Early development evaluation of AZD2738, a substrate for the NK receptors

• Published in: Drug development and industrial pharmacy Vol. 37; no. 6; p. 719
• Main Authors: Sigfridsson, Kalle, Ahlqvist, Matti, Lindsjö, Martin, Paulsson, Stefan
• Format: Journal Article
• Language: English
• Published: England 01.06.2011
• Subjects: Azetidines - administration & dosage; Azetidines - chemistry; Benzamides - administration & dosage; Benzamides - chemistry; Crystallization; Drug Stability; Freezing; Hydrogen-Ion Concentration; Neurokinin-1 Receptor Antagonists; Receptors, Neurokinin-2 - antagonists & inhibitors; Salts; Solubility; Wettability
• ISSN: 1520-5762
• DOI: 10.3109/03639045.2010.538060

The purpose of this study was to investigate whether AZD2738, a dual neurokinin NK1/2 receptor antagonist, is a suitable candidate for further development with an oral immediate release solid dosage form as a possible final product. The neutral form of AZD2738 has only been isolated as amorphous material. In order to search for a solid material with improved physical and chemical stability and more suitable solid-state properties, a salt screen was performed. Mostly crystalline material of fumarate, maleate and chloride salt of AZD2738 were obtained. X-ray powder diffractometry, thermogravimetric analysis, differential scanning calorimetry and dynamic vapor sorption were used to investigate the physicochemical characteristics of the salts. Based on the physicochemical properties, the chloride salt is preferred for continued product development. The chloride salt of AZD2738 is an anhydrate, the crystallization is reproducible, the hygroscopicity is acceptable and just one polymorph was obtained. Notably is that the two obtained polymorphs of the fumarate salt of AZD2738 are monotropically related, whereas the two identified polymorphs for the maleate salt of the compound are enantiotropic. The dissolution behavior and the stability (in aqueous solutions, formulations and solid state) of the salts were also studied and found to be satisfactory, at least at pH >3. Liquid formulations should preferable be stored frozen at pH >3.