preparation and evaluation of modified release ibuprofen microspheres with acrylic polymers

14 Pages·2006·4.09 MB·English

Acta Poloniae Pharmaceutica ñ Drug Research, Vol. 63 No. 6 pp. 521ñ534, 2006 ISSN 0001-6837
Polish Pharmaceutical Society
PREPARATION AND EVALUATION OF MODIFIED RELEASE IBUPROFEN
MICROSPHERES WITH ACRYLIC POLYMERS (EUDRAGIT®) BY QUASI-
EMULSION SOLVENT DIFFUSION METHOD: EFFECT OF VARIABLES
BURCU DEVRIM AND KANDEMIR CANEFE*
Ankara University, Faculty of Pharmacy, Department of Pharmaceutical Technology
06100-Tando(cid:1)an ñ Ankara ñ TURKEY
Abstract:The aim of this study was to prepare and evaluate microspheres containing ibuprofen. Microspheres
were prepared by modified quasi-emulsion solvent diffusion method. The influence of formulation factors
(drug-polymer ratio, volumes of solvent, polyvinyl alcohol concentration and type of polymer) on the mor-
phology, particle size distribution, drug loading capacity, micromeritical properties and the in vitrorelease char-
acteristics of the microspheres were investigated. Physical characterizations of ibuprofen microspheres were
also carried out using scanning electron microscopy, X-ray diffractometry and IR spectrophotometry. It was
found that the yield of preparation was dependent on the initial temperature gradient between the emulsion
phases. When there was an initial difference of temperature between the aqueous phase and dispersed emulsion
phases, yield of preparation was increased distinctly. The drug loading capacities were very high for all for-
mulations of the microspheres which were obtained. Mean particle size changed by changing the drug-polymer
ratio, volumes of solvent or polyvinyl alcohol concentration. The flow properties were much improved over
those of the original crystals. In vitrodissolution results showed that the release rate of ibuprofen was modified
in all formulations. Although ibuprofen release rates from Eudragit®RS microspheres were very slow, they
were fast from Eudragit RL microspheres. These results observed that if Eudragit RS and Eudragit RL are used
in combination, optimum release profiles may be obtained.
Keywords:Ibuprofen; EudragitÆ; microspheres; quasi-emulsion solvent diffusion method; modified release
Ibuprofen, α-methyl-4-(2-methylpropyl)-ben- pheres in order to formulate oral controlled release
zene acetic acid is a non-steroidal anti-imflammato- systems, to protect the gastric mucous membrane
ry, antipyretic and analgesic drug. This drug is indi- from drug irritation or to mask its unpleasant taste.
cated for the relief of mild to moderate pain and Microspheres are one of the microparticulate
inflammation in conditions such as dysmenorrea, systems and are prepared to obtain prolonged or
migraine, postoperative pain, dental pain, in which controlled drug delivery, to improve bioavailability
disorders an immediate available dose is requested. or stability and to target drug to specific sites.
It is also used in chronic disorders as ankylosing Microspheres can also offer advantages like limiting
spondylitis, osteoarthritis and rheumatoid arthritis fluctuation within therapeutic range, reducing side
for all of which a sustained release is desirable (1). effects, decreasing dosing frequency and improving
The usually daily dose by mouth is 1.2 to 1.8 g patient compliance. They spread out more uniform-
divided in different administrations. The drug is ly in the GI tract, thus avoiding exposure of the
readily absorbed from the gastrointestinal tract, and mucosa to high concentration of drug and ensuring
peak plasma concentrations occur about 1 to 2 h more reproducible drug absorption. The risk of dose
after ingestion (2). Unfortunately, ibuprofen causes dumping also seems to be lower than with a single-
a certain irritation in the gastrointestinal mucous unit dosage form (7-9). In this study, ibuprofen
membrane and possesses a bitter taste and aftertaste. microspheres were prepared by a novel technique,
The half-life in plasma is about 2 h. The short half- called the quasi-emulsion solvent diffusion method,
life and the low single administration dose make which was proposed by Kawashima et al. (10).
ibuprofen a very good candidate for the formulation Compared with the solvent evaporation method for
of controlled release multiple-unit dosage forms (3- microsphere preparation, the solidification of the
6). At the same time, great attention has been devot- liquid droplet in this process was much faster.
ed on the possibility to prepare ibuprofen micros- Further, the use of a harmful organic solvent could
* Corresponding author: Tel.: [phone], Fax: [phone], E-mail: [email protected].
