Research Article Fixed Bed Adsorption of Drugs on …downloads.hindawi.com/journals/ijce/2013/752719.pdfInternationalJournalof Chemical Engineering Sol V-2 V-3 TT TC TC TT TC PI P-2

Hindawi Publishing CorporationInternational Journal of Chemical EngineeringVolume 2013 Article ID 752719 7 pageshttpdxdoiorg1011552013752719

Research ArticleFixed Bed Adsorption of Drugs on Silica Aerogel fromSupercritical Carbon Dioxide Solutions

Giuseppe Caputo

Dipartimento di Ingegneria Industriale Universita degli Studi di Salerno via Giovanni Paolo II 132-84084 Fisciano Italy

Correspondence should be addressed to Giuseppe Caputo gcaputounisait

Received 16 March 2013 Accepted 5 June 2013

Academic Editor Jaime Wisniak

Copyright copy 2013 Giuseppe Caputo This is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Supercritical adsorption coupled with the high adsorption capacity of silica aerogel allows the preparation of a new kind of deliverysystems of poor water soluble drugs In order to overcome drawbacks of conventional techniques where the use of liquid solventscan cause the fracture of aerogel porous structure in this work a new adsorption process of drugs from a supercritical mixture isproposed Adsorption takes place from a fluid solution of the drug in supercritical CO

2and ethanol as cosolvent A fixed bed

adsorption plant has been developed to allow fast mixing of fluid phase and effective contact in the adsorption column Theuse of ethanol as cosolvent allows to overcome the limitation of supercritical adsorption due to low solubility of many drugs insupercritical CO

2 Adsorption isotherms were measured for one-model substance nimesulide at 40∘C and breakthrough curve

was experimentally obtainedThedrug loading of the drug into silica aerogel was up to 9 wtThedrug compositewas characterizedusing scanning electron microscopy and release kinetics of the adsorbed drug were also evaluated by in vitro dissolution tests Thedissolution of nimesulide from loaded aerogel is much faster than dissolution of crystalline nimesulide Around 80 of nimesulidedissolves from the aerogel within 6 minutes whereas dissolving 80 of the crystalline drug takes about 90min

1 Introduction

Thepoorwater solubility of somedrugs limited their bioavail-ability A fast dissolving system can be defined as a dosageform for oral administration which when placed in mouthrapidly dispersed or dissolved increasing compliance andefficacy of the therapy Fast dissolving and fast dispersingdrug delivery system may offer a solution to these problemsA possible approach for ensuring maximum bioavailabilityis the increase of drug dissolution rate andor solubility Toimprove the dissolution rate of drugs different techniqueshave been developed [1] The most common approach isbased on particle size reduction that can be achieved by pro-cesses based on micronization or nanosuspension In thefield of supercritical fluids various promising techniquesof micronization of drugs and excipients with supercriticalcarbon dioxide (SC-CO

2) have been developed [2 3] and

also the use of water solvent and the less-expensive supercrit-ical nitrogen is being explored [4ndash6] An alternative way toimprove the availability of a drug is its dispersion on a bio-compatible substrate [7] Silica-based materials used as

substrate are widely employed as additives free flow agentsand drug carriers also in commercial products A special classof silica materials is silica aerogels (SA) They are low-den-sity nanoporous solids with a fine open-pore structure thatexhibits unique properties such as high porosity (90ndash99)high surface area (400ndash1000m2g) and extremely lowdensity(0003ndash015 gcm3) These properties allow them to be usedas host matrix for drug delivery Silica aerogels were recentlyshown to be a potential candidate for oral drug deliverysystems [8ndash10] A promising method to adsorb a drug intoporous substrates is supercritical (SC) deposition or adsorp-tion [8 9 11ndash13] Essentially the process involves the dissolu-tion of the active molecules in a supercritical fluid and theimpregnation of the substrate by its exposure to this solu-tion Supercritical carbon dioxide (SC-CO

2) is commonly

used due to its relatively good solvent power for variousdrugs mild critical temperature (31∘C) low critical pressure(74MPa) and inertness After the removal of the supercrit-ical fluid (SCF) by expansion a drug-loaded matrix free ofsolvent residues is obtained This method takes advantageof the unique properties of SCFs Indeed a SCF possesses a

2 International Journal of Chemical Engineering

unique combination of gas-like and liquid-like properties thatcan be adjusted by small changes in temperature or pressure

Low viscosity and high diffusivity of SC-CO2allow a

rapid equilibration and micropore penetration of the fluidphase within the matrix SCFs also have zero surface tensionthat not only facilitates the rapid permeation and diffusioninto porous substrates but also avoids the pore collapse ofSA that occurs using organic liquids due to capillary stressescaused by the liquid-vapour menisci within pores

Until now SC adsorption within SA has been studiedusing simple batch vessels in which SA and active moleculesare loaded and equilibrated until equilibrium is reached [8 911 12] Because pure SC-CO

