PHARMA SCIENCE MONITOR surani.pdf · physicochemical properties of different formulations, ... controlling the rate of drug ... GRDFs extend significantly the period of time over

Vol-3, Issue-1, Jan-2012 ISSN: 0976-7908 Surani et al

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PHARMA SCIENCE MONITOR AN INTERNATIONAL JOURNAL OF PHARMACEUTICAL SCIENCES

DESIGN, DEVELOPMENT AND EVALUATION OF THE

HYDRODYNAMICALLY BALANCED TABLETS OF CIPROFLOXACIN

HYDROCHLORIDE

Vijaykumar S. Surani*1, Jignesh J. Donga1, Sachin Chauhan1, Tejas Ghelani1, AK

Seth1,Nirmal Shah1, Sharad Kumar1, Yogesh Chand Yadav1, Vipin Saini2

1Department of Pharmacy, Sumandeep Vidyapeeth, Waghodiya, Vadodara, Gujarat, India 2MJRP Health Care & Allied Sciences, MJRP University Jaipur (Rajasrhan).

ABSTRACT Ciprofloxacin HCl has an absorption window in the stomach and in the upper part of the small intestine. The present investigation concerns the development of hydrodynamically balanced tablets of ciprofloxacin, which are designed to prolong the gastric residence time and thereby increase drug bioavailability after oral administration. Five different batches of tablets were fabricated containing Ciprofloxacin, polymers like HPMC K4M, HPMC K15M and Chitosan, along with gas generating agent sodium bicarbonate. The physicochemical properties of different formulations, their buoyancy lag time, total floatation time and swelling index were evaluated. It was found that the hardness of the tablet will effect the buoyancy characteristic of the dosage form. The in vitro release studies (USP XXIII) indicated that the floating dosage forms containing HPMC K15M showed slower release and the integrity of the device was maintained. The % drug release profile was found in the order of F2 > F3 > F6 > F1 > F5 > F4. The in vitro release data was treated with mathematical equations, and it was concluded that release of ciprofloxacin from the tablet follows Peppas model with non-Fickian diffusion. F2 formulation showed better control of drug release with comparison to marketed product. Finally the results had proven that the gas powered Hydrodynamically Balanced Tablets of ciprofloxacin containing HPMC K15M provides a better option for controlled release action and improved bioavailability. Keywords: Gastric residence; Gas generation; Swelling index; Ciprofloxacin. INTRODUCTION

Oral drug delivery is the most widely utilized route of administration among all

the routes that have been explored for systemic delivery of drugs via pharmaceutical

products of different dosage form. Oral route is considered most natural, uncomplicated,

convenient and safe due to its ease of administration, patient acceptance, and cost-

effective manufacturing process.[1,2]



Controlled drug delivery systems have been developed which are capable of

controlling the rate of drug delivery, sustaining the duration of therapeutic activity and/or

targeting the delivery of drug to a tissue.[3,4,5]

One of the most feasible approaches for achieving a prolonged and predictable

drug delivery in the GI tract is to control the gastric residence time (GRT), i.e. gastro

retentive dosage form (GRDF or GRDS).[6]

GRDFs extend significantly the period of time over which the drugs may be

released. They not only prolong dosing intervals, but also increase patient compliance

beyond the level of existing controlled release dosage form.[7,8]

To formulate a successful gastro-retentive drug delivery system, several

techniques are currently used such as hydrodynamically balanced systems (HBS)/

floating drug delivery system[9] , low-density systems[10,11,12], raft systems incorporating

alginate gels[13,14], bioadhesive or mucoadhesive systems[15], high density systems[16],

superporous hydrogels [17] and magnetic systems.[18,19]

MATERIALS AND METHODS

Ciprofloxacin were gift samples from (Zydus cadila Ltd), HPMC K4M and

HPMC K15M (Colorcon Asia Pvt. Ltd.), Chitosan (Central Institute of Fisheries

Technology, Cochin), Sodium bicarbonate (Poona Chemical Laboratory), Lactose

Monohydrate and Magnesium Stearate (Loba Chemie Pvt Ltd.), Hydrochloric Acid (S.D.

Fine Chem. Ltd.). All other reagents and chemicals used were of analytical reagent grade.

