Journal of Pharmaceutical and Biomedical Analysis 160 (2018) 268–275 Contents lists available at ScienceDirect Journal of Pharmaceutical and Biomedical Analysis journal homepage: www.elsevier.com/locate/jpba Diffusion-ordered spectroscopy on a benchtop spectrometer for drug analysis Gaëtan Assemat a,1 , Boris Gouilleux b,1 , Dylan Bouillaud b , Jonathan Farjon b , Véronique Gilard a , Patrick Giraudeau b,c,∗∗ , Myriam Malet-Martino a,∗ a Biomedical NMR Group, Laboratoire SPCMIB, UMR CNRS 5068, Université Paul Sabatier, 118 route de Narbonne, 31062 Toulouse Cedex 9, France b CEISAM CNRS, UMR6230, EBSI Team, Université de Nantes, BP 92208, 2 rue de la Houssinière, 44322 Nantes, France c Institut Universitaire de France, 1 rue Descartes, 75005 Paris Cedex 05, France a r t i c l e i n f o Article history: Received 15 April 2018 Received in revised form 27 July 2018 Accepted 5 August 2018 Available online 6 August 2018 Keywords: Benchtop NMR Low field NMR DOSY NMR Drug analysis a b s t r a c t The first reported two-dimensional diffusion-ordered spectroscopy (DOSY) experiments were recorded at low field (LF) on a benchtop NMR spectrometer using the BPP-STE-LED (bipolar pulse pair-stimulated echo sequence with a longitudinal eddy current delay) pulse sequence which limits phase anomalies and baseline discrepancies. A LF DOSY map was first obtained from a solution of a model pharmaceutical formulation containing a macromolecule and an active pharmaceutical ingredient. It revealed a clear separation between the components of the mixture and gave apparent diffusion coefficients (ADC) values consistent with those measured from the reference high field experiment. LF DOSY was then applied to a real esomeprazole medicine and several gradient sampling schemes (linear, exponential and semi- gaussian (SG)) were compared. With a pulsed field gradient range of 4–70%, the most reliable results were given by the SG ramp. The resulting LF DOSY map obtained after 2.84 h of acquisition confirmed that the diffusion dimension is of prime interest to facilitate the assignment of overcrowded LF spectra although relevant ADC values could not be obtained in part of the spectrum with highly overlapped signals. © 2018 Elsevier B.V. All rights reserved. 1. Introduction Although NMR is not considered as a routine tool in the qual- ity control field due to its high purchase and maintenance costs, the ability of this technique to provide a large amount of informa- tion (structural, qualitative, quantitative, diffusion) could make it an essential tool in pharmaceutical manufacturing industries and quality control laboratories [1]. In the pursuit of a better analyt- ical performance in terms of resolution and sensitivity, modern high-resolution NMR spectrometers rely on higher and higher static magnetic fields provided by large superconducting magnets. While high resolution NMR is competitive with other analytical techniques -allowing micromolar compound detection-, this bulky ∗ Corresponding author at: Biomedical NMR Group, Laboratoire SPCMIB, UMR CNRS 5068, Université Paul Sabatier, 118 route de Narbonne, 31062 Toulouse Cedex 9, France. ∗∗ Corresponding author at: CEISAM CNRS, UMR6230, EBSI Team, Université de Nantes, BP 92208, 2 rue de la Houssinière, 44322 Nantes, France. E-mail addresses: patrick.giraudeau@univ-nantes.fr (P. Giraudeau), martino@chimie.ups-tlse.fr (M. Malet-Martino). 1 These authors contributed equally to this work. and sophisticated instrumentation is not always compatible with demanding industrial environments and usually requires a dedi- cated room and a trained staff to operate technical and cryogenic maintenance. As an alternative, a new generation of compact and cryogen-free low-field (LF) spectrometers has emerged [2]. These permanent magnets have reached a sufficient level of maturity to afford a stable and homogeneous enough static magnetic field to resolve the chemical shift information. They can deliver NMR spectra with a sufficient quality to generalize their use in various fields of application such as chemical process monitoring [2–6], food screening [7–9], quality control of dietary supplements [10] and more recently in drug analysis [11]. However, those spectrome- ters operating at 1 H resonance frequencies between 40 and 80 MHz involve a drastic loss of analytical performances. Besides the loss in sensitivity, the reduction of the frequency dispersion leads to two main drawbacks: i) congested spectra with strong signal overlaps, especially in the case of complex mixtures; ii) ubiquitous second order couplings making the analysis of signal patterns a tricky task in the context of structural elucidation. The recent implementa- tion of gradient coils in commercial LF NMR spectrometers opens the way to modern and efficient experiments, which improve the https://doi.org/10.1016/j.jpba.2018.08.011 0731-7085/© 2018 Elsevier B.V. All rights reserved.