CHAPTER.6 FORMULATION AND EVALUATION OF FAST...

Bhatt S.O. FDT of ondansetron HCl

K. B. I. P. E. R. Kadi Sarva Vishwavidyalaya 70

CHAPTER.6

FORMULATION AND EVALUATION OF FAST DISSOLVING TABLET OF

ONDANSETRON HCl

6.1 Taste making of ondansetron HCl

6.1.1 Development and characterization of taste masked granules of

ondansetron HCl

6.1.1.1 Preparation of drug polymer complex

The drug polymer complex (DPC) was prepared by using different ratio (1:1, 1:3, 1:5)

of ondansetron HCl and Eudragit® EPO. A gel containing ondansetron HCl and Eudragit® EPO

was prepared by gradual addition of 10 % ethanol using a mechanical stirrer in a glass

beaker. The gel was manually extruded through a syringe. The ethanol was evaporated by

keeping the extrudates overnight at room temperature. The solidified gel in the shape of

string was crushed and sieved through sieve sized 280 μm to make the granules.

6.1.1.2 Characterization of drug polymer complex

In-Vitro taste evaluation

The drug polymer complex (DPC) containing 10 mg of ondansetron HCl were mixed

with 10 ml of phosphate buffer (pH 6.8)in a 10 ml syringe by revolving the syringe end to

end for 60 seconds. Thereafter solution of ondansetron HCl was filtered and amount of drug

release was determined spectrophotometrically at 249 nm.

Drug content

DPC equivalent to 10 mg of drug was stirred by using magnetic stirrer with 100 ml of

0.1 N HCl for 60 minutes, till the entire drug leached out from complex, than the solution

was filter through whatman filter paper. Further solution was diluted with 0.1 N HCl and the

drug content was determined spectrophotometrically at 249 nm.

Thermal analysis

DSC analysis was performed using Netzsch DSC 204, Tokyo, Japan. The samples were

heated in a sealed aluminium pans at a rate of 100 °C per min in a 30 to 3000 °C

temperature under nitrogen flow of 40 ml/min.


K. B. I. P. E. R. Kadi Sarva Vishwavidyalaya Page 171

Fourier Transform Infrared (FTIR) Spectroscopy

FTIR spectra were obtained on Shimadzu FTIR Model 8400-S spectrometer. The

spectra was recorded as a dispersion of the sample in potassium bromide in IR disk (2 mg

sample in 200 mg KBr) with the scanning range of 400 to 4000 cm-1 and the resolution was

1 cm -1.

X-ray Diffraction (XRD) studies

X-ray Diffraction analysis was carried out to evaluate the degree of crystallinity. The

pure ondansetron HCl, pure Eudragit EPO, and drug polymer complex (1:5) were subjected

topowder XRD (P.W. 1729, X-Ray Generator, Philips, Netherland) at 2θ angles between 200

and 380 in increments of 0.40.



6.2 Design and optimization of FDT of ondansetron HCl using different

ratio of mcc and lactose

6.2.1 Preparation of tablet

Fast dissolving tablets of ondansetron HCl were prepared by direct compression

method. All the raw materials were passed through a # 60 sieve prior to mixing. Drug

polymer complex (1:5), containing amount equivalent to 10 mg of ondansetron HCl, was

mixed with the other excipients. The powder blend was lubricated with magnesium stearate

and compressed on a 10 station mini press tablet machine (CPMD 3-10, Chamunda Pharma

Machinery Pvt. Ltd., Ahmedabad, India.) equipped with 9 mm concave punch. Composition

of tablets is shown Table 6.1.

Table 6.1 Composition of fast dissolving tablet

Ingredient Value (%)

DPC 24

Ac-Di-Sol 2-6

MCC 0-70

Lactose 100-30

Mag. Stearate 1.5

Saccharine sodium 0.6

Tablet weight=250 mg

6.2.2 Optimization of formulation

Optimization technique based on response surface methodology was utilized.

Response surface methodology can be defined as a statistical method that uses quantitative

data from appropriate experiments to determine and simultaneously solve multivariate

equations. It is generally used to determine the optimum combination of factors that yield a

desired response and describes the response near the optimum. This methodology was

used in the present study to optimize the variables affecting the formulation.



Statistical design

A randomized 3 level full factorial design using two factors was adopted to

systematically study the formulation of FDT of ondansetron HCl. A total of 12 experimental

run with 3 centre points were performed at all possible combination. The independent

variable, were selected on the basis of trials taken during preliminary batches. The

disintegration time and hardness were selected as dependent variable. Different variables

used in full factorial design are shown in Table 6.2. Matrix design for different experimental

run is shown in Table 6.3.

Analysis of response

Response were analysed by Analysis of variance (ANOVA), to identify the

insignificant factors, which were then removed from the full model to generate the reduced

model.

Table 6.2 Variables in 3 level full factorial design

Independent variables-Factor Levels (%)

Low (-1)

Middle (0)

High (+1)

X1= MCC in MCC- Lactose combination 30 50 70

X2= Ac-Di-Sol Concentration 2 4 6

Dependent variable- Response

Y1= Disintegration time (seconds)

Y2= Hardness (kg/cm2)



Table 6.3 Layout of full factorial design

Batch X1: %MCC in Lactose/MCC:Lactose combination

(%) X2: Ac-Di-Sol(%)

OH 1 1 -1

OH 2 0 0

OH 3 -1 0

OH4 0 0

OH5 0 -1

OH6 -1 -1

OH7 0 0

OH8 1 1

OH9 -1 1

OH10 1 0

OH11 0 0

OH12 0 1

Validation of statistical model

Levels of factors were selected at different points and responses predicted by the

statistical models were calculated. Tablets were prepared using these levels and responses

were measured practically. The predicted responses were compared against observed

responses and closeness between them was checked.

Response surface plots

Response surface plots were generated for each response to study the effect of both

factors on each response.

Different constraints were applied (Table 6.4) and on the basis of confirmation

report (Two-sided, Confidence = 95%, n = 1) as shown in Table 6.5, tablets were

prepared.



Table 6.4 Constraints

Name Goal Lower Limit

Upper Limit

X1:MCC in Lactose/MCC:Lactose comination is in range -1 1

X2:Ac-Di-Sol is in range -1 1

DT Target=25 22 38

Hardness Target=4.5 4 4.5

Table 6.5 Confirmation Report (Two-sided, Confidence = 95%, n = 1)

Factor Name Level Low Level

High Level

Std. Dev.

Coding

X1 MCC in Lactose/MCC:Lactose

comination 66 30 70 0.000 Actual

X2 Ac-Di-Sol 4.9 2 6 0.000 Actual

6.2.3 Preparation of optimized batch (OFDT1)

Optimized batch was prepared as method discussed earlier. The formula for

optimized batch (DFDT2) shown in Table 6.6.

Table 6.6 Composition of optimized Batch

Ingredients Quantity (%) Quantity (mg)

DPC 24 60

Ac-Di-Sol 4.9 11

MCC:lactose 66:34 114.4:58.9

Mag. Stearate 1.5 3.75

Saccharine sodium 1 0.6

Tablet weight= 250 mg



6.3 Design and optimization of fast dissolving tablets of ondansetron HCl

using vacuum-drying approach

6.3.1 Preparation of tablets

Composition of fast dissolving tablets is mentioned in Table 6.7. All the raw materials

were passed through a 60 # sieve prior to mixing. Drug polymer complex (1:5), containing

amount equivalent to 10 mg of ondansetron HCl, was mixed with the other excipients. The

powder blend was lubricated with magnesium stearate and compressed on a 10 station mini

press tablet machine (CPMD 3-10, Chamunda Pharma Machinery Pvt. Ltd., Ahmedabad,

India.) equipped with 9 mm concave punch. The tablets were dried in a vacuum oven for 4 h

at a temperature of 60 0C and at a pressure of 300 mm Hg.

