Roderick C. Jones

This study presents an investigation of hydrogenation reactions in a Corning Advanced-Flow Reactor glass lab scale reactor, designed to facilitate mixing in multiphasic reactions. Using ethyl cinnamate as a model substrate, systematic experiments were performed to understand the reactor potential, reaction performance, and practical operational limits using a Box-Behnken Design of Experiments approach, evaluating the effects of temperature, backpressure, and hydrogen gas flow rate. Under our tested conditions, temperature is the main statistically significant factor affecting yield. Additionally, solvent and solvent mixtures were screened with an aim to understand the minimisation of palladium deposition, with methanol–water identified as the optimal medium for reducing catalyst fouling without compromising yield. Substrate scope extension to alkenes and nitro-compounds showcased the versatility and robustness of consistently achieving near-quantitative conversions except for sterically hindered systems. These results establish the Corning Advanced-Flow Reactor as a fast, scalable, efficient, and sustainable platform for fast hydrogenation, advancing the scope of continuous-flow methodologies for chemical synthesis while addressing key challenges of catalyst blockages and process scale-up. Impact of Flow Chemistry The present research demonstrates the transformative impact of flow chemistry on homogeneous Pd-catalysed continuous hydrogenation overcoming traditional batch limitations. Traditional batch hydrogenation suffers from poor H₂ mass transfer, inconsistent mixing, and heat management challenges, particularly with exothermic hydrogenations prone to runaway reactions. The Corning Advanced Flow Reactor (AFR) eliminates these limitations through its microchannel design, delivering 10–100 × enhanced heat/mass transfer vs. batch systems. The key advantages realized are: Enhanced Safety: No headspace H₂ accumulation thereby preventing thermal runaways. Scalability: Proven hydrodynamic validation from lab-to-production via numbering-up; eliminates batch geometric scale-up uncertainties. Precision: Residence time control, H₂ stoichiometry, and temperature gradients enables systematic optimization unattainable in batch. A batch equivalent would compromise safety, yield reproducibility, and commercial viability. This work establishes AFR as the scalableplatform for homogeneous hydrogenation directly translating lab discoveries into pharmaceuticals/fine chemicals manufacturing. In shortthis work would not be achievable in a batch reactor setup.

A continuously operated single-stage mixed suspension–mixed product removal (MSMPR) crystallizer was developed for the continuous cooling crystallization of 2-chloro-N-(4-methylphenyl)propanamide (CNMP) in toluene from 25 to 0 °C. The conversion of the previous batch to a continuous process was key to developing a methodology linking the synthesis and purification unit operations of CNMP and gave further insight in the development of continuous process trains for active pharmaceutical ingredient materials. By monitoring how parameters such as cooling and agitation rates influence particle size and the yield, two batch start-up strategies were compared. The second part of the study focused on developing and optimizing the continuous cooling crystallization of CNMP in the MSMPR crystallizer in relation to the yield by determining the effects of varying the residence time and the agitation rates. During the MSMPR operation, the plot of the focused beam reflectance measurement total counts versus time oscillates and reaches an unusual state of control. Despite the oscillations, the dissolved concentration was constant. The yield and production rate from the system were constant after two residence times, as supported by FTIR data. The overall productivity was higher at shorter residence times (τ), and a productivity of 69.51 g/h for τ = 20 min was achieved for the isolation of CNMP.

A lab-scale bubble column was investigated as an alternative means to achieve a low-temperature binary solvent swap of solutions containing pharmaceutical materials at atmospheric pressure, for batch and continuous configurations. The rate of solvent evaporation was predicted by first-principles vapor–liquid equilibrium (VLE) thermodynamic modeling and compared to experimentally achieved results. For batch configurations, evaporation rates of up to 5 g/min were achieved at gas flow rates up to 2.5 L/min (0.21 m/s superficial velocity) and temperatures up to 50 °C. This achieved 99 mol % purity of the desired solvent within three “put and take” evaporations from a 50:50 starting mixture. The evaporation rate profiles for the duration of the experiments were calculated, and the changing concentration profile was predicted within satisfactory error margins of <5%. Continuous process modeling explored a multistage equilibrium configuration and could predict the approach to attaining steady-state operation for various operating conditions. All rates of evaporation and resulting changes in solution concentration were measured, and direct comparison of model predictions fell within instrumentation error margins, as previously. This underlined the capability of the model to provide accurate representations of predicted evaporation rates and binary solution concentration changes during operation.

