78

PREPARATION OF OKRA GUM FLOATING DRUG DELIVERY SYSTEM TABLETS OF OFLOXACIN AND THEIR EVALUATION

In recent years, hydrophilic polymers, especially gums, have been extremely popular

in developing oral controlled release formulations. Their success is linked to the various

factors such as economy, easy to manufacture in large scale, low incidence of uncontrolled

release and established tabletting technology for manufacturing. With proper control of the

manufacturing process of hydrophilic matrices, reproducible release profiles are possible.

There is an immediate release of a small amount of active principle from these matrices but

there is no risk of dumping a large part of the dose. Their safe form and inherent advantages

over other systems justify the well deserved attention of hydrophilic matrices.

Hydrophilic cellulose polymers such as HPMC, Methylcellulose and

Hrdroxypropylcellulose have been majorly employed in the formulation of GRDDS106-111.

There are very few reports on the applicability of Okra gum as rate controlling polymers in

the design of GRDDS. Hence, in the present investigation it was aimed to evaluate Okra gum

as carrier in the design of GRDDS using Ofloxacin as model drug.

6.1 Pre formulation studies

6.1.1 Determination of Ofloxacin solubility112

Solubility study of the active drug was investigated in four different media as follows:

1) Purified water

2) 0.1 N Hydrochloric acid (HCl), (pH 1.1 4) USP

3) Acetate buffer pH 4.5, USP

4) Phosphate buffer pH 6.8, USP

Required quantity of above media was transferred in to a volumetric flask and heated

up to 37±0.5 oC using magnetic stirrer provided with heat. Excess amount of Ofloxacin was

79

added to the above volumetric flask until the saturation point occurs. The total quantity of

drug added was recorded. Stirring was continued up to 5 hours at 37±0.5oC. The sample was

filtered through 0.45 µm membrane filter (Millipore). A measured quantity of filtered sample

was transferred in to another volumetric flask and made further dilutions. The absorbance was

measured using UV visible spectrophotometer (Shimadzu, USA) at 294 nm.

Ofloxacin has shown highest solubility in 0.1N HCl (Table 6.1). The solubility of

Ofloxacin in water, pH 4.5 Acetate buffer and pH 6.8 Phosphate buffer was almost similar

which was in the range of 60-79 mg/ml, indicating the high solubility of the drug in the lower

pH. The solubility was graphically represented in Fig. 6.1.

Table 6.1: Solubility data of Ofloxacin in various pH media

Media Solubility (mg/ml)

Water 60.26

0.1 N HCl 105.7

pH 4.5 Acetate buffer 79.25

pH 6.8 phosphate buffer 73.17

Fig. 6.1: Graphical representation of Ofloxacin solubility in various pH media

0

20

40

60

80

100

120

Water 0.1 N HCl pH 4.5 Acetate buffer

pH 6.8 phosphate buffer

Solu

bilit

y (m

g/m

l)

Media

80

6.1.2 Construction of standard calibration curves for Ofloxacin

Stock solutions were prepared by dissolving in all the media. Standard calibration

curves in different media were constructed using above stock solutions. The samples were

scanned for λmax at the UV range of 200-400 nm. After 1 day again the samples were scanned

for λmax. From the above stock solutions different concentrations (Table 6.2) of the solutions

were prepared and standard calibration curves were prepared by plotting the absorbance

values vs. concentration.

Standard calibration curve (Fig. 6.2) was constructed by scanning the 10μg/ml solution

of Ofloxacin in different buffer solutions used in the solubility study. The standard graph of

Ofloxacin in 0.1N HCl showed a good linearity with R2 of 0.999, in the concentration range of

2-10 μg/ml.

Table 6.2: Standard concentrations Vs absorbances of Ofloxacin

S. No Concentration (μg /ml) Absorbance (294 nm)

1 2 0.15831

2 4 0.30478

3 6 0.46615

4 8 0.68205

5 10 0.86125

81

Fig. 6.2: Standard plot of Ofloxacin

6.1.3 Multimedia dissolution of Ofloxacin marketed formulation

In vitro dissolution study of the marketed product (ZANOCIN–OD 400mg) was

carried out to compare the drug release profile with that of the formulated Ofloxacin floating

tablets. The same dissolution method used for the formulations was used for the marketed

formulation. In addition dissolution was also carried out in pH 6.8 phosphate buffer to study

the release of the drug (Table 6.3).

Marketed product details

Product name: ZANOCIN–OD

Label Claim: 400mg

Batch No.: 1811114

Expiry date: 08/2012

Mfg. by: Ranbaxy Laboratories Limited

00.10.20.30.40.50.60.70.80.9

1

0 2 4 6 8 10 12

Abs

orba

nce

Conc (µg/ml)

82

Dissolution Parameters

Apparatus : USP Type I (Basket)

Medium : 900 ml of 0.1N HCl

900 ml of pH 6.8 Phosphate buffer

RPM : 50

Temperature : 37 ± 0.5oC

Sampling Volume : 10 ml

Sampling Time : 0.5, 1, 1.5, 2, 3, 4, 6 and 8 hours.

Table 6.3: Drug release of marketed formulation

Time

(Hrs)

Cumulative percent

( S.D. n=3) Ofloxacin released

0.1N HCl pH 6.8 buffer

0.5 13.814 2.252

1 20.017 3.331

1.5 23.663 4.163

2 26.188 4.972

3 34.807 6.896

4 40.444 8.595

6 52.034 12.035

8 63.5 13.392

R2 0.951 0.969

83

Dissolution in 0.1N HCl showed a release of 63.5% at the end of 8 hours where as dissolution

in pH 6.8 phosphate buffer showed a release of only 13.39% which clearly shows that

Ofloxacin is poorly soluble in higher pH conditions.

