6-Particle Encapsulation in Crosslinked Hydrogel...Particle Encapsulation in Crosslinked Hydrogel...

Journal of Materials Science and Engineering B 2 (10) (2012) 539-550

Particle Encapsulation in Crosslinked Hydrogel Networks: Particle Distribution Optimization

Karem A. Court1, Jackeline Jerez2, Rodolfo J. Romañach2 and Madeline Torres-Lugo1

1. Department of Chemical Engineering, University of Puerto Rico, Mayagüez Campus, PO Box 9000, Mayagüez, Puerto Rico,00681

2. Department of Chemistry, University of Puerto Rico, Mayagüez Campus, PO Box 9000. Mayagüez, Puerto Rico, 00681 Received: July 10, 2012 / Accepted: August 12, 2012 / Published: October 25, 2012. Abstract: Particle encapsulation in hydrogel membranes was performed to examine which physical factors are involved in particle distribution within membranes. This investigation focused on the examination of the physicochemical interactions between particles and crosslinked hydrogel networks for the creation of homogenously dispersed particles in a membrane. For this purpose factors such as particle charge, concentration, and membrane charge were examined to ascertain their effect on particle dispersion within the matrix. Anionic hydrogels composed of methacrylic acid (MAA), cationic hydrogels composed of N,N-dimethyl amino ethyl methacrylate (DMAEM), and neutral hydrogels composed of 2-hydroxyethyl methacrylate (HEMA) were utilized to encapsulate functionalized silica particles. Particle distribution was analyzed by Scanning Electron Microscopy and Near Infrared Chemical Imaging (NIR-CI). A new method was developed to evaluate the distribution of particles throughout the membranes. NIR-CI results indicated that neutral membranes with low particle concentration showed better particle distribution. Key words: Chemical crosslinker hydrogels, particle, near infrared chemical imaging, polymers, membranes, dispersion.

Nomenclature

DMAEM: (N, N-dimethyl amino) ethyl methacrylate HEMA: 2-hydroxyethyl methacrylate MAA: Methacrylic acid NIR-CI: Near infrared chemical imaging pI: Isoelectric point SEM: Scanning Electron Microscopy TEM: Transmission Electron Microscopy

1. Introduction

Many pharmaceutical drug products are sold as solid oral dosage forms. Although the advantages of solid oral dosage forms are highly recognized, there are exceptions to their practicality, such as the difficulty to medicate children especially when tablets are large. A large number of drugs also have solubility problems, which make their formulation development difficult. Polymeric gel strips are a potentialssible delivery method for drugs with poor solubility, where it should

Corresponding author: Madeline Torres-Lugo, professor, Ph.D., research field: Biomedical Engineering. E-mail: [email protected].

be possible to disperse small drug particles throughout the gel strip. Such systems possess the challenge that the particulate that includes the active ingredient must be homogeneously dispersed within the membrane to guarantee the necessary dosage.

Crosslinked hydrogels may be used to prepare gel strips. These polymeric materials are excellent candidates for drug delivery because they retain large amounts of water, are environmentally responsive and biodegradable [1-3]. The understanding on how charge and composition affect the distribution of particles within a matrix is of utmost importance. Studied particles possessedhave a diameter of 100 µm which are interesting for the pharmaceutical industry as since many marketed drugs have similar particle sizes around 100 µm.

Several researchers have investigated the phenomena of particle encapsulation within substrates. Observations regarding morphology, thermosensitivity, particle size distribution, and

DAVID PUBLISHING

D


540

adhesion between dissimilar solids have been studied. Particles including magnetic nanocrystals [4], poly-N-isopropylacrylamide (PNiPAM) microgel particles [5]), polyisobutyleneparticles [6] and different pairs of organic and inorganic nanoparticles [7] have been studied by confocal fluorescence microscopy, static light scattering, scanning electron microscopy, transmission electron microscopy or scanning probe microscopy [4-7]. These studies provided valuable information, but the physical and chemical factors that interfere in the homogenous distribution of particles in polymers were not thoroughly examined.

