The following specification describes the nature of the invention, and the manner in which it has to be performed:

Field of the Invention

The present application is patent of addition of our co-pending application number 1462/CHE/2005. The present invention relates to novel polymorph of Ceftiofur sodium of formula (I) as a crystalline product. This invention further relates to a process for the reparation of novel polymorph of Ceftiofur sodium.

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 in nature.

US patent No. 5,721,359 claims crystalline Ceftiofur free acid and process for the preparation of same.

US patent No. 4,937,330 claims a process for the preparation of Ceftiofur sodium. According to this patent Ceftiofur sodium is isolated from aqueous tetrahydrofuran as a unique solid phase characterized by birefringent lath- and rod- shaped particles. 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 large scale preparation.

In our PCT publication WO 2007/042917 (Indian Application No. 1462/CHE/2005) a novel polymorph of crystalline Ceftiofur Sodium having moisture content in the range of 7.0 to 11.0 % is provided and is named as Form D.

In our PCT publication WO 2010/020871 (Indian Application No. 2047/CHE/2008) a novel polymorph of anhydrous crystalline Ceftiofur Sodium (Form A) having moisture content in the range of 0.4-2.0% and Ceftiofur sodium monohydrate (Form M) having moisture content in the range of 3.0-4.5 % are provided. In our continued research we have identified novel crystalline form of

Ceftiofur sodium having moisture content in the range of 4.6 to 7.0% and having a distinct PXRD pattern, which is having good stability over conventional amorphous product. Objectives of the Invention

The primary objective of the present invention is to provide a novel crystalline polymorph of Ceftiofur sodium of formula (I) having moisture content in the range of 4.6-7.0 % hereinafter called as Form O of Ceftiofur sodium, which is having good stability than conventional amorphous Ceftiofur sodium.

Yet another objective of the present invention is to provide a pharmaceutical composition containing crystalline polymorph of Form O of Ceftiofur sodium. Still another objective of the invention is to provide a process for the preparation of crystalline polymorph of Form O of Ceftiofur sodium.

Summary of the Invention Accordingly, the present invention provides novel crystalline polymorph of

Ceftiofur sodium (Form O) of formula (I), having moisture content in the range of 4.6-7.0 % and having substantially the same X-ray diffractogram as set out in FIG. 1.

The present invention also provides a process for the preparation of Form O of Ceftiofur sodium which comprises controlled drying of hydrated polymorph of Ceftiofur sodium (Form D) at a temperature in the range of 35 to 50° C & under vacuum till the moisture content reaches 4.6 to 7.0 %.

Description of Figures

Figure 1: Powder XRD pattern of novel crystalline form of Ceftiofur sodium of formula (I) (Form O).

Figure 2: DSC comparison of Form O of present invention and Form D (as provided WO 2010/020871).

The PXRD is measured using Diffractometer of following features:

Detailed Description of the Invention

In an embodiment of the present invention, novel crystalline polymorph of Ceftiofur sodium (Form O) of formula (I) having moisture content in the range of 4.6-7.0 % is characterized by X-ray powder diffraction peaks (±0.2°2Θ) as shown in the following table- 1 :

Table-1

26.51 11.0

26.71 10.0

27.53 22.1

27.81 26.2

28.80 9.5

29.55 9.6

29.95 9.5

30.21 15.3

31.63 11.3

32.78 22.5

35.59 13.8

35.90 9.6

38.74 10.1

39.59 9.0

In one more embodiment of the present invention, the crystalline polymorph of Ceftiofur sodium (Form O) of formula (I) having moisture content 4.6-7.0 % is obtained by controlled drying of hydrated Ceftiofur sodium (Form D) under vacuum at a temperature in the range of 35 to 50° C for 1-3 hours till the moisture content reaches 4.6 to 7.0 %. The obtained Ceftiofur Form O is handled for the further operation preferably under dehumidified area. The moisture content of Ceftiofur sodium is measured by using Karl-Fisher technique. The Ceftiofur sodium obtained according to the present invention is stored under inert condition, for example packed under nitrogen atmosphere. Figure 2, clearly indicates the DSC of Form O of Ceftiofur sodium obtained present invention is different from the Form D.

The starting material of the present invention can be prepared or obtained by utilizing the process available in the prior art (for example prepared by utilizing the technique available in WO 2007/042917). 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.

In one more embodiment of the present invention, the Ceftiofur sodium obtained according to the present invention having good stability over conventional amorphous Ceftiofur sodium and also has less residual solvent over the amorphous sample prepared by prior art.

The following table provides a comparison of physical characteristics of amorphous and crystalline Ceftiofur Sodium (Form O). From this table, it is evident that the crystalline Ceftiofur Sodium Form-O has better physical characteristics than amorphous material.

Table-2

Comparison between Amorphous and Crystalline Ceftiofur sodium (Form O)

The crystalline Ceftiofur Sodium (Form O) prepared according to this invention has good stability for longer period and purity because of which the potency of crystalline Ceftiofur sodium is maintained over a long shelf life period unlike the amorphous Ceftiofur Sodium.

Form O of Ceftiofur sodium obtained according to the present invention may be used for the same indications as Ceftiofur sodium provided by a prior art process or Ceftiofur sodium currently on the market. Form O of 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 Form O of 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; US 4,902,683, US 5,079,007, US 5,013,713, and US 5,721,359. Apart from the conventional formulation that are described for the Ceftiofur sodium formulation may also contain chelating agent like ethylenediamine 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, Form D, Form M, Form A of Ceftiofur sodium along with crystalline Ceftiofur sodium (Form O). Accordingly the present invention provides a pharmaceutical composition comprising one or more of Ceftiofur sodium selected from Form O, amorphous form, Form D, Form M, and Form A. The pharmaceutical composition may also contain conventional buffer and/or base.

Many other beneficial results can be obtained by applying the 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.

Example 1:

Preparation of Ceftiofur sodium crystalline (Form O):

The crystalline Ceftiofur sodium having moisture content of about 7.0-11 % (prepared according to the process provided in WO 2007/042917) was dried under vacuum at 45 °C for 1 hour.

The powder XRD pattern substantially same as depicted in Fig-1 & Table- 1

Purity: 99.77 %. Moisture content: 6.43 %. Advantages:

• Enhanced stability even at elevated temperature.

• High purity.

• Good Colour, flow-properties and high bulk density.

• Suitable dissolubility & improved shelf life.

Example 2:

Preparation of buffered Ceftiofur sodium:

Form O (or Form D or both) of crystalline sterile Ceftiofur sodium was blended with lyophilized mixture of potassium dihydrogen orthophosphate and sodium hydroxide (prepared according to the process provided in 2023/CHE/2007) till to get uniform pH.