WO2011100282A2

WO2011100282A2 - Imatinib mesylate polymorphs

Info

Publication number: WO2011100282A2
Application number: PCT/US2011/024137
Authority: WO
Inventors: Vamsi Krishna Mudapaka; Sesha Reddy Yarraguntla; Venu Nalivela; Vamsee Krishna Muppidi; Rajesham Boge
Original assignee: Dr Reddys Laboratories Ltd; Dr Reddys Laboratories Inc
Current assignee: Dr Reddys Laboratories Ltd; Dr Reddys Laboratories Inc
Priority date: 2010-02-09
Filing date: 2011-02-09
Publication date: 2011-08-18
Anticipated expiration: 2012-08-09
Also published as: WO2011100282A3

Abstract

The present application relates to crystalline forms of imatinib mesylate and process for preparation thereof.

Description

IMATINIB MESYLATE POLYMORPHS

INTRODUCTION

Aspects of the present application relate to crystalline forms of imatinib mesylate and process for preparation thereof. 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.

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-I 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 2008/1 12722 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. WO2008/150481 A2 describes a method of preparing crystalline imatinib mesylate form beta, from crystalline imatinib mesylate Form IV.

Adin ef a/., 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 ef a/., 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 ef 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 al., in U.S. Patent Application Publication No. 2008/0234286 A1 , describes a stable micronized amorphous form, having a water content in the range of 3.2-5%.

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. 209/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 forms of imatinib mesylate designated as Form-Y, Form-Y', Form-Z, and processes for preparation thereof.

In an aspect, the present application provides a crystalline form of imatinib mesylate, which is designated herein as "Form-Y." Form-Y may be characterized using one or more analytical methods.

In one embodiment, there is provided a crystalline Form-Y of imatinib mesylate characterized by an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 1 , Figure 4, or Figure 5.

In one embodiment, there is provided a crystalline Form-Y of imatinib mesylate characterized by an X-ray powder diffraction (XRPD) pattern comprising two or more of the characteristic peaks located at about 6.1 , 8.7, 1 1.5, 14.5, 18.0,

18.7, 20.1 , 21.9, or 22.5 ± 0.2 degrees 2-theta.

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

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

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

c) isolating the obtained solid; and

d) drying the solid to afford crystalline Form-Y of imatinib mesylate. In an aspect, the present application provides a crystalline form of imatinib mesylate, which is designated herein as "Form-Y¹." Form-Y' may be characterized using one or more analytical methods.

In one embodiment, there is provided a crystalline Form-Y' of imatinib mesylate characterized by an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 8 or Figure 9.

In an aspect, the present application provides a process for the preparation of crystalline Form-Y' of imatinib mesylate, comprising:

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

b) optionally, adding a seed material;

c) adding an ether solvent;

d) isolating the obtained solid; and

e) drying the solid to afford crystalline Form-Y' of imatinib mesylate.

In one aspect, the present invention provides a crystalline form of imatinib mesylate, which is designated herein as "Form-Z." Form-Z may be characterized using one or more analytical methods.

In one embodiment, there is provided a crystalline Form-Z of imatinib mesylate characterized by an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 10.

In one embodiment, there is provided a crystalline Form-Z 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, 8.0, 13.9, 16.6, 17.0, 17.3, 18.4, 19.0, 20.2, 22.2, or 24.2 ± 0.2 degrees 2-theta.

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

a) providing a solution of imatinib mesylate in dimethylsulphoxide;

b) combining the solution of step a) with a halogenated hydrocarbon solvent;

c) isolating the solid obtained; and

d) optionally, drying the solid to afford crystalline Form-Z of imatinib mesylate. The crystalline Form-Y, Form-Y', and Form-Z 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.

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

In an aspect, the present application provides a pharmaceutical formulation comprising crystalline Form-Y' of imatinib mesylate and at least one pharmaceutically acceptable excipient.

