NZ630300A - Crystalline imatinib mesylate process - Google Patents

Abstract

The present disclosure relates to a process for preparation of crystalline non-needle shaped Form-SA of Imatinib mesylate (4-[(4-Methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-phenyl]benzamide methanesulfonate). The disclosure also relates to crystalline Form-SA obtained by the process of the present disclosure, the said Form-SA being substantially pure, stable, non-needle shaped and characterized by X-ray powder diffraction pattern comprising of atleast five 2θ° peaks selected from 10.67, 12.90, 15.34, 19.49, 19.80, 26.06, 26.32 and 28.89 ± 0.05 2θ°. The disclosure further relates to pharmaceutical compositions comprising non-needle shaped crystalline Form-SA of Imatinib mesylate, useful for the treatment of cancer.

Description

CRYSTALLINE IMATINIB TE PROCESS FIELD OF THE INVENTION The present ion relates to a process for ation of crystalline non-needle shaped Form-SA of ib mesylate (I).

The invention also relates to crystalline Form—SA obtained by the process of the present invention, the said Form—SA being substantially pure, stable, non—needle shaped and characterized by X—ray powder diffraction pattern comprising of at least five 20° peaks selected from 10.67, 12.90, 15.34, 19.49, 19.80, 26.06, 26.32 and 28.89 i 0.05 20".

The invention further relates to pharmaceutical compositions comprising non—needle shaped crystalline Form—SA of Imatinib mesylate, useful for the treatment of cancer.

INTRODUCTION Imatinib mesylate (I) is chemically known as 4—[(4-Methyl—1—piperazinyl)methy1]—N— [4—methyl—3 —[[4—(3 -pyridinyl)-2—pyrimidinyl] amino] —phenyl]benzamide esulfonate.

N| \ .CH3SO3H Imatinib mesylate is a tyrosine-kinase inhibitor used in the treatment of multiple cancers and is sold under the trade name GLEEVEC/GLIVEC®. Imatinib is used in chronic myelogenous leukemia (CML), intestinal stromal tumors (GISTs) and a number of other malignancies. The US. Food and Drug Administration (FDA) has approved Imatinib as first— line treatment for Philadelphia chromosome ositive Chronic myelogenous ia (CML), both in adults and children. The drug is approved in multiple Ph—positive cases CML, including after stem cell transplant, in blast crisis, and newly diagnosed. The FDA first granted approval for advanced GIST patients in 2002. Later in 2012, Imatinib was approved also for The drug is use after the surgical l of KIT—positive tumors to help prevent recurrence. also approved in unresectable sitive GISTS.

Further FDA has approved imatinib for use in adult patients with relapsed or refractory Ph-positive Acute lymphoblastic leukemia (ALL), myelodysplastic/ myeloproliferative diseases associated with platelet—derived growth factor receptor gene re-arrangements, aggressive systemic mastocytosis (ASM) without or an unknown D816V e-KIT on, hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukemia (CEL) who have the FIPlLl-PDGFROL fusion kinase (CHIC2 allele deletion) or FIPlLl-PDGFRO. fusion kinase negative or unknown, unresectable, recurrent and/or metastatic dermatofibrosarcoma protuberans. Recently on 25 January 2013, Gleevec has been approved for use in children with Ph+ ALL. mann et al in EP 564409 Al initially disclosed the preparation of Imatinib in free form (not as a salt). Further Zimmermann et al in US 6,894,051 B1 described at and [3 crystal forms of Imatinib Mesylate.

Zimmermann et al in US’051 disclosed that the ystal form of 4-(4-methylpiperazin- l—ylmethyl)-N—[4-methyl—3-(4—pyridinyl) pyrimidin-2 -ylamino) phenyl] benzamide e sulfonate i.e. Imatinib mesylate is characterized by needle—shaped ls and is hygroscopic. It mentioned that in this form, the crystals are not particularly well—suited to pharmaceutical formulation as solid dosage forms, because their physical ties, for example their flow characteristics, are unfavorable.

