Description:Method of preparation of Bromfenac Sodium sesquihydrate and uses thereof
Field of the Invention
The present invention relates a method of preparation of Bromfenac Sodium Sesquihydrate salts. More particularly, the present invention relates to a method of preparation of Bromfenac Sodium Sesquihydrate which is primarily used to treat inflammation and pain associated with certain eye conditions.
Background of the Invention
Bromfenac sodium sesquihydrate is a nonsteroidal anti-inflammatory drug (NSAID) used to treat inflammation and pain in conditions like arthritis and postoperative ophthalmic inflammation. There are several methods for preparing this compound, each with its own advantages and challenges.
Solvent recrystallization is one of the methods, wherein bromfenac is dissolved in a suitable solvent (like water or an organic solvent) at an elevated temperature and then allowed to crystallize as the solution cools. In such cases, selecting the right solvent is a major challenge. The solvent needs to be able to dissolve bromfenac sodium sesquihydrate at elevated temperatures but also allow it to crystallize upon cooling. Further, controlling the rate of cooling is important for obtaining high purity crystals. Rapid cooling can lead to the formation of impurities or different polymorphs.
Bromfenac sodium sesquihydrate can also be obtained by reacting Bromfenac with Sodium Hydroxide in water. Controlling the pH of the reaction mixture is crucial. The reaction typically requires a specific pH range for optimal yield and purity. Efficient mixing of reactants to ensure complete conversion of bromfenac to its sodium salt and removing water from the final product are another challenge, as excess water leads to lower yields or impurities.
Bromfenac can be converted to its sodium salt form through ion exchange chromatography. However, optimization of the ion exchange conditions is crucial for high yield and purity. Controlling the elution conditions to ensure selective elution of bromfenac sodium sesquihydrate without contaminants is critical. Regeneration of the ion exchange resin for repeated use can be technically challenging.
Another method involves freeze drying or employing a lyophilizing a aqueous solution of bromfenac sodium sesquihydrate by drying under vacuum to remove water. Controlling the rate of drying to prevent the formation of amorphous solids or impurities is a challenging factor here.
Overall, the key technical challenges in preparing bromfenac sodium sesquihydrate include selection of appropriate solvents, reactants, and conditions to ensure high yield and purity, controlling parameters such as pH, temperature, and drying rate to prevent degradation or formation of impurities, efficient removal of water without causing loss of product or decomposition.
Each of the above methods has their advantages and limitations, and the choice of method often depends on factors such as the desired purity, yield, scalability, and equipment availability. There is still a need to develop an improved method for synthesis of bromfenac sodium sesquihydrate, overcomes challenges and obviates complexity associated with the prior arts.
Summary of the Invention
It is one of the objectives of the present invention to provide a method for preparation of Bromfenac sodium sesquihydrate which is cost effective & commercially viable with improved yield & quality.
It is one of the objectives of the present invention to provide a method for preparation of Bromfenac sodium sesquihydrate which efficiently removes insoluble impurities.
It is one of the objectives of the present invention to provide a method for preparation of Bromfenac sodium sesquihydrate which avoids employing high boiling solvent like Dimethoxy ethane in the manufacturing process which is difficult to remove by drying upto 100 ppm as per ICH guidelines in API.
In accordance with one embodiment of the present invention, there is provided a method of preparing Bromfenac Sodium Sesquihydrate (Formula-III), comprising obtaining Sodium 2-(2-amino-3-(4-bromobenzoyl) phenyl) acetate (Formula-II) as a crude yellow solid prepared without using an inert atmosphere, dissolving the crude solid in Methanol, stirring and filtering the same at 25-30°C to remove undissolved particles and adding water followed by concentrating the solution to form a sludge under vacuum at 50-55°C; and adding a solvent mixture of a secondary ether and one or more alcohols or ketone to the sludge upon detection of moisture content ranging between 28 to 45% for crystallizing the Bromfenac Sodium Sesquihydrate (Formula-III) as a yellow solid.
