Engineering reaction and crystallization and the impact on filtration, drying, and dissolution behaviors: The study of acetaminophen (paracetamol) by in-process controls

Acetaminophen was synthesized by reacting p-aminophenol with acetic anhydride. Overall materials balance was compiled. Three different crystallization paths (i.e., cases I, II, and III) involving various modes in agitation and addition of sodium hydroxide were taken to produce acetaminophen particles with different particle size distributions (PSDs) and polymorphism. The concentration profile of acetaminophen, temperature, and pH values throughout reaction and crystallization were monitored mainly by in-process control (IPC). The rates of nucleation, crystal growth, and agglomeration during crystallization were quantified by the mixed-suspension mixed-product removal (MSMPR) formalism. The average specific cake resistance for filtration, Krischer rate-moisture plot for drying, Carr's index for powder flowability, and dissolution rate for drug delivery of acetaminophen crystals generated in cases I, II, and III were thoroughly studied and compared.