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FORMULATION AND EVALUATION OF DULOXETINE HYDROCHLORIDE
DELAYED RELEASE PELLETS WITH THE AID OF NON IONIC BARRIER LAYER
PROJECT SUBMITTED TO
Jawaharlal Nehru Technological University, Kakinada
In Partial Fulfillment of the Requirement for the Award of the Degree
MASTER OF PHARMACY
in
PHARMACEUTICS
In Collaboration with
Pellets Pharma Limited
Submitted by
Ms. PUVVADA VIJAYA SRI
Reg. No. 137N1S0301
(2013 – 2015)
Under the Guidance of
Mr. PUTTA SAI KRISHNA, M. Pharm., (Ph. D)
Assistant Professor
Department Of Pharmaceutics
VIJAYA INSTITUTE OF PHARMACEUTICAL SCIENCES FOR WOMEN
Enikepadu, Vijayawada 1

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CONTENTS
1. INTRODUCTION, AIM & OBJECTIVES
2. DRUG PROFILE
3. EXPERIMENTAL METHODOLOGY
4. RESULTS & DISCUSSION
5. SUMMARY
6. CONCLUSION
7. REFERENCES

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1. INTRODUCTION1
 Oral drug delivery is the most oldest and predominant route.
 Most of the scientists facing the challenge with the oral drug delivery systems is
destruction of acid liable drugs in the GIT.
 Delayed drug release is the best approach to resist the drug degradation in the acidic
medium. It can be achieved by the application of enteric coating.
 Pellets are the better solid dosage forms due to its less travel time from stomach to
duodenum, when compared with enteric coated tablets require approximately half an
hour to more than 8 hours.
 Duloxetine is an acid liable drug and it requires enteric coating for delayed drug release
Drug + HPMCP Phthalamide
Drug + HPMCAS Succinamide

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AIM & OBJECTIVES
AIM: The present study was aimed to formulate and evaluate Duloxetine Hydrochloride
delayed release pellets with the opadry white as non interactive layer and by using HPMC
P 55 as an enteric coated polymer.
OBJECTIVES: The main objectives are as follows
 To develop stable barrier layer between the drug and the enteric polymer with opadry
white to prevent the reaction between the drug and enteric polymer.
 To perform evaluation tests for the prepared formulations initially and after the
accelerated stability studies.
 To optimize formulations based on the evaluation tests of assay and in vitro dug release
after 3 months stability studies as per ICH guidelines.

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2. DRUG PROFILE2
Duloxetine HCl which is categorized as antidepressant drug is used to treat various
diseases such as major depressive disorder fibromyalgia, diabetic peripheral neuropathic
pain, premenstrual disphoretic disorder and stress incontinence.
PHYSICO CHEMICAL PROPERTIES: STRUCTURE:
Molecular
Formula
C18H19NOS HCl
Molecular
Weight
333.8755 g/mol
IUPAC NAME (3S)-N-methyl-γ-(1naphthyloxy)-2-
thiophenepropylamine hydrochloride
Appearance White to off white colour solid

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MECHANISM OF ACTION:
Duloxetine is a potent dual inhibitor of neuronal serotonin and nor epinephrine
reuptake and its potentiates serotonergic and noradrenergic activity in the CNS.
PHARMACOKINETICS:
Absorption: Orally administered duloxetine hydrochloride is well absorbed from
the intestine. The absolute oral bioavailability of duloxetine ranged from 32% to
80% . Tmax of 6 hours.
Distribution: Duloxetine is approximately 96% bound to human plasma proteins.
Volume of distribution is 1640 L.
Metabolism: The major biotransformation pathways involve oxidation of the
naphthyl ring followed by conjugation and further oxidation.
Excretion: The elimination half-life of duloxetine ranges from 8 to 17 hours.

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3. EXPERIMENTAL METHODOLOGY
3.1 PRE-FORMULATION STUDIES
A) Determination of Physico-Chemical Properties of Drug:
a) Solubility Analysis
b) Micromeritic Properties
B) Determination of Drug - Excipient Compatibility Studies:
a) FTIR Studies - 4000 – 400 cm-1
b) Physical compatibility studies (Accelerated stability studies)
3.2 ESTIMATION OF DULOXETINE HCl
A) Construction of Calibration Curve with pH 6.8 Phosphate Buffer:
B) Construction of Calibration Curve with 0.1N HCl:

