WO2011158255A1

WO2011158255A1 - Process for preparation of stable imatintb mesylate alpha form

Info

Publication number: WO2011158255A1
Application number: PCT/IN2011/000398
Authority: WO
Inventors: Srinivas Simhadri; Krishna Sumanth Peraka; Ashwini Nangia
Original assignee: Aptuit Laurus Private Limited
Priority date: 2010-06-16
Filing date: 2011-06-14
Publication date: 2011-12-22

Abstract

The present invention provides a process for preparation of stable, free flowing, non-hygroscopic crystalline alpha form of Imatinib mesylate. The present invention also provides a pharmaceutical composition using the stable, free flowing, non hygroscopic crystalline alpha form of Imatinib mesylate of the present invention.

Description

PROCESS FOR PREPARATION OF STABLE IMATINTB MESYLATE ALPHA FORM

PRIORITY

[0001] This application claims the benefit under Indian Provisional

Application no. 1676/CHE/2010 filed June 16, 2010 and entitled "AN IMPROVED PROCESS FOR THE PREPARATION OF STABLE IMATINIB MESYLATE ALPHA FORM", the contents of which are incorporated by reference herein.

FIELD OF THE INVENTION

[0002] The present invention generally relates to a process for the preparation of stable Imatinib mesylate alpha (a) form, and to a pharmaceutical compositions containing the same.

BACKGROUND OF THE INVENTION

[0003] Imatinib is the international non-proprietary name of 4-(4- methylpiperazin- 1 -yl methyl)-N-[4-methyl-3-(4-pyridin-3-yl) pyrimidin-2-ylamino) phenyl]-benzamide. Imatinib is currently used for the treatment of patients with certain types of leukaemia (most commonly chronic myeloid leukaemia) and a rare type of cancer known as gastro-intestinal stromal tumour (GIST). The structural formula of imatinib mesylate is given below:

FORMULA I

[0004] Imatinib is 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. [0005] 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.

[0006] This process disclosed for preparing alpha crystalline form not only involves several steps, such as isolation of crude methanesulfonate crystals from the reaction mixture, evaporating ethanol from the reaction mixture and re-suspending the methanesulfonate salt in the same solvent, but also is cumbersome and does not give reproducible results.

[0007] 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.

[0008] The '627 patent involves additional manufacturing step of concentrating the reaction mixture to a pre-defined volume and also resulting imatinib mesylate contains large excess of isopropanol as organic residual volatile and thus additional process steps required to remove, which in turn result to an increase in the manufacturing cycle time and decrease in the product yield.

[0009] U.S. Patent 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, micronizing the product in order to change the undesirable crystalline needle form and obtain desirable physical properties of the solid.

[0010] U.S. Patent Application No. 2006/0223816 Al ("the ^!816 publication"), describe a stable, free-flowing imatinib mesylate alpha-form, which is substantially free of the beta- form. This publication describes 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.

[0011] U.S. Patent publication No. 2007/0197545 ("the '545 publication"), describe 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 C_2-6 aliphatic alcohols and mixtures thereof, optionally with the addition of CM 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 C aliphatic alcohols.

[0012] International Patent publication WO 2006/048890 ("the '890 publication") describes 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.

[0013] International Patent publication WO 2007/136510 ("the '510 publication") describes 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.

[0014] International Patent publication WO 2009/151899 ("the '899 publication") describes 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).

[0015] In view of the limitations associated with the alpha form and methods of producing the alpha form, there is a need for an improved alpha form of imatmib mesylate, which exhibits excellent physical properties, stable, non-hygroscopic imatinib mesylate alpha form, without the need for micronization, and a simple, reproducible and straightforward method of producing such a product, which can be carried out using variety of solvents such as anisole, γ-butyro lactone, C alcohol, xylenes or mixtures thereof.

SUMMARY OF THE INVENTION

[0016] The present invention relates to a process for preparation of a stable, free flowing, non-hygroscopic crystalline alpha form of imatinib mesylate, which is substantially free of the beta form and having low content of organic residual volatile impurities, reproducibly obtained from industrially safe solvents such as anisole, γ- butyro lactone, C alcohol, xylenes or mixtures thereof. The process of the present invention produces stable, free flowing, non-hygroscopic crystalline alpha form of imatinib mesylate, which is suitable for pharmaceutical compositions, which avoids additional process steps like micronization of the imatinib mesylate crystals.

