Research,June 2009;8 (31:-257-264

TropicalJournalof Pharmaceutical
@ Pharmacotherapy Group,
Facultyof Pharmacy,Universityof Benin,
BeninCity, 300001Nigeria.
All rightsreserved,

Available online at http://www.tjpr.org

ResearchArticle

A Stability Indicating HPLC Method for the

Determination
of Meloxicamin Bulk and Commercial
Formulations
FarzanaS Bandarkarl* and Pradeep R Vavia2
lDepartmentof Pharmaceutics, Facultyof Pharmacy,KuwaitlJniversity,Kuwait,zFacultyof Pharmacy,IJniversity
Instituteof ChemiealTechnology,
Mumbai,lndia

Abstract
Purpose: The presentstudy was undertakento developa validated,rapid, simple and economic
stabilltyindicatingreversephaseHPLCmethodfor estimatingmeloxicam(MLX)in bulk and commercial
preparations.
iltbthod: Reversedphasechromatographicanalysiswas pertormedon a C18 Hi Q Sil column with
acetonitrile-water-glacialacetic
acid[55:40:5(% vfuflat aflow rateof lmUminand detectionwavelength
of 355 nm. Systemsuitabilitytesls essentralfor the assuranceof qualityperformanceof the method
wereperformed.Thedrug wassubjectedfo sfressdegradationstudiesunderacidic, basicand oxidative
conditions. The methodwas validatedfor accuracy,precision,repraducibility,specificity,robustness,
limit of detection (LOD) and limit of quantification(LQQ) , as per lnternationalConferenceon
Harmonization(ICH) guidelines.
Besults: A singlesharppeak was obtainedfor MLXat Rt of 6.8 ! 0.01min.Thepolynomialregression
data for the calibrationplotsexhibitedgood linearrelationship(r = 0.9995)overa concentrationrangeof
4-20p9/ml and the linear regressionequationwas y = 57257.38x+ 3443.07.Accuracyranged from
99.27ta 100.78%and the /" coefficientof variation(CV) tor both intra-dayand intendayprecisionwas
lessthan2%. MLXshowedminordegradationpeak in acidicconditionsat Rt of 2.24min.TheLODand
LOQvalueswere 360ng/mland 510ng/ml,respectively.
Conclusion:Theproposedmethodgavegood resolution of MLXand itsdegtadants.Systemsuitability
testsand statisticalanalysispertormedprove that the methodis precise,accurateand reproducible,and
hencecan be employedfor routineanalysisof MLXin bulkand commercialformulations.

Key words: Meloxicam, Reverse phase stabitityindicating HPLC, Stress degradation,Butk and
commercialtormulations.

Received:23 Nov 2008 Revised accepted:3 Mar 2009

*Corrcsponding author: E-mail: farzana@hsc.edu.kw;pradeepvavia@yahoo.com;Tel: 4l965 249ffi901;

