Effect of Oiling-Out during Crystallization on Purification of an Intermediate Compound

When oiling-out occurs, a second liquid phase is formed, and the composition of "the mother phase", where crystals nucleate and grow, changes because the target material and impurities are distributed into each phase according to their own distribution ratios. Although oiling-out is generally considered undesirable, if oiling-out changes the composition of impurities and lowers the content of impurities in the mother phase, then it could be effective for purification. In this paper, we explored the effect of oiling-out on purification of an intermediate compound and found the following: Long water addition time and large seed amount each lowered the content of impurity A (Imp-A) and Imp-B. On the other hand, the content of Imp-C was not changed by long water addition time and was increased with a large seed amount. Process analytical technology data indicated that oiling-out was suppressed by the large seed amount. These results indicate that oiling-out changed the composition of the mother phase and inhibited the incorporation of Imp-C into the crystals. Our findings could be developed into a new purification technique utilizing oiling-out during crystallization.