Journal of Colloid and Interface Science 356 (2011) 573–578

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Journal of Colloid and Interface Science

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Poorly water-soluble drug nanoparticles via an emulsion-freeze-drying approach

Neil Grant, Haifei Zhang ⇑Department of Chemistry, University of Liverpool, Crown Street, Liverpool L69 7ZD, United Kingdom

a r t i c l e i n f o a b s t r a c t

Article history:Received 14 December 2010Accepted 15 January 2011Available online 22 January 2011

Keywords:Poorly water-soluble drugsNanoparticlesFreeze dryingEmulsion

0021-9797/$ - see front matter � 2011 Elsevier Inc. Adoi:10.1016/j.jcis.2011.01.056

⇑ Corresponding author. Fax: +44 151 7943588.E-mail address: zhanghf@liv.ac.uk (H. Zhang).

Low water solubility of a high percentage of pharmaceuticals is a big issue for pharmaceutical applica-tions due to the resulting low bioabsorption and hence limited therapeutic efficacy. Preparation of drugnanoparticles has been one of the mostly investigated routes to address this problem. In this study, wereported the preparation of nanoparticles via an emulsion-freeze-drying approach. Indomethacin (IMC,a poorly water-soluble drug) nanoparticles were formed in situ within porous poly(vinyl alcohol). TheIMC nanoparticles could be released into water to form stable nanodispersions simply by rapid dissolu-tion of the porous polymeric scaffold. This study focused on how preparation conditions including phasevolume ratios in the emulsions and the concentrations of polymer, surfactant and drug influenced theformation of IMC nanoparticles. It was concluded that the loading and size of IMC nanoparticles couldbe easily tuned by changing the preparation conditions.

� 2011 Elsevier Inc. All rights reserved.

1. Introduction

A wide range of organic materials are poorly soluble in water.Typical examples are poorly water-soluble drugs. Lipinski reportedthat 31.2% of a group of 2246 compounds synthesized in academiclaboratories between 1987 and 1994 had solubility equal to or lessthan 20 lg/ml [1]. The low bioavailability resulted from the lowwater solubility is a great concern in pharmaceutical researchand industry. Overcoming the problem of drug solubility is thusof great interest. Various efforts have been made to address thisproblem by delivery in nanocarriers and by nanoparticles engi-neering. A wide range of carriers such as polymer capsules and mi-celles, cyclodextrin complexations and lipid-based formulationshave been investigated in an effort to enhance the inherent solubil-ity of the drugs [2,3]. In the method of nanoparticles engineering,poorly water-soluble drugs are micronized to produce small parti-cles at the level of micrometers and nanometers [4–6]. Accordingto the Nernst–Brunner/Noyes–Whitney equation, the dissolutionrate of an organic compound is proportional to the surface areaavailable for dissolution [6]. Therefore, the dissolution rate ofpoorly water-soluble drugs could be increased substantially viareducing particle size to nanometer range. Based on the calculationby the Stokes equation, nanoparticles with sizes <300 nm will notsettle for a density of particles of 1.15 and g of 1, which is essentialfor many potential applications [7].

Drug nanoparticles can be prepared by ‘‘top–down’’ and ‘‘bot-tom-up’’ approaches. For the top–down approach, the size of largedrug nanoparticles is reduced mainly by means of high pressure

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homogenization, milling, or microfluidization [8–10]. For the bot-tom-up approach, the drug nanoparticles are formed from mole-cules in a solution or in an emulsion. Emulsion evaporation,solvent displacement, solvent diffusion and rapid freezing havebeen widely used to prepare drug nanoparticles [11–14]. As a typeof green and sustainable solvents, supercritical fluids (particularlysupercritical carbon dioxide) has been explored to produce drugparticles in the processes of rapid expansion, rapid expansion toaqueous solutions, and anti-solvent effect on organic drug solu-tions [4,15–17].

