The Economics of Cryogenic Chemistry in API Development


In API development, some steps may require extremely cold, cryogenic conditions—as low as minus 80o C—to achieve the desired molecular transformation. Due to rising demand for this specialized capability, PCI Synthesis has made a significant investment in our cryogenic capability that includes in a 1,000-gallon reactor capable of running low temperature chemical reactions at research, development, pilot and commercial scale.

As we discussed in our previous blog, “How cryogenic capabilities aid API development,” performing some steps under cryogenic conditions has certain advantages.

Extreme cold can limit impurities and enable the processing of highly reactive compounds such as organolithium reagents. Some reactions that are most often performed under these low temperature conditions include:

  • Halogen-metal exchange (e.g. Li).
  • Li, Na metal reductions.
  • Selective deprotonation and subsequent stereoselective, regioselective and chemoselective reactions.
  • Stereoselective, regioselective and chemoselective reductions of ketones, Imines and Esters.
  • Asymmetric reactions such as Michael additions.
  • Selective Freidel-Crafts Acylation (e.g. with Oxalyl Chloride).
  • Low temperature Swern Oxidations.

nic conditions can improve reaction selectivity, eliminate or reduce unwanted side reactions and prevent ice crystals from forming. There’s also the safety factor, which is always a concern: running reactions under cold conditions can limit the volatility of compounds until their conversion to a less volatile compound is completed, improving safety.

Why we added the 1,000-gallon cryogenic capacity

Two recent projects, and others in the pipeline, convinced us to add this unique large-scale cryogenic capacity.  One was a successful New Chemical Entity (NCE) we supplied for a Phase 1 clinical trial. It needed to be scaled up for Phase 2. To get the desired outcome, one of the multiple steps necessitated a temperature of -78o C to build the molecule. We needed more cryogenic capabilities to deliver the goods quickly.

We also have been supplying a generic for many years that involves a cryogenic step to make the starting materials.  We and our customer wanted to assure a secure supply. In order to de-risk the project, we made the commitment to become an approved alternative supplier by bringing the cryogenic capacity in-house. We made a 20-fold leap from a 50-gallon tank that was used primarily in R&D to the current 1,000-gallon tank.

The economics of cryogenics

Our significant capital investment included not just the vessel itself but also new utilities and temperature control systems for the fully automated control single loop system. Tremendous time and effort was spent. It took several months for the engineering alone. As well, the system requires a steady supply of liquid nitrogen to chill down the operating vessel rather than chilled water.

For our sponsors, does it cost more if a step in the chemistry requires cryogenics?  Due to the high capital and maintenance costs, it has to. Readers of this blog know that we charge $7,500 per week for lab work and $75,000 a week in our manufacturing suites. Cryogenics adds 15 to 20% to the weekly cost.

But it also adds tremendous value. The main beneficiaries are our customers. Not only can doing all the chemistry in-house save time and de-risk projects, but it can save sponsors significant costs.

For example, suppose 10 kilos of a product that has a cryogenic step are needed. With a small reactor, one kilo a week can be produced, at the cost of $75,000 per week over 10 weeks. The total cost would be $750,000. But with a large reactor, all of the product needed can be made in one or two batches and take just two weeks. That would incur an incremental cost of just $200,000, a savings of more than $500,000.

Want to learn more about Cryogenic Chemistry?

Many sponsors choose PCI Synthesis for this ability to scale-up and save them money in the process. Not only do we usually catch any potential problems in our kilo lab before going into full-scale and more expensive manufacturing, but we can scale projects as they progress from lab to clinical trials to commercialization.

Our customers tell us they greatly appreciate the fact that with our ability to scale up they do not incur the considerable costs and lost time in transferring technology from a CRO to a CMO every time larger quantities of a drug product are required.


Adding large-scale cryogenic capabilities dovetails with our commitment to providing our customers with complete service offerings. In particular, with our unique ability to scale up according to sponsor needs, we can take our sponsors from NCE development through clinical trials and commercialization. Our sponsor avoid having to start over, and having to incur the expense and stress of transferring the technology when large scale manufacturing with cryogenic steps involved is required.

For another article on cryogenics, check out: “Cryogenics: How Cryogenic Capabilities Aid API Development.” Or to ask us questions, please call us at (978) 462-5555.