To study such phenomena, several techniques can be employed including: transmission electron microscopy, static light scattering, scanning probe microscopy and scanning electron microscopy. All these techniques are qualitative methods; where an image of the sample is always obtained [5, 8-10]. However, these techniques require special preparations, are time consuming, or are difficult to apply in on-line pharmaceutical processes.

An alternative that is commonly employed in the pharmaceutical industry is near infrared chemical imaging (NIR-CI). Chemical imaging is an innovative technique that combines imaging and spectroscopy to obtain spatial and spectral information from a sample. NIR-CI unites the chemical selectivity of vibrational spectroscopy and the potential of image visualization. Additionally, it is a multidisciplinary technique that combines two important aspects: spectroscopy and image processing [11]. The combination of both aspects creates a more complete instrument, which can be applied for the determination of ingredient distribution in solids, semi-solids, powders, suspension and liquids [12].

This work focuses on the use of crosslinked hydrogels to study the interaction of particles within the encapsulation substrate. In this preliminary stage, silica particles were used as a model system as different particle charges are available. A strategy was designed to create hydrogels with thoroughly dispersed particles

to study the effect of particle charge and concentration, and evaluate the effect on composition, charge and characteristics of the hydrogel on the dispersion of particles. For this purpose, silica particles of 100 µm in diameter were employed. Again this eseparticle size was were selected as many current pharmaceutical dosages possess similar size. These particles possessed positive, negative, and neutral charges as the result of surface functionalization. Two particle concentrations were used: 2.2 w/w% and 4.4 w/w%. Polymeric crosslinked hydrogel membranes were selected as to possess three different charges: anionic, methacrylic acid (MAA), cationic, (N, N-dimethyl amino) ethyl methacrylate (DMAEM, and neutral: 2-hydroxyethyl methacrylate (HEMA). Also, these systems are crosslinked, which provide a different source of immobilization.

The distribution of silica particles under the various processing conditions is described. NIR-chemical imaging and scanning electron microscopy were used to evaluate particle distribution within the hydrogel. NIR-CI was used since it does not require sample preparation and provides spatially-resolved chemical characterization of the novel gel strips prepared in this study. NIR-CI spectra consist of overtones of C-H, N-H, S-H and O-H stretching vibrational modes, and combination bands where two or more vibrations combine. Both methods provided valuable qualitative and quantitative information about particle distribution on each of the aforementioned systems.

2. Experiments

2.1 Particle Encapsulation in Crosslinked Hydrogels

Hydrogels were prepared by free radical polymerization. Different monomers were employed including MAA, DMAEM, and HEMA and the crosslinker was poly(ethylene glycol) dimethacrylate (PEGDMA 1,000) (n = 1,000) (Poly Sciences Inc. Warrington, PA). The monomer and crosslinker were dissolved in a solution of 1:1 v/v deionized


541

water/ethanol (Fisher Scientific, Pittsburgh, PA). The monomer to solvent molar ratio for DMAEM and MAA was 3:2 and 2:5 for HEMA. The crosslinker concentration was 1:5 for DMAEM, 12 mol% for MAA and 0.6 mol% for HEMA. Unfunctionalized silica particles were used as well as aminated and carboxylated. The particles had 100 µm of diameter (Corpuscular, Cold Spring, NY). The UV initiator was 2-hydroxycyclohexyl phenyl ketone (Sigma-Aldrich, Milwaukee, WI). Hydrochloric acid 6N and sodium hydroxide 5 M was used to change the pH of the pre-polymeric solution. The monomer, crosslinker and diluents were weighed in an amber bottle with septum screw caps. The particles were added after the pre-polymeric solution was sonicated and a clear mixture was observed. The initiator was added and the mixture was again sonicated and placed in the inert glove box (Cole-Parmer Instrument Co., Vernon Hills, IL). The mixer was bubbled with nitrogen for 20 minutes. Bubbles were eliminated to facilitate a homogeneous polymerization by allowing the solution to rest for five minutes. The mixture was pulled by capillarity between two microscopeslides separated by Teflon spacers of 0.30 inches wide and irradiated with UV radiation from a mercury lamp as the ultraviolet light source (EXFOS Lite, Mississauga, Ontario) under a nitrogen atmosphere for a specific time for each monomer. Hydrogels possessed an approximate thickness of 700 µm. Particles of 100 µm, 1 µm and 100 nm diameters were encapsulated in the hydrogels.

