INTRODUCTION:
Bilayer tablets
Bilayer tablets are prepared with one layer of drug for immediate release while second
layer designed to release drug, later, either as second dose or in an extended release
manner. Bilayer tablet is suitable for sequential release of two drugs in combination,
separate two incompatible substances, and also for sustained release tablet in which one
layer is immediate release as initial dose and second layer is maintenance dose.
Advantages of Bilayer tablet
1. Bilayer tablet is suitable for preventing direct contact of two drugs and thus to
maximize the efficacy of combination of two drugs
2. Patient convenience is improved because fewer daily doses are required
compared to traditional delivery systems.
3. Patient compliance is enhanced leading to improved drug regimen efficacy
4. Beta-blocker and calcium channel blocker combination exerts a superior effect
on blood pressure, blood pressure variability, baro reflex sensitivity and reduces
end-organ damage.
5. Bilayer tablets can be designed in such a manner as to modify releases as either
of the layers can be kept as extended and the other as immediate release.
Carvedilol is a nonselective β-adrenergic blocking agent with α-blocking
activity. It is used in the management of hypertension and angina pectoris, and
as an adjunct to standard therapy in sympathomatic heart failure.
MATERIALS AND METHODS
Materials
Carvedilol phosphate was obtained as a
samples from Aurobindo Pharma
Ltd,Hyderabad.HPMC K100M, Hydroxy prophyl methyl cellulose, Eudragit RSPO,
Eudragit RLPO, Crospovidone, Croscarmellose sodium, sodium starch glycolate were
obtained as a samples from Yarrow chemicals pvt ltd, Mumbai. Magnesium stearates,
Talc were obtained as a sample from Karnataka Fine chemical Banga.
METHODS:
Preparation of bilayer tablets [7, 8, 13]
In the present investigation Bilayer tablets of Carvedilol were formulated by wet
granulation technique and direct compression technique.
Immediate release layer granules for bilayer tablets of Carvedilol[47, 48]:
Direct compression granulation method[7]
1
The drug, polymers and other excipients used for Immediate (IR) layer was dried
properly and passed through sieve # 80 and accurately weighed sufficient quantity .of
components were thoroughly mixed in a porceline mortar for a period of 15 mins. The
mixture were passed through # 20 and lubricated with magnesium stearate by further
blend for 3 mins and finally talc was added to the blend which is ready for the
compression.
Procedure for Control release layer granules for bilayer tablets of Carvedilol
Non aqueous wet granulation [8]
The drug, polymers and other excipients used for controlled release (CR) layer was
dried properly and passed through sieve # 80 and accurately weighed sufficient quantity
of components were premixed in a porceline mortar for a period of 10 mins. The
powder mix was granulated by using 99% w/w isopropyl alcoholic solution. The
granules were allowed to dry in ambient condition followed by subjected to tray drier at
40°C until properly dried. The dried granules were passed through # 20 and lubricated
with magnesium stearate by further blending for 3 mins and finally talc was added to
the blend which is ready for the compression.
Compression of Bilayer matrix tablets[13]
The 210mg of equivalent weight of pre weighed Carvedilol granules of Sustained
release layer were first subjected in the die cavity and slightly compressed to adjust
uniform spreading of the 40 mg of equivalent weight of pre weighed Carvedilol
granules of Immediate release layer was subsequently placed in the die cavity and
compressed with an constant pressure and speed.
4.4 Compatibility study
The compatability study was carried out for the Carvedilol, Hpmc K 100M, Eudragit
RSPO and Eudragit RLPO alone and combinations at ambient condition and 40°C /
75% RH for a period of one month and samples were subjected for FTIR and DSC
study for their characterization of possible interaction b/w drug and career in solid state.
Drug and Excipient compatability studies by FT-IR and DSC
Fourier-transformation infrared (FTIR) spectroscopy[15]
To investigate any possible interaction between the drug and the utilized polymers
(Hpmc K100M, Eudragit RSPO, and Sodium starch glycolate), IR spectrum of pure
drug (Carvedilol) and its physical mixture was carried by using FTIR the range selected
was from 400cm-1 to 4000 cm-1 in table no.7,8.
