PROCESS FOR PREPARING CRSYTALLINE ALPHA-FORM OF IMATINIB MESYLATE

INTRODUCTION The present application relates to processes for preparing crystalline alpha-form of Imatinib mesylate.

BACKGROUND OF THE INVENTION

Imatinib mesylate has a chemical name 4-[(4-Methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyhdinyl)-2-pyhmidinyl]amino]-phenyl]benzamide methanesulfonate and can be represented by structural Formula I.

Imatinib is a protein-tyrosine kinase inhibitor and is available in products sold by Novartis using the trademark GLEEVEC, in the form of tablets containing imatinib mesylate equivalent to 100 mg or 400 mg of imatinib free base.

U.S. Patent No. 6,894,051 ("the '051 patent"), disclosed two polymorphic forms of mesylate salt of imatinib viz: alpha-crystal form and a beta-crystal form and the processes for their preparation. The '051 patent also discloses that the crystalline alpha-form is characterized by needle-shaped crystals having a hygroscopic nature, which make them "not particularly well suited to pharmaceutical formulation as solid dosage forms, because their physical properties, for example their flow characteristics, are unfavorable". The process disclosed in the '051 patent for the preparation of the alpha-crystalline form comprises suspending imatinib base in ethanol, adding methane sulfonic acid dropwise to the said solution, heating the solution to reflux and filtering; evaporating the filtrate to 50%, filtering off the residue; evaporating the mother liquor to dryness; suspending the residue and filtered material in ethanol; dissolving under reflux conditions by simultaneously adding water; cooling overnight, filtering and drying to obtain alpha-crystalline form.

This process disclosed for preparing alpha crystalline form not only involves several steps, but also is cumbersome and does not give reproducible results.

U.S. Patent No. 7,638,627 ("the '627 patent") disclosed a method of preparing crystalline imatinib mesylate alpha form comprises suspending imatinib base in isopropanol, adding methane sulfonic acid, heating the solution to reflux and concentrating the reaction mixture to a minimum volume, cooling the reaction mixture and isolating the needle-shaped hygroscopic alpha-crystalline form.

The '627 patent involves additional manufacturing step of concentrating the reaction mixture to a pre-defined volume resulting imatinib mesylate contains large excess of isopropanol as organic volatile and thus additional process steps required to remove the residual solvent, which in turn results to an increase in the manufacturing cycle time and decrease in the product yield.

U.S. Patent Application publication No. 2007/0265288 ("the '288 publication") described a method of preparing crystalline imatinib mesylate alpha form by suspending imatinib base in an alcoholic or ketone solvent, adding methane sulfonic acid, heating the solution to reflux, cooling the reaction mixture and isolating the alpha-crystalline form; however, the '288 publication teaches additional step of micronizing the product in order to change the undesirable crystalline needle form and obtain desirable physical properties of the solid.

U.S. Patent Application Publication No. 2006/0223816 Al ("the '816 publication"), described a stable, free-flowing imatinib mesylate alpha-form, which is substantially free of the beta- form. This publication described a process, which comprises: a. mixing imatinib base with an organic solvent selected from ketones, nitriles and cycloalkanes (more particularly methyl ethyl ketone, methyl isobutyl ketone, 4-methylcyclohexanone, cyclohexane, acetonitrile and mixtures thereof); b. heating to dissolve; c. adding methanesulfonic acid; d. allowing the crystals to precipitate; e. isolating the precipitated crystal of imatinib mesylate alpha-form, with seeding. The process described in the '816 publication necessarily involves seeding with an alpha-crystal form of imatinib mesylate and also involves the use of solvents like 4-methylcyclohexanone, which are not only expensive for industrial use but also not suitable for handling in industrial scale production.

U.S. Patent Application publication No. 2007/0197545 ("the '545 publication"), described a process for the preparation of alpha-crystal form of imatinib mesylate which involves the use of not more than 0.99 equivalents of methanesulfonic acid, per equivalent of imatinib, in a solvent selected from the group consisting of C2-6 aliphatic alcohols and mixtures thereof, optionally with the addition of aliphatic alcohols. The '545 publication also discloses a process involving the use of solvents selected from the group consisting of esters of lower carboxylic acids and aliphatic alcohols.

