DESIGN AND EVALUATION OF BILAYER SUSTAINED RELEASE ANTI-HYPERTENSIVE TABLET

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1
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“DESIGN AND EVALUATION OF BILAYER SUSTAINED
RELEASE ANTI-HYPERTENSIVE TABLET”
Mr. Ishwar Marotrao Jadhav
(M.Pharm)
Research Guide By. Ass. Prof. Chavhan G.C.
Department of Pharmaceutics
S.B.S.P.M’ s. B. Pharmacy College, Ambajogai

2. 1.Introduction
2.Aim and Objective
3.Drug Profile
4.Literature Review
5.List of Material
6.List of Equipment
7.Experimental Work
8.Summary
9.Reference

3.  Bilayer tablets are the medicines which consist of two
same or different drugs combined in a single dose and
development of different drug release profile i.e.
Immediate release with Sustained release.
.
3

4.  Sustain release dosage form type of dose which is dosage
form in which a Portion i.e. [initial dose] of the drug is
released immediately, in order to achieve desired therapeutic
response more promptly and the
 remaining i.e.[maintenance dose] is the released slowly there
by achieving a therapeutic level which is prolonged but not
maintained constant.
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5.  Aim : The aim of present study of design sustained release Bi-layer tablet
of Antihypertensive drug for improved drug delivery.
 Objective :
• To develop stable formulation of Antihypertensive drugs.
• To develop improved beneficial technology to overcome the shortcoming
of the single tablet.
• To design modified release drug product for optimization of therapeutic
regimen.
• To ensure safety and to improve efficacy of drug as well as patient
compliance.
• To study the effect of concentration of polymer on drug release.
• Evaluation of pre-compression parameters such as angle of repose, bulk
density, tapped Density, Carr’s index and Haunser’s ratio.
.
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6. Advantages of SR Tablet Disadvantages of SR Tablet
 The frequency of drug
administration can be reduced
 Improved patient compliance.
 The sustainable blood level can
maintain.
 Controlled drug absorption
 Reduction in adverse and side
effects
 Increased cost than
conventional dosage form
 Rapid withdrawal of action is
not possible.
 Difficulty in dose adjustment of
drugs
 More rapid development of
tolerance
 Drugs that absorbed from
stomach and upper part of GI
tract
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7.  Chemical Name :- Propanolol
 Molecular Formula :- C16H12C1NO2
 Average weight :- 259.3434
 Melting point :- 158-168ºc
 pKa :- 9.42
 Color :- White Powder
 Odour :- Odourless
 Solubility :- Practically insoluble in Ether, Benzene, ethyl
acetate
 Biological half-life :- 2-3Hr
 Blood Protein binding :- 80-95%
 MOA :- Non Selective Beta Receptor Antagonist
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8. Researcher Re search Title Journal
Reddy et al., Formulation and Evaluation of Bilayer Tablets of
Ramipril as Immediate Layer and Propranolol
Hydrochloride as Sustained Layer
Asian Journal of Pharmaceutics
• Jan-Mar 2018 • 12 (1)
Sunil et al., Design and evaluation of lornoxicam bilayered
tablets for biphasic release
Brazilian Journal of
Pharmaceutical Sciences
vol. 48, n. 4, oct./dec., 2012
Khandai et
al.,
Development of propranolol hydrochloride
matrix tablets: An investigation on effects of
combination of hydrophilic and hydrophobic
matrix formers using multiple comparison
analysis
International Journal of
Pharmaceutical sciences
Review and Research March
2010
1(2):1-7
Kotta Kranthi
Kumar et al.,
Formulation and evaluation of Sustained release
bilayer tablets of glimepiride and metformin
HCL
. 8

