CRL-40,940 vs CRL-40,941: Flmodafinil and Fladrafinil — One Oxygen Atom, One Digit, Two Distinct Compounds

Two development codes that look like typos of each other. CRL-40,940 — Flmodafinil and CRL-40,941 — Fladrafinil sit one digit apart on the Lafon sulfinylacetamide development ladder and one oxygen atom apart on the periodic table. The note below fixes identity (CAS, formula, MW, synonyms), the prodrug relationship, atypical DAT pharmacology, the LC-HRMS method that separates them, the 2026 WADA S6 listing, and packaging guidance from 1 MG to 10 G.

1. CRL-40,940 vs CRL-40,941 — Family Snapshot

Both compounds descend from the same medicinal-chemistry program that produced modafinil (CRL-40,476) and adrafinil (CRL-40,028) at Laboratoire L. Lafon (later Cephalon / Teva). The "CRL-40" prefix is the Lafon internal code; the last three digits are sequential. The two entries separated here — 940 and 941 — are the bis-(p-fluoro) phenyl ring-substituted analogues of modafinil and adrafinil respectively, also known as flmodafinil and fladrafinil.

2. Identity Table — CAS, Formula, Synonyms, UNII

The identifiers below are the unambiguous way to disambiguate the two at the bench. Note the UNII codes (FDA Substance Registration System) and the EPA CompTox Dashboard IDs — both are independent of CAS and resolve to distinct registry entries.

3. The Lafon Sulfinylacetamide Family — Where They Sit Next to Modafinil and Adrafinil

The two compounds are best understood as the di-fluorinated rung of the Lafon eugeroic ladder. The family tree, in four members:

1. Modafinil (CRL-40,476) — parent acetamide, C₁₅H₁₅NO₂S, 273.35 g·mol⁻¹, CAS 68693-13-3. The wakefulness-promoting drug approved in the US (1998) and EU (1997) as Provigil; Schedule IV in the US.
2. Armodafinil — the (R)-enantiomer of modafinil, C₁₅H₁₅NO₂S, 273.35 g·mol⁻¹, CAS 112111-43-0. Approved as Nuvigil; same scaffold, longer apparent duration.
3. Adrafinil (CRL-40,028) — modafinil's N-hydroxyl prodrug, C₁₅H₁₅NO₃S, 289.35 g·mol⁻¹, CAS 63547-13-7. Never approved; once sold in France as Olmifon. The "adrafinil → modafinil" liver conversion is the textbook example of an N-dehydroxylation prodrug pair.
4. CRL-40,940 (flmodafinil) and CRL-40,941 (fladrafinil) — the di-fluoro analogues of modafinil and adrafinil respectively, made by replacing both phenyl hydrogens at the para position with fluorine. Two new C–F bonds in each molecule.

The Lafon program was assigned to Cephalon in 2001 and is now part of Teva. The 1984 patent that disclosed the halogenated sulfinyl-acetohydroxamic acid series (US 4,489,095) is the original IP record for both CRL-40,940 and CRL-40,941. NLS Pharma subsequently picked up flmodafinil for the indications listed by the source materials (chronic fatigue syndrome in preclinical status; idiopathic hypersomnia, narcolepsy, ADHD, Alzheimer's disease — development now discontinued for the latter four).

4. Mechanism — Atypical DAT Inhibition and Selectivity Profile

Both compounds sit in the atypical DAT-inhibitor class — the same pharmacological family as modafinil, which dissociates from classical psychostimulants on three grounds: weak locomotor activation, low sigma-1 receptor binding, and the absence of broad monoamine release. The published receptor affinities for flmodafinil (CRL-40,940) at human monoamine transporters, from the medicinal-chemistry literature, are:

Why "atypical"

• Classical psychostimulants (methylphenidate, amphetamine) release dopamine through the transporter or block reuptake with strong locomotor activation. Flmodafinil blocks reuptake with substantially weaker locomotor effect.
• DAT occupancy of ~83 % in rodent voltammetry (Keighron et al., 2019) is higher than methylphenidate at therapeutic exposure — yet the wakefulness phenotype is described as "clean," without anxiogenic or sympathetic tone.
• Unlike modafinil, flmodafinil does not induce cytochrome P450 isoforms — a meaningful difference for metabolic-stability work and for chronic-dosing studies (drug-drug interaction surface is reduced).

5. CRL-40,940 (Flmodafinil) — Research Profile

CRL-40,940 is the more data-rich of the two. The published literature covers dopamine transporter voltammetry, comparative SAR against modafinil and adrafinil, and a preclinical program at NLS Pharma in chronic fatigue syndrome.

