WO2009147626A2

WO2009147626A2 - Anhydrous amorphous form of imatinib mesylate

Info

Publication number: WO2009147626A2
Application number: PCT/IB2009/052336
Authority: WO
Inventors: Keshav Deo; Sanjay Desai; Dhiraj Rathod; Irfan Vohra; Ojas Gandhi; Piyush Fadadu; Chirayu Mistry
Original assignee: Alembic Limited
Priority date: 2008-06-06
Filing date: 2009-06-03
Publication date: 2009-12-10
Also published as: WO2009147626A3

Abstract

The present invention relates to an anhydrous amorphous form of Imatinib mesylate and a process for preparation thereof.

Description

Description Title of Invention: ANHYDROUS AMORPHOUS FORM OF

IMATINIB MESYLATE

Field of invention

[1]

[2] The present invention relates to an anhydrous amorphous form of Imatinib mesylate and a process for preparation thereof. [3] [4] The structural formula of Imatinib mesylate is represented by formula (I)

[6]

Background of the invention

[7]

[8] The chemical name of Imatinib is 4-[(4-Methyl- l-piperazinyl)methy I]-ZV -

[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]phenyl]benzamide, molecular formula is C₂CiH₃₁N₇O and molecular weight is 493.60. The current pharmaceutical product containing this drug is being sold as its mesylate salt by Novartis using tradename Gleevec, in a form of oral tablets.

[9]

[10] 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 turner, gastrointestinal cancer, prostate cancer, neurological cancer, myeloma and glioblastoma. It is also used in the treatment of, pulmonary fibrosis, rheumatoid arthritis and thrombocythemia.

[H]

[12] Polymorphism, the occurrence of different crystal forms, is a property of some molecules and molecular complexes. A single molecule, like Imatinib, may give rise to a variety of crystalline forms having distinct crystal structures and physical properties like melting point, X-ray diffraction pattern, infrared absorption fingerprint, and solid state NMR spectrum, thermogravimetric analysis (¹TGA'), and differential scanning calorimetry ('DSC) which have been used to distinguish polymorphic forms.

[13]

[14] The difference in the physical properties of different crystalline forms results from the orientation and intermolecular interactions of adjacent molecules or complexes in the bulk solid. Accordingly, polymorphs are distinct solids sharing the same molecular formula yet having distinct advantageous physical properties compared to other crystalline forms of the same compound or complex.

[15]

[16] One of the most important physical properties of pharmaceutical compounds is their solubility in aqueous solution, particularly their solubility in the gastric juices of a patient. For example, where absorption through the gastrointestinal tract is slow, it is often desirable for a drug that is unstable to conditions in the patient's stomach or intestine to dissolve slowly so that it does not accumulate in a deleterious environment. Different crystalline forms or polymorphs of the same pharmaceutical compounds can and reportedly do have different aqueous solubility. It enlarges the repertoire of materials that a formulation scientist has available for designing, for example, a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristic.

[17]

[18] A process for preparing Imatinib is set forth in U.S. Pat. No.5,521,184.

[19]

[20] US Patent no. 6,894,051 discloses α-crystal form and β-crystal form of Imatinib mesylate. The process for preparation of β-crystal form comprise dijesting another amorphous or crystal forms with polar solvent such as MeOH, EtOH, acetone, DMF, DMAc, dioxane, water optionally seeding with β-crystal.

[21]

[22] US Patent no. 7,300,938 discloses Form Hl of Imatinib mesylate hydrate and

Amorphous Imatinib mesylate hydrate. The process for preparation of Form Hl comprise dissolving imatinib free base in a chlorinated solvent such as chloroform, MDC, EDC, adding methanesulfonic acid and isolating form Hl by filtration. The process for preparation of amorphous Imatinib mesylate hydrate comprises dissolving Imatinib mesylate in a mixture of methanol/water and then vacuum drying the solution.

[23]

[24] PCT application WO2005077933 discloses α₂ form of Imatinib mesylate. The process for prep of α₂ form comprise adding methane sulfonic acid to Imatinib base in IPA and heating at 40-80⁰C for 30 min and then cooling.

[25] [26] PCT application WO2007023182 discloses delta (δ) and epsilon (ε) form of Imatinib mesylate. The process for prep of delta (δ) form comprise dissolving Imatinib mesylate in water, charged it to microreactor, dried with nitrogen to get precipitates which is suspended in acetone/MeOH and aged at 55⁰C. The process for prep of epsilon(ε) form comprise dissolving Imatinib mesylate in water, charged it to microreactor, dried with nitrogen to get precipitates which is suspended in ethyl acetate/95% ethanol and aged at 55⁰C.

