DESC:FIELD OF THE INVENTION

The present invention relates to an improved process for the preparation of Cefuroxime of formula (I) and pharmaceutically acceptable salts thereof. Specifically, the present invention discloses a process for the preparation of Cefuroxime sodium of formula (II) which is essentially free of color impurities. More preferably, the present invention relates to a process for the preparation of stable Cefuroxime sodium.

BACKGROUND OF THE INVENTION

Cefuroxime is a valuable broad spectrum antibiotic and having activity against wide range of gram-positive and gram-negative microorganisms. IUPAC name of Cefuroxime is (6R,7R)-3-{[(Aminocarbonyl)oxy]methyl}-7-{[(2Z)-2-(2-furyl)-2-(methoxyimino)acetyl]amino}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid. Cefuroxime sodium is physiologically acceptable non-toxic salt of Cefuroxime.

Cefuroxime may be administered, in human or veterinary medicine, as a non-toxic derivative, i.e. one which is physiologically acceptable at the dosage at which it is administered. Such non-toxic derivatives conveniently include those salts, e.g. alkali metal, alkaline earth metal and organic base salts which on admixture with sterile, pyrogen-free water form aqueous solutions or suspensions for injection.

In US Patent No. 3,974,153 the sodium salt of Cefuroxime is described as being a substance well suited to administration on injection and recognised as being an antibiotic of outstanding value. For convenience, this sodium salt hereinafter be referred to as Cefuroxime sodium.

The preparation of Cefuroxime sodium involves the condensation of 3-hydroxymethyl-7-amino cephalosporinc acid with (fur-2-yl)-2-methoxyimino acetic acid to produce (6R,7R)-7-[Z-2-(fur-2-yl)-2-methoxyiminoacetamido]-3-hydroxymethylceph-3-em-4-carboxylic acid. Carbamoylation of resulting acid with isocyanate of formula RNCO, wherein R is a labile substituent to get Cefuroxime, followed by converting the Cefuroxime into its sodium salt using mixture of water soluble sodium salt.

US patent 4,775,750 discloses the process for the preparation of the Cefuroxime sodium which comprises reacting (6R,7R)-7-[Z-2-(fur-2-yl)-2-methoxyimino-acetamido]-3-hydroxymethyl- ceph-3-em-4-carboxylic acid with a halosulphonyl isocyanate in an alkyl acetate solvent, hydrolysing the resulting intermediate product, forming Cefuroxime sodium by the addition of the sodium salt of a week acid. The product obtained from this patent suffers in non-acceptable color and low purity. Reprocessing is needed to get sterile Cefuroxime sodium.

US patent 4,277,601 describes the process for the preparation of Cefuroxime sodium as its THF solvate in-situ manner. The process described in this patent involves the usage of multiple organic solvent system and thereby making the process complicated. Moreover, recrystallization is needed to get the sterile Cefuroxime sodium.

Chinese patent CN110857307 discloses the use of a micro-channel reactor to reduce the operating temperature and time in the purification process of the crude product of Cefuroxime sodium to prepare high-purity and high-yield cephalosporin for injection. However, many types of solvents are used in the preparation process of this method, and improper operation is likely to leave solvents, which affects the quality and safety of product.

Chinese patent CN113788843 discloses purification/rework process of Cefuroxime sodium by preparing a phosphate Buffer salt solution, decoloring with activated carbon and crystallization by adding seed crystals and resin into the Cefuroxime sodium solution. However, usage of resin and seed crystals makes this process costly and not viable at industrial scale.

The problem of poor stability of Cefuroxime sodium products is generally reflected in the fast color change. Cefuroxime sodium color changes rapidly in the early stage. The problem of rapid color changes has attracted more and more attention from various manufacturers. The processes disclosed in the prior art fail to control the undesirable color impurities in Cefuroxime sodium. Consequently, there is a need for an improved manufacturing process for the preparation of Cefuroxime sodium, which is simple, environment friendly, economically viable and industrially feasible with essential control on color impurities and should attain desired pH.

The main challenge during the preparation of Cefuroxime sodium, is the purity of the Cefuroxime sodium, which is found to be inadequate as yellow color impurities increases on storage, which in turn makes the product non-suitable for industrial scale. Owing to strict regulatory requirements, high quality standards have to be met and the spectrum of by-products needs to be carefully monitored. For reasons of product safety and for the good of the patient, the by-product spectrum and/or the presence of individual contaminants are kept in permissible limit in order to comply the regulatory requirement. There is another operational challenge like multiple times decantation of solvent to remove by-product/impurities in lactic acid route. Further in sterile area time-cycle in lactic acid route is high due to which process results low productivity and hence not favorable at industrial scale.

In spite of progress made compared to the original processes, there is still a need for synthesis stable Cefuroxime sodium, which is stable for prolonged period of time, possess high chemical purity and does not require special manufacturing conditions and allow easier handling during synthesis and meets all pharmacopoeial requirements.

