Tubocurarine (16-22-6) Physical and Chemical Properties
Tubocurarine
Plant-derived benzylisoquinoline alkaloid historically used as a non-depolarizing neuromuscular blocker; relevant to API research, formulation development and analytical QC.
| CAS Number | 16-22-6 |
| Family | Benzylisoquinoline alkaloids |
| Typical Form | Crystalline powder (free base or chloride salts) |
| Common Grades | EP, USP |
Tubocurarine is a benzylisoquinoline alkaloid belonging to the class of quaternary ammonium natural products. Structurally it is built from fused isoquinoline-derived rings bearing multiple methoxy and phenolic substituents and a permanently charged nitrogen center (formally monocationic). The molecular formula is \(\ce{C37H41N2O6+}\); the quaternary nitrogen converts the molecule to a fixed cation under all normal aqueous conditions, which strongly influences both pharmacokinetic and physical behavior.
Electronically, the molecule combines localized aromatic systems with polar substituents (two hydrogen-bond donors and seven acceptors, topological polar surface area 80.6 Å2). Although computed XLogP3 is 6, the permanent positive charge and high polarity markedly reduce passive membrane permeation and effective lipophilicity in aqueous media; consequently renal excretion and limited tissue redistribution dominate elimination. The quaternary ammonium character also eliminates a classical protonation equilibria (no free tertiary-base pKa for the ionized form).
Tubocurarine has established clinical and historical importance as a non-depolarizing nicotinic antagonist used to induce skeletal muscle relaxation during anesthesia. Its clinical utility is limited by a relatively long duration of action and side effects including histamine release and cardiovascular effects; modern practice has largely replaced it with agents that have more favorable pharmacokinetics and safety profiles. Common commercial grades reported for this substance include: EP, USP.
Basic Physicochemical Properties
Density and Solid-State Form
Physical description: Solid; reported as white to light-tan crystalline alkaloid, odorless. Crystals form hexagonal and pentagonal microplatelets from water; the substance can exist in various hydrated forms (including pentahydrate in chloride salts). Multiple solid-state forms (anhydrous and hydrated salts) have been described for chloride and other salt forms; hydrates form readily in moist atmospheres.
Melting Point
Multiple melting/decomposition points have been reported for different salt/hydrate forms and preparations. Reported values include: - "Needles from water; mp: 268 °C (effervescence); specific optical rotation: -258 deg @ 20 °C (c=0.38) for the anhydrous salt /Chloride, l-Form/". - "Anhydrous material (dec 274–275 °C) takes up water in moist atm until pentahydrate stage, dec approximately 270 °C. Specific optical rotation: +190 deg @ 22 °C/D; +219 deg @ 23 °C/D (c=0.785 in methanol). UV max (H2O): 280 nm (E=118, 1%, 1 cm). /Chloride, d-Form/". - "Crystals, dec about 236 °C (effervescence); specific optical rotation: +185 deg @ 25 °C/D ; to +195 °C (c=0.5 in H2O) ... /Dimethyl ether/".
If a specific preparation is being handled, the melting/decomposition behavior should be attributed to that salt/hydrate form because decomposition temperatures differ with hydration and counterion.
Solubility and Dissolution Behavior
Solubility reports vary by salt form and solvent: - "Solublity (25 °C): approx 50 mg/l water; but supersaturated solutions are formed readily. Solubility also reported as approximately 1 g/40 ml water; approximately 1 g/75 ml ethanol. Also soluble in methanol. Insoluble in pyridine, chloroform, benzene, acetone, ether. /Chloride, d-Form/". - "Soluble in water, dil sodium hydroxide, Sparingly sol in alcohol, in dil HCl, chlorform. Practically insoluble in benzene, ether. /Dimethyl ether/". - Reported numerical solubility: 3.23e-04 g/L (value provided without additional contextual detail). - Other statements: "SOL IN WATER APPROX 300 MG/100 ML" (crystal-specific report).
Interpretation: water solubility depends strongly on counterion, hydration state and crystallinity; supersaturation and variable hydrate formation are commonly observed. The permanently charged species is more water-soluble than neutral benzylisoquinolines but crystalline salts can show relatively low apparent solubility and form supersaturated or metastable phases.
