Enhanced production of α-form indomethacin using the antisolvent crystallization method assisted by N2 fine bubbles

In this study, using the gas-liquid interfaces near fine bubbles as new crystallization fields where nucleation proceeds dominantly, a crystallization technique to enhance the production of α-form Indomethacin (IMC) at a constant temperature was developed. IMC is reported to show a complicated polymorphism that consists of five true polymorphs and a wide range of solvate forms, which are collectively named the β-form. IMC was crystallized using the antisolvent method assisted by nitrogen (N2) fine bubbles. In the regions around the minute gas-liquid interfaces, local supersaturation increases because of the accumulation of IMC, which is caused by the negative electric charge on the fine-bubble surface. Hence, the rate of crystal nucleation increases, and the crystallization of metastable polymorph is enhanced. At a solution temperature of 298 K, a saturated IMC-EtOH solution and water as an antisolvent were mixed by two different addition orders, as follows: the IMC-EtOH/H2O system: water was quickly added into a saturated IMC-EtOH solution; the H2O/IMC-EtOH system: a saturated IMC-EtOH solution was rapidly added into water. While water was mixed with the saturated IMC-EtOH solution, N2 fine bubbles with an average diameter of 25 µm were continuously supplied to the mixed solution using a self-supporting bubble generator and IMC was crystallized within a crystallization time of 5 min. In both systems, the supersaturation ratio in the bulk solution (lnC0/CS) was varied in the range of 1.5-5.7 by controlling the addition volume of water or saturated IMC-EtOH solution. For comparison, antisolvent crystallization free of fine bubbles was performed. The results show that in both systems, N2 fine-bubble injection enhanced the production of metastable α-form at ln(C0/CS) below 3.5, and decreased the required ln(C0/CS) for the high-yield crystallization of α-form.