A bubble column was investigated as a method to achieve a desired and controllable rate of evaporation of a pharmaceutical solution. Applying a thermodynamic model to predict the rate of evaporation, all predicted values were observed to have accuracies within the bounds of instrumentation errors (<5% absolute). The developed model accounted for the measured effect of reduced vapor pressure, caused by the dissolved solids as a function of their concentration. A general method to obtain accurate measurement of this effect is introduced and applied, improving the accuracy of model predictions. Consistent and repeatable evaporation rates ranging from 0.7 to 6.9 g/min were achieved experimentally, and errors between predicted rates and observed ranged from 0.219% to 4.19% absolute. This demonstrates a controllable and flexible method for the evaporation of process streams which can be compared to harsher conventional methods such as boiling. The column was configured in a continuous mode and coupled to a downstream crystallizer (MSMPR). Using the column as a controllable concentrator, the concentration of a dilute feed stream of paracetamol in methanol was increased in a single equilibrium stage. The column demonstrated the ability to concentrate the solution in flow by 179%, delivering a flow of 2 ml/min of concentrated liquor to the MSMPR. The MSMPR achieved steady‐state of control, measured by offline dissolved concentration analysis and particle count by FBRM in situ, highlighting the applicablity of the column to perform reliably in a continuous tandem.

A novel process, sequential coupled‐batch diastereomeric crystallization is presented for the resolution of racemic mixtures. This strategy utilized a preferential crystallization of diastereomeric salt followed by sequential coupled diastereomeric salt resolution of racemic ibuprofen with the resolving agent (S)‐lysine utilizing a novel small scale pneumatic liquid exchange design to couple two batch crystallizers. Results were compared to conventional sequential resolution via seeded isothermal batch crystallization. Diastereomeric salt resolution was developed using the ternary phase diagram of the isolated (R)‐ibuprofen‐(S)‐lysine and (S)‐ibuprofen‐(S)‐lysine salts and optimized empirically with the aid of process analytical technology. Sequential coupled‐batch crystallization was found to be capable of increasing the yield of both salts while maintaining purity. This gave an increase in both the productivity and yield (20.5% for (S)‐ibuprofen‐(S)‐lysine) compared to the equivalent sequential batch (17.7% for (S)‐ibuprofen‐(S)‐lysine) crystallization methodology. Single crystals of the (S)‐ibuprofen‐(S)‐lysine were isolated, and its single crystal structure determined. © 2018 American Institute of Chemical Engineers AIChE J, 65: 604–616, 2019

Two independent samples of the title compound, alternatively 2-chloro-N-(4-methylphenyl)propanamide, C₁₀H₁₂ClNO,1, were studied using CuKα,1a, and MoKα,1b, radiation as part of a continuous crystallization study. The molecule crystallizes with disorder in the Cl/terminal methyl positions [occupancies for the major disorder component of 0.783 (2) in1aand and 0.768 (2) in1b] and exhibits N—C bond lengths of 1.3448 (19), 1.344 (2) Å, C=O bond lengths of 1.2233 (18) and 1.2245 (19) Å and an acetamide moiety C—N—C—C torsion angle of 179.00 (13), 178.97 (14) ° for1aand1b, respectively. In the crystal, chains along theaaxis are formedviaN—H...O hydrogen bonds between acetamide groups, as well as C—H...O interactions. These chains arrange themselves into parallel running stacks which display weak C—Cl...O=C halogen bonding as well as weak C—H...π interactions.