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Dispersion of a saturated gas in a supersaturated solution has been previously reported to promote nucleation rates during batch crystallization, leading to the exploration of this technique as a cost-effective method to control crystal size distributions. Despite the mechanisms are still unknown, it has been hypothesized that the presence of a flowing gas could promote variations in the flow pattern inside the crystallizer, leading to improved mass transfer and higher rates of secondary nucleation through an increased number of crystal collisions. In this work, we have constructed a lab-scale MSMPR crystallizer with self-induced gas dispersion to investigate the applicability of this technique in continuous crystallization. The effect of different gas hold-ups has been evaluated at high supersaturations and for two different suspension densities. Results show a very limited variation in the overall mass deposition rate, and reductions in the mean FBRM chord length not exceeding 5 μm for the highest investigated gas hold-up (12%). Studying the effect of impeller speed under the same conditions, we found that an increased mixing intensity has a similar impact as gas dispersion, with a mean chord length reduction of 4 μm when the impeller speed was increased from 800 to 950 rpm. These results suggest that the promotion of nucleation kinetics with gas dispersion is limited to systems where crystallization kinetics can be significantly affected by mixing, and demonstrate a limited applicability for crystal size distribution control in continuous MSMPR crystallizers.

A flow setup for base liberation of 3-(N,N-dimethylamino)propyl chloride hydrochloride and solvent-free separation of the resulting free base has been developed. Production in flow profits from an on-demand approach, useful for labile aminoalkyl halides. The requirement for obtaining a dry product has been fulfilled by the simple use of a saturated NaOH solution, followed by isolation of the liquid phases by gravimetric separation. The flow setup has an E factor reduction of nearly 50%, and a distillation step has been avoided. The method exemplifies how flow chemistry can be exploited to simplify, improve, and optimize manufacturing processes.

A mathematical model describing the separation of enantiomers by simultaneous preferential crystallization in a coupled crystallizer configuration is developed. The model was validated against experimental data for a chemical model compound, the conglomerate forming system of asparagine monohydrate in water. The kinetic parameters required were taken from available literature sources and simulations compared to experimental data. Simulations were found to be in good agreement with experimental data. Additional model simulations suggest that the separation process can be improved by increasing the mean residence time of the liquid phase in the crystallizers, and the mass of seeds supplied. Reducing the size of seed crystals will also lead to an improved separation. The model can also be used to simulate the performance of the crystallization process for a racemic compound forming system. The racemic compound and the pure enantiomer can be separated simultaneously in each crystallizer, having sufficient enr...

A reactor setup consisting of two reactors in series has been implemented for a full-scale, heterogeneous Grignard alkylation. Solutions pass from a small filter reactor into a static mixer reactor with multiple side entries, thus combining continuous stirred tank reactor (CSTR) and plug flow reactor (PFR) technologies. Through the use of the reactor train in combination with in-line NIR analysis, on scale a 35% reduction in solvent volume was realized, and the formation of a key impurity was suppressed. The mini-reactor solution achieved many of the economic advantages attributed to microreactor technology, while avoiding the difficulties associated with handling of solids in microreactors.

The experimental realization of a continuous preferential crystallization process, consisting of two mixed-flow crystallizers coupled via crystal-free liquid exchange streams and with only the liquid phases operating continuously, is addressed. Experiments in triplicate, using the conglomerate-forming system of dl-asparagine monohydrate in water, were conducted, and the achievement of nearly racemic composition of the liquid phase in the crystallizers was verified. An experiment was also carried out using seed crystals of a smaller average particle size than used in the reference experiments. Successful enantioseparation by crystal growth, with the repeatability being within ±10% deviation, was obtained. However, slow crystal growth, due to a low surface integration rate, led to a negligible consumption of the desired enantiomer added in the feed solution, resulting in low productivities. Productivities, yields, and purities of solid products were influenced by the morphological differences in the seed cr...

Inline near-infrared (NIR) spectroscopy has been used to monitor a continuous synthesis of an active pharmaceutical ingredient (API) intermediate by a Grignard alkylation reaction. The reaction between a ketone substrate and allylmagnesium chloride may form significant impurities with excess feeding of the Grignard reagent beyond the stoichiometric ratio. On the other hand, limiting this reagent would imply a loss in yield. Therefore, accurate dosing of the two reactants is essential. A feedforward–feedback control loop was conceived in order to maintain the reaction as closely as possible to the stoichiometric ratio, leading the path to full process automation. The feedback control loop relies on NIR transmission measurements performed in a flow cell where, in contrast to labor-intensive offline HPLC analytical methods, the whole reaction product can be scanned in real time without sample dilution. A robust PLS (projection to latent structures) model was developed with a satisfactory standard error of prediction, providing quantification of the ketone substrate in solutions with a high variability of the major solution component - the alkoxide product. In addition, model performance supervision tools such as the spectral residuals or simple plots of pretreated spectra can assist in the identification of spectral outliers, which in this case could be related to Grignard reagent excess. If the sampling time of the NIR instrument is short enough, manipulating the inputs to the reactor may be used to obtain information about its dynamic behavior. This information is very useful for process control design, assessment of analytical tools and definition of sampling times. In this work, a systematic procedure for chemometric model building is followed, after which a discussion is made on some of the potential applications that can be found when exploiting the fast and rich information provided by NIR spectroscopy.

The applicability of four different heterogeneous palladium catalysts has been evaluated for the Buchwald–Hartwig amination reaction between p-bromotoluene and piperazine in the presence of the base NaO-t-Bu. The catalyst that provided the highest selectivity toward the desired amination reaction was found to be a polymer-supported palladium dichloride/triphenylphosphine catalyst. Experimental investigations of the catalyst in a reactor setup showed that the undesired reduction reaction of the aryl halide was dominant when the catalyst was reused and washed in solvent prior to reaction and when additional reactants were added to an already reacted reaction mixture. A significant washout of triphenylphosphine and palladium from the catalyst was also identified during the course of reaction and separation.

The Buchwald−Hartwig amination reaction between p-bromotoluene and piperazine in the presence of the homogeneous catalytic system Pd(dba)2/(±)-BINAP and the base NaO-t-Bu was investigated in two different classes of solvents: aprotic, nonpolar and aprotic, polar. The reaction was carried out using microwaves as the heating source, and it was found that the product distribution was strongly dependent on the class of the solvent. Based on the experimental results the selectivity towards the desired monosubstituted aryl piperazine was calculated, and it was found that the most appropriate solvent for the Buchwald−Hartwig amination reaction under the conditions applied was m-xylene.