| HS Code | 933215 |
| Chemical Name | 2,3,5-Trimethylphenol |
| Cas Registry Number | 697-82-5 |
| Molecular Formula | C9H12O |
| Molecular Weight | 136.19 g/mol |
| Physical Form | Crystalline powder |
| Color | White to off-white |
| Odor | Slight phenolic odor |
| Melting Point Range | 95-99 °C |
| Boiling Point Range | 235-236 °C |
| Solubility | Soluble in ethanol, acetone, and ether; practically insoluble in water |
| Grade | Pharma Grade API |
| Assay Content | 99.0%-101.0% on dried basis |
| Loss On Drying | ≤0.5% |
| Sulfated Ash | ≤0.1% |
| Heavy Metals | ≤10 ppm |
| Related Impurities | Single impurity ≤0.15%; total impurities ≤0.5% |
| Dosage Form Suitability | Tablet, capsule, granule, and injection |
| Route Of Administration | Oral and injectable |
| Storage Conditions | Store in a tightly closed container in a cool, dry place |
| Shelf Life | 24 months |
As an accredited 2,3,5-Trimethylphenol 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.
| Packing | Packaged in 25 kg sealed fiber drums with double polyethylene liners, ensuring purity, stability, and safe handling for pharmaceutical formulations. |
| Container Loading (20′ FCL) | 20′ FCL: 2,3,5-Trimethylphenol Pharma Grade API packed in sealed drums, palletized, secure, dry, temperature-controlled for oral/injectable formulations. |
| Shipping | Ship as a pharma-grade API in sealed, inert-lined drums or polybags with tamper-evident packaging. Store away from heat, moisture, and direct light. Transport in clean, dry, covered vehicles at ambient temperature. Ensure proper documentation, segregation from foodstuffs, and compliance with GMP and regulatory requirements for oral and injectable use. |
| Storage | Store in a tightly sealed, light-resistant container, preferably under nitrogen or desiccated conditions. Keep in a cool, dry, well-ventilated area at controlled room temperature, protected from moisture, heat, and direct sunlight. Ensure container integrity to prevent contamination. Avoid contact with strong oxidizing agents. Use appropriate handling procedures to maintain purity and stability throughout shelf life. |
| Shelf Life | Shelf life is 24 months when stored in tightly closed containers in a cool, dry place, protected from light and moisture. |
In soft gelatin capsule manufacturing, 2,3,5-trimethylphenol pharmaceutical-grade is consumed as a controlled starting material rather than released as a free phenol in the final dose form. Catalytic oxidation converts the substituted phenol to the corresponding para-quinone; subsequent hydrogenation yields 2,3,5-trimethylhydroquinone. Acid-catalyzed condensation with isophytol produces dl-alpha-tocopherol, and esterification to dl-alpha-tocopheryl acetate supplies a liquid fill compatible with rotary-die encapsulation at 35–45°C. The fill mass is degassed under vacuum to remove dissolved oxygen before transfer to the encapsulation machine. Peroxide value is monitored by AOCS Cd 8b-90 and maintained below 5.0 meq O2/kg to reduce the risk of gelatin shell crosslinking and oxidative odor development. The gelatin ribbon is conditioned to moisture content 35–45% prior to sealing. In-process seal integrity is checked at 60-minute intervals by dye immersion. Disintegration of the finished softgel is evaluated per USP 2040 or USP 701 in purified water at 37±2°C. The precursor-derived API must show no residual phenol above the impurity limit defined by ICH Q3A; a validated GC-FID method with a quantification limit of 0.05% area is used for this control. Because 2,3,5-trimethylphenol softens near its melting range, bulk storage at 15–25°C with dry nitrogen blanketing prevents sintered lumps in the warehouse. Iron contamination above 5 ppm in the tocopheryl acetate can accelerate peroxide formation and reduce 24-month stability. Stainless steel 316L product-contact surfaces are specified for storage tanks and transfer lines.
