F0RM 2
THE PATENTS ACT 1970
(39 of 1970)
&
The Patents [Amendment] Rules, 2006
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION
Novel Process For The Preparation Of Polymorphic Form Of Imatinib Mesylate
2. APPLICANT
NAME : Sterling Biotech Limited
NATIONALITY : IN
ADDRESS : 43, Atlanta Building, Nariman Point, Mumbai - 400021
3. PREAMBLE TO THE DESCRIPTION
COMPLETE
The following specification particularly describes the invention and the manner in which it is to be performed.

Field of the Invention
The present invention relates to a novel process for preparing polymorphic forms of imatinib
mesylate. In particular, the invention relates to preparation of a and (3 forms of imatinib
mesylate. More specifically, the present invention relates to preparation of both a and p forms
of 4- [(4-methylpiperazin-1 -yl)methyl]-N-(4-methyl-3 - {[4-(pyridin-3 -yl)pyrimidin-2-
yl]amino}phenyl) benzamide methanesulphonic acid, employing anhydrous and hydrated form of a particular solvent.
Background of the Invention Imatinib is the International non-proprietary name of 4-[(4-methylpiperazin-l-yl)methyl]-A^-(4-methyl-3-{[4-(pyridin-3-yl)pyrimidin-2-yl]amino}phenyl)benzamide. It is known as tyrosine kinase inhibitor and is approved under the trademark "Gleevec" by the US Food & Drug Administration and sold by Novartis for treatment of chronic myelogenous leukemia (CML), gastrointestinal stromals (GISTs) and some other diseases. Imatinib is usually administered orally in the form of suitable salt mostly methane sulphonic addition salt.
EP564409 and US 5521184 first reported a process for the preparation of 4-[(4-
methylpiperazin-l-yl)methyl]-N-(4-methyl-3-{[4-(pyridin-3-yl)pyrimidin-2-
yl] amino }phenyl)benzamide and the use thereof, especially as an anti-tumor agent. However
it does not specify any crystal modifications.
There are various Patent Applications, WO99/03854, US2006/0030568, WO2005/077933, WO2005/095379, WO2004/106326, WO2006/048890, US2009/0012296 that apparently describe crystalline forms of imatinib mesylate designated into various forms like HI, I, and II, beta-crystal form and also amorphous.
PCT Publication No. WO1999/03854 (Its equivalent patent US 6894051) has disclosed two crystalline polymorphic forms alpha and beta of methane sulfonic acid addition salts of imatinib. This patent described that alpha form exist in needle shape and beta form exist in non-needle shape. The alpha form was shown as highly hygroscopic and not stable. The process involved precipitating of such alpha form from non alcoholic solvent which was tedious. This patent also teaches us the method to make the beta form but by dissolving

another crystal form especially alpha form or using amorphous starting material of methane sulfonic acid addition salts of imatinib with suitable polar solvent especially an alcohol like methanol or also a ketone especially acetone. This transformation from alpha form into beta form can be spontaneous in solution. This is achieved by digesting the alpha form in methanol for two days.
Thus WO99/03854, US2006/0030568, US 6894051 disclosing the process for preparation of forms alpha and beta as described above were shown as cumbersome and inconsistent as it involved evaporation of both filtrate and the mother liquor. As per the prior art, the process was not reproducible and they are not well suited for pharmaceutical compositions.
WO 2005/077933 (US 2008/0255138) discloses the form a 2. Here Imatinib mesylate is formed by suspending Imatinib base in organic solvent consisting of methanol, Isopropyl ether, toluene, cyclohexane and Isopropyl alcohol most preferring Isopropyl alcohol and adding methane sulfonic acid, cooling and filtering to obtain the α2 crystal form.
WO2005/095379 (US 7732601) describes a method of preparing alpha form using reduced quantity of methanesulphonic acid per mole imatinib in the reaction mixture of alcohol selected from the group consisting of C2-C6 aliphatic alcohols and the mixtures thereof, mainly n-propyl alcohol, isopropylalcohol, n-butyl alcohol, tert-butyl alcohol, and the mixtures thereof with ethyl alcohol, and then optionally adding a solvent selected from the group consisting of esters formed from a C1-C4 aliphatic alcohol and formic acid, acetic acid, or propionic acid, then cooling and seeding with the alpha crystal form at temp close to crystallization. As per the prior art the process is not reproducible or viable on large industrial scale.
Even US patent application 2006/0223816 has similar process where seeding with alpha crystals are necessary in the reaction mixture. The only difference is in the order of addition for the reaction where imatinib base is heated with organic solvent to dissolve then seeding with crystals of imatinib mesylate alpha-form; separately preparing a solution of methanesulphonic acid in the organic solvent and then gradually adding to the imatinib base solution allowing the mixture to cool, to precipitate crystals of imatinib mesylate in substantially pure alpha-form. The above two patents have a drawback that without