2.2 Determination of Zeta Potential

The net charge of the silica particles was studied with dynamic light scattering by using a BI-90 plus particle size analyzer and zeta potential analyzer (Brookhaven Instruments Corporation, Holtsville, NY). The particle suspension was diluted with deionized water until a clear suspension was observed. KCl was added to the suspension where the salt concentration was 1 mM to keep the conductivity constant. The solution pH was changed from 2.0 to 10.0 with KOH

and HNO3 solutions with concentration of 0.1 M and 0.001 M. The zeta potential for plain, aminated and carboxylated particles was determined.

2.3 Scanning Electron Microscopy

Hydrogels were placed in ethanol for at least 12 hours. Hydrogels were cut with a razor blade and dried by critical point drying. Samples were coated with gold and observed under scanning electron microscopy. The membranes were observed from the top and cross-sectional area. This technique allowed a qualitative observation of the distribution of the particles inside the membrane.

2.4 Near Infrared Chemical Imaging

The near infrared chemical imaging was performed using a SyNIRgiTMNIR Spectral Imaging System (Malvern Instruments, UK). The imaging system consists of a liquid crystal tunable filter (LCTF) coupled with an NIR sensitive Focal Plane Array (FPA) detector. The diffuse reflectance image of the sample was passed through the LCTF, and imaged onto a 320 × 256 pixel FPA. The area interrogated by each pixel was 17.5 × 17.5 µm, giving an imaging area of 4.35 × 5.44 mm. The spectrum was measured with 1 scan, in a spectral range of 1,200-2,450 nm, at 10 nm steps. The data collected was processed using the ISys® software version 5.0.0.14. Three membrane areas of each synthesized membrane were scanned with the NIR-CI. Background correction was performed by dividing the sample cube with the background, after subtracting the dark cube from both sample and background. All spectra were transformed from reflectance (R) to log (1/R) values. Bad pixels and pixels that were outside of the strip were then overwritten using the system’s software. The remaining spectra were mean centered and scaled to unit variance. Finally, the standard normal variate transform was calculated and the second derivative of the spectra obtained with the Savitzky Golay method with 9 points and a 3rd grade polynomial.


542

3. Results and Discussion

3.1 Measurements of Zeta Potential

The zeta potential of silica particles can vary when

Fig. 1 Zeta Potential for functionalized silica particles at various pH’s. ● unfuntionalized silica, ▲ silica with carboxyl groups and ■ silica with amine groups.

placed in contact with the pre polymeric solution. For this purpose, particle suspension pH was changed from 2.0 to 10.0 to determine the isoelectric point (pI) of particles. The measurement of zeta potential was performed by suspending the particles in deionized water changing the pH from 3.0 to 10.0 to observe particle behavior under the same conditions of the monomer solution. The isoelectric point for each of the silica samples is shown in Fig. 1. The lowest pI was 3.5,

for non-functionalized particles, followed by a pI of 4.5 for the carboxylated group particles, and 8.0 for the aminated particles. In this particular case MAA has a pKa of 4.66 and DMAEM 8.0., Theseis values are important because the pre-polymeric solution pH was modified to values according to each set of particles and the polymer charge should not change.

3.2 Scanning Electron Microscopy

After particle charge was analyzed, a qualitative particle distribution study was performed. For this purpose, all membranes were observed by SEM. Fig. 2 presents an example of SEM images of the 100 µm particles for the three polymers with three particle charges at high concentration (4.4 w/w%). SEM images confirm that the silica particles were encapsulated inside the hydrogel. These images also provide a qualitative idea of the particle distribution within the hydrogel.

