WO2021212253A1 - Ibrutinib gluconolactone co-crystal and preparation method therefor - Google Patents

Abstract

An ibrutinib gluconolactone co-crystal and a preparation method therefor, the stability of the gluconolactone co-crystal is not inferior to that of an ibrutinib free base, and said co-crystal can be make into a drug. The state of a co-crystal powder is more favorable for sieving, has small loss, high yield and insignificant static electricity. The co-crystal bulk density and tap density are not much different from that of the ibrutinib free base; however, significant differences in the angle of repose are present, and the fluidity thereof is significantly better than that of the free base. Moreover, the formula of the co-crystal as a main component has the best mixing uniformity, and satisfies preparation production requirements.

Description

Ibrutinib gluconolactone co-crystal and preparation method thereof Technical field

The invention relates to the field of crystal formations, in particular to the co-crystal of ibrutinib gluconolactone and a preparation method thereof.

Background technique

Ibrutinib was first developed by Celera Genomics in 2007 and then transferred to Pharmacyclics in California. In 2011, Jassen, a subsidiary of Johnson & Johnson, participated in the joint development. The drug was approved by the FDA in November 2013 for the treatment of patients with mantle cell lymphoma (MCL) who have previously received lenalidomide or other medications at least once. Ibrutinib is the first once-daily, single preparation, oral Bruton's tyrosine kinase (BTK) inhibitor. Currently, the approved indications for ibrutinib include: ① recurrent mantle cell lymphoma (MCL); ② recurrent chronic lymphocytic leukemia (CLL); ③ 17p deletion chronic lymphocytic leukemia; ④ Waldenstrom's macroglobulinemia (WM) ); ⑤ recurrent border zone lymphoma (MZL) ⑥ chronic graft versus host disease (cGVHD).

Ibrutinib is a small molecule inhibitor of Bruton's tyrosine kinase (BTK), which forms a covalent bond with the cysteine residue in the active site of BTK, resulting in inhibition of BTK enzyme activity. BTK is a signal molecule of B-cell antigen receptor (BCR) and cytokine receptor pathway. The role of BTK is to activate the pathways required for B-cell transport, chemotaxis and adhesion by sending signal commands to the B-cell surface receptors. Non-clinical studies have shown that Ibrutinib inhibits malignant B-cell proliferation and survival in vivo, as well as cell migration and substrate adhesion in vitro. Patients with recurrent B-cell lymphoma took ibrutinib at a dose of ≥2.5 mg/kg/day (based on a per capita body weight of 70 kg, the average daily dose of ibrutinib was greater than 175 mg/day), and peripheral observations were observed 24 hours later More than 90% of the BTK active sites of blood monocytes are occupied.

The chemical name of Ibrutinib is: 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1Hpyrazolo[3,4-d]pyrimidine-1-基]-1-piperidinyl]-2-propen-1-one, the structural formula is shown in formula II:

The molecular structure of ibrutinib was first reported in the patent document WO2008039218.

In the patent WO2013184572, three crystalline forms of the free base, A, B and C, are reported, and a variety of solvates are reported at the same time: ibrutinib methyl isobutyl ketone (D), ibrutinib toluene Compound (E), Ibrutinib methanolate (F). The marketed Ibrutinib capsules use the active ingredient with crystal form A as the raw material, but this crystal form has the disadvantages of high static electricity and poor fluidity during the preparation process, which adversely affects the preparation production process and personnel safety ,There are security risks.

In patents WO2016160604 and WO2016156127, co-crystals formed by ibrutinib and different organic acids are reported, including: benzoic acid, succinic acid, 3-hydroxybenzoic acid, nicotine amide, 4-aminobenzoic acid, salicylic acid, Sorbic acid, fumaric acid, salicylamide, trans-cinnamic acid, 4-hydroxybenzoic acid, 1-hydroxy-2-naphthoic acid, sulfamic acid, 1,5-dinaphthalenesulfonic acid, 2-ethoxy Benzamide, 4-aminosalicylic acid, stearic acid, fumaric acid and succinic acid.

Patent WO2016050422, WO2016206662 and WO2016207172 report the co-crystal formed by ibrutinib and inorganic acid. The inorganic acid includes hydrochloric acid and sulfuric acid.

The aforementioned eutectic compound formed by ibrutinib and organic acid and inorganic acid also did not overcome the shortcomings of high static electricity and poor fluidity. Therefore, it is of great practical significance to provide a new and stable organic acid co-crystal of Ibrutinib.

Summary of the invention

In view of this, the present invention provides ibrutinib gluconolactone co-crystal and a preparation method thereof. Ibrutinib gluconolactone co-crystal powder state is more conducive to sieving, with small loss, high yield, and not obvious static electricity. Using the same prescription and the same mixing process, the formulation of the co-crystal of Ibrutinib gluconolactone as the main drug has the best mixing uniformity, which meets the requirements of preparation production. Ibrutinib free base is difficult to mix evenly.

