Cabergoline (21-20-9) Physical and Chemical Properties
Cabergoline
Ergoline-derived small-molecule dopamine D2 receptor agonist provided as a solid active pharmaceutical ingredient for formulation, analytical and development workflows.
| CAS Number | 21-20-9 |
| Family | Ergoline derivatives (dopamine agonists) |
| Typical Form | Powder or crystalline solid |
| Common Grades | EP, JP, USP |
Cabergoline is a semisynthetic ergoline derivative of the N-acylurea class; the molecular composition is \(\ce{C26H37N5O2}\). Structurally it consists of an ergoline tetracyclic core bearing a carboxamide at the 8‑position (ergoline-8-carboxamide) that is N‑substituted with a 3-(dimethylamino)propyl side chain and an ethylcarbamoyl moiety. The molecule contains a tertiary dialkylamino function and multiple amide/urea functionalities that define its polar surface and sites for protonation and hydrolytic cleavage. The ergoline nucleus confers a rigid, polycyclic scaffold with defined stereocentres (three defined atom stereocentres reported) and relatively low conformational flexibility in the core, while peripheral aliphatic linkers provide rotatable bond flexibility (RotatableBondCount = 8).
Electronically, cabergoline presents a mixed profile: the dialkylamino group imparts basicity and the urea/acylamide motifs provide hydrogen-bonding acceptor/donor capacity (HBondDonorCount = 2; HBondAcceptorCount = 4), producing a moderate topological polar surface area (TPSA = 71.7 Ų) compatible with membrane permeability and CNS penetration for a drug of its size. Computed and experimental lipophilicity values indicate moderate lipophilicity (XLogP = 3.4; reported LogP = 2.6), consistent with a balance between hydrophobic ergoline core and polar substituents. The molecule is a neutral covalent unit (Formal Charge = 0) in its free base form.
Pharmacologically, cabergoline is a long‑acting dopamine D2 receptor agonist with clinical utility in management of hyperprolactinaemia and Parkinsonian symptoms; it is formulated for oral administration. Chemically, the primary liabilities are hydrolytic cleavage of the acylurea bond and possible oxidative transformations on the ergoline core; metabolic data indicate predominant hepatic metabolism via hydrolysis of the acylurea linkage rather than extensive cytochrome P450 oxidation. Common commercial grades reported for this substance include: EP, JP, USP.
Basic Physicochemical Properties
Density and Solid-State Form
Physical description: Solid. Multiple single‑crystal structures and crystallographic datasets have been reported (CCDC numbers: 124405, 245288, 246008), indicating characterized crystalline forms. No experimentally established numeric bulk density value for the solid is available in the current data context.
Melting Point
Reported melting point range: 102–104 \(\,^\circ\mathrm{C}\). This sharp melting range is consistent with a crystalline, low‑polymorphism pharmaceutical solid suitable for standard melting‑point controlled quality assessment.
Solubility and Dissolution Behavior
Reported aqueous solubility: described as "Insoluble" with a quantitative entry of 6.40e-02 \(\mathrm{g}\,\mathrm{L}^{-1}\). The free base form shows low aqueous solubility at neutral pH; protonation of the tertiary dialkylamino group under acidic conditions will substantially increase aqueous solubility, so salt formation (or formulation approaches such as cocrystals, amorphous dispersions, or use of solubilising excipients) is typically required to achieve acceptable dissolution rates for oral solid dosage forms. Lipophilicity (LogP values noted below) and modest TPSA suggest membrane permeation is achievable once solubilised.
Chemical Properties
Acid–Base Behavior and Qualitative pKa
No experimentally established numeric \(\mathrm{p}K_a\) value for cabergoline is available in the current data context. Qualitatively, the 3‑(dimethylamino)propyl tertiary amine is the primary basic centre and will be protonated under acidic to near‑physiological conditions, increasing aqueous solubility. The urea/acylcarbamoyl functionalities are weakly acidic/basic and are not expected to dominate ionization under typical formulation or physiological pH.
Reactivity and Stability
Cabergoline is chemically susceptible to hydrolytic cleavage at the acylurea (acyl‑urea) bond; this pathway is the principal metabolic route in vivo (predominant hepatic hydrolysis). Cytochrome P450–mediated oxidation is reported to be minimal, indicating lower susceptibility to oxidative biotransformation relative to hydrolytic cleavage. As with many ergoline derivatives, the polycyclic core can be sensitive to strong oxidising/reducing conditions and extreme pH; formulation and storage in neutral, dry conditions minimises degradation. Standard forced‑degradation studies should evaluate hydrolysis, oxidative degradation, and photostability for specifications.
Molecular Parameters
Molecular Weight and Formula
Molecular formula: \(\ce{C26H37N5O2}\).
Molecular weight (reported): 451.6.
Exact/monoisotopic mass: 451.29472544.
LogP and Structural Features
Computed XLogP: 3.4 (XLogP3-AA).
Reported experimental LogP: 2.6.
