Five Cocrystal Forms of Antitumor Drug Temozolomide with <i>p</i>-Hydroxybenzoic Acid: Structure, Computational Analysis, Characterizations, Stability, and Transformation
Hongmei Yu, Baoxi Zhang, Wenhui Xing, Meiju Liu, Dezhi Yang, Guorong He, Fengfeng Wang, Li Zhang, Ningbo Gong, Yang Lü, Guanhua Du
Abstract
Temozolomide (TMZ) is a first-line antitumor drug but suffers from troubling stability issues related to degradation during storage and processing. In this paper, cocrystallization of TMZ with p-hydroxybenzoic acid (PHBA) produced five forms including one methanolate, one hydrate, two polymorphic forms in 2:1, and one solvent-free form in 1:1 ratio, designated as TMZ/PHBA/MeOH (1:1:1, S1), TMZ/PHBA/H2O (1:1:1, S2), TMZ/PHBA (2:1-form I, S3; 2:1-form II, S4), and TMZ/PHBA (1:1, S5). Except for S5, the other four forms were characterized and evaluated in detail by single-crystal X-ray diffraction. Powder X-ray diffraction, Fourier transform infrared spectroscopy, thermal analysis, and stability test were conducted for all five forms. The crystal form differences are mainly ascribed to the incorporation of solvent/water molecules, supramolecular synthon distinctions, and conformation flexibility of TMZ. The feeding ratio of starting components and the solvent used in the experiments both play a decisive role in the resulting form.