度他雄胺破坏

Stress Degradation Studies on Dutasteride

and Development of a Stability-Indicating

HPLC Assay Method for Bulk Drug

and Pharmaceutical Dosage Form

D.V.Subba Rao1,2,&,P.Radhakrishnanand1,2

1Reference Standard Laboratory,United States Pharmacopeia-India Private Limited,ICICI Knowledge Park,Turkapally,Shameerpet, Hyderabad500078,India;E-Mail:d_venkatasubbarao@yahoo.co.in

2Department of Chemistry,Jawaharlal Nehru Technological University,Kukatpally,Hyderabad500072,India

Received:2October2007/Revised:25December2007/Accepted:30January2008

Online publication:17April2008

Abstract

A simple stability-indicating LC method has been developed for the quantitative determina-

tion of dutasteride in bulk drug samples and in pharmaceutical dosage forms in the presence

of degradation products.The retention time of dutasteride is about7min.The drug was

subjected to stress conditions of hydrolysis,oxidation,photolysis and thermal degradation.

Degradation was found to occur under hydrolysis and to a lesser extent under oxidation

conditions but the compound was stable to photolytic and thermal stress.The assay of stress

samples was calculated against a reference standard and the mass balance was found close

to99.3%.The developed method was validated with respect to linearity,accuracy,precision

and ruggedness.

Keywords

Column liquid chromatography

Stability-indicating assay

Stress studies

Dutasteride

Introduction

Dutasteride,(5a,17b)-N-(2,5-bis(trifluo-romethyl)phenyl)-3oxo-4-azaandrost-l-ene-17-carboxamide(Fig.1),is a potent and specific dual5alpha-reductase inhibitor for the treatment of benign prostatic hyperplasia(BPH)and lower urinary tract symptoms(LUTS)[1,2].It was approved in October2002by USFDA

and has been approved in several coun-

tries[3,4].

Dutasteride inhibits the conversion of

testosterone to5a-dihydro testosterone

(DHT)[2].DHT is the androgen pri-

marily responsible for the initial devel-

opment and subsequent enlargement of

the prostate gland.DHT is converted

from testosterone by the enzyme

5a-reductase,which exists as two

isoforms,Type1and Type2.Type1

5a-reductase is found primarily in the

skin and liver,but has also been found

in prostatic tissue in BPH.Type2

5a-reductase is found in the prostate[2].

Rapid liquid chromatography–

tandem mass spectrometry assay of

dutasteride in human plasma[5]and

mass spectral fragmentation reactions of

a therapeutic4-azasteroid and related

compounds[6]have been reported.

The current drug stability test guide-

line Q1A(R2)issued by the Interna-

tional Conference on Harmonization

(ICH)[7]suggests that stress studies

should be carried out on a drug to

establish its inherent stability,leading to

identification of degradation products

and hence supporting the suitability of

proposed analytical procedures.It also

requires that analytical test procedures

should be stability-indicating and that

they should be fully validated.

Accordingly,the aim of the present

study was to establish the stability of

dutasteride through stress studies under

a variety of ICH-recommended test

conditions[7–9]and to develop a sta-

bility-indicating assay method[10–12].

So far,to our knowledge no stability-

indicating LC assay method for

dutasteride has been developed.The aim