inoculating the seeds of proper crystal form, crystallization has a random nature that means either alpha form or beta form or their mixture is formed.
Polish patent application No. P-366885 filed on April 2, 2004 in which the equimolar amounts of methanesulfonic acid and 4-[(4-methylpiperazin-l-yl)methyl]-N-(4-methyl-3-{[4-(pyridin-3-yl)pyrimidin-2-yI]amino}phenyI)benzamide is carried out in ethyl alcohol or in a mixture of ethyl alcohol with another C1-C4 aliphatic alcohols and then ester of carboxylic acid is added in the reaction mixture to give the a form. But here two different solvents are used, the second of which causes the precipitation of the acid addition from the reaction mixture. Further the method also requires the inoculation with the seed crystals of a form.
WO2006/048890 discloses non-needle shaped alpha crystal form by a process comprising subjecting a solution of imatinib mesylate in a polar aprotic solvent wherein the solvent is an alcohol or aqueous alcohol solvent selected from a group consisting of methanol, ethanol, isopropanol, n-butanol, iso-butanol, tert-butanol and water or mixture thereof to thin film drying.
WO2006/024863 describes a process for the preparation of alpha crystal form of compound by suspending the imatinib base in a solvent selected from isopropanol, n-propanol, n-butanol, t-butanol or methyl isobutylketone, then adding methane sulphonic acid and heating the mixture to induce the formation of alpha crystal form. However this process teaches micronizing the product in order to change the undesirable crystalline needle form and obtain desirable physical properties of the solid.
In the view of the abovementkmed limitations associated with formation of alpha (a) and beta (p) form of imatinib mesylate, there is a need for refined process for a and p form which exhibits all physical properties that does not even need micronization, nor does it require seeding with crystals or adding more than one solvent, yet which is simple, reproducible and eco-friendly method for industrial scale-up using safe solvents.
Summary of the Invention
It is a principle object of present invention to provide improved process for producing alpha (a) and beta (p) form of imatinib mesylate to solve the above-mentioned drawbacks.

The present invention relates to preparation of both a and p forms of 4-[(4-methylpiperazin-
l-yl)memyl]-N-(4-memyl-3-{[4-(pyridin-3-yl)pyrimidin-2-yl]amino}phenyl) benzamide
methanesulphonic acid (imatinib mesylate), employing anhydrous and hydrated form of a particular solvent. By using anhydrous solvent alpha form of imatinib mesylate is formed and by using hydrated solvent beta form of imatinib mesylate is formed.
The present invention in accordance with a first embodiment provides a process for the preparation of alpha crystal form of compound of Formula I (Imatinib mesylate)

wherein the said process comprises:
(a) suspending or dissolving the compound of the Formula II (Imatinib) in an anhydrous
solvent


(b) adding mixture of methanesulphonic acid and an anhydrous solvent at a controlled rate and at a temperature 25-30°C to the suspension or solution formed in step (a);
(c) heating the mixture formed in step (b) to reflux temperature for a sufficient amount of time to induce the formation of alpha crystal form; and
(d) cooling the mixture to room temperature, then stirring the mixture at room temperature for a sufficient amount of time for the formation of alpha crystal form and isolating the alpha crystal form of Formula I.
The present invention in accordance with a second embodiment provides a process for the preparation of beta crystal form of compound of Formula I (lmatinib mesylate):

wherein the said process comprises:
(a) suspending or dissolving the compound of the Formula II (lmatinib) in an hydrated solvent


