Claims:1. A process for the preparation of Cefuroxime Axetil ß-sulfoxide impurity of compound of Formula (IIa),

Formula (IIa)
the process comprising the steps of
a) Oxidizing the Cefuroxime Axetil of Formula (I) and

Formula-I
b) isolating the compound of Formula (IIa).

2. A novel process for the preparation of Cefuroxime Axetil a-sulfoxide impurity of compound of Formula (IIb),

Formula-IIb
the process comprising the steps of
a) Oxidizing 2-cephem (?2)-ester of Formula III and

Formula-III
b) isolating the compound of Formula IIb.

3. The process according to claim 1 or 2, wherein the oxidation is carried out in the presence of oxidizing agent and in the suitable solvent.

4. The process according to claim 3, wherein the oxidizing agent is selected from the group comprising one or more of hydrogen peroxide, sodium peroxide, peracetic acid, m-chloro perbenzoic acid, trifluoro peracetic acid, 2,4-dinitroperbenzoic acid, oxone, persulfuric acid, sodium hypochlorite, sodium hypobromite, sodium perborate, pyridine-N-oxide, N-methylmorpholine-N-oxide, sodium permanganate, potassium permanganate, chromium trioxide ,Collins reagent, Jones reagent, Sarett reagent, ozone and oxygen.

5. The process according to claim 3, wherein the suitable solvent is selected from the group comprising one or more of methanol, ethanol, isopropyl alcohol, dichloromethane, methyl tert-butyl ether, ethyl tert-butyl ether, diethyl ether, di-tert-butyl ether, acetamide, dimethyl formamide, ethyl acetate, propyl acetate, butyl acetate, toluene, n-hexane, benzene, heptane and water.

6. The process according to claim 3, wherein the oxidizing agent is selected from m-chloro perbenzoic acid.

7. The process according to claim 3, wherein the suitable solvent is dichloromethane.

8. The process according to claim 3, wherein the oxidation is carried out at temperature in between range of 0°C to 5°C.

9. The process according to claim1 or 2, wherein the HPLC purity of compound of Formula (IIa) or Formula (IIb) is greater than 97%.

10. The Cefuroxime Axetil a, ß sulfoxide of compound of formula (IIa) or Formula (IIa) obtained according to claim 1 or 2, is used as reference standards in a qualitative analysis of Cefuroxime Axetil drug substance.
, Description:Field of Invention

The present invention relates to a novel process for preparing the impurities of Cefuroxime Axetil. More particularly the present invention relates to a novel process for preparing Cefuroxime Axetil a, ß sulfoxides impurities. In further aspect the present invention provides the use of Cefuroxime Axetil a, ß sulfoxides impurity as reference markers and/or reference standard.

Background of the invention

Cefuroxime axetil is the l-acetoxyethyl ester of (6R, 7R)-3 carbamoyloxymethyl-7-[(Z)-2-(fur-2-yl)-2-methoxyiminoacetamido]ceph-3-em-4-carboxylic acid of Formula (I)

Formula-I
and is described in U.S. Patent No: 4,267,320 A. Cefuroxime axetil is a particularly valuable cephalosporin since it may be administered orally. The compound has been shown to possess good antibiotic activity, following oral administration, against a broad spectrum of gram-positive and gram-negative bacteria and has high stability to p lactamases.

Cephalosporin esters may conventionally be prepared by the acylation of an appropriate 7-aminocephalosporin with a compound serving to introduce a preformed 7-substituent, or by esterification of the 4-carboxyl group of the corresponding cephalosporin 4-carboxylic acid, for example by reaction with a haloester to introduce the desired esterifying group. These general processes are described in U.S. Patent No: 4,267,320 A for the preparation of Cefuroxime Axetil.

GB 2218094 A describes the preparation of Cefuroxime Axetil and derivatives thereof in which the sulphoxide group in the cephalosporin nucleus is converted to the sulphide as the last major chemical step in the synthesis, by a reduction reaction.

Pharmaceutical Research, Volume: 8, Issue: 7, Pages: 893-8, Journal, 1991 describes the forced degradation hydrolysis study of Cefuroxime Axetil during storage results a, ß sulfoxides. However the syntheses have not been reported.

It is known in the art that impurities present in an active pharmaceutical ingredient ("API") may arise from degradation of the API, for example, during storage or during the manufacturing process, including the chemical synthesis.

