WO2011108953A1 - PROCESS FOR PREPARATION OF POLYMORPHIC FORM α AND NEW POLYMORPHIC FORM OF IMATINIB MESYLATE ISOLATED IN THAT PROCESS - Google Patents

PROCESS FOR PREPARATION OF POLYMORPHIC FORM α AND NEW POLYMORPHIC FORM OF IMATINIB MESYLATE ISOLATED IN THAT PROCESS Download PDF

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WO2011108953A1
WO2011108953A1 PCT/PL2011/000028 PL2011000028W WO2011108953A1 WO 2011108953 A1 WO2011108953 A1 WO 2011108953A1 PL 2011000028 W PL2011000028 W PL 2011000028W WO 2011108953 A1 WO2011108953 A1 WO 2011108953A1
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polymorphic form
imatinib mesylate
characterized
temperature
imatinib
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PCT/PL2011/000028
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French (fr)
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Tomasz Kozluk
Robert WOŹNIAK
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Tomasz Kozluk
Wozniak Robert
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Abstract

In the present invention, the process of preparation of imatinib mesylate polymorphic form α, in the reaction of equimolar amounts of imatinib base and methanesulfonic acid in the mixture of isopropyl alcohol and diisopropyl ether or in methylene dichloride is disclosed. According to the present invention polymorphic form α of imatinib mesylate is obtained as microcrystalline form or granulated form characterized by high bulk density. The present invention also relates to new polymorphic form N of imatinib mesylate and its use in the process of preparation of polymorphic form α.

Description

Process for preparation of polymorphic form a and new polymorphic form of imatinib mesylate isolated in that process

Field of invention

The present invention relates to the process for preparation of polymorphic form a of imatinib mesylate. Preferably, the present invention relates to preparation of polymorphic form a of imatinib mesylate characterized by high bulk density.

The present invention also relates to the new polymorphic form of imatinib mesylate isolated in that process and its use for preparation of polymorphic form a.

Background of the invention

Imatinib, 4-[(4-methylpiperazyn- 1 -yl)methyl] -N- [4-methyl-3 - [(4-pyridin-3 -yl- pyrimidin-2-yl)amino]phenyl]benzamide, as a selective inhibitor of tyrosine kinases, was disclosed in European Patent Application EP 0 564 409 Al . It is represented by the structural formula:

Figure imgf000002_0001

Imatinib is indicated for the treatment of patients with Philadelphia chromosome positive (PH+) chronic myeloid leukemia (CML) and with Kit-positive gastrointestinal stromal tumours (GIST) including unresectable and/or metastatic malignant disease and resected disease post-surgery, for use in adult patients with newly diagnosed PH+ acute lymphoblastic leukemia (ALL) in combination with chemotherapy, and as single agent for patients with relapsed or refractory Ph+ALL.

The active ingredient of imatinib tablets marketed as Gleevec® or Glivec® is imatinib acid addition salt with methanesulfonic acid (imatinib mesylate). Therapeutic daily dose of imatinib in treatment in humans varies from 100 mg to 800 mg of imatinib active ingredient. In medical practice tablets are administered comprising 100 mg or 400 mg of imatinib, ie. 119,5 or 478 mg of imatinib mesylate respectively. The process of manufacturing tablets of high active substance content is a challenge from technological point of view, especially when small size unit dosage form is required for the patients' convenience.

In the European Patent EP 1 501 485 Bl the„compact" coated tablet, containing from 30% to 80% by weight of imatinib active substance calculated on the total tablet mass, was disclosed. Tablets were manufactured in wet granulation process using active substance and binding agent forming the inner phase, followed by mixing the obtained granulate with the pharmaceutically accepted excipients forming the outer phase, then compressing the mixture into the cores and coating the cores. In the examples of tablet formulations containing polymorphic form β of imatinib mesylate were only revealed.