In accordance with one embodiment of the present invention, there is provided a method of preparing Bromfenac Sodium Sesquihydrate (Formula-III), comprising obtaining Sodium 2-(2-amino-3-(4-bromobenzoyl) phenyl) acetate (Formula-II) as a crude yellow solid prepared without using an inert atmosphere, dissolving the crude solid in Methanol, stirring and filtering the same at 25-30°C to remove undissolved particles and adding water followed by concentrating the solution to form a sludge under vacuum at 50-55°C; and adding a solvent mixture of a secondary ether and one or more alcohols or ketone to the sludge upon detection of moisture content ranging between 28 to 45% for crystallizing the Bromfenac Sodium Sesquihydrate (Formula-III) as a yellow solid, wherein said ketone is selected from Acetone, Methyl Ethyl Ketone (MEK), Methyl Isopropyl Ketone (MIPK) and Methyl Isobutyl Ketone (MIBK).
In accordance with one embodiment of the present invention, there is provided a method of preparing Bromfenac Sodium Sesquihydrate (Formula-III), comprising obtaining Sodium 2-(2-amino-3-(4-bromobenzoyl) phenyl) acetate (Formula-II) as a crude yellow solid prepared without using an inert atmosphere, dissolving the crude solid in Methanol, stirring and filtering the same at 25-30°C to remove undissolved particles and adding water followed by concentrating the solution to form a sludge under vacuum at 50-55°C; and adding a solvent mixture of a secondary ether and one or more alcohols or ketone to the sludge upon detection of moisture content ranging between 28 to 45% for crystallizing the Bromfenac Sodium Sesquihydrate (Formula-III) as a yellow solid, wherein said method further comprises of further comprises of adding the solvent mixture of acetone and Diisopropyl ether (DIPE) in a ratio of 1:2 to 1:4 to the sludge.
In accordance with one embodiment of the present invention, there is provided a method of preparing Bromfenac Sodium Sesquihydrate (Formula-III), comprising obtaining Sodium 2-(2-amino-3-(4-bromobenzoyl) phenyl) acetate (Formula-II) as a crude yellow solid prepared without using an inert atmosphere, dissolving the crude solid in Methanol, stirring and filtering the same at 25-30°C to remove undissolved particles and adding water followed by concentrating the solution to form a sludge under vacuum at 50-55°C; and adding a solvent mixture of a secondary ether and one or more alcohols or ketone to the sludge upon detection of moisture content ranging between 28 to 45% for crystallizing the Bromfenac Sodium Sesquihydrate (Formula-III) as a yellow solid, wherein said method further comprises of adding the solvent mixture of ethanol and Diisopropyl ether (DIPE) in a ratio of 1:2 to 1:4 to the sludge.
In accordance with one embodiment of the present invention, there is provided a method of preparing Bromfenac Sodium Sesquihydrate (Formula-III), comprising obtaining Sodium 2-(2-amino-3-(4-bromobenzoyl) phenyl) acetate (Formula-II) as a crude yellow solid prepared without using an inert atmosphere, dissolving the crude solid in Methanol, stirring and filtering the same at 25-30°C to remove undissolved particles and adding water followed by concentrating the solution to form a sludge under vacuum at 50-55°C; and adding a solvent mixture of a secondary ether and one or more alcohols or ketone to the sludge upon detection of moisture content ranging between 28 to 45% for crystallizing the Bromfenac Sodium Sesquihydrate (Formula-III) as a yellow solid, wherein said method further comprises of adding the solvent mixture of methanol and Diisopropyl ether (DIPE) in a ratio of 1:2 to 1:4 to the sludge.
In accordance with one embodiment of the present invention, there is provided a method of preparing Bromfenac Sodium Sesquihydrate (Formula-III), comprising obtaining Sodium 2-(2-amino-3-(4-bromobenzoyl) phenyl) acetate (Formula-II) as a crude yellow solid prepared without using an inert atmosphere, dissolving the crude solid in Methanol, stirring and filtering the same at 25-30°C to remove undissolved particles and adding water followed by concentrating the solution to form a sludge under vacuum at 50-55°C; and adding a solvent mixture of a secondary ether and one or more alcohols or ketone to the sludge upon detection of moisture content ranging between 28 to 45% for crystallizing the Bromfenac Sodium Sesquihydrate (Formula-III) as a yellow solid, wherein said method further comprises stirring the mixture of secondary ether and ethanol and cooling the mixture to 0 to 5 °C, filtering the same and drying under vacuum oven to produce Bromfenac Sodium Sesquihydrate (Formula-III) as a yellow solid.