Chemical stability of pharmaceutical molecules is a matter of great concern as it affects the safety and efficacy of the drug product. The FDA and ICH guidances state the requirement of stability testing data to understand how the quality of a drug substance and drug product changes with time under the influence of various environmental factors.

Forced degradation is a process that involves degradation of drug products and drug substances at conditions more severe than accelerated conditions and thus generates degradation products that can be studied to determine the stability of the molecule

Forced degradation is carried out to produce representative samples for developing stability-indicating methods for drug substances and drug products. A minimal list of stress factors suggested for forced degradation studies must include acid and base hydrolysis, thermal degradation, photolysis, oxidation and may include freeze–thaw cycles and shear. There is no specification in regulatory guidelines about the conditions of pH, temperature and specific oxidizing agents to be used.

Conventional methods (e.g., column chromatography) or hyphenated techniques (e.g., LC–MS, LC–nuclear magnetic resonance (NMR)) can be used in the identification and characterization of the degradation products. Use of these techniques can provide a better insight into the structure of the impurities that could add to the knowledge space of potential structural alerts for genotoxicity and the control of such impurities with tighter limits .It should be noted that structural characterization of degradation products is necessary for those impurities formed during formal shelf-life stability studies and above the qualification threshold limit.

Thus, there is a need in the art for a method for determining the level of degradation impurities in Cefuroxime Axetil drug substance and characterizing the impurities.

Researchers and developers in drug manufacturing understand that a compound in a relatively pure state can be used as a "reference standard" (a "reference marker" is similar to a reference standard but it is used for qualitative analysis) to quantify the amount of the compound in an unknown mixture.

There are known impurities of cefuroxime, e.g. a,ß sulfoxides of compound Formula (IIa) or (IIb) as degradation impurities of Cefuroxime Axetil drug substance are known in the art.

Formula (IIa)

Formula (IIb)

The objective of the present invention is to provide a novel process for the preparation of Cefuroxime Axetil a, ß sulfoxides impurities of compound Formula (IIa) or Formula (IIb) and its use as a reference standard

Summary of the Invention

In one aspect, the present invention relates to a novel process for the preparation of ß- sulfoxide impurity of compound of Formula (IIa),

Formula (IIa)

the said process includes the steps of
a) Oxidizing the Cefuroxime Axetil of Formula (I) and

Formula-I
b) isolating the compound of Formula (IIa).

In another aspect, the present invention provides the use of Cefuroxime Axetil a, ß sulfoxides impurity of compound of Formula (IIa) or Formula (IIb) as a reference standard.
Description of the Invention

For purposes of the present invention, the following terms are defined below.

As used herein, the term “reference standard” refers to a compound that may be used both for quantitative and qualitative analysis of an active pharmaceutical ingredient. A reference marker” is used only for qualitative analysis, while a reference standard may be used for quantitative or qualitative analysis, or both. Hence, a reference marker is a subset of a reference standard, and is included within the definition of a reference standard.

All ranges recited herein include the endpoints, including those that recite a range "between" two values. The terms such as "about", "general", "substantially" and the like are to be construed as modifying a term or value such that it is not an absolute. Such terms will be defined by the circumstances and the terms that they modify as those terms are understood by those skill in the art. This includes, at the very least, a degree of expected experimental error, technique error and instrument error for a given technique used to measure a value.

As used herein, the term "Suitable solvent" means a single or a combination of two or more solvents.

As used here in the term "isolation" may include filtration, filtration under vacuum, centrifugation, and decantation.

In one aspect, the present invention relates to a novel process for the preparation of ß-sulfoxide impurity of compound of Formula (IIa), the said process includes the steps of
a) oxidizing Cefuroxime Axetil of Formula (I) and
b) isolating the compound of Formula (IIa).

In another aspect, the process for the preparation of compound of Formula (IIb) includes the step of oxidizing 2-cephem (?2)-ester of Formula (III)

Formula-III
and isolating the a-sulfoxide impurity of compound of Formula (IIb).

In another aspect, the oxidation of Cefuroxime Axetil of Formula (I) or 2-cephem (?2)-ester compound of Formula (III) is carried out in the presence of oxidizing agent and in the suitable solvent.