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3.3 FORMULATION OF DULOXETINE HCL PELLETS:
Drug Layering
Ingredient (kg) F1 F2 F3 F4 F5 F6 F7 F8 F9
Sugar Spheres 0.572 0.550 0.527 0.505 0.482 0.460 0.438 0.416 0.394
Duloxetine HCl 0.250 0.250 0.250 0.250 0.250 0.250 0.250 0.250 0.250
HPMC E5 0.037 0.037 0.037 0.037 0.037 0.037 0.037 0.037 0.037
Talc 0.012 0.012 0.012 0.012 0.012 0.012 0.012 0.012 0.012
Cross Povidone 0.025 0.025 0.025 0.025 0.025 0.025 0.025 0.025 0.025
Purified Water 1.640 1.640 1.640 1.640 1.640 1.640 1.640 1.640 1.640
Barrier Coating
2.5% 5% 7.5% 10% 12.5% 15% 17.5% 20% 22.5%
Opadry White 0.022 0.044 0.067 0.089 0.112 0.134 0.156 0.178 0.200
Purified Water 0.830 0.830 0.830 0.830 0.830 0.830 0.830 0.830 0.830
Enteric Coating
HPMCP-55 0.050 0.050 0.050 0.050 0.050 0.050 0.050 0.050 0.050
TEC 0.005 0.005 0.005 0.005 0.005 0.005 0.005 0.005 0.005
Talc 0.005 0.005 0.005 0.005 0.005 0.005 0.005 0.005 0.005
IPA 0.330 0.330 0.330 0.330 0.330 0.330 0.330 0.330 0.330
Acetone 0.500 0.500 0.500 0.500 0.500 0.500 0.500 0.500 0.500
Protective Coating
Opadry White 0.020 0.020 0.020 0.020 0.020 0.020 0.020 0.020 0.020
Talc 0.002 0.002 0.002 0.002 0.002 0.002 0.002 0.002 0.002
Purified Water 0.330 0.330 0.330 0.330 0.330 0.330 0.330 0.330 0.330
Total 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000 1.000

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METHOD OF PREPARATION OF DULOXETINE HCL PELLETS:
A) Drug Loading / Drug Layering: 30 % solid
content of suspension was prepared.
FBC Process Parameters for Drug coating
S. No Process Parameters Drug Coating
1. Inlet Temperature (°C) 50-55
2. Outlet Temperature (°C) 34-38
3. Product Temperature (°C) 38-42
4. Atomization Air (bar) 0.4-0.8
5. Spray Rate (gm/min) 3-6
6. Spray Pump Speed 5-7
7. Air Flow (CFM) 47-55
8. Absolute Humidity (gm/kg) 8
Stir the mixture for 15 minutes
by using remi mixer until it
forms a uniform suspension
Cross Povidone and talc was
added to the above dispersion
Duloxetine HCl was added for
the above mixture and stir to
get uniform dispersion
HPMC E5 mixed with water in
a beaker

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B) Barrier Coating: Major step of the coating process.
Non interactive or separating layer of opadry white
was developed between the drug and enteric layer.
FBC Process Parameters for Barrier Coating
S. No Process Parameters Barrier Coating
Prepared coating solution was
sprayed on to the drug layered
pellets.
5 % of excess was prepared to
recover any loss during the
practical work.
Different concentrations of (2.5
%, 5 % .....22.5 %) of opadry
white suspensions were
prepared
Opadry white dispersed in
purified water and mix it until
formation of white colour
suspension

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C) Enteric Coating: 6 % w/w of enteric coating suspension was prepared.
S. No Process Parameters Enteric Coating
FBC Process Parameters for Enteric Coating
Finally talc was added and
mixed with the help of remi
mixer
Separately, TEC was added to
the acetone and mixed for few
minutes, then add this mixture
to the above suspension with
continuous stirring.
Accurately weighed 5 %
HPMC P 55 and added to the
Isopropyl alcohol

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S. No Process Parameters Top Coating
Protective layer coated pellets
were collected and finally sifted
to separate any formed fines or
agglomerates
The resulting suspension was
coated on the enteric coated
pellets
Opadry white and talc
dispersed in the purified water
and mixed well
FBC Process Parameters for Top Coating
D) Top / Protective Coating: 2 % w/w opadry white top coating suspension was
prepared to protect pellets from the absorption of moisture from atmosphere.

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×100
3.4 EVALUATION TESTS FOR FINISHED DULOXETINE HCL PELLETS
A) Surface Morphology: The morphology of pellets was examined by scanning electron
microscopy. Samples are freeze dried, cross sectioned and then placed onto aluminum
stubs coated with adhesive.
B) Flow Property Characterization3:
a) Angle of Repose: Tan θ = h / r
b) Bulk Density & Tapped Density: c) Carr’s Index & Hausner’s Ratio:
C) Pellet Size Distribution: #18, #20, #25, #30 and #35 ASTM sieves
D) Friability: 10 gms of pellets were weighed, combined with 15 steel beads and placed in
the friabilator and was rotated at a rate of 25 rpm for 5 minutes.

