WO2012049576A1 - Crystalline sodium salt of cephalosporin antibiotic - Google Patents
Crystalline sodium salt of cephalosporin antibiotic Download PDFInfo
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- WO2012049576A1 WO2012049576A1 PCT/IB2011/053746 IB2011053746W WO2012049576A1 WO 2012049576 A1 WO2012049576 A1 WO 2012049576A1 IB 2011053746 W IB2011053746 W IB 2011053746W WO 2012049576 A1 WO2012049576 A1 WO 2012049576A1
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- WIPO (PCT)
- Prior art keywords
- ceftiofur sodium
- crystalline
- sodium
- ceftiofur
- moisture content
- Prior art date
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
- C07D501/36—Methylene radicals, substituted by sulfur atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
- A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
- A61K31/546—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine containing further heterocyclic rings, e.g. cephalothin
Definitions
- 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.
- 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.
- 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.
- the present invention provides novel crystalline polymorph of
- 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 %.
- 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:
- 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°2 ⁇ ) as shown in the following table- 1 :
- 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.
- 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 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
- 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.
- 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.
- the crystalline Ceftiofur sodium having moisture content of about 7.0-11 % was dried under vacuum at 45 °C for 1 hour.
- 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.
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- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Cephalosporin Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a novel polymorph of Ceftiofur sodium as a crystalline product. The present invention also provides a process for the preparation of a novel polymorph of crystalline Ceftiofur sodium of formula (I).
Description
CRYSTALLINE SODIUM SALT OF CEPHALOSPORIN ANTIBIOTIC
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:
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
26.71 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)
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.
Claims
1. Crystalline Ceftiofur sodium of formula (I)
2. Crystalline Ceftiofur sodium of formula (I) as claimed in claim 1, having the moisture content in the range of 4.6 to 7.0 %.
3. Crystalline Ceftiofur sodium of formula (I) as claimed in claim 2, having the moisture content in the range of 5.5 to 7.0 %.
4. A process for the preparation of crystalline polymorph of Ceftiofur sodium of formula (I) as claimed in claim 1 comprises drying the hydrated Ceftiofur sodium at a temperature in the range of 35 to 50° C under vacuum till the moisture content reaches 4.6 to 7.0 %.
5. A process as claimed in claim 4, wherein hydrated Ceftiofur sodium having moisture content in the range of 7.0 to 14.0 %.
6. A process as claimed in claim 4, wherein the drying is performed under vacuum for 1-3 hours.
7. Crystalline Ceftiofur sodium of formula (I) as claimed in claim 1, having the same X-ray diffractogram as set out in Fig.1.
8. A pharmaceutical composition comprising the crystalline Ceftiofur sodium of claim 1 and buffer.
9. Physical admixture of crystalline Ceftiofur sodium according to claim 1 or 2, with lyophilized composition of potassium dihydrogen orthophosphate and sodium hydroxide.
10. A pharmaceutical composition comprising Ceftiofur sodium selected from Form O, amorphous form, Form D, Form M, Form A or mixture thereof.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN3033CH2010 | 2010-10-13 | ||
| IN3033/CHE/2010 | 2010-10-13 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2012049576A1 true WO2012049576A1 (en) | 2012-04-19 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IB2011/053746 WO2012049576A1 (en) | 2010-10-13 | 2011-08-26 | Crystalline sodium salt of cephalosporin antibiotic |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004039811A2 (en) * | 2002-10-29 | 2004-05-13 | Lupin Limited | A method for manufacture of ceftiofur |
| WO2007042917A1 (en) * | 2005-10-12 | 2007-04-19 | Orchid Chemicals And Pharmaceuticals Limited | Crystalline sodium salt of cephalosporin antibiotic |
| WO2010020871A2 (en) * | 2008-08-22 | 2010-02-25 | Orchid Chemicals & Pharmaceuticals Limited | Crystalline sodium salt of cephalosporin antibiotic |
-
2011
- 2011-08-26 WO PCT/IB2011/053746 patent/WO2012049576A1/en active Application Filing
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004039811A2 (en) * | 2002-10-29 | 2004-05-13 | Lupin Limited | A method for manufacture of ceftiofur |
| WO2007042917A1 (en) * | 2005-10-12 | 2007-04-19 | Orchid Chemicals And Pharmaceuticals Limited | Crystalline sodium salt of cephalosporin antibiotic |
| WO2010020871A2 (en) * | 2008-08-22 | 2010-02-25 | Orchid Chemicals & Pharmaceuticals Limited | Crystalline sodium salt of cephalosporin antibiotic |
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