design, preparation and in vitro characterization of

Sridhar et al. European Journal of Biomedical and Pharmaceutical Sciences

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271

DESIGN, PREPARATION AND IN VITRO CHARACTERIZATION OF DULOXETINE

THE TRANSDERMAL PATCH

*B. Sridhar and Dr. G. Praveen Kumar

Pharmaceutics, Sahasra Institute of Pharmaceutical Sciences, Hasanparthy Mandal, Vangapahad Village, Warangal,

Telangana India.

Article Received on 05/01/2021 Article Revised on 25/01/2021 Article Accepted on 15/02/2021

INTRODUCTION

Transdermal drug delivery (TDD) is an appropriate mode

of medicine distribution for administering the medicine

right into the body across the skin. TDD is not a new

idea; for hundreds of years, people make use of drug on

the skin for recovery local injuries.[1]

Nevertheless, it

takes even more emphasis current age as a valuable

mode of medicine delivery. It is becoming prominent in

medical practice each day as a result of its potentiality of

using the option of oral and injectable dose forms.

Numerous advantages are noticed for TDD prep work,

such as- evasion of first-pass metabolic rate, delivery of

stable mixture of the medicine for an extended time,

decrease of adverse effects, easy application and

elimination of TDD films/patches, person approval, and

so on.[2,3]

Moreover, it is possible to reduce the potential

hazards (side effects) of the medication by instilling

TDD medication via skin rather than intravenous mixture

(a remarkable setting of drug delivery).[4]

Duloxetine is a twin serotonin as well as norepinephrine

reuptake inhibitor. It was initially discovered in 1993 as

well as established by Eli Lilly and Business as

LY248686.[5]

Duloxetine initially received approval from

the FDA in August, 2004 as Cymbalta for the therapy of

Major Depressive Disorder. It has given that gotten

approval for a range of signs including the treatment of

neuropathic discomfort, Generalized Anxiety disorder,

osteo arthritis, and stress urinary incontinence.

Duloxetine remains to be explored for the therapy of pain

in cancer cells, surgery, as well as more. IUPAC name is

methyl [(FOUR)-3-(naphthalen-1-yloxy)-3-(thiophen-2-

yl)propyl] amine. Molecular weight is 297.417.

Duloxetine hydrochloride (DXH) struggles with

inadequate solubility and consequently inadequate

absorption, which eventually causes inadequate

bioavailability.

Fig 1: Chemical structure of Duloxitine.

MATERIALS

The Duloxetine was supplied by Sunpharma, Hyderabad,

India, Ethyl cellulose N45 from Colorcon Asia Pvt. Ltd,

Hpmck15m from Loba Chemie, Methanol was of high

SJIF Impact Factor 6.044 Research Article ejbps, 2021, Volume 8, Issue 3, 271-282.

European Journal of Biomedical AND Pharmaceutical sciences

http://www.ejbps.com

ISSN 2349-8870

Volume: 8

Issue: 3

271-282

Year: 2021

*Corresponding Author: B. Sridhar Pharmaceutics, Sahasra Institute of Pharmaceutical Sciences, Hasanparthy Mandal, Vangapahad Village, Warangal, Telangana India.

DOI: https://doi.org/10.17605/OSF.IO/KF5XJ

ABSTRACT

Transdermal drug delivery (TDD) is an acceptable mode of drug delivery for administering the drug into the body

across the skin. Duloxetine is a dual serotonin and norepinephrine reuptake inhibitor. The formulation developed

by using polymers such as Ethyl cellulose n45, HPMCk15m polymers are used in different trails in different

quantity is used. The Dibutyl phthalate is used as plasticizer and DMSO (Dimethyl sulfoxide) used as permeation

enhancer. The formulation s F1-F9 are formulated. After completion of formulation the evaluation parameters are

performed. The evaluation parameters values for optimized formulation such as, The Thickness of the transdermal

patch is found to be,0.28, The drug content study was found to be, 98.89 %, The moisture loss studies found to be,

7.68%, The moisture absorption studies found to be, 10.46%, The weight variation of patch was found to be,

199mg, The In-vitro drug release studies found to be, 99.34, The all performed evaluation parameters are found to

be values within the limits of range.

