(409g) Design of a Continuous Crystallization for a Drug Substance Using a Dynamically Mixed Reactor

The pharmaceutical industry has predominantly relied on batch processes for manufacturing of drug substance as well as drug products. However, longer campaign times, labor-intensive nature of batch manufacturing and batch to batch variations in the product quality pose significant drawbacks. In view of this, the Pharma industry is turning towards continuous manufacturing, going beyond flow chemistry to continuous crystallization and downstream operations for the synthesis of drug substances. Continuous crystallization offers many advantages such as better control over the solid form and particle size, and the potential for an end-to-end continuous manufacturing process.

The current work describes the design of a continuous crystallization process for a drug substance in order to integrate with upstream and downstream continuous processes. It was not only important to achieve the targeted solid state form (trihydrate, Form I) but also ensure that the filtration rate could be increased to enable integration with the downstream continuous filter and minimize the cleaning frequency. The presented case study discusses in detail the approach, starting from lab-scale batch experimentation to development of a continuous crystallization process at lab followed by scale-up design for a capacity of multi-tons per month.

As a first step, fundamental solubility data was collected followed by identification of critical parameters impacting nucleation and transformation between the various forms. It was observed that the solvent (alcohol) to antisolvent (water) ratio, seed loading and temperature had a significant impact on the solid form. A batch crystallization process was first established by combining antisolvent and cooling crystallization to consistently generate the desired Form I, while ensuring the absence of other solid forms.

The translation of the batch process to continuous was initially attempted in MSMPRs in series but proved unsuccessful as an undesired form started to appear over time despite seeding. It was hypothesized that several more MSMPRs would be required to achieve the desired form but this would occupy a huge footprint and increase hold-up at scale. While plug flow reactors would be suitable, the risk of fouling is high, particularly when flow rates are reduced to achieve sufficient residence time. Scouting for an appropriate technology lead to evaluation of dynamically mixed reactors from AM Technologies®, which were able to handle a slurry and provide a mixing profile close to plug flow decoupled from the residence time. At lab scale, the Coflore® Agitated Cell Reactor (ACR), which is a bench-top mechanical agitated reactor comprising ten small cells, was able to aid in controlled crystallization of the desired Form 1 with well defined crystals and a consistent particle size distribution. Since additional reactors and residence time were required to gradually cool the slurry from 65°C to 25°C, the ACR was combined with three CSTRs in series (forming a mixed suspension mixed process set up). The trials were executed by combining a stream of alcohol containing the dissolved solute (at 65°C) and another stream of hot water containing seeds (at 65°C) in the ACR. The slurry exiting from the reactor was continuously transferred into the CSTRs, where it was subjected to stage-wise cooling in each CSTR. The residence times were designed to achieve maximum crystallization in the ACR and minimize secondary nucleation in the subsequent CSTRs.

After establishing the success and robustness of the continuous crystallization process at lab-scale, the process was scaled up in a 100L, production-scale version of the dynamic mixing reactor - Coflore® Rotating Tubular Reactor (RTR). Optimization of the process parameters revealed that maintenance of higher temperatures (~65 ^°C), , enhanced mass transfer at the point of nucleation along with the presence of Form 1 seeds, and higher ratios of anti-solvent were critical for achieving the desired polymorph while low mixing shear aided in crystal growth. The growth of these fine, needle-shaped crystals was essential to achieving a sufficiently high filtration rate for the downstream continuous separation of solids. The RTR, which operates as a ten-stage, actively mixed, self-baffled reactor, provided high wall shear with radial mixing while maintaining a low mixing shear, thus enabling crystal growth and improving the filtration rate while minimizing fouling.

In summary, the work presents key aspects of design and scale-up of a continuous crystallization for a drug substance with regard to both process and technology selection. One of the main advantages of this continuous process was consistency in the solid form, particle size distribution resulting in improved filtration of the slurry, and ability to integrate with upstream and downstream continuous processes.

Internal communication number: IPDO IPM-00637