In another aspect, the present application provides a pharmaceutical formulation comprising crystalline Form-Z of imatinib mesylate and at least one pharmaceutically acceptable excipient.

BRIEF DESCRIPTION OF THE DRAWING

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

Figure 2 is an illustrative example of a differential scanning calorimetry ("DSC") curve of crystalline Form-Y of imatinib mesylate, prepared according to Example 1.

Figure 3 is an illustrative example of a thermogravimetric analysis ("TGA") curve of crystalline Form-Y of imatinib mesylate, prepared according to Example 1.

Figure 4 is an illustrative example of an X-ray powder diffraction pattern of crystalline Form-Y of imatinib mesylate, prepared according to Example 1 (Sample - 1).

Figure 5 is an illustrative example of an X-ray powder diffraction pattern of crystalline Form-Y of imatinib mesylate, prepared according to Example 2.

Figure 6 is an illustrative example of a DSC curve of crystalline Form-Y of imatinib mesylate, prepared according to Example 2.

Figure 7 is an illustrative example of a TGA curve of crystalline Form-Y of imatinib mesylate, prepared according to Example 2. Figure 8 is an illustrative example of an X-ray powder diffraction pattern of crystalline Form-Y' of imatinib mesylate, prepared according to Example 3.

Figure 9 is an illustrative example of an X-ray powder diffraction pattern of crystalline Form-Y' of imatinib mesylate prepared according to Example 4.

Figure 10 is an illustrative example of an X-ray powder diffraction pattern of crystalline Form-Z of imatinib mesylate, prepared according to Example 5.

DETAILED DESCRIPTION

Crystalline forms Form-Y, Form-Y', and Form-Z of imatinib mesylate may be characterized by any one or more analytical results which may include X-ray powder diffraction ("XRPD") patterns, differential scanning calorimetry ("DSC") curves, and thermogravimetric analysis ("TGA") curves.

In one embodiment, there is provided a crystalline Form-Y of imatinib mesylate characterized by an X-ray powder diffraction (XRPD) pattern comprising two or more of the characteristic peaks located at about 6.1 , 8.7, 1 1.5, 14.5, 18.0, 18.7, 20.1 , 21.9, or 22.5 ± 0.2 degrees 2-theta.

In one aspect, there is provided a crystalline Form-Y of imatinib mesylate.

Crystalline Form-Y of imatinib mesylate may be characterized using one or more of the following analytical methods: its XRPD pattern, substantially in accordance with Figure 1 , Figure 4, or Figure 5; its DSC curve, substantially in accordance with Figure 2 or Figure 6; and its TGA curve, substantially in accordance with Figure 3 or Figure 7.

In embodiments, there is provided a crystalline Form-Y of imatinib mesylate characterized by XRPD pattern, substantially in accordance with Figure 1. ln embodiments, there is provided a crystalline Form Y of imatinib mesylate characterized by its DSC curve, substantially in accordance with Figure 2.

In embodiments, there is provided a crystalline Form-Y of imatinib mesylate characterized by its TGA curve, substantially in accordance with Figure 3.

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

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

c) isolating the obtained solid; and

d) drying the solid to afford crystalline Form-Y of imatinib mesylate. The individual steps are separately described herein below.

Step a) includes providing a solution of imatinib and methanesulfonic acid in methanol. The solution of imatinib and methanesulfonic acid may be obtained by the combining imatinib with the solvent, followed by the addition of methanesulfonic acid. Any form of imatinib is acceptable for forming a solution, such as a crystalline or amorphous form. 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 solvent, e.g., from about -10°C to about reflux temperature of methanol. The solution may be prepared at lower temperatures, such as below 20°C, or in the range of about -5°C to about 0°C. The solution may be optionally treated with activated charcoal or sodium sulfate, and then filtered to remove the carbon or sodium sulfate. The solution may optionally be filtered by passing through paper, glass fiber, or other membrane material, or a bed of a clarifying agent such as Celite®. Depending upon the equipment used, as well as the concentration and temperature of the solution, the filtration apparatus may need to be heated or cooled to avoid undesired crystallization.

