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Research Article ISSN 2277-3657
Available online at
www.ijpras.com
Volume 1, issue 3 (2012), 60-72
International Journal of
Pharmaceutical Research &
Allied Sciences
60
Formulation and Evaluation of Mouth Dissolving Film of Ropinirole
Hydrochloride by Using Pullulan Polymers
Ms. Mital S. Panchal*, Mr. Hiren Patel, Mrs. Aarti Bagada, Dr. K.R.Vadalia
Shree H. N. Shukla Institute of Pharmaceutical Education and Research,
B/H -Marketing Yard, Nr. Lalpari Lake, Amargadh (Bhichari), Rajkot-360002
Corresponding E-mail: mitalpanchal17@yahoo.com
Subject: Formulation Science
Abstract:
The present work aimed at preparing mouth dissolving films of Ropinirole Hydrochloride with the purpose of
developing a dosage form for a very quick onset of action, which is very convenient for administration, without
the problem of swallowing and using water. The films of Ropinirole Hydrochloride were prepared by using
polymers such as pullulan and PEG 400 as plasticizer, by a solvent casting method. Formulation batches were
formulated with the help of 3
2
full factorial designs. The fast dissolving oral films were designed using optimal
design and numerical optimization technique was applied to find out the best formulation. The formulated
mouth dissolving films were evaluated for physical characteristics such as uniformity of weight, thickness,
folding endurance, drug content uniformity, surface pH, percentage elongation, and tensile strength, and gave
satisfactory results. The formulations were subjected to disintegration, In-vitro drug release tests and stability
study. The FTIR and DSC studies revealed that no physicochemical interaction between excipients and drug. A
marked increase in the % drug release was exhibited by mouth dissolving films of Ropinirole Hydrochloride
containing pullulan as a polymer at 60 sec., when compared to other polymers films. Mouth dissolving film of
Ropinirole Hydrochloride containing pullulan as polymer showed 99.48 ± 0.18 % drug release at 60 sec. Mouth
dissolving films of Ropinirole Hydrochloride containing pullulan showed better tensile strength (9.67 ± 0.064
g/mm
2
), Percentage elongation (21.59 ± 0.29 %), folding endurance (88.00 ± 1.00 No. of folds), in-vitro
disintegration time (20.33 ± 0.57 sec.), surface pH (6.60 ± 0.10 pH), thickness (0.07 ± 0.01 mm) and percentage
content uniformity (99.53 ±0.37 %). Stability studies revealed that optimized formulation was stable. Mouth
dissolving films of Ropinirole Hydrochloride can be considered suitable for clinical use in the treatment of
parkinson’s disease and rest leg syndrome, where a quicker onset of action for a dosage form is desirable along
with the convenience of administration.
Keyword:
Mouth dissolving film of Ropinirole Hydrochloride, Pullulan, Polyethylene glycol 400, Solvent
casting method, Parkinson disease
Introduction:
Ropinirole Hydrochloride is an orally active,
dopamine receptor agonist used in the treatment of
Parkinson disease Parkinson’s disease is one the
most baffling and complex of neurological
disorder.[1] The term parkinsonism is used for a
motor syndrome whose main symptoms are tremor
at rest, stiffness, slowing of movement and postural
instability.[2] Ropinirole Hydrochloride is the drug
of choice used in the treatment of Parkinson
disease.[2,7] By definition, a solid dosage form that
dissolves or disintegrates quickly in the oral cavity,
resulting in solution or suspension without the need
for the administration of water, is known as an oral
fast-dispersing dosage form. Mouth Dissolving
Film is also known as Fast dissolving film, Quick
dissolving film, Rapid dissolving film, Oral thin
film (OTF), Orally Dissolving Films (ODF).
Bioavailability of drug in film dosage form is
greater than the convectional dosage form.[3]
Special features of Mouth Dissolving Film
[4]
• Thin elegant films
• Various sizes
• Unobstructive
• Mucoadhesion
• Quick dissolving
• Fast disintegrating
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61
• Rapid release
Advantages of Mouth Dissolving Film [5]
• Larger surface area promotes rapid
disintegration and dissolution in the oral
cavity.
• Oral films are flexible and thus less fragile as
compared to ODTs. Hence, there is ease of
transportation and during consumer handling
and storage.
• Precision in the administered dose.
• No risk of choking
• Good mouth feel
• With the help of Mouth dissolving film drug
delivery system those drugs can be given to
the patients that are not crushed and not
injected by patients.