4.5 Differential scanning calorimeter study[15]Further the compatibility between drug
and polymer was detected by Differential scanning calorimeter study. Thermo grams
were obtained by using a differential scanning calorimeter (NETZSCH, DSC 200PC,
2
Japan) at a heating rate 10o C/min over a temperature range of 35-250o C. The sample
was hermetically sealed in an aluminium crucible. Nitrogen gas was purged at the rate
of 10 ml/min for maintaining inert atmospheres.
PRECOMPRESSION PARAMETERS[7, 8]
a) Bulk density
The bulk volume (Vb) and weight of powder (M) was determined. The bulk
density was calculated using the formula.
(b) Tapped density
The tapped density (ρt) was calculated using the formula.
d) Hausner ratio
Hausner ratio (HR) is an indirect index of ease of powder flow. It is
calculated by the following formula
Where Lower Hausner ratio (<1.25) indicates better flow
properties than higher ones (> 1.25)
(e) Angle of repose
Angle of Repose was determined using funnel method. The blend was poured through a
funnel that can be raised vertically until a specified cone height (h) was obtained.
Radius of the heap (r) was measured and angle of repose (θ) was calculated using the
formula
Tan ө = h/r
Therefore; θ = tan -1 h/r
Where θ is angle of repose, h is a high of cone, r is a radius of cone
(c) Compressibility index
The simplest way for measurement of flow of powder is its compressibility, an
indication of the ease with which a material can be induced to flow is given by
compressibility index (I) which is calculated as follows
Where, ρt = Tapped density, ρb = Bulk density
POST COMPRESSION PARAMETERS[7, 8, 11]
3
Tablet Thickness and size7
Thickness and diameter was measured using venire caliper.
Tablet Hardness
The hardness of tablet of each formulation was measured by Monsanto hardness
tester. The hardness was measured in kg/cm2.
Friability
Friability is the measure of tablet strength. Twenty tablets were weighed accurately and
placed in the tumbling apparatus that revolves at 25 rpm dropping the tablets through a
distance of six inches with each revolution. After 4 min, the tablets were weighed and
the percentage loss in tablet weight was determined.
% loss = [(Initial wt. of tablets – Final wt. of tablets)/ Initial wt. of tablets] ×100
Uniformity of weight
Twenty tablets were selected at random and the average weight was calculated. Weight
Variation was calculated and compared with I. P. standards.
Determination of drug content[9]
Three tablets were powdered and powder equivalent to weight of one tablet (100mg)
was transferred to 100ml volumetric flask containing distilled water. For ensuring
complete solubility sonication was done for 30mins.Solution was suitably diluted and
the absorbance was determined by UV-Visible spectrophotometer at 250nm.
In vitro drug release studies[9, 11]
The prepared matrix tablets were subjected to in-vitro dissolution studies using an 8
station USP dissolution apparatus. The dissolution studies were carried out in pH 1.2
for 3 hrs, in pH 6.8 for 4 hr & pH 7.4 for 4 hrs at 37 ± 0.50 c and 50 rpm. At regular
time interval, 5 ml of sample was withdrawn from the dissolution medium and replaced
with equal volume of methanol. After filtration and appropriate dilution, the samples
were analyzed at 234 nm for carvedilol against blank using UV-Visible
spectrophotometer. The amount of drug present in the samples was calculated using
standard curve.
Data Analysis [14]
The dissolution profile of most satisfactory formulation was fitted to zero order, first
order and Higuchi model to ascertain the kinetic modeling of the drug release.
Cumulative percent drug released versus time (Zero order kinetic model)
Log cumulative percent drug remaining versus time (First order kinetic model)
Cumulative percent drug released versus square root of time (Higuchi’s model).
Log percentage drug released Vs log time (Peppas plots).
Stability Studies[15, 16]
The purpose of stability testing is to provide evidence on how the quality of a drug
substance or drug product varies with time under the influence of a variety of
4
environmental factors such as temperature, humidity and light and to establish a re-test
period for the drug substance or a shelf life for the drug product and recommended
storage conditions.
