The Pharma Innovation Journal 2019; 8(6): 1271-1278

ISSN (E): 2277- 7695

ISSN (P): 2349-8242
NAAS Rating: 5.03 Formulation development and evaluation of immediate
TPI 2019; 8(6): 1271-1278
© 2019 TPI release tablets containing antihypertensive agent
www.thepharmajournal.com
Received: 16-04-2019 amlodipine besylate and valsartan
Accepted: 20-05-2019

Dhananjay Patil Dhananjay Patil, Bhagyashri Sonagra, Rupesh Deore, Anuradha Bhalerao
Department of Pharmaceutics-
K.B.H.S.S Institute of and Vinod Bairagi
Pharmacy Malegaon Nasik,
Maharashtra, India Abstract
The main aim of this study was to formulate the immediate release tablet containing Amlodipine besylate
Bhagyashri Sonagra
as calcium channel blocker and Valsartan as angiotensin II receptor blocker. The advantage of this
Department of Pharmaceutics-
K.B.H.S.S Institute of
combination therapy for hypertension include better blood pressure control by synergistic combination of
Pharmacy Malegaon Nasik, angiotensin II receptor blocker with calcium channel blocker. The objective of the present study was to
Maharashtra, India formulate and evaluate an oral administrable tablet containing Amlodipine besylate and Valsartan by
different granulation technique. The tablets were prepared using different excipients and crospovidone is
Rupesh Deore used as a disintegrant.
Department of Pharmaceutics- The prepared tablets were evaluated for various pre-compression characteristics like angle of repose, bulk
K.B.H.S.S Institute of density, tapped density, Carr’s index, Hausner's ratio and post-compression characteristics like
Pharmacy Malegaon Nasik, appearance, weight variation, hardness, thickness, disintegration, friability, In vitro dissolution study etc.
Maharashtra, India The stability studies were carried out for the optimized batch for three months and it showed no
significant changes in the physicochemical parameters and in vitro release pattern. The present study
Anuradha Bhalerao concludes that combined pill has the potential to improve the management of hypertensive patients with
Department of Pharmaceutics- additional cardiovascular risk factors and reducing prescription costs.
K.B.H.S.S Institute of
Pharmacy Malegaon Nasik,
Maharashtra, India
Keywords: Formulation development, immediate release, antihypertensive agent

Vinod Bairagi Introduction

Department of Pharmaceutics- The release of drug from the conventional tablet dosage form and its absorption from the GIT
K.B.H.S.S Institute of depends upon two main processes: First- the disintegration of tablet into granules and second-
Pharmacy Malegaon Nasik,
Maharashtra, India
dissolution of these granules through the GIT into the blood. Disintegration is the rate-limiting
step in case of highly soluble drugs whereas dissolution is the rate limiting step in case of
drugs with low solubility.
The release of drug from an immediate release dosage form can be achieved by placing the
drug in a layer or coating that is sufficiently thin to allow fast penetration by gastrointestinal
fluid which then leaches the drug at a rapid rate.
Pharmaceutical products designed for oral delivery and currently available on the prescription
and over-the-counter markets are mostly the immediate release type, which are designed for
immediate release of drug for rapid absorption.
Disintegrating agents are substances routinely included in tablet formulations and in some hard
shell capsule formulations to promote moisture penetration and dispersion of the matrix of the
dosage form in dissolution fluids. Super disintegrant improve disintegrant efficiency resulting
in decreased use levels when compared to traditional disintegrants.
Traditionally, starch has been the disintegrant of choice in tablet formulation, and it is still
widely used. For instance, starch generally has to be present at levels greater than 5% to
adversely affect compatibility, especially in direct compression. Drug release from a solid
dosage form can be enhanced by addition of suitable disintegrant [1, 2].
Hypertension, commonly referred to as “high blood pressure”, is a medical condition where
the pressure is chronically elevated, is one of the commonly found diseases, affecting most of
the populations in the world. So, for treating hypertension effectively is main criterion of this
Correspondence
Dhananjay Patil
study. For treating hypertension, commonly used drugs include angiotensin receptor blockers,
Department of Pharmaceutics- ACE inhibitors, α blockers, β blockers, calcium channel blocker, diuretics and combination of
K.B.H.S.S Institute of any of these categories in immediate action required. The advantage of this combination
Pharmacy Malegaon Nasik, therapy for hypertension include better blood pressure control by synergistic combination of
Maharashtra, India
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angiotensin II receptor blocker with calcium channel blocker. Amlodipine besylate and Valsartan and dissolved in
phosphate buffer (pH 6.8). Diluted the solution to 100ml
Materials and Methods with phosphate buffer (pH 6.8). Further 10 ml of this
Materials solution was diluted to 100ml with phosphate buffer (pH
Amlodipine besylate, Valsartan, microcrystalline Cellulose 6.8). The resultant solution was scanned for absorption
dicalcium phosphate and sodium starch glycolate were maxima (λmax) spectro photo metrically between 200nm
received as gift sample from Glochem Pharma, and Roguette and 400nm [5].
Pharma, Mumbai respectively. All other chemicals and 3. Infrared spectroscopy: IR spectrum of drug was
reagents used were of analytical reagent grade. measured in the solid state as potassium bromide (KBr)
mixture. The pure Amlodipine besylate and Valsartan
Methods was previously ground and mixed thoroughly with KBr,
1. Solubility studies: Buffers of different pH were prepared an infrared transparent matrix at 1:100 (sample: KBr)
according to the procedure in IP 2012. 1 g drug was ratio, respectively. The KBr pellets were prepared by
weighed and transferred to 200 ml volumetric flask. 100 applying 10-12 metric ton of pressure in a motorized
ml of each buffer was added to the respective flasks and pellet press (Kimaya engineers, India). The pellets were
flasks were placed on mechanical shaker adjusted at 150 then scanned over a wave range of 4000 – 400 cm-1 and
rpm for 24 hours. After 24 hours, each solution was spectra was obtained by using a Shimadzu –IR Prestige-
filtered using 0.45μm nylon filter. The solubility of the 21 spectrophotometer [5].
drug in different buffers was determined initially and at
the end of 24 hours after shaking [4]. Formulation of tablets
2. UV spectroscopy: Accurately weighed about 100 mg of

