IMATINIB MESYLATE POLYMORPHS

INTRODUCTION

Aspects of the present application relates to crystalline forms of imatinib mesylate designated as form-R, form-S, and processes for their preparation. Further aspects relate to the use of the crystalline forms in the preparation of pharmaceutical compositions.

The drug compound having the adopted name "imatinib mesylate" has a chemical name 4-[(4-methyl-1 -piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-phenyl]benzamide methanesulfonate and is structurally represented by Formula I.

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

Zimmermann et al., in U.S. Patent No. 6,894,051, describe two crystalline forms of imatinib mesylate, the alpha-form, and the beta-form. Zimmermann et al., in U.S. Patent No. 7,544,799, describe a crystalline form of a methanesulfonic acid addition salt of imatinib having non-needle shaped crystals, and its pharmaceutical composition. Parthasaradhi et al., in U.S. Patent No. 7,300,938, describe crystalline imatinib mesylate form H1, imatinib mesylate hydrate, amorphous imatinib mesylate hydrate, and processes for the preparation thereof.

Adin et al., in U.S. Patent Application Publication No. 2006/0223816 A1, describe a stable, free-flowing imatinib mesylate alpha-form, which is substantially free of the beta-form. Pathi et al., in U.S. Patent Application Publication No. 2007/0265288 A1, describe a method of preparing crystalline imatinib mesylate alpha-form, involving the use of an alcohol or ketone solvent. Szczepek et a/., in U.S. Patent Application Publication No. 2007/0197545 A1, describe a process for the preparation of alpha-crystal form of imatinib mesylate. Weisman et ai, in U.S. Patent Application Publication No. 2008/0234286 A1, describes a stable micronized amorphous form of imatinib mesylate, having a water content in the range of 3.2-5%.

International Application Publication No. WO 2005/077933 A1 describes an alpha 2-crystalline form of imatinib mesylate and a process for the preparation of the imatinib mesylate polymorphic form. International Application Publication No. WO 2006/054314 A1 describes crystalline form-l and form-ll of imatinib mesylate, and processes for preparation thereof. International Application Publication No. WO 2006/048890 A1 describes a non-needle shaped alpha-crystalline form of imatinib mesylate and a process for its preparation. International Application Publication No. WO 2007/136510 A2 describes crystalline imatinib mesylate, wherein the crystalline form is a solvate. Further, this application describes crystalline imatinib mesylate Forms IV (ethanol solvate), V, VI (1,3-dioxalane solvate), VII (nitromethane solvate), VIII (2-propanol solvate), IX, X (ethanol solvate), XI, XIII, XIV (2-propanol solvate), XV (mono-solvate of acetic acid), XVI (hemi-solvate of acetic acid), an amorphous form, and a process for preparing crystalline imatinib mesylate form-alpha. International Application Publication No. WO 2007/023182 A1 describes crystalline forms delta and epsilon of imatinib mesylate and processes for the preparation thereof. International Application Publication No. WO 2007/059963 A1 describes crystalline forms F, G, H, I, and K of imatinib mesylate and processes for the preparation thereof. International Application Publication No. WO 2008/027600 A2 describes a solid solution comprising imatinib and a solid solvent, and its process. International Application Publication No. WO 2008/112722 A2 describes a solid dispersion of imatinib mesylate comprising imatinib mesylate and a pharmaceutically acceptable carrier, wherein the carrier is a cellulose derivative. International Application Publication No. WO 2008/150481 A2 describes a method of preparing crystalline imatinib mesylate form beta, from crystalline imatinib mesylate form IV International Application Publication No. WO 2011/023146 A1 describes polymorphic forms Z1 and Z2, hydrates and also co-crystals of imatinib mesylate with inorganic salts, in particular NaCI and KCI and process for the preparation thereof. International Application Publication No. WO 2011/100282 A2 describes crystalline forms of imatinib mesylate such as form-Y, form-Y', form-Z, and process for the preparation thereof. International Application Publication No. WO 2011108953 A1 describes process for the preparation of imatinib mesylate form-a. Further, it also describes imatinib mesylate form-N and processes for its preparation.

