Measurements, Thermodynamic Modeling, and a Hydrogen Bonding Study on the Solubilities of Metoprolol Succinate in Organic Solvents

Abstract

The solubilities of metoprolol succinate (a cardioselective β1 adrenergic receptor) in methanol, ethanol, n-propanol, isopropanol, n-butanol, ethyl acetate, and acetone were measured at temperatures ranging from (278.2 to 318.2) K using a solid⁻liquid equilibrium method. The solubility of metoprolol succinate increases with increasing temperature. At a fixed temperature, the solubility decreases in the order methanol > ethanol > n-butanol > n-propanol > isopropanol > acetone > ethyl acetate. The enthalpy of fusion and the melting point of metoprolol succinate were determined by differential scanning calorimetry. The thermodynamic properties of the dissolution process, determined by a van't Hoff analysis, have been obtained and are discussed. The modified Apelblat equation, Wilson model, and non-random two-liquid (NRTL) model were employed to correlate the solubilities of metoprolol succinate in different solvents. Finally, a quantitative structure⁻property relationship (QSPR) study of physical properties of solvents and density functional theory simulations of hydrogen-bonding structure were carried out to give the explanation for the sequence of solubility in alcohols. The density functional theory (DFT) calculations well illustrated that the solubility of metoprolol succinate in various alcohols can be mainly attributed to the intra- and intermolecular hydrogen bonds in metoprolol succinate-solvent complexes.

Keywords: dissolution enthalpy; hydrogen bonding; metoprolol succinate; solubility; thermodynamic model.

Figure 1

The differential scanning calorimetry (DSC) thermogram of metoprolol succinate.

Figure 2

Modified van’t Hoff plot of the mole fraction solubility of metoprolol succinate in selected solvents: (□) methanol; (■) ethanol; (∆) n-propanol; (▲) isopropanol; (○) n-butanol; (●) ethyl acetate; (◊) acetone.

Figure 3

Interactions between metoprolol succinate and methanol; The dashed lines indicate hydrogen bonds of O–H with a distance (Unit: Å, 1 angstrom = 0.1 nm).