INTRODUCTION:

Solubility is one of the determinants of oral bioavailability of a drug. Due to poor aqueous solubility, many drug candidates become unsuccessful to reach market in spite of exhibiting potential pharmacodynamic activity. Also poorly aqueous soluble drugs currently in the market are administered at much higher individual does than actually desired to achieve necessary plasma levels .This leads to associated toxicity problems which reduce the benefits of therapy, patient convenience as well as patient compliance. Therefore, many strategies have been worked out to improve the aqueous solubility as well as release rate of such drugs from dosage forms and many more are under constant investigation¹.

Solid dispersions (SD) are one of the most promising strategies to improve the solubility and dissolution rate of poorly water – soluble drugs².

It is able to produce a local increase in the solubility (within the solid solution) and as the carrier dissolves, the drug comes into close contact with the dissolution medium. Solid dispersion of one or more active ingredients in an inert carrier or matrix at solid state prepared by melting (fusion), solvent evaporation or melting – solvent evaporation method. Broadly speaking there is however only two methods of preparing solid dispersions, namely fusion and solvent evaporation processes^3-4.Many hydrophilic excipients like polyethylene glycols, poloxamers and mannitol can be used to enhance the dissolution of drugs^5-6.

Diacerein is a new anti-inflammatory analgesic and antipyretic drug, developed specially for the treatment of osteoarthritis. It is highly effective in relieving the symptoms of osteoarthritis. It has novel mode of action that differentiates it from NSAIDs. Diacerein does not inhibit the synthesis of prostaglandins. Diacerein is 4, 5-Bis ( acetyloxy)- 9,10,dioxo-2-anthracene carboxylic acid soluble in 4,4 dimethylformamide and DMSO, insoluble in water, methanol, chloroform. Rehin, the active metabolite of Diacerein, directly inhibits IL-1 synthesis and release invitro and down modulate IL-1 induced activities. IL-1 plays fundamental role in osteoarthritis pathophysiology and cartilage destruction. It also inhibits IL-1 induced expression of cartilage degrading enzymes. Diacerein is very sparingly soluble in water (0.010mg/ml). The poor solubility (classified as BCS class II drug) and wettability of DIA give rise to difficulties in dissolution behavior of pharmaceutical formulation meant for oral or parenteral use, which may lead to variation in bioavailability^7-8. Many approaches have been carried out to enhance its solubility as like complexation with β CD and HPβCD^9-10.

Hence in the present investigation solid dispersions of DIA were formulated with the aim to improve its pharmaceutical properties (i.e. solubility and dissolution) by using water soluble carrier like polyethylene glycol ( PEG 4000 and PEG 6000 ) and surface active carrier like poloxamer (PXM 407).

MATERIALS:

DIA was obtained from Emcure Pharm. Ltd., Pune as a gift sample; PEG 4000 and PEG 6000 were obtained from Qualigens, Mumbai and PXM 407 was obtained from Signet Chemical Pvt. Ltd., Mumbai. All other chemicals used were of analytical grade.

METHODS:

Estimation of Diacerein:

Diacerein contents were estimated by UV Spectrophotometric method by measuring the absorbance at 344 nm (Figure No. 1). The method was validated for linearity, accuracy, precision and interference. The method obeyed Beers law in the concentration range of 10-60 μg/ml (r = 0.9979) ^[11]

Figure No 1: Spectrum of Diacerein

Preparation of solid dispersions:

The solid dispersions of DIA were prepared by using solvent evaporation and melt method.

I. Solvent evaporation method:

Solid dispersions containing diacerein with PEG-4000, with PEG-6000 and with PXM-407 as carrier in ratio of 1:1, 1:2 and 1:3 were prepared by solvent evaporation method. The drug and carrier were weighed according to the specified ratio. Diacerein and polymer dissolved in methanol in porcelain dish. The solution was stirred till slurry was formed. The solid dispersions were stored in hot air oven maintain at 45^oC for 24hrs to remove the residual solvents. The dispersions were triturated in a mortar and passed through sieve (No.60) to get uniform sized particle ^[11].

II. Melt method:

Solid dispersions containing diacerein with PEG-4000, with PEG-6000 and with PXM-407 as carrier in ratio of 1:1, 1:2 and 1:3 were prepared by melt method. The drug and carrier were weighed according to the specified ratio. The solid dispersions were prepared by heating accurately weighed amounts of drug and carrier in a closed teflon container in an oil bath at 80°C. The mixtures were stirred repeatedly and after 10 min cooled either at room temperature. Finally the SD were triturated in a mortar and passed through sieve (No. 60). The DIA-SD formulations are summarized in Table No. 1^[12].