Indian Patent Application No. 1208/MUM/2003 describes a substantially amorphous form of imatinib mesylate and a process for preparation thereof. Indian Patent Application No. 1209/MUM/2003 describes a gamma form of imatinib mesylate, comprising imatinib mesylate in a stable, substantially amorphous form comprising about 1.5 to 5% w/w water and a process for the preparation thereof.

The discovery of new polymorphic forms enlarges selection of materials with which formulation scientists can design a pharmaceutically acceptable dosage form of a drug with a targeted release profile or other desired characteristics. Despite the aforementioned disclosures mentioning various polymorphic forms, there remains a need for new polymorphic forms of imatinib mesylate, which are useful in the preparation of pharmaceutical compositions and have industrially feasible preparation processes.

SUMMARY OF THE INVENTION

Aspects of the present application relate to crystalline form of imatinib mesylate designated as form-R and process for preparation thereof.

In one embodiment, there is provided a crystalline form-R of imatinib mesylate characterized by X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 1.

In one embodiment, there is provided a crystalline form-R of imatinib mesylate characterized by an X-ray powder diffraction (XRPD) pattern comprising two or more of the characteristic peaks located at about 6.6, 9.9, 15.0, 16.4, 16.9, 19.8, or 20.6 ± 0.2 degrees 2-theta.

In an aspect, the present application provides a process for the preparation of crystalline form-R of imatinib mesylate, comprising:

a) providing a solution of imatinib and methanesulphonic acid in methanol;

b) adding hydrochloric acid;

c) adding an ether solvent to the solution of step b);

d) isolating the solid; and

e) drying the solid at 90-135°C to afford crystalline form-R of imatinib mesylate.

In an aspect, the present application provides a pharmaceutical composition comprising crystalline form-R of imatinib mesylate and at least one pharmaceutically acceptable excipient.

Another aspect of the present application relate to crystalline form of imatinib mesylate designated as form-S and process for preparation thereof.

In one embodiment, there is provided a crystalline form-S of imatinib mesylate characterized by X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 2.

In one embodiment, there is provided a crystalline form-S of imatinib mesylate characterized by X-ray powder diffraction (XRPD) pattern comprising two or more of the characteristic peaks located at about 8.5, 10.0, 13.1, 15.0, 16.4, 17.0, 19.8, 20.6, 21.3, 21.7, 22.1, 22.8, or 23.1 ± 0.2 degrees 2-theta.

In an aspect, the present application provides a process for the preparation of crystalline form-S of imatinib mesylate, comprising:

a) providing a solution of imatinib and methanesulphonic acid in methanol;

b) adding hydrochloric acid;

c) adding an ether solvent to the solution of step b);

d) isolating the solid; and

e) drying the solid at 150-170°C to afford crystalline form-S of imatinib mesylate.

In an aspect, the present application provides a pharmaceutical composition comprising crystalline form-S of imatinib mesylate and at least one pharmaceutically acceptable excipient.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 is an illustrative example of an X-ray powder diffraction pattern of crystalline form-R of imatinib mesylate, prepared according to Example 2.

Figure 2 is an illustrative example of an X-ray powder diffraction pattern of crystalline form-S of imatinib mesylate, prepared according to Example 3.

DETAILED DESCRIPTION

Aspects of the present application relate to crystalline form of imatinib mesylate designated as form-R and process for preparation thereof.

Crystalline forms form-R of imatinib mesylate may be characterized by any one or more analytical results which may include X-ray powder diffraction ("XRPD") pattern.

In one embodiment, there is provided a crystalline form-R of imatinib mesylate characterized by an X-ray powder diffraction (XRPD) pattern comprising two or more of the characteristic peaks located at about 6.6, 9.9, 15.0, 16.4, 16.9, 19.8, or 20.6 ± 0.2 degrees 2-theta.