Research applications in the literature

• DAT probe in voltammetry and microdialysis — Keighron et al. (2019) used flmodafinil to map dopamine dynamics in the nucleus accumbens shell, showing greater DAT occupancy than modafinil at equivalent doses.
• Comparative SAR across the eugeroic series — flmodafinil is the standard para-fluoro reference against which armodafinil, esmodafinil, adrafinil, fladrafinil and CE-123 are profiled.
• Wakefulness circuit mapping — used to identify the dopaminergic component of wake-promoting circuits separately from orexinergic or histaminergic contributions.
• Cognitive / attention readouts — preclinically examined for attention, working memory and time-on-task endpoints under baseline and sleep-restricted conditions.
• Preclinical ME/CFS program (NLS Pharma) — in development for chronic fatigue syndrome as of January 2024 (preclinical stage). Earlier NLS programs in narcolepsy, idiopathic hypersomnia, ADHD and Alzheimer's disease were discontinued.

Why flmodafinil over modafinil as a probe

• No CYP induction (modafinil induces CYP3A4 and CYP2C19 in chronic exposure).
• Greater apparent DAT selectivity over SERT (12-fold) and negligible σ₁ binding — fewer off-target channels to deconvolute.
• Two para-fluorines create a stable, electron-poor benzhydryl motif that resists the major hepatic amide-cleavage and oxidation pathways of the unhalogenated parent.

6. CRL-40,941 (Fladrafinil) — Prodrug Relationship and Anti-Aggression Readout

CRL-40,941 is the N-hydroxyl analogue — structurally one oxygen away from CRL-40,940 — and the published record consistently treats it as a prodrug precursor to flmodafinil, paralleling the adrafinil-to-modafinil relationship in the unhalogenated series (Krug et al., 2026).

The prodrug case

• Both compounds share the same downstream metabolite set: flmodafinil acid (hydrolysis of the sulfinylacetamide to the carboxylic acid) and flmodafinil sulfone (oxidation of the sulfoxide to the sulfone) are the principal metabolites detected after administration of either parent (Krug et al., 2026).
• When CRL-40,941 is administered, an offset appears before flmodafinil reaches its plasma maximum — the kinetic signature of a compound being converted to its N-dehydroxylated analogue in vivo.
• The +16 Da mass difference between 941 and 940 is precisely the mass of one oxygen; the loss of water (H₂O, 18 Da) from CRL-40,941 with retention of two hydrogens would yield a different balance. The N-dehydroxylation mechanism is consistent with the literature on adrafinil (CRL-40,028 → modafinil CRL-40,476), where the same transformation is well characterized.

Distinctive readouts for CRL-40,941

• Anti-aggressive effect in animal models — fladrafinil is reported to reduce aggression in animal paradigms, an effect that adrafinil (the unhalogenated parent prodrug) does not produce. The effect is described as 3–4× more potent than adrafinil in the same model.
• Pharmacokinetics are still being characterised as of 2026 — the on-line pharmacokinetic data for CRL-40,941 are substantially thinner than for CRL-40,940 or modafinil, and most of what is published addresses its appearance as a metabolite rather than as a primary administered compound.

7. Head-to-Head Comparison Table

8. Analytical Verification — Why One Oxygen Defeats Metabolite-Only Methods

Identity work for these two compounds has moved steadily toward LC-HRMS in the past three years. Three independent method papers form the verification backbone:

• Bakota & Nandrea (2025) — Kansas City Human and Animal Food Laboratory (FDA). LC-HRMS on a Thermo Q-Exactive, Thermo Hypersil Gold C18 column, acetonitrile extraction from dietary supplement matrix. The validated method separates modafinil from four novel unscheduled modafinil analogues: adrafinil, CRL-40,940, CRL-40,941, and N-methyl-4,4-difluoromodafinil. Standard curve 10 ng/mL – 450 ng/mL. Confirmation by retention time + exact mass of parent ion + exact mass of fragment ions. Journal of Dietary Supplements 22(2):329–344, PMID 39466147, doi:10.1080/19390211.2024.2417673.
• Krug et al. (2026) — German Sport University Cologne, Center for Preventive Doping Research. LC-HRMS quantification of both compounds and their metabolites in urine and dried blood spots; limits of detection 0.2–4 ng/mL. Principal metabolites identified as flmodafinil acid and flmodafinil sulfone. Drug Testing and Analysis 18(8):1076–1087, PMID 42210629, doi:10.1002/dta.70100.
• Dowling et al. (2017) — thermal-degradation study. Under GC-injector conditions, modafinil-family compounds form 1,1,2,2-tetraphenylethane and its tetra-fluoro analogue — the thermal degrades are mass-loss relevant for any GC-based screen. LC methods should be preferred over GC for the parent compound. Drug Testing and Analysis 9(3):518–528, PMID 27928893, doi:10.1002/dta.2142.

