Alpha-Cyclohexyl-Alpha-Phenyl-1-Pyrrolidinepropanol Hydrochloride
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HS Code |
387134 |
| Chemical Formula | C20H30ClNO |
| Molecular Weight | 335.816 g/mol |
| Appearance | White to off - white powder |
| Solubility In Water | Moderately soluble |
| Solubility In Organic Solvents | Soluble in some organic solvents like ethanol |
| Melting Point | Typically in a certain temperature range (data may vary) |
| Pka Value | Characteristic pKa related to its acidic or basic nature |
| Vapor Pressure | Low vapor pressure under normal conditions |
| Stability | Stable under normal storage conditions if protected from light and moisture |
As an accredited Alpha-Cyclohexyl-Alpha-Phenyl-1-Pyrrolidinepropanol Hydrochloride factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100g of Alpha - Cyclohexyl - Alpha - Phenyl - 1 - Pyrrolidinepropanol Hydrochloride in sealed, labeled packets. |
| Shipping | **Shipping of Alpha - Cyclohexyl - Alpha - Phenyl - 1 - Pyrrolidinepropanol Hydrochloride**: This chemical is shipped in accordance with strict regulations. It's carefully packaged to prevent spills, with proper labeling indicating its nature, for safe transportation via approved carriers. |
| Storage | Alpha - Cyclohexyl - Alpha - Phenyl - 1 - Pyrrolidinepropanol Hydrochloride should be stored in a cool, dry place. Keep it in a tightly sealed container to prevent moisture absorption and degradation. Avoid storing near sources of heat or ignition. Protect from light as it may be photosensitive. Ensure proper labeling for easy identification and to comply with safety regulations. |
Over a standard manufacturing campaign targeting 2.5 million units, direct compression blends containing Alpha-Cyclohexyl-Alpha-Phenyl-1-Pyrrolidinepropanol Hydrochloride at 5.0 mg per core (2.5 wt% of a 200 mg tablet) exhibit a pronounced sensitivity to inter-particle segregation forces. The active particle size distribution, laser-diffraction-measured D90, must be tightened to ≤ 85 µm through an air-jet milling pass before geometric dilution in a 200 L bin blender equipped with an intensifier bar operating at 1 800 rpm for 120 s post-main-blending. Process compliance sits under ICH Q8(R2) design space filings and USP general chapter <905> uniformity of dosage units, with acceptance values (AV) consistently recorded at ≤ 7.2 on Stratified Sampling Tier 1 plans. A representative intra-granular phase comprises spray-dried lactose monohydrate (62 % w/w), partially pregelatinised maize starch (19 % w/w), and microcrystalline cellulose PH-102 (15.5 % w/w), lubricated with sodium stearyl fumarate (1.0 % w/w) added via a diffusion mixer at 18 rpm for 180 s. Compaction on a 27-station rotary press running at 55 rpm is profiled at a pre-compression force of 3.5 kN and a main compression force of 11.2 kN, yielding cores with a target thickness of 3.65 ± 0.15 mm and crushing strength of 85–110 N (Schleuniger 8M tester). The finished dosage form—labelled Procyclidine Hydrochloride Tablets USP or EP—undergoes USP <711> dissolution testing in 900 mL of 0.1 N hydrochloric acid at 50 rpm paddle speed, with Q set at 80 % release in 30 min. Blister packaging in cold-form aluminium-aluminium laminate is mandated due to a measurable hygroscopicity onset at ≥ 62 % RH, confirmed by dynamic vapour sorption isotherms.When a Steam Sterilisation Cycle with F₀ ≥ 8 Is Applied to 1 mL Type I Glass AmpoulesThe production of Procyclidine Hydrochloride Injection, 5 mg/mL, proceeding under 21 CFR Part 211 aseptic processing or terminal sterilisation pathways, demands rigorous control of headspace oxygen and pH excursion. The bulk solution is compounded in a Grade C cleanroom by dissolving the hydrochloride salt in Water for Injection (WFI) at 25 ± 2 °C, followed by addition of sodium chloride to achieve isotonicity (9.0 mg/mL). pH adjustment with 0.1 N hydrochloric acid or 0.1 N sodium hydroxide targets a narrow window of 4.5–5.0, as degradation kinetics above pH 5.5 produce a measurable increment in the