WO2006035291A1

WO2006035291A1 - Crystalline forms of cefdinir potassium

Info

Publication number: WO2006035291A1
Application number: PCT/IB2005/002858
Authority: WO
Inventors: Nitin Maheshwari; Ashok Prasad; Mohan Prasad; Yatendra Kumar
Original assignee: Ranbaxy Laboratories Limited
Priority date: 2004-09-27
Filing date: 2005-09-27
Publication date: 2006-04-06

Abstract

The present invention relates to a novel crystalline potassium salt of cefdinir - cefdinir potassium tetrahydrate, processes for its preparation, pharmaceutical compositions including cefdinir potassium tetrahydrate, and methods of treating bacterial infections using cefdinir potassium tetrahydrate. In addition, the present invention also relates to a mixture of cefdinir potassium dihydrate and cefdinir potassium tetrahydrate, processes for its preparation, pharmaceutical compositions including the mixture, and methods of treating bacterial infections using mixtures of cefdinir potassium dihydrate and cefdinir potassium tetrahydrate. Further it also relates to processes for preparing pure cefdinir and cefdinir potassium dihydrate from cefdinir potassium tetrahydrate.

Description

CRYSTALLINE FORMS OF CEFDINIR POTASSIUM

Field of Invention

The present invention relates to a novel crystalline potassium salt of cefdinir - cefdinir potassium tetrahydrate of Formula I,

FORMULA I processes for its preparation, pharmaceutical compositions including cefdinir potassium tetrahydrate, and methods of treating bacterial infections using cefdinir potassium tetrahydrate. In addition, the present invention also relates to a mixture of cefdinir potassium dihydrate and cefdinir potassium tetrahydrate, processes for its preparation, pharmaceutical compositions including the mixture, and methods of treating bacterial infections using mixtures of cefdinir potassium dihydrate and cefdinir potassium tetrahydrate. Further it also relates to processes for preparing pure cefdinir and cefdinir potassium dihydrate from cefdinir potassium tetrahydrate.

Background of the Invention

Cefdinir potassium is chemically known as potassium 7-[2-(2-aminothiazol-4-yl)- 2-hydroxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate (syn isomer) of formula II,

FORMULA II and is disclosed in US 4,559,334. Cefdinir is a third generation cephalosporin antibiotic for oral administration and has a broader antibacterial spectrum than other orally administrable antibiotics. Cefdinir is particularly effective against Staphylococci and Streptococci. Although US 4,559,334 describes the use of the potassium salt of cefdinir as a starting material for the synthesis of several esters of cefdinir, the synthesis or physical characteristics of cefdinir potassium have not been described at any stage. The patent describes preparation of cefdinir sodium via chromatography followed by lyophilization. The salt obtained by the given process is amorphous, hygroscopic and believed to be less than optimal for use in pharmaceutical compositions. Therefore, there is a need for pure and stable crystalline salts of cefdinir that are suitable for pharmaceutical preparations at an industrial scale; there also is a need for suitable methods for their preparation. Our Indian patent application 1242/DEL/2001 discloses preparation of cefdinir potassium dihydrate of formula III.

FORMULA III Summary of the Invention

A first aspect of the present invention provides a novel crystalline cefdinir potassium tetrahydrate of formula I. A second aspect of the present invention provides crystalline cefdinir potassium tetrahydrate having characteristic XRD as depicted in Figure L A third aspect of the present invention provides crystalline cefdinir potassium tetrahydrate having characteristic IR as depicted in Figure II. A fourth aspect of the present invention provides crystalline cefdinir potassium tetrahydrate having characteristic DSC as depicted in Figure III. A fifth aspect of the present invention provides crystalline cefdinir potassium tetrahydrate having characteristic XRD peaks at 2Θ values of 8.2 ± 0.2, 11.26 ± 0.2, 18.22 ± 0.2, 20.8 ± 0.22, 22.58 ± 0.2, 23.72 ± 0.2, 24.28 ± 0.2, 25.82 ± 0.2, 26.34 ± 0.2, 26.68 ± 0.2, 26.84 ± 0.2, 27.3 ± 0.2, 27.82 ± 0.2, 27.96 ± 0.2 and 28.62 ± 0.2

