Salmeterol (26-15-7) Physical and Chemical Properties
Salmeterol
Long-acting beta-2 adrenergic agonist small molecule frequently handled as an API in pharmaceutical development, formulation and analytical workflows.
| CAS Number | 26-15-7 |
| Family | Phenylethanolamine beta2‑agonists |
| Typical Form | Powder or crystalline solid |
| Common Grades | BP, EP, JP, USP |
Salmeterol is a small-molecule long-acting beta-2 adrenergic receptor agonist belonging to the phenylethanolamine/phenol ether structural class. The core scaffold comprises a substituted m‑cresol (saligenin) motif bearing a hydroxymethyl substituent and a 1‑hydroxy‑2‑aminoethyl side chain; the basic amine is extended by a long aralkyl/alkoxy lipophilic tail (a 6‑(4‑phenylbutoxy)hexyl fragment). These combined features give the molecule a bifunctional character: a polar, hydrogen-bonding “head” (catechol/diol‑like saligenin moiety and vicinal diols) responsible for receptor interaction and a long hydrophobic tail that provides high lipophilicity and exosite binding at the receptor surface.
Electronically, salmeterol presents multiple hydrogen-bond donors (secondary and primary hydroxyls, a secondary/tertiary amine depending on protonation) and acceptors (ether and hydroxyl oxygens), producing significant intramolecular and intermolecular hydrogen-bonding capacity. The base has a moderately high basicity (see pKa below), so the protonation state near physiological pH influences both aqueous solubility and tissue distribution. The long lipophilic tail increases membrane affinity and overall partitioning into lipid phases, accounting for measured logP/logKow values in the low‑to‑mid single digits and for the drug’s prolonged residence at the beta‑2 receptor (pharmacokinetic and pharmacodynamic depot effects).
Hydrolytically the molecule lacks readily hydrolyzable esters or labile acetal groups; oxidative metabolism (hepatic CYP450 oxidation, notably CYP3A4) and O‑dealkylation of the phenylalkyl side chain are the principal chemical/biotransformation pathways. Salmeterol is generally nonvolatile, thermally stable in its solid form within typical pharmaceutical storage ranges, and is handled as a low‑solubility, lipophilic pharmaceutical intermediate/active ingredient in inhalation formulations. Common commercial grades reported for this substance include: BP, EP, JP, USP.
Basic Physicochemical Properties
Density and Solid-State Form
Physical description: Solid. The substance is isolated and formulated principally as a crystalline solid (free base) and as its xinafoate salt in inhalation products. The solid state contains multiple polar functional groups capable of intermolecular hydrogen bonding, which, together with the extended hydrophobic tail, favors dense crystal packing with limited aqueous solubility.
Melting Point
Melting point: 75.5-76.5 °C (also reported as 75.7-76.5 °C and 75.5 - 76.5 °C in available experimental records). The relatively low-to-moderate melting range is consistent with a molecule that combines several polar hydroxyl groups with a long flexible aliphatic/aryl tail; polymorphism and salt formation (e.g., xinafoate) can alter observed melting behavior.
Solubility and Dissolution Behavior
Solubility: Sparingly soluble; reported numeric solubility 2.26e-03 g/L. The free base is poorly water‑soluble because of the large hydrophobic side chain despite multiple hydroxyls and a basic amine. The xinafoate salt form exhibits substantially different solvation: "Soluble in methanol, slightly soluble in ethanol, chloroform and isopropanol; sparingly soluble in water /Xinafoate salt/." In practice, formulation for inhalation exploits low aqueous solubility by delivering microgram doses suspended or micronized in dry powder or aerosol systems; solvent selection for analytical preparations typically relies on polar organic solvents (methanol, acetonitrile).
Chemical Properties
Acid–Base Behavior and Qualitative pKa
Dissociation constant: pKa = 11.2 /Estimated/. The basic aliphatic amino group is the principal protonation center; with an estimated \( \mathrm{p}K_a\) near 11.2, the free base is largely unprotonated at physiological pH, but protonation can increase aqueous solubility and influence distribution and protein binding. The molecule contains multiple phenolic/hydroxyl groups that are substantially less acidic than the basic amine and do not confer significant acidity in biological pH ranges.
Reactivity and Stability
Salmeterol is chemically stable under normal handling and storage (room temperature, protected from strong oxidants and direct heat). Hydrolysis is not a significant degradation pathway due to absence of labile ester or anhydride functionalities. Oxidative metabolism (biotransformation) is the main chemical route in vivo—predominantly hepatic CYP3A4‑mediated aliphatic hydroxylation (alpha‑hydroxysalmeterol) and minor O‑dealkylation of the phenylalkyl ether. Photolysis is not expected to be significant since the molecule lacks strong chromophores absorbing above \(290 \,\mathrm{nm}\). For formulated products (xinafoate salt), shelf stability information indicates typical commercial inhalation formulations are stable for extended periods (see Stability/Shelf Life).
Molecular Parameters
Molecular Weight and Formula
Molecular formula: \(\ce{C25H37NO4}\).
Molecular weight: 415.6.
Exact/monoisotopic mass: 415.27225866.
LogP and Structural Features
Partitioning descriptors: XLogP (computed) = 3.9; experimental/estimated LogP values reported as 4.2 and log Kow = 4.15 /Estimated/. The combination of multiple hydroxyl groups and a basic amine with a long hydrophobic tail yields a net lipophilicity in the range reported; this supports strong membrane partitioning, substantial protein binding (reported ~96% in plasma), and low aqueous solubility. Topological polar surface area (TPSA) = 82 (indicative of moderate polar surface area compatible with oral/inhalation pharmacology and limited passive blood–brain barrier penetration).
Additional computed descriptors: Hydrogen bond donor count = 4; hydrogen bond acceptor count = 5; rotatable bond count = 16; heavy atom count = 30; formal charge = 0 (free base); complexity = 403.
Structural Identifiers (SMILES, InChI)
SMILES: C1=CC=C(C=C1)CCCCOCCCCCCNCC(C2=CC(=C(C=C2)O)CO)O
InChI: InChI=1S/C25H37NO4/c27-20-23-18-22(13-14-24(23)28)25(29)19-26-15-7-1-2-8-16-30-17-9-6-12-21-10-4-3-5-11-21/h3-5,10-11,13-14,18,25-29H,1-2,6-9,12,15-17,19-20H2
InChIKey: GIIZNNXWQWCKIB-UHFFFAOYSA-N
Identifiers and Synonyms
Registry Numbers and Codes
CAS number: 26-15-7.
Additional registry and identifier codes (present in available identifier lists) include UNII 2I4BC502BT and the InChIKey given above.
Synonyms and Brand-Independent Names
Common synonyms and systematic names recorded for the substance include: Salmeterol; 2-(hydroxymethyl)-4-[1-hydroxy-2-[6-(4-phenylbutoxy)hexylamino]ethyl]phenol; GR 33343X; SALMETEROL (USAN/INN). A larger set of depositor-supplied synonyms and alternate names exists reflecting salts, formulations and trade/designation variants; selection above highlights the INN/USAN and principal systematic IUPAC description.
Industrial and Pharmaceutical Applications
Role as Active Ingredient or Intermediate
Salmeterol is used as an active pharmaceutical ingredient (API) — a long-acting beta‑2 adrenergic receptor agonist (LABA) — indicated for maintenance treatment of asthma (in combination with inhaled corticosteroids), prevention of exercise‑induced bronchospasm, and maintenance therapy for chronic obstructive pulmonary disease (COPD). The free base and salt forms (notably the xinafoate salt) are employed in inhalation aerosols and dry powder inhaler formulations. Mechanistically it provides prolonged bronchodilation by high‑affinity engagement of the beta‑2 receptor active site with additional exosite binding via the long lipophilic tail.
Formulation and Development Contexts
Formulation approaches exploit the low systemic exposure at therapeutic inhaled doses and the molecule’s lipophilicity: typical dosage forms include metered‑dose inhalers and dry powder inhalers delivering microgram doses (e.g., 21–50 µg per actuation/inhalation depending on product and salt form). Solubility limitations of the free base favor use of organic solvents for analytical standards and necessitate particle engineering (micronization, carrier selection) for dry powder formulations. The xinafoate salt alters solid‑state and solubility properties and is commonly used in marketed inhalation products.
Specifications and Grades
Typical Grade Types (Pharmaceutical, Analytical, Technical)
Typical grade concepts applicable to salmeterol include pharmaceutical/API grade (for drug substance in finished medicinal products), analytical standards (for assay and impurity profiling in development and QC), and technical/industrial grades (for research and nonclinical use). The xinafoate salt is typically the form specified for finished inhalation products, while the free base may be used in intermediate syntheses or certain analytical contexts.
General Quality Attributes (Qualitative Description)
Key quality attributes monitored for API and intermediate lots include identity (structure, stereochemistry where applicable), assay/potency (content relative to \(\ce{C25H37NO4}\) reference), impurity profile (related substances and degradation products), residual solvents, particle size distribution for inhalation lots, and polymorphic form. Stability under specified storage conditions and compatibility with propellants or device components are critical for inhalation product performance. Commercial grades reported for this substance include: BP, EP, JP, USP.
Safety and Handling Overview
Toxicological Profile and Exposure Considerations
Salmeterol exhibits typical sympathomimetic pharmacology; therapeutic inhaled doses produce low systemic exposure, but overdose or systemic exposure can cause excessive beta‑adrenergic stimulation (tachycardia, arrhythmia, hypokalemia, hyperglycemia, QT prolongation). Reported adverse effects include cardiovascular events, paradoxical bronchospasm, and hypersensitivity reactions. Chronic high‑dose or long‑term exposure in animal studies has produced rodent‑specific proliferative changes in reproductive organs at high doses. Protein binding in plasma is high (~96%), reducing free plasma concentrations. For occupational handling, the main exposure routes of concern are inhalation and dermal contact during manufacture; airborne particulate control and dermal protective measures are appropriate.
Storage and Handling Guidelines
Storage recommendations for commercial inhalation products and the API include protection from extreme temperature and moisture: typical inhalation powder/devices are stored at room temperature \(20\text{–}25 \,^\circ\mathrm{C}\) in a dry place away from heat and sunlight; metered‑dose inhalers may have manufacturer‑specified storage ranges (e.g., \(2\text{–}30 \,^\circ\mathrm{C}\) for certain devices). Handle the powdered API under local exhaust ventilation or containment to limit inhalation exposure; use appropriate personal protective equipment (gloves, eye protection, respiratory protection as required). For detailed hazard, transport and regulatory information, users should refer to the product‑specific Safety Data Sheet (SDS) and local legislation.
