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.Bisoprolol
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.
