WO2023098848A1

WO2023098848A1 - Osimertinib co-crystal, preparation method, and application as drug or in pharmaceutical formulation

Info

Publication number: WO2023098848A1
Application number: PCT/CN2022/136087
Authority: WO
Inventors: 刘晓忠; 郑和校; 李郡; 靳奇峰
Original assignee: 湖南湘源美东医药科技有限公司
Priority date: 2021-12-03
Filing date: 2022-12-02
Publication date: 2023-06-08

Abstract

Involved are an osimertinib co-crystal, a preparation method therefor, and an application thereof as a drug or in a pharmaceutical formulation, more particularly for treating non-small cell lung cancer. The co-crystal has good solubility, good stability and process developability and the like; and the preparation method is simple and low in cost, and has an important value for optimization and development of the drug in the future.

Description

Osimertinib co-crystal, preparation method and application as medicine or in pharmaceutical preparations

technical field

The present invention relates to a co-crystal formed by osimertinib, a preparation method thereof and its application as a medicine or in a pharmaceutical preparation for treating non-small cell lung cancer, especially for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC), Patients whose tumors have an epidermal growth factor receptor (EGFR) exon 19 deletion or exon 21 L858R mutation, and who treat metastatic EGFR T790M mutation-positive NSCLC whose disease follows EGFR tyrosine kinase inhibitor (TKI) therapy or later develop.

technical background

Lung cancer is one of the most common malignant tumors in the world, and it has become the first cause of death from malignant tumors in urban population in my country. Non-small cell lung cancer includes squamous cell carcinoma (squamous cell carcinoma), adenocarcinoma, and large cell carcinoma. Compared with small cell carcinoma, its cancer cells grow and divide more slowly, and spread and metastasize relatively later. Non-small cell lung cancer accounts for about 80% of all lung cancers, and about 75% of the patients are in the advanced stage when they are discovered, and the 5-year survival rate is very low.

Most patients who take gefitinib (Iressa), domestic conmana, and erlotinib hydrochloride (Tarceva) will develop T790M mutation after drug resistance, and there is no alternative drug for these patients The patient has almost no possibility of continued survival. The listing of Tagrisso (osimertinib), a new drug for advanced non-small cell lung cancer (NSCLC) developed by AstraZeneca in the United Kingdom, has brought hope to such patients.

Sweden AstraZeneca Co., Ltd. discloses various crystal forms of free base or its salt in patent CN105348266B (free base has crystal form A, crystal form B, crystal form C, crystal form D, crystal form E, crystal form F, crystal form Form K; its methanesulfonate has crystal form A and crystal form B). Among them, crystal form D, crystal form E, and crystal form F are all hydrates, and their solubility is not high; in addition, in the case of alternatives, compared with their salt crystal forms, the three crystal forms are not conducive to improving the biological properties of drugs. Utilization and efficacy.

Osimertinib mainly acts by binding to the Cys-797 residue, and for this site, AZD9291 will produce C797S mutation acquired drug resistance after an average of about 9.6 months of clinical use. The original research company adopted osimertinib mesylate for clinical research. However, mesylate has the problems of high toxicity, high hygroscopicity and high humidity and is easy to deliquesce, so it is not suitable for use in pharmaceuticals under selective conditions. Therefore, it is necessary to develop drugs with high bioavailability, low toxicity and longer drug resistance time.

Drug co-crystallization technology refers to the crystal formed by the combination of active pharmaceutical ingredient (API) and co-crystal former (CCF) under the action of hydrogen bond or other non-covalent bonds. From a chemical point of view, the API molecule itself has not changed. Therefore, the original drug effect is still maintained, but the solubility, bioavailability, stability and other aspects of the co-crystal drug will be greatly improved, especially for the development of some oral pharmaceutical preparations.

Therefore, improving the basic structure of osimertinib drug using co-crystal technology can improve its properties, such as solubility, stability, permeability, and bioavailability. A series of co-crystals of osimertinib and gallic acid, citric acid, salicylic acid, fumaric acid, 4-aminobenzoic acid and 3,4-dihydroxystyrene acid as co-crystal precursors in the present invention . The co-crystals of the present invention may meet one or more objectives such as, but not limited to, improved solubility, stability and bioavailability and more permeability in pharmaceutical applications.

Contents of the invention

The present invention relates to co-crystals of osimertinib and gallic acid, citric acid, salicylic acid, fumaric acid, 4-aminobenzoic acid and 3,4-dihydroxystyrene acid.

In some embodiments, the active substance is selected from osimertinib, and in some embodiments, the co-crystal precursor is selected from gallic acid, citric acid, salicylic acid, fumaric acid, 4-aminobenzoic acid and 3 ,4-Dihydroxystyrene acid.

