Formulation
of Valsartan Fast Dissolving Tablets Using Novel Co
Processed Superdisintegrants
A. Pavan Kumar*, V. Sai Kishore, T. E. Gopala Krishna
Murthy and K. Madhu Babu,
Bapatla College of
Pharmacy, Bapatla-522101
ABSTRACT:
The present investigation deals with formulation of valsartan fast dissolving tablets using co processed superdisintegrant. Crospovidone
and SSG were used for preparation of co processed superdisintegrant
by physical mixing and solvent evaporation method in three different ratios
(1:1, 1:2, and 1:3). Six formulations are formulated with co processed superdisintegrant and are evaluated for weight variation,
hardness, wetting time, water absorption ratio, disintegration time and
dissolution studies and all formulations complies with pharmacoepial
standards. Formulation made with co processed crospovidone
and SSG in 1:1 ratio was found to be best out of all formulations. Present
investigation concludes dissolution rate of valsartan
fast dissolving tablets were influenced by ratios of individual superdisintegrants
employed for co processed superdisintegrant and
method used for preparation of co processed superdisintegrant
(physical mixing vs solvent evaporation).
KEYWORDS: Valsartan, Crospovidone, Sodium starch glycolate,
Co processing.
INTRODUCTION:
Valsartan is an ACE inhibitor, effectively used in
the treatment of hypertension1 and belongs to biological classification
II (low solubility and high permeability). The solubility is rate limiting step
for absorption of valsartan, solubility can be
enhanced by formulating valsartan as fast dissolving
tablets. Various superdisintegrants like SSG, crospovidone, croscarmellose
sodium etc were proved to be best for formulating fast dissolving tablets. SSG
act by swelling and crospovidone act by wicking
mechanism2. Single disintegrate is not sufficient to enhance
solubility of some active pharmaceutical ingredients so combination of disintegrants required to attain desired solubility. One
such approach to attain combination of disintegrating mechanism is co
processing of superdisintegrant.
Coprocessing is defined as combining two or more
established excipients intracting at the sub particle
level, the objective of which is to provide a synergy of functionality
improvement as well as masking the undesirable properties of individual3,
4. Coprocessing of excipient
could lead to formation of excipients with superior properties compared with
the simple physical mixture of their components or with individual components
example Ludipress, Cellactose,
and Starlac5. In the present investigation valsartan
fast dissolving tablets were formulated by using novel co processed superdisintegrant comprising of SSG and Crosspovidone.
Sodium starch glycolate was chosen because of its
higher swelling capacity, good flow rate and its swelling capacity will not be
altered by the presence of hydrophobic excipients like magnesium stearate, talc6 etc. Crosspovidone
was chosen because of its higher compressibility than compared to other super
disintegrants7, high capillary action and pronounced hydration
capacity 8. The rate of and extent of liquid uptake and
swelling of crospovidone are not reduced in 0.1 N
hydrochloric acid than compared with aqueous medium9.
Combination of
swelling and wicking type superdisintegrant is more
efficient than compared to individual superdisintegrant
why because the medium required for swelling will be brought in to tablet if
wicking type of disintegrant is also there. The bulk
density of SSG is different from crospovidone, the
bulk density of SSG is more than compared to crospovidone.
Usage of physical mixture of SSG and crospovidone is
limited because it may prone to segregation when used with high speed tableting machines. Co processed superdisintegrant
may overcome the problem of segregation. With the view of above information an
attempt was made to develop fast dissolving tablets of valsartan
by adopting novel co processed superdisintegrant.
MATERIALS AND METHODS:
Valsartan was obtained from
Natco Pharma, Hyderabad,
India. Crosspovidone, Sodium starch glycolate, MCC, talc and magnesium stearate
were purchased from SD fine Chemicals Ltd, Mumbai. All other materials used
were of analytical grade.
