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.⁵ A 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 and into that Effervescent Mixtures was used for rapid disintegration.⁶ Hence an approach of combination of these two techniques that is preparation of effervescent mixture based solid dispersion was followed to improve the solubility and bioavailability of the model drug aceclofenac.

MATERIALS AND METHODS:

Aceclofenac was obtained from NuLife Pharmaceuticals Pune, as a gift sample. PVP K-30, Citric acid, Tartaric acid and Sodium bicarbonate 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) formulation F2, F3, F4 (as shown in Table No 1) 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

C. Preparation of Effervescent Mixture based Solid Dispersion using PVP K-30:

The drug Aceclofenac in combination with PVP-K30 and effervescent mixture in different ratio (as shown in Table No.1), were heated in a porcelain dish to obtain crystals of together effervescent mixture based solid dispersion of aceclofenac using PVP-K30.⁹

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.¹⁰

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

Table No.1: Details of formulations

Formu lation code

Carrier

Ratio

Method

F10

F11

F12

F13

Drug/PVP K-30

Drug/PVP K-30/EM

1:1

1:1.5

1:2

1:1;1

1:1.5:1.5

1:2:2

1:2:3

1:2:4

1:2:5

1 :2:6

1:2:7

1:2:8

Solid Dispersion

(Hot melt method)

F0- Lab Tablet, F1-Marketed Tablet,( F2 -F3- F4)-Formulation of Drug:PVP K-30, (F5-F6-F7-F8-F9-F10-F11-F12-F13) Formulation of Drug:PVP K-30:EM

3. In vitro Release studies:

Accurately weighted amount of sample (as shown in Table No 2) 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 (as shown in Table No 3) 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:

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) or hydroxy group of effervescent mixture (at 1216.3 cm^-1) may support intermolecular hydrogen bonding between drug and carrier in solid dispersion(as shown in Fig No 1,2,3). 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 three compounds by FTIR.

Fig 1: FTIR spectrum of Aceclofenac.

Fig 2: FTIR spectrum of Aceclofenac and PVP.

Fig 3: FTIR spectrum of Aceclofenac: PVP:EM

2. Differential Scanning Calorimetry (DSC):

Pure Aceclofenac showed a melting endotherm at 153°C(as shown in Fig No 4). No peak was observed in the thermo grams of effervescent mixture based SDs indicating amorphous for when compared.(as shown in Fig No 4,5,6,7,8)

Fig 4: DSC of Aceclofenac:

Pure Aceclofenac showed a melting endotherm at 153°C(as shown in Fig No 4).

Fig 5: DSC of Effervescent mixture:

Pure Effervescent mixture showed a melting endotherm at 190°C(as shown in Fig No 5).

Fig 6: DSC of PVP-K30:

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

Fig 7: 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 7)..

Fig 8: DSC of Aceclofenac:PVP K-30:EM:

Pure Aceclofenac showed a melting endotherm at 151°C and Pure PVP K-30 and Effervescent Mixture showed a melting endotherm at 95°C and 191⁰C (as shown in Fig No 8).

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). 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 effervescent mixture based SDs(as shown in Fig No 9). These observations indicate the enhanced dissolution of effervescent mixture based SDs with increase in the concentration of carriers possibly due to the increase in surface area, particle size reduction and fast disintegration of tablet in the course of the Effervescent Mixture based solid dispersion preparation, polymorphic transformation of drug crystals and chemical interaction between drug, carrier and effervescent mixture.

Table 2: Depicts different formulation showing %drug release

Time (min.)	F0	F1	F2	F3	F4	F5	F6	F7
0	0	0	0	0	0	0	0	0
1	--	--	--	--	--	--	--	--
2	--	--	--	--	--	--	--	--
3	--	--	--	--	--	--	--	--
4	--	--	--	--	--	--	--	--
5	6.643	4.643	7.8	8.389	8.597	17.467	18.253	18.253
10	11.819	9.499	16.795	18.174	18.956	30.235	36.047	36.047
15	18.827	16.02	27.827	30.112	33.538	38.404	43.407	43.407
20	26.414	23.648	35.644	37.916	40.278	48.342	51.909	51.909
25	34.858	31.872	41.587	44.952	50.825	57.059	64.129	64.129
30	42.901	38.373	48.335	50.941	61.586	62.35	73.332	73.332
35	49.602	46.148	54.155	59.47	71.283	69.028	79.278	79.278
40	57.148	51.399	58.085	68.209	77.408	76.802	87.481	87.481
45	62.927	55.663	65.144	71.81	82.737	83.046	89.079	89.079
50	67.689	59.655	71.283	76.418	84.736	82.124	84.977	84.977
55	67.138	59.212	71.115	76.234	84.479	81.535	84.349	84.349
60	67.059	59.128	70.801	75.906	84.131	80.969	83.81	83.81

Time (min.)	F8	F9	F10	F11	F12	F13
0	0	0	0	0	0	0
1	--	--	--	23.27	15.108	24.837
2	--	--	--	37.288	28.288	28.104
3	--	--	--	55.126	37.765	39.638
4	--	--	--	65.13	50.569	52.272
5	24.929	34.631	40.499	73.187	62.028	61.328
10	42.893	53.805	62.328	86.875	86.673	84.292
15	62.276	67.668	77.422	96.093	96.271	96.383
20	80.417	80.735	93.297	--	--	--
25	92.747	95.594	96.881	--	--	--

Fig 9: Depicts different formulation showing %drug release in phosphate buffer pH 7.4

4. Stability studies:

The stability of optimized Effervescent Mixture Based SDs F11 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 Effervescent Mixture Based 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 Effervescent Mixture Based Solid Dispersion was stable at the studied temperature.

Table No.3: Stability Study Data for 1 Month

Formulation	Appearance	Drug Content (%)	% Drug Release in 7.4 pH
F11	Dry Tablet	95.71	93.079

Stability Study Data for 2 Months

Formulation	Appearance	Drug Content (%)	% Drug Release in 7.4 pH
F11	Dry Tablet	94.65	92.053

Stability Study Data for 3 Months

Formulation	Appearance	Drug Content (%)	% Drug Release in 7.4 pH
F11	Dry Tablet	94.24	91.059

DISCUSSION:

The solubility of the model drug Aceclofenac was enhanced by forming its Solid Dispersion with PVP K-30. In order to further enhance the solubility, a breakthrough approach of combination of solid dispersion technique and effervescence was followed to develop an Effervescent Mixture based Solid Dispersion formulation.The optimized formulation F-11 i.e.Effervescent Mixture based Solid Dispersion tablet showed a percentage drug release of 96% in 15 min as compared to that of the 16% in 15 min of F-1 i.e. the marketed conventional formulation and the formulation F12 and F13 shows the same percentage of drug release but it increases the cost of material and size of the tablet so formulation F11 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 26.04.2011 Modified on 19.06.2011

Research J. Pharm. and Tech. 4(11): Nov. 2011; Page 1682-1686