RU2365587C1 - Roentgen-amorphous water-free modification of 4-[(4-methyl-1-piperazinyl)methyl]-n-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]-amino]-phenyl]benzamide of methane sulfonate and method of obtaining it - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry and describes novel roentgen-amorphous modification of 4-[(4-methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]-amino]-phenyl]benzamide of methane sulfonate (imatinib mesilate - international non-patented name) and method of obtaining it, consisting in evaporating initial substance of imatinib mesilate at temperature 170-215°C in vacuum 5×10^-3 - 3×10^-5 torr and condensing on cooled to (-)100 - (-)196°C surface.

EFFECT: obtaining of novel imatinib mesilate modification which can be used in pharmaceutical industry and medicine as anti-leucosis cytostatic medication for therapy of oncological diseases.

2 cl, 6 ex, 7 dwg

Description

The invention relates to organic chemistry and relates to a new x-ray amorphous anhydrous modification of 4 - [(4-methyl-1-piperazinyl) methyl] -N- [4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino ] phenyl] benzamide methanesulfonate (imatinib mesylate - the international nonproprietary name) and a method for its preparation, which can be used in the pharmaceutical industry and medicine as an anti-leukemia cytostatic drug for the treatment of cancer.

There are 13 known crystalline modifications of imatinib mesylate described in patent applications No. WO 2004/106326 A1 dated 12/09/2004, WO 2005/077933 A1 dated 08/25/2005, US 2005/0234069 A1 dated 10/20/2005, WO 2006/048890 A1 dated 11.05. 2006, US 2006/0223816 A1 of 10/05/2006, WO 2006/054314 A1 of 05/26/2006, WO 2007/023182 A1 of 03/01/2007, WO 2007/059963 A1 of 05/31/2007, US 2007/0197545 A1 of 23.08. in 2007 and characterized by X-ray fluorescence (XRF) - specific set of diffraction peaks (d, Å) and the intensity (I _rel), IR - spectroscopic studies - a specific set of characteristic bands defined temperature values mp Nia (106-227 ° C), form micron crystallite size and amount of water. The similarity of the claimed modification with the given analogues is the similarity of their chemical formulas.

The closest analogue is X-ray amorphous 4 - [(4-methyl-1-piperazinyl) methyl] -N- [4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] phenyl] benzamide methanesulfonate hydrate described in international application WO 2004/106326 A1 dated 10/20/2005), which is characterized by a weak X-ray amorphous halo and the presence of crystalline hydrated water in an amount of 2.2-3.2 wt.% of imatinib mesylate.

These modifications get one of the other “wet methods”, varying the conditions: the parameters of the preparation of solutions and emulsions, isothermal extracts, cooling, heating, as well as the conditions of separation from water, organic solvents or their mixtures by various methods. In other words, obtaining this or that modification presupposes the obligatory presence of dissolution (emulsification) stages and their further isolation from solutions in one way or another (crystallization from solutions, vacuum drying, spray drying, lyophilization and others).

Known modifications are white to yellow powders. They are readily soluble in water, sparingly soluble in ethanol (95-96%) and practically insoluble in chloroform.

The similarity of the claimed modification with the known analogue lies in the similarity of the diffraction patterns obtained by x-ray phase analysis on the studied powders.

The difference of the claimed modification from the known analogue is the absence of crystalline water in the chemical formula.

The claimed modification is obtained by the method consisting in the fact that the initial substance of imatinib mesylate is evaporated at a temperature of 170-215 ° C in a vacuum of 5 × 10 ^-3 -3 × 10 ^-5 Torr and condensed on chilled to (-) 10 - (-) 196 ° C surface.

The objective of the invention in the search for new modifications, which in comparison with the known analogues have several advantages.

The objective of the invention is also to develop a method for producing such a modification.

The problem is solved by the proposed new X-ray amorphous anhydrous imatinib mesylate modification, characterized by an X-ray amorphous halo in the diffractogram (Fig. 3) and an IR spectrum (Fig. 5, spectrogram 2), and a method for its preparation. The claimed modification can be used as an anti-leukemic cytostatic drug for the treatment of cancer.

The claimed nanodispersed X-ray amorphous anhydrous modification of 4 - [(4-methyl-1-piperazinyl) methyl] -N- [4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] phenyl] benzamide methanesulfonate represents It is a light fluffy powder from white to light yellow in color, easily soluble in water, moderately in ethyl alcohol (95-96%) and practically insoluble in chloroform.