A sixth aspect of the present invention provides a process for the preparation of cefdinir potassium tetrahydrate, the process comprises crystallizing out cefdinir potassium tetrahydrate from a solution thereof in a suitable solvent followed by drying. A seventh aspect of the present invention provides a mixture of cefdinir potassium dihydrate and cefdinir potassium tetrahydrate. An eighth aspect of the present invention provides a mixture of cefdinir potassium dihydrate and cefdinir potassium tetrahydrate having characteristic XRD as depicted in Figure IV. A ninth aspect of the present invention provides a mixture of cefdinir potassium dihydrate and cefdinir potassium tetrahydrate having characteristic XRD peaks at 20 values of 11.24 ± 0.2, 12.06 ± 0.2, 18.24 ± 0.2, 19.1 ± 0.2, 19.28 ± 0.2, 21.38 ± 0.2, 22.84 ± 0.2, 23.72 ± 0.2, 24.3 ± 0.2, 25.06 ± 0.2, 25.5 ± 0.2, 25.82 ± 0.2, 26.72 ± 0.2 and 27.96 ± 0.2.

A tenth aspect of the present invention provides a process for the preparation of a mixture of cefdinir potassium dihydrate and cefdinir potassium tetrahydrate, the process comprising drying a wet cake of cefdinir potassium under reduced pressure at ambient temperature.

A eleventh aspect of the invention provides a process for preparing cefdinir potassium tetrahydrate from cefdinir potassium dihydrate, the process comprising keeping cefdinir potassium dihydrate in a humid atmosphere with water vapor at about 20 to 40°C for 15 to 25 hours. A twelfth aspect of the invention provides a process for preparing cefdinir potassium dihydrate from cefdinir potassium tetrahydrate comprising air-drying cefdinir potassium tetrahydrate at above 4O⁰C or above 50°C.

A thirteenth aspect of the invention provides a process for the manufacture of pure cefdinir characterized in that crystalline cefdinir potassium tetrahydrate is obtained from crude cefdinir, optionally recrystallized one or more times, and then converted to the free acid, i.e., cefdinir.

A fourteenth aspect of the invention provides pure cefdinir, preferably crystalline, prepared by the process of the present invention. A fifteenth aspect of the present invention provides pharmaceutical compositions that include cefdinir potassium tetrahydrate with one or more pharmaceutically acceptable carriers and excipients. The pharmaceutical compositions include oral dosage forms such as tablets, capsules, liquid orals, suspensions and the like; and topical dosage forms such as cream, lotions, ointments and the like. A sixteenth aspect of the present invention also provides pharmaceutical compositions that include mixtures of cefdinir potassium dihydrate and cefdinir potassium tetrahydrate along with pharmaceutically acceptable carriers and excipients.

A seventeenth aspect of the present invention provides a method of treating bacterial infections comprising administering to a mammal in need thereof a therapeutically effective amount of cefdinir potassium tetrahydrate.

An eighteenth aspect of the present invention provides a method of treating bacterial infections comprising administering to a mammal in need thereof a therapeutically effective amount of mixture of cefdinir potassium dihydrate and cefdinir potassium tetrahydrate. Accordingly, in one general aspect there is provided a crystalline cefdinir potassium tetrahydrate of formula I.

Embodiments of the crystalline cefdinir potassium tetrahydrate may include one or more of the following features. For example, the crystalline cefdinir potassium tetrahydrate may have a characteristic XRD of Figure I. The crystalline cefdinir potassium tetrahydrate has characteristic XRD peaks at 2Θ values of 8.2 ± 0.2, 11.26 ± 0.2, 18.22 ± 0.2, 20.8 ± 0.22, 22.58 ± 0.2, 23.72 ± 0.2, 24.28 ± 0.2, 25.82 ± 0.2, 26.34 ± 0.2, 26.68 ± 0.2, 26.84 ± 0.2, 27.3 ± 0.2, 27.82 ± 0.2, 27.96 ± 0.2 and 28.62 ± 0.2. The crystalline cefdinir potassium tetrahydrate has a characteristic IR of Figure II. The crystalline cefdinir potassium tetrahydrate may have a characteristic DSC of Figure III. The crystalline cefdinir potassium tetrahydrate may be present in a pharmaceutical composition that further includes one or more pharmaceutically acceptable carriers and excipients.

