Citicoline (CDP-Choline) Reference Standard — CAS 987-78-0, C₁₄H₂₆N₄O₁₁P₂, inner salt

1. What this material is

This page describes citicoline supplied as an analytical reference material: a weighed quantity of a single identified substance, intended as the point of comparison against which another sample is measured. It is the reagent a method is calibrated against, not an article for consumption.

Citicoline is a pyrimidine nucleotide. A cytosine base sits on a β-D-ribofuranose ring; the ring's 5′-position carries a diphosphate bridge; and the far end of that bridge carries a choline residue through its quaternary nitrogen. The molecule is therefore a zwitterion in its own right — a permanent positive charge on the quaternary ammonium, a negative charge on the phosphate — which is why the registry and European law both describe the marketed substance as an inner salt [1][5]. Biochemically it is the activated intermediate of the Kennedy pathway, the step at which choline is committed to phosphatidylcholine synthesis; that role was established in 1957 [28] and is set out in the modern review literature [38].

It is also, unusually for this catalogue, a compound with three simultaneous regulatory identities. It is an authorised medicine in several countries and carries the anatomical-therapeutic-chemical code N06BX06 [8]. It is an authorised novel food in the European Union, with a specification, quantitative limits and a mandatory labelling statement written into a Commission implementing regulation [5]. And it has no marketing authorisation in Poland at all [10]. A laboratory that meets this substance in a sample — a customs laboratory, a contract testing house, a university group — is therefore identifying a molecule whose legal status depends on which side of a border and which product category it is standing in.

Two neighbouring cards in this catalogue turn on related problems and are worth reading against this one. Alpha-GPC is the other choline donor here, and it fails in a mirror-image way: it has a positional isomer that mass spectrometry cannot resolve, a published and validated quantitative ³¹P NMR method [26], and no deposited phosphorus spectrum to run it against. Citicoline has neither the method nor the spectrum. Procaine hydrochloride is the catalogue's clearest illustration of the other half of the problem — that a salt is a different substance with a different molar mass from the base it is made of, and that a weighing is only meaningful once you say which one you have.

The terms on which this and every other reference material here is supplied are collected in the reference standards category.

2. Identity and registry codes

Three rows in that second table decide something practical later, and are worth pausing on. The formal charge is zero while the molecule carries two full charges — a permanently cationic quaternary nitrogen and an anionic phosphate. That is what inner salt means, and it is why the pH of a mobile phase is a far weaker lever here than a chemist's instinct suggests (section 6). XLogP3 −4 is an extreme value even among polar compounds; the lipophilic end of this catalogue, bromantane, sits at the opposite extreme, and no single reversed-phase method covers both. Ten rotatable bonds makes this a conformationally floppy molecule, which matters both for the ion-mobility data in section 8 and for any attempt to predict retention from structure.

3. Which citicoline: forms, records and one contaminated number

Before any chemistry, the bookkeeping — because for this substance the identity question is not what but which. Three distinct problems attach to the name citicoline, and each of them can put the wrong number on a certificate.

3.1 Two commercial forms, and a 4.50% difference in molar mass

Citicoline is traded in two forms that are chemically different substances with different registry entries, different CAS numbers and different masses.

The InChIKeys differ in the first block, which is the skeleton hash. That is the strongest possible statement of non-identity: these are not two spellings of one substance, they are two substances. The practical consequence is arithmetic. A fixed weighing of 1000 mg delivers 2.048 mmol if it is the inner salt and 1.960 mmol if it is the sodium salt — 4.3% fewer moles from the same reading on the same balance. A calibration curve built on the wrong assumption is biased by that amount before the first injection, and no amount of chromatographic care recovers it.

The same trap in a more familiar form is the reason procaine hydrochloride is described on its own page by salt and not by base: the counter-ion is part of the formula weight, and the formula weight is the only thing that converts a mass into a mole count.

3.2 The record that looks identical and reports no stereochemistry

This matters because of how identity checks are usually automated. A script that matches on formula and accurate mass — the two fields any mass spectrometer hands you — cannot distinguish the two records at all, and if it lands on the flat one it will report a substance with four unresolved stereocentres. That is a materially different statement from what the authentic record says, and it is exactly the statement that would send a purchaser looking for a chiral separation that this compound does not need (section 4).

The picture is completed by four further records that resolve from the same names or the same formula [1][2][4]:

A name search for citicoline returns dozens of identifiers. The number that is unambiguous is not the name and not the mass — it is the full InChIKey, and for the material described here it is RZZPDXZPRHQOCG-OJAKKHQRSA-N.

3.3 A CAS number in the record that belongs to something else

The authentic record keeps a list of removed synonyms — strings that were once attached to it and have since been withdrawn. Among the 51 entries on that list there is exactly one string in CAS format: 125602-26-8. Looking that number up does not fail. It resolves cleanly, to a completely unrelated substance: a protected arginine derivative with the formula C₂₂H₃₆N₄O₇S and a molecular mass of 500.6 [1].

This is a contamination of the record, not a superseded CAS number for citicoline; the substance has no deprecated registry numbers that we could find. The danger is specific and mechanical: a script that harvests CAS-shaped strings from a synonym list, rather than reading the single authoritative field, will pick up a number for a different compound whose mass is close enough (500.6 against 488.32) not to look absurd. The correct and only CAS number for the substance described here is 987-78-0, confirmed independently by the registry [1] and by the text of the European regulation [5].

3.4 A name in the market that has no chemistry behind it

4. Structure and stereochemistry

The registry states the stereochemistry of this compound without ambiguity. Quoted verbatim from the record [1]:

Four defined, zero undefined. This is a single, fully specified stereoisomer, not a mixture and not a partially resolved structure. The configuration is carried in the systematic name as (2R,3S,4R,5R) and in the isomeric SMILES string as four explicit stereo-marked centres; the InChIKey's second block, OJAKKHQRSA, is the hash of that stereochemical layer, which is why it differs from the flat record discussed in section 3.2.

