A crystal form of a pyrimidine aniline compound, a preparation method and application thereof

Abstract

The present application relates to a polymorph of acid salt of pyrimidine aniline compound, preparation method and application. Specifically, the present application discloses a polymorph of acid salt of compound of formula (A) and a preparation method thereof, and application of the polymorph. According to the results of comprehensive thermodynamic stability relationship and solid state property evaluation, the present application provides that the citrate salt crystal form I of formula (A) is a preferred crystal form, the physicochemical properties are stable, and the crystal form can be better used in clinic.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry technology, specifically relating to the crystal form of compounds used as kinase inhibitors, their preparation methods, and applications. Background Technology

[0002] Epidermal growth factor receptor (EGFR) belongs to the receptor tyrosine kinase (RTK) family, which includes EGFR / ERBB1, HER2 / ERBB2 / NEU, HER3 / ERBB3, and HER4 / ERBB4. EGFR activates its tyrosine kinase activity through homodimerization or heterodimerization, subsequently phosphorylating its substrate, thereby activating multiple downstream pathways associated with it within the cell, such as the PI3K-AKT-mTOR pathway involved in cell survival and the RAS-RAF-MEK-ERK pathway involved in cell proliferation. Mutations or amplifications of EGFR can lead to the activation of EGFR kinases, resulting in various human diseases, such as malignant tumors. For example, in non-small cell lung cancer (NSCLC) patients, approximately 10% of patients in the United States have EGFR mutations, while the proportion of patients with EGFR mutations in Asian patients can reach nearly 50%. Meanwhile, the incidence of HER2 mutations in NSCLC patients is approximately 2-4%.

[0003] EGFR mutations mainly include deletions, insertions, and point mutations. Exon 19 deletions and the L858R point mutation in exon 21 account for nearly 90% of EGFR mutations. For cancer patients with these EGFR mutations, currently marketed EGFR-TKIs include first-generation drugs such as Iressa, Tarceva, and Gefitinib; second-generation drugs such as Afatinib and Dacomitinib; and third-generation drug Osimertinib. The remaining 10% of EGFR mutations mainly involve exons 18 and 20 of EGFR, with exon 20 insertion mutations accounting for approximately 9% of all EGFR mutations. For cancer patients with HER2 mutations, the most common HER2 mutation is an insertion mutation in exon 20 of HER2.

[0004] TAK-788 has shown efficacy in treating exon 20 insertion mutations in EGFR and HER2. This compound is already marketed in the United States, and its reported clinical trial results show an objective response rate of 43%. Recently, DZD9008 has been reported to be effective in treating advanced non-small cell lung cancer with EGFR or HER2 mutations, with an objective response rate of approximately 40% for EGFR exon 20ins, which is not entirely satisfactory.

[0005] Therefore, developing new compounds with EGFR / HER2 kinase inhibitory activity and better pharmacodynamic and pharmacokinetic properties has become an important research project for developing novel anti-tumor drugs, which will ultimately be used in the treatment of human tumors and other diseases.

[0006] Patent application number (PCT / CN2023 / 081557) discloses a series of compounds used as EGFR / HER2 kinase inhibitors, which exhibit very good EGFR / HER2 inhibitory activity. This patent application discloses a compound with the structural formula shown in formula (A).

[0007]

[0008] Currently, there are no reports of patents regarding the crystal form of the acid salt of this compound. Screening and developing crystal forms for the compound shown in formula (A) to find stable and reliable crystal forms will ensure the quality stability of the compound, enabling better application in pharmaceuticals, drug formulations, and future clinical use. This will achieve stable and controllable drug quality, better dissolution, and higher bioavailability, thereby avoiding safety issues such as side effects caused by toxic impurities due to drug instability. This will be of great significance for future advancements. Summary of the Invention

[0009] The purpose of this invention is to provide a crystal form of an acid salt of a pyrimidine aniline compound, its preparation method, and its application.

[0010] In a first aspect, the present invention provides an acid salt crystal form of a compound of formula A, said crystal form being selected from the group consisting of: citrate crystal form I, maleate crystal form I, maleate crystal form II, oxalate crystal form I, oxalate crystal form II, methanesulfonate crystal form I, and methanesulfonate crystal form II.

[0011]

[0012] in,

[0013] The X-ray powder diffraction pattern of the citrate crystal form I includes three or more (e.g., four or five) characteristic peaks at 2θ values ​​selected from the following groups: 6.9±0.2°, 7.9±0.2°, 13.3±0.2°, 16.0±0.2°, and 18.6±0.2°.

[0014] In another preferred embodiment, the X-ray powder diffraction pattern of the citrate crystal form I includes five or more (e.g., 6, 7, 8, 9) characteristic peaks at 2θ values ​​selected from the following group: 6.9±0.2°, 7.9±0.2°, 11.4±0.2°, 13.3±0.2°, 15.7±0.2°, 16.0±0.2°, 16.7±0.2°, 18.6±0.2°, 19.2±0.2°, 20.8±0.2°.

[0015] In another preferred embodiment, the X-ray powder diffraction pattern of the citrate crystal form I includes six or more (e.g., 7, 8, 9, 10) characteristic peaks at 2θ values ​​selected from the group consisting of: 6.9±0.2°, 7.9±0.2°, 11.4±0.2°, 13.3±0.2°, 14.9±0.2°, 15.7±0.2°, 16.0±0.2°, 16.7±0.2°, 17.2±0.2°, 18.6±0.2°, 19.2±0.2°, 20.8±0.2°, 21.0±0.2°, 22.9±0.2°, 23.8±0.2°, and 27.1±0.2°.

[0016] In another preferred embodiment, the X-ray powder diffraction pattern of the citrate crystal form I has characteristic peaks at the following 2θ values: 3.5±0.2°, 6.9±0.2°, 7.4±0.2°, 7.9±0.2°, 10.0±0.2°, 10.3±0.2°, 10.7±0.2°, 11.4±0.2°, 13.3±0.2°, 13.9±0.2°, 14.9±0.2°, 15.7±0.2°, 16.0±0.2°, 1 6.7±0.2°, 17.2±0.2°, 17.8±0.2°, 18.6±0.2°, 19.2±0.2°, 20.8±0.2°, 21.0±0.2°, 21.4±0.2°, 21.7±0.2°, 22.9±0.2°, 23.8±0.2°, 24.8±0.2°, 25.8±0.2°, 27.1±0.2°, 27.3±0.2°, 27.6±0.2°, 28.5±0.2°.

[0017] In another preferred embodiment, the citrate crystal form I has X-ray powder diffraction data as shown in Table 5.

[0018] In another preferred embodiment, the X-ray powder diffraction pattern of citrate crystal form I is substantially as follows: Figure 1 As shown.

[0019] In another preferred embodiment, the thermogravimetric analysis spectrum of citrate crystal form I is essentially as follows: Figure 2 As shown.

[0020] In another preferred embodiment, the differential scanning calorimetry spectrum of citrate crystal form I is substantially as follows: Figure 2 As shown.

[0021] In another preferred embodiment, the citrate crystal form I exhibits an endothermic peak at an onset temperature of 200.33±2℃ during differential scanning calorimetry testing.

[0022] In another preferred embodiment, the citrate crystal form I exhibits significant weight loss at 150℃-230℃ (preferably 160℃-220℃), with a weight loss of 5% or more, preferably 10% or more, and more preferably 15% or more.

[0023] In another preferred embodiment, the weight loss is weight loss caused by decomposition, and there is no obvious weight loss before decomposition.

[0024] In another preferred embodiment, the acetone solvent residue in the citrate crystal form I is less than 2%, preferably less than 1%.

[0025] In another preferred embodiment, the citrate crystal form I is the amorphous form.

[0026] In another preferred embodiment, in the citrate crystal form I, the equivalent ratio of the compound of formula A to citric acid is 0.8-1.2:0.8-1.2, preferably 0.9-1.1:0.9-1.1, more preferably 0.95-1.05:0.95-1.05, for example 1:1.05 or 1:1.

[0027] In another preferred embodiment, the citrate crystal form I is triclinic, space group P1.

[0028] In another preferred embodiment, the cell parameters of citrate crystal form I are: α=69.2800(10)°, β=82.1490(10)°, γ=85.5730(10)°, Z = 2.

[0029] The X-ray powder diffraction pattern of the maleate crystal form I includes three or more (e.g., four or five) characteristic peaks at 2θ values ​​selected from the following group: 6.7±0.2°, 9.6±0.2°, 14.3±0.2°, 14.6±0.2°, and 23.5±0.2°.

[0030] In another preferred embodiment, the X-ray powder diffraction pattern of the maleate crystal form I includes five or more (e.g., 6, 7, 8, 9, 10) characteristic peaks at 2θ values ​​selected from the following group: 6.7±0.2°, 8.1±0.2°, 9.6±0.2°, 14.3±0.2°, 14.6±0.2°, 15.8±0.2°, 16.4±0.2°, 20.2±0.2°, 22.4±0.2°, 23.5±0.2°.

[0031] In another preferred embodiment, the X-ray powder diffraction pattern of the maleate crystal form I includes six or more (e.g., 7, 8, 9, 10, 11, 12) characteristic peaks at 2θ values ​​selected from the following group: 6.7±0.2°, 8.1±0.2°, 9.6±0.2°, 14.3±0.2°, 14.6±0.2°, 15.8±0.2°, 16.4±0.2°, 19.4±0.2°, 19.9±0.2°, 20.2±0.2°, 21.4±0.2°, 22.4±0.2°, 23.5±0.2°, 24.6±0.2°.

[0032] In another preferred embodiment, the X-ray powder diffraction pattern of the maleate crystal form I has characteristic peaks at the following 2θ values: 6.7±0.2°, 7.8±0.2°, 8.1±0.2°, 9.6±0.2°, 14.3±0.2°, 14.6±0.2°, 15.8±0.2°, 16.4±0.2°, 18.7±0.2°, 19.0±0.2°, 19.4±0.2°, 19.9±0.2°, 20.2±0.2°, 21.4±0.2°, 22.4±0.2°, 23.1±0.2°, 23.5±0.2°, 24.6±0.2°, 25.5±0.2°, and 26.1±0.2°.

[0033] In another preferred embodiment, the maleate crystal form I has X-ray powder diffraction data as shown in Table 6.

[0034] In another preferred embodiment, the X-ray powder diffraction pattern of maleate crystal form I is substantially as follows: Figure 6 As shown.

[0035] In another preferred embodiment, the thermogravimetric analysis spectrum of maleate crystal form I is essentially as follows: Figure 7 As shown.

[0036] In another preferred embodiment, the differential scanning calorimeter of maleate crystal form I is substantially as follows: Figure 7 As shown.

[0037] In another preferred embodiment, the maleate crystal form I exhibits an endothermic peak at onset temperatures of 136.54±2℃ and 157.99±2℃ in differential scanning calorimetry.

[0038] In another preferred embodiment, the maleate crystal form I exhibits significant weight loss at 60℃-170℃ (preferably 70℃-160℃), with a weight loss of more than 3%, and more preferably more than 5%.

[0039] In another preferred embodiment, the acetone solvent residue in the maleate crystal form I exceeds 3%, preferably exceeds 5%.

[0040] In another preferred embodiment, the maleate crystal form I is a solvate.

[0041] In another preferred embodiment, in the maleate crystal form I, the equivalent ratio of the compound of formula A to maleic acid is 0.8-1.2:0.8-1.2, preferably 0.9-1.1:0.9-1.1, more preferably 0.95-1.05:0.95-1.05, for example 1:1.05 or 1:1.

[0042] The X-ray powder diffraction pattern of the maleate crystal form II includes three or more (e.g., four or five) characteristic peaks at 2θ values ​​selected from the following groups: 6.9±0.2°, 10.6±0.2°, 14.5±0.2°, 16.5±0.2°, and 17.0±0.2°.

