Enhancement
of Dissolution Rate Studies on Solid Dispersion of Aceclofenac
S. Lakshmi Thotacherla*, A. M. Shamsunisha, Y. Sirisha, C. Valarmathi, K. L. Senthilkumar, Ezhilmuthu, A. Vasanthan, P. Sumathy
Department of Pharmaceutics, Padmavathi
ABSTRACT:
Aceclofenac is a Non-
Steroidal Anti Inflammatory drug indicated
for the relief
of pain and
inflammation, associated
with rheumatoid arthritis, osteo arthritis, ankylosing,
spondylitis. The percentage of dissolution rate of
drug released from pure Aceclofenac was obtained
26.48% in 180min. The aim of
the study was
to enhance the
dissolution rate on
solid dispersion of Aceclofenac by using
PEG6000 as carrier in
three different ratios
such as ACF:PEG6000-1:1, 1:2 and 1:4 by fusion
method or melting
method. The percentage of
drug release of Aceclofenac
from solid dispersions
ACF:PEG6000-1:1,1:2 and 1:4 was
59.65%,84.75%,98.34% respectively in
180min. Aceclofenac from
solid dispersions due
to enhancing effect
of PEG6000.
INTRODUCTION:
Solid – dispersion technology can be used to improve
the invitro and invivo
dissolution properties of slightly water soluble drugs and to control the
dissolution rate of fully water soluble drugs. Solid dispersion systems have
been considered over the last 20 years as a means of increasing the solubility
dissolution and absorption of poorly water soluble
drugs. The effect of the particle size of the drug on their dissolution rates
and biological availability was reviewed comprehensively by Fincher. For drugs
whose GI absorption is rate limited by dissolution reduction of the particle
size generally increases the rate of absorption and or total bioavailability.
This commonly occurs for drugs with poor water solubility. For example the
therapeutic dose of Griseofulvin was reduced to 50%
by micronization and is also produced a more constant
and reliable blood level. The commercial dose of Spironolactone
was also decreased to half by just a slight reduction to particle size. Such
enhancement of drug absorption could further be increased several fold if a
micronized product was used.
Reduction of particle size can be easily and directly
accomplished by the first four methods and the resultant fine particles may not
produce the expected faster dissolution and absorption. This primarily text is
possible when aggregation and agglomeration of the fine particles due to their
increased surface energy and the subsequent stronger vanderwaals
attraction between nonpolar molecules. Another
inherent disadvantage of these pure fine powders of poorly soluble drugs is
their poor wettability in water. The significance of
the solid dispersion technique was strengthened by the demonstration of Chiou and Riegelman of the fast
and almost complete absorption of the insoluble Griseofulvin
in man and dogs while the commercial micronized Griseofulvin
was incompletely absorbed (30 – 60 %). They used polyethylene glycol6000 as a
dispersion carrier. The main advantages of using water soluble polymers as
carriers are their no toxicity and general applicability to most drugs.
The
significance of the solid dispersion technique was strengthened by the
demonstration of Chiou and Riegelman
of the fast and almost complete absorption of the insoluble Griseofulvin
in man and dogs while the commercial micronized Griseofulvin
was incompletely absorbed (30 – 60 %). They used polyethylene glycol 6000 as a
dispersion carrier. The main advantages of using water – soluble polymers as
carriers are their no toxicity and general applicability to most drugs.
METHODS EMPLOYED TO IMPROVE DISSOLUTION
RATE OF DRUGS
1.
Solubility enhancement:
a.
Buffering the pH
of the diffusion layer. Eg. Buffered aspirin tablets.
b.
Use of salts of
weak acids and weak bases. Eg. Sodium and potassium
salts of penicillin.
c.
Use of solvates
and hydrates. Eg. Ampicillin
trihydrate.
d.
Use of selected
polymeric forms. Eg. Digoxin
– hydroquinone
e.
Prodrug approach Eg. 2, 2-disodium
phosphate ester of methasone.
2.
Increasing the surface area:
a.
Micronization or particle size reduction.
b.
Use of surfactants
(to increase surface area by proper wetting).
c.
Solid dispersions
using highly water soluble carriers.
METHODS OF PREPARATION OF SOLID
DISPERSION
METHODS
OF PREPARATION: basically there are three methods
1.
Melting method.
2.
Solvent method.
3.
Melting-Solvent
method.
1.
Melting method.
