adnan final ppt

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FORMULATION DEVELOPMENT AND

EVALUATION OF A PULSATILE DRUG

DELIVERY SYSTEM FOR RANOLAZINE

Research Student

ADNAN G . KHAN

Research Guide

Dr. Nazma N . Inamdar

M. C. E. Societys

ALLANA COLLEGE OF PHARMACY,

CAMP, PUNE

2011-2013

Seat.no.1806


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INTRODUCTIONPULSATILE DRUG DELIVERY SYSTEM

Pulsatile drug delivery system is a controlled drug delivery system in

which there is rapid and transient release of a certain amount of drug

molecules within a short time-period immediately after a predetermined

off release period.

CLASSIFICATION OF PULSATILE DRUG DELIVERY

SYSTEM

Capsule-based system Osmotic system

Delivery system with soluble or erodible membranes

Delivery system with repturable coating

Systems based on change in membrane permeability

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CLASSIFICATION OF PDDS BASED ON STIMULI INDUCED

Temperature induced system

Chemically induced system

DISEASES REQUIRING PULSATILE DELIVERY Asthama

Arthritis

Cardiovascular diseases

Diabetes mallitus

Hypercholestrolemia

Peptic ulcer

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24-h clock diagram of the peak time of selected human circadianrhythm with reference to the day-night cycle

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Drug release profile of pulsatile drug delivery system

A: Ideal sigmoidal release

B & C: Delayed release after initial lag time.

The first pulsed delivery formulation that released the active substance at a

precisely defined time point was developed in the early 1990s.

In this context, the aim of the research was to achieve a so-called sigmoidal

release pattern (pattern A in Figure).

Thus, the major challenge in the development of pulsatile drug delivery system is

to achieve a rapid drug release after the lag time. Often, the drug is released overan extended period of time (patterns B & C in Figure).

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MERITS:

Predictable, reproducible and short gastric residence time Improve bioavailability

Limited risk of local irritation

No risk of dose dumping

Flexibility in design

Improve stability

DEMERITS:

Lack of manufacturing reproducibility and efficacy Batch manufacturing process

Higher cost of production

Trained/skilled personal needed for manufacturing

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Introduction to RanolazineCategory: Calcium channel blocker

Mechanism of action of Ranolazine

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Advantages over other drugs of same category:

It does not significantly alter either the heart rate or blood pressure.

Least side effects.

It is equally effective for angina relief in diabetics and non

diabetics.

The FDA recommended that it should be reserved for the patients

who had not an adequate response with other anti-anginal drugs

such as Trimetazidine, Perhexiline, Nicorandil, Bosentan and

Ivabradine.

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OBJECTIVES OF THE STUDY

Improved patient convenience and compliance

Reduction in total dose administration

Improved efficiency in treatment

Loss frequency of drug administration

Obtaining constant drug blood levels

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EXPERIMENTAL WORK

Drug characterization

Organoleptic PropertiesMelting PointSolubilityMicromeritic Properties

FTIRUV-Visible SpectroscopySEMPXRD

Excipient characterization

Organoleptic PropertiesSolubility

FTIR

Drug-Excipient compatibility study

FT-IRSEM

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Ingredients F1 F2 F3 F4 F5 F6 F7 F8

Ranolazine 500 500 500 500 500 500 500 500

Lactose 75 75 30 28.5 27 25.5 24 24

Micro crystalline cellulose 25.5 24 75 75 75 75 75 75

Magnesium stearate 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5

Starch mucilage 10 10 10 10 10 10 10 10

Talc 3 3 3 3 3 3 3 3

Sod.Starch glycolate 7.5 9 3 4.5 6 7.5 9 9

Composition of Pulsatile Ranolazine Tabletsformulations

(TRIAL BATCHES)

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Sr.No Ingredient F1 F2 F3 F4 F5 F6 F7 F8

1 E S 100 :

E L 100

0.75:0.7

5

1:1 1.5:1.

