(M1430-08-54) Solubility Enhancement Using Anionic Poly(meth)Acrylate-Based Solid Dispersions

Purpose: Most developed pharmaceutical drugs and approximately 90% of drug candidates are poorly water-soluble, resulting in low dissolution rates and oral bioavailability. One of such drug candidates is clotrimazole, which is a cationic BCS class II drug. Solubilization of poorly water-soluble drugs is important in the development of drug products. Solid dispersion technologies (e.g. spray drying technique) convert poorly soluble crystalline actives into amorphous form dispersions within a polymeric matrix¹. Poly(meth)acrylates are amorphous in nature, have minimum hygroscopicity and have relatively high Tg value. Due to their appreciable solubility in a wide range of volatile organic solvents, they are carriers of choice for the formulation of solid dispersions of poorly soluble drugs by solvent processes. Hence, anionic poly(meth)acrylates can be specifically used for solubility enhancement of drugs, which have better absorption from intestine. The purpose of this study was to evaluate anionic poly(meth)acrylates as carrier polymer for solubility enhancement improvement of poorly water-soluble drug in intestinal pH using spray drying technology and study the stability of the formulations.

Methods: Clotrimazole exhibits first pass metabolism and short elimination half-life (2 h) which leads to low plasma concentration and accounts for its highly variable bioavailability in humans. Thus, clotrimazole was selected as model drug for this study. Anionic poly(meth)acrylate polymer (EUDRAGIT^® L 100-55) was chosen for solubility enhancement and was selected as a carrier polymer. Solid dispersions were prepared by dissolving EUDRAGIT^® L 100-55 in a 1:1 ratio in ethanol:water in a 9:1 ratio under continuous stirring conditions. Clotrimazole was added to the polymer solution and stirred well to get the clear solution. The spray solution solid concentration was maintained at 5% w/w. The clear solution obtained was spray dried using a lab-scale spray dryer (BUCHI, B-290) with an inert loop (BUCHI, B-295) attachment. An inlet temperature of 60°C and an outlet temperature of 40 - 43°C were maintained for the spray drying process. Nitrogen pressure of 7 bar and 50 mm flowmeter height was maintained during the entire process. Spray drying was done at a spray rate of 6 - 7 g/min and 90% aspirator rate to obtain solid dispersions as fine particles. Spray dried particles were evaluated for visual appearance, conversion to amorphous form by Differential Scanning Calorimetry (DSC), X-ray Powder Diffraction (XRPD) and dissolution rate in discriminating media (by USP type II apparatus). The solid dispersions prepared were packed in HDPE containers with and without desiccant and subjected to accelerated stability conditions of 40°C / 75% RH. Evaluation: Spray dried powder was analyzed for in vitro dissolution in buffer pH 6.8 with 0.05% sodium lauryl sulphate at 50 RPM 37^°C using USP II paddle apparatus (DS 8000 LABINDIA, India). All samples were analyzed using HPLC UV (Dionix Ultimate 3000, Thermo Scientific, USA) at 217 nm.

Results: In-vitro dissolution showed more than 73% of drug release within 30 min for spray dried solid dispersion while pure drug exhibited about 15% drug release after 30 min. Spray dried solid dispersions of clotrimazole with EUDRAGIT^® L 100-55 in a 1:1 ratio showed almost complete and faster dissolution compared to its own physical mixture (Figure 1). Such dissolution enhancement could be attributed to the conversion of crystalline clotrimazole to its amorphous form in spray dried solid dispersions. This was indicated by the absence of drug melting endotherm in DSC thermogram (Figure 2). This was further confirmed by the absence of characteristic diffraction peaks in the XRPD profile of solid dispersion (Figure 3).

Conclusion: Solubility of clotrimaozle was improved up to five times with the use of EUDRAGIT^® L 100-55 based solid dispersions. DSC and XRPD studies confirmed complete conversion of crystalline drug into amorphous state. Thus, this study proved that EUDRAGIT^® L 100-55 can be used as an effective carrier polymer to generate stable solid dispersions using spray drying for improving solubility of poorly soluble drugs.

Figure 1: Comparative dissolution profile of clotrimazole formulations

Figure 2: DSC Thermograms of clotrimazole formulations

Figure 3: XRPD Profiles of clotrimazole formulations