SK562010A3 - Alpha crystalline form of Imatinib mesylate with new habit and method for its preparation and use - Google Patents

Abstract

It is described an alpha crystalline form of imatinib mesylate with a new habit, a method for its preparation and its use in therapy.

Description

Field of the invention

Imatinib mesylate, 4- (4-methylpiperazin-1-ylmethyl) -N- [4-methyl-3 - [(4-pyridin-3-yl) pyrimidin-2-ylamino] phenyl] benzamide mesylate, formula (I), belongs to the class of protein tyrosine kinase inhibitors. These enzymes are found in some receptors on the surface of cancer cells, including receptors involved in stimulating cells for uncontrolled division. Imatinib mesylate is used as an active ingredient in the cytostatic Glivec for the treatment of e.g. chronic myelocytic leukemia (CML), gastrointestinal tumors (GIST).

BACKGROUND OF THE INVENTION

Imatinib mesylate is disclosed in EP 0564 409.

US 6894051 discloses that the polymorphic modification of α-form Imatinib mesylate exists in needle habit. It is documented that the needle crystal of the polymorphic α-form of Imatinib mesylate is hygroscopic, unstable and unsuitable for pharmaceutical operations e.g. grinding, tabletting.

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A number of patent WO 2005/095379, US 6894051, W02010 / 014022 provides a dot-matrix for the preparation of α-form of Imatinib mesylate and the use of alcohol or C _4.

WO2007 / 136510 protects the use of other polymorphic modifications and solvents selected from the group of npropanol, water, acetic acid, 1,2-propylene carbonate, ethylene glycol dimethyl ether, tert-butyl methyl ether for the preparation of the α-form Imatinib mesylate.

In US 2006/0223816, ketones, cycloalkanes and acetonitrile or mixtures thereof are applied for the preparation.

WO1999 / 03854 protects the crystalline α- and β-form of Imatinib mesylate. The process for preparing the crystalline α-form comprises suspending Imatinib base in ethanol and gradually adding methanesulfonic acid at elevated temperature, filtering, then concentrating the filtrate to half volume and re-filtering. Subsequently, the filtrate is concentrated to dryness, suspended in ethanol and dissolved by addition of water. After cooling, filtration and drying, the crystalline needle form is obtained. This is again hygroscopic and unstable.

WO2006 / 024863 protects the stable needle crystalline α-form of Imatinib mesylate, while it is emphasized that this form is not identical to the unstable needle crystal α-form of Imatinib mesylate according to WO 1999/03854. The process for preparing a stable needle crystalline α-form comprises suspending or dissolving Imatinib base in a solvent, adding methanesulfonic acid sequentially, heating the mixture, inducing the α-form, cooling and filtering the α-form over time. C2-C4 alcohols and ketones are used as solvents. The authors protect the process without the use of water, obtaining an anhydrous form, obtaining a substance with a water content of <2%.

WO 2006/048890 protects Imatinib mesylate in crystalline α-form in a shape characterized as "non-needle" and non-hygroscopic, and a method of drying α-form solutions on a film evaporator under reduced pressure. By repeating the process according to the invention of WO 2006/048890, we have found that the process is non-reproducible, the product obtained is inconsistent, consisting of the α-form of Imatinib mesylate in a needle

3/20 and a non-needle crystal form. It was also observed that the purity of the product was reduced under the stated operating conditions.

US 2002/0114844 and 2006/0078573 disclose modification of the habit of griseofulvin crystals using antisolvents in precipitation. The modification of the habit of phenytoin crystals using various solvents is described in Int. J. Pharm. 250, 85-97, 2003. The impact of habit change on some physicochemical properties of Ibuprofen is discussed by Drug Dev. Ind. Pharm. 27, 803-809 (2001).

It is clear that there is no technologically reproducible procedure for the preparation of Imatinib mesylate resulting in a stable α-form. The present invention solves the problems of preparing the stable α-form of Imatinib mesylate with reference to previous publications in that the crystalline α-form of Imatinib mesylate is obtained with a novel habit and is disclosed in claim 1.