Therefore, in order to provide stable Cefuroxime sodium, there is a need to control/minimize the formation of color impurities as contaminants in the finished product, though they are present in very minimal quantities. The absolute understanding of impurities provides room for improving the synthetic processes to control and if, inherently being formed, their understanding provides the scope to develop processes for removal of impurities in the simplest possible manner.

In summary, the Cefuroxime sodium obtained by the prior arts has very small crystal particles, generally poor stability and develops higher color grade. Therefore, to improve the manufacturing process and improve the stability of Cefuroxime sodium becomes a problem to be solved.

With our continued search and intense investigation, we finally achieved a process for the preparation Cefuroxime sodium, which overcomes all difficulties in prior art and makes the process industrially viable and yield the stable Cefuroxime sodium that too in better quality. Cefuroxime sodium obtained from the instant invention is highly stable and achieved pH in desirable pharmacopoeial limits. Cefuroxime sodium obtained from instant invention is also highly stable and does not develop color impurity on storage for longer time.

The Cefuroxime sodium produced by the process of instant invention is highly stable and pure and is extremely suitable for further processing, for example for the preparation of highly pure sterile Cefuroxime or an ester of Cefuroxime such as Cefuroxime axetil in a high degree of purity.

OBJECT OF THE INVENTION:

The principal object of the present invention is to overcome or alleviate at least one of the deficiencies of prior art and provide a useful alternative for the preparation of Cefuroxime sodium which is suitable for human consumption.

According to one object of the present invention, there is provided a process for the preparation of stable Cefuroxime sodium.

It is another object of the present invention to provide a simple, economic and efficient process for the preparation of Cefuroxime sodium, which is stable on storage for prolonged period of time.

It is yet another object of the present invention to provide Cefuroxime sodium essentially free of color impurities.

It is yet another object of the present invention, there is provided a simple, commercially viable, economical and environment friendly process for preparing stable Cefuroxime sodium in high yield with high purity.

It is yet another object of the present invention, there is provided a process for the preparation of stable Cefuroxime sodium with pH of pharmacopoeial limits.

It is yet another object of the present invention, there is provided a process for the preparation of stable Cefuroxime sodium using Buffer.

It is yet another object of the present invention, there is provided a process for the preparation of stable Cefuroxime sodium using Disodium hydrogen phosphate Buffer.

SUMMARY OF THE INVENTION

In accordance with the present invention, there is provided a process for the preparation of stable Cefuroxime sodium, the process comprising using Buffer.

In accordance with the present invention, there is provided a process for the preparation of stable Cefuroxime sodium, the process comprising using Disodium hydrogen phosphate Buffer.

The purpose of this invention is to provide a novel method that is more suitable for industrialized production, technology is simple, product purity and yield of Cefuroxime sodium is high.

According to one aspect of the present invention there is provided an efficient and cost effective process for the preparation of stable Cefuroxime sodium of Formula II from Cefuroxime acid of Formula I, as shown in scheme-1.

Stable Cefuroxime sodium is efficiently prepared from Cefuroxime acid using Buffer. Using Buffer, preferably Disodium hydrogen phosphate Buffer, stable Cefuroxime sodium is efficiently prepared from Cefuroxime acid.

DETAIL DESCRIPTION OF THE INVENTION

While this specification concludes with claims particularly pointing out and distinctly claiming that, which is regarded as the invention, it is anticipated that the invention can be more readily understood through reading the following detailed description of the invention and study of the included examples.

The present invention relates to a process for the preparation of Cefuroxime sodium of Formula II

comprising the steps of:
(i) mixing Cefuroxime acid of Formula I with solvent;

(ii) adding Buffer to the reaction mixture;
(iii) optionally heating the reaction mixture;
(iv) optionally adding activated carbon to the reaction mixture;
(v) filtering the reaction mixture;
(vi) optionally heating the reaction mixture;
(vii) adding salt forming agent to the reaction mixture; and
(viii) isolating Cefuroxime sodium of Formula II.

In step (i), solvent is selected from the group comprising of alcohol, ketone, water or mixture thereof. Alcohol is selected from the group comprising of C1-C4 alcohol such as methanol, ethanol, propanol, isopropanol, butanol, isobutyl alcohol, tert-butanol and the like and mixture thereof. Alcohol solvent is preferably methanol. Ketone solvent is selected from the group comprising of acetone, methyl ethyl ketone, methyl iso-butyl ketone and the like and mixture thereof. Ketone solvent is preferably acetone. Solvent is most preferably mixture of methanol, acetone and water.

