WO2006010978A1

WO2006010978A1 - Cefdinir polymorphic forms, and imidazole salt

Info

Publication number: WO2006010978A1
Application number: PCT/IB2004/002171
Authority: WO
Inventors: Siddiqui Mohammed Jaweed Mukarram; Rashid Abdul Rehman Khan; Avinash Seshrao Mane
Original assignee: Wockhardt Ltd
Current assignee: Wockhardt Ltd
Priority date: 2004-06-30
Filing date: 2004-06-30
Publication date: 2006-02-02
Anticipated expiration: 2006-12-30

Abstract

A new crystalline Syn-7-[2-(2-amino-4-thiazolyl)-hydroxyiminoacetamido]-3-vinyl-3cephem-4-carboxylic acid-imidazole salt and polymorphic forms C, D and amorphous form of Syn-7-[2-(2-amino-4-thiazolyl)hydroxyimino-acetamido]-3-vinyl-3-cephem-4-carboxylic acid is also disclosed herein.

Description

Cefdinir polymoφhic forms, and imidazole salt

FIELD OF THE INVENTION

The present invention relates to a novel crystalline form of ,yy«-7-[2-(2-aminothiazolyl)- 2-hydroxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylic acid (Cefdinir) - imidazole salt having Formula (I)

Cefdinir-Imidazole salt

which can be used for preparing a cephalosporin antibiotic, e.g., Cefdinir. The said ^" Cefdinir-imidazole salt provides an improved process for isolation of pure, crystalline and amorphous Cefdinir. An efficient process for isolation of Cefdinir in more than 99 % HPLC purity is also discussed herein. Polymorphic crystalline Forms C & D and an amorphous form, their respective preparation methods and characteristics based on specific Infra Red and X-ray powder diffraction values are also discussed in this invention.

BACKGROUND OF THE INVENTION

Cefdinir is chemically known as _«yn-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino- acetamido]-3-vinyl-3-cephem-4-carboxylic acid. This molecule was disclosed first time in U.S. Patent No. 4,559,334. It is a third generation Cephalosporin antibiotic and has broader antibacterial spectrum over the general gram positive and gram negative bacteria than other antibiotics for oral administration. It has been reported that Cefdinir has an excellent antibacterial activity against Staphylococci and Sreptococci. Cefdinir preferably is used in form of monohydrate as antibiotic discussed in J. Antibiotics, Vol. XLI, No. 6, 829 (1988) by Y. Inamoto, et al.

U.S. Patent No. 4,559,334 discloses a manufacturing process of Cefdinir. The process comprises the reaction of 7-amino-3-vinyl-3-cephem-4-carboxylic acid ester with haloacetyloxyacetic acid followed by nitrosation to produce the amino protected ester derivative of Cefdinir. Amino function was made free by treating the intermediate product with thiourea followed by hydrolysis to yield Cefdinir. The patent also discloses Cefdinir sodium salt and ester derivatives of Cefdinir. According to the procedure disclosed in this patent Cefdinir was isolated by chromatographic purification on nonionic adsorption resin followed by pH adjustment to 2.0 with 10 % hydrochloric acid while its sodium salt was isolated by chromatographic purification followed by lyophilization.

Cefdinir may be obtained in impure form according to the known production processes such as disclosed in U.S. Patents 4,559,334; 4,870,168; 6,093,814, WO 92/7840, WO 01/79211, JP 2/000790, JP 4/173781 and JP 1/238587. Since, Cefdinir is synthesized through a complicated reaction consisting of 4 steps from the expensive 7-amino-3-vinyl-3- cephem-4-carboxylic acid derivative impurities increases due to formation of side products or degradation of the molecule and also increases the cost of its production.

PCT application No. WO 98/452299 and U.S. Patent No. 6,350,869 disclose processes for production of crystalline 7-(Z)-[2-(2-aminothiazolyl-4-yl)-2-hydroxyimino- acetamido]-3-vinyl-3-cephem-4-carboxylic acid / dicyclohexylammonium salt having formula

It is known that Cefdinir is unstable under basic conditions described in J. o Pharmaceutical Sciences Vol. 85, No. 9, 976 (1996) and degrades heavily in presence of amines, e.g., terf-octylamine under similar conditions. Dicyclohexylamine is a strong base with pKa Value = 10.4 (The Merck Index 13th Edition, Sr. No. 3122, Page No. 545). The yield of Cefdinir dicyclohexylamine salt isolated from crude Cefdinir is not reported in the above reference. The Cefdinir purified by making dicyclohexyl amine salt is isolated in lesser yield due to above discussed factor.