In an aspect, the present application provides a process for the preparation of crystalline form-R of imatinib mesylate, comprising:

a) providing a solution of imatinib and methanesulphonic acid in methanol;

b) adding hydrochloric acid;

c) adding an ether solvent to the solution of step b);

d) isolating the solid; and

e) drying the solid at 90-135°C to afford crystalline form-R of imatinib mesylate.

The individual steps are separately described herein below. Imatinib prepared by any method known in the art can be used as starting material.

Step a) includes providing a solution of imatinib and methanesulfonic acid in methanol. The solution of imatinib and methanesulfonic acid may be provided by combining imatinib with methanol, followed by the addition of methanesulfonic acid. Any form of imatinib such as a crystalline or amorphous form may be used for forming a solution. The quantity of methanol used for providing a solution may range from about 5 mL to about 15 ml_, or about 10 ml_, per gram of imatinib base. The solution may be prepared at any temperatures up to the boiling point of the methanol, e.g., from about -10°C to about reflux temperature of methanol. In an embodiment, solution may be prepared at temperatures ranging from about 25° to about 35° C.

Step b) includes adding hydrochloric acid to the solution of step a). Hydrochloric acid used in step b) may be concentrated hydrochloric acid (32-36%) or an aqueous solution of concentrated hydrochloric acid. In an embodiment, about 0.1 equivalent to about 0.35 equivalents of concentrated hydrochloric acid per gram of imatinib base may be used.

The addition of hydrochloric acid may be performed at any temperatures, including about -10°C to about 40°C. The obtained reaction mass may be stirred for about 15 minutes to about 2 hours. In an embodiment, hydrochloric acid addition may be performed at about 25° to about 35° C and stirred for about 5 minutes.

Step c) includes adding ether solvent to a solution of step b). The ether solvent in step c) is used as an anti-solvent and may be selected from diethyl ether, diisopropyl ether, methyl tertiary-butyl ether (MTBE), or the like. The quantities of the ether solvent used may range from about 10 mL to about 45 mL, or about 15 mL per gram of imatinib base. The addition of ether solvent may be performed at any temperatures, including about -10°C to about 40°C and the reaction mass is stirred for about 15 minutes to about 2 hours at the desired temperature, or longer.

Step d) includes isolating the solid from the reaction mass of step c). The solid may be isolated using general techniques known to persons skilled in the art. For example, the solid may be isolated by using techniques such as slow solvent evaporation, rapid evaporation, slow cooling, and rapid cooling. In an embodiment, the reaction mass of step c) is subjected to slow solvent evaporation at a temperature of about 20° C to about 40° C. After isolation, the solid may optionally be washed with a suitable solvent such as diethyl ether, diisopropyl ether, methyl tertiary-butyl ether (MTBE), or the like.

Step e) includes drying the solid at a temperature from about 90 ° C to about 135° C to afford crystalline form-R of imatinib mesylate. The solid obtained in step d) is dried at about 90° C to about 135° C in an air tray dryer for a period of from about 1 hour to about 5 hours to obtain crystalline form-R of imatinib mesylate. Alternately, the solid obtained in step d) is initially dried at temperature from about 70° to about 80° C in vacuum tray dryer and further subjected to drying at about 90° C to about 140° C in an air tray dryer to obtain crystalline form-R of imatinib mesylate. Drying can be carried out until the residual solvent content reduces to the desired amount such as an amount 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 crystalline form-R of imatinib mesylate produced according to the processes of the present application is sufficiently stable for commercial purposes and useful for making pharmaceutical dosage forms for the treatment of diseases, including, but not limited to, Philadelphia positive chronic myeloid leukemia. The crystalline form-R of imatinib mesylate obtained by the process of the present application may have a polymorphic purity of greater than about 95%, greater than about 98%, greater than about 98.5%, greater than about 99.0%, or greater than about 99.5%. The crystalline form-R of imatinib mesylate obtained by the process of the present application may be utilized for the preparation of amorphous as well as other crystalline polymorphs. In one embodiment, the present application provides pharmaceutical compositions comprising crystalline form-R of imatinib mesylate and at least one pharmaceutically acceptable excipient.

