CN113135917A

CN113135917A - Amorphous substance of ibrutinib and medicinal composition thereof

Info

Publication number: CN113135917A
Application number: CN202010049961.7A
Authority: CN
Inventors: 赵紫岭; 王守亮
Original assignee: Beijing Saisiyuan Biomedical Technology Co ltd
Current assignee: Beijing Saisiyuan Biomedical Technology Co ltd
Priority date: 2020-01-16
Filing date: 2020-01-17
Publication date: 2021-07-20

Abstract

The invention discloses an amorphous substance of ibrutinib, which uses Cu-Ka radiation, and has no sharp diffraction peak in an X-ray powder diffraction spectrum expressed by degree 2 theta, wherein the X-ray powder diffraction is shown in figure 1. Compared with the existing ibrutinib crystal form, the ibrutinib amorphous substance has the advantages that the solubility is obviously increased, the mobility is better, the bioavailability of a pharmaceutical preparation is favorably improved, and the amorphous substance shows good stability under the condition of an accelerated test. In addition, the invention also provides a preparation method and a medicinal composition of the amorphous substance.

Description

Amorphous substance of ibrutinib and medicinal composition thereof

Technical Field

The invention relates to an amorphous form of a pharmaceutical compound, in particular to an amorphous form of 1- [3(R) - [ 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3, 4-d ] pyrimidin-1-yl ] piperidin-1-yl ] -2-propen-1-one, a preparation method and a pharmaceutical composition thereof.

Background

Ibrutinib (chemical name 1- [3(R) - [ 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3, 4-d ] pyrimidin-1-yl ] piperidin-1-yl ] -2-propen-1-one) was approved by the U.S. Food and Drug Administration (FDA) as a single therapeutic for mantle cell lymphoma on 13 days 11 months 2013, also known as Ibrutinib. The target preparation prepared from Ibrutinib can selectively inhibit Bruton Tyrosine Kinase (BTK), and can be used for treating Chronic Lymphocytic Leukemia (CLL) and Mantle Cell Lymphoma (MCL). MCL and CLL both belong to B cell non-Hodgkin lymphoma, have difficult healing and easy recurrence, and the common chemoimmunotherapy has no targeting property and often causes serious adverse reaction. Ibrutinib can be combined with BTK targeting necessary for B lymphocyte formation, differentiation, information transmission and survival to irreversibly inhibit the activity of BTK and effectively inhibit the proliferation and survival of tumor cells; and the oral drug can be absorbed quickly, the maximum blood concentration can be achieved within 1-2 h, and adverse reactions are mild and micro, so that the oral drug becomes a new choice for treating CLL and MCL.

Ibrutinib (Ibrutinib) was first developed by Celera gene technology, usa (Celera Genomics), which is known for the mapping of "human genomes"; in 2006, Celera transferred the right to develop this drug to the United states biopharmaceutical pharmaceuticals corporation; in 2011, the grandfather son corporation of Yankee corporation (Jassen) collaborated with the pharmaceutical corporation of America until approved for marketing.

United states biopharmaceutical pharmaceuticals corporation disclosed in patent CN104736178A 3 anhydrous hydrate crystal forms (crystal form a, crystal form B, crystal form C, respectively) and 3 solvates (methyl isobutyl ketone solvate crystal form D, toluene solvate crystal form E, methanol solvate crystal form F, respectively). Wherein, the solubility of the crystal form A and the crystal form B is not high under the condition that the pH value is 7-8, and the two crystal forms are not beneficial to improving the bioavailability and the curative effect of the medicine. In addition, in alternative cases, the solvate forms (form D, form E, form F) are generally not suitable for direct use as pharmaceutical forms, relative to the anhydrate forms.

Suzhou Jingyun pharmaceutical science and technology, Inc. describes in its patent application CN104327085A (publication No.) another crystal form of 1- [3(R) - [ 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3, 4-d ] pyrimidin-1-yl ] piperidin-1-yl ] -2-propen-1-one and a method for its preparation.

