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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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Dandagi et al. World Journal of Pharmacy and Pharmaceutical Sciences
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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Dandagi et al. World Journal of Pharmacy and Pharmaceutical Sciences
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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