[0043] In another preferred embodiment, the X-ray powder diffraction pattern of the maleate crystal form II includes five or more (e.g., 6, 7, 8, 9, 10) characteristic peaks at 2θ values ​​selected from the group consisting of: 6.9±0.2°, 10.6±0.2°, 14.5±0.2°, 15.5±0.2°, 16.1±0.2°, 16.5±0.2°, 17.0±0.2°, 19.4±0.2°, 21.5±0.2°, and 22.0±0.2°.

[0044] In another preferred embodiment, the X-ray powder diffraction pattern of the maleate crystal form II includes six or more (e.g., 7, 8, 9, 10, 11, 12) characteristic peaks at 2θ values ​​selected from the group consisting of: 6.9±0.2°, 9.8±0.2°, 10.6±0.2°, 14.5±0.2°, 15.5±0.2°, 16.1±0.2°, 16.5±0.2°, 17.0±0.2°, 19.4±0.2°, 21.5±0.2°, 22.0±0.2°, 23.1±0.2°, 25.2±0.2°, 25.8±0.2°, and 27.3±0.2°.

[0045] In another preferred embodiment, the X-ray powder diffraction pattern of the maleate crystal form II has characteristic peaks at the following 2θ values: 6.9±0.2°, 9.8±0.2°, 10.6±0.2°, 14.5±0.2°, 15.5±0.2°, 16.1±0.2°, 16.5±0.2°, 17.0±0.2°, 19.4±0.2°, 21.1±0.2°, 21.5±0.2°, 22.0±0.2°, 23.1±0.2°, 24.2±0.2°, 25.2±0.2°, 25.8±0.2°, and 27.3±0.2°.

[0046] In another preferred embodiment, the maleate crystal form II has X-ray powder diffraction data as shown in Table 7.

[0047] In another preferred embodiment, the X-ray powder diffraction pattern of the maleate crystal form II is substantially as follows: Figure 8 As shown.

[0048] In another preferred embodiment, the thermogravimetric analysis spectrum of maleate crystal form II is essentially as follows: Figure 9 As shown.

[0049] In another preferred embodiment, the differential scanning calorimeter of maleate crystal form II is substantially as follows: Figure 9 As shown.

[0050] In another preferred embodiment, the maleate crystal form II exhibits an endothermic peak at onset temperatures of 47.27±2℃ and 162.78±2℃ in differential scanning calorimetry.

[0051] In another preferred embodiment, the maleate crystal form II exhibits weight loss of 0.5% or more, preferably 1% or more, at 15°C-60°C (preferably 20°C-55°C).

[0052] In another preferred embodiment, the maleate crystal form II exhibits weight loss at 15°C-60°C (preferably 20°C-55°C), corresponding to an endothermic peak at 45-75°C in differential scanning calorimetry.

[0053] In another preferred embodiment, the residual methyl tert-butyl ether solvent in the maleate crystal form II is less than 2%, preferably less than 1%.

[0054] In another preferred embodiment, the maleate crystal form II remains stable at 90-130°C, and the crystal form does not change.

[0055] In another preferred embodiment, the maleate crystal form II is a hydrate or a water-absorbing, non-crystalline form.

[0056] In another preferred embodiment, in the maleate crystal form II, the equivalent ratio of the compound of formula A to maleic acid is 0.8-1.2:0.8-1.2, preferably 0.9-1.1:0.9-1.1, more preferably 0.95-1.05:0.95-1.05, for example 1:1.05 or 1:1.

[0057] The X-ray powder diffraction pattern of the oxalate crystal form I includes three or more (e.g., four or five) characteristic peaks at 2θ values ​​selected from the following groups: 9.4±0.2°, 12.0±0.2°, 12.7±0.2°, 13.7±0.2°, and 21.4±0.2°.

[0058] In another preferred embodiment, the X-ray powder diffraction pattern of the oxalate crystal form I includes five or more (e.g., 6, 7, 8, 9, 10, 11) characteristic peaks at 2θ values ​​selected from the following group: 6.8±0.2°, 9.4±0.2°, 12.0±0.2°, 12.7±0.2°, 13.7±0.2°, 14.0±0.2°, 19.9±0.2°, 20.6±0.2°, 21.4±0.2°, 22.5±0.2°, 24.9±0.2°.

[0059] In another preferred embodiment, the X-ray powder diffraction pattern of the oxalate crystal form I includes six or more (e.g., 7, 8, 9, 10) characteristic peaks at 2θ values ​​selected from the group consisting of: 6.8±0.2°, 9.0±0.2°, 9.4±0.2°, 10.6±0.2°, 12.0±0.2°, 12.7±0.2°, 13.7±0.2°, 14.0±0.2°, 14.2±0.2°, 15.3±0.2°, 19.1±0.2°, 19.9±0.2°, 20.6±0.2°, 21.4±0.2°, 22.5±0.2°, 23.6±0.2°, and 24.9±0.2°.

[0060] In another preferred embodiment, the X-ray powder diffraction pattern of the oxalate crystal form I has characteristic peaks at the following 2θ values: 6.8±0.2°, 9.0±0.2°, 9.4±0.2°, 10.6±0.2°, 12.0±0.2°, 12.7±0.2°, 13.7±0.2°, 14.0±0.2°, 14.2±0.2°, 15.3±0.2°, 19.1±0.2°, 19.9±0.2°, 20.6±0.2°, 21.4±0.2°, 22.5±0.2°, 22.9±0.2°, 23.2±0.2°, 23.6±0.2°, and 24.9±0.2°.

[0061] In another preferred embodiment, the oxalate crystal form I has X-ray powder diffraction data as shown in Table 8.

[0062] In another preferred embodiment, the X-ray powder diffraction pattern of the oxalate crystal form I is substantially as follows: Figure 10 As shown.

[0063] In another preferred embodiment, the thermogravimetric analysis spectrum of the oxalate crystal form I is essentially as follows: Figure 11 As shown.

[0064] In another preferred embodiment, the differential scanning calorimeter of the oxalate crystal form I is substantially as follows: Figure 11 As shown.

[0065] In another preferred embodiment, the oxalate crystal form I exhibits an endothermic peak at an onset temperature of 205.45±2℃ in differential scanning calorimetry testing.

[0066] In another preferred embodiment, the oxalate crystal form I loses weight at 80℃-220℃ (preferably 90℃-210℃), with a weight loss of 3% or more, preferably 4% or more.

[0067] In another preferred embodiment, the acetone solvent residue in the oxalate crystal form I exceeds 20%, preferably exceeds 30%.

[0068] In another preferred embodiment, the oxalate crystal form I is an acetone solvate.

[0069] In another preferred embodiment, the oxalate crystal form I is transformed into oxalate crystal form II after being heated to 180-200°C.

[0070] In another preferred embodiment, in the oxalate crystal form I, the equivalent ratio of the compound of formula A to oxalic acid is 0.8-1.2:0.8-1.2, preferably 0.9-1.1:0.9-1.1, more preferably 0.95-1.05:0.95-1.05, for example 1:1.05 or 1:1.

[0071] The X-ray powder diffraction pattern of the oxalate crystal form II includes three or more (e.g., 4, 5, 6, 7) characteristic peaks at 2θ values ​​selected from the following groups: 9.5±0.2°, 12.2±0.2°, 12.7±0.2°, 13.7±0.2°, 14.5±0.2°, 19.9±0.2°, 24.8±0.2°.

[0072] In another preferred embodiment, the X-ray powder diffraction pattern of the oxalate crystal form II includes five or more (e.g., 6, 7, 8, 9, 10, 11) characteristic peaks at 2θ values ​​selected from the following group: 9.1±0.2°, 9.5±0.2°, 10.6±0.2°, 12.2±0.2°, 12.7±0.2°, 13.7±0.2°, 14.3±0.2°, 14.5±0.2°, 19.9±0.2°, 21.9±0.2°, 23.1±0.2°, 24.8±0.2°.

[0073] In another preferred embodiment, the X-ray powder diffraction pattern of the oxalate crystal form II includes six or more (e.g., 7, 8, 9, 10, 11, 12) characteristic peaks at 2θ values ​​selected from the group consisting of: 6.8±0.2°, 9.1±0.2°, 9.5±0.2°, 10.6±0.2°, 12.2±0.2°, 12.7±0.2°, 13.7±0.2°, 13.8±0.2°, 14.3±0.2°, 14.5±0.2°, 19.9±0.2°, 21.1±0.2°, 21.9±0.2°, 23.1±0.2°, 23.8±0.2°, and 24.8±0.2°.

[0074] In another preferred embodiment, the X-ray powder diffraction pattern of the oxalate crystal form II has characteristic peaks at the following 2θ values: 6.8±0.2°, 9.1±0.2°, 9.5±0.2°, 10.6±0.2°, 12.2±0.2°, 12.7±0.2°, 13.7±0.2°, 13.8±0.2°, 14.3±0.2°, 14.5±0.2°, 15.2±0.2°, 17.2±0.2°, 19.1±0.2°, 19.3±0.2°, 19.9±0.2°, 21.1±0.2°, 21.9±0.2°, 23.1±0.2°, 23.8±0.2°, and 24.8±0.2°.

[0075] In another preferred embodiment, the oxalate crystal form II has X-ray powder diffraction data as shown in Table 9.

[0076] In another preferred embodiment, the X-ray powder diffraction pattern of the oxalate crystal form II is substantially as follows: Figure 12 As shown.

[0077] In another preferred embodiment, the thermogravimetric analysis spectrum of the oxalate crystal form II is essentially as follows: Figure 13 As shown.

[0078] In another preferred embodiment, the differential scanning calorimeter of the oxalate crystal form II is substantially as follows: Figure 13 As shown.

[0079] In another preferred embodiment, in the differential scanning calorimetry test of the oxalate crystal form II, there is an endothermic peak at an onset temperature of 203.22±2℃.

[0080] In another preferred embodiment, the oxalate crystal form II does not exhibit significant weight loss before decomposition.

[0081] In another preferred embodiment, the oxalate crystal form II is amorphous.

[0082] In another preferred embodiment, in the oxalate crystal form II, the equivalent ratio of the compound of formula A to oxalic acid is 0.8-1.2:0.8-1.2, preferably 0.9-1.1:0.9-1.1, more preferably 0.95-1.05:0.95-1.05, for example 1:1.05 or 1:1.

[0083] The X-ray powder diffraction pattern of the methanesulfonate crystal form I includes three or more (e.g., four, five, or six) characteristic peaks at 2θ values ​​selected from the following group: 11.0±0.2°, 16.7±0.2°, 19.2±0.2°, 22.1±0.2°, 23.4±0.2°, and 25.0±0.2°.

[0084] In another preferred embodiment, the X-ray powder diffraction pattern of the methanesulfonate crystal form I includes five or more (e.g., 6, 7, 8, 9, 10, 11) characteristic peaks at 2θ values ​​selected from the following group: 8.8±0.2°, 10.2±0.2°, 11.0±0.2°, 15.6±0.2°, 16.7±0.2°, 17.0±0.2°, 18.5±0.2°, 19.2±0.2°, 22.1±0.2°, 23.4±0.2°, 25.0±0.2°.

[0085] In another preferred embodiment, the X-ray powder diffraction pattern of the methanesulfonate crystal form I includes six or more (e.g., 7, 8, 9, 10, 11, 12) characteristic peaks at 2θ values ​​selected from the group consisting of: 8.8±0.2°, 10.2±0.2°, 11.0±0.2°, 15.6±0.2°, 16.7±0.2°, 17.0±0.2°, 17.6±0.2°, 18.5±0.2°, 19.2±0.2°, 19.6±0.2°, 20.3±0.2°, 21.5±0.2°, 22.1±0.2°, 22.7±0.2°, 23.4±0.2°, and 25.0±0.2°.

