Multicomponent Crystals of Clozapine with Improved Solubility: A Combined Theoretical and Experimental Strategy on Coformer Screening and Structure–Property,Crystal Growth & Design

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Multicomponent Crystals of Clozapine with Improved Solubility: A Combined Theoretical and Experimental Strategy on Coformer Screening and Structure–Property
Crystal Growth & Design ( IF 3.2 ) Pub Date : 2023-08-30 , DOI: 10.1021/acs.cgd.3c00683
Chunrong Li ₁ , Chuntao Zhang ₁ , Yirui Yan ₂ , Wendong Liang ₁ , Jikun Xu ₁ , Wei Chen ₃

Affiliation

It is extremely challenging but greatly significant to predict the appropriate cocrystal/salt coformers for the design and preparation of functional multicomponent crystals without an inefficient “trial-error method”. The crystal engineering approach was employed to evaluate 46 coformers and obtain eight new clozapine (CLZ) multicomponent crystals so as to improve CLZ solubility. Potential coformers were initially screened by the conductor-like screening model for real solvents (COSMO-RS) approach, Cambridge Structural Database molecular complementarity analysis, and Hansen solubility parameters (HSPs) method with success hit rates of 82.4, 55.6, and 52.2%, respectively. Furthermore, eight multicomponent crystals of CLZ with maleic acid, oxalic acid, fumaric acid, succinic acid, and citric acid were investigated to reveal the detailed crystal structures and the properties, via single-crystal X-ray diffraction (SCXRD), powder X-ray diffraction, Fourier-transformed infrared spectroscopy, differential scanning calorimetry, solubility, RH (relative humidity) stability, and dynamic water vapor adsorption tests. Their relationship between crystal structures and intermolecular interactions were also discussed. The structures of eight multicomponent crystals were first resolved by SCXRD, proving the transfer of protons from the carboxyl radical of the acid to the CLZ piperazine. Four of eight the multicomponent crystals not only achieved higher water solubility than CLZ but also showed excellent humidity stability. Additionally, Hirshfeld surface analysis and molecular electrostatic potential surface analysis were carried out to investigate interactions in multicomponent crystals and the provenance of salt crystals. Finally, the atoms-in-molecules analysis was performed to compare the interaction energy and assess the strength of intermolecular hydrogen bonds within the multicomponent crystals. This study not only diversified the solid form of CLZ and demonstrated the practicability of the COSMO-RS screening method but also served as a role model for the selection of coformers for the preparation of multicomponent crystals.

中文翻译：

溶解度提高的氯氮平多组分晶体：共聚体筛选和结构-性能的理论与实验相结合的策略

在不使用低效的“试错法”的情况下，预测用于设计和制备功能性多组分晶体的合适的共晶/盐共形成物极具挑战性，但意义重大。采用晶体工程方法对46种共形成体进行了评价，获得了8种新的氯氮平（CLZ）多组分晶体，以提高CLZ的溶解度。通过真实溶剂的类导体筛选模型（COSMO-RS）方法、剑桥结构数据库分子互补分析和汉森溶解度参数（HSP）方法初步筛选了潜在的共形成物，成功命中率分别为82.4%、55.6%和52.2%。分别。此外，CLZ 的八种多元晶体与马来酸、草酸、富马酸、琥珀酸、通过单晶 X 射线衍射 (SCXRD)、粉末 X 射线衍射、傅里叶变换红外光谱、差示扫描量热法、溶解度、RH（相对湿度）研究了柠檬酸和柠檬酸的详细晶体结构和性质。稳定性和动态水蒸气吸附测试。还讨论了它们的晶体结构和分子间相互作用之间的关系。首先通过 SCXRD 解析了八种多组分晶体的结构，证明了质子从酸的羧基转移到 CLZ 哌嗪。八个多组分晶体中的四个不仅比 CLZ 具有更高的水溶性，而且还表现出优异的湿度稳定性。此外，进行赫什菲尔德表面分析和分子静电势表面分析来研究多组分晶体中的相互作用和盐晶体的来源。最后，进行分子中原子分析以比较相互作用能并评估多组分晶体内分子间氢键的强度。这项研究不仅使CLZ的固体形态多样化，证明了COSMO-RS筛选方法的实用性，而且为选择用于制备多组分晶体的共形成体提供了榜样。进行分子中原子分析是为了比较相互作用能并评估多组分晶体内分子间氢键的强度。这项研究不仅使CLZ的固体形态多样化，证明了COSMO-RS筛选方法的实用性，而且为选择用于制备多组分晶体的共形成体提供了榜样。进行分子中原子分析是为了比较相互作用能并评估多组分晶体内分子间氢键的强度。这项研究不仅使CLZ的固体形态多样化，证明了COSMO-RS筛选方法的实用性，而且为选择用于制备多组分晶体的共形成体提供了榜样。

更新日期：2023-08-30

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