A complex of physicochemical methods of analysis was carried out to identify the obtained substance. Initially, the methods of nuclear magnetic resonance ( ¹ H NMR) and thin layer chromatography established the identity of the chemical formulas of the original 4 - [(4-methyl-1-piperazinyl) methyl] -N- [4-methyl-3 - [[4- (3- pyridinyl) -2-pyrimidinyl] amino] phenyl] benzamide methanesulfonate and a new x-ray amorphous anhydrous modification of imatinib mesylate. In addition, the Fischer method determined the amount of water in the initial substance and the X-ray amorphous modification obtained from it.

To clarify the essence of the claimed technical solution, the following drawings are attached to the description.

Figure 1. NMR spectrum of the starting substance of imatinib mesylate.

Figure 2. NMR spectrum of an X-ray amorphous anhydrous modification of imatinib mesylate.

Figure 3. A typical diffraction pattern of an X-ray amorphous anhydrous modification of imatinib mesylate.

Figure 4. X-ray diffraction pattern of the original substance imatinib mesylate.

Figure 5. Typical IR spectra in the range of 450-5500 cm ^{-1 of the} initial imatinib mesylate (1) and the X-ray amorphous anhydrous modification obtained from it (2).

6. Typical IR spectra in the range of 5300-12500 cm ^{-1 of the} initial substance imatinib mesylate (1) and the X-ray amorphous anhydrous modification obtained from it (2).

7. Kinetics of dissolution of the initial substance imatinib mesylate and the X-ray amorphous anhydrous modification obtained from it in hexane with saturated methyl alcohol.

The chemical shifts of the initial and obtained substances were determined in its saturated solution in deuterated dimethyl sulfoxide (DMCO-D ₆ ) on a VXR-400 high-resolution NMR spectrometer (VARIAN, USA). The obtained data are shown in Figs. 1 and 2. A comparison of the results presented in Fig. 1 (the initial imatinib mesylate) with the data shown in Fig. 2 (X-ray amorphous anhydrous modification of imatinib mesylate) shows that the NMR spectra of the starting and obtained substances almost identical and there are no bands corresponding to the molecules of crystalline hydrated water, i.e. the resulting material is anhydrous 4 - [(4-methyl-1-piperazinyl) methyl] -N- [4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] phenyl] benzamide methanesulfonate.

The results of determining the amount of water by the Fischer method in the initial and obtained substances showed that the initial substance imatinib mesylate contains 0.5 ± 0.2 wt.% Water, and the obtained X-ray amorphous modification 0.3 ± 0.1 wt.% N ₂ O. In other words, the amount of water when we receive an X-ray amorphous modification of imatinib mesylate decreases.

The chromatographic mobility of the initial imatinib mesylate and the X-ray amorphous anhydrous modification obtained from it was determined by upward thin layer chromatography (TLC) on 0.25 mm thick Silicagel 60 F ₂₅₄ (Merck) plates. For chromatography of the samples, a standard chamber (20 cm × 20 cm × 8 cm) (Desaga) saturated with vapors of the mobile phase was used. Compounds were detected by absorption in the UV region at λ = 254 nm. It turned out that R _f spots of the original substance and the modifications obtained from it are the same. In addition, the purity of the original imatinib mesylate (0.27%) and the x-ray amorphous anhydrous modification obtained from it (0.18%) practically do not differ.

This indicates that, upon modification of the initial imatinib mesylate, the decomposition of the substance does not occur.

Thus, the experimental results obtained by NMR spectroscopy and thin-layer chromatography clearly indicate that the obtained substance is anhydrous 4 - [(4-methyl-1-piperazinyl) methyl] -N- [4-methyl-3 - [[4 - (3-pyridinyl) -2-pyrimidinyl] amino] phenyl] benzamide methanesulfonate.

To confirm that the obtained substance is a new X-ray amorphous anhydrous modification, X-ray phase analysis, IR spectroscopic studies, determination of the melting temperature, determination of the specific surface, as well as determination of the density of the powder in free filling (bulk mass) were carried out.

