WO2012090221A1

WO2012090221A1 - Novel salts of imatinib

Info

Publication number: WO2012090221A1
Application number: PCT/IN2011/000895
Authority: WO
Inventors: Kumar Kamlesh Laxmi Singh; Chetan Jayantibhai VASAVA; Nikhil Amar SINGH; Gulab Khushalrao PATHE
Original assignee: Cadila Healthcare Limited
Priority date: 2010-12-29
Filing date: 2011-12-27
Publication date: 2012-07-05

Abstract

The present inventiin discloses pharmaceutically acceptable salts of imatinib of Formula (II) wherein in S represent the acid selected from the group consisting of oxalic acid, ptoluene sulfonic acid, naphthalene sulfonic acid, benzene sulfonic acid, nitric acid, phosphoric acid, acetic acid, maleic acid, fumaric acid, amino acids like lysine, lysine HC1, arginine; which forms a salt with imatinib.

Description

NOVEL SALTS OF IMATINIB

FIELD OF THE INVENTION

The invention relates to imatinib and its pharmaceutically acceptable salts. The invention also relates to improved processes for the preparation of imatinib and its pharmaceutically acceptable salts. The invention also relates to pharmaceutical compositions that includes the therapeutically effective amount of pharmaceutically acceptable salts of imatinib.

BACKGROUND OF THE INVENTION

Imatinib, is chemically known as 4-[(4-methylpiperazin-l -yl)methyl]-N-[4- methyl-3-[[(4-pyridin-3-yl)pyrimidin-2-yl)]amino]phenyl]benzamide and represented by compound of Formula (I). Imatinib is in a class of protein-tyrosine kinase inhibitors. It works by blocking the action of the abnormal protein that signals cancer cells to multiply.

(I)

Imatinib acts as tyrosine kinase inhibitor and protein kinase inhibitor. It also acts as single transduction inhibitor. It is highly specific for BCR-ABL, the enzyme associated with chronic myelogenous leukemia and certain forms of acute lymphoblastic leukemia. It inhibits the transmembrane receptor KIT and platelet- derived growth factor (PDGF) receptors. It is used as Antineoplastic. It is used in the treatment of all kind of cancer such as leukemia, solid tumor, gastrointestinal cancer, prostate cancer, neurological cancer, myeloma and glioblastoma. It is also used in the treatment of, pulmonary fibrosis, rheumatoid arthritis and thrombocythemia.

U.S. Patent No. 5,521 , 184 discloses N-phenyl-2-pyrimidine amine compounds including Imatinib.

U.S. Patent No. 6,894,051 discloses mesylate salt of imatinib. The patent discloses that imatinib mesylate salt can exist in needle-shaped a-crystalline form or non-needle-shaped β-crystalline form. It is reported that β-crystalline form has improved properties. The efforts to improve the property of imatinib mesylate salt has work out continuously and various polymorphic forms are reported in several patent applications.

U.S. Patent Application No. 20090264438 discloses several crystalline forms of imatinib mesylate namely designated as Form IV, Form V, Form VI, Form VII, Form VIII, Form IX, Form X, Form XI, Form XII, Form XIII, Form XIV, Form XV and Form XVI.

International (PCT) publication WO 2004/106326 discloses novel crystalline Form HI of imatinib mesylate by using chlorinated solvent.

International (PCT) publication WO 2005/077933 discloses novel a.2 crystalline form of imatinib mesylate. The a2 crystalline form is stable and less hygroscopic in nature and suitable for Formulation development.

International (PCT) publication WO 2006/054314 discloses two crystalline polymorphic forms of imatinib mesylate designated as Form I and Form II. Both the polymorphs are reported as stable form under normal condition.

International (PCT) publication WO 2007/023182 discloses crystalline Form δ and Form ε of imatinib mesylate and international (PCT) publication WO 2007/059963A1 discloses crystalline Form F, G, H, I and K of imatinib mesylate.

Therefore, it is desirous to improve the properties of imatinib for pharmaceutical use.

International (PCT) publication WO 2005/075454 discloses imatinib acid addition salts like tartrate, citrate, maleate, fumarate, succinate, benzoate, besylate, palmoate, formate, malonate, napsylate, salysilate, cyclohexane sulfamate, lactate, mandalate, glutarate, adipate, squarate, vallinate, oxaloacetate, ascorbate and sulfate salts. According to the disclosure, only tartrate, malonate and succinate salt are having higher solubility.

Although imatinib mesylate provides good pharmaceutical activity, it would be beneficial to find other forms of imatinib since, imatinib forms having advantageous properties for pharmaceutical use.

OBJECTS OF THE INVENTION

It is an object of the present invention to provide pharmaceutically acceptable salts of imatinib.

Another object of the present invention is to provide processes for preparing pharmaceutically acceptable salts of imatinib. Yet another object of the present invention is to provide a pharmaceutical composition comprising pharmaceutically acceptable salts of imatinib.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG.l : X-ray diffraction pattern of imatinib maleate crystalline form.

FIG.2: Differential Scanning Calorimetry of imatinib maleate crystalline form.

FIG.3: Infrared spectrum of crystalline imatinib maleate crystalline form.

FIG.4: X-ray diffraction pattern of imatinib phosphate amorphous form.

FIG.5: Differential Scanning Calorimetry of imatinib phosphate amorphous form.

FIG.6: X-ray diffraction pattern of imatinib lysinate crystalline form.

FIG.7: Differential Scanning Calorimetry of imatinib lysinate crystalline form.

FIG.8: Infrared spectrum of crystalline imatinib lysinate crystalline form.

FIG.9: X-ray diffraction pattern of imatinib oxalate crystalline form.

FIG.10: Differential Scanning Calorimetry of imatinib oxalate crystalline form.

FIG.l 1: Infrared spectrum of crystalline imatinib oxalate crystalline form.

FIG.12: X-ray diffraction pattern of imatinib tosylate amorphous form.

FIG.13: X-ray diffraction pattern of imatinib tosylate crystalline form.

FIG.14: Differential Scanning Calorimetry of imatinib tosylate crystalline form.

FIG.15: Infrared spectrum of crystalline imatinib tosylate crystalline form.

FIG.16: X-ray diffraction pattern of imatinib nitrate crystalline form.

FIG.17: Differential Scanning Calorimetry of imatinib nitrate crystalline form.

FIG.18: Infrared spectrum of crystalline imatinib nitrate crystalline form.

FIG.19: X-ray diffraction pattern of imatinib arginate crystalline form.

FIG.20: Differential Scanning Calorimetry of imatinib arginate crystalline form.

FIG.21: Infrared spectrum of crystalline imatinib arginate crystalline form.

FIG.22: X-ray diffraction pattern of imatinib maleate crystalline form as per reference

Example-9.

FIG.23: Differential Scanning Calorimetry of imatinib maleate crystalline form as per reference Example-9.

DETAILED DESCRIPTION OF THE INVENTION

It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention and specific examples provided herein without departing from the spirit or scope of the invention. Thus, it is intended that the present invention cover the modifications and variations of this invention that come within the scope of any claims and their equivalents. The present inventors have found that by preparing pharmaceutically acceptable salts of imatinib free base in crystalline form, the formation of impurities can be minimized and better purity and chemical stability can be achieved. The inventors have developed different acid addition salts of imatinib which exhibit improved physiochemical properties like melting point, solubility, toxicology, and improved stability under various stress conditions.

The term "elevated temperature" used herein means, heating the reaction mixture either heterogeneous or homogeneous at a temperature from about 35°C to boiling point of solvent. In particular, from about 35°C to about 100°C. The term "ambient temperature" used herein means, slurrying the reaction mixture either heterogeneous or homogeneous at a temperature from about 0°C to about 35°C of solvent.

"Suitable solvent" means a single or a combination of two or more solvents. The present invention relates to imatinib (I) and its pharmaceutically acceptable salts thereof, to the processes for their preparation and isolation, and to pharmaceutical compositions comprising the same.

(I)

The present inventors have prepared certain salt forms of imatinib and structurally characterized them as described herein. The salts forms are also referred as , pharmaceutically acceptable salts of imatinib. These salts can be oxalate, p-toluene sulfonate, naphthalene sulfonate, benzene sulfonate, nitrate, phosphate, acetate, maleate, fumarate, lysinate, lysinate HC1, arginate salts of imatinib.

In one aspect, the present invention provides pharmaceutically acceptable salts of imatinib of Formu

(II) wherein in S represent the acid selected from the group consisting of oxalic acid, p- toluene sulfonic acid, naphthalene sulfonic acid, benzene sulfonic acid, nitric acid, phosphoric acid, acetic acid, maleic acid, fumaric acid, amino acids like lysine, lysine HC1, arginine; which forms a salt with imatinib.

The novel pharmaceutically acceptable salts of the invention are expected to provide potential advantages over other reported salts of imatinib. Without limitations these advantages may include improved purity profile, improved pharmacokinetics properties desirable for modified release, immediate release and injectable dosage forms, ease of pharmaceutical processing, discovery of novel polymorphs, improved stability. In summary, a combination of these improved properties of novel salt of imatinib is expected to provide improved overall treatment outcomes.

Accordingly in first aspect, the invention relates to new salts of imatinib, namely imatinib oxalate, imatinib besylate, imatinib nitrate, imatinib tosylate, imatinib napsylate, imatinib phosphate, imatinib maleate, imatinib fumarate, imatinib arginate, imatinib lysinate, imatinib lysinate HC1 compounds or its hydrate. The compound may be isolated and/or purified or it may be part of a composition. The compound may be in solid form including crystalline forms but is not limited thereto. Preferred compounds are in the form of crystalline imatinib salts or its hydrate.

