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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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Related in: MedlinePlus

(a) 1st and (b) 2nd heating TMDSC experiments. Reversing (dashed line) signals show changes in glass transition and heat capacities. Non-reversing (solid line) signals show changes due to bisoprolol-valsartan interaction and enthalpy relaxation of valsartan (form AR), cold crystallization of bisoprolol, enthalpy relaxation of co-amorphous mixtures and valsartan (form AM).
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Fig4: (a) 1st and (b) 2nd heating TMDSC experiments. Reversing (dashed line) signals show changes in glass transition and heat capacities. Non-reversing (solid line) signals show changes due to bisoprolol-valsartan interaction and enthalpy relaxation of valsartan (form AR), cold crystallization of bisoprolol, enthalpy relaxation of co-amorphous mixtures and valsartan (form AM).

Mentions: TMDSC was employed to separate the kinetic and thermodynamic processes during heating for a selected number of samples. The total heat flow in a DSC experiment is the sum of the heat flow associated with the sample’s heat capacity and a second term associated with physical or chemical transformations (48, 49). By imposing a time-dependent modulation on the temperature ramp, time-dependent DSC decomposes the overall heat flow in a reversing and non-reversing heat-flow rate, corresponding to “thermodynamic” and kinetically limited processes, respectively. Figure 4a shows the reversing and non-reversing heat-flow rates obtained from TMDSC as a function of temperature for the pure components and physical mixtures in 80/20, 50/50 and 20/80 (w/w) ratios. TMDSC separates the relaxation enthalpy of valsartan, observed in the non-reversing signal, from the change in heat capacity at glass transition observed in the reversing signal. The non-reversing curves for the 20/80 and 50/50 physical mixtures (solid lines) clearly show the enthalpy relaxation peak ascribed to valsartan (form AR) and a broad endotherm most probably due to physical or chemical change of bisoprolol fumarate. The enthalpy relaxation in the mixtures is difficult to estimate precisely due to peak overlap, but the values are approximately 70 and 50% lower than expected (ΔH50%VAL ~4 J g−1 compared to 50% ΔHVAL = 13 J g−1, and ΔH80%VAL ~11 J g−1 compared to 80% ΔHVAL = 21 J g−1). It was not possible to estimate the value of enthalpy relaxation for the 80/20 mixture. The reversing curves of the physical mixtures, dashed lines in Fig. 4a, show only one event i.e. the glass transition. It is clear that there is a change in the glass transition temperature of valsartan in the 50/50 and 80/20 physical mixtures, and in its heat capacity in all mixtures. Standard DSC experiments performed for twelve physical mixtures from 0 to 100% of bisoprolol show the same behaviour (Figure 2S, supplementary material) as observed in TMDSC on the selected samples. In the physical mixtures with 90% bisoprolol by weight, the melting peak is broadened but can still be observed, while the melting peak was not identified with 80% or less bisoprolol in the mixture.Fig. 4


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)

(a) 1st and (b) 2nd heating TMDSC experiments. Reversing (dashed line) signals show changes in glass transition and heat capacities. Non-reversing (solid line) signals show changes due to bisoprolol-valsartan interaction and enthalpy relaxation of valsartan (form AR), cold crystallization of bisoprolol, enthalpy relaxation of co-amorphous mixtures and valsartan (form AM).
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig4: (a) 1st and (b) 2nd heating TMDSC experiments. Reversing (dashed line) signals show changes in glass transition and heat capacities. Non-reversing (solid line) signals show changes due to bisoprolol-valsartan interaction and enthalpy relaxation of valsartan (form AR), cold crystallization of bisoprolol, enthalpy relaxation of co-amorphous mixtures and valsartan (form AM).
Mentions: TMDSC was employed to separate the kinetic and thermodynamic processes during heating for a selected number of samples. The total heat flow in a DSC experiment is the sum of the heat flow associated with the sample’s heat capacity and a second term associated with physical or chemical transformations (48, 49). By imposing a time-dependent modulation on the temperature ramp, time-dependent DSC decomposes the overall heat flow in a reversing and non-reversing heat-flow rate, corresponding to “thermodynamic” and kinetically limited processes, respectively. Figure 4a shows the reversing and non-reversing heat-flow rates obtained from TMDSC as a function of temperature for the pure components and physical mixtures in 80/20, 50/50 and 20/80 (w/w) ratios. TMDSC separates the relaxation enthalpy of valsartan, observed in the non-reversing signal, from the change in heat capacity at glass transition observed in the reversing signal. The non-reversing curves for the 20/80 and 50/50 physical mixtures (solid lines) clearly show the enthalpy relaxation peak ascribed to valsartan (form AR) and a broad endotherm most probably due to physical or chemical change of bisoprolol fumarate. The enthalpy relaxation in the mixtures is difficult to estimate precisely due to peak overlap, but the values are approximately 70 and 50% lower than expected (ΔH50%VAL ~4 J g−1 compared to 50% ΔHVAL = 13 J g−1, and ΔH80%VAL ~11 J g−1 compared to 80% ΔHVAL = 21 J g−1). It was not possible to estimate the value of enthalpy relaxation for the 80/20 mixture. The reversing curves of the physical mixtures, dashed lines in Fig. 4a, show only one event i.e. the glass transition. It is clear that there is a change in the glass transition temperature of valsartan in the 50/50 and 80/20 physical mixtures, and in its heat capacity in all mixtures. Standard DSC experiments performed for twelve physical mixtures from 0 to 100% of bisoprolol show the same behaviour (Figure 2S, supplementary material) as observed in TMDSC on the selected samples. In the physical mixtures with 90% bisoprolol by weight, the melting peak is broadened but can still be observed, while the melting peak was not identified with 80% or less bisoprolol in the mixture.Fig. 4

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
Related in: MedlinePlus