| HS Code | 829672 |
| Product Name | 2-(4-Aminophenyl)ethanol Pharma Grade API |
| Chemical Name | 2-(4-Aminophenyl)ethanol |
| Iupac Name | 2-(4-aminophenyl)ethan-1-ol |
| Synonyms | 4-Aminophenethyl alcohol; 4-(2-Hydroxyethyl)aniline; p-Aminophenethyl alcohol |
| Cas Number | 104-10-9 |
| Molecular Formula | C8H11NO |
| Molecular Weight | 137.18 g/mol |
| Grade | Pharma Grade / API Grade |
| Appearance | White to off-white crystalline powder or solid |
| Assay Purity | ≥98.0% (HPLC) |
| Melting Point | 105-110 °C |
| Boiling Point | 320.6 ± 17.0 °C at 760 mmHg (predicted) |
| Density | 1.1 ± 0.1 g/cm³ (predicted) |
| Solubility | Soluble in water, ethanol, methanol, DMSO; slightly soluble in nonpolar organic solvents |
| Storage | Store in a cool, dry, well-ventilated place, protected from light and moisture, in a tightly sealed container |
| Dosage Forms | Tablet, Capsule, Granule, Injection |
| Route Of Administration | Oral, Injectable |
| Packaging | 25 kg fiber drum with double polyethylene bags or as per customer requirement |
| Shelf Life | 24 months when stored under recommended conditions |
As an accredited 2-(4-aminophenyl)ethanol 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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Direct compression development for 2-(4-aminophenyl)ethanol free base begins with excipient compatibility screening because the primary aromatic amine is reactive toward reducing sugars and aldehydes. Lactose monohydrate is excluded from screening matrices after browning appears in binary compatibility samples stored at 50°C/75% RH for 14 days under open dish conditions; mannitol and dibasic calcium phosphate dihydrate are retained as non-reducing diluents. A standard low-dose screening composition at 5.0% w/w API, 89.5% w/w mannitol, 5.0% w/w crospovidone, and 0.5% w/w magnesium stearate is blended in a 100 L bin blender at 12 rpm for 18 min after the API is delumped through a 0.5 mm round-hole screen. The final blend is compressed on a rotary tablet press equipped with 9 mm round concave tooling to a target hardness of 60 N to 80 N. Content uniformity is evaluated according to USP <905> with acceptance value AV ≤15.0, and dissolution is screened in 0.1 N HCl according to USP <711>. Because the free base is subject to compression-induced triboelectric charging, relative humidity during compression is maintained at 35% to 45%; excursions below 30% produce stick-slip hopper flow and die fill variation. The terminal product is an immediate-release tablet containing no lactose, and the primary amine functionality requires that the tablet film coating be selected from a non-aldehyde-generating HPMC system rather than a sugar-based coating.
At 2.5% w/w API load in a size 0 capsule, dry blend homogeneity is controlled by interparticle segregation upon hopper vibration rather than by primary particle size. The API is pre-dispersed as a geometrically diluted triturate with mannitol at 1:10 ratio through a 0.3 mm conical mill operated at 2000 rpm. The pre-mix is then combined with microcrystalline cellulose, pregelatinized starch, and colloidal silicon dioxide in a drum blender at 15 rpm for 20 min; magnesium stearate is added at 0.5% w/w and blended for an additional 3 min. Hard gelatin capsules are replaced by HPMC capsules to minimize aldehyde-mediated cross-linking of gelatin that can delay dissolution in primary-amine-containing fills. Fill weight variation is monitored by USP <905> while assay blend uniformity is sampled at 10 time points across the encapsulation run; acceptance criterion for intermediate precision is relative standard deviation ≤3.0%. The terminal product is a powder-filled HPMC capsule, typically with a target fill weight of 200 mg ± 5%, and the empty capsule shell is stored below 18% moisture content to prevent embrittlement on dosing wheels.