Freeze drying is a process where a solution is frozen in contactwith a cold liquid or in a cold environment, and the frozen sampleis then placed in a freeze dryer to remove the frozen solvent undervacuum. Water-based solutions are usually processed by freezedrying to produce drug or protein particles. The freeze-drying tech-nique has been developed recently to construct advanced porousmaterials [18,19]. A spray freezing of solutions and emulsions intocold liquid has been developed to prepare microparticles with sig-nificantly enhanced water solubility [20,21]. The rapid freezingtechnique with emphasis on thin film freezing has also been em-ployed to produce drug nanoparticles [22]. However, the porestructure of the scaffold and its influence on drug particles hasnot been investigated. We developed a new method to prepareporous organic nanocomposites by freeze-drying emulsions [23].In this method, an organic compound (an organic dye) was dis-solved in an organic solvent which was then emulsified into anaqueous polymer solution to form an oil-in-water emulsion.Freeze-drying of the emulsion led to the formation of organicnanoparticles inside the porous polymer. The porous materialscould be rapidly dissolved in water to release the organic nanopar-ticles to form a stable aqueous nanodispersion. Aqueous triclosan

Table 1Preparation conditions for the emulsions and characterization data for the formed IMC nanoparticles.

Entry PVA (wt.%) SDS (wt.%) IMC (wt.%) Oil volume (%) Droplet size (lm) Particles size (nm)

S1 5 5 0.1 50 27 ± 13 151 ± 22S2 5 5 0.1 75 8 ± 5 188 ± 35S3 5 5 0.1 80 10 ± 5 230 ± 28S4 5 0 0.1 50 102 ± 54 227 ± 28S5 5 1 0.1 50 85 ± 48 244 ± 45S6 5 10 0.1 50 11 ± 5 195 ± 28S7 2 5 0.1 50 65 ± 36 185 ± 23S8 1 5 0.1 50 101 ± 50 169 ± 27S9 5 5 0.05 50 Not measured 137 ± 33S10 5 5 0.5 50 Not measured 286 ± 54

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nanoparticle dispersions were formed this way and an enhancedbiocidal activity was demonstrated compared to triclosan aqueousethanol solution.

For the commonly-used water-in-oil emulsion approach, thedrug nanoparticles are normally formed in the water phase by emul-sion solvent diffusion [14], emulsion dilution [24], or the extractionof organic solvent from the emulsions for example by supercriticalfluids [17]. However, for the purpose of storage, characterizationor some applications, the recovery of the nanoparticles via the re-moval of solvent is required and is still a challenge. Common tech-niques include spray drying, freeze drying and ultrafiltrationwhich are energy intensive or with limited yields. A salt flocculationmethod was recently proposed to recover amorphous nanoparticles[25]. It was noticed that although drug nanoparticles engineeringtechniques were successful for enhancing the dissolution propertiesof poorly water-soluble drugs, there were limitations such asparticle aggregation and poor wettability. Hot-melt extrusion ofmicronized itraconazole particles with hydrophilic polymers wasdemonstrated to overcome some of the limitations [26].

In this report, we extended the approach of freeze-drying emul-sions to produce poorly water-soluble drug nanoparticles. Indo-methacin (IMC), a poorly water-soluble non-steroidal drug for thetreatment of inflammation and pain, was used as a model drugand processed to prepare IMC nanoparticles within porous hydro-philic poly(vinyl alcohol) (PVA). The IMC nanoparticles could bereleased into water instantly to form aqueous nanoparticle disper-sions via the dissolution of PVA. The effects of PVA concentration,surfactant concentration and IMC concentration on the size and sur-face charge of IMC nanoparticles were investigated in details. In thismethod, all the drug molecules were turned into nanoparticles andentrapped within the dissolvable porous polymers. In principle,there is no need to recover the nanoparticles and the nanoparticlesmay be formulated when required by dissolving into water or othersuitable solvent. Also because the nanoparticles were formed in theporous polymer, the aggregation of IMC nanoparticles could beavoided. The materials were formed in the format of monolith ratherthan powders and thus easy to be handled, stored, and transported.

2. Experimental

2.1. Materials

IMC (>99%), PVA (Mw 9–10K, 80% hydrolyzed), sodium dodecylsulphate (SDS, P99%), and O-xylene (anhydrous, 97%) were pur-chased from Sigma–Aldrich and used as received. Distilled waterwas used in all cases.

2.2. Preparation of IMC nanoparticles within the porous polymer

IMC was dissolved in O-xylene at the concentration of 0.05, 0.1,0.5 wt.%. Xylene is a Class 2 solvent with a concentration limit

2170 ppm for pharmaceutical applications. O-xylene has a meltingpoint around �25 �C which is suitable for the freeze-drying pro-cess. PVA was dissolved in water to make aqueous solutions atthe concentration of 1, 2 and 5 wt.%. SDS was used as a surfactantand dissolved in aqueous PVA solutions at the concentrations of1 wt.%, 5 wt.% and 10 wt.%. To form an oil-in-water emulsion, theIMC solution was added into the aqueous PVA-SDS solution drop-wise while stirring at 500 rpm using a lab stirrer for 15 min. Thevolume ratio of oil phase to aqueous phase in the emulsions wasvaried at 50:50, 75:25 and 80:20.

