The robustness of the flash thermal racemization of optically active 1-phenylethylamine over Pd/γ-AlO was studied by applying split-plot design-of-experiments (DoE), where the effects of temperature, flow rate, and concentration (3-factors) on the e.e. and selectivity (2-responses) were examined and quantified. The same effects were also interrogated using multivariate ramps in transient flow to produce response surfaces for the reaction space. The same set of optimal conditions for the process was identified by both approaches, and the same relationships between the variables were observed: while the extent of racemization (e.e.) can be directly correlated to temperature, a more complex relationship between temperature and flow rate on the selectivity was uncovered.

Photochemical transformations have garnered renewed interest over the past decade for their ability to enable unique reactions under mild conditions. However, scaling up such processes, particularly in multiphase systems (e.g., gas-liquid), remains challenging. Previously, we demonstrated the potential of the photochemical rotor-stator spinning disc reactor (pRS-SDR) for scaling the photooxidation of α-terpinene to ascaridole, though the system was limited by the light source, resulting in suboptimal operation in a photon-limited regime. In this work, we unlock the full potential of the pRS-SDR by integrating a high-powered light source (up to 652 W optical output) specifically designed for the reactor. The results show that the high gas-liquid mass transfer rates achievable in the pRS-SDR allow for significant productivity improvements under high irradiance (16.3 kg day at 92% α-terpinene conversion and 2.52 W cm in a 27 mL irradiated volume), representing an order of magnitude increase compared to our previous study. However, the photooxidation of β-citronellol exhibited notable limitations, highlighting the importance of selecting appropriate model reactions when evaluating intensified photochemical reactors.

We report the development and optimization of a scalable flow process for metallaphotoredox (Ir/Ni) C-O coupling, a mild and efficient approach for forming alkyl-aryl ethers, a common motif in medicinal and process chemistry settings. Time-resolved infrared spectroscopy (TRIR) highlighted the amine as the major quencher of the photocatalyst triplet excited state, along with the formation of an Ir(II) species that, in the presence of the Ni cocatalyst, has its lifetime shortened, suggesting reductive quenching of Ir(III)*, followed by reoxidation facilitated by the Ni cocatalyst. TRIR and batch reaction screening was used to develop conditions transferrable to flow, and many processing benefits of performing the reaction in flow were then demonstrated using a simple to construct/operate, small-footprint FEP coil flow reactor, including short (<10 min) space times and reduced catalyst loadings (down to 0.1 mol % Ir, 1 mol % Ni) while retaining good yield/conversion. Scalability was demonstrated by increasing the length or diameter of the FEP coil flow reactor tubing, however, due to suspected mass transfer/mixing limitations, the yield decreased upon scale-up in some cases. Therefore, we applied a modified version of our previously reported photochemical Taylor Vortex Flow Reactor (PhotoVortex), where Taylor vortices and a short-irradiated path length allow photochemical reactions to be performed efficiently via excellent mixing. In a small PhotoVortex (8 mL irradiated volume), we have demonstrated projected productivities around 1 kg day and >10 kg day in a large PhotoVortex (185 mL irradiated volume) with good product yields (>90%) and low catalyst loadings (0.1 to 0.5 mol % of [Ir{dF(CF)ppy}dtbbpy]PF), enabled by excellent mixing ensuring sufficient mass transfer between short-lived photoexcited and other transient species.

The choice of method for drug amorphization depends on various factors, including the physicochemical properties of the active pharmaceutical ingredients, the desired formulation, and scalability requirements. It is often important to consider a combination of methods or the use of excipients to further enhance the stability and performance of the amorphous drug. This study presents a comparison of techniques including melt quench, hot melt extrusion, solvent evaporation, ball milling, and lyophilization used for the preparation of amorphous ibrutinib. The amorphous material was thoroughly investigated using numerous techniques to examine changes in the physicochemical properties, stability, and degradation pathways of the drug product. During the examination, the temperature was discovered to be a key parameter for controlling the solubility and permeability of ibrutinib, which is influenced by the presence of the degradation product. We found that this degradation product could potentially polymerize and increase the molecular weight. The quantity, polymerization rate, and structure of the impurity can be regulated by the temperature variation during the amorphization processes. Additionally, the molecular weight of the degradation product was determined using Zimm plot analysis, which appeared for the first time in the literature for molecules of this category.

