Citalopram (59729-33-8) Physical and Chemical Properties
Citalopram
A small-molecule SSRI pharmaceutical ingredient commonly handled as an API for formulation development, analytical reference standards and R&D in medicinal chemistry and pharmaceutical manufacturing.
| CAS Number | 59729-33-8 |
| Family | SSRIs (Selective Serotonin Reuptake Inhibitors) |
| Typical Form | Powder or crystalline solid |
| Common Grades | BP, EP, USP |
Citalopram is a racemic small-molecule antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. Chemically it is a 1,3-dihydro-2-benzofuran derivative bearing a para-fluorophenyl substituent, a 5-cyano (nitrile) functionality on the benzofuran ring and a basic tertiary 3-(dimethylamino)propyl side chain. The structure combines an aromatic bicyclic core (benzofuran) that provides lipophilicity and pi-character with a tertiary aliphatic amine that confers basicity and the capacity for salt formation; the molecule contains one undefined stereocenter and is typically encountered as the racemate in commercial products.
Electronically and pharmacokinetically relevant features include a single tertiary amine with an experimental/basic \(\mathrm{p}K_a\) in the high single digits (see below), a topological polar surface area of 36.3 Å^2 (\(\text{TPSA}=36.3\)) and no hydrogen-bond donors. These properties produce a moderately lipophilic neutral free base (XLogP ~3.2; experimental LogP ~3.76) with good membrane permeability but limited intrinsic aqueous solubility; protonation of the tertiary amine (salt formation) increases aqueous solubility substantially, which is exploited in pharmaceutical formulations. Metabolic liability is dominated by hepatic \(N\)-demethylation and related oxidative transformations; the molecule is not hydrolytically labile under neutral conditions but is susceptible to photolytic and oxidative pathways in the environment and to decomposition at elevated temperatures with release of corrosive combustion gases.
Citalopram is a marketed pharmaceutical active ingredient used primarily to treat major depressive disorder and related indications, and it is commonly formulated as the hydrobromide salt for oral dosage forms (tablets, solution, capsules). Common commercial grades reported for this substance include: BP, EP, USP.
Basic Physicochemical Properties
Density and Solid-State Form
Physical description: solid; fine white to off-white powder. Crystalline forms have been reported from different solvents (e.g., crystals from isopropanol or acetone) and different solid forms (free base, salts, enantiomeric salts) exhibit distinct morphology and melting behaviour.
No experimentally established value for density is available in the current data context.
Melting Point
Reported melting points depend on form and preparation: - MP: 182–188 (reported range, unspecified unit in source) - MP: 182–183 (crystals from isopropanol; associated comment in source) - MP: 178 \(\,^\circ\mathrm{C}\) (single value reported) - MP: 147–148 \(\,^\circ\mathrm{C}\) (reported for crystals from acetone; associated with escitalopram/oxalate forms in source)
These disparate values reflect differences between free base, salt forms and polymorphs/enantiomers; confirm the specific material (free base vs hydrobromide/oxalate; racemate vs S-enantiomer) before using an MP for processing or QC.
Solubility and Dissolution Behavior
- Solubility class (free base): sparingly soluble in water; soluble in ethanol and many organic solvents; freely soluble in methanol and DMSO. One description: "sparingly soluble in water and soluble in ethanol."
- Salt solubility (hydrobromide): reported water solubility for citalopram hydrobromide: 15,460 mg·L^{-1} at 22 \(\,^\circ\mathrm{C}\) (explicitly attributed to the hydrobromide salt in the source).
- Partitioning and solubility metrics: XLogP3-AA = 3.2 (computed); experimental LogP reported as 3.76; LogS reported as −4.7.
- Practical implications: the free base is moderately lipophilic and exhibits limited aqueous solubility at neutral pH; conversion to a protonated salt (hydrobromide) or formulation approaches (salt selection, cosolvents, surfactants) are used in product development to achieve acceptable dissolution and bioavailability. Solubility is strongly pH-dependent because the tertiary amine is protonatable (see acid–base section).
Chemical Properties
Acid–Base Behavior and Qualitative pKa
Citalopram contains a single basic tertiary amine and behaves as a weak base. Reported dissociation constants include: - Basic \(\mathrm{p}K_a = 9.38\) (labelled Basic pKa in experimental properties) - \(\mathrm{p}K_a = 9.78\) (alternate reported value)
At physiological pH the tertiary amine is predominantly protonated for values below the \(\mathrm{p}K_a\), so the molecule exists largely as a cation in blood and aqueous formulations at neutral pH. Salt formation (e.g., hydrobromide) stabilizes the protonated form and increases aqueous solubility relative to the free base.
