The Use of Cooling Crystallization in an Ionic Liquid System for the Purification of Pharmaceuticals

The application of ionic liquids (ILs) as solvents is frequently discussed in the context of their tunability, with the potential to tailor the solvent system uniquely to the process being investigated. Instead, here we study the potential for a single IL, 1-ethyl-3-methylimidazolium bis­(trifluoromethanesulfonyl)­imide ([C₂C₁Im]­[NTf₂]), to be used for the cooling crystallization of a wide range of active pharmaceutical ingredients (APIs). [C₂C₁Im]­[NTf₂] was selected on the basis of its thermal stability, low reactivity, and miscibility with solvents of moderate polarity, which suggests that it is miscible with liquids that possess polarities comparable to those of many API molecules. The overwhelming majority of APIs tested were soluble at >50 wt % within [C₂C₁Im]­[NTf₂] at elevated temperatures despite their relatively poor solubility at room temperature. This dramatic effect was ascribed to the miscibility of most of the molten APIs with the IL. The solubility curves for nine APIs were measured, which established the potential use of this IL as a crystallization solvent. Finally, cooling crystallizations were conducted using acetaminophen containing common impurities as models. The cooling crystallizations within [C₂C₁Im]­[NTf₂] were found to produce acetaminophen in similar or greater purity with substantially improved yields relative to those of a number of control cooling and antisolvent crystallizations