WO2010089729A1

WO2010089729A1 - Processes for the preparation of cefozopran, its salts and polymorphic forms thereof

Info

Publication number: WO2010089729A1
Application number: PCT/IB2010/050596
Authority: WO
Inventors: Neera Tewari; Kallimulla Mohammad; Bishwa Prakash Rai; Mashkoor Hussain
Original assignee: Ranbaxy Laboratories Limited
Priority date: 2009-02-09
Filing date: 2010-02-09
Publication date: 2010-08-12

Abstract

The present invention relates to processes for the preparation of cefozopran of Formula (I), its salts and polymorphic forms thereof.

Description

PROCESSES FOR THE PREPARATION OF CEFOZOPRAN, ITS SALTS AND

POLYMORPHIC FORMS THEREOF

Field of the Invention

The present invention relates to processes for the preparation of cefozopran, its salts and polymorphic forms thereof.

Background of the Invention

Cefozopran is a cephem-type antibiotic, which is chemically (6R,7R)-7-{ [(2Z)-2- (5-amino-l,2,4-thiadiazol-3-yl)-2-(methoxyimino)acetyl]amino}-3-(imidazo[l,2- b]pyridazin-l-ium-l-ylmethyl)-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylate, as depicted in Formula I.

FORMULA I Cefozopran or its salts are active against both Gram-positive and Gram- negative bacteria. Cefozopran monohydrochloride is available in the market for the treatment of bacterial infections.

U.S. Patent No. 4,864,022 describes a process for the preparation of cefozopran by reacting the hydrochloride salt of 7β-amino-3-[(imidazo[l,2-b]pyridazinium-l-yl)methyl]- 3-cephem-4-carboxylate of Formula II with the hydrochloride salt of 2-(5-amino- 1,2,4- thiadiazol-3-yl)-2(Z)-methoxyiminoacetyl chloride of Formula III in the presence of a base at -2O⁰C to 0⁰C.

FORMULA II

FORMULA III

The cefozopran obtained is further treated with hydrochloric acid, the precipitate is suspended in water, the pH is adjusted to 3 and the reaction mixture is chromatographed using a column of MCI gel, CHP-20P® (Mitsubishi-Kasei, Japan) with water and aqueous acetonitrile. The fractions are concentrated and the residue is lyophilized to obtain cefozopran. U.S. Patent No. 4,864,022 does not disclose whether cefozopran is in the form of salt or free base. U.S. Patent No. 4,864,022 also describes a process for the preparation and isolation of the hydrochloride salt of 2-(5-amino-l,2,4-thiadiazol-3-yl)- 2(Z)-methoxyiminoacetyl chloride of Formula III.

U.S. Patent No. 5,998,611 describes a process for the preparation of cefozopran by reacting 7β-amino-3-[(imidazo[l,2-b]pyridazinium-l-yl)methyl]-3-cephem-4-carboxylate of Formula II with 2-(5-amino-l,2,4-thiadiazol-3-yl)-2(Z)-methoxyiminoacetyl chloride of Formula III in the presence of sodium acetate and water under ice-cooling. The insoluble matter was separated by filtration and the filtrate obtained is purified by reverse phase chromatography using ammonium acetate/aqueous methanol as the mobile phase. The main fraction is lyophilized to obtain cefozopran as a free base with 97.5% HPLC purity. U.S. Patent No. 5,998,611 also discloses that by employing chromatographic steps for isolation, the risk of thermal decomposition of cephem compounds is avoided. Japanese Publication No. 10-291993 A2 describes a process for the preparation of cefozopran by reacting hydrogen chloride or a hydrogen iodide salt of 7β-amino-3- [(imidazo[l,2-b]pyridazinium-l-yl)methyl]-3-cephem-4-carboxylate of Formula II with S- 1 ,3-benzothiazol-2-yl-(2Z)-(5-amino- 1 ,2,4-thiadiazol-3-yl)(methoxyimino)ethanethioate of Formula IVa in the presence of methanol and a base.

FORMULA IVa

Cefozopran is isolated as a free base in the above process using chromatographic separation. U.S. Patent No. 4,978,752 discloses a crystallization process for the preparation of crystalline cefozopran free base by suspending cefozopran free base in water, treating with IN hydrochloric acid to obtain a solution, adjusting the pH to about 4 with anhydrous sodium carbonate and allowing the mixture to stand at room temperature for 3 hours to isolate the crystals. U.S. Patent No. 4,978,752 also provides processes for preparing acetone, ethanol, methanol and N, N-dimethylformamide solvates of cefozopran monohydrochloride from crystalline cefozopran free base. The solvates of cefozopran monohydrochloride are characterized in U.S. Patent No. 4,978,752 by their XRPD patterns, lattice spacing (d) and solvent content.

The processes provided in prior art for preparing cefozopran or its hydrochloride salt involves economically unviable methods, such as column chromatography for purification, and lyophilization methods for obtaining the final product. Further, the reaction of 7β-amino-3-[(imidazo[l,2-b]pyridazinium-l-yl)methyl]-3-cephem-4- carboxylate of Formula II with 2-(5-amino-l,2,4-thiadiazol-3-yl)-2(Z)- methoxyiminoacetylchloride of Formula III requires temperature conditions lower than 0⁰C. The employment of chromatographic and lyophilization methods and maintenance of lower temperature conditions are not preferable on a commercial scale and thus are not economical. Further, the prior art processes for preparing cefozopran require the isolation of 2-(5-amino-l,2,4-thiadiazol-3-yl)-2(Z)-methoxyiminoacetyl chloride of Formula III or its salts or S-l,3-benzothiazol-2-yl-(2Z)-(5-amino-l,2,4-thiadiazol-3- yl)(methoxyimino)ethanethioate of Formula IV before reacting with 7β-amino-3- [(imidazo[l,2-b]pyridazinium-l-yl)methyl]-3-cephem-4-carboxylate of Formula II.

Brief Description of the Figures

Figure 1 depicts the X-Ray Powder Diffractogram (XRPD) of polymorphic Form I of cefozopran hemihydrochloride.

Figure IA provides the table of X-Ray Powder Diffractogram (XRPD) of polymorphic Form I of cefozopran hemihydrochloride.

Figure 2 depicts the Fourier- TransForm Infra-red (FTIR) spectrum of polymorphic Form I of cefozopran hemihydrochloride.

Figure 3 depicts the X-Ray Powder Diffractogram (XRPD) of polymorphic Form II of cefozopran hemihydrochloride. Figure 3 A provides the table of X-Ray Powder Diffractogram (XRPD) of polymorphic Form II of cefozopran hemihydrochloride.

Figure 4 depicts the Fourier-TransForm Infra-red (FTIR) spectrum of polymorphic Form II of cefozopran hemihydrochloride.

Figure 5 depicts the X-Ray Powder Diffractogram (XRPD) of polymorphic Form III of cefozopran hemihydrochloride.

Figure 5A provides the table of X-Ray Powder Diffractogram (XRPD) of polymorphic Form III of cefozopran hemihydrochloride.

Figure 6 depicts the X-Ray Powder Diffractogram (XRPD) of polymorphic Form A of cefozopran monohydrochloride. Figure 7 depicts the X-Ray Powder Diffractogram (XRPD) of polymorphic Form

Al of cefozopran monohydrochloride.

Figure 8 depicts the X-Ray Powder Diffractogram (XRPD) of polymorphic Form B of cefozopran monohydrochloride. Figure 8A provides the table of X-Ray Powder Diffractogram (XRPD) of polymorphic Form B of cefozopran monohydrochloride.

Figure 9 depicts the X-Ray Powder Diffractogram (XRPD) of polymorphic Form A2 of cefozopran monohydrochloride. Figure 9A provides the table of X-Ray Powder Diffractogram (XRPD) of polymorphic Form A2 of cefozopran monohydrochloride.