Formula-II
(b) adding mixture of methanesulphonic acid and an hydrated solvent at a controlled rate and at a temperature 25-30°C to the suspension or solution formed in step (a);
(c) heating the mixture formed in step (b) to reflux temperature for a sufficient amount of time to induce the formation of beta crystal form; and
(d) cooling the mixture to room temperature, then stirring the mixture at room temperature for a sufficient amount of time for the formation of beta crystal form and isolating the beta crystal form of Formula I.
It will be noted that the process of preparing alpha and beta form of imatinib mesylate, in accordance with present invention does not need micronization step, nor does it require for seeding with crystals, or adding more than one solvent in contrast of prior arts. Further, the particle size of the alpha and beta form of imatinib mesylate obtained by the process of present invention is in micronized form, hence does not need to micronization in contrast of prior arts.
Brief Description of the Accompanying Drawings
Further objects of the present invention together with additional features contributing thereto
and advantages accruing there from will be apparent from the description of preferred
embodiments of the present invention which are shown in the accompanying drawing figures.
Fig 1: Illustrates a powder X-ray diffraction pattern for imatinib mesylate a form.
Fig 2: Illustrates a powder X-ray diffraction pattern for imatinib mesylate p form.
Fig 3: Illustrates the DCS curve of the product obtained as per the process of the present
invention for preparing imatinib mesylate a form.

Fig 4: Illustrates the DCS curve of the product obtained as per the process of the present
invention for preparing imatinib mesylate |3 form.
Fig 5: Illustrates the powder X-ray diffraction pattern for imatinib mesylate amorphous form.
Detailed description of the Invention
While this specification concludes with claims particularly pointing out and distinctly claiming that, which is regarded as the invention, it is anticipated that the invention can be more readily understood through reading the following detailed description of the invention and study of the included drawings.
The steps of a method may be providing more details that are pertinent to understanding the embodiments of the present invention and so as not to obscure the disclosure with details that will be readily apparent to those of ordinary skill in the art having benefit of the description herein.
The terms "comprises", "comprising", or any other variations thereof, are intended to cover a non-exclusive inclusion, such that a process or method that comprises a list of steps does not include only those steps but may include other steps not expressly listed or inherent to such process or method.
wherein the said process comprises:
Accordingly, the present invention provides a process for the preparation of alpha crystal form of compound of Formula I


(a) suspending or dissolving the compound of the Formula II in an anhydrous solvent

Formula-II
(b) adding mixture of methanesulphonic acid and an anhydrous solvent at a controlled rate and at a temperature 25-30°C to the suspension or solution formed in step (a);
(c) heating the mixture formed in step (b) to reflux temperature for a sufficient amount of time to induce the formation of alpha crystal form; and
(d) cooling the mixture to room temperature, then stirring the mixture at room temperature for a sufficient amount of time for the formation of alpha crystal form and isolating the alpha crystal form of Formula I.
In an embodiment of the present invention, the anhydrous solvent is an ester or an alcohol, or mixture thereof.
In another embodiment of the present invention, the ester is a C2-C10 ester.
In yet another embodiment of the present invention, the ester is an ethyl acetate, isopropyl acetate or butyl acetate or mixture thereof.
In still another embodiment of the present invention, the alcohol is a C1-C6 alcohol.
In a farther embodiment of the present invention, the alcohol is a methanol, ethanol, isopropyl alcohol or butanol or mixture thereof.

In a farther more embodiment of the present invention, the water content of anhydrous solvent is less then 0.10% w/w.
In another embodiment of the present invention, said compound of Formula I obtained by the process has a water content not more than 1%.
Further, the present invention also a process for the preparation of beta crystal form of compound of Formula I:

Formula-I
wherein the said process comprises:
(a) suspending or dissolving the compound of the Formula II in an hydrated solvent


(b) adding mixture of methanesulphonic acid and an hydrated solvent at a controlled rate and at a temperature 25-30°C to the suspension or solution formed in step (a);
(c) heating the mixture formed in step (b) to reflux temperature for a sufficient amount of time to induce the formation of beta crystal form; and
(d) cooling the mixture to room temperature, then stirring the mixture at room temperature for a sufficient amount of time for the formation of beta crystal form and isolating the beta crystal form of Formula I.
In an embodiment of the present invention, the hydrated solvent is an ester or an alcohol, or mixture thereof.
In another embodiment of the present invention, the hydrated ester is a C2-C10 ester.
In yet another embodiment of the present invention, the hydrated ester is an ethyl acetate, isopropyl acetate or butyl acetate or mixture thereof.
In still another embodiment of the present invention, the hydrated alcohol is a C1-C6 alcohol
In a further embodiment of the present invention, the hydrated alcohol is a methanol, ethanol, isopropyl alcohol or butanol or mixture thereof.
In a further more embodiment of the present invention, the water content of hydrated solvent is more then 0.50% w/w.
In another embodiment of the present invention, said compound of Formula I obtained by the process has a water content not more than 1%.
The fundamentally important feature of the present invention is that by using anhydrous and hydrated form of a particular solvent, especially ethyl acetate, both a and p forms of 4-[(4-methylpiperazin-l-yl)methyl]-Ar-(4-methyl-3-{[4-(pyridin-3-yl)pyrimidin-2-yl]amino}phenyl)benzamide methanesulphonic acid can be prepared.