In step (ii), Buffer is selected from the group comprising of disodium hydrogen phosphate, sodium di-hydrogen phosphate, di-potassium hydrogen phosphate, potassium di-hydrogen phosphate, di-ammonium hydrogen phosphate, ammonium di-hydrogen phosphate, ACES Buffer, PIPES Buffer, MOPS Buffer, MOPSO Buffer, 2,6-lutidine and the like. Buffer is preferably disodium hydrogen phosphate or di-potassium hydrogen phosphate. Buffer is more preferably disodium hydrogen phosphate. It should be appreciated that the Buffer in the present invention is not limited to the above type, those skilled in the art can select any appropriate Buffer and within scope of the present invention.

In step (iii), heating the reaction is carried out at temperature from about 20oC to about 40oC, preferably about 25oC-35oC and most preferably about 30oC-35oC.

In step (vi), heating the reaction is carried out at temperature from about 20oC to about 40oC, preferably about 25oC-35oC and most preferably about 30oC-35oC. This reaction is carried out for about 1 hr to about 5hrs or till the completion of the reaction. This reaction is preferably carried out for 2 hr to 3 hr.

In step (vii), salt forming agent is selected from the group comprising of sodium 2-ethyl hexanoate, sodium 2-ethyl heptanoate, sodium 2-ethyl octanoate, sodium 2-ethyl nonanoate and the like. Salt forming agent is preferably sodium 2-ethyl hexanoate. It should be appreciated that the salt forming agent in the present invention is not limited to the above type, those skilled in the art can select any appropriate salt forming agent and within scope of the present invention.

In an embodiment, the present invention relates to a process for the preparation of Cefuroxime sodium of Formula II

comprising the steps of:
(i) mixing Cefuroxime acid of Formula I with alcohol and ketone solvent;

(ii) adding Buffer to the reaction mixture;
(iii) optionally heating the reaction mixture;
(iv) optionally adding activated carbon to the reaction mixture;
(v) filtering the reaction mixture;
(vi) optionally heating the reaction mixture;
(vii) adding salt forming agent to the reaction mixture; and
(viii) isolating Cefuroxime sodium of Formula II.

In step (i), alcohol is selected from the group comprising of C1-C4 alcohol such as methanol, ethanol, propanol, isopropanol, butanol, isobutyl alcohol, tert-butanol and the like and mixture thereof. Alcohol solvent is preferably methanol. In step (i), ketone solvent is selected from the group comprising of acetone, methyl ethyl ketone, methyl iso-butyl ketone and the like and mixture thereof. Ketone solvent is preferably acetone. Solvent is most preferably mixture of methanol and acetone.

In step (ii), Buffer is selected from the group comprising of disodium hydrogen phosphate, sodium di-hydrogen phosphate, di-potassium hydrogen phosphate, potassium di-hydrogen phosphate, di-ammonium hydrogen phosphate, ammonium di-hydrogen phosphate, ACES Buffer, PIPES Buffer, MOPS Buffer, MOPSO Buffer, 2,6-lutidine and the like. Buffer is preferably disodium hydrogen phosphate or di-potassium hydrogen phosphate. Buffer is more preferably disodium hydrogen phosphate. It should be appreciated that the Buffer in the present invention is not limited to the above type, those skilled in the art can select any appropriate Buffer and within scope of the present invention.

In step (iii), heating the reaction is carried out at temperature from about 20oC to about 40oC, preferably about 25oC-35oC and most preferably about 30oC-35oC.

In step (vi), heating the reaction is carried out at temperature from about 20oC to about 40oC, preferably about 25oC-35oC and most preferably about 30oC-35oC. This reaction is carried out for about 1 hr to about 5hrs or till the completion of the reaction. This reaction is preferably carried out for 2 hr to 3 hr.

In step (vii), salt forming agent is selected from the group comprising of sodium 2-ethyl hexanoate, sodium 2-ethyl heptanoate, sodium 2-ethyl octanoate, sodium 2-ethyl nonanoate and the like. Salt forming agent is preferably sodium 2-ethyl hexanoate. It should be appreciated that the salt forming agent in the present invention is not limited to the above type, those skilled in the art can select any appropriate salt forming agent and within scope of the present invention.

In an embodiment, the present invention relates to a process for the preparation of Cefuroxime sodium of Formula II

comprising the steps of:
(i) mixing Cefuroxime acid of Formula I with alcohol, ketone and water;

(ii) adding Buffer to the reaction mixture;
(iii) optionally heating the reaction mixture;
(iv) optionally adding activated carbon to the reaction mixture;
(v) filtering the reaction mixture;
(vi) optionally heating the reaction mixture;
(vii) adding salt forming agent to the reaction mixture; and
(viii) isolating Cefuroxime sodium of Formula II.

In step (i), alcohol is selected from the group comprising of C1-C4 alcohol such as methanol, ethanol, propanol, isopropanol, butanol, isobutyl alcohol, tert-butanol and the like and mixture thereof. Alcohol solvent is preferably methanol. In step (i), ketone solvent is selected from the group comprising of acetone, methyl ethyl ketone, methyl iso-butyl ketone and the like and mixture thereof. Ketone solvent is preferably acetone. Solvent is most preferably mixture of methanol, acetone and water.

