preparation and evaluation of controlled release matrix pellets of ketoprofen

ISSN No: 2321 – 8630, V – 1, I – 1, 2014 Journal Club for Pharmaceutical Sciences (JCPS)

Manuscript No: JCPS/RES/2014/16, Received on: 03/08/2014, Revised on: 09/08/2014, Accepted On: 13/08/2014

RESEARCH ARTICLE

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Preparation and Evaluation of Controlled Release Matrix Pellets of Ketoprofen

Patel DY*1, Joshi DM1, Shah AD1 1A.P.M.C. College of Pharmaceutical Education and Research,

Motipura, Himatnagar Gujarat, India.

ABSTRACT

Pellets are well accepted technique to control the drug release from the dosage form to improve bioavailability, reduce absorption difference in patients, reduce the dosing frequency and adverse effects during prolong treatment. The main objective of the present study is to prepare and evaluate controlled release pellets of Ketoprofen by extrusion sheronization method, with release rate retarding polymers using as carrier for oral administration in view to achieve oral controlled release of the drug and to protect the gastric mucous membrane from drug irritation. Ketoprofen is potent NSAID having anti-inflammatory, analgesic, antipyretic properties. It is readily absorbed from the gastrointestinal tract and peak plasma concentrations occur about 0.5–2 h after a dose, but it causes a certain irritation in the gastrointestinal mucous membrane and possesses a bitter taste and aftertaste. The half-life in plasma is about 2–3 hr. Preformulation studies performed were comply with the standards. Compatibility studies revealed there was no interaction between the drug and polymers. The various evaluation parameters were given the positive results. In-vitro dissolution studies were showed that the release of drug from pellets was optimum. It was also observed that drug release increases sharply as well as the release best fit to the zero order release kinetics.All the pellets were stable with respective storage condition.

KEYWORDS

Controlled release, Sodium alginate, Ethyl cellulose, Pellets

INTRODUCTION

Controlled drug delivery systems designed

to deliver drug at predetermined rates for

predefined periods of time and have been

used to overcome the shortcoming of

conventional drug formulations. The term

pellets describes a monolithic spherical

structure with the drug or therapeutic agent

distributed throughout the matrix either as a

molecular dispersion or as a dispersion of

particles (in the 700 - 1200μm size ranges)

for use as carries of drugs and other

therapeutic agents1. Ketoprofen is readily

*Address for Correspondence:

Yogesh D. Patel, Pharmaceutics Department, A.P.M.C. College of Pharmaceutical Education and Research, Motipura, Himatnagar – 383001, Gujarat, India Email: [email protected]

mailto:[email protected]

