e u r o p e a n j o u r n a l o f p h a r m a c e u t i c a l s c i e n c e s 3 3 ( 2 0 0 8 ) 306–312

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Drug loading into �-cyclodextrin granules using asupercritical fluid process for improved drug dissolution

Khaled Husseina, Michael Turkb, Martin A. Wahla,∗

a Pharmazeutische Technologie, Eberhard-Karls-Universitat Tubingen, Auf der Morgenstelle 8, D-72076 Tubingen, Germanyb Institut fur Technische Thermodynamik und Kaltetechnik, Universitat Karlsruhe, Engler-Bunte-Ring 21, D-76131 Karlsruhe, Germany

a r t i c l e i n f o

Article history:

Received 30 May 2007

Received in revised form

12 November 2007

Accepted 3 January 2008

Published on line 11 January 2008

Keywords:

Controlled particle deposition

Supercritical fluid

�-Cyclodextrin granules

a b s t r a c t

To improve dissolution properties of drugs, a supercritical fluid (SCF) technique was used to

load these drugs into a solid carrier. In this study, granules based on �-cyclodextrin (�CD)

were applied as a carrier for poor water-soluble drug and loaded with a model drug (ibupro-

fen) using two different procedures: controlled particle deposition (CPD), SCF process and

solution immersion (SI) as a conventional method for comparison.

Using the CPD technique, 17.42 ± 2.06 wt.% (n = 3) ibuprofen was loaded into �CD-granules,

in contrast to only 3.8 ± 0.15 wt.% (n = 3) in the SI-product. The drug loading was confirmed as

well by reduction of the BET surface area for the CPD-product (1.134 ± 0.07 m2/g) compared to

the unloaded-granules (1.533 ± 0.031 m2/g). Such a reduction was not seen in the SI-product

(1.407 ± 0.048 m2/g). The appearance of an endothermic melting peak at 77 ◦C and X-ray

patterns representing ibuprofen in drug-loaded granules can be attributed to the amount

Ibuprofen

Enhanced dissolution

of ibuprofen loaded in its crystalline form. A significant increase in drug dissolution was

achieved by either drug-loading procedures compared to the unprocessed ibuprofen.

In this study, the CPD technique, a supercritical fluid process avoiding the use of toxic or

organic solvents was successfully applied to load drug into solid carriers, thereby improving

the water-solubility of the drug.

face and a non-polar cavity interior. CDs can interact with

1. Introduction

An increasing number of poorly water-soluble drug candi-dates in pharmaceutical sciences provide challenges for theoral formulation since their water-solubility and rate of disso-lution are a limiting step for their absorption and biologicalavailability (Horter and Dressman, 2001). Several strategiesfor enhancing water-solubility and dissolution rate of thesedrugs have been attempted; including particle size reductionto the nanoscale (Turk et al., 2002), preparation of solid dis-

persions (Abu and Serajuddin, 1999) and drug loading in solidporous carriers (Vallet-Regi et al., 2001; Charnay et al., 2004;Andersson et al., 2004; Salonen et al., 2005a,b). Cyclodextrin

∗ Corresponding author. Tel.: +49 7071 2974552; fax: +49 7071 295531.E-mail address: Martin.Wahl@uni-tuebingen.de (M.A. Wahl).

0928-0987/$ – see front matter © 2008 Elsevier B.V. All rights reserved.doi:10.1016/j.ejps.2008.01.003

© 2008 Elsevier B.V. All rights reserved.

and their derivatives, however, have been successfully appliedin the pharmaceutical industry as solubility enhancer becauseof the ability to form inclusion complexes with poorly water-soluble drugs (Fromming and Szejtli, 1994; Loftsson et al.,2004).

Cyclodextrins (CDs) are cyclic oligosaccharides consist-ing of six, seven or eight glucose molecules. The molecularstructure of these glucose derivatives, which approximates atruncated cone or torus, generates a hydrophilic exterior sur-

appropriately sized molecules to result in the formation ofinclusion complexes (Fromming and Szejtli, 1994; Loftsson etal., 2004). These complexes show improved dissolution prop-

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e u r o p e a n j o u r n a l o f p h a r m a c e u

rties compared to the pure drug or simple physical mixingf drug and CD, as reported previously (Charoenchaitrakool etl., 2002; Hussein et al., 2007; Al-Marzuoqi et al., 2007).