Summary of the Invention

In one general aspect there is provided a process for the preparation of cefozopran or it salts, wherein the process includes: a) reacting (2Z)-(5-amino-l,2,4-thiadiazol-3-yl)(methoxyimino)ethanoic acid of

Formula V with a compound of Formula VI in the presence of a solvent

FORMULA VI wherein R is

or

to obtain a compound of Formula IV

FORMULA IV wherein R is as defined above, b) reacting the compound of Formula IV with 7β-amino-3-[(imidazo[l,2- b]pyridazinium-l-yl)methyl]-3-cephem-4-carboxylate of Formula II or its salts in the presence of a solvent

FORMULA II to obtain cefozopran or its salts, and c) isolating cefozopran or its salts from the reaction mixture thereof without using any chromatographic method.

Embodiments of the present aspect may include one or more of the following features. For example, the isolation of the cefozopran or its salts from the reaction mixture may be done without the use of any chromatographic method. Further, step b) may be completed without isolating the reaction mixture of step a).

In another general aspect there is provided a hemihydrochloride form of cefozopran.

Embodiments of the present aspect may include one or more of the following features. For example, the hemihydrochloride form of cefozopran may include a chloride content in the range of about 2% to about 5%. In yet another general aspect there is provided polymorphic Form I of cefozopran hemihydrochloride having an XRPD, which includes characteristic d-spacing [A] values substantially at 3.614, 4.065, 4.272, 4.706, 5.624, 7.209, 8.547.

Embodiments of the present aspect may include one or more of the following features. For example, the polymorphic Form I of cefozopran hemihydrochloride omay further include characteristic d-spacing [A] values substantially at 2.417, 2.512, 2.579, 2.712, 3.059, 3.167, 3.271, 3.422, , 3.814, 5.408, 6.337, 6.979, and 9.586. The polymorphic Form I of cefozopran hemihydrochloride may further be characterized by the XRPD pattern substantially as illustrated in Figure 1. In another general aspect there is provided polymorphic Form II of cefozopran hemihydrochloride having an XRPD, which includes characteristic d-spacing [A] values substantially at 3.423, 3.540, 3.673, 4.162, 4.776, 5.577, 8.055.

Embodiments of the present aspect may include one or more of the following features. For example, the polymorphic Form II of cefozopran hemihydrochloride may further include characteristic d-spacing [A] values substantially at 2.663, 3.121, 3.283, 3.937, 6.202, 6.920, 8.870 and 24.990. The polymorphic Form II of cefozopran hemihydrochloride may further be characterized by the XRPD pattern substantially as illustrated in Figure 3.

In another general aspect there is provided polymorphic Form III of cefozopran hemihydrochloride having an XRPD comprising characteristic d-spacing [A] values substantially at 3.154, 3.393, 3.751, 4.511, 6.297 and 9.241.

Embodiments of the present aspect may include one or more of the following features. For example, the polymorphic Form III of cefozopran hemihydrochloride may further be characterized by the XRPD pattern substantially as illustrated in Figure 5. In another general aspect there is provided a process for the preparation of cefozopran hemihydrochloride, wherein the process includes: a) forming a solution comprising cefozopran and hydrochloric acid and having a pH of about 2.5 or below; b) treating the solution of step a)with an organic base to attain a pH of about 3.5 to about 4.5; and c) isolating cefozopran hemihydrochloride from the mixture thereof.

In another general aspect there is provided a process for the preparation of polymorphic Form I of cefozopran hemihydrochloride, wherein the process includes: a) forming a solution comprising cefozopran, N,N-dimethylformamide and hydrochloric acid and having a pH of about 2.5 or below, b) treating the solution of step a) with an organic base to attain a pH of about 3.5 to about 4.5 to obtain cefozopran hemihydrochloride, and c) treating the cefozopran hemihydrochloride obtained in step b) with a Ci_₅ alkanol to obtain polymorphic Form I of cefozopran hemihydrochloride. In another general aspect there is provided a process for the preparation of polymorphic Form II of cefozopran hemihydrochloride, wherein the process includes: a) forming a solution comprising cefozopran and hydrochloric acid and having a pH of about 2.5 or below; b) treating the solution of step a) with an organic base to attain a pH of about 3.5 to about 4.5 to obtain cefozopran hemihydrochloride; and c) treating the cefozopran hemihydrochloride obtained in step b) with a C_3-6 ketone to obtain polymorphic Form II of cefozopran hemihydrochloride.

In yet another general aspect there is provided a process for the preparation of polymorphic Form III of cefozopran hemihydrochloride, wherein the process includes: a) treating polymorphic Form I of cefozopran hemihydrochloride with water and a C3-6 ketone, and b) isolating polymorphic Form III of cefozopran hemihydrochloride from the reaction mixture thereof.

In another general aspect there is provided polymorphic Form A of cefozopran monohydrochloride characterized by the XRPD pattern substantially as illustrated in Figure 6. In yet another general aspect there is provided polymorphic Form Al of cefozopran monohydrochloride characterized by the XRPD pattern substantially as illustrated in Figure 7.

In another general aspect there is provided polymorphic Form A2 of cefozopran monohydrochloride having an XRPD, which includes characteristic d- spacing [A] values substantially at 3.410, 3.496, 3.718 and 5.749.

Embodiments of the present aspect may include one or more of the following aspects. For example, the polymorphic Form A2 of cefozopran monohydrochloride may further be characterized by the XRPD pattern substantially as illustrated in Figure 7. In another general aspect there is provided polymorphic Form B of cefozopran monohydrochloride having an XRPD, which includes characteristic d-spacing [A] values substantially at 2.742, 3.203, 3.388, 3.489, 3.715, 3.955, 4.430, 4.746, 5.208, 5.750.

Embodiments of the present aspect may include one or more of the following aspects. For example, the polymorphic Form B of cefozopran monohydrochloride may further include characteristic d-spacing [A] values substantially at 2.296, 2.340, 2.419, 2.504, 2.585, 2.606, 2.682, , 2.814, 2.847, 2.898, 3.087, 3.146, 3.318, 3.343, 3.642, 3.838, 3.883, 3.997, 4.076, 4.153, 4.585, 4.658, 4.977, 5.057, 5.578, 5.697, 6.255, 7.033, 7.276, 7.756, 10.050 and 12.835. The polymorphic Form B of cefozopran monohydrochloride may also be further characterized by the XRPD pattern substantially as illustrated in Figure 8.

In another general aspect there is provided a process for the preparation of polymorphic Form A of cefozopran monohydrochloride, wherein the process includes: a) treating cefozopran free base or cefozopran hemihydrochloride with hydrochloric acid in the presence of a C_3-6 ketone; and b) isolating polymorphic Form A of cefozopran monohydrochloride from the reaction mixture thereof.

In another general aspect there is provided a process for the preparation of polymorphic Form Al of cefozopran monohydrochloride, wherein the process includes: a) treating cefozopran free base or cefozopran hemihydrochloride with hydrochloric acid in the presence of C_1-5 alkanol; and b) isolating polymorphic Form Al of cefozopran monohydrochloride from the reaction mixture thereof. In another general aspect there is provided a process for the preparation of cefozopran monohydrochloride, wherein the process includes: a) treating cefozopran free base with hydrochloric acid in the presence of water; and b) isolating cefozopran monohydrochloride from the mixture thereof. In another general aspect there is provided a process for the preparation of polymorphic Form B of cefozopran monohydrochloride, wherein the process includes: a) treating cefozopran free base with hydrochloric acid in the presence of water to obtain a solution; b) precipitating cefozopran monohydrochloride from the solution of step a); and c) treating the cefozopran monohydrochloride obtained in step b) with water and tetrahydrofuran to obtain polymorphic Form B of cefozopran monohydrochloride .