Different crystal forms of 1- [3(R) - [ 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3, 4-d ] pyrimidin-1-yl ] piperidin-1-yl ] -2-propen-1-one may have differences in solubility and stability, so that the dissolution and release of the pharmaceutical composition in vitro are influenced, and the bioavailability of the pharmaceutical composition in vivo is further influenced. Therefore, the development of different forms of 1- [3(R) - [ 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3, 4-d ] pyrimidin-1-yl ] piperidin-1-yl ] -2-propen-1-one is of far-reaching interest.

Disclosure of Invention

The invention aims to provide an amorphous 1- [3(R) - [ 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3, 4-d ] pyrimidin-1-yl ] piperidin-1-yl ] -2-propen-1-one, which has the advantages of good fluidity and stability, simple and convenient preparation method, increased solubility of ibrutinib, better contribution to improving the bioavailability of a pharmaceutical preparation and the like.

In order to achieve the purpose, the technical scheme provided by the invention is as follows:

an amorphous 1- [3(R) - [ 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3, 4-d ] pyrimidin-1-yl ] piperidin-1-yl ] -2-propen-1-one which has no sharp diffraction peak in an X-ray powder diffraction spectrum expressed in degrees 2 theta using Cu-Ka radiation.

Preferably, the X-ray powder diffraction spectrum has a broad peak between 3.0 and 70.0, as shown in FIG. 1.

The invention provides a preparation method of an amorphous substance of ibrutinib, which comprises the following steps:

dissolving 0.3g of ibrutinib in 2ml of tetrahydrofuran, and stirring at room temperature to dissolve the ibrutinib clearly;

adding 4ml of isopropanol into the solution obtained in the step I at room temperature, wherein the volume ratio of tetrahydrofuran solvent to isopropanol solvent is 5: 1-1: 5;

and thirdly, adding the solution obtained in the second step into 20ml of a solvent I cooled to the temperature of minus 20 ℃, separating out a white viscous substance under stirring, pouring out a liquid, and drying under reduced pressure to obtain an amorphous substance of ibrutinib.

Preferably, the solvent I is selected from one or any combination of saturated alkane and cycloalkane containing 8 carbon atoms and less.

The invention provides another preparation method of an amorphous substance of ibrutinib, which comprises the following steps:

dissolving 0.5g of ibrutinib in 5ml of organic solvent, and stirring at room temperature to dissolve; concentrating and drying under reduced pressure to obtain an amorphous ibrutinib product.

Further, the organic solvent is selected from one of dichloromethane and trichloromethane or any mixture thereof, and the mass-to-solvent volume ratio is 0.05-0.5.

The amorphous substance has high dispersibility, and because the crystalline substance molecules are orderly arranged and the structural units are uniform, the energy of intermolecular interaction is weakened, and the total molecular energy is in a stable state; on the contrary, the molecules in the solid substance in the amorphous state have higher surface free energy than the molecules in the crystalline solid substance, so that the solubility of the amorphous drug is obviously increased, the absorption of the drug by organisms is facilitated, and the bioavailability of the drug is further improved.

The amorphous substance of the ibrutinib can keep good physical stability and chemical stability under the conditions of high temperature, illumination and high humidity, so that the invention has wide application prospect.

It is another object of the present invention to provide a pharmaceutical composition comprising the above amorphous substance.

In the invention, the X-powder diffraction test instrument and the test conditions are as follows: rigaku D/max-rA type X-ray diffractometer (Japan science); cu target, graphite curved crystal monochromator, tube voltage of 40kv, tube current of 100mA, wavelength

The scanning range is 3-70 degrees.

The related substance high performance liquid chromatography detection conditions and the method comprise the following steps: octadecylsilane chemically bonded silica is used as a filler for chromatographic conditions and system applicability; the mobile phase is phosphoric acid water and acetonitrile, and isocratic elution is carried out (45: 55); the detection wavelength is 258 nm; the theoretical plate number is not less than 5000 calculated according to the peak of 1- [3(R) - [ 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3, 4-d ] pyrimidin-1-yl ] piperidin-1-yl ] -2-propen-1-one. The separation degree of the 1- [3(R) - [ 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3, 4-d ] pyrimidine-1-yl ] piperidine-1-yl ] -2-propylene-1-ketone and adjacent impurity peaks meets the requirement.