In general, the oxidizing agent is selected from the group comprising one or more of peroxides selected from hydrogen peroxide, alkali or alkaline peroxides such as sodium peroxide; peracids selected from peracetic acid, m-chloro perbenzoic acid, trifluoro peracetic acid, 2,4-dinitroperbenzoic acid, oxone and persulfuric acid; hypohalite such sodium hypochlorite, sodium hypobromite; perborates such as sodium perborate; N-oxides such as pyridine-N-oxide, N-methylmorpholine-N-oxide; permanganates such as sodium permanganate, potassium permanganate; chromium compounds such as chromium trioxide ,Collins reagent, Jones reagent, Sarett reagent; ozone and oxygen.

In general, suitable solvent for oxidation is selected from the group comprising one or more of alcohol, halogenated solvent, acetates, ether, hydrocarbon, water or mixture thereof. The alcohol selected from the group comprising one or more of methanol, ethanol, isopropyl alcohol and the like; the halogenated solvent selected from the group comprising one or more of dichloromethane; the ether selected from the group comprising one or more of methyl tert-butyl ether, ethyl tert-butyl ether, diethyl ether, di-tert-butyl ether and the like; the amides selected from the group comprising one or more of dimethyl acetamide and dimethyl formamide and the like; the acetate selected from the group comprising one or more of ethyl acetate, propyl acetate, butyl acetate and the like; hydrocarbon selected from the group comprising one or more of toluene, n-hexane, benzene, heptane and the like.

In general, the oxidation of Cefuroxime Axetil according to the present invention is carried out at temperature in between range of 0°C to 5 °C.

The process of the present invention is depicted in the following scheme 1:

Scheme-I

In another aspect, the present invention provides the use of Cefuroxime Axetil a, ß sulfoxides impurity of compound of Formula (IIa) or (IIb) as reference standards in a qualitative analysis of Cefuroxime Axetil drug substance.

In another aspect, the present invention provides Cefuroxime Axetil a, ß sulfoxides impurity of compound of Formula (IIa) or (IIb) prepared according to the present invention having HPLC purity of greater than 97%.

In another aspect, a pharmaceutical composition of Cefuroxime Axetil is substantially free of a, ß sulfoxides of compound of Formula (IIa) or Formula (IIb).

According to the present invention, a pharmaceutical composition comprising Cefuroxime Axetil, wherein HPLC content of a, ß sulfoxides impurity of compound of Formula (IIa) or Formula (IIb) is not more than 0.1%; preferably not more than 0.05%.

In another aspect, the pharmaceutical composition comprising Cefuroxime Axetil, wherein the HPLC content of total sulfoxide degradation impurities of Formula (IIa) and Formula (IIb) is not more than 0.1%; preferably not more than 0.05%.

According to the present invention, the Cefuroxime Axetil pharmaceutical composition is stable under normal temperature, hereby facilitating the storage and transportation thereof.

The present invention may further be illustrated by the following examples which may be provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents may be apparent to those skilled in the art and may be intended within the scope of the present invention.

Examples

Example1: Preparation of compound of Formula (IIa)
Cefuroxime axetil (25 g) in 375ml of dichloromethane (375 mL) was cooled to 0-5°C and m-chloro perbenzoic acid (13 g) was added in lots, the reaction mass stirred for 3hrs. After completion of the reaction, the reaction mass was quenched by water (250 mL) and dichloromethane (500 mL) was added and stirred for 15min. The organic layer was separated and the aqueous layer was again extracted with organic solvent (250 mL) .The combined organic extracts was washed with water (250 mL) and evaporated the solvent on rotavapour at 40-45° C to get the residue. The residue was purified by column chromatography using silica gel as stationary phase and 5% Methanol: DCM as mobile phase to get the compound of Formula (IIb).
HPLC Purity: >97%
1H-NMR (DMSO, 400MHZ) d ppm: 9.35-9.37 (d,1H), 7.81 (s,1H), 7.01-7.03 (m,1H), 6.72-6.73 (m,1H), 6.60-6.62 (m,3H), 5.88-5.91 (m,1H), 4.96-5.01 (m,2H), 4.50-4.53 (d,1H), 3.88 (s,3H), 3.58-3.63 (d,2H), 2.04-2.06 (s,3H), 1.48-1.49 (d,3H)
13C NMR (DMSO, 400MHz) d ppm: 168.5, 162.65, 161.46, 158.41, 156.20, 145.44, 145.21, 144.73, 123.67, 123.03, 112.75, 111.97, 88.26, 66.23, 62.33, 62.24, 57.97, 45.63, 20.51, 19.14.