03 Hiral

Available at www.ijmpronline.
com 31 Int J Mod Pharm Res/Vol 1/Issue 2/Sup/Dec 12

Hiral et al.,Dispersible tablets of cefixime

Volume 1, Issue 4

FORMULATION DEVELOPMENT AND EVALUATION OF THE DISPERSIBLE
TABLET OF CEFIXIME

Hiral Patel*, Naresh Patel, Hitesh Patel
SLPTPMC, Amreli, Gujarat, India

Received 05 Dec 2012; Revised 17Dec 2012; Accepted 23 Dec 2012

Key words: Dispersible tablet, Pharmaceutical exicipients, Disintegrants, Disintegrating
Time.

INTRODUCTION
Tablets are solid preparations each containing asingle dose of one or more active substances
andusually obtained by compressing uniform volumes ofparticles. Tablets are intended for
oraladministration. Some are swallowed whole, after being chewed, some are dissolved or
dispersedin water before being administered and some areretained in the mouth where the
active substance isliberated
[1]
.Tablets are the most widely used dosage formbecause of its
convenience in terms of self administration, compactness and ease in manufacturing. But
paediatric and geriatric patients may encounter inconvenience in swallowing it. To overcome
INTERNATIONAL J OURNAL OF
MODERN PHARMACEUTICAL RESEARCH
Research Article
ABSTRACT

In present research work, dispersible tablets of cefixime were formulated using direct compression
technique using various granulation techniques and different disintegrating agents by various
Pharmaceutical Exicipients. Cefixime is an advanced-generation, broad-spectrum cephalosporin
antibiotic approved for the treatment of acute bacterial exacerbation of chronic bronchitis (AECB),
group-A beta haemolytic streptococcal pharyngotonsillitis, and uncomplicated skin/skin structure
infections in adult and adolescent patients. Cefixime has slightly bitter taste, poor flow propertyand
poor water solubility. In this research work, initially the poor flow property was improved by
comparing various granulation techniques via Trial-1 wet granulation, Dry granulation Trial-2 Lactose,
Micro crystalline cellulose powder (MCCP), Carboxymethylcellulose (CMC) Calcium, Sodium lauryl
Sulphate (SLS), and Croscarmellose Sodium (CCS) and Polyvinylpyrrolidone (PVP) K30 and Trial-3
by Dry granulation MCCP, Maize starch and PVP K30. The optimized formulation i.e. Trial-3MCCP,
Maize starch, PVP K30 was incorporated with various Disintegrnat like SSG, CCS and Crospovidone
which is encoded as Trial-3A, Trial-3B and Trial-3C respectively. The prepared tablets were evaluated
by various post-compession parameters. Among 3 Batches Trial-3C using Crospovidone was found
optimized since it had expressed Disintegrating Timeof 20 sec and 99.98 0.023 % CDR within
55min and furthermore also found better when compared with other marketed ODT of Cefixime.

ISSN
2319 5878

Available at www.ijmpronline.com 32 Int J Mod Pharm Res/Vol 1/Issue 2/Sup/Dec 12


this problem, in recent years increasingattention has been focused in formulating
fastdissolving and dispersible tablets that are intended todissolve or disintegrate rapidly in the
mouth. Tabletdisintegration has been considered as the ratelimiting step in faster drug
release.
[2]

