Chapter 4
Formulation
of
Sustained Release Tablet
of
Acecloftnac containing
Synthetic Polymer
Chapter4 Aceclofenac Containing Synthetic Polymer
4. Formulation of Sustained Release Tablet of Aceclofenac containing
Synthetic Polymer
4.1. Introduction:
Hydrophilic matrices are widely used to develop oral sustained release formulations.
They can be used for controlled release of both water soluble and insoluble drugs. The
release of drugs varies with the nature of the matrix and also with the complex interaction
of swelling, diffusion and erosion process [I]. Oral controlled release dosage forms have
been developed to restrict this system to specific regions of the gastrointestinal tract, to
improve the pharmacological activity and to reduce toxicity [2]. The most important
method of fabricating controlled release formulations is incorporation of the drug in a
matrix containing a hydrophilic, rate controlling polymer like HPMC [3]. Hydrophilic
polymer matrix systems are widely used because of their flexibility to provide a desirable
drug release profile, cost effectiveness and broad regulatory acceptance [4]. Aceclofenac
(AC) [2-(2',6'-dichlorophenyl)amino]phenylacetoxyacetic acid is a phenylacetic acid
derivative with potent analgesic and anti-inflammatory properties. The high concentration
with rapid drug absorption causes adverse effects to GIT. To improve the therapeutic
efficacy of Aceclofenac and reduce the severity of upper GJ tract side-effects a dosage
form with modified release properties should be prepared.
Thus, the objective of the present study was to develop a controlled release formulation
of AC as matrix tablets, prepared by using different concentrations of HPMC (K 15M).
The Sustained Release of Anti-inflammatory Drugs 95
Chapter 4 Aceclofenac Containing Synthetic Polymer
4.2. Introduction to HPMC (Hydroxy propyl methyl cellulose) [5]:
4.2.1. Synonyms: Methocel; hydroxyl propyl methyl ether; metolose; pharmacoat
4.2.2. Chemical name: Cellulose, 2- hydroxyl propyl methyl ether
4.2.3. Functional category:
Coating agent, film former, rate controlling polymer for sustained release, stabilizing
agent; suspending agent, tablet binder, viscosity increasing agent.
4.2.4. Description: It is white or creamy white colored fibrous or granular powder.
4.2.5. Typical properties:
Acidity/alkalinity: pH=S.S-8.0 for 1% solution
Ash: 1 .5-3% depending upon the grade.
Melting point: 190-200°c
Solubility: soluble in cold water, forming a viscous colloidal solution. Insoluble
in chloroform, ethanol and ether. Certain grade of HPMC is soluble in aqueous
acetone solutions.
4.2.6. Stability and storage condition:
HPMC powder is a stable material although, it is hygroscopic after drying. Solutions are
stable at pH 3-ll.increasing temperature reduced viscosity of solution. HPMC undergoes
a reversible sol to gel transformation upon heating and cooling respectively. The gel point
is 50-90 °c .depending upon the grade and concentration .Aqueous solution is enzyme
resistance, providing good viscosity stability during long term storage. Aqueous solutions
are liable to microbial spoilage and should be preserved with antimicrobial preservatives
.When used as a viscosity increasing agents in ophthalmic solution; benzalkonium
The Sustained Release of Anti-inflammatory Drugs 96
Chapter 4 Aceclofenac Containing Synthetic Polymer
chloride is commonly used for this purpose. HPMC should be stored in a well closed
container.
4.2.7. Method of manufacturing:
A purified form of cellulose, obtained from cotton linters or wood pulp, is reacting with
sodium hydroxide solution to produce swollen alkali cellulose which is chemically more
reactive than unreacted cellulose. The alkali cellulose is then treated with chloromethane
and propylene oxide to produced methyl hydroxyl propyl ether of cellulose. The fibrous
reaction product is then purified and ground to a fine, uniform powder or granules.
4.2.8. Safety:
The WHO has not specified an acceptable daily intake for HPMC the level consumed is
not considered to represent a hazard to health. LDso (mouse, IP): 5g/Kg LDso( rat,IP):
5.2 g/Kg
4.2.9. Handling precautions:
HPMC dust may be irritant to the eyes and eye protection is recommended .excessive
dust generation should be avoided to minimize the risk of explosion. HPMC is
combustible.
