Kinetics, Thermodynamics, and Scale-Up of an Azeotropic Drying Process: Mapping Rapid Phase Conversion with Process Analytical Technology

Distillation processes with several solid-state phases and dynamic multicomponent liquid-phase compositions can be challenging to understand and scale up because of complexity of the thermodynamics combined with process dynamics and kinetics. Often, development scientists will eschew the most efficient process because of the challenges in generating the necessary information and knowledge required to reproducibly implement it. Herein, we report the robust development of such a process: how it was characterized with in-line process analytical technology, off-line analytics, process modeling, and bench-top experiments and ultimately translated to a manufacturing scale. Through this exercise, we discovered a new solid phase and elucidated a canonical example of kinetic control and pseudoequilibrium. The detailed understanding of the thermodynamics and kinetics of the underlying physicochemical phenomena was used to define a simple control strategy that was implemented on an industrial scale to isolate the desired anhydrous crystal form. In this process, a crystalline dihydrate of a pharmaceutical intermediate was converted into an anhydrous form during distillation drying in a slurry. Water was removed by azeotropic distillation in acetonitrile at atmospheric pressure, while replenishing with dry acetonitrile. Below the critical water activity of conversion, the dihydrate was found to transform reliably and quickly into the anhydrate. Therefore, a concentrated slurry of the anhydrous form was obtained, which was telescoped into the subsequent, water-sensitive reaction. The discovery of an intermediate hemihydrate form added complexity to the system and presented a risk thermodynamically but was found to be kinetically difficult to access. In practice, the dihydrate rapidly converted directly to the anhydrate, and a molecular structural rationale for this behavior is proposed. The characterization and development of this process were enabled by in situ Raman spectroscopy and Fourier-transform infrared spectroscopy for determination of real-time solid-state form and solution water content, respectively. These tools allowed for construction of a process phase map as a function of temperature, water content, and slurry density while at the same time characterizing the kinetics of form transformations between dihydrate, hemihydrate, and anhydrous phases under relevant processing conditions. In addition, multiple off-line analytical techniques were utilized to fully characterize the solid phases, and ternary diagrams were used to explain the thermodynamics of the system and kinetic pathways. Based on this work, the process was transferred to an industrial scale and successfully executed using only a single off-line Karl Fischer measurement as a control strategy.