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Molecular Insights into Warfarin Sodium 2-Propanol Solvate Solid Form Changes and Disproportionation Using a Low
Harsh S Shah1,2,3, Kaushalendra Chaturvedi1,2,3, Rutesh H Dave1
1Department of Pharmaceutical Sciences, Arnold and Marie Schwartz College of Pharmacy, Long Island University, 75 Dekalb Ave, Brooklyn, New York11201, United States.
Molecular Pharmaceutics
|March 10, 2021
Summary
Warfarin sodium tablets may fail due to crystalline warfarin sodium converting to a noncrystalline form, leading to poor dissolution and absorption. This solid-state instability is a potential cause of clinical failures for this narrow therapeutic index drug.
Area of Science:
- Pharmaceutical Sciences
- Drug Delivery
- Solid-State Chemistry
Background:
- Warfarin sodium tablets exhibit variable dissolution profiles, raising concerns about patient safety and therapeutic efficacy.
- Discrepancies in warfarin sodium dissolution may be linked to its solid-state properties and potential transformations under storage conditions.
Purpose of the Study:
- To investigate the conversion of crystalline warfarin sodium (WARC) to noncrystalline warfarin sodium (WARN) under stress conditions.
- To understand how this transformation impacts warfarin sodium dissolution and in vivo performance.
- To identify potential failure modes in oral warfarin therapy due to drug product instability.
Main Methods:
- Development of a low-volume, two-stage dissolution method simulating gastrointestinal tract conditions.
- Exposure of warfarin sodium tablets to controlled stress conditions (room temperature, 75% RH) for one week.
- Solid-state characterization using powder X-ray diffractometry (PXRD) and differential scanning calorimetry (DSC).
Main Results:
- Warfarin sodium tablets showed a ~23% decrease in drug release after one week of storage under stress conditions.
- The observed decline in dissolution supports the hypothesis that noncrystalline warfarin sodium converts to the poorly soluble unionized form more rapidly than the crystalline form.
- Solid-state characterization confirmed the disproportionation of warfarin sodium to its unionized form post-dissolution studies.
Conclusions:
- The solid-state instability of warfarin sodium, specifically the conversion from crystalline to noncrystalline forms, is a likely cause of dissolution failures.
- This transformation can lead to poor bioavailability and potential clinical failures in patients undergoing oral warfarin therapy.
- Instability of the drug substance's solid state is a critical factor in the performance of narrow therapeutic index drug products.
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