Duloxetine (18-10-5) Physical and Chemical Properties
Duloxetine
Small-molecule SNRI active pharmaceutical ingredient used across drug development, formulation and analytical workflows.
| CAS Number | 18-10-5 |
| Family | Serotonin–Norepinephrine Reuptake Inhibitors (SNRI) |
| Typical Form | Powder or crystalline solid |
| Common Grades | EP, USP |
Duloxetine is a small-molecule pharmaceutical belonging to the structural class of aryl‑ether substituted phenyl/heteroaryl propanamine antidepressants (serotonin–norepinephrine reuptake inhibitors, SNRI). The molecule contains a substituted naphthyl ether linked to a chiral, N‑methylated 3‑propanamine bearing a thiophene substituent; the structure presents one defined stereocenter (S‑enantiomer in the active form) and an ionizable secondary amine. Key electronic features are a nonpolar polycyclic naphthalene chromophore that contributes to lipophilicity and a localized basic center (the secondary amine) that is protonated under physiological/acidic conditions, producing readily isolable salt forms (notably the hydrochloride) used in oral formulations.
Functionally, the compound is moderately lipophilic (log P values around 4), has low aqueous solubility in its free base form, and a topological polar surface area consistent with good central nervous system penetration. The basic amine exhibits a measurable dissociation constant in mixed solvent systems, and the molecule is chemically susceptible to acid‑mediated hydrolysis pathways that can reduce oral bioavailability unless formulation measures (e.g., enteric coating, salt formation) are employed. The naphthyl moiety is a likely site for oxidative metabolism and photochemical/oxidative degradation under forced conditions, while the tertiary sulfur‑containing heterocycle (thiophene) contributes to overall aromatic stabilization.
Pharmaceutically, duloxetine is widely used as an oral active pharmaceutical ingredient for mood and chronic pain indications; the hydrochloride salt is the formulation form commonly encountered in drug products. Common commercial grades reported for this substance include: EP, USP.
Basic Physicochemical Properties
Density and Solid-State Form
Physical description: Solid; reported as a white to slightly brownish white solid. No experimentally established value for the crystalline or bulk density of the free base is available in the current data context. A flash point value of 9.7 °C (49.5 °F) (closed cup) is reported for a material form, indicating flammability concerns for volatile or solvent‑exposed forms during handling and processing.
Melting Point
No experimentally established value for this property is available in the current data context.
Solubility and Dissolution Behavior
Reported aqueous solubility (free base, experimental context unspecified): \(2.96\times10^{-3}\,\mathrm{g}\,\mathrm{L}^{-1}\). The free base is therefore only sparingly soluble in water; pharmaceutically relevant formulations employ the hydrochloride salt to increase aqueous solubility and enable reproducible oral dosing. The molecule is reported to be susceptible to hydrolysis in acidic environments; this chemical liability has practical formulation consequences (enteric coatings or salt forms are used to protect the drug during gastric transit). Measured experimental partitioning descriptors are consistent with moderate–high lipophilicity (see LogP entries below), which correlates with slow dissolution in aqueous media for the non‑salt form and a tendency for high protein binding in plasma.
Chemical Properties
Acid–Base Behavior and Qualitative pKa
The molecule contains a protonatable secondary amine. A reported dissociation constant in a dimethylformamide:water (66:34) mixture is \(\mathrm{p}K_a = 9.6\). In physiological aqueous media the basic center will be predominantly protonated at neutral pH, favoring formation of water‑soluble salts (e.g., hydrochloride). Salt selection and pH control are therefore important levers to tune solubility, dissolution rate and absorption.
Reactivity and Stability
Duloxetine is reported to be stable under recommended storage conditions. Chemical reactivity considerations from experimental summaries and safety data include incompatibility with strong oxidizing and strong reducing agents, strong acids, acid chlorides/anhydrides, and alkali metals. The presence of a naphthyl chromophore suggests susceptibility to photodegradation (direct photolysis) under UV exposure and metabolic oxidation (naphthyl hydroxylation is a major metabolic pathway). Acid‑mediated hydrolysis is a practical stability concern for the free base during formulation and administration. For processing and emergency response, use of explosion‑proof equipment and control of ignition sources is recommended because of flammability and vapour hazards for certain material preparations.
Molecular Parameters
Molecular Weight and Formula
- Molecular formula: C18H19NOS
- Molecular weight: 297.4 (reporting unit: \(\mathrm{g}\,\mathrm{mol}^{-1}\))
- Exact/monoisotopic mass: 297.11873540
LogP and Structural Features
- Computed XLogP3 (descriptor): 4.3
- Experimental/other reported LogP: 4
These values indicate moderate–high lipophilicity, consistent with the polyaromatic naphthyl and thiophene substituents. The topological polar surface area (TPSA) is 49.5 \(\text{Å}^2\), a value compatible with central nervous system penetration. Hydrogen bond counts: donor = 1, acceptor = 3; rotatable bond count = 6. High protein binding (>90% reported) and a large apparent volume of distribution (reported Vd ≈ 1620–1800 L) are consistent with the lipophilic profile and extensive tissue distribution.
