Development & Evaluation of Pulsatile Drug Delivery System for Chronotherapeutic Release of Metoprolol Succinate using Press-coating Method

1. Under Guidance:
MR. G.SARAVANAN [M.Pharm. (Ph.D.)]
DR. SAMUEL GEORGE INSTITUTE OF
PHARMACEUTICAL SCIENCES

2. 1
OBJECTIVEs
 To formulate and evaluate an oral pulsatile drug delivery system
using superdisintegrants and natural polymers to achieve time
release of metoprolol succinate, based on chronopharmaceutical
approach for the treatment of hypertension and to mimic the
circadian rhythm of the disease by releasing the drug with a distinct
predetermined lag time.
 To overcome all the challenges of conventional dosage forms.
 To achieve highly desirable therapeutic effect & to minimize side
effects.

3. PLAN OF WORK
 Preparation of therapeutic powder.
 Preformulation study of prepared therapeutic powder
i) Angle of Repose ii) Bulk Density
iii) Hausner’s Ratio iv) Compressibility Index
 Compatibility studies of drug with excipients by FT- IR.
 Formulation design (core tablet) of Metoprolol succinate tablets by direct compression
 Evaluation of post-compression parameters
 Thickness Average weight Disintegration time
 Hardness Wetting time Drug Content
 Friability Water absorption Ratio

4. PLAN OF WORK
 Obtaining Calibration curve for drug.
 In-Vitro Dissolution rate of formulations (core tablets) and selection of best
formulation.
 Coating of the optimized formulation with polymers in different proportions by
press coating method.
 Evaluation of post-compression parameters of coated tablets.
 In-Vitro Dissolution rate of formulations (coated tablets) and drug release
kinetics.
 Evaluation of Stability Studies.

5. INTRODUCTION
 The term "chrono” basically refers to the observation that every
metabolic event undergoes rhythmic changes in time.
 Chronotherapeutics refers to a treatment method in which in vivo
drug availability is timed to match rhythms of disease, in order to
optimize therapeutic outcomes and minimize side effects.
 Drug Absorption, distribution, metabolism and elimination are
influenced by many different physiological functions of the body
which may vary with time of day.

6.  When possible daily variations in pharmacokinetics may be
responsible for time dependent variations in drug effects
 When symptoms of a disease are clearly circadian phase-dependent
 When drugs have a narrow therapeutic range.
 When the drug has some serious adverse effects that can be avoided
or minimized because they are related to time of administration
need of chronopharmacokinetics

7. S. NO TYPE OF RHYTHM DESCRIPTION
1. Circadian Rhythms “Circa” means about and “dies” means day. These lasts for about one day i.e.
24hrs
2. Ultradian Rhythms Oscillations are of shorter duration i.e. less than 24 hrs.
3. Infradian Rhythms Oscillations those are longer than 24 hrs.
4. Circaseptan Oscillations that lasts for 7 days
5. Circamensual Oscillations that lasts for 30 days
6. Circa-annual rhythms These rhythms last for year.
Body RHYTHMS
TYPE OF RHYTHM DESCRIPTION
Circadian Rhythms “Circa” means about and “dies” means day. These
lasts for about one day i.e. 24hrs
Ultradian Rhythms Oscillations are of shorter duration i.e. less than 24
hrs.
Infradian Rhythms Oscillations those are longer than 24 hrs.
Circaseptan Oscillations that lasts for 7 days
Circamensual Oscillations that lasts for 30 days
Circa-annual rhythms These rhythms last for year.

8. CIRCADIAN PATTERNS OF VARIOUS DISEASES

9. PULSATILE DRUG DELIVERY SYSTEM
It targets to release drugs in a programmed manner i.e.
at appropriate time and at a suitable site of action as per
the pathophysiological need of the disease; and is
designed for chronopharmacotherapy (time drug
therapy) which is based on circadian rhythm.

