Chemical shift imaging with chemical gradients: one-shot analytical methods to determine pH-dependent and solvent-dependent physical properties of APIs Krzysztof Baj a , Sylvain Demanze b , Matthew Wallace c and Jonathan A. Iggo a a Department of Chemistry, University of Liverpool, United Kingdom, b Oncology R&D,AstraZeneca, United Kingdom, c School of Pharmacy, University of East Anglia, United Kingdom 1 H Chemical Shift Imaging with a chemical gradient (CSI-CG) provides an efficient, one-shot method for the determination of pKa. This paper will describe the extension of the method to mixed solvents to manage limited solubility of many APIs in water and to act as a physiological biomimicry and explores the extension of the method to 19 F – fluorine is often present in APIs – as the NMR reporter nucleus. Several pulse sequences for water suppression have been evaluated and automation routines developed to allow the use of sample changers for high throughput of data acquisition in an industrial setting. Water signals are suppressed using excitation sculpting while pre-saturation can be used to suppress a second solvent peak if required, Figure 1. Employing 19 F would streamline data processing of particularly complex analytes with a very crowded 1 H spectra. This requires simultaneous acquisition of both 1 H and 19 F images, i.e. a multi-receiver instrument not available to the group. We have, therefore, adopted an alternative approach in which an HFH sandwich is acquired. The pH in each slice of the 19 F-CSI is obtained by interpolation from two 1 H-CSI experiments, Figure 2. Finally, we are exploring adapting the one-shot method to study pH and solvent-dependent conformational changes. The ultimate goal of the project is to provide a tool for measuring multiple structural properties in a function of any variable if the gradient of the latter is obtainable in an NMR tube.
Figure 1. Pulse sequence for double solvent suppression 1 H Chemical Shift Imaging.
Figure 2. 1 H-CSI image and 19 F-CSI image of Flurbiprofen in the presence of a pH gradient recorded as part of a HFH sequence. 4-fluorotoluene was added as a pH-insensitive 19 F reference (*).
References 1. M. Wallace, D. J. Adams and J. A. Iggo, Anal. Chem. , 2018, 90 , 4160-4166. 2. G. Schenck, Department of Chemistry , 2021. 3. P. Trigo-Mourino, C. Merle, M. R. Koos, B. Luy and R. R. Gil, Chemistry , 2013, 19 , 7013-7019.
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