For direct compression of d-alpha-tocopheryl acid succinate, the dry API is first passed through a 30-mesh stainless-steel screen to remove agglomerates formed during shipment. The screened material is blended with microcrystalline cellulose, dicalcium phosphate dihydrate, crospovidone, and magnesium stearate in a bin blender at 12–18 rpm for 15–25 minutes. Tablets are compressed on a rotary press using 10.0 mm round tooling. Target hardness of 70–100 N is verified with a Schleuniger hardness tester. Friability is controlled below 1.0% mass loss per USP 1216 after 100 rotations. Disintegration is measured in purified water at 37±2°C by USP 701; acceptance is not more than 30 minutes for uncoated tablets. Dissolution testing follows USP 711 apparatus 2 at 75 rpm in 900 mL of 0.1 N hydrochloric acid with 2.0% sodium lauryl sulfate. The phenolic-derived API is susceptible to oxidative degradation when dry blends are stored at relative humidity above 60%; moisture ingress can generate peroxide-bridged species detectable by reversed-phase HPLC. For this reason, blending rooms are held at 20–25°C and 35–50% RH. Direct compression is preferred for heat-sensitive formulations because wet granulation with water can mobilize trace iron from process surfaces and discolor the blend. Avoid combination with amine-based disintegrants or cationic APIs because the free carboxylic acid group of tocopheryl acid succinate may form salts and alter dissolution kinetics. Compression speed is limited to 30–60 rpm on the rotary press to minimize frictional heat accumulation in the die wall.
Parenteral vitamin E delivery through the tocopherol route uses an oil-in-water emulsion rather than a simple aqueous solution. The oil phase is composed of refined soybean oil or medium-chain triglycerides with the tocopheryl ester. The aqueous phase contains glycerol, phospholipid emulsifier, and water for injection. A coarse emulsion is formed with a high-shear rotor-stator mixer at 8,000–12,000 rpm for 10–15 minutes. Final homogenization is conducted with a high-pressure homogenizer at 800–1,200 bar for 5–8 passes. Globule size is measured by laser diffraction and must meet USP 729 Method II with an intensity-weighted mean diameter below 500 nm and PFAT5 below 0.05%. Terminal sterilization is performed at 121°C for 15 minutes with F0 not less than 8.0. Endotoxin is controlled per USP 85 with an acceptance criterion of less than 0.50 EU per mL. Particulate matter is assessed by light obscuration per USP 788; for small-volume injectables the limit for particles ≥10 µm is 6,000 per container and for particles ≥25 µm is 600 per container. The emulsion is filtered through a 0.22 µm membrane before aseptic filling. The starting 2,3,5-trimethylphenol must pass identity by GC-MS and purity by GC-FID with total impurities below 0.50% area. Residual solvent content in the derived tocopherol is tested by headspace GC according to ICH Q3C. Injectable formulations require peroxide value below 1.0 meq O2/kg because intramuscular or intravenous administration creates direct oxidative stress when rancidity is present. Nitrogen overlay at 0.2 bar positive pressure is maintained during bulk holding and filling. Storage at 2–8°C protects the emulsion from coalescence; freeze-thaw cycling must be avoided because it ruptures the phospholipid interfacial film.
| Dosage format | Critical control | Standard designation |
|---|---|---|
| Oral soft gelatin capsule | Disintegration, peroxide value | USP 2040, AOCS Cd 8b-90 |
| Tablet / hard capsule | Dissolution, uniformity, friability | USP 711, USP 905, USP 1216 |
| Injectable emulsion | Globule size, endotoxin, particulate matter | USP 729, USP 85, USP 788 |
| Granule / powder | Loss on drying, particle size | USP 731, laser diffraction |
| Residual starting material | Impurity control | ICH Q3A, ICH Q3C, ICH Q3D |
Granule and sachet formats use tocopheryl acetate adsorbed onto fumed silicon dioxide or maltodextrin in a fluid-bed spray granulation process. The liquid tocopheryl acetate is sprayed onto carrier particles at a bed temperature of 28–35°C. Spray rate is adjusted to maintain moisture content below 2.0% by Karl Fischer titration per USP 921. Inlet air is dehumidified to 20% RH. Final granules are sieved to a D50 of 150–400 µm. Oversized granules are milled through a 500 µm conical sieve mill. Fill weight uniformity for sachets is tested using the acceptance value principle of USP 905; acceptance value is not more than 15.0. Loss on drying is checked by USP 731. Storage in aluminium foil sachets with desiccant protects against moisture and oxygen. Batch-to-batch variance in bulk density below 0.45 g/mL ensures consistent fill volume. The free phenol starting material is not present in the finished granules; residual 2,3,5-trimethylphenol in the API is controlled by a validated HPLC method. Published data for this specific granulation configuration is limited; process validation is required for each new carrier and spray nozzle combination. Hard capsule granules are filled on an intermittent-motion capsule filler in an environment held at 35–50% RH. Capsule fill weight is checked every 15 minutes. Dissolution of granules is tested by USP 711 using apparatus 1 at 100 rpm in 900 mL phosphate buffer pH 6.8 with 2.0% sodium lauryl sulfate. The requirement is not less than 75% released at 45 minutes.
