WO2006054314A1

WO2006054314A1 - Polymorphic forms of imatinib mesylate

Info

Publication number: WO2006054314A1
Application number: PCT/IN2005/000273
Authority: WO
Inventors: Amala Kishan Kompella; Bhujanga Rao Adibhatla Kali Satya; Khadgapathi Podili; Nannapaneni Venkaiah Chowdary
Original assignee: Natco Pharma Limited
Priority date: 2004-11-17
Filing date: 2005-08-11
Publication date: 2006-05-26

Abstract

The present invention relates to novel crystalline polymorphic Form I & Form II of imatinib mesylate and methods for their preparation. The Form I is prepared by slurrying imatinib mesylate α2 or β polymorphic Form in chloroform and water with heating and distilling off water followed by filtration. Form II is prepared by lyophilizing an aqueous solution of polymorph α2 or β. The invention also relates to pharmaceutical composition containing the new Forms useful for the treatment of chronic myelogenous leukemia and accelerated stress conditions for the treatment of chronic myelogenous leukemia and accelerated stress conditions.

Description

POLYMORPHIC FORMS OF IMATINIB MESYLATE

Field of invention:

The present invention relates to novel crystalline Form I and Form II of imatinib mesylate and processes for the preparation of the said Forms. Imatinib mesylate has the formula given below. The invention also relates to pharmaceutical composition containing the novel crystalline Forms I & II of imatinib mesylate.

Background of the invention: Imatinib mesylate which is N- {5-[4-(4-mehylpiperizino methyl)-benzoylamido]-2- methylphenyl}-4-(3-pyridinyl)-2-pyrimidine amine having the formula I given above is approved under the trademark" Gleevec" by the US Food and Drug Administration for the treatment of chronic myelogenous leukemia after the failure of Interferon Alpha. It has also been approved for the treatment of patients with kit [CD 117] positive unresectable and/or metastatic malignant Gastro Intestinal Stromal Tumors (GISTS). Recently it has been approved for the treatment of pediatric patients with Philadelphia chromosome positive (Ph +} chronic myeloid leukemia in chronic phase. It is known that Imatinib mesylate exists in two polymorphic forms α and β (WO 99/03854). Another new polymorphic form named α₂ was disclosed in our co pending Indian patent application No. 706/CHE/04 filed on 20^th July 04, titled ""Novel stable α₂ crystal form of imatinib mesylate and pharmaceutical composition containing it

Important solid-state properties of a pharmaceutical substance are its rate of dissolution in aqueous fluid. The rate of dissolution of an active ingredient in a patient's stomach fluid may have therapeutic consequences because it imposes an upper limit on the rate at which an orally administered active ingredient may reach the blood stream. The solid- state form of a compound may also affect its behavior on compaction and its storage stability.

These practical physical characteristics are influenced by the conformation and orientation of molecules in the unit cell, which defines a particular polymorph form of a substance. The polymorphic form may give rise to thermal behavior different form that of the amorphous material (or) another polymorphic form.

Thermal behavior is measured in the laboratory by such techniques as capillary melting point, Thermo Gravimetric Analysis (TGA) and Differential Scanning Calorimetry (DSC), and may be used to distinguish some polymorphic forms from others. A particular polymorphic form may also give rise to distinct properties that may be detectable by X-Ray Powder Diffraction (XRPD) solid-state ¹³CNMR spectrometry and infrared spectrometry.

The various characteristics and properties of the polymorphic forms of a substance. E.g. shape, color, density and the like, will make one polymorphic form preferable over the others for production and /or pharmaceutical compounding. As a result, a very first step in the processes of product development of a new pharmaceutical agent is the determination of whether it exists in polymorphic forms and if so which of such form possesses advantages for the eventual commercial pharmaceutical application. In the case of Imatinib mesylate, β form is offered commercially under the trade name Gleevec ® / Glivec® The discovery of new polymorphic forms of a pharmaceutically useful compound provides a new opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for designing, for example, a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristic.

It is known that polymorphic forms of the same drug may have substantial differences in certain pharmaceutically important properties. Therefore, there is a continuing need for new forms of Imatinib mesylate and new methods of their preparation.

