Introduction to Melatonin
Melatonin (CAS 73-31-4), chemically N-acetyl-5-methoxytryptamine, is an indole-based compound best known as the hormone produced by the pineal gland to help regulate the body’s circadian rhythm. It is also manufactured at scale as a bulk ingredient: it is sold as a dietary-supplement raw material in many markets, is used as an active pharmaceutical ingredient (API) and reference standard, and appears in cosmetic formulations and in plant and agricultural research.
For buyers of bulk melatonin, the practical questions are about identity and purity, the synthetic or bio-based route by which it is made, the specification it must meet, and how its regulatory status varies from country to country. This article covers the chemistry, properties, industrial production, specifications, analytical control and sourcing of melatonin, and it deliberately stays within non-medical, technical boundaries.
PolyBlueChem can supply melatonin (CAS 73-31-4) as a bulk raw material; see the melatonin product page for the current specification.
Chemical Identity and Structure
Melatonin is a small, neutral molecule built on the indole ring system, the same scaffold found in the amino acid tryptophan and the neurotransmitter serotonin. It carries three features that define both its chemistry and its commercial handling requirements:
- Indole ring — a benzene ring fused to a pyrrole ring, providing the chromophore and the reactive positions.
- 5-Methoxy group (–OCH₃) — at the 5-position of the indole ring.
- N-Acetyl group (–COCH₃) — on the side-chain nitrogen, giving the molecule its “acetamide” character.
| Property | Value |
|---|---|
| Common name | Melatonin |
| Chemical name | N-Acetyl-5-methoxytryptamine |
| CAS number | 73-31-4 |
| Molecular formula | C13H16N2O2 |
| Molecular weight | 232.28 g/mol |
| SMILES | COc1ccc2[nH]cc(CCNC(C)=O)c2c1 |
| Appearance | White to off-white crystalline powder |
| Class | Indole alkaloid / acetamide (hormone) |
Physical and Chemical Properties
Melatonin is a crystalline solid with modest water solubility and good solubility in alcohols and other polar organic solvents. Its properties drive both its formulation (for example as a tablet or capsule ingredient) and its analytical control (principally HPLC).
| Property | Typical value / behaviour |
|---|---|
| Appearance | White to off-white crystalline powder |
| Melting point | Approx. 116–118 °C |
| Solubility in water | Slightly soluble (on the order of a few grams per litre) |
| Solubility in ethanol | Readily soluble |
| Log P (octanol/water) | Approx. 1.6 (moderately lipophilic) |
| pKa | Weakly acidic/basic character typical of the indole and amide groups |
| Photostability | Light-sensitive; degrades under prolonged light exposure |
| Typical assay | 99.0–101.0% (HPLC, on the dried basis) |
Because melatonin is an indole compound, it is sensitive to strong oxidants and to prolonged exposure to light and heat. These sensitivities govern the packaging and storage requirements described later.
Stability, Storage and Handling
Melatonin is reasonably stable as a dry powder when protected from light and moisture, but it degrades when exposed to excessive light, heat and oxygen. Practical handling rules follow directly from this:
- Keep it dark. Store in light-resistant, tightly closed containers. Photooxidation is the main degradation pathway.
- Keep it cool and dry. Store in a cool, dry place away from heat sources; avoid long exposure to elevated temperatures.
- Control pH in solution. Melatonin is more stable in mildly acidic media; strongly alkaline conditions accelerate degradation, which matters when preparing solutions or analytical standards.
- Protect from oxidants. Keep away from strong oxidising agents.
- Work cleanly. For API and supplement use, follow good manufacturing and hygiene practice and use the packaging specified by the customer’s quality system.
These requirements are the reason melatonin is normally supplied as a powder for tabletting and encapsulation, where the bulk material is protected from air and light until the dosage form is sealed.
Biosynthesis and Biological Context
Understanding how melatonin is made in nature helps frame the industrial routes. In living organisms, melatonin is produced from the amino acid tryptophan by a short, well-characterised enzyme sequence:
- Tryptophan is converted to serotonin (5-hydroxytryptamine) via hydroxylation and decarboxylation.
- Serotonin is acetylated by arylalkylamine N-acetyltransferase (AANAT) to give N-acetylserotonin.
- N-Acetylserotonin is O-methylated by acetylserotonin O-methyltransferase (ASMT/HIOMT) to give melatonin.
This pathway is the biological blueprint, and it is also the basis for emerging bio-based production, in which engineered micro-organisms are designed to carry out the same conversions from simple carbon sources or from tryptophan. In humans and animals the molecule acts as a chronobiotic signal; from a supply standpoint, however, the relevant point is that melatonin is a well-defined, chemically stable small molecule that can be produced by more than one route.
