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J. of Supercritical Fluids 164 (2020) 104892

Contents lists available at ScienceDirect

The Journal of Supercritical Fluids

j our na l ho me page: www.elsev ier .com/ locate /supf lu

ansoprazole loading of polymers by supercritical carbon dioxidempregnation: Impacts of process parameters

rezu Ameri a,b, Gholamhossein Sodeifian a,b,c,∗, Seyed Ali Sajadian a,b,d

Department of Chemical Engineering, Faculty of Engineering, University of Kashan, 87317-53153, Kashan, IranLaboratory of Supercriritcal Fluids and Nanotechnology, University of Kashan, 87317-53153, Kashan, IranModeling and Simulation Centre, Faculty of Engineering, University of Kashan, 87317-53153, Kashan, IranSouth Zagros Oil and Gas Production, National Iranian Oil Company, 7135717991, Shiraz, Iran

i g h l i g h t s

Lansoprazole was successfullyimpregnated onto PVP and HPMC forthe first time.The effect of temperature, pressureimpregnation and time was investi-gated.Impregnation process was optimizedusing BBD.Rise in temperature had the mosteffect on drug loading.The structure and behavior of drugand polymers were analyzed.

g r a p h i c a l a b s t r a c t

r t i c l e i n f o

rticle history:eceived 5 December 2019eceived in revised form 30 April 2020ccepted 4 May 2020vailable online 12 May 2020

a b s t r a c t

This is the first work to load HPMC and PVP by the lansoprazole (LPZ) through supercritical solventimpregnation (SSI). The process was carried out at laboratory scale under various sets of conditions interms of pressure (150−250 bar), temperature (308−328 K), and impregnation time (60−180 min). Theresults showed that an increase in any of the investigated parameters increased the drug loading, andthat the temperature imposed the strongest effect on the drug loading. Moreover, impregnation loadingsonto the PVP and HPMC were found to range from 0.56% to 0.61% and from 1.16% to 1.30%, respectively.

eywords:ansoprazoleVPPMC

mpregnationupercritical fluid (SCF)

For both polymers, the best results were obtained at a pressure of 250 bar and a temperature of 328 Kwith an impregnation time of 180 min. The processed drug was further investigated by XRD, SEM, DSC,FTIR, and DLS analyses. The final results indicated superior loading of the drug onto the HPMC rather thanthe PVP.

© 2020 Elsevier B.V. All rights reserved.

upercritical solvent impregnation (SSI)

∗ Corresponding author.E-mail address: [email protected] (G. Sodeifian).

ttps://doi.org/10.1016/j.supflu.2020.104892896-8446/© 2020 Elsevier B.V. All rights reserved.

1. Introduction

Being among the most commonly used drugs for gas-trointestinal disorders, the lansoprazole (LPZ) is available in

various forms, including capsules, dispersible tablets, andenteric-coated suppositories. Chemically speaking, LPZ refersto 2-(2-benzimidazolysulfinylmethyl)-3methyl-4-(2,2,2-trifl-

https://doi.org/10.1016/j.supflu.2020.104892http://www.sciencedirect.com/science/journal/08968446http://www.elsevier.com/locate/supfluhttp://crossmark.crossref.org/dialog/?doi=10.1016/j.supflu.2020.104892&domain=pdfmailto:[email protected]://doi.org/10.1016/j.supflu.2020.104892

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A. Ameri, G. Sodeifian and S.A. Sajadian

oroethoxy) pyridine [1]. Thanks to its function as a gastric protonump inhibitor (PPI), it has been applied as a prophylactic or ther-peutic agent for the treatment of the gastritis disease, digestivelcer, reflux esophagitis, upper gastrointestinal hemorrhage, gas-ric cancer, postoperative stress-resulted ulcer, and the illnessesssociated with the helicobacter pylori [2–4].

Solubility is a significant factor that affects not only the drugesign, but also its separation and purification procedures. As aethanol-soluble compound, the LPZ exhibits very low solubility

n ethanol, relatively low solubility in ethyl acetate and acetoni-rile, and just a little solubility in ether, with the compound beingnsoluble in hexane and water. Measurements have indicated a

ater-solubility of 0.044 mg/mL for this drug [2,5,6].A common approach to increasing the solubility and bioavail-

bility of a drug inside the human body is to reduce the drugarticle size. There are several methods for synthesizing nano-sizedarticles, each of which leading to the preparation of nanoparti-les with different properties. Recently, supercritical fluids (SCFs)ave been proposed as suitable media for the production of micro-nd nano-sized particles of drugs [7]. Common SCF processes haveeturned promising results; these include gas anti-solvent (GAS),apid expansion of the supercritical solution (RESS), supercriticalnti-solvent (SAS), particles from gas-saturated solution (PGSS),nd solution-enhanced dispersion by supercritical fluids (SEDS)8–11]. However, it is still difficult to control the characteristicsf the particles produced through these processes, especially in thease of coprecipitation of active compounds together with carrieraterials. As an alternative for obtaining a drug delivery system,

mpregnation in supercritical carbon dioxide can be used to incor-orate the active compound into previously formed particles of thearrier material [10].

Among others, outstanding properties of the SCFs includeiquid-range density, superior solvating power, low viscosity, andnhanced diffusivity and mass transfer coefficient, which makehem good candidates for replacing the organic solvents in a largeumber of applications in the industrial context (e.g. chemicalnd biochemical reactions, separation and purification processes,nd particle synthesis schedules) as well as more recent applica-ions related to the processing of polymers and other materials12–17]. The carbon dioxide offers numerous favorable proper-ies, including moderate critical pressure and temperature (7.38

Pa and 304 K, respectively), non-toxicity, non-flammability, non-xplosiveness and abundant availability at high levels of purity.oreover, under ambient pressure and temperature conditions,

O2 is gaseous and therefore its separation at the end of the pro-ess requires a depressurization stage. Besides, SC−CO2 has biocidalroperties [18–20]. Thanks to its unique characteristics, the car-on dioxide has been extensively used as a supercritical solvent

n the chemical processes encountered in the pharmaceutical andiochemical industries where miniaturization of the drug parti-les is a preliminary objective for the ultimate goal of enhancedioavailability of the drug in the body [21–28].

