FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
(See section l0 and rule 13]
1. Title of the invention: "STABLE CEFIXIME ORAL FORMULATION WITH IMPROVED BIOAVAILABILITY"
2. Macleods Pharmaceuticals Ltd., an Indian Company, having its Registered Office at 304 - Atlanta Arcade, Opp. Leela Hotel, Marol Church Road, Andheri (East), Mumbai - 400 059, Maharashtra, India.
3. The following specification describes the invention.

FIELD OF THE INVENTION
The invention relates to an oral cefixime formulation with improved bioavailability
and stability profile comprising a combination of inorganic alkalizing agents and at
least one more pharmaceutically acceptable excipient. The invention particularly
relates to an oral cefixime tablets, capsules, and powder for oral solution.
Stable oral cefixime formulation of the present invention employs combination of
inorganic alkalizing bicarbonates, such as surface modified sodium bicarbonate and
potassium bicarbonate.
The invention further relates to process for preparation of stable oral cefixime
formulation using a combination of inorganic alkalizing carbonates. Formulation of
the invention is stable and exhibits improved in-vitro and in-vivo drug release
profile, resulting intoenhanced bioavailability.
BACKGROUND OF THE INVENTION
Cefixime is a third-generation semi-synthetic cephalosporin antibiotic, like
ceftriaxone and cefotaxime. Chemically, Cefixime is 7-[2-(2-amino-4-thiazolyl)-2-
(carboxymethoxyimino) acetamido]-3-vinyl-3-cephem-4-carboxylic acid. Many
organisms resistant to penicillins and some cephalosporins due to the presence of
beta-lactamases, may be susceptible to cefixime; because it is highly stable in the
presence of beta-lactamase enzymes. Its antibacterial effect results from inhibition of
mucopeptide synthesis in the bacterial cell wall.
Cefixime is used in the treatment of variety of infections caused by susceptible
strains of the microorganisms like Escherichia coli, Haemophilus influenzae,
Staphylococcus pyogenes, Streptococcus pneumoniae, Neisseria gonorrhoeae and
some other Gram positive and Gram negative organisms.
Cefixime is available under trade name Suprax by Lupin in the form of film coated
tablets, chevvable tablets, capsules and powder for suspension. These formulations
are to be administered by oral route and indicated for treatment of uncomplicated
urinary tract infection, otitis media, pharyngitis, tonsillitis, acute and chronic

bronchitis and so on. However, currently available formulations suffer from the
problem of low and variable bioavailability as cefixime is not soluble in water after
its oral administration. It is a BCS class-II drug and is slowly and incompletely
absorbed from the gastro intenstinal tract, resulting into the poor bioavailability of
about 40-50%.
Cefixime is also amenable to the absorption of moisture, which may lead to the
unstable formulation and the solid dosage form may be seen having mottled surfaces
when traditional excipients are used in a tablet formulation.
Elaborative research has been carried to formulate novel cefixime formulations with
improved solubility in the prior art.
Gastroretentive and effervescent dosage forms are described in the prior art for
enhancing bioavailability of cefixime.
Research paper titled 'Formulation and Evaluation of Gas Powered Systems of
Cefixime tablets for Controlled Release' by Raghvendra Rao N.G. et al in
International Journal of Pharma and Bio-Sciences deals with the gastroretentive
dosage form which controls the drug release and exhibits increased bioavailability
owing to its retention in the gastric cavity over the desired time period.
Another research paper titled 'Formulation and in-vitro evaluation of gastric oral
floating tablets of cefixime for controlled release' in Research Journal of
Pharmaceutical, Biological and Chemical Sciences (July-Sept , vol 1, issue 3, page
no. 141, 2010) highlights that use of sodium carbonate increases drug release as well
as floating time, thus leading to improved bioavailability. In vivo drug release
information is not provided in this paper to substantiate the result on bioavailability
enhancement.
PCT application WO2011078832 relates to effervescent cefixime formulations
comprising cefixime and at least one binder, preferably povidone and can also
include one or more pharmaceutically acceptable excipients such as effervescent acid
and base called as effervescent couple. Improved solubility of such formulations is