4.2.10. Regulatory status:
Accepted as a food additive in Europe. Included in the FDA, Included in non parenteral
medicines licensed in the UK.
4.2.11. Related substances:
Hydroxy propyl cellulose, hydroxy propyl methyl cellulose methyl cellulose.
The Sustained Release of Anti-inflammatory Drugs 97
Chapter4 Aceclofenac Containing Synthetic Polymer
4.2.12. Application:
It is used in oral and topical pharmaceutical formulation. In oral, as a binder ,in film
coating , as a extended release tablet matrix In topical , as a suspending and thickening
agent ,as a emulsifying agent and stabilizing agent in topical gels .
It is also used in cosmetics and food product.
The Sustained Release of Anti-inflammatory Drugs 98
Chapter 4 Aceclofenac Containing Synthetic Polymer
4.3. Introduction to Micro crystalline cellulose (MCC) [6]:
4.3.1. Synonym: Avice!, Cellulose gel, crystalline cellulose, E460, Emocel, Fibrocel,
Vivace!.
4.3.2. Chemical Name: cellulose
4.3.3. Empirical formula: (C6 H1005) n. where n = 220.
4.3.4. Molecular weight: 36000.
4.3.5. Functional Category:
Tablet and capsule diluents, suspending agent, adsorbent and tablet disintegrant.
4.3.6. Application:
Primarily used as diluents in tablets and capsule fonnulation where it is used in the both
wet granulation and direct compression in tablet and capsule formulation. It also has
some lubricant and disintegrant property.
4.3.7. Description:
It occurs as a white color, tasteless, crystalline powder composed of porous particles.
4.3.8. Solubility:
Slightly soluble in 5% sodium hydroxide solution, practically insoluble in water.
4.3.9. Stability and Storage condition:
It is stable, though hygroscopic material. The bulk material should be stored in well
closed container in a cool and dry place.
4.3.1 0. Incompatibility:
Incompatible with strong oxidizing agent.
The Sustained Release of Anti-inflammatory Drugs 99
Chapter4 Aceclofenac Containing Synthetic Polymer
4.3.11. Safety:
It is generally regarded as a nontoxic and non irritant material.
4.3.12. Pharmaceutical uses:
Pharmaceutically, primarily as a binder/diluent in oral tablet formulations, where it is
used in both direct compression and wet granulation methods. In addition to its use as
binder/ diluent, MCC also has some lubricant and disintegrant properties that makes it
useful in tableting.
The Sustained Release of Anti-inflammatory Drugs 100
Chapter 4 Aceclofenac Containing Synthetic Polymer
4.4. Aim of present work
Synthetic polymers are approved by US FDA and vanous agencies as compared to
natural polymers. The present work was undertaken to explore the use of synthetic
pharmaceutical excipient in the formulation of Aceclofenac tablet for pharmaceutical
dosage form. So, plan of work was carried out as follows;
I. Formulation of Aceclofenac tablet containing synthetic polymer like HPMC and
MCC using it's at various concentration.
2. Pharmaceutical Formulation Parameters: Hardness, Friability, Content
Uniformity, dissolution profile of tablets, comparison of dissolution profile in
different dissolution media, comparison of dissolution profile with marketed
formulation, water uptake and mass loss study.
3. In vitro Dissolution data were fitted to various models.
4. Stability study
The Sustained Release of Anti-inflammatory Drugs 101
Chapter4 Aceclofenac Containing Synthetic Polymer
4.5. Methods:
4.5.1. Preparation of tablets
All formulations were prepared by the direct compression method. AC, polymer and
other Excipients were mixed in a double cone blender for 15 min [7]. The amounts of
polymer and other ingredients are given in Table 4.1. The quantities of ingredients
required for preparing sustained release formulations were compressed using a single
punch-tableting machine (Cadmach ®Machinery Co. Pvt. Ltd., India) equipped with 6.5
mm circular, flat and plain punches. The batch size of each formulation for each drug was
I 00 tablets.
