(328d) Development of a Fixed Bed , Gas Liquid Flow Reactor for Pharmaceutical Applications

Jason Mustakis Pfizer Worldwide R&D, Groton, CT 06340, USA

Hydrogenation is a very atom efficient, green transformation frequently encountered in the synthesis of modern pharmaceutical molecules. Operating large batch hydrogenators introduces a number of challenges due to the multiphase nature of the reaction and the specialized infrastructure required. These reactors rely on mechanical means for the dispersion of hydrogen which frequently leads to scale up challenges, while frequent handling of potentially pyrophoric catalyst leads to safety concerns. Trickle bed reactors provide an alternative solution, the gas dispersion is controlled by the flow rate and reactor geometry, the handling of the catalyst is also reduced and the flow set up provides an easy way to terminate the reaction during a safety event. Additionally, the geometry and size of the reactor allows access to significantly greater operating pressure which can open the space for alternative chemistry. Fixed bed reactors also provide a way to intensify the hydrogenation operation, providing production flexibility and reducing the size of the reactors enabling flexibility of operations. This is in line with the new small volume specialized medications found in modern pharmaceutical development pipelines.

Trickle bed technology is widely developed in the chemical industry however, its adaptation by the pharmaceutical industry has been very slow and it application introduces a series of additional challenges. Our goal is to design a trickle bed reactor that is flexible enough to support a project throughout its development lifecycle, starting with clinical supplies and enabling small scale manufacturing capability without the need for specialized infrastructure. The relative low production rates required by this application are dictating that such trickle bed operates on conditions that have not been well studied in literature before and in flow regimes that are controlled primarily by surface tension. This reactor will be used either as a standalone batch process replacement or in coordination of other flow capable unit operations.

Operating a trickle bed also offers a number of challenges due to the high localized catalyst loading that leads to interesting heat and mass transfer issues. The complexity of pharmaceutical molecules of requires catalysts to have high activity and selectivity. Catalyst activity is of special interest, as it is important for achieving the column size reduction, while temperature variations may lead to selectivity challenges. Localized starvation of catalyst from hydrogen can lead to side reactions, as well as, catalyst deactivation which will affect the productivity goals. Powder carbon supported precious metal catalysts (PCPMC) are commonly applied in pharmaceutical batch process due to their large surface area as they combine high activity and robustness. However, due to their particle size, they cannot be directly applied in trickle bed applications (pressure drop, bed cracking, fine migration). The smaller size of the column also does not allow us to utilize structure supports found in the classical TBR reactor. Due to chemistry considerations we have the desire to stay with carbon supported catalyst and we are exploring a wide range of morphology from large powders to granular and spherical particles with narrow distribution. Overall, we are exploring catalyst in the range of 80 and 800 micron. Mechanical strength is a consideration, as large pressure drops can affect typical activated carbon, generating fines which then can contribute to pressure increases. Spherical carbon based catalyst offer a number of advantages such as mechanical strength and predictable flow characteristics while maintaining the high surface area that is characteristic of carbon supported PMC. We will describe the journey of the development of a TBR suitable for pharmaceutical application from lab scale to a cGMP environment. We will be examining the main factors affecting the mass and heat transfer performance of the reactor, as well as, catalyst selection as we develop methodologies to scale from batch operations to fixed bed a cGMP environment.