a Department of Physical Chemistry, School of Pharmacy and Pharmaceutical Sciences , Hoshi University , Tokyo , Japan.
b Central Research Laboratories, School of Pharmacy and Pharmaceutical Sciences , Hoshi University , Tokyo , Japan.
Pharm Dev Technol. 2019 Apr;24(4):479-486. doi: 10.1080/10837450.2018.1514521. Epub 2018 Sep 11.
Clozapine (CLZ) is an atypical antipsychotic medication used in the treatment of schizophrenia and is poorly soluble in water (0.05 mM). In this study, we have investigated the effect of β-cyclodextrin (CD) and its derivatives on the solubility of CLZ. The solubility of the CLZ was measured to generate a phase solubility diagram, and the interaction between CLZ and sulfobutyl ether-β-cyclodextrin (SBE-β-CD) in aqueous solution was observed by H- and 2D rotating-frame Overhauser enhancement spectroscopy (ROESY)-NMR methods. Moreover, the synergistic effect of SBE-β-CD and water-soluble polymers, including polyvinylpyrrolidone, hydroxypropyl methylcellulose, carboxymethylcellulose sodium salt, polyvinyl alcohol, sodium alginate, and propylene glycol alginate (PGA), on the solubility of CLZ was investigated. The results show that the solubility of CLZ with 1 w/v% PGA was 7.6 mM, which was almost four times greater than that of CLZ without PGA in a 15 mM SBE-β-CD solution. In contrast, the solubility of CLZ with 1 w/v % PGA in an aqueous solution decreased by one-third relative to that of CLZ in a 15 mM SBE-β-CD solution. 2D ROESY-NMR indicated that a CLZ/SBE-β-CD/PGA ternary complex formed. It was found that the combination of PGA and SBE-β-CD enhanced the solubility of CLZ.
氯氮平（CLZ）是一种用于治疗精神分裂症的非典型抗精神病药物，其在水中的溶解度较差（0.05mM）。在这项研究中，我们研究了β-环糊精（CD）及其衍生物对 CLZ 溶解度的影响。通过测定 CLZ 的溶解度生成了相溶解度图，并通过 H 和二维旋转框架 Overhauser 增强光谱（ROESY）-NMR 方法观察了 CLZ 与磺丁基醚-β-环糊精（SBE-β-CD）在水溶液中的相互作用。此外，还研究了 SBE-β-CD 与水溶性聚合物（包括聚乙烯吡咯烷酮、羟丙基甲基纤维素、羧甲基纤维素钠盐、聚乙烯醇、海藻酸钠和丙二醇藻酸盐（PGA））对 CLZ 溶解度的协同作用。结果表明，在 1 w/v%PGA 存在下，CLZ 的溶解度为 7.6mM，在 15 mM SBE-β-CD 溶液中 CLZ 的溶解度几乎增加了四倍。相比之下，在含有 1 w/v%PGA 的水溶液中 CLZ 的溶解度相对于在含有 15 mM SBE-β-CD 的溶液中 CLZ 的溶解度降低了三分之一。2D ROESY-NMR 表明形成了 CLZ/SBE-β-CD/PGA 三元复合物。结果发现，PGA 和 SBE-β-CD 的组合增强了 CLZ 的溶解度。