Particle distribution of the 100 µm silica particles presented different behaviors as evidenced by Fig. 2. Some membranes showed clusters, as for example MAA with positive particles. Other membranes contained a more dispersed particle distribution such as DMAEM with negative particles (Fig. 2). Fig. 2 is a sample of a set of photograph sictures that was taken

Fig. 2 SEM images of 100 um particles encapsulated in hydrogels membranes of various composition.

Particle charge: Negative Neutral Positive

HEMA

MAA

DMAEM

Pa

from approxSEM, howevthat the arelarger 100 µ

To obtainwas employ

3.3 Near Inf

NIR-CI wµm particlesmarketed drumagnificatioNIR-CI is nthat these sidiscrete entiwith and wsecond derivare minimumin the spectru1,360 nm, 1are at 1,330

Fig. 4 NIR sHEMA and (c

article Encap

imately 1 mmver, has somea evaluated

µm particles. n a more quaned as well.

frared Chemic

was employed s, which are ougs have sim

on used was 17not capable oize such as 1ties. Derivati

without particvative was calm peaks that cum. The princ,730 nm, 1,92nm, 1,700 nm

spectra of encac) MAA.

psulation in C

m2 each hydroe limitations ris, which too

ntitative view

cal Imaging

to study the of interest sincilar particle s7.5 µm per piof detecting 1 µm or 100ve spectra fro

cles are showlculated so thcorrespond to cipal bands fo20 nm and 2

m, 1,920 nm a

apsulated 100

Crosslinked H

ogel combinatregarding theo limited for

w of samples,

encapsulated ce many curreizes. The NIRxel, thereforeparticles sma

0 nm particleom each hydrwn in Fig. 4he chemical ba

maximum poor DMAEM a,260 nm, HE

and 2,260 nm

um silica part

Hydrogel Netw

tion. fact r the

NIR

d 100 ently R-CI e, the aller

es as rogel 4. A ands oints are at EMA m and

MA2,26inte

SsystNIRof tspepartnot chesilicimalocaimabe streobsDMat 1obt

ticles and plain

works: Partic

AA are located60 nm. Eacerpreted yieldiSubtle differetems with andR-CI was usethe chemicalctra of the hticles were anfound (data

emical imagesca particles inage of a hydration of the sage based on t

obtained sinetching vibraterved betwee

MAEM and M1,730 nm andained with t

n hydrogels fo

cle Distributio

d at 1,350 nmch of these ing valuable cences are obd without partd to understal compositiohydrogels at nalyzed and ca not shown)s for encapsun DMAEM. Frogel and thesilica particlethe C-H stretnce the firstions for the en 1,700 nm

MAA polymerd for HEMA the C-H over

or various conf

on Optimizati

m, 1,730 nm, 1NIR-CI ba

chemical infobserved in thicles as eviden

and the spatian of the hydthe different

chemical diff). Fig. 5 presulated negativFig. 5a is the darker areas

es. In additionching of the p

st overtone aliphatic hyd-1,800 nm [

r the C-H banat 1,700 nm.rtone band of

figuration. (a)

on 543

1,920 nm andands can beormation [14].he spectra ofnced in Fig. 4

al distributiondrogels. Thet pH withoutferences weresents severalvely charged

e microscopics indicate then, a chemicalpolymers canof the C-H

drocarbons is[12]. For thed is observed Fig. 5b wasf DMAEM.

DMAEM, (b)

3

d e . f 4. n e t e l d c e l n H s e d s .

)


544

Fig. 5 DMAEM with negative 100 um encapsulated particles, (a) Conventional microscopy, (b) NIR image at 1,730 nm, (c) NIR image at 1,920 nm, (d) NIR image at 1,350 nm, (e) NIR image at 2,260 nm.

Images were also obtained for the O-H stretch, and Fig. 5c shows the O-H combination at 1,920 nm. The O-H bands are broad and their position can vary according to the hydrogen bonding environment [12].

The NIR-CI spectra included the overtone of silanol O-H stretching bands from the silica particles at 1,330-1,360 nm, and the combination band at 22,260 nm. Fig. 5d describes the location of the silica particles, and is similar to the conventional microscopy image Fig. 5a while Fig. 5e presents the chemical image of silanol combination band at 2,260 nm. Fig. 5e corresponds to Fig. 5d and Fig. 5a, and indicates the location of the silica particles.

