P

Sa

J

a

b

c

a

ARR1AA

KTSSS

1

Ah(It

(wos(

R

0h

International Journal of Pharmaceutics 441 (2013) 50– 55

Contents lists available at SciVerse ScienceDirect

International Journal of Pharmaceutics

jo ur n al homep age: www.elsev ier .com/ locate / i jpharm

harmaceutical nanotechnology

olubilization of the poorly water soluble drug, telmisartan, using supercriticalnti-solvent (SAS) process

unsung Parka,b, Wonkyung Choa,b, Kwang-Ho Chaa,b, Junhyun Ahna,c, Kang Hana,c, Sung-Joo Hwanga,c,∗

Yonsei Institute of Pharmaceutical Sciences, Yonsei University, 162-1 Songdo-dong, Yeonsu-gu, Incheon 406-840, Republic of KoreaCollege of Pharmacy, Chungnam National University, 220 Gung-dong, Yuseong-gu, Daejeon 305-764, Republic of KoreaCollege of Pharmacy, Yonsei University, 162-1 Songdo-dong, Yeonsu-gu, Incheon 406-840, Republic of Korea

r t i c l e i n f o

rticle history:eceived 11 September 2012eceived in revised form9 November 2012ccepted 12 December 2012vailable online 20 December 2012

eywords:elmisartanupercritical anti-solvent processolid dispersionolubility

a b s t r a c t

Telmisartan is a biopharmaceutical classification system (BCS) class II drug that has extremely low watersolubility but is freely soluble in highly alkalized solutions. Few organic solvents can dissolve telmisartan.This solubility problem is the main obstacle achieving the desired bioavailability. Because of its uniquecharacteristics, the supercritical anti-solvent (SAS) process was used to BCS class II drug in a variety ofways including micronization, amorphization and solid dispersion. Solid dispersions were prepared usinghydroxypropylmethylcellulose/polyvinylpyrrolidone (HPMC/PVP) at 1:0.5, 1:1, and 1:2 weight ratios ofdrug to polymer, and pure telmisartan was also treated using the SAS process. Processed samples werecharacterized for morphology, particle size, crystallinity, solubility, dissolution rate and polymorphic sta-bility. After the SAS process, all samples were converted to the amorphous form and were confirmed tobe hundreds nm in size. Solubility and dissolution rate were increased compared to the raw material. Sol-ubility tended to increase with increases in the amount of polymer used. However, unlike the solubilityresults, the dissolution rate decreased with increases in polymer concentration due to gel layer forma-

tion of the polymer. Processed pure telmisartan showed the best drug release even though it had lowersolubility compared to other solid dispersions; however, because there were no stabilizers in processedpure telmisartan, it recrystallized after 1 month under severe conditions, while the other solid dispersionsamples remained amorphous form. We conclude that after controlling the formulation of solid disper-sion, the SAS process could be a promising approach for improving the solubility and dissolution rate oftelmisartan.

. Introduction

Telmisartan, which was approved by the U.S. Food and Drugdministration (FDA) in 1998, is a very well known drug for treatingypertension. Its mechanism is to block the angiotensin receptorARB) and it shows a high affinity for angiotensin II type 1 receptors.t has a long duration of action, with the longest half-life of any ofhe ARBs.

According to the biopharmaceutic classification system (BCS)Löbenberg and Amidon, 2000), telmisartan is a BCS class II drugith low water solubility, but high permeability. The goal for devel-

ping a BCS class II drug dosage form is to improve the waterolubility and dissolution rate of a drug by reducing the particle sizeKim et al., 2007; Perrut et al., 2005), forming inclusion complexes

∗ Corresponding author at: 162-1, Songdo-dong, Yeonsu-gu, Incheon 406-840,epublic of Korea. Tel.: +82 32 749 4518; fax: +82 32 749 4105.

E-mail addresses: sjh11@yonsei.ac.kr, sjhwang@cnu.ac.kr (S.-J. Hwang).

