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Your Location：Home>Product Center >> Pharmaceutical API >> Oxcarbazepine
  • Oxcarbazepine
Name:Oxcarbazepine
CAS No:28721-07-5

PRODUCT DESCRIPTION

【Name】
Oxcarbazepine
【Iupac name】
5-oxo-6H-benzo[b][1]benzazepine-11-carboxamide
【CAS Registry number】
28721-07-5
【Synonyms】
Trileptal
GP 47680
5H-Dibenz(b,f)azepine-5-carboxamide, 10,11-dihydro-10-oxo-
Oxcarbazepine (USAN)
Trileptal (TN)
Oxcarbazepine [INN]
Oxcarbazepina [INN-Spanish]
10,11-Dihydro-10-oxo-5H-dibenz(b,f)azepine-5-carboxamide
Oxcarbazepinum [INN-Latin]
【EINECS(EC#)】
249-188-8
【Molecular Formula】
C15H12N2O2 (Products with the same molecular formula)
【Molecular Weight】
252.27
【Inchi】
InChI=1/C15H12N2O2/c16-15(19)17-12-7-3-1-5-10(12)9-14(18)11-6-2-4-8-13(11)17/h1-8H,9H2,(H2,16,19)
【Canonical SMILES】
C1C2=CC=CC=C2N(C3=CC=CC=C3C1=O)C(=O)N
【MOL File】
28721-07-5.mol

Chemical and Physical Properties

【Appearance】
White to off-white crystalline powder
【Density】
1.329g/cm3
【Melting Point】
218 - 224 C
【Boiling Point】
457
【Vapour】
1.52E-08mmHg at 25°C
【Refractive Index】
1.661
【Flash Point】
230
【Solubilities】
Appearance:White to off-white crystalline powder
Transport Information:20kgs 
Hazard Symbols:UN NO.
【Color/Form】
white
【Computed Properties】
Molecular Weight:252.26798 [g/mol]
Molecular Formula:C15H12N2O2
XLogP3-AA:1.7
H-Bond Donor:1
H-Bond Acceptor:2
Rotatable Bond Count:0
Tautomer Count:4
Exact Mass:252.089878
MonoIsotopic Mass:252.089878
Topological Polar Surface Area:63.4
Heavy Atom Count:19
Formal Charge:0
Complexity:382
Isotope Atom Count:0
Defined Atom Stereocenter Count:0
Undefined Atom Stereocenter Count:0
Defined Bond Stereocenter Count:0
Undefined Bond Stereocenter Count:0
Covalently-Bonded Unit Count:1
Feature 3D Acceptor Count:2
Feature 3D Donor Count:1
Feature 3D Ring Count:3
Effective Rotor Count:1.4
Conformer Sampling RMSD:0.6
CID Conformer Count:8

Safety and Handling

【Hazard Codes】
UN NO.
【Transport】
20kgs
【Formulations/Preparations】
Oral: Suspension: 300 mg/5 mL Trileptal (with alcohol and propylene glycol), (Novartis). Tablets, film-coated: 150 mg Trileptal (scored), (Novartis), 300 mg Trileptal (scored), (Novartis), 600 mg Trileptal (scored), (Novartis).
【Exposure Standards and Regulations】
The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl oxcarbazepine, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.
【Octanol/Water Partition Coefficient】
log Kow = 1.11 (est)
【Disposal Methods】
SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

Use and Manufacturing

【Use and Manufacturing】
Methods of Manufacturing

Reaction of 10-methoxy-5H-dibenz(b,f)azepine with phosgene gives the 5-chlorocarbonyl compound, treatment with NH3 affords 10-methoxy-5H-dibenz(b,f)azepine-5-carboxamide, which is hydrolyzed with diluted HCl to oxcarbazepine.
Nitration of 5-cyano-5H-dibenz(b,f)azepine with NaNO3 in acetic anhydride/acetic acid gives 5-cyano-10-nitro-5H-dibenz(b,f)azepine, which is treated with BF3 and powdered iron in acetic acid.
【Usage】

The keto derivative of Carbamazepine. Used as an anticonvulsant

Biomedical Effects and Toxicity

【Biological Activity】
Anticonvulsant; protects mice and rats against generalized tonic-clonic seizures induced by electroshock. Thought to act via inhibition of sodium channel activity.
【Pharmacological Action】
- Drugs used to prevent SEIZURES or reduce their severity.
【Therapeutic Uses】
Oxcarbazepine is indicated for monotherapeutic or adjunctive therapeutic use in the treatment of partial seizures in adults and children ages 4 to 16 with epilepsy. /Included in US product labeling/
/EXPL THER:/ ... Oxcarbazepine /was compared/ with acamprosate in relapse prevention in recently withdrawn alcohol-dependent patients. /They/ investigated the efficacy and safety of oxcarbazepin (vs acamprosate) by conducting a 24-week randomized, parallel-group, open-label, clinical trial on 30 acutely detoxified alcoholic patients. Survival analyses (Kaplan-Meier) were performed to look for evidence of a longer "survival" of patients receiving oxcarbazepine. ... After withdrawal, time to severe relapse and time to first consumption of any ethanol by oxcarbazepin patients were not longer than for acamprosate patients. Abstinent patients in both study groups showed a significantly lower obsessive compulsive drinking scale-German version (OCDS-G) than relapsed patients. No undesired effects occurred when oxcarbazepin patients consumed alcohol. ... It is noteworthy that oxcarbazepine is well tolerated, even when alcohol is on board. ... [Croissant B et al; Alcohol Clin Exp Res 30 (4): 630-5 (2006)]
【Biomedical Effects and Toxicity】
Oxcarbazepine is completely absorbed. Food does not alter the rate and extent of absorption of oxcarbazepine.
Both oxcarbazepine and its active 10-monohydroxy metabolite (MHD) are distributed into milk in humans.
Elimination: Renal: greater than 95%, with more than 99% of the dose excreted in the form of metabolites. Fecal: less than 4%.
Oxcarbazepine is an antiepileptic drug with a chemical structure similar to carbamazepine, but with different metabolism. Oxcarbazepine is rapidly reduced to 10,11-dihydro-10-hydroxy-carbazepine (monohydroxy derivative, MHD), the clinically relevant metabolite of oxcarbazepine. MHD has (S)-(+)- and the (R)-(-)-enantiomer, but the pharmacokinetics of the racemate are usually reported. The bioavailability of the oral formulation of oxcarbazepine is high (>95%). It is rapidly absorbed after oral administration, reaching peak concentrations within about 1-3 hours after a single dose, whereas the peak of MHD occurs within 4-12 hours. At steady state, the peak of MHD occurs about 2-4 hours after drug intake. The plasma protein binding of MHD is about 40%. Cerebrospinal fluid concentrations of MHD are in the same range as unbound plasma concentrations of MHD. Oxcarbazepine can be transferred significantly through the placenta in humans. Oxcarbazepine and MHD exhibit linear pharmaco-kinetics and no autoinduction occurs. ... [May TW et al; Clin Pharmacokinet 42 (12): 1023-42 (2003)] PubMed Abstract
Gas chromatography--mass spectrometry (GC/MS) was used to determine plasma levels of oxcarbazepine and its main metabolite in a newborn girl and her oxcarbazepine-treated mother during the first five post partum days. At delivery the maternal and neonatal plasma concentrations were in the same range, indicating considerable placental transfer of both substances. In spite of ingestion of both substances via breast milk, there was no accumulation in the baby. On the fifth post partum day oxcarbazepine and 10-hydroxy-carbazepine (10-OH-CB) levels in plasma in the newborn were only 12 and 7%, respectively, of the values found on the first day after delivery. [Bulau P et al; Eur J Clin Pharmacol 34 (3): 311-3 (1988)] PubMed Abstract
To determine potential changes in the plasma concentrations of oxcarbazepine and its metabolites during pregnancy and puerperium. Five women receiving oxcarbazepine monotherapy were followed prospectively during pregnancy and the puerperium. Four women were enrolled in the first trimester, and one woman, 2 weeks before delivery. Steady-state concentrations of oxcarbazepine, its active R-(-)- and S-(+)-monohydroxy derivatives (MHD), and the additional metabolite carbamazepine-10,11-trans-dihydrodiol (DHD) were measured at regular intervals by an enantioselective HPLC assay. In all samples, S-(+)-MHD was the most abundant compound in plasma and accounted almost entirely for the amount of active moiety (defined as the molar sum of oxcarbazepine, R-(-)-MHD, and S-(+)-MHD) found in the circulation. The dose-normalized concentrations of active moiety decreased markedly during gestation and, in four of the five patients, increased strikingly after delivery. Plasma concentrations of S-(+)-MHD mirrored closely the levels of the active moiety. Plasma concentrations of the parent drug and other metabolites also tended to decrease during pregnancy and to increase after delivery. During treatment with oxcarbazepine, S-(+)-MHD is by far the most abundant active compound in plasma. The concentration of this metabolite as well as the active moiety may decrease markedly during pregnancy and may increase severalfold after delivery. Because of these striking pharmacokinetic changes, the clinical response should be monitored closely in oxcarbazepine-treated women throughout pregnancy and the puerperium. [Mazzucchelli I et al; Epilepsia 47 (3): 504-9 (2006)] PubMed Abstract
... The concentration of the oxcarbazepine metabolite 10-hydroxycarbazepine (MHD) in nine pregnancies among seven women before, during, and after pregnancy /was assessed/. The mean dose-corrected concentration of MHD was decreased during pregnancy (analysis of variance, p = 0.0016), being 72% (SD = 13%) in the first trimester, 74% (SD = 17%) in the second trimester, 64% (SD = 6%) in the third trimester, and 108% (SD = 18%) after pregnancy vs the dose-corrected concentration before pregnancy. /10-Hydroxycarbazepine/ [Christensen J et al; Neurology 67 (8):1497-9 (2006)] PubMed Abstract
This two-part, open-label study evaluated the pharmacokinetics, safety, and tolerability of oxcarbazepine as combination therapy in 112 children 2 to 12 years old with inadequately controlled epilepsy. Part I was a pharmacokinetic study in children stratified by age (2-5 years and 6-12 years) and randomized to receive a single oxcarbazepine dose of 5 mg/kg or 15 mg/kg. Mean specific AUC and t(1/2) values of the active metabolite (MHD) were approximately 30% lower in younger children compared with older children, regardless of dose. Part II was a 4-month safety, tolerability, and pharmacokinetic study in which children received oxcarbazepine doses of 11 to 68 mg/kg/day. The mean specific oxcarbazepine daily dose was 38% higher in younger children compared with older children. Similarly, mean trough plasma MHD concentrations were 34% lower in younger children. ... [Rey E et al; J Clin Pharmacol 44 (11): 1290-300 (2004)] PubMed Abstract
... Transplacental passage and placental tissue concentrations of oxcarbazepine and its metabolites were determined. Maternal venous blood, cord blood, and placental tissue samples from 12 mothers using oxcarbazepine during pregnancy alone or in combination with other antiepileptic drugs were collected. ... Maternal venous concentrations of oxcarbazepine and its major metabolites were at same range as cord blood concentrations (oxcarbazepine in maternal serum, 0.19 +/- 0.16 ug/ml, and in cord serum, 0.21 +/- 0.19 ug/mL; 10-hydroxy-10,11-dihydrocarbamazepine (10-OH-CBZ) in maternal serum, 5.69 +/- 2.49 ug/mL, and in cord serum, 5.23 +/- 1.44 ug/mL; 10,11-trans-dihydroxy-10,11-dihydrocarbamazepine (10,11-D) in maternal serum, 0.29 +/- 0.22 ug/mL, and in cord serum, 0.28 +/- 0.14ug/mL). Oxcarbazepine(0.17 +/- 0.16 ug/g placental tissue), 10-OH-CBZ (3.49 +/- 1.34 ug/g placental tissue) and 10,11-D (0.25 +/- 0.11 ug/g placental tissue) were detected in the placental tissue. The amount of oxcarbazepine detected from placental tissue was 0.01% of the daily dose. Oxcarbazepine, like other antiepileptic drugs, is transferred significantly through the placenta in humans. [Myllynen P et al; Epilepsia 42 (11): 1482-5 (2001)] PubMed Abstract

Environmental Fate and Exposure Potential

【Environmental Fate/Exposure Summary】
TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 360(SRC), determined from a structure estimation method(2), indicates that oxcarbazepine is expected to have moderate mobility in soil(SRC). Volatilization of oxcarbazepine from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 6.9X10-13 atm-cu m/mole(SRC), using a fragment constant estimation method(3). Oxcarbazepine is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 7.6X10-9 mm Hg(SRC), determined from a fragment constant method(4). Biodegradation data were not available(SRC, 2007).
AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 360(SRC), determined from a structure estimation method(2), indicates that oxcarbazepine is not expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 6.9X10-13 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). According to a classification scheme(5), an estimated BCF of 
ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), oxcarbazepine, which has an estimated vapor pressure of 7.6X10-9 mm Hg at 25 deg C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase oxcarbazepine may be removed from the air by wet or dry deposition(SRC). Oxcarbazepine contains chromophores that absorb at wavelengths >290 nm(3) and therefore may be susceptible to direct photolysis by sunlight(SRC).

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