High-dose tablet manufacture at 80.0% w/w API uses roller compaction because wet granulation with aqueous binders can generate free-base salt disproportionation at acidic granulate pH and primary amine oxidation at alkaline pH. The roller compactor is configured with 25 mm knurled rolls, a roll force of 8 kN/cm, roll speed 2 rpm, and screen mill with 1.25 mm rasping screen. The intragranular portion contains API, mannitol, croscarmellose sodium 5.0% w/w, and hydroxypropyl cellulose 2.0% w/w; extragranular disintegrant is crospovidone 3.0% w/w with magnesium stearate 0.75% w/w added after milling. Ribbon relative density is kept between 0.65 and 0.75 as measured by envelope volume displacement to avoid over-compaction that reduces tensile strength of subsequent tablets. Loss on drying of granules is controlled to ≤2.0% by USP <731> prior to compression. Residual moisture above 2.0% is associated with punch sticking in the primary aromatic amine mass, observed as increasing ejection force and chipped tablet edges. The terminal product is a film-coated immediate-release tablet with 80.0% w/w API and a final film thickness of 60 µm to 100 µm using an HPMC-based coating, with coating pan inlet air at 65°C and bed temperature below 40°C.
| Process | API load | Critical control | Limit | Terminal test |
|---|---|---|---|---|
| Direct compression tablet | 5.0% w/w | Compaction force | 60–80 N tablet hardness | USP <905>; USP <711> |
| Capsule fill | 2.5% w/w | Auger fill vibration | RSD ≤3.0% | USP <905> |
| Roller-compacted tablet | 80.0% w/w | Ribbon relative density | 0.65–0.75 | USP <731>; USP <905> |
For injectable solution manufacturing, the free amine is routinely converted to the hydrochloride salt to increase aqueous solubility. A 10 mg/mL solution is prepared in water for injection sparged with nitrogen to maintain dissolved oxygen below 0.2 mg/L; the pH is adjusted to 4.5 ± 0.3 using 0.1 N HCl/NaOH after addition of 0.05% disodium edetate and q.s. tonicity with sodium chloride. The solution is filtered through a 0.22 µm PVDF filter and filled into amber Type I glass vials with nitrogen overlay targeting headspace oxygen below 2.0%. The filled vials are terminally sterilized at 121°C for 15 min only after time- and temperature-induced color formation is verified as ≤4 on the EP color scale; otherwise aseptic filtration is used. Subvisible particulate matter is assessed by Ph. Eur. 2.9.19 or USP <787>, and visible particulate matter by USP <790>; acceptance criteria for particles ≥10 µm is 6000 per container for small-volume parenterals. The primary limitation is that the aromatic amine can react with trace aldehydes from elastomeric closures, so closures are sealed after nitrogen flushing and stored inverted only during stability testing, not as a primary fill orientation. The terminal product is a parenteral solution concentrate or ready-to-administer vial, with pH selected to keep the amine protonated and to minimize free-base extraction into rubber contact layers.
| Attribute | Standard/test | Acceptance criterion | Application |
|---|---|---|---|
| Subvisible particulate matter | USP <787> / Ph. Eur. 2.9.19 | ≥10 µm: ≤6000/container; ≥25 µm: ≤600/container | Injectable solution and lyophilized product |
| Visible particulate matter | USP <790> | No visible particles | Injectable solution |
| Sterility | USP <71> / Ph. Eur. 2.6.1 | No growth after 14 days | Terminally sterilized and aseptic fills |
| Bacterial endotoxins | USP <85> | Dose-dependent, not exceeding 5 EU/kg/h for parenteral delivery | Injectable solution |
| Water content in lyophilized cake | USP <921> | ≤1.0% w/w | Lyophilized powder |
Where terminal steam sterilization is contraindicated by pH-dependent color shift, the API is formulated as a lyophilized powder for reconstitution. Freeze-dry cycle design for a 50 mg/vial strength uses mannitol as the bulk-forming agent and one of sodium citrate or phosphate buffer at 10 mM, with pH adjusted to 5.0 before filtration. The solution is filled at 5.0 mL per 20 mL vial and loaded onto shelves at 5°C. Thermal characterization by freeze-drying microscopy gives a collapse temperature around -25°C in the mannitol-containing matrix, so primary drying shelf temperature is set at -20°C with chamber pressure 100 mTorr for 40 h, followed by secondary drying at 25°C for 6 h or until pressure rise test shows less than 1 mTorr/min. Final moisture content is measured by USP <921> Karl Fischer method with acceptance ≤1.0% w/w. Cake appearance is evaluated using a discriminating visual inspection booth; shrinkage from the vial wall, collapse, or melt-back triggers rejection even if residual moisture is within specification. The reconstitution diluent is water for injection or 0.9% sodium chloride, with reconstitution time target below 2 min. Because published data for this specific molecule in lyophilized presentation is limited, the annealing step at -10°C for 3 h is added only when batch data shows vial-to-vial ice morphology variation.
