Application of Selective Crystallization Methods To Isolate the Metastable Polymorphs of Paracetamol: A Review

Paracetamol is a popular antipyretic and analgesic active pharmaceutical ingredient that is used worldwide in the production of several millions of tablets and other dosage forms every year. Paracetamol has three fully characterized polymorphs (forms I, II, and III), and also two high pressure polymorphs with unknown crystal structure (forms IV and V). Form I is the most stable polymorph, but unfortunately, it is not appropriate for direct compression into tablets due to its weak compression properties. On the other hand, forms II and III exhibit better compression properties; however, they are more difficult to harvest and isolate. This has been motivating the development of a diversity of crystallization methods that allow the selective production of forms II and III of paracetamol, which includes crystallization from melts, crystallization from liquid solutions, application of high pressures, seeding, heterogeneous nucleation, contact line crystallization, reaction coupling, ultrasound assisted crystallization, and multicomponent crystallization. In this review, we present a brief description of these methods and summarize their main advantages and disadvantages.