| HS Code | 956547 |
| Product Name | Trans-4-methylcyclohexylamine Pharma Grade API |
| Chemical Name | trans-4-methylcyclohexan-1-amine |
| Synonyms | trans-4-Methylcyclohexanamine; trans-4-Methylcyclohexyl amine |
| Cas Number | 2523-55-9 |
| Molecular Formula | C7H15N |
| Molecular Weight | 113.20 g/mol |
| Chemical Family | Cycloaliphatic amine |
| Grade | Pharma Grade |
| Api Status | Active Pharmaceutical Ingredient |
| Purity | ≥99.0% (GC) |
| Assay | 98.0%–102.0% |
| Appearance | Colorless to pale yellow liquid |
| Odor | Amine-like odor |
| Boiling Point | 151–154 °C |
| Density | 0.85 g/cm³ at 25 °C |
| Flash Point | 43 °C |
| Dosage Forms | Tablet, Capsule, Granule, Injection |
| Routes Of Administration | Oral, Injectable |
| Storage Conditions | Store in a cool, dry, well-ventilated place; keep container tightly closed; protect from light and moisture |
| Shelf Life | 24 months when stored as recommended |
| Packaging | 25 kg drum or as per customer requirement |
As an accredited Trans-4-methylcyclohexylamine 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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In sulfonylurea API manufacture, trans-4-methylcyclohexylamine functions as the nitrogen donor for trans-4-methylcyclohexyl isocyanate, which is coupled to a substituted benzenesulfonamide intermediate in the synthesis of glimepiride. The free amine itself is not typically compressed as a finished tablet active ingredient in any current USP or Ph. Eur. monograph; rather, it is consumed upstream and the resulting sulfonylurea is formulated into oral solid dosage forms. Plant-scale handling of the free amine requires inert blanketing because it absorbs carbon dioxide and can form carbamate salts on exposure to ambient air. In continuous API trains, the amine is fed into a phosgenation reactor maintained at 0–5 °C, with triphosgene supplied as a 1.0–1.2 molar equivalent in toluene. The isocyanate intermediate is then distilled under vacuum at 60–65 °C head temperature and stored under nitrogen before coupling. Residual amine in the isolated sulfonylurea is controlled below the ICH Q3A qualification threshold of 0.15% for a maximum daily dose up to 2 g/day. This upstream control determines whether downstream tablet batches meet content uniformity acceptance criteria under USP <905> with an acceptance value not exceeding 15.0. Because glimepiride is a low-dose API with commercial tablet strengths of 1 mg, 2 mg, 3 mg, 4 mg, 6 mg, and 8 mg, primary amine carryover from T4MCHA can alter crystalline habit, hygroscopicity, and excipient compatibility. For this reason, the material is specified with a chiral purity of not less than 99.0% and a trans isomer content above 99.5% in the pharma grade certificate of analysis, though published data for this specific configuration is limited. The downstream dosage form relies on particle size distribution of the milled sulfonylurea rather than on the amine itself; therefore the application of T4MCHA is indirect but essential to chemical identity, impurity profile, and batch-to-batch reproducibility. Equipment used for the phosgenation step is dedicated glass-lined steel with rupture-disc protection, and cleaning validation after each campaign follows 21 CFR 211.67.
Blend uniformity in low-dose sulfonylurea tablets derived from T4MCHA is limited by the cohesive nature of the milled API and the electrostatic charging of fine particles during high-shear mixing. In a direct compression line equipped with a 10 ft³ V-blender and an intensifier bar, the API preblend is passed through a 600 µm sieve, blended with lactose monohydrate and microcrystalline cellulose, and lubricated with magnesium stearate for 3–5 min. The optimum lubricant level is maintained below 0.5 wt% because higher levels increase disintegration time beyond the 30 min limit of USP <701> for immediate-release tablets. Blend uniformity is assessed at six sampling points after 10 min of mixing; the relative standard deviation must be below 5.0% before compression. Batch records show that demixing occurs when the API median particle size D50 exceeds 75 µm, while particles below 10 µm cause punch sticking. The compressed tablets are tested for content uniformity per USP <905>; acceptance value above 10.0 triggers investigation even though the pharmacopoeial limit is 15.0. In production-scale tablet presses operating at 60–80 rpm, capping is controlled by maintaining granulation moisture between 2.0% and 3.5% when wet granulation is used. For a low-dose sulfonylurea tablet derived from T4MCHA, wet granulation with povidone K30 at 3.0–4.0% w/w and purified water yields more robust content uniformity than direct compression, but residual isocyanate impurities can hydrolyze during the drying step and produce the free amine, which must be re-quantified by HPLC.