[27]

[28] However, no patent/ patent application of prior art disclose an anhydrous amorphous

Imatinib mesylate or its process for preparation.

[29]

[30] It has been disclosed in prior art that the amorphous forms of a number of drugs exhibit different dissolution characteristics and in some cases different bio- availability patterns when compared to crystalline forms (Konne T., Chem. Pharm. Bull., 38, 2003 (1990)). For some therapeutic indications one bioavailability pattern may be favored over another. Amorphous forms of a number of drugs have been disclosed to exhibit different dissolution characteristics and in some cases different bioavailability patterns when compared to crystalline forms. The present invention aims to provide a novel amorphous form of Imatinib mesylate and a process for preparation thereof.

[31]

[32] The present invention is directed to a novel anhydrous amorphous form of Imatinib mesylate.

[33]

[34]

Object of the invention

[35]

[36] Therefore, it is an object of the present invention to provide an anhydrous amorphous form of Imatinib mesylate.

[37]

[38] Another object of the present invention is to provide a process for preparation of an anhydrous amorphous form of Imatinib mesylate.

[39]

Summary of the invention

[40]

[41] Accordingly, present invention, provides an anhydrous amorphous form of Imatinib mesylate.

[42] The present invention provides a process for preparation of an anhydrous amorphous form of Imatinib mesylate comprising steps of [43] (i) adding Imatinib free base in a suitable solvent system;

[44] (ii) adding methane sulfonic acid;

[45] (iii) spray drying the solution obtained above in step (ii)

[46] The present invention provides a process for preparation of an anhydrous amorphous form of Imatinib mesylate comprising steps of

[47] (i) dissolving Imatinib meaylate in a suitable solvent system;

[48] (ii) spray drying the solution obtained above in step (i)

[49]

Brief description of the drawings [50] [51] FIG. 1 shows the X-ray powder diffraction pattern of an anhydrous amorphous form of Imatinib mesylate (I). [52]

Detailed description of the invention [53] [54] The present invention provides an anhydrous amorphous form of Imatinib mesylate having XRD characteristics as shown in FIG. 1. [55] [56] The present invention provides a process for preparation of an anhydrous amorphous form of Imatinib mesylate form Imatinib free base. [57] [58] The present invention provides a process for preparation of an anhydrous amorphous form of Imatinib mesylate comprising steps of [59] (i) adding Imatinib free base in a suitable solvent system;

[60] (ii) adding methane sulfonic acid;

[61] (iii) spray drying the solution obtained above in step (ii)

[62] [63] Thus, methane sulfonic acid is added to a mixture of Imatinib free base in a suitable solvent system. The reaction mixture is stirred for about 10 to 15 min to get clear solution. The solution is spry dried at about 6O⁰C to about 8O⁰C. The solid is isolated under anhydrous condition to give an anhydrous amorphous form of Imatinib mesylate. [64] [65] The suitable solvent system is selected from one component system, two component system and three component system. The one component system comprises single solvent which is selected from the group comprising an alcohol and water. The examples of alcohols includes but not limited to Ci_-6 alcohol such as methanol, ethanol, propanol, butanol, isopropanol, sec-butanol and the like or mixtures thereof.

[66]

[67] The two component system comprises a homogeneous mixture of solvents wherein one solvent is an alcohol or water. The solvent is selected from alcohols, water, ketones, ethers, esters, nitriles, chlorinated solvents, aromatic hydrocarbons. The examples of solvent includes but not limited to methanol, ethanol, propanol, butanol, isopropanol, sec-butanol, water, acetone, methyl ethyl ketone, methyl isobutyl ketone, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, tetrahydrofuran, methyl tertbutyl ether, diisopropyl ether, diethyl ether, toluene, chlorobenzene, ace- tonitrile, ethyl acetate, methyl acetate, butyl acetate and the like or mixtures thereof. The combination of solvent is selected from alcohol/water, ketone/alcohol, ketone/ water, nitrile/alcohol, nitrile/water, chlorinated solvent/alcohol, ether/alcohol, aromatic hydrocarbon/alcohol. The examples of two component system includes but not limited to methanol/water, acetone/methanol, acetone/propanol, acetone/water, acetonitrile/ methanol, acetonitrile/water, methylethylketone/ethanol, dichloromethane/methanol, diethyl ether/methanol, toluene/methanol and the like or mixtures thereof.

[68]

[69] The three component system comprises a homogeneous mixture of solvents wherein one solvent is any alcohol or water. The solvent is selected from alcohols, water, ketones, ethers, esters, nitriles, chlorinated solvents, aromatic hydrocarbons or mixtures thereof as described above.