Cell: UN)65 995i175A7;Fax: N%5-ir968ttit

TropJ PharmRes,June 2009;8(3):257

 Bandarkar & Vavia

INTRODUGTION analysis of the drug in pharmaceutical

dosageforms. In the methodproposed,the
Meloxlcam(MLX), is an oxicam derivative mobile phase was used directlyfor the
and a memberof the enolicacid group of dilutionof the formulationafterfiltration,and
non-steroidal anti-inflammatory drugs then furtherused for analysis.Directuse of
(NSAIDs)1'2. lt is chemically designated as 4- the mobile phaseas diluentfor formulations
hydroxy-2-methyt-N-(5- methyl-2-thiazolyl) - in quantitativeanalysisminimizeserrorsthat
2H -1,2-benzothiazine-3-carboxamide-1,1- occur duringtediousextractionprocedures.
dioxide. MLX exhibits anti.inflammatory, Themethodwasvalidatedin accordance with
analgesic and anti-pyretic activities, ICHguidelines".
especiallyin variouschronicconditions,like
osteoarthritis, rheumatoidarthritis,pauciar- EXPERIMENTAL
ticular and polyarticular course juvenile
rheumatoidarthritis''*.The mechanismof Materials
action of MLX is believedto be due to
inhibitionof prostaglandin synthesis,primarily MLX was receivedas a gift from Unichem
via inhibitionof cyclooxygenase-2 (COX-2). Lab. Ltd., Mumbai,India.Acetonitrile (HPLC
In contrastwith otherNSAlDs,it has ne_ither - grade)was purchasedfrom Merck,India.
acutenorchronicgastrointestinal toxicitf. Milliporepuriticationsystem was used for
high purity water. All other chemicalsand
Various analytical^techniques ^ viz, UV reagentsemployedwere of analyticalgrade
spectrophotometryo-o, fluorimetry",capillary and were purchased from S.D. Fine
electrophoresis",pulse.. polarography'", Chemicals, India.
electrochemical oxidation".electrochemical
reductionl2 and voltametryiS are reportedfor Ghromatography method
the analysis of MLX in pharmaceuticals.
HPLCis the mostcommonlyusedmethodfor The chromatograph systemcomprisedof a
analysis of MLX. An extensiveliterature Jasco PU-980pump equippedwith a Jasco
survey reveals few HPLC methods for UV-975detectorand a Rheodyneinjector
estimationof MLX in pharmaceutical dosage witha 2O-microlitre loop.Dataintegration was
forms as well as biologicalfluids;however, done using a Borwin software package
not all of these are stabilityindicatingand V1.21.Sampleswereinjectedintoa Hl-Q-Sil
some of them make use of buffer in the C-18column(4.6x 250mm,5 p particlesize).
mobilephase. Mostof the reportedmethods Mobilephase flow rate was 1ml/min.The
either do not include stress degradation drug was analyzed at a wavelengthof
studiesor are not completelyvalidated,and 355nm.
they are cumbersome, time-consuming and
expensivelo-17. Methoddevelopment
Methodvalidationis an essentialstep in drug Initialtrial experimentswere conducted,with
analysis. The process confirms that the a viewto selecta suitablesolventsystemfor
analytical procedure employed for the the accurateestimationof the drug and to
analysisis suitablefor its intendeduse and achievegood resolutionbetweenthe drug
shows reliabilityof the resultsproducedby and the degradation products.The suitability
anymethod. of the mobilephasewasdecidedon the basis
of the sensitivityof the assay,suitabilityfor
The primaryobjectiveof the presentwork stability studies, time required for the
was thus to developand validatea stability analysis,ease of preparation,and use of
indicatingHPLC method for MLX, which readily available cost-effectivesolvents.
could also be employed for the routine These includedmethanol-water(50:50 %

TropJ Pharm Res,June 2009;I (3):25e

 Bandarkar & Vavia

v/v), acetonitrile-water,(50:50 % v/v), concentrations (8, 12 and 16 pg/ml) was

(60:40 "/"vN), acetonitrile-
acetonitrile-water
water-gfaciafaceticacid (54:44:2o/"vlv) and
aceticacid (55:40:5
acetonitrile-water-glacial
q/ovlv).A mobilephasesystemcomprising of
aceticacid (55:40:5
acetonitrile-water-glacial
T" vlv) was foundto be optimum.The same
solventmixturewas usedfor the extractionof
the drug from the lormulationcontaining
excipients.The solventswere mixed,filtered
through a membranefilter of 0.45 micron
poreanddegassedbeforeuse.
Methodvalidation
Linearity
A seriesof standardcurveswere prepared
over a concentration rangeof 4 - 20 pg/ml
from a stock solutionof MLX (1mg/ml)in
acetonitrile.Dilutionswere preparedin the
mobilephase:acetonitrile-water-glacialacetic
acid (55:40:5 'hvlv). The procedure for
analysisfollowsthat describedearlierunder
the subsection,'Chromatography method'.
The data from peak area versus drug
concenlrationplots were treated by linear
least square regression analysis. The
standardcurveswereevaluatedfor intra-day
and inter-day reproducibility. Each
experiment was repeatedin triplicate.
Precision
Precisionis the measureof how closethe
datavaluesare to eachotherfor a numberof
measurementsunder the same analytical analyzed by the proposed method. The
conditions. The three components of
precision, i.€., repeatability,intermediate Recovery(%),RSD(%)andstandarderrorof
precisionand reproducibility, in accordance mean (SEM) were calculated for each
with ICH recommendations, weredetdrmined concentration..
as follows:
Repeatability
Iniectionrepeatability:Five injectionsof 12
pg/mL solutionof MLX were analyzedand
%RSDcalculated for injectionrepeatability.
Intra-dayvariation: Measurement of intra-day noiselevel.The LODwas calculated
variationof MLX solutionsat three different
carriedout by injectingthe sampleson the
sameday at differenttime intervals.
Analysisrepeatability:lt was obtainedby
determiningthe relativestandarddeviation
(HSD) of replicatesamples(n=3) of the
accuracystudy.
I ntermediateprecision(I nter'day variation)
Measurement of inter-dayvariationof MLX
(8,
solutionsat threedifferentconcentrations
12 and 16 Ug/mL)in triplicateon three
consecutive days determined the
intermediate precision.
Reproducibility
The reproducibilityof the method was
checkedby determiningprecisionon the
same instrument,but by a differentanalyst.
For both intra-dayand inter-dayvariation,
solutions of MLX at three different
concentrations (8, 12, and 16 pg/ml) were
analyzedin triplicate.
Accuracy
Accuracyis the measureof how close the
experimental value is to the true value.
Recoverystudiesby the standardaddition
methodwereperformedwith a viewto iustify
the accuracy of the proposed method.
Previouslyanalyzedsamples of MLX (12
pg/ml)werespikedwith 50, 100,and 150%
extra MLX standardand the mixtureswere
experiment was performed in triplicate.
LODand LOQ
ln order to estimate the limit of detection
(LOD)and limitof quantitation(LOQ)values,
the blanksamplewas injectedsix timesand
the peak areaof this blankwas calculatedas
as three