Step b) includes adding ether as an anti-solvent to a solution of a). Anti- solvents that may be used for the preparation of imatinib mesylate Form-Y include, but are not limited to, ethers such as diethyl ether, diisopropyl ether, methyl tertiary- butyl ether (MTBE), or the like. The quantities of anti-solvent used may range from about 10 mL to about 45 mL, or about 40 mL, per gram of imatinib base. The addition of anti-solvent may be performed at any temperatures, including about -10°C to about 30°C. The obtained suspension may be stirred for about 15 minutes to about 2 hours, or longer, to enhance the extent of crystallization. Useful temperatures for maintaining a suspension may range from about -5°C to about 35°C.

Step c) includes isolating a solid from the mixture of step b). The solid may be isolated from the suspension using general techniques known to persons skilled in the art for separating solids from liquids. For example, the solid may be isolated by using techniques such as, for example, filtration by gravity or by suction, centrifugation, decantation, or the like. After isolation, the solid may optionally be washed with a suitable solvent such as diethyl ether, diisopropyl ether, MTBE, or the like.

Step d) includes drying the solid to afford crystalline Form-Y of imatinib mesylate. The obtained solid of imatinib mesylate may be dried. The drying of solid material may be carried out under suitable conditions to afford the desired crystalline form of imatinib mesylate, substantially free of residual solvents. Drying may be carried out at reduced pressures, such as more than about 500 mm Hg, at temperatures such as about 35°C to about 60°C or higher, or about 45°C. Drying may be suitably carried out in equipment such as a rotary dryer, tray dryer, vacuum oven, air oven, humidity dryer, fluidized bed dryer, spin flash dryer, flash dryer, or combinations thereof. The drying of solid can be carried out in a controlled humidity environment having a relative humidity ("RH"), such as below 75% RH or between about 30 to 75% RH, at temperatures such as about 20- 50°C. Exposure to an environment containing relative humidity can reduce the residual solvent content. The humidification drying may be performed for any desired time periods that achieve the desired product purity and residual solvent content, such as times from about 1 hour to about 30 hours, or longer. Drying may also be carried out for shorter or longer periods of time depending on the product specifications. The product obtained from the humidity drying may be further dried using any of the suitable drying techniques mentioned above, especially to remove the water content. Optionally, the said drying may be carried out in three stages, the first being drying under reduced pressure in a tray dryer, the second being drying under controlled humidity environment and third step being drying under reduced pressure in a tray dryer.

The crystalline Form-Y of Imatinib mesylate obtained by the process of the present application may have a polymorphic purity of greater than about 95%, or greater than about 98%, or greater than about 98.5%, or greater than about 99.0%, or greater than about 99.5%.

The crystalline Form-Y 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 formulations comprising crystalline Form-Y of imatinib mesylate and at least one pharmaceutically acceptable excipient.

The crystalline Form-Y of imatinib mesylate produced according to a process of the present invention is sufficiently stable for commercial purposes. Crystalline Form-Y is useful for making pharmaceutical dosage forms for the treatment of diseases, including, but not limited to, Philadelphia positive chronic myeloid leukemia.

In an aspect, the present application provides a crystalline form of imatinib mesylate, which is designated herein as "Form-Y¹." Form-Y' may be characterized using one or more analytical methods.

The crystalline Form-Y' of imatinib mesylate characterized by an X-ray powder diffraction pattern having peak reflections at about 6.1 , 8.7, 1 1.5, 14.5, 18.0, 18.7, 20.1 , 21.9, or 22.5 ± 0.2 degrees 2-theta obtained by the process of present application may be represented by an X-ray powder diffraction substantially as described in Figure 8 or Figure 9.