Dissolution rate measurement conditions and methods: measured according to the first method of 0931 of the four general rules of the pharmacopoeia 2015 year edition.

Taking the capsule prepared by the product, according to a dissolution determination method, taking 900ml of 0.05M potassium dihydrogen phosphate buffer solution (containing 3.0% w/v Tween 20 and adjusting pH value to 6.8 by using phosphoric acid) as a dissolution medium, rotating at 100 r/min, taking a proper amount of solution after 60 minutes by the method operation, filtering, discarding the primary filtrate, and taking the subsequent filtrate to dilute as a test solution. An appropriate amount of a 1- [3(R) - [ 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3, 4-d ] pyrimidin-1-yl ] piperidin-1-yl ] -2-propen-1-one control was precisely weighed, and a solution containing about 150. mu.g of 1- [3(R) - [ 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3, 4-d ] pyrimidin-1-yl ] piperidin-1-yl ] -2-propen-1-one per 1ml was prepared with water as a control solution. Taking the above two solutions, measuring absorbance at 258nm wavelength by ultraviolet-visible spectrophotometry (0931 first method of the four-part general rule of the pharmacopoeia 2015 edition of China), and calculating the dissolution amount of each capsule according to absorbance by external standard method.

Characterization of 1- [3(R) - [ 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3, 4-d ] pyrimidin-1-yl ] piperidin-1-yl ] -2-propen-1-one

One, stability

Test samples: 1- [3(R) - [ 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3, 4-d ] pyrimidin-1-yl ] piperidin-1-yl ] -2-propen-1-one prepared in example 1.

1. Grinding test

An appropriate amount of sample was taken and added to an agate mortar, and the sample was taken after grinding with a pestle in the vertical direction, and the index was measured and compared with the results before grinding, and the results are shown in table 1.

TABLE 1 grinding test

2. Illumination test (5000lxs)

A proper amount of samples were taken and placed under the condition of illumination intensity of 5000lxs for 20 days, samples were taken and measured on the 5 th and 20 th days, and the results were compared with the 0 th day for appearance, and the results are shown in Table 2.

TABLE 2 light test

3. Accelerated test (60 ℃ C.)

Taking a proper amount of samples, placing at 60 ℃ for 20 days, sampling and measuring on the 5 th day and the 20 th day respectively, sampling and measuring crystal powder data, comparing appearances, testing indexes and comparing results with 0 day, wherein the results are shown in a table 3.

TABLE 3 accelerated test (60 ℃ C.)

4. High humidity test

An appropriate amount of 1- [3(R) - [ 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3, 4-d ] pyrimidine-1-yl ] piperidine-1-yl ] -2-propylene-1-ketone raw material is uniformly distributed into an open culture dish, the thickness is less than or equal to 5mm, the culture dish is placed in a constant temperature and humidity incubator with room temperature (about 25 ℃) and relative humidity of 90 +/-5%, samples are respectively taken on the 5 th day and the 20 th day for determination, and the results are compared with the results of the 0 th day, and the results are shown in Table 4.

TABLE 4 high humidity test (room temperature, relative humidity, 90. + -. 5%)

Solubility

The test is carried out according to the general examples of the Chinese pharmacopoeia 2015 year edition. The method comprises the following steps: an appropriate amount of 1- [3(R) - [ 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3, 4-d ] pyrimidin-1-yl ] piperidin-1-yl ] -2-propen-1-one was weighed precisely, a certain amount of solvent was slowly added, shaking was vigorously performed every 5 minutes for 30 seconds, and the dissolution in 30 minutes was observed, and the results are shown in Table 5.

