Kinetics and population balance modeling of antisolvent crystallization of polymorphic indomethacin

Abstract 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 α-IMC and γ-IMC were first time determined on the basis of experiments and the population balance equation (PBE). It was found that γ-IMC has an advantage in the secondary nucleation rate. A higher temperature was more unfavorable for obtaining γ-IMC under the same supersaturation because the γ-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 γ-IMC only affected the polymorphic composition at the early stage of antisolvent crystallization. The growth rate of α-IMC is the key in effectively controlling the polymorph outcome.