INTERNATIONAL JOURNAL OF PHARMACEUTICAL … 684.pdfload cell grip, the lower one was fixed and upper one was movable.Film strips with dimensionso

Research Article CODEN: IJPRNK IMPACT FACTOR: 1.862 ISSN: 2277-8713 Maulik Mehta, IJPRBS, 2014; Volume 3(2): 950-968 IJPRBS

Available Online at www.ijprbs.com 950

FORMULATION AND EVALUATION OF QUICK DISSOLVING FILM OF MIRTAZAPINE

MAULIK R. MEHTA, KIRAN CHOKHAWALA, CHHAGAN N. PATEL

Department of pharmaceutics and pharmaceutical technology, shri sarvajanik pharmacy college, shri sarvajanik vidhya sankul, near arvind baug, Mehsana, Gujarat, India.

Accepted Date: 19/04/2014; Published Date: 27/04/2014

Abstract: Mirtazapine is an anti depressant drug, a selective serotonin-reuptake inhibitor. Quick release films of Mirtazapine were prepared with the purpose of developing a dosage form for a very quick onset of action, which is beneficial in managing severe conditions of depression, aiding in developing a dosage form which was very convenient for administration, without the problem of swallowing and using water. The films of Mirtazapine were prepared by using polymers such as HPMC E15 LV and PEG 400 as plasticizer, by a solvent casting method. The polymers HPMC E15 LV and other excipient was selected based on preliminary trials. Formulation batches were formulated with the help of 32 full factorial designs. The fast dissolving oral films were optimized by using experimental design optimization technique was applied to find out the best formulation. The optimized formulation (batch F2) containing HPMC E15 and PEG 400 showed greater drug dissolution (more than 90% within 10 min), satisfactory In vitro disintegration time (16 sec) and physicomechanical properties that are suitable for mouth dissolving film. Stability study of optimized formulation showed that optimized formulation was stable at accelerated environment condition.

Keywords: Mirtazapine, Quick Dissolving Film, 32Full Factorial Design, Solvent Casting Method, HPMC, Polyethylene Glycol

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Corresponding Author: DR. MAULIK R. MEHTA

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Maulik Mehta, IJPRBS, 2014; Volume 3(2): 950-968



INTRODUCTION

The oral mucosa is composed of an outermost layer of stratified oral epithelium Below this lies a basement membrane, a lamina propria followed by the submucosa as the intra oral films technology layer. The epithelium is similar to stratified squamous epithelia found in the rest of the body in that it has a mitotically active basal cell layer, advancing through a number of differentiating intermediate layers to the superficial layers, where cells are shed from the surface of the epithelium The turnover time for the buccal epithelium has been estimated at 5-6 days and this is probably representative of the oral mucosa as a whole. The oral mucosal thickness varies depending on the site: the buccal mucosa measures at 500-800 μm, while the mucosal thickness of the hard and soft palates, the floor of the mouth, the ventral tongue and the gingivae measure at about 100-200 μm. The composition of the epithelium also varies depending on the site in the oral cavity. The mucosa of the gingivae and hard palate are keratinized similar to the epidermis which contain ceramides and acylceramides (neutral lipids) which have been associated with the barrier function. The mucosa of the soft palate, the sublingual and the buccal regions, however, are not keratinized which are relatively impermeable to water and only have small amounts of ceramide. They also contain small amounts of neutral but polar lipids, because of the diverse structures and functions of the mainly cholesterol sulfate and glucosyl ceramides. The non keratinized epithelia have been found to be considerably more permeable to water than keratinized epithelia.

Fast Dissolving Film :

Fast dissolving films, a new drug delivery system for the oral delivery of the drugs, was developed based on the technology of the transdermal patch. The delivery system consists of a very thin oral films, which is simply placed on the patient’s tongue or any oral mucosal tissue, instantly wet by saliva the films rapidly hydrates and adheres onto the site of application. It then rapidly disintegrates and dissolves to release the medication for oromucosal absorption or with formula modifications, will maintain the quick-dissolving aspects allow for gastrointestinal absorption to be achieved when swallowed. In contrast to other existing, rapid dissolving dosage forms, which consist of liophylisates, the rapid films can be produced with a manufacturing process that is competitive with the manufacturing coral films technology of conventional tablets.Oral films have hit the mainstream in the last few years as a new way of freshening the breath.