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

b) optionally, adding a seed material;

c) adding an ether solvent;

d) isolating the obtained solid; and

e) drying the solid to afford crystalline Form-Y' of imatinib mesylate. The individual steps are separately described herein below.

Step a) includes providing a solution of imatinib and methanesulfonic acid in methanol. The solution of imatinib and methanesulfonic acid may be obtained by the combining imatinib with the solvent, followed by the addition of methanesulfonic acid. Any form of imatinib is acceptable for forming a solution, such as a crystalline or amorphous form. 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 solvent, e.g., from about -10°C to about reflux temperature of methanol. The solution may be prepared at lower temperatures, such as below 20°C, or in the range of about -5°C to about 0°C. The solution may be optionally treated with activated charcoal or sodium sulfate, and then filtered to remove the carbon or sodium sulfate. The solution may optionally be filtered by passing through paper, glass fiber, or other membrane material, or a bed of a clarifying agent such as Celite®. Depending upon the equipment used, as well as the concentration and temperature of the solution, the filtration apparatus may need to be heated or cooled to avoid undesired crystallization.

Step b) includes optionally adding a seed material

The seed material may optionally be added to the solution of step a). Seed material that may be used in step b) may be the crystalline Form-Y or crystalline Form-Y of imatinib mesylate. The seed material of crystalline Form-Y or crystalline Form-Y' of imatinib mesylate may be prepared by a process as described in the present application.

Step c) includes adding an ether solvent. The ether solvent may be added to the solution of step a) or to that of step b) depending on the seeding operation. Preferably, the ether solvent is added to an admixture of step b). The ether solvent that may be used as anti-solvents for the preparation of imatinib mesylate Form-Y include, but are not limited to, diethyl ether, diisopropyl ether, methyl tertiary- butyl ether (MTBE), or the like. The quantities of anti-solvent used may range from about 10 mL to about 45 mL, or about 40 mL, per gram of imatinib base. The addition of anti-solvent may be performed at any temperatures, including about -10°C to about 30°C. The obtained suspension may be stirred for about 15 minutes to about 2 hours, or longer, to enhance the extent of crystallization. Useful temperatures for maintaining a suspension may range from about -5°C to about 35°C.

Step d) includes isolating a solid from the mixture of step b). The solid may be isolated from the suspension using general techniques known to persons skilled in the art for separating solids from liquids. For example, the solid may be isolated by using techniques such as, for example, filtration by gravity or by suction, centrifugation, decantation, or the like. After isolation, the solid may optionally be washed with a suitable solvent such as diethyl ether, diisopropyl ether, MTBE, or the like.

Step e) includes drying the solid to afford crystalline Form-Y' of imatinib mesylate. The obtained solid of imatinib mesylate may be dried. The drying of solid material may be carried out under suitable conditions to afford the desired crystalline form of imatinib mesylate, substantially free of residual solvents. Drying may be carried out at reduced pressures, such as more than about 500 mm Hg, at temperatures such as about 35°C to about 60°C or higher, or about 45°C. Drying may be suitably carried out in equipment such as a rotary dryer, tray dryer, vacuum oven, air oven, humidity dryer, fluidized bed dryer, spin flash dryer, flash dryer, or combinations thereof. The drying of solid can be carried out in a controlled humidity environment having a relative humidity ("RH"), such as below 75% RH or between about 30 to 75% RH, at temperatures such as about 20- 50°C. Exposure to an environment containing relative humidity can reduce the residual solvent content. The humidification drying may be performed for any desired time periods that achieve the desired product purity and residual solvent content, such as times from about 1 hour to about 30 hours, or longer. Drying may also be carried out for shorter or longer periods of time depending on the product specifications. The product obtained from the humidity drying may be further dried using any of the suitable drying techniques mentioned above, especially to remove the water content. Optionally, the said drying may be carried out in three stages, the first being drying under reduced pressure in a tray dryer, the second being drying under controlled humidity environment and third step being drying under reduced pressure in a tray dryer.

