INTRODUCTION:

Aceclofenac is a potent anti-inflammatory, analgesic agent indicated for acute and chronic treatment of rheumatoid arthritis, osteoarthritis and ankylosing spondylitis.¹ As the aceclofenac drug is poorly water soluble many approach has been done to increase its solubility.² The most attractive option for increasing the release rate is improvement of the solubility through salt formulation, solubilisation and particle size reduction which help to increase dissolution rate and thereby oral absorption and bioavailability of poorly water soluble drugs.³ In 1961 Sekiguchi and Obi developed a practical method where by many of the limitations with the bioavailability enhancement of poor water-soluble drugs can be over come.⁴ This method, which was later termed solid dispersion, it is a technique in which dispersion of one or more active ingredients in an inert carrier or matrix at solid state prepared by the melting, solvent evaporation or melting-solvent method.⁵A Hot Melt technique was used which was characterized by important features such as increase in surface area and possible control of particles size. In addition, it is a one stage continuous process, easy to scale-up and only little dependent on the solubility of drug and polymer.⁶

Hence an approach of these techniques that is preparation of solid dispersion was followed to improve the solubility and bioavailability of the drug aceclofenac.

MATERIALS AND METHODS:

Aceclofenac was obtained from NuLife Pharmaceuticals Pune, as a gift sample. PVP K-30 was obtained from Research-Lab Fine Chem Industries, Mumbai.

A. Preparation of Aceclofenac Tablets:

Mix Aceclofenac, Eudragit and Dicalcium phosphate dihydrate for 10min. In a separate container, Dibutyl phthalate and Isopropyl alcohol was added until a homogenous mixture was formed. This was added slowly to Aceclofenac content material to form loose aggregates of blend and pass through 8 mesh sieve onto paper lined tray. The granules were dried in a low humidity and then passed through 20 mesh screen into blending vessels. Magnesium stearate was added after passing through 250µm sieve to dried granules and was blend for 2min.⁷

B. Preparation of solid dispersion:

Hot melt method was used for the preparation of solid dispersions. The drug aceclofenac in combination with PVP-K30 in different ratio of (1:1, 1:1.5, 1:2) as shown in Table No 1 of formulation F2, F3, F4 were heated in a porcelain dish to obtain crystals of aceclofenac and PVP-K30. Hot Melt was carried out using laboratory scale heating mantle.⁸

Table No.1: Details of formulations

Formulation code

Carrier

Ratio

Method

Lab Tablets

Marketed Tablet

Drug/PVP K-30

1:1

1:1.5

1:2

Solid

Dispersion

(Hot Melt Technique)

F0- Lab Tablet, F1-Marketed Tablet,( F2 -F3- F4)-Formulation of Drug:PVP K-30.

Evaluation of solid dispersion:

Evaluation of tablets was done by following parameters.

1. FT-IR of pure drug and all preparations

For FT-IR study, the pellets were prepared for all the formulation and Aceclofenac using potassium bromide. The pellets were subjected to FT-IR instrument (Jasco Corporation FTIR spectrometer) for obtaining of IR spectra.⁹

2. Differential Scanning Calorimeter (DSC):

DSC studies were carried out using DSC 821e instrument equipped with an intracooler (Mettler-Toledo, Switzerland). Indium/zinc standards were used to calibrate the DSC temperature and enthalpy scale. The samples were hermetically sealed in aluminium pans and heated at a constant rate of 10°C/min over a temperature range of 25–175°C. Inert atmosphere was maintained by purging nitrogen gas at flow rate of 50 ml/min.¹⁰

3. In vitro Release studies:

Accurately weighted amount of sample as shown in was taken for dissolution studies. An aliquots of sample were withdrawn at predetermined intervals of time and analyzed for drug release by measuring the absorbance at 274nm (phosphate buffer pH 7.4 was used as dissolution medium) The volume withdrawn at each time intervals replaced with same amount of fresh quantity of dissolution medium.¹¹

4. Stability studies:

Stability studies of selected formulation were carried out by keeping them at ambient room temperature conditions for 3 months at 40^oC and 75% relative humidity (RH) in the stability chamber Periodically (initial, 1, 2 and 3 months. All the formulation was subjected to drug content analysis after stability studies.¹²

RESULTS AND DISCUSSION:

1. FTIR spectrum of drug and its preparation:

A decrease in the intensity of peak of –NH group of Aceclofenac (at 3319.3 cm^-1 ) or ternary amide peak of PVP K-30 (at 1642.3 cm^-1) (as shown in Fig no 1 and 2) may support intermolecular hydrogen bonding between drug and carrier in solid dispersion. A decrease in the intensity of bands may also be due to the amount of compounds. Thus it can be concluded with some reservation, the absence of interaction between drug and PVP K-30 compounds by FTIR.