[0017] In accordance with one embodiment of the present invention, a process for the preparation of stable, free flowing, non-hygroscopic crystalline alpha form of imatinib mesylate, comprising:

a) providing a suspension or solution of imatinib base in an organic solvent, wherein the organic solvent is selected from the group consisting of anisole, γ- butyro lactone, C alcohol, xylenes and mixtures thereof; b) adding methane sulfonic acid;

c) optionally, heating the mixture formed in step b) to about ambient temperature to about reflux temperature;

d) cooling the reaction mixture to ambient temperature;

e) isolating the imatinib mesylate alpha form.

[0018] In accordance with a second embodiment of the present invention, a process for the preparation of stable, non-hygroscopic crystalline alpha form of imatinib mesylate, comprising:

a) providing a solution or suspension of imatinib mesylate in an organic solvent at a temperature of about ambient temperature to about reflux temperature, wherein the organic solvent is selected from the group consisting of anisole, γ- butyro lactone, C alcohol, xylenes and mixtures thereof;

b) cooling the reaction mixture to ambient temperature;

c) isolating imatinib mesylate alpha form.

[0019] In accordance with a third embodiment of the present invention, a pharmaceutical compositions comprising stable, non-hygroscopic crystalline alpha form of imatinib mesylate prepared by the processes of the present invention and at least one pharmaceutically acceptable excipient. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Fig. 1 illustrates a powder X-ray diffraction pattern (XRPD) of imatinib mesylate alpha form prepared according to Example 1.

[0021] Fig. 2 illustrates a characteristic differential scanning calorimeter

(DSC) thermogram of imatinib mesylate alpha form prepared according to Example 1.

[0022] Fig. 3 illustrates a powder X-ray diffraction pattern (XRPD) of imatinib mesylate alpha form of the present invention after 6 months of storage under ambient conditions.

[0023] Fig. 4 illustrates a characteristic differential scanning calorimeter

(DSC) thermogram of imatinib mesylate alpha form of the present invention after 6 months of storage under ambient conditions.

[0024] Fig. 5 illustrates a powder X-ray diffraction pattern (XRPD) of imatinib mesylate alpha form prepared according to Example 2. DETAILED DESCRIPTION OF THE INVENTION

[0025] The present invention relates to processes for preparation of a stable, free flowing, non-hygroscopic crystalline alpha form of imatinib mesylate, which is substantially free of the beta form and having low content of organic residual volatile impurities, reproducibly obtained from industrially safe solvents such as anisole, γ- butyro lactone, xylenes, C_w alcohol or mixtures thereof. The process of the present invention produces stable, free flowing, non-hygroscopic crystalline alpha form of imatinib mesylate, which is suitable for pharmaceutical compositions, which avoids the use of micronizing the resulting crystals.

[0026] A stable, free flowing, non-hygroscopic crystalline alpha form of imatinib mesylate can be characterized by its X- ray powder diffraction pattern (XRPD), and Differential Scanning Calorimeter (DSC), as well as by other analytical techniques.

[0027] The X-ray powder diffraction pattern can be measured by an X-ray powder Diffractometer equipped with a Cu-anode (λ=1.54 Angstrom), X-ray source operated at 45kV, 40 mA and a Ni filter is used to strip K-beta radiation. Two-theta calibration is performed using an NIST SRM 640c Si standard. The sample was analyzed using the following instrument parameters: measuring range=2-50° 2Θ; step width=0.017°; and measuring time per step=5 sec.

[0028] The Differential Scanning Calorimetric thermogram can be measured by Differential Scanning Calorimeter (DSC 822, Mettler Toledo) at a scan rate of

10°C per minute with an Indium standard.