2is used as solvent themaximum

amount of active compound that can be loaded on SA is lim-ited by its solubility in SC-CO

2at given condition of temper-

ature and pressure One way to increase the solubility is theincrease of pressure of SC-CO

2as shown in a previous work

in the case of nimesulide [12] an alternative is the use of acompatible and benign cosolvent which increases the solubil-ity of the active compound in the fluid phaseThe fluid phasecomposed by SC-CO

2and cosolvent must satisfy the condi-

tion that the mixture is supercritical at the operating pressureand temperature Indeed if a liquid phase is formed the aero-gel structure could be damaged and polluted by the cosolvent

In this work the adsorption of a model drug on SAwas studied using a new experimental apparatus properlydesigned for this purpose The best way to deal with SC-fluidmixture is to use a continuous process in which the fluidphase is continuously pumped in an adsorption column con-taining the SA matrix Because a fundamental stage ofthe process is the formation of the ternary mixture SC-CO2organic solventactive compound a mixing stage has

been provided that allows a fast and effective solubilizationof the components

The new experimental plant has been tested with nime-sulide as active compound and ethanol as solvent Nimesulidehas been chosen for comparison purposes because in a previ-ous study [12] its adsorption from pure SC-CO

2and using a

batch mode apparatus was studied Adsorption isotherm andbreakthrough curve of the column at 40∘C were determinedLoaded SAs were characterized by in vitro dissolution test tostudy the properties of the composite material and its poten-tiality for applications

2 Materials and Methods

21 Materials Hydrophilic silica aerogel (SA) in form ofmonolithic blockswas purchased fromMerketech Int (USA)The nominal density is 01 gcm3 the surface area is 800m2gand the mean pore size is about 20 nm Deposition experi-ments were performed using cubic blocks of 1 cm obtained bycutting SA monoliths with a knife Nimesulide (purity 98)was purchased from Sigma-Aldrich Italy CO

2research grade

48 was purchased from SON (Italy) All products were usedas received

22 Methods Samples of the loaded SA were observed byField Emission Scanning Electron Microscopy (FE-SEM)(LEO 420 USA) operating at 5 kV Crushed fragments of the

sample were dispersed on a carbon tab previously stuck toan aluminium stub and coated with gold palladium (layerthickness 250 A) using a sputter coater (mod 108A AgarScientific UK) Several FE-SEM images from different partsof the sample were taken for each run to verify the powderuniformity

Drug dissolution profiles were obtained with a UnitedStates Pharmacopeial Convention (USP) apparatus 2 consist-ing of Varian 7025 paddle dissolution tester (Varian AgilentTechnologies Italia spa Italy) All studieswere run accordingto the USP 25 paddlemethod 150 rpm 900mL of dissolutionmedium 119879 = 372 plusmn 01∘C and sink conditions (119888 lt 02 cs)The adsorbed SA monoliths were coarsely crushed in a mor-tar and suspended in water Then the aqueous solution wascontinuously pumped to a flow cell in a spectrophotometerand absorbances were recorded at 396 nm The compositionof the dissolution medium was 02M KH

2PO402M NaOH

(ph 74) according to USP 25 plus 05 wv of Tween 80

3 Apparatus

The laboratory plant is described in Figure 1 It is made by316 stainless steel tested for a maximum pressure of 30MPaat 200∘C It mainly consists of two feed lines used to deliverthe CO

2and the liquid solution and three main vessels

mixer adsorption column and separator CO2 stored in a

vessel is delivered to the mixer by a volumetric pump (P1)(Milroyal tipo MD140G6M35J) through a one-way valve(V1015840-1) and onoff valve (V4) The head of the pump is cooledby a thermostatic bath (C) to avoid cavitation of CO

2 The

liquid solution is delivered by a membrane pump (P2) (LewaGermany type LDB) from a graduated cylinder

The mixer is a stainless steel autoclave (NWA GmbHGermany) having an internal volume of 100mL closed onthe bottom and on the top with two finger tight clamps Thetop cap holds three 18 inch ports Mixing is provided by animpeller mounted on the top cap and driven by a variablevelocity electric motor The autoclave is heated by thin bandheaters (H) (Watlow USA mod STB4E3A9) whose thermalcontrol is guaranteed by a PID controller (Watlow USA)The temperature inside the cylinder is measured by a K-type thermocouple with an accuracy of plusmn01∘C Pressure ismeasured by a digital gaugemanometer (Parker USA)Mixerwas designed to provide a contacting volume and a residencetime sufficient to allow the dissolution of SC-CO

2in the

liquid solution up to the saturation conditionsThe adsorption column is a 316 SS cylindrical vessel

with an internal volume of 50 cm3 It is packed with a silicaaerogel bedThe pressure inside the column is maintained bya micrometric valve MV2 heated by electric heaters to avoidclocking during CO