U.S. Patent 4,935,507 and U.S. Patent application 2003/0204082 Al disclose two different crystalline forms of Cefdinir. The '507 patent claims diffraction angles (°) at about 14.7, 17.8, 21.5. 22.0, 23.4, 24.5 and 28.1 for crystalline 7-[2-(2-aminothiazol-4- yl)-2-hydroxyimino-acetamido]-3-vinyl-3-cephem-4-carboxylic acid. The '082 patent application describes a new crystalline form of Cefdinir obtained between a temperature between about O⁰C to about +6⁰C from a dilute aqueous solution of Cefdinir in the presence of at least one organic solvent, in a total percentage (v/v on the aqueous solution) not exceeding 10 % and at a pH between about 1.5 to about 3.0. The X-ray diffraction spectrum of the crystalline Cefdinir obtained in the '082 patent application showed specific d-space values (in angstrom) at about 15.24, 11.30, 10.90, 7.51, 5.66, 5.48, 4.91, 4.76, 4.55, 4.23, 4.17, 3.99, 3.74, 3.64, 3.53, 3.46, 3.39, 3.26, 3.17, 3.08, 2.96, 2.89, 2.82, 2.81, 2.63, 2.57, 2.54, 2.39, 2.31, 1.99 and 1.97.

SUMMARY OF THE INVENTION

The present invention is directed to a new process for the preparation of highly pure crystalline _tyn-7-[2-(2-amino-4-thiazolyl)-2-hydroxyiminoacetamido]-3-vinyl-3-cephem-4- carboxylic acid (Cefdinir), which has potential applications as anti-microbial agent.

In a first embodiment, the invention is directed to a crystalline Cefdinir-imidazole salt and its manufacturing process from crude Cefdinir having chemical Formula (II)

Cefdinir

The Cefdinir- imidazole salt is prepared by reacting crude Cefdinir with imidazole in a mixture of acetone and water from about 25⁰C to about 3O⁰C. In another aspect of the invention, the same salt is produced in a mixture of acetone and methanol by stirring at about 25⁰C to about 30° C.

According to another embodiment, the present invention is directed to a process for the preparation of crystalline Cefdinir Form C by dissolving Cedinir-imidazole salt in aqueous ethyl acetate and adjusting the pH about 2.5 by sulfuric acid and filtrating the crystals.

In another embodiment, the present invention provides a process for the preparation of crystalline Cefdinir Form D by dissolving Cefdinir-imidazole salt in water at about 55⁰C followed by adjusting the pH at 2.5 by addition of sulfuric acid and filtering the crystals.

In yet another embodiment, the invention is directed to a process for the preparation of amorphous Cefdinir by dissolving Cedinir-imidazole salt in formic acid and pouring the solution slowly into aqueous methanol.

The Cefdinir-imidazole salt, crystalline Forms C & D and amorphous Cefdinir prepared in the present invention are characterized based on specific Infra Red and X-Ray Powder Diffraction peaks. BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 is an Infra Red Spectrum of crystalline ,yyn-7-[2-(2-amino-4-thiazolyl)-2- hydroxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylic acid - imidazole salt.

Figure 2 is an X-Ray Diffraction Pattern (XRD) of crystalline S3>/z-7-[2-(2-amino-4- thiazolyl)-2-hydroxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylic acid - imidazole salt.

Figure 3 is an Infra Red Spectrum of crystalline 5yn-7-[2-(2-amino-4-thiazolyl)-2- hydroxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylic acid Form C.

Figure 4 is an X-Ray Diffraction Pattern (XRD) of crystalline 5yn-7-[2-(2-amino-4- thiazolyl)-2-hydroxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylic acid Form C.

Figure 5 is an Infra Red Spectrum of crystalline j)w-7-[2-(2-ammo-4-thiazolyl)-2- hydroxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylic acid Form D.

Figure 6 is an X-Ray Diffraction Pattern (XRD) of crystalline 5y«-7-[2-(2-amino-4- thiazolyl)-2-hydroxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylic acid Form D.

Figure 7 is an Infra Red Spectrum of amorphous yyn-7-[2-(2-amino-4-thiazolyl)-2- hydroxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylic acid.

Figure 8 is an X-Ray Diffraction Pattern (XRD) of amorphous yyn-7-[2-(2-amino-4- thiazolyl)-2-hydroxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylic acid.

DETALED DESCRIPTION OF THE INVENTION

The present invention relates to a process for the manufacture and efficient isolation process of 5yn-7-[2-(2-amino-4-thiazolyl)-2-hydroxyiminoacetamido]-3-vinyl-3-cephem-4- carboxylic acid (Cefdinir) by making its imidazole salt and its subsequent hydrolysis in acidic medium. The preparatory processes of polymorphic Forms C & D and amorphous Cefdinir are also disclosed in aqueous and organic solvents or mixtures thereof.

