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Volume 105
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Application of design of experiments for optimizing solvent ratios in ceritinib spherical crystallization
Iva Zokić a, Jasna Prlić Kardum a *, Mirta Sabol a, Valentina Travančić b
a Department of Mechanical and Thermal Process Engineering, Faculty of Chemical Engineering and Technology, University of Zagreb, Trg Marka Marulića 19, 10000, Zagreb, Croatia
b Teva Global Small Molecule CMC, Particle Engineering Department, Teva Pharmaceuticals, Prilaz baruna Filipovića 25, 10000, Zagreb, Croatia
10.1016/j.partic.2025.08.009
Volume 105, October 2025, Pages 249-258
Received 2 June 2025, Revised 16 July 2025, Accepted 7 August 2025, Available online 21 August 2025, Version of Record 29 August 2025.
E-mail: jprlic@fkit.unizg.hr
Highlights

• Systematic study of solvent ratio impact on spherical crystal roundness.

• Use of experimental design for optimization of ceritinib spherical crystallization.

• High roundness of crystals confirmed by micrograph analysis.

• Improved granulometric properties of ceritinib for better tabletability.


Abstract

The granulometric properties of active pharmaceutical ingredients (APIs) have significance in the pharmaceutical industry because they affect the handling of powders and thus the efficiency of their production. Ceritinib, an anaplastic lymphoma kinase inhibitor used in the treatment of non-small cell lung cancer, exhibits platy crystals, which results in low flowability and compressibility and negatively affects its production and pharmaceutical application. Spherical crystallization is a promising method for improving the granulometric properties of APIs by transforming unfavorable particle shapes into a more favorable spherical form.

The aim of this research was to improve the granulometric properties of ceritinib through a combined spherical crystallization method in a system containing tetrahydrofuran as the solvent, water with polyvinylpyrrolidone as the antisolvent, and heptane as the bridging liquid. Experimental design was employed to examine and mathematically describe the influence of the solvent fractions in the selected system on the roundness of the obtained crystals and consequently their compressibility. Spherical crystals of ceritinib with high roundness and improved compressibility compared to powdered ceritinib were obtained. The enhanced powder characteristics facilitate the optimization of the production process, potentially minimizing the necessary number of process steps and increasing efficiency.


Graphical abstract
Keywords
Ceritinib; Compressibility; Experimental design; Spherical crystallization
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