Fs

MK

a

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0d

J. of Supercritical Fluids 55 (2010) 778–785

Contents lists available at ScienceDirect

The Journal of Supercritical Fluids

journa l homepage: www.e lsev ier .com/ locate /supf lu

ormation of submicron poorly water-soluble drugs by rapid expansion ofupercritical solution (RESS): Results for Naproxen

ichael Türk ∗, Dennis Boltenarlsruhe Institute of Technology (KIT), Institut für Technische Thermodynamik und Kältetechnik, Engler-Bunte-Ring 21, 76131 Karlsruhe, Germany

r t i c l e i n f o

rticle history:eceived 7 June 2010eceived in revised form5 September 2010ccepted 16 September 2010

eywords:issolution behaviour

a b s t r a c t

Numerous results of multitude investigations indicate that the particular properties of supercritical flu-ids can be conveniently exploited for the formation of submicron particles. In case of pharmaceuticalsubstances the poor dissolution behaviour and therewith bioavailability of drugs in biological media canbe enhanced dramatically by reduction of the particle size. In this paper we report the application of RESS(Rapid Expansion of Supercritical Solutions) and RESSAS (Rapid Expansion of Supercritical Solution intoAqueous Solution) to produce submicron particles of Naproxen, a poorly water-soluble drug. Therebythe effect of various process conditions on the obtained product properties was investigated. The exper-

aproxenoorly water-soluble drugESSESSAS

imental results show, that the RESS processing of Naproxen leads to particles in the range from 0.56 to0.82 �m which is about 22 times smaller than the unprocessed powder. RESSAS experiments show, thatstabilized Naproxen particles have an average diameter of 0.3 �m for drug concentrations up to 1 g/dm3

in 0.4 wt% PVP solution while expansion into a 0.4 wt% Tween® 80 solution produced particles 8 �m indiameter. Furthermore, it is shown that the improved dissolution behaviour of the processed powder

size a

depends on the particlemedia.

. Introduction

The production and utilization of nanoparticles is an increas-ng field for industrial and scientific applications, such as advanced

aterials, catalysts, semiconductors, optical components and pre-ursor materials used in ceramic and pharmaceutical industry. Inase of the later one, the poor dissolution behaviour and therewithioavailability of drugs in biological media can be enhanced dra-atically by reduction of the particle size. The disadvantages of the

ommon particle size reduction techniques (milling and grinding,pray-drying, freeze-drying, high-pressure homogenization, ballnd air jet milling) are often degradation of the product, a broadarticle size distribution and cumbersome solids handling. How-ver, numerous results of multitude investigations indicate thathe particular properties of supercritical fluids (SCFs) can be con-eniently exploited for the formation of submicron particles forlarge number of applications such as pharmaceutical technol-

gy [1–6]. SCFs are characterized by densities very close to those

f liquids and mass transfer properties (viscosities and diffusivi-ies) ranging between those of gases and liquids, which make themttractive solvents for separations and reactions. At the same tem-erature, the viscosity of a gas is typically less than one order of

∗ Corresponding author. Tel.: +49 721 608 2330.E-mail address: tuerk@kit.edu (M. Türk).

896-8446/$ – see front matter © 2010 Elsevier B.V. All rights reserved.oi:10.1016/j.supflu.2010.09.023

nd hence increased surface area and on the pH-value of the dissolution

© 2010 Elsevier B.V. All rights reserved.

magnitude lower than the viscosity of SCFs, but the density is liq-uid like. Thus, depending upon the fluid density, the fluid behavesas a specific solvent for a specific substance at one pressure, butas a non-solvent at another pressure. In addition, processes usingSCFs are characterized by their ease of solvent and product recov-ery; solvent-free products can be obtained in a single processingstep by partial system depressurization. Among the SCFs, super-critical carbon dioxide (sc-CO2) is particularly attractive since it isinexpensive, non-flammable, non-toxic, and leaves no residue inthe treated medium.

