PREPARATION AND EVALUATION OF PARECOXIB MICROSPONGE HYDROGEL SUSTAINED RELEASED TABLET

Article Info: Received 14 May 2019; Accepted 14 June. 2019 DOI: https://doi.org/10.32553/jbpr.v8i3.615 Address for Correspondence: Maruthi. N, PG Department of Pharmaceutics, SJM College of Pharmacy, SJMIT Campus, NH4, Chitradurga577502, Karnataka, India. Conflict of interest statement: No conflict of interest ABSTRACT: Microsponges are the polymeric drug delivery systems composed of porous microspheres. They are tiny sponge like spherical particles that consists of myriad of inter-connecting voids within a non-collapsible structure with a large porous surface. The present work is to formulate and evaluate the Parecoxib Microsponge Hydrogel Sustained Release Tablet. The Microsponges of Parecoxib is prepared by Quasiemulsion solvent diffusion method using Ethyl cellulose and Eudragit RS100 as polymers and Di-butyl phthalate as Plasticizer. And they are characterized for FTIR studies, production yield, particle size analysis, DSC and SEM. The production yields of formulations were from 77.77 to 82.75. FTIR and DSC studies are revealed that the drug and polymer are compatible with each other during preparation. The average diameter of Microsponge is ranged from 536.9 nm to 489.7. Parecoxib Microsponge hydrogel were prepared as sustained release tablets by using sustained release polymers like MCC, Magnesium stearate, Lactose and talc. Preformulation of Microsponge granules were carried out by various parameters and post formulation were carried out by In-vitro dissolution studies, hardness, friability and weight variation tests. Formulation F3 shows good results for the drug release kinetics as controlled release and F6 formulation shows good results for the in-vitro dissolution studies for sustained release.


INTRODUCTION
The term "Drug Delivery" covers a very extensive range of techniques used to deliver therapeutic agents into the human body. Drugs are administered with a main aim of curing patient ailments. Drugs are never administered in their pure form but are converted in a suitable formulation so that its onset and intensity of action as well as total duration of action can be checked. Among the various routes of drug delivery oral route is most widely used route of drug delivery. But conventional dosage form offers few limitations which could be resolved by modifying the existing dosage form.

Sustained Release Drug Delivery System:
Among the various routes of drug delivery oral route is most preferred route. But conventional dosage form offers few limitations which could be resolved by modifying the existing dosage form. Sustained and controlled drug delivery system helps in constant plasma drug concentration and retards the release rate of drug thereby extending the duration of action. There are various formulation strategies for sustained release tablets among which diffusion system serves as an important tool.
Hence the problem like poor patient compliance, multiple dosing, and see-saw fluctuations can be easily minimized. They can be formulated by either direct compression or wet granulation method by using a variety of hydrophilic or hydrophobic polymers 1 .

Materials:
Parecoxib was procured from Dr. J Timmasetty, HOD and Professor, Department of Pharmaceutics, Bapuji College of Pharmacy, Davanagere as gift sample, Ethyl cellulose and Di-butyl-phthalate was supplied from Loba Chemie Pvt. Ltd, Dichloromethane was supplied from S.D Fine chemicals Ltd, Mumbai, Eudragit RS 100 was supplies from Yarrow Chemicals Pvt. Ltd. And polyvinyl alcohol was supplied from Fisher Scientific India Pvt. Ltd.

Preparation of Parecoxib Microsponge by Quasi Emulsion Solvent Method:
Microsponges were prepared by quasi emulsion solvent diffusion method. Various concentrations of polymers (Eudragit RS 100 and Ethyl cellulose) and drug (Parecoxib) was dissolved in 20 ml of Dichloromethane which acts as internal phase. The drug is dissolved under ultra-sonication at 350 C for 15 minutes. Then weighed 1gm of PVA was dissolve in 180 ml of water using water bath or magnetic stirrer not exceeding to 600 C and pour remaining 20 ml of water which acts as an external phase. Internal phase containing drug and polymer is poured to external phase (PVA and water), to this, add 1 ml of Dibutyl Phthalate for the plasticity enhancement. Stirred the above solution using a propeller at 1200 rpm for 2 hrs at room temperature. Microsponges were settles at the bottom. The liquid is poured through Whattmen filter paper then the Microsponges were collected on the filter paper then dried at room temperature for 12 hrs 2 .

Percentage Yield
The prepared Microsponges of all batches were accurately weighed. The measured weight of prepared Microsponges was divided by total amount of all the excipients and drug used in the preparation of the Microsponges gives the total percentage yield of Microsponges. It was calculated by using following equation 3 .

