Mechanistic Understanding of Solid–Solid Phase Transition Based on In Situ Single-Crystal-to-Single-Crystal Transformations: A Case Study of AZD5462

Polymorphism in active pharmaceutical ingredients is a critical factor influencing their physicochemical properties and performance in pharmaceutical applications. This study investigates the polymorphic solid–solid phase transition of a single crystal of AZD5462, a novel oral agonist of relaxin family peptide receptor 1 (RXFP1), being developed for the treatment of cardiorenal diseases. Utilizing in situ single-crystal-to-single-crystal (SCSC) transformations, we investigated the structural changes occurring between polymorphs within an enantiotropic system. Various analytical techniques, including thermal analysis and X-ray diffraction, were also employed to characterize these transitions. The results revealed a reversible phase transition between AZD5462 Form A and Form G, driven by temperature-induced crystal and molecular conformational changes. This highlights the potential of SCSC transformations as a valuable tool in the study of polymorphic behavior in pharmaceutical compounds, offering a deeper mechanistic understanding that can facilitate the understanding of polymorphic transformation.

药用活性成分的多晶型现象（polymorphism）是影响其理化性质与医药应用性能的关键因素。本研究针对AZD5462单晶的固-固相变（solid–solid phase transition）展开探究：AZD5462是一款正处于心肾疾病治疗研发阶段的新型松弛素家族肽受体1（relaxin family peptide receptor 1，RXFP1）口服激动剂。研究采用原位单晶-单晶（single-crystal-to-single-crystal，SCSC）转变技术，对互变体系（enantiotropic system）内不同多晶型间的结构变化进行了系统考察；同时结合热分析（thermal analysis）、X射线衍射（X-ray diffraction）等多种分析手段对该类相变行为进行表征。结果显示，AZD5462的A晶型与G晶型之间存在可逆相变，该相变由温度诱导的晶体及分子构象变化（conformational changes）所驱动。本研究证实了SCSC转变技术作为药用化合物多晶型行为研究工具的应用潜力，可为多晶型转变的机制提供更为深入的阐释，助力对该类相变过程的理解。