The particular properties of SCFs can be conveniently exploitedfor the production of submicron particles for pharmaceutical appli-cations such as injectable, inhalable, and controlled release drugformulations. However, an increasing number of newly developedpharmaceutical substances are poorly soluble in both aqueousand organic media. The low bioavailability of such drugs can beimproved by reducing the particle size. From former work it isknown that the RESS process (Rapid Expansion of SupercriticalSolutions) is a promising route to produce submicron organic par-ticles [7]. In RESS experiments with different substances a meanparticle size ≤1 �m was reached which leads to improved dissolu-

tion behaviour in in vitro test systems [7]. In RESS, the material tobe processed is dissolved at high pressure (pE = p0) in a SCF (usuallyCO2). After heating to the desired pre-expansion temperature (T0)an extremely fast phase change from the supercritical to the gas-like state takes places during the expansion through a heated nozzle

M. Türk, D. Bolten / J. of Supercritic

Nomenclature

c drug concentration (g/dm3)cS surfactant concentration (wt%)dN inner diameter of the capillary nozzle (�m)�hfus enthalpy of fusion (kJ/mol)l length of the capillary nozzle (�m)L length of the expansion chamber (m)M molar mass (g/mol)p pressure (MPa)pC critical pressure (MPa)pE pressure in the extraction unit (=extraction pres-

sure) (MPa)p0 pressure at capillary inlet (=pre-expansion pres-

sure) (MPa)t time (s)tR dimensionless timeT temperature (K)TC critical temperature (K)TE temperature in the extraction unit (=extraction

temperature) (K)TM melting temperature (K)TN nozzle temperature (K)T0 temperature at capillary inlet (=pre-expansion tem-

perature) (K)V volume of the expansion chamber (m3)x particle size (�m)y2 solute mole fraction in the fluid phase (mol/mol)

tcngcwwppp

((

((

EctuTatc

b

((

A USP dissolution apparatus [10,11] was used for in vitro testing

Greek symbols� density (kg/m3)

o ambient pressure and temperature. The decrease in densityauses high supersaturation values (105–108) and therewith highucleation rates (≤1026 cm−3 s−1) [7]. This leads to uniform crystalrowth which enables the formation of submicron (<1 �m) parti-les. In case that nucleation occurs, particles grow by coagulation,hich is the growth by collision of particles, and by condensation,hich is the deposition of molecules on the particles surface. Thearticle size, size distribution and morphology (crystalline or amor-hous) of the obtained RESS product can be influenced by variousrocess parameters:

a) extraction and pre-expansion temperature and pressureb) nozzle geometry, diameter and length

(c) residence time, pressure and temperature in the expansion unitd) solubility in SCF and nature of solute–solvent interaction.e) Prior to precipitation, the degree of supersaturation depends

strongly on the solutes equilibrium mole fraction at the prevail-ing temperature and pressure during the expansion and henceon the phase behaviour of the respective binary mixture.

An interesting modification of the RESS process is RESSAS (Rapidxpansion of Supercritical Solution into Aqueous Solution) thatonsists of 2 steps. The first is to expand the supercritical solu-ion into a liquid solution instead of a gas, and the second is tose surfactants to stabilize the particles in aqueous solutions [8].hus, based on former work, we explore the possibility to producequeous suspensions of Naproxen by RESSAS with an average par-

icle size less than obtained from RESS experiments at Naproxenoncentrations of about 1 g/dm3.

The paper is organized as follows: After an introduction into theasic principle of the RESS and RESSAS process, we report on:

al Fluids 55 (2010) 778–785 779

a) the use of RESS to produce submicron Naproxen particles,b) the use of RESSAS to stabilize submicron Naproxen particles,

and(c) results of dissolution experiments performed with dissolution

media at different pH-values.

The main conclusions and further perspectives are summarizedat the end of the paper.

2. Experimental

2.1. Materials and methods

CO2 (Linde AG; Germany) was chosen as supercritical solventsince it is a non-flammable, inexpensive, and non-toxic solvent.Supercritical CO2 (sc-CO2) allows processing at moderate tem-peratures, and it is particularly attractive for a wide variety ofapplications because it is chemically inert and environmentallyacceptable. Naproxen, a poorly water-soluble drug, is a mem-ber of the arylacetic acid group of nonsteroidal anti-inflammatorydrugs and was obtained from Sigma–Aldrich (Germany). The watersoluble polymer Polyvinylpyrrolidone (PVP) and the non-ionic sur-factant Polyoxyethylene sorbitan monooleate (Tween®80) werepurchased from Carl Roth (Germany). PVP is often used as anadditive (E-number E1201) and as stabilizer in different foodapplications. Tween®80 is approved by the U.S. Food and DrugAdministration for use as an excipient in either oral or parenteraldelivery formulations. The anionic surfactant Sodium dodecyl sul-phate (SDS) was purchased from Carl Roth GmbH & Co. (Germany).

Differential Scanning Calorimetry (DSC 204 Phoenix, Netzsch;Germany) was used for physical characterization (melting pointand enthalpy of fusion) of the unprocessed and the processed pow-ders. The sample (≈5 mg/run) was heated in an aluminium standardpan under a nitrogen gas flow of 20 ml/min. A heating rate of5 K/min was used up to a maximum temperature of 473 K.

