Supporting complex syntheses with automated specialized reactors and high-integrity data

19th Jan 2024

In order to successfully scale a process, it is essential to establish a thorough understanding of the reaction process and safety data. Technology and data play a crucial role in achieving a comprehensive understanding to make well-informed process decisions.

Automated specialized reactors are a prime example of a technology that not only enhances process efficiency, but also fosters a more informed and efficient approach to process scale-up. Several automated specialized reactors available include Mettler-Toledo EasyMaxes, HEL Polyblocks, Reaction Calorimetry Pressurized Glass Reactors, Parr Reactors, and Mya 4 Reaction Station. The automated specialized reactors are not only beneficial due to the automation but also due to the respective software, if available, that collects and processes data on a reaction’s heat flow, reaction enthalpy, and other important properties. This data collection and processing enables precise control of parameters like temperature, pressure, and stirring speed that may be critical for process scale-up. Scientists can utilize this valuable reaction data to refine and optimize reaction conditions, ultimately leading to safer and more efficient process scale-up. These reactors provide utility across a wide range of chemical syntheses, but they are especially useful for reactions with strong exotherms and other potential scale-up risks.

In this blog, we’ll discuss a few practical use cases that demonstrate how reactor data can aid in mitigating risk and optimizing reaction conditions. We’ll also highlight how Sterling is using automated, specialized reactors today.

Hydrogenation reactions are widely used in active pharmaceutical ingredient (API) development, but hydrogen’s highly flammable nature makes these reactions both challenging and hazardous. Additional challenges can emerge as hydrogenation reactions scale-up, including inefficient mixing due to mass transfer limitations, and precise temperature and pressure requirements that must be continually monitored. For exothermic reactions, it is especially crucial to ensure controlled reaction conditions on a small scale prior to transitioning to the plant, as onsite hazards can be much more significant if not properly controlled.

Sterling, specifically its Wisconsin facility, uses Mettler-Toledo EasyMax glass and pressure reactors, coupled with the respective data collection and processing software, and can simultaneously assess multiple reaction parameters that may impact results down the line. These parameters include agitation speed, pressure, catalytic efficiency, and more. For hydrogenation reactions in particular, leveraging these reactors from the very start to monitor exothermic reactions enables our team to optimize reaction conditions and monitor progression prior to moving to a larger scale to minimize risk of highly exothermic processes. Furthermore, due to the independent chambers, scientists can examine multiple reaction parameters and conditions at once to understand what should be modified for precise control of the exotherm.

An example of leveraging Sterling’s automated specialized reactors includes our team optimizing a reaction’s hydrogenation conditions, at 45rea PSIG and 45°C on a three gram scale with various catalyst loading, using the EasyMax102 pressure reactors for process scale-up. Once catalyst loading was screened and optimized, further evaluation for pressure and temperature were executed to finalize the ideal conditions. Our team analyzed the data produced by the reactors and confirmed they could safely scale the reaction, and our team successfully scaled the process up to 29 grams using a Reaction Calorimetry Pressurize Glass Reactor with the optimized conditions. The data collected during the experiment confirmed the exotherm was low risk for process scale-up. After proving success at 29 gram scale, we further scaled to a 67 gram demo batch, successfully, using the Parr Hydrogenator Reactor. This was done in preparation for a large-scale 15 kilograms for plant manufacturing batch. The use of different types of automated specialized reactors in tandem with their respective data collection and processing software provided the reaction data needed to ensure the team could successfully and safely scale the process without encountering unanticipated challenges or risks in the plant. The use of automated specialized reactors provides a better predictive outcome, seen from the above example, than round bottom flask or jacketed reactors. Furthermore, data collected with the automated specialized reactors can be used with complimentary modelling software, Dynochem for example, to further optimize process scale-up.

Crystallization is integral in determining particle characteristics like size, solubility and purity. Uncontrolled crystallization can present challenges during process scale-up and can have an impact on final particle results, leading to challenges in formulation or pharmacokinetics. Some of the most common crystallization challenges include uneven mixing, slowed heat and mass transfer, and temperature control, among others.

One of the most important factors in the crystallization process is cooling rate. Cooling too fast can lead to smaller, less uniform crystals and lower crystallinity. By using the automated specialized reactors for scale-up, scientists can monitor and optimize the cooling rate, and other critical factors, to ensure consistency, stability, and reproducibility during crystallisation, especially as a process scales. Compared to jacketed reactors with external heating and cooling systems, a common method used in crystallization, the automated specialized reactors enable greater precision and control when running reactions over long periods of time with software data collection and processing.

Additionally, automated specialized reactors support the generation of a metastable zone for crystallizations to reduce the probability of nucleation. For example, our team used a crystallization platform to identify an ideal zone for seeding. After identifying optimal conditions, we reproduced these conditions using an EasyMax102 reactor to successfully scale the crystallization while achieving our desired particle size and uniformity. Additionally, some automated specialized reactors, such as EasyMax402, can be used with focus beam reflectance measurement and particle video microscope probes to further maximize data collection and precision in the desired particle characteristics.

A data-driven approach to risk assessment and reaction optimization

Automated specialized reactors are highly versatile, with capabilities to support a variety of chemical reactions. While two use cases were covered here, our team at Sterling is continually exploring new ways to improve processes and mitigate risk using this technology, among others.

If you’re interested in learning more about how we can maximize safety and efficiency in your API development program, speak to an expert.

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