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Submitted by
S.Marimuthu
Reg no: 01108912025
Under the guidance of,
Mr. A. Shanmugarathinam., M.Pharm., (ph.D)LecturerDepartment of pharmaceutical technology,Anna University TiruchirappalliTiruchirappalli-24
FORMULATION AND STUDY OF THE EFFECT OF
FORMULATION VARIABLES ON SUSTAINED RELEASE
CEFUROXIME AXETIL FLOATING MICROSPHERES
INTRODUCTION
Microspheres:
Microspheres are characteristically free flowing powder, ideally having
a particle size less than 200µm and are widely used as a carrier for controlled
release.
Method of preparation:
Single emulsion technique
Double emulsion technique
Polymerization
Spray drying
Solvent evaporation
Flow chart for solvent evaporation method
Drug and polymer dissolved in organic
solvent
Continuous phase with surfactant
Emulsification with aid of surfactant
Evaporation of organic solvent with
the aid of stirring
Filtration and drying
Powdered microspheres
Need of Gastro retention
More often the oral drug absorbtion is unsatisfactory and highly variable between
individuals to individuals, despite excellent Invitro release patterns of the dosage
form
The reason for that, especially variability of gastric transit time in the GI tract.
So the researcheres has involved in the development of gastroretentive dosage forms.
Different techniques for Gastro retention
Floating drug delivery system
Bioadhesive system
High density system
Swelling & expanding system
Floating drug delivery system
In floating drug delivery system, one such approach is floating
microspheres (Hollow microspheres)
Hollow microspheres are low density Spherical particles with out core
that have sufficient buoyancy to float over gastric contents and remain
in stomach for Prolonged period.
Mechanism of hollow microspheres formation
Advantage of floating microspheres
Improves patient compliance
Enhances the bioavailability
Controlled release of drug for prolonged period
Site specific drug delivery to stomach
Reduces the adverse reactions
Superior to single unit floating dosage forms due to no risk of dose dumping
Infectious diseases
0
1
2
3
4
5
6
1
Whooping cough
Tetanus
measules
Malaria
Diarrhea
RespiratoryinfectionRound worm
Tuberculosis
Hepatitis
millions
Global deaths due to infectious diseases
Drug profile
Name : Cefuroxime axetil
Molecular formula : C20H22N4O10S
Molecular weight : 510.48
Pharmacologic class : Second-generation cephalosporin
Therapeutic class : Anti-infective Use: : Treatment of susceptible infections of the upper and lower respiratory tract, otitis media, sepsis, uncomplicated
gonorrhea.
• Mechanism of Action Inhibits bacterial cell wall synthesis
• Protein binding: 33% to 50%
• Bioavailability: Tablet: Fasting: 37%; Following food: 52%
• Half-life elimination: Children: 1-2 hours; Adults: 1-2 hours.
• Dose: 250-500 mg, bid dose
HYPOTHESIS
The drug cefuroxime axetil has low oral bioavailability (37 -52%)
and it prescribed as bid or tid dose because of its short biological half life (1-
2 hrs). The reduced oral bioavailability of drug due to
1. Drug degraded in the intestinal environment.
2. Drug follows saturation absorption kinetics .
So if the drug formulated as a gastroretentive microspheres, the oral
bioavailability of drug can be increased by avoiding the entry of drug in to
the intestine and can increasing the dosing interval of drug by sustained
release microspheres.
OBJECTIVES
• To improve the oral bioavailability of the drug cefuroxime axetil by
preparing gastroretentive microspheres.
• To reduce the dosing frequency of the drug cefuroxime axetil by preparing
sustained release microspheres.
• To characterize the effect of stirring time, continuous phase volume,
dispersing phase volume, and drug to polymer ratio on the properties of
microspheres.
EXPERIMENTAL METHODS
Preformulation studies
Solubility studies:
Cefuroxime axetil:
The drug cefuroxime axetil found to be freely soluble in ethanol,
dichloromethane, acetone and dichloromethane. But the drug cefuroxime
axetil slightly soluble in water.
Ethylcellulose:
The polymer ethylcellulose found to be freely soluble in ethanol,
dichloromethane and chloroform. But it insoluble in water.
Standard Graph for Cefuroxime Axetil in 0.1 N Hcl
Concentration µg/ml
Absorbance
2 0.0905
4 0.1737
6 0.2583
8 0.3435
10 0.4369
COMPATIBILITY STUDIES
FT-IR spectra of cefuroxime axetil pure drug
Spectrum Name: Cefuroxine Axetil pure drug
4000.0 3000 2000 1500 1000 400.0
0.0
10
20
30
40
50
60
70
80
90
100.0
cm-1
%T
3469.20
2947.20
2822.94
1779.191677.68
1595.39
1390.21
1332.45
1245.28
1157.45
1071.34
943.12
873.25
757.52
592.10487.65
FT-IR spectra for Ethyl cellulose polymer
Spectrum Name: Ethil Cellulose.
