DESC:RELATED PATENT APPLICATION(S):

This application claims the priority to and benefit of Indian Patent Application No. 202141030967 filed on July 09, 2021; the disclosures 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 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, penta-methylene 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.

Freeze-drying is particularly done in pharmaceutical substances that are sensitive to heat since other techniques of drying the does not provide desirable results as they result in decomposition or degradation of the substances. The freeze-drying technique comprises two types of drying, primary and secondary. Primary drying involves the removal of unfrozen liquids by applying vacuum pressures and secondary drying involves the sublimation of the frozen liquid components by applying vacuum pressures.

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.

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).

Atracurium besylate undergoes ester hydrolysis in acid conditions; Hoffmann elimination in basic conditions; and non-enzymic decomposition in physiological conditions. Hence Atracurium besylate is stored at temperatures below 8°C in a pH of 3 to 4.
The Publication Journal of Chromatography 1988, 435, pages 425-433 disclose potential impurities of Atracurium besylate are 2,2’-(3,11-dioxo-4,10-dioxotridecamethylene)bis(1,2,3,4-tetrahydropapaverinium) and 2-methyl-2,2’-(3,11-dioxo-4,10-dioxotridecamethylene)bis(1,2,3,4-tetrahydropapaverinium) as mentioned below.

This Publication Journal of Chromatography 1988, 435, pages 425-433 also disclose other impurities as mentioned below.

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. Laudanosine is major degradation product of Atracurium besylate.

Hence many of the processes for the preparation of Atracurium besylate disclose the use of any pharmaceutical acceptable excipient during the freeze-drying process to have desirable effect.

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. The freeze-drying process as in the Patent application involves the rapid cooling of the solution of Atracurium besylate to a temperature range of -20°C to -30°C; primary drying for 20 hours by applying a vacuum of 0.700 mbar in a temperature range of -30°C to 0°C and then secondary drying up to 10°C under reduced pressure.

Therefore, there remains a need for a simple commercially viable process to prepare a freeze-dried composition of Atracurium besylate without co-solvents or any pharmaceutical acceptable excipients.

OBJECTS OF THE INVENTION:

The primary object of the present invention is to provide an efficient and commercially viable process for the preparation of Atracurium besylate.

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

Yet another object of the invention is to provide an improved process for the preparation of freeze-dried composition of Atracurium besylate without co-solvents or any pharmaceutical acceptable excipients.

SUMMARY OF THE INVENTION:

The present invention discloses an improved process for the preparation of Atracurium besylate, particularly freeze-dried composition of Atracurium besylate without use of any co-solvents or any pharmaceutical acceptable excipients.

The main aspect 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 an aqueous solution of Atracurium besylate in a freeze-drying apparatus at about 5 ± 5°C;
(ii) decreasing the temperature in the freeze-drying apparatus from 5 ± 5°C to -45 ± 5°C;
(iii) primary drying the aqueous solution of Atracurium besylate in freeze-drying apparatus at a temperature of -45 ± 5°C under reduced pressure;
(iv) increasing the temperature in the freeze-drying apparatus gradually from -45 ± 5°C to 20 ± 5°C under reduced pressure;
(v) secondary drying the aqueous solution of Atracurium besylate in freeze-drying apparatus at a temperature of 20 ± 5°C under reduced pressure; and
(vi) storing the resulted freeze-dried composition of Atracurium besylate at 5°C in nitrogen atmosphere.

The aqueous solution of Atracurium besylate of step (i) of the said process is obtained either by dissolving Atracurium besylate in water or by result of process for preparing Atracurium besylate.

The aqueous solution of Atracurium besylate of step (i) of the said process is in a concentration in the range of 3-4 mg/ml.

The pH of the aqueous solution of Atracurium besylate of step (i) of the said process is adjusted between 3.5-4.0.

The pH of the aqueous solution of Atracurium besylate is adjusted with 0.1% aqueous benzene sulfonic acid solution.

The aqueous solution of Atracurium besylate of step (i) of the said process is filtered through a 0.2-micron filter.

The reduced pressure in the said process is in the range of 10mTorr to 250mTorr.

The step (iii) of primary drying the aqueous solution of Atracurium besylate in freeze-drying apparatus is carried out under reduced pressure of about 125mTorr.

The step (v) of secondary drying the aqueous solution of Atracurium besylate in freeze-drying apparatus is carried out under reduced pressure of about 75mTorr.

In the present process for the preparation of freeze-dried composition of Atracurium besylate the temperature is changed gradually step by step.

DETAILED DESCRIPTION OF THE INVENTION:

Accordingly, in one aspect the present invention discloses and describes an improved process for the preparation of Atracurium besylate, particularly freeze-dried composition of Atracurium besylate without the use of any co-solvents or any pharmaceutical acceptable excipients.

The freeze-dried Atracurium besylate composition obtained from the process of the present invention contains Atracurium besylate only, without any solvents or any pharmaceutical acceptable ingredients.

A process for the preparation of freeze-dried composition of Atracurium besylate comprising the steps of:
(i) providing an aqueous solution of Atracurium besylate in a freeze-drying apparatus at about 5 ± 5°C;
(ii) decreasing the temperature in the freeze-drying apparatus from 5 ± 5°C to -45 ± 5°C;
(iii) primary drying the aqueous solution of Atracurium besylate in freeze-drying apparatus at a temperature of -45 ± 5°C under reduced pressure;
(iv) increasing the temperature in the freeze-drying apparatus gradually from -45 ± 5°C to 20 ± 5°C under reduced pressure;
(v) secondary drying the aqueous solution of Atracurium besylate in freeze-drying apparatus at a temperature of 20 ± 5°C under reduced pressure; and
(vi) storing the resulted freeze-dried composition of Atracurium besylate at 5°C in nitrogen atmosphere.
The aqueous solution of Atracurium besylate according to the step (i) of the present invention is obtained either by dissolving Atracurium besylate in water or by result of process for preparing Atracurium besylate.