[0029] The present invention provides a process for the preparation of stable, free flowing, non-hygroscopic crystalline alpha form of imatinib mesylate, comprising:

a) providing a suspension or solution of imatinib base in an organic solvent; b) adding methane sulfonic acid;

d) cooling the mixture to ambient temperature;

e) isolating the imatinib mesylate alpha form. wherein the organic solvent is selected from the group consisting of anisole, γ-butyro lactone, xylenes, C alcohol; and mixtures thereof.

[0030] The starting material, imatinib base used in the process of the present invention is known in the art and can be prepared by any known method, for example, imatinib base can be synthesized by the process mentioned in EP 564409B 1 , the content of which is incorporated herein by reference. Any polymorphic form of the compound, such as crystalline or amorphous forms, including solvates and hydrates, may also be utilized.

[0031] The process of suspending or dissolving the imatinib base in an organic solvent comprises combining the imatinib base with the solvent or it can be obtained directly from a reaction in which imatinib base is synthesized.

[0032] The organic solvent include, but are not limited to anisole, γ-butyro lactone; xylenes such as ortho, meta, para xylene; C alcohol such as methanol, ethanol, isopropanol, butanol and the like; and mixture thereof. Preferably the organic solvent is anisole, γ-butyro lactone, isopropanol and mixtures thereof, more preferably mixture of isopropanol with anisole or γ-butyro lactone.

[0033] Optionally, the organic solvent contains less than about 20% water by volume, more preferably, less than about 10% water by volume, and, most preferably, less than about 2% water by volume.

[0034] Imatinib base can be present in any amount that will produce the stable, free flowing, non-hygroscopic crystalline alpha form upon the process of the present invention. Preferably, the imatinib is present in an amount of about 1 to about 50 volumes of the solvent, more preferably about 5 to about 40 volumes, most preferably about 10 to about 30 volumes, still most preferably about 15 to about 25 volumes. One skilled in the art would understand that depending on the choice of solvent, the amount of imatinib used may be varied.

[0035] The imatinib base and the solvent used may be heated to form a suspension or clear solution of imatinib base. The temperature suitable for suspension or dissolving imatinib base depends on the solvent used and the amount of imatinib base in the solution. Typically, the reaction is heated at a temperature of at least about 30°C to about reflux; preferably, the reaction is heated at about 40°C to about 90°C, more preferably about 50°C to about 60°C. Increasing the amount of imatinib base would generally require the use of higher temperatures. Routine experimentation will provide the approximate range of suitable temperatures for a given solvent and amount of imatinib base.

[0036] The methane sulfonic acid in the abovementioned step b) may be used in the range of about 0.9 to about 1.1 moles per mole of imatinib base, preferably about 1 mole per mole of imatinib base.

[0037] Methane sulfonic acid can be added in the form of as it is solution or optionally dissolved in the solvent used for the reaction. The quantity of the solvent used to prepare a solution of methanesulfonic acid may range between about 1 and about 10 ml, per gram of imatinib base. The way of addition of methane sulfonic acid is not particularly critical.

[0038] The temperatures at which methanesulfonic acid can be added to the mass of step a) may range from about 10°C to about reflux temperature of the solvent. Any other temperatures may also be acceptable, as long. as a solution or suspension of imatinib base is provided. Preferably the addition of methane sulfonic acid can be added at a temperature of about 25°C to about 85°C, more preferably at about 25°C to about 60°C.

[0039] Optionally, further heating the mixture formed in step b) to about ambient temperature to about reflux temperature, preferably at about 55°C to about 1 10°C, more preferably at about 70°C to about 90°C.

[0040] Step d) of the foregoing process includes, cooling the resultant reaction mass at a temperature from about 40°C or less, more preferably at temperature below 30°C; such that the resulting imatinib mesylate alpha form can be isolated by conventional techniques. Any temperature is acceptable as long as the imatinib mesylate alpha form is obtained selectively and completely.

[0041] The resultant imatinib mesylate can be isolated by crystallization, solvent precipitation, concentrated by subjecting the solution to heating, spray drying, freeze drying, evaporation on rotary evaporator under vacuum, agitated thin film evaporator (ATFE) and the like, preferably isolated by crystallization. The imatinib mesylate can be recovered by any conventional technique known in the art, for example filtration. Typically, if stirring is involved, the temperature during stirring can range from about -10°C to about + 30°C, preferably at about 20°C to about 30°C. The imatinib mesylate alpha form obtained from the present invention is isolated by filtration.