It was r emphasized that under certain conditions, however, it is possible to obtain 4—(4—methylpiperazin—l —ylmethyl)—N-[4-methyl3 -(4—pyridin-3 -yl) pyrimidin—2—yl amino) phenyl] benzamide methane sulfonate in a crystal form which is not —shaped, this crystal form being described as B-crystal form. The B-crystal form of Imatinib mesylate is ed as having the advantage of its flow properties being substantially more favorable than those of the (it-crystal form. This crystal form has the further advantage of being thermodynamically more stable at temperatures below 140°C. Also applicant of US’051 bes that the B—crystal form is less hygroscopic than the d-crystal form and thus also stores better and is easier to process.

Besides 0t and [3 crystal forms various other polymorphic forms of Imatinib mesylate and the process for preparation thereof have been described in patent publications W02004/106326, W02005/095379, , /O223816, /048890, WO2007/023182, W02007/059963 and WOZOl 1/108953.

Imatinib mesylate being an important anticancer eutic agent, additional and ed ways of preparing ib mesylate salt may be of immense value to pharmaceutical science and the healtheare of cancer patients. Further exploring new forms of pharmaceutically active / useful compounds such as ib mesylate may provide an opportunity to improve the drug performance teristics of such products. Hence, there exists a need for the further development of new stable crystalline form of ib mesylate and economically viable processes for its preparation, which may be commercially up scalable, safer for handling, less time consuming and with better and consistent quality parameters.

The inventors of this application have developed a process which provides a stable rphic crystalline form of Imatinib mesylate, designated as Form—SA, which is non— hygroscopic, non—needle shaped and thus has easy handling properties. The process of this invention provides the crystalline Form-SA of Imatinib mesylate in a substantially pure form, which is without any detectable impurities/ contamination of any other previously known crystalline forms of Imatinib mesylate.

SUMMARY OF INVENTION Particular aspects of the present invention relate to a process for preparation of lline non-needle shaped Form-SA of ib mesylate (I). Crystalline Form-SA of Imatinib mesylate obtained by the process of the present invention is found to be substantially pure, stable and non-needle shaped.

(EH3 N n C] N \ \ N I I T / / CH3SO3H HN\ j 0 (I) In one aspect according to the present invention, it es process for the preparation of crystalline non-needle shaped Form-SA of Imatinib mesylate (I), comprising the steps of: a) Providing a solution of Imatinib base in the mixture of isopropyl alcohol and a cyclic arbon or ether solvent; b) Stirring the reaction mass at RPM of not less than 100 rotations per minute; c) Adding on of methane sulfonic acid and isopropyl alcohol to the reaction mass in time duration of not less than 30 mins; d) Heating the reaction mass to a temperature ranging between 60-75 C’C; e) Cooling the on mass to ambient temperature of 25-30 C’C in time duration of not less than 4 hours. t) Recovering the non-needle shaped crystalline Form-SA.

In another aspect, the present ion provides crystalline non—needle shaped Form-SA of Imatinib mesylate, which is characterized by i. X-ray powder diffraction pattern comprising of at least five 20° peaks selected from .67, 12.90, 15.34, 19.49, 19.80, 26.06, 26.32 and 28.89 i 0.05 20°; ii. X—ray powder diffraction pattern with absence of 20° peak at about 25.08 20°; iii. Non-needle shaped crystals; iv. Particle size distribution of dgo ranging from 90 to 130 um.

In another aspect, crystalline non—needle shaped Form—SA of Imatinib mesylate ed by the process of the present invention is having HPLC purity of at least 99.8 % and moisture content of less than 0.5%. The crystalline A of Imatinib mesylate as obtained by the process of the present ion is without any detectable impurities/ contamination of any other previously known lline forms of Imatinib mesylate.

In a further aspect, the present ation also relates to a pharmaceutical composition comprising crystalline non—needle shaped Form—SA of Imatinib mesylate of the present application and at least one or more pharmaceutically acceptable excipients. Such ition is substantially free of any other usly known crystalline forms of ib mesylate.

Further particular aspects of the invention are detailed in the description- part of the specification, wherever appropriate.