The supercritical solvent impregnation (SSI) has emerged asn effective method to incorporate active compounds into mate-ials for different applications. In particular, SSI is an innovativeechnique to produce pharmaceutical composite systems [29–31].sing this process, one can load the active compound onto exist-

ng carrier medium particles, making it simpler to control theharacteristics of the ultimate product. This is because of the inde-endence of the stages wherein the carrier medium particles are

ormed and then the active compound is loaded on the previ-usly formed particles. Three methodologies have been developed

or implementing the SSI process, namely static, semi-dynamic,nd dynamic methods. The balance of interactions among therug, impregnation support and the SCF make the drug molecules

mpregnate in the carrier medium; this ends up with the adsorption

Supercritical Fluids 164 (2020) 104892

of the drug molecules, which herein refers to the physicochemicalattachment of the drug molecules onto the polymeric matrix sup-port [32]. When applied to polymers, the plasticizing effect (glasstransition temperature depression) and the swelling effect of theSCF on glassy polymers can influence solute loading and impreg-nation [33]. Moreover, the SSI has been employed in several fieldswithin the chemical and food industry. The most common casesinclude the bioactive impregnation, supercritical aerogel impreg-nation, porous scaffolds, polymer dyeing and drug-loaded implants[33–39].

Mining into the previously published literature showed thatRojas et al. [31] investigated supercritical impregnation for foodapplications and reviewed the investigated impregnation parame-ters. In addition, the effects of the processing variables of the SSIprocess (pressure, temperature, depressurization rate and time)were discussed in terms of the incorporation of active compoundsinto polymer structures.

Bouledjouidja et al. [40] investigated the application ofSC−CO2 to impregnate ciprofloxacin (CIP) and dexamethasone 21-phosphate disodium (DXP) in intraocular lenses (IOLs). Optimaloperating conditions for P-HEMA IOLs were determined by inves-tigating different parameters including the temperature, pressure,the rate of pressure changes, cosolvent application, and the impreg-nation time. In all cases, the DXP exhibited further impregnationin P-HEMA, as compared to the CIP. In another work, the authorsstudied several drug components and IOLs combinations anddemonstrated that an effective and in-depth impregnation is influ-enced by different parameters including the temperature, pressure,the rate of pressure changes, cosolvent application, and the impreg-nation time. In all cases, the sustained release was observed whilepreserving the optical properties of the IOLs [41–43].

Costa et al. [44] sought to improve particular eye diseases.They used the SCF impregnation method, considered the optimalexperimental conditions (T =40 ◦C, P = 170 bar, ti =90 min), andimpregnated the commercially available silicon-based hydrogelcontact lenses (Balafilcon A) using a pair of anti-glaucoma drugs,namely acetazolamide and timolol maleate. Results showed thatthe drug-loaded contact lenses could not only treat the eye disease,but also mitigate the unwanted side effects.

Examining the SC impregnation of food packaging films for thepurpose of improved antioxidant characteristics, Bastante et al.[45] suggested that, unlike other approaches to the preparation ofantioxidant films, the SSI provides a film with antioxidant capabil-ity immediately upon the manufacturing, making the final productsolvent-free. Tang et al. [46] employed the SC impregnation toload the ibuprofen onto already prepared chitosan film. Investi-gating the contributions from the pressure and temperature intothe morphology of the chitosan film upon loading the ibuprofen,an improvement in the drug loading capacity (DLC) was observedin comparison to similar methods, with DLC increasing from 7.9 to130.4% during this process. In addition, the drug release could becontrolled to minimize the precipitation. Bouledjouidja et al. [47]applied two processes, namely incipient wetness and SC impreg-nation, to load fenofibrate, a slightly water-soluble drug, into silicasamples with an ordered mesoporous structure. The results indi-cated superior yield of the latter method within shorter processingtimes. In another study, Belizón et al. [38] conducted a studywhere antioxidant mango polyphenols were SC-impregnated into afood-grade multilayer PET/PP film to achieve enhanced food pack-aging for the ultimate goal of increasing the product shelf lifewhile maintaining its flavor and safety requirements. Varona et al.[10] presented a research on the production of natural pesticides,

instead of chemicals, to make the essential oil a sort of efficientadditive for the livestock farming industry. The essential oil fromlavandin was further impregnated into modified starch using theSC impregnation method. The results showed higher loading per-

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Table 1Review of some published works on the subject-matter of impregnation in various contexts (e.g. the food and pharmaceutical industries).

Compound Method Cosolvent Material Pressure(MPa)

Temperature(◦C)

Depressurizationrate (MPa/min)

Time (h) Highest impregnationpercentage (wt/wt)%

References

Ketoprofene Semi static – PVP(polyvinylpyrrolidone)

19 40 to 60 120 58 [52]

Flurbiprofen Semi static – P(MMA-EHA-EGDMA)

10 to 18 35 to 40 3 and 5 0.82 [53]

�-tocopherylacetate

Semi static – Silica mesoporous 8 to 15 40 1 53 [54]

Roxythromycin Static – PLLA films 8 to 30 40 to 70 in 10 minutes 0.5 to 2 10.5 [55]Lavandin oil Static – Modified starch

powder10, 11 and12

40 to 50 0.07 to 0.15 2 15 [10]

Lactulose Static anddynamic

Ethanol:water Chitosan scaffoldsand microspheres

10 100 0.6, 1 and 3.3 1 and 3 8.6 [56]

Lecithin anderythorbate

Static Ethanol HDPE, high-densitypolyethylene films

20.7 65 0.75 [57]

Flax oil Static anddynamic

Ethanol b-glucan aerogels 15 and 30 40 and 60 2, 6 and 8 65.39 [58]

Indomethacin Static – PLA/PLGA 18 40 6 to 0.2 1 [59]Oregano Essential

oilStatic – Starch

microspheres8 to 15 40 to 50 0.0083 to 0.11 3, 6 and 24 [60]

Natamycin Static Ethanol Alginate films 20 40 2.5, 4 and 14 16.29 [61]Thymol Static – LLDPE films 7, 9 and 12 40 4 1.3 [62]Cinnamaldehyde Static – Cassava starch

films15 and 25 35 1 and 10 3 and 15 0.25 [63]

Ketoprofen Static – PLLA, PET and PPfilms

10 to 35 40 to 1400.0017, 0.1 and0.06

332.5

[64]Aspirin Static – 8.1Indomethacin Static Ethanol–water PVP and Soluplus 10 and 15 60 and 70 in 30 s 2 [65]2-nonanone Static – LLDPE films 12, 17 and

2240 1 and 10 3 0.34 [66]

Thymol Static – Starch gels 15.5 35 0.3 24 4.02 [67]Thymol Static – Cellulose acetate

films10, 15 and20

35 and 50 0.3 2 to 32 72.26 [68]

