Studies in Dissolution Enhancement of Ezetimibe by Solid Dispersions in Combination with a Surface Adsorbent

The aim of this investigation was to improve the dissolution properties of the water-insoluble drug ezetimibe (EZE) and potentially improve bioavailability. A combination of melt and adsorption techniques was employed for the preparation of solid dispersions. PEG 4000, PEG 6000, and Gelucire 44/14 were used as hydrophilic carriers, and lactose monohydrate was used as an adsorbent. Phase solubility curves are of AL type, indicating a linear relationship between drug solubility and carrier concentration. Dissolution studies reveal an improvement of in vitro drug release. Mathematical modeling indicates that drug release data are best described by the Korsmeyer–Peppas model, with Fickian diffusion as the possible drug-release mechanism. Physicochemical characterization of solid dispersions by Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), and powder X-ray diffraction (PXRD) suggests a reduction in drug crystallinity following dissolution enhancement. Hence, the present investigation reveals that the dissolution characteristics of EZE could be ameliorated in a solid dispersion. INTRODUCTION Out of several methods employed to enhance the dissolution characteristics of poorly water-soluble drugs, solid dispersion techniques have been widely reported by various researchers with encouraging results for different drugs. However, a solid dispersion system is somewhat limited by poor flow properties and poor stability. The processing variables of solid dispersions can be improved by the addition of adsorbent in the solid dispersion melt, thereby increasing the effective surface area of the drug leading to improved dissolution (1, 2). Various carriers have been used to prepare solid dispersion systems; among those, polyethylene glycols (PEG) and Gelucire 44/14 are employed in the present investigation. PEGs are used because of their low toxicity, high water solubility, low cost, and availability in a wide range of molecular weights. Gelucire 44/14 is a mixture of glycerol and PEG 1500 esters of long-chain fatty acids. The suffixes 44 and 14 refer to its melting point and its hydrophilic/lipophilic balance (HLB), respectively. PEG 4000, PEG 6000, and Gelucire 44/14 have been used successfully to improve the dissolution properties of poorly water-soluble drugs by preparing solid-dispersion systems (3–5). However, the solid dispersions prepared with these carriers are sticky and difficult to handle. Hence, they must be used in amalgamation with an adsorbent to improve their flow properties. Ezetimibe (EZE), 1-(4–fluorophenyl) –3(R)-[3-(4–fluorophenyl) –3(S) hydroxy-propyl]-4(S)-(4-hydroxyphenyl)-2azetidinone, is the first lipid-lowering drug that inhibits the intestinal uptake of cholesterol without affecting the absorption of fat-soluble nutrients. It is indicated as a monotherapy or in combination with statins for the treatment of hypercholesterolemia (6). EZE, being practically insoluble in water, exhibits a low dissolution profile in gastrointestinal fluids with variable bioavailability. Thus, researchers have investigated different approaches to ameliorate the dissolution characteristics of EZE (7–9) and optimize bioavailability with a less variable pharmacokinetic profile. In the present investigation, an attempt was made to improve the dissolution properties of EZE by preparing free-flowing solid dispersions. A combination of solid dispersion and adsorption techniques was employed for the preparation of the solid systems, using lactose monohydrate as adsorbent. The prepared solid dispersions were characterized by Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), and powder X-ray diffraction (PXRD). MATERIALS AND METHODS Materials EZE was kindly gifted by Mepro Pharmaceuticals Ltd. (Surendranagar, India). Gelucire 44/14 was a generous gift sample from Gattefosse Pvt. Ltd. (Mumbai, India). PEG 4000 and PEG 6000 were purchased from Sisco Research Lab Pvt. Ltd. (Mumbai, India). All reagents were of analytical grade. Double-distilled water was used throughout the work. Methods Phase Solubility Phase solubility studies were carried out as described by Higuchi and Connors (10). A quantity of EZE (about 10 mg) that exceeded its solubility was added to flasks containing 25 mL of solutions of different polymer *Corresponding author. diss-18-03-07.indd 55 8/31/2011 3:26:40 PM dx.doi.org/10.14227/DT180311P55