FORM 2
THE PATENTS ACT, 1970 (39 of 1970) & THE PATENT RULE 2003
PROVISIONAL SPECIFICATION
(See Section 10; rule 13)
NEW POLYMORPH OF IMATINIB MESYLATE
RELIANCE LIFE SCIENCES PVT.LTD an Indian Company having its Registered Office at Dhirubhai Ambani Life Sciences Centre, R-282, TTC Area of MIDC, T h an e Belapu r Road, Rabale, Navi Mumbai-400 701 Maharashtra India.
The following specification particularly describes and ascertains the nature of this invention and the manner in which it is performed:-

TECHNICAL FIELD
The present invention relates to a new crystalline polymorph of imatinib mesylate. In particular the present invention provides a new R-form of imatinib mesylate which is rod -shaped and has a different XRD pattern as compared to the conventional forms of imatinib mesylate.
BACKGROUND ART
Imatinib is chemically known as 4-(4-methylpiperazin-l-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl) pyrimidin-2ylamino) phenyl] benzamide, is represented by the following structure of formula (])
The compound Imatinib mesylate is sold under the brand name GLIVEC® for the treatment of Chronic Myeloid Leukemia (CML) and gastrointestinal stromal tumors (GIST). It has also been approved for the treatment of patients with kit [ CD 117] positive unresectable and recently it has been approved for the treatment of pediatric patients with Philadelphia chromosome positive (Ph +) chronic myeloid leukemia in chronic phase.

Formula I
The preparation of Imatinib and its use, especially as an anti-tumor agent, are described in EP-A- 0 564 409. The compound is exemplified in these publications only in free form (not as a salt). Imatinib Mesylate, the alpha and the beta crystal form thereof, as well as its pharmaceutical use are described in US 6,894,051.

Various polymorphs of imatinib has been disclosed in the prior art such as H-] form in PCT application WO 2004/106326, Form 1 and II in PCT application WO 2006/054314, Delta and epsilon crystal form in WO 2007/023182, F,G, H,I and K crystal form in WO2007/059963, α2was disclosed in Indian patent application No. 706/CHE/04
Thus, in general the prior art provides two main forms of imatinib namely; alpha form which is needle shaped and beta form is which is non needle shaped. Further Alam et al (Solid-state characterization of Imatinib mesylate a and β forms) in their disclosure has characterized alpha form as rod shaped and beta form as plate shaped.
Imatinib is a drug used to treat certain types of cancer. It is used in treating chronic myelogenous leukemia (CML), gastrointestinal stromal tumors (GISTs) and other cancers. It is the first member of a new class of agents that act by specifically inhibiting a certain enzyme that is characteristic of a particular cancer cell, rather than non-specifically inhibiting and killing all rapidly dividing cells.
Imatinib is often cited as an example of pharmaceutical industry innovation, hence looking to the need of the hour, the inventors of the present invention has successfully developed a stable new crystalline polymorphic form of Imatinib mesylate which is depicted as R form in the specification. This R form has the solubility profile similar to alpha form and the stability is similar to beta form. Further this R form has its unique XRD data and is in no way similar to alpha and beta forms.
STATEMENT OF THE INVENTION:
The present invention provides a stable new crystalline polymorphic form of Imatinib mesylate. In particular the present invention provides for a new R-form of imatinib mesylate which is rod shaped with XRD characterized by additional peaks at 26.99 angle 2 0 with (24.5%) intensity.
The present invention also provides a process and the compositions of the new R- form of imatinib mesylate which remains stable."

OBJECTIVE OF THE INVENTION:
It is the aim of the present invention to provide a new crystalline polymorphic form of Imatinib mesylate with unique XRD data which is in no way similar to the known alpha and beta forms of imatinib mesylate.
It is the aim of the present invention to provide a new crystalline R-form of imatinib mesylate.
ft is the aim of the present invention to provide an efficient process that consistently provides the R-form in the form of rod shaped crystals.
It is the aim of the present invention to provide a formulation of R-form of imatinib mesylate.
It is the aim of the present invention to provide a process of the formulation which does not alter the stability of the R-form imatinib mesylate.
SUMMARY OF INVENTION
The present invention relates to new crystalline polymorphic R-form of methanesulphoinc acid addition salt of 4-(4-methyIpiperazin-l-yImethyO-N-[4-methyl-3-(4-pyridin-3-yl) pyrimidin-2ylamino) phenyl] benzamide (imatinb mesylate). Formula (II) in quantitative yield and in consistency.

