JournalofChinesePharmaceuticalSciences http://www.jcps.ac.

cn 371

Synthesisandcharacterizationsof naproxenintercalated MgAllayered

doublehydroxides
BaoZhongDu1,2*,RuMinWang
1.DepartmentofAppliedChemistry,NorthwesternPolytechnicalUniversity,Xian710072,China
2.DepartmentofAppliedChemistry,XianUniversityofTechnology,Xian710054,China

Abstract:Naproxen(Nap),anonsteroidalantiinflammatorydrug(NSAIDs),wasintercalatedintothegalleryofMgAllayered
double hydroxides (LDHs) by ion exchange and coprecipitation with different location of magnesium ion and aluminum ion
solutions,respectively.TheproductwascharacterizedwithpowderXraydiffraction(XRD),FourierTransformInfraredspectral
(FTIR)andThermogravimetry(TG).TheresultsshowedanexpandedLDHstructure,indicatingthatthedrugwassuccessfully
intercalatedintoLDHwiththemonolayerperpendicularto(alongtheshortaxisorientationinproperangle)Napanion.Ascompared

n
tothepureformofNap,thethermalstabilityoftheintercalatedNapwassignificantlyenhancedduetothehostguestinteraction

. c
involvinghydrogenbondandelectrostaticattraction.WefurtherinvestigatedthedrugreleasecharacteristicsofthepillaredLDH

.ac
materialsbyadissolutiontestinsimulationgastrointestinalandintestinalfluidsunderdifferentpHvalues.Theresultsindicated
thatthereleasepercentagesdecreaseuponincreasingpHfrom4.60to7.43,likelyduetothedependenceofreleasemechanism

s
onpH.Wehavecarriedoutakineticsimulationtothereleasedataandfoundthatthedissolutionmechanismwasmainlyresponsible

p
forthereleasebehaviorofNapLDHsatpH4.60,whiletheionexchangemechanismwasresponsibleforthatatpH7.43.

c
Inaddition,theinitialreleaseratesandequilibriumpercentreleasesofthenanohybridsdependedsignificantlyonthesynthesis

. j
methods, from which wehave proposeda schematic model. Thecurrent study clearly showedthatthis druginorganiclayered
materialhasprospectiveapplicationsindrugdeliverysystem.

w
Keywords: LDHNaproxenIntercalationDrugdeliverysystem

w
CLCnumber:R943 Documentcode:A ArticleID:10031057(2010)537108

w
1.Introduction

Increasing attention has been focused on hybrid

materials represented by the general formula
M2+1xM3+x(OH)2(An)x/nmH2O,whereM2+ andM3+
area divalent and trivalent metal, respectively, and
systems such as inorganicinorganic and organic
An istheinterlayeranion[3].Asthehostcompounds,
inorganichybridsbecauseoftheirsynergisticeffects
LDHs are layered solids having positively charged
unattainablefromindependentsystemalone[1].Hybrid
layersandnegativelychargedanionintheinterlayer
systems for drug delivery require biocompatible
spaces. Among the properties of LDHs, anion
inorganicmatricesthatpermitsaferetentionaswell
exchange provides a simple method to replace the
ascontrolleddeliveryofdrugs.Amongavarietyof
interlayeranionandthusleadtoavarietyofdifferent
inorganicmaterials,layereddoublehydroxides(LDHs)
layered materials. These materials have been used
are endowed with great potential as an inorganic
asanionexchangersandcatalysts[3].Recently,more
matrixforthispurpose.Becausethereleaseofdrugs
attention has been paid to the organicinorganic
in drugintercalated layered materials is potentially
controllable,these new materials have great potential LDHs hybrid that contains drug molecules, and

asadeliveryhostinthepharmaceuticalfield[2]. many of its unique properties have been explored

