PREAMBLE TO THE DESCRIPTION

An invention to narrate and describe the commercial process for the synthesis of imatinib mesylate a-form and also to define the steps involved in its preparation.

The following Complete Specification describes the nature of the invention and the manner, in which it is to be performed.
STABLE a-CRYSTAL FORM OF IMATINIB MESYLATE AND PROCESS FOR

PREPARATION THERE OF

Field of the invention:
The invention given herein pertains to stable, free flowing and non-hygroscopic a-crystal polymorph of methane sulfonic acid addition salt of 4-(4-methyl piperazin-1-yl methyl)-N-[4-methyl(3-(4-pyridin-3-yl) pyrimidin-2-yl amino)phenyl]-benzamide of formula-I and process for the preparation thereof.

Background of the invention:
Imatinib, sold by the Novartis as GleevecTM is used for the treatment of chronic myeloid leukemia (CML), malignant gastro intestinal tumors and other solid tumors.
US patent no. 6894051 describes a and ß crystalline forms of imatinib mesylate. The a crystalline described in that patent is described as hygroscopic and unstable and the process for the crystal involves a number of unit operations making it cumbersome.
WO 2004/106326, relating to H1 crystal of imatinib mesylate, makes use of chlorinated solvents, which are undesirable on account of its hazaradous properties.
WO 2005/095379 teaches preparation of a-polymorph of imatinib mesylate using sub molar equivalents (0.95 – 0.99) of methane sulfonic acid in an alkanol or a mixture of alkanol and alkanoic acid ester. The process requires seeding with a-crystals. The process is a little lengthy and inconsistent for repeatability. Use of mixed solvents of alkanol and alkanoic ester is not favourable as it leads to small amount of undesired form.
WO 2006/024863 describes a process which produces non-inform a-crystals requiring micronization. It is likely to result in non-uniform crystals.
US patent 2006/0223816 A1 describes formation of a-polymorph of imatinib mesylate using class III as well as class II solvents. Repeating this process it was observed that at temperatures close to 70-80OC, impurities formation were more and at <15OC filteration of addition salt took several hours. Additionally the initiation of a-crystals formation needed seeding by a-crystals.
US patent 2007/0197545 A1 describes formation of a-polymorph of imatinib methane sulfonate as well as forms I and II of imatinib di methane sulfonate salts. The criticality of the mole ratio of base to acid in the formation of mono and di salt is studied in detail. The formation of a-polymorph is carried out in a mixture of ethyl alcohol and an alkanol selected from C1-C4 alkanol. Mixture of solvents is not desirable for an individual process. It was observed in our hand that any solvent which has solubility in water or tends to be hygroscopic gave inconsistent result in the formation of pure a-crystal polymorph.
Considering the fact that the methods described in the preceding paragraph have limits in terms of simplicity and consistency in the formation of the required polymorphic crystals, it was decided to develop a simple methodology, which will give the a-polymorph in stable form.

Summary of the invention
The present application describes a simple, facile and industrially operational methodology in order to achieve consistent results in terms of yield and quality of the required crystalline polymorph. This invention yields a stable, free flowing and non-hygroscopic a-crystal polymorph substantially free of ß-crystal polymorph.
In one embodiment of the invention a free flowing, stable and non-hygroscopic a-polymorph is obtained by conducting salt formation in a water immiscible or partially miscible organic solvent or a mixture there of.
In another embodiment of the invention a free flowing, stable and non-hygroscopic a-polymorph is formed by performing the reaction in a alkanoic acid ester or a alkanone.
In yet another embodiment of the present invention, the formation of a-polymorph is achieved by using C1-4 alkanoic acid ester, an alkanone or a mixture of C1-4 alkanoic acid ester and an alkanone there of.
In a further embodiment of the present invention, the selective formation of a-polymorph is achieved by mixing a suspension or a partially soluble solution of imatinib base with a solution of methane sulfonic acid under stirring.
In one more further embodiment of the present invention by conducting the salt formation at 20-80OC.
The ideal solvents, which give consistent formation of free flowing, stable and non-hygroscopic a-polymorph is achieved by conducting salt formation in a solvent selected from the group methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, methyl propionate, ethyl propionate, methyl butanoate, ethyl butanoate or a mixture there of, acetone, ethyl methyl ketone, methyl iso butyl ketone or a mixture there of or a mixture of an alkanoic acid ester and an alkanone.
The formation of a-crystal polymorph is carried out, preferably, in an alkanoic acid ester or an alkanone or a mixture there of under stirring at a temperature of 20-80OC.