The aqueous solution of Atracurium besylate of step (i) of the present process is in a concentration in the range of 3-4 mg/ml.

Before subjecting the aqueous solution of Atracurium besylate to freeze drying process the pH of the solution is adjusted upto 4 ± 0.1, preferably the pH of the solution is adjusted between 3.5-4.0.

The step of adjusting the pH of aqueous solution of Atracurium besylate is preferably done with 0.1% aqueous benzene sulfonic acid solution.

The aqueous solution of Atracurium besylate of step (i) of the present process is filtered through a 0.2-micron filter.

The reduced pressure in the said process is in the range of 10mTorr to 250mTorr.

Preferably, the step of primary drying the aqueous solution of Atracurium besylate in freeze-drying apparatus according to the step (iii) may be carried out under reduced pressure of about 125mTorr.

Preferably, the step of secondary drying the aqueous solution of Atracurium besylate in freeze-drying apparatus at a temperature of 20±5°C according to the step (v) may be carried out under reduced pressure of about 75mTorr.

Surprisingly the inventors of the present invention found that the present process involving (i) the primary drying at -45 ± 5°C under reduced pressure; (ii) secondary drying at a temperature of 20 ± 5°C under reduced pressure and (iii) changing the temperature gradually that is step by step is effectively used for the freeze-drying Atracurium besylate compositions without degradation or decomposition of Atracurium besylate.

The freeze-dried Atracurium besylate composition resulted in the present invention contains Atracurium besylate only, without pharmaceutical acceptable ingredients.

The inventors were able to achieve the freeze-dried Atracurium besylate composition without the use of co-solvents as disclosed in the patent application IN 1599/MUM/2013 or other pharmaceutical acceptable excipients as disclosed in Patent CN 100531734 and Patent application IN 1641/MUM/2014.

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

EXAMPLE

Example-1: Preparation of freeze-dried Atracurium besylate

An aqueous solution of Atracurium besylate solution in a concentration in the range of 3.33 mg/ml at a pH of 3.5-4.0 was filtered through a 0.2-micron filter. The filtered Atracurium besylate solution was poured in a tray and was placed onto a freeze-drying tray, which was then introduced into a freeze-drying chamber at a temperature of 5°C. The temperature of the chamber was gradually decreased to -45°C. When the temperature of chamber reaches to -45°C, the vacuum pump is turned on and the pressure in vacuum gauge is adjusted to 125mTorr. The product in the tray dried for 3 hours 30 minutes at -45°C and at a pressure of 125mTorr; 4 hours at -30°C and at a pressure of 125mTorr; 7 hours at -15°C and at a pressure of 125mTorr; and 6 hours 30 minutes at -5°C and at a pressure of 125mTorr; and 8 hours at 0°C at 125mTorr successively. After completion of this gradual drying, the temperature of chamber was gradually increased to 20°C, for secondary drying for 5 hours at 20°C at 75mTorr; and 4 hours at 25°C at 75mTorr successively. The freeze-dried product was then stored at 5°C at 75mTorr. Yield: 7 gm; Purity: 98.7 %; Total impurities 1.35 % w/w.
,CLAIMS:1. A process for the preparation of freeze-dried composition of Atracurium besylate comprising the steps of:
(i) providing an aqueous solution of Atracurium besylate in a freeze-drying apparatus at about 5 ± 5°C;
(ii) decreasing the temperature in the freeze-drying apparatus from 5 ± 5°C to -45 ± 5°C;
(iii) primary drying the aqueous solution of Atracurium besylate in freeze-drying apparatus at a temperature of -45 ± 5°C under reduced pressure;
(iv) increasing the temperature in the freeze-drying apparatus gradually from -45 ± 5°C to 20 ± 5°C under reduced pressure;
(v) secondary drying the aqueous solution of Atracurium besylate in freeze-drying apparatus at a temperature of 20 ± 5°C under reduced pressure; and
(vi) storing the resulted freeze-dried composition of Atracurium besylate at 5°C in nitrogen atmosphere.

2. The process as claimed in claim 1, wherein the aqueous solution of Atracurium besylate of step (i) is obtained either by dissolving Atracurium besylate in water or by result of process for preparing Atracurium besylate.

3. The process as claimed in claim 1, wherein the aqueous solution of Atracurium besylate of step (i) is in a concentration in the range of 3-4 mg/ml.

4. The process as claimed in claim 1, wherein the pH of the aqueous solution of Atracurium besylate of step (i) is adjusted between 3.5-4.0.

5. The process as claimed in claim 4, wherein the pH of the aqueous solution of Atracurium besylate is adjusted with 0.1% aqueous benzene sulfonic acid solution.
6. The process as claimed in claim 1, wherein the aqueous solution of Atracurium besylate of step (i) is filtered through a 0.2-micron filter.

7. The process as claimed in claim 1, wherein the said reduced pressure is in the range of 10mTorr to 250mTorr.

8. The process as claimed in claim 1, wherein the step (iii) of primary drying the aqueous solution of Atracurium besylate in freeze-drying apparatus is carried out under reduced pressure of about 125mTorr.

9. The process as claimed in claim 1, wherein the step (v) of secondary drying the aqueous solution of Atracurium besylate in freeze-drying apparatus is carried out under reduced pressure of about 75mTorr.

10. The process as claimed in claim 1, wherein the temperature is changed gradually step by step.