Procyclidine (18-11-5) Physical and Chemical Properties
Procyclidine
Centrally acting anticholinergic small molecule (tertiary amine) relevant to neurology therapeutics and commonly handled as an API or analytical reference for formulation and QC.
| CAS Number | 18-11-5 |
| Family | Pyrrolidines (tertiary amine) |
| Typical Form | Powder or crystalline solid |
| Common Grades | BP, EP |
Procyclidine is a tertiary alcohol bearing a bulky alpha-disubstituted propanol motif: an alpha‑cyclohexyl and alpha‑phenyl substitution on the propan‑1‑ol skeleton with a pendant pyrrolidinyl tertiary amine at the 3‑position. Structurally it is a member of the pyrrolidine class and can be described as a tertiary‑amine, tertiary‑alcohol small molecule. The combination of a nonpolar cyclohexyl/phenyl pair and a basic pyrrolidine gives a molecule with low polar surface area and a single hydrogen‑bond donor (the tertiary alcohol OH), while the pyrrolidine nitrogen provides a protonatable center under acidic conditions.
Electronically and physicochemically, the low topological polar surface area and limited hydrogen‑bonding capacity favour membrane permeability and central nervous system penetration; experimental and computed lipophilicity values (XLogP ≈ 4.1, LogP ≈ 4.2) are consistent with this. The tertiary amine is protonatable in physiological to acidic pH ranges, producing a cationic species that increases aqueous solubility and plasma protein binding; the tertiary alcohol remains essentially nonionized across the physiological pH range. Metabolic transformations reported for related compounds and for procyclidine include oxidative hydroxylation of the cyclohexyl ring and subsequent di‑ and polyhydroxylated derivatives, reflecting hepatic phase I oxidative metabolism of the alicyclic moiety.
Medically, procyclidine has been used as a centrally acting muscarinic (anticholinergic) agent for symptomatic treatment of parkinsonian syndromes and drug‑induced extrapyramidal disorders; the compound crosses the blood–brain barrier and exerts antimuscarinic activity at central M‑type receptors. Common commercial grades reported for this substance include: BP, EP.
Basic Physicochemical Properties
Density and Solid-State Form
No experimentally established numeric density value for this property is available in the current data context. The substance is reported in the solid state and is isolated as crystalline material: "Crystals from petroleum ether" and is described experimentally as a solid.
Melting Point
Reported melting behavior is consistent and reproducible. Provided experimental values include: - 86 - 85.5 to 86.5 °C - 86 °C
When presenting melting points in technical specifications choose the narrow experimental range "85.5 to 86.5 °C" to represent typical batch behavior; present literature values commonly report \(85.5\)–\(86.5\,^\circ\mathrm{C}\).
Solubility and Dissolution Behavior
Solubility entries show differing experimental contexts: - "Moderately soluble in water, ~ 30 mg/ml" (reported as approximate) - \(9.84\times 10^{-3}\,\mathrm{g}\,\mathrm{L}^{-1}\) (as reported in another experimental determination)
These values indicate that aqueous solubility is highly dependent on the physical form (free base versus salt), pH, and experimental conditions. The free base (neutral tertiary amine) will exhibit low intrinsic aqueous solubility consistent with the high lipophilicity (LogP ≈ 4.1–4.2), whereas a protonated salt form (e.g., hydrochloride) will be substantially more water‑soluble. In formulation or analytical work, control of pH and use of the hydrochloride salt are standard strategies to increase dissolution and batch‑to‑batch reproducibility.
Chemical Properties
Acid–Base Behavior and Qualitative pKa
No experimentally established numeric \(\mathrm{p}K_a\) value for this property is available in the current data context. Qualitatively, the molecule contains a tertiary aliphatic amine (pyrrolidine) which is the single basic center and will be protonated under acidic to neutral conditions, forming a water‑soluble cation. The tertiary alcohol is not significantly acidic or ionizable in the physiologically relevant pH range. Protonation of the pyrrolidine nitrogen increases aqueous solubility and reduces lipophilicity relative to the neutral free base.
Reactivity and Stability
Procyclidine is chemically stable under normal handling conditions for tertiary amines/tertiary alcohols but will undergo decomposition at elevated temperature. Reported thermal decomposition produces toxic nitrogen oxides ("When heated to decomposition it emits toxic fumes of NOx"). The molecule is susceptible to hepatic oxidative metabolism (hydroxylation of the cyclohexyl ring and further dihydroxylated metabolites have been identified), indicating sites of metabolic vulnerability rather than hydrolytic instability. Standard precautions for tertiary amine/tertiary alcohols—avoid strong oxidizers and excessive heat—are appropriate.
Molecular Parameters
Molecular Weight and Formula
- Molecular formula: C19H29NO
- Molecular weight: 287.4 (nominal)
When used in stoichiometric calculations, express the molar mass as \(287.4\,\mathrm{g}\,\mathrm{mol}^{-1}\).
LogP and Structural Features
Calculated and experimental lipophilicity indicators reported: - XLogP: 4.1 - LogP (experimental): 4.2
Other computed descriptors relevant to ADME and formulation: - Topological Polar Surface Area (TPSA): \(23.5\,\text{Å}^2\) - Hydrogen bond donor count: 1 - Hydrogen bond acceptor count: 2 - Rotatable bond count: 5
These values reflect a compact, moderately flexible, lipophilic molecule with low polar surface area—properties consistent with efficient blood–brain barrier penetration and high plasma protein binding. The combination of aromatic and alicyclic hydrophobic groups with a single basic center drives central distribution and partitioning into lipid phases.
