ParticleView: Video Case Studies

For this crystallization process, real time microscopy was used to understand the mechanism that was causing slow filtration of the isolated material. The first important crystallization mechanism that was observed was the growth and agglomeration of the seeds soon after they were added to a supersaturated solution. Next something interesting happened. Fine needles began to grow out of the agglomerated seeds, forming delicate dendritic structures. This is something that would be very difficult to see with an off-line microscope because the mechanical action of sampling would probably destroy them. The final mechanism observed makes it very clear why the filtration rate is slow. The delicate needles broke away, resulting in a significant secondary nucleation event, which was accelerated by a fast cooling rate towards the end of the process. So to review: three mechanisms are revealed here: seed growth and agglomeration, dendritic growth, and secondary nucleation. Using this mechanistic insight two actions can be taken: first, look at how the seeds are prepared and try to avoid this dendritic growth; and secondly, look at slower cooling to minimize the secondary nucleation.

For this crystallisation process, real time microscopy was used to study the kinetics of polymorph conversion. Initially, the temperature of the starting solution was increased before an initiator was added to start the crystallisation. Almost immediately nucleation began and crystals grew into boulder like morphology. As the crystallization proceeded a transition point was reached where the stable form long thin needles began to nucleate. Over time the metastable form dissolved allowing the stable form to nucleate and then grow. Information like this helps understand the process conditions which impact polymorph formation, transformation and end point. The hold time chosen in production might be critical and a faster or more consistent transformation may be possible at different temperatures.

For this crystallization process real -time microscopy was used to understand the mechanism that was causing a poor impurity profile in the final product. This was a process where cooling was used to initiate spontaneous nucleation. Initially block like crystals appeared and began to grow but quickly it becomes clear that agglomeration is going to play a critical role in this process. Over time the agglomeration continues with few individual crystals observed. Instead, long chains of agglomerates form, likely trapping impurities as they do so. Eventually these agglomerates begin to grow themselves, and we see the primary crystals in each agglomerate increase in size. Clearly this is a system prone to heavy agglomeration, meaning a review of the solvent chosen, or maybe the mixing conditions, will be needed to minimize the impact and resolve the impurity rejection issue.