TABLE 51- [3(R) - [ 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3, 4-d ] pyrimidin-1-yl ] piperidin-1-yl ] -2-propen-1-one solubility test

Solvent(s)	Amount of sample (g)	Adding solvent (ml)	Dissolution behavior	Conclusion
					Ethanol	1.00210	Less than 100ml	Completely dissolve	Slightly soluble
Methanol	1.10084	Less than 10ml	Completely dissolve	Is easy to dissolve
					Methylene dichloride	1.00356	Less than 10ml	Completely dissolve	Is easy to dissolve
DMF	1.10092	Less than 10ml	Completely dissolve	Is easy to dissolve
					Water (W)	0.10009	1000ml	Is not completely dissolved	Is almost insoluble
0.1M HCL	1.00056	Less than 10ml	Completely dissolve	Is easy to dissolve
					0.1M NaOH	0.11012	Greater than 1000ml	Is not completely dissolved	Is almost insoluble

A series of tests verify that the stability under the conditions of high temperature, illumination, high humidity, mechanical force and the like is researched. It can be seen that the 1- [3(R) - [ 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3, 4-d ] pyrimidin-1-yl ] piperidin-1-yl ] -2-propen-1-one of the present invention is suitable for formulation.

Drawings

FIG. 1 is an X-ray diffraction pattern of an amorphous form of 1- [3(R) - [ 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3, 4-d ] pyrimidin-1-yl ] piperidin-1-yl ] -2-propen-1-one according to the invention.

FIG. 2 is an X-ray diffraction pattern of an amorphous form of 1- [3(R) - [ 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3, 4-d ] pyrimidin-1-yl ] piperidin-1-yl ] -2-propen-1-one of the present invention after milling.

FIG. 3 is an X-ray diffraction pattern of an amorphous 1- [3(R) - [ 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3, 4-d ] pyrimidin-1-yl ] piperidin-1-yl ] -2-propen-1-one of the present invention when exposed to light for 5 days.

FIG. 4 is an X-ray diffraction pattern of an amorphous 1- [3(R) - [ 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3, 4-d ] pyrimidin-1-yl ] piperidin-1-yl ] -2-propen-1-one of the present invention when exposed to light for 20 days.

FIG. 5 is an X-ray diffraction pattern of an amorphous 1- [3(R) - [ 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3, 4-d ] pyrimidin-1-yl ] piperidin-1-yl ] -2-propen-1-one of the present invention tested for 5 days

FIG. 6 is an X-ray diffraction pattern of an amorphous 1- [3(R) - [ 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3, 4-d ] pyrimidin-1-yl ] piperidin-1-yl ] -2-propen-1-one of the present invention tested for 20 days

FIG. 7 is an X-ray diffraction pattern of an amorphous 1- [3(R) - [ 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3, 4-d ] pyrimidin-1-yl ] piperidin-1-yl ] -2-propen-1-one of the present invention when tested at high humidity for 5 days.

FIG. 8 is an X-ray diffraction pattern of an amorphous 1- [3(R) - [ 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3, 4-d ] pyrimidin-1-yl ] piperidin-1-yl ] -2-propen-1-one of the present invention after 20 days of high humidity testing.

Detailed Description

The following examples and drawings are intended to describe the present invention more specifically, but the present invention is not limited to the contents of the following examples.

Example 1

Dissolving 10g of 1- [3(R) - [ 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3, 4-d ] pyrimidin-1-yl ] piperidin-1-yl ] -2-propen-1-one in 60ml of tetrahydrofuran, adding 120ml of isopropanol into the solution, adding the mixed solution into 600ml of n-heptane cooled to-20 ℃, precipitating white viscous substances under stirring, pouring out liquid, and drying under reduced pressure to obtain an amorphous substance of ibrutinib, wherein the X-ray diffraction pattern of the obtained product is shown in figure 1.

Example 2

Dissolving 30g of 1- [3(R) - [ 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3, 4-d ] pyrimidine-1-yl ] piperidine-1-yl ] -2-propylene-1-ketone in 300ml of dichloromethane, and stirring at room temperature to dissolve the solution; concentrating and drying under reduced pressure to obtain an amorphous substance of ibrutinib, wherein the X-ray diffraction spectrum of the obtained product is basically consistent with that of the product in the example 1.

