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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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(a) 13C solution-state NMR spectrum of bisoprolol in D2O at 25°C, 13C CPMAS NMR spectra of (b) crystalline and (c) quench-cooled (amorphous) bisoprolol at −20°C. Asterisks (*) denote spinning sidebands. Arrows (↓) denote signals that are thought to arise from polymorphic or enantiomeric impurities.
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Fig5: (a) 13C solution-state NMR spectrum of bisoprolol in D2O at 25°C, 13C CPMAS NMR spectra of (b) crystalline and (c) quench-cooled (amorphous) bisoprolol at −20°C. Asterisks (*) denote spinning sidebands. Arrows (↓) denote signals that are thought to arise from polymorphic or enantiomeric impurities.

Mentions: Figure 5 shows the 13C solution-state spectrum of bisoprolol and 13C CP MAS NMR spectra of crystalline and quench-cooled (amorphous) bisoprolol. Due to the instability of the amorphous form at room temperature, spectra for both solid forms were acquired at −20°C i.e. below the glass transition temperature. Standard NMR techniques (COSY, HSQC and HMBC) were used to assign the solution-state spectrum. The solid-state spectrum was assigned using solution-state NMR data and spectral editing techniques: interrupted decoupling (dipolar dephasing) and depolarization experiments (inversion times from 25 to 100 μs). The resulting assignments are presented in Table I. The assignment of the solid-state spectra contains ambiguities due to its lower resolution and the differences in chemical shifts between the solution and solid state. Some of these ambiguities could, in principle, be resolved by computational prediction of chemical shifts given a crystal structure (51), but they are not significant for this study. Only one signal is observed for each site of bisoprolol and the two chemically distinct sites of the fumarate ion, indicating that the asymmetric unit cell contains a single bisoprolol molecule and a half molecule of fumarate. The spectrum of the crystalline material shows a set of low intensity signals, denoted by arrows in Fig. 5. Since there is no evidence from solution-state NMR of corresponding levels of chemical impurities, these signals could potentially arise from a second polymorphic form, or, more probably, enantiomeric “defects” (e.g. a R-molecule occupying a site otherwise occupied by S molecules). The low level of these signals (corresponding to about 1% of material) prevents further characterization. The spectrum of the quench-cooled form exhibits the expected general broadness of the resonances due to the range of local environments. These spectra vary slightly from experiment to experiment, presumably reflecting differences in cooling rates used to obtain the amorphous form. Standard NMR techniques were used to assign the solution-state spectrum of valsartan. The solid-state spectrum assignment was done based on solution-state data and by computational prediction of chemical shifts. Detailed solid-state NMR studies of pure valsartan will be published separately.Fig. 5


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) 13C solution-state NMR spectrum of bisoprolol in D2O at 25°C, 13C CPMAS NMR spectra of (b) crystalline and (c) quench-cooled (amorphous) bisoprolol at −20°C. Asterisks (*) denote spinning sidebands. Arrows (↓) denote signals that are thought to arise from polymorphic or enantiomeric impurities.
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4300422&req=5

Fig5: (a) 13C solution-state NMR spectrum of bisoprolol in D2O at 25°C, 13C CPMAS NMR spectra of (b) crystalline and (c) quench-cooled (amorphous) bisoprolol at −20°C. Asterisks (*) denote spinning sidebands. Arrows (↓) denote signals that are thought to arise from polymorphic or enantiomeric impurities.
Mentions: Figure 5 shows the 13C solution-state spectrum of bisoprolol and 13C CP MAS NMR spectra of crystalline and quench-cooled (amorphous) bisoprolol. Due to the instability of the amorphous form at room temperature, spectra for both solid forms were acquired at −20°C i.e. below the glass transition temperature. Standard NMR techniques (COSY, HSQC and HMBC) were used to assign the solution-state spectrum. The solid-state spectrum was assigned using solution-state NMR data and spectral editing techniques: interrupted decoupling (dipolar dephasing) and depolarization experiments (inversion times from 25 to 100 μs). The resulting assignments are presented in Table I. The assignment of the solid-state spectra contains ambiguities due to its lower resolution and the differences in chemical shifts between the solution and solid state. Some of these ambiguities could, in principle, be resolved by computational prediction of chemical shifts given a crystal structure (51), but they are not significant for this study. Only one signal is observed for each site of bisoprolol and the two chemically distinct sites of the fumarate ion, indicating that the asymmetric unit cell contains a single bisoprolol molecule and a half molecule of fumarate. The spectrum of the crystalline material shows a set of low intensity signals, denoted by arrows in Fig. 5. Since there is no evidence from solution-state NMR of corresponding levels of chemical impurities, these signals could potentially arise from a second polymorphic form, or, more probably, enantiomeric “defects” (e.g. a R-molecule occupying a site otherwise occupied by S molecules). The low level of these signals (corresponding to about 1% of material) prevents further characterization. The spectrum of the quench-cooled form exhibits the expected general broadness of the resonances due to the range of local environments. These spectra vary slightly from experiment to experiment, presumably reflecting differences in cooling rates used to obtain the amorphous form. Standard NMR techniques were used to assign the solution-state spectrum of valsartan. The solid-state spectrum assignment was done based on solution-state data and by computational prediction of chemical shifts. Detailed solid-state NMR studies of pure valsartan will be published separately.Fig. 5

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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