Scheme 1
The present invention as explained in above scheme 1 is directed to a process for making the polymorphic forms of methane sulfonic acid salt of 4-[(4-methylpiperazin-l-yl) methyl]-7V-(4-methyl-3-{[4-(pyridin-3-yl)pyrimidin-2-yl]amino}phenyl)benzamide.
The solvents employed in the present invention are more benign compared to other solvents used in the prior art. Hence, the solvents employed in the present invention are eco-friendly.
In one embodiment, the invention recounts to a process for preparing Imatinib mesylate in substantially pure a form using anhydrous Ethyl acetate.
As explained in Fig 1, the present invention recounts to a crystalline imatinib mesylate, which is characterized by data given by XRD pattern with peaks at 20 degree as given below in Table 1.
Table-1

Main diffraction peaks of Imatinib
mesylate a Form
No. of 2 theta value Relative
peak (0) intensity

1 4.90 48.25
2 10.47 71.53
3 14.92 66.56
4 16.52 34.44
5 17.51 39.27
6 17.73 56.07
7 18.09 82.48
8 18.63 100.00
9 21.30 62.45
10 21.69 67.08
11 22.62 20.55
12 23.19 25.40
13 23.82 32.36
14 24.99 55.88
15 28.56 46.10
In another embodiment, the present invention recounts to a process for preparing Imatinib mesylate substantially purely β form in 1% aqueous Ethyl acetate.
As explained in Fig 2, the present invention recounts to β crystalline imatinib mesylate, which is characterized by data given by XRD pattern with peaks at 20 degree as given below in Table 2.
Table-2

Main diffraction peaks of Imatinib mesylate β Form
No. of peak 2 theta value
(o) Relative intensity
1 9.77 38.33
2 13.91 32.28
3 14.11 27.05
4 14.68 22.81
5 17.49 66.75

6 18.18 86.36
7 18.93 18.34
8 20.06 65.29
9 20.60 100.00
10 21.15 85.31
11 22.08 72.09
12 22.75 40.25
13 23.77 42.15
14 29.73 20.00
IS 30.85 21.73
Yet in another embodiment, the present invention recounts to a process for preparing Imatinib mesylate amorphous form in chlorinated solvent especially chloroform.
The following non-limiting examples illustrate specific embodiments of the present invention. They are, however, not intended to be limiting the scope of present invention in any way:
Example 1: Preparation of Imatinib mesylate a form in Ethyl acetate
Imatinib base (2.0g) was suspended in 50 ml ethyl acetate. Methanesulphonic acid (0.38 g) in 10 ml ethyl acetate was added slowly during 30 minutes at Room Temperature (RT). The suspension was heated to reflux temperature for one hour (hr) and was slowly brought to RT. The suspension was stirred at RT for 30 minutes, filtered and washed with 4 ml ethyl acetate and dried for 6 hr at 60°C. The yield was 2.0 g (84.0%). Melting point 225.97°C (by DSC).
Example 2: Preparation of Imatinib mesylate β form in 1% aq. Ethyl acetate
Imatinib base (2.0g) was suspended in 50 ml aq. ethyl acetate. Methanesulphonic acid (0.38 g) in 10 ml aq. ethyl acetate was added slowly during 30 minutes at RT. The suspension was heated to reflux temperature for one hr and was slowly brought to RT. The suspension was stirred at RT for 30 minutes, filtered and washed with 4 ml aq. ethyl acetate and dried for 6 hr at 60°C. The yield was 2.0 g (84.0%). Melting point 215.22°C (by DSC).

