Pharmaceutical cocrystals and salts are extensively researched in recent years due to their ability to tune the physicochemical properties of active pharmaceutical ingredients (APIs). A model API, olanzapine, an atypical antipsychotic drug classified as Biopharmaceutical Classification System class II, is used in this study. Cocrystals and salts of olanzapine are discovered using solvent drop grinding and ball milling. Appropriate coformers were selected based on a combination of hydrogen-bond propensity (HBP) and hydrogen-bond coordination (HBC) calculations. Eight new multicomponent phases of olanzapine, including one cocrystal hydrate with phenol; four anhydrous salts with salicylic acid, terephthalic acid, anthranilic acid, 3-hydroxybenzoic acid, and 2-aminoterephthalic acid; one salt dihydrate with terephthalic acid; and one salt solvate with 3-hydroxybenzoic acid and acetonitrile, have been discovered and characterized by PXRD and DSC. One reported cocrystal (olanzapine-resorcinol) has also been considered for the dissolution test. All these newly formed solid phases followed the “ΔpK_a rule of 3”. The crystal structures of cocrystal/salts were determined by single-crystal X-ray (sc-XRD) diffraction. With the collected single-crystal data, the crystal packings were found to be primarily stabilized via strong hydrogen bonds between carboxyl, phenolic hydroxyl of co-formers/salt-formers with the piperazine and diazepine nitrogen of olanzapine, which confirmed the predicted result from the HBP and HBC calculations. HPLC coupled with UV–vis detector was used in the solubility and dissolution test instead of UV–vis spectroscopy, to avoid the peak overlap between olanzapine and co-formers/salt-formers. A threefold increase in the solubility was observed in olanzapinium 3-hydroxybenzoate and olanzapinium anthranilate, and an almost fivefold increase in solubility of olanzapinium 2-aminoterephthalate.

近年来，药物共晶和盐因其能够调节活性药物成分 (API) 的理化特性而受到广泛研究。本研究使用模型 API 奥氮平，这是一种被归类为生物制药分类系统 II 类的非典型抗精神病药物。使用溶剂滴磨和球磨发现了奥氮平的共晶和盐。基于氢键倾向 (HBP) 和氢键配位 (HBC) 计算的组合选择合适的共形成剂。奥氮平的八种新多组分相，包括一种与苯酚的共晶水合物；水杨酸、对苯二甲酸、邻氨基苯甲酸、3-羟基苯甲酸和2-氨基对苯二甲酸的四种无水盐；一种对苯二甲酸盐二水合物；以及一种与 3-羟基苯甲酸和乙腈形成的盐溶剂化物，已被发现并通过 PXRD 和 DSC 进行表征。一种报道的共晶（奥氮平-间苯二酚）也被考虑用于溶出度测试。所有这些新形成的固相都遵循“Δpķ_一3”的规则。共晶/盐的晶体结构通过单晶 X 射线 (sc-XRD) 衍射确定。通过收集到的单晶数据，发现晶体堆积主要通过共形成物/盐形成物的羧基、酚羟基与奥氮平的哌嗪和二氮杂氮之间的强氢键稳定，这证实了预测结果HBP 和 HBC 计算。在溶解度和溶出度测试中使用 HPLC 和 UV-vis 检测器代替 UV-vis 光谱，以避免奥氮平和共形成物/盐形成物之间的峰重叠。观察到 olanzapinium 3-hydroxybenzoate 和 olanzapinium anthranilate 的溶解度增加了三倍，而 olanzapinium 2-aminoterephthalate 的溶解度增加了近五倍。