DESC:RELATED PATENT APPLICATION

This application claims the priority to and benefit of Indian Provisional Patent Application No. 202141044458 filed on September 30, 2021; the disclosure of which are incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to an efficient, simple, cost effective and industrially viable process for the purification of Sugammadex sodium. More particularly, the present invention provides an improved drying process for reducing the residual organic solvents from the solid Sugammadex sodium.

BACKGROUND OF THE INVENTION

Sugammadex sodium, a modified gamma cyclodextrin, is the active ingredient in the USFDA approved drug product BRIDION® and is indicated for the reversal of neuromuscular blockade induced by rocuronium bromide and vecuronium bromide in adults undergoing surgery.

Sugammadex sodium i.e. 6-Per-deoxy-6-per-(2-carboxyethyl)thio-?-cyclodextrin sodium, is an octa substituted ?-cyclodextrin derivative with a lipophilic core and a hydrophilic periphery, and has the following structure.

PCT publication WO 01/40316 discloses 6-mercapto-cyclodextrin derivatives including Sugammadex as useful compounds in the reversal of drug-induced neuromuscular block. This publication discloses a process for preparation of Sugammadex sodium which involves iodination of ?- cyclodextrin in presence of triphenylphosphine (PPh3) and dimethylformamide to obtain 6-per-deoxy-6-per-iodo-?-cyclodextrin as a yellow solid, reacting the iodo-?-cyclodextrin compound with 3-mercaptopropionic acid in presence of sodium hydride and dimethylformamide to obtain 6-Per-deoxy-6-per-(2-carboxyethyl)thio-?-cyclodextrin (Sugammadex), sodium salt as white solid.

Sugammadex is a modified ?-cyclodextrin from its natural state by placing eight carboxyl thio ether groups at the sixth carbon positions which extend the cavity size allowing greater encapsulation of the rocuronium molecule.

A plurality of exposed hydroxyl groups are present in the molecule, hydrogen bonds can be formed with solvent molecules wrapped in the cavity. The conventional methods of drying using atmospheric pressure or under a reduced pressure are difficult to control the residual solvent(s) below the standard limit of ICH for achieving better product quality.

Sugammadex sodium is conveniently prepared by the addition of non-solvent to aqueous solution of Sugammadex solution or by the crystallization of Sugammadex in a mixture of water and an organic solvent. The conventional methods of drying using atmospheric pressure or under a reduced pressure are difficult to control the residual solvent to below the standard limit of ICH for better product quality.

Particularly, the concentration of residual solvents is strictly regulated because of their inherent toxicity according to the International Conference on Harmonisation (ICH) Q3C guidance. The level of residual solvent is varied according to the formulation and the solvent. The class 3 solvents (Ethanol, 1-Propanol, 1-Butanol, Acetone, Ethyl Acetate) are regarded as less toxic and lower risk to human health than class 1 and 2 residual solvents having ICH limit lower than 5000 PPM.

The general methods for drying residual organic solvents may be suitably carried out using equipment such as air tray drier, vacuum tray drier, vacuum oven, air oven, fluidized bed drier, spin flash drier, flash drier, and the like, at atmospheric pressure or under reduced pressure.

Above mentioned methods require high temperature, pressure and prolonged drying which can cause degradation, colour generation and crystal instabilities and other instabilities.

The Patent application JP1025851980 discloses drying method of penicillin-cephalosporins by contacting a low-boiling point organic solvent with water vapor gas flow under reduced pressure to remove low-boiling point organic solvent. The penicillin-cephalosporins are susceptible to adhesion of organic solvents and easily contain organic solvent(s) used during the purification and preparation. These contained organic solvents are difficult to remove by vacuum drying though these have low boiling point. The ability of the penicillin-cephalosporins to absorb water vapour in air is used for drying in this Patent application. This process allows penicillin-cephalosporins to absorb moisture uniformly in a short period without dissolving them.

The Patent US 5981751 discloses a method for removing residual organic solvent molecules from within the crystal structure of a pharmaceutical drug substance, characterised in that the pharmaceutical drug substance is dried in the presence of water vapour, such that residual organic solvent molecules are displaced with water vapour molecules. The method particularly used to remove aliphatic alcohols, for example ethanol or propanol. The method comprises applying a drying process to the substance in the presence of water vapour, whereby (a) substantially all of the residual solvent molecules in the crystal structure are replaced by water vapour molecules; and/or (b) the substance becomes substantially free from residual organic solvent molecules.

