title: Physicochemical characteristics of sunitinib malate and its process-related impurities.
abstract: In this article, details of crystal and molecular structures of sunitinib malate (SUM), an anticancer therapeutic, and its key synthetic intermediate are presented. Both these compounds were also characterized spectroscopically and thermally. SUM crystallizes in the monoclinic P2(1) space group with two molecules in the asymmetric part of the unit cell, whereas the intermediate crystallises in the triclinic P-1 space group with four independent molecules in the asymmetric unit. The three-dimensional structure of SUM consists of two different layers of molecules. The first one is built of the malic anions, whereas the other layer consists of more hydrophobic sunitinib molecules. This layer is formed by two types of molecules creating a herring bond-like pattern with pairs of neighboring cations forming the V-shape arrangement of molecules. The V-shaped pairs of molecules form ribbons by fitting into two neighboring V shapes. The characteristic V-shape assemble of the moieties is hold together with three C-H…F weak interactions. Besides, process-related impurities of SUM were identified and their structures confirmed by separate synthesis. These impurities were fully characterized by spectroscopic and crystallographic methods as well as by differential scanning calorimetry and thermogravimetric analysis. The H-, (13)C-, and (15)N-nuclear magnetic resonance signals were fully assigned structurally and the resulting structures were confirmed by Fourier-transformed infrared spectroscopy. It was the herein elaborated synthesis of impurity-free SUM that allowed for growing of its single crystals suitable for X-ray crystallographic studies. Comparison of the powder X-ray diffraction pattern for SUM with that derived from single-crystal X-ray crystallographic analysis indicated that SUM formed the polymorph I crystal phase, which is also encountered in its pharmaceutical formulation.
authors.affiliation: Pharmaceutical Research Institute, Warszawa 01-793, Poland.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Sidoryk
authors.forename: Maura
authors.initials: M
authors.lastname: Malińska
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Bańkowski
authors.forename: Marek
authors.initials: M
authors.lastname: Kubiszewski
authors.forename: Marta
authors.initials: M
authors.lastname: Łaszcz
authors.forename: Magdalena
authors.initials: M
authors.lastname: Bodziachowska-Panfil
authors.forename: Magdalena
authors.initials: M
authors.lastname: Kossykowska
authors.forename: Tomasz
authors.initials: T
authors.lastname: Giller
authors.forename: Andrzej
authors.initials: A
authors.lastname: Kutner
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Woźniak
mesh_terms: D055598:Chemical Phenomena; D018360:Crystallography, X-Ray / Q000379:methods; D004340:Drug Contamination; D007211:Indoles / Q000737:chemistry* / Q000302:isolation & purification*; D011758:Pyrroles / Q000737:chemistry* / Q000302:isolation & purification*; D000077210:Sunitinib
chemical_list: D007211:Indoles; D011758:Pyrroles; D000077210:Sunitinib