Table 6.7 Composition of fast dissolving tablet

Ingredients Quantity (%)

DPC 24

Camphor 0-40

Mannitol 10-50

Mag. Stearate 1.5

Lactose q. s. to 250

Tablet weight=250 mg

6.3.2 Optimization of formulation

Optimization technique based on response surface methodology was utilized.

Response surface methodology can be defined as a statistical method that uses quantitative

data from appropriate experiments to determine and simultaneously solve multivariate

equations. It is generally used to determine the optimum combination of factors that yield a

desired response and describes the response near the optimum. This methodology was

used in the present study to optimize the variables affecting the formulation.

Statistical Design

A randomized 3 level full factorial design using two factors was adopted to

systematically study the formulation of FDT of ondansetron HCl. A total of 12 experimental



run with 3 centre points were performed at all possible combination. The independent

variable, were selected on the basis of trials taken during preliminary batches. The

disintegration time and hardness were selected as dependent variable. Different variables

used in full factorial design are shown in Table 6.8. Matrix design for different experimental

run is shown in Table 6.9.

Table 6.8 Variables in 3 level full factorial design

Independent variables-Factor Levels (%)

Low (-1)

Middle (0)

High (+1)

X1= Mannitol 30 40 50

X2= Camphor 10 20 30

Dependent variable- Response

Y1= Disintegration time (seconds)

Y2= Hardness (kg/cm2)

Table 6.9 Layout for full factorial design

Run X1: Mannitol (%) X2: Camphor (%)

OV 1 -1 -1

OV 2 0 0

OV 3 0 0

OV4 0 -1

OV5 1 0

OV6 1 1

OV7 0 0

OV8 0 1

OV9 -1 1

OV10 0 0

OV11 -1 0

OV12 1 -1



Analysis of response

Response were analysed by Analysis of variance (ANOVA), to identify the


model.


Levels of factors were selected at different points and responses predicted by the

statistical models were calculated. Tablets were prepared using these levels and responses

were measured practically. The predicted responses were compared against observed

responses and closeness between them was checked.

Response surface plots

Response surface plots were generated for each response to study the effect of both

factors on each response.

Different constraints were applied (Table 6.10) and on the basis of confirmation

report (Two-sided, Confidence = 95%, n = 1) as shown in Table 6.11, tablets were

prepared.

Table 6.10. Constraints

Name Goal Lower Limit Upper Limit

X1:Mannitol In range -1 1

X2:Camphor In range -1 1

Hardness Target=4 1.2 4.9

DT Target = 32 8 35

Table 6.11. Confirmation Report (Two-sided, Confidence = 95%, n = 1)

Factor Name Level Low Level High Level Std. Dev. Coding

X1 Mannitol 38 30 50 0.000 Actual

X2 Camphor 13 10 30 0.000 Actual



6.3.3 Preparation of optimized batch (OFDT2)

Optimized batch was prepared as method discussed earlier. The formula for

optimized batch (DFDT2) shown in Table 6.12.

Table 6.12 Composition of optimized batch (OFDT2)

Ingredients Quantity (%) Quantity (mg)

DPC 24 60

Camphor 13 32.5

Mannitol 38 95

Mag stearate 1.5 3.75

Lactose Qs to 100 % Qs to 100 %

6.4 Evaluation of fast dissolving tablets of ondansetron HCl

6.4.1 Pre-compression characterization

The quality of tablet was generally dictated by the quality of physicochemical

properties of blends. There were many formulations and process variables involved in

mixing steps all these can affect the characteristic of blend produced. The characterization

parameters for evaluating the flow property of mixed blends includes bulk density, tapped

density, Hausner’s ratio, compressibility index and angle of repose.

Bulk density

Apparent bulk density (ρb) was determined by pouring the blend in to a graduated

cylinder. The bulk volume (Vb) and weight of powder (M) was determined [160-163]. The

bulk density was calculated using the formula:-

Tapped density

The measuring cylinder containing a known amount of tablet blend was tapped 100

times using density apparatus. The constant minimum volume (Vt) occupied in the cylinder



after tapping and the weight (M) of the blend was measured [160-163]. The tapped density

(ρt) was calculated using formula

Compressibility index

Compressibility is the simplest way for the measurement of powder flow property. It

is an indication of ease with which a material can be induced to flow [160-163]. it is

expressed as compressibility index (I), which can be calculated as follows:-

Where, ρt = Tapped density; ρb = bulk density

Limits for compressibity index are shown in Table 6.13.

Table 6.13 Compressibility index as an indication of powder flow properties

Compressibility Index (%) Type of flow

>12 Excellent

12-16 Good

18-21 Fair to passable

23-35 Poor

33-38 Very poor

>40 Extremely poor

Hausner’s ratio

Hausner’s ratio (HR) is an indirect index of ease of powder flow. It was calculated by

the following formula:-

Where, ρt = Tapped density; ρb = bulk density

Lower Hausner’s ratio (<1.25) indicates better flow properties than higher ones [160]



Angle of repose

Angle of repose was determined using the funnel method. The blend was poured

through a funnel that can be raised vertically until a specified cone height (h) was obtained.

Radius was measured and angle of repose was determined using the formula [164-166].

Therefore,

(

)

Where, θ is angle of repose; h is the height of cone; r is radius of cone.

Limits of angle of repose are shown in Table 6.14.

Table 6.14 Angle of repose as an indication of powder flow properties

Angle of repose(θ) Type of flow

<25 Excellent

25-30 Good

30-40 Passable

>40 Very poor

6.4.2 Post compression characterization

After compression, the prepared tablets were evaluated for organoleptic

characteristics like color, taste, odor, diameter, thickness and physical characteristics like

hardness, friability, disintegration time, wetting time.

General appearance

The general appearance of a tablet, its visual identification and over all elegance is

essential for consumer acceptance. This include tablet’s size, shape, odor, color, taste,

surface texture etc [167]



Tablet thickness

Tablet thickness is an important characteristic in reproducing appearance and also in

counting by suing filling equipment. Some filling equipment utilizes the uniform thickness of

the tablets as a counting mechanism. Thickness of tablets was recorded using micrometer

(Mityato, Japan).

Weight variation

The weight variation test would be satisfactory method of determining the drug

content uniformity. As per USP [168], twenty tablets were taken and weighted individually.

Average weight was calculated and compared the individual weight to average weight.

Weight variation limits are given in Table 6.15.

Table 6.15 Weight variation limit for tablets as per USP

Average weight of tablet (mg) Maximum % difference allowed

130 or less 10

130-324 7.5

More than 324 5

Hardness

Hardness of the tablet is defined as the force applied across the diameter of the

tablet in order to break the tablet. The resistance of the tablet to chipping, abrasion or

breakage under condition of storage transformation and handling before usage depends on

its hardness. Hardness of the tablet of each formulation was determined using Pfizer

Hardness taster [167-169].

Friability

Friability of tablets was determined using Roche friabilator apparatus. This device

subjects the tablet to the combined effect of abrasion and shock in a chamber, revolving at

25 rpm and dropping the tablet at the height of 6 inch in each revolution. Pre-weighed

sample of tablets was placed in the friabilator and were subjected to 100 revolutions.

