CN105622614B

CN105622614B - Ibrutinib amorphous substance and preparation method thereof

Info

Publication number: CN105622614B
Application number: CN201510952168.7A
Authority: CN
Inventors: 罗斌; 左小勇; 雷皇书; 肖进迈
Original assignee: Chongqing Pharmaceutical Research Institute Co Ltd
Current assignee: Chongqing Pharmaceutical Research Institute Co Ltd
Priority date: 2015-12-18
Filing date: 2015-12-18
Publication date: 2021-02-26
Anticipated expiration: 2035-12-18
Also published as: CN105622614A

Abstract

The invention discloses a method for preparing an amorphous ibrutinib substance, which comprises the following steps: 1) adding ibrutinib into a benign organic solvent, and heating to completely dissolve the ibrutinib; 2) adding the solution into an anti-solvent, and stirring and solidifying, wherein the temperature of an anti-solvent system is maintained below 5 ℃ in the adding process; 3) filtering, and drying the solid under reduced pressure to obtain an ibrutinib amorphous substance. The amorphous substance obtained by the method is stable and suitable for preparation.

Description

Ibrutinib amorphous substance and preparation method thereof

Technical Field

The invention belongs to the field of medicines, and particularly relates to an amorphous ibrutinib substance and a preparation method thereof.

Background

Ibrutinib (Ibrutinib) is chemically 1- [ (3R) -3- [ 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-D ] pyrimidin-1-yl ] -1-piperidyl ] -2-propen-1-one, and the structural formula is shown as follows.

Ibrutinib is a Bruton's Tyrosine Kinase (BTK) inhibitor for the treatment of Chronic Lymphocytic Leukemia (CLL) and Mantle Cell Lymphoma (MCL). Both MCL and CLL belong to B cell non-Hodgkin lymphoma, and have the characteristics of difficult cure and easy recurrence, and the commonly used chemoimmunotherapy has no targeting property and often causes grade 3 or 4 adverse reactions. Ibrutinib irreversibly inhibits BTK by selectively and covalently binding with cysteine residue (Cys-481) of the active site of BTK of a target protein, thereby effectively preventing tumor migration from B cells to lymphoid tissues adapted to the growth environment of the tumor and becoming a new choice for treating CLL and MCL.

Preparation methods and therapeutic uses of ibrutinib have been disclosed in PCT application patents WO2008039218 and WO2013003629, respectively. PCT application WO2013184572 discloses various crystalline forms such as A, B, C, D and amorphous forms, which are prepared by dissolving an ibrutinib compound with dichloromethane and then removing the solvent by rotary evaporation. However, the method has the disadvantages of undefined technical process operating conditions, poor reproducibility, weak stability of the prepared amorphous substance, easy conversion into other crystal forms or formation of mixed crystals, and unsuitability for industrial production.

Disclosure of Invention

The invention aims to provide a stable amorphous ibrutinib (namely an amorphous substance) and a preparation method thereof, the method overcomes the problems of poor reproducibility and stability in the prior art, the reproducibility of the method is good, and the prepared amorphous ibrutinib has good stability and is suitable for industrial production.

The invention provides an amorphous ibrutinib substance, which has an X powder diffraction pattern with characteristic peaks shown in figure 1.

The IR spectrum of the ibrutinib amorphous substance of the present invention has the characteristic absorption peak shown in fig. 2.

The method for preparing the ibrutinib amorphous substance comprises the following steps:

1) adding ibrutinib into a benign organic solvent, and heating to completely dissolve the ibrutinib;

2) adding the solution into an anti-solvent, and stirring and solidifying, wherein the temperature of an anti-solvent system is maintained below 5 ℃ in the adding process;

3) filtering, and drying under reduced pressure to obtain the ibrutinib amorphous substance.

In the above method of the present invention, in step 1), the heating temperature is from 30 ℃ to the reflux temperature of the solvent, preferably from 50 ℃ to the reflux temperature, and the benign organic solvent is selected from the group consisting of: methanol, ethanol, isopropanol, butanol; acetone, butanone; ethyl acetate, methyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, toluene, N, N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide, and ethylene glycol dimethyl ether; the temperature step of the anti-solvent system in the step 2) is preferably-20-5 ℃; more preferably-20 ℃ to 0 ℃; the antisolvent is water or a mixed solution of water and an organic solvent selected from methanol, ethanol, isopropanol, acetone, tetrahydrofuran, 2-methyltetrahydrofuran, heptane, hexane, ethyl acetate, methyl acetate and the like in any proportion. In the step 3), the drying is reduced pressure drying, and the drying temperature is 30-70 ℃, preferably 50-70 ℃.

