New Insights On Warfarin Sodium 2-Propanol Solvate Solid-State Changes Using A Multivariate Approach

A primary anticoagulant narrow therapeutic index warfarin sodium poses a high risk of thrombosis or excessive bleeding with a sudden death. The root cause for these risks is not well established. It was hypothesized that the solid form changes in warfarin sodium 2-propanol solvate (WAR(C)) at the molecular level are indirectly responsible for warfarin therapy associated clinical risks. Therefore, the current research work focused on systematically studying solid form changes and 2-propanol content by factoring in environmental conditions. WAR(C) transformed into desolvated WAR(C) (WAR(DES)) to noncrystalline (WARN(C)) form after exposure to high temperature stress for a prolonged time. On the contrary, WAR(C) transformed directly into WAR(NC) at high percent relative humidity. These transformations were monitored and statistically quantified for predicting WAR(C) solid-state composition at a given storage condition. Additionally, WAR(DES) was computationally derived using crystal structure refinement tools. Stressed WAR(C) tablets exhibited impaired dissolution profiles in comparison to unexposed tablets. Clearly, compromised structural integrity of WAR(C) could answer WAR(C) therapy failures. Armed with these results and understanding, designing a quality dosage form and controlling of the quality of warfarin sodium tablets during processing should now be achievable.