Teaching Old Drugs New Tricks

Jun 19, 2014

James Frahill, who is a Research Analyst at the Pfizer Process Development Centre (Cork, Republic of Ireland) spoke to Bethany Degg of The Column about the role of the chromatographer in the pharmaceutical process development group at Pfizer.

Q. What are the main objectives of your research group?


PHOTO CREDIT: JORG GREUEL/GETTY IMAGES
A: We are a pharmaceutical process development group. We are tasked with developing new synthetic routes to active pharmaceutical ingredients (APIs) that are already established products in the market place. The group uses novel synthetic chemistry, new technology, and innovation tools to design and deliver these new processes. This approach has led us in the past to deliver processes that include flow chemistry technology, enantioselective enzyme reactions, phase transfer catalysts, and more.

Q. How do you use analytical chemistry to develop new synthetic routes to APIs?


James Frahill
A: The analytical support underpinning the process development activities is a critical part of delivering these new processes. The analytics that support the process development gives us our understanding of what is happening in the process. We monitor reaction rates, product formation and purity, impurity profiles, and so on. In order to achieve a high standard of process understanding, we are continually developing new analytical methods, both spectroscopic and chromatographic, to cope with the changing matrix of the samples generated by the developing chemistry. The analytical activities in the group cover a range of tasks such as quality testing of isolated intermediates and APIs, identification and structural elucidation of unknown compounds or impurities formed in the new chemistry, analysis of enantiomers, and identification and control of any possible genotoxic impurities (GTIs) and on-line process analytical technology such as UV and IR measurements made at the reaction itself.

Typically, the methods developed during the process development are evolved into the analytical test methods that are validated and are filed with regulatory bodies during the process filing.

In the drive to get better process understanding the analytical group leverages any useful technology available in the market place to deliver the results required. We have recently expanded our collection of detectors by adding a charged aerosol detector (CAD) and a quadrupole time-of-flight (Q-TOF) mass spectrometer to our array of orthogonal chromatography systems which include reverse-phase high performance liquid chromatography (HPLC) and ultrahigh-pressure liquid chromatography (UHPLC), non aqueous reverse-phase HPLC, normal phase HPLC, and supercritical fluid UHPLC.

Q. What is the focus of your research at the present time?

A: At the moment I am working on impurity identification. I am analyzing samples generated by our new process chemistry using LC–QTOF-MS. I use the high resolution of the instrument in MS mode to generate the molecular formulae for the peaks of interest. We then conduct MS–MS experiments on each of the impurities and determine the structure of the impurities by assigning structures to the fragment ions generated in the MS–MS experiment.

Nobody can claim to be able to do de novo structural elucidation using MS and MS–MS data alone, but given the limited amount of transformations possible in a pharmaceutical chemistry reaction, we can elucidate structures from the data with a high degree of confidence. We then synthesize the proposed structure and confirm its identity under the original analytical technique.