Structure–property correlation is an important aspect in crystal engineering which has direct applications in the development of pharmaceutical solid dosage forms. In this manuscript, we present a combined structural, thermal and computational study of seven new cocrystals and cocrystal solvates of an antipsychotic drug, olanzapine, with three coformers (hydroquinone, resorcinol and catechol) and attempt to understand the effect of solid-state molecular packing on the thermal properties (desolvation and melting behaviour). The cocrystals were designed by utilizing the robust hydrogen-bonded synthons between the drug and coformers, while the cocrystal solvates were obtained by the isostructural replacement of toluene in a previously reported multicomponent structure by benzene, xylene and ethyl benzene. The positional variations of hydroxyl groups in coformer molecules had a remarkable influence on the crystal packing of cocrystals. The olanzapine–hydroquinone (OLZ–HQ) combination in 1 : 1 stoichiometry crystallized as cocrystal solvates that was attributed to the persistent formation of rectangular hydrogen-bonded grid networks with inherent hydrophobic cavities for aromatic guest molecule inclusion. In contrast, the olanzapine–resorcinol (OLZ–RES) and olanzapine–catechol (OLZ–CAT) combinations in 1 : 1 stoichiometry resulted in non-solvated cocrystals and can be classified as pharmaceutical cocrystals. The desolvation patterns of cocrystal solvates were explained based on the structural similarities and dissimilarities, host–guest interactions, void types (closed vs. open), void size (narrow and wide), packing coefficients and boiling points of the guest molecules. Solid-state DFT calculations were performed to assess the desolvation energies, stabilization energies of desolvated systems and lattice energies of all cocrystals and cocrystal solvate systems and the results were correlated with the experimental observations. The solvent molecules play an important role in the structure stabilization, rendering the crystal lattice of the OLZ–HQ structure energetically feasible and compensating for the loss of packing density rather than simply occupying the void space in the crystal structure. The large melting point differences and thermal stabilities of two anhydrous cocrystals (M.P. of OLZ–RES is 196 °C and M.P. of OLZ–CAT is 135 °C) were also explained on the basis of packing coefficients and lattice energy calculations.

中文翻译：

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晶体堆积对奥氮平共晶体和共晶体溶剂化物的热性能的影响：计算的见解

结构-性质的相关性是晶体工程中的重要方面，其在药物固体剂型的开发中具有直接的应用。在本手稿中，我们提出了抗精神病药物olanzapine的七个新共晶体和共晶体溶剂化物与三种共形成物（对苯二酚，间苯二酚和邻苯二酚）的结构，热学和计算学组合研究，并试图了解固态分子堆积的作用的热性能（去溶剂化和熔化行为）。通过利用药物和共形成剂之间牢固的氢键合子来设计共晶，同时通过甲苯，二甲苯和乙苯等以前报道的多组分结构中甲苯的异结构置换获得共晶溶剂化物。共形成分子中羟基的位置变化对共晶体的晶体堆积有显着影响。化学计量比为1的奥氮平-对苯二酚（OLZ-HQ）组合结晶为共晶溶剂化物，这归因于矩形氢键网格网络的持续形成，该网格网络具有固有的疏水腔，可用于芳香族客体分子。相反，化学计量比为1：1的奥氮平-间苯二酚（OLZ-RES）和奥氮平-邻苯二酚（OLZ-CAT）组合会导致非溶剂化共晶体，可归类为药物共晶体。共晶溶剂化物的去溶剂化模式是根据结构上的相似点和不同点，主客体相互作用，空隙类型（封闭 1化学计量法结晶为共晶体溶剂化物，这归因于矩形氢键网格网络的持续形成，该矩形氢键网格网络具有固有的用于芳族客体分子的疏水腔。相反，化学计量比为1：1的奥氮平-间苯二酚（OLZ-RES）和奥氮平-邻苯二酚（OLZ-CAT）组合会导致非溶剂化共晶体，可归类为药物共晶体。共晶溶剂化物的去溶剂化模式是根据结构上的相似点和不同点，主客体相互作用，空隙类型（封闭 1化学计量法结晶为共晶体溶剂化物，这归因于矩形氢键网格网络的持续形成，该矩形氢键网格网络具有固有的用于芳族客体分子的疏水腔。相反，化学计量比为1：1的奥氮平-间苯二酚（OLZ-RES）和奥氮平-邻苯二酚（OLZ-CAT）组合会导致非溶剂化共晶体，可归类为药物共晶体。共晶溶剂化物的去溶剂化模式是根据结构上的相似点和不同点，主客体相互作用，空隙类型（封闭 化学计量比为1：1的奥氮平-间苯二酚（OLZ-RES）和奥氮平-邻苯二酚（OLZ-CAT）组合会导致非溶剂化共晶体，可归类为药物共晶体。共晶溶剂化物的去溶剂化模式是根据结构上的相似点和不同点，主客体相互作用，空隙类型（封闭 化学计量比为1：1的奥氮平-间苯二酚（OLZ-RES）和奥氮平-邻苯二酚（OLZ-CAT）组合会导致非溶剂化共晶体，可归类为药物共晶体。共晶溶剂化物的去溶剂化模式是根据结构上的相似点和不同点，主客体相互作用，空隙类型（封闭与开孔），空隙尺寸（窄和宽），堆积系数和客体分子的沸点。进行了固态DFT计算，以评估所有共晶体和共晶体溶剂化物体系的去溶剂化能，去溶剂化系统的稳定能以及晶格能，并将结果与​​实验结果相关联。溶剂分子在结构稳定中起着重要作用，使OLZ-HQ结构的晶格在能量上可行，并能补偿堆积密度的损失，而不是简单地占据晶体结构中的空隙。两种无水共晶的熔点差和热稳定性（OLZ–RES的MP为196°C，MP为