Several methods have been developed for preparing solidomplexes, including powder mixing, kneading, precipitation,reeze drying (Fromming and Szejtli, 1994; Cabral-Marques,994) and recently supercritical fluid methods (Van Hees et al.,999; Charoenchaitrakool et al., 2002; Bandi et al., 2004; Turkt al., 2007; Hussein et al., 2007; Al-Marzuoqi et al., 2007). Mostf these studies applied this complex in powder or aggregateorm and only few works reported the use of cyclodextrin inosage forms for oral application like tablets, capsules or gran-les. A preparation of a CD complex as granules containingrugs was reported by Ghorab and Adeyeye (2001). The authors

n this study prepared ibuprofen-�-cyclodextrin granules byixing the drug and �-cyclodextrin (�CD) in a conventionalet granulation process. In 1998, Gazzaniga et al. investigated

he use of �CD as a pelletization agent with microcrystallineellulose (MCC) in an extrusion/spherounization process.he addition of MCC conferred mechanical strength to thebtained pellets and reduced the amount of �CD in the finalormulation. In a related work, Gainotti et al. (2004) producedrug-free pellets of �CD and MCC using a high-shear mixernd loaded the obtained pellets with ibuprofen using powdernd solution layering processes.

It was the aim of our study to investigate the possibility tooad preformed granules with a drug by means of supercrit-cal fluid technology. This process is a single-step procedurevoiding the use of probably toxic organic solvents and therebyoxic residues. In contrast to the work of others, our pro-ess uses a supercritical solution of the drug (ibuprofen incCO2) for loading of the drug-free granules containing �CD,CC and polyvinylpyrrolidon (PVP). These granules were pre-

ared by a wet granulation process and PVP was added to theormulation due to the synergistic effect to �CD in increas-ng the water-solubility of drugs (Loftsson, 1998; Valero et al.,003; Cirri et al., 2004). A defined fraction with a size of about–2 mm of drug-free granules was chosen to be loaded withmodel drug (ibuprofen) either by controlled particle depo-

ition (CPD) as an alternative method for drug loading intoolid carriers, a single-step and toxic-free process, or by theolution immersing (SI) method as conventional method foromparison. The drug-loaded granules were characterised forheir loading yield (UV spectroscopy), crystallinity (differentialcanning calorimetry and X-ray diffraction), the specific sur-ace area (nitrogen adsorption) and morphologically (scanninglectron microscopy). Finally, their dissolution properties wereested at pH 6 using a flow-through cell dissolution apparatus.

. Materials and methods

.1. Materials

buprofen 50 (Knoll Pharmaceuticals, Nottingham, Unitedingdom) was used as a model-drug with limited water-

olubility. �-cyclodextrin (�CD, Cavamax® W7, Wacker Chemieunchen, Germany), polyvinylpyrrolidon (PVP, Kollidon® 25,

ASF, Ludwigshafen, Germany) and microcrystalline cellu-ose (MCC, Avicel® PH 102, FMC Biopolymer, Cork, Ireland)

l s c i e n c e s 3 3 ( 2 0 0 8 ) 306–312 307

were used in the production of drug-free granules. CO2

(M = 44.01 g/mol, Air Liquide, Germany) was chosen as super-critical solvent since it is a non-flammable, inexpensive andnon-toxic solvent. Hanks balanced salt solution (HBSS) (con-taining (g/l): CaCl2 0.14, KCl 0.40, KH2PO4 0.06, MgCl2·6H2O0.10, MgSO4·7H2O 0.10, NaCl 8.00, Na2HPO4·2H2O 0.06, d-glucose 1.00, 0.1 N NaOH solution q.s.) buffered with 5.07 g/lHEPES (pH 7.4) or 2.13 g/l MES (pH 6.0) was used as solventto determine drug content and drug release. All materialsand solvents were of the purest grade available and used asobtained from Merck (Darmstadt, Germany).