Continuous crystallization has gained substantial interest due to its high product reproducibility, high labor efficiency, and low capital and production costs. Continuous seeding is preferable and often even required in the application of pharmaceuticals, which presents a bottleneck in continuous crystallization. This work proposes to apply ultrasound for continuous in situ seeding in the continuous reactive crystallization of an aromatic amine. Flow crystallization experiments with both ultrasound and conventionally prepared seeds were conducted. It was found that sonication initiated nucleation and continuously produced crystals in a stable manner. The nucleation rate could be controlled by adjusting the sonication power, highlighting the advantages of the sonicated seed generation strategy. Experiments under different flow conditions demonstrated that a higher flow rate combined with an appropriate sonication power was favorable for robust particle quality, reduced likelihood of clogging, and better reproducibility. Compared with the conventional addition of seed crystals, sonication-induced crystallization achieved higher yields and produced products with a narrow and unimodal size distribution. All sonicated experiments exhibited high robustness, indicating the feasibility and reliability of this method as a replacement for conventional seeding techniques in the continuous reactive crystallization of the studied compound. In summary, using ultrasound for continuous in situ seeding of the aromatic amine offers unique advantages in process robustness and product quality control, providing a promising strategy for continuous crystallization of similar systems.

Control of powder properties is crucial for industrial processes across the food, pharmaceutical, agriculture, and mineral processing industries, and granulation is an important tool for providing agglomerated particles with controllable properties. However, existing granulation processes are not readily integrated with other processing steps and are not appropriate for some types of materials. Adding resonant acoustic-based granulation to the toolkit has the potential to widen the achievable parameter space and, importantly, integrate granulation into chemistry and blending operations that are already being performed on the RAM platform, resulting in process intensification. Here, we demonstrate the formation of granules with particle sizes of ca. 1-3 mm in LabRAM II and examine the formation mechanisms in the context of common wet granulation processes. The RAM granulation process followed here involves first forming a large "doughball" agglomerate and then driving its breakup by evaporating the solvent, while impacting the doughball against the container walls. We show that this process is similar to the destructive nucleation model for high-shear wet granulation with the solvent evaporation in our case leading to the decrease in the liquid saturation of the doughball, a corresponding decrease in its tensile strength, and the acceleration in the RAM establishing the impact pressure when the doughball contacts the walls. This work provides a foundation for granulation process design with a resonant acoustic mixer and, through its link to existing granulation mechanisms, provides a path to a deeper understanding of the process.

The development of sustainable trifluoromethylations of enamides is of great interest to the pharmaceutical industry. Herein, we demonstrate a sustainable direct electrochemical trifluoromethylation method in a microflow cell, using Langlois reagent, without the need for a supporting electrolyte, oxidants, or any additive under mild conditions. This method can be applied to various substrates with a yield of up to 84%. Additionally, the batch process yielded significantly less (22%), highlighting the microflow cell's efficiency.

This report presents a rapid, ecofriendly technique for the formation of commonly used -bromo and -iodinating reagents by reacting readily available -chloro derivatives with inorganic bromide and iodide salts. All reagents were easily handled, commercially available, and bench stable. This strategy illustrates the expeditious formation of these halogenating reagents in multigram scale in high-yields and purity with an operationally straightforward recrystallization. The mechanistic details suggest an in situ generation of an interhalogen species.

A catalyst-in-bag system facilitates the recovery and recycling of chiral dirhodium carboxylate catalysts used for enantioselective, intermolecular cyclopropanation. The catalyst-in-bag system incorporates a soluble enantioselective dirhodium complex catalyst within a reusable, commercial dialysis membrane. Dirhodium catalysts of different sizes are examined, and two catalysts with molecular weights above 2400 Da are well-retained by the membrane. The catalyst Rh(-TPPTTL) [TPPTTL = (1,3-dioxo-4,5,6,7-tetraphenylisoindolin-2-yl)-3,3-dimethylbutanoate] is explored in enantioselective cyclopropanation reactions under a variety of conditions. The Rh(-TPPTTL) catalyst, when contained in the catalyst-in-bag system, provides high yields and enantioselectivities, akin to the homogeneous catalyst in solution, with negligible rhodium permeation out of the bag over five catalytic cycles. The catalyst-in-bag approach facilitates recovery of the expensive rhodium metal and ligand, with only ppm level Rh detected in the reaction products. The flexible and expandable catalyst-in-bag system can be accommodated in vessels of different shapes and dimensions.

The knowledge of the reactivity of -nitrosamines (NSAs) with common organic reagents in synthesis is essential in determining their presence in pharmaceutical products, if formed and retained during synthesis. In this study, we carried out a comprehensive survey of the Reaxys database for all reactions in which the NSA functional group is consumed. Very different reactivities for different classes of NSAs, e.g., ,-dialkylnitrosamines and ,-diphenylnitrosamine, were identified, suggesting substrates which should be included in any future reactivity screening. A classification of NSAs based on their reactivities, and corresponding reagents and transformations, was drawn up based on the data. Furthermore, the survey identified missing areas in the reported reactivities of NSAs with different reagents. This led to an experimental reactivity screening of 8 commercial NSAs with common synthetic reagents in the Mirabilis tool for purge assessment. The results showed NaSO in 1 M aqueous NaOH at 50 °C to be highly effective at destroying NSAs without damaging other organic compounds.

