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,

Seat.no.1806

CAMP, PUNE
2011-2013

INTRODUCTION
PULSATILE 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 circadian rhythm 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 over an extended period of time (patterns B & C in Figure). 05

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 Ranolazine
Category: 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 Properties Melting Point Solubility Micromeritic Properties

Excipient characterization

FTIR UV-Visible Spectroscopy SEM PXRD

Organoleptic Properties Solubility

FTIR

Drug-Excipient compatibility study

FT-IR SEM
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Composition of Pulsatile Ranolazine Tablets formulations (TRIAL BATCHES)

Ingredients
Ranolazine Lactose Micro crystalline cellulose Magnesium stearate Starch mucilage

F1
500 75 25.5 1.5 10

F2
500 75 24 1.5 10

F3
500 30 75 1.5 10

F4
500 28.5 75 1.5 10

F5
500 27 75 1.5 10

F6
500 25.5 75 1.5 10

F7
500 24 75 1.5 10

F8
500 24 75 1.5 10

Talc
Sod.Starch glycolate

3
7.5

3
9

3
3

3
4.5

3
6

3
7.5

3
9

3
9

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Coating Composition Coating solution polymer and solvent ratios profile (TRIAL BATCHES)
Sr.No 1 2 Ingredient F1 E S 100 : E L 100 DiButylPthalate DiEthylPthalate Isopropyl alcohol Acetone
0.75:0.7 5 1:1 F2 1:1 1:1 F3 1.5:1. 5 1:1 F4 F5 F6 1.75:1.7 5 1:1 F7 1.75:1.7 5 1:1 F8 1:2 1:1

1:1.75 1.75 :1 1:1 1:1

70:30

70:30 70:30

70:30

70:30

70:30

70:30

70:30

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Selection of optimized batch

Selection of independent variables Parameters Lactose Eudragit l/s 100 Variable X1 X2

Formulation of batch
Levels of variable VARIABLES ( -1) X1 X2 23.5 (mg) 1.5 (g) (0) 24.5 (mg) 3 (g) LEVELS (+1) 24 (mg) 4.5 (g)

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Composition of different batches based on factorial design

Batch code F1 F2 F3 F4 F5 F6 F7 F8 F9 23.5 23.5 23.5 24 24 24 24.5 24.5 24.5 Independent variables X1 (lactose) X2 (eudragit l /s 100) 1.5 3 4.5 1.5 3 4.5 1.5 3 4.5

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Evaluation of tablets
Thickness Hardness Uniformity of weight Uniformity of content Friability In-vitro drug release from tablets Stability studies

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RESULT AND DISCUSSIONS

DRUG CHARACTERIZATION
A. Organoleptic Properties:
Sr. No. 1. 2. 3. 4. Appearance Colour Odour Taste Nature Observations White Slight Slightly Bitter Slightly hygroscopic

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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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

Sr.No. 1. 2 2. 3. 4.

Solvents Distilled water 7.5 P B Ethanol Methanol Acetone

Observations Very Slightly Soluble Soluble Sparingly Soluble Soluble Insoluble

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D. Micromeritic Properties:

Micromeritic Properties of Ranolazine

Sr. No 1 2 3 4 5 Parameter BULK DENSITY TAPPED DENSITY % COMPRASIBILITY HAUSNER RATIO ANGLE OF REPOSE Observations 0.471 0.681 30.85 1.445 30.26

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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
0.7

0.6

0.5 ABSORBANCE y = 0.006x - 0.0007 R = 0.9995

0.4

0.3

0.2

0.1

0 0 20 40 60 CONCENTRATION 80 100 120

Calibration curve of ranolazine in 7.5 P B

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G. FT-IR spectrum of drug

cm-1 3350 3328 1686

Functional groups -NH stretch (amine) -OH stretch (hydroxyl) -C=O stretch (Aliphatic)

1641, 1592 1128

-Aromatic (two bonds) -C=C Stretching bonds

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H.SEM OF RANOLAZINE

SEM Image of ranolazine at 1000x resolution

SEM Image of ranolazine at 1500x resolution

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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 1. 2. 3. 4.