2.2. Preparation and evaluation of drug-free granules

The drug-free granules depending on �CD were produced by awet granulation process. Powder mixture (Turbula T2C mixer,15 min, 42 rpm) of �CD (160 g) and MCC (40 g) was kneadedwith 150 ml of PVP-aqueous solution (10 wt.%) using a Z-bladekneader (LK 5, Erweka, Heusenstamm, Germany). The wetmass was forced through a 3.5-mm screen by hand. Theformed granules were dried at 40 ◦C for 20 min and sieved toobtain granules with particle size of 1–2 mm.

The water content in the selected fraction of �CD-granuleswas determined by infrared drying method. A sample (1 g) ofgranules was placed on an IR-balance (Mettler P160 and Met-tler LP12, Mettler Toledo, Giessen, Germany) and dried to aconstant weight. The water content was calculated from themass loss.

The friability was measured according to Gainotti et al.(2004) using an Erweka friability tester (Heusenstamm, Ger-many). The granules friability was calculated from the loss ofmass and expressed as the percentage of the initial mass.

2.3. Loading procedures

The selected fraction (1–2 mm) of the granules was loaded witha model drug (ibuprofen) using the controlled particle deposi-tion method, a new developed, single-step, supercritical fluidprocess avoiding the use of toxic solvents and with solutionimmersing as conventional method for comparison.

2.3.1. Drug loading by supercritical CO2

Drug loading experiments were performed in a high-pressurecell (published previously by Hussein et al. (2007)) based ona static mode at a pressure of 24.7 MPa and a temperatureof 39.5 ◦C using the same technique as previously described(Hussein et al., 2005, 2007; Turk et al., 2004, 2007).

Weighed amounts of ibuprofen (13.0 g) and �CD-granules(8.0 g) were placed into separate cartridges inside the high-pressure cell and placed in a constant temperature waterbath. Prior to the loading experiments, the whole systemwas evacuated for 5 min to remove atmospheric moisture andair. Then, the required amount of liquid CO2 (437.14 ± 3.55 g)was condensed into the high-pressure cell and heated to thedesired temperature. As soon as the desired pressure in thehigh-pressure cell was reached, the exposure time was fixed

to 15.5 h. At the end of the experiments, depressurizationoccurred within 30 s. The same condition was used to investi-gate the effect of scCO2 on the drug-free granules with absenceof the drug.

u t i c

308 e u r o p e a n j o u r n a l o f p h a r m a c e

2.3.2. Drug loading by solution immersingThis method is widely used for drug loading (Vallet-Regi etal., 2001; Charnay et al., 2004; Andersson et al., 2004; Salonenet al., 2005a,b) and based on immersing drug-free carriers inan organic solution of the drug. In this study, n-hexane wasselected as loading solution, since ibuprofen has a good solu-bility in this solvent but the carrier (�CD-granules) has not. Aweighted amount of �CD-granules (1 g) was placed in a metalbasket with sieve form and immersed in 200 ml saturated solu-tion of ibuprofen in n-hexane (54 mg/ml). The basket rotatedwith 50 rpm at room temperature for 2 h. At the end of theloading period, the obtained sample was washed with 10 mln-hexane to remove unbound ibuprofen crystals and dried for24 h at room temperature.

2.4. Characterisation of the drug-loaded granules

2.4.1. Determination of total drug contentThe total amount of the loaded drug was determined usingUV photometry. The drug-loaded granules (100 mg) weredispersed in 10 ml HBSS buffer pH 7.4 and placed in anultrasonic bath for 1 h, the resulted suspension was filteredthrough a 45 �m cellulose nitrate membrane filter (Sartorius,Gottingen, Germany) and measured by a UV–VIS spec-trophotometer (550 S, PerkinElmer, Uberlingen, Germany) at264 nm.

2.4.2. Determination of crystalline drug contentThe fraction of ibuprofen loaded in crystalline form canbe estimated and quantified from the melting peak datausing differential scanning calorimetry (DSC) measurement.This use of the thermal analysis as analytical device todetermine the crystalline drug amount has been reportedpreviously (Mura et al., 2003; Salonen et al., 2005a,b). Thethermal behaviour of the granules before and after the load-ing process was evaluated using a Mettler DSC 820 TA 8000(Mettler Toledo, Giessen, Germany). A sample (5–10 mg perrun) was placed in perforated 40 �l aluminum standard pan,covered with a punched lid. The heating sequences werecarried out within a temperature range from 25 to 150 ◦Cat a heating rate of 5 ◦C/min and purged continuously withnitrogen gas (10 ml/min). The amount of crystalline ibupro-fen in the samples was estimated from the area under themelting peak of ibuprofen in the sample compared to themelting peak area obtained by an ibuprofen standard, asfollows:

ACD = ASample

Aib(1)

where, ACD is the amount of crystalline drug in the sample,ASample is the area under the melting peak of ibuprofen inthe sample, and Aib is the area under the melting peak of astandard amount if ibuprofen.