9. Researcher Re search Title Journal
Hernawan et al., Formulation and in vitro study of
propranolol hydrochloride controlled
release from carboxymethyl chitosan-
based matrix tablets
Indo. J. Chem., 2013, 13 (3),
242 - 247
R. Nagaraju et al Formulation and Evaluation of Bilayer
Sustained Release Tablets of Salbutamol
and Theophylline
International Journal of
Pharmaceutical Sciences and
Nanotechnology, Vol 2 No 3
(2009): October-December
2009
MA Naeem et al Development and Evaluation of
Controlled-Release Bilayer Tablets
Containing Microencapsulated Tramadol
and Acetaminophen
https://www.ajol.info/index.p
hp/tjpr/index
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10. Sr.No. Material IR Material SR
1 Propranolol Propranolol
2 Sodium starch Glycolate Ethyl cellulose
3 Mannitol HPMC k15
4 Aerosil HPMC 100
5 Polyvinylpyrrolidone k 30 Mg. sterate
6 Mg. Sterate Microcrystalline Cellulose
7 Colorant talc
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11. Sr.no. Equipment
1 Digital weighing balance
2 Tablet Machine
3 Monsanto Hardness tester
4 Dissolution test apparatus
5 UV-1700 spectrophotometer
6 PH Meter
7 Vernier caliper
8 Stability chamber
9 IR
10 Roche friabillator
11 Stability chamber
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12. A. Literature survey
B. Selection of drug and excipient
C. Preliminary study of drug
1) Physical Characterization
a) Bulk Density
b) Tapped Density
c) Angle of repose
d) Hauser’s ratio
D. Preparation of tablet
E. Evaluation of Prepared tablet
F. Post Compression test
a) Hardness
b) Friability
c) Disintegration
d) Weight variation
e) Drug Content
f) In-Vitro drug release
g) Stability study
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13.  Pre-formulation Study
The phase of research & development in which
preformulation characterizes the physical, chemical properties
of new drug substances, in order to develop stable, safe and
effective dosage forms.
.
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14.  The solubility of a solid substance is defined as the
concentration at which the solution phase is in equilibrium
with a given solid phase at a stated temperature and pressure
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Descriptive Term Parts of solvent Required For 1 Part
Of solute
Very Soluble Less than 1
Freely Soluble From 1 to 10
Soluble From 10 to 30
Sparingly Soluble From 30 to 100
Slightly Soluble From 100 to 1,000
Very Slightly Soluble From 1,000 t0 10,ooo
Practically insoluble or
insoluble
Greater than or Equal to 10,000

15.  The flow properties of blend of powder were determined by angle of
repose. The improper flow of powder is due to frictional forces between
the particles. These friction forces were quantified by angle of repose.
Angle of repose was calculated by following formula:
𝜃 = 𝑡𝑎𝑛 − 1(ℎ)/𝑅
 Where, h= height of pile;
r= radius of the base of the pile
θ = angle of repose.
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Angle of Repose (º) Type of Flow
<25 Excellent
25-30 Good
30-40 Poor
>40 Very Poor

16.  Bulk Density :-Weighed quantity of Propranolol HCL were
transferred into a 50ml measuring Cylinder without tapping
during transfer the volume occupied by granules was
measured.
Bulk density (ρ) = Weight of sample /Bulk volume
 Tapped Density :-Weighed quantity of Propranolol was taken
into a graduated cylinder, volume occupied by granules was
noted down. Then cylinder was subjected to 500/ 750 and
1250 taps in tapped density tester (Electro Lab USPII)
According to USP , the blend was subjected for 500 taps the
% Volume variation was calculated by following formula.
Tapped density (ρb) =Weight of sample /Tapped volume
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17.  Compressibility Index:
The compressibility index of the granules was determined by
the Carr’s compressibility index
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Tapped density– poured density
Carr’s index (%) = X 100
Tapped density
Caee’s Index % Type of Flow
5-15 Excellent
12-16 Good
18-21 Fair to possible
23-35 Poor
33-38 Very poor

18. It is measurement of frictional resistance of the drug. It was
determined by the ratio of tapped density and bulk density.
Hausner Ratio =Tapped density/bulk density
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Flow Character Hausner Ratio
Excellent 1.00-1.11
Good 1.12-1.18
Fair 1.19-1.25
Passable 1.26-1.34
Poor 1.35-1.45
Very poor 1.46-1.59
Very very poor >1.60