The crystalline Form-Y' of Imatinib mesylate obtained by the process of the present application may have a polymorphic purity of greater than about 95%, or greater than about 98%, or greater than about 98.5%, or greater than about 99.0%, or greater than about 99.5%.

The crystalline Form-Y' 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 formulations comprising crystalline Form-Y' of imatinib mesylate and at least one pharmaceutically acceptable excipient.

The crystalline Form-Y' of imatinib mesylate produced according to a process of the present invention is sufficiently stable for commercial purposes. Crystalline Form-Y' is useful for making pharmaceutical dosage forms for the treatment of diseases, including, but not limited to, Philadelphia positive chronic myeloid leukemia.

a) providing a solution of imatinib mesylate in dimethylsulphoxide; b) combining the solution of step a) with a halogenated hydrocarbon solvent;

c) isolating the solid obtained; and

d) optionally, drying the solid to afford crystalline Form-Z of imatinib mesylate.

The individual steps are separately described herein below. Step a) includes providing a solution of imatinib mesylate in dimethylsulfoxide. The solution of imatinib mesylate may be obtained by the combining imatinib mesylate with dimethylsulfoxide or it may be obtained from a reaction step in which the compound is prepared. Any form of imatinib mesylate is acceptable for forming a solution, such as a crystalline or amorphous form. The quantity of dimethylsulfoxide used for providing a solution may range from about 2 ml_ to about 20 ml_, or more, per gram of imatinib mesylate. The solution may be prepared at any temperatures up to the boiling point, e.g., from about 0°C to about reflux temperature of dimethylsulfoxide. In embodiments, the solution may be prepared at temperatures from about 60°C to about 95°C. The solution may optionally be treated with activated charcoal and then filtered to remove the carbon. The solution may optionally be filtered by passing through paper, glass fiber, or other membrane material, or a bed of a clarifying agent such as Celite®. Depending upon the equipment used, as well as the concentration and temperature of the solution, the filtration apparatus may need to be heated or cooled to avoid undesired crystallization.

Step b) includes combining the solution of step a) with a halogenated hydrocarbon solvent. Halogenated hydrocarbon solvents such as dichloromethane or chloroform may be used as an anti-solvent for crystallizing the material from the solution of step a). Any other suitable solvents other than halogenated hydrocarbon solvents that can crystallizes the material from the solution of step a) may also be used as an anti-solvent as long as it provides Form Z of the present application The quantities of anti-solvent used may range from about 20 mL to about 60 ml_, or about 50 mL, per gram of imatinib mesylate. Adding the solution of step a) to the anti-solvent, or adding an anti-solvent to the solution of step a), to initiate crystallization process are both within the scope of the present application In embodiments, the solution of step a) is added to the anti-solvent. The addition may be performed at temperatures ranging from about - 10°C to about 25°C. In specific embodiments, the solution of step a) is added to anti-solvent, e.g., dichloromethane, precooled to temperatures in the range from about 0°C to about -5°C. The mixture obtained may be stirred for a time from about 15 minutes to about 3 hours, or longer, within the same temperature range to enhance the extent of crystallization. Step c) includes isolating the solid obtained. The solid may be isolated from the suspension using general techniques known to persons skilled in the art for separating solids from liquids. For example, the solid may be isolated by using techniques such as, for example, filtration by gravity or by suction, centrifugation, decantation, or the like. After isolation, the solid may optionally be washed with the anti-solvent used in step b).

Step d) includes optionally drying the solid, to afford crystalline Form-Z of imatinib mesylate. The drying of solid material may be carried out under suitable conditions to afford the desired crystalline form of imatinib mesylate, substantially free of residual solvents. Drying may be carried out at reduced pressures, such as more than about 500 mm Hg, at temperatures from about 50°C to about 70°C, or about 60°C.