Integration of the melting peaks was done using STARe

software, version 8.10 (Mettler Toledo, Giessen, Germany).Since the area under the melting peak of the sample dependson the sample amount, the calculated ibuprofen amount wasnormalized by the sample size.

a l s c i e n c e s 3 3 ( 2 0 0 8 ) 306–312

2.4.3. X-ray diffractionX-ray diffraction (XRD) patterns of different samples werecarried out using a G600 Guinier diffractometer (Huber Diffrak-tionstechnik, Rimsting, Germany) with mono-chromaticCuK�1 radiation (l = 1.54056 A). The voltage and current wereat 40 kV and 30 mA. The diffraction patterns were recorded inthe range of 5◦ ≤ 2� ≤ 60◦, with a step size of 0.025◦ and a 5 stime per step.

2.4.4. Specific surface area by gas adsorptionThe specific surface area was determined using nitrogen gasadsorption at a temperature of −196 ◦C based on the Brunauer,Emmett and Teller (BET) method. A quantity of test gran-ules, providing a surface area of at least 1 m2, was accuratelyweighed and analysed using a SA 3100 Beckman Coultersystem (Beckman Coulter, Krefeld, Germany), the outgas tem-perature was 30 ◦C and the outgas time 360 min. The surfacearea was calculated using a SA-VIEWTM software, version 2.12(Beckman Coulter, Krefeld, Germany).

2.4.5. Scanning electron microscopyScanning electron microscopy (SEM) images were obtained byusing a DSM 940 scanning electron microscope (Carl Zeiss,Oberkochen, Germany). The samples were coated with gold,by employing a Sputter Coater (E 5100, Bio-Rad, Munchen,Germany).

2.4.6. Drug release studiesThe dissolution experiments were carried out with a Stricker(1969) flow-through cell dissolution apparatus (Sartorius,Gottingen, Germany). About 25 mg of ibuprofen or an equiv-alent amount of drug-loaded granules was added to thedissolution vessel containing 100 ml HBSS buffer pH 6and rotating at 1.2 rpm and temperature of 37 ◦C. Samplesof 4 ml were collected during 120 min, filtered through amembrane filter (45 �m pore size; Cellulose Nitrate, Sar-torius, Gottingen, Germany) and replaced with an equalvolume of the dissolution fluid, giving a final dissolu-tion volume of 140 ml during a 120 min experiment. Thefiltrates were assayed spectrophotometrically (UV–VIS spec-trophotometer 550 S, PerkinElmer, Uberlingen, Germany)at 264 nm. The dissolution coefficient (Kw) was calcu-lated according to the Weibull equation (Heinrich et al.,1986) in order to describe the kinetic parameter of thecurve. The coefficient corresponds to the time point when63.2% of the drug is dissolved. The dissolution coefficientand the amount of drug (wt.%) released at 120 min wereselected as parameters for evaluating the efficacy of theloaded granules to improve the water-solubility of ibupro-fen.

2.4.7. Statistical analysisThe statistically evaluation of data was analyzed by Stu-dent’s t-Test and multiple comparisons by one-way analysis

of variance (ANOVA) followed by Tukey posterior test for mul-tiple comparisons using GraphPad Prism software, version 4.0for Windows (California, USA, http://www.graphpad.com). Avalue of p < 0.05 was considered significant.

e u r o p e a n j o u r n a l o f p h a r m a c e u t i c a l s c i e n c e s 3 3 ( 2 0 0 8 ) 306–312 309

Table 1 – Physicochemical characterisation parameters of the unprocessed, scCO2 treated and drug-loaded granules(n = 3, values are mean ± S.D.)