Objectives of the present invention

Therefore, the main objective of the present invention is to provide novel crystalline polymorphic Forms I & II of Imatinib mesyalte

Another objective of the present invention is to provide processes for the preparation of novel crystalline polymorphic Forms I & II of Imatinib mesyalte

Yet another objective of the present invention is to provide a novel pharmaceutical compositions containing the novel crystalline polymorphic Forms I or II of Imatinib mesyalte or their mixtures

Description of the invention:

The present invention relates to novel crystalline Forms I and II of imatinib mesylate and processes for the preparation of the said forms. The new Form -I and Form - II is stable, and usually retains crystalline structure after heating to 60 -70°C overnight (at least about 8 hours). But prolonged heating of either of the Forms or heating at a temperature above 70°C results in the conversion to the α₂ Form disclosed in our above mentioned [Indian application No. 706/CHE/04]. The term "stable" as used herein refers to a polymorphic change of less than about 5% by weight, more preferably less than about 2%

Accordingly, the present invention provides novel crystalline Forms I & II of Imatinib

Mesylate which are stable at room temperature and even at temperatures upto 70⁰C freely soluble in water and having the XRD characteristics given in the Table-I and Table-II below.

TABLE-I: XRD characteristics of Form - 1

TABLE-II: XRD characteristics of Form - II

XRPD patterns were recorded using an x-ray powder diffractometer (Bruker AXS D5000) in transmission mode (Cu K alpha 1, PSD).

IR absorption spectra were measured in the spectral range 4000-400 cm<-l > on a Bruker IFS48. Spectral resolution was 2 cm<-l>. Sample preparation was performed generally as KBr disk.

We have also observed that it is possible to convert the Form I to Form II and to convert Form II to Form I depending on the operating conditions chosen.

According to another feature of the present invention, there is provided a process for the preparation of the novel imatinib mesylate polymorph Form I which comprises slurring OC₂ or β polymorphic Form of imatinib mesylate in chloroform and water with heating and distilling off water and filtering to obtain the novel Form I According to another feature of the invention there is provided a process for the preparation of the novel imatinib mesylate Form II which comprises lyophilizing an aqueous solution of α₂ or β. Polymorph Forms of imatinib mesylate and filtering to obtain the Form II

Determination of the presence of Imatinib mesylate Form-β in Imatinib mesylate Form-I and Form-II prepared by the above defined processes of the present invention may be made by analysis for the presence of various peaks associated with Form-β particularly at 9.7, 13.9, 18.2, 20.0, 20.6, 21.1, 22.1, 22.7, 23.8, 29.8, 30.8 ± 0.2 degree 2θ.(WO99/03854).

Determination of presence of Imatinib mesylate Form-α₂ in Imatinib mesylate Form-I and Form-II prepared by the above defined processes of the present invention may be made by analysis for the presence of various peaks associated with Form-α₂ particularly at 4.84, 10.4, 14.86, 16.40, 17.60, 18.05, 18.57, 19.03, 21.2, 21.58, 23.1, 23.69, 24.85, 28.47 ± 0.2 degree 2Θ [Indian application No. 706/CHE/04]

The characterization of the different new Forms I and II of imatinib mesylate was done from their X-ray powder diagrams, differential scanning calorimetry diagrams and IR spectra, as well as by their water soluble values determined according to the Karl Fischer method. The said diagrams and spectra are illustrated in the drawings accompanying this specification. .

In the drawings,

Fig.l represents the X-Ray Powder Diffraction (XRPD) pattern which substantially depicts a typically pure sample of Imatinib Mesylate of Form-I prepared by the process of the present invention. The 2Θ values and intensities are tabulated in Table- 1 given above Fig - 2 represents the IR spectrum of Form-I Fig - 3 represents the DSC thermogram of Form-I Fig. -4 represents the XRPD spectrum of Form-II Fig -5 represents the IR spectrum of Form-II Fig -6 represents the DSC thermogram of Form-II

As already mentioned, the different novel polymorphic Forms I and II of imatinib mesylate obtained in reproducible ways clearly differ from the reported β and α₂ Forms in their X-ray powder diffraction spectra and differential scanning calorimetry diagrams, as well as in the water content values according to Karl Fische. These forms can also be distinguished from their IR spectra.