Formula (II) The present disclosure provides a new polymorph of imatinib mesylate. In particular the present invention provides a polymorph which has the solubility profile comparable to

alpha form and the stability profile comparable to beta form with a characteristic suitable for pharmaceutical compositions.
In particular this form is characterized by rod shaped crystals that is designated as R-form in this invention.
In one embodiment, the present invention provides a new crystalline R-form of imatinib mesylate which is characterized by additional peaks in XRD.
In one embodiment, the present invention provides an efficient process for the preparation of the new crystalline R-form. In preferred embodiment the present invention provides a process that is reproducible and gives consistent yields.
In one embodiment, the present invention provides a new R-form form that is of purity of atleast 99%, remains dry at 93% relative humidity and is stable at 40°C and 75 % RH.
In one embodiment the present invention provides formulations of the new R-form.
BRIEF DESCRIPTION OF DRAWINGS
The following drawings form part of the present specification and are included to further demonstrate certain aspects of the present disclosure, the inventions of which can be better understood by reference to one or more of these drawings in combination with the detailed description of specific embodiments presented herein.
Figure 1 : Microscopic photograph of R- form
Figure 2 : Microscopic photograph of Beta-form
Figure 3: XRD data of R-form
Figure 4: DSC data of R- form
Figure 5;FTIR data of R -form

DESCRIPTION OF EMBODIMENTS
DEFINITIONS:
The term "imatinib" as used herein refers to the base form of of 4-(4-methylpiperazin-l-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl) pyrimidin-2ylamino) phenyl] benzamide
The term " rod shaped " as used herein is plate shaped or rod like shaped as characterized in the figures.
The term R- form as used herein refers to the beta form which has XRD pattern given in table 1
The term "new polymorph" or "new crystalline form" as used herein refers to rod shaped or R- form of imatinib mesylate as characterized by XRD and figures.
PREFERRED EMBODIMENTS AND THE SCOPE
The invention relates to Imatinib mesylate R-form comprising rod shaped crystals structure having following properties:
1. Solubility similar to alpha form
2. Stability similar to beta form
3. This form remains dry at 93% RH and stable at 40°C and 75%RH
4. This form is characterized by rod shaped crystals as displayed in figure 1.
5. This form displays some additional peaks in XRPD data of R-form peaks in the XRPD data of R-from, particularly at 26.99 angle 2 0 with (24.5%) intensity is the main distinguished feature of R-form not reported in a-form and (3-form.
6. This form has a different melting point.
Thereby the present invention states that this particular R-from is a novel polymorph of Imatinib mesylate.
Process parameters:
Methane sulphonic acid in absolute alcohol is added to a suspension of Imatinib base in ethanol at 25-30 °C and the suspension is refluxed for 3 and half hrs, cooled and filtered,

to get the R-form. If the moisture content in alcohol is > 1 %, repetition of the above experiment leads to formation of the Beta polymorph. Substitution of Ethanol with Isopropyl alcohol also leads to formation of beta polymorph if the moisture content in isopropyl alcohol is greater than > 1.1 %.
The present invention has studied the effect of various solvents on the polymorphism of crystalline imatinib mesylate. It was observed that alcoholic solvents preferably gave the R- form. Further alcoholic solvent such as ethanol favored the formation of R- form and the solvent such as isopropanol gave the beta form if the moisture in IPA is greater than 1.1%. The moisture content of the alcohols when critically maintained gave consistent R-form.
The present invention has also studied the effect of addition temperature of methane sulfonic acid to the imatinib base. It was noted that the room temperature i.e 25-30°C gave consistently the R- form.
The time for the formation of imatinib mesylate R- form was about 3.5 hours at reflux temperature of 62-65 °C.
The R- form of the present invention is characterized by
1. Unique peaks in the XRD particularly at 26.99 angle 2 9 with (24.5%) intensity.
2. Remains dry at 93% RH and is stable at 40 °C and 75% RH.
3. Rod shaped crystals.displaying.in fig. 1 below, . .
4. FTIR data of R-form, does not match with a-form and (3-form,
5. Slightly differs in melting point (DSC) from reported (3-form.
Thereby stating this particular R-from is a novel polymorph of Imatinib mesylate.
EXAMPLES -
The following examples are included to demonstrate preferred embodiments of the invention.. It should be appreciated by those of skill in the art that the techniques disclosed in the examples which follow represent techniques discovered by the inventor

