Clonidine Hydrochloride (4205-91-8) Physical and Chemical Properties
Clonidine Hydrochloride
Crystalline hydrochloride salt of clonidine, an imidazoline-derived small molecule supplied for API manufacture, analytical standards, and formulation development.
| CAS Number | 4205-91-8 |
| Family | Imidazoline derivatives |
| Typical Form | Powder or crystalline solid |
| Common Grades | BP, EP, JP, USP |
Clonidine hydrochloride is the monohydrochloride salt of an imidazoline-derived adrenergic agent; chemically it is an N-(2,6-dichlorophenyl)-4,5-dihydro-1H-imidazol-2-amine hydrochloride and belongs to the imidazoline/imidazoline‑amine structural class. The molecule comprises a dichlorophenyl aromatic moiety connected to a reduced imidazoline (2‑imidazoline) ring; the salt form places an additional proton on the basic imidazoline nitrogen and supplies a chloride counter‑ion, yielding the molecular composition \(\ce{C9H10Cl3N3}\). Electronically, the dichloro substitution increases aromatic electron withdrawal and lipophilicity, while the protonated imidazoline provides a localized positive charge and multiple hydrogen‑bond donors, producing a zwitterion‑free cationic salt at typical handling conditions.
These structural elements dictate class‑level physicochemical behavior: the imidazoline center confers basicity and high propensity for protonation under acidic to neutral conditions (hence stable as a hydrochloride salt for formulation), while the dichlorophenyl ring contributes to membrane permeability and receptor affinity. The salt form increases aqueous dissolution relative to the free base and favors formulation into oral, parenteral and topical presentations. Metabolically and pharmacologically the molecule acts centrally as an alpha‑2 adrenergic agonist; this central activity is consistent with moderate lipophilicity coupled with a protonatable heterocycle that allows blood–brain barrier penetration in the unionized/proton‑equilibrated state.
From an industrial and regulatory perspective, clonidine hydrochloride is used as an active pharmaceutical ingredient with multiple approved and investigational indications where its central sympatholytic action is exploited (antihypertensive, ADHD, adjunct analgesic uses and others). Common commercial grades reported for this substance include: BP, EP, JP, USP.
Basic Physicochemical Properties
Density and Solid-State Form
No experimentally established value for this property is available in the current data context. Qualitatively, clonidine hydrochloride is handled as the crystalline hydrochloride salt of the imidazoline amine; salts of this type are typically isolated as white to off‑white crystalline powders and are chosen in pharmaceutical development to improve handling and dissolution compared with the free base.
Melting Point
No experimentally established value for this property is available in the current data context.
Solubility and Dissolution Behavior
No experimentally established quantitative solubility values are available in the current data context. Qualitatively, conversion of the basic imidazoline free base to the hydrochloride salt increases aqueous solubility and dissolution rate versus the neutral base, which facilitates oral and parenteral formulation. The salt will generally show pH‑dependent solubility with maximal solubility in acidic to mildly neutral aqueous media where the imidazoline is protonated; excipient choice and particle size will strongly influence dissolution performance in solid oral dosage forms.
Chemical Properties
Acid–Base Behavior and Qualitative pKa
No experimentally established value for this property is available in the current data context. From the structural class, the 2‑imidazoline ring contains a basic sp2‑type nitrogen(s) that is readily protonated to form the hydrochloride salt; therefore the compound behaves as a basic pharmaceutical with the protonated (salt) form predominating under acidic to physiological conditions. Protonation stabilizes the cation and is the rationale for using the monohydrochloride salt for drug formulations.
Reactivity and Stability
Clonidine hydrochloride, like many protonated heterocyclic amine salts, is chemically stable under normal storage conditions when protected from extreme temperature, light and moisture. The dichloroaromatic substituents are relatively inert to hydrolytic cleavage; the imidazoline ring can be susceptible to strong oxidizing or strongly basic hydrolytic conditions that open the heterocycle, so formulation and manufacturing should avoid prolonged exposure to harsh acid/base or oxidative reagents. For detailed degradation pathways and compatibility with excipients or primary packaging, batch‑specific stability studies are required.
Molecular Parameters
Molecular Weight and Formula
- Molecular formula: \(\ce{C9H10Cl3N3}\)
- Molecular weight: 266.6 \(\mathrm{g}\,\mathrm{mol}^{-1}\)
- Exact mass (monoisotopic): 264.994030
LogP and Structural Features
No experimentally established value for logP is available in the current data context. Structural descriptors and counts available from computed properties indicate low to moderate polar surface area and limited conformational flexibility, consistent with moderate lipophilicity: - Topological polar surface area (TPSA): 36.4 - Hydrogen bond donor count: 3 - Hydrogen bond acceptor count: 1 - Rotatable bond count: 2
The combination of the dichlorophenyl ring (increasing lipophilicity) and a protonatable imidazoline (increasing aqueous solubility as the hydrochloride) is consistent with a molecule optimized for central nervous system activity while remaining sufficiently soluble for oral and parenteral dosing.