• Improved patient compliance
• Ease of swallowing and no need of water has
led to better acceptability amongst the
dysphagic patients
• Dosage form can be consumed at any place
and anytime as per convenience of the
individual.
• Enhanced oral bioavailability of molecules
that undergo first pass effect.
• Bypassing the first pass effect leads to
reduction of dose which can lead to reduction
in side effects associated with the molecules.
• Mouth Dissolving Films are typically the size
of a postage stamp and disintegrate on a
patient’s tongue in a matter of seconds for the
rapid release of one or more APIs.
Ideal Characteristic of a suitable Drug
Candidate [5]
• The drug should have pleasant taste.
• The drug to be incorporated should have low
dose up to 40 mg.
• The drugs with smaller and moderate
molecular weight are preferable.
• The drug should have good stability and
solubility in water as well as in saliva.
• It should be partially unionized at the pH of
oral cavity.
• It should have the ability to permeate oral
mucosal tissue.
Primary concerns when manufacture Mouth
dissolving films [5, 6]
• Selection of the API: It is very important part
of the process. The selection of API depends
on the potency of API, dose, as well as
therapeutic efficacy. Most suitable API for
ODF includes anti-allergic, antihistaminic,
anti-parkinson, sleeping aids and analgesic
drugs are preferred selection.
• Selection of the Film formers: The film
should be tough enough to physically handle
and the robustness of the film depends on type
of polymer used. Also the film has to be
easily disintegrated in saliva or water to get
immediate action. At least 45% w/w polymer
should be present in the formulation in order
to get good formulation. Along with various
polymers Pullulan, gelatin, HPMC and HPC
are the most commonly used polymers in film
formulation.
• Plasticizer: Plasticizer provides the efficient
plasticity to the ODF formulation. One has to
be careful in determining the plasticizer
concentration. Selection plasticizer depends
on compatibility citrate, PEG 400, glycerin
and triacetin.
• Taste masking: The taste masking is a
prerequisite in the case of oral formulation.
Natural as well as artificial sweeteners are
used to improve the taste as well as intended
to be dissolve and disintegrate in the oral
cavity. The classical source of sugar is
sucrose, fructose, glucose and dextrose.
Saccharine, Sucralose and aspartame are fall
in to the artificial sweetener category
Table I: List of some marketed products available as mouth dissolving film [6]
No: Drugs API Manufacturer/
Distributor Use
1. Listerine® Cool Mint Pfizer, Inc. Mouth Fresheners
2. Benadryl Diphenyhydramine HCL
(12.5 mg or 25 mg) Pfizer Anti allergic
3. Suppress® Menthol (2.5 mg) InnoZen®, Inc. Cough suppressants
4. Klonopin
Wafers Clonazepam ( 0.125mg, 0.25mg,
0.5mg, 1mg and 2mg) Solvay
Pharmaceuticals Treatment of
anxiety
5. Theraflu Dextromethorphan HBR
(15 mg) Novartis Anti allergic
6. Orajel Menthol/pectin (2mg/30mg) Del Mouth ulcer
7. Gas-X Simethicone (62.5 mg) Novartis Anti Flatuating
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62
8. Chloraseptic Benzocaine/menthol (3mg/3mg) Prestige Sore throat
9. Sudafed PE Phenylephrine Wolters Kluwer
Health, Inc. Relieving
congestion
10. Triaminic Diphenyhydramine HCL
(12.5 mg) Novartis Anti allergic
Materials and methods:
Materials:
Ropinirole Hydrochloride, Aspartame (Sunrise
Remedies Pvt. Ltd.Santej, Ahmedabad) Pullulan
(Hayashibara Company Ltd, Japan)and Sucralose
(Alkem Lab. Ltd. Ankleshwar, Gujarat) were
obtained as a gift sample. Polyethylene glycol 400
and sodium chloride were purchased from S.D Fine
Chemicals Ltd, Boisar, India. All the chemicals
were used as received without any further treatment
and purification.
Methods
:
1. PREFORMULTAION STUDIES [10}
Preformulation may be described as a phase of the
research and development process where the
formulation scientist characterizes the physical,
chemical and mechanical properties of new drug
substances, in order to develop stable, safe and
effective dosage forms. Ideally the preformulation
phase begins early in the discovery process such
that the appropriate physical and chemical data
is available to aid the selection of new chemical
entities that enter the development process. During
this evaluation, possible interaction with various
inert ingredients intended for use in final dosage
form was also considered in the present study. The
following data must be considered.