[0086] In another preferred embodiment, the X-ray powder diffraction pattern of the methanesulfonate crystal form I has characteristic peaks at the following 2θ values: 8.8±0.2°, 10.2±0.2°, 11.0±0.2°, 15.6±0.2°, 16.7±0.2°, 17.0±0.2°, 17.6±0.2°, 18.5±0.2°, 19.2±0.2°, 19.6±0.2°, 20.3±0.2°, 21.5±0.2°, 22.1±0.2°, 22.7±0.2°, 23.4±0.2°, 25.0±0.2°, and 29.7±0.2°.

[0087] In another preferred embodiment, the methanesulfonate crystal form I has X-ray powder diffraction data as shown in Table 10.

[0088] In another preferred embodiment, the X-ray powder diffraction pattern of the methanesulfonate crystal form I is substantially as follows: Figure 14 As shown.

[0089] In another preferred embodiment, the thermogravimetric analysis spectrum of the methanesulfonate crystal form I is essentially as follows: Figure 15 As shown.

[0090] In another preferred embodiment, the differential scanning calorimeter of the methanesulfonate crystal form I is substantially as follows: Figure 15 As shown.

[0091] In another preferred embodiment, during the differential scanning calorimetry test of the methanesulfonate crystal form I, an endothermic peak is present at an Onset temperature of 256.06±2℃.

[0092] In another preferred embodiment, the methanesulfonate crystal form I does not exhibit significant weight loss before decomposition.

[0093] In another preferred embodiment, the acetone solvent residue in the methanesulfonate crystal form I does not exceed 2%, preferably not more than 1%.

[0094] In another preferred embodiment, the methanesulfonate crystal form I is amorphous.

[0095] In another preferred embodiment, in the methanesulfonate crystal form I, the molar ratio of compound A to methanesulfonic acid is 0.9-1.1:0.9-1.1, preferably 0.95-1.05:0.95-1.05, for example 1:1.05 or 1:1.

[0096] The X-ray powder diffraction pattern of the methanesulfonate crystal form II includes three or more (e.g., four, five, or six) characteristic peaks at 2θ values ​​selected from the following groups: 7.3±0.2°, 8.8±0.2°, 9.9±0.2°, 10.9±0.2°, 13.1±0.2°, and 14.2±0.2°.

[0097] In another preferred embodiment, the X-ray powder diffraction pattern of the methanesulfonate crystal form II includes five or more (e.g., 6, 7, 8, 9, 10) characteristic peaks at 2θ values ​​selected from the group consisting of: 7.2±0.2°, 7.3±0.2°, 8.8±0.2°, 9.9±0.2°, 10.9±0.2°, 13.1±0.2°, 14.2±0.2°, 16.6±0.2°, 16.9±0.2°, and 22.1±0.2°.

[0098] In another preferred embodiment, the X-ray powder diffraction pattern of the methanesulfonate crystal form II includes six or more (e.g., 7, 8, 9, 10, 11, 12) characteristic peaks at 2θ values ​​selected from the group consisting of: 7.2±0.2°, 7.3±0.2°, 8.8±0.2°, 9.9±0.2°, 10.9±0.2°, 12.5±0.2°, 13.1±0.2°, 14.2±0.2°, 14.9±0.2°, 16.6±0.2°, 16.9±0.2°, 22.1±0.2°, 22.6±0.2°, and 23.4±0.2°.

[0099] In another preferred embodiment, the X-ray powder diffraction pattern of the methanesulfonate crystal form II has characteristic peaks at the following 2θ values: 7.2±0.2°, 7.3±0.2°, 8.8±0.2°, 9.4±0.2°, 9.9±0.2°, 10.9±0.2°, 12.5±0.2°, 13.1±0.2°, 14.2±0.2°, 14.9±0.2°, 16.6±0.2°, 16.9±0.2°, 17.3±0.2°, 19.3±0.2°, 21.4±0.2°, 22.1±0.2°, 22.6±0.2°, and 23.4±0.2°.

[0100] In another preferred embodiment, the methanesulfonate crystal form II has X-ray powder diffraction data as shown in Table 11.

[0101] In another preferred embodiment, the X-ray powder diffraction pattern of the methanesulfonate crystal form II is substantially as follows: Figure 16 As shown.

[0102] In another preferred embodiment, the thermogravimetric analysis spectrum of the methanesulfonate crystal form II is essentially as follows: Figure 17 As shown.

[0103] In another preferred embodiment, the differential scanning calorimeter of the methanesulfonate crystal form II is substantially as follows: Figure 17 As shown.

[0104] In another preferred embodiment, in the differential scanning calorimetry test of the methanesulfonate crystal form II, there is an endothermic peak at 35-120℃ (peak value approximately 75.83±2℃), which is a dehydration peak; there is a set of crystal transformation peaks at 160-200℃; and there is an endothermic peak at 240-270℃, which is the melting peak of methanesulfonate crystal form I after crystal transformation.

[0105] In another preferred embodiment, the residual methyl tert-butyl ether solvent in the methanesulfonate crystal form II is no more than 2%, preferably no more than 1%, and more preferably no more than 0.5%.

[0106] In another preferred embodiment, the methanesulfonate crystal form II is amorphous.

[0107] In another preferred embodiment, in the methanesulfonate crystal form II, the molar ratio of the compound of formula A to methanesulfonic acid is 0.9-1.1:0.9-1.1, preferably 0.95-1.05-0.95-1.05, for example 1:1.05 or 1:1.

[0108] In another preferred embodiment, the crystal form is citrate crystal form I.

[0109] A second aspect of the present invention provides a method for preparing the acid salt crystal form of the compound of formula A described in the first aspect of the present invention, wherein the method is selected from the group consisting of:

[0110] Method 1:

[0111] Compound A is mixed with a first solvent, and a first acid reagent is added, causing crystallization to occur; the first solvent is selected from methanol, acetone, and acetonitrile.

[0112] Method 2:

[0113] (a) The compound of formula A is mixed with a second solvent and then with a second acid reagent to obtain an acid salt of the compound of formula A; the second solvent is selected from one or more of 1,2-dichloroethane, methanol, acetone and acetonitrile;

[0114] (b) The acid salt of compound A is mixed with a third solvent, suspended and crystallized, and the crystals are precipitated; the third solvent is selected from one or more of dichloromethane, acetone, tetrahydrofuran, acetonitrile, and methyl tert-butyl ether.

[0115] Method 3:

[0116] (c) The acid salt crystal form of a compound of formula A is heated to a certain temperature and then transformed into crystal.

[0117] In another preferred embodiment, the compound represented by formula A is a free alkali crystal form I.

[0118] In another preferred embodiment, the ratio of compound A to the second solvent is 50-250 g / L.

[0119] In another preferred embodiment, the first acid reagent and the second acid reagent are each independently selected from the group consisting of: citric acid, oxalic acid, maleic acid, methanesulfonic acid, fumaric acid, L-tartaric acid, hydrochloric acid, L-malic acid, acetic acid, benzoic acid, phosphoric acid, and succinic acid.

[0120] In another preferred embodiment, the second solvent is selected from one or more of 1,2-dichloroethane and methanol.

[0121] In another preferred embodiment, the third solvent is selected from acetone and methyl tert-butyl ether.

[0122] In another preferred embodiment, the method includes:

[0123] (a1) The compound of formula A is mixed with a second solvent and then mixed with citric acid to obtain the citrate of the compound of formula A; the second solvent is selected from one or more of 1,2-dichloroethane and methanol;

[0124] (b1) The citrate of compound A is mixed with a third solvent, suspended and crystallized to obtain citrate I of compound A; the third solvent is acetone.

[0125] In another preferred embodiment, the equivalent ratio of the compound of formula A to citric acid is 0.8-1.2:0.8-1.2, preferably 0.9-1.1:0.9-1.1, more preferably 0.95-1.05:0.95-1.05, for example 1:1.05 or 1:1.

[0126] In another preferred embodiment, step (a1) is performed at 0-10°C, for example, 5°C.

[0127] In another preferred embodiment, the salt formation reaction time of step (a1) is 8-20 h, for example 16 h.

[0128] In another preferred embodiment, step (a1) further includes removing the second solvent by vacuum rotary evaporation.

[0129] In another preferred embodiment, in step (b1), the suspension-to-crystal conversion includes: reacting for 16-24 hours, then transferring the solution sample to 0-10°C, and transferring the adhesive to a high-low temperature cycle (50-5°C) to continue the reaction for 3 days.

[0130] In another preferred embodiment, the method includes:

[0131] (a2) The compound of formula A is mixed with a second solvent and then mixed with maleic acid to obtain the maleate salt of the compound of formula A; the second solvent is selected from one or more of 1,2-dichloroethane and methanol;

[0132] (b2) The maleate salt of compound A is mixed with a third solvent, suspended and crystallized to obtain maleate salt crystal form I of compound A; the third solvent is acetone.

[0133] In another preferred embodiment, the equivalent ratio of the compound of formula A to maleic acid is 0.8-1.2:0.8-1.2, preferably 0.9-1.1:0.9-1.1, more preferably 0.95-1.05:0.95-1.05, for example 1:1.05 or 1:1.

[0134] In another preferred embodiment, step (a2) is performed at 0-10°C, for example, 5°C.

[0135] In another preferred embodiment, the salt formation reaction time of step (a2) is 8-20 h, for example 16 h.

[0136] In another preferred embodiment, step (b2) includes: after reacting at room temperature for 12-20 hours, filtering the resulting suspension.

[0137] In another preferred embodiment, the method includes:

[0138] (a3) The compound of formula A is mixed with a second solvent and then mixed with maleic acid to obtain the maleate salt of the compound of formula A; the second solvent is methanol;

[0139] (b3) The maleate salt of compound A is mixed with a third solvent, suspended and crystallized to obtain maleate salt form II of compound A; the third solvent is methyl tert-butyl ether.

[0140] In another preferred embodiment, the equivalent ratio of the compound of formula A to maleic acid is 0.8-1.2:0.8-1.2, preferably 0.9-1.1:0.9-1.1, more preferably 0.95-1.05:0.95-1.05, for example 1:1.05 or 1:1.

[0141] In another preferred embodiment, step (a2) is performed at room temperature, for example, 15-40°C.

[0142] In another preferred embodiment, the salt formation reaction time of step (a2) is 1-6 hours, for example, 4 hours.

[0143] In another preferred embodiment, step (b2) includes: after reacting for 12-20 hours, filtering the resulting suspension.

[0144] In another preferred embodiment, the method includes:

[0145] (a4) The compound of formula A is mixed with a second solvent and then mixed with oxalic acid to obtain the oxalate of the compound of formula A; the second solvent is one or more of 1,2-dichloroethane and methanol;

[0146] (b4) The oxalate of compound A is mixed with a third solvent, suspended and crystallized to obtain oxalate crystal form I of compound A; the third solvent is acetone.

[0147] In another preferred embodiment, the equivalent ratio of the compound of formula A to oxalic acid is 0.8-1.2:0.8-1.2, preferably 0.9-1.1:0.9-1.1, more preferably 0.95-1.05:0.95-1.05, for example 1:1.05 or 1:1.

[0148] In another preferred embodiment, step (a4) is performed at 0-10°C, for example, 5°C.

[0149] In another preferred embodiment, the salt formation reaction time of step (a4) is 8-20 h, for example 16 h.

[0150] In another preferred embodiment, in step (b4), the suspension-to-crystal conversion includes: reacting for 20 hours, filtering the resulting suspension, transferring the solution sample to 5°C, and transferring the adhering material to a high-low temperature cycle (50-5°C) to continue the reaction.

[0151] In another preferred embodiment, the method includes:

[0152] (c5) The oxalate crystal form I of compound A is heated to a certain temperature and transformed to obtain oxalate crystal form II.

[0153] In another preferred embodiment, the oxalate crystal form I of compound A is heated to 180-200°C to obtain oxalate crystal form II.