Table 1: Formulation code for solid dispersions

Carriers for dispersion	Ratio	Solvent evaporation method	Melt method
PEG-4000	1:1	A1	A4
	1:2	A2	A5
	1:3	A3	A6
PEG-6000	1:1	B1	B4
	1:2	B2	B5
	1:3	B3	B6
PXM-407	1:1	C1	C4
	1:2	C2	C5
	1:3	C3	C6

Characterization of solid dispersion:

I Assay of drug content:

The drug content was calculated by dissolving SDs equivalent to 10 mg drug into 10 ml of phosphate buffer (pH 6.8) and then filtered through 0.45 μ filter and assayed for drug content using UV double beam (schimadzu) spectrophotometer at 344 nm (Figure No. 1). Three replicates were prepared, and the average drug contents were estimated. Actual drug content was calculated for all batches using the equation: ^[13].

II Saturation solubility study:

The saturation solubility studies on pure drug, and solid dispersion prepared by solvent evaporation and melt method were conducted. Plain DIA and SDs in excess quantity were placed in separate glass-stoppard flasks containing 10 mL of distilled water. The samples were placed in a laboratory shaker at 37 °C until equilibrium was achieved (48 h).Finally the aliquots solution were filtered by using whatman filter paper ( grade 41) and after a suitable dilutions of the titrate, the drug concentration was determined spectrophotometrically at 344nm. All solubility measurements were performed in triplicate^{12, 14}.

III Fourier transform infra-red spectroscopy:

IR spectrum of powder Diacerin and its different solid dispersions of the drug and polymer ratios 1:1, 1:2 and 1:3 respectively were recorded using Schimadzu Fourier transform infrared spectrophotometer by KBr disc method. The scanning range was 3900 to 250 cm‐1 and the resolution was 4 cm^‐^1,11.

IV Differential scanning calorimetric analysis:

The DSC measurements were performed on a Mettler Toledo differential scanning calorimeter. All accurately weighed samples were placed in sealed aluminum pans, before heating under nitrogen flow (20 mL/min) at a scanning rate of 10⁰C min^-1 from 40 to 250^oC. An empty aluminum pan was used as reference^15.

V In vitro drug release:

Dissolution study was carried out by using USP II apparatus-for 2 hr. The stirring rate was 100 rpm. Phosphate buffer pH 6.8 was used as medium (900 ml) and was maintained at 37 ± 5⁰C. Quantities of each type of solid dispersion of diacerein equivalent to 50 mg of diacerein were subjected to dissolution test. Accurately weighed 50 mg of diacerein was used as control and was subjected to similar test. 10 ml of an aliquot of the dissolution medium was withdrawn at predetermined time intervals and was replaced by equivalent amount of fresh medium kept at same temperature and sample solutions were filtered through Whatman filter paper no.41. The filtrates were analyzed by UV- visible spectrophotometer at 344 nm for phosphate buffer (pH 6.8). Drug concentration in the sample was determined from the standard calibration curve. Each dissolution rate test was repeated thrice and average values were reported¹¹.

RESULT AND DISCUSSION:

Determination of drug content:

The drug content of DIA solid dispersion was found to be in the range 97.77 ± 0.10 to 101.45 ± 0.03 and these values are within acceptable range. The uniformity of drug content for DIA- SDs formulations are shown in Table No. 2.

Table 2: Percentage drug content of solid dispersion

Carriers for dispersion	Ratio	Solvent evaporation method	Melt method
PEG-4000	1:1	98.80 ± 0.38	99.95 ± 0.53
	1:2	98.11 ± 0.29	99.56 ± 0.07
	1:3	99.19 ± 0.11	98.25 ± 0.42
PEG-6000	1:1	99.30 ± 1.22	101.45 ± 0.03
	1:2	99.42 ± 0.19	99.55 ± 0.28
	1:3	100.54 ± 0.24	98.68 ± 0.41
PXM-407	1:1	100.64 ± 0.21	99.66 ± 0.20
	1:2	98.47 ± 0.04	97.77 ± 0.10
	1:3	97.78 ± 0.14	97.98 ± 1.40

Saturation solubility study:

The solubility profile of DIA was found to be 0.0097mg/ml, and drug release was found to be only 41.52% in 2 hr during in vitro dissolution study, suggesting a strong need to enhance the solubility and dissolution of DIA. The improvement in solubility was observed for all solid dispersions. Increase in weight fraction of carriers resulted in an increased in the solubility of all solid dispersion systems. Maximum solubility enhancement was found in 1:3 ratio of DIA: PXM 407 prepared by melt method. Enhancement in saturation solubility was found to be in order of PXM 407 > PEG 6000 > PEG 4000. The saturation solubility for DIA- SDs formulations are shown in Table No. 3.