Recent advances in Novel Drug Delivery System(NDDS) aims to enhance safety and efficacy
of drugmolecule by formulating a convenient dosage formfor administration and to achieve
better patientcompliance. Tablets are the most widely utilized oraldose format. A novel tablet
concept which offers easeof oral administration and increasedpatient compliance is the
fastdissolving/disintegrating tablet (FDDT)
[3]
. Dispersible tablets are uncoated tablets
intended tobe dispensed in water before administration giving ahomogenous dispersion. The
tablets produced musthave the ability to form adequate dispersion which isuniform and stable
when placed in water. The chiefadvantage is quicker absorption and onset of clinicaleffects.
They are generally prepared for geriatric or paediatric patients or for those who are
havingdifficulty in swallowing tablets. They comprise oftotally water soluble excipients and
components.Dispersible tablets disintegrate either rapidly inwater, to form a stabilized
suspension, so, its preferred for paediatric patients who cannot swallow asolid dosage form
and the API is unstable ifformulated in liquid formulation, also helpful forpatients having
prolonged illness who are prone tonauseatic sensations if they have to swallow a tablet.The
added advantage of this formulation is fasteronset of action as compared to standard
compressedtablet.
[4]
The properties of the water dispersible tablet,such as porosity, hardness,
disintegration time andincrease in viscosity after dispersion are necessary toinvestigate during
manufacturing which decides theproduct performance. Dispersible tablets as definedin Ph.
Eur. are uncoated or film coated tabletsintended to be dispersed in water beforeadministration
giving a homogeneous dispersion.Typically a dispersible tablet is dispersed in about 5-15 ml
of water and the resulting dispersion isadministered to the patient.
[5]

Cefixime is an advanced-generation, broad-spectrum cephalosporin antibiotic approved for
the treatment of acute bacterial exacerbation of chronic bronchitis (AECB), group-A
betahemolytic streptococcal pharyngotonsillitis, anduncomplicated skin/skin structure
infections in adult and adolescent patients. Cefixime has slightly bitter taste, poor flow
propertyand poor water solubility.So in case of acutebacterial exacerbation of chronic
bronchitis (AECB) group-A beta-haemolytic streptococcal pharyngo tonsillitis, and
uncomplicated skin/skin structure infections it requireimmediate release of drug from the
dosage form, which make Cefixime suitable candidate for dispersible tablets.
[6]
The purpose


of the study to formulate Dispersible tablet of Cefixime is to provide fast release of drug,
enhanced dissolution and solubility of drug, rapid onset of action may improved bioavaibility
and improve dispersion of the drug in water bycompression technique using various
granulation techniques and different disintegrating agents by various Pharmaceutical
Exicipients and also not compared with the marketed formulations which have not been done
yet.
Flow properties of Pure drug and Granules Bland
Angle of repose
[8-13]

Where h =height of the heap and r =radius of the heap.
Density and compressibility measurement
[8-13]

Bulk density

Tapped density

Carrs index (or) % compressibility
Carrs index (%) =[(TBD LBD) 100] / TBD
Where,
Dt is the tapped density of the powder.
Db is the bulk density of the powder.
Hausners ratio
Hausner ratio is an indirect index of ease of powder flow. It is calculated by the following
formula.

DRUG-EXCIPIENT PHYSICAL COMPATIBILITY STUDY
[8,12]
Differential scanning calorimetry (DSC) measurements were carried out on a scanning
calorimeter (DSC Q10 V9.0 Build 275, UniversalV4.1D TA Instruments). The instrument
was calibrated using indium as standard. Samples (5-10mg) were placed in sealed aluminium


pans and heatedfrom 70oC to 160oC at a rate of 10oC/min undernitrogen atmosphere (60
ml/min), with empty pan asreference.
General Formulation Design Cefixime Dispersible Tablet

Table 1: General Formulation Design Cefixime Dispersible Tablet
Ingredients Drug excipients ratio
Binder 3%
Disintegrant 0.5%
Diluent 1:1
Wetting agent 0.5%
Lubricants 2%
Glidant 1%
Sweetener 2.5%
Flavour 2.5%

Procedure for granulation
Accurately weigh all the ingredients, Pass Lactose, MCCP, CMC Calcium, SLS, CCS from
sieve no. 40#, Mix all the above sifted materials and granulate manually by binder solution of
water and PVP K30, Dry the above wet mass at 60
o
C for 1 hours in FBD. Dried materials sift
through sieve 20#. Final sifting the remaining ingredients except Cefixime and aerosil,
through sive no 40#.Cefixime and aerosil is passed through Sieve no 30#and co-sift.
Magnesium stearate is sifted and kept separately.Mix all the above sifted materials with
granules in polybag except magnesium stearate than mix the magnesium stearate at the time
of compression for 5 minutes.
[6,8]

Determination Flow properties of Granules Blend:
The various flow properties like Angle of repose, Bulk density, tapped density, carrs
compressibility and hausner ratio as per procedure mentioned above.



