The optimization of multistep chemical syntheses is critical for the rapid development of new pharmaceuticals. However, concatenating individually optimized reactions can lead to inefficient ...multistep syntheses, owing to chemical interdependencies between the steps. Herein, we develop an automated continuous flow platform for the simultaneous optimization of telescoped reactions. Our approach is applied to a Heck cyclization‐deprotection reaction sequence, used in the synthesis of a precursor for 1‐methyltetrahydroisoquinoline C5 functionalization. A simple method for multipoint sampling with a single online HPLC instrument was designed, enabling accurate quantification of each reaction, and an in‐depth understanding of the reaction pathways. Notably, integration of Bayesian optimization techniques identified an 81 % overall yield in just 14 h, and revealed a favorable competing pathway for formation of the desired product.
An autonomous continuous flow platform for the rapid development of multistep synthetic pathways is reported. New multipoint sampling and Bayesian optimization techniques were combined, enabling simultaneous identification of optimum reaction conditions within a pharmaceutical process. The short optimization times achieved are promising for development of telescoped reactions in the future.
An automated continuous flow reactor system equipped with inline analysis, was developed and applied in the self-optimisation of a nanoparticle catalysed reaction. The system was used to optimise the ...experimental conditions of a gold nanoparticle catalysed 4-nitrophenol reduction reaction, towards maximum conversion in under 2.5 hours. The data obtained from this optimisation was then used to generate a kinetic model, allowing us to predict the outcome of the reaction under different conditions. By combining continuous flow nanoparticle synthesis with this approach, the development timeline for these emerging catalysts could be significantly accelerated.
An automated continuous flow reactor system for the optimisation of nanoparticle catalysed reactions, demonstrated through the optimisation of a gold nanoparticle catalysed nitrophenol reduction reaction.
For the discovery of new candidate molecules in the pharmaceutical industry, library synthesis is a critical step, in which library size, diversity, and time to synthesise are fundamental. In this ...work we propose stopped-flow synthesis as an intermediate alternative to traditional batch and flow chemistry approaches, suited for small molecule pharmaceutical discovery. This method exploits the advantages of both techniques enabling automated experimentation with access to high pressures and temperatures; flexibility of reaction times, with minimal use of reagents (μmol scale per reaction). In this study, we integrate a stopped-flow reactor into a high-throughput continuous platform designed for the synthesis of combinatory libraries with at-line reaction analysis. This approach allowed ∼900 reactions to be conducted in an accelerated timeframe (192 hours). The stopped flow approach used ∼10% of the reactants and solvents compared to a fully continuous approach. This methodology demonstrates a significantly improved synthesis success rate of smaller libraries by simplifying the implementation of cross-reaction optimisation strategies. The experimental datasets were used to train a feed-forward neural network (FFNN) model providing a framework to guide further experiments, which showed good model predictability and success when tested against an external set with fewer experiments. As a result, this work demonstrates that combining experimental automation with machine learning strategies can deliver optimised analyses and enhanced predictions, enabling more efficient drug discovery investigations across the design, make, test and analysis (DMTA) cycle.
Combining experimental stopped flow automation with machine learning strategies can deliver optimised conditions and enhanced predictions, enabling more efficient design, make, test and analysis (DMTA) cycles.
In this study, changes in the adsorbed amount and surface structure of sodium hexametaphosphate (SHMP) were investigated for aluminum-doped TiO2 pigment undergoing milling. Relaxation NMR was ...utilized as a potential at-line technique to monitor the effect of milling on surface area and surface chemistry, while XPS was used primarily to consider the dispersant structure. Results showed that considerable amounts of weakly adsorbed SHMP could be removed with washing, and the level of dispersant removal increased with time, highlighting destructive effects of sustained high-energy milling. Nonetheless, there were no significant chemical changes to the dispersant, although increases to the bridging oxygen (BO) peak full width at half-maximum (FWHM) suggested some chemical degradation was occurring with excess milling. Relaxation NMR revealed a number of important features. Results with unmilled material indicated that dispersant adsorption could be tracked with pseudo-isotherms using the relative enhancement rate (R sp), where the R sp decreased with dispersant coverage, owing to partial blocking of the quadrupolar surface aluminum. Milled samples were also tracked, with very accurate calibrations of surface area possible from either T 1 or T 2 relaxation data for systems without dispersant. Behavior was considerably more complicated with SHMP, as there appeared to be an interplay between the dispersant surface coverage and relaxation enhancement from the surface aluminum. Nevertheless, findings highlight that relaxation NMR could be used as a real-time technique to monitor the extent of milling processes, so long as appropriate industrial calibrations can be achieved.
