Malpani Amol et al
Original Research Manuscript
Article History: Received on: 09-08-09 Accepted on: 02-09-09
Int.J.Ph.Sci, May-August 2009; 1(1):132-139 Available online from: www.ijps.info Copyright ® 2009 www.ijps.info
FORMULATION OF LISINOPRIL DIHYDRATE TABLET AND STUDY EFFECT OF EXTENT OF GRANULATION ON RESPONSE VARIABLES Malpani Amol*, Panda Bibhu Prasad, Rao Bhanoji M. E. Department of Pharmaceutics, Roland Institute of Pharmaceutical Sciences, Berhampur, Orissa, India. ABSTRACT Lisinopril dihydrate is an official drug in British Pharmacopoeia and United State Pharmacopoeia. It is one of the widely used ACE inhibitor for long time. Present study includes formulation and evaluation of Lisinopril dihydrate tablet. Present study also shows that how extent of granulation i.e. granulation time affect the particle size distribution, tablet hardness, friability, disintegration and drug release as response variables. Because granulation time is very crucial and critical parameter of tablet formulation which can affect badly if it was not optimized. Among the all trials for Lisinopril dihydrate tablet formulation Trial 7 gives better release pattern in three different media as well as other tablet evaluation parameters. When this formulation is taken for the study of effect of granulation time, the significant variation in particle size distribution as well as drug release was seen.
KEYWORDS: ACE inhibitor, Granulation time, Rapid mixer granulator.
Di-calcium phosphate dihydrate used because it reduces
INTRODUCTION Lisinopril Dihydrate, an ACE inhibitor about 12 hrs
[2]
[1]
has half life
. So, it is not suitable candidate for
impurity in final formulation
[3, 4]
and Maize starch
plays dual role as binder and disintegrant. Trial 7
controlled release formulation. Tablet dosage form is
among these formulations shows better results.
preferable because other than tablet dosage form not
Mixing and agglomeration of particles in wet
having good shelf life in case of Lisinopril due to its
granulation have been studied extensively
degradation, which imparts the impurity in formulation.
optimal endpoint can be thought of as the factor
Seven formulations were prepared by wet granulation.
affecting a number of granule properties. With so many
Email address of correspondence author:
variables involved in a granulation process, numbers of
[email protected]
researchers studied different factors in attempt to arrive at an optimum response
Int.J.Ph.Sci, May-August 2009; 1(1):132-139 www.ijps.info
[7-15]
[5, 6]
. The
. The final goal of any
132
Malpani Amol et al
granulation process is a solid dosage form, such as
sieve mixed in rapid mixer granulator (RMG) for 15
tablets. Therefore, when optimizing a granulation
minutes. Sift starch for paste through 100 mesh sieve
process, it stands to reason to include, alongside the
and prepare the 10% paste as binder.
end-point factor, the tablet processing parameters [7].
Granulate for 10 minutes in RMG (75 RPM) along with chopper on, with racking after 5 min., dry the wet mass
MATERIALS AND METHODS
at 60°C till the LOD reaches less than 4.0 % w/w. Rasp
Materials used in formulation of tablets were Lisinopril
the dried granule through 30 mesh sieve. Sift extra-
dihydrate (Alkem Laboratories Ltd.), Di-calcium
granular material through 60 mesh sieve. Mix the
phosphate dihydrate (Universal impex corp.), MCC
rasped granule and sifted dried starch in blender for 20
101, Pearlitol 25C, Maize starch, Red iron oxide and
minutes. Add sifted magnesium stearate for 5 minutes.
Magnesium stearate (S.D. fine chemicals).
Compressed the above blend obtained in with 8mm punches.
METHOD OF FORMULATION OF TABLETS Take required quantity of ingredients as given in Table 1. Sift intra-granular materials through 40 mesh sieve except starch and colour screened through 200 mesh
Trials 1 2 3 4 5 6 7
Intra-Granulation (mg/tab) LD DCPD P25C MCC101 20 97 40 45 20 102 40 10 20 102 40 20 101 40 20 111 40 20 115 36 20 96 36 -
EVALUATION
OF
MS 20 30 10 20 20 36
RIO 1 1 1 1 1 1 1
PRECOMPRESSION
Binder (mg/tab) SP 5 5 5 5 5 5 4
ExtraGranulation (mg/tab) DMS MSt 2 10 2 10 2 30 3 10 3 10 3 14 3
Table 1: Formulation of Lisinopril dihydrate tablets for 20 mg LD- Lisinopril Dihydrate, DCPDDi Calcium Phosphate Dihydrate, P25C- Pearlitol 25C, MCC101Microcrystalline Cellulose, MSMaize Starch, RIO- Red Iron Oxide, SP- Starch Paste, DMSDried Maize Starch, MStMagnesium Stearate.
ml graduated cylinder. The volumes occupied by the
PARAMETERS [16]
samples were recorded. Bulk density was calculated.