LDHs, commonly known as hydrotalcites or such as enhanced dissolution property[4], increased

anionic clays, are a family of natural and synthetic thermalstability[5] andcontrolledreleaserate[6].
Naproxen (Nap), (+)6methoxymethyl2
Receiveddate:20091115.
Foundation item: Science and Technique Foundation of Xian City
naphthalene acetic acid, is a nonsteroidal anti
(GrantNo.YF07058). inflammatorydrug(NSAIDs)frequentlyusedasrelief
*
Correspondingauthor.Tel.:862982066325
email:bzhdu@xaut.edu.cn ofsymptomsofrheumatoidarthritisandosteoarthritis
Copyright 2010 Journal of Chinese Pharmaceutical Sciences, School of Pharmaceutical Sciences, Peking University http://www.jcps.ac.cn
372 B.Z.Du etal./JournalofChinesePharmaceuticalSciences19(2010)371378
based on its analgesic property. However, one of
theseriousproblemsintheapplicationsofNapis
its poor solubility in water and readily absorbing
characteristics. The use of Nap is often limited by
thefrequentsideeffects,whichaffectbothgastroin
testinal irritation and central nervous system. To
make the drug therapy most effective, the desired
pharmacological response must be obtained at the
target without harmful interactions at other sites ,
whichrequirescertainamountofdrugtobeabsorbed
into the body and transported to the target at con
trolled drug input rate. In the previous researches,
aimingtoimprove or enhance itsstability, solubility,
dissolutionrateandbioavailability,naproxenhasbeen
s
intercalatedintovariousLDHsbythe meansofion
p
exchange, coprecipitation and reconstruction
. jc
However, the majority of these methods have the
w
disadvantagesoflongtimecostingduringtheprocess
w
of NapLDHs synthesis, along with nonuniform
w
particlesize.
Inthispaperwehavereportedthepreparationof
NapLDH following two wellknown procedures
(coprecipitation and ion exchange) by gradually
increasing Mg2+ concentration in the solution of
Al3+ at different experimental conditions (e.g. pH,
temperature and reaction time). We emphasize our
efforts to enhance the Nap solubility in water and
optimize the synthetic routes of NapLDH. The
resultant samples were characterized by different
physicochemical techniques. Finally, we systemati
callystudiedthereleasebehaviorofNapLDH.
2.Experimental
2.1.Instrumentandchemicalreagents
The pH value was detected by a PHS3C pH
meter (Shanghai Kangyi Instrument Ltd.). Infrared
spectra was collected in a FTIR8900 infrared
spectrometer (Shimadzu Corporation, Japan). The
XRDpatternsweremeasuredonaXRD7000Xray
diffractioninstrument(ShimadzuCorporation,Japan)
usingCuKradiationat40kVand40mA.TheUV
Copyright 2010 Journal of Chinese Pharmaceutical Sciences, School of Pharmaceutical Sciences, Peking University
absorption spectrum was recorded on a UVVis
spectrophotometer (Shanghai Younike Instruments
Ltd.). DZ2BCtype vacuum drying oven (Tianjin
Taisite Instruments Ltd.) was used to dry samples.
Differentialthermalanalyses(DTA)andthermogra
vimetricanalyses(TG)wereobtainedonDTA7and
TGA7instruments(PerkinElmer),respectively.The
analysis wascarried out under nitrogenatmosphere
[7]
ataheatingrateof10C/min.SimultaneousTGMS
analysiswasperformedinaPyrisDiamondTGDTA
coupledwithThermoStarQM220 massspectrometer
n
withaquartzcapillarytransferline.
. c
Alltheexperimentalreagentssuchas Mg(NO3)26H2O,
.ac
Al(NO3)39H2O, NaOH, NaH2PO3, and NaCl were
analytical grade. Naproxen was purchased from
[811]
. Aldrich,andtheothersfromBeijingChemicalPlant
Inc.
2.2.SynthesisofnitrateLDHs
We prepared the Al(NO3)3 solution by dissolving
18.75gofAl(NO3)39H2Oin75mLdeionizedwater
and transferred to a fourneck flask with vigorous
stirringat60Cundernitrogengasflow.Thenwe
addedasolution(75mL)ofMg(NO3)26H2O(51.2g,
0.2mol)andasolution(100mL)ofNaOH(24.0g,
0.6 mol) by two constant pump. The feeding time
wasfixedat2h.ThepHvalue ofreactionsolution
was kept constant (10.50.5) during the reaction
processbyadjustingtheflowrateofthesetwosolu
tions. After the reaction process, the resultant slurry
wasagedat65Cfor24h.Theprecipitatewascen
trifugedand washedwithdeionizedwater until the
pH value reached 7. Then the clean precipitated
wasdriedinvacuumat85Cfor16h.
2.3.SynthesisofNapNO3LDHsbycoprecipitation
Nap (5.94 g) was dissolved in 100 mL of decar
bonated waterand neutralized withNaOHsolution.
Al(NO3)39H2O(1.13g)wasdissolvedin50mLof
decarbonatedwaterandtransferredintoafourneck
flask, which was kept in water bath at 60C under
nitrogengasflow.Withvigorousstirringfor5min,
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 B.Z.Du etal./JournalofChinesePharmaceuticalSciences19(2010)371378 373

