Formulation
and Evaluation of Ibuprofen Solid-Dispersions Prepared by Solvent Evaporation
Technique
M.
Surendra* and T. Venkateswara
Rao
Department of pharmaceutics, Bapatla College of Pharmacy, Bapatla,
Guntur (D.t), Andhra Pradesh
ABSTRACT:
Solid dispersion is the science of dispersing
one (or) more active ingredients in an inert carriers (or) matrix at solid
state prepared by melting solvent method (or) solvent evaporation method.
Sparingly water soluble drugs often show an erratic dissolution profile in
gastrointestinal fluids which
consequently results variable oral bio-availability. To improve the dissolution
and bioavailability of these drugs, various techniques such as solvent
evaporation method, melting method, super critical fluid process, spray drying,
lyophilisation, melt agglomeration, extrusion
kneading method. The various inert carriers such as acids, polymeric materials,
insoluble (or) enteric polymers, surfactants etc. PEG, PVP, lactose, Mannitol, Cyclodextrins and HPMC
were used to increased solubility. Solid dispersions were prepared by solvent
evaporation method. Solid dispersions of ibuprofen were prepared to increase
its aqueous solubility using carriers such as mannitol,
urea, and sorbitol. Ibuprofen solid dispersions were
prepared in 1:1, 1:2 and 1:3 ratios of the drug to carriers (w/w). The prepared
solid dispersion were evaluated for physical parameters like Angle of repose,
Bulk density, Carr’s index, Hausner ratio and Invitro drug release studies. Invitro drug
release profile of solid dispersions were comparatively evaluated and also
studied against pure Ibuprofen. Higher dissolution rate were exhibited by solid
dispersions containing 1:3 ratio of Ibuprofen with urea, the rate of drug
release was depended on the type, ratio of drug to carrier and method of dispersions.
KEYWORDS: Solid dispersions, Ibuprofen, carriers,
solvent evaporation method.
INTRODUCTION:
Solid dosage forms have many advantages over
other types of oral dosage forms because of their easiest way of administering,
greater stability, accurate dosage and easy production. Therefore, most of the
new chemical entities (NCE) under development are intended to use solid dosage
forms that originate an effective in vivo plasma concentration. In fact, most
NCEs are poorly water soluble drugs, and despite their high permeability, are
only absorbed in the upper small intestine, rather the ileum.
Consequently, if these drugs are not
completely released, will have low bioavailability. Therefore, solid
dispersions are one of the most successful strategies to improve drug release
of poorly soluble drugs. These can be defined as molecular mixtures of poorly
water soluble drugs in hydrophilic carriers, which present a drug release
profile that is driven by the polymer properties.
Advantages:
·
Improving
drug bioavailability by changing their water solubility.
·
Avoiding
dose dumping.
·
Reducing
local irritation.
·
Achieving
a more reproducible drug release rate.
·
Minimizing
erratic drug absorption.
·
They
are easier to produce and more applicable.
·
Solid
dispersions are more acceptable to patients than solubilization
products, since they give rise to solid oral dosage forms instead of liquid as solubilization products usually do.
·
Milling
or micronization for particle size reduction is
commonly performed as approaches to improve solubility, on the basis of the
increase in surface area.
Various strategies investigated by several
investigators include:
§ Fusion method
§ Solvent evaporation method
§ Lyophilization technique
§ Melt agglomeration process
§ Extruding method
§ Spray drying method
§ Use of surfactant
§ Electrostatic spinning method
§ Super critical fluid technology
Solvent evaporation method:
v The solvent evaporation method consists of
the solubilization of the drug and carrier in a
volatile solvent that is later evaporated. In this method, the thermal
decomposition of drugs or carriers can be prevented, since organic solvent
evaporation occurs at low temperature.
v A basic process of preparing solid
dispersions of this type consists of dissolving the drug and the polymeric
carrier in a common solvent, such as ethanol, chloroform, or a mixture of
ethanol and dichloromethane. Normally, the resulting films are pulverized and
milled. Differences in solvent evaporation processes are related to the solvent
evaporation procedure, which usually include vacuum drying, heating of the
mixture on a hot plate, slow evaporation of the solvent at low temperature, the
use of a rotary evaporator, a stream of nitrogen, spray-draying, freeze-drying
and the use of supercritical fluid (SCF).
v Spray drying is one of the most commonly
used solvent evaporation procedures in the production of solid dispersions. It
consists of dissolving or suspending the drug and carrier, then spraying it
into a stream of heated airflow to remove the solvent.
v Another common process is the
co-precipitation method, in which a non-solvent is added drop wise to the drug
and carrier solution, under constant stirring. In the course of the non-solvent
addition, the drug and carrier are co-precipitated to form microparticles.