Another aspect of the present application relate to crystalline form of imatinib mesylate designated as form-S and processes for preparation thereof.

Crystalline form form-S of imatinib mesylate may be characterized by any one or more analytical results which may include X-ray powder diffraction ("XRPD") patterns.

In one embodiment, there is provided a crystalline form-S of imatinib mesylate characterized by X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 2.

In one embodiment, there is provided a crystalline form-S of imatinib mesylate characterized by X-ray powder diffraction (XRPD) pattern comprising two or more of the characteristic peaks located at about 8.5, 10.0, 13.1, 15.0, 16.4, 17.0, 19.8, 20.6, 21.3, 21.7, 22.1, 22.8, or 23.1 ±0.2 degrees 2-theta.

In an aspect, the present application provides a process for the preparation of crystalline form-S of imatinib mesylate, comprising:

a) providing a solution of imatinib and methanesulphonic acid in methanol;

b) adding hydrochloric acid;

c) adding an ether solvent to the solution of step b);

d) isolating the solid; and

e) drying the solid at 150-170°C to afford crystalline form-S of imatinib mesylate.

The individual steps are separately described herein below. Imatinib prepared by any method known in the art can be used as starting material.

Step a) includes providing a solution of imatinib and methanesulfonic acid in methanol. The solution of imatinib and methanesulfonic acid may be provided by combining imatinib with methanol, followed by the addition of methanesulfonic acid. Any form of imatinib such as a crystalline or amorphous form may be used for forming a solution. The quantity of methanol used for providing a solution may range from about 5 mL to about 15 ml_, or about 10 ml_, per gram of imatinib base. The solution may be prepared at any temperatures up to the boiling point of the methanol, e.g., from about -10°C to about the reflux temperature of methanol. In an embodiment, the solution may be prepared at temperatures ranging from about 25° to about 35° C.

Step b) includes adding hydrochloric acid to the solution of step a). Hydrochloric^cid used in step b) may be concentrated hydrochloric acid (32-36%) or an aquexius solution of concentrated hydrochloric acid. In an embodiment, about 0.1 equivalent to about 0.35 equivalents of concentrated hydrochloric acid per gram of imatinib base may be used. The addition of hydrochloric acid may be performed at any temperatures, including about -10°C to about 40°C. The obtained reaction mass may be stirred for about 15 minutes to about 2 hours. In an embodiment, hydrochloric acid addition may be performed at about 25° to about 35° C and stirred for about 5 minutes.

Step c) includes adding ether solvent to a solution of step b). Ether solvent in step c) is used as an anti-solvent and may be selected from diethyl ether, diisopropyl ether, methyl tertiary-butyl ether (MTBE), or the like. The quantities of ether-solvent used may range from about 10 mL to about 45 ml_, or about 15 mL per gram of imatinib base. The addition of ether solvent may be performed at any temperatures, including from about -10°C to about 40°C and the reaction mass is stirred for about 15 minutes to about 2 hours at the desired temperature, or longer.

Step d) includes isolating the solid from the reaction mass of step c). The solid may be isolated using general techniques known to persons skilled in the art. For example, the solid may be isolated by using techniques such as slow solvent evaporation, rapid evaporation, slow cooling, and rapid cooling. In an embodiment, reaction mass of step c) is subjected to slow solvent evaporation at a temperature of about 20° C to about 40° C. After isolation, the solid may optionally be washed with a suitable solvent such as diethyl ether, diisopropyl ether, methyl tertiary-butyl ether (MTBE), or the like.

