Process development Reaction conversion, monitoring

In Section 8.2, the aim of analysis is emphasized especially for the API (active pharmaceutical ingredient) and the drug product. The workflows and the rationale at major decision points during synthetic processing steps where HPLC can be applied in process development are elaborated upon. For example, a fast method is needed to monitor reaction conversion of two components. However, a more complex method would be needed for stability-indicating purposes where multiple degradation products, synthetic by-products, and excipient peaks need to be resolved from the active pharmaceutical ingredient. 

Reed and coworkers developed a strategy for automatic continuous online monitoring of polymerization (ACOMP). The method may be used during the initial development of the polymerization process, its optimization and monitoring of the continuous reaction. ACOMP automatically dilutes samples from the reactor and measures its properties, e.g., refractive index, near infrared (NIR) spectra, LSc, [ ]], etc., from which it computes evolution of MW, MWD, degree of conversion, copolymer composition (in copolymerization) and others. The method has been applied to a variety of the free radical homo- and co-polymerizations, including the reactions in emulsion or suspension. ... 

Reetz and coworkers developed a highly efficient method for screening of enantioselectivity of asymmetrically catalyzed reactions of chiral or prochiral substrates using ESI-MS [60]. This method is based on the use of isotopically labeled substrates in the form of pseudo-enantiomers or pseudo-prochiral compounds. Pseudo-enantiomers are chiral compounds which are characterized by different absolute configurations and one of them is isotopically labeled. With these labeled compounds two different stereochemical processes are possible. The first is a kinetic separation of a racemic mixture, the second the asymmetric conversion of prochiral substrates with enantiotopic groups. The conversion can be monitored by measuring the relative amounts of substrates or products by electrospray mass spectrometry. Since only small amounts of sample are required for this method, reactions are easily carried out in microtiter plates. The combination of MS and the use of pseudo-enantiomers can be used for the investigation of different kinds of asymmetric conversion as shown in Fig. 3 [60]. 

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