Table 1: Formulation of tablets by different methods

Sr. no. Ingredients Quantity (mg/tab)
By Direct compression (F1) By slugging approach (F2) By wet granulation (F3)
Dry mix I Dry mix II
Dry mix
1 Amlodipine besylate 10.00 10.00 10.00 -
2 Valsartan 160.00 160.00 - 160.00
3 Microcrystalline cellulose 75.25 71.00 87.00 85.50
4 Crospovidone 30.00 30.00 - 30
5 Colloidal silicon dioxide - 1.50 - -
6 Magnesium stearate - 3.00 - -
7 Pregelatinised Starch - - 15.00 -
8 Dicalcium phosphate - - 79.50 -
Granulation make by water
Prelubrication
9 Crospovidone 10.00 12.00
19.00
10 Colloidal silicon dioxide 0.75 10.00
Lubrication
11 Magnesium stearate 3.00 3.00 3.00
Total weight 300 300 490
Coating
12 Opa. dry yellow 9.00 9.00 14.70
13 Water qs qs qs
Targeted weight 309 309 504

Evaluation Bulk density was calculated by following formula,

A) Physical evaluation of tablet blend
Angle of repose [8] Bulk density = M/Vo
Angle of repose was determined by measuring the height of
the cone of the powder and calculating the angle of repose Where,
from following formula. M = mass of powder
Vo = apparent unstirred volume
tanθ = h/r
Mass of powder ( )
Where, Bulk Density (g/ml) =
bulk volume of the powder (Vo)
h = height of cone
r = radius of powder cone Tapped density [8]
The tapped density was determined by pouring 20 gm sample
Bulk density [8] through a glass funnel into a 100 ml graduated cylinder. The
Bulk density was determined by pouring gently 20 gm of cylinder was tapped from height of 2 inches until a constant
sample through a glass funnel into a 100 ml graduated volume obtained. Volume occupied by the sample after
cylinder. The powder was carefully leveled without tapping was recorded and tapped density was calculated by
compacting it and the apparent volume was measured (Vo). following formula,
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Weight of powder
Tapped Density (g/ml) =
Tapped volume of the powder

Carr’s index [8]