[70]

[71] The present invention provides another process for preparation of an anhydrous amorphous form of Imatinib mesylate form Imatinib mesyalte.

[72]

[73] The present invention provides a process for preparation of an anhydrous amorphous form of Imatinib mesylate comprising steps of

[74] (i) dissolving Imatinib meaylate in a suitable solvent system;

[75] (ii) spray drying the solution obtained above in step (i)

[76]

[77] Imatinib mesylate is added to a suitable solvent system and stirred for about 10 to 15 min.

[78]

[79] The clear solution is spry dried at about 6O⁰C to about 8O⁰C. The solid is isolated under anhydrous condition to give an anhydrous amorphous form of Imatinib mesylate.

[80]

[81] The suitable solvent system taken is selected as mentioned earlier.

[82] [83] The following example illustrates the invention further. It should be understood, however, that the invention is not confined to the specific limitations set forth in the individual example but rather to the scope of the appended claims.

[84]

[85] Example-1

[86] Preparation of an anhydrous amorphous form of Imatinib mesylate

[87] Imatinib free base (10.0 g) was added to methanol (30ml) and stirred for 10 to 15 min. Methane sulfonic acid (1.9 g) was added slowly to the above reaction mixture. The reaction mixture was stirred for 10 to 15 min to get clear solution. The solution was spray dried at about 6O⁰C to about 8O⁰C. The solid was isolated under anhydrous condition to get an anhydrous amorphous Imatinib mesylate (11.0 g)

[88] XRD is as shown in FIG. 1.

[89]

[90] Example-2

[91] Preparation of an anhydrous amorphous form of Imatinib mesylate

[92] Imatinib mesylate (10.0 g) was added to methanol (33ml) and stirred for about 10 to

15 min to get clear solution. The solution was spry dried at about 6O⁰C to about 8O⁰C. The solid was isolated under anhydrous condition to give an anhydrous amorphous Imatinib mesylate (10.0 g).

[93]

Claims

[Claim 1] What is claimed is

[Claim 2] 1. An anhydrous amorphous Imatinib mesylate.

[Claim 3]

[Claim 4] 2. An anhydrous amorphous Imatinib mesylate of claim 1, further characterized by an X-ray powder diffraction pattern as in FIG. 1.

[Claim 5]

[Claim 6] 3. A process of preparation of an anhydrous amorphous form of Imatinib mesylate comprising steps of

(i) adding Imatinib free base in a suitable solvent system;

(ii) adding methane sulfonic acid;

(iii) spray drying the solution obtained above in step (ii)

[Claim 7]

[Claim 8] 4. A process for preparation of an anhydrous amorphous form of Imatinib mesylate comprising steps of

(i) dissolving Imatinib meaylate in a suitable solvent system; (ii) spray drying the solution obtained above in step (i)

[Claim 9]

[Claim 10] 5. The process as claimed in claim 3 or 4, wherein the suitable solvent system is selected from one component system, two component system and three component system.

[Claim 11]

[Claim 12] 6. The process as claimed in claim 5, wherein one component system comprises single solvent selected from the group comprising alcohol and water.

[Claim 13]

[Claim 14] 7. The process as claimed in claim 6, wherein the alcohol is selected from Ci-₆ alcohol such as methanol, ethanol, propanol, butanol, iso- propanol, sec-butanol, tert-butanol.

[Claim 15]

[Claim 16] 8. The process as claimed in claim 5, wherein two component system comprises a homogeneous mixture of solvents wherein one solvent is an alcohol or water.

[Claim 17]

[Claim 18] 9. The process as claimed in claim 5, wherein three component system comprises a homogeneous mixture of solvents wherein one solvent is any alcohol or water.

[Claim 19]

[Claim 20] 10. The process as claimed in claim 8 or 9, the solvent is selected from alcohols, water, ketones, ethers, esters, nitriles, chlorinated solvents, aromatic hydrocarbons or mixtures thereof.

[Claim 21]

[Claim 22] 11. The process as claimed in claim 10, wherein the solvent is selected from methanol, ethanol, propanol, butanol, isopropanol, sec-butanol, tert-butanol, water, acetone, methyl ethyl ketone, methyl isobutyl ketone, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, tetrahydrofuran, methyl tertbutyl ether, diisopropyl ether, diethyl ether, toluene, chlorobenzene, acetonitrile, ethyl acetate, methyl acetate, butyl acetate or mixtures thereof.

[Claim 23]

[Claim 24] 12. The process as claimed in claim 3 or 4, wherein spray drying is done at a temperature from about 6O⁰C to about 8O⁰C.