Another aspect of the present invention relates to the process for preparing novel salt of imatinib of Formula (II)

(II)

wherein in S represent the acid selected from the group consisting of oxalic acid, p- toluene sulfonic acid, naphthalene sulfonic acid, benzene sulfonic acid, nitric acid, phosphoric acid, acetic acid, maleic acid, fumaric acid, amino acids like lysine, lysine HC1, arginine, which comprises reacting imatinib of Formula (I) with acid selected from the group consisting of oxalic acid, p-toluene sulfonic acid, naphthalene sulfonic acid, benzene sulfonic acid, nitric acid, phosphoric acid, acetic, acid, maleic acid, fumaric acid, amino acids like lysine, lysine HC1, arginine to give the novel pharmaceutically acceptable salts of Formula (II). The reaction of acid with imatinib (I) may be particularly performed in organic solvent or in mixture with water.

Another aspect of the present invention relates to a pharmaceutical composition comprising therapeutically effective amount of imatinib salt of Formula (II), a pharmaceutically acceptable excipient. The composition can be an immediate release dosage form or an extended release dosage form and embraces tablets as well as pellets/beads/spheroids or other encapsulated forms.

The compound can be in isolated and/or purified form, but such is not required. The compound includes various physical forms of the salt including dissolved forms, oil or liquid forms, and solid forms including amorphous and crystalline forms.

The imatinib salts (II) may be isolated, if desired, by precipitation, evaporation, spray drying, or other conventional techniques known in the art.

The novel pharmaceutically acceptable salts of imatinib are typically in a crystalline form. Crystalline forms include imatinib salts with organic acid such as described above, anhydrates, hydrates, and solvates.

The imatinib free base can be prepared by known methods in the art e.g. process described in EP-A-0564409 A or U.S. Patent No. 5,521,184.

In another aspect of the present invention, there is provided a crystalline form of imatinib maleate.

The crystalline form of imatinib maleate may be characterized by X-ray powder diffraction pattern having characteristic peaks at about 6.0°, 11.0°, 14. , 15.2°, 16.5°, 17.2°, 18.2°, 19.2°, 21.9°, 23.9°, 27.5° and 29.3° (2Θ); or Differential scanning calorimetry having endothermic peak at about 171.3°C.

The crystalline form of imatinib maleate may be further characterized by a PXRD pattern substantially as depicted in FIG. 1.

The crystalline form of imatinib maleate may be characterized by differential scanning calorimetry substantially as depicted in FIG;2 The crystalline form of imatinib maleate may be characterized by IR spectra 3444, 3281, 1647, 1557, 1525, 1450, 1417, 1357, 866, and 648 cm^"1. It may also be characterized by IR spectra substantially as depicted in FIG. 3.

In another aspect of the invention there is provided a process for the preparation of crystalline form of imatinib maleate. The process includes suspending imatinib free base and maleic acid in one or more suitable solvent, optionally adding one or more suitable co-solvents, removing the solvents and obtaining the crystalline form of imatinib maleate.

The suitable solvents comprise one or more of C1-C5 alcohol solvents, hydrocarbons like toluene, xylene, methylene dichloride, chlorobenzene, water and mixtures thereof. In particular, the mixture of methanol and methylene dichloride. An co-solvent can be optionally added. The suitable co-solvent comprises from one or more of aliphatic ethers like methyl tert-butyl ether, diisopropyl ether, and the like, hydrocarbons like cyclohexane, hexane, heptane, toluene, xylene, and the like, ketones like acetone, methylisobutyl ketone, methyl ethyl ketone and the like. In Particular, the co-solvent may be acetone.

The embodiments of the process for the preparation of crystalline form of imatinib maleate include treating imatinib free base in mixture of methanol and methylene dichloride with maleic acid solution in acetone at about 25°C to 80°C, for example, at reflux temperature of mixture, followed by cooling to ambient temperature.

The crystalline imatinib maleate may have particle size distributions, wherein the 10^th volume percentile particle size (Di₀) is less than about 20 μπι, the 50th volume percentile particle size (D50) is less than about 50 um, or the 90^th volume percentile particle size (D90) is less than about 250 um, or any combination thereof.

In another aspect of the present invention, there is provided imatinib phosphate. In particular, the imatinib phosphate may be obtained in amorphous form. The amorphous imatinib phosphate may be characterized by X-ray powder diffraction pattern substantially as depicted in FIG. 4 and by Differential scanning calorimetry having endothermic peak at about 197.9°C. It may also be characterized by Differential scanning calorimetry substantially as depicted in FIG. 5.

In another aspect of the invention there is provided a process for the preparation of amorphous form of imatinib phosphate. The process includes suspending imatinib free base with maleic acid in the presence of one or more suitable solvents, removing the solvents, optionally adding one or more suitable anti-solvents, and obtaining the amorphous form of imatinib phosphate.

The suitable solvents comprise one or more of C1-C5 alcohol solvents, hydrocarbons like toluene, xylene, methylene dichloride, chlorobenzene, water and mixtures thereof. In particular, the mixture of methanol and methylene dichloride. An anti-solvent can be optionally added. The suitable anti-solvent comprises from one or more of aliphatic ethers like methyl tert-butyl ether, diisopropyl ether, and the like, hydrocarbons like cyclohexane, hexane, heptane, toluene, xylene, and the like, ketones like acetone, methylisobutyl ketone, methyl ethyl ketone and the like. In Particular, the anti-solvent may be n-hexane.

The embodiments of the process for the preparation of amorphous form of imatinib phosphate include treating imatinib free base in mixture of methanol and methylene dichloride with maleic acid solution in methanol at about 25°C to 80°C, for example, at reflux temperature of mixture, followed by removal of solvent. The residue may be treated with mixture of methanol and methylene dichloride followed by addition of anti-solvent like n-hexane to obtain amorphous form of imatinib phosphate.

In another aspect of the present invention, there is provided a crystalline form of imatinib lysinate.

. The crystalline form of imatinib lysinate may be characterized by X-ray powder diffraction pattern having characteristic peaks at about 5.9°, 1 1.9°, 17.1°, 18.0°, 18.6°, 19.7°, 24.2°, and 25.1° (2Θ); or Differential scanning calorimetry having endothermic peaks at about 86.8°, 208.4° and 255.7°C.

The crystalline form of imatinib lysinate may be further characterized by a PXRD pattern substantially as depicted in FIG. 6.

The crystalline form of imatinib lysinate may be characterized by differential scanning calorimetry substantially as depicted in FIG.7. The crystalline form of imatinib lysinate may be characterized by IR spectra 3281, 2123, 2794, 1647, 1587, 1575, 1425, 1415, 1290, 1008, 858, 810 and 796 cm^"1. It may also be characterized by IR spectra substantially as depicted in FIG. 8.

In another aspect of the invention there is provided a process for the preparation of crystalline form of imatinib lysinate. The process includes suspending imatinib free base with lysine hydrochloride in the presence of one or more suitable solvents, optionally adding one or more suitable co-solvents, removing the solvents and obtaining the crystalline form of imatinib lysinate:

The suitable solvents comprise one or more of C1 -C5 alcohol solvents, hydrocarbons like toluene, xylene, methylene dichloride, chlorobenzene, water and mixtures thereof. In particular, the mixture of methanol and methylene dichloride. A co-solvent can be optionally added. The suitable co-solvent comprises from one or more of aliphatic ethers like methyl tert-butyl ether, diisopropyl ether, and the like, hydrocarbons like cyclohexane, hexane, heptane, toluene, xylene, and the like, ketones like acetone, methylisobutyl ketone, methyl ethyl ketone and the like. In Particular, the co-solvent may be acetone.

The embodiments of the process for the preparation of crystalline form of imatinib lysinate include treating imatinib free base in mixture of methanol and methylene dichloride with lysine at about 25°C to 80°C, for example, at reflux temperature of mixture, followed by addition of co-solvent acetone and again refluxing the obtained reaction mixture followed by cooling to ambient temperature to obtain crystalline imatinib lysinate.

The crystalline imatinib lysinate may have particle size distributions, wherein the 10^th volume percentile particle size (Dio) is less than about 20 μπι, the 50th volume percentile particle size (D₅o) is less than about 50 μιη, or the 90^th volume percentile particle size (D90) is less than about 250 μπι, or any combination thereof.

In another aspect of the present invention, there is provided a crystalline form of imatinib oxalate.

The crystalline form of imatinib oxalate may be characterized by X-ray powder diffraction pattern having characteristic peaks at about 5.9°, 10.5°, 11.9°, 12.8°, 13.7°, 15.8°, 16.3°, 17.Γ, 18.0°, 18.5°, 18.9°, 19.7°, 20.9°, 22.7°, 23.9°, 25.9°, 26.6° and 28.3° (20); or Differential scanning calorimetry having endothermic peaks at about 195.4° and 219.9°C.

The crystalline form of imatinib oxalate may be further characterized by a

PXRD pattern substantially as depicted in FIG. 9.

The crystalline form of imatinib oxalate may be characterized by differential scanning calorimetry substantially as depicted in FIG.10 The crystalline form of imatinib oxalate may be characterized by IR spectra 3437, 3279, 1724, 1581, 1452, 1413, 1186, 1022, 810, 707, and 572 cm^"1. It may also be characterized by IR spectra substantially as depicted in FIG. 11.