6.2 Characterization of the designed GRDDS granules

6.2.1 Bulk density113

20gms of material was introduced into a dry 100 ml cylinder, without compacting,

granules were carefully leveled without compacting and the unsettled apparent volume, Vo,

was read. The bulk density was calculated, in grams per ml, using the formula.

(M) / (Vo)

Where, M = Total mass of the material

6.2.2 Tapped density

After carrying out the procedure as given in the measurement of bulk density the

cylinder containing the sample was tapped manually 100 times initially followed by an

additional tap of 100 times until difference between succeeding measurement was less than

2% and then tapped volume Vf, was measured to the nearest graduated unit. The tapped

density was calculated, in grams per ml, using the formula:

(M) / (Vf)

6.2.3 Measurement of powder compressibility

The compressibility index and Hausner’s ratio are measures of the propensity of a

powder to be compressed. As such, they are measures of the relative importance of

interparticulate interactions. In free-flowing materials, such interactions are generally less

significant, and the bulk and tapped densities will be closer in value. For poorer flowing

materials, there are frequently greater interparticle interactions and a greater difference

84

between the bulk and tapped densities will be observed. These differences are reflected in the

Compressibility index and the Hausner ratio, which are calculated using the following

formulae.

6.2.4 Compressibility index

Compressibility is indirectly related to the relative flow rate, cohesiveness and particle

size of a powder. The compressibility of a material can be estimated from the tap and bulk

density measurements (Table 6.4).

Table: 6.4 Compressibility index range

S. No. % Compressibility index Flowability

1 5-15 Excellent

2 12-16 Good

3 18-21 Fair-passable

4 23-35 Poor

5 33-38 Very poor

6 <40 Very Very Poor

Compressibility index were calculated using the formula:

Compressibility index=T.D-B.D/T.D*100

6.2.5 Hausner’s ratio114:

It indicates the flow property of the powder and measured by the ratio of tapped

density to bulk density (Table 6.5)

85

Table: 6.5 Hausner ratios range

Hausner ratio=T.D\B.D

Where,

T.D= Tapped density, B.D= Bulk density.

6.2.6 Angle of repose

The fixed funnel method was employed to measure the angle of repose. A funnel was

secured with its tip at a given height ‘h’ above a graph paper that was placed on a flat

horizontal surface. The blend was carefully pored through the funnel until the apex of the

conical pile just touched the tip of the funnel. The radius, r of the base of the conical pile was

measured (Table 6.6). The angle of repose, θ, was calculated using the following formula:

θ = tan-1 h/r

Table 6.6: Relationship between angle of repose (θ) & powder flow

Hausner’s ratio Properties

0 -1.2 Free flowing

1.2 -1.6 Cohesive powder

S. No. Angle of repose (θ) degrees Flow

1 < 25 Excellent

2 25-30 Good

3 30-40 * Passable

4 40 & above Very poor

86

Bulk density, Tapped density, Compressibility index, Hausner’s ratio and Angle of repose of

raw materials and formulations were calculated and results were tabulated in Table 6.7 and

Table 6.10.

Table 6.7: Preformulation studies for the raw materials

Contents Bulk densitya

(gm/ml) Tapped densitya

(gm/ml)

Compressibility index (%)

Hausner’s ratio

Angle of reposea

(θ)

Ofloxacin 0.426 0.624 17.84 1.22 29°461

PVPK30 0.358 0.457 13.94 1.48 28°391

Okra gum 0.632 0.702 10.45 1.20 28°091

Magnesium stearate 0.456 0.651 31.92 1.27 30°241

Dicalcium phosphate 0.435 0.458 39.24 1.68 29°261

a= (n=3) Mean±SD

6.3 EXPERIMENTAL INVESTIGATIONS

6.3.1 Preparation of GRDDS: In order to enhance the flow and compaction properties, the

drug sufficient for a batch of 100 tablets was passed through mesh number 60 and granulated

by using 5% w/v polyvinyl pyrrolidone solution. The wet mass was passed through sieve

number 12 and the obtained granules were dried in a hot air oven at not more than 50°C until

LOD (loss on drying) reaches within 2 to 3%. Dried granules were passed through sieve

number 16. The polymer and effervescent agent, sufficient for a batch of 100 tablets according

to the formulae were passed through mesh number 40 and thoroughly mixed with dried drug

granules to ensure complete mixing. Then the blend was lubricated with magnesium stearate.

Tablets containing Ofloxacin equivalent to 400 mg were compressed directly by using 21.0 x

10.0 mm, caplet shaped plain punches on 16 stations rotary compression machine (M/s.

Cadmach machinery Co. Pvt. Ltd., India) at the hardness of 4 to 5 kg/cm2.

87

6.3.2 Evaluation of tablets115: The floating properties of the tablets prepared by the above

method were evaluated by determining floating lag time and floating time. The tablets were

also subjected to various quality control tests such as uniformity of weight, hardness, and

friability tests and drug release studies.

6.3.2.1 Floating lag time and floating time: The time taken by the tablet to emerge on to the

surface of the liquid (floating lag time) after adding to the dissolution medium was measured

using stopwatch. The time up to which the tablet float constantly on the surface (floating time)

was evaluated in a dissolution vessel filled with 900 ml of simulated gastric fluid without

pepsin, maintained at a temp. 37±0.50C, paddle rotation 50 rpm (n=5).