A) Drug - Excipient Compatibility Study
Excipients are integral components of almost all
pharmaceutical dosage forms. The successful
formulation of a stable and effective solid dosage
form depends on the careful selection of the
excipients, which are added to facilitate
administration, to promote the consistent release
and bioavailability of the drug and protect it from
degradation. API and excipients were been
thoroughly mixed in predetermined ratio given in
below table and passed through the 40# sieve. The
blend was filled in transparent glass vials and were
closed with gray coloured rubber stoppers and
further sealed with aluminum seal and charged in
to stress condition at above condition. Similarly
API should also be kept at all condition as for the
samples. Samples were withdrawn for analysis
within two day of sampling date as per the
compatibility study plan. Physical observation
should be done at every week up to 1 month and
FTIR studies and DSC Studies were carried out to
determine the compatibility of excipients with the
drug
• Fourier transform Infrared Spectroscopy
Figure I: FTIR Study
• Drug-Excipient Compatibility Studies by
DSC
DSC thermograms of pure drug (Ropinirole
Hydrochloride) and its physical mixture with
polymers (Pullulan, HPMC, PVA) were carried out
to investigate any possible interaction between the
drug and the utilized polymer (Pullulan, HPMC,
PVA). The selected heating rate is from 50°C to
300°C at an increase of 20°C per minute using
Differential Scanning Calorimeter (shimadzu
corporation, Japan).
2. ANALYTICAL METHOD DEVELOPMENT
2.1. Calibration curve of Ropinirole
Hydrochloride
Calibration curve for Ropinirole Hydrochloride
was developed in 6.8 pH phosphate buffer.
2.2. Calibration curve of Ropinirole
Hydrochloride in phosphate buffer pH 6.8
From Standard stock solution of 100 µg/mL,
appropriate aliquots were taken into different
volumetric flasks and volume was made up to 10
mL with phosphate buffer pH 6.8, so as to get drug
concentrations of 2, 4, 6, 8, 10, 12, 14, 16, 18, 20,
22, 24, 26 and 28 µg/mL. The absorbance of these
drug solutions were estimated at λ
max
250 nm.
3. PREPARATION OF MOUTH
DISSOLVING FILM BY SOLVENT
CASTING METHOD
The MDF of Ropinirole hydrochloride using
polymers were prepared by solvent casting method.
An aqueous solution of the polymers was prepared
in distilled water. Ropinirole hydrochloride was
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63
added to the aqueous polymeric solution. This was
followed by addition of plasticizers like PEG 400.
Sweeteners like aspartame and sucralose were also
added to the above solution. Citric acid and flavour
were also mixed with it. The solution was casted on
a petridish (diameter 9 cm) and dried at room
temperature for 24 hr. The film was carefully
removed from the petridish, checked for any
imperfections and cut into the required size to
deliver the equivalent dose (3 x 2 cm
2
) per strip.
The samples were stored in a dessicator at relative
humidity 30-35 % until further analysis. [11]
4. PREPARATION OF MOUTH DISSOLVING
FILM OF ROPINIROLE HCL BY USING 3
2
FULL FACTORIAL DESIGNS
4.1. Optimization of Mouth dissolving Film
Formulation Using 3
2
Full Factorial Designs
It is desirable to develop an acceptable
pharmaceutical formulation in shortest possible
time using minimum number of man-hours and raw
materials. Traditionally pharmaceutical
formulations after developed by changing one
variable at a time approach. The method is time
consuming in nature and requires a lot of
imaginative efforts. Moreover, it may be difficult to
develop an ideal formulation using this classical
technique since the joint effects of independent
variables are not considered. It is therefore very
essential to understand the complexity of
pharmaceutical formulations by using established
statistical tools such as factorial design. In addition
to the art of formulation, the technique of factorial
design is an effective method of indicating the
relative significance of a number of variables and
their interactions. [14]
The number of experiments required for these
studies is dependent on the number of independent
variables selected. The response (Y
i
) is measured
for each trial.
2
222
2
111211222110
XbXbXXbXbXbbY +++++=
Where Y is the dependent variable, b
0
is the
arithmetic mean response of the nine runs and b
i
is
the estimated coefficient for the factor X
i
. The main
effects (X1 and X
2
) represent the average result of
changing one factor at a time from its low to high
value. The interaction terms (X
1
X
2
) show how the
response changes when two factors are
simultaneously changed.