Loss on drying
Tapped density
0.5g of sample was accurately weighed and the powder
Tapped density was determined by using Electrolab
was kept in a Mettler Toledo apparatus for 5 min. at
density tester, which consists of a graduated cylinder
105ºC and the moisture content was calculated.
mounted on a mechanical tapping device. Volume was
Bulk density
noted against pre-weighed sample and taped density is
Bulk density of Lisinopril was determined by pouring
calculated using following formula.
gently 25 g of sample through a glass funnel into 100
Tapped density = Wt. of sample in gm / Tapped volume.
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Malpani Amol et al
Powder flow characteristics
Hauser’s Ratio = Tapped Density / Bulk Density.
Compressibility index and the closely related Hausner
Sieve analysis
ratio have become the simple, fast, and popular
The procedure involves the Electromagnetic Sieve
methods of predicting powder flow characteristics.
shaking of the sample through the series of successively
Both the compressibility index and the Hausner ratio
arranged sieves (sieve no.20, 30, 60, 80, 100 and
were determined by following formula.
receiver), and weighing of the portion of the sample
Carr’s Index = [(Tapped Density - Bulk Density) /
retained on each sieve and calculate percentage retained
Tapped Density] ×100,
on each sieve.
Table 2: Pre compression parameters of all trials Loss on drying (%w/w) Dried Granules
Final blend
Bulk density (gm/ml)
1
3.91
3.68
0.483
0.6
19.500
1.242
2
3.5
3.37
0.488
0.597
18.258
1.223
3
3.85
3.66
0.473
0.582
18.729
1.230
4
4.18
4.11
0.487
0.593
17.875
1.218
5
3.99
3.87
0.473
0.587
19.421
1.241
6
3.98
3.78
0.493
0.595
17.143
1.207
7
4
3.76
0.501
0.657
23.744
1.311
Trial No.
EVALUATION
OF
POSTCOMPRESSION
Tap density (gm/ml)
Carr's index (%)
Hauser’s ratio
Hardness indicates the ability of a tablet to withstand
PARAMETERS [16]
mechanical shocks while handling. The hardness of the
Weight variation test
tablets was determined using “Dr. Schleuniger hardness
Twenty tablets were weighed and the average weight
tester”. It is expressed in Newton (N). Ten tablets were
was calculated. The individual weight was compared
randomly picked and hardness of the same tablets from
with the average weight.
each formulation were determined .The average with
Uniformity of thickness
SD was calculated.
Ten tablets were picked from formulations randomly
Friability test
and thickness was
measured individually using
The friability of tablets was determined using “Roche
“Vernier-caliper (Mitutoyo, Japan)”. It is expressed in
Friabilator”. It is expressed in percentage (%). Twenty
millimeter and average with Standard deviation (SD)
tablets
was calculated.
transferred into friabilator. The friabilator was operated
Hardness test
at 25 rpm for 4 minutes. The tablets were weighed
were
initially
weighed
(W
initial)
and
again (W final). The % friability was calculated by,
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134
Malpani Amol et al
% Friability = (Wt. initial – Wt. final / Wt. initial) x 100
basket of dissolution apparatus; the temperature of
Disintegration time [17]
dissolution media was maintained at 37±0.5 0C with
It is determined by using USP device which consist of 6
stirring speed of 50 rpm throughout the study. Aliquots
glass tubes that are 3 inches long, open at one end and
of dissolution media containing 10 ml of samples were
held against 10 mesh screen at the bottom end of basket
withdrawn at time interval of 5, 10, 15, 20, 30 minutes
rack assembly. To test for disintegration time, one
and 5 ml of fresh dissolution media maintained at the
tablet is placed in each tube and the basket arch is
same temperature was replaced after each withdrawal.
positioned in a1 liter beaker of water at 37 0C ± 2 0C.A
The samples were analyzed by HPLC at 215 nm.
standard motor driven device is used to move the basket
Optimization of Granulation Time
assembly up and down.
For this study we take 3 batches of big size i.e. 6000
Assay
tablets. Each batch was subject to granulation in Rapid
Assay was done by HPLC method using solvent
Mixing Granulator with impeller at speed 150 RPM for
mixture of 1 volume of methanol and 4 volumes of
12min, 6min and 3min respectively and with chopper at
water and procedure done as per United State
speed 2500 RPM for 12min, 6min, 3min respectively.
Pharmacopoeia.
