FORM 2
THE PATENTS ACT 1970
(39 of 1970)
AND
The Patents Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10 and rulel3)
1. TITLE OF THE INVENTION:
"POLYMORPHIC FORMS OF TYROSINE KINASE INHIBITOR"


2. APPLICANT:
(a) NAME: CIPLA LTD.
(b)NATIONALITY: Indian Company incorporated under the Indian Companies ACT, 1956
(c) ADDRESS: 289, Bellasis Road, Mumbai Central, Mumbai - 400 008, Maharashtra, India
3. PREAMBLE TO THE DESCRIPTION:
The following specification describes the invention.




2009

Field of the Invention
The present invention relates to polymorphic forms of tyrosine kinase inhibitor, dasatinib and processes for preparation thereof. In particular, the invention relates to solvates of N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-l-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazolecarboxamide (Dasatinib) and processes for preparation thereof.
Background and prior art
Dasatinib, chemically described as N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-l-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazolecarboxamide, is a tvrosine kinase inhibitor.

Dasatinib it is used to treat chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL) when other cancer treatments have not been effective. It slows the growth and spread of cancer cells in the body. Dasatinib is a multiply-targeted tyrosine kinase inhibitor, which affect systems of cellular division and survival, and are frequently over-expressed or abnormally active in cancer cells. By targeting these systems, Dasatinib is designed to reduce the growth and viability of various types of cancer.
Dasatinib and its salts are claimed first in US patent 6596746. The patent discloses preparation of Dasatinib by refluxing 2-(6-chloro-2-methyl-pyrimidin-4-y!amino)-thiazole-5-carboxylic acid (2-chloro-6-methyl-pheny])-amide with 2-piperazin-l -yl-ethanol for 2 hours in the presence of water. The patent also discloses prodrugs and solvates, preferably hydrate of the compound.
WO2005077945 application claims process for preparation of Dasatinib as well as preparation of its key intermediates. The application covers various polymorphic forms of

Dasatinib like crystalline monohydrate, Neat form N-6, Neat form T1H1-7 and also covers solvates such as ethanol solvate and butanol solvate. The processes for preparation of these forms and solvates are also disclosed using various solvents like methanol, ethanol, propanol, i-propanol, butanol, pentanol, N-methyl pyrolidone, dimethylamine and water. There is still a need for developing new polymorphic forms of Dasatinib. which are more suitable for pharmaceutical use.
Polymorphism is the ability of a compound to crystallize in two or more crystalline phases with different arrangement and/or conformations of the molecules in the crystal lattice. Because of different arrangement and/or conformations of the molecules, polymorphs exhibit different chemical and physical properties such as solubility profiles, melting points, dissolution profiles, thermal and/or photostability, shelf life, suspension properties and physiological absorption rates, which consequently have significant effect, on its clinical performance.
In many stages of processing, substances are exposed to solvent or solvent vapors. The most prominent procedures are precipitation, crystallization or recrystallization from a suitable solvent or solvent mixture to separate the desired substance. However, sometimes during processing, stabilizing interaction of a solute and solvent or a similar interaction of solvent with groups of insoluble material occurs which leads to the formation of solvate. Solvate is a crystalline molecular compound in which molecules of solvent of crystallization are incorporated into the host lattice. Solvate may be hemi-solvate, mono-solvate, di-solvate and the like and it depends upon ratio of number of molecules or moles of compound per molecule or mole of solvent present in the solvate. For example, a solvate may comprise a 1:1 relationship (mono-solvate), a 2:1 relationship (hemi-solvate), a 1:2 relationship (di-solvate), or the like, of compound to solvent. The discovery of new polymorphic forms and solvates of a pharmaceutically useful compound provides a new opportunity to improve the performance characteristics of a pharmaceutical product.
The study, characterization and understanding of the solid forms as polymorphs, solvates and hydrates are of major importance within the pharmaceutical industry. Infra-red spectrum, differential scanning colorimetry (DSC) and X-ray diffraction pattern are key tools in these areas. Thermal behavior of the molecule is measured using
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thermogravimetric analysis (TGA). These tools offer not only form fingerprinting but in some circumstances also insights into the crystalline arrangements of molecules.
Objects of the invention
The object of the present invention is to provide novel crystalline solvates of Dasatinib.
Another object of the present invention is to provide processes for the preparation of novel polymorphic forms of Dasatinib.
Summary of the Invention
The present invention relates to novel crystalline solvates of Dasatinib and methods for preparation thereof.
In one embodiment, the present invention provides hemi-ethanolate form of Dasatinib.
designated as 'Form F.
Form I exhibits X-ray powder diffraction pattern having characteristic peaks (expressed
in degrees 26 (± O.2°0)) at one or more of the following positions: 7.0, 14.2, 16.6, 18.5,
23.7 and 30.4. Also thermal behavior of Form 1 is observed by Thermo gravimetric
analysis.
In second embodiment, the present invention provides a novel tetrahydrofuran solvate of Dasatinib, designated as 'Form IF.
Form II of the present invention exhibits X-ray powder diffraction pattern having characteristic peaks (expressed in degrees 20 (± 0.2°0)) at one or more of the following positions: 5.8, 14.6, 18.5, 21.7, and 22.6. Also thermal behavior of Form II is observed by Thermo gravimetric analysis.
In third embodiment, the present invention provides a novel acetonate of Dasatinib, designated as 'Form III*.
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Form III exhibits X-ray powder diffraction pattern having characteristic peaks (expressed in degrees 20 (± O.2°0)) at one or more of the following positions: 12.2, 14.6 and 22.7. Also thermal behavior of Form III is observed by Thermo gravimetric analysis.
In fourth embodiment, the present invention is directed to preparation of polymorphic Form I by crystallizing Dasatinib from ethanol or aqueous ethanol at ambient temperature followed by isolation of the crystals.
In fifth embodiment, the present invention is directed to preparation of polymorphic Form II by crystallizing Dasatinib from tetrahydrofuran or aqueous tetrahydrofuran at ambient temperature followed by isolation of the crystals.
In sixth embodiment, the present invention is directed to preparation of polymorphic Form III by crystallizing Dasatinib from acetone at ambient temperature followed by isolation of the crystals.
Brief Description of the drawings
Fig 1. shows X-ray powder diffraction spectrum of polymorphic form I of Dasatinib. Fig 2. shows Thermogravimetric analysis curve of polymorphic form I of Dasatinib. Fig 3. shows X-ray powder diffraction spectrum of polymorphic form II of Dasatinib. Fig 4. shows Thermogravimetric analysis curve of polymorphic form II of Dasatinib. Fig 5. shows X-ray powder diffraction spectrum of polymorphic form III of Dasatinib. Fig 6. shows Thermogravimetric analysis curve of polymorphic form III of Dasatinib.
Detailed description of the invention
The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.
The present invention is directed to crystalline solvates of Dasatinib. Solvates of the present invention have been found to be stable, reproducible and exhibit higher purity and good dissolution profile. Different polymorphic forms can have differing solubilities and