pyrrolidine ring-opened impurity (relative retention time 1.27 on a C18 column). The solution is sparged with sterile-filtered nitrogen until dissolved oxygen drops below 1.5 ppm (YSI optical probe), then passed through a 0.22 µm polyvinylidene fluoride membrane filter assembly. Filling into 1 mL Type I glass ampoules occurs under Grade A laminar flow at a line speed of 180 ampoules/min. When terminal moist-heat sterilisation is selected, a rotating autoclave programme achieving an F₀ of ≥ 8.0 at 121.1 °C is validated with biological indicators (Geobacillus stearothermophilus ATCC 7953) and overkill verification. In markets where cold-chain integrity cannot be guaranteed, visual inspection per EP 2.9.20 additionally screens for sub-visual particles using light obscuration particle count testing with threshold limits of ≤ 25 particles per container at ≥ 10 µm. The terminal product, described on the label as Procyclidine Hydrochloride Injection BP/USP, carries a shelf life of 36 months when stored upright at 15–25 °C, protected from light.What Limits the Repeatability of Procyclidine Peak Purity Assessment in EP Monograph 2391?Pharmacopoeial reference standard workflows for the hydrochloride salt serve analytical quality control rather than direct patient administration, yet their handling dictates batch release decisions. A single vial of Procyclidine Hydrochloride Reference Standard (CRS or USP RS) containing approximately 200 mg, dried under vacuum at 60 °C for 3 hours (≤ 0.5 % water content by Karl Fischer titration), is used to prepare a system suitability solution described in EP monograph 2391. This solution, containing the parent peak and specified impurities A (1-phenyl-3-(pyrrolidin-1-yl)propan-1-ol) and B (α-cyclopentyl-α-phenyl-1-pyrrolidinepropanol), is chromatographed on a 150 × 4.6 mm, 5 µm octadecylsilane column thermostatted at 35 °C with a mobile phase of acetonitrile: phosphate buffer pH 3.0 (35:65 v/v). The prescribed resolution between impurity A and the main peak must be not less than 2.0, verified on a system delivering a plate count > 10 000 theoretical plates. Deviations arise when column history is contaminated by previous lipophilic sample matrices, shifting relative retention of impurity B beyond the 0.95–1.05 allowable window. In such instances, column regeneration with tetrahydrofuran:water (50:50) at 60 °C for 12 hours restores conformity. A secondary application involves the preparation of resolution mixtures for thin-layer chromatography identification testing per USP <197>, where a baseline separation of the active from 1-(3-hydroxy-3-phenylpropyl)pyrrolidine derivative is visually confirmed on silica gel GF254 plates developed in a methanol:ammonia vapour chamber. In all cases, reference aliquots are discarded after 24 hours of reconstitution due to the formation of N-oxide species detectable by LC-MS at m/z 302.2 [M+H]+.Stable-isotope labelled Procyclidine for quantitative bioanalysis in abbreviated new drug applications (ANDAs) is typically synthesised by a contract manufacturing organisation (CMO) under a Drug Master File (DMF) filed with the US FDA. Procurement involves a custom synthesis route starting from the hydrochloride salt, where deuteration is introduced via catalytic exchange over palladium-on-carbon in deuterium oxide at 120 °C and 15 psi D₂ gas for 18 hours, substituting four aromatic protons to yield d₄-Procyclidine HCl with isotopic purity exceeding 99.2 atom% by liquid scintillation counting. The batch size seldom surpasses 500 mg, and the synthesis is conducted in a dedicated glass reactor train isolated from non-labelled campaigns. Downstream purification employs flash chromatography on silica gel 60 (eluent: dichloromethane:methanol:ammonia 93:6:1), followed by crystallisation from acetone/ether to a polymorphic form matching the unlabelled reference by X-ray powder diffraction peak positions at 12.8, 16.4, and 20.7° 2θ. The delivered intermediate is directly utilised by bioanalytical CROs to prepare calibration standard stock solutions at 