It is well known that imatinib mesylate may crystallize in some polymorphic forms. WO 99/03854 discloses two polymorphic forms, a and β, of imatinib mesylate that significantly differ in physico-chemical properties. The polymorphic form β crystallizing in ethanol is thermodynamically stable and its plate-like crystals have relatively good processing parameters. Polymorphic form a crystallizes as elongated needle-like crystals, which are fragile and very hygroscopic. Unfavorable flow properties of polymorphic form a crystals and as well as its mixtures with pharmaceutical excipients is the main disadvantage encountered in technology. It seems obvious, the hygroscopic polymorphic form a is not suitable active substance for the output of tablets in wet granulation process.

The process for preparation of tablets or granulate containing from 25 to 80% of imatinib mesylate polymorphic form a, is disclosed in European Patent EP 1 762 230 Bl . Following that process coated tablets of suitable hardness and abrasion resistance may be obtained when dry granulation process is performed prior to tablet compression of granulate or tablet core. It was claimed, that particle size of at least 80% by weight of active substance amounts from 0,01 to 1,0 mm. In the examples, only tablets of total mass 195 mg containing 119,5 mg of imatinib mesylate were disclosed. Following the procedure and suggested ratio of drug substance and pharmaceutical excipients, one may produce tablet of total mass 800 mg, which contains 400 mg of imatinib mesylate. This is unacceptable as regards patient's compliance.

Some research groups focused on discovering new polymorphic forms of better physico-chemical properties, which resulted in identification of, among others, the following chemical entities: form HI and imatinib mesylate hydrate (WO 2004/106326), form a2 (WO 2005/077933), needless form a (WO 2006/048890), forms I and II (WO 2006/054314), forms δ and ε (WO 2007/023182), forms F, G, H, I and K (WO 2007/059963), and also imatinib dimesylate, which is formed in the reaction of equimolar amount of base and methanesulfonic acid (WO 2005/095379). According to patent application WO 99/03854 imatinib mesylate is obtained in the reaction of imatinib base and methanesulfonic acid in methyl or ethyl alcohol. Under described reaction conditions, esters of methanesulfonic acid are likely to be formed. These toxic by-products may contaminate the active substance, thus causing the danger to human health. Preclinical studies proved high biological activity of methyl and ethyl esters of methanesulfonic acids as DNA alkylating agents. These compounds even at trace amounts (<5 ppm) may cause mutagenic, cancerogenic and teratogenic changes. On account of potent genotoxic effect of methanesulfonic acid esters, European Medicines Agency advises the pharmaceutical manufacturers to take particular precautions to produce the pharmaceutically active substances deprived of alkyl sulfonates impurities.

In the literature there were shown many examples regarding preparation of imatinib mesylate in the reaction of imatinib base and methanesulfonic acid in isopropyl alcohol or in its mixture with other solvents. According to the process disclosed in WO 2005/095379, the reaction is carried out in the mixture of isopropanol and aliphatic alcohols, yielding formation of needle-like crystals of polymorphic form a. According to patent application WO 2005/077933, crystallization of imatinib mesylate in isopropanol results in formation of polymorphic form oc2, which is characterized by thermal stability and non needle-like crystal shape. However, results of our experiments, performed following drying conditions issued in this disclosure, proved that imatinib mesylate when dried at 80°C for 6 h did not meet the pharmaceutically accepted level of residual solvents content, that is less than 0.5% of isopropanol. Nor vacuum drying at 150°C for 7 days resulted in removal of isopropanol to less than 1%. The results of thermogravimetric investigation showed (Fig. 8.), that only temperature raise above 180°C yields imatinib mesylate crystalline solid free of residual isopropanol. Unfortunately, highly elevated temperatures are not recommended in pharmaceutical processes due to the possibility of degradation of active substance.

