Impurity Occurrence and Removal in Crystalline Products from Process Reactions

The behavior of impurities when subjected to crystallizations, and related processes such as recrystallization and reslurrying, has been reviewed with a particular focus on the years 2000-2015, but also including significant cases from outside that period. Small molecule pharmaceuticals and similar small organic molecules are included but not biomolecules, inorganics, or minerals. Phase impurities are only covered when a phase transformation is involved with the management of an impurity. Introductory examples illustrating some general features of crystallization as a method of purification are presented, as well as approaches to quantifying the effectiveness of purification. The review classifies cases based on the behavior of the specific impurities covered. The classes of behavior observed are the removal by washing, recrystallization, or reslurrying (Class I), impurities not being removed by these operations (Class II), and impurities which are removed in conjunction with a phase transformation (Class III). Examples of each of these types of behavior are presented, with many processes producing impurities which fall into more than one of these classes. Studies on the inclusion of extraneous molecules into crystalline materials are also covered. These particularly include the incorporation of compounds as solid solutions, but also eutectic formation and inclusion at surfaces during crystal growth. The relationship between types of impurities and behavior during processing is also examined.