[0042] The resultant imatinib mesylate alpha form may optionally be further dried. Drying can be suitably carried out in a tray dryer, vacuum oven, air oven, fluidized bed drier, spin flash dryer, flash dryer and the like. The drying can be carried out at a temperature ranging from about 30°C to about 100°C, preferably at about 70°C to about 80°C. The drying can be carried out for any desired time until the required product purity is achieved, e.g., a time period ranging from about 1 hour to about 30 hours, preferably about 20 hours.

[0043] The present invention further provides a process for the preparation of stable, free flowing, non-hygroscopic crystalline alpha form of imatinib mesylate, comprising: a) providing a solution of imatinib mesylate in an organic solvent at a temperature of about ambient temperature to about reflux temperature, wherein the organic solvent is selected from anisole, γ-butyro lactone, xylenes, C_1-4 alcohol and mixtures thereof; followed by carrying out the steps b) to e) as described above.

[0044] The organic solvent include, but are not limited to anisole, γ-butyro lactone; xylenes such as ortho, meta, para xylene; Ci_-4 alcohol such as methanol, ethanol, isopropanol, butanol and the like; and mixture thereof. Preferably the organic solvent is anisole, γ-butyro lactone, isopropanol and mixtures thereof, more preferably mixture of isopropanol with anisole or γ-butyro lactone.

[0045] The imatinib mesylate and the solvent used may be heated to form a suspension or clear solution of imatinib mesylate. The temperature suitable for suspension or dissolving imatinib mesylate depends on the solvent used and the amount of imatinib mesylate in the solution or suspension. Typically, the reaction is heated at a temperature of at least about 30°C to about reflux; preferably, the reaction is heated at about 40°C to about 90°C, more preferably about 50°C to about 60°C.

[0046] By performing the process of the present invention, substantially pure imatinib mesylate can be obtained with a degree of purity as determined by HPLC greater than or equal to about 99%, preferably greater than or equal to about 99.5% and more preferably greater than or equal to about 99.8%.

[0047] The process of the present invention provides, it can prevent the transformation of the resulting alpha-form crystals into another form, e.g., the imatinib mesylate beta-form. According to one aspect of the present invention, the formation of the beta-form crystals is not observed even after incubating the crystallization mixture, containing the alpha-form crystals, for prolonged periods in the reaction vessel overnight, as determined by using the XRPD and DSC technique.

[0048] A crystalline stable, free flowing, non-hygroscopic alpha form of imatinib mesylate obtained according to the process of the present invention, when packaged in a transparent low density polyethylene bag that is tagged and placed inside another sealed transparent low density polyethylene bag and finally placed in a high density polyethylene container, is stable during storage at ambient temperature for at least about one year. Stored crystalline alpha-form of imatinib mesylate of the present invention retains its crystalline nature and it can be characterized by any one or more of: an XRPD diffraction pattern, and a DSC curve.

[0049] The '627 patent discloses preparation of imatinib mesylate from isopropanol solvent results imatinib mesylate containing large excess of isopropanol traces as organic residual volatile, and thus additional process steps such as extended period of drying required to remove. In contrast, the process herein described arrives at imatinib mesylate, which may be isolated from a variety of solvent system of the present invention such as mixture of isopropanol with anisole or γ-butyro lactone and contains substantially low content of organic residual volatiles.

[0050] The present invention further provides imatinib mesylate, obtained by the processes described herein, having relatively low content of one or more organic volatile impurities.

[0051] The present invention provides imatinib mesylate obtained using the process of the described herein, may have a residual solvent content that is within the limits given by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use ("ICH") guidelines. The guideline solvent level depends on the type of solvent but is not more than about 5000 ppm, or about 4000 ppm, or about 3000 ppm.