According to X-ray phase analysis (XRD), performed on a Rigaku D / MAX-2500 diffractometer (Rigaku, Japan) using CuKα radiation, the obtained substance is an X-ray amorphous modification of 4 - [(4-methyl-1-piperazinyl) methyl] -N- [4 -methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] phenyl] benzamide methanesulfonate, which is characterized by a powerful X-ray amorphous halo (Fig. 3), unlike other modifications, which are characterized by a set of diffraction maxima (d , Å) and their intensity (I _rel ,%) or weak X-ray amorphous halo characteristic of the X-ray amorphous crystal hydrate modification (Patents: WO 2004/106326 A1 of 12/09/2004, US 2005/0234069 A1). For comparison, figure 4 shows the results of XRD of the original imatinib mesylate, which is crystalline.

IR spectroscopic studies were performed in 2 areas. In the range of 450–5500 cm ^{–1, the} IR spectra of the starting substance and nanodispersed X-ray amorphous modification were obtained on a Varian-2000 FT-IR IR-Fourier spectrometer (USA) with a diffuse reflection attachment from Harrick & K ⁰ . Sample powder was poured onto the surface of the ZnSe crystal, pressed with a sealing press, and measured. To increase the signal-to-noise ratio, the spectrum was accumulated and averaged over 300 scans. The resolution was 4 cm ^-1 . The results are shown in figure 5. It can be seen that in the region of 1100-1400 cm ^{-1 the} spectra differ. In addition, the absence of intense absorption in the 3200-3400 region

cm ^-1 in the IR spectra of the initial imatinib mesylate and the X-ray amorphous modification obtained from it indicates that there is no crystalline hydrate in the samples.

In the range of 5300-12500 cm ^-1 (near region), the spectrum was recorded on a Vector 22 / N IR Fourier spectrometer (Bruker) with a diffuse reflection attachment equipped with a flexible optical waveguide. Sample powder was poured onto the surface of the quartz plate, pressed against the window of the light waveguide, and measurements were performed. The accumulation and averaging of the spectrum was carried out over 200 scans. The resolution was 8 cm ^-1 . The results are presented in Fig.6. It is seen that in the region of 5800-7000 cm ^{-1 the} spectra differ.

Thus, the experiments showed that the use of IR spectroscopy in various areas makes it possible to distinguish between the initial substance and the X-ray amorphous anhydrous modification obtained from it.

The melting temperature of the samples was determined according to GF 11 edition (method 1A - in the capillary). It turned out that the melting point of the obtained X-ray amorphous anhydrous modification is (135-137) ° С, and that of the initial substance (214-216) ° С.

The specific surface was determined by the method of low-temperature nitrogen adsorption and calculated by BET when measuring the amount of adsorbed N ₂ at one point (P / P _s ~ 0.3) (Single Point). The measurements were carried out on a flow analyzer of the specific surface Q - surf of Thermo Electron Corp. It turned out that the specific surface area of the initial substance imatinib mesylate is 0.32 m ² / g. Determination of the density of the powder of the original substance in free filling showed that its bulk density is 0.5 g / cm ³ .

The specific surface of the X-ray amorphous anhydrous modification of imatinib mesylate is 25-47 m ² / g (depends on the conditions of receipt). Determination of the powder density of the obtained modification in free filling showed that its bulk density is 0.005-0.055 g / cm ³ depending on the conditions of preparation.

Thus, the experimental results of XRD, IR spectroscopy, determination of the melting temperature, determination of the specific surface and bulk density clearly indicate that the obtained substance is a new X-ray amorphous anhydrous modification. It is characterized by diffraction patterns that are different from others, IR spectra in the regions of 110-1400 cm ^-1 and 5800-7000 cm ^-1 , melting temperature (T _PL = 135-137) ° С, specific surface area (25-47 m ² / g) and bulk density (0.005-0.055 g / cm ³ ).

A method for producing an X-ray amorphous anhydrous modification of 4 - [(4-methyl-1-piperazinyl) methyl] -N- [4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] phenyl] benzamide methanesulfonate in that the initial substance of imatinib mesylate is evaporated at a temperature of 170 ... 215 ° C in a vacuum of 5 × 10 ^-3 ... 3 × 10 ^-5 Torr and condensed on a surface cooled to -100 ... -196 ° C.

When the evaporator temperature decreases below 170 ° С, the sublimation of imatinib mesylate decreases and the formation of particles of a new phase passes from the stage of nucleation to the stage of their growth with subsequent crystallization. An X-ray amorphous anhydrous modification of imatinib mesylate cannot be obtained. An increase in the temperature of the evaporator above 215 ° C leads to a partial thermal decomposition of the initial preparation, which leads to contamination of the resulting X-ray amorphous modification with thermal decomposition products of the initial substance.

