DESC:FORM 2

THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003

COMPLETE SPECIFICATION
(Section 10 and Rule 13)

AN IMPROVED PROCESS FOR THE PURIFICATION OF
L-GLUTAMINE

AUROBINDO PHARMA LTD HAVING CORPORATE OFFICE AT
THE WATER MARK BUILDING,
PLOT NO.11, SURVEY NO.9,
HITECH CITY, KONDAPUR,
HYDERABAD, 500 084,
TELANGANA, INDIA
AN INDIAN ORGANIZATION

The following specification particularly describes and ascertains the nature of this invention and the manner in which the same is to be performed.
FIELD OF INVENTION

The present invention related to a process for the purification of L-Glutamine of Formula I having specific bulk density and Hausner ratio.

Formula I
BACKGROUND OF THE INVENTION

L-Glutamine (I) is chemically known as L-glutamic acid-5-amide. L-Glutamine (I) is an amino acid indicated to reduce the acute complications of sickle cell disease in adult and pediatric patients. L-Glutamine (I) is being marketed in the US under the brand name Endari®.

Glutamine occurs in white crystals or crystalline powder. L-Glutamine (I) crystallizes from methanol and water and melting point is at 186º to 189ºC.

Solvent medium and mode of crystallization play very important role to get a pure form of the compound. There are prior-art procedures reported for the crystallization of L-Glutamine (I).

Acta Crystallographica (1952), 5, 644-53 reported single crystalline data of L-Glutamine (I) and its recrystallization from water at a temperature between 0 and 5°C.

US 2,762,841 discloses a purification process of L-Glutamine (I), wherein crude L-Glutamine (I) purified from acetone and water by recrystallization. The purity of L-Glutamine by HPLC maximum achieved to 96% with this recrystallisation.

US 3,105,852 discloses crystallization of L-Glutamine (I) from methanol and water.

The above two crystallization processes disclosed in US ‘852 and US ‘841 are capable to produce L-Glutamine (I) crystals with bulk density below 0.25 g/mL.

JP 04257551 discloses a purification of L-Glutamine, wherein crude L-Glutamine is dissolved in water, the pH was adjusted to 5.5 with dilute aqueous ammonia, followed by addition of carbon/seed crystal of L-Glutamine and addition of methanol to produce pure L-Glutamine.

DE1124044 discloses purification of L-glutamine from warm water and precipitated by adding ethanol to produce pure L-Glutamine.

The above purification processes disclosed in above prior-art processes is capable to produce L-Glutamine (I) crystals with bulk density below 0.25 g/mL. L-Glutamine (I) obtained by above processes has uneven particle size distribution and low density of crystalline products resulting in the difficulty of separation of L-glutamine crystals from a liquid, granulation and constant volume packaging is difficult. The crystallization process in the production process is a key step that restricts product quality.

Hence, there is a need for an improved process for the purification of L-Glutamine with spherical agglomerated crystals having specific bulk density, Hausner ratio with high purity and yield.

The advantage of the present invention is to produce L-Glutamine (I) with spherical agglomerated crystals having specific bulk density and Hausner ratio, with improved flow properties

OBJECTIVE OF INVENTION

The main objective of the present invention is to provide a simple and cost effective process for the purification of L-Glutamine (I), which is industrially viable.

SUMMARY OF THE INVENTION

The main embodiment of the present invention is to provide a process for the purification of L-Glutamine (I);

Formula I
with spherical agglomerated crystals having bulk density 0.43-0.47 and Hausner ratio between 1.19-1.25, which comprises:
(i) dissolving L-Glutamine (I) in a first solvent;
(ii) heating the reaction mass at a suitable temperature;
(iii) adjusting pH by adding a base to step (ii);
(iv) adding a second solvent; and
(v) isolating pure L-Glutamine (I) with spherical agglomerated crystals.

Another embodiment of the present invention is to provide L-Glutamine (I) with spherical agglomerated crystals having bulk density 0.43-0.47 and Hausner ratio between 1.19-1.25.

