7. Design and development of rapidly dissolving films using ion exchange resin for taste masking

Transcription

1 List of Tables Table no. Title 7.1 Preliminary trial for formation of drug-resinate complex at different CTZ to resin ratio 7.2 Preliminary trials for film formation 7.3 Experimental trial for film separation using Teflon petridish 7.4 Formulation of RDF using different amount of xanthan gum and plasticizer 7.5 Optimization of ingredients for RDF formulation using HPC-LF 7.6 Optimization of swelling and stirring time of resin 7.7 Trials using lower ratio of drug: resin (cetirizine hydrochloride: Tulsion 335) 7.8 Formulation of film containing optimized ratio of Cetirizine hydrochloride: Tulsion In-vitro dissolution study of batch F Evaluation of mechanical properties of batch F Composition of batches for simplex lattice design 7.12 Response table for simplex design batches 7.13 Composition and result of check point batch for in-vitro disintegration study 7.14 Composition and result of check point batch for mechanical property study 7.15 Stability studies of optimized batch 175

2 List of Figures Figure no. Title 7.1a ESEM of HPMC E3 LV at 150x magnification 7.1b ESEM of Cetirizine hydrochloride at 350x magnification 7.1c ESEM of resin Tulsion 335 at 100x magnification 7.1d ESEM of resin film at 100x magnification 7.2 Differential scanning calorimetry study (DSC) of various samples 7.3a X ray diffraction study (XRD) of cetirizine hydrochloride 7.3b X ray diffraction study (XRD) of resin Tulsion c X ray diffraction study (XRD) of physical mixture PMR2 7.3d X ray diffraction study (XRD) of physical mixture PMR3 7.3e X ray diffraction study (XRD) of resin containing film 7.4 Contour plot for in-vitro disintegration time 7.5 Contour plot for tensile strength 7.6 Contour plot for % elongation 7.7 Contour plot for elastic modulus 176

3 7.1 Introduction A film or strip comprises of a water soluble polymer due to which the film or strip dissolves when placed on the tongue in the oral cavity. The first oral strips were developed by Pfizer named as Listerine pocket packs and were used for mouth freshening. Chloraseptic relief strips were the first therapeutic oral thin films which contained benzocaine and were used for the treatment of sore throat (1,2). The RDF are formulated using fast disintegrating polymers also possessing good film forming properties like Hydroxypropyl methylcellulose (HPMC), pullulan and Hydroxypropylcellulose (HPC) (3). Cetirizine hydrochloride (CTZ) is an orally active and selective H1-receptor antagonist used in allergic rhinitis and chronic urticaria. It is a white, crystalline water soluble drug possessing bitter taste (4,5). Due to sore throat conditions, the patient experiences difficulty in swallowing a tablet type of dosage form. Thus, a RDF would serve as an ideal dosage form for the patients. Ion exchange resins are high molecular weight polymers with cationic and anionic functional groups. Due to high molecular weight, they are not absorbed by the body which makes them safe. The most frequently employed polymeric network is a copolymer of styrene and divinylbenzene. Ion exchange resins contain positively or negatively charged sites and are accordingly classified as either cation or anion exchanger. They are further classified as inorganic and organic resins. Ion exchange resins are used in formulations for stabilization of sensitive components, sustained release of drugs, providing tablet disintegration and taste. Drug resin complex dissociation does not occur under salivary ph conditions. This suitably masks the unpleasant taste and odor of the drug (6,7). Tulsion 335 is a weak acid cation exchange polyacrylic resin with carboxylic acid as functional group. It is supplied in powder form having no side reaction and good taste ability. Due to bitter taste of CTZ, taste was tried using ion exchange resin, Tulsion 335 (8). 177

