WO2003018578A1 - Method for producing beta form of crystalline anhydrous aztreonam - Google Patents

Abstract

A process is described for producing anhydrous β-form of ((Z)-2-[[[(2-amino-4-thiazolyl)[[trans-(2S,3S)-2-methyl-4-oxo-1-sulfo-3-azetidinyl]carbamoyl]methylene]amino]oxy]-2-methylpropionic acid (also known as Aztreonam).

Description

This invention relates to a method for producing crystalline anhydrous β-form of ((Z)-2-[[[(2-amino-4-thiazolyl)[[trans-(2S,3S)-2-methyl-4-oxo-l-sulfo-3-azetidinyl]- carbamoyl]methylene]amino]oxy]-2-methylpropionic acid (also known as Aztreonam)

Aztreonam of Formula I is a synthetic monocyclic beta-lactam antimicrobial agent, active against gram-negative organism.

Formula

A number of references disclose the preparation of Aztreonam such as US Patent 4,775,670 and US Patent 5, 194,604 amongst others. Aztreonam is known to exhibit polymorphism and four distinct crystalline forms designated as α-, β-, γ- and δ- forms have been reported in US Patent 4,826,973. The α-form is in the form of hydrated crystals, it typically contains 7-14% of water and has a poor storage stability. It is desirable to convert it to β-form that is anhydrous, substantially non-hygroscopic and possesses good flowability, low surface area, enhanced solid state stability and is well suited for use as a pharmaceutical agent.

US Patent 4,946,838 describes preparation of β-form by crystallization of the α-form from anhydrous alcohol where Aztreonam α-form is dissolved in absolute methanol or absolute ethanol at 55° to 60°C and under these conditions α-form dissolves momentarily and then recrystallises spontaneously as the β-form. This procedure is not suitable for sterile preparation as Aztreonam does not remain in solution long enough to perform aseptic filtration.

In US Patent 4,946,838, another process to prepare β-form has been disclosed wherein α-form is dissolved as triethylamine salt in an anhydrous ethanol and then β-form is obtained by adding anhydrous hydrogen chloride solution. While this process is suitable for sterile filtration, however the intended product is contaminated with triethylamine hydrochloride.

In yet another procedure described in US Patent 4,946,838, the α-form is treated with silylating agent in an aprotic solvent such as acetonitrile to obtain a solution of Aztreonam as silyl derivative and β-form is then precipitated by addition of ethanol. The yield reported is very low and silylation step is necessary to dissolve α-form. The aim of the present invention is to alleviate these problems. DETAILED DESCRIPTION OF THE INVENTION

The instant invention relates to a novel process to produce highly pure sterile crystalline anhydrous Aztreonam β-form. The present invention enables the preparation of a solution of the α-form Aztreonam in absolute ethanol without using trialkylamine or silylating agent, and this solution can be sterile filtered to crystallise sterile β-form.

Specifically, the instant invention involves dissolving the α-form in absolute ethanol at low temperature. The α-form of Aztreonam dissolves in absolute ethanol at a temperature varying from -10°C to +15°C and crystallizes out as β-form on raising the temperature to 50°C to 55°C. Crystallization of Aztreonam does not occur from this solution if maintain at -10°C to +15°C. This unusual solubility characteristic of Aztreonam α-form has not been reported hitherto in literature. However, similar solubility behaviour of a different antibiotic namely, cefotaxime sodium has been described in US Patent 4,912,21 1 , example 6. Such a solution of α-form can be treated with carbon to remove colour and also can be passed through the 0.2 micron sterile filter for aseptic preparation.

The α-form is dissolved in anhydrous alkanol, preferably absolute ethanol, at -10°C to +15°C, most preferably at 5°C to 10°C. This solution, maintained at this temperature, is treated with activated carbon and is filtered through clarification filter and a sterile filter to obtain a sterile solution. The anhydrous β-form of Aztreonam is then crystallised by raising the temperature of the sterile filtrate to 50°C to 55°C. The product is then filtered and dried in vacuum. The β-form prepared by this process is a suitable pharmaceutical agent for blending with a basic- material, such as L-arginine, for intravenous and intramuscular administration.

Major advantage realised in the present invention compared to the prior art is the process simplicity. Prior art procedure requires an additional step wherein addition of trialkylamine or silylation is necessary to dissolve α-form for sterile filtration; in the present procedure, the α-form is directly dissolved in ethanol at low temperature to obtain a solution which is suitable for sterile β-form preparation.

Preparation of the β-form from the α-form can be accomplished by the procedure described in the following preparation.

Example

Aztreonam α-form (40 g) was added to pre-cooled absolute ethanol (2400 ml) at 8-10°C and stirred for 30 minutes to obtain a clear solution. This solution was treated with activated carbon (1 g) for 15 minutes at 8-10°C. The suspension was filtered through celite and the residue was washed with ethanol (50 ml). The filtrate was then warmed to 50-55°C slowly over a period of 2 hours to crystallize β-form. The hot suspension was cooled to 15-20°C, stirred for 1 hour and filtered. The crystals were dried in vacuo to obtain 33 g of the product which was confirmed to be the β-form by IR spectrum, powder X-ray diffraction pattern and differential scanning calorimetry.

Claims

WE CLAIM:

1 A process for the preparation of the ((Z)-2-[[[(2-amino-4-thiazolyl)[[/n s'-(2S,3S)- 2-methyl-4-oxo-l-sulfo-3-azetidinyl]carbamoyl]methylene]amino]oxy]-2- methylpropionic acid (Aztreonam) which comprises dissolving the α-ibrm of Aztreonam in absolute ethanol at a temperature of -10°C to +15°C and warming the solution to 50-55°C after sterile filtration to crystallise anhydrous β-form.

Dated this the 27^th day of August 2001

Aurobindo Pharma Limited _/ ^ < ibka£f£aX^

Ms. Nanda Bhaskara LEGAL OFFICER FOR THE APPLICANTS