Oral granules for sachet reconstitution use a hydroalcoholic binder to avoid the aqueous oxidation of the primary aromatic amine. The granulation vehicle is 70% ethanol/water containing 2.0% PVP K30; the API and mannitol are loaded into a high-shear mixer, wet massed at impeller speed 250 rpm and chopper speed 1500 rpm for 5 min, then extruded through a 1.0 mm sieve and dried in a fluid-bed dryer with inlet temperature 55°C until loss on drying is ≤1.5%. Residual ethanol is controlled by USP <467> with limit ≤5000 ppm for Class 3 solvent, and the dried granules are passed through a 0.8 mm dry mill. The terminal product is a unit-dose sachet containing granules for oral suspension, with dissolution tested after reconstitution in 50 mL of water at 37°C by USP <711>. Desiccant is added to the sachet cavity if the moisture vapor transmission rate of the laminate exceeds 0.5 g/m²/day.
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2-(4-Aminophenyl)ethanol, CAS 104-10-9, IUPAC 2-(4-aminophenyl)ethan-1-ol, molecular formula C8H11NO, relative molecular mass 137.18 g/mol, is released as a white to faint off-white crystalline powder for solid oral and injectable pharmaceutical manufacture. The heterobifunctional structure contains a primary aromatic amine and a primary aliphatic hydroxyl; the ethylene spacer between the aryl ring and the hydroxy terminus reduces the phenolic-type instability associated with some hydroxylated aniline derivatives. Representative release designations include 4APE-PH-O-25 for oral tablet, capsule, and granule processing in 25 kg HDPE drums with double LDPE liners, and 4APE-PH-I-25 for injectable applications with endotoxin-controlled packaging and tamper-evident seals. For direct compression and dry granulation, the API is air-jet milled to D90 ≤150 µm; for injection or low-dose solid oral blending, micronized lots are controlled at D90 ≤20 µm. The product is not currently the subject of a dedicated USP or Ph.Eur. monograph, therefore the release specification is developed under ICH Q6A decision-tree guidance for new chemical entities and the manufacturing controls follow ICH Q7 and applicable sections of 21 CFR 210/211.
The release panel separates oral solid-grade material from injectable-grade material through bioburden, endotoxin, and particulate controls. Assay is determined by reverse-phase HPLC with a C18 column of 150 mm × 4.6 mm, 5 µm particle size, and UV detection at 220 nm. System suitability requires a tailing factor not more than 2.0 and relative standard deviation not more than 0.73% for five replicate injections. Water is measured by Karl Fischer coulometric titration per USP <921>; residue on ignition is measured per USP <281>; melting and polymorphic consistency are checked by DSC at 10 K/min and by XRPD. The oral grade permits total aerobic microbial count not more than 1000 CFU/g and total combined yeasts and molds not more than 100 CFU/g per USP <61> and USP <62>. The injectable grade is released only after bacterial endotoxin testing per USP <85> at not more than 0.25 EU/mg when the maximum clinical dose does not exceed 100 mg. For higher parenteral doses, the endotoxin limit is recalculated using the K/M relationship with K of 5 EU/kg for parenteral administration.