SUMMARY OF THE INVENTION

The invention solves the above problems by preparing a novel habit of the crystalline α-form Imatinib mesylate, wherein:

The first object of the present invention is the crystalline α-form of Imatinib mesylate with a novel habit, which is substantially more stable than the prior art crystalline α-form of Imatinib mesylate described in the patents mentioned in the "Prior Art" section.

A second object of the present invention is a process for the preparation of the crystalline α-form of Imatinib mesylate with a novel habit, which has a significantly lower hygroscopic character.

It is a further object of the invention to provide a crystalline α-form of Imatinib mesylate with a novel habit, suitable for use in a solid release formulation, in particular for use in the form of tablets.

The discovery of the crystalline α-form of Imatinib mesylate with a new habit as a pharmaceutically useful form provides new opportunities to improve properties and effects

4/20 pharmaceutical products. This expands the range of forms whose formulations are available for formulation design.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to the crystalline α-form of Imatinib mesylate with a novel habit and to a process for its preparation. These forms have a lower hygroscopicity compared to the known acicular form.

The present inventors have found that in particular the novel habits of the crystalline α-form of Imatinib mesylate in this invention provide considerable advantages. They exhibit low hygroscopicity and good processability for pharmaceutical formulations into solid dosage forms, especially in the form of capsules or tablets.

The process according to the invention is characterized by:

a) suspending or dissolving the compound of formula I in a solvent and heating at a defined temperature

b) adding a co-solvent and heating at a defined temperature to form a solution

c) cooling the mixture and isolating the crystalline α-form of Imatinib mesylate with a new habitat and occasionally

d) micronizing the crystals to the desired size

According to the present invention, solvents selected from the group of butyl acetate, butyl lactate, ethyl lactate, alcohols C4 to C6, preferably 3-methyl-1-butanol or 2-, are used to prepare crystalline α-form of Imatinib mesylate by dream habit in step (a). methyl 2-butanol and water. In step (a), a temperature of 40 to 160 ° C, preferably the boiling point of the solvent, is used.

The co-solvents used in step (b) are solvents selected from: ketones such as acetone, methyl ethyl ketone, isobutyl methyl ketone; ethers such as propyl ether, dibutyl ether, dimethoxy ethane, 2-isopropoxyethanol, butyloxyethanol. Obviously, a large amount of co-solvent may lead to the excretion of the substance in oily form. It is therefore preferable to add the co-solvent with stirring. Conversely, in some cases, a large amount of co-solvent may lead to a dilute solution from which the product

5/20 long time respectively. up to partial concentration. In step (b), a temperature of 40 to 140 ° C, preferably the boiling point of the reaction mixture, is used. In step (c), the crystallization mixture is cooled to a temperature of 0 ° C to 40 ° C, preferably to a temperature of 0 ° C to 5 ° C. The cooling rate is chosen so that the formation of nuclei is high and at the same time crystals of appropriate size are formed. If the cooling rate is high, the crystals are small and difficult to filter and wash. The cooling rate is selected in the range 0.05 to 2K / min. For practical reasons, a cooling rate of 0.2 to 1K / min is preferably selected.

The isolation in step (c) is carried out by filtration, preferably under reduced pressure, or by centrifugation. The filter cake may be washed with an inert solvent under isolation conditions such as C 1 -C 4 alcohols or ketones such as acetone.

In XRPD diffractograms of the products obtained by the process of the invention, sharp diffraction peaks unambiguously indicate the crystalline polymorphic form α. For comparison, FIG. no. 3 shows the corresponding corresponding acicular form. No significant differences are observed between the diffractogram of the acicular form and the α-form diffraction pattern with the new flat and flat form respectively. isometric habit, respectively. in the corresponding d-values.

The intensity of some diffraction peaks varies slightly, which is probably due to crystal failure, crystal size, or preferential crystal orientation. Sharp, interrelated diffraction patterns are present in all diffractograms, which clearly excludes the presence of a polymorphic modification other than the α-form of Imatinib mesylate.

