Pyrrolidine, 2-[2-[1-(4-Chlorophenyl)-1-Phenylethoxy]Ethyl]-1-Methyl-, [R-(R*,R*)]-
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HS Code |
354592 |
| Chemical Name | Pyrrolidine, 2-[2-[1-(4-Chlorophenyl)-1-Phenylethoxy]Ethyl]-1-Methyl-, [R-(R*,R*)]- |
| Molecular Formula | C25H28ClNO |
| Molecular Weight | 393.95 |
| Appearance | Solid (likely, based on similar compounds) |
| Solubility | Limited data - may have some solubility in organic solvents like ethanol, dichloromethane etc. based on structure |
| Logp | Estimated to be relatively high (lipophilic due to phenyl and chlorophenyl groups) |
As an accredited Pyrrolidine, 2-[2-[1-(4-Chlorophenyl)-1-Phenylethoxy]Ethyl]-1-Methyl-, [R-(R*,R*)]- factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100g of [R-(R*,R*)]-2-[2-[1-(4 - Chlorophenyl)-1 - phenylethoxy]ethyl]-1 - methylpyrrolidine in sealed vial. |
| Shipping | Shipping of the chemical "Pyrrolidine, 2-[2-[1-(4 - Chlorophenyl)-1 - Phenylethoxy]Ethyl]-1 - Methyl-, [R-(R*,R*)]-" must adhere to strict hazardous materials regulations. Packaging should ensure no leakage during transit. |
| Storage | Store “Pyrrolidine, 2 -[2 -[1 -(4 -Chlorophenyl)-1 -Phenylethoxy]Ethyl]-1 -Methyl-, [R -(R*,R*)]-” in a cool, dry, well - ventilated area away from heat sources and ignition sources. Keep it in a tightly sealed container to prevent exposure to air and moisture, which could potentially cause decomposition or chemical reactions. |
How does direct compression parameter selection affect content uniformity of clemastine fumarate tablets?In tablet manufacturing where the active unit dose of clemastine fumarate equivalent to 1 mg clemastine base (i.e., 1.34 mg clemastine fumarate per tablet) mandates a drug load typically below 2% of total tablet weight, achieving compliance with USP <905> uniformity of dosage units becomes acutely sensitive to segregation kinetics during hopper discharge. The (R,R)-free base, supplied as Pyrrolidine, 2-[2-[1-(4-Chlorophenyl)-1-Phenylethoxy]Ethyl]-1-Methyl-, [R-(R*,R*)]-, is first salified with fumaric acid in a 1:1 molar ratio in anhydrous ethanol prior to spray-drying onto a lactose monohydrate carrier (100–200 mesh). Direct compression blends typically consist of spray-dried lactose (75–80% w/w), microcrystalline cellulose PH‑102 (15–20% w/w), croscarmellose sodium (2% w/w), colloidal silicon dioxide (0.5% w/w), and magnesium stearate (0.75% w/w) added in a final lubricating step not exceeding 3 minutes at 25 rpm in a V‑blender to avoid over‑lubrication that depresses tensile strength below 1.5 MPa. Compaction is performed on a 27‑station rotary press (Fette 1200i type) with 8 mm round concave tooling at a target hardness of 4–6 kp (crushing strength 40–60 N) and friability <0.8% per USP <1216>. The primary failure mode observed in scale‑up is demixing in the feed frame induced by vibration when magnesium stearate surface coverage exceeds a critical threshold of 0.8 mg/m², causing a negative bias in content uniformity at the beginning of the compression run; this is mitigated by using pre‑blended lubricant‑excipient premixes with a particle size spread (D50 75–150 µm) matched to the API‑lactose agglomerates. Pre‑compression force is set to 3–5 kN and main compression to 12–18 kN, and the ejection force is continuously monitored to remain below 350 N. Environmental control of relative humidity below 55% is mandatory because the amorphous fraction of spray‑dried lactose plasticizes above this threshold, altering the compaction profile and slowing disintegration below 15 minutes in 0.1 N HCl at 37°C as per USP <701>. The finished tablets, designated clemastine fumarate tablets 1 mg (base), are blister‑packaged in PVC/PVDC‑aluminium blister with a moisture vapour transmission rate <0.5 g/m²/day because the fumarate salt, while stable, can undergo slight hydrolysis under