Design andvevaluation of enteric coated tablets of Ramipril

1. DESIGN AND EVALUATION OF ENTERIC COATED TABLETS OF
RAMIPRIL
Sonali S. Suryawanshi*, Dr.A.B. Gangurde, Dr. V.A. Bairagi
email address : sur.sonal97@gmail.com
Department of Pharmaceutics, K.B.H.S.S. Trust’s Institute of pharmacy,
Bhaygaon road, Malegaon camp, Malegaon, Nashik-423105
email address : sur.sonal97@gmail.com
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2. Abstract
The present study was an attempt to formulate and evaluate enteric coated tablet of Ramipril
for the treatment of hypertension. In the present study the immediate release core tablets
were prepared by direct compression by using various proportions of different
superdisintegrants. The optimized core tablet were then coated with pH sensitive polymers
like Eudragit L-100, Cellulose Acetate Pthalate(CAP) in different concerntration. The
prepared tablets were evaluated in terms of their physical characteristics and in-vitro release
study. 2.5% seal coating on core tablets was optimized and 9% enteric coating on seal coated
tablets was performed using Cellulose Acetate Pthalate (60%), triethyl citrate (10%) and
IPA:DCM (60:40) EC5 which gives the highest dissolution release profile.
Keywords: Ramipril, Enteric coating, Eudragit L-100, Cellulose Acetate Pthalate,
Introduction:
Ramipril is an angiotensin converting Enzyme Inhibitor, Antihypertensive agent. It is
chemically(2S,3aS,6aS)-1-[(2S)-2-[[(2S)-1-ethoxy-1-oxo-4phenylbutan-2-yl]amino]
propanoyl] 3,3a, 4, 5,6,6a-hexahydro-2H cyclopenta [d] pyrrole-2-carboxylic acid. Ramiprilat
is an active metabolite of Ramipril,competes with angiotensin I for binding at the angiotensin
converting enzyme,blocking the conversion of angiotensin I to angiotensin II. As angiotensin
II is a vasoconstrictor and a negative feedback mediator for renin activity, lower
concerntration results in decrease in blood pressure and an increase in plasma renin. Ramipril
is used in the treatment of hypertension, post myocardial infarction, cardiac stroke, and
cardiovascular diseases. It is a BCS class –II, pKa 5.2, drug. Elimination half life is 13-17hr.
The absorption of the Ramipril after oral administration is 50%-60%. The Ramipril having
poor water solubility which results in the low bioavailability i.e.28% The common side
effects arise after administrattion of Ramipril are vomiting, nausea, headache, dizziness,
vertigo.To solve the above cited problems, enteric coated tablets of Ramipril is better
alternative. The Enteric Coated Tablets have potential advantages over conventional dosage
forms, with their improved patient compliance; convenience bioavailability and rapid onset of
action had drawn the attention of many manufacturers over a decade. It avoid side effects like
nausea, vomiting, headache, dizziness by enteric coating and provides fast dissolution by
preparing immediate release tablets.
Material and methods:
Materials:
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3. Ramipril was obtained from Ajanta Pharma, Aurangabad as a gift sample. Sodium starch
glycolate, Crosscarmellose sodium and Crospovidone used as superdisintegrants obtained
from Research Lab Fine Chem Industry. Eudragit L-100, Cellulose Acetate Pthalate used as
pH sensitive polymer obtained from Pallav chemicals.
Methods:
Preparation of Immediate release tablet
Immediate release tablets of Ramipril were formulated by incorporating Ramipril
superdisintegrants like sodium starch glycolate, croscarmellose sodium,and crospovidone ,
Avicel, Lactose, Talc etc.were prepared by direct compression. Initially the core tablet
excipients were dry blended for 10 min, followed by the addition of talc. The powder
components were further blended for 5 min. Direct compression of tablet was done in rotary
compression tablet machine (Rimek mini press I)
Table 1.1 Formulation development of Immediate release tablet of Ramipril
Sr.
No.