In Osimertinib (active pharmaceutical ingredient API) and gallic acid, citric acid, salicylic acid, fumaric acid, 4-aminobenzoic acid and 3,4-dihydroxystyrene acid (co-crystal precursor) by When hydrogen-bonded together, the co-crystals of the present invention are formed. In some embodiments, other non-covalent bonds and covalent interactions may also exist in the co-crystal.

One aspect of the invention contemplates osimertinib-based co-crystals that provide sufficient levels of bioavailability to be therapeutically effective in pharmaceutical applications and to maintain levels for a therapeutically effective period of time.

Compared with osimertinib, the osimertinib co-crystal designed in the present invention has better solubility and stability, is convenient for storage and use; and can be directly used in the preparation of solid preparations, and has good powder properties.

Description of drawings

Figure 1 shows the X-ray powder diffraction (XRPD) pattern of osimertinib and gallic acid co-crystal.

Figure 2 shows the X-ray powder diffraction (XRPD) pattern of osimertinib and citric acid co-crystal.

Figure 3 shows the X-ray powder diffraction (XRPD) pattern of osimertinib and salicylic acid co-crystal.

Figure 4 shows the X-ray powder diffraction (XRPD) pattern of the co-crystal of osimertinib and fumaric acid.

Figure 5 shows the X-ray powder diffraction (XRPD) pattern of the co-crystal of osimertinib and 4-aminobenzoic acid.

Figure 6 shows the X-ray powder diffraction (XRPD) pattern of the co-crystal of osimertinib and 3,4-dihydroxystyrene acid.

Figure 7 shows the effect of osimertinib co-crystal on the viability of NCI-H1975 cells.

Figure 8 shows the effect of osimertinib co-crystal on the viability of NCI-H1975/OSIR cells. The invention relates to a co-crystal of osimertinib and a preparation method thereof. The co-crystal contains osimertinib and the co-crystal precursors gallic acid, citric acid, salicylic acid, fumaric acid, 4-aminobenzoic acid and 3,4-dihydroxystyrene acid.

In some embodiments, osimertinib and gallic acid are combined in a 1:1 ratio. The co-crystal has an XRPD pattern comprised of 5.620°, 8.600°, 14.280°, 15.879°, 17.341°, 18.739°, 20.180° and 24.400° (rounded to 5.6°, 8.6°, 14.3°, 15.9°, respectively , 17.3°, 18.7°, 20.2° and 24.4°) (corresponding to

d-spacing) peaks at diffraction angles 2θ of ±0.2°. In some embodiments, the co-crystal comprises an XRPD pattern at diffraction angles 2Θ of 5.620°, 8.600°, 14.280°, 15.879°, 17.341°, 18.739°, 20.180°, and 24.400° ± 0.1°. In some embodiments, the co-crystal comprises an XRPD pattern at diffraction angles 2Θ of 5.620°, 8.600°, 14.280°, 15.879°, 17.341°, 18.739°, 20.180°, and 24.400° ± 0.05°. In some embodiments, the co-crystal comprises an X-ray diffraction pattern as shown in FIG. 1 . In some embodiments, the co-crystal has an X-ray diffraction pattern substantially similar to that shown in FIG. 1 .

In some embodiments, osimertinib and citric acid are combined in a 1:1 ratio. The co-crystal contained an X-ray diffraction pattern as shown in FIG. 2 . In some embodiments, the co-crystal has an X-ray diffraction pattern substantially similar to that shown in FIG. 2 .

In some embodiments, osimertinib and salicylic acid co-crystal are combined in a 1:1 ratio. The co-crystal has an XRPD pattern comprised of 5.700°, 12.560°, 15.040°, 18.220°, 18.739°, 19.381°, 19.918° and 25.040° (rounded to 5.7°, 12.6°, 15.0°, 18.2°, respectively , 18.7°, 19.4°, 19.9 and 25.0°) (corresponding to

d-spacing) peaks at diffraction angles 2θ of ±0.2°. In some embodiments, the co-crystal comprises an XRPD pattern at diffraction angles 2Θ of 5.700°, 12.560°, 15.040°, 18.220°, 18.739°, 19.381°, 19.918° and 25.040°±0.1°. In some embodiments, the co-crystal comprises an XRPD pattern at diffraction angles 2Θ of 5.700°, 12.560°, 15.040°, 18.220°, 18.739°, 19.381°, 19.918° and 25.040° ± 0.05°. In some embodiments, the co-crystal comprises an X-ray diffraction pattern as shown in FIG. 3 . In some embodiments, the co-crystal has an X-ray diffraction pattern substantially similar to that shown in FIG. 3 .

