formulation of aceclofenac matrix...

------ --- -~-~--~~-~----.

Chapter 5

Formulation

of

Aceclofenac Matrix Tablet

containing

Synthetic and Natural

Polymers

Chapter 5 Aceclofenac Matrix Tablet Containing Synthetic & Natural Polymers

5. Formulation of Aceclofenac Matrix Tablet containing

Synthetic and Natural Polymers.

5.1. Introduction:

Several matrixes based sustained release products of Aceclofenac have been reported

based on their use as either a hydrophilic or hydrophobic polymers [1-7]. The reported

sustained release formulations of Aceclofenac did not involve any attempt to prevent

drug release in the upper GI tract. The matrix system of a polymer intended with drugs

provides long duration of treatment and reduced adverse effects in patients. An attempt

has been made here to achieve a better therapeutic profile through tablets with various

viscosity of HPMC, Guar gum and ethyl cellulose. The in vitro release of the

experimental formulation, which showed a release profile similar to that of the

innovator's product, was compared with that of a commercially sustained release

formulation. Furthermore, the purpose of the study was also to establish an in vitro

release rate profile for various prepared Aceclofenac matrix sustained release tablet and a

commercial formulation.

In India natural gums and mucilage have been well known for their medicinal use. In the

modem era they are widely used in the pharmaceutical industry as thickeners, water

retention agents, emulsifier, gelling agent, suspending agents, binders, film formers and

sustained release agents. Apart from their use in the medicinal products, other uses have

been found in cosmetics, textiles, paints and paper-making. Demand for these substances

is increasing and new sources are being developed. India, due to its geographical and

environmental position, has traditionally been a good source for such products among the

The Sustained Delayed Release of Anti-inflammatory Drugs 118


Asian countries. Natural gums and mucilage are preferred to semi-synthetic and synthetic

excipient due to their lack of toxicity, low cost, ready availability, soothing action and

non-irritant nature [8 - 11].

Though a variety of polymeric substances are available to serve as release retarding

matrix material, there is a continued need to develop new, safe and effective release

retarding material. Oral drug delivery systems continue to dominate the market despite

the advancements made in newer drug delivery systems such as transderrnal, liposome,

microspheres, etc.

5.1.1. Disadvantages of synthetic polymers

The synthetic polymers have certain disadvantages such as high cost, toxicity,

environmental pollution during synthesis, non-renewable sources, side effects, Jess

patient compliance.

Acute and chronic adverse effects (skin and eye irritation) have been observed in

workers handling the related substances methyl methacrylate and poly-(methyl

methacrylate) (PMMA) [12].

2 Reports on adverse reactions to povidone primarily concern the formation of

subcutaneous granulomas at the injection site formulated with povidone. Evidence

also exist that povidone may accumulate in organs following intramuscular

injections [ 13].

3 Acute oral toxicity studies in animals indicated that carbomer-934P had a low oral

toxicity at a dose up to 8 g/kg when administered without fatalities occurring.

Carbomer dust is irritating to the eyes, mucous membranes and respiratory tract. So,

gloves, eye protection and dust respirator are recommended during handling [14].



4 Studies in rats have shown that 5% polyvinyl alcohol aqueous solution injected

subcutaneously can cause anemia and can infiltrate into various organs and tissues

[I 5].

5 Some disadvantages of biodegradable polymers in tissue engineering application

are their poor biocompatibility, release of acidic degradation products, poor process

ability and loss of mechanical property very early during degradation. It was studied

that poly glycolides, polylactides and their co-polymers have an acceptable

biocompatibility but shown systemic or local reactions due to acidic degradation

products. An initial mild inflammatory response has been reported by using poly

(propylene fumarate) on rat implant studies [I 6].

5.1.2. Advantages of natural gums & mucilages (17- 19]

The advantages of natural plant based materials includes

]. Biodegradable

2. Biocompatible and non toxic

3. Low cost

4. Renewable source

5. Environmental-friendly processing

6. Local availability (especially in developing countries)

7. Better patient tolerance as well as public acceptance

8. From edible sources


- -----------------------------


5.1.3. Disadvantages of natural gums & mucilages (20]

I. Microbial contamination

2. Batch to batch variation

3. Uncontrolled rate of hydration

4. Thickening nature

5. Drop in viscosity on storage



5.2. Introduction to Methocel K4M [21 ].

5.2.1. Synonyms: HPMC, Pharmacoat, Metolose, Methocel.

5.2.2. Chemical name & CAS registry no.: Cellulose, 2- Hydroxypropylmethylether

(9004-65-3)

5.2.3. Empirical formula:

The Ph. Eur. describes Hydroxypropylmethylcellulose (HPMC) as partly -0-methylated

& -0- (2-hydroxypropylated) cellulose. It is available in a several grades, which vary in

viscosity & extent of substitution. Grades may be distinguished by appending a number

of indicative of apparent viscosity, in milipascal seconds of 2% w/v solution measured at

20°C.

5.2.4. Molecular weight: Approx.l 0000-1500000 daltons.

5.2.5. Description: Tasteless, odorless, white or creamy- white coloured fibrous or

granular powder.

