Deferasirox

Product Overview

Deferasirox (development codes ICL-670／CGP-72670), developed by Novartis of Switzerland and marketed as Exjade, is the first routinely usable oral iron chelator approved by the US FDA, and is recommended in Europe as first-line therapy for thalassemia patients over 6 years of age with iron overload.

Structural design: the molecule centers on a 1,2,4-triazole ring, with an o-hydroxyphenyl group at each of the 3- and 5-positions and a p-carboxyphenyl group at the 1-position (N1). The oxygen atoms of the two phenolic hydroxyl groups, together with a nitrogen atom of the triazole ring, form the tridentate coordination site.

Chelation mechanism: deferasirox is highly selective for ferric iron (Fe³⁺); two deferasirox molecules chelate one Fe³⁺ ion (2:1 stoichiometry), forming a stable iron complex. This 2:1 ratio is the key to its effectiveness as a small molecule in removing body iron — and also explains why its administered dose (mg/kg) is significantly higher than its chelation capacity.

Excretion pathway: the iron complex is excreted mainly via the bile／feces (unlike deferoxamine, which is excreted mainly in urine), one of the reasons for its effectiveness in transfusional iron overload (iron is deposited mainly in the reticuloendothelial system of the liver, spleen, and bone marrow).

Metabolism: CYP450-catalyzed oxidative metabolism is minor in humans (approx. 8%); glucuronidation is the main metabolic pathway, followed by biliary excretion.

Clinical value: phase II and III clinical trials and pharmacokinetic studies have demonstrated a favorable safety and tolerability profile, significant reduction of cardiac and hepatic iron burden, and oral administration with better patient compliance than deferoxamine, which requires subcutaneous/intravenous infusion.

Technical Specifications

• Standards: CHP／USP／EP (EP has listed “Deferasirox for system suitability CRS” and “Deferasirox CRS” reference standards, indicating that it has an EP monograph)

• Specification: 0.99 (purity ≥99.0%, HPLC); reagent grade commonly ≥98.0% (HPLC)

• CAS No.: 201530-41-8 (EINECS 685-491-5; UNII V8G4MOF2V9; MDL MFCD09951804／MFCD09751362)

• Molecular formula: C₂₁H₁₅N₃O₄

• Molecular weight: 373.36 (consistent across ChemicalBook, CAS-derived pages, and MOLBASE); TCI records 373.37; calculated values of 373.362／373.368／373.4 also reported. Exact mass 373.1063

• Appearance: off-white to white solid powder; TCI describes it as a white to gray to brown powder or crystals; the literature records crystallization from ethanol

• Purity (HPLC): ≥ 99.0%

• Melting point: 260–262 ℃ (consistent across ChemicalBook, 科普中国, 化源网, MOLBASE, Guidechem, and other sources; recommended value). Note: CAS Common Chemistry records 256–258 ℃, differing from the above range by approx. 4 ℃ — both are measured/recorded values from their respective sources, not repeated measurements under the same conditions; the source should be noted when quoting. The above values are also not publicly verifiable official pharmacopoeial melting points

• Specific optical rotation: not applicable — the molecule contains no chiral center (no stereocenter, no E／Z geometric isomerism center)

• Chemical name: 4-[3,5-bis(2-hydroxyphenyl)-1,2,4-triazol-1-yl]benzoic acid; IUPAC: 4-[3,5-bis(2-hydroxyphenyl)-1,2,4-triazol-1-yl]benzoic acid

• Stereochemistry: no stereocenters; tautomeric description differences exist within the molecule for 1H-1,2,4-triazole (1H and 3H forms)

• Solubility: soluble in DMSO (approx. 10 mg/mL); slightly soluble in acetone; very slightly soluble in methanol and ethanol; practically insoluble in water (aqueous solubility approx. 0.02 mg/L at 25 ℃; another source records 0.038 mg/mL at 37 ℃). This extremely low water solubility is the key problem to be solved in oral formulation development

• Acid dissociation constant (pKa): pKa1 = 4.57, pKa2 = 8.71, pKa3 = 10.56 (Nick); in a water/DMSO system (C_DMSO = 0.20), reported as pKa1 = 4.61, pKa2 = 10.12, pKa3 = 12.08 (Steinhauser) — the systems differ and the values are not directly comparable

• Calculated physicochemical parameters: density approx. 1.40 ± 0.1 g/cm³ (another source records 1.472); boiling point approx. 672.1 ± 65.0 ℃ (calculated); flash point approx. 360.3 ± 34.3 ℃; refractive index approx. 1.699; LogP (calculated XLogP3) approx. 3.8 (values vary widely across sources, from approx. 1.09 to approx. 6.43 — the calculation method must be noted when quoting); hydrogen bond donors 3／acceptors 6; rotatable bonds 4; topological polar surface area approx. 107.95–109 Ų; heavy atom count 28

• Marketed dosage forms: dispersible tablets for oral administration after dispersion in suspension; a film-coated tablet form (Jadenu) is also available

• Storage conditions: protect from light, store under inert gas at 2–8 ℃; some sources recommend freezing at −20 ℃; DMSO solutions can be stored at −20 ℃ for up to 1 month

Applications

• Chronic iron overload due to blood transfusions (core indication): for chronic iron overload caused by repeated blood transfusions in patients ≥2 years of age (e.g., β-thalassemia, sickle cell disease, myelodysplastic syndromes, and other diseases requiring long-term transfusion)

• Iron overload in non-transfusion-dependent thalassemia syndromes (NTDT): for the treatment of iron overload in patients with non-transfusion-dependent thalassemia syndromes (approved in some countries/regions)

• Clinical benefit: significantly reduces cardiac and hepatic iron burden and iron-overload-related organ damage; oral administration significantly improves patient compliance compared with deferoxamine, which requires subcutaneous or intravenous infusion

• Investigational/expansion directions: the literature reports pro-apoptotic effects of deferasirox on myeloid leukemia cells in vitro and in vivo (targeting caspase), showing antileukemic effects independent of iron status; studies have also explored its use in reversible renal dysfunction caused by Fanconi syndrome — all of the above are investigational directions, not approved indications

• Pharmacology and mechanism research: used in studies of Fe³⁺-selective chelation, determination of the 2:1 chelation stoichiometry and complex stability constants, iron metabolism and iron-overload animal models, and effects of iron chelators on tumor cell proliferation and apoptosis

• Formulation and manufacturing: used in formulation development of dispersible tablets (oral suspension) and film-coated tablets; because the API is practically insoluble in water, the core of formulation work is improving wettability, dispersibility, and dissolution; key manufacturing control points include related substances (particularly triazole ring synthesis by-products and bisphenol-substituted isomers), assay, polymorphic form, and residual solvents; suitable for analytical method development and validation, stability studies, impurity reference standards, and GMP scale-up and CMO／CDMO contract manufacturing

Safety notice: This product is an active pharmaceutical ingredient (API) intended only for legitimate industrial, research, and pharmaceutical manufacturing use; it is not for end-user clinical use or self-medication guidance. The finished product is a prescription drug that must be prescribed by a physician experienced in the treatment of iron overload, with regular monitoring of serum ferritin, hepatic and renal function, and hearing and vision. Common adverse reactions include gastrointestinal reactions (nausea, vomiting, diarrhea, abdominal pain), rash, and elevated serum transaminases. Risks requiring focused monitoring include renal impairment (elevated serum creatinine, proteinuria, Fanconi syndrome), hepatic injury (rare but potentially fatal hepatic failure), gastrointestinal bleeding (especially in elderly patients and those on concomitant anticoagulant/antiplatelet therapy — fatal gastrointestinal hemorrhage has been reported), and myelosuppression (cytopenias). Patients with severe renal impairment (creatinine clearance <40 mL/min) or hepatic impairment should use with caution or not at all, with dose adjustment or discontinuation per the labeling. The API’s GHS classification is acute oral toxicity category 4 and acute aquatic hazard category 1 (H302, H410, WGK 3). When handling, wear protective gloves, protective clothing, and eye/face protection; avoid dust inhalation, and release to the environment is strictly prohibited (very toxic to aquatic organisms with long-lasting effects).

Product information: please contact us. This information is for reference only.