All four centres sit on one small part of the molecule: the β-D-ribofuranose ring of the cytidine half. C-1′ carries the glycosidic bond to the cytosine nitrogen and fixes the anomeric configuration; C-2′ and C-3′ carry the two secondary hydroxyls; C-4′ carries the exocyclic carbon that leads to the phosphate. The choline half of the molecule contributes nothing: it is a straight chain of two carbons between a quaternary nitrogen and an oxygen, with no stereocentre in it at all.

What the four centres mean, and what they do not

Because the compound is a single defined stereoisomer with no undefined centres, chiral chromatography is not the identity problem here. That is a genuine difference from other cards in this catalogue. Tadalafil carries two defined centres and shares its exact mass with a family of stereoisomers that mass spectrometry cannot separate, so for that compound the chiral question is the identity question. For citicoline the stereochemistry is inherited intact from the ribose of the biological or synthetic starting material, and no realistic manufacturing route produces the wrong diastereomer as a bulk component.

What the stereochemistry does mean is this: the ribose configuration is the part of the molecule that degradation attacks, not the part that manufacturing gets wrong. Cleavage of the glycosidic bond releases free cytosine; hydrolysis of the diphosphate bridge releases 5′-cytidylic acid and phosphate. Both processes destroy the intact molecule while leaving fragments that are chemically similar to it and chromatographically very close to it. The stereochemistry is stable; the connectivity around it is not. That is the subject of the next three sections.

5. The core problem: a molecule that will not stay on the column

Read the computed descriptors again as a set, because together they close off nearly every standard analytical lever at once [1]:

The permanent cationic charge is the part that surprises people. With an ordinary amine, raising the pH converts the ammonium to a free base and retention returns. A quaternary ammonium has no proton to lose: it stays charged in acid, in base, and everywhere between. L-DOPA is the useful contrast in this catalogue — also a very polar, poorly retained zwitterion, but one whose charge state does respond to pH and whose primary amine offers a handle for derivatisation. Citicoline offers neither.

The literature confirms this is a real difficulty rather than a local one, and it does so in an unusually sharp way. The single published bioequivalence study of citicoline — a regulatory-grade study, done properly, published in a peer-reviewed analytical journal — quantified choline, the metabolite, and not citicoline itself [23]. Its title says so explicitly. When a registration-grade study measures the breakdown product rather than the parent, the parent is not easy to measure.

6. Methods that fail, and methods that work

What does work

These are starting points for method development anchored in published work, not validated procedures, and they are offered as such:

• Ion-pair reversed-phase chromatography. The classical answer for charged nucleotides, and the historical anchor for this compound class is the separation of water-soluble choline metabolites published in 1985 [17]. A cationic analyte needs an anionic pairing agent; the technique is well established for nucleotides as a class, and section 10 quantifies exactly how thinly it has been applied to this particular substance.
• Hydrophilic-interaction chromatography. The textbook case for an analyte at logP −4: the property that destroys reversed-phase retention becomes the retention mechanism itself. Under this mode the parent compound and its more-polar hydrolysis products elute in a sensible order rather than all at once.
• Anion-exchange chromatography, which addresses the phosphate end of the molecule directly and separates mono- from diphosphate on charge — that is, on precisely the difference between the intact substance and its principal impurity.
• Mass-spectrometric detection rather than ultraviolet. The compound ionises well in both polarities: the deposited spectra include [M+H]⁺ at m/z 489.11, [M−H]⁻ at 487.10 and the doubly protonated species at 245.06 [1][13]. Section 9 sets out which transitions carry information.
• Quantitative phosphorus-31 NMR. This is the technique that answers this molecule's central question, and section 9 explains both why it is the right one and why the public record cannot support it. A validated quantitative ³¹P method exists for the related choline phosphate alpha-GPC, determining a positional isomeric impurity in the range of roughly 0.03–0.25% by weight [26]; the approach transfers in principle, but the reference data for citicoline does not exist.
• Non-chromatographic determination. Two published routes deliberately sidestep the separation problem. A potentiometric ion-selective electrode exploits the quaternary cation directly [20], and a spectrofluorimetric method uses fluorescence quenching of eosin Y [21]. Both are orthogonal to chromatography, which is exactly what makes them valuable for a laboratory that does not wish to fight an ion-pair method.
• Stability-indicating chromatography, for which the closest published precedent determines citicoline alongside piracetam [19]. The caveat is stated plainly in section 10: even that method is a method for a mixture, not for the substance alone.

Compare how differently this plays out for compounds whose detection is trivial. Methylene blue is intensely coloured and can be quantified by absorbance almost carelessly; mebicar sits at the opposite pole, with no useful chromophore at all. Citicoline occupies an awkward middle: it has a chromophore, it is simply shared with every one of its degradation products, so the detector that sees it cannot tell you what it is seeing.

7. A specification written into law, read back by the mass spectrum

Most substances in a catalogue like this have no legally binding specification at all. Citicoline is an exception, and the exception is useful, because Commission Implementing Regulation (EU) 2017/2470 — the Union list of novel foods — contains a full monograph-style specification for it. These are not marketing figures; they are the numbers that appear in the Official Journal [5].

Two honest caveats belong with that paragraph. First, the fragment assignments above are our reading of the deposited masses — each one checked against a calculated elemental composition, consistent with the known chemistry of nucleotide diphosphates, but not a quotation from a published fragmentation study; no such study for this compound was found. Second — and more important for anyone treating this as a specification — the regulation quoted here is food law, not pharmacopoeial law. It is the authorised specification for citicoline as a novel food ingredient in the European Union. Whether a monograph for this substance exists in the European or United States Pharmacopoeia we did not establish and do not assert; those are different texts under a different regime, and the two must not be conflated.

