Process for the production of beta lactam crystals

FIELD OF THE INVENTION

This invention relates to a process for the production of crystallised Sulbactam Sodium.

Sulbactam Sodium, in combination with beta lactam antibiotics, is useful for administration to patients with serious infections.

Specifically this invention relates to a crystallisation process using aqueous Isopropyl Alcohol; the product thus obtained can be easily dried, when compared to methods described in prior art; the residual solvent content is less than 0.1%.

BACKGROUND OF THE INVENTION

Sulbactam Sodium, in combination with beta lactam antibiotics, is a pharmaceutical agent which is used in the treatment of moderate to severe infections caused by strains of microorganisms in conditions such as nosocomial pneumonia due to Staphylococcus aureus; intraabdominal infections, specifically appendicitis and peritonitis due to Escherichia coli, skin and skin structure infections, including cellulitits, cutaneous abscesses and ischemic/diabetic foot infections due to Staphylococcus aureus ; and gynecologic infections, specifically postpartum endometritis or pelvic inflammatory disease due to Escherichia coli. The seriousness of these infections highlights the need for a readily available and dependable treatment.

Polymicrobial infections often include pathogens that produce beta-lactamase enzymes. These enzymes commonly cause resistance to penicillins and cephalosporins. Without treatment these microbes would multiply and thrive unimpeded, with serious or critical consequences to the patient. Basically, Sulbactam permanently inactivates &<?tø-lactamases, allowing beta lactam antibiotics to destroy susceptible bacteria.

Sulbactam Sodium can be obtained by methods known in prior art. For instance in United States Patent Application [US4234579] Sulbactam Sodium is prepared by adding a Sodium Ethylhexanoate solution in Ethyl Acetate over a Sulbactam Acid solution in Ethyl Acetate. The product thus obtained should be dried at 100 ⁰ C in high vacuum, in order to completely remove the solvent, Ethyl Acetate.

In International Patent Application [WO 1987006230] Sulbactam Sodium is obtained again with Ethyl Acetate as solvent and Ethylhexanoate as sodium salt.

In Czech Patent Application [CS262013] Sulbactam Sodium is obtained yet again with Ethyl Acetate as solvent and Ethylhexanoate as sodium salt.

In Czech Patent Application [CS240398] Sulbactam Sodium is obtained in a system of Butanol and Butyl Acetate as solvents and Ethylhexanoate as sodium salt.

In Polish Patent Application [PL163690] Sulbactam Sodium is obtained in a biphasic system, Butanol and water, and bicarbonate as sodium salt.

Concerning the latter two references, Ethyl Acetate has been replaced by less volatile solvents, thus making the drying of the product even more difficult.

Drying a beta-lactam product, such as Sulbactam, at temperatures as high as 100 ⁰ C results unavoidably in degradation, because of the instability of such molecule.

On the other hand, the regulatory specifications on residual solvents are increasingly stricter; the market requirements push as well to lesser solvent contents.

Consequently, there is a need for a process for the industrial manufacture of Sulbactam Sodium which can overcome those problems, i.e. drying temperature and residual solvent content.

BRIEF SUMMARY OF THE INVENTION

Surprisingly it has now been found that when crystallising Sulbactam Sodium from aqueous Isopropyl Alcohol, the product can be dried at temperatures as low as, for instance, 20 to 40 ⁰ C. Furthermore, the residual Isopropyl Alcohol content is very low, typically less than 0.1%.

The main advantages of the present invention are, therefore, low drying temperature and low residual solvent content, both leading to a product of superior quality.

Amongst additional advantages of the present invention can be cited the high yield attainable and the use of only one organic solvent, easily recoverable; both advantages being also important from an industrial point of view.

DETAILED DISCLOSURE

The crystallisation of Sulbactam Sodium is carried out following the invention described in this patent: essentially a solution of Sulbactam Sodium in aqueous Isopropyl Alcohol is treated with additional aqueous Isopropyl Alcohol thus leading to the crystallisation of Sulbactam Sodium.

Sulbactam Sodium is readily soluble in water; thus the proportion of Isopropyl Alcohol to water is of utmost importance, in order to provide supersaturation which is the driving force for the crystallisation. It has been found the optimal range for this proportion to be from 5 to 25 parts in volume of Isopropyl Alcohol to 1 part of water, preferably from 7 to 15 parts in volume of Isopropyl Alcohol to 1 part of water and more preferably around 10 parts in volume of Isopropyl Alcohol to 1 part of water.

The solution of Sulbactam Sodium in aqueous Isopropyl Alcohol can be obtained either by dissolving solid Sulbactam Sodium or by reacting Sulbactam Acid with a sodium salt such as, for instance, Sodium 2-Ethylhexanoate, Sodium Carbonate or Sodium Hydrogen Carbonate, in the same crystallising mixture, aqueous Isopropyl Alcohol.

When the starting material is Sulbactam Sodium, the amount of water is advantageously the minimum amount needed to dissolve it: from 0.6 to 2.0, preferably from 0.9 to 1.5 litres of water per kilogram of starting material.

When the starting material is Sulbactam Acid, the amount of water can be variable but advantageously is in the range of from 0.2 to 2.0, preferably from 0.5 to 1.5 litres of water per kilogram of starting material.

