Pharmaceutical analysis by NMR can accommodate strict impurity thresholds: The case of choline

Prabhakar S Achanta; Matthias Niemitz; J Brent Friesen; Fatkhulla K Tadjimukhamedov; Anton Bzhelyansky; Gabriel I Giancaspro; Shao-Nong Chen; Guido F Pauli

doi:10.1016/j.jpba.2022.114709

Pharmaceutical analysis by NMR can accommodate strict impurity thresholds: The case of choline

J Pharm Biomed Anal. 2022 May 30:214:114709. doi: 10.1016/j.jpba.2022.114709. Epub 2022 Mar 5.

Authors

Prabhakar S Achanta¹, Matthias Niemitz², J Brent Friesen³, Fatkhulla K Tadjimukhamedov⁴, Anton Bzhelyansky⁴, Gabriel I Giancaspro⁴, Shao-Nong Chen⁵, Guido F Pauli⁶

Affiliations

¹ Department of Pharmaceutical Sciences, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, IL 60612, USA; Pharmacognosy Institute, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, IL 60612, USA.
² NMR Solutions Limited, Tulliportinkatu 3 A 8, 70100 Kuopio, Finland.
³ Pharmacognosy Institute, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, IL 60612, USA; Center for Natural Product Technologies (CENAPT), College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, IL 60612, USA; Physical Sciences Department, Rosary College of Arts and Sciences, Dominican University, 7900 West Division Street, River Forest, IL 60305, USA.
⁴ The United States Pharmacopeial Convention, 12601 Twinbrook Pkwy, Rockville, MD 20852, USA.
⁵ Department of Pharmaceutical Sciences, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, IL 60612, USA; Pharmacognosy Institute, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, IL 60612, USA; Center for Natural Product Technologies (CENAPT), College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, IL 60612, USA.
⁶ Department of Pharmaceutical Sciences, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, IL 60612, USA; Pharmacognosy Institute, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, IL 60612, USA; Center for Natural Product Technologies (CENAPT), College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, IL 60612, USA. Electronic address: gfp@uic.edu.

Abstract

The ICH guidelines recommend reporting thresholds for regular impurities in drug substances at the level of 0.05% or 0.03% (w/w) depending on the maximum daily intake. Therefore, any instrumental method of analysis applicable to the impurity analysis should be able to detect and quantify the analytes at those levels. This investigation was designed to verify the suitability of ¹H NMR spectroscopy for the detection of impurities, as a first step in the process before attempting quantification. In order to minimize demand on equipment, this study employed a 400 MHz instrument for structural confirmation and signal assignments of choline (1) and O-(2-hydroxyethyl)choline (2), a known impurity. The limit of detection (LOD) of 2 in 10 mg of 1 was established as 0.01% on a 400 MHz instrument and 2% on a 60 MHz (benchtop) NMR spectrometer. Thus, impurities for which quantification is required are readily detected at 400 MHz or above. These results are in contrast to the widespread belief that ¹H NMR sensitivity is insufficient for pharmaceutical impurity analysis. The choice of solvent was recognized as a critical parameter for ¹H NMR LOD analysis. Furthermore, publicly available NMR raw data (HMDB) proved to be valuable for unveiling the otherwise cryptic information hidden in complex signal patterns via ¹H NMR iterative Full Spin Analysis. Finally, the study uncovered the less noticed, yet characteristic, ¹⁴N-¹H coupling in the -N⁺(CH₃)₃ groups, adding strong arguments for the Raw NMR Data Initiative. Collectively, the data prove that the analytical capabilities of high-field NMR easily fulfill the ICH requirements for detection of impurity in the presence of an actual substance of interest which makes it a step closer to achieving regulatory standards.

Keywords: (1)H NMR spectroscopy; Benchtop NMR; Choline chloride; Limit of Detection.

MeSH terms

Choline*
Chromatography, High Pressure Liquid / methods
Drug Contamination*
Magnetic Resonance Imaging / methods
Magnetic Resonance Spectroscopy / methods
Pharmaceutical Preparations

Substances

Pharmaceutical Preparations
Choline

Grants and funding

U41 AT008706/AT/NCCIH NIH HHS/United States