In accordance with one embodiment of the present invention, there is provided a method of preparing Bromfenac Sodium Sesquihydrate (Formula-III), comprising obtaining Sodium 2-(2-amino-3-(4-bromobenzoyl) phenyl) acetate (Formula-II) as a crude yellow solid prepared without using an inert atmosphere, dissolving the crude solid in Methanol, stirring and filtering the same at 25-30°C to remove undissolved particles and adding water followed by concentrating the solution to form a sludge under vacuum at 50-55°C; and adding a solvent mixture of a secondary ether and one or more alcohols or ketone to the sludge upon detection of moisture content ranging between 28 to 45% for crystallizing the Bromfenac Sodium Sesquihydrate (Formula-III) as a yellow solid, wherein said method further comprises dissolving the crude solid in Methanol and stirring the same at 25-30°C for a definite period of time to filter out the undissolved solid, and concentrating the filtrate with the addition of water under vacuum at 50-55 °C to form the sludge, and adding and stirring a mixture of Methanol and water in the sludge, followed by bringing the temperature down to 0-5 °C and maintaining it for 2h.
In accordance with one embodiment of the present invention, there is provided a method of preparing Bromfenac Sodium Sesquihydrate (Formula-III), comprising hydrolyzing 7-(4-bromobenzoyl) indolin-2-one (Formula-I) with aqueous alkali hydroxide, preferably NaOH, in the presence of high boiling solvent such as Toluene and polar solvent such as ethanol or methanol at 70 -75 °C without using inert atmosphere, adding Diisopropyl ether and ethanol or DIPE and methanol in the ratio of 1:2 to 1:4 to isolate the crude bromfenac Sodium, obtaining Sodium 2-(2-amino-3-(4-bromobenzoyl) phenyl) acetate (Formula-II) as a crude yellow solid, dissolving the crude solid in Methanol, stirring and filtering the same at 25-30°C to remove undissolved particles and adding water followed by concentrating the solution to form a sludge under vacuum at 50-55°C, and adding a solvent mixture of a secondary ether and one or more alcohols or ketone to the sludge upon detection of moisture content ranging between 28 to 45% for crystallizing the Bromfenac Sodium Sesquihydrate (Formula-III) as a yellow solid.
Detailed Description of the Invention
The particulars shown herein are by way of example and for purposes of illustrative discussion of the various embodiments of the present invention only and are presented in the cause of providing what is believed to be the most useful and readily understood description of the principles and conceptual embodiments/aspects of the invention. In this regard, no attempt is made to show details of the invention in more detail than is necessary for a fundamental understanding of the invention, the description making apparent to those skilled in the art how the several forms of the invention may be embodied in practice.
While this specification concludes with claims particularly pointing out and distinctly claiming that, which is regarded as the invention, it is anticipated that the invention can be more readily understood through reading the following detailed description of the invention and study of the included examples.
In accordance with one embodiment, there is provided a method for preparing Sodium 2-(2-amino-3-(4-bromobenzoyl) phenyl) acetate (Formula-II), comprising adding 100g of 7-(4-bromobenzoyl) indolin-2-one (Formula-I) in a stirring mixture of Toluene (680ml) and Ethanol (230ml) in a RB flask and heated the reaction mixture to 60-65 °C, and then charged 67ml of 33% of aqueous solution of sodium hydroxide in to the reaction mixture, wherein the temperature of the reaction mixture is increased to 70-75°C and maintained by stirring for 7-8 hrs, wherein after completion of the reaction, the reaction mixture is cooled to 25-30°C and a mixture of Di-isopropyl ether (940ml) and Ethanol (470ml) is added into it, wherein the temperature of the reaction mixture is further brought down to 5-10°C with stirring and is maintained for 2hrs, wherein the solid is filtered and suck dried for 2 hrs to obtain 95g crude Sodium 2-(2-amino-3-(4-bromobenzoyl) phenyl) acetate (Formula-II) as a yellow solid having HPLC Purity: 99.59 %