In yet another general aspect there is provided a process for the preparation of polymorphic Form A2 of cefozopran monohydrochloride, wherein the process includes: a) treating cefozopran monohydrochloride with hydrochloric acid in the presence of water to obtain a solution; b) treating the mixture obtained in step a) with a base and a C_1-3 alkanol; and c) isolating polymorphic Form A2 of cefozopran monohydrochloride from the reaction mixture thereof. Detailed Description of the Invention

The present invention provides for a process for the preparation of cefozopran or it salts, wherein the process includes: reacting (2Z)-(5-amino-l,2,4-thiadiazol-3-yl)(methoxyimino)ethanoic acid of Formula V with a compound of Formula VI in the presence of a solvent

FORMULA V

R

FORMULA VI wherein R is

or

N-N

-AJ- CH, to obtain a compound of Formula IV,

FORMULA II to obtain cefozopran or its salts, and c) isolating cefozopran or its salts from the reaction mixture thereof without the use of a chromatographic method.

The 2-(Z)-(5-amino-l,2,4-thiadiazol-3-yl)(methoxyimino)ethanoic acid of Formula V is reacted with the compound of Formula VI in the presence of a solvent. The solvent may be water, a water miscible organic solvent, for example, tetrahydrofuran, or a water immiscible solvent, for example, dichloromethane, or mixtures thereof. The reaction may be carried out in the presence of an organophosphorus compound, for example, triphenylphosphine, and optionally a base. The base may be an organic or inorganic base. The base may be an alkylamine, such as, tributylamine or triethylamine. The reaction may be carried out at a temperature of between about O⁰C to about 4O⁰C, for example, between about O⁰C to about 25⁰C. The reaction may be facilitated by stirring the reaction mixture to obtain the compound of Formula IV.

The compound of Formula IV is reacted with 7β-amino-3-[(imidazo[l,2- b]pyridazinium-l-yl)methyl]-3-cephem-4-carboxylate of Formula II or its salts, for example, hydrochloride salt or hydrogen iodide salt. The reaction is carried out in the presence of a solvent and a base. The solvent may be water, a water-miscible organic solvent, for example, tetrahydrofuran, or a water-immiscible solvent, for example, dichloromethane, or mixtures thereof. The base may be an organic or inorganic base. The base may be an alkylamine, for example, tributylamine or triethylamine. The reaction may be carried out at a temperature of between about 1O⁰C to about 5O⁰C, for example, between about 15⁰C to about 3O⁰C. The reaction may be carried out for about 1 hour to about 100 hours, or it may be carried out for about 3 hours to about 20 hours. The reaction may be facilitated by stirring the reaction mixture. The cefozopran may be isolated as a free base or as a salt by contacting with an acid, for example, hydrochloric acid. The isolation of cefozopran as a free base or as a salt is carried out without using any chromatographic method. Cefozopran or its salts may be isolated from the reaction mixture by filtration, solvent evaporation, precipitation, decantation, or a combination thereof.

In another aspect of the present invention there is provided a process for the preparation of cefozopran or it salts, wherein the process includes: a) reacting (2Z)-(5-amino-l,2,4-thiadiazol-3-yl)(methoxyimino)ethanoic acid of Formula V with a compound of Formula VI in the presence of a solvent,

FORMULA V

R

S S

R

FORMULA VI wherein R is

or

N-N

S' ^CH3 to obtain a compound of Formula IV,

FORMULA IV wherein R is as defined above, b) reacting the compound of Formula IV, without isolating from the reaction mixture of step a), with 7β-amino-3-[(imidazo[l,2-b]pyridazinium-l- yl)methyl]-3-cephem-4-carboxylate of Formula II, or its salts

FORMULA II to obtain cefozopran or its salts, and c) isolating cefozopran or its salts from the reaction mixture thereof.

The 2-(Z)-(5-amino-l,2,4-thiadiazol-3-yl)(methoxyimino)ethanoic acid of Formula V is reacted with the compound of Formula VI in the presence of a solvent. The solvent may be a water miscible organic solvent, for example, tetrahydrofuran or water, or mixtures thereof. The reaction may be carried out in the presence of an organophosphorus compound, for example, triphenylphosphine, and optionally a base. The base may be an organic or inorganic base. The base may be an alkylamine, for example, tributylamine or triethylamine. The reaction may be carried out at a temperature of between about 0⁰C to about 4O⁰C, or between about O⁰C to about 25⁰C. The reaction may be facilitated by stirring the reaction mixture to obtain the compound of Formula IV. The compound of Formula IV is not isolated from the reaction mixture. The 7β-amino-3-[(imidazo[l,2- b]pyridazinium-l-yl)methyl]-3-cephem-4-carboxylate of Formula II, or its salts, for example, hydrochloride salt or hydrogen iodide salt, are added to the reaction mixture containing the compound of Formula IV or the reaction mixture containing the compound of Formula IV is added to 7β-amino-3-[(imidazo[l,2-b]pyridazinium-l-yl)methyl]-3- cephem-4-carboxylate of Formula II or its salts, for example, hydrochloride salt or hydrogen iodide salt.

The compound of Formula IV is reacted with 7β-amino-3-[(imidazo[l,2- b]pyridazinium-l-yl)methyl]-3-cephem-4-carboxylate of Formula II or its salts in the presence of a base. The base may be an organic or inorganic base. The base may be an alkylamine, for example, tributylamine or triethylamine. The reaction may be carried out at a temperature of between about 1O⁰C to about 5O⁰C, or at between about 15⁰C to about 3O⁰C. The reaction may be carried out for about 1 hour to about 100 hours, or for about 3 hours to about 20 hours. The reaction may be facilitated by stirring the reaction mixture. The cefozopran, for example, crystalline cefozopran free base, or its salts may be isolated from the reaction mixture by filtration, solvent evaporation, decantation, or a combination thereof.

Another aspect of the present invention provides for cefozopran hemihydrochloride. The cefozopran hemihydrochloride of the present invention has chloride content in the range of about 2% to about 5%, for example, about 3% to about

4%. Yet another aspect of the present invention provides for polymorphic Form I of cefozopran hemihydrochloride. Form I of cefozopran hemihydrochloride has substantially the same XRPD pattern as depicted in Figure 1. The XRPD of Form I of cefozopran hemihydrochloride shows characteristic d-spacing [A] values substantially at 2.41, 2.51, 2.57, 2.71, 3.05, 3.16, 3.27, 3.42, 3.61, 3.81, 4.06, 4.27, 4.70, 5.40, 5.62, 6.33, 6.97, 7.20, 8.54 and 9.58. Form I of cefozopran hemihydrochloride has substantially the same FTIR pattern as depicted in Figure 2. Polymorphic Form I of cefozopran hemihydrochloride may include about 10% to about 15%, for example, about 12% to about 14%, of N, N- dimethylf ormamide .

The present invention also provides for polymorphic Form II of cefozopran hemihydrochloride. Form II of cefozopran hemihydrochloride has substantially the same XRPD pattern as depicted in Figure 3. The XRPD of Form II of cefozopran hemihydrochloride shows characteristic d-spacing [A] values substantially at 2.66, 3.12, 3.28, 3.42, 3.54, 3.67, 3.93, 4.16, 4.77, 5.57, 6.20, 6.92, 8.05, 8.87 and 24.99. Form II of cefozopran hemihydrochloride has substantially the same FTIR pattern as depicted in Figure 4. Polymorphic Form II of cefozopran hemihydrochloride may include about 10% to about 15%, for example, about 12% to about 14%, of N, N-dimethylformamide.

Another aspect of the present invention provides for polymorphic Form III of cefozopran hemihydrochloride. Polymorphic Form III of cefozopran hemihydrochloride has substantially the same XRPD pattern as depicted in Figure 5. The XRPD of Form III of cefozopran hemihydrochloride shows characteristic d-spacing [A] values substantially at 3.15, 3.39, 3.75, 4.51, 6.29 and 9.24.

The present invention also provides for a process for the preparation of cefozopran hemihydrochloride, wherein the process includes: a) forming a solution comprising cefozopran and hydrochloric acid and having a pH of equal to or less than about 2.5; b) treating the solution of step a) with an organic base to attain a pH of about 3.5 to about 4.5; and c) isolating cefozopran hemihydrochloride from the mixture thereof.

