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Formulation and evaluation of reconstitutable suspensions containing

ibuprofen-loaded Eudragit microspheres

Article in Acta Poloniae Pharmaceutica - Drug Research · July 2011

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Acta Poloniae Pharmaceutica ñ Drug Research, Vol. 68 No. 4 pp. 593ñ599, 2011 ISSN 0001-6837
Polish Pharmaceutical Society

FORMULATION AND EVALUATION OF RECONSTITUTABLE

SUSPENSIONS CONTAINING IBUPROFEN-LOADED
EUDRAGIT MICROSPHERES
BURCU DEVRIM*, ASUMAN BOZKIR and KANDEMIR CANEFE

Ankara University, Faculty of Pharmacy, Department of Pharmaceutical Technology,

06100-Tando!an, Ankara, Turkey

Abstract: The objective of this work was to develop and evaluate reconstitutable suspensions of ibuprofen-
loaded microspheres prepared with an acrylic polymer (Eudragit RS-PMTM). The microspheres were prepared
by the quasi-emulsion solvent diffusion technique. To prepare reconstitutable suspension formulation, the
microspheres used had a mean particle size of 316.6 µm and 99.8% loading efficiency. Xanthan gum was cho-
sen as the suspending agent for the suspension formulations. D-sorbitol was used to impart palatability of sus-
pensions. The amount of D-sorbitol affected sedimentation volume and redispersibility properties of suspen-
sions. The highest improving effect was shown with 20.0% and 25.0% of D-sorbitol concentrations. It was
observed that dispersion media of suspensions showed non-Newtonian flow characteristics. To ensure mini-
mum drug leakage from the microspheres into the suspension, the pH was buffered at 3.60 using citrate buffer.
The ibuprofen content calculated from the suspended microspheres was consistent with that from microspheres
alone. This result indicated that no leakage of drug occurred from the microspheres in the suspension on stor-
age. Moreover, the same release rate of ibuprofen from the microspheres suspension and microspheres alone
indicated that the suspension medium studied did not affect the property of drug release. This study suggested
that stable suspensions of ibuprofen-loaded microspheres could be formulated with 0.6% w/v xanthan gum by
the addition of 20% w/v D-sorbitol.

Keywords: ibuprofen, microspheres, reconstitutable suspension, D-sorbitol

A significant proportion of the populations employed to overcome these drawbacks included

have difficulty in swallowing solid oral dosage the use of ion-exchange resins, saturated drug solu-
forms (1). This problem becomes more acute for the tion as a suspending medium and preparation of dry
administration of sustained action dosage forms due suspensions for reconstitution before use (8). A
to the increase in volume of the delivery system. An reconstitutable suspension can offer several advan-
oral pharmaceutical suspension presents a novel tages such as maintenance of the chemical stability
means of circumventing the potential problems of the active compounds until reconstitution at the
associated with the administration of such systems. start of treatment. The same suspension can be easi-
Microencapsulation of a drug has been sug- ly administered to children of different ages by
gested to control drug release and to reduce or elim- adapting the volume to swallow.
inate gastrointestinal tract irritation (2, 3). The Ibuprofen, is a non-steroidal anti-imflammato-
incorporation of microspheres as a dispersed phase ry, antipyretic and analgesic drug (9). The short
in a suspension has been proposed earlier since these half-life (about 2 h) and the low single administra-
systems may spread out more uniformly in the gas- tion dose make ibuprofen a very good candidate for
trointestinal tract, thereby causing a reduction in the formulation of controlled release multiple-unit
local irritation when compared to a single-unit dosage forms. At the same time, great attention has
dosage form (4ñ7). The formulation of controlled been devoted on the possibility to prepare ibuprofen
release suspensions, however, presents a significant microspheres in order to formulate oral controlled
challenge to pharmaceutical scientists due to the risk release systems, to protect the gastric mucous mem-
of drug leaching to the suspending medium during brane from drug irritation or to mask its unpleasant
storage. Some of the strategies that have been taste (10ñ13).

* Corresponding author: e-mail: [email protected]; phone: +90312 203 31 62, fax: +90312 213 10 81

593
594 BURCU DEVRIM et al.