5.2.6. Functional category: Film former, rate-controlling polymer for sustained release,

stabilizing agent, suspending agent, fixative, tablet binder & filler and viscosity

increasing agent.

5.2.7. Solubility: Soluble in cold water. forming a viscous colloidal solution, practically

insoluble in chloroform, ethanol (95%) and ether, but soluble in mixture of ethanol and

dichloromethane, mixture of methanol and dichloromethane. Typical viscosity value of

2%w/v aqueous solution of methoceL viscosity at 20°C.


----------------------------------------------------


Methocel grades Viscosity (mPas)

•!• K4M 3000-5600.

•!• Kl5M 12000-21000.

•!• K I OOM 80000-120000.

5.2.8. Storage: At temperature not exceeding 32°C in dry area from all sources.

5.2.9. Safety: Non-toxic and Non-irritant.

•!• LD 50(Mouse IP) : 5glkg

•!• LD 50(Rat IP) : 5.2g/kg.

5.2.10. Incompatibilities: With some Oxidizing agents.

5.2.11. Stability: Heat stable and Impact strength.

5.2.12. Pharmaceutical uses:

HPMC is widely used in oral and topical pharmaceutical formulations. In oral products,

Hydroxy propyl methyl cellulose is primarily used as tablet binder in the film coating and

as an extended release tablet matrix concentration of between 2-5% may be used as a

binder in either wet or dry granulation processes. High viscosity grades may be used to

retard the release of drug from the matrix at level of I 0-80% w/w in tablet and capsules.

Hydroxy propyl methylcellulose is also used as suspending agent and thickening agent in

topical preparation, particularly ophthalmic preparation. It is also widely used in

cosmetics and food products.



5.3 Introduction to Guar gum [22].

5.3.1. Non proprietary name: Guar galactomannan.

5.3.2. Europan Pharmacopoeia: Guar galactomannan

5.3.3. United state Pharmacopoeia: Guar Gum

5.3.4. Synonyms: Galactosol, Guar Flour, Jaguar gum.

5.3.5. Chemical name: Galactomannan polysaccharide.

5.3.6. Empirical formula: (C6HI206)n

5.3.7. Molecular weight: Approx. 220000

5.3.8. Functional category:

Suspending agent, tablet binder, tablet disintegrant, viscosity increasing agent.

5.3.9. Pharmacopoeia:

BP, Eur. Pharmacopoeia, and USPNF.

5.3.10. Description:

Odorless or a nearly odorless, white to yellowish-white powder with a bland taste.

5.3.11. Aqueous viscosity: 4860 cps.

5.3.12. Solubility:

Practically insoluble in a organic solvents. In cold or hot water, guar gum disperses and

swells almost immediately to form a highly viscous, thixotropic sol.



5.3.14. Stability and storage condition:

Aqueous guar gum dispersion have a buffering action and are stable between pH 4.0 and

10.5 however, prolonged heating reduces the viscosity of dispersion. Guar gum powder

should be stored in a well-closed container in a cool, dry place.

5.3.15. Incompatibilities:

It is compatible with most other plant hydrocolloids such as tragacanth. Guar gum is

compatible with acetone, tannins, strong acids and alkalis acetone, tannins, strong acids

and alkalis.

5.3.16. Safety:

It is generally regarded as a nontoxic and non-irritant material although excessive oral

consumption may cause gastrointestinal disturbance such as flatulence, diarrhea, or

nausea.

5.3.17. Application:

Guar gum is widely used in oral and topical pharmaceutical formulation. It has also been

investigated in the preparation of sustain release matrix tablets in the place of cellulose

derivatives such as methyl cellulose.

In pharmaceutical, guar gum is used in solid-dosage forms as binder and disintegrant. In

oral or topical products as a suspending, thickening and stabilizing agent.



5.4. Introduction to Ethyl Cellulose [23 - 51].

Ethyl Cellulose Prepared at the 26th JECFA (1982), published in FNP 25 (1982) and

FNP 52 (1992). Metals and arsenic specifications revised at the 57th JECFA (2001). A

group ADI 'not specified' was established at the 35th JECF A (1989).

Ethyl Cellulose is a non-ionic ethyl ether of cellulose, soluble in a wide range of organic

solvents. Typically, ethylcellulose is used as a non-swellable, insoluble component in

matrix or coating systems. When water soluble binders cannot be used in dosage

processing because of water sensitivity of the active ingredient, ethylcellulose is often

chosen.

Ethylcellulose can be used to coat one or more active ingredients of a tablet to prevent

them from reacting with other materials or with one another. It can prevent discoloration

of easily oxidizable substances such as ascorbic acid, allowing granulations for easily

compressed tablets and other dosage forms. Ethylcellulose can be used on its own or in

combination with water-soluble polymers to prepare sustained release film coatings that

are frequently used for the coating of micro-particles, pellets and tablets.

DEFINITION: Ethyl ether of cellulose, prepared from wood pulp or cotton by treatment

with alkali and ethylation of the alkali cellulose with ethyl chloride. The article of

commerce can be specified further by viscosity.

5.4.1. Nonproprietary Names:

BP: Ethylcellulose

PhEur: Ethylcellulose

USP-NF: Ethylcellulose


------------------~-------


5.4.2. Synonyms:

Aquacoat ECD; Aqualon; Ashacel; E462; Ethocel; ethylcellulosum; Surelease.

