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JournalofPharmaceuticalandBiomedicalAnalysis

29(2002)195–201

/locate/jpba

Determinationofthebindingparameterconstantsof

Renagel

®

capsulesandtabletsutilizingtheLangmuir

approximationatvariouspHbyionchromatography

ngen*,XiChen,en,,

DonghuiWang,EugeneZhorov

GelTexPharmaceuticals,

153

SecondA6enue,Waltham,MA

02451

,USA

Received30July2001;receivedinrevisedform11January2002;accepted29January2002

Abstract

Sevelamerhydrochlorideisacross-linkedpolymericamine;itistheactiveingredientinRenagel

®

capsulesand

merhydrochlorideisindicatedforthecontrolofhyperphosphatemiainpatientswithend-stagerenal

dingparameterconstantsofsevelamerhydrochlorideweredeterminedusingtheLangmuirapproxi-

mationforthreedifferentdosageformsatpH4.0,eedosageformswereRenagel

®

403mg

capsules,Renagel

®

400mgtabletsandRenagel

®

ultsdemonstratetheequivalencyofallthree

ultsalsodemonstrateashiftinthebindingmechanismfrompH4.0to7.0.©2002

htsreserved.

Keywords

:

Sevelamerhydrochloride;Ionchromatography;Langmuir;Quaternaryamines;Hydrogel;Renagel

®

uction

Sevelamerhydrochlorideistheactiveingredient

inRenagel

®

merhy-

drochloride,across-linkedpoly(allylaminehydro-

chloride),isanovelphosphatebinderusedforthe

reductionofserumphosphatelevelsinpatients

withend-stagerenaldisease(ESRD)[1–4].The

advantageofsevelamerhydrochlorideforESRD

overexistingtherapies,suchascalciumoralu-

*.:+1-781-434-3515;fax:+1-

781-672-5823.

E-mailaddress

:

rswearingen@(ngen).

minumsupplementation,isthatitisnon-ab-

sorbed,leadingtoanimprovedsafetyprofile.

Animportantaspectoftheanalyticalcharac-

terizationofsevelamerhydrochloridetabletsisto

demonstrateequivalencytothecapsuledosage

uctureofsevelamerhydrochlorideis

nesinsevelamerhydro-

chloridemaybindphosphateionicallyand

throughhydrogenbonding.

Thispaperdescribesthemethodologyandpro-

ceduresforthedeterminationofthebindingcon-

stantsatthreedifferentpHlevelsutilizingthe

risonofthese

bindingconstantsdemonstratestheequivalencyof

0731-7085/02/$-seefrontmatter©htsreserved.

PII:S0731-7085(02)00007-9

ngenetal.

/

.

29(2002)195–201

thetabletdosageformtothecapsuledosageform

dingofthedibasic

phosphateanionandmonobasicphosphateanion

isalsodiscussed.

alsandmethods

2

.

1

.Chemicals

Sevelamerhydrochloridewasobtainedfrom

GelTexPharmaceuticals,Inc.(Waltham,MA).

N,N-Bis(hydroxyethyl)-2-aminoethanesulfonic

acid(BES)wasobtainedfromSigmaChemical

Company(,MO).Potassiumphosphate,

monobasic(KH

2

PO

4

)and1Naqueoussodium

hydroxidewereobtainedfromAldrichChemical

Company,Inc.(Milwaukee,WI).Sodiumchloride

andsodiumhydroxidepelletswerefromVWR

ScientificProducts(WestChester,PA).Allchemi-

calswereofACSgradeorhigherandwereused

withoutfurtherpurifizedwaterwas

obtainedfromanin-houseBarnsteadNanopure

System(Barnstead/ThermolyneCorporation,

Dubuque,IA).

ureofsevelamerhydrochloride;(a,b=number

ofprimaryaminegroups)a+b=9;(c=numberofcross-link-

inggroups)c=1;(n=fractionofprotonatedamines)n=0.4;

(m=largenumbertoindicateextendedpolymernetwork).

2

.

2

.Apparatus

ADionex(DionexCorporation,Sunnyvale,

CA)DX-500ICsystemwasusedforphosphate

stemconsistsofanAS50au-

tosampler,GP50quaternarygradientpump,

CD20conductivitydetector,andPeakNetsoft-

warecontrolanddataacquisition(version5.10d).

SeparationswereperformedusingaDionexAS-

11analyticalcolumn(4×250mm

2

)andanAG-

11guardcolumn(4×40mm

2

).Suppressionwas

achievedwithanASRS-IIanionselfregenerating

swereshaken

usingaLablineHeatedOrbitalShakerModelNo.

4628(LablineInstruments,MelrosePark,IL).

Injectionloopvolumewas100mlwithafull

injectionsetting.

2

.

3

.Samplepreparation

Threeindividualsetsofaqueousphosphateso-

lutionswerepreparedatthefollowingconcentra-

tions:38.7,30.0,14.5,10.0,7.5,5.0,2.5and1.0

tofphosphatesolutionswerepre-

paredsothatafinalpHof4.0,5.5and7.090.3

wasobtainedaftertheadditionofRenagel

®

cap-

sulesandtablets,utions

contained100mMBESand80mMNaCl.

Forthe403mgcapsuleand400mgtablet,one

unitdosewasplacedinto150mlofeachphos-

800mgtablet,oneunit

dosewasplacedinto300mlofeachphosphate

solutioninordertokeepthephosphatetopoly-

merratioconstant.

ThesolutionsatpH4.0werepreparedby

addingthecapsulesandtabletstoasetofphos-

phatesolutions,whichhadnopriorpHadjust-

eirdisintegration,approximately3

mlof1NHClwasaddedtoallsolutionswiththe

exceptionof300mlsolutions(800mgtablets)at

38.7and30.0mMphosphateinwhichapproxi-

mately6and5mlwereadded,

pHofthefinalsolutionswasapproximatelypH

hesampleswerepreparedinduplicate.

ThesolutionsatpH5.5werepreparedbyad-

justingthepHofasetofphosphatesolutionsto

pH4.0,volumetrically,-

imately2–4mlof1NNaOHwasaddedperliter