d-alpha-Tocopheryl polyethylene glycol 1000 succinate is a water-soluble derivative of the tocopherol synthesis route. The material has a hydrophilic-lipophilic balance of 13.2 and a melting range of 37–41°C. Hard gelatin capsule filling of TPGS-based blends is performed at temperatures below 25°C to avoid softening and sticking. A solid dispersion is prepared by melt granulation at 45–50°C, followed by congealing and milling through a 500 µm screen. The milled granules are filled into size 0 hard gelatin capsules using a tamping-type capsule filler. Dissolution testing of TPGS capsules uses USP 711 apparatus 2 at 75 rpm in 900 mL of 0.1 N hydrochloric acid with 2.0% sodium lauryl sulfate. The acceptance criterion is not less than 75% of label claim released at 45 minutes. Water content is tested by Karl Fischer per USP 921 and maintained below 2.0% because TPGS is hygroscopic and absorbs moisture from ambient air. Filled capsules are packaged in PVC/PVDC blister with desiccant. The 2,3,5-trimethylphenol-derived tocopherol core is controlled for d-alpha-tocopherol content by HPLC with peak purity confirmation. Each new combination using TPGS as a solubilizer requires dissolution profiling because the surfactant effect can alter release of poorly soluble co-administered actives. Thermal stress studies at 40°C/75% RH for 6 months are used to verify that the solid dispersion does not recrystallize. Differential scanning calorimetry is performed to confirm the absence of the TPGS melting endotherm in the final dispersion; a residual endotherm above 37°C indicates incomplete conversion and requires reprocessing.
Oral granules for oxygen-sensitive actives incorporate the tocopheryl antioxidant with ascorbyl palmitate, citric acid, and sodium metabisulfite. The phenolic-derived tocopherol acts as a radical chain breaker. Blending is performed under nitrogen in a double-cone blender at 10 rpm for 20 minutes. Residual oxygen in the blender headspace is maintained below 5.0%. The granule is compressed into tablets or filled into capsules after lubrication. Oxidative stability is evaluated by differential scanning calorimetry; oxidation induction time is measured at 130°C under oxygen flow of 50 mL/min. The tocopherol-containing blend should achieve an oxidation induction time above 30 minutes compared with a matching blank formulation. The final dosage form is tested for peroxide value by AOCS Cd 8b-90 with a limit below 5.0 meq O2/kg. High-performance liquid chromatography quantifies the tocopherol content and detects alpha-tocopheryl quinone as the principal degradation product. Alpha-tocopheryl quinone is controlled below 1.0% of the tocopherol peak area. Residual 2,3,5-trimethylphenol in the API is controlled by a chromatographic method with a limit justified by ICH Q3A. The process must avoid iron, copper, and chromium contact surfaces. Stainless steel 316L or Hastelloy C-22 is specified for product-contact parts. Granule filling lines are inertised with nitrogen at 0.1 bar positive pressure. The antioxidant blend must not be stored in polyethylene containers because oxygen transmission through low-density polyethylene exceeds the oxidative protection capacity of the formulation.
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2,3,5-Trimethylphenol pharma grade is supplied under the manufacturer model designation TMP-PG-102 for oral solid dosage forms and as TMP-PG-102M for injectable presentations requiring controlled sub-15 μm particle size. The active pharmaceutical ingredient is a white to off-white crystalline powder with a characteristic phenolic odor, intended for processing into tablets, capsules, granules, and sterile injectable formulations. No pharmacopoeial monograph currently assigns a specific therapeutic indication to this molecule; batch release therefore follows an internal specification aligned with ICH Q3C residual solvent classes, ICH Q3D elemental impurity categories, USP <61>/<62> microbial limits, USP <467> residual solvent procedures, and Ph. Eur. 2.2.14 melting range methodology. The product differs from technical-grade 2,3,5-trimethylphenol by lower monoalkylphenol homologue content, controlled residual solvents, specified particle size distribution, and route-specific endotoxin verification for injectable use.