International Application publication WO 2006/048890 A1 ("the '890 publication") described a non-needle shaped alpha-crystalline form of imatinib mesylate and a process for its preparation, which includes subjecting a solution of imatinib mesylate in a suitable solvent (which may be a polar protic or aprotic solvent, a non-polar solvent, water or mixture thereof) to agitated thin film drying under atmospheric pressure and/or under vacuum.

International Patent publication WO 2007/136510 A2 ("the '510 publication") described processes for preparing crystalline imatinib mesylate of form alpha comprising; providing a solution of imatinib mesylate in ethylene glycol dimethyl ether, and admixing the solution with t-butyl methyl ether to form a suspension comprising the crystalline form; crystallizing from 1,2-propyleen carbonate; or slurrying other crystalline forms of imatinib mesylate in solvents selected from ethylacetate, n-propanol, acetone and mixtures thereof.

International Application publication No. WO 2009/151899 ("the '899 publication") described a method of preparing a non-hygroscopic, stable crystalline imatinib mesylate alpha-form which involves the use of ether solvent, such as cyclic ethers (tetrahydrofuran, pentahydropyran, and the like) and acyclic ethers (dimethyl ether, diethyl ether, methyl tertiary butyl ether, and the like).
International Application publication No. WO2011/158255 A1 ("the '255 publication") described a process for preparing stable crystalline alpha form of imatinib mesylate which involves the use of organic solvent selected from the group consisting of v-butyrolactone, xylenes, C1-4 alcohol and mixtures thereof or a mixture isopropanol and anisole.

International Application publication No. WO2011/099039 A1 ("the '039 publication") described a process for the preparation of alpha crystals of imatinib mesylate by reacting imatinib base with methanesulphonic acid in anhydrous solvent, wherein the solvent is selected from alcoholic and ketonic solvents.

Indian patent application publication No. IN1445/DEL/2010 (the '1445 publication) described a process for the preparation of pure alpha form of imatinib mesylate which involves the use of isopropanol as the solvent.

International Application publication No. WO2011/157450 A1 ("the '450 publication") described a process of conversion of any form of imatinib mesylate to imatinib mesylate form alpha which involves combining imatinib mesylate with water and/or a mixtu8re of water with alcohols C1-C4 and optionally 0.01-10% molar excess of methanesulfonic acid with respect to imatinib salt. Further, the '450 publication also discloses a process for preparation of imatinib mesylate form alpha without seeding procedure.

In view of the limitations associated with methods of producing the alpha-form of imatinib mesylate, there is a need for an improved and reproducible process for preparing stable, non-hygroscopic, non-needle shaped crystalline alpha-form of imatinib mesylate without the need for micronization.
SUMMARY In an embodiment, the present application provides a process for preparing non-needle shaped crystalline alpha-form of imatinib mesylate, comprising:

a) providing a suspension of imatinib base in 2-butanol;

b) optionally, seeding with crystals of alpha-form of imatinib mesylate;

c) adding methane sulphonic acid at a temperature of about 20 °C to about65°C;

d) heating the mixture of step c) to a temperature of about 50°C to about 100°C maintaining at the same temperature for 15 to 90 minutes;

e) cooling the mixture to a temperature of about 25°C to about 50°C and isolating the crystalline alpha-form of imatinib mesylate.

In an embodiment, the present application provides a process for preparing non-needle shaped crystalline alpha-form of imatinib mesylate with out seeding, comprising:

a) providing a suspension of imatinib base in 2-butanol;

b) heating the mixture of step b) to a temperature of 45°C to 65°C;

c) adding methane sulphonic acid at a temperature of 45°C to 65°C;

d) maintaining at a temperature of 45°C to 65°C for 15 minutes to 2 hours;

e) cooling the mixture to a temperature of about 25°C to about 35°C and isolating the crystalline alpha-form of imatinib mesylate.

