Towards Automatic, Green Solvent System Standardization Method Development by Combining Robotics, Reference Analysis, and Spectroscopy

Standardized solvent mixtures, which are necessary for reproducible and scalable reactions, are prepared with precise measurements and techniques. To ensure accurate volumes and concentrations, analysts use Class A calibrated glassware or gravimetric methods to dilute stock reagents. Several analytical techniques are used to ensure standardization of these solvent mixtures. Volumetric titrations (acid–base, redox, etc.) are used to determine exact concentrations of reagent solutions, and Karl Fischer titration targets water content in solvents down to ppm levels. Physical property checks like refractive index and density measurements confirm a solvent’s identity and purity by comparing to known standards, while chromatography (HPLC/GC) or spectroscopy (IR/UV) may also be employed to detect impurities. Most of these reference assays require significant expertise, time, and consumables.

In this paper, we demonstrate a modular, automated pathway for the preparation of laboratory scale (scalable from 75 mL up to 250 mL) solvent mixtures; illustrated with 1-butanol and isopropyl acetate and their associated moisture values. The moisture values ranging from 50 to 150 ppm are automatically determined in triplicate by KF titration and then linked to NIR spectral data. The linked data is then used to create models for the concentration of both 1-butanol and isopropyl acetate, as well as the moisture contaminant. We then show independent validation of the models and explore the impact of model transfer between spectrometers on analytical performance.

The automatic preparation of the series allows scientists to build and test solvent systems with minimal manual labor, while the models developed for NIR allow the preparation and analysis of solvent mixtures without the use of toxic reagents.