2expansion From the exit of the column

the gaseous flow of CO2and solvent is sent to a gravimetric

gasliquid separator that is a Pyrex element properlydesigned for the separation of the solvent from the gasstream At the inlet port of the separator an impact surfaceis provided to improve separation The liquid is collected atthe bottom of the cylinder where a probe connected to anUV spectrophotometer allows the continuous measurementof the liquid composition The separator has been designed

International Journal of Chemical Engineering 3

SolV-2 V-3 TT TC

TC

TT

TC

PI

P-2

C

H

Vessel

Column

F

Separator FE

TT

TC

FV998400-1 V-4V-1

P-1

SV-1

TW-1

MV-1

MV-2

CO2

V-5

Figure 1 Continuous plant for the adsorption of drugs from supercritical carbon dioxide solutions P-1 P-2 pumps C cooling bath V1015840-1one way valve V-1 V-2 V-3 V-4 V-5 onoff valve TW-1 three-way valve SV-1 security valve H heater F filter MV-1 MV-2 micrometricvalves FE rotameter

to condense ethanol At the exit of the separator a rotameter(FE) is used to measure CO

2flow rate

The design of the separator has been based on themethodproposed by Treybal [14] The input data were liquid densitygas density at given temperature and their flow rates Thedesign procedure has been the following (1) the limitingvelocity is calculated on the basis of the ratio between thedensity of the gas and the liquid (2) the surface of the sepa-rator is calculated from the limit velocity and the volumetricflow rate of the gas (3) a tentative residence time is assumedand the volume of the separator is calculated

4 Results and Discussion

Supercritical adsorption has been carried out in a continuousmode until saturation of the SA bed is reached SC-CO

2

and a liquid solution (ethanol + nimesulide) after mixing arecontinuously delivered to the high pressure adsorption col-umn

Because the phase behavior of the ternary systemCO2EtOHNime is not available our analysis starts from the

binary systemCO2EtOHThemiscibility curve of the binary

system CO2EtOH is shown in Liparoti et al [15] It is thus

assumed that the effect of nimesulide on the phase behavioris negligible This assumption is reasonable considering thelow concentration of nimesulide (lt025wt) The tempera-ture and pressure conditions (40∘C and 10MPa) have beenselected considering the following factors (a) thermolabilityof the drug (b) formation of a single fluid phase betweenCO2ethanolnimesulide verified by direct visual observation

of the system behavior in a high pressure view cell It wasverified that at the selected operating conditions nimesulidedoes not precipitate from fluid phase

At this condition of temperature and pressure the effectof the weight ratio CO

2EtOH (119877) on the drug loading has

been studied Experiments have been carried out using SAbed with a 119871119863 of 94 and pumping 150mL of EtOH solution

Table 1 Adsorption data of nimesulide on silica aerogel at differentvalues of the CO2EtOH weight ratio (119877)119882nime is the mass fractionof nimesulide in the solution time is the duration of the experimentuntil bed saturation is reached andEff is the efficiency of adsorption

119877 XCO2 119882nime Loading Time Eff

72 088 0000047 048 94 92634 078 0000856 10 75 93315 061 00015 28 50 96109 048 000197 54 60 92306 038 000245 89 37 948

with nimesulide concentration of 3mgmL All the operatingpoints comprised between 038 and 088 CO

2mole fraction

fall in the one-phase region of the phase diagram In Table 1the obtained drug loadings are reported

The variation of nimesulide loading on SA with respectto the concentration of nimesulide in the fluid solution isreported in Figure 2 Because each experiment has beencarried out for a time corresponding to the saturation of thebed loading represents the maximum quantity of nimesulidethat can be absorbed on SA at the given conditions As aconsequence the curve of Figure 2 represents the absorptionisotherm of nimesulide on SA at 40∘C

As expected the loading of nimesulide on SA increaseswith increasing concentration of nimesulide in the fluidphase The maximum loading obtained is 885wt corre-sponding to 2277mg of nimesulide adsorbed in the bedBrunauer et al [16] classified the isotherms that are convexupward throughout (type I) as ldquofavorablerdquo to uptake of solutewhereas the ones that are concave upward throughout (typeIII) as ldquounfavorablerdquo to uptake of solute According to thisclassification the isotherm obtained at 40∘C is favorable

These data must be compared with the loading of nime-sulide on SA reported by Caputo et al [12] obtained usingpure CO

2as solvent At 40∘C the maximum loading was


10

8

6

4

2

000005 0001 00015 0002 00025 0003

Wnime (gnimegtot)

Load

ing

(wt

)

0

Figure 2 Adsorption isotherm for nimesulide on silica aerogel at40∘C10MPa

merely 14 six times lower than that obtained using EtOHascosolvent Moreover adsorption with pure CO

2was carried

out at a much higher pressure (225MPa) to increase the sol-ubility of nimesulide

FromTable 1 it is clear that an increase of ethanol fractionincreases the nimesulide loading This result is due to twoconcomitant effects (a) increase of the concentration ofnimesulide in the fluid phase (b) the competitive adsorptionof CO