KEYWORDS: Duloxetine, Transdermal patch, Ethyl cellulose N45, Hpmck15m.



272

performance liquid chromatography (HPLC) grade. All

other reagents and solvents were of analytical reagent

grade

METHODOLOGY

PREFORMULATION STUDIES[6-13]

ORGANOLEPTIC CHARECTERS

Preformulation studies like organoleptic characters such

as taste, odour, color can be observed by visually.

SOLUBILITY STUDIES

The drug solubility parameter carried out by water,

ethanol, methanol, DMSO, acetone, the results are kept

in Results.

FTIR STUDIES: The pure drug, Duloxetine and the

physical mixtures of drug and polymers were mixed

separately with IR grade KBr and corresponding pellets

were prepared and scanned in wavelength region

between 4000 to 400 cm-1. The spectra of the drug were

compared with polymers.

CALIBRATION OF DULOXETINE IN

METHANOL

PREPARATION OF STANDARED STOCK

SOLUTION

10mg of Duloxetine drug was taken and dispensed the

drug was dissolved in 10ml of volumetric flask it is

1000ppm.

Preparation of 2nd

stock solution

Take 1ml of sample from 1st stock solution and diluted

with medium make up to mark in 10 ml of volumetric

flask it is 100ppm.

To take 1ml of from 2nd

stock solution and make up to 10

ml of volumetric flask with medium it is 10ppm this is

kept under absorbance in U.V visible spectroscopy at

224 nm. The absorbance is high the serial dilutions are

prepared like 2,4,6,8,10 and check absorbance in U.V

visible spectroscopy.

CALIBRATION OF DULOXETINE IN WATER

PREPARATION OF STANDARED STOCK

SOLUTION

10mg of Duloxetine drug was taken and dispensed the

drug was dissolved in 10ml of volumetric flask it is

1000ppm.

Preparation of 2nd

stock solution

Take 1ml of sample from 1st stock solution and diluted

with medium make up to mark in 10 ml of volumetric

flask it is 100ppm.

To take 1ml of from 2nd

stock solution and make up to 10

ml of volumetric flask with medium it is 10ppm this is

kept under absorbance in U.V visible spectroscopy at

224nm. The absorbance is high the serial dilutions are

prepared like 2,4,6,8,10 and check absorbance in U.V

visible spectroscopy.

FORMULATION TABLE OF DULOXETINE TRANSDERMAL PATCH

Table No: 1: Formulation design of the Duloxetine patches.

Ingredient’s F1 F2 F3 F4 F5 F6 F7 F8 F9 Duloxetine 80 80 80 80 80 80 80 80 80 HPMC k15m 10 - 10 20 20 30 30 40 40 Ethyl cellulose N45 - 10 10 - 20 - 30 - 40 DBP (plasticizer) 2ml 2ml 2ml 2ml 2ml 2ml 2ml 2ml 2ml DMSO (permeation enhancer) 3ml 3ml 3ml 3ml 3ml 3ml 3ml 3ml 3ml Water q.s q.s q.s q.s q.s q.s q.s q.s q.s Methanol q.s q.s q.s q.s q.s q.s q.s q.s q.s

PROCEDURE

The Duloxetine transdermal patch prepared by solvent

casting method.

Polymer solution: The polymers which are selected for

Duloxetine patch dissolved in respective solvents such as

water and methanol. Kept under for stirring at 500rpm

for 1hr.

Drug solution: The drug solution was added after

formation viscous nature and keeps stirring for

homogeneous mixing of polymer and drug solution.

Then add plasticizer DBP (dibutyl phthalate) and add

permeation enhancer such as dmso. The drug and

polymeric mixture poured into the petriplate and dry it

24hrs for at 450c. After drying by using sharp blades the

patch was removed.