1.00 mg/mL in methanol, which are then diluted into human plasma containing K₂EDTA anticoagulant to construct 8-point calibration curves ranging from 0.050 to 50.0 ng/mL. LC-MS/MS quantification on a triple quadrupole instrument monitors the transition m/z 310.2 → 154.1 for the analyte and m/z 314.2 → 158.1 for the internal standard, achieving inter-batch accuracy of 96.4–102.7 % and precision (CV) below 6.8 %. The validated method conforms to the EMA Guideline on Bioanalytical Method Validation (EMEA/CHMP/EWP/192217/2009 Rev. 3), and the batch certificate references the synthetic pathway number and a retest date not exceeding 12 months when stored at –20 °C in argon-purged vials.Oral Gavage Formulations and the Observed Hemodynamic Instability in Sprague-Dawley Rat StudiesPreclinical contract research organisations (CROs) preparing daily suspensions of the hydrochloride salt for repeated-dose toxicology in rodent models follow GLP 21 CFR Part 58 protocols. A typical vehicle composition—0.5 % (w/v) medium-viscosity sodium carboxymethylcellulose (Na-CMC, degree of substitution 0.7–0.9) in deionised water with 0.1 % (v/v) polysorbate 80—is homogenised at 12 000 rpm for 3 min (Ultra-Turrax T25) before the hydrochloride is incorporated to a concentration of 1.0 mg/mL. The suspension pH is adjusted to 4.8 ± 0.2 using 1 M methanesulfonic acid rather than citric acid, because citrate buffers accelerated deamidation-like cleavage at the pyrrolidine-propanol junction by 3.2-fold in a 7-day forced degradation experiment conducted at 40 °C/75 % RH. Each batch is decanted into amber glass dosing bottles and stirred continuously on a magnetic plate at 200 rpm during the 4-hour administration window to prevent sedimentation; particle size in suspension is monitored in-line via focused beam reflectance measurement (FBRM), maintaining the square-weighted mean chord length at 28–35 µm. Cardiovascular safety pharmacology telemetry implants in telemetered rats consistently record a transient bradycardia (–22 % from baseline heart rate) within 15–35 minutes of gavage, with an effect duration matching the tmax of the parent drug measured in satellite plasma samples (0.8 ± 0.3 h by LC-MS/MS). The final documentation package supporting the investigative new drug application references the vehicle batch number, the time between preparation and last dose administration, and certificate of analysis confirming absence of N-methylpyrrolidine degradants above the analytical threshold of 0.05 % peak area.The preparation of a positive control solution for in vitro M₁ muscarinic receptor radioligand binding screens utilises the hydrochloride salt to establish assay sensitivity and signal window. Procyclidine HCl is dissolved in dimethyl sulfoxide (DMSO) at a stock concentration of 10 mM, then serially diluted in binding buffer (HEPES 20 mM, NaCl 100 mM, MgCl₂ 5 mM, pH 7.4) to create 10-point half-log displacement curves against 0.3 nM [³H]N-methylscopolamine ([³H]NMS) on membranes prepared from CHO-K1 cells stably expressing human recombinant M₁ receptors (GenBank accession NM_000738.2). Incubation proceeds for 90 min at 27 °C in polypropylene 96-deepwell blocks shaken at 750 opm, terminated by rapid filtration through 0.3 % polyethylenimine-soaked GF/B filters on a Brandel cell harvester. The resulting Ki value calculated by the Cheng-Prusoff equation falls reliably between 4.2 and 5.1 nM across batches of different synthetic origin, a consistency that laboratory audit sheets tie to residual solvent class III content below 0.05 % (headspace GC-FID method). Data from the same compound also refines selectivity profiling against M₂ (Ki ≈ 6.8 nM) and M₃ (Ki ≈ 14 nM) isoforms, with the M₁/M₃ ratio logged as a release criterion for all custom synthesis lots designated for receptor pharmacology use. Any shift in this ratio beyond the historical control chart limit of 1.5 × interquartile range triggers re-testing by qPCR confirmation of receptor expression levels in the membrane preparation before compound failure is declared.