The crystalline cefdinir potassium tetrahydrate may be present in a mixture of cefdinir potassium dihydrate and cefdinir potassium tetrahydrate. The mixture of cefdinir potassium dihydrate and cefdinir potassium tetrahydrate may have the characteristic XRD of Figure IV. The mixture of cefdinir potassium dihydrate and cefdinir potassium tetrahydrate may have characteristic XRD peaks at 2Θ values of 11.24 ± 0.2, 12.06 ± 0.2, 18.24 ± 0.2, 19.1 ± 0.2, 19.28 ± 0.2, 21.38 ± 0.2, 22.84 ± 0.2, 23.72 ± 0.2, 24.3 ± 0.2, 25.06 ± 0.2, 25.5 ± 0.2, 25.82 ± 0.2, 26.72 ± 0.2 and 27.96 ± 0.2. The mixture of cefdinir potassium dihydrate and cefdinir potassium tetrahydrate may have the characteristic IR of Figure V. The mixture of cefdinir potassium dihydrate and cefdinir potassium tetrahydrate may be in a pharmaceutical composition that further includes one or more pharmaceutically acceptable carriers and excipients.

The mixture of cefdinir potassium dihydrate and cefdinir potassium tetrahydrate may be made by drying a wet cake of cefdinir potassium under reduced pressure at ambient temperature. The wet cake of cefdinir potassium may be dried at about 20 to 4O⁰C under reduced pressure.

In another general aspect there is provided a process for the preparation of cefdinir potassium tetrahydrate of Formula I, the process including crystallizing out cefdinir potassium tetrahydrate from a solution of cefdinir potassium in a suitable solvent.

Embodiments of the process may include one or more of the following features. For example, the solution of cefdinir potassium may be obtained by adding a potassium salt of a weak acid to a suspension or solution of cefdinir in a suitable solvent. The suitable solvent may be a water miscible polar organic solvent in admixture with water. The product may be obtained by drying after crystallizing. The drying may be carried out at about 25 to 4O⁰C. In another general aspect there is provided a process for preparing cefdinir potassium tetrahydrate from cefdinir potassium dihydrate. The process includes keeping cefdinir potassium dihydrate in a humid atmosphere with water vapor at about 20 to 4O⁰C for about 15 to 25 hours. In another general aspect there is provided a process for preparing cefdinir potassium dihydrate from cefdinir potassium tetrahydrate. The process includes air-drying cefdinir potassium tetrahydrate at a temperature above 4O⁰C.

In another general aspect there is provided a method of treating bacterial infections. The method includes administering to a mammal in need thereof a pharmaceutical composition that includes a therapeutically effective amount of cefdinir potassium tetrahydrate.

Embodiments of the method may include one or more of the following features or those described above. For example, the pharmaceutical composition may further include a therapeutically effective amount of cefdinir potassium dihydrate. The details of one or more embodiments of the inventions are set forth in the description below. Other features, objects and advantages of the inventions will be apparent from the description and claims.

Description of the Drawings

Figure I is an X-Ray Diffraction (XRD) pattern of cefdinir potassium tetrahydrate Figure II is an infrared (IR) spectrum of cefdinir potassium tetrahydrate

Figure III is a differential scanning calorimetry (DSC) of cefdinir potassium tetrahydrate

Figure IV is an XRD of a mixture of cefdinir potassium dihydrate and cefdinir potassium tetrahydrate Figure V is an IR spectrum of a mixture of cefdinir potassium dihydrate and cefdinir potassium tetrahydrate.

