CrystEngComm, 2014, Advance Article
DOI: 10.1039/C4CE01127A, Paper
Manishkumar R. Shimpi, Scott L. Childs, Dan Bostrom, Sitaram P. Velaga
aDepartment of Health Sciences Luleå University of Technology, Luleå, Sweden
bRenovo Research, Atlanta, USA
cThermal Energy Conversion Laboratory, Department of Applied Physics and Electronics, Umeå University, Umeå S-90187, Sweden
Two new cocrystals of ezetimibe were identified and scale-up. Ezetimibe-proline cocrystal showed improved apparent solubility and physical stability.
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
-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 (1
H-NMR) and single crystal XRD. The dissolution properties and stability of cocrystals were determined. Single-crystal X-ray diffraction data were obtained for EZT
cocrystal and formamide solvate of ezetimibe. All three systems were crystallized in non-centrosymmetric orthorhombic space group P
= 4. Robust O–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.