Change in glycine polymorphs induced by minute-bubbles injection during antisolvent crystallization

摘要

Glycine of the simplest amino acid is widely used as drug substances of medicines, chelating and buffer agents of cosmetics, and food additives of seasoning and preservative. Glycine has three polymorphs of most stable γ-form, metastable α-form and unstable β-form under atmospheric temperature and pressure. The thermodynamic stability of the three polymorphs of glycine at atmospheric temperature and pressure is in the order γ-form > γ-form > β-form [1]. Polymorphs can exhibit different particle morphology and physicochemical properties such as solubility, density, heat capacity, melting point, thermal conductivity, and optical activity, which can have a great influence on the process acceptability, bioavailability, filtration, and tablet processes of pharmaceutical, food, and specialty materials [2]. Therefore, to improve the functionality of this organic crystal for better glycine utilization, the control of polymorphism is essential in the crystallization process. One common type of batch-crystallization operation that is widely utilized 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]. However, the considerable amount of antisolvent is necessary for the selective crystallization of polymorph with low stability, as the generated polymorph changes in order of stable form, metastable form, and unstable form with an increase in supersaturation of the bulk solution [4]. In this study, the micron-scale bubble formation technique that enables the generation of local supersaturation in the regions around the gas-liquid interfaces was applied to antisolvent crystallization of glycine polymorphs. 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 [5]. Because glycine 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 generation of crystal nuclei is faster and a less stable polymorph can be expected to crystallize. In this paper, we report the effects of minute-bubble injection on polymorphism of glycine during antisolvent crystallization using methanol.