The infrared spectrum of Form-I as a KBr tablet has the characteristic absorptions at the following wavelengths (in cm<-l>, f for weak, m for average, F for strong):

3500 (f), 3277 (m), 2980 (m), 2694(f), 1644 (F), 1578 (F), 1554 (f), 1538 (F), 1507 (f), 1478 (m), 1451 (F), 1419 (m), , 1324 (f), 1308 (f), 1290 (m), 1260 (f), 1205 (m), 1159 (F)₅ 1059 (f), 1038 (F), 1006 (f), 983 (m), , 909(f), 876 (f), 851 (f ), 797 (m), 770 (f), 742 (m), 708 (m), 664 (f), 646(f), 610(f), 583 (f), 552(m), 528(m), 455 (f)

The infrared spectrum of Form-II as a KBr tablet has the characteristic absorptions at the following wavelengths (in cm<-l>, f for weak, m for average, F for strong):

3300 (f), 2786(f), 1646 (F), 1584 (F), 1557(m), 1530 (F), 1452 (F), 1401(F), 1290 (m), 1194(F), 1042 (F), 985 (m), , 898(f), 878 (f), 803 (m), 773 (m), 753 (f), 706 (f), 687 (f), 648(f), 607(f), , 550(m), 525(f).

According to another embodiment of the present invention there is also provided Pharmaceutical formulations containing the novel polymorphic Forms I, or II imatinib

mesylate or their mixtures along with ^{one or more} pharmaceutically acceptable excipients or adjuvants. Selection of excipients or adjutants and their amounts may be readily determined by a person in the art based upon experience and consideration of standard procedures and reference works in the field.

Diluents may also be used to increase the bulk of a solid pharmaceutical composition, and to may make the pharmaceutical dosage form easier for the patient to handle. Diluents which may be employed may include, for example, microcrystalline cellulose (e.g. Avicel(R)), microfine cellulose, lactose, starch, pregelitinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates (e.g. Eudragit(R)), potassium chloride, powdered cellulose, sodium chloride, sorbitol and talc.

Solid pharmaceutical compositions that are compacted into a dosage form, such as capsules may include excipients whose functions include helping to bind the active ingredient and other excipients together after compression.

Binders which may be employed for solid pharmaceutical compositions include acacia, alginic acid, carbomer (e.g. carbopol), carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g. Klucel(R)), hydroxypropyl methyl cellulose (e.g. Methocel(R)), liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates, povidone (e.g. Kollidon(R), Plasdone(R)), pregelatinized starch, sodium alginate and starch.

The dissolution rate of a compacted solid pharmaceutical composition in the patient's stomach may be increased by the addition of a disintegrant to the composition. Disintegrants which may be employed for the purpose may include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g. Ac-Di-SoI(R), Primellose(R)), colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g. Kollidon(R), Polyplasdone(R)), guar gum, magnesium aluminum silicate, methyl cellulose, macrocrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (e.g. Explotab(R)) and starch.

Glidants can be added to improve the flowability of a non-compacted solid composition and to improve the accuracy of dosing. Excipients that may function as glidants and which can be employed in the composition of the present invention may include colloidal silicon dixoide, magnesium trisilicate, powdered cellulose, starch, talc and tribasic calcium phosphate.

When a dosage form such as a capsule is made by the compaction of a powdered composition, the composition is subjected to pressure from a punch and dye. Some excipients and active ingredients have a tendency to adhere to the surfaces of the punch and dye, which can cause the product to have pitting and other surface irregularities. A lubricant can be added to the composition to reduce the adhesion and ease the release of the product from the dye. Lubricants which can be used may include magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc and zinc stearate.

Flavoring agents and flavor helps the dosage form more palatable to the patient. Common flavoring agents and flavor enhancers for pharmaceutical products can be employed which include maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol, and tartaric acid.

Solid compositions may also be dyed using any pharmaceutically acceptable colorant to improve their appearance and/or facilitate patient identification of the product and unit dosage level.

The dosage form of the present invention may be a capsule containing the composition, preferably a powdered or granulated solid composition of the invention, within either a hard or soft shell. The shell may be made from gelatin and optionally contain a plasticizer such as glycerin and sorbitol, and an opacifying agent or colorant.

The active ingredient and excipients may be formulated into compositions and dosage forms according to methods known in the art.