The crystalline Form-Z of Imatinib mesylate obtained by the process of the present application may have a polymorphic purity of greater than about 95%, or greater than about 98%, or greater than about 98.5%, or greater than about 99.0%, or greater than about 99.5%.

The crystalline Form-Z of imatinib mesylate obtained from the present application may be utilized for the preparation of amorphous as well as other crystalline polymorphs.

In an aspect, the present application provides pharmaceutical formulations comprising crystalline Form-Z of imatinib mesylate, together with 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, etc., 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 58:91 1-929. 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. Differential scanning calorimetric analyses reported herein were carried out using a DSC Q1000 model from TA Instruments with a ramp of 10°C/minute up to 200°C. The starting temperature was 20°C and ending temperature was 200°C. Thermogravimetric analysis analyses reported herein were carried out using a TGA Q500 V6.4 Build 193 from TA Instruments, with a ramp of 10°C/minute up to 200°C.

Generally, a diffraction angle (2Θ) 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 (2Θ ± 0.2°) of 7.9°" means "having a diffraction peak at a diffraction angle (2Θ) of 7.7° to 8.1°. 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 confirm its identity with Form-Y, Form- Y', or Form-Z 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. Celite™ is flux-calcined diatomaceous earth. Celite™ is a registered trademark of World Minerals Inc. A "halogenated hydrocarbon solvent" is an organic solvent containing a carbon bound to a halogen. "Halogenated hydrocarbon solvents" include, but are not limited to, dichloromethane, 1 ,2-dichloroethane, trichloroethylene, perchloroethylene, 1 ,1 ,1 - trichloroethane, chloroform, carbon tetrachloride, or the like. The acronym MTBE is methyl tert-butyl ether. Polymorphs are different solids sharing the same molecular formula, yet having distinct physical properties when compared to other polymorphs of the same formula.

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.

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 confirms its identity with Form-Z 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 terms crystalline Form-Y, crystalline Form-Y', and crystalline Form-Z may refer to purer forms of crystalline imatinib mesylate, they may refer to purer forms of the same polymorph of crystalline 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 crystalline Form-Y of imatinib mesylate.

Imatinib (15 g) is suspended in methanol (150 mL) at about 25 to about 30°C and the mixture is cooled to about 0°C to -10°C. Methanesulfonic acid (1.86 mL) is added at the same temperature with stirring for about 20 minutes. Methyl tertiary- butyl ether (600 mL) is added over 10 minutes and the mixture is stirred for about 1 hour at about 0°C to 20°C. The suspension is filtered under a nitrogen atmosphere, washed with MTBE (25 mL) and suction dried for about 10 minutes to obtain a moist solid (Sample 1 ). The moist solid is dried at about 45°C for about 140 hours in a vacuum tray dryer (VTD). Samples are collected at intervals such as at 30 hours (Sample 2), at 60 hours (Sample 3) and at 140 hours (Sample 4), for analysis. Yield: 8.7 g (58%).

Analysis Results

Parameter Sample 1 Sample 2 Sample 3 Sample 4

Methanol 42,536 ppm 16,200 ppm 10,640 ppm -

Drying in humidity chamber.

1 g of Sample 2 is placed in a humidity chamber having 40% RH at 30°C and dried for about 20 hours, and then is analyzed to give the following results:

Methanol: not detected.

MTBE: 2,567 ppm.

Moisture: 6.54% by the Karl Fischer method.

DSC peaks: 70°C and 128°C, represented as Figure 2.

XRPD: Figure 1.

TGA: curve of Figure 3.

EXAMPLE 2: Preparation of crystalline Form-Y of imatinib mesylate.