8. Physicochemical data: measured, legislated, and absent

This section attributes every number to the source that carries it, because for this compound the sources cover different ground and one of them is a legal text rather than a measurement. Where values disagree, the disagreement is shown rather than resolved.

8.1 What the compound record actually contains

The experimental properties section of the registry record holds one class of measurement and nothing else: collision cross section, from drift-tube ion mobility [1]. There is no melting point, no boiling point, no solubility figure in any solvent, no acid dissociation constant, no density, no refractive index, no specific rotation, and no physical description. That is a finding about the record, established by reading the whole of it, not a gap in a search.

Note the spread in the negative-ion values: 200.64, 205.9 and 208.41 Å² for the same ion of the same molecule, a range of nearly 4%. That is not a contradiction to be resolved by picking one; it is what happens when a flexible molecule with ten rotatable bonds is measured against three different calibrations. Anyone using a collision cross section as an identity criterion should match the calibration as well as the number.

8.2 The physical constants that come from a legal text

The only official statements about the appearance and behaviour of this material as a solid come not from a chemistry database but from the Union list [5]: white crystalline powder, and pH 2.5–3.5 for a 1% solution. The second figure is more informative than it looks. A one per cent aqueous solution of this substance is distinctly acidic, which follows from the free hydroxyl on the bridging phosphate, and which matters directly for solution stability — a diphosphate bridge is not at its most stable in acid.

That the substance is genuinely crystalline is corroborated independently by the oldest literature on it: crystallisation from yeast was reported in 1956 [15], and the molecular structure was solved by X-ray diffraction in 1975 [14]. The 1975 paper remains the only crystallographic determination of this molecule we could identify, and it is therefore the single hard anchor for any statement about conformation or solid-state geometry.

8.3 The physicochemical paper that exists, and where it lives

8.4 Solubility, and why we give no number

No solubility value for this compound exists in the registry in any solvent [1]. What can be said without inventing anything: a zwitterionic nucleotide with a computed logP of −4 and a polar surface area of 214 Å² is a water-soluble compound and a poorly soluble one in non-polar organic solvents, and the regulation's own use of a 1% aqueous solution as the pH test condition [5] establishes that at least that concentration dissolves. Beyond that we give no figure, because there is none to give. Determine it on your own material, and record the temperature when you do.

The contrast with the better-characterised end of this catalogue is instructive. For a compound such as paracetamol, decades of pharmacopoeial work mean that melting range, solubility and spectra are all tabulated and mutually consistent. For citicoline — a compound with a longer clinical history than most of the catalogue — the corresponding table is empty. Clinical volume and analytical characterisation are independent quantities, and this substance is the clearest example of the gap between them.

9. Spectra: mass spectrometry and nothing else

The missing phosphorus spectrum is the centre of this page

Phosphorus-31 is close to an ideal nucleus for this problem. It is spin one-half, it is 100% naturally abundant, and its chemical shift range is wide enough that a diphosphate bridge, a phosphate monoester and free inorganic phosphate occupy clearly separated regions of the spectrum. One quantitative ³¹P measurement therefore answers the question that this molecule's specification is built around — is the P–O–P bridge intact, and how much monophosphate and free phosphate is present — without a chromatographic separation, without a chromophore, and without needing a response factor for an ultraviolet detector.

There is no such reference spectrum in the public record for this compound. And this is not an artefact of where we looked: a search of the biomedical index for this substance together with phosphorus NMR returns four papers, and all four are in-vivo or in-cellulo studies — the detection of CDP-choline inside cultured tumour cells, where the shift positions were shown to depend on pH [24], and the accumulation of the compound in erythrocytes in a haemolytic disorder [25]. Not one of them is a characterisation of reference material. The nucleus has been used to find this molecule in tissue; it has never been used, publicly, to certify a sample of it.

What the mass spectra can and cannot settle

The deposited mass spectra are genuinely useful and should be used. The negative-ion fragment set gives a direct readout of the two regulated impurity classes (section 7), and the doubly protonated precursor produces a rich 97-peak spectrum that is far more distinctive than any single transition. What mass spectrometry cannot do here is distinguish the authentic stereochemically defined substance from the flat record's connectivity (section 3.2), because they are the same set of atoms in the same arrangement; nor can it settle whether the material in hand is the inner salt or the sodium salt once the sodium is stripped or added in the source. Those are questions for the certificate and the elemental composition, not for the mass spectrometer.

10. What the literature actually says

The literature on citicoline is substantial. It is also distributed extremely unevenly, and the distribution — not the total — is what a laboratory buying a standard needs to know. The measurements below were taken with positive controls, so that a low count can be distinguished from a failed query.

10.1 Analytical chemistry: two laboratories, one mixture, no standalone method

The pattern in the analytical literature is unusual enough to be worth stating directly. Three published quantitative methods determine citicoline by chromatography or by optical spectroscopy, and all three determine it in the same combination — with piracetam: a stability-indicating chromatographic method for the pair [19], a spectrofluorimetric method for citicoline in the presence of co-formulated piracetam [21], and a spectrophotometric method for the pair in tablet form [22]. Two of those three are the same laboratory. References [19] and [21] carry an identical set of five authors — Abdelrahman, Ahmed, Omar, Derayea and Abdelwahab — listed in a different order; only [22] is an independent group. A citation count of three therefore overstates the independent methodological base, which is two. There is in addition a potentiometric method using an ion-selective electrode, which stands alone [20], and a modern chromatographic separation of the phosphocholine / CDP-choline pair developed for enzyme assay work [18].