Appearance Color Odor Taste Nature

Observations White Characteristic Tasteless Fine powder

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B. Solubility study Solubility of Eudragit L and S 100 is checked as follows Solubility of Eudragit L and S 100
Sr. No 1 2 3 Solvents Distilled water Ethanol Chloroform Observations Insoluble Soluble Soluble

4 5

Acetone 0.05 M HCL

Soluble 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

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A. IR spectroscopy

Drug-Excipient Compatibility Study

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B. SEM OF FORMULATION MIXTURE

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

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

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PRECOMPRESSED PARAMETERS

Batch code F F F F F F F F F 1 2 3 4 5 6 7 8 9

Angle of repose () 24.80.32 27.40.08 28.40.21 28.40.06 25.80.15 26.20.07 28.10.09 27.20.09 26.20.07

Bulk density (g/cm3) 0.490.013 0.510.013 0.470.02 0.550.025 0.490.012 0.440.006 0.510.002 0.540.04 0.440.006

Tapped density (g/cm3) 0.550.014 0.580.002 0.530.012 0.590.0112 0.560.012 0.490.021 0.580.001 0.56 0.013 0.490.021

Carrs index (%) 10.909 12.068 11.320 6.779 12.5 10.204 12.068 12.056 10.204

Hausners ratio 1.122 1.137 1.127 1.072 1.142 1.113 1.137 1.124 1.113

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EVALUATION OF TABLET PARAMETERS

*Formulation Code F1

*Uniformity of *Hardness Thickness(mm) (kg/cm2) (SD) (SD) 5.95 0.030 8.6 0.54

Friability % *Weight(mg) (SD) (SD) 0.201 6701.095

*Drug Content(%) (SD) 100.00.77

F2
F3 F4 F5 F6 F7 F8 F9

5.09 0.081
5.80 0.034 5.90 0.036 5.46 0.050 5.95 0.032 5.80 0.034 5.95 0.030 5.95 0.032

9.9 0.44
11.70.19 8.9 0.26 10.30.57 9.3 0.65 11.70.19 8.6 0.54 9.3 0.65

0.264
0.226 0.247 0.193 0.144 0.226 0.201 0.144

7211.507
6991.000 6981.577 7381.141 7102.141 6991.000 6701.095 7102.141

97.553.07
98.100.32 97.383.11 98.780.76 99.880.16 98.100.32 100.00.77 99.880.16

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EVALUATION OF COATED TABLET PARAMETERS

Formulation Code F1 F2 F3 F4 F5 F6 F7 F8 F9

Uniformity of Thickness(mm) 5.96 0.042 5.99 0.038 5.85 0.018 5.89 0.072 5.68 0.056 5.97 0.033 5.85 0.018 5.96 0.042 5.97 0.033

Hardness (kg/cm2)
10.5 0.55 9.9 0.84 11.7 0.24 10.5 0.63 9.8 0.11 11.1 0.14 11.7 0.24 10.5 0.55 11.1 0.14

Weight variation
7400.085 7331.024 7461.021 7520.099 7481.018 7291.028 7461.021 7400.085 7291.028

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BEST FIT MODELS FOR ALL FORMULATION

Formulat Zero ion Order

First Order

F1 F2 F3 F4 F5 F6 F7 F8 F9

0.9589 0.9584 0.9590 0.9594 0.9571 0.9583 0.9538 0.9547 0.9571

0.8069 0.7750 0.8016 0.8117 0.7724 0.7950 0.8460 0.8921 0.8807

Higuchi Matrix Model 0.9011 0.8381 0.8398 0.8406 0.8433 0.8414 0.9340 0.9390 0.8452

Peppas Plot

Hixson Crowell

n Value

Best Fit Model

0.9665 0.9672 0.9672 0.9058 0.8956 0.9653 0.9623 0.9624 0.9637

0.8386 0.8901 0.9011 0.9675 0.9641 0.9021 0.8841 0.8476 0.9335

0.9860 0.9212 0.9789 0.9716 0.8806 0.9212 0.9789 0.9860 0.9212

Peppas Peppas Higuchi Peppas Peppas Higuchi Higuchi Peppas Peppas

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In-Vitro Drug Release from Ranolazine Tablets

For all formulations dissolution study was carried out. The percentage release for all formulation was calculated.