All Rights Reserved by “Journals Club & Co.” 88

absorbed from the gastrointestinal tract and

peak plasma concentrations occur about

0.5–2 h after a dose, but it causes a certain

irritation in the gastrointestinal mucous

membrane and possesses a bitter taste and

aftertaste.2 The half-life in plasma is about

2–3 hr. The short half-life and the low

single administration dose make ketoprofen

a very good candidate for the formulation

of controlled release dosage forms. The

main objective of the present study was to

prepare and evaluate controlled release

pellets of ketoprofen by extrusion

sheronization method, with release rate

retarding polymers, such as ethyl cellulose

and sodium alginate using as carrier for oral

administration in view to achieve oral

controlled release of the drug and to protect

the gastric mucous membrane from drug

irritation or to mask its unpleasant taste.3

The pellet dosage form can be prepared as a

capsule or tablet. Formulation of drug into

pellet form may reduce gastric irritation as

well as gastrointestinal side effects, because

the drug is released slowly over a period of

time, therefore avoiding high drug

concentration in the stomach. Pellet dosage

form also allows drug to be absorbed

gradually, therefore reducing the incidence

of side effects by preventing high Cmax. A

major advantage of pellet dosage form is

that the pellets are less sensitive to the

effect of stomach emptying. Because there

are numerous pellets within a capsule, some

pellets will gradually reach the small

intestine and deliver the drug, where as a

single tablet may be delayed in the stomach

for a long time due to erratic stomach

emptying. The fluctuating drug

concentrations in blood and tissues caused

by conventional dosage forms lead to an

insufficient influence on the mechanisms of

disease and are related to the excessive use

of a drug.2

MATERIALS & METHODS

Materials

Ketoprofen was obtained from Torrent

pharma, Ahmedabad,Gujarat, India as gift

sample. It is insoluble in water; soluble in

alcohol and methyl alcohol. Micro

crystalline cellulose pH 101 (MCC) was

procured from Signet Chemicals, Mumbai,

India. It is a white colourless, odorless,

tasteless and crystalline powder.Ethyl

Cellulose was obtained from SD fine -

Chem Ltd., Mumbai, India. Sodium

alginate was obtained from SD fine -Chem

Ltd., Mumbai, India. It is a white to

yellowish brown filamentous, grainy,

granular or powdered forms of the sodium

salt of alginic acid. β-cyclodextrin was

obtained from Yarrow Chem Products,

Mumbai, India.

Preparation of Ketoprofen Inclusion

Complexation by Kneading Method

The binary system of Ketoprofen and β-

cyclodextrins in different ratios (1:1) were


triturated in a mortar with a small volume

of water: ethanol (1:1 v/v,3 ml) solvent

blend.4 The thick slurry was kneaded for 45

mins, and then the mass was dried in for

2 days. The dried product was crushed,

pulverized and sieved through 100 mesh.5

The solid dispersions thus obtained were

stored in a well-closed container. Solubility

study and drug content test were carried

out.7

Evaluation of Ketoprofen-βcyclodextrin Inclusion Complexation Solubility study6 Solubility study was carried out by taking solid dispersion in 3 ml of phosphate buffer pH 7.4 and distilled water, sonicated for one hour and maintained at temperature 37º for 72 h. The content of ketoprofen was determined spectrophotometrically at 256 nm. Drug content6 Solid dispersion equivalent to 100 mg of drug was weighed, transferred in to a flask (100 ml) and first dissolved in 10 mL of solvent methanol and then make up the volume up to 100 mL with 7.4 pH buffer

solution. The solution filtered through 0.45μ filters was measured using UV-Visible spectrophotometer at 260nm (λmax). To avoid the interference of the excipients, placebo blend was also treated similarly and kept as blank. Preparation of Pellets8 Extrusion-Spheronization process used for pellets preparation. Accurately weighed amount of drug, microcrystalline cellulose, sodium alginate and ethyl cellulose were mixed in the mortar-pastel. Solvent water was used for the wet massing to make the dump mass of optimum moisture content. Then this mass was kept in extruder for getting extrudes. The wet extrudes were placed in an oven for optimum % LOD (Loss on drying). If there was higher moisture then extrudes stick with each other and if it was less then there were chances of fine particles. After this stage extrudes were placed in spheronizer for getting sphere pellets. The prepared spherical pellets were placed in hot air oven to dry for 30 minutes. Composition of F1 to F9 batches prepared by trial and error method show in table 1 and 2.

Table 1 : Composition of Drug and Excipients of F1 to F5

Ingredients F1

(mg)

F2

(mg)

F3

(mg)

F4

(mg)

F5

(mg)

Ketoprofen

inclusion complex

200 200 200 200 200

Microcrystalline

cellulose

267.50 240.02 212.52 240.02 212.52

Sodium alginate 55 82.5 110 55 82.5

Ethyl cellulose 27.5 27.5 27.5 55 55

Total weight(mg) 550 550 550 550 550


Table 2 : Composition of drug and Excipients of F6 to F9

Ingredients F6

(mg)

F7

(mg)

F8

(mg)

F9

(mg)

Ketoprofen inclusion

complex

200 200 200 200

Microcrystalline

cellulose

185.02 185.02 157.52 130.02

Sodium alginate 110 55 82.5 110

Ethyl cellulose 55 82.5 82.5 82.5

Total weight(mg) 550 550 550 550

Characterization and Evaluation of

Pellets

Bulk density9

Weigh accurately 25 g of powder mixture

(M), which was previously passed through

20 # sieve and transferred in 100 ml

graduated cylinder. Carefully level the

powder without compacting, and read the

unsettled apparent volume (V0). Calculate

the apparent bulk density in gm/ml by the

following formula

Bulk density = Weight of powder / Bulk

volume ……………(1)