521
522 BURCU DEVRIM and KANDEMIR CANEFE
be avoided, and the reduced pressure and/or the between the emulsion phases, drug-polymer ratio,
heating to evaporate the solvent would be unneces- volumes of ethanol and stirring speed) to obtain
sary in this method (11). The rare coalescence of a spherical particles. Then the influences of formula-
microspheres observed in the process did not require tion variables on the microsphere properties were
the addition of antiadhesion agents, such as magne- examined and the microsphere formulations suitable
sium stearate and talc, which are often used in the to achieve our goal were determined.
evaporation method.
Acrylic polymers are widely used as tablet EXPERIMENTAL
coatings and as retardants of drug release in sus-
tained release formulations (12, 13). Methacrylate Reagents and equipment
copolymers (Eudragits) have recently received Reagents: ibuprofen (Eczac(cid:2)ba(cid:3)(cid:2)), Eudragit®
increased attention for modified dosage forms RS PM, Eudragit® RS 100, Eudragit® RL 100
because of their inertness, solubility in relatively (Rˆhm-Pharma), ethanol (Riedel de-HaÎn),
non-toxic solvents and availability of resins with polyvinyl alcohol (PVA 72 000), sodium hydroxide,
different properties (14-16). Eudragit® RS and potassium dihydrogen phosphate (Merck). The other
Eudragit®RL polymers are copolymers of poly(eth- chemicals were of analytical grade and distilled
ylacrylate, methyl-methacrylate and chlorotri- water was used for all experiments.
methyl-ammonioethyl methacrylate), containing an
amount of quaternary ammonium groups between Equipment: UV spectrophotometer (Shimadzu
4.5-6.8% and 8.8-12% for RS and RL, respectlively UV-1202), pH meter (Meter Lab), laser diffrac-
(17). The copolymer Eudragit RS PM®differs from tometer (Sympatec HELOS-H0728), X-ray diffrac-
Eudragit® RS 100 in that it contains 0.5% talc. tometer (Rigaku, D-Max/2200), IR-spectropho-
Eudragit® RS and Eudragit® RL are insoluble in tometer (Jasco, FT/IR 420), dissolution tester
water and digestive juices, but they are permeable (Aymes), SEM analysis (JEOL JSM-840A).
and both have pH-independent release profiles. The
permeability of Eudragit® RS and RL in aqueous METHODS
media is due to the presence of quaternary ammoni-
um groups in their structure; Eudragit® RL has a Preparation of microspheres
greater proportion of these groups and as such is In order to produce the microspheres, modi-
more permeable than Eudragit®RS (18, 19). fied quasi-emulsion solvent diffusion method was
In this study, ibuprofen loaded microspheres used (20). Weighed amounts of ibuprofen and
were prepared by using quasi-emulsion solvent dif- acrylic polymer were dissolved in 5 mL of ethanol
fusion method. Firstly, we investigated some formu- at 45OC. The formed ethanolic solution was poured
lation variables (initial difference of temperature into water containing polyvinyl alcohol (0.025-
Table 1. Formulations of the microspheres.
Formulation Ibuprofen Eudragit® PVA Ethanol (mL)
code (%) (%) 72.000 (%)
F1 100 - 0.05 5
F2 80 20 0.05 5
(RSPM)
F3 75 25 0.05 5
(RSPM)
F4 71.43 28.57 0.05 5
(RSPM)
F5 66.67 33.33 0.05 5
(RSPM)
F6 66.67 33.33 0.05 3
(RSPM)
F7 66.67 33.33 0.05 6
(RSPM)
F8 66.67 33.33 0.025 5
(RSPM)
F9 66.67 33.33 0.1 5
(RSPM)
F10 66.67 33.33 0.05 5
(RS100)
F11 66.67 33.33 0.05 5
(RL100)
*Microspheres were produced with the agitation speed of 450 rpm.
Preparation and evaluation of modified release ibuprofen microspheres... 523
microspheres of ibuprofen were measured. Before
measuring the X-ray powder diffractogram, the
microspheres were crushed into powder because
they were too big to measure. The data were collect-
ed in the continuous scan mode using step size of
0.01O2θ. The scanned 2 range was 2θto 35O.
Infrared spectroscopy
Infrared spectra of the pure drug and of the
microspheres were determined using an IR-spec-
trophotometer (Jasco, FT/IR 420), using the KBr
disk technique (about 10 mg sample for 100 mg of
dry KBr). The scanning range used was from 4000
to 200 cm-1at a scan period of 3 min.