A 3
2
randomized full factorial design was utilized
in the present study. In this design two factors were
evaluated, each at three levels, and experimental
trials were carried out at all nine possible
combinations. The design layout and coded value
of independent factor is shown in Table 4.11 and
Table 4.12 respectively. The factors were selected
based on preliminary study. The concentration of
Plasticizer PEG 400 (X
1
) and concentration of
Polymer (X
2
) were selected as independent
variables. The formulations of the factorial batches
(F1 to F 27) are shown in Table: 4.13, 4.14 & 4.15.
Table II: 3
2
Full Factorial design layout
Batch code X
1
X
2
F1 -1 -1
F2 -1 0
F3 -1 +1
F4 0 -1
F5 0 0
F6 0 +1
F7 +1 -1
F8 +1 0
F9 +1 +1
Table III: Coded value for plasticizer conc. &
polymer concentration
Coded
value Concentration
of Plasticizer
(mg)
Concentration of
Polymers
Concentration (mg)
-1 112.8 200
0 169.2 300
1 225.6 400
Table IV: Formulations of Mouth dissolving film using pullulan as polymer
Ingredients F1 F2 F3 F4 F5 F6 F7 F8 F9
Ropinirole HCL(mg) 32 32 32 32 32 32 32 32 32
Pullulan (mg) 200 300 400 200 300 400 200 300 400
PEG 400 (mg) 112.8 112.8 112.8 169.2 169.2 169.2 225.6 225.6 225.6
Citric Acid (mg) 70 70 70 70 70 70 70 70 70
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64
Aspartame (mg) 20 20 20 20 20 20 20 20 20
Sucralose (mg) 30 30 30 30 30 30 30 30 30
Strawberry (mL) 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1
Distilled Water (mL) 10 10 10 10 10 10 10 10 10
5 EVALUATION OF MOUTH DISSOLVING
FILMS OF ROPINIROLEYDROCHLORIDE
5.1. Measurement of mechanical properties of
the film [11, 12]
Tensile strength of films was determined using an
apparatus fabricated in laboratory. A small film
strip (3 × 2 cm
2
) was cut and fixed to assembly.
The weight required to break the film was noted
and simultaneously film elongation was measured
with the help of pointer mounted on the assembly.
Measurements were done in triplicate for each
batch. The mechanical properties tensile strength
and % elongation were calculated for the mouth
dissolving film from the above measurements.
Tensile strength is the ratio of maximum stress
applied to a point at which the film specimen
breaks and can be computed from the applied force
at rupture to the crossectional area of the fractured
film as a mean of three measurements and
described in the equation-
Tensile strength =
Force at break (N)
Initial cross sectional
area of the film (mm
2
)
Percentage elongation was calculated by the
following equation-
Figure II: Image of instrument used for
measurement of mechanical properties
5.2. Folding Endurance
This test was performed by cutting the mouth
dissolving film of size 3 × 2 cm
2
. The films were
folded at same place until it breaks apart. [13]
5.3. In-vitro disintegration studies
Disintegration time study was slightly modified to
mimic the in-vitro and in-vivo conditions. For the
study, film as per the dimensions (3 x 2 cm
2
)
required for dose delivery were placed on a
stainless steel wire mesh containing 10 mL distilled
water. Time required for the film to break and
disintegrate was noted as in-vitro disintegration
time. Since, the film is expected to disintegrate in
the mouth in presence of saliva; only 10 mL of
medium was used. [14]
5.4. Weight variation test
3 × 2 cm
2
film was cut at three different places in
the cast film. The weight of each film strip was
taken and then weight variation observed. [15]
5.5. Surface pH Measurement
The surface pH of Mouth dissolving film is
determined in order to investigate the possibility of
any side effects in vivo. As an acidic or alkaline pH
may cause irritation to the oral mucosa, it is
determined to keep the surface pH as close to
% Elongation = Increase in length × 100
Original length
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65
neutral as possible. A combined pH electrode is
used for this purpose. Film is slightly wet with the
help of water. The pH is measured by bringing the
electrode in contact with the surface of the oral
film. This study is performed on three films of each
formulation and mean ± S.D calculated. [16]
5.6. Thickness Test
The thickness of the film can be measured by
micrometer screw gauge at different 5 strategic
locations. This is helpful in determination of
uniformity in the thickness of the film & this is
directly related to the accuracy of dose in the film.
