FIELD OF INVENTION

The present invention provides cefixime trihydrate (I) with reduced surface area and high stability. BACKGROUND OF THE INVENTION

Cefixime is an orally active third generation broad spectrum cephalosporin antibiotic and is more potent against gram negative bacteria. Cefixime is commonly used to treat various infections caused by susceptible isolates of the designated bacteria. Cefixime and cefixime trihydrate (I) are disclosed in patent US 4,409,214; the patent discloses process for preparation of cefixime and isolation of cefixime trihydrate (I) from a mixture of ethanol and water. Various processes for preparation as well as purification of cefixime and cefixime trihydrate (I) are available in the literature.

The present invention provides cefixime trihydrate (I) with reduced surface area and high stability with respect to content of impurity Al. The present invention provides a detailed study of surface area of cefixime trihydrate (I) and the content of impurity Al of cefixime trihydrate (I). The impurity Al is one of the stereoisomer of impurity A which is provided in the British pharmacopeia monograph of cefixime and is as depicted below.

Impurity A In the present invention it was surprisingly found that cefixime trihydrate (I) with a surface area of less than 1.2 m /gm is highly stable with respect to impurity Al which is less than 0.5% by area percentage of HPLC.

Stability and control of impurity content in a pharmaceutical product is very desirable, in order to reduce adverse side effect and improve the shelf life. SUMMARY OF THE INVENTION

The present invention provides cefixime trihydrate (I) with surface area of less than 1.2 m /gm containing impurity Al less than 0.5% by area percentage of HPLC.

DETAILED DESCRIPTION OF THE INVENTION

In the preferred embodiment, the present invention provides cefixime trihydrate (I) with surface area of less than 1.2 m /gm. The surface area is measured by Brunauer-Emmett- Teller (BET) method. In another embodiment, the present invention provides cefixime trihydrate (I) with surface area of less than 1.2 m /gm and the content of impurity Al of less than 0.5% by area percentage of HPLC.

In yet another embodiment, the present invention provides process for preparation of cefixime trihydrate (I) with surface area of less than 1.2 m /gm.

Various process for purification of cefixime trihydrate (I) were carried out in our endeavor to obtain stable cefixime trihydrate (I). Physical and chemical parameters of the Cefixime trihydrate (I) samples were determined. All the experimental parameters which could alter the physical and chemical properties of cefixime trihydrate (I) were thoroughly studied. After a detailed study it was observed that there was a correlation between experimental parameters and the surface area of cefixime trihydrate (I) obtained and stability of cefixime trihydrate (I).

It was observed that different experimental parameters utilized in the purification step altered the surface area of cefixime trihydrate (I) obtained. Further studies revealed that the purification procedure carried out at a certain RPM (Rotation per minute of the stirrer) played a pivotal role in obtaining cefixime trihydrate (I) with the required surface area.

From the studies carried out in the present invention it is revealed that cefixime trihydrate (I) with surface area of less than 1.2 m /gm is stable (entries 2 and 3 of Table 1). As the surface area of cefixime trihydrate (I) increases impurity Al formation also increases (entry 1 of Table 1). The impurity Al appeared at RRT 0.75 in the HPLC chromatogram. Correlation between RPM of the experiment, surface area of cefixime trihydrate (I) and content of impurity Al during stability was studied and the results obtained are depicted below in Table 1. Table 1: Stability study of cefixime trihydrate (I).

*RH= Relative humidity.

Table 1 shows that stability of cefixime trihydrate (I) depends on the surface area, which in turn depends on the RPM employed in the purification of cefixime trihydrate (I). Stability of cefixime trihydrate (I) was studied at 40 ± 2°C RH 75±5% RH.

The present invention provides process for preparation of cefixime trihydrate (I) with surface area of less than 1.2 m /gm comprising the steps of: i) adjusting pH of cooled aqueous solution of cefixime trihydrate (I) to 5.8-6 using base, ii) optionally treating with EDTA and carbon, iii) stirring the mixture at low RPM, iv) adjusting pH of the mixture to 4.8-5.0 using acid, v) adding ketone solvent, vi) heating the mixture to 34-38°C, vii) adjusting pH to 2.4-2.5 slowly using acid, viii) cooling the mixture, and ix) isolating the solid. Cefixime trihydrate (I) is prepared by methods known in the literature.

The process for preparation of cefixime trihydrate (I) is carried out at low RPM. The term "low RPM" means RPM less than 400, preferably less than 100, more preferably less than 60.

In the process for preparation of cefixime trihydrate (I) use of ethylenediaminetetraacetic acid (EDTA) and carbon treatment is optional so as to improve colour quality of the product.

The pH of 5.8 to 6 is achieved by using base selected from alkaline solutions of sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate and the like, preferably sodium hydroxide.

The pH of 4.8 to 2.4 is achieved by using acid selected from inorganic acids like hydrochloric acid, sulfuric acid and the like, preferably hydrochloric acid. In operation (vii) the pH is adjusted to 2.4-2.5 slowly using acid. "Slowly" means over a period of 60-300 minutes. The ketone solvent is selected form acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl isopropyl ketone, acetophenone; preferably acetone.

The mixture is cooled to 0-10°C, preferably 0-5°C.

The solid can be isolated by common techniques known in the art like filtration, concentration etc. The present invention is further illustrated by the following representative examples and does not limit the scope of the invention. EXAMPLES

I. Details of HPLC methods for analysis are provided below:

Variables Details

HPLC model Shimadzu LC-2010 equipped with pump,

injector, UV detector and recorder

Column: Inertsil ODS 3V (250mm x 4.6mm) 5μπι

Detector: UV at 254 nm.

Column temp.: 40°C

Buffer: 0.05M Ammonium in HPLC grade water

Mobile phase A: buffer and methanol (95:05) pH-4.2

Mobile phase B: buffer and methanol (50:50) pH-4.2

Sample preparation: 1000 ppm in Diluent (pH-7.0 phosphate

buffer)

Injection volume: 20 ml

Mode of elution: Gradient

Flow: 1.5 mL/minute.

Run time: 70 minutes

Impurity Al RRT 0.75

Cefixime trihydrate (I) RRT 1

II. Details for surface area analyser are provided below: Instrument: Smart Srob 93, based on dynamic BET principal.

System: 30% nitrogen and 70% Helium gas mixture is passed over the sample, the absorbed nitrogen is used to calculate surface area.

Operating temperature: -15°C to 40°C Experiment 1:

A mixture of cefixime trihydrate (I) (5.0 kg) and water (55 liters) was cooled to 4-8°C. The pH was adjusted to 5.8 to 6°C with 5% sodium hydroxide solution (18.5 liters). EDTA (0.05 kg) and activated carbon (0.5 kg) was added and the mixture stirred for 30 minutes. The mixture was filtered. The filtrate was collected in the reactor and the RPM of the stirrer was maintained to 36.0±2. The pH of the filtrate was adjusted to 4.8 to 5 with 10% HCl solution (0.25 liters) at 4-8°C. A mixture of water (30.0 liter) and acetone (30.0 liter) was added to it and heated at 34-38°C. The pH was adjusted to 2.4 to 2.5 with 10% HCl solution (5.5 liters) in 275 minutes. The mixture was cooled to 0 to 5°C and filtered, washed with water (50 liter) and dried. Surface area: 0.55 m /gm; content of impurity Al by HPLC: 0.04 % (initial), 0.17% (15 days) and 0.22% (1 month).