EVALUATION PARAMETERS

PHYSICAL APPEARANCE

All the prepared Duloxetine films were observed for

color, clarity, flexibility, and smoothness.

FOLDING ENDURANCE

The folding endurance is one of the evaluation

parameters. Folding endurance of the patches was

resolved by repeatedly folding at the same place till it

broke. The number of folding of patch was done till



273

without braking of prepared transdermal patch. This was

repeated for all formulated Duloxetine patches for 3

times and the mean values plus standard deviation was

calculated.

THICKNESS OF THE FILM The thickness of each film was measured by using screw

gauze. The thickness was measured at three different

places on each film and the average thickness of the film

was taken as the thickness of the film.

WEIGHT UNIFORMITY: - The prepared patches are

to be dried at 600C for 4hrs before testing. A specified

area of 4.52 cm2

of patch is to be cut in different parts of

the patch and weigh in digital balance. The average

weight and standard deviation values are to be calculated

from the individual weights.

FLATNESS

Flatness was estimated by randomly selected five

longitudinal strips were cut out from mediated patch of

each formulation; the length of each strip was calculated

before and after kept at room temperature for 30 minutes.

Variation in length due to non uniformity of flatness was

calculated by percent constriction, with 0% constriction

as 100% flatness.

DRUG CONTENT

The buccal films (2 cm2) were added to conical flask

containing 100 ml of phosphate buffer pH 7.4 contain

0.5%SLS. This was then stirred with magnetic bead at

400 rpm for 2 hrs. The contents were filtered and the

filtrate was analysed spectrophotometrically for drug

content at 268 nm. Similarly, a blank was prepared from

buccal films without drug.

Where, DT = Total amount of the drug in the patch

Da = the amount of drug released

Conditions

Medium: Phosphate buffer pH 7.4 containing 0.5% SLS

RPM: 200

Temperature: 37 ± 0.50C

Time intervals: 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12hours

MOISTURE ABSORPTION STUDIES

The films were dispensed accurately and kept in a

aluminum chloride containing desiccators to maintain

79.50% RH. After 3 days, the films were taken out and

weighed. The percentage of moisture uptake was

calculated using the following formula.

%moisture uptake content=Final wt-Intial wt/Intial

wtΧ100

MOISTURE LOSS STUDIES

Three films were weighed individually and kept in a

desiccator containing calcium chloride at 370C for 24

hrs. Then the final weight was noted when there was no

further change in the weight of the patch. The percentage

of moisture loss was calculated using the following

formula.

IN-VITRO DRUG RELEASE STUDIES: In-vitro

dissolution studies carried out by using A modified Franz

diffusion cell was used for Duloxetine transdermal patch.

The dissolution medium is 7.4 ph phosphate buffers. In

Franz diffusion cell the medium was poured about 10ml

the semipermeable membrane kept around the Franz

diffusion cell. The dissolution studies kept for 12 hours.

The time intervals minted for 1hr. The 1ml of aliquoted

was withdrawn and same amount of sample replaced in

diffusion cell. The withdrawn aliquot was diluted with

7.4 ph phosphate buffer. The absorbance analyzed under

U.V visible spectroscopy at the 224nm.

KINETIC PROFILE

Kinetics and mechanism of drug release from all

formulation was evaluated on the basis of zero order,

Higuchi equation and Pappas model. Correlation

coefficient (r2) and slop value for each equation was

calculated from Microsoft excel. Zero order plot for all

formulations were found to be linear in both dissolution

medium. That indicates it may follow zero order

mechanism. Higuchi plot was found to be linear, which

indicates diffusion may be the mechanism of drug

release for each formulation. Peppas plot was found good

linear, n > 0.5 for all formulations, indicated that drug

release may follow anomalous diffusion. Zero order plot

for F4 formulation was found to be linear in both

dissolution medium, it considered as a best fit for drug

release.