due to fast disintegration of the solid dosage form by reaction of acid-base couple with gastric acid. Another PCT application WO2011078821 also describes effervescent tablet and granule formulation by employing acid-base couple for preparing patient compliant formulation.
Thus prior art references relate to the new formulations like floating, effervescent or gastroretentive tablets as alternative formulations to enhance absorption and bioavailability. But these novel formulations need specialized equipments and thus add to the cost of production. The drug release from such formulations is incomplete, resulting into lower bioavailability. Hence it is preferable to improve existing oral swaliowable formulations which provide reliable in-vitro and in-vivo release profiles.
After rigorous experimentation it has been found by inventors of the present invention that oral cefixime formulation such as tablets, capsules or powder for oral solution prepared using a combination of inorganic alkalizing agents and at least one more pharmaceutically acceptable excipient, resulted in formulation with enhanced in-vitro drug release and in-vivo plasma profile. Inventors of the present invention carried out extensive trials to select a combination of inorganic alkaline agents such as one surface modified carbonate and one more alkalizing agent. Optimized combination of potassium bicarbonate and surface modified sodium bicarbonate in specific ratio resulted in stable cefixime formulation with improved bioavailability. Thus first object of the present invention is to provide stable oral cefixime formulation with improved bioavailabilty.
Second object of the present invention is to provide stable oral cefixime formulation with improved bioavailability by using a combination of inorganic alkalizing agents such as potassium carbonate and surface modified sodium bicarbonate. Another aspect of the present invention is to provide the process for preparation of oral cefixime formulation which is simple, cost effective, employs traditional equipments and industrially viable.

SUMMARY OF THE INVENTION
The present invention provides a stable pharmaceutical formulation with improved bioavailabilty comprising cefixime as an active ingredient and
a. a combination of inorganic alkalizing agents and
b. at least one pharmaceutically acceptable excipient.
Particularly the present invention provides an oral cefixime tablet formuiation and powder for oral solution formulation with improved stability and bioavailability profile, comprising.
a. a combination of inorganic alkalizing agents and
b. at least one pharmaceutically acceptable excipient,
Stable cefixime tablet and powder for oral solution formulation of the present invention employs combination of inorganic bicarbonates as alkalizing agents, wherein one inorganic alkalizing agent is potassium bicarbonate and another alkalizer is surface modified sodium bicarbonate.
The formulation of present invention shows improved in-vitro drug release as compared to formulation devoid of such combination of inorganic alkalizing agents. The invention also provides a process for preparation of stable cefixime tablet and powder for oral solution formulation using potassium bicarbonate and surface modified sodium bicarbonate,
DETAILED DESCRIPTION OF THE INVENTION
Cefixime is available in the market from Lupin with brand name Suprax in the form of different dosage forms like swallow tablets, chewable tablets, capsules and powder for suspension. It is used for treating infections caused by certain Gram positive and Gram negative bacteria. Suprax film coated tablets contain the excipients such as dibasic calcium phosphate, microcrystalline cellulose, pregelatinized starch, sodium lauryl sulphate, hypromellose, light mineral oil,

magnesium stearate and titanium dioxide. In this formulation, dibasic calcium
phosphate is used as an alkalizing agent.
Cefixime to be used in scope of the present invention can be in the form of its
solvates, hydrates, esters, enantiomers, racemates, organic salts, inorganic salts,
polymorphs, crystal and amorphous forms or in free form and/or a combination
thereof. Further cefixime used in scope of the present invention can be any of the
monohydrate, dehydrate, trihydrate and/or anhydrate forms.
Cefixime is a drug with low solubility and resultant poor and variable bioavailability.
Different methods are known to a person skilled in the art for increasing solubility of
the active ingredients such as micronization, cyclodextrin complexation, use of water
soluble polymers, preparation of solid dispersion and the like. All such methods used
for solubilization add to the formulation steps and increase time and cost
consumption.
Instead of employing any new technique for increasing solubility, proper choice and
optimization of excipient can be tried to enhance stability as well as solubility of the
formulation.
For the purpose of this invention, alkalizing agents were tried to increase stability
and solubility of cefixime.
The alkaline excipients were selected from the group such as sodium bicarbonate.
sodium carbonate, potassium carbonate, magnesium carbonate, calcium carbonate;
alkaline hydroxides such as sodium hydroxide, potassium hydroxide or magnesium
hydroxide; alkaline phosphate such as disodium hydrogen phosphate, dipotassium
hydrogen phosphate and dicalcium phosphate and mixtures thereof.
According to one embodiment the present invention contains a combination of
inorganic alkalizing agents and at least one more pharmaceutically acceptable
excipient.