4 7.2 Materials and equipments Materials used Materials Name of Company Cetirizine hydrochloride Gifted by Troikaa Pharmaceuticals Ltd, Ahmedabad HPMC E3 LV Gifted by Colorcon Asia Pvt Ltd, Goa Hydroxy propyl cellulose (HPC LF) Gifted by Signet Chemical Corporation, Mumbai Tulsion 335 Gifted by Thermax India Pvt Ltd, Pune Sucralose Gifted by Alkem Lab Ltd., Ankleshwar, Gujarat Polyethylene glycol (M Wt 400) S.D.Fine Chem Ltd, Mumbai Passion fruit flavour Pentagon trading company, Ahmedabad All other chemicals used were of analytical grade and were used without any purification. Double distilled water was used for the study Equipments used Equipments Magnetic stirrer Hot air oven Humidity oven Universal testing machine Fourier transfer infra-red spectrophotometer USP dissolution apparatus XXIV Environment scanning electron microscope Differential scanning calorimeter X ray diffractometer Name of Company Remi, India EIE Instruments, Ahmedabad, India EIE Instruments, Ahmedabad, India Lloyd, UK model LR 100 K, UK Jasco FTIR model 6100, Japan Electrolab, Mumbai, India Philips, XL 30 model, The Netherlands Perkin- Elmer, Pyris-I, MA, USA Philips, X pert MPD, The Netherlands 178

5 7.3 Method of preparation of rapidly dissolving films and its evaluation Preparation of rapidly dissolving films The RDF of CTZ were prepared using ion exchange resin by solvent casting method (9). Drug-resinate complex was prepared by dispersing the resin in water and stirring for 2 h. CTZ was added to it and the suspension was stirred for sufficient time and filtered. The drug-resinate complex was allowed to dry in hot air oven at 60 C. The dry drug-resinate complex was passed through sieve 20#. The drug loading in the complex was determined. The drug-resinate complex equivalent to the required dose of drug was dispersed in 5 ml distilled water. HPMC E3 LV and HPC LF were dissolved separately in 5 ml distilled water and xanthan gum was added to it. The solution was stirred uniformly. This solution was added to the drug-resinate complex dispersion. Plasticizer PEG 400, sweetener sucralose and flavour was added to the mixed dispersion and stirred well. The dispersion was casted on a teflon petridish (diameter 9 cm) and dried at room temperature for 24 h. The film was carefully removed, checked for any imperfections and cut into the required size to deliver the equivalent dose (2 x 2 cm 2 ) per strip. The samples were stored in a dessicator at relative humidity % until further analysis. Film samples with air bubbles, cuts or imperfections were excluded from the study. Diameter of petridish selected = 8.97 cm Surface area of petridish = cm 2 No. of strips =16 Estimation of drug loading The amount of drug present in the drug-resinate complex was evaluated. Amount of drugresinate complex equivalent to 10 mg CTZ was dissolved in 900 ml 0.1 N HCl. The content of CTZ was estimated by UV-visible spectrophotometer at 231 nm. 179

6 7.3.2 Evaluation The RDF were evaluated for the following parameters- 1. Fourier transfer infra red spectroscopy (FTIR) 2. Measurement of mechanical properties of the RDF (10,11) 3. In-vitro disintegration studies (9,12,13) 4. In-vivo disintegration studies (13) 5. In-vitro dissolution studies (13,14) 6. Environment Scanning electron microscopy (ESEM) (15,16) 7. DSC study (15,16) 8. XRD study (15,16) 9. Taste evaluation (17) The details of the evaluation procedures are similar to those mentioned in chapter 3 section

7 7.4 Results and discussion Preformulation study Preformulation study for the drug and excipients was conducted. No drug-excipient or excipient-excipient interaction was observed Preliminary trials The preliminary trials were undertaken for preparing taste masked drug-resinate complex. Various ratios of CTZ to resin were taken and drug-resin complexes were evaluated for taste property. Calculation for drug loading 0.25 g CTZ is present in 1.25 g complex 10 mg CTZ will be present in 50 mg complex 160 mg CTZ will be present in 800 mg complex 50 mg drug-resinate complex was dissolved in 0.1N HCl and absorbance was measured at 231 nm using UV-visible spectrophotometer. Table 7.1 Preliminary trial for formation of drug-resinate complex at different CTZ to resin ratio Ingredients (mg)/batch* CT1 CT2 CT3 CT4 CT5 CTZ Tulsion Distilled water (ml) Total Time (h) CTZ: Tulsion 335 1:1 1:1 1:2 1:2 1:4 Taste Very Very Bitter Bitter Acceptable bitter bitter * Batch size 16 strips As shown in Table 7.1, lower ratios of CTZ to Tulsion 335 i.e. batches CT1 to CT4 could not produce taste of the drug-resinate complex. Batch CT5 containing 1: 4 of CTZ to Tulsion 335 produced taste of the drug-resinate complex. Further trials 181