In step (ii), Buffer is selected from the group comprising of disodium hydrogen phosphate, sodium di-hydrogen phosphate, di-potassium hydrogen phosphate, potassium di-hydrogen phosphate, di-ammonium hydrogen phosphate, ammonium di-hydrogen phosphate, ACES Buffer, PIPES Buffer, MOPS Buffer, MOPSO Buffer, 2,6-lutidine and the like. Buffer is preferably disodium hydrogen phosphate or di-potassium hydrogen phosphate. Buffer is more preferably disodium hydrogen phosphate. It should be appreciated that the Buffer in the present invention is not limited to the above type, those skilled in the art can select any appropriate Buffer and within scope of the present invention.

In step (iii), heating the reaction is carried out at temperature from about 20oC to about 40oC, preferably about 25oC-35oC and most preferably about 30oC-35oC.

In step (vi), heating the reaction is carried out at temperature from about 20oC to about 40oC, preferably about 25oC-35oC and most preferably about 30oC-35oC. This reaction is carried out for about 1 hr to about 5hrs or till the completion of the reaction. This reaction is preferably carried out for 2 hr to 3 hr.

In step (vii), salt forming agent is selected from the group comprising of sodium 2-ethyl hexanoate, sodium 2-ethyl heptanoate, sodium 2-ethyl octanoate, sodium 2-ethyl nonanoate and the like. Salt forming agent is preferably sodium 2-ethyl hexanoate. It should be appreciated that the salt forming agent in the present invention is not limited to the above type, those skilled in the art can select any appropriate salt forming agent and within scope of the present invention.

In an embodiment, the present invention relates to a process for the preparation of Cefuroxime sodium of Formula II

comprising the steps of:
(i) mixing Cefuroxime acid of Formula I with methanol, acetone and water;

(ii) adding disodium hydrogen phosphate Buffer to the reaction mixture;
(iii) optionally heating the reaction mixture;
(iv) optionally adding activated carbon to the reaction mixture;
(v) filtering the reaction mixture;
(vi) optionally heating the reaction mixture;
(vii) adding sodium-2-ethyl hexanoate to the reaction mixture; and
(viii) isolating Cefuroxime sodium of Formula II.

In step (iii), heating the reaction is carried out at temperature from about 20oC to about 40oC, preferably about 25oC-35oC and most preferably about 30oC-35oC.

In step (vi), heating the reaction is carried out at temperature from about 20oC to about 40oC, preferably about 25oC-35oC and most preferably about 30oC-35oC. This reaction is carried out for about 1 hr to about 5hrs or till the completion of the reaction. This reaction is preferably carried out for 2 hr to 3 hr.

Cefuroxime acid of Formula I, used as starting material in Scheme-1 is prepared according to the known methods of prior art.

After completion of the reaction, the resulting Cefuroxime sodium obtained according to present invention is highly stable. Cefuroxime sodium as per instant invention does not develop yellow color upon storage for longer duration.

Cefuroxime sodium obtained by the process of the instant invention is in fact substantially pure, and in particular substantially free from the impurities. The expression "substantially pure” means having HPLC purity equal to or greater than 99.7%, preferably HPLC purity equal to or greater than 99.8% and most preferably HPLC purity greater than 99.9%.

According to the present invention Cefuroxime sodium is isolated from the reaction mixture by conventional methods like filtration and the like, as reported in the literature.

The problem has been solved by inventors by providing an improved process with the use of specific Buffer, which allows formation of stable Cefuroxime sodium with desired pH. Buffer plays a vital role in achieving stable Cefuroxime sodium with better yield and high purity. By using Disodium hydrogen phosphate Buffer, stable Cefuroxime sodium with high yield and high purity is achieved.

European Pharmacopoeia requires pH of Cefuroxime sodium 5.5 to 8.5, whereas US Pharmacopoeia and Indian Pharmacopoeia requires pH of Cefuroxime sodium 6.0 to 8.5.

Several experiments have been carried out to find impact of Buffer on yield, pH and Color value of Cefuroxime sodium.

Table 1 shows impact of Buffer on pH and color value of Cefuroxime sodium. Using Sodium lactate and Sodium acetate as per prior art results in lower yield and higher color value of Cefuroxime sodium. While using Sodium-2-ethyl hexanoate route without Buffer as per prior art results in lower pH and higher color value. But, using Buffer with Sodium-2-ethyl hexanoate as per instant invention results in stable Cefuroxime sodium with desired pH, higher yield and very low color value.

