DESC:RELATED PATENT APPLICATION:

This application claims the priority to and benefit of Indian Provisional Patent Application No. 202141021915 filed on May 15, 2021 titled “AN IMPROVED PROCESS FOR THE PREPARATION OF ATRACURIUM BESYLATE”; the disclosure of which are incorporated herein by reference.

FIELD OF THE INVENTION:

The present invention relates to a process for the preparation of Atracurium besylate. More particularly, the present invention relates to a process for the preparation of freeze-dried composition of Atracurium besylate.

BACKGROUND OF THE INVENTION:

Atracurium besylate is an active pharmaceutical ingredient (API) used as an intermediate-duration, nondepolarizing, skeletal muscle relaxant. Atracurium besylate is administered intravenously during surgery and to facilitate mechanical ventilation and endotracheal intubation. Atracurium besylate is designated as 2-(2-carboxyethyl)-1,2,3,4-tetrahydro-6,7-dimethoxy-2-methyl-1-veratrylisoquinolinium benzenesulfonate, pentamethylene ester and is represented by the structural formula I.

Isoquinoline derivatives including Atracurium besylate having pharmacological properties which make them useful as neuromuscular blocking agents and synthesis thereof is disclosed in the U.S. Pat. No. 4,179,507. This Patent also discloses a process for preparing freeze dried Atracurium besylate.
The Patent US 8158152 assigned to SciDose discloses the process of freeze-drying an active pharmaceutical ingredient involving the steps of: dissolving the active pharmaceutical ingredient in one or more hydrophilic solvent to form a solution; adding one or more lipophilic non-solvents to the formed solution; freezing the resultant mixture to obtain frozen solid; and vacuum drying the frozen solid to yield the freeze-dried composition of the active pharmaceutical ingredient.

The Patent US 8242265 assigned to Texcontor Etablissement discloses the process of freeze-drying an active pharmaceutical ingredient involving the steps of: dissolving said compound in carbonated water to form a solution and freeze drying said solution. The carbonate water is used to decrease the degradation of active pharmaceutical ingredient during the process.

Besides different freeze-drying processes available in literature, the sensitive nature of Atracurium besylate to heat, light and pH makes the process more difficult. Further this active pharmaceutical ingredient is not stable in basic medium.

Atracurium besylate contains four sites at which different stereochemical configurations can occur. The symmetry of the molecule, however, results in only ten, instead of sixteen, possible different isomers. As per the drug label information Atracurium besylate injection slowly loses potency with time at the rate of approximately 6% per year under refrigeration (5°C).

The Patent CN 100531734 discloses a process for the preparation of freeze-dried composition of Atracurium besylate involving the freeze drying the aqueous solution of Atracurium besylate with sugar and organic acid.

The Patent application IN 1641/MUM/2014 assigned to Neon Laboratories discloses a process for the preparation of freeze-dried composition of Atracurium besylate involving the freeze drying the aqueous solution of Atracurium besylate with polyvinyl pyrrolidone. The polyvinyl pyrrolidone was added to minimize degradation of atracurium besylate during and after the process.

The Patent application IN 1599/MUM/2013 assigned to Neon Laboratories discloses a process for the preparation of freeze-dried composition of Atracurium besylate involving the freeze drying the aqueous solution of Atracurium besylate with tertiary butanol as a co-solvent.

Therefore, there remains a need for a simple commercially viable process to prepare a freeze-dried composition of Atracurium besylate.

OBJECTIVES OF THE INVENTION:

The main objective of the present invention is to provide an improved process for the preparation of Atracurium besylate.

Another main objective of the present invention is to provide an improved process for the preparation of freeze-dried composition of Atracurium besylate.

Another objective of the present invention is to provide a simple, and commercially viable process to prepare Atracurium besylate, more preferably freeze-dried composition of Atracurium besylate.

A further objective of the present invention is to provide a process to decrease or reduce the content of residual organic solvents content in the freeze-dried composition of Atracurium besylate, and thus increase the quality of the freeze-dried composition of Atracurium besylate.

