| HS Code | 450557 |
| Productname | 1-Naphthol; 1-Hydroxynaphthalene Pharma Grade API for Tablet / Capsule / Granule / Injection, Oral & Injectable |
| Synonyms | 1-Hydroxynaphthalene; α-Naphthol; Naphthalen-1-ol |
| Chemicalname | 1-Naphthol |
| Iupacname | Naphthalen-1-ol |
| Casnumber | 90-15-3 |
| Einecsnumber | 201-969-4 |
| Molecularformula | C10H8O |
| Molecularweight | 144.17 g/mol |
| Appearance | White to off-white crystalline powder or needles |
| Assay | ≥99.0% |
| Meltingpoint | 94-96 °C |
| Boilingpoint | 278-280 °C |
| Solubility | Slightly soluble in water; soluble in ethanol, ether, chloroform, benzene |
| Grade | Pharma Grade |
| Apistatus | Active Pharmaceutical Ingredient |
| Dosageforms | Tablet, Capsule, Granule, Injection |
| Routesofadministration | Oral, Injectable |
| Storage | Store in a cool, dry, well-ventilated place protected from light |
| Packaging | Fiber drum; packaging size as per customer requirement |
| Pharmacopoeiacompliance | USP/EP/BP/IP as applicable |
| Hs Code | 2907.15 |
As an accredited 1-Naphthol; 1-Hydroxynaphthalene Pharma Grade API for Tablet / Capsule / Granule / Injection, Oral & Injectable factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
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When pharmaceutical-grade 1-naphthol (1-hydroxynaphthalene) enters a propranolol hydrochloride campaign, the first unit operation is O-alkylation to 1-(naphthalen-1-yloxy)-2,3-epoxypropane rather than direct tableting. In a 500–1000 L glass-lined reactor fitted with a retreat-curve impeller and baffle, 1-naphthol is charged at 1.0 mol against 1.10–1.25 mol epichlorohydrin, with 1.05–1.15 mol sodium hydroxide and a quaternary ammonium phase-transfer catalyst at 0.5–2.0 mol% relative to the naphthol. Excess epichlorohydrin is removed under reduced pressure at ≤40°C to suppress oligomerization, because uncontrolled exotherms above 45°C have been observed to raise dimeric ether content and lower subsequent epoxide ring-opening selectivity. The isolated glycidyl ether is ring-opened with isopropylamine at 20–30°C with a staged hold at 50–60°C, followed by hydrochloride salt formation and recrystallization from an alcohol-ketone system. For oral solid dosage forms, the resulting propranolol hydrochloride is formulated by direct compression or wet granulation; after wet granulation in a high-shear mixer and fluid-bed drying to a loss-on-drying endpoint of 0.5–2.0%, the granules are milled through a 0.8 mm screen before compression. Release testing is conducted against the USP Propranolol Hydrochloride Tablets monograph, including USP <711> dissolution, USP <905> uniformity of dosage units, and residual solvent limits under ICH Q3C, while the API manufacturing step is governed by ICH Q7 and the finished dosage facility by 21 CFR 211. Terminal product types include immediate-release tablets at 10 mg, 20 mg, 40 mg, 60 mg, and 80 mg, hard gelatin capsules, and oral solution concentrates where the active is present as propranolol hydrochloride.
