Polymorph control of glycine by antisolvent crystallization using nitrogen minute-bubbles

Abstract

In this study, utilizing the gas–liquid interfaces around minute-bubbles as new nucleation fields, a crystallization technique to control polymorphism under constant temperature was developed. Glycine, which has three polymorphs of stable γ-form, metastable α-form, and unstable β-form under atmospheric temperature and pressure, was crystallized using the antisolvent method supplying nitrogen (N2) minute-bubbles. In the regions near the minute gas–liquid interfaces, higher local supersaturation generates because of the accumulation of glycine and antisolvent caused by the negative electric charge on the minute-bubble surface; hence, the nucleation rate is higher and a less stable polymorph can be expected to crystallize. At a solution temperature of 303K, methanol as an antisolvent was mixed into the saturated glycine solution. The mixture ratio of methanol was varied in the range of 20–60vol% to control supersaturation of glycine in the bulk solution. While mixing methanol with the saturated glycine solution, N2 bubbles with different average diameters of 10–2000μm were continuously supplied to the mixed solution, and glycine was produced within the crystallization time of 5min. Antisolvent crystallization without the bubble supply was carried out for comparison. The results indicated that bubble injection and minimizing bubble size led to the expansion of the generation region of β-form and the reduction of supersaturation ratio in the bulk solution necessary for the generation of β-form during antisolvent crystallization.