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100 90 80 70 60 50 40 30 Sr.no. Time F1 F2 F3 F4 F5 F6 F7 F8

20
10 0 1 2 3 4 5 6 7 8 9 10 11 12

Plot of cumulative %release against time in ranolazine pulsatile tablets (trial batches)
Sr. no. 1 2 3 4 5 6 7 8 9 10 11 Time Hrs 0 1 2 3 4 5 6 7 8 9 10 F1 0 0.124 1.115 3.247 25.222 41.337 55.309 61.474 62.467 71.221 81.247 F2 0 0.103 1.115 3.462 27.664 43.785 51.356 61.68 70.235 74.543 84.256 F3 0 0,009 1.253 3.889 24.221 43.225 49.456 60.38 65.436 76.382 90.12 F4 0 0.091 1.007 2.542 27.654 44.554 61.708 66.436 69.436 77.328 91.35 F5 0 0.098 1.051 2.221 29.985 49.356 62.254 62.989 70.367 83.367 88.25 F6 0 0.103 1.004 2.227 30.542 43.358 55.254 60.36 65.254 85.081 83.778 F7 0 0.008 1.213 3.077 31 53.798 56.947 66.578 72.975 80.173 91.45 F8 0 0.042 1.354 3.116 32.333 55.963 59.47 59.793 73.36 84.507 92.546

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plot of cumulative %release against time in Ranolazine pulsatile release tablets (factorial batches)
Sr.no 1 2 3 4 5 6 7 8 9 10 Time hr. 0 1 2 3 4 5 6 7 8 9 0 F1 F2 0 F3 0 F4 0 F5 0 F6 0 F7 0 F8 0 F9 0

0.126
1.253 2.507 33.395 48.226 58.54 68.08 71.196 83.563

0.103
1.025 2.621 32.94 48.271 59.656 68.605 72.359 82.427

0.114
1.253 2.735 33.145 48.898 60.454 68.618 73.113 82.988

0.103
1.287 2.963 33.373 49.126 61.708 68.643 73.252 84.744

0.091
1.344 2.849 35.309 52.544 65.13 69.792 74.618 83.367

0.103
1.31 2.621 34.17 51.404 62.849 69.559 74.271 85.081

0.08
1.356 3.077 35.423 53.798 67.637 69.899 75.534 80.173

0.091
1.333 3.191 36.79 55.963 68.211 70.803 76.45 84.507

0.091
1.344 2.849 35.309 52.544 65.13 69.792 74.618 84.164

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10

98.13

98.906

98.408

98.31

99.221

98.852

95.408

95.761

95.839

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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 Software Factor Coding: Actual release Design Points 99.22 95.4

4.50

release

3.90

96

B : e u d r a g it

X1 = A: lactose X2 = B: eudragit

3.30

98

97

2.70

2.10

99

96

1.50 23.50 23.70 23.90 24.10 24.30 24.50

A: lactose

Contour plot showing effect of formulation variables on cumulative % drug release at 10 hr(Y1)

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Design-Expert Software release Color points by value of release: 99.22 95.4

99.00 100.00

Predicted vs. Actual

P r e d ic te d

98.00

97.00

96.00

95.00

95.00

96.00

97.00

98.00

99.00

100.00

Actual

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) 10 F5 20 30 Hardness kg/cm2 Drug content uniformity (%) 99.06 99.4 98.8

10.60 11.07 11.65

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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 release formulation. 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-vitro drug release, the batch F 5 possessed the highest potential to release the drug gradually for more than 10 hrs. It was observed from the overall studies that, ranolazine possesses the potential for pulsed release from the tablet.

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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): 67189. 8. Binders HJ, Foster ES, Budinger ME, Hayslett JE. Mechanism of electroneutral sodium chloride absorption in distal colon of the rat. Gastroenterology.1987; 93:44955.

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