Preformulation evaluation of AZD1305, an oxabispidine intended for oral and intravenous treatment

Abstract

Aim: AZD1305 is a novel, water-soluble investigational antiarrhythmic agent for restoration and maintenance of sinus rhythm in atrial fibrillation patients. The present studies were performed to evaluate the possibility for further development of the compound.Methods: A set of technical approaches were used, including X-ray powder diffractometry, differential scanning calorimetry, thermogravimetrical analysis, dynamic vapor sorption, scanning electron microscopy, salt screen, and liquid chromatography.Results: AZD1305 is a crystalline oxabispidine and its neutral form is a base with a pKa of 9.9. The substance degrades with higher temperature and lower pH. The free base of the solid substance is stable at 25°C (closed container), 40°C/75% relative humidity (open container), and at 50°C (closed container) for at least 3 months. The free base of AZD1305 is polymorphic with two known forms. Both forms are non-hygroscopic ansolvates with melting points of approximately 90°C. No salt was found with overall improved properties. The substance had a strong odor, which was reduced by increased particle size.Conclusions: The free base of AZD1305 seemed to be the most suitable agent for product development even though it has a fairly low melting point and occurred as two different crystal forms. Form B was the most stable thermodynamically in the temperature interval of interest.