Guanfacine (29110-47-2) Physical and Chemical Properties
Guanfacine
A small‑molecule, selective alpha‑2 adrenergic agonist API used in pharmaceutical development and manufacturing for antihypertensive and ADHD product development, formulation, and analytical QC.
| CAS Number | 29110-47-2 |
| Family | Acetamides (arylacetamides) |
| Typical Form | Powder or crystalline solid |
| Common Grades | BP, EP, USP |
Guanfacine is a small-molecule, centrally acting adrenergic alpha-2A receptor agonist belonging to the acetamide/guanidine structural class. Structurally it is an N‑(diaminomethylidene) acetamide substituted with a 2,6‑dichlorophenyl ring; the neutral free‑base molecular formula is \(\ce{C9H9Cl2N3O}\). The molecule combines a relatively electron‑rich aromatic ring (dichlorophenyl) with a highly polar amidino/guanidine-like functionality linked through an acetamide spacer, producing a zwitterion‑capable pattern of hydrogen bonding and protonation under acidic conditions.
Electronically and conformationally, the compound presents two hydrogen‑bond donors and one hydrogen‑bond acceptor with a topological polar surface area of 81.5 Ų, and only two rotatable bonds. These features produce moderate polarity and limited conformational flexibility. Measured and computed partitioning descriptors vary by method (see Molecular Parameters), but overall indicate modest lipophilicity compatible with central nervous system exposure when formulated appropriately. The amidine/guanidine-like center confers basic character and the substance is commonly handled and formulated either as the free base or as a more water‑soluble monohydrochloride salt.
Common commercial grades reported for this substance include: BP, EP, USP.
Basic Physicochemical Properties
Density and Solid-State Form
Physical description: Solid. Crystallographic data are available (CCDC Number 267877 and associated crystal structure depositions), indicating a defined crystalline solid state for the free base under conditions used for structure determination. No experimental bulk density value for the powder or single crystal is provided in the current data context.
Melting Point
Multiple experimental melting ranges are present in the data: 213-216 and 225 - 227 °C. Such variation between published melting ranges is consistent with differences in sample form, purity, analytical method, measurement atmosphere, or the presence of different solid forms (free base versus salt/polymorph). The related monohydrochloride salt is listed separately (related CAS 29110-48-3) and may exhibit distinct thermal behaviour.
Solubility and Dissolution Behavior
Solubility entries in the current data context include "1mg/mL" and "1.39e-01 g/L". These correspond to approximate aqueous solubility on the order of 10^-3 to 10^-1 g·L^-1 depending on sample form and measurement conditions (expressed equivalently as \(1\ \mathrm{mg}\,\mathrm{mL}^{-1}\) and \(1.39\times10^{-1}\ \mathrm{g}\,\mathrm{L}^{-1}\)). The free base has limited aqueous solubility; conversion to the monohydrochloride salt is a standard approach to increase water solubility for formulation and analytical purposes. Solubility is expected to be strongly pH‑dependent because of protonation of the amidine/guanidine center.
Chemical Properties
Acid–Base Behavior and Qualitative pKa
Guanfacine contains an amidino/guanidine-like functionality that is protonatable; accordingly it exists as a free base and forms more water‑soluble protonated salt forms (e.g., monohydrochloride). No experimentally established numeric \(\mathrm{p}K_a\) value for the principal protonation equilibrium is available in the current data context.
Reactivity and Stability
As an acetamide bearing a basic amidino substituent, guanfacine is chemically stable under routine laboratory handling and solid storage conditions. In biological systems it undergoes oxidative metabolism: enzymatic oxidation by CYP3A4 yields 3‑hydroxyguanfacine, which is subject to subsequent conjugation (glucuronidation or sulfation). From a preparative/processing perspective, standard precautions apply to avoid strong hydrolysis or extreme oxidative conditions; salt formation (hydrochloride) is used to improve aqueous stability and handling for pharmaceutical formulations.
Molecular Parameters
Molecular Weight and Formula
- Molecular formula: \(\ce{C9H9Cl2N3O}\)
- Molecular weight: 246.09 g·mol^-1
LogP and Structural Features
- XLogP3‑AA: 2 (computed)
- Experimental LogP values present in the data: 0.857 and 1.7
- Topological Polar Surface Area (TPSA): 81.5 Ų
- Hydrogen bond donors: 2
- Hydrogen bond acceptors: 1
- Rotatable bond count: 2
These descriptors indicate moderate lipophilicity combined with a nontrivial polar surface area. The balance of XLogP/TPSA and the presence of a protonatable amidine/guanidine functional group support CNS exposure in appropriately designed formulations while also permitting salt formation to aid aqueous dissolution.
Structural Identifiers (SMILES, InChI)
- SMILES:
C1=CC(=C(C(=C1)Cl)CC(=O)N=C(N)N)Cl - InChI:
InChI=1S/C9H9Cl2N3O/c10-6-2-1-3-7(11)5(6)4-8(15)14-9(12)13/h1-3H,4H2,(H4,12,13,14,15) - InChIKey:
INJOMKTZOLKMBF-UHFFFAOYSA-N
Identifiers and Synonyms
Registry Numbers and Codes
- CAS number: 29110-47-2
- Related CAS (mono‑hydrochloride): 29110-48-3
- European Community (EC) number: 249-442-8
- UNII: 30OMY4G3MK
- ChEBI: CHEBI:5558
- ChEMBL: CHEMBL862
- DrugBank: DB01018
- InChIKey: INJOMKTZOLKMBF-UHFFFAOYSA-N
Synonyms and Brand-Independent Names
Selected synonyms and alternative names found in the current information set include: Guanfacine; N-(diaminomethylidene)-2-(2,6-dichlorophenyl)acetamide; N‑carbamimidoyl‑2‑(2,6‑dichlorophenyl)acetamide; BS 100‑141; Estulic; Tenex; Guanfacine hydrochloride; Guanfacina; Guanfacinum. (These names reflect INN, deposited synonyms and registered synonyms used in pharmaceutical and chemical contexts.)
Industrial and Pharmaceutical Applications
Role as Active Ingredient or Intermediate
Guanfacine is an approved active pharmaceutical ingredient used as a centrally acting alpha‑2 adrenergic agonist. Clinically it has been indicated for hypertension and, in extended‑release formulations, for attention deficit hyperactivity disorder (ADHD) in pediatric and adult populations. The substance is used as the free base and commonly as the monohydrochloride salt in medicinal products.
Formulation and Development Contexts
Pharmacokinetic properties relevant to formulation and development documented in the data include approximately 80% oral bioavailability; a mean elimination half‑life of 17 hours (range reported 10–30 hours), a volume of distribution of 6.3 L·kg^-1, and ~70% plasma protein binding. Both immediate‑release and extended‑release oral dosage forms have been characterized (examples of Cmax and Tmax values for specific doses are present in clinical pharmacology summaries). Metabolism is mainly via CYP3A4 to 3‑hydroxyguanfacine with subsequent conjugation. These attributes inform selection of salt form, release profile, and dosing regimen during development.
Specifications and Grades
Typical Grade Types (Pharmaceutical, Analytical, Technical)
Typical commercial grade categories applicable to an active pharmaceutical ingredient such as guanfacine include pharmaceutical grade (for formulated drug products), analytical grade (for impurity profiling and method development), and technical grade (for research and non‑clinical use). Where formal pharmacopoeial monographs apply, pharmaceutical‑grade material is analyzed and released against compendial criteria appropriate to the intended market.
Documented commercial grades: BP, EP, USP.
General Quality Attributes (Qualitative Description)
Key quality attributes for guanfacine raw material and salts include identity (structure and stereochemistry where applicable), assay/potency, residual solvents, inorganic and organic impurities (including related substances), water content, particle size distribution (affecting dissolution), and microbiological limits for specific applications. Salt selection (monohydrochloride) is a principal quality decision when aqueous solubility and crystalline form are performance drivers.
Safety and Handling Overview
Toxicological Profile and Exposure Considerations
Human pharmacology and clinical safety notes indicate central alpha‑2 adrenergic agonist activity with expected pharmacodynamic effects such as potential hypotension and bradycardia; patients are counselled regarding syncope risk in clinical use. Clinical data summarized indicate no consistent association with clinically apparent liver injury during therapeutic use. Toxicological classification statements present in hazard summaries include acute oral toxicity and reproductive/organ toxicity categories—these reflect aggregated hazard notifications and may depend on impurity profile and specific formulations.
As a general precaution for handling the solid chemical: avoid ingestion, inhalation of dust, and prolonged skin contact; use appropriate engineering controls and personal protective equipment (PPE) such as gloves, eye protection, and lab coat in laboratory and processing environments. Limit releases to the environment and avoid discharge to waterways without appropriate treatment, consistent with aquatic hazard annotations.
Storage and Handling Guidelines
Store in a cool, dry, well‑ventilated place in tightly closed containers protected from direct sunlight and strong oxidants. Solid material in crystalline form should be stored to maintain anhydrous conditions where required by the formulation or analytical SOPs. For detailed hazard, transport and regulatory guidance consult the product‑specific Safety Data Sheet (SDS) and applicable local legislation.