The present inventors have focused on developing the process resulting in stable polymorphic form of imatinib mesylate. The process is expected not only to eliminate the possibility of contamination with toxic, lower alkyl esters of methanesulfonic acid, but also to enable removal of solvent under relatively mild conditions. Obtained this method imatinib mesylate is expected to meet the ICH requirements (International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use), which regard pharmaceutically accepted level of impurities and residual solvents assay of pharmaceuticals for human use.

Brief description of the invention

The purpose discussed above was accomplished when the reaction of addition of imatinib and methanesulfonc acid was performed under different conditions that those revealed in the literature up till now.

The present invention relates to the preparation of polymorphic form a of imatinib mesylate in the reaction of equimolar amount of imatinib base and methanesulfonic acid, in the mixture of isopropyl alcohol and diisopropyl ether or in methylene dichloride.

Process according to the invention is characterized by:

(a) suspending imatinib base in a mixture of isopropyl alcohol and diisopropyl ether or in methylene dichloride and stirring the solution at temperature from -10°C to reflux,

(b) adding methanesulfonic acid, concentrated or diluted with solvent, to the reaction mixture,

(c) stirring the reaction mixture at temperature from -10°C to reflux, (d) cooling down the reaction mixture to temperature 0 - 25°C and leaving until the product crystallization is complete,

(e) isolating the crystalline product from the reaction mixture,

(f) drying the isolated product under vacuum at temperature from 60 to 160°C, then

(g) optionally, when the process of imatinib mesylate preparation was carried out in methylene di chloride, after step (f) crystalline product is heated at temperature above 160°C or it is subject to maceration in isopropyl alcohol, yielding polymorphic form a.

Brief description of the figures

Fig. 1 represents XRPD pattern of imatinib mesylate polymorphic form a obtained according to the present invention,

Fig. 2 represents IR spectra of imatinib mesylate polymorphic form a obtained according to the present invention,

Fig. 3 presents DSC curve of imatinib mesylate polymorphic form a obtained according to the present invention,

Fig. 4 presents 1 H-NMR spectra of imatinib mesylate polymorphic form a, obtained according to the present invention

Fig. 5 represents XRPD pattern of imatinib mesylate polymorphic form N,

Fig. 6 represents IR spectra of imatinib mesylate polymorphic form N,

Fig. 7 represents DSC curve of imatinib mesylate polymorphic form N,

Fig. 8 represents TGA curve of imatinib mesylate reproduced according to WO 2005/077933,

Fig. 9 represent the microscopic view of polymorphic form a of imatinib mesylate in macrocrystalline form,

Fig. 10 represents the microscopic view of polymorphic form a of imatinib mesylate in granulated form,

Fig. 1 1 represents the microscopic view of polymorphic form N of imatinib mesylate. Detailed description of the invention

In one embodiment of the invention, the process is performed in the mixture of isopropyl alcohol and diisopropyl ether at temperature range from +10°C to reflux. Preferably, the process is carried out in the mixture containing from 10 to 90% of diisopropyl ether volume, more preferably about 30% of diisopropyl ether volume. The process according to the present invention enables preparation of reproducible, pure, homogenous polymorphic form a of imatinib mesylate characterized by HPLC purity higher than 99,5 % and content of residual solvent lower than 0,5 %.

The term„pure polymorphic form a of imatinib mesylate" defines the compound, which is deprived of other crystalline impurities such as imatinib free base, polymorphic form β of imatinib mesylate, imatinib dimesylate, at quantities detectable by DSC, IR or XRPD techniques.