Chemical Properties
Acid–Base Behavior and Qualitative pKa
No experimentally established value for this property is available in the current data context.
Qualitative note: the isolated structure exists as a permanently charged quaternary ammonium cation (formal charge +1), so classical acid–base pKa for protonation is not applicable to the quaternary center. Metabolic N‑demethylation (minor hepatic pathway) converts the quaternary character to tertiary amines in metabolites, which can display acid–base equilibria.
Reactivity and Stability
Stability characteristics from experimental reports: - Sensitive to light (noted for chloride forms). - When heated to decomposition, the compound emits toxic fumes of nitroxides. - Shelf-life and handling notes indicate that the anhydrous material absorbs moisture to form hydrates; hydrates and salts have different decomposition behavior.
Reactivity considerations: the molecule contains phenolic hydroxyls and methoxy groups adjacent to aromatic systems; oxidative degradation of phenolic moieties and oxidative N‑demethylation (in vivo) are chemically plausible. Quaternary ammonium character confers low volatility and reduces susceptibility to acid–base hydrolysis, but thermal decomposition and photodegradation can occur.
Molecular Parameters
Molecular Weight and Formula
- Molecular weight: 609.7 (as reported).
- Molecular formula: \(\ce{C37H41N2O6+}\).
- Exact mass / Monoisotopic mass: 609.29646203.
- Formal charge: 1.
- Heavy atom count: 45.
- Defined atom stereocenter count: 2.
LogP and Structural Features
- XLogP (computed): 6.
- Topological Polar Surface Area (TPSA): 80.6.
- Hydrogen bond donors: 2.
- Hydrogen bond acceptors: 7.
- Rotatable bond count: 2.
- Complexity: 990.
Interpretation: the computed high XLogP arises from a largely aromatic, polycyclic scaffold; however, the permanent positive charge and substantial polar substituents substantially reduce effective passive distribution into lipophilic compartments. Measurable pharmacokinetic behavior (rapid renal excretion, low tissue penetration) reflects the ionized, hydrophilic disposition despite the computed lipophilicity of the neutral scaffold.
Structural Identifiers (SMILES, InChI)
- SMILES:
CN1CCC2=CC(=C3C=C2[C@@H]1CC4=CC=C(C=C4)OC5=C6[C@@H](CC7=CC(=C(C=C7)O)O3)[N+](CCC6=CC(=C5O)OC)(C)C)OC - InChI:
InChI=1S/C37H40N2O6/c1-38-14-12-24-19-32(42-4)33-21-27(24)28(38)16-22-6-9-26(10-7-22)44-37-35-25(20-34(43-5)36(37)41)13-15-39(2,3)29(35)17-23-8-11-30(40)31(18-23)45-33/h6-11,18-21,28-29H,12-17H2,1-5H3,(H-,40,41)/p+1/t28-,29+/m0/s1 - InChIKey:
JFJZZMVDLULRGK-URLMMPGGSA-O
(Identifiers shown exactly as reported.)
Identifiers and Synonyms
Registry Numbers and Codes
- CAS (as reported for this entry): 16-22-6
- EC Number: 886-985-5
- UNII: W9YXS298BM
- ChEBI: CHEBI:9774
- ChEMBL: CHEMBL339427
- DrugBank: DB01199
- HMDB: HMDB0015330
- KEGG: C07547
- DSSTox Substance ID: DTXSID0048393
Other registry and internal collection identifiers are present in analytical and pharmacological sources; the list above reflects primary registry keys reported.
Synonyms and Brand-Independent Names
Common synonyms (selected from reported names): - Tubocurarine - d‑Tubocurarine - Tubocurare - Tubocurarin - (+)-Tubocurarine - Tubocurarine ion / Tubocurarine cation - Delacurarine - Isoquinoline alkaloid - Tubocurarine chloride (and various hydrate/salt forms)
(IUPAC and extended systematic stereochemical names also exist for the quaternary species and its chloride salts; proprietary and removed synonyms have been documented for salt and hydrate forms.)
Industrial and Pharmaceutical Applications
Role as Active Ingredient or Intermediate
Tubocurarine is a classical non-depolarizing neuromuscular blocking agent and nicotinic receptor antagonist. Its primary historical application was as an intravenous skeletal muscle relaxant to facilitate surgical anesthesia, intubation and procedures requiring profound muscle relaxation. It acts by competitive blockade of post-synaptic nicotinic acetylcholine receptors at the neuromuscular junction.