Industrial Synthesis of Melatonin
Almost all commercial melatonin is produced by chemical synthesis. The strategies fall into two broad families: building or installing the 5-methoxyindole skeleton and then attaching the N-acetyl side chain, or taking an available indole precursor and elaborating it. A widely used commercial approach acetylate 5-methoxytryptamine, which supplies both the correctly substituted indole and the aminoethyl side chain.
| Stage | Purpose | Notes |
|---|---|---|
| 1. Indole precursor | Provide the 5-methoxyindole skeleton | From 5-methoxyindole, 5-methoxytryptamine, or a tryptophan-derived precursor |
| 2. Side-chain assembly | Install or retain the 2-aminoethyl chain at C-3 | Mannich/gramine chemistry or available tryptamine derivatives |
| 3. N-Acetylation | Convert the primary amine to the acetamide | Acetic anhydride or acetyl chloride, with a base such as pyridine or triethylamine |
| 4. Isolation and purification | Obtain a pure, colourless solid | Crystallisation and/or chromatography; control of related substances |
| 5. Drying and milling | Deliver the required particle size and moisture | Controlled drying; milling and screening to specification |
The N-acetylation step is the defining reaction of nearly every commercial route, because 5-methoxytryptamine is a convenient, well-defined intermediate that already carries the correct substitution pattern. Alternative routes build the indole ring directly (for example by Fischer indole synthesis from a suitably substituted phenylhydrazine and an aldehyde or ketone bearing the amide side chain), but these are less common at commercial scale.
Bio-based and Fermentation Production
Bio-based melatonin is an active area of development rather than the dominant commercial route. The idea is to engineer micro-organisms (typically E. coli or yeast) to express the enzymes of the natural pathway and to convert tryptophan, serotonin or a simple carbon source into melatonin in a bioreactor. The melatonin is then recovered from the fermentation broth and purified.
The attraction is a potentially lower environmental footprint and the use of renewable feedstocks, and the challenge is titre, yield and the cost of downstream purification. For most buyers today, chemically synthesised melatonin remains the standard, with bio-based material available in limited volumes and mainly for customers who specifically require it.
Specifications and Quality Standards
Melatonin is supplied against pharmacopoeial or customer specifications, with the assay and the related-substances profile being the most important quality parameters. A representative specification is shown below; the exact limits depend on the grade and the customer’s quality system.
| Parameter | Typical specification |
|---|---|
| Appearance | White to off-white crystalline powder |
| Assay (HPLC, dried basis) | 99.0–101.0% |
| Identification | IR and/or HPLC retention consistent with the reference standard |
| Loss on drying | ≤ 0.5% |
| Residue on ignition | ≤ 0.1% |
| Heavy metals | ≤ 10 ppm (as Pb) |
| Related substances | Individual and total limits set by monograph or customer |
| Residual solvents | Within the limits of the applicable guideline |
| Microbiological limits | Total plate count and specified organisms within set limits |
Because melatonin is used in supplement and pharmaceutical applications, buyers should confirm that the material is produced and tested against a recognised standard (for example a USP or Ph. Eur. monograph for melatonin) and that a certificate of analysis (COA) accompanies each batch.
Grades and Product Forms
- Supplement / nutraceutical grade: the largest volume; the material used to make tablets, capsules and gummies.
- API / pharmacopoeial grade: produced and documented to a pharmacopoeial monograph for pharmaceutical use.
- Cosmetic grade: for leave-on and rinse-off cosmetic formulations.
- Reference standard: high-purity, fully characterised material for analytical use.
- Particle size / form: melatonin is generally supplied as a crystalline powder; particle size is agreed where flow or blend uniformity matters.
Applications Overview
Melatonin is used across several sectors. The table below is written from a raw-material standpoint and does not make medical claims; users are responsible for complying with the regulatory rules that apply to their finished product.
| Sector | Use of melatonin |
|---|---|
| Dietary supplements | Raw material for tablets, capsules and gummies marketed as sleep-support supplements in jurisdictions where this is permitted |
| Pharmaceuticals | API and reference standard where the material is regulated as a medicine |
| Cosmetics and personal care | Antioxidant-type ingredient in some skincare formulations |
| Plant and agricultural research | Studied as a signalling molecule affecting plant stress responses and development |
| Analytical and research use | Reference material, receptor and assay studies |
Two points deserve care. First, melatonin’s status differs sharply between markets: it is sold as a dietary supplement in the United States, while in many European countries it is regulated as a prescription medicine, and rules for its use in cosmetics and in food vary. Second, melatonin is an active molecule, so cosmetic and supplement claims are tightly regulated; suppliers and formulators should confirm the permitted claims and limits in each target market.