Vitamin K3 and D3 Static – Alginate aerogelspheres

15 and 20 40 0.3 1 to 24 ∼12 [36]

Vitamin D3 Static – Alginate aerogelspheres

8 5, 15, 25 and 35 1 to 24 ∼12 [22]

Eugenol Static Ethanol LLDPE films 10, 12 and15

45 0.5, 1 and 1.5 24 6 [69]

Phytol Static – Silica and alginateaerogels

200 40 0.2 28 and 32 30.1 [70]

Thymol Static – Cellulose acetatefilms

10 35 2 and 5 63.84 [71]

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Table 1 (Continued)


Temperature(◦C)



References

Phytosterols Semi Static – Nanoporous starchaerogels

45 70 1 L/min(atmosphericconditions)

3 5.5 [72]

CIP Static EthanolP-HEMA

8 to 20 35 0.2 0.5 to 4 0.41[40]

DXP Static Ethanol 8 to 20 35 0.2 2 1.45Olive leaf extract

and caffeic acidStatic Ethanol PET/PP films 10, 20, 30

and 4035 and 55 0.1 and 10 0 to 4 [73]

Clove essential oil Static – LLDPE films 12 and 20 25, 35 and 45 3 4.02 [16]Phytosterols Semi dynamic – Nanoporous starch

aerogels45 70, 90 and 120 1 L/min

(atmosphericconditions)

4 9.9 [35]

Thmoquinone andR-(+)-pulegone

Static – LDPE films 10 and 15 45 0.5 and 2 2 and 4 5.59 [74]


Temperature(◦C)

DepressurizationRate (MPa/min)


References

Thmoquinone andR-(+)-pulegone

Static – LDPE/Sepiolitenanocompositefilms

9 and 13 45 0.5 and 2 2 and 4 8.6 [75]

Thymol Static – LDPE/C20A 12 40 1 and 10 0.25 to 5 1.19 [76]Cinnamaldehyde Static – PLA films 9 and 12 40 0.1 to 10 3 13 [77]Thymol Static – PLA films 9 and 12 40 0.1 to 1 3 20.5 [78]MLE(mango leaf

extract)Static Methanol

and ethanolPolyester Tissue 40 and 50 35 and 55 0.06, 0.11 and 2.5 22 55.8 [79]

Thymol Static – PLA/nanofibers 12 40 1 22 24 [78]ZnO/NiO

nanocompositeStatic Methanol Ordered

mesoporousAlumina

20 50 4 10.33 [80]

Cinnamaldehyde Static – PLA electrospunmats

12 40 1 3 3.29 [81]

Methyle gallat Static Ethanol PET/PP films 10 and 20 35, 45 and 55 0.2 3, 15 and 22 0.004 [38]Thymol Static – LDPE/Cloisite 20A

nanocompositefilms

9, 12 and15

40 10 0.5 to 5 1.62 [78]

Carvedilol Static – PVP, HPMC,Soluplus andEudragit

30 100 1.5 2 [82]

Thymol Static – PLA 20 to 30 100 to 120 0.05 2 and 24 19.8[83]Thymol Dynamic – PLA 30 100 0.064 ± 0.017 2 to 5 1.1 ± 0.019

Thymol extract Semi Static – PLA 30 100 0.064 ± 0.17 2 to 5 0.7 ± 0.07Hydromorphone Static – PLGA

microparticles14 40 0.5 to 1 9.2 [26]

Carvacrol Static – Cellulose acetate 21 50 0.3 to 36 0.5 to 2 31.4 [84]Carvone Static – LDPE films 7.6 to 9.7 35 and 60 0.6 2 to 4 4.8 [85]

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Table 1 (Continued)


Temperature(◦C)



References

Eugenol Static Ethanol Polyamid fiber 8 to 12 60 0.5 to 5 2 15 [86]Nimesulide Static – Polycaprolactone 10 to 20 35, 40, 50 and

601 4 and 8 35 [87]

Eutectic blend(LA:MA)

Static – Gauze 10 40 in 1 minute 1 [88]

Lycopene Static – HydrolysedCollagen (LLHC)

15 and 25 50 and 60 in 15 minutes 0.75 8.5 [89]

Nitrendipine Static Ethanol PLLA-PEG-PLLA 10 to 20 35, 45 and 55 2 10.5 [90]Caffeine Static – MG-MOF-74 10 40 2 2 to 24 34.3

[91]Caffeine Static – MIL-53(Al) 10 40 2 2 to 24 32.1Carvacrol Static – MG-MOF-74 10 40 2 2 to 24 30.1Carvacrol Static – MIL-53(Al) 10 40 2 2 to 24 34�-tocopheryl(TOC) Static – PP, PET and PP/PET 17 40 0.1 2 to 48 3.2 mg TOC/cm2 film [92]Tetraethoxysilane(TEOS) Static – Celgard membrane 30 to 43 40 24 [93]Cinnamaldehyde Static – PLA 12 40 1 11

[94]Cinnamaldehyde Static – PLA/C30B 12 40 1 12Thymol Static – PLA 12 40 1 16Thymol Static – PLA/C30B 12 40 1 17

Temperature(◦C)



References

Acetazolamide Static Ethanol andwater

Silica-basedhydrogels

17 40 0.06 1.30 1.97 [44]

�-tocopheryl Static – Ultra-highmolecular weightPE

10−30 130−170 – – 1 [95]

Acetazolamide Static Ethanol andwater

Silica-basedhydrogels

15−20 40−50 0.06 1,2 and 3 1.97 [96]

Ketoprofen Static – PLGA 6.5−30 25−55 – – 57Timolol maleate Static Ethanol and

waterSilica-basedhydrogels

17 40 – – 1.8 [44]

Ibuprofen Static – PVP 10 40 – – 30 [50]Piroxam Static – PVP 10−60 40 – – 3.9 [97]Tranilast Static Ethanol PLLA 22 80−120 – – 0.9 [98]Acetylsalicylic acid Static – PLLA 8−10 40 2−30 mL/min 3 29 [99]Triflusal Static – PMMA 15−20 35−40 0.2−0.4 12−16 21.7 [100]Ibuprofen Static – PMMA 13.8−20.7 40−50 – – 25 [15]Cefuroxime sodium Static Ethanol PMMA 8−20 35−60 – 1−5 0.063 [101]Megesterol acetate Static – PVP 13 40 – – 0.08 [102]Nimesulide Static – PVP 16−19 45 – – 9.7 [102]Ppaclitaxel Static Ethanol P(D.L)LA 20 40 – 3−5 0.13 [103]Acetylsalicylic acid Static – PP 10−35 40−130 – 3 5 [64]Progesterone Static – PU 15.2 45 – – 8 [104]Hydroxycoumarin Static – PU 15 40 – – 0.3 [105]

6 / J. of Supercritical Fluids 164 (2020) 104892

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Table 2Uncoded and coded levels of independent variables used in the BBD for impregnationof LPZ/PVP and LPZ/HPMC.