[17]
5.7. Uniformity of drug content
A film of size 3 × 2 cm
2
is cut and put in 30 mL of
volumetric flask containing solvent. This is then
shaken in a mechanical shaker for 1 hr to get a
homogeneous solution and filtered. The drug is
determined spectroscopically after appropriate
dilution. [18]
5.8. Taste evaluation
Taste acceptability was measured by a taste panel
(n=5) with 3 mg drug and subsequently film
sample containing 3 mg drug held in mouth until
disintegration, then spat out and the bitterness level
was then recorded. The volunteers were asked to
gargle with distilled water between the drug and
film sample administration. The scale for the
bitterness study was as follows: [14]
+ = very bitter
++++ = tasteless/taste masked
++ = moderate to bitter
+++++ = excellent taste masking
+++ = slightly bitter
5.9. In-vitro dissolution studies
The in-vitro dissolution studies were conducted
using simulated saliva (300 mL). The dissolution
studies were carried out using USP dissolution
apparatus XXIV (Electrolab, Mumbai, India) at 37
± 0.5 °C and at 50 rpm using specified dissolution
media. Each film with dimension (3 x 2 cm
2
) was
placed on a stainless steel wire mesh with sieve
opening 700µm. The film sample placed on the
sieve was submerged into dissolution media.
Samples were withdrawn at 0, 15, 30 and 60 sec.
time intervals and filtered through 0.45µm
whatman filter paper and were analyzed
spectrophotometrically at 250 nm. To maintain the
volume, an equal volume of fresh dissolution
medium maintained at same temperature was added
after withdrawing samples. The absorbance values
were converted to concentration using standard
calibration curve previously obtained by
experiment. The dissolution testing studies were
performed in triplicate for all the batches. [14]
5.10. Environment scanning electron
microscopy (ESEM)
The surface morphology of the film was observed
using Environment scanning electron microscope
(Philips, XL 30, The Netherlands). The film sample
was placed in the sample holder and the
photomicrographs were taken using tungsten
filament as electron source and GSE detector at
65x and 350x magnification. [14]
5.11. Stability Study of Mouth Dissolving Film
of Ropinirole Hydrochloride
Stability of a drug has been defined as the ability of
a particular formulation in a specific container, to
remain within its physical, chemical, therapeutic
and toxicological specifications.The purpose of
stability study is to provide evidence on the quality
of a drug substance or drug product which varies
with time under the influence of a variety of
environmental factors such as temperature,
humidity and light. Recommended storage
conditions, re-test periods and shelf-lives are to be
established.The International Conference of
Harmonization (ICH) Guidelines titled, “stability
testing of New Drug substance and products”
(QIA) describes the stability test requirements for
drug registration application in the European
Union, Japan and the United States of America.
ICH specifies the length of study and storage
conditions
Long-term testing: - 25
0
C ± 2
0
C / 60 % RH ± 5%
for 12 months.
Accelerated testing: - 40
0
C ± 2
0
C/ 75 % RH ± 5%
for 6 months.
Accelerated Stability studies were carried out at 40
0
C / 75 % RH for the best formulations for 1
month.
Method:
The best formulation was assessed their
accelerated stability with respect to their l
appearance, in-vitro disintegration time, surface pH
& drug release characteristics after storing them at
40 ± 2
0
C / 75 ± 5 % RH for 1 month. [28]
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66
Results & Discussion:
A) Drug-Excipient Compatibility Studies by
FT-IR
a) Fourior Transform Infrared Spectroscopy
Figure III: FT-IR Spectra of Ropinirole
Hydrochloride
Figure IV: FT-IR Spectra of Ropinirole
Hydrochloride with Pullulan Polymer
Figure V: FT-IR spectra of mouth dissolving
film of Ropinirole HCL prepared by using
pullulan as polymer
Pure drug Ropinirole Hydrochloride
spectra showed sharp characteristic peaks at 1350
cm
-1
(-CH
3
bending), 1456 cm
-1
(C=C stretching),
1700 cm
-1
(C=O stretching) and 3150 cm
-1
(N-H
stretching). All the above characteristic peaks of
drug appear in the spectra of all other spectra of
drug with polymer mixtures and formulations of
mouth dissolving film at the same wave number,
indicating no modification or interaction between
the drug and the excipients.
From this it can be concluded that the drug
has maintained its identity without losing its
characteristic properties. It will not show any
adverse effect in action of the formulation and
helps to study desired parameters in the present
study.
b)
Drug-Excipients Compatibility Studies
by Differential Scanning Calorimetry Study
Figure VI: DSC spectras of Ropinirole
Hydrochloride and Physical mixture of
Ropinirole Hydrochloride and Pullulan
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67
Samples were analyzed by DSC using shimadzu
corporation, Japan. The samples were placed into a
pieced aluminium sample container. The studies
were performed under static air atmosphere in the
temperature range of 50
0
C-300
0
C at a heating rate
of 20
0
C
per min. The peak temperatures were
determined after calibration with a standard.