Example 3: Preparation of Imatinib mesylate a form in isopropyl acetate
Imatinib base (2.0g) was suspended in 20 ml isopropyl acetate; methanesulphonic acid (0.38 g) in 5 ml isopropyl acetate was added slowly during 30 minutes at RT. The suspension was heated to reflux temperature for one hour and was slowly brought to RT. The suspension was stirred at RT for 30 minutes, filtered and washed with 4 ml isopropyl acetate and dried for 6 hr at 60°C. The yield was 1.8g (75.63%).
Example 4: Preparation of Imatinib mesylate a form in tert. butyl acetate
Imatinib base (2.0g) was suspended in 20 ml tert. butyl acetate, methanesulphonic acid (0.38 g) in 5 ml tert. butyl acetate was added slowly during 30 minutes at RT. The suspension was heated to reflux temperature for one hour and was slowly brought to RT. The suspension was stirred at RT for 30 minutes, filtered and washed with 4 ml tert. butyl acetate and dried for 6 hr at 60°C. The yield was 1.9g (79.8%).
Example 5: Preparation of Imatinib mesylate a form in methanol
Imatinib base (2.0g) was suspended in 10 ml methanol; methanesulphonic acid (0.38 g) in 1 ml methanol was added slowly during 30 minutes at RT. The suspension was heated to reflux temperature for one hour and was slowly brought to RT. The suspension was stirred at RT for 30 minutes, filtered and washed with 2 ml methanol and dried for 6 hr at 60°C. The yield was 1.5g (63.02%).
Example 6: Preparation of Imatinib mesylate p form in Methanol and water mixture
Imatinib base (50.0 g) was suspended in 75.0 ml methanol, heat to 40-45°C methanesulphonic acid (9.73 g) in 6.25 ml purified water was added slowly during 30 minutes at 40-45°C. The suspension was stirred at 40-45°C for I hr and was slowly brought to RT. The suspension was stirred at RT for 6 hr, filtered and washed with 5 ml methanol and dried for 6 hr at 60°C. The yield was 50.0 g (83.71%). The bulk density of Imatinib mesylate is 0.40 g/ml and the tapped bulk density is 0.60 g/ml.
Example 7: Preparation of Imatinib mesylate a form in ethanol
Imatinib base (2.0g) was suspended in 20 ml ethanol; methanesulphonic acid (0.38 g) in 5 ml ethanol was added slowly during 30 minutes at RT. The suspension was heated to reflux

temperature for one hour and was slowly brought to RT. The suspension was stirred at RT for 30 minutes, filtered and washed with 4 ml ethanol and dried for 6 hr at 60°C. The yield was 1.9g(79.8%).
Example 8: Preparation of Imatinib mesylate form p in 1% aq. ethanol with heating
Imatinib base (2.0g) was suspended in 50 ml 1% aq. ethanol, methanesulphonic acid (0.38 g) in 10 ml 1% aq. ethanol was added slowly during 30 minutes at RT. The suspension was heated to reflux temperature for one hr and was slowly brought to RT. The suspension was stirred at RT for 30 minutes, filtered and washed with 4 ml 1% aq. ethanol and dried for 6 hr at 60°C. The yield was 1.8 g (75.63%).
Example 9: Preparation of Imatinib mesylate a form in isopropanol
Imatinib base (2.0 Kg) was suspended in 50 liter isopropanol; methanesulphonic acid (389.38 g) in 10 liter isopropanol was added "slowly during 30 minutes at RT. The suspension was heated to reflux temperature for one hour and was slowly brought to RT. The suspension was stirred at RT for 30 minutes, filtered and washed with 4 liter isopropanol and dried for 6 hr at 60°C. The yield was 2.0 Kg (84.03%).
Example 10: Preparation of Imatinib mesylate form β in 1% aq. Isopropyl alcohol with heating
Imatinib base (2.0g) was suspended in 50 ml 1% aq. isopropyl alcohol, methanesulphonic acid (0.38 g) in 10 ml 1% aq. isopropyl alcohol was added slowly during 30 minutes at RT. The suspension was heated to reflux temperature for one hr and was slowly brought to RT. The suspension was stirred at RT for 30 minutes, filtered and washed with 4 ml 1% aq. isopropyl alcohol and dried for 6 hr at 60°C. The yield was 2.2 g (92.43%).
Example 11: Preparation of Imatinib mesylate a form in isobutanol
Imatinib base (2.0g) was suspended in 20 ml isobutanol; methanesulphonic acid (0.38 g) in 5 ml isobutanol was added slowly during 30 minutes at RT. The suspension was heated to reflux temperature for one hour and was slowly brought to RT. The suspension was stirred at RT for 30 minutes, filtered and washed with 4 ml isobutanol and dried for 6 hr at 60°C. The yield was 1.6g (67.22%).