In some embodiments, osimertinib and fumaric acid cocrystal are combined in a 1:1 ratio. The co-crystal has an XRPD pattern comprised of 5.019°, 10.001°, 11.398°, 13.282°, 13.619°, 15.120°, 15.939° and 18.221° (rounded to 5.0°, 10.0°, 11.4°, 13.3°, respectively , 13.6°, 15.1°, 15.9° and 18.2°) (corresponding to

d-spacing) peaks at diffraction angles 2θ of ±0.2°. In some embodiments, the co-crystal comprises an XRPD pattern at diffraction angles 2Θ of 5.019°, 10.001°, 11.398°, 13.282°, 13.619°, 15.120°, 15.939°, and 18.221° ± 0.1°. In some embodiments, the co-crystal comprises an XRPD pattern at diffraction angles 2Θ of 5.019°, 10.001°, 11.398°, 13.282°, 13.619°, 15.120°, 15.939°, and 18.221° ± 0.05°. In some embodiments, the co-crystal comprises an X-ray diffraction pattern as shown in FIG. 4 . In some embodiments, the co-crystal has an X-ray diffraction pattern substantially similar to that shown in FIG. 4 .

In some embodiments, osimertinib and 4-aminobenzoic acid co-crystal are combined in a 1:1 ratio. The co-crystal has an XRPD pattern. In some embodiments, the co-crystal comprises an X-ray diffraction pattern as shown in FIG. 5 . In some embodiments, the co-crystal has an X-ray diffraction pattern substantially similar to that shown in FIG. 5 .

In some embodiments, the 2,2-di-n-propylacetamide and 3,4-dihydroxystyrene acid co-crystals are combined in a 1:1 ratio. The co-crystal has an XRPD pattern comprised of 5.660°, 7.358°, 9.261°, 9.900°, 11.321°, 11.779°, 12.418° and 14.241° (rounded to 5.7°, 7.4°, 9.3°, 9.9°, respectively , 11.3°, 11.8°, 12.4° and 14.2°) (corresponding to

d-spacing) peaks at diffraction angles 2θ of ±0.2°. In some embodiments, the co-crystal comprises an XRPD pattern at diffraction angles 2Θ of 5.660°, 7.358°, 9.261°, 9.900°, 11.321°, 11.779°, 12.418°, and 14.241° ± 0.1°. In some embodiments, the co-crystal comprises an XRPD pattern at diffraction angles 2Θ of 5.660°, 7.358°, 9.261°, 9.900°, 11.321°, 11.779°, 12.418°, and 14.241° ± 0.05°. In some embodiments, the co-crystal comprises an X-ray diffraction pattern as shown in FIG. 6 . In some embodiments, the co-crystal has an X-ray diffraction pattern substantially similar to that shown in FIG. 6 .

The co-crystal of the present invention comprises: gallic acid, citric acid, salicylic acid, fumaric acid, 4-aminobenzoic acid and 3,4-dihydroxystyrene acid as co-formers; and Osimertinib, as co-former and active pharmaceutical ingredient (API).

In some embodiments, gallic acid, citric acid, salicylic acid, fumaric acid, 4-aminobenzoic acid and 3,4-dihydroxystyrene acid and osimertinib are combined in a 1:1 ratio.

The solid state of the co-crystal of the present invention is any crystalline polymorph or other mixture. Co-crystals can also be made in amorphous form, which can be combined with any crystalline form. In other embodiments, the solid state of the co-crystal is an amorphous form, different forms of the co-crystal of the present invention can be obtained by different crystallization processes, and the co-crystal can be made into an amorphous form using known techniques.

The co-crystals of the present invention can be prepared by methods comprising:

(a) The gallic acid, citric acid, salicylic acid, fumaric acid, 4-aminobenzoic acid and 3,4-dihydroxystyrene acid are respectively dissolved or suspended in a solvent, and the solution can be optionally or the dispersion is heated to a temperature above room temperature and below the boiling point of said solution or dispersion;

Preferably, for the gallic acid, the solvent used is selected from ethanol, acetonitrile; for the citric acid, the solvent used is selected from acetonitrile, ethanol, preferably acetonitrile; for the salicylic acid, the solvent used is selected from ethanol, acetonitrile, preferably Ethanol; for the fumaric acid, the solvent used is selected from water, ethanol; for the 4-aminobenzoic acid, the solvent used is selected from water, ethanol, preferably water; for the 3,4-dihydroxystyrene Acid, the solvent used is selected from acetonitrile, ethanol, preferably ethanol;

(b) adding osimertinib to dissolve or suspend in a solvent together with or after step (a);

(c) The reaction time can be selected from 0.1-24 hours, during which the temperature described in (a) is kept and stirred;

(d) cooling the solution or dispersion of steps (a), (b), (c) to ambient temperature or below;

(e) optionally evaporating some or all of said solvent; and

(f) The resulting co-crystals are filtered off.