The powder X-ray diffraction (XRD) pattern of the unpro-cessed solutes and the micronized substances were determined byusing a Guinier instrument (System G600, mono-chromate CuK�radiation, � = 1.54056 × 10−10 m, Huber Diffraktionstechnik GmbH;Germany). The diffractograms have been collected in a 2� range of5–60.

Particle size distributions (PSD) were determined with a CoulterLS 230 and LS 13320 (Beckmann Coulter; Germany). This equip-ment allows the analysis of particles in a range of sizes between0.04 and 2000 �m applying a laser diffraction method. Particle sizemeasurements were made within 2 days after the production ofthe suspensions.

Since in case of non-spherical and/or agglomerated particles on-line measurement technique can lead to incurrent results of theparticle size distribution, Scanning Electron Micrographs (SEMs)were made using a scanning electron microscope (DSM 940 A, CarlZeiss, Germany; or Stereoscan S4-10, Cambridge Scientific Instru-ments; UK). The samples were coated with platinum by means ofa Sputter Coater (E 5100, Bio-Rad; Germany).

Polymer molar mass distributions (MMD) were measuredvia size exclusion chromatography (SEC) using the eluentN,N-dimethyl acetamide (99%) from Acros Organics (Belgium) con-taining 0.1% LiBr (99%) from Sigma–Aldrich (Germany). The SECset-up was calibrated using polystyrene standards (PSS) of lowpolydispersity [9].

of drug dissolution at 310 ± 0.5 K. An excess amount of the poorlysoluble drug was placed into the dissolution medium (250 ml).Samples were withdrawn, during the initial stage (≤10 min) every2 min, after that every 10 min, and always replaced with an equal

780 M. Türk, D. Bolten / J. of Supercritic

Table 1Physical properties of the substances investigated.

Substance M [g/mol] TC [K] �C [g/dm3] TMa [K] �hfus

ia [kJ/mol]

CO2 44.01 304.1 467.6 – –Naproxen 230.3 – – 427.7 31.4Tween®80 1310 – – – –

afaomAs1T

wpr

2

FtAm

pmehizrts

Fc

PVP K25 7641b – – –

a From [12].b PDI = MW/MN = 4.1 from [9].

mount of fresh dissolution medium. A similar procedure was usedor solubility measurements: Excess amounts of the drugs weredded to the thermostated dissolution vessel containing 250 mlf dissolution medium. These mixtures were then agitated with aagnetic stirrer for a period of 24 h at a temperature of 310 ± 0.5 K.ll samples were filtered through a membrane filter with a poreize of 0.2 �m and the drug content was determined by HPLC (Typ100, Agilent LiChrospher 100-5 RP18, 125 mm × 4 mm, Agilentechnologies; Germany).

All materials and solvents were of the purest grade available andere used without further purification. In Table 1 some importanthysical properties of the materials used in this study are summa-ized.

.2. RESS process

The laboratory scale RESS apparatus is shown schematically inig. 1. The continuous apparatus is designed for experiments in theemperature range from 300 to 600 K and pressures up to 40 MPa.

more detailed description of the RESS apparatus and the experi-ental procedure can be found elsewhere in the literature [13,14].In all experiments, the gaseous CO2 is liquefied, sub-cooled, and

ressurized to the desired pressure with a diaphragm pump. Toinimize the unsteadiness of the flow and to accelerate thermal

quilibrium, pure CO2 flows through the bypass section into theigh-pressure vessel and is expanded through a capillary nozzle

nto the expansion chamber. The CO2 mass flow through the noz-le was measured with a mass flow meter. After equilibrium iseached, the bypass section is closed and the sc-CO2 flows throughhe pre-heater and the extraction column where the solute is dis-olved in sc-CO2. The pre-expansion pressure (p0) is maintained at

E

D

A

B

C

ig. 1. Schematic diagram of the RESS apparatus: A, solvent supply; B, chiller; C, diaphraghamber; I, sample for SEM; J, vent.

al Fluids 55 (2010) 778–785

the same pressure as at the extraction column. Then, the supercriti-cal solution flows through a tube into a high-pressure vessel wherethe pre-expansion temperature (T0) is adjusted and is expandedthrough a capillary nozzle (l/dN = 10, dN = 50 �m) down to ambientconditions inside the expansion chamber. Samples are collectedonto SEM stages located on the sampling device at a distance of300 mm to the nozzle exit [13,14].