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50 mg of Duloxetine HCl was taken
into a 50 ml volumetric flask and
make up the volume to 50 ml with
diluting solvent
5 ml of filtrate was transferred to a
50 ml volumetric flask and make up
to 50 ml with diluting solvent.
Pellets (2 gm) were grinded and take
25 mg equivalent of sample was
diluted to 50 ml of diluting solvent
From the above take 5 ml of filtrate
and diluted to 25 ml with diluting
solvent.
E) Determination of Water content: Around 50ml of methanol was taken in titration
vessel of Karl Fischer titrator. Pellets were grinded to fine powder in a dry motor
then, 500 mg of the sample transferred quickly to the titration vessel, stirred to
dissolve and titrated with Karl Fischer reagent to the end point.
F) Assay of Duloxetine HCl Pellets:
Mobile Phase & Diluting Solvent: Mixture of 5 % triethyl amine, acetonitrile and
water in the ratio of 20:50:30 was prepared.
Standard Preparation: Test Preparation:

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Chromatographic Conditions of HPLC:
Column: 250 x 4.6 mm, C18, 5 micron
Flow Rate: 0.57 ml/min
Injection Volume: 20 µl
Run Time : 7 min
Detector: UV 290 nm
G) In vitro Dissolution Studies7:
Apparatus : USP Type  (Basket)
Medium : 0.1 N HCl & pH 6.8 Phosphate buffer
Volume : 1000 ml
RPM : 100
Temperature : 37.0 ± 0.50 C
Time : 120, 130, 140, 150, 160, 170, 180, 190, 200 and 210 min
Absorbance : 290 nm
Procedure: The standard solution
was injected in 5 replicates. Test
solution was injected in duplicate.

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H) Stability Studies4:
Weigh 30 gm of of Duloxetine HCl pellets and were made into 3 packs containing 10gm
each by packing in HDPE bags and stored at accelerated stability conditions.
After 3 months, samples were studied for, assay and In vitro evaluation.
I) Drug Release Kinetics5:
Zero Order Release
First order Release
Higuchi Model
Korsmeyer Peppas model
Hixson Crowell Plot

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4. RESULTS & DISCUSSION
4.1 PRE-FORMULATION STUDIES:
A) Solubility Analysis: Duloxetine HCl was very slightly soluble in water, very soluble in
dimethylsiloxane and freely soluble in ethanol and isopropyl alcohol.
B) Micromeritic Properties:
S. No Parameter Obtained Values
1 Particle Size (µm) 12.06 ± 0.46
2 Angle of Repose (0) 19.26 ± 0.74
3 Bulk Density (gm/cc) 0.562 ± 0.08
4 Tapped Density (gm/cc) 0.634 ± 0.05
5 Compressibility Index (%) 11.35 ± 1.0
6 Hausner’s Ratio 1.12 ± 0.04
Mean  S.D. of three determinations

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C) Drug and Excipient Compatibility Studies:
FTIR Spectra for the Pure Duloxetine HCl
FTIR Spectra for Duloxetine HCl + HPMC E5 FTIR Spectra for Duloxetine HCl + HPMCP 55
FTIR Spectra for Duloxetine + Opadry White

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S. No Functional Groups
Wave
Numbers (cm-1)
Range of Absorption
Frequencies
Drug
1 C-H Stretching 3062.52 3000-3100
2 C-O Stretching 1186.90 1000-1300
3 C=C Stretching 1634.25 1620-1680
4
C-N Stretching
1223.27
1180-1360
5 Thiophene 1463.81 1400-1500
FTIR Interpretations of Duloxetine HCl:
Inference: Spectral peaks wave numbers of Duloxetine HCl are within the
standard range of absorption frequencies. Mixture of drug and excipient
peaks also reflected at the same region and there were no supplemental peaks
when compared with the standard peaks of Duloxetine HCl.

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D) Drug and Excipient Physical Compatibility Studies:
S. No Drug and Excipient Mixture
Drug +
Excipient
Ratio
Initial 3 Months
1 Duloxetine HCl 1 gm White to off –
white powder
NCC
2 Duloxetine HCl + HPMC E5 1:1 Off – white
Powder
Pink coloured
powder
3 Duloxetine HCl + Talc 1:1 Off – white
Powder
NCC
4 Duloxetine + TEC 1:1 Off – white
Powder
NCC
5 Duloxetine HCl + Crosspovidone 1:1 Off – white
Powder
NCC
6 Duloxetine HCl + HPMC P- 55 1:1 Off – white
Powder
Pink coloured
powder
7 Duloxetine HCl + Opadry White 1:1 Off – white powder NCC
Observations after 3 Months of Accelerated Stability Studies
After stability studies, physical mixtures of drug with HPMC P 55 and HPMC E5 showed
a change in colour from off white to pink indicating that they were not compatible with
duloxetine HCl on storage.