In order to achieve the above-mentioned purpose of the invention, the present invention provides the following technical solutions:

The present invention provides ibrutinib gluconolactone co-crystals, the structure of which is shown in formula I and exists in an anhydrous and solvent-free form;

It exhibits at least 3 high-intensity peaks as 2θ values in any combination in the X-ray powder diffraction pattern recorded by Cu-Kα radiation at 25°C: 5.807°(±0.1°), 16.445°(±0.1°) , 21.459°(±0.1°), 23.998°(±0.1°) or 26.769°(±0.1°).

In some specific embodiments of the present invention, it exhibits at least 3 of the following characteristic peaks as 2θ values in any combination in an X-ray powder diffraction pattern recorded at 25°C using Cu-Kα radiation: 18.493°(±0.1° ), 19.133°(±0.1°), 26.769°(±0.1°), 27.371°(±0.1°).

Those skilled in the art should understand that the relative intensity of diffraction can vary depending on many factors such as the method of preparing the sample and the type of instrument used. In addition, under certain circumstances, part of the above-mentioned peaks may not be detectable. In fact, the peaks listed above are only the significant peaks identified by the applicant. The complete list of peaks (although small in many cases) is given in Figure 3.

Again, this is a comprehensive list of peaks identified by the applicant. Based on the relative intensities of many of these peaks, the skilled person will understand that the analysis of the same polymorphic form on another instrument by a different researcher may not be able to identify all the small peaks identified above. The peaks in the table are only Provided as a comprehensive list. For the purpose of identification, it is believed that the peaks identified in Figure 3, especially the mid-strength peaks, are more characteristic for the existence of the polymorphs of the present invention.

It is worth noting that for the X-ray powder diffraction pattern of the above-mentioned crystal form, the characteristic peaks of the X-ray powder diffraction pattern may be between one machine and another machine and between one sample and another sample. There will be slight changes. The value may differ by about 1 unit, or by about 0.8 unit, or by about 0.5 unit, or by about 0.3 unit, or by about 0.1 unit, so the value given cannot be considered For absolute. Similarly, the values given in the differential scanning calorimetry graphs of the above-mentioned crystal forms cannot be regarded as absolute.

In some specific embodiments of the present invention, its differential scanning calorimetry curve shows an endothermic peak in the range of 141.7°C to 159.7°C; the endothermic melting peak is 148.4°C.

In some specific embodiments of the present invention, its infrared spectrum has characteristic absorption peaks at 3469.26 cm-1, 3436.21 cm-1, 3062.46 cm-1, 1725.95 cm-1, 1653 cm-1, and 1520.7 cm-1.

In some specific embodiments of the present invention, the thermogravimetric analysis chart is shown in FIG. 2. The thermogravimetric analysis curve shows a weight loss of 0.705% when heated to 185.92℃; when heated to 212.71℃, a weight loss of 10.297%; when heated to 240.17℃, a weight loss of 20.385%.

In some specific embodiments of the present invention, the proton nuclear magnetic resonance spectrum is shown in FIG. 5.

On the basis of the above research, the present invention also provides a method for preparing the ibrutinib gluconolactone co-crystal, taking the crude product of the compound represented by formula I and dissolving it in a solvent for crystallization.

In some specific embodiments of the present invention, the solvent includes acetonitrile, isopropanol, acetone/methyl tert-butyl ether, methanol, ethanol, tetrahydrofuran/methyl tert-butyl ether, dichloromethane/methyl tert-butyl ether One or a mixed solvent of two or more of the base ethers. More preferably, the solvent is selected from acetonitrile and methanol.

In some specific embodiments of the present invention, the crystallization includes:

(1) by concentrating the solvent; or

(2) By cooling to ambient temperature or cooling to any temperature between 25°C and 30°C; or

(3) by adding seed crystals of the ibrutinib gluconolactone co-crystal; or

(4) Through any combination of (1), (2) or (3).

In some specific embodiments of the present invention, the method for preparing the crude product of the compound represented by formula I is: the free base of ibrutinib is dissolved in a solvent by heating, and gluconolactone is added under insulation conditions to prepare the compound as shown in formula (I ) The crude product of the indicated compound;

The solvent includes one or more of acetonitrile, isopropanol, acetone/methyl tert-butyl ether, methanol, ethanol, tetrahydrofuran/methyl tert-butyl ether, dichloromethane/methyl tert-butyl ether More preferably, the solvent is selected from: acetonitrile and methanol.

So the heating temperature is 40℃～80℃.