Table 4.1. Composition of sustained release matrix tablets of Aceclofenac
Formulations Aceclofenac HPMC MCC Talc Mg- Total
(mg) Kl5M (mg) (mg) stearate
(mg) (mg)
Fl 200 10 80 5 5 300
F2 200 20 70 5 5 300
F3 200 30 60 5 5 300
F4 200 40 50 5 5 300
4.5.2. Evaluation of matrix tablets
Quality control tests for the matrix tablets, such as hardness. friability and drug content
were determined using the reported procedure.
Drug content of 20 tablets were determined after finely powdered and an amount
equivalent to 200 mg of Aceclofenac tablet powder was accurately weighed and
The Sustained Release of Anti-inflammatory Drugs 102
Chapter 4 Aceclofenac Containing Synthetic Polymer
transferred to a I 00 mL volumetric flask and extracted with phosphate buffer (pH 7.2).
The mixture was then filtered and I mL of the filtrate was suitably diluted and analyzed
at 275 nm for Aceclofenac using a UVNisible double beam spectrophotometer (UV-
1700, Shimadzu, Japan). The method was validated for linearity, precision and accuracy.
Hardness \Vas determined by taking 6 tablets from each fonnulation using a digital tablet
hardness tester (Electro lab Ltd, India).
Friability was detennined using 20 tablets in a Roche® friabilator (Eiectrolab Pvt. Ltd ..
India), which was rotated for 4 min at 25 rpm.
4.5.3. In vitro drug release
Release of AC was determined using a six stage dissolution rate test apparatus [8] (Type
IL TDL - 08, Electrolab India, Mumbai) at 50 rpm. The dissolution rate was studied
using 900 mL of phosphate buffer (pH 7.2). The temperature was maintained at 37 ± 0.2
0 C. Samples of 5 mL each \vere withdrawn at different time intervals, filtered through
Whatman filter paper No. 1 (Auroco Pvt Ltd, Thailand) and replaced \Vith an equal
amount of fresh dissolution medium. Samples were suitably diluted and analyzed for AC
content spectrophotometrically. Release studies were conducted in triplicate. The rate and
mechanism of release of both drugs from the prepared matrix tablets were analyzed by
fitting the dissolution data into the various models:
4.5.4. Swelling and Erosion
Swelling and erosion studies were performed on twelve tablets using the method
described by Reynold et a/. [9] in phosphate buffer (pH 7.2) at 37 oc_ The experiment
was repeated three times for each individual time interval. Swelling and erosion studies
were carried out at a stirring speed of 100 rpm (paddle type).
The Sustained Release of Anti-inflammatory Drugs 103
Chapter 4 Aceclofenac Containing Synthetic Polymer
4.5.5. Stability study:
The tablets were charged for the accelerated stability studies as per ICH guidelines
(40±2°C and 75±5% RH) for a period of 6 months in stability chambers. They were
placed in flint vials and hermetically sealed with rubber plugs and aluminum caps. The
samples were taken out at 15, 30, 60, 90and 180 days and evaluated for the drug content
and physical parameters like color change, hardness, friability and cumulative drug
release (n=3).
The Sustained Release of Anti-inflammatory Drugs 104
Chapter 4 Aceclofenac Containing Synthetic Polymer
4.6. Result and Discussion:
4.6.1. Physical characterization oftablets
All formulations were prepared according to the formula g1ven m Table 4.1. The
prepared matrix tablets were evaluated for various physical properties, as indicated in
Table 4.2. All the batches were produced under similar conditions to avoid processing
variables. The hardness of the tablets was found in between 5.3 ± 0.2 to 6.2 ± 0.4kg/cm2•
The percentage friability of all formulations was between 0.1 and 1.0 %. The results of
the hardness and friability tests indicate good handling properties of prepared tablets. The
mean drug content in the tablets was 99.9 ± 2.3 %.
Table 4.2. Tablets Properties of Compressed Tablets.
Formulations Hardness (kg em-") Friability(%) Drug Content (%)
F1 5.8 ± 0.3 0.5 ± 0.1 98.9 ± 3.8
F2 5.3 ± 0.2 0.7 ± 0.1 99.7 ± 2.5
F3 6.2 ± 0.4 0.2 ± 0.1 100.7 ± 1.3
F4 5.9 ± 0.3 0.4 ± 0.1 100.2 ± 1.1
4.6.2. In vitro drug release
Formulations containing Aceclofenac (200 mg) were developed by the simple direct
compression method using HPMC K 15M. The effect of polymer level on the release of
water insoluble AC was studied for tablets containing 5, I 0, 15 and 20 % HPMC K 15M
(formulations FI-F4, respectively). Data are shown in Table 4.3 and Fig. 4.1.
