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Bisoprolol and bisoprolol-valsartan compatibility studied by differential scanning calorimetry, nuclear magnetic resonance and X-ray powder diffractometry.

Skotnicki M, Aguilar JA, Pyda M, Hodgkinson P - Pharm. Res. (2014)

Bottom Line: Strong interactions between bisoprolol fumarate and valsartan were observed above 60 C, resulting in the formation of a new amorphous material.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutical Technology, Poznań University of Medical Sciences, ul. Grunwaldzka 6, 60-780, Poznań, Poland.

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.

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13C CPMAS NMR spectra of each API and physical mixtures in different concentrations at 38 and 80°C.
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Fig7: 13C CPMAS NMR spectra of each API and physical mixtures in different concentrations at 38 and 80°C.

Mentions: Figure 7 shows the 13C NMR spectra of bisoprolol, valsartan and 70/30 and 50/50 physical mixtures at 38 and 80°C. The spectra at 38°C correspond to appropriately weighted combinations of the spectra of the pure drugs, showing no evidence of interactions between the components at ambient temperature. There are changes in the aromatic region (C-9, C-11) for the 70% bisoprolol/valsartan mixture, implying increased molecular mobility of phenyl ring. This observation is puzzling, and may simply reflect a strong sensitivity of this spectral feature to sample temperature. The spectrum of the 50/50 (w/w) physical mixture changes significantly at 80°C, Fig. 7h, with the peaks associated with the bisoprolol having much lower intensities. There are also some subtle changes in the valsartan resonances, e.g. some sharpening of the methyl carbon (C-1), suggesting an increase in mobility, and a slight decrease in intensity of C-11, but these are difficult to interpret with confidence. In contrast to the DSC results, there are no significant changes observed at 80°C for the 70/30 and 80/20 physical mixtures in comparison to the pure drugs (data not shown).Fig. 7


Bisoprolol and bisoprolol-valsartan compatibility studied by differential scanning calorimetry, nuclear magnetic resonance and X-ray powder diffractometry.

Skotnicki M, Aguilar JA, Pyda M, Hodgkinson P - Pharm. Res. (2014)

13C CPMAS NMR spectra of each API and physical mixtures in different concentrations at 38 and 80°C.
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4300422&req=5

Fig7: 13C CPMAS NMR spectra of each API and physical mixtures in different concentrations at 38 and 80°C.
Mentions: Figure 7 shows the 13C NMR spectra of bisoprolol, valsartan and 70/30 and 50/50 physical mixtures at 38 and 80°C. The spectra at 38°C correspond to appropriately weighted combinations of the spectra of the pure drugs, showing no evidence of interactions between the components at ambient temperature. There are changes in the aromatic region (C-9, C-11) for the 70% bisoprolol/valsartan mixture, implying increased molecular mobility of phenyl ring. This observation is puzzling, and may simply reflect a strong sensitivity of this spectral feature to sample temperature. The spectrum of the 50/50 (w/w) physical mixture changes significantly at 80°C, Fig. 7h, with the peaks associated with the bisoprolol having much lower intensities. There are also some subtle changes in the valsartan resonances, e.g. some sharpening of the methyl carbon (C-1), suggesting an increase in mobility, and a slight decrease in intensity of C-11, but these are difficult to interpret with confidence. In contrast to the DSC results, there are no significant changes observed at 80°C for the 70/30 and 80/20 physical mixtures in comparison to the pure drugs (data not shown).Fig. 7

Bottom Line: Strong interactions between bisoprolol fumarate and valsartan were observed above 60 C, resulting in the formation of a new amorphous material.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutical Technology, Poznań University of Medical Sciences, ul. Grunwaldzka 6, 60-780, Poznań, Poland.

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.

Show MeSH