Open Digital Reference Materials Unchain Controlled Substance Analysis

Yu Tang; Sinan Wang; Cuifen Fang; Ruiqi Zheng; Ping Xu; J Brent Friesen; Shao-Nong Chen; Yi Wang; Guido F Pauli; Yiyu Cheng

doi:10.1021/acs.analchem.5c00109

Open Digital Reference Materials Unchain Controlled Substance Analysis

Anal Chem. 2025 Jul 2. doi: 10.1021/acs.analchem.5c00109. Online ahead of print.

Authors

Yu Tang^{1

2}, Sinan Wang¹, Cuifen Fang³, Ruiqi Zheng¹, Ping Xu⁴, J Brent Friesen^{4

5}, Shao-Nong Chen⁴, Yi Wang^{1

2

6}, Guido F Pauli⁴, Yiyu Cheng¹

Affiliations

¹ Pharmaceutical Informatics Institute, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
² Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, Hangzhou 310018, China.
³ Zhejiang Institute for Food and Drug Control & NMPA Key Laboratory for Quality Evaluation of Traditional Chinese Medicine (Traditional Chinese Patent Medicine), Hangzhou 310057, China.
⁴ Department of Pharmaceutical Sciences, Retzky College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois 60612, United States.
⁵ Physical Sciences Department, Rosary College of Arts and Sciences, Dominican University, River Forest, Illinois 60305, United States.
⁶ State Key Laboratory of Chinese Medicine Modernization, Innovation Center of Yangtze River Delta, Zhejiang University, 314102, Jiaxing, China.

PMID: 40601392
DOI: 10.1021/acs.analchem.5c00109

Abstract

Digital reference materials (dRMs) can conceptually overcome the intrinsically limited availability and accessibility of identical reference materials (iRMs) that persistently impede the chemical analysis of rare and controlled substances, respectively. Quantum mechanics (QM)-driven ¹H iterative functionalized spin analysis (HifSA) is digital by nature and capable of referencing molecules with high specificity and full instrumental portability in the form of HifSA profiles by decoding their "nuclear genotype" in the form of the key ¹H spin parameters including chemical shifts (δ) and coupling constants (J). This study establishes the proof-of-concept for replacing iRMs with open dRMs for controlled Ephedra alkaloids (ephedrine, pseudoephedrine, methylephedrine) by producing their fully field-scalable HifSA profiles and adopting them for the qualitative and quantitative analysis of E. sinica and traditional Chinese medicines as a E. sinica-containing multicomponent mixture. QM-derived qHNMR (QM-qHNMR) results were corroborated via classical integral-based qHNMR (INT-qHNMR) and HPLC-UV methods. Furthermore, extending this method to 12 congeneric phenylethylamines created a starting set of open dRMs within the space of controlled substances. The remarkable congruence and near-identical (within a few 10 mHz) coupling constants in the monosubstituted benzenes (AA'BB'C spin systems) cross-validated the trueness of the dRM profiles. In addition, QM-qHNMR analysis of Ephedra alkaloids across a range of magnetic field strength equivalent to 60-600 MHz for ¹H confirm the portable nature of the dRMs and highlight their contribution to the sustainability and wider application in analytical chemistry. Practical aspects of HifSA profiling and QM-qHNMR are covered by comparing two software tools, Cosmic Truth (CT) and ChemAdder. Expanding the open dRM concept more broadly within chemical analysis advances the analytical toolbox for complex mixtures, fosters simultaneous identification and quantification of multiple target analytes, and eliminates the need for iRMs.