What is absent from that list is a validated, standalone, stability-indicating chromatographic method for citicoline as a single substance. The closest published work is a method for a mixture; the most rigorous published bioanalytical work measured the metabolite instead [23]. This is why section 6 offers starting points rather than procedures.

10.2 Production: two authorised routes, two literatures

European law authorises citicoline from two sources with an identical specification: chemical synthesis, and fermentation with a genetically modified E. coli strain [5]. Both routes have a literature, and the distinction matters to a purchaser because trace impurity profiles differ even where the main specification does not.

The biosynthetic definition of the molecule dates to 1957 [28]. The industrial fermentation route traces to enzymatic production of pyrimidine nucleotides using Corynebacterium ammoniagenes and recombinant E. coli cells, published in 1997 [29] — the earliest published precedent we found for a route of the kind the regulation names, although the regulation identifies its authorised strain (BCT19/p40k) and no source we consulted links that strain to this paper. Modern work on that route covers multi-enzyme systems driven by an ATP donor module [32], enzyme engineering for high-salt conditions [33], production in living cells through engineered substrate and energy metabolism [34], and the design of one-pot industrial systems [35]. On the chemical side, efficient synthesis of the compound and its analogues was published in 2015 [30] and an improved selective-phosphorylation route in 2016 [31]; a 2024 review surveys the field as a whole [36]. There is even a demonstration that the diphosphate bridge can form without any enzyme at all [37] — which is a reminder that a bond formed that easily is not an especially strong one.

10.3 Clinical and pharmacological literature, reported as literature

Everything in this subsection is a bibliographic fact about published work. None of it is a statement about the material sold on this page, and none of it constitutes a claim of any property or effect of this reagent.

The compound's biochemical role in the Kennedy pathway is set out in a standard review [38]. Pharmacological reviews of the compound in central-nervous-system contexts exist from 2005 [39] and, in the most extensive single treatment, an eighty-nine-page update published in 2022 [45]. A critical review published in 2014 is titled, tellingly, Facts, Doubts and Unresolved Issues [41], and a 2019 review by Polish authors asks in its title whether this is a superior form of choline — that is, poses the comparison as a question [42]. A large international multicentre randomised trial in acute ischaemic stroke was published in 2012 [43], and the Cochrane systematic review of that indication appeared in 2020 [44]. A randomised trial concerning memory function in healthy older adults was published in 2021 [46], and the compound remains under investigation in newer trials, including a protocol published in 2024 for a study in lung injury [47].

11. Regulatory status

Every statement in this section was measured against a named document, and every negative was measured with a positive control that fired on the same document. A search returning zero proves nothing unless the instrument is shown to be pointing at the right text.

12. Hazard classification, and how thin it is

The three hundred-per-cent figures need reading carefully, because a reader who sees H315, 100% will reasonably infer an industry consensus. What it means here is two out of two. Two companies filed, and the two agreed. That is the second-weakest basis the inventory permits, and it is a very long way from the aggregated classification of a widely notified industrial chemical.

Two further qualifications belong beside it. First, the classification is not harmonised, so it is not legally binding anywhere in the European Union, and another supplier may lawfully classify the same substance differently. Second, no acute toxicity values are present in the record itself — the corresponding sections are pointers to external tables that carry no values in the record as we read it. The classification therefore rests on self-notification, and the underlying study data is not visible from the record.

What follows from that for practical work is not complacency but the opposite: treat the three irritation statements as the minimum reasonable assumption, not as a complete hazard profile, and record in your own risk assessment that the classification derives from two notifications and is unharmonised.

13. Handling, weighing and storage

The weighing arithmetic, done explicitly

Three separate factors stand between a reading on a balance and a mole count for this substance, and they compound.

The point of that table is not that any particular lot sits at the worst case. It is that a purity figure quoted without a basis is not a specification. “Ninety-nine per cent” means one thing as-is and another on dry matter, and for a compound whose legal specification is written explicitly on dry matter with a separate water tolerance beside it, the difference is not academic. Ask for the assay basis and the water content on the lot documentation, and calculate from those.

This is a milder version of a problem that recurs across polar and salt-forming reference materials. For alpha-GPC the same conversation is dominated by hygroscopicity, because that compound takes up water while it is being weighed. For citicoline the water is bounded by a legal limit rather than by a measured uptake rate — which is a better position to be in, but only if the number on the certificate tells you where inside that bound your lot sits.

14. What we certify and what we do not

15. Terms of supply

This material is supplied as a laboratory reagent and analytical reference material, for in-vitro laboratory use by qualified personnel in an appropriately equipped facility. It is not a medicinal product, not a dietary supplement, not a food, feed or cosmetic ingredient, not a novel food placed on the market as such, and it is not supplied for administration to humans or animals in any form or by any route.

By ordering, the purchaser confirms that they are a professional user acquiring the material for laboratory purposes; that they will handle it in accordance with section 13 and their own institutional risk assessment; that they will not administer it to humans or animals, nor supply it to any person who intends to; and that they are responsible for compliance with all laws applicable at the destination. That last point carries particular weight for this substance, because it is an authorised medicine in some jurisdictions, an authorised food ingredient under quantitative limits in the European Union, and an unregistered chemical in Poland — three regimes, one molecule.

Every unit is supplied with lot documentation. Section 14 sets out precisely which statements that documentation covers and which it does not. The general conditions applying to this and every other reference material in the range are collected in the reference standards category.

Nothing on this page is medical or nutritional advice, nor an offer of a medicinal product or a food. Statements in sections 10 and 11 describe published research and the regulatory position of the substance in various jurisdictions; they describe neither this article nor any use of it.

16. Questions and answers

What is the correct molecular formula and mass?

