Crystallization Behavior of Ceritinib: Characterization and Optimization Strategies

Abstract

Because of the specific thermodynamic properties of active pharmaceutical ingredients, the process of crystallization often meets implementation challenges in the pharmaceutical industry. Therefore, it is essential to select the appropriate method and system for the crystallization of a drug. Ceritinib, an active ingredient in the treatment of lung cancer, was formed as a result of pH modification during the cooling crystallization of ceritinib dihydrochloride solution. By carrying out processes in various solvent systems, several polymorphs were produced. A combination of forms B and C was generated in the ethanol–water system, resulting in smaller crystals. The acetone–water system produced pure form A, which has larger crystals and is more applicable for forthcoming studies. To additionally enhance granulometric properties, ceritinib form A was recrystallized in tetrahydrofuran at different temperatures using antisolvent crystallization. Crystallization at a higher saturation temperature results in larger and more compact crystals, which enhances filtration and drying.

Development of a Calibration Model for Real-Time Solute Concentration Monitoring during Crystallization of Ceritinib Using Raman Spectroscopy and In-Line Process Microscopy

“…Ceritinib can exhibit three different crystalline forms. Ceritinib form A has characteristic X-ray Powder Diffraction (XRPD) peaks at angles 10.63 [31,32]. The results of the XRPD analysis verify that the crystallization of ceritinib dihydrochloride in acetone-water yielded ceritinib form A (Figure 4).…”

“…All solvents were purchased from Lachner (Neratovice, Czech Republic). Ceritinib form A was synthesized following the preparation steps described by Zokić et al [32]. Ceritinib dihydrochloride (Hui Chem Co., Ltd., Shanghai, China) was dissolved in an acetone-water solvent mixture, followed by pH modification with sodium hydroxide and cooling crystallization.…”