Yamashita Hiroyuki, Sun Changquan Calvin
Analytical Research Laboratories, Technology, Astellas Pharma Inc., Tsukuba-shi, Ibaraki, 305-8585, Japan.
Pharmaceutical Materials Science and Engineering Laboratory Department of Pharmaceutics College of Pharmacy, University of Minnesota, Minneapolis, Minnesota, 55455, U.S.A.
Pharm Res. 2017 Dec 29;35(1):4. doi: 10.1007/s11095-017-2309-x.
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.
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.
IDR of CBZ-GLA in a pH 1.2 HCl solution was improved when GLA was present in the solution. Precipitation of CBZ·2HO 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.
The excess GLA increased the aqueous solubility of CBZ·2HO and, thereby, reduced the propensity to precipitation of CBZ·2HO 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.
使用可溶性共晶体是递送难溶性药物的一种有前景的策略。然而，溶解过程中难溶性晶型的沉淀阻碍了共晶体片剂的成功开发。本研究旨在了解通过使用过量共形成剂来改善可溶性共晶体溶解性能的机制。
研究了卡马西平（CBZ）与戊二酸（GLA）形成的高溶性共晶体。评估了过量GLA对溶解度和固有溶解速率（IDR）的影响。还测量了GLA溶液的粘度。使用粉末X射线衍射法检查粉末和颗粒的固体形式。测量不同比例的共晶体和GLA混合物的IDR，以确定在水性环境中维持CBZ-GLA高溶解速率的合适配方。
当溶液中存在GLA时，CBZ-GLA在pH 1.2 HCl溶液中的IDR得到改善。当GLA浓度≥100 mg/mL时，消除了CBZ·2H₂O的沉淀。IDR的提高伴随着CBZ在GLA溶液中的溶解度增加和溶液粘度升高。IDR曲线趋势与通过溶液粘度归一化的溶解度曲线匹配良好。共晶体和GLA的混合物在模拟肠液中导致IDR提高。
过量的GLA增加了CBZ·2H₂O的水溶性，从而通过降低过饱和度降低了溶解过程中CBZ·2H₂O沉淀的倾向。该策略使得能够开发出一种溶解速率比CBZ-GLA显著提高的CBZ-GLA制剂。