Example 12: Preparation of Imatinib mesylate a form in tert. Butanol
Imatinib base (2.0g) was suspended in 20 ml tert. butanol methanesulphonic acid (0.38 g) in 5 ml tert. butanol was added slowly during 30 minutes at RT. The suspension was heated to reflux temperature for one hour and was slowly brought to RT. The suspension was stirred at RT for 30 minutes, filtered and washed with 4 ml tert. Butanol and dried for 6 hr at 60°C. The yield was 1.7g (71.42%).
Example 13: Preparation of Imatinib mesylate β form in Methanol, ethyl acetate and water mixture
Imatinib base (2.0 Kg) was suspended in 3.0 liter methanol and ethyl acetate (1:1) mixture, heat to 40-45°C, methanesulphonic acid (389.38 g) in 250 ml purified water was added slowly during 30 minutes at 40-45°C. The suspension was stirred at 40-45°C for 1 hr and was slowly brought to RT. The suspension was stirred at RT for 6 hr, filtered and washed with 1 liter ethyl acetate and dried for 6 hr at 60°C. The yield was 2.0 Kg (84.03%). The bulk density of Imatinib mesylate is 0.44 g/ml and the tapped bulk density is 0.77 g/ml.
The other examples conducted with different anhydrous and hydrated solvents.
Example 14: Preparation of Imatinib mesylate form a in Acetonitrile
Imatinib base (2.0g) was suspended in 80 ml acetonitrile, methanesulphonic acid (0.38 g) in 10 ml acetonitrile was added slowly during 30 minutes at RT. The suspension was heated to reflux temperature for one hr and was slowly brought to RT. The suspension was stirred at RT for 30 minutes, filtered and washed with 4 ml acetonitrile and dried for 6 hr at 60°C, The yield was 1.6 g (67.2%).
Example 15: Preparation of Imatinib mesylate form p in 1% aqueous Acetonitrile with heating
Imatinib base (2.0g) was suspended in 50 ml 1% aq. acetonitrile, methanesulphonic acid (0.38 g) in 10 ml 1% aq. acetonitrile was added slowly during 30 minutes at RT. The suspension was heated to reflux temperature for one hr and was slowly brought to RT. The suspension was stirred at RT for 30 minutes, filtered and washed with 4 ml 1% aq. acetonitrile and dried for 6 hr at 60°C. The yield was 1.9 g (79.83%).

Example 16: Preparation of Imatinib mesylate form a in ethyl acetate and Acetonitrile mixture
Imatinib base (2.0g) was suspended in 50 ml acetonitrile and ethyl acetate mixture, methanesulphonic acid (0.38 g) in 10 ml mixture of solvent was added slowly during 30 minutes at RT. The suspension was heated to reflux temperature for one hr and was slowly brought to RT. The suspension was stirred at RT for 30 minutes, filtered and washed with 4 ml solvent mixture and dried for 6 hr at 60°C. The yield was 1.9 g (79.8%).
Example 17: Preparation of Imatinib mesylate form a in Toluene and Acetonitrile mixture with heating
Imatinib base (2.0g) was suspended in 50 ml toluene and acetonitrile mixture, methanesulphonic acid (0.38 g) in 10 ml mixture of solvent was added slowly during 30 minutes at RT. The suspension was heated to reflux temperature for one hr and was slowly brought to RT. The suspension was stirred at RT for 30 minutes, filtered and washed with 4 ml solvent mixture and dried for 6 hr at 60°C. The yield was 2.0 g (84.0%).
Details of the experiments conducted with different anhydrous solvents and with 1% water mixture of solvents are tabulated in Table-3
Table-3

s.
N. Example No. Solvent Yield DSC XRP D

Anhydrous Hydrated Input Output

1 1 EA - 2.0g 2.0g 225.9°C α
2 2 - l%aqEA 2.0g 2.0g 215°C β
3 3 Isopropyl acetate - 2.0g 1.8g - α
4 4 tert. Butyl acetate - 2.0g 1.9g - α
5 5 MeOH - 2.0 g 1-5 g 225.44°C α
6 6 - l% aq MeOH 50.0g . 50.0g - β
7 7 EtOH - 2.0g 1.9g 217.6°C α
8 8 - l%aqEtOH 2.0g 1.8g 220°C β
9 9 IPA - 2.0Kg 2.0Kg 229°C α