According to the preferred embodiment of the present invention, cefixime tablet formulation and powder oral solution formulation employs combination of two inorganic bicarbonates.
According to the most preferred embodiment of the present invention, cefixime formulation is comprised of a combination of alkalizing agents such as potassium bicarbonate and surface modified sodium bicarbonate.
Surface modified sodium bicarbonate is commercially available as Effersoda® from SP1 Pharma. It is prepared by drying and partially desiccating sodium bicarbonate, wherein the surface of sodium bicarbonate particles gets converted to sodium carbonate. Primarily it contains 83 to 90% w/w sodium bicarbonate and 10-17% w/w sodium carbonate. The outer layer of sodium carbonate absorbs moisture from the atmosphere or composition and forms sodium sesquicarbonate, which is stable up to 70°C. Effersoda is used in many effervescent and gastroretentive formulations of cefixime along with organic acid to enhance drug release; but it is not used tilJ date for improving stability and in-vivo plasma profile of immediate release cefixime formulation.
Surface modified sodium bicarbonate takes care of moisture ingress in the formulation and thus improves stability of the formulation. It was observed during series of experiments that cefixime composition prepared using either of sodium bicarbonate or potassium bicarbonate alone or combination of sodium bicarbonate and potassium carbonate showed surface mottling. But optimized combination of potassium bicarbonate and surface modified sodium bicarbonate resulted in a stable formulation.
According to one embodiment, amount of combination of alkalizing agents employed in the formulation is from 10 to 50% w/w of the weight of the formulation. According to one more embodiment, preferred amount of alkalizing bicarbonate agents used in the formulation is from 15 to 40% wAv of the weight of the formulation. According to most preferred embodiment of the present invention,

combination of alkalizing bicarbonates is used in amount such as 20 to 30% w/w of
the weight of the formulation. According to preferred embodiment of the present
invention, two carbonates are used in the formulation in the ratio 1:1.
According to one more embodiment of the present invention, combination of surface
modified alkaline excipient with potassium bicarbonate is used for preparing stable
cefixime formulation with improved bioavailability.
Further cefixime. may contain, in addition to combination of inorganic alkalizing
agents, other pharmaceutically acceptable excipients chosen from, but not limited to,
diluents, disintegrants, binders, fillers, anti-adherents, coating agents, plasticizers,
organic solvents, lubricants, glidants, sweetners, flavouring agents and the like
known to the art used either alone or in combination thereof.
Fillers that can be used in the present invention include microcrystalline cellulose,
lactose, sugars, starches, modified starch, mannitol, sorbitol and other polyols,
dextrin, dextran and maltodextran, and the like or mixtures thereof.
Binders that can be used in the present invention include starch, cellulose, sugars,
polyethylene glycols, hydroxypropyl methylcellulose, ethylcellulose, hydroxyethyl
cellulose, methylcellulose, carboxy methylcellulose, sodium carboxy
methylcellulose, gelatin, acacia gum, tragacanth, polyvinylpyrrolidone, alginic acid,
carbomer, dextrin, gelatin, guar gum, hydroxypropyl cellulose, maltose, polyethylene
oxide, and the like or mixtures thereof.
According to one more embodiment of the present invention, disintegrating agents
include cross-linked sodium carboxy methylcellulose, cross-linked
polyvinylpyrrolidone, cross-linked carboxymethyl starch, starches, microcrystalline
cellulose, magnesium aluminum silicate, potassium polacrilin, sodium starch
glycolate. low-substituted hydroxypropyl cellulose, and the like or mixtures thereof.
The formulation may further contain one or more different glidants such as
magnesium, calcium and zinc stearate, calcium behenate, sodium stearyl fumarate,