SUMMARY OF THE INVENTION:

Accordingly, in one aspect the present invention provides an improved process for the preparation of freeze-dried composition of Atracurium besylate comprising the steps of:

(i) providing a solution of Atracurium besylate in water;
(ii) adjusting the pH of solution obtained in step (i) below 5;
(iii) optionally, washing the solution obtained in step (ii) with water immiscible solvent or its mixtures thereof;
(iv) purging with nitrogen gas to the solution obtained in step (ii) or step (iii) for 15 minutes to 180 minutes at a temperature between 5°C to 45°C;
(v) applying vacuum to the purged solution obtained in step (iv) for 15 minutes to 120 minutes at a temperature between 5°C to 45°C; and
(vi) freeze-drying the Atracurium besylate solution obtained in step (v) in a nitrogen atmosphere.

The process as described above, wherein said pH adjustment in step (ii) is done by using organic acid or inorganic acid or its mixture thereof.

The process as described above, wherein said acid is organic acid.

The process as described above, wherein said organic acid is benzene sulphonic acid.

The process as described above, wherein said step of adjusting the pH of the solution below 5 as in step (ii) is in the pH range between 3 to 4.

The process as described above, wherein said water immiscible solvent in step (iii) is non-polar solvents such as n-hexane, hexane, heptane, n-heptane, and toluene; or polar solvents such as tetrahydrofuran, ethyl acetate tert-butyl methyl ester; or its mixture thereof.

The process as described above, wherein said water immiscible solvent is n-hexane or n-heptane.

The process as described above, wherein the step (iv) and step (v) are repeated one time.

The process as described above, wherein the step (iv) and step (v) are repeated two times.

The process as described above, wherein the step (iv) and step (v) are repeated three times.

The process as described above, wherein the residual organic solvents content in the freeze-dried composition of Atracurium besylate obtained by the process is characterized by:
- dichloromethane content is not more than 600 PPM;
- tert-butyl methyl ether content is not more than 5000 PPM;
- ethyl acetate content is not more than 5000 PPM.

The process as described above, wherein the residual organic solvents content in the freeze-dried composition of Atracurium besylate obtained by the process is characterized by:
- dichloromethane content is not more than 10 PPM;
- tert-butyl methyl ester content is not more than 20 PPM;
- ethyl acetate content is not more than 10 PPM.

DETAILED DESCRIPTION OF THE INVENTION:

Accordingly, the present invention describes and provides a process for the preparation of Atracurium besylate, more particularly, provides an improved process for the preparation of freeze-dried composition of Atracurium besylate.

The process is simple, and commercially viable process for the preparation of Atracurium besylate and/or a freeze-dried composition of Atracurium besylate. The process decreases or reduces the content of residual organic solvents in freeze-dried composition of Atracurium besylate obtained by the process, thus increases quality of freeze-dried composition of Atracurium besylate.

One embodiment of the present invention is to provide a process for the preparation of freeze-dried composition of Atracurium besylate comprising the steps of:

(i) providing a solution of Atracurium besylate in water;
(ii) adjusting the pH of solution obtained in step (i) below 5;
(iii) optionally, washing the solution obtained in step (ii) with water immiscible solvent or its mixtures thereof;
(iv) purging with nitrogen gas to the solution obtained in step (ii) or step (iii) for 15 minutes to 180 minutes at a temperature between 5°C to 45°C;
(v) applying vacuum to the purged solution obtained in step (iv) for 15 minutes to 120 minutes at a temperature between 5°C to 45°C; and
(vi) freeze-drying the Atracurium besylate solution obtained in step (v) in a nitrogen atmosphere.

Step-(i): The providing a solution of Atracurium besylate in water as in step (i) of the above said process of the present invention may be done by dissolving the Atracurium besylate in water or the reaction mass containing Atracurium besylate in water.

Step-(ii): This step comprises adjusting the pH of solution obtained in step (i) below 5, which may be done by using organic acid or inorganic acid or its mixture thereof. In one embodiment, the adjusting the pH of solution obtained in step (i) below 5 as in step (ii) of the above said process of the present invention is done by employing solution of any organic acids, wherein the organic acid is selected from the group comprising acetic acid, benzoic acid, benzene sulfonic acid or its mixtures thereof, preferably benzene sulfonic acid.