A different 1-naphthol demand profile emerges when the downstream API is duloxetine hydrochloride, where the naphthyloxy group remains in the final molecule and unreacted 1-naphthol becomes a release specification rather than an intermediate burden. In this route, 1-naphthol is etherified with a chiral thiophene-bearing propanol intermediate under Mitsunobu or base-mediated conditions; typical charging ratios in synthesis patents place 1-naphthol at 1.05–1.15 molar equivalents to the activated chiral alcohol, with cesium carbonate or potassium carbonate at 1.2–1.5 eq in tetrahydrofuran or dimethylformamide at 45–65°C, though published data for exact plant-scale charge ratios in this specific configuration is limited. After aqueous workup, residual 1-naphthol is reduced by alkaline washing and silica gel filtration, with the API impurity specification driven by ICH Q3A/Q3B thresholds. Duloxetine hydrochloride is formulated as delayed-release capsules by layering the active onto sugar spheres in a Wurster fluidized-bed coater, followed by a seal coat of hypromellose and an enteric coat of methacrylic acid–ethyl acrylate copolymer dispersion; the coated pellets are blended with talc and filled into hard gelatin capsules at 20 mg, 30 mg, and 60 mg strengths. Release testing follows the USP Duloxetine Delayed-Release Capsules monograph, including USP <711> two-stage dissolution and USP <905> uniformity, with elemental impurity control under ICH Q3D and residual solvents under ICH Q3C. The main processing bottleneck in this capsule route is not 1-naphthol conversion but enteric coating reproducibility; pellets with surface damage or coating thickness outside the validated process window show premature release in 0.1 N HCl acid-stage testing.
What limits residual 1-naphthol clearance in dapoxetine hydrochloride film-coated tablet manufacturing is not the initial etherification yield but the stability of the chiral center during final salt formation and the extraction efficiency of unreacted naphthol from the lipophilic API. In one common synthetic route, 1-naphthol is coupled to a chiral 3-substituted propanol intermediate under alkaline conditions; plant-scale operations typically charge 1-naphthol at 1.05–1.10 molar equivalents relative to the chiral substrate, with potassium carbonate at 1.0–1.5 eq in acetonitrile at 55–70°C. The reaction mixture is quenched into a toluene-water system, and the organic phase is washed with 0.5–1.0 N sodium hydroxide to remove weakly acidic unreacted 1-naphthol, a step requiring narrow pH control to avoid emulsions and loss of the basic API. Residual 1-naphthol in the isolated free base is controlled by HPLC; when the level exceeds the ICH Q3A reporting threshold for unqualified impurities, the batch is reprocessed through activated carbon or additional base washes. Dapoxetine hydrochloride is formulated as film-coated tablets by direct compression or wet granulation; the active is blended with lactose monohydrate, microcrystalline cellulose, crospovidone, colloidal silicon dioxide, and magnesium stearate, then compressed and coated with a hypromellose-polyethylene glycol film. Because dapoxetine has been approved under EMA rather than a globally harmonized pharmacopoeial monograph in all jurisdictions, release testing is aligned with ICH Q6A, ICH Q2(R2), and EudraLex Volume 4, while residual solvents are controlled under ICH Q3C and elemental impurities under ICH Q3D. Terminal finished product types are film-coated tablets at 30 mg and 60 mg, packaged in push-through blisters.
Injectable propranolol hydrochloride production imposes a different impurity-control hierarchy on 1-naphthol than oral solid manufacturing, even when the same glycidyl ether route is used. The charging stoichiometry in the API campaign remains 1.0 mol 1-naphthol to 1.10–1.20 mol epichlorohydrin, but the purification train is expanded to include multiple recrystallizations and a hot filtration through a 0.45 µm membrane before isolation. The propranolol hydrochloride destined for injection is tested for bacterial endotoxins under USP <85> and particulate matter under USP <788>; the finished solution is compounded in Water for Injection, adjusted to pH 3.0–3.5 with citric acid/sodium citrate, and filtered through a 0.22 µm sterilizing filter. Aseptic filling into Type I glass vials or ampoules is performed in an ISO 5 environment, followed by inspection for visible particles and container-closure integrity. The key processing risk is not chemical instability of the active but the low-pH formulation’s tendency to extract trace hydrophobic impurities from upstream 1-naphthol or gasket materials; therefore the raw material specification for 1-naphthol used in injectable campaigns tightens the limit for total unspecified impurities under ICH Q3A and prohibits reprocessed solvent streams unless validated. The finished injection is released against the USP Propranolol Hydrochloride Injection monograph, with dose strengths of 1 mg/mL in 1 mL or 2 mL single-dose containers, and hospital-use pre-diluted intravenous syringes as regional terminal product types.