[0154] In another preferred embodiment, the method includes:

[0155] (a6) The compound of formula A is mixed with a second solvent and then mixed with methanesulfonic acid to obtain the methanesulfonate salt of the compound of formula A; the second solvent is selected from one or more of 1,2-dichloroethane and methanol;

[0156] (b6) The methanesulfonate of compound A is mixed with a third solvent, suspended and crystallized to obtain methanesulfonate crystal form I of compound A; the third solvent is acetone.

[0157] In another preferred embodiment, the equivalent ratio of the compound of formula A to methanesulfonic acid is 0.8-1.2:0.8-1.2, preferably 0.9-1.1:0.9-1.1, more preferably 0.95-1.05:0.95-1.05, for example 1:1.05 or 1:1.

[0158] In another preferred embodiment, step (a6) is performed at 0-10°C, for example, 5°C.

[0159] In another preferred embodiment, the salt formation reaction time of step (a6) is 8-20 h, for example 16 h.

[0160] In another preferred embodiment, step (a6) further includes: after the reaction is completed, removing the solvent by vacuum rotary evaporation.

[0161] In another preferred embodiment, step (b6) includes the following steps: reacting at room temperature for 20 hours and then filtering the resulting suspension.

[0162] In another preferred embodiment, the method includes:

[0163] (a7) The compound of formula A is mixed with a second solvent and then mixed with methanesulfonic acid to obtain the methanesulfonate salt of the compound of formula A; the second solvent is methanol;

[0164] (b7) The methanesulfonate of compound A is mixed with a third solvent, suspended and crystallized to obtain the methanesulfonate crystal form II of compound A; the third solvent is methyl tert-butyl ether.

[0165] In another preferred embodiment, the equivalent ratio of the compound of formula A to methanesulfonic acid is 0.8-1.2:0.8-1.2, preferably 0.9-1.1:0.9-1.1, more preferably 0.95-1.05:0.95-1.05, for example 1:1.05 or 1:1.

[0166] In another preferred embodiment, step (a7) is performed at room temperature, for example, 15-40°C.

[0167] In another preferred embodiment, the salt formation reaction time of step (a7) is 1-6 hours, for example, 4 hours.

[0168] In another preferred embodiment, step (b7) includes the following steps: after reacting for 18-36 hours, filtering the resulting suspension.

[0169] A third aspect of the present invention provides a pharmaceutical composition comprising an acid salt crystal form of the compound of formula A as described in the first aspect of the present invention, and a pharmaceutically acceptable carrier.

[0170] A fourth aspect of the present invention provides the use of the acid salt crystal form of the compound of formula A described in the first aspect of the present invention for the preparation of a pharmaceutical remedy, said pharmaceutical remedy being used for purposes selected from the group consisting of:

[0171] 1) Treat diseases or conditions related to EGFR and HER2 regulation;

[0172] 2) Treatment of tumors;

[0173] 3) Inhibits cell proliferation.

[0174] In another preferred embodiment, the disease or condition related to EGFR and HER2 regulation includes one or more of tumors, sarcomas, and pain.

[0175] In another preferred embodiment, the cells are selected from the group consisting of: breast cancer cells, cervical cancer cells, colon cancer cells, lung cancer cells, gastric cancer cells, rectal cancer cells, pancreatic cancer cells, brain cancer cells, skin cancer cells, oral cancer cells, prostate cancer cells, bone cancer cells, kidney cancer cells, ovarian cancer cells, bladder cancer cells, liver cancer cells, fallopian tube tumor cells, peritoneal tumor cells, melanoma cells, glioma cells, glioblastoma cells, head and neck cancer cells, papillary renal cell carcinoma cells, leukemia cells, lymphoma cells, myeloma cells, and thyroid tumor cells.

[0176] In another preferred embodiment, the tumor is one or more of the following: breast cancer, cervical cancer, colon cancer, lung cancer, stomach cancer, rectal cancer, pancreatic cancer, brain cancer, skin cancer, oral cancer, prostate cancer, bone cancer, kidney cancer, ovarian cancer, bladder cancer, liver cancer, fallopian tube tumor, peritoneal tumor, melanoma, glioma, glioblastoma, head and neck cancer, papillary renal tumor, leukemia, lymphoma, myeloma, and thyroid tumor.

[0177] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here. Attached Figure Description

[0178] Figure 1 This is the X-ray powder diffraction pattern of citrate crystal form I of the present invention;

[0179] Figure 2 This is the DSC-TGA spectrum of citrate crystal form I of this invention;

[0180] Figure 3 This is the X-ray powder diffraction pattern of the free alkali crystal form I of this invention;

[0181] Figure 4 This is a PLM diagram of the free alkali crystal form I of the present invention;

[0182] Figure 5 This is the DSC-TGA spectrum of the free alkali crystal form I of this invention;

[0183] Figure 6 This is the X-ray powder diffraction pattern of maleate crystal form I of the present invention;

[0184] Figure 7 This is the DSC-TGA spectrum of maleate crystal form I of the present invention;

[0185] Figure 8 This is the X-ray powder diffraction pattern of maleate crystal form II of the present invention;

[0186] Figure 9This is the DSC-TGA spectrum of maleate crystal form II of the present invention;

[0187] Figure 10 This is the X-ray powder diffraction pattern of oxalate crystal form I of the present invention;

[0188] Figure 11 This is the DSC-TGA spectrum of oxalate crystal form I of the present invention;

[0189] Figure 12 This is the X-ray powder diffraction pattern of oxalate crystal form II of the present invention;

[0190] Figure 13 This is the DSC-TGA spectrum of oxalate crystal form II of the present invention;

[0191] Figure 14 This is the X-ray powder diffraction pattern of methanesulfonate crystal form I of the present invention;

[0192] Figure 15 This is the DSC-TGA spectrum of methanesulfonate crystal form I of the present invention;

[0193] Figure 16 This is the X-ray powder diffraction pattern of the methanesulfonate crystal form II of this invention;

[0194] Figure 17 This is the DSC-TGA spectrum of the methanesulfonate crystal form II of this invention;

[0195] Figure 18 This is a single crystal structure diagram of citrate crystal form I of the present invention. Detailed Implementation

[0196] Through long-term and in-depth research, the inventors have prepared a series of crystal forms of acidic salt compounds of formula A with excellent stability, especially citrate crystal form I. The crystal forms of this invention not only possess excellent stability but also exhibit superior pharmacokinetics and higher in vivo exposure compared to the free base crystal forms. Based on this, the inventors completed this invention.

[0197] Crystal form

[0198] Crystal form refers to the solid state in which a drug exists. Drug crystal form research is essentially the study of the fundamental state of a drug. Only with a sufficient and comprehensive understanding of the crystal forms of chemical drugs can we find more suitable solid crystal forms for treating diseases. Drug crystal form can affect the physicochemical properties of drugs, directly influencing the basis for their clinical therapeutic effects. Different crystal forms of the same drug may exhibit significant differences in appearance, solubility, melting point, dissolution rate, and bioavailability, thus affecting the drug's stability, bioavailability, and efficacy. Therefore, studying the stable crystal form of a compound is of great significance.

[0199] The active ingredient of a drug generally exists in two or more crystalline forms, known as drug polymorphs. Different polymorphs have different solubilities and dissolution rates, affecting the drug's clinical therapeutic effect by causing changes in bioavailability in the body. Differences in drug polymorphs may affect its dissolution and absorption in the body, thus impacting bioavailability, clinical efficacy, and safety. Simultaneously, the stability of drug polymorphs is also crucial. To improve drug bioavailability, reduce toxicity, and enhance therapeutic efficacy, greater emphasis must be placed on drug polymorph stability. Stable polymorphs ensure the physicochemical stability of the drug dosage form during preparation and storage, maintaining good solubility and bioavailability, and ensuring equivalence between batches of the drug. The same drug often has multiple polymorphs; currently, the polymorph with better therapeutic effects and most suitable for clinical use is called the dominant drug polymorph.

[0200] This invention screened the crystal forms of the acid salt of the compound shown in formula (A) to identify as many different crystal forms as possible. The screened crystal forms were identified by powder X-ray diffraction (XRPD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), 1H NMR, and high performance liquid chromatography (HPLC). Furthermore, thermodynamic stability and hygroscopicity studies were conducted to determine the dominant drug citrate crystal form I, providing a reference for crystal form selection in subsequent pharmacokinetic and animal experiments.

[0201] Further pharmacokinetic studies have shown that the citrate crystal form I represented by formula (A) provided by this invention is easily absorbed and has good stability in vivo, exhibiting excellent blood drug concentration distribution and high bioavailability. Furthermore, its good physical stability results in a longer shelf life, which is highly beneficial for drug quality control in later formulation development, enabling the drug to achieve better therapeutic effects.

[0202] In this invention, a citrate crystal form I of compound A is provided, wherein the X-ray powder diffraction pattern of citrate crystal form I has characteristic peaks at the following 2θ values: 6.9±0.2°, 7.9±0.2°, 13.3±0.2°, 16.0±0.2°, and 18.6±0.2°.

[0203] In another preferred embodiment, the X-ray powder diffraction pattern of the citrate crystal form I has characteristic peaks at the following 2θ values: 6.9±0.2°, 7.9±0.2°, 11.4±0.2°, 13.3±0.2°, 15.7±0.2°, 16.0±0.2°, 16.7±0.2°, 18.6±0.2°, 19.2±0.2°, and 20.8±0.2°.

[0204] In another preferred embodiment, the X-ray powder diffraction pattern of the citrate crystal form I has characteristic peaks at the following 2θ values: 3.5±0.2°, 6.9±0.2°, 7.4±0.2°, 7.9±0.2°, 10.0±0.2°, 10.3±0.2°, 10.7±0.2°, 11.4±0.2°, 13.3±0.2°, 13.9±0.2°, 14.9±0.2°, 15.7±0.2°, 16.0±0.2°, 16 0.7±0.2°, 17.2±0.2°, 17.8±0.2°, 18.6±0.2°, 19.2±0.2°, 20.8±0.2°, 21.0±0.2°, 21.4±0.2°, 21.7±0.2°, 22.9±0.2°, 23.8±0.2°, 24.8±0.2°, 25.8±0.2°, 27.1±0.2°, 27.3±0.2°, 27.6±0.2°, 28.5±0.2°.

[0205] In another preferred embodiment, the X-ray powder diffraction pattern of citrate crystal form I is substantially as follows: Figure 1 As shown.

[0206] In another preferred embodiment, the citrate crystal form I has the following characteristics: Figure 2 The thermogravimetric analysis spectrum and differential scanning calorimetry spectrum are shown.

[0207] In another preferred embodiment, the citrate crystal form I belongs to the triclinic crystal system, space group P-1, and its unit cell parameters are... α=69.2800(10)°, β=82.1490(10)°, γ=85.5730(10)°, Z = 2.

[0208] In another preferred embodiment, the compound of formula (A) also has a crystal form selected from the group consisting of: maleate crystal form I, maleate crystal form II, oxalate crystal form I, oxalate crystal form II, and methanesulfonate crystal form II.

[0209] The X-ray powder diffraction pattern of maleate crystal form I has characteristic peaks at the following 2θ values: 6.7±0.2°, 9.6±0.2°, 14.3±0.2°, 14.6±0.2°, and 23.5±0.2°.

[0210] The X-ray powder diffraction pattern of the maleate crystal form II has characteristic peaks at the following 2θ values: 6.9±0.2°, 10.6±0.2°, 14.5±0.2°, 16.5±0.2°, and 17.0±0.2°.

[0211] The X-ray powder diffraction pattern of the oxalate crystal form I has characteristic peaks at the following 2θ values: 9.4±0.2°, 12.0±0.2°, 12.7±0.2°, 13.7±0.2°, and 21.4±0.2°.

