on designing particulate carriers for encapsulation and ...€¦ · nano- or micro-particulates are...

Powder Technology xxx (2012) xxx–xxx

PTEC-08745; No of Pages 9

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Powder Technology

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On designing particulate carriers for encapsulation and controlledrelease applications

Wenjie Liu a, Winston Duo Wu a, Cordelia Selomulya a,⁎, Xiao Dong Chen a,b

a Department of Chemical Engineering, Monash University, VIC 3800 Australiab Department of Chemical and Biochemical Engineering, College of Chemistry and Chemical Engineering, Xiamen University, 361005 Fujian Province, P.R. China

⁎ Corresponding author.E-mail address: [email protected] (C.

0032-5910/$ – see front matter © 2012 Elsevier B.V. Alldoi:10.1016/j.powtec.2012.02.012

Please cite this article as: W. Liu, et al., On dnol. (2012), doi:10.1016/j.powtec.2012.02.0

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

Keywords:Evaporation induced self-assemblyMatrix compositionMicrofluidic jet spray dryingUniform microparticlesEncapsulationControlled release

A microfluidic jet spray drying technique was used to encapsulate hydrophilic drug in uniform microparti-cles, while tailoring their controlled release functionalities. The effects of different matrix compositions onthe release behaviour of a model drug were conducted by spray drying an aqueous polymeric dispersion ofa neutral copolymer based on ethyl acrylate and methyl methacrylate (Eudragit® NE) as the main encapsu-lating matrix. Lactose and silica nanoparticles were used as additives to modify the matrix compositions, withvitamin B12 as the model drug. Evaporation-induced self-assembly of a model drug (vitamin B12) and the ma-trix materials due to their colloidal interactions produced microparticles with specific morphologies for im-mediate or prolonged releases. Having lactose distributed homogeneously in the matrix resulted insignificantly faster and almost complete release due to enhanced swelling of the polymeric matrix with thedissolution of lactose. In contrast, silica nanoparticles existed mainly at the surface of the particles, due tothe slower diffusion of nanoparticles within the droplets upon drying, which could be responsible for the ini-tial burst release of vitamin B12 molecules with erosion of nanoparticles upon contact with the buffer. Theseoutcomes demonstrated the capability to tune the particle response(s) from the knowledge of material prop-erties, with the understanding of release mechanisms elucidated from monodisperse particles of differentcompositions.

© 2012 Elsevier B.V. All rights reserved.

1. Introduction

Pharmaceutical research is increasingly focusing onnewand effectivedrug delivery systems that can achieve desirable therapeutic efficiencywhile minimizing any side effects [1]. Nano- or micro-particulates arepotential delivery vehicles to administer therapeutic molecules in a con-trolledmanner [2,3]. Comparedwith traditional monolithic (single-unit)formulations, these particulates offer numerous advantages, includingreduced risk of dose dumping, increased bioavailability, and low proba-bility of inducing local irritations [4–7]. For the design of tailored madepharmaceutical particles, key factors that determine their efficacy areparticle morphology (including size and shape) [8–10], drug loading[11], and most importantly, drug release profiles [12]. Thus, well-defined and easily of an ideal drug carrier. Specifically in the applicationof hydrophilic drugs, fast release is generally encountered upon contactwith an aqueous release medium. A common strategy to achieve con-trolled release is to encapsulate hydrophilic drug molecules into arelatively hydrophobic matrix – the use of which often incurs the in-volvement of organic solvents in the synthesis process. In this study,we aim to develop a simple, waste-free synthesis process of uniform

Selomulya).

rights reserved.

esigning particulate carriers12

hydrophilic drug-loaded microparticles with well-controlled physico-chemical properties and controlled release functionalities.