STABILITY STUDIES: - Stability of a drug has been

defined as the stability of a particular formulation,

specific container, to remain within its physical,

chemical, therapeutic and toxicological specifications

throughout its shelf life. The purpose of the stability

testing is to provide information on the quality of a drug

substance or its product, which varies with time under

the effect of environmental factors such as temperature,

humidity and light. Recommended storage conditions,

re-test periods and shelf lives are to be established.



274

RESULTS

PRE- FORMULATION STUDIES

ORAGANOLEPTIC CHARACTERS

Table No: 2: Organoleptic characteristics of the Duloxetine drug.

Properties Results

Description White crystals

Taste Tasteless

Odor Bitter

Color White colour

Discussion: The organoleptic properties of Duloxetine

were found to be white to off white in colour, odourless

and slightly unpleasant in taste and were as per the

specifications.

SOLUBILITY

Table no 3: Solubility studies of the Duloxetine.

Solvent Solubility properties of drug (1gm) Water Soluble

Discussion: Duloxetine was found to be soluble in water.

CALIBRATION CURVE IN METHANOL

Table no: 4: Calibration curve values of the

Duloxetine in methanol.

S.NO Concentration (µg/ml) Absorbance(nm)

1 0 0

2 10 0.18

3 20 0.35

4 30 0.51

5 40 0.69

6 50 0.89

Fig.No: 2 picture showing calibration curve in acetone.

CALIBRATION CURVE IN WATER

Table no: 5: Showing table calibration curve values of the Duloxetine in water.

S.NO Concentration (µg/ml) Absorbance(nm) 1 0 0 2 10 0.19 3 20 0.35 4 30 0.49 5 40 0.65 6 50 0.82



275

Fig. No: 3 showing picture of calibration curve in water.

FTIR STUDIES

Fig.no: 4. FTIR study of pure drug of Duloxetine.

Fig.no:5 The FTIR spectra of the Duloxetine drug +ethyl cellulose N45+hpmc k15m.



276

Compatibility studies were performed using FTIR

spectrophotometer. The FTIR spectrum of Pure drug and

physical mixture of drug and polymers were studied. The

characteristic absorption peaks were observed at

1146.57cm-1

, 1087.98 cm-1

, cm-1

, 687cm-1

, 2934cm-1

for

the pure Duloxetine and absorption peaks were observed

at 1148.650 cm-1

, 1085cm-1

, 680 cm-1

, 1716 cm-1

, 2850

cm-1

for drug and polymer mixture show that how they

were in official limits (±100 cm-1

) the drug is compatible

with excepients.

EVALUATION STUDIES FOR DULOXETINE TRANSDERMAL PATCH F1-F4

Table no: 6: Showing table evaluation values of the Duloxetine patch.

Formulation code F1 F2 F3 F4

Thickness (mm) 0.26± 1.2 0.26± 1.3 0.25±1.7 0.26±1.6

Weight variation (mg) 181 ± 1.2 184 ± 1.2 191±1.4 197±1.2

Drug content Uniformity 97.41±0.3 97.56 ±0.4 98.24±0.6 98.52±0.5

Folding endurance 304 ± 2 302±1 301±8 300±8

Swelling index 27.22 31.53 30.62 32.60

% of moisture loss 5.61 6.53 7.79 7.88

% of moisture absorption 11.23 11.78 12.12 11.22

EVALUATION STUDIES FOR ATENLOOL TRANSDERMAL PATCH F5-F9

Table no: 7: Showing table evaluation values of the Duloxetine patch.

Formulation code F5 F6 F7 F8 F9 Thickness (mm) 0.27± 1.2 0.29± 1.3 0.28±1.7 0.31±1.6 0.30±1.8 Weight variation (mg) 194 ± 1.2 197 ± 1.2 199±1.4 199±1.2 201±1.8 Drug content Uniformity 98.51±0.3 97.26 ±0.4 98.89±0.6 97.82±0.5 98.44±0.8 Folding endurance 299 ± 2 298 ±1 301±8 300±8 300±9 Swelling index 21.22 29.53 32.62 29.60 30 %of moisture loss 7.8 6.98 7.68 7.2 5.65 % of moisture absorption 11.6 11.43 10.46 11.56 11.23

The above all the formulations under kept for the

evaluation studies such as the weight variation, folding

endurance, drug content, swelling index all F1-F9

formulations come under within range of limits.