[0212] The X-ray powder diffraction pattern of the oxalate crystal form II has characteristic peaks at the following 2θ values: 9.5±0.2°, 12.2±0.2°, 12.7±0.2°, 13.7±0.2°, and 24.8±0.2°.

[0213] The X-ray powder diffraction pattern of the methanesulfonate crystal form II has characteristic peaks at the following 2θ values: 7.3±0.2°, 9.9±0.2°, 10.9±0.2°, 13.1±0.2°, and 14.2±0.2°.

[0214] In another preferred embodiment, the X-ray powder diffraction pattern of the maleate crystal form I has characteristic peaks at the following 2θ values: 6.7±0.2°, 8.1±0.2°, 9.6±0.2°, 14.3±0.2°, 14.6±0.2°, 15.8±0.2°, 16.4±0.2°, 19.4±0.2°, 19.9±0.2°, 20.2±0.2°, 21.4±0.2°, 22.4±0.2°, and 23.5±0.2°.

[0215] The X-ray powder diffraction pattern of the maleate crystal form II has characteristic peaks at the following 2θ values: 6.9±0.2°, 10.6±0.2°, 14.5±0.2°, 15.5±0.2°, 16.1±0.2°, 16.5±0.2°, 17.0±0.2°, 19.4±0.2°, 21.5±0.2°, and 22.0±0.2°.

[0216] The X-ray powder diffraction pattern of the oxalate crystal form I has characteristic peaks at the following 2θ values: 6.8±0.2°, 9.0±0.2°, 9.4±0.2°, 10.6±0.2°, 12.0±0.2°, 12.7±0.2°, 13.7±0.2°, 14.0±0.2°, 14.2±0.2°, 15.3±0.2°, 19.9±0.2°, 20.6±0.2°, 21.4±0.2°, 22.5±0.2°, 23.6±0.2°, and 24.9±0.2°.

[0217] The X-ray powder diffraction pattern of the oxalate crystal form II has characteristic peaks at the following 2θ values: 6.8±0.2°, 9.1±0.2°, 9.5±0.2°, 10.6±0.2°, 12.2±0.2°, 12.7±0.2°, 13.7±0.2°, 13.8±0.2°, 14.3±0.2°, 14.5±0.2°, 15.2±0.2°, 17.2±0.2°, 19.3±0.2°, 19.9±0.2°, 21.1±0.2°, 21.9±0.2°, 23.1±0.2°, 23.8±0.2°, and 24.8±0.2°.

[0218] The X-ray powder diffraction pattern of the methanesulfonate crystal form I has characteristic peaks at the following 2θ values: 5.4±0.2°, 8.8±0.2°, 10.2±0.2°, 11.0±0.2°, 15.6±0.2°, 16.7±0.2°, 17.0±0.2°, 17.6±0.2°, 18.5±0.2°, 19.2±0.2°, 19.6±0.2°, 20.3±0.2°, 21.5±0.2°, 22.1±0.2°, 23.4±0.2°, 25.0±0.2°, and 29.7±0.2°.

[0219] The X-ray powder diffraction pattern of the methanesulfonate crystal form II exhibits characteristic peaks at the following 2θ values: 7.2±0.2°, 7.3±0.2°, 8.8±0.2°, 9.4±0.2°, 9.9±0.2°, 10.9±0.2°, 12.5±0.2°, 13.1±0.2°, 14.2±0.2°, 14.9±0.2°, 1 6.6±0.2°, 16.9±0.2°, 17.3±0.2°, 18.1±0.2°, 19.3±0.2°, 19.5±0.2°, 19.9±0.2°, 21.4±0.2°, 22.1±0.2°, 22.6±0.2°, 23.4±0.2°, 24.2±0.2°, 26.3±0.2°.

[0220] Preparation method

[0221] This invention also provides a method for preparing the acid salt crystal form of compound A, preferably, a method for preparing citrate crystal form I, characterized in that the method is selected from the group consisting of:

[0222] Method 1: Dissolve the free alkali compound of formula A in an organic solvent, stir, then add citric acid, continue stirring, and separate the solid and liquid to obtain citrate crystal form I;

[0223] Method 2: Add an organic solvent to the citrate of compound A, suspend and crystallize, and separate the solid and liquid phases to obtain citrate crystal form I.

[0224] In another preferred embodiment, the method is selected from the group consisting of:

[0225] Method 1: Mix the compound shown in Formula A with solvent m, add citric acid, and crystallize out; the solvent m is selected from methanol, acetone, and acetonitrile.

[0226] Method 2: Mix the citrate of the compound shown in Formula A with solvent n, suspend and crystallize to precipitate; the solvent n is selected from one or a mixture of dichloromethane, acetone, tetrahydrofuran, and acetonitrile.

[0227] In another preferred embodiment, the compound represented by formula A is a free alkali crystal form I.

[0228] use

[0229] The present invention provides the use of the acid salt crystal form of compound A, preferably, the use of citrate crystal form I in the preparation of medicaments for the prevention and / or treatment of diseases with EGFR, HER2-mediated pathological features.

[0230] In another preferred embodiment, the diseases characterized by EGFR, HER2-mediated pathology include cancer, sarcoma, and pain.

[0231] In another preferred embodiment, the cancer is one or more of the following: breast cancer, cervical cancer, colon cancer, lung cancer, stomach cancer, rectal cancer, pancreatic cancer, brain cancer, skin cancer, oral cancer, prostate cancer, bone cancer, kidney cancer, ovarian cancer, bladder cancer, liver cancer, fallopian tube tumor, peritoneal tumor, melanoma, glioma, glioblastoma, head and neck cancer, papillary renal tumor, leukemia, lymphoma, myeloma, and thyroid tumor.

[0232] Pharmaceutical Compositions and Administration

[0233] The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of one or more of the aforementioned acid salt crystal forms and a pharmaceutically acceptable carrier.

[0234] Since the acid salt crystal form of the present invention has excellent EGFR / HER2 kinase inhibitory activity, the crystal form of the present invention can be used to treat, prevent and alleviate diseases related to EGFR / HER2 kinase inhibition.

[0235] The pharmaceutical compositions of the present invention comprise, within a safe and effective range, the acidic salt crystal form of the present invention or a pharmacologically acceptable salt thereof, and a pharmacologically acceptable excipient or carrier. "Safe and effective range" refers to an amount of the crystal form of the present invention sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000 mg of the crystal form of the present invention per dose, more preferably, 10-1000 mg of the crystal form of the present invention per dose. Preferably, "one dose" is one capsule or tablet.

[0236] "Pharmaceutically acceptable carriers" refer to one or more compatible solid or liquid fillers or gelling substances that are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here refers to the ability of the components in the composition to interact with the crystal form of the present invention and to blend with each other without significantly reducing its efficacy. Examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as... Wetting agents (such as sodium dodecyl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0237] The pharmaceutical composition is an injection, capsule, tablet, pill, powder, or granule.

[0238] There are no particular limitations on the administration of the crystal form or pharmaceutical composition of the present invention. Representative administration methods include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and local administration.

[0239] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following components: (a) fillers or compatibilizers, such as starch, lactose, sucrose, glucose, mannitol, and silica; (b) binders, such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) humectants, such as glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or cassava starch, alginate, certain complex silicates, and sodium carbonate; (e) slowing agents, such as paraffin; (f) absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, such as kaolin; and (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, or mixtures thereof. Buffers may also be included in the dosage forms of capsules, tablets, and pills.

[0240] Solid dosage forms such as tablets, sugar pills, capsules, pellets, and granules can be prepared using coatings and shells, such as casings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compound from such compositions can be delayed in a portion of the digestive tract. Examples of encapsulating components that can be used are polymeric substances and waxes. If necessary, the active compound may also be formed into microcapsules with one or more of the excipients described above.

[0241] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, e.g., ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures of these substances.

[0242] In addition to these inert diluents, the composition may also contain auxiliaries such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and fragrances.

[0243] In addition to the active compound, the suspension may contain suspending agents such as ethoxylated isooctadecyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0244] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents, or excipients include water, ethanol, polyols, and suitable mixtures thereof.

[0245] Dosage forms of the crystal forms of the present invention for topical administration include ointments, powders, patches, sprays, and inhalers. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be necessary.

[0246] The crystal form of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds.

[0247] The treatment method of the present invention can be used alone or in combination with other treatment methods or drugs.

[0248] When using the pharmaceutical composition, a safe and effective amount of the crystal form of the present invention is applied to the mammal (such as a human) requiring treatment. The dosage administered is the pharmaceutically considered effective dose. For a person weighing 60 kg, the daily dose is typically 1–2000 mg, preferably 50–1000 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the patient's health condition, which are all within the scope of the skill of a skilled physician.

[0249] Compared with the prior art, the present invention has the following main advantages:

[0250] 1) The crystal form described has excellent stability and high solubility;

[0251] 2) Compared with free alkali crystal form I, the citrate crystal form I of the present invention has better pharmacokinetic properties and higher in vivo exposure in animals.

[0252] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Unless otherwise stated, percentages and parts are by weight.

[0253] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as are familiar to those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to the methods of this invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0254] The abbreviations used in this invention are as follows:

[0255] DSC Differential Scan Calorimetry

[0256] DVS Dynamic Water Vapor Adsorption

[0257] HPLC (High Performance Liquid Chromatography)

[0258] NMR mass spectrometry

[0259] PLM polarizing microscope

[0260] TGA thermogravimetric analysis

[0261] XRPD X-ray powder diffraction

[0262] Fasting simulated intestinal fluid FaSSIF

[0263] Satiety-mimicking intestinal fluid (FeSSIF)

[0264] Simulated Gastric Fluid

[0265] The technical solution of the present invention will be described in detail below.

[0266] 1. Synthesis of the compound shown in formula (A)

[0267]

[0268] The specific preparation steps are the same as described in patent PCT / CN2023 / 081557, and the synthesis route is as follows:

[0269]

[0270] The obtained solid of formula (A) was used to prepare a free alkali crystal form according to the method provided in patent PCT / CN2023 / 081557, and the free alkali crystal form was used as the starting material to carry out salt preparation experiments.

[0271] 2. Preparation and characterization of the acid salt of the compound shown in formula (A)

[0272] The 12 acids used in the salt type screening of this invention are shown in Table 1.

[0273] Table 1 Information on Acids

[0274]

[0275]

[0276] The solvent information used in the salt type screening of this invention is shown in Table 2.

[0277] Table 2 Solvent Information

[0278]

[0279] 2.1 Raw material characterization

[0280] The prepared free alkali crystal form I was fully characterized by XRPD ( Figure 3 )&PLM( Figure 4 This indicates that the free alkali crystal form is an irregularly shaped crystal with good crystallinity. (DSC) Figure 5 The curve shows an endothermic peak at 230℃, which should be a melting peak. The TGA curve shows no significant weight loss before decomposition. ¹H-NMR detected 0.85% THF and 0.09% heptane solvent residue. The results are summarized in Table 3 below.

[0281] Table 3 Characterization results of starting materials

[0282]

[0283]

[0284] 2.2 Visually assessed solubility

[0285] The solubility of free alkali crystal form I was roughly determined visually in 18 solvents at room temperature. The results are shown in Table 4. Except for good solubility in DCM and DCE, the solubility was poor in most of the tested solvents.

[0286] Table 4. Visually inspected solubility results

[0287]

[0288] 2.3 Salt Form Preparation

[0289] 2.3.1 Citrate Crystal Form I

[0290] Weigh 50 mg of free alkali crystal form I into a sample vial and dissolve it in 0.5 mL of DCE at room temperature. Then add a citric acid MeOH solution (0.1 M, 1.05 eq.). After reacting at 5 °C for 16 hours, remove the solvent by vacuum rotary evaporation. Add 1 mL of Acetone to the concentrated product and suspend for crystallization at room temperature. After reacting for 20 hours, transfer the solution sample to 5 °C, and transfer the adhering material to a high-low temperature cycle (50–5 °C) for another 3 days. The filtered solid is dried under vacuum at 50 °C and then characterized.