TropJ PharmRes,June 2009;I (3):259

 Banda*ar & Vavia
times the noise level while ten times the
noisevaluegavethe LOQ.
Robustness
The robustness of the method was
determined to assessthe effectof smallbut
deliberatevariationof the chromatographic
conditionson the determinationof MLX.
Robustnesswas determined by using
reagentsfrom two differentlots and two
differentmanufacturers.
Samplesolution stability
The stabilityof the drug in solutionduring
analysis was determined by repeated
analysisof samplesduring the course of
experimentation on the same day and also
after storageof the drug solutiontor 72 h
underlaboratory benchconditions(25t 1 t)
and under refrigeration (8 t 0.5 t). An
accuratelyweighed quantityof the puredrug
was dissolvedin acetonitrileand suitably
diluted with mobile phase to get a final
concentrationof 12 pg/ml.The solutionwas
subjectedto HPLCanalysisimmediately and
aftera periodof 24,48 and72h.
Speciticity/SeIectivity
The specificity
of the methodwas determined
by exposingthe samplesolution(12 pg/mL)
to acidic(0.1 M HCI),basic(0.1 M NaOH),
and oxidising(3% H2O2)stress conditions.
Thesampleswererefluxedfor 10 h at 100eC,
filteredandanalyzed.
Systemsuitability
tests
The chromatographicsystems used for
analysesmust pass the system suitability
limitsbeforesampleanalysiscancommence.
The capacityfactor(K),injectionrepeatability
(as described earlier in the subsection,
'Precision'),
tailingfactor(T),theoretical
plate
number (N) and resolution(Rs) for the
principalpeak and its degradationproduct
were the parameterstestedon a 12 pg/ml
sampleof MLX to assistthe accuracyand
precision
of the developedHPLCsystem.
Analysisof MLXin marketedtablets
Ten tablets (strength:15 mg/tablet)were
crushedand trituratedwell in a mortar.A
powdersample,equivalent to 1Smgof MLX,
was accuratelyweighedand transferred to a
25ml volumetric flask. The drug was
extracted into acetonitrile and mixed
thoroughly for 30 min usinga sonicator.
The
solutionwasfilteredthrough0.45micronpore
filteraftermakingup the volume,adequately
dilutedwith mobilephase and analyzedby
the proposedHPLCmethod.The possibility
of interferenceof excipients
withthe analysis
wasstudied.
Dataanalysis
plot,SD, RSD,
The r valuefor the calibration
and SEM were determinedusing Microsoft
Excel2007application.
RESULTS
Methoddevelopment
aceticacid (55:40:5
Acetonitrile-water-glacial
'/"vlv\ was selectedas the optimummobile
phase.Underthese conditionsthe retention
time and taifingfactorwere 6.8 + 0.01 min
and 1.13 respectively. A typical
chromatogram is represented
in Fig.1A.
Methodvalidation
Linearity
Peak area versus drug concentration was
plottedto constructa standardcurvefor MLX.
The polynomialregressionfor the calibration
plots showed good linear relationshipwith
coefficient r = 0.9995+ 0.0092;
of correlatiofi,
slope = 57257.38+ 165.74and intercept=
3443.07 + 97.56 (n = 6) over the
concentration range studied.The range of
was set at 4 - 2Apg/ml
reliablequantification
as no significantdifferencewas observedin
TropJ PharmRes,June2009;8 (3):260
 Bandarkar & Vavia

the slopes of the standardcurves in this measuringinter-dayvariationfor triplicate

range. The linear regressiondata for the
calibrationplot is indicativeof a good linear
relationship between peak area and
concentrationover a wide range. The
correlationcoefficientwas indicativeof high
significance.The low valuesof the standard
deviation,the standarderrorof slope,andthe
intercept of the ordinate showed the
calibrationplotdid notdeviatefromlinearity.
Precision
Precisionwas measuredin accordancewith
ICH recommendations.Five consecutive
of 12 pg/ml solutionof MLXby the
injections
proposedmethodshowedexcellentinjection
repeatabilitywith RSD of only 0.47o/".
Repeatability of sample injection was
determined as intra-day
variationwhileinter-
mediate precision was determined by
determinationof MLX at three different
concentrations. The results of the
of repeatability,
determination intermediate
precisionand reproducibilityare listed in
Table 1. Reproducibilitywas checkedby
measuringthe precisionof the proposed
method with analysisbeing performedby
anotherperson.Thelow RSDvaluesindicate
of the
the repeatabilityand reproducibility
method.
Recovery
The recoveryof the method,determinedby
spikinga previouslyanalyzedtest solution
with additionaldrug standardsolution,was
foundto be in the rangeof 99.27- 100.78o/o.
The valuesof recoveryf/"1, RSD (%) and
SEMlistedin Table2 indicatethe methodis
accurate.

Table1: Precision
of method

Intra-day and inter-dayprecision

Conc. (lntra-dayprecision)
Repeatability precision(lnter-day)
Intermediate
(pg/ml) Meanarea+ SD- SEMr RSD(%) Meanareat SEMT RSD(%)
SD-
8 452863t 2963 1710.74 0.654 450238r 8645 4991.34 1.92
12 670795r 5896 3404.15 0.879 6 6 9 1 2 5t 5 4 6 3 3154.16 0.816
16 897092r 7368 4254.04 0.821 892560! 4756 2745.96 0.533
Reproducibility
Conc. Repeatability (lntra-dayprecision) precision(pter- day)
Intermediate
(pg/ml) Meanareal SD SEM' RSD MeanareatSD SEM' RSD(%)
I 45 8 2 1 t6 5 1 3 2 2 9 6 3.05 1.120 4498221 1384 799.08 0.308
12 687125r 6861 3961.32 0.998 671527! 4974 2871.82 0.74"t
16 894234r 4893 2825.06 0.547 901681t 4566 2636.26 0.506
*n=3
|SEM = standardenorof mean
Table 2: Accuracyof method