Melatonin in Dosage Forms
Because the effective amount of melatonin in a finished product is very small, the raw material is normally supplied as a fine crystalline powder that must be blended and filled with great attention to uniformity. The table below summarises the practical considerations for the main dosage forms.
| Dosage form | Raw-material requirement | Key considerations |
|---|---|---|
| Tablets | Powder with controlled particle size and good flow | Blend uniformity at low dose; lubrication and compaction; protection from light during processing |
| Capsules | Free-flowing powder or granulate | Uniform fill weight; avoidance of segregation in the blend |
| Gummies and soft confections | Powder dispersed in a gel or syrup | Thermal exposure during processing; dispersion and homogeneity; light protection |
| Liquid and sublingual formats | Material soluble or dispersible in the chosen vehicle | Solution stability and pH; light protection; excipient compatibility |
Two formulation constraints recur. First, the low use level means that good mixing and, where necessary, pre-dilution or a carrier are essential to avoid content-uniformity failures. Second, melatonin is light-sensitive, so processing and packaging should limit light exposure and the finished product should be protected from light and moisture.
Market and Supply Overview
Melatonin is a mature, well-established bulk product with broad, global demand from the supplement industry and smaller pharmaceutical, cosmetic and research markets. Its supply characteristics are typical of a specialty organic powder:
- Production base. Manufactured mainly in China and India, with a number of producers offering supplement and pharmacopoeial grades.
- Grades. Most volume moves as supplement-grade powder; pharmacopoeial-grade material commands a premium because of the tighter documentation and testing.
- Price drivers. Raw-material costs for the indole intermediates, plant utilisation, energy and packaging costs, and the grade and documentation required.
- Quality differentiators. Assay and related-substances profile, colour and appearance, particle size, and depth of documentation (GMP, residual-solvent and regulatory statements).
- Packaging. Typically supplied in fibre drums or cartons with light-resistant inner liners; small research quantities are supplied in amber bottles.
Buyers with a regulated use should treat the documentation package as part of the specification, because two suppliers offering the same assay can differ markedly in how completely they can support a regulated market.
Analytical Methods and Quality Control
Melatonin is controlled largely by chromatographic methods. The main techniques are:
- HPLC (often with UV detection): the standard method for assay and related substances.
- LC-MS: for trace identification and for confirmation where high sensitivity is required.
- IR and NMR: for identity confirmation and structure verification.
- Loss on drying, residue on ignition and heavy metals: standard pharmacopoeial tests.
- Microbiological testing: for supplement and API grades.
A robust COA reports the assay, identification, related substances, residual solvents where relevant, heavy metals, moisture and microbiological results, together with the method references and the batch number.
Regulatory Status and Safety
Melatonin’s regulatory classification is unusually varied and is the single most important commercial consideration for a bulk buyer.
- United States: marketed as a dietary supplement; melatonin is not an FDA-approved over-the-counter drug.
- European Union: in many member states melatonin is regulated as a prescription medicine, and its use in food supplements and cosmetics is restricted or subject to national rules.
- Other markets: classification ranges from supplement to prescription medicine, so the same bulk material can only be sold into a given market once the finished-product rules are satisfied.
From a handling standpoint melatonin is an ordinary organic powder, but as an active ingredient it should be handled with standard good practice for APIs and supplement raw materials, including appropriate dust control and personal protective equipment. Documentation supplied by the manufacturer typically includes the COA, safety data sheet (SDS) and, where relevant, GMP and regulatory statements. Buyers should confirm that the documentation matches their intended market before ordering.
Procurement and Sourcing Guide
A practical checklist when buying bulk melatonin:
- Grade and standard. Confirm whether you need supplement grade, pharmacopoeial (API) grade, cosmetic grade or reference standard, and require the matching documentation.
- Assay and related substances. Check the assay range and the related-substances limits; these define purity far more usefully than a single headline figure.
- Certification. Ask for a per-batch COA and, if you need it, GMP, non-GMO, halal or kosher status.
- Regulatory fit. Confirm the material is acceptable in your target market, given the differing classifications described above.
- Particle size and form. Specify particle size if blend uniformity or tabletting behaviour is critical.
- Packaging and storage. Choose light-resistant, moisture-tight packaging and store cool and dry.
- Consistency. Ask for recent batch history if assay or colour is critical to your process.
PolyBlueChem can supply melatonin (CAS 73-31-4) as a bulk raw material. To request current specifications, a COA or a quotation, contact the PolyBlueChem team.