Tapped density9

Weigh accurately 25 g of powder mixture,

which was previously passed through 20 #

sieve and transfer in 100 ml graduated

cylinder. Then mechanically tap the

cylinder containing the sample by raising

the cylinder and allowing it to drop under

its own weight using mechanically tapped

density tester that provides a fixed drop of

14± 2 mm at a nominal rate of 300 drops

per minute. Tap the cylinder for 500 times

initially and measure the tapped volume to

the nearest graduated units, repeat the

tapping an additional 750 times and

measure the tapped volume to the nearest

graduated units. Calculate the tapped bulk

density in gm/ml by the following

formula: Tapped density = Weight

of powder / Tapped ……..(2)

Carr’s Index10

The compressibility index of the powder

mixture was determined by Carr‟s

compressibility index. It is a simple test to

evaluate the BD and TD of a powder and

the rate at which it packed down. The

formula for Carr’s index is as below:

Carr’s index (%) = [(TD-BD) x100]/TD

……………….(3)


Hausner’s Ratio10

The Hausner’s ratio is a number that is

correlated to the flow ability of a powder

or granular material.

Hausner’s ratio = TD / BD

……………….(4)

Angle of Repose11

The angle of repose of powder mixture

was determined by the funnel method. The

accurately weight powder blend were

taken in the funnel. The height of the

funnel was adjusted in such a way the tip

of the funnel just touched the apex of the

powder blend. The powder blend was

allowed to flow through the funnel freely

on to the surface. The diameter of the

powder cone was measured and angle of

repose was calculated using the following

equation.

tanФ=h/r …(5)

Where, h and r are the height and radius of

the powder cone respectively.

Drug Content Analysis

To determine the drug content, weight of

the crushed pellets equivalent to 100 mg of

drug was weighed, transferred in to a flask

(100 ml) and first dissolved in 10 mL of

solvent methanol12 and then make up the

volume up to 100 mL with 0.1 N HCl. The

solution filtered through 0.45μ filters was

measured using UV-Visible

spectrophotometer at 256nm (λmax). To

avoid the interference of the excipients,

placebo blend was also treated similarly

and kept as blank. Standard solution was

prepared by weighing accurately 100 mg

of Ketoprofen separately and following the

similar dilution procedure. From the

absorbance of the test solution, the amount

of drug in the solution was calculated.

In vitro Drug Release

The in vitro drug release study was carried

out using USP dissolution test apparatus 2

(paddle method). The dissolution test was

performed in 900 ml of 0.1N HCl

maintained at 37±0.5 °C for two hour at a

paddle speed of 50 rpm. A sample (10 ml)

of the solution was withdrawn from the

dissolution apparatus hourly, and the

samples were replaced with fresh

dissolution medium. The samples were

filtered through 0.45 µ membrane filter

and diluted to a suitable concentration with

respective media. Absorbance of these

solutions was measured at λmax of the

drugs in that media using double beam UV

visible spectrophotometer. Dissolution

medium was replaced with phosphate

buffer pH 6.8 after two hours for further

study.

Comparison of Dissolution Profiles for

Selection Optimum Batch

The similarity factor (f2) given by SUPAC

guidelines for a modified release dosage


form was used as a basis to compare

dissolution profiles. The dissolution

profiles are considered to be similar when

f2 is between 50 and 100. The dissolution

profiles of products were compared using

an f2 which is calculated from following

formula:

………….. (7)

Where, n is the dissolution time and Rt and

Tt are the reference (here is the theoretical

dissolution profile of ketoprofen) and test

dissolution value at time t. All batches (F1

to F9) were compared with theoretical

profile for calculation of similarity factor.

Fourier Transform- Infrared

Spectroscopic Analysis (FT- IR)

FT-IR spectroscopy was carried out to

check the compatibility between drug and

polymer. The FT-IR spectra of drug with

polymers were compared with the standard

FT-IR spectrum of the pure drug.

