7. design and development of rapidly dissolving films...

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

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________________________________________________________________________ Renuka Mishra Nirma University 175

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 335

7.9 In-vitro dissolution study of batch F2

7.10 Evaluation of mechanical properties of batch F2

7.11 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


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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 335

7.3c 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


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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 masking. 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 masking ability. Due to bitter taste of CTZ, taste

masking was tried using ion exchange resin, Tulsion 335 (8).


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7.2 Materials and equipments

7.2.1 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.

7.2.2 Equipments used

Equipments Name of Company

Magnetic stirrer Remi, India

Hot air oven EIE Instruments, Ahmedabad, India

Humidity oven EIE Instruments, Ahmedabad, India

Universal testing machine Lloyd, UK model LR 100 K, UK

Fourier transfer infra-red

spectrophotometer

Jasco FTIR model 6100, Japan

USP dissolution apparatus XXIV Electrolab, Mumbai, India

Environment scanning electron microscope Philips, XL 30 model, The Netherlands

Differential scanning calorimeter Perkin- Elmer, Pyris-I, MA, USA

X ray diffractometer Philips, X’pert MPD, The Netherlands


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7.3 Method of preparation of rapidly dissolving films and its evaluation 7.3.1 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 cm2) per strip. The samples were stored in a

dessicator at relative humidity 30-35 % 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 = 63.34 cm2

No. of strips =16

Estimation of drug loading

The amount of drug present in the drug-resinate complex was evaluated. Amount of drug-

resinate 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.


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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 3.


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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.

7.4.1 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 masking 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 160 160 160 160 160

Tulsion 335 160 160 320 320 640

Distilled water (ml) 10 10 10 10 10

Total Time (h) 4 6 4 6 6

CTZ: Tulsion 335 1:1 1:1 1:2 1:2 1:4

Taste masking Very

bitter

Very

bitter

Bitter Bitter Acceptable

* 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 masking of the drug-resinate complex. Batch CT5 containing 1: 4 of

CTZ to Tulsion 335 produced taste masking of the drug-resinate complex. Further trials


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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 complex

/distilled water

(mg / 5ml)

800 800

HPMC E3 LV 400 400

Xanthan gum 25 30

PEG 400 240 240

Distilled water (ml) 5 5

Film separation No No

Taste masking +++++ +++++


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.


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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)

800 800 800 800

HPMC E3 LV 400 400 500 600

Xanthan gum 40 30 10 10

PEG 400 160 240 390 420

Distilled water (ml) 5 5 5 5

Film uniformity Yes Brittle Non-uniform Non-uniform

In-vitro disintegration time

(sec)

100 100 60 65

In-vivo disintegration time

(sec)

35 35 - -

CTZ: Tulsion 335 1:4 1:4 1:4 1:4

Taste masking +++++ +++++ +++++ +++++


Table 7.3 indicates that complete taste masking 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-


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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 complex

/distilled water

(mg/ 5ml)

800 800 800 800

HPMC E3 LV 500 500 500 500

Xanthan gum 10 20 20 10

PEG 400 260 260 390 390

Distilled water (ml) 5 5 5 5

Film separation Yes, non-

uniform

Yes, non-

uniform

Yes, non-

uniform

Yes, non-

uniform


(sec)


(sec)

65

45

90

-

80

-

60

-

Taste masking +++++ +++++ +++++ +++++


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.


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Table 7.5

Optimization of ingredients for RDF formulation using HPC-LF

Ingredients (mg)/ Batch * R9 R10 R11 R12 R13# R14# R15#

Drug-resin complex

/distilled water

(mg/ 5ml)

800 800 800 800 900 900 900

HPMC E3 LV 500 500 600 600 400 400 400

HPC LF - - - - 200 200 100

Xanthan gum 20 15 10 20 10 20 10

PEG 400 520 520 560 560 600 600 600

Distilled water (ml) 5 5 5 5 5 5 5

Film separation Yes,

non

uniform

Yes ,

non

uniform

Yes,

non-

uniform

Non-

uniform

Yes,

uniform

Yes Non-

uniform

In-vitro disintegration

time (sec)

75

65 85 95 65

120 65

Taste masking +++++ +++++ +++++ +++++ +++++ +++++ +++++

* 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


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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)

1 1 1 2 2 2

Stirring time(h) 1 2 4 1 2 4

Taste masking ++++ ++++ +++++ ++++ +++++ +++++

Drug loading

(%)

