Experimental and DFT simulation study of a novel felodipine cocrystal: Characterization, dissolving properties and thermal decomposition kinetics

In this study, a new cocrystal of felodipine (Fel) and glutaric acid (Glu) with a high dissolution rate was developed using the solvent ultrasonic method. The prepared cocrystal was characterized using X-ray powder diffraction, differential scanning calorimetry, thermogravimetric (TG) analysis, and infrared (IR) spectroscopy. To provide basic information about the optimization of pharmaceutical preparations of Fel-based cocrystals, this work investigated the thermal decomposition kinetics of the Fel-Glu cocrystal through non-isothermal thermogravimetry. Density functional theory (DFT) simulations were also performed on the Fel monomer and the trimolecular cocrystal compound for exploring the mechanisms underlying hydrogen bonding formation and thermal decomposition. Combined results of IR spectroscopy and DFT simulation verified that the Fel-Glu cocrystal formed via the N-H center dot center dot center dot O=C and C=O center dot center dot center dot H-O hydrogen bonds between Fel and Glu at the ratio of 1:2. The TG/derivative TG curves indicated that the thermal decomposition of the Fel-Glu cocrystal underwent a two-step process. The apparent activation energy (E-a) and pre-exponential factor (A) of the thermal decomposition for the first stage were 84.90 kJ mol(-1) and 7.03 x 10(7) min(-1), respectively. The mechanism underlying thermal decomposition possibly involved nucleation and growth, with the integral mechanism function G(alpha) of alpha(3/2). DFT calculation revealed that the hydrogen bonding between Fel and Glu weakened the terminal methoxyl, methyl, and ethyl groups in the Fel molecule. As a result, these groups were lost along with the Glu molecule in the first thermal decomposition. In conclusion, the formed cocrystal exhibited different thermal decomposition kinetics and showed different E-a,A, and shelf life from the intact active pharmaceutical ingredient. (C) 2018 Elsevier B.V. All rights reserved.