Tablets were dedusted using a soft muslin cloth and reweighed. The friability (F %) was

determined by the formula



Where, W0 is the initial weight of the tablets before the test and W is the weight of the

tablet after test [167,170]

Drug content

The test is obligatory for tablets containing less than 10 mg or less than 10 % w/w of

active ingredient. This test was performed as per Indian Pharmacopoeia, 1996. A tablet was

crushed and dissolved 1 ml of dilute hydrochloric acid and 30 ml of distilled water. This

solution was shaken for 15 min. the volume of this solution was made up to 50 ml with

distilled water and centrifuged. Five milliliters of the clear supernatant was mixed with 10

ml of 0.1 N HCl, and made up to 100 ml with distilled water. The absorption of the solution

was determined spectrophotometrically at 249 nm. The same procedure was followed for

another nine tablets.

Disintegration time

The disintegration time was measured using a modified disintegration method.

According to this method, a petri dish of 10-cm diameter was filled with 10 mL of phosphate

buffer pH 6.8, the tablet was carefully placed at the center of the petri dish, and the time

necessary for the complete disintegration of the tablet into fine particles was noted as

disintegration time [171].

Wetting time

A piece of tissue paper folded twice was kept in a culture dish (internal diameter 5.5

cm) containing 6 mL of purified water. A tablet having a small amount of amaranth powder

on the upper surface was placed on the tissue paper. The time required to develop a red

colour on the upper surface of the tablet was recorded as the wetting time [172].

Dissolution studies

Tablet test condition for the dissolution rate studies were used according USP

specification using USP 24, type II apparatus. The dissolution medium was 900 ml of 0.1 N

HCl (pH 1.2). The temperature of the dissolution medium and the rate of agitation were

maintained at 37± 0.50 °C and 50 rpm respectively. Aliquots of 10 ml of dissolution medium

were withdrawn at specific time interval and the volume replaced by fresh dissolution



medium, pre warmed to 37± 0.50 °C. The drug concentration was determined

spectrophotometrically at 249nm using UV spectrophotometer (Shimadzu S 1800, Japan).

Scanning electron microscopy (SEM)

The optimized tablet was also observed by scanning electron microscope (ESEM TMP

with EDAX, Philips, Holland). Pictures were taken at an excitation voltage of 30 kv and a

magnification of 120 X.

6.5 In vivo study for optimized ondansetron HCl fast dissolving tablet

6.5.1 Pharmacokinetic Studies

Sample preparation

In a 10 ml capacity glass tube, 1 ml plasma was mixed with 50 µl of saturated sodium

carbonate solution and 5 ml of dichloromethane and mixture was stirred by rotary mixer for

15 min at room temperature. The mixture was centrifuged for 5 min at 5000 rpm and 4.5 ml

of the organic phase was transferred into another test tube and evaporated to dryness at

40°C under a stream of nitrogen. The residue was reconstituted in 100 µl of mobile phase

and a volume of 20 µl was injected into the HPLC for analysis [204].

Seven-week-old male wistar rats were used in the present experiment. Their mean

weight was 264.66 ± 8.96 g in the range of 259-275 g. Animals were housed in a room

maintained on a 12 hrs light/dark cycle at 23±2 °C with free access to food and water.All the

animal experiments were performed according to the guideline of local animal ethical

committee (Ref no- BU/BT/185/11-12). The Test (OFDT 1) formulation and Reference

(Ondem MD) were administered to the rats by gastric intubation method after calculating

the animal dose [174]. Blood samples were withdrawn after 0, 0.50, 1, 2, 4 and 6 hrs. from

different animals at each time (n=3).

Pharmacokinetics and statistical analyses

The following pharmacokinetics parameters were calculated using non-

compartmental methods: area under the plasma concentration–time curve from zero to the

last measurable Ondansetron concentration sample time (AUC0-t), area under the plasma

concentration–time from zero extrapolated to infinite time AUC0-∞, maximum plasmatic

drug concentration (Cmax) and time to reach Cmax(tmax), terminal rate constant (Kel) and

terminal half-life (t1/2). Cmax and tmax were obtained directly from the concentration–time



curve. AUC0–t was calculated using the linear trapezoidal method. Kel was calculated by

applying a log-linear regression analysis to at least the last three quantifiable concentrations

of ondansetron; t1/2 was calculated as 0.693/Kel [175].

For the purpose of bioequivalence analysis AUC0–t, AUC0–∞and Cmax were considered

as primary variables. Bioequivalence between the products was determined by calculating

90% confidence intervals (90% CI) for the ratio of Cmax, AUC0–t and AUC0–∞ values for the test

and reference products, using logarithmic trans-formed data. Analysis of variance (ANOVA)

was used to assess product, group and period effects. The products were considered

bioequivalent if the 90%CI for AUC0–t andC max fell within 80–125%.

6.5.2 Pharmacodynamic Study

Method

As discussed earlier.

6.5.3 General procedure

Behavioral testing was always conducted during the same period of the day. The

procedure was performed in three consecutive phases.

Pre-conditioning phase

This phase consisted of three consecutive days. Animals were subjected individually

to the apparatus in untreated condition with the guillotine doors open for 15 min per trial.

After the third baseline trial the preference for one of the two compartments was calculated

by taking the mean time spent in the compartments over the three baseline trials.

Conditioning phase

The mice were assigned randomly to the treatment groups (vehicle, lithium sulphate

(160 mg/kg), Zofer MD (10 mg/kg), Ondem MD (10 mg/kg) and OFDT1 (10 mg/kg) with

lithium sulphate, in a volume of 5 mL/kg body weight). The mice were treated with the

conditioning drug on one day and the vehicle on the alternate day. Each mice was exposed

to an equal number of drug pairings with both the compartments. The treatment lasted for

8 days (four pairings).



Post-conditioning phase

On the day following the conditioning phase, drugs were not administered to

animals and they were placed in the apparatus with the doors open and the time spent in

the preferred compartment was recorded during the 15 min test session.

Experimental set up for the study is shown in Table 6.16.

Table 6.16 Experimental setup for ondansetron HCl

Group Treatment

Group I Treated with vehicle

Group II Treated with Lithium sulphate

Group III Treated with Comp I (Zofer- MD, Sun Pharmaceutical Ltd) + Lithium

sulphate

Group IV Treated with Comp II (Ondem-MD 8, Alkem Laboratories Ltd.) + Lithium

sulphate

Group V Treated with Comp III (OFDT 1) + Lithium sulphate

6.6 Stability study

6.6.1 Selection of fast dissolving tablets

The results of tablet characterizations of different batches were compared and

optimized batch OFDT1 and OFDT2 were selected for stability studies.

The optimized fast dissolving tablets were packed in wide mouth air tight glass

container. Stability studies were carried out according to ICH and WHO guidelines as shown

in Table (6.17).

Table 6.17 Conditions as Per ICH Protocol

Time (Month) Conditions

0

250 C ± 20 C and 60 ± 5% RH 400 C ± 20 C and 75 ± 5% RH 3

6


K. B. I. P. E. R. Kadi Sarva Vishwavidyalaya 7

6.6.2 Physical and chemical stability

The tablets are withdrawn after end of period and analysed for physical

characterization and drug content. The drug content data obtained was fitted in to first

order equation to determine the kinetics of degradation. Accelerated stability data were

plotted according to Arrhenius equation to determine the shelf life at 250 C.[178-180]

K= Ae-Ea/RT

T10% = 0.104/ K

Where, K is specific reaction constant; A is Arrhenius factor; T is absolute temperature; R is

Gas constant; Ea is energy of activation.