Table 1
Route Experiment type Example Cefuroxime Sodium
Yield w/w pH Color Value @450nm
Sodium Lactate & Sodium Acetate route Prior art Comparative example 1 0.93 6.5 0.207
Prior art Comparative example 2 0.92 6.73 0.180
Sodium-2-ethyl hexanoate route without Buffer Prior art Comparative example 3 1.008 4 0.119
Prior art Comparative example 4 1.002 4.23 0.126
Sodium-2-ethyl hexanoate route with Buffer Instant invention Example 1 1.01 6.54 0.009
Example 2 1.008 6.21 0.011
Example 3 1.0 6.53 0.008
Example 4 1.002 5.95 0.048
Example 5 1.001 6.30 0.063
Example 6 1.0 6.67 0.059
Example 7 1.0 6.2 0.043
Example 8 1.003 6.74 0.081
Example 9 1.00 6.67 0.073

Table 2 shows changes in color value of Cefuroxime sodium vs. time. Using Sodium lactate and Sodium acetate without Buffer as per prior art results in higher color value of Cefuroxime sodium as well as higher increase in this value during holding time. Whereas using Sodium lactate and Sodium acetate with Buffer results in change in color from almost white powder to powder with yellow tinge within two weeks. While using Buffer with Sodium-2-ethyl hexanoate as per instant invention results in stable Cefuroxime sodium having color of white powder even after one month.

Table 2: Cefuroxime Sodium
Route Holding Time at 20-25°C temp Description Color Value @450nm
Sodium Lactate &
Sodium Acetate without Buffer Before Holding Light yellow powder 0.207
after 7 days Light yellow powder 0.250
after 15 days Light yellow powder 0.267
after 30 days Light yellow powder 0.292

Sodium Lactate &
Sodium Acetate with Buffer Before Holding Almost White powder 0.080
after 7 days Almost White powder 0.081
after 15 days Almost White with Yellow tinge powder 0.087
after 30 days Light yellow powder 0.100

Sodium-2-ethyl hexanoate
route with Buffer
(Instant Invention) Before Holding Almost White powder 0.053
after 7 days Almost White powder 0.057
after 15 days Almost White powder 0.059
after 30 days Almost White powder 0.081

ADVANTAGES OF THE INVENTION

Compared with prior art, the beneficial effects of the present invention are:
1. Process of the instant invention results in stable Cefuroxime sodium.
2. Cefuroxime sodium as per process of instant invention is stable on storage for prolonged period of time.
3. Cefuroxime sodium prepared according process of instant invention is essentially free of color impurities.
4. Purity and yield of Cefuroxime sodium prepared according process of instant invention is high as compare to prior art.
5. Cefuroxime sodium prepared according process of instant invention meets pharmacopoeial limits of pH and appearance/description requirement.
6. Operational time cycle of the instant invention is very lesser than prior art process.
7. Quantity of solvent is significantly reduced in the process of instant invention as compare to prior art process by avoiding multiple times decantation of solvent.

Having described the invention with reference to certain preferred embodiments, other embodiments will become apparent to one skilled in the art from consideration of the specification. The invention is further defined by reference to the following examples describing in detail and are not intended and should not be interpreted as a limitation thereon. Modifications to reaction conditions, for example, temperature, duration of the reaction or combinations thereof, are envisioned as part of the present invention.

EXAMPLES

Comparative Example 1
Preparation of Cefuroxime sodium by Sodium Lactate & Sodium Acetate route
Preparation of Sodium acetate trihydrate solution:
13.25gm sodium lactate was added to 180 ml of methanol at 25-30°C. Then Sodium acetate trihydrate solution (8.75gm Sodium Acetate Trihydrate dissolve in 21.5ml Water for Injection) was added to reaction mixture and the temperature was raised to 30°C-32°C. Reaction mixture was filtered through micron filter. Temperature of reaction mixture was raised to 42°C-45°C. Then 500ml of micron filtered acetone was added to this reaction mixture and stirred the solution.
Preparation of Cefuroxime sodium: 50g Cefuroxime acid was added to a mixture of 375 ml of acetone & 200 ml of methanol. The temperature of reaction mixture was raised to 38°C-42°C & stirred. Then 3.0g of activated carbon was added & cool the reaction mixture to 28°C-32°C. The reaction mixture was filtered through Hyflo bed followed by micron filter & washed with 100 ml of acetone. Then Sodium acetate trihydrate solution, as prepared above, was added to this reaction mixture and stirred. After settling, decantation of solvents was performed multiple times by using acetone. Then reaction mixture was filtered and washing was done by using mixture of acetone and Water for Injection. The product Cefuroxime sodium was dried in vacuum tray dryer.
Yield- 0.93w/w
pH of Cefuroxime sodium: 6.5
Color Value @450nm of Cefuroxime sodium: 0.207

