FORMULATION AND EVALUATION OF ORAL FLOATING IN SITU

www.wjpps.com Vol 9, Issue 10, 2020.

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Dandagi et al. World Journal of Pharmacy and Pharmaceutical Sciences

FORMULATION AND EVALUATION OF ORAL FLOATING IN SITU

GEL OF CEFIXIME TRIHYDRATE BY USING ß-CYCLODEXTRIN

COMPLEXATION TECHNIQUE FOR SOLUBILITY ENHANCEMENT

Jinal Patel, Panchaxari Dandagi*, Sujay Hulyalkar and Bapu Desai

KLE Academy of Higher Education and Research, KLE College of Pharmacy,

Department of Pharmaceutics, JNMC Campus, Belagavi-590010, Karnataka, India.

ABSTRACT

Purpose: Cefixime Trihydrate is third generation cephalosporin

antibiotic which is slowly and incompletely absorbed from

gastrointestinal tract after oral administration as it is an acidic drug

with pH 2.6 & 4.1[pKa(strong acidic) = 3.45, pKa(strong basic) =

2.92] thus to improve gastro retentive time and therapeutic effect with

sustained release it is formulated as floating in situ gelling system.

Methods: Attempted to enhance the solubility of drug by preparing

water soluble complexes of drug by using cyclodextrin inclusion

complexation technique. In situ gel formulations were designed using

gellan gum and sodium alginate as gelling agent, calcium carbonate as

gas generating agent and sodium citrate as complexing agent. Results:

All the formulation showed floating within 60 secs and had total

floating time of 20h. Formulation F2 considered as ideal because it

showed maximum drug release i.e. 89.02% following higuchi‟s diffusion mechanism.

Conclusion: The in situ gelling systems formed gel instaneously when comes in contact with

SGF and floats for longer duration. Enhanced the gastro retentive time of Cefixime

Trihydrate in stomach. The drug content of solution and gel was within acceptable range of

85 to 115% which ensured dose uniformity in the formulation. The drug content was

maximum for F2. Drug entrapment efficiency of all the formulations was found to be more

than 95% which indicates that there was no significant loss of drug during formulation and

Drug released maximum.

WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES

SJIF Impact Factor 7.632

Volume 9, Issue 10, 2613-2625 Research Article ISSN 2278 – 4357

*Corresponding Author

Dr. Panchaxari Dandagi

KLE Academy of Higher

Education and Research,

KLE College of Pharmacy,

Department of

Pharmaceutics, JNMC

Campus, Belagavi-590010,

Karnataka, India.

Article Received on

18 August 2020,

Revised on 08 Sept. 2020,

Accepted on 28 Sept. 2020

DOI: 10.20959/wjpps202010-17492


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KEYWORDS: Cefixime Trihydrate, Entrapment efficiency, Gastrointestinal tract, Gellan

gum, Higuchi,s diffusion, In situ gel, Ionic gelation, Sodium alginate.

INTRODUCTION

Oral drug delivery is one of the simplest routes of delivery of drugs for systemic and local

effect. Liquid oral dosage forms are more convenient to administer as compared to solid

dosage forms but cannot achieve the sustained release effect due to less residential time in the

GIT. The development of in-situ gel systems has received considerable attention over the past

few years as it provides the best way to overcome problems of immediate release and short

GI residence of liquids. In-situ gel forming drug delivery systems are capable of releasing

drug in a sustained manner maintaining relatively constant plasma profiles. The in-situ gel

dosage form is a liquid before administration and after it comes in contact with gastric

contents gets converted to gel which floats on gastric contents. The tablet/capsule floating

dosage forms are stable as compared to liquids but the problem with them is that they are

needed to swallow as a whole unit. In case of dosage adjustment these cannot be broken in

halves as these are also designed for controlled release and floating ability also depends on

dimensions of tablets. Elderly patients, children and some patient with certain disease

conditions have difficulties to swallow tablet/capsule dosage forms. Also in case of dosage

adjustments these floating solid dosage forms are needed to be available in different

strengths. Oral floating in-situ gel formulation have some advantages like ease of

administration, enhance bioavailability of the drug, reduce dosing frequency, improve patient

compliance and its production is less complex and so lowers the investment.[1,2]