Table 2: Formulation of granules
Ingerdients Granules 1 Granules 2 Granules 3
Lactose 60 52 ----
MCCP 89 97 108
Maize starch --- --- 49
PVP K30 3 3 3
CMC Calcium 17 --- ----
SLS 2 2 ----
CCS 6 6 ----
Water Q.S Q.S Q.S
Total 177 160 160

Table 3: Formulation of dispersible tablet

Ingredients
Trial 1

Trial 2
by compaction of
API and CMC
Calcium.
Trial 3
by
compaction of
API, CMC
Calcium,
CCS, SLS.
Qty. taken for 1 tablet in (mg)
Cefixime 100 100 100
Lactose monohydrate --- ---- ----
Granules 177 160 160
MCCP --- ---- ----
CMC Calcium --- 17 17
SLS --- ---- 2
CCS --- ---- 6
PVP K30 --- ---- ----
Pipperment DC 117 2.5 2.5 2.5
Bitter masking agent 2.5 2.5 2.5
Neotam 1 1 1
Crospovidone 2 2 2
Aerosil 3 3 3
Magnesium Stearate 3 3 3
Water Q.S ---- ----

Crosspovidone is added because of its erodision effect and better super disintegrant compare
to CCS and incorporation of CCS is because of its good swelling effect which necessary to
formulate a better dispersible tablet.


Table 4: Formulation Design for using Disintegrants before Compression of Optimized
Trial-3

Ingredients
Trial 3A
SSG
Trial 3B
CCS
Trial 3C
CROSSPOVIDONE
qty. taken for 1 tablet in (mg)
Cefixime 100 100 100
Granules
(MCCP+MAIZE
STRACH+PVP
K30+WATER)

160

160

160
CMC Calcium 17 17 17
SLS 2 2 2
CCS ---- 8 ----
Crospovidone ---- ---- 8
SSG 8 ---- ----
Magnesium Stearate 4 4 4
Pipperment DC 117 2.5 2.5 2.5
Bitter masking agent 2.5 2.5 2.5
Neotam 1 1 1
Aerosil 3 3 3
SLS 1 1 1
Magnesium Stearate 3 3 1.5

SLS added in both as intragranular and as well as extra granular because SLS intragranular
plays a vital role as it act as a surface active agent which helps to disintegrate the granules
while SLS added in extra granular because its help in immediate disrupt of the dispersible
tablet when comes in contact with water due to insoluble in water.
EVALUATION OF DISPERSIBLE TABLETS
[6,8,11-14]

Weight variation
Twenty tablets were weighed individually and the average weight was determined. The %
deviation was calculated and checked for weight variation. Not more than 2 of the individual
weight deviate from the average weight and none deviate by more than twice of that
percentage.
Thickness
The thickness of prepared tablets was measured using a Verniercaliper. Five tablets from
each batch were used for this test. The mean and standard deviation of each batch were
calculated.



Appearance
The general appearance and elegance of tablet was identified visually, which include tablet
size, shape, color, presence or absence of an odor, taste, surface texture etc.
Hardness
Tablet hardness (tablet crushing strength) is defined as the force required for breaking a tablet
in a diametric compression test. Tablets required a certain amount of hardness or strength to
withstand mechanical shocks of manufacturing, packaging, and shipping. Hardness of the 5
tablets from each batch was measured using Monsanto hardness tester.
Friability
Friability test is performed to assess the effect of friction and shocks, which may often cause
tablet to chip, cap or break. Friability of the tablets was determined using Roche Friabilator
(Erection and Instrumentation Engineers). This device subjects the tablets to the combined
effect of abrasions and shock in a plastic chamber revolving at 25 rpm and dropping the
tablets at a height of 6 inches in each revolution. Preweighed sample of tablets were placed in
the Friabilator and were subjected to 100 revolutions. Tablets were deducted using a soft
muslin cloth and reweighed. The friability (f) is given by the formula.