2.3. RESSAS process

During the RESSAS experiments the sc-CO2/Naproxen mixture isexpanded through a heated capillary nozzle (l/dN = 10, dN = 50 �m)directly into the aqueous surfactant solution (usually 50 cm3). Tobring the expanded solution, and hence the particles being formed,into rapid contact with the surrounding aqueous surfactant solu-tion, the nozzle is located at the bottom of the expansion chamber.The temperature of the aqueous surfactant solution is measured bya thermocouple, which is immersed in the liquid. To suppress thefoam produced during RESSAS, dried pressurized air can be blowndown on top of the foam into the expansion chamber. More detailsabout the apparatus and the experimental procedure can be foundelsewhere in literature [7,8].

3. Results

Experimental data for the equilibrium SLG-line and for the sol-ubility of the binary sc-CO2/Naproxen system has already beenpublished in a previous paper [14].

3.1. RESS modelling

Beside the experiments, the RESS process was investigated bymodelling for a better understanding of the mechanisms of par-ticle formation and growth, and therefore, to be able to identifyoptimized process conditions with regard to particle size and dis-tribution.

For these calculations, a steady-state flow field model was used[15,16]. The modelling consists of mass, momentum and energybalance and an equation of state. In the capillary nozzle inlet regionan additional pressure drop is included while for the flow inside thecapillary nozzle, friction and heat exchange is considered. Particle

F

GI

J

H

m pump; D, bypass; E, extraction unit; F, heating; G, capillary nozzle; H, expansion

M. Türk, D. Bolten / J. of Supercritical Fluids 55 (2010) 778–785 781

0 1x10-1 2x10-1 3x10-110

100

p0 = 30 MPa; y

2 = 4,53E-5

p0 = 25 MPa; y

2 = 3,74E-5

p0 = 20 MPa; y

2 = 2,68E-5

p0 = 15 MPa; y

2 = 1,33E-5

x NV [

nm

]

t [s]

TE = 323 K p

E = p

0

T0 = 383 K L = 0,3 m

(a)

0 1x10-1

2x10-1

1

10

100

(b)

TE = 323 K p

E = p

0 = 20 MPa

T0 = 363 K L = 0,3 m

x NV [

nm

]

t [s]

y2 = 2,68E-5

y2 = 1,34E-5

y2 = 2,68E-6

y2 = 1,34E-6

FN

fetpdptfa[bttdw

aap

10-2 10-1 100 101 102 1030,0

0,2

0,4

0,6

0,8

1,0(a)

(b)

(c)

(d)

particle size [µm]

10-2 10-1 100 101 102 103

particle size [µm]

0,0

0,2

0,4

0,6

0,8

1,0

Q3[-

]Q

3[-]

(a)

(b)

(e)

(f)

ig. 2. (a) Effect of pre-expansion pressure, p0, and (b) solute mole fraction, y2, ofaproxen in sc-CO2 on calculated particle size, xNV, inside the expansion chamber.

ormation and growth is considered by solving the general dynamicquation for simultaneous nucleation, condensation, and coagula-ion. Thus, the simulation program is able to predict nucleation rate,article number concentration, average particle size, and the stan-ard deviation as function of the axial distance along the expansionath. The nucleation rate is obtained using the classical nucleationheory within this modelling approach. Hence, the obtained valuesor the nucleation rate rely on the validity of the classical nucle-tion theory. Molecular dynamics simulations of the RESS process17,18] presented in the subsequent paper provide nucleation ratesased on molecular interactions only. They can be used as input forhe fluid dynamics modelling of the complete process. The calcula-ions here are based on the following process conditions: l/dN = 10,N = 50 �m and L = 0.3 m. The air supply to the expansion chamberas set to 300 dm3/h.

Fig. 2 shows the calculated mean particle size of Naproxen asfunction of the residence time, t, the pre-expansion pressure, p0,nd the Naproxen mole fraction, y2 and clarifies the influence of tworocess parameters on particle size. Both, a lower solubility and a

Fig. 3. PSD of Naproxen: unprocessed (a), RESS processed at p0 = 20 MPa andT0 = 323 K (b), T0 = 343 K (c) and T0 = 363 K (d) and at T0 = 323 K and p0 = 25 MPa (e)and p0 = 30 MPa (f).

shorter residence time of the particles in the expansion chamberresults in smaller particles. The former one leads to a higher dilu-tion of the particles which inhibit post-expansion particle growthwhile the latter one leads to less time available for particle growthin the expansion chamber. Similar findings were previously pub-lished by various authors [5]. Thus from the theoretical calculationsdiscussed above follows, that it should be possible to form particlessmaller than 50 nm. The inability to approach the theoretical lowerlimit is likely due to particle growth during collisions in the free jet.Thus, measures such as spraying the supercritical solution directlyinto an aqueous surfactant solution should result in smaller par-ticles due to minimizing flocculation and agglomeration resultingfrom particle collisions.