The above process disclosed in the Patent US 5981751 was exemplified for Sugammadex sodium in the Patent application publication CN 113004437. The patent application discloses a method of reducing solvent residue in Sugammadex sodium through closed container filled with an aqueous medium, residual solvent in the product is replaced by moisture in the closed environment. This method needs 14 hours of time to balance the humidity level and requires 24 hours for drying.

Besides different processes for the purification of Sugammadex sodium there remains a need of an efficient, simple, and industrially viable process to remove the residual solvent in Sugammadex sodium, for achieving the quality of the product.

OBJECTIVES OF THE INVENTION

The main objective of the present invention is to provide an improved drying process for reducing the residual organic solvents from the solid Sugammadex sodium.

Another objective of the present invention is to provide an efficient, simple, and industrially viable process for the purification of Sugammadex sodium and/or to remove the residual solvent in Sugammadex sodium, for achieving the quality of the product.

Another objective of the present invention is to provide an improved drying process for preparing Sugammadex sodium having residual organic solvent less than 4000 ppm.

SUMMARY OF THE INVENTION

The main aspect of the present invention is to provide an improved drying process for preparing Sugammadex sodium having residual organic solvent less than 4000 ppm comprising the steps of:
(i) placing solid Sugammadex sodium and water in an apparatus separately;
(ii) applying vacuum between 450-550 mm of Hg to the placed Sugammadex sodium in the apparatus at a temperature 25°C to 60°C for 1 to 4 hours;
(iii) holding the vacuum in the apparatus at a temperature of 25°C to 60°C for 2 to 8 hours;
(iv) repeating the steps from step (ii) to step (iii) at least once;
(v) releasing the vacuum slowly using nitrogen; and
(vi) drying the solid Sugammadex sodium under vacuum at a temperature of 70°C to 75°C for 10 to 20 hours.

The above process, wherein the apparatus is selected from vacuum dryer, vacuum desiccator, or vacuum oven. In one embodiment in the above process, the apparatus is vacuum dryer.

The above process, wherein the ratio of water and Sugammadex sodium in step (i) is about 0.5 ml to 4 ml for 1 gm of Sugammadex sodium.

In one embodiment in the above process, the ratio of water and Sugammadex sodium in step (i) is about 2 ml for 1 gm of Sugammadex sodium.

The above process, wherein the process of applying vacuum in the apparatus in step (ii), is carried out at a temperature ranging between 25°C to 60°C for 1 to 4 hours.

In one embodiment in the above process, the process of applying vacuum in the apparatus in step (ii), is carried out at a temperature ranging between 45°C to 50°C for 3 hours.

The above process, wherein the process of repeating the steps from step (ii) to step (iii) in step (iv) is carried out at least 2 times.

The above process, wherein the process of drying the solid Sugammadex sodium in step (vi) is carried out at a temperature of 70°C to 75°C for 10 to 20 hours.

In one embodiment in the above process, the process of drying the solid Sugammadex in step (vi) is carried out for 10 to 15 hours.

In one embodiment in the above process, the process of drying the solid Sugammadex in step (vi) is carried out for 10 hours.

The above process, wherein the residual organic solvents in Sugammadex sodium may be alcohols such as ethanol, methanol; esters such as ethyl acetate; amide such as dimethyl formamide; nitriles such as acetonitrile; ketones such as acetate or mixtures thereof.

In one embodiment in the above process, the residual organic solvent in Sugammadex sodium is less than about 4000 ppm.

In one embodiment in the above process, the residual organic solvent in Sugammadex sodium is less than about 2000 ppm.

In one embodiment in the above process, the residual ethanol solvent is less than about 4000 ppm.

In one embodiment in the above process, the residual ethanol solvent is less than about 2000 ppm.

DETAILED DESCRIPTION OF THE INVENTION

Accordingly, in one aspect the present invention discloses and provides an improved drying process for reducing the residual organic solvents from the solid Sugammadex sodium.

