Structural Changes of Sodium Warfarin in Tablets Affecting the Dissolution Profiles and Potential Safety of Generic Substitution

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.

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Materials

Preparation of Tablets

For the evaluation of warfarin solid-state stability, commercial tablets “A” from a Czech market were used, and tablets “B” and “C” were prepared. Tablets “A” contained 5.40 mg of warfarin sodium isopropanol clathrate per tablet, which was equivalent to 5.00 mg of warfarin sodium. The excipients for “A” were lactose monohydrate, cellulose microcrystalline, corn starch, colloidal silicon dioxide and magnesium stearate. Tablets “A” were packed in PVC/Al clear blister (10 tablets in blister and five blisters in a paper box). For the preparation of the “B” tablets, warfarin sodium isopropanol clathrate (WSC; Pliva, Zagreb, Croatia) was used (5.40 mg in one tablet). For the preparation of “C” tablets, the amorphous form of warfarin sodium (WSA) was used (5.00 mg in one tablet). The common excipients of “B” and “C” were Di-Cafos^® 92-14 70% (calcium hydrogen phosphate, Budenheim KG, Germany), Avicel^® PH 101 25% (microcrystalline cellulose, FMC BioPolymer, USA), Ac-Di-Sol^® 2% (sodium croscarmellose, FMC BioPolymer, Philadelphia, PA, USA) and magnesium stearate 1% (Peter Greven GmbH & Co. KG, Bad Münstereifel, Germany). The WSA and tablets “B” and “C” were prepared by direct compression according to the methodology described previously.

Preparation of Binary Mixtures (Warfarin/Excipient)

For the study of warfarin/excipient interactions, binary mixtures of WSC or WSA with Di-Cafos^® 92-14, microcrystalline cellulose (MCC), starch, colloidal silica and lactose monohydrate (Tablettose^® 80) were prepared by mixing the individual components in a 1:3 ratio (w/w, warfarin/excipient). The ratio 1:3 was chosen as acceptable compromise when the amount of excipient remains significantly high to considerably affect the active compound and promote structural and physicochemical changes. Simultaneously, the amount of the active compound is still sufficient to observe the induced structural changes spectroscopically with high signal-to-noise ratio in acceptable experimental time.

Muselík, J.; Urbanova, M.; Bartoníčková, E.; Palovčík, J.; Vetchý, D.; Czernek, J.; Janisova, L.; Velychkivska, N.; Franc, A.; Brus, J. Structural Changes of Sodium Warfarin in Tablets Affecting the Dissolution Profiles and Potential Safety of Generic Substitution. Pharmaceutics 2021, 13, 1364. https://doi.org/10.3390/pharmaceutics13091364

excipients formulation