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4.2 ESTIMATION OF DULOXETINE HCl:
S. No
Concentration
(µg/ml)
Absorbance at
(290 nm)
1 2 0.154 ± 0.003
2 4 0.332 ± 0.002
3 6 0.542 ± 0.003
4 8 0.682 ± 0.001
5 10 0.840 ± 0.002
y = 0.0861x - 0.0066
R² = 0.9953
0
0.2
0.4
0.6
0.8
1
1.2
0 5 10 15
Absorbance
Concentration (µg / ml)
S. No
Concentration
(µg/ml)
Absorbance at
(290 nm)
1 2 0.210 ± 0.002
2 4 0.401 ± 0.003
3 6 0.572 ± 0.002
4 8 0.810 ± 0.003
5 10 0.988 ± 0.001
y = 0.0983x + 0.0067
R² = 0.9976
0
0.2
0.4
0.6
0.8
1
1.2
1.4
0 5 10 15
Absorbance
Concentration (µg/ml)
Construction of Calibration Curve with 0.1 N HCl
Construction of Calibration Curve with 6.8 pH Phosphate Buffer

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4.3 EVALUATION TESTS FOR FINISHED DULOXETINE HCl PELLETS:
A) Flow Property Characterization:
Ranged between 22.110 - 25.140 indicating that the good flow properties of pellets.
Range of 9 – 14 for Carr’s index and hausner’s ratio between 1.09 -1.16 was found to be
within the I.P limits
S. No Formulation Angle of
Repose (0)
Bulk Density
(gm/ml)
Tapped
Density
(gm/ml)
Carr’s Index
(%)
Hausner’s
Ratio
1 F1 22.26 ± 0.012 0.98 ± 0.010 1.14 ± 0.012 14.0 ± 0.16 1.16 ± 0.014
2 F2 25.01 ± 0.014 0.95 ± 0.014 1.08 ± 0.015 12.0 ± 0.13 1.14 ± 0.017
3 F3 24.03 ± 0.011 0.98 ± 0.012 1.12 ± 0.014 12.5 ± 0.15 1.14 ± 0.015
4 F4 22.11 ± 0.016 0.98 ± 0.012 1.13 ± 0.013 13.2 ± 0.12 1.15 ± 0.013
5 F5 23.10 ± 0.014 0.97 ± 0.013 1.09 ± 0.012 11.0 ± 0.15 1.12 ± 0.011
6 F6 24.01 ± 0.012 0.96 ± 0.014 1.05 ± 0.014 9.0 ± 0.11 1.09 ± 0.013
7 F7 22.89 ± 0.015 0.97 ± 0.012 1.09 ± 0.013 12.0 ± 0.13 1.12 ± 0.012
8 F8 24.54 ± 0.013 0.98 ± 0.011 1.14 ± 0.011 14.0 ± 0.11 1.16 ± 0.011
9 F9 25.14 ± 0.015 0.98 ± 0.013 1.13 ± 0.012 13.2 ± 0.12 1.15 ± 0.012

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B) Scanning Electron Microscope (SEM):
C) Pellet Size Distribution:
SEM photomicrograph showed that pellets
were spherical shape and had smooth
surface.
S. No Formulation
Code
Pellet Size
Distribution (%)
1 F1 94.4 ± 1.4
2 F2 96.2 ± 1.2
3 F3 95.1 ± 1.2
4 F4 93.5 ± 1.4
5 F5 96.3 ± 0.9
6 F6 93.4 ± 1.6
7 F7 94.2 ± 1.3
8 F8 95.6 ± 1.3
9 F9 94.3 ± 1.5
The formulated pellets were within the
size range of 710 – 1000 µm, based on
the maximum weight of the pellets
distributed between the 18 - 25 sieve
size mesh.

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D) Friability and water content determination:
The prepared pellets showed friability of less than 1 % of weight loss.
Obtained water content values were ranged between the 1.22 % - 1.39 % which are
within the acceptable limits of below 1.5 %.
S. No Formulation Code Friability (%) % Water Content
1 F1 0.54 ± 0.016 1.22 ± 0.012
2 F2 0.42 ± 0.015 1.35 ± 0.015
3 F3 0.56 ± 0.013 1.16 ± 0.013
4 F4 0.59 ± 0.016 1.28 ± 0.012
5 F5 0.41 ± 0.014 1.39 ± 0.015
6 F6 0.32 ± 0.014 1.24 ± 0.015
7 F7 0.68 ± 0.012 1.32 ± 0.014
8 F8 0.65 ± 0.015 1.18 ± 0.012
9 F9 0.52 ± 0.013 1.27 ± 0.013

