INTERNATIONAL JOURNAL OF PHARMACEUTICAL … 1234.pdfMansi M. Soni, IJPRBS, 2016; Volume 5(2):...

Research Article CODEN: IJPRNK Impact Factor: 5.567 ISSN: 2277-8713 Mansi M. Soni, IJPRBS, 2016; Volume 5(2): 101-123 IJPRBS

Available Online at www.ijprbs.com 101

FORMULATION AND EVALUATION OF FAST DISSOLVING FILM OF LURASIDONE

HCl

MS. MANSI M. SONI1,2, DR. KANU R. PATEL2

1. Research scholar, Gujarat Technological University, Gujarat.

2. Department of Pharmaceutics, Shri B. M. Shah College of Pharmaceutical Education and Research, Modasa- 383315, Gujarat, India.

Accepted Date: 10/04/2016; Published Date: 27/04/2016

Abstract: Lurasidone HCl is an atypical antipsychotic drug which is used for the treatment of schizophrenia. Schizophrenia is one of the psychotic mental disorders and characterized by symptoms of thought and social problem. It acts an antagonist at dopamine (D2) and serotonin (5- HT2A and 5-HT7) receptors. Fast dissolving film of Lurasidone HCl were prepared with the purpose of fast dissolving dosage form for very rapid onset of action, faster drug release and provide better patient compliance, which is beneficial in managing several condition like depression, sudden episodes, mentally ill and dysphasia. Developing dosage form was very convenient for the administration without the problem of swallowing and water. Lurasidone HCl is a poorly soluble drug hence to make

it solubilise it is formulated as drug- inclusion complex by kneading method using - cyclodextrin in 1:1 ratio to enhanced the solubility of drug. The inclusion complex was investigated by FTIR, DSC, in- vitro dissolution study and saturation solubility study. Lurasidone HCl fast dissolving films were prepared by using different polymer such as HPMC E5, Pullulan, HPMC E15 and propylene glycol as a plasticizer. The film prepared by solvent casting method. The 32 factorial design was applied for optimization of concentration of pullulan polymer and plasticizer propylene glycol. The prepared film was evaluated by various parameters like thickness, tensile strength, % elongation, folding endurance, disintegration time and in- vitro drug release study. From statistical analysis design, the film (batch F3) with pullulan (1.5%) and propylene glycol (25%) was giving a good disintegration time (30 sec), sufficient tensile strength (0.220) and high % drug release (98.35%). Thus increase the solubility and dissolution rate of Lurasidone HCl helpful to increase the bioavailability and provide immediate action for schizophrenic patients.

Keywords: Lurasidone HCl, Fast dissolving film, - cyclodextrin, solvent casting method, pullualan polymer,

propylene glycol

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Mansi M. Soni, IJPRBS, 2016; Volume 5(2): 101-123



INTRODUCTION

Among the different route for the administration of drug like oral, parenteral, nasal, transdermal.

But oral route are most preferred and acceptable for the administration of dosage form which

include painless, easy of administration, more patients compliance and patients friendly dosage

form. The most common drawback for oral dosage form are difficulty in swallowing, leading to

patient’s incompliance particularly in case of pediatric, geriatric, bedridden, nauseous and

mentally ill patients. In such case a new interest of fast dissolving (tablets and films) product will

be advantageous show greater patients’ acceptability and convenience. Fast dissolving drug

delivery system has become increasingly important because of their unique property. They were

first developed in the late 1970s as an alternative to conventional dosage form. [1]

Fast dissolving films are solid dosage form that dissolve or disintegrates within 1 min. when

placed in the mouth without drinking water or chewing. After disintegrating in mouth, enhanced

the clinical effect of drug through absorption from mouth pharynx and esophagus as the saliva

passes down into stomach. In such cases, bioavailability of drug is significantly greater than

conventional dosage form. Fast dissolving film consist of thin film which is prepared by using

hydrophilic polymer which has rapidly dissolve on tongue or oral cavity and definitely eliminate

the fear of chocking. It is an ultra thin strip (50-150 microns thick) of postage stamp size with an

active agent and other excipients developed. Most fast dissolving films are having taste masked

active ingredients. These taste masked active ingredients are swallowed by the saliva of patients

with soluble excipients. [2]

Technology catalysts forecasts the market for drug products in oral thin film formulation was

valued of $500 million in 2007 and could reach $2 billion in 2012. The fast dissolving dosage

market could produce revenues of $13 billion by 2015. [3] More important prescription of FDF has

been now approved in US, EU, and Japan which are the three major regions. These approved Rx

films, have potential to dominate over other oral dosage forms of the same drugs. It seems that

the value of the overall oral thin film market will grow significantly. [4]

DEFINITION OF FDF: - Fast dissolving films are

most advance form of solid dosage form due to its

flexibility. It improve efficacy of active

pharmaceutical ingredients (API) dissolving in the

short duration oral cavity after the contact with

less amount of saliva as compare to tablet.[5]



ADVANTAGE OF FAST DISSOLVING FILM [14, 15]

Orally dissolving films can be administered without water, anywhere, any time. Highly

convenient feature for patients who are travelling

Due to the presence of larger surface area, film provides rapid disintegrating and dissolution

in the oral cavity.