5.4.3. Chemical names: Cellulose ethyl ether, ethyl ether of cellulose

5.4.4. C.A.S. number: 9004-57-3

5.4.5. Empirical Formula and Molecular Weight

Ethylcellulose is partially ethoxylated. Ethylcellulose with complete ethoxyl substitution

(OS= 3) is C12H2J06 (C12H220s)n C12H230s where n can vary to provide a wide variety

of molecular weights. Ethylcellulose, an ethyl ether of cellulose, is a long-chain polymer

of b-anhydroglucose units joined together by acetal linkages.

5.4.6. Assay: Not less than 44% and not more than 50% of ethoxyl groups (-OC2H5) on

the dried basis (equivalent to not more than 2.6 ethoxyl groups per anhydroglucose unit).

5.4.7. DESCRIPTION: Free-flowing, white to light tan powder

5.4.8. IDENTIFICATION:

5.4.8.1. Solubility: Practically insoluble in water, in glycerol, and in propane-] ,2-diol,

but soluble in varying proportions in certain organic solvents, depending upon the

ethoxyl content. Ethyl cellulose containing less than 46-48% of ethoxyl groups is freely

soluble in tetrahydrofuran, in methyl acetate, in chloroform, and in aromatic hydrocarbon

ethanol mixtures. Ethylcellulose containing 46-48% or more of ethoxyl groups is freely

soluble in ethanol, in methanol, in toluene, in chloroform, and in ethyl acetate.

5.4.8.2. Film forming test: Dissolve 5 g ofthe sample in 95 g of an 80:20 (w/w) mixture

of toluene-ethanol. A clear, stable, slightly yellow solution is formed. Pour a few ml of

the solution onto a glass plate, and allow the solvent to evaporate. A thick, tough

continuous, clear film remains. The film is flammable.


----------------------------------


5.4.8.3. pH: Neutral to litmus (1 in 20 suspension)

0

5.4.8.4. Loss on drying: Not more than 3% (105 , 2 h)

5.4.8.5. Sulfated ash: Not more than 0.4%, Test 1 g of the sample (Method I)

5.4.8.6. Lead: Not more than 2 mg/kg

5.4.9. Functional Category

Coating agent, flavoring agent, tablet binder, tablet filler, and viscosity increasing agent.



Table 5.1. Various grades of Ethyl cellulose with their applications.

Grade

EC N 7

Ph arm

EC N 10

Ph arm

EC N 14

Ph arm

EC N 22

Ph arm

EC N 50

Ph arm

EC N

100

Ph arm

EC T 10

Ph arm

Viscosity Applications

(mPas)%

w/w

6-8

8- II

12- 16

18-24

18-24

80- 105

8- II

Microencapsulation,

Tablet Coating- Film coating for sustained release.

Tablet Binder - Plastic flow, suitable for direct compression,

injection molding and melt extrusion.

Taste Masking

Directly compressible, micronized grade with high ethoxy

content and low viscosity for optimum compactibility and good

powder flow. Eliminates the need for solvents m direct

compression controlled release matrices.


- ---------------------------------.


5.4.10. Applications in Pharmaceutical Formulation or Technology

The main use of ethyl cellulose in oral formulations is as a hydrophobic coating agent for

tablets and granules. Ethyl cellulose coatings are used to modify the release of a drug, to

mask an unpleasant taste, or to improve the stability of a formulation; for example, where

granules are coated with ethyl cellulose to inhibit oxidation. Modified-release tablet

formulations may also be produced using ethyl cellulose as a matrix former.

Ethyl cellulose, dissolved in an organic solvent or solvent mixture, can be used on its

own to produce water-insoluble films. Higher-viscosity ethyl cellulose grades tend to

produce stronger and more durable films. Ethyl cellulose films may be modified to alter

their solubility, by the addition of hypromellose or a plasticizer.

Drug release through ethyl cellulose-coated dosage forms can be controlled by diffusion

through the film coating. This can be a slow process unless a large surface area (e.g.

pellets or granules compared with tablets) is utilized. In those instances, aqueous ethyl

cellulose dispersions are generally used to coat granules or pellets. Ethyl cellulose-coated

beads and granules have also demonstrated the ability to absorb pressure and hence

protect the coating from fracture during compression.

High-viscosity grades of ethylcellulose are used in drug microencapsulation. Release of a

drug from an ethylcellulose microcapsule is a function ofthe microcapsule wall thickness

and surface area. In tablet formulations, ethylcellulose may additionally be employed as a

binder, the ethylcellulose being blended dry or wet granulated with a solvent such as

ethanol (95%). Ethylcellulose produces hard tablets with low friability, although they

may demonstrate poor dissolution. Ethylcellulose has also been used as an agent for

delivering therapeutic agents from oral (e.g. dental) appliances. In topical formulations,



ethylcellulose JS used as a thickening agent in creams, lotions, or gels, provided an

appropriate solvent is used. Ethylcellulose has been studied as a stabilizer for emulsions.

Ethylcellulose is additionally used in cosmetics and food products.

