Solid–liquid slurries are
vital and increasingly prevalent
in the pharmaceutical and chemical industries. Despite the importance
of these heterogeneous systems, process control and optimization are
fundamentally hindered by a lack of compatible real-time analytical
techniques. We present herein an online HPLC monitoring platform enabling
access to real-time compositional information on slurries. We demonstrate
the system by investigating the heterogeneous synthesis reaction of
tetrabenazine. Furthermore, we integrated our online HPLC platform
with the orthogonal monitoring techniques of a pH probe and a microscopic
imaging probe to provide additional mechanistic insight. These combined
insights enable the optimization of tetrabenazine synthesis in terms
of reaction time, byproduct formation, and diastereomeric purity of
the final product.
Automated chemical synthesizers have become more common in recent years but struggle to apply rigid procedures to broad substrate scopes. We have developed an adaptive auto‐synthesizer that uses online HPLC and FTIR measurements to adapt to the changing reactivities of different substrates, allowing precise control of reaction conditions. To do so, we designed a flexibly‐timed procedure consisting of specific actions performed by our platform when specific reaction‐monitoring checkpoints are met. Online HPLC allowed our system to autonomously separate, label and quantify most reaction components, with orthogonal FTIR enabling non‐UV active species to be additionally tracked. We tested our platform with CDI‐mediated multistep amidation reactions using a variety of different acid and amine substrates. To demonstrate the high reproducibility and control afforded by our system, we determined the relative rates of both acid activation and subsequent amidation, providing insight into substrate reactivities and the reaction mechanism.
N-Oxide incorporation into thiazole-containing conjugated materials can have substantial effects on both the electronic and physical properties. A notably strong non-covalent S–O interaction is observed between the N-oxide and neighbouring sulfur.
Kinetic investigations can provide critical mechanistic information for the optimization of the reaction parameters and reaction development. Modern kinetic analyses such as RPKA and VTNA provide many advantages over traditional initial rate methods and are especially powerful when coupled with reaction monitoring technologies. While these are robust analytical methods, the lack of careful observation and optimization can lead to misinterpretation of the data. In this Perspective, we highlight some commonly overlooked considerations in kinetic studies based on our experiences and present a general guide to proper optimization of reactions and analytics prior to acquiring kinetic data.
Current PAT tools struggle to provide real time solid-phase composition data for crystallizations. HPLC offers a variety of benefits over other solution-phase PATs and can be used to infer solid-phase...
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