At the end, the resulted microparticle suspension is
filtered and dried.
v Spin-coated films is a new process to
prepare solid dispersions by the solvent evaporation method, which consists of
dissolving drug and carrier in a common solvent that is dropped onto a clean
substrate highly spinned. Solvent is evaporated
during spinning. This process is indicated to moisture sensitive drugs since it
is performed under dry conditions.
v The use of organic solvents, the high
preparation cost and the difficulties in completely removing the solvent are
some of the disadvantages associated with solvent evaporation methods. Moreover,
it is also possible that slight alterations in the conditions used for solvent
evaporation may lead to large changes in product performance.
MATERIALS AND METHOD:
Ibuprofen was procured from a gift sample of
M/S Hetero drugs pvt Ltd., Hyderabad, mannitol, urea, sorbitol were obtained from Hi Media Laboratories pvt Ltd, Mumbai. All other reagents used were of AR grades
and procured locally.
Preparation:
Solid dispersions of Ibuprofen with mannitol, urea and sorbitol were
prepared in the ratio of 1:1, 1:2, 1:3. The required amount of drug and polymer
was dissolved in 50 ml CHCl3, in a beaker. The solvent may complete
evaporation of solvent for 48 hrs. The obtained mass was pulverised
and shifted to #80, and sample were stored in a desiccator for studies.
Evaluation of Solid
dispersions:
Angle of repose:
The
angle of repose of granules was determined by fixed funnel method. The
accurately weighed granules from each formulation batch were taken into a
funnel. The height of the funnel was adjusted in such a way that the tip of the
funnel just touches the apex of the heap of the granules. The granules were
allowed to flow through the funnel freely onto the surface. The diameter of the
powder cone was measured and angle of repose was calculated by using the
following equation8. The angle of repose and types of flow was shown
in table.
Where h=height of the pile, cm r=radius of the base of the pile, cm
Angle of repose as
indicated of powder flow properties.
|
Angle of repose(degrees) |
Type of flow |
|
<20 |
Excellent |
|
20-30 |
Good |
|
30-34 |
Passable |
|
>40 |
Very
poor |
Bulk density:
Granules which
were previously weighed, both loose bulk density (LBD) and tapped bulk density
(TBD) were determined. A suitable quantity of powder from each formulation was
transferred into a 100ml-graduated cylinder. After the initial volume was
observed, the cylinder was fixed on the density apparatus and the time knob was
set for tapping and measured the final volume after tapping. The bulk density
of the powder was calculated.
LBD=
weight of the powder/volume of the packing
TBD= weight of the
powder/tapped volume of the packing
Compressibility index:
Compressibility
index is an important measure that can be obtained from the bulk and tapped
densities. In theory, the less compressible a material the more flowable it is. A material having values of less than 20 to
30% is defined as the free flowing material.
Compressibility
Index:
|
% Compressibility Index |
Flow ability |
|
5-15 |
Excellent |
|
12-16 |
Good |
|
18-21 |
Fair to possible |
|
23-35 |
Poor |
|
33-38 |
Very poor |
|
> 40 |
Extremely poor |
Hausner’s ratio:
|
Hausner ratio |
Type of flow |
|
<1.25 |
Indicate
good flow(=20% carr’s) |
|
>1.25 |
Indicate
poor flow(=33% carr’s) |
|
1.25-1.5 |
Added
glidant normally improves |
Invitro dissolution study:
Invitro dissolution study for Ibuprofen and its
dispersions equivalent to 200 mg of drug, were carried out in 900ml at 37°C
using USP-II (paddle) apparatus with an agitation of 100 rpm for 30 min. The
5ml samples were withdrawn at different time intervals(5,10,15,20,25,30 min)
was filtered and analyzed by UV-visible spectrophotometrically at 222 nm. The
same amount of samples were replaced by fresh medium at constant temperature.
RESULTS AND DISCUSSION:
The granules of different ratio of mannitol, urea and sorbitol were
evaluated for physical properties like Angle of Repose, LBD, TBD,
Compressibility Index and Hausner’s ratio. The
results were reported in Table 1.The
results of Angle of Repose (θ) for the formulations ranged from
19.059±0.021 to 29.236±0.192 and the results of LBD and TBD ranged from
0.432±0.035 to 0.434±0.013 and 0.451±0.022 to 0.458±0.034.The results of
Compressibility Index (%) for the formulations ranged from 5.099±0.035 to 5.934±0.043
and the results of Hausner’s ratio ranged from
1.054±0.085 to 1.108±0.053. In Table 2.The
results of angle of repose (θ) for the formulations ranged from
21.573±0.021 to 26.419±0.023 and the results of LBD and TBD ranged from
0.393±0.053 to 0.405±0.052 and 0.412±0.034 to 0.426±0.024.The results of
Compressibility Index (%) for the formulations ranged from 4.513±0.045 to
4.929±0.085 and the results of Hausner’s ratio ranged
from 1.047±0.043 to 1.052±0.035. In Table
3. The results of Angle of Repose (θ) for the formulations ranged from
21.419±0.083 to 28.314±0.074 and the results of LBD and TBD ranged from
0.402±0.035 to 0.418±0.053 and 0.423±0.034 to 0.440±0.056.The results of
Compressibility Index (%) for the formulations ranged from 4.964±0.087 to
5.011±0.097 and the results of Hausner’s ratio ranged
from 1.052±0.043 to 1.053±0.053.From the above studies the results of Angle of
repose (<30) indicate good flow properties of granules. This was further
supported by compressibility index (<15), also Hausner’s
ratio (<1.25). All these results indicate that the granules having free
flowing nature.
