Effects of Moisture and Residual Solvent on the Phase Stability of Orthorhombic Paracetamol

Purpose
At high relative humidity (RH), orthorhombic paracetamol (form II) crystallized from ethanol transforms to monoclinic (form I) faster than such crystallized from the melt. The present study attempts to elucidate the reasons for this difference in stability.
Methods
The transformation of form II was investigated by powder X-ray diffraction, optical microscopy, gravimetric moisture sorption, thermogravimetry, and vibrational spectroscopy.
Results
Solution-grown form II was found to be always contaminated with form I nuclei but still transforms much faster than corresponding physical mixtures of the pure forms in high RH, at a rate that is depending on the RH and the size of the crystals. A 0.1–0.6% w/w mass loss, inversely related to the initial monoclinic content, was observed during transformation of solution-grown form II, and was found to be due to residual ethanol that could not be removed by grinding, indicating incorporation by a solid solution mechanism.
Conclusions
Moisture triggers the growth of existing form I nuclei but it exerts a weaker effect on nucleation, and the presence of residual ethanol greatly accelerates the transformation.