8 were carried out using the above ratio of CTZ to Tulsion 335 and film formation was tried in next trial batches. Table 7.2 Preliminary trials for film formation Ingredients (mg)/ Batch * CT6 CT7 Drug-resin /distilled water (mg / 5ml) complex HPMC E3 LV Xanthan gum PEG Distilled water (ml) 5 5 Film separation No No Taste * Batch size 16 strips Initial trials for film separation were carried out using glass petridish but film separation could not be achieved. Alternatively, Teflon petridish was used in the next trials. 182

9 7.4.2 Experimental trials Table 7.3 Experimental trial for film separation using Teflon petridish Ingredients (mg)/ Batch * R1 R2 R3 R4 Drug-resin complex /distilled water (mg / 5ml) HPMC E3 LV Xanthan gum PEG Distilled water (ml) Film uniformity Yes Brittle Non-uniform Non-uniform In-vitro disintegration time (sec) In-vivo disintegration time (sec) CTZ: Tulsion 335 1:4 1:4 1:4 1:4 Taste * Batch size 16 strips Table 7.3 indicates that complete taste was obtained using 1: 4 ratio of drug to resin. As the amount of xanthan gum was decreased, the in-vitro disintegration time also decreased. Batch R3 had acceptable in-vitro disintegration time but the RDF formed were non-uniform as the drug, polymer and resin were not uniformly distributed. In-vitro disintegration time study was performed to mimic in-vivo conditions. In-vivo disintegration time was also performed to have an insight in the actual disintegration of the RDF. Therefore, 10 ml distilled water was selected as disintegration medium. However, it was observed that there was significant difference between in-vitro and in- 183

10 vivo disintegration time. This might be due to absence of salivary enzymes in the in-vitro disintegration medium. Table 7.4 Formulation of RDF using different amount of xanthan gum and plasticizer Ingredients (mg)/ Batch * R5 R6 R7 R8 Drug-resin /distilled water (mg/ 5ml) complex HPMC E3 LV Xanthan gum PEG Distilled water (ml) Film separation Yes, nonuniform In-vitro disintegration time (sec) 65 Yes, nonuniform Yes, nonuniform Yes, nonuniform 60 In-vivo disintegration time (sec) Taste * Batch size 16 strips Table 7.4 indicates as complete uniform film could not be formed in batches R5 to R8; further trials were required to be taken by varying the amount of HPMC E3 LV and xanthan gum. Uniform films could not be obtained even by using higher amount of PEG 400 as indicated in batches R7 and R8. 184

11 Table 7.5 Optimization of ingredients for RDF formulation using HPC-LF Ingredients (mg)/ Batch * R9 R10 R11 R12 R13# R14# R15# Drug-resin /distilled water (mg/ 5ml) complex HPMC E3 LV HPC LF Xanthan gum PEG Distilled water (ml) Film separation In-vitro time (sec) disintegration Yes, non uniform Yes, non uniform Yes, nonuniform Nonuniform Yes, uniform Yes Nonuniform Taste * Batch size 16 strips, # calculation for 18 strips Batches R9 to R12 were formulated with HPMC E3 LV alone as film forming polymer. It was observed that HPMC E3 LV could not produce uniform films so addition of another film forming agent HPC-LF was tried in the next formulations. HPC LF was added to HPMC E3 LV as film forming polymer to obtain desired film property, strength and uniformity in batches R13 to R15. It was observed that batch R14 containing 20 mg xanthan gum had unacceptably high in-vitro disintegration time 120 sec although the film obtained was uniform. If the amount of HPMC E3 LV was reduced to 400 mg along with 10 mg xanthan gum, uniform film could not be obtained although acceptable in-vitro 185