Coded levels Pressure (X1, bar) Temperature (X2, K) Time (X3, min)


ormance through the SC impregnation method, as compared toimilar approaches including PGSS. Being a highly crystalline andlightly water-soluble drug, the indomethacin has been used forhe treatment of ankylosing spondylitis, rheumatoid arthritis, acuteout disease, and osteoarthritis [48–50]. Gnog et al. [51] used a SCIethod wherein chitosan was utilized as a polymer to enhance

he indomethacin solubility through extending its surface arear making the drug stabilized. Table 1 presents a comprehensiveeview of the previously published works on the subject-matter ofmpregnation in various contexts (e.g. the food and pharmaceuticalndustries).

The two polymers used in this work, namely hydroxypropylethylcellulose (HPMC) and poly(N-vinyl-2-pyrrolidone) (PVP),

ffered the following advantages when utilized as a coating mate-ial: (1) controlling the release mechanism and pattern as well as

echanical characteristics of the drug, (2) enhancing the forma-ion and storage stability of the film, and (3) presenting potentialsor developing site-specific drug delivery systems by which theastrointestinal tract could be treated [106–111]. The HPMC is aatural polymer material that is mainly derived from cellulose asaw material [4]. It is a water-soluble compound exhibiting pHtability and significant thickening and adhesion properties. Pos-essing an amide ring, the poly(N-vinyl-2-pyrrolidone) (PVP) is aolar molecule, making it suitable for hydrogen bonding. It is sol-ble in water and many other polar solvents. The main featuresf the PVP include (1) a wide range of solubilities and solvent-ompatibilities, (2) physiological neutrality, and (3) ability to formlms and complexes with other materials.

Our investigations showed no previous report on the impreg-ation of HPMC and PVP polymers with LPZ drug by SSI. Therefore,he present study discusses the application of impregnation ofrugs onto the polymers for improving the drug solubility in theody. For this purpose, the effects of three important parame-ers, namely temperature, impregnation time, and pressure, onhe impregnation process were examined. Additionally, the struc-ure and behavior of the impregnated drug nanoparticles werenalyzed through scanning electron microscopy (SEM), dynamicight scanning (DLS), differential scanning calorimetry (DSC), X-rayiffraction (XRD) analysis, and Fourier transform infrared (FTIR)pectroscopy.

. Material and methods

.1. Materials

Lansoprazole (LPZ) (CAS no. 103577-45-3) with a minimumurity of 99% was provided by Amin Pharmaceutical Company (Isfa-an, Iran). Fadak Company (Kashan, Iran) served as the provider ofarbon dioxide (CO2) (CAS No. 124-38-9) at a purity beyond 99.99%.hese two materials were used as received with no further purifi-ation. The PVP, with an average molecular weight of Mw ∼ 40,000/mole, and HPMC, with a viscosity of 4000 cPs (HPMC K4M), wererocured from Sigma Aldrich (Germany). For each experiment, 100g of the powdered polymer, in pure form, was compacted (with

o additives) in a hydraulic tablet press (Perkin Elmer, Hydraulis-he Presse) under a load of 10 tons to change the powder to a tabletith a diameter of 5 mm. The chemical structures of PVP, LPZ andPMC are presented in Fig.1.

.2. Methods

.2.1. Design of experimentDesign of experiments (DOE) is a quality-focused approach that

acilitates the process of product design and manufacturing. Usinghis method, the researcher can develop the whole production

−1 150 308 600 200 318 120+1 250 328 180

process by designing sub-processes that are resilient to environ-mental factors [112]. Among others, this methodology providesfor examining the impacts of different variables on the responseand modeling the relationships among them to identify the mostsignificant input parameters affecting the output [113]. Variousapproaches to the DOE have been presented. As a common DOEtechnique, the three-level Box-Behnken design (BBD) has beenemployed to optimize the process parameters for LPZ-impregnatedPVP and HPMC through SC-CO2. In this work, the BBD was appliedto study not only the main effects of pressure (150−250 bar), tem-perature (308.2–328.2 K), and impregnation time (60−180 min),but also their interaction effects and quadratic impacts on the drugloading. For this purpose, as shown in Table 2, the considered vari-ables were designated as pressure (X1), temperature (X2), and time(X3) and examined at three levels coded as -1, 0, and 1, indicatinghigh, intermediate and low values, respectively. For the sake of sta-tistical calculations, the relationship between the coded and actualvalues was described as follows:

Xi =Zi − Zo�Z

(1)

where Xi is the coded value of the respective variable, Zi is the actualvalue corresponding to the Xi, and Z0 denotes the actual value atthe center point. Accordingly, �Z expresses the step change of theconsidered variable.

The three variables were mathematically modelled using aquadratic polynomial model whose coefficients were calculatedthrough a multiple regression analysis. The general form of thismodel is as follows:

Y = A0 +3∑

i=1Aixi +

3∑

i=1Aiix

2i +

3∑

i=1

3∑

j>1

Aijxixj + ε (2)

where Y represents the predicted response, Ao is a constant coef-ficient, Ai is the first-order linear coefficient, Aii is the quadraticcoefficient, Aij is the coefficient of interaction, xi and xj are codedlevels of the respective independent variable, and ε is the asso-ciated random error [114]. Statistical analysis was performedusing Design-Expert software (version 7.0.0). Analysis of variance(ANOVA) provides a summary of the considered parameters, theireffects on the dependent variable, and the significance of theireffects (p-value and F-value) [115,116]. The so-called adjustedcoefficient of determination, R2 adj., was used to evaluate thegoodness-of-fit of the regression model. Finally, response surfaceswere drawn in a 3D space to determine the optimum set of condi-tions for loading.