Detailed description of the invention
It has been observed that a free flowing, stable and non-hygroscopic a-crystal polymorph with consistent particle size, is formed, by conducting the salt formation in an alkanoic acid ester, a mixture of alkanoic acid esters, an alkanone, a mixture of alkanones and a mixture of alkanoic acid ester and a alkanone under stirring at a temperature of 0-80OC.
In one embodiment of the invention the salt formation is preferably carried out in an alkanoic acid ester R1-COOR2 where R1 is methyl, ethyl & propyl and R2 is methyl, ethyl, propyl and butyl or mixtures there of, an alkanone R1 CO R2 where R1 is methyl, ethyl and isobutyl and R2 is methyl or mixture there of and a mixture of an alkanoic acid ester and an alkanone.
It is preferable to use to an alkanoic acid ester, a mixture of alkanoic acid ester, an alkanone, a mixture of alkanone and a mixture of an alkanoic acid ester and an alkanone.
It is more preferable to use an alkanoic acid ester or an alkanone. It is most preferable to use an alkanoic acid ester.
The suitable solvents are methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate or a mixture there of, or acetone, methyl ethyl ketone, methyl iso butyl ketone or mixtures there or mixture of an alkanoic acid ester and an alkanone.
It is more preferable to use an alkanoic acid ester or an alkanone or a mixture of an alkanoic acid ester and an alkanone.
It is most preferable to use an industrially available alkanoic acid ester.
In another embodiment of the present invent, the salt formation is carried at a temperature of 10-80OC.
It is preferable to use a temperature of 15-80OC.
It is more preferable to use a temperature of 20-70OC.
It is most preferable to use temperature between 50-60OC.
In yet another embodiment of the present invention, the mole ratio methane sulfonic acid to that of imatinib base is preferably 0.95 to 1.0.
It is more preferable to use a mole ratio of 0.98 to 1.0.
It is most preferable to use equi molar ratio of methane sulfonic acid and base.
It is preferable to use a 10-40 volumes of solvent. It will be more preferable to use 15-30 volumes of solvent.
It is preferable to conduct the salt formation at 15 to 80OC. It is more preferable to form salt at 25 to 70OC.
It is most preferable to form a-polymorph crystals of imatinib mesylate at 30 to 65OC.
As per the findings of this applicants the preferable solvents are ethyl acetate and butyl acetate.
Formation of a-polymorph is achieved by adding a solution of methane sulfonic acid in an organic solvent to a partially soluble suspension of imatinib base in the same organic solvent under stirring at a temperature of 30 to 75OC, preferably at 50-60OC. The addition of the methane sulfonic acid may be preferably done in
1 - 6 hrs and more preferably 1 - 2 hrs. The maintenance, after completion of addition, preferably, is 1-2 hrs and more preferably 1 – 1.5 hrs.
The process is very simple, easily operational resulting in the formation of stable, free flowing, non-hygroscopic a-polymorphic crystals of imatinib methane sulfonate. Additionally the preferential a-polymorph crystal formation takes place without seeding by a-crystals.
The solvents used in this invention include methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, methyl propionate, ethyl propionate, methyl butanoate, ethyl butanoate and mixtures there of.
The process reported herein is quite rugged since it can be performed at wide range of temperatures preferably 20-80OC, more preferably 25-75OC and mot preferably 30-70OC. The mole ratio of acid to base is 1 : 1, wherein, one can achieve selective formation of a-polymorph, which is easily filtered and dried.
The process gives, a free flowing, non-hygroscopic and stable a-polymorph substantially free of ß-polymorph in at least 88.5% yield and at least 95% yield. By proper choice of conditions, such as solvent and temperature, HPLC purity of 99.5 and above can be obtained.
The identification of a-crystal polymorph has been confirmed by studying their IR, DSC and XRD.
Figure i gives IR spectra,
figure ii gives the DSC and figure iii gives the XRD.
Thus the applicants have developed a rugged method for the formation of a-crystal polymorph, which has excellent physical properties such as easy filterability, drying properties, stability and non-hygroscopic nature.