12 disintegration time could be obtained. The in-vitro disintegration time and in-vivo disintegration time for the optimized batch R13 were 65 sec and 30 sec respectively which might be due to addition of minimum quantity of xanthan gum to the optimized amount of film forming polymers. Uniformity of the film was lost in batch R15 as HPC LF amount was decreased. Table 7.6 Optimization of swelling and stirring time of resin Using (1:4) ratio of CTZ: Tulsion 335 Batch A1 A2 A3 A4 A5 A6 Swelling time (h) Stirring time(h) Taste Drug (%) loading * All quantities are in mg It was observed that using 1:4 ratio of CTZ: Tulsion 335, optimum taste was achieved in batches A3, A5 and A6. Highest drug loading was observed with batches A6 having 2 h of swelling time and 4 h of stirring time. Further trials were decided to be taken using lower ratio of CTZ: Tulsion 335 to check effect of swelling time and stirring time on the taste property. Table 7.7 Trials using lower ratio of drug: resin (Cetirizine hydrochloride: Tulsion 335) Batch B1 B2 B3 C1 C2 C3 CTZ: Tulsion 335 1:3 1:3 1:3 1:2 1:2 1:2 Swelling time (h) Stirring time (h) Taste Drug loading (%) * All quantities are in mg 186

13 When the ratio of CTZ: Tulsion 335 was lowered to 1:2 as shown in batches C1 to C3, optimum taste could not be achieved. When the ratio of CTZ: Tulsion 335 was 1:3, optimum taste was achieved in batch B3 with 2 h of swelling time and 4 h of stirring time with drug loading 98%. Thus, swelling time of 2 h and stirring time of 4 h were selected for the film formation. Table 7.8 Formulation of film containing optimized ratio of Cetirizine hydrochloride: Tulsion 335 Ingredients (mg)/ Batch * F2 Drug-resin complex 720 /distilled water (mg/ 5ml) HPMC E3 LV 400 HPC LF 200 Xanthan gum 0.1% PEG Distilled water (ml) 5 Film separation Yes In-vitro disintegration time 65 (sec) In-vivo disintegration time (sec) 30 Taste Drug loading (%) * All quantities are in mg The preliminary optimized film F2 had acceptable properties which included excellent taste, in-vitro disintegration time 65 sec and in-vivo disintegration time 30 sec. 187

14 Table 7.9 In-vitro dissolution study of batch F2 The in-vitro dissolution study of batch F2 was taken in 0.1N HCl (900 ml) as shown below- Time (min) Cumulative % drug release Table 7.10 Evaluation of mechanical properties of batch F2 Thickness (µm) 180 Tensile strength (N/mm 2 ) 28.3 % Elongation 4.24 Elastic modulus Study of mechanical properties indicates that batch F2 possessed high tensile strength indicating toughness of the film. % Elongation value indicates moderate to poor ductile nature of the film. High elastic modulus value indicated stiff nature of the materials used in the film namely HPC LF along with HPMC E3 LV. 188

15 Environment scanning electron microscopy (ESEM) Figure 7.1a shows the ESEM of HPMC E3 indicated irregular shaped particles at 150x magnification. Figure 7.1b shows CTZ particles could not be seen distinct as such. On dispersing it in acetone cylindrical distinct particles could be observed at 350x magnification. ESEM of resin showed uniform particles at 100x magnification at Figure 7.1c. The optimized film batch F2 is shown in Figure 7.1d at 100x magnification showed uniform film with resin particles entrapping CTZ particles. Figure7.1a ESEM of HPMC E3 LV at 150x magnification 189

16 Figure 7.1b ESEM of CTZ at 350x magnification Figure 7.1c ESEM of resin Tulsion 335 at 100x magnification 190

17 Figure 7.1d ESEM of resin film at 100x magnification 191

18 Differential scanning calorimetry study Figure 7.2 Differential scanning calorimetry study (DSC) of various samples DSC scan shown in Figure 7.2 indicated sharp endothermic peak of CTZ indicating melting at C. DSC scan of resin (Resin 335) indicated broad endothermic peak at 225 C. The DSC scan of physical mixture PMR2 containing drug to resin ratio 1:3 indicated a peak at 64 C followed by further decomposition. The endothermic peak corresponding to CTZ was absent in PMR2, R1 and R2. The films R1 and R2 prepared by inclusion complex at drug to resin ratio 1:2 and 1:3 showed peak at C and C respectively which indicates some inherent change in the compound followed by further decomposition. 192

19 X ray diffraction study Figure7.3a X ray diffraction study (XRD) of cetirizine hydrochloride Figure 7.3b X ray diffraction study (XRD) of resin Tulsion

20 Figure 7.3c X ray diffraction study (XRD) of physical mixture PMR2 Figure 7.3d X ray diffraction study (XRD) of physical mixture PMR3 194

21 Figure 7.3e X ray diffraction study (XRD) of resin containing film XRD analysis was performed to confirm the results of DSC studies. X ray diffraction (XRD) is a useful method for determination of complexation in powder or microcrystalline state. XRD of CTZ as indicated in Figure 7.3a showed sharp peaks at 8.3, 18.29, 18.79, 23.97, 25 and θ positions with height , 99.15,119.24,130.9 and cps indicating crystalline nature of the drug. XRD of resin Tulsion 335 in Figure 7.3b showed crystalline nature with peak at θ positions with height cps. The physical mixture PMR2, PMR3 at CTZ to resin ratio 1:2 and 1:3 respectively in Figure 7.3c and 7.3d indicated significant decrease in intensity of peaks of CTZ indicating transformation to amorphous state as peaks at 8.3, 18.29, 25 and θ positions with height 80, 120, 30 and 100 cps (PMR2) and peaks at 8.08, 18.73, and θ positions with height 8.25, 71.71, and cps (PMR3). The XRD of film shown in Figure 7.3e exhibits only 1 peak for film R2. Film R2 contains drug to resin ratio 1:3 shows complete absence of peak of CTZ which indicated complete inclusion complex formation responsible for taste of CTZ. 195

22 Simplex lattice design (18,19) Optimization by experimental design leads to the evolution of a statistically valid model to understand the relationship between independent and dependent variables. The application of simplex lattice experimental design is well documented in pharmaceutical literature. They are particularly appropriate in formulation optimization procedures where the total quantity of ingredients under consideration must be constant. The three component system is represented as an equilateral triangle in two dimensional spaces. Seven batches are prepared one at each vertex, one half way between vertices and one at the centre point. Each vertex represents a formulation consisting of the maximum amount of one component, with the other two components at the minimum level. The formulation represented half way between the two vertices contained the average of the minimum and maximum amounts of the two ingredients represented by two vertices. The seventh point contains one-third of each ingredient and it lies in the centre of the equilateral triangle. A polynomial first order linear interactive model may be evolved using the values of dependent and independent variables. Y= B 1 X 1 + B 2 X 2 + B 3 X 3 + B 12 X 1 X 2 + B 23 X 2 X 3 + B 13 X 1 X 3 + B 123 X 1 X 2 X 3 Where Y is the response parameter and B i.are estimated coefficients for the factors Xi. The main effects ( X 1,X 2 and X 3 ) represents the average results of changing one factor at a time from its low to high value. The interaction terms(x 1 X 2, X 2 X 3, X 1 X 3 ) show how the response changes when two or more factors are simultaneously changed. The effect of amount of HPMC E3 LV, amount of HPC LF and amount of plasticizer PEG 400 on the film properties namely film separation, in-vitro disintegration time and mechanical properties was studied using simplex lattice design. The amount of HPMC E3 LV (X 1 ), HPC-LF (X 2 ) and PEG 400 (X 3 ) were chosen as independent variables. The design layout and the responses of the seven batches of the simplex lattice design are shown in Table The mechanical properties i.e tensile strength, % elongation, elastic modulus, in-vitro disintegration time were selected as dependent variables. The 196

23 coefficients for the simplex lattice design were calculated using the specified procedure (19). Table 7.11 Composition of batches for simplex lattice design Variable levels in coded form Transformed values Batch X 1 X 2 X 3 D D D D D D D Independent variables Coded Actual values (in mg) X 1 =amount of HPMC E3 LV values X1 X2 X3 X 2 =amount of HPC LF X 3 = amount of PEG Transformed % = actual%-minimum% maximum%-minimum% In-vitro disintegration studies and mechanical property studies were carried out for batches D1 to D7 as described in chapter

