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Chemical shift imaging with chemical gradients: efficient one-shot analytical methods to determine pH dependent physical properties of APIs

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  • Full or part time
    Dr Jon Iggo
  • Application Deadline
    No more applications being accepted
  • Funded PhD Project (European/UK Students Only)
    Funded PhD Project (European/UK Students Only)

Project Description

The protonation state of an API influences its solubility, membrane permeability, clearance from the body, conformation and ability to bind to a target protein. pKa is therefore an important factor in the targeted design of pharmaceutical compounds. Indeed, about two-thirds of the approved pharmaceutical compounds contain ionizable groups. Traditionally, the pH dependent properties of APIs have been determined using titrimetric methods that are both time consuming and laborious, even when robotic sample changers are available. The pH of a sample must be adjusted manually between successive NMR experiments and an entire morning of instrument and analyst time can be required to analyse a single compound.

This collaborative project with AstraZeneca and Dr Matthew Wallace at UEA will develop and extend our efficient, one-shot method employing Chemical Shift Imaging (CSI) in the presence of a controlled pH gradient that allows collection of a full NMR dataset on just single sample in a single imaging experiment. Provisional work in aqueous solution has demonstrated massive savings in cost and time. For example, it is possible to measure the pKa of an API in a single 20 minute imaging experiment with just 2 mM of compound.1 In this project, the methods will be extended to the determination of pKa in non-aqueous and in mixed solvents and to the identification of the protonation site in multiprotic/basic compounds. Slice-selective 2D NMR methods will also be developed to study pH dependent conformational changes that can influence the bio-availability of an API and its ability to bind to the target protein. These methods will also be applied to study self-assembly processes, protein-ligand interactions and other molecular recognition events; all of which are currently hot areas in medicinal chemistry.

In our method, the pH is varied continuously within a standard NMR sample tube and a full dataset collected by performing localised NMR measurements. The pH and ionic concentrations can be measured directly by 1H NMR without the need for electrochemical probes.1,2 The one shot NMR method has many advantages over conventional titrimetric, photometric and electrochemical methods: a single solution of the analyte is required eliminating the tedious need to prepare multiple solutions at different pH; the amount of material consumed in the experiment is dramatically reduced; NMR methods are relatively insensitive to the presence of impurities; the method can be made self-correcting for ionic strength and; in DMSO, is insensitive to low levels of water.

The successful applicant will be based in Liverpool and will have the opportunity to undertake periods of study at AstraZeneca’s Oncology R&D Centre in Cambridge and at UEA. The successful applicant will receive “hands-on” training in the application of advanced NMR methods (spatially resolved, multipulse, multidimensional, gradient, direct and inverse experiments) and will be expected to run all their own NMR experiments and to interact with other members of the NMR research groups. The successful applicant will, therefore, gain advanced experience in the design of NMR experiments and in the use of state-of-the-art NMR spectrometers, not simply be a service user. The Department of Chemistry, University of Liverpool, has an extensive analytical capability, including mass spectrometry, IR, GC, HPLC, ICP, BET surface area measurement, single crystal, and powder XRD, etc. The successful applicant will have the opportunity to receive training in each of these techniques as appropriate.

Applications are encouraged from highly motivated candidates with a strong interest in the application of NMR spectroscopy to complex chemical problems and who have, or expect to have, at least a 2:1 degree or equivalent in Chemistry or Pharmacy. The successful candidate will start in October 2020.Applications should be made as soon as possible but no later than 27th March 2020. Some teaching duties may be required.

Informal enquiries are also encouraged and should be addressed to Dr Jonathan Iggo, [Email Address Removed]

To apply for this opportunity, please visit:

Funding Notes

The award will pay tuition fees and a maintenance grant for 3.5 years (currently £15.009 p.a.) for candidates meeting the eligibility requirements of the EPSRC – please refer to the EPSRC website:


1. Wallace, M., Adams, D. J. & Iggo, J. A. “Titrations without the Additions: The Efficient Determination of pK(a) Values Using NMR Imaging Techniques.” Analytical Chemistry, 2018, 90, 4160-4166.

2. Wallace, M., Hicks, T., Khimyak Y. K. & Angulo, J. “Self-Correcting Method for the Measurement of Free Calcium and Magnesium Concentrations by 1H NMR” Analytical Chemistry, 2019, 91, 14442-14450.

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