Indian Patents. 268372:CRYSTALLINE CEFTIOFUR SODIUM AND PROCESS FOR ITS PREPARATION

Title of Invention	CRYSTALLINE CEFTIOFUR SODIUM AND PROCESS FOR ITS PREPARATION
Abstract	The present invention relates to novel polymorph of Ceftiofur sodium as a crystalline product. The present invention also provides a process for the preparation of crystalline Ceftiofur sodium of formula (I).

Full Text	Field of the Invention The present invention relates to novel polymorph of Ceftiofur sodium as a crystalline product. This invention further relates to a process for the preparation of Ceftiofur sodium as a crystalline product. Background of the Invention Ceftiofur, a semisynthetic cephalosporin, is a broad-spectrum antibiotic against both Gram-positive and Gram-negative bacteria including beta-lactamase- producing bacterial strains and anaerobes. Its antibacterial activity results from the inhibition of mucopeptide synthesis in the cell wall in a similar fashion to other cephalosporins. Ceftiofur is used in the treatment of respiratory infections in cattle and pigs. The chemical designation is 7-[[(2-amino-4- thiazolyl)(methoxyimino)acetyl]amino]-3-[[2-furanylcarbonyl)thio]methyl]-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid. The sodium and hydrochloride salts are administered intramuscularly and intravenously. Ceftiofur is first disclosed in US patent no. 4,464,367, which also discloses a process for preparing Ceftiofur and its sodium salt. US patent No. 4,902,683 claims crystalline hydrochloride salt of Ceftiofur. According to this patent the conventional free acid and its sodium salt are unstable and are obtained as amorphous nature. US patent No. 5,721,359 claims a crystalline Ceftiofur free acid and a process for the preparation of the same. US patent No. 4,937,330 claims a process for the preparation of Ceftiofur sodium, though this patent mentioned the Ceftiofur sodium obtained according to this patent as a crystal form, this patent does not provide the X-ray diffraction pattern of the said crystal. According to this patent Ceftiofur sodium salt as isolated from aqueous tetrahydrofuran as a unique solid phase characterized by birefringent lath- and rod-shaped particles. However the x-ray diffraction of this unique gave no diffraction pattern. Moreover further treatment with a dry organic solvent (e.g., acetone or ethanol) produces solvent-free amorphous Ceftiofur sodium upon drying. Hence all the prior art literature reported so far provide amorphous Ceftiofur sodium, and, owing to the amorphous nature, the conventional Ceftiofur sodium is less stable. Further, owing to the amorphous nature, purification is very difficult, and hence not preferable in industrial point of view. Hence all the prior art literature reported so far provide amorphous Ceftiofur sodium, and, owing to the amorphous nature, the conventional Ceftiofur sodium is less stable. Further, owing to the amorphous nature, purification is very difficult, and hence not preferable in industrial point of view. In our continued research we have identified a process for the preparation of Ceftiofur sodium as a crystalline product, which is having good stability over conventional amorphous product. None of the prior art suggests or event motivates the present invention. Objectives of the Invention The primary objective of the invention is to provide a crystalline salt of Ceftiofur sodium of formula (I), which is having good stability than conventional amorphous Ceftiofur sodium. Another objective of the present invention is to provide a pharmaceutical composition containing crystalline salt of Ceftiofur sodium. Still another objective of the invention is to provide a process for the preparation of Ceftiofur sodium in crystalline form. Summary of the Invention Accordingly, the present invention provides novel crystalline form of Ceftiofur sodium of formula (I) having substantially the same X-ray diffractogram as set out in FIG. 1. The present invention also provides a process for the preparation of novel crystalline form of Ceftiofur sodium, which comprises the steps of: i) obtaining Ceftiofur sodium in water, ii) optionally adding an organic solvent, iii) adding alkaline or alkaline earth metal salts selected from group comprising of sodium chloride, sodium bicarbonate, sodium sulphate, sodium bromide and potassium dihydrgen orthophospate and or mixture there of, and