Polymorphic form a of imatinib mesylate obtained in the process according to the present invention is characterized by X-ray powder diffraction pattern recorded with CuKa, λ = 1,54056A, having the characteristic peaks represented by the reflection angles 2Θ [°], inter-planar spacing d [A] and relative intensities I/I0 [%], as depicted in the table below:

2Θ [°] d [A] I/Io [%]

5.00 17.68 31.5

10.56 8.38 92.3

11.34 7.80 12.5

11.97 7.39 17.9

12.28 7.21 15.5

13.96 6.35 10.9

15.01 5.90 62.3

16.61 5.34 35.3

17.58 5.04 37.4

17.83 4.98 54.1

18.18 4.88 69.2

18.71 4.74 100.0

19.18 4.63 83.9

21.37 4.16 64.9 21.75 4.09 65.5

22.74 3.91 21.6

23.26 3.82 26.2

23.82 3.73 24.3

24.91 3.57 58.0

25.08 3.55 46.5

27.51 3.24 14.3

28.10 3.18 14.3

28.64 3.12 43.1

X-Ray powder diffraction pattern (XRPD) is depicted on Fig. 1.

The IR spectrum (in KBr) of polymorphic form of imatinib mesylate, obtained according to the invention is depicted on Fig. 2. This IR spectrum differs from IR spectrum of polymorphic form β within the whole spectral range.

The DSC curve of imatinib mesylate, obtained according to the present invention is depicted on Fig. 3. Melting point was determined as extrapolated value 226.4°C and „onset" 225.0°C, which remains in accordance with published analytical data regarding imatinib mesylate polymorphic form a. Melting point of polymorph a is about 10°C higher than melting point of polymorph β (about 217°C).

Polymorphic form a of imatinib mesylate can be isolated from the crystallization mixture, consisting of isopropyl alcohol and diisopropyl ether, either as microcrystalline form or granulate, depending on the method of drying.

Microcrystalline form of imatinib mesylate polymorph a, which is characterized by particle size below 20 μηι, is obtained when drying the crystals under vacuum in a tray drier, at temperature 120-140°C, preferably about 130°C, for about 24 h. Shape and size of obtained that method crystals is illustrated by the microscopic view depicted on Fig. 9.

Granulate of imatinib mesylate polymorphic form a is obtained, when crystals are dried under similar conditions in a rotary drier; it is characterized by about 200 μιη particle size. Shape and size of granulate is illustrated by microscopic view depicted on Fig. 10.

Bulk density of imatinib mesylate polymorphic form a depends on the method of drying, measurements data are collected in the table below: Polymorph a of Loose bulk density Tapped bulk density imatinib mesylate [g/ml] [g/ml]

Microcrystalline

0.20 - 0.25 0.30 - 0.35

form

Granulated form 0.50 - 0.60 0.60 - 0.70

Granulated form of polymorphic form a of imatinib mesylate is mainly used in pharmaceutical technology to manufacture solid dosage forms, especially capsules. Due to significantly higher bulk density of granulate in comparison with that of microcrystalline form, capsules of smaller size can be filled with the same amount of imatinib mesylate. Hard gelatin capsules can be filled with granulate of imatinib mesylate itself or its mixture with pharmaceutically accepted excipients.

In another embodiment of the invention, the process of preparation of imatinib mesylate polymorphic form a is carried out in methylene dichloride. To the suspension of imatinib base in methylene dichloride, methanesulfonic acid or its solution in methylene dichloride is added, the reaction mixture is stirred at temperature from -10°C to reflux, preferably at temperature about 20°C, crystallization mixture is cooled down, if necessary, to room temperature, the crystalline product is isolated from the mixture and it is dried under vacuum at temperature from 60 to 160°C.

Unexpectedly it was proved, crystalline imatinib mesylate isolated from the crystallizing mixture, resulting from the reaction of imatinib base and methanesulfonic acid in methylene dichloride, is the new polymorphic form, named Form N.

Polymorphic form N of imatinib mesylate, obtained according to the present invention is characterized by crystalline homogeneity, HPLC purity higher than 99.5%, contents of residual solvent below 0.05 % and particle size below 20 μιη (Fig. 11).