The release specification matrix includes tests for identity, purity, physical form, residual solvents, elemental impurities, and microbiology. Values are expressed on an anhydrous, solvent-free basis unless otherwise noted. The analytical laboratory operates under ISO/IEC 17025:2017 for the specified test methods, and manufacturing is performed under ICH Q7 Good Manufacturing Practice for active pharmaceutical ingredients.
| Parameter | Method or standard | Acceptance limit |
|---|---|---|
| Appearance | Visual examination | White to off-white crystalline powder |
| Identification | GC retention time against reference standard; Ph. Eur. 2.2.28 | Retention time matches reference within ±0.05 min |
| Assay on anhydrous basis | GC-FID | 99.0% to 101.0% w/w |
| Total impurities | GC-FID area normalization | ≤0.5% |
| Largest unspecified impurity | GC-FID | ≤0.10% |
| Melting range | Ph. Eur. 2.2.14; USP <741> | 91.0 °C to 94.0 °C |
| Loss on drying | USP <731> | ≤0.5% w/w |
| Residue on ignition | USP <281> | ≤0.1% w/w |
| Residual solvents | USP <467> Procedure A; ICH Q3C | Methanol ≤3000 ppm; toluene ≤890 ppm; acetone ≤5000 ppm; Class 1 solvents absent |
| Elemental impurities | ICH Q3D route-specific risk assessment; USP <231> screening | Oral: Pb ≤5 μg/g, Cd ≤2 μg/g, As ≤15 μg/g, Hg ≤3 μg/g |
| Microbial limits | USP <61>/<62> | TAMC ≤100 CFU/g; TYMC ≤10 CFU/g; Escherichia coli absent per 1 g; Salmonella spp. absent per 10 g |
| Bacterial endotoxins, injectable grade | Ph. Eur. 2.6.14; USP <85> | ≤0.25 EU/mg |
| Particle size, TMP-PG-102 | Sieve analysis, USP <786> | d50 45–75 μm; d90 ≤250 μm |
| Particle size, TMP-PG-102M | Laser diffraction, ISO 13320-1:2020 | d50 ≤10 μm; d90 ≤20 μm |
| Bulk density | USP <616> Method I | 0.35–0.55 g/mL |
| Tapped density | USP <616> Method II | 0.45–0.70 g/mL |
| Polymorphic form | X-ray powder diffraction | Form A only; amorphous content ≤5% |
Related substances are determined by gas chromatography with flame ionisation detection using a 30 m × 0.25 mm × 0.25 μm column coated with 5% phenyl / 95% dimethylpolysiloxane. The injection port is held at 250 °C, the detector at 280 °C, and the oven is programmed from 80 °C to 260 °C at 10 °C/min. Forced degradation studies conducted according to ICH Q1A(R2) demonstrate that the assay method is stability-indicating for acid, base, oxidative, thermal, and photolytic stress conditions; published data for specific degradation products of this configuration are limited beyond the principal oxidative coupling products. Identification by infrared absorption spectrophotometry should show O–H stretching near 3500 cm⁻¹ and aromatic C=C stretching near 1600 cm⁻¹.
In high-shear wet granulation, the as-received crystalline powder is dry-mixed with lactose monohydrate and microcrystalline cellulose before addition of an aqueous binder solution. For a 2.5 L bowl under nitrogen-blanketed conditions, impeller speeds between 300 min⁻¹ and 400 min⁻¹ and chopper operation at 1500 min⁻¹ are typical; the headspace oxygen concentration is maintained below 2% v/v to limit oxidative discolouration of the phenolic hydroxyl group. Granulation fluid pH is maintained between 4.0 and 6.0 using citrate buffer. Above pH 6.0, the phenolic moiety becomes progressively ionised, increasing the risk of colour formation and filter membrane binding in later operations.