Poorly

aqueous soluble drugs are generally associated with certain problems such as slow drug

absorption which eventually leads to insufficient and variable bioavailability. To enhance the

solubility of poorly water soluble drugs, various techniques are used which includes ß-

cyclodextrin complexation. ß cyclodextrin trap drug molecule inside its cavity and change its

physicochemical properties which leads to form water soluble complexes of drug. Solubility

enhancement of drug by β-cyclodextrin was done by simple complexation approach using

kneading method. This technique have several advantages like it enhances solubility,

enhances bioavailability, enhances stability, taste masking, prevent admixture

incompatibilities.[3,4]

Cefixime Trihydrate is third generation cephalosporin antibiotic with biological half-life 3-4

hours. It exhibit bactericidal activity by inhibiting cell wall synthesis. It is used in the


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treatment of otitis media, uncomplicated urinary tract infections, pharyngitis, tonsillitis, acute

bronchitis, uncomplicated gonorrhoea. It belongs to BCS class IV have very poor water

solubility (55.11 mg/L) which is one of the reason for its low oral bioavailability (40-50%).

After oral administration cefixime is slowly and incompletely absorbed from gastrointestinal

tract. Solubility of drug can be enhanced by preparing water soluble complexes of Cefixime

trihydrate by using ß cyclodextrin complexation. It is an acidic drug with pH 2.6 & 4.1. So, it

is primarily absorbed from stomach [pKa (strong acidic) = 3.45, pKa (strong basic) = 2.92]

thus to improve therapeutic effect and bioavailability it is formulated as floating drug

delivery system. It is formulated as “in-situ” floating gel to achieve controlled release with

improved gastric retention.[5,6,7]

MATERIALS AND METHODS

Materials

Cefixime Trihydrate was obtained as a gift sample from Lupin Pharmaceuticals. Gellan gum

was obtained from Sisco Research Laboratory. Sodium alginate, Calcium chloride, Calcium

carbonate and Hydroxy propyl β cyclodextrin were obtained from Hi Media, Mumbai.

Sodium citrate and Hydrochloric acid was obtained from Nice Laboratory. Deionised water

was obtained from Basic science research laboratrory. Methanol was obtained from S.D. Fine

chemicals Ltd. Mumbai.

Methods

Preparation of inclusion complex of Cefixime Trihydrate

Cefixime-Cyclodextrin inclusion complexes were prepared by using different weight ratios

(1:1, 1:2, 1:3) of Cefixime and β-cyclodextrin/HP- β-cyclodextrin. Firstly, β-

cyclodextrin/HP- β-cyclodextrin was dissolved in methanol and triturated to get slurry like

consistency. Then cefixime was incorporated into the slurry by triturating continuously for 45

minutes. This mixture was dried, pulverized and stored for further use.[11,12]

Preparation of in situ gelling solutions

Gellan gum (0.5 – 1.0% w/v) and Sodium alginate (1.0 – 2.0% w/v) solutions of different

concentrations were prepared by dissolving these gelling agents in deionized water

containing sodium citrate (0.5% w/v) and calcium chloride (0.15% w/v). These solutions

were heated up to 60 °C to 90 °C with continuous stirring by using magnetic stirrer. Calcium

carbonate (1.0% w/v) and Cefixime Trihydrate inclusion complex (equivalent to 100 mg/5ml)

were added after cooling the solution below 40 °C with continuous stirring to form uniform


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dispersion. These prepared solutions were stored at room temperature until further

use.[13,14,15,16]

Evaluation of inclusion complex of Cefixime Trihydrate

Solubility

100mg of Cefixime trihydrate inclusion complex was dissolved in a beaker containing 25 ml

of distilled water. The samples were kept in metabolic shaker for 24 hours, sonicated for half

an hour, filtered and the filtrate was analyzed by using UV Spectrophotometer at 287nm.[13,14]

Drug content

100 mg of Cefixime Trihydrate inclusion complexes were dissolved individually in 100 ml

0.1N HCl in a volumetric flask. From that 10ml of solution was withdrawn and diluted up to

100ml in volumetric flask. From this solution 1ml was withdrawn and diluted up to 10ml in

volumetric flask. The samples were analyzed under UV spectrophotometer at 287nm

wavelength.

In vitro dissolution study

Dissolution studies were carried out using USP type II (paddle apparatus). The dissolution

medium used was 900 ml of 1.2 pH 0.1N HCl. The temperature was maintained at

37±0.50˚C with continuous stirring at the rate of 50 rpm. 5ml of the samples were withdrawn

at the time intervals of 10, 20, 30, 40, 50 and 60 minutes and sync condition was maintained.