The solution comprising cefozopran and hydrochloric acid may be prepared by dissolving cefozopran free base or cefozopran monohydrochloride in a solvent and the pH of about 2.5 or below, for example from about 1 to about 2.2, may be attained by treating the solution with hydrochloric acid. Cefozopran free base or cefozopran monohydrochloride obtained according to the methods provided in, for example, U.S. Patent No. 4,978,752, may be used as the starting material. The hydrochloric acid may be in the form of a solution or gas. The solvent may be a water- miscible solvent, for example, N,N-dimethylformamide. The solvent may be used alone or as a mixture, for example, a mixture of N,N-dimethylformamide and water. The solution comprising cefozopran and hydrochloric acid and having a pH of about 2.5 or below is treated with an organic base to attain a pH of about 3.5 to about 4.5. The organic base may be an alkylamine, for example, tributylamine or triethylamine. The formation of cefozopran hemihydrochloride may be effected by stirring the reaction mixture and cefozopran hemihydrochloride may be isolated by filtration, distillation, concentration, decantation, or a combination thereof.

Another aspect of the present invention provides for a process for the preparation of polymorphic Form I of cefozopran hemihydrochloride, wherein the process comprises: a) forming a solution comprising cefozopran, N,N-dimethylformamide and hydrochloric acid and having a pH of equal to or less than about 2.5; b) treating the solution of step a) with an organic base to attain a pH of about 3.5 to about 4.5 to obtain cefozopran hemihydrochloride; and c) treating the cefozopran hemihydrochloride obtained in step b) with a C_1-5 alkanol to obtain polymorphic Form I of cefozopran hemihydrochloride.

The solution comprising cefozopran, N,N-dimethylformamide and hydrochloric acid may be prepared by dissolving cefozopran free base or cefozopran monohydrochloride in N,N-dimethylformamide. The pH of about 2.5 or below, for example, from about 1 to about 2.2, may be attained by treating the solution with hydrochloric acid. Cefozopran free base or cefozopran monohydrochloride obtained according to the methods provided in, for example, U.S. Patent No. 4,978,752, may be used as the starting material. The hydrochloric acid may be in the form of a solution or gas. N,N-dimethylformamide may be used alone or as a mixture with a solvent- miscible with N,N-dimethylformamide, for example, water. The solution comprising cefozopran, N,N-dimethylformamide and hydrochloric acid and having a pH of about 2.5 or below is treated with an organic base to attain a pH of between about 3.5 to about 4.5. The organic base may be an alkylamine, for example, tributylamine or triethylamine. The cefozopran hemihydrochloride so obtained is treated with a Ci_₅ alkanol, for example, isopropanol. The treatment with C_1-5 alkanol may be accompanied by stirring the mixture of cefozopran hemihydrochloride, and a C_1-5 alkanol. The stirring may be carried out for about 10 minutes to about 10 hours, or from about 20 minutes to about 5 hours. Form I of cefozopran hemihydrochloride may be isolated from the mixture by removal of the solvent by filtration, decantation, or a combination thereof.

Yet another aspect of the present invention provides a process for the preparation of polymorphic Form II of cefozopran hemihydrochloride, wherein the process includes: a) forming a solution comprising cefozopran and hydrochloric acid and having a pH of equal to or less than about 2.5; b) treating the solution of step a) with an organic base to attain a pH of about 3.5 to about 4.5 to obtain cefozopran hemihydrochloride; and c) treating the cefozopran hemihydrochloride obtained in step b) with a C₃-₆ ketone to obtain polymorphic Form II of cefozopran hemihydrochloride.

The solution comprising cefozopran, N,N-dimethylformamide and hydrochloric acid may be prepared by dissolving cefozopran free base or cefozopran monohydrochloride in N,N-dimethylformamide. The pH of about 2.5 or below, for example, from about 1 to about 2.2, may be attained by treating the solution with hydrochloric acid. Cefozopran free base or cefozopran monohydrochloride obtained according to the methods provided in, for example, U.S. Patent No. 4,978,752, may be used as the starting material. The hydrochloric acid may be in the form of a solution or gas. N,N-dimethylformamide may be used alone or as a mixture with a solvent- miscible with N,N-dimethylformamide, such as water. The solution comprising cefozopran, N₅N- dimethylformamide and hydrochloric acid and having a pH of about 2.5 or below is treated with a base to attain a pH of about 3.5 to about 4.5. The organic base may be an alkylamine, for example, tributylamine or triethylamine. The cefozopran hemihydrochloride so obtained is treated with a C_3-6 ketone, for example, acetone. The treatment with C₃_₆ ketone may be accompanied by stirring the mixture of cefozopran hemihydrochloride, and a C₃-₆ ketone. The stirring may be carried out for about 10 minutes to about 10 hours, for example, from about 20 minutes to about 5 hours. Form II of cefozopran hemihydrochloride may be isolated from the mixture by removal of the solvent, for example, by filtration, decantation, or a combination thereof. Another aspect of the present invention provides for a process for the preparation of polymorphic Form III of cefozopran hemihydrochloride, wherein the process includes: a) treating polymorphic Form I of cefozopran hemihydrochloride with water and a C₃_₆ ketone; and b) isolating polymorphic Form III of cefozopran hemihydrochloride from the reaction mixture thereof. Polymorphic Form I of cefozopran hemihydrochloride used as the starting material may be prepared according to the previous aspects of the present invention. Polymorphic Form I of cefozopran hemihydrochloride is treated with water and a C_3-6 ketone, for example acetone. The treatment with water and the C₃_₆ ketone may be accompanied by stirring a mixture of cefozopran hemihydrochloride, water and the C₃_₆ ketone. The stirring may be carried out for about 10 minutes to about 10 hours, for example, from about 1 hour to about 5 hours. Form III of cefozopran hemihydrochloride may be isolated from the mixture by removal of the solvent, for example, by filtration, decantation, or a combination thereof. In yet another aspect, the present invention provides for polymorphic Form A of cefozopran monohydrochloride. Form A of cefozopran monohydrochloride has substantially the same XRPD pattern as depicted in Figure 6. The XRPD of Form A of cefozopran monohydrochloride is characterized by a halo between 2Θ values of about 20 and about 30. Another aspect of the present invention provides for polymorphic Form Al of cefozopran monohydrochloride. Form Al of cefozopran monohydrochloride has substantially the same XRPD pattern as depicted in Figure 7. The XRPD of Form Al of cefozopran monohydrochloride shows two minor halos between 2Θ values of about 10 and about 20, and between 2Θ values of about 30 and 40, and a major halo between 2Θ values of about 20 and about 30.

The present invention also provides for polymorphic Form A2 of cefozopran monohydrochloride. The polymorphic Form A2 of cefozopran monohydrochloride has substantially the same XRPD pattern as depicted in Figure 9. The XRPD of Form A2 of cefozopran monohydrochloride shows characteristic d-spacing [A] values substantially at 3.41, 3.49, 3.71 and 5.74.

Another aspect of the present invention provides for polymorphic Form B of cefozopran monohydrochloride. Form B of cefozopran monohydrochloride has substantially the same XRPD pattern as depicted in Figure 8. The XRPD of Form B of cefozopran monohydrochloride shows characteristic d-spacing [A] values substantially at 2.29, 2.34, 2.41, 2.50, 2.58, 2.60, 2.68, 2.74, 2.81, 2.84, 2.89, 3.08, 3.14, 3.20, 3.31, 3.34, 3.38, 3.48, 3.64, 3.71, 3.83, 3.88, 3.95, 3.99, 4.07, 4.15, 4.43, 4.58, 4.65, 4.74, 4.97, 5.05, 5.20, 5.57, 5.69, 5.75, 6.25, 7.03, 7.27, 7.75, 10.05 and 12.83.

Another aspect of the present invention provides for a process for the preparation of polymorphic Form A of cefozopran monohydrochloride, wherein the process includes: a) treating cefozopran free base or cefozopran hemihydrochloride with hydrochloric acid in the presence of a C₃-₆ ketone; and b) isolating polymorphic Form A of cefozopran monohydrochloride from the reaction mixture thereof.

