Enhanced production of unstable polymorph by antisolvent crystallization supplying minute-bubbles

Differences in physical and chemical properties between polymorphic compounds (e.g. solubility, dissolution rate, chemical reactivity, resistance to degradation, bioavailability) are highly significant for the pharmaceutical industry, which requires effective methods to control polymorphism of organic crystals [1, 2]. In particular, to improve the functionality such as solubility or bioavailability for better utilization of organic crystals, the destabilization of crystal structure is indispensable in the crystallization process. One common type of batch-crystallization operation that is widely used in the pharmaceutical, food, and chemical industries is antisolvent crystallization. In this technique, a solute is crystallized from solution by the addition of an antisolvent that effectively reduces the original solubility of the solute and thus increases the supersaturation in the bulk solution [3,4]. However, the considerable amount of antisolvent is necessary for the selective crystallization of unstable polymorph, because the generated polymorph changes in order of stable form, metastable form, and unstable form with an increase in supersaturation of the bulk solution [5]. In this study, the micron-scale bubble technique that enables the generation of local supersaturation in the regions around the gas-liquid interfaces was applied to antisolvent crystallization. Minimizing bubble diameter in gas-liquid systems helps achieve the following: i) acceleration of mass transfer and reactive absorption with an increase in the gas-liquid interfacial area, ii) increase in the average residence time of the bubbles with a decrease in buoyancy, and iii) occurrence of interactions at the gas-liquid interface caused by electrification of minute-bubbles [6, 7]. Because solute and antisolvent are accumulated near the gas-liquid interfaces by the residence of minute-bubbles with surface potential in the liquid phase for a long period of time, the production of a less stable polymorph and the shift in the overall solid-liquid equilibrium can be expected to occur. In this paper, we report the combined effects of nitrogen (N2) minute-bubbles and methanol as an antisolvent on polymorphism in cases where glycine with three polymorphs of stable γ-form, metastable αform, and unstable ß-form was selected as an object of crystallization.