In a preferred embodiment, the process of the present invention for preparing an amorphous form of ibrutinib comprises the steps of:

1) adding ibrutinib into a benign organic solvent, heating to 50-reflux temperature, and completely dissolving to obtain a solution;

2) adding the solution into an anti-solvent, stirring and solidifying, wherein the temperature of an anti-solvent system is maintained at-20-5 ℃ in the adding process;

3) filtering, drying under reduced pressure to obtain Ibrutinib amorphous substance at 50-70 deg.C,

wherein the benign organic solvent in step 1) is selected from: methanol, ethanol, isopropanol, acetonitrile, butanone and tetrahydrofuran, the antisolvent in the step 2) is selected from water or a mixed solvent of water and methanol, ethanol, isopropanol, acetone or heptane, and the water is preferably ice water.

In another embodiment, the method for preparing an amorphous ibrutinib substance comprises dissolving ibrutinib and a high molecular weight polymer in an organic solvent, and spray-drying or evaporating the solvent to obtain an amorphous substance (also called an ibrutinib solid dispersion).

Preferably, in the method of the present invention, the high molecular polymer is vinylpyrrolidone and/or poloxamer, and the organic solvent is selected from: methanol, ethanol, isopropanol, acetone, ethyl acetate, methyl acetate, tetrahydrofuran, dichloromethane, preferably ethanol or dichloromethane.

Specifically, the method for preparing the ibrutinib amorphous substance comprises the steps of dissolving ibrutinib and a high molecular material in an organic solvent, and performing spray drying or solvent evaporation to obtain an ibrutinib solid dispersion, namely the amorphous substance, wherein the organic solvent is ethanol or dichloromethane.

The powder diffraction pattern of the amorphous ibrutinib prepared by all the methods of the invention has the characteristics of figure 1 and also has the characteristic IR absorption peak of figure 2.

The invention further aims to provide a pharmaceutical composition which comprises the ibrutinib solid dispersion and pharmaceutically acceptable auxiliary materials.

The pharmaceutically acceptable auxiliary materials comprise a diluent, a disintegrant, a glidant, a lubricant or a stabilizer. These adjuvants are all customary in the art.

Compared with the product obtained by the prior art, the stability of the amorphous ibrutinib substance provided by the preparation method is more stable, the operation is simple and convenient, and the industrial scale-up production is easy to realize.

Description of the drawings.

Fig. 1 is an XRPD pattern of an amorphous form of ibrutinib prepared in accordance with the present invention.

FIG. 2 shows the IR spectrum of an amorphous form of ibrutinib prepared in accordance with the present invention.

Detailed description of the preferred embodiments.

The present invention will be further described with reference to the following examples, which will enable those skilled in the art to more fully understand the spirit of the present invention, but will not limit the scope of the present invention in any way.

The X-ray powder diffractogram of the present invention was collected on a Shimadzu XRD-6000X-ray diffractometer of Japan. The parameters of the X-ray powder diffraction analysis method provided by the invention are as follows:

x-ray reflectance parameters: CuKa

CuKa source (a = 1.54063A)

Voltage: 40 kilovolt (Kv)

Current: 30 milliampere (mA)

Divergent slit: automatic

Scanning mode: continuous

Scanning range: 3 to 40 DEG

Sampling step length: 0.02 degree

Scanning speed: 2 degrees/minute.

Example 1

Adding 1.0g of ibrutinib into 6.0ml of methanol, heating to 50 ℃, and stirring to dissolve. Adding the solution into 18g of ice-water mixed solution, controlling the temperature below 5 ℃, stirring and curing for 30 minutes, filtering, drying a filter cake at 50 ℃ under reduced pressure to constant weight to obtain 0.96g of white solid, and performing HPLC: 99.57 percent. Testing for X-ray powder diffraction with an XRPD as shown in figure 1; the infrared spectrum is shown in figure 2.

Example 2

5.0g of ibrutinib is added into 25.0ml of ethanol, heated to 65 ℃, stirred and dissolved clearly. Adding the solution into a mixed solution of 100g of ice and 30g of ethanol, controlling the temperature between minus 20 ℃ and 0 ℃, stirring and curing for 2 hours, filtering, drying a filter cake at 70 ℃ under reduced pressure to constant weight to obtain 4.8g of white solid, and performing HPLC: 99.77 percent. The XRPD of the test sample is the same as that of example 1 through X-ray powder diffraction test, and the test infrared spectrum is basically consistent with that of example 1, namely the amorphous ibrutinib is obtained.

Example 3

Ibrutinib 1.0g is added into acetonitrile 10.0ml, heated to reflux, stirred to dissolve out. Adding the solution into a mixed solution of 18g of ice and 3.0g of acetone, controlling the temperature below 0 ℃, stirring and curing for 4 hours, filtering, drying a filter cake at 60 ℃ under reduced pressure to constant weight to obtain 0.87g of white solid, and performing HPLC: 99.37 percent. The XRPD of the test sample is the same as that of example 1 through X-ray powder diffraction test, and the test infrared spectrum is basically consistent with that of example 1, namely the amorphous ibrutinib is obtained.

