互变异构药物分子共晶和晶体盐的固体核磁共振研究

Unlike in solution, in which different tautomeric forms can be observed and manipulated by adjusting the medium properties, in the solid state tautomeric compounds are usually present exclusively in the most stable tautomeric form. This project focuses on the solid state R&D of tautomeric drug molecules. By using cocrysals and crystalline salt formation, different tautomeric form and ionization states of these drugs may be fixed via supramoleclar stabilization. The crystalline complexes obtained from the screening process will be subjected to in-deepth solid state NMR measurement, combined with single-crystal or powdered XRD analysis and DFT calculations. For these crystalline complexes, the tautomeric and ionization state of drug molecule and intermolecular interactions will be carefully determinated. Spectral characteristics of different tautomeric/ionization forms and supramolecular synthons of these samples will be summarized. Energy mechanism for the stable existence of diffrent tautomeric/ionization forms in crystalline complexes will be revealed theoretically. Additionlly, phase-transformations among different crystalline complexes composed with same starting materials will be investegated. A serials of novel cocrystals and salts of tautomeric drug molecules will be demonstrated, which must improve our understanding towards tautomerism in solid state, and attract industrial attention to the property modifacations and IP development of tautomeric drug molecules by using cocrystal and salt formation. Furthermore, experience and rules extracted from this study and references can be used to guide the solid form screening, and a complete set of solid state analysis strategy towards the crystalline complexes of tautomeric drug molecules will be provided. We also believe that the achievements of this project will make a significant contribution to the pharmaceutcal Quality by Design objective in solid state.

有机分子的互变异构现象在溶液中被广泛观察到，但固态下此类化合物常以单一的最稳定互变异构形式存在。本项目针对互变异构药物分子，通过引入客体小分子与其形成分子间相互作用，稳定其不同的互变异构形式和离子状态，进而生成新颖的药物共晶和晶体盐。项目主要通过固体核磁共振技术、晶体学分析手段和理论计算，解析晶体复合物中分子的互变异构/离子状态和分子间相互作用，总结超分子合成子种类和谱学指纹规律，理解互变异构分子不同互变异构/离子形式稳定存在的能量机制，探讨组分相同的不同晶体复合物之间的转化关系。项目丰富的案例展示一方面会加深我们对药物分子在固态下互变异构现象的理解，另一方面也会引起业界对通过成共晶和盐改善此类药物性能和拓展知识产权的关注。研究成果有助于互变异构药物分子晶体复合物高效筛选和固相解析策略的完善，将为药物固相研发的质量源于设计理念提供有力支撑。

有机分子的互变异构现象在溶液中被广泛观察到，但固态下此类化合物常以单一的最稳定互变异构形式存在。本项目旨在通过超分子相互作用形成晶体复合物，从而稳定获得化合物的不同互变异构形式。对项目所使用的药物分子而言，获得的新颖药物共晶和晶体盐同时可以扩大药物的固相形式范围，为改善药物的理化性能提供选择。项目改进了一套基于分子表面静电势能的共晶虚拟筛选方案。综合使用超分子合成原则、pKa原则、结构相似性原则和表面静电势能作用，项目对11个药物化合物和2个可药用小分子进行了晶体复合物筛选。共获得了50个晶体复合物，并对5个原料化合物进行了结构方面的新探讨。项目在司坦唑醇、磺胺二甲基嘧啶、厄贝沙坦、安赛蜜等多个品种上观测到了全面的互变异构和离子状态，并总结了其中的核磁共振谱学指纹和新颖超分子合成子作用。结合理论计算，热分析和相转化实验探讨了起始原料相同的不同晶体复合物之间的稳定和转化关系。项目丰富的案例展示加深了我们对药物分子在内的有机化合物在固态下互变异构现象的理解。同时也提示可以通过形成共晶来稳定药物不同互变异构形式，进而改善此类药物性能和拓展知识产权。项目实施为互变异构药物分子晶体复合物高效发现提供了虚拟筛选与机械化学和溶液法实验筛选结合的策略，获得的新颖合成子可用于指导新的共晶筛选，谱学指纹及其建立过程可用于无单晶样品的分子离子状态判定。项目实施将在互变异构和共晶研究领域为药物固相研发的质量源于设计理念提供支撑。