Kinetic Modeling of Dissolution Data13,14

To analyze the in vitro release data various kinetic models were used to describe the release kinetics. The zero order rates describe the systems where the drug release rate is independent of its concentration. The first order describes the release from system where release rate is concentration dependent. Higuchi (1963) described the release of drugs from insoluble matrix as a square root of time

dependent process based on fickian diffusion. The Hixson-Crowell cube root law describes the release from systems where there is a change in surface area and diameter of particles or tablets. C=K0×t ……………………....... (8) Where, K0 = Zero-order rate constant expressed in units of concentration/time t = Time Log C = Log C0 - K1 × t / 2.303 ……………………………….….. (9) Where, C0 = Initial concentration of drug K1 = First order constant Q=KH×t1/2 ………….. (10) Where, KH = Constant reflecting the design variables of the system Q0

1/3–Qt1/3=KHC×t ………….. (11)

Where,

Qt = Amount of drug remained in time t

Q0 = Initial amount of the drug in tablet

KHC = Rate constant for Hixson-Crowell

rate equation

The following plots were made using the

in vitro drug release data

Cumulative % drug release vs. time

(Zero order kinetic model),

Log cumulative of % drug remaining

vs. time (First order kinetic model),

Cumulative % drug release vs. square

root of time (Higuchi model),

Cube root of initial concentration

minus the cube root of percentage of

drug remaining in the matrix vs. time

(Hixson-Crowell cube root law).

10011logX50 X

5.02

12

n

tttt TRwnf


Kinetic study of dissolution data of

batches F6 are depicted in Table.

RESULT AND DISCUSSION

From table 3 concluded that solubility of

poorly water-soluble Ketoprofen can be

improved by using inclusion complexation

with β-cyclodextrin. This might be due to

solubilising effect of water soluble β

cyclodextrin carriers.only drug show low

solubility. By formulation of inclusion

complexation with β cyclodextrin, there

was increase solubility. At the ratio of 1:1

(Ketoprofen: β-CD) solubility of drug was

found 0.51±0.124 in water.

From table 4 result of In-vitro drug release

of batches F1 to F9 ,in F6 formulation was

found highest amount of drug release

about 98.40 % w/w. it was found that F6

batch gives drug release up to 12 hrs.

Similarity factor were calculated for all

formulations, considering theoretical

profile as the reference standard. The

values for the same are depicted in table 5.

It can be seen that formulations F1 to F4

and F7 to F9 have low f2 similarity

values(less than 50). Suggesting that these

formulation show greatest deviation from

theoretical profile as compared to other

formulated products. F5 and F6

formulations show f2 values between 50-

75 indicating low differences of

dissolution profiles with that theoretical

profile. The values of similarity factor (f2)

for the batch F6 showed maximum value

68.78. Hence, formulation batch F6 was

considered as optimize batch.

The kinetics of the dissolution data were

well fitted to zero order, first order,

Higuchi model, Hixson-Crowell and

korsmeyer-peppas model as evident from

regression coefficients.

Here F6 formulation follows zero order

release kinetics as depicted in Table 6. In

case of the controlled release formulations,

diffusion, swelling and erosion are the

three most important rate controlling

mechanisms. To find out release

mechanism the in vitro release data were

fitted in Korsmeyer-Peppas equation, the

formulations F6 showed high linearity (R2:

0.9868), with a comparatively high slope

(n) values of >0.6, which appears to

indicate a coupling of diffusion and

erosion mechanisms. Hence, diffusion

coupled with erosion might be the

mechanism for the drug release.

The FTIR spectra of drug alone and in

combination with different excipients show

that main functional group peak remain

intact in the spectrum of drug with excipient

which shows compatibility between drug

and selected excipients.


Table 3 : Data of Ketoprofen- β Cyclodextrin Inclusion Complex Ratio

Ratio of

Ketoprofen: β-CD

Drug content

(%)

Solubility(mg/ml) in

water

Solubility(mg/ml) in

7.4 ph buffer sol.

Drug only 98.76±2.56 0.047±0.12 0.37±0.23

1:1 96.56±2.26 0.51±0.124 2.56±0.38

Table 4 : In-vitro Drug Release of Batches F1 to F9

Time

(hrs.)