1-1-Hydroxyquinolin-4-ones represent a broad class of biologically active heterocycles having an exocyclic N,O motif. Electrosynthesis offers direct, highly selective, and sustainable access to 1-hydroxyquinol-4-ones by nitro reduction. A versatile synthetic route starting from easily accessible 2-nitrobenzoic acids was established. The broad applicability of this protocol was demonstrated on 26 examples with up to 93% yield, highlighted by the naturally occurring antibiotics Aurachin C and HQNO. The practicability and technical relevance were underlined by multigram scale electrolysis.

Mixing is one of the most important nonchemical considerations in the design of scalable processes. While noninvasive imaging approaches to deliver a quantifiable understanding of mixing dynamics are well-known, the use of imaging to verify computational fluid dynamics (CFD) models remains in its infancy. Herein, we use colorimetric reactions and our kinetic imaging software, , to explore (i) the correlation of imaging kinetics with pH probe measurements, (ii) feed point sensitivity for Villermaux-Dushman-type competing parallel reactions, and (iii) the use of experimental imaging kinetic data to qualitatively assess CFD models. We report further evidence that the influences of the stirring rate, baffle presence, and feed position on mixing in a tank reactor can be informatively captured with a camcorder and help experimentally verify CFD models. Overall, this work advances scarce little precedent in demonstrating the use of computer vision to verify CFD models of fluid flow in tank reactors.

Perylene diimides (PDI) have an extraordinary ability to activate both energy and electron transfer processes upon light excitation; however, their extremely low solubility has hindered their wide use as photocatalysts. Here, we show that the combination of solid-supported PDIs with continuous flow photochemistry offers a promising strategy for process intensification and a scalable platform for heterogeneous photocatalysis. The photocatalyst immobilized onto glass beads is highly efficient, easy to separate, and extremely reusable, with a broad synthetic application range. Using the photo-oxidation of -butyl sulfide as a benchmark reaction, we demonstrate that immobilized PDI are highly active, outperforming reported homogeneous photosensitizers, and capable of extensive reuse (turnover number (TON) >57,000 over 2 months). Transferring the process from batch to flow results in a 10-fold reduction in irradiation time and an increase in the space-time yield by a factor of 33 (40 vs 1338 mmol h L batch vs flow). What is more, the same catalyst sample can be used for the preparation of a range of sulfoxides, the aza-Henry reaction between nitromethane and N-Ar tetrahydroisoquinolines, and the photo-oxidation of furfural with high catalytic activity. Overall, our work combines the remarkable photocatalytic properties of PDI with inert, easy-to-handle glass beads, producing hybrid materials that are reusable and can be adapted for performing heterogeneous photocatalysis in a range of scalable photochemical reactors.

A continuous flow approach for the aerobic photo-oxidation of benzylic substrates to ketone and aldehyde products is presented. The resulting process exploits UV-A LEDs (375 nm) in combination with a Corning AFR reactor that ensures effective gas-liquid mixing and leads to short residence times of 1 min. A variety of benzylic substrates are converted to their corresponding carbonyl products, and scalability is demonstrated to produce multigram quantities of products within a few hours. Overall, this continuous flow approach offers several improvements over alternative oxidation methods due to the combined use of air as an oxidant and SAS (sodium anthraquinone-2 sulfonate) as a water-soluble photocatalyst. The use of greener and safer conditions together with process intensification principles renders this flow approach attractive for further industrial applications.

Herein, we describe two practical approaches to synthesize ()-(+)-1,2-epoxy-5-hexene from inexpensive and readily available raw materials and reagents. The first approach is a two-step sequence, involving an epoxidation with -chloroperoxybenzoic acid (mCPBA) and a chiral resolution with (salen)Co(II), producing ()-(+)-1,2-epoxy-5-hexene in 24-30% overall yield. The second approach utilizes readily available ()-epichlorohydrin as the starting material and features an epoxide ring-opening reaction with allylMgCl and the NaOH-mediated ring closure reaction. Development of this two-step process affords -(+)-1,2-epoxy-5-hexene in overall isolated yields of 55-60% with an exceptional purity profile. Both approaches have been successfully demonstrated on 100-200 g scales.