378-5173/$ – see front matter © 2012 Elsevier B.V. All rights reserved.ttp://dx.doi.org/10.1016/j.ijpharm.2012.12.020

© 2012 Elsevier B.V. All rights reserved.

(Al-Marzouqi et al., 2006; Jun et al., 2007; Peeters et al., 2002) andsolid dispersion techniques (Chiou and Riegelman, 1971; Ford andElliott, 1985; Kim et al., 2006), thereby increasing the bioavailabil-ity.

However, not many of these techniques has been used to modifythe solubility of telmisartan because of its unique solubility charac-teristics; it has extremely low solubility in water but high solubilityin alkalized conditions (Tran et al., 2008). Methylene chloride is theone of the few organic solvents dissolves telmisartan, but alkaliz-ing agents more effectively dissolve telmisartan than methylenechloride. Developing a telmisartan tablet with sufficient solubilityand dissolution rates has proven difficult (Park et al., 2011). Thus,modifying telmisartan solubility is challengeable.

In the present study, a supercritical anti-solvent (SAS) processwas used, an alternative process for formulating nano-size solid

dispersion particles with low residual organic solvents and goodflowability (Jun et al., 2005, 2007; Kim et al., 2007). Here, telmis-artan was used as a model of poorly water soluble drug, and theSAS process was used to prepare solid dispersions of telmisartan

al of P

wdrih

2

2

bHwmLcg

2

wrpaeS(s0aoKsvccasmtoctTpbp

2

w

2

dtS1

J. Park et al. / International Journ

ith the aim of increasing solubility. We used polyvinylpyrroli-one K30 (PVP) and hydroxypropyl-methylcellulose 645 (HPMC) asecrystallization inhibitors. The physical properties of telmisartann solid dispersions were characterized and the effects of variousydrophilic solid dispersion carriers were investigated.

. Materials and methods

.1. Materials

Telmisartan was obtained from TEVA Ltd. (Chorigon, Israel). Car-on dioxide (CO2) with high purity of 99.9% was supplied fromanmi Gas Co., Ltd. (South Korea). Polyvinylpyrrolidon K30 (PVP)as obtained from BASF Co., Ltd. (Germany) and hydroxypropyl-ethylcellulose 645 (HPMC) was obtained from Hanmi Pharm. Co.,

td. (Korea). All organic solvents were of high performance liquidhromatography (HPLC) grade. All other chemicals were of reagentrade.

.2. Sample preparation

Solid dispersion samples composed of PVP/HPMC (SDP/SDH)ere prepared with drug/polymer in 1/0.5, 1/1, and 1/2 in weight

atios by means of supercritical anti-solvent system (SAS) andure telmisartan was applied SAS process to obtain micronizedmorphous particles. The SAS process was performed using thexperimental equipment as previously described (Kim et al., 2008).C-CO2 was pumped into the top of the particle precipitation vesselapproximately 1.9 l) through the outer capillary of the two-flowpray nozzle (drug solution was sprayed into the vessel via the.1 mm dimension of central capillary tube and a secondary co-xial pathway surrounding the central capillary tube for passagef the SC-CO2) at a constant rate using a Suflux pump (Model No.MB01HK1F, USA) until the desired pressure was obtained. A drugolution was prepared by dissolving telmisartan in an organic sol-ent consisting of a 1:1 (v/v) mixture of ethanol and methylenehloride and adding the appropriate amount of PVP/HPMC. The con-entration of drug to mixed organic solvents was fixed to 25 mg/mlnd this concentration was decided after screening study (data nothown). Meanwhile, SC-CO2 continued to flow through the vessel toaintain a steady pressure. The conditions of the particle precipita-

ion vessel were investigated at a temperature of 45 ◦C and pressuref 12 MPa. The residual solvent (SC-CO2, ethanol and methylenehloride) was drained out of the particle precipitation vessel byhe backpressure regulator (Tescom, model 26-1723-24-194, UK).he precipitation vessel was slowly depressurized to atmosphericressure. Precipitated particles were collected from the wall andottom (retained by a 0.1 �m metal frit and paper filter) of thearticle precipitation vessel and stored in a refrigerator at 4 ◦C.