talc, magnesium trisilicate, stearic acid, palmitic acid, carnauba wax. silicon dioxide, and the like or mixtures thereof.
The present invention also relates to a process for preparing the formulation as described above. In a first embodiment of this aspect of the present invention, the process for the preparation of such improved composition comprises:
i) mixing the active agent with a combination of two inorganic alkalizing
agents and one more pharmaceuticafly acceptable excipient such as filler and disintegrant. ii) granulating the materials using binder solution iii) blending the granules with glidant, remaining amount of filler and
disintegrant and lubricating granules with suitable lubricant iv) compressing the lubricated blend to tablets and coating with polymer solution
In a further embodiment of the present invention, the process for preparation of stable cefixime tablet formulation comprises:
i) mixing cefixime with combination of potassium bicarbonate and surface
modified sodium bicarbonate, microcrystalline cellulose and crospovidone, ii) granulating the materials using povidone solution
iii) blending the granules with colloidal silicon dioxide, remaining amount of microcrystalline cellulose and crospovidone and lubricating granules with magnesium stearate iv) compressing the lubricated blend to tablets and coating with low viscosity Hydroxypropyl methyl cellulose coating solution In a further embodiment of the present invention . the process for preparation of stable cefixime powder oral solution comprises:

i) mixing cefixime with combination of potassium carbonate and surface
modified sodium bicarbonate and one more pharmaceutically acceptable excipient such as diluent, flavouring agent, sweetening agent
ii) blend the mixture and fill the blend in appropriate bottle
In the further embodiment the composition of the present invention is in the form of a solid dosage form, such as tablets, capsules, granules, powder oral solution or the like. The tablets can be prepared by either direct compression, dry compression or by granulation. In one embodiment of the present invention, the oral composition is prepared by compression or compaction. The granulation technique is either aqueous or non-aqueous. The non-aqueous solvent used is selected from ethanol, isopropyl alcohol, ethyl acetate, methyl t-butyl ether and methylene chloride. In one embodiment, the composition of the present invention is in the form of compacted tablets, compressed tablets, molded tablets, and the like, in one embodiment , the composition of the present invention is in the form of oral solution.
The following examples are only intended to further illustrate the invention, in more detail, and therefore these examples are not deemed to restrict the scope of the invention in any way.
BRIEF DESCRIPTION OF Figure No. 1
Figure No. 1 is a graphical representation of release profile for tablets of various formulations of experimental trials
EXAMPLES
Various experimental trials were carried out using following compositions:
1. Cefixime Tablets prepared using surface modified Sodium bicarbonate (Effersoda) alone as alkalizing agent: Batch no. 010(1449)040A

2. Cefixime Tablets prepared using sodium bicarbonate alone as alkalizing agent: Batch no. 010(1449)040B
3. Cefixime Tablets prepared using Potassium bicarbonate alone as alkalizing agent: Batch no. 010(1449)040C
4. Cefixime Tablets prepared using combination of sodium bicarbonate and Potassium bicarbonate as alkalizing agent: Batch no. 010(1449)040D
5. Cefixime Tablets prepared using combination of surface modified sodium bicarbonate and Potassium bicarbonate as alkalizing agent:
Batch no. 008(1449)024A
6 Cefixime Oral solution prepared using combination of surface modified
sodium bicarbonate and Potassium bicarbonate as alkalizing agent: Batch no. 008(1449)0248
Process for preparation of Cefixime Tablets:
Cefixime, microcrystalline cellulose, surface modified sodium bicarbonate, potassium bicarbonate and crospovidone were sifted through appropriate sieve and mixed well. The blend was granulated with povidone solution in Isopropyl Alcohol. The granules were dired and sieved to appropriate size. The granules were blended with colloidal silicon dioxide, microcrystalline cellulose and crospovidone. The granules were lubricated with magnesium stearate. The lubricated blend was compressed into tablets which were subsequently coated using coating solution containing Hypromellose in isopropyl alcohof and methylene chloride. These cefixime compositions were evaluated for hardness and disintegration time.

The compositions are tabulated in table I
Table 1: Cefixime tablets prepared using different alkalizing agents