Particle size analysis
The particle size of the microspheres was
determined by laser diffractometry using Sympatec
HELOS (H0728) particle size analyzer. In this
study, filtered and degassed purified water was used
Figure 1. Preparation procedure of microspheres. as a carrier fluid. About 0.3-0.5 mg of microspheres
were dispersed in purified water in the sample unit
and were circulated 2000 times per minute. Each
determination was carried out in triplicate.
0.1% w/v) and stirring continuously with a pro- Determination of the bulk density
peller type agitator (Model RZR-2000; Heidolph Determination of the bulk density of the
Electro). The system was thermally controlled at microspheres was obtained by a tapping method and
20OC. Ethanol solution was finely dispersed in the found in g/mL (21, 22). 10 mL of microspheres were
aqueous phase as discrete droplets. The finely dis- weighed and were tapped 20 times. Upon tapping
persed droplets of the polymer solution of the drug the volume was measured again. Bulk density was
were solidified in the aqueous phase via counter determined according to the ratio of the mass and
diffusions of ethanol and water out of and into the volume of the microspheres.
droplets. After 30 min of stirring, the microspheres
were separated by filtration, washed twice with 50 Determination of repose angle
mL of water and then dried in oven at 37OC for 24 Determination of the repose angle was
h. Dried microspheres were stored in desiccator obtained for 10 g microspheres (23). For this study,
containing CaCl . Three independent batches were microspheres were poured into a conical flask which
2
prepared. In Figure 1, the processing of this tech- had a 0.9 cm diameter and was placed 10 cm above
nique is illustrated. The representative formulations the surface. Repose angle was calculated according
for the preparation of microspheres are tabulated in to the tangent of the ratio of the height and diameter
Table 1. of the bulk.
Microspheres dried at 37OC were then weighed
and the yield of microsphere preparation was calcu- Determination of drug loading capacity
lated using the Eq. (1): Drug loading capacity of the microspheres was
determined by dissolving accurately weighed por-
The amount of microspheres obtained (g)
Percent yield = ñññññññññññññññññññññññññññññññññññ×100 (1) tions for each batch in ethanol which dissolves both
The theoretical amount (g)
the active agent and the polymer (24). Filtration of
CONTROLS ON MICROSPHERES microspheres was done by using Whatman No. 42
filter with a porosity of 2.5 µm. The dissolved drug
PowderX-ray diffractometry amount was measured spectrophotometrically at
Powder X-ray diffractometric analyses were 264 nm. The polymer does not interfere with the
performed using an X-ray diffractometer (Rigaku, assay at this wavelength. The drug loading capacity
D-Max/2200). Diffraction of raw crystals and was calculated according to Eq. (2).
524 BURCU DEVRIM and KANDEMIR CANEFE
Assayed drug content 1-L dissolution vessel and 7.5 cm diameter paddle,
Drug loading capacity = ññññññññññññññññññññññññ×100 (2)
Theoretical drug content assembled as per the USP 24 Physical Test section
on dissolution. The vessel was partially immersed in
SEM analysis a suitable water bath that permitted holding the tem-
The shape and surface characteristics of micros- perature inside the vessel at 37 ± 0.5OC during the
pheres were observed by a scanning electron micro- test and keeping the bath fluid in constant, smooth
scope (JEOL JSM-840A). The samples were dusted motion. The paddle used as the stirring element was
onto double sided tape on an aluminum stub and sput- formed a blade and a shaft. The shaft was positioned
ter-coated with gold particles in an argon atmosphere. so that its axis was not more than 2 mm at any point
from the vertical axis of the vessel, and rotated
In vitrodissolution studies smoothly without significant wobble. The distance
The dissolution rate of pure drug and the drug of 25 ± 2 mm between the blade and the inside bot-
release rate from the microspheres were studied tom of the vessel was maintained during the test.
using USP 24 Type 2 (paddle) method (25). The The dissolution medium was agitated at 50 rpm for
USP paddle method was followed using a standard the duration of the test. The samples per batch were
Figure 2. X-ray diffraction patterns of original crystals (A), F5 (B), F10 (C) and F11 (D).
