(61a) Minipharm: A Miniaturized Pharmaceutical Manufacturing Platform for Process Development

The traditional approach to pharmaceutical manufacturing is to use consecutively larger batch processes for scale-up; however, there is an alternative that is gaining support: continuous manufacturing. Continuous pharmaceutical manufacturing consists of the integration of multiple unit operations, from synthesis to purification, in a single manufacturing process which can improve scalability, while reducing equipment resource requirements and processing time between unit operations. Small-scale continuous manufacturing would allow companies to implement end-to-end processes that reduce chemical usage, require smaller liquid volume when compared to traditional batches, and have smaller space requirements. The motivation for this paper was to detail the development of an end-to-end miniaturized pharmaceutical manufacturing platform (MiniPharm) with a reconfigurable, modular design to carry out flow reaction, extraction, and crystallization unit operations while utilizing process analytical technology (PAT) tools for molecule identification and quantification. A major advantage for the platform is its ability to simultaneously screen purification routes. Two purification routes following synthesis were compared to determine the impact of unit configuration on product purity. In order to achieve these results, the platform implements two process configurations: synthesis, followed by nitrogen-segmented anti-solvent crystallization and synthesis followed by inline extraction, separation, and nitrogen-segmented crystallization. Nitrogen-segmented crystallization is of particular interest because it allows for the segments to act as individual crystallizers. The aforementioned approach to continuous crystallization has not been demonstrated in an integrated design with continuous reaction and flow extraction unit operations.

The compound selected in this study was Diphenhydramine hydrochloride (DPH). The reaction consists of a single step and has been shown as an example of atom economy due to the direct synthesis of the final product without the necessity of an extraction/solvent swap step. The reaction provided an opportunity for development of the platform with a molecule that is suitable for continuous small-scale production. Platform development included individual unit operation characterization and the coupled unit operation screening prior to the complete design integration. Initial unit operation studies provided valuable insight into system parameters necessary for system integration.

The implementation of PAT was critical from the start of platform development. Monitoring of the module performance was achieved with the use of Ultra high performance liquid chromatography (UPLC) and Mass Spectrometry. Characterization of crystal products was carried out using powder x-ray diffraction (XRD) and Raman spectroscopy. Imaging of the crystallization process in segmented flow was monitored by using an optical camera. Crystal morphology and size distribution data was measured using Malvern Morphologi G3. Reactor module development consisted of a screening multiple residences at various temperatures to determine product concentration. Initial extraction development focused on pH adjustment for product recovery; however, Thin Layer Chromatography (TLC) results provided insight into a non-pH adjusted approach to isolate DPH. Crystallization module development began with cooling only crystallization, but was expanded to include a combined anti-solvent and cooling approach to allow for enhanced product recovery.

In this study, the development of an integrated, reconfigurable platform was detailed for Diphenhydramine hydrochloride process development. PAT tools were used to determine the performance of unit operations in the integrated system. Finally, products from the simultaneous purification routes were compared to determine the effectiveness of additional purification steps on the final product purity. Implementation of the process development framework in a multi-step reaction will be explored in future studies.