After granulation their all micromeritics, in process as
In vitro drug release study
well as dissolution test was done for all three batches as
Dissolution study of tablet performed in USP II
per official standards and compare drug release with
(paddle) dissolution test apparatus (Electrolab TDT
marketed
O8L) using 900ml of 0.1N HCl as an official
machine speed, impeller tip speed and relative swift
dissolution media. The tablet was loaded into an each
volume should be same for all 3 batches during study.
[16]
product
.
Environmental
condition,
Table 3: Post compression parameters of all trials Trial No.
Average wt.(mg) ±SD
Thickness (mm) ±SD
Hardness (N) ±SD
Disintegration time(min.)
Friability w/w)
1
210±2.73
3.40±0.01
50±2.88
2.0 -2.10
0.15
99.24
2
210±2.56
3.40±0.02
50±3.11
1.45-1.50
0.16
98.93
3
210±2.39
3.40±0.03
50±3.52
45-50sec
0.21
99.43
4
210±1.98
3.40±0.02
50±3.03
2
0.12
101.2
5
210±1.87
3.40±0.02
55±2.44
2.10-2.15
0.1
100.5
6
210±2.25
3.40±0.02
65±2.56
2.20-2.30
0.08
100.1
7
210±1.74
3.41±0.02
65±2.33
2.25-2.30
0.08
100.7
Int.J.Ph.Sci, May-August 2009; 1(1):132-139 www.ijps.info
(%
Assay (%)
135
Malpani Amol et al
Figure 1: Sieve analysis study of final trial
Figure 2: Comparative drug release profile of all formulations.
Sieve Analysis of Final Trial 20#
30#
60#
80#
20# 30# 0.3% 3% Base 49%
100#
60# 12%
Base
80# 4%
100# 32%
Figure 3: Dissolution profile of trial 7 in three different media
Figure 4: Graphical representation of effect of extent of granulation on particle size distribution Effect on Particle Size Distribution
% Retained Material
70 60 50 40 30 20 10 0 20#
30#
40 #
60 #
80 #
100 #
BASE
Sieve Size High Granulation
Medium Granulation
Low Granulation
Figure 5: Graphical representation of effect of extent of granulation on drug release. Effect of Extent of Granulation on Drug Release Marketed product curve
High granulation curve
Medium granulation curve
Low granulation curve
Cumulative % drug release
100 90 80 70 60 50 40 30 20 10 0 0
5
10
15
20
25
30
Time in minutes
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Malpani Amol et al
Table 4: Effect of granulation time on tablet properties Compression Parameters Parameter
High
Medium
Low
Trial no.
A
B
C
Batch Size (tabs)
6000
6000
6000
RMG (capacity)
5.0 L
5.0 L
5.0 L
Impeller Time (min.)
12
6
3
Impeller Speed( rpm)
150
150
150
Chopper Time (min.)
12
6
3
Chopper Speed( rpm)
2500
2500
2500
25ºC/55%RH
25ºC/55%RH
25ºC/55%RH
TD (gm/ml)
0.769
0.6
0.8
BD (gm/ml) Micrometrics of lubricated CI (%) granule HR
0.625
0.483
0.615
18.73
19.50
23.13
1.23
1.24
1.3
LOD
4.24%
4.86%
4.99%
20#
1.2
1.1
0.8
30#
1.1
8.5
6.21
40 #
19.25
3.5
7.5
30.3
12
8.5
80 #
6
3.5
13.06
100 #
6.75
26
3.37
BASE
34.7
45
60.56
Weight Variation (%)
-0.60
1.70
1.90
Thickness( mm)±%SD
3.50±0.03
3.50±0.02
3.50±0.02
75±2.8
75±2.34
75±4.6
Friability (100rtn’s)
0.04
0.06
0.06
D.T (min.)
3
3
2
65.9
86.61
91.1
96.03 99.1 100.46
98.1 99.4 100.9
Granulation
Granulation In RMG
Environmental Conditions
Sieve Analysis% Retained 60 #
Compression Parameters Hardness (N)±%SD
Minutes DR Profile Innovator Vs 5 Trial at 0.1N HCl,50RPM,Paddle, 900ml 10 volume 15 30
Marketed product 75.2
91.68 75.01 97.17 85.25 99.57 91.3
F1- Value
12.71
9.41
13.39
F2 Value
48.37
62.83
55.59
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137
Malpani Amol et al
RESULTS AND DISCUSSION Prepared seven formulations of immediate release Lisinopril dihydrate tablet in different proportions of ingredients
were
evaluated
for
their
different
parameters like pre-compression parameters (see Table 2), post- compression parameters (see Table 3), sieve analysis of trial 7 (see Figure 1), Drug release profile of all formulations compared with marketed product (see Figure 2) and drug release of trial 7 in three different media (see Figure 3).
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