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E) Assay of Duloxetine HCl: Results of all formulations ranged between 97.05 –
99.43 % and according to USP (90 – 110 %), it was found to be within the limits
S. No Formulation Code Drug Content (%)
1 F1 98.16 ± 0.4
2 F2 99.05 ± 0.5
3 F3 98.22 ± 0.3
4 F4 98.54 ± 0.6
5 F5 97.86 ± 0.9
6 F6 98.23 ± 0.6
7 F7 97.05 ± 0.7
8 F8 99.43 ± 0.6
9 F9 99.26 ± 0.4

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F) In vitro Drug Release Studies:
Time (min) F1 F2 F3 F4 F5 F6 F7 F8 F9
0 0 0 0 0 0 0 0 0 0
120 0.91 ± 0.02 0.87 ± 0.03 0.89 ± 0.02 0.90 ± 0.04 0.88 ± 0.03 0.85± 0.05 0.86 ± 0.02 0.89 ± 0.04 0.87 ± 0.03
130 29.18 ± 0.6 26.84 ± 1.0 28.93 ± 0.6 26.32 ± 0.4 28.13 ± 0.7 27.21 ± 1.2 27.90 ± 0.8 29.21 ± 0.6 28.68 ± 1.1
140 43.54 ± 1.2 41.26 ± 0.9 44.59 ± 1.4 42.65 ± 0.5 43.65 ± 1.5 43.16 ± 1.8 44.62 ± 0.5 46.78 ± 0.7 45.41 ± 0.8
150 56.13 ± 0.8 55.92 ± 0.4 57.46 ± 0.9 55.52 ± 0.4 57.56 ± 0.6 56.33 ± 0.8 58.17 ± 2.0 59.23 ± 1.0 58.87 ± 0.8
160 68.62 ± 0.7 68.28 ± 0.6 69.58 ± 0.7 67.92 ± 0.6 69.19 ± 0.9 68.72 ± 1.0 70.39 ± 0.6 71.54 ±0.5 69.83 ± 0.8
170 79.02 ± 0.9 78.05 ± 0.5 80.22 ± 1.3 78.37 ± 0.9 81.72 ± 0.5 80.60 ± 0.5 82.42 ± 0.7 82.67 ± 0.8 80.74 ± 1.5
180 89.25 ± 0.8 87.27 ± 0.8 88.94 ± 1.2 87.96 ± 0.6 89.54 ± 1.3 88.09 ± 0.7 89.25 ± 1.2 90.82 ± 0.9 90.14 ± 0.7
190 94.85 ± 1.0 92.53 ± 0.7 92.71 ± 0.5 93.02 ± 0.4 93.49 ± 0.6 94.24 ± 1.1 94.76 ± 0.9 94.68 ± 0.8 95.87 ± 1.0
200 96.22 ± 0.5 94.69 ± 0.3 95.19 ± 0.8 97.37 ± 0.8 95.49 ± 0.8 96.48 ± 0.9 96.71 ± 0.5 97.20 ± 0.4 97.69 ± 0.5
210 97.41± 0.7 96.13 ± 0.9 97.85 ± 1.2 98.07 ± 0.7 96.54 ± 1.1 98.20 ± 0.5 97.58 ± 0.8 98.26 ± 0.6 99.04 ± 0.5

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-20
0
20
40
60
80
100
120
0 50 100 150 200 250
Time (min)
F1
F2
F3
F4
%DrugRelease
-20
0
20
40
60
80
100
120
0 50 100 150 200 250
Time (min)
F5
F6
F7
F8
F9
%DrugRelease
Comparative in vitro Drug Release Profiles of Duloxetine HCl Enteric Coated Pellets from
Formulations F1 – F4 & F5 – F9
After 2 hours of dissolution studies in 0.1 N HCl drug release was found to be
0.91 %, 0.87 %, 0.89 %, 0.90 %, 0.88 %, 0.85 %, 0.86 %, 0.89 % and 0.87 %
within the limits.
5 % coating of HPMCP 55 was enough to resist the drug release in acidic medium.
As the concentration of HPMC P 55 is constant in all formulations similar % cumulative
drug release of above 95 % was found after 90 minutes in pH 6.8 phosphate buffer.