Alternatively, the crystalline α-form of Imatinib mesylate with a new habit can be prepared by reacting Imatinib base and adding methanesulfonic acid in step (b) in an organic co-solvent under the above conditions.

Another advantage of the crystalline α-form of Imatinib mesylate with the novel habit of the present invention is, in particular, the uniformity of the product, as a result of which their mechanical processing properties (filtration, drying, grinding, etc.) are improved. The filtration performance of the products of the crystalline α-form Imatinib mesylate was compared with the novel habit obtained by the process of the invention and the needle form. The products obtained from the following solvents (preferred order) were found to have the most advantageous properties in this regard: 2-methyl-2-butanol-isopropyloxyethanol-butyl lactate-propyl ether> ethyl lactate-butyl acetate> butyl lactate-isobutyl methyl ketone > water 6/20 acetone, whereby, as expected, the rate of cooling during crystallization substantially affects the crystal size.

For verification, the behavior of the crystalline α-form of Imatinib mesylate with the new habitat (II), respectively. (III), and the crystalline α-form of Imatinib mesylate with acicular habitus (I) monitored when exposed to a defined humidity. These crystalline forms were left in the stability chamber to the point where equilibrium was reached. The water content was measured for each form by the Karl Fischer method (% water content was calculated on a dried basis).

The crystalline α-form of Imatinib mesylate with a new habit (flat or isometric) was found to be less hygroscopic than its known acicular form at 85% r.h at 23 ° C with a weight gain of <0.5%.

The lower hygroscopicity of the crystalline α-form of Imatinib mesylate with the new habit is an advantage for its processing and storage in crystalline form. Such a crystalline form of Imatinib mesylate also has good mechanical properties.

In a further aspect of the invention there are provided compositions comprising the crystalline α-form of Imatinib mesylate with a novel habit. The method of preparation according to the invention depends on the skill of the person skilled in the art. The crystalline salts of the present invention may advantageously be formulated into pharmaceutical compositions.

In this case, the main active ingredient is used in combination with some of the elements such as binders, fillers, diluents, disintegrants, lubricants and coatings as desired. Solid oral dosage forms, such as hard gelatin capsules and tablets, are preferred. In the compositions of the present invention, the amount of salt ranges from 5% to 85%, most preferably 5% to 35% by weight.

Diluents that may be included in the present invention are preferably selected from the group of natural or artificial carbohydrates such as lactose, sucrose, glucose, starches, sorbitol and microcrystalline cellulose. Similarly, preferred binders are starches, sugars, cellulose and derivatives thereof, gelatin and polyvinylpyrrolidone. Starch and microcrystalline cellulose are preferred in use as good disintegrants. Particularly preferred is Avicel (TM), a type of commercial microcrystalline cellulose.

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Lubricants used for solid dosage forms are selected from the group consisting of talc, silica, magnesium stearate, glidant, aerosol, stearic acid and stearin. Magnesium stearate is particularly preferred.

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Brief description of the pictures

Figure 1 shows the Fourier transform infrared spectra of the FTIR crystalline α-form of Imatinib mesylate measured on a Nicolet Spectrometer, Impact 410. ATR measurement technique, Omnic version 5.2 program was used for measurement.

Fig. 2 shows photographs from a scanning electron microscope (SEMScanning Elecron Microscope). SEM crystal records were measured on a JEOL 840-A SEM, using Thompson Scientific WINEDS and DIPs Software under the conditions: Accelerating voltage 15kV, probe current 1.10 ' ^1θ Α. All samples were covered with a thin layer of gold.

Figure 3 represents an illustrative diffractogram (XRPD-X-ray powder diffraction) for the crystalline α-forms of Imatinib mesylate. The measurement was performed on a STOE powder diffractometer, type Θ / 2Θ diffractometer with cobalt lamp, voltage 40 kV / 20 mA.