6.6.3 Comparison of dissolution profile

In recent years, FDA has placed more emphasis on a dissolution profile comparison

in the area of post-approval changes biowaivers. A dissolution profile comparison between

pre-change and post-change product or with different strength, helps assure similarity in

product performance and signal bioequivalence.

Among several methods investigated for dissolution profile comparison, f2 is the

simplest one.

f2= 50* log {*1 + (1/n) ∑t=1n (Rt - Tt)2] -0.5 * 100}

Where Rt and Tt are the cumulative percentage drug dissolved at each of the selected n time

points of the reference (before storage) and test (after storage) product respectively. When

the two profile are identical, f2 = 100. An average difference of 10% at all measured time

point’s results in f2 value 50. FDA sets a standard of f2 value in between 50 to 100; indicate

similarity between two dissolution profiles. [181-183]



RESULT and DISCUSSION

6.7 Characterization of taste masked granules of ondansetron HCl

In vitro taste evaluation

In vitro taste evaluation of different ratios of taste masked drug polymer complex

(DPC) was determined in phosphate buffer (pH 6.8) and in 0.1 N HCl (pH 1.2). Results are

shown in Table 6.18.

Table 6.18 In-Vitro taste evaluation

Drug Polymer Ratio in DPC % Drug Dissolve in Phosphate Buffer

(pH 6.8)†

% Drug Content in 0.1 N HCl (pH 1.2)†

1:1 2.0±0.21 98.42±0.25

1:3 0.82±0.15 98.72±0.41

1:5 0.41±0.05 99.12±0.08

† Results are the mean of 3 observations ± SD

Percentage drug content of drug polymer complex in 0.1 N HCl (pH 1.2) was found to

be 98.42 to 99.16. The drug release in phosphate buffer (pH 6.8) was found least with drug

polymer complex ratio (1:5). It showed that appreciable amount of drug was not released as

the drug particles were coated by the polymer. Thus complete taste masking was achieved.

DPC (1:5) was selected as an optimized ratio for the development of formulation.

Thermal analysis

Figure (6.1- 6.4) represented DSC Thermogram of ondansetron HCl, Eudragit® EPO,

drug-polymer physical mixture and drug polymer complex.



Figure 6.1 DSC Thermogram of ondansetron HCl

Figure 6.2 DSC Thermogram of Eudragit® EPO



Figure 6.3 DSC Thermogram of physical mixture

Figure 6.4 DSC Thermogram of drug polymer complex



Thermal profile of pure product exhibited a single endothermic effect corresponding

to the melting of ondansetron HCl (T fus 186.4770 C, ∆H fus 107. 379 J/g) while amorphous

nature of polymer. The DSC curve of physical mixture showed progressive broadening and

lowering of drug melting temperature and concomitant reduction of its enthalpy. In DSC

curve of DPC total disappearance of drug melting temperature. These finding suggest the

formation of new solid phase with lower degree of crystallinity.

FT-IR spectroscopy

Figure (6.5- 6.8) represented FT-IR spectroscopy of ondansetron HCl, Eudragit® EPO,

drug-polymer physical mixture and drug polymer complex. Interpretation of FT-IR is shown

in Table 6.19.

Figure 6.5 FT-IR spectra of ondansetron HCl

45060075090010501200135015001650180019502100240027003000330036003900

1/cm

30

40

50

60

70

80

%T

34

94

.17

34

13

.15

33

77

.47

32

46

.31

27

23

.58

26

67

.64

25

48

.05

24

63

.18

23

61

.91

21

30

.45

19

20

.20

18

45

.94

16

39

.55

15

32

.50

14

80

.42

14

59

.20

14

02

.30

13

38

.64

12

81

.74

12

44

.13

12

02

.66

11

30

.32

10

85

.96

10

44

.49

10

16

.52

91

5.2

5

84

9.6

7

76

2.8

7

66

5.4

6

59

9.8

8

54

4.9

1

Ondansetron HCl



Figure 6.6 FT-IR spectra of Eudragit® EPO

Figure 6.7 FT-IR spectra of physical mixture



Figure 6.8 FT-IR spectra of DPC

The FTIR spectrum of drug and polymer showed no significant shift or reduction in

intensity of peaks of ondansetron HCl. However, the FT-IR spectrum of DPC was found to

exhibit some significant difference in the characteristic peaks of ondansetron HCl, revealing

modification of drug environment. As shown in Figure 6.5, a broad band of bonded –OH of

ondansetron HCl was observed from 3412 to 3245.31 cm-1. DPC showed the absence of

peak at 3412 to 3245.31 cm-1 suggest the formation of complexation of drug with polymer

[205].

Table 6.19 Interpretation of FT-IR spectra

Functional group Band width

OH stretching -

C=O stretching 1730.02 cm-1

C-C stretching 2952.15 cm-1

C=N stretching 1640.41 cm-1



X- Ray Diffraction

Figure (6.9- 6.12) represented the X- ray diffraction pattern of ondansetron HCl,

Eudragit® EPO, drug-polymer physical mixture and drug polymer complex.

Figure 6.9 X-ray diffractogram of ondansetron HCl

Figure 6.10 X-ray diffractogram of Eudragit® EPO



Figure 6.11 X-ray diffractogram of physical mixture

Figure 6.12 X-ray diffractogram DPC



The x-ray diffractogram of ondansetron HCl confirms its crystalline nature, as

evidenced from the number of sharp and intense peak, (Figure 6.9). The diffractogram of

polymer (Eudragit EPO) showed diffused peak, indicating the amorphous nature (Figure

6.10) while the diffraction pattern of drug polymer physical mixture showed simply the sum

of characteristic peaks of pure drug and the diffused peaks of polymer, indicating presence

of drug in crystalline state. However the diffraction pattern of DPC represents complete

disappearance of crystalline peaks of drug (Figure 6.12) especially those situated between

200 and 600 (2θ). These finding suggest the formation of new solid phase with a lower

degree of crystallinity due to complexation which coincides with the conclusion of

Fernandes and Veiga [206].

6.8 Evaluation of FDT of ondansetron HCl prepared using different ratio of

mcc and lactose

6.8.1 Characterization of tablet

The preliminary trial batches were prepared using the formula given in Table 6.1 by

direct compression technique in order to study the effect of superdisintegrants and diluents

on the disintegration time and hardness. Results of the different batches showed a wide

variation in the disintegration time (22- 51 seconds) and hardness (3.4- 4.7 kg/cm2). On the

basis of these results, dependent and independent variable were selected and to

systematically study, different factorial batches (OH1 to OH12) were prepared and

evaluated.

Formulations OH1 to OH12 were characterized for different parameters as shown in

Table (6.20)

Friability of all the formulation was below 1% indicates that the tablets had good

mechanical resistance. Good uniformity of drug content was observed in all the

formulations. The weight variation results revealed that average % deviation of 20 tablets of

each formulation was less than ±7.5%, which provide good uniformity in all formulations.