Imatinib (5 g) is suspended in methanol (50 mL) at about 25°C to about 30°C and is cooled to about 0°C to -10°C. Methanesuifonic acid (0.62 mL) is added at the same temperature and the mixture is stirred for about 20 minutes. Methyl tertiary- butyl ether (200 mL) is added over 10 minutes and the mixture is stirred for about 1 hour at about 0°C to 20°C. The suspension is filtered under a nitrogen atmosphere, washed with MTBE (8 mL) and suction dried for about 10 minutes, to obtain a moist solid. The moist solid is dried at about 45°C for about 22 hours in a vacuum tray dryer (VTD). The obtained solid is placed in a humidity chamber (conditions of humidity chamber: 40% RH at 30°C) and dried for about 22 hours, to obtain 2.91 g of the title compound. Analysis gives the following results:

Methanol: 296 ppm.

MTBE: 5056 ppm.

XRPD: represented as Figure 5.

DSC peaks: 73°C and 129°C, represented as Figure 6.

TGA wt. loss: 6.165%, represented as Figure 7.

EXAMPLE 3: Preparation of crystalline Form-Y' of imatinib mesylate.

Imatinib (10 g) and methanol (100 mL) are charged into a round bottom flask and stirred at 27°C. Cooled the suspension to about 0°C to -5°C and methanesuifonic acid (1.30 ml_) is added at the same temperature. The mixture is stirred for about 15 minutes to obtain a clear solution, filtered, and the filtrated transferred to a round bottom flask. Charged Imatinib mesylate (Form-Y) seed material (0.2 g) at about -3°C and added methyl tertiary-butyl ether (150 mL) over 30 minutes and the mixture is stirred for about 1 hour at about 0°C to -5°C. The suspension is filtered under a nitrogen atmosphere, washed with MTBE (40 mL). The obtained solid is dried at 45°C for about 4 hours in a vacuum tray dryer (VTD), stopped the drying and material left overnight under vacuum. The obtained solid is placed in a humidity chamber (conditions of humidity chamber: 45% RH at 30°C) for about 23 hours. The solid obtained is dried at about 45°C for about 4 hours in a vacuum tray dryer (VTD) to obtain 10.51 g of the title compound.

Analysis gives the following results:

Methanol: 8752 ppm.

MTBE: 2287 ppm.

XRPD: Figure 8

EXAMPLE 4: Preparation of crystalline Form-Y¹ of imatinib mesylate. Imatinib (60 g) and methanol (600 mL) are charged into a round bottom flask and stirred at 27°C. Cooled the suspension to about 0°C to -10°C and methanesulfonic acid ( 1.68 g) is added at the same temperature. The mixture is stirred for about 15 minutes to obtain a clear solution. Charged Imatinib mesylate (Form-Y) seed material (1.2 g) at about -4°C and added methyl tertiary-butyl ether (1200 mL) over 30 minutes and the mixture is stirred for about 75 minutes at about 0°C to -5°C. The suspension is filtered under a nitrogen atmosphere, washed with MTBE (240 mL). The obtained solid is dried at about 45°C for about 23 hours in a vacuum tray dryer (VTD). The obtained solid is placed in a humidity chamber (conditions of humidity chamber: 45% RH at 30°C) for about 42 hours. The solid obtained is dried at about 45°C for about 5 hours in a vacuum tray dryer (VTD) to obtain 63.89 g of the title compound. Analysis gives the following results

HPLC purity: 99.91%

Methanol: 6888 ppm.

MTBE: 1419 ppm.

XRPD: Figure 9 EXAMPLE 5: Preparation of crystalline Form-Z of imatinib mesylate.

Imatinib mesylate (5 g) and dimethylsulfoxide (15 ml.) are mixed at about 27°C, heated to about 90°C for dissolution, and filtered to remove any particles. Dichloromethane (250 ml_) in a separate vessel is cooled to about -3°C. Imatinib mesylate solution in dimethylsulfoxide is added to the precooled dichloromethane at the same temperature and stirred for 1 hour at about -3°C to about 0°C. The formed solid is collected by filtration, washed with dichloromethane (10 ml_), suction dried, and finally dried at about 60°C in a vacuum tray dryer. Yield: 220 mg. XRPD pattern: Figure 10.