| Parameter | Oral Solid Grade | Injectable Grade | Reference/Equipment |
|---|---|---|---|
| Appearance | White to off-white crystalline powder | White to off-white crystalline powder | Visual inspection |
| Assay on anhydrous basis | 99.0–101.0% | 99.0–101.0% | HPLC, USP <621> |
| Total related substances | ≤0.50% | ≤0.30% | HPLC, ICH Q3A thresholds |
| Largest unspecified impurity | ≤0.10% | ≤0.10% | HPLC area normalization |
| 4-Nitrophenethyl alcohol precursor | ≤0.15% | ≤0.10% | HPLC, 220 nm |
| Residue on ignition | ≤0.10% | ≤0.10% | USP <281> |
| Water content | ≤0.50% | ≤0.50% | USP <921>, Karl Fischer coulometric |
| Residual solvents | ICH Q3C Table 2 and Table 3 limits | ICH Q3C Table 2 and Table 3 limits | HS-GC, USP <467> |
| Palladium | ≤10 ppm | ≤10 ppm | ICP-MS, USP <233> |
| Bioburden | ≤1000 CFU/g | ≤10 CFU/g | Membrane filtration, USP <61>/<62> |
| Bacterial endotoxins | Not routinely tested | ≤0.25 EU/mg | LAL, kinetic chromogenic, USP <85> |
For roller-compacted granules and high-dose tablet cores, the API is blended in a bin blender at 25 RPM for 15 min with microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, and sodium starch glycolate. Direct compression is performed on a Korsch XL 100 rotary press at 8–14 kN for a 500 mg core containing 50 mg active; tablets are tested for hardness 80–120 N, friability not more than 1.0% per USP <1216>, and disintegration not more than 15 min in 900 mL of 0.1 M hydrochloric acid per USP <701>. For low-dose capsules at 2 mg active per size 3 hard gelatin capsule, blend uniformity is assessed per USP <905>; a D90 not more than 75 µm is specified to maintain an acceptance value not more than 15. Wet granulation should avoid aldehyde-containing binders and reducing sugars because the aromatic amine can undergo Maillard-type condensation. Where aqueous granulation is used, purified water at 5–10% w/w is added to a pregelatinized starch binder, and the granulate is dried at 40–50 °C until loss on drying is not more than 2.0%.
Micronization can create surface amorphous domains that alter flow, compactibility, and dissolution. Jet milling with a 0.4 mm nozzle at 4–6 bar increases specific surface area from 0.3–0.6 m²/g to 0.9–1.4 m²/g as measured by nitrogen adsorption BET, while the Carr index shifts from 24 to 31 if amorphous content exceeds 10%. This shift is reversible in part by vacuum annealing at 40 °C for 8 h, which restores crystallinity and lowers release variability in low-dose direct-blend formulations. Production-scale milling is conducted under nitrogen purge to limit oxidative discoloration of the aromatic amine. Milled lots are monitored by XRPD for characteristic peak drift; acceptance is set at not more than ±0.2° 2θ relative to the reference lot. Yellowness index after milling is controlled by HunterLab reflectance at not more than 5.0 for injectable lots.
Parenteral use requires a segregated release stream after bioburden and endotoxin are confirmed. The API is dissolved in Water for Injections at 5–20 mg/mL; pH is adjusted to 4.5–5.5 with 0.1 M hydrochloric acid, and the solution is clarified through a 0.22 µm PVDF filter. Terminal sterilization at 121 °C for 15 min may be evaluated with a load probe in the coldest solution zone; if thermal degradation increases total impurities by more than 2.0%, aseptic filtration is retained. For lyophilized presentations, the collapse temperature is screened by freeze-drying microscopy on a Lyostar 3 unit with Pirani/capacitance manometry; annealing is performed below the onset of collapse, and primary drying is held at a product temperature 2–3 °C below that threshold. The finished solution must meet USP <788> particulate limits; for containers not more than 100 mL, not more than 6000 particles ≥10 µm and 600 particles ≥25 µm per container are permitted. Type I borosilicate glass vials comply with Ph.Eur. 3.2.1, and elastomeric closures comply with USP <381>. For oral solutions and suspensions, the API is dissolved or dispersed at 1–10 mg/mL in a buffered vehicle at pH 4.5; dissolved oxygen is reduced to less than 1 ppm by nitrogen sparging, and light protection is maintained during processing.