Preparation and evaluation of modified release ibuprofen microspheres... 525
Figure 3. IR-spectra of original crystals (A), F5 (B), F10 (C) and F11 (D).
tested in 900 mL of pH 6.8 phosphate buffer as dis- through a 2.5 µm filter (Whatman No. 42). The ini-
solution medium. To improve wetting of the micros- tial volume of the release medium was maintained
pheres, a small amount of surfactant (Polysorbate by adding equivalent amount of fresh medium after
80, 0.1% w/v) was added to the dissolution media. each sampling. The absorption of the samples was
Accurately weighed samples of ibuprofen or micros- recorded at a wavelength of 264 nm spectrophoto-
pheres were added to dissolution medium kept at 37 metrically. From the absorbance readings, cumula-
± 0.5OC. In order to keep the total surface area of the tive percentage of ibuprofen dissolved was calculat-
microsphere samples constant and thus to get com- ed. Ibuprofen sink conditions were determined in
parable results, the release studies all were carried phosphate buffer pH 6.8 (using an amount of drug
out with 350 µm size fractions of microspheres pre- equivalent to three times of the dose in the pharma-
pared. An aliquot of the release medium was with- ceutical formulation in 900 mL of medium) and
drawn at predetermined time intervals and passed were maintained during all measurements.
526 BURCU DEVRIM and KANDEMIR CANEFE
Table 2. Mean particle size of microspheres.
Formulation Mean particle size Standart deviation % 95 C.L.
code (µm)
F1 131.85 0.14 0.08
F2 170.73 0.16 0.09
F3 180.84 0.76 0.44
F4 269.99 0.40 0.23
F5 316.65 0.34 0.20
F6 1595.65 0.27 0.16
F7 89.21 0.18 0.10
F8 618.12 0.20 0.12
F9 185.72 0.54 0.31
F10 272.96 0.20 0.12
F11 391.03 0.15 0.09
*C.L.: Confidence limits
Table 3. Bulk density of the microspheres. Table 4.Repose angle of the microspheres.
Formulation Bulk Standart % 95 C.L*. Formulation Repose Standart % 95 C.L.*
code density deviation code angle deviation
(g/mL) F1 23.68 0.510 0.426
F1 0.544 0.004 0.003 F2 24.52 0.824 0.589
F2 0.513 0.009 0.006 F3 23.23 0.168 0.120
F3 0.524 0.008 0.006 F4 23.71 0.827 0.393
F4 0.515 0.008 0.006 F5 18.06 0.566 0.180
F5 0.532 0.004 0.003 F6 22.45 0.583 0.417
F6 0.427 0.010 0.007 F7 23.27 0.619 0.443
F7 0.501 0.004 0.003 F8 22.21 0.142 0.102
F8 0.514 0.005 0.003 F9 20.58 0.687 0.492
F9 0.515 0.007 0.005 F10 21.26 0.636 0.455
F10 0.507 0.007 0.005 F11 24.61 0.110 0.092
F11 0.450 0.006 0.004
* C.L.: Confidence limits
* C.L.: Confidence limits
Figure 4. Mean particle sizes of microspheres (n = 3).
Preparation and evaluation of modified release ibuprofen microspheres... 527
Table 5. Results of the drug loading capacity.
Formulation Theoretical Assay Drug loading Standart
code drug content drug content capacity deviation % 95 C.L.*
(%) (%) (%)
F1 100 97.16 97.16 0.12 0.287
F2 80 79.29 99.11 0.49 0.777
F3 75 73.98 98.64 0.26 0.203
F4 71.43 70.43 98.60 0.25 0.266
F5 66.67 66.53 99.79 0.28 0.180
F6 66.67 65.74 98.61 0.11 0.273
F7 66.67 66.22 99.33 0.26 0.270
F8 66.67 64.13 96.19 0.30 0.192
F9 66.67 63.47 95.20 0.18 0.188
F10 66.67 66.10 99.15 0.15 0.154
F11 66.67 68.64 102.95 0.35 0.368
*C.L.: Confidence limits
Figure 5. Yield of preparation (n = 3).