iv) isolating Ceftiofur as crystalline product. Description of Figures Figure 1: Powder XRD pattern of crystalline form of Ceftiofur sodium of formula (I), analyzed by X-Ray Powder Diffractometer of following features: Detailed Description of the Invention In an embodiment of the present invention, novel crystalline form of Ceftiofur sodium of the formula (I) is characterized by X-ray powder diffraction with data given in the following table: In another embodiment of the present invention, novel crystalline form of Ceftiofur sodium of the formula (I) having an X-ray diffraction pattern which comprises the following characteristic peaks (±0.26): 9.68, 14.56, 14.74, 17.48, 19.88, 20.58, 21.14, 21.42, 21.92, 22.36, 23.94, 24.16, 25.08, 25.56, 28.30, 28.54, 28.76 in 20. Further the novel Ceftiofur crystalline sodium according to this invention having moisture content in the range of 7.0 to 11%. In an embodiment of the present invention, the organic solvent used in step (ii) is selected from THF, acetone, ethyl acetate, butyl acetate, ethyl methyl ketone, diglyme, butanone, dioxane, DMF, ethyl acetate and the like. The starting material of the present invention can be prepared or obtained by utilizing the process available in the prior art. Accordingly Ceftiofur sodium prepared according to prior art method was dissolved in water in the presence or absence of organic solvent, to the resultant solution alkaline or alkaline earth metal salts like sodium chloride were added. The resultant solution was optionally cooled to yield Ceftiofur sodium as crystalline product. In one more embodiment of the present invention, the crystalline Ceftiofur sodium of Formula 1 herein are useful as the active antibiotic drug compound in pharmaceutical dosage forms which will permit and provide higher bulk density forms of Ceftiofur. Crystalline materials are preferred in most pharmaceutical applications since crystalline forms have better flow properties, and are thermodynamically more stable than amorphous forms of the same substance. This thermodynamic stability is reflected in the lower solubility and improved physical stability of the crystalline form. The regular packing of the molecules in the crystalline solid denies the incorporation of chemical impurities. Hence crystalline materials generally possess higher chemical purity than their amorphous counterparts. The following Table provides a comparison of physical characteristics of amorphous and crystalline Ceftiofur Sodium. From this table it is evident that the crystalline Ceftiofur Sodium has better physical characteristics than amorphous material. Table-1 Comparison between Amorphous and Crystalline Ceftiofur sodium The following Tables (Table 2 & 3) provide stability data of crystalline Ceftiofur Sodium prepared according to this invention. From this it table it is evident that the crystalline Ceftiofur Sodium prepared according this invention is a very stable and a highly pure material, which is clearly indicated by total RS (Related substances) analysis & the stability data. Table-2 Stability at 40±2° C & 75±5% RH Table-3 Because of the good stability and purity of Crystalline Ceftiofur sodium as indicated by the above said tables, the potency of Crystalline Ceftiofur sodium is maintained over a long shelf period unlike the amorphous Ceftiofur Sodium. In one more embodiment of the present invention the Ceftiofur sodium obtained according to the present invention having good stability over conventional Ceftiofur sodium also has less residual solvent over the amorphous sample prepared by prior art. Crystalline Ceftiofur sodium obtained according to the present invention may be used in the same indications as Ceftiofur sodium provided by a prior art process or Ceftiofur sodium currently on market. Crystalline Ceftiofur sodium according to this invention useful as the active antibiotic drug compound in pharmaceutical dosage forms for treating valuable mammalian animals and humans to treat bacterial infections in that valuable animal or human, and more particularly useful as a veterinary antibiotic drug to treat valuable animals such as cattle, swine, horses, sheep, goats, dogs and cats to fight the effects of bacterial infections caused by susceptible organisms, such as Pasturella hemolitica, Pasturella multiocida, Salmonella typhimurium, Salmonella choleraeasuis, Actinbacillus plearopneumoniae, Streptococcus