IN VITRO DRUG RELEASE STUDIES OF ALL FORMULATIONS F1-F9

Table no: 8: Showing table In-vitro drug release values of the Duloxetine patch.

Time F1 F2 F3 F4 F5 F6 F7 F8 F9

0 0 0 0 0 0 0 0 0 0

1 21.52 23.22 19.5 14.45 17.65 16.82 19.31 17.2 18.86

2 33.53 31.53 20.65 24.45 27.65 29.56 27.52 23.56 35.75

3 46.6 48.40 31.65 34.85 36.65 42.78 40.46 42.33 45.85

4 59.5 67.52 42.87 47.65 48.52 57.54 60.75 52.90 67.22

5 78.6 81.75 56.32 57.88 61.75 67.28 74.78 65.54 78.65

6 96.56 97.52 68.65 69.71 74.88 77.93 90.78 76.88 87.83

7 - 105.85 72.56 77.83 77.82 87.75 94.32 87.12 91.85

8 - - 82.86 89.78 88.54 94.65 99.34 95.76 94.74



277

10.5. ALL COMPARATIVE DRUG RELEASE PROFILE GRAPH

Fig.No:6 showing picture of the all comparative graphs of F1-F9.

COMPARATIVE DRUG RELEASE PROFILE OF GRAPH F1-F3

Table no: 9: Comparative In-vitro values of the Duloxetine patch F1-F3.

Time F1 F2 F3 0 0 0 0 1 21.52 23.22 19.5 2 33.53 31.53 20.65 3 46.6 48.40 31.65 4 59.5 67.52 42.87 5 78.6 81.75 56.32 6 96.56 97.52 68.65 7 - 105.85 72.56 8 - - 82.86

Fig.No:7 showing picture of comparative graphs of F1-F3.



278

COMPARATIVE DRUG RELEASE PROFILE FOR F4-F6


Time F4 F5 F6 0 0 0 0 1 14.45 17.65 16.82 2 24.45 27.65 29.56 3 34.85 36.65 42.78 4 47.65 48.52 57.54 5 57.88 61.75 67.28 6 69.71 74.88 77.93 7 77.83 77.82 87.75 8 89.78 88.54 94.65

Fig.No:8 Showing picture of comparative graphs of F4-F6.

COMPARATIVE DRUG RELEASE PROFILE FOR F7-F9


Time F7 F8 F9 0 0 0 0 1 19.31 17.2 18.86 2 27.52 23.56 35.75 3 40.46 42.33 45.85 4 60.75 52.90 67.22 5 74.78 65.54 78.65 6 90.78 76.88 87.83 7 94.32 87.12 91.85 8 99.34 95.76 94.74



279

Fig. No: 9 Showing picture of comparative graphs of F7-F9.

KINETIC STUDY FOR THE OPTIMIZED FORMULATION(F7)

Table no: 12: Kinetic values of the Duloxetine patch optimized F7.

Time %cdr Log T √T Log%cdr ARA Log%ARA 0 0 1 0 1 100 2 1 19.31 0 1 1.26 81.79 1.912 2 27.52 0.30103 1.414 1.45 71.38 1.853 3 40.46 0.47712 1.732 1.61 58.44 1.766 4 60.75 0.60206 2 1.77 40.38 1.606 5 74.78 0.69897 2.236 1.87 24.35 1.386 6 90.78 0.778151 2.449 1.95 10.47 1.019 7 94.32 0.845098 2.645 1.98 4.35 0.634 8 99.34 0.90309 2.828 1.99 0.35 -0.455

ZERO ORDER PLOT

Fig.No:10 zero order equation.



280

FIRST ORDER PLOT

Fig.No:11 First order equation.