The formed emulsion in a glass beaker was rapidly frozen in li-quid nitrogen and then transferred to a freeze dryer (VirTis Advan-tage) with shelf temperature at �30 �C. The freeze-drying processwas carried out for 48 h to remove both water and O-xylene. TheIMC nanoparticles were formed directly in the porous polymersduring the freeze-drying process. All the freeze-dried samples werekept in a dessicator. Table 1 summarizes the preparation condi-tions and characterization data for the formed IMC nanoparticles.Droplet sizes were not measured for samples S9 and S10 becauseit was believed that the change of IMC concentration would not af-fect the size of droplets.

2.3. Characterization

The droplets sizes of the formed emulsions were measuredusing a Malvern Mastersizer 2000 with a Hydro 2000 SM disper-sion unit. The emulsion (3 drops) was added to the dispersion unitcontaining approximately 100 ml water with a stirring rate of1200 rpm.

A Hitachi S-4800 field emission scanning electron microscope(SEM) was used to reveal the pore structure at 3 kV. The driedmaterials were sectioned to reveal the internal porous structures.The samples were adhered to an aluminium stub using a silver col-loidal suspension and allowed to dry. A sputter coater (EMITECHK550X) was used to coat the samples with gold at 40 mA for3 min. The powder X-ray diffraction (PXRD) patterns were ob-tained using a Panalytical X’ Pert Pro diffractometer with Co Karadiation operated at 40 mA and 40 kV.

The IMC nanoparticles-loaded porous polymer was rapidly dis-solved in water. The resulting IMC nanodispersions were analyzedat 25 �C using a Malvern Zetasizer equipped with a zeta potentialdetector with a backscattering detection at 173�. The scatteringintensity signal for the detector was passed through a correlatorwhere the data were analyzed by the software to give a size distri-bution. The size and zeta potential of the hydrated IMC nanoparti-cles in water were obtained. Each measurement was repeated atleast three times and the average data were used to plot the fig-ures. Ten microlitres of a diluted IMC nanodispersion was droppedonto holey carbon filmed copper grids (400 mesh) and allowed todry overnight. A scanning transmission electron microscopic(STEM) detector attached to the Hitachi S-4800 SEM was used toobserve the dry IMC nanoparticles at 30 kV.

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3. Results and discussion

An emulsion is a mixture of two immiscible phases with onephase dispersed in another. In this study, organic solutions wereemulsified in aqueous phase to form oil-in-water (O/W) emulsion.0.1 wt.% IMC solution was firstly emulsified into an aqueous solu-tion containing 5% PVA and 5% SDS at oil:water = 50:50. Theformed emulsion was frozen and freeze-dried to produce a porousmaterial while the IMC nanoparticles were formed in situ withinthe macropores. The formed IMC nanoparticles were supportedwithin porous PVA, which prevented the nanoparticles from aggre-gating. Due to its highly interconnected porosity, the materialcould be rapidly dissolved in water and a clear dispersion contain-ing IMC nanoparticles was thus produced. The dynamic laser scat-tering (DLS) measurement showed that the size of IMCnanoparticles in water was around 130 nm. This was further con-firmed by observing dry IMC particles with a STEM monitor. Asshown in Fig. 1, the sizes of dry IMC nanoparticles were in therange of 100–300 nm.

The formation of emulsion was the key to producing IMC nano-particles within porous PVA during the freeze-drying process. The

Fig. 1. The STEM image of IMC nanoparticles (black) on holey carbon TEM grids(grey).

Fig. 2. SEM images of porous PVA with IMC nanoparticles prepared from the emulsionsdistributions of the emulsions containing different volume percentage of oil phase. (e) T

volume ratios of organic solution to water phase could be easilyvaried. This would affect the loading of the drug nanoparticlesand the porosity of the porous polymers. The concentrations ofPVA, SDS and IMC in the emulsions were further investigated in or-der to demonstrate the effect on the size and surface charge of theresulting IMC nanoparticles.

