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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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Standard DSC curves of crystalline bisoprolol showing 1st heating, cooling (glass transition of amorphised material) and 2nd heating (glass transition, cold crystallisation, melting of re-crystallised material). All runs obtained at a 10°C min−1 heating rate.
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Fig2: Standard DSC curves of crystalline bisoprolol showing 1st heating, cooling (glass transition of amorphised material) and 2nd heating (glass transition, cold crystallisation, melting of re-crystallised material). All runs obtained at a 10°C min−1 heating rate.

Mentions: Figure 2 shows the standard DSC traces of crystalline bisoprolol with 10°C min−1 heating rate, cooling the sample to −50°C at 10°C min−1 and a second heating. On the first heating, the DSC curve shows one sharp endothermic peak with an onset at 102.3 ± 0.3°C and an enthalpy of fusion ΔHBISO = 110 ± 2 J g−1 due to melting. Three events are observed on the second run: a glass transition at −3.6 ± 0.9°C with a change of heat capacity (ΔCp) of 0.51 ± 0.02 J g−1 K−1, followed by a cold crystallization exotherm at 24.2 ± 0.6°C (ΔH = 39 ± 2 J g−1) and a melting peak with onset at 95.4 ± 1.4°C (ΔH = 85 ± 1 J g−1). The lower values of the melting temperature and ΔH in the second heating may be due to differences in morphology in the re-crystallized phase of sample compared to the original crystalline material. There may be nanocrystalline domains present in the re-crystallized sample, which can lower the peak of melting, and/or the re-crystallization of the amorphous material may be incomplete. Both starting and re-crystallized material showed birefringence under polarized light microscopy, confirming their crystalline nature.Fig. 2


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)

Standard DSC curves of crystalline bisoprolol showing 1st heating, cooling (glass transition of amorphised material) and 2nd heating (glass transition, cold crystallisation, melting of re-crystallised material). All runs obtained at a 10°C min−1 heating rate.
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig2: Standard DSC curves of crystalline bisoprolol showing 1st heating, cooling (glass transition of amorphised material) and 2nd heating (glass transition, cold crystallisation, melting of re-crystallised material). All runs obtained at a 10°C min−1 heating rate.
Mentions: Figure 2 shows the standard DSC traces of crystalline bisoprolol with 10°C min−1 heating rate, cooling the sample to −50°C at 10°C min−1 and a second heating. On the first heating, the DSC curve shows one sharp endothermic peak with an onset at 102.3 ± 0.3°C and an enthalpy of fusion ΔHBISO = 110 ± 2 J g−1 due to melting. Three events are observed on the second run: a glass transition at −3.6 ± 0.9°C with a change of heat capacity (ΔCp) of 0.51 ± 0.02 J g−1 K−1, followed by a cold crystallization exotherm at 24.2 ± 0.6°C (ΔH = 39 ± 2 J g−1) and a melting peak with onset at 95.4 ± 1.4°C (ΔH = 85 ± 1 J g−1). The lower values of the melting temperature and ΔH in the second heating may be due to differences in morphology in the re-crystallized phase of sample compared to the original crystalline material. There may be nanocrystalline domains present in the re-crystallized sample, which can lower the peak of melting, and/or the re-crystallization of the amorphous material may be incomplete. Both starting and re-crystallized material showed birefringence under polarized light microscopy, confirming their crystalline nature.Fig. 2

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