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Preparation and characterisation of
nanoparticles containing ketoprofen
and acrylic polymers prepared by
emulsion solvent evaporation method
a

b

b

Le Thi Mai Hoa , Nguyen Tai Chi , Le Huu Nguyen & Dang Mau
Chien

a

a

Laboratory for Nanotechnology (LNT), Vietnam National
University , Community 6, Linh Trung Ward, Thu Duc District, Ho
Chi Minh City , Vietnam
b

Faculty of Pharmacy, The University of Medicine and Pharmacy
at Ho Chi Minh City , 41 Dinh Tien Hoang, Ben Nghe Ward, District
1, Ho Chi Minh City , Vietnam
Published online: 14 Jul 2011.

To cite this article: Le Thi Mai Hoa , Nguyen Tai Chi , Le Huu Nguyen & Dang Mau Chien (2012)
Preparation and characterisation of nanoparticles containing ketoprofen and acrylic polymers
prepared by emulsion solvent evaporation method, Journal of Experimental Nanoscience, 7:2,
189-197, DOI: 10.1080/17458080.2010.515247
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Journal of Experimental Nanoscience
Vol. 7, No. 2, March–April 2012, 189–197

Preparation and characterisation of nanoparticles containing ketoprofen
and acrylic polymers prepared by emulsion solvent evaporation method
Le Thi Mai Hoaa*, Nguyen Tai Chib, Le Huu Nguyenb and Dang Mau Chiena

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a

Laboratory for Nanotechnology (LNT), Vietnam National University, Community 6, Linh Trung
Ward, Thu Duc District, Ho Chi Minh City, Vietnam; bFaculty of Pharmacy, The University of
Medicine and Pharmacy at Ho Chi Minh City, 41 Dinh Tien Hoang, Ben Nghe Ward, District 1,
Ho Chi Minh City, Vietnam
(Received 25 January 2010; final version received 9 August 2010)
We have prepared polymeric drug nanoparticles by oil in water (O/W) emulsion
solvent evaporation method. We used acetone as solvent for polymer and water as
non-solvent. The purpose of this study is to use the emulsion solvent evaporation
method in order to prepare nanoparticles and to investigate the effects of the
various processing parameters to the characteristics of the nanoparticles. In this
research, we use two different forms of acrylic polymers, Eudragit E100 and
Eudragit RS. It was found that the size of the nanoparticles depends on different
parameters such as the polymer concentration in the organic solvent, surfactant
concentration and the volume ratio of oil and water phases. The morphology
structure is investigated by transmission electron microscope (TEM). TEM
images confirmed that the nanoparticles produced were spherical in shape and the
successfully prepared nanoparticles with size 80 nm. The size distribution is

measured by laser dynamic light scattering. The size distribution of the nanoparticles was found in the range from 50 to 150 nm. Investigation of Fourier
transform infrared spectroscopy indicated the absence of the interactions between
the drug and polymer. X-ray diffraction patterns of nanoparticles containing
ketoprofen, Eudragit E100 and Eudragit RS showed the amorphous structure.
Keywords: drug delivery; Eudragit; emulsion evaporation method; polymeric
nanoparticle; ketoprofen

1. Introduction
Nanoparticle of drugs involves forming drug-loaded particles with diameters ranging from
1 to 1000 nm. Nanoparticles are defined as solid, submicron-sized drug carriers that may
or may not be biodegradable [1,2]. Drug nanoparticles can be further classified into
nanocapsules and nanospheres based on their structure [3]. Nanocapsules are vesicular
systems in which the drug is confined to a cavity consisting of an inner liquid core
surrounded by a polymeric membrance. Nanospheres have a matrix type of strucutre.
Drugs may be absorbed at the sphere surface or encapsulated within the particle. The drug

*Corresponding author. Email:
ISSN 1745–8080 print/ISSN 1745–8099 online
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is either solubilised in the polymer matrix to form an amorphous particle or embedded in
the polymer matrix as crystallites [4].