19.  Blends preparation of immediate release layer:-
The Propranolol layer was prepared by using direct
compression method. All the ingredients except Mg. Stearate
and Aerosil were passed through sieve No: 40, weighed and
mixed for 15 mints and finally blended well in ascending order
of their weights. Magnesium Stearate and Aerosil were passed
through sieve No: 60 and mixed it to the above blend. Finally
colorant was added and blended uniformly and compressed in a
16 station automatic punching machine with a punch size of 10
mm.
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20.  Drug and all the excipient except the magnesium stearate
were accurately weighed and passed through #80mesh
screen. Then the sieved blend was transferred to a poly bag
and mixed for 5 minutes. The magnesium stearate as
lubricant was added and mixed again for 2 minutes.
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21. 1 21
Sr.no Ingredient IR 1 IR 2 IR 3 SR 1 SR 2 SR 3 SR 4 SR 5 SR 6
1 Propranolol 25 25 25 55 55 55 55 55 55
2 Sodium starch Glycolate 5 7.5 10 - - - - - -
3 Mannitol 60 57.5 55 - - - - - -
4 Aerosil 2.5 2.5 2.5 - - - - - -
5 Polyvinylpyrrolidone k 30 5 5 5 - - - - - -
6 Mg. Sterate 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5
7 Colorant Q.S Q.S Q.S - - - - - -
8 Ethyl cellulose - - - 27.5 82.5 -- - - -
9 HPMC k15 - - - - - 27.5 82.5
10 HPMC 100 - - - - - - - 27.5 82.5
11 Microcrystalline Cellulose - - - 162.5 107.5 162.5 107.5 162.5 107.5
12 talc - - - 2.5 2.5 2.5 2.5 2.5 2.5
Total 100 100 100 250 250 250 250 250 250

22.  Weight Variation:-
The USP weight variation test is done by weighing 20 tablets
individually, calculating the average weight and comparing the
individual weights to the average.
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Sr.no Average weight of tablet (mg) Maximum Difference
Allowed
1 130 or less 10
2 130-324 7.5
3 324 < 5

23. 1 23
The hardness of each batch of tablet was checked by using
Monsanto hardness tester. The hardness was measured in terms of
kg/cm2. 5 tablets were chosen randomly and tested for hardness.
The average hardness of 5 determinations was recorded.
 Friability
20 tablets were weighed and placed in the plastic chamber of Roches
friabilator. The chamber was then rotated for 4 minutes at 25 rpm.
During each revolution tablets fall from a distance of 6 inches. After
100 revolutions the tablets were removed and weighed again.
Friability (%) = 𝑊1−𝑊2/W1
Where, w1 was the initial weight of tablets before friability
testing,w2 was the weight of tablets after the test

24. Drug Release Studies for Immediate release layer
 It is determined by using USP XXIII (basket method) dissolution
apparatus.
 The basket was rotate at a speed of 100 rpm and temp. of 37 ±
0.5°C was maintained.
 The dissolution medium used was 900 ml of 0.1N HCL (pH 1.2) for
2 hours.
 Aliquots (5 ml) of sample were collected at predetermined time
intervals (5, 10, 15, 20, 25 and 30min) From the dissolution
apparatus and it was replaced with equal volume of fresh
dissolution medium. The aliquots withdrawn were filtered through
0.45μm Millipore filters
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25.  It is determined using USP XXIII (basket method) dissolution
apparatus.
 The basket was rotate at a speed of 100 rpm and temperature of
37
 ± 0.5°C was maintained.
 The dissolution medium used was 900 ml of 0.1N HCL (pH 1.2) for
the initial 2hours followed by study in simulated intestinal fluid
Phosphate buffer solution (pH 6.8). Aliquots (5 ml) of sample were
collected at predetermined time intervals (1, 2, 4, 6, 8, 10, 12, 16,
20, and 24 hrs) from the dissolution apparatus and it was replaced
with equal volume of fresh dissolution medium. The aliquots
withdrawn were filtered through 0.45μm Millipore filters.
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26.  The in vitro dissolution of Propranolol bilayer tablets were
determined using USP XXIII (basket method) dissolution apparatus.
 The basket was allowed to rotate at a speed of 100 rpm and
temperature of 37 ± 0.5°C was maintained.
 The dissolution medium used was 900 ml of 0.1N HCL (pH 1.2) for
the initial 2hours followed by study in simulated intestinal fluid
Phosphate buffer solution (pH 6.8).
 Aliquots (5 ml) of sample were collected at predetermined time
intervals (1, 2, 4, 6, 8, 10, 12, 16, 20, and 24 hrs. from the
dissolution apparatus and it was replaced with equal volume of
fresh dissolution medium. The aliquots withdrawn were filtered
through 0.45μm Millipore filters.
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27. Dissolution test apparatus USP type ||
Speed 50 rpm
Stirrer Paddle type
Volume of medium 900 ml
Volume of withdrawn 5 ml
Medium used 7.4 phosphate buffer
Temperature 37±0.5ºC
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28.  Pre-formulation studies:-
Organoleptic characterization of Propranolol
 Angle of Repose Bulk drug
 The drug to good flow property
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29.  Determination of Bulk density and Tap density
 Powder Compressibility and Hausner’s ratio
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Sr.no Material Bulk
Density
(gm/ml)
Average bulk
Density
(gm/ml)
Tapped
Density
(gm/ml)
Average
Tapped
Density
(gm/ml)
1
Propranolol
HCL
0.364
0.359
0.531
0.533
2 0.358 0.536
3 0.357 0.532
Material Compressibility Hausner’s ratio
Propranolol HCL 22.64 1.34