Fig 1: FTIR spectrum of Aceclofenac.

Fig 2: FTIR spectrum of Aceclofenac and PVP.

2. Differential Scanning Calorimetry (DSC):

Pure Aceclofenac showed a melting endotherm at 153°C(as shown in Fig No 3). No peak was observed in the thermo grams of Solid Dispersions indicating amorphous for when compared.(as shown in Fig No 3,4,5)

Fig 3: DSC of Aceclofenac:

Pure Aceclofenac showed a melting endotherm at 153°C (as shown in Fig no 3)

Fig 4: DSC of PVP-K30:

Pure PVP K-30 showed a melting endotherm at 95°C (as shown in Fig no 4)

Fig 5: DSC of Aceclofenac:PVP K-30:

Pure Aceclofenac showed a melting endotherm at 143° and Pure PVP K-30 showed a melting endotherm at 86°C indicating no interaction(as shown in Fig No 5)..

Invitro drug release:

Dissolution rate of Aceclofenac increases with the increase in the concentration of carriers when the dissolution test was carried in phosphate buffer pH 7.4 (as shown in Table no 2 and Figure 6). This may be due to increase in the surface area, particle size reduction and fast disintegration of tablet. Dissolution of the Aceclofenac increase with increasing proportions of carriers and T50% and T70%values were more with the Solid Dispersion. These observations indicate the enhanced dissolution of Solid Dispersion preparation with increase in the concentration of carriers possibly due to the increase in surface area, particle size reduction in the course of the solid dispersion preparation, polymorphic transformation of drug crystals and chemical interaction between drug and carrier.

Fig 6: Depicts different formulation showing %drug release in phosphate buffer pH 7.4

Table 2: Depicts different formulation showing %drug release

Time (min.)	F0	F1	F2	F3	F4
5	4.643	6.643	7.811	8.389	8.597
10	9.499	11.819	16.795	18.174	18.956
15	16.02	18.827	27.827	30.112	33.538
20	23.648	26.414	35.644	37.916	40.278
25	31.872	34.858	41.587	44.952	50.825
30	38.373	42.901	48.335	50.941	61.586
35	46.148	49.602	54.155	59.47	71.283
40	51.399	57.148	58.085	68.209	77.408
45	53.267	62.927	65.144	71.81	82.737
50	55.663	67.689	71.283	76.418	84.736

4. Stability studies:

The stability of optimized Solid Dispersion F4 was monitored up to 3 months at 40^oC and 75% relative humidity (RH) in the stability chamber Periodically (initial, 1 and 3 months for Solid Dispersion samples were removed and characterized by in-vitro drug release . It was found that there was minute decrease in drug release profile (as shown in Table No.3).This shows that the prepared Solid Dispersion were stable at the studied temperature

Table No.3: Stability Study Data for 1 Month

Formulation	Appearance	Drug Content (%)	% Drug Release in 7.4 pH
F4	Dry Tablet	83.71	81.079

Stability Study Data for 2 Months

Formulation	Appearance	Drug Content (%)	% Drug Release in 7.4 pH
F4	Dry Tablet	83.65	80.053

Stability Study Data for 3 Months

Formulation	Appearance	Drug Content (%)	% Drug Release in 7.4 pH
F4	Dry Tablet	82.24	79.059

DISCUSSION:

The solubility of the model drug Aceclofenac was enhanced by forming its Solid Dispersion with PVP K-30.The optimized formulation F-4 i.e Solid Dispersion tablet showed a percentage drug release of 84% in 50 min as compared to that of the 67% in 50 min of F-1 i.e. the marketed conventional formulation, so formulation F4 was taken as a optimized formulation .This explains the competency of the technical approach followed for solubility enhancement of Aceclofenac.

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Received on 08.06.2011 Modified on 17.06.2011

Research J. Pharm. and Tech. 4(8): August 2011; Page 1307-1310