to function well in the practice of the invention, and thus can be considered to constitute preferred modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention.
EXAMPLE 1 : Preparation of the novel R crystal form ( R- form)
Process A: Synthesis of Imatinib mesylate R- form
Imatinib ase, chemically 4-(4-methylpiperazin-]-ylmethyl)-N-[4-methyI-3-(4-pyridin-3-yl) pyrimidin-2ylarnino) phenyl] benzamide (5 gms) suspended in ethanol (moisture less than 1%) 50 ml at 25 °C; charged methanesulfonic acid (0.993 gms) in 20 ml ethanol dropwise during 20 minutes at 25 °C; reaction mass heated to reflux at 75-80 °C; for 3 ½ hrs, and cooled gradually to 20-25 °C during 40-45 min. filter, residue washed with ethanol 30 ml, wet product dried at 65 °C for 6-8 hrs to obtain 5.54 gms (93% yield), (HPLC purity 99.89%), R-form. Microscopy showing rod shaped crystal Fig.l
Process B: Synthesis of Imatinib mesylate P-form (process for the preparation of a crystalline form as per WO 2006/024863) if moisture in IPA is greater than 1 %. it leads to formation of p-crystal form
Imatinib base, chemically 4-(4-methylpiperazin-l-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl) pyrimidin-2ylamino) phenyl] benzamide (5 gms) suspended in Isopropyl alcohol (moisture 4. 1%) (60 ml) at 40 °C; charged methanesulfonic (0.993 gms) in 15 ml isopropyl afcohoi dropwise during 20 mm. at 40 °C, reaction mass becomes clear after the acid addition and reaction mass heated to reflux at 80-90 °C; turbidity observed after 10 min. during refluxing and reflux continued for 2hrs, and cooled gradually to 40-45 °C during 30 min., reaction mass filter, residue washed with 20 ml IPA ,wet product dried at 65 °C for 6-8 hrs to obtain 4.63 gms (77.5% yield), β-form. Microscopy big plates Fig.2

Comparative Study data:

S no. Water
content
in% Temp. °C Solvent Polymorph Microscopy Reaction
time in
hrs MeSo3H
(molar
ratio) Yield
%
1 0.9 20-25 Ethanol R-form Rod shaped 3.5 1 93
2 4.1 35-40 IPA β -form Big plates 2.5 1.02 77.5
3 1.8 30-35 IPA β -form Big plates 2.5 1.02 94
4 1 20-25 Ethanol β -form Big plates 0.5 1.02 71.5
EXAMPLE 4: Characterization of the new form
The following instruments and conditions were used for the analysis of the polymorph whose results are detailed in a tabulated form later in the specification:
1. DSC : Melting point is determined by means of DSC thermogram using a
SHIMAZZU , DSC-60. DSC ("differential scanning calorimetry")
Condition: [Temp program]
Start temp 50.0
Temp Rate Hold temp Hold time
[C/min] [C] [min]
5.00 250.0 0
2. FTIR (Fourier transform infrared spectrophotometer)
Make : SHIMADZU, IRPrestige-21
Sample preparation : KBr pellets
3. Microscope: For microscopy used Olympus microscope with 40X lens

4. HPLC: Used Agilent 1200, VWD detector, system gradient
Instrument conditions are: CHROMA TOGRAPHIC SYSTEM:
1 Mobile phase : A : B (Gradient)
2 Buffer : 7.5 g 1-Octane sulfonic acid sodium salt in 1000
ml of water adjusted to pH 3.0 with ortho phosphoric acid.
3 Column : Symmetry CI8, 150X4.6, 3.5 u
4 Wavelength : 240 nm
5 Flow rate : l.0 ml/min

6 Column temperature : 27°C
7 Diluent : Water : Methanol (45 : 55 v/v)
8 Run time : 65.0 min
9 Injection volume : 20.0 u.1
Gradient Program

Time (Min) % Mobile phase A % Mobile phase B
0.0 100 0
15.0 80 20
45.0 35 65
55.0 35 65 .
60.0 100 0
65.0 100 0
5. XRPD:
XRD diffraction was performed on X-Ray powder diffractometer. P analytical X' pert Pro powder diffractometer. Cu-tube scanning parameters: CuKa radiation, X= 1.54060A Continuous scan at a rate of 0.0170 °2 theta/ 5 J .0404 sec. Start position 2.0084 °2 theta and end position 39.9884 °2 theta.

(A) COMPARATIVE XRPD DATA OF IMATINIB MESYLATE a-Form, p- Form
(Reported) AND R-FORM Table:!

