非典型氢键供体型API的结晶规律和机理研究

There are two problems with the preparation of crystals of the atypical hydrogen bond donor-type active pharmaceutical ingredient (API). The first is that solvent-free crystals are difficult to obtained, and the second is that solvent screening experiments for solvates preparation are numerous and time consuming. In fact, the atypical hydrogen bond donor-type API has the basic conditions for the formation of weak intermolecular interactions such as atypical hydrogen bonds. Therefore, a new idea of regulation of the crystal structure of atypical hydrogen bond donor-type API based on the weak intermolecular interaction such as atypical hydrogen bonds was proposed. While, there have been no reports about how to promote crystal structures basing on the weak intermolecular interactions such as atypical hydrogen bonds. Using 4 kinds of atypical hydrogen bond donor-type APIs such as spironolactone as the model drugs, by experiments, quantum chemistry calculation, molecular dynamics simulation in combination with spectrum analysis, this project will carry out two main research parts: the crystallization rules and mechanism of the solvates and solvent-free crystals. Through the research above, it was expected to elucidate the mechanism of API-solvent molecules recognition, to find out the formation law of the weak intermolecular interactions such as non-typical hydrogen bonds between API molecules, to reveal the API molecular conformation, intermolecular interaction sites and interaction modes that affect the binding stability of API-solvent, API-API in solution, and provide theoretical basis for the regulation of crystal structures of the atypical hydrogen bond donor-type API. The research results of this project would have broad application prospects and high scientific value, and be beneficial to enhance the level of crystallization technology in China's pharmaceutical industry.

制备非典型氢键供体型药物活性成分（API）的晶体存在两个问题：1-晶态非溶剂化合物难求，2-溶剂化合物的溶剂筛选盲目。其实，非典型氢键供体型API具备形成非典型氢键等弱相互作用的基本条件。因此，本项目提出基于非典型氢键等分子间弱相互作用调控API晶体结构的思路，相关研究鲜有报道。为此，本项目以螺内酯等4种非典型氢键供体型API为模型药物，采用实验研究、分子模拟与光谱分析相结合的方法，开展非典型氢键供体型API溶剂化合物、非溶剂化合物的结晶规律和机理研究，旨在阐明1）API-溶剂分子的识别机制，2）API分子间非典型氢键等弱相互作用的形成规律，3）结晶溶液中影响API-溶剂、API-API结合稳定性的API分子构象、分子间相互作用位点和相互作用方式，为调控非典型氢键供体型API的晶体结构提供理论依据。研究成果具有较高的应用价值和理论意义，有助于我国制药工业结晶技术水平的提升。

药物活性成分（API）通常制备成晶体。含有典型的氢键供体和氢键受体的API可以通过自身分子间典型氢键构筑晶体结构。对于非典型氢键供体型API，如何基于API-API之间非典型氢键以及API-溶剂分子之间氢键调控晶体结构？本项目以依托考昔(ETR) 和奥美拉唑钠(OMS)两种非典型氢键供体型API为模型药物，采用实验研究、分子模拟与光谱分析相结合的方法，围绕非典型氢键供体型API溶剂化合物和非溶剂化合物的结晶规律和机理、固液平衡相图、共晶组装机理四方面开展研究。首次制备出ETR的6种单溶剂化物、 1种双溶剂化物、6种共晶和1种共晶溶剂化物并解析了晶体结构。阐明溶剂的氢键供体能力决定ETR非溶剂化物晶型I和V的形成，溶剂极性决定ETR溶剂化物的形成，ETR分子上磺酰基与溶剂分子之间的相互作用强弱是影响ETR晶型Ⅰ成核快慢的关键因素，砜甲基和吡啶环两个极性官能团在ETR溶剂化物自组装过程中起到了重要的作用。证明了ETR晶型V和晶型I是为互变体系，热力学转晶温度为（353.45±0.10）K，测定了OMS-溶剂1-溶剂2三元相图，表达了溶剂化物之间、溶剂化物与非溶剂化物之间的相转变关系。OMS无水物结晶相区较小，升高温度有利于制备无水物。热力学计算表明，溶解过程与脱水都为熵驱动过程。OMS一水合物转变为OMS甲醇溶剂化物、OMS一水合物转变为OMS乙醇溶剂化物，OMS乙醇溶剂化物转变为OMS甲醇溶剂化物是熵驱动过程。降低温度有利于通过甲醇溶剂化物或乙醇溶剂化物制备一水物。在所有的共晶和共晶溶剂化物中，甲基吡啶氮和氯吡啶氮作为了氢键受体而非砜基氧，因为吡啶氮的电子活性更高，范德华相互作用在ETR共晶的分子组装中起重要作用。项目研究结果可用于指导非典型氢键供体型API多晶型、溶剂化合物和共晶等新晶态的溶剂/配体筛选和晶体结构调控，具有较高的应用价值和理论意义。