Reactivity and Stability
- Storage stability: described as "stable under recommended storage conditions" for pharmaceutical-grade material (properties associated with the hydrobromide salt).
- Thermal decomposition: when heated to decomposition the material can evolve toxic combustion products, including nitrogen oxides, hydrogen fluoride and hydrogen bromide (notable for halogenated aromatic fragments and bromide-containing salts).
- Chemical incompatibilities: incompatibility with strong oxidizing agents is reported for salt forms.
- Environmental/abiotic fate: citalopram exhibits measurable resistance to biodegradation in activated sludge tests (no significant biodegradation in 28 days in one study) and a measured aquatic photolysis half-life of about 39 days under simulated sunlight for the hydrochloride form; hydrolysis is not expected to be a major environmental pathway because the molecule lacks hydrolytically labile functional groups.
- Metabolic reactivity: metabolic transformations are dominated by hepatic \(N\)-demethylation (producing demethylcitalopram and further didemethyl metabolites), \(N\)-oxidation and deamination pathways; these processes are enzymatically mediated (CYP2C19, CYP3A4, CYP2D6 and monoamine oxidases in some tissues).
Molecular Parameters
Molecular Weight and Formula
- Molecular formula: C20H21FN2O
- Molecular weight: 324.4 (use as \(\,324.4\ \mathrm{g}\,\mathrm{mol}^{-1}\))
- Exact mass / monoisotopic mass: 324.16379146
LogP and Structural Features
- Computed XLogP3-AA: 3.2
- Reported experimental LogP: 3.76
- Reported LogS: −4.7 Structural parameters relevant to ADME:
- Topological polar surface area (TPSA): 36.3 (\(\text{Å}^2\))
- Hydrogen-bond donor count: 0
- Hydrogen-bond acceptor count: 4
- Rotatable bond count: 5
- Formal charge (neutral free base): 0 (but protonates in acidic media)
Interpretation: the combination of a moderate LogP, low TPSA and absence of H-bond donors favors membrane permeability and central nervous system penetration for the neutral species; protonation at physiological/acidic pH increases aqueous solubility and reduces lipophilicity correspondingly.
Structural Identifiers (SMILES, InChI)
- SMILES: CN(C)CCCC1(C2=C(CO1)C=C(C=C2)C#N)C3=CC=C(C=C3)F
- InChI: InChI=1S/C20H21FN2O/c1-23(2)11-3-10-20(17-5-7-18(21)8-6-17)19-9-4-15(13-22)12-16(19)14-24-20/h4-9,12H,3,10-11,14H2,1-2H3
- InChIKey: WSEQXVZVJXJVFP-UHFFFAOYSA-N
Identifiers and Synonyms
Registry Numbers and Codes
- CAS Registry Number: 59729-33-8
- EC number: 261-891-1
- UNII: 0DHU5B8D6V
- ChEBI: CHEBI:77397
- ChEMBL: CHEMBL549
- DrugBank: DB00215
- KEGG: C07572 (and a KEGG drug ID D07704)
- Other common identifiers from analytical records: InChIKey WSEQXVZVJXJVFP-UHFFFAOYSA-N
Synonyms and Brand-Independent Names
Reported synonyms and alternative names include: - citalopram - 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-carbonitrile (IUPAC) - Cipram / Cipramil - Celexa - Nitalapram - Citalopramum (INN-Latin) - Bonitrile
(These are representative synonyms and trade names that have been associated with the chemical structure in registries and vendor descriptions; confirm the accepted nonproprietary name for regulatory filings.)
Industrial and Pharmaceutical Applications
Role as Active Ingredient or Intermediate
Citalopram is used as an active pharmaceutical ingredient (API) in oral dosage forms for the treatment of major depressive disorder and related psychiatric indications. It functions pharmacologically as a selective serotonin reuptake inhibitor (SSRI), increasing serotonergic neurotransmission through inhibition of the serotonin transporter. The marketed pharmaceutical is typically supplied as the hydrobromide salt to improve aqueous solubility and control pharmacokinetics.
Formulation and Development Contexts
Citalopram is developed and formulated for oral administration in tablets, capsules and oral solutions; formulation choices often exploit the hydrobromide salt to meet dissolution and bioavailability targets. The racemic mixture is the historical clinical product, while the S-enantiomer (escitalopram) is recognized as the more pharmacodynamically active enantiomer and is treated separately in product development. Typical formulation considerations include salt form selection, control of polymorphism, and analytical methods for potency, enantiomeric composition and impurity profiling.