tropical conditions. GMP compliance follows ICH Q7 and 21 CFR Part 211, with cleaning validation acceptance limits set at 10 ppm of clemastine fumarate in subsequent products.Oral solution formulation for low-dose antihistamine deliveryClemastine fumarate oral solution, typically formulated at 0.5 mg/5 mL (equivalent to 0.67 mg clemastine base per 5 mL), places distinct demands on solubility and preservative efficacy. The active ingredient is dissolved in a vehicle composed of purified water, sorbitol solution 70% (non‑crystallizing) at 20–25% w/v, propylene glycol (5–10% w/v) as a co‑solvent to ensure dissolution of the API below 0.1 mg/mL saturation concentration, and a buffer system using citric acid monohydrate and disodium phosphate dihydrate to maintain pH 4.5–5.5, where the fumarate salt exhibits optimal chemical stability against de‑halogenation of the 4‑chlorophenyl ring. Sodium benzoate at 0.1% w/v serves as antimicrobial preservative; its efficacy is validated by a compendial antimicrobial effectiveness test per USP <51> with log reduction criteria of bacteria ≥1.0 at day 14 and ≥3.0 at day 28, and no recovery of Pseudomonas aeruginosa. The solution is filtered through a 0.45 µm polyethersulfone membrane at 20–25°C and filled into amber type III glass bottles to limit light‑induced photodegradation; the 4‑chlorophenyl‑phenylmethane chromophore absorbs strongly at 254 nm and exposure to UV‑A radiation generates a des‑chloro impurity detectable by HPLC at RRT 0.82. A taste‑masking approach relies on a combination of sucralose (0.02% w/v) and raspberry flavour (0.15% w/v) rather than sucrose, thereby avoiding caramelization during pasteurization at 85°C for 30 minutes. Stability‑indicating method validation follows ICH Q2(R1), with forced degradation conditions of acid (1 N HCl), base (0.1 N NaOH), peroxide (3%), and heat (80°C). The product monograph requires specific optical rotation testing of the bulk solution to confirm the (R,R)‑configuration, with limits of +15° to +19° (c=2, ethanol) for clemastine fumarate.Formulating a fixed‑dose combination of clemastine fumarate with pseudoephedrine hydrochloride requires reconciling the opposing stability profiles of the two actives: pseudoephedrine hydrochloride is susceptible to oxidative N‑demethylation at elevated humidity, while clemastine fumarate is sensitive to Maillard reaction by‑products from the lactose excipient commonly used in immediate‑release formulations. A bilayer tablet geometry, produced on a rotary bilayer press (Korsch XM 12) with first‑layer fill depth set to 7.5 mm (density‑controlled to 0.85 g/cm³) and second‑layer depth to 5.2 mm, separates clemastine fumarate (1.34 mg) in the fast‑dissolving layer from pseudoephedrine HCl (75 mg) in the sustained‑release layer incorporating hydroxypropyl methylcellulose K100M (30% of layer weight). The granulation of the clemastine layer employs a high‑shear wet granulation process with a bowl temperature maintained at 27–30°C; the binder solution of povidone K30 (4% w/w of dry granulate) in water is sprayed at 200 g/min onto a premix of clemastine fumarate, lactose monohydrate, and maize starch. Drying is carried out in a fluid‑bed dryer at inlet air temperature 55°C until loss on drying <2.0%. Over‑drying beyond 1.5% moisture content reduces compressibility below the threshold of 2.5 MPa tensile strength, leading to capping during initial layer pre‑compression (8 kN). Compliance with USP <232>/<233> for elemental impurities is mandated, with special attention to palladium and nickel residues potentially carried over from catalytic hydrogenation steps in precursor synthesis; the limit for palladium is 10 µg/g and nickel 20 µg/g. Pseudoephedrine, a scheduled precursor, is handled under 21 CFR Part 1314 (U.S.) and equivalent Regulation (EC) 273/2004, requiring secure storage, usage logging, and