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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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1H MAS NMR spectra of (a) bisoprolol, (b) valsartan (form AR), (c) valsartan (form AM), (d) 50/50 physical mixture of bisoprolol/valsartan (solid line) (e) 50/50 physical mixture of bisoprolol/valsartan heated to 80°C (solid line). (d) and (e) show also the sum spectra of valsartan and bisoprolol (dashed line). Spectra were recorded at an MAS rate of 53 kHz. Sharper resonances in physical mixtures indicate increased mobility (amorphisation) of the mixture (d–e).
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Fig11: 1H MAS NMR spectra of (a) bisoprolol, (b) valsartan (form AR), (c) valsartan (form AM), (d) 50/50 physical mixture of bisoprolol/valsartan (solid line) (e) 50/50 physical mixture of bisoprolol/valsartan heated to 80°C (solid line). (d) and (e) show also the sum spectra of valsartan and bisoprolol (dashed line). Spectra were recorded at an MAS rate of 53 kHz. Sharper resonances in physical mixtures indicate increased mobility (amorphisation) of the mixture (d–e).

Mentions: To investigate the potential involvement of the COOH and NH groups in the interaction between the drugs, 1H MAS NMR studies were also performed using very fast magic-angle spinning (53 kHz) to reduce the line-broadening associated with the strong dipolar interactions between 1H spins (54). Four different resonances are distinguishable in the fast MAS 1H spectrum of bisoprolol, Fig. 11a, corresponding to methyl (≈0.7 ppm), methylene, methine, hydroxyl, amine (2–5.5 ppm), aromatic (≈7 ppm) protons and also a low intensity signal at ≈ 10.4 ppm corresponding to an acid proton bonded to amine group. Figure 11b and c show spectra of the two valsartan forms, clearly showing differences in the hydrogen bonding region at 12–18 ppm. Figure 11d shows spectra of physical mixture of both APIs (solid line) and the sum of spectra of the pure materials (dashed line) The lines of the physical mixture are slightly sharper than the sum spectrum, confirming increased mobility at the onset of transition; increasing the spinning rate of the sample of untreated physical mixture to 63 kHz resulted in the sample volume expanding, presumably as the increased frictional heating triggered the interaction at about 60–80°C. This volume expansion is consistent with the crystalline bisoprolol transforming into an amorphous form with lower density. Figure 11e shows the spectra of the physical mixture heated in an oven to 80°C and cooled to room temperature. The lines are now significantly sharper than the spectrum of the pure materials, due to increased molecular mobility in the amorphised material. The spectrum also shows changes in the hydrogen bonding region i.e. in acidic and tetrazole protons signals arising from valsartan, which implies a change of hydrogen bonding due to amorphisation and/or deprotonation of these acidic carbons. The differences in overall mobility were confirmed by static 1H NMR; the bandshape of untreated physical mixture is measurably broader (Δυ½ = 37.6 kHz) then that from the mixture heated to 80–85°C and recorded at room temperature (Δυ½ = 28.9 kHz), consistent with increased motion in the amorphised material (Figure 4S, supplementary material).Fig. 11


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)

1H MAS NMR spectra of (a) bisoprolol, (b) valsartan (form AR), (c) valsartan (form AM), (d) 50/50 physical mixture of bisoprolol/valsartan (solid line) (e) 50/50 physical mixture of bisoprolol/valsartan heated to 80°C (solid line). (d) and (e) show also the sum spectra of valsartan and bisoprolol (dashed line). Spectra were recorded at an MAS rate of 53 kHz. Sharper resonances in physical mixtures indicate increased mobility (amorphisation) of the mixture (d–e).
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Related In: Results  -  Collection

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Fig11: 1H MAS NMR spectra of (a) bisoprolol, (b) valsartan (form AR), (c) valsartan (form AM), (d) 50/50 physical mixture of bisoprolol/valsartan (solid line) (e) 50/50 physical mixture of bisoprolol/valsartan heated to 80°C (solid line). (d) and (e) show also the sum spectra of valsartan and bisoprolol (dashed line). Spectra were recorded at an MAS rate of 53 kHz. Sharper resonances in physical mixtures indicate increased mobility (amorphisation) of the mixture (d–e).
Mentions: To investigate the potential involvement of the COOH and NH groups in the interaction between the drugs, 1H MAS NMR studies were also performed using very fast magic-angle spinning (53 kHz) to reduce the line-broadening associated with the strong dipolar interactions between 1H spins (54). Four different resonances are distinguishable in the fast MAS 1H spectrum of bisoprolol, Fig. 11a, corresponding to methyl (≈0.7 ppm), methylene, methine, hydroxyl, amine (2–5.5 ppm), aromatic (≈7 ppm) protons and also a low intensity signal at ≈ 10.4 ppm corresponding to an acid proton bonded to amine group. Figure 11b and c show spectra of the two valsartan forms, clearly showing differences in the hydrogen bonding region at 12–18 ppm. Figure 11d shows spectra of physical mixture of both APIs (solid line) and the sum of spectra of the pure materials (dashed line) The lines of the physical mixture are slightly sharper than the sum spectrum, confirming increased mobility at the onset of transition; increasing the spinning rate of the sample of untreated physical mixture to 63 kHz resulted in the sample volume expanding, presumably as the increased frictional heating triggered the interaction at about 60–80°C. This volume expansion is consistent with the crystalline bisoprolol transforming into an amorphous form with lower density. Figure 11e shows the spectra of the physical mixture heated in an oven to 80°C and cooled to room temperature. The lines are now significantly sharper than the spectrum of the pure materials, due to increased molecular mobility in the amorphised material. The spectrum also shows changes in the hydrogen bonding region i.e. in acidic and tetrazole protons signals arising from valsartan, which implies a change of hydrogen bonding due to amorphisation and/or deprotonation of these acidic carbons. The differences in overall mobility were confirmed by static 1H NMR; the bandshape of untreated physical mixture is measurably broader (Δυ½ = 37.6 kHz) then that from the mixture heated to 80–85°C and recorded at room temperature (Δυ½ = 28.9 kHz), consistent with increased motion in the amorphised material (Figure 4S, supplementary material).Fig. 11

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