Phase equilibrium thermodynamics, quantum chemistry and molecular dynamic simulations for cocrystal systems formed by nicotinamide, benzoic acid and solvent

Cocrystal phase diagram can guide the synthesis of cocrystal using solvent crystallization method. Although the nicotinamide (NTA)-benzoic acid (BA) cocrystal, NTA·BA, has been produced in solvents for several years, no information is available regarding the cocrystal phase equilibrium relevant to the systems. This article takes the NTA·BA cocrystal as the research object, through the isothermal saturation technique, the solubilities were firstly measured comprehensively at 298.15, 308.15, and 318.15 K for the NTA + BA + ethanol/isopropanol/acetone systems. Nine cocrystal phase diagrams were created. Three pure solids were included in each ternary system, which were NTA, BA, and NTA cocrystal with BA (NTA·BA, 1:1, mole ratio). In addition, each ternary system yielded two invariable point, five solid crystalline areas, and three curves of saturation with solutions. In the preferred solvents, the cocrystal exhibits exceptional stability. By examining these cocrystal diagrams, the cocrystal crystallization behavior in solvent was better understood, and the stable cocrystal locations in particular solvents were identified. Subsequently the improved solubility product and solution complexation model was used here to link the mutual solubilities along the crystalline curves of the NTA·BA cocrystal, producing the highest value of relative standard error of 3.69 %. Finally, based on the research of molecular dynamic simulation and quantum chemistry, the hydrogen-bonding and vdW forces are advantageous interactions when forming the NTA·BA cocrystal. The cocrystal phase diagram determined in this contribution could guide the production and separation of the NTA·BA cocrystal in a solvent.