24 Table 7.12 Response table for simplex design batches Batch X 1 X 2 X 3 In-vitro disintegration Mechanical properties time (sec) Tensile strength (N/mm 2 ) % Elongation Elastic modulus (N/mm 2 ) D D D D D D D Results and discussion In-vitro disintegration time of batches D1 to D7 are shown in Table 7.12 and Figure The results indicate that on increasing amounts of HPMC E3 LV and HPC LF the in-vitro disintegration time increases. Plasticizer PEG 400 was required in higher concentrations to obtain the desired in-vitro disintegration characteristics. As observed in batch D1, higher amount of HPMC E3 LV exhibited high in-vitro disintegration time of 90 sec and similarly batch D2 containing higher amount of HPC-LF also exhibited high in-vitro disintegration time 115 sec. Batch D3 containing lower amounts of HPMC E3 LV and HPC-LF had minimum in-vitro disintegration time 65 sec. Batch D4 containing combination of HPMC E3 LV and HPC-LF has unacceptably higher in-vitro disintegration time 100 sec. Batches D5 and D6 also had higher in-vitro disintegration time i.e. 85 sec and 105 sec. Batch D7 containing equal proportion of the three variables produced in-vitro disintegration time 75 sec. As per results of mechanical properties of 198

25 batch D1 and D2, addition of plasticizer PEG 400 decreased tensile strength, increased % elongation and decreased elastic modulus. A polynomial first order linear interactive model equation relating to in-vitro disintegration time of batches D1 to D7 is shown in equation (1). Y disintegration time =90X X X 3-10X 1 X X 1 X X 2 X 3-645X 1 X 2 X (1) Figure 7.4 Contour plot for in-vitro disintegration time Design-Expert Software in vitro disintegration time Design Points 115 A: HPMC E3 LV X1 = A: HPMC E3 LV X2 = B: HPC LF X3 = C: PEG B: HPC LF in vitro disintegration time C: PEG 400 Figure 7.4 shows contour plot of results based on equation (1) using Design Expert software (7.1.6 version). Formulations with in-vitro disintegration time <70 sec were found in a specific region containing low levels of HPMC E3 LV, L-HPC and high levels of PEG 400. Maximum in-vitro disintegration time was obtained using highest amount of HPC-LF. Mechanical properties of batches D1 to D7 are shown in Table Figure 7.5, 7.6 and 7.7 show contour plot of results based on equation (2), (3) and (4) using Design Expert (7.1.6 version). 199

26 A polynomial first order linear interactive model equation relating to mechanical properties namely tensile strength, % elongation and elastic modulus of batches D1 to D7 is shown in equation (2), (3) and (4). Y tensile strength =3.79X X X X 1 X X 1 X X 2 X 3-4.8X 1 X 2 X (2) Y % Elongation =2.995X X X X 1 X X 1 X X 2 X X 1 X 2 X (3) Y elastic modulus =164.95X X X X 1 X X 1 X X 2 X X 1 X 2 X 3 ---(4) Figure7.5 Contour plot for tensile strength Design-Expert Software A: HPMC E tensile strength Design Points X1 = A: HPMC E3 X2 = B: HPC LF X3 = C: PEG B: HPC LF tensile strength C: PEG

27 Figure 7.5 shows that combination of HPMC E3 LV and HPC LF were able to produce films with desirable tensile strength (3.0 N/mm 2 ). Higher amount of HPMC E3 LV and HPC LF produced films with very higher tensile strength. Addition of plasticizer PEG 400 decreased the tensile strength. Figure 7.6 Contour plot for % elongation Design-Expert Software % elongation Design Points A: HPMC E X1 = A: HPMC E3 X2 = B: HPC LF X3 = C: PEG B: HPC LF % elongation C: PEG 400 Figure 7.6 shows that higher amount of HPMC E3 LV along with varying amount of HPC LF films were obtained with desired % elongation (4.5). Combination of very high amount of HPMC E3 LV along with HPC LF produced films with very high % elongation. 201

28 Figure 7.7 Contour plot for elastic modulus Design-Expert Software A: HPMC E elastic modulus Design Points X1 = A: HPMC E3 X2 = B: HPC LF X3 = C: PEG B: HPC LF elastic modulus C: PEG 400 Figure 7.7 indicates that low amount of HPMC E3, HPC LF and higher amount of PEG 400 are desirable for films with elastic modulus of 100 N/mm 2. The highest value of elastic modulus is obtained using a combination of HPMC E3 LV and HPC LF. Addition of PEG 400 decreased elastic modulus. Selection of best batch The selection of best batch was done as per the following criteria set for the rapidly dissolving films. The desired values of in-vitro disintegration time was below 70 sec, tensile strength 3 N/mm 2, % elongation values between 3 and 4.5, elastic modulus 100 N/mm 2. Thus, only batch D3 was found to be acceptable in the above optimum range although it had slightly lower tensile strength value and slightly higher in-vitro disintegration time. 202