Name of
Ingredients
Number of Formulation
(Qty in mg)
F1 F2 F3 F4 F5 F6 F7 F8 F9
1 Ramipril 20 20 20 20 20 20 20 20 20
2 Croscarmellose 7.5 15 22.5 - - - - - -
3 Cross povidone - - - 7.5 15 22.5 - - -
4 Sodium Starch
glycolate
- - - - - - 7.5 15 22.5
5 Lactose 94 86.5 79 94 86.5 79 94 86.5 79
6 Avicel pH101 15 15 15 15 15 15 15 15 15
7 Talc 6 6 6 6 6 6 6 6 6
8 Sodium saccharin 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5
9 Aerosil 6 6 6 6 6 6 6 6 6
Total weight 150 150 150 150 150 150 150 150 150
Evaluation of powder blend:
Angle of repose
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4. The angle of repose of powder blend was determined by the funnel method. The accurately
weighed powder blends were taken in the funnel. The height of the funnel was adjusted in
such a way the tip of the funnel just touched the apex of the powder blend. The powder blend
was allowed to flow through the funnel freely on to the surface. The diameter of the powder
cone was measured and angle of repose was calculated using the following equation (Cooper
and Gun, 1986). tan𝜃𝜃 = h/ 𝑟𝑟
Where, h and r are the height and radius of the powder cone respectively.
Bulk density and tapped density A quantity of 2gm of powder blend from each formula,
previously shaken to break any agglomerates formed, was introduced into 10ml measuring
cylinder. After that the initial volume was noted and the cylinder was allowed to fall under its
own weight on to a hard surface from the height of 2.5cm at second intervals. Tapping was
continued until no further change in volume was noted. Bulk density (ρB) and tapped density
(ρT) were calculated using the following equations (Aulton and Wells, 1998):
ρB= Weight of the powder blend/Untapped Volume of the packing
ρT=Weight of the powder blend/Tapped Volume of the packing
Compressibility Index The Compressibility Index of the powder blend was determined by
Carr’s compressibility index using the formula (Martin, 2001).
Carr's index (%) = 𝜌𝜌𝜌𝜌 −𝜌𝜌𝜌𝜌 𝜌𝜌𝜌𝜌 ×100
Hausner’s ratio The Hausner’s ratio is a number that is correlated to the flowability of a
powder or granular material. The ratio of tapped density to bulk density of the powders is
called the Hausner's ratio. It is calculated by the following equation (Martin, 2001).
H = 𝜌𝜌𝜌𝜌 /𝜌𝜌𝜌𝜌
Evaluation parameters of core tablets
Appearance Twenty tablets of each formulation were taken to check any discoloration or
degradation of drug in the tablets by visual method. If any discoloration or black spots
appears, it shows the degradation or decomposition of the drug in the tablet formulation.
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5. Weight variation test To study weight variation, twenty tablets of the formulation were
weighed using a Sartorius electronic balance and the test was performed according to the
official method.
Hardness The hardness of five tablets was determined using the dial type hardness tester and
the average values were calculated.
Thickness The thickness and diameter of the tables was determined by using vernier calipers.
Five tablets were used, and average values were calculated.
Friability The friability of ten tablets was measured by Roche friabilator and average values
were calculated.
Drug Content:
From each batch of prepared tablets, ten tablets were collected randomly and powdered. A
quantity of powder equivalent to 200 mg was transferred to 250 ml volumetric flask. 50 ml of
pH 6.8 phosphate buffer was added and then the solution was subjected to Sonication for a
period of about 30 min. The solution was made up to 250 ml with 6.8 phosphate buffer.The
solution was filtered and suitable dilutions were prepared with pH 6.8 phosphate buffer and
then drug content was estimated by recording the absorbance at 210 nm by using UV-visible
spectrophotometer.
Disintegration time:
Disintegration test of core tablets was carried out in the six tablet basket rack USP
disintegration apparatus. One tablet was introduced into each tube of the basket rack
assembly of the disintegration apparatus without disc. The assembly was positioned in the
beaker containing disintegration media maintained at 37±2°C
In vitro dissolution studies The in vitro dissolution study of uncoated tablets of Ilaprazole
was determined using USP dissolution testing apparatus II (paddle type). The dissolution test
was performed using 900ml of 8.0 pH phosphate buffer, at 37±0.5°C and 100rpm. A sample
(10ml) of the solution was withdrawn from the dissolution apparatus at regular interval for 60
minutes, and the samples were replaced with fresh dissolution medium. The samples were
filtered through a 0.45μm membrane filter and absorbance of these solutions was measured at
240nm using UV/Vis double beam spectrophotometer (LABINDIA). Cumulative percentage
of drug release was calculated using the equation obtained from a standard curve.