C₁₄H₂₆N₄O₁₁P₂, molecular mass 488.32 g·mol⁻¹, monoisotopic mass 488.10733165 Da. Two independent authorities state the same formula and the same mass: the compound registry [1] and Commission Implementing Regulation (EU) 2017/2470 [5]. Note that this molecule contains two phosphorus atoms — 12.69% of its mass — so any formula for citicoline without phosphorus in it is a formula for something else.

Am I buying the inner salt or the sodium salt, and does it matter?

It matters by 4.3% of your mole count. The two forms are different substances with different registry entries: the inner salt is CAS 987-78-0 at 488.32 g·mol⁻¹ [1], the sodium salt is CAS 33818-15-4 at 510.31 [2]. Their InChIKeys differ in the first block, which is the strongest available statement that they are not the same compound. The form named in the European specification is the inner salt [5]. Always read the CAS number on the documentation rather than the product name.

Why does my reversed-phase method show a single sharp peak at the void volume?

Because nothing separated. With a computed logP of −4 and a polar surface area of 214 Å² [1], this analyte is not retained on C18, and neither are its hydrolysis products — 5′-cytidylic acid, cytidine, inorganic phosphate. They all leave together in the unretained band. A single peak in that position is evidence of no separation, not of a pure substance. Ion-pair, hydrophilic-interaction or anion-exchange chromatography are the directions that work; section 6 sets out the reasoning.

Can I not just adjust the pH to get retention?

No, and this is the part that surprises people. The choline end of the molecule is a quaternary ammonium: it carries a permanent positive charge at every pH and has no proton to lose. The phosphate end can be titrated, the ammonium cannot. That is what makes this a zwitterion with a formal charge of zero rather than an ordinary ionisable compound.

Is it chiral, and do I need a chiral separation?

It has four defined atom stereocentres and zero undefined, configuration (2R,3S,4R,5R), all four on the ribose ring [1]. It is a single, fully specified stereoisomer, so chiral separation is not the identity problem here. Note also that neither phosphorus atom is a stereocentre — each carries two equivalent oxygens — which is why the count is four and not six.

A database match gave me four undefined stereocentres. Which is right?

You have landed on the flat record. Registry entry CID 13013858 carries the same formula, the same molecular mass and the same monoisotopic mass, and its InChIKey shares the first block but ends -UHFFFAOYSA-N instead of -OJAKKHQRSA-N [3]. It is the same connectivity drawn without stereochemistry, and it reports defined 0 / undefined 4. Formula and accurate mass cannot tell the two records apart; only the full InChIKey can.

Why is there no NMR spectrum, and why does that matter more here than usual?

There is no deposited ¹H, ¹³C or ³¹P spectrum, no infrared, no Raman and no ultraviolet data — only mass spectrometry [1]. The phosphorus gap is the consequential one. Phosphorus-31 is spin one-half and 100% naturally abundant, and it separates diphosphate, monophosphate and free phosphate in a single quantitative measurement, which is exactly the question this substance's specification asks. Four papers link this compound to phosphorus NMR and all four are in-vivo or in-cellulo studies [24][25]; none characterises reference material.

What are the two impurities I should be looking for?

European law names them: 5′-cytidylic acid at not more than 1.0% and free phosphoric acids at not more than 0.1% [5]. Both are hydrolysis products of the diphosphate bridge, and the collision cell breaks the same bonds that water does: the deposited negative-ion spectrum shows the cytidine monophosphate portion at m/z 304.04 and the metaphosphate anion at 78.96 [13]. Do not read those fragment masses as the masses of the impurities themselves — deprotonated 5′-cytidylic acid is 322.045, eighteen units above the fragment, which is the cyclised form (section 7).

What does “≥98% of dry matter” mean in practice?

It means the assay is calculated after the water is subtracted, and the water is separately capped at 5.0% loss on drying [5]. A compliant lot sitting at both limits contains 931 mg of substance per 1000 mg weighed, which is 1.907 mmol against a nominal 2.048 — 6.9% lower. A purity figure quoted without its basis does not tell you which of those numbers applies to your calibration.

Is this substance hygroscopic?

No hygroscopicity study for it exists in any registry we can reach, so we do not assert a rate of water uptake. What exists is the legal tolerance above: up to 5.0% of a compliant lot may be water. Store dry, weigh promptly, and ask for the measured water content of your lot. This is a different situation from alpha-GPC, where water uptake during weighing is the documented handling problem.

What is the melting point?

Unknown. No registry we can reach carries one, nor a boiling point, a density, an acid dissociation constant or a numerical solubility [1]. The single indexed paper devoted to this compound's physicochemical characteristics dates from 1983 and has no digital object identifier at all [16]. If you determine a melting point on this material, you will have generated a datum that is not currently public.

Is it a controlled substance, and is it on the anti-doping list?

Not scheduled in Poland [11] and not scheduled in the United States [12]; not named on the 2026 prohibited list [9]. Each of those negatives was measured with a control that fired on substances known to be in the same document. Separately, it is an authorised medicine in several countries outside the European Union and an authorised food ingredient inside it — neither of which is the same thing as being controlled.

Can I use the European novel food specification as my acceptance criteria?

You can use it as the most authoritative public specification for the substance, and it is quoted in full in section 7. But be clear about its regime: it is food law, not pharmacopoeial law [5]. Whether a pharmacopoeial monograph exists for this compound we did not establish and do not assert. If your work is under a pharmacopoeial framework, verify that separately rather than importing the food specification into it.

What does the hazard classification actually rest on?

Two notifications, from two companies. The 100% figures beside H315, H319 and H335 mean two out of two, not an industry consensus [1]. There is no harmonised classification, so nothing about it is legally binding in the European Union and another supplier may classify differently. Treat it as the minimum reasonable assumption rather than a complete hazard profile.

Is there anything I should know before building a bibliography on this compound?