A number of studies have been done to develop synthesis methodsto control the particle properties [13–15], while most of the tech-niques to form monodisperse particles require the use of organicsolvents with prolonged chemical reactions and separation steps.Herein, a microfluidic jet spray drying technique was utilized to real-ize a single-step and waste-free particle production process, ensuringclose to 100% encapsulation of the therapeutic agent, and preventingwastage of expensive drugs [16]. Most industrial or lab scale spraydryers (e.g. Bend Research [17]) produce particles with wide size/morphology distribution, whereas the particles obtained from oursystem consistently show uniform properties (both in size andshape). This feature is beneficial to understand the design of pharma-ceutical particles. Although spray drying of monodisperse particleshas also been reported by Vehring's group [18,19], the use of a vibrat-ing orifice generator to produce monodisperse droplets encouragesdroplet–droplet interactions (mainly collisions) during the evapora-tion process due to the relatively close spacing between the droplets.Thus the droplet generator has to be operated in the ‘droplet-on-demand’ mode, which limits the production yield. Here, a microfluidicaerosol nozzle able to handle various precursors (including nanoparticlesuspensions and viscous polymers) developed in our group is used as themonodisperse droplet generator [20,21], with a specially designed

for encapsulation and controlled release applications, Powder Tech-

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O

C2H5

O

CH3

O

O

CH3

... ...

Fig. 1. Chemical structure of Eudragit® NE.

2 W. Liu et al. / Powder Technology xxx (2012) xxx–xxx

(in-house) microfluidic jet spray dryer, to prepare uniform, non-agglomerated microparticles with controllable particle size [22].The microfluidic aerosol nozzle is able to continuously operate forseveral hours, ensuring sufficient production yields of various func-tional particles [23–26]. In addition, a unique feature of our spraydrying system is the use of relatively low air velocities to increasethe residence time of the droplets during drying process, so thatheat-sensitive materials can be dried under a relatively low dryingtemperature [27].

Meanwhile, we managed to avoid the use of any organic solventsthat often reduce biocompatibility of the products, by using a water-based encapsulation material (aqueous polymer dispersion, Eudra-git® NE 30D). Eudragit® NE is a neutral copolymer of poly-methacrylic acid esters (Fig. 1), which is swellable but not solublein an aqueous environment, independent of the pH values. Differentadditives, in the form of lactose and silica nanoparticles, both ofwhich are biocompatible and commonly used as food or pharma-ceutical excipients and approved by the U.S. Food and Drug Admin-istration (FDA) [28], were incorporated into the polymericmicroparticles to regulate the drug release kinetics, using vitaminB12 as the model drug. Highly monodispersed microparticles withdistinctive morphologies and easily tunable drug release kinetics(immediate or sustained) were successfully obtained. The uniquestructures were shown to be directly related to the evaporation-induced self assembly, based on the colloidal interactions of thecomponents.

2. Material and methods

2.1. Materials

Eudragit® NE 30D (30% aqueous dispersion of polymeric nano-particles with an average particle size of 162.8 nm±3.5 nm asmeasured by dynamic light scattering) was kindly provided byEvonik Degussa Industries (Australia). Upon drying at room tem-perature, droplets containing the initially dispersed polymernanoparticles fused into a continuous film (Fig. S1, Supporting In-formation), thus providing effective barriers for controlled drug lib-eration. Vitamin B12 (VB12), alpha-D-lactose monohydrate, Ludox®HS-30 silica nanoparticles (30% solid suspension of SiO2 nanoparticleswith an average particle size of 12.0 nm±0.7 nm as measured by dy-namic light scattering), and phosphate buffer saline (PBS, pH=7.4, con-sisting of 0.138 M NaCl, 0.0027 M KCl, 0.01 M Na2HPO4 · 2H2O, and

Ho

Precusor preparation

Fig. 2. Schematic diagram of the

Please cite this article as: W. Liu, et al., On designing particulate carriersnol. (2012), doi:10.1016/j.powtec.2012.02.012

0.00176 M KH2PO4) were purchased from Sigma-Aldrich (Australia)and used without further purification. Deionized water (Milli-Q) wasused in all precursor preparation.

