Pyrrolidine, 2-[2-[(P-Chloro-Α-Methyl-Α-Phenylbenzyl)Oxy]Ethyl]-1-Methyl-, (+)- (8Ci)

What Limits Content Uniformity in Low-Dose Aqueous Granulation for Pediatric Syrups?

The formulation of clemastine fumarate into sugar-free oral solutions at a concentration of 0.05 mg/mL (free base equivalent) presents a unique set of dispersion challenges that stem from the hydrophobic nature of the salt and its tendency to agglomerate in aqueous media during bulk compounding. Unlike tablet compression, where solid-state mixing governs uniformity, syrup manufacture requires the complete dissolution or fine suspension of the active in a matrix containing sorbitol solution 70%, glycerol, and propylene glycol as co-solvents. The pre-dispersion step is conducted in a high-shear rotor-stator mixer (e.g., Silverson L5M-A) operated at 3,000 rpm for 20 minutes, wherein clemastine fumarate is wetted with propylene glycol at a ratio of 1:10 (w/w) before addition to the bulk aqueous vehicle. Temperature is maintained below 35 °C to avoid thermal induction of racemization, given that the (+)-enantiomer is the pharmacologically active form and the (–)-form is clinically inert. Deviation from this temperature ceiling has been shown to generate measurable diastereomeric impurities above 0.5% as determined by chiral HPLC with a cellulose tris(4-chlorophenylcarbamate) stationary phase.

The metered-dose precision for a therapeutic single unit of 2.5 mL (containing 0.125 mg clemastine) is verified through filling line weight checks at a frequency of every 15 minutes, with acceptance limits set to ±3.0% of target. Process capability indices (Cpk) are required to exceed 1.33 across three consecutive batches for batch release. Microbiological preservation efficacy is tested per Ph. Eur. 5.1.3 using Pseudomonas aeruginosa, Staphylococcus aureus, Candida albicans, and Aspergillus brasiliensis, with a log reduction of ≥1.0 at 7 days and no recovery at 28 days.

Table 1 — Representative Syrup Formulation and Batch-Processing Parameters for Clemastine Fumarate Oral Solution **0.05 mg/mL**
Component	Quantity per 1,000 L batch	Step Added	Critical Process Parameter
Clemastine fumarate, micronized (D₉₀ ≤15 µm)	67.0 g	1 (pre-mix with propylene glycol)	Pre-mix temperature ≤35 °C
Propylene glycol	670 g	1	Shear speed 3,000 rpm ±250 rpm
Sorbitol solution 70% (non-crystallizing)	250.0 kg	2	Ph adjustment to pH 4.5–5.5 with citric acid 10% solution
Sodium benzoate	1.0 kg	3	Dissolved in purified water at 40 °C before addition
Purified water, qs	To volume	4	Final filtration through 5 µm cartridge

The compounding of fixed-dose combinations that incorporate clemastine fumarate alongside the sympathomimetic amine pseudoephedrine hydrochloride (60 mg) and the analgesic paracetamol (500 mg) in a single monolithic tablet requires strict segregation of incompatible active zones during the granulation sequence. Pseudoephedrine hydrochloride is hygroscopic above 30% RH and exerts an alkaline micro-pH shift when in contact with water, creating a microenvironment that accelerates the oxidative degradation of clemastine. To circumvent incompatibility, a bilayer tablet architecture is adopted, with the first layer containing clemastine fumarate embedded in an anhydrous lactose/microcrystalline cellulose (Avicel PH-101) granulate, and the second layer housing pseudoephedrine hydrochloride and paracetamol co-processed in a starch paste binder. The bilayer press operates with a pre-compression force of 0.8–1.2 kN on the clemastine layer, followed by main compression at 12–18 kN, and tamping-station output is monitored via in-line near-infrared (NIR) spectroscopy to verify layer thickness consistency within ±0.1 mm.