Table No.3: Result of saturetion solubility of diacerien soild dispertion

Carriers for dispersion	Ratio	Solvent evaporation method mg/ml	Melt Method mg/ml
PEG-4000	1:1	0.267 ± 0.67	0.386 ± 0.78
	1:2	0.361 ± 0.64	0.471 ± 0.44
	1:3	0.489 ± 0.08	0.547 ± 0.19
PEG-6000	1:1	0.340 ± 0.28	0.454 ± 1.19
	1:2	0.502 ± 0.64	0.579 ± 0.01
	1:3	0.597 ± 0.09	0.661 ± 0.81
PXM-407	1:1	0.565 ± 0.32	0.632 ± 0.33
	1:2	0.654 ± 0.34	0.782 ± 0.04
	1:3	0.751 ± 0.84	0.828 ± 0.91

FT-IR spectroscopy:

FTIR studies carried out to detect the possible interactions between diacerein, PEG-4000, PEG- 6000 and PEX-407 in solid dispersion. The characteristics peak of diacerein, PEG-4000, PEG- 6000 and PEX-407 and their solid dispersion are shown in Figure No.2. Comparing the spectra of solid dispersion prepared by solvent evaporation method and melt method with pure diacerein, PEG-4000, PEG- 6000 and PEX-407 revealed that SDs showed spectra with broader and shifted bands suggesting formation of H bonds between carbonyl group of DIA and hydroxyl group of host cavity. The other peaks are same as of DIA in solid dispersion confirming intactness of drug and no interaction with carriers there were no differences in the position of absorption bands of DIA.

(A)

(B)

(C)

(D)

(E)

(F)

(G)

(H)

(I)

(J)

Figure No.2: FT-IR of DIA, pure carriers and different solid dispersion system (A) DIA; (B) PEG-4000; (C) PEG-6000; (D) PXM-407; (E) SD with PEG-4000 prepared by melt method; (F) SD with PEG-4000 prepared by solvent evaporation method; (G) SD with PEG-6000 prepared by melt method; (H) SD with PEG-6000 prepared by solvent evaporation method; (I) SD with PXM-407prepared by melt method; and (J) SD with PXM-407prepared by solvent evaporation method

Differential scanning Calorimetry:

The DSC thermograms of DIA, PXM-407, and solid dispersion (DIA: PXM- 407 [1:3] prepared by melt method) are shown in figure 3A, 3B, and 3C respectively. Pure DIA showed sharp endotherm peak at 218 ºC, corresponding to melting point of DIA. DSC thermogram of PXM 407 was characterized by endothermic peak with high intensity at about 58⁰C which corresponds to the melting point of PXM 407. In case of DIA: PXM- 407 (1:3) solid dispersion prepared by melt method, there was shift of the DIA endotherm. Absence of peak for the drug indicates that the drug is distributed homogenously in an amorphous state within the solid dispersions without any interaction The shift and reduced in the intensity of DIA endothermic peak suggest better solubilization in carrier.

Figure 3A: DSC thermogram of DIA

Figure 3B: DSC thermogram of PXM- 407

Figure 3C: DSC thermogram of DIA with PXM-407 (1:3) prepared by melt method

In vitro dissolution studies:

The in vitro release profile of DIA from PEG 6000, PEG 4000 and PXM 407 solid dispersions (prepared by melt and solvent evaporation method) are shown in figure 4A, 4B and 4C. According to observations, drug release was increased with increasing the concentration of carriers. Solid dispersions prepared by melt method shows faster dissolution of drug than solvent evaporation method. Out of all the carriers PXM 407 shows faster dissolution; this may be due to the molecular and colloidal dispersion of drug in hydrophilic carrier matrix of poloxamer. This behavior further could be explained by physico-chemical properties of poloxamer. PXM 407 is composed of hydrophilic polyethylene glycol polymers, which leads to higher hydrophilic lipophilic balance (HLB) value and has greater tendency to solubilize into the water.

Figure 4A: Dissolution profiles of Diacerein and its solid dispersions prepared with PEG-4000 by melt method and solvent evaporation method

Figure 4B: Dissolution profiles of Diacerein and its solid dispersions prepared with PEG-6000 by melt method and solvent evaporation method.

Figure 4C: Dissolution profiles of Diacerein and its solid dispersions prepared with PXM-407 by melt method and solvent evaporation method.

CONCLUSION:

The solubility and dissolution rate of DIA was increased from solid dispersion prepared by melt method by using PXM 407 without any physical and chemical interaction. Solid dispersion prepared by melt method showed more a greater increase in the dissolution of DIA than solvent evaporation method. Solid dispersion of DIA: PXM 407 showed faster release than from that of PEG 4000 and PEG 6000 solid dispersions.

ACKNOWLEDGEMENT:

The authors are thankful to Dr. Avinash D. Despande, Director of Pharmacy, and Padm.Dr. D. Y. Patil Institute of Pharmaceutical Sciences and Research, Pimpri, Pune for providing necessary facilities. The authors are also thankful to Emcure Pharm. Ltd., Pune for providing gift sample of pure drug. Qualigens, Mumbai and Signet Chemical Pvt. Ltd., Mumbai for providing gift sample of excipients.

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Received on10.02.2011 Modified on 11.03.2011

Research J. Pharm. and Tech. 4(6): June 2011; Page 932-937