3.1. Ratio of oil to water in the emulsions

The ratios of oil:water at 50:50, 75:25 and 80:20 (v/v) wereinvestigated in this study. With a higher percentage of oil phasein the emulsion, a higher porosity of the materials and a higherloading of IMC nanoparticles were expected after the freeze-dryingprocess [23]. Fig. 2a–c shows the porous structure of the materialsformed from emulsions containing 50 v/v%, 75 v/v% and 80 v/v% oilphase. For the material made from the emulsion containing 50 v/v%oil phase, the emulsion-templated spherical pores were observeddispersing in the ice-templated porous matrix. There were somelarge emulsion-templated pores, which were due to the coales-cence of the emulsion droplets before frozen. The pores becamemore interconnected with the increase of oil volume percentagein the emulsions, with the number of spherical pores increasedand the size of the pores decreased at the same time (Fig. 2a–c).The IMC nanoparticles could not be seen in the pores of the PVAat these magnifications. Due to the low contrast between the or-ganic nanoparticles and the polymer, it was very difficult to iden-tify the IMC nanoparticles in the PVA.

The formed emulsions were analyzed using a Mastersizer. Itwas found that the size of emulsion droplets decreased when ahigher percentage of oil phase was present in the emulsion. Thesize distributions of emulsion droplets are shown in Fig. 2d. Thepeak size decreased from 27 lm (27 ± 13 lm) for 50 v/v% emulsionto the peak sizes of 8 lm (8 ± 5 lm) for 75 v/v% emulsion and 7 lm(10 ± 5 lm) for 80 v/v% emulsion. The observed decrease of emul-sion droplets sizes was consistent with the change of pore sizes indry porous materials as shown by SEM images in Fig. 2a–c. The IMCnanoparticle dispersions formed from these materials were ana-lyzed by DLS. It could be seen that the size of nanoparticles in-creased with the increase of oil phase volume in the emulsions

containing (a) 50 v/v%, (b) 75 v/v% and (c) 80 v/v% oil phase. (d) The droplet sizehe size of IMC nanoparticles in water as measured by DLS.

Fig. 3. UV spectra of porous PVA/IMC nanoparticles composites dissolved in water.The materials were made from the emulsions containing different percentage of oilphase. The inset shows the UV absorbance versus oil phase percentage.

576 N. Grant, H. Zhang / Journal of Colloid and Interface Science 356 (2011) 573–578

(Fig. 2e). However, most of the IMC nanoparticles produced are stillsmaller than 300 nm.

The increased loading of IMC nanoparticles was demonstratedby dissolving 0.05 g samples each in 10 ml water and then ana-lyzed by UV–vis spectroscopy. The IMC nanoparticles in watershowed a maximum absorption at 320 nm. Fig. 3 shows the in-creased absorption at 320 nm corresponding to the increasing vol-ume ratio of IMC organic solution in the emulsions. An additionalsample made of the emulsion containing 66 v/v% IMC solutionwas included in Fig. 3. In the inset in Fig. 3, the UV absorption ofIMC nanoparticles was plotted against the volume ratio of oilphase in the emulsions. The loading of IMC nanoparticles isincreased three times when the emulsion contains 75 v/v oil phase

Fig. 4. Emulsions were prepared with 50 v/v% oil phase but various SDS concentratioemulsions. (b) The porous structure of the material made from the emulsion containing n10 wt.% SDS. (d) The size distributions of IMC nanoparticles in water measured by DLS.

(water:oil = 1:3), compared to the sample made from the emulsioncontaining 50 v/v% oil phase (water:oil = 1:1). The loading of IMCnanoparticles followed a linear relationship to the oil phase vol-ume percentage in the originally formed emulsions. For an emul-sion, the volume percentage of the droplet phase can be varied ina wide range, e.g., 10–95%. It is therefore possible to effectivelycontrol the loading of drug nanoparticles in the porous materialsby varying the volume ratio of organic phase in the emulsion.

