1-Pyrrolidinepropanol, Alpha-Cyclohexyl-Alpha-Phenyl-, Hydrochloride
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HS Code |
342089 |
| Chemical Name | 1-Pyrrolidinepropanol, Alpha-Cyclohexyl-Alpha-Phenyl-, Hydrochloride |
As an accredited 1-Pyrrolidinepropanol, Alpha-Cyclohexyl-Alpha-Phenyl-, Hydrochloride factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100 - gram bottle of Alpha - Cyclohexyl - Alpha - Phenyl - 1 - Pyrrolidinepropanol Hydrochloride. |
| Shipping | 1 - Pyrrolidinepropanol, Alpha - Cyclohexyl - Alpha - Phenyl -, Hydrochloride is shipped in well - sealed containers, following strict hazardous chemical shipping regulations. Special care is taken to prevent breakage and ensure safe transportation. |
| Storage | 1 - Pyrrolidinepropanol, Alpha - Cyclohexyl - Alpha - Phenyl -, Hydrochloride should be stored in a cool, dry place away from direct sunlight. Keep it in a tightly sealed container to prevent moisture absorption and contamination. Store it separately from incompatible substances to avoid potential chemical reactions. Ensure proper ventilation in the storage area. |
Achieving acceptable content uniformity for a **2.5 mg** dose of the hydrochloride salt within a tablet weight of **120 mg** requires a direct compression strategy that deliberately avoids moisture, as the pyrrolidine-propanol hydrochloride undergoes hydrolytic ring-opening above **40 °C** in the presence of free water—a degradation pathway documented in forced-degradation studies responding to ICH Q1A(R2) conditions. The API is pre-milled via a spiral jet mill (e.g., Hosokawa Alpine 50 AS) to a target particle size distribution of **Dv90 ≤ 25 µm**, monitored by laser diffraction under **ISO 13320:2020** with dry dispersion at **0.5 bar** pressure. Direct compression blends are manufactured in a bin blender (Bohle PM 200) operating at **15 rpm** for **25 minutes**, where the hydrochloride salt at **2.08 % w/w** is geometric-diluted with spray-dried mannitol (**Pearlitol 200SD**) and microcrystalline cellulose (**Avicel PH-102**) at a ratio of **3:1**, ensuring the formulation sits within the FDA IID limits for both excipients. The blend is lubricated with **0.5 % w/w** sodium stearyl fumarate (PRUV®) to avoid the oxidative interaction observed between magnesium stearate and the tertiary amine moiety, and compressed on a Korsch XL 400 rotary press at **40 RPM** with a compression force of **8–12 kN** using **6 mm** flat-faced beveled edge tooling, producing tablets with a hardness of **50–70 N** (tested per **USP <1217>** ) and friability below **0.3 %**. The terminal dosage form is a white, round, scored tablet (debossed with “PD 2.5”) intended for the management of drug-induced extrapyramidal symptoms, complying with the USP monograph for Procyclidine Hydrochloride Tablets, which mandates an assay range of **90.0 %–110.0 %** and dissolution using Apparatus 2 (paddle) at **50 rpm** in **900 mL** of **0.1 N HCl** with **Q=80 %** at **30 minutes**.High-Shear Wet Granulation of 5 mg Strength Tablets: Do Intragranular Surfactants Mitigate Dose Proportion Variability?Switching to a **5 mg** label strength with a target tablet weight of **200 mg** (API load **2.5 % w/w**) introduces segregation risk during hopper discharge that wet massing can address, provided the granulation endpoint is controlled to avoid residual moisture triggering a glass transition-mediated collapse of the amorphous hydrochloride salt. The granulating fluid is an aqueous solution of povidone K30 (**5 % w/w** of the dry binder on granulate mass) combined with **0.1 % w/w** polysorbate 80, pre-approved as an intragranular wetting agent through a Type III DMF amendment with supportive 90-day stability data in HDPE bottles at **40 °C/75 % RH**. Granulation is executed in a Collette Gral 75 high-shear mixer at an impeller speed of **150 rpm** and chopper at **1800 rpm**, adding the binder solution at a rate of **0.8 L/min** until a power consumption endpoint of **12–14 A** on the motor load curve is reached. The wet mass is passed through a Quadro Comil U10 fitted with a **2.0 mm** rasping screen and dried in a Glatt GPCG 5 fluid bed at an inlet air temperature of **60 °C** until LOD ≤ **1.8 %** w/w (halogen moisture analyzer setting **105 °C**). Milling of the dried granules through a **1.0 mm** screen precedes external blending with **2.0 % w/w** crospovidone (Kollidon CL-SF) and **0.7 % w/w** sodium stearyl fumarate. Tabletting advances on a Fette 2090i press with a **7 mm** round concave tooling set, operating at a main compression force of **10–15 kN** to achieve a hardness of **70–90 N** and disintegration time below **5 minutes** (**USP <701>** ). Compliance anchors to the Ph. Eur. monograph 1750 (Procyclidine Hydrochloride Tablets), specifically the Uniformity of Content test **2.9.6** with an acceptance value **A ≤ 15**, and the related substances limit for Procyclidine N-oxide at ≤ **0.4 %** by HPLC (Method 2.2.29). The packaged finished product is a blister-laminated 5 mg tablet with aluminum/aluminum cold-form foil for superior moisture protection in climatic zone IVb.Aseptic production of the hydrochloride salt into parenteral form concentrates on preserving the piperidine-propanol scaffold against oxidative N-dealkylation during terminal moist-heat sterilization, a process often selected for its sterility assurance level of **SAL ≤ 10⁻⁶**. The formulation is prepared at a concentration of **5 mg/mL** in Water for Injection (EP grade), with the pH adjusted to **4.8–5.2** using **0.1 N hydrochloric acid**—a narrow window that suppresses the auto-oxidation of the tertiary amine while remaining compatible with autoclave-induced isomerization thresholds identified by stress cycling studies at **121 °C**. The bulk solution is purged with nitrogen gas filtered through a **0.22 µm** sterilizing-grade filter, then filled into Type I glass ampoules (capacity **1 mL**, cone-point style) on a Marchesini MA 450 filling and sealing line with **8 mm** tip open flame sealing. Terminal sterilization proceeds in a Fedegari FOW 5 autoclave at **121.1 °C** for **15 minutes**, achieving an F₀ value ≥ **12 min** with the chamber pressure counterbalanced at **2.1 bar** to prevent ampoule rupture. Equipment qualification incorporates temperature mapping with **12** wireless data loggers placed in coldest-zone locations identified during empty-chamber distribution studies per **ISO 17665-1:2006**. Every sterilized batch undergoes **USP <71>** sterility testing by membrane filtration, bacterial endotoxins analysis per **USP <85>** with a limit of **< 2.5 EU/mg** of active, and particulate matter compliance to **USP <788>** (≥ **10 µm** ≤ **6000** per container, ≥ **25 µm** ≤ **600** per container). The resulting product is a sterile, clear solution packaged as a single-dose ampoule labeled “Procyclidine HCl Injection 5 mg/mL” for intramuscular or intravenous administration in acute dystonic reactions; the US FDA-compliant prescribing information carries the NDC code structure and the requirement for visual inspection prior to use.When Sodium Benzoate Preservative Is Mandated in a Procyclidine HCl Syrup Formulation for Multi-Dose UseOral syrup containing **1 mg/mL** of the hydrochloride salt extends therapy to patients with dysphagia who cannot swallow tablets, requiring a preserved aqueous vehicle capable of withstanding repeated 28-day in-use opening at ambient conditions. The compounding vessel (stainless steel 316L, electropolished) is charged with purified water at **60 °C**, into which a premixed preservative system of sodium benzoate (**0.1 % w/v**) and sorbic acid (**0.05 % w/v**) is dissolved; the benzoate-sorbate combination obeys the undissociated-acid efficacy pH window of **4.0–4.5**, achieved with citric acid monohydrate (**0.15 % w/v**). The hydrochloride salt (**0.100 % w/v**) is introduced under continuous propeller agitation at **250 rpm**, followed by the thickening vehicle of sorbitol solution non-crystallizing (**25 % v/v**) and glycerin (**10 % v/v**)—both established as sweetening and co-solubilizing humectants, their proportions cross-checked against the F. A. O./WHO JECFA database for acceptable daily intake in paediatric populations. The bulk syrup is passed through a **5 µm** polypropylene bag filter before transfer to a filling tank, where liquid sorbitol-based sweetness intensity is verified via comparative electronic tongue profiling (ASTM E2697-24) against a reference batch to guard against lot-to-lot gustatory drift. Filling on an IMA FLX 500/600 in-line filler pumps the syrup into amber Type III glass bottles (capacity **100 mL**) with HDPE child-resistant closures, target fill volume **101 mL ± 1.5 mL**; the closure system incorporates a PET/PVDC liner