ICH specifies the length of study and storage conditions.
Long-term Testing : 250C  20C/60 % RH  5% for 3 Months.
Accelerated Testing: 400C  20C/75 % RH  5% for 3 Months.
Method
The selected formulations were packed in amber- colored bottles, which were tightly
plugged with cotton and capped with aluminum. They were then stored at 25 ºC / 60%
RH, and 40 ºC / 75% RH for 90 days and evaluated for their hardness, friability, drug
content, disintegration time and in vitro dissolution study.
Results and discussions
The blended powders were evaluated for angle of repose, loose bulk density, tapped
bulk density, compressibility index, Hauser’s Ratio and drug content etc. The prepared
tablets were subjected to thickness, weight variation test, hardness, friability, drug
content.
FTIR Study:
IR of pure drug Carvedilol exhibited characteristics absorption bands in the IR region
as mentioned below:
The peak at 3341.55 may be due to NH-Amines (M) stretch, 1588.12 may be due to
NH-Amines (M) bend, 1443.03 may be due to C-H-Alkanes (V) scissoring and bending
& 1303 may be due to C-N-Amines (M) stretch, 1213.30 may be due to C-OAlcohol(S) stretch.
The IR spectrum of the formulation showed that there is no significant evidence for
interaction between drug and the polymer. Peaks of both drug as well as formulation
were observed and interpreted. So this clearly suggests that drug, polymers and
excipients used for the current study have not found any interaction. There is no
significant or any shift in the positions of the characteristic absorption bands of drug in
the formulations.
Differential scanning calorimeter study:
Fig -14, 16, 18. DSC thermogram of pure drug has shown a melting endotherm at
120.05°C. The thermogram of physical mixture of Carvedilol and polymers Eudragit
RSPO and Eudragit RLPO also showed the Carvedilol melting endotherm at 120.93°C,
and Carvedilol with Hpmc K100M shows peak at about 119.86°C, which may be
because of the presence of polymers in the physical mixture. However DSC
thermogram of Carvedilol alone and components of Carvedilol, Sodium starch
5
glycolate, Crosspovidone, Crooscarmellose sodium Hpmc K100M, Eudragit RSPO and
Eudragit RLPO investigated components exhibited the characteristic endothermic peak
of Carvedilol, indicating the absence of interaction between the components. However
the intensity of drug endothermic peak was noticeable increase. Carvedilol was
formulated as fast dissolving layer using Sodium starch glycolate, Crosspovidone,
Caross carmellose sodium as super disintegrants in different concentration. And it
prepared as Sustained release layer using matrix forming material like Hpmc K100M,
Eudragit RSPO and Eudragit RSPO in different combination.
Pre-compression parameter
Flow properties of the immediate release layer were evaluated by determining the
bulk density 0.45±0.04 to 0.50±0.06, tapped density 0.53±0.01 to 0.58±0.03, angle of
Repose28.29±0.06 to 31.21 ±0.04, Carr’s index 11.30±0.01 to 16.09±0.02 and
Hausner’s ratio 1.13±0.08 to1.18±0.08 in table no 9..Flow properties of the Sustaine
release layer granules were evaluated by determining the bulk density 0.454±0.04 to
0.468±0.06, tapped density 0.54±0.01 to 0.59±0.03, angle of Repose23.1±0.06 to 30.1
±0.04, Carr’s index 15.6±0.01 to 23.0±0.02 and Hausner’s ratio 1.19±0.08 to1.26±0.08
in table no 10.
Post- compression parameter
The % weight variation was within pharmacopoeia limits of ±5% of weight. The
weights variations range from 1.4±0.01to 2.4±0.02. Hence all the tablets were found to
be uniform with low standard deviation values. The measured hardness of tablets of
each batch ranged between 6.13±0.25 to 6.6±0.20 kg/cm2. This ensures good handling
characteristics of all batches. The values of friability test were tabulated in table no 11,
12. The friability was in the range 0.22±0.03 to 0.44±0.05%., so, less than 1% in all
formulations ensuring that the tablets were mechanically stable and the drug content
was in the range 97.05±.02 to 99.66 ± 0.05 shown in table no 11, 12. The present study
reveals to control the drug release by increasing the concentration of as a retarding
agent.
