Under Guidance:

MR. G.SARAVANAN [M.Pharm. (Ph.D.)]

DR. SAMUEL GEORGE INSTITUTE OF

PHARMACEUTICAL SCIENCES

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.

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

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.

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.

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

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.

CIRCADIAN PATTERNS OF VARIOUS DISEASES

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.

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

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.

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.

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.

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

CLASSIFICATION OF PULSATILE DRUG

DELIVERY TECHNOLOGIES

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.

APPLICATIONS

Asthma: E.g. Theophylline

Gastro Intestinal Diseases: E.g. Ranitidine Arthritis: E.g. Ibuprofens

Cardiovascular Diseases: E.g. Verapamil Cancer: E.g. Methotrexate

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

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

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.

Incompatibilities

oxidizing agents amines - - - Cationic

Surfactants,

Oxidizing

agents

acetone,

ethanol,

tannins

acid, alkalis,

and iron salts

Quaternary

Ammonium

Compounds

EXPERIMENTAL INVESTIGATIONS

0

0.01

0.02

0.03

0.04

0.05

0.06

0 5 10 15

AB

SO

RB

AN

CE

CONCENTRATION (µg/ml)

CALIBRATION CURVE FOR THE ESTIMATION OF METOPROLOL SUCCINATE

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

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

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

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

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)

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

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

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

% D

ru

g R

ele

ase

Time (min.)

F1

F2

F3

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

%

D

ru

g R

ele

ase

Time (min.)

F4

F5

F6

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

% D

ru

g R

ele

ase

Time (min.)

F7

F8

F9

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

% D

ru

g R

ele

ase

Time (min.)

F3

F6

F9

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

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

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

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

Pe

rc

en

ta

ge

D

ru

g

Re

le

as

e

Time (Hours)

P1

P2

P3

P4

P5

P6

P7

Experimental results

ZERO ORDER PLOT OF METOPROLOL

SUCCINATE PULSATILE TABLETS

0

20

40

60

80

100

120

0 2 4 6 8 10

Am

ou

nt

of

Dr

ug

Re

le

as

e

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 1L

og

% D

ru

g R

el

ea

se

Log Time (Hours)

P1

P2

P3

P4

P5

P6

P7

DISSOLUTION RATE KINETICS

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

Cu

mu

la

tiv

e %

Dr

ug

Re

le

as

ed

Time (Hours)

Before Stability

Studies

After Stability

Studies

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.

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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–

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