In contrast to Medicinal Chemistry, which involves design and synthesis of pharmaceutical compounds at the discovery phase, Process Chemistry is concerned with the development and optimization of drug synthesis for manufacturing. Many factors must be considered in scaling the drug development process including: reaction yield, processing time, and costs associated with resource consumption and environmental impact.

• Continuous flow reactor systems are becoming more common in the process optimization phase as they can overcome traditional limitations of typical batch reactors, such as high-pressure requirements, suboptimal yields, and excessive material consumption. 

• Implicit to the method development of continuous flow reactors are high performance syringe pumps which supply precise volumes of precursors, often under temperature and pressure-controlled conditions. 

• As such, only syringe pump instruments with suitable high-performance metrics can function efficiently in this critical stage of drug development.

Process Chemistry Considerations

Cost efficiency is the main driver for chemical process development. Pharmaceutical companies consider each element of a drug synthesis route, weighing factors such as material costs and volume-time output (VTO) heavily. As the material costs include raw materials, reagents, solvents, and all consumables, this factor is essential in the selection of one synthetic route over another.

Yield, or the amount of product obtained in a chemical reaction, is another key factor in process development. Although multiple strategies can be employed for optimization, process reaction yield plays a critical role in planning the correct route and fine-tuning reaction conditions. After a synthesis route is decided upon, a course of exhaustive optimization is taken in order to streamline each reaction step and maximize the product yield.

Volume-time output (VTO) is an important consideration associated with reactor occupancy for a given process. A costly reaction in terms of VTO is one in which reactor hours are excessive and/or the volume of reaction is suboptimal. A high VTO can be a detriment to the entire process development cycle – regardless of the material costs and yield.

Continuous Flow Process Development

Continuous Flow Processing technologies arose from the inherent challenges and limitations of conventional batch reactors. With the latter, parameters including time, temperature, order as well as type of reactant are exhaustively scouted. If more product is needed, larger vessels are employed. Inevitably, efficiency issues arise from the challenges in process optimization and variations due to vessel/process scaling. Loss of efficiency translates to limited yields, higher VTO, and higher costs.

Much progress has been made in the development and use of continuous flow reactors, particularly for small-scale chemical synthesis. The technology is increasingly gaining ground in pharmaceutical drug development as well, as the cost benefits associated outweigh the practical challenges in many cases. Continuous flow approaches may possess distinct advantages over batch reactor processing in terms of safety, quality control, and throughput – all factors that play into cost efficiency of drug production.

Features and benefits of continuous flow reactors include:

• Reduction in the consumption of material
• The ability to rapidly screen reaction conditions
• The ability to design and optimize scalable reaction methodology
• The ability to directly compare reaction conditions with process efficiency
• Better safety, product stability, and more efficient resource usage including space.

Strategies in Continuous Flow Method Development

In the micro or lab-scale phase of method development, reaction flow cell and chamber configurations must be chosen to suit the chemical nature of the reactants and products. The chosen setup must also address reagent safety, as well as necessary temperature and pressure conditions.

Lab-scale reactor flow cells and chambers have an absolute necessity for reagent delivery which is typically provided by automated syringe pumps connected inline to the flow devices. Features and benefits of high performance syringe pumps include:

• The time-scale of reactions can be scouted and optimized with syringe pumps capable of wide flow rate ranges – from mL to nL scale. The end result can be significant reductions in reaction time and processing rate.
• The chemical compatibility and resilience to both solvent and solvent-free reagents is an important syringe pump parameter. Effects include more efficient reaction condition scouting and lower chances for side-reactions, contaminants, and pump failure.
• The ability to fine-tune dual-barrel syringe pumps to adjust flow and mixing rates accelerates the process of method optimization.
• Accurate and precise delivery of reactants ensures method characterization is maintained with high confidence. This is important in assessing the robustness of a method and the feasibility for scale-up.
• The ability to handle defined pressure and temperature parameters is conducive to superior reactor performance.
• Options for exchanging pumps barrels enables a broad range of reagents and reaction conditions to be explored without breaking down the setup.
• Programmable operation ensures reliable and reproducible reaction conditions are attained, particularly those involving multiple stepwise events.

Summary

Upon development of continuous flow methods and optimization of each reaction step, the next stage is the design of strategies for up-scaling operations. The ability to optimize and connect the reaction steps at the micro or lab-scale has serious implications on the feasibility of large-scale operations. The performance and capabilities of the syringe pump system has a direct impact on the continuous flow reactor design – and ultimately its success in large-scale manufacturing.

This article was written by LabX and published in conjunction with Chemyx.

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Chemyx Inc. develops and manufactures microsyringe pump and high-pressure syringe pumps for a variety of R&D and manufacturing applications in biotech, pharma, chemical and oil & gas. Widely recognized for fluidic precision and innovative technology, the company is one of the market leaders in precision dosing, microfluidics, mass spec calibration and in related applications.

Chemyx syringe pumps are designed with advanced, highly durable materials that provide extreme laboratory precision at the best value to our customers. For more specific application requirements, Chemyx scientists also build custom units and can provide additional OEM manufacturing services that expand our customers’ offerings in the market.

A leader in innovation, Chemyx was the first company to develop the next-generation syringe pump with an interactive LCD interface and integrated syringe database. Today, Chemyx continues to push advancements in the laboratory services industry to facilitate and further the research of the world’s scientists, academics, and manufacturing companies.

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