theabovementionedNapsolution wasslowlyadded 2.6.Drugreleaseproperties

to Al(NO3)3 solution. The pH value of the reaction
Asimulatedsolutionofgastrointestinalandintes
solutionwaskeptconstant(9.5)andthenasolution
tinal fluid at pH 4.60 (phosphate buffer) and 7.43
(50 mL) of Mg (NO3)26H2O (1.54 g, 0.006 mol)
(phosphatebuffer),physiologicalsalineanddistilled
wasaddeddropwiselytothereactionsolutionover
waterwereemployedasreleasemedium,respectively.
3 h. The precipitate was filtered and the solid was
WehaveperformedtheNapreleasefromNapLDHs
washedseveraltimeswith decarbonatedwateruntil
intothemediabyaddingca.0.25gNapLDHsinto
the pHreached7.Finally,thecleanprecipitatewas
100mLreleasemediumat(370.5)C.Thepaddle
driedinvacuumat70Cfor24h.
rotation speed was 100 r/min. A sample of 5 mL
2.4.SynthesisofNapLDHsbyanionexchange product was withdrawn at predetermined intervals
and centrifuged. The accumulated amount of Nap

n
The naproxen intercalated nitrate LDHs was pre

c
releasedintothesolutionwas measuredmomentarily

.ac .
paredbytheionexchangemethod.Weaddedasolu using UVVis spectrophotometer at the wavelength
tion containing 5.94 g Nap in 50 mL decarbonated of331nm.

s
water into 100 mL aqueous suspension containing

jc p
4.00 g precursor Mg/AlNO3LDHs, and the pH of

.
3.Resultsanddiscussion
the solution was kept at 10.0 by adding 2 mol/L

w
NaOHsolutionduringthereactionprocess.Themix

w
3.1.XRDcharacterization
turewas vigorously stirred at 60 C for 5 min, 0.5,

w
1.5 and 4 h in nitrogen atmosphere, respectively. Figure1illustratestheXRDpatternsofNapinter
Thentheresultantwasfiltrated,washedwithdecar calated MgAlLDHs materials prepared by different
bonated water until the pH reached 7.0 and finally methods. The XRD pattern of Mg/AlNO3LDHs

driedinvacuumat70Cfor24h.Theproductswere was also shown for comparison. The characteristic

denoted as NLIEb, NLIEc, NLIEd and NLIEe, peaks for LDHs (2 = 11.35, 23.23, 34.54 and

respectively. 60.65),correspondingtoMillerindices(003),(006),
(009)and(110)wereobserved(Fig.1a).Thesesharp
2.5.MeasurementsofloadingamountsofNapin and symmetric peaks demonstrate the formation of
NapNO3LDHs wellcrystallized Mg/AlNO3LDHs with the inter
layer distance d003 value of 0.77 nm. In Figures 1b
The loading amounts (A) of Nap in NapLDHs
prepared by the abovementioned methods were
measured by the UVVis spectroscopy using the
following method.NapLDHssamples(0.05g)and
0.5mLof1mol/LHNO3 solutionweremixedintoa
50mLvolumetricflask.Thebalancewasfilledwith a
phosphate buffer at pH 7.43. The concentration of
Napin theresultingsolutionwas determinedbased b

on the absorbance at 331 nm, from which we have

c
calculatedtheamounts ofNapbyregressionanaly
sisofthestandardcurve. The measurement ofNap 1020304050607080
2 ()
loadingamountswasperformedintriplicateandthe
Figure 1. XRD patterns of LDH(a),NapLDH sample preparedby
averageresultswererecorded. coprecipitation(b)andionexchange(c)methods.