The cefozopran used as the starting material may be in the form of a free base or hemihydrochloride. Cefozopran free base may be prepared according to the methods provided in, for example, U.S. Patent No. 4,978,752. Cefozopran hemihydrochloride may be prepared according to the previous aspects of the present invention. Cefozopran free base or cefozopran hemihydrochloride is treated with hydrochloric acid in the presence of C₃-₆ ketone, for example, acetone. The hydrochloric acid may be in the form of a solution or gas. The treatment with hydrochloric acid may be carried out, for example, by purging hydrogen chloride gas into a mixture of cefozopran free base or cefozopran hemihydrochloride and C₃-₆ ketone followed by stirring the reaction mixture for about 10 minutes to about 10 hours. Form A of cefozopran monohydrochloride may be isolated from the mixture by filtration, distillation, concentration, decantation, or a combination thereof.

Also provided for is a process for the preparation of polymorphic Form Al of cefozopran monohydrochloride, wherein the process includes: a) treating cefozopran free base or cefozopran hemihydrochloride with hydrochloric acid in the presence of Ci_₅ alkanol; and b) isolating polymorphic Form Al of cefozopran monohydrochloride from the reaction mixture thereof.

The cefozopran used as the starting material may be in the form of a free base or hemihydrochloride. Cefozopran free base may be prepared according to the methods provided in, for example, U.S. Patent No. 4,978,752. Cefozopran hemihydrochloride may be prepared according to the previous aspects of the present invention. Cefozopran free base or cefozopran hemihydrochloride is treated with hydrochloric acid in the presence of a Ci-₅ alkanol, for example, isopropanol. The hydrochloric acid may be in the form of a solution or gas. The treatment with hydrochloric acid may be carried out by treating a mixture of cefozopran free base or cefozopran hemihydrochloride and Ci_₅ alkanol with a solution of hydrochloric acid in C_1-5 alkanol, followed by stirring the reaction mixture for about 10 minutes to about 10 hours. Form Al of cefozopran monohydrochloride may be isolated from the mixture by filtration, distillation, concentration, decantation, or a combination thereof.

Another aspect of the present invention provides for a process for the preparation of cefozopran monohydrochloride, wherein the process includes: a) treating cefozopran free base with hydrochloric acid in the presence of water; and b) isolating cefozopran monohydrochloride from the mixture thereof.

The cefozopran free base may be prepared according to the methods provided in, for example, U.S. Patent No. 4,978,752. The cefozopran free base is treated with hydrochloric acid in the presence of water to obtain a solution. The use of any other solvent is not needed. The hydrochloric acid may be used in concentrated form or as aqueous solution or as a gas. The solution obtained may optionally be purified by treating with carbon and filtered subsequently. The cefozopran monohydrochloride may be precipitated as a solid by the addition of an aqueous sodium hydroxide solution and by stirring at about O⁰C to about 4O⁰C, or at about 2O⁰C to about 25⁰C. The cefozopran monohydrochloride may be isolated by filtration, decantation, solvent evaporation, or a combination thereof. The cefozopran monohydrochloride may be further washed with water or a water-miscible organic solvent, or a combination thereof. Another aspect of the present invention provides for a process for the preparation of polymorphic Form B of cefozopran monohydrochloride, wherein the process includes: a) treating cefozopran free base with hydrochloric acid in the presence of water to obtain a solution; b) precipitating cefozopran monohydrochloride from the solution of step a); and c) treating the cefozopran monohydrochloride obtained in step b) with water and tetrahydrofuran to obtain polymorphic Form B of cefozopran monohydrochloride .

The cefozopran free base may be prepared according to the methods provided in, for example, U.S. Patent No. 4,978,752. The cefozopran free base is treated with hydrochloric acid in the presence of water to obtain a solution. The hydrochloric acid may be used in concentrated form or as aqueous solution or as a gas. The solution so obtained may optionally be purified by treating with carbon and filtered subsequently. The cefozopran monohydrochloride may be precipitated as a solid by the addition of aqueous sodium hydroxide solution and by stirring at about O⁰C to about 4O⁰C, or at about 2O⁰C to about 25⁰C. The cefozopran monohydrochloride obtained is treated with water and tetrahydrofuran. The treatment may be carried out by using water and tetrahydrofuran together or in optional order of succession. Tetrahydrofuran may be used in a volume of about two times or more to the volume of water. The treatment may be carried out by passing water and tetrahydrofuran through cefozopran monohydrochloride or by slurrying, or a combination thereof. The polymorphic Form B of cefozopran monohydrochloride obtained may be optionally further dried at about 4O⁰C to about 6O⁰C.

The present invention also provides for a process for the preparation of polymorphic Form A2 of cefozopran monohydrochloride, wherein the process includes: a) treating cefozopran monohydrochloride with hydrochloric acid in the presence of water to obtain a solution; b) treating the mixture obtained in step a) with a base and a C_1-3 alkanol; and c) isolating polymorphic Form A2 of cefozopran monohydrochloride from the reaction mixture thereof. Cefozopran monohydrochloride used as a starting material may be prepared according to the previous aspect of the present invention. Cefozopran monohydrochloride is treated with hydrochloric acid in the presence of water to obtain a solution. The hydrochloric acid may be used in concentrated form or as an aqueous solution or as a gas. The solution so obtained is treated with a base and a C_1-3 alkanol, for example, isopropanol. The treatment may be carried out by using the base and the C_1-3 alkanol together or in optional order of succession. The base may be an organic or inorganic base. The base may be, for example, triethylamine or tributylamine. After or while treating with a base and a Ci_₃ alkanol, the reaction mixture may be stirred for about 1 minute to about 1 hour, for example, about 5 minutes to about 10 minutes. Polymorphic Form A2 of cefozopran monohydrochloride may be isolated from the mixture by filtration or decantation, or a combination thereof. The polymorphic Form A2 of cefozopran monohydrochloride may be optionally further dried at about 4O⁰C to about 6O⁰C.

The XRPD of the samples were determined using X-Ray diffractometer, Rigaku Corporation, RU-H3R, Goniometer CN2155A3, X-Ray tube with Cu target anode, Power: 40 KV, 100 Ma, Scanning speed: 2 deg/min step: 0.02 deg, Wave length: 1.5406 A.

As one skilled in the art would appreciate, the values specified for d-spacings herein are approximate and expected to have a certain amount of variability and/or error. As such, the specified values herein should be understood to include values slightly above or below the stated value, and these variations should be construed to be encompassed by the d- spacing values listed.

The FTIR spectra of the samples were recorded on a Perkin-Elmer 16 PC instrument, as potassium bromide pellets.

While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

EXAMPLES

Example 1: Preparation of 7β-Amino-3-r(Imidazori,2-BlPyridazinium-l-Yl)Methyll-3- Cephem-4-Carboxylate Hydrochloride

Step a: 7-aminocephalosporanic acid (100 g), dichloromethane (700 ml), hexamethyldisilazane (180 g) and imidazole (1 g) were combined together at 2O⁰C to

25⁰C. The reaction mixture was heated to reflux temperature for 5 hours to obtain a clear solution and cooled to -1O⁰C to -8⁰C.

Step b: Iodine (84 g) and dichloromethane (400 ml) were combined together at 2O⁰C to 25⁰C, stirred for 5 minutes to 10 minutes and cooled to 1O⁰C to 15⁰C. Hexamethyldisilane (80 g) was added to the mixture in 30 minutes to 40 minutes at 1O⁰C to 25⁰C. The reaction mixture was heated to reflux temperature for 4 hours and cooled to 5⁰C to 1O⁰C.