Yes, two things. A widely cited 2006 mechanistic paper on CDP-choline was retracted in 2013 [40] and still returns readily in searches. And two indexes disagree about the first author of two papers in this field [15][22]; we cite the cross-publisher record in both cases and say so rather than choosing quietly.

Does the same class of problem affect other products here?

The specific problems on this page are its own, but the general lesson is not. Coluracetam and noopept each have their own identity question, set out on their own pages. What such compounds share is that a single confirmatory technique is rarely enough, and that the confirmatory technique which works for one is usually the one that fails for the next.

What purity is guaranteed?

Section 14 sets out what is and is not certified. Lot documentation accompanies the material and states the method used, the assay basis and the water content. We do not print a catalogue purity figure, because for this substance in particular a purity number without a named basis is not a specification — it is a number.

References

Registry and regulatory sources

1. National Center for Biotechnology Information. 2026. "PubChem Compound Summary for CID 13804, Citicoline." PubChem. https://pubchem.ncbi.nlm.nih.gov/compound/13804.
2. National Center for Biotechnology Information. 2026. "PubChem Compound Summary for CID 36605, Citicoline Sodium." PubChem. https://pubchem.ncbi.nlm.nih.gov/compound/36605.
3. National Center for Biotechnology Information. 2026. "PubChem Compound Summary for CID 13013858, Cytidine-5′-Diphosphocholine." PubChem. https://pubchem.ncbi.nlm.nih.gov/compound/13013858.
4. National Center for Biotechnology Information. 2026. "PubChem Compound Summary for CID 13805." PubChem. https://pubchem.ncbi.nlm.nih.gov/compound/13805.
5. European Commission. 2017. "Commission Implementing Regulation (EU) 2017/2470 of 20 December 2017 Establishing the Union List of Novel Foods in Accordance with Regulation (EU) 2015/2283 of the European Parliament and of the Council on Novel Foods." Official Journal of the European Union, CELEX 32017R2470. https://eur-lex.europa.eu/legal-content/EN/TXT/?uri=CELEX%3A32017R2470.
6. EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA). 2013. "Scientific Opinion on the Safety of 'Citicoline' as a Novel Food Ingredient." EFSA Journal 11 (10): 3421. https://doi.org/10.2903/j.efsa.2013.3421.
7. EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA), Dominique Turck, Torsten Bohn, Jacqueline Castenmiller, Stefaan De Henauw, Karen Ildico Hirsch-Ernst, Helle Katrine Knutsen, Alexandre Maciuk, et al. 2024. "'Citicoline' and Support of the Memory Function: Evaluation of a Health Claim Pursuant to Article 13(5) of Regulation (EC) No 1924/2006." EFSA Journal 22 (7): e8861. https://doi.org/10.2903/j.efsa.2024.8861.
8. World Health Organization Collaborating Centre for Drug Statistics Methodology. 2026. "ATC/DDD Index — N06BX06 Citicoline." https://atcddd.fhi.no/atc_ddd_index/.
9. World Anti-Doping Agency. 2026. "World Anti-Doping Code International Standard: Prohibited List 2026." https://www.wada-ama.org/en/prohibited-list.
10. Urząd Rejestracji Produktów Leczniczych, Wyrobów Medycznych i Produktów Biobójczych. 2026. "Rejestr Produktów Leczniczych." https://rejestry.ezdrowie.gov.pl/rpl/search/public.
11. Minister Zdrowia. 2024. "Obwieszczenie w sprawie wykazu substancji psychotropowych, środków odurzających oraz nowych substancji psychoaktywnych." Dziennik Ustaw. https://isap.sejm.gov.pl/.
12. United States Drug Enforcement Administration, Diversion Control Division. 2026. "Controlled Substances — Alphabetical Order." https://www.deadiversion.usdoj.gov/schedules/orangebook/c_cs_alpha.pdf.
13. MassBank of North America. 2026. "Cytidine 5′-Diphosphocholine — LC-MS/MS Spectra PT207070 and PT201910." MoNA, University of California, Davis. https://mona.fiehnlab.ucdavis.edu/.

Structure, solid form and physicochemistry

14. Viswamitra, M. A., T. P. Seshadri, M. L. Post, and Olga Kennard. 1975. "Molecular Structures of Cytidine-5′-Diphosphate and Cytidine-5′-Diphospho-Choline, and Their Role in Intermediary Metabolism." Nature 258 (5535): 497–501. https://doi.org/10.1038/258497a0. The title is given here as recorded by the cross-publisher registry; the biomedical index records the penultimate word as intermidiary.
15. Lieberman, I., L. Berger, and W. T. Gimenez. 1956. "Crystallization of Cytidine Diphosphate Choline from Yeast." Science 124 (3211): 81. https://doi.org/10.1126/science.124.3211.81. Author order is given here as recorded by the cross-publisher registry; the biomedical index lists a different first author for the same paper.
16. Sanchez, M. C., J. M. Fernandez, E. Forne, J. Castello, A. Sacristan, and J. A. Ortiz. 1983. "CDP-choline: Physico-chemical Characteristics." Arzneimittelforschung 33 (7A): 1011–1012. PubMed 6684450. https://pubmed.ncbi.nlm.nih.gov/6684450/. No digital object identifier exists for this paper; the issue number is 7A.