In an embodiment, the present application provides a process for preparing crystalline alpha-form of imatinib mesylate, comprising:

a) providing a suspension of imatinib base in a mixture of 2-butanol and acetone;

b) adding methane sulphonic acid at a temperature of about 25°C to about 35°C;

c) heating the mixture of step b) to a temperature of about 50°C to about 60°C maintaining at the same temperature for 15 to 60 minutes;

d) cooling the mixture to a temperature of about 25°C to about 35°C and isolating the crystalline alpha-form of imatinib mesylate.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 is X-Ray powder diffraction ("XRPD") pattern of the crystalline alpha-form of imatinib mesylate prepared according to Example 1.

Figure 2 is X-Ray powder diffraction ("XRPD") pattern of the crystalline alpha-form of imatinib mesylate prepared according to Example 2, Example 6 and Example 7.

Figure 3 is X-Ray powder diffraction ("XRPD") pattern of the crystalline alpha-form of imatinib mesylate prepared according to Example 3.

DETAILED DESCRIPTION

The present application provides processes for preparing non-needle shaped crystalline alpha-form of imatinib mesylate, which is non-hygroscopic, convenient to handle, and suitable for preparation of solid pharmaceutical dosage forms.

In an embodiment, the present application provides a process for preparing non-needle shaped crystalline alpha-form of imatinib mesylate, comprising:

a) providing a suspension of imatinib base in 2-butanol;

b) optionally, seeding with crystals of alpha-form of imatinib mesylate;

c) adding methane sulphonic acid at a temperature of about 20°C to about65°C;

d) heating the mixture of step c) to a temperature of about 50°C to about 100°C maintaining at the same temperature for 15 to 90 minutes;

e) cooling the mixture to a temperature of about 25°C to about 50°C and isolating the crystalline alpha-form of imatinib mesylate.

Imatinib base used in the process of the present application can be obtained from processes disclosed in the art, for example U.S. Patent No. 5,521,184 or any other processes.

The process of providing a suspension of imatinib base in 2-butanol comprises combining imatinib base with 2-butanol and maintaining at a temperature ranging from about 22°C to about 65°C. The seed crystals of the alpha-form of imatinib mesylate used in the process of the present application may be obtained from a process disclosed in the art or from the process of the present application. The seeding with crystals of alpha-form of imatinib mesylate may optionally be carried out. The molar quantities of methanesulfonic acid that may be used ranges from 1.0 to 1.05 moles, per mole of imatinib base. In embodiments, the molar quantity of methane sulfonic acid used is 1.05 mole, per mole of imatinib base. Methane sulfonic acid may be added as such or in the form of solution dissolved in 2-butanol or methyl isobutyl ketone. The temperatures at which methanesulfonic acid may be added to the mixture obtained in step b) may range from about 22°C to about 65°C. In an embodiment, methanesulfonic acid may be added at temperatures in the range of about 22°C to about 35°C.

The mixture obtained in step c) is heated to a temperature of about 50°C to about 100°C and maintained at the same temperature for a period of about 15 minutes to about 90 minutes to obtain crystalline alpha-form of imatinib mesylate. The reaction mixture thus obtained is cooled to a temperature in the range of about 25°C to about 48°C and the product may be obtained by isolation, followed by drying. Drying may be suitably carried out using equipment such as a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer and the like. The drying may be carried out at temperatures about 35°C to about 95°C, preferably at temperatures about 85 °C to about 90 °C, more preferably at temperatures about 60°C to about 65°C, with or without vacuum for desired time until the desired product purity is achieved.

In an embodiment, the present application provides a process for preparing non-needle shaped crystalline alpha-form of imatinib mesylate with out seeding, comprising:

a) providing a suspension of imatinib base in 2-butanol;

b) heating the mixture of step b) to a temperature of 45°C to 65°C;

c) adding methane sulphonic acid at a temperature of 45°C to 65°C;

d) maintaining at a temperature of 45°C to 65°C for 15 minutes to 2 hours;

e) cooling the mixture to a temperature of about 25°C to about 35°C and isolating the crystalline alpha-form of imatinib mesylate.

Imatinib base used in the processes of the present application can be obtained from processes disclosed in the art, for example U.S. Patent No. 5,521,184 or any other processes.