6.3.2.2 Uniformity of weight: According to IP twenty tablets were selected at random,

weighed together and then individually for the determination of uniformity of weight of

tablets. The mean and standard deviation were determined.

6.3.2.3 Hardness: Five tablets were selected at random and the hardness of each tablet was

measured on Monsanto hardness tester.

6.3.2.4 Friability: The friability test was carried out in Roche Friabilator. Ten tablets were

weighed (wo) initially and put in a rotating drum. Then, they were subjected to 100 falls of 6

inches height. After completion of rotations, the tablets were again weighed (w).

The percent loss in weight or friability (f) was calculated by the given formula.

100 x w

w1f0

6.3.2.5 Estimation of drug content: From each batch of the prepared tablets, five tablets

were randomly collected and powdered. A quantity of powder equivalent to 400 mg was

transferred into a 100 ml volumetric flask sufficient amount of methanol was added and

shaken for 20 minutes. The solution was filtered through 0.4 µm membrane filter and finally

made up to 100ml with methanol. The solution was suitably diluted with distilled water and

88

assayed for the drug content at 294 nm, using a double beam UV spectrophotometer

(Shimadzu, USA).

6.3.2.6 Differential scanning calorimetry (DSC): Differential scanning calorimetry of pure

Ofloxacin, Ofloxacin Okra gum compressed tablet was performed in the temperature range of

30°C to 300°C using Shimadzu DSC-50 Thermal analyser under static nitrogen atmosphere of

30ml/min. Samples were placed in an aluminum pan and heated at a rate of 10°C/minute with

an empty pan as reference. The thermogram was shown in Fig. 6.3.

Fig. 6.3: DSC thermogram of pure Ofloxacin, Okra gum and optimized formulation

6.3.2.7 Infrared Spectroscopy (IR): Infrared spectra of the pure Ofloxacin and Ofloxacin-

Okra gum compressed tablet were determined from mineral acid mull using Pekin-Elmer

841IR spectrophotometer. A FT-IR was used for the analysis in the frequency range between

4000 and 400 cm-1, and 4 cm-1 resolution. The results were the means of 6 determinations. A

quantity equivalent to 2 mg of pure drug was used for the study. The spectra were shown in

Figs. 6.4 and 6.5.

89

6.3.2.8 In vitro drug release studies: Dissolution test was carried out using USP XXIV

(model DISSO 2000, M/s. Labindia) rotating basket method (apparatus 1). The stirring rate

was 100 rpm. 0.1 N Hydrochloric acid was used as dissolution medium (900 ml) and was

maintained at 371C. Samples of 5 ml were withdrawn at predetermined time intervals,

filtered and replaced with 5 ml of fresh dissolution medium. The collected samples were

suitably diluted with distilled water, wherever necessary and were analyzed for the Ofloxacin

at 294 nm by using a double beam UV spectrophotometer (Shimadzu, USA). Each dissolution

study was performed for three times and mean values were taken.

6.4 Drug release kinetics: The analysis of drug release mechanism from a pharmaceutical

dosage form is an important but complicated process and it is practically evident in the case of

matrix systems. As a model-dependent approach, the dissolution data were fitted to five

popular release models such as zero-order, first-order, diffusion, erosion and exponential

equations, which have been described in the literature. The order of drug release from matrix

systems was described by using zero order kinetics or first orders kinetics. The mechanism of

drug release from matrix systems was studied by using Higuchi equation, Erosion equation

and Peppas-Korsemeyer equation.

6.4.1 Zero order release kinetics116: It defines a linear relationship between the fractions of

drug released versus time.

Q = kot

Where, Q is the fraction of drug released at time t and ko is the zero order release rate

constant. A plot of the fraction of drug released against time will be linear if the release obeys

zero order release kinetics.

6.4.2 First order release kinetics117: Wagner assuming that the exposed surface area of a

tablet decreased exponentially with time during dissolution process suggested that drug

90

release from most slow release tablets could be described adequately by apparent first order

kinetics. The equation used to describe first order kinetics is

ln (1-Q) = k1t

Where, Q is the fraction of drug released at time t and k1 is the first order release rate constant.

Thus, a plot of the logarithm of the fraction of drug remained against time will be linear if the

release obeys first order release kinetics.

6.4.3 Higuchi equation118: It defines a linear dependence of the active fraction released per

unit of surface (Q) on the square root of time.

Q = k2t½

Where, K2 is the release rate constant.

A plot of the fraction of drug released against square root of time will be linear if the

release obeys Higuchi equation. This equation describes drug release as a diffusion process

based on the Fick’s law, square root time dependent.

6.4.4 Erosion equation119: This equation defines the drug release based on tablet erosion

alone.

Q = 1-(1-k3t) 3

Where, Q is the fraction of drug released at time t, k3 is the release rate constant. Thus, a plot

between [1-(1-Q) 1/3] against time will be linear if the release obeys erosion equation.

6.4.5 Power Law120: In order to define a model, which will represent a better fit for the

formulation, dissolution data was further analyzed by Peppas and Korsemeyer equation

(Power law).

Mt \ M =k.t n

91

Where, Mt is the amount of drug released at time t and M is the amount released at time,

thus the Mt \ M is the fraction of drug released at time t, k is the kinetic constant, and n is the

diffusional exponent. To characterize the mechanism for both solvent penetration and drug

release n can be used as abstracted in Table 6.8. A plot between log of Mt \ M against log of

time will be linear if the release obeys Peppas and Korsemeyer equation and the slope of this

plot represents ‘n’ value.