Detailed Description of Invention

The inventors have now found that a potassium salt of cefdinir also may be obtained as a pure crystalline tetrahydrate using a simple and efficient process. This crystalline salt may be conveniently formulated into tablets, suspensions, injectables and other pharmaceutical forms. Furthermore, it has been found that an efficient purification of cefdinir may be achieved by crystallizing it as cefdinir potassium tetrahydrate and then converting it back to cefdinir.

A solution of cefdinir potassium may be obtained by adding a potassium salt of a weak acid to a suspension or solution of cefdinir in a suitable solvent. The solution of cefdinir may be obtained either by dissolving cefdinir in a suitable solvent or directly from a reaction in which cefdinir is formed. Cefdinir used as the starting material may be obtained by any of the methods known in the art viz., US 4,559,334; US 4,870,168; US 6,093,814; WO 92/7840, Japanese patent applications JP 04173781, JP 01238587 and JP 02000790 (publication numbers).

Often, when the potassium salt of a weak acid is added to a suspension of cefdinir in a suitable solvent the cefdinir potassium tetrahydrate starts crystallizing out even before cefdinir has gone into solution completely. Such a process is within the meaning of the process of the present invention. The weak acid whose potassium salt may be used for forming the potassium salt of cefdinir may be either an organic acid or an inorganic acid. Examples of suitable potassium salts include potassium acetate, potassium carbonate, potassium bicarbonate and the like.

According to the present invention, the term "suitable solvent" may be any water miscible polar organic solvent in admixture with water. Suitable water miscible polar organic solvents include ketones such as acetone and ethyl methyl ketone; lower alcohols such as methanol, ethanol, propanol, and isopropanol; nitriles such as acetonitrile; cyclic ethers such as tetrahydrofuran and dioxane; and mixtures thereof.

The crystallization may be performed at any suitable temperature depending on the solvent used. However, crystallization works well when performed at a temperature between 0 and 3O⁰C, including the range of 5-10⁰C.

The isolated product may be dried in a hot air oven at about 25 to 4O⁰C to obtain cefdinir potassium tetrahydrate. The temperature range of about 30 to 35°C works well to obtain cefdinir potassium tetrahydrate. Cefdinir potassium tetrahydrate may be prepared by keeping cefdinir potassium dihydrate in a desiccator with water vapor at about 25 to 30°C for 20 hours, although other times may be operable.

The preparation of mixtures of cefdinir potassium dihydrate and cefdinir potassium tetrahydrate described in the eighth aspect comprises drying of a wet cake of cefdinir potassium obtained from the reaction mixture in which cefdinir potassium is formed. The wet cake of cefdinir potassium may be dried at about 20 to 4O⁰C under reduced pressure. A temperature range of about 25 to 30°C works well. The XRD and IR results shown in Figures FV and V, respectively, can be expected for the mixture under these conditions. It has been observed that when cefdinir potassium tetrahydrate or cefdinir potassium dihydrate is subjected to drying at about 45 to 50⁰C under reduced pressure, the cefdinir loses most of the water and becomes amorphous. The amorphous form is highly unstable and picks up water at ambient temperatures and converts to a mixture of cefdinir potassium dihydrate and cefdinir potassium tetrahydrate. When air dried at about 5O⁰C, they convert into cefdinir potassium dihydrate.

The product described in the eleventh aspect may be obtained as crystal A as cited in US 4,935,507, which is incorporated herein by reference. Alternatively, an amorphous form of cefdinir similar to that produced by the method of US 4,559,334 may also be obtained via this purification process. Conversion of cefdinir potassium tetrahydrate to cefdinir may be easily accomplished by suspending in water and acidifying to obtain the free acid, i.e., cefdinir.

"Crude cefdinir" is cefdinir prepared by any of the methods known in the art and which contains anti-isomer, polymeric impurities or any other impurity, which may arise during production or storage, such as degradation products. Crude cefdinir may be a solid or exist in a solvent, e.g., in a mixture resulting directly from a reaction for the synthesis of cefdinir.