Specifications and Grades
Typical Grade Types (Pharmaceutical, Analytical, Technical)
Typical commercial grade categories relevant to this API include: - Pharmaceutical / drug-substance grade (for use in finished medicinal products) - Analytical reference standards (high-purity materials for method development and QC) - Technical research-grade material (for R&D and nonclinical assays)
Common commercial grades reported for this substance include: BP, EP, USP.
General Quality Attributes (Qualitative Description)
Pharmaceutical-grade citalopram is characterized qualitatively by: controlled assay/potency, low residual solvents, well-defined polymorphic form and particle size distribution for manufacturability, tight impurity limits (including related substances such as N‑desmethyl and didesmethyl derivatives), and appropriate residual metal/counter-ion specifications for salts. Stability under recommended storage conditions and control of hygroscopicity (where relevant for salts) are routine quality attributes. Specific acceptance criteria (assay limits, impurity thresholds) must be obtained from product specifications and pharmacopeial monographs applicable to the grade in use.
Safety and Handling Overview
Toxicological Profile and Exposure Considerations
- Pharmacotoxicology: citalopram is an SSRI with known central nervous system effects (therapeutic and adverse). Notable systemic toxicities include common adverse effects (nausea, dizziness, somnolence, sexual dysfunction), and more serious concerns such as QTc prolongation and, in rare cases, torsade de pointes and other arrhythmias at high exposures. Antidepressant therapies including citalopram carry a boxed warning for increased risk of suicidal thoughts and behaviors in children, adolescents and young adults; clinical monitoring is required in these populations.
- Overdose and acute effects: symptoms of overdose reported include dizziness, sweating, nausea, vomiting, tremor, somnolence, tachycardia and—rarely—seizures, coma and serious cardiac events. Management is supportive; due to large volume of distribution dialysis is generally of limited benefit.
- Pharmacokinetic markers relevant to exposure: reported mean terminal half-life ≈ 35 hours; volume of distribution ≈ 12 \(\mathrm{L}\,\mathrm{kg}^{-1}\); systemic clearance ≈ 330 \(\mathrm{mL}\,\mathrm{min}^{-1}\) (values reported in clinical pharmacology summaries). These parameters explain once-daily dosing and accumulation to steady state over several days.
- Drug interactions and metabolic considerations: citalopram is metabolized primarily via CYP2C19 and CYP3A4 (to demethylcitalopram) and further by CYP2D6; coadministration with inhibitors of these enzymes or in CYP2C19 poor metabolizers may raise exposures and necessitate dose adjustments. Concomitant use with other serotonergic agents increases the risk of serotonin syndrome. SSRIs can increase bleeding risk when used with antiplatelet agents or anticoagulants.
- Occupational exposure: potential routes include inhalation of dust and dermal contact during manufacture or handling of the solid bulk material; standard precautions to avoid dust generation and to prevent dermal/ocular exposure are recommended.
For clinical safety and detailed toxicology (including reproductive and neonatal concerns, dosing limits, and boxed warnings), consult the product-specific prescribing information and formal regulatory labeling. For detailed hazard, transport and regulatory information, users should refer to the product-specific Safety Data Sheet (SDS) and local legislation.
Storage and Handling Guidelines
- Recommended storage temperatures reported for commercial material: store at 20 \(\,^\circ\mathrm{C}\) to 25 \(\,^\circ\mathrm{C}\) with permitted excursions 15–30 \(\,^\circ\mathrm{C}\); alternate recommended storage for certain salt forms in documents may specify refrigerated conditions (2–8 \(\,^\circ\mathrm{C}\)) for specific formulations—follow the manufacturer’s specification for the supplied material.
- Handling: avoid dust formation; provide local exhaust ventilation at points where dust may be generated; use gloves and eye protection suitable for chemical handling; for higher airborne concentrations use appropriate respiratory protection certified to local standards.
- Spill and disposal: contain and collect solids with methods that minimize dust formation; prevent entry to drains; dispose of surplus or waste material through licensed waste contractors in accordance with applicable hazardous pharmaceutical disposal regulations. For handling of contaminated packaging and small spills, follow the product SDS and local waste regulations.
- Firefighting and decomposition: extinguish fire with water spray, alcohol-resistant foam, dry chemical or CO2; wear self-contained breathing apparatus if required; decomposition can release corrosive and toxic gases (NOx, HF, HBr), so use full firefighting PPE and respiratory protection.
