Continuous flow reactor systems are becoming more common in chemical processing as they can overcome traditional limitations of typical batch reactors, such as high-pressure requirements, suboptimal yields, and excessive material consumption. Nonetheless, batch reactor systems offer process versatility without the need for breaking containment and include rather straightforward scaleability options. Here we highlight a few of the pros and cons of each system – with an emphasis on pharmaceutical manufacturing.
Process Chemistry Considerations
Cost efficiency is the main driver for chemical process development. As such, a pharmaceutical company considers 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 technology advancements and 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 gaining significant ground in pharmaceutical drug development, as the cost benefits associated outweigh the practical challenges in many cases. Continuous flow approaches may possess 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.
Batch Reactor Process Development
A dominant attribute of batch reactor systems is versatility. A universal batch system which involves a relatively basic setup, allows for many different operations to be conducted without the need for loss of containment or the need for individual reactor (re)design. This is particularly valuable in processes involving caustic or toxic reactants, or high potency products, in which breakdown would entail significant time and resource losses.
The containment vessel of a batch reactor allows for exchange of different agitation and heating or cooling mechanisms ideally suited for the reaction process. The shape, speed, and baffle arrangement can be specified – as well as use of alternative agitation techniques such as ultrasonic mixing. Heating and cooling systems serve to control thermal properties associated with chemical reactions, and as such, batch reactors can make use of a single external jacket, half coil jacket, or constant flux jacket, according to the specified requirements of the process.
Beyond versatility, advantages of batch reactor systems include:
- Relatively basic design and relative ease of fabrication and modification.
- Widespread usage in applications ranging from food and beverage, to pharmaceutical manufacturing, to small-scale research fermentation processes.
- The ability to scale an optimized process with relative ease by increasing the size and/or number of reaction vessels.
- The lack of a need for extensive reaction cell (re)design and fabrication iterations during method optimization.
With those considerations in mind, the choice of continuous over batch systems may come down to the particular reaction process(es) and the need for high throughput production and reliability – the former excelling in both. Batch reaction vessels may be advantageous for well-defined processes – and may save considerable upfront costs in reactor design and fabrication. Of course, important considerations also include infrastructure, maintenance, staff, and operations.