BRIEF PTION OF THE DRAWINGS Fig. 1 is an example of X~ray powder diffraction (“XRPD”) pattern of crystalline Form—SA of ib mesylate Fig. 2 is an example of a microscopic View of Form-SA of Imatinib mesylate Fig. 3 is an example of a Differential Scanning Calorimetry (“DSC”) curve of Form-SA of Imatinib mesylate ABBREVIATIONS API Active Pharmaceutical Ingredient DIPE Di-Isopropyl Ether DPE pyl Ether DSC Differential Scanning Calorimetry _i HPLC High—Performance Liquid Chromatography IPA Iso-Propyl Alcohol MTBE Methyl Tert-Butyl Ether RPM Rotations Per Minute THF TetraHydroFuran l XRPD X—Ray Powder Diffraction ‘l DETAILED DESCRIPTION As set forth herein, embodiments of the present invention relate to a reproducible and efficient process for preparation of crystalline non—needle shaped Form—SA of Imatinib mesylate (I) in high yield. lline Form-SA of Imatinib mesylate obtained by the process of the present ion is found to be substantially pure, stable and non—needle .

In one embodiment of the present application, it provides a process for the preparation of crystalline non-needle shaped Form-SA of Imatinib mesylate (I), comprising the steps of: ‘EH3 N n [I N \ II E:\ N / / CH3SO3H HN\ j 0 (I) a) ing a solution of Imatinib base in the mixture of isopropyl alcohol and a cyclic arbon or ether solvent; b) Stirring the reaction mass at RPM of not less than 100 rotations per minute; 0) Adding solution of methane sulfonic acid and isopropyl alcohol to the reaction mass in time duration of not less than 30 mins; d) Heating the reaction mass to a temperature ranging between 60-75 °C; e) Cooling the reaction mass to ambient ature of 25-30 0C in time duration of not less than 4 hours. t) Recovering the edle shaped crystalline Form—SA.

The dual steps of the process according to the present invention for preparing crystalline non-needle shaped Form—SA of Imatinib mesylate (I) are detailed separately herein below.

Step 3) comprises providing a solution of Imatinib base in the e of isopropyl alcohol and a cyclic hydrocarbon or ether solvent; Imatinib base from any source is provided as a on in the e of isopropyl alcohol (IPA) and a cyclic hydrocarbon or ether solvent. The cyclic hydrocarbon solvent to be used in this reaction may be selected from C5-C7 hydrocarbon like cyclopentane, cyclohexane and cycloheptane; and ether solvent may be selected from diethyl ether, DIPE, DPE, MTBE or THF.

The ratio of amount of isopropyl alcohol and the cyclic hydrocarbon/ ether solvent, used for this reaction is very important for the desired end product characteristics. Preferably, isopropyl alcohol and cyclic hydrocarbon or ether solvent are used in the ratio ranging from 7:3 to 8:2 (v/v). In a particular ment, for 80 ml IPA, 20 ml of cyclohexane was used to In another particular prepare the solvent mixture for providing a solution of Sorafenib base. ment, for 4200 ml IPA, 1800 ml of DIPE was used to prepare the solvent mixture for providing a solution of Sorafenib base.

Step b) comprises stirring the reaction mass at RPM of not less than 100 ons per minute; The reaction mass obtained from step a) is subjected to stirring. It has been found by the ors of this ation that stirring plays a very critical role in obtaining the desired characteristics of the end product i.e. Form-SA of Imatinib mesylate. For a commercially viable process to obtain Form SA of Imatinib mesylate, stirring shall be performed at RPM of at least not less than 100 rotations per minute.

In a preferred embodiment stirring of the reaction mass is performed at RPM of about 0 rotations per minute for commercial scale batches. For laboratory scale batches, RPM of 200—250 rotations per minute shall be maintained while stirring. Importance of the role played by rate of stirring of the on, can be gauged from the fact that, when stirring RPM of less than 100 rotations per minute is used in this reaction, the end t Imatinib mesylate is not obtained as Form-SA i.e. the end product is not obtained in pure form and shows the presence of needle shaped crystals and other impurities. Thus controlled stirring conditions of not less than 100 rotations per minute shall be maintained throughout this reaction to obtain the desired end product as crystalline non—needle shaped A of lmatinib mesylate.