suis, Haemophilus somnus, E. coli, Staphylococcus aureus and the like, some of which are commonly associated with diseases in animals, such as bovine respiratory disease and swine respiratory disease. In one more embodiment of the present invention the crystalline Ceftiofur sodium prepared according to the present invention may be administered in any conventional dosage form in any conventional manner, routes of administration and dosage form are exemplified in various prior art related to Ceftiofur and also exemplified in US 4,464,367; U.S. 4,902,683, U.S. 5,079,007, U.S. 5,013,713, and US 5,721,359. Apart from the conventional formulation that are described the Ceftiofur sodium formulation may also contain chelating agent like ethylene diamine tetraacetic acid (EDTA) or a buffer like sodium citrate along with or with out conventional excipient. The pharmaceutical composition may also contain amorphous Ceftiofur sodium along with crystalline Ceftiofur sodium. Surprisingly, it has been observed that the crystalline Ceftiofur sodium as well as mixture of crystalline Ceftiofur sodium along with amorphous material are non-hygroscopic, whereas conventional amorphous Ceftiofur sodium is highly hygroscopic in nature. Because of the hygroscopic nature, amorphous form is relatively less stable. Many other beneficial results can be obtained by applying disclosed invention in a different manner or by modifying the invention with the scope of disclosure. The present invention is provided by the examples below, which are provided by way of illustration only and should not be considered to limit the scope of the invention. Preparation of Crystalline Ceftiofur sodium: Example 1: To a clear solution of Ceftiofur sodium (5.0 g) in water (100 ml) was added sodium chloride (5 g) at ~ 30 °C slowly. The resultant suspension was stirred for 1.0 Hr at 10 °C. The solid obtained was filtered washed with water and dried to yield crystalline Ceftiofur sodium in pure form. Yield: 2.5 g Purity: 99.79 %. Moisture content: 9.84 %. Advantages: • None of the prior art suggests the preparation of Ceftiofur sodium as crystalline. All the prior art process provides amorphous Ceftiofur sodium, whereas present invention provides Crystalline Ceftiofur sodium. • Good stability even at elevated temperature. • High purity and non-hygroscopic nature. • Good flow-properties and high bulk density. Example 2: To a clear solution of Ceftiofur sodium (5.0 g) in water (62.5 ml) was added a solution of sodium chloride (5 g) in water (20 ml) at 10 - 30 °C slowly. The resultant suspension was stirred for 1.0 Hr at 10 - 30 °C. The solid obtained was filtered, washed with water (2.5 ml) and dried to yield crystalline Ceftiofur sodium in pure form. Yield: 3.0 g; Purity: 99.8 %. Moisture content: 9.17 % Example 3: To a clear solution of Ceftiofur sodium (5.0 g) in water (100 ml) were added acetone (1 ml) and sodium chloride (5 g) at 10 - 30 °C slowly. The resultant suspension was stirred for 1.0 Hr at 10-30 °C. The solid formed was filtered, washed with water and dried to yield Ceftiofur sodium in pure form. Yield: 2.6 g Purity: 99.68 %. Moisture content: 7.92 % Example 4: To a clear solution of Ceftiofur sodium (5.0 g) in water (100 ml) were added THF (1 ml) and sodium chloride (5 g) at 10 - 30 °C. The resultant suspension was stirred for 1.0 Hr at 10 - 30 °C. The solid obtained was filtered, washed with water and dried to yield Ceftiofur sodium in pure form. Yield: 2.6 g Purity: 99.71 %. Moisture content: 8.63 % Example 5: To a clear solution of Ceftiofur sodium (5.0 g) in water (100 ml) were added Ethyl acetate (1 ml) and sodium chloride (5 g) at 10 - 30 °C. The resultant suspension was stirred for 1.0 Hr at 10 - 30 °C. The solid formed was filtered, washed with water and dried to yield Ceftiofur sodium in pure form. Yield: 2.55 g Purity: 99.69 %. Example 6: Preparation of Ceftiofur Sodium: To a clear solution of Ceftiofur sodium crude (50.0 g) in water (1000 ml) was added sodium chloride (50 g) at 10-30 °C slowly. The resultant mixture was stirred for 6.0 Hr at 10-30 °C. Filtering the solid, washing with water (25 ml) and drying afforded crystalline Ceftiofur sodium in pure form (30 g; purity by HPLC 99.80%). Moisture content: 9.45 % Example 7: Preparation of Ceftiofur Sodium: To a clear solution of Ceftiofur sodium crude (50.0 g) in water (1000 ml) was added sodium