In accordance with another embodiment of the present invention, there is provided a method for preparing Sodium 2-(2-amino-3-(4-bromobenzoyl) phenyl) acetate (Formula-II), comprising adding 10g of 7-(4-bromobenzoyl) indolin-2-one (Formula-I) with stirring in a mixture of Toluene (68ml) and Ethanol (23ml) in a RB flask and heated the reaction mixture to 60-65 °C, and then charged 6.7ml of 33% of aqueous solution of sodium hydroxide in to the reaction mixture, wherein the temperature of the reaction mixture is increased to 70-75°C and maintained with stirring for 7-8hr, wherein after completion of the reaction, the reaction mixture is cooled to 25-30°C and 75ml of Di-isopropyl ether added into it, wherein the temperature of the reaction mixture is further brough down to 5-10°C with stirring and maintained for 2hr, wherein the solid is filtered and suck dried for 2hr to obtain 10.2g of crude Sodium 2-(2-amino-3-(4-bromobenzoyl) phenyl) acetate (Formula-II) as a yellow solid with HPLC Purity 97.40 %.

In accordance with another embodiment of the present invention, there is provided a method for preparing Sodium 2-(2-amino-3-(4-bromobenzoyl) phenyl) acetate (Formula-II), comprising adding 10g of 7-(4-bromobenzoyl) indolin-2-one (Formula-I) with stirring in a mixture of Toluene (68ml) and Ethanol (23ml) in a RB flask and heated the reaction mixture to 60-65 °C, and then charged 6.7ml of 33% of aqueous solution of sodium hydroxide in to the reaction mixture, increasing the temperature of the reaction mixture to 70-75°C and maintaining it with stirring for 7-8 hrs, wherein after completion of reaction, the reaction mixture is cooled to 25-30°C and solvent mixture of 80ml di-isopropyl ether and 47ml Methanol is added into it, wherein the temperature of reaction mixture is brought down to 5-10°C with stirring and maintained for 2hr, the solid is filtered and suck dried for 2hr to obtain 5.97 g of a crude Sodium 2-(2-amino-3-(4-bromobenzoyl) phenyl) acetate (Formula-II) as a yellow solid. HPLC Purity: 99.57%