The release rate was found to be decreasing as the concentration of polymer increased
from 5 to 20 %. Water insoluble Aceclofenac formulations Fl, F2 and F3 containing 5,
The Sustained Release of Anti-inflammatory Drugs 105
Chapter 4 Aceclofenac Containing Synthetic Polymer
I 0 and I5 % HPMC, respectively, were able to sustain the drug release for 8, I 0 and 12
hours, respectively. For F1 96.1 %of the drug was released within 8 hours, for F2 94.4%
within I 0 hours and for F3 94.2 % within I2 hours. Formulations F I and F2 underwent
swelling; then gradually erosion could take place, resulting in slower release due to the
hydrophobic nature of the drug. In the case of formulation F3, I5 % of HPMC was
sufficient to sustain the drug release for 12 hours. On increasing the quantity of HPMC
up to 20 %, the release of the drug was too slow and only 78.2% of the drug was released
within I2 hours.
It was observed that when the polymer concentration was increased, the drug release rate
decreased. This is due to the higher degree of the swelling because of higher
concentration of polymers. However, further increase in polymer concentration did not
significantly affect the drug release rate. Water insoluble drug required a smaller amount
of polymer to sustain the release as compared to the water soluble drug because the
hydrophobic nature of the drug restricts the penetration of the solvent inside the matrix,
which retarded drug release from the matrix [I 0-13].
From formulations FI, F2, F3 and F4, where hydrophobic drug was combined with
hydrophilic polymer, no burst release was observed. It has been reported that if more than
20% of the drug is released in the first hour of dissolution, this may indicate a chance of
dose dumping. So, there is a probability of dose dumping for formulations containing
hydrophilic drug with hydrophilic polymer HPMC.
Formulation F1 to F4 showed high linearity with the zero-order equation (R2 = 0.959-
0.990). The value of release exponent n ranged from 0.9IO to 1.000 in case of
formulations F1 to F4 containing Aceclofenac [14-19].
The Sustained Release of Anti-inflammatory Drugs I06
Chapter 4 Aceclofenac Containing Synthetic Polymer
Table 4.3. In vitro Drug Release from Formulations.
Time Fl F2 F3 F4
(hr)/Formulation
0 0 0 0 0
I 25 ± 1.0 22 ± 1.0 20 ± 0.9 12 ± 0.5
2 35 ± 1.5 32 ± 1.4 28 ± 1.2 19± 0.7
3 47 ± 1.8 42 ± 1.7 36 ± 1.6 27 ± 1.0
4 57± 2.0 53± 1.9 44 ± 1.8 33 ± 1.2
5 67 ± 2.2 62 ± 2.3 54± 2.1 40 ± 1.3
6 77 ± 2.8 70 ± 2.6 62 ± 2.5 47 ± 1.4
7 89 ± 3.0 78 ± 3.1 69 ± 3.2 55± 1.5
8 96.1 ± 3.2 86 ± 3.3 76± 2.9 62 ± 1.5
9 90 ± 3.5 82 ± 3.1 69 ± 1.6
10 94.4 ± 3.5 88 ± 3.2 75 ± 1.7
12 94.2 ± 3.2 80 ± 1.8
The Sustained Release of Anti-inflammatory Drugs 107
Chapter 4 Aceclofenac Containing Synthetic Polymer
--+--Batch F1 -Batch F2 - -Batch F3 ----*--Batch F4
Fig. 4.1. In vitro dissolution of various batches (Fl to F4).
The linear regression analysis is given in Table 4.4. The kinetic data of formulations F1
to F4 showed good fit in the with the zero-order equation (R2 = 0.959-0.990) [20]. The
value ofrelease exponent n ranged from 0.910 to 1.000 in case of formulations F1 to F4
with Aceclofenac.
