| m-Aminobenzoic acid(m-ABA)is an indispensable pharmaceutical intermediate in synthesis of analgesics,antihypertensive drugs,vasodilators,and other well-known drugs.In order to solve the problems of m-ABA Form Ⅰ produced in industry,such as small particle size,caking,the possibility of polymorphic transformation,and poor chemical stability,we studied m-ABA Form Ⅰ from three aspects of crystallization thermodynamics,crystal morphology and powder properties,which significantly improved the crystal quality of m-ABA and production efficiency of the downstream products.The solubility of m-ABA Form Ⅰ in twelve single solvents was measured by a gravimetric method.The solubility data was correlated by four thermodynamic models including the modified Apelblat equation,van’t Hoff equation,λh equation,and the Wilson model.And the calculated ARD% values indicate that the correlation results are in good agreement with the experimental data.The data and discussions are helpful for the design and optimization of the crystallization of m-ABA.Two methods of spherical crystallization of m-ABA Form Ⅰ in single-solvent system have been developed.Compared with the traditional method of spherical crystallization in multiple-solvents system,the method has advantages of high efficiency and green for environmental protection.The adhesion free energies of m-ABA in different solvents were calculated based on Lifshitz-van der Waals acid-base theory in the study of spherical agglomerates.Water,isopropanol,ethylene glycol,methanol and ethanol were selected as the single-solvent systems,and the spherical agglomerates of m-ABA were successfully prepared.The formation mechanism of m-ABA spherical agglomerates was elucidated with the help of in-situ Pixact Crystallization Monitoring system.Combined with theoretical calculation,it was proved that the formation of m-ABA spherical agglomerates in a single-solvent system was related to the hydrogen-bond-acceptor and hydrogen-bond-donor capacities of the solvents.Single-factor analysis method was used to systematically investigate the effects of stirring speed,terminal temperature and supersaturation on spherical agglomerates of m-ABA,and the size and shape of the spherical agglomerates were controlled.Besides,m-ABA spherulites were obtained in acetone by evaporation and in ethylene glycol by cooling crystallization,respectively.The growth process of m-ABA spherulites were observed by scanning electron microscopy and thermal platform microscope.The properties of spherical agglomerates,spherulites,and needle-like crystals have been tested.The experimental results show that spherical crystals have better fluidity,anti-caking property,chemical stabilities and crystal form stability than needle-like crystals. |
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