3.2. RESS experiments

In these investigations, the extraction temperature, TE, was fixedto 313 K, while T0 was varied from 323 to 363 K, and p0 from 20 to30 MPa. Typical experimental results are depicted in Figs. 3 and 4and summarized in Table 2. These results show that both, parti-cle size and PSD were significantly reduced by the RESS process.Unprocessed Naproxen had a median diameter (x50,3) of approxi-mately 15.2 �m with a wide PSD ranging from 1.3 (x10,3) and 46.7(x90,3) �m. However, independent from the pre-expansion con-ditions the RESS experiments lead to particles sizes in the range

between 0.56 and 0.82 �m. This result is in accordance with RESSexperiments performed with CO2/Cholesterol, CO2/Phytosterol,CO2/Ibuprofen, and CHF3/Griseofulvin which lead to particle sizesin the range between 0.17 and 0.33 �m [7]. Obviously the Naproxen

782 M. Türk, D. Bolten / J. of Supercritical Fluids 55 (2010) 778–785

F K (b)(

pcpcts

TP(

ig. 4. SEM of Naproxen: unprocessed (a), RESS processed at p0 = 20 MPa and T0 = 323f).

articles produced by RESS are 22 times smaller than the unpro-

essed material. Fig. 4 shows SEM images of unprocessed androcessed Naproxen particles. The RESS processed primary parti-les are small rod-like crystals with lengths up to 0.82 �m and ahickness of less than 0.05 �m. These results are confirmed by atudy on the formation of pure Naproxen nanoparticles which has

able 2rocess conditions and PSD for unprocessed and processed Naproxen particlesTE = 313 K, TN = T0 + 5 K, pE = p0, dN = 50 �m).

T0 [K] p0 [MPa] x10,3 [�m] x50,3 [�m] x90,3 [�m] �a

(a) Unprocessed 1.33 15.2 46.7 1.5(b) 323 20 0.02 0.70 1.08 1.2(e) 323 25 0.36 0.82 2.06 2.5(f) 323 30 0.32 0.66 1.61 2.9(c) 343 20 0.51 0.70 1.10 1.2(d) 363 20 0.35 0.70 1.51 2.4(g)b 343 20 0.26 0.56 2.00 5.6

a � = (x90 − x10)/2x50.b In this RESS experiment, a nozzle with an inner diameter of dN = 75 �m was used.

, T0 = 343 K (c) and T0 = 363 K (d) and at T0 = 323 K and p0 = 25 MPa (e) and p0 = 30 MPa

been published by the group of Signorell [19]. The formation of sub-micron sized Naproxen particles represents a marked improvementon a former study, which reported the formation of micro-particleswith irregular shape and sizes between 1 and 15 �m [20]. As is illus-trated in Fig. 5, similar DSC curves and XRD patterns were observedfor the unprocessed material and the Naproxen particles producedby RESS. On the basis of the DSC measurements, and XRD investi-gations, it was confirmed that the processed Naproxen is still in acrystalline state. However, the heat of melting and melting temper-ature obtained from DSC analysis and the intensity of the XRD peaksof the processed substances were slightly lower compared with theunprocessed material. These results indicate a slight reduction inthe degree of crystallinity of Naproxen after processing with RESS.

3.3. RESSAS experiments

First exploratory RESSAS experiments were carried out to inves-tigate the influence of surfactant type and concentration on particlesize and drug loadings in the surfactant solutions. Based on the RESS

M. Türk, D. Bolten / J. of Supercritical Fluids 55 (2010) 778–785 783

450425400375350

(g)

(f)

(e)

(d)

(c)

(b)

hea

t fl

ow

[a.

u.]

temperature [K]

(a)

40302010

(g)

(f)

(e)

(d)

(c)

(b)inte

nsi

ty [

a.u

.]