The present invention also provides the ibrutinib gluconolactone co-crystal or the ibrutinib gluconolactone co-crystal prepared by the method for preparing Bruton's tyrosine kinase (BTK) Inhibitor or preparation to prevent and/or treat recurrent mantle cell lymphoma (MCL), recurrent chronic lymphocytic leukemia (CLL), 17p deletion chronic lymphocytic leukemia, Waldenstrom's macroglobulinemia (WM), recurrent border zone lymphoma (MZL) and/or chronic graft versus host disease (cGVHD) in medicine.

The present invention also provides a pharmaceutical composition or pharmaceutical preparation, comprising the ibrutinib gluconolactone co-crystal or the ibrutinib gluconolactone co-crystal prepared by the method and a pharmaceutical Acceptable excipients.

The present invention provides a crystalline form of ibrutinib gluconolactone co-crystal. The ibrutinib gluconolactone co-crystal has a compound with the structure shown in formula I. The present invention further relates to a method of preparing the crystal form.

The experimental results of the present invention show that, according to the comparison of the data in Table 2 and Table 3, the stability of the ibrutinib gluconolactone co-crystal is not inferior to that of ibrutinib free base, and it has druggability. According to the sieving yield in Table 4 and the phenomena observed after sieving, it can be seen that the state of the co-crystal powder of Ibrutinib gluconolactone is more conducive to sieving, with small loss, high yield, and insignificant static electricity. According to the results in Table 5 and Table 6, it can be seen that the bulk density and tap density of the co-crystal of ibrutinib gluconolactone are not much different from the free base of ibrutinib, but the angle of repose is significantly different. The fluidity of sugar lactone co-crystal is obviously better than that of free base. According to the results in Tables 7 and 8, it can be seen that using the same prescription and the same mixing process, the formulation of the Ibrutinib gluconolactone co-crystal as the main drug has the best mixing uniformity, which meets the requirements of preparation production. Ibrutinib free base is difficult to mix evenly.

Description of the drawings

In order to explain the embodiments of the present invention or the technical solutions in the prior art more clearly, the following will briefly introduce the drawings that need to be used in the description of the embodiments or the prior art.

Figure 1 shows the compound of formula (I): 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1Hpyrazolo[3,4-d]pyrimidine-1- DSC of the co-crystal of phenyl]-1-piperidinyl]-2-propen-1-ketogluconolactone;

Figure 2 shows the compound of formula (I): 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1Hpyrazolo[3,4-d]pyrimidine-1- Yl]-1-piperidinyl]-2-propene-1-ketogluconolactone co-crystal TGA;

Figure 3 shows the compound of formula (I): 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1Hpyrazolo[3,4-d]pyrimidine-1- Yl]-1-piperidinyl]-2-propene-1-ketogluconolactone co-crystal XRPD;

Figure 4 shows the compound of formula (I): 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1Hpyrazolo[3,4-d]pyrimidine-1- Yl]-1-piperidinyl]-2-propene-1-ketogluconolactone co-crystal IR;

Figure 5 shows a compound of formula (I): 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1Hpyrazolo[3,4-d]pyrimidine-1- H-NMR of co-crystal of phenyl]-1-piperidinyl]-2-propen-1-ketogluconolactone.

Detailed ways

The invention discloses a co-crystal of Ibrutinib gluconolactone and a preparation method thereof. Those skilled in the art can learn from the content of this article and appropriately improve the process parameters. In particular, it should be pointed out that all similar replacements and modifications are obvious to those skilled in the art, and they are all deemed to be included in the present invention. The method and application of the present invention have been described through the preferred embodiments. It is obvious that relevant persons can make changes or appropriate changes and combinations to the methods and applications described herein without departing from the content, spirit and scope of the present invention to achieve and Apply the technology of the present invention.

The present invention aims to provide a crystalline co-crystal of Ibrutinib gluconolactone, as shown in formula I:

In one aspect of the present invention, the compound of formula I has a sufficient crystalline form. The compound of formula I is usually named 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1Hpyrazolo[3,4-d]pyrimidin-1-yl]- 1-piperidinyl]-2-propene-1-ketogluconolactone co-crystal.

In one aspect of the present invention, the crystal form of the compound of formula I exists in an anhydrous, solvent-free form.

Ibrutinib gluconolactone co-crystal crystal form can be identified by its melting start point and powder X-ray diffraction pattern.

DSC test results show that there is an endothermic peak in the range of 141.7°C to 159.7°C, and the peak value is 148.4°C, which is the melting temperature.