Advantages

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



Due to the presence of larger surface area, films provide rapid disintegrating and dissolution in the oral cavity.

Oral dissolving films are flexible and portable in nature so they provide ease in transportation, during consumer handling and storage.

Suitability for geriatric and pediatric patients, who experience difficulties in swallowing mentally ill, the developmentally disable and the patients who are un-cooperative, or are on reduced liquid intake plans or are nauseated.

Beneficial in cases such as motion sickness, acute pain, suede episodes of allergic attack or coughing, where an ultra rapid onset of action required.

As compared to liquid formulations, precision in the administered dose is ensured from each films of the film.

The dosage form can enter in the systemic circulation without undergoing first-pass hepatic metabolism.

The first pass effect can be avoided, so reduction in the dose which can lead to reduction in side effects associated with the molecule.

Patients suffering from dysphagia, emesis, hypertension, heart attack, asthma, motion sickness, paralysis and mental disorders prefer this dosage form as they are not capable to swallow large quantities of water.[10]

MATERIAL AND METHOD:

Mirtazapine was obtained from Torent Pharmaceutical Pvt. Ltd. Various grade of Hydroxypropylmethylcellulose (Yarrow Chem. Products, Mumbai, India), Polyethylene glycol 200, Polyethylene glycol 400, Polyethylene glycol 600 (S.D. Fine Chemical Limited, Mumbai, India), Propylene Glycol, Glycerin (Chemdyes Corporation Ahmedabad, India) were used as a film base material. Aspartame (Yarrow Chem. Products, Mumbai, India) as a sweetener and Citric Acid (Yarrow Chem. Products, Mumbai, India).

Preparation of Strip:

Accurately weighed quantity of drug was dissolved in 5 ml water. Specified amount of polymer and other excipients were dissolved in 10 ml water. The polymeric solution was added to the prepared drug solution. The above mixture of solution was casted in petri plate and kept for



drying at room temperature. Dried strip was removed safely from petriplate, cut in 2×2 cm2 size and stored in aluminium foil.

Evaluation of Strip:

1) Transparency and Surface texture

Transparency and Surface texture were evaluated by visual appearance of oral strip and categorized in various levels such as best, good, medium, bad for transparency and smooth and rough for surface texture. [9,11]

2) Film thickness

A thickness of the film should be calculated by using micrometer screw gauge at 5 different strategic locations. This is essential to ascertain uniformity in the thickness of the film as this is directly related to the dose in the strip. [9]

3) Tensile strength

The tensile strength of the patch was evaluated by using the tensilometer.It consists of two load cell grip, the lower one was fixed and upper one was movable.Film strips with dimensionso f2×2 cm2 were fixed between these cell grips and force was gradually applied till the film break.The tensile strength was taken directly from the dial reading in kg [9,12]

It is calculated by following equation:

Tensilestrength=F/A

Where,

F=Breakforce,

A=Areaoffilminmm2

4) Folding endurance

Folding endurance is determined by repeated folding of the strip at the same place till the strip breaks. The number of times the film is folded without breaking is computed as the folding endurance value. [9]

5) Disintegration time



Six strips of 2×2cm2 were kept in the disintegration tester(USPED-2L) at room temperature in tubes in the environment of water until they disintegrate and that time have been measured. The disintegration time limit of 30 seconds or less for orally disintegrating tablets describeding CDER guidance can be applied to fast dissolving oral film.Disintegration time will vary depending on the formulation but typically the disintegration range from 4to30 seconds. Although no official guidance is available for oral fast disintegrating films.[12]

6) In vitro drug release test

Dissolution profile of mirtazapine was carried out in a beaker containing 30 ml of the simulated salivary pH 6.8 as a dissolution medium, maintained at 37±0.5°C. The medium was stirred at 100 rpm with magnetic stirrer. Aliquatos of the medium were withdrawn at regular interval of 1 min and the same amount was replaced with fresh medium. Samples were analysed for cumulative percentage drug release by UV spectrophotometrically at 288nm. Three trials were carried out for all the samples and average was taken. [14]

