A chromatographic separation was achieved on a Hichrom RPB18 (250 · 4.6 mm, 5 l) column using water and mixture of acetonitrile and methanol (1:1 ratio) as mobile phase. Forced degradation studies were performed on bulk samples of anastrozole using acid, base, hydrogen peroxide, heat and UV light. Degradation of the drug substance was observed in base hydrolysis. Degradation product formed under base hydrolysis was found to be Imp-C. The sample solution and mobile phase were found to be stable up to 48 h.
A simple and precise RPâ€HPLC method was developed and validated for the determination of anastrazole in pharmaceutical dosage forms. Chromatography was carried out on an Inertsil ODS (250x4.6mm) C18 column using a mixture of Buffer:Acetonitrile (60:40) as the mobile phase at a flow rate 1.0 ml/min. The analyte was monitored using UV detector at 215 nm .The Retention time of the drug is 6.431 min for anastrazole.
D. Vijaya bharathi et al
LC and LC-MS/MS study of forced decomposition behavior of anastrozole and establishment of validated stability-indicating analytical method for impurities estimation in low dose anastrozole tablets
Separation of anastrozole from its potential impurities, degradation products and five anastrozole related compounds as main impurities were achieved on Inertsil ODS-3V, 250mm-4.6mmi.d, 5m analytical column using reversed phase high performance liquid chromatography (RP-HPLC). The elution of impurities employed time dependent gradient programmed mobile phase consisting of water as mobile phase-A and acetonitrile as mobile phase-B at column flow rates of 1 ml/min and at 215 nm UV detection. The same method was also extended to LC-MS/MS studies which were carried out to identify the degradation product.
Arvind G Jangid et al
A simple, selective and rapid validated method for estimation of anastrazole in human plasma by liquid chromatography-tandem mass spectrometry and its application to bioequivalence study.
A rapid, simple and specific method for estimation of anastrazole in human plasma was validated using letrozole as internal standard. The analyte and internal standard were extracted from plasma using simple solid-phase extraction. The compound were separated on a reverse-phase column with an isocratic mobile phase consisting of 0.1% formic acid in water and acetonitrile (12 : 88, v/v) and detected by tandem mass spectrometry in positive ion mode.
Jifen He, Yi Zhang et al
An ultra performance liquid chromatography-tandem mass spectrometry method for determination of anastrozole in human plasma and its application to a pharmacokinetic study
In this the Plasma sample pretreatment involved a one-step extraction with diethyl ether of 500 µL plasma. The chromatographic separation was carried out on an Acquity UPLCTM BEH C18 column with a mobile phase consisting of methanol-10 mmol/L ammonium acetate (75:25, v/v) at a flow rate of 0.30 mL/min.
Gustavo D. Mendes et al
Anastrozole quantification in human plasma by high-performance liquid chromatography coupled to photospray tandem mass spectrometry applied to pharmacokinetic studies
The analyte and the I.S. were extracted from 200 μl of human plasma by liquid-liquid extraction using a mixture of diethyl ether:dichloromethane (70:30, v/v) solution. Extracts were removed and dried in the organic phase then reconstituted with 200 μl of acetonitrile:water (50:50; v/v). The extracts were analyzed by high performance liquid chromatography coupled with photospray tandem mass spectrometry (HPLC-MS-MS). Chromatography was performed isocratically on a Genesis, C18 4 μm analytical column (100 mm - 2.1 mm i.d.).
4.0 DRUG PROFILE
Anastrozole
Synonyms: Anastrozol, Anastrazol, Arimidex
Chemical structure
Anastrozole
IUPAC Name: 2-[3(1-cyano-1-methyl-ethyl)-5-(1H-1, 2, 4-triazol-1-yl methyl) phenyl]-2-methyl-propinenitrile
Class:- Cumene derivative
Physico-Chemical Data
Molecular formula: C17H19N5
Molecular mass : 293.4
Color : White to off white powder
Melting point : 81-82ÌŠC
Drug Category : Antineoplastic Agent, Hormonal, Aromatase Inhibitors
SOLUBILITY:
Anastrozole has moderate aqueous solubility (0.5 mg/mL at 25°C);
Solubility is independent of pH in the physiological range. Anastrozole is freely soluble in methanol, acetone, ethanol, and tetrahydrofuran, and very soluble in acetonitrile.
CLINICAL PHARMACOLOGY
Mechanism of action
Anastrozole belongs to the class of drugs known as non-steroidal aromatase inhibitors. It inhibits the enzyme known as aromatase, which is responsible for converting androgens to estrogen. In breast cancer the growth of tumors stimulated by estrogen. The main cause of breast cancer in Postmenopausal women is conversion of adrenally generated androstenedione to estrone by aromatase in adipose tissue, with further conversion of estrone to estradiol.
Pharmacokinetic properties
Absorption
According to radio labelled drug studies, Anastrozole absorbs rapidly into the systemic circulation and achieves maximum plasma concentration within 2 hours after administration of dose
The rate of absorption decreases in presence of food at the same time food does not affect the overall absorption of anastrozole.
Distribution:
The pharmacokinetics of anastrozole are linear over the dose range of 1 to 20 mg and do not change with repeated dosing.
Anastrozole pharmacokinetics exhibits linearity over a range of 1 to 20 mg and they are constant with repeated dosing.
The plasma half-life of Anastrozole is 40-50 hours.
Anastrozole plasma concentration achieves steady-state concentration within 7 days after once daily dising of 1 mg
After 7 days of daily dosing The plasma concentration will be three to four times higher when compared with plasma concentration after a single dose of anastrozole.
Anastrozole binds to plasma proteins about 40%.
Metabolism:
Metabolism of anastrozole takes place by different mechanisms like N-dealkylation, hydroxylation and glucuronidation.
Three metabolites which are formed from the metabolism of anastrozole are
1) Triazole,
2)A glucuronide conjugate of hydroxyl-anastrozole, and
3)A glucuronide conjugate of anastrozole itself
These metabolites are identified and isolated from human plasma or urine.
Triazole is the main metabolite of anastrozole, but lack of pharmacological activity.
Excretion
The process of elimination of anastrozole takes place primarily by metabolism i.e about 85%.Very less amount of the drug excreated unchangrd through renal route
This information is revealed from the radio labelled studies conducted in the postmenopausal women.
The elimination of anastrozole occurs slowly with a half-life of 50-hours.
Pharmacokinetics have not at been studied in children.
Contraindications
Anastrozole is contraindicated in patients who are hypersensitive to anastrozole.
In pregnant and lactating women.
Adverse Drug Reactions:
Adverse drug reactions of Anastrozole are mild to moderate.
Carpal tunnel syndrome
Vaginal bleeding reported during the first few weeks of administration.
Hot flashes
Sore throat
Depression
Nausea, vomiting and headache
Joint pains
Blisters or peeling skin
Breast pain
Dry mouth
Dizziness etc.
Drug Interactions
Anastrozole inhibits the drugs mediated with cytochrome-P450 metabolism when ever it is co-administered with such type of drugs.
There are no significant change in the anti coagulant activity and any other drug interactions were observed when Anastrozole. administered along withWarfarin
Tamoxifen and Anastrozole should not be co administered because it results in decrease in efficacy of both the dosage forms .
Dosage and administration
The patients taking anastrozole should be postmenopausal.
There is no necessity to change dose in elderly patients.
In patients with mild to moderate hepatic impairment and renal impairment there is no need to do changes in dose required.
Missed dose
The patients should follow the dosage regimen without skipping.
If they miss the dose the dose should be taken at least before 12 hours of the next dose.
The overdose should not be taken after taking the due dose
Administration
Anastrozole is administered with fluids.
The patients should take the daily dose at the same time, without skipping.
Over dosage
Acute toxicity was observed in animals at a dose greater than 45 mg/kg.
Different doses of Anastrozole up to 60 mg in a single dose were administered in male volunteers and the dose up to 10 mg was given to postmenopausal women with advanced breast cancer.
The dosages were well tolerated in both males and women.
There is no evidence of toxic symptoms with over dose of Anastrozole.
There is no antidot to treat the toxicity developed by the over dosage of Anastrozole.