3.2. Concentration of SDS

Increasing the surfactant concentration during the preparationof emulsions led to the formation of emulsions with smaller drop-lets. The concentrations of SDS were varied at 0, 1, 5, 10 wt.% withall the emulsions containing 50 v/v% oil phase. The sizes of theemulsion droplets (the peak size as shown in Fig. 4a) were de-creased from 105 lm, 90 lm, 30 lm to 10 lm. There was little dif-ference in droplet sizes for the emulsions formed with 1 wt.% SDSand without SDS. This suggested that the presence of 1 wt.% SDSdid not contribute significantly to stabilize the emulsion droplets.The size change of emulsion droplets was also confirmed by SEMimaging of the freeze-dried porous materials. As shown inFig. 4b, very large spherical pores resulted from the oil drops inthe emulsion containing no SDS were observed. When the SDSwas added in the emulsion at the concentration of 1 wt.%, a similarpore structure was observed. When the concentration of SDS wasfurther increased to 5 wt.% and 10 wt.%, the sizes of the sphericalpores were decreased and narrower pore size distributions wereobserved (Figs. 2a and 4c).

The DLS measurement showed that IMC particles with a broadsize range (70–600 nm, peak size at 200 nm) were formed whenthere was no SDS in the emulsion (Fig. 4d). In general, the additionof SDS in the emulsion preparation narrowed the size distribution

ns at 0 wt.%, 1 wt.%, 5 wt.%, and 10 wt.%. (a) The droplet size distributions of theo SDS. (c) The porous structure of the material made from the emulsion containing

Fig. 5. (a) The droplet size distributions of the emulsions containing PVA at the concentration of 1 wt.%, 2 wt.%, and 5 wt.%. (b) The zeta potential of the IMC nanoparticlesproduced from these emulsions.

Fig. 6. The emulsions with the IMC concentrations at 0.05 wt.%, 0.1 wt.%, and 0.5 wt.% were processed to produce aqueous IMC nanoparticle dispersions. (a) The sizedistributions of IMC nanoparticles. (b) The zeta potential of IMC nanoparticles.

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of IMC nanoparticles and also appeared to reduce the particles size,although an exception was observed that the size of IMC particlesprepared from the emulsion with 5 wt.% SDS seemed smaller thanthose particles prepared from the emulsion containing 10 wt.% SDS(Fig. 4d). The zeta potential measurement of the IMC nanoparticledispersions showed similar results, indicating that the surfacecharges or the adsorption of SDS molecules on the IMC nanoparti-cles was similar although the amount of SDS present in the suspen-sion was different.

A surfactant is used to reduce surface tension and stabilize thedroplet phase in an emulsion. The type and concentration of thesurfactant can be selected to tune the size of the droplets. In gen-eral, and as observed in this study, the size of the droplets de-creases with the increase of the surfactant concentration. Thiscan in turn affect the size of formed nanoparticles and the stabilityof the nanoparticles when the material is dissolved in water to re-lease the nanoparticles. Different types of surfactants such as ionicsurfactants and non-ionic polymer surfactant may be used to sta-bilize the O/W emulsions. For pharmaceutical applications wherebiocompatibility and toxicity of the surfactants are important,the use of surfactants needs to be selected carefully. For example,bio-surfactants such as phospholipids may be used.

3.3. Concentration of PVA

PVA was dissolved in the continuous aqueous phase of theemulsions. It was known that PVA could act like a co-surfactant

to stabilize an O/W emulsion. After freeze drying, PVA could pro-vide a material matrix to support the formed IMC nanoparticles.The concentrations of PVA were varied at 1 wt.%, 2 wt.%, and5 wt.% in this study. As can be observed in Fig. 5a, the sizes ofemulsion droplets are increased with the decrease of PVA concen-tration. After freeze-drying, the produced porous materials showedsimilar pore structures but their pore volumes increased with thedecrease of PVA concentration. From the DLS measurement ofthe IMC nanoparticle dispersions, it appeared that the size of IMCnanoparticles did not change with the variation of PVA concentra-tion. However, the zeta potential of the IMC nanoparticles shiftedto a larger negative value at the PVA concentration of 1 wt.%(Fig. 5b). In the aqueous dispersion, PVA can adsorb to the surfaceof IMC particles, which may be competing with SDS molecules forthe adsorption. The fewer amounts of PVA molecules in the disper-sion may allow a larger number of SDS molecules on IMC particles.This is highly likely to result in higher negative surface charges andhence a higher zeta potential.