[0052] The present invention provides a imatinib mesylate, obtained by the process disclosed herein, having less than about 800 parts per million (ppm) methanol, ethanol, preferably less than about 500 ppm; less than about 4000 ppm of isopropanol, preferably less than about 3000 ppm; less than about 500 ppm of methylene chloride, preferably less than about 100 ppm; less than about 500 ppm of toluene, preferably less than about 100 ppm; less than about 500 ppm of dimethyl formamide, preferably less than about 100 ppm; less than about 4000 ppm of anisole, preferably less than about 3000 ppm; less than about 4000 ppm of γ-butyro lactone, preferably less than about 3000 ppm and less than about 100 ppm of pyridine, preferably less than about 10 ppm. The present invention further provides imatinib mesylate, obtained by the process disclosed herein, having less than about 10 ppm methanol, less than about 3350 ppm isopropanol, less than about 3.7 ppm methylene chloride, less than about 2 ppm toluene, less than about 13 ppm dimethyl formamide, less than about 3900 ppm anisole, and less than about 2.5 ppm pyridine.

[0053] The present invention further provides a pharmaceutical composition comprising a therapeutically effective amount of stable alpha form of imatinib mesylate of the present invention with at least one pharmaceutically acceptable carrier or other excipients.

[0054] Suitable pharmaceutically acceptable carrier which can be used in combination with imatinib mesylate include, but are not limited to, hydrophilic substances like polymers of N-vinylpyrrolidone, commonly known as polyvinyl pyrrolidines ("PVP" or "povidone"), gums, cellulose derivatives, cyclodextrins, gelatins, hypromellose phthalates, sugars, polyhydric alcohols, polyethylene glycols, polyethylene oxides, polyoxyalkylene derivatives, methacrylic acid copolymers, polyv nylalcohols, propylene glycol derivatives and the like. Other pharmaceutically acceptable excipients that are of use include, but are not limited to, film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants and the like.

[0055] The following examples are provided to enable one skilled in the art to practice the invention and are merely illustrative of the invention. The examples should not be read as limiting the scope of the invention as defined in the claims.

EXAMPLES

[0056] EXAMPLE 1

Preparation of crystalline alpha form of imatinib mesylate (from a mixture of Isopropanol + Anisole). Into a 3 liter 4 necked round bottom flask fitted with a mechanical stirrer and a reflux condenser was charged imatinib base (100 gms), anisole (750 ml) and isopropanol (1500 ml) under nitrogen atmosphere at temperature of about 25°C to about 35°C. Heated the temperature to about 50°C to about 55°C and added methane sulfonic acid (20.05 gms). Stirred for 30 minutes and again heated to temperature to about 75°C to about 85°C ^'and stirred for 2 hours at the same temperature. Cooled the solution to temperature of about 25°C to about 35°C and stirred for 2 hours. Filtered the resultant product and washed with isopropanol (200 ml). The wet product was dried at 75°C to 80°C under reduced pressure to provide the title compound Yield: 1 10 gms.

[0057] The XRD is set forth in Fig. 1

[0058] The DSC is set forth in Fig. 2

[0059] Residual solvents:

[0060] The resultant crystalline alpha form of imatinib mesylate was packed in a low density polyethylene bag and stored for 6 months at 42°C/75% RH, and the X- ray powder diffraction pattern for stored material is substantially as set forth in Fig. 3 and differential scanning calorimetric (DSC) thermogram as set forth in Fig. 4.

[0061] EXAMPLE 2

Preparation of crystalline alpha form of imatinib mesylate (from γ-butyrolactone)

Into a 1 liter 4 necked round bottom flask fitted with a mechanical stirrer and a reflux condenser was charged imatinib base (100 gms) and γ-butyrolactone (500 ml) under nitrogen atmosphere at temperature of about 25°C to about 35°C. Stirred for 10 minutes at the same temperature and added methane sulfonic acid solution (19.53 g of methane sulfonic acid diluted with 130 ml of γ-butyrolactone). Stirred for 4 hours at about 25 °C to about 35°C and filtered the resultant product and washed with γ- butyrolactone (100 ml). The wet product was dried at 75°C to 80°C under reduced pressure to provide the title compound Yield: 110 gms.