5.4.11. Stability and Storage Conditions

Ethylcellulose is a stable, slightly hygroscopic material. It is chemically resistant to

alkalis, both dilute and concentrated, and to salt solutions, although it is more sensitive to

acidic materials than are cellulose esters.

Ethylcellulose is subject to oxidative degradation in the presence of sunlight or UV light

at elevated temperatures. This may be prevented by the use of antioxidant and chemical

additives that absorb light in the 230-340nm range.

5.4.12. Incompatibilities

Incompatible with paraffin wax and microcrystalline wax.

5.4.13. Method of Manufacture

Ethylcellulose is prepared by treating purified cellulose (sourced from chemical-grade

cotton linters and wood pulp) with an alkaline solution, followed by ethylation of the

alkali cellulose with chloroethane as shown below, where R represents the cellulose

radical:

5.4.14. Safety

Ethylcellulose is widely used in oral and topical pharmaceutical formulations. It is also

used in food products. Ethylcellulose is not metabolized following oral consumption and

is therefore a noncalorific substance. Because ethylcellulose is not metabolized it is not

recommended for parenteral products; parenteral use may be harmful to the kidneys.



Ethylcellulose ts generally regarded as a nontoxic, non-allergenic, and nonirritating

material. As ethylcellulose is not considered to be a health hazard, the WHO has not

specified an acceptable daily intake. The highest reported level used in an oral product is

308.8 mg in an oral sustained release tablet.



5.5. Aim of present work

The present work was undertaken usmg various pharmaceutical excipient m the

formulation of Aceclofenac tablet for pharmaceutical dosage form. So, plan of work was

carried out as follows;

1. Formulation of Aceclofenac tablet containing various polymer like HPMC

(different grades), Guar Gum and Ethyl cellulose using at various concentrations.

2. Pharmaceutical Formulation Parameters: Hardness, Friability, Formulation of

sustained release tablet of Aceclofenac using different amount of HPMC, Guar

Gum and Ethyl Cellulose, dissolution profile of tablets.

3. Stability study



5.6. Methods:

5.6.1. Preparation ofMatrix tablets

The tablets were prepared by wet granulation technique. The compositions of the tablet

formulations are given in Table 5.2. Weighed amounts of Aceclofenac, retardant (HPMC,

Guar gum, ethylcellulose and diluents (lactose), were taken into a bowl by passing

through a 40 mesh screen and mixed manually for 5 min. Then the blend was granulated

with PVPK-30 using water as the granulating agent. The mass was dried in a hot air oven

at 50°C and sieved through a 30 mesh screen. Magnesium stearate was then added to the

dried, sieved granules and mixed for about 5 min in a poly-bag. The produced mixture

was compressed into tablets using a 12 station tablet compression machine, (Rotary

Tablet Machine, Rimek - II, Karnavati Engg., Ahmedabad, India) equipped with an II

mm biconcave-faced punches. The selected batch (Batch G) was coated using the coating

formula as given in Table 5.3 and using a laboratory coater under controlled condition.

The efficiency of mixing was verified by the determination of drug content.

5.6.2. Coating

Batch G was coated using a laboratory coater (Model GAC-250, Gansons ltd, Mumbai,

India) under controlled condition.



Table 5.2. Composition of sustained release tablet formulation.

Ingredients A B c D E F G H I J

Aceclofenac 200 200 200 200 200 200 200 200 200 200

Methocel 25 -- --- --- -- -- 40 -- -- --

K4M

Methocel -- 25 -- -- -- -- -- 15 -- --

K15M

Methocel -- -- 20 -- -- -- -- -- 10 --

K100M

Guar gum -- -- -- 30 -- -- -- -- -- 60

Ethyl -- -- -- -- 20 -- -- -- -- --

cellulose

HPMC -- -- -- -- -- 50 -- -- -- --

15cps

Lactose 62.5 62.5 67.5 57.5 67.5 37.5 47.5 72.5 77.5 27.5

Povidone 7.5 7.5 7.5 7.5 7.5 7.5 7.5 7.5 7.5 7.5

Purified q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s.

water

Mg- 5 5 5 5 5 5 5 5 5 5

stearate

Total 300 300 300 300 300 300 300 300 300 300



Table 5.3. Composition of Coating containing Sustained Release Tablet.

Ingredients Quantity Per Tablet (mg)

H.P.M.C (6CPS) 7.5

Isopropyl alcohol 0.13

Methylene chloride 0.32

Titanium dioxide 1.65

PEG 6000 0.85

Castor oil 2.50

Ponceaur 4 R supra color 0.9

5.6.3. Physiochemical characterization of tablets

The weight variation was evaluated on I 0 tablets using an electronic balance (Digital

Balance- AUX -220 Uniblock Technology, Shimazdu, Japan). Tablet hardness was

determined for 10 tablets using a Monsanto (Standard type) tablet hardness tester and

Friability Test Apparatus USP XXIII, Model EF2, Friabilator, Electrolab India, Mumbai,

India, for 4 min at 25 rpm.

5.6.4. In-vitro release rate studies

The in vitro dissolution study was carried out using USP Type II dissolution apparatus.