Interpretation: the molecule is moderately lipophilic, with calculated and measured lipophilicity consistent with oral bioavailability when suitably formulated. TPSA = 71.7 Ų, HBondDonorCount = 2 and HBondAcceptorCount = 4, RotatableBondCount = 8; these parameters are consistent with a relatively druglike yet large small‑molecule ligand capable of CNS exposure. Molecular complexity is high (Complexity = 713), reflecting the polycyclic ergoline scaffold and stereochemical definition (DefinedAtomStereocenterCount = 3).
Structural Identifiers (SMILES, InChI)
SMILES: CCNC(=O)N(CCCN(C)C)C(=O)[C@@H]1C[C@H]2[C@@H](CC3=CNC4=CC=CC2=C34)N(C1)CC=C
InChI: InChI=1S/C26H37N5O2/c1-5-11-30-17-19(25(32)31(26(33)27-6-2)13-8-12-29(3)4)14-21-20-9-7-10-22-24(20)18(16-28-22)15-23(21)30/h5,7,9-10,16,19,21,23,28H,1,6,8,11-15,17H2,2-4H3,(H,27,33)/t19-,21-,23-/m1/s1
InChIKey: KORNTPPJEAJQIU-KJXAQDMKSA-N
(Identifiers provided exactly as recorded above.)
Identifiers and Synonyms
Registry Numbers and Codes
CAS Registry Number: 21-20-9.
Related CAS (diphosphate): 85329-89-1.
EC number: 627-031-8.
UNII: LL60K9J05T.
Additional registry identifiers (as supplied): ChEBI: CHEBI:3286; ChEMBL: CHEMBL1201087.
Synonyms and Brand-Independent Names
Common synonyms and nonproprietary names documented include: cabergoline; Dostinex; Cabaser; FCE‑21336; cabergolina; cabergolinum; Velactis; FCE 21336. Several systematic nomenclature strings and salt forms (e.g., diphosphate) are also recorded.
Industrial and Pharmaceutical Applications
Role as Active Ingredient or Intermediate
Cabergoline is used as an active pharmaceutical ingredient (API) with dopaminergic (D2 receptor agonist) activity. Therapeutic indications include treatment of hyperprolactinaemia (e.g., prolactin‑secreting adenomas) and symptomatic management in Parkinsonian syndromes. Veterinary uses include lactation suppression/abrupt drying‑off aids in herd management under veterinary product registrations.
Formulation and Development Contexts
Oral solid dosage forms (tablets) are standard commercial presentations, with tablet strengths cited at 0.5 mg and 1 mg in listed formulations. Given the low aqueous solubility of the free base, formulation strategies for immediate or sustained release generally address dissolution rate via salt selection, particle size reduction, use of solubilising excipients or formulation into well‑designed oral solid matrices. Long elimination half‑life (reported terminal half‑life ~63–69 hours) underpins dosing regimens and supports infrequent dosing; formulation design must consider pharmacokinetic persistence and potential for accumulation.
Specifications and Grades
Typical Grade Types (Pharmaceutical, Analytical, Technical)
Typical commercial grade categories for small‑molecule APIs are applicable: pharmaceutical (pharmacopeial/commercial API grade), analytical reference standards, and technical or research grades for nonclinical use. The pharmacopeial reference grades recorded for cabergoline include EP, JP and USP.
General Quality Attributes (Qualitative Description)
Quality attributes critical for cabergoline API and material include identity and stereochemical purity (three defined stereocentres), assay/potency, related‑substance profile (hydrolytic and oxidative degradation products), residual solvents, heavy metals, and microbial limits. Given the metabolic susceptibility at the acylurea bond, control of degradation products arising from hydrolysis is a key specification focus. Particle size distribution, polymorphic form and residual solvent limits are typical manufacturing‑control parameters for tablets and reference standards.
Safety and Handling Overview
Toxicological Profile and Exposure Considerations
Hazard classification descriptors reported include acute oral toxicity, skin and eye irritation, and respiratory tract irritation (aggregated hazard statements include H302: harmful if swallowed; H315: causes skin irritation; H319: causes serious eye irritation; H335: may cause respiratory irritation). Pharmacologically, cabergoline is a potent dopamine agonist and systemic exposure produces on‑target effects (e.g., suppression of prolactin, dopaminergic CNS effects) as well as off‑target risks associated with ergoline derivatives (valvular heart disease and fibrotic reactions have been reported in clinical contexts). Side effects observed clinically include nausea, dizziness, hypotension, sleep disturbances, peripheral oedema, and neuropsychiatric events; overdose may present with syncope, hallucinations or vasoconstrictive complications. Protein binding is moderate (40–42%).
As with all APIs, exposure routes of concern for handlers are dermal contact, inhalation of dust and accidental ingestion. Engineering controls, good laboratory practice and appropriate personal protective equipment reduce occupational exposure.
Storage and Handling Guidelines
Store as a dry, well‑closed container in a cool environment protected from prolonged exposure to moisture and light. Avoid strong oxidants and extremes of pH. Use standard controls for dust generation and provide appropriate local exhaust ventilation when handling powders at scale. For detailed hazard, transport and regulatory information, users should refer to the product‑specific Safety Data Sheet (SDS) and local legislation.
