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.

Department of NMR Spectroscopy Institute of Macromolecular Chemistry Czech Academy of Sciences Heyrovsky sq 2 162 06 Prague 6 Czech Republic

Department of Pharmaceutical Technology Faculty of Pharmacy Masaryk University Palackého třída 1946 1 612 00 Brno Czech Republic

Materials Research Centre Faculty of Chemistry Brno University of Technology Purkyňova 464 118 612 00 Brno Czech Republic

Zobrazit více v PubMed

Erener S. Diabetes, infection risk and COVID-19. Mol. Metab. 2020;39:101044. doi: 10.1016/j.molmet.2020.101044. PubMed DOI PMC

Bultas J., Karetová D. New oral anticoagulants—Aspects surrounded by silence. Remedia. 2015;25:127–134.

Harper P., Young L., Merriman E. Bleeding risk with dabigatran in the frail elderly. N. Engl. J. Med. 2012;366:864–866. doi: 10.1056/NEJMc1112874. PubMed DOI

Hernandez I., Baik S.H., Piñera A., Zhang Y. Risk of bleeding with dabigatran in atrial fibrillation. JAMA Intern. Med. 2015;175:18–24. doi: 10.1001/jamainternmed.2014.5398. PubMed DOI PMC

Ringleb P.A. Thrombolytics, anticoagulants, and antiplatelet agents. Stroke. 2006;37:312–313. doi: 10.1161/01.STR.0000200560.01068.65. PubMed DOI

Godman B., Malmström R.E., Diogene E., Jayathissa S., McTaggart S., Cars T., Alvarez-Madrazo S., Baumgärtel C., Brzezinska A., Bucsics A., et al. Dabigatran-a continuing exemplar case history demonstrating the need for comprehensive models to optimize the utilization of new drugs. Front. Pharmacol. 2014;5:109. doi: 10.3389/fphar.2014.00109. PubMed DOI PMC

Kow C.S., Sunter W., Bain A., Zaidi S.T.R., Hasan S.S. Management of outpatient warfarin therapy amid COVID-19 pandemic: A practical guide. Am. J. Cardiovasc. Drugs. 2020;20:301–309. doi: 10.1007/s40256-020-00415-z. PubMed DOI PMC

Hohnloser S.H., Oldgren J., Yang S., Wallentin L., Ezekowitz M., Reilly P., Eikelboom J., Brueckmann M., Yusuf S., Connolly S.J. Myocardial ischemic events in patients with atrial fibrillation treated with dabigatran or warfarin in the RE-LY (Randomized evaluation of long-term anticoagulation therapy) trial. Circulation. 2012;125:669–676. doi: 10.1161/CIRCULATIONAHA.111.055970. PubMed DOI

Douxfils J., Buckinx F., Mullier F., Minet V., Rabenda V., Reginster J.Y., Hainaut P., Bruyère O., Dogné J.M. Dabigatran etexilate and risk of myocardial infarction, other cardiovascular events, major bleeding, and all-cause mortality: A systematic review and meta-analysis of randomized controlled trials. J. Am. Heart Assoc. 2014;3:e000515. doi: 10.1161/JAHA.113.000515. PubMed DOI PMC

Zeeshan M., Jehan F., O’Keeffe T., Khan M., Zakaria E.R., Hamidi M., Gries L., Kulvatunyou N., Joseph B. The novel oral anticoagulants (NOACs) have worse outcomes compared with warfarin in patients with intracranial hemorrhage after TBI. J. Trauma Acute Care Surg. 2018;85:915–920. doi: 10.1097/TA.0000000000001995. PubMed DOI

Chokesuwattanaskul R., Thongprayoon C., Tanawuttiwat T., Kaewput W., Pachariyanon P., Cheungpasitporn W. Safety and efficacy of apixaban versus warfarin in patients with end-stage renal disease: Meta-analysis. Pacing Clin. Electrophysiol. 2018;41:627–634. doi: 10.1111/pace.13331. PubMed DOI

Russo-Alvarez G., Martinez K.A., Valente M., Bena J., Hu B., Luxenburg J., Chaitoff A., Ituarte C., Brateanu A., Rothberg M.B. Thromboembolic and major bleeding events with rivaroxaban versus warfarin use in a real-world setting. Ann. Pharmacother. 2018;52:19–25. doi: 10.1177/1060028017727290. PubMed DOI

You J.H. Novel oral anticoagulants versus warfarin therapy at various levels of anticoagulation control in atrial fibrillation—A cost-effectiveness analysis. J. Gen. Intern. Med. 2014;29:438–446. doi: 10.1007/s11606-013-2639-2. PubMed DOI PMC

Zhu J., Alexander G.C., Nazarian S., Segal J.B., Wu A.W. Trends and variation in oral anticoagulant choice in patients with atrial fibrillation, 2010–2017. Pharmacotherapy. 2018;38:907–920. doi: 10.1002/phar.2158. PubMed DOI PMC

