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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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Chemical structures of (a) bisoprolol fumarate (M = 766.96 g mol−1) and (b) valsartan (M = 435.52 g mol−1) with the carbons numbered. The chemical structure of bisoprolol fumarate is that of the neutral molecules, as conventionally given. The material is, however, expected to be in a salt form as a solid, with the fumaric acid present as a doubly de-protonated fumarate ion and with the bisoprolol assumed to be protonated at its NH site.
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Fig1: Chemical structures of (a) bisoprolol fumarate (M = 766.96 g mol−1) and (b) valsartan (M = 435.52 g mol−1) with the carbons numbered. The chemical structure of bisoprolol fumarate is that of the neutral molecules, as conventionally given. The material is, however, expected to be in a salt form as a solid, with the fumaric acid present as a doubly de-protonated fumarate ion and with the bisoprolol assumed to be protonated at its NH site.

Mentions: Cardiovascular diseases (CVDs), such as coronary heart disease, heart failure, cerebrovascular disease or hypertension, are the major cause of death in developed countries (1). Bisoprolol fumarate (BISO), or (RS)-1-((alpha-(2-isopropoxyethoxy)-p-tolyl)oxy)-3-(isopropylamino)-2-propanol fumarate (2:1), Fig. 1a, is a beta1-selective (cardioselective) adrenoceptor blocking agent (2). Valsartan (VAL), or N-[p-(o-1H-tetrazol-5-ylphenyl)benzyl]-N-valeryl-L-valine, Fig. 1b, is a potent, highly specific angiotensin II type 1 (AT1) receptor antagonist (3). Both agents are used in the management of hypertension and heart failure (2, 3). Both are administered orally in a capsule or tablet form and may be used alone or in combination, but there is no single dosage form currently on the market containing both bisoprolol and valsartan. Combining drugs with synergistic mechanism of action in one dosage form (fixed-dose combination, FDC) has potential benefits, such as improved efficacy, reduced dosing, lower cost or enhanced patient compliance (4). Combination therapy has been shown to reduce CVD complications by more than 80% (4), and strong interest has been expressed by the pharmaceutical industry to develop an all-in-one pill (multicomponent cardiovascular pill, MCCP or polypill) containing an angiotensin-converting enzyme (ACE) inhibitor, beta-blocker, aspirin and statin (5). Both bisoprolol and valsartan (as an alternative for an ACE inhibitor) are good candidates for a two-ingredient FDC or MCCP.Fig. 1


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)

Chemical structures of (a) bisoprolol fumarate (M = 766.96 g mol−1) and (b) valsartan (M = 435.52 g mol−1) with the carbons numbered. The chemical structure of bisoprolol fumarate is that of the neutral molecules, as conventionally given. The material is, however, expected to be in a salt form as a solid, with the fumaric acid present as a doubly de-protonated fumarate ion and with the bisoprolol assumed to be protonated at its NH site.
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig1: Chemical structures of (a) bisoprolol fumarate (M = 766.96 g mol−1) and (b) valsartan (M = 435.52 g mol−1) with the carbons numbered. The chemical structure of bisoprolol fumarate is that of the neutral molecules, as conventionally given. The material is, however, expected to be in a salt form as a solid, with the fumaric acid present as a doubly de-protonated fumarate ion and with the bisoprolol assumed to be protonated at its NH site.
Mentions: Cardiovascular diseases (CVDs), such as coronary heart disease, heart failure, cerebrovascular disease or hypertension, are the major cause of death in developed countries (1). Bisoprolol fumarate (BISO), or (RS)-1-((alpha-(2-isopropoxyethoxy)-p-tolyl)oxy)-3-(isopropylamino)-2-propanol fumarate (2:1), Fig. 1a, is a beta1-selective (cardioselective) adrenoceptor blocking agent (2). Valsartan (VAL), or N-[p-(o-1H-tetrazol-5-ylphenyl)benzyl]-N-valeryl-L-valine, Fig. 1b, is a potent, highly specific angiotensin II type 1 (AT1) receptor antagonist (3). Both agents are used in the management of hypertension and heart failure (2, 3). Both are administered orally in a capsule or tablet form and may be used alone or in combination, but there is no single dosage form currently on the market containing both bisoprolol and valsartan. Combining drugs with synergistic mechanism of action in one dosage form (fixed-dose combination, FDC) has potential benefits, such as improved efficacy, reduced dosing, lower cost or enhanced patient compliance (4). Combination therapy has been shown to reduce CVD complications by more than 80% (4), and strong interest has been expressed by the pharmaceutical industry to develop an all-in-one pill (multicomponent cardiovascular pill, MCCP or polypill) containing an angiotensin-converting enzyme (ACE) inhibitor, beta-blocker, aspirin and statin (5). Both bisoprolol and valsartan (as an alternative for an ACE inhibitor) are good candidates for a two-ingredient FDC or MCCP.Fig. 1

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