Impinging Jet Micromixing to Solve the Problem of Small Crystal Size without Milling.

CA2044706, Crystallization Method to Improve Crystal Structure and Size expired June 14^th 2011 in Canada and the family member US5314506 expired May 24^th 2011 in the United States. The invention addresses the general problem, how to obtain a reproducible micronization of a pharmaceutical compound without milling.

Crystallization is a process step that has for a very long time has only been scaled up empirically.  

One standard crystallization procedure contacts a supersaturated solution of the substrate with an appropriate anti-solvent in a stirred vessel. The anti-solvent initiates primary nucleation as it mixes into the supersaturated solution of active and these seeds then grow. The process can be modified by using preformed seed crystals and/or further aging of the solid, once formed, which digests the crystals to change their initial sizes and/or polymorphic forms. In order to get the smaller crystals, preferred for their greater bioavailability, the saturated solution needs to be added into the anti-solvent in order to get very rapid formation of many tiny seeds. Using this reverse addition methodology a concentration gradient cannot be avoided in a large reactor because the introduction of feed solution into the anti-solvent in the stirred vessel does not afford a thorough mixing of the two fluids prior to the initiation of crystallization.  The presence of these concentration gradients and heterogeneous fluid environment both interferes with optimal crystal structure creation and allows greater entrainment of impurities. On scale even the fastest bulk mixing cannot smooth out the microenvironments in which the seeds form. Furthermore, in a large bulk reactor the number of seeds present at the beginning of the nucleation process is very different from the seeds present in the bulk when the last of the supersaturated solution enters the tank. On scale stirring cannot handle the micromixing requirement.

Another standard crystallization procedure cools a solution of the desired product in order to bring the solution to its supersaturation point, but cooling in batch processing is a slow process that becomes even slower as the batch size increases. Although the solvent gradient is solved, there is a thermal gradient and in any case the crystals are larger with the slower process. The characterisrtics of size, purity, and stability are difficult to control.

The technology taught in CA2044706 pumps both solution and anti-solvent as two impinging jets of fluid that because of their small volumes and high velocities create almost instantly a region of high intensity micromixing where they collide. Once the fast crystallization has occurred, the mixture of solution and anti-solvent can be accumulated and filtered when all the material has been processed or it can be collected after any other appropriate time.

This impinging jet technology removes the problem of scale. Larger scale just translates into a longer period pumping the same streams together. The heterogeneous slurry in which the seed crystals form becomes a function of the pumping rates, the concentration of solute in solvent and anti-solvent,  and the radii of the columnar jets of colliding fluids.  All the parameters come within engineering control.  Because of this, the surface area, crystallinity, stability and purity can be optimized. Because a milled quality material is available directly, a step is saved and the noise, dust, yield loss, equipment cost and worker exposure hazard of milling are by-passed.

The entry of this manufacturing technology into the public domain in 2011 was a significant development. 

CA2349136 is still more interesting. This is the same inventive idea but incorporates a reaction involving elements from each of the two impinging liquid jets. For example this could be used to form a salt from the free base form of a pharmaceutical in one stream and a solution of an appropriate acid in the second stream. Thus we can intuit the formation and instantaneous crystallization of a desired salt and its crystallization into micro crystals.  The US equivalent US6558435B2 expired May 6^th 2003. The Canadian attempt became a dead application August 15^th 2007.