sulphate (100 g) at 10-30 °C slowly. The resultant mixture was stirred for 6.0 Hr at 10-30 °C. Filtering the solid, washing with water (25 ml) and drying afforded crystalline Ceftiofur sodium in pure form (28 g; purity by HPLC 99.70%). Example 8: Preparation of Ceftiofur Sodium Sterile: To a suspension of Ceftiofur sodium (15 g) in water (75 ml) was added sodium bicarbonate to adjust the pH to 7.0 - 8.5. To the resulting mixture was added a solution of potassium dihydrogen orthophosphate (0.36 g) in water (8.6 ml). The pH of the solution was adjusted to 6.5 - 7.0 using sodium bicarbonate. The resulting solution was filtered through 0.2 \i filter and lyophilized to get pure Ceftiofur sodium sterile. Example 9: Preparation of Ceftiofur hydrochloride: To a suspension of crystalline Ceftiofur sodium (10 g) in water (30ml) was added THF (87 ml) at 10-30 °C. To that sodium chloride (14 g) was added. pH of the solution was adjusted to 2.5 -3.5. Organic layer pH was adjusted to 0.5-1.5 using cone. HC1. Addition of diisopropyl ether followed by filtration yielded pure title compound.] Example 10: Crystalline Ceftiofur sodium from Ceftiofur hydrochloride: To a suspension of ceftiofur hydrochloride (25 g) in water (400 ml) was added sodium bicarbonate till to get clear solution (pH 6.5 - 8.5). To the clear solution, a solution of sodium chloride (22.5 g) in water (100 ml) was added slowly and the resultant suspension was stirred for 1.0 hr at 10 - 30 °C. The solid obtained was filtered and washed with water (2.5 ml) to yield crystalline Ceftiofur sodium in pure form. Yield 7.5 g; purity 99.74 %; Moisture content: 10.08 % Example 11: Preparation of Ceftiofur sodium crystalline buffered with potassium dihydrogen orthophosphate: Crystalline Ceftiofur sodium (100 g) was blended with potassium dihydrogen orthophosphate (2.4 g) and sodium bicarbonate till to get uniform pH. We claim: 1. Novel crystalline salt of Ceftiofur sodium of formula having substantially the same X-ray diffractogram as set out in FIG. 1. 2. A process for the preparing Ceftiofur sodium of formula (I) having substantially the same X-ray diffractogram as set out in FIG. 1, which comprises the steps of: i) obtaining Ceftiofur sodium in water, ii) optionally adding an organic solvent iii) adding alkaline or alkaline earth metal salts, and iv) isolating Ceftiofur sodium as crystalline product. 3. A process as claimed in claim 2, wherein the organic solvent is selected from THF, acetone, ethyl methyl ketone, diglyme, butanone, dioxane, acetonitrile, methanol, ethanol, isopropyl alcohol, ethylacetate or DMF. 4. A process as claimed in claim 2, wherein alkaline or alkaline earth metal salts used in step (iii) is selected from group comprising of sodium chloride, sodium bicarbonate, sodium sulphate, sodium bromide, potassium dihydrogen orthophospate or mixture there of. 5. A pharmaceutical composition comprising the crystalline Ceftiofur sodium of claim 1 having substantially the same X-ray diffractogram as set out in FIG. 1, and a pharmaceutically acceptable carrier and/or buffer. 6. Physical admixture of crystalline Ceftiofur sodium according to claim 1, with potassium dihydrogen orthophosphate and sodium bicarbonate. 7. Novel crystalline Ceftiofur sodium of formula (I) having an X-ray diffraction pattern, which comprises the characteristics peaks of 9.68, 14.56, 14.74, 17.48, 19.88, 20.58, 21.14, 21.42, 21.92, 22.36, 23.94, 24.16, 25.08, 25.56, 28.30, 28.54, 28.76 (±0.20), in 20. 8. Novel crystalline Ceftiofur Sodium as claimed in claim 10, having the moisture content in the range of 7.0 to 11%. 9. A pharmaceutical composition comprising a mixture of crystalline Ceftiofur Sodium as claimed in claim 1 with amorphous Ceftiofur sodium. 10. A process for the crystalline Ceftiofur sodium of formula (I) having an X-ray diffraction pattern, which comprises the characteristics peaks of 9.68, 14.56, 14.74, 17.48, 19.88, 20.58, 21.14, 21.42, 21.92, 22.36, 23.94, 24.16, 25.08, 25.56, 28.30, 28.54, 28.76 (±0.20) in 20, which comprises the steps of: i) dissolving Ceftiofur sodium in water, ii) optionally adding an organic solvent iii) adding alkaline or alkaline earth metal salts selected from group comprising of sodium chloride, sodium bicarbonate, sodium sulphate, sodium bromide and potassium/sodium dihydrgen orthophospate or mixture there of, and iv) isolating Ceftiofur as crystalline product.