The first overtone of OH in silica has been reported to be at about 1,390 nm and the combination bands in

2,240 nm, 2,250 nm and 2,210 nm [12]. However, the position of the overtone and combination bands can be affected by hydrogen bonding and in this study they are observed at 1,330-1,360 nm, and 2,260 nm, respectively. Thus the NIR-CI images facilitated spectral interpretation by indicating the location of the silica particles.

The O-H band assignments were also confirmed in an experiment where silica particles were placed over a gel strip. In this experiment strong O-H bands were observed at the locations that corresponded to the silica particles. The behavior of silica as a desiccant was clearly observed and these O-H bands are assigned to the water adsorbed by the gel. On the other hand when silica was encapsulated the strong silanol bands did not

(a)

(b)

(d)

(c)

(e)


545

correspond with strong water bands. The silanol O-H bands at 1,360 nm and 2,260 nm were chosen to evaluate the particle distribution, and chemical images were obtained with both bands. Fig. 6 shows the NIR chemical images for membranes with low particle concentrations and Fig. 7 for membranes with high particle concentrations at 2,260 nm. At a low concentration the membrane with greatest number of clusters is the positive membrane with negative particles. At a high concentration the membranes with larger clusters are negative membranes with neutral particles and positive membranes with negative particles. For low and high concentration this behavior was observed for the different areas of all the membranes. After a qualitative observation of all the chemical images it was observed that ionic membranes created larger clusters in contrast with

neutral membranes, which created smaller clusters regardless of the location of the particle charge.

3.4 Evaluation of Particle Distribution

Given our qualitative observation of the behavior of particles encapsulated in crosslinked networks, a quantitative method was developed to evaluate the distribution of particles. For this purpose, chemical images obtained at 2,260 nm were converted to a binary image with ISys® software. The ISys® software creates a black and white image and a binary matrix where 1 represents silicaand 0 represents the polymer.

The binary image was divided into 16 equal squares each with 5,120 pixels as shown in Fig. 8. For each area, R was calculated as a function of the number of pixels of silica according to Eq. (1).

Fig. 6 NIR chemical images of hydrogel membrane with 100 µm particles and low concentration (2.2 w/w%). System: (a1) HEMA and neutral particles, (a2) HEMA with positive particles (a3) HEMA with negative particles, (b1) MAA with neutral particles (b2) MAA with positive particles (b3) MAA with negative particles (c1) DMAEM with neutral particles (c2) DMAEM with positive particles (c3) DMAEM with negative particles.

Pa

546

Fig. 7 NIR cHEMA and nparticles (b2) with positive

Fig. 8 Examnegatively chBlack is silica

A box plowhere the tothe 75th awhiskers we

article Encap

chemical imagneutral particle

MAA with poparticles(c3) D

mple of a binarharged particlea and white is p

ot was createdop and bottomand 25th pere calculated

psulation in C

ges of hydrogeles, (a2) HEMAsitive particles

DMAEM with

ry image of Des at 2,260 nmpolymer.

d to representm of the box ercentile, re

d by calculati

Crosslinked H

ls membrane wA with positives (b3) MAA witnegative partic

MAEM with sm with 16 squ

t the R valuesis represented

espectively. ing the 1.5 v

Hydrogel Netw

with 100 µm pae particles (a3)th negative parcles.

silica ares.

(1)

s and d by The

value

of tis tconwheconstruchamaxa minclsegron oleft R-vwashomthosoutl

works: Partic

articles and hig) HEMA with rticles (c1) DM

he interquartithe median. nsidered outliere the R

ncentration ofucture is reprarge while thximum value

minimum valuludes a total oregated sampone half of th

with only values was os not encamogeneous dse samples lier values clo

cle Distributio

gh concentratinegative parti

MAEM with ne

ile range (IQRData points iers. Fig. 9 values for

f each particresented. Thee y-axis indiof one (1), co

ue of zero (0of 32 values ople was preparhe hydrogel w

polymer.. Tbserved for

apsulated, (distribution iwhere boxesose to the wh

on Optimizati

ion (4.4 w/w%)cles, (b1) MAAutral particles

R).The line inoutside the illustrates thlow and h

cle charge ane abscissa is ticates the R orresponding ), for the polof R for each red by deposi

whereas the oThe greatest

samples whe(Fig. 9). Tisare consides are small hiskers.