According to one embodiment, the present invention is directed to a manufacturing process of -ryn-7-[2-(2-amino-4-thiazolyl)-2-hydroxyiminoacetamido]-3-vinyl-3-cephem-4- carboxylic acid. The schematic presentation of synthetic process of 5yn-7-[2-(2-amino-4- thiazolyl)-2-hydroxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylic acid Formula (II) is shown in Scheme I:

Scheme I

CH₂CI₂ZTEAMSCI ^Ethyl acetate / Methanol

Foπnic acid / Water / Toluene Acetone / IPE / Imidazole / Methanol / Water

In the present invention, it is observed that impure Cefdinir may be purified by converting Cefdinir into a crystalline salt of Cefdinir with imidazole. Imidazole is a weak base with pKa Value = 6.92 (The Merck Index, 13^th Edition, Sr. No. 4935, Page No. 882) resulting formation of salt without degradation. Cefdinir imidazole salt may be conveniently used to produce highly pure Cefdinir. Moreover, Cefdinir imidazole salt of Formula I is a very useful intermediate in obtaining different new forms of Cefdinir, e.g.

Forms C & D and the amorphous form.

I

A detailed synthetic process of the .τyn-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino- acetamido]-3-vinyl-3-cephem-4-carboxylic acid its imidazole salt and different polymorphic forms are disclosed herein:

(a) Reaction of (Z)-2-(2-Tritylaminothiazol-4-yl)-2-trityloxyimino acetic acid (III) with benzhydril-7-amino-3-vinyl-3-cephem-4-carboxylate hydrochloride (IV)

(Z)-2-(2-Tritylaminothiazol-4-yl)-2-trityloxyimino acetic acid (III) is treated with methanesulfonyl chloride in dichloromethane using triethylamine as base. The mixture is stirred for one hour at about -10⁰C and allowed to react further for 1 hour. The temperature used for the reaction is from about -5⁰C to O⁰C. Benzhydril-7-amino-3-vinyl-3- cephem-4-carboxylate hydrochloride (IV) is reacted with mixed anhydride of 2-(2- tritylaminothiazol-4-yl)-2-(syn)trityloxyimino acetic acid (III) obtained by reaction with methanesulfonyl chloride in dichloromethane to give benzhydril-7-[2(2-tritylaminothiazol-4- yl)-2-(syn)trityloxyimino acetamido]-3-vinyl-3-cephem-4-carboxylate (V) in 80% yield using usual extraction procedure. The reagents used to prepare mixed anhydride of Formula III compound other than methanesulfonyl chloride may be p-toluene sulfonyl chloride, pivaloyl chloride, ethylchloro-formate, isobutyl chloroformate or a complex obtained from dimethylformamide and phosphorous oxychloride, sulfonyl chloride, thionyl chloride or oxalyl chloride in presence of organic base, e.g. triethylamine and tributylamine etc.

(b) Hydrolysis of Benzhydril-7-[(Z)-2-(tritylaminothiazol-4-yl)-2-trityloxyiminoacetamido]- 3-vinyl-3-cephem-4-carboxylate Crystalline compound of Formula V is converted to crude Cefdinir in a single step using 85 to 95 % aqueous formic acid, preferably 90% aqueous formic acid from about 10⁰C to about 5O⁰C, preferably about 25° to about 35⁰C. Impure Cefdinir is obtained by concentrating the mixture under vacuum followed by diluting with organic solvent, e.g., acetone, ethyl acetate or di-isopropyl ether etc. or dilution with water. The product is isolated by conventional centrifugation or filtration methods. Crude Cefdinir thus obtained is found in more than 95 % HPLC purity and about 92 to about 95 % yield. Cefdinir in the free form or in the form of a solvate such as hydrate, e.g., monohydrate or in pure form may be obtained from compound of Formula I by dissolving it in water and acidifying the solution with dilute acid to pH from 2.0 to 3.0 preferably between about 2.4 to about 2.8. Precipitated Cefdinir is isolated by conventional filtration or centrifugation techniques.

(c) Preparation of 5'y/t-7-[2-(2-amino-4-thiazolyl)-2-hydroxyiminoacetamidol-3-vinyl-3- cephem-4-carboxylic acid - imidazole salt

