Development of a Continuous Process for SN2 Amination: Towards a Total Synthesis for Albuterol Sulfate in Flow

Continuous pharmaceutical manufacturing involves converting chemical reactants into active pharmaceutical ingredients via chemical transformation in interconnected vessels and flow reactors. These techniques and the associated advantages can be an essential strategy for reducing manufacturing costs and addressing shortages of lifesaving drugs, such as albuterol sulfate. Manufacturing of albuterol sulfate has historically only been performed in a batch operation mode, highlighting the opportunity to enhance the production approach to continuous. This work discusses the development of the primary reaction, an SN2 amination, in the continuous, end-to-end manufacturing of albuterol sulfate. Batch studies were conducted to observe process variable effects as well as determination of kinetic parameters. Laminar and plugged flow models were developed for predicting conversion of the starting material for both a first and second order reaction. Results showed optimal process conditions when the reaction was performed in isopropanol at 40°C, with an initial concentration of the limiting reagent to be 100 mg/ml. The laminar flow model for a second order reaction was most accurate at predicting conversion of the starting material in flow and indicated a necessary residence time of 30 minutes to achieve complete conversion. NMR was investigated as a potential process analytical technology for live reaction monitoring and process control. Key reaction species were identified and calibrated to enable quantification of amount present

Advanced Synthesis and Rational Design of Support Structures for Nobel Metal Heterogeneous Catalysis: Towards Enhanced Activity and Continuous Processes

The field of catalysis has a wide-ranging impact. Our group has identified the constant need for improved catalytic activity in high-impact applications such as hydrosilylation and cross-coupling reactions. For these reactions, precious metal catalysts often exhibit markedly better performance than their counterparts, but they can be a significant process cost that decreases overall economic efficiencies. To address this challenge, we explored support structures that can enhance catalytic activity at low metal loadings and improve precious metal recovery through simple filtration. We found that a platinum on graphene nanoplatelet catalyst (PtGNP) synthesized via strong electrostatic adsorption with microwave irradiation (SEA-MW) exhibits high activity compared to the industrially relevant Karstedt’s catalyst for hydrosilylation reactions. Due to the inherent high surface area of the GNPs, we focused our attention on developing a more robust catalyst for their use in packed bed reactors. We successfully developed a facile method for depositing GNPs onto 0.5 mm gamma-alumina particles. We used a modified controlled surface tension method to reduce platinum nanoparticles onto the surface of the GNP/alumina material. The resulting catalyst performed exceptionally well in a packed bed, generating pressures that were easily handled on a commercially available packed bed reactor platform. Lastly, we deployed a rational design approach toward a 3D printed fixed bed reactor that could be functionalized with active palladium nanoparticles for Suzuki cross-coupling reactions. The intended benefit of this approach is to provide practical, efficient, and low-cost methods for the synthesis and use of precious metal nanoparticles

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[front] For Insurance That Insures, Join Southern Aid Society of Virginia Inc., Home Office 527 N.2nd St. Richmond, Virginia, Insures Against Sickness, Accidents, & Death, A.D. Price, Pres., Thos. M. Crump, Sec., B.L. Jordan, Asst. Sec.https://scholarscompass.vcu.edu/postcard/1299/thumbnail.jp

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