Filtration drying is an important unit operation to monitor for pharmaceutical primary manufacturing both from a kinetic and a quality perspective. Process analytical technologies (PAT), such as Raman spectroscopy, Near Infrared spectroscopy (NIRS), gas chromatography (GC), and mass spectrometry (MS) have been used to monitor filtration and drying to provide real-time solvent content. However, each of these instruments has limitations, such as the requirement for at-scale calibration experiments by Raman and NIRS, and the inability to translate the solvent content in the headspace to the wet cake by GC and MS. Additional PAT challenges include the large material demand in even the smallest scale-down filter dryers, and the lack of representative measurements in a heterogeneous gas-solid sample matrix.

To address some of these challenges, a rotary evaporator (rotovap) with PAT interfaces was developed in our lab. This unique rotovap PAT interface reduces the material demand for collection of a drying curve to ~1g scale and provides improved sampling of both wet cake and headspace for drying kinetics than the aforementioned PAT methods. Multiple drying case studies were carried out using the rotavap PAT interface and are illustrated herein. Initial slurry and final solid solvent levels were collected and submitted for reference measurements such as gas chromatography (GC). These were not only taken for the purpose of method calibration via the partial least squares (PLS) approach, but also used to rescale predicted solvent content by vibrational spectroscopy to capture accurate drying dynamics in the wet cake. Such a PAT interface was then applied to different experimental conditions (such as N2 flow rate and drying temperatures) to capture drying kinetics from both wet cake and headspace. To the best of authors’ knowledge, this is the very first time the drying kinetics was reported based upon the correlation of residual solvent in both wet cake and headspace. Such a correlation not only demonstrates the value of the rotavap PAT interface for collecting useful filtration drying data in a material-sparing manner, but also is expected to streamline the process development of API filtration drying steps via not only determining the drying end-point, but also providing real-time drying data for kinetic modeling across scale and across different filtration dryer designs.