2.2.2. Supercritical carbon dioxide impregnation experimentsThe SC-CO2 impregnation tests were performed at lab scale, as

schematically demonstrated in Fig. 2. The batch apparatus usedin this work was made up of a CO2 cylinder, a filter (Hylok, 6000psi), a refrigerator, a high-pressure liquid CO2 pump (Haskel pump,MSHP-110), a heating coil, an impregnation cell containing thepolymers and the drug, an oven (AE−60), a magnetic stirrer, a vent,

and a controller. Pressure measurements (WIKA) were performedat an accuracy of ±1 bar. In order to maintain the temperature atthe desired level, the equilibrium cell was mounted in an oven(Froilabo model, AE−60, France) wherein the temperature mea-

A. Ameri, G. Sodeifian and S.A. Sajadian / J. of Supercritical Fluids 164 (2020) 104892 7

Fig. 1. Chemical structures of PVP, LPZ and HPMC.

s of su

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Fig. 2. Experimental apparatu

urements were conducted at an accuracy of ±0.1 K. The cell wasurther equipped with poly-modulus PT100 sensors with a digitalcreen indicating the set and actual temperatures. At each run, 1000

10 mg of LPZ was charged into the 100-ml static cell. The LPZ wasituated in the bottom chamber of the cell, with the consideredolymer tablet (100 mg) fitted in the upper chamber. In order toeep the undissolved LPZ inside the cell, the high-pressure equi-

ibrium cell had its both sides sealed with stainless steel sinteredisks (less than 1 �m). Furthermore, both polymers were separated

nside the cell and covered with mesh filter bags (1 �m), and theame procedure was adopted to impregnate both of them.

In each test, firstly, the gaseous CO2 was forced to pass through-�m pores of a filter before having it liquefied by reducing its tem-erature down to 273 K in the refrigerator unit. Next, the liquefiedO2 at 60 bar (the pressure at the CO2 storage tank) was subjectedo pressurization using the reciprocating pump, with the pressurealues recorded both from the pressure gauge and the pressureransducer. During this stage, the inlet valve was kept open untilhe desired temperature and pressure were reached. The activengredient (LPZ) was thoroughly mixed with SC-CO2 using a mag-etic stirrer (200 rpm) and the LPZ-saturated SC-CO2 was brought

nto contacted with the polymers for some static time, leading towelling and impregnation of the polymers. Afterwards the cellas discharged at a constant pressure rate (5 bar/min, based on

reliminary test) before removing the sample from the impregna-ion cell. In order to determine the drug loading, the LPZ contentf the polymer was evaluated by UV–vis spectroscopy (UNICO-802 UV–vis). For this purpose, 10 mg of impregnated polymer

percritical CO2 impregnation.

was introduced into a 5-mL container and then the container wasfilled with methanol. After the impregnation test, the sample wasleft at lab temperature for 3 h. Subsequently, for the sake of thespectrophotometry testing, the sample was sonicated for 10 minto ensure complete dissolution. The concentration of the LPZ inthe solution was evaluated by absorbance measurements at 284nm. Upon the absorbance measurements, the relationship betweenthe LPZ concentration (C) and the absorbance (A) was expressedby a linear function. Stock solutions were sequentially diluted toobtain standard solutions. The standard solution was prepared inthe concentration range of 5−100 �g/mL. The calibration equationobtained for the calibration curve of LPZ was A = 0.0086 C + 0.001at a high regression coefficient (0.996). The following equation wasused to evaluate the drug impregnation loading:

Drug loading% = amount of drug loadingamount of polymers

∗ 100 (3)

Each experiment was performed in triplicate and average valuesof loading were reported as the final result.

2.2.3. Particle analysisIn this study, DLS, DSC, SEM, FTIR spectroscopy, and XRD anal-

yses were utilized to determine the properties of the synthesizedparticles. The particle size distribution was studied using DLS anal-

ysis on a NANOPHOX particle sizer (Sympatec GmbH, Germany)equipped with a He-Ne laser producing 10-mW laser beams at awavelength of 623 nm and operating at a scattering angle of 90◦.To prepared the DLS samples, 10 mg of impregnated polymer was

8 / J. of

iwapiootaaprsc9suddbayNlnuassc

3

3

tpeiilwa6afommtctLst×pL

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L


ntroduced into a 5-mL container and then the container was filledith deionized water. The prepared samples were stirred for 1 h

t lab temperature and then sonicated for 20 min to ensure com-lete dissolution before the DLS testing. The samples were further

nvestigated in terms of thermal stability based on DSC analysisn a DSC 404 F3 Pegasus (NETZSCH, Germany). Here some 5 mgf each sample was heated from an initial temperature of 30 ◦Co a final temperature of 300 ◦C at a heating rate of 10 ◦C/min inn aluminum-made standard pan, with the samples subjected ton atmosphere of argon flowing at 10 mL/min. Morphology of thearticles was characterized by SEM analysis on a VEGA 3 XMU appa-atus (TESCAN, Czech Republic). For this purpose, the samples wereputter-coated with an alloy of gold and palladium using a SDC005oater machine (BAL-TEC, Switzerland) at ambient temperature for0 s. For the sake of FTIR analysis, a mixture of the sample (3 mg) andpectral-grade potassium bromide (KBr of 300 mg) was preparedsing pestle and mortar. The mix was then pressed to obtain a KBrisk. The samples had their crystal structures examined using pow-er XRD analysis on a X

′pert Pro MPD (PANalytical, Netherlands)

ased on Cu-K� radiation (� =0.154 nm) at room temperature in 2� range of 10−80◦. The Brunauer–Emmett–Teller (BET) anal-sis was conducted to evaluate the surface area of the sample by2 adsorption/desorption with an automated gas adsorption ana-

yzer (BELSORP-mini II, Japan) at the boiling temperature of liquiditrogen (–196 ◦C). Prior to the analysis, the samples were degassednder vacuum at 300 ◦C for 2 h. The nitrogen gas was injected into

sample and a reference chamber to calculate the relative pres-ures during the monolayer deposition on the sample. Finally, thepecific surface area of the sample was measured on the BET plotsonsidering the relative pressures.

. Results and discussion

.1. Optimization and validation of the model

Response surface methodology (RSM), and RSM-BBD in par-icular, refers to a well-known approach to DOE and optimalarametrization. As stated before, three variables were consid-red in this study, namely the pressure, the temperature, and thempregnation time. These were studied in certain ranges represent-ng three levels (designated as −1, 0, and +1) to calculate optimaloading of LPZ/PVP and LPZ/HPMC. For this purpose, experiments

ere designed in a pressure range of 150−250 bar, a temper-ture range of 308−328 K, and an impregnation time range of0−180 min. Table 3 reports the obtained values of the LPZ/PVPnd LPZ/HPMC loading after the impregnation process upon per-orming a total of 17 experiments with the RSM-BBD. The resultsf ANOVA are tabulated in Tables 4 and 5, suggesting the bestodel out of the linear, two-factor interaction (2FI), and quadraticodels. In this study, the quadratic model was applied for predic-

ion and optimization of the impregnation loading. The last twoolumns of Tables 4 and 5 are important for specifying the parame-ers expressed in Tables 6 and 7. Based on the obtained p-values forPZ/PVP (Table 4), the following parameters were found to imposeignificant effects on the yield of impregnation loading: tempera-ure, time, pressure, pressure × time, time × time, and temperature

temperature. On the other hand, the temperature, pressure, time,ressure × time, and time × time imposed significant effects on thePZ/HPMC loading.

