FIELD OF THE INVENTION
The present invention relates to an process for the production of Penicillanic Acid compounds more specifically it relates to a process for the production of Sulbactam Sodium.
BACKGROUND OF THE INVENTION
ß-lactam antibiotics are one of the most well-known and widely used of the classes of antibacterial agent. These compounds are characterized in that they have a nucleus consisting of a ß-lactam ring fused to either a thiazolidine or a dihydro-1 3-thiazine ring. When the nucleus contains a thiazolidine ring  the compounds are usually referred to as penicillins  whereas when the nucleus contains a dihydrothiazine ring  the compounds are referred to as cephalosporins.
However  despite the wide use and acceptance of the ß-lactam antibiotics as valuable chemotherapeutic agents  they suffer from the major drawback that certain members are not active against certain microorganisms. These microorganisms show resistance to a given ß-lactam antibiotic and produce ß-lactamase enzymes. ß-lactamases are the enzymes which cleave the ß-lactam ring of penicillins and cephalosporins to give products which are devoid of antibacterial activity.
But  there are certain substances which have the ability to inhibit ß-lactamases. When this ß-lactamase inhibitor is used in combination with a penicillin or cephalosporin it can increase or enhance the anti-bacterial effectiveness of the penicillin or cephalosporin against certain microorganisms.
Penicillanic acid 1 1-dioxide and its esters readily hydrolyzable in vivo such as Sulbactam Sodium are potent inhibitors of microbial ß-lactamases. It is considered that when these inhibitors are used in combination with ß-lactam antibiotics  there is an enhancement of antibacterial effectiveness.
To produce Sulbactam Sodium  there is the requirement of a process which is industrially applicable  cost effective and moreover significantly feasible for industrial scale production.
Hence  there is a need of such a process for the production of these ß-lactamase inhibitors i.e Sulbactam Sodium which can permanently inactivates beta-lactamases and allows beta-lactam antibiotics to destroy susceptible bacteria in an efficient and industrially scalable manner.
SUMMARY
It is an object of the invention to provide a process for the production of a beta-lactamase inhibitor compounds preferably Sulbactam Sodium.
It is another object of the invention to provide a process for production of Sulbactam Sodium wherein the process comprises dissolving acid form of Sulbactam in an organic medium and then adding 1:1 aqueous HCl to it. Thereafter  mixing the resulting solution and separating the organic and inorganic layers. Further  NaCl solution is added to the separated organic layer to form a first solution. A second solution of sodium salt in the organic medium is prepared in a separate flask. Finally  reacting the first solution with the second solution to produce Sulbactam Sodium solution. The Sulbactam Sodium solution is then stirred  washed  filtered and crystallized in the organic medium to obtain the desired sulbactam sodium crystals which complies with the pharmacopeia requirement.
It is yet another object of the invention  to provide a process for the production of sulbactam sodium which is industrially scalable and provides recovery of inputted materials.
It is yet another object of the invention  to provide a process which gives the improved yield of the Sulbactam Sodium of above 88%.
DETAILED DESCRIPTION OF THE INVENTION
In the detailed description of the invention  numerous specific details are described to provide a thorough understanding of the various embodiments of the invention. However  one skilled in the relevant art will recognize that an embodiment of the invention can be practiced without one or more of the specific details  or with other apparatus  systems  assemblies  methods  components  materials  parts  and/or the like. In other instances  well-known structures  materials  or operations are not specifically shown or described in detail to avoid obscuring aspects of embodiments of the invention.
The various aspects of the present invention leading to a process for the production of Sulbactam Sodium are detailed below.
The invention provides to the art  a process for the production of a beta-lactamase inhibitor more specifically it provides a process for the production of Sulbactam Sodium. 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.
The invention provides a method for the production of sulbactam sodium which is quite efficient  efficacious and proves to generate significant feasibility for an industrial scale production of Sulbactam Sodium.
In an embodiment of the invention  the process for the production of Sulbactam Sodium comprises dissolving acid form of Sulbactam in an organic medium and adding 1:1 aqueous HCl to it; mixing the resulting solution and separating the organic and inorganic layers formed; adding sodium chloride solution to the separated organic layer to form a first solution; preparing a second solution of sodium salt in the organic medium. After that  reacting the first solution with the second solution to produce Sulbactam Sodium solution. The resulting solution is then stirred  washed  and filtered. Then it is finally crystallized in the organic medium to obtain the crystals of sulbactam sodium which complies with the pharmacopeia requirement.
In a further embodiment of the invention  the organic medium used in the process for the production of sulbactam sodium is an ester preferably Ethyl Acetate (EA).
In another embodiment of the invention  HCl is used for proper dissolution of Sulbactam acid into the organic medium.
In another embodiment of the invention  Sodium Chloride (NaCl) solution which is added to the organic layer formed after the addition of aqueous HCl to the sulbactam acid solution is saturated till 3% molar concentration. NaCl is used for washing of the organic layer and removing the aqueous part from the separated organic layer.
In another embodiment of the invention  the sodium salt complex is 2-sodium ethyl hexanoate which is prepared in the organic medium. This sodium salt solution (Second Solution) is slowly added to the Sulbactam acid solution (First Solution) till the pH of the solution reaches in range of 6.8 to 7.2.