4000.0 3000 2000 1500 1000 400.0
0.0
10
20
30
40
50
60
70
80
90
100.0
cm-1
%T
3970.96
3430.87
2978.04
2908.17
2130.64
1711.12
1591.39
1374.42
1227.18
1110.55
917.35
879.88
584.78
535.35
FT-IR spectra of mixture of cefuroxime axetil and Ethyl cellulose (1:1)
Spectrum Name: Cefuroxime +Ethyl cellulose.
4000.0 3000 2000 1500 1000 400.0
0.0
10
20
30
40
50
60
70
80
90
100.0
cm-1
%T
3472.16
2979.46
2935.75
2612.59
2369.07
1738.67
1677.66
1597.64 1385.231335.44
1215.44
1070.83
946.26
876.48
759.23
588.62
Comparison of functional group region in the IR- spectrum
Functional
group of drug
Corresponding
region in the
spectrum of
pure drug (cm-)
Corresponding
region in the
spectrum of
drug and polymer
mixer (cm-1)
Limits (cm-1)
C – S (stretch) 592.1 584.78 705 - 570
C = O
(carbonyl)1677.681 1677.66 1760 - 1670
C – N
( stretch)1071.34 1070.83 1090 - 1020
NH - amide 3469.20 3472.16 3500 - 3300
C - C 943.12 946.26 1300 - 700
The spectrum of a mixture of drug and polymer was compared with the
standard spectra of drug and polymer. It could be observed that, very slight
shift in the region which confirms there was no drug and polymer
interaction.
PREPARATION OF MICROSPHERESMicrospheres prepared by solvent evaporation method
Variables used in the microspheres formulations
Materials used F1 F2 F3 F4 F5 F6 F7 F8 F9
Drug: polymer
ratio1: 1.5 1: 1.5 1: 1.5 1: 1.5 1: 1.5 1: 1.5 1: 1.5 1: 1 1: 2
Organic phase
volume (ml)10 10 10 16 5 10 10 10 10
Aqueous phase
volume (ml)50 100 150 100 100 100 100 100 100
Stirring time
(min)30 30 30 30 30 60 90 30 30
Physical characterization of microspheres
1. Percentage yield
Percentage yield = (Weight of microspheres recovered / weight of non
volatile component added) x 100
2. Particle size determination – by optical microscopic method
3. Drug entrapment efficiency [DEE]
DEE = [amount of drug actually present / theoretical drug loaded expected]
x 100.
4. Bulk density
Density = Weight of microspheres taken (gm) / Volume occupied by
microspheres in (ml)
5. Floating behavior of microspheres
Percentage buoyancy = (weight of microspheres floated after time t / Initial
weight of microspheres) x100
6. Morphological study using SEM
7. In-vitro release in 0.1N Hcl
8. In-vitro release kinetic studies
RESULTS
Percentage yield : 68.8 to 82.5%
Drug entrapment efficiency : 60.7 to 75.7%
Mean particle size : 58.52 to 77.36µm
Percentage buoyancy : 62.12 to 81.23%
Bulk density : 0.2610 to 0.5217 gm/ml
In-vitro release : 73.47 % to 89.78%
SEM photographs of microsphere formulation F9
SEM Photograph of formulation F9 at 5000 magnification level
SEM Photograph of formulation F9 at 15000 magnification level
Photographs revealed that, the microspheres were spherical and uneven surfaces. This tendency of the microspheres surface was most probably resulted from the mechanism of solvent evaporation
Discussion
Preparation of microspheres
The Cefuroxime axetil sulfate is a slightly water soluble drug, so aqueous
solution used as a continuous phase in the preparation of microspheres
which reduces the partition of drug in to the continuous phase. Tween 80
used as emulsifying agent which has the HLB value of 15 and is expected
to reduce the interfacial tension between the two immiscible phases.
Solvent combination
In this study mixture of ethanol and dichloromethane used for the
microspheres preparation. Because when non- polar solvent
dichloromethane used alone the polymer get precipitated rapidly at the
time of mixing with water. So to reduce the non- polarity of the
dichloromethane, ethanol was added to that solvent. During microspheres
formation ethanol gets diffused in to the water and dichloromethane was
evaporated.
Effect of continuous phase volume
In microspheres preparation, when the continuous phase volume was
increased from 50 ml to 100 ml and 150 ml
The yield and entrapment efficiency was decreased due to increasing the
partition of drug in to the continuous phase when the continuous phase
volume was increased
Continuous phase volume does not have significant effect on particle size,
floating behavior, and in- vitro release of drug from microspheres.