Patients suffering from repeated emesis, dysphasia, and motion sickness prefer this dosage

form as they are unable to swallow large quantity of water.

As fast dissolving thin oral films are flexible, they are easy to carry, store and handle,

which is not the case with orally disintegrating tablets (fragile and brittle).

As the oral mucosa is being highly vascularised, drugs directly enter the systemic circulation

without undergoing first‐pass hepatic metabolism. This results in improved oral

bioavailability of molecules.

These films can be manufactured through economically feasible no sophisticated procedures

and uncomplicated equipment.

Improve patient compliance.

Good mouth feels property and no risk of chocking.

RATIONAL FOR SELECTION OF DRUG

Lurasidone HCl is an atypical antipsychotic drug and belongs to BCS class II drug hence low

solubility in biological fluid. Its gastrointestinal absorption is only 9-19%, so lower the

bioavailability. It is having small dose (20-80 mg) so it can be good candidate for film. It is having

log P value 5.6 i.e. drug is lipophilic in nature. It has longer half life 18 hours so when dosage form

is administered it gives immediate effect and thus effect will stay for prolong period of time. The

present research work focussed on increase the solubility and dissolution rate of Lurasidone HCl

by complexation technique helpful to increase the bioavailability of drug and prepared film

provide minimum disintegration time and faster dissolution rate. Some mental patients hide

tablets under the tongue and then spit upon leaving the medical staff, resulting in “Fake drug”

phenomenon so greatly influenced the effect of drug.



MATERIAL AND METHOD

Lurasidone HCl was received as a gift sample from Apotex Pharma Pvt. Ltd, Banglore. Pullulan

film forming polymer was received from Kumar organic product Ltd, Banglore. BenecelTM E5 and

BenecelTM E15 were received from Ashland Industries Europe GMBH, Switzerland. Propylene

glycol as plasticizer, Aspartame as sweetners and citric acid as saliva stimulating agent were

received from S. D. Fine chemicals Pvt. Ltd, Mumbai.

METHOD

PREFORMULATION STUDIES

These methods help in studying the physicochemical properties of drug and polymer and develop

safe, stable and effective dosage form.

Description

The organoleptic properties of drug were determined including colour, odour, taste and its

solubility.

Melting point

The melting point of drug was determined by melting point apparatus using capillary method.

The melting point was determined by introducing small amount of drug substance filled in the

capillary tube which was previously sealed on one end. The capillary tube attached to graduated

thermometer and constant heat was applied with assembly suspended in the theil’s tube

containing paraffin bath. The temperature at which the drug started to melt was noted as melting

point.

Determination of λ max

UV spectrophotometric study of Lurasidone HCl was carried out to identify λ max of drug in 0.1N

HCl and 6.8 pH phosphate buffer. The prepared solution was scanned from 200 to 400 nm in UV

spectrophotometer. The wavelength of the maximum absorption was noted and UV spectrum

was recorded. [8]

Standard calibration curve of Lurasidone HCl

A stock solution of Lurasidone HCl of concentration 100μg/ml was prepared in 0.1 N HCl and 6.8

phosphate buffer. The calibration curves were constructed using standard solution in the range

10-100μg/ml diluted with appropriate solvent. The assignments were represented in figure 2 &

3.



FTIR spectroscopy

The drug was characterized by FTIR spectroscopy. In the present study pure drug Lurasidone HCl

was mixed with the dried powder of potassium bromide. Then this mixture was compressed into

the transparent disc under high pressure special dies. This disc was placed in IR spectrometer and

spectra were recorded. The scanning range was 4000 to 400cm-1

PREPRATION OF INCLUSION COMPLEX

Lurasidone inclusion complex was prepared by physical mixture and kneading method using

drug: - cyclodextrin (carrier) in different ratio, viz. 1:0.5 to 1:3. Water was selected as common

solvent for the preparation of inclusion complex. [9]

Physical mixture method: - Accurately weighed amount of drug and - cyclodextrin were

taken in to glass mortar and then mixed for 10 min. to get good mixture. Then product was

stored in the desiccator for further study.

Kneading method: - Accurately weighed amount of drug and - cyclodextrin were taken in to

glass mortar and then water was added in small quantity and mixture was kneaded for 45

min and then dried in oven at 40°C. The product obtained was pulverized and pass through

mesh (#) 80 and stored in desicator for further study.