.3. Scanning electron microscopy (SEM)

Scanning electron microscopy (SEM; JSM-7000F, Jeol Ltd., Japan)as employed for morphological analysis of the particles.

.4. Particle size analysis

The mean particle size of the samples was determined by

ynamic light scattering (DLS) using an electrophoretic light scat-ering spectrophotometer (ELS-8000, Otsuka Electronics, Japan).amples were dispersed in mineral oil and sonicated for 10 min at20 W (Branson 8210, Branson Ultrasonics Co., Danbury, CT, USA).

harmaceutics 441 (2013) 50– 55 51

2.5. Differential scanning calorimetry (DSC)

DSC measurements were carried out using a DSC S-650 (ScincoCo. Ltd., Korea). Samples of 3–4 mg were accurately weighed andsealed in aluminum pans. Measurements were performed over25–300 ◦C at a heating rate of 10 ◦C/min. An empty pan was usedfor reference; indium, tin, and zinc were used to calibrate baseline,temperature, and enthalpy at a heating rate of 10 ◦C/min. A nitrogenflow rate of 40 ml/min was used for each DSC run to purge.

2.6. Powder X-ray diffraction (PXRD)

Powder X-ray diffraction patterns were recorded on a Rigakupowder X-ray diffraction system (Model D/MAX-2200 Ultima/PC,Japan) with Ni-filtered Cu K� radiation. Samples were run over themost informative range from 5◦ to 60◦ of 2�. The step scan modewas performed with a step size of 0.02◦ at a rate of 2◦/min.

2.7. Solubility studies

Saturation solubility of samples was determined in distilledwater at 37 ± 0.1 ◦C. Samples were placed in a shaking water bath(60 rpm) for 24 h, which was previously determined to be an ade-quate time for equilibration. Suitable aliquots were withdrawn atcertain time intervals and filtered using a 0.45 �m nylon syringefilter. The filtrate was diluted with mobile phase, and the concentra-tion of telmisartan was determined by HPLC. Sodium lauryl sulfate(SLS) was used at a different concentration (0–1%, w/v) in water tomodify the dissolution medium. An excess amount of telmisartan(approximately 100 mg) was placed in 10 ml of SLS solutions andthey were placed in a shaking water bath (60 rpm) for 24 h. Suit-able aliquots were withdrawn at certain time intervals and filteredusing a 0.45 �m nylon syringe filter. The filtrate was diluted withmobile phase, and the concentration of telmisartan was determinedby HPLC. Chromatographic analysis were performed as describedby Tran et al. (2008) using a Waters HPLC system consisting of apump (Model 600, USA), an auto-sampler (Model 717 plus, USA),and a UV detector (Model 486 Tunable Absorbance Detector, USA).A C18 reverse phase column (�BondapakTM, Waters, USA) was usedat room temperature. The mobile phase consisted of a 75:25 (%, v/v)mixture of methanol and 51.8 mM ammonium acetate. The injec-tion volume was 20 �l, and the flow rate was 1.0 ml/min. The signalwas monitored at 296 nm.

2.8. Powder dissolution study

Powder dissolution studies were performed according to theUSP XXVIII paddle method using UDT-804 (Logan InstrumentsCorp., USA). The stirring speed was 50 rpm, and the temperaturewas maintained at 37 ± 0.1 ◦C. Each test was carried out in 900 ml ofdistilled water containing 0.25% (w/v) of SLS. Accurately weightedsamples containing an equivalent amount of telmisartan (20 mg)were placed in the dissolution medium, and 5 ml aliquot sam-ples were withdrawn at given time intervals and filtered usinga 0.45 �m nylon syringe filter. At each sampling time, an equalvolume of the test medium was replaced. Filtered samples wereappropriately diluted with the mobile phase and analyzed for drugconcentration by HPLC.

2.9. Physical stability study

A physical stability study was performed at a temperature of40 ◦C with a humidity of 75% RH for 1 month. Samples were sealedand kept under the severe condition described above, and the crys-tallinity of the drug in solid dispersions was measured by PXRD.