85.7 87.2 98.8 89 88 100.1

* All quantities are in mg

It was observed that using 1:4 ratio of CTZ: Tulsion 335, optimum taste masking 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 masking 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) 2 2 2 2 2 2

Stirring time (h) 1 2 4 1 2 4

Taste masking +++ ++++ +++++ +++ +++ ++++

Drug loading (%) 87 97 98 84.2 87.5 96.1



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When the ratio of CTZ: Tulsion 335 was lowered to 1:2 as shown in batches C1 to C3,

optimum taste masking could not be achieved. When the ratio of CTZ: Tulsion 335 was

1:3, optimum taste masking 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

/distilled water

(mg/ 5ml)

720

HPMC E3 LV 400

HPC LF 200

Xanthan gum 0.1%

PEG 400 528

Distilled water (ml) 5

Film separation Yes


(sec)


(sec)

65

30

Taste masking +++++

Drug loading (%) 100.1


The preliminary optimized film F2 had acceptable properties which included excellent

taste masking, in-vitro disintegration time 65 sec and in-vivo disintegration time 30 sec.


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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

2 39.56

5 52.52

10 55.41

15 70.85

30 84.13

60 99.41

120 100

240 98.73

Table 7.10

Evaluation of mechanical properties of batch F2

Thickness (µm) 180

Tensile strength (N/mm2) 28.3

% Elongation 4.24

Elastic modulus 803.8

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.


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7.4.2.1 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


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Figure 7.1b

ESEM of CTZ at 350x magnification

Figure 7.1c

ESEM of resin Tulsion 335 at 100x magnification


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Figure 7.1d

ESEM of resin film at 100x magnification


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7.4.2.2 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 220.4°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 79.08°C and

80.20°C respectively which indicates some inherent change in the compound followed by

further decomposition.


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7.4.2.3 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 335


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Figure 7.3c

X ray diffraction study (XRD) of physical mixture PMR2

Figure 7.3d X ray diffraction study (XRD) of physical mixture PMR3


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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 33.16° 2θ positions with height 130.59,

99.15,119.24,130.9 and 91.93 cps indicating crystalline nature of the drug. XRD of resin

Tulsion 335 in Figure 7.3b showed crystalline nature with peak at 72.4 2θ positions with

height 102.6 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 33.16 2θ

positions with height 80, 120, 30 and 100 cps (PMR2) and peaks at 8.08, 18.73, 20.83

and 23.57 2θ positions with height 8.25, 71.71, 73.67 and 18.48 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 masking of CTZ.


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7.4.2.4 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= B1X1 + B2X2 + B3X3 + B12X1X2 + B23X2X3 + B13X1X3 + B123X1X2X3

Where Y is the response parameter and Bi……….are estimated coefficients for the

factors Xi. The main effects ( X1,X2 and X3) represents the average results of changing

one factor at a time from its low to high value. The interaction terms(X1X2, X2X3, X1X3)

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 (X1), HPC-LF (X2) and PEG 400 (X3) were chosen as independent variables. The

design layout and the responses of the seven batches of the simplex lattice design are

shown in Table 7.11. The mechanical properties i.e tensile strength, % elongation, elastic

modulus, in-vitro disintegration time were selected as dependent variables. The


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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 X1 X2 X3

D1 1 0 0

D2 0 1 0

D3 0 0 1

D4 0.5 0.5 0

D5 0.5 0 0.5

D6 0 0.5 0.5

D7 0.33 0.33 0.33

Actual values (in mg) Coded

values X1 X2 X3

0 400 200 528

1 500 300 628

0.5 450 250 578

Independent variables

X1=amount of HPMC E3 LV

X2=amount of HPC LF

X3= amount of PEG 400

0.33 433 233 561

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 3.3


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Table 7.12

Response table for simplex design batches

Mechanical properties

Batch X1 X2 X3 In-vitro

disintegration

time (sec) Tensile

strength

(N/mm2)

%

Elongation

Elastic

modulus

(N/mm2)

D1 1 0 0 90 3.79 3.00 165

D2 0 1 0 115 3.50 5.36 95.3

D3 0 0 1 65 1.92 2.70 105.2

D4 0.5 0.5 0 100 5.23 3.61 193.7

D5 0.5 0 0.5 85 2.64 4.02 91.8

D6 0 0.5 0.5 105 4.06 5.52 86.4

D7 0.33 0.33 0.33 75 4.11 4.66 152.6

Results and discussion

In-vitro disintegration time of batches D1 to D7 are shown in Table 7.12 and Figure 7.11.