In another embodiment of the invention  the reaction of sulbactam acid and 2-ethyl sodium hexanoate in Ethyl Acetate medium gives a solution Sulbactam Sodium. This final solution of sulbactam sodium is then stirred  washed  filtered and thereafter  crystallized in chilled Ethyl Actetate solution to obtain the crystals of the Sulbactam Sodium. The crystals are then dried and weighed.
In another embodiment of the invention  the process for the production of Sulbactam Sodium is a temperature regulated process. The temperature required for the process is 0-10oC.
The process of the invention allows for the good recovery of materials used in the process that translates the process into a quite efficient  efficacious and proves to generate significant feasibility for an industrial scale production of Sulbactam Sodium. The yield of sulbactam sodium obtained by the process of the present invention is above 88%.
Penicillanic acid 1 1-dioxide and its esters readily hydrolyzable in vivo like Sulbactam Sodium are potent inhibitors of microbial ß-lactamases. The invention provides the process for production of Sulbactam Sodium which enhances the effectiveness of ß-lactam antibiotics  using penicillanic acid 1 1-dioxide i.e. Sulbactam acid.
Sulbactam Sodium produced by the reaction of Sulbactam acid and 2-ethyl sodium hexanoate  has the capability of permanently inactivating beta-lactamases and allowing beta-lactam antibiotics to destroy susceptible bacteria.
Several variations in the processes and the methods herein disclosed will suggest themselves to those skilled in the art. However  it is to be understood that the present disclosure relates to the preferred embodiment of the invention which is for purposes of illustration only and not to be construed as limiting the scope of the invention.
A pharmaceutical composition containing the product obtained according to the process of the invention has no need to be formulated with additional auxiliaries.
The present invention will now be illustrated in greater detail with reference to Examples  but the present invention should not be interpreted as being restricted thereto.

EXAMPLES:
Example 1
In a flask 400mL of Ethyl Acetate (EA) and 50mL of DM water are charged at temperature 0-5oC. At the same temperature 50 gm Sulbactam acid is added to the flask. Also  1:1 aqueous HCl (6.5mL + 6.5mL) is added to the flask and stirred till complete dissolution. The organic layer is separated and washed with saturated NaCl solution (< 3% molar concentration). The solution contents are then filtered and labeled as Solution A which is kept at temperature 8-10oC.
In another flask  25% 2-Ethyl sodium hexanoate is prepared in Ethyl Acetate and is labeled as Solution B. Contents of Solution B is added to the cooled Solution A until pH of the final solution reaches in range of 6.8 to 7.2. The contents of final solution are stirred for 10min  filtered and are washed with chilled EA (25mL*3) to obtain the crystals of the Sulbactam Sodium. The crystals are then dried to yield 45-46 gm. Further  350-370 ml of Ethyl acetate is recovered. The product obtained complies with the pharmacopeia requirement.
Raw Materials and their Inputs Required For Example 1
Raw material Input Recoveries
Sulbactam Acid 50gm
Ethyl Acetate 400+75 ml 350-370 ml
DM Water 50 ml
HCl 6.5 ml
Sodium Chloride 35 gm
2-ethyl sodium hexanoate 155 ml (25%)
Yield 45-46 gm

CLAIMS
We Claim:
1. A process for the production of Sulbactam Sodium wherein said process is characterized by steps comprising:
a. dissolving sulbactam acid in an organic medium;
b. adding a solution of 1:1 aqueous HCl to the solution from step (a);
c. separating organic layer and inorganic layer;
d. adding NaCl solution to the organic layer formed in step (c) to form a first solution;
e. preparing a second solution by dissolving a sodium salt in the organic medium;
f. reacting the first solution with the second solution to form Sulbactam Sodium solution; and
g. adding the organic medium to wash the Sulbactam Sodium solution and to induce crystallization of Sulbactam Sodium.
2. The process according to claim 1  wherein said organic medium is an ester preferably ethyl acetate.
3. The process according to claim 1  wherein the NaCl used in step (d) is saturated till molar concentration of 3%.
4. The process according to claim 1  wherein the sodium salt is 2-ethyl sodium hexanoate.
5. The process according to claim 1  wherein the second solution is added to the first solution for the reaction till pH of the Sulbacatam Sodium solution reaches in range of 6.8 to 7.2.
6. The process according to claim 1  characterized in that said process is carried out at a temperature of 0-10oC.
7. A process for the production of Sulbactam Sodium wherein said process is characterized by steps comprising:
a. dissolving sulbactam acid in ethyl acetate;
b. adding a solution of 1:1 aqueous HCl to the solution from step (a);
c. separating organic layer and inorganic layer;
d. adding NaCl solution to the organic layer formed in step (c) to form a first solution;
e. preparing a second solution by dissolving 2-ethyl sodium hexanoate in ethyl acetate;
f. reacting the first solution with the second solution to form Sulbactam Sodium solution; and
g. adding ethyl acetate to wash the Sulbactam Sodium solution and to induce crystallization of Sulbactam Sodium.
8. The process according to claim 7  wherein the NaCl used in step (d) is saturated till molar concentration of 3%.
9. The process according to claim 7  wherein the second solution is added to the first solution for the reaction till pH of the Sulbactam Sodium solution reaches in range of 6.8 to 7.2.
10. The process according to claim 7  characterized in that said process is carried out at a temperature of 0-10oC.