10. Advantages of P.D.D.S.
 It increases absorption and bioavailability at target site of absorption.
 These systems are beneficial for the drugs having
chronopharmacological behavior where night time dosing is required.
 Loss of drug by extensive first pass metabolism is prevented
 No risk of dose dumping
 Improved patient compliance

11. Disadvantages of P.D.D.S.
 Dosage form design requires highly educated professionals.
 Immediate withdrawal of drug is not possible.
 Homogenicity of the coated barrier is mandatory to assure the
predictability of the lag time.
 Unpredictable In Vivo In Vitro Correlation.
 Pulsatile delivery drugs are costly, raw material is not easily available
with multiple manufacturing steps.

12. MECHANISM of DRUG RELEASE
FROM P.D.D.S.
Diffusion: Drug solutions diffuse across the release coat
to the exterior when water diffuses into the interior of
the particle.
Erosion: Drug erodes gradually with time
Osmosis: Due to osmotic pressure developed the drug is
forced out of the particle into the exterior.

13. Method's FOR PREPARATION of P.D.D.S.
 Press coating method
 Dry coating method
 Pan coating method
PRESS COATING METHOD
Polymers are passed through a screen and used for the time-release
outer shells. Initially 50% of coat powder is placed in the die cavity
then, the core tablet is carefully positioned at the center of die cavity.
The remaining equivalent powder is filled in the die, and the content is
compressed under a compression force.

14. Method's OF DEVELOPMENT of P.D.D.S.
1. Time Controlled system
2. Multiparticulate System
3. Externally Regulated System
4. Internally stimuli induced system

15. CLASSIFICATION OF PULSATILE DRUG
DELIVERY TECHNOLOGIES

16. PULSATILE DRUG DELIVERY TECHNOLOGy
CHRONOTOPIC TECHNOLOGY
Chronotopic system is basically composed of a drug-containing core
provided with an outer release controlling coating. The outer barrier
when exposed to the aqueous fluids undergoes a glassy-rubbery
transition. In the hydrated state, they are subject to permeability
increase, dissolution or mechanical erosion phenomena, which delay the
delivery of drugs from the core.

17. APPLICATIONS
 Asthma: E.g. Theophylline
 Gastro Intestinal Diseases: E.g. Ranitidine
 Arthritis: E.g. Ibuprofens
 Cardiovascular Diseases: E.g. Verapamil
 Cancer: E.g. Methotrexate

18. DRUG PROFILE
Metoprolol succinate
IUPAC NAME : 1-(Isopropyl amino)-3-[4-(2-Methoxyethyl) Phenoxy] Propan-2-Ol
Succinate
CHEMICAL FORMULA : (C15H25NO3)2. C4H6O4
PHYSICAL APPEARANCE : White Crystalline powder
MOLECULAR WEIGHT : 652.815
ACTIVITY : Anti-anginal; Antihypertensive
ROUTE OF ADMINISTRATION : Oral, IV
DOSAGE RANGE : 50 to 400 mg once daily

19. MECHANISM OF ACTION : Blocks the action of the sympathetic nervous
system; there by reducing the heart rate and is useful in treating abnormally
rapid heart rhythms.
PHARMACOKINETIC PROPERTIES : BIOAVAILABILITY : 12%
HALF-LIFE : 3-7 Hours
METABOLISM : Enzyme-CYP2D6
EXCRETION : Renal
PHARMACOLOGY : Selective, Moderately lipophilic
MEDICAL USES : Treatment of heart failure, Hypertension, Angina, Acute
myocardial infarction, Supraventricular tachycardia, Ventricular tachycardia
DRUG PROFILE
Metoprolol succinate