5

1:1.75 1.75

:1

1.75:1.7

5

1.75:1.7

5

1:2

2 DiButyl-Pthalate

DiEthyl-

Pthalate

1:1 1:1 1:1 1:1 1:1 1:1 1:1 1:1

3 Isopropyl

alcohol

Acetone

70:30 70:30 70:30 70:30 70:30 70:30 70:30 70:30

Coating Composition Coating solution polymer and solvent ratios profile

(TRIAL BATCHES)

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Parameters Variable

Lactose X1

Eudragit l/s 100 X2

VARIABLES

LEVELS

( -1) (0) (+1)

X1 23.5 (mg) 24.5 (mg) 24 (mg)

X2 1.5 (g) 3 (g) 4.5 (g)

Selection of optimized batch

Selection of independent variables

Formulation of batchLevels of variable

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Batch code Independent variables

X1 (lactose) X2 (eudragit l /s 100)

F1 23.5 1.5

F2 23.5 3

F3 23.5 4.5

F4 24 1.5

F5 24 3

F6 24 4.5

F7 24.5 1.5

F8 24.5 3

F9 24.5 4.5

Composition of different batches based on factorial design

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Evaluation of tablets

Thickness

Hardness

Uniformity of weight

Uniformity of contentFriability

In-vitrodrug release from tablets

Stability studies

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RESULT AND DISCUSSIONS

Sr. No. Appearance Observations

1. Colour White

2. Odour Slight

3. Taste Slightly Bitter

4. Nature Slightly hygroscopic

DRUG CHARACTERIZATION

A. Organoleptic Properties:

B. Melting Point:

The melting point of ranolazine was found to be 120C. This was comparable with its

literature value of 118C-122C.

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Sr.No. Solvents Observations

1. Distilled water Very Slightly Soluble

2 7.5 P B Soluble

2. Ethanol Sparingly Soluble

3. Methanol Soluble

4. Acetone Insoluble

C. Solubility Profile

The solubility study of ranolazine in different solvents was studied and is depicted in table

below.

Solubility profile of Ranolazine

The results of solubility profile confirmed that the drugs had considerable solubility in

phosphate buffer (P B) 7.5 for which the drugs formulation was being developed

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Sr. No Parameter Observations

1 BULK DENSITY 0.471

2 TAPPED DENSITY 0.681

3 % COMPRASIBILITY 30.85

4 HAUSNER RATIO 1.445

5 ANGLE OF REPOSE 30.26

D.Micromeritic Properties:

Micromeritic Properties of Ranolazine

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E. UV-Visible Spectroscopy:

UV Scan of ranolazine

This max value is compellable to that of the literature value i.e. 272 nm. It

conforms the identity of ranolazine.

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F. Calibration Curve

Calibration curve of ranolazine in 7.5 P B

y = 0.006x - 0.0007

R = 0.9995

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0 20 40 60 80 100 120

ABSORBANCE

CONCENTRATION

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cm-1 Functional groups

3350 -NH stretch (amine)

3328 -OH stretch (hydroxyl)

1686 -C=O stretch (Aliphatic)

1641, 1592 -Aromatic (two bonds)

1128 -C=C Stretching bonds

G. FT-IR spectrum of drug

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H.SEM OF RANOLAZINE

SEM Image of ranolazine at 1000x resolution

SEM Image of ranolazine at 1500x resolution 23


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I. PXRD OF RANOLAZINE

PXRD image of ranolazine

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Exipient Characterization

A. Organoleptic properties

The Eudragit L and S 100 was subjected to organoleptic evaluation. The results

obtained shown in the table below.

Organoleptic properties of Eudragit L and S 100

Sr. No Appearance Observations

1. Color White

2. Odor Characteristic

3. Taste Tasteless

4. Nature Fine powder

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B. Solubility study

Solubility of Eudragit L and S 100 is checked as follows

Solubility ofEudragit L and S 100Sr. No Solvents Observations

1 Distilled water Insoluble

2 Ethanol Soluble

3 Chloroform Soluble

4 Acetone Soluble

5 0.05 M HCL Slightly soluble

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C. FTIR Study Of Eudragit L and S 100

IR spectrum of EUDRAGIT S 100

IR spectrum of EUDRAGIT L 100 27


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Drug-Excipient Compatibility StudyA. IR spectroscopy

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SEM Image of Physical mixture of the Formulation at 300x resolution

SEM Image of Physical mixture of the Formulation at 500x resolution

B. SEM OF FORMULATION MIXTURE

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Batch

code

Angle of

repose ()

Bulk density

(g/cm3)

Tapped density

(g/cm3)

Carrs index

(%)

Hausners

ratio

F 1 24.80.32 0.490.013 0.550.014 10.909 1.122

F 2 27.40.08 0.510.013 0.580.002 12.068 1.137

F 3 28.40.21 0.470.02 0.530.012 11.320 1.127F 4 28.40.06 0.550.025 0.590.0112 6.779 1.072

F 5 25.80.15 0.490.012 0.560.012 12.5 1.142

F 6 26.20.07 0.440.006 0.490.021 10.204 1.113

F 7 28.10.09 0.510.002 0.580.001 12.068 1.137

F 8 27.20.09 0.540.04 0.56 0.013 12.056 1.124F 9 26.20.07 0.440.006 0.490.021 10.204 1.113

PRECOMPRESSED PARAMETERS

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*Formulation

Code

*Uniformity of

Thickness(mm)