Morphology study using SEM
The morphological studies were carried out by ZEISS EVO. US Scanning Electron Microscope (SEM), connected with fine coat, JEOL JFC-1100E Ion sputter. The sample was loaded on copper sample holder and sputter coated with carbon followed by Gold 4 .

Morphological study using DSC
Differential scanning calorimetry (DSC) study was carried out to evaluate thermal behaviour and thermo tropic characteristics of the drug. Nearly 5 mg sample ( Parecoxib pure drug /ethyl cellulose /formulation F6) were sealed in aluminum pan followed by heating at a rate of 10°C/min over temperature range of 40-300°C under nitrogen atmosphere of flow rate 10 ml/min and thermogram (Mettler-Toledo DSC 821e, Switzerland) was obtained 5 .

Particle size determination
Particle size determination was done by Zeta potential analyser (Zetasizer) of Malvern Instruments Ltd. The instruments were designed to measure the size, shape and charge of particles. The average particle size was calculated as per the result.

Drug content studies
The weight equivalent to 100 mg of drug was taken and transferred to a 100 ml standard flask. 25 ml of ethanol and 25 ml of 7.4 pH phosphate buffer were added and shaken for about half an hour and the volume was made up to 100 ml with 7.4 pH phosphate buffer. The above solution was filtered and 5 ml of filtrate was taken and diluted to 100 ml with 7.5 pH phosphate buffer. The absorbance of the resulting solution was measured at 245 nm and the content of Parecoxib was calculated 6 .

Determination of pH
Required quantity of prepared Microsponge was taken in suitable container and measured its pH by using digital pH meter. Microsponges were stable up to the pH range from 1 to 11 7 .
Determination of viscosity 8,9 All formulated Microsponges were subjected to viscosity measurement by using a Brookfield digital viscometer (Analytical Technologies) by using spindle #2 at room temperature. The measurement of consistency of the Microsponge hydrogel was done by dropping a cone attached to a holding rod from distance of 10cm in such a way that, it should fall on centre of the glass cup filled with Microsponge. The distance travelled by the cone was measured.
In vitro diffusion study 10,11 Cellophane membrane was used for this study in Frantz Diffusion Cell. 100mg of Microsponge is placed in donor compartment with which is filled phosphate buffer 7.4. The membrane was mounted between the compartments of the Frantz Diffusion Cell. Reservoir compartment was filled with phosphate buffer 7.4. The study was carried out at 37± 1o and speed was adjusted to 100 to 120 rpm and it is carried out for 24 hours. 5 ml of sample was withdrawn from reservoir compartment by the help of hypodermic syringes at half an hour interval for 2 hours, then one hour interval for 10 hours and finally 6 hrs to next 24 hrs. And absorbance was measured spectrophotometrically at 245nm. Each time the reservoir compartment was replenished with the 5 ml fresh volume of phosphate buffer 7.4 pH solution to maintain constant volume.

A. Bulk density and tapped \ true density:
Both bulk density (BD) and Tapped / True density were determined. Powder of Microsponge was taken in a 10ml measuring cylinder and initial volume was write and tapped at height of 2.5cm at 2-second intervals until no further change in volume was noted after tapping. BD and TD calculated using the following formula.

B. Determination of carr's index:
The compressibility index of the powder determined by the Carr's Compressibility index as shown in following formula

C. Determination of the angle of repose:
Angle of repose was measured for the Microsponge powder, to observe the flow properties of powders. The Funnel method was used; the powder was allowed to pass freely through a funnel and poured onto a horizontal plane, fixed base diameter, free of vibration petri dish to form a cone. The funnel height was maintained at approximately 2-4 cm from the tip of the powder pile in order to minimize the impact of the falling powder on the tip of the cone. The tan of angle of repose (θ) was calculated after measuring the height (h) of the cone of the powder. This follows following formula where, h is the height of the pile in centimetre, r is the radius of the pile in centimetre

D. Determination of hausner's ratio
Hausner's ratio is a number that is correlated to the flow ability of a powder or granular material. The Hausner ratio is calculated by the formula where the freely settled bulk density of the powder, and the tapped density of the powder. A Hausner ratio greater than 1.25 is considered to be an indication of poor flowability. The formula is below mentioned 12 .