Example 4

Adding 1.0g of ibrutinib into 10.0ml of butanone, heating to 60 ℃, and stirring to dissolve. Adding the solution into a mixed solution of 30g of ice and 10.0g of heptane, controlling the temperature below-5 ℃, stirring and curing for 15 minutes, filtering, drying a filter cake at 30 ℃ under reduced pressure to constant weight to obtain 0.9g of white solid, and performing HPLC: 99.52 percent. The XRPD of the test sample is the same as that of example 1 through X-ray powder diffraction test, and the test infrared spectrum is basically consistent with that of example 1, namely the amorphous ibrutinib is obtained.

Example 5

1.0g of ibrutinib is added into 8.0ml of tetrahydrofuran, heated to reflux and stirred to be dissolved clearly. Adding the solution into 30g of ice, controlling the temperature at 0-5 ℃, stirring and curing for 15 minutes, filtering, drying a filter cake at 70 ℃ under reduced pressure to constant weight to obtain 0.80g of white solid, and performing HPLC: 99.41 percent. The XRPD of the test sample is the same as that of example 1 through X-ray powder diffraction test, and the test infrared spectrum is basically consistent with that of example 1, namely the amorphous ibrutinib is obtained.

Example 6

Adding 1.0g of ibrutinib amorphous substance and 2.5g of polyvinylpyrrolidone into 20ml of dichloromethane, stirring at normal temperature to obtain a clear solution, and performing spray drying on the obtained solution to obtain a powdery ibrutinib solid dispersion. The XRPD of the test sample is the same as that of example 1 through X-ray powder diffraction test, and the test infrared spectrum is basically consistent with that of example 1, namely the amorphous ibrutinib is obtained.

Mixing and stirring 1.0g of ibrutinib solid dispersion, 1.0g of D-mannitol, 0.3g of sodium carboxymethylcellulose, 0.05g of talcum powder, 0.02g of magnesium stearate, 0.01g of calcium gluconate and 0.01g of sodium alginate to prepare the ibrutinib pharmaceutical composition.

Stability test

The stability of influencing factors of the amorphous ibrutinib substance prepared by the method is investigated, and compared with the method disclosed by the prior art WO2013184572, the method adopts dichloromethane to dissolve the ibrutinib compound, and then rotary evaporation is carried out to remove dichloromethane solvent to obtain the amorphous ibrutinib substance (comparative example), and the stability of the amorphous ibrutinib substance is investigated.

The results show that the stability of the ibrutinib amorphous substance obtained by the preparation method is obviously more stable than that of the product obtained by the prior art.

The above description is only an embodiment of the present invention, but the scope of the present invention is not limited thereto, and any changes or substitutions that can be made by those skilled in the art without inventive work within the technical scope of the present invention are included in the scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the protection scope defined by the claims.

Claims

1. An amorphous ibrutinib substance, which has an X powder diffraction pattern with characteristic peaks as shown in figure 1.

2. A process for preparing the amorphous form of ibrutinib of claim 1 comprising the steps of:

3) filtering, and drying the solid under reduced pressure to obtain an ibrutinib amorphous substance.

3. The process of claim 2, step 1) heating is at a temperature of from 30 ℃ to the reflux temperature of the solvent.

4. The method of claim 3, wherein the heating temperature is between 50 ℃ and reflux temperature.

5. The method of claim 2, wherein the benign organic solvent in step 1) is selected from the group consisting of: methanol, ethanol, isopropanol, butanol; acetone, butanone; ethyl acetate, methyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, toluene, N, N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide, and ethylene glycol dimethyl ether.

6. The method of claim 5, wherein the benign organic solvent is selected from the group consisting of: methanol, ethanol, isopropanol, butanone, acetonitrile, and tetrahydrofuran.

7. The process of claim 2 wherein the temperature of the anti-solvent system in step 2) is controlled to be in the range of-20 ℃ to 5 ℃.

8. The method according to claim 2, wherein the anti-solvent is water or a mixed solvent of water and an organic solvent selected from the group consisting of methanol, ethanol, isopropanol, acetone, tetrahydrofuran, 2-methyltetrahydrofuran, heptane, hexane, ethyl acetate and methyl acetate at any ratio.

9. The method according to claim 2, wherein the anti-solvent is water or a mixed solvent of water and methanol, ethanol, isopropanol, acetone, tetrahydrofuran or heptane.

10. The method of claim 2, wherein the drying temperature in step 3) is 30 ℃ to 70 ℃.

11. The method of claim 9, wherein the drying temperature is 50 ℃ to 70 ℃.