(SD)

*Hardness

(kg/cm2)

(SD)

Friability %

(SD)

*Weight(mg)

(SD)

*Drug

Content(%)

(SD)

F1 5.95 0.030 8.6 0.54 0.201 6701.095 100.00.77

F2 5.09 0.081 9.9 0.44 0.264 7211.507 97.553.07

F3 5.80 0.034 11.70.19 0.226 6991.000 98.100.32

F4 5.90 0.036 8.9 0.26 0.247 6981.577 97.383.11

F5 5.46 0.050 10.30.57 0.193 7381.141 98.780.76

F6 5.95 0.032 9.3 0.65 0.144 7102.141 99.880.16

F7 5.80 0.034 11.70.19 0.226 6991.000 98.100.32

F8 5.95 0.030 8.6 0.54 0.201 6701.095 100.00.77

F9 5.95 0.032 9.3 0.65 0.144 7102.141 99.880.16

EVALUATION OF TABLET PARAMETERS

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Formulation

Code

Uniformity of

Thickness(mm)

Hardness (kg/cm2) Weight variation

F1 5.96 0.042 10.5 0.55 7400.085

F2 5.99 0.038 9.9 0.84 7331.024

F3 5.85 0.018 11.7 0.24 7461.021

F4 5.89 0.072 10.5 0.63 7520.099

F5 5.68 0.056 9.8 0.11 7481.018

F6 5.97 0.033 11.1 0.14 7291.028

F7 5.85 0.018 11.7 0.24 7461.021

F8 5.96 0.042 10.5 0.55 7400.085

F9 5.97 0.033 11.1 0.14 7291.028

EVALUATION OF COATED TABLET PARAMETERS

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Formulat

ion

Zero

Order

First

Order

Higuchi

Matrix

Model

Peppas

Plot

Hixson

Crowell

n

Value

Best Fit

Model

F1 0.9589 0.8069 0.9011 0.9665 0.8386 0.9860 Peppas

F2 0.9584 0.7750 0.8381 0.9672 0.8901 0.9212 PeppasF3 0.9590 0.8016 0.8398 0.9672 0.9011 0.9789 Higuchi

F4 0.9594 0.8117 0.8406 0.9058 0.9675 0.9716 Peppas

F5 0.9571 0.7724 0.8433 0.8956 0.9641 0.8806 Peppas

F6 0.9583 0.7950 0.8414 0.9653 0.9021 0.9212 Higuchi

F7 0.9538 0.8460 0.9340 0.9623 0.8841 0.9789 HiguchiF8 0.9547 0.8921 0.9390 0.9624 0.8476 0.9860 Peppas

F9 0.9571 0.8807 0.8452 0.9637 0.9335 0.9212 Peppas

BEST FIT MODELS FOR ALL FORMULATION

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In-Vitro Drug Release from Ranolazine Tablets

Forall formulations dissolution study was carried out. The percentage release

for all formulation was calculated.

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Plot of cumulative %release against time in ranolazine

pulsatile tablets (trial batches)Sr. no. Time F1 F2 F3 F4 F5 F6 F7 F8

Hrs

1 0 0 0 0 0 0 0 0 0

2 1 0.124 0.103 0,009 0.091 0.098 0.103 0.008 0.0423 2 1.115 1.115 1.253 1.007 1.051 1.004 1.213 1.354

4 3 3.247 3.462 3.889 2.542 2.221 2.227 3.077 3.116

5 4 25.222 27.664 24.221 27.654 29.985 30.542 31 32.333

6 5 41.337 43.785 43.225 44.554 49.356 43.358 53.798 55.963

7 6 55.309 51.356 49.456 61.708 62.254 55.254 56.947 59.47

8 7 61.474 61.68 60.38 66.436 62.989 60.36 66.578 59.793

9 8 62.467 70.235 65.436 69.436 70.367 65.254 72.975 73.36

10 9 71.221 74.543 76.382 77.328 83.367 85.081 80.173 84.50711 10 81.247 84.256 90.12 91.35 88.25 83.778 91.45 92.546

0

10

20

30

40

50

60

70

80

90

1 2 3 4 5 6 7 8 9 10 11 12

Sr.no.