Comparative Example 2
Preparation of Cefuroxime sodium by Sodium Lactate & Sodium Acetate route
Preparation of Sodium acetate trihydrate solution:
13.25gm sodium lactate was added to 180 ml of methanol at 25-30°C. Then Sodium acetate trihydrate solution (8.75gm Sodium Acetate Trihydrate dissolve in 21.5ml Water for Injection) was added to reaction mixture and the temperature was raised to 30°C-32°C. Reaction mixture was filtered through micron filter. Temperature of reaction mixture was raised to 42°C-45°C. Then 500ml of micron filtered acetone was added to this reaction mixture and stirred the solution.
Preparation of Cefuroxime sodium: 50g Cefuroxime acid was added to a mixture of 375 ml of acetone & 200 ml of methanol. The temperature of reaction mixture was raised to 38°C-42°C & stirred. Then 2.86g of activated carbon was added & cool the reaction mixture to 28°C-32°C. The reaction mixture was filtered through Hyflo bed followed by micron filter & washed with 100 ml of acetone. Then Sodium acetate trihydrate solution, as prepared above, was added to this reaction mixture and stirred. After settling, decantation of solvents was performed multiple times by using acetone. Then reaction mixture was filtered and washing was done by using mixture of acetone and Water for Injection. The product Cefuroxime sodium was dried in vacuum tray dryer.
Yield- 0.92w/w
pH of Cefuroxime sodium: 6.73
Color Value @450nm of Cefuroxime sodium: 0.180

Comparative Example 3
Preparation of Cefuroxime sodium by Sodium-2-ethyl hexanoate route without Buffer
50g of Cefuroxime acid was added to a mixture of 400 ml of acetone & 200 ml of methanol. The temperature of reaction mixture was raised to 30°C-35°C & stirred. Then 3.0g of activated carbon was added. The reaction mixture was filtered through Hyflo bed followed by micron filter & washed with 100 ml of acetone. Then Sodium-2-ethyl hexanoate (SEH) solution (21.5g SEH into 150ml acetone) was slowly added to this reaction mixture and stirred the crystallized reaction mass. The product Cefuroxime sodium was filtered and dried in vacuum tray dryer.
Yield- 1.008 w/w
pH of Cefuroxime sodium: 4.0
Color Value @450nm of Cefuroxime sodium: 0.119

Comparative Example 4
Preparation of Cefuroxime sodium by Sodium-2-ethyl hexanoate route without Buffer
50g of Cefuroxime acid was added to a mixture of 400 ml of acetone & 200 ml of methanol. The temperature of reaction mixture was raised to 30°C-35°C & stirred. Then 3.0g of activated carbon was added. The reaction mixture was filtered through Hyflo bed followed by micron filter & washed with 100 ml of acetone. Then Sodium-2-ethyl hexanoate (SEH) solution (21.5g SEH into 150ml acetone) was slowly added to this reaction mixture and stirred the crystallized reaction mass. The product Cefuroxime sodium was filtered and dried in vacuum tray dryer.
Yield- 1.002 w/w
pH of Cefuroxime sodium: 4.23
Color Value @450nm of Cefuroxime sodium: 0.126

Example 1 (Instant invention)
Preparation of Cefuroxime sodium by Sodium-2-ethyl hexanoate route with Buffer
50g of Cefuroxime acid was added to a mixture of 400 ml of acetone & 200 ml of methanol. The temperature of reaction mixture was raised to 30°C-35°C & stirred. Then Disodium hydrogen phosphate Buffer solution (2.0g Disodium hydrogen phosphate dihydrate into 37.5ml of water for injection) was slowly added to this reaction mixture. Then 3.0g of activated carbon was added to this reaction mixture and stirred. The reaction mixture was filtered through Hyflo bed followed by micron filter & washed with 100 ml of acetone. Then Sodium-2-ethyl hexanoate (SEH) solution (21.5g SEH into 150 ml acetone) was slowly added to this reaction mixture and stirred the crystallized reaction mass. The product Cefuroxime sodium was filtered and dried in vacuum tray dryer.
Yield- 1.01 w/w
pH of Cefuroxime sodium: 6.54
Color Value @450nm of Cefuroxime sodium: 0.009

Example 2 (Instant invention)
Preparation of Cefuroxime sodium by Sodium-2-ethyl hexanoate route with Buffer
100g of Cefuroxime acid was added to a mixture of 800 ml of acetone & 400 ml of methanol. The temperature of reaction mixture was raised to 30°C-35°C & stirred. Then Disodium hydrogen phosphate Buffer solution (4.0g Disodium hydrogen phosphate dihydrate into 75ml of water for injection) was slowly added to this reaction mixture. Then 6.0g of activated carbon was added to this reaction mixture and stirred. The reaction mixture was filtered through Hyflo bed followed by micron filter & washed with 200 ml of acetone. Then Sodium-2-ethyl hexanoate (SEH) solution (43g SEH into 300 ml acetone) was slowly added to this reaction mixture and stirred the crystallized reaction mass. The product Cefuroxime sodium was filtered and dried in vacuum tray dryer.
Yield- 1.008 w/w
pH of Cefuroxime sodium: 6.21
Color Value @450nm of Cefuroxime sodium: 0.011