In some embodiments, the specific conditions of the process can be adjusted, and the appropriate ratios are in the following molar ranges: 1:0.1-1:20, 1:0.2-1:20, 1:0.3-1:20, 1:0.3-1:20, 0.4-1:20, 1:0.5-1:20, 1:0.6-1:20, 1:0.7-1:20, 1:0.8-1:20, 1:0.9-1:20, 1:1- 1:20, 1:2-1:20, 1:3-1:20, 1:4-1:20, 1:5-1:20, 1:6-1:18, 1:7-1: 15. 1:8-1:13, 1:9-1:12 or 1:10-1:11. In some embodiments, a suitable ratio is about 1:1 (molar). In some embodiments, the period of time for pulping or stirring the mixture may be in the range of: 0.1-24 hours, 0.2-12 hours, 0.25-6 hours, 0.3-2 hours, 0.4-1 hours, or 0.5-1 hours Hour. In some embodiments, the time period for pulping or stirring the mixture may be about 0.5 hours. In some embodiments, co-crystal compounds can be obtained by drying, filtering, centrifuging, pipetting, or combinations thereof. In some embodiments, co-crystal compounds can be obtained by centrifugation.

Example 1

Add 51.1mg (0.3mmol) gallic acid and 3ml ethanol to a 25ml eggplant-shaped bottle, stir for 0.5 hours to dissolve, add 50mg (0.1mmol) osimertinib, heat to 60°C, stop heating after stirring for 4 hours, and cool to room temperature , spin-dried the solvent, and dried under vacuum at 40°C to obtain the crude co-crystal, which was detected as amorphous by XRPD.

Example 2

Add 51.1mg (0.3mmol) of gallic acid and 3ml of acetonitrile into a 25ml eggplant-shaped bottle, stir for 0.5 hours to dissolve, then add 50mg (0.1mmol) of osimertinib, heat to 60°C, stop heating after stirring for 4 hours, and cool to At room temperature, the solvent was spin-dried and dried in vacuum at 40°C to obtain the crude co-crystal, which had characteristic peaks detected by XRPD.

Example 3

Add 34.07mg (0.2mmol) of gallic acid and 3ml of ethanol into a 25ml eggplant-shaped bottle, stir for 0.5 hours to dissolve, then add 100mg (0.2mmol) of osimertinib, heat to 60°C, stir for 6 hours, then naturally cool to room temperature, Then, the reactant was ice-bathed to 0-5°C, stirred for 3 hours, and filtered to obtain a crude crystal, which was treated with ethanol and heptane, and dried under vacuum at 40°C to obtain 109.80 mg of co-crystal. It was determined to be amorphous and the ratio was 1:1 by XRPD and HPLC detection.

Example 4

Add 34.07 mg (0.2 mmol) of gallic acid and 3 ml of acetonitrile into a 25 ml eggplant-shaped bottle, stir for 0.5 hour, then add 100 mg (0.2 mmol) of osimertinib, heat to 60 ° C, stir for 6 hours, and then naturally cool to room temperature. The reactant was ice-bathed to 0-5°C, stirred for 3 hours, filtered to obtain crude crystals, treated with acetonitrile and heptane, and dried in vacuum at 40°C to obtain 113.36 mg of co-crystals. Through XRPD and HPLC detection, determine the crystal form and the ratio is 1:1.

Example 5

Add 68.14 mg (0.4 mmol) of gallic acid and 5 ml of acetonitrile into a 25 ml eggplant-shaped bottle, stir for 0.5 hour, then add 200 mg (0.4 mmol) of osimertinib, heat to 60 ° C, stir for 6 hours, then cool naturally to room temperature, then The reactant was ice-bathed to 0-5°C, stirred for 3 hours, filtered to obtain crude crystals, treated with acetonitrile and heptane, and dried under vacuum at 40°C to obtain 231.27 mg of co-crystals. Through XRPD and HPLC detection, determine the crystal form and the ratio is 1:1.

Example 6

Add 57.68mg of citric acid (0.3mmol) and 3ml of acetonitrile into a 25ml eggplant-shaped bottle, stir for 0.5 hours to dissolve, add 50mg (0.1mmol) of osimertinib, heat to 60°C, stop heating after stirring for 4 hours, and cool to room temperature , spin-dried the solvent, and dried under vacuum at 40°C to obtain the crude co-crystal, which was detected as amorphous by XRPD.

Example 7

Add 38.45mg (0.2mmol) of citric acid and 3ml of acetonitrile into a 25ml eggplant-shaped bottle, heat to 60°C, stir for 0.5 hours to dissolve, add 100mg (0.2mmol) of osimertinib, stir for 6 hours and then cool to room temperature naturally. The reactant was ice-bathed to 0-5°C, stirred for 3 hours, filtered to obtain crude crystals, treated with acetonitrile and heptane, and dried under vacuum at 40°C to obtain 77.85 mg of co-crystals. It was determined to be amorphous and the ratio was 1:1 by XRPD and HPLC detection.