Throughout this application, various publications are referenced. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art as known to those skilled therein as of the date of the application described and claimed herein.

While particular embodiments of the present application have been illustrated and described, it would be obvious to those skilled in the art that various other changes and modifications can be made without departing from the spirit and scope of the application. It is therefore intended to cover in the appended claims all such changes and modifications that are within the scope of this invention.

Claims

CLAIMS:

1. A crystalline form of imatinib mesylate, which is "Form-Y'."

2. The crystalline form of imatinib mesylate of claim 1 with an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 8 or Figure 9.

3. The crystalline form of imatinib mesylate of claim 1 with an X-ray powder diffraction (XRPD) pattern comprising two or more of the characteristic peaks located at about 6.1 , 8.7, 1 1.5, 14.5, 18.0, 18.7, 20.1 , 21.9, or 22.5 ± 0.2 degrees 2-theta.

4. A pharmaceutical formulation comprising crystalline Form-Y' of imatinib mesylate of any one of claims 1 to 3 and at least one pharmaceutically acceptable excipient.

5. A process for the preparation of crystalline Form-Y' of imatinib mesylate of any one of claims 1 to 3, comprising:

a) providing a solution of imatinib and methanesulphonic acid in methanol; b) adding a seed material;

c) adding an ether solvent;

d) isolating the obtained solid; and

e) drying the solid to afford crystalline Form-Y' of imatinib mesylate.

6. The process of claim 5, wherein the ether used in step c) is diethyl ether, diisopropyl ether, or methyl tertiary-butyl ether (MTBE).

7. The process of claim 5, wherein step e) comprises drying the product in a vacuum tray dryer, in a humid environment, or in both.

8. A crystalline form of imatinib mesylate, which is "Form-Y."

9. The crystalline form of imatinib mesylate of claim 8 with an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 1 , Figure 4, or Figure 5.

10. The crystalline form of imatinib mesylate of claim 8 with an X-ray powder diffraction (XRPD) pattern comprising two or more of the characteristic peaks located at about 6.1 , 8.7, 1 1.5, 14.5, 18.0, 18.7, 20.1 , 21 .9, or 22.5 ± 0.2 degrees 2-theta.

1 1. A pharmaceutical formulation comprising crystalline Form-Y of imatinib mesylate of any one of claims 8 to 10 and at least one pharmaceutically acceptable excipient.

12. A process for the preparation of crystalline Form-Y of imatinib mesylate of any one of claims 8 to 10, comprising:

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

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

c) isolating the obtained solid; and

d) drying the solid to afford crystalline Form-Y of imatinib mesylate.

13. The process of claim 12, wherein the ether used in step b) is diethyl ether, diisopropyl ether, or methyl tertiary-butyl ether (MTBE).

14. The process of claim 12, wherein step d) comprises drying the product in a vacuum tray dryer, in a humid environment, or in both.

15. A crystalline form of imatinib mesylate, which is "Form Z."

16. The crystalline form of imatinib mesylate of claim 15 with an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 10.

17. The crystalline form of imatinib mesylate of claim 15 with an X-ray powder diffraction (XRPD) pattern comprising two or more of the characteristic peaks located at about 6.6, 8.0, 13.9, 16.6, 17.0, 17.3, 18.4, 19.0, 20.2, 22.2, or 24.2 ± 0.2 degrees 2-theta.

18. A pharmaceutical formulation comprising crystalline Form-Z of imatinib mesylate of any one of claims 15 to 17 and at least one pharmaceutically acceptable excipient.

19. A process for the preparation of crystalline Form-Z of imatinib mesylate of any one of claims 15 to 17, comprising:

c) isolating the solid obtained; and

20. The process of claim 19, wherein the halogenated hydrocarbon solvent used in step b) is dichloromethane or chloroform.