2Θ [°]

(a)

Fa(

rfpTwSsts

iwwttaipcpNp[N07t

10-2 10-1 100 101 102 1030,0

0,2

0,4

0,6

0,8

1,0

Q3

[-]

particle size [µm]

unprocessed

RESS

RESSAS

(Tween 80)

RESSAS

(PVP K25)

ig. 5. DSC and XRD of Naproxen: unprocessed (a), RESS processed at p0 = 20 MPand T0 = 323 K (b), T0 = 343 K (c) and T0 = 363 K (d) and at T0 = 323 K and p0 = 25 MPae) and p0 = 30 MPa (f), T0 = 343 K, p0 = 20 MPa and dN = 75 �m (g).

esults obtained for Naproxen, the RESSAS experiments were per-ormed at an extraction temperature of TE = 313 K, a pre-expansionressure of p0 = pE = 20 MPa, and a pre-expansion temperature of0 = 343 K. In these experiments the aqueous surfactant solutionas held at a temperature of 298 K and the spray time was 60 min.

ome more details such as molar mass distribution of PVP K25,aturation solubility of unprocessed Naproxen in aqueous solu-ions, and experimental data for the surface tension of aqueous PVPolutions are published in a former paper [21].

First, as a control, the sc-CO2/Naproxen solution was sprayednto pure water. In this case, RESSAS produced Naproxen particles

ith an average size of 5 �m and a drug loading of 0.18 g/dm3

ere obtained. The result of spraying a sc-CO2/Naproxen mix-ure into an aqueous PVP K25 is shown in Fig. 6. For comparison,he PSD for the unprocessed material and the RESS product islso included. Obviously, the water soluble polymer PVP K25s able to impede particle agglomeration and growth. Naproxenarticles with 0.3 �m in diameter were stabilized for drug con-entrations as high as 1.1 g/dm3 in 0.4 wt% PVP solution. Thesearticles are about 50 times smaller than the unprocessedaproxen powder and 2 times smaller than the obtained RESSroduct. A similar result was obtained for a 1 wt% PVP solution

21]. In opposite thereto, Tween®80 is not able to stabilize theaproxen particles in a sufficient way. When expanding into a.4 wt% Tween®80 solution, the size of the stabilized particles is.8 �m, which is half of the unprocessed powder and about 11imes larger than the particles obtained from RESS experiments.

Fig. 6. PSD of Naproxen: unprocessed, RESS processed (TE = 313 K; p0 = pE = 20 MPaand T0 = 343 K) and RESSAS processed (TE = 313 K; p0 = pE = 20 MPa and T0 = 343 K)with either 0.4 wt% PVP K25 or 0.4 wt% Tween®80.

In addition, the obtained Naproxen concentration of 0.5 g/dm3

is comparatively low. On the other hand, our former RESSASexperiments demonstrate that Ibuprofen nanoparticles with anaverage size of 0.17 �m and a drug concentration of 2.4 g/dm3

could be stabilized in 1 wt% Tween®80 solutions. Further exper-iments show also that in a 1 wt% Tween®80 solution Salicylicacid concentrations of 4.6 g/dm3 could be stabilized with parti-cle diameters of about 0.2 �m and that Phytosterol particles witha 0.38 �m in diameter could be stabilized at a drug concentra-tion of 4.5 g/dm3. The use of a SDS solution instead of Tween®80results in a stable aqueous suspension of Phytosterol nanoparticles,where the average particle size is 0.1 �m at a drug concentra-tion of 5.6 g/dm3 [8]. Thus, this point requires more detailedexperimental and theoretical investigations of the effects of thedifferent solute–surfactant interactions.

Comparing our RESSAS results obtained for the systemsdescribed above with data published in literature, we note that theaverage diameters of our nanoparticles are in the same range asthe Ibuprofen and Naproxen nanoparticles produced by Pathak etal. [22,23] and the Tetraphenylporphyrin nanoparticles producedby Sane and Thies [24].

3.4. Dissolution kinetics studies

First of all, solubility measurements of Naproxen, and forcomparison of Ibuprofen, were conducted at different pH-values.As shown in Fig. 7 for Naproxen, the solubility increases from28 mg/dm3 at pH = 2.0 up to 175 mg/dm3 at pH = 6.8. A similar resultwas obtained for Ibuprofen [25].

Dissolution testing of the two poorly water-soluble drugs,Ibuprofen and Naproxen, was performed at 310 K and pH = 2.0.The dissolution profiles of the original material and the processedNaproxen are shown in Fig. 8 [26]. As a basis for comparison, thedissolution rate coefficient (kW) is calculated as the reciprocal ofthe time after which 63.2% of the unprocessed amount of drug hasdissolved. In Fig. 9 the kW value of the unprocessed material and theprocessed drugs are shown. The dissolution rate coefficient of themicronized Ibuprofen was found to be 0.14 min−1 which is 6 timeshigher than that of the unprocessed material and for Naproxen

the kW of the RESS product is 1.2 times higher than that of theunprocessed material. The comparatively low improvement of thedissolution behaviour might be a result of the rod shaped Naproxenparticles with lengths up to 0.82 �m and a thickness of less than0.05 �m instead of the very small (0.23 �m) spherical Ibuprofen

784 M. Türk, D. Bolten / J. of Supercritic

0

50

100

150

200

6,85,54,62,0

CN

apro

xen /

[mg

dm

-3]

T = 310 K

pH-value

Fig. 7. Saturation concentration of Naproxen at T = 310 K vs. pH-value of the disso-lution medium.