The samples were filtered, diluted and analyzed by UV Spectrophotometer at 287nm.

Evaluation of in situ gel

Physical Appearance and pH

Clarity of solution is one of the most important characteristic of preparation. The clarity of

solutions was determined by visual inspection under black and white background. The pH

was measured by using a calibrated digital pH meter at 25°C.[19,20,21]

Viscosity

Viscosity of all the formulations was determined using a Brookfield digital viscometer by

using spindle number 2 at 50 rpm. The sample temperature was controlled at 251°C before

each measurements.


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In vitro gelation study

Evaluation for gelling capacity can be measure by visualization method. In this method, 5ml

of 0.1 N HCL was taken in glass tube and maintained at 37°C±1°C. Various parameters like

the time taken for in situ gel formation, visual stiffness of gel and the duration of gel remains

intact was observed.

In vitro floating study

The in vitro floating study was determined using USP dissolution apparatus having 500 ml of

simulated gastric fluid (pH 1.2) at 37°C. The time that formulation took to emerge on the

medium surface (floating lag time) and the time that formulation constantly floated on the

dissolution medium surface (duration of floating) were noted by visual observation.

Drug content

The drug content of solution was carried out by dissolving 5 ml of solution (equivalent to 100

mg of drug) in distilled water in such way to obtain 10mcg/ml concentration of solution. The

drug content of gel was carried out by dissolving 5 ml of the solution (equivalent to 100 mg)

to 100 ml of simulated gastric fluid (0.1 N HCl, pH 1.2) to obtain 10mcg/ml concentration of

solution. Both the sample was filtered and analyzed under UV spectrophotometer at 287nm.

Entrapment efficiency

Entrapment efficiency of drug loaded in situ gel was determined by comparing ratios of drug

content in gel with that of sol. Gel was separated from fluid carefully and proceeded for

determination of content as mentioned above.

The Entrapment efficiency (EE %) was determined by following equation;

In vitro Drug Release

The release of Cefixime Trihydrate inclusion complex from the in situ gel preparations was

determined as described by Zatz and Woodford (1987) with some modification using USP

dissolution test apparatus (USP type II) with a paddle stirrer at 50 rpm. This speed was slow

enough to avoid the breaking of gelled formulation and was maintaining with the mild

agitation conditions believed to exist in vivo. The dissolution medium used was 900 ml of 0.1

N HCl (pH 1.2), and temperature was maintained at 37°C. 5 ml of formulation was drawn up


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in to the dissolution vessel containing dissolution medium with help of pipette without much

disturbance. 5ml of sample from dissolution medium was withdrawn at different time interval

up to 8 hrs and sync condition was maintained. The samples were diluted and analyzed under

UV spectrophotometer at λmax of 287nm.[19,20,22]

Release Kinetics

To analyse the mechanism for the release and release rate kinetics of the dosage form, the

data obtained was fitted in to Zero order, First order, Higuchi matrix, Krosmeyer-peppas and

Hixson-crowell model. The best fitting model was selected by comparing the r² values

obtained from different equations.[23,24]

Stability Studies

Short term stability studies for the ideal formulation F2 was performed at both room

temperature and accelerated temperatures. The in situ gel was stored in amber coloured

bottles and tightly capped. The room temperature storage condition was 25±5˚C and 65% RH

and the conditions for accelerated stability studies was 40±2˚C temperature at Relative

Humidity of 75±5%.[25]

RESULTS AND DISCUSSION

Evaluation Studies

Solubility

Solubility of cefixime Trihydrate pure drug was found to be 51.58 mg/L. The inclusion

complex of drug with HP β-CD showed better solubility in water than β-CD complexes. The

inclusion complex of drug with HP β-CD in ratio 1:1 prepared by kneading method showed

highest solubility that is 1510.9 mg/L.

Drug content

The drug content of inclusion complexes of drug in all the ratios of HP β-CD and β-CD was

found to be more than 80%. This shows that there is minimum amount of drug loss during

complexation. (Table No.1)

In Vitro dissolution

All the prepared inclusion complexes showed increment in %CDR over pure Cefixime.