Siguret V., Pautas E., Gouin-Thibault I. Warfarin therapy: Influence of pharmacogenetic and environmental factors on the anticoagulant response to warfarin. Vitam. Horm. 2008;78:247–264. doi: 10.1016/s0083-6729(07)00012-x. PubMed DOI

Ghate S.R., Biskupiak J.E., Ye X., Hagan M., Kwong W.J., Fox E.S., Brixner D.I. Hemorrhagic and thrombotic events associated with generic substitution of warfarin in patients with atrial fibrillation: A retrospective analysis. Ann. Pharmacother. 2011;45:701–712. doi: 10.1345/aph.1P593. PubMed DOI

Bird S.T., Flowers N., Zhao Y., McKean S., Izem R., Wernecke M., Kozlowski S., MaCurdy T.E., Kelman J.A., Graham D.J. Healthy user bias in comparative safety studies for brand-name vs. generic products: The example of warfarin. Clin. Pharmacol. Ther. 2019;106:1037–1045. doi: 10.1002/cpt.1498. PubMed DOI

Hellfritzsch M., Rathe J., Stage T.B., Thirstrup S., Grove E.L., Damkier P., Pottegård A. Generic switching of warfarin and risk of excessive anticoagulation: A Danish nationwide cohort study. Pharmacoepidemiol. Drug Saf. 2016;25:336–343. doi: 10.1002/pds.3942. PubMed DOI

Hope K.A., Havrda D.E. Subtherapeutic INR values associated with a switch to generic warfarin. Ann. Pharmacother. 2001;35:183–187. doi: 10.1345/aph.10207. PubMed DOI

Bongiorno R.A., Nutescu E.A. Generic warfarin: Implications for clinical practice and perceptions of anticoagulation providers. Semin. Thromb. Hemost. 2004;30:619–626. doi: 10.1055/s-2004-861503. PubMed DOI

Nguyenpho A., Ciavarella A.B., Siddiqui A., Rahman Z., Akhtar S., Hunt R., Korang-Yeboah M., Khan M.A. Evaluation of in-use stability of anticoagulant drug products: Warfarin sodium. J. Pharm. Sci. 2015;104:4232–4240. doi: 10.1002/jps.24657. PubMed DOI

Rahman Z., Korang-Yeboah M., Siddiqui A., Mohammad A., Khan M.A. Understanding effect of formulation and manufacturing variables on the critical quality attributes of warfarin sodium product. Int. J. Pharm. 2015;495:19–30. doi: 10.1016/j.ijpharm.2015.08.065. PubMed DOI

Kasim N.A., Whitehouse M., Ramachandran C., Bermejo M., Lennernas H., Hussain A.S., Junginger H.E., Stavchansky S.A., Midha K.K., Shah V.P., et al. Molecular properties of WHO essential drugs and provisional biopharmaceutical classification. Mol. Pharm. 2004;1:85–96. doi: 10.1021/mp034006h. PubMed DOI

Gao D., Maurin M.B. Physical chemical stability of warfarin sodium. AAPS PharmSci. 2001;3:E3. doi: 10.1208/ps030103. PubMed DOI PMC

Haines S.T. Substituting warfarin products: What’s the source of the problem? Ann. Pharmacother. 2011;45:807–809. doi: 10.1345/aph.1Q063. PubMed DOI

Zhang X., Wen H., Fan J., Vince B., Li T., Gao W., Kinjo M., Brown J., Sun W., Jia-ng W., et al. Integrating In vitro, modeling, and In vivo approaches to investigate warfarin bioequivalence. CPT Pharmacomet. Syst. Pharmacol. 2017;6:523–531. doi: 10.1002/psp4.12198. PubMed DOI PMC

Franc A., Muselík J., Zeman J., Lukášová I., Kurhajec S., Bartoníčková E., Galvánková L., Mika F., Dominik M., Vetchý D. The effect of amorphous and crystal sodium warfarin and its content uniformity on bioequivalence of tablets. Eur. J. Pharm. Sci. 2018;125:120–129. doi: 10.1016/j.ejps.2018.09.022. PubMed DOI

Muselík J., Franc A., Doležel P., Goněc R., Krondlová A., Lukášová I. Influence of process parameters on content uniformity of a low dose active pharmaceutical ingredient in a tablet formulation according to GMP. Acta Pharm. 2014;64:355–367. doi: 10.2478/acph-2014-0022. PubMed DOI

Zhang X. CERSI Workshop FDA. U.S. Food and Drug Administration; Silver Spring, MD, USA: 2016. Bioequivalence and characterization of generic drugs: Substitutability of generic drugs: Perceptions and reality.