Cefdinir may be obtained with a purity of 99% or more by the processes of the invention described herein.

In the following section preferred embodiments are described by way of examples to illustrate the processes of the invention. These examples are not intended in any way to limit the scope of the present invention and several variants of these examples would be evident to persons of ordinary skill in the art.

EXAMPLES Example 1 Preparation of cefdinir potassium tetrabydrate

Potassium acetate (70 g) was added to a suspension of cefdinir (200 g) in a mixture of water (1000 ml) and acetone (1000 ml) at 25-3O⁰C. The reaction mixture was stirred at this temperature for three hours. The reaction mixture was then cooled to 10⁰C and stirred for about two hours. The crystals were filtered, washed with aqueous acetone followed by acetone. The product was then dried at 25-3O⁰C in a hot air oven to obtain 189g of the title compound, i.e., cefdinir potassium tetrahydrate.

Yield: 94.5%

Water content: 14.58%

HPLC Purity: 99.5 % K-content (w/w): 7.7 % Example 2 Preparation of cefdinir potassium tetrahydrate

Cefdinir potassium dihydrate (5 g, water content: 8.42%) was kept in a desiccator, saturated with water vapors, at 25 to 3O⁰C for twenty hours to obtain cefdinir potassium tetrahydrate. The resulting cefdinir potassium tetrahydrate has an XRD pattern that matches that of the XRD pattern of Fig I.

Yield: 5.28g

Water content: 14.14%

Example 3 Preparation of a mixture of cefdinir potassium tetrahydrate and cefdinir potassium dihydrate A wet cake of cefdinir potassium (80 g) was dried at 25 to 3O⁰C under reduced pressure for fifteen hours to obtain 59 g of a mixture of cefdinir potassium tetrahydrate and cefdinir potassium dihydrate. The XRD pattern of the mixture is depicted in Fig IV.

Yield: 59g Water content: 9.50%

Example 4 Preparation of pure cefdinir

Cefdinir potassium tetrahydrate (5 g, water content: 14.58%) was suspended in distilled water (150 ml) at 25 to 3O⁰C. The pH of the mixture was adjusted to 2.4 - 2.5 by adding dilute hydrochloric acid at 25 to 3O⁰C and stirring was continued at this temperature for two hours. The solid obtained was filtered, washed with water and dried to obtain 3.5 g of cefdinir.

Yield: 90.0%

Water content: 1.1% HPLC Purity: 99%

Example 5 Preparation of cefdinir potassium dihydrate

Cefdinir potassium tetrahydrate (5 g, water content: 14.58%) was dried at 50-55°C in a hot air oven for about fifteen hours to get cefdinir potassium dihydrate. Yield: 4.6g

Water content: 8.4%

While several particular forms of the inventions have been described, it will be apparent that various modifications and combinations of the inventions detailed in the text can be made without departing from the spirit and scope of the inventions. For example, therapeutically effective amounts of cefdinir potassium tetrahydrate and mixtures of cefdinir potassium tetrahydrate with cefdinir potassium dihydrate may be combined with one or more pharmaceutically acceptable carrier and excipients to form dosage forms. The dosage forms may be administered for the treatment of bacterial infections. Accordingly, it is not intended that the inventions be limited, except as by the appended claims.

Claims

We Claim: 1. A crystalline cefdinir potassium tetrahydrate of formula I.

2. The crystalline cefdinir potassium tetrahydrate of claim 1 , wherein the crystalline cefdinir potassium tetrahydrate has a characteristic XRD of Figure I.

3. The crystalline cefdinir potassium tetrahydrate of claim 1 , wherein the crystalline cefdinir potassium tetrahydrate has characteristic XRD peaks at 2Θ values of 8.2 ± 0.2,11.26 ± 0.2, 18.22 ± 0.2, 20.8 ± 0.22, 22.58 ± 0.2, 23.72 ± 0.2, 24.28 ± 0.2, 25.82 ± 0.2, 26.34 ± 0.2, 26.68 ± 0.2, 26.84 ± 0.2, 27.3 ± 0.2, 27.82 ± 0.2, 27.96 ± 0.2 and 28.62 ± 0.2.