Preferably the pH below 5 of solution as in step (ii) of the present invention is between 3 to 4.

Step-(iii): This step comprises the washing the solution obtained in step (ii) with water immiscible solvent or its mixtures thereof. In one embodiment this step (iii) is an optional step. In one embodiment the water immiscible solvent as in step (iii) of the present invention is selected from the group comprising of aromatic hydrocarbon such as toluene and xylene; aliphatic hydrocarbon such as n-pentane, n-hexane, petroleum ether, cyclohexane, and mixtures thereof. In one embodiment said water immiscible solvent in step (iii) is non-polar solvents such as n-hexane, hexane, heptane, n-heptane, and toluene; or polar solvents such as tetrahydrofuran, ethyl acetate tert-butyl methyl ester; or its mixture thereof. In one preferred embodiment water immiscible solvent used in step (iii) is n-hexane. In another preferred embodiment water immiscible solvent used in step (iii) is n-heptane.

Step-(iv): This step comprises purging with nitrogen gas to the solution obtained in step (ii) or step (iii) for 15 minutes to 180 minutes at a temperature between 5°C to 45°C. According to one embodiment, step-(iv) is accomplished with the washed aqueous solution while nitrogen purging is at a temperature of about 5°C to about 45°C for at least 60 minutes, preferably at a temperature of about 30°C to about 35°C for about 60 minutes to about 180 minutes, and more preferably at a temperature of about 20°C to about 25°C for about 60 minutes to about 80 minutes.

Step-(v): This step comprises applying vacuum to the purged solution obtained in step (iv) for 15 minutes to 120 minutes at a temperature between 5°C to 45°C. According to one embodiment, in step-(v) is accomplished with the purged aqueous solution while under vacuum at a temperature of about 25°C to about 45°C for at least 30 minutes, preferably at a temperature of about 30°C to about 40°C for about 30 minutes to about 120 minutes, and more preferably at a temperature of about 30°C to about 35°C for about 30 minutes to about 45 minutes.

In one embodiment the steps (iv) and (v) may be repeated. In one embodiment, preferably the steps (iv) and (v) are repeated for one time or more times such as two times or three times, most preferably repeated the process steps for two times.
In one embodiment, the step (iv) and step (v) are repeated for one time.
In one embodiment, the step (iv) and step (v) are repeated for two times.
In one embodiment, the step (iv) and step (v) are repeated for three times.

Step-(vi): This step comprises the freeze-drying the Atracurium besylate solution obtained in step (v) in a nitrogen atmosphere.

According to one embodiment, in step-(vi) while freeze drying the solution obtained in step (v), the process step is carried out at a temperature of about -10°C to about -78°C, preferably at a temperature of about -40°C to -78°C.

Surprisingly the inventors of the present invention found that the step of purging nitrogen followed by application of vacuum atleast onetime to the pH adjusted solution of Atracurium besylate decreases the content of residual organic solvents in Atracurium besylate. The residual organic solvents such as ethyl acetate, tert-butyl ether, dichloromethane, toluene, tertiary butanol, isopropyl alcohol, acetone, and acetonitrile are generally found in Atracurium besylate. Thus, the process of the present invention increases the quality of the freeze-dried composition of Atracurium besylate.

In one embodiment, the residual organic solvents content in the freeze-dried composition of Atracurium besylate obtained by the process of the present invention is such that dichloromethane content is not more than 600 PPM; tert-butyl methyl ether content is not more than 5000 PPM; ethyl acetate content is not more than 5000 PPM.

In another embodiment, preferably the residual organic solvent content in the freeze-dried composition of Atracurium besylate obtained by the process of the present invention is such that dichloromethane content is not more than 10 PPM; tert-butyl methyl ether content is not more than 20 PPM; ethyl acetate content is not more than 10 PPM.

