Large-scale crystallization of a pure metastable polymorph by reaction coupling

A maximum of more than 40 g of acetaminophen Form II crystals with a yield of 65 mol % is made reproducibly in a 500 mL reactor by coupling the acetylation of p-aminophenol with the neutralization of acetic acid before the crystallization of acetaminophen Form II crystals. This novel working principle involves a sudden drop of the solubility of acetaminophen from the acetic acid-water environment to the acetate-water system in addition to temperature cooling but without agitation. This particular processing pathway is capable of maintaining a large supersaturation for quite some time for the system to enter the metastable zone of Form II with respect to the acetate-water system. The large amount of Form II crystals so produced are then isolated by filtration and oven drying to prevent Form II crystals in the mother liquor from transforming to the thermodynamically stable Form I crystals by the Ostwalds rule of stages.