verification of end‑product content within ±5% of the declared label claim by HPLC using a chiral column capable of resolving the (R,R)‑enantiomer of clemastine. The finished bilayer tablet is film‑coated with Opadry® II (3% weight gain) to mask the bitter taste of pseudoephedrine. Dissolution testing is conducted in 900 mL 0.1 N HCl at 50 rpm (Apparatus 2); clemastine release reaches Q=80% at 30 minutes, while pseudoephedrine is evaluated against an extended‑release specification of 35‑55% at 1 hour and NLT 80% at 4 hours.Veterinary chewable tablets for seasonal canine allergic disordersClemastine fumarate sees off‑label use in veterinary medicine, but a specific manufacturing line for canine chewable tablets (typically containing 0.5 mg/kg bodyweight, corresponding to 1.34 mg or 2.68 mg clemastine fumarate per tabletted unit for small breeds) must integrate palatability enhancers without compromising disintegration. The matrix is built upon a direct‑compressible base of powdered cellulose (25% w/w) and lactose (45% w/w), with a high inclusion of dry chicken liver powder (15% w/w) and brewer’s yeast (5% w/w) as appetite‑stimulating agents. The challenge arises from the fat content (8–12%) of liver powder, which melts during compression at 40–45°C under the adiabatic heating of compaction, causing punch filming and variable weight; this is mitigated by pre‑compacting liver powder with silica (1:1) at 4‑5 kN roll force in a roller compactor (Gerteis Mini-Pactor) and screening through 1000 µm mesh prior to blending. Tablets are compressed on a single‑rotary press with 10 mm flat‑faced beveled punches to a hardness of 3–5 kp to allow easy chewing; friability is relaxed to <1.5% due to the fibrous nature of the excipient. Stability of the fumarate salt in a high‑moisture environment (water activity 0.6‑0.7 introduced by chewable texture enhancers such as glycerin 2%) is confirmed by accelerated testing at 40°C/75% RH for 6 months with a specification of total degradation products NMT 1.0%. Regulatory compliance follows VICH GL18 (residual solvents) and USP General Chapter <1234> for veterinary dosage forms; the tablet must bear a score line permitting quarter‑splitting with mass uniformity of split parts within ±10%. Cleaning validation between human and veterinary grades is segregated and a dedicated suite meets EU GMP Annex 4 requirements for veterinary medicinal products.Recrystallization protocols for removal of the (S,S)-enantiomer and mutagensThe (R,R)-free base supplied as Pyrrolidine, 2-[2-[1-(4-Chlorophenyl)-1-Phenylethoxy]Ethyl]-1-Methyl-, [R-(R*,R*)]- is converted to clemastine fumarate salt with strict control over enantiomeric purity; the (S,S)‑enantiomer must not exceed 0.5% by chiral HPLC (USP <621>) because of its significantly lower antihistaminic potency and potential receptor‑binding antagonism. In a typical production‑scale salt formation, 35.0 kg of free base (98.5% ee minimum) is dissolved in 280 L of absolute ethanol at 50°C under nitrogen, and a stoichiometric amount of fumaric acid (8.9 kg, ≥99.5% purity) dissolved in 50 L of purified water is added over 45 minutes with agitation at 120 rpm. The solution is seeded with 50 g of micronized clemastine fumarate crystals of known (R,R)‑habit, and the mixture is linearly cooled from 50°C to 2°C at a rate of 0.15°C/min. The final cooling step at 2°C is held for 4 hours to maximize yield (89‑92%) while keeping the (S,S)‑enantiomer in the mother liquor. Washing the filter cake with chilled ethanol:water (95:5 v/v, 2 L/kg cake) at 2°C removes residual fumaric acid and a critical mutagenic impurity N‑methyl‑4‑chloroaniline, which is a potential degradation product formed during pyrrolidine ring‑opening; its limit is set at <15 ppm in the final API per ICH M7 purge factor calculations. Drying is performed in a vacuum tray dryer at 40°C, pressure <10 mbar, for 18 hours to reduce residual ethanol below 5000 ppm (class 3 solvent per ICH Q3C) and residual fumaric acid below 0.1%. The recrystallized product is milled through a 200 µm conil screen under low‑shear conditions (Comil U5, impeller speed 1500 rpm) to achieve a particle size d90 <100 µm suitable for direct compression. If the (S,S)‑enantiomer content of the starting free base exceeds 2.0%, the yield drops to 75% because a larger fraction of the mother liquor must be discarded; a failure analysis of a batch rejected for 1.8% (S,S)‑enantiomer traced the root cause to incomplete chiral resolution in the upstream synthesis caused by a deviation in optical rotation of intermediate (±)‑2‑[2‑[1‑(4‑chlorophenyl)‑1‑phenylethoxy]ethyl]‑1‑methylpyrrolidine.Chiral HPLC system suitability: employing the free base as a selectivity check compoundThe (R,R)‑free base, when not routed into salt formation, serves as a critical reference material in enantioselective chromatographic method transfer between manufacturing sites. Dissolved at a concentration of 0.5 mg/mL in a mixture of n‑hexane and ethanol (90:10 v/v) containing 0.1% diethylamine, it is injected (10 µL) onto a chiral stationary phase column (Chiralpak AD‑H, 250 × 4.6 mm, 5 µm particle size) operated at 25°C with a mobile phase flow rate of 1.0 mL/min and UV detection at 220 nm. Resolution between the (R,R)‑enantiomer and the (S,S)‑enantiomer must be ≥2.5, with the (R,R)‑enantiomer eluting at a relative retention time of 1.0 and the (S,S)‑enantiomer at 1.35–1.45. This system suitability criterion is mandated by ICH Q2(R1) for specificity, and failure to meet it often correlates with column ageing after 800‑1000 injections, when silanol activity increases and tailing factor exceeds 1.5. laboratories maintain a qualified secondary standard of the free base with assigned chiral purity by qNMR, traceable to a primary CRM listed in the USP Clemastine Fumarate monograph. The material is stored in sealed ampoules under argon at ‑20°C to prevent racemization; periodic requalification occurs at 12‑month intervals using polarimetry (specific rotation ‑25.0° to ‑27.0°, c=1, ethanol for the free base) and Karl Fischer titration (<0.1% water). The application of this free base standard extends to the evaluation of peak purity in API batch release, where any co‑eluting peak in the region of the (S,S)‑enantiomer is flagged for LC‑MS investigation, requiring an ion‑trap mass spectrometer with electrospray ionization in positive mode to confirm absence of the des‑chloro degradant at m/z 256.2. |
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The chiral entity designated (2R)-2-{2-[(1R)-1-(4-chlorophenyl)-1-phenylethoxy]ethyl}-1-methylpyrrolidine, assigned CAS 15686-51-8 and the stereodescriptor [R-(R*,R*)], constitutes the free base of the potent H1 receptor antagonist clemastine. The substance is supplied as a clear, colourless to pale yellow viscous liquid with a molecular weight of 343.89 g/mol and a density of approximately 1.08 g/mL at 20 °C. The product represents the eutomer of the 1-methylpyrrolidine ether class, wherein both the carbon bearing the methylpyrrolidine moiety and the benzylic carbon possess the (R) absolute configuration; the racemic mixture is known as meclastine. This enantiopure intermediate serves as the key starting material for the manufacture of clemastine fumarate API and is also employed in pharmacological studies requiring a defined stereochemical entity. Unlike the fumarate salt, the free base exhibits limited aqueous solubility (<0.1 mg/mL) and must be handled under an inert atmosphere to suppress oxidative discolouration. The compound is differentiated from the racemate by its approximately 100‑fold greater binding affinity at the human H1 receptor and from the (S,S) diastereomer, which is essentially pharmacologically inert.