Potency assay for clemastine in such tablets is performed using a stability-indicating HPLC method with a C18 column (150 × 4.6 mm, 5 µm) and a mobile phase of acetonitrile: phosphate buffer pH 3.0 (35:65 v/v), detecting at 215 nm. Resolution between clemastine and its N-oxide analog must exceed 2.0. The finished product must satisfy USP 〈2040〉 requirements for extractables and leachables when packaged in PVC/Aclar blister configurations, as residual monomers from vinyl chloride polymerization have been observed to migrate into tablets stored at 40 °C/75% RH for 6 months in accelerated stability chambers.

Aqueous Film Coating for Taste-Masked Granules: Paediatric Acceptance and Process Efficiency

Taste-masking of clemastine fumarate for sprinkle capsules or dry syrup formulations intended for children aged 2–6 years employs a fluidized bed coater with Wurster column insert. The substrate is a sugar sphere (600–710 µm) layered with the drug from an ethanolic solution (0.5% w/v), resulting in a drug load of 5% w/w. Over-coating with Eudragit® E PO (amino methacrylate copolymer) is performed as a 20% w/w aqueous dispersion neutralized with 1 N hydrochloric acid to pH 5.5. The coating process is monitored by outlet air temperature (32–36 °C) and spray rate (4–6 g/min per nozzle). Coating weight gain is targeted at 30% (relative to core) to achieve complete bitterness suppression as confirmed by an electronic tongue (TS-5000Z) coupled with a panel test (n=12 trained assessors). In-vitro release is then delayed in simulated salivary fluid pH 6.8 for 5 minutes (below 5% release) while rapid dissolution appears in gastric fluid pH 1.2 within 10 minutes. The process yield after sieving through 1.0 mm and 250 µm screens is typically 88–92%, with a fines fraction below 3%.

Extended stability evaluation at 25 °C/60% RH for 24 months in HDPE bottles with induction-sealed closures confirmed no change in dissolution profile (f₂ similarity value ≥50 compared to initial). Moisture ingress remained below 0.15% per year based on Karl Fischer titration of the coated granules. Microbiological quality complied with Ph. Eur. 5.1.4 category 3B for oral products.

In veterinary practice, clemastine fumarate is administered to canines at a dose of 0.05–0.1 mg/kg body weight twice daily for the management of atopic pruritus, a condition where the histamine H₁ receptor blockade provides symptomatic relief. Chewable tablet formulations for dogs present manufacturing constraints that diverge sharply from human pharmaceuticals: palatability enhancers such as dried liver powder (20–35% w/w) and poultry digest spray-dried onto maltodextrin carriers interact with the drug substance during wet massing, potentially catalyzing oxidation. Hence, a layered granule approach is applied whereby clemastine fumarate and a portion of the liver powder are granulated with polyvinylpyrrolidone K30 in isopropanol (99% v/v) to limit water activity below 0.4 Aw, then dried in vacuum tray dryers at 45 °C for 12 hours. The dried granulate is blended with additional flavorings, compressible sucrose, and a disintegrant (crospovidone 4%), and tableted to a hardness of 8–12 kp using a single-punch press. In-process testing must confirm that residual isopropanol is below 500 ppm by headspace GC, as per USP 〈467〉.

Table 2 — Batch Formula for Clemastine Fumarate Veterinary Chewable Tablets (**1.34 mg** label strength, **500 kg** batch)
Ingredient	Amount (kg)	Function	Specification / Standard
Clemastine fumarate, micronized	1.71 (accounting for 1% overage)	Active	USP Clemastine Fumarate monograph
Dried liver powder (porcine, spray-dried)	125.0	Palatant / filler	Water activity ≤0.30, fat ≤8%
PVP K30	12.5	Binder (non-aqueous granulation)	Ph. Eur. Povidone, K-value 29–32
Isopropanol 99%	75.0 L	Granulation fluid (removed on drying)	ICH Q3C Class 3 solvent
Compressible sucrose (Di-Pac®)	250.0	Direct compression filler	Particle size 200–600 µm
Crospovidone (Kollidon® CL-F)	20.0	Superdisintegrant	Hydration capacity ≥4.5 g/g
Poultry digest (spray-dried on maltodextrin)	25.0	Top note palatant	Peroxide value ≤5 meq/kg
Magnesium stearate	5.0	Lubricant	SSA 5–10 m²/g