In accordance with another embodiment of the present invention, there is provided a method for preparing Sodium 2-(2-amino-3-(4-bromobenzoyl) phenyl) acetate (Formula-II), wherein adding 10g of 7-(4-bromobenzoyl) indolin-2-one (Formula-I) with stirring in a mixture of Toluene (68ml) and methanol (23ml) in a RB flask and heating the reaction mixture to 60-65 °C, and then charged 6.7ml of 33% of aqueous solution of sodium hydroxide in to the reaction mixture, increasing the temperature of the reaction mixture to 70-75°C and maintaining by stirring for 7-8hr, wherein after completion of reaction, the temperature of the reaction mixture is cooled down to 25-30°C and solvent mixture of 90ml di-isopropyl ether and 30ml Methanol is added into it, wherein the temperature of the reaction mixture is brought down to 5-10°C with stirring and maintained for 2hr, wherein the solid is filtered and suck dried for 2hr to obtain 7.38g of a crude Sodium 2-(2-amino-3-(4-bromobenzoyl) phenyl) acetate (Formula-II) as a yellow solid with HPLC Purity of 99.59%.

In accordance with an exemplary embodiment of the present invention, there is provided a method for preparing Bromfenac Sodium Sesquihydrate (Formula-III):

To a solvent mixture of 1,2-Dimethoxyethane (450ml) and water (90ml), charged crude 90g of Sodium 2-(2-amino-3-(4-bromobenzoyl) phenyl) acetate (Formula-II) from one of the above embodiments, is kept under stirring for purification, heated the reaction mass to reflux and hot filtered to remove insoluble particle, concentrated the filtrate to a sludge under vacuum, followed by adding 2.7L of methanol into the sludge under stirring at 25-30°C and maintained for 30 min to dissolve and filtered the insoluble through celite bed, 90ml of water is added into the obtained filtrate and concentrate under vacuum to obtain sludge which is added with stirring a mixture of di isopropyl ether (450ml) and ethanol (225ml), cooled to 0-5 ° C, filtered the solid, and dried under vacuum oven to obtain a Bromfenac Sodium Sesquihydrate (Formula-III) as a yellow solid. Yield: 79.3g HPLC purity; 99.48%. Assay; 100.93%, Moisture content (w/w%):6.97.
In accordance with another exemplary embodiment of the present invention, there is provided a method for preparing Bromfenac Sodium Sesquihydrate (Formula-III):
Dissolved 45g of the crude solid Sodium 2-(2-amino-3-(4-bromobenzoyl) phenyl) acetate (Formula-II) from one of the above embodiments in 1.35L of Methanol under stirring at 25-30°C for 1hr and filtered out the undissolved solid. Concentrated the filtrate with the addition of 45ml of water under vacuum at 50-55 °C to get sludge and then charged with stirring a mixture of di-isopropyl ether (225ml) and ethanol (112.5ml) into it. Brought down the temperature 0-5 °C and maintain for 2h. Filtered & dried the yellow solid under vacuum in VTD to furnish Bromfenac Sodium Sesquihydrate (Formula-III). Yield: 40.65g HPLC Purity: 99.33%. Moisture Content (%): 7.11 , Assay : 99.57%.
In accordance with another exemplary embodiment of the present invention, there is provided a method for preparing Bromfenac Sodium Sesquihydrate (Formula-III):
Dissolved 10g of the crude solid Sodium 2-(2-amino-3-(4-bromobenzoyl) phenyl) acetate (Formula-II) from one of the above embodiments in 300ml of Methanol under stirring at 25-30°C for 1hr and filtered out the undissolved solid, concentrated the filtrate with the addition of 10ml of water under vacuum at 50-55 °C to obtain sludge and then charged with stirring a mixture of di-isopropyl ether (60ml) and methanol (15ml) into it, the temperature is brought down to 0-5 °C and maintained for 2h, filtered & dried the yellow solid under vacuum in VTD to furnish Bromfenac Sodium Sesquihydrate (Formula-III). Yield : 8.0g HPLC Purity: 99.69%., Assay: 100.91%, Moisture content (%): 6.82.
In accordance with another exemplary embodiment of the present invention, there is provided a method for preparing Bromfenac Sodium Sesquihydrate (Formula-III):
Dissolved 10g of the crude solid Sodium 2-(2-amino-3-(4-bromobenzoyl) phenyl) acetate (Formula-II) from one of the above embodiments in 300ml of Methanol under stirring at 25-30°C for 1hr and filtered out the undissolved solid, concentrated the filtrate with the addition of 10ml of water under vacuum at 50-55 °C to get sludge and then charged with stirring a mixture of di-isopropyl ether (50ml) and acetone (25ml) into it, the temperature is brought down to 0-5 °C and maintained for 2h. Filtered & dried the yellow solid under vacuum in VTD to furnish Bromfenac Sodium Sesquihydrate (Formula-III). Yield: 79g HPLC Purity: 99.54%. Assay (OAB); 100.75%, Moisture content (%); 6.85.