Step c) comprises adding solution of methane sulfonic acid and isopropyl alcohol to the reaction mass in time duration of not less than 30 mins; To the properly stirred reaction mass of step b), while continuing the stirring a solution of methane sulfonic acid and isopropyl alcohol is added in time duration of not less than 30 mins. In this step, methanesulfonic acid and pyl alcohol are used in the ratio ranging from 1:1 to 1:3 (w/V-methanesulfonic acid: isopropyl alcohol). In one of the particular embodiment methanesulfonic acid and pyl alcohol are used in the ratio of 1:1, for e.g. 79.10 g of methanesulfonic acid solution with 80 ml of isopropyl alcohol was added to the reaction mass. This step is carried out at room temperature.

The addition of on of methane ic acid and isopropyl alcohol to the reaction mass obtained in step b) shall be performed slowly in time duration of not less than 30 mins. If a faster addition of this solution is done to the on mass obtained in step b) then the end product does not comply to the characteristics of crystalline edle shaped Form—SA of lmatinib mesylate.

Step d) comprises heating the on mass to a temperature ranging between 60—75 °C; After the completion of the addition of solution of methane sulfonic acid and isopropyl alcohol to the reaction mass, in step c) the reaction mass is heated to a temperature of 60—75 0C, along with the uous controlled stirring. In one of the preferred embodiment the reaction mass is preferably heated to a temperature of 70-75 0C. The reaction mass is maintained at this raised temperature for time duration of 2-5 hours, depending upon the progress of the on as is monitored intermittently during the on.

Step e) comprises cooling the reaction mass to ambient temperature of 25-30 °C in time duration of not less than 4 hours.

The heated reaction mass obtained from step d) is cooled gradually to an ambient temperature of 25-30 °C in time duration of not less than 4 hours. In one of the particular embodiment the reaction temperature was allowed to cool down from 70 °C to 27 °C in time duration of 5 hours. To maintain the characteristic properties of the end product to be obtained as crystalline edle shaped Form-SA of lmatinib mesylate the cooling of the reaction mass shall not be performed forcefully or abruptly at a faster rate. The cooling rate may required to be lled mechanically in heres where the normal room temperature is sub— 25 °C, so as to avoid abrupt cooling.

Step 1) ses recovering the lline non—needle shaped form of Imatinib mesylate designated as Form-SA.

The reaction mass ed from step e) is filtered and given washing with an alcoholic solvent. Alcoholic solvent for this reaction step may be selected from C1—C4 alcohol. In one of the red ment, the filtered reaction mass obtained in this step is given washing with IPA. The amount of alcoholic solvent used in this reaction ranges from 1-3 times (w/v) w.r.t. the amount of Imatinib base used initially in step a). The material obtained after the alcoholic solvent washing is then dried under reduced pressure conditions to recover the crystalline non— needle shaped form of Imatinib mesylate designated as Form-SA. According to the requirement, raised temperature of 70—140 °C may also be utilized during the drying of the end product under reduced pressure conditions. Reduced pressure conditions may be suitably ed by a person skilled in the art.

Process of recovering the crystalline non—needle shaped Form—SA of Imatinib mesylate may further comprise processes but not limited to tional ses including scrapping and if required filtering from slurry which may be carried out at room ature for the suitable durations to retain the crystalline form characteristics of Form-SA.

The process d impurities that appear in the impurity profile of Imatinib te in the formation may be substantially d by the process of the present invention resulting of crystalline Form-SA of high purity. The merit of the process according to the present invention resides in that - product isolated after drying is directly obtained as crystalline non— needle shaped Form—SA of Imatinib mesylate.

