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

I I N N T T E E R R N N AA T T I I O O N N AA L L J J O O U U R R N N AA L L O O F F U U N N I I V V E E R R S S AA L L

P P H H AA R R M M AA C C Y Y AA N N D D L L I I F F E E S S C C I I E E N N C C E E S S

Research Article!!!

Rece ived: 14-09-2011; Accepted: 16-09-2011; Published Online: 17-09-2011

SYNTHESIS OF HPMC AND ITS APPLICATION AS COATING MATERIAL FORSUSTAINED 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

Keywords:

HPMC, synthesis, coating,sustained release, diltiazem

HCl

For Correspondence:

Barde L.N.

Sharad Pawar College of

Pharmacy, Wanadongri,Hingna Road, Nagpur-

441110

E-mail:[email protected]

ABSTRACT

The Polymeric films are finding an ever increasing range of applications in research, development and dosage form design tocoat drug particles to produce product with a sustained release,

pharmaceutical therapeutic action. For synthesis of HPMC, Rawmaterial 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 morereactive. Then it is treated with methyl chloride in which sodium is

replaced by hydroxymethyl group, by undergoing nucleophillicsubstitution reaction to produced intermediate product and sodiumchloride as bi-product. Then the intermediate is reacted with

propylene oxide then again by undergoing nucleophillicsubstitution reaction, propylene oxide replaces sodium of alkalicellulose and obtaining hydroxyl propyl methyl cellulose (HPMC)

polymer. The manner in which methyl chloride and propyleneoxide are added to alkali cellulose is described by two terms, thedegree of substitution and the molar substitution. The synthesizedHPMC polymer used as coating for sustained release DiltiazemHCl tablet and compared with different grades of polymer HPMCK 100 and HPMC K 15. We found that the synthesized HPMC

polymer is superior for sustained release pattern than marketedHPMC K 100 and HPMC K 15 as per drug dissolution study.

Pharmaceutical Sciences


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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. Coating 1 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 gasinlet and a reflux condenser. At the bottom of this glass assembly, there is a heating mantle for

maintaining temperature of reaction.

Figure 1: Reaction assembly for synthesis of HPMC polymer


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Synthesis of Cellulose from Cotton and Wood Pulp 3 :

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 60-70 C. Then this solution was

filtered and particles which were retained on the filter paper were washed with distilled water 3-

4 times and dried it in a hot air oven at 30-35 C 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 70-80 C. Then this solution was

filtered and particles which were retained on the filter paper were washed with distilled water 3-

4 times and dried it in a hot air oven at 30-35 C for 10 -15 minutes. After that it was finelycrushed in mortar and pestle and weighed.

Synthesis of HPMC polymer 4,5 :

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 70-80 0C. 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 polymer 6:

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.

Identification test Observation

I II III IV

1. 10 ml of solution A is heated in water

bath with constant stirring at a

temperature above 50 oC, the solution

becomes cloudy or a flocculent

precipitate is formed. On cooling, the

solution becomes clear or slightly

opalescent.

Complies

the test.

Complies

the test.

Complies

the test.

Complies

the test.

2. Place 1ml of solution A on glass-plate.

After evaporation of the water, a thin

film is produced.

Complies

the test.

Complies

the test

Complies

the test.

Complies

the test.

3. To 10 ml of solution A, add 0.3 ml of

2M acetic acid and 2.5 ml of 10% w/v

solution of tannic acid; a yellowish

white flocculent precipitate is produced

which dissolves in 6M ammonia

Complies

the test.

Complies

the test.

Complies

the test.

Complies

the test.

4. To 10 ml of solution A, add 10 ml of

1M sodium hydroxide or 1M

hydrochloric acid. In either case the

mixture remains stable.

Complies

the test.

Complies

the test.

Complies

the test.

Complies

the test.


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Table 2:- Evaluation of HPMC Polymers

Sr.

No.Parameters

Polymer batches

ObservationHPMC K

15

HPMC

K 100Synthesized HPMC

1. AppearanceOpalescent, very low

viscous colloidal solutionComplies Complies Complies

2. Solubility

Insoluble in hot water,

acetone, ethanol and

slowly dissolves in cold

water.

Complies Complies Complies

3.Viscosity

(cps)

Viscous solution of

8%w/v polymer was

obtained.

27 38 52

4. Filmformation

A clear brittle film formsupon evaporation of water.

Complies Complies Complies

5.Loss on

drying (%)- 5.6 7.2 8.4

6. pH - 6.8 7.5 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 indicate the

OH bending of hydroxyl group. Another peak at 2920-2860 cm-1 indicates C-H stretching of

alkane. Peak at 1745 cm-1 indicate the C-O stretching of carbonyl group of ester.


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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 60 0C for 2 hours

and finally retained through sieve no 40.