Sr.
No. Ingredients 010(1449) 040A 010(1449) 040 B 010(1449) 040C 010(1449) 040D 008(1449) 024A

mg/tab mg/tab mg/tab mg/tab mg/tab
1 Cefixime 206.00 206.00 206.00 206.00 206.00
2 Microcrystalline cellulose PHI 12 52.25 52.25 52.25 52.25 52.25
3 Surface modified Sodium bicarbonate (Effersoda) 111.75 - -- -- 55.87
4 Sodium bicarbonate(Plain) -- 111.75 -- 55.87 --
5 Potassium bicarbonate(Plain) -- -- 111.75 55.88 55.88
6 Povidone (PVP-K 30) 12 12 12 12 12
7 Colloidal Hydrated silica (Sylloid AL1FP) 5 5 5 5 5
8 Crospovidone 14 14 14 14 14
9 Magnesium Stearate 4 4 4 4 4
Weight of core tablets 405.00 405.00 405.00 405.00 405.00
Coating
10 Idealmoist shield (IJMS1031)# 15.4 15.4 15.4 15.4 15.4
11 Isopropyl Alcohol IP 124 124 124 124 124
12 Dichloromethane BP 186 186 186 186 186
Weight gain 11.00 11.00 11.00 11.00 11.00
Weight of Coated tablets 416.00 416.00 416.00 416.00 416.00
Table 2: Evaluation of Cefixime formulations having different alkalizing agents

Core Tablets 0(0(1449) 040A 0(0(1449) 040B 0(0(1449) 040C 010(1449) 040D 008(1449) 024A
Hardness 82-84 N 73-75 N 80-85N 68-70N 100-105N
DT in minutes (Water) 1.50 min 1,42 min 1.0 min imin 1 min 30 sec
Coated
DT in minutes
(Water) 2.40-2.50 min 2.20-2,30 min 1.40-1.50 min 2.10-2.20 min 1.40-2.0 min

Cefixime formulations were evaluated for dissolution in 0.1 N HCl and the results were tabulated in Table 3. The comparative dissolution as represented in Figure No.l showed that drug release was enhanced in product 08(149)024A containing effersoda and potassium bicarbonate as compared to other batches. Table 3: Comparative Dissolution Profile of Cefixime formulations

% Dissolution in 0.1N HC1,900 ml,Basket,100rpm

Product 010(1449)
040A 010(1449) 040B 010(1449) 040C 010(1449) 040D 008(1449)
024A
Time Points ↓

with Effersoda with NaHC03 with KHC03 with NaHC03+ KHC03 with
Effersoda+
KHC03
0 min 0.0 0.0 0.0 0.0 0.0
10 mins 64.8 59.3 59.9 59.8 73.8
15 mins 71.2 65.5 64.4 66.6 81.5
20 mins 75.1 69.8 67.6 70.4 87.1
30 mins 81.3 76.0 73.0 76.3 90.0
45 mins 88.6 82.8 79.9 82.9 93.7
Cefixime formulation prepared using combination of potassium bicarbonate and
surface modified sodium bicarbonate was evaluated for drug release profile and
compared with other marketed formulations as shown in table 4 below:
Table 4: Comparative dissolution profile of Macleods' formulation with marketed formulation
Dissolution Parameters:0.lN HC1,900 ml,Basket,100rpm

Product Cefolac 200 Taxim O Zifi 200 Suprax D 400 008(1449)024A With Effersoda+ KHC03
Time Points ↓.

0 min 0.0 0.0 0.0 0.0 0.0
10 mins 32.4 44.9 42.8 42.5 73.8
15 mins 46.6 54.8 50.3 50.3 81.5
20 mins 55.9 60.5 58.9 55.2 87.1
30 mins 66.9 71.7 59.8 61.4 90.0
45 mins 76.7 75.0 65.8 68.3 93.7

Table 5: Cefixime Tablets 200 mg Stability Data 010(1449)040A

Assay Description Dissolution
Condition

0.1 N HC1 Time In Minutes 7.2 PB#


10 15 20 30 45 45
Initial 97.7 White circular biconvex film
coated tablets 64.8 71.2 75.1 81.3 88.9 97.1
] M 40/75% 104.4 White circular biconvex film coated tablets 67.0 74.4 78.8 84.6 90.7 100.2
2M 40/75% 96.1 White circular biconvex film coated tablets 65.4 71.9 76.2 81.7 85.6 98.7
3M 40/75% 96.6 White circular biconvex film coated tablets 66.0 71.1 73.6 76.9 81.0 96.2
3M 30/75% 97.1 White circular biconvex film coated tablets 68.1 73.3 77.3 82.6 86.7 95.0
3M 25/60% 98.4 While circular biconvex film coated tablets 69.2 73.3 78.0 83.3 85.7 96.2
6M 40/75% 95.5 White circular biconvex film coated tablets 69.1 72,8 78.3 82.9 87.1 95,0