The DSC thermograph of ropinirole hydrochloride
exhibits endothermic peak at 246.41 °C
corresponding to its melting point. All polymer and
drug mixtures showed endothermic peak 240 °C to
255 °C range. So, results indicate that weak
interaction occurs between drug and polymer
.
B) Calibration curve of Ropinirole Hydrochloride in Phosphate buffer pH 6.8
Table V: Absorbance-concentration data for standard curve of Ropinirole Hydrochloride
Concentration (ìg/mL) Absorbance Average
(± S.D.)
I II III
0 0.000 0.000 0.000 0.000 ±0.000
1 0.501 0.499 0.500 0.500 ± 0.001
2 0.078 0.079 0.076 0.078 ± 0.002
4 0.124 0.123 0.124 0.123 ± 0.001
6 0.189 0.190 0.189 0.189 ± 0.001
8 0.255 0.255 0.255 0.255 ± 0.000
10 0.328 0.330 0.330 0.330 ± 0.001
12 0.398 0.395 0.397 0.397 ± 0.002
14 0.462 0.461 0.461 0.461 ± 0.000
16 0.512 0.510 0.509 0.510 ± 0.002
18 0.597 0.595 0.596 0.596 ± 0.001
20 0.627 0.627 0.625 0.627 ± 0.001
22 0.680 0.680 0.680 0.680 ± 0.000
24 0.715 0.714 0.717 0.715 ± 0.002
26 0.797 0.797 0.796 0.797 ± 0.001
28 0.858 0.859 0.857 0.858 ± 0.001
Note: Values are mean value of 3 observation (N=3), and values in parenthesis are standard
deviation (± SD)
Figure VII: Absorbance-concentration profile for standard curve of Ropinirole HCL.
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68
C) Evaluation of formulation Mouth Dissolving Films of 3
2
Full Factorial design
Table VI: Evaluation of Mouth Dissolving Film Formulation Batches F1 to F9
Note: Values are mean value of 3 observation (N=3), and Values in parenthesis are standard deviation (± SD).
Batch
No.
Tensile
Strength
(g/mm
2
)
%
Elongation Weight (mg) Folding
Endurance
In-vitro
Disintegration
time (sec)
pH Thickness
(mm)
% Drug
Content
Score for
Taste
Masking
F1 9.19 ± 0.025 20.24 ± 1.20 63.67 ± 1.50 85.33 ± 3.21 19.67 ± 0.58 6.53 ± 0.06 0.07 ± 0.01 99.21 ± 0.48 ++++
F2 9.33 ± 0.110 42.29 ± 0.88 77.50 ± 0.70 90.67 ± 3.05 22.33 ± 1.52 6.78 ± 0.08 0.08 ± 0.02 99.36 ± 0.21 +++++
F3 9.53 ± 0.080 61.10 ± 0.14 80.00 ± 0.23 94.00 ± 2.15 24.00 ± 0.00 6.83 ± 0.03 0.11 ± 0.01 99.37 ± 0.56 ++++
F4 9.67 ± 0.064 21.59 ± 0.29 65.33 ± 0.68 88.00 ± 1.00 20.33 ± 0.57 6.60 ± 0.10 0.07 ± 0.01 99.53 ± 0.37 +++++
F5 10.8 ± 0.085 43.78 ± 0.45 77.66 ± 1.53 93.33 ± 3.51 22.10 ± 0.57 6.88 ± 0.13 0.09 ± 0.00 99.37 ± 1.25 +++++
F6 12.03 ± 0.112 62.05 ± 0.30 81.50 ± 0.50 96.67 ± 2.52 23.00 ± 0.00 6.95 ± 0.05 0.11 ± 0.02 99.25 ± 0.81 +++++
F7 13.21 ± 0.155 22.24 ± 0.75 65.40 ± 0.77 92.33 ± 1.64 22.00 ± 1.00 6.56 ± 0.22 0.08 ± 0.01 99.06 ± 0.67 ++++
F8 15.60 ± 0.085 45.69 ± 0.81 78.00 ± 0.38 97.00 ± 1.82 23.66 ± 0.58 6.90 ± 0.15 0.09 ± 0.00 99.59 ± 0.26 +++++
F9 16.33 ± 0.121 62.94 ± 0.91 81.96 ± 0.21 104.12 ± 2.30 24.00 ± 0.00 6.86 ± 0.03 0.12 ± 0.01 99.90 ± 0.13 ++++
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69
Tensile Strength:
We observed that increase in the concentration of
polymer reflects the changes in all other variables.