According to one embodiment, imidazole salt of 5)>rt-7-[2-(2-amino-4-thiazolyl)— 2- hydroxy-iminoacetamido]-3-vinyl-3-cephem-4-carboxylic acid is obtained by suspending crude yyn-7-[2-(2-amino-4-thiazolyl)-2-hydroxyiminoacetamido]-3-vinyl-3-cephem-4- carboxylic acid in suitable polar solvent. Suitable polar solvents include N, N- dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, tetrahydrofuran, alcohols or acetone etc. or combination with water or mixtures of solvents. In particular, suitable solvents include aqueous alcohols, e.g., methanol, ethanol, isopropanol or butanol etc. The preferable ratio of solvent may be methanol or acetone or in combination with water in various ratios, e.g., about 5 : 1, 10 : 1, 20 : 1, 50 : 1, or 100 : l.This reaction is typically undertaken from about 1O⁰C to about 5O⁰C and more preferably between 15⁰C to 35⁰C. Reaction time are typically, between about 1 and about 6 hours, preferably being between about 2 to about 4 hours. The slurry thus obtained is cooled between about O⁰C to about 25⁰C. The crystals obtained using this process are more than 99.5 % pure by HPLC analysis and in 95.5 % isolated yield. Melting point of the title compound is between about 146 to about 148° C. Similarly, in aqueous acetone Cefdinir is formed in more than 99.3 % HPLC purity and in 92.10 % isolated yield. Characterization of 5v»-7-r2-(2-amino-4-thiazolyl)-2-hvdroxyimino-acetamido1-3-vinyl-3- cephem-4-carboxylic acid-imidazole salt

(I) Melting Point

Melting point of the Imidazole salt of yyn-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino- acetamido]-3-vinyl-3-cephem-4-carboxylic acid-imidazole salt is observed in the range of 146⁰C to 148⁰C.

(II) Infra Red Spectrum

Infra Red spectrum of 5yn-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-3-vinyl-3- cephem-4-carboxylic acid-imidazole salt that include peaks at about 3389, 3312, 3155, 2987, 2828, 1768, 1658, 1579, 1533, 1389, 1346, 1173, 1119, 1040, 993, 893, 822, 790, 751 and 630 cm ¹ (Figure 1).

(III) X-Ray Powder Diffraction

X-Ray Powder Diffraction (2 theta) pattern of s3w-7-[2-(2-amino-4-thiazolyl)-2- hydroxyimino-acetamido]-3-vinyl-3-cephem-4-carboxylic acid-imidazole salt is characterized that include peaks at about 9.32, 12.42, 13.02, 13.58, 14.68, 15.14, 16.70, 17.74, 18.70, 19.02, 19.52, 20.16, 21.42, 21.46, 21.80, 22.16, 22.56, 23.52, 24.02, 24.38, 25.12, 25.92, 26.14, 26.26, 27.10, 27.64, 28.40, 29.44, 29.74, 30.06, 31.24, 31.50, 31.86, 32.44, 33.94, 34.08, 34.58, 34.96, 36.08 and 38.66° (Figure 2).

(d) Preparation of syn-7-[2-(2-amino-4-thiazolyl)-2-hydroxyiminoacetamidol-3-vinyl-3- cephem-4-carboxylic acid Form C

5yn-7-[2-(2-Amino-4-thiazolyl)-2-hydroxyimino-acetamido]-3-vinyl-3-cephem-4-carboxylic acid-imidazole salt is dissolved in polar organic solvent, or mixtures of organic solvents or aqueous organic solvents. Suitable polar solvents include, aliphatic esters, more preferably ethyl acetate at a temperature from about 25⁰C to about 37⁰C. The organic solvent is preferably taken less than 20 % in water (v/v). pH of the reaction mixture is kept from about 1.0 to about 5.0, more preferably from about 2.0 to about 3.0. Infra Red spectrum of 5yn-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-3-vinyl-3-cephem-4-carboxylic acid Form C include peaks at about 3315, 2984, 2361, 1760, 1666, 1613, 1541, 1426, 1353, 1301, 1190, 1136, 1045, 1013, 911, 814, 791, 761, 630 and 570 cm ¹ (Figure 3). X- Ray Powder Diffraction (2 theta) pattern of 5yn-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino- acetamido]-3-vinyl-3-cephem-4-carboxylic acid Form C that include peaks at about 5.44, 9.18, 10.88, 15.06, 15.50, 17.86, 18.62, 20.72, 20.90, 21.42, 22.340, 23.88, 24.26, 25.68, 26.22, 26.42, 27.80, 28.34, 28.80, 30.46, 32.10, 35.82, 38.60, 38.72 and 39.32° (Figure 4).

(e) Preparation of -ryn-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamidol-3-vinyl-3- cephem-4-carboxylic acid Form D