A decrease in vacuum of less than 5 × 10 ^-3 Torr leads to a decrease in the rate of sublimation and the formation of particles of a new phase passes from the stage of nucleation to the stage of their growth with subsequent crystallization. An X-ray amorphous modification of imatinib mesylate cannot be obtained. An increase in the vacuum in the reactor of more than 3 × 10 ^-5 Torr is impractical due to economic and hardware difficulties.

An increase in the temperature of the condenser above -100 ° C leads to a decrease in the rate of condensation of imatinib mesylate and the formation of particles of a new phase passes from the stage of nucleation to the stage of growth of nuclei with subsequent crystallization. An X-ray amorphous modification of imatinib mesylate cannot be obtained. Reducing the temperature of the condenser below -196 ° C is impractical due to economic and hardware difficulties.

The possibility of carrying out the invention is illustrated by the following examples, but is not limited to.

Example 1. The original substance imatinib mesylate in an amount of 3 g was evaporated at a temperature of 215 ° C in vacuum 3 × 10 ^-5 Torr. Vapors were condensed on a surface cooled to -196 ° С. The obtained preparation according to TLC is imatinib mesylate. The yield was 87 wt.%. According to the XRD data, the obtained substance is characterized by a powerful X-ray amorphous halo inherent in the X-ray amorphous modification of imatinib mesylate (Fig. 3). According to the results of IR spectroscopy, the obtained powder is characterized by IR spectra inherent in the X-ray amorphous anhydrous modification of imatinib mesylate (Fig. 5, spectrogram 2, and Fig. 6, spectrogram 2). The melting point of the obtained substance (T _PL = 135-137 ° C) - coincides with the melting point of the nanodispersed X-ray amorphous modification of imatinib mesylate. The specific surface of the obtained substance is 47.0 m ² / g, and the bulk density of the powder is 0.005 g / cm ³ . The results of determining the amount of water in the obtained sample by the Fisher method showed that it is equal to 0.2 wt.%. The results obtained indicate that the substance is a new X-ray amorphous anhydrous modification of imatinib mesylate.

Example 2. The original substance imatinib mesylate in an amount of 1 g was evaporated at a temperature of 215 ° C in vacuum 6 × 10 ^-4 Torr. Vapors were condensed on a surface cooled to -196 ° С. The obtained preparation according to TLC is imatinib mesylate. The yield was 89 wt.%. According to the XRD data, the obtained substance is characterized by a powerful X-ray amorphous halo inherent in the X-ray amorphous anhydrous modification of imatinib mesylate (Fig. 3). According to the results of IR spectroscopy, the obtained powder is characterized by IR spectra inherent in the X-ray amorphous anhydrous modification of imatinib mesylate (Fig. 5, spectrogram 2, and Fig. 6, spectrogram 2). The melting point of the obtained substance (T _PL = 135-137 ° C) coincides with the melting point of the X-ray amorphous modification of imatinib mesylate. The specific surface area of the obtained substance is 31.2 m ² / g, and the bulk density of the powder is 0.025 g / cm ³ . The results of determining the amount of water in the obtained sample by the Fisher method showed that it is 0.3 wt.%. The results obtained indicate that the substance is a new X-ray amorphous anhydrous modification of imatinib mesylate.

Example 3. The original substance imatinib mesylate in an amount of 1 g was evaporated at a temperature of 170 ° C in a vacuum of 8 × 10 ^-4 Torr. Vapors were condensed on a surface cooled to -196 ° С. The obtained preparation according to TLC is imatinib mesylate. The yield was 83 wt.%. According to the XRD data, the obtained substance is characterized by a powerful X-ray amorphous halo inherent in the X-ray amorphous anhydrous modification of imatinib mesylate (Fig. 3). According to the results of IR spectroscopy, the obtained powder is characterized by IR spectra inherent in the X-ray amorphous anhydrous modification of imatinib mesylate (Fig. 5, spectrogram 2, and Fig. 6, spectrogram 2). The melting point of the obtained substance (T _PL = 135-137 ° C) coincides with the melting point of an X-ray amorphous anhydrous modification of imatinib mesylate. The specific surface of the obtained substance is equal to 39.5 m ² / g, and the bulk density of the powder is equal to 0.045 g / cm ³ . The results of determining the amount of water in the obtained sample by the Fisher method showed that it is equal to 0.35 wt.%. The results obtained indicate that the substance is a new X-ray amorphous anhydrous modification of imatinib mesylate.

