Process analytical technology (PAT) is fast becoming an integral part of many active pharmaceutical ingredient (API) production facilities. The incorporation of early PAT devices, such as pH probes for example, was shown to increase process efficiency and safety by acting on data in real time and by eliminating sampling. PAT applications, such as online redox, NIR, and sophisticated particle size analysis, increase (in real time) detailed knowledge of processes, thus affording increased robustness and greater straight-through processing (right-first-time) opportunities. Modern developments in analytical technologies provide chemical and analytical insights for all types of chemical reactions and process monitoring such as drying, distillations, crystallizations, hydrogenations, and others. This article will discuss two applications; each is very different from the other. The first application, redox monitoring, is a traditional PAT application used to monitor differences in the oxidation state of two reaction constituents. Our discussion will describe an oxidation/reduction (redox) application used to monitor the reduction of excess bromine with sodium bisulfite using an online probe. The second application is crystallization and granulation monitoring using a Lasentec Focused Beam Reflectance Measurement (FBRM) instrument for the optimization of a crystallization and granulation process in manufacturing (reference information is publicly available on this equipment; visit the Mettler-Toledo website at:  http:// www.lasentec.com/method_of_measurement.html).

Diastereoselectivity in the reduction of alpha-alkoxy-, alpha-acyloxy-, and alpha-alkylamino-substituted ketones with polymethylhydrosiloxane (PMHS) in the presence of fluoride ion catalysis was investigated. High syn-selectivity was observed in the reduction of alpha-alkoxy, alpha-acyloxy, and alpha-dialkylamino ketones. Reduction of alpha-monoalkylamino ketone proceeded in anti-selective manner with moderate selectivity. The observed selectivity is explained based on Felkin-Anh and Cram-chelate models.

A de novo three-step-one-pot process for the formation of PF-04191834 was developed. This methodology employed inexpensive, odorless and readily available commodity chemical isooctyl-3-mercaptopropionate as sulfur source, which could be a general alternative to the popular TIPS-SH in the formation of diarylthioethers via Migita coupling. A kinetic study revealed that at high temperature, reductive elimination could be the rate-limiting step in the catalytic cycle, which opens pathways for the generation of undesired impurities. By proper control of the reaction conditions, the desired API was synthesized in >70% crude yield and in 55% isolated yield after vigorous purifications. This process was successfully demonstrated on 20 kg scale.

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Experimental design and mathematical modeling techniques were used in the optimization of a Pinner quench process. The detailed effects of water, agitation, and temperature on both product yield and quality were elucidated. Significant improvements in both yield (5%) and throughput (>50%) were attained. This work demonstrates how the use of experimental design techniques in chemical process development adds value by allowing efficient optimization of a given synthetic step. The progress of the project from initial lab-scale investigations to full plant-scale implementation is described.