Example 3 (Instant invention)
Preparation of Cefuroxime sodium by Sodium-2-ethyl hexanoate route with Buffer
50g of Cefuroxime acid was added to a mixture of 450 ml of acetone, 200 ml of methanol and 50 ml of water. The temperature of reaction mixture was raised to 30°C-35°C & stirred. Then Disodium hydrogen phosphate Buffer solution (2.0g Disodium hydrogen phosphate dihydrate into 25ml of water for injection) was slowly added to this reaction mixture. Then 3.0g of activated carbon was added to this reaction mixture and stirred. The reaction mixture was filtered through Hyflo bed followed by micron filter & washed with 100 ml of acetone. Then Sodium-2-ethyl hexanoate (SEH) solution (21.5g SEH into 150 ml acetone) was slowly added to this reaction mixture and stirred the crystallized reaction mass. The product Cefuroxime sodium was filtered and dried in vacuum tray dryer.
Yield- 1.00 w/w
pH of Cefuroxime sodium: 6.53
Color Value @450nm of Cefuroxime sodium: 0.008

Example 4 (Instant invention)
Preparation of Cefuroxime sodium by Sodium-2-ethyl hexanoate route with Buffer
100g of Cefuroxime acid was added to a mixture of 900 ml of acetone & 400 ml of methanol. The temperature of reaction mixture was raised to 30°C-35°C & stirred. Then Diammonium hydrogen phosphate Buffer solution (3.0g Diammonium hydrogen phosphate into 150ml of water for injection) was slowly added to this reaction mixture. Then 6.0g of activated carbon was added to this reaction mixture and stirred. The reaction mixture was filtered through Hyflo bed followed by micron filter & washed with 200 ml of acetone. Then Sodium-2-ethyl hexanoate (SEH) solution (42g SEH into 450 ml acetone) was slowly added to this reaction mixture and stirred the crystallized reaction mass. The product Cefuroxime sodium was filtered and dried in vacuum tray dryer.
Yield- 1.002 w/w
pH of Cefuroxime sodium: 5.95
Color Value @450nm of Cefuroxime sodium: 0.048

Example 5 (Instant invention)
Preparation of Cefuroxime sodium by Sodium-2-ethyl hexanoate route with Buffer
100g of Cefuroxime acid was added to a mixture of 900 ml of acetone & 400 ml of methanol. The temperature of reaction mixture was raised to 30°C-35°C & stirred. Then Ammonium dihydrogen phosphate Buffer solution (2.6g Ammonium dihydrogen phosphate into 150ml of water for injection) was slowly added to this reaction mixture. Then 6.0g of activated carbon was added to this reaction mixture and stirred. The reaction mixture was filtered through Hyflo bed followed by micron filter & washed with 200 ml of acetone. Then Sodium-2-ethyl hexanoate (SEH) solution (42g SEH into 450 ml acetone) was slowly added to this reaction mixture and stirred the crystallized reaction mass. The product Cefuroxime sodium was filtered and dried in vacuum tray dryer.
Yield- 1.001 w/w
pH of Cefuroxime sodium: 6.30
Color Value @450nm of Cefuroxime sodium: 0.063

Example 6 (Instant invention)
Preparation of Cefuroxime sodium by Sodium-2-ethyl hexanoate route with Buffer
100g of Cefuroxime acid was added to a mixture of 900 ml of acetone & 400 ml of methanol. The temperature of reaction mixture was raised to 30°C-35°C & stirred. Then Potassium hydrogen phosphate Buffer solution (4.0g Potassium hydrogen phosphate into 150ml of water for injection) was slowly added to this reaction mixture. Then 6.0g of activated carbon was added to this reaction mixture and stirred. The reaction mixture was filtered through Hyflo bed followed by micron filter & washed with 200 ml of acetone. Then Sodium-2-ethyl hexanoate (SEH) solution (42g SEH into 450 ml acetone) was slowly added to this reaction mixture and stirred the crystallized reaction mass. The product Cefuroxime sodium was filtered and dried in vacuum tray dryer.
Yield- 1.00 w/w
pH of Cefuroxime sodium: 6.67
Color Value @450nm of Cefuroxime sodium: 0.059

Example 7 (Instant invention)
Preparation of Cefuroxime sodium by Sodium-2-ethyl hexanoate route with Buffer
100g of Cefuroxime acid was added to a mixture of 900 ml of acetone & 400 ml of methanol. The temperature of reaction mixture was raised to 30°C-35°C & stirred. Then Potassium dihydrogen phosphate Buffer solution (3.2g Potassium dihydrogen phosphate into 150ml of water for injection) was slowly added to this reaction mixture. Then 6.0g of activated carbon was added to this reaction mixture and stirred. The reaction mixture was filtered through Hyflo bed followed by micron filter & washed with 200 ml of acetone. Then Sodium-2-ethyl hexanoate (SEH) solution (42g SEH into 450 ml acetone) was slowly added to this reaction mixture and stirred the crystallized reaction mass. The product Cefuroxime sodium was filtered and dried in vacuum tray dryer.
Yield- 1.00 w/w
pH of Cefuroxime sodium: 6.20
Color Value @450nm of Cefuroxime sodium: 0.043

