Make The Most of Antisolvent Crystallization

A number of factors can affect solids' formation.

By Wayne Genck, Genck International

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Pharmaceutical and fine chemical makers frequently rely on antisolvent crystallization, also known as precipitation crystallization, salting out or drowning out, to generate a solid from a solution in which the product has high solubility. The technique is used for a variety of applications such as polymorph control, purification from a reaction mixture and yield improvement.

Antisolvent crystallization achieves supersaturation and solidification by exposing a solution of the product to another solvent (or multiple ones) in which the product is sparingly soluble. The process can be semi-batch or continuous.

Although this technique has the potential to achieve a controlled and scalable size distribution, it's not without problems. The product requires purification or separation steps to remove the antisolvent(s). In addition, large changes in volume can hinder batch productivity and present agitation difficulties for minimum stir volume.

Here, either the antisolvent is added to the product solution (normal addition) or the product solution is added to the antisolvent (reverse addition).

Normal addition. Figure 1 presents typical operating curves for this mode and a representative equilibrium solubility curve. The metastable zone (MZ) is the area between B-C and D-E. From point A to point B, antisolvent addition will proceed without crystallization because the solution concentration is below the equilibrium solubility. At point B, the solubility curve is reached. As antisolvent addition continues, supersaturation will develop. The amount of supersaturation created prior to nucleation is system specific and depends on the addition rate, mixing, primary or secondary nucleation rate, growth rate, feed location and the amount and type of impurities present in solution.

If the main goal is growth, the presence of a sufficient amount of seed and a slow antisolvent addition rate may allow the concentration in solution to remain completely in the MZ as crystallization proceeds. The closer the solution concentration profile is to the equilibrium solubility curve (B-C), the higher the possibility of achieving an all-growth process.

A system without seed or a fast addition rate can develop a high degree of supersaturation, which can result in rapid precipitation or crash out at point B″, in the labile zone beyond the MZ. Primary nucleation could be followed by continued nucleation and some growth (B″-C), eventually achieving equilibrium some time after all the antisolvent is added. If the concentration is allowed to go to point B″, the system also is subject to oiling out or agglomeration.

A common procedure for achieving growth while minimizing the possibility for seed dissolution is shown in curve B′-F-C. Antisolvent addition is stopped and seed is added at point B′, where the system is slightly supersaturated. (In situ measuring devices based on, e.g., Fourier transform infrared or ultraviolet can be used to determine when the concentration reaches point B′.) Also, the seed may be added in a slurry with the antisolvent starting before point B is reached to assure staying within the MZ.

Crystallization then is allowed to progress to relieve the supersaturation without the addition of more antisolvent (B′-F). Given enough time, the solution will closely approach the equilibrium solubility value (point F) while developing adequate surface area to primarily achieve growth during the addition of the remaining antisolvent. With this increased surface area and a sufficiently slow addition rate, the solution concentration can approach the equilibrium solubility for the remainder of the addition (F-C).

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