on

). System: (a1)A with neutrals (c2) DMAEM

nside the boxwhisker are

he box plots,high particlend membranethe particles’value with ato silica, and

lymer. Fig. 9condition. A

iting particlesther half wasvariation in

ere the silicaTherefore, aered towhenand possess

) l

M

x e , e e ’ a d 9 A s s n a a n s


547

Fig. 9 Averageparticle distributions in (a1) positive membrane 2.2 w/w% (a2) positive membrane 4.4 w/w%,(b1) negative membrane 2.2 w/w% (b2) negative membrane 4.4 w/w%, (c1) neutral membrane 2.2 w/w% (c2) neutral membrane 4.4 w/w%.

One of the most homogenous particle distributions was observed in neutral membranes with high concentration of neutral particles. A minimum variation in R was observed with outlier values really close to whiskers, as evidenced in Fig. 9c2, where the data distribution goes from approximately 0.0 to 0.1

with the outliers. Heterogeneous distributions were observed when the values of R are more dissimilar as in the positive membrane with high concentration of negative particles (Fig. 9b2, where the R goes from approximately 0.0 to 0.7). The neutral membrane shows a better particle distribution for all particle

Ran

ge: N

umbe

r Sili

ca P

ixel

s/To

tal P

ixel

Num

ber

Charge particles


548

charges (Figs. 9c1 and 9c2). The boxes and whisker are smaller when compared with the others membranes. The highest spread goes from 0.0 to 0.4 for neutral particles with low concentration (Fig. 9c1) including outliers and negative particles with high concentration (Fig. 9c2) including outliers. This evaluation confirms that the neutral membranes demonstrated a more homogenous distribution. Positive and negative membranes showed a more heterogeneous distribution.

3.5 Possible Explanations for Cluster Formation

The physical and chemical factors that affect the distribution of particles in polymers are not fully understood. Some of the previously studied systems include particles encapsulated in thermoplastic polymers, which form polymer films by the evaporation of a solvent [7]. However, the systems evaluated in this study consist of particles encapsulated in crosslinked hydrogels, which form crosslined membranes during the polymerization process. Therefore, the process is more complex and more than one factor and/or theory may be necessary to explain the observations. In this work, different charge membranes and particles with two concentrations were prepared in order to observe the particle distribution. The 100 µm silica particles were analyzed and the principal observation is that the utilization of neutral membranes resulted in the more homogenous particles distributionsis for neutral membranes, regardless of the particle charge. A Mmore heterogeneous distributionsis were observed in positive and negative membranes.

Several factors could explain these results. The first factor to consider is the differences in the density of the silica particles. The silica particles are denser than the pre-polymeric solution, so the particles could sediment due to the gravitational force generating clusters while the polymerization reaction was occurring. Silica density is 2.65 g/cm3 while the density of the monomers is 0.93 g/cm3 for DMAEM, 1.07 g/cm3 for HEMA and 1.02 g/cm3 and for MAA. However, the

difference between the studied particles distributions in ionic and neutral membranes cannot be attributed solely to the density properties of silica and hydrogels. The monomers have similar densities, approximately 1 g/cm3, and for this reason the effect of density on particle distribution should be similar for the three membranes. At the beginning of the polymerization process the system is liquid, when polymerization starts the viscosity of the medium increases until the solid final conformation is obtained. Thus, density effects are only present at the beginning of the process.