%CDR of pure Cefixime was found to be 40.45% at the end of 1 hr. Formulation of Cefixime

with HPβCD in different ratios of 1:1, 1:2, and 1:3 showed release of 93.78%, 84.1%,


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78.90% respectively. Formulation of Cefixime with βCD in different ratios of 1:1, 1:2, and

1:3 showed release of 71.18%, 68.88%, 66.45% respectively. Inclusion complexes with

HPβCD showed better %CDR than βCD. Because of presence of hydroxy group in HPβCD

significant improvement in in vitro drug release is observed. (Table No.1) and (Table No.2)

Evaluation of in situ gel

Physical appearance and pH

All prepared formulations were found to be white milky and clear. pH values for all the

formulations was found to be satisfactory in the range of 6.6 to 7.0 as tabulated in Table No.

3.

Viscosities

The results of viscosity measurement of the formulations (solutions and gel) F1 – F6 are

tabulated in Table No. 4. The order of viscosity of formulations containing gellan gum was

F3 > F2 > F1 respectively and the order of viscosity of formulations containing sodium

alginate was F6 > F5 > F4. The observed increase in viscosity with increase in concentration

has been noted previously and was attributed to a consequence of increasing chain interaction

with polymer concentration. The formulations showed a marked increase in viscosity with

increasing concentration of sodium alginate and gellan gum.

In vitro gelation study

Optimum viscosity and gelling capacity (speed and extent of gelation). The formulation

should have ability to undergo a rapid sol–gel transition due to ionic interaction. The gelation

characteristics were assessed on an ordinal scale ranging between + and +++ as shown in

Table 3. Formulations F1and F4 were found to form gels immediately but could not retain

their integrity for 24 hrs. Formulations F2, F3, F5 and F6 were found to form gels

immediately and retain their integrity for more than 24 hrs.

In Vitro floating Study

Prepared formulations was evaluated in SGF. Ca2+ ions react with gelling agent to produce

cross-linking polymer chains (gelation) that provides gel barrier at the surface of the

formulation, entrapping the released carbon dioxide in the formed gel network producing

buoyant formulation. Cross linked three-dimensional gel network restrict the further diffusion

of carbon dioxide and drug molecules and has resulted in extended period of floating and

drug release respectively. The floating lag time of all the formulation was found to be less


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than 1 min and the duration of floating for all formulations was found to be more than 24 hrs

except F1 and F4 as tabulated in Table No. 3.

Drug content

The drug content was found to be in acceptable range for all formulations. Percentage drug

content of solutions was found to be in the range of 96.13 to 98.82% and percentage drug

content of gels was found to be in the range of 92.88 to 97.03%. Results show that there is

insignificant loss of drug during formulation.

Entrapment efficiency

Drug entrapment efficiency of formulations was found to be in the range of 96.61 to 98.19%.

In vitro drug release

The cumulative percentage drug release from formulations (F4 – F6) containing different

concentration of gellan gum (0.5, 0.75, 1.0% w/v). At the end of 8 hrs drug release found to

be 64.82%, 89.02%, 76.79% respectively for formulations F1, F2, F3.

Figure No. 2 and Table No. 5 shows the cumulative percentage drug release from

formulations (F1 – F3) containing different concentration of sodium alginate (1.0, 1.5, 2.0%

w/v). At the end of 8 hrs drug release found to be 73.16%, 84.98%, 62.41% respectively for

formulations F4, F5, F6. By this concluded F2 showed maximum drug release i.e. 89.02%.

(Table no.4)

Release kinetics

All the formulations in this study were best expressed by Higuchi‟s diffusion equation, as the

plots showed high linearity (r2=0.9799 to 0.9949. To confirm the diffusion mechanism, the

data were fitted to Korsmeyer-peppas model. All formulations showed good linearity

(r2=0.8973 to 0.9493), with slope (n) values ranging from 0.2328 to 0.3413 indicating that the

release mechanism was Fickian release (n0.45).

Stability studies

The room temperature storage condition was 25±5˚C and 65% RH and the conditions for

accelerated stability studies was 40±2˚C temperature at Relative Humidity of 75±5%.

Stability was tested for 30 days. No significant changes were observed in final formulation

F2. Therefore, it is concluded to be stable.


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Table 1: Data showing results for evaluation of cefixime trihydrate inclusion complex

with hpβcd.