52 J. Park et al. / International Journal of Pharmaceutics 441 (2013) 50– 55

Fig. 1. DSC traces of particles. (a) Raw telmisartan, (b) PPT (processed micronizedamorphous telmisartan without polymer), (c) SDH1:0.5 (telmisartan solid disper-sion with HPMC 1:0.5, drug:additive), (d) SDH1:1 (telmisartan solid dispersion withH(s

3

3

FwHpspodefH

gasDPtsei1

3

R(9iwt(

PMC 1:1), (e) SDH1:2 (telmisartan solid dispersion with HPMC 1:2), (f) SDP1:0.5telmisartan solid dispersion with PVP 1:0.5), (g) SDP1:1 (telmisartan solid disper-ion with PVP 1:1), and (h) SDP1:2 (telmisartan solid dispersion with PVP 1:2).

. Results and discussion

.1. Characterization of solid dispersion

DSC curves of unprocessed and processed particles are shown inig. 1. For unprocessed, raw telmisartan, a sharp endothermic peakas observed at 268.44 ◦C, which is melting point of telmisartan.owever, no endothermic peak was observed in the DSC curve forrocessed pure micronized telmisartan without polymer (PPT). Forolid dispersions with PVP (SDP) and HPMC (SDH), the endothermiceak also disappeared. The lack of an endothermic peak in the DSCf both SDPs and SDHs indicates that the drug was molecularlyispersed and existed in an amorphous form (Jun et al., 2005; Kimt al., 2006; Tran et al., 2008; Yagi et al., 1996). This amorphousorm might arise due to hydrogen bonding between the drug andPMC/PVP which inhibits crystallization (Jun et al., 2005).

The PXRD patterns of telmisartan and its solid dispersions areiven in Fig. 2. The PXRD pattern of raw telmisartan had three char-cteristic peaks of high intensity at 6.8◦, 14.2◦ and 22.3◦ which areimilar to those reported in the literature (Tran et al., 2008). TheSC results revealed, no characteristic peaks for PPT. Similarly, theXRD patterns of SDPs and SDHs showed no characteristic peaks ofelmisartan. PVP and HPMC may act as anti-plasticizers or suppres-ors of crystal growth by adsorbing to the crystal surfaces (Fakest al., 2009; Konno and Taylor, 2006; Yoshioka et al., 1995), form-ng an amorphous solid dispersion (Fakes et al., 2009; Kohri et al.,999).

.2. Solubility and dissolution study

The saturated solubility of samples is summarized in Table 1.aw telmisartan is very slightly soluble in distilled water0.23 �g/ml of telmisartan) even with its large mean particle size of91 nm. However, all processed samples showed increased solubil-

ty from 6- to 38-fold (Table 1). An increase in solubility of poorlyater soluble drugs has been attributed to changes in the crys-

alline form, which was confirmed by the DSC and PXRD resultsAbdul-Fattah and Bhargava, 2002; Kim et al., 2006, 2008; Leuner

Fig. 2. Powder X-ray diffraction patterns of the particles. (a) Raw telmisartan, (b)PPT, (c) SDH1:0.5, (d) SDH1:1, (e) SDH1:2, (f) SDP1:0, (g) SDP1:1, and (h) SDP1:2.

and Dressman, 2000), micronization of the particles (Zhang et al.,2009), and the enhanced wetting properties of PVP and HPMC bylowering surface tension for solid dispersions (Abdul-Fattah andBhargava, 2002; Akbuga et al., 1988; Kim et al., 2006). Moreover,saturated solubility increased with respect to the amount of water-soluble polymeric carrier used. Since HPMC is a more hydrophobicwater-soluble cellulose polymer than PVP, it more easily forms ahydrophobic drug crystal surface to that inhibits recrystallizationof drugs in supersaturated solutions (Hasegawa et al., 1985). Dueto this ability, the HPMC solid dispersion has a higher apparentsolubility than PVP. This result has been confirmed by many otherresearchers (Cilurzo et al., 2002; Hasegawa et al., 1985; Suzuki andSunada, 1998).