0

25

50

75

100

3020100

dis

solv

ed a

mo

un

t [%

]

unprocessed

RESS processed

Fb

piwIrcpo

FN

t [min]

ig. 8. Dissolution profile (in buffer solution at T = 310 K, pH = 2.0) of Naproxenefore and after RESS processing.

articles [8,16]. However, this point requires more detailed exper-mental and theoretical investigations and is part of our ongoing

ork. Additional dissolution experiments were performed with

buprofen and pH = 4.5, 5.5 and 6.8. In agreement with our previousesults [7], the difference in the dissolution rate between unpro-essed and micronized particles becomes smaller with increasingH-value of the dissolution medium. Therefore, at pH = 7.4, the kWf the RESS product is 2 times higher than that of the unprocessed

ig. 9. Dissolution rate coefficient of unprocessed and micronized Ibuprofen andaproxen at T = 310 K and pH = 2.0 and Ibuprofen at pH = 7.4.

[

[

[

al Fluids 55 (2010) 778–785

material. However at present it should be noticed that it is notalways clear whether the improved dissolution behaviour is due tothe reduced particle size and degree of crystallinity, and/or moreor less effective wetting due to adding surfactant to the dissolutionmedia, and/or change of pH-value of the dissolution media. Thus,in accordance with results published in literature [7], these exper-imental results confirm that dissolution rates do not only dependon the surface area and particle size of the processed powder, butare greatly affected by other physico-chemical characteristics suchas crystal morphology and wettability that may reduce the benefitof micronization [26].

4. Conclusion

Submicron Naproxen particles were produced by rapid expan-sion of supercritical solution into air or an aqueous surfactantsolution to minimize particle growth during collisions in the freejet and to prevent particle agglomeration.

The experimental results presented in this paper shows that theRESS processing of Naproxen leads to rod shaped particles in therange from 0.56 to 0.82 �m which is about 22 times smaller thanthe unprocessed powder.

From theoretical calculations follow, that it should be possibleto form particles as small as 0.1 �m. Therefore, RESSAS experimentswere performed to minimize particle growth. These experimentsdemonstrate that Naproxen concentrations up to 1 g/dm3 could bestabilized with particle diameters of 0.3 �m.

Furthermore it was shown that submicron Naproxen andIbuprofen particles produced by RESS show an improved dissolu-tion rate compared to the original material.

Acknowledgements

This work was supported by the German Research founda-tion (DFG) by the grants Tu 93/7-1 and 7-2, which the authorsgratefully acknowledge. Good and trustworthy cooperation withinthis project with Th. Kraska (University Cologne, Germany) and A.Weber (Technical University Clausthal, Germany) is acknowledgedgratefully. The authors thank Mrs. Sabrina Müller for conductingthe dissolution measurements.

References

[1] S.-D. Yeo, E. Kiran, Formation of polymer particles with supercritical fluids: areview, Journal of Supercritical Fluids 34 (2005) 287–308.

[2] E. Reverchon, R. Adami, Review:, Nanomaterials and supercritical fluids, Journalof Supercritical Fluids 37 (2006) 1–22.

[3] M. Bahrami, S. Ranjbarian, Production of micro- and nano-composite parti-cles by supercritical carbon dioxide, Journal of Supercritical Fluids 40 (2007)263–283.

[4] A. Tandya, R. Mammucari, F. Dehghani, N.R. Foster, Dense gas processing ofpolymeric controlled release formulations, International Journal of Pharma-ceutics 328 (2007) 1–11.

[5] K. Mishima, Biodegradable particle formation for drug and gene delivery usingsupercritical fluid and dense gas, Advanced Drug Delivery Reviews 60 (2008)411–432.

[6] A. Martin, M.J. Cocero, Micronization processes with supercritical fluids: fun-damentals and mechanisms, Advanced Drug Delivery Reviews 60 (2008)339–350.

[7] M. Türk, Manufacture of submicron drug particles with enhanced dissolu-tion behaviour by rapid expansion processes, Journal of Supercritical Fluids47 (2009) 537–545.