In this study, the preparation of a reconsti- Electro, Germany). The system was thermally con-
tutable suspension of ibuprofen was developed by trolled at 20OC. After 30 min of stirring, the micros-
using ibuprofen microspheres prepared with an pheres were separated by filtration, washed twice
acrylic polymer (EudragitÆ RS PMTM). The micros- with 50 mL of water and then dried in oven at 37OC
pheres were prepared by the quasi-emulsion solvent for 24 h. Dried microspheres were stored in a desic-
diffusion technique. Microspheres were distributed cator containing CaCl2.
in dry mixture and reconstituted with required vol- From the different microsphere formulation
ume of water to form oral liquid suspensions. The variables used, a formulation with desired character-
repose angle, sedimentation volume and redis- istics was chosen to prepare suspension formula-
persibility, rheological properties, pH values, leak- tions. The chosen microsphere formulation was pre-
age of drug from suspended microspheres and drug pared using 2 g of ibuprofen, 1 g of Eudragit RS
release properties of suspension during storage were PM, 5 mL of ethanol and 200 mL of polyvinyl alco-
investigated. hol solution (0.05% w/v).

EXPERIMENTAL Preparation of the dry mixtures for reconsti-

tutable suspensions
Reagents and equipment In the suspension formulations, xanthan gum
Ibuprofen (Eczac"ba#", Turkey), Eudragit RS was used as suspending agent. To impart palatabili-
PMTM (Rˆhm-Pharma, Germany), xanthan gum ty, D-sorbitol was used as a polyol. Citric acid and
(Aldrich, Germany), D-sorbitol (Sigma, Germany), sodium citrate were used as pH modifiers. To pro-
polyvinyl alcohol (m.w. = 72 000), sodium lauryl sul- duce dry mixture for reconstitution, all the powder
fate, citric acid and sodium citrate (Merck, Germany). components were reduced to more or less the same
All other chemicals were of analytical grade and dis- particle size. Ingredients present in small quantities
tilled water was used for all experiments. (buffer components, sodium benzoate and sodium
Scanning electronic microscopy (SEM) (Jeol lauryl sulfate) were mixed homogeneously. The
Model JSM-6400, Tokyo, Japan), optical micro- same procedure was followed for xanthan gum and
scope (Nikon AFM, USA), Brookfield viscometer ibuprofen-loaded microspheres (equivalent to 200
(Model DV II, Brookfield Engineering Laboratories mg of ibuprofen/dose). Such ingredients were mixed
Inc., Stouchton, USA), pH meter (Meter Lab PHM with a portion of D-sorbitol according to the princi-
201, France), UV spectrometer (Shimadzu UV- ple of the geometric dilution. The representative for-
1202, Japan), dissolution tester (Aymes, Turkey). mulations for the preparation of dry mixtures are
tabulated in Table 1.
Preparation of microspheres To prepare the reconstituted suspension, 10 mL
In order to prepare the microspheres, modified of water was added to the dry suspension powder in
quasi-emulsion solvent diffusion method was used two steps and stirred with spoon until a homogenous
as described in previous studies (14ñ19). Briefly, product was obtained.
weighed amount of ibuprofen and acrylic polymer
were dissolved in ethanol at 45OC. The formed SEM analysis
ethanolic solution was poured into water containing The shape and surface morphology of micros-
polyvinyl alcohol and was stirring continuously with pheres were investigated by scanning electron
a propeller type agitator (RZR-2000, Heidolph microscopy (SEM). For the sample preparation, a

Table 1. Compositions of the dry mixtures for reconstitutable suspension formulations.

