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Cynthia A. Challener is a contributing editor to Pharmaceutical Technology.
Low-temperature chemistry enables performance of more challenging and selective chemistry.
As the pharmaceutical industry matures, the complexity of new drug candidates is increasing. More complex molecules are more challenging to synthesize, often requiring advanced chemistry techniques to ensure both high yields and high selectivity. Sophisticated chemistry such as exotic catalytic transformations are used more widely as a result. Many of these reactions are highly sensitive to temperature and pressure, with control of one or both of these reaction conditions improving the selectivity and yields of desired products, particularly in cases where undesired impurities have similar structures and physical characteristics. Low-temperature chemistry, and in particular cryogenic chemistry at temperatures down to -80 °C, can facilitate transformations that cannot be achieved at higher temperatures.
In the past few years, there has been an increase in the number of new API projects being brought to contract development and manufacturing organizations that require low-temperature chemistry. New routes to existing products that are designed to improve efficiency and productivity also more often involve cryogenic processes, according to Jean-Pierre Pilleux, site director at Novasep’s Chasse-sur-Rhône facility in France. “As novel APIs become more and more complex, cryogenic conditions are often mandatory to obtain the required selectivity. For example, processes employing organometallic chemistry can be critical in API synthesis,” adds Jean-Baptiste Guillermin, head of process development at the Chasse-sur-Rhône plant.
Use of low temperature can influence the reaction pathway, particularly for reactions in which desired and undesired products differ only slightly from an energetic standpoint, whether with respect to stereo-, regio-, or chemoselectivity. Reactions involving unstable intermediates, notably organometallic reagents, that cannot be conducted at or near room temperature are often possible at much lower temperatures. In addition, processing involving gaseous reagents can be easier to implement at low temperature.
“Cryogenic chemistry is an enabling technology that can allow the limiting of impurities, performance of processes with highly reactive compounds, improvement of reaction selectivity, elimination or reduction of unwanted side reactions, prevention of ice crystal formation, and reduction of the volatility of compounds for greater safety,” notes Ed Price, president and CEO of PCI Synthesis.
Running large-scale cryogenic processes is an entirely different proposition than performing low-temperature chemistry in the lab, according to Price. “In the lab, glassware can be placed in an acetone/dry ice bath. For commercial production, heat transfer fluids must be pumped through jacketed vessels using sophisticated pump technology (costing five to six times that of conventional pumps) and complex control systems,” he explains.
In addition, specialized analytical tools are required; measuring cryogenic temperatures cannot be achieved with normal mercury or alcohol thermometers because they freeze. Platinum resistance thermometers that exhibit well-defined electrical resistance behavior as a function of temperature must be employed instead.
“The need for specific and expensive equipment means that the capex [capital expenditure] for newcomers can be significant,” observes Pilleux. He adds that greater energy consumption and handling of unstable intermediates also must be considered. In addition, while there are always challenges going from small to large scale, scaling cryogenic chemistry and processing is significantly more complicated because extreme temperatures must be delivered and maintained, according to Price.
“Running processes under such cold conditions is as much an art as a science. These reactions are very touchy and sensitive. They have to be run very specifically, which involves controlling an entire system of pumps and heat exchangers to reach, maintain, and control the temperature as the reaction progresses,” he notes. For that reason and based on 40 years of experience running cGMP cryogenic processes, Pilleux considers process robustness to be key. “Understanding the impact of reaction parameters using a quality-by-design approach during development, coupled with close interactions between chemists and chemical engineers using thermal modeling allows the efficient prediction of scale-up parameters for such highly demanding processes,” he states.
The need for strict control of the reaction temperature throughout the entire reaction mixture can pose challenges as well. The addition of reactive reagents to such processes may lead to the generation of local exotherms that must be removed via efficient mixing and good heat exchange properties of the reactors, according to Pilleux.
In addition, the low surface area-to-volume ratio of batch reactors restrains the size of vessels for production. In fact, it is not just the need to achieve and maintain low temperatures that is challenging. It is the fact that batch processing has not changed dramatically from a technology standpoint for decades, according to Price. “Pharmaceutical plants today look similar to those in operation 20–30 years ago,” he says.
For certain chemistries, there is no other option than to perform them at low temperature. “It goes back to the perennial organic chemistry battle between yield, cycle time, and impurities. Achieving the required purity levels is always the first priority. In early development phases, the goal is to deliver high-purity products, and the economics of the process are not as important. That comes into play if a candidate progresses to later clinical stages. If the process cannot be performed economically at low temperature, another route will need to be identified,” Price comments.
It is important during development, he notes, to gain an extensive understanding of the process and determine the warmest reaction temperature that won’t cause significant problems and the potential benefits that can be gained if the reaction is performed at the lowest possible temperature.
In many cases, gains in yield and selectivity can overcome the additional costs of running a process at cryogenic temperatures. For instance, Prices notes that a product that is produced in multiple small batches can cost significantly more and take more time to manufacture than if that product is produced in one or two large-scale cryogenic runs.
Some reactions that are most often performed under extreme low temperature conditions, according to Ed Price, president and CEO of PCI Synthesis, include:
As drug candidates continue to become more sophisticated, demand for processing under extreme conditions, including cryogenic temperatures, will continue to grow. “The question then becomes, how do we incorporate novel engineering/processing solutions that really move the needle for drug manufacturing?” according to Price. Manufacturing on a smaller scale in a continuous manner to obtain the same yields and throughputs of larger equipment could be one answer, he notes.
Guillermin agrees. “Reactors having a higher surface-to-volume ratio and more efficient mixing can be used to increase the productivity of low-temperature processes and avoid the potential for high-temperature hot spots,” he says. “Continuous flow reactors are a breakthrough solution.”
Novasep is, in fact, focusing on the development of flow-chemistry solutions at production scale in order to offer alternatives to batch processes. “This technology generally enables the use of less extreme temperature conditions and control of very short reaction times, even at production scale, allowing the production of unstable intermediates that cannot be obtained under batch conditions-and with a reduced energy cost. These technologies are rapidly expending and Novasep has built a strong expertise in this domain,” says Guillermin.
Late in 2017, Novasep also initiated a €4-million ($4.7-million) investment to expand its low temperature capability at its Chasse-sur-Rhône facility and address the increasing market demand for cryogenic processes. The company now has a total low-temperature capacity of 35 m3. The investment includes the installation of a new cGMP cryogenic production line capable of operating at temperatures as low as -80 °C and is equipped with a 4000L Hastelloy reactor, filter drier, and cleanroom. The cGMP pilot-plant capabilities were also expanded with the addition of a new stream comprising a 400L Hastelloy reactor, filter drier, and cleanroom.
PCI Synthesis, meanwhile, added a 1000L jacketed reactor specifically designed for cryogenic chemistry to meet the needs of two recent projects including a new chemical entity moving from Phase I to Phase II and a generic API for which its client wished to de-risk the supply chain by adding PCI as an approved alternate supplier with in-house cryogenic capacity.
In addition to the 1000-gallon Hastelloy C reaction vessel, the system comprises three separate heat exchangers for liquid nitrogen, steam, and glycol; a specially designed pump; and control valves and control logic. The reactor is housed in a special suite and is paired with a 50-gallon glass-lined reactor for workups and additional processing and a 3-m2 Hastelloy pressure drier.
Vol. 42, No. 8
When referring to this article, please cite it as C. Challener, “Increasing API Complexity Drives Demand for Cryogenic Capabilities" Pharmaceutical Technology 42 (8) 2018.