At capsule filling lines, the free amine is not handled directly; however, residual trans-4-methylcyclohexylamine from the sulfonylurea route is monitored because it can partition into the capsule shell during long dwell times. Hard gelatin capsules filled with glimepiride granulate at 0.5 mg to 4 mg per capsule require a particle size distribution with not more than 30% fines below 75 µm to prevent powder bridging in the dosator. Capsule fill weight variance is controlled at ±3.0% for individual capsules and ±2.0% for the mean of 20 capsules, following USP <905> acceptance value criteria. The granulation process uses a high-shear granulator with impeller speed of 150–200 rpm and chopper speed of 1,500–2,000 rpm; wet massing time is held between 3 min and 5 min because longer massing dissolves lactose fines and creates oversized granules. Drying in a fluid-bed dryer at 60 °C inlet air temperature until loss on drying reaches 1.5–2.5% is followed by dry milling through a 0.8 mm screen. During development, the residual T4MCHA content in the final granulate is quantified by LC-MS/MS with a limit of quantification of 0.05 µg/g; published data for this specific configuration is limited, but ICH Q3A thresholds apply to the amine if it is classified as an ordinary impurity. Cleaning validation for capsule machines uses swab sampling on product-contact surfaces with acceptance of 10 ppm for the isocyanate derivative and 0.1 µg/cm² for the free amine, consistent with 21 CFR 211.67 and ICH Q3A principles.
Injectable-grade synthesis routes impose a different control sequence because trans-4-methylcyclohexylamine is entered into a route that must satisfy EMA/CHMP and ICH Q3C residual solvent limits before the final parenteral API is crystallized. The free amine is not filled into vials as a finished injectable active; instead, any injectable-grade sulfonylurea candidate derived from this intermediate is processed through bacterial-retentive filtration at 0.22 µm and lyophilized or aseptically filled. Sterility assurance relies on ISO 13408-1 and Ph. Eur. 5.1.1, with terminal sterilisation at 121 °C for 15 min only if solution stability permits. Because the amine is a primary amine, nitrosamine formation potential in injectable formulations must be assessed under ICH M7 and EMA/CMDh guidance; any nitrosating source is excluded from the buffer system. Container closure integrity for injectable vials is tested by USP <1207> vacuum decay or high-voltage leak detection. Endotoxin limits are set according to USP <85>; the acceptance criterion is calculated from the maximum patient dose and the route of administration. Particulate matter limits for small-volume injectables follow USP <788> with not more than 6,000 particles per container at 10 µm and not more than 600 particles at 25 µm. A formulation containing the derived sulfonylurea at 0.1 mg/mL requires pH adjustment with dilute hydrochloric acid if precipitation occurs above pH 5.0, but published data for this specific injectable configuration is limited. The use of T4MCHA-derived API in injectable form remains constrained by the absence of an approved parenteral glimepiride monograph in major compendia; process capability is therefore defined experimentally at pilot scale.
When the free amine is used as a chiral resolving agent, the downstream particle size of the resolved acid is influenced by diastereomeric salt crystallization. The amine is added to a stirred mixture of the racemate in isopropanol/water 85:15 v/v at 40–50 °C; the less soluble diastereomeric salt crystallizes upon controlled cooling to 5 °C over 6–8 h. Filtration through a pressure nutsche fitted with 5 µm polypropylene cloth yields a wet cake that is washed with chilled isopropanol and dried under vacuum at 40 °C. Salt stoichiometry is controlled at 1.0:1.0 molar ratio because excess amine produces agglomerates and reduces enantiomeric excess below 99.0%. The diastereomeric salt is then converted to the free acid with dilute hydrochloric acid and extracted into methyl tert-butyl ether. The resolved acid is later formulated into tablets or capsules after salt formation with sodium or calcium. This resolution process is sensitive to cooling rate; jacketed reactors with a heating/cooling ramp of 0.1 °C/min produce narrow crystal size distributions with D90 below 200 µm. Agitation above 300 rpm in a 500 L reactor causes secondary nucleation and fines generation, which complicates filtration and leads to filter cloth blinding. The residual amine content in the resolved acid is limited to 0.10% w/w to avoid altering dissolution of the final oral dosage form. Because enantiomeric purity is a critical quality attribute, the chiral purity is verified by chiral HPLC with a detection limit of 0.05%.