It is also one of the simple methods to evaluate flow property Percentage weight loss was calculated. A loss of less than 0.5
of a powder by comparing the bulk density and tapped to 1 % in weight was generally acceptable.
density. Carr’s index is also known compressibility index and
which was calculate as, Disintegration study [9]
The process of breakdown of a tablet into smaller particles is
Tapped density − Bulk density called as disintegration. The disintegration time of a tablet
Carr ′ s index = × 100
Tapped density was determined using disintegration test apparatus. The
disintegration test was carried out using USP disintegration
Hausner’s ratio [8] test apparatus-II. Tablets were placed individually in each
It provides an indication of the degree of densification that tube of disintegration test apparatus and discs were placed
could result from vibration of feed hopper. Lower the over each tablet. Distilled water (900 ml) was used as the
Hausner’s ratio better is the Flow ability. medium which is maintained at 37 ± 2°C and the time taken
for each tablet to disintegrate completely was recorded.
Tapped density
Hausner ratio 
Bulk density Dissolution study [10]
In-vitro release profile studies of immediate release Tablets
B) Evaluation of tablets were carried out using USP type II dissolution apparatus.
Weight variation test [9] Tablet was kept in a flask having paddle rotated at 75 rpm.
Twenty tablets of each formulation were weighed individually The medium used for release rate study was 900 ml 6.8 pH
using an electronic balance. The average weight was phosphate buffer. During the course of study whole assembly
calculated and individual tablet was compared with the was maintained at 37˚C ± 0.5oC and 5 ml sample was
average value and the deviation was recovered. withdrawn at time interval 5, 10, 15, 30 and 45 min. The
samples were analyzed by HPLC for calculating the amount
Dimension of drug released.
Compressed tablets were selected randomly from each batch
and thickness, length was measured by using digital vernier Stability study [18, 19]
caliper. Thickness was measured in mm for all batches. The formulation for stability testing was selected on the basis
of optimization results. The batch with optimum dissolution
Hardness [9] results (Batch F3) was selected for stability purposes.
Hardness of the tablets was measured using Pfizer hardness According to ICH guidelines Accelerated stability studies are
tester. The hardness was measured in Newton (N) for tablets testing at 400C±20C/75±5%RH for a specific period up to 3
of each batch. months. The tablets were checked before stability studies for
parameters like physical appearance, hardness, assay, weight
Friability test [9] variation, and % drug release of the drug.
Friability test is performed to assess the effect of friction and
shocks, which may often cause tablet to chip, cap or break. Results and Discussion
Roche friabilator was used for the purpose. (according to USP Solubility studies
monograph 1216 - tablets with a unit weight equal to or less The solubility of amlodipine besylate in water, 0.01N HCl,
than 650 mg, take a sample of whole tablets corresponding as pH 1.2 buffer, pH 4.5 acetate buffer and pH 6.8 phosphate
near as possible to 6.5 gm.) Pre-weighed sample of tablets buffer was reported as 757.75, 1823.77, 1724.38, 1055.97 and
was placed in the friabilator, which was then operated for 100 1949.42 respectively. From the above discussion, it is
revolutions/min. Tablets were dusted and reweighed. The concluded that the amlodipine besylate is sparingly soluble in
percentage friability was calculated by, pH 6.8 phosphate buffer solution.

Fig 1: Solubility in ml/g of amlodipine besylate

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The solubility of Valsartan in water, 0.01N HCl, pH 1.2 respectively. From the above discussion, it is concluded that
buffer, pH 4.5 acetate buffer and pH 6.8 phosphate buffer was the Valsartan is sparingly soluble in pH 6.8 phosphate buffer
reported as 649.61, 741.07, 568.65, 613.96 and 1302.8 solution.

Fig 2: Solubility in ml/g of Valsartan

UV spectroscopy

Table 2: Preparation of standard calibration curve of amlodipine besylate (λmax364)

Sr. No Conc. ppm Absorbance
1 0 0
2 5 0.153
3 10 0.234
4 15 0.356
5 20 0.542
6 25 0.648

Fig 3: Calibration curve of Amlodipine besylate in pH 6.8 phosphate buffer

Table 3: Preparation of standard calibration the curve of valsartan (λmax249)

Sr. No Conc. ppm Absorbance
1 0 0
2 5 0.216
3 10 0.324
4 15 0.433
5 20 0.541
6 25 0.649

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Fig 4: Calibration curve of Valsartan in pH 6.8 phosphate buffer

Infrared spectroscopy peak at 721.30 shows C-Cl bending, 2852.72 shows –C-H
Amlodipine besylate: IR spectra are shown in fig.6. The pure stretching, 2920.23 shows C-H stretching and 1269.16 shows
amlodipine besylate showed various characteristic peaks at C-O stretching.
721.30, 2852.72, 1303.88, 2920.23 and 1269.16 cm-1. The

Fig 5: IR spectra of amlodipine besylate

Valsartan: IR spectra are shown in fig.7. The pure drug an aromatic compound may be present, 2982.88 shows C-H
Valsartan showed various characteristic peaks at 2982.88, stretching, 1479.40 shows CH2bending and 1730.15 shows
1730.15, 1479.40 and 759.92 cm-1. The peak at 759.92 shows CO stretching.