According to one embodiment, Crystalline Form D of Cefdinir is obtained by dissolving 5yn-7-[2-(2-amino-4-thiazolyl)-2-hydroxyiminoacetamido]- 3-vinyl-3-cephem-4- carboxylic acid-imidazole salt in deionized water between about 30°C to 100⁰C temperature followed by cooling about below 2O⁰C. The preferable pH of the reaction mixture is adjusted between about 2 to about 5.0 more particularly between about 2 to 3.0 for precipitating the title compound. The preferable volume ratio of water in Cefdinir- imidazole salt is between about 20 to 40 times, more particularly about 30 times (v/w). The preferable acid used for pH adjustment is sulfuric acid. Infra Red spectrum of syn-1- [2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-3-vinyl-3-cephem-4-carboxylic acid Form D is characterized by the following peaks at about 3304, 2983, 2882, 2361, 1756, 1667, 1610, 1541, 1465, 1423, 1351, 1286, 1189, 1134, 1047, 1014. 992, 813, 651 and 627 cm^"1 etc (Figure 5). X-Ray Powder Diffraction (2 theta) pattern of .yyn-7-[2-(2-amino-4- thiazolyl)-2-hydroxyimino-acetamido]-3-vinyl-3-cephem-4-carboxylic acid Form D is characterized that include peaks at about 8.40, 10.58, 10.70, 10.94, 11.64, 11.74, 11.68, 14.00, 14.22, 14.90, 15.04, 15.24, 15.52, 18.18, 18.76, 19.16, 21.12, 21.26, 21.42, 21.60, 21.90, 22.30, 22.42, 22.66, 23.70, 23.04, 23.94, 24.22, 24.44, 24.52, 24.72, 25.10, 25.36, 25.68, 25.84, 25.98, 26.12, 26.40, 26.65, 27.06, 27.380, 27.520, 27.760, 28.14, 28.54, 28.66, 28.940, 32.10, 36.32 and 39.08° (Figure 6). (f) Preparation of amorphous 5yw-7-[2-(2-amino-4-thiazolyl)-2-hydroxyiminoacetamido]-3- vinyl-3-cephem-4-carboxylic acid

According to one embodiment, amorphous ,yy«-7-[2-(2-amino-4-thiazolyl)-2- hydroxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylic acid is obtained by dissolving syn- 7-[2-(2-amino-4-thiazolyl)-2-hydroxyiminoacetamido]- 3-vinyl-3-cephem-4-carboxylic acid- imidazole salt in organic acid, preferably formic acid or acetic acid. The ratio of Cefdinir -imidazole salt to formic acid is about 1 to 5 times (w/v) preferably 2 times. The acid soluble Cefdinir-imidazole salt is added slowly to the aqueous alcohol between about - 2O⁰C to -5°C. The volume ratio of alcohol is preferably below 20 % in water. Infra Red spectrum of amorphous jy/z-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-3-vinyl- 3-cephem-4-carboxylic acid is characterized by the following peaks at about 3306, 2361, 1765, 1634, 1533, 1352, 1167, 1056, 1013, 917, 855, 729, 622, 568 and 490 cm ¹ (Figure 7). X-Ray Powder Diffraction (2 theta) pattern of the amorphous yyn-7-[2-(2-amino-4- thiazolyl)-2-hydroxyimino-acetamido]-3-vinyl-3-cephem-4-carboxylic acid is shown in Figure 8.

The following examples, illustrate the process of the invention but is by means intended for limiting the scope of the invention.

Examples EXAMPLE 1

Benώydril-y-^Z^-itritylaminothiazol-^y^^-trityloxyiminoacetamidoJ-S-vinyl-S-cephem^- carboxylate (V).

(Z)-2-(2-Tritylaminothiazol-4-yl)-2-trityloxyimino acetic acid (III, 25.0 gm) is taken in dichloromethane and treated with methanesulfonyl chloride (6.40) in presence of triethylamine base (5.7 gm) at -1O⁰C. The reaction mixture is stirred for 1 hour at -5⁰C to O⁰C and cooled to -10⁰C followed by treatment with benzhydril-7-amino-3-vinyl-3-cephem- 4-carboxylate hydrochloride (IV, 16.0 gm). The combined reaction mixture is stirred for 2 hours at 0⁰C. Completion of the reaction is monitored by HPLC. After the said time mixture is poured under stirring into water (250 ml) and layers are separated. Organic layer concentrated under vacuum and residue stirred with methanol (100 ml). Slurry is stirred for 1 hour and filtered, washed with methanol and dried to obtain 32.0 gm of title compound. Yield : 82.26% and HPLC purity: 98.5 %.

EXAMPLE 2

Crude Syn-7-[2-(2-amino-4-thiazolyl)-2-hydroxyiminoacetamido]-3-vinyl-3-cephem-4- carboxylic acid (Cefdinir)

Product (160 gm) obtained from Example 1 is dissolved in 10 % aqueous formic acid (650 ml) and stirred at 3O⁰C for 4 hours. Clear solution is concentrated under vacuum. Residue is diluted with di-isopropyl ether and stirred for 1 hour followed by filtration of the crystals. The crystals are washed with cold di-isopropyl ether and dried to get 56.24 gm of crude Cefdinir. Yield: 93.0 %, HPLC purity: 96.0 % .

