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Issue 38, 2014
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New cocrystals of ezetimibe with l-proline and imidazole

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The objectives of the study were to screen and prepare cocrystals of anti-cholesterol drug ezetimibe (EZT) with the aim of increasing its solubility and dissolution rate. Thermodynamic phase diagram based high throughput screening was performed using wet milling/grinding or solution crystallization methods. A large number of coformers were tested and the resulting solids were preliminarily characterized using X-ray powder diffraction (PXRD) and Raman spectroscopy. Potential cocrystals of EZT with L-proline and imidazole and a solvate formamide were identified in the screening experiments. The cocrystal hits were further characterized by differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), solution Proton nuclear magnetic resonance spectroscopy (1H-NMR) and single crystal XRD. The dissolution properties and stability of cocrystals were determined. Single-crystal X-ray diffraction data were obtained for EZT, EZT-IMI cocrystal and formamide solvate of ezetimibe. All three systems were crystallized in non-centrosymmetric orthorhombic space group P212121 with Z = 4. Robust O–H⋯O, O–H⋯N, N–H⋯O and C–H⋯O hydrogen bonds played an important role in all these crystal structures. EZT-PRO cocrystal showed improved apparent solubility and solid state stability.

Graphical abstract: New cocrystals of ezetimibe with l-proline and imidazole

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Supplementary files

Article information

02 Jun 2014
27 Jul 2014
First published
18 Aug 2014

CrystEngComm, 2014,16, 8984-8993
Article type
Author version available

New cocrystals of ezetimibe with L-proline and imidazole

M. R. Shimpi, S. L. Childs, D. Boström and S. P. Velaga, CrystEngComm, 2014, 16, 8984
DOI: 10.1039/C4CE01127A

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