Abstract
In this article the crystal structures of the starting material TZ-5 and the key intermediate TZ-6 of temozolomide (TZ-7), an anticancer therapeutic agent, are presented, together with their spectroscopic and thermal characteristics. Both compounds crystallize in the triclinic P-1 space group. X-ray crystallography studies proved that the compound TZ-6 exists as a monohydrate. A complete structural assignment was obtained for the signals in the 1H-, 13C- and 15N-nuclear magnetic resonance spectra and the structures were confirmed by Fourier-Transform infrared and Raman spectroscopy. The article describes the importance of the high purity of TZ-6 during the small-scale plant production of TZ-7 in a desired polymorphic form III with the purity higher than 99.50%, according to an HPLC method.
Highlights
A complete physicochemical characterization has recently become required by both the U.S Food and Drug Administration (FDA) [1] and by the European Medicine Agency (EMA) [2], for active pharmaceutical ingredients (API), and for all key synthetic intermediates
In this article the complete physicochemical characteristics of temozolomide intermediate and starting material have been determined by the following methods: 1H, 13C- and 15N-nuclear magnetic resonance (NMR), infrared (IR) and Raman spectroscopy, as well as by thermal analyses
TZ-6 and TZ-5 were assigned to the respective atoms using one- and two-dimensional techniques (g-HSQC and g-HMBC (1H-13C and 1H-15N-NMR, Table 1)
Summary
A complete physicochemical characterization has recently become required by both the U.S Food and Drug Administration (FDA) [1] and by the European Medicine Agency (EMA) [2], for active pharmaceutical ingredients (API), and for all key synthetic intermediates. A well documented impurity profile, the identification and physicochemical characteristic of a starting material and intermediate products are necessary for an API registration. In this article the complete physicochemical characteristics of temozolomide intermediate and starting material have been determined by the following methods: 1H-, 13C- and 15N-nuclear magnetic resonance (NMR), infrared (IR) and Raman spectroscopy, as well as by thermal analyses. Single crystals of both compounds were obtained and their X-ray structures were solved. High-performance liquid chromatography (HPLC) methods for the purity determination of TZ-5 and TZ-6 were evaluated
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