this can have a potentially major effect on the bioavailability of the drug when ingested. Thus, the discovery of new polymorphic forms of Dasatinib provides new opportunity to improve its performance, characteristics and significant contribution to the prior art.
The present invention also provides methods for preparation of solvates. The solvates obtained are pure, non-hygroscopic and methods used in the preparation are safe, environmental friendly, economical and simple.
Thus, crystalline solvates of the present invention are readily distinguished from one another and also from previously reported forms and solvates by examination of characteristic X-ray diffraction patterns and curves obtained in Thermo gravimetric
analysis.
In one aspect the present invention provides crystalline Dasatinib 'Form I
Dasatinib Form I of the present invention is further characterized by X-ray powder diffraction spectrum shown in fig 1 having characteristic peaks (expressed in degrees 20 (±0.2°9)) at one or more ofthe following positions: 6.5, 7.0, 11.8, 14.2, 16.6, 18.5, 19.0, 23.7, and 30.4.
The thermal behavior of Form I is measured by thermogravimetric analysis (TGA) as shown in fig.2. The weight loss is 3.5-4.5% when the sample is scanned between 40°C-180°C.
Dasatinib Form I is prepared by dissolving Dasatinib in the solvents selected from ethanol or aqueous ethanol at reflux. The mixture is stirred for 30 mins - 1 hour at reflux. The solution is gradually cooled, filtered and dried.
In another aspect the present invention provides crystalline Dasatinib 'Form IF.
Dasatinib Form II of the present invention exhibits X-ray powder diffraction pattern (XRPD) as shown in Fig 3. The X-ray powder diffraction pattern is expressed in terms of