Sekiguchi and obi first proposed the melting or fusion method,
to prepare fast release solid dispersion dosage forms. In this method, the
physical mixture of drug and water-soluble carrier is heated directly until it
is melted. The melted mixture is then cooled and solidified in an ice bath
under vigorous stirring. The final mass is crushed, pulverized and sieved. The
dispersion can also be cooled through the process of spray congealing using
spray-drying equipment. The melted material is sprayed onto cold metal
surfaces, which forms pellets of the dispersion. This does not require grinding
and therefore no alteration of the crystal modification of the drug occurs. In addition, this dispersion can be cooled at
a controlled rate. Fusion system can also be done by a slight modification.
Here the homogenous melt was poured in the form of a thin layer onto a ferrite
plate or stainless steel plate and cooled by flowing air or water onto the
opposite side of the plate. The solidified masses were stored in the
desiccators at ambient temperature.
2. Solvent
Evaporation Method:
This method involves dissolving the drug and carrier in
a suitable organic solvent, followed by evaporation of the solvent to form
solid dispersion. The mass was then stored in a
desiccators, pulverized and sieved. Solvent removal is accomplished by various
means. The most common approach is the application of reduced pressure at a
fixed temperature to evaporate the organic solvent. Temperatures
of 125°C for 25 minutes. 115°C for one hour, -5°C and reduced pressure
followed by drying for 12 hours in vacuum has been used. Spray drying is
another approach by which solvent removal can be accomplished and it is probably
the fastest way of removing solvent. The freeze-drying technique is also
employed to prepare solid dispersions by removal of aqueous solutions.
3.
Melting-Solvent Method:
The drug is first dissolved in a suitable liquid
solvent and solution is then incorporated directly into a melt of PEG obtained
below 70 °C without removing the liquid solvent. It was shown that 5 – 10 % w/w of liquid-components would be incorporated into PEG
6000 without significant loss of its solid property.
MATERIALS AND METHODS:
MATERIALS:
1.
Drug – Aceclofenac.
2.
Polyethylene
glycol 6000.
3.
Methanol.
4.
Potassium dihydrogen phosphate.
5.
Sodium hydroxide.
6.
Distilled water.
INSTRUMENTS
1.
Electronic single
pan balance.
2.
Water bath.
3.
Desiccators.
4.
Digital tablet
dissolution test apparatus – LAB INDIA DISSO 2000
5.
UV
spectrophotometer – shimadzu – UV -1700.
6.
pH – meter.
PREPARATION OF REAGENTS
PREPARATION OF PHOSPHATE BUFFER SOLUTION
- pH 7.4:
13.61
grams of potassium dihydrogen phosphate and 3.128
grams of sodium hydroxide were dissolved in 2 liters of distilled water.
PREPARATION OF ACECLOFENAC SOLID
DISPERSION BY FUSION METHOD:
Aceclofenac
with polyethylene glycol 6000 (PEG-6000) solid dispersions in different
proportions 1:1 (1g of drug: 1 g of polymer) 1:2 (1g of drug: 2 g of polymer)
and 1:4 (1g of drug: 4 g of polymer) were prepared by fusion method.
Weighed
quantities of aceclofenac and PEG 6000 in three
different proportions were mixed respectively in a clean, dried china dish. The
china dish was placed on a water bath and heated.
The
drug carrier mixture was melted by increasing the temperature with constant
stirring. The stirring was continued until a homogenous mass was resulted. Then
the melt was poured on a clean, dried tile and cooled in room temperature. The
resulting solidified mass dried in desiccators. The dried material was
pulverized and passed through sieve.no.80. The product was stored in an tight
container and kept in desiccators for further studies
PREPARATION OF STANDARD CURVE:
An
accurately weighed quantity of 100 mg of Aceclofenac
was transferred to clean and dried 100 ml standard flasks. It is dissolved in
small quantity of methanol and made up to 100 ml with the same.
From
this primary stock solution, 10 ml was pipette out, transferred into a separate
standard flask and diluted to 100 ml with phosphate buffer pH – 7.4.
From
this secondary stock solution, 1ml, 2ml, 3ml, 4ml, 5ml, 6ml, 7ml, 8ml, 9ml, and
10ml were pipette out and diluted to 100ml with phosphate buffer pH 7.4 to give
a concentration of 1,2,3,4,5,6,7,8,9, and 10 µ/ml. the absorbance of the
resulting solutions were measured at 275nm using the buffer solution as blank
by UV-spectrophotometer.