Specifically in the case of the polymer we observed
that as the concentration of polymers increase,
viscosity of the solvent system which was to be
casted was increases. It affects thickness and
brittleness of the film. A result showed that as the
concentration of polymer increases, tensile strength
of mouth dissolving film increases. A Result
showed that as the concentration plasticizer
increases tensile strength and % elongation of
mouth dissolving film also increases.
Folding Endurance:
Folding endurance gives an indication of brittleness
of the film. A result showed that as the
concentration of polymer and plasticizer increases,
folding Endurance of mouth dissolving film
increases.
Weight variation measurement
A result showed that as the concentration of
polymer increases weight of film also increases.
In-vitro disintegration time
In vitro disintegrating time for mouth dissolving
film of pullulan was ranges from 19.67 ± 0.58 to
24.00 ± 0.00 sec. In vitro disintegrating time for
mouth dissolving film of HPMC 15 CPS was
ranges from 34.67 ± 1.53
to 42.00 ± 1.00
sec. All
the formulations found to gave minimum
disintegration time as compared to other
preparations.
Surface pH
Surface pH of all mouth dissolving films prepared
by using different polymers was found to be in the
range of 6.5 to 7 pH, which was close to the neutral
pH, which indicated that films may have less
potential to irritate the sublingual mucosa, and
hence, more acceptable by the patients.
Thickness Measurement
Thickness of mouth dissolving film depends on the
concentration of polymer. Thickness of all mouth
dissolving film was measured with micrometer
screw gauge. All the mouth dissolving formulations
of different polymers are show thickness value in
the range of 0.07 ± 0.01 to 0.15 ± 0.02 mm. A
result of thickness measurement showed that as the
concentration of polymer increases, thickness of
mouth dissolving film.
Content uniformity
All the mouth dissolving films were found to
contain an almost uniform quantity of the drug, as
per content uniformity studies indicating
reproducibility of the technique. Drug content in
the films was evaluated and the values were found
to be between 99.36 to 100.78 % for three different
cuts from each film. As per the USP requirements,
the films found to meet the criteria for content
uniformity. No significant difference in the drug
content among the films indicated good content
uniformity.
Taste masking evaluation
Taste masking was evaluated by human panel
volunteers. The taste masking of all formulation
was evaluated by human panel volunteers. A result
shows that excellent taste masking was found in all
formulations except some formulations which
shows taste masked of drug bitter taste only.
In-vitro Dissolution Study:
Table VII: In-vitro drug dissolution study of
formulation batches F1 to F9
Note: Values are mean value of 3 observation
(N=3), and Values in parenthesis are standard
deviation (± SD).
Figure VIII: Dissolution profile of formulation
batches F1 to F9
Effect of Polymer concentration
In-vitro drug release study results showed that
as the concentration of polymer increases, drug
release of mouth dissolving films decreases.
Batch
No. In-vitro percentage drug
release at 60 sec.
F1 97.58 ± 0.18
F2 86.25 ± 0.31
F3 84.51 ± 0.31
F4 99.48 ± 0.18
F5 89.69 ± 0.31
F6 86.10 ± 0.36
F7 99.52 ± 0.18
F8 89.51 ± 0.31
F9 85.89 ± 0.36
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70
Effect of Plasticizer concentration
In-vitro drug release study result showed that
as the concentration of plasticizer increases, drug
release of mouth dissolving films also increases.
Statical Analysis:
Figure IX: Contour plot of formulation batches
F1 to F9
Figure X: Response surface curve of
formulation batches F1 to F9
Here, contour plots, surface plots, main effect
and interaction effect plots were drawn using the
Statgraphic 16.1.17. These types of plots are useful
in study of the effects of two factors on the
response at one time.
• Contour Plot
Analysis of contour plot of formulation
Batches F1 to F9, shown in Figure No: 5.17,
reveals that the contour area was acceptable
with % drug release value above 99 %. Thus,
the working range to get an acceptable product
was at the point A. Batch 4 containing pullulan
as a polymer fall in the acceptable area. And it
showed higher % drug release than the other
batches.