Table 6.20 Characterization of fast dissolving tablets

Parameters Thickness Weight Friability Drug Content Wetting

time

Formulations (mm) (mg) (%) (%) (Seconds)

OH1 3.8±0.12 250.5±1.13 0.28±0.17 99.0±1.21 20±1.29

OH2 3.9±0.73 249.8±1.71 0.35±0.40 99.38±1.14 21±1.42

OH3 3.9±0.21 251.0±1.62 0.41±0.59 98.57±1.11 28±1.20

OH4 3.9±0.31 248.5±1.20 0.35±0.49 97.51±1.33 25±1.38

OH5 3.9±0.12 250.8±1.21 0.34±0.27 99.29±1.22 28±1.05

OH6 3.8±0.51 249.±1.32 0.42±0.38 96.92±1.41 21±1.29

OH7 3.9±0.26 250±1.28 0.31±0.47 98.49±1.71 20±1.14

OH8 3.9±0.50 251.0±1.11 0.28±0.24 97.54±1.29 15±1.44

OH9 3.9±0.30 250.0±1.24 0.31±0.40 98.29±1.31 22±1.04

OH10 3.8±0.21 249.5±1.17 0.28±0.62 99.74±1.30 18±1.29

OH11 3.8±0.20 250.0±1.07 0.36±0.55 100.5±1.42 20±1.19

OH12 3.9±0.21 250±1.28 0.29±0.63 98.5±1.19 18±1.28

Data are expressed as mean S.D. (n = 3)

Statistical design

A statistical model incorporating interactive and polynomial terms was used to

evaluate the responses.

Y= b0 + b1 X1+ b2 X2+ b12 X1 X2 + b12 X1

2 + b22 X2

2 + b12b2 X1

2 X2

Y is the measured response associated with each factor-level combination, b0 is the

arithmetic mean response of the total 12 runs; X1 and X2 are the factors studied, bi is the

regression coefficient for factor Xi computed from the observed response Y. The main

effects (X1 and X2) represent the average result of changing one factor at a time from its low

to high value. The interaction terms (X1X2) show how the response changes when two

factors are simultaneously changed. The polynomial terms (X12 and X2

2) are included to



investigate nonlinearity. Two conclusions could be drawn from the equation: (1) a

coefficient with a negative sign increases the response when the factor level is decreased

from a higher level to a lower level, and (2) the factor with a higher absolute value of the

coefficient and a lower significance value P” has a major effect on the response variables.

The dependent variables, disintegration time and hardness showed a wide variation

(Table 6.21). The data clearly indicates that the response variables are strongly dependent

on the selected independent variables. The high values of the correlation coefficient for

disintegration time and the hardness indicate a close fit.

Table 6.21 Results of each experimental run in full factorial design

Batch Response

Disintegration time (Y1) Hardness (Y2)

OH1 30±0.98 4.5±0.29

OH2 30±0.52 4.1±0.17

OH3 34±0.49 3.9±0.44

OH4 30±0.73 4.1±0.98

OH5 35±0.31 4.2±1.0

OH6 30±0.78 3.8±0.29

OH7 30±0.71 4.2±0.37

OH8 22±0.82 4.7±0.59

OH9 32±0.39 4.2±0.71

OH10 26±0.63 4.6±0.33

OH11 29±0.57 4.1±0.20

OH12 26±0.43 4.4±0.51


The fitted equations (full and reduced) relating the responses to the transformed

factor are shown in Table 6.24. Analysis of variance (ANOVA) was carried out to identify the




model. Results of ANOVA is represented in Table (6.22- 6.23).

Table 6.22 ANOVA for response surface reduced cubic model for disintegration time

Response model

Sum of square

Df Mean square

F value P value R2 Adeq.

Precision

DT 131.50 5 26.30 21.04 <0.0001 0.9460 15.811

Table 6.23 ANOVA for response surface reduced quadratic model

Response model

Sum of square

Df Mean square


Precision

Hardness 0.76 3 0.25 45.14 <0.0001 0.9442 20.785

The Model F-value of 21.04 and 45.14 for didintegration time and hardness implies

the model is significant. There is only a 0.01% chance that a "Model F-Value" this large

could occur due to noise. Value of prob>F less than 0.0500 indicate that model term are

significant. Values greater than 0.1000 indicate the model term are not significant. "Adeq

Precision" measures the signal to noise ratio. A ratio greater than 4 is desirable, ratio of

15.811 and 20.785 indicates an adequate signal. This model can be used to navigate the

design space.

Table 6.24 Summary of result of regression analysis

Model* (DT)

b0 b1 b2 b12 b12 b2

2 b12b2

FM 30 -0.30 -4.50 -2.5 -1 - 3

RM 29.79 -4.33 -4.50 - - - -

Model* (Hardness)

b0 b1 b2 b12 b12 b2

2 b12b2

RM 4.17 0.32 0.13 - - 0.13 -

*FM indicate full model; RM indicate reduced model

For disintegration time, the coefficients of X1 and X2 that is, b1 and b2 respetively,

bear a negative sign, thus on increasing the concentration of MCC in MCC-Lactose



combination and conentration of Ac-Di-Sol, a decrease in disintegration time is observed.

For hardness, the coefficients of X1 and X2 that is, b1 and b2 respetively, bear a positive sign

thus on increasing the concentration of MCC in MCC-Lactose combination and conentration

of Ac-Di-Sol, a increase in hardness is observed.


To validate the statistical model checkpoint batches, CP1 and CP2 were prepared

according to the formula. Comparison of predicted values and experimental values for check

point batches are shown in Table 6.25. From the response surface plot (Figure 6.13- 6.14)

and the calculations from the statistical equation obtained by regression, the results

revealed the close match of the experimental results. Thus, we can conclude that the

statistical model is mathematically valid. Overlay plot for hardness and DT is shown in Figure

6.15.

Table 6.25 Comparison of predicted values and experimental values for check point batches

Formulation code

Predicted Values

(DT)

Experimental Values (DT)

Residual Predicted

Values (Hardness)

Experimental Values

(Hardness) Residual

CP1 X1= +0.5

X2= 1 22.64 21±1.02 1.6 4.59 4.3±0.98 0.29

CP2 X1= +1

X2= +0.5 23.74 22±1.14 1.74 4.58 4.4±1.01 0.18

The best batch was selected after considering the requirements of an FDT. To full fill

these requirements, disintegration time and hardness was targeted to 25 s and 4.5 kg/cm2

respectively. The batches dissolution rates were also considered and batches with higher

dissolution rates were given priority. Different constraints were applied; responses were

predicted at 95% CI and they are found in range, which showed the robustness of the

statistical model (Table 6.26). Further, solution with desirability 1 was selected, as shown in

(Table 6.27).



Table 6.26 Predicted response at 95% confidence (n=1)

Response Prediction Std Dev SE (n=1) 95% PI low 95% PI high

DT 25 1.11803 1.25177 21.937 28.0629

Hardness 4.5 0.075 0.08386 4.3066 4.6934

Table 6.27 Predicted desirability

Number MCC Ratio Ac-Di-Sol DT Hardness Desirability

1 66.00 4.90 25 4.5 1.000

Figure 6.13 Response surface plot for disintegration time

Design-Expert® SoftwareFactor Coding: ActualDT

Design points above predicted valueDesign points below predicted value35

22

X1 = A: MCC RATIOX2 = B: Ac-Di-Sol

-1.00

-0.50

0.00

0.50

1.00

-1.00

-0.50

0.00

0.50

1.00

22

24

26

28

30

32

34

36

D

T

A: MCC RATIO B: Ac-Di-Sol



Figure 6.14 Response surface plot for hardness

Figure 6.15 Overlay plot for disintegration time and hardness

Design-Expert® SoftwareFactor Coding: ActualOverlay Plot

DTHardness

Design Points

X1 = A: MCC RATIOX2 = B: Ac-Di-Sol

-1.00 -0.50 0.00 0.50 1.00

-1.00

-0.50

0.00

0.50

1.00Overlay Plot

A: MCC RATIO

B: A

c-

Di-

So

l

DT: 25.000

Hardness: 4.500

4

DT: 25.000Hardness: 4.500X1 0.79X2 0.44



6.8.2 Characterization of optimized batch (OFDT1)

To determine the suitability of the powder blend for tablet compression, optimized

FDT (OFDT 1) was characterized for various flow properties as shown in Table (6.28).