Full Text

Field of the Invention
The present invention relates to novel polymorph of Ceftiofur sodium as a crystalline product. This invention further relates to a process for the preparation of Ceftiofur sodium as a crystalline product.

Background of the Invention
Ceftiofur, a semisynthetic cephalosporin, is a broad-spectrum antibiotic
against both Gram-positive and Gram-negative bacteria including beta-lactamase-
producing bacterial strains and anaerobes. Its antibacterial activity results from the
inhibition of mucopeptide synthesis in the cell wall in a similar fashion to other
cephalosporins. Ceftiofur is used in the treatment of respiratory infections in cattle
and pigs. The chemical designation is 7-[[(2-amino-4-
thiazolyl)(methoxyimino)acetyl]amino]-3-[[2-furanylcarbonyl)thio]methyl]-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid. The sodium and hydrochloride salts are administered intramuscularly and intravenously.
Ceftiofur is first disclosed in US patent no. 4,464,367, which also discloses a process for preparing Ceftiofur and its sodium salt.

US patent No. 4,902,683 claims crystalline hydrochloride salt of Ceftiofur. According to this patent the conventional free acid and its sodium salt are unstable and are obtained as amorphous nature.
US patent No. 5,721,359 claims a crystalline Ceftiofur free acid and a process for the preparation of the same.
US patent No. 4,937,330 claims a process for the preparation of Ceftiofur sodium, though this patent mentioned the Ceftiofur sodium obtained according to this patent as a crystal form, this patent does not provide the X-ray diffraction pattern of the said crystal. According to this patent Ceftiofur sodium salt as isolated from aqueous tetrahydrofuran as a unique solid phase characterized by birefringent lath- and rod-shaped particles. However the x-ray diffraction of this unique gave no diffraction pattern. Moreover further treatment with a dry organic solvent (e.g., acetone or ethanol) produces solvent-free amorphous Ceftiofur sodium upon drying.
Hence all the prior art literature reported so far provide amorphous Ceftiofur sodium, and, owing to the amorphous nature, the conventional Ceftiofur sodium is less stable. Further, owing to the amorphous nature, purification is very difficult, and hence not preferable in industrial point of view.
Hence all the prior art literature reported so far provide amorphous Ceftiofur sodium, and, owing to the amorphous nature, the conventional Ceftiofur sodium is less stable. Further, owing to the amorphous nature, purification is very difficult, and hence not preferable in industrial point of view.

In our continued research we have identified a process for the preparation of Ceftiofur sodium as a crystalline product, which is having good stability over conventional amorphous product. None of the prior art suggests or event motivates the present invention.
Objectives of the Invention
The primary objective of the invention is to provide a crystalline salt of Ceftiofur sodium of formula (I), which is having good stability than conventional amorphous Ceftiofur sodium.
Another objective of the present invention is to provide a pharmaceutical composition containing crystalline salt of Ceftiofur sodium.
Still another objective of the invention is to provide a process for the preparation of Ceftiofur sodium in crystalline form.
Summary of the Invention
Accordingly, the present invention provides novel crystalline form of Ceftiofur sodium of formula (I)

having substantially the same X-ray diffractogram as set out in FIG. 1.

The present invention also provides a process for the preparation of novel crystalline form of Ceftiofur sodium, which comprises the steps of:
i) obtaining Ceftiofur sodium in water,
ii) optionally adding an organic solvent,
iii) adding alkaline or alkaline earth metal salts selected from group comprising of sodium chloride, sodium bicarbonate, sodium sulphate, sodium bromide and potassium dihydrgen orthophospate and or mixture there of, and
iv) isolating Ceftiofur as crystalline product.
Description of Figures
Figure 1: Powder XRD pattern of crystalline form of Ceftiofur sodium of formula (I), analyzed by X-Ray Powder Diffractometer of following features:

Detailed Description of the Invention
In an embodiment of the present invention, novel crystalline form of Ceftiofur sodium of the formula (I) is characterized by X-ray powder diffraction with data given in the following table:

In another embodiment of the present invention, novel crystalline form of Ceftiofur sodium of the formula (I) having an X-ray diffraction pattern which comprises the following characteristic peaks (±0.26): 9.68, 14.56, 14.74, 17.48, 19.88, 20.58, 21.14, 21.42, 21.92, 22.36, 23.94, 24.16, 25.08, 25.56, 28.30, 28.54, 28.76 in 20. Further the novel Ceftiofur crystalline sodium according to this invention having moisture content in the range of 7.0 to 11%.
In an embodiment of the present invention, the organic solvent used in step (ii) is selected from THF, acetone, ethyl acetate, butyl acetate, ethyl methyl ketone, diglyme, butanone, dioxane, DMF, ethyl acetate and the like.