Table 6.8: Diffusion exponent and solute release mechanism for cylindrical shape

Diffusion exponent Overall solute diffusion mechanism 0.45

0.45 < n < 0.89

0.89

n > 0.89

Fickian diffusion

Anomalous (non-fickian) diffusion

Case II transport

Super Case II transport

92

Fig. 6.4: IR spectra of pure Ofloxacin

93

Fig. 6.5: IR spectra of formulation EF6

94

Table 6.9: Composition of Okra gum GRDDS tablets of Ofloxacin

Table 6.10: Characterization of designed GRDDS granules

Contents Bulk densitya

(gm/ml)

Tapped densitya

gm/ml)

Compressibility

index

Hausner’s

ratio

Angle of

reposea (θ)

OF1 0.456 0.603 18.02 1.16 29°161

OF2 0.523 0.631 21.69 1.58 29°891

OF3 0.458 0.589 16.33 1.23 27°651

OF4 0.536 0.689 20.36 1.25 30°251

OF5 0.502 0.756 18.96 1.23 27°121

OF6 0.469 0.698 17.12 1.49 28°631

a=(n=3) Mean±SD

Ingredient (mg/tablet)

Formulation code

OF1 OF2 OF3 OF4 OF5 OF6

Ofloxacin 400 400 400 400 400 400

PVPK30 10 10 10 10 10 10

Okra gum 150 100 75 60 50 35

Magnesium stearate 10 10 10 10 10 10

Sodium bicarbonate 50 50 50 50 50 50

Dicalcium phosphate 30 80 105 120 130 145

95

Table 6.11: Tabletting characteristics of GRDDS prepared from Okra gum

Formulation Weight a

(mg)

Drug contenta

(%)

Hardness a

(kg/cm2)

Friability b

(%)

Lag time

(min)

Swelling index a (%)

OF1 650.261.44 98.62 0.18 4.74 0.32 0.48 180 109.360.06

OF2 650.851.25 99.24 1.54 4.82 0.49 0.32 160 94.220.81

OF3 650.651.28 99.74 0.97 5.14 0.24 0.26 145 87.411.04

OF4 650.191.37 99.94 1.48 5.06 0.56 0.35 130 79.660.74

OF5 650.220.87 98.94 0.42 5.06 0.56 0.47 120 74.120.18

OF6 650.030.66 98.36 1.22 5.06 0.56 0.28 90 69.310.46

a MeanS.D., n = 10 tablets

b Mean, n = 10 tablets

96

6.5 RESULTS AND DISCUSSION

The quality control tests such as uniformity of weight, hardness, friability and drug content for all

the formulations prepared according to the formulae (Table 6.9) was carried out and the results

were given in Table 6.11. All the formulations complied with compendia standard of IP. The

weight variation of the tablets was within the IP limits. (Not more than two of the individual

weights deviate from the average weight by more than 5% and none deviates by more than 10%).

The hardness for all the formulations was found to be in the range of 5-6 Kg/cm2 and was

satisfactory. For all the batches prepared the friability values was found to be less than 1%. All

the formulations satisfied the content of the drug as they contained 1002% of the drug when

assayed spectrophotometrically. Derived properties were calculated all the formulations and

results were shown in Table 6.10.

6.5.1 Effect of Okra gum on the floating properties and dissolution profile of Ofloxacin

from GRDDS:

The in vitro dissolution studies of the prepared tablets revealed that the Okra gum

behaved depending on the concentration used in the tablet preparation as shown in Table 6.12

Fig. 6.6. Generally, in hydrophilic matrix controlled release tablets, the initial burst release

observed was due to two factors. If the surface area of the polymer was not large enough to cover

the drug particle at the surface of the matrix, there was a great chance of burst effect in drug

release. Secondly, if the polymer does not hydrate quickly, the surface barrier cannot be formed

immediately, which may cause a large portion of drug to be released during the initial phase of

release profile. Thus, the surface area as well as the hydration rate of the polymer can play an

important role in drug release from floating tablets, especially at the beginning of the release

profile. The quick hydration and subsequent gel formation are the most important properties for

an excipient to be used in the controlled release formulation.

97

In Okra gum floating tablets, no initial burst effect was observed due to its quick

hydration and immediate formation of gel structure around the tablet. The influence of hardness

of tablets on release kinetics was not very important for hydrophilic matrices. To prevent the

partial or total disintegration, in the present work the compression force of the tablet machine

was so adjusted to obtain tablets whose hardness level was between 5-6 Kg/cm2. The increase in

the polymer content with the constant amount of drug (higher polymer-drug ratio) resulted in

decreased release rate of drug due to the formation of a matrix of low porosity and high

tortuosity, which would presumably allow gel strength, diffusion and erosion.

Table 6.12: Cumulative percent Ofloxacin released from various concentrations of Okra gum containing Ofloxacin GRDDS formulations

Time (hrs)

Cumulative percent ( S.D. n=3) drug released

OF1 OF2 OF3 OF4 OF5 OF6

0.5 1.250.85 2.211.02 3.891.47 4.120.74 5.460.12 6.230.34

1.0 3.120.22 5.320.58 7.620.49 9.220.38 10.470.54 11.360.69

2.0 6.141.21 7.610.37 11.210.69 13.550.55 14.361.32 16.470.22

3.0 8.691.32 12.350.65 17.650.59 19.320.61 21.471.22 22.171.02

4.0 15.130.44 18.330.98 22.810.21 25.290.74 26.350.96 28.651.32

5.0 21.640.65 25.641.22 29.441.02 31.220.35 33.650.74 35.670.98

6.0 24.160.36 32.670.96 37.740.54 39.661.22 41.670.65 42.611.32

7.0 -- 35.641.02 41.620.84 43.741.25 49.170.66 53.211.02

8.0 -- -- 47.310.96 49.030.66 55.390.12 62.611.32

9.0 -- -- -- 57.740.33 63.450.22 68.740.54

10.0 -- -- -- -- 69.140.27 74.740.42

12.0 -- -- -- -- -- 76.320.66

98

Fig. 6.6: Dissolution profiles of Okra gum GRDDS tablets of Ofloxacin, OF1 to OF6 formulations