9. 2026 WADA Listing and Regulatory / Export Risk

On 1 January 2026, both compounds were added by name to the WADA Prohibited List under S6 (Stimulants), sub-list S6.A (non-specified stimulants). The published USADA summary is explicit on nomenclature:

• CRL-40,940 — listed as "2-[Bis(4-fluorophenyl)methylsulfinyl]acetamide (flmodafinil)" — S6.A non-specified.
• CRL-40,941 — listed as "2-[bis(4-fluorophenyl) methylsulfinyl]-N-hydroxyacetamide (fladrafinil)" — S6.A non-specified.

Outside sport — country-by-country picture

• United States (FDA) — neither compound has an IND; both are unapproved for any human or veterinary use. Neither is a controlled substance under the federal Controlled Substances Act, but state analogue statutes act, can capture research-use material.
• European Union — neither is a scheduled narcotic or psychotropic under the UN conventions. Several member states regulate psychoactive substances by effect rather than by list, and may treat them as prescription-only or research-only at the national level.
• United Kingdom — Psychoactive Substances Act 2016 captures compounds supplied for their psychoactive effect; both fall within the scope of the act for supply.
• Australia (TGA) — neither is in Schedule 4 or Schedule 8; both fall under unscheduled / research-only supply expectations.
• China — domestic precursor / new psychoactive substance regulation applies; export is governed by the chemical weapons and drug administration frameworks and requires an explicit RUO destination and COA.

For export shipments of reference standards, the minimum paperwork stack is: commercial invoice with CAS number, signed COA (HPLC purity + identity by NMR or LC-MS), Safety Data Sheet, end-use statement ("research use only — not for human consumption"), and the destination's import permit where required. The HS classification most commonly applied is 2930.90 (organo-sulphur compounds) or 2924.29 (other cyclic amides); the relevant tariff should be confirmed with the destination customs broker on a shipment-by-shipment basis.

10. Packaging, COA, Storage and Sourcing Checklist

Both compounds are supplied as research-grade powder in standard analytical packaging grades. The available pack sizes cover analytical reference work through scale-up validation:

COA requirements at intake

• HPLC purity — ≥ 98 % (UV detection). CoBAS should declare the method, column, mobile phase, detection wavelength and the integrator report.
• Identity confirmation — ¹H NMR in CDCl₃ or DMSO-d₆, or LC-MS accurate-mass parent ion matching theoretical m/z within ≤ 5 ppm.
• Residual solvent — GC-headspace profile against ICH Q3C limits for the solvents used in synthesis or recrystallisation.
• Water content — Karl Fischer titration; relevant for any assay where the active is weighed as the parent rather than as a salt or hydrate.
• Heavy metals — ICP-MS or USP <232>/<233> panel for the intended use.

Storage conditions

• Solid bulk: −20 °C, desiccated, protected from light. Both compounds are stable as the dry powder under these conditions for at least 24 months in published stability data.
• DMSO stocks: prepare at known concentration (e.g., 10 mM), aliquot, store at −20 °C or below, protected from light. Avoid repeated freeze-thaw cycles.
• Working solutions: prepare fresh; use within the same working day for cell-based work.

11. Frequently Asked Questions

12. Conclusion

CRL-40,940 (flmodafinil) and CRL-40,941 (fladrafinil) are two distinct research compounds separated by a single oxygen atom and a single digit in their development codes — and that is the entire difference between a parent DAT inhibitor and its N-hydroxyl prodrug candidate. The mass delta is 16 Da; the molecular formulas differ by one oxygen; the IUPAC names differ by a single N-hydroxyl group; and the downstream metabolite pool is identical. Routine downstream screens against flmodafinil acid or flmodafinil sulfone cannot tell which two molecules were given. The reliable evidence for unambiguous assignment is the accurate-mass signal of the parent compound itself.

For research sourcing, the practical consequences are:

• The CAS number is the disambiguator of record — 90280-13-0 for CRL-40,940, 90212-80-9 for CRL-40,941. Quotation, COA, and SDS must each carry the CAS.
• The 2026 WADA listing has made both compounds routine confirmation targets for accredited doping-control laboratories; reference standards for either should be supported by an LC-HRMS-grade COA.
• Packaging is supplied in 1 MG, 10 MG, 100 MG, 1 G, 5 G and 10 G grades, all shipped under a research-use-only end-use statement.

The next note in this cluster covers the broader Lafon sulfinylacetamide family and the analogues that sit further out on the SAR ladder — modafinil, armodafinil, adrafinil and the N-methyl-4,4-difluoromodafinil reference standard already named in the FDA laboratory's analytical method.