Membrane charge appears to be an important factor, according to our results. In neutral hydrogels van der Waals forces are present. For those particles that either by sedimentation or simply by chance are close to each other. These Van der Waals forces are caused by associations in the changing polarizations of nearby particles and depend on the relative orientation of the molecules. These forces are weaker than regular chemical bonds and the Coulombic force, facilitating particle dispersion and increasing homogeneity in the neutral hydrogel membrane. The particles were most probably dispersed along the matrix while the reaction was occurring and fewer clusters were created in neutral hydrogels. Negative and positive membranes showed a different behavior. Chemical imaging indicateds particle aggregation in both hydrogels for all the particle charges. Ionic hydrogel membranes presented more aggregation. These particular systems consist of carboxyl and amine moieties, which could promote further interactions due to Coulomb’s law. The result is then that larger clusters were observed. Therefore, the neutral charge favored dispersion.

The work of Santander-Ortega supports the idea of the importance of electrostatic interactions since it reports that bare poly(lactic-co-glycolic acid) (PLGA) particles lose their colloidal stability when electrolytes are added to the solution, due to the DLVO theory (named after Derjaguin and Landau, Verwey and Overbeek) [13]. The DLVO theory analyzes the attractive (VA) and the repulsive (VE) forces between


549

two approaching particles. The total interaction potential Vt is obtained by the sum of VA and VE. The attractive interaction depends on the van der Waals dispersion forces and the repulsive interaction is created by the overlapping of the electrical double layers of the charged particles and also depends on the ionic strength of the medium or solvent. Adding electrolytes to the solution can decrease VE making VA forces higher and reducing the colloidal stability of the particles leading to particle aggregation [13]. This could explain the particle aggregation observed in anionic and cationic, MAA and DMAEM, membranes,membranes; because charged structures can reduce the repulsive term and the total interaction Vt is due to the attractive term. In neutral membranes this interaction is not present and the total interaction tends to the repulsive force keeping a higher colloidal stability.

Other possible explanation for the membrane charge factor can be related to the investigation of Zaccone et al. where the stability of colloidal system of styrene-acrylate copolymer particles and potassium sterate anionic surfactant molecules were analyzed [14]. Different surfactant concentrations were used to create bare, partial coverage, complete coverage and saturated particles concluding that the aggregation depends on the coverage of the particle. Partially covered particles presented less stability and more aggregation than fully covered particles and at higher concentration of surfactant micelles are formed leading to depletion and destabilization [14]. In this particular study particles could interact with the ionic moieties of the monomer solution. However, since the monomer solution pH is modified as to ensure particle charge, it is possible that ions in solution could quench particle or monomer charge, thus promoting limited particle/monomer interactions. This could lead to loss of stability creating larger clusters, which are observed in ionic hydrogels. Doing the analogy with the aforementioned study by Zaccone, et al. [15], one could argue that there was a partial coverage of the particles by the pre polymeric

solution. From the results and discussion presented herein, it

is certain that the process of particle dispersion in solid matrices is complex. However, it appears that particle density and substrate charge are important. Further research must focus on the in depth understanding of such factors.

4. Conclusions

NIR-CI and SEM techniques were employed to assess particle distribution in hydrogels. NIR-CI provided a larger area and provided different images according to the chemical bond evaluated, although the analysis was limited to particles of about 100 µm diameter. Many currently marketed drugs have D50 values near 100 µm, therefore the study of this particle size is also important. Particle charge,and concentration, and membrane charge were examined to ascertain their effect on particle dispersion within the matrix. Ionic membranes generated a heterogeneous particle distribution and neutral membranes created a more homogenous particle distribution. Qualitative analysis concluded that the particle distribution studied in these hydrogels depends on two factors: the particle density and membrane charge. The silica particles are denser than the pre-polymeric solution so the particles sediment due to the gravitational force generating clusters while the polymerization reaction was occurring. The second factor: membrane charge, for neutral hydrogels only weak Van der Waals forces are present, allowing repulsion between particles and a more homogenous distribution. Positive and negative hydrogels presented more ionic interactions that made particle distribution more heterogeneous. DLVO theory agrees with these observations since addition of electrolytes to the particle solution could decrease repulsive forces making attractive forces higher and reducing the colloidal stability of the particles facilitating their aggregation. Finally, future investigation will include the study of silica particles in a colloidal system to further understand particle


550

attraction and repulsion interactions.