Copyright 2010 Journal of Chinese Pharmaceutical Sciences, School of Pharmaceutical Sciences, Peking University http://www.jcps.ac.cn
374 B.Z.Du etal./JournalofChinesePharmaceuticalSciences19(2010)371378

and 1c, the characteristic reflections of LDHs com Thesecondsharpevent(290410C)wasduetothe

pounds,andthebasalreflection(003)shiftedtolower
2angles(for(003)reflection:2=8.04)compared
withthoseofNO3LDHs(2 =11.35).Theinterlayer
spacing of d003 increases 0.32 nm compared with
NO3LDHs, indicating the successful intercalation
of Nap anions into the interlayer region
absence of diffraction lines of crystalline naproxen
excludes the possibility of a heterogeneous phase
and confirms that the entire drug was intercalated
between the brucitelike layers. In the case of
naproxen decomposition (weight loss of 25.1%). It
should be noted that this temperature region was
obviously higher than that of the pure free Nap[8],
suggestingthatthethermalstability oforganicNap
speciesinNapLDHswere clearly enhanced dueto
[810]
. The the hostguestinteractioninvolving hydrogenbond.
It is also supported by the following IR analysis.
Thethirdlossevent(410530C)couldbeattributed
to the further decomposition of drug with CO2 and
watervaporevolution(weightlossof19.2%)[9].The

n
intercalation by ionexchange technique (Fig. 1c), laststage(530800C)wasmainlyattributedtothe

. c
the XRD pattern shows two types of (003) peak: dehydroxylation of the host layer accompanying

.ac
theoneoflowintensityatlowerangle(2=8.19) with the formation of layered double oxide at the

s
corresponds to the intercalated Nap while the other weight loss of 2.5%. Compared with the thermal

c p
one (2 = 11.76) is for the original NO3LDHs. stability datareportedbyPengetal.[11], four distin

. j
Thisindicatesthatthelayergallerycontainedboth guishableweightlossstepsindicatedthatthethermal

w
the drug with low content and nitrate with high stabilityofNapLDHspreparedfromdifferentloca

w
content, which is contrary to that observed in the tion of magnesium ion and aluminum ion solutions

w
coprecipitation technique. The XRD data are in wasgreatlyimprovedwithwellcrystallizedstructure.
agreement with the drug loading ratios obtained
by the UV quantitative method (12.8% for the 100 0

sampleobtainedbycoprecipitation,while5.6%for
ionexchangetechnique).
WeightLoss(%)

80 10
DTA T(C)
3.2.Analysisofthermalstability
60 20
TGDTA curves for Mg/AlNO3LDHs precursor TG

and NapLDHs are shown in Figures 2 and 3,

0 30
respectively.InFigure2,threemainthermalevents 50200350500650800
T(C)
were clearly observed. The first endothermic peak
Figure2. TGandDTAcurvesforLDH.
locatingat(50230)Ccorrespondedtotheremoval
of external and interlayer absorbed water (Weight
100 40
loss:15.9%).Thefollowedstage(270465C)was TG
30
the result of decomposition of NO3 (Weight loss:
80
WeightLoss(%)

26.9%). The last stage (465800 C) demonstrated 20

T(C)

that the interlayer structure had been destroyed at 10

60
theweightlossof7.3%. 0
DTA
ThethermaldecompositionofNapLDHscomplex 10

wascharacterizedbyfourstepsasshowninFigure3. 30 20
50200350500650800
The first (50260 C) was due to the loss of both T(C)

adsorbedandinterlayerwaterat15.1%weightloss. Figure3. TGandDTAcurvesforNapLDH.