I) Preformulation study:[20]

The API and granules evaluated for the angle of repose and compressibility index.

II) Compatibility Studies:

They provide framework for the drug in combination with the excipients in the

fabrication of the dosage form and establish that active drug has not undergone

degradation. This can be confirmed by carrying out infrared light absorption scanning

spectroscopy. It is one of the most powerful analytical technique for chemical

identification of drug.

Method:- The pure drug and its formulation were subjected to IR studies. In the present

study, the potassium bromide disc (pellet) method was employed.

III) Formulation of Hydrodyamically Balanced Tablets:



Floating matrix tablets containing ciprofloxacinn were prepared by direct

compression technique using varying concentrations of different grades of polymers with

sodium bicarbonate.

All the ingredients except magnesium stearate were blended in glass mortar

uniformly. After sufficient mixing of drug as well as other components, magnesium

stearate was added and further mixed for additional 2-3 minutes. The tablets were

compressed. The composition of all formulations was given in Table 1.

IV) Evaluation of Hydrodynamically Balanced Tablets:

The compressed tablets were tested for hardness, thickness, diameter, weight

variation, drug content uniformity, buoyancy/floating test, sweling index and comparative

in vitro drug release profile with the marketed formulation. [20,21,22].

Buoyancy / Floating Test:[23]

The time between introduction of dosage form and its buoyancy on the simulated

gastric fluid and the time during which the dosage form remain buoyant were measured.

The time taken for dosage form to emerge on surface of medium called Floating Lag

Time (FLT) or Buoyancy Lag Time (BLT) and total duration of time by which dosage

form remain buoyant is called Total Floating Time (TFT).

Swelling Study:[24,25]

The swelling behaviour of a dosage form is measured by studying its weight gain

or water uptake. The dimensional changes can be measured in terms of the increase in

tablet diameter and/or thickness over time. Water uptake is measured in terms of percent

weight gain, as given by the equation.

Where, Wt = Weight of dosage form at time t.

W0 = Initial weight of dosage form

Effect of hardness on Buoyancy Lag Time (BLT) or Floating Lag Time (FLT):[26]

Tablets of batch F2 possessed quick buoyancy lag time and good total floating

time, so formulation F2 was selected to study the effect of hardness on buoyancy lag

time. The tablets of batch F2 were compressed at three different compression pressures to



get the hardness of 5kg/cm2, 7kg/cm2 and 9kg/cm2. The tablets were evaluated for

Buoyancy Lag Time.

In-vitro Dissolution Study:[27]

In-vitro release studies were carried out using USP XXIII dissolution test

apparatus. 900ml of 0.1N HCl (pH 1.2) was filled in dissolution vessel and the

temperature was set at 370C0.10C. For the study ring/mesh assembly was used. The

speed was set at 50 rpm. 1ml of sample was withdrawn at predetermined time intervals

for 8 hours and same volume of fresh medium was replaced. The samples were analyzed

for drug content against 0.1N HCl as a blank at max 274nm using U.V.

spectrophotometer.

Curve fitting analysis:

The release mechanism of ciprofloxacin from the matrix system was studied by

fitting the obtained dissolution data to following equation using PCP DISSO V2

software.

i) Korsmeyer – Peppas equation

ii) Zero order equation

iii) Higuchi square root equation

TABLE 1: COMPOSITION OF HYDRODYNAMICALLY BALANCED

TABLETS OF CIPROFLOXACIN (IN MG)

Ingredients F1 F2 F3 F4 F5 F6

Ciprofloxacin 500 500 500 500 500 500

HPMC K4M 200 - 100 - - 100

HPMC K15M - 200 100 - 100 -

Chitosan - - - 200 100 100

Sodium Bicarbonate 80 80 80 80 80 80

Lactose 10 10 10 10 10 10

Magnesium Stearate 10 10 10 10 10 10



TABLE 2: ANGLE OF REPOSE, COMPRESSIBILITY INDEX

Batch Angle of Repose () Compressibility Index (%)