The starting material of the present invention can be prepared or obtained by utilizing the process available in the prior art. Accordingly Ceftiofur sodium prepared according to prior art method was dissolved in water in the presence or absence of organic solvent, to the resultant solution alkaline or alkaline earth metal salts like sodium chloride were added. The resultant solution was optionally cooled to yield Ceftiofur sodium as crystalline product.
In one more embodiment of the present invention, the crystalline Ceftiofur sodium of Formula 1 herein are useful as the active antibiotic drug compound in pharmaceutical dosage forms which will permit and provide higher bulk density forms of Ceftiofur.
Crystalline materials are preferred in most pharmaceutical applications since crystalline forms have better flow properties, and are thermodynamically more stable than amorphous forms of the same substance. This thermodynamic stability is reflected in the lower solubility and improved physical stability of the crystalline form. The regular packing of the molecules in the crystalline solid denies the incorporation of chemical impurities. Hence crystalline materials generally possess higher chemical purity than their amorphous counterparts.
The following Table provides a comparison of physical characteristics of amorphous and crystalline Ceftiofur Sodium. From this table it is evident that the crystalline Ceftiofur Sodium has better physical characteristics than amorphous material.

Table-1 Comparison between Amorphous and Crystalline Ceftiofur sodium

The following Tables (Table 2 & 3) provide stability data of crystalline Ceftiofur Sodium prepared according to this invention. From this it table it is evident that the crystalline Ceftiofur Sodium prepared according this invention is a very stable and a highly pure material, which is clearly indicated by total RS (Related substances) analysis & the stability data.
Table-2 Stability at 40±2° C & 75±5% RH

Table-3 Because of the good stability and purity of Crystalline Ceftiofur sodium as indicated by the above said tables, the potency of Crystalline Ceftiofur sodium is maintained over a long shelf period unlike the amorphous Ceftiofur Sodium.
In one more embodiment of the present invention the Ceftiofur sodium obtained according to the present invention having good stability over conventional Ceftiofur sodium also has less residual solvent over the amorphous sample prepared by prior art.
Crystalline Ceftiofur sodium obtained according to the present invention may be used in the same indications as Ceftiofur sodium provided by a prior art process or Ceftiofur sodium currently on market. Crystalline Ceftiofur sodium according to this invention useful as the active antibiotic drug compound in pharmaceutical dosage forms for treating valuable mammalian animals and humans to treat bacterial infections in that valuable animal or human, and more particularly useful as a veterinary antibiotic drug to treat valuable animals such as cattle, swine, horses, sheep, goats, dogs and cats to fight the effects of bacterial infections caused by susceptible organisms, such as Pasturella hemolitica, Pasturella multiocida, Salmonella typhimurium, Salmonella choleraeasuis, Actinbacillus plearopneumoniae, Streptococcus suis, Haemophilus somnus, E. coli,

Staphylococcus aureus and the like, some of which are commonly associated with diseases in animals, such as bovine respiratory disease and swine respiratory disease.
In one more embodiment of the present invention the crystalline Ceftiofur sodium prepared according to the present invention may be administered in any conventional dosage form in any conventional manner, routes of administration and dosage form are exemplified in various prior art related to Ceftiofur and also exemplified in US 4,464,367; U.S. 4,902,683, U.S. 5,079,007, U.S. 5,013,713, and US 5,721,359.
Apart from the conventional formulation that are described the Ceftiofur sodium formulation may also contain chelating agent like ethylene diamine tetraacetic acid (EDTA) or a buffer like sodium citrate along with or with out conventional excipient. The pharmaceutical composition may also contain amorphous Ceftiofur sodium along with crystalline Ceftiofur sodium. Surprisingly, it has been observed that the crystalline Ceftiofur sodium as well as mixture of crystalline Ceftiofur sodium along with amorphous material are non-hygroscopic, whereas conventional amorphous Ceftiofur sodium is highly hygroscopic in nature. Because of the hygroscopic nature, amorphous form is relatively less stable.
Many other beneficial results can be obtained by applying disclosed invention in a different manner or by modifying the invention with the scope of disclosure.

The present invention is provided by the examples below, which are provided by way of illustration only and should not be considered to limit the scope of the invention.
Preparation of Crystalline Ceftiofur sodium: Example 1:
To a clear solution of Ceftiofur sodium (5.0 g) in water (100 ml) was added sodium chloride (5 g) at ~ 30 °C slowly. The resultant suspension was stirred for 1.0 Hr at 10 °C. The solid obtained was filtered washed with water and dried to yield crystalline Ceftiofur sodium in pure form. Yield: 2.5 g Purity: 99.79 %. Moisture content: 9.84 %.
Advantages:
• None of the prior art suggests the preparation of Ceftiofur sodium as crystalline. All the prior art process provides amorphous Ceftiofur sodium, whereas present invention provides Crystalline Ceftiofur sodium.
• Good stability even at elevated temperature.
• High purity and non-hygroscopic nature.
• Good flow-properties and high bulk density.
Example 2:
To a clear solution of Ceftiofur sodium (5.0 g) in water (62.5 ml) was added a solution of sodium chloride (5 g) in water (20 ml) at 10 - 30 °C slowly. The resultant suspension was stirred for 1.0 Hr at 10 - 30 °C. The solid obtained was