Time

F1

F2

F3F4

F5

F6

F7

F8

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Sr.no Time hr. F1 F2 F3 F4 F5 F6 F7 F8 F9

1 0 0 0 0 0 0 0 0 0 0

2 1 0.126 0.103 0.114 0.103 0.091 0.103 0.08 0.091 0.091

3 2 1.253 1.025 1.253 1.287 1.344 1.31 1.356 1.333 1.344

4 3 2.507 2.621 2.735 2.963 2.849 2.621 3.077 3.191 2.849

5 4 33.395 32.94 33.145 33.373 35.309 34.17 35.423 36.79 35.309

6 5 48.226 48.271 48.898 49.126 52.544 51.404 53.798 55.963 52.544

7 6 58.54 59.656 60.454 61.708 65.13 62.849 67.637 68.211 65.13

8 7 68.08 68.605 68.618 68.643 69.792 69.559 69.899 70.803 69.792

9 8 71.196 72.359 73.113 73.252 74.618 74.271 75.534 76.45 74.618

10 9 83.563 82.427 82.988 84.744 83.367 85.081 80.173 84.507 84.164

11 10 98.13 98.906 98.408 98.31 99.221 98.852 95.408 95.761 95.839

plot of cumulative %release against time in Ranolazine pulsatile release tablets (factorial batches)

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Regression Analysis:

Response surface plot showing effect of formulation variables on percent drug

release (YI) at 10 hr

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Design-Expert SoftwareFactor Coding: Actualrelease

Design Points99.22

95.4

X1 = A: lactoseX2 = B: eudragit

23.50 23.70 23.90 24.10 24.30 24.50

1.50

2.10

2.70

3.30

3.90

4.50release

A: lactose

B

:

e

u

d

ra

g

it

96

96

9798

99

Contour plot showing effect of formulation variables on cumulative % drug

release at 10 hr(Y1)

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Design-Expert Softwarerelease

Color points by value ofrelease:

99.22

95.4

Actual

P

re

d

icte

d

Predicted vs. Actual

95.00

96.00

97.00

98.00

99.00

100.00

95.00 96.00 97.00 98.00 99.00 100.00

Correlation between actual and predicted values for cumulative % drug

release at 10 hr (Y1)

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Accelerated stability study

Based on the results of the % drug release study the optimized batch was selected. The

batch F 5 possessed the highest potential to release the drug gradually for more than 10 hrs

in a controlled manner

It shows slight decrease in drug release of tablets after 1 months of period.

Table :-Drug release profile for tablet kept for Stability Study.

Results in Table confirmed that the prepared formulations were stable at the studied

temperature.

Formulation

Code

Tested after time

(in days)

Hardness kg/cm2 Drug content

uniformity (%)

F5

10 10.60 99.06

20 11.07 99.4

30 11.65 98.8

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Conclusion

Various approaches were tried for the assessment of pulsatile release of ranolazine

with the aid of eudragit L and S 100 as polymers.

No interaction between the drug and excipient was noted, and drug-excipient

compatibility study FTIR confirmed no interaction between the drug and polymer.

Pulsatile tablet of ranolazine showed promising results to be a controlled releaseformulation.

Performance enhancement was done by optimization of the proportion of eudragit

L and S 100 in the formulation. Selection of optimized batch was done as per

performance evaluation.

It was observed that in the in-vitrodrug release, the batch F 5possessed the highest

potential to release the drug gradually for more than 10 hrs.

It was observed from the overall studies that, ranolazinepossesses the potential for

pulsed release from the tablet. 41


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Delivery Technology 2004;4(5):1-11.

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4. Sarasija S, Pathak S. Chronotherapeutics: Emerging role of biorhythms in optimizing Drug

therapy. Ind. J. Pharm. Sci. 2005;67(2):135-40.

5. Bernard RC. Ranolazine for the treatment of chronic angina and potential use in other

cardiovascular conditions. American Heart Association, Inc.Circulation.2006; 113:2462-2472.

6. Nash DT, Nash SD. Ranolazine for chronic stable angina. Int. J. Pharm. The Lancet, 2009;

373(9665): 722 .

7. Jawad E, Arora R. Chronic stable angina pectoris. Disease-a-Mounth. 2008 Sep; 54(9): 671-

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8. Binders HJ, Foster ES, Budinger ME, Hayslett JE. Mechanism of electroneutral sodium

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15. Dawoodbhai S, Rhodes C.T. Pharmaceutical and cosmetic uses of talc .Drug Delivery

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