Example 8

Add 76.9mg (0.4mmol) of citric acid and 5ml of acetonitrile into a 25ml eggplant-shaped bottle, heat to 60°C, stir for 0.5 hours to dissolve, add 200mg (0.4mmol) of osimertinib, stir for 6 hours, then cool naturally to room temperature, then The reactant was ice-bathed to 0-5°C, stirred for 3 hours, filtered to obtain crude crystals, treated with acetonitrile and heptane, and dried in vacuum at 40°C to obtain 180.57 mg of co-crystals. It was determined to be amorphous and the ratio was 1:1 by XRPD and HPLC detection.

Example 9

Add 41.47mg (0.3mmol) salicylic acid and 3ml ethanol to a 25ml eggplant-shaped bottle, stir for 0.5 hours, add 50mg (0.1mmol) osimertinib, heat to 60°C, stop heating after stirring for 4 hours, and cool to room temperature , spin-dried the solvent, and dried under vacuum at 40°C to obtain the crude co-crystal, which was detected as amorphous by XRPD.

Example 10

Add 27.65mg (0.2mmol) of salicylic acid and 3ml of ethanol into a 25ml eggplant-shaped bottle, stir for 0.5 hours to dissolve, add 100mg (0.2mmol) of osimertinib, heat to 60°C, stir for 6 hours and then naturally cool to room temperature, Then, the reactant was ice-bathed to 0-5°C, stirred for 3 hours, and filtered to obtain a crude crystal, which was treated with ethanol and heptane, and dried under vacuum at 40°C to obtain 113.14 mg of co-crystal. Through XRPD and HPLC detection, determine the crystal form and the ratio is 1:1.

Example 11

Add 55.3mg (0.4mmol) of salicylic acid and 5ml of ethanol into a 25ml eggplant-shaped bottle, stir for 0.5 hours to dissolve, add 200mg (0.4mmol) of osimertinib, heat to 60°C, stir for 6 hours, then cool naturally to room temperature, Then, the reactant was ice-bathed to 0-5°C, stirred for 3 hours, and filtered to obtain a crude crystal, which was treated with ethanol and heptane, and dried under vacuum at 40°C to obtain 223.18 mg of co-crystal. Through XRPD and HPLC detection, determine the crystal form and the ratio is 1:1.

Example 12

Add 34.82mg (0.3mmol) fumaric acid and 3ml water into a 25ml eggplant-shaped bottle, stir for 0.5 hours, add 50mg (0.1mmol) osimertinib, heat to 60°C, stop heating after stirring for 4 hours, and cool After reaching room temperature, the solvent was spin-dried and dried in vacuum at 40°C to obtain the crude co-crystal, which had characteristic peaks detected by XRPD.

Example 13

Add 34.82mg (0.3mmol) fumaric acid and 3ml ethanol into a 25ml eggplant-shaped bottle, stir for 0.5 hours, add 50mg (0.1mmol) osimertinib, heat to 60°C, stop heating after stirring for 4 hours, and cool After reaching room temperature, the solvent was spin-dried and dried in vacuum at 40°C to obtain the crude co-crystal, which had characteristic peaks detected by XRPD.

Example 14

Add 23.21mg (0.2mmol) fumaric acid and 3ml water into a 25ml eggplant-shaped bottle, stir for 0.5 hours to dissolve, add 100mg (0.2mmol) osimertinib, heat to 60°C, stir for 6 hours and then cool naturally to At room temperature, the reactant was ice-bathed to 0-5°C, stirred for 3 hours, filtered to obtain crude crystals, treated with water and heptane, and dried in vacuum at 40°C to obtain 106.77 mg of co-crystals. Through XRPD and HPLC detection, determine the crystal form and the ratio is 1:2.

Example 15

Add 46.42mg (0.4mmol) fumaric acid and 3ml water into a 25ml eggplant-shaped bottle, stir for 0.5 hours to dissolve, add 100mg (0.2mmol) osimertinib, heat to 60°C, stir for 6 hours and then cool naturally to At room temperature, the reactant was ice-bathed to 0-5°C, stirred for 3 hours, filtered to obtain crude crystals, treated with water and heptane, and dried in vacuum at 40°C to obtain 125.17 mg of co-crystals. Through XRPD and HPLC detection, determine the crystal form and the ratio is 1:2.

Example 16

Add 92.84mg (0.8mmol) of fumaric acid and 6ml of water into a 25ml eggplant-shaped bottle, heat to 60°C, stir for 0.5 hours to dissolve, add 200mg (0.4mmol) of osimertinib, stir for 6 hours and then cool naturally to At room temperature, the reactant was ice-bathed to 0-5°C, stirred for 3 hours, filtered to obtain crude crystals, treated with water and heptane, and dried in vacuum at 40°C to obtain 220.86 mg of co-crystals. Through XRPD and HPLC detection, determine the crystal form and the ratio is 1:2.