2on SA is reduced and more adsorption sites are avail-

able for nimesulide molecules

41 Breakthrough Curve Themost important criterion in thedesign of fixed-bed adsorption systems is the prediction ofcolumn breakthrough curve which determines the operatinglife of the bed and regeneration time When the fluid phasestarts flowing in to the bed the top of the adsorbent incontact with the gas stream quickly adsorbs the solute duringfirst contact The gas stream leaving the bed is practicallyfree from the solute As the volume of fluid getting fromthe bed increases an adsorption zone of mass transfer getsdefined In this zone adsorption is complete and it movesdownwards through the bed in relation to time until thebreakthrough occurs When this zone reaches the end of thebed the solute cannot be adsorbed any longer This momentis called ldquobreakpointrdquo The plot obtained after this point givesthe concentration history and is called breakthrough curveWhen the mass transfer zone leaves the bed the bed iscompletely saturated adsorption does not occur and theoutlet stream has the same concentration as one enters

The breakthrough curve for the adsorption of nimesulideon SA at 40∘C and 10MPa is shown in Figure 3 This figureshows the relative effluent concentration against the elutiontime The general pattern of the breakthrough curve was asexpectedThe effluent concentration first increased graduallyand then increased sharply before reaching the value of theinlet concentration

Relat

ive c

once

ntra

tion

1

08

06

04

02

0

0 10 20 30 40 50 60Time (min)

Figure 3 Breakthrough curve for adsorption of nimesulide on silicaaerogel bed from a stream of CO

2and ethanol at 40∘C flow rate =

689mLmin 119883CO2 = 0378 1198620nime = 000174mgmL bed 119871119863 =97

The starting point of the curve is shifted of 15min Thistime corresponds to the dead time of the process due toresidence time of the fluid phase in themixer After 35min theconcentration of nimesulide in the effluent stream starts toincrease significantly (0114mgmL) This point correspond-ing to 10 of inlet concentration can be assumed as break-point Indeed after this time the concentration increasedsharply and reached a value of 50 of the inlet concentrationafter only 3minutes 38min represents the apparent half-timeof the bed Taking into account the dead time of the plant thereal half-time is 23 minutes

42 Mass Balance In the transition regime all the solute fedto the column is used to saturate the bed So the mass balancecan be written as

IN = ACC (1)

with

IN = 1198761198620(119905lowastminus 1199050)

ACC = (119882satminus1198820) 120588bed119878119871

(2)

where 119876 is the volumetric flow rate of the fluid phase(mLmin) 119862

0is the concentration of adsorbate in the fluid

phase (gmL) 119905lowast is the ideal half-time 1199050is the mixing time

119882sat is the saturation concentration of adsorbate in the solid

phase (mgadsmgsol)1198820 is the concentration of the adsorbatein the solid phase at time 119905

0 120588bed is the density of the bed

(gcm3) and 119878 and 119871 are the cross-section and the length ofthe bed respectively

The mass balance is thus

1198761198620(119905lowastminus 1199050) = (119882

satminus1198820) 120588bed119878119871 (3)


(a) (b)

(c) (d)

Figure 4 FE-SEM photographs of (a) not treated SA and SA samples loaded with different amount of nimesulide (b) 10 wt (c) 54 wt(d) 89 wt

from which

(119905lowastminus 1199050) =(119882

satminus1198820) 120588bed119878119871

1198761198620

(4)

by substituting the following values 119882satminus 1198820= 00885

120588bed = 01 gcm3 119878 = 20096 cm2 119871 = 15 cm 119876 =

689mLmin1198620= 000174 gmL an half time of 3723min is

obtained a very good agreementwith 38min obtained experi-mentally

43 Adsorption Efficiency The efficiency of the adsorption isone of the main parameters of the process It is an expressionof the quantity of drug adsorbed with respect to the drug fedto the column

Eff =nimeadsnimefed

times 100 (5)

with

nimefed = 1198620 times 119876 times (119905lowastminus 1199050) (6)

by substituting the following values related to experiment at119877 = 06 (see Table 1) 119876 = 689mLmin 119862

0= 174mgmL

119905lowastminus 1199050= 20min a value of 240mg of nimesulide is obtained

Thus the efficiency is

Eff = 2277240= 948 (7)

Very similar values were obtained for other experiments

44 Characterization of Silica Aerogel after Adsorption Silicaaerogel samples were analyzed by FE-SEM to observe themorphology of thematerial before and after loading FE-SEMimages taken at the same magnification (60K magnification)for samples obtained at 1 54 and 89 wt are reported inFigure 4 Also an FE-SEM image of SA before loading isreported