The process of providing a suspension of imatinib base in 2-butanol comprises combining imatinib base with 2-butanol and maintaining at a temperature ranging from about 25°C to about 65°C.
The suspension obtained in step a) is heated to a temperature of 45°C to 65°C, preferably to a temperature of about 50°C to about 60°C; more preferably to a temperature of 60°C to 65°C.
Methane sulfonic acid may be added as such or in the form of solution dissolved in 2-butanol. The molar quantities of methanesulfonic acid that may be used ranges from 1.0 to 1.05 moles, per mole of imatinib base. In embodiments, the molar quantity of methane sulfonic acid used is 1.05 mole, per mole of imatinib base. The temperatures at which methanesulfonic acid may be added to the mixture obtained in step b) may range from 45°C to 65°C. In an embodiment, methanesulfonic acid may be added at temperatures in the range of 60°C to 65°C or at a temperature of 50°C to 60°C;

The mixture obtained in step c) is maintained at a temperature of 45°C to 65°C for a period of about 15 minutes to about 2 hours to obtain crystalline alpha-form of imatinib mesylate. The reaction mixture thus obtained in step c) is cooled to a temperatures in the range of about 25°C to about 35°C and the product may be obtained by isolation, followed by drying. Drying may be suitably carried out using equipment such as a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer and the like. The drying may be carried out at temperatures about 35°C to about 80°C, with or without vacuum for desired time until the desired product purity is achieved.

In an embodiment, the present application provides a process for preparing crystalline alpha-form of imatinib mesylate, comprising:

a) providing a suspension of imatinib base in a mixture of 2-butanol and acetone;

b) adding methane sulphonic acid at a temperature of about 25°C to about 35°C;

c) heating the mixture of step b) to a temperature of about 50°C to about 60°C maintaining at the same temperature for 15 to 60 minutes;

d) cooling the mixture to a temperature of about 25°C to about 35°C and isolating the crystalline alpha-form of imatinib mesylate.

Imatinib base used in the processes of the present application can be obtained from processes disclosed in the art, for example U.S. Patent No. 5,521,184 or any other processes.

The process of providing a suspension of imatinib base in a mixture of 2-butanol and acetone comprises combining imatinib base with a mixture of 2-butanol and acetone and maintaining at a temperature ranging from about 25°C to about 35°C.

Methane sulfonic acid may be added as such or in the form of solution dissolved in 2-butanol or acetone. The molar quantities of methanesulfonic acid that may be used ranges from 1.0 to 1.05 moles, per mole of imatinib base. In embodiments, the molar quantity of methane sulfonic acid used is 1.05 mole, per mole of imatinib base. The temperatures at which methanesulfonic acid may be added to the mixture obtained in step b) may range from about 25°C to about 35°C.

The mixture obtained in step b) is heated to a temperature of about 50°C to about 60°C and maintained at the same temperature for a period of about 15 minutes to about 2 hours to obtain crystalline alpha-form of imatinib mesylate. In an embodiment, the mixture obtained in step b) is heated to a temperature of about 55°C to about 60°C. The reaction mixture thus obtained in step c) is cooled to a temperatures in the range of about 25°C to about 35°C and the product may be obtained by isolation, followed by drying. Drying may be suitably carried out using equipment such as a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer and the like. The drying may be carried out at temperatures about 35°C to about 80°C, with or without vacuum for desired time until the desired product purity is achieved.

In an embodiment, crystalline alpha-form of imatinib mesylate obtained from a process of present application has a particle size distribution with D10 less than about 10 urn, D50 less than about 50 urn, and D90 less than about 100 urn.

The D10, D5o and D90 values are useful ways for indicating a particle size distribution. D90 refers to a particle size value for which at least 90 volume percent of the particles have a size smaller than the value given. Likewise D50 and D10 refer to the values for the particle size for which 50 volume percent, and 10 volume percent, respectively, of the particles have a size smaller than the value given.
In an embodiment, the present application provides pharmaceutical formulations comprising a non-needle shaped crystalline alpha-form of imatinib mesylate and one or more pharmaceutically acceptable excipients. A crystalline form of imatinib mesylate can be characterized by its X-ray powder diffraction pattern, as well as by other analytical techniques. All of the XRPD data reported herein were generated using a Bruker AXS D8 Advance powder X-ray diffractometer, with a copper K-a radiation source (1.5418 A°).

