药物胶体形成及转晶中的分子组装机理研究

Drug gelling seriously affected the solution crystallization operation and the crystal quality. The traditional idea was to inhibit gelling, but difficult to implement. Through the preliminary work, the project group found that drug gel can transform into crystals with large size, perfect crystal habit and different crystal forms. Therefore, a new idea of gel-to-crystal transformation was proposed to solve the crystallization difficulty of the drug which is apt to gel. At present, the researches on drug gelling and gel-to-crystal transformation have rarely been reported, and the relevant theories were lack. So the in-depth study on the rules and mechanisms was urgently needed. Using cefotaxime sodium, cefquinome and erythromycin ethylsuccinate as model drugs, referencing the research methods in the fields of gelation and crystallization, by multi-scale characterization and online monitoring experiments in combination with simulation, this project will carry out two main research parts: (1) the rules for gelation and gel-to-crystal transition, (2) the mechanisms for gelation and gel-to-crystal transition. Through the research above, it was expected to reveal the interactions among the drug molecules and the drug-solvent molecules, and the formation laws of short-range order 3-D networks in the gel, clarify the molecular assembly rules in the transition process of drug gel to crystals, reveal the nucleation and growth mechanism during the transition process, and provide the experimental and theoretical basis for the regulation of crystal structure and morphology. The achievements in this project would have broad application prospects and high scientific value, and be beneficial to the promotion of crystallization technological level improvement in China's pharmaceutical industry.

药物成胶严重影响溶液结晶过程操作以及晶体质量。传统溶液结晶的思路是如何抑制成胶，但实施难度大。前期工作发现，药物胶体可以转晶，且晶体粒度大、形态好，并有多晶型现象。为此，本项目提出一个新思路——胶体转晶——来解决易成胶药物结晶难题。目前，有关药物成胶及转晶研究报道稀少，相关理论缺乏，急需对此开展深入研究。本项目以头孢噻肟钠、头孢喹肟和琥乙红霉素为模型药物，借鉴凝胶和结晶领域的研究方法，通过多尺度表征和在线监测实验，结合模拟，开展（1）药物成胶与转晶规律研究和（2）药物成胶与转晶机理研究。旨在揭示胶体中药物分子间、药物与溶剂分子间相互作用，及其形成短程有序三维网络的规律；阐释药物胶体向晶体转变过程中的分子组装规则，明晰胶体转晶的成核和生长机理，为实现晶体结构和形态的调控提供实验和理论依据。研究成果具有广阔的应用前景，而且有较高的科学价值，将有助于促进我国制药工业结晶技术水平的提升。

药物成胶严重影响溶液结晶操作及晶体质量。本项目以第三代头孢类抗生素头孢噻肟钠（CTX）、兽用抗生素头孢喹肟（CFQ）和大环内酯类抗生素琥乙红霉素（EES）为模型药物，开展药物成胶和转晶的规律与机理研究。研究结果包括：1、EES胶状物属于超分子凝胶；CTX胶状物是液液相分离的油相；CFQ胶状物既不是凝胶也不同于油相。2、溶剂极性和氢键供受体能力是影响药物成胶和转晶的两个重要因素。对CTX，溶剂极性越强，越有利于形成CTX胶体；在氢键供体能力值和氢键受体能力值都大于0.5的溶剂中形成的胶体能够转晶。对CFQ，溶析剂氢键供体能力越弱，CFQ与溶析剂的相互作用越弱，CFQ与水的相互作用越强，越容易形成胶状物。对EES，胶凝溶剂的介电常数在18.3~37.5之间，Hansen极性力参数δp在6.1~18 MPa1/2之间，Kamlet−Taft极化性参数π*在0.48~0.88之间。3、揭示了CTX胶状物转晶机理：CTX胶状物中CTX与溶剂之间的极性相互作用被相对更强、具有专一性和方向性的氢键替代，特别是CTX中COO-与水分子形成氢键，CTX通过水分子桥连促成了CTX胶体转向三维周期结构。揭示了CFQ无定型转晶机理：在无定型和晶体溶解度差的推动下，无定型溶解伴随成核和生长；无定型中少量水的存在保持了CFQ分子一定的迁移性，促进了CFQ中C=O 与NH2间氢键等分子间相互作用的形成以致三维周期结构。揭示了EES胶凝机理：EES分子中的羰基、酯基和糖苷键等多个含氧官能团通过氢键与氢键供体溶剂分子形成二元或三元凝胶因子，胶凝因子以层状堆积方式自组装为凝胶纤维，并以晶体失配成核和生长机理形成空间网络结构，包裹溶液胶凝。4、分别基于实测二元和三元相图开发了EES凝胶和晶态CFQ制备方法。本项目开发的CFQ晶体和EES凝胶的制备方法拥有自主知识产权，探明的药物胶体成因以及从分子水平上解释的成胶和转晶机理推动了晶体工程理论的发展。