INTRODUCTION:
Poorly water soluble drugs are increasingly
becoming a problem in terms of obtaining the satisfactory dissolution within
the gastrointestinal tract that is necessary for good bioavailability. It is
not only existing drugs that cause problems but it is the challenge to ensure that
new drugs are not only active pharmacologically but have enough solubility to
ensure fast enough dissolution at the site of administration, often the
gastrointestinal tract[1]. Improvement of oral bioavailability of poorly water soluble drug remains one of the most
challenging aspects of drug development. By many estimates up to 40% of new
chemical entities discovered by the Pharmaceutical industry today are poorly
soluble or lipophilic compounds[2].
The solubility issues complicating the
delivery of these new drugs also affect the delivery of many existing drugs.
The main possibilities for improving dissolution according to Noyes-Whitney
equation are to increase the surface area available for dissolution by
decreasing the particle size of the solid compound and/or by optimizing the
wetting characteristics of the compound surface, to decrease the boundary layer
thickness, to ensure sink conditions for dissolution and, last but definitely
not least, to improve the apparent solubility of the drug under physiologically
relevant conditions [3]. The solubilization
of drug compound is the selection of an appropriate salt form, or for liquid
drugs, adjustment of pH of the solution. Traditional approaches to drug solubilization include either chemical or mechanical
modification of the drug molecule, or physically altering the macromolecular
characteristics of aggregated drug particles [4].
Ibuprofen (IBU) is a non-steroidal anti-inflammatory drug (NSAID).
Ibuprofen is used for relief of symptoms of arthritis, primary dysmenorrhea,
fever, and as an analgesic, especially where there is an inflammatory
component. Ibuprofen is practically insoluble in water, thereby exhibits low
bioavailability after oral administration. Therefore, the improvement of
ibuprofen bioavailability from its oral solid dosage form is an important issue
for enhancing its bioavailability and therapeutic efficiency [5].
The usage of natural polymers as drug carriers is on increasing
side because of their low cost, biocompatibility and biodegradability. Guar Gum
is a natural gum ground endosperm of the seeds from Cyamompsis
tetragonolobus (L.) Taub. Belonging to family ‘Leguminosae’, mainly consisting of high molecular weight
(50,000-8,000,000) polysaccharides composed of galactomannans;
mannose: galactose ratio is about 2:1[6].
The wider application of Guar gum is due to its unique features such as high
swelling and water retention capacity, high viscosity properties and abundant
availability. Guar gum is used in solid-dosage forms as a binder and disintegrant. However, it is reported that the swelling
ability of the carrier profound influence on the improvement of dissolution
rate of poorly water-soluble drugs [7].
MATERIALS AND
METHODS:
Materials
Ibuprofen was
obtained as gift sample from Shandong-Xinhua Pharm. Co. Ltd. China, Guar gum
(GG) was obtained from sigma Aldrich, and other ingredients were used for study
were of commercial grade, purchased from SD. Fine chem.
Methods
Preparation of modified guar gum
Preparation of MGG was done
by heating method. Briefly, powdered gum
was taken in a porcelain bowl and subjected to heating using sand bath for
different time periods at different temperatures. The results of swelling capacity and
viscosity studies revealed that the modified forms possessed swelling property
similar to GG, but viscosity was decreased as a function of temperature and
time period of heating. However, it was observed that GG samples were charred,
when heated at 150 °C. In the preparation of modified form of GG, no further
change in viscosity of GG was observed by heating it at 125 °C for more than 2
h. Hence, these conditions of heating at 125 °C for 2 h were selected to
prepare modified form of GG. The prepared modified form of GG was finally
re-sieved (100 mesh) and stored in airtight container at 25°C[8].
Characterization of GG and
MGG
Swelling and water retention capacity
The swelling and water
retention capacity of the GG and MGG were estimated by a slightly modified
method [9, 10]. About 1.0 g of GG powder was accurately weighed and
transferred to a 100 ml stoppered measuring cylinder.
The initial volume of the powder in the measuring cylinder was noted. The
volume was made up to 100-ml mark with distilled water. The cylinder was stoppered and was shaken gently and set aside for 24 h. The
volume occupied by the gum sediment was noted after 24 h. Swelling
capacity of GG/MGG was expressed in terms of swelling index as follows. Swelling index (SI) was expressed as a
percentage and calculated according to the following equation:
Where, X0 is the
initial height of the powder in graduated cylinder and Xt
denotes the height occupied by swollen gum after 24 h. The contents from the
measuring cylinder from the above test were filtered through a muslin cloth and
the water was allowed to drain completely into a dry 100 ml graduated cylinder.
The volume of water collected was noted and the difference between the origina1
volume of the mucilage and the volume drained was taken as water retained by
the sample referred as water retention capacity or water absorption capacity of
the polysaccharide.
Viscosity measurement
The viscosity of 1% (w/ v) GG/MGG solution was measured according
to the USP XXX, NF XXIV, at 37 °C using a Brookfield, DV-II Pro Viscometer and
Spindle 62 (LV2) [11].
Preparation of co-grinding
mixtures
Co-grinding mixtures (CM) of IBU and GG or MGG were obtained by
grinding a physical mixture of IBU and GG or MGG in a 1:9 weight ratio for 20
minutes in a ceramic mortar and sieved through 100 mesh.
“CM-GG” represents the co-grinding mixture of IBU and GG, and “CM-MGG”
represents the co-grinding mixture of IBU and MGG. To ascertain the effect of method, carrier,
or both on the dissolution rate of IBU, IBU alone was ground for 20 minutes and
the resultant product represented as IBU1. All the samples were stored in a
desiccators at room temperature[12].
Preparation of physical
mixtures
The physical mixtures of IBU and GG or MGG were obtained by simple
blending with spatula of the IBU and GG or MGG in a 1:9 wt/wt ratio (drug:
polymer). PM-GG and PM-MGG represents the physical mixtures of NM-GG and
NM-MGG, respectively.
Compatibility study of
co-grinding and physical mixtures
Differential scanning calorimetry
Differential scanning calorimetry (DSC)
curves were obtained by a differential scanning calorimeter (DSC 60, TA-60WS,
Shimadzu, Japan) at a heating rate of 10°C/min from 30 to 300°C in an air atmosphere[13].
Infrared spectroscopic
studies
Fourier–transformed infrared
(FT–IR) spectra were obtained on a Shimadzu, FT-IR 8400 using the KBr disk method (2 mg sample in 200 mg KBr).
The scanning range was 450 to 4000 cm-1 and the resolution was 1 cm-1[14].
Solubility studies
The apparent solubility of
IBU, IBU1, co-grinding mixtures, and physical mixtures was determined in water
at 37°C. For each preparation, an equivalent of 50 mg of drug was added to 50
ml of water in a conical flask with Teflon-lined screw caps. The conical flasks
were kept on a shaker incubator maintained at 37 ± 0.5°C for 24 hours. After
shaking, the flasks were kept equilibrated in an incubator at 37 ± 0.5°C for 12
hours. Then solution was filtered through a 0.45-µm Millipore filter and the
filtrate was assayed spectrophotometrically at 221 nm[15].
In vitro dissolution rate
studies
Dissolution
rates from different solid mixtures were determined in 900 ml of Phosphate
buffer solution (pH 7.2) at 37°C with a stirrer rotation speed of 100 RPM using
the USP XXIII dissolution rate test apparatus employing a paddle stirrer
(Method II). A 5-ml aliquot of dissolution medium was withdrawn at 5, 10, 15,
20, 30, 40, 50, 60, and 90 min with a pipette. The samples were suitably
diluted and assayed spectrophotometrically at 221 nm. Each dissolution rate
test was repeated 3 times[16].
Statistical analysis
All the data of solubility
studies and in vitro dissolution rate studies were analyzed statistically by
ANOVA (analysis of variance) test.
RESULTS &
DISCUSSION:
Characterization of GG and
MGG
Swelling, water retention capacity and Viscosity measurement
The results of the characterization of the GG and MGG are given in
Table No. 1. The results indicated that the viscosity of MGG was markedly lower
when compared to GG. The swelling and water retention capacity of MGG was not
reduced significantly rather than that of the GG (P < 0.05). Due to the swelling nature of the carrier, the
extensive surface of carrier is increased during dissolution, and the
dissolution rate of deposited drug is markedly enhanced. Water retention
capacity of carrier is the amount of water retained in it that indicates
ability of carrier towards hydrophilic nature.
Table No. 1: Characterization of guar gum and modified guar gum
(mean ± S. D.*)
|
Product |
Viscosity (cps) |
Swelling Index (%) |
Water retention capacity (ml) |
|
GG |
4521± 108 |
2508 ± 62.92 2367 ± 76.38 |
26.53 ± 3.05 |
|
MGG |
1645 ± 91 |
19.50 ± 1.18 |
*n=3
Differential scanning calorimetry (DSC)
The
DSC thermo grams of IBU, IBU1, GG, and MGG are compared with those for
co-grinding mixtures and physical mixtures in Figure 1. The DSC thermo grams of
physical mixtures as well as co-grinding mixtures showed peak corresponding to the melting point of
pure IBU, indicating the absence of chemical interaction between IBU and GG or
MGG.