Disintegration test
The device to test disintegration use is 6 glass tubesthat are 3 inches long, open at the top and
heldagainst a 10 mesh screen at the bottom end to thebasket rack assembly. To test for
disintegration time,one tablet is placed in each tube, and the basket rack is positioned in a 1
litre beaker of water, Phosphate buffer pH 6.8 at body temperature such that the tablet remain
2.5 cm belowthe surface of the liquid on their upward movementand descend not closer than
2.5 cm from the bottomof beaker. A standard motor device is use to move thebasket assembly
containing the tablet up and down through a distance of 5-6 cm at a frequency of 28-32cycles
per minute. To be in compliance with USPstandards the tablets must disintegrate and all
theparticles must pass through 10 mesh sieve in the timespecified
Dissolution test of optimized Trial batch
[6,8]

The tablets were evaluated for in vitro drug release was carried out using USP dissolution
apparatus. The following conditions were applied. For dispersible tabletUSP Dissolution
apparatus Type II (Paddle) Media Phosphate buffer pH 6.8 Volume of dissolution medium
900ml Speed of paddle rotation 50 RPM temperature 37.0 0.5C Sampling point 5, 10, 15,


30, 45, & 60 min interval, 5ml sample withdrawn and further diluted. The absorbance was
taken at 257 nm determined by UV (shimadzu-1800).
Stability study
[17]

The stability study was carried out for optimized formulation as per ICH guidelines (Feb.
2003). Various ICH storage conditions are available which are as 25C 2C (60%
5%RH), 30C 2C (65% 5%RH) and 40C 2C (75% 5%RH). The Cefixime DT of
the best formulation were placed in screw capped glass and stored at various ICH storage
condition for a period of 60 days. The samples were analyzed for physical appearance,
Disintegrating Time and for the % CDR at regular interval of 15 day.
[17]

RESULTS AND DISCUSSION
Preformulation parametersphysical mixture
Table 5: Preformulation parameters
Sr. No. Bulk
density
gm/ml
Tapped
density
gm/ml
Carrs
index
%
Hausners
ratio
Angle of
repose
Pure Drug 0.276 0.368 25% 1.33 46
Trial 1 0.482 0.597 14% 1.17 25
Trial 2 0.529 0.616 13% 1.14 23
Trial 3 0.623 0.717 11% 1.11 20

The taste of the Cefixime was checked and it was found very bitter, odour found pungent and
colour was found yellowish white.The angle of repose for the Cefixime found 46
0
.It is
compared with which indicates poor flow property.The bulk density for Cefixime was found
0.276gm/ml. The tapped density for Cefixime was found 0.368gm/ml. The Carrs index for
Cefixime found 25.00%. It is compared with which indicates poor flow property. The
Hausners ratio for Cefixime found to 1.33, It is compared with which indicates poor flow
property. The angle of repose for the physical mixture of Cefixime found in range 20
0
to
25
0
.The bulk density for the physical mixture of Cefixime was found in range 0.482gm/ml to
0.623gm/ml.The tapped density for the physical mixture of Cefixime was found in
range0.597gm/ml to 0.717gm/ml. The Carrs index for the physical mixture of the Cefixime
was found in range 11% to 14%. The Hausners ratio for the physical mixture of the