Structural Identifiers (SMILES, InChI)
- SMILES:
C1CN=C(N1)NC2=C(C=CC=C2Cl)Cl.Cl - InChI:
InChI=1S/C9H9Cl2N3.ClH/c10-6-2-1-3-7(11)8(6)14-9-12-4-5-13-9;/h1-3H,4-5H2,(H2,12,13,14);1H - InChIKey:
ZNIFSRGNXRYGHF-UHFFFAOYSA-N
The compound is canonicalized for cheminformatics purposes.
Identifiers and Synonyms
Registry Numbers and Codes
- CAS number: 4205-91-8
- European Community (EC) number: 224-121-5
- UNII: W76I6XXF06
- ChEBI ID: CHEBI:3758
- ChEMBL ID: CHEMBL1705
- DSSTox Substance ID: DTXSID8044670
Synonyms and Brand-Independent Names
Reported synonyms and alternative names include: Clonidine Hydrochloride; Clonidine Monohydrochloride; Clonidine HCl; N-(2,6-dichlorophenyl)-4,5-dihydro-1H-imidazol-2-amine; 2-(2,6‑Dichlorophenylamino)-2‑imidazoline hydrochloride. MeSH/entry terms include ST‑155. A broader list of depositor‑supplied synonyms and historical names is associated with this substance for use in procurement and regulatory documentation.
Industrial and Pharmaceutical Applications
Role as Active Ingredient or Intermediate
Clonidine hydrochloride is used predominantly as an active pharmaceutical ingredient (API). Clinically it is applied as a centrally acting alpha‑2 adrenergic agonist with antihypertensive activity and additional therapeutic roles where sympathetic outflow modulation is desired. It has documented uses as an oral and parenteral antihypertensive, for attention‑deficit hyperactivity disorder (ADHD) in certain formulations, as an adjunct in analgesic regimens (including epidural adjuncts for severe cancer pain), and for various off‑label or secondary indications such as management of withdrawal syndromes, migraine prophylaxis, and ocular pressure reduction in glaucoma contexts. It is also the basis for investigational and pediatric formulations noted in regulatory planning.
Formulation and Development Contexts
As the hydrochloride salt the substance is compatible with oral solid dosage forms (tablets, extended release systems), parenteral solutions for infusion, topical ophthalmic vehicles and transdermal systems. Development considerations include control of particle size distribution for dissolution performance, selection of excipients that do not interact with the imidazoline salt (ionic interactions, strong oxidants), and assessment of stability under intended storage and sterilization conditions for parenteral use. The salt form simplifies aqueous formulation but requires attention to osmolality and pH in injectable preparations.
Specifications and Grades
Typical Grade Types (Pharmaceutical, Analytical, Technical)
Typical grade concepts applicable to clonidine hydrochloride are pharmaceutical (API, pharmacopeial reference standards and compendial grades), analytical (reference standards for identity and assay), and technical/industrial grades for research and raw material supply. Reported compendial/industrial grade labels associated with this substance include: BP, EP, JP, USP.
General Quality Attributes (Qualitative Description)
Quality attributes that are routinely controlled for API supply include assay/potency (mass fraction of active compound), identity (spectroscopic and chromatographic confirmation), residual solvents and inorganic impurities (including chloride balance), water content (loss on drying), polymorphic form and particle size distribution. For pharmaceutical use, provenance documentation, batch traceability and certificates of analysis aligned with pharmacopoeial monographs (where applicable) are standard expectations. Specific numerical limits and acceptance criteria are determined by the purchasing specification and applicable compendia.
Safety and Handling Overview
Toxicological Profile and Exposure Considerations
Clonidine hydrochloride is an active pharmacological agent with significant central nervous system effects; the hazard classifications reported include acute toxicity categories. Hazard statement codes associated with acute toxicity in some notifications include H301 (Toxic if swallowed) and H330 (Fatal if inhaled), with aggregated signal word "Danger." Acute toxicity data reported include LD50 values of 150 mg/kg (oral, rat) and 30 mg/kg (oral, dog). Clinical signs of overdose include miosis (pupil constriction), drowsiness, initial hypertension followed by hypotension, bradycardia, hypothermia, respiratory depression and reduced reflexes. There is no specific antidote; management is supportive and may include atropine for bradycardia, intravenous fluids or vasopressors for hypotension, and naloxone as an adjunct for severe respiratory depression where clinically indicated. Exposures via inhalation, ingestion or dermal contact should be minimized in manufacturing and laboratory settings.
Storage and Handling Guidelines
Handle clonidine hydrochloride as a potent pharmacologically active salt: use appropriate engineering controls (local exhaust, closed transfers) to minimize dust and aerosol generation, and wear suitable personal protective equipment (gloves, eye protection and respiratory protection when dust or aerosol exposure is possible). Store in tightly closed containers in a cool, dry, well‑ventilated area away from oxidizing agents and strong bases. Segregate from incompatible materials and follow controlled access procedures for APIs. For detailed hazard, transport and regulatory information, users should refer to the product‑specific Safety Data Sheet (SDS) and local legislation.