In-vitro release study
A hydrophilic and hydrophobic matrix controlled release system is a dynamic
system composed of polymer-wetting, hydration and dissolution. At the same time,
other soluble excipients or drug(s) will also wet, dissolve and diffuse while
the insoluble ingredients will be held in place until the polymer erodes or
dissolves. Since the diffusional release of soluble drug such as Carvedilol may
primarily be controlled by the gel thickness (diffusion layer), increasing polymer
level tends to decrease drug release. The most common explanation of the effect
6
of increase in the polymer level on drug release is that, it results in the increase
in the thickness of the gel layer, which retards drug diffusion out of tablet.
Dissolution studies of prepared bilayer matrix tablets were carried out in pH 1.2
for first 3 hours, pH 6.8 for 4 hour and pH 7.4 for 4 hour shown in table no.14, 15.
The samples were analyzed spectrophotometrically at 240 nm.
Data analysis
To study the release mechanism of bilayer matrix tablets, various dissolution
models were applied to the in-vitro release profiles of different formulations. The
kinetic models included zero order, first order, and Higuchi and KorsmeyerPeppas equations. As observed from the Table no: 15 the values of correlationcoefficient (r2) for all the formulations were high enough to evaluate the drug
dissolution behavior by equation. Kinetic results revealed that, the formulations
F4 & F7 followed first order kinetics as correlation coefficient (r2) values
(0.996-0.997) are higher than that of zero order release kinetics, the formulations
F5, F6, F8 followed zero order release kinetic as correlation coefficient (r2)
values between 0.957-0.983, indicating that diffusion, and erosion were
involved in the release process. The formulations (F2, F3) followed higuchi
release as correlation coefficient (r2) values between 0.987-0.983, indicating that
diffusion involved in the release process. The formulation (F1) followed Pappas
release as correlation coefficient (r2) value 0.990, indicating that
diffusion
involved in the release process.
Stability Stability study
The selected formulation was subjected to stability studies for 90 days at ambient
condition (25ºC in 60%RH) and at elevated temperature (40±2°C in 75%RH), in- vitro
permeation study was performed on every 3months and showed negligible change in
permeation profile in table no.16, 17. Stability data revealed that there was no
significant change in bilayer matrix tablet properties with aging at different storage
condition.
5. Conclusion
The following conclusions can be drawn from the results obtained.
•
The screening of super disintegrants by direct granulation method for IM layer
and polymers with wet granulation method for SR layer was effective tool to
utilized in the optimization technique
•
Hence, Bilayer matrix tablets containing Hpmc k 100m, Eudragit rspo, Eudragit
rlpo (F2) of Carvedilol showed promising results compared with other
formulations.
REFERENCES
1. Chien YW. Novel drug delivery system. Informa Healthcare. 2nd edition
7
revised and expanded.2010; 50:139-40.
2. Gilber SB and Neil RA. Tablets. In Leon Lachman, Herberta Liebermann and
Joseph L Kanig. The theory and practice of Industrial pharmacy. 3rd ed. Lea
and Febiger. 1987; p. 293-94, 330-31, 430-31.
3. Lieberman HA, Liberman L, Schwartz B. Pharmaceutical dosage form: Tablet
volI. CBS publishers and distributors.2nd edition revised and expanded.
2008;1:179-81, 274-5.
4. Sonara GS, Jain DK, More DM. Preparation and in vitro evaluation of bilayer
and floating-bioadhesive tablets of rosiglitazone maleate. Asian J Pharm
Sci2007; 2(4):161-9.
5. Vogeleer J. Bilayer tablets- why special technology required: The courtoyR292F tablet press, designed for quality bilayer tablets.2002; 1(1):1-6.
6. Chatterjee B, Pal TK. Development and invitro evaluation of micronized
sustained release matrix tablet of carvedilol. IJPSR. 2010; 1(10): 96-102.
7. Venkateswarlu BS et al, Formulation development and evaluation of fast
dissolving tablets of carvedilol. J Chem Pharm Res. 2010, 2(1): 196-210.