Example 4. The initial substance imatinib mesylate in an amount of 0.5 g was evaporated at a temperature of 215 ° C in a vacuum of 5 × 10 ^-3 Torr. Vapors were condensed on a surface cooled to -196 ° С. The obtained preparation according to TLC is imatinib mesylate. The yield was 86 wt.%. According to the XRD data, the obtained substance is characterized by a powerful X-ray amorphous halo inherent in the X-ray amorphous anhydrous modification of imatinib mesylate (Fig. 3). According to the results of IR spectroscopy, the obtained powder is characterized by IR spectra inherent in the X-ray amorphous anhydrous modification of imatinib mesylate (Fig. 5, spectrogram 2, and Fig. 6, spectrogram 2). The melting point of the obtained substance (T _PL = 135-137 ° C) coincides with the melting point of an X-ray amorphous anhydrous modification of imatinib mesylate. The specific surface of the obtained substance is equal to 33.4 m ² / g, and the bulk density of the powder is 0.05 g / cm ³ . The results of determining the amount of water in the obtained sample by the Fisher method showed that it is equal to 0.22 wt.%. The results obtained indicate that the substance is a new X-ray amorphous anhydrous modification of imatinib mesylate.

Example 5. The original substance imatinib mesylate in an amount of 2.5 g was evaporated at a temperature of 170 ° C in a vacuum of 3 × 10 ^-5 Torr. Vapors were condensed on a surface cooled to -100 ° C. The obtained preparation according to TLC is imatinib mesylate. The yield was 82 wt.%. According to the XRD data, the obtained substance is characterized by a powerful X-ray amorphous halo inherent in the X-ray amorphous anhydrous modification of imatinib mesylate (Fig. 3). According to the results of IR spectroscopy, the obtained powder is characterized by IR spectra inherent in the X-ray amorphous anhydrous modification of imatinib mesylate (Fig. 5, spectrogram 2, and Fig. 6, spectrogram 2). The melting point of the obtained substance (T _PL = 135-137 ° C) coincides with the melting point of an X-ray amorphous anhydrous modification of imatinib mesylate. The specific surface area of the obtained substance is 27.2 m ² / g, and the bulk density of the powder is 0.054 g / cm ³ . The results of determining the amount of water in the obtained sample by the Fisher method showed that it is equal to 0.4 wt.%. The results obtained indicate that the substance is a new X-ray amorphous anhydrous modification of imatinib mesylate.

Example 6. The original substance imatinib mesylate in an amount of 0.3 g was evaporated at a temperature of 170 ° C in a vacuum of 5 × 10 ^-3 Torr. Vapors were condensed on a surface cooled to -100 ° C. The obtained preparation according to TLC is imatinib mesylate. The yield was 72 wt.%. According to the XRD data, the obtained substance is characterized by a powerful X-ray amorphous halo inherent in the X-ray amorphous anhydrous modification of imatinib mesylate (Fig. 3). According to the results of IR spectroscopy, the obtained powder is characterized by IR spectra inherent in the X-ray amorphous anhydrous modification of imatinib mesylate (Fig. 5, spectrogram 2, and Fig. 6, spectrogram 2). The melting point of the obtained substance (T _PL = 135-137 ° C) coincides with the melting point of an X-ray amorphous anhydrous modification of imatinib mesylate. The specific surface of the obtained substance is equal to 25.0 m ² / g, and the bulk density of the powder is equal to 0.055 g / cm ³ . The results of determining the amount of water in the obtained sample by the Fisher method showed that it is equal to 0.35 wt.%. The results obtained indicate that the substance is a new X-ray amorphous anhydrous modification of imatinib mesylate.

Example 7. The original substance imatinib mesylate in an amount of 1 g was evaporated at a temperature of 215 ° C in a vacuum of 8 × 10 ^-5 Torr. Vapors were condensed on a surface cooled to -180 ° С. The obtained preparation according to TLC is imatinib mesylate. The yield was 86 wt.%. According to the XRD data, the obtained substance is characterized by a powerful X-ray amorphous halo inherent in the X-ray amorphous anhydrous modification of imatinib mesylate (Fig. 3). According to the results of IR spectroscopy, the obtained powder is characterized by IR spectra inherent in the X-ray amorphous anhydrous modification of imatinib mesylate (Fig. 5, spectrogram, 2 and Fig. 6, spectrogram 2). The melting point of the obtained substance (T _PL = 135-137 ° C) coincides with the melting point of an X-ray amorphous anhydrous modification of imatinib mesylate. The specific surface area of the obtained substance is 42.4 m ² / g, and the bulk density of the powder is 0.029 g / cm ³ . The results of determining the amount of water in the obtained sample by the Fisher method showed that it is equal to 0.4 wt.%. The results obtained indicate that the substance is a new X-ray amorphous anhydrous modification of imatinib mesylate.