F1 23.30' 13.18

F2 25.77' 16.67

F3 24.28' 15.48

F4 27.56' 17.34

F5 28.88' 16.41

F6 26.98' 14.13

TABLE 3: PHYSICAL PROPERTIES OF TABLETS OF BATCH F1 TO F6

Batches Diameter

(mm)

Thickness

(mm)

Hardness

(Kg/cm2)

Friability

(%)

Avg. Weight

(mg)

Content

uniformity (mg)

F1 12.12 4.86 5.5 0.98 800.65 96.8

F2 12.11 4.84 5.4 0.74 801.5 99.3

F3 12.12 4.82 5.1 0.93 799.55 97.8

F4 12.11 4.86 5.3 0.88 800.05 97.1

F5 12.11 4.88 5.5 0.81 801.65 98.3

F6 12.11 4.87 5.5 0.89 800.25 97.3

TABLE 4: TABLET DENSITY, BUOYANCY LAG TIME, TOTAL FLOATING

TIME

Batch Tablet Density

(g/cc)

Buoyancy Lag Time

(Sec)

Total Floating

Time (hrs)

F1 0.92 60 sec >12 hrs

F2 0.81 47 sec >12 hrs

F3 0.88 53 sec >12 hrs

F4 0.98 133 sec >6 hrs

F5 0.96 100 sec >10 hrs

F6 0.97 109 sec >9 hrs



TABLE 5: SWELLING INDEX OF TABLETS OF BATCH F1 TO F6

Swelling Index (%)

Time F1 F2 F3 F4 F5 F6

1 hr 78 80 77 74 74 75

2 hrs 127 133 128 118 123 120

3 hrs 150 164 158 142 144 148

4 hrs 169 186 173 162 164 167

5 hrs 180 202 184 168 175 182

TABLE 6: EFFECT OF HARDNESS ON BUOYANCY LAG TIME OF BATCH F2

Hardness in kg/cm2 Buoyancy Lag Time (sec)

4kg/cm2 47

5kg/cm2 102

7kg/cm2 480

9kg/cm2 650

TABLE 7: CUMULATIVE % DRUG RELEASED FROM TABLET

FORMULATIONS F1 TO F6

Time (hrs)

F1 F2 F3 F4 F5 F6 Marketed Product

1 22.5 20.7 21.6 25.2 23.4 21.9 24.3

2 32.4 31.5 33.3 48.6 38.7 32.8 34.2

3 49.5 46.8 47.7 59.4 57.6 48.6 48.6

4 58.5 53.1 56.7 67.5 61.2 57.4 59.4

5 70.2 62.1 64.8 81.9 71.1 66.6 66.6

6 75.6 68.4 69.3 97.2 77.4 74.7 74.7

7 80.1 73.8 76.5 -- 85.5 78.9 78.9

8 83.7 78.3 79.2 -- 88.2 81.9 81.9

9 91.8 84.3 87.3 -- 92.7 90.7 90.7

10 93.6 89.4 91.8 -- 96.3 92.3 92.3



TABLE 8: MODEL FITTING OF THE RELEASE PROFILES USING THREE

DIFFERENT MODELS (R-VALUES)

Mathematical Models

Batch No. Zero order

Higuchi

Matrix Peppas

'n' values Best Fit

Model

F1 0.9356 0.9868 0.9914 0.6885 Peppas

F2 0.9517 0.9862 0.9949 0.6842 Peppas

F3 0.9403 0.9897 0.9948 0.6736 Peppas

F4 0.9777 0.977 0.9906 0.7612 Peppas

F5 0.9109 0.987 0.9914 0.6476 Peppas

F6 0.9385 0.9684 0.9905 0.6765 Peppas

Figure 1 Photograph of in vitro buoyancy study of F2 batch



Figure 2 Swelling Index of Tablets of Batch F1 to F6

Figure 3

The plot of Buoyancy lag time (sec) V/s hardness (kg/cm2)



Figure 4 In-Vitro dissolution profile of batch F2 and marketed product

Figure 5

In-Vitro dissolution profile of all batches and marketed product



Figure 6 In-Vitro dissolution profile of batch F2 and marketed product

RESULTS AND DISCUSSION

Hydrodynamically balanced tablets of ciprofloxacin were prepared and evaluated

for their use as gastroretentive drug delivery systems to increase its local action and

bioavailability.