Example 17

Add 46.42mg (0.4mmol) of fumaric acid and 6ml of water into a 25ml eggplant-shaped bottle, heat to 60°C, stir for 0.5 hours to dissolve, add 200mg (0.4mmol) of osimertinib, stir for 6 hours and then cool naturally to At room temperature, the reactant was ice-bathed to 0-5°C, stirred for 3 hours, filtered to obtain crude crystals, treated with water and heptane, and dried in vacuum at 40°C to obtain 216.89 mg of co-crystals. Through XRPD and HPLC detection, determine the crystal form and the ratio is 1:1.

Example 18

Add 41.17mg (0.3mmol) 4-aminobenzoic acid and 3ml water into a 25ml eggplant-shaped bottle, stir for 0.5 hours, add 50mg (0.1mmol) osimertinib, heat to 60°C, stop heating after stirring for 4 hours, and cool After reaching room temperature, the solvent was spin-dried, and dried in vacuum at 40°C to obtain a crude co-crystal, which was detected as amorphous by XRPD.

Example 19

Add 27.45mg (0.2mmol) of 4-aminobenzoic acid and 3ml of water into a 25ml eggplant-shaped bottle, heat to 60°C, stir for 0.5 hours to dissolve, add 100mg (0.2mmol) osimertinib, stir for 6 hours and then cool naturally to At room temperature, the reactant was ice-bathed to 0-5°C, stirred for 3 hours, filtered to obtain crude crystals, treated with water and heptane, and dried in vacuum at 40°C to obtain 58.23 mg of co-crystals. It was determined to be amorphous and the ratio was 1:1 by XRPD and HPLC detection.

Example 20

Add 54.9mg (0.4mmol) of 4-aminobenzoic acid and 5ml of water into a 25ml eggplant-shaped bottle, heat to 60°C, stir for 0.5 hours to dissolve, add 200mg (0.4mmol) osimertinib, stir for 6 hours and then cool naturally to At room temperature, the reactant was ice-bathed to 0-5°C, stirred for 3 hours, filtered to obtain crude crystals, treated with water and heptane, and dried in vacuum at 40°C to obtain 167.93 mg of co-crystals. It was determined to be amorphous and the ratio was 1:1 by XRPD and HPLC detection.

Example 21

Add 54.09mg (0.3mmol) of 3,4-dihydroxystyrene acid and 3ml of acetonitrile into a 25ml eggplant-shaped bottle, stir for 0.5 hours, add 50mg (0.1mmol) of osimertinib, heat to 60°C, and stir for 4 hours Heating was stopped, cooled to room temperature, the solvent was spin-dried, and dried in vacuum at 40°C to obtain a crude co-crystal, which had characteristic peaks detected by XRPD.

Example 22

Add 36.06mg (0.2mmol) of 3,4-dihydroxystyrene acid and 3ml of acetonitrile into a 25ml eggplant-shaped bottle, heat to 60°C, stir for 0.5 hours, add 100mg (0.2mmol) osimertinib, and stir for 6 hours Naturally cooled to room temperature, the reactant was ice-bathed to 0-5°C, stirred for 3 hours, filtered to obtain crude crystals, treated with acetonitrile and heptane, and dried in vacuum at 40°C to obtain 112.13 mg of co-crystals. Through XRPD and HPLC detection, determine the crystal form and the ratio is 1:1.

Example 23

Add 72.12mg (0.4mmol) 3,4-dihydroxystyrene acid and 5ml acetonitrile into a 25ml eggplant-shaped bottle, heat to 60°C, stir for 0.5 hours, add 200mg (0.4mmol) osimertinib, and stir for 6 hours Naturally cooled to room temperature, the reactant was ice-bathed to 0-5°C, stirred for 3 hours, filtered to obtain crude crystals, treated with acetonitrile and heptane, and dried in vacuum at 40°C to obtain 235.44 mg of co-crystals. Through XRPD and HPLC detection, determine the crystal form and the ratio is 1:1.

Example 24

The inhibitory effect of osimertinib co-crystal on the proliferation of NCI-H1975 cells and NCI-H1975/OSIR cells was detected by MTT method. As shown in Figures 7 and 8, osimertinib co-crystal can effectively enhance the effect on NCI-H1975 cells and NCI-H1975/OSIR cells, stronger than osimertinib itself, and osimertinib co-crystals have stronger lethality to the two types of cells. When the concentration of osimertinib reaches 20 μM, NCI-H1975 cells The survival rate is only about 30%, and the survival rate of NCI-H1975/OSIR cells is also lower than 50%, indicating that the osimertinib co-crystal enhances the anti-tumor effect of the drug and shows a strong anti-tumor effect.