Residual solvent monitoring in coated oral forms begins with headspace gas chromatographic method development rather than wet chemistry because the low-molecular-weight amine is poorly retained on reversed-phase columns without derivatization. For coated oral solids, trans-4-methylcyclohexylamine is not a coating component, but its volatile nature requires headspace gas chromatographic monitoring after tablet film coating. The coating pan exhaust gas is not the concern; residual amine from the API synthesis can migrate into the coating layer during aqueous film coating. Coated tablets are dried at 45–50 °C for 30 min before residual solvent analysis by headspace GC with flame ionization detection. Toluene and isopropanol are limited by ICH Q3C residual solvent classes; toluene is a Class 2 solvent with a permitted daily exposure of 8.9 mg/day and a concentration limit of 890 ppm. Free trans-4-methylcyclohexylamine is monitored at a reporting threshold of 0.05% under ICH Q3A. Detection of the amine in the coating layer above 0.1% indicates incomplete removal during API drying and triggers rework. Film-coated tablets formulated with polyvinyl alcohol-based coatings show lower amine partitioning than hypromellose-based coatings in development studies, but published data for this specific configuration is limited. Dissolution testing in 0.1 N hydrochloric acid at 37 °C by USP <711> Apparatus II with paddle speed 75 rpm is used to verify that residual amine does not alter release of the sulfonylurea API. The acceptance criterion is not less than 80% dissolved in 30 min for immediate-release tablets, though this criterion belongs to the derived API and not to T4MCHA itself. These controls are documented in the pharmaceutical quality system under ICH Q7 and EU GMP Chapter 5.
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Trans-4-methylcyclohexylamine Pharma Grade API for Tablet / Capsule / Granule / Injection, Oral & Injectable is the trans-configured primary amine with molecular formula C7H15N, molecular weight 113.20 g/mol, and CAS registry 2523-55-9. The substance is a clear liquid at 20–25 °C and is supplied as a pharmaceutical-grade free base for downstream solid and parenteral processing. This product designation defines isomeric purity and residual-solvent control; it is not a finished dosage form and carries no assigned therapeutic indication. Site-specific model or grade codes are assigned in the quality agreement and certificate of analysis.
Published industrial data for finished tablet, capsule, granule, and injectable configurations using this exact molecule are limited. The liquid state of the free base imposes the main processing constraint: direct-compression tableting is not technically feasible without prior conversion to a solid salt or adsorption onto a porous carrier. This restriction arises from physical state, not from a compendial exclusion.
In the trans isomer, the amino and methyl groups occupy 1,4-positions on opposite faces of the cyclohexane ring. In the lower-energy chair conformation, the substituents adopt a diequatorial arrangement; the cis isomer alternates axial and equatorial positions. This stereochemical difference changes capillary gas-chromatographic retention on polar columns and permits isomeric-ratio testing by GC-FID. A pharmaceutical-grade trans specification requires a trans/cis area ratio controlled within statistically derived release limits. No public compendial monograph assigns a universal acceptance value for this exact molecule. A mixed isomeric grade is therefore not interchangeable, because cis-isomer carryover can alter retention, salt formation, and crystallization behavior in downstream processing.
Identity testing should include infrared absorption spectrophotometry and gas chromatography. The material must match the reference trans configuration and show no unidentified peaks above the related-substances reporting threshold. Compared with cyclohexylamine, the 4-methyl substituent alters boiling range, polarity, and steric environment around the amino group. The difference is critical for pharmaceutical control: an industrial mixed-grade 4-methylcyclohexylamine may have a broader distillation cut and a higher cis-isomer content, but it lacks the lot-controlled impurity profile expected in a pharma-grade API.