Eqs. (4) and (5) are derived from the ANOVA results for thePZ/PVP and LPZ/HPMC loadings, respectively:

PZ/PVP Loading = 0.83 + 0.18x1 + 0.10x2 + 0.076x3 + 0.037x21− 0.036x22 + 0.022x23 − 0.010x1x2 + 0.017x1x3+ 0.08x2x3 + Error (4)

Supercritical Fluids 164 (2020) 104892

LPZ/HPMC Loading = 0.94 + 0.2x1 + 0.12x2 + 0.092x3 + 0.023x21− 0.038x22 + 0.028x23 − 0.015x1x2 + 0.020x1x3 + 0.09x2x3+ Error (5)

For the LPZ/PVP system, the coefficient of determination (R2)and adjusted coefficient of determination (R2 adj.) were cal-culated as 0.9929 and 0.9837, respectively, indicating a goodagreement between the experimental data and predicted valuesof the response. For the LPZ/HPMC system, however, the R2 and R2

adj. were found to be 0.9920 and 0.9817, respectively, reflecting adivergence of less than 0.02. Upon changing the effective parame-ters, the drug loading on the PVP and HPMC changed in the rangesof 0.56–1.16% and 0.61–1.30%, respectively.

3.2. Effects of operating parameters on the loading ofimpregnated LPZ/HPMC and LPZ/PVP

A number of previous works have reported the use of SCimpregnation of active pharmaceutical ingredients for controllingthe release of active ingredients of drug products (see Table 1),where the effects of different parameters on the output havebeen analyzed. In this study, effects of temperature, pressure andimpregnation time were examined on the impregnation processof LPZ on PVP and HPMC using SC-CO2. Figs. 3a, b and c show 3Dgraphs of the obtained response surfaces for the LPZ/HPMC system,while Figs. 3d, e and f represent the same for the LPZ/PVP system.

3.2.1. Effect of temperatureThe SSI process is a complex process governed by thermo-

dynamic conditions and mass transfer phenomena between theinvolved components: the CO2 as the carrier, the active ingredient,and the matrix. The solubility, the diffusivity and the affinity of theactive ingredient with the matrix are known to affect the process,as does the thermodynamic behavior of the polymer (swelling andplasticizing effects) [38]. The temperature effects on sorption anddiffusivity of CO2 in polymers show opposite trends. Accordingly,with increasing the temperature, the sorption decreases while thediffusivity increases. The combined effect of sorption and diffusioncan be seen by the permeability [117–120]. Generally speaking,with increasing the CO2 sorption into polymers, one can tailor thepolymer properties such a way to obtain a new morphology, e.g.desired pore size distribution. The greater the swelling, the quickerand more complete the impregnation-related diffusion [121,122].The temperature can directly affect the solvating power and diffu-sivity of CO2 and the thermodynamic behaviors of both the polymer(swelling and plasticizing effect) and the active ingredient. In gen-eral, the solubility of LPZ in CO2 increases with temperature (abovethe crossover point) [123], positively affecting the impregnation ofthe active ingredient. In this work, the effect of temperature wasevaluated in the range of 308–328 K. The LPZ impregnation intoeach polymer at different temperatures and a fixed pressure of 200bar is presented in Figs. 3a and d. According to the figures, withincreasing the temperature from 308 K to 328 K, the drug load-ing on the HPMC and PVP increased, positively contributing to theimpregnation of the HPMC and PVP. The same increasing trend wasobserved at a pressure of 150 bar, although a decline in LPZ solubil-ity was reported in our previous work [123]. Accordingly, a pressureof 210 bar was determined as the crossover pressure of LPZ, beyond

which an increase in temperature negatively affected the LPZ sol-ubility. As shown in Fig. 4a, a slight drop of solubility from 2.96 ×10−4 to 2.01 × 10−4 molar fraction was seen when the temperaturewas increased from 308 to 328 K at 150 bar [123]. This solubility


Fig. 3. Response surface plots for the LPZ loading in HPMC (first column): (a) time and temperature, (b) time and pressure and (c) pressure and temperature. Response surfaceplots for the LPZ loading in PVP (second column): (e) time and temperature (f) pressure and time (g) temperature and pressure.

10 A. Ameri, G. Sodeifian and S.A. Sajadian / J. of Supercritical Fluids 164 (2020) 104892

Table 3BBD matrix of three independent parameter for impregnation of LPZ/PVP and LPZ/HPMC.

Std. order Independent variable Responses

Pressure Temperature Time Actual RSM Actual RSM

X1 P (bar) X2 T(K) X3 t(min) Loading (LPZ/PVP) Loading (LPZ/PVP) Loading (LPZ/HPMC) Loading (LPZ/HPMC)

1 0 200 −1 308 −1 60 0.56 0.54 0.61 0.592 0 200 +1 328 −1 60 0.93 0.91 1.02 1.023 0 200 −1 308 +1 180 0.75 0.77 0.86 0.864 0 200 +1 328 +1 180 1.08 1.10 1.21 1.235 −1 150 −1 308 0 120 0.65 0.65 0.72 0.726 −1 150 +1 328 0 120 0.97 0.97 1.10 1.087 +1 250 −1 308 0 120 0.77 0.77 0.84 0.868 +1 250 +1 328 0 120 1.16 1.16 1.30 1.309 −1 150 0 318 −1 60 0.70 0.72 0.78 0.8110 −1 150 0 318 +1 180 0.78 0.76 0.87 0.8711 +1 250 0 318 −1 60 0.69 0.71 0.81 0.8112 +1 250 0 318 +1 180 1.09 1.07 1.26 1.2313 0 200 0 318 0 120 0.83 0.83 0.95 0.9414 0 200 0 318 0 120 0.83 0.83 0.95 0.9415 0 200 0 318 0 120 0.81 0.83 0.94 0.9416 0 200 0 318 0 120 0.84 0.83 0.91 0.9417 0 200 0 318 0 120 0.83 0.83 0.95 0.94

Table 4RSM model adequacy analysis of LPZ/PVP.

source Std.Dev R-square Adjusted R-square Predicted R-square Sequential P-value Lack of fitP- value PRESS

Linear 0.057 0.8987 0.8753 0.7903


Table 7RSM model ANOVA analysis of LPZ/HPMC.