In the present work total six formulations were prepared using hydrophilic

polymers and complete composition of all batches shown in Table 1. Polymers used were

HPMC K4M, HPMC K15M and Chitosan. The drug release from hydrophilic matrix

tablets was controlled by a hydrated viscous layer formed at the tablet periphery, this gel

layer was act as a barrier to drug release. The compressed tablets were evaluated for

various post formulation parameters as mentioned in methodology. Compatibility studies

were performed using IR spectrophotometer which indicates that the drug is compatible

with the formulation components.

The values obtained for angle of repose and compressibility index for all

formulations are tabulated in Table 2. This indicates good flow property of the powder

blend.

The dimensions determined for formulated tablets were tabulated in Table 3.

Tablets mean thickness (n=3) were almost uniform in all the six formulations. The



measured hardness of tablets of each batch ensures good handling characteristics of all

batches. The % friability was less than 1% in all the formulations ensuring that the tablets

were mechanically stable. The percentage of drug content was found to be within

acceptable limits. All the tablets passed weight variation test as the % weight variation

was within the pharmacopoeial limits of 5% of the weight.

Tablet density:

To provide good floating behavior in the stomach, the density of the device

should be less than that of the gastric contents (1.004g/cm3). All the batches showed

density below than that of gastric fluid (1.004). The values are shown in Table 4.

When tablet contacts the test medium, tablet expanded (because of swellable

polymers) and there was liberation of CO2 gas (because of effervescent agent, NaHCO3).

Hence, The density of the dosage form was decreased due to this expansion and upward

force of CO2 gas generation. This action plays an important role in ensuring the floating

capability of the dosage form.

Buoyancy Study:

On immersion in 0.1N HCl solution pH (1.2) at 370C, the tablets floated and

remained buoyant without disintegration. Table 5 shows the results of Buoyancy study.

From the results it can be concluded that the batch containing only HPMC polymers

showed good Buoyancy lag time (BLT) and Total floating time (TFT). Formulation F2

containing HPMC K15M showed good BLT of 47 sec, while the formulation containing

only chitosan and in combination with HPMC K15M showed highest BLT and TFT of

less than 12 hrs. This may be due to the amount of polymer and gas generating agent,

which were kept constant in the present study. The gas generated cannot be entrapped

inside the gelatinous layer, and it escapes leading to variation in BLT and TFT. Tablet

floating properties shown in figure 1.

Swelling Study:

Swelling ratio describes the amount of water that is contained within the hydrogel

at an equilibrium and is a function of the network structure, hydrophilicity and ionization

of the functional groups.

Swelling study was performed on all the batches for 5 hr. The result of swelling

index is given in Table 5. While the plot of swelling index against time (hr) is depicted in



Fig. 2. From the results it was concluded that swelling increases as the time passes

because the polymer gradually absorb water due to hydrophilicity. The outermost

polymer hydrates, swells and a gel barrier is formed at the outer surface. As the

gelatinous layer progressively dissolves and/or is dispersed, the hydration swelling

release process is repeated towards new exposed surfaces, thus maintaining the integrity

of the dosage form.

In the present study, the higher swelling index was found for tablets of batch F2

containing HPMC K15M having nominal viscosity of 15,000 cps. Thus, the viscosity of

the polymer had major influence on swelling process, matrix integrity, as well as floating

capability, hence from the above results it can be concluded that linear relationship exists

between swelling process and viscosity of polymer.

Effect of hardness on Buoyancy Lag Time:

The effect of hardness on buoyancy lag time for batch F2 was studied. The result

was tabulated in Table 6. The plot of floating lag time (sec) V/s hardness (kg/cm2) is

depicted in Fig. 3. Batch F2 was selected for the study because it showed buoyancy lag

time of 47 sec at hardness of 4kg/cm2.

Buoyancy of the tablet was governed by both the swelling of the hydrocolloid

particle on surface when it contacts the gastric fluid which in turn results in an increase in

the bulk volume and the porosity of the tablet. On increasing the hardness of the tablets

results in increased buoyancy lag time which might be due to high compression resulting

in reduction of porosity of the tablet and moreover, the compacted hydrocolloid particles

on the surface of the tablet cannot hydrate rapidly when the tablet reaches the gastric

fluid and as a result of this, the capability of the tablet to float is significantly reduced.

