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.