Process chemistry
Additionally, the many complex factors associated with chemical plant engineering (for example, heat transfer and reactor design) and drug formulation will be treated cursorily.
Cost efficiency is of paramount importance in process chemistry and, consequently, is a focus in the consideration of pilot plant synthetic routes.
Most large pharmaceutical process chemistry and manufacturing divisions have devised weighted quantitative schemes to measure the overall attractiveness of a given synthetic route over another.
This approach describes the process of eliminating workup and purification steps from a reaction sequence, typically by simply adding reagents sequentially to a reactor.
Low yields are typically indicative of unwanted side product formation, which can raise red flags in the regulatory process as well as pose challenges for reactor cleaning operations.
Inconsistencies in E-factor or PMI computations may arise when choosing to consider the waste associated with the synthesis of outsourced intermediates or common reagents.
For example, if an isolation step is particularly difficult or slow, it could become the bottleneck for API synthesis, in which case the reproducibility and optimization of that operation become critical.
In 2006, Van Aken, et al.[5] developed a quantitative framework to evaluate the safety and ecological impact of a chemical process, as well as minor weighting of practical and economical considerations.
Macrocyclization is a recurrent challenge for process chemists, and large pharmaceutical companies have necessarily developed creative strategies to overcome these inherent limitations.
An interesting case study in this area involves the development of novel NS3 protease inhibitors to treat Hepatitis C patients by scientists at Boehringer Ingelheim.
For the unoptimized reaction: This VTO value was considered prohibitively high and a steep investment in a dedicated plant would have been necessary even before launching Phase III trials with this API, given its large projected annual demand.
Recently, large pharmaceutical process chemists have relied heavily on the development of enzymatic reactions to produce important chiral building blocks for API synthesis.
The widest range of applications come from ketoreductases and transaminases, but there are isolated examples from hydrolases, aldolases, oxidative enzymes, esterases and dehalogenases, among others.
[11] One of the most prominent uses of biocatalysis in process chemistry today is in the synthesis of Januvia®, a DPP-4 inhibitor developed by Merck for the management of type II diabetes.
The traditional process synthetic route involved a late-stage enamine formation followed by rhodium-catalyzed asymmetric hydrogenation to afford the API sitagliptin.
This process suffered from a number of limitations, including the need to run the reaction under a high-pressure hydrogen environment, the high cost of a transition-metal catalyst, the difficult process of carbon treatment to remove trace amounts of catalyst and insufficient stereoselectivity, requiring a subsequent recrystallization step before final salt formation.
[12][13] Merck's process chemistry department contracted Codexis, a medium-sized biocatalysis firm, to develop a large-scale biocatalytic reductive amination for the final step of its sitagliptin synthesis.
The engineered transaminase contained 27 individual point mutations and displayed activity four orders of magnitude greater than the parent enzyme.
Additionally, the enzyme was engineered to handle high substrate concentrations (100 g/L) and to tolerate the organic solvents, reagents and byproducts of the transamination reaction.
A case study of particular interest involves the development of a fully continuous process by the process chemistry group at Eli Lilly and Company for an asymmetric hydrogenation to access a key intermediate in the synthesis of LY500307,[15] a potent ERβ agonist that is entering clinical trials for the treatment of patients with schizophrenia, in addition to a regimen of standard antipsychotic medications.
After extensive optimization, it was found that in order to reduce the catalyst loading to a commercially practical level, the reaction required hydrogen pressure up to 70 atm.
An additional concern was that the hydrogenation product has an unfavorable eutectic point, so it was impossible to isolate the crude intermediate in more than 94 percent ee by batch process.
Because of this limitation, the process chemistry route toward LY500307 necessarily involved a kinetically controlled crystallization step after the hydrogenation to upgrade the enantiopurity of this penultimate intermediate to >99 percent ee.