FE-SEM images reveal that all samples have the samemorphology and no nimesulide crystals were formed on theSA surface also at the higher loading The presence of nime-sulide within SA matrix is clearly revealed by Energy Disper-sive X-ray spectroscopy (EDX) spectrum In Figure 5 EDXof SA sample adsorbed at 54 wt is shown The spectrumcontains Si peak characteristic of the aerogel and S peakcharacteristic of nimesulide Therefore we can conclude thatthe drug is adsorbed on the interior of the pores of SA atmolecular level

We studied also the dissolution rate of the drug in vitroSolution of phosphate buffer at pH = 74 was chosen asdissolution medium following the recommendation of USPharmacopeia The dissolution profile of the drug from thepowdered loaded aerogel was compared with that of the purecrystalline drug Release kinetics are shown in Figure 6 Thedissolution of nimesulide from loaded aerogel is much fasterthan dissolution of crystalline nimesulide Around 80 ofnimesulide dissolves from the aerogel within 6 minuteswhereas dissolving 80 of the crystalline drug takes about90minThus the use of hydrophilic aerogels as a carrier pro-motes fast release of the drug This effect can be explained byboth an increase of specific surface area of the drug adsorbed


0 1 2 3 4 5 6 7 8 9 10

C

Fe

O

Cr

Si

S

Cr

Cr

Fe Fe

Figure 5 EDX spectrum of nimesulidesilica aerogel

100

80

60

40

20

00 50 100 150 200

Times (min)

Nim

esul

ide r

eleas

ed (

)

Not treated SASAnime 91wt

Figure 6 Release kinetics of nimesulide in buffer phosphate at pH =74

on the aerogel and its noncrystalline structure in this stateIn the case of the crystalline drug even with a very smallparticle size the crystal should be destroyed before the drugcan be actually dissolved If the drug is adsorbed on theaerogel this step is eliminated and the dissolution process isaccelerated Another important effect is the partial collapseof aerogel structure in water Hydrophilic aerogels are rapidlywetted with water so the drug molecules are surroundedwith water allowing a fast dissolution of drugs [8]

5 Conclusions

In this study it was demonstrated that the supercriticalfluid adsorption is an effective way to incorporate low watersoluble drugs into a microporous silica aerogel

The use of a fixed bed adsorption column fed with a sup-ercritical CO

2solution with ethanol cosolvent allows to

obtain a pure drug delivery system at high drug contentIndeed it was possible to prepare SA samples containingup to 9wt of nimesulide Moreover the process is highly

efficient in terms of quantity of drug adsorbed with respectto the drug fed to the column (gt94) With respect to con-ventional techniques that use liquid as eluent SC-CO

2offer

the advantage to preserve the 3D porous structure of theaerogel Indeed low viscosity and high diffusivity of SC-CO

2

(or SC-mixtures) coupled with zero surface tension allow therapid permeation and diffusion into aerogel micropores butalso avoid the pore collapse of SA that occurs using organicliquids due to capillary stresses caused by the liquid-vapourmenisci within pores

The SAnimesulide composite has an enhanced dissolu-tion rate that can be explained by both the increase in thespecific surface area of the adsorbed drug and its noncrystal-line structure in the formulation

One limitation of the proposed process is related to thehigh cost associatedwith high-pressure plantwhen comparedto wet processes at atmospheric pressure However resultsencourage the development of industrial application of theproposed process

References

[1] S Pinnamaneni N G Das and S K Das ldquoFormulationapproaches for orally administered poorly soluble drugsrdquo Phar-mazie vol 57 no 5 pp 291ndash300 2002

[2] P York U B Kompella and B Y Shekunov Supercritical FluidTechnology for Drug Development Marcel Dekker New YorkNY USA 2004

[3] E Reverchon G Caputo S Correra and P Cesti ldquoSynthesisof titanium hydroxide nanoparticles in supercritical carbondioxide on the pilot scalerdquo Journal of Supercritical Fluids vol26 no 3 pp 253ndash261 2003

[4] G Caputo S Liparoti R Adami and E Reverchon ldquoUse ofsupercritical CO

2and N

2as dissolved gases for the atomization

of ethanol and waterrdquo Industrial amp Engineering ChemistryResearch vol 51 no 36 pp 11803ndash11808 2012

[5] G Caputo R Adami and E Reverchon ldquoAnalysis of dissolved-gas atomization supercritical CO

2dissolved in waterrdquo Indus-

trial amp Engineering Chemistry Research vol 49 no 19 pp 9454ndash9461 2010

[6] M A Rodrigues J Li L Padrela A Almeida H A Matosand E G de Azevedo ldquoAnti-solvent effect in the production oflysozyme nanoparticles by supercritical fluid-assisted atomiza-tion processesrdquo Journal of Supercritical Fluids vol 48 no 3 pp253ndash260 2009

[7] AMHilleryAW Lloyd and J SwarbrickDelivery undTarget-ing Taylor amp Francis London UK 2001

[8] I Smirnova S Suttiruengwong and W Arlt ldquoFeasibility studyof hydrophilic and hydrophobic silica aerogels as drug deliverysystemsrdquo Journal of Non-Crystalline Solids vol 350 pp 54ndash602004

