Thermodynamic stability analysis of m-nisoldipine polymorphs

Two polymorphic crystal forms of m-nisoldipine (1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid methyl 2-methylpropyl ester) were characterized by X-ray powder diffraction and IR-spectroscopy. The solubility of the two polymorphs in water at 25, 31, 37, 42, and 49 °C was investigated; the values obtained were used to calculate the thermodynamic parameters of the phase transition. The results show that the two forms A and B are enantiotropic. The temperature of polymorphic phase transition was 47 °C, and the values of ΔGA,Bθ, ΔHA,Bθ, and ΔSA,Bθ at 25 °C were 2.47, 36.01, and 112.48 J · mol−1 · K−1, respectively. Form A is thermodynamically stable below the transition temperature; it accorded with interaction energies of the two forms obtained from Density Function Theory (DFT) calculations on the hydrogen-bonding and π-stacking interactions. The character of the solid-state decomposition, studied using DSC analysis, showed that the activation energies of decomposition of the polymorphs A and B after melting at high temperatures were 109.80 and 59.14 kJ · mol−1, respectively. It is conclusion that melted states of polymorphs A and B reserved “the memories” of their respective crystalline state. Furthermore, phase transition of the polymorphs was not found under solid-state grinding conditions. Moisture sorption/desorption experiments showed that the two forms of m-nisoldipine are nonhygroscopic.

Graphical abstractSolubility method was used to investigated the thermodynamic properties and phase transition of two new polymorphs A, B of m-nisoldipine, a dihydropyridine calcium ion antagonist.Figure optionsDownload full-size imageDownload as PowerPoint slideHighlights► New enantiotropic polymorphs of m-nisoldipine were presented. ► Solubility method was used to investigate the thermodynamic stability. ► The thermodynamic stability accorded with interaction energies of the two forms.