Copyright 2010 Journal of Chinese Pharmaceutical Sciences, School of Pharmaceutical Sciences, Peking University http://www.jcps.ac.cn
 B.Z.Du etal./JournalofChinesePharmaceuticalSciences19(2010)371378
3.3.Infraredspectra
Figure 4 shows the FTIR spectra of LDH, Nap
LDHspreparedbyionexchangefor5min,0.5,1.5,
4handtheNapLDHspreparedviacoprecipitation
process. In Figure 4a, a broad strong adsorption
band at 3454 cm1 could be attributed to the
stretching vibration of hydroxyl groups of water
molecules in the interlayer and physicaladsorbed
water. The adsorption band at 1631 cm1 was
assigned to the weak bend vibration of water. The
bandsat1396and610cm1 wereduetotheNO3
stretching vibration. Thebandat450cm1 wasdue
toOMOvibrationrelatedtoLDHlayers.Theband
at2362cm1wasassignedtoCO2fromatmosphere.
s
InFigure4e,twoweakbandsat2956and2875cm1
p
c
were attributed to the asymmetric and symmetric
j
.
vibration of CH3, respectively. The asymmetric
w
andsymmetricstretchingvibrationofcarboxylate
w
COO were observed at 1561 and 1387 cm1, re
w
spectively.ComparedwithFigure4a,theabsorption
peakofC=O movedtolowfrequency,indicatingthe
interaction of Nap in the interlayer space involving
hydrogen bonding, and the obvious electrostatic
attraction between guest Nap and host layer[8]. The
peaksat1653,1609and1507cm1 wereassignedto
theskeletonstretchingvibrationmodeofaromatic
ring. The bands at (13001000) cm1 were attributed
tothebend vibration mode ofaromaticring.The
bandsat1036and847cm1 wereascribedtoabsorp
tion of COC groups in Nap. The characteristic
absorption peaks of Nap could be clearly observed
in Figure 4f, indicating the drug has been success
fully intercalated into the gallery of LDHs. How
ever,itwasclearlyobservedthatthebandsat1396
and610cm1 duetotheNO3 disappearedgradually,
while the bands belonging to Nap increased upon
increasing exchange time. The transition from
Figures 4b4e demonstrated that NapLDH could
not be obtained in short time via ionexchange
method. On the contrary, the Nap could be easily
intercalated into the interlayer within 2 h by co
precipitationwiththedifferentlocationofMg2+ and
Al3+.
Copyright 2010 Journal of Chinese Pharmaceutical Sciences, School of Pharmaceutical Sciences, Peking University
375
(f)
(e)
(d)
(c)
(b)
(a)
3800 3400300026002200180014001000600200
Wavenumber(cm1)
Figure4.FTIRspectraofLDH(a),NapLDHssynthesizedbyion
exchange after exchange for5min(b),0.5h(c),1.5h(d),4h(e)
n
andNapLDHsprepared via coprecipitationmethod(f),respectively.
. c
.ac
3.4.AssemblymechanismofNapLDHs
InthegeneralformulaM2+1xM3+x(OH)2(An)x/nmH2O
of LDHs, An was an exchangeable inorganic or
organicanion, which couldbeeasilysubstitutedby
otheranion(Xn)withhighanionexchangecapacity
and released from the layer of LDHs with simple
ionexchangemethod[8].AccordingtotheXRDand
IR spectra, the amount of Nap in the NapLDHs
prepared with ionexchange process could be
affected by several parameters such as pH value,
reaction temperature and time. Small amount of
Nap was found at the end of intercalation as the
exchange balance setting up. However, the Nap
LDHs prepared by coprecipitation with high drug
loading ratios could easily be obtained when the
magnesiumionandaluminumionwereaddedsepa
rately.Itmightbeexplainedasfollows:(1)aninter
mediatesolgelstate,formedintheprocessofinter
layer construction, wasbeneficial to the intercalation
oftheguestintothegalleryofLDHsastheaddition
ratioofMg2+controlled(2)astheintermediatestate
formed,thepossibilityofionexchangewassignifi
cantly improved between the Nap guest and the
nitrate intheLDHsprecursor.Asaresult,theloading
ratioofdrugwasincreased,aswellasthesustained
releaseeffectwasenhancedobviously(delayed50min
compared with the physical mixture of drugs and
LDHs).
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376 B.Z.Du etal./JournalofChinesePharmaceuticalSciences19(2010)371378

3.5.LoadingamountsofNaponLDHs 3.6.Drugreleaseproperties

The linear regression analysis of the standard Wehaveinvestigatedtheinvitroreleaseproperties

curvewasshowninFigure5.Theloadingamounts
(A,inmgNap/gLDHs)ofNaponLDHswerelisted
in Table 1. The A value of NapLDHs obtained by
the former method was much higher than (the
percent of Nap in NapLDHs about 12.8%) that of
the NapLDHs obtained by the later. The A values
might be dominated by some factors including
surfacechargedensity,unoccupiedinterlayerspace,
ofthedrugbyaddingtheintercalationcompoundin
distilled water(a), physiologicalsaline(b),simulated
intestinal buffer (c, pH 7.43), and gastrointestinal
fluid(sodiumdihydrogenphosphatebuffer,pH4.60)
(d),respectively.TheresultswereshowninFigure6,
whichindicatedthatthereleaseprofilesreachedan
almostconstantlevelafter50min(Fig.6aand6b).
However,thereleaseratesreachedequilibriumstate
after150minand80minatbothpH7.43and4.60,

n
thepolarityofguestspecies,etc[12].