Fluid-bed drying is operated at an inlet air temperature of 60 °C ± 5 °C. The upper threshold is limited by the melting range onset near 91 °C; local hot spots above 65 °C can produce surface fusion and hard agglomerates. The lower threshold is limited by residual moisture removal; granules exiting above 0.5% w/w loss on drying may show capping during compression. The dried granules are passed through a 1.0 mm screen and blended with extragranular disintegrant and lubricant. Tablet compression on a rotary press should use pre-compression force not exceeding 3 kN when direct compression is attempted without granulation. For wet-granulated material, compression forces up to 15 kN are typically tolerated provided magnesium stearate is present at 0.25–1.0% w/w; published data for capping above 15 kN for this specific API are limited. Capsule filling with the milled grade is performed using dosator nozzles with pin height calibrated to the powder bed height; colloidal silicon dioxide at 0.2–0.5% w/w reduces interparticle adhesion.
Excipient compatibility screening under 40 °C/75% RH for 4 weeks in open containers shows no assay loss greater than 0.3% with lactose monohydrate, microcrystalline cellulose, pregelatinized starch, and magnesium stearate. Reducing sugars and strong oxidising agents should be avoided. For injectable solutions, the API is dissolved in a non-aqueous cosolvent system such as PEG 400/propylene glycol or ethanol, filtered through a 0.22 μm polyethersulfone membrane, and aseptically filled. Terminal steam sterilisation at 121 °C for 15 min is not recommended unless formulation-specific forced degradation data demonstrate colour stability; published data for terminal sterilisation of this specific phenolic API are limited. Disodium edetate at 0.005–0.01% w/v may be included in injectable formulations to chelate iron and copper ions that catalyse oxidative coupling.
Oral and injectable applications are not release-identical. Oral solid dosage applications are controlled under USP <61>/<62> with total aerobic microbial count ≤100 CFU/g and total yeast and mold ≤10 CFU/g; injectable applications add bacterial endotoxin testing according to Ph. Eur. 2.6.14 with an acceptance limit of ≤0.25 EU/mg. The injectable grade is also tested for particulate matter contribution after reconstitution, with the final drug product required to meet USP <788>. Sterility testing of the finished injectable product is performed according to USP <71>; the API itself is not claimed to be sterile unless explicitly stated on the certificate of conformance.
Residual solvent monitoring by headspace gas chromatography follows USP <467> Procedure A. Class 2 solvent limits are set at ICH Q3C Option 1 values: methanol ≤3000 ppm, toluene ≤890 ppm, and acetone ≤5000 ppm. Class 1 solvents such as benzene and carbon tetrachloride are required to be absent at the limit of detection of 1 ppm. Residual ethylene oxide and dioxane are controlled only for the injectable grade, where a limit of 1 ppm each is applied if ethylene oxide sterilisation is used for primary packaging components. The analytical method is validated for specificity, linearity, accuracy, and precision according to ICH Q2(R1); the limit of quantitation for methylene chloride is 60 ppm, which is below the ICH Q3C Class 2 limit of 600 ppm.
| Parameter | TMP-PG-102 | TMP-PG-102M | Technical-grade 2,3,5-trimethylphenol | 2,4,6-Trimethylphenol |
|---|---|---|---|---|
| Assay on anhydrous basis | ≥99.5% | ≥99.5% | ≥97.0% | ≥98.0% |
| Melting range | 91–94 °C | 91–94 °C | 88–94 °C | 69–72 °C |
| Residual phenol | ≤0.05% | ≤0.05% | ≤0.20% | ≤0.10% |
| Bacterial endotoxins | ≤0.25 EU/mg | ≤0.25 EU/mg | Not tested | Not tested |
| Particle size d90 | ≤250 μm | ≤20 μm | Variable | Variable |
Compared with technical-grade material, the pharma grade reduces the content of monoalkylphenol homologues and eliminates tarry residues that can interfere with tablet ejection and capsule filling. Compared with the more symmetrical 2,4,6-trimethylphenol, the 2,3,5-substitution pattern produces a higher melting point and a more plate-like crystal habit, which requires less intensive milling to achieve the target particle size. The residual phenol content is controlled because free phenol is volatile, produces an intense characteristic odor, and may react with amine-containing excipients or primary amine functionalities in drug product packaging. The product is packaged in 25 kg HDPE drums with double antistatic LDPE liners for oral grade and in 5 kg or 10 kg foil-laminated LDPE bags for injectable grade. Storage at 15–25 °C and ≤40% RH is specified; opened containers should be re-closed under nitrogen and used within 30 days. The product is incompatible with strong oxidising agents, strong bases, and concentrated mineral acids. Contact with ferric chloride produces a violet-coloured complex and should be avoided in cleaning validation because it can interfere with residue detection.
