kilomentor

Crystallization is a process step that has for a very long time generally defied attempts to scale it up. A solution is to crystallize by continuous micromixing small volumes and accumulating the resulting slurry in a large reservoir for isolation at scale.

One standard crystallization variant 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 is adaptable to 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. Using such a methodology, in order to get the smaller crystals preferred for enhanced bioavailability, the saturated solution needs to be added into the anti-solvent to get many tiny seeds forming rapidly. Using this reverse addition technology 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 both of the concentration gradients and a heterogeneous fluid environment 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 abolished, it is replaced by a themal gradient. In any case the crystals are undesirably larger with the slower process. The characteristics of size, purity and stability are difficult to control with the technology.

Technology is now coming off patent that may solve this problem in may cases. Particle size is more important for drug substances because of te relationship with bioavailability. Most drugs are provided as pharmaceutically acceptable salts and consequently it is the particle size of these salts that is of most commercial importance.

CA2044706, Crystallization Method to Improve Crystal Structure and Size, expires June 14^th, 2011 in Canada and the corresponding US5314506 expires May 24^th 2011. The invention addresses the general problem, how to obtain a reproducible micronization of a pharmaceutical compound without milling. The patents are assigned to Merck.

The technology taught in CA2044706 teaches pumping both solution and antisolvent in impinging jets of fluid that because of their small volumes and high velocities create almost instantly, where they collide, a region of high intensity micromixing. Once the fast crystallization has occurred the mixture of solution and antisolvent 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 heterogenous 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 these parameters are within engineering control. Because of this the surface area, crystallinity, stability and purity can be optimized. Because the equivalent of a milled material is available directly, a step is saved and the noise, dust, yield loss, equipment cost and exposure hazard of milling are all by-passed.

Preparation and Crystallization of Pharmaceutical Salts using Impinging Jet Micromixing Technology.

Some bimolecular reactions proceed in superior yield if both reactants are added simultaneously to a pot of solvent so that the concentrations of both reactants is kept low. Formation of pharmaceutical salts can benefit from such a process. Two impinging jets of solutions, one containing the substrate molecule and the other either the pharmaceutical acid or pharmaceutical base required to make a pharmaceutical salt can be implemented. As above, where the jets collide the intense micromixing both form the salt and cause nucleation into small seed crystals. This is taught in CA2349136. The advantages are the same. The process is completely under control of the engineering, product can be synthesized in micronized form in a single step with a single piece of equipment.. The US equivalent, US6558435B2, expired May 6^th 2003. The Canadian family member application died August 15^th 2007. They are now free to use.

Crystallization of micron sized controlled particle size may be becoming easier not harder on scale!

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