20. s
EXCIPIENTS PROFILE
MICRO
CRYSTALLINE
CELLULOSE
LACTOSE
SPRAY-
DRIED
CROS-
POVIDONE
CROS-
CARMELLOSE
SODIUM
SODIUM
STARCH
GLYCOLATE
XANTHUM
GUM
GUAR GUM MAGNESIUM
STEARATE
TALC
Empirical
Formula
(C6H10O5)n C12H22O11 [C6H9NO] n C12H10Ca3O14.
4H2O
C24H44O6Na (C35H49029)n (C6H12O6)n C36H70MgO4 Mg6
(Si2O5)4(OH) 4
Functional
Category
Diluent,
Disintegrant
Diluent, Filler Tablet
Disintegrant
Disintegrant Tablet and
Capsule
disintegrant
Gelling,
Stabilizing
agent
binder,
disintegrant
Tablet and
Capsule
lubricant
Glidant,
diluent,
lubricant
Description white, odorless,
crystalline
powder
white
crystalline,
odorless &
sweet.
white, fine,
tasteless,
odorless
Insoluble in
water
Insoluble in
water
white-
colored,
odorless
odorless,
white to
yellowish-
white
fine, light
white
fine, white to
grayish-white,
odorless
Melting
Point
260-2700C 223 °C - - - 2700C 2200C 117-1500C 1500°C.
Solubility Water soluble water and
ethanol
water
insoluble
water
insoluble
insoluble in
methylene
chloride
water
soluble
water
soluble
benzene and
ethanol
Organic
solvents and
water.
Incompati
bilities
oxidizing agents amines - - - Cationic
Surfactants,
Oxidizing
agents
acetone,
ethanol,
tannins
acid, alkalis,
and iron salts
Quaternary
Ammonium
Compounds

21. EXPERIMENTAL INVESTIGATIONS
0
0.01
0.02
0.03
0.04
0.05
0.06
0 5 10 15
ABSORBANCE
CONCENTRATION (µg/ml)
CALIBRATION CURVE FOR THE ESTIMATION OF METOPROLOL SUCCINATE

22. METHODOLOGY
STAGE1
Formulation of Rapid Release Core Tablets by Direct
Compression
STAGE2
Formulation of Mixed Blend for Barrier Layer
STAGE 3
Preparation of Press - Coated Tablets

23. FORMULATION OF METOPROLOL
SUCCINATE CORE TABLETS
INGREDIENTS F1
(mg)
F2
(mg)
F3
(mg)
F4
(mg)
F5
(mg)
F6
(mg)
F7
(mg)
F8
(mg)
F9
(mg)
Metoprolol Succinate 100 100 100 100 100 100 100 100 100
Microcrystalline
Cellulose
20.5 20.5 20.5 20.5 20.5 20.5 20.5 20.5 20.5
Lactose spray –dried 20.5 18.25 16 20.5 18.25 16 20.5 18.25 16
Cros - Povidone 3 5.25 7.5 - - - - - -
Cross-carmellose
Sodium
- - - 3 5.25 7.5 - - -
Sodium Starch
Glycolate
- - - - - - 3 5.25 7.5
Magnesium Stearate 3 3 3 3 3 3 3 3 3
Talc 3 3 3 3 3 3 3 3 3
TOTAL 150 150 150 150 150 150 150 150 150

24. 1. BULK DENSITY:
LBD = weight of the powder/ volume of the packing
TBD = weight of the powder/tapped volume of packing
2. CARR’S INDEX:
Carr’s index = TBD – LBD ×100/TBD
3. HAUSNER’S RATIO:
Hausner’s ratio = TBD/ LBD
4. ANGLE OF REPOSE:
Tan θ = h/ r
CHARACTERIZATION OF POWDERS
PREFORMULATION STUDIES

25.  POST COMPRESSION PARAMETERS
 GENERAL APPEARANCE
 SIZE AND SHAPE
 THICKNESS:
 HARDNESS:
 FRIABILITY
 WEIGHT VARIATION
 WETTING TIME
 WATER ABSORPTION RATIO
 SWELLING INDEX
 DISINTEGRATION TIME
 DRUG CONTENT
 IN VITRO DISSOLUTION STUDY
 DRUG – EXCIPIENT COMPATABILITY STUDIES
INFRARED SPECTROSCOPY
 STABILITY STUDIES
CHARACTERIZATION

26. 3867.95 O-H (Stretching)
3620.64 N-H (Stretching)
1552.65 Aromatic rings
1374.58 -O-C (Stretching)
1234.41 C-O-C (Stretching)
583.86 C-H (Bending)
DRUG – EXCIPIENT COMPATABILITY
STUDIES
3867.95 O-H (Stretching)
3620.64 N-H (Stretching)
1552.65 Aromatic rings
1374.58 -O-C (Stretching)
1234.41 C-O-C (Stretching)
583.86 C-H (Bending)