Table 6.28 Physical properties of optimized tablet blend

Sr no. Formulation

Code

Bulk density (mg/ml)

Tapped Density (mg/ml)

Hausner’s Ratio

Carr’s Index (%)

Angle of Repose

(°θ)

1 OFDT 1 0.49±0.29 0.65±0.37 1.32±0.59 24.61±1.05 25.38±0.28


The tablet blend showed good flow ability (angle of repose < 300).Further optimized

FDT (OFDT 1) was characterized for different parameters as shown in Table (6.29).

Table 6.29 Characterization of optimized tablet (OFDT 1)

Parameters Thickness Diameter Weight Friability Drug

Content Wetting

time

Formulations (mm) (mm) (mg) (%) (%) (Seconds)

OFDT 1 3.9±058 9.0±0.38 250±1.49 0.29±1.58 99.98±1.78 15±0.88





each formulation was less than ±7.5 %, which provide good uniformity in all formulations.

Comparison of predicted responses and observed values for the disintegration time

and hardness (Table 6.30) were in close agreement, and the models were found to be valid.

Thus, full factorial design with two factors can be successfully used to optimize the

formulations.

Table 6.30 Comparison of predicted responses and observed values

Predicted Values

(Disintegration time)

Experimental Values


Predicted Values

(Hardness)

Experimental Values

(Hardness)

25±0.4743 24±0.91 4.50±0.085 4.3±0.42




Figure 6.16 showed the in vitro drug release profile of all factorial batches and

optimized batch and it was found to be more than 95% in 4 minutes than compare to 90 %

in 10 minutes for marketed product (ONDEM MD8).

Figure 6.16 In vitro drug release profile of OFDT1 and formulation OH1- OH12.

6.9 Evaluation of fast dissolving tablets prepared using vacuum drying

technique

6.9.1 Characterization of tablets

The preliminary trial batches were prepared using the formula given in Table 6.12

using vacuum drying technique in order to study the effect of subliming material and

diluents on the disintegration time and hardness. Results of the different batches showed a

wide variation in the disintegration time (5- 91 seconds) and hardness (1- 4.9 kg/cm2). On

the basis of these results, dependent and independent variable were selected and to

systematically study, different factorial batches (OH1 to OH12) were prepared and

evaluated.

Formulations OV1 to OV12 were characterized for different parameters as shown in

Table (6.31).

0

20

40

60

80

100

120

0 2 4 6 8

%C

DR

Time (min.)

OFDT1OH1OH2OH3OH4OH5OH6OH7OH8OH9OH10OH11OH12



Table 6.31 Characterization of fast dissolving tablets

Parameters Thickness Weight Friability Drug Content Wetting

time

Formulations (mm) (mg) (%) (%) (Seconds)

OV1 3.9±0.18 249.5±1.25 0.32±0.54 101±1.42 25±1.48

OV2 3.9±0.57 250.2±1.47 0.64±0.47 100.5±1.17 14±1.59

OV3 3.8±0.29 251±1.59 0.67±0.53 99.59±1.31 13±1.28

OV4 3.9±0.48 248±1.25 0.24±0.44 98.79±1.19 24±1.39

OV5 3.8±0.72 250±1.39 0.58±0.27 99.08±1.28 19±1.25

OV6 3.8±0.59 249.5±1.28 1.2±0.39 97.82±1.49 4±1.29

OV7 3.8±0.76 250±1.45 0.56±0.58 97.75±1.77 14±1.44

OV8 3.9±0.58 250±1.28 1.8±0.37 99.50±1.25 5±1.57

OV9 3.8±0.39 250.5±1.39 1.6±0.48 99.29±1.33 5.5±1.04

OV10 3.9±0.71 249.8±1.40 0.62±0.47 99.10±1.28 12±1.43

OV11 3.9±0.28 250.5±1.25 0.72±0.53 99.62±1.48 7±1.41

OV12 3.8±0.29 251±1.32 0.24±0.63 97.2±1.73 22±1.29



mechanical resistance except formulations OV6, OV8 and OV9 (% friability was more than

1). Uniformity of drug content was observed in all the formulations. The weight variation

results revealed that average % deviation of 20 tablets of each formulation was less than

±7.5%, which provide good uniformity in all formulations.

Statistical design


evaluate the responses.

Y= b0 + b1 X1+ b2 X2+ b12 X1 X2 + b12 X1

2 + b22 X2

2 + b1 b22 X1 X2

2

Y is the measured response associated with each factor-level combination, b0 is the

arithmetic mean response of the total 12 runs; X1 and X2 are the factors studied, bi is the

regression coefficient for factor Xi computed from the observed response Y. The main



effects (X1 and X2) represent the average result of changing one factor at a time from its low

to high value. The interaction terms (X1X2) show how the response changes when two

factors are simultaneously changed. The polynomial terms (X12 and X2

2) are included to

investigate nonlinearity. Two conclusions could be drawn from the equation: (1) a

coefficient with a negative sign increases the response when the factor level is decreased

from a higher level to a lower level, and (2) the factor with a higher absolute value of the

coefficient and a lower significance value P” has a major effect on the response variables.


evaluate the responses. The dependent variables, disintegration time and hardness showed

a wide variation (Table 6.32) 11 s to 35 s and 1.2 to 4.9 kg/cm2 respectively. The data clearly

indicates that the response variables are strongly dependent on the selected independent

variables. The high values of the correlation coefficient for disintegration time and the

hardness indicate a close fit.

The fitted equations (full and reduced) relating the responses to the transformed

factor are shown in Table 6.35. Analysis of variance (ANOVA) was carried out to identify the


model. Results of ANOVA are shown in Table (6.33- 6.34).

Table 6.32 Results of each experimental run in full factorial design

Batch Response

Disintegration time (Y1) Hardness (Y2)

OV1 35±0.89 4.2±1.51

OV2 23±0.57 3±1.32

OV3 23±0.73 3±1.57

OV4 33±0.59 4.6±1.28

OV5 28±0.96 3.3±1.34

OV6 8±0.62 1.5±1.52

OV7 23±0.71 3.1±1.24

OV8 11±0.67 1.3±1.29



OV9 12±0.91 1.2±1.47

OV10 22±0.85 3±1.19

OV11 15±0.89 2.7±1.28

OV12 32±0.90 4.9±1.30


Table 6.33 ANOVA for response surface reduced cubic model for disintegration time

Response model

Sum of square

Df Mean square


Precision

DT 892.75 6 148.79 343.37 <0.0001 0.9976 52.708

The Model F-value of 343.37 implies the model is significant. There is only

a 0.01% chance that a "Model F-Value" this large could occur due to noise. "Adeq Precision"

measures the signal to noise ratio. A ratio greater than 4 is desirable. The ratio of

52.708 indicates an adequate signal. This model can be used to navigate the design space.

Table 6.34 ANOVA for response surface reduced quadratic model for hardness

Response model

Sum of square

df Mean square F value P value R2 Adeq.

precision

Hardness 16.16 4 4.04 1885.53 <0.0001 0.9991 126.057

The Model F-value of 1885.53 implies the model is significant. There is only a 0.01%

chance that a "Model F-Value" this large could occur due to noise.Values of "Prob > F" less

than 0.0500 indicate model terms are significant. "Adeq Precision" measures the signal to

noise ratio. A ratio greater than 4 is desirable. The ratio of 126.057 indicates an adequate

signal. This model can be used to navigate the design space.



