Abstract
At present, the risk of generic substitutions in warfarin tablets is still being discussed. The aim of this study was to assess whether API interactions with commonly used excipients may affect the safety of generic replacement of warfarin sodium tablets. These interactions were observed during an accelerated stability study, and the effect of the warfarin solid phase (crystalline/amorphous form) as well as the API particle size distribution was studied. Commercial tablets and prepared tablets containing crystalline warfarin or amorphous warfarin were used. In addition, binary mixtures of warfarin with various excipients were prepared. The structural changes before and after the stability study were monitored by dissolution test in different media, solid-state NMR spectroscopy and Raman microscopy. During the stability study, the conversion of the sodium in warfarin to its acid form was demonstrated by some excipients (e.g., calcium phosphate). This change in the solid phase of warfarin leads to significant changes in dissolution, especially with the different particle sizes of the APIs in the tablet. Thus, the choice of suitable excipients and particle sizes are critical factors influencing the safety of generic warfarin sodium tablets.
Highlights
Hypercoagulation is among the most common causes of morbidity and mortality in industrialized countries, and is appearing worldwide in connection with medication and vaccination for COVID-19 [1]
novel oral anticoagulants (NOAC) were intended to reduce the frequency of International Normalized Ratio (INR) monitoring, reduce the risk of interactions between drugs and food, reduce the incidence of major bleeding, and accelerate the onset of action [2]
There are a range of spectroscopic methods that allow monitoring of structural changes and transformations of active pharmaceutical ingredients (APIs) at the atomic resolution level [31,32]
Summary
Hypercoagulation is among the most common causes of morbidity and mortality in industrialized countries, and is appearing worldwide in connection with medication and vaccination for COVID-19 [1]. Despite the introduction of stricter rules for NOAC treatments that further reduce the risks [6], warfarin is still the drug of choice for many physicians; its use has been discussed in the context of COVID-19 [7]. This trend was intensified by the finding that warfarin provides better protection against heart attacks than some promising NOACs [8,9]. Several other comparative studies have been performed that have not clearly shown that NOACs are safer than warfarin in all indications [10,11,12]
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