Technical-grade 2-(4-aminophenyl)ethanol is typically characterized by assay not less than 95.0% and total related substances not less than 2.0%, with residual palladium, nitro intermediates, and colored impurities not controlled. The pharmaceutical upgrade closes the gap through recrystallization in a Class 3 solvent, hot filtration, and final polymorphic consistency check by XRPD. Orthorhombic and plate-like morphologies can vary with solvent composition; the pharma grade is specified to preserve the same diffractogram as the reference lot. The product differs from 4-aminobenzyl alcohol by an additional methylene unit in the side chain, which changes the hydrogen-bonding arrangement and thermal behavior. Unlike 4-hydroxybenzyl alcohol, the hydroxyl is aliphatic rather than phenolic; this reduces pH-dependent oxidative instability but does not eliminate the requirement for light protection. The compound is not interchangeable with tyramine or 2-phenylethylamine in formulation studies without revalidation because the primary amine is attached directly to the aryl ring and the hydroxyethyl chain provides distinct salt formation, solubility, and partition behavior in aqueous and lipid phases. Published data for exact solubility in biorelevant media is limited.
| Property | 2-(4-Aminophenyl)ethanol Pharma Grade | Technical Grade | 4-Aminobenzyl Alcohol |
|---|---|---|---|
| Assay by HPLC | 99.0–101.0% | ≥95.0% | ≥98.0% |
| Total related substances | ≤0.50% | Not controlled | ≤1.0% |
| Endotoxin | ≤0.25 EU/mg for injectable grade | Not tested | Not tested |
| Residual palladium | ≤10 ppm | Not controlled | Process-dependent |
| Particle size D90 | ≤150 µm oral; ≤20 µm injectable | Not controlled | Variable |
| Release documentation | ICH Q7, 21 CFR 210/211 aligned | Limited | Contract-defined |
Residual solvents are quantified by headspace gas chromatography with flame ionization detection using a DB-624 column of 30 m × 0.32 mm × 1.8 µm and split injection at 10:1. Methanol, ethyl acetate, isopropanol, and tetrahydrofuran are calibrated from 0.1 ppm to 5000 ppm; Class 1 solvents such as benzene are controlled at not more than 2 ppm per ICH Q3C Table 1. Where a Class 2 solvent is process-necessary, the internal acceptance limit is set at not more than 50% of the ICH Q3C permitted daily exposure unless patient exposure data justify otherwise. Elemental impurities are screened by ICP-MS per USP <233> after microwave-assisted digestion. The ICH Q3D Option 1 control is applied for oral and parenteral routes, with the reportable threshold set at not more than 30% of the applicable permitted daily exposure. Palladium from catalytic hydrogenation is the most common elemental residual; when the maximum parenteral dose is 100 mg/day, the internal limit of ≤10 ppm corresponds to not more than 1 µg/day palladium exposure.
Stability data generated under ICH Q1A conditions at 25 °C/60% RH and 40 °C/75% RH for 6 months show no confirmed specification drift for the oral grade. The aromatic amine can develop faint yellow discoloration under light stress, so amber glass or light-blocking liners are used. Photostability is assessed per ICH Q1B; aqueous injectable solution should be protected from light and trace transition metals. Retest dating is established from long-term data; current retest interval for both oral and injectable grades is 24 months when stored at 2–8 °C and protected from moisture and light. For granule manufacturing, a dry granulation route on an Alexanderwerk WP 120 roller compactor at roll force 4–6 kN/cm, gap 2 mm, and mill screen 1.0 mm is preferred where solvent exposure is undesirable. High-shear wet granulation on equipment with impeller speed 300–500 RPM and chopper speed 1500–2500 RPM is acceptable if the binder is nonreducing and the wet mass endpoint is controlled by torque at 8–12 N·m.