With the hydrophobic backbone and hydroxyl groups on poly-mer chains, PVA can be an extra stabilizer at the oil–water inter-face. Thus, by decreasing the concentration of PVA, theemulsification capability is reduced, leading to larger droplet sizes.With the main purpose of PVA here is to form a porous scaffold tosupport the formation of nanoparticles, the choice of polymers canbe very flexible. In principle, any water-soluble hydrophilic poly-mer depending on the requirements for specific applications maybe used in this method. For example, widely used polymer addi-

Fig. 7. PXRD spectra of as-purchased IMC (a) and IMC nanoparticles (b) prepared inthis study.

578 N. Grant, H. Zhang / Journal of Colloid and Interface Science 356 (2011) 573–578

tives in drug formulations such as hydroxypropyl methyl cellulose,poly(ethylene glycol), and polyvinylpyrrolidone may be used inthis process.

3.4. Concentration of IMC

IMC nanoparticles were formed from the sublimation of the fro-zen solvent in the droplet phase of a frozen emulsion during thefreeze-drying process. The concentrations of IMC solutions werevaried at 0.05 wt.%, 0.1 wt.%, and 0.5 wt.%. As measured by DLS,the size of the nanoparticles changed with the change in IMC con-centration (Fig. 6a). The peak sizes of the IMC nanoparticles werearound 250 nm, 150 nm, and 155 nm for the emulsions made fromIMC solutions at 0.5 wt.%, 0.1 wt.%, and 0.05 wt.% respectively. Itshould be noted that there were additional small peaks at around25 nm and 6 nm for the IMC nanoparticles made from the emul-sion containing 0.05 wt.% IMC solutions. The zeta potential wassimilar for the IMC nanoparticles made from the emulsion contain-ing 0.1 wt.% and 0.5 wt.% IMC solution. A larger negative zeta po-tential was observed for IMC nanoparticles prepared from theemulsion containing 0.05 wt.% IMC solutions. This was likely dueto the higher ratio of SDS to IMC, which means more SDS moleculescould adsorb to the surface of IMC nanoparticles.

During the freezing process, IMC could concentrate in the drop-lets before the emulsion was completely frozen [19]. The removalof water and the organic solvent during freeze drying could pro-duce the IMC nanoparticles within porous PVA. It is reasonableto observe that a higher concentration of IMC and hence a largernumber of IMC molecules in the droplets have led to the formationof larger IMC nanoparticles. This is clearly demonstrated in Fig. 6. Itwas also noticed that a lower IMC concentration resulted in smal-ler particles with a broad particle size distribution. Fig. 7 shows thePXRD patterns of as-purchased IMC and IMC nanoparticles. Beforeprocessing, the IMC XRD spectrum shows sharp peaks indicatingthe presence of crystalline phase. Due to the fact that IMC concen-trates during a rapid freezing process and IMC nanoparticles areformed during the freeze-drying stage while the samples beingkept frozen, it is believed that there is no room for IMC moleculesto re-organize and form crystalline nanoparticles. As shown inFig. 7b, amorphous IMC nanoparticles were produced using themethod of freeze-drying emulsions. This may be advantageousfor enhancing the drug’s solubility in water. It has been shown thatpoorly water-soluble amorphous pharmaceuticals particularly inthe form of microparticles could improve wettability and increasedintrinsic dissolution rate [27].

4. Conclusions

Poorly water-soluble drug (IMC) nanoparticles were formedin situ within porous hydrophilic polymer (PVA) scaffold byfreeze-drying O/W emulsions. The IMC nanoparticles were sup-ported within the pores and thus prevented from aggregation.The corresponding aqueous nanoparticle dispersions could beformed instantly by dissolving nanoparticles–polymer compositesin water due to the highly porous structure of the polymeric scaf-folds. The formulations of the emulsions were very important forthe preparation of IMC nanoparticles. Effects of oil phase volumepercentage in the emulsion, the concentration of the surfactant(SDS), the concentration of polymer (PVA), and the concentrationof IMC were investigated. It was possible to tune the loading andsize of the IMC nanoparticles by varying these parameters. The ef-fect on zeta potential of IMC nanoparticles was also studied. Thismethod might be regarded as a general route to prepare poorlywater-soluble organic (drug) nanoparticles to enhance water solu-bility or use directly for potential applications [28].

Acknowledgements

This research was funded by the EPSRC through a DTA student-ship (NG) and the support of the Grant EP/F016883/1 (HZ). We aregrateful for the access to the facilities in the Centre for Materials Dis-covery and in Prof. Rannard’s laboratory. We would also like to thankDr. Lyndsey Ritchie and Dr. James Jones for XRD measurements.

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