The activity of the obtained X-ray amorphous anhydrous modification of imatinib mesylate was determined by determining the time of dissolution in water and the kinetics of dissolution in hexane saturated with methanol. The experiments were carried out in comparison with the original substance imatinib mesylate. This kind of experiment is very important for further prediction of the behavior of the drug in the biological environment and its assimilation in the body.

The dissolution kinetics of imatinib mesylate was studied using a standardized dissolution test, which is an apparatus with a capacity of 25 ml for dissolution, with automatic sampling and registration of the concentration of the compound that passes into the solution using an HP 8452A spectrophotometer at a wavelength of 300 nm. The scan time was 1 s, the sampling interval was 1 min. The error in setting the wavelength was 1 nm with a spectral bandwidth of 2 nm. Photometric accuracy was less than 0.005 units. absorption with a gentle baseline of 0.002 units. absorption. The noise level was less than 0.001 units. absorption.

The concentration of the studied compounds passing through the membrane at maximum release was 0.8 mg / L, the registration time was 15 minutes.

The experimental technique was as follows. 20 ml of methane saturated with methanol was poured into the device’s capacity, a magnetic stirrer was turned on at 50 rpm, 120 mg of imatinib mesylate, the initial substance or an X-ray amorphous anhydrous modification obtained from it, were placed there and the dissolution kinetics was determined. The results are presented in Fig.7. It can be seen that the new X-ray amorphous anhydrous modification dissolves in the hexane-methanol system 2 times faster than the original substance.

The determination of the time of dissolution of imatinib mesylate in water was carried out according to the following procedure. A 100 mg sample of the preparation was placed with stirring with a magnetic stirrer at 50 rpm in 5 ml of distilled water, and the dissolution time was determined with a stopwatch. It turned out that for the initial substance imatinib mesylate, the dissolution time in water was 25-30 s, and for an X-ray amorphous anhydrous modification it was 2-3 s.

The experiments on determining the time of dissolution in water and the kinetics of dissolution in hexane saturated with methanol showed that the new X-ray amorphous anhydrous modification of imatinib mesylate is more active compared to the original substance, which should affect the reduction of its absorption into the body, increase its biological activity.

Thus, we synthesized a new X-ray amorphous anhydrous modification of 4 - [(4-methyl-1-piperazinyl) methyl] -N- [4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] phenyl ] benzamide methanesulfonate, which has increased activity to dissolution processes compared with the original substance, and a method for its preparation. The obtained modification is characterized by diffraction patterns different from other ones, IR spectra in the regions of 110-1400 cm ^-1 and 5800-7000 cm ^-1 , melting point (T _PL = 135-137 ° С), specific surface (25-47 m ² / g ) and bulk density (0.005-0.055 g / cm ³ ).

From the foregoing, we can conclude that the claimed x-ray amorphous anhydrous modification of 4 - [(4-methyl-1-piperazinyl) methyl] -N- [4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl ] amino] phenyl] benzamide methanesulfonate is new and has improved biological properties compared with known analogues.

Claims (2)

1. X-ray amorphous modification of 4 - [(4-methyl-1-piperazinyl) methyl] -N- [4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] phenyl] benzamide methanesulfonate , characterized in that it does not contain crystalline hydrate water and has an X-ray amorphous halo in the diffractogram (Fig. 3) and an IR spectrum such as that shown in Fig. 5, spectrogram 2. 2. A method for producing an X-ray amorphous anhydrous modification of 4 - [(4-methyl-1-piperazinyl) methyl] -N- [4-methyl-3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] phenyl ] benzamide methanesulfonate, which consists in the fact that the initial substance imatinib mesylate is evaporated at a temperature of 170-215 ° C in a vacuum of 5 · 10 ^-3 -3 · 10 · ⁵ Torr and condense on chilled to (-) 100 - (-) 196 ° From the surface.

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