Fig 6: IR spectra of Valsartan

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Table 4: Physical evaluation of Tablet blend

Sr. No. Parameters F1 F2 F3
Angle of Repose 44 47 39
Tapped density(g/ml) 0.521 0.646 0.785
Bulk density (g/ml) 0.373 0.466 0.67
Compressibility Index (%) 26.8 27.9 17
Hausner's ratio 1.32 1.36 1.18

Table 5: Evaluation parameters of Tablets

Trial F1 F2 F3
Targeted wt per tablet (mg) 309 309 504
Thickness (mm) 5.17 5.19 5.6
Length (mm) 12.97 12.92 16.06
width (mm) 6.97 6.92 8.06
Hardness(N) 168 120 170
Disintegration time 2min 20sec 1min 59sec 1min 32sec
99.2% 98.5% 99.5%
Assay (%) Amlodipine besylate valsartan
101.2% 100.1% 101.9%

Evaluation of tablets profile, the better drug release observed for amlodipine
Dissolution profile besylate and Valsartan by wet granulation method. Immediate
The influence of different granulation method on the release tablets prepared by using wet granulation showed the
dissolution of amlodipine besylate and valsartan from tablets drug release 88.2% for amlodipine besylate and 98.8% for
is shown in fig.8 and fig.9 respectively. From the dissolution valsartan.

Table 6: Dissolution profile for amlodipine besylate

Time F1 F2 F3
0 0 0 0
5 38.2 37.8 49.8
10 47.7 51.6 58.6
15 59.2 56.6 69.4
20 64.9 59.1 79.8
30 72.4 63.2 85.6
45 78.1 65.5 87.9
60 84 70.9 88.2

Fig 7: Dissolution profile of development trials. (For amlodipine besylate)

Table 7: Dissolution profile for valsartan

Time F1 F2 F3
0 0 0 0
5 90.5 91.3 94.3
10 91.7 93.9 97.6
15 92.3 95.1 97.7
20 92.8 95.5 97.9
30 95.02 97.8 98.4
45 95.3 98.1 98.6
60 97.5 98.3 98.8

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Fig 8: Dissolution profile of development trials. (For Valsartan)

Stability study

Table 8: Stability batch observation

Storage condition Room Temperature 40 0C/75%RH
Initial 3 Months
Formulation Batch F3 F3
Parameters - -
Appearance Light Yellow Colored Light Yellow Colored
Hardness(N) 130 130
Width(mm) 8.05 8.05
Thickness(mm) 5.51 5.53
Length(mm) 16.05 16.05
Assay of Amlodipine besylate 98.23% 98.76%
Assay of Valsartan 99.45% 99.41%

Table 9: Stability Dissolution Profile of Batch F3

Sr. no. Time Initial 3 months (F3 Batch)
Amlodipine besylate Valsartan Amlodipine besylate Valsartan
1. 0 0 0 0 0
2. 5 49.8 94.3 50.1 93.2
3. 10 58.6 97.6 57.2 97.4
4. 15 69.4 97.7 71.9 97.6
5. 20 79.8 97.9 77.4 97.9
6. 30 85.6 98.4 84.3 98.5
7. 45 87.9 98.6 86.4 98.6
8. 60 88.2 98.8 87.9 98.8

Fig 9: Stability Dissolution Profile of Batch F3

Footnotes: drug A- Amlodipine besylate drug B- Valsartan

Conclusion granulation is the key process in the production. Granules of

In this work, successfully developed immediate release tablet different formulations were evaluated for pre-compression
of Amlodipine besylate and Valsartan in combination. In this parameters which indicate good flow properties of the
study, the tablet prepared by the wet granulation method and granules. The prepared tablets of different formulation were
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evaluated for post-compression parameters. The in vitro drug manufacturing. Available from http/www.pharmapedia.
release characteristics were studied using USP dissolution com.
apparatus type II for both the Amlodipine besylate and 15. Parikh DM. ‘Theory of granulation Handbook of
Valsartan indicated that the formulation F3 was the optimized Pharmaceutical Granulation Technology‘, 2nd edition
formulation. publishing house, Bombay. 2005, 7-33p.
The optimized tablet formulation F3 showed satisfactory 16. Guidance for industry. Bioavailability and
results in several in vitro tests also optimize batch tablets were bioequivalence studies for orally administered drug
stable and retain their pharmaceutical properties over a period products –general consideration, US Department of
of 3 months at 400C /75% RH. Health and human services FDA, CDER.
17. Bansal M, Sai Madhav Reddy K. 'Formulation and
Acknowledgment evaluation of IR Tablets of Zaltoprofen', International
The authors are thankful to Dr. Dhananjay Patil for their Journal of pharmaceutical and Biosciences. 2011:
support. We are also thankful to Glochem pharma and 2(4):1230-1235.
Roguette pharma for providing Amlodipine besylate, 18. ICH guidelines Q1A (R2), guidelines for industry,
Valsartan, microcrystalline cellulose Dicalcium phosphate stability testing of new drug substance and products
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