The crystalline non—needle shaped Form-SA of Imatinib mesylate described herein may be characterized by X—ray powder diffraction pattern (XRPD) and Thermal techniques such as differential scanning calorimetry (DSC) analysis. The samples of crystalline non—needle shaped Form—SA of Imatinib mesylate were analyzed by XRPD on a Bruker AXS D8 Advance Diffractometer using X-ray source - Cu Ka radiation using the wavelength 1.5418 A and lynx Eye detector. DSC was done on a Perkin Elmer Pyris 7.0 instrument. Illustrative examples of ical data for the crystalline non—needle shaped Form—SA of Imatinib mesylate obtained in the examples are set forth in the Figs. 1-3.

Another embodiment of the present invention provides lline non-needle shaped Form—SA of lmatinib mesylate obtained by the process ing to the present invention.

Form-SA of lmatinib mesylate is found adequately stable to handle and store for longer time (alteast up to more than 6 months) without any significant or measurable change in its logy and physicochemical characteristics. Crystalline non-needle shaped A of lmatinib mesylate obtained according to the process of the present invention is substantially pure i.e. it is found to have final API HPLC purity of more than 99.8 % w/w, with moisture content of not more than 0.5%.

Crystalline non-needle shaped Form-SA of lmatinib mesylate, is a non—hygroscopic crystalline solid, which is characterized by- i. X-ray powder ction pattern comprising of at least five 20° peaks selected from .67, 12.90, 15.34, 19.49, 19.80, 26.06, 26.32 and 28.89 i 0.05 20°; ii. X—ray powder diffraction pattern with absence of 20° peak at about 25.08 20°; iii. Non—needle shaped crystals; iv. Particle size distribution of dgo ranging from 90 to 130 um.

The crystalline Form-SA of lmatinib mesylate as obtained by the process of the present invention is without any detectable impurities/ contamination of any other previously known crystalline forms of lmatinib mesylate.

The process of the present ion provides non—needle shaped crystals up to extent of 100%, with the absence of any -shaped crystals in the obtained end product i.e. crystalline A.

In one of the embodiments the lline Form-SA of lmatinib mesylate shows plate, flake, Lath or equant type of crystal shapes, having absence of any trace of needle type crystalline material. The Visual observation of the crystalline material obtained by process of the present invention provides physical shape information about the crystals to be present as plates, stacked plates, agglomerate of plates, spherulite or radial clusters, conglomerate of different shapes but no presence of any acicular al which es any needle type le or pointed slender material is observed.

In a further embodiment according to this specification, the invention also relates to a composition containing Crystalline non—needle shaped Form—SA of lmatinib mesylate, which is ntially free of any other known forms of lmatinib te.

The Crystalline non-needle shaped Form-SA of lmatinib mesylate obtained by the process of the present application may be formulated as solid compositions for oral administration in the form of capsules, s, pills, powders or granules. In these compositions, the active product is mixed with one or more pharmaceutically acceptable excipients. The drug substance can be formulated as liquid compositions for oral administration including solutions, suspensions, syrups, elixirs and emulsions, containing ts or vehicles such as water, sorbitol, glycerin, propylene glycol or liquid paraffin.

In one embodiment of the present invention, it also includes premix comprising one or more pharmaceutically acceptable excipients in the range of 1 to 50% w/w with crystalline non-needle shaped Form-SA of Imatinib mesylate, while retaining the crystalline nature of the premix.

The compositions for parenteral administration can be suspensions, emulsions or aqueous or non—aqueous sterile solutions. As a solvent or vehicle, ene glycol, polyethylene glycol, vegetable oils, ally olive oil, and able organic esters, e.g. ethyl oleate, may be employed. These compositions can contain nts, especially g, emulsifying and sing . The sterilization may be carried out in several ways, e.g. using a iological filter, by incorporating sterilizing agents in the composition, by irradiation or by heating. They may be prepared in the form of sterile compositions, which can be dissolved at the time of use in sterile water or any other sterile injectable medium. ceutically acceptable excipients used in the compositions comprising crystalline non—needle shaped Form—SA of ib mesylate according to the present application include, but are not limited to diluents such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, ol, sorbitol, sugar and the like; binders such as acacia, guar gum, anth, gelatin, pre-gelatinized starch and the like; disintegrants such as starch, sodium starch glycolate, pregelatinized starch, rmellose sodium, colloidal silicon dioxide and the like; lubricants such as stearic acid, magnesium te, zinc stearate and the like; glidants such as dal silicon dioxide and the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants, waxes and the like. Other pharmaceutically acceptable excipients that are of use include but not limited to film formers, plasticizers, colorants, flavoring agents, sweeteners, Viscosity enhancers, preservatives, antioxidants and the like.