[8] M. Türk, R. Lietzow, Formation and stabilization of submicron particles via rapidexpansion processes, Journal of Supercritical Fluids (2008) 346–355.

[9] S. Beuermann, Universität Potsdam, Private Communication, 2009.10] The United States Pharmacopeia (USP 32), United States Pharmacopeial Con-

vention, Inc., Rockville, MD, 2009.11] Deutsches Arzneibuch, Methoden zur Pharmazeutischen Technologie,

Deutscher Apotheker Verlag, Stuttgart, 1996.12] M. Türk, Th. Kraska, Experimental and theoretical investigation of the phase

behaviour of Naproxen in supercritical CO2, Journal of Chemical & EngineeringData 54 (2009) 1592–1597.

rcritic

[

[

[

[

[

[

[

[

[

[

[

[

ical Chemistry B 109 (2005) 19688–19695.

M. Türk, D. Bolten / J. of Supe

13] M. Türk, G. Upper, P. Hils, Formation of composite drug – polymer particles byCo-precipitation during the rapid expansion of supercritical fluids, Journal ofSupercritical Fluids 39 (2006) 253–263.

14] M. Türk, R. Signorell, In situ characterization of drug nanoparticles by FTIR-Spectroscopy, in: C.S.S.R. Kumar (Ed.), Nanotechnologies for the Life Sciences,Vol. 3 Nanosystem Characterization Tools in the Life Sciences, Wiley-VCH,Weinheim, 2005, Chapter 6, pp. 208–240, ISBN 3-527-31383-4.

15] B. Helfgen, Simulation der Strömung und der Partikelbildung bei der schnellenExpansion überkritischer Lösungen (RESS) zur Herstellung pharmazeutischerNanopartikeln, Doctoral thesis, Universität Karlsruhe (TH), Cuvilier Verlag, Göt-tingen, 2001.

16] M. Türk, B. Helfgen, P. Hils, R. Lietzow, K. Schaber, Formation of nanoscaledrugs by Rapid Expansion of Supercritical Solutions (RESS): Experimental andtheoretical investigations, in: G. Brunner (Ed.), Supercritical Fluids as Solventsand Reaction Media, Elsevier B.V, 2004, Chapter 3.3, pp. 449–462, ISBN: 0444515747.

17] F. Römer, Th. Kraska, Molecular Dynamics Simulation of Naphthalene ParticleFormation by Rapid Expansion of a Supercritical Solution, Journal of Physical

Chemistry C 113 (2009) 19028–19038.

18] F. Römer, T. Kraska, Molecular Dynamics simulation of the formation of phar-maceutical particles by Rapid Expansion of a Supercritical Solution, J. Supercrit.Fluids 55 (2010) 769–777.

19] M. Gadermann, S. Kular, H. Ali, R. Al-Marzouqi, Signorell, Formation ofnaproxen–polylactic acid nanoparticles from supercritical solutions and their

[

[

al Fluids 55 (2010) 778–785 785

characterization in the aerosol phase, Physical Chemistry Chemical Physics 11(2009) 7861–7868.

20] J.-H. Kim, T.E. Paxton, D.L. Tomasko, Microencapsulation of naproxen usingrapid expansion of supercritical solutions, Biotechnology Progress 12 (1996)650–661.

21] D. Bolten, M. Türk, Production and stabilization of submicron organic parti-cles of pharmaceutical relevance by rapid expansion processes, in: Proceedingsof the 12th European Meeting on Supercritical Fluids, Graz, (Austria) 12.5 9,2010.

22] P. Pathak, M.J. Meziani, T. Desai, Y.-P. Sun, Nanosizing drug particles in super-critical fluid processing, Journal of the American Chemical Society 126 (2004)10842–10843.

23] P. Pathak, M.J. Meziani, T. Desai, Y.-P. Sun, Formation and stabilization ofibuprofen nanoparticles in supercritical fluid processing, Journal of Supercrit-ical Fluids 37 (2006) 279–286.

24] A. Sane, M.C. Thies, The formation of fluorinated tetraphenylporphyrinnanoparticles via rapid expansion processes: RESS vs. RESOLV, Journal of Phys-

25] M. Türk, Supercritical CO2 as novel particle formation media: applicationsto the formation of organic and inorganic materials, in: Proceedings ofthe 12th European Meeting on Supercritical Fluids, Graz, (Austria) 12.5 9,2010.

26] S. Müller, diploma thesis, Karlsruhe Institute of Technology (KIT), 2010.