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

Abstract

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.

The Effect of Dissolved Gases as Impurities on Crystallization

“…There is a dramatic decrease in growth rate from the degassed solutions to the other four, gas‐saturated solutions. Waldschmidt et al 13 concluded that, in the case of ciclopirox, crystals can be free from macroscopic inclusion when using degassed solutions or solutions saturated with non‐oxygen‐containing gases. Contrary to this phenomenon, the experimental results of Seidel and Ulrich 14 showed that lowering the gas content as much as possible by degassing resulted in an increase in cavity size by up to 50 % in the system of salicylic acid, indicating that the gas content in the solutions has a negative influence on the formation of cavities.…”

“…Thus, it can be deduced that, e.g., when CO 2 is dissolved in a solution, the solute shows a high potential to change the solubility. Besides that, dissolved gases have a vital effect on the formation of cavities or mother liquid inclusions, leading to an increased impurity of the product 13, 14. Therefore, trace amounts of dissolved gases could also be regarded as one type of impurities that should not be underestimated.…”

Generation of Crystalline Microcontainers of Salicylic Acid

“…But cavity‐ respectively inclusion‐containing crystals are not only formed by such a phase transformation. They are also described to appear, e.g., during cooling crystallization, evaporative crystallization, or additive‐induced precipitation from solution 4–6. The mechanism of this phenomenon is explained by inhibited diffusion and mass transport during crystal growth 6.…”

“…Thus, the center part of a crystal face is not able to grow, which leads to the formation of inclusions. The inhibition of diffusion and mass transport is discussed to be caused or intensified by impurities or even nano or micro gas bubbles in the solutions 4, 6, 7.…”

“…To clarify the mechanism of inclusion formation in more detail, Waldschmidt et al 4, 7 investigated several parameters which might influence the generation of liquid inclusions using ciclopirox as model substance which is crystallized from solution. They described that addition of dust and the change of the stirring rate did not have any influence on inclusion formation.…”