Intensified and continuous membrane crystallization process: control of pharmaceutical active ingredients quality – MEMCRYST

Crystallization is one of the major unit operation to produce, purify or separate solid compounds or products. Whatever the technology, a fine control of the mass and/or heat transfer, i.e. supersaturation, is a key parameter to reach the physical quality of the product (purity, polymorphism, shape, crystal size distribution, specific surface, density...).
In a pharmaceutical industrial context, the process chosen for several decades is the batch crystallization by cooling, in a stirred-tank reactor whose capacity is selected according to the needs of the market. A very good control of the polymorphism and the particles size is ensured both at the scale of the hundreds of litters and at the ten cubic meters.
On the other hand, antisolvant crystallization processes are difficult to perform at these same industrial scales. In fact, the chemical components mix is unsatisfying and leads to heterogeneous local supersaturation. In addition, the room for improvement regarding the operating parameters is usually low to modulate the physical quality of the active ingredients obtained with this procedure. Purification and grinding steps are often required downstream to obtain the intended specifications of the final product. Therefore, the development of a robust and easily scale-up continuous process, allowing a fine control of the supersaturation, could be of great interest in many industrial areas.

MEMCRYST aims to study a revolutionary concept of continuous membrane crystallization process. It is an innovative technology that can be considered because of the increased performance of membranes that could give the French industry a competitive advantage.
The project focuses on two modes of supersaturation studied up to the industrial scale: the addition of an antisolvant in a solute/solvent mixture through a porous membrane, thanks to a pressure gradient, which reduces the solubility and induces crystallization; reverse antisolvant, based on pervaporation solvent removing, leads to even lower solubility, thus reducing polymorphic transitions.
The mass transfer through the membrane allows a fine control of the supersaturation and therefore a perfect control of the physical quality of the crystals obtained. In addition, the high modularity of membrane processes makes it very interesting for the pharmaceutical industry working in batches of various sizes. The crystallization by antisolvant, and even more by reverse antisolvant, also allows accessing to very low final solubility, thus achieving very high yields and limiting from the risk of polymorphic transitions. A clear improvement in the control of crystallization process requires a technological breakthrough and membrane processes can now be the answer to this issue.

In 3 workpackages, the project will focus on different microporous and composite membrane materials in order to study the performance of both processes regarding the physical quality of the product and the industrial feasibility (WP1). The results obtained will be used to enrich and validate the developed models (WP2) that will take into account hydrodynamics and crystallization mechanisms. The objective will be to calculate concentration profiles for a prediction of the crystallization location in the membrane module. Finally, the most industrially promising technology will be developed at a pilot scale (TRL 6-7). The performance of the process (WP3) will be compared to the experimental results obtained at lab scale and to the numerical results. The use will then be extended to the production of molecules of interest.