Formulation of Parecoxib Microsponge Sustained Release Tablets
The formulated and evaluated Parecoxib Microsponges were prepared as Sustained Release tablets. The Microsponge tablets were prepared as follows: First weighed all the tablet ingredients according to the required formula. Then prepared 10% starch paste by adding starch to the 100 ml water to 250 ml beaker and heat it until to get a smooth paste. Then blended the ingredients in mortar and pestle and add 100 mg of previously prepared Microsponge hydrogel to above. Then add sufficient quantity of starch paste to above blended powders and finally damp mass is prepared. This prepared mass was passed through sieve no #10 for the granules. This granule were dried under thermostatic ovens like tray drier until the moisture is completely removed. Then the dried granules were proceeded to further sieving (no #22 and #44) to make coarse and fines. Add 15% of fines to that of the total weight of coarse and finally add 2 % of talc. The tablets were compressed into flat-faced punches of 10 mm diameter using Rimek Mini Press-I single sided rotary multiple station tablet compression machine.

Post formulation studies of Parecoxib loaded Microsponge tablets
Weight variation: 10 tablets are selected randomly and weighed individually and collectively and % of weight variation is calculated by following formula.

Hardness of tablet:
The mechanical strength of the tablet was determined by using Monsanto hardness tester. This tester has a graduated scale which gives the reading in Kg/cm 2 . The tablet to be tested was placed between the spindle and anvil. The desired pressure needed to hold the tablet in position is applied by moving the screw knob in clockwise direction. The scale was moved so that the indicator rested at zero. The pressure was applied till the tablet breaks. The reading were noted.

Thickness of tablet:
Thickness of tablet is evaluated by using micrometre screw gauge. Test is carried out randomly on ten tablets and average values are calculated.
Friability: 10 tablets are weighed and placed in fribilator. The chamber is rotated for 4 minutes at a speed of 25 r.p.m. the tablets are removed from the chamber and weighed again. Loss in weight indicates friability. The tablets to be considered of good quality if loss in weight is less than 0.8%.

In vitro dissolution studies:
In vitro dissolution study of tablets was performed using USP XXIV type II (type II) dissolution apparatus (3 7 ± 0.5, 900 mL, 50 rpm) in phosphate buffer pH 7.4 for a period of 24 h. Aliquots were taken out at every 1 hour interval for 24 h, and the volume was replaced with an equivalent amount of aliquots of fresh dissolution medium. The samples were withdrawn and analysed spectrophotometrically at 245 nm respectively 13 .

UV spectrometric study
This Parecoxib showed maximum absorption at wavelength 245nm in phosphate buffer pH 7.4. The standard calibration curve obeys Beer's law and gives linear curve and the R 2 value is not greater than 0.999 14 .

FTIR studies
For the compatibility studies between drug and polymer selected are subjected to FTIR studies. IR spectrum of pure drug and polymer and physical mixture of drug and polymer (formulation) was recorded.
The IR spectra shows sharp peak at 3372 cm -1 due to presence of amine group (NH) and it shows the peak at 1678 cm -1 due to the presence of C=O groups corresponding to ketone groups. And presence of alkenes (C=C), the spectra shows peak at 1618 cm -1 . These similar peaks are obtained in formulation also. It indicates that the pure drug functional groups peaks were present in all the formulations without changes in the peaks position 15 .

SEM studies
The SEM images of formulation F3 and F6 reveals that the microsponges were highly porous in nature and pore size is less than 1μ with discrete spherical and smooth in surface.

Particle size analysis
The particle size determination of Microsponge formulation was carried out by particle size analyser (Zetasizer, Malvern) and recorded. The average diameter of the Microsponges was found to be 536 nm to 412nm. Particle size of Microsponges was increased on increasing in the polymer content and they were mention in

pH studies
The pH of all six formulations were performed by pH meter and it shown in the pH range of 6.2 to 6.9 as shown in Table no 3. The formulation F6 shows highest pH compare to other formulation. By changing different polymers in different concentration in the formulation may lead to changes in the pH of the preparation.

Viscosity studies
It was performed for all six Microsponge formulations. The viscosity is in the range of 2138 to 2497 cps. Formulation F6 shows highest viscosity range. These were free flowing in nature and optimum range. The values are mention in Table No. 3

Pre formulation studies of Parecoxib loaded Microsponge tablets
The blended granules with Microsponges were subjected to various preformulation studies like true density, bulk density, angle of repose, carr's index and finally hausner's ratio. The results were mentioned in Table no. 6. All preformulation studies shows that excellent flow property and they are in within the IP limits.