7) Drug content

A specified area of strip (2cm×2cm) was dissolved in 100 ml water in volumetric flask and shaken continuously for 10 min. Filter the solution by 0.45μm membrane filter paper. After filtration,1ml of solution was withdrawn from the solution and diluted up to10ml with water. The absorbance of the solution was measured at 288nm and concentration was calculated and determined the drug content. [15,16,17]

8) Calculation for film casting

Oral dose of Mirtazapine was 7.5 mg 15 mg 30 mg and 45 mg. in this research work, the dose of Mirtazapine was decided 15 mg due to similar strength of present drug containing conventional tablets were widely available in the market. A films of 2 cm × 2 cm dimension (4 cm2) was planned to be prepared which should contain 15 mg of Mirtazapine. But the mould i.e. glass petridish for casting of films has 38.46 cm2 area. So total amount of Mirtazapine required to be added in the films casting solution (15 mL) was 144.22 mg

Drug Excipient Compatibility Study:

1) FTIR Study for Compatibility

Drug-excipients interactions play a vital role in the release of drug from formulation. Fourier transform infrared spectroscopy has been used to study the physical and chemical interaction between drug and the excipients used. Fourier transform infrared (FTIR) spectra of Mirtazapine,



HPMC E15 and mixture of drug and Excipients were recorded using KBr mixing method on FTIR instrument.

2) Differential Scanning Calorimetry Study

The DSC study of mirtazapine oral strip was performed using DSC instrument (DSC60). The DSC study carried out on pure drug, HPMCE15, mixture of Mirtazapine and Excipients. The thermogram of mirtazapine oral strip was obtained by Differential scanning calorimeter (DSC) on Shimadzu C-60.2mg of amount was taken in aluminum cell and scanned at 30°Cto300°C, at 20-30ml/min nitrogen flow rate against blank DSC aluminum cell as a reference.[12]

Optimization of Final Formulation 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 HPMC E15 (X1) and amount of Polyethylene glycol 400 (X2) on responses 32full factorial design was used. In this design HPMC E15 and Polyethylene glycol 400 were used as independent variables while disintegration time, in- vitro drug release at 10 min, tensile strength were selected as response variables. Trials were taken at all possible combinations. The detailed layout of factorial batches is shown in table 1. The equations relating independent variables and responses were obtained by subjecting the results to statistical evaluation. Design – Expert 9.0.0.7 was used to perform multiple linear regressions to determine the control factors that significantly affect the responses.

Polynomial equation for 32full factorial design: Y = ß0+ ß1X1+ ß2X2+ ß11X11+ ß22X22+ ß12X1X2 was used. In this equation Y is the dependent variable, ß0 is the arithmetic mean response of the nine runs, ß1 to ß12 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.

Preliminary Screening

Preliminary trial for selection of polymer

Oral strips were prepared by using various film forming polymers such as HPMC E5, HPMC E15 LV premium and HPMC E50.



Table 1: Preliminary trial for selection of polymer

Table 2: Preliminary trial for selection of palsticizer

Name of ingredient

Batch (Quantity in mg/38.46cm2) B5 B6 B7 B8 B9

Mirtazapine 144.22 144.22 144.22 144.22 122.22 HPMC E15 200 200 200 200 200 PEG 200 (20 % w/w of polymer)

40 (36μl)

- - - -

PEG 400 (20 % w/w of polymer)

- 40 (36μl)

- - -


- - 40 (36μl)

- -

Propylene Glycol (20 % w/w of polymer)

- - - 40 (39 μl)

-

Glycerin (20 % w/w of polymer)

- - - - 40 (32 μl)

Citric acid 10 10 10 10 10

Aspartame 10 10 10 10 10

Distilled water(ml) 15 15 15 15 15

Name of ingredient Batch (Quantity in mg/38.46cm2) B1 B2 B3 B4

Mirtazapine 144.22 144.22 144.22 144.22 HPMC E3 200 - - - HPMC E5 200 - - HPMC E15 - 200 -

