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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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TH NK YOU