Pharmaceutically acceptable excipients used in the compositions of crystalline non- needle shaped A of Imatinib mesylate of the present ation may also comprise to include the pharmaceutically acceptable carriers used for the preparation of solid dispersion, wherever utilized in the desired dosage form preparation.

EXAMPLES -1 o- Example-01: s for preparation of crystalline non—needle shaped A of Imatinib mesylate using IPA and C—6 cyclic hydrocarbon solvent 50 g of Imatinib base was added to a mixture of 80 m1 of pyl alcohol & 20 ml of cyclohexane. Stirring of the reaction mixture was performed at RPM of 200 rotations per minute. To the stirring reaction mass was added the solution of methanesulfonic acid (0.985 g) and 2 ml of isopropyl l within 30 mins at RT. After the completion of this addition, reaction mass was heated to 75 °C and this raised temperature along with controlled stirring at 200 RPM was maintained for 3 hrs. Then the reaction mass was slowly cooled to 25 °C in 4 hrs. The reaction mass was then filtered, washed with 10 ml of isopropyl alcohol (IPA) and dried under vacuum at 120—1300C for 24 hrs, to obtain the crystalline non—needle shaped Form— SA of Imatinib mesylate having XRPD r to Fig-1, Microscopic View similar to Fig-2 and DSC thermogram similar to Fig-3.

Yield: 5.2 g; HPLC purity: 99.85 %; Moisture Content 0.40% (by KF) Example-02: Process for preparation of crystalline non—needle shaped Form—SA of Imatinib mesylate using IPA and ether t 300.0 g of Imatinib base was added to a mixture of 4200 ml of isopropyl alcohol & 1800 m1 of DIPE. Stirring of the reaction mixture was performed at RPM of 140 rotations per minute. To the stirring on mass was added the solution of methanesulfonic acid (59.10 g) and 150 ml of isopropyl alcohol within 30 mins at RT. After the completion of this addition, reaction mass was heated to 70 °C and the raised temperature along with controlled stirring at 140 RPM was maintained for 3 hrs. The reaction mass was slowly cooled to 27 CC in 5 hrs.

The reaction mass was then filtered, washed with 600 ml of pyl l (IPA) and dried under vacuum at 80 °C for 24 hrs, to obtain the crystalline non-needle shaped Form-SA of Imatinib mesylate having XRPD similar to Fig-1 and DSC thermogram similar to Fig-3.

Yield: 329.0 g; HPLC purity: 99.89 %; Moisture Content 0.42% (by KF) Example-03: Process for preparation of crystalline non—needle shaped Form-SA of Imatinib mesylate using IPA and DPE. 400.0 g of ib base was added to a mixture of 5600 m1 of isopropyl alcohol & 2400 ml of DPE. ng of the reaction mixture was performed at RPM of 130 rotations per minute. To the stirring reaction mass was added the solution of esulfonic acid (79.10 g) and 80 ml of isopropyl alcohol within 30 mins at RT. After the completion of this addition, reaction mass was heated to 70 °C and the raised temperature along with controlled ng at 130 RPM was ined for 3 hrs. Then the reaction mass was slowly cooled to 25 °C in 5 hrs. The reaction mass was then filtered, washed with 800 ml of isopropyl alcohol (IPA) and dried under vacuum at 80 °C for 24 hrs, to obtain the crystalline non—needle shaped Form-SA of lmatinib mesylate having XRPD similar to Fig—l and DSC thermogram r to Fig-3.