In another aspect of the invention there is provided a process for the preparation of crystalline form of imatinib oxalate. The process includes suspending imatinib free base with oxalate in the presence of one or more suitable solvents, optionally adding one or more suitable co-solvents, removing the solvents and obtaining the crystalline form of imatinib oxalate.

The suitable solvents comprise one or more of C1 -C5 alcohol solvents, hydrocarbons like toluene, xylene, methylene dichloride, chlorobenzene, water and mixtures thereof. In particular, the mixture of methanol and methylene dichloride. A co-solvent can be optionally added. The suitable co-solvent comprises from one or more of aliphatic ethers like methyl tert-butyl ether, diisopropyl ether, and the like, hydrocarbons like cyclohexane, hexane, heptane, toluene, xylene, and the like, alcohols like methanol, ethanol, isopropanol, butanol and the like. In Particular, the co-solvent may be isopropanol.

The embodiments of the process for the preparation of crystalline form of imatinib oxalate include treating imatinib free base in mixture of methanol and methylene dichloride with oxalic acid dihydrate solution in isopropanol at about 25°C to 80°C, for example, at reflux temperature of mixture, followed by cooling to ambient temperature to obtain crystalline imatinib oxalate.

The crystalline imatinib oxalate may have particle size distributions, wherein the 10^th volume percentile particle size (Djo) is less than about 20 μπι, the 50th volume percentile particle size (D50) is less than about 50 μηι, or the 90^th volume percentile particle size (D90) is less than about 250 μπι, or any combination thereof.

In another aspect of the present invention, there is provided a crystalline form of imatinib tosylate.

The crystalline form of imatinib tosylate may be characterized by X-ray powder diffraction pattern having characteristic peaks at about 4.6°, 9.1°, 10.8°, 12.5°, 13.7°, 14.2°, 15.4°, 17.2°, 18.2°, 19.0°, 21.5°, 23.0°, 23.7°, 24.9°, 27.3°, and 28. (20); or Differential scanning calorimetry having endothermic peak at about 1 0.3°C.

The crystalline form of imatinib tosylate may be further characterized by a PXRD pattern substantially as depicted in FIG. 13.

The crystalline form of imatinib tosylate may be characterized by differential scanning calorimetry substantially as depicted in FIG.14. The crystalline form of imatinib tosylate may be characterized by IR spectra 3456, 3254, 1647, 1535, 1452, 1417, 1182, 1 120, 1033, 1010, 800, 682, 567 cm^"1. It may also be characterized by IR spectra substantially as depicted in FIG. 15.

In another aspect of the invention there is provided a process for the preparation of crystalline form of imatinib tosylate. The process includes suspending imatinib free base with tosylate in the presence of one or more suitable solvents, optionally adding one or more suitable anti-solvents, removing the solvents and obtaining the crystalline form of imatinib tosylate.

The suitable solvents comprise one or more of C1 -C5 alcohol solvents, hydrocarbons like toluene, xylene, methylene dichloride, chlorobenzene, water and mixtures thereof. In particular, the solvent may be ethanol. An anti-solvent can be optionally added. The suitable anti-solvent comprises from one or more of aliphatic ethers like methyl tert-butyl ether, diisopropyl ether, and the like, hydrocarbons like cyclohexane, hexane, heptane, toluene, xylene, and the like, alcohols like methanol, ethanol, isopropanol, butanol and the like. In Particular, the anti-solvent may be cyclohexane.

The embodiments of the process for the preparation of crystalline form of imatinib tosylate include treating imatinib free base in ethanol with p-toluene sulfonic acid at about 25°C to 80°C, for example, at reflux temperature of solvent, followed by removal of solvent, and treating the residue with cyclohexane followed by cooling to ambient temperature to obtain crystalline imatinib tosylate.

The crystalline imatinib tosylate may have particle size distributions, wherein the 10^th volume percentile particle size (Dio) is less than about 20 um, the 50th volume percentile particle size (D50) is less than about 50 μπι, or the 90^th volume percentile particle size (D90) is less than about 250 um, or any combination thereof.

In another aspect of the present invention, there is provided a crystalline form of imatinib nitrate.

The crystalline form of imatinib nitrate may be characterized by X-ray powder diffraction pattern having characteristic peaks at about 5.8°, 6.9°, 8.4°, 9.5°, 10.1°, 13.9°, 1-4.3°, 15.9°, 17.4°, 17.6°, 18. , 20.5°, 21.9°, 24.9°, 25.4°, 25.9°, 26.7°, 27.8°, and 28.0° (20); or Differential scanning calorimetry having endothermic peak at about 159°C.

The crystalline form of imatinib nitrate may be further characterized by a PXRD pattern substantially as depicted in FIG. 16.

The crystalline form of imatinib nitrate may be characterized by differential scanning calorimetry substantially as depicted in FIG.17. The crystalline form of imatinib nitrate may be characterized by IR spectra 3429, 3005, 1635, 1575, 1531, 1350, 794, and 667 cm^"1. It may also be characterized by IR spectra substantially as depicted in FIG. 18.

In another aspect of the invention there is provided a process for the preparation of crystalline form of imatinib tosylate. The process includes suspending imatinib free base with tosylate in the presence of one or more suitable solvents, optionally adding one or more suitable anti-solvents, removing the solvents and obtaining the crystalline form of imatinib tosylate. The suitable solvents comprise one or more of Q-C5 alcohol solvents, hydrocarbons like toluene, xylene, methylene dichloride, chlorobenzene, water and mixtures thereof. In particular, the solvent may be ethanol. An anti-solvent can be optionally added. The suitable anti-solvent comprises from one or more of aliphatic ethers like methyl tert-butyl ether, diisopropyl ether, and the like, hydrocarbons like cyclohexane, hexane, heptane, toluene, xylene, and the like, alcohols like methanol, ethanol, isopropanol, butanol and the like. In Particular, the anti-solvent may be cyclohexane.

The crystalline imatinib tosylate may have particle size distributions, wherein the 10^th volume percentile particle size (D10) is less than about 20 um, the 50th volume percentile particle size (D50) is less than about 50 μπι, or the 90^th volume percentile particle size (D90) is less than about 250 um, or any combination thereof.

In another aspect of the present invention, there is provided a crystalline form of imatinib arginate.

The crystalline form of imatinib arginate may be characterized by X-ray powder diffraction pattern having characteristic peaks at about 6.0°, 12.0°, 15.9°, 17.1°, 16.0°, 19.7°, 20.9°, 24.2° and 27.3° (29); or Differential scanning calorimetry having endothermic peaks at about 212.6°C and 238.7°C.

The crystalline form of imatinib nitrate may be further characterized by a PXRD pattern substantially as depicted in FIG. 19.

The crystalline form of imatinib nitrate may be characterized by differential scanning calorimetry substantially as depicted in FIG.20. The crystalline form of imatinib nitrate may be characterized by IR spectra 3281, 2929, 2796, 1647, 1452, 1417, 1327, 1290, 1010, 810, and 796 cm^"1. It may also be characterized by IR spectra substantially as depicted in FIG. 21.

In another aspect of the invention there is provided a process for the preparation of crystalline form of imatinib arginate. The process includes suspending imatinib free base with arginine in the presence of one or more suitable solvents, optionally adding one or more suitable co-solvents, removing the solvents and obtaining the crystalline form of imatinib arginine.

The suitable solvents comprise one or more of Q-C5 alcohol solvents, hydrocarbons like toluene, xylene, methylene dichloride, chlorobenzene, water and mixtures thereof. In particular, the solvent may be ethanol. A co-solvent can be optionally added. The suitable co-solvent comprises from one or more of aliphatic ethers like methyl tert-butyl ether, diisopropyl ether, and the like, hydrocarbons like cyclohexane, hexane, heptane, toluene, xylene, and the like, ketones like acetone, methyl ethyl ketone, methyl isobutyl ketone and the like. In Particular, the co-solvent may be acetone.

The embodiments of the process for the preparation of crystalline form of imatinib arginate include treating imatinib free base in mixture of methanol and methylene dichloride with arginine at about 25°C to 80°C, for example, at reflux temperature of solvent, followed by removal of solvent, and treating the residue with acetone followed by cooling to ambient temperature to obtain crystalline imatinib arginate.

The crystalline imatinib arginate may have particle size distributions, wherein the 10^th volume percentile particle size (Djo) is less than about 20 um, the 50th volume percentile particle size (D50) is less than about 50 μτη, or the 90^th volume percentile particle size (D90) is less than about 250 um, or any combination thereof.

In another aspect of the invention, there is provided a process for the preparation of crystalline imatinib acid addition salts comprising:

(a) suspending imatinib free base in a suitable organic solvent,

(b) adding suitable acid,

(c) heating the reaction mixture,

(d) optionally adding suitable anti-solvent or co-solvent, and

(e) obtaining crystalline imatinib acid addition salts.