010(1449)0408

Condition Assay Description Dissolution

0.1 IN HCI, Time In Minutes 7.2 PB #

to 15 20 30 45 45
White circular
Initial 96.8 biconvex film coated tablets 59.3 65.5 69.8 76.0 82.8 95.4
Off white circular
1M 40/75% 102.8 biconvex film coated tablets 66.5 73.6 79.9 84.6 90.7 99.4
Off white circular
2M 40/75% 96.3 biconvex film coated tablets 61.3 67.7 72.1 76.4 84.0 96.7
Off white circular
3M 40/75% 95,7 biconvex film coated tablets 62.5 64.9 68,3 75.3 77.3 95.3
Off white circular
3M 30/75% 96.6 biconvex film coated tablets 65.3 65.0 70.0 72.5 82.6 95.3
Off white circular
3M 25/60% 97.0 biconvex film coated tablets 59.2 66.2 70.4 73.6 82.7 96.1
Off white circular
6M 40/75% 94.8 biconvex film coated tablets 60.7 64.6 73.3 76.9 80.6 92.8
7.2 PB #: pH 7.2 Phosphate Buffer

010(1449)040C

Condition Assay Description Dissolution

0.1 NHCI, Time In Minutes 7.2 PB

10 15 20 30 45 45
Initial 97.2 White circular biconvex film coated tablets 59.9 64.4 67.6 73.0 79.9 94.6
Off white circular
1M 40/75% 102.2 biconvex film coated tablets 67.9 73.1 76.4 81.0 86.1 98.1
Off white circular
2M 40/75% 97.1 biconvex film coated tablets 66.7 71.5 75.1 79.4 81.5 96.6
Off white circular
3M 40/75% 95.0 biconvex film coated tablets 69.9 77.0 76.2 77.4 79,0 96.0
Off white circular
3M 30/75% 95.6 biconvex film coated tablets 69.2 74.0 76.1 78.6 85.-5 96.4
Off white circular
3M 25/60% 96.3 biconvex film coated tablets 68.7 71.3 76.5 80.2 85.0 97.3
Off white circular
6M 40/75% 95.1 biconvex film coated tablets 68.2 73.4 76.7 81.4 86.4 95.3
7.2 PB#: pH 7.2 Phosphate Buffer

010(1449)040D

Condition Assay Description Dissolution

0.1 NHCI,Time In Min utes 7.2 PB


10 15 20 30 45 45
Initial 96.4 White circular biconvex film coated tablets 59. 8 66. 6 70.4 76.3 82.9 96.2
1M 40/75% 104.1 Off white circular
biconvex film coated
tablets 71. 0 80. 2 76.7 88.0 91.6 100.6
2M 40/75% 95.6 Off white circular
biconvex film coated
tablets 63. 1 70. 8 76.5 81.7 86.9 97.6
3M 40/75% 93.5 Off white circular
biconvex film coated
tablets 66.
7 73. 6 77.9 82.7 91.6 95.5
3M 30/75% 95.1 Off white circular
biconvex film coated
tablets 67. 3 75. 4 78.8 85.3 96.2 94.5
3M 25/60% 95.9 Off white circular
biconvex film coated
tablets 66.
5 74. 4 77.8 83.5 94.3 96.3
6M 40/75% 94.6 Off white circular
biconvex film coated
tablets 65. 9 75. 6 76.5 86.1 94.1 94.8
7.2 PB #: pH 7.2 Phosphate Buffer

