Thermal cycling for crystallization control
The key quality attributes of Active Pharmaceutical Ingredients (API) are particle shape and size distribution. The control of those parameters can be very challenging when handling compounds with a strong tendency for forming needles or thin plates. Two case studies are presented herein illustrating how thermal cycling can be employed in a batch cooling crystallisation process to transform the undesired plate-like and needle-like morphology into thicker multi-layered plates or rod-like crystalline particles with a narrower size distribution.
The presented case studies indicate that thermal cycling can efficiently improve both particle morphology and size distribution, resulting in improved filterability, powder flowability, and higher resistance to attrition and breakage. Although the mechanisms behind thermal cycling are still debated, we hypothesise that upon sufficiently fast cooling, solute molecules precipitate on surface of existing crystals as semi-crystalline or amorphous layer which binds neighbouring particles, creating larger and robust polycrystalline structures.