Hiroyuki Yamashita1,2, Changquan Calvin Sun3,4. 1. Analytical Research Laboratories, Technology, Astellas Pharma Inc., Tsukuba-shi, Ibaraki, 305-8585, Japan. 2. Pharmaceutical Materials Science and Engineering Laboratory Department of Pharmaceutics College of Pharmacy, University of Minnesota, Minneapolis, Minnesota, 55455, U.S.A. 3. Pharmaceutical Materials Science and Engineering Laboratory Department of Pharmaceutics College of Pharmacy, University of Minnesota, Minneapolis, Minnesota, 55455, U.S.A.. sunx0053@umn.edu. 4. , Minneapolis, U.S.A.. sunx0053@umn.edu.
Abstract
PURPOSE: The use of soluble cocrystals is a promising strategy for delivering poorly soluble drugs. However, precipitation of poorly soluble crystal form during dissolution hinders the successful tablet development of cocrystals. This work was aimed to understand the mechanisms for improving dissolution performance of a soluble cocrystals by using excess coformer. METHODS: A highly soluble carbamazepine (CBZ) cocrystal with- glutaric acid (GLA) was studied. Impact of excess GLA on solubility and intrinsic dissolution rate (IDR) was assessed. Viscosity of GLA solutions was also measured. Solid form of powders and pellets was examined using powder X-ray diffractometry. IDRs of cocrystal and GLA mixtures in different ratios were measured to identify a suitable formulation for maintaining high dissolution rate of CBZ-GLA in an aqueous environment. RESULTS: IDR of CBZ-GLA in a pH 1.2 HCl solution was improved when GLA was present in the solution. Precipitation of CBZ·2H2O was eliminated when GLA concentration was ≥100 mg/mL. The improved IDR was accompanied by higher solubility of CBZ in GLA solution and increased solution viscosity. The trend in IDR profile matched well with the solubility profile normalized by solution viscosity. Mixture of cocrystal and GLA led to improved IDR in simulated intestinal fluid. CONCLUSIONS: The excess GLA increased the aqueous solubility of CBZ·2H2O and, thereby, reduced the propensity to precipitation of CBZ·2H2O during dissolution by lowering the degree of supersaturation. This strategy allowed development of a CBZ-GLA formulation with a significantly enhanced dissolution rate than CBZ-GLA.
PURPOSE: The use of soluble cocrystals is a promising strategy for delivering poorly soluble drugs. However, precipitation of poorly soluble crystal form during dissolution hinders the successful tablet development of cocrystals. This work was aimed to understand the mechanisms for improving dissolution performance of a soluble cocrystals by using excess coformer. METHODS: A highly soluble carbamazepine (CBZ) cocrystal with- glutaric acid (GLA) was studied. Impact of excess GLA on solubility and intrinsic dissolution rate (IDR) was assessed. Viscosity of GLA solutions was also measured. Solid form of powders and pellets was examined using powder X-ray diffractometry. IDRs of cocrystal and GLA mixtures in different ratios were measured to identify a suitable formulation for maintaining high dissolution rate of CBZ-GLA in an aqueous environment. RESULTS: IDR of CBZ-GLA in a pH 1.2 HCl solution was improved when GLA was present in the solution. Precipitation of CBZ·2H2O was eliminated when GLA concentration was ≥100 mg/mL. The improved IDR was accompanied by higher solubility of CBZ in GLA solution and increased solution viscosity. The trend in IDR profile matched well with the solubility profile normalized by solution viscosity. Mixture of cocrystal and GLA led to improved IDR in simulated intestinal fluid. CONCLUSIONS: The excess GLA increased the aqueous solubility of CBZ·2H2O and, thereby, reduced the propensity to precipitation of CBZ·2H2O during dissolution by lowering the degree of supersaturation. This strategy allowed development of a CBZ-GLA formulation with a significantly enhanced dissolution rate than CBZ-GLA.
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