Comparative example 1

Add 39.38mg (0.3mmol) of L-leucine and 3ml of water into a 25ml eggplant-shaped bottle, heat to 60°C, stir for 0.5 hours, add 50mg (0.1mmol) of osimertinib, stir for 4 hours, then naturally cool to room temperature , spin to dry the solvent, and dry at 40°C in vacuum to obtain the crude product. The XRPD detection pattern of the sample overlapped with that of osimertinib, and no co-crystal was formed.

Comparative example 2

Add 27.65mg (0.2mmol) of salicylic acid and 5ml of ethanol into a 25ml eggplant-shaped bottle, stir for 0.5 hours to dissolve, add 200mg (0.4mmol) of osimertinib, heat to 60°C, stir for 4 hours and then naturally cool to room temperature. Then the reactant was ice-bathed to 0-5°C, stirred for 1 hour, filtered to obtain a crude product, treated with ethanol and heptane, and dried in vacuum at 40°C to obtain 168.44 mg of a sample. Through XRPD detection, the pattern of the sample detected by XRPD overlapped with the pattern of osimertinib, and no co-crystal was formed.

Comparative example 3

Add 51.1mg (0.3mmol) of gallic acid and 3ml of toluene into a 25ml eggplant-shaped bottle, stir for 0.5 hours to dissolve, add 50mg (0.1mmol) of osimertinib, heat to 60°C, stop heating after stirring for 4 hours, and cool to room temperature , the solvent was spin-dried, and detected by XRPD, and the XRPD detection sample spectrum overlapped with the gallic acid spectrum, and no co-crystal was formed.

Comparative example 4

Add 76.9mg (0.4mmol) of citric acid and 5ml of acetonitrile in a 25ml eggplant-shaped bottle, react at room temperature (25°C), stir for 0.5 hours to dissolve, add 200mg (0.4mmol) Osimertinib, stir for 6 hours and then cool naturally to At room temperature, the reactant was ice-bathed to 0-5°C, stirred for 3 hours, filtered to obtain crude crystals, treated with acetonitrile and heptane, and dried in vacuum at 40°C to obtain 186.22 mg of co-crystals. Through XRPD detection, the pattern of the sample detected by XRPD overlapped with the pattern of osimertinib, and no co-crystal was formed.

Osimertinib co-crystal inhibits non-small cell lung cancer in rats

Take 200 μL (2×106 cells) of human lung adenocarcinoma A549 cell suspension in the logarithmic growth phase and undergo back puncture, select irradiated nude rats, and inject the cell suspension into the armpit of the right forelimb to construct rat non-small cell For the lung cancer model, a tumor with a length and width of about 0.4 cm × 0.4 cm after 5 days under the skin of the right armpit was considered as a successful model.

The rats were randomly divided into 3 groups, 20 in each group. ①The 20 rats in the treatment group were given 50 mg/kg (calculated as osimertinib) osimertinib and osimertinib co-crystal by gavage for 14 days continuously. ②The 20 rats in the model group were administered with normal saline (50mg/kg) for 14 days after successful modeling. ③ The 20 rats in the control group were not modeled, and were only administered intragastrically with normal saline (50 mg/kg) for 14 consecutive days. At the end of the treatment, the animals were sacrificed, the tumor tissues were dissected, and the tumor tissues of the three groups of rats were weighed and the tumor inhibition rates were calculated. Use a vernier caliper to measure the short diameter (W) and long diameter (L) of the transplanted tumor, and calculate the volume of the tumor: V=W2×L×0.52; tumor inhibition rate (%)=(average tumor mass of the blank tumor-bearing group- Average tumor mass of each experimental group)/average tumor mass of blank tumor-bearing group×100%.

Compared with the control group, the tumor weight and tumor volume in the model group and the treatment group increased significantly; compared with the model group, the tumor weight decreased and the tumor inhibition rate increased significantly in the treatment group. And in the treatment group, the tumor inhibition rate of osimertinib co-crystal was significantly higher than that of osimertinib group and osimertinib mesylate group.

Solubility test

Solubility test data are shown in Table 1.

Table 1

stability test

Stability test data are shown in Table 2-Table 3.

Table 2

table 3

Claims

A co-crystal formed by osimertinib as an active substance and other compounds as a co-crystal precursor; wherein the co-crystal precursor is selected from one or more of the following compound classes: fumaric acid, 4-Aminobenzoic acid, gallic acid, 3,4-dihydroxystyrene acid, citric acid, salicylic acid.
The co-crystal of claim 1, wherein said osimertinib and said co-crystal precursor fumaric acid, 4-aminobenzoic acid, gallic acid, 3,4-dihydroxystyrene acid, citric acid, Salicylic acid is combined in a 1:1 ratio.
The co-crystal of claim 1 selected from the group consisting of:

Contains a co-crystal of osimertinib and fumaric acid combined in a 1:1 ratio,

Contains a co-crystal of osimertinib and 4-aminobenzoic acid combined in a 1:1 ratio,