Table 6.35 Summary of result of regression analysis

Model* (DT)

b0 b1 b2 b12 b12 b2

2 b1 b22

FM 22.58 -6.50 -11.50 -0.25 -0.75 -0.25 -8.25

RM 22.58 -6.50 -11.50 - - - -8.25

Model* (Hardness)

b0 b1 b2 b12 b12 b2

2 b1 b22

RM 3.02 0.27 -1.62 -0.10 - -0.067 -

For disintegration time, the coefficients of X1 and X2 that is, b1 and b2 respetively,

bear a negative sign, thus on increasing the concentration of mannitol and conentration of

camphor, a decrease in disintegration time is observed. For hardness, the coefficients of X1

and X2 that is b1 and b2 respetively, bears a positive sign and negative sign respectively, thus

on increasing the concentration of mannitol an increase in hardness andon increasing the

conentration of camphor, decrease in hardness is observed.


To validate the statistical model checkpoint batches, CP1 and CP2 were prepared

according to the formula. Comparison of predicted values and experimental values for check

point batches are shown in Table 6.36. From the response surface plot (Figure 6.17- 6.18)

and the calculations from the statistical equation obtained by regression, the results

revealed the close match of the experimental results. Thus, we can conclude that the

statistical model is mathematically valid. Overlay plot for disintegration time and hardness

are shown in Figure 6.19.



Table 6.36 Comparison of predicted values and experimental values for check point batches

Formulation code

Predicted Values

(DT)

Experimental Values (DT)

Residual Predicted

Values (Hardness)

Experimental Values

(Hardness) Residual

CP1 X1= +1

X2= +0.75 15.81 17±1.24 1.1 1.96 2±0.89 0.04

CP2 X1= +0.75

X2= +1 9.76 11±1.17 1.24 1.4 1.6±0.95 0.02


The best batch was selected after considering the requirements of an FDT. To full fill

these requirements; concentration of mannitol was set 38% and concentration of camphor

13%. The batches dissolution rates were also considered and batches with higher dissolution

rates were given priority. Different constraints were applied; responses were predicted at

95% CI and they are found in range, which showed the robustness of the statistical model

(Table 6.37). Further, solution with desirability 1 was selected, as shown in Table (6.38).

Table 6.37 Predicted response at 95% confidence (n=1)

Response Prediction Std Dev SE (n=1) 95% PI low 95% PI high

Hardness 4.045 0.046291 0.0194 3.9296 4.1670

DT 29.954 0.658281 0.3320 28.0581 31.8506

Table 6.38 Predicted desirability

Number Mannitol Camphor Hardness DT Desirability

1 38 13 4.04 29.95 1.000 Selected



Figure 6.17 Response surface plot for disintegration time

Figure 6.18 Response surface plot for hardness

Design-Expert® SoftwareFactor Coding: ActualDT

Design points above predicted valueDesign points below predicted value35

8

X1 = A: MannitolX2 = B: Camphor

-1.00

-0.50

0.00

0.50

1.00

-1.00

-0.50

0.00

0.50

1.005

10

15

20

25

30

35

D

T

A: Mannitol

B: Camphor

Design-Expert® SoftwareFactor Coding: ActualHardness

Design points above predicted valueDesign points below predicted value4.9

1.2


-1.00

-0.50

0.00

0.50

1.00

-1.00

-0.50

0.00

0.50

1.00

1

2

3

4

5

H

ard

ne

ss

A: Mannitol B: Camphor



Figure 6.19 Overlay plot for DT

6.9.2 Characterization of optimized batch (OFDT2)

To determine the suitability of the powder blend for tablet compression, optimized

FDT (OFDT 2) was characterized for various flow properties as shown in Table (6.39).

Table 6.39 Physical properties of optimized tablet blend

Sr no. Formulation

Code

Bulk density (mg/ml)

Tapped Density (mg/ml)

Hausner’s Ratio

Carr’s Index

(%)

Angle of Repose

(°θ)

1 OFDT 2 0.48±0.29 0.68±0.58 1.41±0.58 29.41±1.45 29.0±0.54


The tablet blend showed good flow ability (angle of repose < 300). Further optimized FDT

(OFDT 1) was characterized for different parameters as shown in Table (6.40).

Table 6.40 Characterization of optimized tablet (OFDT 2)

Parameters Thickness Diameter Weight Friability Drug

Content Wetting

time

Formulations (mm) (mm) (mg) (%) (%) (Seconds)

OFDT 2 3.9±0.72 9.0±0.24 250±1.38 0.36±0.89 99.57±1.18 23±0.68


Design-Expert® SoftwareFactor Coding: ActualOverlay Plot

DTHardness

Design Points


-1.00 -0.50 0.00 0.50 1.00

-1.00

-0.50

0.00

0.50

1.00Overlay Plot

A: Mannitol

B: C

am

ph

or

DT: 32.000

DT: 32.000

Hardness: 4.000

4

DT: 29.954Hardness: 4.048X1 -0.20X2 -0.70






each formulation was less than ±7.5%, which provide good uniformity in all formulations.

Figure 6.20 showed a micrograph of the cross section of a high porosity fast

dissolving tablet. It was found that many porous cavities in the tablet were formed due to

the sublimation of camphor.

Figure 6.20 SEM micrograph of the cross sectional view of optimized tablet

after sublimation

Comparison of predicted responses and observed values for the disintegration time

and hardness (Table 6.41) were in close agreement, and the models were found to be valid.

Thus, full factorial design with two factors can be successfully used to optimize the

formulations.

Table 6.41 Comparison of predicted vs observed response

Predicted Values


Experimental Values (Disintegration

time)

Predicted Values

(Hardness)

Experimental Values

(Hardness)

29.944±0.65 28±0.81 4.04±0.046 4.0±1.025




Figure 6.21 showed the in vitro drug release profile of all factorial batches and

optimized batch and it was found to be more than 95% in 4 minutes than compare to 90 %

in 10 minutes for marketed product (ONDEM MD8).

Figure 6.21 In vitro drug release profile of all factorial batches and optimized batch

6.10 Comparison of optimized formulation with marketed products

Table 6.42 represented the comparison of optimized formulation with market

product.

Table 6.42 Comparison of optimized formulations with market products

Formulation Hardness (kg/cm2)

Disintegration time (Sec) Friability

(%)

ONDEM MD 8 2± 1.0 30.00 ± 1.4 0.74 ± 0.5

ZOFER- MD 2.6 ± 1.7 50.21 ± 0.7 0.67 ± 1.0

ONDENZ DT 2.5 ± 1.5 45.03 ± 0.5 0.61 ± 1.1

OFDT1 4.4 ± 0.4 24.0 ± 0.9 0.29 ± 1.02

OFDT2 4.0 ± 1.0 28.0 ± 0 .81 0.36 ± 0.89


-20

0

20

40

60

80

100

120

0 2 4 6 8

% C

DR

Time (min.)

OFDT 2

OV1

OV2

OV3

OV4

OV5

OV6

OV7

OV8

OV9

OV10

OV11

OV12



0

20

40

60

80

100

120

0 2 4 6 8 10 12

% C

DR

Time (sec.)

OFDT1

OFDT2

ONDEM MD 8

Optimized formulations OFDT1 and OFDT2 were compared with various marketed

product of ondansetron HCl. Result showed that both the optimized formulations were

superior in terms of hardness, disintegration time and friability. Figure 6.22 represented the

In vitro dissolution of OFDT1 and OFDT2 with market product (ONDEM MD) in 0.1 N HCl.