In general, the suitable organic solvent comprises one or more of alcoholic solvent like methanol, ethanol, isopropanol, n-butanol, heptanol, decanol, dodecanol and the like, hydrocarbon solvents like toluene, xylene, methylene dichloride, chlorobenzene and the like. In particular, the suitable organic solvent is one or more of methanol, isopropanol, acetone, toluene, methylene dichloride and methyl tert-butyl ether or mixture thereof. More particular, the suitable solvent may be mixture of methanol and methylene dichloride. Further the process parameters includes addition of suitable anti-solvent or co- solvent comprises from one or more of hydrocarbons like n-hexane, heptane, cyclohexane and the like, ethers like diisopropylether, methyltert-butyl ether, tetrahydrofuran and the like, ketonic solvents like acetone, methyl ethyl ketone, methyl isobutyl ketone and the like, esters like ethyl acetate, butyl acetate, isopropyl acetate and the like. In particular, n-hexane, n-heptane, cyclohexane, acetone and the like may be used as anti-solvent or co-solvent based on the solubility of imatinib salts.

The embodiments include suspending imatinib freebase in suitable solvent comprises from methanol, isopropanol, methylene dichloride, toluene and methyl tert- butyl ether or mixture thereof. The suitable acid is added to the imatinib freebase solution in suitable solvent and heated the reaction mixture. The reaction mixture can be heated from about 35°C to about 90°C, particularly at about reflux temperature of solvent.

In general, the suitable acid comprises from one or more of oxalic acid, p- toluene sulfonic acid, naphthalene sulfonic acid, benzene sulfonic acid, nitric acid, phosphoric acid, acetic acid, maleic acid, fumaric acid, amino acids like lysine, lysine HC1, arginine and the. like.

Optionally, the heated solution of imatinib freebase and suitable acid can be treated with suitable antisolvent selected from the group consisting of hydrocarbon solvent, ethers, ketones or esters. Hydrocarbon comprises one or more of toluene, xylene, ethylbenzene, n-hexane, heptane, cyclohexane and the like, ketones comprises one or more of acetone, methyl ethyl ketone, methyl isobutyl ketone and the like ethers comprises one or more of diisopropylether, methyltert-butyl ether, tetrahydrofuran and the like, esters comprises one or more of ethyl acetate, butyl acetate, isopropyl acetate and the like.

Further, the obtained crystalline imatinib acid addition salts, can be isolated by the known techniques reported in the art followed by drying.

The present invention also provides a process for preparing crystalline form of imatinib maleate, which comprises treating imatinib with maleic acid.

The reaction is preferably carried out in suitable solvent. The solvent system is preferably selected so as to facilitate the salt reaction and to allow subsequent separation of the resulting maleate. Advantageously, both imatinib and the maleic acid are dissolvable, at least partly, in the solvent system, at least at elevated temperatures. In the process, a mixture, slurry, or solution of imatinib and a solven may be contacted with a maleic acid, or conversely, a mixture, slurry, or solution of maleic acid and a solvent may be contacted with Imatinib. In another embodiment, both partners may be combined with a solvent system prior to being contacted together, whereby the solvent system used for maleic acid may be identical with or different from the solvent system used for the imatinib. The solvent system can be comprised of a single solvent or a mixture of solvents. When two or more solvents are used, a two phase reaction scheme may be used wherein the Imatinib and maleic acid are primarily reacted in one phase and the resulting imatinib maleate compound is primarily present in the other phase due to, inter alia, solubility differences, etc. Suitable solvents include water, a lower alcohol (Ci-C₆) such as methanol, ethanol, isopropanol, n-propanol, n-butanol, iso-butanol, tert- butanol; ester such as ethyl acetate, isopropyl acetate, butyl acetate, iso-butyl acetate; ketone such as acetone, methyl ethyl ketone, methyl tert-butyl ketone; ether such as tetrahydrofuran, diethyl ether, diisopropyl ether, dioxane; chlorinated solvent like methylene dichloride, ethylene dichloride, chloroform, chlorobenzene, hydrocarbon solvents like toluene, xylene, hexane, eye lohexane, heptanes; polar solvents like dimethyl formamide, N-methyl pyrrolidone, Ν,Ν-dimethyl acetamide, dimethyl sulfoxide and the like.

The temperature of contact of imatinib and maleic acid in the solvent system is from ambient to the boiling point of the solvent system, with elevated temperatures, but generally less than the boiling point, being preferred. It is not required that a complete solution is formed in this step, i.e,. a slurry or two phase solution are also possible, though a single solution is generally preferred.

The Imatinib maleate compound can be isolated or recovered from the salt forming reaction by any convenient means. For example, the imatinib maleate compound can be precipitated out of a solution or reaction mixture. The precipitation may be spontaneous depending upon the solvent system used and the conditions. Alternatively, the precipitation can be induced by reducing the temperature of the solvent, especially if the initial temperature at contact is elevated. The precipitation may also be facilitated by reducing the volume of the solution/solvent or by adding a contra solvent, i.e. a liquid miscible with the solvent in which the imatinib maleate is less soluble. Seed crystals of imatinib maleate may also be added to help induce precipitation. The precipitated imatinib maleate compound can be isolated by conventional methods such as filtration or centrifugation, optionally washed and dried, preferably under diminished pressure. Alternatively, imatinib maleate can be isolated by evaporating the solvent and collecting residue. Such a method generally leads to an oil or solid amorphous form of imatinib maleate. Similarly, an amorphous solid form of the imatinib maleate compound can be recovered by spray drying a solution containing the imatinib maleate compound.

In the preferred embodiment, Imatinib base (I) is dissolved in mixture of methanol and methylene dichloride and treated with maleic acid solution in acetone to solid form of imatinib maleate.

The present invention also provides a process for preparing imatinib nitrate, which comprises treating imatinib with nitric acid.

The reaction is preferably carried out in suitable solvent. The solvent system is preferably selected so as to facilitate the salt reaction and to allow subsequent separation of the resulting nitrate. In the process, a mixture, slurry, or solution of imatinib and a solvent may be contacted with a nitric acid, or conversely solution of nitric acid and a solvent may be contacted with Imatinib. In another embodiment, both may be combined with a solvent system prior to being contacted together, whereby the solvent system used for nitric acid may be identical with or different from the solvent system used for the imatinib. The solvent system can be comprised of a single solvent or a mixture of solvents. When two or more solvents are used, a two phase reaction scheme may be used wherein the imatinib and nitric acid are primarily reacted in one phase and the resulting Imatinib nitrate compound is primarily present in the other phase due to, inter alia, solubility differences, etc. Suitable solvents include water, a lower alcohol (Q- C₆) such as methanol, ethanol, isopropanol, n-propanol, n-butanol, iso-butanol, tert-butanol; ester such as ethyl acetate, isopropyl acetate, butyl acetate, iso-butyl acetate; ketone such as acetone, methyl ethyl ketone, methyl tert-butyl ketone; ether such as tetrahydrofuran, diethyl ether, diisopropyl ether, dioxane; chlorinated solvent like methylene dichloride, ethylene dichloride, chloroform, chlorobenzene, hydrocarbon solvents' like toluene, xylene, hexane, cyclohexane, heptanes; polar solvents like dimethyl formamide, N-methyl pyrrolidone, N,N-dimethyl acetamide, dimethyl sulfoxide and the like.

The temperature of contact of imatinib and nitric acid in the solvent system is from ambient to the boiling point of the solvent system, with elevated temperatures, but generally less than the boiling point, being preferred. It is not required that a complete solution is formed in this step, i.e. a slurry or two phase solution are also possible, though a single solution is generally preferred.

The imatinib nitrate compound can be isolated or recovered from the salt forming reaction by any convenient means. For example, the Imatinib nitrate can be precipitated out of a solution or reaction mixture. The precipitation may be spontaneous depending upon the solvent system used and the conditions. Alternatively, the precipitation can be induced by reducing the temperature of the solvent, especially if the initial temperature at contact is elevated. The precipitation may also be facilitated by reducing the volume of the solution/solvent or by adding a contra solvent, i.e. a liquid miscible with the solvent in which the imatinib nitrate is less soluble. Seed crystals of imatinib nitrate may also be added to help induce precipitation. The precipitated imatinib nitrate compound can be isolated by conventional methods such as filtration or centrifugation, optionally washed and dried, preferably under diminished pressure.

Alternatively, Imatinib nitrate can be isolated by evaporating the solvent and collecting residue. Such a method generally leads to an oil or solid amorphous form of Imatinib nitrate. Similarly, an amorphous solid form of the Imatinib nitrate compound can be recovered by spray drying a solution containing the Imatinib nitrate compound.

In the preferred embodiment, imatinib base (I) is dissolved in methylene dichloride and methanol and treated with nitric acid solution in methanol. The Imatinib nitrate salt is isolated by using acetone and n-hexane solvent.

The present invention also provides a process for preparing crystalline form of Imatinib tosylate, which comprises treating Imatinib with p-toluene sulfonic acid.

The reaction is preferably carried out in suitable solvent. The solvent system is preferably selected so as to facilitate the salt reaction and to allow subsequent separation of the resulting tosylate. Advantageously, both Imatinib and the p-toluene sulfonic acid are dissolvable, at least partly, in the solvent system, at least at elevated temperatures. In the process, a mixture, slurry, or solution of Imatinib and a solvent may be contacted with a p-toluene sulfonic acid, or conversely, a mixture, slurry, or solution of p-toluene sulfonic acid and a solvent may be contacted with imatinib. In another embodiment, both partners may be combined with a solvent system prior to being contacted together, whereby the solvent system used for p-toluene sulfonic acid may be identical with or different from the solvent system used for the Imatinib. The solvent system can be comprised of a single solvent or a mixture of solvents. When two or more solvents are used, a two phase reaction scheme may be used wherein the Imatinib and p-toluene sulfonic acid are primarily reacted in one phase and the resulting Imatinib tosylate compound is primarily present in the other phase due to, inter alia, solubility differences, etc. Suitable solvents include water, a lower alcohol (Cr C₆) such as methanol, ethanol, isopropanol, n-propanol, n-butanol, iso-butanol, tert-butanol; ester such as ethyl acetate, isopropyl acetate, butyl acetate, iso-butyl acetate; ketone such as acetone, methyl ethyl ketone, methyl tert-butyl ketone; ether such as tetrahydrofuran, diethyl ether, diisopropyl ether, dioxane; chlorinated solvent like methylene dichloride, ethylene dichloride, chloroform, chlorobenzene, hydrocarbon solvents like toluene, xylene, hexane, cyclohexane, heptanes; polar solvents like dimethyl formamide, N-methyl pyrrolidone, Ν,Ν-dimethyl acetamide, dimethyl sulfoxide and the like.