Still another embodiment of the present invention provides a pharmaceutical composition comprising, (L)-Glutamine (I) prepared by the above process and one of more pharmaceutical excipient(s) thereof.

DETAILED DESCRIPTION OF THE INVENTION

The main embodiment of the present invention to provide a process for the purification of L-Glutamine (I) with spherical agglomerated crystals having bulk density 0.43-0.47 and Hausner ratio between 1.19-1.25.

Spherical crystallization is defined as an agglomeration process that transforms crystals directly into compact spherical forms during the crystallization. It also enables co-precipitation of drug and encapsulating particle size enlargement in the form of spherical particle. Spherical crystallization is an effective alternative to improve the dissolution rate of drugs. This can be achieved by various methods such as spherical agglomeration, quasi-emulsion solvent diffusion, Ammonia water method, Crystallo-co agglomeration and neutralization method. Agglomerates exhibit improved secondary characteristics, like flowability and compressibility, so that direct tableting or coating is possible without further processing (mixing, agglomerates, sieving, etc.).

The main purpose of this work was to improve the flowability property by Crystallo-co agglomeration technique.

Crystallo-co-agglomeration (CCA) technique involves simultaneous crystallization and agglomeration of drug from the suitable solvent and addition of an anti-solvent.

Spherical agglomeration is a process of formation of aggregates of crystals held together by liquid bridges. The agglomerates are formed by agitating the crystals in a liquid suspension and properties of the particles designed vary significantly as compared to the fine crystalline material. These agglomerates are found to have good flowability and compressibility. This technique can also be exploited to increase solubility, dissolution and hence bioavailability of poorly soluble drugs.

The process of the present invention comprises, L-Glutamine (I) is dissolved in a first solvent, the reaction mass is heated at a suitable temperature followed by adjusting pH by adding a base and a second solvent; then pure L-Glutamine (I) is isolated with spherical agglomerated crystals having bulk density 0.43-0.47 and Hausner ratio between 1.19-1.25.
.
The first solvent comprises water or an alcohol selected from C1-C3 straight or branched chain alcohol such as methanol, ethanol, n-propanol and isopropyl alcohol. The second solvent comprises an ether selected from tetrahydrofuran, dioxane, diisopropylether, diethylether, 2-methyltetrahydrofuran, cyclopentyl methyl ether, methyl tert-butyl ether, diglyme or monoglyme; an alcohol selected from C1-C10 straight or branched chain alcohol such as methanol, ethanol, isopropyl alcohol, 1-butanol, 2-butanol, 2-methyl-2-propanol, 1-pentanol, 2-pentanol, 2,2-dimethyl-1-propanol, 2,2,2-trimethyl ethanol, 1-decanol, benzyl alcohol; hydrocarbon solvent selected from the group toluene, benzene, o-xylene, m-xylene, p-xylene; water; acetone; acetonitrile; ethyl acetate; methylene chloride; DMF; an aliphatic hydrocarbon selected from C1-8 carbon atoms containing straight chain or branched chain or cycloalkane substituted cycloalkane or mixture thereof.

The reaction mass is heated at suitable temperature ranges from -10 to 65 ºC.

The suitable base comprises aqueous ammonia, triethylamine, diethylamine, diethyl aminopyridine, pyridine lithium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate or mixture thereof.

The pH of the reaction mass is adjusted to 5 to 8.

Still another embodiment, the present invention provides L-Glutamine (I) having a bulk density not less than 0.30 g/mL, preferably not less than 0.35 g/mL, more preferably not less 0.40 g/mL.

Still another embodiment of the present invention provides L-Glutamine (I) having Hausner ratio between 1.19-1.25.

Still another embodiment of the present invention provides a pharmaceutical composition comprising, (L)-Glutamine (I) prepared by the above process and one of more pharmaceutical excipient(s) thereof.

The following example(s) illustrate the nature of the invention and are provided for illustrative purposes only and should not be construed to limit the scope of the invention.

EXAMPLE-1:
L-Glutamine (10 g) was dissolved in water (10 vol, 100 ml) into the reactor at 55-60°C, the reaction mixture was added to pre cooled methanol (40 vol, 400 ml) at -10 to -5 °C and the solid was filtered and washed with methanol 1 vol, (10 ml). The product was dried at 60-65°C under reduced pressure (NLT 650 mmHg) till LOD is < 0.5% w/w it took 5-6 h to achieve this result.
Yield: 9.6 g [0.96 w/w, based on L-Glutamine input weight)
Bulk density: 0.32 g/mL

EXAMPLE-2:

L-Glutamine (75 g) was dissolved in water (10 vol, 750 ml) into the reactor at 55-60°C and adjusted the reaction mass pH to 7.01 with aqueous ammonia. Then reaction mixture was added to precooled methanol (40 vol, 3000 ml) at -10 to -5 °C and filter the solid and washed with methanol 1 vol, (75 ml). The product was dried at 60-65°C under reduced pressure (NLT 650 mmHg) till LOD is < 0.5% w/w it took 5-6 h to achieve this result.
Yield: 65 g [0.86 w/w, based on L-Glutamine input weight)
Bulk density: 0.43 g/mL

EXAMPLE-3:

L-Glutamine (40 g) was dissolved in water (10 vol, 400 ml) into the reactor at 55-60°C and adjusted the reaction mass pH to 6.93 with aqueous ammonia. Then reaction mixture was added to methanol (40 vol, 1600 ml) at 25-30 °C and the solid was filtered and washed with methanol 1 vol, (40 ml). The product was dried at 60-65°C under reduced pressure (NLT 650 mmHg) till LOD is < 0.5% w/w it took 5-6 h to achieve this result.
Yield: 36.5 g [0.91 w/w, based on L-Glutamine input weight)
Bulk density: 0.42 g/mL

EXAMPLE-4:
L-Glutamine (20 g) was dissolved in water (10 vol, 200 ml) into the reactor at 55-60°C and adjusted the reaction mass pH to 6.95 with aqueous ammonia. Then reaction mixture was added to methanol (40 vol, 800 ml) at 40-45 °C and the solid was filtered and washed with methanol 1 vol, (20 ml). Dried the product at 60-65°C under reduced pressure (NLT 650 mmHg) till LOD is <0.5% w/w it took 5-6 hr to achieve this result.
Yield: 14 g [0.70 w/w, based on L-Glutamine input weight)
Bulk density: 0.48 g/mL ,CLAIMS:WE CLAIM:

1. A process for the purification of L-Glutamine (I);

Formula I
with spherical agglomerated crystals having bulk density 0.43-0.47 and Hausner ratio between 1.19-1.25, which comprises:
(i) dissolving L-Glutamine (I) in a first solvent;
(ii) heating the reaction mass at a suitable temperature;
(iii) adjusting pH by adding a base to step (ii);
(iv) adding a second solvent; and
(v) isolating pure L-Glutamine (I) with spherical agglomerated crystals.

2. The process as claimed in claim 1, wherein the first solvent comprises water or an alcohol selected from C1-C3 straight or branched chain alcohol such as methanol, ethanol, n-propanol and isopropyl alcohol.

3. The process as claimed in claim 1, wherein the suitable base comprises aqueous ammonia, triethylamine, diethylamine, diethyl aminopyridine, pyridine lithium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate or mixture thereof.

4. The process as claimed in claim 1, wherein the second solvent comprises an ether selected from tetrahydrofuran, dioxane, diisopropylether, diethylether, 2-methyltetrahydrofuran, cyclopentyl methyl ether, methyl tert-butyl ether, diglyme or monoglyme; hydrocarbon solvent selected from the group toluene, benzene, o-xylene, m-xylene, p-xylene; water; acetone; acetonitrile; ethyl acetate; methylene chloride; DMF; an aliphatic hydrocarbon selected from C1-8 carbon atoms containing straight chain or branched chain or cycloalkane substituted cycloalkane or mixture thereof.

5. A pharmaceutical composition comprising, (L)-Glutamine (I) prepared by the process claimed in claim 1 and one of more pharmaceutical excipient thereof.