在结构信息的辅助下控制API中的多态性和溶剂化物同构,例如,分子构象或通过氢键缔合,对新药的工业发展至关重要,由于结晶产物的溶解度不同,溶出度曲线,可压缩性,或熔化温度。最终制剂的稳定性和药物粉末的技术因素进一步强调了精确结晶方案的重要性。当使用具有相当大的构象自由度和大量氢键供体或受体的高度柔性分子(例如,氟康唑,FLU).这里,冷却和悬浮结晶被应用于获得FLU的多晶型物和溶剂化物,一种广泛使用的唑类抗真菌剂,具有高分子柔韧性和几种已报道的多晶型物。四种多晶型中的每一种,FLUI,II,III,或者IV,可以从同一组醇(MeOH,EtOH,isPrOH)和DMF通过仔细控制结晶条件。第一次,获得了两种类型的FLU同构通道溶剂化物(9个新结构)。通过在Tol中冷却结晶制备I型溶剂化物,ACN,DMSO,BuOH,和BuON。在DCM中形成的II型溶剂化物,ACN,nPrOH,和BuOH在悬浮实验期间。我们根据新获得的溶剂化物及其去溶剂化产物的结构分析,提出了两种溶剂化物的去溶剂化途径。I型溶剂化物通过氢键键合的链重排去溶剂化为FLU形式I。II型溶剂化物去溶剂化首先导致同构去溶剂化,然后通过氢键二聚体重排转变为FLU形式II。将溶剂介导的相变与结构分析和固态NMR相结合,由周期性电子结构计算支持,使我们能够阐明FLU的相互关系和转化途径。
Control over polymorphism and solvatomorphism in API assisted by structural information, e.g., molecular conformation or associations via hydrogen bonds, is crucial for the industrial development of new drugs, as the crystallization products differ in solubility, dissolution profile, compressibility, or melting temperature. The stability of the final formulation and technological factors of the pharmaceutical powders further emphasize the importance of precise crystallization protocols. This is particularly important when working with highly flexible molecules with considerable conformational freedom and a large number of hydrogen bond donors or acceptors (e.g., fluconazole, FLU). Here, cooling and suspension crystallization were applied to access polymorphs and
solvates of FLU, a widely used azole antifungal agent with high molecular flexibility and several reported polymorphs. Each of four polymorphic forms, FLU I, II, III, or IV, can be obtained from the same set of alcohols (MeOH, EtOH, isPrOH) and DMF via careful control of the crystallization conditions. For the first time, two types of isostructural channel solvates of FLU were obtained (nine new structures). Type I
solvates were prepared by cooling crystallization in Tol, ACN, DMSO, BuOH, and BuON. Type II
solvates formed in DCM, ACN, nPrOH, and BuOH during suspension experiments. We propose desolvation pathways for both types of solvates based on the structural analysis of the newly obtained
solvates and their desolvation products. Type I
solvates desolvate to FLU form I by hydrogen-bonded chain rearrangements. Type II solvates desolvation leads first to an isomorphic desolvate, followed by a phase transition to FLU form II through hydrogen-bonded dimer rearrangement. Combining solvent-mediated phase transformations with structural analysis and solid-state NMR, supported by periodic electronic structure calculations, allowed us to elucidate the interrelations and transformation pathways of FLU.