Cefixime Trihydrate : HP-β-Cyclodextrin complex

Ratio Solubility

(mg/L)

Drug Content

(mg) %CDR

1:1 1510.9 46.46 93.78

1:2 1315.8 32.80 84.1

1:3 1040.2 23.04 78.90

Table 2: Data showing results for evaluation of cefixime trihydrate inclusion complex

with βcd.

Cefixime Trihydrate : β-Cyclodextrin complex

Ratio Solubility

(mg/L)

Drug Content

(mg) %CDR

1:1 1064.6 43.04 71.18

1:2 310.9 31.09 68.88

1:3 225.6 22.07 66.45

Table 3: Data showing results of evaluation of in situ gel.

Formulation

code Appearance pH

In vitro

floating lag

time (min)

In vitro

floating

time (hrs)

Gelling

capacity

F1 White milky

solution 6.7 ± 0.05 <1 20 ++

F2 White milky

solution 6.9 ± 0.05 <1 >24 +++

F3 White milky

solution 6.6 ± 0.1 <1 >24 +++

F4 White milky

solution 6.8 ± 0.05 <1 20 ++

F5 White milky

solution 6.9 ± 0.1 <1 >24 +++

F6 White milky

solution 7.0 ± 0.1 <1 >24 +++

Table 4: Data showing results of evaluation of in situ gel.

Formulation

code

Viscosity

(Sol)

(cps)

Viscosity

(Gel)

(cps)

%Drug

Content

(Gel)

%Drug

Content

(Sol)

%Drug

Entrapment

Efficiency

%CDR

F1 249 802 93.94 ± 0.7 96.86 ± 0.1 96.97 ± 0.9 64.82 ± 0.44

F2 252 879 97.03 ± 0.6 98.82 ± 0.3 98.19 ± 0.9 89.02 ± 0.46

F3 292 952 94.83 ± 0.3 97.84 ± 0.1 96.92 ± 0.2 76.79 ± 0.46

F4 308 827 94.34 ± 0.7 97.11 ± 0.3 97.15 ± 1.0 73.16 ± 0.66

F5 312 873 95.97 ± 0.4 97.84 ± 0.3 98.08 ± 0.3 84.98 ± 0.46

F6 366 932 92.88 ± 0.5 96.13 ± 0.3 96.61 ± 0.2 62.41 ± 0.48


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Fig. 1: Comparison of in vitro release profile of Cefixime Trihydrate pure drug with the

ideal formulation F2.

CONCLUSION

Inclusion complex of Cefixime Trihydrate was prepared by using HPβCD for solubility

enhancement and significant changes have been observed in solubility of the drug.

Compatibility study of drug and polymer was determined by IR spectrophotometer. The IR

spectra revealed that there was no interaction between polymers and drugs, hence they are

compatible. The pH of all formulations was found to be satisfactory within the range of 6.6 -

7.0 thus there would be no irritation to patients upon administration of the formulation. In

vitro gelation studies revealed that, the in situ gelling systems formed gel instaneously when

comes in contact with SGF and floats for longer duration. The formed gel would enhance the

gastro retentive time of Cefixime Trihydrate in stomach. The drug content of solution and gel

was within acceptable range of 85 to 115% which ensured dose uniformity in the

formulation. The drug content was maximum for F2. Drug entrapment efficiency of all the

formulations was found to be more than 95% which indicates that there was no significant

loss of drug during formulation. The in vitro release studies revealed that, initially there was

burst effect then followed by sustained release. The formulation F2 showed maximum drug

release and was considered as ideal formulation based on several parameters such as

Viscosity, In vitro Floating time, Drug content, Drug entrapment efficiency and In vitro drug

release. Ideal formulation F2 was compared with pure drug formulation which shows


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significant increase in in vitro drug release. The results of kinetic data suggested that all the

formulations followed Higuchi model by diffusion mechanism. The „n‟ values obtained from

Korsmeyer Peppas equation suggested that, all the formulations showed drug release by

Fickian diffusion mechanism. Stability studies were carried out for 30 days as per ICH

guidelines in normal conditions and accelerated conditions. Cefixime Trihydrate in situ gel

was found to be stable at the end of 30 days.

ACKNOWLEDGEMENTS

Authors are thankful to Lupin Pharmaceuticals for providing Cefixime Trihydrate as a gift

sample for this work. The authors are also thankful to the KLE College of Pharmacy,

Belagavi for providing instruments to carry out this work.

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FORMULATION AND EVALUATION OF ORAL FLOATING IN SITU