The: temperature of contact of imatinib and p-toluene sulfonic acid in the solvent system is from ambient to the boiling point of the solvent system, with elevated temperatures, but generally less than the boiling point, being preferred. It is not required that a complete solution is formed in this step, i.e. a slurry or two phase solution are also possible, though a single solution is generally preferred.

The imatinib tosylate compound can be isolated or recovered from the salt forming reaction by any convenient means. For example, the Imatinib tosylate can be precipitated out of a solution or reaction mixture. The precipitation may be spontaneous depending upon the solvent system used and the conditions. Alternatively, the precipitation can be induced by reducing the temperature of the solvent, especially if the initial temperature at contact is elevated. The precipitation may also be facilitated by reducing the volume of the solution/solvent or by adding a contra solvent, i.e. a liquid miscible with the solvent in which the imatinib tosylate is less soluble. Seed crystals of Imatinib tosylate may also be added to help induce precipitation. The precipitated imatinib tosylate compound can be isolated by conventional methods such as filtration or centrifugation, optionally washed and dried, preferably under diminished pressure.

Alternatively, imatinib tosylate can be isolated by evaporating the solvent and collecting residue. Such a method generally leads to an oil or solid amorphous form of imatinib tosylate. Similarly, an amorphous solid form of the Imatinib tosylate compound can be recovered by spray drying a solution containing the imatinib tosylate compound. In another aspect of the invention, there is provided amorphous form of imatinib tosylate characterized by X-ray powder diffraction pattern substantially as depicted in FIG.12.

The amorphous imatinib tosylate is obtained by spray drying the solution of imatinib tosylate in one or more of suitable solvent comprises acetone, methanol, ethanol, isopropanol, acetonitrile, ethyl acetate, isopropyl acetate and the like.

In the preferred embodiment, imatinib base (I) is dissolved in ethanol and treated with p-toluene sulfonic acid. Imatinib tosylate salt is isolated by using cyclohexane.

The present invention also provides a process for preparing crystalline form of imatinib phosphate, which comprises treating imatinib with phosphoric acid.

The reaction is preferably carried out in suitable solvent. The solvent system is preferably selected so as to facilitate the salt reaction and to allow subsequent separation of the resulting phosphate. Advantageously, both Imatinib and the phosphoric acid are dissolvable, at least partly, in the solvent system, at least at elevated temperatures. In the process, a mixture, slurry, or solution of imatinib and a solvent may be contacted with a phosphoric acid, or conversely, a mixture, slurry, or solution of phosphoric acid and a solvent may be contacted with imatinib. In another embodiment, both partners may be combined with a solvent system prior to being contacted together, whereby the solvent system used for phosphoric acid may be identical with or different from the solvent system used for the imatinib. The solvent system can be comprised of a single solvent or a mixture of solvents. When two or more solvents are used, a two phase reaction scheme may be used wherein the imatinib and phosphoric acid are primarily reacted in one phase and the resulting imatinib phosphate compound is primarily present in the other phase due to, inter alia, solubility differences, etc. Suitable solvents include water, a lower alcohol (Cj- C₆) such as methanol, ethanol, isopropanol, n-propanol, n-butanol, iso-butanol, tert-butanol; ester such as ethyl acetate, isopropyl acetate, butyl acetate, iso-butyl acetate; ketone such as acetone, methyl ethyl ketone, methyl tert-butyl ketone; ether such as tetrahydrofuran, diethyl ether, diisopropyl ether, dioxane; chlorinated solvent like methylene dichloride, ethylene dichloride, chloroform, chlorobenzene, hydrocarbon solvents like toluene, xylene, hexane, cyclohexane, heptanes; polar solvents like dimethyl formamide, N- methyl pyrrolidone, Ν,Ν-dimethyl acetamide, dimethyl sulfoxide and the like. The temperature of contact of imatinib and phosphoric acid in the solvent system is from ambient to the boiling point of the solvent system, with elevated temperatures, but generally less than the boiling point, being preferred. It is not required that a complete solution is formed in this step, i.e. a slurry or two phase solution are also possible, though a single solution is generally preferred.

The imatinib phosphate compound can be isolated or recovered from the salt forming reaction by any convenient means. For example, the imatinib phosphate can be precipitated out of a solution or reaction mixture. The precipitation may be spontaneous depending upon the solvent system used and the conditions. Alternatively, the precipitation can be induced by reducing the temperature of the solvent, especially if the initial temperature at contact is elevated. The precipitation may also be facilitated by reducing the volume of the solution/solvent or by adding a contra solvent, i.e. a liquid miscible with the solvent in which the imatinib phosphate is less soluble. Seed crystals of imatinib phosphate may also be added to help induce precipitation. The precipitated imatinib phosphate compound can be isolated by conventional methods such as filtration or centrifugation, optionally washed and dried, preferably under diminished pressure.

Alternatively, imatinib phosphate can be isolated by evaporating the solvent and collecting residue. Such a method generally leads to an oil or solid amorphous form of imatinib phosphate. Similarly, an amorphous solid form of the imatinib phosphate compound can be recovered by spray drying a solution containing the imatinib phosphate compound.

In the preferred embodiment, Imatinib base (I) is dissolved in mixture of methylene dichloride and methanol and treated with phosphoric acid. Imatinib phosphate isolated by using n-hexane.

The present invention also provides a process for preparing imatinib acetate, which comprises treating imatinib with acetic acid. The reaction is preferably carried out in suitable solvent. The solvent system is preferably selected so as to facilitate the salt reaction and to allow subsequent separation of the resulting acetate. In the process, a mixture, slurry, or solution of imatinib and a solvent may be contacted with a acetic acid, or conversely, a mixture, slurry, or solution of acetic acid and a solvent may be contacted with imatinib. In another embodiment, both partners may be combined with a solvent system prior to being contacted together, whereby the solvent system used for acetic acid may be identical with or different from the solvent system used for the imatinib. The solvent system can be comprised of a single solvent or a mixture of solvents. When two or more solvents are used, a two phase reaction scheme may be used wherein the imatinib and acetic acid are primarily reacted in one phase and the resulting imatinib acetate compound is primarily present in the other phase due to, inter alia, solubility differences, etc. Suitable solvents include water, a lower alcohol (Ci-C₆) such as methanol, ethanol, isopropanol, n-propanol, n-butanol, iso-butanol, tert-butanol; ester such as ethyl acetate, isopropyl acetate, butyl acetate, iso-butyl acetate; ketone such as acetone, methyl ethyl ketone, methyl tert-butyl ketone; ether such as tetrahydrofuran, diethyl ether, diisopropyl ether, dioxane; chlorinated solvent like methylene dichloride, ethylene dichloride, chloroform, chlorobenzene, hydrocarbon solvents like toluene, xylene, hexane, cyclohexane, heptanes; polar solvents like dimethyl formamide, N-methyl pyrrolidone, Ν,Ν-dimethyl acetamide, dimethyl sulfoxide and the like.

The temperature of contact of imatinib and acetic acid in the solvent system is from ambient to the boiling point of the solvent system, with elevated temperatures, but generally less than the boiling point, being preferred. It is not required that a complete solution is formed in this step, i.e. a slurry or two phase solution are also possible, though a single solution is generally preferred.

The imatinib acetate compound can be isolated or recovered from the salt forming reaction by any convenient means. For example, the imatinib acetate can be precipitated out of a solution or reaction mixture. The precipitation may be spontaneous depending upon the solvent system used and the conditions. Alternatively, the precipitation can be induced by reducing the temperature of the solvent, especially if the initial temperature at contact is elevated. The precipitation may also be facilitated by reducing the volume of the solution/solvent or by adding a contra solvent, i.e. a liquid miscible with the solvent in which the Imatinib acetate is less soluble. Seed crystals of imatinib acetate may also be added to help induce precipitation. The precipitated imatinib acetate compound can be isolated by conventional methods such as filtration or centrifugation, optionally washed and dried, preferably under diminished pressure.

Alternatively, imatinib acetate can be isolated by evaporating the solvent and collecting residue. Such a method generally leads to an oil or solid amorphous form of Imatinib acetate. Similarly, an amorphous solid form of the imatinib acetate compound can be recovered by spray drying a solution containing the imatinib acetate compound. In the preferred embodiment, imatinib base (I) is dissolved in ethanol and treated with acetic acid to obtain imatinib acetate, which is isolated by using n-hexane.

