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Polymorphic forms of bisoprolol fumarate

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Abstract

Bisoprolol fumarate is a beta blocker-type drug substance which has been well known for several decades. However, no relevant data can be found in the literature about its crystal polymorphism. The purpose of this paper was to present two anhydrous forms (Form I and Form II) and a hydrate of bisoprolol fumarate substance. Crystalline forms were studied by various solid-state analytical methods: Fourier transform infrared (FT-IR) spectroscopy, X-ray powder diffraction (XRPD), dynamic vapor sorption (DVS) and thermoanalytical methods (thermogravimetry and differential scanning calorimetry). Thermodynamic stability and solubility of the presented polymorphs were also investigated. Both FT-IR and XRPD methods were found to be suitable for the characterization of the different crystal structures. Thermoanalytical measurements showed that (1) Form I and Form II own clearly different melting points and (2) both Form II and hydrate forms can transform into Form I at higher temperature values. Results of the DVS measurements prove that both Form I and Form II became metastable under extremely humid conditions (> 80% RH) and converted into the hydrate. Thermodynamic stability studies showed that Form I and Form II polymorphs are in enantiotropic relationship with an enantiotropic point at about 40–45 °C. Solubility studies indicated that all of the prepared forms are highly soluble, and no difference was found between them. Considering the recommendations of the corresponding International Conference of Harmonization guideline, it can be stated that no specification is required for crystal polymorphism in case of this substance.

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Acknowledgements

The authors would like to thank to Zoltán Varga for his useful advices, to Győző Csonka-Kis, Fanni Fekete and Györgyi Benéné Csuta for their help in the experimental work, to Rozália Lídia Vanyur and Péter Gábor Tonka-Nagy for their contribution in the solubility studies and to Attila Virág for the technical support.

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Authors and Affiliations

  1. Laboratory of Polymorphism Research, Finished Product Analytical Development Division, Directorate of Finished Product Development, Egis Pharmaceuticals PLC, Keresztúri út 30-38, Budapest, 1106, Hungary

    Ádám Detrich & Kata Judit Dömötör

  2. Drug Substance Pilot Plant, Drug Substance Development Division, Directorate of Drug Substance Development, Egis Pharmaceuticals PLC, Keresztúri út 30-38, Budapest, 1106, Hungary

    Kata Judit Dömötör & Imre Markovits

  3. Laboratory of Finished Product Analytical Development 3, Finished Product Analytical Development Division, Directorate of Finished Product Development, Egis Pharmaceuticals PLC, Bökényföldi út 116-120, Budapest, 1165, Hungary

    Miklós Tamás Katona

  4. Technical Purchasing Division, IT and Instrument Procurement Department, Technical Directorate, Egis Pharmaceuticals PLC, Keresztúri út 30-38, Budapest, 1106, Hungary

    Judit Vargáné Láng

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  1. Ádám Detrich
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  2. Kata Judit Dömötör
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  3. Miklós Tamás Katona
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Correspondence to Ádám Detrich.

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Detrich, Á., Dömötör, K.J., Katona, M.T. et al. Polymorphic forms of bisoprolol fumarate. J Therm Anal Calorim 135, 3043–3055 (2019). https://doi.org/10.1007/s10973-018-7553-8

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  • DOI: https://doi.org/10.1007/s10973-018-7553-8

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