The study was carried out in 900 ml of phosphate buffer pH 7.5 from 2 to 12 h. The

dissolution medium was kept in a thermostatically controlled water bath, maintained at

37 ± 0.5°C. The paddle was lowered so that the lower end of the stirrer was 25 mm above

the base of the beaker. The pre-weighed tablet was then introduced into the dissolution


----------


jar and the paddle was rotated at I 00 rpm. At different time intervals, 5 ml sample was

withdrawn and analyzed spectrophotometrically at 275 nm for drug release. At each time

of withdrawal, 5 ml of fresh corresponding medium was replaced into the dissolution

flask.

5.6.5. Stability studies

Stability studies were conducted on Aceclofenac matrix tablet containing 11.4% of

HPMCK4M (G) to assess their stability with respect to their physical appearance, drug

content and drug release characteristics after storing them at 40° C/ 75% RH for 6

months. Samples were withdrawn at 0, 90 and 180 days for evaluation of appearance,

drug content and in vitro drug release.


------------------------------------


5. 7. RESULTS AND DISCUSSION

5. 7 .1. Results of Physical Properties:

The physical properties of the finished good are shown in Table 5.4. The following

parameters; weight uniformity, drug content, thickness, hardness and friability were

calculated. Tablets prepared by wet granulation were uniform in weight and thickness

and complied with the USP 32 requirements. From the obtained data in Table, the

percentage of drug contents in prepared tablets was found to be within the range of 99.08

to 104.5%. The values of the disintegration time of the prepared tablets were within the

allowable range of the USP 32 for uncoated tablets. The friability of the tablets was

higher than marketed products. Generally, the values for friability ranged from 0.12 to

0.45%, which was an acceptable value according to the USP 32 requirements. The

prepared tablets showed hardness levels in the range of3.0 to 7.0 kg/sq.cm.



Table 5.4. Physical properties of the prepared Aceclofenac sustained release tablets.

Batch Code Weight variation Thickness Hardness Friability (%)

(%) (mm) (kg/cm2)

A 300± 2.0 3.9 ± 0.2 5-6 0.24

B 302 ± 2.5 3.8 ± 0.2 5-7 0.26

c 304 ± 1.5 3.6 ± 0.2 4-7 0.12

D 299± 2.0 3.6 ± 0.2 5-6 0.15

E 302 ± 2.5 3.7± 0.2 3-5 0.45

F 300 ± 2.5 3.7 ± 0.2 5-7 0.20

G 300 ± 1.5 3.6 ± 0.2 5-6 0.20

H 301 ± 2.5 3.7 ± 0.2 5-6 0.35

I 300 ± 2.0 3.7 ± 0.2 4-6 0.15

J 303 ± 1.5 3.8 ± 0.2 5-6 0.25



5.7.2. Results of Assay & In vitro Drug Release:

Aceclofenac is highly soluble (199mg/ 250 ml) in an alkaline medium (pH 6.5-7 .5) and

is reported. Therefore, dissolution studies were carried out in a phosphate buffer pH (7.5)

for 0 -12 h. This medium was considered as most suitable as the drug was freely soluble

at this pH and it also mimics the alkaline environment of the small intestine. The

selection of wet granulation technique for matrix tablet preparation was based on a

previously reported study which suggested wet granulation in time and energy

consumption when compared to direct compression. In our study, the use of water as a

granulating vehicle was based on the partial solubility of PVPK-30 in this granulating

vehicle which resulted in providing the necessary adhesion between the various matrix

components and precluded the use of a separate binder.



Table 5.5. Assay and in vitro release profile of the prepared Aceclofenac sustained

release tablets.

Batch Assay % %Drug %Drug %Drug %Drug %Drug Code (%) Drug released Released released released released

Release (After 2 (After 4 (After 6 (After 8 (After 12 (At h) h) h) h) h) time zero)

A 104.5 ± 0 32 ± 1.5 49 ± 1.7 71 ± 2.0 86 ± 2.2 99± 2.5

0.35

B 99.08 ± 0 16± 0.5 27 ± 0.8 31 ± 1.0 44 ± 1.3 54± 1.5

0.39

c 99.75 ± 0 9± 0.1 19 ± 0.5 27 ± 0.7 40 ± 1.0 45 ± 1.3

0.42

D 99.33 ± 0 13 ± 0.5 23 ± 0.7 33 ± 0.8 48 ± 1.5 60 ± 1.7

0.50

E 99.46 ± 0 22 ± 0.8 41 ± 1.0 73 ± 1.5 85 ± 1.8 98 ± 2.0

0.49

F 100.05 0 51± 2.0 75 ± 2.5 87 ± 2.5 96± 2.8 99 ± 3.0

± 0.34

G 100.75 0 22 ± 0.8 40 ± 1.0 60 ± 1.5 71 ± 1.8 93 ± 2.0

± 0.28

H 99.89 ± 0 21 ± 0.8 35 ± 1.5 51 ± 1.8 61 ± 2.0 68 ± 2.2

0.44

I 101.11 0 13 ± 0.5 25 ± 0.7 33 ± 1.0 47 ± 1.4 60 ± 1.6

±0.25

J 102.33 0 20 ± 0.8 32 ± 1.0 69 ± 1.5 90 ± 2.3 96 ± 2.3

± 0.35

Results are the mean± S.E.M. of three independent experiments.