8. dissolution of carvedilol marketed formulations. IJCRGG. 2010; 2(2):1047-50.
9. Sharma A. Jain CP. Preparation and characterization of solid dispersions of
carvedilol with PVP K30. Res Pharm Sci. 2010; 5(1): 49-56.
10. Doddayya H, Prakash G, Azharuddin M, Rajagopal HU, Sarfaraz MD. Design
and characterization of bilayer controlled release matrix tablets of losartan
potassium. Int J Pharma Res. 2010; 2(4): 34-9.
11. Apurba SA, Atiqul HP, Dilasha S, Golam K, Reza J. Investigation of in vitro
release kinetics of Carbamazepine from Eudragit rspo and rlpo matrix tablets.
Trop J Pharm Res. April 2009; 8 (2):145-52.
12. Latha K, Uhumwangho MU, Sunil SA, Srikanth MV, Ramana MKV.
Development of an optimised losartan potassium press-coated tablets for
chronotherapeutic drug delivery. Trop J Pharm Res. 2011; 10 (5): 551-8.
13. Margret C, sandip, Muruganantham V, debjit, kumudhavalli , Jayakar B.
Formulation and evaluation of sustained release matrix tablets of zidovudine.
Int J Curr Pharma Res 2009; 1(1):14-31.
14. http://en.wikipedia.org/wiki/Carvedilol
15. ICH Guideline available at:
www.tga.health.gov.au/docs/pdf/euguide/ich/273699r2en.pdf
Table No 1: Composition of Carvedilol Sustained release layer
INGREDIENTS
F1
F2
F3
F4
F5
F6
F7
F8
Carvedilol
18
18
18
18
18
18
18
18
8
Hpmc K100M
15
10
10
15
15
10
10
15
Eudragit RSPO
15
15
25
25
25
15
25
15
Eudragit RLPO
25
25
15
15
25
15
25
15
Microcrystaline
cellulose
125 130
130
125
115
110
110
115
Magnesium
stearate
5
5
5
5
5
5
5
5
Talc
5
5
5
5
5
5
5
5
Table No 2: Composition of Carvedilol Immediate release layer
Ingredients
F1
F2
F3
F4
F5
F6
F7
F8
Carvedilol
7
7
7
7
7
7
7
7
Lactose
30
30
30
30
30
30
30
30
Sodiumstarch
glycolate
0.5
1
1
1
0.5
1
1
0.5
0.5
1
1
0.5
1
1
0.5
0.5
Cross povidone
0.5
0.5
1
1
0.5
1
0.5
1
Magnesium
stearate
0.3
0.3
0.3
0.3
0.3
0.3
0.3
0.3
Talc
0.3
0.3
0.3
0.3
0.3
0.3
0.3
0.3
Crosscarmellose
sodium
Table No 7: Compatibility studies of Carvedilol
Pure Carvedilol
9
Functional group
Range
Observed range
in pure drug
NH-Amines (M)stretch
3500-3300
3341.55
NH-Amines (M)bend
1650 -1580
1588.12
C-H-Alkanes(V)scissoring
and bending
1470-1350
1443.03
C-N-Amines (M)stretch
1340-1020
1303.00
C-O-Alcohol(S)stretch
1260-1000
1213.30
Table No 8: Interpretation of IR of pure drug and polymers
Observed values
Sl
no.
1
Name of Standard Eudragit
Eudragit rlpo Hpmc k100m
pure drug value of rspo with with drug(cm-1) with drug
drug
drug
(cm-1)
(cm-1)
(cm-1)
Carvedilol
Polymer
combination
with drug
(cm-1)
3500-3300 3340.61
3333.80
3342.80
3340.74
1650
1580
- 1589.80
1648.80
1587.90
1587.18
1470-1350 1449.59
1455.05
1442.87
1450.04
1340-1020 1303.22
1307.87
1333.37
1304.14
1260-1000 1215.12
1218.19
1213.47
1214.10
Pre-compression parameters of optimization series.
Table No 9: Pre-compression parameters for Carvedilol fast dissolving layer.