HPMC E50 - - - 200


40mg (36 μl)

40mg (36 μl)

40mg (36 μl)

40mg (36 μl)

Citric acid 10 10 10 10

Aspartame 10 10 10 10 Distilled water(ml) 15 15 15 15



Table 3: Optimization formulations composition of 32 full factorial batches

RESULTS AND DISCUSSION:

Table 4: Evaluation of preliminary batch of plasticizer

Table 5: Evaluation of preliminary batch of plasticizer

Batch No Transparency Surface Texture Tensile Strength (Kg/cm2)*

Disintegration Time(sec)

B5 Good Smooth 0.197±0.01 36.3±0.42 B6 Best Smooth 0.254±0.01 25.1±0.57 B7 Good Smooth 0.223±0.01 32.4±0.66 B9 Rough Rough 0.196±0.01 40.1±0.33 Values are expressed as mean ± S.D, n=3

Batch (Quantity in mg/38.46cm2)

Ingredients F1 F2 F3 F4 F5 F6 F7 F8 F9

Mirtazapine(mg) 144.22 144.22 144.22 144.22 144.22 144.22 144.22 144.22 144.22

HPMC E15 LV 150 150 150 200 200 200 250 250 250

PEG 400 % 20 25 30 20 25 30 20 25 30

Citric acid

(mg)

10 10 10 10 10 10 10 10 10

Aspartame(mg) 10 10 10 10 10 10 10 10 10

Distilled water

(mL)

15 15 15 15 15 15 15 15 15

Batch No

Transparency Surface Texture

Tensile Strength (Kg/cm2)

Brittleness Disintegration Time(sec)

B1 Good Rough 0.140±0.03 Medium 46.7±3.38 B2 Medium Rough 0.165±0.01 Medium 35.5±2.19 B3 Best Smooth 0.250±0.01 Low 25.1±0.57 B4 Medium Rough 0.175±0.04 Medium 40±0.66 Values are expressed as mean ± S.D, n=3



In the preliminary trial it was found that HPMC E15 containing strip gave best transparency, smooth surface texture, moderate tensile strength, low brittleness and least disintegration time; 5% aspartame containing strip gave best transparency, smooth surface texture and sweet in taste; Polyethylene glycol 400 containing strip gave best transparency, smooth surface texture, moderate tensile strength, very low brittleness and least disintegration time.

Drug Excipient Compatability Study:

1) FTIR Study for Compatibility

The FTIR spectra of Mirtazapine showed a characteristic peaks of Mirtazapine appeared at 3245 (N-H stretching), 711 (C-Cl stretching).

It was observed that there were no changes in these main peaks in the FTIR spectra of a mixture of drug and excipients.The FTIR study demonstrate that no physical or chemical interactions of Mirtazapine with other excipients.

Figure1:FT-IRSpectra of Mirtazapine

Figure 2: FT-IR Spectra of Mirtazapine with Excipients



2)Differential Scanning Calorimetry Study

The DSC thermogram of Mirtazapine, HPMC E15 and mixture of Mirtazapine and other excipients are shown in below figure. The thermogram of pure Mirtazapine show melting endotherm at 116⁰C. The thermogram of HPMC E15 show melting endotherm at 75.67⁰C and thermogram of mixture of Mirtazapine and other excipients show melting endotherm at 116 ⁰C which indicates there is no significant changein melting endotherm of pure drug.

Figure 3: DSC Thermogram of Mirtazapine

Figure 4: DSC Thermogram of Mirtazapine with Excipients

Optimization of Final Formulation using 32 Full Fctorial Design



Table 6 (a): Evaluation of Prepared Batches for Optimized Formulation

Batch EVALUATION PARAMETERS

Thickness#

(mm) Tensile Strength* (kg/cm2)

Transparency Surface Texture

F1 0.11±0.00 0.156±0.02 Transparent Smooth F2 0.11±0.00 0.165±0.02 Transparent Smooth F3 0.11±0.01 0.187±0.01 Transparent Smooth F4 0.11±0.00 0.213±0.01 Transparent Smooth

F5 0.11±0.00 0.303±0.01 Transparent Rough F6 0.11±0.01 0.327±0.02 Transparent Smooth

