Crystallization and Transformation of Acetaminophen Trihydrate

Acetaminophen is both polymorphic and prone to the formation of a trihydrate. The recently discovered trihydrate is a lath-like crystalline form that is highly metastable with respect to conversion to the thermodynamically stable form I polymorph. While the trihydrate is physically stable in ice-cold aqueous suspension (with up to 50% propylene glycol or glycerol), conversion of trihydrate takes place at temperatures above 5 °C via a solution-mediated transformation pathway to produce form I. On drying, the optically transparent trihydrate laths transform to an opaque, micronized form I. The metastable trihydrate is characterized as a maximally solvated form that appears to defy Ostwald's rule of stages and thus behaves fundamentally differently from the highly metastable polymorph form III.