• Response Surface plot
From the in vitro drug release study observed
that as concentration of polymer increase, %
drug release was decreased and as the
concentration of plasticizer increase, % drug
release was increased. But prediction of results
of % drug release, response surface plot was
plotted for graphical representation of results.
So, figure showed common effect of
plasticizer and polymer concentration. We can
conclude from the contour plot for formulation
batch F1 to F9 that, % drug release was
decreased as the concentration of polymer
increased and % drug release was increased as
the plasticizer concentration increased.
Equations relating independent variables and
response
The relationship between the independent variables
and the response variables was estimated by
subjecting the results to statistical evaluation.
Statgraphics software was used to perform multiple
linear regressions to determine the control factors
that significantly affect the responses.
Control Factors: Polymer concentration, plasticizer
concentration
Response: % drug release at 60 sec.
Table VIII: Regression analysis plots of
measured response for formulation batches F1
to F9
Coefficient Estimate
Constant 127.132
X2 -0.2844
X1 0.155969
X2
2
0.000370
X1X2 -0.0000248
X1
2
-0.000381
The fitted model was:
Y = 127.132 + 0.155969*X1 - 0.2844*X2 -
0.0000248*X2*X1 - 0.000381*X1
2
+
0.000370*X2
2
Validity of Equations:
The experimental values and predicted values of
each response are shown in Table. The percentage
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71
relative error of each response was calculated using
the following equation:
Percentage Relative Error = (│Predicted value –
Experimental value│/ Predicted value) × 100
Table IX: Response (In-vitro drug release) of
check point batch for pullulan mouth dissolving
film
Response
s Experimenta
l Predicte
d values %
Relativ
e error
Y1 99.48 99.67 0.19
The percentage relative error for the checkpoint
batches were in the range of 0 to 8.5. It was
concluded that the experimental values and
predicted values showed good agreement with each
other. This proved the validity of the equations.
Environment scanning electron microscopy
(ESEM)
Figure XI: ESEM of batch F4 film at 500x
magnification
Stability study
Table X: Evaluation of formulation F4
kept for
stability at 40 ºC /75 %RH
TIME
(sec) In-vitro
Disintegration
time
Surface
pH Appearance
Initial 20.33 ± 0.57 6.60 ±
0.10 White
1
month 21.20 ± 0.10 6.57 ±
0.03 Slight
Yellow
Note: Values are mean value of 3 observation
(N=3), and values in parenthesis are standard
deviation (± SD)
Table XI: In-vitro drug release study of
formulation F4 kept for stability at 40 ºC/75 %
RH
TIME
(sec)
%CDR (± SD)
1
st
Day
After 2 Month
0 0.00 ± 0.00 0.00 ± 0.00
15
48.96 ± 0.19 48.12 ± 0.19
30
70.21 ± 0.48 69.97 ± 0.52
60
99.48 ± 0.18 99.37 ± 0.36
Note: Values are mean value of 3 observation
(N=3), and values in parenthesis are standard
deviation (± SD)
Short-term stability studies were performed for
formulation F4 at 45 ± 1°C for 1 month. The
samples were analyzed for in vitro disintegration
time, surface pH, appearance and in vitro drug
release studies. The results are given in table no:
5.32 and 5.33. No appreciable difference was
observed for the above parameters.
Photograph of formulation of mouth dissolving
film
Figure XII: Photograph of mouth dissolving
film containing pullulan polymer
Conclusion:
The results of the present study indicated that
pullulan could be used as a film forming polymer
for formulation of mouth dissolving film
containing Ropinirole hydrochloride. The amount
of plasticizer PEG 400 was critical for film
formation and separation properties. Taste masking
was achieved using combination of sweeteners,
flavours and citric acid. Type of flavouring agent
was critical for producing taste masking of mouth
dissolving film. Acceptable mechanical properties
were obtained in the batch F4 with in vitro
disintegration time of 20 sec. The optimized batch
F4 was found to be stable for a period of 1 month
at 25 °C/40 %RH. One dependent variable was
selected to see the effect of polymers and multiple
regressions was applied. The experimental (from
check point batch) and predicted (from multiple
regression equation) values were close to each
other. It was concluded that the check point batch
Available online at www.ijpras.com
72
was the optimized batch with the fulfillment of all
the desirability.
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Mital Panchal, Hiren Patel, Aarti Bagada,
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“
Formulation and Evaluation of
Mouth Dissolving Film of Ropinirole
Hydrochloride by Using Different Polymers” ” Int.
J. of Pharm. Res. & All. Sci.2012; Volume 1, Issue
3,60-72
