Incidence of crystal growth conditions on the formation of macroscopic liquid inclusions in ciclopirox crystals

Using an accurate and rigorous protocol, the crystal growth behavior in solution of the antifungal drug ciclopirox was investigated with the aim to identify the experimental factors responsible for the appearance of macroscopic inclusions of saturated solution. Counterintuitively, these inclusions are produced only when the relative supersaturation is below a critical threshold; simultaneously the crystals exhibit a hexagonal morphology. An increase in the driving force leads to a rod-shaped morphology without inclusion and without any change of the crystal phase, as confirmed by X-ray diffraction. The correlation between this morphological transition and the occurrence of liquid inclusions could be rationalized by considering the associated change of growth rates of {(1 1 1)} and {(1 1 -1)} faces. However, the nature of the solvent, the presence of impurities and diffusion in solution appeared to have no detectable incidence on the formation of liquid inclusions, inducing that the presumed contribution of a chemical adsorption phenomenon—side products or solvents—could not be established.

► Formation of macroscopic liquid inclusions inside ciclopirox crystals cannot be rationalized using the established crystal growth theories.
► By contrast with usual behavior, liquid inclusions appear only at low supersaturation, resulting from growth inhibition of specific faces.
► Growth rate becomes dramatically larger when supersaturation is beyond a critical threshold, resulting in a morphological transition.
► Formation of liquid inclusions can be correlated with large changes in relative growth rates of specific faces, most probably related to distinct crystal growth mechanisms.