Table 1: Ingredient and method of preparation for inclusion complex

METHOD DRUG : CARRIER RATIO CARRIER USED IN METHOD

Physical mixture method

1:0.5

- Cyclodextrin 1:1

1:2

1:3

Kneading method

1:0.5

- Cyclodextrin

1:1

1:2

1:3



Evaluation of inclusion complex

Phase solubility studies

Phase solubility was performed according to method reported by Higuchi and Connors. Excess

quantity of inclusion complex, equivalent to 5 mg of drug was added to 100ml conical flask

containing 20ml 0.1 N HCl and mixtures were shaken for 24 hour at 1000rpm at room

temperature in rotary flask shaker. After shaking 2 ml aliquots were withdrawn at 1 hour intervals

and filter through whatman filter paper No.41. The filtrate was diluted and analyzed

spectrophotometrically at 316 nm against suitable blank using UV visible spectrophotometer.

In Vitro Dissolution Study of prepared inclusion complex

The in vitro dissolution study of inclusion complex was performed as described in Indian

Pharmacopoeia 2010 using USP type II Paddle apparatus (Electrolab, TDT08L). Quantity of solid

dispersion equivalent to 5 mg of drug was kept in a flask of the dissolution apparatus containing

900ml of 0.1 N HCl as a dissolution media maintaining the temperature at 37 ± 0.50C and at a

speed of 50 rpm. Aliquot of dissolution medium (10ml) was withdrawn at a specific time intervals

and the samples were replaced with fresh dissolution medium. Sample was filtered through

whatman filter paper. Sample was analyzed spectrophotometrically at 316 nm against suitable

blank using UV visible spectrophotometer.

Differential scanning calorimetry (DSC)

Differential scanning calorimetry (DSC) has been one of the most widely used calorimetric

techniques to study the solid state interaction of drug with - CD. Samples of weight

approximately 5 mg were taken in aluminum pans and heated over a temperature range of 30 to

300 °C at a constant rate of 10° C/min with purring of nitrogen (50ml/min) using alumina as a

reference standard in a DSC.

Drug- polymer interaction analysis of inclusion complex

Fourier transform Infrared (FTIR) spectra of pure drug Lurasidone HCl and its inclusion complex

were recorded by KBr disc method. The inclusion complex was mixed with the dried powder

potassium bromide. Then this mixture was compressed into the transparent disc under high

pressure special dies. This disc was placed in IR spectrometer and spectra were recorded. The

scanning range was 4000-400cm.-1



FORMULATION DESIGN OF ORAL FAST DISSOLVING FILM

Procedure for preparation of film

The film prepared by solvent casting method. Accurately weighed quantity of drug was dissolved

in 5 ml water. Specified amount of polymer and other excipients were dissolved in 15 ml water.

The polymeric solution was added to the drug solution. The above mixture of solution was casted

in petridish and drying at room temperature. Dried strip was removed safely from petridish, cut

in 2*2 cm2 size. [10]

The area and number of films prepared for each batch can be calculated as follows:

The oral dose of Lurasidone HCl = 5 mg

Total area of petridish = 72.345 cm2

Each film area = 2×2 = 4 cm2

Number of films in batch =72.345/4 = 18.08 film

Total amount of Lurasidone HCl inclusion complex required: Dose of one film * No of film

required : 10 * 18.08

: 180.8 mg

Preparation of Lurasidone HCl fast dissolving film using 32 full factorial design

From the results of preliminary screening studies the optimization was carried out using design

of expert (DOE) approach. To study the effect of 2 independent variables i.e. amount of pullulan

polymer (X1) and amount of propylene glycol (X2) on responses 32full factorial design was used.

While disintegration time, tensile strength, drug release at 10 min were selected as dependent

variable. Trials were taken at all possible combinations. The detailed layout of factorial batches

is shown in table 2. The equation relating independent variables and dependent variables were

obtained by subjecting the result to statistical evaluation.

Polynomial equation for 32 full factorial design: Y = bo + b1X1 + b2X2 + b11X1 X1 + b22X2X2 + b12X1X2

was used. In this equation Y is the dependent variable, bo is the arithmetic mean response of the

nine runs, b1 to b12 are the coefficients for factors.

The significant factors in the equations were selected using a stepwise forward and backward

elimination for the calculation of regression analysis. The terms of full model having non-

significant p value (p> 0.05) have negligible contribution and they were neglected.