One embodiment of the present invention is to provide an improved drying process for preparing Sugammadex sodium having residual organic solvent less than 4000 ppm comprising the steps of:

(i) placing solid Sugammadex sodium and water in an apparatus separately;
(ii) applying vacuum between 450-550 mm of Hg to the placed Sugammadex sodium in the apparatus at a temperature 25°C to 60°C for 1 to 4 hours;
(iii) holding the vacuum in the apparatus at a temperature of 25°C to 60°C for 2 to 8 hours;
(iv) repeating the steps from step (ii) to step (iii) at least once;
(v) releasing the vacuum slowly using nitrogen; and
(vi) drying the solid Sugammadex sodium under vacuum at a temperature of 70°C to 75°C for 10 to 20 hours.

The providing of Sugammadex sodium and water separately in the apparatus according to the step (i) of the present invention is suitable for applying vacuum, preferably the water in the apparatus may be in the range of 0.5 ml to 4 ml for 1 gm of Sugammadex sodium; preferably, 1 ml for 1 gm of Sugammadex sodium and more preferably, 2 ml for 1 gm of Sugammadex sodium.

The step of applying vacuum to the placed Sugammadex sodium according to the step (ii) of the present invention is done at a vacuum 450-550 mm of Hg for 1 to 8 hours, preferably 1 to 4 hours at a temperature of 25°C to 60°C, preferably at 45°C to 50°C for 3 hours.

The step of maintaining or holding the vacuum according to the step (iii) of the present invention is done at a temperature of 25°C to 60°C for 2 to 8 hours, preferably at 45°C to 50°C for 3 hours.

Repeating the steps from step (ii) to step (iii) according to the step (iv) of the present invention is done for at least once, preferably repeating the steps till the residual organic solvent content in the sample is less than 4000 ppm. In one embodiment the process of repeating the steps from step (ii) to step (iii) in step (iv) is carried out at least 2 times.

Preferably the drying of the solid Sugammadex sodium under vacuum according to the step (vi) of the present invention may be done in tray drier.

The step of drying of solid Sugammadex sodium according to the step (vi) of the present invention may be carried out at a temperature of 70 °C to 75 °C for 10 to 20 hours, preferably for 10 to 15 hours, more preferably for 10 hours.

The residual organic solvents in Sugammadex sodium may be alcohols such as ethanol, methanol; esters such as ethyl acetate; amide such as dimethyl formamide; nitriles such as acetonitrile; ketones such as acetate or mixtures thereof.

The residual organic solvents in Sugammadex sodium are displaced with water molecules, when applying and holding the vacuum to solid Sugammadex sodium in an apparatus containing water as disclosed in the Patent US 5981751. The drying of Sugammadex sodium after displacing the residual organic solvents with water molecules results in Sugammadex sodium that is substantially free of residual organic solvent(s).

The present inventors observed that the drying of Sugammadex sodium requires more than 20 hours under vacuum at 70 to 75? to achieve Sugammadex sodium that is substantially free of residual organic solvent(s). Drying the Sugammadex sodium for long time causes degradation of Sugammadex sodium and is time consuming.

Surprisingly, the inventors of the present invention have found that repeating the steps of applying and holding the vacuum with solid Sugammadex sodium in an apparatus containing water atleast once effectively reduces the drying time under vacuum at 70 to 75? to achieve Sugammadex sodium that is substantially free of residual organic solvent(s).

The inventors of the present invention have found that the Sugammadex sodium, resulted by repeating the steps of applying and holding the vacuum with solid Sugammadex sodium in an apparatus containing water atleast once, requires less than 20 hours under vacuum at a temperature of 70? to 75?.

The sodium content in Sugammadex sodium according to the present invention is in a range of about 7% w/w to about 9% w/w, or about 7.5% w/w to about 8.5% w/w, or about 7.8% w/w to about 8.2% w/w.

Drying may be suitably carried out using equipment such as air tray drier, vacuum tray drier, vacuum oven, air oven, fluidized bed drier, spin flash drier, flash drier, vacuum desiccator, and the like, under reduced pressure.

The dried product may optionally be subjected to a particle size reduction technique to obtain desired particle sizes and distributions.

Milling or micronization may be performed before drying, or after the completion of drying of the product. Techniques that may be used for particle size reduction include, without limitation sifting; milling using mills, such as, for example, ball, roller, or hammer mills, or jet mills, including, for example, air jet mills; or any other conventional technique.

The starting material of the present invention is crude or pure Sugammadex sodium obtained by any method known in the prior arts.