2.2. Preparation of uniform microparticles

The schematic diagram for the single-step particle fabricationprocess is displayed in Fig. 2, while the detailed design of the rig isshown in Fig. S2 (Supporting Information). Briefly, the precursors(compositions as shown in Table 1) were fed into a 1.5 L stainlesssteel reservoir and atomized by a specially designed micro-fluidicaerosol nozzle [20]. Dehumidified instrument air was used to forcethe precursor in the reservoir to jet through the orifice of the nozzle.A piezoelectric pulse was exerted to break the liquid jet into drop-lets. The liquid flow rate and the frequency of piezoelectric pulseapplied were adjusted to best achieve a monodisperse droplet for-mation. The droplet generation mode was monitored by a digitalSLR camera (Nikon, D90) with a speed-light (Nikon SB-400) and amicro-lens (AF Micro-Nikkor 60 mm f/2.8D). The droplets formedwere air-dispersed and dried in the chamber of a micro-fluidic jetspray dryer [16]. The set temperature of the heated air gun provid-ing hot air to the drying chamber was maintained at 180 °C. Thisprovided an inlet temperature of 146 °C and an outlet temperatureof 83 °C, respectively. The conditions were kept constant for all theruns to exclude the influence of drying conditions on the resultingparticles.

t air

Atomization

Dispersing Air

Cooling Water

Particle production yield is up to several grams per hour

particle fabrication process.



Table 1Compositions of precursors used for spray drying.

Formulationnumber

Eudragit®NE (w/v)

Lactose(w/v)

Silicananoparticles(w/v)

VB12

(w/w) a

Particlesize(μm)

Encapsulationefficiency (%)

E4 4% 0% / 1/30 100.55±4.68

94.54±2.75

E3L1 3% 1% / 1/30 85.55±3.36

98.98±0.57

E2L2 2% 2% / 1/30 77.94±3.49

94.30±1.35

E1L3 1% 3% / 1/30 70.65±4.51

98.71±0.83

E4S0.1 4% / 0.1% 1/30 98.10±4.77

95.16±4.19

E4S0.5 4% / 0.5% 1/30 114.81±4.66

95.35±5.29

a The amount of Vitamin B12 was added according to the drug excipients ratio.

3W. Liu et al. / Powder Technology xxx (2012) xxx–xxx

2.3. Characterization of microparticles

The morphology and structure of microparticles before and afterdrug release tests were characterized by scanning electron microsco-py (SEM, JEOL 7001 F, Japan). Images of microparticles were alsorecorded by light microscopy (Motic B1-223A, UK). The average

Fig. 3. SEM photographs of spray-dried m


particle size and size distribution were analyzed using the softwarepackage Motic Images Plus 2.0 ML and ImageJ. The type of particlesize employed was Ferret's diameter, and at least 500 particles werecalculated for each sample. Powder X-ray diffraction (PXRD) patternsof raw VB12 and spray dried particles were collected using a HollandPhilips 1130 X-ray diffractometer with Ni-filtered Cu Kα radiation(λ=1.5405 Å). The tube voltage and amperage were set at 40 kVand 25 mA. Each sample was scanned between 5 and 30 °C in 2θwith a step size of 0.02 °C.

2.4. In vitro drug release test

The release profiles of VB12 from spray-dried microparticles werestudied in phosphate buffer saline (PBS, pH 7.4) at 37 °C using a shak-ing incubator (100 rpm). In a typical experiment, the drug-loaded mi-croparticles (50 mg) were added into 100 mL conical flask, and 50 mLof PBS release mediumwas transferred into a flask. At certain time in-tervals, 1 mL samples were removed and replaced with an equivalentquantity of the release medium. Collected samples were transferredinto 1.7 mL microtubes, centrifuged for 5 min at 10,000 rpm (Healforce, Neofuge 23R), and subjected to assay immediately. The contentof VB12 in the release medium was measured by a microplate reader(SpectraMaxM2e, Molecular devices) at the wavelength of maximum

icroparticles (inset scale bar: 20 μm).



5 10 15 20 25 30

Inte

nsity

2θ (o)

VB12

E4

E2L2

E4S0.5

Fig. 4. Powder X-ray diffraction patterns for raw vitamin B12 and spray dried micropar-ticles (E4, E2L2, and E4Si0.5).


absorbance (361 nm). The release data presented for each data pointwas the average of three test trials.