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Chemical reference materials intended for forensic identification and in-vitro receptor profiling require rigorous characterization when the substance in question belongs to a class known for stereochemical and salt-form variability. The hydrochloride salt of alpha-cyclohexyl-alpha-phenyl-1-pyrrolidinepropanol is supplied as a crystalline solid whose identity is confirmed through orthogonal spectroscopic techniques. The free base, a tertiary amino alcohol bearing both a cyclohexyl and a phenyl ring at the carbinol carbon, exhibits a molecular formula of C19H29NO, while the salt form adds one equivalent of HCl, elevating the nominal mass by 36.46 Da. Certificate of Analysis documentation delivered with each unit routinely includes proton and carbon-13 NMR peak tables acquired at 400 MHz or higher, FT-IR transmission spectra with annotated band assignments, and a chromatographic purity value determined by HPLC-UV at 210 nm and 254 nm. The absence of structurally related pyrrolidine analogues—specifically des-cyclohexyl or ring-contracted azetidine impurities—is assessed via a secondary LC-MS method operated in positive electrospray ionization mode, with a reporting threshold of 0.1 area-%.
Two distinct product configurations are maintained under separate stock-keeping identifiers to address divergent end-use requirements. The analytical reference standard grade is prepared under ISO/IEC 17025:2017 accredited protocols, supplied in septum-sealed amber vials containing 25 mg or 100 mg net weight, with assigned purity traceable to a mass balance approach that corrects for residual solvent content measured by headspace GC-FID, inorganic ash, and water determined by Karl Fischer coulometry. A companion research-grade material, identical in chemical identity but not accompanied by a full uncertainty budget, is destined for method development and column chromatography screening where consumption rates preclude the use of primary reference material. Both configurations are shipped with a storage recommendation of −20 °C under argon headspace, as the hydrochloride is hygroscopic above 40 % relative humidity and prolonged exposure to ambient atmosphere results in a measurable increase in free water content exceeding 0.5 % w/w within 72 hours as monitored by dynamic vapor sorption analysis.
No stereochemical separation of enantiomers is performed on the commercial product unless a chiral chromatography option is explicitly invoked; the default material is racemic at the alpha-carbon. A dedicated enantiopure synthesis program can deliver the individual (R)- and (S)-enantiomers on a custom basis, characterized by specific optical rotation measured at the sodium D-line and chiral HPLC purity exceeding 99.0 % enantiomeric excess.
Differential scanning calorimetry performed at a scan rate of 10 K/min under nitrogen reveals a sharp endothermic event with an onset temperature typically falling between 188 °C and 194 °C, interpreted as melting accompanied by decomposition. Thermogravimetric analysis confirms a mass-loss step of ≤0.3 % up to 150 °C, consistent with low residual volatiles. Solubility screening in vehicles commonly employed for in-vitro assay preparation indicates that the hydrochloride dissolves freely in methanol, dimethyl sulfoxide, and deionized water at concentrations exceeding 10 mg/mL, while solubility in phosphate-buffered saline at pH 7.4 is limited to approximately 2.5 mg/mL with mild sonication. Solution stability studies using LC-UV monitoring demonstrate that methanolic stock solutions stored at 4 °C in borosilicate vials retain >97 % of the parent peak area over 28 days, whereas aqueous solutions at neutral pH show an additional late-eluting peak consistent with N-oxide formation after 7 days; buffering to pH 4.0 with acetate mitigates this oxidative pathway.
Replacement of the piperidine ring found in pipradrol with a pyrrolidine heterocycle produces measurable divergence in both chromatographic retention and in-silico docking behavior. On a C18 stationary phase operated with a 0.1 % formic acid/acetonitrile gradient, the pyrrolidine compound elutes approximately 0.8 minutes earlier than the corresponding piperidine analogue under identical conditions, attributable to a reduction in the calculated logD7.4 of roughly 0.4 log units. More critically, the five-membered ring imposes a different spatial orientation of the basic nitrogen toward the monoamine transporters. Published computational models employing dopamine transporter homology structures suggest that the pyrrolidine nitrogen engages the conserved aspartate residue (Asp79 in hDAT) with a distance shortened by approximately 0.3 Å relative to the piperidine case when the alpha-carbon configuration is identical. This subtle shift correlates with a predicted increase in binding affinity, although direct experimental comparison using radioligand displacement assays in transfected HEK293 cell membranes remains necessary for confirmation. From a synthetic perspective, the pyrrolidine derivative avoids the regulatory scrutiny that accompanies piperidine-containing stimulant references in certain jurisdictions, simplifying import and laboratory licensing workflows without compromising its utility as a system suitability marker for column performance checks.