Several microencapsulation methods are available for the preparation of drug
nanoparticles. In the general microencapsulation technique using oil in water (O/W)
emulsion system, the drug is dissolved, dispersed or emulsified in an organic polymer
solution, which is then emulsified in an external aqueous or oil phase. As the organic
solvent is removed by evaporation, the drug and polymer are precipitated in the droplets,
thus forming the nanosphere or nanocapsules. The emulsion solvent evaporation
technique was fully developed at the end of the 1970s and has been used successfully in
the preparation of microspheres made from several biocompatible polymers such as
poly(D,L-lactide-co-glycolide) [5,6] and Eudragit [7]. More recently, an emulsion solvent
diffusion method was proposed by Kawashima et al. [8,9]. The technique of emulsion
solvent evaporation offers several advantages; it is preferred to other preparation methods
such as spray drying, sonication and homogenisation, etc., because it requires only mild
conditions such as ambient temperature and constant stirring. Thus, a stable emulsion can
be formed without compromising the activity of the drug. The general emulsification
solvent evaporation method used to produce nanoparticles involves a number of
processing and materials parameters: power and duration of energy applied, aqueous
phase volume, polymer and drug concentration in the organic phase, polymer molecular
weight, polymer end groups, solvent volume and surfactant concentration. Each of these
processing and materials parameters influences the size and/or the drug content of the
nanoparticles.
In drug delivery, nanoparticles should readily be biocompatible and biodegradable.
These properties, as well as targeting and controlled release, can be affected by
nanoparticle material selection and by surface modification. Materials such as synthetic
polymers, proteins or other natural macromolecules are used in the preparation of
nanoparticles. Drug nanoparticles have potential applications in the administration of
therapeutic molecules such as tissue targeting in cancer therapy, controlled release, carrier
action for the delivery of peptides and increase in the solubility of drug [10].
The purpose of this study is to use the emulsion solvent evaporation method in
order to prepare nanoparticles using two different forms of acrylic polymers, Eudragit
E100 and Eudragit RS, and to investigate the effect of various processing parameters

on particle size and the characteristics of nanoparticles. The processing parameters
include polymer concentration in the organic phase, polyvinyl alcohol (PVA)
concentration in the aqueous phase, the volume ratio of oil and water phases. The
drug material used is ketoprofen, widely used in the treatment of rheumatoid arthritis
and osteoarthritis.

2. Experimental
2.1. Materials
The pharmaceutical drug is a well-known anti-inflammatory agent, the generic name of
which is ketoprofen. It is made up of three groups: a phenyl group (–C6H5), a benzoyl
group (–C6H4–CO) and an acetic chain (–CH–COOH). Ketoprofen is practically not
soluble in water.


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The polymers used in this study are Eudragit E100 and Eudragit RS. They are
insoluble in acid and water, whereas they are soluble in organic solvents such as acetone,
ethanol, etc.
Bidistilled water was used as non-solvents. PVA was used as an emulsifying agent.
All materials were obtained from commercial sources and used as received: ketoprofen
(USP-30; Ro¨hm Pharma, Darmstadt, Germany), Eudragit E100, Eudragit RS (Merck,
Germany), PVA, acetone (Merck, German).

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2.2. Preparation of the drug nanoparticles
In this study, nanoparticles are prepared by emulsification solvent evaporation method

using sonication. An organic phase consisting of polymer (Eudragit E100 or RS) and drug
(ketoprofen) dissolved in acetone (10 mL). This organic phase is added to an aqueous
phase containing a surfactant (PVA, concentration 0.5%, 90 mL) to form an O/W type
emulsion. The volume ratio of oil and water phases was 1 : 9. This emulsion is broken
down into nanodroplets by applying external energy through a sonicator. These
nanodroplets form nanoparticles upon evaporation of the highly volatile organic solvent.
The organic solvent evaporates during magnetic stirring at 300 rpm under atmospheric
condition for 2 h.
We studied the effect of various processing parameters on particle size. The processing
parameters include polymer concentration in the organic phase, PVA concentration in the
aqueous phase and volume ratio of oil and water phases.