Sodium lauryl
Formulation Xanthan gum D-sorbitol Citric acid Sodium citrate Sodium benzoate
sulfate
code (%) (%) (%) (%) (%)
(%)
S1 0.6 5 1.44 0.72 0.2 0.05
S2 0.6 10 1.44 0.72 0.2 0.05
S3 0.6 15 1.44 0.72 0.2 0.05
S4 0.6 20 1.44 0.72 0.2 0.05
S5 0.6 25 1.44 0.72 0.2 0.05
 Formulation and evaluation of reconstitutable suspensions containing... 595

Figure 1. Scanning electron micrographs of microspheres

Figure 2. Dependence of sedimentation volume of suspensions on the concentration of D-sorbitol

Figure 3. Rheological properties of suspension formulations containing different amounts of D-sorbitol

596 BURCU DEVRIM et al.

Figure 4. Ibuprofen release profiles from microspheres and S4 suspension formulation after standing for 1 day and after standing for 10
days

small aliquot of the microparticles were mounted Hu

F = ñññ (2)
onto metal stubs using double-sided adhesive tape. H0
Excess microparticles were removed by tapping the
stub sharply. After being vacuum-coated with a thin Determination of the redispersibility
layer (100ñ150 $) of gold at 25 mA current and 10-5 The redispersibility of a suspension was evalu-
Torr pressure for 200 s, the microparticles were ated qualitatively. The test consisted of manually
examined by SEM operated at 15 kV accelerating shaking the cylinder after the sedimentation experi-
voltage. ments were completed. Based on the time and the
effort required to convert the sediment to homoge-
Microscopy studies nous suspension, the formulations were evaluated.
The microscopic observation of suspended One inversion was considered as 100% easy to be
microspheres was determined using an optical redispersed. Every additional inversion decreased
microscope. the percent ease of redispersibility by 5% (21).

Repose angle Rheological studies

For measurement a repose angle of suspension The rheological profile of each formulation
powder, it was passed through a conical flask which after constitution, in terms of viscosity, was deter-
had a 0.9 cm diameter and was laced 10 cm above mined by using the Brookfield viscometer. All meas-
the horizontal surface. The height (h) of the heap urements were performed at a controlled temperature
formed was measured with a cathetometer and the of 25 ± 1OC using spindle LV 4. The flow curve was
radius (r) of the cone base was also determined. plotted between shear rate and shear stress.
Repose angle (Φ) was calculated from following
equation (19): pH values
Φ = tan-1 (h / r) (1) The pH of suspensions was measured with the
aid of a pH meter.
Determination of the sedimentation volume
To study the sedimentation in reconstituted Determination of the leakage of drug from sus-
suspension, the sedimentation volume was meas- pended microspheres
ured at selected time intervals during storage with- An aliquot of 0.5 mL was withdrawn from the
out agitation for a period of 10 days and was record- suspensions for determination of leakage of drug
ed in terms of the ratio of the ultimate settled height from suspended microspheres during storage. The
(Hu) to the original height (Ho), as expressed in the aliquot was filtered and the microspheres washed
following equation (20): with water to remove the suspending vehicle and
 Formulation and evaluation of reconstitutable suspensions containing... 597

Table 2. Physical properties of suspension powder.

Formulation Angle of repose % Ease of pH
code (O) ± SD* redispersibility (after reconstitution)
S1 26.85 ± 0.15 70 3.58
S2 27.08 ± 0.01 70 3.58
S3 27.14 ± 0.08 80 3.59
S4 27.30 ± 0.15 90 3.60
S5 27.30 ± 0.57 90 3.59
*Values represent the mean ± SD of three experiments.

