A homemade setup was designed in order to investigate the influence of gas bubbling on the crystal growth of the active pharmaceutical ingredient ciclopirox. It appears from these experiments performed in stagnant and isothermal conditions that gases containing oxygen atoms (air, dioxygen, nitrous oxide, and carbon dioxide) lead to high crystal growth rates and promote the formation of liquid inclusions whereas gases free from oxygen (nitrogen, helium, argon, dihydrogen), as well as degassing treatments, cause a dramatic decrease in growth rates and give rise to crystals deprived of liquid inclusions. It could also be demonstrated by hot-stage optical microscopy that, beside the evolution of fluid inclusions upon heating and/or maturation toward negative crystals, all liquid inclusions contain, at the temperature of crystal growth, gas bubbles in equilibrium with a saturated solution. Furthermore, an AFM study revealed that liquid inclusions are produced specifically during the growth of rough faces presenting a high potential for physical adhesion/ adsorption and possibly gas bubble nucleation. An original explanation based on a local growth inhibition is therefore proposed, and the large contribution of microbubbles in the formation of macroscopic fluid inclusions, but also in the global growth kinetics suggests that the role of gaseous matter in crystal growth mechanisms of organic materials has probably been, up to now, underestimated.

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Crystals of three organic compounds grown several decades ago have been retrieved from a cellar of the Facult e de Pharmacie of Paris. The presence of liquid inclusions in these large particles has provided a unique opportunity to investigate the effects of aging on these macroscopic defects. Beside their evolution toward a shape of negative crystals, it appeared that all liquid inclusions contain a (sometimes large) gaseous bubble in equilibrium with the saturated solution. Hotstage microscopy analyses revealed that bubbles disappear upon heating, and form back on cooling with hysteresis. Furthermore, it could be established from the combination of structural, crystal growth, and morphological studies with detailed physical characterizations that the formation of inclusions is probably due to a local growth inhibition during the development of faces situated at the extremities of elongated particles, possibly involving in some cases a structural disorder. Our results also suggest that adhesion and/or heteronucleation of gaseous microbubbles on fast-growing faces could constitute a key step during the formation of macroscopic liquid inclusions. Thus, the role of gaseous matter during crystal growth of organic compounds has been so far probably underestimated.