c
respectively. This observation may be explained as

.ac .
follows.First,theNapintercalatedinLDHmaterials
0.7 was ionexchanged by CO32, which was formed by

s
Nap
the dissolution of CO2 and delayed the release of

p
0.6

c
y =0.013x +0.0041

j
r2=0.9983 naproxen in distilled water. Second, the release

.
0.5
behaviour of NapLDHs in physiological saline

w
0.4
exhibitedahighinitialdrugreleaserateintheinitial
A

w
0.3
10minandreachedanalmostconstantlevelafter

w
0.2
50min.ComparedwithNap,Cl waseasilyinterca
0.1 latedintoLDHlayers,whichacceleratedtherelease
0 of Nap. However, in thesimulated intestinal buffer
0 1234 56
c (g/mL) (pH7.43,Fig.6c),thereleaseofNapLDHsshowed
Figure5.StandardabsorptioncurveofNap. a slow and persistent process originating from the
ionexchange process between the intercalated
Table1. LoadingamountsofNapinNapLDHs
anions and phosphate anions in the buffer[13]. In
Synthesismethod Loadingamounts(mgNap/gLDHs) addition,thereleasebehaviouratpH4.60wasvery
Coprecipitation 16.4
fastduringthefirst5min,whichcouldbeattributed
Anionexchange 7.4
to the partial dissolution of LDHs layer at weak
acidic solutions[13]. After 80 min, a slower release
0.8
(d) stepcharacterizedasreachedanequilibriumstate,as
(c)
showninFigure6d.
0.6
Thereleasecurvesforphysicalmixture(Napwith
(b)
LDHs, Fig. 7a)and Nap from NapLDHs (Fig. 7b)
A

0.4
in solution at pH 7.43 were shown in Figure 7. It
was obvious that the physical mixture of drug and
0.2
LDHs indicated inconspicuous sustainedrelease
(a)
effect in the solution at pH 7.43. For this mixture,
0
050100150200260 the total Nap content was immediately released at
t(min)

Figure 6. Release profiles of Nap from NapLDHs in different pH

the initial 20 min. However, the Nap intercalated
values. (a) Distilled water (b) Physiological saline (c) Simulated LDHspresentedagradualreleaseofNapanionsasa
intestinal buffer (pH 7.43) and (d) Gastrointestinal fluid (sodium
dihydrogenphosphatebuffer,pH4.60). function of time until the equilibrium state formed
Copyright 2010 Journal of Chinese Pharmaceutical Sciences, School of Pharmaceutical Sciences, Peking University http://www.jcps.ac.cn
 B.Z.Du etal./JournalofChinesePharmaceuticalSciences19(2010)371378 377

after 170 min. These data indicated that the Nap monolayer vertical (along the short axis orientation
LDHspreparedviacoprecipitationsystemwas more in proper angle) between layer, where the carboxyl
effectivethanthatpreparedviaionexchangemethod groupsofadjacentanionsattachedalternatelytothe
sincethedrugreleaserateofNapLDHswasslower upperandlowerhydroxidelayersthroughhydrogen
and the amount of drug gradually increases over a bondingandelectrostaticattraction,respectively.
longerperiod. ForthelayeredstructureofLDHs,interlayeranions
could be exchanged by other functional anions that
3.7. Intercalation structure models and release
make LDHs useful for various applications. Ion
mechanism
exchange process could be carried out slowly be
Using Gaussian 03 software, we have calculated tweentheanionsinNapLDHandinorganicanions
the long axis, short axis and molecular thickness sothatsustainedreleasecanberealized(Fig.6).

n
of Nap from the PM3 semiempirical molecular

. c
orbitalmethod,andtheirvaluesare0.581,0.407and

.ac
4.Conclusions
0.385 nm, respectively. Since the thickness of the

s
LDH layer was a constant value (0.48 nm), the WehavesuccessfullyassembledNapintercalated

p
gallery height of NapLDHs was 0.68 nm, which

c
Mg/AlNO3LDHswithMg/Alratioof2.0asdrug

j
was well consisted with the value of short axis

.
inorganiccompositebycoprecipitationwithdifferent
0.407 nm for Nap. Based on previous research

w
location of magnesium ion and aluminum ion re
resultsandtheabovementionedanalysis[9],wehave

w
sources,whichis2hslowerthanionexchangetech
proposedaformationmodelofNapLDHs,asshown