From the SEM images in Fig. 3, it is clear that the raw telmis-artan is comprised of large needle like crystals of irregular length.Conversely, PPT had a smaller size with an irregular shape. SASprocessed solid dispersions showed relatively regularly shapedcrystals of sub-micron size. SDPs showed dependency of smallerparticle size on higher concentration of the polymer and morespherical particles; however, for SDHs, polymer concentrationdependency was not detected. SDHs showed spherically shapedparticles connected by small bridges.

For the dissolution study, the dissolution medium was modifiedwith SLS. Phase solubility increased linearly from 21.6-fold (com-pared with water) at 0.1% SLS to 143.5-fold at 1% SLS as summarizedin Table 2. This significant increase was attributed to the micellarsolubilization by SLS (Amidon et al., 1982). As a result of phase sol-ubility effect on SLS, 0.25% of SLS is used for dissolution medium tohave appropriate concentration of telmisartan (20 mg).

The dissolution profiles of telmisartan and solid dispersions areshown in Fig. 4 and summarized in Table 3. The dissolution rate wasexamined for 60 min by plotting the percentage of dissolved telmis-artan against the function of time. Even micronized particles tendedto adsorb air and float on the surface of the medium (Bhattacharet al., 2002; Perrut et al., 2005). All the samples exhibited fasterdrug release than unprocessed raw telmisartan. That is becausethis aerophilization had relatively less effect on the dissolution thanformation of a high energy amorphous phase (Akbuga et al., 1988),decrease in particle size and reduction of surface tension of the dis-solution medium (Nielsen et al., 2006; Thybo et al., 2007). During

the first 10 min, there was an approximately a 3–8-fold increasein the amount of drug in solution from the solid dispersions com-pared to unprocessed raw telmisartan. However, when comparingthe two different polymers, SDHs showed faster drug release; this

J. Park et al. / International Journal of Pharmaceutics 441 (2013) 50– 55 53

Table 1Mean particle size and solubility of the drug and its solid dispersions.

Raw telmisartan PPT SDH1:0.5 SDH1:1 SDH1:2 SDP1:0.5 SDP1:1 SDP1:2

Mean particle sizea (nm) Needle-like shape withirregular length

740 ± 21.4 446.8 ± 37.0 499.6 ± 65.6 464.3 ± 12.6 601.7 ± 95.0 509.7 ± 62.2 375.1 ± 25.7

Solubilityb (�g/ml) 0.23 ± 0.06 1.39 ± 0.23 3.48 ± 0.44 7.12 ± 0.38 8.74 ± 0.30 2.53 ± 0.45 4.95 ± 0.40 6.30 ± 0.11

n = 3, mean ± S.D.a Mean particle size measured by DLS.b Saturated solubility was measured after 24 h at 37 ± 0.5 ◦C.

Fig. 3. SEM images of the particles. (a) Raw telmisartan, (b) PPT, (c) SDH1:0.5, (d) SDH1:1, (e) SDH1:2, (f) SDP1:0.5, (g) SDP1:1, and (h) SDP1:2.

Fig. 4. Dissolution study in distilled water containing SLS 0.25% (w/v). (a) Raw telmisartan, (b) PPT, (c) SDH1:0.5, (d) SDH1:1, (e) SDH1:2, (f) SDP1:0.5, (g) SDP1:1, and (h)SDP1:2.

54 J. Park et al. / International Journal of Pharmaceutics 441 (2013) 50– 55

Table 2Effect of sodium lauryl sulfate on solubility of telmisartan.

SLS (%, w/v) 0 0.1 0.25 0.5 1

Solubility (�g/ml) 0.23 ± 0.06 4.87 ± 0.38 31.04 ± 0.44 68.08 ± 0.81 143.57 ± 0.76

Table 3Dissolution rate at 10 and 60 min.