4. The crystalline cefdinir potassium tetrahydrate of claim 1, wherein the crystalline cefdinir potassium tetrahydrate has a characteristic IR of Figure II.

5. The crystalline cefdinir potassium tetrahydrate of claim 1 , wherein the crystalline cefdinir potassium tetrahydrate has a characteristic DSC of Figure III.

6. The crystalline cefdinir potassium tetrahydrate of claim 1, the crystalline cefdinir potassium tetrahydrate being in a pharmaceutical composition further comprising one or more pharmaceutically acceptable carriers and excipients.

7. The crystalline cefdinir potassium tetrahydrate of claim 1 , wherein the crystalline cefdinir potassium tetrahydrate is present in a mixture of cefdinir potassium dihydrate and cefdinir potassium tetrahydrate.

8. The crystalline cefdinir potassium tetrahydrate of claim 7, wherein the mixture of cefdinir potassium dihydrate and cefdinir potassium tetrahydrate has the characteristic XRD of Figure IV.

9. The crystalline cefdinir potassium tetrahydrate of claim 7, wherein the mixture of cefdinir potassium dihydrate and cefdinir potassium tetrahydrate has characteristic XRD peaks at 20 values of 11.24 ± 0.2, 12.06 ± 0.2, 18.24 ± 0.2, 19.1 ± 0.2, 19.28 ± 0.2, 21.38 ± 0.2, 22.84 ± 0.2, 23.72 ± 0.2, 24.3 ± 0.2, 25.06 ± 0.2, 25.5 ± 0.2, 25.82 ± 0.2, 26.72 ± 0.2 and 27.96 ± 0.2.

10. The crystalline cefdinir potassium tetrahydrate of claim 7, wherein the mixture of cefdinir potassium dihydrate and cefdinir potassium tetrahydrate has the characteristic IR of Figure V.

11. The crystalline cefdinir potassium tetrahydrate of claim 7, wherein the mixture of cefdinir potassium dihydrate and cefdinir potassium tetrahydrate is in a pharmaceutical composition further comprising one or more pharmaceutically acceptable carriers and excipients.

12. The crystalline cefdinir potassium tetrahydrate of claim 7, wherein the mixture of cefdinir potassium dihydrate and cefdinir potassium tetrahydrate is made by drying a wet cake of cefdinir potassium under reduced pressure at ambient temperature.

13. The crystalline cefdinir potassium tetrahydrate of claim 12, wherein the wet cake of cefdinir potassium is dried at about 20 to 4O⁰C under reduced pressure.

14. A process for the preparation of cefdinir potassium tetrahydrate of Formula I,

the process comprises crystallizing out cefdinir potassium tetrahydrate from a solution of cefdinir potassium in a suitable solvent.

15. The process of claim 14, wherein the solution of cefdinir potassium is obtained by adding a potassium salt of a weak acid to a suspension or solution of cefdinir in a suitable solvent.

16. The process of claim 14, wherein the suitable solvent is a water miscible polar organic solvent in admixture with water.

17. The process of claim 14, wherein the product is obtained by drying after crystallizing.

18. The process of claim 17, wherein drying is carried out at about 25 to 40°C.

19. A process for preparing cefdinir potassium tetrahydrate from cefdinir potassium dihydrate, the process comprising keeping cefdinir potassium dihydrate in a humid atmosphere with water vapor at about 20 to 4O⁰C for about 15 to 25 hours.

20. A process for preparing cefdinir potassium dihydrate from cefdinir potassium tetrahydrate comprising air-drying cefdinir potassium tetrahydrate at a temperature above 40°C.

21. A method of treating bacterial infections comprising administering to a mammal in need thereof a pharmaceutical composition comprising a therapeutically effective amount of cefdinir potassium tetrahydrate.

22. The method of claim 21, wherein the pharmaceutical composition further comprises a therapeutically effective amount of cefdinir potassium dihydrate.