Make The Most of Antisolvent Crystallization

A number of factors can affect solids' formation.

By Wayne Genck, Genck International

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Reverse addition. If small particles are desired, it instead may make sense to add product solution to the antisolvent. Figure 2 shows this method. The solubility in the antisolvent is quite low at point A. Due to the low solubility, the supersaturation ratio will increase rapidly (E-F) before there's sufficient seed surface area to achieve any significant growth. If the addition is fast enough, growth will be minimized — resulting in a nucleation-controlled environment and formation of very fine particles. Even with slower addition and seed present, the low equilibrium solubility can create high supersaturation ratios throughout the addition and lead to the production of small particles.

A potential problem for all crystallization methods — but especially for reverse addition — is the tendency for organic compounds to oil out or agglomerate as fine particles into amorphous undefined structures. One possible cause of oiling out is that drops of the product solution are surrounded by the antisolvent, in which the solubility is very low, and this low solubility creates localized regions with very high supersaturation ratios. Before mixing to the molecular level is achieved, the localized high supersaturation forces the product out of solution without allowing sufficient time for ordering of molecules to enable crystal development. The resulting oily particles have a tendency to clump together before the occluded solvent migrates throughout the solution. As the mixture is aged, the oiled-out particles may transform into amorphous solids or become crystalline. Solids developed in this manner will likely have poor lattice structure.

Problems that may ensue include:
• large drops of coalesced oil that won't disperse and can harden into a gum/waxy material;
• agitation difficulties due to the size and physical characteristics of the wax;
• occlusion of impurities and solvent in the wax; and
• complications in downstream recovery and washing.

Another problem is that the fine particles may stick together. Strong agglomerates may survive intact but weak ones may reduce in size with continued mixing or subsequent handling such as pumping or centrifuging.

Clearly scaleup of reverse addition can be difficult due to the large deviations from equilibrium.

Seeding. As with all crystallization techniques, seeding may help avoid excessive nucleation. The seed can be added as a powder or in slurry form with the antisolvent. The latter often is preferred for ease of handling and reduced contamination. In addition, the seed can be conditioned via Oswald ripening.

Adding seed with the antisolvent offers an advantage over the traditional method of putting seed in at a single time — which poses the risk of adding too soon (seeds dissolve) or too late (nucleation has already occurred).

The limited solubility of seed in the antisolvent means a seed slurry can be prepared beforehand. This mixture normally will represent a small amount of the total antisolvent charge. It then is added near the saturation point until the MZ is reached. The antisolvent in this slurry reduces the solubility, causing the mixture to achieve supersaturation, which is relieved in the presence of the added seeds. The goal is to stay within the MZ, thereby promoting growth with limited nucleation via secondary mechanisms.

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