Step c: The solution of step b) was added to the solution of step a) at -1O⁰C to O⁰C over a 30 minute to 40 minute duration and stirred for 2 hours at 5⁰C to 1O⁰C. Imidazo[l,2,b]pyridazine (153 g) was dissolved in dichloromethane (200 ml) at 2O⁰C to 25⁰C and added to the reaction mixture at 5⁰C to 1O⁰C over a 15 minute to 20 minute duration. The reaction mixture was heated to 35⁰C to 38⁰C for 5 hours and cooled to -5⁰C to O⁰C. A cooled (5⁰C to 1O⁰C) mixture of methanol (250 ml) and concentrated hydrochloric acid (80 ml) was added to the reaction mixture at -5⁰C to O⁰C in 30 minutes duration to obtain a pH of 2 to 2.5. The reaction mixture was stirred at O⁰C to 5⁰C for 60 minutes. The slurry was filtered, washed with methanol (300 ml) and dried by suction. The solid obtained was suspended in de-mineralized water (500 ml) at 1O⁰C to 15⁰C. The pH was adjusted to about 8.0 with 10% w/v sodium hydroxide solution (200 to 250 ml) at 1O⁰C to 15⁰C to obtain a clear solution. Dichloromethane (500 ml) was added to the reaction mixture and stirred for 10 minutes to 15 minutes. The aqueous layer was separated and cooled to 1O⁰C. The pH of the aqueous layer was adjusted to about 0.8 with 6 N hydrochloric acid solution (120 to 140 ml) at 1O⁰C to 15⁰C. The pH was readjusted to about 2.2 using 10% w/v sodium hydroxide solution (100 to 120 ml) and stirred for 60 minutes at 1O⁰C at a pH of about 2.2. The solid was filtered, washed with acetone (200 ml) and dried by suction. The wet solid obtained (150-160 g) was suspended in de- mineralized water (500 ml) at 1O⁰C to 15⁰C. The pH was adjusted to about 8.0 with 10% w/v sodium hydroxide solution (100 to 120 ml) to obtain a clear solution. The pH of solution was readjusted to about 6.7 with 2 to 3 ml of 6 N hydrochloric acid solution and activated carbon (10 g) was added at 1O⁰C. The reaction mixture was stirred for 20 minutes at 1O⁰C to 15⁰C, filtered and washed with de-mineralized water (300 ml). The pH was readjusted to about 2.2 with 6 N hydrochloric acid solution (40 to 50 ml) at 1O⁰C to 15⁰C and stirred for 60 minutes at 1O⁰C to 15°C. The solid was filtered, washed with acetone (200 ml) and air dried at 4O⁰C to 45⁰C to obtain the title compound.

Yield: 100 g Example 2: Preparation of S-l^-Benzothiazol-l-Yl (2z)-(5- Amino- l,2,4-Thiadiaζol-3- Yl)(Methoxyimino)Ethanethioate

(Z)-2-(5-amino-l,2,4-thiadiazole-3yl)methoxyiminoacetic acid (100 g) and 2,2'- dithio(bis)benzothiazole (214 g) were added at O⁰C to 5⁰C to a solution of triphenylphosphine (168.6 g) in dichloromethane (600 ml). Triethylamine (76 ml) was added to the reaction mixture in 60 minutes duration at O⁰C to 5⁰C and stirred for 5 hours at O⁰C to 5⁰C. The reaction mixture was filtered through a centrifuge, washed with dicholoromethane (200 ml) and spun for 30 minutes to 60 minutes. The solid was air dried at 4O⁰C to 45⁰C to obtain the title compound. Yield: 149 g

Example 3: Preparation of Cefozopran Monohydrochloride

7β-amino-3-[(imidazo[l,2-b]pyridazinium-l-yl)methyl]-3-cephem-4-carboxylate hydrochloride (100 g) and 5^r-l,3-benzothiazol-2-yl (2Z)-(5-amino-l,2,4-thiadiazol-3- yl)(methoxyimino)ethanethioate (240 g) were added to a mixture of tetrahydrofuran (1.0 L) and water (350 ml) at 15⁰C to 2O⁰C. A mixture of tributylamine in tetrahydrofuran (70 g/70 ml) was added to the reaction mixture in 20 minutes duration at 15⁰C to 25⁰C to attain a pH of 6.8 to 7.2 and stirred for 5 hours at 25⁰C to 3O⁰C. The reaction mixture was cooled to 1O⁰C to 15⁰C and a mixture of dichloromethane (1.5 L) and de-mineralized water (200 ml) was added at 1O⁰C to 15⁰C. The reaction mixture was stirred for 15 minutes and the layers were separated. Vacuum was applied to the water layer to remove excess tetrahydrofuran at 15⁰C to 2O⁰C. 6 N hydrochloric acid (40 ml) was added to the reaction mixture at 1O⁰C to 15⁰C over a 5 minute to 10 minute duration to attain a pH of about 1.4. Enoantichromos carbon (10 g) and Celite (10 g) were added to the reaction mixture and stirred for 20 minutes at 1O⁰C to 15⁰C. The reaction mixture was filtered through the Celite bed and washed with water (300 ml). N,N-dimethylformamide (100 ml) was added to the filtered solution at 1O⁰C followed by slow addition of isopropanol (4.5 L) in 4 hours to 5 hours at 5⁰C to 1O⁰C. The mixture was stirred for 4 hours at O⁰C to 5⁰C, filtered and washed with isopropanol (500 ml) and ethanol (200 ml) under nitrogen atmosphere. The solid was dried under reduced pressure at 4O⁰C to 45°C to obtain the title compound.

Yield: 45.0 g

Example 4: Preparation of Cefozopran

2,2'-disulfanediylbis(5-methyl-l,3,4-thiadiazole) (12.4 g) and (2Z)-(5-amino- 1,2,4- thiadiazol-3-yl)(methoxyimino)ethanoic acid (6.5 g) were suspended in tetrahydrofuran (100 ml) and triphenylphosphine (12.4 g) was added at 2O⁰C to 25⁰C. The reaction mixture was stirred for 30 minutes to obtain 5^r-(5-methyl-l,3,4-thiadiazol-2-yl)(2Z)-(5- amino- l,2,4-thiadiazol-3-yl)(methoxyimino) ethanethioate in solution. The reaction mixture was cooled to 15⁰C to 2O⁰C and diluted with water (80 ml). 7-amino-3- (imidazo[l,2-b]pyridazinium-l-yl)-methyl-3-cephem-4-carboxylate hydrogen iodide (10 g) was added to the reaction mixture, followed by n-tributylamine (25 ml) over a period of 30 minutes. The reaction mixture was stirred for 18 hours at 2O⁰C to 25⁰C. The resultant solid was filtered and washed with tetrahydrofuran (2 X 20 ml) and dried at 40° to 45⁰C to obtain title compound as a crystalline solid.

Yield: 9.2 g HPLC Purity: 98%

Example 5: Preparation of Cefozopran

2,2'-disulfanediylbis(5-methyl-l,3,4-thiadiazole) (12.4 g) and (2Z)-(5-amino- 1,2,4- thiadiazol-3-yl)(methoxyimino)ethanoic acid (6.5 g) were suspended in tetrahydrofuran (100 ml) and triphenylphosphine (12.4 g) was added at 2O⁰C to 25⁰C. The reaction mixture was stirred for 30 minutes to obtain 2-mercapto-5-methyl-l,3,4-thiadiazolyl-(Z)- 2-(2-amino-l,2,4-thiadiazol-3-yl)-2-methoxyiminoacetate in solution. The reaction mixture was cooled to 15⁰C to 2O⁰C and diluted with water (80 ml). 7-Amino-3- (imidazo[l,2-b]pyridazinium-l-yl)-methyl-3-cephem-4-carboxylate hydrogen iodide (10 g) was added to the reaction mixture, followed by triethylamine (25 ml) over a period of 30 minutes. The reaction mixture was stirred for 18 hours at 2O⁰C to 25⁰C. The resultant solid was filtered and washed with tetrahydrofuran (2 X 20 ml) and dried at 4O⁰C to 45⁰C to obtain title compound as a crystalline solid.