Step e) includes drying the solid at a temperature from about 150 °C to about 170°C to afford crystalline form-S of imatinib mesylate. The solid obtained in step d) is dried at about 150° C to about 170° C in an air tray dryer for a period of about 1 hour to about 5 hours to obtain crystalline form S of imatinib mesylate. Alternately, the solid obtained in step d) is initially dried at temperature of about 70° to about 80° C in vacuum tray dryer and further subjected to drying at about 150° C to about 170° C in an air tray dryer to obtain crystalline form S of imatinib mesylate. Drying can be carried out until the residual solvent content reduces to the desired amount such as an amount that is within the limits given by the International Conference on Harmonization of Technical Requirements for Registration tsf Pharmaceuticals for Human Use ("ICH") guidelines.

The crystalline form-S of imatinib mesylate produced according to the processes of the present application are sufficiently stable for commercial purposes and useful for making pharmaceutical dosage forms for the treatment of diseases, including, but not limited to, Philadelphia positive chronic myeloid leukemia. The crystalline form-S of imatinib mesylate obtained by the process of the present application may have a polymorphic purity of greater than about 95%, greater than about 98%, greater than about 98.5%, greater than about 99.0%, or greater than about 99.5%.

The crystalline form-S of imatinib mesylate obtained by the process of the present application may be utilized for the preparation of amorphous as well as other crystalline polymorphs.

In one embodiment, the present application provides pharmaceutical compositions comprising crystalline form-S of imatinib mesylate and at least one pharmaceutically acceptable excipient.

The occurrence of different polymorphs is possible for some compounds. A single compound may give rise to a variety of solids having distinct physical properties, such as X-ray diffraction patterns, infrared absorption spectra, and NMR spectra. This variation in solid forms may be significant and may result in differences with respect to bioavailability, stability, and other differences for formulated pharmaceutical products. Because polymorphic forms can vary in their physical properties, regulatory authorities require that efforts shall be made to identify all polymorphic forms, e.g., crystalline, amorphous, solvated, efc., of new drug substances.

The existence and possible numbers of polymorphic forms for a given compound cannot be predicted, and there are no "standard" procedures that can be used to prepare polymorphic forms of a substance. However, new forms of a pharmaceutically useful compound may provide an opportunity to improve the performance characteristics of pharmaceutical products. Further, discovery of additional polymorphic forms, including solvate polymorphs, may help in the identification of the polymorphic content of a batch of an active pharmaceutical ingredient. For example, in some cases, different forms of the same drug can exhibit very different solubility and different dissolution rates.

Crystalline forms are characterized by scattering techniques, e.g., x-ray diffraction powder pattern, by spectroscopic methods, e.g., infra-red, 13C nuclear magnetic resonance spectroscopy, and by thermal techniques, e.g., differential scanning calorimetry or differential thermal analysis. The compound of this invention is best characterized by the X-ray powder diffraction pattern determined in accordance with procedures that are known in the art. For a discussion of these techniques see J. Haleblian, J. Pharm. Sci. 1975 64:1269-1288, and J. Haleblian and W. McCrone, J. Pharm. Sci. 1969 58:911-929. The PXRD data reported herein were obtained using copper Ka radiation, and were obtained using a Bruker AXS D8 Advance Powder X-ray Diffractometer. It may be noted that one skilled in the art may easily recognize the presence or absence of the certain peaks located in an X-ray powder diffraction pattern and which are characteristic of other crystalline forms.

Generally, a diffraction angle (29) in powder X-ray diffractometry may have an error in the range of ± 0.2°. Therefore, the aforementioned diffraction angle values should be understood as including values in the range of about ± 0.2°. Accordingly, the present invention includes not only crystals whose peak diffraction angles in powder X-ray diffractometry completely coincide with each other, but also crystals whose peak diffraction angles coincide with each other with an error of about ±.0.2°. Therefore, in the present specification, the phrase "having a diffraction peak at a diffraction angle (20 ± 0.2°) of 19.8°" means "having a diffraction peak at a diffraction angle (20) of 19.6° to 20.0°. Although the intensities of peaks in the x-ray powder diffraction patterns of different batches of a compound may vary slightly, the peaks and the peak locations are characteristic for a specific polymorphic form. Alternatively, the term "about" means within an acceptable standard error of the mean, when considered by one of ordinary skill in the art. The relative intensities of the PXRD peaks can vary depending on the sample preparation technique, crystal size distribution, various filters used, the sample mounting procedure, and the particular instrument employed. Moreover, instrument variation and other factors can affect the 2-theta values. Therefore, the term "substantially" in the context of PXRD is meant to encompass that peak assignments.can vary by plus or minus about 0.2.degree. Moreover, new peaks may be observed or existing peaks may disappear, depending on the type of the machine or the settings (for example, whether a Ni filter is used or not).