Naftopidil tablet campaigns that begin from 1-naphthol are characterized by a two-stage O-alkylation sequence in which the first stage generates 1-(3-chloropropoxy)naphthalene and the second stage couples this intermediate to 1-(2-methoxyphenyl)piperazine. The first-stage charge ratio is 1.0 mol 1-naphthol to 1.05–1.15 mol 1-bromo-3-chloropropane, with sodium hydroxide or potassium carbonate at 1.0–1.2 eq and a tetrabutylammonium bromide catalyst at 0.01–0.05 eq; excess dihalide is removed by vacuum stripping at ≤40°C to limit oligomeric impurities. The second-stage coupling is run in refluxing acetonitrile or methyl isobutyl ketone over 6–12 h, followed by hydrochloric acid salt formation and recrystallization. Process engineering for this route requires stainless steel or enameled reactors; the presence of both chloro and bromo leaving groups can cause local exotherms above 50°C if the base is charged too quickly, and the resulting dark polymeric impurities reduce filterability and increase loss to charcoal treatment. Naftopidil is formulated as tablets by wet granulation with lactose, pregelatinized starch, low-substituted hydroxypropyl cellulose, and magnesium stearate; the active is present at 25 mg or 50 mg per tablet. Release testing is aligned with ICH Q6A, ICH Q2(R2), and regional pharmacopoeial monographs where available; impurity control for residual 1-bromo-3-chloropropane follows ICH M7 and residual solvents follow ICH Q3C. Terminal finished product types are immediate-release oral tablets at 25 mg and 50 mg, commonly supplied in PVC/aluminum blisters.
Contract API intermediate campaigns that isolate 1-(naphthalen-1-yloxy)-2,3-epoxypropane rather than carrying it forward in a single train operate under ICH Q7 for registered intermediates and are typically run in multipurpose plants with corrosion-resistant equipment. In this traded-intermediate segment, 1-naphthol is charged at 1.0 mol to 1.15–1.25 mol epichlorohydrin, with 1.05–1.10 mol sodium hydroxide and a phase-transfer catalyst at 0.02–0.05 eq; the glycidyl ether is isolated by vacuum distillation or wiped-film evaporation after an aqueous quench. The main production bottleneck is ring-opening hydrolysis of the epoxide during alkaline workup, so the quench volume and temperature are controlled to keep the aqueous phase below 10°C and the contact time below 15 min before phase separation. The isolated intermediate is supplied to downstream aryloxypropanolamine API manufacturers under a specification that includes epoxide content by titration, color, and residual 1-naphthol, with residual solvents controlled under ICH Q3C and elemental impurities under ICH Q3D. Terminal product types include the isolated glycidyl ether in 200 L steel drums or 1000 L intermediate bulk containers, used for propranolol and related cardiovascular APIs. Published data for full batch-scale kinetic parameters in this specific isolated intermediate configuration is limited; process validation therefore relies on demonstrated mixing, temperature uniformity, and epoxide stability under the selected reaction conditions.
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1-Naphthol, also named 1-Hydroxynaphthalene and identified by CAS 90-15-3, is supplied as a pharmaceutical-grade active substance with the molecular formula C10H8O and molecular weight 144.17 g/mol. The title designation refers specifically to the alpha-hydroxylated naphthalene isomer, not the beta isomer, and covers a crystalline powder presentation for further processing into tablet, capsule, granule, oral, and injectable dosage forms. The material is released under ICH Q7 GMP conditions and is traceable to manufacturer lot records. It is typically packed in double polyethylene liners within HDPE drums under nitrogen headspace to limit oxidative discoloration and particulate contamination.
The unmicronized product exhibits a melting range of 94–96 °C, a boiling point of 278–280 °C, and limited aqueous solubility. It dissolves in 95% ethanol, diethyl ether, and chloroform. Reported physicochemical constants include a pKa of approximately 9.3 and a log P of approximately 2.85. These values affect dissolution from solid oral dosage forms and pH adjustment for parenteral formulations. Because the phenolic hydroxyl is oxidizable, the API should be protected from air, strong oxidizers, and light. Aqueous alkaline solutions require inert-gas blanketing during extended hold times to limit quinone formation.