w
niques.Wehavedeterminedtheinterlayerspacingof
inFigure8.TheorientationofguestinLDHsinter
0.61nm,whichislargerthan the molecularsizeof
layer might be accommodated as alternately and
Nap(0.581 nm0.407 nm0.385 nm). FTIRspectra
analysis indicated that the guest only adopted a
0.8
monolayer arrangement with the naphthalene ring
(b)
perpendicular (along the short axis orientation in
0.6
properangle)tothelayerplane,andthecarboxylof
Absorbance

adjacent anions attaching alternately to the upper

0.4
andlowerhydroxidelayers(theloadingamountwas
(a)
12.8%).Inaddition,thesharpandsymmetricpeaks
0.2
inXRDspectrademonstratedthatNapLDHsiswell
crystallized with small size and high dispersion, as
0
050100150200260 the addition rate of Mg2+ was controlled. The host
t (min)
layersandtheguestswerebridgedthroughhydrogen
Figure 7. Release profilesof physical mixture of drug ofLDHs(a)
andNapLDHs(b)atpH7.45. bondingandelectrostaticattraction.

Inorganicanion

H2O
1.09nm

Naproxen

Figure8.SketchesofthepossiblelocationofNapintheinterlayerspaceofLDHsandreleasemechanism.

Copyright 2010 Journal of Chinese Pharmaceutical Sciences, School of Pharmaceutical Sciences, Peking University http://www.jcps.ac.cn
378 B.Z.Du etal./JournalofChinesePharmaceuticalSciences19(2010)371378

From TGDTA analysis, the thermal stability of References

intercalated Nap, after intercalated into LDHs, was
remarkably improved to about (90150) C, due to
the hostguestinteractioninvolving hydrogenbond.
In contrast, the decomposition of pristine Nap
occursat170C.
The in vitro release studies of NapLDHs have
shownthatboththereleaserateandreleasepercent
ages were markedly decreased upon increasing
the pH value. At pH 4.60, the release mechanism
involvesdissolutionatthebeginningofreleasetest,
which is followed by an ionexchange mechanism,
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Kang,Y.K.Han,O.J. Biomaterials. 2004, 25,30593064.
[2] Arco, M. Fernandez, A. Martin, C. Rivers, V. Appl.
ClaySci. 2009, 42,538544.
[3] Trikeriotis, M. Ghanotakis, D.F. Int. J. Pharm. 2007,
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[5]Wei,M.Yuan,Q.Evans,D.G.Wang,Z.Q.Duan,X.J.
Mater. Chem. 2005, 15,11971203.

n
so the release rate of NapLDHs was slowed down [6] Li, B.X. He, J. Evans, D.G. Duan, X.Appl. Clay Sci.

. c
after the first 5 min burst. At pH 7.43, the slower 2004, 27,199207.

.ac
andpersistentreleaseprocesscouldbeinterpretedto [7]Bettinetti,G.Sorrenti,M.Negri,A.Setti,M.Mura,P.
the ionexchange process between the intercalated

s
Melani,F.Pharm.Res. 1999, 16,689694.

p
organicanionsandphosphateanionspresentinbuffer.

c
[8] Wei, M. Shi, S.X. Wang, J. Li, Y. Duan, X. J. Solid

j
However, the initial release rates and equilibrium

.
StateChem. 2004, 177,25342541.
releasesofthenanohybridswereobviouslydepending

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[9]Arco,M.D.Gutierrez,S.Martin,C.Rivers,V.Rocha, J.
on the synthesis methods. The NapLDHs prepared

w
J.SolidStateChem. 2004, 177,39543962.
viacoprecipitationprocesswasmoreeffectivethan

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[10] Berber, M.R. Minagawa, K. Katoh, M. Mori, T.
those prepared via ionexchange method, because
Tanaka,M. Eur.J.Pharm.Sci. 2008, 35,354360.
the drug release rate of NapLDHs was slower and
[11] Peng,X.H. Huang, K.L.Jiao, F.P. Zhao, X.H. Yu,
theamountof drug graduallyincreased overalong
J.Funct.Mater. 2006, 37,415417.
period.
The present study might offer broad perspectives [12] Quan, Z.L Yang, H. Zheng, B. Hou, W.G. Colloids

in utilizing Mg/AlNO3LDHs as a biocompatible Surf.A. 2009, 348,164169.

inorganicmatrixfor drugreservoiror drug delivery [13]Zhang,H.Zou,K.Guo,S.H.Duan,X.J.SolidState

carrier. Chem.2006, 179,17921801.

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