F7 0.11±0.00 0.355±0.01 Transparent Rough

F8 0.12±0.00 0.367±0.02 Transparent Rough

F9 0.12±0.00 0.375±0.02 Transparent Smooth * Values are expressed as mean ± S.D, n=3

Table 6 (b): Evaluation of Prepared Batches for Optimized Formulation

Batch EVALUATION PARAMETERS

Folding Endurance

Disintegration Time(sec)*

Drug Content* %CPR at 10 min*

F1 225±3.2 14.33±0.57 99.03±0.68 98.44±0.90 F2 250±2.6 16.33±1.52 101.22±0.38 100.37±0.85 F3 262±2.2 22.33±2.51 100.70±0.38 100.5±1.25 F4 248±2.2 15.33±2.31 96.00±0.60 93.74±1.72 F5 245±3.2 15.33±1.52 101.20±0.66 100.4±0.49 F6 245±3.7 23.66±2.88 98.20±0.66 94.11±0.70

F7 278±4.2 32.00±2.66 97.20±0.26 84.96±2.48

F8 215±2.3 37.66±3.78 98.22±0.63 76.68±1.34

F9 233±3.3 45.33±3.78 96.70±0.26 68.10±1.01 * Values are expressed as mean ± S.D, n=3,



Table 7: Cumulative Percentage Release of Prepared Batches F1 to F5

Time (min)

(%) Cumulative Percentage Release*

F1 F2 F3 F4 F5 F6 F7 F8 F9

0 0 0 0 0 0 0 0 0 0 2 54.62±

1.50 50.44±1.15 58.81±2.21 51.61±1.57 66.20±0.54 58.81±1.140 14.86±2.03 12.76±0.82 19.04±0.51

4 92.97±0.78 63.36±1.55 82.20±1.44 54.99±1.29 75.92±0.61 82.20±1.40 25.69±2.96 23.60±1.40 25.69±0.78

6 97.36±1.20 95.11±0.85 97.31±1.27 61.57±2.25 88.90±0.61 86.84±0.97 42.57±1.58 46.75±0.96 34.20±0.40

8 97.90±1.28 99.82± 0.85 99.93±1.27 78.66±1.97 99.85±0.49 93.60±0.21 53.27±1.16 67.93±0.40 40.67±0.40

10 98.44±0.90 100.37±0.85 100.5±1.25 93.74±1.72 100.4±0.49 94.11±0.70 84.96±2.48 76.68±1.34 68.10±1.01

*Values are expressed as mean ± S.D, n=3

Figure 5: In vitro Drug Release of Batches F1 to F9

In vitro dissolution studies were performed to compare the release of drug from nine different formulations (F1-F9). The drug release from different formulations are presented in figure 5

The batches F1-F6 showed more than 90% drug release within 10 min. In vitro dissolution studies were performed to compare the release of drug from nine different formulations (F1-F9).

Statistical Analysis of Factorial Design Batches

Full and reduced model for disintegration time



The summary of regression analysis and ANOVA for disintegration time is shown in table 8. The contour plot and 3D surface plot are shown in figure 6 and figure 7 respectively.Reduced model is obtained by rejecting insignificant factors in full model equation. From the reduced model it was found that variable X1i.e. concentration of HPMCE15, X2 i.e. Polyethylene glycol 400 and X1

2

shows positive effect on response Y1. As its concentration increases, disintegration time of film increases. It can be qualitatively concluded that X1, X2 andX1

2 had significant effect on the response.

Table 8: Summary Output of Regression Analysis and Anova for Disintegration Time

C0EFFICIENTS

Coefficient Coefficient value P-value b0 16.00 0.0010 b1 10.33 0.0002 b2 4.83 0.0023 b11 1.25 0.1314 b22 10.00 0.0014 b12 2.50 0.0618

Figure 6: Contour Plot of Response 1 (Disintegration Time)

Design-Expert® SoftwareFactor Coding: Actualdisintegration (sec)

Design Points45

14

X1 = A: HPMC E15X2 = B: peg 400

150.00 175.00 200.00 225.00 250.00

20.00

22.00

24.00

26.00

28.00

30.00disintegration (sec)

A: HPMC E15 (mg)

B: p

eg 4

00 (%

) 20

20

30

40

DF SS MS F P-Value Prob >F

Regression 5 999.58 199.92 135.79 0.0010 Residual 3 4.42 1.47 Total 8 1004.00 Significant



Figure 7: 3D Surface Plot of Response 1 (Disintegration Time)

Full and Reduced Model for Tensile Strength

The summary of regression analysis and ANOVA for tensile strength is shown in table 9. The contour plot and 3D surface plot are shown in figure 8 and figure 9 respectively. Reduced model is obtained by rejecting insignificant factors in full model equation. From the reduced model it was found that variable X1 i.e. concentration of HPMCE15, X2 i.e. polyethylene glycol X1

2 shows positive effect on response Y3. As its concentration increases, tensile strength of film increases. It can be qualitatively concluded that X1, X2 and X1

2 had significant effect on the response.

Table 9: Summary Output of Regression Analysis and Anova for Tensile Strength.

C0EFFICIENTS

Coefficient Coefficient value P-Value b0 0.29 0.0344 b1 0.098 0.0051 b2 0.028 0.1307 b11 -2.750 0.8767 b22 -0.013 0.5992 b12 -9.500 0.7079

Design-Expert® SoftwareFactor Coding: Actualdisintegration (sec)

Design points above predicted valueDesign points below predicted value45

14

X1 = A: HPMC E15X2 = B: peg 400

20.00

22.00

24.00

26.00

28.00

30.00

150.00 175.00

200.00 225.00

250.00

10

20

30

40

50

disinteg

ratio

n (sec

)

A: HPMC E15 (mg)

B: peg 400 (%)


Regression 5 0.063 0.013 11.85 0.0344 Residual 3 3.187E-003 1.062E-003 Total 8 0.066 Significant

Full Model

Y2=0.29+0.098X1+0.028X2-2.750X12-0.013X22-9.500X1X2



Figure8 : Contour Plot of Response 2 (Tensile strength)

Figure 9: 3D Surface Plot of Response 2 (Tensile strength)

Full and reduced model for In vitro drug release

The summary of regression analysis and ANOVA for In vitro drug release is shown in table 10. The contour plot and 3D surface plot are shown in figure 10 and figure 11 respectively. Reduced model is obtained by rejecting insignificant factors in full model equation. From the reduced model it was found that variable X1 i.e. concentration of HPMCE15, X2 i.e. polyethylene glycol

Design-Expert® SoftwareFactor Coding: Actualtensile strengt (kg/cm2)

Design Points0.375

0.156

X1 = A: HPMC E15X2 = B: peg 400

150.00 175.00 200.00 225.00 250.00

20.00

22.00

24.00

26.00

28.00

30.00tensile strengt (kg/cm2)

A: HPMC E15 (mg)

B: p

eg 4

00 (%

)

0.15

0.2 0.25 0.3

0.35

Design-Expert® SoftwareFactor Coding: Actualtensile strengt (kg/cm2)

Design points above predicted valueDesign points below predicted value0.375

0.156

X1 = A: HPMC E15X2 = B: peg 400

20.00 22.00

24.00 26.00

28.00 30.00

150.00

175.00

200.00

225.00

250.00

0.1

0.15

0.2

0.25

0.3

0.35

0.4

tens

ile s

treng

t (kg

/cm

2)

A: HPMC E15 (mg)B: peg 400 (%)

Reduced model

Y2=0.29+0.098X1+0.028X2



and X12 shows negative effect on response Y3. As its concentration of HPMC E 15 AND PEG 400

increases decrease percentage drug release of the films.

Table 10: Summary Output of Regression Analysis and Anova for In vitro drug release.

C0EFFICIENTS

Coefficient Coefficient Value P-Value b0 97.76 0.0194 b1 -11.60 0.0038 b2 -2.40 0.1878 b11 -4.73 0.0720 b22 -7.91 0.0483 b12 -2.51 0.3815

Figure 10: Contour Plot of Response 3 (% CPR) at 10 min.