EXAMPLE 3

Sy n- 7-[2- (2-amino-4-thiazolyl) -2-hydroxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylic acid imidazole salt (I). Method 1

Crude Syn-7-[2-(2-amino-4-thiazolyl)-2-hydroxyiminoacetamido]-3-vinyl-3-cephem-4- carboxylic acid (25.0 gm) as obtained in Example 2 is suspended in methanol (425 ml) and water (25.0 ml) and treated with imidazole (4.5 gm) under stirring. Stirring is continued at 25⁰C to 30⁰C for 2 to 3 hours for complete crystallization. Slurry is then cooled to 1O⁰C to 15⁰C and stirred further for 1 hour. The crystals formed are filtered, washed with cold methanol and dried to obtain 28.0 gm of the title compound. Yield : 95.50%, Melting point: 146° to 148°C (decomposition) and HPLC purity: 99.6% .

Method 2

Crude ₁Syn-7-[2-(2-amino-4-thiazolyl)-2-hydroxyiminoacetamido]-3-vinyl-3-cephem-4- carboxylic acid (25.0 gm) obtained in Example 2 is suspended in a mixture of acetone (125 ml) and water (50 ml). Imidazole (4.5 gm) is added to the solution under stirring at 25 to 30⁰C. Imidazole salt of Cefdinir crystallizes from solution and is diluted with acetone (750 ml). It is stirred for 1 hour at 25° to 30⁰C and cooled to 5⁰C to 8°C and further stirred for 2 hours. The crystals are filtered, washed with cold acetone and dried to obtain 27.0 gm of titled compound. Yield: 92.10%, Melting point: 146° to 148⁰C (decomposition) and HPLC purity : 99.4%.

EXAMPLE 4

Pure syn-7-[2-(2-amino-4-thiazolyl)-2-hydroxyiminoacetamidoJ-3-vinyl-3-cephem-4- carboxylic acid (Cefdinir Formula II).

5y/i-7-[2-(2-amino-4-thiazolyl)-2-hydroxyiminoacetamido]-3-vinyl-3-cephem-4- carboxylic acid-imidazole salt (25.0 gm) is dissolved in water (500 ml) between 3O⁰C to 35⁰C. pH of the solution is lowered to 5.0 by addition of dilute sulfuric acid and charcoal is added. Reaction mixture is stirred for 30 minute at 30° to 35⁰C and filtered through celite bed. pH of the solution is adjusted to 2.5 to 2.7 between 30° to 35⁰C. Slurry of the product is cooled to 5⁰C and stirred for 2 hours for compete crystallization. The crystals are filtered, washed with cold water and dried to obtain 19.20 gm of crystalline Cefdinir. Yield : 90.10% and HPLC purity : 99.5 %.

EXAMPLE 5

Syn-7-[2-(2-amino-4-thiazolyl)-2-hydroxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylic acid Form C

5y«-7-[2-(2-amino-4-thiazolyl)-2-hydroxyiminoacetamido]-3-vinyl-3-cephem-4- carboxylic acid-imidazole salt (10 gm) is dissolved in 350 ml water, containing 14 % ethyl acetate (v/v) at 3O⁰C. pH of the solution is adjusted to 2.5 by drop wise addition of 10% sulfuric acid (v/v). The same condition is maintained under stirring for 2 hours at 30⁰C, filtered, washed with deionized water and dried to get title compound. Yield : 94.0 % and HPLC purity : 99.80 %.

EXAMPLE 6

Syn- 7-[2- (2-amino-4-thiazolyl) -2-hydroxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylic acid Form D

5yn-7-[2-(2-amino-4-thiazolyl)-2-hydroxyiminoacetamido]-3-vinyl-3-cephem-4- carboxylic acid -imidazole salt (10.0 gm) is dissolved in 300 ml deionized water at 55⁰C. The resulting solution is cooled to 30⁰C and decolorized with carbon (1.0 gm). The solution is cooled to 5°C to 7°C and corrected to pH 2.5 by drop wise addition of 10% sulfuric acid (v/v). It is stirred for 2 hours at the same temperature and left for 14 hours. The crystals of Form D thus obtained is filtered, washed with deionized water and dried. Yield: 90.0 % and HPLC purity : 99.60 %.

EXAMPLE 7

Syn-7-[2-(2-amino-4-thiazolyl)-2-hydroxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylic acid amorphous

A cold solution of water (200 ml) containing 15 % methanol (v/v) is slowly added to a solution of Cefdinir-imidazole salt (10 gm) taken in 20 ml formic acid at -15⁰C. After the complete addition the suspension is stirred at the same temperature for 1 hour. Amorphous Cefdinir thus precipitated is filtered, washed with deionized water and dried. Yield: 90.0 % and HPLC purity : 99.10 %.