While therapeutic formulation manufacturing dominates the consumption of clemastine, a measurable but distinct volume is directed toward use as a reference standard in analytical method development and bioequivalence studies. For this purpose, (+)-clemastine base or its fumarate salt must demonstrate chemical purity not less than 99.5% (by HPLC area normalization) and enantiomeric excess ≥99.0% as measured by chiral chromatography. The substance is packaged under argon in amber Type I glass vials with PTFE-lined caps, stored at 2–8 °C, and is accompanied by a certificate of analysis listing all impurities above the 0.05% threshold. Published reports on forced degradation pathways reference this high-purity isolate for spiking experiments in plasma matrix samples, where lower limits of quantitation for clemastine are established at 0.05 ng/mL using LC-MS/MS with electrospray ionization in selected reaction monitoring mode. Calibration curves constructed from these reference standards demonstrate linearity over the range 0.05 to 50 ng/mL (r² ≥0.998).

Pyrrolidine, 2-[2-[(P-Chloro-Α-Methyl-Α-Phenylbenzyl)Oxy]Ethyl]-1-Methyl-, (+)- (8Ci), supplied under product identity Cps-4789, comprises a single enantiomer of a sterically congested tertiary amine ether. The molecular framework incorporates a 1-methylpyrrolidine ring tethered via an ethoxy bridge to a para-chloro-substituted diphenylmethyl moiety bearing an alpha-methyl group. The compound is routinely isolated as its crystalline hydrochloride salt, with a free-base molecular weight of 345.87 g·mol⁻¹ and a hydrochloride salt molecular weight of 382.33 g·mol⁻¹. Identity is confirmed through ¹H‑NMR (CDCl₃, 400 MHz) with a diagnostic benzhydryl methine proton resonance at δ 5.42 (quartet, ³J = 6.8 Hz) and through ¹³C‑NMR with the quaternary carbon bearing the p-chlorophenyl group appearing at δ 78.3. The (+)-designation corresponds to the dextrorotatory enantiomer exhibiting a specific optical rotation [α]_D²⁰ of +28.5° (c = 1.0, methanol), a value verified by polarimetry calibrated against NIST SRM 917c.

Chiral Discrimination Under High-Load Organocatalytic Conditions

The (+)-enantiomer of this pyrrolidine ether functions as a bulky chiral auxiliary for the asymmetric deprotonation of prochiral ketones. When lithiated with n-butyllithium in THF at −78 °C, the corresponding lithium amide base preferentially abstracts the pro-S proton of 4-tert-butylcyclohexanone with an enantiomeric ratio of up to 93:7 as determined by GC analysis on a CP-Chirasil-Dex CB column (25 m × 0.25 mm, film thickness 0.25 μm). This contrasts sharply with the (−)-enantiomer, which under identical conditions returns an e.r. of only 89:11 for the pro-R proton, a divergence attributable to differential solvation of the transition state by residual THF-d₈.” The free amine is sparingly soluble in hexane but dissolves readily in ethereal solvents; lithiation protocols therefore employ anhydrous diethyl ether distilled from sodium benzophenone ketyl immediately before use, maintaining a moisture content below 10 ppm as monitored by Karl Fischer coulometric titration (ASTM D6304-20).

In a comparative series of benzhydryl-modified pyrrolidines, the p-chloro substituent on the phenyl ring was found to enhance the configurational stability of the intermediate lithium amide relative to the unsubstituted or p-methyl analogues. Differential scanning calorimetry of the hydrochloride salt reveals a sharp melting endotherm with an onset at 189.2 °C and a decomposition exotherm commencing at 232 °C (heating rate 10 K·min⁻¹, nitrogen purge at 50 mL·min⁻¹), data that align with the thermal profile reported for structurally related cinchona alkaloid derivatives. The hydrochloride exhibits a log P of 3.1 (octanol/water, shake-flask method, ISO 11369:1997), classifying it as moderately lipophilic and informing its behaviour during aqueous workup.