Compared with 4-methylcyclohexanone and 4-methylcyclohexanol, which are commonly used as intermediates, the primary amine is more corrosive and more reactive toward electrophiles. Compared with cyclohexylamine, the 4-methyl group increases molecular weight by 14.03 g/mol and changes the amine’s handling profile. These differences affect salt stoichiometry, residual-solvent purging, and analytical retention. The trans isomeric grade is not interchangeable with a mixed cis/trans technical grade; the latter may be acceptable for industrial rubber or surfactant use but not for pharmaceutical applications requiring isomeric identity.
| Property | Value or range | Method or reference |
|---|---|---|
| Molecular weight | 113.20 g/mol | Calculated from C7H15N |
| Physical state | Clear liquid at 20–25 °C | Visual inspection |
| Boiling range | 149–151 °C at 101.3 kPa | Distillation |
| Density | Approximately 0.85 g/mL at 25 °C | Oscillating U-tube or pycnometer |
| Flash point | Closed cup below 40 °C | GHS/SDS classification |
| Conjugate acid pKa | Approximately 10.6 in water at 25 °C | Potentiometric titration |
Values in the table are reported from general industrial chemical data; batch-specific certificate-of-analysis results are used for release, because distillation cut width, water content, and isomer ratio influence these properties. The conjugate acid pKa is approximately 10.6, meaning the free base is protonated below roughly pH 9. This pH-dependent ionization is used to adjust aqueous solubility for salt formation and injectable processing.
Release testing for water content should follow USP <921> Method Ia or Ph. Eur. 2.5.12. A low water limit is technically relevant because the free base can react with carbon dioxide and water to form carbamates. The exact limit is assigned from stability data, not from a public monograph. Assay by gas chromatography may be performed on a polar capillary column with flame ionization detection; related substances are quantitated by area normalization or external standard against the reference material.
For tablet and capsule manufacture, the free base cannot be directly compressed. Two practical routes are available: conversion to a pharmaceutically acceptable salt, such as the hydrochloride, or deposition onto an inert adsorbent. For carrier loading, synthetic amorphous silica with pore volume above 1.0 mL/g and surface area in the 250–300 m²/g range can be evaluated because internal porosity accommodates liquid APIs and helps maintain powder flow. However, the primary amine can hydrogen-bond to silanol groups, which may retard release or alter content uniformity. The maximum loading must be determined by percolation testing on the selected carrier; published data for this specific configuration is limited.
Wet granulation in an aqueous binder is not the first-line route for the free base because pH-dependent ionization and partial miscibility can delay endpoint attainment and produce variable granule strength. If the amine is first adsorbed or converted to a salt, granulation can proceed in a high-shear mixer or fluid-bed granulator. Process control should rely on impeller torque or net power draw rather than fixed water quantity. In high-shear granulation of an adsorbed liquid API, the transition from pendular to funicular liquid bridges can occur over a narrow water-addition range; reaching the capillary state too quickly consolidates the wet mass and can choke the wet mill. Pilot-scale batches with a 10 L vertical granulator and a 1.5 mm screen are typically used to establish the operating range before scale-up. This statement reflects general solid-dosage scale-up practice, not product-specific data.
Drying of granules containing the free base or its salt should use fluid-bed drying at inlet temperatures below 60 °C unless stability data justify higher temperatures. The free base is volatile and flammable; higher drying temperatures can reduce assay and increase headspace amine concentration. For adsorbed free-base granules, loss on drying should be monitored by moisture balance or Karl Fischer titration rather than by fixed drying time, because silica-based carriers can retain water and create local high-moisture regions. If a non-aqueous granulation vehicle is selected, ethanol or isopropanol may be used with appropriate explosion protection; residual alcohol is controlled by headspace GC and must meet the relevant compendial limit.