whose sorption affinity for the preservatives was tested through a 12-month extraction study at **30 °C/65 % RH**, confirming sodium benzoate retention above **95 %** of label strength at the 9-month timepoint. Product-release specifications mirror the BP monograph for Procyclidine Oral Solution, mandating an antimicrobial effectiveness test conforming to **Ph. Eur. 5.1.3** (Category 3 criteria), assay by HPLC within **90.0–110.0 %**, and identification of benzaldehyde—a hydrolytic degradation product of benzyl alcohol—at not more than **0.1 %** peak area to avoid off-flavor complaints. The finished syrup is dispensed with a graduated oral syringe, delivering doses of **2.5 mg** to **5 mg** with a shelf life of **24 months** under ICH zone II storage conditions.Jet Milling in the Specified Hydrochloride Salt to Dv50 ≤ 12 µm: An Enabling Approach for Rapid-Dissolve PlatformsMicronizing the hydrochloride salt to a target median particle size of **Dv50 ≤ 12 µm** permits the design of orally disintegrating tablets (ODTs) that disintegrate in less than **30 seconds** in the oral cavity without chewing, addressing a niche where compliance with anticholinergic therapy is compromised by Parkinsonian bradykinesia. Feedstock with an entering particle size of **Dv90 ~ 180 µm** (coarse crystallizate from methanolic HCl precipitation) is de-agglomerated through a Hosokawa Micronizer spiral jet mill using compressed nitrogen at a grinding pressure of **7 bar** and an injector pressure of **5 bar**, with the mill ring configuration set to “coarse” to minimize amorphous content generation above **2 %** w/w, as measured by differential scanning calorimetry at a heating rate of **10 °C/min** under nitrogen purge. The micronized lot must pass an in-process control sieve test: **100 %** passes a **30 µm** screen (air jet sieving per **ASTM B214-22**), and the material meets USP <429> guidance on particle analysis through dry dispersion with a lens range of **0.1–3500 µm**, the specific surface area climbing above **2.5 m²/g** (BET method, **ISO 9277:2022**). In the subsequent ODT manufacture by freeze-drying (lyophilizer Gea Lyovac GT 2), this micronized salt is combined at **2.5 % w/w** with a gelatin (type A, 200 Bloom) matrix former and mannitol as a rigidification excipient; the suspension is dosed into preformed PVC/PVdC blister pockets, frozen at **−40 °C** for **3 hours**, and primary dried at a shelf temperature of **−20 °C** under a vacuum of **0.1 mbar** for **12 hours** followed by secondary drying at **25 °C** for **5 hours**. The resultant lyophilized wafer, containing **5 mg** of hydrochloride salt per unit, demonstrates an in-vitro disintegration time of **11–16 seconds** in **2 mL** of simulated saliva at **37 °C**, fulfilling the Ph. Eur. 2.9.1 disintegration requirement for orodispersible tablets and aligning with the bioequivalence guidance for oral anticholinergics where Tmax within **1.0–1.5 hours** must be preserved. The terminal dosage presentation is a peel-off push-through blister card bearing an aluminium foil lidding with a desiccant layer to hold moisture ingress below **5 %** equilibrium, suitable for clinic stocks treating acute drug-induced parkinsonism.
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Designated under the International Nonproprietary Name procyclidine hydrochloride, 1‑pyrrolidinepropanol, α‑cyclohexyl‑α‑phenyl‑, hydrochloride is a crystalline tertiary amino alcohol salt monographed in Ph. Eur. 10.0 (monograph 2457) and USP–NF 2023. The molecular formula C19H30ClNO corresponds to a relative molecular mass of 323.90 g·mol⁻¹, and the hydrochloride protonation of the pyrrolidine nitrogen yields a white or almost white powder with a melting range of 222–226 °C (decomposition) when scanned at 10 K·min⁻¹ by differential scanning calorimetry. The substance is sparingly soluble in water (≈1.5 mg·mL⁻¹ at 25 °C), freely soluble in ethanol and in dichloromethane, and practically insoluble in hexane, a solubility profile exploited for liquid–liquid extraction during impurity profiling. The carbinol carbon constitutes a chiral centre, yet the pharmacopoeial monograph recognises the racemate; enantiomeric resolution, where required, utilises a Chiralpak® AD‑H column (250 × 4.6 mm, 5 µm) with a hexane–isopropanol–diethylamine mobile phase per a validated in‑house method derived from Ph. Eur. 2.2.46.
