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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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X-ray diffractograms of crystalline bisoprolol, amorphous valsartan (form AR) and a 50/50 (w/w) physical mixture of bisoprolol/valsartan (form AR) at (a) 25°C and (b) 80°C.
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Fig10: X-ray diffractograms of crystalline bisoprolol, amorphous valsartan (form AR) and a 50/50 (w/w) physical mixture of bisoprolol/valsartan (form AR) at (a) 25°C and (b) 80°C.

Mentions: XRPD patterns of the 50/50 physical mixture, Fig. 10, show peaks corresponding to bisoprolol at 25°C. Although some studies suggest that the lack of observed interactions via XRPD at ambient temperature proves that DSC is a more sensitive technique (27, 53), variable-temperature XRPD experiments are necessary in order to meaningfully compare the two methods. A decrease of signal intensity from the crystalline bisoprolol component starts at about 60°C (data not shown), and at 80°C the XRPD pattern implies that the material is fully amorphous. In the second heating, the amorphous halo observed from 0 to 60°C confirms that the material remains amorphous (data not shown), as found by other methods. In contrast to the solid-state NMR results on 70/30 and 80/20 mixtures, but in agreement with DSC, XRPD measurements on the 70/30 physical mixture showed only partial amorphisation of bisoprolol, with some of bisoprolol remaining in its crystalline state (Figure 3S, supplementary material).Fig. 10


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)

X-ray diffractograms of crystalline bisoprolol, amorphous valsartan (form AR) and a 50/50 (w/w) physical mixture of bisoprolol/valsartan (form AR) at (a) 25°C and (b) 80°C.
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4300422&req=5

Fig10: X-ray diffractograms of crystalline bisoprolol, amorphous valsartan (form AR) and a 50/50 (w/w) physical mixture of bisoprolol/valsartan (form AR) at (a) 25°C and (b) 80°C.
Mentions: XRPD patterns of the 50/50 physical mixture, Fig. 10, show peaks corresponding to bisoprolol at 25°C. Although some studies suggest that the lack of observed interactions via XRPD at ambient temperature proves that DSC is a more sensitive technique (27, 53), variable-temperature XRPD experiments are necessary in order to meaningfully compare the two methods. A decrease of signal intensity from the crystalline bisoprolol component starts at about 60°C (data not shown), and at 80°C the XRPD pattern implies that the material is fully amorphous. In the second heating, the amorphous halo observed from 0 to 60°C confirms that the material remains amorphous (data not shown), as found by other methods. In contrast to the solid-state NMR results on 70/30 and 80/20 mixtures, but in agreement with DSC, XRPD measurements on the 70/30 physical mixture showed only partial amorphisation of bisoprolol, with some of bisoprolol remaining in its crystalline state (Figure 3S, supplementary material).Fig. 10

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