10
10 - l%aq IP A 2.0g 2.2g 214°C β
11 11 Isobutanol - 2.0g 1.6g - α
12 12 tert. Butanol - 2.0g 1.7g - α
33 14 ACN - 2.0g I6g 230.9°C α
14 15 - l%aqACN 2.0g 1.9g 216°C β
15 - Dioxane - l.Og Sticky solid
16 - - l%aq Dioxane 1-Og Sticky solid
17 Acetone - 3.0g 33g 225.3°C α
DSC: Differential Scanning Calorimetry
XRD: X-Ray Diffraction
RT : Room Temperature
IMA: Imatinib mesylate
MeOH: Methanol
IPA: Isopropyl alcohol
EA: Ethyl acetate
ACN: Acetonitrile
EtOH: Ethanol
Example 18: Preparation of Imatinib mesylate amorphous form in chloroform
Imatinib base (l.Og) was suspended in 20 ml chloroform. Methanesulphonic acid (0.19 g) in 5 ml chloroform was added slowly during 30 minutes at RT. The suspension was heated to reflux temperature for one hr and was slowly brought to RT. The suspension was stirred at RT for 30 minutes, and solvent was recovered completely under vacuum at 40°C. The yield was 0.9 g (75.63%).

We Claim:
1. A process for the preparation of alpha crystal form of compound of Formula I

wherein the said process comprises:
(a) suspending or dissolving the compound of the Formula II in an anhydrous solvent

(b) adding mixture of methanesulphonic acid and an anhydrous solvent at a controlled rate and at a temperature 25-30°C to the suspension or solution formed in step (a);
(c) heating the mixture formed in step (b) to reflux temperature for a sufficient amount of time to induce the formation of alpha crystal form; and

(d) cooling the mixture to room temperature, then stirring the mixture at room temperature for a sufficient amount of time for the formation of alpha crystal form and isolating the alpha crystal form of Formula I.
2. The process according to claim 1, wherein the anhydrous solvent is an ester or an alcohol, or mixture thereof.
3. The process according to claim 1, wherein the ester is a C2-C10 ester.
4. The process according to claim 1, wherein the ester is an ethyl acetate, isopropyl acetate or butyl acetate or mixture thereof.
5. The process according to claim 1, wherein the alcohol is a C1-C6 alcohol,
6. The process according to claim 1, wherein the alcohol is a methanol, ethanol, isopropyl alcohol or butanol or mixture thereof.
7. The process according to claim 1, wherein the water content of anhydrous solvent is less then 0.10% w/w.
8. The process according to claim 1, wherein the said compound of Formula I obtained by the process has a water content not more than 1%.
9. A process for the preparation of beta crystal form of compound of Formula I:


wherein the said process comprises;
(a) suspending or dissolving the compound of the Formula II in an hydrated solvent

(b) adding mixture of methane sulphonic acid and an hydrated solvent at a controlled rate and at a temperature 25-30°C to the suspension or solution formed in step (a);
(c) heating the mixture formed in step (b) to reflux temperature for a sufficient amount of time to induce the formation of beta crystal form; and
(d) cooling the mixture to room temperature, then stirring the mixture at room temperature for a sufficient amount of time for the formation of beta crystal form and isolating the beta crystal form of Formula I.

10. The process according to claim 9, wherein the hydrated solvent is an ester or an alcohol, or mixture thereof.
11. The process according to claim 9, wherein the hydrated ester is a C2-C10 ester.
12. The process according to claim 9, wherein the hydrated ester is an ethyl acetate, isopropyl acetate or butyl acetate or mixture thereof.
13. The process according to claim 9, wherein the hydrated alcohol is a C1-C6 alcohol
14. The process according to claim 9, wherein the hydrated alcohol is a methanol, ethanol, isopropyl alcohol or butanol or mixture thereof.
15. The process according to claim 9, wherein the water content of hydrated solvent is more then 0.50% w/w.
16. The process according to claim 9, wherein the said compound of Formula I obtained by the process has a water content not more than 1%.