The fourth industrial revolution is gaining momentum in the pharmaceutical industry. However, particulate processes and suspension handling remain big challenges for automation and the implementation of real-time particle size analysis. Moreover, the development of antisolvent crystallization processes is often limited by the associated time-intensive experimental screenings. This work demonstrates a fully automated modular crystallization platform that overcomes these bottlenecks. The system combines automated crystallization, sample preparation, and immediate crystal size analysis via online laser diffraction (LD) and provides a technology for rapidly screening crystallization process parameters and crystallizer design spaces with minimal experimental effort. During the LD measurements, to avoid multiple scattering events, crystal suspension samples are diluted automatically. Multiple software tools, i.e., LabVIEW, Python, and PharmaMV, and logic algorithms are integrated in the platform to facilitate automated control of all the sensors and equipment, enabling fully automated operation. A customized graphical user interface is provided to operate the crystallization platform automatically and to visualize the measured crystal size and the crystal size distribution of the suspension. Antisolvent crystallization of ibuprofen, with ethanol as solvent and water with Soluplus (an additive) as antisolvent, is used as a case study. The platform is demonstrated for antisolvent crystallization of small ibuprofen crystals in a confined impinging jet crystallizer, performing automated preplanned user-defined experiments with online LD analysis.

The development of a continuous flow reactor for stereospecific glycosylation reactions with deoxy sugars is described. This apparatus that permits optimizing the selectivity of glycosylation reactions based on the stability of the activated intermediate is described. By coupling a flow apparatus with HPLC analysis, we can optimize the yield of TsCl-mediated -linked deoxy sugar construction in a matter of hours. In all cases, results from continuous flow processing translate into improved results in batch-scale reactions, as demonstrated by competition experiments. This is the result of carrying out optimization to identify the ideal temperature for the reaction of the activated intermediate, as opposed to the initial activation conditions. Such an approach allows for the rapid development of highly selective glycosylation reactions in cases in which classical neighboring group participation is not possible.

A packed reactor bed incorporating a polymer-supported isothiourea HyperBTM catalyst derivative has been used to promote the enantioselective synthesis of a range of heterocyclic products derived from α-azol-2-ylacetophenones and -acetamides combined with alkyl, aryl, and heterocyclic α,β-unsaturated homoanhydrides in continuous flow via an α,β-unsaturated acyl-ammonium intermediate. The products are generated in good to excellent yields and generally in excellent enantiopurity (up to 97:3 er). Scale-up is demonstrated on a 15 mmol scale, giving the heterocyclic product in 68% overall yield with 98:2 er after recrystallization.

A robust supported catalyst that is made up of copper nanoparticles on Celite has been successfully prepared for the selective transfer hydrogenation of aromatic nitrobenzenes to anilines under continuous flow. The method is efficient and environmentally benign thanks to the absence of hydrogen gas and precious metals. Long-term stability studies show that the catalytic system is able to achieve very high nitrobenzene conversion (>99%) when working for up to 145 h. The versatility of the transfer hydrogenation system has been tested using representative examples of nitroarenes, with moderate-to-excellent yields being obtained. The packed bed reactor (PBR) permits the use of a setup that can provide products via simple isolation by SPE without the need for further purification. The recovery and reuse of either EG or the ion-exchange resin leads to consistent waste reduction; therefore, E-factor distribution analysis has highlighted the environmental efficiency of this synthetic protocol.

C-Glycosyl compounds (C-glycosides) are a class of saccharide derivatives with improved stability over their O-linked counterparts. This paper reports the synthesis of several -2-(C-glycosyl)acetates via a tandem Wittig-Michael reaction from pyranoses (cyclic hemiacetals) using continuous flow processing, which gave improvements compared to reactions conducted in round-bottom flasks. Products were isolated in yields of >60% from reactions of benzyl-protected xylopyranoses, glucopyranoses, and galactopyranoses at higher temperatures and pressures, which were superior to yields from batch procedures. A two-step procedure involving the Wittig reaction followed by Michael reaction (intramolecular oxa-Michael) of the unsaturated ester obtained in the presence of DBU was developed. Reactions of protected mannopyranose gave low yields in corresponding reactions in flow due to competing C-2 epimerization.

A simple and benign continuous flow oxidation protocol for the selective conversion of primary and secondary alcohols into their respective aldehyde and ketone products is reported. This approach makes use of catalytic amounts of TEMPO in combination with sodium bromide and sodium hypochlorite in a biphasic solvent system. A variety of substrates are tolerated including those containing heterocycles based on potentially sensitive nitrogen and sulfur moieties. The flow approach can be coupled with inline reactive extraction by formation of the carbonyl-bisulfite adduct which aids in separation of remaining substrate or other impurities. Process robustness is evaluated for the preparation of phenylpropanal at decagram scale, a trifluoromethylated oxazole building block as well as a late-stage intermediate for the anti-HIV drug maraviroc which demonstrates the potential value of this continuous oxidation method.