(164a) PAT Applied to Understanding and Controlling the Removal of Dissolved Gases From Processes in API Development

Process analytical technology (PAT) is a valuable tool for obtaining data to determine fundamental parameters used to construct predictive process models. For example, equilibrium constants and rate constants can be obtained for processes that involve multiple phases by using real-time data from analyzers simultaneously monitoring each of the phases. This ?multi-dimentional? approach to understanding the process is an aid to fully defining the design space in a Quality by Design approach to process development.

Over the years, adverse events have occurred in commercial pharmaceutical processes whose root causes were found to be dissolved gases. In this presentation, a general methodology will be described for understanding and modeling the removal ? and resistance to removal ? of undesirable gases from processes. More specifically, these methodologies will be described in the development of the commercial process to produce the compound semagacestat, which is under development for the treatment of Alzheimer's disease. In this process, residual CO2 that is generated during a Boc-deprotection step results in the formation of an impurity in the coupling step that follows. This impurity results in reduced yield and a product quality concern, because it is not removed during work-up. Complete removal of the CO2 prevents the formation of this impurity and is the objective for this work.

The presentation will include a description of the methodology using Mid-IR and mass spectrometry to simultaneously monitor the liquid and gas phases, respectively, of the process. Treatment of the data to construct models for obtaining and utilizing Henry's law constants and mass transfer coefficients will be described. A second model will be presented that aids in the selection of the most appropriate PAT monitoring technology for process control, and to establish the control points.