Online NMR and HPLC as a Reaction Monitoring Platform for Pharmaceutical Process Development

Detector response is not always equivalent between detectors or instrument types. Factors that impact detector response include molecular structure and detection wavelength. In liquid chromatography (LC), ultraviolet (UV) is often the primary detector; however, without determination of UV response factors for each analyte, chromatographic results are reported on an area percent rather than a weight percent. In extreme cases, response factors can differ by several orders of magnitude for structurally dissimilar compounds, making the uncalibrated data useless for quantitative applications. While impurity reference standards are normally used to calculate UV relative response factors (RRFs), reference standards of reaction mixture components are typically not available during route scouting or in the early stages of process development. Here, we describe an approach to establish RRFs from a single experiment using both online nuclear magnetic resonance (NMR) and LC. NMR is used as a mass detector from which ...