HIGUCHI PLOT

Fig.No:12 higuchi equation.

KROSS MAYER PEPPAS

Fig.No:13 krossmayer peppas equation.



281

Table no: 13: Showing table kinetic values of the Duloxetine patch optimized F7.

S.no Zero

oreder First

order Higuchi

Krossmayer

peppas Code R

2 R2 R

2 R2

F7 0.980 0.806 0.934 0.108

It was concluded that the optimized formulation F7,

followed zero order release where the regression value

was found to be 0.980 It was also found that the drug

was released by diffusion as the regression in Higuchi’s

plot was 0.934.

STABILITY STUDIES

There was no significant change in physical and

chemical properties of the Duloxetine of Optimized

formulation F-7 after 3 Months of stability studies.

Parameters quantified at various time intervals were

shown;

Table 14: Results of stability studies of optimized formulation F-7.

Formulation

Code Parameters Initial 1

st Month 2

nd Month 3

rd Month

Limits as per

Specifications

F-7 25

0C/60%RH

% Release 99.34 98.64 98.57 99.18

Not less than

85 %

Table 15: Stability dissolution profile of F-6 for 1st, 2nd & 3rd months.

S.NO. TIME(Hrs) intial F-7 1M F-7 2M F7 3M

1 0 0 0 0 0

2 1 19.31 15.50 16.26 17.50

3 2 27.52 26.50 27.20 28.30

4 3 40.46 44.48 40.45 41.75

5 4 60.75 62.10 57.65 58.46

6 5 74.78 77.27 74.24 76.32

7 6 90.78 88.36 87.52 88.82

8 7 94.32 94.58 94.55 93.47

9 8 99.34 98.64 98.57 99.18

Stability dissolution profile of F-7for 1st, 2nd & 3rd months

STABILITY STUDY GRAPH

Fig.No:14 Stability graph.

SUMMARY

The main aim and objective are to development and

characterization of Duloxetine patch. The Duloxetine

transdermal patch is formulated by using different

polymers the plasticizer and permeation enhancers are

also used in the formulation. First the review literature is



282

carried out for the selection of drug and selection of

polymers and all excipients.

Before going to develop the formulation the pre

formulation studies are carried out. They are appearance,

color, odor. The compatibility studies carried out such as

FTIR studies the drug and excipient compatibility study

carried out they are compatible with each other.

The formulation developed by using polymers such as

Ethyl cellulose n45, HPMCk15m polymers are used in

different trails in different quantity is used. The Dibutyl

phthalate is used as plasticizer and DMSO (Dimethyl

sulfoxide) used as permeation enhancer. The formulation

s F1-F9 are formulated. After completion of formulation

the evaluation parameters are performed.

The evaluation parameters values for optimized

formulation such as,

The Thickness of the transdermal patch is found to be,

0.28

The drug content study was found to be, 98.89 %

The moisture loss studies found to be, 7.68%

The moisture absorption studies found to be, 10.46%

The weight variation of patch was found to be, 199mg

The In-vitro drug release studies found to be, 99.34%

The all performed evaluation parameters are found to be

values within the limits of range.

After completion of drug release studies, the kinetic data

was calculated for optimized formulation it fallows the

zero order and fallows higuchi equation.

The stability studies are performed for optimized

formulation for 90days at accelerated stability studies.

There is no degradation in drug release and drug content

studies.

CONCLUSION

The development and characterization of Duloxetine

transdermal patch is developed by using synthetic

polymers such as HPMC k45, Ethyl cellulose n45 were

used. The Di butyl phthalate is used as plasticizer and Di

methyl sulfoxide is used as permeation enhancer. The

patch is formulated by applying by solvent casting

method. After formulation development the evaluation

parameters performed all came under the range of limits.

The drug release the optimized formulation F7 was

found to be 99.34%. The kinetic profile performed for

optimized formulation they follow the zero order and

higuchi equation. The stability studies carried out for 90

days there is no degradation in optimized formulation in

drug release and drug content studies.

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