[9] I Smirnova S Suttiruengwong M Seiler and W Arlt ldquoDisso-lution rate enhancement by adsorption of poorly soluble drugson hydrophilic silica aerogelsrdquo Pharmaceutical Developmentand Technology vol 9 no 4 pp 443ndash452 2005

[10] U Guenther I Smirnova and R H H Neubert ldquoHydrophilicsilica aerogels as dermal drug delivery systemsmdashdithranol as amodel drugrdquoEuropean Journal of Pharmaceutics and Biopharm-aceutics vol 69 no 3 pp 935ndash942 2008

[11] I Smirnova J Mamic and W Arlt ldquoAdsorption of drugs onsilica aerogelsrdquo Langmuir vol 19 no 20 pp 8521ndash8525 2003


[12] G Caputo M Scognamiglio and I De Marco ldquoNimesulideadsorbed on silica aerogel using supercritical carbon dioxiderdquoChemical Engineering Research and Design vol 90 no 8 pp1082ndash1089 2012

[13] G Caputo I DeMarco and E Reverchon ldquoSilica aerogel-metalcomposites produced by supercritical adsorptionrdquo Journal ofSupercritical Fluids vol 54 no 2 pp 243ndash249 2010

[14] R E Treybal Mass-Transfer Operations McGraw-Hill NewYork NY USA 3rd edition 1980

[15] S Liparoti R Adami G Caputo and E Reverchon ldquoSupercri-tical assisted atomization polyvynilpyrrolidone as carrier fordrugs with poor solubility in waterrdquo Journal of Chemistry vol2013 Article ID 801069 5 pages 2013

[16] S Brunauer L S Deming W E Deming and E Teller ldquoOn atheory of the van der Waals adsorption of gasesrdquo Journal of TheAmerican Chemical Society vol 62 no 7 pp 1723ndash1732 1940

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unique combination of gas-like and liquid-like properties thatcan be adjusted by small changes in temperature or pressure

Low viscosity and high diffusivity of SC-CO2allow a

rapid equilibration and micropore penetration of the fluidphase within the matrix SCFs also have zero surface tensionthat not only facilitates the rapid permeation and diffusioninto porous substrates but also avoids the pore collapse ofSA that occurs using organic liquids due to capillary stressescaused by the liquid-vapour menisci within pores

Until now SC adsorption within SA has been studiedusing simple batch vessels in which SA and active moleculesare loaded and equilibrated until equilibrium is reached [8 911 12] Because pure SC-CO

2is used as solvent themaximum

amount of active compound that can be loaded on SA is lim-ited by its solubility in SC-CO

2at given condition of temper-

ature and pressure One way to increase the solubility is theincrease of pressure of SC-CO

2as shown in a previous work

in the case of nimesulide [12] an alternative is the use of acompatible and benign cosolvent which increases the solubil-ity of the active compound in the fluid phaseThe fluid phasecomposed by SC-CO

2and cosolvent must satisfy the condi-

tion that the mixture is supercritical at the operating pressureand temperature Indeed if a liquid phase is formed the aero-gel structure could be damaged and polluted by the cosolvent

In this work the adsorption of a model drug on SAwas studied using a new experimental apparatus properlydesigned for this purpose The best way to deal with SC-fluidmixture is to use a continuous process in which the fluidphase is continuously pumped in an adsorption column con-taining the SA matrix Because a fundamental stage ofthe process is the formation of the ternary mixture SC-CO2organic solventactive compound a mixing stage has

been provided that allows a fast and effective solubilizationof the components

The new experimental plant has been tested with nime-sulide as active compound and ethanol as solvent Nimesulidehas been chosen for comparison purposes because in a previ-ous study [12] its adsorption from pure SC-CO

2and using a

batch mode apparatus was studied Adsorption isotherm andbreakthrough curve of the column at 40∘C were determinedLoaded SAs were characterized by in vitro dissolution test tostudy the properties of the composite material and its poten-tiality for applications

2 Materials and Methods

21 Materials Hydrophilic silica aerogel (SA) in form ofmonolithic blockswas purchased fromMerketech Int (USA)The nominal density is 01 gcm3 the surface area is 800m2gand the mean pore size is about 20 nm Deposition experi-ments were performed using cubic blocks of 1 cm obtained bycutting SA monoliths with a knife Nimesulide (purity 98)was purchased from Sigma-Aldrich Italy CO

2research grade

48 was purchased from SON (Italy) All products were usedas received

22 Methods Samples of the loaded SA were observed byField Emission Scanning Electron Microscopy (FE-SEM)(LEO 420 USA) operating at 5 kV Crushed fragments of the

sample were dispersed on a carbon tab previously stuck toan aluminium stub and coated with gold palladium (layerthickness 250 A) using a sputter coater (mod 108A AgarScientific UK) Several FE-SEM images from different partsof the sample were taken for each run to verify the powderuniformity