The present invention also provides a process for preparing imatinib oxalate, which comprises treating imatinib with oxalic acid in alcohols or ketonic solvent to give Imatinib oxalate. In the preferred embodiment, imatinib base (I) is dissolved in alcoholic solvent and treated with oxalic acid to obtain Imatinib oxalate. Preferably, alcoholic solvent comprises form methanol, ethanol, isopropanol, n-propanol, n- butanol, iso-butanol, tert-butanol ketonic solvent comprises from acetone, methyl ethyl ketone, methyl tert-butyl ketone.

The invention further provides process for preparation of imatinib arginate salt.

The process comprises reacting imatinib base with arginine.

The reaction is preferably carried out in suitable solvent. The solvent system is preferably selected so as to facilitate the salt reaction and to allow subsequent separation of the resulting arginate. Advantageously, both imatinib and arginine are dissolvable, at least partly, in the solvent system, at least at elevated temperatures. In the process, a mixture, slurry, or solution of imatinib and a solvent may be contacted with a arginine, or conversely, a mixture, slurry, or solution of arginine and a solvent may be contacted with imatinib. In another embodiment, both partners may be combined with a solvent system prior to being contacted together, whereby the solvent system used for arginine may be identical with or different from the solvent system used for the imatinib. The solvent system can be comprised of a single solvent or a mixture of solvents. When two or more solvents are used, a two phase reaction scheme may be used wherein the imatinib and arginine are primarily reacted in one phase and the resulting imatinib arginine compound is primarily present in the other phase due to, inter alia, solubility differences, etc. Suitable solvents include water, a lower alcohol (Cr C₆) such as methanol, ethanol, isopropanol, n-propanol, n-butanol, iso-butanol, tert-butanol; ester such as ethyl acetate, isopropyl acetate, butyl acetate, iso-butyl acetate; ketone such as acetone, methyl ethyl ketone, methyl tert-butyl ketone; ether such as tetrahydrofuran, diethyl ether, diisopropyl ether, dioxane; chlorinated solvent like methylene dichloride, ethylene dichloride, chloroform, chlorobenzene, hydrocarbon solvents like toluene, xylene, hexane, cyclohexane, heptanes; polar solvents like dimethyl formamide, N-methyl pyrrolidone, Ν,Ν-dimethyl acetamide, dimethyl sulfoxide and the like. The temperature of contact of imatinib and arginine in the solvent system is from ambient to the boiling point of the solvent system, with elevated temperatures, but generally less than the boiling point, being preferred. It is not required that a complete solution is formed in this step, i.e. a slurry or two phase solution are also possible, though a single solution is generally preferred.

The imatinib arginate compound can be isolated or recovered from the salt forming reaction by any convenient means. For example, the imatinib arginate can be precipitated out of a solution or reaction mixture. The precipitation may be spontaneous depending upon the solvent system used and the conditions. Alternatively, the precipitation can be induced by reducing the temperature of the solvent, especially if the initial temperature at contact is elevated. The precipitation may also be facilitated by reducing the volume of the solution/solvent or by adding a contra solvent, i.e. a liquid miscible with the solvent in which the Imatinib arginate is less soluble. Seed crystals of Imatinib arginate may also be added to help induce precipitation. The precipitated Imatinib arginate compound can be isolated by conventional methods such as filtration or centrifugation, optionally washed and dried, preferably under diminished pressure.

Alternatively, imatinib arginate can be isolated by evaporating the solvent and collecting residue. Such a method generally leads to an oil or solid amorphous form of Imatinib arginate. Similarly, an amorphous solid form of the Imatinib arginate compound can be recovered by spray drying a solution containing the imatinib arginate compound.

In the preferred embodiment, imatinib base (I) is dissolved in mixture of methanol and methylene dichloride and treated with arginine solution in acetone :water to obtain Imatinib arginate.

The invention further provides process for preparation of imatinib lysine HCl salt. The process comprises reacting imatinib base with lysine HCl.

The reaction is preferably carried out in suitable solvent. The solvent system is preferably selected so as to facilitate the salt reaction and to allow subsequent separation of the resulting lysinate HCl. Advantageously, both imatinib and lysine HCl are dissolvable, at least partly, in the solvent system, at least at elevated temperatures. In the process, a mixture, slurry, or solution of imatinib and a solvent may be contacted with lysine HCl, or conversely, a mixture, slurry, or solution of lysine HCl and a solvent may be contacted with imatinib. In another embodiment, both partners may be combined with a solvent system prior to being contacted together, whereby the solvent system used for lysine HC1 may be identical with or different from the solvent system used for the imatinib. The solvent system can be comprised of a single solvent or a mixture of solvents. When two or more solvents are used, a two phase reaction scheme may be used wherein the imatinib and lysine HC1 are primarily reacted in one phase and the resulting imatinib lysine HC1 compound is primarily present in the other phase due to, inter alia, solubility differences, etc. Suitable solvents include water, a lower alcohol (Cj- C6) such as methanol, ethanol, isopropanol, n-propanol, n-butanol, iso- butanol, tert-butanol; ester such as ethyl acetate, isopropyl acetate, butyl acetate, iso- butyl acetate; ketone such as acetone, methyl ethyl ketone, methyl tert-butyl ketone; ether such as tetrahydrofuran, diethyl ether, diisopropyl ether, dioxane; chlorinated solvent like methylene dichloride, ethylene dichloride, chloroform, chlorobenzene, hydrocarbon solvents like toluene, xylene, hexane, cyclohexane, heptanes; polar solvents like dimethyl formamide, N-methyl pyrrolidone, Ν,Ν-dimethyl acetamide, dimethyl sulfoxide and the like..

The temperature of contact of imatinib and lysine HC1 in the solvent system is from ambient to the boiling point of the solvent system, with elevated temperatures, but generally less than the boiling point, being preferred. It is not required that a complete solution is formed in this step, i.e., a slurry or two phase solution are also possible, though a single solution is generally preferred.

The imatinib lysinate HC1 compound can be isolated or recovered from the salt forming reaction by any convenient means. For example, the imatinib lysinate HC1 can be precipitated out of a solution or reaction mixture. The precipitation may be spontaneous depending upon the solvent system used and the conditions. Alternatively, the precipitation can be induced by reducing the temperature of the solvent, especially if the initial temperature at contact is elevated. The precipitation may also be facilitated by reducing the volume of the solution/solvent or by adding a contra solvent, i.e. a liquid miscible with the solvent in which the imatinib lysinate HC1 is less soluble. Seed crystals of imatinib lysinate HC1 may also be added to help induce precipitation. The precipitated imatinib lysinate HC1 compound can be isolated by conventional methods such as filtration or centrifugation, optionally washed and dried, preferably under diminished pressure.

Alternatively, imatinib lysinate HC1 can be isolated by evaporating the solvent and collecting residue. Such a method generally leads to an oil or solid amorphous form of imatinib lysinate HCl. Similarly, an amorphous solid form of the imatinib lysinate HCl compound can be recovered by spray drying a solution containing the imatinib lysinate HCl compound.

In the preferred embodiment, imatinib base (I) is dissolved in mixture of methanol and methylene dichloride and treated with lysinate HCl solution in methanol: water to obtain imatinib lysinate HCl.

The invention further provides process for preparation of imatinib lysinate salt. The process comprises reacting imatinib base with lysine.

The reaction is preferably carried out in suitable solvent. The solvent system is preferably selected so as to facilitate the salt reaction and to allow subsequent separation of the resulting lysinate. Advantageously, both imatinib and lysine are dissolvable, at least partly, in the solvent system, at least at elevated temperatures. In the process, a mixture, slurry, or solution of imatinib and a solvent may be contacted with a lysine, or conversely, a mixture, slurry, or solution of lysine and a solvent may be contacted with Imatinib. In another embodiment, both partners may be combined with a solvent system prior to being contacted together, whereby the solvent system used for lysine may be identical with or different from the solvent system used for the imatinib. The solvent system can be comprised of a single solvent or a mixture of solvents. When two or more solvents are used, a two phase reaction scheme may be used wherein the imatinib and lysine are primarily reacted in one phase and the resulting imatinib lysinate compound is primarily present in the other phase due to, inter alia, solubility differences, etc. Suitable solvents include water, a lower alcohol (Cr C₆) such as methanol, ethanol, isopropanol, n-propanol, n-butanol, iso-butanol, tert-butanol; ester such as ethyl acetate, isopropyl acetate, butyl acetate, iso-butyl acetate; ketone such as acetone, methyl ethyl ketone, methyl tert-butyl ketone; ether such as tetrahydrofuran, diethyl ether, diisopropyl ether, dioxane; chlorinated solvent like methylene dichloride, ethylene dichloride, chloroform, chlorobenzene, hydrocarbon solvents like toluene, xylene, hexane, cyclohexane, heptanes; polar solvents like dimethyl formamide, N-methyl pyrrolidone, Ν,Ν-dimethyl acetamide, dimethyl sulfoxide and the like..

The temperature of contact of imatinib and lysinate in the solvent system is from ambient to the boiling point of the solvent system, with elevated temperatures, but generally less than the boiling point, being preferred. It is not required that a complete solution is formed in this step, i.e., a slurry or two phase solution are also possible, though a single solution is generally preferred.

The imatinib lysinate compound can be isolated or recovered from the salt forming reaction by any convenient means. For example, the imatinib lysinate can be precipitated out of a solution or reaction mixture. The precipitation may be spontaneous depending upon the solvent system used and the conditions. Alternatively, the precipitation can be induced by reducing the temperature of the solvent, especially if the initial temperature at contact is elevated. The precipitation may also be facilitated by reducing the volume of the solution/solvent or by adding a contra solvent, i.e. a liquid miscible with the solvent in which the imatinib lysinate is less soluble. Seed crystals of imatinib lysinate may also be added to help induce precipitation. The precipitated Imatinib lysinate compound can be isolated by conventional methods such as filtration or centrifugation, optionally washed and dried, preferably under diminished pressure.

