Crystallisation Design Space: Avoiding a Hydrate in a Water-Based Process

Many compounds can exist in either hydrated or anhydrous crystalline forms. The demands of robust processing and consistent product performance usually mean that only one of these two forms is desired, and that mixtures are unacceptable. Where the crystallisation is preceded by a phase separation and a distillation, liquid−liquid, vapor−liquid and solid−liquid equilibria all affect the outcome. The theory behind these equilibria is presented to show how they intersect. This approach is applied to a practical example in which a nominally “nonaqueous” liquid layer is separated from an “aqueous” layer and then distilled with simultaneous crystallisation. In-line technology is used in the laboratory to assist in the definition of a “Design Space”— an area in which this complicated isolation process operates robustly at scale using simple, conventional measurements.