FORM 2
THE PATENTS ACT, 1970
(39 OF 1970)
COMPLETE SPECIFICATION (See section 10)
SUBSTANTIALLY AMORPHOUS FORM OF AN ANTICANCER AGENT AND PROCESS FOR PREPARATION THEREOF
SUN PHARMACEUTICAL INDUSTRIES LIMITED
A company incorporated under the laws of India having their office at ACME PLAZA, ANDHERI-KURLA ROAD, ANDHERI (E), MUMBAI-400 059, MAHARASHTRA, INDIA
The following specification paticularly describes and ascertains the nature of this invention and the manner in which it is to be performed.

SUBSTANTIALLY AMORPHOUS FORM OF AN ANTICANCER AGENT AND PROCESS FOR PREPARATION THEREOF
The present invention provides a novel substantially amorphous form of an anticancer agent, namely, 4-[(4-Methyl-l-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]phenyl]benzamide methanesulfonate, commonly known as imatinib mesylate and process for preparation thereof. Imatinib is represented by a compound of formula 1,

Formula 1
and the mesylate salt of imatinib (Gleevec®) has been approved for the treatment of chronic myeloid leukemia.
United States Patent No. 5521184 (equivalent Indian reference not available, referred to
as the '184 patent hereinafter) discloses N-phenyl-2-pyrimidine amine compounds
including compound of formula 1. The preparation of 4-[(4-Methyl-l-
piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl] amino] phenyl]
benzamide, a compound of formula 1, i.e. has been exemplified in Example 21 of the ' 184 patent in the form of base only and not as a salt thereof.
United States Patent Application No. 20020115858 (equivalent of WO 99/03854, equivalent Indian reference not available) discloses that the methanesulfonic acid addition salt of imatinib (imatinib mesylate) can exist in needle-shaped form designated as alpha-crystal form or non-needle-shaped crystals, especially the beta-crystal form. In the worked out examples the alpha-crystal form is digested in methanol for 2 days to

obtain the beta-crystal form, or the seeding is done to initiate the crystallization of beta-crystal form.
The object of the present invention is to provide a novel stable substantially amorphous form of imatinib mesylate in a reproducible manner.
Another object of the invention is to provide such a form in a simple, viable process.
Still another embodiment of the present invention is to provide pharmaceutical formulations containing substantially amorphous form of imatinib mesylate.
An additional embodiment of the present invention is to provide pharmaceutical methods of treatment using substantially amorphous form of imatnib mesylate.
BRIEF DESCRIPTION OF THE FIGURES
The present invention provides a novel, stable, substantially amorphous form of 4-[(4-Methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl] amino] phenyl] benzamide methanesulfonate (imatinib mesylate) comprising 1.5 to 5% w/w water. This form of imatinib mesylate is referred to as y-form herein.
Fig 1- is X-ray powder diffractogram of y-form of imatinib mesylate. Fig 2- is IR spectrum of y-form of imatinib mesylate.
The term substantially amorphous as referred to herein means that at least 99.5% of the imatinib mesylate is in amorphous form.
The present invention provides a process for preparation of y-form of imatinib mesylate, comprising, concentrating a solution of imatinib mesylate in a polar protic, aprotic, non-polar solvent or aqueous mixtures thereof. The concentration of the solution can be

carried out at atmospheric pressure or under vacuum or by using rotary drier, preferably at temperature between the range of about 20°C to about 120°C.
In one embodiment the present invention provides a process for preparation of y-form of imatinib mesylate comprising, subjecting a solution of imatinib mesylate in a polar protic, aprotic, non-polar solvent or aqueous mixtures thereof to freeze drying.
In another embodiment the present invention provides a process for preparation of y-form of imatinib mesylate comprising, subjecting a solution of imatinib mesylate in a polar protic, aprotic, non-polar solvent or aqueous mixtures thereof to spray drying.
In a preferred embodiment the present invention provides a process for preparation of y-form of imatinib mesylate comprising, subjecting a solution of imatinib mesylate in methanol to spray drying. The process may be carried out at temperature between the range of room temperature to about 90°C.
In a preferred embodiemt the y-form of the imatinib mesylate contains water between the range of about 1.5 to about 4.5% w/w.
In a specific embodiment the y-form of imatinib mesylate of the present invention had a X-Ray powder diffraction pattern as given in Figure 1.
The y-form of imatinib mesylate of the present invention can be conveniently formulated and processed into tablets by dry granulation and direct compression methods.
The following examples are given by way of illustration only and not to be construed as limiting.

Examples
Example 1
Imatinib mesylate (2.0 gm) is dissolved in a mixture of methanol:water (1:1, 2.0 ml) at 45-50°C temperature to get clear solution. The solution was concentrated completely under vacuum at 50-55°C temperature and kept under vacuum at same temperature for 1 hour to obtain the y-form of imatinib mesylate (1.9 gm).
Example 2
Imatinib mesylate (2.0 gm) is dissolved in a mixture of water (6.0 ml) at 25-30°C temperature to get clear solution. The solution was subjected to freeze drying to obtain y-form of imatinib mesylate (1.9 gm).
Example 3
Imatinib mesylate (2.0 gm) is dissolved in a mixture of methanol:water (5:1, 20 ml) at 25-30°C temperature to get clear solution. The solution was subjected to spray drying to obtain the y-form of imatinib mesylate (1.6 gm).

Stability data for Imatinib mesylate gamma form

The above data shows that the y-form of imatinib mesylate of the present invention is stable both in terms of water content and its chemical stability.

Claims
1. A process for preparation of y-form of imatinib mesylate comprising preparing a solution of imatinb mesylate in a solvent and removing the solvent by concentrating the solution to recover the y-form of imatinib mesylate.
2. A process as claimed in claim 1, wherein the solution is concentrated at atmospheric pressure.
3. A process as claimed in claim 1, wherein the solution is concentrated under vacuum.
4. A process as claimed in claim 1, wherein the solution is concentrated by freeze-drying.
5. A process as claimed in claim 1, wherein the solution is concentrated by spray-drying.
6. A process as claimed in claim 4 or 5, wherein the solution of imatinib mesylate is in methanol-water.
7. A process as claimed in claims 1 to 6, substantially as herein described and illustrated
in examples 1 to 3.
Dated this 29th day of October 2004.
DILIP SHANGHVI CHAIRMAN AND MANAGING DIRECTOR SUN PHARMACEUTICAL INDUSTRIES LIMITED