10
Batch
code
Bulk density
(gm/cm3)
Tappeddensity Carr’s
Hausner Angel of
3
(gm/cm )
Index (IC) ratio(HR) repose(θ)
F1
0.50
0.58
14.5
1.14
31.21
F2
0.49
0.56
13.7
1.15
30.23
F3
0.48
0.53
11.5
1.13
29.76
F4
0.49
0.53
11.3
1.14
29.53
F5
0.49
0.56
13.2
1.16
28.42
F6
0.5
0.58
14.79
1.15
29.78
F7
0.47
0.54
15.36
1.18
30.11
F8
0.45
0.57
16.09
1.17
28.29
Table No 10: Pre-compression parameters for Carvedilol Sustained release layer.
Batch
code
Bulkdensity Tappeddensity Carr’sindex
(gm/cm3)
(gm/cm3)
(IC)
Hausner
ratio (HR)
Angel of
repose(θ)
F1
0.455 ± 0.29 0.5918 ± 0.19
21.5 ±0.13
1.24±0.16
30.1 ±0.28
F2
0.468 ±0.32
23 ± 0.17
1.26±0.17
29.3 ±0.25
F3
0.457 ± 0.39 0.577 ± 0.32
21.4 ±0.23
1.23±0.14
29.3 ±0.23
F4
0.454 ± 0.25 0.54 ± 0.19
20.8 ±0.31
1.26±0.14
29.2 ±0.23
F5
0.455 ± 0.27 0.573 ± 0.39
18.7 ±0.33
1.24±0.12
27.4 ±0.35
F6
0.454 ± 0.31 0.552 ± 0.15
18.8 ±0.41
1.26±0.16
27.2 ±0.25
F7
0.454 ± 0.42 0.556 ± 0.27
15.6 ±0.28
1.19±0.13
26.1 ±0.55
F8
0.468 ± 0.4
19.9 ±0.09
1.22±0.19
29.2 ±0.43
0.594± 0.27
0.585 ± 0.3
Post-compression parameters of optimization series.
Table No 11: Post compression parameters of F1-F4 bilayer layer matrix tablet.
11
SL.
No
1.
2.
3.
4.
5.
TESTS
Thickness
(mm)*
Hardness*
(kg/cm2)
Friability*
(%)*
Average
weight*(m
g)
Weight
variation*
SPECIFICATION
F-1
F-2
F-3
F-4
3.42 – 3.78 mm
3.53±0.05
3.76±0.01
3.51±0.05
3.51±0.01
5.5 - 7.0 kg/cm2
6.13±0.25
6.6±0.20
6.2±0.35
6.2±0.26
0.25±0.04
0.35±0.02
0.23±0.04
0.25±0.01
239
240
244
234
1.4%
2.4%
1.3%
Not more than 1%
202- 253 mg
± 7.4% from the
average weight
2.0%
Table No 12: Post-compression parameters of F5-F8 optimization series.
SL.
No
TESTS
SPECIFICATION
F-5
F-6
F-7
F-8
1.
Thickness
(mm)*
3.45 – 3.78 mm
3.42±0.0
2
3.53±0.04
3.62±0.02
3.53±0.01
2.
Hardness*
(kg/cm2)
5.3 - 7.0 kg/cm2
6.4±0.25
6.2±0.43
6.4±0.35
6.3±0.15
3.
Friability*
(%)*
Not more than 1%
0.22±0.0
3
0.42±0.04
0.44±0.05
0.34±0.03
4.
Average
weight*
(mg)
202- 253 mg
225
237
251
239
5.
Weight
variation*
± 7.6% from the
average weight
2.2%
2.7%
1.5%
2.4%
Table No 13: Curve fitting data of the release rate profile of formulation
12
FORMULA
Correlation coefficients(R)
FIRST
HIGUCHI
ORDER
0.987
0.989
0.958
0.987
0.910
0.991
0.996
0.990
0.847
0.877
0.906
0.913
0.997
0.987
0.924
0.932
ZERO
ORDER
0.953
0.966
0.988
0.952
0.957
0.972
0.959
0.983
F1
F2
F3
F4
F5
F6
F7
F8
PEPPAS
0.990
0.98
0.950
0.989
0.891
0.945
0.985
0.944
Table No 14: Invitro dissolution profile data of optimized formulations F1-F4 of
Carvedilol bilayer matrix tablets.
