(422c) Complete Synthesis for Albuterol Sulfate in Flow: Development of a Continuous Process for SN2 Amination

Continuous processes are finding increased adoption in pharmaceutical manufacturing due to advantages provided over traditional batch processing such as reduced footprint, cycle time, and manufacturing costs in addition to improved quality control. We propose a small-scale, modular, continuous manufacturing system to capitalize on these advantages and address critical shortages of lifesaving drugs like Albuterol. This talk highlights the optimization of the first step of the reaction sequence for the end-to-end continuous manufacturing of Albuterol Sulfate. Kinetic parameters were collected through batch experiments and used to develop conversion models for tubular reactor design. The model and the reactor designs were validated in a series of flow experiments.

Batch amination reactions were conducted at a range of temperatures (0-70 °C) and reactant concentrations (C_Diol = 10-100 mg/mL) to verify the reaction mechanism, determine the reaction rate constants, and optimize the amination reaction. Quantitative and qualitative analysis of the intermediate product purity was determined by means of LC-UV and LC-MS. Batch reactions were conducted at 20, 40, and 60 °C in MeOH and IPA. Reaction rate constants and activation energies were determined for comparison between theory and experiment in tubular flow reactors. Continuous amination reactions were conducted in a Vapourtec E-series flow reactor for a range of temperatures (30-60 °C), residence times (3.67-60 mins), and inner tubing diameters (1/16-1/8 in.). The overall flow rate of reactants was maintained at a 4:1 molar ratio, and the temperature was maintained constant. Samples were collected at the outlet of the flow reactor and analyzed via HPLC to quantify the presence of each major species.

At low temperatures (0 °C), the reaction rate was slow, limiting formation of the major impurity, a dimer. Higher temperatures increased dimer formation and reduced production of the desired product. An optimal temperature range was observed to exist from ~20-40 °C. Conversion of the diol to the amination product at 40 °C was largely consistent at concentrations ranging from 20-100 mg/mL, with reduced conversions observed at dilute concentrations (i.e., C_Diol < 20 mg/mL). Kinetics studies demonstrate that the amination reaction is a second order reaction. The experimental exiting concentration of the starting material as a function of residence time was in reasonable agreement with reactor design models for first and second order reactions. This suggests that the experimental conditions in flow nearly approximate pseudo-first order reaction in laminar flow.