Calculations of dissolution test results kinetically production method were its simplicity, low cost,
Dissolution test results obtained from the paddle success with poor aqueous solubility drugs and the
method in pH 6.8 phosphate buffer were studied by production of microspheres of relatively high drug
using SPSS for Windows 11.0 according to zero order, loading, as reported by Pignatello et al. (18). In this
first order, Hixson-Crowell and Higuchi kinetics. process, the drug and polymer were dissolved in a
solvent such as ethanol. The final solution was dis-
Statistical analysis persed into an aqueous phase with constant agita-
The data obtained from the particle size, encap- tion, forming o/w emulsion droplets. The solvent
sulation efficiency and release rate determination and water counter-diffused out of and into the
studies of ibuprofen microspheres were analyzed droplets, respectively. The diffused water within the
statistically with ANOVA and t-test by using SPSS droplets may decrease the drug and polymer solubil-
for Windows 11.0. ities. Both components co-precipitated and contin-
ued ethanol diffusion resulted in further solidifica-
DISCUSSION AND CONCLUSION tion, producing matrix-type microspheres, as shown
in Figure 6. First, the effect of initial difference of
Modified quasi-emulsion solvent diffusion temperature between the aqueous phase and dis-
method was used to prepare ibuprofen micros- persed emulsion phases on the microsphere forma-
pheres. The reasons to choose this method as the tion was investigated. When there was no difference
528 BURCU DEVRIM and KANDEMIR CANEFE
Figure 6. Scanning electron micrographs of microspheres and their surfaces prepared from the formulations given in Table 1 (A) F2, (B)
F5, (C) F6, (D) F7, (E) F10 and (F) F11.
of initial temperature gradient between the emulsion ing sequence. Due to the heat transfer, the rapid
phases, as reported by Kawashima et al. (10), solidification of droplets by precipitation of polymer
microspheres coalesced together and the resultant at the droplet surface prevented the coalescence and
yield of microspheres was relatively low. fusion of droplets. As a consequence, the yield of
Conversely, no coalescence was observed by initial microspheres varied from 65 to 89.9%. Then, vari-
temperature gradient between the continuous and ous formulations with different drug-polymer ratios
dispersed emulsion phases as in our study. The and ethanol volume were tried and stirring speed
inhibitory effect on the coalescence of droplets was changed to obtain spherical particles. When
observed with increase in the gradient temperature amount of drug and polymer in dispersed phase was
between the emulsion phases may be explained by too high (drug-polymer ratio was 1:1, w/w) no
influence of this factor on the microsphere harden- spherical particles were obtained. These results
Preparation and evaluation of modified release ibuprofen microspheres... 529
Figure 6 (cont.). Scanning electron micrographs of microspheres and their surfaces prepared from the formulations given in Table 1 (A)
F2, (B) F5, (C) F6, (D) F7, (E) F10 and (F) F11.
show that the amount of solid, thus the viscosity of of 10 mL was used, the resulting ethanol phase was
the inner phase is an important factor for the prepa- very dilute. The addition of the two phases together
ration of microspheres. Keeping the drug amount produced rapid intermixing of the phases, resulting
and the solvent volume constant, spherical particles in immediate precipitation of drug and polymer
were obtained as the amount of polymer was before droplets could form. Hence, no microspheres
decreased to give a drug-polymer ratio of 2:1, 3:1 or were produced. With increasing concentration of
4:1. The ethanol volume of the inner phase also ibuprofen, the recoveries of spherical matrices
influenced microsphere formation in the various increased rapidly. At a concentration of 1.25 g/mL,
batches. The microsphere yield declined sharply as the loss of microspheres due to adhesion to the pro-
larger volumes of ethanol or less viscous dispersed peller and vessel wall became relatively larger than
phase solutions were used. When a solvent volume the recovered amount, since the volume of ethanol
530 BURCU DEVRIM and KANDEMIR CANEFE
Figure 6 (cont.). Scanning electron micrographs of microspheres and their surfaces prepared from the formulations given in Table 1 (A)
F2, (B) F5, (C) F6, (D) F7, (E) F10 and (F) F11.
solution was small (2 mL). Three different stirring mer ratio, volume of ethanol, type of polymer and
speeds (400, 450 and 500 rpm) were selected and it concentration of polyvinyl alcohol (Table 2). It was
was observed that particle size of microspheres observed that when polymer amount increased, par-
decreased with the increasing of the stirring speed, ticle size of the microspheres increased (p < 0.05).
but at 500 rpm, because of the turbulence of aqueous F5 formulation produced with 33.33% polymer con-
phase, the polymer stuck around the paddle of the centration had bigger particle size than F2 formula-
mixer and a great loss of the polymer was indicated. tion produced with 20% polymer concentration.
Therefore, as a stirring speed of 450 rpm for the Increasing the polymer load led to a more viscous
preparation of microspheres was suitable. solution. When the viscous polymeric solution was
According to the particle size analysis, it was poured into the aqueous phase, larger droplets and
found that particle size was dependent on drug-poly- thus larger microspheres, were formed.