2.3. Characterisation of nanoparticles
We investigate the characterisation of nanoparticles, such as particle size and size
distribution, morphology, crystallinity.
The particle size distribution was determined by dynamic light scattering (HORIBA
LB-550-Japan).
Infrared (IR) absorption spectra of raw materials and nanoparticles in the wavelength
region 4000–400 cmÀ1 were recorded using a Fourier transform infrared (FT-IR)
spectrometer (TEMSORTM37 – Bruner, USA).
Particle morphology were observed using a transmission electron microscope (TEM;
JEM-1400, Japan) using an acceleration voltage of 100 kV.
The crystallinity of the particles was studied using X-ray diffraction (XRD; D8
Advance – Bruker, German).

3. Results and discussion
3.1. Effect of various processing parameter on the size of particles
3.1.1. Effect of polymer concentration in the organic phase
The ketoprofen nanoparticles were prepared using polymer Eudragit E100, the volume
ratio of oil and water phases was 1 : 9, the PVA concentration in the aqueous phase was

0.5%. The polymer concentration is varied from 3% (w/v) to 15% (w/v). Figure 1 shows
the effect of polymer concentration in the organic phase on the particle size. An increase in


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300

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Particle size (nm)

250

200

150

100

50

0

0

5

10

Polymer concentration (mg

15

20

ml–1)

Figure 1. Effect of polymer concentration in the organic phase on the particle size.

the concentration of polymer in a fixed volume of organic solvent leads to a gradual
increase in nanoparticle diameter. Increasing polymer concentration causes increase in the
viscosity, thus leading to an increase of the emulsion droplet size. The viscous forces
oppose the shear stresses in the organic phase and the final size and size distribution of
particles depends on the net shear stress available for droplet breakdown. The importance
of polymer concentration in controlling the size of particles produced by the general
emulsification process has previously been reported for other poly(lactic-co-glycolic acid)/
poly lactic acid (PLGA/PLA) system [11].
3.1.2. Effect of PVA concentration in the aqueous phase
The ketoprofen nanoparticles were prepared using polymer Eudragit E100; the volume
ratio of oil and water phases was 1 : 9; the polymer concentration is 5%. The PVA
concentration in the aqueous phase is varied from 0.5% (w/v) to 2% (w/v). Figure 2 shows
the effects of PVA concentration in the aqueous phase on the particles size. As the PVA
concentration increases, the size of particles gradually increases due to high aqueous phase
viscosity, the viscosity increase reduces the net shear stress available for droplet
breakdown. Zweers et al. have reported an increase in the size of PLGA nanoparticles
at high PVA concentrations [11].
3.1.3. Effect of the volume ratio of oil and water phases
The ketoprofen nanoparticles were prepared using polymer Eudragit E100; the polymer

concentration was 5% (w/v); the PVA concentration in the aqueous phase was 0.5% (w/v).
The volume ratio of oil and water phases was varied. Figure 3 shows the effects of the


Journal of Experimental Nanoscience
400
350

250
200
150
100
50
0

0.5

1

1.5

2

2.5

3

PVA concentration (%)

Figure 2. Effect of PVA concentration in the aqueous phase on the particle size.

1000

800
Particle size (nm)

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Particle size (nm)

300

600

400

200
0

0.2

0.4
0.6
Oil/ Water ratio

0.8

1

Figure 3. Effect of the volume ratio of oil and water phases on the particle size.

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Figure 4. TEM images of the nanoparticles containing: 10% (w/w) ketoprofen and 90% (w/w)
Eudragit E100 (a) and 10% (w/w) ketoprofen and 90% (w/w) Eudragit RS (b).

volume ratio of oil and water phases on the particle size. As the volume ratio of oil and
water phases is higher than 0.6, the size of particles increases rapidly.

3.2. The charateristics of nanoparticle
The morphology of nanoparticles prepared was studied using TEM. Figure 4(a) shows
TEM images of the nanoparticles containing 10% (w/w) ketoprofen and 90% (w/w)
Eudragit E100. Figure 4(b) shows TEM images of nanoparticles containing 10% (w/w)
ketoprofen and 90% (w/w) Eudragit RS. In both Figure 4(a) and (b), crystallinity or grain
boundaries were not found. TEM images show that the nanoparticles were spherical,
amorphous and smooth. The size of the particles was 80 nm. The formation of an
amorphous polymer-drug structure has been observed.
IR spectroscopy was used to study the interactions between the drug and the polymers.
Figure 5 shows IR spectra of the nanoparticles at a wavenumber range 4000–400 cmÀ1.
Ketoprofen has a carboxylic acid group, which can interact with the function groups of the
polymer.
The carbonyl peaks in the IR spectra of ketoprofen were recorded at 1694 and
1654 cmÀ1. From Figure 5, it can be seen that the Eudragit E100 and Eudragit RS

materials exhibit quite similar spectra. The strong stretching vibration of the carbonyl
moiety of ester groups could be identified for both the materials at 1732 cmÀ1. For the
nanoparticles containing ketoprofen, Eudragit E100 and Eudragit RS, the position of the
ester peak at 1732 cmÀ1 was not changed.
The carboxylic acid group of the ketoprofen molecule interacted with the polymer,
leading to the disruption of the carbonxylic acid dimer of the crystalline ketoprofen.


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Figure 5. Infrared spectra at wavenumber of 4000 to 400 cmÀ1 of the nanoparticles containing:
(a) 10% (w/w) ketoprofen and 90% (w/w) Eudragit E100 and (b) 10% (w/w) ketoprofen and 90%
(w/w) Eudragit RS.

Eudragit E100 is a polymer containing secondary amino groups capable of accepting a
proton from an acid molecule. The peaks correspoding to the amino groups have been
identified at 2820 and 2770 cmÀ1. However, any change in the position of these peaks was
not observed when ketoprofen was incorporated in the nanoparticles. Therefore, it was
concluded that ketoprofen drug mainly interacted with ester groups of the Eudragit E100
polymer, similar to Eudragit RS.
Figure 6 shows the particle size distribution of nanoparticles containing: ketoprofen
and Eudragit E100 (Figure 6(a)), ketoprofen and Eudragit RS (Figure 6(b)). Size
distribution were determined by dynamic light scattering in aqueous solution, the size of
the particles was in the range from 50 to 150 nm and the mean diameter was 80 nm. Based
on these results, we can see the sonication method is suited to produce small size
nanoparticles (5300 nm diameter) with narrow size distribution.

Figure 7 shows XRD patterns of the nanoparticles: 10% (w/w) ketoprofen and 90%
(w/w) Eudragit E100 (Figure 7(a)), 10% (w/w) ketoprofen and 90% (w/w) Eudragit RS
(Figure 7b). In Figure 7(a) and (b), XRD showed diffraction pattern of the amorphous
structure and no crystallinity. We can conclude that the nanoparticles prepared was
amorphous, as peaks corresponding to diffraction from drug crystal lattice were not
detected.

4. Conclusion
Polymeric drug nanoparticles were prepared by emulsion solvent evaporation method. We
investigated the effect of various processing parameters on particle size and characteristics


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(a) 15.00

q (%)

Undersize

100.0

0.001

Diameter (nm)

(b) 16.00

1.000

6.000

Undersize

100.0

q (%)

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1.000

1.000
0.001

Diameter (nm)

1.000
6.000

Figure 6. The particle size distribution of nanoparticles containing: (a) 10% (w/w) ketoprofen and
90% (w/w) Eudragit E100 and (b) 10% (w/w) ketoprofen and 90% (w/w) Eudragit RS.

Figure 7. XRD patterns of the nanoparticles containing: 10% (w/w) ketoprofen and 90% (w/w)
Eudragit E100 (a) and 10% (w/w) ketoprofen and 90% (w/w) Eudragit RS (b).

of nanoparticle. Increase in different parameters such as the polymer concentration in the
organic solvent, surfactant concentration, the volume ratio of oil and water phases led to
increase in the size of particles. The TEM observation shows the surface morphological
features; morphology of particles was spherical and homogenerous. The size distribution

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197

of the nanoparticles was found in the range from 50 to 150 nm and the mean diameter was
80 nm. The interaction between the drug and the polymer was determined by FT-IR. The
carboxylic group of the ketoprofen molecule interacts with the Eudragit, which was
observed in our studies. XRD patterns of nanoparticles showed the amorphous structure.

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