Original Research Manuscript
Article History: Int.J.Ph.Sci, May-August 2009; 1(1):132-139 Received on: 09-08-09 Available online from: www.ijps.info Accepted on: 02-09-09 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.
INTRODUCTION
Lisinopril Dihydrate, an ACE inhibitor [1] has half life about 12 hrs [2]. So, it is not suitable candidate for controlled release formulation. Tablet dosage form is preferable because other than tablet dosage form not having good shelf life in case of Lisinopril due to its degradation, which imparts the impurity in formulation.
Seven formulations were prepared by wet granulation.
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Di-calcium phosphate dihydrate used because it reduces impurity in final formulation [3, 4] and Maize starch plays dual role as binder and disintegrant. Trial 7 among these formulations shows better results.
Mixing and agglomeration of particles in wet granulation have been studied extensively [5, 6]. The optimal endpoint can be thought of as the factor affecting a number of granule properties. With so many variables involved in a granulation process, numbers of researchers studied different factors in attempt to arrive at an optimum response [7-15]. The final goal of any
granulation process is a solid dosage form, such as tablets. Therefore, when optimizing a granulation process, it stands to reason to include, alongside the end-point factor, the tablet processing parameters [7].
MATERIALS AND METHODS
Materials used in formulation of tablets were Lisinopril dihydrate (Alkem Laboratories Ltd.), Di-calcium phosphate dihydrate (Universal impex corp.), MCC 101, Pearlitol 25C, Maize starch, Red iron oxide and Magnesium stearate (S.D. fine chemicals).
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
sieve mixed in rapid mixer granulator (RMG) for 15 minutes. Sift starch for paste through 100 mesh sieve and prepare the 10% paste as binder.
Granulate for 10 minutes in RMG (75 RPM) along with chopper on, with racking after 5 min., dry the wet mass at 60°C till the LOD reaches less than 4.0 % w/w. Rasp the dried granule through 30 mesh sieve. Sift extra- granular material through 60 mesh sieve. Mix the rasped granule and sifted dried starch in blender for 20 minutes. Add sifted magnesium stearate for 5 minutes.
Compressed the above blend obtained in with 8mm punches.
Table 1: Formulation of Lisinopril dihydrate tablets for 20 mg
LD- Lisinopril Dihydrate, DCPD- Di Calcium Phosphate Dihydrate, P25C- Pearlitol 25C, MCC101- Microcrystalline Cellulose, MS- Maize Starch, RIO- Red Iron Oxide, SP- Starch Paste, DMS- Dried Maize Starch, MSt- Magnesium Stearate.
EVALUATION OF PRECOMPRESSION
PARAMETERS [16]
Loss on drying
0.5g of sample was accurately weighed and the powder was kept in a Mettler Toledo apparatus for 5 min. at 105ºC and the moisture content was calculated.
Bulk density
Bulk density of Lisinopril was determined by pouring gently 25 g of sample through a glass funnel into 100
ml graduated cylinder. The volumes occupied by the samples were recorded. Bulk density was calculated.
Tapped density
Tapped density was determined by using Electrolab density tester, which consists of a graduated cylinder mounted on a mechanical tapping device. Volume was noted against pre-weighed sample and taped density is calculated using following formula.
Tapped density = Wt. of sample in gm / Tapped
Intra-Granulation (mg/tab)
Binder (mg/tab)
Extra- Granulation (mg/tab)
Trials LD DCPD P25C MCC101 MS RIO SP DMS MSt
1 20 97 40 45 1 5 - 2
2 20 102 40 10 20 1 5 10 2
3 20 102 40 - 30 1 5 10 2
4 20 101 40 - 10 1 5 30 3
5 20 111 40 - 20 1 5 10 3
6 20 115 36 - 20 1 5 10 3
7 20 96 36 - 36 1 4 14 3
Powder flow characteristics
Compressibility index and the closely related Hausner ratio have become the simple, fast, and popular methods of predicting powder flow characteristics.
Both the compressibility index and the Hausner ratio were determined by following formula.
Carr’s Index = [(Tapped Density - Bulk Density) / Tapped Density] ×100,
Hauser’s Ratio = Tapped Density / Bulk Density.
Sieve analysis
The procedure involves the Electromagnetic Sieve shaking of the sample through the series of successively arranged sieves (sieve no.20, 30, 60, 80, 100 and receiver), and weighing of the portion of the sample retained on each sieve and calculate percentage retained on each sieve.
Table 2: Pre compression parameters of all trials
Loss on drying (%w/w) Trial No.
Dried Granules Final blend
Bulk density (gm/ml)
Tap density (gm/ml)
Carr's index (%)
Hauser’s ratio
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
EVALUATION OF POSTCOMPRESSION
PARAMETERS [16]
Weight variation test
Twenty tablets were weighed and the average weight was calculated. The individual weight was compared with the average weight.
Uniformity of thickness
Ten tablets were picked from formulations randomly and thickness was measured individually using
“Vernier-caliper (Mitutoyo, Japan)”. It is expressed in millimeter and average with Standard deviation (SD) was calculated.