When the co-crystal form of ibrutinib gluconolactone is substantially pure and essentially anhydrous and solvent-free, it is at 5.807°(±0.1°), 16.445°(±0.1°) , 21.459°(±0.1°), 23.998°(±0.1°), 26.769°(±0.1°) 2θ X-ray powder diffraction patterns with special high-intensity peaks. Furthermore, the crystal form has a temperature range of 5.807°(±0.1°), 16.445°(±0.1°), 18.493°(±0.1°), 19.133°(±0.1°), 21.459°(±0.1°), 23.998°( ±0.1°), 26.769°(±0.1°), 27.371°(±0.1°) 2θ X-ray powder diffraction patterns with characteristic peaks.

It is worth noting that for the X-ray powder diffraction pattern of the above-mentioned crystal form, the characteristic peaks of the X-ray powder diffraction pattern may be between one machine and another machine and between one sample and another sample. There will be slight changes. The value may differ by about 1 unit, or by about 0.8 unit, or by about 0.5 unit, or by about 0.3 unit, or by about 0.1 unit, so the value given cannot be considered For absolute. Similarly, the values given in the differential scanning calorimetry graphs of the above-mentioned crystal forms cannot be regarded as absolute.

The infrared spectrum of the co-crystal form of ibrutinib gluconolactone has characteristics at 3469.26cm-1, 3346.21cm-1, 3062.46cm-1, 1729.95cm-1, 1653cm-1, and 1520.7cm-1. Absorption peak.

In another aspect of the present invention, there is provided a method for preparing the crystal form of the compound of formula I, by crystallization of the crude compound of formula I in a suitable solvent, the solvent is selected from: acetonitrile, isopropanol, acetone/methyl tert-butyl ether, methanol, Ethanol, tetrahydrofuran/methyl tert-butyl ether, dichloromethane/methyl tert-butyl ether, more preferably the solvent is selected from: acetonitrile, methanol.

In another aspect of the present invention, there is provided a method for preparing the crystal form of the compound of formula I. The free base of ibrutinib is dissolved in acetonitrile or methanol by heating, gluconolactone is added under heat preservation, and crystallization is performed after cooling, followed by conventional The separation means separates the solid crystal form, and after drying, the crystal form of the compound of formula I is obtained.

The invention will now be described with reference to the following non-limiting examples.

The present invention adopts internationally recognized X-ray powder diffraction method (XRPD), DSC, TGA, IR, H-NMR to study and characterize the co-crystal of ibrutinib gluconolactone.

the term:

XRPD: X-ray powder diffraction;

DSC: Differential Scanning Calorimetry;

TGA: Thermogravimetric analysis;

IR: infrared spectrum analysis;

H-NMR: Proton nuclear magnetic resonance spectrum.

Measurement conditions and methods:

The X-ray powder diffraction pattern of the present invention is collected on a Panalytical Empyrean X-ray powder diffractometer. The parameters of the X-ray powder diffraction method of the present invention are as follows:

X-ray reflection parameters: Cu-Ka;

Voltage: 40 thousand volts (kV);

Current: 40 milliamperes (mA);

Incident slit: 0.6MM;

Receiving slit: 5.7MM;

Scanning range: from 3 to 70 degrees;

Sampling step length: 0.02 degrees;

Measuring time per step: 0.2 seconds/step.

The scan parameters are shown in Table 1.

Table 1 XRPD test parameters

No	2θ	d	I/I o	I,cps	FWHM
1	5.807	15.2071	37.6	5476	0.39
2	8.072	10.9434	1.3	196	To
3	10.800	8.1850	12.9	1875	0.53
4	11.281	7.8368	6.6	968	0.28
5	12.486	7.0834	9.9	1448	0.39
6	13.387	6.6088	6.2	901	0.28
7	13.798	6.4128	12.2	1782	0.42
8	14.457	6.1218	13.4	1957	0.28
9	15.295	5.7883	2.8	402	To
10	15.801	5.6039	6.7	982	0.28
11	16.445	5.3858	36.3	5290	To
12	16.814	5.2686	7.8	1130	0.28
13	17.412	5.0888	4.5	654	0.20
14	17.983	4.9287	23.4	3400	0.39
15	18.493	4.7937	26.8	3896	0.28
16	19.133	4.6349	27.6	4016	0.34
17	19.991	4.4378	7.6	1111	0.42
18	20.711	4.2851	6.3	915	0.25
19	21.459	4.1375	44.0	6403	0.34
20	21.866	4.0613	29.9	4349	0.31
twenty one	22.729	3.9091	27.0	3926	0.25
twenty two	23.998	3.7051	100	14561	0.25
twenty three	24.754	3.5937	3.2	469	To
twenty four	25.766	3.4547	3.0	430	To
25	26.769	3.3276	23.0	3342	0.28
26	27.371	3.2557	17.2	2511	0.25
27	27.856	3.2001	9.5	1386	0.20
28	29.090	3.0671	7.2	1048	0.36
29	30.713	2.9086	2.1	300	To
30	31.344	2.8515	10.3	1506	0.31
31	32.354	2.7648	2.5	367	0.25
32	33.882	2.6435	2.3	339	To
33	34.348	2.6087	7.6	1110	0.28
34	35.206	2.5470	1.5	220	To
35	36.428	2.4644	3.6	520	To
36	37.749	2.3811	4.4	646	0.28
37	39.279	2.2918	7.4	1078	0.25
38	39.700	2.2685	3.3	478	0.28
39	40.701	2.2150	1.7	242	0.34
40	42.929	2.1050	7.5	1098	0.25
41	43.549	2.0765	1.9	281	To
42	46.835	1.9382	2.1	311	To
43	48.782	1.8653	3.0	432	0.28
44	50.028	1.8217	3.2	467	0.34