Reaction Scheme
In accordance with another exemplary embodiment of the present invention, there is provided a method for preparing Bromfenac Sodium Sesquihydrate (Formula-III):
Dissolved 5g of the crude solid Sodium 2-(2-amino-3-(4-bromobenzoyl) phenyl) acetate (Formula-II) from one of the above embodiments in 150ml of Methanol under stirring at 25-30°C for 1hr and filtered out the undissolved solid, concentrated the filtrate with the addition of 10ml of water under vacuum at 50-55 °C to obtain sludge and then charged with stirring a mixture of Methanol (15ml) and Water (3.8ml.) under stirring, the temperature is brought down to 0-5 °C and maintained for 2h, filtered and dried the yellow solid under vacuum in VTD to furnish Bromfenac Sodium Sesquihydrate (Formula-III). Yield :1.9g, Purity: 99.37%, Moisture content: 6.71%, Assay – 100.57%.
In one of the above embodiments, high boiling solvent of class-2 Dimethoxy ethane (100ppm) is replaced with class-3 methanol (3000ppm), enabling residual solvent limit to be achieved easily in case of Methanol during drying of the solid, wherein Methanol is capable of removing insoluble impurities encountered during the preparation of Bromfenac Sodium Sesquihydrate (Formula-III).
It is to be understood that while the invention has been described in conjunction with the preferred specific embodiments thereof, that the description and examples given above are intended to illustrate and not to limit the scope of the invention. Other aspects, advantages and modifications within the scope of the invention will be apparent to those skilled in the art to which the invention pertains. Accordingly, the appended claims are intended to cover all embodiments of the invention and modifications thereof that do not depart from the spirit and scope of the invention. , Claims:We Claim:
1. A method of preparing Bromfenac Sodium Sesquihydrate (Formula-III), comprising:
obtaining Sodium 2-(2-amino-3-(4-bromobenzoyl) phenyl) acetate (Formula-II) as a crude yellow solid prepared without using an inert atmosphere;
dissolving the crude solid in Methanol, stirring and filtering the same at 25-30°C to remove undissolved particles and adding water followed by concentrating the solution to form a sludge under vacuum at 50-55°C;
adding a solvent mixture of a secondary ether and one or more alcohols or ketone to the sludge upon detection of moisture content ranging between 28 to 45% for crystallizing the Bromfenac Sodium Sesquihydrate (Formula-III) as a yellow solid.

2. The method as claimed in claim 1, wherein said ketone is selected from Acetone, Methyl Ethyl Ketone (MEK), Methyl Isopropyl Ketone (MIPK) and Methyl Isobutyl Ketone (MIBK).

3. The method as claimed in claim 1, further comprises of adding the solvent mixture of acetone and Diisopropyl ether (DIPE) in a ratio of 1:2 to 1:4 to the sludge.

4. The method as claimed in claim 1, further comprises of adding the solvent mixture of ethanol and Diisopropyl ether (DIPE) in a ratio of 1:2 to 1:4 to the sludge.

5. The method as claimed in claim 1, further comprises of adding the solvent mixture of methanol and Diisopropyl ether (DIPE) in a ratio of 1:2 to 1:4 to the sludge.

6. The method as claimed in claim 1, further comprises stirring the mixture of secondary ether and ethanol and cooling the mixture to 0 to 5 °C, filtering the same and drying under vacuum oven to produce Bromfenac Sodium Sesquihydrate (Formula-III) as a yellow solid.

7. The method as claimed in claim 1, further comprises dissolving the crude solid in Methanol and stirring the same at 25-30°C for a definite period of time to filter out the undissolved solid, and concentrating the filtrate with the addition of water under vacuum at 50-55 °C to form the sludge, and adding and stirring a mixture of Methanol and water in the sludge, followed by bringing the temperature down to 0-5 °C and maintaining it for 2h.

8. A method of preparing Bromfenac Sodium Sesquihydrate (Formula-III), comprising:
hydrolyzing 7-(4-bromobenzoyl) indolin-2-one (Formula-I) with aqueous alkali hydroxide, preferably NaOH, in the presence of high boiling solvent such as Toluene and polar solvent such as ethanol or methanol at 70 -75 °C without using inert atmosphere;
adding Diisopropyl ether and ethanol or DIPE and methanol in the ratio of 1:2 to 1:4 to isolate the crude bromfenac Sodium;
obtaining Sodium 2-(2-amino-3-(4-bromobenzoyl) phenyl) acetate (Formula-II) as a crude yellow solid;
dissolving the crude solid in Methanol, stirring and filtering the same at 25-30°C to remove undissolved particles and adding water followed by concentrating the solution to form a sludge under vacuum at 50-55°C; and
adding a solvent mixture of a secondary ether and one or more alcohols or ketone to the sludge upon detection of moisture content ranging between 28 to 45% for crystallizing the Bromfenac Sodium Sesquihydrate (Formula-III) as a yellow solid.