Kinetics and population balance modeling of antisolvent crystallization of polymorphic indomethacin

This work focuses on an important problem that is the modeling and control of polymorphic crystallization of indomethacin (IMC) in which one of the crystal forms consists of hair-like crystals. The lack of kinetic knowledge impedes the seeking for methods of efficient polymorph control of IMC. Herein, kinetics of antisolvent crystallization of alpha-IMC and gamma-IMC were first time determined on the basis of experiments and the population balance equation (PBE). It was found that gamma-IMC has an advantage in the secondary nucleation rate. A higher temperature was more unfavorable for obtaining gamma-IMC under the same supersaturation because the gamma-IMC was at a disadvantage in both primary nucleation and growth rates. According to the results of population balance modeling, the primary nucleation rate of gamma-IMC only affected the polymorphic composition at the early stage of antisolvent crystallization. The growth rate of alpha-IMC is the key in effectively controlling the polymorph outcome