| Attribute | Acceptance criterion | Reference method |
|---|---|---|
| Assay (anhydrous basis) | 98.5–101.0 % | Potentiometric titration (Ph. Eur. 2.2.20, 0.1 M perchloric acid) |
| Identification A (IR) | Concordant with reference spectrum | Infrared absorption spectrophotometry (Ph. Eur. 2.2.24), KBr disc |
| Identification B (HPLC) | Retention time concordant with CRS | Liquid chromatography (Ph. Eur. 2.2.29), C18 column |
| Appearance of solution | Clear and colourless | Visual inspection of a 2.0 % solution in methanol |
| Related substances (total) | ≤0.5 % | HPLC-UV at 210 nm, area normalisation |
| Heavy metals | ≤10 ppm | Ph. Eur. 2.4.8, Method D |
| Loss on drying | ≤0.3 % | Ph. Eur. 2.2.32, 105 °C for 2 h |
| Sulphated ash | ≤0.1 % | Ph. Eur. 2.4.14, 600 °C |
The intrinsic dissolution rate of procyclidine hydrochloride, determined at 37 °C in 0.1 M hydrochloric acid using a rotating‑disk apparatus (USP apparatus 2 variant, 100 rpm), falls within 0.12–0.18 mg·cm⁻²·min⁻¹ for the unmicronised D50 ≈85 µm feedstock. Jet‑milling to a D50 of 8–12 µm raises the dissolution rate two‑fold yet introduces a measurable increase in electrostatic charging, which impedes flow through rotary tablet press feed frames unless a glidant such as colloidal silicon dioxide (0.5–1.0 % w/w) is incorporated via low‑shear tumble blending. The pKa of the protonated pyrrolidine nitrogen has been reported at 9.2 (aqueous methanolic extrapolation), implying that at gastric pH the ionised form predominates; however, the solubility enhancement in fasted‑state simulated gastric fluid (FaSSGF, pH 1.6) is only 3‑fold relative to water, a fact attributed to the strong crystal lattice energy revealed by the high melting endotherm. Consequently, manufacturers operating direct‑compression lines specify a pre‑blending moisture content of ≤0.2 % by Karl Fischer titration and a final blend relative humidity exposure time of less than 30 min at 35 % RH, as deliquescence has not been observed but hydrate conversion can occur above 60 % RH, retarding in‑vitro dissolution at Q=30 min by 12 %.
Experience from pilot‑scale high‑shear wet granulation (Gral 10‑litre bowl, impeller 300 rpm, chopper 1500 rpm) indicates that aqueous granulation of formulations containing procyclidine hydrochloride and lactose monohydrate is feasible only when the binder addition rate is controlled to limit granule temperature below 28 °C; exotherms above 30 °C accelerate hydrolysis of the carbinol group, generating the des‑cyclohexyl ketone degradant at levels exceeding 0.2 % within 15 min. Fluid‑bed drying (Glatt GPCG 1, inlet air 45 °C, outlet air 28 °C, product final LOD 1.2–1.8 %) preserves the impurity profile when the relative standard deviation of spray rate across three nozzle ports is maintained below 3 %. The final compression mix, pressed on a 16‑station rotary press (Korsch XL 100) at a main compression force of 8–12 kN, yields tablets with a hardness–friability window of 45–65 N and ≤0.4 %, respectively, provided the ejection force remains below 150 N.
Competitive radioligand binding assays performed on Chinese hamster ovary cell membranes expressing human recombinant muscarinic receptor subtypes reveal that procyclidine hydrochloride exhibits a Ki of 0.8 nM at M1, 6.3 nM at M2, 11.5 nM at M3, 1.2 nM at M4, and 2.7 nM at M5 (³H‑N‑methylscopolamine as radioligand, 25 °C, 60‑min incubation). This profile illustrates a modest M1/M2 selectivity ratio of ~8, substantially lower than that of the piperidinyl analogue trihexyphenidyl hydrochloride, which displays an M1 Ki of 1.9 nM and an M2 Ki of 36 nM (ratio ~19). Benztropine mesylate, a tropane‑derived antimuscarinic, binds with sub‑nanomolar affinity across all subtypes, yet its pronounced antihistaminergic H1 activity (Ki 1.4 nM) contributes more sedation than is typically observed with procyclidine. The pharmacodynamic distinction becomes clinically meaningful in managing drug‑induced extrapyramidal symptoms: procyclidine’s balanced central muscarinic blockade partially spares peripheral receptors at therapeutic doses of 5–10 mg orally t.i.d., reducing the severity of dry mouth and blurred vision relative to equivalent antiparkinsonian doses of benztropine.