[0062] The XRD is set forth in Fig. 5 [0063] EXAMPLE 3

Preparation of crystalline alpha form of imatinib mesylate (from Anisole)

Into a 3 liter 4 necked round bottom flask fitted with a mechanical stirrer and a reflux condenser was charged imatinib base (50 gms) and Anisole (1500 ml) under nitrogen atmosphere at temperature of about 25°C to about 35°C. Heated the temperature to about 50°C to about 55°C and added methane sulfonic acid solution (9.8 gms of methane sulfonic acid diluted with 65 ml of Anisole) over a period of 30 minutes at the same temperature. Stirred for 10 minutes and again heated to temperature to about 100°C to about 110°C and stirred for one hour at the same temperature. Cooled the solution to temperature of about 25°C to about 35°C and maintained for 2 hours. Filtered the resultant product and washed with Anisole (50 ml). The wet product was dried at 80°C to 85°C under reduced pressure to provide the title compound Yield: 54 gms.

[0064] It will be understood that various modifications may be made to the embodiments disclosed herein. Therefore the above description should not be construed as limiting, but merely as exemplifications of preferred embodiments. For example, the functions described above and implemented as the best mode for operating the present invention are for illustration purposes only. Other arrangements and methods may be implemented by those skilled in the art without departing from the scope and spirit of this invention. Moreover, those skilled in the art will envision other modifications within the scope and spirit of the specification appended hereto.

Claims

A process for the preparation of stable crystalline alpha form of imatinib mesylate, comprising:

a) providing a suspension or solution of imatinib base in an organic solvent,

b) adding methane sulfonic acid;

c) optionally, heating the reaction mixture of step b) to about ambient temperature to about reflux temperature;

d) cooling the mixture to ambient temperature;

e) isolating the imatinib mesylate alpha form.

wherein the organic solvent is selected from the group consisting of anisole, γ- butyrolactone, xylenes, C alcohol and mixtures thereof.

The process of claim 1 , wherein the C alcohol is selected from methanol, ethanol, isopropanol, and butanol.

The process of claim 1 , wherein the organic solvent is mixture of isopropanol and anisole.

The process of claim 1 , wherein the organic solvent is mixture of isopropanol and γ-butyrolactone.

The process of claim 1 , wherein the molar ratio of imatinib base to methane sulfonic acid are about 1 :0.9 to about 1 : 1.1.

The process of claim 1 , wherein the solution or suspension of imatinib base in an organic solvent is provided at temperature of about 30°C to about 90°C. The process of claim 1 , wherein the solution or suspension of imatinib base in an organic solvent is provided at a temperature of about 50°C to about 60°C. The process of claim 1 , wherein the addition of methane sulfonic acid is carried out at a temperature of about 50°C to about 60°C.

The process of claim 1 , wherein the temperature in step c) is about 60°C to about 1 10°C.

The process of claim 1 , wherein the temperature in step c) is about 75°C to about 85°C.

The process of claim 1 , wherein the crystalline alpha form of imatinib mesylate characterized by XRD pattern substantially in accordance with Figure. 01. The process of claim 1, wherein the crystalline alpha form of imatinib mesylate characterized by differential scanning calorimetric (DSC) thermogram substantially in accordance with Figure. 02.

a) providing a suspension or solution of imatinib base in a mixture of isopropanol and anisole,

b) heating the solution to about 50°C to about 55°C,

c) adding methane sulfonic acid to the resultant reaction mixture, d) heating the resulting reaction mixture to about 75°C to 85°C, e) cooling the reaction mixture to about 25°C to about 35°C,

f) isolating the imatinib mesylate alpha form.

Imatinib mesylate contain less than about 10 ppm methanol; less than about 3350 ppm isopropanol; less than about 3.7 ppm methylene chloride; less than about 2 ppm toluene; less than about 13 ppm dimethyl formamide; less than about 3900 ppm anisole and less than about 2.5 ppm pyridine.

A pharmaceutical composition comprising the stable crystalline alpha form imatinib mesylate according to any of claims 1-14, together with one or more pharmaceutically acceptable excipients.