28
G) Accelerated Stability Studies: After accelerated stability studies drug content
and In vitro dissolution studies were determined.
Time (min) F1 F2 F3 F4 F5 F6 F7 F8 F9
0 0 0 0 0 0 0 0 0 0
120 25.52 ± 0.6 23.08 ± 0.8 20.30 ± 0.6 18.27 ± 0.4 15.84 ± 0.6 11.31 ± 0.5 6.23 ± 0.7 2.36 ± 0.4 1.94 ± 0.5
130 35.56 ± 1.0 34.26 ± 0.6 31.79 ± 1.2 31.03 ± 0.7 30.15 ± 0.8 29.68 ± 1.1 28.90 ± 0.8 29.05 ± 0.6 27.90 ± 0.9
140 44.63 ± 0.8 43.92 ± 0.5 40.56 ± 0.9 42.35 ± 0.6 42.47 ± 1.0 40.54 ± 0.8 42.86 ± 0.6 44.15 ± 0.7 43.03 ± 0.6
150 50.28 ± 0.6 50.73 ± 0.7 47.48 ± 0.6 49.07 ± 0.8 52.95 ± 0.9 49.33 ± 0.7 54.71 ± 1.2 57.92 ± 0.9 57.12 ± 1.4
160 52.41 ± 0.8 55.12 ± 0.5 54.76 ± 1.3 56.32 ± 0.7 59.91 ± 0.6 58.42 ± 1.0 64.27 ± 0.9 68.09 ± 0.7 69.06 ± 0.8
170 55.31 ± 0.5 58.45 ± 0.9 57.60 ± 0.6 61.61 ± 1.0 64.40 ± 1.2 65.60 ± 0.6 72.42 ± 0.9 77.82 ± 0.8 79.14 ± 0.7
180 57.42 ± 0.9 60.89 ± 0.7 60.12 ± 0.5 65.40 ± 0.9 67.63 ± 0.4 72.89 ± 0.9 80.15 ± 0.5 88.05 ± 1.1 87.05 ± 0.7
190 58.03 ± 0.6 61.02 ± 1.0 62.43 ± 0.9 67.82 ± 0.7 69.34 ± 0.7 77.24 ± 1.1 86.61 ± 1.0 93.52 ± 0.9 92.28 ± 0.8
200 59.04 ± 0.4 61.98 ± 0.9 63.44 ± 0.7 68.05 ± 1.3 70.42 ± 0.5 81.80 ± 0.8 90.34 ± 0.6 95.84 ± 0.5 95.77 ± 0.6
210 59.04 ± 0.4 62.71 ± 0.8 65. 39 ± 0.5 68.12 ± 0.9 71.89 ± 0.4 83.47 ± 0.6 92.58 ± 0.8 96.35 ± 0.5 97.02 ± 0.4
Mean ± S.D of two determinations
In Vitro Drug Release of Duloxetine HCl Pellets after Accelerated Stability Studies

29
According to the USP acceptance criteria Duloxetine HCl pellets of 25 % w/w should
release not less than 75 % within 70 min. But the formulations F1 – F6 showed the drug
release of 58.03 %, 61.02 %, 62.43 %, 67.82 % and 69.34 % at 70 min.
F6 – F9 showed the drug release of 77.24 %, 86.61 %, 93.52 % and 92.28 % at 70 min
within the acceptable limits.
0
20
40
60
80
100
120
F1 F2 F3 F4 F5 F6 F7 F8 F9
Initial After 3 Months Accelerated
%CumulativeDrugRelease
Formulation Code
Comparative Representation of % Cumulative Drug Release Before and after Stability Studies

30
Formulation
Code
After 3 Months Stability Studies (40 ºC / 75 % RH)
Assay (%) In Vitro Drug Release (%)
at 210 min
% Cumulative of Drug Release
in 0.1 N HCl
Initial After Stability Initial After Stability Initial After Stability
F1 98.16 ± 0.4 61.12 ± 1.0 97.41 ± 0.7 59.04 ± 0.4 0.91 ± 0.02 25.52 ± 0.6
F2 99.05 ± 0.5 63.52 ± 0.8 96.13 ± 0.9 62.17 ± 0.8 0.87 ± 0.03 23.08 ± 0.8
F3 98.22 ± 0.3 66.87 ± 0.9 97.85 ± 1.2 65.39 ± 0.5 0.89 ± 0.02 20.30 ± 0.6
F4 98.54 ± 0.6 68.92 ± 0.8 98.07 ± 0.7 68.12 ± 0.9 0.90 ± 0.04 18.27 ±0.4
F5 97.86 ± 0.9 74.43 ± 0.6 96.54 ± 1.1 71.89 ± 0.4 0.88 ± 0.03 15.84 ± 0.6
F6 98.23 ± 0.6 85.68 ± 0.7 98.20 ± 0.5 83.47 ± 0.6 0.85 ± 0.05 11.31 ± 0.5
F7 97.05 ± 0.7 93.82 ± 0.5 97.58 ± 0.8 92.58 ± 0.8 0.86 ± 0.02 6.23 ± 0.7
F8 99.43 ± 0.6 97.41 ± 0.4 98.26 ± 0.6 96.35 ± 0.5 0.89 ± 0.04 2.36 ± 0.4
F9 99.26 ± 0.4 98.37 ± 0.6 99.04 ± 0.5 97.02 ± 0.4 0.87 ± 0.03 1.94 ± 0.5
Comparison between Initial Results and after Stability Results of Drug
Content and In Vitro Drug Release Studies