Polymorphic form N of imatinib mesylate is characterized by X-ray powder diffraction pattern recorded with CuKa, λ = 1,54056A, having the characteristic peaks represented by the reflection angles 2Θ [°], inter-planar spacing d [A] and relative intensities I I0 [%], as depicted in the table below:

2Θ [°] d [A] Mo [%] 2Θ [°] d [A] I/I0 [%]

4.99 17.71 17.0

10.15 8.72 78.4

10.78 8.21 22.7

11.92 7.43 6.2

12.54 7.06 12.9

13.95 6.35 11.8

14.17 6.25 8.2

15.72 5.64 21.6

16.94 5.24 1 1.6

17.78 4.99 9.8

18.78 4.72 23.3

20.46 4.34 100.0

21.33 4.17 12.4

22.1 1 4.02 9.3

22.60 3.93 8.6

23.34 3.81 5.8

23.89 3.73 19.6

24.35 3.66 7.6

25.63 3.48 7.4

27.06 3.30 9.7

28.64 3.12 6.1

X-Ray powder diffraction pattern (XRPD) is depicted on Fig. 5.

The IR spectrum (in KBr) of polymorphic form N of imatinib mesylate obtained according to the invention is depicted on Fig. 2. This IR spectrum differs from IR spectrum of polymorph β within the whole spectral range.

The DSC curve of imatinib mesylate obtained according to the present invention is depicted on Fig. 6. Main absorption bands are presented in the table below. They are compared with data collected for polymorphic form a, which were obtained according to the first embodiment of the invention and the absorption bands of polymorphic form β, obtained according to the description revealed in WO 2005/095379:

Figure imgf000010_0001
Figure imgf000011_0001

On DSC curve depicted on Fig. 7, within temperature range 140 - 160°C, endothermic effect of melting point of imatinib mesylate polymorphic form N is observed. Within 180 - 200°C temperature range, exotermic effect is shown, which is characteristic of recrystallization process of polymorph a. At temperature above 220°C endothermic effect of melting point of polymorphic form a is observed with its maximum at 225.6°C.

Polymorphic form N of imatinib mesylate is stable at temperature up to 160°C, but upon heating at temperature from 160°C to 200°C it transforms into polymorph a. Maceration in isopropyl alcohol also results in transformation of polymorph N into polymorphic form a . Polymorphic form N as well as polymorphic form a of imatinib mesylate, obtained according to the present invention show advantageous physico-chemical properties. Both polymorphic forms crystallize as non needle-like crystals (Fig. 9 and 11), therefore they are useful in the process of solid dosage forms manufacture. Implementation of suitable drying conditions influences formation of polymorphic form a of imatinib mesylate as granulate, characterized by particle size of about 200 μπι (Fig. 10). Theses properties enable direct capsules filling with granulate. The content of residual solvent is detected significantly below the level of pharmacopoeian requirements. Polymorphic form N and polymorphic form a of imatinib mesylate are thermodynamically stable under storage conditions and also under long-term and accelerated stability measurements conditions.

The present invention is further illustrated by the following, non-limiting examples. Examples

Analytical methods

X-ray powder diffraction patterns (XRPD) were recorded on the X'Pert Pro by PANalytical powder diffractometer with copper radiation CuKa, λ = 1,54056A, with the following measurement parameters:

• 2Θ scanning range: 3° - 50°

• Scanning rate Δω: 0.5 min.

• Step sizeA20: 0.026°

1H-NMR and 13C-NMR spectra were recorded on Bruker Avance DRX 500 MHz spectrometer.

DSC data were obtained using differential scanning calorimeter Du Pont Thermal Analyst System 2100, within temperature range 30-260°C, with heat flow 5°C/min. Melting point was determined as extrapolated value and„onset" value. Example 1.

To the mixture of isopropyl alcohol and diisopropyl ether (100 ml) at volume ration 7:3 imatinib base (5 g) was added. To the resulting suspension the solution of methanesulfonic acid (0.660 ml) in isopropyl alcohol (3 ml) was added dropwise at room temperature within 10 min. The mixture was refluxed for 3 h. The solution was gradually cooled down within 5 h. The solid was filtered off and washed with isopropyl alcohol. The product was dried under vacuum at 130°C for 24 h in a tray drier. Polymorphic form a of imatinib mesylate was obtained in 5.80 g (97%) yield, as microcrystalline form (Fig. 9) characterized by loose bulk density 0.23 g/ml and tapped bulk density 0.34 g/ml.