Excipient selection requires compatibility screening under ICH Q1A. The primary amine reacts with carbonyl-containing excipients; lactose monohydrate may generate Schiff-base adducts during storage. Mannitol or anhydrous dibasic calcium phosphate is a more appropriate filler if stability data at 40 °C/75% RH for 6 months show no new impurity peaks above the qualification threshold. Tablet compression of salt or adsorbed formulations should be run on an instrumented rotary press to track compression force, ejection force, and die-wall pressure. Magnesium stearate at 0.25–1.0% w/w is usually screened; higher levels may retard dissolution if the amine salt has marginal solubility. Disintegration and dissolution testing of the finished dosage form follow USP <701> and USP <711>, respectively, but these are dosage-form controls, not API-release tests.
For capsule filling, the adsorbed liquid intermediate can be filled into hard gelatin or HPMC capsules after particle-size adjustment. The powder should exhibit a Carr index below 25% and a Hausner ratio below 1.25 for consistent fill weight on a tamping-pin or dosing-disk machine. These are general flow benchmarks; they must be measured with the selected carrier. Fill weight must account for the carrier load, and the hygroscopicity of the carrier should be evaluated because water uptake above 60% RH may plasticize gelatin and accelerate amine-carbon dioxide reactions. Product-specific sorption data for this amine are limited.
Residual solvent control for a pharmaceutical-grade primary amine is based on the manufacturing route. If dichloromethane remains, the ICH Q3C Option 2 limit is 6.0 mg/day; for toluene, the corresponding limit is 8.9 mg/day. Class 3 solvents are limited to 50 mg/day or 0.5% w/w. Elemental impurities are assessed under ICH Q3D, with compendial testing by ICP-MS for arsenic, cadmium, mercury, and lead unless route-specific risk assessment removes the need. No product-specific public monograph establishes lower limits, so site-specific release limits must be traceable to process capability and stability data.
| Control | Limit or basis | Reference |
|---|---|---|
| Dichloromethane, if present | 6.0 mg/day | ICH Q3C Option 2 |
| Toluene, if present | 8.9 mg/day | ICH Q3C Option 2 |
| Class 3 solvents | 50 mg/day or 0.5% w/w | ICH Q3C |
| Elemental impurities | Permitted daily exposure by route | ICH Q3D |
For aqueous injectable dosage, the free base is generally converted to a hydrochloride salt by stoichiometric reaction with hydrochloric acid. The salt has pH-dependent aqueous solubility and can be dissolved in Water for Injection; the target solution pH is typically below 6.0 to maintain protonation and minimize free-base phase separation. Buffers containing phosphate or carbonate should be evaluated for incompatibility because amine salts can form insoluble derivatives or promote carbon dioxide uptake at alkaline pH. Published formulation data for this specific amine salt are limited; forced degradation and pH-rate profiling under ICH Q1A are required before finalizing a parenteral formulation.
Parenteral-grade material must be controlled for bacterial endotoxins using USP <85> or Ph. Eur. 2.6.14. The acceptance criterion is dose-based. For intravenous administration, the upper endotoxin limit is 5 USP Endotoxin Units/kg of body weight per hour; the material limit is derived from the maximum planned dose and administration rate. Particulate matter in the finished injectable must comply with USP <788> or Ph. Eur. 2.9.19. Heat sterilization of the free base is constrained by flammability and volatility; therefore, the preferred route is aseptic filtration of the dissolved salt solution through a 0.22 µm membrane after pH adjustment. Filter compatibility must be confirmed because primary amines can adsorb to nylon membranes and may extract additives from some membrane polymers.
For oral solutions or drops, the same salt-formation approach applies. The free base has low aqueous miscibility; protonation below pH 9 improves solubility. Taste masking, pH control, and oxygen-sensitive packaging are route-specific development barriers, and published formulation data for this exact molecule are limited.
Storage of the free base should be under dry nitrogen in tightly sealed containers. The primary amine reacts with atmospheric carbon dioxide to form carbamates, and water uptake can liberate amine vapor and raise headspace pressure. Refrigerated storage at 2–8 °C is commonly specified for primary-amine APIs, but the retest interval must be assigned from batch stability data. Transfer lines and receiving vessels should be rated for flammable liquids, with local exhaust ventilation, because the closed-cup flash point is below 40 °C. Contact with strong oxidizing agents, acids, and acid chlorides must be avoided. Opened containers should be blanketed with dry nitrogen and resealed under positive nitrogen pressure.