Analytical methods

17. Liscovitch, M., A. Freese, J. K. Blusztajn, and R. J. Wurtman. 1985. "High-Performance Liquid Chromatography of Water-Soluble Choline Metabolites." Analytical Biochemistry 151 (1): 182–187. https://doi.org/10.1016/0003-2697(85)90069-7.
18. Brault, J. P., and J. A. Friesen. 2016. "Characterization of Cytidylyltransferase Enzyme Activity through High Performance Liquid Chromatography." Analytical Biochemistry 510: 26–32. https://doi.org/10.1016/j.ab.2016.07.018.
19. Abdelrahman, Maha M., Amal B. Ahmed, Mahmoud A. Omar, Sayed M. Derayea, and Nada S. Abdelwahab. 2020. "Development and Validation of Stability Indicating Chromatographic Methods for Simultaneous Determination of Citicoline and Piracetam." Journal of Separation Science 43 (15): 2981–2988. https://doi.org/10.1002/jssc.202000346.
20. Kamel, Ayman H., Abd El-Galil E. Amr, Hoda R. Galal, and Abdulrahman A. Almehizia. 2020. "Novel Validated Analytical Method Based on Potentiometric Transduction for the Determination of Citicoline Psychostimulant/Nootropic Agent." Molecules 25 (15): 3512. https://doi.org/10.3390/molecules25153512.
21. Omar, Mahmoud A., Amal B. Ahmed, Nada S. Abdelwahab, Maha M. Abdelrahman, and Sayed M. Derayea. 2020. "Spectrofluorimetric Approach for Determination of Citicoline in the Presence of Co-formulated Piracetam through Fluorescence Quenching of Eosin Y." Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 236: 118337. https://doi.org/10.1016/j.saa.2020.118337.
22. Rahate, Kalpana Pravin, Akhila Sivadas, Aiswarya Sathi, and Kavya Sathi. 2013. "Development and Validation of Spectrophotometric Methods for Simultaneous Estimation of Citicoline and Piracetam in Tablet Dosage Form." Journal of Pharmacy and Bioallied Sciences 5 (3): 202–207. https://doi.org/10.4103/0975-7406.116818. Author order is given here as recorded by the cross-publisher registry; the biomedical index lists a different first author.
23. Sarkar, Amlan Kanti, Debotri Ghosh, Dhiman Haldar, Pradipta Sarkar, Bhaswati Gupta, Sujata Ghosh Dastidar, and Tapan Kumar Pal. 2012. "A Rapid LC-ESI-MS/MS Method for the Quantitation of Choline, an Active Metabolite of Citicoline: Application to In Vivo Pharmacokinetic and Bioequivalence Study in Indian Healthy Male Volunteers." Journal of Pharmaceutical and Biomedical Analysis 71: 144–147. https://doi.org/10.1016/j.jpba.2012.07.003.
24. Kuesel, A. C., G. Graschew, W. E. Hull, W. Lorenz, and H. W. Thielmann. 1990. "³¹P NMR Studies of Cultured Human Tumor Cells: Influence of pH on Phospholipid Metabolite Levels and the Detection of Cytidine 5′-Diphosphate Choline." NMR in Biomedicine 3 (2): 78–89. https://doi.org/10.1002/nbm.1940030206.
25. Petersen, A., and N. Borregaard. 1997. "A Family with Chronic Haemolysis and Selective Accumulation of Erythrocyte CDP-choline." Leukemia 11 (8): 1373–1376. https://doi.org/10.1038/sj.leu.2400689.
26. Sun, Ling, Yujuan Fan, Qiaoqiao Wang, Lili Xiang, Haiyun Han, and Dongying Chen. 2022. "Validated Quantitative ³¹P NMR Spectroscopy for Positional Isomeric Impurity Determination in L-α-Glycerylphosphorylcholine (L-α-GPC)." Journal of Pharmaceutical and Biomedical Analysis 221: 115067. https://doi.org/10.1016/j.jpba.2022.115067. This method concerns a related choline phosphate, not citicoline.
27. Kluska, Mariusz, Joanna Jabłońska, Dorota Prukała, and Wiesław Prukała. 2025. "Occurrence, Properties, Applications and Analytics of Cytosine and Its Derivatives." Molecules 30 (17): 3598. https://doi.org/10.3390/molecules30173598.