its 29-values at one or more of the following positions: 5.8, 14.6, 18.1, 18.5, 21.4, 21.7, and 22.6
The thermal behavior of Form II is measured by TGA as shown in fig 4. The weight loss is 11-12% when the sample is scanned at 40°C-290°C.
Dasatinib Form II is prepared by dissolving Dasatinib in the solvents selected from tetrahydrofuran or aqueous tetrahydrofuran at reflux. The mixture is stirred for 30 mins -1 hour at reflux. The solution is gradually cooled, filtered and dried.
In another aspect the present invention provides crystalline Dasatinib 'Form III'.
Dasatinib Form III of the present invention exhibits X-ray powder diffraction pattern (XRPD) as shown in Fig 5 having characteristic peaks (expressed in degrees 20 (± O.2°0)) atone or more of the following positions: 11.6, 12.2, 14.6, 22.0, and 22.7.
The thermal behavior of Form III is measured by TGA is shown in fig 6. The weight loss is 6.0-7.0% when the sample is scanned between 40°C-290°C.
Dasatinib Form III is prepared by dissolving Dasatinib in the solvents selected from acetone or aqueous acetone at reflux. The mixture is stirred for 30 mins - 1 hour at reflux. The solution is gradually cooled, filtered and dried.
Form I, 11 or 111 of the present invention may be used in the form of a pharmaceutical composition which comprises form I, II or III of the present invention with at least one non-toxic pharmaceutical^ acceptable diluent or carrier. The compositions may be in a form suitable for oral, rectal, parenteral or topical administration for which purposes it may be formulated into tablets, capsules, aqueous or oily suspensions, dispersible powders, suppositories, sterile injectable aqueous or oily suspensions, gels, creams or ointments. The forms of the present invention may be co-administered with, one or more known drugs.
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The invention is further illustrated by the following examples. It will be apparent to those skilled in the art, that many modifications, both to materials and methods can be practiced without departing from the purpose and intent of this invention. The examples that follow are not intended to limit the scope of the invention as described herein above or as claimed below.
Examples
Example 1
Preparation of N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyI)-l-
piperazinyI]-2-methyI-4-pyrimidinyl]amino]-5-thiazoIecarboxamide(Dasatiiiib)
2-(6-Chloro-2-methyl-pyrimidin-4-yIamino)-thiazoIe-5-carboxylic acid (2-chloro-6-methyl-phenyl)-amide (10 gms) was condensed with N-(2-hydroxylethyl) piperazine (16.3 gms) in n-butanol (60 ml) at room temperature. The reaction mixture was heated to reflux for 6 hours. After completion of the reaction, the reaction mixture is cooled to 20-25°C and stirred for 30 minutes. The solution is filtered, washed with n-butanol and sucked dried. The Dasatinib thus obtained was dried at 60-65°C under vacuum (Yield: 11 gms). The product is further taken for crystallization.
Example 2
Preparation of crystalline form I of Dasatinib
Dasatinib (10 gms) as prepared in example 1 was added to 80% ethanol (150 ml) at ambient temperature. The mixture was heated to reflux and stirred at reflux for 30 minutes and filtered through hyflo. The solution was gradually cooled to 10-15°C and constantly stirred for 3 hours. The suspension was filtered, washed and suck dried. The solid was dried at 50-55°C under vacuum for 10-12 hours to yield crystals of Form I (Yield: 7 gms). Crystalline polymorph thus obtained was further characterized by XRD and TGA
Example 3
Preparation of crystalline form I of Dasatinib
Dasatinib (10 gms) as prepared in example 1 was added to mixture of 8:2 specially purified denatures spirit (SPDS):water (150 ml) at ambient temperature. The mixture was heated to reflux and stirred at reflux for 30 minutes and filtered through hyflo. The

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solution was gradually cooled to 10-15°C and constantly stirred for 3 hours. The suspension was filtered, washed and suck dried. The solid was dried at 50-55°C under vacuum for 10-12 hours to yield crystals of Form 1 (Yield: 7 gms). Crystalline polymorph thus obtained was further characterized by XRD and TGA.
Example 4
Preparation of crystalline polymorph Form II of Dasatinib
5 gms of Dasatinib as prepared in example 1 was added to mixture of tetrahydrofuramwater (9:1) (175 ml) at ambient temperature. The mixture was heated to reflux and stirred at reflux for 30 minutes. The solution thus obtained was gradually cooled to 25-27°C and constantly stirred for 18-20 hours. The solution was filtered, washed and suck dried. The solid was dried at 50-55°C under vacuum for 10-12 hours to yield crystalline solid of Form II (Yield: 3.2 gms). Crystalline polymorph thus obtained was further characterized by XRD and TGA
Example 5
Preparation of crystalline polymorph Form III of Dasatinib
Dasatinib (10 gms) as prepared in example 1 was added to mixture of acetone:water (9:1) (350 ml) at ambient temperature. The mixture was heated to reflux and stirred at reflux for 30 minutes and filtered through hyflo. The solution was gradually cooled to 20-25°C and constantly stirred for 12 hours. The suspension was further cooled filtered, washed and suck dried. The solid was dried at 50-55°C under vacuum for 10-12 hours to yield crystals of Form III (Yield: 5.6 gms). Crystalline polymorph thus.
Dated this 31st day of March 2009
Dr. P. Aruna Sree Agent for the Applicant