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 pK_a 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.

Keywords::

• Drug delivery
• early development
• odor
• polymorphs
• salt-screen
• smell
• solid-state
• stability

Acknowledgments

We thank Anne Juppo for valuable discussions regarding solid dosage formulations, Hans Carlsson for guidance regarding granulation experiments and Hong Wan for performing the CE/MS measurement.

Declaration of interest

All authors are employees of AstraZeneca. The authors report no conflicts of interest.