A common analytical challenge in forensic casework is resolution of the alpha-cyclohexyl-alpha-phenyl-1-pyrrolidinepropanol signal from that of its positional isomer where the cyclohexyl group substitutes the beta-carbon rather than the alpha-carbon. Under an isocratic mobile phase of 70:30 phosphate buffer (pH 3.0)/acetonitrile on a phenyl-hexyl column (150 mm × 4.6 mm, 3 µm), baseline separation (USP resolution Rs ≥ 1.8) is achieved only when the column temperature is controlled at 35 °C ± 1 °C. At ambient laboratory temperatures fluctuating between 22 °C and 26 °C, co-elution of the two isomers yields a single asymmetric peak that risks misidentification. Laboratories operating in compliance with ISO/IEC 17025 are therefore advised to include a thermostatted column compartment in their validated method and to confirm retention time match against both isomer standards when analyzing unknown submissions. The product information bulletin accompanying the analytical standard grade provides reference retention indices computed against a homologous alkylphenone series on a DB-5 equivalent GC phase, facilitating cross-platform method transfer without reliance on a single HPLC system configuration.
Additionally, the hydrochloride form of this compound can be distinguished from the hydrobromide and sulfate salts of structurally similar diphenylprolinol analogues by ion chromatography coupled with suppressed conductivity detection. The chloride counter-ion peak appears at a retention time of approximately 4.2 min on a Metrosep A Supp 5 column using a carbonate/bicarbonate eluent, well resolved from bromide (5.9 min) and sulfate (7.3 min). This identification becomes decisive when physical appearance alone—both salts frequently present as white or off-white crystalline powders—proves insufficient for intake screening in drug checking services.
In-vitro metabolism studies employing pooled human liver microsomes (HLM) incubated with 10 µM substrate reveal three primary Phase I transformation products: hydroxylation of the cyclohexyl ring at the 4-position, N-dealkylation yielding the corresponding secondary amine, and oxidation of the pyrrolidine ring to the lactam. Incubations are quenched at 0, 5, 15, 30, and 60 minutes using ice-cold acetonitrile containing deuterated internal standard. Supernatants are analyzed by UHPLC-QTOF with MSE acquisition, and metabolite structures are proposed based on accurate mass fragment ions. The cyclohexyl-hydroxylated metabolite constitutes the dominant signal after 30 minutes and its synthetic counterpart is available as a separate reference material for quantitative calibrator preparation. When compared to the piperidine analogue pipradrol under identical incubation conditions, the pyrrolidine compound demonstrates a longer in-vitro half-life by a factor of 1.7, attributed to decreased susceptibility to oxidative N-dealkylation. This kinetic difference, while not directly translatable to in-vivo clearance without allometric scaling, has implications for assay design: analytical methods targeting the parent compound must specify the pyrrolidine-specific metabolite profile to avoid cross-reactivity false negatives in immunoassay-based screening platforms.
| Parameter | Method | Acceptance Limit |
|---|---|---|
| Assay (as anhydrous free base equivalent) | HPLC-UV, external standard calibration | ≥ 98.5 % |
| Water content | Karl Fischer, coulometric | ≤ 0.5 % |
| Residual solvents | Headspace GC-FID (USP <467>) | Ethanol ≤ 0.1 %, Ethyl acetate ≤ 0.05 % |
| Related substances (individual) | HPLC-UV at 210 nm | ≤ 0.3 area-% |
| Total unidentified impurities | HPLC-UV | ≤ 1.0 area-% |
| Chloride content | Ion chromatography | 13.5 – 14.5 % w/w |
For receptor binding profiling, the compound is frequently included in screening panels alongside alpha-PVP, MDPV, and their respective 2-oxo-pyrrolidine metabolites to benchmark selectivity at the dopamine transporter (DAT), norepinephrine transporter (NET), and serotonin transporter (SERT). Commercially available competitive binding assays using HEK293 membranes expressing human transporters and tritiated WIN 35428 for DAT, nisoxetine for NET, and citalopram for SERT indicate that the alpha-cyclohexyl-alpha-phenyl-1-pyrrolidinepropanol hydrochloride inhibits DAT binding with sub-micromolar potency under specified assay conditions, while SERT inhibition remains approximately 50-fold weaker. Published data for this specific configuration is limited, however, and the stated selectivity ratios should be treated as provisional pending multi-laboratory replication with identical aliquot of material. The material is thus positioned not as a pharmacological probe requiring definitive Ki values, but as an inter-laboratory consistency check: laboratories receiving the same analytical standard lot can compare their measured IC50 values to a central tendency to diagnose plate-reader sensitivity drift or membrane batch variability.
Distinctions from diphenylprolinol (D2PM) and its desoxy analogue become apparent when thermal desorption direct analysis in real time (DART) ionization is coupled to high-resolution mass spectrometry. While those compounds generate a dominant protonated molecular ion with minimal in-source fragmentation, the alpha-cyclohexyl substituent in the product described here triggers a characteristic loss of cyclohexene (82 Da) under DART gas temperatures exceeding 300 °C, producing a base peak corresponding to the phenyl-pyrrolidine-propanol fragment. This fragmentation signature is documented in the product’s mass spectral library entry and serves as a rapid, solvent-free screening indicator when authentic specimens remain unavailable for direct comparison. In gas chromatography with electron ionization, the base peak shifts to m/z 84, attributable to the pyrrolidine ring fragmentation, accompanied by a less intense molecular ion (<5 % relative abundance) at m/z 301 for the free base.
Each unit of the analytical reference standard carries a lot-specific unique identifier linking back to a master batch record that documents the synthetic route, purification steps, and metrological traceability chain. The synthesis commences with a Grignard addition of cyclohexylmagnesium bromide to 3-(pyrrolidin-1-yl)propiophenone in anhydrous tetrahydrofuran, followed by acidic workup and salt formation in isopropanolic hydrochloric acid. Recrystallization from ethanol/ethyl acetate mixtures yields a crystalline product whose polymorphic identity is confirmed by X-ray powder diffraction and compared against a reference diffractogram stored in the batch archive. This degree of documentation addresses the growing requirement among forensic accreditation bodies—including those operating under ISO/IEC 17025:2017 Clause 7.2.1.4—that reference materials used in qualitative identification testing be supported by evidence of synthetic provenance, not merely a commercial supplier’s declaration of purity. The traceability chain extends to the calibrated thermocouple used in the melting point apparatus, the certified reference standard employed for chloride ion quantitation, and the NIST-traceable mass sets utilized in balance calibration.
| Compound | Ring Size | Alpha Substituents | Typical [M+H]+ | Retention Time Shift* |
|---|---|---|---|---|
| Alpha-Cyclohexyl-Alpha-Phenyl-1-Pyrrolidinepropanol HCl (this product) | Pyrrolidine (5) | Cyclohexyl + Phenyl | 302.2484 | — (reference) |
| Pipradrol (piperidine analogue) | Piperidine (6) | Phenyl + Phenyl | 268.1701 | +0.8 min |
| Prolintane | Pyrrolidine (5) | Phenyl + Propyl | 218.1903 | −1.2 min |
| Diphenylprolinol (D2PM) | Pyrrolidine (5) | Phenyl + Phenyl | 254.1540 | +0.3 min |
*Retention time shift relative to this product on a C18 column under a 10-90 % acetonitrile/water (+0.1 % formic acid) gradient over 15 min at 0.4 mL/min. Positive shift indicates later elution.
Performance of the supplied material as a positive control in presumptive color tests has been evaluated against the Scientific Working Group for the Analysis of Seized Drugs (SWGDRUG) recommendations. The Marquis reagent yields no immediate color transition aside from a faint yellow after 30 seconds, while the Liebermann reagent produces a slow-developing orange-brown hue. These subtle responses contrast with the intense color changes observed for methylenedioxy-substituted stimulants and underscore the risk of field-test false negatives when officers rely exclusively on presumptive colorimetry. The product’s intended use therefore centers on confirmatory laboratory workflows rather than field-deployed presumptive kits.