Dissolution rate (%)

Raw telmisartan PPT SDH1:0.5 SDH1:1 SDH1:2 SDP1:0.5 SDP1:1 SDP1:2

D 13.9 100.2 98.0 84.7 73.8 95.2 58.6 45.599.2

D

rItai2efolsettsoItolmp

stpr

FR(

10

D60 30.4 98.3 98.4

10 is the dissolution rate in 10 min; D60 is the dissolution rate in 60 min.

esult was expected based on the results of our solubility studies.nterestingly, higher solubility was obtained at higher weight frac-ions of polymer, while the higher dissolution rates were obtainedt lower weight fractions of PVP and HPMC. These results are sim-lar to those obtained by several other researchers (Ishikawa et al.,000; Pandit and Khakurel, 1984; Tantishaiyakul et al., 1996; Thybot al., 2007). Pandit and Khakurel (1984) suggested two factorsor this phenomenon: (a) the polymer has little solubilizing actionn the drug and (b) at higher polymer concentrations the carriereaches out during dissolution and forms a concentrated layer ofolution around the drug particles, which may either be free ormbedded in the carrier; the migration of the released drug par-icles to the bulk of the dissolution medium is slowed down, andhe decrease in dissolution rate is due to a viscosity effect. Sinceolubility study result showed that polymer has solubilizing effectn telmisartan, the reason might be due to forming a layer. Alsoshikawa et al. (2000) reported that, HPMC forms a gel layer onhe surface of the particle due to swelling of HPMC in the presencef water. Therefore, the more HPMC that is used, the thicker theayer formed (Ju et al., 1995) with telmisartan. Consequently, the

ore polymer that is used, the slower the drug is released from theowder.

PPT showed the fastest dissolution rate among all the otheramples. Although it also showed the lowest solubility compared

o other solid dispersions, no polymers formed layers around thearticles, and it had the smallest particle size, thus, the drug waseleased quickly.

ig. 5. Powder X-ray diffraction patterns of particles after 1 month at 40 ◦C and 75%H. (a) Raw telmisartan, (b) PPT, (c) SDH1:0.5, (d) SDH1:1, (e) SDH1:2, (f) SDP1:0.5,g) SDP1:1, and (h) SDP1:2.

98.9 100.0 98.8 87.6

3.3. Physical stability study

The physical stability of solid dispersions was investigated usingPXRD. The samples were stored under severe conditions at 40 ◦Cand 75% RH for 1 month. SDHs and SDPs did not show any significantchanges in these conditions, indicating there was no recrystalliza-tion of telmisartan which maintained its amorphous state (Fig. 5).However, PPT was recrystallized during the storage period, indicat-ing that PVP and HPMC are effective recrystallization inhibitors fortelmisartan.

4. Conclusions

Solid dispersions of telmisartan with PVP/HPMC and micronizedamorphous telmisartan were prepared using the SAS process. Themean particle size of SAS processed samples was smaller than thatof unprocessed telmisartan. The results of DSC and PXRD studiesshowed that all SAS processed samples initially existed in the amor-phous state. The solubility and dissolution rates of SDHs, SDPs andPPT were markedly higher than for unprocessed raw telmisartan.However, dissolution studies demonstrated that when more poly-mers were used, slower dissolution rates were achieved due to theformation of a polymer layer; therefore, PPT showed the highestdissolution rate. Physical stability studies, however, showed thatPPT tends to recrystallize. Therefore, further studies are necessaryto determine the concentrations of polymers needed to increase thesolubility and dissolution rate of telmisartan while maintaining itsstability. The results of this study suggest that the preparation oftelmisartan solid dispersion using SAS process could be a promis-ing approach for improving the solubility and dissolution rate oftelmisartan.

Acknowledgement

This work was supported by the Yonsei University ResearchFund of 2011.

References

Abdul-Fattah, A.M., Bhargava, H.N., 2002. Preparation and in vitro evaluation of soliddispersions of halofantrine. Int. J. Pharm. 235, 17–33.

Akbuga, J., Gursoy, A., Kendi, E., 1988. The preparation and stability of fast releasefurosemide–PVP solid dispersion. Drug Dev. Ind. Pharm. 14, 1439–1464.