1H-NMR [DMSO d6), 5 (ppm): 10.20 (s, 1H), 9.59-9.35 (m, 1H), 9.28 (d, J = 1.73 Hz, 1H), 8.99 (s, 1H), 8.69 (dd, J = 4.75, 1.59 Hz, 1H), 8.52 (d, J = 5.13 Hz, 1H), 8.48 (q, 1H)], 8.10 (d, J = 1.79 Hz, 1H), 7.96 (d, J = 8.06 Hz, 2H), 7.53 (ddd, J = 8.04, 4.81, 0.63 Hz, 1H), 7.50 (dd, J = 8.23, 2.11 Hz, 1H), 7.49-7.45 (m, 1H), 7.44 (d, J = 5.15 Hz, 1H), 7.22 (d, J = 8.46 Hz, 1H), 3.65 (s, 2H), 3.37 (dq, 3H), 3.22-2.99 (m, 2H), 2.99-2.84 (m, 2H), 2.80 (s, 3H), 2.36 (s, 3H), 2.24 (d, J = 7.81 Hz, 3H) - Fig. 4.

The product was characterized by XRPD (Fig. 1), IR (Fig. 2) and DSC (Fig. 3) as polymorphic form a. Residual solvents - below 3000 ppm.

Example 2. To the mixture of isopropyl alcohol and diisopropyl ether (100 ml) at volume ration 6:4 imatinib base (5 g) was added. To the resulting suspension the solution of methanesulfonic acid (0.660 ml) in diisopropyl ether (3 ml) was added dropwise at room temperature within 10 min. The mixture was refluxed for 6 h. The solution was gradually cooled down within 5 h. The solid was filtered off and washed with diisopropyl ether. The product was dried under vacuum at 130°C for 24 h in a tray drier. Form a of imatinib mesylate was obtained in 5.73 g (96%) yield. The identity of the product was confirmed by Ή-NMR and its polymorphic form was proved by IR, XRPD and DSC methods.

Example 3.

To the mixture of isopropyl alcohol and diisopropyl ether (100 ml) at volume ration 7:3 imatinib base (5 g) was added. To the resulting suspension the solution of methanesulfonic acid (0.660 ml) in the mixture of isopropyl alcohol and diisopropyl ether (3 ml) was added dropwise at room temperature within 10 min. The mixture was heated at 40°C and stirred for 6 h. The solution was gradually cooled down within 5 h. The solid was filtered off and washed with the mixture of isopropyl alcohol and diisopropyl ether. The product was dried under vacuum at 130°C for 24 h in a tray drier. Form a of imatinib mesylate was obtained in 5.82 g (97%) yield. The identity of the product was confirmed by 1H-NMR and its polymorphic form was proved by IR, XRPD and DSC methods.

Przyklad 4.

To the mixture of isopropyl alcohol and diisopropyl ether (195 1) at volume ration 7:3 imatinib base (10 kg) was added. To the resulting suspension the solution of methanesulfonic acid (1320 ml) in isopropyl alcohol (6 1) was added dropwise at room temperature within 15 min. The mixture was refluxed and stirred for 3 h. The solution was gradually cooled down within 5 h. The solid was filtered off and, washed with isopropyl alcohol. The product was dried under vacuum at 130°C for 24 h in a tray drier. Form a of imatinib mesylate was obtained in 11.5 kg (96%) yield. The identity of the product was confirmed by 1H-NMR and its polymorphic form was proved by IR, XRPD and DSC methods.

Example 5.

