INTERNATIONAL JOURNAL OF PHARMACEUTICAL RESEARCH AND BIO-SCIENCE

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1 INTERNATIONAL JOURNAL OF PHARMACEUTICAL RESEARCH AND BIO-SCIENCE FORMULATION AND EVALUATION OF FAST DISSOLVING FILM OF LURASIDONE HCl MS. MANSI M. SONI 1,2, DR. KANU R. PATEL 2 1. Research scholar, Gujarat Technological University, Gujarat. 2. Department of Pharmaceutics, Shri B. M. Shah College of Pharmaceutical Education and Research, Modasa , 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 3 2 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 Corresponding Author: MS. MANSI M. SONI Access Online On: PAPER-QR CODE How to Cite This Article: 101

2 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 ( 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 The fast dissolving dosage market could produce revenues of $13 billion by [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] 102

3 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 which is not the case with orally disintegrating tablets (fragile and brittle). handle, 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. 103

4 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. Benecel TM E5 and Benecel TM 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 μg/ml diluted with appropriate solvent. The assignments were represented in figure 2 &

5 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 Kneading method 1:0.5 1:1 1:2 1:3 1:0.5 1:1 1:2 1:3 - Cyclodextrin - Cyclodextrin 105

6 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 cm

7 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 cm 2 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 = cm 2 Each film area = 2 2 = 4 cm 2 Number of films in batch =72.345/4 = film Total amount of Lurasidone HCl inclusion complex required: Dose of one film * No of film required : 10 * : mg Preparation of Lurasidone HCl fast dissolving film using 3 2 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 3 2 full 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 3 2 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 nonsignificant p value (p> 0.05) have negligible contribution and they were neglected. 107

8 Table 2: Composition of factorial design formulation of Lurasidone HCl FORMULATION BATCH CODE INGREDIENTS F1 F2 F3 F4 F5 F6 F7 F8 F9 Solid dispersion Eq. to 5mg of Lurasidone HCl 180.8mg mg mg mg mg mg mg mg 180.8mg Pullulan (%w/v) Propylene Glycol (%w/w) Micro Crystalline Cellulose (%w/w) Citric Acid (mg) Aspartame (mg) Flavor (ml) Distilled Water (ml) 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 cm 2 ) 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 108

9 Drug content was carried out by this standard method. In this method the film (2x2 cm 2 ) 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 cm 2 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 In- vitro dissolution study Initial length of strip 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 cm 2 ) was kept in a flask of the dissolution apparatus containing 900ml of 0.1N HCl as a dissolution media maintaining the temperature at 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. 109

10 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 C / % 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 State Color Odour Taste Water Solubility RESULTS Crystalline powder White to off white powder Odourless Bitter 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 P H 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,

11 ABSORBANCE Research Article CODEN: IJPRNK Impact Factor: ISSN: Figure 1: UV spectrum of Lurasidone HCl in 0.1 N HCl y = x R² = abs CONCENTRATION (μg/ml) abs Linear (abs) Figure 2: Calibration curve of Lurasidone HCl in 0.1 N HCl 111

12 ABSORBANCE Research Article CODEN: IJPRNK Impact Factor: ISSN: y = x R² = abs CONCENTRATION abs Linear (abs) Figure 3: Calibration curve of Lurasidone HCl in 6.8 p H 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 mg/ml. The complexation by kneading method 1:1 ratio shows maximum saturation solubility 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 Series 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) 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 112

13 % CDR Research Article CODEN: IJPRNK Impact Factor: ISSN: 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 TIME (min) Figure 5: In- vitro dissolution study of inclusion complex Pure drug PM 1 PM 2 PM 3 PM 4 KM 1 KM 2 KM 3 KM 4 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 113

14 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 formulation of Observation C-H stretching No interaction Isocyanides No interaction Aryl group No interaction Aromatic group No interaction C-H bending No interaction 114

15 75 %T Lurasidone HCl /cm Figure 8: FTIR spectra of Lurasidone HCl 90 %T 85 Lurasidone HCl betacd+formulation Lurasidone HCl /cm Figure 9: FTIR spectra of Lurasidone HCl + -CD complex 100 %T Lurasidone HCl+ Formultion Lurasidone HCl+ Formultion11 Lurasidone HCl /cm 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

16 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 F F F F F F F F F 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/mm 2 ) SD FOLDING ENDURANCE SD % ELONGATION SD SURFACE P H SD F F F F F F F F F 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 % 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. 116

17 % CDR Research Article CODEN: IJPRNK Impact Factor: ISSN: 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 F TIME (min) Figure 11: In-vitro drug release of factorial batches F1 to F9 F1 F2 F3 F4 F5 F6 F7 F8 F9 117

18 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 only. When we kept pullulan polymer constant and the concentration of propylene glycol increased from 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 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 118

19 > 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. 119

20 Table 8: Evaluation parameter and in- vitro dissolution of check point batch CHECK POINT EVALUATION PARAMETER BATCH (CP1) Disintegration time Tensile strength Drug release at 10 (sec) (N/ mm 2 ) min. P O P O P O X1= +0.5 X2= 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 3 2 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) PARAMETER FOLDING DISINTEGRATION TIME TENSILE BATCH ENDURANCE (sec) STRENGTH INITIAL AFTER 1 MONTH % DRUG CONTENT 120

21 % CDR Research Article CODEN: IJPRNK Impact Factor: ISSN: % CDR BEFORE STABILITY STUDY % CDR AFTER STABILITY STUDY TIME (min) 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) Dissimilarity factor (f1 value) Limit (0-15) 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 Here, the value of similarity factor (f2) of optimized batch was therefore it was considered as similar compare to the dissolution profile of freshly prepared films. The dissimilarity factor (f1) found to be 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. 121

22 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, 3 2 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 % 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 1. Mundhe B, Kadam V, Jadhav S and Bharkad V: A short review on fast dissolving oral film. World J. Pharmacy & Pharma. Sci. 2014; 3(3): Khatoon N, Rao NGR, Reddy MB: Overview on fast dissolving oral films. Int. J. Chem. Pharm. Sci. 2013; 1(1): 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):

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