Clinical use has declined in favor of agents with more predictable durations and fewer adverse cardiovascular effects, but the compound remains a prototypical curare alkaloid for pharmacological studies and as a starting point for semisynthetic derivatives (e.g., metocurine).
Formulation and Development Contexts
Documented pharmaceutical preparations include chloride salts and hydrated forms; the chloride USP preparation has been marketed as sterile solution concentrations (examples reported: 3 mg/mL and 15 mg/mL solutions for injection). Derivatization (methylation to yield dimethyl or other quaternary derivatives) produces semisynthetic analogs with different potency and pharmacokinetics. For formulation work, counterion selection, hydrate control and control of crystalline form are critical for consistent solubility and dosing performance.
If a concise, product-specific application summary is required for procurement or development, selection should be made on the basis of the salt form, grade and required pharmacokinetic/handling profile.
Specifications and Grades
Typical Grade Types (Pharmaceutical, Analytical, Technical)
Typical grade concepts applicable to tubocurarine and its salts: - Pharmaceutical grade (e.g., USP) — intended for sterile injectable formulations; controlled for identity, potency and safety-related impurities. - Pharmacopoeial/European Pharmacopoeia grade (EP) — standardized for inter-laboratory consistency, especially for clinical use. - Analytical grade — for assay and analytical reference standards. - Technical / research grade — for non-clinical research and preparative chemistry.
Reported commercial grades for this substance include: EP, USP.
General Quality Attributes (Qualitative Description)
Quality attributes to consider for procurement and specification: - Salt form and hydration state (chloride, iodide, pentahydrate, anhydrous) strongly influence solubility, optical rotation and melting/decomposition behavior. - Optical rotation is a sensitive indicator of enantiomeric purity and hydrate/salt form (reported values vary by preparation). - Control of residual solvents and counterion purity is important for injectable formulations. - Photostability and moisture uptake should be assessed; light sensitivity and hydrate formation are noted.
Exact assay limits, impurity thresholds and certificate-of-analysis requirements should be defined case by case; specific numeric acceptance criteria are not provided here.
Safety and Handling Overview
Toxicological Profile and Exposure Considerations
High-level toxicology and exposure observations: - Mechanism: competitive antagonism of nicotinic acetylcholine receptors at the neuromuscular junction causing flaccid paralysis; histamine release and ganglionic blockade contribute to hypotension and bronchospasm. - Acute human hazard: respiratory paralysis can occur at clinical or supraclinical doses; an intravenous dose of 30 mg has been reported to produce respiratory arrest in most adults within minutes for certain salt forms. - Non-human toxicity (selected reported values): LD50 Rat ip 210 µg/kg; LD50 Rat im 500 µg/kg; LD50 Mouse ip 410 µg/kg; LD50 Mouse sc 560 µg/kg (values reported as provided). - Interactions: a wide range of drugs (certain aminoglycoside antibiotics, magnesium salts, quinidine, etc.) potentiate neuromuscular blockade; cholinesterase inhibitors (e.g., neostigmine) antagonize the block when reversal is indicated and are used clinically with antimuscarinic protection (atropine). - First aid and treatment: for severe exposure, support respiration and circulation; reversal of neuromuscular blockade with anticholinesterase agents plus antimuscarinic protection is standard clinical practice when indicated.
This substance is biologically active and potentially lethal by paralyzing respiratory muscles; handling by trained personnel with appropriate medical support is required for clinical administration.
Storage and Handling Guidelines
- Storage: store at controlled room temperature; avoid freezing for aqueous or formulated preparations. Protect from light for light‑sensitive salt forms.
- Handling: use appropriate personal protective equipment to prevent exposure by injection or other routes; avoid inhalation of powders and control dust. Use engineering controls for containment and ventilation when handling bulk crystalline material.
- Disposal: dispose of wastes in accordance with local regulations and institutional practices for hazardous pharmaceutical and toxic chemical waste; avoid environmental release.
For detailed hazard, transport and regulatory information, users should refer to the product-specific Safety Data Sheet (SDS) and local legislation.