Table 2: Composition of factorial design formulation of Lurasidone HCl

INGREDIENTS

FORMULATION BATCH CODE

F1 F2 F3 F4 F5 F6 F7 F8 F9

Solid dispersion Eq. to 5mg of Lurasidone HCl

180.8mg 180.8 mg

180.8 mg

180.8

mg

180.8

mg

180.8 mg

180.8 mg

180.8

mg

180.8mg

Pullulan (%w/v) 1.5 1.5 1.5 2 2 2 2.5 2.5 2.5

Propylene Glycol (%w/w) 15 20 25 15 20 25 15 20 25

Micro Crystalline

Cellulose (%w/w)

5 5 5 5 5 5 5 5 5

Citric Acid (mg) 10 10 10 10 10 10 10 10 10

Aspartame (mg) 40 40 40 40 40 40 40 40 40

Flavor (ml) 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1

Distilled Water (ml) 20 20 20 20 20 20 20 20 20

Evaluation parameters of fast dissolving film [11]

Weight of film

Oral fast dissolving films were weighed on analytical balance and average weight can be

determined for each film. It is useful to ensure that a film contains the proper amount of

excipients and API.

Thickness of film

Thickness of film can be measured by micrometer screw gauge or digital vernier callipers at

different point of film i.e. central and four corners. And mean thickness of film are calculated.

In- vitro disintegration time

The disintegration time is the time when a film breaks or disintegrates. The film (2*2 cm2) was

placed in glass petridish containing 10ml 0.1 N HCl. The time required for breaking of film was

noted as in- vitro disintegration time. The disintegration time limit of 30 sec or less for orally

disintegrating tablets describing CDER guidance can be applied to fast dissolving oral film.

Although no official guidance is available for oral fast disintegrating films. [12]

% Drug content



Drug content was carried out by this standard method. In this method the film (2x2 cm2) was

taken and transferred into 100ml volumetric flask. The film was dissolved in 40ml methanol and

the volume was made up to mark with 0.1N HCl to get 1000µg/ml solution (Primary stock

solution). From this 10ml solution was taken out from above solution and diluted with 0.1N HCl

up to 100ml to get 100µg/ml solution (Secondary stock solution). The solution was measured

against 0.1N HCl as a blank at 316 nm using UV visible spectrophotometer.

Tensile strength

Tensile strength is the maximum stress applied to a point at which the strip specimen breaks.

Tensile strength of the film was evaluated by using tensilometer. It consists of two load cell grip,

the lower one was fixed and upper one was movable. 2*2 cm2 films were fixed between these

cell grips and force was applied till the film break. It is calculated by the applied load at rupture

divided by the cross sectional area of the strip as given in the equation below:

Tensile strength = Load at failure

Strip thickness * Strip width

Folding endurance

Folding endurance is determined by repeated folding of the film at the same place until the film

breaks. The number of times the film is folded without breaking is calculated as the folding

endurance value.

Percentage elongation

When stress is applied, a film sample stretches, and this stress is referred to as strain. Strain is

basically the deformation of the film divided by the original dimension of the sample. As the

plasticizer content increase, the elongation of film is observed.

Percentage elongation = Increase in length of strip *100

Initial length of strip

In- vitro dissolution study

Here the in vitro dissolution test was performed using USP paddle apparatus. Sample of

Lurasidone HCl films were exactly weighed. In this case the film of (2x2 cm2) was kept in a flask

of the dissolution apparatus containing 900ml of 0.1N HCl as a dissolution media maintaining the

temperature at 37 0.5°C and at a speed of 50 rpm. Aliquot of dissolution medium (10ml) was

withdrawn at a specific time interval and the sample was replaced with fresh dissolution medium.



Sample was filter through whatman filter paper. The filtrate was analyzed

spectrophotometrically at 316nm against blank using UV visible spectrophotometer.

Accelerated stability studies

The stability studies were carried out on the most satisfactory formulations as per ICH guidelines

Q1C. Stability studies on the optimized formulation of oral fast dissolving film is carried out to

determine the effect of temperature and humidity on the stability of the drug. The most

satisfactory optimized formulation were sealed in an aluminium pouch and sample were kept in

humidity chamber at 40 + 20°C / 75 + 5% RH condition for 1 month. At the end of studies, samples

were analyzed for the % Drug content, in-vitro dissolution and appearance. [13]

RESULTS AND DISCUSSION

Characterization of Lurasidone HCl

The received sample was identified by various test and results shown in table 3

Table 3: Characterization of Lurasidone HCl

PARAMETER RESULTS

State Crystalline powder

Color White to off white powder

Odour Odourless

Taste Bitter

Water Solubility Practically insoluble in water. It is soluble in methanol and sparingly soluble in chloroform and acetonitrile.

Melting point 286°C

Ultraviolet absorption spectroscopy

The maximum absorption value of Lurasidone HCl was found at 316nm in 0.1N HCl and 6.8 PH

Phosphate buffer. Therefore 316nm were recorded as λmax of the pure drug Lurasidone HCl.

