A Molecular Simulation Approach to Control the Crystallization of Pharmaceutical Compounds During Dissolution

CTS-9526328 Nair Rodriquez-Hornedo密歇根大学摘要该项目旨在了解在表面活性剂存在下亚稳态固相溶解过程中控制结晶的分子过程。目标包括确定亚稳态固相在稳定分子晶体成核中的作用，并解释表面活性剂缔合对成核机理和晶体形态的影响。实验将使用二水卡马西平作为模型药物和两种类型的表面活性剂，脂肪族长链表面活性剂和胆盐。分子模拟将被用来研究结晶学参数和主要晶面的分子结构的作用。关键问题是溶解的亚稳相的晶面是否促进了稳定晶相的形核。如果在非常低的过饱和度下发生成核，溶液中的药物浓度可能永远达不到所需的水平。关于表面活性剂对成核和结晶的影响的结果将对制药工业特别有用，并可能对特种化学品的制造产生影响。

CTS - 9526328 Nair Rodriquez-Hornedo University of Michigan ABSTRACT The project aims at understanding the molecular processes that control crystallization during dissolution of metastable solid phases in the presence of surfactants. The objectives include identifying the role of metastable solid phases on the nucleation of stable molecular crystals and explaining the effects of surfactant association on nucleation mechanism and crystal morphology. Experiments will be performed using dihydrate carbamazepine as a model drug and two types of surfactant, aliphatic long-chain surfactants and bile salts. Molecular modeling will be used to study the role of crystallographic parameters and molecular structure of dominant crystal faces. The key question is whether nucleation of the stable crystalline phase is enhanced by crystal surfaces of the dissolving metastable phase. If nucleation occurs at very low supersaturations, the drug concentration in solution may never reach the desired levels. The results on the effects of surfactants on nucleation and crystallization will be particularly useful to the pharmaceutical industry and may also have an impact on the manufacturing of specialty chemicals.