Engel G L, Farid N A, Faul M M, Richardson L A, Winneroski L L
Biopharmaceutics Department, Lilly Research Laboratories, A Division of Eli Lilly and Company, Indianapolis, IN 46285, USA.
Int J Pharm. 2000 Apr 5;198(2):239-47. doi: 10.1016/s0378-5173(00)00350-1.
LY333531 is a potent protein kinase C(beta) (PKC(beta)) inhibitor currently under development for the treatment of diabetic complications. Seven salts of LY333531 (hydrochloride, sulfate, mesylate, succinate, tartrate, acetate and phosphate) were evaluated during the early phase of development. Physical property screening techniques including microscopy, DSC, TGA, XRPD, hygroscopicity and solubility were utilized to narrow the selection to two salts: the mesylate and hydrochloride. Identification of the optimal salt form was based upon solubility, bioavailability, physical stability and purity. During the evaluation process three hydrated forms (anhydrate, monohydrate, and tetrahydrate) of the hydrochloride salt were identified. The mesylate salt was found to give only one, a monohydrate. Processing parameters (e.g. filtration rate, crystal form stability) demonstrated that the anhydrate was the preferred form of the hydrochloride salt. Bioavailability studies in dogs indicated that the C(max) and area under the plasma concentration vs. time curve (AUC) for LY333531 and its active metabolite, LY338522, following administration of the mesylate salt were approximately 2.6 times those obtained after the LY333531 HCl dose. This difference was presumed to be due primarily to the fact that the mesylate was five times more soluble than the hydrochloride salt in water. These factors led to selection and development of LY333531 mesylate monohydrate as the active pharmaceutical ingredient for clinical evaluation.
LY333531是一种强效的蛋白激酶C（β）（PKC（β））抑制剂，目前正处于研发阶段，用于治疗糖尿病并发症。在研发的早期阶段，对LY333531的七种盐（盐酸盐、硫酸盐、甲磺酸盐、琥珀酸盐、酒石酸盐、醋酸盐和磷酸盐）进行了评估。利用包括显微镜检查、差示扫描量热法（DSC）、热重分析法（TGA）、X射线粉末衍射法（XRPD）、吸湿性和溶解度在内的物理性质筛选技术，将选择范围缩小到两种盐：甲磺酸盐和盐酸盐。最佳盐形式的确定基于溶解度、生物利用度、物理稳定性和纯度。在评估过程中，确定了盐酸盐的三种水合形式（无水物、一水合物和四水合物）。发现甲磺酸盐只有一种一水合物形式。工艺参数（如过滤速率、晶型稳定性）表明，无水物是盐酸盐的首选形式。在犬类中的生物利用度研究表明，给予甲磺酸盐后，LY333531及其活性代谢物LY338522的Cmax和血浆浓度-时间曲线下面积（AUC）约为给予LY333531盐酸盐后获得值的2.6倍。这种差异据推测主要是由于甲磺酸盐在水中的溶解度比盐酸盐高五倍。这些因素导致选择并开发了LY333531甲磺酸盐一水合物作为用于临床评估的活性药物成分。