316nm λ max was selected for calibration curve and further experiment. The UV spectrum of

Lurasidone HCl and calibration curve in 0.1 N HCl and 6.8 phosphate buffer was showed in figure

1, 2, 3.



Figure 1: UV spectrum of Lurasidone HCl in 0.1 N HCl

Figure 2: Calibration curve of Lurasidone HCl in 0.1 N HCl

y = 0.0085x + 0.0045

R² = 0.9954

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

0 20 40 60 80 100 120

AB

SO

RB

AN

CE

CONCENTRATION (μg/ml)

abs

abs

Linear (abs)



Figure 3: Calibration curve of Lurasidone HCl in 6.8 pH phosphate buffer

PHASE SOLUBILITY STUDY OF INCLUSION COMPLEX

From the solubility data of Lurasidone HCl, it was clearly revealed that the solubility of pure drug

is 0.148 mg/ml. The complexation by kneading method 1:1 ratio shows maximum saturation

solubility 1.235 mg/ml as compared to other method. Therefore 1:1 ratio was optimization for

solubility enhancement. On this basis, it was found that drug was dispersed uniformly throughout

the solid dispersion. The solubility data of Lurasidone HCl was showed in figure 4.

Figure 4: Phase solubility study of Lurasidone HCl

In-vitro dissolution study of prepared inclusion complex

The prepared inclusion complexes were subjected to in- vitro dissolution studies and studies for

variables affecting the dissolution profile of Lurasidone HCl. The results were depicted in figure

y = 0.0079x - 0.0397

R² = 0.9909

-0.2

0

0.2

0.4

0.6

0.8

0 20 40 60 80 100 120

AB

SO

RB

AN

CE

CONCENTRATION

abs

abs

Linear (abs)

0

0.2

0.4

0.6

0.8

1

1.2

1.4

Pure

drug

PM 1

(1:0.5)

PM 2

(1: 1)

PM 3

(1: 2)

PM 4

(1: 3)

KM 1

(1: 0.5)

KM 2

(1 : 1)

KM 3

(1:2)

KM 4

(1 : 3)

Series1



5. From the in- vitro release data, it was found that drug release of pure drug was up to 42.21%

whereas drug release from kneading method was exhibited 97.45% (KM 2) in 18 min. The

increased dissolution rate may be due to higher solubility of - CD in dissolution medium and

better wettability of Lurasidone HCl in the complex.

Figure 5: In- vitro dissolution study of inclusion complex

Differential scanning calorimetry (DSC)

The DSC thermogram of Lurasidone HCl and inclusion complex (- CD carrier) are shown in below

figure 6 & 7. The thermogram of pure Lurasidone HCl showing melting endothermic peak at

286°C. The thermogram of inclusion complex showing melting endothermic peak at 257°C. The

drug: - CD melting endotherm was shifted toward left side of thermogram. This is because of

conversion of the Lurasidone HCl to its amorphous form during the process of complexation with

- CD which indicates successful complexation with - CD.

Figure 6: DSC thermogram of Lurasidone HCl

0

20

40

60

80

100

120

0 5 10 15 20

% C

DR

TIME (min)

Pure drug

PM 1

PM 2

PM 3

PM 4

KM 1

KM 2

KM 3

KM 4



Figure 7: DSC thermogram of inclusion complex (drug: -CD)

Drug excipients compatibility study by FTIR

From the FTIR study sample Lurasidone HCl was identified. FTIR spectra of pure drug and inclusion

complex and film forming polymer were shown in figure 8,9,10. From the result of IR spectra,

pure drug and - CD containing inclusion complex () as well as physical mixture of polymer

showed similar functional peak. This similarity in peak indicates that the compatibility of drug

with - CD as well as film forming polymer. And no physical or chemical interaction between drug

and other excipients used. The frequency of functional group of Lurasidone HCl compare with -

CD and physical mixture of polymer are shown in table 4.

Table 4: Comparison of FTIR peak with -CD and physical mixture

Functional group Frequency of pure drug

Frequency of - CD complex

Frequency of formulation

Observation

C-H stretching 2937.68 2935.76 2935.76 No interaction

Isocyanides 2231.71 2229.79 2229.79 No interaction

Aryl group 1693.56 1687.77 1687.77 No interaction

Aromatic group 1502.60 1502.60 1502.60 No interaction

C-H bending 1390.72 1396.51 1396.51 No interaction



Figure 8: FTIR spectra of Lurasidone HCl

Figure 9: FTIR spectra of Lurasidone HCl + -CD complex

Figure 10: FTIR spectra of Lurasidone HCl + formulation

EVALUATION PARAMETER OF FACTORIAL BATCHES OF FAST DISSOLVING FILM

All the prepared fast dissolving films were evaluated for their physicochemical parameters like

disintegration time, thickness, folding endurance, tensile strength, % drug content and values are

shown in table 5 and 6.