Figure 4 shows Differential Compensation Calorimetry (DSC) records for crystalline α-forms of Imatinib mesylate. DSC measurements were performed using a Perkin-Elmer DSC-7 instrument (Perkin-Elmer, USA) with Pyris software. The temperature scale was calibrated using In, Sn and Zn. The enthalpy scale was calibrated for the enthalpy of melting In. The 3-4 mg samples were placed in a standard molded aluminum dish using nitrogen as the purge gas. Endothermic peaks are upward on the recordings. Records are corrected to baseline. The heating rate was 10 C / min, in the temperature range 100-250 C.

In the following examples, a process for preparing the crystalline α-form of Imatinib mesylate with a novel habit according to the present invention is described. The examples serve only others

8/20 illustrating the present invention without limiting its scope to the described examples.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

Preparation of crystalline α-form of Imatinib mesylate with needle habit according to WO 2005/95379, Example 16.

A mixture of 0.3g Imatinib base and 2.37ml ethanol is heated to 75 ° C and 39.065µl methanesulfonic acid is added. Subsequently, 10.8 ml of isopropanol are gradually added. The reaction mixture was cooled, stirred for 4 hours, and allowed to stand overnight. Filter through a frit S2, wash with ethyl acetate (1.32ml). 0.35 g of crystalline α-form Imatinib mesylate with needle habit was obtained (SEM in Figure 2a, XRPD in Figure 3). Melting point: 225-227 ° C, DSC-223.2 ° C (onset). Drying loss determined by thermogravimetry (TG) <0.2%.

Example 2

Preparation of crystalline α-form of Imatinib mesylate

A mixture of 53 mg of the product of Example 1 and 1.2 ml of butyl lactate is heated to boiling and filtered through a 0.22 µm filter. 3.1 ml of n-propyl ether as cosolvent are added to the solution at 90 ° C with vigorous stirring. The mixture was then cooled in a thermostat to 5 ° C at a rate of 1.5K / min. The precipitated crystals were filtered off and washed on a filter with 2 x 0.5 ml acetone. 47 mg of crystalline α-form Imatinib mesylate with flat habitat was obtained (SEM in Figure 2, XRPD in Figure 3). Melting point: 224-226 ° C. Drying loss determined by thermogravimetry (TG) <0.1%.

Example 3

Preparation of crystalline and form of Imatinib mesylate

Analogously to Example 2 except that 2-methyl-2-butanol and 2-isopropoxyethanol are used as co-solvent. 49mg of the crystalline α-form of Imatinib mesylate with isometric habitat was obtained (SEM in Figure 2, XRPD in Figure 3). Melting point: 225-226 ° C, DSC-225 ° C (onset). Drying loss determined by thermogravimetry (TG) <0.2%.

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Example 4

Preparation of Pharmaceutical Formulation Imatinib mesylate Form of Example 3 Silica

Crosspovidone

Klucel

Magnesium stearate

Avicel

86mg lmg

16mg

9mg

2mg

86mg

All components were weighed together, mixed and tabletted, XRPD analysis confirmed the α-form.

Example 5

Preparation of crystalline α-form of Imatinib mesylate

A mixture of 0.6 g of the product of Example 1 and 1 ml of distilled water is heated to boiling and filtered through a 0.22 µm filter. The solution was gradually added to 15 mL of acetone at 55 ° C with vigorous stirring. The mixture is then cooled in a thermostat to 5 ° C at a rate of 0.5K / min. The precipitated crystals are filtered off and washed on a 2x0.5 ml acetone filter. 0.5g of the crystalline α-form of Imatinib mesylate with isometric habitat was obtained (SEM in Figure 2, XRPD in Figure 3). Melting point: 225-227 ° C, DSC223.1 ° C (onset). Drying loss determined by thermogravimetry (TG) <0.35%.

Example 6

Preparation of crystalline α-form of Imatinib mesylate

A mixture of 0.3g Imatinib base and 1.8ml ethyl lactate is heated to 105 ° C and 39.065µl methanesulfonic acid is added. Subsequently, 12.4 ml of 4-methyl-2-pentanone are gradually added and the mixture is stirred for a further 30 minutes at this temperature. The reaction mixture was cooled, stirred for 4 hours without heating and allowed to stand overnight. Filter through sintered S-2, washing with acetone (2 x 0.7ml). 0.3 µg of crystalline α-form Imatinib mesylate with flat habitat was obtained. Melting point: 225-227 ° C. Drying loss determined by thermogravimetry (TG) <0.1%.

