Pharmaceutical process analysis by mass spectrometry

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Clinton, R., 2005. Pharmaceutical process analysis by mass spectrometry. PhD, Nottingham Trent University.

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Abstract

The optimisation of chemical and pharmaceutical production is achieved by having full control of the manufacturing process. Novel and developing processes must be thoroughly characterised to determine the reaction mechanisms, reaction rates and critical operating parameters. Mass spectrometry has the potential to be a powerful technique for process analysis, but reaction mixtures frequently pose a problem for online monitoring by mass spectrometry, because the concentrations of the reactants and products exceed the working limits of the spectrometer. This thesis describes the development and evaluation of membrane interfaces for mass spectrometry with potential for the direct monitoring of organic process reactions.

A single-stage microporous membrane-based interface was developed for realtime mass spectrometric monitoring of the starting materials and products of a highly concentrated process reaction mixture of pharmaceutical importance. The liquid-liquid interface was directly connected to the atmospheric pressure chemical ionisation source of a quadrupole mass spectrometer (APCI-MS). A significant level of dilution of the concentrated reaction mixture was achieved in a single step using the interface. The combination of the membrane inlet with APCI-MS was 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 real-time MS analysis.

The preparation of supported semi-permeable silicone membranes has been investigated. Supported semi-permeable silicone membranes were cast onto both nylon and polypropylene net support materials and incorporated into a membrane probe device. The supported silicone membranes were evaluated for their potential in process analysis and for screening, however the membrane probes took too long to detect a variation in the analyte concentration. This time scale was not appropriate for process monitoring where the analyte concentration must be monitored in as close to real-time as possible.

A membrane inlet device incorporating a semi-permeable silicone membrane was developed as a diluting interface between a concentrated reaction mixture and the electron ionization source of a quadrupole mass spectrometer. The potential of the interface for the headspace analysis of the volatile components of the mixture was demonstrated. The reactants and products of an early stage, pharmaceutical intermediate process were analysed by headspace membrane inlet mass spectrometry, with dilution of the concentrated reaction mixture achieved in a single step. Headspace sampling combined with membrane inlet mass spectrometry allowed the reaction components of the Mannich reaction of dimethylamine with formaldehyde and parahydroxyacetophenone to be monitored on-line in real time.

Item Type:

Thesis

Creators:

Clinton, R.

Date:

2005

ISBN:

9781369324440

Identifiers: