Flutamide
Section snippets
Chemical Names
2-Methyl-N-[4-nitro-3-(trifluoromethyl)phenyl]propanamide α,α,α-trifluoro-2-methyl-4′-nitro-m-propionotoluidide 4′-nitro-3′-trifluoromethylisobutyranilide
Nonproprietary Names
Flutamide
Proprietary Names
Drogenil, Eulexin, Euflex, Flucinom, Flugeril, Fugerel, Sebatrol
Empirical
C11H11F3N2O3
Structural
Molecular Weight
276.22
CAS Number
13311-84-7
Appearance
Flutamide is a pale yellow crystalline powder [l].
Uses and Applications [2,3,4]
Flutamide is an acetanilide, nonsteroidal, orally active anti-androgen. It exerts its anti-androgenic action by inhibiting androgen uptake and/or by inhibiting nuclear binding of androgen in
Methods of Preparation
Three general methods have been described for the synthesis of flutamide.
Flutamide may be prepared according to the procedure outlined in Scheme 1 [5]. Isobutyryl chloride is added in a slow dropwise fashion to a stirred cooled solution of 4-nitro-3-trifluoromethyl-anilinein pyridine. The reaction mixture is then heated in a steam bath. The resulting mixture is cooled and poured into ice water and filtered. The crude anilide is washed with water and crystallized from benzene to obtain
Particle Morphology
A photomicrograph was obtained using a Nikon Eclipse E800 system at 100X, with the sample dispersed in Dow 200 oil. As the photomicrograph in Figure 1 indicates, flutamide particles have an elongated (needlelike) shape, and the individual particle size is in the 25μm range.
The particle size distribution was determined using a Sympatec HELOS Laser Diffraction Particle Size Analyzer, with the sample being suspended in 0.1% polysorbate 80.The results are summarized in Figure 2, and yield a mean
Compendial Tests
The compendial tests for flutamide USP are given in the drug substance monograph [12]. The specified testing consists of compound identification, melting range, loss on drying, residue on ignition, heavy metals, chromatographic purity and assay.
Solid-state Stability
Flutamide shows no loss of potency in the solid state when stored in sealed amber glass bottles at room temperature for up to five years [17].
Solution-Phase Stability
The stability of flutamide was studied over a wide pH range in 3:2 phosphate buffer / ethanol at refrigerated, room temperature, and 45°C for 1 and 2 weeks [17]. The flutamide concentration was 1.0 mg/mL, and solutions of flutamide in USP ethanol were included as a control. In addition, methanolic solutions of flutamide (0.4 mg/mL) were exposed to 500
Adsorption
Analysis of plasma, urine, and feces following a single oral 200 mg dose of tritium labeled flutamide to human volunteers showed that the drug is rapidly and completely absorbed. Following a single 250 mg oral dose to normal adult volunteers, the biologically active alpha-hydroxylated metabolite reaches maximum plasma concentrations in about 2 hours, indicating that it is rapidly formed from flutamide.
Distribution
In male rats, neither flutamide nor any of its metabolites is preferentially accumulated in
Acknowledgments
The authors wish to thank the following individuals from the Schering- Plough Research Institute for their assistance: Janet Hatolski for providing the analytical standard used for generation of spectral and other in-house data of flutamide, Rebecca Osterman for obtaining the NMR spectra, Yao Ing for obtaining the mass spectrum, Charles Eckhart for the laser diffraction particle size data, Susan Pasternak for obtaining the DSC/TGA thermograms, Kenneth Cappel for obtaining the x-ray diffraction
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