Al-Marzouqi, A.H., Shehatta, I., Jobe, B., Dowaidar, A., 2006. Phase solubility andinclusion complex of itraconazole with beta-cyclodextrin using supercriticalcarbon dioxide. J. Pharm. Sci. 95, 292–304.

Amidon, G.E., Higuchi, W.I., Ho, N.F.H., 1982. Theoretical and experimental studiesof transport of micelle-solubilized solutes. J. Pharm. Sci. 71, 77–84.

Bhattachar, S.N., Wesley, J.A., Fioritto, A., Martin, P.J., Babu, S.R., 2002. Dissolutiontesting of a poorly soluble compound using the flow-through cell dissolutionapparatus. Int. J. Pharm. 236, 135–143.

Chiou, W.L., Riegelman, S., 1971. Pharmaceutical applications of solid dispersionsystems. J. Pharm. Sci. 60, 1281–1302.

al of P

C

F

F

H

I

J

J

J

K

K

K

K

J. Park et al. / International Journ

ilurzo, F., Minghetti, P., Casiraghi, A., Montanari, L., 2002. Char-acterization of nifedipine solid dispersions. Int. J. Pharm. 242,313–317.

akes, M.G., Vakkalagadda, B.J., Qian, F., Desikan, S., Gandhi, R.B., Lai, C., Hsieh, A.,Franchini, M.K., Toale, H., Brown, J., 2009. Enhancement of oral bioavailabil-ity of an HIV-attachment inhibitor by nanosizing and amorphous formulationapproaches. Int. J. Pharm. 370, 167–174.

ord, J.L., Elliott, P.N.C., 1985. The effect of particle size on some in-vitro and in-vivoproperties of indomethacin–polyethylene glycol 6000 solid dispersions. DrugDev. Ind. Pharm. 11, 537–549.

asegawa, A., Kawamura, R., Nakagawa, H., Sugimoto, I., 1985. Dissolution mech-anism of solid dispersions of nifedipine with enteric coating agents. YakugakuZasshi 105, 586–592.

shikawa, T., Watanabe, Y., Takayama, K., Endo, H., Matsumoto, M., 2000. Effect ofhydroxypropylmethylcellulose (HPMC) on the release profiles and bioavailabil-ity of a poorly water-soluble drug from tablets prepared using macrogol andHPMC. Int. J. Pharm. 202, 173–178.

u, R.T.C., Nixon, P.R., Patel, M.V., 1995. Drug release from hydrophilic matrices. 1.New scaling laws for predicting polymer and drug release based on the poly-mer disentanglement concentration and the diffusion layer. J. Pharm. Sci. 84,1455–1463.

un, S.W., Kim, M.-S., Jo, G.H., Lee, S., Woo, J.S., Park, J.-S., Hwang, S.-J., 2005. Cefuroxime axetil solid dispersions prepared using solutionenhanced dispersion by supercritical fluids. J. Pharm. Pharmacol. 57,1529–1537.

un, S.W., Kim, M.-S., Kim, J.-S., Park, H.J., Lee, S., Woo, J.-S., Hwang, S.-J., 2007. Prepa-ration and characterization of simvastatin/hydroxypropyl-[beta]-cyclodextrininclusion complex using supercritical antisolvent (SAS) process. Eur. J. Pharm.Biopharm. 66, 413–421.

im, E.-J., Chun, M.-K., Jang, J.-S., Lee, I.-H., Lee, K.-R., Choi, H.-K., 2006. Preparationof a solid dispersion of felodipine using a solvent wetting method. Eur. J. Pharm.Biopharm. 64, 200–205.

im, M.-S., Jin, S.-J., Kim, J.-S., Park, H.J., Song, H.-S., Neubert, R.H.H., Hwang, S.-J.,2008. Preparation, characterization and in vivo evaluation of amorphous ator-vastatin calcium nanoparticles using supercritical antisolvent (SAS) process. Eur.J. Pharm. Biopharm. 69, 454–465.

im, M.-S., Lee, S., Park, J.-S., Woo, J.-S., Hwang, S.-J., 2007. Micronization of cilosta-

zol using supercritical antisolvent (SAS) process: effect of process parameters.Powder Technol. 177, 64–70.