Amount(%)of Theoretical Conc.lound Recovery RSD(%) SEM

drugaddedto content (pg/ml)t SD. (%)
analvte (uq/ml)
0 12 11.94t0.182 99.51 1.52 0.105
50 18 1 8 . 1 4t 0 . 1 3 7 100.78 0.76 0.079
100 24 23.91t 0.201 99.63 0.84 0 . 11 6
150 30 29.78r 0.164 99.27 0.55 0.094
*n=3
|SEM = standard error of mean

TropJ PharmRes,June2009;8 (3):261

 Bandarkar & Vavia

Detection and Quantification Iimits HCl,0.1M NaOH,and3% HrO,areshownin

product(Fig1D)eluted
Fig 2. A degradation
The limit of detectionwas found to be 360 timeof 2.24! 0.03min.The
witha retention
ng/ml where the drug could be detected results from stress testing, including
withoutany noise.The limit of quantification separationol the degradationproductand
was 510 ng/ml.This indicatedthe method quantification of MLXafterexposureto stress
can be used for detectionand quantification conditions,showthat the methodis stability-
of MLX over a very wide range of indicating.
concentrations.
.d .ffi

Robustness li^
There was no significantchange in the
tl\
i lL
retention time of MLX when reagents I
lfiB
t.n

(acetonitrileand glacial acetic acid) from

different lots and different manufacturers ttl
wereused.The concentration of the solution
analyzedwas 12 pg/ml and the % RSD
rangedfrom 0.078 to 1.286 %. The low
valuesof the RSD indicatedthe robustness
of the method.

Stability l& g 6_{0 a,e r0@

Figure 1: Chromatographic illustration of

There was no significantchangein analyte degradation products of MLX; (A) MLX;(B)
composition(sample concentration= 12 Oxidativecondition;(C) Basiccondition;(D) Acidic
pg/mL) over a period ol 72 h. The mean condition
RSD betweenpeak areas,for the samples
storedunderrefrigeration(8 t 1t) and at
laboratory
temperature (25 t 1t) was found
to be 0.990% and 0.771% respectively,
suggestingthat the drug solutioncan be
storedwithoutany degradation overthe time
*tF",,
GHt
interval
studied.

Specificity
"?\
Acidiccondition
The specificity of the methodwas determined
by exposing12 pg/mLsamplesolutionsof
MLXto stressconditions, i.e.,0.1 M HCl,0.1
M NaOH, and 3% HrOr. There was no
degradation of MLXin the presence of 0.1 M
NaOHor 3o/oHrO, and no significant change i-=
'- ./z
+ *,*/)"r.,
in peak areaand retentiontime of MLX was
observed(Fig 1). However,in the presence
of 0.1N HCl, it was foundthat therewas a
substantial changein the peak areaof MLX, pathwayfor
Figure2: Proposeddegradation
but not in the retentiontime.Chromatograms meloxicam
obtainedfromMLXaftertreatmentwith0.1 M