Yield: 9.2 g HPLC Purity: 98%

Example 6: Preparation of Cefozopran

2,2'-disulfanediylbis(l,3-benzothiazole) (129.9 g) and (2Z)-(5-amino- 1,2,4- thiadiazol-3-yl)(methoxyimino)ethanoic acid (65.8 g) were suspended in tetrahydrofuran (1200 ml). Triphenyl phosphine (102 g) was added to the reaction mixture followed by n- tributylamine (30 g) over the period of 10 minutes at 2O⁰C. The reaction mixture was stirred for 30 minutes to obtain S-l,3-benzothiazol-2-yl(2Z)-(5-amino-l,2,4-thiadiazol-3- yl)(methoxyimino) ethanethioate in solution. The reaction mixture was cooled to 15⁰C to 2O⁰C and diluted with water (800 ml). 7-amino-3-(imidazo[l,2-b]pyridazinium-l-yl)- methyl-3-cephem-4-carboxylate hydrogen iodide (100 g) was added to the reaction mixture, followed by n-tributylamine (70 g) over the period of 30 minutes. The reaction mixture was stirred for 18 hours at 2O⁰C to 25⁰C. The resultant solid was filtered, washed with tetrahydrofuran (2 X 200 ml) and dried at 4O⁰C to 45⁰C to obtain title compound as a crystalline solid.

Yield: 102 g HPLC Purity: 98.2%

Example 7: Preparation of Cefozopran

2,2'-disulfanediylbis(l,3-benzothiazole) (129.9 g) and (2Z)-(5-amino- 1,2,4- thiadiazol-3-yl)(methoxyimino)ethanoic acid (65.8 g) were suspended in tetrahydrofuran (1200 ml). Triphenyl phosphine (102 g) was added to the reaction mixture followed by triethylamine (30 g) over the period of 10 minutes at 2O⁰C. The reaction mixture was stirred for 30 minutes to obtain S-l,3-benzothiazol-2-yl(2Z)-(5-amino-l,2,4-thiadiazol-3- yl)(methoxyimino)ethanethioate in solution. The reaction mixture was cooled to 15⁰C to 2O⁰C and diluted with water (800 ml). 7-amino-3-(imidazo[l,2-b]pyridazinium-l-yl)- methyl-3-cephem-4-carboxylate hydrogen iodide (100 g) was added to the reaction mixture, followed by triethylamine (50 g) over a period of 30 minutes. The reaction mixture was stirred for 18 hours at 2O⁰C to 25⁰C. The resultant solid was filtered, washed with tetrahydrofuran (2 X 200 ml) and dried at 4O⁰C to 45⁰C to obtain title compound as a crystalline solid.

Yield: 102 g

HPLC Purity: 98.2%

Example 8: Preparation of Polymorphic Form I of Cefozopran Hemihydrochloride: Cefozopran hydrochloride (100 gm) was added to N, N-dimethylformamide (300 ml) at 2O⁰C to 25⁰C portion- wise in 5 minutes to 10 minutes. Water (50 ml) was added to the mixture with fast stirring at 2O⁰C to 25⁰C to obtain a clear solution. The pH of the solution was adjusted to 1.0 to 2.2 with 35% aqueous hydrochloric acid solution at 2O⁰C to 25⁰C followed by the addition of activated carbon (5 g) and stirring for 5 minutes to 10 minutes. The mixture was filtered and washed with N, N-dimethylformamide (100 ml) at 2O⁰C to 25⁰C. The pH was readjusted to 3.5 to 4.5 with tributylamine (10 to 20 ml), stirred for 60 minutes to 90 minutes at 2O⁰C to 25⁰C, filtered and washed with N, N- dimethylformamide (100 ml) and isopropanol (200 ml). The solid obtained was stirred in isopropanol (500 ml) for 2 hours, filtered, washed with isopropanol (100 ml) and dried at 4O⁰C to 45⁰C to obtain the title compound.

Chloride Content: 3.4% w/w

N, N-dimethylformamide Content (by NMR): 11.8% w/w

Yield: 70.O g

Example 9: Preparation of Polymorphic Form Ii of Cefozopran Hemihydrochloride

Cefozopran hydrochloride (100 gm) was added to N, N-dimethylformamide (300 ml) at 2O⁰C to 25⁰C portion- wise in 5 minutes to 10 minutes. Water (50 ml) was added to the mixture with fast stirring at 2O⁰C to 25⁰C to obtain a clear solution. The pH of the solution was adjusted to 1.0 to 2.2 with 35% aqueous hydrochloric acid solution at 2O⁰C to 25⁰C followed by the addition of activated carbon (5 g) and stirring for 5 minutes to 10 minutes. The mixture was filtered and washed with N, N-dimethylformamide (100 ml) at 2O⁰C to 25⁰C. The pH was readjusted to 3.5 to 4.5 with tributylamine (10 to 20 ml), stirred for 60 minutes to 90 minutes at 2O⁰C to 25⁰C, filtered and washed with N, N- dimethylformamide (100 ml) and acetone (200 ml). The solid obtained was stirred in acetone (500 ml) for 2 hours, filtered, washed with acetone (100 ml) and dried at 4O⁰C to 45⁰C to obtain the title compound.

Chloride Content: 3.7% w/w Yield: 75 g N, N-dimethylFormamide Content (by NMR): 13% w/w

Example 10: Preparation of Polymorphic Form Iii of Cefozopran Hemihvdrochloride

Polymorphic Form I of cefozopran hemihydrochloride (10 g) was suspended in acetone (100 ml). Water (5 ml) was added to the suspension and stirred for 2 hours. The solid was filtered, washed with acetone (20 ml) and dried at 4O⁰C to 45⁰C to obtain the title compound.

Chloride Content: 3.4% w/w Yield: 8.0 g

Example 11 : Preparation of Polymorphic Form A of Cefozopran Monohvdrochloride

Polymorphic Form III of cefozopran hemihydrochloride (7.0 g) was suspended in acetone (70 ml) and hydrochloric acid (gas) was purged into the suspension. The reaction mixture was stirred at 15⁰C to 2O⁰C for 60 minutes. The solid was filtered, washed with acetone (15 ml) and dried at 4O⁰C to 45⁰C under reduced pressure to obtain the title compound.

Chloride Content: 6.8% Yield: 6.O g Example 12: Preparation of Polymorphic Form Al of Cefozopran Monohydrochloride

Polymorphic Form I of cefozopran hemihydrochloride (500 g) was suspended in isopropanol (2.5 L). Isopropanolic hydrochloric acid (20% w/w; 250 g) was added to the suspension. The reaction mixture was stirred for 2 hours. The solid was filtered and washed with isopropanol (500 ml) followed by ethanol (500 ml) and dried at 4O⁰C to 45⁰C under reduced pressure to obtain the title compound.

Chloride Content: 6.7% Yield: 300 g

Example 13: Preparation of Polymorphic Form B of Cefozopran Monohydrochloride

Cefozopran free base (100 g) was suspended in water (400 ml). The suspended slurry was cooled to 1O⁰C to 15⁰C and 12 N hydrochloric acid (200 ml) was added over the period of 20 minutes to 25 minutes to obtain a clear solution. Enoantichromos carbon (10 g) was added to the solution and stirred for 30 minutes at 1O⁰C to 15⁰C. The solution was filtered through a Celite bed and washed with water (200 ml). The resultant solution was filtered through 0.45 μ filter. 20% w/v aqueous sodium hydroxide solution (300 ml) was added to the filtered solution over the period of 30 minutes to 45 minutes at 2O⁰C to 25⁰C. The resultant slurry was stirred for 2 hours at 2O⁰C to 25⁰C and 1 hour at 10⁰C to 15⁰C. The solid was filtered and washed with water (200 ml) followed by tetrahydrofuran (2 X 200 ml; one slurry washing followed by running washing). The solid was dried at 50⁰C to 55°C for 16 hours to obtain title compound.

Yield: 80 g HPLC purity: 99%

Residual solvent content (μg/g): methanol - 17; ethanol - 47; acetone - not detected; isopropanol - not detected; tetrahydrofuran - 23; Example 14: Preparation of Polymorphic Form A2 of Cefozopran Monohydrochloride

Cefozopran monohydrochloride (10 g), as prepared according to Example 13, was suspended in water (40 ml) and 12 N hydrochloric acid (20 ml) was added slowly at 10⁰C to 15°C. Triethylamine (12 g) was added slowly to the solution obtained at 10⁰C to 15°C. The mixture was stirred for 5 minutes and isopropanol (350 ml) was added at 10⁰C to 15°C. The resultant precipitate was filtered and washed with isopropanol (2 X 20 ml). The solid was dried at 50⁰C to 55°C for 12 hours to obtain title compound.