0

10

20

30

40

50

60

70

80

90

0 2 4 6 8 10 12

Cum

ulat

ive

% d

rug

rele

ased

Time(hrs)

OF1

OF2

OF3

OF4

OF5

OF6

99

6.6 Release kinetics

Linear regression plots for the dissolution profile of OF1 to OF6 for (a) Zero order plot,

(b) Peppas plot, (c) Higuchi plot (d) erosion are shown in Fig. 6.7. The release rate constants as

shown in Table 6.14 revealed that the release rate increased as the proportion of Okra gum

decreased and correlation coefficient values as shown in Table 6.13 confirmed zero order kinetics

for the formulations OF1 to OF6. In order to establish the mechanism of drug release, the

dissolution data were fitted to the exponential equation (Mt /Mα=Ktn). The linear correlation

coefficients of the slopes and slope values shown in Table 6.14 indicated that the release kinetics

for OF1-OF6 conformed to non-fickian diffusion (i.e. square root of time profile) with erosion.

This classical Higuchi type of release mechanism can be explained as a result of the rapid

hydration of the polymer molecules on the surface of the tablets, which results in a gel or a

highly viscous solution surrounding the matrix that restricts water penetration into the center. The

net result was a reduction in the rate of drug release as a function of time. This was confirmed by

the linearity of the plot obtained when cumulative amount of drug released was plotted as a

function of square root of time (Fig.6.7). The tablet did not disintegrate during the course of

dissolution, though it was swollen confirming the above mechanism of diffusion.

The mechanism of release of drug from the prepared floating tablets was by diffusion as

evidenced above. The drug was released into dissolution medium by diffusion mechanism where

the formation of gel layer on the hydrated surfaces occurs during dissolution, then the solvent

penetrates into the gel layer, enters into the core of dosage form to solubilise the drug and the

drug solution comes out into the medium. The thickness of the gel layer acts as a barrier and if

the thickness increases which normally occurs with increase in polymer concentration does not

allow the solvent molecule to enter into the gel structure and release of the drug ceases at this

point. Though formulations OF1 to OF6 were able to release the drug with zero order, which was

a desirable feature for any controlled release dosage forms but they failed to release the drug

within 12 hours of dissolution. This may be due to the formation of a very thick gel layer of Okra

100

gum due to its high swelling nature which acts as a barrier preventing the entry of dissolution

medium into core of the tablet. Another factor that may be responsible for the failure of the

dosage form to release the drug was the poor solubility nature of Ofloxacin. When the

concentration of polymer was increased gradually, the release of drug decreased proportionally

as evidenced by the results shown above.

Drug: Okra gum concentration Vs drug release rate constant plotted as shown in Fig. 6.8.

For the concentrations of drug : Okra gum 1:0.37, 1:0.25, 1:0.19, 1:0.15, 1:0.13 and 1:0.10 a

straight line with linear regression 0.9896 obtained indicating good correlation between Okra

gum concentration and release kinetics. Further, release rate constant Vs swelling index was

plotted and shown in Fig. 6.9. These results clearly suggested that a good correlation between

drug release and polymer concentration was possible below 20 percent of Okra gum. The

prepared formulations followed diffusion mechanism of release as evidenced by Higuchi

equation, which states that

Q = [D ε/τ (2C-εCS) CSt) 1/2

Where Q is the amount of drug released per unit area of exposed surface in time t.

This showed that the surface area of tablet may influence the amount of drug released.

The results showed that it was possible to prepare Okra gum GRDDS tablets of

Ofloxacin. From the various formulations prepared, OF6 gave consistent release extended over a

period of 12 hours. Hence this formulation can be considered as an optimum formulation for oral

controlled release of Ofloxacin. This formulation was further studied in order to improve the

floating lag time and duration of floating.

101

Table 6.13: Correlation coefficients (‘r’ values) of release kinetics of Okra gum GRDDS tablets of Ofloxacin

Table 6.14: Kinetic parameters of Okra gum GRDDS tablets of Ofloxacin

Formulation Zero order First order Peppas

equation Erosion equation

Higuchi equation

OF1 0.9770 0.9741 0.9889 0.9842 0.9821

OF2 0.9860 0.9812 0.9886 0.9851 0.9874

OF3 0.9968 0.9856 0.9935 0.9826 0.9919

OF4 0.9972 0.9810 0.9943 0.9916 0.9927

OF5 0.9986 0.9690 0.9964 0.9849 0.9925

OF6 0.9989 0.9680 0.9976 0.9856 0.9912

Formulation Zero order release rate

constant (mg/hr)

Peppas equation

‘n’ value

OF1 4.19 0.87

OF2 5.26 0.78

OF3 5.90 0.65

OF4 6.61 0.56

OF5 6.79 0.52

OF6 7.00 0.47

102

(a) (b)

(c) (d)

Fig. 6.7: Linear regression plots for the dissolution profiles from OF1-OF6 (a) Zero order plot (b) Peppas plot (c) Higuchi plot and (d) Erosion plot