A composition for tableting or capsule filling may be prepared by dry blending. In dry blending, some or all of the active ingredients and excipients in powder form are blended The blend is screened and/or milled, dried and then screened and/or milled to the desired particle size. The granulate may then be tableted, or other excipients may be added prior to tableting, such as a glidant and/or a lubricant As an alternative to dry granulation, a blended composition may be compressed directly into a compacted dosage form using direct compression techniques. Direct compression produces a more uniform tablet without granules. Excipients that are particularly well suited for direct compression tableting include microcrystalline cellulose; spray dried lactose, dicalcium phosphate dihydrate and colloidal silica. The proper use of these and other excipients in direct compression tableting is known to those in the art with experience and skill in particular formulation challenges of direct compression tableting.

A capsule filling of the present invention may comprise any of the aforementioned blends and granulates that were described with reference to tableting, however, they are not subjected to a final tableting step.

The dosage used is preferably from about 120mg to 360mg of imatinib mesylate, more preferably about 120 mg of imatinib mesylate of form I or form II

The different novel polymorphic Forms I & II of imatinib mesylate of the present invention are suitable in the same way as the commercially available β -polymorph Form for use as tyrosine kinase inhibitors and thus making them available as alternative medicaments for the treatment of cancer. The details of the invention are given in the Examples provided below which are given for illustration only and therefore should not be construed to limit the scope of the present invention

Example-l:

Preparation of crystalline polymorphic Form 1 of Imatinib mesylate:

A) Preparation of crystalline polymorphic Form ar- form of Imatinib mesylate

Imatinib base (200 gms) was suspended in 2.5 L of ϊsopropanol. Methane sulfonic acid (38.9 gms) in 400 ml anhydrous Isopropanol was added slowly during 20 minutes at room temperature. The reaction mass was heated to 75-8O⁰C for 30 minutes and slowly cooled to 40-45°C during 45 minutes. Filtered at 40-45⁰C and washed with 250 ml Isopropanol. The wet cake was dried for 6 hours at 8O⁰C. The yield was 170 gms (71%) Melting range - 223-227⁰C, DSC Thermogram 227°C (Peak)

B) Preparation of crystalline Form I of Imatinib mesylate:

Imatinib mesylate α₂ crystal form obtained by the process described in step A above was suspended in 500 _mi water and 5-litre chloroform. Distilled off water completely along with chloroform during 4-6 hours at normal pressure. Cooled to room temperature and stirred at the same temperature till crystal formation is completed. Filtered and washed chloroform. The wet cake was dried under vacuum at 50-60⁰C. The yield was 163 gms of crystalline form I of imatinib mesylate

Melting range -122.6-138.9°C, DSC Thermogram 138.9°C (Peak) XRPD as shown in Fig-1 Sc, IR spectrum as shown in Fig-2 DSC thermogram as shown in Fig-3 Water content by karl-fischer - 0.6 % Example-2; Preparation of crystalline Form I of imatinib mesylate:

A) Preparation of crystalline β- Form of imatinib mesylate:

Imatinib base (0.25 Kg) was suspended in 12 L of acetone Methane sulfonic acid (48.6 gms) in 0.5 L acetone was added slowly during 30 minutes at room temperature. The reaction mass was heated to reflux temperature for 30 minutes and was slowly brought to room temperature during 45 minutes. Filtered and washed with 1 L acetone and dried for 6 hours at 65°C. The yield was 255 gms (85%) Melting range- 215-217⁰C, DSC Thermogram 217⁰C (Peak) XRPD as shown in Fig-4, IR spectrum as shown in Fig-5 DSC thermogram as shown in Fig-6

B) Preparation of crystalline Form I of Imatinib mesylate:

Crystalline β- Form of Imatinib mesylate obtained by the process described in A above was suspended in 750 ml water and 7.5 litre chloroform. Distilled off water completely along with chloroform during 4-6 hours at normal pressure. Cooled to room temperature and stirred at the same temperature till crystal formation is completed. Filtered and washed chloroform. The wet cake was dried under vacuum at 50-60⁰C. The yield was 230 gms of crystalline Form I of imatinib mesylate. Melting range -122.6-138.9⁰C, DSC Thermogram 138.9⁰C (Peak)

Example-3:

Preparation of crystalline Form II of imatinib mesylate: A) Preparation of crystalline β- Form of imatinib mesylate: Imatinib base (0.25 Kg) was suspended in 12 L of acetone. Methane sulfonic acid (48.6 gms) in 0.5 L acetone was added slowly during 30 minutes at room temperature. The reaction mass was heated to reflux temperature for 30 minutes and was slowly brought to room temperature during 45 minutes. Filtered and washed with 1 L acetone and dried for 6 hours at 65°C. The yield was 255 gms (85%) Melting range- 215-217°C, DSC Thermogram 217°C (Peak) B) Preparation of crystalline Form II of Imatinib mesylate:

15 gms of crystalline β- Form of imatinib mesylate obtained by the process described in A above was dissolved in 40 ml of water. The solution was frozen in a bath containing dry ice and acetone and freezing-dried (lyophilizated) for 4 days at -45°C. 14.8 gms of crystalline Form II of imatinib mesylate was obtained. Melting range-108.5°C, DSC Thermogram 108.5°C (Peak) Water content by karl-fischer - 4.56 %

Example-4: Preparation of imatinib mesylate form-II;

A) Preparation of crystalline a?.- Form of Imatinib mesylate:

Imatinib base (200 gms) was suspended in 2.5 L of isopropanol. Methane sulfonic acid (38.9 gms) in 400 ml anhydrous Isopropanol was added slowly during 20 minutes at room temperature. The reaction mass was heated to 75-80°C for 30 minutes and slowly cooled to 40-45°C during 45 minutes. Filtered at 40-45°C and washed with 250 ml Isopropanol. The wet cake was dried for 6 hours at 80°C. The yield was 170 gms (71%) Melting range - 223-227°C, DSC Thermogram 227°C (Peak)

B) Preparation of crystalline Form II of Imatinib mesylate:

15 gms of crystalline ay- Form of imatinib mesylate obtained by the process described in step A above was dissolved in 40 ml of water. The solution was frozen in a bath containing dry ice and acetone and freezing-dried (lyophilizated) for 4 days at -45⁰C. 14.9 gms of crystalline Form II of imatinib mesylate was obtained.

Melting range-106-108.5°C, DSC Thermogram 108.5⁰C (Peak) Water content by karl-fischer - 4.6 % ExampIe-5:

Conversion of crystalline Form I of imatinib mesylate to Form-II :

15 gms of imatinib mesylate Form - 1 obtained by the process described in the Example 1 was dissolved in 40 ml of water . The solution was frozen in a bath containing dry ice and acetone and freezing-dried (lyophilizated) for 4 days at -45°C . 15.0 gms of crystalline Form II of imatinib mesylate were obtained. Melting range-106-108.5°C₅ DSC Thermogram 108.5°C (Peak) Water content by karl-fischer - 4.9 %

Example-6 : Conversion of crystalline Form II of imatinib mesylate to Form-I ;

25 gms of Imatinib mesylate Form -II obtained by the process described in Example 3 was suspended in 75 ml water and 0.75 liter chloroform. Distilled off water completely along with chloroform during 1-2 hours at normal pressure. Cooled to room temperature and stirred at the same temperature till crystal formation is completed. Filtered and washed chloroform. The wet cake was dried under vacuum at 50-60⁰C. The yield was 25 gms of crystalline Form I of imatinib mesylate. Melting range -127-138.9°C, DSC Thermogram 138.9°C (Peak)

Example - 7

Capsules containing 120 mg of active ingredient of the Form-I described in the Examples 1 and 2 having the following composition are prepared in customary manner.

Average weight: 245 mg /capsule *Equivalent to 100 mg Example - 8

Capsules containing 120 mg of active ingredient of the compound describe in the Examples 3 and 4 having the following composition are prepared in customary manner.

Average weight: 230 mg/capsule * Equivalent to 100 mg

Advantages of the invention

1. The novel stable polymorphic Form -I and Form-II of imatinib mesylate compares well with the β and α₂ polymorphic Forms in stability

2. The process produces the novel stable crystalline polymorphic Form -I and Form-II of imatinib mesylate consistently.

3. The novel crystalline polymorphic Form -Form and I -II prepared are suitable for pharmaceutical applications, which were hitherto not known.