100 Q) Ill cu

80 Q)

Q) ... C) 60 ::::J ... "0

~ 40 0

E 20 E ::::J

(.) 0 0 2 4 6

Time (hrs)

8

-+-A_._s ~c

Figure. 5.1. In vitro Drug Release of Batches of Acelofenac.

100 Q) (/)

n:s 80 Q)

Q) ... C) 60 ::::J ...

"0

~ 0 40

E 20 E ::::J

0 0 0 2 4 6

Time (hrs)

8

~D --c-E -.-F


The Sustained Delayed Release of Anti-inflammatory Drugs

10 12

10 12

142


100 (I) 1/)

ro 80 (I)

(I) ... C) 60 ::I ... "0

~ 40 0

E 20 E ::I

(.) 0 0 2 4 6 8 10 12

Time (hrs)

--+-- H -----1 --+-- J


Results of In vitro data are shown in Table 5.5. and Figure 5.1., 5.2., and 5.3. The in vitro

drug r(?lcase studies of thes~: 1:1blets showed that the cumulative drug release was in the

following order F>E>A>J>G>H>I>D>B>C. This might be due to the nature, viscosity

and concentration of the various polymers used, that is different viscosity containing

HPMC, Guar gum and ethyl c~.;Julose and has a powerful retardant property resulting in

matrix formation which is required for sustained release fonnulation. The similarity in

the release profiles of marketed tablet and fonnulation G was compared by making use of

the "Model independent approach". A simple model independent approach uses a

difference factor (fl) and a similarity factor (f2) to compare dissolution profiles. For G

formulation, when compared with marketed tablet, fl and f2 values were found to be 2.44

and 82.89 respectively, indicating a good equivalence between these two formulations.

The release profiles of the matrix tablets of aceclofenac containing varying proportions of

HPMC K4M that is, A and G, respectively



The same result has been seen in matrix formulation C and I containing HPMCKlOOM.

Higher concentration with low viscosity HPMC 15cps containing formulation F does not

sustain the release rate of aceclofenac tablet. That indicated that HPMC6cps has no

longer sustaining the tablet due to its low viscosity. The release pattern of aceclofenac

from the matrices made with 7.5% w/w of hydrophobic polymer Guar gum indicates that

the hard matrix had been formed and decreased the release rate. However, on subsequent

increase from 7.5 to 20% w/w of drug, there was no appreciable decrease in the release

rate and extension in duration of release. This indicated that a tight non-porous matrix

had been formed in the former case and addition of more polymers could not modify the

matrix character any further.

Film coating was applied over the tablet to mask the bitter taste of aceclofenac. No

significant difference was observed in the release profile of coated and uncoated tablets at

pH 7.5 phosphate buffer medium. Also, since 90% drug release was attained in about 11-

12 h, it can be expected that drug release would be complete within the residence time of

the dosage form in the GI tract. The reason was attributed to the preferential solubility of

the drug above pH 6.0 and HPMC 6cps is likely to be soluble from pH 1.2 to 6.8. This is

due to the formation of a porous and eroded matrix upon dissolution of HPMC 6cps at a

higher pH. No significant difference was observed in the release profile of different

batches of each matrix formulation, indicating that the manufacturing process employed

was reliable and reproducible. Also, the release kinetics remained unaltered for up to one

year of storage and there were no changes in the tablet's characteristics, suggesting that

Aceclofenac was stable in HPMC K4M matrices [52- 55].



The data for stability studies carried out for G formulation at 40°C with 75% RH for 180

days revealed no considerable differences in drug content and dissolution rate. In

conclusion, matrix embedding technique using HPMCK4M as the retardant has

successfully extended the release of aceclofenac from its tablet formulations. In the

present case, we found that the incorporation of HPMC K4M in the matrix not only

helped to provide good initial retardation in the release but also helps to enhance the

overall release rate of the drug after a suitable lag time. The manufacturing method

employed is simple and easily adaptable in the conventional tablet.



5.8. Conclusions

In the present study, the formulation and production technology of Aceclofenac 200 mg

hydrophilic matrix tablets have been developed, which produced SR formulation with

good physical characteristics, predictable and reproducible drug release profiles. This

study demonstrated that Methocel K4 MCR provides a reliable sustained release matrix

formulation recommendation for high dose and BCS II class drugs such as Aceclofenac.



5.9. REFERENCES

I. Khan GM, Meidan VK (2001). Drug release kinetics from tablet matrices based upon

ethyl cellulose ether-derivatives: A comparison between different formulations. Drug

Dev. Ind. Pharm. 1: 355-360.

2. Vueba ML, Batista de Carvalho LA, Veiga F, Sousa JJ (2006). Pina ME Influence of

cellulose ether mixtures on ibuprofen release: MC25, HPC and HPMC KIOOM.

Pharm. Dev. Techno!. 11: 213-228.

3. Rekhi GS, Jambekhar SS (1995). Ethylcellulose: A polymer review. Drug Dev. Ind.

Pharm. 21:61-77.

4. Vueba ML, Batista de Carvalho LA, Veiga F, Sousa JJ, Pina ME (2005). Role of

cellulose etherpolymers on ibuprofen release from matrix tablets. Drug Dev. Ind.