In one embodiment, most preferably the residual organic solvents content in the freeze-dried composition of Atracurium besylate obtained by the process of the present invention is such that dichloromethane content is not in detectable limit; tert-butyl ether content is not more than 12; and ethyl acetate content is not in detectable limit.

The amount (in PPM) of residual organic solvents such as amount of solvents Dichloromethane, Tert-Butyl methyl ether, Ethyl acetate, and Tert-Butanol as present in the Atracurium besylate before and after the process of the present invention are provided in Table-I.

The process of the present invention may be applied to process for preparing freeze dried composition of cis-atracurium besylate.

Certain specific aspect and embodiment of the present invention will be explained in detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the invention in any manner.

EXAMPLES

Example-1: Preparation of Atracurium besylate from Atracurium oxalate
A solution of Atracurium oxalate (50.0 g) in water (500 ml) was adjusted to a pH of 7-8.5 with 5% aq. sodium bicarbonate solution followed by the addition of toluene (250 ml) to form a biphasic mixture. The organic layer was separated from the biphasic mixture and was concentrated under vacuum at 55oC to obtained residue. To the residue, acetonitrile (75.0 ml), benzyl alcohol (1.0 mL), sodium bicarbonate (0.39 g) and methyl benzene sulfonate (95.0 g) were added and stirred for 23±2°C for 48±2.0 hours. The progress of the reaction was monitored by HPLC. After completion of the reaction, the reaction mass was quenched with chilled water (1250 ml) and the pH was adjusted of the mass to 3.0-4.5 by the addition of 0.1% of aqueous benzenesulfonic acid solution. The reaction mass was then washed with toluene (500 ml). The washed aq. layer was extracted with dichloromethane (150 ml). The organic layer was combined, washed with water (150 ml) and concentrated under vacuum to obtain a residue. The obtained residue was dissolved in acetonitrile (50 ml) and isopropyl alcohol (50 ml) followed by the addition of ethyl acetate (1000 ml). The contents were stirred for 1.5±0.5 hours at 30±5°C. The resulted gummy mass was separated by decanting the solvents from the contents. The gummy mass was then dissolved in dichloromethane (100 ml) to form a solution. The solution was added to methyl tert-butyl ether (1000 ml) at 30±5°C and stirred the mass for 5.5±0.5 hours at 30±5°C. The resultant solid was filtered, washed with methyl tert-butyl ether (50 ml) and dried. % Yield: 70%; Purity by HPLC: 98.62%.

Example-2: Preparation of freeze-dried Atracurium besylate
Atracurium besylate (3.0 g) obtained in example-1 was dissolved in water (90 ml) at 2±3°C to obtain a solution. The pH of the solution was adjusted to 3.5- 4.0 using 0.1% of aqueous solution of benzene sulfonic acid. The aqueous solution washed with n-heptane (9.0 ml) at 22±3°C. Nitrogen gas was purged into the washed aqueous solution for 30±10 minutes at 25±5°C followed by application of vacuum for 30±10 minutes at 25±5°C. Nitrogen purging and vacuum was repeated two more times. The pH of the resultant solution was maintained 3.5-4.0 using 0.1% of aqueous solution of benzene sulfonic acid. The filtrate was freeze dried under vacuum to obtain freeze dried Atracurium besylate. % Yield: 80.0%; Purity by HPLC: 98.54%.

Example-3: Preparation of freeze dried Atracurium besylate
Atracurium besylate (8.0 g) obtained in example-1 was dissolved in water (240 ml) at 2±3°C to obtain a solution. The pH of the solution was adjusted to 3.5- 4.0 using 0.1% of aqueous solution of benzene sulfonic acid. The aqueous solution washed with n-heptane (24 ml) at 22±3°C. Nitrogen gas was purged into the washed aqueous solution for 30±10 minutes at 25±5°C followed by application of vacuum for 30±10 minutes at 25±5°C. Nitrogen gas was again purged into the above solution at 25±5°C for 30±10 minutes followed by application of vacuum for 30±10 minutes at 25±5°C. Nitrogen purging and application of vacuum was repeated one more time for above solution for 30±10 minutes at 25±5°C. The pH of the resultant solution was maintained 3.5-4.0 using 0.1% of aqueous solution of benzene sulfonic acid. The pH adjusted solution was filtered and filtrate was freeze dried under vacuum to obtain freeze dried Atracurium besylate. % Yield: 80.0%; Purity by HPLC: 98.54%.