A polymorphic form may be described by reference to patterns, spectra, or other graphical data as "substantially" shown or depicted in a figure, or by one or more data points. It will be appreciated that patterns, spectra, and other graphical data can be shifted in their positions, relative intensities, or other values due to a number of factors known to those of skill in the art. For example, in the crystallographic and powder X-ray diffraction arts, shifts in peak positions or the relative intensities of one or more peaks of a pattern can occur because of, without limitation, the equipment used, the sample preparation protocol, preferred packing and orientations, the radiation source, operator error, method and length of data collection, or the like. However, those of ordinary skill in the art will be able to compare the figures herein with patterns, etc. generated for an unknown form of, in this case, imatinib mesylate, and to confirm its identity with form-R or form-S disclosed herein. The same holds true for other techniques which may be reported herein.

DEFINITIONS

The following definitions are used in connection with the present invention unless the context indicates otherwise.

The term "anti-solvent" refers to a liquid that, when combined with a solution of imatinib mesylate, reduces solubility of the imatinib mesylate in the solution, causing crystallization or precipitation in some instances spontaneously, and in other instances with additional steps, such as seeding, cooling, scratching and/or concentrating.

An "ether solvent" is an organic solvent containing an oxygen atom -O-bonded to two other carbon atoms. "Ether solvents" include but are not limited to diethyl ether, diisopropyl ether, methyl t-butyl ether, glyme, diglyme, tetrahydrofuran, 1,4-dioxane, dibutyl ether, dimethylfuran, 2-methoxyethanol, 2-ethoxyethanol, anisole, C2-6ethers, or the like.

A polymorphic form may be described by reference to patterns, spectra, or other graphical data as "substantially" shown or depicted in a figure, or by one or more data points. It will be appreciated that patterns, spectra, and other graphical data can be ^lffted in their positions, relative intensities, or other values due to a number of factors known to those of skill in the art. For example, in the crystallographic and powder X-ray diffraction arts, shifts in peak positions or the relative intensities of one or more peaks of a pattern can occur because of, without limitation, the equipment used, the sample preparation protocol, preferred packing and orientations, the radiation source, operator error, method and length of data collection, or the like. However, those of ordinary skill in the art will be able to compare the figures herein with patterns, etc. generated for an unknown form of, in this case, imatinib mesylate, and confirms its identity with form-R, or form-S disclosed herein. The same holds true for other techniques which may be reported herein.

In addition, where a reference is made to a figure, it is permissible to, and this document includes and contemplates, the selection of any number of data points illustrated in the figure that uniquely define that crystalline form, within any associated and recited margin of error, for purposes of identification.

The term crystalline form-R or form-S may refer to purer forms of imatinib mesylate or they may refer to different polymorphs of imatinib mesylate. They may be solvates, be mixtures of polymorphs, or have different crystal defects.

All percentages and ratios used herein are by weight of the total composition and all measurements made are at about 25°C and about normal pressure, unless otherwise designated. All temperatures are in degrees Celsius unless specified otherwise. As used herein, "comprising" (open ended) means the elements recited, or their equivalent in structure or function, plus any other element or elements which are not recited. The terms "having" and "including" are also to be construed as open ended. As used herein, "consisting essentially of means that the invention may include ingredients in addition to those recited in the claim, but only if the additional ingredients do not materially alter the basic and novel characteristics of the claimed invention. All ranges recited herein include the endpoints, including those that recite a range "between" two values. Whether so indicated or not, all values recited herein are approximate as defined by the circumstances, including the degree of expected experimental error, technique error, and instrument error for a given technique used to measure a value.

