Growth of high-quality metastable crystal of acetaminophen using solution-mediated phase transformation at low supersaturation

We improved the crystal quality of the metastable phase of a pharmaceutical compound acetaminophen (form II) using solution-mediated phase transformation (SMPT) combined with the control of supersaturation and crystal size. Form II crystals grew at low supersaturation via SMPT of the trihydrate at low temperature (10 °C). While crystal growth rate was low compared to the 20 °C condition, crystals had many defects such as solution inclusions or cracks at 20 °C, but few at 10 °C. The ratio of form II crystals with any defects was small (12%), about 1/3 that of the 20 °C condition. Since the concentration gradient on the crystal surface was relatively small at low bulk supersaturation, high-quality crystals grew uniformly. However, large crystals (>∼0.8 mm) were still defective even at low supersaturation, because concentration gradient is large on large surfaces. Using a new seed-dipping process, obtained crystals were small and uniform in size (∼0.4 mm), and the ratio of defective crystals was reduced to 6%. Powder X-ray diffraction analysis revealed that form II crystals were ∼6 times more temporally stable than in the 20 °C condition. We found that high-quality crystals of metastable phase with high temporal stability could be realized by low supersaturation and reduction of the crystal size via SMPT.