Contains a co-crystal of osimertinib and gallic acid combined in a 1:1 ratio,

Contains a co-crystal of osimertinib and 3,4-dihydroxystyrene acid combined in a 1:1 ratio,

A co-crystal comprising osimertinib and citric acid combined in a 1:1 ratio, and

Contains a co-crystal of osimertinib and salicylic acid combined in a 1:1 ratio.
The co-crystal of claim 1, comprising a co-crystal of osimertinib and fumaric acid combined in a 1:1 ratio, having a range of , X-ray diffraction powder diffraction (XRPD) patterns of peaks at diffraction angles 2θ at 15.939° and 18.221°±0.2°.
The co-crystal of claim 1, comprising a co-crystal of osimertinib and 4-aminobenzoic acid combined in a 1:1 ratio, having an amorphous X-ray Diffraction Powder Diffraction (XRPD) pattern.
The co-crystal of claim 1, comprising a co-crystal of osimertinib and gallic acid combined in a 1:1 ratio, having a range of and the X-ray diffraction powder diffraction (XRPD) pattern of the peak at the diffraction angle 2θ of 24.400°±0.2°.
The co-crystal of claim 1, which comprises a co-crystal of osimertinib and 3,4-dihydroxystyrene acid combined in a 1:1 ratio, having an °, 11.779 °, 12.418 ° and 14.241 ° ± 0.2 ° of diffraction angle 2θ of the peak X-ray diffraction powder diffraction (XRPD) pattern.
The co-crystal of claim 1, comprising a co-crystal of osimertinib and citric acid combined in a 1:1 ratio, having an amorphous X-ray Diffraction Powder Diffraction (XRPD) pattern.
The co-crystal of claim 1 , comprising a co-crystal of osimertinib and salicylic acid combined in a 1:1 ratio, having a range of ° and 25.040 ° ± 0.2 ° of the peak of the diffraction angle 2θ of the X-ray diffraction powder diffraction (XRPD) pattern.
A pharmaceutical composition comprising the co-crystal compound according to any one of claims 1-9, optionally further comprising a pharmaceutically acceptable carrier.
The pharmaceutical composition of claim 10, wherein said compound exists in the solid state of any crystalline polymorph or amorphous form or a mixture thereof.
A method for preparing the co-crystal according to claim 11, comprising the steps of:

(a) respectively dissolving or suspending the co-crystal precursors gallic acid, citric acid, salicylic acid, fumaric acid, 4-aminobenzoic acid, and 3,4-dihydroxystyrene acid in a solvent, optionally heating the solution or dispersion to a temperature above room temperature and below the boiling point of said solution or dispersion;

Preferably, for the gallic acid, the solvent used is selected from ethanol, acetonitrile; for the citric acid, the solvent used is selected from acetonitrile, ethanol, preferably acetonitrile; for the salicylic acid, the solvent used is selected from ethanol, acetonitrile, preferably Ethanol; for the fumaric acid, the solvent used is selected from water, ethanol; for the 4-aminobenzoic acid, the solvent used is selected from water, ethanol, preferably water; for the 3,4-dihydroxystyrene Acid, the solvent used is selected from acetonitrile, ethanol, preferably ethanol;

(b) adding osimertinib to dissolve or suspend in a solvent together with or after step (a);

(c) The reaction time can be selected from 0.1-24 hours, during which the temperature described in (a) is kept and stirred;

(d) cooling the solution or dispersion of steps (a), (b), (c) to ambient temperature or below;

(e) optionally evaporating some or all of said solvent; and

(f) The resulting co-crystals are filtered off.
The co-crystal comprising osimertinib and gallic acid combined at a ratio of 1:1 prepared by the method of claim 12 has an XRPD pattern as shown in FIG. 1 .
The co-crystal comprising osimertinib and citric acid combined at a ratio of 1:1 prepared by the method of claim 12 has an XRPD pattern as shown in FIG. 2 .
The co-crystal comprising osimertinib and salicylic acid combined at a ratio of 1:1 prepared by the method of claim 12 has an XRPD pattern as shown in FIG. 3 .
The co-crystal comprising osimertinib and fumaric acid combined at a ratio of 1:1 prepared by the method of claim 12 has an XRPD pattern as shown in FIG. 4 .
The co-crystal comprising osimertinib and 4-aminobenzoic acid combined at a ratio of 1:1 prepared by the method of claim 12 has an XRPD pattern as shown in FIG. 5 .
The co-crystal comprising osimertinib and 3,4-dihydroxystyrene acid combined at a ratio of 1:1 prepared by the method of claim 12 has an XRPD pattern as shown in FIG. 6 .
Use of the co-crystal according to any one of claims 1-9 or the pharmaceutical composition according to any one of claims 10-11 in the preparation of medicines for treating non-small cell lung cancer.