Drug-free granules Drug-free granules treatedwith scCO2

CPD-granules SI-granules

Total ibuprofen content (wt.%) – – 17.42 ± 2.06 (A)a 3.8 ± 0.15 (B)a

Crystalline ibuprofen content (wt.%) – – 3.12 ± 1.14 (A)a 0.9 ± 0.4 (B)a

Specific area BET (m2/g) 1.533 ± 0.031 (A)b 1.520 ± 0.164 (A)b 1.134 ± 0.070 (B)b 1.407 ± 0.048 (A)b

3

3

Ta4clg

3

3Tstlb

FgS

Values marked with different letters differ significantly.a t-Test; p < 0.05, n = 3.b ANOVA; p < 0.05; Tukey; n = 3.

. Results

.1. Drug-free granules

he friability of drug-free granules based on �-CD/MCC/PVPs obtained by the wet granulation process was found to be.59 ± 0.76 wt.%. A similar friability was reported earlier withomparable granules produced by high-shear-mixing granu-ation process (Gainotti et al., 2004). The water content of theranules was 15.1 ± 0.47 wt.%.

.2. Drug-loaded granules

.2.1. Degree of drug loadinghe total amount of ibuprofen loaded into granules (Table 1)

hows superior loading yield in the CPD method comparedo the drug adsorbed by solution immersing. A part of theoaded ibuprofen was found in crystalline form, which coulde observed by the appearance of the endothermic melting

ig. 1 – DSC thermograms of pure ibuprofen (A), drug-freeranules (B), drug-free granules treated with scCO2 (C),I-granules (D) and CPD-granules (E).

Fig. 2 – X-ray diffractograms of pure ibuprofen (A),

drug-free granules (B), drug-free granules treated withscCO2 (C), SI-granules (D) and CPD-granules (E).

peak of ibuprofen at about 77 ◦C in the drug-loaded gran-ules (Fig. 1). This amount was quantified by integration ofthe melting peak of ibuprofen; this fraction was higher in theCPD-product (Table 1).

3.2.2. Characterisation of the loaded granulesThe investigation of the thermal behaviour of the pure ibupro-fen by DSC shows an endothermic melting peak at about77 ◦C (Fig. 1A). The drug-free granules (Fig. 1B) exhibit a broadendothermic dehydration peak in the range of 80–120 ◦C, thesame peak can be seen in the drug-free granules treatedwith scCO2 (Fig. 1C) which demonstrates thermal stabilityof �CD-granules in the scCO2 experimental procedure. Theendothermic melting peak at 77 ◦C appears in granules loadedby SI and CPD (Fig. 1D and E) indicating that a part of the

ibuprofen is loaded in crystalline form.

The X-ray diffraction of pure ibuprofen and the unpro-cessed drug-free granules (Fig. 2A and B) exhibited seriesof intense peaks indicative of their crystallinity. Drug-free

310 e u r o p e a n j o u r n a l o f p h a r m a c e u t i c a l s c i e n c e s 3 3 ( 2 0 0 8 ) 306–312

ure

cant improvement in drug dissolution with 92 wt.% dissolvedamount after 2 h was observed, independent of the drug load-ing method.

Table 2 – Dissolution rate coefficient according toWeibull (Kw ± S.D.) and amount of ibuprofen dissolvedafter 120 min (%, ±95% CI)

Product Kw (min−1) Dissolved amount of drug(wt.%) after 120 min

CPD-granules 0.053 ± 0.002 (A) 91.94 ± 0.80 (A)

Fig. 3 – SEM micrograph of drug-free granules (A), p

granules treated with scCO2 (Fig. 2C) show the same intensepatterns as unprocessed granules. The diffractogram of thegranules loaded by the SI method (Fig. 2D) shows patternsof unloaded-granules, but not of crystalline drug. Although,these have been found in the DSC, this fraction (0.9 ± 0.4 wt.%)seems to be too small to be detected in the XRD. Patterns ofibuprofen at 14.02◦, 16.65◦ and 20.29◦ were seen in the CPDmaterial (Fig. 2E) indicating the presence of ibuprofen in itscrystalline state, that agree with DSC results.

A significant reduction in BET-surface area of the CPD-granules compared to unloaded-granules and SI-granules(Table 1) was observed supporting the drug content resultssince the CPD-granules have the highest drug loading.

