CN104817536A - Non-acicular α crystal form of imatinib mesylate suitable for pharmaceutical use and preparation method thereof - Google Patents

Abstract

The present invention relates to 4- [ (4-methyl-1-piperazine) methyl group represented by the formula (1)]-N- [ 4-methyl-3- [ [4- (3-pyridine) -2-pyrimidine]Amino group]Phenyl radical]-aniline methanesulfonate, i.e. imatinib mesylate in the form of a non-acicular alpha crystal, and a process for its preparation. The non-acicular alpha crystal form has good stability and fluidity, is suitable for industrial production, and is very suitable for application of pharmaceutical preparations.

Description

Non-acicular α crystal form of imatinib mesylate suitable for pharmaceutical use and preparation method thereof

technical field

The present invention relates to the field of chemical synthesis, in particular to 4-[(4-methyl-1-piperazine) methyl]-N-[4-methyl-3-[[4-(3-pyridine)-2-pyrimidine ]Amino]phenyl]-aniline mesylate, i.e. imatinib mesylate non-needle α crystal form and a preparation method thereof.

Background technique

Imatinib mesylate (trade name Gleevec) is the world's first tinib-based targeted anti-tumor drug developed and produced by Swiss Novartis. The US FDA approved this drug for marketing in 2001.

According to current patent reports, imatinib mesylate has a variety of crystal forms, known as α crystal form, β crystal form, H1 crystal form, α2 crystal form, I crystal form, II crystal form, δ crystal form, ε Crystal form, F crystal form, G crystal form, H crystal form, I crystal form and K crystal form, etc. U.S. Patent US6894051 discloses two crystal forms of imatinib mesylate: needle-like α crystal form and non-acicular β-crystal form. The patent mentions that the obtained α-crystal form is needle-like, has hygroscopicity and poor fluidity, Not suitable for solid drug development. In addition, the preparation method disclosed in this patent is obtained by recrystallization in aqueous ethanol solution and cooling; the preparation method has poor stability and is unfavorable for industrial production.

Studies have found that there is also a non-needle crystal form in the α crystal form. WO2006048890 mentions that a non-needle α crystal form with a crystal aspect ratio of 1:1 or 1:2 has the advantages of no hygroscopicity and good stability, but does not improve the disadvantage of poor fluidity. It is generally believed that the fluidity parameter of a crystal form is a key reference factor for whether the crystal form is suitable for use in pharmaceutical preparations, and a crystal form with poor fluidity will lead to insufficient mixing of raw and auxiliary materials during the preparation process, or make the preparation process more difficult.

Therefore, it is necessary to develop a non-acicular α crystal form with good stability and good fluidity and a preparation method thereof.

Contents of the invention

The purpose of the present invention is to solve the above-mentioned technical problems, and provide a non-needle α-crystal form with good stability and certain fluidity, which is suitable for the application of pharmaceutical preparations and a preparation method thereof.

The object of the present invention is to provide a non-acicular α crystal form of imatinib mesylate, the external shape of the crystal form is spherical.

Preferably, the particle size d(0.9) of the crystal form is ≥ 50 μm.

Preferably, the particle size of the crystal form d(0.5)=15-50 μm.

Preferably, the particle size of the crystal form d(0.1)≤10 μm.

Preferably, the bulk density of the crystal form is not less than 0.2 g/cm ³ .

Preferably, the angle of repose of the crystal form is less than 30°.

Another object of the present invention is to provide a method for preparing the non-acicular α crystal form, comprising the following steps:

Forming imatinib and methanesulfonic acid into a salt in an alcohol-halogenated hydrocarbon-water three-phase system, then stirring and crystallizing in a solvent, separating and drying to obtain the non-acicular α crystal form of imatinib mesylate.

Preferably, the alcohol is selected from methanol, ethanol and/or isopropanol, more preferably isopropanol.

Preferably, the halogenated hydrocarbon is selected from dichloromethane and/or chloroform, more preferably chloroform.

Preferably, in the three-phase system, the volume ratio of alcohol-halogenated hydrocarbon-water is 10:1-2:1.

The stirring method includes mechanical stirring and ultrasonic vibration.

A particularly preferred method is to add imatinib to a mixed solution of isopropanol and chloroform, add methanesulfonic acid and water to form a salt, wherein the volume ratio of isopropanol, chloroform and water is 10:1:1; Ultrasonic vibration crystallization, after the crystallization is complete, filter and blow dry to obtain the imatinib mesylate non-needle α crystal form of the present invention.

The invention has the advantages that the non-needle α crystal form suitable for pharmaceutical use is rapidly and efficiently prepared through the three-phase crystallization system, and the obtained product has high yield and good purity. The non-needle α crystal form prepared by the process of the invention has better stability and good fluidity, is suitable for industrial production, and is very suitable for the application of pharmaceutical preparations.

Description of drawings

Fig. 1 is a photomicrograph of the non-needle α crystal form of imatinib mesylate, the compound of formula 1.

Fig. 2 is a partially enlarged micrograph of the non-needle α crystal form of imatinib mesylate, the compound of formula 1.

Fig. 3 is an X-ray diffraction diagram of the non-acicular α crystal form of imatinib mesylate, the compound of formula 1.

detailed description

The content of the present invention will be specifically described below in conjunction with the drawings and embodiments, but the protection content of the present invention is not limited to the specific embodiments.

