title: Bisoprolol and bisoprolol-valsartan compatibility studied by differential scanning calorimetry, nuclear magnetic resonance and X-ray powder diffractometry.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Pharmaceutical Technology, Poznań University of Medical Sciences, ul. Grunwaldzka 6, 60-780, Poznań, Poland.
authors.forename: Marcin
authors.initials: M
authors.lastname: Skotnicki
authors.forename: Juan A
authors.initials: JA
authors.lastname: Aguilar
authors.forename: Marek
authors.initials: M
authors.lastname: Pyda
authors.forename: Paul
authors.initials: P
authors.lastname: Hodgkinson
mesh_terms: D017298:Bisoprolol / Q000032:analysis* / Q000737:chemistry*; D002152:Calorimetry, Differential Scanning / Q000379:methods; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D013777:Tetrazoles / Q000032:analysis* / Q000737:chemistry*; D014633:Valine / Q000031:analogs & derivatives* / Q000032:analysis / Q000737:chemistry; D000068756:Valsartan; D014961:X-Ray Diffraction / Q000379:methods*
chemical_list: D013777:Tetrazoles; D000068756:Valsartan; D014633:Valine; D017298:Bisoprolol