Phase Equilibrium Thermodynamics For The Synthesis Of Aminopyridine And 4-aminobenzoic Acid Co-crystal In Solvents

As important derivatives of benzene and pyridine,4-aminobenzoic acid and aminopyridine both have electron pair donors and acceptors,and the cocorystal formed between them has attracted academic attention as a potential nonlinear optical material.However,such cocorystal synthesis is based on the phase diagram of aminopyridine+4-aminobenzoic acid+solvent ternary system.At present,there is no literature report on the solubility of aminopyridine and 4-aminobenzoic acid cocrystal and the thermodynamic properties of phase equilibrium of cocrystal synthesis.In this work,the phase equilibrium thermodynamics of synthesis of 4-aminobenzoic acid-aminopyridine cocrystal in solvent was studied.The solvents that are conducive to the cocrystal synthesis were screened,and the ternary system phase diagram of 4-aminobenzoic acid+aminopyridine+solvent was constructed,which has important practical significance for the industrial production and promotion of 4-aminobenzoic acid-4-aminobenzoic acid cocrystal,and provides basic data for further research of 4-aminobenzoic acid-aminopyridine cocrystal.The solubility data of 2-aminopyridine in thirteen neat solvents were determined using the iso-thermal dissolution method,including methanol,ethanol,n-propanol,isopropanol,n-butanol,isobutanol,acetonitrile,n-hexane,cyclohexane,n-propyl acetate,amyl acetate,N,N-dimethylformamide(DMF)and N-methyl-2-pyrrolidine(NMP).The mole fractions of 2-aminopyridine in equilibrium liquid phase rose with increasing temperature and followed the decreasing order in different solvents:NMP>DMF>methanol>ethanol>n-propanol>n-butanol>n-propyl acetate>amyl acetate>isopropanol>isobutanol>acetonitrile>n-hexane>cyclohexane.The λh equation,NRTL model,modified Apelblat equation,and Wilson model were used to correlate them.The greatest root-mean-square deviation value and relative average deviation value obtained were 160.4×10-4 and 4.46×10-2,respectively.The mixing characteristics,infinitesimal concentration activity coefficient,and reduced excess enthalpy were also calculated.Furthermore,the degree and type of interactions of solute-solvent and solvent-solvent were identified utilizing the relationship analysis of Kamlet and Taft linear solvation energy of solvent effect.The solubility data for the ternary system of 2-aminopyridine+4-aminobenzoic acid+ethanol/ethyl acetate,the ternary system of 3-aminopyridine + 4-aminobenzoic acid+ethanol/ethyl acetate,and the ternary system of 4-aminopyridine+4-aminobenzoic acid+ethanol/isopropanol were determined using the Schreinemakers’ wet residue method at 298.15 K.The corresponding ternary phase diagrams were constructed.The changes in solvent resulted in changes in various crystallization zones.At the same temperature and under the same solvent conditions,the crystalline zone of 2-aminopyridine-4-aminobenzoic acid cocrystal is larger than that of 3-aminopyridine/4-aminopyridine and 4-aminobenzoic acid cocrystal,which is more advantageous in the ethyl acetate solvent.Therefore,ethyl acetate is more conducive to the formation of cocrystal.In addition,the equilibrium cocrystal products were characterized using TG/DSC,PXRD,infrared spectroscopy,and crystal morphology.It is advantageous to use quantitative molecular surface analysis to study the weak interaction between different molecules in the solution system through ESP analysis,ALIE analysis and RDG analysis.The charge distribution in the molecular structure of aminopyridine compounds and 4-aminobenzoic acid can be visualized through the van der Waals surface of molecules colored by electrostatic potential,and the reaction active site of molecules can be inferred.There are a large number of hydrogen bonds and van der Waals forces.The large area of electron rich regions is conducive to the formation of cocrystal,which has important reference value for the study of cocrystal.