[0291] The DSC and TGA results for citrate crystal form I are as follows: Figure 2 As shown, TGA lost 16.8% of its weight at 164-218℃, which should be due to decomposition. There was no significant weight loss before decomposition. NMR results showed 0.74% acetone solvent residue. Based on the above results, the obtained citrate should be in the amorphous form. Single-crystal structure analysis of the citrate crystal form I was performed, and the results are as follows. Figure 18 As shown.

[0292] Its powder X-ray diffraction pattern is as follows Figure 1 As shown in Table 5:

[0293] Table 5

[0294] 2θ(°) relative strength 2θ(°) relative strength 3.5 3.1％ 21.7 6.3％ 6.9 100.0％ 21.9 1.8％ 7.4 14.5％ 22.9 17.6％ 7.9 54.3％ 23.3 4.5％ 9.6 2.0％ 23.8 14.5％ 10.0 7.6％ 24.3 4.2％ 10.3 2.1％ 24.8 7.5％ 10.7 3.3％ 25.1 2.4％ 11.4 25.4％ 25.8 9.5％ 13.3 80.6％ 26.2 4.1％ 13.9 9.1％ 26.6 3.4％ 14.9 18.9％ 27.1 13.7％ 15.7 31.0％ 27.3 6.2％ 16.0 41.6％ 27.6 7.2％ 16.7 22.9％ 28.1 2.6％ 17.2 18.5％ 28.5 6.6％ 17.8 8.0％ 29.1 1.8％ 18.6 43.5％ 30.0 2.3％ 19.2 28.6％ 30.6 3.8％ 19.7 4.1％ 34.9 2.0％ 20.8 24.6％ 36.9 3.0％ 21.0 16.5％ 37.8 2.4％ 21.4 9.4％

[0295] 2.3.2 Maleate crystal form I

[0296] Weigh 50 mg of the free alkali crystal form into a sample vial and dissolve it in 0.6 mL of 1,2-dichloroethane at room temperature. Then add a prepared methanol solution of maleic acid (0.1 M, 1.05 eq.). After reacting at 5 °C for 16 h, remove the solvent by vacuum rotary evaporation. Add 1 mL of acetone to the concentrated product and suspend for crystallization at room temperature. After reacting for 20 h, filter the resulting suspension. The filtered solid is dried under vacuum at 50 °C for characterization.

[0297] The DSC and TGA results for maleate crystal form I are as follows: Figure 7 As shown. NMR results showed 5.44% acetone solvent residue, and TGA lost 5.5% weight at 72-152℃, which may be a solvate, named maleate crystal form I.

[0298] Its powder X-ray diffraction pattern is as follows Figure 6 As shown in Table 6:

[0299] Table 6

[0300] 2θ(°) relative strength 2θ(°) relative strength 6.7 100.00％ 20.2 14.80％ 7.8 7.60％ 20.6 3.50％ 8.1 15.50％ 21.1 2.00％ 9.6 30.50％ 21.4 10.60％ 10.2 4.20％ 21.8 3.60％ 11.2 2.00％ 22.4 13.90％ 12.9 4.40％ 23.1 8.70％ 13.8 4.10％ 23.5 17.80％ 14.3 34.80％ 23.9 6.10％ 14.6 19.40％ 24.6 9.40％ 15.2 5.20％ 25.5 7.00％ 15.8 15.30％ 26.1 8.40％ 16.0 4.30％ 26.4 4.90％ 16.4 16.20％ 28.1 2.20％ 16.6 3.90％ 28.3 3.10％ 18.7 8.70％ 28.7 3.10％ 19.0 7.00％ 29.6 2.50％ 19.4 10.50％ 30.2 2.00％ 19.9 13.30％ 32.5 1.70％ 34.0 2.40％

[0301] 2.3.3 Maleate crystal form II

[0302] Weigh 50 mg of free base crystal form I into a sample vial and add it to 0.2–0.5 mL of MeOH (white suspension) at room temperature. Then add a prepared 0.1 M maleic acid methanol solution (0.1 M, 1.05 eq.). After reacting at room temperature for about 4 h, add 6 mL of methyl tert-butyl ether and continue reacting for 20 h. Filter the suspension, dry it under vacuum, and then characterize it.

[0303] The DSC and TGA results for maleate crystal form II are as follows: Figure 9 As shown. NMR results showed 0.37% methyl tert-butyl ether residue. TGA showed a weight loss of 1.3% at 23.5-50℃, and corresponding DSC showed an endothermic peak at 47-71℃. After heating to 120℃ with DSC, the crystal form, DSC and TGA did not change after heating. It is speculated that maleate crystal form II may be hydrated or a hygroscopic amorphous form.

[0304] Its powder X-ray diffraction pattern is as follows Figure 8 As shown in Table 7:

[0305] Table 7

[0306] 2θ(°) relative strength 2θ(°) relative strength 6.9 100.0％ 19.1 4.0％ 7.3 3.2％ 19.4 10.6％ 8.7 1.2％ 20.0 1.8％ 9.8 6.5％ 20.2 3.3％ 10.6 22.5％ 21.1 5.7％ 11.1 1.1％ 21.5 9.8％ 11.6 3.1％ 22.0 10.9％ 13.0 1.3％ 22.4 1.4％ 14.2 3.2％ 22.8 2.0％ 14.5 15.7％ 23.1 8.3％ 15.0 2.4％ 24.2 6.4％ 15.5 8.4％ 25.2 6.9％ 16.1 11.3％ 25.8 6.8％ 16.5 23.7％ 26.8 3.6％ 17.0 16.1％ 27.3 6.6％ 17.3 3.4％ 28.5 1.4％ 17.7 1.6％ 29.5 0.8％ 18.1 2.2％ 30.1 2.4％ 18.6 3.6％ 32.4 1.0％

[0307] 2.3.4 Oxalate Crystal Form I

[0308] Weigh 50 mg of free alkali crystal form I into a sample vial and dissolve it in 0.6 mL of 1,2-dichloroethane at room temperature. Then add oxalic acid (1.05 eq) in methanol or DCE solution. After reacting at 5 °C for 16 h, remove the solvent by vacuum rotary evaporation. Add 1 mL of acetone to the concentrated product and suspend for crystallization at room temperature. After reacting for 20 h, filter the resulting suspension. Transfer the solution sample to 5 °C, and transfer the adhering material to a high-low temperature cycle (50-5 °C) to continue the reaction. The filtered solid is dried under vacuum and characterized to obtain oxalate crystal form I.

[0309] The DSC and TGA results for oxalate crystal form I are as follows: Figure 11 As shown. According to NMR, it contains approximately 0.49 mol of acetone, and the corresponding TGA shows a 4.9% weight loss at 100-200℃. The XRPD changes after heating oxalate crystal form I to 190℃, leading to the conclusion that oxalate crystal form I is an acetone solvate.

[0310] Its powder X-ray diffraction pattern is as follows Figure 10 As shown in Table 8:

[0311] Table 8

[0312] 2θ(°) relative strength 2θ(°) relative strength 6.8 36.9％ 22.5 37.3％ 9.0 28.8％ 22.9 25.3％ 9.4 67.9％ 23.2 24.0％ 10.6 28.7％ 23.6 32.7％ 12.0 100.0％ 24.3 11.9％ 12.7 62.7％ 24.9 47.4％ 13.7 50.3％ 25.9 9.1％ 14.0 38.1％ 26.2 7.9％ 14.2 31.6％ 26.4 12.2％ 15.3 31.3％ 26.7 10.3％ 15.6 10.5％ 27.4 7.5％ 16.9 11.5％ 27.6 6.2％ 17.6 12.4％ 28.3 9.5％ 18.2 15.3％ 28.8 3.2％ 18.6 12.7％ 29.1 4.2％ 19.1 28.5％ 29.6 3.7％ 19.5 8.2％ 30.9 8.0％ 19.9 45.4％ 32.1 4.2％ 20.6 46.9％ 32.5 3.1％ 21.1 8.6％ 34.0 3.0％ 21.4 56.2％ 36.2 3.1％ 22.1 8.9％

[0313] 2.3.5 Oxalate Crystal Form II

[0314] The sample obtained after heating oxalate crystal form I to 190℃ was characterized to yield oxalate crystal form II. TGA results showed no significant weight loss before decomposition. DSC and TGA results are as follows: Figure 13 As shown. Therefore, oxalate crystal form II may be amorphous.

[0315] The powder X-ray diffraction pattern of oxalate crystal form II is as follows: Figure 12 As shown in Table 9:

[0316] Table 9

[0317]

[0318]

[0319] 2.3.6 Methanesulfonate crystal form I

[0320] Weigh 50 mg of free alkali crystal form I and dissolve it in 0.6 mL of DCE at room temperature. Add a prepared methanol solution of methanesulfonic acid (1.05 eq). After reacting at 5 °C for 16 h, remove the solvent by vacuum rotary evaporation. Add 1 mL of acetone to the concentrated product and suspend for crystallization at room temperature. After reacting for 20 h, filter the resulting suspension. Dry the filtered solid under vacuum at 50 °C for at least 3 h before characterization.

[0321] The DSC and TGA results for methanesulfonate crystal form I are as follows: Figure 15 As shown, there was no significant weight loss before decomposition, and the DSC showed only one endothermic peak at 258℃, which should be a melting peak. The NMR showed 0.33% acetone solvent residue, and the salt formation ratio of free base to methanesulfonic acid was approximately 1:1, indicating that methanesulfonate crystal form I should be amorphous.

[0322] The powder X-ray diffraction pattern of methanesulfonate crystal form I is as follows: Figure 14 As shown in Table 10:

[0323] Table 10

[0324]

[0325]

[0326] 2.3.7 Methanesulfonate crystal form II

[0327] Weigh 50 mg of free alkali crystal form I into a sample vial and add it to 0.2 mL of MeOH at room temperature, followed by the addition of a methanol solution of methanesulfonic acid (1.05 eq). After reacting at room temperature for approximately 4 hours, add 6 mL of methyl tert-butyl ether. Continue the reaction for 1 day, then filter the suspension, dry it under vacuum at 50 °C, and characterize it.

[0328] The DSC and TGA results for mesylate crystal form II are as follows: Figure 17 As shown, a weight loss of 0.9% was observed between 23-80℃, with an endothermic peak at 76℃ as indicated by DSC. NMR showed only 0.18% methyl tert-butyl ether residue. When methanesulfonate crystal form II was heated to 120℃ using DSC and immediately subjected to XRPD analysis, no crystal form transformation occurred. The weight loss was likely due to surface-adsorbed water. Therefore, it is inferred that methanesulfonate crystal form II is an amorphous form. Methanesulfonate crystal form II exhibits a set of transformation peaks between 168-189℃. Heating methanesulfonate crystal form II to 210℃ resulted in transformation to methanesulfonate crystal form I. The endothermic peak at 257℃ for methanesulfonate crystal form II should be the melting point after the transformation to crystal form I.

[0329] The powder X-ray diffraction pattern of methanesulfonate crystal form II is as follows: Figure 16 As shown in Table 11:

[0330] Table 11

[0331]

[0332]

[0333] This invention employs methods such as pre-salting followed by suspension-to-crystal conversion and direct salt formation to experiment with the preparation of salts from free base crystal form I and different acids in various solvent systems. The characterization results for salt formation with acids such as phosphoric acid, fumaric acid, L-malic acid, hydrochloric acid, and methanesulfonic acid are summarized in Table 12.