Sugammadex sodium may conveniently be prepared in a desired solid-state form using techniques known in the art, preferably obtained by the addition of non-solvent to aqueous solution of Sugammadex solution or by the crystallization of Sugammadex in a mixture of water and an organic solvent. The organic solvent is selected from the group comprises of alcohols such as ethanol, methanol; esters such as ethyl acetate; amide such as dimethyl formamide; nitriles such as acetonitrile; ketones such as acetate or mixtures thereof.

The starting material for preparing a desired polymorphic form include crystalline forms, amorphous, or mixtures of amorphous and crystalline forms of Sugammadex in any proportions, obtained by any method in the state of art.

Sugammadex sodium having residual organic solvent content less than 4000 ppm, preferably less than 2000 ppm is obtained by the process of the present invention.

Sugammadex sodium having ethanol content less than 4000 ppm, preferably less than 2000 ppm is obtained by the process of the present invention.

Certain specific aspects and embodiments of the present invention will be better understood in connection with the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner.

EXAMPLES

Example 1: Purification process of Sugammadex sodium
Sugammadex sodium (50 gm) in tray drier with uniform sample surface thickness was placed in a vacuum drier along with water (200 ml) placed below the tray drier containing Sugammadex sodium and closed. (a) a vacuum between 450-550 mm of Hg was applied inside the vacuum drier at a temperature of 25°C to 30°C for 1 hour; (b) after one hour of the application, vacuum was stopped and maintained the contents in the vacuum drier under holding vacuum at a temperature of 25°C to 30°C for 5 hours with water exposure; (c) after 5 hours of maintenance, vacuum was slowly released using nitrogen.

The step (a) to step (c) of drying cycle was then repeated for 2 times with the fresh top up water placed in the drier. The water apparatus was removed from the drier and the resultant solid was dried in tray drier under vacuum at 70°C to 75°C for 10 hours; cooled under vacuum for 45 minutes; released the vacuum under nitrogen; and packed the solid in polybag kept in nitrogen atmosphere. Yield: 96.25 %; Ethanol content by GC-HS: 184.7 ppm.

Example 2: Purification process of Sugammadex sodium
Sugammadex sodium (30 gm) in tray drier with uniform sample surface thickness was placed in a vacuum drier along with water (120 ml) placed below the tray drier containing Sugammadex sodium closed. (a) a vacuum between 450-550 mm of Hg was applied inside the vacuum drier at a temperature of 25°C to 30°C for 1 hour; (b) after one hour of the application, vacuum was stopped and maintained the contents in the vacuum drier under holding vacuum at a temperature of 25°C to 30°C for 6 hours with water exposure; (c) after 6 hours of maintenance, vacuum was slowly released using nitrogen.

The step (a) to step (c) of drying cycle was then repeated for 2 times with the fresh top up water placed in the drier. The water apparatus was removed from the drier and the resultant solid was dried in tray drier under vacuum at 70°C to 75°C for 10 hours; cooled under vacuum for 45 minutes; released the vacuum under nitrogen; and packed the solid in polybag kept in nitrogen atmosphere. Yield: 96.4 %; Ethanol content by GC-HS: 52.3 ppm.

Example 3: Purification process of Sugammadex sodium
Sugammadex sodium (10 gm) in tray drier with uniform sample surface thickness was placed in a vacuum drier along with water (20 ml) placed below the tray drier containing Sugammadex sodium within the vacuum drier and closed. (a) a vacuum between 450-550mm of Hg was applied inside the vacuum drier at a temperature of 25°C to 30°C for 1 hour; (b) after one hour of the application, vacuum was stopped and maintained the contents in the vacuum drier under holding vacuum at a temperature of 25°C to 30°C for 3 hours with water exposure; (c) after 3 hours of maintenance vacuum was slowly released using nitrogen.

The step (a) to step (c) of drying cycle was then repeated for once with the fresh top up water placed in the drier. The water apparatus was removed from the drier and the resultant solid was dried in tray drier under vacuum at 70°C to 75°C for 10 hours; cooled under vacuum for 45 minutes; released the vacuum; and packed the solid in polybag kept in nitrogen atmosphere. Yield: 98.0 %; Ethanol content by GC-HS: 476 ppm.