-100

102030405060708090

100

0 5 10 15

Cum

ulat

ive

% d

rug

rele

ased

Time (hrs)

OF1

OF2

OF3

OF4

OF5

OF60

0.20.40.60.8

11.21.41.61.8

2

-0.5 0 0.5 1 1.5

Log

cum

ulat

ive

% d

rug

rele

ased

Log time (hrs)

OF1

OF2

OF3

OF4

OF5

OF6

-20-10

0102030405060708090

0 1 2 3 4

Cum

ulat

ive

% d

rug

rele

ased

Time 1/2 (hrs)

OF1

OF2

OF3

OF4

OF5

OF6

-0.05

0

0.05

0.1

0.15

0.2

0.25

0.3

0.35

0.4

0.45

0 5 10 15

1-(1

-Q)1/

3

Time (hrs)

OF1

OF2

OF3

OF4

OF5

OF6

103

Fig. 6.8: Drug: Okra gum concentration Vs Release rate constant for Ofloxacin

Okra gum GRDDS tablets OF1-OF6

Fig. 6.9: Swelling Index (%) Vs Release rate constant for Ofloxacin Okra gum GRDDS

tablets OF1-OF6

0

1

2

3

4

5

6

7

8

0 0.1 0.2 0.3 0.4 0.5 0.6

Zero

ord

er r

elea

se ra

te c

onst

ant (

mg/

hr)

Drug:Polymer(1:Polymer)

0

1

2

3

4

5

6

7

8

0 20 40 60 80 100 120

Zero

ord

er r

elea

se ra

te c

onst

ant (

mg/

hr)

Swelling Index(%)

104

6.7 Effect of effervescent agent on the floating properties and dissolution profile of

Ofloxacin from GRDDS:

The floating lag time mainly depends up on the concentration of effervescent agent

present in the matrix. In the present study sodium bicarbonate was used as effervescent agent, as

it is cheap and safe. Sodium bicarbonate when comes in contact with gastric fluid generates

carbon dioxide, that gas gets entrapped within the hydrated gel matrix. This entrapped gas

decreases density of the tablet and produces an upward motion of the dosage form and maintains

its buoyancy. The effervescent agent was responsible for decreasing the duration of floating from

EF1 to EF6.

GRDDS represented as EF1, EF2, EF3, EF4, EF5 and EF6 (Table 6.15) contained the

sodium bicarbonate in the concentrations of 9.2%,10.8%,12.3%,13.8%,15.3%,16.9% w/w of total

formula were selected to study the effect of effervescent concentration on lag time. It was found

that increasing the amount of sodium bicarbonate decreased the floating lag time was given in

Table 6.16 and shown in Fig. 6.10. Among the various formulae prepared, formulation EF6 was

having less lag time compared to others, as it contained higher amount of effervescent agent. As

the amount of sodium bicarbonate increases, more amount of gas gets entrapped in the hydro gel

and the lag time decreases.

The floating lag time decreased in the rank order: EF6 > EF5 > EF4 > EF3 > EF2 > EF1.

Although the release rate mainly depends on the concentration of the hydrophilic

polymer, the entrapped gas within the hydro gel also influences the release of the drug from the

matrix. GRDDS represented as EF2, EF4 and EF6 contained sodium bicarbonate in the

concentrations of 10.8%, 13.8%, and 16.9% w/w of total formulation were selected to study the

effect of effervescent on drug release. These concentrations were selected to obtain more

discriminative dissolution profiles. The data of dissolution profiles of GRDDS as a function of

concentration of effervescent agent were given in Table 6.17 and dissolution profiles were shown

in Fig. 6.11. From this, it was observed that as the concentration of sodium bicarbonate increases,

105

increased release rates were obtained. It was found that formulation EF6 produced

increased dissolution rates compared to EF4 and EF2 as it contained higher concentration of

effervescent. By increasing the concentration of sodium bicarbonate, the porosity produced by

the entrapped gas increases and as a result release rate was found to be increased. It was also

suggested that entrapped gas acts as a transport barrier and improves the release rate of the drug

from hydrophilic matrices. The drug release rate increased in the rank order: EF6 >EF5> EF4

>EF3> EF2>EF1.

Table 6.15: Formulae of GRDDS containing varying concentrations of effervescent agent

Ingredient (mg/tablet)

EF1 EF2 EF3 EF4 EF5 EF6

Ofloxacin 400 400 400 400 400 400

PVPK30

15

15

15

15

15

15

Okra gum

35

35

35

35

35

35

Sodium bicarbonate 60 70 80 90 100 110

Magnesium stearate 10 10 10 10 10 10

Dicalcium phosphate 130 120 110 100 90 80

Table 6.16: Tabletting characteristics of GRDDS prepared from Okra gum

a Mean S.D. , n = 10 tablets b Mean, n = 10 tablets

Formulation Weighta

(mg) Drug

contenta (%)

Hardness a (kg/cm2)

Friability b (%)

Lag time (min)

Swelling index a(%)

EF1 650.220.36 99.620.25 4.740.32 0.48 45 67.220.13

EF2 650.851.54 98.240.54 4.820.49 0.32 30 64.310.75

EF3 650.651.35 98.740.76 5.140.24 0.26 15 60.781.12

EF4 650.191.49 98.460.34 5.060.56 0.45 5 57.410.84

EF5 650.261.12 99.940.68 5.060.56 0.45 1 54.170.43

EF6 650.261.60 98.350.22 5.06 0.56 0.45 0.25 51.110.46

106

Fig .6.10: Effect of sodium bicarbonate on floating lag time

Table 6.17: Cumulative percent drug released from GRDDS containing varying concentrations of effervescent agent