Examples:
The following examples illustrate this invention. This should not be miscrued in limiting the application of this invention in any way. The person skilled in the art may vary the parameters within the scope this invention.
Example 1
To a suspension of imatinib base (99 g, 0.2 mole), stirred at 40-60OC in methyl acetate (2 lts), was added a solution of methane sulfonic acid (19.22 g, 0.2 mole) in methyl acetate (100 ml) during 1.5 – 2hrs. After the addition, the reaction mixture was stirred at that temperature for 1-2 hr and filtered. The solid was washed with the same solvent and dried under vacuum at 40-50OC.
The yield is 90% and HPLC purity is 99.5%.
Example 2
To a suspension of imatinib base (99 g, 0.2 mole), stirred at 40-60OC in ethyl acetate (2 lts), was added a solution of methane sulfonic acid (19.22 g, 0.2 mole) in ethyl acetate (100 ml) during 1.5 – 2hrs. After the addition, the reaction mixture was stirred at that temperature for 1-2 hr and filtered.
The solid was washed with the same solvent and dried under vacuum at 40-50OC.
The yield is 95% and HPLC purity is 99.85%.
Example 3
To a suspension of imatinib base (99 g, 0.2 mole), stirred at 40-60OC in propyl acetate (2 lts), was added a solution of methane sulfonic acid (19.22 g, 0.2 mole) in propyl acetate (100 ml) during 1.5 – 2hrs. After the addition, the reaction mixture was stirred at that temperature for 1-2 hr and filtered. The solid was washed with the same solvent and dried under vacuum at 40-50OC.
The yield is 89% and HPLC purity is 99.5%.
Example 4
To a suspension of imatinib base (99 g, 0.2 mole), stirred at 40-60OC in butyl acetate (2 lts), was added a solution of methane sulfonic acid (19.22 g, 0.2 mole) in butyl acetate (100 ml) during 1.5 – 2hrs. After the addition, the reaction mixture was stirred at that temperature for 1-2 hr and filtered. The solid was washed with the same solvent and dried under vacuum at 40-50OC.
The yield is 91% and HPLC purity is 99.5%.
Example 5
To a suspension of imatinib base (99 g, 0.2 mole), stirred at 40-60OC in isopropyl acetate (2 lts), was added a solution of methane sulfonic acid (19.22 g, 0.2 mole) in isopropyl acetate (100 ml) during 1.5 – 2hrs. After the addition, the reaction mixture was stirred at that temperature for 1-2 hr and filtered. The solid was washed with the same solvent and dried under vacuum at 40-50OC.
The yield is 90% and HPLC purity is 99.4%.
Example 6
To a suspension of imatinib base (99 g, 0.2 mole), stirred at 40-60OC in methyl propionate (2 lts), was added a solution of methane sulfonic acid (19.22 g, 0.2 mole) in methyl propionate (100 ml) during 1.5 – 2hrs. After the addition, the reaction mixture was stirred at that temperature for 1-2 hr and filtered. The solid was washed with the same solvent and dried under vacuum at 40-50OC.
The yield is 88.5% and HPLC purity is 98.8%.
Example 7
To a suspension of imatinib base (99 g, 0.2 mole), stirred at 40-60OC in ethyl propionate (2 lts), was added a solution of methane sulfonic acid (19.22 g, 0.2 mole) in ethyl propionate (100 ml) during 1.5 – 2hrs. After the addition, the reaction mixture was stirred at that temperature for 1-2 hr and filtered. The solid was washed with the same solvent and dried under vacuum at 40-50OC.
The yield is 89% and HPLC purity is 99.3%.

CLAIMS:

We claim

1. A process for the preparation of substantially pure a-polymorph of imatinib

mesylate by adding a solution of methane sulfonic acid, dissolved in an
organic solvent, preferably alkanoic acid ester to a stirred suspension or
sparingly soluble suspension of imatinib base in the same organic solvent,
preferably alkanoic acid ester.

2. A claim, as claimed in claim 1, wherein the alkanoic acid ester is methyl acetate, ethyl acetate, propyl acetate, iropropyl acetate, butyl acetate, methyl propionate, ethyl propionate, propyl propionate, isopropyl propionate, methyl butanoate, ethyl butanoate or a mixture there of
3. A claim, as claimed in claim 2, wherein the alkanoic acid ester is methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate or mixture there of
4. A claim, as claimed in claims 2 and 3, where in the alkanoic acid ester is methyl acetate, ethyl acetate or their mixture.
5. A claim, as claimed in claim 1, wherein the addition of methane sulfonic acid to imatinib base is carried out at 20-80OC, preferably at 50-60OC.
6. A claim, as claimed in claim 1, wherein the crystals of imatinib mesylate formed are substantially pure a-polymorph, >99.5%.
7. A claim, as claimed in claims 1 and 6, wherein the crystals of imatinib mesylate formed are substantially pure a-polymorph, which shows in an X-ray diffraction diagram lines having a relative line intensity, as compared to the most intense line in the diagram, of about 20% or more at the following angles of refraction 2theta: 4.9O, 10.5O, 14.9O, 16.5O, 17.7O, 18.2O, 18.7O, 19.2O, 21.4O, 21.7O, 22.7O, 23.2O, 23.8O, 25.0O and 28.6O.
8. A claim, as claimed in claims 1 and 6, wherein the crystals of imatinib mesylate formed are substantially pure a-polymorph, which has a melting range of 223 – 226OC in differential scanning calorimetry (DSC) thermogram.

9. A claim, as claimed in claims 1 and 6, wherein the crystals of imatinib mesylate formed are substantially pure a-polymorph, which has the IR spectrum absorption bands using a KBr pellets at 3033, 2924, 2824, 2707, 1660, 1575, 1527, 1447, 1317, 1220, 1163, 1036, 807 and 554 cm-1.
10. A claim, as claimed in claim 1, wherein a-polymorph is formed in not less that 85% yield and preferably not less than 95% yield.
11. A claim, as claimed in claim 1, wherein the HPLC purity of a-polymorph is not less than 99% and preferably not less than 99.5%.

The invention relates to stable, free flowing and non-hygroscopic a-crystalline form of methane sulfonic acid salt of 4-(4-methyl piperazin-1-yl methyl)-N-[4-methyl-3-(4-pyridin-3-yl)pyrimidin-2-yl amino)phenyl]-benzamide (imatinib mesylate). A process for the preparation of the a-crystal polymorph is also described.