Structural Identifiers (SMILES, InChI)
SMILES: CNCCC@@HOC2=CC=CC3=CC=CC=C32
InChI: InChI=1S/C18H19NOS/c1-19-12-11-17(18-10-5-13-21-18)20-16-9-4-7-14-6-2-3-8-15(14)16/h2-10,13,17,19H,11-12H2,1H3/t17-/m0/s1
InChIKey: ZEUITGRIYCTCEM-KRWDZBQOSA-N
Identifiers and Synonyms
Registry Numbers and Codes
- CAS number: 18-10-5
- EC number: 601-438-0
- UNII: O5TNM5N07U
- ChEBI: CHEBI:36795
- ChEMBL: CHEMBL1175
- DrugBank: DB00476
- ATC code: N06AX21
(Additional registry identifiers and database accession codes are available in product and regulatory documentation.)
Synonyms and Brand‑Independent Names
Common synonyms and systematic names reported for the compound include: Duloxetine; (S)-Duloxetine; LY248686; (3S)-N‑methyl‑3‑naphthalen‑1‑yloxy‑3‑thiophen‑2‑ylpropan‑1‑amine; duloxetina; Yentreve. Note that pharmaceutical products are typically supplied as the duloxetine hydrochloride salt in dosage forms.
Industrial and Pharmaceutical Applications
Role as Active Ingredient or Intermediate
Duloxetine is used as an active pharmaceutical ingredient (API) in systemic oral medicines targeting major depressive disorder, generalized anxiety disorder and a range of chronic pain conditions (including diabetic peripheral neuropathy, fibromyalgia and chronic musculoskeletal pain). It is also used in some regulatory jurisdictions for stress urinary incontinence in women. The hydrochloride salt is the formulation form used in marketed products.
Formulation and Development Contexts
Key formulation considerations derive from the molecule's low free‑base aqueous solubility, susceptibility to acid‑mediated degradation in gastric conditions, and moderate–high lipophilicity. Typical pharmaceutical strategies include conversion to the hydrochloride salt to increase aqueous solubility and use of enteric coatings or modified release dosage forms to mitigate gastric hydrolysis and to control absorption kinetics. Oral bioavailability is reported to be approximately 50% with substantial interindividual variability; Tmax can be delayed by formulation factors and food. Extensive hepatic metabolism (primarily CYP1A2 and CYP2D6) governs elimination and informs drug–drug interaction risk during development.
Specifications and Grades
Typical Grade Types (Pharmaceutical, Analytical, Technical)
In commercial supply chains, duloxetine is encountered in pharmaceutical‑grade material intended for use as an API, and in analytical reference standards. Typical grade concepts include pharmaceutical (for formulation of drug products), and analytical/technical grades for QC and research. The substance is provided in pharmaceutically acceptable salt forms (most commonly the hydrochloride) for manufacturing and formulation use.
Reported commercial grades: EP, USP.
General Quality Attributes (Qualitative Description)
Quality attributes that are controlled for API and excipient manufacturing include identity, assay/potency, related substances/impurity profile (including residual solvents and process‑related impurities), enantiomeric purity (defined stereocenter), particle size/distribution for solid‑dosage processing, and residual counter‑ions for salts. Given the substance’s propensity for acid‑mediated transformation and oxidative metabolism, specifications typically address stability‑related degradants and photostability. Certificate of analysis and batch‑specific documentation are used to ensure traceability and conformity to pharmacopeial or purchaser specifications.
Safety and Handling Overview
Toxicological Profile and Exposure Considerations
Duloxetine possesses pharmacologic activity associated with serotonin and norepinephrine reuptake inhibition; clinical safety concerns relevant to occupational and clinical exposure include hepatotoxicity risk, serotonergic toxicity (serotonin syndrome) in the presence of additional serotonergic agents, and neuropsychiatric effects that require clinical monitoring in patients. Reported acute oral LD50 values in rodents: oral, rat LD50 male = \(491\,\mathrm{mg}\,\mathrm{kg}^{-1}\); female = \(279\,\mathrm{mg}\,\mathrm{kg}^{-1}\). The compound is highly protein bound (>90%), and hepatic metabolism predominates; individuals with hepatic impairment exhibit markedly increased exposure and reduced clearance. Overdose can produce CNS depression, seizures, serotonin syndrome, autonomic instability and, in severe cases, fatal outcomes.
Because duloxetine is an active pharmaceutical, avoid uncontrolled environmental release and follow appropriate pharmaceutical waste handling regulations. For clinical use, established boxed warning information for antidepressant class effects and suicide risk in certain age groups is part of product labeling and clinical risk management.
Storage and Handling Guidelines
Recommended storage conditions for material handling and long‑term retention include keeping containers tightly closed in a dry, well‑ventilated place; an indicated recommended storage temperature for some material presentations is −20 °C. For manufacturing and laboratory operations, use standard pharmaceutical good manufacturing practice (GMP) controls: engineering controls to limit inhalation exposure, closed systems where feasible, and suitable local exhaust ventilation. Personal protective equipment (PPE) recommended for handling includes chemically resistant gloves, eye/face protection and protective clothing; in situations with potential airborne exposure, use appropriately certified respiratory protection. For spills, remove ignition sources, ventilate the area, avoid release to drains, and collect material with non‑sparking tools into suitable containers for disposal per local regulations.
For acute exposure management: there is no specific antidote for duloxetine; supportive care and symptomatic treatment are the mainstays. In suspected serotonergic toxicity, serotonin antagonists and aggressive supportive measures may be required. For detailed hazard, transport and regulatory information, users should refer to the product‑specific Safety Data Sheet (SDS) and local legislation.