(R-form) Reported (P-form) EP 0998473 Reported (a-form) WO 2006/024863
Angle 29 Intensity % Angle 2 9 Intensity % Angle 2 9 Intensity %
9.94 12.25 9.70 40 4.87 14
10.14 19.78 NR NR 10.4 51
10.72 10.11 NR NR 11.1 12
14.14 46.13 13.9 26 11.8 16
14.30 15.93 NR
- NR 12.1 13
14.96 19.09 14.7 23 14.8 47
17.36 13.65 NR NR 16.4 28
17.68 -95.70 17.5 57 17.6 58
18.38 93.28 18.2 90 18.0 60
19.12 27.99 NR NR 18.5 100
19.52 10.72 NR NR 19.0 77
20.03 31.85 20.0 65 19.7 17
20.26 . 48.8 20.6 76 2102 77
20.80 100 21.1 100 21.4 71
21.96 13.35 NR NR 21.6 68
22.30 35.05 22:1 89 22.40 26
22.94 30.87 22.7 38 22.5 32
23.95 20.22 23.8 44 23.0 36
25.53 16.91 NR NR 23.6 40
26.99 24.51 NR NR 24.8 73
29.33 10.13 NR NR 26.2 18
29.94 23.00 29.8 23 27.1 29

31.05
8.34 30.8 20 27.8 32
27.9 36
28.4 66
31.8 21
38.0 19
38.9 19
39.2 20
39.3 22
39.5 22
42.9 20
43.0 22
43.2 21
45.5 20
45.96 21

(R-form) Reported (P-form)

3285 cm-1 (characters tics)
FTIR Absent Kef Solid state characterization oflmatinib mesylate [alpha J and [beta J form M.S etal
NIPER, India

3196 cm-1 -

3340 cm-1 -
Not needle shaped ( plate shaped picture) as
MICROSCOP Rod shaped per EP 0998473 B1, US 6894051 B1,
Y WO99/03854,US7544799 B2
Melting point 218-222 217-225
(DSC) i
(B) Stability study data of R-form at 40 °C and 75% RH (Accelerated)

Testing Acceptance criteria Results
parameter
Initial 1M 2M 3M
Descriptions An off white to pale yellow powder White powder White powder White powder White powder
IR spectrum of
Identification bylR Test sample should concordant with spectrum of working standard. concordan t concordan t concord ant concordant
Water content byKF NMT 1.0% w/w 0.37 0.43 0.48 0.48
Related Substan ce [by HPLC]
a) Known
impurities
1. Impurity-1 NMT 0.15% w/w ND ND ND ND
2. Impurity-2 NMT 0,15% w/w ND ND ND ND
3. Impurity-3 NMT 0.15% w/w 0.04 ND ND ND
b) Unknown NMT 0.10% w/w 0.02 ND 0.04 0.04
impurity
RRT = 0.81
c) Total impurities NMT 1.0% w/w 0.06 ND 0.04 ND
Assay [by Between 98.05%
HPLC] to 102.0%/w (on 99.47 99.37 99.18 99.48
(on anhydrous) anhydrous)
Stable Stable Stable
*ND = Not detected Below 0.02% w/w impurities disregarded.

(C) Comparative Solubility data of β- form and R-form is as follows :

Sno. Solvent β- polymorph Our (R-form)
1 Water 1 gms IS ml lgms/2.8 ml
2 DMSO 1 gms /30 ml lgms/20ml
3 Methanol 1 gms /60 ml lgms/60 ml
(D) Comparative Humidity study of Imatinib mesylate (R-form) with β- form
Water content value are found at 25°C (% value for the final water content refer to dry weight)

Polymorph Initial 60% RH for 45 hrs 75% RH for 45 hrs
Descri pti on %KF Molar Descripti on %KF Molar Descri ption %KF Molar
R-form White powder 0.4 0.06 White powder 0.44 0.07 White powder 0.44 0.07
Beta form Off
white
powder 0.4 0.07 Off white powder 0.48 0.07 Off
white powder 0.48 0.07

Polymorph 95% RH for 45 hrs
Description %KF Molar
R-form Light yellow tinge powder 0.61 0.09
Beta form Light yellow powder 0.66 0.10

All of the compositions and methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. While the compositions and methods of this invention have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations may be applied to the compositions and/or methods and in the steps or in the sequence of steps of the methods described herein without departing from the concept, spirit and scope of the invention. More specifically, it will be apparent that certain agents that are chemically or physiologically related may be substituted for the agents described herein while the same or similar results would be achieved. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the invention as defined by the appended claims.