The growth of acetaminophen polymorphic crystals and the solution-mediated phase transition from trihydrate to form II in agarose gel were investigated. The form II crystals grown in gels, presumably because of the agarose content, dissolved less rapidly at high temperatures and were more stable than in water. The trihydrate crystals in the gel were also expected to be stabilized by containing agarose, but in fact the fine morphology resulted in reduced stability. The solution-mediated phase transition from trihydrate to form II via form II seeding took longer in the gel because the gel slowed down the dissolution of the trihydrate by hindering the dispersion of the form II seeds and delayed the growth of form II by reducing the diffusion rate of the molecules dissolved from the trihydrate. Delays in solution-mediated phase transition and changes in stability for crystals grown in gels indicate the effectiveness of gels in controlling polymorphisms in pharmaceutical compounds.

It is known that interfaces have various impacts on crystallization from a solution. Here, we describe crystallization of acetaminophen using a microflow channel, in which two liquids meet and form a liquid–liquid interface due to laminar flow, resulting in uniform mixing of solvents on the molecular scale. In the anti‐solvent method, the microflow mixing promoted the crystallization more than bulk mixing. Furthermore, increased flow rate encouraged crystal formation, and a metastable form appeared under a certain flow condition. This means that interface management by the microchannel could be a beneficial tool for crystallization and polymorph control.

It has been reported that cavitation bubbles (air–liquid interface) by femtosecond laser and ultrasonic irradiations are effective for metastable phase crystallization in polymorph control. It has also been noted that cavitation bubbles are generated by mechanical shock when dropping a vial. Here we describe the crystallization of acetaminophen by drop impact. In the condition where spontaneous nucleation did not occur, the drop impact produced the metastable form (form II) and trihydrate. This supports the potency of the air–liquid interface in metastable phase formation. Furthermore, crystallization by drop impact is a completely new phenomenon, and new developments are expected in the future.