To the mixture of isopropyl alcohol and diisopropyl ether (100 ml) at volume ration 7:3 imatinib base (5 g) was added. To the resulting suspension the solution of methanesulfonic acid (0.660 ml) in the mixture of isopropyl alcohol and diisopropyl ether (3 ml) at the same proportion was added dropwise at room temperature within 10 min. The mixture was heated at 40°C and stirred for 6 h. The solution was gradually cooled down within 5 h. The solid was filtered off and washed with the mixture of isopropyl alcohol and diisopropyl ether. The product was dried in a rotary vacuum drier at 130°C for 24 h . Form a of imatinib mesylate was obtained in 5.78 g (97%) yield as granulate (Fig. 11), characterized by loose bulk density 0.58 g/ml and tapped bulk density 0.67 g/ml. The identity of the product was confirmed by 1 H-NMR and its polymorphic form was proved by IR, XRPD and DSC methods.

Example 6.

Imatinib base (50 g) was added to methylene dichloride (1500 ml). To the resulting suspension the solution of methanesulfonic acid (6.60 ml) in methylene dichloride (30 ml) was added at room temperature within 10 min. The solution was stirred at room temperature for 22 h. The solid was filtered off and washed with methylene dichloride. The product was dried under vacuum at 110°C for 24 h. Polymorphic form N of imatinib mesylate was obtained in 50.83 g (84%) yield. The identity of the product was confirmed by 1 H-NMR and polymorphic form was proved by IR (Fig. 5), XRPD (Fig. 6) and DSC (Fig. 7). The content of residual methylene dichloride was below 30 ppm.

Example 7.

The product obtained in example 6 (2 g) was added to isopropyl alcohol (60 ml). The resulting suspension was refluxed and stirred for 2 h. The solution was cooled down to room temperature and the solid was filtered off and washed with isopropyl alcohol. The product was dried under vacuum at 1 10°C for 24 h. Polymorphic form a of imatinib mesylate was obtained in 1.95 g (97%) yield. The identity of the product was confirmed by 1 H-NMR and polymorphic form was proved by IR, XRPD and DSC.

Example 8.

The product obtained in example 6 (10 g) was placed in a vacuum drier. The crystalline solid was heated at 170°C for 24 h. After cooling down the product was milled. Polymorphic form a of imatinib mesylate was obtained in 9.90 g (99%) yield. The identity of the product was confirmed by 1 H-NMR and polymorphic form was proved by IR, XRPD and DSC

