Impact of Gas Composition in the Mother Liquor on the Formation of Macroscopic Inclusions and Crystal Growth Rates. Case Study with Ciclopirox Crystals

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.