Yield: 418.0 g; HPLC purity: 99.92 %; Moisture Content 0.36 % (by KF) While theforegoingpages provide a detailed description ofthe preferred embodiments ofthe invention, it is to be understood that the ption and examples are illustrative only of the principles ofthe invention and not limiting. Furthermore, as many changes can be made to the invention without departingfrom the scope ofthe invention, it is intended that all material contained herein be interpreted as illustrative ofthe invention and not in a limiting sense.

Claims (10)

1. Claims: 1) Process for the preparation of lline non-needle shaped A of Imatinib mesylate (1) characterized by X-ray powder diffraction pattern comprising of atleast five 20° peaks selected from 10.67, 12.90, 15.34, 19.49, 19.80, 26.06, 26.32 and 28.89 i 0.05 20°, comprising the steps of: N m C] N \ \ N . I T 7:: / / CH3SO3H HN\ 0 (I) a) providing a solution of ib base in the solvent mixture comprising of isopropyl alcohol and a cyclic arbon or isopropyl alcohol and ether solvent; b) stirring the reaction mass at RPM of not less than 100 rotations per minute; c) adding solution of methane sulfonic acid and isopropyl alcohol to the reaction mass under stirring in time duration of not less than 30 mins; d) heating the reaction mass under stirring to a temperature ranging between 60—75 0C; e) cooling the reaction mass under stirring to ambient temperature of 25—30 °C in time on of not less than 4 hours; and t) ring the non-needle shaped crystalline A.
2. 2) Process for the preparation of crystalline non-needle shaped Form—SA of Imatinib mesylate, according to claim 1, wherein cyclic hydrocarbon solvent is selected from C5—C7 hydrocarbon and ether solvent is selected from diethyl ether, DIPE, DPE, MTBE or THF.
3. 3) Process for the preparation of crystalline non—needle shaped Form-SA of Imatinib mesylate, ing to claim 1, wherein in step a) isopropyl alcohol and cyclic hydrocarbon or ether solvent are used in the ratio ranging from 7:3 to 8:2 (WV).
4. 4) Process for the preparation of crystalline edle shaped Form—SA of Imatinib mesylate, according to claim 1, where in step c) methanesulfonic acid and isopropyl alcohol are used in the ratio ranging from 1:1 to 1:3 (w/v—methanesulfonic acid: isopropyl alcohol).
5. 5) Process for the preparation of crystalline non-needle shaped Form-SA of Imatinib te, according to claim 1, wherein ng of the reaction mass is med at RPM of 0 rotations per minute for commercial scale batches and at RPM of 200-250 rotations per minute for tory scale batches.
6. 6) Process for the preparation of crystalline non-needle shaped Form—SA of Imatinib mesylate, according to claim 1, wherein step f) further ses the steps of: i. Filtering the reaction mass; ii. Washing with an alcoholic t; iii. Drying under reduced re ions to recover the crystalline non—needle shaped form of lmatinib mesylate designated as Form—SA.
7. 7) Crystalline non-needle shaped Form—SA of Imatinib mesylate obtained by the process according to any of the claims 1 to 6.
8. 8) Crystalline Form—SA of Imatinib mesylate characterized by i. X-ray powder diffraction pattern comprising of atleast five 20° peaks selected from 10.67, 12.90, 15.34, 19.49, 19.80, 26.06, 26.32 and 28.89 i 0.05 20°; and ii. X—ray powder diffraction pattern with absence of 20° peak at about 25.08 20°; and iii. Non—needle shaped crystals; and iv. Particle size distribution of dgo ranging from 90 to 130 um.
9. 9) Crystalline Form—SA of Imatinib mesylate as claimed in claim 8, wherein crystalline Form-SA of lmatinib mesylate has HPLC purity of at least 99.8 % and moisture content less than 0.5% w/w.
10. 10) A pharmaceutical composition comprising non—needle shaped A of Imatinib mesylate as claimed in claim 8, and at least one or more pharmaceutically acceptable excipients. «*4 ~~« Ware/.vmu-vw‘; . V1.1; SW~V .(Sui:WWW”:} 3 I”275”§§¥:{£“‘: r is“9%:‘3‘3 3 Scale OF - 1 fizz-Theta