45	50.515	1.8053	1.7	241	To
46	51.995	1.7573	2.5	361	To
47	52.866	1.7304	1.6	234	To

The differential scanning calorimetry chart of the present invention is collected on a DSC204F1 differential scanning calorimeter. The method parameters of the differential scanning calorimetry analysis of the present invention are as follows:

Temperature range/℃: 30℃-250℃;

Scanning rate/℃/min: 10℃/min;

Protective gas: nitrogen, 20 ml/min.

The infrared spectrogram test method of the present invention is as follows:

Test instrument: Spectrum 65 Fourier transform infrared spectrometer

Test condition: KBr tablet method

Instrument calibration: use the infrared spectrum absorption peak of the polystyrene film to calibrate the instrument wave number (refer to the Chinese Pharmacopoeia 2015 edition of the four general rules 0402).

Sample preparation conditions: KBr tablet method

Scanning range: 400-4000cm-1

The method parameters of the thermogravimetric analysis of the present invention are as follows:

Temperature range: 30-250℃;

Heating rate: 10°C/min;

Atmosphere: nitrogen, 20 ml/min.

The method parameters of the hydrogen nuclear magnetic resonance spectroscopy described in the present invention are as follows:

Instrument model: Bruker-F-400 nuclear magnetic resonance spectrometer (frequency: 400HMz);

Test solvent: According to the solubility and structural characteristics of this product, select deuterated DMSO as the test solvent.

The raw materials and reagents used in the ibrutinib gluconolactone co-crystal and the preparation method thereof provided by the present invention can be purchased from the market.

The following examples further illustrate the present invention:

Example 1: 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1Hpyrazolo[3,4-d]pyrimidin-1-yl]-1- Preparation of co-crystal of piperidinyl]-2-propen-1-ketogluconolactone

Add 5 ml of acetonitrile to a 50 mL three-necked flask, start stirring, add 500 mg of Ibrutinib free base, heat up to 70°C, keep warm and stir for 30 minutes, and the system will dissolve. Add 222.66 mg of gluconolactone to the solution, continue to stir for 30 minutes, and the system dissolves. Stop heating, cool down to 25～30°C naturally, keep warm and stir for 2 hours. After filtering, the filter cake was rinsed with 1 ml of acetonitrile, and air-dried at 40°C for 8-12 hours to obtain 600 mg of ibrutinib gluconolactone co-crystal, which was a white powder, with a yield of 83%.

Example 2: 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1Hpyrazolo[3,4-d]pyrimidin-1-yl]-1- Preparation of co-crystal of piperidinyl]-2-propen-1-ketogluconolactone

Add 5 ml of isopropanol to a 50 mL three-necked flask, start stirring, add 500 mg of ibrutinib free base, heat up to 80°C, keep warm and stir for 30 minutes, and the system will dissolve. Add 222.66 mg of gluconolactone to the solution, continue to stir for 30 minutes, and the system dissolves. Stop heating, naturally cool down to 25-30°C, keep warm and stir for 2 hours. After filtering, the filter cake was rinsed with 1 ml of isopropanol, and air-dried at 40° C. for 8-12 hours to obtain 240 mg of ibrutinib gluconolactone co-crystal, which was a yellow powder, with a yield of 33%.

Example 3: 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1Hpyrazolo[3,4-d]pyrimidin-1-yl]-1- Preparation of co-crystal of piperidinyl]-2-propen-1-ketogluconolactone

Add 5 ml of acetone to a 50 mL three-necked flask, start stirring, add 500 mg of ibrutinib free base, heat up to 56°C, keep warm and stir for 30 minutes, and the system will dissolve. Add 222.66 mg of gluconolactone to the solution, continue to stir for 30 minutes, and the system dissolves. Stop heating, add 2 ml of methyl tert-butyl ether dropwise, cool to 25-30°C naturally, and keep stirring for 2 hours. After filtering, the filter cake was rinsed with 1 ml of methyl tert-butyl ether, and dried at 40°C with air blowing for 8-12 hours to obtain 480 mg of co-crystal of ibutinib gluconolactone, which was a light yellow powder. The rate is 66%.