Example 4: Purification process of Sugammadex sodium
Sugammadex sodium (100 gm) in tray drier with uniform sample surface thickness was placed in a vacuum drier along with water (200 ml) placed below the tray drier containing Sugammadex sodium within the vacuum drier and closed. (a) a vacuum between 450-550mm of Hg was applied inside the vacuum drier at a temperature of above 45°C to 50°C for 3 hours; (b) after 3 hours of the application, vacuum was stopped and maintained the contents in the vacuum drier under holding vacuum at a temperature of above 45°C to 50°C for 3 hours with water exposure; (c) after 3 hours of maintenance vacuum was slowly released using nitrogen.

The step (a) to step (c) of drying cycle was repeated with the same water apparatus till the sample achieves ethanol content of less than 4000 ppm. The water apparatus was removed from the drier and the resultant solid was dried in tray drier under vacuum at 70°C to 75°C for 10 hours; cooled under vacuum for 45 minutes; released the vacuum; and packed the solid in polybag kept in argon atmosphere. Yield: 96.3 %; Ethanol content by GC-HS: 1762 ppm.

Example 5: Purification process of Sugammadex sodium
Sugammadex sodium (1 kg) in tray drier with uniform sample surface thickness was placed in a vacuum drier along with water (2000 ml) placed below the tray drier containing Sugammadex sodium within the vacuum drier and closed. (a) a vacuum between 450-550mm of Hg was applied inside the vacuum drier at a temperature of above 45°C to 50°C for 3 hours; (b) after 3 hours of the application, vacuum was stopped and maintained the contents in the vacuum drier under holding vacuum at a temperature of above 45°C to 50°C for 3 hours with water exposure; (c) after 3 hours of maintenance, vacuum was slowly released using nitrogen.

The step (a) to step (c) of drying cycle was repeated with the fresh top up water placed in the drier till the sample achieves ethanol content of less than 4000 ppm. The water apparatus was removed from the drier and the resultant solid was dried in tray drier under vacuum at 70°C to 75°C for 10 hours; cooled under vacuum for 45 minutes; released the vacuum; and packed the solid in polybag kept in argon atmosphere. Yield: 87 %; Ethanol content by GC-HS: 1272 ppm.

Comparative Example 1: Purification process of Sugammadex sodium
Sugammadex sodium (50 gm) in tray drier with uniform sample surface thickness was placed in a vacuum drier along with water (200 ml) placed below the tray drier containing Sugammadex sodium within the vacuum drier and closed. (a) a vacuum between 450-550 mm of Hg was applied inside the vacuum drier at a temperature of 25°C to 30°C for 1 hour; (b) after one hour of the application, vacuum was stopped and maintained the contents in the vacuum drier under holding vacuum at a temperature of 25°C to 30°C for 5 hours with water exposure; (c) after 5 hours of maintenance, vacuum was slowly released using nitrogen. The water apparatus was removed from the drier and the resultant solid was dried in tray drier under vacuum at 70°C to 75°C for 10 hours; cooled under vacuum for 45 minutes; released the vacuum under nitrogen; and packed the solid in polybag kept in nitrogen atmosphere. This process comprises the completion of one cycle of drying. Yield: 96.6 %; Ethanol content by GC-HS: 9460 ppm.

Comparative Example 2: Purification process of Sugammadex sodium
Sugammadex sodium (30 gm) in tray drier with uniform sample surface thickness was placed in a vacuum drier along with water (120 ml) placed below the tray drier containing Sugammadex sodium within the vacuum drier and closed. (a) a vacuum between 450-550 mm of Hg was applied inside the vacuum drier at a temperature of 25°C to 30°C for 1 hour; (b) after one hour of the application, vacuum was stopped and maintained the contents in the drier under holding vacuum at a temperature of 25°C to 30°C for 6 hours with water exposure; (c) after 6 hours of maintenance, vacuum was slowly released using nitrogen.

The water apparatus was removed from the drier and the resultant solid was dried in tray drier under vacuum at 70°C to 75°C for 10 hours; cooled under vacuum for 45 minutes; released the vacuum under nitrogen; and packed the solid in polybag kept in nitrogen atmosphere. This process comprises the completion of one cycle of drying. Yield: 96.33 %; Ethanol content by GC-HS: 7500 ppm.

Table containing experimental data on drying process of Sugammadex sodium:
Examples Experimental procedures performed before drying under vacuum at a temperature of 70? to 75? Drying time under vacuum at a temperature of 70? to 75? (in hours) Residual ethanol content by GC-HS in PPM in the Sugammadex sodium before the experiment (in ppm) Amount of Sugammadex sodium for the experiment (g) Yield of the experiment (g) Residual ethanol content by GC-HS in PPM in the Sugammadex sodium after the experiment
(in PPM)
Example-1 Applying vacuum for 1 hour and holding the vacuum for 5 hours with solid Sugammadex sodium in an apparatus containing water and repeating the operation for once. 10 35219 50 38.5 184.7
Example-2 Applying vacuum for 1 hour and holding the vacuum for 6 hours with solid Sugammadex sodium in an apparatus containing water and repeating the operation for once 10 35219 30 19.28 52.3
Example-3 Applying vacuum for 1 hour and holding the vacuum for 3 hours with solid Sugammadex sodium in an apparatus and repeating the operation for once. 10 35219 10 9.8 476
Example-4 Applying vacuum for 3 hour and holding the vacuum for 3 hours with solid Sugammadex sodium in an apparatus containing water and repeating the operation till the sample achieves ethanol content of less than 4000 ppm 10 43148 100 96.3 1762
Example-5 Applying vacuum for 3 hour and holding the vacuum for 3 hours with solid Sugammadex sodium in an apparatus containing water and repeating the operation till the sample achieves ethanol content of less than 4000 ppm 10 43148 1000 870 1272
Comparative Example-1 Applying vacuum for 1 hour and maintaining the vacuum for 5 hours to solid Sugammadex sodium in an apparatus containing water. 10 35219 50 48.3 9460
Comparative Example-2 Applying vacuum for 1 hour and maintaining the vacuum for 6 hours to solid Sugammadex sodium in an apparatus containing water. 10 35219 30 28.9 7500 ,CLAIMS:1. A drying process for preparing Sugammadex sodium having residual organic solvent less than 4000 ppm comprising the steps of:

(i) placing solid Sugammadex sodium and water in an apparatus separately;
(ii) applying vacuum between 450-550 mm of Hg to the placed Sugammadex sodium in the apparatus at a temperature 25°C to 60°C for 1 to 4 hours;
(iii) holding the vacuum in the apparatus at a temperature of 25°C to 60°C for 2 to 8 hours;
(iv) repeating the steps from step (ii) to step (iii) at least once;
(v) releasing the vacuum slowly using nitrogen; and
(vi) drying the solid Sugammadex sodium under vacuum at a temperature of 70°C to 75°C for 10 to 20 hours.

2. The process as claimed in claim 1, wherein the apparatus is selected from vacuum dryer, vacuum desiccator, or vacuum oven.

3. The process as claimed in claim 2, wherein the apparatus is vacuum dryer.

4. The process as claimed in claim 1, wherein the ratio of water and Sugammadex sodium in step (i) is about 0.5 ml to 4 ml for 1 gm of Sugammadex sodium.

5. The process as claimed in claim 4, wherein the ratio of water and Sugammadex sodium in step (i) is about 2 ml for 1 gm of Sugammadex sodium.

6. The process as claimed in claim 1, wherein the process of applying vacuum in the apparatus in step (ii), is carried out at a temperature ranging between 45°C to 50°C for 3 hours.

7. The process as claimed in claim 1, wherein the process of repeating the steps from step (ii) to step (iii) in step (iv) is carried out at least 2 times.

8. The process as claimed in claim 1, wherein the process of drying the solid Sugammadex in step (vi) is carried out for 10 to 15 hours.

9. The process as claimed in claim 1, wherein the process of drying the solid Sugammadex in step (vi) is carried out for 10 hours.

10. The process as claimed in claim 1, wherein the residual organic solvents in Sugammadex sodium may be alcohols, esters, amide, nitriles, ketones, or mixtures thereof.

11. The process as claimed in claim 1, wherein the residual organic solvent in Sugammadex sodium is less than about 4000 ppm.

12. The process as claimed in claim 11, wherein the residual organic solvent in Sugammadex sodium is less than about 2000 ppm.

13. The process as claimed in claim 11, wherein the residual ethanol solvents is less than about 4000 ppm.

14. The process as claimed in claim 11, wherein the residual ethanol solvents is less than about 2000 ppm.