Formulation code
Continuous phase volume
(ml)Yield (%)
Entrap ment efficiency
(%)
F1 50 77.5 68.2
F2 100 73.5 62.1
F3 150 71.75 60.7
Effect of internal phase volume (organic phase)In microspheres preparation, the volume of Internal phase increased
from 5ml to 10ml and 16ml
Particle size of the microspheres decreased with increasing internal phase volume.
This can be explained as in less amount of solvent, the polymer solution was more
viscous which produce larger droplet when poured in to the continuous phase, so
particle size was increased.
Entrapment efficiency of drug in microspheres was decreased with increasing the
internal phase volume. This may due to the movement of drug particle from
internal phase to continuous phase was increased because of decreasing the
viscosity of drug: polymer solution.
Formulation code
Internal phase
volume (ml)
Entrapment efficiency (%)
Particle size (µm)
F4 5 75.7 77.36F1 10 68.2 70.26F5 15 60.9 69.18
Effect of drug: polymer ratio
In microspheres preparation, when the drug: polymer ratio
increased from 1:1 to 1:1.5 and 1:2
Entrapment efficiency of the drug in microspheres was increased with
increasing drug: polymer ratio because increased polymer amount provides
more binding site for the drug molecules.
Particle size of the microspheres was increased with increasing drug:
polymer ratio. This can be explained as when the drug: polymer ratio was
increased the polymer solution was more viscous which produce larger
droplet when poured in to the continuous phase, so particle size was
increased.
In- vitro drug release was decreased with increasing drug: polymer ratio
due to increasing the diffusional path length for drug molecules
Formulation code
Drug: polymer
ratio
Entrapment efficiency (%)
Particle size (µm)
Percentage of drug release
F8 1:1 62.8 63.94 89.78
F1 1:1.5 68.2 70.26 78.99
F9 1:2 74.2 75.68 73.47
In- vitro dissolution
Among the all of the formulation, formulation F8 shows highest drug
release of 89.78% and formulation F9 shows least drug release of 73.47%.
This may be due to the changes in the drug: polymer concentration
(F8- 1:1, F9- 1:2). Only changes in the drug: polymer ratio has significant
effect on the in- vitro drug release. All other variables has not such effect
on the in –vitro drug release.
In- vitro release kinetics
Regression co-efficient (r2) values for microspheres formulations
Kinetic models
F1 F2 F3 F4 F5 F6 F7 F8 F9
Zero order
0.991 0.954 0.995 0.801 0801 0.757 0.776 0.798 0.861
First order
0.978 0.988 0.929 0.981 0.984 0.978 0.99 0.978 0.983
Hiquchi 0.941 0.979 0.927 0.993 0.992 0.997 0.996 0.995 0.984
Hixson- crowell
0.992 0.987 0.943 0.982 0.984 0.981 0.983 0.972 0.985
n and r2 values from Korsemeyer Peppas model
Formulation code
n- values r2 value Mechanism of release
F1 0.853 0.985Case II or Zero order release, (non- fickian) it refers the dominant mechanism for drug transport is due to polymer matrix relaxation
F2 0.621 0.984Anomalous transport (non- fickian), refers to the coupling of Fickian diffusion and polymer matrix relaxation
F3 0.879 0.991Super case II transport. It refers in addition to diffusion, other release mechanism including matrix erosion and polymer relaxation might be involved
F4 0.514 0.991
Anomalous transport (non- fickian), refers to the coupling of Fickian diffusion and polymer matrix relaxation
F5 0.556 0.995F6 0.498 0.996F7 0.537 0.996F8 0.574 0.991F9 0.534 0.981
Most of the formulations follow Hiquchi release kinetics which indicated
that the release was diffusion controlled and also it shows anomalous
transport (non- fickian) which indicated the coupling of Fickian diffusion
and polymer matrix relaxation.
Conclusion
In this research work attempt was made to increase the bioavailability
of cefuroxime axetil by formulating floating microspheres. Formulation
was successfully made and in –vitro evaluation of floating microspheres
shows encouraging results. By these evaluations following statement
can be concluded
(i) No interaction between the drug and polymer was confirmed.
(ii) The desired yield and entrapment efficiency was obtained.
(iii) It shows good buoyancy over 12 hrs in the acidic medium.
(iv) It provides sustained release of drug over more than 12 hours.
(v) Drug release from microspheres follows coupling mechanism of fickian
diffusion and polymer matrix relaxation.
(vi) The drug: polymer ratio has significant effect on the all characteristics of
microspheres but other variables have effect on only few characteristics of
the microspheres.
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