30.  Standard curve of propranolol HCL (λ max)
 Calibration curve of propranolol hydrochloride using HCL (pH 1.2)
30
Sr.no Concentratio
n µg/ml
Absor
bance
1 0 0
2 10 0.237
3 20 0.429
4 30 0.639
5 40 0.860
6 50 1.073
UV curve of propranolol HCL using 0.1N HCL (pH 1.2)
Calibration curve of propranolol HCL using 0.1N HCL (pH 1.2)
Standard curve of propranolol HCL using 0.1N HCL (pH 1.2)

31. 1 31
Sr.
no
Concn.
µg/ml
Absorbanc
e
1 0 0
2 10 0.240
3 20 0.395
4 30 0.598
5 40 0.794
6 50 0.977
Standard curve of propranolol HCL using phosphate buffer (pH 6.8)
UV curve of propranolol HCL using phosphate buffer (pH 6.8)
Calibration curve of propranolol HCL using phosphate buffer (pH 6.8)

32. 32
FTIR spectra of propranolol HCL

33. 1 33

34. 1 34

35. 35

36.  Evaluation parameters of pre-formulation characteristics of powder
blend
1 36
Formulations
Number
Bulk Density
(gm/cc)
Tapped Density
(gm/cc)
Carr’s Index
(%)
Hausner’s
Ratio
Angle of
Repose (θ)
IR 1 0.2785±1.2 0.4500±0.0012 10.21±0.325 1.035±0.0025 26.85±0.14
IR 2 0.2883±1.8 0.3756±0.0014 9.21±0.0456 1.231±0.0014 27.14±0.68
IR 3 0.3240±1.4 0.3932±0.00021 12.54±147 1.0512±0.0056 25.25±0.23
F1 0.2237±1.1 0.3810±0.0045 7.27±0.659 1.177±0.0076 29.73±0.41
F2 0.3642±1.8 0.4120±0.0026 7.58±0.514 1.053±0.0060 25.33± 0.63
F3 0.2836±1.0 0.4120±0.005 7.43±0.760 1.059±0.0088 28.44± 0.35
F4 0.2090±1.6 0.4270±0.0037 13.78±0.386 1.073±0.0053 27.48±0.52
F5 0.3457±0.8 0.4600±0.0024 17.31±0.794 1.224±0.011 31.34± 0.13
F6 0.2882±1.9 0.4880±0.0065 18.42±0.120 1.24±0.0020 28.26±0.43
Formulation
Diameter
(mm)± SD
Thickness
(mm)± SD
Weight
variation
(mg)
Hardness
(kg/cm2)
Friability(%)
Disintegratio
ntime
Drug
content(%)
IR 1 4.25±0.014 1.2±0.065 99.45±0.17 3.7±0.06 0.12±0.07 30±0.10 98.25±0.02
IR 2 3.95±0.016 1.6±0.041 99.25±0.14 3.8±0.32 0.14±0.10 25±0.14 97.65±0.14
IR 3 5.41±0.19 2.1±0.014 100.12±0.014 3.7±0.74 0.19±0.14 15±0.65 99.25±0.19
Post-compression parameter for immediate release tablet