31
Assay of F1 to F6 failed to meet the USP specifications (90 – 110 %) of Duloxetine HCl.
The deviation was probably due to insufficient concentration of barrier layer (opadry
white) to prevent the reaction (degradation) of drug with enteric coating polymer.
But the formulations F8 and F9 showed good results
F1 – F6 showed the drug release as 25.52 %, 23.08%, 20.30 %, 18.17%, 15.84 % and
11.31 %, which clearly depicted that the drug was unstable in acidic phase.
F7, F8 and F9 formulations showed drug release within the limits (less than 10 %) as
6.23 %, 2.36 % and 1.94 %.
From all observations it was be confirmed that F1 – F6 formulations was failed to meet
the specifications due to low load of barrier coating of 2.5 % - 15 % since it leads to
reaction between the enteric polymer and the drug.

32
I) Drug Release Kinetics:
S. No Time
(min)
% Cumulative Drug Release
F8 F9
1 0 2.36 1.94
2 10 29.05 27.90
3 20 44.15 43.73
4 30 57.92 57.12
5 40 68.09 69.06
6 50 77.82 79.14
7 60 88.05 87.05
8 70 93.52 92.28
9 80 95.84 95.77
10 90 96.35 97.02
Zero Order Release Kinetics
y = 1.0063x + 20.031
R² = 0.9128
0
20
40
60
80
100
120
0 20 40 60 80 100
Time (min)
%Cumulativedrugrelease
y = 1.0163x + 19.297
R² = 0.9147
0
20
40
60
80
100
120
0 20 40 60 80 100
Time (min)
%Cumulativedrugrelease

33
S. No Time
(min)
Log % Drug Remaining
F8 F9
1 0 1.989 1.991
2 10 1.836 1.848
3 20 1.728 1.740
4 30 1.599 1.612
5 40 1.470 1.462
6 50 1.297 1.276
7 60 0.981 1.041
8 70 0.614 0.761
9 80 0.255 0.359
10 90 0.110 0.017
First Order Release Kinetics
y = -0.0216x + 2.1581
R² = 0.9544
0
0.5
1
1.5
2
2.5
0 20 40 60 80 100
Log%DrugRemaining
Time (min)
y = -0.0212x + 2.1648
R² = 0.9497
0
0.5
1
1.5
2
2.5
0 20 40 60 80 100
Log%DrugRemaining
Time (min)

34
S. No Square
Root Time
% Cumulative Drug
Release
F8 F9
1 0 2.36 1.94
2 3.162 29.05 27.90
3 4.472 44.15 43.73
4 5.477 57.92 57.12
5 6.324 68.09 69.06
6 7.071 77.82 79.14
7 7.745 88.05 87.05
8 8.366 93.52 92.28
9 8.944 95.84 95.77
10 9.486 96.35 97.02
Higuchi Release kinetics Data
y = 10.815x - 0.7044
R² = 0.9873
-20
0
20
40
60
80
100
120
0 2 4 6 8 10
Square Root Time
y = 10.91x - 1.5723
R² = 0.9872
-20
0
20
40
60
80
100
120
0 2 4 6 8 10
Square Root Time

35
Korsmeyer - Peppas Release Kinetics
S. No Log Time
Log % Cumulative Drug
Release
F8 F9
1 0 0.372 0.287
2 1 1.463 1.445
3 1.301 1.644 1.633
4 1.477 1.762 1.756
5 1.602 1.833 1.839
6 1.698 1.891 1.898
7 1.778 1.944 1.939
8 1.845 1.970 1.965
9 1.903 1.981 1.981
10 1.954 1.983 1.986
y = 0.8189x + 0.4921
R² = 0.9689
0
0.5
1
1.5
2
2.5
0 0.5 1 1.5 2 2.5
Log Time
%LogCumulativedrugrelease
y = 0.8617x + 0.4185
R² = 0.9665
0
0.5
1
1.5
2
2.5
0 0.5 1 1.5 2 2.5
Log Time
%LogCumulativedrugrelease

36
Hixson-Crowell cube-root Model Release Kinetics
S. No Time
Cube Root of % Drug
Remainig
F8 F9
1 0 4.604 4.611
2 10 4.093 4.132
3 20 3.767 3.803
4 30 3.411 3.446
5 40 3.091 3.072
6 50 2.706 2.664
7 60 2.124 2.223
8 70 1.603 1.794
9 80 1.216 1.318
10 90 1.088 1.013
y = -0.0405x + 4.5935
R² = 0.9921
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
5
0 20 40 60 80 100
Time (minutes)
CubeRoot%DrugRemaining
y = -0.0401x + 4.6131
R² = 0.9983
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
5
0 20 40 60 80 100
Time (min)
CubeRoot%DrugRemaining