Example-4: Preparation of freeze dried Atracurium besylate
Atracurium besylate (20 g) obtained in example-1 was dissolved in water (600 ml) at 2±3°C to obtain a solution. The pH of the solution was adjusted to 3.5- 4.0 using 0.1% of aqueous solution of benzene sulfonic acid. The aqueous solution washed with n-heptane (60 ml) at 22±3°C. Nitrogen gas was purged into the washed aqueous solution for 30±10 minutes at 25±5°C followed by application of vacuum for 30±10 minutes at 25±5°C. The pH of the resultant solution was maintained 3.5-4.0 using 0.1% of aqueous solution of benzene sulfonic acid. Then filtered the pH adjusted solution and filtrate was freeze dried under vacuum to obtain freeze dried Atracurium besylate. % Yield: 80.0%; Purity by HPLC: 98.54%.

Table-I: Solvent quantity in Atracurium besylate before the process of the present invention and after the process of the present invention

Solvents Residual Solvent content in Atracurium besylate resulted in Example-1
[before the process of the present invention]
(PPM) Residual Solvent content in Atracurium besylate resulted in Example-2
[after the process of the present invention]
(PPM)
Dichloromethane 12878 0
Tert-Butyl methyl ether 88676 2
Ethyl acetate 28591 0
Tert-Butanol 108 18
,CLAIMS:1. A process for the preparation of freeze-dried composition of Atracurium besylate comprising the steps of:
(i) providing a solution of Atracurium besylate in water;
(ii) adjusting the pH of solution obtained in step (i) below 5;
(iii) optionally, washing the solution obtained in step (ii) with water immiscible solvent or its mixtures thereof;
(iv) purging with nitrogen gas to the solution obtained in step (ii) or step (iii) for 15 minutes to 180 minutes at a temperature between 5°C to 45°C;
(v) applying vacuum to the purged solution obtained in step (iv) for 15 minutes to 120 minutes at a temperature between 5°C to 45°C; and
(vi) freeze-drying the Atracurium besylate solution obtained in step (v) in a nitrogen atmosphere.

2. The process as claimed in claim 1, wherein said pH adjustment in step (ii) is done by using organic acid or inorganic acid or its mixture thereof.

3. The process as claimed in claim 2, wherein said acid is organic acid.

4. The process as claimed in claim 3, wherein said organic acid is benzene sulphonic acid.

5. The process as claimed in claim 1, wherein said step of adjusting the pH of the solution below 5 as in step (ii) is in the pH range between 3 to 4.

6. The process as claimed in claim 1, wherein said water immiscible solvent in step (iii) is non-polar solvents such as n-hexane, hexane, heptane, n-heptane, and toluene; or polar solvents such as tetrahydrofuran, ethyl acetate tert-butyl methyl ester; or its mixture thereof.

7. The process as claimed in claim 6, wherein said water immiscible solvent is n-hexane or n-heptane.

8. The process as claimed in claim 1, wherein the step (iv) and step (v) are repeated one time.

9. The process as claimed in claim 1, wherein the step (iv) and step (v) are repeated two times.

10. The process as claimed in claim 1, wherein the step (iv) and step (v) are repeated three times.

11. The process as claimed in claim 1, wherein the residual organic solvents content in the freeze-dried composition of Atracurium besylate obtained by the process is characterized by:
- dichloromethane content is not more than 600 PPM;
- tert-butyl methyl ether content is not more than 5000 PPM;
- ethyl acetate content is not more than 5000 PPM.

12. The process as claimed in claim 11, wherein the residual organic solvents content in the freeze-dried composition of Atracurium besylate obtained by the process is characterized by:
- dichloromethane content is not more than 10 PPM;
- tert-butyl methyl ester content is not more than 20 PPM;
- ethyl acetate content is not more than 10 PPM.