Table 3. Ibuprofen content values of suspended microspheres. all measurements. The means of six aliquots are
Storage period % Ibuprofen given.
(days) content ± SD*
0 66.53 ± 0.28 RESULTS AND DISCUSSION
1 65.87 ± 0.07
Ibuprofen microspheres were prepared for
2 65.94 ± 0.13
reducing the side effects, masking the characteristic
3 67.31 ± 0.07 irritative taste of ibuprofen and improving the
4 67.76 ± 0.08 bioavailability in previous studies. In our previous
5 67.68 ± 0.24 studies, ibuprofen microspheres were prepared
6 65.63 ± 0.35 using quasi-emulsion solvent diffusion method (18,
19). The reasons to choose this method as the
7 64.38 ± 0.12
microsphere production method were its simplicity,
8 64.07 ± 0.21 low cost, success with poor aqueous solubility drugs
9 65.59 ± 0.19 and the production of microspheres of relatively
10 64.94 ± 0.07 high drug loading. In this study, microspheres pre-
*Values represent the mean ± SD of three experiments.
pared with 2:1 drug to polymer ratio were selected
for suspension formulations since they have higher
loading efficiency and suitable micromeritical prop-
erties to disperse in aqueous medium. According to
the encapsulation efficiency results obtained in our
then dried in oven at 37OC for 24 h. Dried micros- previous study, the drug content of the microspheres
pheres were dissolved with ethanol. The dissolved showed good correlation with the theoretical drug
drug amount was measured spectrophotometrically loadings (19). The drug was uniformly encapsulated
at 264 nm. into the microspheres. The high content of ibuprofen
in microspheres was believed to be due to the poor
In vitro release study solubility of drug in poor solvent. The chosen
Drug release tests on the suspension with microsphere formulation had 99.8% loading effi-
microspheres and the original microspheres were ciency. SEM image of microspheres (Figure 1)
carried out by using the paddle method specified in showed that the microspheres were spherical with a
USP XXVII (22). A suspension sample was quanti- smooth surface. The microspheres used had a mean
tatively transferred to the vessel bottom using a size of 316.6 µm. As indicated in our previous study
syringe. Paddle speed and bath temperature were set that repose angle value of chosen microsphere for-
at 50 rpm and 37 ± 0.5OC, respectively. The samples mulation was under 30O (18.06O). This result demon-
per batch were tested in 900 mL of pH 6.8 phosphate strated that chosen microsphere formulation has
buffer. An aliquot of the release medium was with- suitable flow properties.
drawn at predetermined time intervals and equiva- Because of the risk of drug leaching to the sus-
lent amount of fresh medium was added to the pending medium during storage, suspension formu-
release medium. The absorption of the samples was lations were prepared as dry suspensions for recon-
recorded at a wavelength of 264 nm spectrophoto- stitution before use. Xanthan gum was preferred as
metrically. Sink conditions were maintained during suspending agent and stabilizer in dispersing medi-
598 BURCU DEVRIM et al.

um due to its acceptable toxicological and safety prevented from microspheres. Because of the low
properties for food and pharmaceutical applications. solubility of ibuprofen (pKa 5.2) in the acidic medi-
It is soluble in water and imparts its high viscosity at um, it was unable to diffuse out from the micros-
low concentration with thixotropic flow characteris- pheres to the medium.
tics, which increase with increasing concentration The drug release rate of the suspended micros-
(23, 24). Viscosity of xanthan solutions is unaffect- pheres and dry microspheres were investigated in pH
ed by pH changes between pH 1 and 13. Moreover, 6.8 phosphate buffer, as shown in Figure 4. The
the three-dimensional network formed by the asso- ibuprofen release rate from the suspended micros-
ciated chains makes xanthan gum an efficient stabi- pheres was consistent with that from dry micros-
lizer for suspensions and emulsions (25). Based on pheres. This result indicated that the suspension medi-
results of our preliminary data, 0.6% w/v xanthan um studied did not affect the property of drug release.
gum was used as the suspending agent for the
microsphered suspensions. CONCLUSION
D-sorbitol used to impart palatability, gave a
well-structured vehicle in which the microspheres We can conclude that a liquid pharmaceutical
remained suspended for an extended period. At a preparation for oral administration capable of pro-
xanthan gum concentration of 0.6%, there was a viding a sustained release of ibuprofen was success-
increase in sedimentation volume with increasing D- fully obtained. Stable suspensions of ibuprofen-
sorbitol concentration up to 20.0%. Above this con- loaded microspheres could be formulated at pH 3.60
centration, the suspension was found to be stable with 0.6% w/v xanthan gum by the addition of 20%
even after standing for 10 days, i.e., the sedimenta- w/v D-sorbitol as a coexisting polyol. Leakage of
tion volume was 1.0, as shown in Figure 2. The stud- drug from the microspheres in the reconstituted sus-
ies concerning the sedimentation volume of suspen- pensions was not found to occur on storage for 10
sions clearly indicated that the coexistence of D-sor- days. Finally, the release studies carried out on the
bitol with xanthan gum at the optimum concentra- suspension formulation did not show any statistical-
tion in the dispersion medium are prerequisites for ly significant differences from the profiles of
making coarse microspheres stable in suspension. microspheres alone.
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