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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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Variable-temperature X-ray diffractograms of (a) crystalline and (b) quench-cooled bisoprolol.
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Fig9: Variable-temperature X-ray diffractograms of (a) crystalline and (b) quench-cooled bisoprolol.

Mentions: Figure 9 shows the X-ray diffraction patterns of crystalline and quench-cooled bisoprolol as a function of temperature. The diffraction patterns of the crystalline material at 60 and 80°C show only modest changes of peak intensity and no significant changes in peak position, suggesting that there is no significant structural change during heating, which agrees with the DSC and NMR findings. XRPD of the quench-cooled bisoprolol at 0°C, i.e. below the re-crystallization temperature, shows a characteristic halo pattern confirming its amorphous nature. At 60°C, the material has re-crystallized into the same form as the starting material. However, the diffraction peaks are much weaker, suggesting a lower degree of crystallinity. This is consistent with the lower melting point of bisoprolol in the second heating and the slightly broader and less-resolved NMR resonances of quench-cooled bisoprolol at 60°C, Fig. 6i.Fig. 9


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)

Variable-temperature X-ray diffractograms of (a) crystalline and (b) quench-cooled bisoprolol.
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig9: Variable-temperature X-ray diffractograms of (a) crystalline and (b) quench-cooled bisoprolol.
Mentions: Figure 9 shows the X-ray diffraction patterns of crystalline and quench-cooled bisoprolol as a function of temperature. The diffraction patterns of the crystalline material at 60 and 80°C show only modest changes of peak intensity and no significant changes in peak position, suggesting that there is no significant structural change during heating, which agrees with the DSC and NMR findings. XRPD of the quench-cooled bisoprolol at 0°C, i.e. below the re-crystallization temperature, shows a characteristic halo pattern confirming its amorphous nature. At 60°C, the material has re-crystallized into the same form as the starting material. However, the diffraction peaks are much weaker, suggesting a lower degree of crystallinity. This is consistent with the lower melting point of bisoprolol in the second heating and the slightly broader and less-resolved NMR resonances of quench-cooled bisoprolol at 60°C, Fig. 6i.Fig. 9

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