37
Regression Coefficient (R2) Values of Kinetic Models
Inference: From the kinetic data both the optimized formulations F8 and F9 showed
first order drugs release, as they got regression (R2) value of 0.9544 and 0.9497 and
rate of release was 2.1797 and 2.3209 hr-1 respectively. The mechanism of drug release
from both the formulations F8 and F9 was found to be non fickian diffusion with
erosion, which was confirmed from the n value (0.818 and 0.861 respectively) of
Korsmeyer – Peppas model and regression value (0.9921 and 0.9983) of Hixson -
Crowell model.
Optimised
Formulation
Zero
Order
(R2)
First
Order
(R2)
Higuchi
(R2)
Peppas Model Hixon
Crowell
(R2)
K - Value
(hr-1)
(R2) n
F8 0.9128 0.9544 0.9873 0.9689 0.818 0.9921 2.1797
F9 0.9147 0.9497 0.9872 0.9665 0.861 0.9983 2.3209

38
5. SUMMARY
Micromeritic properties such as particle size, flow properties of Duloxetine HCl were
determined and were found to be good.
Drug and excipient compatibility studies were performed by using FTIR and blends of
drug and excipient were stored at accelerated stability conditions.
Method of estimation of Duloxetine HCl was obeyed the Beer-Lambert’s law and
regression coefficient was found to be 0.9953 in 0.1N HCl and 0.9976 in 6.8 pH
phosphate buffer.
Different formulations of Duloxetine HCl pellets were prepared by using HPMC E5
(5%) as enteric coating layer and Opadry white (2.5 %, 5 %, 7.5 %, 10 %, 12.5 %, 15 %,
17.5 %, 20 % and 22.5 %) as barrier layer.
Post formulation evaluations such as flow properties, friability, water content, size
distribution, assay and in- vitro studies were performed for total nine formulations and
were found to be within the limits.

39
At accelerated stability conditions (45ºC and 75 % RH) all nine formulations were
studied for stability for 3 months.
After 3 months samples were studied for assay and in vitro drug release and
optimization based on the results.
Obtained Results clearly revealed that formulations F8 & F9 which consists of 20 %
& 22.5 % of barrier coating was found to be good without any considerable change
in drug content and in vitro drug release.
Optimized formulations F8 & F9 were studied for drug release kinetics of various
models zero order, first order, Higuchi, Korsmeyers – Peppas and Hixson Crowell.
Kinetics data revealed that optimized formulations F8 and F9 followed first order
kinetics with non Fickian diffusion mechanism.

40
6. CONCLUSION
Duloxetine hydrochloride delayed release pellets were prepared by suspension layering
technique. It was concluded that the stability of formulation was found to be a function of
barrier layer.
Formulations F8, F9 containing 20 %, 22.5 % barrier layer coating met the specifications
and were found to be stable after accelerated stability studies for 3 months. Hence during
shelf life of Duloxetine HCl pellets a non interactive barrier layer was must between the
drug and enteric polymer.

41
7. REFERENCES
1) D. Shravani, P. K. Lakshmi and J. Balasubramaniam; Preparation and Optimization of
Various Parameters of Enteric Coated Pellets using the Taguchi L9 Orthogonal Array
Design and their Characterization; Acta Pharmaceutica Sinica B, 2011; 1 (1): 56 – 63.
2) http://www.accessdata.fda.gov/drugsatfda_docs/nda/2010/022516Orig1s000_EA.pdf.
3) Gohel DK, Jain AJ, Patel KN, Patel BA and Patel PA; Formulation and Evaluation of
Delayed Release Pellets of Duloxetine HCl; International Journal for Pharmaceutical
Research Scholars; 2012; 1 (2): 421 - 436.
4) Prathima Srinivas, Preethi Mylavarapu, Venkata Ramana Reddy and Sadanandam
Formulation and Evaluation of Duloxetine Hydrochloride Delayed Release Enteric Coated
Capsules; International Journal of Pharma and Bio Sciences; 2011; 2 (3): 152 – 172.
5) Gautam Singhvi and Mahaveer Singh; Review: In-Vitro Drug Release Characterization
Models; IJPSR; 2011; 2 (1): 77 - 84.
6) USP 36; general chapter < 1210 > Buffer solutions / Buffers.
7) USP 38 – NF 33; Official Monographs / Duloxetine.

42
ACKNOWLEDGEMENT
I am very thankful to Vijaya Institute of Pharmaceutical Sciences
For Women, Vijayawada and Pellets Pharma Ltd. for their guidance
and providing suitable facilities to carry out this project work.

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