Synthesis Route Comparison and Process Control
Although the reaction chemistry looks simple on paper, the commercial routes differ in raw-material cost, number of steps and the difficulty of controlling impurities. The table compares the main synthetic approaches qualitatively.
| Approach | Starting point | Strengths | Limitations |
|---|---|---|---|
| N-Acetylation of 5-methoxytryptamine | 5-Methoxytryptamine | Short, high-yielding, well understood; the standard commercial route | Depends on the availability and cost of the 5-methoxytryptamine intermediate |
| Elaboration of 5-methoxyindole | 5-Methoxyindole | Builds the side chain from a simple, lower-cost indole | More steps; side-chain chemistry must be controlled carefully |
| Tryptophan-derived route | Tryptophan | Biomass-adjacent starting material for some designs | Requires selective 5-functionalisation and decarboxylation steps |
| Fischer indole synthesis | Substituted phenylhydrazine + carbonyl component | Direct construction of the substituted indole | Less common at scale; regioselectivity and purification challenges |
Whatever the route, process control focuses on the same objectives: achieving high assay with low levels of related substances and residual solvents, controlling colour (a near-colourless product is preferred for supplement and cosmetic use), and delivering a reproducible particle size and moisture content. The final crystallisation and drying steps are where many of these attributes are fixed, so they are monitored closely with in-process and release testing.
Packaging, Labelling and Transport
Melatonin is shipped as a solid powder and is handled as a normal specialty organic chemical for transport purposes, but it should be packed to protect it from light and moisture.
- Primary packaging. Light-resistant, moisture-tight inner liners inside fibre drums or cartons; amber glass for small research quantities.
- Labelling. Product name, CAS number, batch number, net weight, manufacturer, and storage instructions, plus any handling statements required by the destination market.
- Storage during distribution. Keep cool, dry and out of direct sunlight; avoid prolonged high-temperature exposure in transit.
- Documentation in transit. COA, SDS and, for regulated uses, GMP and other statements should travel with or ahead of the shipment.
Frequently Asked Questions
What is melatonin and what is its CAS number?
Melatonin is N-acetyl-5-methoxytryptamine, an indole-based compound used as a supplement and pharmaceutical raw material; its CAS number is 73-31-4. See the melatonin product page for specifications.
What is the molecular formula and molecular weight of melatonin?
C13H16N2O2 and 232.28 g/mol.
How is melatonin manufactured?
Mainly by chemical synthesis, typically by acetylating 5-methoxytryptamine with acetic anhydride or acetyl chloride. Bio-based production by engineered micro-organisms is under development but is not yet the dominant route. More detail is in the related reading below.
What is the typical assay of commercial melatonin?
Usually 99.0–101.0% by HPLC on the dried basis, with related-substances and residual-solvent limits set by the applicable monograph or customer specification.
Is melatonin light-sensitive?
Yes. Melatonin degrades under prolonged light exposure, so it should be stored in light-resistant, tightly closed containers in a cool, dry place.
How does melatonin’s regulatory status differ between countries?
It is a dietary supplement in the United States but is regulated as a prescription medicine in many EU countries, and its use in cosmetics and food varies by market. Buyers must confirm the rules for their target market.
What documents should accompany a melatonin shipment?
At minimum a certificate of analysis (COA) and a safety data sheet (SDS); GMP, non-GMO, halal or kosher statements are available for many grades on request.
Can melatonin be supplied as an API?
Yes, pharmacopoeial-grade melatonin is supplied for pharmaceutical use, subject to the relevant GMP and documentation requirements for the destination market.
Is melatonin a hormone or a supplement ingredient?
Both descriptions apply. Melatonin is a hormone produced naturally in the body and is also manufactured as a bulk raw material that is sold into supplement, pharmaceutical, cosmetic and research markets, depending on the market’s rules.
What is the difference between supplement grade and API grade melatonin?
The molecule is the same; the difference is the standard and documentation. Pharmacopoeial (API) grade must meet a monograph and GMP requirements, while supplement grade is produced to food-supplement specifications. Buyers should match the grade to their regulatory obligation.
References and Disclaimer
References. Pharmacopoeial monographs for melatonin (USP / Ph. Eur.); published chemistry of indole-containing compounds and of the melatonin biosynthetic pathway (tryptophan → serotonin → N-acetylserotonin → melatonin); standard manufacturer technical and regulatory data. Specifications quoted are representative and should be confirmed against the current certificate of analysis.
Disclaimer. This article is provided for general technical and commercial information only and does not constitute medical advice or a specification. It makes no claim about the therapeutic effects of melatonin. Users are responsible for confirming the regulatory status, permitted claims, safe handling and suitability of the material for their own application and market.