Table 1:
Physical properties of granules prepared by solid dispersions with mannitol
|
Formulation |
Drug:
polymer ratio |
Angle of repose(θ) |
Loose bulk
density(g/ml) |
Tapped bulk
density(g/ml) |
Compressibility
index (%) |
Hausner’s
ratio |
|
Drug: Mannitol |
1:1 |
29.236±0.192 |
0.434±0.013 |
0.458±0.034 |
5.240±0.043 |
1.055±0.032 |
|
1:2 |
26.543±0.112 |
0.428±0.042 |
0.451±0.022 |
5.099±0.035 |
1.054±0.085 |
|
|
!:3 |
19.059±0.021 |
0.432±0.035 |
0.455±0.013 |
5.934±0.043 |
1.108±0.053 |
All values
are expressed as Mean± S.d, n=3
Table 2:
Physical properties of granules prepared by solid dispersions with urea
|
Formulation |
Drug:
polymer ratio |
Angle of
repose(θ) |
Loose bulk
density(g/ml) |
Tapped bulk
density(g/ml) |
Compressibility
index (%) |
Hausner’s
ratio |
|
Drug: Urea |
1:1 |
21.573±0.021 |
0.405±0.052 |
0.426±0.024 |
4.929±0.085 |
1.052±0.035 |
|
1:2 |
26.419±0.023 |
0.393±0.053 |
0.412±0.034 |
4.612±0.057 |
1.048±0.045 |
|
|
!:3 |
24.187±0.032 |
0.402±0.052 |
0.421±0.035 |
4.513±0.045 |
1.047±0.043 |
All values
are expressed as Mean± S.d, n=3
Table 3:
Physical properties of granules prepared by solid dispersions with sorbitol
|
Formulation |
Drug:
polymer ratio |
Angle of
repose(θ) |
Loose bulk
density(g/ml) |
Tapped bulk
density(g/ml) |
Compressibility
index (%) |
Hausner’s
ratio |
|
Drug: Sorbitol |
1:1 |
23.314±0.034 |
0.417±0.041 |
0.439±0.032 |
5.011±0.097 |
1.053±0.043 |
|
1:2 |
28.314±0.074 |
0.418±0.053 |
0.440±0.056 |
5.000±0.042 |
1.053±0.053 |
|
|
!:3 |
21.419±0.083 |
0.402±0.035 |
0.423±0.034 |
4.964±0.087 |
1.052±0.043 |
All values
are expressed as Mean± S.d
Solid dispersions of Ibuprofen with mannitol ratio’s like 1:1, 1:2, 1:3 were prepared. Invitro drug release after 30 min for ibuprofen and mannitol solid dispersions was found to be 56. 31%, 67. 30%
and 92.61% respectively. Solid dispersions of Ibuprofen with sorbitol ratio’s like 1:1, 1:2, 1:3 were prepared. Invitro drug release after 30 min for ibuprofen and sorbitol solid dispersions was found to be 63.25%, 66.45%
and 68.33% respectively. Solid dispersions of Ibuprofen with urea ratio’s like
1:1, 1:2, 1:3 were prepared. Invitro drug release
after 30 min for ibuprofen and urea solid dispersions was found to be 84. 34%,
87.16% and 97.47% respectively. So Ibuprofen with urea solid dispersion was
found to be more for 1:3 ratio, when
compare to other two polymers.
The drug release from formulations followed,
as the plot observed in between amount of drug released Vs time were found to be Fig 1.
is pure drug, Fig 2, 3 and 4; is (1:1), Fig 5, 6 and 7; is (1:2) and
Fig 8, 9 and 10; is (1:3) respectively. The corresponding release rate
constant values were shown in Table 4, 5
and 6. To ascertain mechanism of drug release from the above formulations
plots log% drug released Vs log time were plotted. The plots were found to be
linear and the release data was analyzed as Peppas
equation, value of ‘n’ was found to be in the range of 0.3730 to
0.4906,Non-Fickian diffusion mechanism was followed. The above results indicate
that the increasing concentration of carrier content, the drug release was also
increased.