27. Experimental results
CHARACTERIZATION OF METOPROLOL SUCCINATE DRY POWDER WITH SEVERAL
CONCENTRATIONS OF CROS-POVIDONE (F1,F2,F3), CROS-CARMELLOSE SODIUM
(F4,F5,F6) & SODIUM STARCH GLYCOLATE (F7,F8,F9)
FORMULATION
CODE
LOOSE BULK
DENSITY
(gm/ml)
TAPPED
BULK
DENSITY
(gm/ml)
CARR’S INDEX
(%)
HAUSNER’S
RATIO
ANGLE OF
REPOSE (θ)
F1 0.61 ± 0.031 0.64 ± 0.011 6.25 ± 0.042 1.06 ± 0.017 26.65 ± 0.033
F2 0.62 ± 0.021 0.67 ± 0.048 10.40 ± 0.021 1.12 ± 0.014 30.01 ± 0.023
F3 0.42 ± 0.023 0.51 ± 0.021 15.00 ± 0.031 1.19 ± 0.025 28.25 ± 0.026
F4 0.85 ± 0.011 1.04 ± 0.012 15.0 ± 0.010 1.17 ± 0.041 25.05 ± 0.011
F5 0.54 ± 0.042 0.61 ± 0.011 10.0 ± 0.032 1.11 ± 0.012 24.43 ± 0.024
F6 0.42 ± 0.021 0.48 ± 0.021 12.5 ± 0.041 1.14 ± 0.011 23.84 ± 0.022
F7 0.6 ± 0.043 0.66 ± 0.041 9.09 ± 0.011 1.1 ± 0.048 30.02 ± 0.014
F8 0.6 ± 0.041 0.68 ± 0.062 11.7 ± 0.012 1.2 ± 0.054 24.52 ± 0.016
F9 0.6 ± 0.022 0.66 ± 0.042 9.09 ± 0.010 1.1 ± 0.015 25.13 ± 0.021

28. FORMULA
CODE
THICKNESS
(mm)
HARDNESS
(Kg/cm2)
FRIABILITY
(%)
WEIGHT
VARIATION
(mg)
WETTIN
G TIME
(mg)
WATER
ABSORPTIO
N RATIO
DISINTE
-
GRATIO
N TIME
(sec)
DRUG
CONTENT
(%)
F1 2.8 ± 0.02 4.13 ± 0.04 0.686 ± 0.06 149.75 ± 0.22 8.9 198.3 ±0.05 19.5 98.7 ±0.18
F2 3.0 ± 0.03 4.12 ± 0.06 0.698 ± 0.05 151.05 ± 0.25 8.8 194.1 ±0.07 26.3 99.2± 0.10
F3 2.9 ± 0.01 4.15 ± 0.02 0.629 ± 0.08 149.83 ±0.21 9.4 196.5 ±0.03 23.3 99.7 ±0.13
F4 2.9±0.02 4.18 ± 0.01 0.638 ± 0.04 150.28 ± 0.30 9.5 190.8± 0.05 22.3 99.4± 0.12
F5 2.7 ± 0.05 4.20 ± 0.03 0.701 ± 0.07 148.97 ± 0.31 9.3 193.3± 0.04 20.9 98.3± 0.14
F6 3.1 ± 0.02 4.17 ± 0.04 0.674 ± 0.02 149.27 ± 0.28 8.2 182.6± 0.02 25.5 99.8± 0.11
F7 2.7 ± 0.04 4.19 ± 0.05 0.643 ± 0.03 151.13± 0.20 9.4 186.4± 0.03 22.6 98.8 ± 0.1
F8 2.6 ± 0.05 4.16 ± 0.07 0.658 ± 0.09 149.92± 0.24 9.1 179.2± 0.01 25.4 98.9± 0.16
F9 2.8 ± 0.03 4.18 ± 0.02 0.697 ± 0.04 150.33± 0.25 8.9 184.8± 0.07 21.3 99.5± 0.14
PHYSICO -CHEMICAL EVALUATION OF METOPROLOL SUCCINATE
CORE TABLETS
FORMULA
CODE
THICKNESS
(mm)
HARDNESS
(Kg/cm2)
FRIABILITY
(%)
WEIGHT
VARIATION
(mg)
WETTING
TIME
(mg)
WATER
ABSORPT-
ION RATIO
DISINTE-
GRATION
TIME
(sec)
DRUG
CONTENT
(%)
F1 2.8 ± 0.02 4.13 ± 0.04 0.686 ± 0.06 149.75 ± 0.22 8.9 198.3 ±0.05 19.5 98.7 ±0.18
F2 3.0 ± 0.03 4.12 ± 0.06 0.698 ± 0.05 151.05 ± 0.25 8.8 194.1 ±0.07 26.3 99.2± 0.10
F3 2.9 ± 0.01 4.15 ± 0.02 0.629 ± 0.08 149.83 ±0.21 9.4 196.5 ±0.03 23.3 99.7 ±0.13
F4 2.9±0.02 4.18 ± 0.01 0.638 ± 0.04 150.28 ± 0.30 9.5 190.8± 0.05 22.3 99.4± 0.12
F5 2.7 ± 0.05 4.20 ± 0.03 0.701 ± 0.07 148.97 ± 0.31 9.3 193.3± 0.04 20.9 98.3± 0.14
F6 3.1 ± 0.02 4.17 ± 0.04 0.674 ± 0.02 149.27 ± 0.28 8.2 182.6± 0.02 25.5 99.8± 0.11
F7 2.7 ± 0.04 4.19 ± 0.05 0.643 ± 0.03 151.13± 0.20 9.4 186.4± 0.03 22.6 98.8 ± 0.1
F8 2.6 ± 0.05 4.16 ± 0.07 0.658 ± 0.09 149.92± 0.24 9.1 179.2± 0.01 25.4 98.9± 0.16
F9 2.8 ± 0.03 4.18 ± 0.02 0.697 ± 0.04 150.33± 0.25 8.9 184.8± 0.07 21.3 99.5± 0.14
Experimental results