ohri, N., Yamayoshi, Y., Xin, H., Iseki, K., Sato, N., Todo, S., Miyazaki, K., 1999. Improv-ing the oral bioavailability of albendazole in rabbits by the solid dispersiontechnique. J. Pharm. Pharmacol. 51, 159–164.

harmaceutics 441 (2013) 50– 55 55

Konno, H., Taylor, L.S., 2006. Influence of different polymers on the crystalliza-tion tendency of molecularly dispersed amorphous felodipine. J. Pharm. Sci. 95,2692–2705.

Löbenberg, R., Amidon, G.L., 2000. Modern bioavailability, bioequivalence and bio-pharmaceutics classification system. New scientific approaches to internationalregulatory standards. Eur. J. Pharm. Biopharm. 50, 3–12.

Leuner, C., Dressman, J., 2000. Improving drug solubility for oral delivery using soliddispersions. Eur. J. Pharm. Biopharm. 50, 47–60.

Nielsen, A.F., Bertelsen, P., Kristensen, H.G., Kristensen, J., Hovgaard, L., 2006.Investigation and comparison of performance of effervescent and standardpneumatic atomizer intended for soluble aqueous coating. Pharm. Dev. Technol.11, 243–253.

Pandit, J.K., Khakurel, B.K., 1984. In vitro and in vivo evaluation of some fast releasedosage forms of hydrochlorothiazide. Drug Dev. Ind. Pharm. 10, 1709–1724.

Park, J., Park, H., Cho, W., Cha, K.-H., Yeon, W., Kim, M.-S., Kim, J.-S., Hwang, S.-J.,2011. Comparative study of telmisartan tablets prepared via the wet granulationmethod and pritorTM prepared using the spray-drying method. Arch. PharmacalRes. 34, 463–468.

Peeters, J., Neeskens, P., Tollenaere, J.P., Remoortere, P.V., Brewster, M.E., 2002.Characterization of the interaction of 2-hydroxypropyl-beta-cyclodextrin withitraconazole at pH 2, 4, and 7. J. Pharm. Sci. 91, 1414–1422.

Perrut, M., Jung, J., Leboeuf, F., 2005. Enhancement of dissolution rate of poorly-soluble active ingredients by supercritical fluid processes. Part I. Micronizationof neat particles. Int. J. Pharm. 288, 3–10.

Suzuki, H., Sunada, H., 1998. Influence of water-soluble polymers on the dissolutionof Nifedipine solid dispersions with combined carriers. Chem. Pharm. Bull. 46,482–487.

Tantishaiyakul, V., Kaewnopparat, N., Ingkatawornwong, S., 1996. Properties of soliddispersions of piroxicam in polyvinylpyrrolidone K-30. Int. J. Pharm. 143, 59–66.

Thybo, P., Kristensen, J., Hovgaard, L., 2007. Characterization and physical stabilityof tolfenamic acid-PVP K30 solid dispersions. Pharm. Dev. Technol. 12, 43–53.

Tran, P.H.L., Tran, H.T.T., Lee, B.-J., 2008. Modulation of microenvironmental pH andcrystallinity of ionizable telmisartan using alkalizers in solid dispersions forcontrolled release. J. Control. Release 129, 59–65.

Yagi, N., Terashima, Y., Kenmotsu, H., Sekikawa, H., Takada, M., 1996. Dis-solution behavior of probucol from solid dispersion system of probucol-polyvinylpyrrolidone. Chem. Pharm. Bull. 44, 241–244.

Yoshioka, M., Hancock, B.C., Zografi, G., 1995. Inhibition of indomethacin crystalliza-tion in poly(vinylpyrrolidone) coprecipitates. J. Pharm. Sci. 84, 983–986.

Zhang, H.-X., Wang, J.-X., Zhang, Z.-B., Le, Y., Shen, Z.-G., Chen, J.-F., 2009. Microniza-tion of atorvastatin calcium by antisolvent precipitation process. Int. J. Pharm.374, 106–113.