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卡巴他赛溶剂化物的同构性:X射线结构与新溶剂化物的制备

Isostructurality among solvates of cabazitaxel: X-ray structures and new solvates preparation.

作者信息

Xu Wei, Gong Ningbo, Yang Shiying, Zhang Na, He Lan, Du Guanhua, Lu Yang

机构信息

Beijing City Key Laboratory of Polymorphic Drugs, Center of Pharmaceutical Polymorphs, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China.

出版信息

J Pharm Sci. 2015 Apr;104(4):1256-62. doi: 10.1002/jps.24374. Epub 2015 Feb 10.

Abstract

Cabazitaxel is an anticancer drug and its marketed product (form A) is acetone solvate (1:1) (Didier E, Perrin MA. 2005. Patent WO2005/028462 A1). This work describes three crystal structures of cabazitaxel 1:1 solvates with isopropyl alcohol (B), 2-butanol (C), and dioxane (D). These solvates are isostructural with cabazitaxel forming a host framework through hydrogen bonds and the guest solvent molecules located in channels from which they can escape. The host is hydrogen bonded to each other through hydroxyl O1 and sec-amide N3 ', whereas the hydroxyl O2 ' plays an important role in connecting the host to the guest. Moreover, because of the existence of channels in the crystal structure, the solvent-replacement method was established to prepare four new solvates of cabazitaxel with dimethyl formamide (E), cyclohexane (F), n-hexane (G), and ethyl ether (H). All the seven solvates involved in this work were proven to be isostructural by methods of X-ray crystallography and contain the same amount of solvents by thermogravimetric analysis. The single-crystal structures of solvate C-E and the solvates prepared by solvent-replacement method have been reported for the first time.

摘要

卡巴他赛是一种抗癌药物,其上市产品(A型)为丙酮溶剂化物(1:1)(迪迪埃·E,佩兰·M·A。2005年。专利WO2005/028462 A1)。本文描述了卡巴他赛与异丙醇(B型)、2-丁醇(C型)和二氧六环(D型)形成的1:1溶剂化物的三种晶体结构。这些溶剂化物与卡巴他赛同构,通过氢键形成主体框架,客体溶剂分子位于通道中,它们可以从通道中逸出。主体通过羟基O1和仲酰胺N3'相互氢键连接,而羟基O2'在连接主体与客体方面起重要作用。此外,由于晶体结构中存在通道,建立了溶剂置换法来制备卡巴他赛与二甲基甲酰胺(E型)、环己烷(F型)、正己烷(G型)和乙醚(H型)的四种新溶剂化物。通过X射线晶体学方法证明了本文所涉及的所有七种溶剂化物同构,热重分析表明它们含有相同量的溶剂。溶剂化物C-E以及通过溶剂置换法制备的溶剂化物的单晶结构首次被报道。

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