Result showed that In vitro drug release from both the optimized formulations were found

to be more than 95% in 4 minutes than compare to marketed product 90 % in 10 minutes.

Further optimized formulation OFDT1 prepared using MCC: lactose combination as diluent

was found to be optimum in relation to disintegration time, hardness, friability and In-vitro

drug release. Hence, it was selected for further studies.

Figure 6.22 In-Vitro drug releases of OFDT1 and OFDT2 with marketed formulation in

0.1 N HCl

6.11 Pharmacokinetic study of ondansetron HCl fast dissolving tablet

A summary of pharmacokinetic parameter obtained after administration of

reference and test to rats shown in Table 6.43. Average ondansetron plasma concentration–

time profiles after test and reference products administration is shown in Figure 6.23.

Maximum plasma concentration after administration of reference and test was found to be

31.05 ng/ml and 32.5 ng/ml in 120 min and 60 min, respectively. The 90 % confidence



interval for AUC0-t (ng. h/mL), AUC0-∞ (ng. h/mL) and Cmax(ng/mL) for reference and test are

within 85-125% interval proposed by most regulatory agencies (FDA, EMEA, ANVISA). It was

concluded that the two formulations are bioequivalent in their rate and extent of

absorption and, thus, may be used interchangeably, without any prejudice of therapeutic

effect.

Table 6.43 Pharmacokinetic parameter for reference and test after oral administration

Parameters Reference Test (OFDT 1)

AUC0-t (ng. h/mL)* 250.67± 5.83 266.60± 4.092

AUC0-∞ (ng. h/mL)* 295.79± 3.014 309.2± 5.042

Cmax(ng/mL)* 31.05± 4.021 32.5 ± 1.62

Tmax(minute) 120 60

Ke 0.193 ± 1.012 0.225 ± 1.132

t1/2 (h) 3.59 ± 1.198 3.08±0.279

* p>0.05

Figure 6.23 Average ondansetron plasma concentration time profiles after test and

reference products administration

0

5

10

15

20

25

30

35

40

0 2 4 6 8 10

Co

nc.

of

dru

g in

pla

sma

(ng/

ml)

Time (h)

Reference

Test (OFDT 1)



0

100

200

300

400

500

600

700

800

Vehicle(Pre cond.) Lithium Sulphate Zofer-MD+ LiS Ondem-MD8+LiS OFDT 1+LiS

Tim

e Sp

ent

in W

hit

Bo

x

Treatment

Conditioning Post conditioning

6.12 Pharmacodynamic study for ondansetron HCl fast dissolving tablet

Conditioned placed aversion study was performed, in which behavior of animal was

studied after administration of drug. Although the pharmacological mechanism involved in

the conditioned place aversion is not known, a variety of drugs known to produce

gastrointestinal distress and vomiting produce a conditioned place aversion. The antiemetic

agent blocks this conditioned place aversion suggesting that this paradigm may serve as a

procedure to screen antiemetic activity in rodents [207].

It was found that after administration of potent emetic agent, lithium sulphate

animal behaved opposite to their normal physiology. Result shows (Figure 6.24) that animal

treated with fast dissolving tablets of ondansetron HCl spent more time in white box than

compare to market preparation (P<0.05). This shows the better performance of FDT than

compare to market formulations in nauseated condition.

Figure 6.24 Effect of Fast dissolving tablet of ondansetron HCl (Comp III) on conditioned place aversion induced by lithium sulphate (p<0.05)

The findings of pharmacokinetic and Pharmacodynamic study reveal the potential

role of fast dissolving tablets in reducing or management of nausea and vomiting.



6.13 Physical and chemical stability

Discoloration and liquefaction was not observed during storage period. No

significant change in hardness, disintegration time and drug content was observed as shown

in Table (6.44-6.49).

Table 6.44 Effect of storage condition on hardness of optimized tablets

Time period

(months)

At 400 C ± 20 C and 75 ± 5% RH* 250 C ± 20 C and 60 ± 5% RH**

OFDT1 OFDT2 OFDT1 OFDT2

0 4.4±0.68 4.0±0.19 4.4±0.68 4.0±0.19

3 4.2±0.79 3.9±0.25 4.3±0.49 3.9±0.54

6 4.1±0.58 3.8±0.42 4.2±0.44 3.8±0.71


Table 6.45 Results of unpaired t-test for hardness of different optimized tablets

P value (t- test) P value summary

OFDT1* OFDT2* OFDT1** OFDT2**

- - - - -

0.6468 0.7939 0.7988 0.7928 ns

0.4637 0.6025 0.2000 0.2000 ns

ns= not significant

Table 6.46 Effect of storage condition on disintegration time of optimized tablets

Time period

(months)



0 24.00±0.51 31.0±0.47 24.00±0.51 31.0±0.47

3 24.5±0.22 31.4±0.28 24.5±0.43 31.4±0.40

6 24.2±0.38 31.3±0.39 24.7±0.61 31.1±0.47




Table 6.47 Results of unpaired t-test for disintegration time of different optimized tablets



- - - - -

0.2487 0.3468 0.2491 0.3456 ns

0.6278 0.5352 0.2020 0.8297 ns

ns= not significant

Table 6.48 Effect of storage condition on drug content of optimized tablets

Time period

(months)



0 99.98±0.66 99.78±0.52 99.98±0.66 99.78±0.52

3 99.94±0.51 98.82±0.41 99.43±0.67 98.72±0.97

6 99.00±0.89 98.68±0.71 99.12±0.23 98.35±0.91


Table 6.49 Results of unpaired t-test for drug content of different optimized tablets



- - - - -

0.2566 0.1460 0.2765 0.2014 ns

0.0817 0.1080 0.1926 0.1084 ns

ns= not significant



1.98

1.985

1.99

1.995

2

2.005

0 30 60 90

Log

% d

rug

rem

ain

ed

Time (Days)

OFDT1 OFDT2

From the result shown in Table (6.44-6.49), it was concluded that formulations were

stable and no significant change in the percentage drug content, hardness and

disintegration time was to be observed. The drug content of the optimized formulations

were analysed for determination of shelf life of the formulations. [199]

Figure 6.25 showed the degradation kinetics of drug content of ondansetron HCl.

The shelf lives of optimized formulations are shown in Table 6.50, and it was found to be

more than 2 years.

Figure 6.25 Degradation kinetics of drug content of ondansetron HCl FDT

Table 6.50 Shelf life of optimized tablets

Formulation K T10% (Years)

OFDT 1 -0.000096 2.97

OFDT 2 -0.000093 3.06

K is degradation coefficient and (-) sign shows degradation

6.14 Comparison of drug release

Effect of storage on drug release for optimized formulations is shown in Figure (6.26-

6.27). No significant change in drug release was found.



Figure 6.26 Drug release form optimized formulation (OFDT1) before and after storage

Figure 6.27 Drug release form optimized formulation (OFDT2) before and after storage

0

20

40

60

80

100

120

0 2 4 6 8

Cu

mu

lati

ve %

dru

g re

leas

e

Time (min.)

Initial time

After 3 months

After 6 months

0

20

40

60

80

100

120

0 2 4 6 8

Cu

mu

lati

ve %

dru

g re

leas

e

Time (min.)

Initial time

After 3 months

After 6 months



The dissolution similarity (f2) was also calculated to compare before and after

storage dissolution profile (Table 6.51). The f2 value was found to be more than 50,

indicating a close similarity between both the dissolution profiles.

Table 6.51 f2 value for optimized formulations

Formulations OFDT1 OFDT2

Time After 3

months

After 6

months

After 3

months

After 6

months

f2 89 80 88 84

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