2.5. Drug encapsulation efficiency

The total amount of VB12 encapsulated into microparticles was de-termined by dissolving an accurately weighed amount of microparti-cles into 10 ml acetone/water mixture (1:1 ratio). After thedissolution of particles, the obtained solution was subjected to centri-fugation at 10,000 rpm for 5 min, and the amount of VB12 in superna-tant was determined by the microplate reader under 361 nm. Theencapsulation efficiency of VB12 was calculated by dividing theamount of drug encapsulated in the microparticles by the theoreticalamount of drug (calculated from the amount of drug added duringsynthesis). All analyses were performed in triplicate.

3. Results and discussion

3.1. Particle fabrication and particle morphology

By atomizing the precursor into monodisperse droplets (Fig. S3,Supporting Information) that were then dried into individual, non-

0 5 10 15 20 25 30

0

10

20

30

40

50

60

70

80

90

100

Cum

. rel

ease

d V

B12

(%

)

Time (hour)

E4

E2L2

E3L1

E1L3

Fig. 5. Drug release profiles of spray-dried microparticles with different Eudragit® NE:lactose ratios.


agglomerated microparticles, we could achieve particles with uni-form size and morphology (Fig. 3). The mean particle size and sizedistribution were summarized in Table 1, all indicating relatively nar-row distributions. The homogenous properties resulted from eachdroplet experiencing the same drying history, thus ensuring consis-tent functionalities of the microparticles (as demonstrated laterwith high reproducibility of the drug release behaviour). Due to theuniformity of the particles, a direct correlation between the morpho-logical/microstructural properties and the drug release kinetics couldbe obtained, with the knowledge crucial for the design of spray-driedpharmaceutical particles [29,30].

The microparticles were observed to exhibit different morphol-ogies depending on the composition of the precursors (Fig. 3). Micro-particles spray dried from pure Eudragit® NE (composition E4)showed bowl-like shapes, while the incorporation of lactose (E3L1 toE1L3) induced more spherical forms. On the other hand, the additionof silica nanoparticles (E4S0.1 and E4S0.5) increased the shape defor-mation. The different morphologies of these assembled microparti-cles were directly related to their physicochemical properties upondrying [23,31]. Previously we have explained in details these phe-nomena, but for the benefit of the readers, we briefly discussed thedrying behaviour of the specific systems here in relation to theirfinal morphologies [16,29].

Eudragit® NE existed in the form of soft polymeric nanoparticledispersion, with more complex drying behavior than soluble polymersystems due to the presence of the nanoparticles in the droplets [32].The morphological transition of the dried polymeric particles pro-ceeded via buckling of the initial spherical droplets when the defor-mation forces overcome stability forces, leading to non-sphericalmorphologies such as doughnut and mushroom [33–35]. On theother hand, the addition of lactose formed more spherical shapes[36,37], since as a low molecular weight sugar, the lactose moleculeswere more mobile than the dispersed Eudragit® NE nanoparticles.Thus they could quickly replace some of the water molecules duringevaporation to reduce shrinkage [38]. By adding silica nanoparticles,the shapes became more deformed, since the silica nanoparticles

Fig. 6. Optical images of microparticles with different Eudragit® NE: lactose ratios(after drug release, wet state in PBS solution).




also facilitated early skin formation subjected to capillary forces asdrying progressed [16,35].

The drug encapsulation efficiency of each sample as shown inTable 1 indicated almost 100% encapsulation onto the spray-driedmicroparticles. Our encapsulation efficiency here was significantlyhigher than those attainable with wet chemistry-based methods(typicallyb50%) [13] which often suffer significant losses of encapsu-lated ingredients during the washing steps. The PXRD patterns of thesamples were demonstrated in Fig. 4, indicating the crystallinity ofthe raw VB12 and the amorphous state of spray dried formulations.The formation of amorphous materials by spray drying is commonlyencountered, due to limited time available to form crystalline struc-tures during the fast evaporation process [39].