Alternatively, imatinib lysinate can be isolated by evaporating the solvent and collecting residue. Such a method generally leads to an oil or solid amorphous form of Imatinib lysinate Similarly, an amorphous solid form of the Imatinib lysinate compound can be recovered by spray drying a solution containing the imatinib lysinate compound.

The novel salts and process for its preparation described in the present invention is demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of invention.

The novel imatinib salts of the present invention having better solubility properties over the known imatinib mesylate salt as it is highly soluble in water, which requires special care during formulation. It is well known fact in the pharmaceutical technology field that the solubility of the drug plays a major role in drug dissolution and bioavailability profile. The result of the solubility profile of the novel Imatinib salt is mentioned in below Table -1.

Table - 1

Imatinib Freely Slightly Practically

Soluble

Phosphate soluble soluble insoluble

Imatinib Slightly Slightly Practically Practically

Oxalate soluble soluble insoluble insoluble

Imatinib Practically Practically Slightly Practically

Arginate insoluble insoluble soluble insoluble

Imatinib Slightly

Soluble Soluble Slightly soluble Tosylate soluble

Imatinib Practically Practically Slightly Practically

Lysinate HC1 insoluble insoluble soluble insoluble

Imatinib Slightly Slightly Practically

Soluble

Maleate soluble soluble insoluble

Imatinib Freely Slightly Slightly Practically

Mesylate soluble soluble soluble insoluble

In another general aspect, there is provided pharmaceutically acceptable salts of imatinib having purity greater than about 99% by area percentage of HPLC, wherein the pharmaceutically acceptable salts are selected from oxalic acid, p-toluene sulfonic acid, naphthalene sulfonic acid, benzene sulfonic acid, nitric acid, phosphoric acid, acetic acid, maleic acid, fumaric acid, amino acids like lysine, lysine HC1, arginine.

In another general aspect there is provided a pharmaceutical composition comprising a therapeutically effective amount of crystalline imatinib maleate and one or more pharmaceutically acceptable carriers, excipients or diluents, wherein crystalline imatinib maleate is characterized by having X-ray powder diffraction pattern substantially as depicted in FIG.l .

In another general aspect, there is provided a pharmaceutical composition comprising a therapeutically effective amount of a pharmaceutically acceptable salt of imatinib, and one or more pharmaceutically acceptable carriers, excipients or diluents, wherein the pharmaceutically acceptable salt is selected from oxalic acid, p-toluene sulfonic acid, naphthalene sulfonic acid, benzene sulfonic acid, nitric acid, phosphoric acid, acetic acid, maleic acid, fumaric acid, amino acids like lysine, lysine HC1, arginine. In another general aspect, there is provided use of pharmaceutically acceptable salts of imatinib for the treatment of cancer by administering to a patient a therapeutically effective amount of pharmaceutically acceptable salts of rosuvastatin, wherein the pharmaceutically acceptable salts is selected from oxalic acid, p-toluene sulfonic acid, naphthalene sulfonic acid, benzene sulfonic acid, nitric acid, phosphoric acid, acetic acid, maleic acid, fumaric acid, amino acids like lysine, lysine HCl, arginine.

The imatinib pharmaceutically acceptable salts and process for its preparation described in the present invention is demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of invention.

Examples:

Example-1: Preparation of imatinib maleate

To a clear solution of imatinib free base (30 gm, 60.78 mrnol) in 120 ml solution of dichloromethane (105 ml) and methanol (15 ml), added a solution of maleic acid (7.2 gm, 62.03 mmol) in 165 ml acetone dropwise in 15 min with continuous stirring and it was refluxed for 1H. The suspension was cooled to room temperature then to 0 to5 °C and stirred for 1H. The solid compound was filtered and washed with 100 ml acetone (0 to 5 °C) and dried at 50 °C under vacuum (2 mbar) for 4H gave 33.4 gm imatinib maleate.

ExampIe-2: Preparation of Imatinib Oxalate

To a clear solution of imatinib free base (1 gm, 2.02 mmol) in 4 ml solution of methylene dichloride (3.5 ml) and methanol (0.5 ml), added solution of oxalic acid dihydrate (0.255 gm, 2.02 mmol) in 4 ml isopropyl alcohol dropwise with continuous stirring and it was refluxed for 1 H. The suspension was cooled to RT then to 0-5°C and stirred for 1H. The solid was filtered and washed with 2 ml isopropyl alcohol (0-5 °C) and dried at 50°C under vacuum (2 mbar) for 4H gave 1.13 gm imatinib oxalate.

ExampIe-3: Preparation of Imatinib Lysinate

To a clear solution of imatinib free base (1 gm, 2.02 mmol) in 4 ml solution of methylene dichloride (3.5 ml) and methanol (0.5 ml), added solution of lysine (0.37 gm, 2.02 mmol) in solution of methanol (2 ml) and water (0.9 ml) dropwise with continuous stirring and it was refluxed for 2 H. Added 5 ml acetone and further refluxed the suspension for 2 H. The suspension was cooled to RT then to 0-5°C and stirred for IH. The solid was filtered and washed with 2 ml acetone and dried at 50 C under vacuum (2 mbar) for 4H to give 824 mg imatinib lysinate.

Example-4: Preparation of Imatinib Arginate

To a clear solution of imatinib free base (1 gm, 2.02 mmol) in 4 ml solution of methylene dichloride (3.5 ml) and methanol (0.5 ml), added solution of arginine (0.353 gm, 2.02 mmol) in solution of methanol (2 ml) and water (2 ml) dropwise with continuous stirring and it was refluxed for IH. Added 5 ml acetone and further refluxed the suspension for IH. The suspension was cooled to RT then to 0-5°C and stirred for IH. The solid was filtered and washed with 2 ml acetone (0-5°C) and dried at 65 °C under vacuum (2 mbar) for 4H to give 1.16 gm imatinib arginate.

Example-5: Preparation of Imatinib Nitrate

To a clear solution of imatinib free base (2 gm, 4.04 mmol) in 8 ml solution of methylene dichloride (7 ml) and methanol (1 ml), added solution of nitric acid (0.255 gm, 4.04 mmol) in solution of 2 ml methanol dropwise and it was stirred for 2H at RT. Evaporated the solvent completely and dissolved the residue in 15 ml acetone. Added 10 ml n-hexane dropwise in the above clear solution with continuous stirring and stirred the suspension for 30 min at RT. The solid was filtered and washed with 5 ml n- hexane and dried at 60°C under vacuum (2 mbar) for 4H gave 1.78 gm imatinib nitrate. ExampIe-6: Preparation of Imatinib Phosphate

To a clear solution of imatinib free base (2 gm, 4.04 mmol) in 8 ml solution of methylene dichloride (7 ml) and methanol (1 ml), added solution of phosphoric acid (0.27 ml, 4.04 mmol) in solution of 2 ml methanol dropwise with continuous stirring and it was refluxed for IH. Evaporated the solvent completely and dissolved the residue in 6 ml solution of methylene dichloride (4.8 ml) and methanol (1.2 ml) and stirred. Added 15 ml n-hexane dropwise in the above clear solution and stirred the suspension. Added 5 ml methanol and 5 ml n-hexane for proper stirring and stirred the suspension for IH at RT. The suspension was cooled to 0-5°C and stirred for IH. The solid was filtered and washed with 6 ml (2 x 3 ml) n-hexane and dried at 60 °C under vacuum (2 mbar) for 4H gave 1 .97 gm imatinib phosphate in amorphous form.

ExampIe-7: Preparation of Imatinib Tosylate

To a clear solution of imatinib free base (2 gm, 4.04 mmol) in 28 ml ethanol added p-toluene sulphonic acid (0.85 gm, 4.46 mmol) with continuous stirring and it was refluxed for 2H. Evaporated the solvent completely and added 10 ml cyclohexane dropwise in the above clear solution and stirred the suspension for 2H at RT. The suspension was cooled to 0-5°C and stirred for 1H. The solid compound was filtered and washed with 4 ml cyclohexane (0-5°C) and dried at 65°C under vacuum (2 mbar) for 4H gave 2.47 gm imatinib tosylate.

Example-8: Preparation of Imatinib Acetate

To a clear solution of imatinib free base (2 gm, 4.04 mmol) in 28 ml ethanol added acetic acid (0.778 gm, 12.97 mmol) with continuous stirring and it was refluxed for 3H. Evaporated the solvent till 2 volumes of ethanol remains and added 20 ml n- hexane dropwise in the above clear solution and stirred the suspension for 15 min. Heat the RM at 55°C for 15 min and cooled the suspension to RT then to 0-5°C and stirred for 1H. The solid compound was filtered and washed with 4 ml hexane (0-5°C) and dried at 65°C under vacuum (2 mbar) for 4H gave 1.66 gm imatinib acetate.