Yield: 6.5 g

HPLC Purity: 98.44%

Claims

WE CLAIM: 1. A process for the preparation of cefozopran or it salts, wherein the process comprises: a) reacting (2Z)-(5-amino-l,2,4-thiadiazol-3-yl)(methoxyimino)ethanoic acid of Formula V with a compound of Formula VI in the presence of a solvent

FORMULA VI wherein R is

or

to obtain a compound of Formula IV

FORMULA IV wherein R is as defined above, b) reacting the compound of Formula IV with 7β-amino-3-[(imidazo[l,2- b]pyridazinium- 1 -yl)methyl] -3-cephem-4-carboxylate of Formula II or its salts in the presence of a solvent

FORMULA II to obtain cefozopran or its salts, and c) isolating cefozopran or its salts from the reaction mixture thereof without using any chromatographic method. 2. The process of claim 3, wherein the isolation of the cefozopran or its salts from the reaction mixture is done without the use of any chromatographic method. 3. The process of claim 4, wherein step b) is completed without isolating the reaction mixture of step a). 4. A hemihydrochloride form of cefozopran. 5. The hemihydrochloride form of cefozopran of claim 4 comprising a chloride content in the range of about 2% to about 5%. 6. Polymorphic Form I of cefozopran hemihydrochloride having an XRPD comprising characteristic d-spacing [A] values substantially at 3.61, 4.06, 4.27, 4.70, 5.62, 7.20, 8.54. 7. The polymorphic Form I of cefozopran hemihydrochloride of claim 6, further comprising characteristic d-spacing [A] values substantially at 2.41, 2.51, 2.57, 2.71, 3.05, 3.167, 3.27, 3.42, 3.81, 5.40, 6.33, 6.97, and 9.58. 8. The polymorphic Form I of cefozopran hemihydrochloride of claim 7, further characterized by the XRPD pattern substantially as illustrated in Figure 1.

9. Polymorphic Form II of cefozopran hemihydrochloride having an XRPD comprising characteristic d-spacing [A] values substantially at 3.42, 3.54, 3.67, 4.16, 4.77, 5.57, 8.05. 10. The polymorphic Form II of cefozopran hemihydrochloride of claimlO, further comprising characteristic d-spacing [A] values substantially at 2.66, 3.12, 3.28, 3.93, 6.20, 6.92, 8.87 and 24.99. 11. The polymorphic Form II of cefozopran hemihydrochloride of claim 10, further characterized by the XRPD pattern substantially as illustrated in Figure 3. 12. Polymorphic Form III of cefozopran hemihydrochloride having an XRPD comprising characteristic d-spacing [A] values substantially at 3.15, 3.39, 3.75, 4.51, 6.29 and 9.24. 13. The polymorphic Form III of cefozopran hemihydrochloride of claim 12, further characterized by the XRPD pattern substantially as illustrated in Figure 5. 14. A process for the preparation of cefozopran hemihydrochloride, wherein the process comprises: a) forming a solution comprising cefozopran and hydrochloric acid and having a pH of about 2.5 or below; b) treating the solution of step a)with an organic base to attain a pH of about 3.5 to about 4.5; and c) isolating cefozopran hemihydrochloride from the mixture thereof. 15. A process for the preparation of polymorphic Form I of cefozopran hemihydrochloride, wherein the process comprises: a) forming a solution comprising cefozopran, N,N-dimethylformamide and hydrochloric acid and having a pH of about 2.5 or below, b) treating the solution of step a) with an organic base to attain a pH of about 3.5 to about 4.5 to obtain cefozopran hemihydrochloride, and c) treating the cefozopran hemihydrochloride obtained in step b) with a Ci_₅ alkanol to obtain polymorphic Form I of cefozopran hemihydrochloride.

16. A process for the preparation of polymorphic Form II of cefozopran hemihydrochloride, wherein the process comprises: a) Forming a solution comprising cefozopran and hydrochloric acid and having a pH of about 2.5 or below; b) treating the solution of step a) with an organic base to attain a pH of about 3.5 to about 4.5 to obtain cefozopran hemihydrochloride; and c) treating the cefozopran hemihydrochloride obtained in step b) with a C_3-6 ketone to obtain polymorphic Form II of cefozopran hemihydrochloride. 17. A process for the preparation of polymorphic Form III of cefozopran hemihydrochloride, wherein the process comprises: a) treating polymorphic Form I of cefozopran hemihydrochloride with water and a C₃_₆ ketone, and b) isolating polymorphic Form III of cefozopran hemihydrochloride from the reaction mixture thereof. 18. Polymorphic Form A of cefozopran monohydrochloride characterized by the XRPD pattern substantially as illustrated in Figure 6. 19. Polymorphic Form Al of cefozopran monohydrochloride characterized by the XRPD pattern substantially as illustrated in Figure 7. 20. Polymorphic Form A2 of cefozopran monohydrochloride having an XRPD comprising characteristic d-spacing [A] values substantially at 3.41, 3.49, 3.71 and 5.74. 21. The polymorphic Form A2 of cefozopran monohydrochloride of claim 17, further characterized by the XRPD pattern substantially as illustrated in Figure 7. 22. Polymorphic Form B of cefozopran monohydrochloride having an XRPD comprising characteristic d-spacing [A] values substantially at 2.74, 3.20, 3.38, 3.48, 3.71, 3.95, 4.43, 4.74, 5.20, 5.75. 23. The polymorphic Form B of cefozopran monohydrochloride of claim 22, further comprising characteristic d-spacing [A] values substantially at 2.29, 2.34, 2.41, 2.50, 2.58,

2.60, 2.68, , 2.81, 2.84, 2.89, 3.08, 3.14, 3.31, 3.34, 3.64, 3.83, 3.88,

3.99, 4.07, 4.15, 4.58, 4.65,

4.97, 5.05, 5.57,

5.69,

6.25, 7.03, 7.27,

7.75, 10.05 and 12.83. 24. The polymorphic Form B of cefozopran monohydrochloride of claim 23, further characterized by the XRPD pattern substantially as illustrated in Figure 8. 25. A process for the preparation of polymorphic Form A of cefozopran monohydrochloride, wherein the process comprises: a) treating cefozopran free base or cefozopran hemihydrochloride with hydrochloric acid in the presence of a C_3-6 ketone; and b) isolating polymorphic Form A of cefozopran monohydrochloride from the reaction mixture thereof. 26. A process for the preparation of polymorphic Form Al of cefozopran monohydrochloride, wherein the process comprises: a) treating cefozopran free base or cefozopran hemihydrochloride with hydrochloric acid in the presence of C_1-5 alkanol; and b) isolating polymorphic Form Al of cefozopran monohydrochloride from the reaction mixture thereof. 27. A process for the preparation of cefozopran monohydrochloride, wherein the process comprises: a) treating cefozopran free base with hydrochloric acid in the presence of water; and b) isolating cefozopran monohydrochloride from the mixture thereof. 28. A process for the preparation of polymorphic Form B of cefozopran monohydrochloride, wherein the process comprises: a) treating cefozopran free base with hydrochloric acid in the presence of water to obtain a solution; b) precipitating cefozopran monohydrochloride from the solution of step a); and c) treating the cefozopran monohydrochloride obtained in step b) with water and tetrahydrofuran to obtain polymorphic Form B of cefozopran monohydrochloride. 29. A process for the preparation of polymorphic Form A2 of cefozopran monohydrochloride, wherein the process comprises: a) treating cefozopran monohydrochloride with hydrochloric acid in the presence of water to obtain a solution; b) treating the mixture obtained in step a) with a base and a Ci_₃ alkanol; and c) isolating polymorphic Form A2 of cefozopran monohydrochloride from the reaction mixture thereof.