Bisoprolol and Bisoprolol-Valsartan Compatibility Studied by Differential Scanning Calorimetry, Nuclear Magnetic Resonance and X-Ray Powder Diffractometry

Skotnicki, Marcin; Aguilar, Juan A.; Pyda, Marek; Hodgkinson, Paul

Abstract

Purpose The objective of this study was to evaluate the thermal behavior of crystalline and amorphous bisoprolol fumarate and its compatibility with amorphous valsartan. This pharmacologically relevant drug combination is a potential candidate for fixed-dose combination formulation. Methods DSC and TMDSC were used to examine thermal behavior of bisoprolol fumarate. SSNMR and XRPD were applied to probe the solid state forms. The thermal behavior of physical mixtures with different concentrations of bisoprolol and valsartan were examined by DSC and TMDSC, and the observed interactions were investigated by XRPD, solution- and solid-state NMR. Results The phase transitions from thermal methods and solid-state NMR spectra of crystalline and amorphous bisoprolol fumarate are reported. Strong interactions between bisoprolol fumarate and valsartan were observed above 60 C, resulting in the formation of a new amorphous material. Solution- and solid-state NMR provided insight into the molecular nature of the incompatibility. Conclusions A combined analysis of thermal methods, solution- and solid-state NMR and XRPD experiments allowed the investigation of the conformational and dynamic properties of bisoprolol fumarate. Since bisoprolol fumarate and valsartan react to form a new amorphous product, formulation of a fixed-dose combination would require separate reservoirs for bisoprolol and valsartan to prevent interactions. Similar problems might be expected with other excipients or APIs containing carboxylic groups.

Citation

Skotnicki, M., Aguilar, J. A., Pyda, M., & Hodgkinson, P. (2015). Bisoprolol and Bisoprolol-Valsartan Compatibility Studied by Differential Scanning Calorimetry, Nuclear Magnetic Resonance and X-Ray Powder Diffractometry. Pharmaceutical Research, 32(2), 414-429. https://doi.org/10.1007/s11095-014-1471-7

• Journal Article Type: Article
• Acceptance Date: Jul 24, 2014
• Online Publication Date: Aug 13, 2014
• Publication Date: Feb 1, 2015
• Deposit Date: May 13, 2015
• Publicly Available Date: May 20, 2015
• Journal: Pharmaceutical Research
• Print ISSN: 0724-8741
• Electronic ISSN: 1573-904X
• Publisher: Springer
• Peer Reviewed: Peer Reviewed
• Volume: 32
• Issue: 2
• Pages: 414-429
• DOI: https://doi.org/10.1007/s11095-014-1471-7
• Keywords: Bisoprolol, Compatibility, DSC, SSNMR, Valsartan.
• Public URL: https://durham-repository.worktribe.com/output/1408618