Pharm. 31: 65365.

5. Sajeev C, Saha RN (2001). Formulation and comparative evaluation of controlled

release diclofenac tablets prepared by matrix- embedding technique, membrane

barrier technique and combination of the two. Drug Dev. Res. 53: 1-8.

6. Lopes C, Manuel S, Lobo J, Costa P, Pinto J (2006). Directly compressed mini matrix

tablets containing ibuprofen- preparation and evaluation of sustained release. Drug

Dev.lnd. Pharm. 32: 95-106.

7. De Brabander C, Vervaet C, Remon JP (2003). Development and evaluation of

sustained release mini-matrices prepared via hot melt extrusion. J. Control Release

89: 235-247.



8. Kulkarni GT, Gowthamarajan K, Rao BG, Suresh B. Evaluation of binding properties

of Plantago ova/a and Trigone !Ia foenum graecum mucilage. Indian Drugs. 2002; 39

(8):422-425.

9. Anroop B, Bhatnagar SP, Ghosh B, Parcha V. Studies on Ocimum gratissimum seed

mucilage: Evaluation of suspending properties. Indian J Pharm Sci. 2005; 67 (2):206-

209.

10. Bharadia PO, Patel MM, Patel GC, Patel GN. A preliminary investigation on sesbania

gum as a pharmaceutical excipient. Int J Pharm Ex pt. 2004; Oct-Dec: 102-105.

II. Pawar H, D'mello PM. Isolation of seed gum from cassia lora and preliminary

studies of its application as a binder for tablets. Indian Drugs. 2004; 41 (8):465-468.

12. Chang RK, Shukla AJ. Polymethacrylates. In: Raymond CR, Paul JS, Paul JW, ed.

Handbook of Pharmaceutical Excipients. The Pharmaceutical Press and The

American Pharmaceutical Association; 2003:462-468.

13. Hizawa K, Otsuka H, Inaba H, Izumi K, Nakanishi S. Subcutaneous

pseudosarcomatous PVP granuloma. Am J Surg Path. 1984; 8:393-398.

14. Kalen JJ, McGinity JW, Wilber WR. Carbomer -934P. In: Raymond CR, Paul JS,

Paul JW, ed. Handbook of Pharmaceutical Excipients. The Pharmaceutical Press and

The American Pharmaceutical Association; 2003:89-92.

15. Weller PJ, Owen SC. Polyvinylalcohol. In: Raymond CR, Paul JS, Paul JW, ed.

Handbook of Pharmaceutical Excipients. The Pharmaceutical Press and The

American Pharmaceutical Association; 2003:491-492.

16. Khaled AI-T, Jagdish S. Recent Patents on Drug Delivery and Formulation. 2007; I:

65-71.



I 7. Durso OF, Handbook of Water Soluble Gums and Resins. New York, NY: McGraw

Hill, Kingsport Press; I 980:12

I 8. Bhardwaj TR, Kanwar M, Lal R, Gupta A. Natural gums and modified natural gums

as sustained release carriers. Drug Dev Ind Pharm. 2000; 26( 1 0): 1025-1038.

19. Desai A, Shidhaye S, Malke S, Kadam V. Use of natrual release retardant in drug

delivery system. Indian Drugs. 2005; 42(9): 565-575.

20. Kottke KM, Edward MR.Tablet Dosage Forms. In: Banker GS, Rhodes CT,

ed. Modern Pharmaceutics. New York: Marcel Dekker, Inc; 2002:287-333.

21. Raymond C.Rowe, Paul J.Sheskey and Weller P. J., ''Handbook of Pharmaceutical

Excipients", (4th Edn) American Pharmaceutical Association, Washington D. C. and

Royal Pharmaceutical Press, (2003) 297-300.

22. Raymond C.Rowe, Paul J.Sheskey and Weller P. J., "Handbook of Pharmaceutical

Excipients", (4th Edn) American Pharmaceutical Association, Washington D. C. and

Royal Pharmaceutical Press, (2000) 271-273.

23. Ozturk AG et al. Mechanism of release from pellets coated with an ethyl cellulose

based film. J Control Release 1990; 14(3): 203-213.

24. Narisawa S et al. Porosity-controlled ethyl cellulose film coating. IV. Evaluation of

mechanical strength of porous ethyl cellulose film. Chern Pharm Bull 1994; 42(7):

1491-1495.

25. Bodmeier R, Paeratakul 0. The effect of curing on drug release and morphological

properties of ethylcellulose pseudolatex-coated beads. Drug Dev lnd Pharm 1994;

20(9): 1517-1533.


------------


26. Dressman JB et al. Circumvention of pH-dependent release from ethyl cellulose

coated pellets. J Control Release 1995; 36(3): 251-260.

27. lyer U et al. Comparative evaluation of three organic solvent and dispersion-based

ethyl cellulose coating formulations. Pharm Techno) 1990; 14(9): 68-86.

28. Sarisuta N, Sirithunyalug J. Release rate of indomethacin from coated granules. Drug

Dev Ind Pharm 1988; 14(5): 683-687.

29. Porter SC. Controlled-release film coatings based on ethylcellulose. Drug Dev lnd

Pharm 1989; 15(10): 1495-1521.