37. Formulation
Diameter
(mm)± SD
Thickness
(mm)± SD
Weight
variation
(mg)
Hardness
(kg/cm2)
Friability
(%)
Drug content
(%)
F1 7.82±0.012 3.9±0.09 250.89±0.12 7.3±0.04 0.64±0.007 97.75±0.025
F2 7.80±0.002 4.0±0.02 253.88±0.60 7.8±0.03 0.52±0.005 98.25±0.044
F3 7.85±0.007 4.2±0.01 251.12±0.52 8.0±0.07 0.58±0.031 98.31±0.037
F4 7.84±0.022 3.9±0.07 249.81±0.13 6.5±0.04 0.72±0.016 96.23±0.025
F5 8.0±0.015 4.0±0.04 250.80±0.32 6.8±0.08 0.42±0.09 98.37±0.058
F6 7.94±0.010 3.8±0.09 248.92±0.44 7.1±0.03 0.42±0.01 99.12±0.23
F7 7.88±0.021 3.8±0.01 247.69±0.55 6.6±0.01 0.40±0.002 97.61±0.08
F8 8.0±0.014 4.0±0.09 250.01±014 7.2±0.02 0.56±0.025 98.56±0.22
F9 7.89±0.047 4.1±0.01 252.12±0.01 7.1±0.01 0.71±0.012 99.67±0.07
1 37

38.  In - vitro drug release study of immediate release layer of Propranolol
 In - vitro drug release study of Sustained release Bi-layer tablet of Propranolol
1 38
SR. No Time (min) IR-1 IR-2 IR-3
0 0 0 0
1. 5 25.32±0.4
39.40±0.1
0
49.40±0.20
2. 10 40.50±0.10 50.13±1.4 75.30±0.21
3. 15 62.90±0.12
71.23±0.4
1
99.10±0.95
4. 20 78.90±0.21
84.54±0.1
0
5. 25 89.40±0.40 97.90±10
6. 30 98.10±0.11
Time(hrs.) Cumulative percent drug release
F1 F2 F3
0 0 0 0
1 25.12±0.09 18.34±0.43 15.38±0.10
2 40.02±0.12 22.10±0.10 20.90±0.45
3 58.75±0.14 29.24±0.33 25.10±0.12
4 72.41±0.81 35.45±0.12 31.46±0.21
5 80.03±0.28 48.71±0.2 46.13±0.13
6 91.61±0.34 59.99±0.54 52.18±0.43
7 99.13±0.41 68.41±0.55 63.97±0.42
8 72.12±0.10 70.33±0.54
9 77.09±0.22 74.50±0.65
10 82.23±0.12 80.96±0.66
11 85.86± 0.26 82.13±0.10
12 95.12±0.33 95.10±0.23
13 97.54± 0.1 98.51±0.12
In-vitro disintegration data for IR-1, IR-2, and IR-3 Formulation

39.  The pre-formulation studies like angle of repose, bulk density, tapped density Haunser’s ratio and Carr’s index of
all formulations were found to be within the standard limits.
 FTIR studies revealed that there was no chemical interaction between drug and other excipients.
 The powder mixtures were compressed into tablet and evaluated for post-compression parameters like weight
variation, thickness, hardness, friability and drug content. All the formulation batches showed acceptable results.
 The in-vitro drug release was studied with USP Type-II dissolution apparatus in both simulated gastric fluid and
intestine fluid for a period of 24 hours. Results showed that formulations containing higher concentration of
HPMC K15 M i.e. F6 (99.12%) and HPMC k 100 i.e. F9 (99.67%) sustained the drug release over a period of 24
hours.
 The in-vitro drug release follows first order and indicated that non-Fickian could be the mechanism of drug
release.
 Stability studies showed that the tablets formulations were stable throughout the stability period.
 It was concluded that the polymer plays a major role in the formulation of sustain release bilayer tablets of
propranolol. Finally, the study revealed that the release of drug was low when the bilayer tablet contained higher
concentration of polymers
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40. Thank you
.
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