CROSS-REFERENCE TO RELATED APPLICATION

This application claims the benefit of provisional specification no. 1398/DEL/2010 filed on dated 16 June, 2010, filed by the present inventors.

FIELD OF INVENTION

The present invention relates to an improved and efficient process for the synthesis of amoxicillin sodium and particularly for the preparation of sterile amoxicillin sodium.

BACKGROUND OF INVENTION

Sodium salt of amoxicillin is a well known semisynthetic penicillin widely prescribed for intravenous administration which is used as a moderate-spectrum, bacteriolytic, β-lactam antibiotic. The present invention relates to an improved method of preparation of β-lactam antibiotics particularly amoxicillin sodium in sterile form . Among all sodium salts of penicillins such as ampicillin, amoxicillin etc., the preparation procedures for amoxicillin is the most intricate and extreme caution is necessary to maintain sterility of the penicillin at an industrial scale production.

In general, the prior art methods employed for amoxicillin production result into high solvent impurity in the final product and often have to employ complicated procedures to maintain sterility of the product. Prior methods have also contemplated the use of a mixture of solvents such as lower alcohols and suitable esters . This mixture of solvents poses greater difficulty in scaling up to industrial level due to the use of large amount of solvents and also creates complicated and expensive solvent recovery system . I n addition, these processes are associated with unsatisfactory yield and moreover are inconvenient to produce on an industrial scale due to possible precipitations at the phase of the sterilizing filtration with the consequent obstruction of the filter. The invention as embodied herein demonstrates an improved method of preparation of sodium salt of amoxicillin which employs precipitation from non aqueous solvents which have significantly overcome the inefficiencies and drawbacks of such methods. Generally, amoxicillin sodium is prepared by the reaction of a solution of salifiying compound such as sodium-2-ethylhexanoate in methyl acetate with a solution of amoxicillin trihydrate in a mixture of methanol and another C2-C5 lower alcohol and in the presence of a suitable base. The major disadvantage of this process is the low yield and low purity of the product. Low purity is accountable to the use of mixture of alcohols which are present as solvent impurity in the product. Therefore, the process of the present invention involves the use of one alcohol as opposed to a mixture of alcohols, wherein the salt, e.g . sodium, of amoxicillin crystallizes giving excellent yield and quality of the product.

There was thus a clear need to find another industrially feasible process for the synthesis of penicillins more preferably sodium salt of amoxicillin in higher yield and product quality. Therefore a new synthesis for the production of amoxicillin sodium has been found which possesses a number of significant practical and economic advantages in industrial use. It uses solvents which are environmentally acceptable, and gives high yields close to 90% or, in some cases, even more than 90 percent. Furthermore it is economical in operation and the final product obtained is sterile as desirable for medical use.

SUMMARY

It is an object of the invention is to provide a process for preparation of sterile amoxicillin sodium of formula (I) .

Formula (I)

It is still another object of the present invention is to provide an efficient and high yielding process for the preparation of sterile amoxicillin sodium, which is cost effective.

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to an improved process for the production of the salt, preferably sodium salt, of the penicillin antibiotic amoxicillin , wherein the process is characterized by the following steps:

a. dissolving amoxicillin trihydrate in an ester, an alcohol and an alkylamine and passing the solution through sterile filters,

b. dissolving sodium-2-ethylhexanoate in an alcohol and an ester and passing the solution through sterile filters,

c. reacting solution form step a) with solution from step b) ,

d. crystallizing by adding an ester

In an embodiment of the invention , ester used in step a), b) and c) may be selected from but not limited to ethyl acetate, methyl acetate, propyl acetate, t-butyl acetate, isobutyl acetate, methyl propanoate, ethyl proponoate, methyl butanoate, ethyl butanoate or any suitable mixtures thereof.

In another embodiment of the invention , alcohol used in step a) and b) may be selected from but not limited to methanol, ethanol, 1 -butanol, 2-butanol, 2-methyl-1 -propanol, 1 -propanol, 2- propanol or any suitable mixtures thereof.

In another embodiment of the invention , alkylamine used in step a) may be selected from but not limited to secondary alkylamine or tertiary alkylamine or any suitable mixtures thereof.

In another embodiment of the invention , the tertiary alkylamines used in step (a) have alkyl group with carbon atoms in the range from 1 to 20.

In a yet another embodiment of the invention, amoxicillin trihydrate is dissolved in an ester preferably methyl acetate, an alcohol preferably methanol and an organic amine base preferably triethylamine. The solution is constantly stirred and a clear solution is ensured which is passed through sterile filtration system . A solution of sodium-2-ethylhexanoate in an alcohol preferably methanol and an ester preferably methyl acetate is prepared and likewise this solution is also passed through sterile filtration system . The sodium-2-ethyl hexanoate solution is then added to the earlier prepared amoxicillin trihydrate solution. One of ordinary skilled in the art will readily appreciate the significance of a clear solution after every dissolution procedure which is of prime importance to achieve a sterile final product.

When the additions are over, the solution is cooled to a temperature between - 10 °C and 10 ° C, preferably 0 °C to 5 °C and a suitable amount of an ester preferably methyl acetate is added to facilitate the complete precipitation of amoxicillin sodium from the reaction solution . Thereafter, the sterile sodium salt which is precipitated is filtered, washed and dried. The final product i.e. amoxicillin sodium obtained from the process as described herein adheres to all current regulatory requirements for sterility emphasizing processes which are essential for the medical and the pharmaceutical industry.

In a preferred embodiment of the invention, crystallization of amoxicillin sodium in step d) is initiated by the addition of an ester preferably but not limited to methyl acetate at a temperature range from about -10 ^a C to 1 0 ^a C, preferably 0 ^a C to 5 ^a C. The final product is filtered, washed with the same ester used in the process and then dried in a temperature regulated environment.