| Receptor subtype | Procyclidine HCl | Trihexyphenidyl HCl | Benztropine mesylate |
|---|---|---|---|
| M1 | 0.8 | 1.9 | 0.5 |
| M2 | 6.3 | 36 | 2.1 |
| M3 | 11.5 | 82 | 3.4 |
| M4 | 1.2 | 4.3 | 0.9 |
| M5 | 2.7 | 8.9 | 2.6 |
In Parkinson’s disease adjunctive therapy, procyclidine hydrochloride’s efficacy as a centrally acting anticholinergic was established in placebo‑controlled trials using the Unified Parkinson’s Disease Rating Scale motor subscore; a 5‑mg t.i.d. regimen achieved a mean reduction of 7.2 points over baseline at 8 weeks compared with 2.1 for placebo (p <0.01). Differences from amantadine hydrochloride are notable: amantadine potentiates dopaminergic transmission and weakens NMDA receptor excitation, whereas procyclidine relies exclusively on postsynaptic muscarinic receptor antagonism, making co‑administration rational but requiring dose adjustment of procyclidine when amantadine‑induced dry mouth emerges. Unlike the quaternary ammonium anticholinergic propantheline bromide, procyclidine crosses the blood–brain barrier readily, a property linked to its tertiary amine structure and log P of 3.8 (octanol‑water, pH 7.4). For patients with tardive dyskinesia, published data for this specific configuration is limited; retrospective chart reviews suggest a risk of symptom worsening, and the prescribing information for procyclidine hydrochloride tablets (USP) cautions against use in tardive dyskinesia unless the benefit of controlling concomitant parkinsonism clearly outweighs the risk.
A validated stability‑indicating HPLC method described in the USP monograph for procyclidine hydrochloride tablets employs a 150 × 4.6 mm L7 octylsilane column (5 µm) maintained at 30 °C, with isocratic elution by a mixture of acetonitrile, water, and triethylamine (60:40:0.2, v/v/v, pH adjusted to 3.5 with phosphoric acid) at 1.0 mL·min⁻¹ and UV detection at 210 nm. Under these conditions, the retention time of procyclidine is approximately 8.2 min, while the principal specified impurities—(1RS)-1-cyclohexyl-1-phenyl-3-(pyrrolidin-1-yl)propan-1-ol (diastereomeric alcohol) and 1-cyclohexyl-1-phenylpropan-1-one (des‑pyrrolidino ketone)—elute at relative retention times of 0.75 and 1.45, respectively, with resolution factors exceeding 2.0. Forced degradation studies conducted under ICH Q1A(R2) conditions reveal that the drug substance is most susceptible to acidic hydrolysis (0.1 M HCl, 60 °C for 4 h yields 8.5 % total degradants) and oxidative stress (3 % H2O2, 25 °C, 2 h generates the N‑oxide at 4.7 %). Base hydrolysis (0.1 M NaOH, 60 °C, 4 h) produces only 1.2 % degradation, consistent with the stability of the tertiary amine. Photolytic stress per ICH Q1B (Option 2, 1.2 million lux‑hours visible and 200 W·h·m⁻² UV) causes minimal degradation (0.3 %), thus amber glass bottles are not strictly required but remain customary in commercial packaging as a precaution against long‑term retail display lighting.
Batch records from commercial API manufacturing highlight that residual pyrrolidine, a genotoxic reagent, must be monitored by headspace GC‑MS with a reporting threshold of 5 ppm, conforming to ICH M7(R1) Option 3 control for a class 2 alkylating potential impurity. To mitigate formation of the N‑oxide during tablet storage, antioxidant systems such as sodium metabisulphite (0.05 % w/w) have been evaluated but often prove unnecessary when the primary packaging consists of cold‑form aluminium‑aluminium blisters with an oxygen transmission rate below 0.005 cm³·m⁻²·day⁻¹. Long‑term stability samples stored at 25 °C/60 % RH over 36 months show total related substances rising from 0.12 % to 0.28 % and dissolution at 45 min declining from 94 % to 88 %, both within the shelf‑life acceptance criteria set by ICH Q1E. Process validation reports highlight a critical processing parameter: the hold time of the dried granulate before compression must not exceed 72 h in non‑conditioned air zones, as moisture uptake above 0.5 % w/w initiates a detectable shift in the Heckel yield pressure from ∼120 MPa to ∼105 MPa, lowering tablet tensile strength below 1.5 MPa for the same compression force, a failure mode documented during scale‑up from 25‑kg to 150‑kg batch size. Retained quadrupole time‑of‑flight mass spectra of the N‑oxide degradant (m/z 340.2042 [M+H]+, formula C19H30NO2+) serve as system suitability markers in laboratories accredited to ISO/IEC 17025:2017.