40060080011001400170020002600320038001/cm

-15

-7.5

0

7.5

15

22.5

30

37.5

45

52.5

60

67.5

75%T

2937

.68

2360

.9523

33.94

2231

.71

1761

.07

1693

.56

1502

.6014

46.66

1431

.2313

90.72

1367

.5812

86.56

1261

.4911

84.33

976.0

1

779.2

7

742.6

2

Lurasidone HCl

450600750900120015001800210027003300390045001/cm

0

5

10

15

20

25

30

35

40

45

50

55

60

65

70

75

80

85

90%T

2937

.68

2360

.9523

33.94

2231

.71

1761

.07

1693

.56

1502

.6014

46.66

1431

.23 1390

.7213

67.58

1286

.5612

61.49

1184

.33

976.0

1

779.2

774

2.62

3362

.0433

36.96

3275

.2432

44.38

2935

.76 2893

.3228

72.10

2852

.81

2299

.2222

58.72

1687

.7716

70.41

1502

.6014

29.30 14

10.01

1396

.5113

67.58

1288

.49

1155

.4011

49.61

1031

.95

418.5

7

Lurasidone HClbetaCD+formulation2

Lurasidone HCl

4006008001000120014001600180020002400280032001/cm

0

5

10

15

20

25

30

35

40

45

50

55

60

65

70

75

80

85

90

95

100%T

2935

.7629

12.61

1687

.77

1502

.60

1429

.30 1396

.5113

61.79

1338

.6412

88.49

1261

.49

1149

.6111

26.47

1078

.2410

31.95 10

04.95

653.8

960

5.67

569.0

254

9.73

516.9

450

3.44

484.1

5

2937

.68

2360

.9523

33.94

2231

.71

1761

.07

1693

.56

1502

.6014

46.66

1431

.2313

90.72

1367

.58

1286

.5612

61.49

1184

.33

976.0

1

779.2

774

2.62

Lurasidone HCl+ Formultion11Lurasidone HCl

Lurasidone HCl+ Formultion



Table 5: Physicochemical parameter of fast dissolving film of Lurasidone HCl

BATCH % WEIGHT

(mg) SD

THICKNESS

(mm) SD

DISINTEGRATION TIME

(sec) SD % DRUG CONTENT SD

F1 57.21 1.85 0.10 0.015 24 2 93.25 1.99

F2 62.30 2.02 0.12 0.010 28 2 95.29 1.99

F3 65.42 0.97 0.15 0.010 30 2 98.35 1.82

F4 70.05 1.05 0.17 0.015 32 2 102.26 2.09

F5 73.22 0.97 0.20 0.020 34 2 97.25 1.97

F6 77.25 0.97 0.23 0.020 37 2 94.23 2.03

F7 81.10 1.05 0.25 0.020 40 2 92.40 1.97

F8 87.28 1.05 0.28 0.020 42 2 96.33 2.01

F9 92.31 1.01 0.31 0.020 45 2 105.31 1.03

Values are expressed as Average of three determination n = 3

Table 6: Physicochemical parameter of fast dissolving film of Lurasidone HCl

BATCH TENSILE STRENGTH

(N/mm2) SD

FOLDING

ENDURANCE SD % ELONGATION SD

SURFACE PH SD

F1 0.178 0.002 27 2.2 14.70 1.97 6.26 0.01

F2 0.185 0.002 35 2.6 16.10 2.02 6.43 0.01

F3 0.220 0.001 48 2.2 18.27 2.00 6.50 0.02

F4 0.247 0.002 33 2.1 20.02 1.98 6.40 0.03

F5 0.260 0.003 43 2.0 23.10 2.02 6.63 0.02

F6 0.276 0.001 51 2.1 25.63 2.05 6.66 0.01

F7 0.280 0.002 37 2.0 27.31 2.07 6.58 0.03

F8 0.297 0.002 52 2.1 29.15 1.97 6.61 0.02

F9 0.310 0.001 55 2.1 31.46 1.97 6.70 0.02

Values are expressed as Average of three determination n = 3

In vitro dissolution studies of factorial batches F1- F9

The formulated films were subjected for in vitro dissolution studies and the results were shown

in Table 7. Among the nine formulations prepared, formulation F3 was found to release 97.37 %

drug with in 12 min which is desirable for faster absorption and rapid onset of action. Here 0.1 N

HCl (acidic media) is the recommended dissolution medium for Lurasidone HCl by USFDA.

Therefore it was selected as a dissolution medium for present study. Hence all the dissolution

studies carried out in 0.1 N HCl.



