Warfarin is intensively discussed in terms of generic substitution due to particular cases of bleeding, which are attributable to fluctuations in API content or the substitution of crystalline (WSC) for amorphous (WSA) warfarin. The aim of this study was to assess to what extent the in vitro release was affected by the form of API depending on the composition and technology. Bioequivalent tablets containing 5 mg of WSA or WSC prepared by wet granulation or direct compression were used. Furthermore, tablets of the same composition with WSC or WSA prepared by direct compression were evaluated. Raman spectroscopy was used to confirm the presence of WSA or WSC. The dissolution was more influenced by the technology than by the form of API but even tablets with dissimilar profiles were bioequivalent. This is probably due to the precipitation of WSA and WSC in the stomach on a poorly soluble acidic form, which subsequently dissolves in the neutral environment of the small intestine. Recrystallization was demonstrated in the in vitro assay at a pH of 1.2 and 4.5 using Raman spectroscopy and X-ray diffraction. In summary, the content uniformity appears to be the main factor affecting the safety of the treatment.

Department of Pharmaceutics Faculty of Pharmacy University of Veterinary and Pharmaceutical Sciences Palackého 1946 1 Brno Czech Republic

Department of Pharmacognosy and Botany The University of veterinary medicine and pharmacy in Košice Komenského 73 Košice Slovak Republic

Institute of Scientific Instruments of the CAS Královopolská 147 Brno Czech Republic

Materials Research Centre Faculty of Chemistry Brno University of Technology Purkyňova 464 118 Brno Czech Republic

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