Formation of Hemihydrate Crystal form Overcomes Milling Issue Induced by Exposed Functional Groups on Cleavage Plane for a Y5 Receptor Antagonist of Neuropeptide Y

Abstract

This study aimed to investigate the crystal forms of an originally designed Y5 receptor antagonist of neuropeptide Y. Polymorphic screening was performed via solvent evaporation and slurry conversion using various solvents. The obtained crystal forms α, β, and γ were characterized by X-ray powder diffraction analysis. Thermal analysis determined that forms α, β, and γ were hemihydrate, metastable and stable forms, respectively; the hemihydrate and the stable forms were candidates. To arrange the particle size, forms α and γ were subjected to jet milling. However, form γ could not be milled because of powder stiction to the apparatus, whereas form α could be. To investigate this mechanism, single-crystal X-ray diffraction analysis was performed. The crystal structure of form γ was characterized by two-dimensional hydrogen bonding between neighboring molecules. This revealed that the functional groups forming hydrogen bonds were exposed on the cleavage plane of form γ. The three-dimensional hydrogen-bonding network with water stabilized the hemihydrate form, α. These results indicate that the hydrogen bondable groups exposed on the cleavage plane of form γ should result in stiction of the powder and adherence to the apparatus. It was concluded that crystal conversion is a method to overcome the milling issue.