Source Sum of squares df Mean square F value P-Value prob > F Significance

model 0.55 9 0.061 96.12


isHsoB[m3◦

ntp4tifebtw

3

stwtr

Fig. 5. Comparison of FTIR spectrum for (a) HPMC, (b) LPZ, (c) LPZ/HPMC.

ncrease in the impregnation time allows a more in-depth diffu-ion of the drug facilitated by the improved swelling of the polymer.owever, prolonged impregnation times tend to over-enhance the

welling, and the resultant relaxation of the polymer leads to exportf the solute from the polymer during the depressurization [43].ouledjouidja et al. [40] came with a similar finding. Belizon et al.38] considered the effect of impregnation time of PET/PP films with

ethyl gallate (MG) in three different impregnation times, namely, 15, and 22 h, at a constant pressure (100 bar) and temperature (35C). They observed higher MG loading with increasing the impreg-ation time. Goni et al. [76] considered the effect of impregnationime of LDPE/sepiolite nanocomposite films with insecticidal ter-ene ketones in two different impregnation times, namely 2 and

h. They noticed higher loading with increasing the impregna-ion time. Municio et al. [56] reported that the lactulose loadingncreased from 0.40 to 1.45 upon increasing the impregnation timerom 1 to 3 h, confirming the significant effect of the time. Marizzat al. [14,15] identified that the ketoprofen loading can be increasedy extending the impregnation time. Testing different impregna-ion times in the range of 1–4 hr, the best results were achievedith the longest impregnation time, namely 4 h.

.3. Optimum conditions

In the next step, the considered operating parameters (i.e. pres-ure, temperature and impregnation time) were optimized to reachhe maximum loading of LPZ on PVP and HPMC. The optimal values

ere estimated using the RSM model, with its results compared to

he actual data. These parameters were examined in the followinganges:

bar ≤ pressure ≤ 250 bar

Fig. 7. SEM images of pure

Fig. 6. Comparison of FTIR spectrum for (a) PVP, (b) LPZ, (c) LPZ/PVP.

K ≤ temperature ≤ 328 Kmin ≤ time ≤ 180 minFor both the LPZ/PVP and LPZ/HPMC systems, optimal results

(i.e. drug loadings of 1.16% and 1.30% for the PVPV and HPMC poly-mers, respectively) were determined at a pressure of 250 bar, atemperature of 328 K, and an impregnation time of 180 min. Forthe two systems, the drug loading was found to fall in the followingranges:

0.56% ≤ LPZ/PVP ≤ 1.16%0.61% ≤ LPZ/HPMC ≤ 1.3%The results of the actual impregnation tests were well in agree-

ment with those of the RSM. Average drug loading was measuredat 1.18% ± 0.03% and 1.34% ± 0.05% for the PVP and HPMC, respec-tively.

3.4. Characterization of drug–polymer system

FTIR spectra of the LPZ, PVP, HPMC, LPZ/PVP, and LPZ/HPMCare represented in Figs 5 and 6. The FTIR analysis was performedto identify the drug–polymer interactions for the purpose of ana-lyzing the chemical changes occurred during the SSI. The resultsshowed characteristic peaks indicating the stretching vibration ofLPZ (3215.85 cm−1) in relation to the –NH group (disappeared inthe solid dispersion) and the −CH2 stretching vibrations at 2983.75cm−1 (attributed to hydrogen bonding between N atoms on thepyridine ring and O atoms on the sulfonyl). The peaks at 1578.44,

-1
1265.11, 1115.38 and 1036.87 cm referred to C N (aromatic ring),CN (on the pyridine), ether bonding and S O, respectively. Thesepeaks have been previously identified by Bader et al. and Zhanget al. [1,128].
of (a) PVP, (b) HPMC.


P for:

aTofbpnath(

spvrcowrtr

s2at1a

SH

Fig. 8. SEM images of impregnation of LPZ/PV

The spectrum recorded from the LPZ/PVP system exhibited char-cteristic absorption peaks at 3441.97, 2948.37 and 1651.53 cm−1.he broad peak seen at 3441.97 cm-1 was caused by the presencef water, while the ones at 2948.37 cm-1 and 1651.53 cm-1 wereound to be relevant to the stretching vibrations of the C–H and COonds, respectively. After the impregnation test, the characteristiceak of the water molecules (O H, ∼ 3441.97 cm−1) became thin-er. Moreover, upon the impregnation process, the absorption peakt 2948.37 cm-1 (attributed to the C–H bond) was intensified whilehe peak at 1651.53 cm−1 underwent a dramatic reduction; theighest absorption peaks were observed in the fingerprint region900−1100 cm−1) [1].

Analysis of the spectrum recorded from the LPZ/HPMC systemhowed characteristic peaks in certain ranges. Accordingly, theeaks at 3454.24, 2920.86, and 1634 cm−1 belonged to stretchingibrations of the OH, C–H, and CO bonds for six-membered cyclicings, respectively. In the range of 1350−1400 cm−1, the peaksorresponding to the C–O–C bond on the cyclic anhydride werebserved. The peak in the range of 1300−1200 cm-1 was associatedith the C OC bond on the cyclic epoxide. Finally, the peaks in the

anges of 1100−1000 cm-1 and 950−1000 cm−1 were attributed tohe stretching vibrations of ethereal C OC groups and pyranoseing of the HPMC, respectively.

Fig. 5 presents the results of FTIR analysis on the LPZ/HPMCystem impregnated by SC-CO2. The peaks at 3454.24 cm−1 and920.86 cm−1 were associated with −OH stretching vibration andromatic C–H bonding, respectively, and faded out upon impregna-ion. High absorption peaks were observed at 1350−1400 cm-1 and200−1300 cm−1 bands, while the ones in the ranges of 1000–1100nd 900−1000 cm-1 exhibited lower intensities.