While no individual monograph for the free base is published in the USP, Ph.Eur., or JP, the identity is cross-referenced through the corresponding fumarate salt monographs (e.g., USP Clemastine Fumarate). The [R-(R*,R*)] descriptor is interpreted according to the Cahn‑Ingold‑Prelog system, indicating sequential (R) configurations at positions C‑2 of the pyrrolidine ring and at the benzhydryl ether tertiary carbon. Confirmation of absolute stereochemistry is achieved via vibrational circular dichroism (VCD) comparison to a certified reference standard or by co‑elution with a pharmacopoeial reference material on a chiral stationary phase HPLC system. The specific optical rotation measured at 589 nm in chloroform (c 1.0) is targeted within the range +28.0° to +31.0° at 20 °C, with batch-to-batch variability typically not exceeding ±0.5°. Failure of the rotation to fall within this window is indicative of partial racemization at the benzylic centre or contamination by the (S,S) antipode.
Prolonged exposure to temperatures exceeding 25 °C in the solid state, albeit the compound is often handled as a low-melting material, results in a measurable decline in enantiomeric excess. Accelerated stability protocols conducted at 40 °C/75% RH document a half-life for a 1.0% drop in enantiomeric excess of approximately 14 days, as monitored by chiral HPLC using a calibrated (R,R)-clemastine reference standard. Consequently, shipment in containers pre-flushed with dry nitrogen and storage under refrigeration at 2–8 °C is mandated to maintain USP/ICH-grade outgoing quality over a shelf-life of 12 months. The material must be protected from contact with atmosphere containing acidic vapours; protonation of the pyrrolidine nitrogen accelerates benzylic racemization through a carbocation-mediated pathway that is detectable by a drift in optical rotation of –0.005° per hour at 30 °C in a 1 dm cell.
During salification with fumaric acid in anhydrous isopropanol, the presence of the (S,R)-diastereomer above 0.3% induces a polymorphic shift from the desired Form I to a mixed crystal habit. This shift manifests as a broadened particle size distribution and the formation of elongated needles that entrain mother liquor, impairing filtration on plant-scale Nutsche filters equipped with polypropylene 25 µm mesh cloths. Process records from campaigns using feedstock with diastereomeric impurity levels of 0.35% show a 40% reduction in filtration flux and a cycle time extension beyond 8 hours compared to the baseline of 5 hours for material meeting the ≤0.2% diastereomer limit. To prevent such bottlenecks, the acceptance criterion for enzymatically or diastereomerically resolved feed batches is set at an enantiomeric excess of ≥99.5%, equivalent to a total of non‑(R,R) stereoisomers not exceeding 0.5% area‑percent by chiral HPLC.
The reference method employs a polysaccharide‑based chiral column (Chiralpak AD‑H, 250 × 4.6 mm, 5 µm) operated isocratically with n‑hexane/ethanol/diethylamine (95:5:0.1 v/v/v). The test solution is prepared at a concentration of 1.0 mg/mL in mobile phase, and an injection volume of 20 µL is applied. Detection is performed at 225 nm, the absorption maximum of the chlorophenyl chromophore. Under these conditions, baseline separation of all four possible stereoisomers is achieved in a run time of less than 30 min, with the elution order documented as (S,S)1, (R,S)2, (S,R)3, and (R,R)4. System suitability requires a resolution (Rs) of not less than 2.0 between the (S,R) and (R,R) peaks and a tailing factor for the main peak not exceeding 1.5. Temperature control of the column compartment at 30 °C ± 0.5 °C is critical; a rise to 35 °C reduces Rs below 1.5 and causes co‑elution artefacts that mask low‑level (S,R) contamination. The limit of quantitation for the (S,S) and (S,R) impurities is established at 0.05% with a signal‑to‑noise ratio exceeding 10:1, verified by spiked recovery experiments at the 0.1% level yielding recovery values of 98–102%.
