Flexible automation with compact NMR spectroscopy for continuous production of pharmaceuticals

Abstract

Modular plants using intensified continuous processes represent an appealing concept for the production of pharmaceuticals. It can improve quality, safety, sustainability, and profitability compared to batch processes; besides, it enables plug-and-produce reconfiguration for fast product changes. To facilitate this flexibility by real-time quality control, we developed a solution that can be adapted quickly to new processes and is based on a compact nuclear magnetic resonance (NMR) spectrometer. The NMR sensor is a benchtop device enhanced to the requirements of automated chemical production including robust evaluation of sensor data. Beyond monitoring the product quality, online NMR data was used in a new iterative optimization approach to maximize the plant profit and served as a reliable reference for the calibration of a near-infrared (NIR) spectrometer. The overall approach was demonstrated on a commercial-scale pilot plant using a metal-organic reaction with pharmaceutical relevance. Graphical abstract Electronic supplementary material The online version of this article (10.1007/s00216-019-01752-y) contains supplementary material, which is available to authorized users.

Heat on – Calibration of IR Spectroscopy at Process Conditions for Continuous Esterification

“…For a precise analysis an in situ inline ATR probe Fourier Transformation (FT) mid‐infrared spectrometer was integrated into the setup. In addition to the IR spectrometer further an online nuclear magnetic resonance (NMR) spectrometer was added in order to compare the reaction to the offline NMR measurements previously done and to test the possibility to calibrate the IR spectrometer using NMR techniques . The samples were drawn using an autosampler from which the samples were transferred to the NMR tubes with DMSO‐d6 for the autonomous NMR analysis which were cooled at –20 °C until measurement.…”

Current and future requirements to industrial analytical infrastructure—part 2: smart sensors

“…As an example, a case study was made of a given aromatic coupling reaction step (lithiation reaction). The project challenge was to integrate a commercially available low-field NMR spectrometer from a desktop application to the complete requirements of an industrial automation environment, including accurate interpretation of measurement data [6].…”

NMR spectroscopy goes mobile: Using NMR as process analytical technology at the fume hood

“…[23] The quantitative nature of NMR also has the advantage that other more common and inexpensive, but not inherently quantitative in-line techniques such as Flow-IR can be calibrated. [24] In our synthesis (see Scheme 1), benzyl chloride (1) was reacted with magnesium to form the Grignard reagent, benzyl magnesium chloride (2). Figure 3 shows an NMR waterfall plot of the reaction mixture over the time course of the reaction.…”

“…Although it may be some years before Benchtop NMR systems are routinely used by chemists in the fume hood or in chemical plants, the power of Benchtop NMR can be used to support more abundant process analytical tools, such as Flow-IR, which while being more commonplace, are more difficult to extract useful species-specific chemical information. [24] Figure 5 shows a typical IR spectrum of the contents of the Grignard reaction vessel. It is clearly a more complex and overlapped spectrum than the low-field NMR spectrum (Figure 3), and there are no discernable peaks with baseline resolution.…”