A small structural change resulting in improved properties for product development

Abstract

AZD9343 is a water-soluble gamma amino butyric acid (GABA_B) agonist intended for symptomatic relief in gastroesophageal reflux disease (GERD) patients. The compound has good chemical stability in aqueous solutions, as well as in the solid state. Only one crystal modification has been observed to date. This polymorph is slightly hygroscopic (1.5% water uptake at 80% relative humidity (RH)), which is an improvement compared to the structurally similar agonist lesogaberan (AZD3355) which liquefies at 65% RH. Since the substance is very polar and lacks a UV chromophore, conventional separation and detection techniques cannot be used to characterize the substance and its impurities. The analytical techniques are described, focusing on the capillary electrophoresis method with indirect UV detection for assay and purity, the liquid chromatographic method for enantiomeric separation with derivatization with UV chromophore and three complementary nuclear magnetic resonance (NMR) approaches (³¹P-NMR, ¹³C-NMR and ¹H-NMR) for impurities. For oral solutions, it was important to select the right concentration of phosphate buffer for the specific drug concentration and routinely use small additions of EDTA. I.V. solutions containing physiological saline as tonicity modifier could not be stored frozen at −20 °C. Properties of AZD9343 will be discussed in light of experiences from the structurally similar lesogaberan and (2R)-(3-amino-2-fluoropropyl)sulphinic acid (AFPSiA).

• Capillary electrophoresis
• formulation
• NMR spectroscopy
• oral drug delivery
• preformulation
• stability

Acknowledgements

The authors are grateful to Dr Maria Lindqvist for coordinating some of the solid state characterization work and employees at the former AstraZeneca R&D Lund for assistance in obtaining stability data.

Declaration of interest

The authors declared no conflict of interest.