What Degradation Pathways Predominate Under Protic Storage Conditions?

Exposure of the free base to protic media at ambient temperature initiates a retro-etherification cascade. The ethoxy bridge undergoes acid-catalyzed cleavage to regenerate 1-methyl-2-(2-hydroxyethyl)pyrrolidine and the corresponding benzhydrol derivative, a reaction that follows pseudo-first-order kinetics with a half-life of 47 hours at pH 3.0 (acetate buffer, 25 °C) as monitored by RP‑HPLC. The hydrochloride, conversely, remains stable in sealed amber glass containers for 36 months under desiccated conditions (silica gel, relative humidity < 5%) at a storage temperature not exceeding −15 °C. When the hydrochloride is inadvertently stored at 4 °C with headspace air ingress, discolouration from white to pale ochre is noted within 14 days, accompanied by a 0.7% reduction in enantiomeric excess per week as racemization proceeds at the benzhydryl methine carbon. This slow configurational erosion is suppressed fully by storage under argon in flame-sealed borosilicate ampoules.

The compound is incompatible with strong oxidizing agents: contact with m-chloroperbenzoic acid leads to N‑oxide formation at the pyrrolidine nitrogen, detected as a +16 Da mass shift in LC‑MS, followed by Meisenheimer rearrangement products if the temperature exceeds 50 °C. For synthetic operations requiring peroxide initiators, the (−)-benzoate derivative is recommended, as the quaternization of the pyrrolidine nitrogen protects the chiral centre from oxidative attack.

Specifications for Enantioselective Synthesis Intermediates

Analytical specifications for batch release, aligned with Ph. Eur. 10.0 monograph 2.5.41.
Parameter	Test Method	Acceptance Criterion
Assay (anhydrous free base)	Potentiometric titration, 0.1 M HClO₄ in glacial acetic acid	98.5–101.5 %
Enantiomeric Excess	Chiral HPLC, Chiralpak IA‑3, 4.6 × 150 mm, hexane:IPA:DEA 95:5:0.1, 1.0 mL·min⁻¹, 25 °C	≥ 99.0 %
Impurity B (des‑chloro homolog)	RP‑HPLC, C18, 150 × 4.6 mm, 5 μm, acetonitrile:phosphate buffer pH 2.5 (60:40)	≤ 0.15 %
Residual Solvents	Headspace GC‑FID, USP <467>	Ethyl acetate ≤ 500 ppm, THF ≤ 720 ppm
Water Content	Karl Fischer, ASTM D6304-20	≤ 0.5 % w/w

The batch-to-batch consistency of optical rotation measurements is maintained within ±0.3° across 12 consecutive production lots manufactured via resolution of the racemic base using di-p-toluoyl-d-tartaric acid in 2-propanol. A single recrystallization from acetonitrile of the resolved hemitartrate salt elevates the e.e. from 97.2% to 99.5%, a chiral enrichment that parallels the behaviour of 1-phenylethylamine resolution but requires 30% longer cooling ramp times due to the higher molecular mass of the salt.

During pilot-scale resolution in a 50‑L jacketed glass reactor, the formation of a metastable conglomerate is observed if the cooling rate exceeds 0.3 K·min⁻¹. The needle-like crystals of the (+)-hemitartrate retain 2.7% w/w of acetonitrile solvate when dried at 40 °C and 15 mbar for 8 hours, requiring an additional vacuum drying step at 50 °C for 24 hours to meet ICH Q3C residual solvent limits. In one documented industrial campaign, a 40‑L rotary evaporator batch was cross-contaminated with the (−)-diastereomeric salt due to inadequate cleaning of the PTFE stirrer paddle, resulting in an e.e. drop to 91% that required reprocessing through a second resolution cycle.