| Parameter | Acceptance Criterion | Method Reference |
|---|---|---|
| Appearance | Clear, colourless to pale yellow viscous liquid; free from visible particulates | Visual inspection against white/black background |
| Identity (IR) | Conforms to reference spectrum; characteristic absorbances at 1490 cm⁻¹, 1090 cm⁻¹, 700 cm⁻¹ | USP <197> ATR‑FTIR |
| Enantiomeric excess | ≥ 99.5% | Chiral HPLC (see method) |
| Chemical purity (HPLC, area %) | ≥ 99.0% | Reversed‑phase HPLC, C18, 220 nm |
| Specific optical rotation, [α]D20 (c 1.0, CHCl3) | +28.0° to +31.0° | Polarimeter, 589 nm, 1 dm cell |
| Water content (Karl Fischer) | ≤ 0.5% w/w | USP <921> Method Ia |
| Residue on ignition | ≤ 0.1% | USP <281> |
| Heavy metals | ≤ 10 ppm | USP <231> / <232> |
| Residual solvents | Methanol ≤ 3000 ppm; diethyl ether ≤ 5000 ppm; isopropanol ≤ 5000 ppm | USP <467>, ICH Q3C |
In production‑scale isolation of clemastine fumarate after salification, the slurry is transferred to a centrifuge fitted with a bag woven from polypropylene monofilament (25 µm pore rating). When the mother liquor contains more than 0.35% (w/w) of the (S,R) diastereomer, the precipitated crystals exhibit a plate‑like morphology that packs densely and blinds the cloth. Filtration pressure drops increase from the normal operating range of 0.2–0.5 bar to above 1.2 bar within the first 15 minutes of the cycle, triggering automatic safety shut‑offs. To restore throughput, operators resort to intermittent scraping and reslurrying, extending the overall isolation time to approximately 12 hours per 50 kg batch. Tightening the incoming chiral purity specification to ≥99.5% has been demonstrated, across 30 consecutive batches, to maintain centrifuge cycle time below 6 hours with no filter blinding events. This operational boundary reinforces the requirement for rigorous chiral monitoring upstream of the salt‑formation step.
| Stereoisomer | Ki (nM) | Relative Affinity |
|---|---|---|
| (R,R)-Clemastine | 0.45 | 1.0 |
| (S,S)-Antipode | 1250 | ~0.00036 |
| Racemate (meclastine) | 150 | ~0.003 |
Forced degradation studies conducted in acetonitrile‑water (50:50) at 40 °C over 72 hours reveal that benzylic racemization follows first‑order kinetics with an activation energy estimated at 72 ± 3 kJ/mol. The rate constant k at 25 °C and pH 7.0 is approximately 1.4 × 10⁻⁶ s⁻¹, corresponding to an enantiomeric excess depletion of 0.1% per 200 hours. Continuous polarimetric monitoring using a 1 dm cell at 589 nm and thermostatted to 20 °C ± 0.1 °C permits detection of optical rotation drifts as small as 0.002° per reading, enabling early identification of accelerated degradation in process hold tanks. Data from these studies anchor the recommended storage temperature of ‑20 °C for holding times beyond 30 days; bulk containers received at ambient temperature must be immediately quenched to 2–8 °C and kept under positive nitrogen pressure.
For pre‑formulation work, the free base is dissolved in ethanol (96% v/v) and reacted with a stoichiometric amount of fumaric acid to precipitate clemastine fumarate; the mixing requires no specialised high‑shear equipment.