In-vitro Dissolution Study:

The in-vitro drug release profiles of tablet from each batch were shown in Table

7. The plot of % cumulative drug release V/s time (hr) was plotted and depicted as shown

in Fig.4, Fig.5 and Fig.6.

For in-vitro dissolution study ring mesh device was used. The reason is that when

paddle apparatus was used, the tablets would rise and eventually stick to the flange of the

rotating shaft resulting in partial surface occlusion. In case of basket apparatus, it ensures

full exposure of all surfaces of hydrophilic swelling tablets that may stick to bottom of



dissolution vessel if paddle apparatus was used. However, it was observed that after 5-7

hr the tablets had swollen to such an extent that they were completely constricted by the

radius of the basket and completely filled the bottom of the basket. Once the dosage

forms completely fill the basket, tablet is unable to swell further and move in unimpeded

fashion leading to limited drug release. In order to overcome these drawbacks ring mesh

device is employed in the study.

From the in-vitro dissolution data it was found that formulation F4 containing

only chitosan released 97.2% of drug within 6 hr of the study indicating that the polymer

amount was not sufficient to control the drug release. Formulation F5 containing chitosan

along with HPMC K15M showed better control of drug release than chitosan alone, and

released up to 96.3% drug at the end of 10 hr. Tablet of batch F1, F2, F3 and F6

contained same amount of polymer of different grades viz. HPMC K4M, HPMC K15M,

combination of HPMC K4M and K15M and combination of HPMC K15M and Chitosan

which showed drug release around 93.6%, 89.4%, 91.8% and 92.3% respectively. Out of

all the six formulations batch F2 showed better control over drug release indicating that

the release was decreased when the viscosity of the polymer was increased.

Curve Fitting Analysis:

The results of dissolution data fitted to various drug release kinetic equations.

Peppas model was found to be best fitted in all dissolution profile having higher

correlation coefficient (r value) followed by Higuchi model and Zero Order Release

equation.

Korsemeyer-Peppas model indicates that release mechanism is not well known or

more than one type of release phenomena could be involved. The 'n' value could be used

to characterize different release mechanisms as:

n Mechanism

0.5 Fickian diffusion (Higuchi Matrix)

0.5 < n < 1 Non-Fickian diffusion

1 Case II transport



The kinetic values obtained for different formulations are tabulated in Table 8. It

ranges between 0.5 to 1, so it was concluded that the drug release occurred via non-

Fickian diffusion, which shows that the release from initially dry, hydrophilic glassy

polymers that swell when added to water and become rubbery show anomalous diffusion

as a result of the rearrangement of macromolecular chains.

CONCLUSION

From the findings obtained, it can be concluded that:-

Hydrodynamically Balanced Tablets of Ciprofloxacin can be formulated as an

approach to increase gastric residence time and thereby improve its bioavailability.

Among the polymers used to improve the gastric residence, cellulose polymers HPMC

K4M, HPMC K15M showed better control over drug release in comparison to

polysaccharide polymer Chitosan. Formulated tablets gave satisfactory results for various

physicochemical evaluations for tablets like Tablet dimensions, Hardness, Friability,

Weight variation, Tablet density, Swelling index and Content uniformity. Overall, tablets

of batch F2 possessed quick buoyancy lag time and good total floating time. Variation on

hardness on tablet of batch F2 was found to effect the floating lag time of the tablet as

hardness increased. In-vitro release rate showed that the drug release was better

controlled in formulation F2 followed by F3, F6, F1, F5 and F4. Formulated floating

tablets best fitted to Peppas model followed by Higuchi model and Zero order rate

kinetics. The present work can be continued further to prove its stability during shelf life,

in-vivo gastric residence time by using gamma scintigraphy and establishment of in vitro

– in vivo correlation.

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For Correspondence: Vijaykumar S. Surani Email: [email protected]

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PHARMA SCIENCE MONITOR surani.pdf · physicochemical properties of different formulations, ... controlling the rate of drug ... GRDFs extend significantly the period of time over