From the release exponent in the Korsmeyer-Peppas model, it can be suggested that the
mechanism that led to the release of Aceclofenac was an anomalous Non-Fickian
diffusion transport [21 ], which indicates that the drug release occurred through diffusion
in the hydrated matrix and polymer relaxation. In case of Aceclofenac, the mechanism of
drug release shifted from anomalous Non-Fickian diffusion to swelling controlled drug
delivery systems with zero-order kinetics [22-30].
The Sustained Release of Anti-inflammatory Drugs 108
Chapter 4 Aceclofenac Containing Synthetic Polymer
Table 4.4. Kinetics of Drug Release from Aceclofenac Matrix Tablets.
Formulation Drug release kinetics (k) Release
exponent (n)
Zero-order First-order Higuchi Korsmeyer
F1 0.959 0.945 0.904 0.890 0.910
F2 0.985 0.916 0.919 0.936 0.929
F3 0.990 0.908 0.917 0.961 0.967
F4 0.987 0.968 0.905 0.965 1.000
4.6.3. Swelling and Erosion
Swelling and erosion studies indicate that swelling and erosion mechanisms might be
operative during the drug release from matrix formulation F3. It was observed that all the
formulations were initially intact and when they were placed in dissolution media they
gradually formed pores. It was also observed that S\\'elling and erosion increased with
time. Data are shown in Table 4.5 and Figure 4.2. It was observed for all formulations
that swelling and erosion occurred simultaneously in the matrix helping to constant
release of the drug from the matrices [31 ]. Constant release in such situations occurs
because the increase in the diffusion path length due to swelling is compensated by
continuous erosion of the matrix [32]. It was also observed that the formulations
containing the water soluble drug showed higher \Vater uptake and erosion capacity than
the water in soluble drug, because, the former allows the solvent to penetrate the matrix
The Sustained Release of Anti-inflammatory Drugs 109
Chapter 4 Aceclofenac Containing Synthetic Polymer
and form a viscous gel around it, whereas the insoluble drug restricts solvent penetration
inside the matrix and retards matrix swelling and erosion [33-35].
Table 4.5. Swelling and erosion behavior of Formulation F3 containing Aceclofenac
Tablets.
Time (hr) Swelling± S.D. (n=3) (%) Erosion± S.D. (n=3) (%)
0 0 0
I 33 ± 1.5 9±0.5
2 80 ± 2.5 15 ± 0.5
3 90 ± 2.7 18 ± 0.7
4 100 ± 2.9 22 ± 0.7
5 120 ± 3.0 25 ± l.O
6 130 ± 3.0 29 ± l.O
- -
140 c 120 0 'iii ~ 100 w ~ 80 Cl c 60 Qj ~ 40 tiJ
~ 20
0
Time (hr)
-+-Swelling(%) -Erosion(%)
Fig. 4.2. % Swelling and Erosion of Optimized Batch.
The Sustained Release of Anti-inflammatory Drugs 110
Chapter 4 Aceclofenac Containing Synthetic Polymer
3.6.5. STABILITY STUDY:
At the end of the testing period, the matrix tablets were observed for changes in physical
appearance, analyzed for drug content, and subjected to in vitro drug release studies. No
visible changes in the appearance of the matrix tablets were observed at the end of the
storage period. The drug content was found to be 98.4 ± 0.053%. At the end of24 hours
of dissolution testing, the amount of Aceclofenac released from F3 matrix tablets before
storage was 99.83 ± 0.035% whereas that released from the F3 formulation after storage
was 99.27 ± 0.026%. There was no significant difference in the mean amount of
aceclofenac released from F3 matrix tablets after storing for 6 months at 40°C/75% RH.
(t test, p<0.05)
The Sustained Release of Anti-inflammatory Drugs Ill
Chapter4 Aceclofenac Containing Synthetic Polymer
4.7. CONCLUSIONS
Aceclofenac sustained release matrix tablets were prepared successfully using HPMC as
polymer to retard the release and achieve the required dissolution profiles. Results of the
present study demonstrate that drug solubility has a significant effect on the release
kinetics and mechanism of drug release. Water soluble drug required a larger amount of
polymer to sustain the drug release compared to the insoluble drug the mechanism of
drug release followed anomalous non-Fickian diffusion transport and zero-order for water
soluble and insoluble drugs. respectively.
The Sustained Release of Anti-inflammatory Drugs I 12
Chapter 4 Aceclofenac Containing Synthetic Polymer
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