Evaluation of Diltiazem HCl granules:-

Evaluation of granules was done by measuring angle of repose 7, bulk density 8, tapped density 9,

flow rate 10, Carrs index 11 . Bulk and tapped density were found that 0.864g/cm 3, 0.762g/cm 3

respectively which are indicative of good packing density. The results of angle of repose, flow

rate and Carrs index were found to be 28.40 o, 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. Parameter Observation

1. Angle of Repose 28.40 o

2. Flow rate 4.8g/sec

3. Bulk Density 0.762g/cm 3

4. Tapped Density 0.864g/cm 3

5. Carrs index 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 hardness 12 , friability 13, weight variation 14, disintegration 15 and drug

content 16 were performed. hardness, friability, disintegration time and drug content the results

were found to be 6kg/cm 3, 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. Parameter Observation

1. Hardness 6.0 Kg/cm 3

2. Friability 0.7g 0.1%

3. Weight variation (0.146-0.167g) 7.5%

4. Disintegration time 13 min 20 sec

5. Drug content 98.50%

Coating of Diltiazem HCl tablets with synthesized aqueous solution of HPMC polymer 17:

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 100ml 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 Study 18:

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

inMinute

Buffers

used

Cumulative % release of Diltiazem HCl 8% coated tables

Uncoated tablets

BatchesSynthesized

HPMC coated

tab.

Marketed

HPMC K-100

coated tab.

Marketed

HPMC K-15

coated tab.

1 0 pH 1.2 0 0 0 0

2 30 pH 1.2 87.55 8.87 9.95 9.86

3 60 pH 1.2 96.78 18.11 25.37 19.64

4 120 pH 1.2 26.34 34.98 36.74

5 150 pH 1.2 _ 49.98 56.28 58.46

6 180 pH 1.2 _ 52.36 66.62 70.92

7 210 pH 6.8 _ 65.90 72.90 82.14

8 240 pH 6.8 _ 72.88 79.48 90.68

9 270 pH 6.8 _ 81.32 83.74 92.44

10 300 pH 6.8 _ 87.67 89.52 _

11 330 pH 6.8 _ 91.18 91.65 _

12 360 pH 6.8 _ 93.73 _ _


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

HPMC K 15 tablets

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.

0

20

40

60

80

100

120

0 30 60 120 150 180 210 240 270 300 330 360

C u m u

l a t i v e

% d

r u g r e

l e a s e

Dissolu t ion St ud y

Uncoated

Synt hesized HPM C

HPM C K 100

HPM C K 15


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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 :

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JL, editors. The Theory and Practice of Industrial Pharmacy. 3 rd ed. Philadelphia: Lea and

Febiger; 1986. p. 346.

2. Stuart C, Porter, Charles H, Coating of Pharmaceutical Solid-Dosage forms. In: Liberman

HA, Lachman L, Schwartz JB, editors. Pharmaceutical dosage forms: Tablets. 2 nd ed. New

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.


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6. Indian Pharmacopoeia, 6 th ed. Controller of Publications, Govt. of India, New Delhi. 2007; 2:

1208-1209.

7. Reddy M. N., Shirwaikar A. A., A polymer for microencapsulation of Diltiazem HCl for

sustained release by emulsion-solvent evaporation technique, Indian Journal of Pharmaceutical

Sciences, 2000; Vol. 62(4); 2000: 308-310.

8. Staniforth J. Powder flow. In: Aulton M. E., editors. Pharmaceutics: The science of dosage

form design, 2 nd ed. London: Churchill Livingstone; 2002. p. 199.

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form design, 2nd ed. London: Churchill Livingstone; 2002. p. 200.

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and Practice of Industrial Pharmacy. 3 rd ed. Philadelphia: Lea and Febiger; 1987. p. 315-316.





13. Gorden RE, Rosanke TW, Fonner DE.Granulation Technology and tablet characterization

In: Liberman HA, Lachman L, Schwartz JB, editors. Pharmaceutical Dosage Forms: Tablets.2 nd

ed. New York: Marcel Dekker; 1989; 2: 327.

14. Wells JL.Tablet testing. In: Swabrick J, Boylan JC, editors. Encyclopedia of Pharmaceutical

Technology. 2 nd ed.1988; 14: 411.

15. Indian Pharmacopoeia, 4 th ed. Controller of Publications; of Govt. of India, New Delhi: 1996;

1: 734.

16. Indian Pharmacopoeia, 4 th ed. Controller of Publications; of Govt. of India, New Delhi, 1996;

1: 864.


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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. 3 rd ed. Philadelphia: Lea and Febiger;

1987. p. 352-54.

18. USP 30-NF25. United States Pharmacopoeial Convection Inc. Rockville, MD; 2007.p.277.

diltiazem coated

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