Formulation of Sustained Release Tablet...

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



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.



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.



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.



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.



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



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



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).



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).



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,



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


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



--+--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].



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



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.



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


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


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