Open Digital Reference Materials Unchain Controlled Substance Analysis

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.