008(1449)024 A

Condition Assay Description Dissolu tion

0.1 NHCI, Time In Minutes 7.2 PB#

10 15 20 30 45 45
Initial 101.8 White circular biconvex film coated tablets 70.3 75.5 79.7 83.9 89.5 102.8
1M 40/75% 99.1 White circular biconvex film coated tablets 68.2 72.9 78.0 81.4 86.8 101.8
2M 40/75% 98.1 White circular biconvex
film coated tablets 65.9 70.6 74.4 77.9 84.2 93.9
3M 25/60% 103.0 White circular biconvex film coated tablets 72.6 77.8 80.1 82.8 86.5 98.2
3M 30/75% 103.2 White circular biconvex film coated tablets 74.4 78.1 81.5 86.0 90.2 94.8
3M 40/75% 101.2 White circular biconvex film coated tablets 71.9 77.5 78.2 83.1 86.7 91.9
6M 40/75% 100.6 White circular biconvex film coated tablets 67.4 75.1 79.4 83.3 85.5 91.7
7.2 PB #: pH 7,2 Phosphate Buffer
1) Rate of dissolution of 010 (1449)040A prepared with Effersoda alone is low compared with batch 008(1449)024A with Effersoda + Potassium bicarbonate.
2) Colour of the tablets of 010 (I449)040B prepared with Sodium bicarbonate Plain, 010 (I449)040C prepared with Potassium bicarbonate, 010 (1449)040D prepared with Sodium bicarbonate Plain and Potassium bicarbonate turns off white on stability and rate of dissolution is low.
3) There is no colour change in the tablets of 008(1449)024A prepared with Effersoda and Potassium bicarbonate on stability and dissolution rate is faster.

Thus combination of Effersoda and Potassium bicarbonate shows better stability and dissolution in Cefixime Tablets 200 mg
Cefixime Oral solution prepared using combination of surface modified Sodium bicarbonate and potassium bicarbonate:
Each 5 ml of reconstituted solution contains:
Cefixime Trihydrate equivalent to anhydrous Cefixime 100 mg
Batch no: 008(1449)246

Sr. No.
Ingredients Qty/5 ml Qty/bottle

in mg in mg
1 Cefixime Trihydrate 100.00 600.00
3 Surface modified Sodium bicarbonate (Effersoda) 55.87 335.22
3 Potassium bicarbonate 55.88 335.22
4 Mannitol 515.25 3091.5
5 Neotame 5.00 30.00
6 Peppermint flavour 3.00 18.00
7 Pineapple flavour 15.00 90.00
Fill weight per bottle 750.00 4500.00
Process for preparation of Cefixime Oral solution:
Cefixime trihydrate, sodium bicarbonate, potassium bicarbonate, mannltol, and
neotame were dried and sifted through appropriate sieve and blended in blender.
Blend was filled in bottle.
The formulations using combination of surface modified sodium bicarbonate and
potassium bicarbonate were stable over desired period of time, whereas other
compositions show mottled surfaces.
Pharmacokinetic study carried out using Cefixime Tablets comprising combination
surface modified sodium bicarbonate and Potassium bicarbonate showed higher Cmax
and AUC compare to marketed Cefixime Tablets.
Cefixime formulations of the present invention show improved stability and
bioavailability over the formulations containing other alkalizing agents. Such
formulations are easy to prepare and employ traditional equipments.

We claim:
1. A stable pharmaceutical formulation with improved bioavailability
comprising of cefixime as an active ingredient and ,
a, a combination of inorganic alkalizing agents and
b. at least one pharmaceutically acceptable excipient.
2. A stable pharmaceutical formulation with improved bioavailability as claimed in claim 1 where in cefixime formulations are in the form of tablet, capsule and powder oral solution.
3. A stable cefexime tablet formulation with improved bioavailability as claimed in claim 1 is comprising of
a. Cefixime, a combination of inorganic alkalizing agents and
b. at least one pharmaceutically acceptable excipient.
4. A stable cefexime powder oral solution formulation with improved
bioavailability as claimed in claim 1 is comprising of
a. Cefixime, a combination of inorganic alkalizing agents and
b. at least one pharmaceutically acceptable excipient
5. Cefixime formulations as claimed in claim 1,3 and 4 where in a combination of inorganic alkalizing agents are surface modified sodium bicarbonate and potassium bicarbonate.
6. A process for preparation of stable cefixime tablet formulation with improved bioavailability comprises:
i. mixing cefixime with a combination of two inorganic alkalizing agents and
pharmaceutically acceptable excipient. ii. granulating the materials using binder solution iii. blending the granules with glidant,filler, disintegrant and lubricating granules
with suitable lubricant iv. compressing the lubricated blend to tablets and coating with polymer solution

7. A process for preparation of stable cefixime powder oral solution formulation with improved bioavailability comprises:
i. mixing cefixime with combination of potassium carbonate and surface modified sodium bicarbonate and one more pharmaceutically acceptable excipient such as diluent, flavouring agent, sweetening agent
ii. blending the mixture.