Design-Expert® SoftwareFactor Coding: Actual%CPR at 10 min (min)

Design Points100.5

68.1

X1 = A: HPMC E15X2 = B: peg 400

150.00 175.00 200.00 225.00 250.00

20.00

22.00

24.00

26.00

28.00

30.00%CPR at 10 min (min)

A: HPMC E15 (mg)

B: p

eg 4

00 (%

)

80

90

100


Regression 5 1068.53 213.71 17.79 0.0194 Residual 3 36.03 12.02 Total 8 1104.57 Significant

Full model

Y3=97.76-11.60X1-2.40X2-4.73X12-7.91X2

2-2.51X1X2

Reduced model

Y3=97.76-11.60X1-2.40X2



Figure 11: 3D Surface Plot of Response 3 (% CPR) at l0 min.

Verification of Model by Check Point Batch

Check point batch C1 and C2 were selected from the overlay plot of responses. The amount of HPMC E 15 and Polyethylene glycol 400 were selected from overlay plot and according to that predicted responses were given in the table 11. Actual response of C1 and C2 batch was measured and compare with the predicted response of check point batch. All the values of responses were 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 11: Predicted Response and Actual Response of Check Point Batch

Batch Predicted Response Actual Response

D.T. (Sec)

%CPR at 2 min

Tensile Strength (kg/cm2)

D.T. (Sec)

%CPR at 2 min

Tensile Strength (kg/cm2)

C1 17 85 0.175 19 88 0.195

C2 20 81 0.210 22 84 0.211

Optimization of Batch from Overlay Plot

From the overlay plot it was seen that batch F3 fall under the optimized region. So, the F3 batch was selected as the optimized batch.

Short Term Stability Study of Optimized Formulation

In order to determine the change in performance of dosage form on storage, stability study of optimized batch (F2) was carried out at 40±2°C and 75±5% RH in a stability chamber for one month.

Design-Expert® SoftwareFactor Coding: Actual%CPR at 10 min (min)

Design points above predicted valueDesign points below predicted value100.5

68.1

X1 = A: HPMC E15X2 = B: peg 400

20.00

22.00

24.00

26.00

28.00

30.00

150.00 175.00 200.00 225.00 250.00

60

70

80

90

100

110

%CPR

at 1

0 m

in (m

in)

A: HPMC E15 (mg)

B: peg 400 (%)



Table 12: Comparison of Physical Parameters after Stability

Parameters Before Stability Study After Stability Study Thickness (mm) 0.07 ± 0.001 0.007 ± 0.001 Tensile strength (kg/cm2) 0.165 0.296 Transparency Very Good Good Surface texture Smooth Smooth Folding endurance >175 153 Disintegration time (sec.) 16 18 Drug content 101.22 99.87 %CPR at 2 min 100.3 95.45

Samples were withdrawn after 1 month and evaluated for physical properties as well as change in vitro drug release pattern. The similarity factor was applied to study the effect of storage on batch. The optimized formulation stored at 40± 2°C/ 75 ± 5 % RH and it was found stable. Various morphological and mechanical properties evaluation parameters before and after stability were found in range and not any large different between any two parameters. After stability tensile strength, folding endurance and release at 10 min were slightly decreased, and disintegration time was slightly increase, but all value were in accepted range. There was not any change observed in morphological properties like transparency and surface texture. Comparison of drug release after and before stability study were carried out by similarity factor (f2) and it was found in accepted limit

CONCLUSION

It was concluded that the amounts of polymers and plasticizers have significant effect on prepared oral strip. The development of oral strip drug delivery of mirtazapine strip is one of the alternatives routes of administration avoid first pass metabolism and provide immediate action. In addition these formulations enhance patient compliance. A combination of HPMCE15, PEG 400, aspartame showed improved in dissolution and better morphological and mechanical properties to mirtazapine strip. Prepared strips were stable at sort term stability condition for one month that prove prepared dosage form has no effect of storage condition.

REFERNCES:

1 Patel DA, Patel MR, Patel KR, Patel Nm, “Buccal mucosa as a route for systemic drug delivery: a review.”International journal Drug Development & Research 2012, 4(1), 99-116.



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