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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 the APIs and their 50/50 physical mixtures. The broad endothermic peak in the mixture indicates a significant physical or chemical interaction. All runs obtained at a 10°C min−1 heating rate
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Fig3: Standard DSC curves of the APIs and their 50/50 physical mixtures. The broad endothermic peak in the mixture indicates a significant physical or chemical interaction. All runs obtained at a 10°C min−1 heating rate

Mentions: TGA curves (Figure 1S, supplementary material) of the individual components and a 50/50 (w/w) bisoprolol/valsartan (form AR) physical mixture show that the ingredients change individually in the mixture, indicating that no degradation due to interaction of the components takes place. However, the DSC curve of the same physical mixture, Fig. 3, does not show the expected sharp bisoprolol melting peak and instead shows overlapped broad endothermic peaks at around 60–100°C, indicating some physical or chemical interaction has disrupted the crystal lattice of bisoprolol. The total enthalpy of this peak is estimated to be 51 ± 5 J g−1, which is lower than the weighted sum of the enthalpies of the individual components, (ΔHBISO + ΔHVAL)/2 ≈ 68 J g−1, suggesting interaction. Two minima at about 77 and 100°C are observed. The peak with minimum at around 100°C can be ascribed to the enthalpy relaxation peak of valsartan (form AR). This is confirmed by the DSC trace of a physical mixture made with freshly prepared amorphous valsartan (form AM), which shows only the broad peak with one minimum at 77°C, confirming that the peak at 100°C arises from valsartan (form AR). The interaction observed by DSC is also seen in a simple micro- and macroscopic observation; powder samples mixed and heated on the hot-stage to about 60°C convert into a more viscous state, and the material becomes sticky.Fig. 3


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 the APIs and their 50/50 physical mixtures. The broad endothermic peak in the mixture indicates a significant physical or chemical interaction. 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

Fig3: Standard DSC curves of the APIs and their 50/50 physical mixtures. The broad endothermic peak in the mixture indicates a significant physical or chemical interaction. All runs obtained at a 10°C min−1 heating rate
Mentions: TGA curves (Figure 1S, supplementary material) of the individual components and a 50/50 (w/w) bisoprolol/valsartan (form AR) physical mixture show that the ingredients change individually in the mixture, indicating that no degradation due to interaction of the components takes place. However, the DSC curve of the same physical mixture, Fig. 3, does not show the expected sharp bisoprolol melting peak and instead shows overlapped broad endothermic peaks at around 60–100°C, indicating some physical or chemical interaction has disrupted the crystal lattice of bisoprolol. The total enthalpy of this peak is estimated to be 51 ± 5 J g−1, which is lower than the weighted sum of the enthalpies of the individual components, (ΔHBISO + ΔHVAL)/2 ≈ 68 J g−1, suggesting interaction. Two minima at about 77 and 100°C are observed. The peak with minimum at around 100°C can be ascribed to the enthalpy relaxation peak of valsartan (form AR). This is confirmed by the DSC trace of a physical mixture made with freshly prepared amorphous valsartan (form AM), which shows only the broad peak with one minimum at 77°C, confirming that the peak at 100°C arises from valsartan (form AR). The interaction observed by DSC is also seen in a simple micro- and macroscopic observation; powder samples mixed and heated on the hot-stage to about 60°C convert into a more viscous state, and the material becomes sticky.Fig. 3

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