Table 7: In- vitro drug release profile of factorial batch F1- F9

TIME (min)

Cumulative percentage release for different formulation

F1 F2 F3 F4 F5 F6 F7 F8 F9

0 0 0 0 0 0 0 0 0 0

2 50.43 52.41 55.38 51.42 48.46 46.68 41.53 39.56 37.58

4 55.00 58.01 63.8 58.00 61.2 59.00 47.20 46.20 48.2

6 70.60 72.43 74.50 64.63 70.67 73.04 60.11 59.50 63.52

8 78.37 80.42 82.51 71.34 77.44 80.44 67.13 69.15 73.02

10 82.21 85.29 89.40 78.10 82.27 85.31 72.29 75.70 81.01

12 90.09 94.40 97.37 84.94 87.15 90.22 78.67 79.71 79.86

14 - - - 91.84 93.87 95.38 83.50 85.56 88.71

16 - - - - - - 89.38 90.46 92.64

18 - - - - - - 93.72 95.20 95.61

Figure 11: In-vitro drug release of factorial batches F1 to F9

0

20

40

60

80

100

120

0 5 10 15 20

% C

DR

TIME (min)

F1

F2

F3

F4

F5

F6

F7

F8

F9



RESPONSE SURFACE PLOTS

Response surface plot were generated for disintegration time, tensile strength and drug release

at 10 min are shown in figure 12, 13, 14. As the concentration of pullulan polymer increase from

300 to 500, there was a decrease in cumulative % drug release. So polymer retards the drug

releases. When the polymer were present in less concentration (F3) then the cumulative % drug

release at 10 min was 89.40, while when we increase the concentration to highest (F9) then the

cumulative % drug release at 10 min was 81.01 only. When we kept pullulan polymer constant

and the concentration of propylene glycol increased from 15-25 then cumulative % drug release

was slightly increase. The disintegration time increase with increase the concentration of pullulan

and when we kept pullulan polymer constant and the concentration of propylene glycol increase

from 15-25 then very slight change in disintegration time. As the concentration of pullulan

polymer was increase from it showed increase in tensile strength. But effect of Pullulan polymer

lower as compare to propylene glycol as shown in figures.

> 44 < 44 < 40 < 36 < 32 < 28

Figure 12: Response surface plot of disintegration time



> 0.3 < 0.3 < 0.28 < 0.26 < 0.24 < 0.22 < 0.2 < 0.18

Figure 13: Response surface plot of tensile strength

> 86 < 86 < 84 < 82 < 80 < 78 < 76 < 74

Figure 14: Response surface plot of Q10 (min)

VALIDATION OF MODEL BY CHECK POINT BATCH

Check point batch CP1 were selected from the overlay plot of responses. The amount of pullulan

and propylene glycol were selected from surface plot and according to that predicted responses

were given in the table 8. Actual response of CP1 batch was measured and compare with the

predicted value of check point batch. All the value of responses was within the upper and lower

predicted interval. Hence, this model is valid and optimized batch can be selected from the

overlay plot of this model.



Table 8: Evaluation parameter and in- vitro dissolution of check point batch

CHECK POINT BATCH (CP1)

EVALUATION PARAMETER

Disintegration time (sec)

Tensile strength (N/ mm2)

Drug release at 10 min.

P O P O P O

X1= +0.5 X2= -0.5

36.83 34 0.272 0.269 76.78 86.35

P= Predicted value ; O= Observed value

It can be observed that the predicted value and observed value of CP1 for disintegration time,

tensile strength and drug release study were nearly similar with 32 factorial design batches. It can

be revealed that the evolved model can be used for prediction of response i.e. in- vitro dissolution

time of films within the simplex space. Here comparative analysis of the predicted value and

experimental value using paired t- test was carried out. It was shows that there was no significant

difference between tcal (0.59) and ttab (4.30). Hence it complies the t- test because of ttab value

was higher than tcal. In the present research work, no more difference between factorial batches

and one check point composition.

COMPARISION OF STABILITY STUDY OF OPTIMIZED BATCH (F3) BY SIMILARITY AND

DISSIMILARITY FACTOR

The optimized batch F3 formulation was selected for stability study on the basis of high

cumulative % drug release, disintegration time, % drug content and tensile strength. Stability

study of formulation F3 was carried out at 40°C in a humidity chamber having 75 % 5 RH for 30

days. The results of stability studies performed on batch F3 are shown in table 9 and figure 15.

Table 9: Results of stability studies of optimized formulation (F3)

BATCH

PARAMETER

FOLDING ENDURANCE

DISINTEGRATION TIME (sec)

TENSILE STRENGTH

% DRUG CONTENT

INITIAL 48 30 0.220 98.35

AFTER 1 MONTH

46 28 0.218 96.20



Figure 15: In- vitro dissolution profile of formulation F3 after stability studies

SIMILARITY AND DISSIMILARITY FACTOR CALCULATION

Comparison of Similarity and dissimilarity factor calculation for optimized formulation (F3) after

stability study are shown in table 10.