[0334] Table 12

[0335]

[0336]

[0337] 3. Analytical Methods

[0338] 3.1 X-ray powder diffraction (XRPD)

[0339] XRPD diffraction patterns were acquired using a Bruker D2 Phaser. The sample was placed on a smooth, background-free silicon wafer for measurement. Measurement parameters are shown in Table 13.

[0340] Table 13 XRPD Method Parameters

[0341]

[0342] 3.2 Polarizing Microscope (PLM)

[0343] PLM analysis was performed using an Ottoman BK-Pol optical microscope. A small amount of sample was placed on a glass slide, a drop of silicone oil was added to disperse it, a coverslip was then placed on top, and the sample was observed under the microscope.

[0344] 3.3 Differential Scanning Calorimetry (DSC)

[0345] The DSC curves were acquired using a TA instrument with a DSC 250 sensor. The testing method for the DSC 250 instrument was as follows: an appropriate amount of sample was accurately weighed into a perforated aluminum crucible, and the temperature was increased from 25°C to the final temperature at a rate of 10°C / min. Instrument parameters are shown in Table 14.

[0346] Table 14 DSC Analysis Parameters

[0347] instrument TA,250 Sample tray Perforated aluminum crucible Temperature range 25-300℃ heating rate 10℃ / min purge air Nitrogen Flow rate 50 mL / min

[0348] 3.4 Thermogravimetric Analysis (TGA)

[0349] TGA data were acquired using a TGA 550 instrument from TA. An appropriate amount of sample was placed in a pre-peeled aluminum crucible and heated from room temperature to 300°C at a rate of 10°C / min. The temperature program and equipment parameters of the TGA 550 instrument are shown in Table 15.

[0350] Table 15 TGA Analysis Parameters

[0351]

[0352] 3.5 Dynamic Water Vapor Adsorption (DVS)

[0353] Moisture adsorption / desorption data were collected by DVS Intrinsic. Approximately 20–30 mg of sample was placed in a pre-peeled sample chamber and automatically weighed. The sample was dried at 40 °C / 0% RH until dm / dt ≤ 0.002%. After cooling to 25 °C and dm / dt ≤ 0.002%, the test was started using the operating parameters in Table 16.

[0354] Table 16 DVS Analysis Parameters

[0355]

[0356]

[0357] 3.6 Nuclear Magnetic Resonance Mass Spectrometry (NMR Mass Spectrometry) 1 H-NMR)

[0358] NMR data were acquired using a Varian or Bruker 400MHz instrument. Unless otherwise specified, samples were prepared with DMSO-d6 and measured using the parameters shown in Table 17.

[0359] Table 17 NMR Analysis Parameters

[0360] equipment Varian or Bruker frequency 400mHz Number of scans 8 temperature ～25℃

[0361] 3.7 High Performance Liquid Chromatography (HPLC)

[0362] Liquid chromatography analysis was performed using a Shimadzu SPD-20. See Table 18 for the liquid chromatography methods used for solubility and stability.

[0363] Table 18 HPLC Methods

[0364]

[0365]

[0366] 4. Evaluation of the crystal forms of the acid salt and free base of the compound shown in formula (A)

[0367] In this salt type screening study, seven crystal forms were obtained: citrate crystal form I, maleate crystal form I, maleate crystal form II, oxalate crystal form I, oxalate crystal form II, methanesulfonate crystal form I, and methanesulfonate crystal form II.

[0368] Based on the solid-state characterization data of the salts and the results of the free-state crystal form screening, citrate crystal form I, maleate crystal form II, and methanesulfonate crystal form I were selected for solubility, stability, and drug metabolism studies.

[0369] 4.1 Solubility Study

[0370] The solubility of citrate form I, maleate form II, methanesulfonate form I, and free alkali form I was tested in biological media and water at 37°C. All results are shown in Table 19.

[0371] Table 19 Solubility test results of biological solvents in water

[0372]

[0373]

[0374] The three salt forms, citrate form I, maleate form II, and methanesulfonate form I, have better solubility in water and biological solvents (FaSSIF and FeSSIF) than free alkali form I, and their solubility in SGF is comparable.

[0375] 4.2 Solid-state stability study

[0376] Appropriate amounts of citrate crystal form I, maleate crystal form II, and methanesulfonate crystal form I were spread evenly in sample vials and placed openly under five different conditions for 7 days: 80℃ (3d), 60℃, 25℃ / 60%RH, 40℃ / 75%RH, and 25℃ / 90±5%RH. Samples were taken at 3 and 7 days for HPLC and XRPD analysis.

[0377] Stability studies showed that citrate crystal form I did not change significantly in crystal form and chemical purity under the above five conditions; maleate crystal form II transformed into unstable hydrated maleate after 7 days at 25℃ / 90±5%RH, with no significant changes observed under other conditions; methanesulfonate crystal form I did not change in crystal form under the above conditions. The results are summarized in Table 20.

[0378] Table 20 Stability Test Results

[0379]

[0380] (a) The purity values ​​above are the average of the three parallel experiments.

[0381] 4.3 Drug Metabolism Studies

[0382] In vivo drug metabolism experiments were conducted on rats using citrate crystal form I, methanesulfonate crystal form I, and free base crystal form I.

[0383] SD rats were administered citrate crystal form I, mesylate crystal form I, and free base crystal form I via single gavage. Blood samples were collected at different time points to determine the drug concentration in rat plasma after administration and to calculate relevant pharmacokinetic parameters.

[0384] 4.3.1 Preparation of the test sample solution

[0385] The preparation method is as follows:

[0386] Accurately weigh citrate crystal form I, methanesulfonate crystal form I, and free alkali crystal form I, add 5% DMSO, 10% solubil HS-15, and 85% saline, vortex and mix well, then set aside.

[0387] 4.3.2 Analysis of the test solution

[0388] The prepared test solutions were analyzed by the analytical department of this laboratory using LC-MS / MS.

[0389] 4.3.3 Animal Reception and Adaptation

[0390] Fasting (at least 10 hours) began the day before the experiment, but water was allowed. On the day of the experiment, the participants were weighed and marked on their tails. Blank blood samples were collected before drug administration. Blood was collected via tail vein.

[0391] 4.3.4 Sample Collection and Processing

[0392] The blood collection time points are:

[0393] Oral administration: 0.5, 1, 2, 4, 6, 8, 12 and 24 hours after administration.

[0394] Collect 0.1 ml of whole blood into an EDTA-Na2 anticoagulant tube, invert 3-4 times to mix, centrifuge at 10000g for 5 min at 4℃ to separate plasma, and store at -80℃ for later testing. Blood was collected via tail vein.

[0395] Plasma samples were analyzed by the laboratory's analytical department using LC-MS / MS.

[0396] 4.3.5 Pharmacokinetic Analysis

[0397] Based on the drug's blood concentration data, the AUC of the test sample was calculated using the WinNonlin non-compartmental pharmacokinetic model software. 0-last C max Tmax and T 1 / 2 and its mean and standard deviation.

[0398] 4.3.6 Experimental Results

[0399] The main pharmacokinetic parameters in plasma after a single oral gavage administration of citrate crystal form I, mesylate crystal form I, and free base crystal form I are shown in Table 21.

[0400] Table 21 Pharmacokinetic parameters of rats

[0401]

[0402] The above pharmacokinetic results show that the exposure levels of citrate crystal form I and mesylate crystal form I in rats were both higher than those of free alkali crystal form I.

[0403] In summary, citrate crystal form I exhibits good solubility, high exposure in animals, and excellent solid-state stability, making it suitable for further research and development.

[0404] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. An acid salt crystal form of a compound of formula A, characterized in that, The salt crystal form is selected from the following group: citrate crystal form I, maleate crystal form I, maleate crystal form II, oxalate crystal form I, oxalate crystal form II, methanesulfonate crystal form I, and methanesulfonate crystal form II. （A） in, The X-ray powder diffraction pattern of the citrate crystal form I includes characteristic peaks at 6.9±0.2°, 13.3±0.2°, and three or more at 2θ values ​​selected from the following group: 7.9±0.2°, 11.4±0.2°, 15.7±0.2°, 16.0±0.2°, 16.7±0.2°, 18.6±0.2°, 19.2±0.2°, and 20.8±0.2°. The X-ray powder diffraction pattern of maleate crystal form I includes characteristic peaks at 8.1±0.2°, 14.6±0.2° and three or more at 2θ values ​​selected from the following group: 6.7±0.2°, 9.6±0.2°, 14.3±0.2°, 15.8±0.2°, 16.4±0.2°, 20.2±0.2°, 22.4±0.2°, 23.5±0.2°; The X-ray powder diffraction pattern of the maleate crystal form II includes characteristic peaks at 10.6±0.2°, 14.5±0.2°, 16.5±0.2° and two or more at 2θ values ​​selected from the following group: 6.9±0.2°, 15.5±0.2°, 16.1±0.2°, 17.0±0.2°, 19.4±0.2°, 21.5±0.2°, 22.0±0.2°; The X-ray powder diffraction pattern of the oxalate crystal form I includes characteristic peaks at 12.0±0.2°, 20.6±0.2°, and three or more at 2θ values ​​selected from the following group: 6.8±0.2°, 9.4±0.2°, 12.7±0.2°, 13.7±0.2°, 14.0±0.2°, 19.9±0.2°, 21.4±0.2°, 22.5±0.2°, and 24.9±0.2°. The X-ray powder diffraction pattern of the oxalate crystal form II includes characteristic peaks at 12.2±0.2°, 14.5±0.2°, and three or more at 2θ values ​​selected from the following group: 9.1±0.2°, 9.5±0.2°, 10.6±0.2°, 12.7±0.2°, 13.7±0.2°, 14.3±0.2°, 19.9±0.2°, 21.9±0.2°, 23.1±0.2°, 24.8±0.2°; The X-ray powder diffraction pattern of the methanesulfonate crystal form I includes characteristic peaks at 8.8±0.2°, 10.2±0.2° and three or more at 2θ values ​​selected from the following group: 11.0±0.2°, 15.6±0.2°, 16.7±0.2°, 17.0±0.2°, 18.5±0.2°, 19.2±0.2°, 22.1±0.2°, 23.4±0.2°, 25.0±0.2°; The X-ray powder diffraction pattern of the methanesulfonate crystal form II includes characteristic peaks at 7.3±0.2°, 12.5±0.2° and four or more 2θ values ​​selected from the following group: 7.2±0.2°, 8.8±0.2°, 9.9±0.2°, 10.9±0.2°, 13.1±0.2°, 14.2±0.2°, 14.9±0.2°, 16.6±0.2°, 16.9±0.2°, 22.1±0.2°, 22.6±0.2°, and 23.4±0.2°.