F1 F2 F3 F4 F5 F6 F7 F8 F9

0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 1 12.98 11.63 10.00 11.35 11.49 11.90 10.41 10.41 9.87 2 25.30 18.25 22.29 17.44 16.22 17.85 18.78 17.97 16.88 3 37.22 31.99 31.47 32.92 28.31 27.11 27.92 26.29 25.05 4 46.83 39.38 46.57 39.37 34.84 36.48 35.80 33.61 32.09 5 58.04 51.58 56.15 51.71 41.45 43.51 44.32 41.02 38.94 6 70.98 59.85 65.55 62.56 53.00 53.05 50.62 47.15 45.59 7 86.50 74.85 72.62 75.82 58.44 63.23 56.17 53.34 51.90 8 96.23 85.53 82.88 89.09 66.51 72.84 62.59 58.92 56.92 9 93.20 96.60 91.20 96.95 76.56 80.52 68.67 63.47 61.04

10 96.62 96.14 94.34 96.22 83.19 88.01 74.81 68.20 66.29 11 95.46 94.85 91.94 94.93 90.30 94.08 79.79 74.46 71.45 12 96.31 95.70 92.94 96.14 94.12 98.40 89.15 81.47 76.80

Table 5 : Micromeritic Characteristic of Batches F1 to F9

Batches Bulk density Tapped density

Carr’s index (%)

Hausner Ratio

Angle of repose(θ0)

F1 0.52 0.59 13.46 1.13 27.11 F2 0.57 0.61 6.55 1.07 26.35 F3 0.56 0.61 8.19 1.08 25.98 F4 0.51 0.58 12.06 1.13 28.53 F5 0.50 0.59 15.25 1.18 24.37 F6 0.56 0.60 6.67 1.07 23.05 F7 0.53 0.61 13.11 1.15 25.41 F8 0.50 0.59 10.25 1.18 29.39 F9 0.55 0.65 15.38 1.18 29.44


Table 6 : Similarity Factor (f2) value for F1-F9

F1 30.46 F2 38.99 F3 39.87 F4 37.02 F5 66.28 F6 68.78 F7 47.15 F8 36.70 F9 32.80

Table 7 : Kinetic Modeling Data of F6 Batch

F6 Zero order

First Order

Higuchi Plot

Hixon Crowell

Korsmeyer

and

Peppas

R2 0.9950 0.9136 0.9792 0.9574 0.9868

Slope 8.36 0.0793 38.305 0.211 0.8503

Fig. 1 : Dissolution Profile of F1 to F9 Batches


Fig. 2 : FT-IR Spectrum of the Pure Ketoprofen

Fig. 3 : FT-IR Spectra of Physical Mixture of Drug Inclusion Complex, Sodium Alginate and Ethyl Cellulose

CONCLUSION From the present study, it can be

concluded that the prepared matrix pellets

demonstrate the potential use of Sodium

alginate, MCC and ethyl cellulose blend

for the development of controlled drug

delivery systems. β-cyclodextrin , which

used as water soluble carrier for water

insoluble Ketoprofen, increased solubility

of ketoprofen. Drug inclusion

complexation was prepared by kneading

method,1:1 ratio of drug and β-

cyclodextrin optimized ratio which

increase significant solubility of drug. The

results of micromeritic properties and

hausner ratio of the pellets were well

within the limits which indicate good flow

potential for the prepared pellets. From the

FTIR studies, it was observed that there

was no chemical interaction between the

drug and polymers. The drug release rate

was found vary among the formulations

depending on the compositions of

polymers used. Formulation F6 showed

highest amount of drug release 98.40% .

Similarity factor f2 value of formulation

F6 showed 68.78 which is highest value

than other formulation batch so

formulation F6 considered as optimized


batch. The n value of optimized batch,

observed by korsmeyer-peppas model was

found 0.8503, indicated that the drug

release through the polymeric matrix

follows diffusion and erosion mechanism.

Formulation F6 is an ideal formulation for

twice a day administration.

ACKNOWLEDGEMENT Authors wishes to acknowledge Torrent

pharma, Ahmedabad, Gujarat, india for

providing gift sample of drug, ketoprofen.

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HOW TO CITE THIS ARTICLE Patel, D, Y., Joshi, D, M., Shah, A, D. Preparation and Evaluation of Controlled Release Matrix Pellets of Ketoprofen. Journal Club for Pharmaceutical Sciences (JCPS), 1(I), 87-98

preparation and evaluation of controlled release matrix pellets of ketoprofen

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