30. Sadeghi F et al. Study of drug release from pellets coated with surelease containing

hydroxypropylmethylcellulose. Drug Dev lnd Pharm 2001; 27(5): 419--430.

31. Goracinova K et al. Preparation, physical characterization, mechanisms of

drug/polymer interactions, and stability studies of controlled-release solid dispersion

granules containing weak base as active substance. Drug Dev lnd Pharm 1996; 22(3):

255-262.

32. Lin S. Studies on microencapsulation.Theophylline bioavailability after single oral

administration of sustained-release microcapsules. Curr Ther Res Clin Exp I 987;

41(4): 564-573.

33. Pollock D, Sheskey P. Micronized ethylcellulose: opportunities in direct compression

controlled -release tablets. Pharm Techno) 1996; 20(9): 120--130.

34. Klinger GH et al. Formulation of controlled release matrices by granulation with a

polymer dispersion. Drug Dev lnd Ph arm 1990: 16(9): 14 73-1490.

35. Katikaneni Pet al. Ethyl cellulose matrix controlled-release tablets of a water-soluble

drug. Int J Pharm 1995; I 23: 119-125.



36. Kulvanich P et al. Release characteristics of the matrices prepared from co-spray

dried powders of theophylline and ethylcellulose. Drug Dev Ind Pharm 2002; 28:

727-739.

37. Kent DJ, Rowe RC. Solubility studies on ethyl cellulose used in film coating. J Pharm

Pharmacol 1978;30: 808-810.

38. Rowe RC. The prediction of compatibility/incompatibility in blends of ethyl cellulose

with hydroxypropyl methylcellulose or hydroxypropyl cellulose using 2-dimensional

solubility parameter maps. J Pharm Pharmacol 1986; 38: 214-215.

39. Saettone MF et al. Effect of different polymer-plasticizer combinations on 'in vitro'

release oftheophylline from coated pellets. Int J Pharm 1995; 126: 83-88.

40. Beck M, Tomka I. On the equation of state of plasticized ethyl cellulose of varying

degrees of substitution. Macromolecules 1996: 29(27): 8759-8766.

41. Celik M. Compaction of multiparticulate oral dosage forms. Ghebre- Sellassie I, ed.

Multiparticulate Oral Drug Delivery. New York: Marcel Dekker, 1994; 181-215.

42. Robinson DH. Ethyl cellulose-solvent phase relationships relevant to coacervation

microencapsulation processes. Drug Dev Ind Pharm 1989; 15(14-16): 2597-2620.

43. Lavasanifar A et al. Microencapsulation of theophylline using ethyl cellulose: in vitro

drug release and kinetic modeling. J Microencapsul 1997; 14(1): 91-100.

44. Moldenhauer M. Nairn J. The control of ethyl cellulose microencapsulation using

solubility parameters. J Control Release 1992; 22: 205-218.

45. FriedmanMet al. Inhibition of plaque formation by a sustained release delivery

system for cetylpyridinium chloride. Int J Pharm 1988; 44: 243-247.



46. Ruiz-Martinez A et al. In vitro evaluation of benzylsalicylate polymer interaction in

topical formulation. Pharm lnd 2001; 63: 985-988.

47. Melzer E et al. Ethylcellulose: a new type of emulsion stabilizer. Eur J Pharm

Biopharm 2003; 56: 23-27.

48. Sakellariou P et al. The thermomechanical properties and glass transition

temperatures of some cellulose derivatives used in film coating. Int J Pharm 1985; 27:

267-277.

49. Callahan JC et al. Equilibrium moisture content of pharmaceutical excipients. Drug

Dev Ind Pharm 1982; 8(3): 355-369.

50. Velazquez de Ia Cruz G et al. Temperature effects on the moisture sorption isotherms

for methylcellulose and ethylcellulose films. J Food Engin 2001; 48: 91-94.

51. FAO/WHO. Evaluation of certain food additives and contaminants. Thirty-fifth report

of the joint FAO/WHO expert committee on food additives. World Health Organ

Tech Rep Ser 1990: No. 789.

52. Khan GM, Zhu JB (2007). Controlled release coprecipitates of Ibuprofen and

Carbopol 934- Preparation, characterization and In vitro release. Sciences 33: 627-

639.

53. Kuksal A, Tiwary AK, Jain NK, Jain S (2006). Formulation and In Vitro, In Vivo

Evaluation of Extended release Matrix Tablet of Zidovudine: Influence of

Combination of Hydrophilic and Hydrophobic Matrix Formers. AAPS. Pharm. Sci.

Technol. 1: 1-9.

54. Mutalik S, Hiremath D (2000). Formulation and evaluation of chitosan matrix tablets

ofNifedipine. The Eastern. Pharm. I 0: I 09-111.


r Chapter 5 Aceclofenac Matrix Tablet Containing Synthetic & Natural Polymers

55. Reddy R, Mutalik S, Reddy MS (2003).0nce daily sustained release matrix tablets of

nicorandil: Formulation and in vitro evaluation. AAPS. Pharm. Sci. Technol61

(Supp4): 1-9.


formulation of aceclofenac matrix...

Documents