Claims

We Claim:

1 Imidazole salt of Cefdinir having the formula

2 The product of claim 1, in substantially crystalline form.

3 The product of claim 1, having a melting point from about 146⁰C to about 148⁰C.

4 The product of claim 1, wherein 5yn-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino- acetamido]-3-vinyl-3-cephem-4-carboxylic acid-imidazole salt is characterized by an Infra Red Spectroscopy (IR) spectrum that include peaks at about 3389, 3312, 3155, 2987, 2828, 1768, 1658, 1579, 1533, 1389, 1346, 1173, 1119, 1040, 993, 893, 822, 790, 75I aHd OSO Cm ¹.

5 The product of claim 1, wherein 5y«-7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino- acetamido]-3-vinyl-3-cephem-4-carboxylic acid-imidazole salt is characterized by an X- ray powder diffraction (XRD) that include the peaks at about 9.32, 12.42, 13.02, 13.58, 14.68, 15.14, 16.70, 17.74, 18.70, 19.02, 19.52, 20.16, 21.42, 21.46, 21.80, 22.16, 22.56, 23.52, 24.02, 24.38, 25.12, 25.92, 26.14, 26.26, 27.10, 27.64, 28.40, 29.44, 29.74, 30.06, 31.24, 31.50, 31.86, 32.44, 33.94, 34.08, 34.58, 34.96, 36.08 and 38.66°.

6 A process for the manufacturing a compound of formula

the said method comprising, (a) subjecting a compound of the formula

with imidazole in a solvent for a sufficient contact time to form -?yn-7-[2-(2-amino- 4-thiazolyl)-2-hydroxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylic acid-imidazole salt.

(b) isolating the Syn-7-[2-(2-amino-4-thiazolyl)-2-hydroxyiminoacetamido]-3-vinyl-3- cephem-4-carboxylic acid-imidazole salt.

7 The process of claim 6, wherein the molar ratio of 5yn-7-[2-(2-amino-4-thiazolyl)-2- hydroxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylic acid and imidazole is about 1: 1.

8 The process of claim 6, wherein step (a) is carried out in aqueous organic solvent.

9 The process of claim 8, wherein organic solvents are aliphatic alcohols or aliphatic ketones.

10 The process of claim 9, wherein the aliphatic alcohols are methanol, ethanol, 2- propanol or n-butanol and aliphatic ketones are acetone and ethyl methyl ketone.

11 The process of claim 10, wherein more particularly aliphatic alcohol and ketone are methanol and acetone.

12 The process of claim 8-11, wherein the volume ratio of methanol and water is from about 95:5 to about 25:75.

13 The process of claim 12, wherein more particularly methanol and water ratio is 90:10.

14 The process of claim 11, wherein the volume ratio of acetone and water is from about 80:20 to about 40:60.

15 The process of claim 14, wherein more particularly acetone and water ratio is 60:40.

16 The process of claim 6, wherein the contacting step is conducted from about O⁰C to about 5O⁰C.

17 The process of claim 6, wherein contact time is from about 2 to about 4 hours. The process of claim 6, wherein Syrt-7-[2-(2-amino-4-thiazolyl) hydroxyimino- acetamido]-3-vinyl-3-cephem-4-carboxylic acid-imidazole is obtained in more than 99.5 % HPLC purity. A crystalline compound of formula

Form C

and its pharmaceutically acceptable salts. A pharmaceutical composition comprising compound of claim 19. A product of claim 19, wherein crystalline 5yn-7-[2-(2-amino-4-thiazolyl) hydroxyimino-acetamido]-3-vinyl-3-cephem-4-carboxylic acid-imidazole Form C is characterized by an Infra Red Spectrum that include peaks at about 3315, 2984, 2361, 1760, 1666, 1613, 1541, 1426, 1353, 1301, 1190, 1136, 1045, 1013, 911, 814, 791, 761, 630 and 570 cm ¹. A product of claim 19, wherein, crystalline Syn-7-[2-(2-amino-4-thiazolyl)-2- hydroxyimino-acetamido]-3-vinyl-3-cephem-4-carboxylic acid Form C is characterized by an X-ray powder diffraction (XRD) that include peaks at about 5.44, 9.18, 10.88, 15.06, 15.50, 17.86, 18.62, 20.72, 20.90, 21.42, 22.340, 23.88, 24.26, 25.68, 26.22, 26.42, 27.80, 28.34, 28.80, 30.46, 32.10, 35.82, 38.60, 38.72 and 39.32°. A process for the manufacture of a compound having the formula

Form C the said method comprising: (a) contacting 5yn-7-[2-(2-amino-4-thiazolyl) hydroxyimino-acetamido]-3-vinyl-3-cephem- 4-carboxylic acid-imidazole salt in a solvent or solvent mixture in presence of an acid; and

(b) isolating the 5yn-7-[2-(2-amino-4-thiazolyl) hydroxyimino-acetamido]-3-vinyl-3- cephem-4-carboxylic acid Form C.