Drug dissolution profiles were obtained with a UnitedStates Pharmacopeial Convention (USP) apparatus 2 consist-ing of Varian 7025 paddle dissolution tester (Varian AgilentTechnologies Italia spa Italy) All studieswere run accordingto the USP 25 paddlemethod 150 rpm 900mL of dissolutionmedium 119879 = 372 plusmn 01∘C and sink conditions (119888 lt 02 cs)The adsorbed SA monoliths were coarsely crushed in a mor-tar and suspended in water Then the aqueous solution wascontinuously pumped to a flow cell in a spectrophotometerand absorbances were recorded at 396 nm The compositionof the dissolution medium was 02M KH

2PO402M NaOH

(ph 74) according to USP 25 plus 05 wv of Tween 80

3 Apparatus

The laboratory plant is described in Figure 1 It is made by316 stainless steel tested for a maximum pressure of 30MPaat 200∘C It mainly consists of two feed lines used to deliverthe CO

2and the liquid solution and three main vessels

mixer adsorption column and separator CO2 stored in a

vessel is delivered to the mixer by a volumetric pump (P1)(Milroyal tipo MD140G6M35J) through a one-way valve(V1015840-1) and onoff valve (V4) The head of the pump is cooledby a thermostatic bath (C) to avoid cavitation of CO

2 The

liquid solution is delivered by a membrane pump (P2) (LewaGermany type LDB) from a graduated cylinder

The mixer is a stainless steel autoclave (NWA GmbHGermany) having an internal volume of 100mL closed onthe bottom and on the top with two finger tight clamps Thetop cap holds three 18 inch ports Mixing is provided by animpeller mounted on the top cap and driven by a variablevelocity electric motor The autoclave is heated by thin bandheaters (H) (Watlow USA mod STB4E3A9) whose thermalcontrol is guaranteed by a PID controller (Watlow USA)The temperature inside the cylinder is measured by a K-type thermocouple with an accuracy of plusmn01∘C Pressure ismeasured by a digital gaugemanometer (Parker USA)Mixerwas designed to provide a contacting volume and a residencetime sufficient to allow the dissolution of SC-CO

2in the

liquid solution up to the saturation conditionsThe adsorption column is a 316 SS cylindrical vessel

with an internal volume of 50 cm3 It is packed with a silicaaerogel bedThe pressure inside the column is maintained bya micrometric valve MV2 heated by electric heaters to avoidclocking during CO

2expansion From the exit of the column

the gaseous flow of CO2and solvent is sent to a gravimetric

gasliquid separator that is a Pyrex element properlydesigned for the separation of the solvent from the gasstream At the inlet port of the separator an impact surfaceis provided to improve separation The liquid is collected atthe bottom of the cylinder where a probe connected to anUV spectrophotometer allows the continuous measurementof the liquid composition The separator has been designed


SolV-2 V-3 TT TC

TC

TT

TC

PI

P-2

C

H

Vessel

Column

F

Separator FE

TT

TC

FV998400-1 V-4V-1

P-1

SV-1

TW-1

MV-1

MV-2

CO2

V-5



2flow rate




2












72 088 0000047 048 94 92634 078 0000856 10 75 93315 061 00015 28 50 96109 048 000197 54 60 92306 038 000245 89 37 948


2mole fraction







10

8

6

4

2

000005 0001 00015 0002 00025 0003

Wnime (gnimegtot)

Load

ing

(wt

)

0



2was carried







Relat

ive c

once

ntra

tion

1

08

06

04

02

0

0 10 20 30 40 50 60Time (min)






IN = ACC (1)

with

IN = 1198761198620(119905lowastminus 1199050)

ACC = (119882satminus1198820) 120588bed119878119871

(2)









1198761198620(119905lowastminus 1199050) = (119882

satminus1198820) 120588bed119878119871 (3)


(a) (b)

(c) (d)


from which

(119905lowastminus 1199050) =(119882

satminus1198820) 120588bed119878119871

1198761198620

(4)


120588bed = 01 gcm3 119878 = 20096 cm2 119871 = 15 cm 119876 =




Eff =nimeadsnimefed

times 100 (5)

with



0= 174mgmL



Eff = 2277240= 948 (7)






0 1 2 3 4 5 6 7 8 9 10

C

Fe

O

Cr

Si

S

Cr

Cr

Fe Fe


100

80

60

40

20

00 50 100 150 200

Times (min)

Nim

esul

ide r

eleas

ed (

)




5 Conclusions






2offer


2




References





2and N




















RoboticsJournal of





Journal of



RotatingMachinery





VLSI Design



Shock and Vibration







Journal of



Volume 2014


SensorsJournal of





Propagation










SolV-2 V-3 TT TC

TC

TT

TC

PI

P-2

C

H

Vessel

Column

F

Separator FE

TT

TC

FV998400-1 V-4V-1

P-1

SV-1

TW-1

MV-1

MV-2

CO2

V-5



2flow rate




2












72 088 0000047 048 94 92634 078 0000856 10 75 93315 061 00015 28 50 96109 048 000197 54 60 92306 038 000245 89 37 948