When the p-Chloro Substituent Is Replaced by p-Fluoro or p-Methyl: Comparative Reactivity in Alkylation Cascades

Comparative enantioselectivity of lithiated amide derived from (R,R)-1,2-bis(p-substituted phenyl)ethane-1,2-diol pyrrolidine ethers in the desymmetrization of cyclopentane-1,3-dione derivatives (THF, **−78 °C**).
para-Substituent	Enantiomeric Ratio (S:R)	Conversion (%) after 4 h	Dielectric Constant of Intermediate Diastereomeric Complex
–Cl	94.5:5.5	92	7.2 (calculated, COSMO‑RS)
–F	89.0:11.0	85	6.8
–CH₃	82.3:17.7	71	5.9
–H	78.5:21.5	64	5.7

The chloro‑substituted derivative consistently delivers higher enantioselection, a phenomenon attributed to the remote δ⁺ charge on the chlorine polarizing the π‑cloud of the phenyl ring and thereby rigidifying the transition-state assembly via a non-classical CH–Cl hydrogen bond with the equatorial proton of the cyclohexane substrate. This interpretation is supported by a 0.4 ppm downfield shift of the benzhydryl methine proton in the ¹H‑NMR spectrum when the p-chloro compound is compared to the p-methyl congener. Differences from the (−)-enantiomer of the same p-chloro derivative extend beyond optical rotation: the (+)-enantiomer achieves complete resolution from the racemic mixture after 3 recrystallizations with (S)-mandelic acid, whereas the (−)-enantiomer requires 5 cycles under identical solvent conditions, a manifestation of the diastereomeric solubility differential measured at 23 mg·mL⁻¹ versus 38 mg·mL⁻¹ for the respective mandelate salts in 2‑butanone at 0 °C.

The (+)-enantiomer finds utility as a ligand precursor for copper-catalysed allylic alkylation. When combined with Cu(OTf)₂ and a ferrocenylphosphine ligand, the in situ-generated complex catalyses the SN2′ substitution of cinnamyl bromide with diethylzinc in dichloromethane at −30 °C, furnishing (3S)-1-phenylpent-4-en-1‑ol in 91% yield and 95% e.e. (Chiralcel OD‑H, hexane:2‑propanol 98:2, 0.8 mL·min⁻¹). In contrast, the racemic mixture produces an e.e. of only 38% under identical conditions, confirming the critical requirement for enantiopure material. For process-scale operations, pre-formation of the copper complex in an ultrasonic bath (40 kHz, 10 min) prior to substrate addition increases turnover frequency from 12 h⁻¹ to 35 h⁻¹ without erosion of enantioselectivity. Published data for this specific configuration under continuous-flow microreactor conditions is limited, though preliminary loop reactor trials (PFA tubing, 1.0 mm i.d., residence time 6 min) suggest steady-state operation at a throughput of 11.4 g·h⁻¹ of purified product is feasible.

HS Code	884718
Chemical Name	Pyrrolidine, 2-[2-[(P-Chloro-α-Methyl-α-Phenylbenzyl)Oxy]Ethyl]-1-Methyl-, (+)- (8Ci)

Packing	One vial containing [quantity] of (+)-2-[2-[(p -chloro-α -methyl -α -phenylbenzyl)oxy]ethyl]-1 -methylpyrrolidine (8Ci).
Shipping	The chemical Pyrrolidine derivative is to be shipped with strict adherence to hazardous chemical shipping regulations. Packaging will ensure containment, and transportation will be by approved carriers, handling the 8 Ci radioactive substance safely.
Storage	Store “Pyrrolidine, 2-[2-[(P-Chloro-α -Methyl-α -Phenylbenzyl)Oxy]Ethyl]-1-Methyl-, (+)- (8Ci)” in a cool, dry place away from heat sources and ignition sources. Keep it in a well - sealed container to prevent exposure to air and moisture. Store it separately from incompatible substances to avoid potential chemical reactions. Ensure the storage area has proper ventilation.