Preparation of co-processed superdisintegrants10:
The co-processed superdisintegrants were prepared by solvent evaporation
method. A blend of Crospovidone and Sodium starch glycolate (in the ratio of 1:1, 1:2 and 1:3) was added to
10 ml of isopropyl alcohol. Isopropyl alcohol is selected because SSG is
sparingly soluble in ethanol and absence of gel formation. The contents of the
beaker (250 ml capacity) were mixed thoroughly and stirring was continued till
most of isopropyl alcohol evaporated. The wet coherent mass was granulated
through # 60 mesh sieve. The wet granules were dried in a hot air oven at 60ş C
for 20 minutes. The dried granules were sifted through # 60 mesh sieve and
stored in airtight container till further use.
Preparation of valsartan fast dissolving tablets:
The compositions of the tablets are given in Tables 1.
All the ingredients as shown in Table 1 were weighed and mixed in a motor and
pestle for 10 minutes. Compressed into tablets on a rotary multi-station tabletting machine (Cadmach
Machinery Co. Pvt. Ltd., Mumbai) using 7 mm round and flat punches. Tablets
were stored in airtight container and used for further study.
Evaluation of formulated
tablet:
Hardness test:
The compression force required to break the tablet was measured by using Monsanto hardness
tester.
Weight variation:
Weight variation test is done with 20
tablets. It is the individual variation of tablet weight from the average
weight of 20 tablets.
Friability11:
Roche friabilator was used to
determine the friability. Pre weighed tablets were
placed in friabilator and rotated at a speed of 25
rpm for 4 minutes or up to 100 revolutions. The tablets are dropped from
a distance of 6 inches in each revolution. The
tablets were then reweighed after removal of fines and the percentage of weight
loss was calculated.
Content uniformity:
Twenty tablets were powdered, and 10 mg equivalent
weight of valsartan in tablet powder was accurately
weighed and transferred into a 100 ml volumetric flask. Initially, 5 ml
methanol was added and shaken for 10 min. Then, the volume was made up to 100
ml with 6.8 phophate buffer. The solution in the
volumetric flask was filtered, diluted suitably and analyzed
spectrophotometrically at 250 nm.
Wetting time and water
absorption ratio12:
A piece of paper folded twice was kept in a Petri dish
containing 6 ml of purified water. A tablet having a small amount of Rosaline
dye powder on the upper surface was placed on the tissue paper. The time
required to develop a red colour on the upper surface
of the tablet was recorded as the wetting time. The same procedure without
Rosaline dye powder was followed for determining the water absorption ratio R
was determined according to the following equation.
R = [(Wa – Wb)/Wb ]× 100
Where, Wb and Wa were the weights of the tablet before and after water
absorption.
Disintegration test:
The disintegration time for all formulations was
carried out using tablet disintegration test apparatus. Six tablets were placed
individually in each tube of disintegration test apparatus. The water was
maintained at a temperature of 37°±2°C and time taken for the entire tablet to
disintegrate completely was noted.
Fineness of
dispersion13:
This test is performed by placing two
tablets in 100 ml of water and stirring it gently, till the tablets get
completely disintegrated. The formulation is considered to form a smooth
dispersion if the complete dispersion passes through a sieve screen with a
nominal mesh aperture of 710 μm without leaving
a residue on the mesh.
In vitro dissolution studies:
In vitro dissolution studies are performed by using USP
XXVI dissolution test apparatus using 6.8 phosphate buffer as dissolution
medium. The paddles are allowed to rotate at speed of 50 rpm. The dissolution
medium was maintained at a temperature of 37+0.5 OC and samples are
withdrawn at an interval of every 5 min the volume of the withdrawn samples are
replaced by fresh dissolution medium in order to kept the volume of the
dissolution medium as constant. The withdrawn samples are filtered and
absorbance was measured at absorption maxima of 250 nm using UV-visible
spectrophotometer.
Table -1 Composition of ingredients for valsartan fast dissolving tablets:
|
S. NO |
Ingredients |
F1 (PM1:1) |
F2 (PM1:2) |
F3 (PM1:3) |
F4 (SE1:1) |
F5 (SE1:2) |
F6 (SE1:3) |
|
1 |
Valsartan |
80 |
80 |
80 |
80 |
80 |
80 |
|
2 |
Crospovidone:SSG |
10 |
10 |
10 |
10 |
10 |
10 |
|
3 |
MCC |
106 |
106 |
106 |
106 |
106 |
106 |
|
4 |
Talc |
2 |
2 |
2 |
2 |
2 |
2 |
|
5 |
Mg stearate |
2 |
2 |
2 |
2 |
2 |
2 |
PM 1:1- Physical mixture of Crospovidone and SSG in 1:1 ratio; PM 1:2- Physical mixture
of Crospovidone and SSG in 1:2 ratio.