29 Check point batch The three component simplex lattice design was run with 1 check point composition of which is shown in Table Batch RC1 was prepared to validate the derived equation for in-vitro disintegration time. The data for in-vitro disintegration time for the predicted and observed values is shown in Table Table 7.13 Composition and result of check point batch for in-vitro disintegration study Check point batch (RC1) In-vitro disintegration time (sec) X 1 =0.04 X 2 =0.02 X 3 =0.94 Predicted value Observed value The three component simplex lattice design was run with 1 check point composition of which is shown in Table It can be observed that the predicted value and observed value for batch RC1 for in-vitro disintegration study were nearly similar. It can be concluded that the evolved model can be used for prediction of response i.e. in-vitro disintegration time within the simplex space. Batch RC2 was prepared to validate the derived equation for mechanical property study. The data for mechanical property for the predicted and observed values is shown in Table

30 Table 7.14 Composition and result of check point batch for mechanical property study Check point batch (RC2) X 1 = 0.2 X 2 =0.4 X 3 =0.4 Mechanical property Tensile strength (N/mm 2 ) Predicted value % elongation Elastic modulus (N/mm 2 ) Observed value It can be observed that the predicted values and observed values for batch RC2 for mechanical property were nearly similar. It can be concluded that the evolved model can be used for prediction of responses within the simplex space. It could be concluded that by adopting a systematic formulation approach, an optimum point can be reached with minimum efforts in shortest period of time. 204

31 7.4.3 Stability studies Batch D3 was subjected to stability studies at 25 C/40%RH.The samples were sealed in a zip lock bag and packed in a high density polyethylene (HDPE) container for 3 and 6 months stability studies. The in-vitro and in-vivo disintegration and in-vitro dissolution study was carried out. Table 7.15 Stability studies of optimized batch Time In-vitro In-vivo Time (min) for Appearance disintegration disintegration 85% drug before and after time (sec) time (sec) release exposure Initial Acceptable 1 Month Acceptable 3 Months Acceptable 6 Months Acceptable The results in Table 7.15 indicated that RDF containing CTZ were stable when ion exchange resin Tulsion 335 was incorporated as taste agent. The in-vitro disintegration time increased slightly at 3 months and 6 months period from 60 sec to 68 sec. In-vivo disintegration time increased very insignificantly. All RDF subjected to stability studies were physically stable. 205

32 7.5 Conclusion RDF of CTZ were formulated using polymers HPMC E3 LV and HPC-LF. As CTZ is a bitter drug, taste study was carried out using ion exchange resin Tulsion 335. It was observed that taste depended on the ratio of CTZ : Tulsion, its stirring and swelling time. The optimized taste masked complex was used for the formulation of RDF. Desired characteristics of the RDF could not be obtained when HPMC E3 LV was used alone as a film forming polymer. Thus, HPC-LF was used in combination of polymers with HPMC E3 LV. RDF with acceptable properties were obtained using the combination. The RDF were evaluated for various parameters such as in-vitro and invivo disintegration study, in-vitro dissolution study, mechanical properties, ESEM, DSC and XRD study. Optimization of RDF was done by simplex lattice design. The effect of amount of HPMC E3 LV, amount of HPC LF and amount of plasticizer PEG 400 were studied on the film properties namely film separation, in-vitro disintegration time and mechanical properties. Formulations with in-vitro disintegration time <70 sec were found in a specific region containing low levels of HPMC E3 LV, L-HPC and high levels of PEG 400. Higher amounts of HPC-LF exhibited higher in-vitro disintegration time. Combination of lower amount of HPMC E3 LV and higher amount of HPC LF and vice versa were able to produce films with desirable tensile strength (3.0 N/mm 2 ). Increasing amounts of HPMC E3 LV (up to coded value of 0.4) along with varying amount of HPC LF led to production of films with desired % elongation (4.5). The highest value of elastic modulus was obtained by a combination of HPMC E3 LV and HPC LF. RDF formulated using ion exchange resins had excellent taste. In-vitro disintegration time was slightly lower than RDF formulated using cyclodextrin as taste agent and stability was higher. The optimized batch was subjected to stability study at 25 C/40 % RH for 6 months. The RDF was found to be stable for 6 months. 206

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