Structural Identifiers (SMILES, InChI)
- SMILES: C1CCC(CC1)C(CCN2CCCC2)(C3=CC=CC=C3)O
- InChI: InChI=1S/C19H29NO/c21-19(17-9-3-1-4-10-17,18-11-5-2-6-12-18)13-16-20-14-7-8-15-20/h1,3-4,9-10,18,21H,2,5-8,11-16H2
- InChIKey: WYDUSKDSKCASEF-UHFFFAOYSA-N
(Identifiers above are presented as plain text as required for cheminformatics interoperability.)
Identifiers and Synonyms
Registry Numbers and Codes
- CAS: 18-11-5
- EC number: 201-023-0
- UNII: C6QE1Q1TKR
- ChEBI: CHEBI:8448
- ChEMBL: CHEMBL86715
- DrugBank: DB00387
- ATC code: N04AA04
Only explicitly reported registry identifiers are listed here. Use the CAS shown above exactly in procurement or regulatory documentation when required.
Synonyms and Brand‑Independent Names
Common synonyms and alternative names reported include (selection of depositor‑supplied strings): procyclidine, Kemadrine, Tricoloid, Elorine, Lergine, Vagosin, Arpicolin, Spamol, Procyklidin, Triciclidina, Metanin, Osnervan, Procyclidinum, 1‑Cyclohexyl‑1‑phenyl‑3‑(1‑pyrrolidinyl)‑1‑propanol, (±)-Procyclidine, Kemadrin.
When specifying material for regulatory or quality documentation, supply both the INN (Procyclidine) and the salt form where relevant (e.g., hydrochloride) to avoid ambiguity.
Industrial and Pharmaceutical Applications
Role as Active Ingredient or Intermediate
Procyclidine functions pharmaceutically as a centrally acting muscarinic antagonist (anticholinergic) and has been used as an antiparkinson agent and for management of drug‑induced extrapyramidal symptoms. It has been formulated and administered clinically, typically as the hydrochloride salt, to exploit increased water solubility for oral dosage forms. Its primary role in pharmaceutical contexts is as an active pharmaceutical ingredient (API) for symptomatic relief of parkinsonian rigidity and some extrapyramidal signs.
Formulation and Development Contexts
Typical marketed formulations have included oral tablets (example dose level: 5 mg tablets). The free base is lipophilic and presents solubility and dissolution challenges; the hydrochloride salt form is used in solid oral dosage formulations to improve aqueous solubility and bioavailability. Pharmacokinetic data indicate an oral bioavailability on the order of ~75% (reported for clinical dosing), a volume of distribution approximating \(1\,\mathrm{L}\,\mathrm{kg}^{-1}\), and a plasma elimination half‑life of approximately 12 hours under the described clinical conditions—parameters relevant to dosing interval and formulation strategy.
If a concise application summary is required for procurement or process selection and no additional product‑specific information is available: procyclidine is selected in pharmaceutical use for its centrally acting antimuscarinic pharmacology and for formulations where CNS penetration is a desired attribute.
Specifications and Grades
Typical Grade Types (Pharmaceutical, Analytical, Technical)
Typical grade concepts for this class of substances include: - Pharmaceutical (API) grade: material produced to pharmacopeial or manufacturer specification for oral dosage forms (typically supplied as a defined salt, e.g., hydrochloride). - Analytical grade: high‑purity materials intended for use in analytical reference standards. - Technical grade: material for research, development, or nonclinical use where less stringent impurity limits may apply.
Commercial grades explicitly reported for this substance include: BP, EP.
General Quality Attributes (Qualitative Description)
Quality attributes of relevance when specifying material include: - Chemical identity (INN, free base vs. salt) - Purity and impurity profile (organic and inorganic impurities) - Residual solvents and polymorphic form (crystalline habit described as "crystals from petroleum ether") - Assay and related substances testing appropriate to intended use (pharmaceutical vs. analytical) - Microbial limits for materials intended for clinical production
Exact assay limits, impurity thresholds, and certificate of analysis criteria are product‑specific and are not provided here; these must be specified in supply agreements and product specifications.
Safety and Handling Overview
Toxicological Profile and Exposure Considerations
Toxicity metrics reported include: - LD50 (mouse, intravenous): \(60\,\mathrm{mg}\,\mathrm{kg}^{-1}\) (IV, mouse) - LD50 (mouse, intraperitoneal): \(131\,\mathrm{mg}\,\mathrm{kg}^{-1}\) (IP, mouse)
Protein binding has been reported as approximately 100% bound to albumin in plasma. Clinical and case data indicate central anticholinergic effects (e.g., mydriasis, dry mouth, urinary retention) and central nervous system adverse events at higher or misused doses; there are documented reports of psychiatric disturbance and abuse potential under certain conditions. Contraindications and precautions include angle‑closure glaucoma and caution in patients with psychiatric disorders, hypotension, pregnancy or pediatric use where safety/efficacy are not established.
For acute exposure and clinical toxicology, standard supportive and symptomatic treatment applies; first aid and emergency measures include airway support, decontamination, seizure management, and intensive supportive care where required. In thermal decomposition events the material can emit toxic NOx gases; fire/thermal decomposition precautions should be observed.
Storage and Handling Guidelines
Solid material should be stored in tightly closed containers protected from excessive heat. Recommended storage conditions for the hydrochloride tablet form have been reported as below \(40\,^\circ\mathrm{C}\), preferably between \(15\) and \(30\,^\circ\mathrm{C}\). Avoid ignition sources and strong oxidizing agents; control dust generation for powdered material. Use appropriate personal protective equipment (gloves, eye protection, lab coat) and engineering controls (local exhaust, containment) during handling to minimize inhalation or dermal exposure.
For detailed hazard, transport and regulatory information, users should refer to the product‑specific Safety Data Sheet (SDS) and applicable local legislation.