Hardness test
Hardness indicates the ability of a tablet to withstand mechanical shocks while handling. The hardness of the tablets was determined using “Dr. Schleuniger hardness tester”. It is expressed in Newton (N). Ten tablets were randomly picked and hardness of the same tablets from each formulation were determined .The average with SD was calculated.
Friability test
The friability of tablets was determined using “Roche Friabilator”. It is expressed in percentage (%). Twenty tablets were initially weighed (W initial) and transferred into friabilator. The friabilator was operated at 25 rpm for 4 minutes. The tablets were weighed again (W final). The % friability was calculated by,
% Friability = (Wt. initial – Wt. final / Wt. initial) x 100 Disintegration time [17]
It is determined by using USP device which consist of 6 glass tubes that are 3 inches long, open at one end and held against 10 mesh screen at the bottom end of basket rack assembly. To test for disintegration time, one tablet is placed in each tube and the basket arch is positioned in a1 liter beaker of water at 37 0C ± 2 0C.A standard motor driven device is used to move the basket assembly up and down.
Assay
Assay was done by HPLC method using solvent mixture of 1 volume of methanol and 4 volumes of water and procedure done as per United State Pharmacopoeia.
In vitro drug release study
Dissolution study of tablet performed in USP II (paddle) dissolution test apparatus (Electrolab TDT O8L) using 900ml of 0.1N HCl as an official dissolution media. The tablet was loaded into an each
basket of dissolution apparatus; the temperature of dissolution media was maintained at 37±0.5 0C with stirring speed of 50 rpm throughout the study. Aliquots of dissolution media containing 10 ml of samples were withdrawn at time interval of 5, 10, 15, 20, 30 minutes and 5 ml of fresh dissolution media maintained at the same temperature was replaced after each withdrawal.
The samples were analyzed by HPLC at 215 nm.
Optimization of Granulation Time
For this study we take 3 batches of big size i.e. 6000 tablets. Each batch was subject to granulation in Rapid Mixing Granulator with impeller at speed 150 RPM for 12min, 6min and 3min respectively and with chopper at speed 2500 RPM for 12min, 6min, 3min respectively.
After granulation their all micromeritics, in process as well as dissolution test was done for all three batches as per official standards and compare drug release with marketed product [16]. Environmental condition, machine speed, impeller tip speed and relative swift volume should be same for all 3 batches during study.
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)
Assay (%)
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
Figure 1: Sieve analysis study of final trial Figure 2: Comparative drug release profile of all formulations.
Sieve Analysis of Final Trial
30#
3% 60#
12% 80#
4%
100#
32%
Base 49%
20#
0.3%
20# 30# 60# 80# 100# Base
Figure 3: Dissolution profile of trial 7 in Figure 4: Graphical representation of effect
three different media of extent of granulation on particle size distribution
Effect on Particle Size Distribution
0 10 20 30 40 50 60 70
20# 30# 40 # 60 # 80 # 100 # BASE
Sieve Size
% Retained Material
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
0 10 20 30 40 50 60 70 80 90 100
0 5 10 15 20 25 30
Time in minutes
Cumulative % drug release
Marketed product curve High granulation curve Medium granulation curve Low granulation curve
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
Granulation
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
Granulation In RMG
Chopper Speed( rpm) 2500 2500 2500
Environmental Conditions 25ºC/55%RH 25ºC/55%RH 25ºC/55%RH
TD (gm/ml) 0.769 0.6 0.8
BD (gm/ml) 0.625 0.483 0.615
CI (%) 18.73 19.50 23.13
HR 1.23 1.24 1.3
Micrometrics of lubricated granule
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
60 # 30.3 12 8.5
80 # 6 3.5 13.06
100 # 6.75 26 3.37
Sieve Analysis% Retained
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
Hardness (N)±%SD 75±2.8 75±2.34 75±4.6
Friability (100rtn’s) 0.04 0.06 0.06
Compression Parameters
D.T (min.) 3 3 2
Minutes Marketed product
5 75.2 65.9 86.61 91.1
10 91.68 75.01 96.03 98.1
15 97.17 85.25 99.1 99.4
DR Profile Innovator Vs Trial at 0.1N
HCl,50RPM,Paddle, 900ml volume
30 99.57 91.3 100.46 100.9
F1- Value 12.71 9.41 13.39
F2 Value 48.37 62.83 55.59
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).
Result shows granules prepared were having good flow characteristics, in trial 4 shows very fast initial release in early 5 minutes but it does not matches with release pattern of marketed product, it was due to more quantity of starch in extra-granular stage. Among seven formulations, trial 7 shows good results so, sieve analysis and drug release in 3 different media was done, it show better results (see Figure 3).
Micromeritics of granules and in process as well as drug release study was done for all three batches. There were measurable variations found in particle size distribution as well as drug release profile when compared (see Table 4, Figure 4, 5).
CONCLUSIONS
Present finding shows that extent of granulation is very important factor to be considered when formulate tablet dosage form in scale up. There were mensurable deviations observed in Lisinopril dihydrate tablet evaluation parameters like particle size distribution as well as drug release by changing the granulation time during formulation process. Mixing time, compression force and other can also some important variables which can be considered, depend upon formulation and excipients.
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