Novartis-MIT Center for Continuous Manufacturing

Combined cooling and antisolvent crystallization is a critical unit operation in pharmaceutical manufacturing, especially for heat-sensitive or poorly soluble active pharmaceutical ingredients. The model-based design of these systems relies on the accuracy of the underlying growth and nucleation kinetic parameters. Unlike temperature where these kinetic parameters are well-known to follow an Arrhenius relation, their dependency on solvent composition still remains unclear, especially in continuous mixed-suspension, mixed-product removal (MSMPR) systems. In this paper, we use population balance modeling coupled with nonlinear regression to estimate growth and nucleation parameters as a function of both temperature and solvent composition. As solvent composition increases from 44 vol % to 66 vol % solvent, both growth and nucleation rates were observed to decrease monotonically with their values reduced by almost one-third. It was also shown that, if the solvent dependency is ignored, the yield can be overp...

An automated, droplet-flow microfluidic system explores and optimizes Pd-catalyzed Suzuki-Miyaura cross-coupling reactions. A smart optimal DoE-based algorithm is implemented to increase the turnover number and yield of the catalytic system considering both discrete variables-palladacycle and ligand-and continuous variables-temperature, time, and loading-simultaneously. The use of feedback allows for experiments to be run with catalysts and under conditions more likely to produce an optimum; consequently complex reaction optimizations are completed within 96 experiments. Response surfaces predicting reaction performance near the optima are generated and validated. From the screening results, shared attributes of successful precatalysts are identified, leading to improved understanding of the influence of ligand selection upon transmetalation and oxidative addition in the reaction mechanism. Dialkylbiarylphosphine, trialkylphosphine, and bidentate ligands are assessed.

Antimicrobial drug resistance is a growing threat to global public health. Multidrug resistance among the 'ESKAPE' organisms - encompassing Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter spp. - is of particular concern because they are responsible for many serious infections in hospitals. Although some promising agents are in the pipeline, there is an urgent need for new antibiotic scaffolds. However, antibacterial researchers have struggled to identify new small molecules with meaningful cellular activity, especially those effective against multidrug-resistant Gram-negative pathogens. This difficulty ultimately stems from an incomplete understanding of efflux systems and compound permeation through bacterial membranes. This Opinion article describes findings from target-based and phenotypic screening efforts carried out at AstraZeneca over the past decade, discusses some of the subsequent chemistry challenges and concludes with a description of new approaches comprising a combination of computational modelling and advanced biological tools which may pave the way towards the discovery of new antibacterial agents.

The continuous nanofiltration and recycle of a ruthenium diphosphine/diamine catalyst for the asymmetric hydrogenation of α-tetralone is demonstrated in a small scale flow system. Batch experiments show that the catalyst can be recycled under hydrogen pressure. Subsequent transient packed bed experiments serve to characterize the reaction and inform the design of the recycle experiments. The total internal volume of the resulting system is ∼50 mL, making this pilot useful for testing catalyst recyclability via nanofiltration during the early stages of process development. The high-pressure catalyst recycle system is run with an automatic control system to respond to membrane flux decline during the course of operation and enable long duration runs. In 24 h, we achieved a turnover number approaching 5000 for ruthenium diphosphine/diamine catalyst used in the asymmetric hydrogenation of α-tetralone, demonstrating significant reuse of the catalyst since the substrate-to-catalyst ratio in the reactor approach...

The removal of carboxylic acid impurities from amide targets has been accomplished through crystallization featuring a complexing agent in solution. The interaction between the complexing agents and impurities was examined using isothermal titration calorimetry and the free energy of association obtained. From these data, the mechanism of solution association could be elucidated through the use of infrared spectroscopy, density functional theory calculations, and the judicious variation of solvent and complexing agent. Furthermore, the calculations employed were able to predict the free energy of association between the complexing agents and the impurity. This association energy was found to correlate with the improvement in purification that could be achieved by the addition of these complexing agents. Optimal complexing agent choice in a rationally selected crystallization solvent produced improvements in purity of 96%, greater than could be achieved by successive crystallizations. The applicability of ...

In this work, we demonstrated the purification of amoxicillin trihydrate (AMCT) by the formation of 4-hydroxyphenylglycine (4HPG)-coformer complex in solution. Without advanced knowledge of cocrystal formation of 4HPG, a workflow was established to choose the optimal coformer and the amount of coformer to add for a specific target/impurity system. Forty-seven compounds were chosen and screened due to their functional groups having the potential to form heterosynthons with the functional groups on 4HPG. Using solid-state grinding, eleven compounds were selected as coformers for separation experiments because they can form cocrystals with 4HPG but not AMCT. Four compounds, 2-picolinic acid, L-lysine, L-leucine, and L-isoleucine were shown to enhance AMCT purity the most. The purities of the AMCT crystals crystallized from solutions with a 1 : 10 4HPG : AMCT ratio and with these four compounds were significantly greater than that without the addition of coformer and greater than that obtained from a second crystallization from fresh solvent. By varying the coformer-to-4HPG ratio, we can correlate the purification results to the level of complexation in the solution. In addition, the proposed separation method has practical uses and can be applied to expensive products where low yield is unacceptable.

Crystallization processes can be batch or continuous. Potential advantages such as operating at steady state, small equipment size (relative to batch), and ability to recycle are encouraging the pharmaceutical industry to investigate continuous processes. In this work, a continuous cooling crystallization process for the immunosuppressant drug cyclosporine was developed. A multistage mixed suspension mixed product removal (MSMPR) crystallizer was employed which allowed simple analysis of kinetic parameters employing the population balance. Experimentally, the continuous crystallization system was able to operate without any clogging issues for more than four residence times. The experimental yield and purity of the crystals was determined as 71% and 96%, respectively (without recycle) and 87% and 94%, respectively (with recycle). In a batch cooling crystallization experiment, carried out under conditions similar to those of the continuous experiment without recycle, the experimental yield and purity of th...

Set it and forget it: The combination of feedback control and continuous-flow operations in microreactors (see picture) enables online and fully automated reaction optimization. A Heck reaction demonstrates the potential for rapid multivariable reaction optimization while requiring a minimal amount of material. Optimal conditions are quickly scaled-up by a factor of 50. Detailed facts of importance to specialist readers are published as "Supporting Information". Such documents are peer-reviewed, but not copy-edited or typeset. They are made available as submitted by the authors. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.