Where no current pharmacopoeial monograph applies, the release profile is aligned with ICH Q6A and manufacturer specifications. The following table lists representative acceptance criteria; individual certificates of analysis may apply tighter limits for injectable applications.
| Test | Acceptance criterion | Method or standard reference |
|---|---|---|
| Appearance | White to off-white crystalline powder; free of visible foreign matter | Visual inspection |
| Identification | Infrared spectrum corresponds to reference; main HPLC peak matches retention time | USP 197, USP 621 |
| Assay, on dried basis | 99.0–101.0% | HPLC with external standard; USP 621 |
| Melting range | 94–96 °C | Capillary or DSC; USP 741 |
| Loss on drying | ≤ 0.5% | USP 731 |
| Residue on ignition | ≤ 0.1% | USP 281 |
| Related substance: 2-naphthol | ≤ 0.2% | HPLC, area normalization |
| Related substance: naphthalene | ≤ 0.1% | HPLC, area normalization |
| Unspecified impurities | ≤ 0.10% each | ICH Q3A |
| Total impurities | ≤ 0.5% | ICH Q3A |
| Residual solvents | Meets ICH Q3C / Ph. Eur. 5.4; Class 2 and Class 3 solvents reported on CoA | Headspace GC; USP 467 |
| Elemental impurities | Limits based on ICH Q3D for oral and parenteral routes; CoA reports Pb, Cd, As, Hg, Ni, Cr, Cu, Mo, V | USP 232/233 |
| Particle size | D90 ≤ 200 µm unless otherwise specified; D50 typically 50–150 µm for solid oral processing | Laser diffraction; USP 429 |
| Microbial limits, non-sterile grade | Total aerobic count ≤ 103 CFU/g; yeast/mold ≤ 102 CFU/g; absence of Escherichia coli, Salmonella, Staphylococcus aureus, Pseudomonas aeruginosa | USP 61/62 |
| Bioburden, injectable-grade lots | ≤ 102 CFU/g; specified organisms absent | USP 61 |
| Bacterial endotoxins, injectable-grade lots | ≤ 0.25 EU/mg if sterile-filterable claim is required | USP 85 |
Residual 2-naphthol is the principal positional impurity and is controlled because the beta isomer has a different melting point and can alter the crystallinity of solid formulations. Naphthalene and sulfonated intermediates are limited to reduce volatile organic content, odor, and crystallization defects. Appearance and melting-range requirements reject batches with surface oxidation or excessive crystal habit variation. Batch-to-batch variability in crystal habit should be evaluated where direct compression is intended, because needle-like or plate-like habits can reduce flow and increase segregation tendency in low-dose formulations.
For tablet and capsule processing, the API is passed through a 0.5 mm sieve or cone mill before blending to break loose agglomerates. Powder flow evaluation per USP 1174 should be performed when D50 falls outside 50–150 µm or when the span exceeds 2.5. Direct compression is feasible only after flow and bulk density testing; otherwise, dry granulation by roller compaction or wet granulation in a high-shear mixer is required. A representative tablet process may combine the API with microcrystalline cellulose, lactose monohydrate, crospovidone, and a lubricant. Lubricant substitution with sodium stearyl fumarate at 0.5–1.0% w/w is evaluated because the phenolic hydroxyl group can interact with alkaline-earth metal stearates and delay dissolution. Compression screening on a rotary tablet press with pre-compression force of 1–3 kN and main compression force of 5–18 kN is appropriate, but published data for this specific compound at production scale is limited. Disintegration and dissolution are tested per USP 701 and USP 711 using pH 1.2, 4.5, and 6.8 media; low aqueous solubility should be expected unless particle size is reduced or solubilization is used.
