Journal
CHEMICAL ENGINEERING JOURNAL
Volume 428, Issue -, Pages -Publisher
ELSEVIER SCIENCE SA
DOI: 10.1016/j.cej.2021.132591
Keywords
Antisolvent crystallization; Kinetics modeling; Indomethacin; Population balance equation; Polymorph control
Categories
Funding
- National Natural Science Foundation of China [21938009, 21776284, 21878294, 22078332]
- National Key Research and Development Program [2019YFC1904204]
- NSFC-EU project [31961133018]
- External Cooperation Program of BIC, Chinese Academy of Sciences [122111KYSB20190032]
- Chemistry and Chemical Engineering Guangdong Laboratory [1922006]
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This study focuses on the modeling and control of polymorphic crystallization of indomethacin, revealing that gamma-IMC has an advantage in secondary nucleation rate while the growth rate of alpha-IMC is key in controlling the polymorph outcome. Kinetics of antisolvent crystallization of alpha-IMC and gamma-IMC were determined for the first time through experiments and population balance equation, providing insights for efficient polymorph control of IMC.
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.
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