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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 (a–e) crystalline, (f) melted then cooled to 80°C in the rubbery state and (g–j) quench-cooled bisoprolol as a function of calibrated temperature.
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Fig6: 13C CPMAS NMR spectra of (a–e) crystalline, (f) melted then cooled to 80°C in the rubbery state and (g–j) quench-cooled bisoprolol as a function of calibrated temperature.

Mentions: Figure 6a–e shows 13C CP MAS spectra of crystalline bisoprolol as a function of temperature. At low temperature, distinct signals are observed for the phenyl carbons (C-9 and C-11) at 113.0 and 119.3 ppm, indicating that the two halves of the phenyl ring are not related by symmetry in the crystal structure. The phenyl resonances coalescence (at 116.0 ppm) above 60°C, corresponding to increased molecular mobility of phenyl ring. This is commonly observed in molecular solids e.g. Ref. (52) and references therein. Carbon C-8 and C-12 exhibit similar behavior, although this is not clearly resolved due to overlap with the C-7 resonance. Subtle changes in the isopropyl signals (C-1, C-2, C-17 and C-18) are also observed, which are also consistent with increasing local mobility as the sample warms.Fig. 6


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 (a–e) crystalline, (f) melted then cooled to 80°C in the rubbery state and (g–j) quench-cooled bisoprolol as a function of calibrated temperature.
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig6: 13C CPMAS NMR spectra of (a–e) crystalline, (f) melted then cooled to 80°C in the rubbery state and (g–j) quench-cooled bisoprolol as a function of calibrated temperature.
Mentions: Figure 6a–e shows 13C CP MAS spectra of crystalline bisoprolol as a function of temperature. At low temperature, distinct signals are observed for the phenyl carbons (C-9 and C-11) at 113.0 and 119.3 ppm, indicating that the two halves of the phenyl ring are not related by symmetry in the crystal structure. The phenyl resonances coalescence (at 116.0 ppm) above 60°C, corresponding to increased molecular mobility of phenyl ring. This is commonly observed in molecular solids e.g. Ref. (52) and references therein. Carbon C-8 and C-12 exhibit similar behavior, although this is not clearly resolved due to overlap with the C-7 resonance. Subtle changes in the isopropyl signals (C-1, C-2, C-17 and C-18) are also observed, which are also consistent with increasing local mobility as the sample warms.Fig. 6

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