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


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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).

Ydisintegration time=90X1 + 115X2 + 65X3 -10X1X2 + 30X1X3 + 60X2X3 - 645X1X2X3------(1)

Figure 7.4

Contour plot for in-vitro disintegration time

Design-Expert® Software

in vitro disintegration timeDesign Points115

65

X1 = A: HPMC E3 LVX2 = B: HPC LFX3 = C: PEG 400

A: HPMC E3 LV1.000

B: HPC LF1.000

C: PEG 4001.000

0.000 0.000

0.000

in vitro disintegration time

73.4026

73.4026

81.8052

90.2078

90.2078

98.6104

107.013

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 7.12. 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).


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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).

Ytensile strength=3.79X1 + 3.5X2 + 1.92X3 + 6.42X1X2 - 0.86X1X3 + 5.4X2X3 - 4.8X1X2X3

------(2)

Y% Elongation=2.995X1 + 5.362X2 + 2.695X3 - 2.294X1X2 + 4.692X1X3 + 5.978X2X3 +

1.386X1X2X3 ----(3)

Yelastic modulus=164.95X1 + 95.3X2 + 105.18X3 + 254.3X1X2 - 173.26X1X3 - 55.4X2X3 +

754.41X1X2X3---(4)

Figure7.5

Contour plot for tensile strength


tensile strengthDesign Points5.25

1.92

X1 = A: HPMC E3X2 = B: HPC LFX3 = C: PEG 400

A: HPMC E31.000

B: HPC LF1.000

C: PEG 4001.000

0.000 0.000

0.000

tensile strength

2.47554

3.03108

3.58662

4.14216

4.14216

4.6977


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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/mm2). 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


% elongation Design Points5.523

2.695


A: HPMC E31.000

B: HPC LF1.000

C: PEG 4001.000

0.000 0.000

0.000

% elongation

3.21591

3.21591

3.73681

3.73681

4.25772

4.77863

5.29953

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.


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Figure 7.7

Contour plot for elastic modulus


elastic modulus Design Points193.7

86.39


A: HPMC E31.000

B: HPC LF1.000

C: PEG 4001.000

0.000 0.000

0.000

elastic modulus

104.697

123.446

142.194

160.943

179.692

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/mm2. 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/mm2, % elongation values between 3 and 4.5, elastic modulus 100

N/mm2. 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.


________________________________________________________________________


Check point batch

The three component simplex lattice design was run with 1 check point composition of

which is shown in Table 7.13. 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 7.13.

Table 7.13

Composition and result of check point batch for in-vitro disintegration study

Check point batch (RC1) In-vitro disintegration time (sec)

X1=0.04

X2=0.02

Predicted value

Observed value X3=0.94

69 70

The three component simplex lattice design was run with 1 check point composition of

which is shown in Table 7.13. 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

7.14.


________________________________________________________________________


Table 7.14

Composition and result of check point batch for mechanical property study

Check point batch

(RC2)

Mechanical

property

Predicted value Observed value

Tensile strength

(N/mm2)

4.08 3.6

% elongation 5.01 4

X1= 0.2

X2=0.4

X3=0.4

Elastic modulus

(N/mm2)

135 132

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.


________________________________________________________________________


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

disintegration

time (sec)

In-vivo

disintegration

time (sec)

Time (min) for

85% drug

release

Appearance

before and after

exposure

Initial 65 30 30 Acceptable

1 Month 60 30 30 Acceptable

3 Months 65 32 30 Acceptable

6 Months 68 32 30 Acceptable

The results in Table 7.15 indicated that RDF containing CTZ were stable when ion

exchange resin Tulsion 335 was incorporated as taste masking 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.


________________________________________________________________________


7.5 Conclusion

RDF of CTZ were formulated using polymers HPMC E3 LV and HPC-LF. As CTZ is a

bitter drug, taste masking study was carried out using ion exchange resin Tulsion 335. It

was observed that taste masking 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 in-

vivo 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/mm2). 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 masking. In-vitro disintegration

time was slightly lower than RDF formulated using cyclodextrin as taste masking 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.


________________________________________________________________________


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7. design and development of rapidly dissolving films...

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