TropJ PharmRes,June 2009;8 (3):262

 Badarkar & Vavia

SysfernsuitabiIity tests poor peak shapes, and so were not

considered.
The results of the system suitabilitytests
assurethe adequacyof the proposedHPLC The proposedHPLCmethodof analysiswas
method for routine analysisof MLX. The also found to be preciseand accurate,as
capacityfactor (k) was found to be 1.86, depictedby the statisticaldata of analysis.
indicatingthat the MLXpeak is well resolvedHigh values of correlationcoefficienlsand
with respectto the voidvolume.The RSDof small values of intercepts validated the
five consecutiveinjectionsperformedunder linearity of the calibration plots and
the precisiontestwas foundto be 0.47o/oand obedienceto Beer'slaws. The RSD values
thus showsgood injectignrepeatability, The and the slopes and intercepts of the
tailingfactor(T) for MLX peakwas foundto calibration graphs indicate the high
be 1.13,reflecting goodpeaksymmetry.The of the proposedmethod.The
reproducibility
resofution(Rs) for the principlepeak and its
methodwas alsofoundto be robustas there
acid degradationproductwas found to be was no significantchangein the peak area,
6.22, indicatinggood separationof the drug peak shape and retentiontime of MLX.
from its degradation product.The theoretical
Furthermore, the lowvaluesol LODandLOQ
platenumber(N)wasfoundto be 2466,thus indicatethat the methodcan be employed
demonstrating goodcolumnefficiency. over a wideconcentration rangelor linearity.
This method is also highly sensitiveand
Analysis of MLX from marketedtablets could effectivelyseparatethe drug from its
degraded product. MLX is a thiazolyl
A single peak was observedat the retention substituted benzothiazine carboxamide.
time of MLXwhen a suitablydilutedsolution Solulion of MLX is stable at room
of the tablet formulationwas chromato- temperature and when refluxedat 1004Cfor
graphed. No interaction was observed 10 h witha strongbase(NaOH)or hydrogen
betweenMLX and excipientspresentin the peroxidesolution.However,whenrefluxedat
tablets.The MLX contentwas found to be 100eCwith a strong acid (HCl) for 10h,
99.46"/"and the RSD was 0.940/".The low hydrolysisof the amide group takes place,
RSD indicatedthe suitabilityof this method resulting in the formation of the
for routineanalysisof MLXin pharmaceutical corresponding carboxylicacid and amine(Rt
dosageforms. of 2.24 min.).Fig 2 represents the proposed
degradation pathway.
DlscusstoN
As the reportedmethod could effectively
The final decision on mobile phase separatethe drugfrom its degradedproduct,
composition and flow rate was madeon the it can be employedas a stabilityindicating
basisof peakshape,peakarea,tailingfactor, one. The systemsuitabilitytests performed
baselinedrift and time requiredfor analysis. verifiedthe resolution,columnefficiencyand
The solvent system selected [acetonitrile- repeatabilityof the chromatographic system
aceticacid(55:40:5%v/v)lgave
water-glacial and ensuredthat the equipment,electronics,
good resolutionof degradedproduct and and analyticaloperationsfor the samples
drug peak. No internalstandardwas used analyzedcouldbe constitutedas an integral
becauseno extractionor separationstepwas systemthatcanbe evaluatedas a whole.
invofved.Methanol-water(50:50 T"v/v) did
notfurnisha sharp,well-definedpeakandbut CONCLUSION
effecteda high tailing factor (1.82).CIher
mobilephasestried resultedeitherin much The HPLG method developedis accurate,
lower sensitivity,delayedretentiontime or precise,reproducible,
specific,and stability-
indicating.The methodis linearover a wide

TropJ PharmRes,June 2009;8(3):263

 Bandarkar & Vavia
range, economicaland utilizes a mobile
phase which can be easily prepared.All
these factorsmake this methodsuitablefor
quantificationof MLX in bulk drugs and in
pharmaceuticaldosage forms. It can
thereforebe concludedthat use of the
methodcan savemuchtimeand moneyand
it can be usedevenin smalllaboratories
with
very high accuracy and precision.The
methodcan also be used for the routine
analysisof MLX in bulk preparationsof the
drug and in pharmaceutical dosageforms
withoutinterference.
ACKNOWLEDGEMENT
The authors are thankful to Unichem
Ltd.,Mumbai,lndia,for the giftof
Laboratory
MLX.
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