The Batch Nature of Continuous Flow Production via Natural-Abundance Stable Isotopes

Added on:
26 Oct, 2026

By definition, continuous flow (CF) production implies continuity in the products; however, virtually all CF products are derived from batched reactants. Consequently, virtually all aliquots of CF production should retain certain batch characteristics. Roncone, A.; et al. ( Trends Analyt. Chem. 2024, 174, 117666., and references therein) demonstrated the highly specific nature of natural-abundance stable isotopes in individual batches of pharmaceutical and chemical materials. Here, we employ elemental analysis/isotope-ratio mass spectrometry (EA-IRMS) to quantify the natural-abundance stable-isotopic variations in CF production of products. We show that the batch nature of the reactants (6-bromonaphth-2-ol and methyl iodide) is transmitted to the product (6-bromonaphth-2-yl methyl ether). Instead of maintaining a smooth, continuous isotopic composition during CF production, the episodically batch-varying isotopic values (δ13C, δD, δ18O) of the reactant batches are transmitted downstream to the products. Although the batch nature of CF production is evident, only an initial evaluation of using isotope effects to parametrize yield (via fraction remaining of the starting material) is possible with the present relatively narrow range of yields. These early observations open new areas for process research. Beyond demonstrating the batch nature of CF production, there are at least two additional utilities in measuring isotopic compositions during CF production: (i) product authentication (batch/aliquot auditing) and (ii) process understanding (monitoring the continuity of the continuous flow reaction).

Equipment used in this paper: R-Series Flow Chemistry System

  • Jasper JP1
  • Fricke PJ2
  • Andreasson M3
  • Guerzoni M3
  • Pelphrey S4
  • Cunningham T4
  • Epstein O2
  • Karlsson S3
  • Pearson A5
  • Elmore C3
  •   1Molecular Isotope Technologies LLC, 8 Old Oak Lane, Niantic, Connecticut 06357, United States
  • 2Early Oncology R&D, AstraZeneca, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States
  • 3Early Chemical Development, Pharmaceutical Sciences, R&D, AstraZeneca, Gothenburg 43183, Sweden
  • 4Stratum Reservoir Isotech LLC, 1308 Parkland Court, Champaign, Illinois 61821, United States
  • 5Harvard University, Department of Earth and Planetary Sciences, 20 Oxford St., Cambridge, Massachusetts 02138, United States
The Batch Nature of Continuous Flow Production via Natural-Abundance Stable Isotopes
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