PM 1:3 -Physical mixture of Crospovidone and SSG in 1:3ratio; SE 1:1 – Co
processed Crospovidone and SSG in 1:1 ratio.
SE 1:2 – Co processed Crospovidone and SSG in 1:2 ratio. ; SE 1:3– Co processed Crospovidone
and SSG in 1:3 ratio.
Table -2 Physical parameters
of valsartan fast dissolving tablets
|
S. No. |
Parameters |
F1 |
F2 |
F3 |
F4 |
F5 |
F6 |
|
1 |
Average weight
(mg) |
200 + 0.12 |
201 + 0.21 |
200 + 0.24 |
198 + 0.1 |
199 + 0.1 |
198 + 0.3 |
|
2 |
Drug content (%) |
98.3 +
0.25 |
97 + 0.21 |
101.6 +
0.13 |
99.8 +
0.25 |
97.9 +
0.14 |
99.2 +
0.18 |
|
3 |
Disintegration
time (min) |
3 + 0.21 |
5 + 0.23 |
6 + 0.18 |
2.2 + 0.12 |
3.3 + 0.16 |
4 + 0.22 |
|
4 |
Friability (%) |
0.68 +
0.07 |
0.78 +
0.09 |
0.73 +
0.12 |
0.95 + 0.12 |
0.89 +
0.811 |
0.65 +
0.08 |
|
5 |
Hardness (kg/sqcm) |
3.5 + 0.15 |
3 + 0.52 |
4 + 0.24 |
3 + 0.32 |
3.5 + 0.34 |
4 + 0.21 |
|
6 |
Wetting
time (sec) |
79 +
0.34 |
85 +
0.16 |
102 +
0.21 |
69 +
0.26 |
60 +
0.23 |
64 +
0.31 |
|
7 |
Water
absorption ratio |
75 +
0.31 |
70 +
0.26 |
61 +
0.21 |
88 +
0.32 |
79 +
0.21 |
65 +
0.18 |
|
8 |
Fineness of
dispersion. |
Pass |
Fail |
Fail |
Pass |
Pass |
Fail |
Table: 3 Invitro
dissolution kinetics for valsartan fast dissolving
tablets
|
S. No. |
Formulation |
T 50 (min) |
T 90 (min) |
DE 25 (%) |
K (min-1) |
Correlation coefficient values |
||
|
Zero Order |
First Order |
Hixson-Crowell
cube root |
||||||
|
1 |
F1 |
6.8 |
22.6 |
57.1 |
0.102 |
0.92 |
0.97 |
0.96 |
|
2 |
F2 |
11.4 |
37.9 |
46.9 |
0.060 |
0.95 |
0.99 |
0.98 |
|
3 |
F3 |
17.1 |
56.8 |
35.7 |
0.041 |
0.98 |
0.98 |
0.97 |
|
4 |
F4 |
5.1 |
17 |
67.4 |
0.135 |
0.85 |
0.96 |
0.94 |
|
5 |
F5 |
8.7 |
26.9 |
52.1 |
0.079 |
0.94 |
0.98 |
0.96 |
|
6 |
F6 |
13.7 |
45.5 |
42.8 |
0.050 |
0.95 |
0.99 |
0.94 |
RESULTS AND DISCUSSIONS:
Fast dissolving tablets of valsartan were prepared using co-processed superdisintegrants and physical mixture of superdisintegrants. Co-processed superdisintegrants
were prepared by solvent evaporation using crospovidone
and sodium starchglycolate in different ratios (1:1,
1:2. and 1:3). The co processed superdisintegrants
were evaluated for their micrometric properties in comparison with physical
mixture of superdisintegrants. Co processed superdisintegrant offer relatively more flow than compared
to physical mixture of superdisintegrant due to
granule formation.
For each formulation blend of drug and excipient were evaluated for the micrometric properties.
The powder blends are compressed by using direct compression. The micrometric
properties indicate the all the formulations having god flow properties.
