Degradation caused by incompatibility between sodium stearyl fumarate (PRUV) and AZD7986 in the drug product

During compatibility study of the AZD7986 project, a peak of 3 area% at the tail (RRT 1.03) of the active pharmaceutical ingredient (API) was discovered for all tablets containing sodium stearyl fumarate (PRUV) under humid condition (e.g. 50 °C/75% RH), regardless of choice of disintegrant or filler combination. The degradant was needed to be identified to understand the corresponding reaction mechanism and help the final formulation design. Structure elucidation was therefore done by analysis using high resolution mass spectrometry. The degradant was found to be a Michael addition product of the API and fumaric acid. Reaction between deuterated fumaric acid and the API was carried to confirm the proposed structure and reaction mechanism. Fumaric acid was a degradant product of PRUV in the presence of other excipients, revealed by the stability study. The Michael addition reaction needs facilitation by water and basic conditions. The result from this study should serve as a precaution note for projects using PRUV as one of excipients where the API could act as a nucleophile. In such cases the microenvironment should be optimised to minimize the reaction, such as pH adjustment and incorporating protection from moisture.

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