Example 8 (Instant invention)
Preparation of Cefuroxime sodium by Sodium-2-ethyl hexanoate route with Buffer
100g of Cefuroxime acid was added to a mixture of 900 ml of acetone & 400 ml of methanol. The temperature of reaction mixture was raised to 30°C-35°C & stirred. Then Sodium dihydrogen phosphate Buffer solution (3.6g Sodium dihydrogen phosphate into 150ml of water for injection) was slowly added to this reaction mixture. Then 6.0g of activated carbon was added to this reaction mixture and stirred. The reaction mixture was filtered through Hyflo bed followed by micron filter & washed with 200 ml of acetone. Then Sodium-2-ethyl hexanoate (SEH) solution (42g SEH into 450 ml acetone) was slowly added to this reaction mixture and stirred the crystallized reaction mass. The product Cefuroxime sodium was filtered and dried in vacuum tray dryer.
Yield- 1.003 w/w
pH of Cefuroxime sodium: 6.74
Color Value @450nm of Cefuroxime sodium: 0.081

Example 9 (Instant invention)
Preparation of Cefuroxime sodium by Sodium-2-ethyl hexanoate route with Buffer
100g of Cefuroxime acid was added to a mixture of 1500 ml of acetone & 400 ml of methanol. The reaction mixture was stirred at 20°C-25°C temperature. Then Sodium dihydrogen phosphate buffer solution (3.6g Sodium dihydrogen phosphate into 150ml of water for injection) was slowly added to this reaction mixture. Then 6.0g of activated carbon was added to this reaction mixture and stirred. The reaction mixture was filtered through Hyflo bed followed by micron filter & washed with 200 ml of acetone. Then Sodium-2-ethyl hexanoate (SEH) solution (42g SEH into 450 ml acetone) was slowly added to this reaction mixture and stirred the crystallized reaction mass. The product Cefuroxime sodium was filtered and dried in vacuum tray dryer.
Yield- 1.00 w/w
pH of Cefuroxime sodium: 6.67
Color Value @450nm of Cefuroxime sodium: 0.073
,CLAIMS:1. A process for the preparation of Cefuroxime sodium of Formula II

comprising the steps of:
(i) mixing Cefuroxime acid of Formula I with solvent;

(ii) adding Buffer to the reaction mixture;
(iii) optionally heating the reaction mixture;
(iv) optionally adding activated carbon to the reaction mixture;
(v) filtering the reaction mixture;
(vi) optionally heating the reaction mixture;
(vii) adding salt forming agent to the reaction mixture; and
(viii) isolating Cefuroxime sodium of Formula II.

2. The process as claimed in claim 1, wherein solvent in step (i) is selected from the group comprising of alcohol, ketone, water or mixture thereof.

3. The process as claimed in claim 2, wherein alcohol is selected from the group comprising of methanol, ethanol, 1-propanol, isopropyl alcohol, butanol, isobutyl alcohol, tert-butanol and mixture thereof.

4. The process as claimed in claim 2, wherein ketone is selected from the group comprising of acetone, methyl ethyl ketone, methyl iso-butyl ketone and mixture thereof.

5. The process as claimed in claim 1, wherein solvent in step (i) is mixture of methanol, acetone and water.

6. The process as claimed in claim 1, wherein Buffer in step (ii) selected from the group comprising of disodium hydrogen phosphate, sodium di-hydrogen phosphate, di-potassium hydrogen phosphate, potassium di-hydrogen phosphate, di-ammonium hydrogen phosphate, ammonium di-hydrogen phosphate, ACES Buffer, PIPES Buffer, MOPS Buffer, MOPSO Buffer, 2,6-lutidine.

7. The process as claimed in claim 1, wherein Buffer in step (ii) is disodium hydrogen phosphate.

8. The process as claimed in claim 1, wherein heating in step (iii) is carried out at temperature from 25oC-40oC.

9. The process as claimed in claim 1, wherein salt forming agent in step (vii) is selected from the group comprising of sodium 2-ethyl hexanoate, sodium 2-ethyl heptanoate, sodium 2-ethyl octanoate, sodium 2-ethyl nonanoate.

10. A process for the preparation of Cefuroxime sodium of Formula II

comprising the steps of:
(i) mixing Cefuroxime acid of Formula I with methanol, acetone and water;

(ii) adding disodium hydrogen phosphate Buffer to the reaction mixture;
(iii) optionally heating the reaction mixture;
(iv) optionally adding activated carbon to the reaction mixture;
(v) filtering the reaction mixture;
(vi) optionally heating the reaction mixture;
(vii) adding sodium-2-ethyl hexanoate to the reaction mixture; and
(viii) isolating Cefuroxime sodium of Formula II.