Upload
others
View
24
Download
0
Embed Size (px)
Citation preview
------ --- -~-~--~~-~----.
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
Chapter 5 Aceclofenac Matrix Tablet Containing Synthetic & Natural Polymers
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].
The Sustained Delayed Release of Anti-inflammatory Drugs 119
Chapter 5 Aceclofenac Matrix Tablet Containing Synthetic & Natural Polymers
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
The Sustained Delayed Release of Anti-inflammatory Drugs 120
- -----------------------------
Chapter 5 Aceclofenac Matrix Tablet Containing Synthetic & Natural Polymers
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
The Sustained Delayed Release of Anti-inflammatory Drugs 121
Chapter 5 Aceclofenac Matrix Tablet Containing Synthetic & Natural Polymers
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.
The Sustained Delayed Release of Anti-inflammatory Drugs 122
----------------------------------------------------
Chapter 5 Aceclofenac Matrix Tablet Containing Synthetic & Natural Polymers
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.
The Sustained Delayed Release of Anti-inflammatory Drugs 123
Chapter 5 Aceclofenac Matrix Tablet Containing Synthetic & Natural Polymers
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.
The Sustained Delayed Release of Anti-inflammatory Drugs 124
Chapter 5 Aceclofenac Matrix Tablet Containing Synthetic & Natural Polymers
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.
The Sustained Delayed Release of Anti-inflammatory Drugs 125
Chapter 5 Aceclofenac Matrix Tablet Containing Synthetic & Natural Polymers
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
The Sustained Delayed Release of Anti-inflammatory Drugs 126
------------------~-------
Chapter 5 Aceclofenac Matrix Tablet Containing Synthetic & Natural Polymers
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.
The Sustained Delayed Release of Anti-inflammatory Drugs 127
----------------------------------
Chapter 5 Aceclofenac Matrix Tablet Containing Synthetic & Natural Polymers
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.
The Sustained Delayed Release of Anti-inflammatory Drugs 128
Chapter 5 Aceclofenac Matrix Tablet Containing Synthetic & Natural Polymers
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.
The Sustained Delayed Release of Anti-inflammatory Drugs 129
- ---------------------------------.
Chapter 5 Aceclofenac Matrix Tablet Containing Synthetic & Natural Polymers
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,
The Sustained Delayed Release of Anti-inflammatory Drugs 130
Chapter 5 Aceclofenac Matrix Tablet Containing Synthetic & Natural Polymers
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.
The Sustained Delayed Release of Anti-inflammatory Drugs 131
Chapter 5 Aceclofenac Matrix Tablet Containing Synthetic & Natural Polymers
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.
The Sustained Delayed Release of Anti-inflammatory Drugs 132
Chapter 5 Aceclofenac Matrix Tablet Containing Synthetic & Natural Polymers
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
The Sustained Delayed Release of Anti-inflammatory Drugs 133
Chapter 5 Aceclofenac Matrix Tablet Containing Synthetic & Natural Polymers
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.
The Sustained Delayed Release of Anti-inflammatory Drugs 134
Chapter 5 Aceclofenac Matrix Tablet Containing Synthetic & Natural Polymers
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
The Sustained Delayed Release of Anti-inflammatory Drugs 135
Chapter 5 Aceclofenac Matrix Tablet Containing Synthetic & Natural Polymers
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
The Sustained Delayed Release of Anti-inflammatory Drugs 136
----------
Chapter 5 Aceclofenac Matrix Tablet Containing Synthetic & Natural Polymers
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.
The Sustained Delayed Release of Anti-inflammatory Drugs 137
------------------------------------
Chapter 5 Aceclofenac Matrix Tablet Containing Synthetic & Natural Polymers
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.
The Sustained Delayed Release of Anti-inflammatory Drugs 138
Chapter 5 Aceclofenac Matrix Tablet Containing Synthetic & Natural Polymers
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
The Sustained Delayed Release of Anti-inflammatory Drugs 139
Chapter 5 Aceclofenac Matrix Tablet Containing Synthetic & Natural Polymers
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.
The Sustained Delayed Release of Anti-inflammatory Drugs 140
Chapter 5 Aceclofenac Matrix Tablet Containing Synthetic & Natural Polymers
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.
The Sustained Delayed Release of Anti-inflammatory Drugs 141
Chapter 5 Aceclofenac Matrix Tablet Containing Synthetic & Natural Polymers
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
Figure. 5.2. In vitro Drug Release of Batches of Acelofenac.
The Sustained Delayed Release of Anti-inflammatory Drugs
10 12
10 12
142
Chapter 5 Aceclofenac Matrix Tablet Containing Synthetic & Natural Polymers
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
Figure. 5.3. In vitro Drug Release of Batches of Acelofenac.
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 Sustained Delayed Release of Anti-inflammatory Drugs 143
Chapter 5 Aceclofenac Matrix Tablet Containing Synthetic & Natural Polymers
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 Sustained Delayed Release of Anti-inflammatory Drugs 144
Chapter 5 Aceclofenac Matrix Tablet Containing Synthetic & Natural Polymers
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.
The Sustained Delayed Release of Anti-inflammatory Drugs 145
Chapter 5 Aceclofenac Matrix Tablet Containing Synthetic & Natural Polymers
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.
The Sustained Delayed Release of Anti-inflammatory Drugs 146
Chapter 5 Aceclofenac Matrix Tablet Containing Synthetic & Natural Polymers
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.
The Sustained Delayed Release of Anti-inflammatory Drugs 147
Chapter 5 Aceclofenac Matrix Tablet Containing Synthetic & Natural Polymers
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.
The Sustained Delayed Release of Anti-inflammatory Drugs 148
Chapter 5 Aceclofenac Matrix Tablet Containing Synthetic & Natural Polymers
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.
The Sustained Delayed Release of Anti-inflammatory Drugs 149
------------
Chapter 5 Aceclofenac Matrix Tablet Containing Synthetic & Natural Polymers
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.
The Sustained Delayed Release of Anti-inflammatory Drugs 150
Chapter 5 Aceclofenac Matrix Tablet Containing Synthetic & Natural Polymers
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.
The Sustained Delayed Release of Anti-inflammatory Drugs 151
Chapter 5 Aceclofenac Matrix Tablet Containing Synthetic & Natural Polymers
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.
The Sustained Delayed Release of Anti-inflammatory Drugs 152
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.
The Sustained Delayed Release of Anti-inflammatory Drugs 153