-10

0

10

20

30

40

50

0 20 40 60 80 100 120Fl

oatin

g la

gtim

e (m

in)

Amount of Sodiumbicarbonate (mg)

Time (hrs)

Cumulative percent ( S.D, n=3) drug released

EF1 EF2 EF3 EF4 EF5 EF6

0.5 07.271.15 10.560.32 11.310.16 12.65 1.16 14.292.24 18.961.64

1.0 18.250.39 16.980.93 17.330.66 19.740.25 24.160.93 31.952.38

2.0 27.531.66 25.681.47 26.540.14 28.932.14 34.290.53 44.680.47

3.0 29.350.08 30.751.01 33.210.11 35.760.63 43.381.86 50.650.04

4.0 44.682.82 38.151.26 39.740.21 40.981.83 52.731.38 61.041.26

5.0 50.132.11 45.921.67 46.210.14 47.640.34 57.550.56 68.571.85

6.0 56.100.63 52.350.74 54.210.22 58.271.69 67.790.04 75.062.06

7.0 60.941.86 61.840.12 63.230.34 64.120.46 75.841.45 79.451.82

8.0 66.491.24 64.840.68 66.110.47 67.891.32 80.521.18 85.970.64

9.0 70.120.55 69.841.06 72.320.68 74.351.32 83.122.84 92.731.72

10.0 73.510.07 75.231.45 79.171.65 81.561.12 88.310.62 96.882.63

12.0 79.061.48 83.260.65 89.651.32 90.230.65 94.810.71 99.480.82

107

Fig. 6.11: Dissolution profiles of Okra gum GRDDS tablets of Ofloxacin, EF1 to EF6 formulations

The generated gas influences the drug delivery from the tablets in ways that are currently not

well understood. For example, factors that may influence drug delivery include.

a. The presence of entrapped gas within the matrix can affect the diffusion path length of the drug

and thus exerts a release-controlling effect.

b. The presence of entrapped gas within the matrix can affect the rate of surface erosion of the

hydrated gel matrix and thus exerts both a hydrodynamic and a release controlling effect.

c. The presence of entrapped gas and its expanding pressure affects the internal structure of the

hydrated gel and thus exerts both a hydrodynamic and a release controlling effect.

d. The presence of entrapped gas and its expanding pressure affects the influx of the acidic

gastric fluid through the pores of the matrix and thus exerts a release controlling effect.

It should be realized that gas generated in a small volume within the matrix could exert a

high pressure. If this exceeds the capillary pressure due to the surface tension of the aqueous

fluid, then it will cause the aqueous fluid in a pore to be pushed by the gas allowing the gas to

expand until the internal gas pressure equals the capillary pressure. This phenomenon thus would

affect the rate of hydration of the tablet and hence increased dissolution rates were obtained by

increasing the concentration of effervescent agent.

0

20

40

60

80

100

120

0 2 4 6 8 10 12 14

Cum

ulat

ive

% d

rug

rele

ased

Time (hrs)

EF1

EF2

EF3

EF4

EF5

EF6

108

6.8 Drug release kinetics

The values of correlation coefficients (r) obtained by fitting the data to five popular

release models were given in Table 6.18. The drug release from GRDDS (EF1-EF6) prepared by

increasing effervescent agent concentration from 9%-17% followed first order kinetics which

was indicated by r values of first order release model (0.9875-0.9917), slightly higher when

compared to those of zero order release model (0.9020-0.9714). When percent drug remaining

were plotted against time on a semi-logarithmic graph, straight lines were obtained for all the

GRDDS as given in Fig. 6.14a indicating that the release pattern follows first order kinetics.

Plots of log mean percent of drug released versus log time were found to be linear as

given in Fig. 6.14b. The r values of these GRDDS are very nearer to 1 (Table 6.18).

It was found that n values of EF1, EF2, EF3 (Table 6.19) were ranging from 0.27 to 0.39

indicating that the release mechanism followed Fickian diffusion. As the concentration of

effervescent agent increases, it was observed that n values were ranging from 0.45 to 0.68

indicating that the release mechanism followed non-fickian diffusion. The results of the study

indicated that the release of drug from the GRDDS followed first order kinetics via anomalous

(non-fickian) diffusion. The relative contributions of drug diffusion and matrix erosion to drug

release were further confirmed by subjecting the dissolution data to Higuchi model and erosion

model. It was found that diffusion (0.9935–0.9984) as well as erosion (0.9673-0.9878) governs

the drug release from these formulations as indicated by r values.

Though the drug release was governed by diffusion as well as erosion, the contribution of

drug diffusion was found to be slightly higher than that of matrix erosion as indicated by the

higher r values of Higuchi model. From Fig. 6.14c and from Fig. 6.14d it can be concluded that

the drug release was predominately governed by diffusion rather than erosion.

The results showed that it was possible to prepare Okra gum floating tablets of Ofloxacin

for controlled drug delivery. From the various formulations prepared, EF6 showed a floating lag

109

time of less than 15 sec and floating time of more than 24 hrs and on difference in the

floating characteristics was observed among the formulations. Hence, the best formulation was

selected on the basis of dissolution profile (Fig. 6.13) similar to the commercially available

extended release formulation (ZANOCIN-OD). From the GRDDS of SB formulation EF6

showed almost comparable release profiles with commercial formulation. Hence, formulation

EF6 was selected as a promising GRDDS (Table 6.20) in respect of both floating and drug

release properties.