The investigation of morphological changes by SEM showsthat the structure of �CD-granules (Fig. 3A) did not alter afterthe drug loading in the SI- and CPD-granules (Fig. 3C and D).In addition no needle shaped crystals of drug (Fig. 3B) wereobserved on the granules surface.

3.2.3. Drug release studiesDissolution studies were performed at pH 6 in order to eval-uate the efficacy of the loading processes by improvement

ibuprofen (B), SI-granules (C) and CPD-granules (D).

of the water-solubility of ibuprofen. The unprocessed ibupro-fen shows rather slow dissolution (Fig. 4) in this mediumwith a dissolution rate coefficient (Kw) of 0.02 min−1 and onlyabout 80 wt.% dissolved amount after 2 h (Table 2). A signifi-

SI-granules 0.060 ± 0.002 (A) 92.35 ± 1.37 (A)Ibuprofen 0.020 ± 0.001 (B) 80.89 ± 0.61 (B)

Values marked with different letters differ significantly (ANOVA;p < 0.05; Tukey; n = 3).

e u r o p e a n j o u r n a l o f p h a r m a c e u t i c a

FC3

4

TscpeddrTwtp

aGfbbab

�

sfapoo

cd

r

Pharm. Biopharm. 57 (3), 533–540.

ig. 4 – Dissolution profiles of unprocessed ibuprofen,PD-granules and SI-granules in HBSS buffer pH 6 and7 ◦C, (±95% CI; n = 3).

. Discussion

he drug loading into solid carriers to improve their water-olubility is a common process in drug delivery technology. Inontrast to several methods which have been applied in theast (Vallet-Regi et al., 2001; Charnay et al., 2004; Anderssont al., 2004; Salonen et al., 2005a,b; Gainotti et al., 2004) to loadrugs into solid carriers, this study used the controlled particleeposition, intended for precipitation of drugs into solid car-iers from supercritical CO2 solution in a single-step process.he carrier, which was chosen to be loaded, has granules formhich consists of excipients already used in the pharmaceu-

ical industry and prepared by a conventional wet granulationrocess.

The obtained drug-free granules depend on �-cyclodextrinccording to a modified formulation reported previously byainotti et al. (2004), exhibiting mechanical stability with a

riability of 4.59 ± 0.76%. In addition, these granules show sta-ility under scCO2 experimental conditions, since the thermalehaviour (Fig. 1), the crystalline state (Fig. 2) and BET surfacerea (Table 1) of the unprocessed materials were not alteredy treating with scCO2.

In the CPD, about 17.5 wt.% of ibuprofen was loaded intoCD-granules, compared to about 4 wt.% of the drug loaded inolution immersing, which we used as a conventional methodor comparison. The drug loading was confirmed as well by

significant reduction in the BET surface area for the CPD-roduct (Table 1). No reduction in the BET surface area wasbserved in the SI materials due to the rather small amount

f drug loaded in this method.

Only a minor fraction of the drug loaded was found in therystalline form in the DSC thermograms (Fig. 1) and X-rayiffractograms (Fig. 2); this amount could be estimated by inte-

l s c i e n c e s 3 3 ( 2 0 0 8 ) 306–312 311

gration of the melting peak of ibuprofen in the loaded granules(Table 1). Most of the loaded drug was in either an amorphousstate or complexed with �CD. No morphological change couldbe seen in SEM micrographs of the unprocessed/ibuprofen-loaded granules (Fig. 3), which demonstrate that the drugloading was not due to the crystallization of the drug on thesurface.

With regard to the amount of drug dissolved after 2 h andthe dissolution rate coefficient Kw, a significant improvementin the water-solubility of ibuprofen at pH 6 was observed bydrug-loaded �CD-granules compared to the pure drug. Thiswas independent on the drug loading method.

5. Conclusion

The results of this study demonstrate that the controlled parti-cle deposition is a more effective method for loading drugs intosolid carriers when compared to other conventional meth-ods. �CD-granules loaded with a model drug (ibuprofen) showa significant improvement of drug dissolution compared tothe pure drug, independent on drug-loading procedures. Thisdemonstrates that these granules could be good vehicles forpoor water-soluble drugs.

Acknowledgement

The authors would also like to thank M. Crone for perform-ing the CPD experiments. Part of this work was supportedby Deutsche Forschungsgemeinschaft (DFG) Tu 93/6-1 and Wa742/4-1.

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