Biosynthesis and manufacture

28. Borkenhagen, L. F., and E. P. Kennedy. 1957. "The Enzymatic Synthesis of Cytidine Diphosphate Choline." Journal of Biological Chemistry 227 (2): 951–962. PubMed 13463016. https://pubmed.ncbi.nlm.nih.gov/13463016/. No digital object identifier exists for this paper.
29. Fujio, Tatsuro, and Akihiko Maruyama. 1997. "Enzymatic Production of Pyrimidine Nucleotides Using Corynebacterium ammoniagenes Cells and Recombinant Escherichia coli Cells: Enzymatic Production of CDP-Choline from Orotic Acid and Choline Chloride (Part I)." Bioscience, Biotechnology, and Biochemistry 61 (6): 956–959. https://doi.org/10.1271/bbb.61.956.
30. Sun, Qi, Xiao-Chuan Li, Shan-Shan Gong, Jian Sun, Cheng-Jun Wang, and Xing-Cong Wang. 2015. "Efficient Synthesis of Cytidine Diphosphate Choline (CDP-choline) and Its Analogs." Nucleosides, Nucleotides and Nucleic Acids 34 (6): 379–387. https://doi.org/10.1080/15257770.2015.1004340.
31. "Improved Synthesis of Cytidine Diphosphate Choline (CDP-Choline) via Selective Phosphorylation." 2016. Journal of Chemical Research. https://doi.org/10.3184/174751916x14634105913093. The cross-publisher record for this item is the electronic supplementary deposit and carries no author list; none is attributed here.
32. Liu, Yingmiao, Junzhi Wang, Chongmao Xu, Yong Chen, Junjie Yang, Dong Liu, et al. 2017. "Efficient Multi-enzyme-catalyzed CDP-choline Production Driven by an ATP Donor Module." Applied Microbiology and Biotechnology 101 (4): 1409–1417. https://doi.org/10.1007/s00253-016-7874-0. Registered in 2016 and printed in the 2017 issue; the issue year is cited.
33. Zheng, Cheng, Zhenjian Li, Haifeng Yang, Tianyi Zhang, Huanqing Niu, Dong Liu, Junzhi Wang, and Hanjie Ying. 2019. "Computation-Aided Rational Design of a Halophilic Choline Kinase for Cytidine Diphosphate Choline Production in High-Salt Condition." Journal of Biotechnology 290: 59–66. https://doi.org/10.1016/j.jbiotec.2018.11.008.
34. Ren, Yanna, Qi Liu, Haifeng Liu, Xiangshan Zhou, Yuanxing Zhang, and Menghao Cai. 2020. "Engineering Substrate and Energy Metabolism for Living Cell Production of Cytidine-5′-Diphosphocholine." Biotechnology and Bioengineering 117 (5): 1426–1435. https://doi.org/10.1002/bit.27291.
35. Zheng, Cheng, Rongxin Miao, Yingmiao Liu, Yang Cao, Dong Liu, Junzhi Wang, and Hanjie Ying. 2021. "A Procedure to Design One-Pot Multi-enzyme System for Industrial CDP-Choline Production." Applied Biochemistry and Biotechnology 193 (9): 2769–2780. https://doi.org/10.1007/s12010-021-03564-2.
36. Tang, Y., C. Lin, C. Ke, et al. 2024. "Advances in the Synthesis of Cytidine-5′-Diphosphate Choline" (in Chinese). Sheng Wu Gong Cheng Xue Bao / Chinese Journal of Biotechnology 40 (6): 1644–1660. PubMed 38914484. https://pubmed.ncbi.nlm.nih.gov/38914484/. Anchored on the biomedical index because the cross-publisher registry does not hold this record.
37. Mar, A., J. Dworkin, and J. Oró. 1987. "Non-enzymatic Synthesis of the Coenzymes, Uridine Diphosphate Glucose and Cytidine Diphosphate Choline, and Other Phosphorylated Metabolic Intermediates." Origins of Life and Evolution of the Biosphere 17 (3–4): 307–319. https://doi.org/10.1007/BF02386470.

Biochemical role, reviews and clinical literature

38. Fagone, Paolo, and Suzanne Jackowski. 2013. "Phosphatidylcholine and the CDP-choline Cycle." Biochimica et Biophysica Acta (BBA) — Molecular and Cell Biology of Lipids 1831 (3): 523–532. https://doi.org/10.1016/j.bbalip.2012.09.009.
39. Adibhatla, Rao Muralikrishna, and James F. Hatcher. 2005. "Cytidine 5′-Diphosphocholine (CDP-Choline) in Stroke and Other CNS Disorders." Neurochemical Research 30 (1): 15–23. https://doi.org/10.1007/s11064-004-9681-8.
40. Adibhatla, Rao Muralikrishna, James F. Hatcher, Eric C. Larsen, Xinzhi Chen, Dandan Sun, and Francis H. C. Tsao. 2006. "CDP-choline Significantly Restores Phosphatidylcholine Levels by Differentially Affecting Phospholipase A2 and CTP:Phosphocholine Cytidylyltransferase." Journal of Biological Chemistry 281 (10): 6718–6725. https://doi.org/10.1074/jbc.M512112200. Retracted 2013; retraction notice: Journal of Biological Chemistry 288 (11): 7549, https://doi.org/10.1074/jbc.A113.512112. Cited here only to identify the retraction.
41. Grieb, Paweł. 2014. "Neuroprotective Properties of Citicoline: Facts, Doubts and Unresolved Issues." CNS Drugs 28 (3): 185–193. https://doi.org/10.1007/s40263-014-0144-8.
42. Synoradzki, Kamil, and Paweł Grieb. 2019. "Citicoline: A Superior Form of Choline?" Nutrients 11 (7): 1569. https://doi.org/10.3390/nu11071569.
43. Dávalos, Antoni, José Alvarez-Sabín, José Castillo, Exuperio Díez-Tejedor, Jose Ferro, Eduardo Martínez-Vila, Joaquín Serena, Tomás Segura, et al. 2012. "Citicoline in the Treatment of Acute Ischaemic Stroke: An International, Randomised, Multicentre, Placebo-Controlled Study (ICTUS Trial)." The Lancet 380 (9839): 349–357. https://doi.org/10.1016/S0140-6736(12)60813-7.
44. Martí-Carvajal, Arturo J., Claudia Valli, Cristina Elena Martí-Amarista, Ivan Solà, Joan Martí-Fàbregas, and Xavier Bonfill Cosp. 2020. "Citicoline for Treating People with Acute Ischemic Stroke." Cochrane Database of Systematic Reviews 2020 (12): CD013066. https://doi.org/10.1002/14651858.CD013066.pub2.
45. Secades Ruiz, Julio J., and Pietro Gareri. 2022. "Citicolina: revisión farmacológica y clínica, actualización 2022." Revista de Neurología 75 (S05): S1–S89. https://doi.org/10.33588/rn.75s05.2022311.
46. Nakazaki, Eri, Eunice Mah, Kristen Sanoshy, Danielle Citrolo, and Fumiko Watanabe. 2021. "Citicoline and Memory Function in Healthy Older Adults: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial." The Journal of Nutrition 151 (8): 2153–2160. https://doi.org/10.1093/jn/nxab119.
47. Pannu, Sonal, Matthew C. Exline, Joseph S. Bednash, Joshua A. Englert, Philip Diaz, Amy Bartlett, Guy Brock, and Qing Wu. 2024. "SCARLET (Supplemental Citicoline Administration to Reduce Lung Injury Efficacy Trial): Study Protocol for a Single-Site, Double-Blinded, Placebo-Controlled, and Randomized Phase 1/2 Trial." Trials 25 (1). https://doi.org/10.1186/s13063-024-08155-0.