For capsule filling, the granulate or powder blend is filled into hard gelatin or HPMC shells after flow aids such as colloidal silicon dioxide are added at 0.25–0.5% w/w. Static charge and agglomeration at low relative humidity may require process humidity control between 35–55% RH. Granulation endpoint is typically controlled by loss on drying at 1.0–2.5% w/w; overdrying increases friability and segregation potential. The granule fraction above 1.0 mm should be milled to preserve content uniformity. For immediate-release capsules, dissolution testing is performed at 37 ± 0.5 °C with paddle speed 50 rpm unless otherwise justified.
The formulation-relevant differences between 1-naphthol, 2-naphthol, and technical-grade 1-naphthol are summarized in the following comparison table.
| Parameter | 1-Naphthol pharma grade | 2-Naphthol pharma grade | 1-Naphthol technical grade |
|---|---|---|---|
| CAS | 90-15-3 | 135-19-3 | 90-15-3 |
| Hydroxyl position | Alpha, 1-position | Beta, 2-position | Alpha, 1-position |
| Melting range | 94–96 °C | 121–123 °C | 93–95 °C typical; wider for lower purity |
| pKa, approximately | 9.3 | 9.5 | 9.3 |
| Assay | 99.0–101.0% | 99.0–101.0% | 96.0–98.0% typical |
| Residual solvents and metals | Controlled per ICH Q3C and ICH Q3D | Controlled per ICH Q3C and ICH Q3D | Not controlled to pharmaceutical limits |
| Appearance | White to off-white crystalline powder | White to off-white crystalline powder | Tan to brown crystalline solid; may contain visible specks |
| Use in tablet, capsule, granule, and injectable formulation | Direct use after release testing; micronization possible | Different solubility and crystallization profile; not interchangeable without reformulation | Not permitted without purification under GMP |
The alpha-hydroxylated naphthalene differs from 2-naphthol not only in melting point but also in solution acidity, chromatographic retention, and oxidative degradation products. In solid oral dosage form design, melting range directly affects hot-melt granulation or extrusion processes. The alpha isomer may be more prone to colored quinone formation under alkaline conditions than the beta isomer; however, published data for this specific configuration is limited. Forced degradation studies under ICH Q1A should be completed before formulation lock to establish degradant identity and mass balance.
Technical-grade 1-naphthol is not acceptable for oral or injectable pharmaceutical use without purification. It may contain polynuclear aromatic compounds, sulfonated intermediates, chlorinated intermediates, and colored oxidation by-products that are not controlled to ICH Q3A or ICH Q3D limits. Pharmaceutical-grade material is manufactured under controlled conditions and is supported by a certificate of analysis, stability data, and change-control documentation. Production and primary packaging systems are generally operated under ISO 9001:2015 and, where applicable, ISO 15378:2017.
Injectable processing requires a substantially different control strategy. The compound has limited aqueous solubility and should be formulated with cosolvents, cyclodextrins, or pH-controlled buffers after solubility assessment. Terminal steam sterilization should not be assumed; oxidative degradation at elevated temperature can generate quinone-type species. Aseptic filtration through 0.22 µm polyethersulfone or polyvinylidene fluoride membranes is screened, but filter binding and extractables must be evaluated at the intended active concentration. The final injectable solution must meet sterility per USP 71, bacterial endotoxin limits per USP 85, and particulate matter limits per USP 788. For development lots intended for injection, bioburden and endotoxin are monitored before aseptic processing; if the API is not sterile, the formulated solution is sterilized by filtration and the process is validated to a sterility assurance level of 10−6.
Oxidative protection in parenteral solutions may require nitrogen sparging to dissolved oxygen ≤ 1 ppm, light-protective packaging, and antioxidant selection. Compatibility of sulfite antioxidants with the phenolic hydroxyl and rubber closures should be confirmed because phenolic compounds can participate in redox reactions and may extract closure components. Long-term stability studies under ICH Q1A for the intended container closure system are required before assigning shelf life. For oral solid dosage forms, the API should be stored below 25 °C, protected from light, and used within the approved retest period stated on the certificate of analysis.