2mole fraction







10

8

6

4

2

000005 0001 00015 0002 00025 0003

Wnime (gnimegtot)

Load

ing

(wt

)

0



2was carried







Relat

ive c

once

ntra

tion

1

08

06

04

02

0

0 10 20 30 40 50 60Time (min)






IN = ACC (1)

with

IN = 1198761198620(119905lowastminus 1199050)

ACC = (119882satminus1198820) 120588bed119878119871

(2)









1198761198620(119905lowastminus 1199050) = (119882

satminus1198820) 120588bed119878119871 (3)


(a) (b)

(c) (d)


from which

(119905lowastminus 1199050) =(119882

satminus1198820) 120588bed119878119871

1198761198620

(4)


120588bed = 01 gcm3 119878 = 20096 cm2 119871 = 15 cm 119876 =




Eff =nimeadsnimefed

times 100 (5)

with



0= 174mgmL



Eff = 2277240= 948 (7)






0 1 2 3 4 5 6 7 8 9 10

C

Fe

O

Cr

Si

S

Cr

Cr

Fe Fe


100

80

60

40

20

00 50 100 150 200

Times (min)

Nim

esul

ide r

eleas

ed (

)




5 Conclusions






2offer


2




References





2and N




















RoboticsJournal of





Journal of



RotatingMachinery





VLSI Design



Shock and Vibration







Journal of



Volume 2014


SensorsJournal of





Propagation










10

8

6

4

2

000005 0001 00015 0002 00025 0003

Wnime (gnimegtot)

Load

ing

(wt

)

0



2was carried







Relat

ive c

once

ntra

tion

1

08

06

04

02

0

0 10 20 30 40 50 60Time (min)






IN = ACC (1)

with

IN = 1198761198620(119905lowastminus 1199050)

ACC = (119882satminus1198820) 120588bed119878119871

(2)









1198761198620(119905lowastminus 1199050) = (119882

satminus1198820) 120588bed119878119871 (3)


(a) (b)

(c) (d)


from which

(119905lowastminus 1199050) =(119882

satminus1198820) 120588bed119878119871

1198761198620

(4)


120588bed = 01 gcm3 119878 = 20096 cm2 119871 = 15 cm 119876 =




Eff =nimeadsnimefed

times 100 (5)

with



0= 174mgmL



Eff = 2277240= 948 (7)






0 1 2 3 4 5 6 7 8 9 10

C

Fe

O

Cr

Si

S

Cr

Cr

Fe Fe


100

80

60

40

20

00 50 100 150 200

Times (min)

Nim

esul

ide r

eleas

ed (

)




5 Conclusions






2offer


2




References





2and N




















RoboticsJournal of





Journal of



RotatingMachinery





VLSI Design



Shock and Vibration







Journal of



Volume 2014


SensorsJournal of





Propagation










(a) (b)

(c) (d)


from which

(119905lowastminus 1199050) =(119882

satminus1198820) 120588bed119878119871

1198761198620

(4)


120588bed = 01 gcm3 119878 = 20096 cm2 119871 = 15 cm 119876 =




Eff =nimeadsnimefed

times 100 (5)

with



0= 174mgmL



Eff = 2277240= 948 (7)






0 1 2 3 4 5 6 7 8 9 10

C

Fe

O

Cr

Si

S

Cr

Cr

Fe Fe


100

80

60

40

20

00 50 100 150 200

Times (min)

Nim

esul

ide r

eleas

ed (

)




5 Conclusions






2offer


2




References





2and N




















RoboticsJournal of





Journal of



RotatingMachinery





VLSI Design



Shock and Vibration







Journal of



Volume 2014


SensorsJournal of





Propagation










0 1 2 3 4 5 6 7 8 9 10

C

Fe

O

Cr

Si

S

Cr

Cr

Fe Fe


100

80

60

40

20

00 50 100 150 200

Times (min)

Nim

esul

ide r

eleas

ed (

)




5 Conclusions






2offer


2




References





2and N




















RoboticsJournal of





Journal of



RotatingMachinery





VLSI Design



Shock and Vibration







Journal of



Volume 2014


SensorsJournal of





Propagation

















RoboticsJournal of





Journal of



RotatingMachinery





VLSI Design



Shock and Vibration







Journal of



Volume 2014


SensorsJournal of





Propagation











RoboticsJournal of





Journal of



RotatingMachinery





VLSI Design



Shock and Vibration







Journal of



Volume 2014


SensorsJournal of





Propagation









Documents

Research Article Fixed Bed Adsorption of Drugs on …downloads.hindawi.com/journals/ijce/2013/752719.pdfInternationalJournalof Chemical Engineering Sol V-2 V-3 TT TC TC TT TC PI P-2