Claims

Claims
1. Process for preparation of polymorphic form a of imatinib mesylate in the reaction of equimolar amount of imatinib base and methanesulfonic acid, characterized by:
(a) suspending imatinib base in the mixture of isopropyl alcohol and diisopropyl ether or methylene dichloride and stirring the solution at temperature from -10°C to reflux,
(b) adding methanesulfonic acid, concentrated or diluted with solvent, to the reaction mixture,
(c) stirring the reaction mixture at temperature from -10°C to reflux,
(d) cooling the reaction mixture down to temperature 0 - 25°C and leaving the solution for product crystallization,
(e) isolating crystalline product from the reaction mixture,
(f) drying the isolated product under vacuum at temperature from 60 to 160°C, and then
(g) optionally, if the preparation of imatinib mesylate was carried out in methylene dichlorid, after step (f) crystalline product is either heated at temperature above 160°C or it is macerated in isopropyl alcohol, yielding polymorphic form a.
2. The process according to claim 1, characterized by that, the solution of methanesulfonic acid in isopropyl alcohol or diisopropyl ether or their mixture to imatinib base is added and the reaction is carried out in the mixture containing from 10 to 90% of diisopropyl ether volume, at temperature from 40°C to reflux.
3. The process according to claim 2, characterized by that, the reaction is carried out in the mixture containing about 30% of diisopropyl ether volume.
4. The process according to claim 1, characterized by that, 20% solution of methanesulfonic acid in isopropyl alcohol or diisopropyl ether or their mixture.
5. The process according to claim 1, characterized by that, reaction of imatinib base and methanesulfonic acid proceeds in methylene dichloride at temperature from 10 to 30°C, after step (f) imatinib mesylate is isolated as a crystalline solid, which is dried under vacuum at temperature from 60 to 160°C, obtained crystalline product is subsequently heated at temperature above 160°C or it is macerated in isopropyl alcohol, yielding polymorphic form a of imatinib mesylate.
6. The process according to any claim 1-5, characterized by that polymorphic form a of imatinib mesylate is obtained, characterized by X-ray powder diffraction pattern having the reflection angles 2Θ of : 10,6; 12,0; 12,3; 15,0; 18,7; 19,2; 23,3; 24,9; 28,6 ± 0,2°.
7. The process according to any claim 1-6, characterized by that, polymorphic form a of imatinib mesylate is obtained, which is deprived of any contaminations of other polymorphs and crystalline compounds, detected by XRPD, IR and DSC methods.
8. The process according to any claim 1-7, characterized by that, crystalline product in step (f) is dried under vacuum in a tray drier, at temperature 120-140°C, preferably about 130°C, for about 24 h, yielding polymorphic form a of imatinib mesylate in a microcrystalline form characterized by particle size below 20 μηι, loose bulk density 0.20 - 0.25 g/ml and tapped bulk density 0.30 - 0.35 g/ml.
9. The process according to any claim 1-7, characterized by that, crystalline product in step (f) is dried under vacuum in a rotary drier, at temperature 120-140°C, preferably about 130°C, for about 24 h, yielding polymorphic formic form a of imatinib mesylate as granulate, characterized by particle size about 200 μηι, loose bulk density 0.50 - 0.60 g/ml and tapped bulk density 0.60 - 0.70 g/ml.
10. Polymorphic form N of imatinib mesylate, characterized by X-ray powder diffraction pattern having the reflection angles 20 at: 10.2; 10.8; 15.7; 18.8; 20.5;
23.9 ± 0,2°.
1 1. Polymorphic form N of imatinib mesylate according to claim 10, characterized by X-ray powder diffraction pattern as depicted on Fig. 5.
12. Polymorphic form N of imatinib mesylate according to claim 10, characterized by that, HPLC purity is higher than 99.5%, residual solvents assay is lower than 0,05 % and particle size is below 20 μηι.
13. Use of polymorphic form N of imatinib mesylate to obtain polymorphic form a.
14. Use according to claim 13, characterized by that, polymorphic form N is heated at temperature 160-200°C.
15. Use according to claim 13, characterized by that, polymorphic form N is macerated in isopropyl alcohol at temperature above 40°C.
PCT/PL2011/000028 2010-03-04 2011-03-04 PROCESS FOR PREPARATION OF POLYMORPHIC FORM α AND NEW POLYMORPHIC FORM OF IMATINIB MESYLATE ISOLATED IN THAT PROCESS WO2011108953A1 (en)

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WO2012019633A1 (en) * 2010-08-11 2012-02-16 Synthon B.V. Pharmaceutical granulate comprising imatinib mesylate
ITMI20111309A1 (en) * 2011-07-14 2013-01-15 Italiana Sint Spa Process for the preparation of imatinib mesylate
CN103044396A (en) * 2012-12-14 2013-04-17 浙江华海药业股份有限公司 Preparation method of imatinib mesylate alpha-form crystal
EP2604596A1 (en) * 2011-12-16 2013-06-19 Deva Holding Anonim Sirketi Polymorphs of imatinib
WO2013136141A1 (en) 2012-03-13 2013-09-19 Fresenius Kabi Oncology Ltd. An improved process for the preparation of alpha form of imatinib mesylate
EP3007699A4 (en) * 2013-06-12 2017-01-18 Shilpa Medicare Limited Crystalline imatinib mesylate process

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EP3007699A4 (en) * 2013-06-12 2017-01-18 Shilpa Medicare Limited Crystalline imatinib mesylate process

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