed to gain weight on tablets after drying. The tablets were dried by blowing hot air, after drying, gain in tablet weight was measured and release pattern were observed as per USP. Dissolution Study18: Dissolution study was conducted as per USP in different buffers of pH 1.2 and pH 6.8using tablet dissolution apparatus, disso 2000, make labIndia. Dissolution pattern of uncoated, synthesized HPMC coated (8%) observed and compared with marketed HPMC K-100, HPMC K-15 coated Diltiazem HCl tablet have been done. (See Table 5 and Graph 1)

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Table 5:- Dissolution study of uncoated, synthesized HPMC coated and marketed HPMC K-100 and HPMC K-15 Diltiazem HCl coated tablets Sr. No. Time in Minute Buffers used Cumulative % release of Diltiazem HCl 8% coated tables Uncoate d tablets Synthesized HPMC coated tab. 1 2 3 4 5 6 7 8 9 10 11 12 0 30 60 120 150 180 210 240 270 300 330 360 pH 1.2 pH 1.2 pH 1.2 pH 1.2 pH 1.2 pH 1.2 pH 6.8 pH 6.8 pH 6.8 pH 6.8 pH 6.8 pH 6.8 _ _ _ _ _ _ _ _ 0 87.55 96.78 0 8.87 18.11 26.34 49.98 52.36 65.90 72.88 81.32 87.67 91.18 93.73 Batches Marketed HPMC K-100 coated tab. 0 9.95 25.37 34.98 56.28 66.62 72.90 79.48 83.74 89.52 91.65 _ Marketed HPMC K-15 coated tab. 0 9.86 19.64 36.74 58.46 70.92 82.14 90.68 92.44 _ _ _

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Figure No.4: Dissolution study of uncoated, synthesized, marketed HPMC K 100 and HPMC K 15 tablets

Dissolution Study
120 100 Cumulative % drug release 80 Uncoated 60 40 20 0 0 30 60 120 150 180 210 240 270 300 330 360 Synthesized HPMC HPMC K 100 HPMC K 15

Result and Discussion: The hydroxypropyl methyl cellulose (HPMC) polymers synthesized using ingredients in different ratio and their different parameters were evaluated. The IR studies of different polymers showed that the developed HPMC polymers have the presence of propyl and methyl groups indicating the conversion of cellulose to HPMC polymer. The Diltiazem HCl granules were prepared and evaluated for physical parameters like bulk density, tapped density results were found to be 0.864g/cm3, 0.762g/cm3 respectively which is indicative of good packing density. The results of angle of repose, flow rate and Carrs index were found to be 28.40o, 4.8g/sec and 11.80 respectively. These parameters showed good flow property of the granules. The granules were compressed to form the Diltiazem tablets and evaluated for hardness, friability, disintegration time and drug content the results were found to be 6kg/cm3, 0.7%, 13min. 20sec, 98.50% respectively and the tablet also passes the test for weight variation.

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The synthesized HPMC polymer used as coating material for sustained release Diltiazem HCl tablet and compared with different grades of marketed polymer HPMC K 100 and HPMC K 15. We found that the synthesized HPMC polymer is superior for sustained release pattern than marketed HPMC K 100 and HPMC K 15 as per drug dissolution study. The following table shows the Cumulative % release of Diltiazem HCl 8% coated tables, where the drug dissolution from synthesized HPMC polymer (93.73% / 12 hours) is superior than the other grade of HPMC K-100 (91.65% /11 hours) and HPMC K-15 (92.44% / 9 hours) polymer. Hence the synthesized HPMC polymer is superior for coating of sustained release Diltiazem HCl tablet. Conclusion: It can be concluded that, synthesized HPMC coated Diltiazem HCl tablets are superior for sustained release pattern than marketed HPMC K 100 and HPMC K 15 as per drug dissolution study. References: 1. Seitz J.A., Mehta S. P., Yeager J. L., Tablet Coating. In: Lachman L, Liberman HA, Kanig JL, editors. The Theory and Practice of Industrial Pharmacy. 3rd ed. Philadelphia: Lea and Febiger; 1986. p. 346. 2. Stuart C, Porter, Charles H, Coating of Pharmaceutical Solid-Dosage forms. In: HA, Lachman L, Schwartz JB, editors. Pharmaceutical dosage forms: Tablets. 2 York: Marcel Dekker, Inc. 1990; 3: 93. 3. Danhorm W., Preparation of standard cotton cellulose and the proposed method of analysis, Indian Eng Chem. ,1923; Vol. 15(7) : 748-751. 4. Sherff R., Process for synthesis of water soluble methyl, hydroxyl, propyl ether of cellulose. US Patent 1989; 3453261 5. Tenj J., Process for making water soluble alkylhydroxyalkylcellulose ether US Patent 1976;409625. Liberman
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17. James A. S., Mehta S. P., James Y. L., Tablet Coating. In: Lachman L, Liberman H, Kanig J, editors, The Theory and Practice of Industrial Pharmacy. 3rd ed. Philadelphia: Lea and Febiger; 1987. p. 352-54. 18. USP 30-NF25. United States Pharmacopoeial Convection Inc. Rockville, MD; 2007.p.277.

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