Example 3 prescription and preparation method of capsule:

the above amorphous form of 1- [3(R) - [ 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3, 4-d ] pyrimidin-1-yl ] piperidin-1-yl ] -2-propen-1-one was formulated into capsules containing 140mg per tablet using several excipients in the following manner, and the results are shown in Table 6.

TABLE 6 prescription conditions

The preparation process comprises the following steps: the preparation method of the capsule containing the amorphous 1- [3(R) - [ 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3, 4-d ] pyrimidine-1-yl ] piperidine-1-yl ] -2-propylene-1-ketone comprises the steps of uniformly mixing the excipient and the amorphous 1- [3(R) - [ 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3, 4-d ] pyrimidine-1-yl ] piperidine-1-yl ] -2-propylene-1-ketone according to an equivalent incremental method, and filling the mixture into the capsule. The reference crystals are mixed and encapsulated by the same method. The dissolution rate test results of the capsule formulation are shown in Table 7

TABLE 7 comparison of dissolution test results of capsule formulations

Time	Reference crystal	Amorphous material
			30	67.7％	71.3％
45	75.6％	85.7％
			60	86.2％	92.6％

The invention is described above by way of example and is not limited to the contents of the above embodiments. Any other application which directly applies the technical scheme and the principle of the invention to other occasions falls into the protection scope of the invention.

Claims

1. An amorphous form of ibrutinib, which is characterized by having no sharp diffraction peak in an X-ray powder diffraction pattern, as shown in figure 1.

2. A preparation method of an amorphous substance of ibrutinib is characterized by comprising any one of the following steps:

the method A comprises the following steps: dissolving 0.3g of ibrutinib in 2ml of tetrahydrofuran, stirring at room temperature to dissolve the ibrutinib clearly, and then adding 4ml of isopropanol; adding the solution into 20ml of n-heptane cooled to-20 ℃, precipitating white sticky substances under stirring, pouring out liquid, and drying under reduced pressure to obtain amorphous substances of ibrutinib; the method B comprises the following steps: dissolving 0.5g of ibrutinib in 5ml of organic solvent, and stirring at room temperature to dissolve; concentrating and drying under reduced pressure to obtain an amorphous substance of ibrutinib; method C comprises the steps of: dissolving 1.0g of ibrutinib in 8ml of organic solvent, and stirring at room temperature to dissolve; concentrating and drying under reduced pressure to obtain an amorphous substance of ibrutinib; wherein the Ibrutinib amorphous substance is radiated by Cu-Ka, has no sharp diffraction peak in an X-ray powder diffraction spectrum expressed by the degree 2 theta, and has a broad peak between the degree 2 theta of 3.0-70.0.

3. The organic solvent of claim 2, comprising dichloromethane, chloroform or any mixture thereof, wherein the mass to solvent volume ratio is 0.05-0.5.

4. A pharmaceutical composition comprising the amorphous form of claim 1.

5. The pharmaceutical composition of claim 4, comprising ibrutinib, a filler, a disintegrant, a glidant and a lubricant, and other pharmaceutically acceptable excipients.

6. A pharmaceutical composition according to claim 4, wherein the pharmaceutical composition comprises 100 to 600mg of the amorphous form of 1- [3(R) - [ 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3, 4-d ] pyrimidin-1-yl ] piperidin-1-yl ] -2-propen-1-one according to claim 1.

7. The adjuvant according to claim 5 comprises an adjuvant selected from lactose, sucrose, microcrystalline cellulose, silicified microcrystalline cellulose, starch, pregelatinized starch, etc. as a filler, low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, croscarmellose sodium, etc. as a disintegrant, magnesium stearate, calcium stearate, sodium stearyl fumarate, etc. as a lubricant, sodium lauryl sulfate, polysorbate, alkylaryl sulfonate, polyoxyethylene cetyl ether, etc. as a surfactant.