filtered, washed with water (2.5 ml) and dried to yield crystalline Ceftiofur sodium in pure form. Yield: 3.0 g; Purity: 99.8 %. Moisture content: 9.17 %
Example 3:
To a clear solution of Ceftiofur sodium (5.0 g) in water (100 ml) were added acetone (1 ml) and sodium chloride (5 g) at 10 - 30 °C slowly. The resultant suspension was stirred for 1.0 Hr at 10-30 °C. The solid formed was filtered, washed with water and dried to yield Ceftiofur sodium in pure form. Yield: 2.6 g Purity: 99.68 %. Moisture content: 7.92 %
Example 4:
To a clear solution of Ceftiofur sodium (5.0 g) in water (100 ml) were added THF (1 ml) and sodium chloride (5 g) at 10 - 30 °C. The resultant suspension was stirred for 1.0 Hr at 10 - 30 °C. The solid obtained was filtered, washed with water and dried to yield Ceftiofur sodium in pure form. Yield: 2.6 g Purity: 99.71 %. Moisture content: 8.63 %
Example 5:
To a clear solution of Ceftiofur sodium (5.0 g) in water (100 ml) were added Ethyl acetate (1 ml) and sodium chloride (5 g) at 10 - 30 °C. The resultant suspension was stirred for 1.0 Hr at 10 - 30 °C. The solid formed was filtered, washed with water and dried to yield Ceftiofur sodium in pure form. Yield: 2.55 g Purity: 99.69 %.

Example 6:
Preparation of Ceftiofur Sodium:
To a clear solution of Ceftiofur sodium crude (50.0 g) in water (1000 ml) was added sodium chloride (50 g) at 10-30 °C slowly. The resultant mixture was stirred for 6.0 Hr at 10-30 °C. Filtering the solid, washing with water (25 ml) and drying afforded crystalline Ceftiofur sodium in pure form (30 g; purity by HPLC 99.80%). Moisture content: 9.45 %
Example 7:
Preparation of Ceftiofur Sodium:
To a clear solution of Ceftiofur sodium crude (50.0 g) in water (1000 ml) was added sodium sulphate (100 g) at 10-30 °C slowly. The resultant mixture was stirred for 6.0 Hr at 10-30 °C. Filtering the solid, washing with water (25 ml) and drying afforded crystalline Ceftiofur sodium in pure form (28 g; purity by HPLC 99.70%).
Example 8:
Preparation of Ceftiofur Sodium Sterile:
To a suspension of Ceftiofur sodium (15 g) in water (75 ml) was added sodium bicarbonate to adjust the pH to 7.0 - 8.5. To the resulting mixture was added a solution of potassium dihydrogen orthophosphate (0.36 g) in water (8.6 ml). The pH of the solution was adjusted to 6.5 - 7.0 using sodium bicarbonate. The resulting solution was filtered through 0.2 \i filter and lyophilized to get pure Ceftiofur sodium sterile.

Example 9:
Preparation of Ceftiofur hydrochloride:
To a suspension of crystalline Ceftiofur sodium (10 g) in water (30ml) was added THF (87 ml) at 10-30 °C. To that sodium chloride (14 g) was added. pH of the solution was adjusted to 2.5 -3.5. Organic layer pH was adjusted to 0.5-1.5 using cone. HC1. Addition of diisopropyl ether followed by filtration yielded pure title compound.]
Example 10:
Crystalline Ceftiofur sodium from Ceftiofur hydrochloride:
To a suspension of ceftiofur hydrochloride (25 g) in water (400 ml) was added sodium bicarbonate till to get clear solution (pH 6.5 - 8.5). To the clear solution, a solution of sodium chloride (22.5 g) in water (100 ml) was added slowly and the resultant suspension was stirred for 1.0 hr at 10 - 30 °C. The solid obtained was filtered and washed with water (2.5 ml) to yield crystalline Ceftiofur sodium in pure form. Yield 7.5 g; purity 99.74 %; Moisture content: 10.08 %
Example 11:
Preparation of Ceftiofur sodium crystalline buffered with potassium dihydrogen orthophosphate:
Crystalline Ceftiofur sodium (100 g) was blended with potassium dihydrogen orthophosphate (2.4 g) and sodium bicarbonate till to get uniform pH.