A
calibration curve was drawn by plotting absorbance and concentration of drug.
This standard curve was used to estimate the concentration of the drug released
from the solid dispersion formulations of aceclofenac.
Table-1 STANDARD CURVE:
|
S. No |
Concentration (µg/ml) |
Absorbance (275 nm) |
|
1 |
1 |
0.025 |
|
2 |
2 |
0.051 |
|
3 |
3 |
0.074 |
|
4 |
4 |
0.100 |
|
5 |
5 |
0.126 |
|
6 |
6 |
0.150 |
|
7 |
7 |
0.177 |
|
8 |
8 |
0.202 |
|
9 |
9 |
0.228 |
|
10 |
10 |
0.252 |
Figure No-1
Table No-2 COMPARITIVE ASSESSMENT OF THE DISSOLUTION RATE PATTERN
OF ACECLOFENAC PURE DRUG AND FORMULATIONS ACF: PEG 6000 (1:1), ACF: PEG 6000
(1:2) and ACF: PEG 6000
|
S.
No |
Time
in mins |
Percentage
of Drug Release (%) |
|||
|
Pure drug |
Formulations
(Drug : Polymer) |
||||
|
1:1 |
1:2 |
1:4 |
|||
|
1 |
10 |
3.50 |
14.17 |
34.71 |
68.33 |
|
2 |
20 |
5.46 |
22.20 |
40.86 |
75.22 |
|
3 |
30 |
7.60 |
23.67 |
44.43 |
79.83 |
|
4 |
40 |
10.45 |
29.70 |
52.12 |
81.97 |
|
5 |
50 |
12.94 |
36.80 |
56.05 |
82.91 |
|
6 |
60 |
15.26 |
39.87 |
57.13 |
83.13 |
|
7 |
90 |
21.67 |
45.27 |
66.94 |
84.10 |
|
8 |
120 |
23.99 |
50.75 |
71.59 |
87.78 |
|
9 |
150 |
24.88 |
54.43 |
79.10 |
94.77 |
|
10 |
180 |
26.48 |
59.65 |
84.75 |
98.34 |
Figure No-2
RESULTS AND
DISCUSSION:
Aceclofenac
is a potent non steroidal anti-inflammatory drug but poorly
water soluble in nature. So, an opportunity was taken to enhance its aqueous
solubility and thereby bioavailability by preparing it as solid dispersion.
PREPARATION OF SOLID DISPERSION:
Solid
dispersion of aceclofenac with polyethylene glycol
6000 was prepared in 3 different ratios (ACF: PEG 6000 – 1:1, ACF: PEG 6000 –
1:2, and ACF: PEG 6000 – 1:4) by fusion method. The formulations were found to
be fine, free flowing and easy to prepare.
STANDARD CURVE:
The
standard curve relating the absorbance and concentration of aceclofenac
(Table No-1, Figure No-1) was used to estimate the concentration of aceclofenac released from the solid dispersion formulations
and from the marketed samples of aceclofenac.
CONCLUSION:
Ø Solid dispersion of aceclofenac
was prepared by fusion method using carrier polyethylene glycol 6000 in 3
different ratios (ACF: PEG 6000 – 1:1, ACF: PEG 6000 – 1:2, and ACF: PEG 6000 –
1:4) (drug : polymer ratio)
Ø The formulations are fine, free flowing and easy to
prepare.
Ø Drug content estimation revealed that the percentage of
aceclofenac in all the solid dispersion formulations
was between 98% to 100%. The shows that aceclofenac was uniformly dispersed in all the formulations
and there was no wastage during the preparation.
Ø The dissolution studies showed that the carrier PEG
6000 used in the formulation enhanced the invitro
dissolution of aceclofenac from the solid dispersion
formulation than that of the pure drug and formulations.
Ø Out of the three formulations prepared, the formulation
ACF: PEG 6000 – 1:4 showed better release of aceclofenac
than the formulation of ACF: PEG 6000 – 1:2, and ACF: PEG 6000 – 1:1. It
indicates that an increase in the polymer concentration may increase the
dissolution rate.
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Received on 13.05.2009
Accepted on 10.06.2009
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Research Journal of Pharmaceutical
Dosage Forms and Technology.
2(1): Jan. –Feb. 2010, 107-110