Molecular Insights into Warfarin Sodium 2-Propanol Solvate Solid Form Changes and Disproportionation Using a Low Volume Two-Stage Dissolution Approach

Abstract

The current research work focuses on understanding the reported discrepancies and our observations in the dissolution profiles of warfarin sodium tablets and potential patient-based failure modes during oral warfarin therapy. It was hypothesized that freely soluble crystalline warfarin sodium (WARC) at first transforms into noncrystalline warfarin sodium (WARNC) under stress conditions. The WARC → WARNC conversion facilitates the rapid formation of the poorly soluble unionized form, which could lead to dissolution failures and potential poor in vivo performance. Depressed warfarin concentrations locally in the gastrointestinal tract (GIT) may in turn lead to inadequate absorption and thereby affect bioavailability. A low volume two-stage dissolution method was developed to mimic in vivo GIT conditions. Warfarin sodium tablets exposed to room temperature and 75% relative humidity for 1 week showed approximately 23% decrease in drug release. The decline in drug release supports the hypothesis that WARNC is converted to the unionized form faster than WARC does under the same conditions. Solid state characterization (powder X-ray diffractometry and differential scanning calorimetry) data demonstrated the disproportionation of warfarin sodium to unionized warfarin after solubility and dissolution studies. The findings support the hypothesis and a possible failure mode of warfarin sodium tablets. This work is a second case study from our laboratory on narrow therapeutic index drug products in which the instability of the solid state of the drug substance is potentially responsible for observed clinical failures.

Design of pyrazine cocrystals of enzalutamide: a lead from 1,4-dioxane solvates

“…19 The accidental formation of undesirable solvates can also be significant as such outcomes are frequently unanticipated and might alter a product's physiochemical traits. [20][21][22][23] Nonetheless, a few notable marketed solvate medications are also available, including warfarin sodium 2-propanol solvate, 24 darunavir ethanolate, 25 dapagliflozin propanediol monohydrate, 26 trametinib dimethyl sulfoxide solvate, 27 and indinavir sulfate ethanolate. 28 In recent years, researchers have displayed interest towards solid forms that are easily solvated; one prominent example is sulfathiazole.…”

Influence of Co-amorphization on the Physical Stability and Dissolution Performance of an Anthelmintic Drug Flubendazole

“…Various strategies have been developed to improve the bioavailability of small molecules, such as pharmaceutical salts, − cocrystals, pharmaceutical solvates, − gels, and compositions with polymers and cyclodextrins. − Several techniques have been proposed in the literature for improving the pharmaceutically relevant characteristics of FluBZ, including the use of ionic liquids, binary crystals, and nanoemulsions, as well as incorporation in cyclodextrin cavities. − Amorphization is one of the most commonly utilized methods for increasing the apparent solubility and permeability of an active pharmaceutical ingredient (API). , However, amorphous pharmaceuticals are thermodynamically unstable phases that tend to crystallize during manufacture, storage, and dissolution. , Development of a homogeneous single-phase co-amorphous system consisting of an API and a second component, on the other hand, efficiently suppresses crystallization, prolonging the shelf life of a product while keeping the benefits of the amorphous form . Furthermore, combining two synergistic APIs into a co-amorphous system may boost treatment efficiency, potentially leading to attractive fixed-dose combinations. , …”

Understanding the thermal stability of apalutamide crystalline solvates through crystal structure analyses and computational studies

“…6 Although solvates with hazardous compounds are generally considered as an unwanted outcome of the solid form landscape of an API and, therefore, are rarely selected for further development due to toxicity and regulatory concerns, pharmaceutically acceptable solvents can be utilized to modify the crucial physicochemical properties of a compound, including solubility, dissolution rate, stability and particle morphology, which would further affect drug processing. [6][7][8][9][10][11][12] Currently, several drugs formulated as solvates are available on the market. 8,13 It is well known that desolvation of different solvates can be used as a potential route for the preparation of specific or unknown polymorphic forms of single-and multicomponent crystals, which are difficult to attain by conventional crystallization techniques.…”

“…[6][7][8][9][10][11][12] Currently, several drugs formulated as solvates are available on the market. 8,13 It is well known that desolvation of different solvates can be used as a potential route for the preparation of specific or unknown polymorphic forms of single-and multicomponent crystals, which are difficult to attain by conventional crystallization techniques. [14][15][16][17] Desolvation has also been proved as an effective method for the purification of drug compounds (e.g.…”