Acknowledgments

The authors acknowledge the support of National Science Foundation, (ERC research grant: EEC-0540855) for conducting this research work, and MRI grant award 0821113, José Almodovar from Microscopy Center University of Puerto Rico for the SEM images and Dr. Carmen A. Vega for helpful discussions.

References [1] N. Peppas, J.Z. Hilt, A. Khademhosseini, R. Langer,

Hydrogels in biology and medicine: from molecular principles to bionanotechnology, Advanced Materials 18 (2006) 1345-1360.

[2] M. Hamidi, A. Azadi, P. Rafiei, Hydrogel nanoparticles in drug delivery, Advanced Drug Delivery Reviews 60 (2008) 1638-1649.

[3] B. Yu, C. Wang, Y.M. Ju, L.J. West, J. Harmon, F. Moussy, et al., Use of hydrogel coating to improve the performance of implanted glucose sensors, Biosensors Bioelectronic 2 (2008) 1278-1284.

[4] L. Zhang, L. Chen, Q. Wan, Preparation of uniform magnetic microspheres through hydrothermal reduction of iron hydroxide nanoparticles embedded in a polymeric matrix, Chemistry of Materials 20 (2008) 3345-3353.

[5] E. Soulé, G. Eliçabe, Determination of size distributions of concentrated polymer particles embedded in a solid polymer matrix, Particle and Partarticle System Characterization 25 (2008) 84-91.

[6] J. Musch, S. Schneider, P. Lindner, W. Richtering, Unperturbed volume transition of thermosensitive poly-(n-isopropylacrylamide) microgel particles embedded in a hydrogel matrix, Journal of Physical

Chemistry 112 (2008) 6309-6314. [7] L.F. Valadares, E.M. Linares, F.C. Braganca, F.

Galembeck, Electrostatic adhesion of nanosized particles: The cohesive role of water, The Journal Physical Chemistry C 112 (2008) 8534-8544.

[8] O. Guise, C. Strom, Preschilla, STEM-in-SEM method for morphology analysis of polymer systems, Polymer 52 (2011) 1278-1285.

[9] A. Maksumov, R. Vidu, A. Palazoglu, P. Stroeve, Enhanced feature analysis using wavelets for scanning probe microscopy images of surfaces, Journal of Colloid and Interface Science 272 (2004) 365-377.

[10] W. Pyrz, D. Buttrey, Particle size determination using TEM: A discussion of image acquisition and analysis for the novice microscopist, Langmuir 24 (2008)11350-11360.

[11] J.M. Amigo, J. Cruz, M. Bautista, S. Maspoch, J. Coello, M. Blanco, Study of pharmaceutical samples by NIR chemical-image and multivariate analysis, Trends in Analytical Chemistry 27 (2008) 696-713.

[12] A. Gowen, C. O’Donnell, P. Cullen, S. Bell, Recent applications of Chemical Imaging to pharmaceutical process monitoring and quality control, European Journal of Pharmaceutics and Biopharmaceutics 69 (2008) 10-22.

[13] L.G. Weyer, S.C. Lo, Spectra-Structure Correlations in the Near-infrared, Handbook of Vibrational Spectroscopy, John Wiley & Sons Ltd, 2002, pp. 1-22.

[14] M.J.S. Ortega, A.B.J. Reyes, N. Csaba, D.B. González, J.L.O. Vinuesa, Colloidal stability of pluronic F68-coated PLGA nanoparticles: A variety of stabilisation mechanisms, Journal of Colloid and Interface Science 302 (2006) 522-529.

[15] A. Zaccone, H. Wu, M. Lattuada, M. Morbidelli, Correlation between colloidal stability and surfactant adsorption/association phenomena studied by light scattering, The Journal Physical Chemestry B 112 (2008) 1976-1986.

6-Particle Encapsulation in Crosslinked Hydrogel...Particle Encapsulation in Crosslinked Hydrogel...

Documents

Transcript of 6-Particle Encapsulation in Crosslinked Hydrogel...Particle Encapsulation in Crosslinked Hydrogel...