INTRODUCTION:
The poor dissolution of water insoluble drugs is still a substantial
problem confronting the pharmaceutical industry. A great number of new and
possibly, beneficial chemical entities do not reach the public merely because
of their poor oral bioavailability due to inadequate dissolution. Over the
years various solid dosage formulation techniques, to enhance the dissolution
of poorly soluble substances, have been introduced with different degrees of
success. The technique of “liquisolid compacts” is a
new and promising addition towards such a novel aim. The active ingredient in a
solid dosage form must undergo dissolution before it is available for
absorption from gastrointestinal tract. The poor dissolution characteristics of
water soluble drugs are a major challenge for pharmaceutical scientists.
The absorption rate of poorly water soluble drug, formulated as an
orally administrated solid dosage form, is controlled by its dissolution rate
in fluid present at the absorption site, i.e the
dissolution step is often rate determining step in drug absorption. Several
researches have shown that the liquisolid techniques
are the most promising method for promoting dissolution rate of poorly water
soluble drugs1, 2.
The immediate or sustained release tablets or capsules that prepared by liquisolid system combined with inclusion of appropriate
adjutants required for tabletting or encapsulation
such as lubricants and disintegrants or binders. Liquisolid compacts prepared by different solvents which
dissolves the poorly soluble drugs and gives better bioavailability3, 4.
It has been observed that the drug release superiority of liquisolid
tablets is inversely proportional to the aqueous solubility of the contained
drug5.
Atorvastatin calcium is an anti-hyperlipidemic agent
belong to class to statins. Liver is the main site of
action of Atorvastatin. It acts by inhibiting HMG-COA
reductase inhibitor, the enzyme involved in the
conversion of HMG-COA to mevolanate in the
cholesterol biosynthesis. The intestinal permeability of Atorvastatin
was high at physiological intestinal pH of 6-6.5. Its oral bioavailability is
14% and is primarily metabolised through hepatic CYP3A4. The oral bioavailability
of drug depends on factors such as solubility, dissolution and membrane
permeability and as Atorvastatin is a class-II drug.
The solubility and dissolution rate are critical factors in its oral
bioavailability. The present study was aimed to develop an immediate release
formulation for Atorvastatin with different
formulations. Variables to achieve the require dissolution rate and comparative
in-vitro dissolution profiles with the marketed formulation6, 7.
EXPERIMENTAL METHODS:8-10
Materials used:
Atorvastatin calcium- Natco Pvt
Ltd., Hyderabad; Lactose- Qualigens, Mumbai; MCC- Yarrow-Chemproducts;
SSG-S. Dfine Chem, Mumbai;
PG - Qualigens, Mumbai; Magnesium Stearate-
S.Dfine Chem, Mumbai; Talc-
S.Dfine Chem, Mumbai.
Solubility studies:
Solubility studies of atorvastatin calcium
were carried out in methanol, 6.8 phosphate buffer, PG, PEG400 and PEG200.
Saturated solutions were prepared by adding excess amount of atorvastatin ca to the vehicles and subjected to shaking on
the shaker for 24 hr at 25°C under constant vibration. Filtered samples were
diluted appropriately with 6.8 phosphate buffer and Atorvastatin
was determined spectrophotometrically at 246nm.
Binding capacity:
Binding capacity is defined as capacity of powder excipients
to hold liquid without change in their flow properties. It was determined by
the following simple method. A constant weight of 5g of different powder excipients (lactose, MCC, manitol
and starch) were put into a mortar and PG was added in increment of 0.01ml. The
mixture was triturated after each addition to help distribution of the liquid
throughout the powder particles. The volume of the binder required to produce
damp mass was noted.
Preformulation studies:
The preformulation studies like flow
properties, solubility, drug excipient compatibility
studies were determined.
Flow Properties of Atorvastatin
Calcium:
The following flow properties were of granules was determined.
Bulk density and tapped density:
The previously weighed pure drug and or granules (w) were placed
separately into a graduated measuring cylinder and the initial bulk volume (VB)
was noted. It was placed in tapped density tester USP and subjected to constant
tapping at a rate of 200drops/min until a difference between the initial and
final volume was less than 2%. It was recorded as the final (tapped) volume and
various flow properties were recorded with following formulae.
Bulk density = 
Tapped density = 
Compressibility index:
It was calculated by using following formula:
Carr’s index = tapped density-bulk density/tapped
density ×100
The ci value below 15%
indicates good flow of the powder and above 30% indicates poor flow of powder.
Hausner’s ratio:
It was calculated by following formula:
Hausner’s ratio = tapped density / bulk density
Angle of repose (θ):
It was determined by using a funnel whose tip was fixed at a constant
height (H) of 2.5 cm from horizontal surface. The granules and powder were
passed separately through the funnel until the tip of the conical pile touches
to the tip of funnel. The radius of the base of the conical pile is measured as
R (cm). It was determined by following formula;
Angle of repose (θ) =
Tan -1(height/ radius)
Formulation studies:
Liquisolid compacts were prepared by dispersing atorvastatin
in 2 ml of the liquid vehicle and to this carrier: coating material (1:1) was
added in increasing amounts till lumps were formed. These amounts of carrier
and coating materials were enough to maintain acceptable flow and compression
properties. Finally 5% (W/W) of sodium starch glycolate
was added as the disintigrant and 1% (W/W) magnesium stearate and talc were mixed with liquisolid
compact. The final mixture was compressed using the manual tableting
machine to achieve tablet hardness of 6-7kp.
Preparation of liquisolid
compacts:
Several liquisolid compacts were prepared as
follows. Atorvastatin was dispersed in PG with
different ratios ranging from 1:1, 1:3, 1:5, 1:7 (drug: PG). The binary mixture
contains lactose (flowlac)-cabosil.
Lactose as the carrier powder and cabosil as the
coating material was added to the mixture containing the drug and PG under
continuous mixing in a mortar. Depending on the ratio of drug: PG in
formulation, different liquid load factors were employed in our liquisolid preparations. These amounts of the carrier and
coating materials are enough to maintain acceptable flow and compression
properties. Finally 5% (W/W) of sodium starch glycolate
was used as the disintigrant and 1% (W/W) magnesium stearate and talc were mixed with liquisolid
compact. The final mixture was compressed using the manual tableting
machine to achieve tablet hardness of 6-7kp. The Composition of atorvastatin tablets is given in table1.
Evaluation of liquisolid
compacts
The post compressional parameters like
hardness, thickness, friability, disintegration time, drug content and
dissolution studies were conducted or all prepared liquisolid
compacts.
Weight variation:
Twenty tablets were collected randomly and the average weight and
individual weight was calculated with the following formula
%Weight variation = average weight-individual weight/ individual weight
× 100
Thickness:
The thickness of a tablet was measured in mm by using Vernier callipers.
Hardness:
The hardness of the ten tablets was measured by using Varian VK200 Tablet
Hardness Tester and is given in units of KP.
Friability:
Ten Tablets were carefully de dusted prior to testing and weighed
accurately (W0). The tablets were placed in Friabilator (USP)
EF-2. The drum was rotated for 100 times at a speed of 25rpm. The tablets were
collected, de-dusted and accurately weighed (W1). It is calculated
from the fallowing formula.
%Friability = 
Disintegration Test:
The disintegration study was performed for atorvastatin
compacts by sing disintegration apparatus Electrolab
DT tester (USP). For this water was used as the disintegration medium. 6
tablets were placed in 6 tubes of the disintegration apparatus. The time (min)
taken for the compacts to disintegrate was noted.
Determination of drug content of atorvastatin calcium compacts:
Ten AT compacts were weighed accurately and then crushed well in a clean
mortar and pestle. The powder equivalent to25 mg of the drug was weighed and
then transferred to a 100ml volumetric flask. 50ml methanol was added and sonicated for 5min at 27°C. Then the volume was made up to
100ml using methanol. The sample was suitably diluted with pH 6.8 phosphate
buffers and analysed for drug content at 246nm using UV spectrophotometer. The
drug content was calculated using the following formula.
Drug content = = 
In vitro drug release studies of atorvastatin compacts:
In vitro drug release studies of atorvastatin
tablets were carried out using electrlab, US
apparatus-II paddle type apparatus with 6.8 pH buffer as dissolution
media(900ml) the paddle speed was set at 50 rpm and replaced with 5ml of fresh
buffer at the sampling intervals of 5,10,15,20, 30 mins.
The collected samples were analysed at 246nm using UV spectrophotometer.
Stability studies
An ideal dosage form apart from other requirements, it should provide
consistency in drug release throughout its shelf life. The stability of drug
release from tablets developed in this investigation was studied by keeping the
selected formulation under following storage conditions.
1.25±20c/60±5%RH
2.40±20c/75±5%RH
All the products were stored for 2 months. Samples were taken at 30, 60,
and 90 days and subjected to in-vitro dissolution studies and the observed
dissolution data of atorvastatin from the stored
product was presented in the following table.
RESULTS AND DISCUSSIONS:
Solubility:
Different non-volatile solvents such as PEG400, PEG200, PG, were
screened based on their solubility and solubility data was represented in table
2. High solubility was observed from the solvent PG so it was selected for
further studies.
Selection of carriers:
To select the better carrier among the mannitol,
starch, lactose, MCC they were tested for wet point and flow point. Lactose was
selected, as it offered less flow and wet points. The blend containing carrier
and adsorbent was accessed for Binding capacity and observed Binding capacity
was shown in the following table 3.
Micromeritic properties:
The micromeritic properties of all carriers
were within the limits and results were shown in the table no. the material
exhibited desired flow property it was compressed to form a tablet. The tablets
were subjected to various quality control tests and the results were given in a
table no4.
Average weight:
Prepared formulations are subjected to weight variation test as per I.P
acceptance criteria for weight variation test is as follows. The results are
given in table. The observed weight variation was found to be within the
acceptance range78-1239 and thus all the tablets were satisfied the weight variation
test. The results are shown in table no-5.
Hardness:
The hardness of all formulations was tested using Varian VK200 Tablet
Hardness Tester. The data was given in table no 5.
% Friability:
% Friability for all the formulations was carried out in Roche’s friabilator. The % friability range for all formulations
was in between 0.019±0.24- 0.248±0.45 and thus all formulations were satisfied
the friability test. The results are shown in table no-5.
Drug content:
The content of active ingredient test was determined as per I.P
requirement. The results are in between 95.23±0.35-98.89±0.18. The observed
data indicated that tablets are satisfying the drug content requirement. The
results are shown in table no-5.
Disintegration test:
The disintegration test determines for tablets disintegrate with in a
prescribed time when placed in a liquid medium under the prescribed
experimental conditions. According to IP disintegration time for tablets was 30
mins. Disintegration time for all the formulations
was varied from 11.07±0.24-13.36±0.16. The results are shown in table no-5.
Dissolution:
The in-vitro dissolution was carried out for all the formulations under
the prescribed experimental conditions. The time vs %drug release plot was shown in figure 1. The dissolution data follows 1st order rate
kinetics.
The highest drug release was observed for the formulation F8 containing
ATORVASTATIN 20 mg, carrier 505.6 mg, coating material 10 mg, PG 2.5 mg; super disintigrating agent and lubricants of 11.64, 23.45, and 11.64
were added. The selected formulation was selected to stability studies. The
stability studies data was given in table 6.