Brus J. Heating of samples induced by fast magic-angle spinning. Solid State Nucl. Magn. Reson. 2000;16:151–160. doi: 10.1016/S0926-2040(00)00061-8. PubMed DOI

Urbanova M., Gajdosova M., Steinhart M., Vetchy D., Brus J. Molecular-level control of ciclopirox olamine release from poly(ethylene oxide)-based mucoadhesive buccal films: Exploration of structure-property relationships with solid-state NMR. Mol. Pharm. 2016;13:1551–1563. doi: 10.1021/acs.molpharmaceut.6b00035. PubMed DOI

Brus J., Urbanova M., Sedenkova I., Brusova H. New perspectives of 19F MAS NMR in the characterization of amorphous forms of atorvastatin in dosage formulations. Int. J. Pharm. 2011;409:62–74. doi: 10.1016/j.ijpharm.2011.02.030. PubMed DOI

Hušák M., Jegorov A., Czernek J., Rohlíček J., Žižková S., Vraspír P., Kolesa P., Fitch A., Brus J. Successful strategy for high degree of freedom crystal structure determination from powder X-ray diffraction data: A case study for selexipag form I with 38 DOF. Cryst. Growth Des. 2019;19:4625–4631. doi: 10.1021/acs.cgd.9b00517. DOI

Hušák M., Jegorov A., Rohlíček J., Fitch A., Czernek J., Kobera L., Brus J. Determining the crystal structures of peptide analogs of boronic acid in the absence of single crystals: Intricate motifs of ixazomib citrate revealed by XRPD guided by ss-NMR. Cryst. Growth Des. 2018;18:3616–3625. doi: 10.1021/acs.cgd.8b00402. DOI

Urbanova M., Brus J., Sedenkova I., Policianova O., Kobera L. Characterization of solid polymer dispersions of active pharmaceutical ingredients by 19F MAS NMR and factor analysis. Spectrochim. Acta A Mol. Biomol. Spectrosc. 2013;100:59–66. doi: 10.1016/j.saa.2012.02.057. PubMed DOI

Giannini D.D., Chan K.K., Roberts J.D. Carbon-13 nuclear magnetic resonance spectroscopy. Structure of the anticoagulant warfarin and related compounds in solution. Proc. Natl. Acad. Sci. USA. 1974;71:4221–4223. doi: 10.1073/pnas.71.10.4221. PubMed DOI PMC

Valente E.J., Trager W.F., Jensen L.H. The crystal and molecular structure and absolute configuration of (−)-(S)-warfarin. Acta Crystallogr. 1975;31:954–960. doi: 10.1107/S056774087500427X. DOI

Brus J., Czernek J., Kobera L., Urbanova M., Abbrent S., Husak M. Predicting the crystal structure of decitabine by powder NMR crystallography: Influence of long-range molecular packing symmetry on NMR parameters. Cryst. Growth Des. 2016;16:7102–7111. doi: 10.1021/acs.cgd.6b01341. DOI

Deshpande M.D., Scheicher R.H., Ahuja R., Pandey R. Binding strength of sodium ions in cellulose for different water contents. J. Phys. Chem. B. 2008;112:8985–8989. doi: 10.1021/jp8020547. PubMed DOI

Franc A., Kurhajec S., Pavloková S., Sabadková D., Muselík J. Influence of concentration and type of microcrystalline cellulose on the physical properties of tablets containing Cornelian cherry fruits. Acta Pharm. 2017;67:187–202. doi: 10.1515/acph-2017-0019. PubMed DOI

Franc A., Muselłk J., Goněc R., Vetchý D. Biphasic dissolution method for quality control and assurance of drugs containing active substances in the form of weak acid salts. Acta Pharm. 2016;66:139–145. doi: 10.1515/acph-2016-0010. PubMed DOI

Committee for Medicinal Products for Human Use (CHMP) Guideline on the Investigation of Bioequivalence. European Medicines Agency; London, UK: 2010.

Food and Drug Administration . Guidance for Industry. Food and Drug Administration; Rockville, MD, USA: 1997. Dissolution testing of immediate release solid oral dosage forms.

Vercaigne L.M., Zhanel G.G. Clinical significance of bioequivalence and interchangeability of narrow therapeutic range drugs: Focus on warfarins. J. Pharm. Pharm. Sci. 1998;1:92–94. PubMed

Urbanova M., Pavelkova M., Czernek J., Kubova K., Vyslouzil J., Pechova A., Molinkova D., Vyslouzil J., Vetchy D., Brus J. Interaction pathways and structure-chemical transformations of alginate gels in physiological environments. Biomacromolecules. 2019;20:4158–4170. doi: 10.1021/acs.biomac.9b01052. PubMed DOI

Yu Y., Guo H., Pujari-Palmer M., Stevensson B., Grins J., Engqvist H., Edén M. Advanced solid-state 1H/31P NMR characterization of pyrophosphate-doped calcium phosphate cements for biomedical applications: The structural role of pyrophosphate. Ceram. Int. 2019;45:20642–20655. doi: 10.1016/j.ceramint.2019.07.047. DOI

Awa K., Shinzawa H., Ozaki Y. The effect of microcrystalline cellulose crystallinity on the hydrophilic property of tablets and the hydrolysis of acetylsalicylic acid as active pharmaceutical ingredient inside tablets. AAPS PharmSciTech. 2015;16:865–870. doi: 10.1208/s12249-014-0276-7. PubMed DOI PMC