Example 4: 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1Hpyrazolo[3,4-d]pyrimidin-1-yl]-1- Preparation of co-crystal of piperidinyl]-2-propen-1-ketogluconolactone

Add 5 ml of methanol to a 50 mL three-necked flask, start stirring, add 500 mg of Ibrutinib free base, heat up to 65°C, keep warm and stir for 30 minutes, and the system will dissolve. Add 222.66 mg of gluconolactone to the solution, continue to stir for 30 minutes, and the system dissolves. Stop heating, naturally cool down to 25-30°C, keep warm and stir for 2 hours. After filtering, the filter cake was rinsed with 1 ml of methanol, and air-dried at 40° C. for 8-12 hours to obtain 300 mg of co-crystal of Ibrutinib gluconolactone, which was a white powder, with a yield of 42%.

Example 5: 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1Hpyrazolo[3,4-d]pyrimidin-1-yl]-1- Preparation of piperidinyl]-2-propen-1-one gluconate

Add 5 ml of ethanol to a 50 mL three-necked flask, start stirring, add 500 mg of ibrutinib free base, heat up to 78°C, keep warm and stir for 30 minutes, and the system will dissolve. Add 222.66 mg of gluconic acid to the solution and continue to stir for 30 minutes until the system is dissolved. Stop heating, naturally cool down to 25-30°C, keep warm and stir for 2 hours. After filtering, the filter cake was rinsed with 1 ml of ethanol, and air-dried at 40°C for 8-12 hours to obtain 520 mg of ibrutinib gluconolactone co-crystal, which was a white powder, with a yield of 72%.

Example 6: 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1Hpyrazolo[3,4-d]pyrimidin-1-yl]-1- Preparation of co-crystal of piperidinyl]-2-propen-1-ketogluconolactone

Add 5 ml of tetrahydrofuran to a 50 mL three-necked flask, start stirring, add 500 mg of Ibrutinib free base, heat up to 66°C, keep warm and stir for 30 minutes, and the system will be dissolved. Add 222.66 mg of gluconolactone to the solution, continue to stir for 30 minutes, and the system dissolves. Stop heating, add 1 ml of methyl tert-butyl ether dropwise, cool to 25-30°C naturally, and keep stirring for 2 hours. After filtering, the filter cake was rinsed with 1 ml of methyl tert-butyl ether, and dried at 40°C with air blowing for 8-12 hours to obtain 390 mg of co-crystal of Ibrutinib gluconolactone, which was a light yellow powder. The rate is 54%.

Example 7: 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1Hpyrazolo[3,4-d]pyrimidin-1-yl]-1- Preparation of co-crystal of piperidinyl]-2-propen-1-ketogluconolactone

Add 5 ml of dichloromethane to a 50 mL three-necked flask, start stirring, add 500 mg of ibrutinib free base, raise the temperature to 40° C., keep warm and stir for 30 minutes, and the system will dissolve. Add 222.66 mg of gluconolactone to the solution, continue to stir for 30 minutes, and the system dissolves. Stop heating, add 5 ml of methyl tert-butyl ether dropwise, cool to 25-30°C naturally, and keep stirring for 2 hours. After filtration, the filter cake was rinsed with 1 ml of methyl tert-butyl ether, and dried at 40°C with air blowing for 8-12 hours to obtain 580 mg of co-crystal of Ibrutinib gluconolactone, which was a yellow powder. The yield was 80%.

Example 8: 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1Hpyrazolo[3,4-d]pyrimidin-1-yl]-1- Preparation of co-crystal of piperidinyl]-2-propen-1-ketogluconolactone

Add 1000 ml of acetonitrile to a 2L three-necked flask, start stirring, add 100 g of ibrutinib free base, heat up to 70°C, keep warm and stir for 30 minutes, and the system will dissolve. Add 44.53 grams of gluconolactone to the solution, continue to stir for 30 minutes, and the system dissolves. Stop heating, naturally cool down to 25-30°C, keep warm and stir for 2 hours. After filtering, the filter cake was rinsed with 1 ml of acetonitrile, and air-dried at 40°C for 8-12 hours to obtain 118 grams of ibrutinib gluconolactone co-crystal, which was a white powder, with a yield of 82%.