Claims

We Claim:

1. A novel crystalline Form-I and Form - II of Imatinib Mesylate which are stable at a temperature up to 7O⁰C and freely soluble in water having the XRD characteristics in the Tables 1 & II respectively given below TABLE-I: XRD characteristics of crystalline Form - 1 of Imatinib Mesylate

TABLE-II: XRD characteristics of the crystalline Form - II of Imatinib Mesylate

2. A pharmaceutical composition useful for the treatment of chronic myelogenous leukemia and accelerated stress conditions which comprises a novel stable crystalline polymorphic Form I, or Form II or their mixture of Imatinib Mesylate as claimed in claim 1 along with one or more pharmaceutically acceptable excipients or adjuvants commonly employed in such compositions.

3. A Pharmaceutical composition as claimed in claim 2 wherein the composition contains diluents which is selected from microcrystalline cellulose (e.g. Avicel(R)), crospovidone, microfine cellulose, lactose, starch, pregelitinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates (e.g. Eudragit(R)), potassium chloride, powdered cellulose, sodium chloride, sorbitol and talc or their mixtures thereof.

4. A Pharmaceutical composition as claimed in claims 2 & 3 wherein the composition contains binders which is selected from acacia, alginic acid, carbomer (e.g. carbopol), carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g. Klucel(R)), hydroxypropyl methyl cellulose (e.g. Methocel(R)), liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates, povidone (e.g. Kollidon(R), Plasdone(R)), pregelatinized starch, sodium alginate and starch or their mixtures thereof .

5. A Pharmaceutical composition as claimed in claims 2 to 4 wherein the composition contains disintegrants which is selected from alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g. Ac-Di-SoI(R), Primellose(R)), colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g. Kollidon(R), Polyplasdone(R)), guar gum, magnesium aluminum silicate, methyl cellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (e.g. Explotab(R)) or their mixtures .

6. A Pharmaceutical composition as claimed in claims 2 to 5 wherein the composition contains glidants, which is selected from colloidal silicon dixoide, magnesium trisilicate, powdered cellulose, starch, talc and tribasic calcium phosphate or their mixtures.

7. A Pharmaceutical composition as claimed in claims 2 to 6 wherein the composition contains a lubricant which is selected from magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc and zinc stearate or their mixtures.

8. A Pharmaceutical composition as claimed in claims 2 to 7 wherein the composition contains flavoring agents, which is selected from maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol, and tartaric acid or their mixtures.

9. A Pharmaceutical composition as claimed in claims 2 to 8 wherein the dosage form of the composition is a capsule containing the composition, preferably a powdered or granulated solid composition, within either a hard or soft shell.

10. A Pharmaceutical composition as claimed in claim 9 wherein the the shell is made from gelatin

11. A Pharmaceutical composition as claimed in claims 9 & 10 wherein it contain a plasticizer such as glycerin and sorbitol,

12. A Pharmaceutical composition as claimed in claims 10 to 11 wherein it contains and an opacifying agent or a colorant.

13. A Pharmaceutical composition as claimed in claims 10 to 12 wherein the active ingredient present in the composition is in the range of 120mg to 360mg preferably about 120 mg of Form I or Form II.

14. A process for the preparation of the pharmaceutical composition as claimed in claims 2 to 13 which comprises dry blending, the crystalline polymorphic Form I or Form of imatinib mesylate or their mixtures and the excipients, screening the resulting blend and/or milled to the desired particle size, adding other desired ingredients and tableting the resultant granulates.

15. A process for the preparation of the pharmaceutical composition as claimed in claims 2 to 14 which comprises dry blending, the crystalline polymorphic Form I or Form of imatinib mesylate or their mixtures and the excipients, screening the resulting blend and/or milled to the desired particle size, adding other desired ingredients compressing directly into a compacted dosage form using direct compression techniques.

16. A process for the preparation of the pharmaceutical composition as claimed in claim 15 wherein excipients such as microcrystalline cellulose, lactose, crospovidone XL, colloidal silicone dioxide, magnesium stearate and talc.

17. A novel crystalline polymorphic Form I & Form II of Imatinib Mesylate substantially as herein described with reference to the Examples 1 to 5.

18. A process for the preparation of novel crystalline polymorphic Form I & Form II of Imatinib Mesylate substantially as herein described with reference to the Examples 1 to 5.

19. A pharmaceutical composition useful for the treatment of chronic myelogenous leukemia and accelerated stress conditions substantially as herein described with reference to the Examples 7 and 8.