Table 4:
Dissolution kinetics of Ibuprofen with Mannitol by
solid dispersions
|
Formulations |
Correlation
coefficient |
K value (mg/hr) |
T50(min) |
T90(min) |
n |
% DE20 |
|||
|
Zero order |
First order |
Matrix |
Peppas |
||||||
|
Pure drug |
0.6541 |
0.7818 |
0.9520 |
0.9786 |
21.3253 |
25.3 |
84.1 |
0.2421 |
37.28 |
|
1:1 |
0.7372 |
0.8444 |
0.9706 |
0.8120 |
16.8603 |
20.5 |
68.0 |
0.3730 |
42.73 |
|
1:2 |
0.8325 |
0.9269 |
0.9847 |
0.9685 |
14.0600 |
15.3 |
50.9 |
0.4906 |
49.66 |
|
1:3 |
0.8375 |
0.9891 |
0.9884 |
0.9789 |
19.7797 |
7.8 |
26.1 |
0.4722 |
66.02 |
Table
5:Dissolution kinetics of Ibuprofen with
urea by solid dispersions
|
Formulations |
Correlation
coefficient |
K value (mg/hr) |
T50(min) |
T90(min) |
n |
% DE20 |
|||
|
Zero order |
First order |
Matrix |
Peppas |
||||||
|
1:1 |
0.3871 |
0.8063 |
0.8880 |
0.9537 |
51.5578 |
9.3 |
30.9 |
0.1412 |
68.59 |
|
1:2 |
0.5201 |
0.8214 |
0.9224 |
0.9506 |
40.0953 |
9.6 |
32.0 |
0.2232 |
67.02 |
|
1:3 |
0.8684 |
0.8901 |
0.9624 |
0.8773 |
23.7616 |
6.6 |
21.8 |
0.3864 |
61.97 |
Table
6:Dissolution kinetics of Ibuprofen with
sorbitol by solid dispersion
|
Formulations |
Correlation
coefficient |
K value (mg/hr) |
T50(min) |
T90(min) |
n |
% DE20 |
|||
|
Zero order |
First order |
Matrix |
Peppas |
||||||
|
1:1 |
0.7195 |
0.8621 |
0.9718 |
0.9922 |
21.7269 |
17.6 |
58.4 |
0.3200 |
51.71 |
|
1:2 |
0.8587 |
0.9479 |
0.9912 |
0.9844 |
14.2839 |
16.1 |
53.5 |
0.4720 |
47.71 |
|
1:3 |
0.7784 |
0.9139 |
0.9836 |
0.9892 |
19.5658 |
15.5 |
51.6 |
0.3785 |
50.15 |
Fig 1: Invitro Dissolution profiles of Ibuprofen pure drug
Fig 2: Invitro Dissolution profiles of Ibuprofen with mannitol (1:1) ratio
of SDs prepared by solvent evaporation method
Fig
3:Invitro Dissolution profiles of Ibuprofen with urea (1:1) ratio of SDs
prepared by solvent evaporation method
Fig
4:Invitro Dissolution profiles of Ibuprofen with sorbitol
(1:1) ratio of SDs prepared by solvent evaporation method
Fig 5 : Invitro Dissolution profiles of Ibuprofen with mannitol (1:2) ratio
of SDs prepared by solvent evaporation method
Fig
6:Invitro Dissolution profiles of Ibuprofen with urea (1:2) ratio of SDs
prepared by solvent evaporation method
Fig
7:Invitro Dissolution profiles of Ibuprofen with sorbitol
(1:2) ratio of SDs prepared by solvent evaporation method
Fig
8:Invitro Dissolution profiles of Ibuprofen with mannitol
(1:3) ratio of SDs prepared by solvent evaporation method
Fig
9:Invitro Dissolution profiles of Ibuprofen with urea (1:3) ratio of SDs
prepared by solvent evaporation method
Fig
10:Invitro Dissolution profiles of Ibuprofen with sorbitol
(1:3) ratio of SDs prepared by solvent evaporation method
CONCLUSION:
The solid dispersions of Ibuprofen with mannitol, urea and sorbitol
prepared by a solvent evaporation method showed significantly higher drug
dissolution in comparison with pure drug. From the Invitro
dissolution studies of the solid dispersions, the higher drug release was obtained
from 1:3 ratio of Ibuprofen with urea concentration of solid dispersions
prepared by solvent evaporation method. The present work concluded that solid
dispersion technology can be used successfully to enhance the dissolution rate
of poorly soluble drug Ibuprofen
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Received on 14.01.2012
Modified on 12.02.2012
Accepted on 10.03.2012
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Research J.
Science and Tech. 4(1): Jan.-Feb. 2012: 22-27