Table 10: Similarity and dissimilarity factor calculation

Similarity factor (f2 value) Limit (50-100)

86.45

Dissimilarity factor (f1 value) Limit (0-15)

1.76

From the results Table 9 and fig 15 shows dissolution behaviour of optimized batch (F3) before

and after stability studies. The results suggested that the films stored at 40°C/ 75 % RH did not

show any major changes in films and no changes in physical appearance in films. The similarity

factor considered to be similar when f2 is between 50-100. Here, the value of similarity factor (f2)

of optimized batch was 86.45 therefore it was considered as similar compare to the dissolution

profile of freshly prepared films. The dissimilarity factor (f1) found to be 1.76. So it was observed

that fast dissolving films is stable at 40°C/ 75 % RH for 1 month and no change in property and

homogeneous films remained throughout the 30 days.

0

20

40

60

80

100

120

0 2 4 6 8 10 12 14

% C

DR

TIME (min)

% CDR BEFORE

STABILITY

STUDY

% CDR AFTER

STABILITY

STUDY



SUMMARY AND CONCLUSION

Oral fast dissolving films are ideal solid dosage forms for many groups of patients including

pediatrics, geriatrics and psychiatrics as well as those people who have difficulties in swallowing.

Fast dissolving films consist of thin film when put on tongue, dissolve or disintegrate rapidly in

mouth without water and release the drug within a few second.

Lurasidone HCl is an anti-psychotic drug used in treatment of schizophrenia. In this investigation,

the poor solubility of Lurasidone HCl is a major problem. So increase the solubility and dissolution

rate of drug by solid dispersion using cyclodextrin complexation technique. The preparing

complexes played a key role in enhancing the solubility and dissolution rate of Lurasidone HCl.

From the finding obtained, it can be concluded that solubility of Lurasidone HCl was enhanced by

preparing inclusion complexes with - CD carrier in 1:1 ratio using kneading method. After that

Drug- excipients compatibility studies were conducted using FTIR and DSC studies. These studies

revealed that, polymer and - CD used were compatible with drug and no interaction between

drug and polymer.

Different polymers were screened in preliminary studies for the formulation of fast dissolving

film. Amongst all the formulation, pullulan (2%) polymer combine with propylene glycol (20%) as

plasticizer was shown less disintegration time as compare to other formulation. Then two

variables were studied at three levels thus, 32 full factorial design was applied and nine different

formulation were developed by solvent casting method and evaluate the films. From this

formulations, batch F3 containing pullulan (1.5%) and propylene glycol (25%) disintegrate in 30

sec and 97.37 % drug release within 12 min and produced desired physicochemical properties so

considered as best formulation. In- vitro drug release study showed that higher concentration of

polymer retards the drug release rate. Response surface plot also gave idea about how pullulan

& PG concentration affect the result of fast dissolving film. Stability studies were also carried out

for the optimized formulation for 1 month under 40°C / 75% RH that has been proved that

prepared films were stable and no effect on storage condition.

REFERENCES

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J. Pharmacy & Pharma. Sci. 2014; 3(3): 463-475.

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Sci. 2013; 1(1): 63-75.

3. Parmar D, Patel U, Bhimani B: Orally fast dissolving film as dominant dosage for quick release.

Int. J. Pharma. Res. & Bio Sci. 2012; 1(3): 24-41.



4. Siddiqui N, Garg G and Sharma P: A short review on a novel approach in oral fast dissolving

drug delivery system and their patients. Adv. Bio. Res. 2011; 5(6), 291-303.

5. Thakur N, Bansal M, Sharma N, Yadav G and Khare P. Overview A novel approach of fast

dissolving films and their patients. Adv. Bio. Res. 2013; 7(2): 50-58.

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and technology. Int. J. Pharm. Sci. Review. 2011; 9(2): 50-57.

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8. Mittal A, Yadav M, Chaudhary D and Shrivastava B. Enhancement of solubility of Lurasidone

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10. Desai P, Basu B. Design and evaluation of fast dissolving film of Domperidone. Int. Res. J.

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11. Saini S, Nanda A, Dhari J. Formulation, development and evaluation of oral fast dissolving

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12. Koland M, Sandeep VP, Charyulu N. The design and characterization of sublingual films of

Ondansetron Hydrochloride. Int. J. Chem. Sci. 2009; 7(4): 2927-2938.

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film of Montelukast Sodium. World J. Medical Pharm. Bio. Sci. 2011; 1(1): 06-12.

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