The use of automated continuous flow reactors is described, with real-time online Fourier transform infrared spectroscopy (FT-IR) analysis to enable rapid optimization of reaction yield using a ...self-optimizing feedback algorithm. This technique has been applied to the solvent-free methylation of 1-pentanol with dimethyl carbonate using a γ-alumina catalyst. Calibration of the FT-IR signal was performed using gas chromatography to enable quantification of yield over a wide variety of flow rates and temperatures. The use of FT-IR as a real-time analytical technique resulted in an order of magnitude reduction in the time and materials required compared to previous studies. This permitted a wide exploration of the parameter space to provide process understanding and validation of the optimization algorithms.
Today, the generation of kinetic models is still seen as a resource intensive and specialised activity. We report an efficient method of generating reaction profiles from transient flows using a ...state-of-the-art continuous-flow platform. Experimental data for multistep aromatic nucleophilic substitution reactions are collected from an automated linear gradient flow ramp with online HPLC at the reactor outlet. Using this approach, we generated 16 profiles, at 3 different inlet concentrations and 4 temperatures, in less than 3 hours run time. The kinetic parameters, 4 rate constants and 4 activation energies were fitted with less than 4% uncertainty. We derived an expression for the error in the observed rate constants due to dispersion and showed that such error is 5% or lower. The large range of operational conditions prevented the need to isolate individual reaction steps. Our approach enables early identification of the sensitivity of product quality to parameter changes and early use of unit operation models to identify optimal process-equipment combinations
, greatly reducing scale up risks.
Hands‐free optimization: A combination of an automated flow reactor, online analysis, and a control algorithm leads to efficient optimization of reactions to a given product without the need for ...human intervention.
Understanding complex reaction systems is critical in chemistry. While synthetic methods for selective formation of products are sought after, oftentimes it is the full reaction signature, i.e., ...complete profile of products/side-products, that informs mechanistic rationale and accelerates discovery chemistry. Here, we report a methodology using high-throughput experimentation and multivariate data analysis to examine the full signature of one of the most complicated chemical reactions catalyzed by palladium known in the chemical literature. A model Pd-catalyzed reaction was selected involving functionalization of 2-bromo-N-phenylbenzamide and multiple bond activation pathways. Principal component analysis, correspondence analysis and heatmaps with hierarchical clustering reveal the factors contributing to the variance in product distributions and show associations between solvents and reaction products. Using robust data from experiments performed with eight solvents, for four different reaction times at five different temperatures, we correlate side-products to a major dominant N-phenyl phenanthridinone product, and many other side products.
In recent years a number of countries have extended prescribing rights to pharmacists in a variety of formats. The latter includes independent prescribing, which is a developing area of practice for ...pharmacists in secondary care. Potential opportunities presented by wide scale implementation of pharmacist prescribing in secondary care include improved prescribing safety, more efficient pharmacist medication reviews, increased scope of practice with greater pharmacist integration into acute patient care pathways and enhanced professional or job satisfaction. However, notable challenges remain and these need to be acknowledged and addressed if a pharmacist prescribing is to develop sufficiently within developing healthcare systems. These barriers can be broadly categorised as lack of support (financial and time resources), medical staff acceptance and the pharmacy profession itself (adoption, implementation strategy, research resources, second pharmacist clinical check). Larger multicentre studies that investigate the contribution of hospital-based pharmacist prescribers to medicines optimisation and patient-related outcomes are still needed. Furthermore, a strategic approach from the pharmacy profession and leadership is required to ensure that pharmacist prescribers are fully integrated into future healthcare service and workforce strategies.
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