In another embodiment of the invention the temperature during the entire process is maintained at a range from about -1 0 ^a C to 10 ^a C, preferably 0 ^a C to 5 ^a C.

An improvement of the present invention over prior art processes is of particular relevance concerning to its industrial application which is represented by the fact that the amoxicillin trihydrate solution is prepared in the mixture undesired precipitations.

In addition to the advantages of the process, use of isopropanol is avoided which is generally used for dissolution of amoxicillin trihydrate. Furthermore, prior art methods have employed the use acetonitrile which falls under class 2 solvent category and has strict limit in residual form . Therefore, the use of acetonitrile is avoided by the process as embodied in the present invention . According to a preferred embodiment of the process of the invention, amoxicillin trihydrate is dissolved in a solution of an alcohol and methyl acetate containing a suitable organic base and then filtering the same in a solution of sodium-2-ethyl hexanoate in methyl acetate and an alcohol which is previously sterilely filtered. This process renders substantial improvement in the yield and purity of the product. In comparison to the prior art methods for the preparation of sodium salt of amoxicillin , repetitive filtration and crystallization operations are required which often reduce the commercial viability and ultimately lead to losses in yield and, in turn , make the process uneconomical and not environmentally friendly.

A further improvement in the process in accordance with the present invention is that amoxicillin sodium is obtained directly in a sterile ambient, which is of prime importance for a pharmaceutical compound being prepared at an industrial scale. The process as described by the present invention also confers better yield and quality of the product which is feasible at a commercial scale and does not involve any repetitive purification procedures to comply with the sterility standards of a pharmaceutical product.

The compounds and processes of the present invention will be better understood in connection with the following synthetic scheme I which illustrates the methods by which the compounds of the invention may be prepared.

1. CH3COOCH3, Methanol, TEA

2. Sodium-2-ethylhexanoate, CH3COOCH3, Methanol

Scheme I

The method of the present invention is efficient and provides amoxicillin sodium in yield higher as compared to yield achieved in the existing prior art. In accordance with the method as employed in the present invention , amoxicillin sodium is produced with a yield of more than about 90% and more particularly it is sterile and has a significant improvement in the purity. Furthermore, this process exhibits an enhanced efficacy for the preparation of sterile amoxicillin sodium with reference to an increased yield, high purity and better industrial applicability.

While the present invention has been described in terms of their specific embodiments, certain modifications in the process and various crystalline forms of the subject compound including specially designed equipments used are intended to be included within the scope of the present inventions.

The foregoing technique has been found to be distinctly efficacious, both from commercial point of view, as well as from manufacturing point of view, and affords good quality of amoxicillin sodium . Many other beneficial results can be obtained by applying disclosed invention in a different manner or by modifying the invention within the scope of disclosure.

The present invention is illustrated with the following example, which should not be construed as limiting the scope of the invention.

EXAMPLES:

Example 1

Preparation of sterile Amoxicillin Sodium using methyl acetate as solvent

Amoxicillin trihydrate (50g) is dissolved in methyl acetate (92ml_), triethylamine (34g) and methanol (52m l_) . The resulting reaction solution is constantly stirred to a clear solution at temperature of 0-5 ^a C and passed through sterile filtration system . Sodium-2-ethylhexanoate (34g) is dissolved in methyl acetate (92ml_) and methanol (52ml_) and the solution is filtered through sterile filtration system . This solution containing sodium-2-ethylhexanoate is added to the amoxicillin trihydrate solution maintaining the temperature between 0-5 ^s C. After 80 minutes of passing the solution through sterile filtration system, methyl acetate (10 ml_) is added. The resulting precipitate is filtered, washed with methyl acetate (240m l_) and dried at a temperature below 50 ^a C to obtain sterile amoxicillin sodium. Yield >90%

Example 2

Preparation of sterile Amoxicillin Sodium using ethanol as solvent

Amoxicillin trihydrate (50g) is dissolved in ethanol (92m l_) , triethylamine (34g) and methanol (52m l_). The resulting reaction solution is constantly stirred to a clear solution at temperature of 0-5 ^a C and passed through sterile filtration system . Sodium-2-ethylhexanoate (34g) is dissolved in ethanol (92ml_) and methanol (52m l_) and the solution is filtered through sterile filtration system. This solution containing sodium-2-ethylhexanoate is added to the amoxicillin trihydrate solution maintaining the temperature between 0-5 ^a C. After 80 minutes of passing the solution through sterile filtration system, ethanol (10m l_) is added. The resulting precipitate is filtered, washed with ethanol and dried at a temperature below 50 ^a C to obtain sterile amoxicillin sodium . Yield: 67-70%

Example 3

Preparation of sterile Amoxicillin Sodium using acetonitrile as solvent

Amoxicillin trihydrate (50g) is dissolved in acetonitrile (92ml_) , triethylamine (34g) and methanol (52m l_) . The resulting reaction solution is constantly stirred to a clear solution at temperature of 0-5 ^a C and passed through sterile filtration system . Sodium-2-ethylhexanoate (34g) is dissolved in acetonitrile (92ml_) and methanol (52ml_) and the solution is filtered through sterile filtration system. This solution containing sodium-2-ethylhexanoate is added to the amoxicillin trihydrate solution maintaining the temperature between 0-5 ^s C. After 80 minutes of passing the solution through sterile filtration system, sodium thiocyanate (ml_) is added. The resulting precipitate is filtered, washed with acetonitrile (240ml_) and dried at a temperature below 50 ^a C to obtain sterile amoxicillin sodium. Yield: 80-82%.