Table 2: Formula for Optimization of enteric coating polymer
Ingredients EC1 EC2 EC3 EC4 EC5 EC6
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6. Eudragit L 100 50 60 70 - - -
Cellulose Acetate
Pthalate
- - - 50 60 70
Triethyl citrate 10 10 10 10 10 10
Talc 40 30 20 40 30 20
Ferric oxide yellow 0.3 0.3 0.3 0.3 0.3 0.3
IPA : DCM 60:40 60:40 60:40 60:40 60:40 60:40
Coating of tablets:
Coating of tablets was done by dip coating. Enteric Coating of tablet was performed using
two different polymers, Eudragit L 100 and CAP (Cellulose Acetate Pthalate) using three
different concentrations 7%, 9% and 11%, by dip coating. Effect of these two polymers was
compared. Enteric coating was performed on core tablets.Solvent ratio of isopropyl alcohol
(IPA): dicloro methane (DCM) (60:40) was optimized based on its coating effectiveness.
Evaluation parameters of enteric coated tablet:
a. Weight variation test:
To study weight variation, twenty tablets of the formula-tion were weighed using a Sartorius
electronic balance and the test was performed according to the official method.
b. Hardness:
The hardness of five tablets was determined using the pfizer hardness tester and the average
values were calculated.
c. Thickness and diameter :
The thickness and diameter of the tables was determined by using vernier calipers. Five
tablets were used, and average values were calculated.
d. Friability :
The friability of ten tablets was measured by Roche friabilator and average values were
calculated.
e. Percentage weight gain
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7. % Weight gain defined by difference between weight of tablets after coating (Wta) and
weight of tablets before coating (Wtb) divided by weight of tablets before coating. It was
calculated by following equation.
%Weight gain = (𝑊𝑊𝑊𝑊𝑊𝑊‐𝑊𝑊𝑊𝑊𝑊𝑊)/𝑊𝑊𝑊𝑊𝑊𝑊×100
6.12. In vitro Dissolution Studies
Drug release studies were carried out using a USP type II dissolution test apparatus at 100
rpm for 2 hr in 0.1 N HCl (900 ml) maintained at 37±0.5°C. 10 ml of sample was taken and
sample was analyzed using UV spectrophotometer at 240 nm. Then the dissolution medium
was replaced with pH6.8 phosphate buffer (900 ml) and tested for drug release for 1 hr at
same temperature and same rotation speed. After 10, 20, 30, 45 and 60 minutes, 10 ml of the
samples were taken out and 10 ml volume of fresh phosphate buffer pH 6.8 was added to
keep the volume of dissolution medium constant and sample was analyzed using UV
spectrophotometer at 210 nm.
Table No: 3 Flow properties of powder
Formulation
Bulk
Density
(gm/cm2)
Tapped
Density
(gm/cm2)
Carr’s
Index
(%)
Hausner
Ratio
Angle of
Repose (0)
F1
0.3412±
0.013
0.5601±
0.062
34.8466±
1.831
1.6472±
0.238
21.80± 1.22
F2
0.3412±
0.013
0.5265±
0.088
33.83± 1.626
1.5493±
0.304
23.26± 0.87
F3
0.3002±
0.01
0.5185±
0.032
20.91± 4.816
1.7296±
0.146
26.56± 0.84
F4
0.3442±
0.015
0.5033±
0.038
26.92± 1.880
1.3723±
0.0890
23.42± 0.73
F5
0.3281±
0.031
0.4907±
0.069
31.82± 2.201
1.5111±
0.2987
22.17± 1.42
F6
0.3001±
0.031
0.5007±
0.024
15.64± 1.701
1.2111±
0.2231
28.36± 0.46
F7
0.3251±
0.01
0.4804±
0.070
21.98± 2.01
1.3411±
0.2365
28.81± 1.26
F8
0.3201±
0.021
0.5288±
0.069
13.79± 0.201
1.2346±
0.2456
23.48± 1.60
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8. F9
0.3011±
0.071
0.5124±
0.069
33.75± 1.721
1.2903±
0.2389
25.52± 1.20
Table No: 4.Evaluation Parameters of Immediate Release Tablets
Formulation
Weight
variation
mg±SD
Hardness
(Kg/cm2)
±SD
Thickness
(mm)
±SD
Diameter
(mm)
±SD
Friability
(%)
Drug
content
(%)
F1 150.00± 1.153
3.4±
0.2
3.5±0.10 7.0±0.12 0.2811
96.26±
0.230
F2 149.35± 1.758
3.3±
0.26
3.2±0.12 7.25±0.15 0.1696
99.85±
3.602
F3 151.65± 1.094 3.2± 0.25 3.4±0.25 7.1±0.2 0.3251
94.62±
5.445
F4 149.95 ± 2.064
2.6±
0.2
3.5±0.17 7.2±0.13 0.1801
97.98±
1.876
F5 149.5± 2.212
3.0±
0.26
3.6±0.31 7.3±0.17 0.3032
98.67±
0.933
F6 151.12± 2.111
2.9±
0.26
3.4±0.31 7.20±0.17 0.4032
96.95±
1.876
F7 148.00± 2.145
3.4±
0.26
3.30±0.19 7.15±0.14 0.4102
93.25±
3.876
F8 149.99± 1.452
3.0±
0.26
3.5±0.4 6.8±0.18 0.4703
98.98±
1.876
F9 150.15± 1.254
3.2±
0.26
3.7±0.8 6.9±0.11 0.4302
97.00±
2.82
Table no.7.19 Evaluation of enteric coated tablets
Formulation
Weight
variation
mg±SD
Hardness
(Kg/cm2)
±SD
Thickness
(mm)
±SD
Diameter
(mm)
±SD
Friability
(%)
Drug
content
(%)
EC1
163.00±
1.153
6.4±
0.2
3.92±0.10 7.0±0.12 0.2811
94.26±
0.230
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9. EC2
162.35±
1.758
6.3±
0.26
3.94±0.12 7.25±0.15 0.1696
95.05±
3.602
EC3
164.65±
1.094
6.2± 0.25 3.92±0.25 7.1±0.2 0.3251
95.62±
5.445
EC4
162.95±
2.064
6.6±
0.2
3.93±0.17 7.2±0.13 0.1801
97.98±
1.876
EC5 163.5± 2.212
6.0±
0.26
3.6±0.31 7.3±0.17 0.3032
98.67±
0.933
EC6
165.12±
2.111
5.9±
0.26
3.4±0.31 7.20±0.17 0.4032
98.95±
1.876
Figure 1: In-vitro drug release profile of formulations EC1 to EC6 of Ramipril enteric coated
tablets.
RESULT AND DISCUSSION
The results of evaluation of powder blend formulations F1 to F9 mentioned in tableno.3,
suggests that it has fair to passable compression property and moderate flow property. The
core tablets were evaluated for various parameters and their result are mentioned in table 4.
All the batches of core tablet were good in appearance and devoid of any visual deformity.
Weight variation data of all trial batches indicated that they were in range of official
standards and no significant difference between individual weights of tablets from the
average value. Hardness of all the tablets was kept between 6-8 kp. Friability test for direct
-20
0
20
40
60
80
100
120
0 50 100 150 200
%
cumulative
drug
release
Time (min)
The graph of % cumulative drug release Vs Time (min)
EC1
EC2
EC3
EC4
EC5
EC6
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10. compression was in the range of less than 1%. All the batches pass in content uniformity test
as per official requirement. The assay results showed that the percentage drug content was
found to be in the range of 93% to 99% for all the four formulations, which is acceptable as
per the limits prescribed in I.P.
Entric coating was performed using Eudragit L 100 was used in 50%, 60% and 70% w/w in
batches EC1, EC2, EC3 respectively and CAP was also used in same amount respectively in
batches EC4, EC5 and EC6. Solvent IPA:DCM was used in 60:40 ratio to prepare coating
solution. 9% enteric coating was performed in all batches.
Enteric coated tablet of all batches pass in weight gain test. Enteric coated tablet of batches
EC1 and EC4 failed in official disintegration test, while other batches of tablet passed in this
test. The assay result of all the trial batches of enteric coated tablets was within official limit.
Enteric coated tablet of EC1 shows less resistance in 0.1N HCl it may be because it contains
less amount of Eudragit L 100 also it fail in disintegration test. Dissolution profile of EC2
and EC3 containing 60 and 70% w/w of Eudragit L 100 shows that as polymer amount
increases dissolution profile retard and acid resistance increases. EC2 shows better profile
than EC3. EC4 batch gave less resistance in 0.1N HCl and release more than 5% drug. EC5
and EC6 gave sufficient protection of core tablet in 0.1N HCl and did not release more than
5% drug. Dissolution profile of EC5 and EC6 were almost same but EC5 gives highest
dissolution profile and acid resistance than other enteric coated batches. So, enteric coating
formula of EC5 was optimized for further study. In vitro drug release profile of formulations
EC1 to EC6 of Ramipril enteric coated tablets are shown in figure 1. Enteric coated tablets of
optimized batch EC5 were passed in weight variation, hardness, thickness and diameter,
friability,% test as per official requirement as depicted in table 5. The % drug content was
obtained to be 98.67% which is acceptable under the limits. The cumulative % drug release
after 180 minutes.
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