TIME
(hr)
0
%CDR
F1
F2
F3
F4
0
0
0
0
1
16.34
18.05
10.04
17.13
2
26.19
23.96
13.27
24.62
3
38.02
36.63
16.64
35.38
4
45.08
45.83
28.71
43.91
5
52.35
53.17
32.63
52.23
6
61.58
62.94
35.94
59.77
7
70.49
73.47
37.19
65.62
8
78.60
82.30
49.89
73.60
9
81.13
85.32
63.80
77.15
10
83.22
89.73
72.36
79.60
11
87.13
93.25
78.25
82.57
12
90.16
96.44
80.48
85.95
1.2 pH
6.8 pH
7.4 pH
Table No 15: Invitro dissolution profile data of optimized formulations F4-F8 of
Carvedilol bilayer matrix tablets.
13
%CDR
TIME(hr)
F5
F6
F7
F8
0
0
0
0
0
1
16.43
13.68
14.27
14.17
2
20.07
18.78
25.69
17.26
3
22.42
22.93
36.14
21.41
4
27.13
30.06
46.80
27.74
5
33.49
32.76
54.38
37.26
6
39.02
34.21
60.00
40.95
7
47.13
37.70
68.67
43.47
8
52.77
43.63
75.75
56.15
9
75.94
57.76
78.55
68.19
10
87.19
62.91
82.93
76.06
11
89.98
67.40
85.80
80.82
12
92.07
75.72
87.34
83.07
1.2
pH
6.8
pH
7.4
pH
Stability studies
Table No 16: At ambient condition (25±2°C and relative humidity 60± 5%)
Time
Hardness
(Kg/cm2)
Friability
(%)
Drug content Cumulative%drug
(%)
released at 12 hr
Initial
First
Month
Second
Month
6.3±0.23
0.26
98.54±0.69
96.44
6.3±0.29
0.25
98.59±0.8
96.40
6.3±0.30
0.25
98.55±0.57
96.44
Third
96.43
Month
6.3±0.32
0.29
98.67±0.57
Table No 17: At elevated temperature (40±2°C and relative humidity 75± 5%)
14
Time
Hardness
(Kg/cm2)
Friability
(%)
Drug
content (%)
Initial
6.3±0.35
0.27
98.60±0.69
First
Month
6.3±0.26
0.24
98.58±0.84
Second
Month
6.3±0.24
0.26
98.58±0.57
Third
Month
6.3±0.30
0.24
98.62±0.57
Cumulative % drug
released at 12 hr
96.42
96.40
96.40
96.25
Fig- 9: FT-IR spectra of pure Carvedilol
Fig-11: FT-IR spectra of Carvedilol + Eudragit Rspo
15
Fig-12: FT-IR spectra of Carvedilol + Eudragit RlpO
Fig-13: FT-IR spectra of optimized formula
Fig-14: DSC thermogram of Carvedilol
16
Fig-16: DSC thermogram of Carvedilol, Eudragit RSPO, Eudragit RLPO
Fig-18: DSC thermogram of Carvedilol and HPMC
Fig24 bilayer matrix tablets: Dissolution profile of F1-F4 formulations of
Carvedilol
17
Fig 25: Dissolution profile of F5-F8 formulations of Carvedilol bilayer matrix
tablets
RELEASE RATE PROFILE GRAPH FOR OPTIMIZED FORMULA
Fig -26: zero order release kinetics of optimized formulation of Carvedilol
bilayer matrix tablets.
Fig -27: First order release kinetics of optimized formulation of Carvedilol
bilayer matrix tablets.
Fig -28: higuchi model release kinetics of optimized formulation of Carvedilol
bilayer matrix tablets.
18
Fig -29: peppas model release kinetics of optimized formulation of Carvedilol
bilayer matrix tablets.
19