We claim:
1. Novel crystalline salt of Ceftiofur sodium of formula

having substantially the same X-ray diffractogram as set out in FIG. 1.
2. A process for the preparing Ceftiofur sodium of formula (I) having substantially
the same X-ray diffractogram as set out in FIG. 1, which comprises the steps of:
i) obtaining Ceftiofur sodium in water,
ii) optionally adding an organic solvent
iii) adding alkaline or alkaline earth metal salts, and
iv) isolating Ceftiofur sodium as crystalline product.
3. A process as claimed in claim 2, wherein the organic solvent is selected from
THF, acetone, ethyl methyl ketone, diglyme, butanone, dioxane, acetonitrile,
methanol, ethanol, isopropyl alcohol, ethylacetate or DMF.
4. A process as claimed in claim 2, wherein alkaline or alkaline earth metal salts
used in step (iii) is selected from group comprising of sodium chloride, sodium
bicarbonate, sodium sulphate, sodium bromide, potassium dihydrogen
orthophospate or mixture there of.

5. A pharmaceutical composition comprising the crystalline Ceftiofur sodium of claim 1 having substantially the same X-ray diffractogram as set out in FIG. 1, and a pharmaceutically acceptable carrier and/or buffer.
6. Physical admixture of crystalline Ceftiofur sodium according to claim 1, with potassium dihydrogen orthophosphate and sodium bicarbonate.

7. Novel crystalline Ceftiofur sodium of formula (I) having an X-ray diffraction pattern, which comprises the characteristics peaks of 9.68, 14.56, 14.74, 17.48, 19.88, 20.58, 21.14, 21.42, 21.92, 22.36, 23.94, 24.16, 25.08, 25.56, 28.30, 28.54, 28.76 (±0.20), in 20.
8. Novel crystalline Ceftiofur Sodium as claimed in claim 10, having the moisture content in the range of 7.0 to 11%.
9. A pharmaceutical composition comprising a mixture of crystalline Ceftiofur Sodium as claimed in claim 1 with amorphous Ceftiofur sodium.
10. A process for the crystalline Ceftiofur sodium of formula (I) having an X-ray
diffraction pattern, which comprises the characteristics peaks of 9.68, 14.56, 14.74,
17.48, 19.88, 20.58, 21.14, 21.42, 21.92, 22.36, 23.94, 24.16, 25.08, 25.56, 28.30,
28.54, 28.76 (±0.20) in 20, which comprises the steps of:
i) dissolving Ceftiofur sodium in water, ii) optionally adding an organic solvent

iii) adding alkaline or alkaline earth metal salts selected from group comprising of sodium chloride, sodium bicarbonate, sodium sulphate, sodium bromide and potassium/sodium dihydrgen orthophospate or mixture there of, and
iv) isolating Ceftiofur as crystalline product.

Documents:

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Patent Number

268372

Indian Patent Application Number

1462/CHE/2005

PG Journal Number

35/2015

Publication Date

28-Aug-2015

Grant Date

27-Aug-2015

Date of Filing

12-Oct-2005

Name of Patentee

ORCHID CHEMICALS & PHARMACEUTICALS LTD

Applicant Address

ORCHID TOWERS 313, VALLUVAR KOTTAM HIGH ROAD NUNGAMBAKKAM CHENNAI-600 034 TAMIL NADU

Inventors:

#	Inventor's Name	Inventor's Address
1	UDAYAMPALAYAM PALANISAMY SENTHILKUMAR	ORCHID CHEMICALS&PHARMACEUTICALS LTD, 476/14, OLD MAHABALIPURAM ROAD, SHOLINGANALLUR, CHENNAI-600 119
2	KANAGARAJ SURESH KUMAR	ORCHID CHEMICALS&PHARMACEUTICALS LTD, 476/14, OLD MAHABALIPURAM ROAD, SHOLINGANALLUR, CHENNAI-600 119 TAMILNADU INDIA
3	SINGARAVEL MOHAN	ORCHID CHEMICALS&PHARMACEUTICALS LTD, 476/14, OLD MAHABALIPURAM ROAD, SHOLINGANALLUR, CHENNAI-600 119 TAMILNADU INDIA
4	LAKSHMINARAYANAN ARUNKUMAR	ORCHID CHEMICALS&PHARMACEUTICALS LTD, 476/14, OLD MAHABALIPURAM ROAD, SHOLINGANALLUR, CHENNAI-600 119 TAMILNADU INDIA

PCT International Classification Number

C07D 501/00

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA