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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 NMR signal intensity vs. cross-polarization contact time for the CH3 at 14.1 ppm of valsartan and the alkyl signal at 72.9 ppm of bisoprolol in their 50/50 (w/w) physical mixture at 80°C.
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Fig8: 13C NMR signal intensity vs. cross-polarization contact time for the CH3 at 14.1 ppm of valsartan and the alkyl signal at 72.9 ppm of bisoprolol in their 50/50 (w/w) physical mixture at 80°C.

Mentions: Figure 7d shows the spectrum of the 50/50 (w/w) physical mixture of bisoprolol/valsartan heated to 80°C and then cooled to 38°C. The spectrum at 38°C is similar to the spectrum at 80°C, i.e. the reduction in intensities of the peaks associated with crystalline bisoprolol is irreversible. Experiments using longer recycle delays (up to 16 s) confirmed that the loss of these peaks was not an artifact of relaxation times – components with long spin–lattice relaxation would be suppressed in experiments with short relaxation delays between scans. The loss of bisoprolol signals could also be associated with a dramatic increase in molecular mobility, which would selectively reduce the efficiency of cross-polarization for mobile components. However, direct excitation of the 13C spectrum, using recycle delays of up to 50 s, did not reveal signals from mobile components that could be assigned to bisoprolol. To investigate the apparent disappearance of the bisoprolol signals in the 50/50 physical mixture spectrum, the intensities of the methyl (C-1, 14.1 ppm) resonance of valsartan and the alkyl signal at 72.9 ppm of bisoprolol in the binary mixture were measured as a function of the cross-polarization contact time, Fig. 8. The slope of decaying part of the curve, which corresponds to T1ρ relaxation, is similar for both carbons. This is consistent with them being mixed at a molecular level or in domains smaller than 5 nm (34) and also shows that the weakness of the bisoprolol signals is not due to rapid T1ρ relaxation during cross-polarization. The bisoprolol signals are present, but just very weak and broad, presumably as a result of the distribution of local environments and hence dispersion of chemical shifts for each resonance due to amorphisation.Fig. 8


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 NMR signal intensity vs. cross-polarization contact time for the CH3 at 14.1 ppm of valsartan and the alkyl signal at 72.9 ppm of bisoprolol in their 50/50 (w/w) physical mixture at 80°C.
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4300422&req=5

Fig8: 13C NMR signal intensity vs. cross-polarization contact time for the CH3 at 14.1 ppm of valsartan and the alkyl signal at 72.9 ppm of bisoprolol in their 50/50 (w/w) physical mixture at 80°C.
Mentions: Figure 7d shows the spectrum of the 50/50 (w/w) physical mixture of bisoprolol/valsartan heated to 80°C and then cooled to 38°C. The spectrum at 38°C is similar to the spectrum at 80°C, i.e. the reduction in intensities of the peaks associated with crystalline bisoprolol is irreversible. Experiments using longer recycle delays (up to 16 s) confirmed that the loss of these peaks was not an artifact of relaxation times – components with long spin–lattice relaxation would be suppressed in experiments with short relaxation delays between scans. The loss of bisoprolol signals could also be associated with a dramatic increase in molecular mobility, which would selectively reduce the efficiency of cross-polarization for mobile components. However, direct excitation of the 13C spectrum, using recycle delays of up to 50 s, did not reveal signals from mobile components that could be assigned to bisoprolol. To investigate the apparent disappearance of the bisoprolol signals in the 50/50 physical mixture spectrum, the intensities of the methyl (C-1, 14.1 ppm) resonance of valsartan and the alkyl signal at 72.9 ppm of bisoprolol in the binary mixture were measured as a function of the cross-polarization contact time, Fig. 8. The slope of decaying part of the curve, which corresponds to T1ρ relaxation, is similar for both carbons. This is consistent with them being mixed at a molecular level or in domains smaller than 5 nm (34) and also shows that the weakness of the bisoprolol signals is not due to rapid T1ρ relaxation during cross-polarization. The bisoprolol signals are present, but just very weak and broad, presumably as a result of the distribution of local environments and hence dispersion of chemical shifts for each resonance due to amorphisation.Fig. 8

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