Comparative example 1: 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1Hpyrazolo[3,4-d]pyrimidin-1-yl]-1- Preparation of piperidinyl]-2-propen-1-one free base

Dissolve 86g of crude ibrutinib in 516ml of absolute ethanol, raise the temperature to 60°C until the system is clear, add 0.86g of activated carbon, keep at 60°C, stir for 20-30 minutes, and filter while it is hot. While the filtrate is stirred, cool in a water bath, control the temperature at 25-30°C, and add 774ml of purified water dropwise. Addition time: 60-90 minutes. After the addition is complete, stir at 25-30°C for 3 to 4 hours, filter, and filter cake. Rinse once with a system of 129mL ethanol and purified water (1:1.5), the temperature of the obtained solid is controlled at 40±2℃, and dried under reduced pressure (vacuum degree: -0.1MPa) for 12-15 hours to obtain 66g of crude product. Add the crude product to 990ml acetonitrile, stir, increase the temperature, control the temperature at 60～65℃, stir for 20～30 minutes, the system will be dissolved, the temperature will be cooled in the water bath, the cooling rate will be 1℃/min, after 30～40min, the temperature will be controlled at 20～25℃ , Stir and crystallize for 3 to 4 hours, filter, rinse the filter cake with 99ml acetonitrile once, at 40±2℃, vacuum degree: -0.1MPa, dry for 8-15 hours, get 52g white powdery solid, Ibrahimovic Tinib free base.

Test example 1: Ibrutinib gluconolactone co-crystal and ibrutinib free base are used as an experimental comparison of influencing factors

Ibrutinib gluconolactone co-crystal and ibrutinib free base were tested for influencing factors, and the stability was compared. The results are as follows:

Table 2 Experiments on the influencing factors of ibrutinib gluconolactone co-crystal

Table 3 Influencing factors experiment of ibrutinib free base

According to the comparison of the data in Table 2 and Table 3, it can be seen that the stability of the co-crystal of ibrutinib gluconolactone is not inferior to that of ibrutinib free base, and it has druggability.

Test Example 2: Comparison of sieving

A circular sieve with a diameter of 20cm and a mesh number of 100 meshes are used. The type 8411 electric vibrating sieve (Doxu Yuezhou Geotechnical Instrument Factory, Shangyu District, Shaoxing City) is used, and the rotation speed is 1400 rpm. For 20 minutes, collect the materials in the tray under the sieve, observe the phenomena after sieving, including the residual status of the materials on the sieve and the status of large-particle materials, and observe the adsorption of the materials by the sieve. The results are as follows:

Table 4 Comparison of screening results

A one-way analysis of variance is performed on the above yield results, and the results are as follows:

Table 5 Variance analysis results of sieving yield

Source of difference	SS	df	MS	F	P-value	F crit
Between groups	1258.602	1	1258.602	18.26796	0.012908	7.708647
s	275.5867	4	68.89667	/	/	/
total	1534.188	5	/	/	/	/

It can be seen from the above data that there is a significant difference in the sieving yield of the two materials.

According to the sieving yield and the phenomena observed after sieving, the powder state of the co-crystal of Ibrutinib gluconolactone is more conducive to sieving, with small loss, high yield and insignificant static electricity.

Test Example 3: Comparison of the particle size and fluidity of Ibrutinib Gluconolactone co-crystal and Ibrutinib free base

A laser particle size analyzer was used to detect the particle size of the co-crystal of ibrutinib gluconolactone and the free base of ibrutinib with water as the dispersant. The BT-1000 powder comprehensive characteristics tester was used to determine the angle of repose, bulk density and tap density of the co-crystal of ibrutinib gluconolactone and the free base of ibrutinib. The results are as follows:

Table 5 Particle size test results

Product name	D10 (micron)	D50 (micron)	D90 (micron)
Ibrutinib gluconolactone co-crystal	0.692	5.852	41.41
Ibrutinib Free Base	0.844	7.240	52.68

According to the above results, the difference in particle size of the two materials is not too great.

Table 6 Liquidity test results

Product name	Angle of repose (°)	Bulk density (g/ml)	Tap density (g/ml)
Ibrutinib gluconolactone co-crystal	43	0.23	0.40
Ibrutinib Free Base	55	0.25	0.44

According to the above results, the bulk density and tap density of the ibrutinib gluconolactone co-crystal are not much different from the free base of ibrutinib, but the angle of repose is significantly different. The fluidity of the ester co-crystal is significantly better than that of the free base.

Test Example 4: Comparison of the difficulty of mixing in the preparation process

Use FH laboratory mixer (0.5L hopper) to mix the following prescription materials at 8rpm for 30min. A total of 5 points are taken from different positions in the hopper to detect the content of the main drug, calculate the RSD, and evaluate the difficulty of mixing.