Example 7

Preparation of crystalline and form of Imatinib mesylate

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Analogously to Example 2 except that butyl acetate and 2-butyloxyethanol are used as co-solvent. Melting point: 225-226 ° C, DSC-225 ° C (onset). Drying loss determined by thermogravimetry (TG) <0.15%.

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IR spectrum in the region of 10000-100 cm ^-1 Figure 1

FT IR spectrum: crystalline α-form Imatinib mesylate needle habit (upper line), Imatinib mesylate crystallized from ethyl lactate and propyl ether, Imatinib mesylate crystallized from water and acetone, Imatinib mesylate crystallized from butyl lactate and propyl ether, Imatinib mesylate crystallized -methyl-2-butanol and 2-isopropoxyethanol (lower line).

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Figure 2

b)

SEM records: crystalline α-form Imatinib mesylate needle habit (a), Imatinib mesylate crystallized from ethyl lactate and propyl ether (b)

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(D)

SEM records (continued): Imatinib mesylate crystallized from 2-methyl-2-butanol and 2-isopropoxyethanol by slow cooling of mixture (c), Imatinib mesylate crystallized from butyl lactate and propyl ether by rapid cooling of mixture (d),

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IN? 5 <ο-ιό1ο

(D

SEM records (continued): Imatinib mesylate crystallized from ethyl lactate and propyl ether (e), Imatinib mesylate crystallized from water and acetone (d).

15/20 pp 5 <° - Zo Ίο

(G)

SEM records (continued): Imatinib mesylate crystallized from 3-methyl-2-butanol and propyl ether (g)

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Picture no. 3

Powder XRPD diffraction

Theta

XRPD: crystalline α-form of Imatinib mesylate with needle habit (upper line), Imatinib mesylate crystallized from ethyl lactate and propyl ether, Imatinib mesylate crystallized from water and acetone, Imatinib mesylate crystallized from butyl lactate and propyl ether 2, Imatinib -2-butanol and 2-isopropoxyethanol (lower line).

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PP TC-Zofp

Figure 4 DSC records

Normalized Heat FlowEndo Up (W / g)

DSC line / solvent-solvent: MP: (Kofler block) [° C] MP: (DSC, onset) 0 ° C] AH (melting) [J / g] 2503/1 Example 1, needle habit, α-form 224-226 223.2 205.0 2303/9 ethyl lactate-propyl ether 223-226 223.7 202.0 2503/3 butyl lactate-propyl ether 224-226 221.5 196.0 2403/2 water-2-methyl-2-butanol 227-229 223.7 205.8 0804/1 water-acetone 226-227 223.1 203.2

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Claims (5)

PATENT CLAIMS Crystalline Imatinib mesylate in a non-needle shape α-form. 2. Crystalline non-needle α-form Imatinib mesylate characterized by selected X-ray powder diffraction data with d: 3.1335, 3.5842, 4.1333, 4.1873, 4.6644, and 4.7765 values; melting point 221-228 ° C (DSC, onset) and habitus characterized by scanning electron microscope images as in Figures 2b to 2g. 3. A process for preparing crystalline Imatinib mesylate non-carbon-α-form according to claim 1, wherein the crystallization is carried out in a mixture of an organic solvent and a co-solvent or a mixture of water and an organic solvent. A process for the preparation of the crystalline Imatinib mesylate in the non-needle form of the α-form according to claim 3, wherein the organic solvent is butyl acetate, butyl lactate, ethyl lactate, linear or branched alcohols C4 to C6, and as cosolvent are linear or branched C2 ethers to C4 or ketones C3 to C5. Use of crystalline Imatinib mesylate in a non-needle shape α-form for the manufacture of a medicament for the treatment of gastrointestinal stromal tumor and myelocyte leukemia.