2. The acid salt crystal form as described in claim 1, characterized in that, The X-ray powder diffraction pattern of the citrate crystal form I includes characteristic peaks at 6.9±0.2°, 13.3±0.2°, and four or more 2θ values ​​selected from the following group: 7.9±0.2°, 11.4±0.2°, 14.9±0.2°, 15.7±0.2°, 16.0±0.2°, 16.7±0.2°, 17.2±0.2°, 18.6±0.2°, 19.2±0.2°, 20.8±0.2°, 21.0±0.2°, 22.9±0.2°, 23.8±0.2°, and 27.1±0.2°. The X-ray powder diffraction pattern of maleate crystal form I includes characteristic peaks at 8.1±0.2°, 14.6±0.2°, and four or more 2θ values ​​selected from the following group: 6.7±0.2°, 9.6±0.2°, 14.3±0.2°, 15.8±0.2°, 16.4±0.2°, 19.4±0.2°, 19.9±0.2°, 20.2±0.2°, 21.4±0.2°, 22.4±0.2°, 23.5±0.2°, and 24.6±0.2°. The X-ray powder diffraction pattern of the maleate crystal form II includes characteristic peaks at 10.6±0.2°, 14.5±0.2°, 16.5±0.2° and three or more 2θ values ​​selected from the following group: 6.9±0.2°, 9.8±0.2°, 15.5±0.2°, 16.1±0.2°, 17.0±0.2°, 19.4±0.2°, 21.5±0.2°, 22.0±0.2°, 23.1±0.2°, 25.2±0.2°, 25.8±0.2°, 27.3±0.2°; The X-ray powder diffraction pattern of the oxalate crystal form I includes characteristic peaks at 12.0±0.2°, 20.6±0.2°, and four or more 2θ values ​​selected from the following group: 6.8±0.2°, 9.0±0.2°, 9.4±0.2°, 10.6±0.2°, 12.7±0.2°, 13.7±0.2°, 14.0±0.2°, 14.2±0.2°, 15.3±0.2°, 19.1±0.2°, 19.9±0.2°, 21.4±0.2°, 22.5±0.2°, 23.6±0.2°, and 24.9±0.2°. The X-ray powder diffraction pattern of the oxalate crystal form II includes characteristic peaks at 12.2±0.2°, 14.5±0.2°, and four or more 2θ values ​​selected from the following group: 6.8±0.2°, 9.1±0.2°, 9.5±0.2°, 10.6±0.2°, 12.7±0.2°, 13.7±0.2°, 13.8±0.2°, 14.3±0.2°, 19.9±0.2°, 21.1±0.2°, 21.9±0.2°, 23.1±0.2°, 23.8±0.2°, and 24.8±0.2°. The X-ray powder diffraction pattern of the methanesulfonate crystal form I includes characteristic peaks at 8.8±0.2°, 10.2±0.2°, and four or more 2θ values ​​selected from the following group: 11.0±0.2°, 15.6±0.2°, 16.7±0.2°, 17.0±0.2°, 17.6±0.2°, 18.5±0.2°, 19.2±0.2°, 19.6±0.2°, 20.3±0.2°, 21.5±0.2°, 22.1±0.2°, 22.7±0.2°, 23.4±0.2°, and 25.0±0.2°. The X-ray powder diffraction pattern of the methanesulfonate crystal form II includes characteristic peaks at 7.3±0.2°, 12.5±0.2° and five or more at 2θ values ​​selected from the following group: 7.2±0.2°, 8.8±0.2°, 9.9±0.2°, 10.9±0.2°, 13.1±0.2°, 14.2±0.2°, 14.9±0.2°, 16.6±0.2°, 16.9±0.2°, 22.1±0.2°, 22.6±0.2°, and 23.4±0.2°.

3. The acid salt crystal form as described in claim 1, characterized in that, The X-ray powder diffraction pattern of the citrate crystal form I includes characteristic peaks at the following 2θ values: 6.9±0.2°, 7.9±0.2°, 11.4±0.2°, 13.3±0.2°, 15.7±0.2°, 16.0±0.2°, 16.7±0.2°, 18.6±0.2°, 19.2±0.2°, 20.8±0.2°; The X-ray powder diffraction pattern of maleate crystal form I includes characteristic peaks at the following 2θ values: 6.7±0.2°, 8.1±0.2°, 9.6±0.2°, 14.3±0.2°, 14.6±0.2°, 15.8±0.2°, 16.4±0.2°, 20.2±0.2°, 22.4±0.2°, 23.5±0.2°; The X-ray powder diffraction pattern of the maleate crystal form II includes characteristic peaks at the following 2θ values: 6.9±0.2°, 10.6±0.2°, 14.5±0.2°, 15.5±0.2°, 16.1±0.2°, 16.5±0.2°, 17.0±0.2°, 19.4±0.2°, 21.5±0.2°, 22.0±0.2°; The X-ray powder diffraction pattern of the oxalate crystal form I includes characteristic peaks at the following 2θ values: 6.8±0.2°, 9.4±0.2°, 12.0±0.2°, 12.7±0.2°, 13.7±0.2°, 14.0±0.2°, 19.9±0.2°, 20.6±0.2°, 21.4±0.2°, 22.5±0.2°, and 24.9±0.2°. The X-ray powder diffraction pattern of the oxalate crystal form II includes characteristic peaks at the following 2θ values: 9.1±0.2°, 9.5±0.2°, 10.6±0.2°, 12.2±0.2°, 12.7±0.2°, 13.7±0.2°, 14.3±0.2°, 14.5±0.2°, 19.9±0.2°, 21.9±0.2°, 23.1±0.2°, and 24.8±0.2°. The X-ray powder diffraction pattern of the methanesulfonate crystal form I includes characteristic peaks at the following 2θ values: 8.8±0.2°, 10.2±0.2°, 11.0±0.2°, 15.6±0.2°, 16.7±0.2°, 17.0±0.2°, 18.5±0.2°, 19.2±0.2°, 22.1±0.2°, 23.4±0.2°, and 25.0±0.2°. The X-ray powder diffraction pattern of the methanesulfonate crystal form II includes characteristic peaks at the following 2θ values: 7.2±0.2°, 7.3±0.2°, 8.8±0.2°, 9.9±0.2°, 10.9±0.2°, 12.5±0.2°, 13.1±0.2°, 14.2±0.2°, 14.9±0.2°, 16.6±0.2°, 16.9±0.2°, 22.1±0.2°, 22.6±0.2°, and 23.4±0.2°.

4. The acid salt crystal form as described in claim 1, characterized in that, The X-ray powder diffraction pattern of the citrate crystal form I is basically shown in Figure 1; The X-ray powder diffraction pattern of maleate crystal form I is basically shown in Figure 6; The X-ray powder diffraction pattern of the maleate crystal form II is basically shown in Figure 8; The X-ray powder diffraction pattern of the oxalate crystal form I is basically shown in Figure 10. The X-ray powder diffraction pattern of the oxalate crystal form II is basically shown in Figure 12; The X-ray powder diffraction pattern of the methanesulfonate crystal form I is basically shown in Figure 14. The X-ray powder diffraction pattern of the methanesulfonate crystal form II is shown in Figure 16.

5. The acid salt crystal form as described in claim 1, characterized in that, The thermogravimetric analysis spectrum and differential scanning calorimetry spectrum of citrate crystal form I are basically shown in Figure 2; The thermogravimetric analysis spectrum and differential scanning calorimetry spectrum of maleate crystal form I are basically shown in Figure 7; The thermogravimetric analysis spectrum and differential scanning calorimetry spectrum of maleate crystal form II are basically shown in Figure 9; The thermogravimetric analysis spectrum and differential scanning calorimetry spectrum of the oxalate crystal form I are basically shown in Figure 11; The thermogravimetric analysis spectrum and differential scanning calorimetry spectrum of the oxalate crystal form II are basically shown in Figure 13; The thermogravimetric analysis spectrum and differential scanning calorimetry spectrum of the methanesulfonate crystal form I are basically shown in Figure 15; The thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) spectra of the methanesulfonate crystal form II are basically shown in Figure 17.

6. The acid salt crystal form as described in claim 1, characterized in that, The citrate crystal form I belongs to the triclinic crystal system, space group P-1, with cell parameters a = 11.9331(2) Å, b = 13.4684(2) Å, c = 13.6474(2) Å, α = 69.2800(10)°, β = 82.1490(10)°, γ = 85.5730(10)°, V = 2031.32(6) Å3, Z = 2.

7. The acid salt crystal form as described in claim 1, characterized in that, In the citrate crystal form I, the equivalent ratio of compound A to citric acid is 0.8-1.2:0.8-1.2; In the maleate crystal form I, the equivalence ratio of compound A to maleic acid is 0.8-1.2:0.8-1.2; In the maleate crystal form II, the equivalent ratio of compound A to maleic acid is 0.8-1.2:0.8-1.2; In the oxalate crystal form I, the equivalent ratio of the compound of formula A to oxalic acid is 0.8-1.2:0.8-1.2; In the oxalate crystal form I, the equivalent ratio of the compound of formula A to oxalic acid is 0.8-1.2:0.8-1.2; In the methanesulfonate crystal form I, the molar ratio of compound A to methanesulfonic acid is 0.9-1.1:0.9-1.1; In the methanesulfonate crystal form II, the molar ratio of compound A to methanesulfonic acid is 0.9-1.1:0.9-1.

1.

8. The acid salt crystal form as described in claim 1, characterized in that, In the citrate crystal form I, the equivalent ratio of compound A to citric acid is 0.9-1.1:0.9-1.1; In the maleate crystal form I, the equivalence ratio of compound A to maleic acid is 0.9-1.1:0.9-1.1; In the maleate crystal form II, the equivalence ratio of compound A to maleic acid is 0.9-1.1:0.9-1.1; In the oxalate crystal form I, the equivalent ratio of compound A to oxalic acid is 0.9-1.1:0.9-1.1; In the oxalate crystal form I, the equivalent ratio of compound A to oxalic acid is 0.9-1.1:0.9-1.

1.

9. A method for preparing the acid salt crystal form of compound A as described in claim 1, characterized in that, The method includes: (a1) The compound of formula A is mixed with a second solvent and then mixed with citric acid to obtain the citrate of the compound of formula A; the second solvent is selected from one or more of 1,2-dichloroethane and methanol; (b1) The citrate of compound A is mixed with a third solvent, suspended and crystallized to obtain citrate I of compound A; the third solvent is acetone; Alternatively, the method may include: (a2) The compound of formula A is mixed with a second solvent and then mixed with maleic acid to obtain the maleate salt of the compound of formula A; the second solvent is selected from one or more of 1,2-dichloroethane and methanol; (b2) The maleate salt of compound A is mixed with a third solvent, suspended and crystallized to obtain maleate salt crystal form I of compound A; the third solvent is acetone; Alternatively, the method may include: (a3) The compound of formula A is mixed with a second solvent and then mixed with maleic acid to obtain the maleate salt of the compound of formula A; the second solvent is methanol; (b3) The maleate salt of compound A is mixed with a third solvent, suspended and crystallized to obtain maleate salt crystal form II of compound A; the third solvent is methyl tert-butyl ether; Alternatively, the method may include: (a4) The compound of formula A is mixed with a second solvent and then mixed with oxalic acid to obtain the oxalate of the compound of formula A; the second solvent is one or more of 1,2-dichloroethane and methanol; (b4) The oxalate of compound A is mixed with a third solvent, suspended and crystallized to obtain oxalate crystal form I of compound A; the third solvent is acetone; Alternatively, the method may include: (c5) The oxalate crystal form I of compound A is heated to a certain temperature and transformed to obtain oxalate crystal form II; Alternatively, the method may include: (a6) The compound of formula A is mixed with a second solvent and then mixed with methanesulfonic acid to obtain the methanesulfonate salt of the compound of formula A; the second solvent is selected from one or more of 1,2-dichloroethane and methanol; (b6) The methanesulfonate of compound A is mixed with a third solvent, suspended and crystallized to obtain crystal form I of methanesulfonate of compound A; the third solvent is acetone; Alternatively, the method may include: (a7) The compound of formula A is mixed with a second solvent and then mixed with methanesulfonic acid to obtain the methanesulfonate salt of the compound of formula A; the second solvent is methanol; (b7) The methanesulfonate of compound A is mixed with a third solvent, suspended and crystallized to obtain crystal form II of methanesulfonate of compound A; the third solvent is methyl tert-butyl ether.

10. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises the acid salt crystal form of the compound of formula A as described in claim 1, and a pharmaceutically acceptable carrier.

11. Use of the acid salt crystal form of compound A according to any one of claims 1-8 in the preparation of a pharmaceutical product, characterized in that, The drug is used to prevent and / or treat diseases or conditions related to EGFR and HER2 regulation.

12. The use according to claim 11, characterized in that, The diseases or conditions related to EGFR and HER2 regulation include tumors.

13. The use according to claim 12, characterized in that, The tumor mentioned is one or more of the following: breast cancer, colon cancer, lung cancer, stomach cancer, rectal cancer, glioblastoma, and head and neck cancer.

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