Table 7 prescription composition

Prescription composition	Dosage (g)
Main drug (the dosage is based on ibrutinib)	10.0
Microcrystalline cellulose	82.0
Croscarmellose Sodium	4.0
Sodium dodecyl sulfate	1.0
Magnesium stearate	1.0

Table 8 Liquidity test results

Product name	Ibrutinib gluconolactone co-crystal	Ibrutinib Free Base
RSD(%)	1.34	6.87

According to the above results, using the same prescription and the same mixing process, Ibrutinib gluconolactone co-crystal has the best mixing uniformity as the main drug, which meets the requirements of preparation production. Ibrutinib free base is difficult to mix evenly.

The co-crystal of Ibrutinib gluconolactone and its preparation method provided by the present invention have been described in detail above. This article uses specific examples to illustrate the principle and implementation of the present invention. The description of the above examples is only used to help understand the method and core idea of the present invention. It should be pointed out that for those skilled in the art, without departing from the principle of the present invention, several improvements and modifications can be made to the present invention, and these improvements and modifications also fall within the protection scope of the claims of the present invention.

Claims (10)

1. Ibrutinib gluconolactone co-crystal is characterized in that its structure is as shown in formula I and exists in an anhydrous and solvent-free form;

   

   It exhibits at least 3 high-intensity peaks as 2θ values in any combination in the X-ray powder diffraction pattern recorded by Cu-Kα radiation at 25°C: 5.807°(±0.1°), 16.445°(±0.1°) , 21.459°(±0.1°), 23.998°(±0.1°) or 26.769°(±0.1°).
2. The Ibrutinib gluconolactone co-crystal according to claim 1, characterized in that it exhibits at least 3 functions in any combination in an X-ray powder diffraction pattern recorded using Cu-Kα radiation at 25°C. The characteristic peaks of 2θ values are as follows: 18.493°(±0.1°), 19.133°(±0.1°), 26.769°(±0.1°), 27.371°(±0.1°).
3. The Ibrutinib gluconolactone co-crystal according to claim 1 or 2, characterized in that its differential scanning calorimetry curve shows an endothermic peak in the range of 141.7°C to 159.7°C; an endothermic melting peak It was 148.4°C.
4. The ibrutinib gluconolactone co-crystal according to any one of claims 1 to 3, characterized in that its infrared spectrum is at 3469.26 cm ^-1 , 3346.21 cm ^-1 , 3062.46 cm ^-1 , 1729.95 cm ^-1, 1653cm ^-1, 1520.7cm ^-1 at a characteristic absorption peak.
5. A method for preparing the co-crystal of Ibrutinib gluconolactone according to any one of claims 1 to 4, characterized in that the crude product of the compound represented by formula I is dissolved in a solvent for crystallization.
6. The method according to claim 5, wherein the solvent comprises acetonitrile, isopropanol, acetone/methyl tert-butyl ether, methanol, ethanol, tetrahydrofuran/methyl tert-butyl ether, dichloromethane/methyl One or a mixed solvent of two or more of butyl tert-butyl ether.
7. The method according to claim 5 or 6, wherein the crystallization comprises:

   (1) by concentrating the solvent; or

   (2) By cooling to ambient temperature or cooling to any temperature between 25°C and 30°C; or

   (3) by adding seed crystals of the ibrutinib gluconolactone co-crystal; or

   (4) Through any combination of (1), (2) or (3).
8. The method according to any one of claims 5 to 7, wherein the method for preparing the crude product of the compound represented by formula I is: heating and dissolving the free base of ibrutinib in a solvent, and adding gluconic acid to Ester, to obtain a crude product of the compound represented by formula I;

   The solvent includes one or more of acetonitrile, isopropanol, acetone/methyl tert-butyl ether, methanol, ethanol, tetrahydrofuran/methyl tert-butyl ether, dichloromethane/methyl tert-butyl ether Mixed solvents;

   So the heating temperature is 40℃～80℃.
9. The ibrutinib gluconolactone co-crystal according to any one of claims 1 to 4 or the ibrutinib gluconolactone co-crystal prepared by the method according to any one of claims 5 to 7 In the preparation of Bruton's tyrosine kinase (BTK) inhibitors or the preparation of the prevention and/or treatment of recurrent mantle cell lymphoma (MCL), recurrent chronic lymphocytic leukemia (CLL), 17p deletion chronic lymphocytic leukemia, Waldenstrom's giant cell Use in medicine for albuminemia (WM), recurrent border zone lymphoma (MZL) and/or chronic graft-versus-host disease (cGVHD).
10. A pharmaceutical composition or pharmaceutical preparation, characterized in that it comprises the co-crystal of ibrutinib gluconolactone according to any one of claims 1 to 4 or the method according to any one of claims 5 to 7 The prepared co-crystal of Ibrutinib gluconolactone and pharmaceutically acceptable excipients.

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