An organic molecule may crystallize in numerous distinct lattices, and the slow and unpredictable transitions between multiple crystal forms are a significant concern in its pharmaceutical application. Recent results indicate that the transformation of olanzapine (OZPN) from anhydrous to hydrate crystals is mediated by mesoscopic solute-rich clusters. Here we demonstrate the existence of such clusters in undersaturated OZPN solutions in purely aqueous and mixed EtOH/aqueous solvents. The clusters occupy about 10^–8 to 10^–7 of the solution volume and capture ca. 10^–7 to 10^–5 of the dissolved OZPN. The average cluster radius is steady in time at about 35 nm and independent of the OZPN concentration and the solvent composition, whereas the OZPN fraction captured in the clusters is dictated by the solution thermodynamics. Both behaviors are in dire conflict with classical theories of phase transformation and recent aggregation models. They are, however, consistent with the predictions of a model that assumes the formation of OZPN dimers and their decay upon exiting the clusters. We propose that a transient dimer, which may be akin to the centrosymmetric dimer present in all of the 60 known OZPN crystal structures, may underlie cluster formation. The finding of cluster formation in organic systems and the proposed cluster mechanism provide guidance toward enhanced control over nucleation, molecular transitions, and the solid forms in molecular systems.

中文翻译：

---

奥氮平溶液中的中观溶质富集簇

有机分子可能会在许多不同的晶格中结晶，并且多种晶体形式之间的缓慢且不可预测的转变是其药物应用中的重要关注点。最近的结果表明，奥氮平（OZPN）从无水晶体转变为水合物晶体是由介观富集溶质团簇介导的。在这里，我们证明了在纯水和混合EtOH /水性溶剂中的不饱和OZPN溶液中此类簇的存在。群集约占解决方案体积的10 ^–8到10 ^–7，并捕获大约ca。10 ^–7至10 ^–5溶解的OZPN。平均团簇半径在约35 nm处时间稳定，并且与OZPN浓度和溶剂组成无关，而团簇中捕获的OZPN分数由溶液热力学决定。两种行为都与经典的相变理论和最新的聚集模型发生了严重冲突。但是，它们与模型的预测一致，该模型假定OZPN二聚体的形成及其在离开团簇后的衰减。我们建议一个瞬态二聚体，可能类似于在所有60种已知的OZPN晶体结构中存在的向心对称二聚体，可能是簇形成的基础。有机体系中团簇形成的发现和拟议的团簇机理为加强对成核，分子转变，