An in-line study of oiling out and crystallization

The oiling out and crystallization of a pharmaceutical compound from a water-ethanol mixture has been studied using a range of in-line process analytical techniques in order to more fully understand the phenomenon and build in control of its crystallization. Mechanistically, oiling out was found to follow a number of steps. It was shown that, in a well-mixed jacketed vessel, the small oil droplets formed on cooling a supersaturated solution grew and then coalesced into larger droplets, which subsequently crystallized. Cooling a static supersaturated solution of the compound resulted in two liquid layers, which if undisturbed were relatively stable. Chromatographic analysis of these layers showed that they contained each of the components, but in different amounts, and that crystallization occurred in the compound rich phase. In situ measurements showed that the temperature-solubility and the cloud point curve were well separated at lower temperatures but merged at higher temperatures. Identification of a metastable zone allowed a seeding strategy to be pursued, and by using a simple factorial experimental design, conditions that eliminated the oiling of the compound were determined.