3.2. Effects of lactose on the release profile

Fig. 5 showed the in vitro drug release profiles of spray-driedmicroparticles with different Eudragit® NE : lactose ratio. These mi-croparticles possessed very distinct drug release properties, withincreasing lactose content resulted in faster drug release. Microparti-cles with the highest amount of lactose (E1L3) released almost allVB12 in 2 hours, whereas in the absence of lactose (E4), only about40% of total VB12 was released after 32 hours. The high hydrophobic-ity of Eudragit® NE microparticles (E4) possibly contributed to thecomparatively slow release behaviour, preventing water penetrationinto the microparticles. With partial displacement of water-solublelactose in the polymer matrix, the hydrophilicity of the microparticlesincreased, resulting in enhanced water permeability. Thus the in-creased water penetration would facilitate lactose dissolution andthe swelling of the polymeric microparticles. Both effects would re-sult in more contact between the encapsulated drug and the releasemedium, decreasing the barriers for drug diffusion and acceleratingthe release rate. This outcome indicated that lactose could act as a

Fig. 7. SEM photographs of microparticles with different Eudrag


very useful regulator to tune the effective barriers and the speed ofdrug liberation from these microparticulates.

Figs. 6 and 7 showed the optical (wet state in PBS) and SEM (drystate) photographs of the microparticles after drug release tests.Upon contact with the release medium, the shape of pure Eudragit®NE microparticles (Fig. 6, E4) did not show any visible change fromthe as-dried particles (Fig. 3, E4) compared to after the release test(Fig. 7, E4). With less contact with the release medium, the encapsu-lated drug located away from the particle surface would be difficult torelease, consistent with the incomplete release profile. On the otherhand, microparticles with different amount of lactose (E3L1, E2L2,and E1L3) swelled into spherical shapes upon contact with the releasemedium (Fig. 6, E3L1, E2L2, and E1L3), confirming the increased hydro-philicity and water penetration into the microparticles. From SEMphotographs of the dried particles after release tests (Fig. 7, E3L1,E2L2, and E1L3), microparticles of E3L1, E2L2, and E1L3 showed increas-ingly collapsed structures (to varying degrees) in comparison to theoriginal dried particles (Fig. 3, E3L1, E2L2, and E1L3) possibly due tothe removal of some of the lactose originally present in the matrix.

3.3. Effects of silica nanoparticles on the release profile

The drug release profiles of spray-dried microparticles with differ-ent amounts of silica nanoparticles were compared in Fig. 8. Incorpo-ration of silica nanoparticles significantly accelerated VB12 release.With the addition of 0.5% silica, 90% VB12 was released in the initialhalf hour. Even by adding only 0.1% silica, the drug release rate wasconsiderably enhanced, with a 55% release in one hour.

The accelerating effect of silica nanoparticles could be ascribed totheir strong affinity for polar compound like water, producing similareffects as the hydrophilicity of lactose [40,41]. However, it was worthnoting that the mode of acceleration was significantly different thanthat found with lactose as additives. While lactose caused the release

it® NE: lactose ratios (after drug release test, in dry state).



0

10

20

30

40

50

60

70

80

90

100

Time (hour)

E4

E4S

0.1

E4S

0.5

0 1 2 3

0 5 10 15 20 25 30

0

10

20

30

40

50

60

70

80

90

100

Cum

. rel

ease

d V

B12

(%)

Cum

. rel

ease

d V

B12

(%)

Time (hour)

E4

E4S

0.1

E4S

0.5

A

B

Fig. 8. (A) Drug release profiles of spray-dried microparticles with different contents ofsilica nanoparticles; (B) Inset of the release profile at the first 3 h.


profile to accelerate evenly, the addition of silica caused an immediate(burst) release, followed by the slow release rate of the remaining drug.

To understand the cause of this distinctive immediate release be-haviour, the shape and morphology of microparticles after the releasetest were observed (Fig. 9). The microparticles did not show visibleswelling in the release medium after the release test. The absence ofswelling meant that the incorporation of silica nanoparticles did notincrease the permeability and water penetration onto the microparti-cles, so that the drug located in the inner part of microparticles couldnot be released, corresponding to the very slow release rate after theinitial burst. Accordingly, the initial fast release could also be due tothe presence of drug on the particle surface (or near to the particlesurface). The cobalt atoms in VB12 carry partially positive charge,such that the VB12 molecules have affinity to negatively charged sur-faces [42,43]. Since the silica nanoparticles (Ludox® HS-30) used inthis study were negatively charged [44], we proposed that the highsurface amount of VB12 would be accompanied with enrichment ofsilica on the surface of the microparticles. To verify this hypothesis,elemental distribution analysis of the cross section of E4S0.5 micropar-ticles was conducted (Fig. 10). The data showed that silica (i.e. the sil-icon and oxygen elements) was more prolific on the surface of themicroparticles, which might be caused by the evaporation induced