Certain specific aspects and embodiments of the invention will be further described by the following examples.

EXAMPLES

Example 1: Preparation of crystalline Alpha-Form Imatinib Mesylate.

Imatinib base (10.0 g) and 2-butanol (125 ml_) were charged into a round bottom flask at 27°C and stirred. Seed material of crystalline alpha-form of imatinib mesylate (0.5 g) and a solution of methanesulfonic acid (2.08 g dissolved in 30 ml_ of 2-butanol) were added to the flask at 25°c to 30°C and the mixture was heated to a temperature of 80°C to 85°C. The mixture was maintained at the same temperature for about 30 minutes and the obtained suspension was filtered, washed with 2-butanol (35 ml_) and dried in a vacuum tray drier at a temperature of 69°C to give crystalline alpha-form of imatinib mesylate.

Yield: 11.5 g

XRPD: Figure 1.

Example 2: Preparation of crystalline Alpha-Form Imatinib Mesylate.

Imatinib base (20.0 g) and 2-butanol (250 ml_) were charged into a round bottom flask at 26°C and stirred. Seed material of crystalline alpha-form of imatinib mesylate (1.0 g) and a solution of methanesulfonic acid (4.08 g dissolved in 60 ml_ of 2-butanol) were added to the flask and the mixture was heated to a temperature of 95°C to 100°C. The mixture was maintained at the same temperature for about 30 minutes and the suspension was cooled to a temperature of 40°C to 45°C, filtered, washed with 2-butanol (70 ml_) and dried in a vacuum tray drier at a temperature of 65°C to give crystalline alpha-form of imatinib mesylate.

Yield: 21.8 g

XRPD:

Figure 2

Example 3: Preparation of crystalline Alpha-Form Imatinib Mesylate.

Imatinib base (15.0 g) and 2-butanol (187.5 ml_) were charged into a round bottom flask at 26°C and the mixture was heated to a temperature of 50-55°C. Seed material of crystalline alpha-form of imatinib mesylate (0.75 g) and a solution of methanesulfonic acid (3.06 g dissolved in 45 ml_ of 2-butanol) were added to the flask and the mixture was heated to a temperature of 60°C to 65°C. The mixture was maintained at the same temperature for about 30 minutes and the obtained suspension was cooled to a temperature of 40°C to 45°C, filtered, washed with 2-butanol (52.5 ml_) and dried in a vacuum tray drier at a temperature of 65°C to give crystalline alpha-form of imatinib mesylate.

Yield: 16.8 g

XRPD: Figure 3

Example 4: Preparation of crystalline Alpha-Form Imatinib Mesylate.
Imatinib base (15.0 g) and 2-butanol (300 ml_) were charged into a round bottom flask at 26°C and the mixture was heated to a temperature of 60-65°C. A solution of methanesulfonic acid (3.06 g dissolved in 30 ml_ of 2-butanol) was added to the flask and the mixture was stirred at a temperature of 60°C to 65°C for 60 minutes. The mixture was cooled to a temperature of 25-30°C, filtered, washed with 2-butanol (45 ml_) and dried in a vacuum tray drier at a temperature of 65°C to give crystalline alpha-form of imatinib mesylate.

Yield: 15 g

XRPD: Substantially in accordance with Figure 1.

Example 5: Preparation of crystalline Alpha-Form Imatinib Mesylate.

Imatinib base (15.0 g), 2-butanol (150 ml_) and acetone (150 ml_) were charged into a round bottom flask at 26°C and the mixture was stirred. A solution of methanesulfonic acid (3.06 g dissolved in 30 ml_ of 2-butanol) was added to the flask at 27°C and the mixture was heated to a temperature of 55-60°C. The mixture was maintained at the same temperature for about 60 minutes and the suspension was cooled to 25-30°C, filtered, washed with acetone (45 ml_) and dried in a vacuum tray drier at a
temperature of 60-65°C to give crystalline alpha-form of imatinib mesylate

Yield: 15.2 g

XRPD: Substantially in accordance with Figure 1.

Example 6: Preparation of crystalline Alpha Form Imatinib Mesylate.

Imatinib base (50 g) and 2-butanol (500 ml_) were charged into a round bottom flask at 24 °C and stirred for 10 minutes. Seed material of crystalline alpha form of imatinib mesylate (2.5g) and a solution of methane sulfonic acid (10.22 g dissloved in 500 ml_ of Methyl isobutyl ketone) were added to the above flask at 24 °C and the mixture was heated to 90 °C. The mixture was maintained at 90 °C for 1 hour. The reaction mixture was cooled to 45 °C, filtered, washed with methyl isobutyl ketone (150 ml_) and dried in a vacuum tray drier at a temperature of 90 °C to give crystalline alpha-form of imatinib mesylate.
Yield: 59.1 g

XRPD: Figure 2

Example 7: Preparation of crystalline Alpha Form Imatinib Mesylate.

Imatinib base (10 g) and 2-butanol (100 ml_) were charged into a round bottom flask at 22 °C and stirred for 10 minutes. Seed material of crystalline alpha form of imatinib mesylate (500 mg) was added and a solution of methane sulfonic acid (1.4 g dissloved in 150 ml_ of Methyl isobutyl ketone) was added to the above flask for 45 minutes at 22 °C. The reaction mixture was heated to 54 °C maintained at 54 °C for 90 minutes. The reaction mixture was cooled to 31 °C, filtered, washed with methyl isobutyl ketone (50 ml_) and dried in a vacuum tray drier at a temperature of 86 °C to give crystalline alpha-form of imatinib mesylate. Yield: 11.25 g XRD: Figure 2

We Claim:

1. A process for preparing non-needle shaped crystalline alpha-form of imatinib mesylate comprising:

(a) providing a suspension of imatinib base in 2-butanol;

(b) heating to a temperature from about 45 °C to about 65 °C;

(c) adding methane sulphonic acid at about 45 °C to about 65 °C and maintaining at a temperature of about 45 °C to about 65 °C for 15 minutes to about 120 minutes;

(d) cooling the mixture to a temperature of about 25 °C to about 35 °C and isolating the crystalline alpha form of imatinib mesylate.

2. The process of claim 1, wherein in step (c) the molar quantity of methane sulphonic acid is about 1.02 to about 1.05 moles, per mole of imatinib base.

3. The process of claim 1, wherein in step (c) methane sulphonic acid is added as such or by dissolving in 2-butanol.

4. A process for preparing non-needle shaped crystalline alpha-form of imatinib mesylate comprising:

(a) providing a suspension of imatinib base in a mixture of 2-butanol and acetone;

(b) adding methane sulphonic acid at a temperature of about 25 °C to about 35 °C;

(c) heating the mixture of step (b) to a temperature of about 50 °C to about 60 °C and maintaining at the same temperature for 15 to 60 minutes;

(d) cooling the mixture to a temperature of about 25 °C to about 35 °C and isolating the crystalline alpha form of imatinib mesylate.

5. The process of claim 5, wherein in step (b) the molar quantity of methane sulphonic acid used is about 1.02 to about 1.05 moles, per mole of imatinib base.

6. The process of claim 5, wherein in step (b) methane sulphonic acid is added as such or by dissolving in 2- butanol.

7. A process for preparing non-needle shaped crystalline alpha-form of imatinib mesylate comprising:

(a) providing a suspension of imatinib base in 2-butanol;

(b) adding methane sulphonic acid at temperature of about 20 °C to about 65 °C.

(c) heating the mixture of step (b) to a temperature of about 50 °C to about 100 °C and maintaining a the same temperature for 15 to 90 minutes;

(d) cooling the mixture to a temperature of about 25 °C to about 50 °C and isolating the crystalline alpha form of imatinib mesylate.

8. The process of claim 9, wherein in step (b) the molar quantity of methane sulphonic acid used is about 1.02 to about 1.05 moles, per mole of imatinib base.

9. The process of claim 9, wherein in step (b) methane sulphonic acid is added as such or by dissolving in 2-butanol or methyl isobutyl ketone.

10. The process of claim 5, further comprising seeding with crystalline alpha form imatinib mesylate before the addition of methane sulphonic acid.