Example 1

Add 18.7g of imatinib to 400ml of isopropanol and 40ml of chloroform, stir mechanically for 5-10min, and heat to 60-70°C; add 3.6g of methanesulfonic acid and 40ml of water, and continue mechanically stirring for 2-3h after adding, And cooled to 25~30°C, filtered, and the obtained solid was air-dried at 70~80°C for 6~7 hours to obtain 20.2 g of white solid, yield: 90.4%, purity: 99.6%. The appearance inspection combined with the XRPD pattern determined that the obtained crystal form was imatinib mesylate non-needle α crystal form, its microscopic picture is shown in Figure 1, and its XRPD pattern is shown in Figure 2.

Example 2

Add 7.2g of imatinib to 160ml of isopropanol and 32ml of chloroform, stir mechanically for 5-10min, and heat to 60-70°C; add 1.4g of methanesulfonic acid and 16ml of water, continue mechanically stirring for 2-3h after adding, And cooled to 25~30°C, filtered, and the obtained solid was air-dried at 70~80°C for 6~7 hours to obtain 7.94 g of white solid, yield: 92.3%. It can be confirmed through appearance inspection combined with XRPD spectrum that the obtained product is non-needle α crystal form, and the obtained crystal form is spherical form as shown by microscopic photos.

Example 3

Add 9.8 g of imatinib base to 140 mL of ethanol and 14 mL of chloroform, stir mechanically for 5-10 min, heat to 60-70 °C, add 1.9 g of methanesulfonic acid and 14 mL of water, continue mechanically stirring for 2-3 h after adding, Cool to 25~30°C, filter, and air-dry the obtained solid at 70~80°C for 6~7 hours to obtain 10.3 g of imatinib mesylate salt, yield: 88.2%, which can be confirmed by appearance inspection and XRPD pattern , the obtained product is non-needle α crystal form, and the obtained crystal form is spherical form as shown by microscopic photos.

Example 4

Add 18.7g of imatinib to 400ml of isopropanol and 40ml of chloroform, ultrasonically oscillate for 5-10min, and heat to 60-70°C; add 3.6g of methanesulfonic acid and 40ml of water, and react for 2-3h after adding ultrasonic shock, and Cool to 25-30°C, filter, and air-dry the obtained solid at 70-80°C for 6-7 hours to obtain 22.3 g of white solid, yield: 94.9%, purity: 99.7%. It can be confirmed through appearance inspection combined with XRPD patterns that the obtained product is in the non-needle α crystal form, and the obtained crystal form is spherical in microscopic photographs.

The particle size, bulk density, and angle of repose detection data of the non-needle α crystal form obtained in Examples 1-4

Experimental example 1 Stability experiment

Instrument model: D/Max-RA Japan Rigaku X-ray powder diffractometer

Rays: monochromatic Cu-Ka rays (l=1.5418 Å)

Scanning mode: q/2q, scanning range: 3-45 ^o

Temperature range: 294K Voltage: 40KV

The comparison of X-ray diffraction data is shown in Table 2.

The crystal form obtained in Example 1 of the present invention was subjected to an accelerated stability experiment at a temperature of 40°C±2°C and a relative humidity of 75%±5%, and the obtained results were as follows:

Table 2 Comparison table of X-ray diffraction data of accelerated stability test samples

Experimental conclusion: after 9 months of accelerated experimentation, the X-ray diffraction spectrum is consistent with the initial data, and no crystal transformation occurs, indicating that the crystal form provided by the present invention has good stability.

Experimental example 2 Stability experiment

table 3

Experimental conclusion: the non-acicular α crystal form provided by the present invention has good stability.

Claims (12)

1. Non-acicular α crystal form of the compound of formula (1) . 2. The non-acicular α crystal form of the compound of formula (1) according to claim 1, wherein the external shape of the crystal form is spherical. 3. The non-acicular α crystal form of the compound of formula (1) according to claim 2, characterized in that the particle size of the crystal form d(0.9)≥50 μm. 4. The non-acicular α crystal form of the compound of formula (1) according to claim 3, characterized in that, the particle size of the crystal form is d(0.5)=15-50 μm. 5. The non-acicular α crystal form of the compound of formula (1) according to claims 3 and 4, characterized in that the particle size of the crystal form d(0.1)≤10 μm. 6. The non-acicular α crystal form of the compound of formula (1) according to claim 1, wherein the bulk density of the crystal form is not less than 0.2 g/cm ³ . 7. The non-acicular α crystal form of the compound of formula (1) according to claim 1, wherein the angle of repose of the crystal form is less than 30°. 8. The method for preparing the non-needle α crystal form of the compound of formula (1) according to any one of claims 1 to 6, said method is to crystallize with an alcohol-halogenated hydrocarbon-water three-phase system, comprising the following steps: a, salting imatinib and methanesulfonic acid; b. Stir and crystallize in a solvent; c, separated and dried. 9. The preparation method according to claim 7, wherein the alcohol is selected from methanol, ethanol and/or isopropanol, preferably isopropanol. 10. The preparation method according to claim 7, characterized in that, the halogenated hydrocarbon is selected from dichloromethane and/or chloroform, preferably chloroform. 11. The preparation method according to claim 7, wherein the stirring comprises mechanical stirring and ultrasonic vibration. 12. The preparation method according to claim 7, characterized in that the volume ratio of alcohol-halogenated hydrocarbon-water is 10:1~2:1.