self-assembly during the fast spray drying process [34]. Since silicain this case existed as nanoparticles, their diffusion as solutes in thedroplets during drying would be slower than the polymer, so thatthey would be mostly fixed on the shell of the particles [24]. SEMphotos in Fig. 9 showed that although the shapes of the particlesafter release tests were almost unchanged, both systems containingsilica nanoparticles demonstrated noticeably eroded surface charac-teristics, illustrating the removal of silica that also confirmed the sur-face enrichment of nanoparticles in the spray-dried microparticles.

3.4. Further discussion

The strikingly distinct drug release behaviours from each formula-tion could be directly related to the interactions between each of theelements composing the microparticles. Schematic diagrams of thepossible release mechanism(s) from each system as they came intocontact with buffer are presented in Fig. 11. For particles of pureEudragit® NE, the polymer existed as a continuous matrix form inthe spray dried microparticles, as depicted in Fig. 11A. Consideringthe low molecular weight (1355 g/mol) and high water solubility ofVB12 (50 g/L), the drug molecules would distribute homogeneouslywithin the entire particle. Upon contact with the release medium,water penetrating into the particles was hindered by the high hydro-phobicity of the polymer, resulting in limited particle swelling anddrug release. In the Eudragit® NE— lactose system, lactose with smal-ler molecular weight (342 g/mol) and higher water solubility (216 g/L) than VB12, should dissolve upon contact with the release medium.The dissolution of lactose present in the matrix would open up moreinternal channels to facilitate particle swelling and accelerated drugrelease (Fig. 11B). The dissolving of lactose was also evidenced fromthe collapsed structures of the particles after the release tests(Fig. 7). Particles composed of Eudragit® NE and silica nanoparticlesdisplayed shells enriched with mainly silica nanoparticles, while thehydrophobic polymer was distributed uniformly throughout thestructure (Fig. 11C). With this configuration, VB12 existing near thesurface would be easily released with the erosion of the nanoparti-cles, resulting in a burst release, while the release of the rest of thedrug located inside was largely avoided. The modeling of drug releasekinetics from these data (Fig. S4, Supporting Information) also con-firmed the effects of lactose in enhancing particle swelling and therelaxational contribution on drug release, while the microparticlesof pure Eudragit® NE and those with silica nanoparticles were mainlylimited by diffusion-controlled release mechanism.

4. Conclusion

Monodisperse microparticles as particulate drug carriers are use-ful for tailoring their behaviour in the release of any encapsulated in-gredient. We demonstrated a strategy to generate uniform polymericmicroparticles with adjustable release behaviors to encapsulate hy-drophilic drug without the use of any organic solvent, via microfluidicjet spray drying. Both the morphologies and release profiles (immedi-ate or sustained) could be directly controlled from the composition ofprecursors due to the colloidal interactions during evaporation in-duced self-assembly. Due to the uniformity of the particles, the re-lease mechanism(s) could be elucidated from particles of differentmatrix compositions, with the outcomes demonstrating the capabilityto tune the particle response(s) from the knowledge of materialproperties.

Appendix A. Supplementary data

Supplementary data to this article can be found online at doi:10.1016/j.powtec.2012.02.012.


doi:10.1016/j.powtec.2012.02.012

doi:10.1016/j.powtec.2012.02.012


Fig. 10. Elemental distribution maps of the cross-section of an E4S0.5 microparticle.

Fig. 9. Optical images (wet state in PBS solution) and SEMphotographs (dry state) ofmicroparticleswith different contents of silica nanoparticles after drug release test (inset scale bar: 10 μm).


Please cite this article as: W. Liu, et al., On designing particulate carriers for encapsulation and controlled release applications, Powder Tech-nol. (2012), doi:10.1016/j.powtec.2012.02.012


A.

B.

C.

Fig. 11. Schematic diagrams of possible release mechanisms from different microparticles.


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