24 The process of claim 23, wherein step (a) is carried out in aqueous organic solvent.

25 The process of claim 24, wherein organic solvent is an ester.

26 The process of claim 25, wherein more preferably ester is ethyl acetate.

27 The process of claim 23, wherein step (a) is carried out in presence of sulfuric acid.

28 The process of claim 23, wherein pH of the reaction mixture is adjusted from about 1.0 to about 5.0.

29 The process of claim 23, wherein reaction time in step (a) is from about 30 minute to 4 hours.

30 The process of claim 24, wherein organic solvent is less than 20 % in water.

31 A crystalline compound of formula

Form D

and its pharmaceutically acceptable salts.

32 A pharmaceutical composition comprising compound of claim 31.

33 The product of claim 31, wherein crystalline Sy«-7-[2-(2-amino-4-thiazolyl) hydroxyimino-acetamido]-3-vinyl-3-cephem-4-carboxylic acid-imidazole Form D is characterized by an Infra Red Spectrum that include peaks at about3304, 2983, 2882, 2361, 1756, 1667, 1610, 1541, 1465, 1423, 1351, 1286, 1189, 1134, 1047, 1014. 992, 813, 651 and 627 cm ¹ .

34 The product of claim 31, wherein crystalline Sy«-7-[2-(2-amino-4-thiazolyl)-2- hydroxyimino-acetamido]-3-vinyl-3-cephem-4-carboxylic acid Form D is characterized by an X-ray powder diffraction (XRD), that include peaks at about 8.40, 10.58, 10.70, 10.94, 11.64, 11.74, 11.68, 14.00, 14.22, 14.90, 15.04, 15.24, 15.52, 18.18, 18.76, 19.16, 21.12, 21.26, 21.42, 21.60, 21.90, 22.30, 22.42, 22.66, 23.70, 23.04, 23.94, 24.22, 24.44, 24.52, 24.72, 25.10, 25.36, 25.68, 25.84, 25.98, 26.12, 26.40, 26.65, 27.06, 27.380, 27.520, 27.760, 28.14, 28.54, 28.66, 28.940, 32.10, 36.32 and 39.08°. 35 A process for the manufacture of a compound having the formula

Form D the said method comprising:

(c) contacting Sy«-7-[2-(2-amino-4-thiazolyl) hydroxyiminoacetamido]-3-vinyl-3-cephem- 4-carboxylic acid-imidazole salt in a solvent mixture in presence of an acid; and

(d) isolating the 5yn-7-[2-(2-amino-4-thiazolyl)-hydroxyiminoacetamido]-3-vinyl-3- cephem-4-carboxylic acid Form D.

36 The process of claim 35, wherein step (a) is carried out in water.

37 The process of claim 35, wherein step (a) is carried out in presence of sulfuric acid.

38 The process of claim 35, where pH of the reaction mixture is between about 2.0 to about 5.0.

39 The process of claim 35, wherein reaction time in step (a) is from about 30 minute to about 4 hours.

40 The process of claim 35, wherein volume of water is about 20 to about 40 times in comparison to 5y«-7-[2-(2-amino-4-thiazolyl)-hydroxyimino-acetamido]-3-vinyl-3- cephem-4-carboxylic acid (v/w).

41 An amorphous compound of formula

and its pharmaceutically acceptable salts.

42 A pharmaceutical composition comprising compound of claim 41.

43 A product of claim 41, wherein an amorphous 5yn-7-[2-(2-amino-4-thiazolyl) hydroxyimino-acetamido]-3-vinyl-3-cephem-4-carboxylic acid is characterized by an Infra Red Spectrum, that include the following peaks at about 3306, 2361, 1765, 1634, 1533, 1352, 1167, 1056, 1013, 917, 855, 729, 622, 568 and 490 cm ¹ .

44 A process for the manufacture of a compound having the formula

Amorphous

the said method comprising:

(a) contacting Syn-7-[2-(2-amino-4-thiazolyl) hydroxyiminoacetamido]-3-vinyl-3-cephem-4- carboxylic acid-imidazole salt in a solvent and in presence of an acid; and

(b) isolating the amorphous Syn-7-[2-(2-amino-4-thiazolyl)-hydroxyiminoacetamido]-3- vinyl-3-cephem-4-carboxylic acid.

45 The process of claim 44, wherein step (a) is carried out in aqueous organic solvent.

46 The process of claim 45, wherein more particularly organic solvent is an aliphatic alcohol.

47 The process of claim 46, wherein more preferably alcohol is methanol.

48 The process of claim 44, wherein step (a) is carried out in presence of an organic acid.

49 The process of claim 44, wherein more preferably said acid is formic acid. The process of claim 44, wherein ratio of Cefdinir-imidazole salt and formic acid is about 1 :5, more preferably 1:2 (w/v). The process of claim 44, wherein reaction time in step (a) is from about 30 minute to 4 hours.