Certain specific aspects and embodiments of the present application will be explained in more detail with reference to the following examples, which are provided for purposes of illustration only and should not be construed as limiting the scope of the present application in any manner.

EXAMPLES

EXAMPLE 1: Preparation of imatinib mesylate.

Imatinib (10 g) is suspended in methanol (100 mL) at 25-30°C and the mixture is stirred at 25-30°C. Methanesulfonic acid (1.34 mL) is added at the same temperature and stirred for 5-10 minutes to give a clear solution. Concentrated hydrochloric acid (0.66 mL) is added to the above solution at 25-30°C and stirred for 2-5 minutes at 25-30°C. Methyl tertiary-butyl ether (150 mL) is added to the above reaction mixture and the obtained reaction mixture is subjected to slow solvent evaporation at room temperature (25-30°C). The obtained compound is collected by filtration, washed with Methyl tertiary-butyl ether (40 mL), suction dried for 5-10 minutes, and dried at about 80°C for about 10-12 hours in a vacuum tray dryer (VTD) to give 8.7 g of the title compound.

EXAMPLE 2: Preparation of crystalline form-R of imatinib mesylate.

Imatinib mesylate (2.6 g) prepared according to the Example 1 is dried in an air tray dryer at 135°C for 1 hour to obtain crystalline form-R of imatinib mesylate. XRPD pattern: Figure 1

EXAMPLE 3: Preparation of crystalline form-S of imatinib mesylate.

Imatinib mesylate (2.9 g) prepared according to the Examplel is dried in an air tray dryer at 160°C for 2 hours to obtain crystalline form-S of imatinib mesylate. XRPD pattern: Figure 2

Claims:

1. A process for the preparation of crystalline form-R of imatinib mesylate characterized by X-ray powder diffraction pattern with characteristic peaks located at about 8.5, 10.0, 13.1, 15.0, 16.4, 17.0, 19.8, 20.6, 21.3, 21.7, 22.1, 22.8, or 23.1 + 0.2 degrees 2-theta, comprising:

a) providing a solution of imatinib and methanesulphonic acid in methanol;

b) adding hydrochloric acid;

c) adding an ether solvent to the solution of step b);

d) isolating the solid; and

e) drying the solid at 90-135°C to afford crystalline form-R of imatinib mesylate.

2. A process for the preparation of crystalline form-S of imatinib mesylate characterized by X-ray powder diffraction pattern with characteristic peaks located at about 8.5, 10.0, 13.1, 15.0, 16.4, 17.0, 19.8, 20.6, 21.3, 21.7, 22.1, 22.8, or 23.1 ± 0.2 degrees 2-theta, comprising:

a) providing a solution of imatinib and methanesulphonic acid in methanol;

b) adding hydrochloric acid;

c) adding an ether solvent to the solution of step b);

d) isolating the solid; and

e) drying the solid at 150-170°C to afford crystalline form-S of imatinib mesylate.

3. The process of claims 1 and 2, wherein the hydrochloric acid used in step b) is concentrated hydrochloric acid (32-36%) or an aqueous solution of concentrated hydrochloric acid.

4. The process of claims 1 and 2, wherein the amount of concentrated hydrochloric acid used in step b) is about 0.1 equivalent to about 0.35 equivalents per gram of imatinib base.

5. The process of claims 1 and 2, wherein the hydrochloric acid is added at temperatures about -10°C to about 40°C.

6. The process of claims 1 and 2, wherein the ether solvent used in step c) is selected from diethyl ether, diisopropyl ether, methyl tertiary-butyl ether (MTBE), or the like.

7. The process of claims 1 and 2, wherein the ether solvent is added at temperatures about -10°C to about 40°C.

8. The process of claims 1 and 2, wherein the reaction mixture in step c) obtained after the addition of ether solvent is optionally subjected to slow solvent evaporation.