Real-time monitoring of a pharmaceutical process reaction using a membrane interface combined with atmospheric pressure chemical ionisation mass spectrometry

A single-stage membrane-based interface has been developed for real-time mass spectrometric monitoring of the starting materials and products of a highly concentrated pharmaceutical process reaction mixture. The interface was directly connected to the atmospheric pressure chemical ionisation source of a quadrupole mass spectrometer (APCI-MS). Dilution of the concentrated reaction mixture was achieved in a single-step by using the interface with a precision of 3.2% for replicate samples. The combination of the membrane inlet with APCI-MS is demonstrated for the Michael addition reaction of phenylethylamine and acrylonitrile in ethanol using a hydrophobic polyvinylidene fluoride microporous membrane. The reaction was monitored throughout its course, allowing the endpoint to be determined based on the relative concentrations of the reaction precursors and products. The device required minimal analyst intervention, reducing sample preparation and handling prior to on-line real-time MS analysis.