Cefixime was found in range 1.11 to 1.17. It shows that the improved flow property of the
Cefixime after granulation technique and different formulation used in three trial. From
Trial-1 using granules,Trial-2 using granules and compaction of API and CMC Calcium,
Trial-3 using granules and compaction of API, CMC calcium, CCS, SLS.The bulk density,
tapped density, carrs index,hausners ratio and angle of repose of the trial 3 shows the
excellent flow property when compared to others.
Post-compression parameters
Post-compression parameters show all batches was evaluated for Thickness, Hardneess, D.T.
and % friability and was found within I.P. limit. Trial-3 i.e. base granule-2 batch shows better
results having thickness 3.81-3.85 mm, hardness 5.5-6 kg/cm
2
, friability 0.75% and lowest
Disintegrating Time of 1.5 mins which was found better than other batches. So Batch Trial-3
was optimized batch for further tableting procedure. Above optimized batch Trial-3 was
further incorporated with different Disintegrating agent viz SSG, CCS and Crosspovidone
and batches encoded as TRIAL-3A, TRIAL-3B andTRIAL-3C respectively. The resultant
formulation shows little variation in Thickness, Hardneessand % friability but remarkable
difference in Disintegrating Time. The Disintegrating Time was found 2 Mins, 54 secs and 20
sec of TRIAL-3A, TRIAL-3B and TRIAL-3C respectively and further proceed for
evaluating.

Table 7: Post-compression Parameters offormulated tablets characteristics
PROPERT
IES
TRIAL-1 TRIAL-2

TRIAL-3

TRIAL-
3A
(SSG)
TRIAL-
3B
(CCS)
TRIAL-3C
(CROSSPOV
IDONE)
Thickness 3.81-3.84 mm 3.82-3.85 mm 3.81-3.85
mm
4.81-4.84
mm
4.82-4.85
mm
4.91-5.00 mm
Hardness
4-6 kg/cm
2
5-7 kg/cm
2

5.5-6
kg/cm
2

6-8 kg/cm
2

5-7
kg/cm
2

4-6 kg/cm
2

D.T. 8 mins 12 mins 1.5 mins 2 mins 54 secs 20 secs
% Friability 0.7 % 0.78 % 0.75 % 0.67 % 0.8 % 0.55 %
Avg. Wt. 300mg 300mg 300mg 300mg 300mg 300mg

Comparison of optimized Formulation Trial -3c with Marketed Formulations:
The Optimized Batch Trial-3C was compared with marketed Cefixime brands. There were no
much more differences found in all 3 compared tablets in Shape, hardness, taste, colour and %
friability but D.T. was minimum of optimized formulation i.e. 20 secs comparing to Brand-1 54 secs


and Brand-2, 1.1 mins. So it provesTrial-3C was formulation which shows better disintegration time
of Cefixime Dispersible Tablet than the marketed brands.

Table 8: Comparison of Optimized Formulation Trial-3C with marketed Dispersible
Formulations
PARAMETERS Brand-1 Brand-2
CP DT
(OPTIMIZED
BATCH
Trial- 3C)
Avg. Wt. 300 mg 300 mg 300 mg
Thickness 3.9-3.93 mm 4.13-4.15 mm 4.91-5.00 mm
Hardness 5.5 kg/cm
2
4.5 kg/cm
2
4.2kg/cm
2

% Friability 0.55% 0.60% 0.50%
D.T. 54 seconds 1.1 min 20 seconds

In-vitro Dissolution profile. The in- vitro dissolution profile of optimized batch Trial-3C shows 99.98 .5
% CDR within just 40 to 55 mins of time which is impacting that Crosspovidone fast disintegrating
agent comparing to SSG and CCS

Figure 1: Dissolution Profile of Optimized Formulation Trial-3C

CONCLUSION
In case of acute bacterial exacerbation of chronic bronchitis (AECB) group-A beta-
haemolytic streptococcal pharyngotonsillitis, and uncomplicated skin/skin structure infections
it require immediate release of drug from the dosageform, which make Cefixime suitable
candidate for dispersible tablets. Initially the poor flow property was improved by comparing


various granulation techniques and Trial-3 by Dry granulation MCCP, Maize starch and PVP
K30 gives satisfactory improvement in flow properties of drug. The optimized formulation
i.e. Trial-3 MCCP, Maize starch, PVP K30 was incorporated with various Disintegrnats like
SSG, CCS and Crospovidone which is encoded as Trial-3A, Trial-3B and Trial-3C
respectively. Among 3 Batches Trial-3C using Crospovidone was found optimized since it
had expressed Disintegrating Time of 20 sec and 99.98 0.023 % CDR within 55min and
furthermore also found better when compared with other marketed ODT of Cefixime.

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