The tablets were evaluated for the various physical
parameters such are weight variation, hardness, friability, wetting time, water
absorption ratio, in vitro disintegration time and fineness of dispersion
(Table 2). Tablets are obtained with uniform weight due to uniform die fill,
weight variation limits were within the pharmacopeia specifications. The drug
content was found in between 98.3 to 101.6 %. The hardness of the tablets
between 3 to 4 kg/cm2. Friability of the tablet was below 1% indicating good
mechanical strength. Wetting time and water absorption ratios are measured as
the procedures described earlier. Wetting time and water absorption ratios were
found in between 60 to 102 sec and 61 to 88 respectively. Wetting time is
closely related to the inner structure of the tablet. This showed that wetting
process was very rapid in almost all formulations. The disintegration time was
ranges from 2.2 to 6 min.
All the formulations follow
first order kinetics and drug release profiles are shown in Figure 1. The
dissolution kinetics of the valsartan fast dissolving
tablets were shown in Table 3. The dissolution rate followed first-order kinetics as the graphs
drawn between log % drug unreleased vs time were
found to be linear.
Three formulations were made with physical mixture of crospovidone and SSG (1:1, 1:2, 1:3). The dissolution rate
was found to be influenced by ratios of superdisintegrant
employed in physical mixture of superdisintegrants.
Based on the dissolution rate, the order of drug release from the three
formulations was F1> F2> F3. The
formulation prepared with physical mixture of superdisintegrants
(Crospovidone: SSG) in 1:1 ratio (F1) was
offered relatively rapid release of Valsartan when
compared with other ratios employed in this investigation.Another
three formulations were made with co processed crospovidone
and SSG (1:1, 1:2, 1:3). The dissolution
rate was found to be influenced by ratios of superdisintegrant
employed in co processed superdisintegrants. Based on
the dissolution rate, the order of drug release from the three formulations was
F4> F5> F6. The formulation prepared
with co-processed superdisintegrants (Crospovidone: SSG) in 1:1 ratio (F4) was offered
relatively rapid release of Valsartan when compared
with other ratios employed in this investigation.
Figure:
1
Dissolution profiles of Valsartan fast dissolving
tablets formulated with physical mixture of Crospovidone
and SS (1:1,1:2,1:3) and co-processed Crospovidone
and SSG (1:1,1:2,1:3) :
F1 -
Formulation made with physical mixture of Crospovidone
and SSG in 1:1 ratio. (◊)
F2 -
Formulation made with Physical mixture of Crospovidone
and SSG in 1:2 ratio. ()
F3 -
Formulation made with Physical mixture of Crospovidone
and SSG in 1:3ratio. (Δ)
F4 -
Formulation made with Co processed Crospovidone and
SSG in 1:1 ratio. (x)
F5 -
Formulation made with Co processed Crospovidone and
SSG in 1:2 ratio. ( X )
F6 - Formulation
made with Co processed Crospovidone and SSG in 1:3
ratio. (○ )
The formulation made with co-processed superdisintegrants
(Crospovidone: SSG) in 1:1 ratio (F4)
offered relatively rapid release of Valsartan than
compared to formulation made with physical mixture of superdisintegrants
(Crospovidone: SSG) in 1:1 ratio (F1).
This data reveals, dissolution rate of valsartan
influenced by ratios of individual superdisintegrants
employed in combination of superdisintegrants in both
physical mixing and co processing (1:1, 1:2, 1:3) and type of combination of superdisintegrants (physical mixing vs
co-processing) employed.
CONCLUSION:
The present investigation
concludes co processed superdisintegrants exhibits
good flow characterstics than compared to physical
mixture. Co processed SSG and crospovidone was found
to be well suited for formulation of valsartan fast
dissolving tablets. Dissolution rate of valsartan
fast dissolving tablets was influenced by ratios of individual superdisintegrants employed for co processed superdisintegrant and method used for preparation of co
processed superdisintegrant (physical mixing vs solvent evaporation).
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Received on 16.12.2011
Accepted on 25.01.2012
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Research
Journal of Pharmaceutical Dosage Forms and Technology. 4(1): Jan. - Feb., 2012,
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