DSC thermogram of Ofloxacin showed an endothermic peak at 184.10 C, where as the

formulation EF6 showed at 186.3o C (Fig. 6.3) revealing the occurrence of no interaction or

complexation between Ofloxacin and Okra gum during the manufacturing process.

The principal absorption peaks of Ofloxacin (as shown in Fig. 6.4) at 3416 cm-1

(stretching of Hydroxyl group), 1712 cm-1 (stretching of Keto group) were observed in both the

pure Ofloxacin and in the prepared formulation. The IR spectra as shown in Fig. 6.5 also proved

that there was no interaction or complexation occurred between Ofloxacin and Okra gum in the

prepared formulation.

110

Table 6.18: Correlation coefficients (r values) of release kinetics of GRDDS prepared from various concentrations of effervescent agent

CF : Commercial extended release formulation (ZANOCIN-OD)

Table 6.19: Kinetic parameters of GRDDS prepared from various concentrations of effervescent agent.

Formulation k1 (h-1) n

EF1 0.8810.016 0.27

EF2 0.582 0.005 0.35

EF3 0.465 0.024 0.39

EF4 0.379 0.045 0.68

EF5 0.324 0.009 0.57

EF6 0.314 0.008 0.51

CF 0.370 0.012 0.54

k1 : First order release rate constant

n : Diffusional exponent derived from Peppas equation

CF : Commercial extended release formulation (ZANOCIN-OD)

Formulation Zero order First order Higuchi

equation

Erosion

equation

Peppas

equation

EF1 0.9261 0.9875 0.9984 0.9852 0.9932

EF2 0.9441 0.9884 0.9935 0.9867 0.9915

EF3 0.9713 0.9883 0.9966 0.9673 0.9960

EF4 0.9632 0.9917 0.9918 0.9757 0.9938

EF5 0.9020 0.9892 0.9928 0.9751 0.9957

EF6 0.9544 0.9901 0.9964 0.9758 0.9975

CF 0.9714 0.9932 0.9985 0.9878 0.9989

111

Fig. 6.12: Swelling Index (%) Vs release rate constant for Ofloxacin Okra gum GRDDS

tablets EF1-EF6

Table 6.20: Cumulative percent drug released from experimental formulation (EF6) versus commercial extended release formulation (ZANOCIN-OD)

Time (hrs) Cumulative percent ( S.D. n=3) Ofloxacin

released

EF6 CF

0.5 18.96 1.64 18.70 1.92

1.0 31.95 2.38 26.75 0.58

2.0 44.68 0.47 39.74 1.16

3.0 50.65 0.04 54.55 0.08

4.0 61.04 1.26 62.34 1.06

5.0 68.57 1.85 69.09 0.64

6.0 75.06 2.06 74.55 2.15

7.0 79.45 1.82 78.44 1.88

8.0 85.97 0.64 83.38 0.46

9.0 92.73 1.72 95.06 2.62

10.0 96.88 2.63 98.96 1.24

12.0 99.48 0.82 --

0

0.05

0.1

0.15

0.2

0.25

0.3

0.35

0.4

0 20 40 60 80

Firs

t ord

er r

ate

cons

tant

(h-1

)

Swelling Index(%)

112

Fig. 6.13: Comparison of drug release between optimized formulation (EF6) and

ZANOCIN-OD

0

20

40

60

80

100

120

0 2 4 6 8 10 12 14

Cum

ulat

ive

% d

rug

rele

ased

Time (hrs)

EF6Zanocin-OD

113

(a) (b)

(c) (d )

Fig. 6.14: Linear regression plots for the dissolution profiles from EF1-EF6 (a) First order plot (b) Peppas plot (c) Higuchi plot and (d)

Erosion plot

0

0.5

1

1.5

2

2.5

0 2 4 6 8 10 12 14

Log

cum

ulat

ive

% d

rug

unre

leas

ed

Time (hrs)

EF1

EF2

EF3

EF4

EF5

EF60

0.5

1

1.5

2

2.5

-0.5 0 0.5 1 1.5

Log

cum

ulat

ive

% d

rug

rele

ased

Log time (hrs)

EF1

EF2

EF3

EF4

EF5

EF6

-20

0

20

40

60

80

100

120

0 1 2 3 4

Cum

ulat

ive

% d

rug

rele

ased

Time1/2(hrs)

EF1

EF2

EF3

EF4

EF5

EF6 00.10.20.30.40.50.60.70.80.9

0 5 10 15

1-(1

-Q)1/

3

Time (hrs)

EF1

EF2

EF3

EF4

EF5

EF6

114

(a) (b)

( c ) (d )

Fig. 6.15: Linear regression plots for the dissolution profile of ZANOCIN-OD (a) First order plot (b) Peppas plot (c) Higuchi plot and (d) Erosion plot

0

0.5

1

1.5

2

2.5

0 2 4 6 8 10 12

Log

cum

ulat

ive

%dr

ug u

n re

leas

ed

Time ( hrs)

0

0.5

1

1.5

2

2.5

-0.5 0 0.5 1 1.5

Log

cum

ulat

ive

%dr

ug r

elea

sed

Log time (hrs)

0

20

40

60

80

100

120

0 0.5 1 1.5 2 2.5 3 3.5

Cum

ulat

ive

% d

rug

rele

ase

Time 1/2(hrs)

00.10.20.30.40.50.60.70.80.9

0 2 4 6 8 10 12

1-(1

-Q)1/

3

Time (hrs)

115