Reference ExampIe-9: Preparation of Imatinib Maleate (WO 2008/136010, Expt. No. 2)

To a suspension of imatinib free base (2 gm, 4.05 mmol) in 10 ml methanol, added solution of maleic acid (0.44 gm, 3.79 mmol) in 4 ml methanol dropwise with continuous stirring in 30 min and it was refluxed for 3H. The solution was cooled to RT then to 0 to 5°C and stirred for 1H. Filtered the solid compound, washed with 2 ml methanol (0 to 5 °C) and dried at 60 °C under vacuum (2 mbar) for 4H gave 0.932 gm imatinib maleate. XRD (FIG.22)

Claims

We Claim:

1. Pharmaceutically ac

(II)

wherein in S represent the acid selected from the group consisting of oxalic acid, p- toluene sulfonic acid, naphthalene sulfonic acid, benzene sulfonic acid, nitric acid, phosphoric acid, acetic acid, maleic acid, fumaric acid, amino acids like lysine, lysine HC1, arginine; which forms a salt with imatinib.

2. Cyrstalline imatinib maleate characterized by one or more of X-ray powder diffraction having characteristic peaks at about 6.0°, 11.0°, 14.1°, 15.2°, 16.5°, 17.2°, 18.2°, 19.2°, 21.9°, 23.9°, 27.5° and 29.3° (2Θ), or X-ray powder diffraction substantially as depicted in FIG. l or Differential scanning calorimetry having endothermic peak at about 171.3°C, or differential scanning calorimetry substantially as depicted in FIG.2.

3. Imatinib Phosphate.

4. The imatinib phosphate as claimed in claim 3, which is amorphous.

5. The amorphous imatinib phosphate characterized as claimed in claim 4 characterized by X-ray powder diffraction substantially as depicted in FIG.4 or differential scanning calorimetry substantially as depicted in FIG.5.

6. Imatinib Lysinate.

7. The imatinib lysinate as claimed in claim 5, which is crystalline.

8. The crystalline imatinib lysinate as claimed in claim 6 characterized by one or more of X-ray powder diffraction having characteristic peaks at about 5.9°, 1 1.9°, 17.1°, 18.0°, 18.6°, 19.7°, 24.2°, and 25. (2Θ), or X-ray powder diffraction substantially as depicted in FIG.6 or Differential scanning calorimetry having endothermic peak at about peaks at about 86.8°, 208.4° and 255.7°C, or differential scanning calorimetry substantially as depicted in FIG.7.

9. Imatinib Oxalate.

10. The imatinib oxalate as claimed in claim 9, which is crystalline.

11. The crystalline imatinib oxalate as claimed in claim 10 characterized by one or more of X-ray powder diffraction having characteristic peaks at about 5.9°, 10.5°, 11.9°, 12.8°, 13.7°, 15.8°, 16.3°, 17.1°, 18.0°, 18.5°, 18.9°, 19.7°, 20.9°, 22.7°, 23.9°, 25.9°, 26.6° and 28.3° (2Θ), or X-ray powder diffraction substantially as depicted in FIG.9 or Differential scanning calorimetry having endothermic peak at about 195.4° and 219.9°C, or differential scanning calorimetry substantially as depicted in FIG.10.

12. Imatinib Tosylate.

13. The imatinib tosylate as claimed in claim 12, which is amorphous.

14. The imatinib tosylate as claimed in claim 12, which is crystalline.

15. The amorphous imatinib tosylate as claimed in claim 13 characterized by X-ray powder diffraction substantially as depicted in FIG.12.

16. The crystalline imatinib tosylate as claimed in claim 13 characterized by one or more of X-ray powder diffraction having characteristic peaks at about 4.6°, 9.1°, 10.8°, 12.5°, 13.7°, 14.2°, 15.4°, 17.2°, 18.2°, 19.0°, 21 .5°, 23.0°, 23.7°, 24.9°, 27.3°, and 28.1° (2Θ), or X-ray powder diffraction substantially as depicted in FIG.13 or Differential scanning calorimetry having endothermic peak at about 150.3°C, or differential scanning calorimetry substantially as depicted in FIG.14.

17. Imatinib Nitrate.

18. The imatinib nitrate as claimed in claim 17, which is crystalline.

19. The crystalline imatinib nitrate as claimed in claim 18, which is characterized by one or more of X-ray powder diffraction having characteristic peaks at about 5.8°, 6.9°, 8.4°, 9.5°, 10.1°, 13.9°, 14.3°, 15.9°, 17.4°, 17.6°, 18.1°, 20.5°, 21.9°, 24.9°, 25.4°, 25.9°, 26.7°, 27.8°, and 28.0° (2Θ), or X-ray powder diffraction substantially as depicted in FIG.16 or Differential scanning calorimetry having endothermic peak at about 159°C, or differential scanning calorimetry substantially as depicted in FIG.17.

20. Imatinib Arginate.

21. The imatinib arginate as claimed in claim 20, which is crystalline.

22. The crystalline imatinib arginate as claimed in claim 21 , which is characterized by one more of X-ray powder diffraction having characteristic peaks at about 6.0°, 12.0°, 15.9°, 17.1°, 16.0°, 19.7°, 20.9°, 24.2° and 27.3° (2Θ), or X-ray powder diffraction substantially as depicted in FIG.20 or Differential scanning calorimetry having endothermic peak at about 212.6°C and 238.7°C, or differential scanning calorimetry substantially as depicted in FIG.21.

23. Crystalline imatinib maleate having particle size distributions wherein the 10^th volume percentile particle size (D₁₀) is less than about 50 um, the 50^th volume percentile particle size (D₅o) is less than about 250 um, or the 90^th volume percentile particle size (D90) is less than about 500 um, or any combination thereof.

24. A process for the preparation of crystalline imatinib acid addition salts, the process comprising:

(a) suspending imatinib free base in a suitable organic solvent,

(b) adding suitable acid,

(c) heating the reaction mixture,

(d) optionally adding suitable anti-solvent or co-solvent, and

(e) obtaining crystalline imatinib acid addition salts.

25. The process as claimed in claim 24, wherein the suitable organic solvent comprises one or more of alcoholic solvent like methanol, ethanol, isopropanol, n-butanol, heptanol, decanol, dodecanol and the like, hydrocarbon solvents like toluene, xylene, methylene dichloride, chlorobenzene and the like.

26. The process as claimed in claim 1 1, wherein the suitable anti-solvent or co-solvent comprises one or more of comprises from one. or more of hydrocarbons like n- hexane, heptane, cyclohexane and the like, ethers like diisopropylether, methyltert- butyl ether, tetrahydrofuran and the like, ketonic solvents like acetone, methyl ethyl ketone, methyl isobutyl ketone and the like, esters like ethyl acetate, butyl acetate, isopropyl acetate and the like.

27. The process as claimed in claim 24, wherein suitable acid addition salts comprises one or more of oxalic acid, p-toluene sulfonic acid, naphthalene sulfonic acid, benzene sulfonic acid, nitric acid, phosphoric acid, acetic acid, maleic acid, fumaric acid, amino acids like lysine, lysine HC1, arginine and the like.

28. A process for the preparation of crystalline imatinib maleate, the process comprising

(a) suspending imatinib free base and maleic acid in one or more of suitable solvent;

(b) optionally adding one or more of suitable co-solvent;

(c) removing the solvents; and

(d) obtaining the crystalline form of imatinib maleate, wherein crystalline imatinib maleate may be characterized by X-ray powder diffraction substantially as depicted in FIG.l or differential scanning calorimetry substantially as depicted in FIG.2.

29. The process as claimed in claim 28, wherein suitable solvent comprises one or more of C1 -C5 alcohol solvents, hydrocarbons like toluene, xylene, methylene dichloride, chlorobenzene, water and mixtures thereof.

30. The process as claimed in claim 28, wherein suitable co-solvent comprises one or more of aliphatic ethers like methyl tert-butyl ether, diisopropyl ether, and the like, hydrocarbons like cyclohexane, hexane, heptane, toluene, xylene, and the like, ketones like acetone, methylisobutyl ketone, methyl ethyl ketone and the like.

31. Pharmaceutically acceptable salts of imatinib having purity greater than about 99% by area percentage of HPLC, wherein the pharmaceutically acceptable salts are selected from oxalic acid, p-toluene sulfonic acid, naphthalene sulfonic acid, benzene sulfonic acid, nitric acid, phosphoric acid, acetic acid, maleic acid, fumaric acid, amino acids like lysine, lysine HC1, arginine.

32. A pharmaceutical composition comprising a therapeutically effective amount of crystalline imatinib maleate and one or more pharmaceutically acceptable carriers, excipients or diluents, wherein crystalline imatinib maleate is characterized by having X-ray powder diffraction pattern substantially as depicted in FIG.l .

33. A pharmaceutical composition comprising a therapeutically effective amount of a pharmaceutically acceptable salt of imatinib, and one or more pharmaceutically acceptable carriers, excipients or diluents, wherein the pharmaceutically acceptable salt is selected from oxalic acid, p-toluene sulfonic acid, naphthalene sulfonic acid, benzene sulfonic acid, nitric acid, phosphoric acid, acetic acid, maleic acid, fumaric acid, amino acids like lysine, lysine HC1, arginine.

34. Use of pharmaceutically acceptable salts of imatinib for the treatment of cancer by administering to a patient a therapeutically effective amount of pharmaceutically acceptable salts of rosuvastatin, wherein the pharmaceutically acceptable salts is selected from oxalic acid, p-toluene sulfonic acid, naphthalene sulfonic acid, benzene sulfonic acid, nitric acid, phosphoric acid, acetic acid, maleic acid, fumaric acid, amino acids like lysine, lysine HC1, arginine.