29. Experimental results
DISSOLUTION DATA OF METOPROLOL SUCCINATE CORE TABLET OF
SEVERAL CONCENTRATIONS OF CROS - POVIDONE
TIME PERCENTAGE DRUG
RELEASE
F1 F2 F3
0 00 00 00
5 49.90 75.10 93.27
10 74.78 89.67 97.03
15 86.23 96.05 99.98
20 95.72 99.49 -
25 99.49 - -
0
20
40
60
80
100
120
0 10 20 30
%DrugRelease
Time (min.)
F1
F2
F3

30. Experimental results
DISSOLUTION DATA OF METOPROLOL SUCCINATE CORE TABLET OF
SEVERAL CONCENTRATIONS OF CROS-CARMELLOSE SODIUM
TIME PERCENTAGE DRUG
RELEASE
F4 F5 F6
0 00 00 00
5 60.87 79.85 91.80
10 75.60 88.69 94.74
15 87.70 94.09 95.72
20 93.27 95.56 -
25 95.07 - -
0
20
40
60
80
100
120
0 10 20 30
%DrugRelease
Time (min.)
F4
F5
F6

31. Experimental results
DISSOLUTION DATA OF METOPROLOL SUCCINATE CORE TABLET OF
SEVERAL CONCENTRATIONS OF SODIUM STARCH GLYCOLATE
TIME PERCENTAGE DRUG
RELEASE
F7 F8 F9
0 00 00 00
5 48.43 79.52 93.76
10 66.27 86.40 97.85
15 83.45 97.20 98.67
20 96.05 97.85 -
25 97.52 - -
0
20
40
60
80
100
120
0 10 20 30
%DrugRelease
Time (min.)
F7
F8
F9

32. Experimental results
COMPARISON OF DISSOLUTION DATA
TIME PERCENTAGE DRUG
RELEASE
F3 F6 F9
0 0 0 0
5 93.27 91.80 93.76
10 97.03 94.74 97.85
15 99.98 95.72 98.67
0
20
40
60
80
100
120
0 5 10 15 20
%DrugRelease
Time (min.)
F3
F6
F9

33. Experimental results
FORMULATION OF METOPROLOL SUCCINATE PRESS - COATED
TABLETS WITH OPTIMIZED FORMULATION USING POLYMERS
INGREDIENTS P1
(mg)
P2
(mg)
P3
(mg)
P4
(mg)
P5
(mg)
P6
(mg)
P7
(mg)
Metoprolol Succinate
Core Tablet (Cros-
Povidone)
150 150 150 150 150 150 150
Xanthum Gum 300 - 225 200 150 100 75
Guar Gum - 300 75 100 150 200 225
TOTAL 450 450 450 450 450 450 450

34. FORMULATION
CODE
THICKNESS
(mm)
HARDNESS
(Kg/cm2)
FRIABILITY
(%)
WEIGHT
VARIATION
(mg)
SWELLING
INDEX
(%)
DRUG
CONTENT
(%)
P1 6.79 ± 0.03 5.60 ±0.30 0.718 ± 0.10 449.78 ± 0.22 21.2 ± 0.09 99.34 ± 0.13
P2 6.86 ± 0.02 5.62 ±0.25 0.708 ± 0.09 450.02 ±0.15 63.9 ± 0.01 98.27 ± 0.15
P3 6.82 ± 0.04 5.51 ± 0.30 0.690 ± 0.06 449.67 ± 0.29 38.9 ± 0.03 99.23 ± 0.12
P4 6.85 ±0.01 5.53 ± 0.23 0.701 ± 0.05 449.77 ± 0.25 33.4 ± 0.17 97.85 ± 0.17
P5 6.80 ± 0.05 5.57 ± 0.27 0.702 ± 0.07 451.07 ± 0.18 45.5 ± 0.10 98.66 ± 0.12
P6 6.76 ± 0.03 5.55 ±0.26 0.697 ± 0.03 450.01 ± 0.13 28.3 ± 0.12 98.56 ± 0.11
P7 6.87 ± 0.02 5.59 ±0.20 0.701 ± 0.08 449.32 ± 0.28 53.8 ± 0.06 99.23 ± 0.14
Experimental results
EVALUATION OF METOPROLOL SUCCINATE PUSATILE TABLETS WITH
OPTIMIZED FORMULATION USING POLYMERS
FORMULATION
CODE
THICKNESS
(mm)
HARDNESS
(Kg/cm2)
FRIABILITY
(%)
WEIGHT
VARIATION
(mg)
SWELLING
INDEX
(%)
DRUG
CONTENT
(%)
P1 6.79 ± 0.03 5.60 ±0.30 0.718 ± 0.10 449.78 ± 0.22 21.2 ± 0.09 99.34 ± 0.13
P2 6.86 ± 0.02 5.62 ±0.25 0.708 ± 0.09 450.02 ±0.15 63.9 ± 0.01 98.27 ± 0.15
P3 6.82 ± 0.04 5.51 ± 0.30 0.690 ± 0.06 449.67 ± 0.29 38.9 ± 0.03 99.23 ± 0.12
P4 6.85 ±0.01 5.53 ± 0.23 0.701 ± 0.05 449.77 ± 0.25 33.4 ± 0.17 97.85 ± 0.17
P5 6.80 ± 0.05 5.57 ± 0.27 0.702 ± 0.07 451.07 ± 0.18 45.5 ± 0.10 98.66 ± 0.12
P6 6.76 ± 0.03 5.55 ±0.26 0.697 ± 0.03 450.01 ± 0.13 28.3 ± 0.12 98.56 ± 0.11
P7 6.87 ± 0.02 5.59 ±0.20 0.701 ± 0.08 449.32 ± 0.28 53.8 ± 0.06 99.23 ± 0.14

35. TIME
(HOURS)
PERCENTAGE DRUG RELEASE
P1 P2 P3 P4 P5 P6 P7
0 00 00 00 00 00 00 00
1 10.58 8.25 5.09 3.94 2.37 6.75 2.94
2 21.23 18.07 12.47 9.49 8.67 14.39 6.36
3 34.85 31.69 24.23 21.25 18.49 27.98 14.57
4 47.61 44.42 37.84 35.11 31.69 41.47 27.93
5 60.73 58.28 51.18 47.82 45.38 54.26 42.46
6 72.52 70.19 64.24 61.64 58.25 67.12 55.71
7 83.48 81.77 76.51 74.33 71.21 79.11 68.32
8 95.75 94.63 89.18 87.21 83.06 91.42 80.59
Experimental results
DISSOLUTION DATA OF METOPROLOL SUCCINATE PULSATILE
TABLETS
TIME
(HOURS)
PERCENTAGE DRUG RELEASE
P1 P2 P3 P4 P5 P6 P7
0 00 00 00 00 00 00 00
1 10.58 8.25 5.09 3.94 2.37 6.75 2.94
2 21.23 18.07 12.47 9.49 8.67 14.39 6.36
3 34.85 31.69 24.23 21.25 18.49 27.98 14.57
4 47.61 44.42 37.84 35.11 31.69 41.47 27.93
5 60.73 58.28 51.18 47.82 45.38 54.26 42.46
6 72.52 70.19 64.24 61.64 58.25 67.12 55.71
7 83.48 81.77 76.51 74.33 71.21 79.11 68.32
8 95.75 94.63 89.18 87.21 83.06 91.42 80.59

36. Experimental results
DISSOLUTION PROFILES OF METOPROLOL SUCCINATE PRESS – C OATED TABLETS
WITH OPTIMIZED FORMULATION USING XANTHUM GUM AND GUAR GUM.
0
20
40
60
80
100
120
0 2 4 6 8 10
PercentageDrug
Release
Time (Hours)
P1
P2
P3
P4
P5
P6
P7

37. Experimental results
ZERO ORDER PLOT OF METOPROLOL
SUCCINATE PULSATILE TABLETS
0
20
40
60
80
100
120
0 2 4 6 8 10
AmountofDrugRelease
Time (Hours)
P1
P2
P3
P4
P5
P6
P7
PEPPAS PLOT OF METOPROLOL
SUCCINATE PULSATILE TABLETS
0
0.5
1
1.5
2
2.5
0 0.5 1Log%DrugRelease
Log Time (Hours)
P1
P2
P3
P4
P5
P6
P7
DISSOLUTION RATE KINETICS

38. PARAMETER BEFORE STABILITY STUDIES AFTER STABILITY STUDIES
Appearance Off-White Off-White
Drug Content (%) 99.23 ± 0.14 99.10 ±0.08
Drug Release after 8hrs
(%)
80.59 ± 0.13 80.09 ± 0.07
Stability studies
PARAMETER BEFORE
STABILITY
STUDIES
AFTER
STABILITY
STUDIES
Appearance Off-White Off-White
Drug
Content (%)
99.23±0.14 99.10±0.08
Drug
Release
after 8hrs
(%)
80.59±0.13 80.09±0.07
STABILITY STUDIES OF OPTIMIZED FORMULATION (P7) AT ROOM
TEMP. (300C – 400C)
0
10
20
30
40
50
60
70
80
90
0 2 4 6 8 10
Cumulative%DrugReleased
Time (Hours)
Before Stability
Studies
After Stability
Studies

39. CONCLUSION
The research work aimed and succeeded to formulate
pulsatile release tablets of metoprolol succinate by using
direct compression technique for chronopharmacotherapy
of hypertension by providing sufficient lag time for timed
release of the drug.
The optimized formulation is considered to be P7 which is
composed of polymer Guar gum and Xanthum gum in
the ratio 3:1 with the core tablet inside(formulation F3)
containing 7.5% cros-povidone as superdisintegrant.

40. references
 Bhargavi.T. Chronopharmacokinetics. Asian Journal of Pharmaceutics, 2011,
Vol. 5, And Tropical Journal Of Pharmaceutical Research, 2009, Vol. 8 (5):467 –
475.
 Rajan K. Verma and Sanjay Garg. Current Status of Drug Delivery Technologies
and Future Directions. Pharmaceutical Technology On-Line, 2001, Vol. 25 (2): 1–
14.
 Abhishek Mallikarjun Motagi. Development and Evaluation of Time-Controlled
Pulsatile Release Lisinopril Tablets with Swelling and Rupturable Layers. Rajiv
Gandhi University of Health Sciences.
 Suresh V. Gami, Mukesh C. Gohel, Rajesh K. Parikh, Laxman D. Patel, Vipul P.
Patel. Design And Evaluation Study Of Pulsatile Release Tablets of Metoprolol
Succinate. An International Journal of Pharmaceutical Sciences, ISSN: 0976-
7908, 2012 Vol. 3(2):171-181.
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