SEM images of the pure polymers are presented in Fig. 7. TheEM images of the impregnation process of the LPZ onto PVP andPMC show how the drug nanoparticles were incorporated into the

(a) run 1, (b) run 5, (c) run 15, (d) optimum.

polymer matrices (see Figs 8 and 9). The SEM images clearly indicatethe drug nanoparticles that were possibly originated upon loadingthe drugs onto the polymers. As shown in Figs 8d and 9d, the opti-mum LPZ nanoparticles ended up being well distributed throughthe PVP or HPMC particles. Results of DLS analysis (Figs 10 and 11)demonstrate the uniform dispersion of the drug particles acrossthe PVP and HPMC. The symmetry on these figures highlights theeffectiveness of combining the SC-CO2 with impregnation methodto prevent the drug growth.

The DSC results further shed light on the fact that the PVP andHPMC could prevent the LPZ particle growth, with the polymericstabilizers controlling the growth of nanoparticles. Figs 12 and 13show the results of DSC analyses on pure LPZ, pure PVP, pure HPMC,and LPZ/PVP and LPZ/HPMC impregnated systems. The graph of thepure LPZ shows a peak at 180 ◦C, indicating the melting point ofthe drug. Also, a sharp endothermic peak was seen immediatelyafter the melting point, which is in agreement with the publisheddata for this drug [1] and the DSC graph for pure lansoprazoleanalysis by Bader et al. [128]. From the DSC results for the PVP,a broad endotherm ranging from 40 ◦C to 127 ◦C was observed,because of the presence of residual moisture in the PVP. Associatedwith the water loss, this large endotherm over the temperaturerange 50–130 ◦C has also been seen in other works [129–132].Based on the DSC results for the pure HPMC, the endothermictransition starts from 35 and extends to 75 ◦C, with a broad peakobserved in the midway, confirming some of previously reportedworks [133,134]. Generally, diffusion of SC-CO2 into a polymerspecies results in the swelling of the polymer and changes in itsmechanical and physical properties. The most important effect ofthis kind is the reduction of the glass transition temperature (Tg)

of a glassy polymer subjected to SC-CO2, often simply called plasti-cization. The polymer plasticization results from the ability of CO2to interact with the basic sites on the polymer molecules [43]. Sev-


Fig. 9. SEM images of impregnation of LPZ/HPMC for: (a) run1, (b) run 5, (c) run 15, (d) optimum.

condi

epetp◦

Fig. 10. DLS graphs for optimum

ral researchers reported that the Tg decreases with increasing theressure [135–137]. For example in the case of PMMA, the pres-nce of oxygen atoms promotes the interactions with SC-CO2 and

hus reduces the Tg for many glassy polymers [43]. The glass tem-erature of the PVP has been reportedly measured at around 163C (155–160 ◦C in the present research) [138]. In the case of HPMC,

tion with impregnation LPZ/PVP.

only a tiny change in the baseline is observed around 177 ◦C. Thischange corresponds to the polymer Tg, being in agreement with apreviously reported value (196 ◦C) [139,140].

In addition, it was observed that the melting point of LPZchanged after the impregnation test. From the peaks obtained after


Fig. 11. DLS graphs for optimum condition with impregnation LPZ/HPMC.

PZ, PV

tt

bsdb1bbitHtupoate

Fig. 12. DSC analysis results of L

he impregnation tests, the drug was found to be well dispersedhrough both polymers.

XRD analyses were performed on the LPZ, PVP and HPMC, bothefore and after the impregnation tests, to evaluate their crystaltructure, with the results shown in Figs. 14 and 15. Based on theiffraction pattern obtained from the original LPZ, it was found toe well crystalline with characteristic peaks at 11.331◦, 14.160◦,6.835◦, 17.454◦, 22.262◦, 24.906◦, and 27.716◦. These peaks haveeen reported for post-impregnation samples in a previous worky Zhang et al. [1], with the degree of crystallinity decreased upon

mpregnation. The obtained XRD pattern showed no characteris-ic peak corresponding to the LPZ in the impregnated PVP andPMC. This was linked to the too small size of the LPZ particles that

urn the substance from the crystalline state to amorphous statepon SC-CO2 impregnation. Furthermore, given that the loadingroceeded to no more than 2%, no crystallinity-related peak was

bserved in the XRD pattern but rather only the amorphous halosnd plasticization of the polymers were there. The surface area ofhe polymers was also measured. Based on the results, the HPMCxhibited a larger surface area (44.83 m2/g) than the PVP (33.52

P before and after the process.

m2/g), possibly due to higher drug loading onto the HPMC. Theresults of FTIR, DLS, SEM, DSC, and XRD analyses suggested that thedrug was only partially miscible in the considered polymers.

4. Conclusion

Supercritical CO2-assisted impregnation represents a novelapproach to the development of green chemistry in the phar-maceutical industry. The impregnation of LPZ onto two differentpolymers, namely PVP and HPMC, using the supercritical solvent-impregnation method was investigated. After evaluating theoperating conditions at lab scale, effects of pressure (150−250 bar),temperature (308−328 K) and impregnation time (60−180 min) onthe drug loading were investigated by RSM-BBD through a total of17 tests. Based on the results, any increase in either of the threeparameters led to improvement of the drug loading onto the PVP

and HPMC. Indeed, for both of the considered polymers, the opti-mal results were achieved at a pressure of 250 bar, a temperatureof 328 K, and an impregnation time of 176 min. Based on the testresults, impregnation loading of LPZ on the PVP and HPMC ranged in


Fig. 13. DSC analysis results of LPZ, HP

Fig. 14. XRD pattern of LPZ before and after processes (a) LPZ, (b) PVP, (c) LPZ/PVP.

FL

0hoFPttr

modified starch, J. Supercrit. Fluids 58 (2011) 313–319.

ig. 15. XRD pattern of LPZ before and after processes: (a) LPZ, (b) HPMC, (c)PZ/HPMC.

.56–1.16% and 0.61–1.30%, respectively, with the drug exhibitingigher loadings onto the HPMC rather than PVP under the same lab-ratory conditions. The samples were further characterized usingTIR, DLS, SEM, DSC, and XRD analyses. The interactions of theVP and the HPMC with the LPZ were studied by FTIR analysis;

he post-impregnation particle size and distribution were charac-erized by monitoring DLS patterns and SEM studies. Finally, theesults showed that the drug was miscible in the polymers.

MC before and after the process.

Declaration of competing interest

The authors declare that they have no known competing finan-cial interests or personal relationships that could have appeared toinfluence the work reported in this paper.

Acknowledgement

The authors would like to thank the University of Kashan,research deputy, for providing financial support of this project(Grant #Pajoohaneh-1398/4). Moreover, the authors would liketo thank the laboratory of supercritical fluids in the University ofKashan for providing experimental facilities.

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