The crystallisation medium, aqueous Isopropyl Alcohol, can be used in a separate mode; explicitly Sulbactam Sodium can be dissolved in water alone and the solution treated with anhydrous Isopropyl Alcohol to obtain the crystallisation. In a similar approach, Sulbactam Acid can be dissolved in aqueous Isopropyl Alcohol and the solution treated with a solution of Sodium 2-Ethylhexanoate in anhydrous Isopropyl Alcohol to achieve the crystallisation

Since the product obtained following the present invention is used parenterally, the solution can be sterilised prior to the crystallisation step; the sterilisation can be performed by, for example, a sterilising filtration through a suitable membrane filter.

The process can be carried out at temperatures from 10 to 60 ⁰ C, preferably from 20 to 50 ⁰ C and more preferably from 30 to 40 ⁰ C.

After crystallisation, the crystals can be collected by filtration, optionally washed with fresh solvent, aqueous or anhydrous Isopropyl Alcohol, and finally dried at a temperature of 20 to 70 ⁰ C, preferably from 30 to 60 ⁰ C and more preferably from 35 to 40 ⁰ C.

In a preferred embodiment of the present invention, Sulbactam Sodium is dissolved in aqueous Isopropyl Alcohol and the solution thus obtained is treated with an additional amount of aqueous Isopropyl Alcohol, resulting in the crystallisation of Sulbactam Sodium; the crystallised Sulbactam Sodium is collected by filtration and dried.

In an another preferred embodiment of the present invention, Sulbactam Sodium is dissolved in water at a temperature of 35 to 40 ⁰ C, the solution thus obtained filtered through a sterilising membrane filter, the line rinsed with aqueous Isopropyl Alcohol and the filtrate treated with an amount of Isopropyl Alcohol, while maintaining the temperature above 30 ⁰ C, resulting in the crystallisation of Sulbactam Sodium; after cooling at around 20 to 25°C, the crystallised Sulbactam Sodium is collected by filtration, the crystals rinsed with Isopropyl Alcohol and dried at 35-40 ⁰ C in vacuum.

In a further another preferred embodiment of the present invention, Sulbactam Acid is dissolved in aqueous Isopropyl Alcohol and the solution thus obtained is treated with a solution of Sodium 2-Ethylhexanoate in aqueous Isopropyl Alcohol, resulting in the crystallisation of Sulbactam Sodium; the crystallised Sulbactam Sodium is collected by filtration and dried.

In a yet preferred embodiment of the present invention, Sulbactam Acid is dissolved in aqueous Isopropyl Alcohol at a temperature of 35 to 40 ⁰ C, the solution thus obtained filtered through a sterilising membrane filter, the line rinsed with aqueous Isopropyl Alcohol and the filtrate treated with solution of Sodium 2-Ethylhexanoate in Isopropyl Alcohol, while maintaining the temperature above 30 ⁰ C, resulting in the crystallisation of Sulbactam Sodium; after cooling at around 20 to 25°C, the crystallised Sulbactam Sodium is collected by filtration, the crystals rinsed with Isopropyl Alcohol and dried at 35-40 ⁰ C in vacuum.

EXPERIMENTAL METHODS Example 1

In a 25OmL reactor, 46.6 g (0.20 MoI) of Sulbactam Acid [chemical name: (2S,5R)-3,3- dimethyl-7-oxo-4-thia-l-azabicyclo[3.2.0]heptane-2-carboxyli c acid 4,4-dioxide] 35mL of water and 214 mL of Isopropyl Alcohol are loaded. The mixture is stirred until complete solution, filtered through a 0.2 microns polyamide membrane and the filtrate loaded into a second IL reactor. The first reactor and the filter are rinsed with 19 mL of Isopropyl Alcohol into the second reactor. The temperature is adjusted to 30-35 ⁰ C.

A solution of 35.0 g (0.21 MoI) of Sodium 2- Ethylhexanoate in 117 mL of Isopropyl Alcohol is prepared; the solution is filtered through a 0.2 microns polyamide membrane and the filtrate added to the Sulbactam solution. The first quart of solution is added throughout 10 minutes, after which time the system is seeded with 0.5 g of Sulbactam Sodium and the rest of sodium salt is added for about 100 minutes. The temperature is adjusted to 20-25 ⁰ C, the system is stirred for about 30 minutes and the crystals are filtered, washed with twice 58 mL of Isopropyl Alcohol and dried in vacuum at 35-40 ⁰ C until constant weight.

48.2 g (95% yield) of Sulbactam Sodium are obtained, with the following analytical characteristics:

Example 2

In a 250 mL reactor, 51.0 g (0.20 MoI) of Sulbactam Sodium [chemical name: sodium (2S,5R)- 3,3-dimethyl-7-oxo-4-thia-l-azabicyclo[3.2.0]heptane-2-carbo xylate 4,4-dioxide] and 54mL of water are loaded. The temperature is adjusted to 35-40 ⁰ C and the mixture is stirred until complete solution, filtered through a 0.2 microns polyamide membrane and the filtrate loaded into a second IL reactor. The first reactor and the filter are rinsed with a mixture of 4 mL of water and 7 mL of Isopropyl Alcohol into the second reactor. The temperature is adjusted to 35-40 ⁰ C.

A total of 606 mL of Isopropyl Alcohol is filtered through a 0.2 microns polyamide membrane and the filtrate added to the Sulbactam solution. The first quart of solution is added throughout 10 minutes and the rest is added for about 50 minutes. The temperature is adjusted to 20-25 ⁰ C, the system is stirred for about 30 minutes and the crystals are filtered, washed with 58 mL of Isopropyl Alcohol and dried in vacuum at 35-40 ⁰ C until constant weight.

46.4 g (91% yield) of Sulbactam Sodium are obtained, with the following analytical characteristics: