Crystal, pharmaceutical composition and preparation method and application thereof

Abstract

The present application relates to a pharmaceutical composition of a crystal form A of a compound of formula I. The composition has excellent storage stability and dissolution performance, and the crystal form A has good stability, reduced hygroscopicity and good bioavailability. The pharmaceutical composition and the crystal form A have very important meanings for improving the production and quality control of medicines, the development prospect of solid oral preparations and the like.

Description

Technical Field

[0001] The present invention belongs to the technical field of medicinal chemistry, and particularly relates to crystal forms of compounds used as kinase inhibitors, their preparation methods and applications. Background Art

[0002] The tropomyosin receptor kinase (TRK) family belongs to the transmembrane receptor tyrosine kinases (RTKs) and is involved in regulating synaptic growth and function maintenance in the mammalian nervous system, the occurrence and development of memory, and protecting neurons from damage. TRK kinases are a class of nerve growth factor receptors, and the family consists of highly homologous tropomyosin-related kinase A (TRKA), tropomyosin-related kinase B (TRKB), and tropomyosin-related kinase C (TRKC), which are encoded by the NTRK1, NTRK2, and NTRK3 genes, respectively. The complete TRK kinase includes three parts: an extracellular region, a transmembrane region, and an intracellular region. Like other RTKs, after the extracellular region of the TRK kinase binds to the corresponding ligand, it forms a dimer, which can cause autophosphorylation of the intracellular region of the TRK kinase, thereby activating its own kinase activity and further activating the downstream signal transduction pathway. TRK kinases affect cell proliferation, differentiation, metabolism, and apoptosis through downstream pathways such as Ras / MAPK, PI3K / AKT, and PLCγ. When the NTRKs genes undergo fusion or mutation, it will alter or eliminate the extracellular receptor (Greco, A. et al, Mol. Cell. Biol. 1995, 15, 6118; Oncogene 1998, 16, 809). Without ligand binding, the fused or mutated TRK protein is in a highly activated kinase activity state, which can continuously activate the downstream signal transduction pathway, leading to abnormal regulation of the TRK kinase downstream signal pathway, inducing cell proliferation, and promoting tumor occurrence and development. NTRKs gene fusions occur in a variety of adult and pediatric solid tumors, including breast cancer, colorectal cancer, non-small cell lung cancer, papillary thyroid cancer, Spitzoid melanoma, glioma, and various sarcomas. In common cancers such as non-small cell lung cancer and colorectal cancer, the incidence of NTRK gene fusions is relatively low, approximately 1%-3%. However, in some rare cancers such as infantile fibrosarcoma and secretory breast carcinoma, the incidence of NTRK gene fusions can reach over 90%. The earliest TPM3-TRKA fusion protein was discovered in colon cancer cells. Subsequently, more types of NTRK fusion proteins, such as CD74-NTRKA, MPRIP-NTEKA, QKI-NTRKB, ETV6-NTRKC, BTB1-NTRKC, etc., were found in different clinical tumor patient samples, such as breast cancer, non-small cell lung cancer, papillary thyroid cancer, Spitzoid melanoma, glioma, etc. Therefore, in recent years, NTRK fusion proteins have become an effective anti-cancer target and a hot spot in anti-cancer drug research and development.With the further in-depth understanding of TRK kinases in recent years, more types of TRK fusion proteins and mutation types have been discovered (Russo, M. et.al Cancer; Discovery, 2016, 6, 36; Drilon, A. et al, Annals of Oncology, 2016, 27, 920). Therefore, there is an urgent need in clinical practice to develop new NTRK inhibitors with better activity and a wider range of effects to solve the treatment problems of tumors caused by these NTRK protein fusions or mutations.

[0003] ROS1 (c-ros oncogene 1 receptor kinase) is a tyrosine protein kinase encoded by the ROS1 proto-oncogene in the human body. It is located on chromosome 6q22.1 and belongs to the insulin receptor gene of tyrosine kinase. It consists of three parts: an intracellular tyrosine kinase active region, a transmembrane region, and an extracellular region, encoding a chimeric protein with tyrosine kinase activity. The basic structure is composed of an extracellular N-terminal ligand-binding region (amino acids 1 - 1861), a transmembrane region (amino acids 1862 - 1882), and a tyrosine kinase active region (amino acids 1883 - 2347) composed of 464 amino acids at the intracellular C-terminal. When the ROS1 gene undergoes rearrangement, the extracellular region is lost, and the transmembrane region and the intracellular tyrosine kinase region are retained. The rearrangement sites mainly occur in exons 32 - 36 of the ROS1 gene. ROS1 gene mutations mainly occur in lung cancer patients, with a patient proportion of 1% - 2%. In NSCLC, the ROS1 gene mainly fuses with SLC34A2 and CD74, continuously activating the ROS1 tyrosine kinase region and downstream signaling pathways such as JAK / STAT, PI3K / AKT, and RAS / MAPK, thereby causing tumorigenesis. It has been confirmed in a large number of literatures and clinically that by inhibiting the activity of mutant ROS1 kinases, it is possible to treat diseases caused by overactivation of ROS1, especially cancer. Currently, the marketed drugs for the treatment of ROS1-positive non-small cell lung cancer are crizotinib and entrectinib, both of which belong to the first-generation small-molecule ROS1 inhibitors. However, during the treatment with crizotinib or entrectinib, drug resistance occurs approximately around 15 months, and disease progression occurs. Among patients with drug resistance, the most common drug resistance mutations are solvent front mutations such as G2032R. For patients with drug resistance, there is currently no marketed treatment drug. Therefore, there is an urgent need to develop new inhibitors for ROS1, especially new ROS1 inhibitor drugs for clinical treatment that target drug resistance caused by first-generation ROS1 inhibitors such as crizotinib or entrectinib.

[0004] 2-5% of non-small cell lung cancer (NSCLC) cases are anaplastic lymphoma kinase (ALK)-rearranged. Anaplastic lymphoma kinase is a receptor-type protein tyrosine phosphokinase of the insulin receptor superfamily. ALK was initially discovered in anaplastic large cell lymphoma as an activated fusion oncogene. Subsequently, successive studies have found fusion forms of ALK in various cancers, including systemic histiocytosis, inflammatory myofibroblastic carcinoma, non-small cell lung cancer, etc. The mutations and abnormal activities of ALK in various cancers have made it a drug target for treating ALK-positive cancers. Currently, multiple ALK kinase inhibitors have been marketed. With the clinical application of these drugs, patients will develop drug-resistant mutations, such as the G1202R drug-resistant mutation, which causes these drugs to lose their efficacy.

[0005] With the further in-depth understanding of kinases such as ROS1, NTRK, and ALK in recent years, and the increase in clinically drug-resistant patients, there is an urgent need in clinical practice to develop new tyrosine kinase inhibitors with better activity and a wider range of effects to solve the treatment problems of tumors caused by the fusion or mutation of kinase proteins such as ROS1, NTRK, and ALK.

[0006] Patent document CN112867717A discloses a kinase inhibitor that can act on carcinogenic proteins such as NTRK, ALK, and / or ROS1 simultaneously - the compound TY-2136b shown in the following formula I, and the chemical name of its free base is (R)-3-(5,5-dimethyl-4,5-dihydro-1,2,4-oxadiazol-3-yl)-N-(1-(2,3,5-trifluorophenyl)ethyl)pyrazolo[1,5-a]pyrimidin-5-amine:

[0007]

[0008] Drugs need to be present in solution for absorption, but such precipitation may affect the degree and rate of drug absorption. Compounds with pH-dependent solubility (especially basic compounds) may exhibit undesirable pharmacokinetic properties, such as poor absorption or low bioavailability, which can lead to significant inter-patient and intra-patient variability. Therefore, there is a need to discover improved dosage forms of TY-2136b with favorable dissolution and pharmacokinetic profiles and showing good storage stability.

[0009] There has been no report on the preparation of the preparation of the above formula I compound. In order to deliver the therapeutic benefits of TY-2136b to patients in need, TY-2136b needs to be formulated into a pharmaceutical composition, especially a solid dosage form suitable for oral administration. Therefore, there is a need for a quality-stable TY-2136b pharmaceutical preparation with good in vivo dissolution, high bioavailability, good storage stability, and accelerated stability.

[0010] In addition, no literature has been found to report on the crystal forms of the above-mentioned compound of Formula I. Those skilled in the art understand that discovering compound forms that are beneficial to the purification and quality control of pharmaceutical compounds is of great significance for improving characteristics such as drug production, quality control, and the development prospects of solid oral preparations. Since the crystal forms of different drugs can affect the formulation druggability, bioavailability, and efficacy of the drugs, the study of drug crystal forms is of great significance. Therefore, due to the performance of TY-2136b, such as formulation druggability, quality control, and bioavailability in terms of stability, fluidity, etc., still need to be improved. For this reason, it is necessary to develop a suitable form of the above-mentioned compound and its preparation method. SUMMARY OF THE INVENTION

[0011] One or more embodiments of the present application provide a pharmaceutical composition, which comprises:

[0012] Crystal Form A of the monohydrate of the compound of Formula I

[0013]

[0014] and a pharmaceutically acceptable carrier, excipient or vehicle;

[0015] wherein the Crystal Form A has characteristic peaks at one or more of 9.35±0.2°, 11.42±0.2°, 12.06±0.2°, 18.71±0.2°, and 21.16±0.2° in the X-ray powder diffraction pattern expressed in 2θ angle.

[0016] In one or more embodiments, the Crystal Form A in the X-ray powder diffraction pattern expressed in 2θ angle further has characteristic peaks at one or more of 9.97±0.2°, 13.16±0.2°, 19.15±0.2°, 19.97±0.2°, and 21.00±0.2°.

[0017] In one or more embodiments, the Crystal Form A has an X-ray powder diffraction pattern substantially as Figure 5 shown.

[0018] In one or more embodiments, the pharmaceutical composition is prepared as an oral preparation.

[0019] In one or more embodiments, the Crystal Form A has a thermogravimetric analysis spectrum and a differential scanning calorimetry spectrum substantially as Figure 6 shown.

[0020] In one or more embodiments, the Crystal Form A is monoclinic, space group P2(1), and the unit cell parameters are α = γ = 90° β = 93.349(8)°, with the deviation factor R 1= 0.0562, Z = 4.

[0021] In one or more embodiments,

[0022] wherein the pharmaceutical composition comprises the following components in parts by weight:

[0023] Component Parts by weight Crystal form A 2.5-40 First diluent 10-70 Second diluent 10-70 Glidant 0.5-5 Disintegrant 1-15 Lubricant 0.2-10 Coating material 1-10 .

[0024] In one or more embodiments, the D90 of the crystalline form A is 17 - 523 μm, for example 17 - 191 μm;

[0025] In one or more embodiments, the first diluent is selected from mannitol, lactose, anhydrous calcium hydrogen phosphate, or a combination thereof.

[0026] In one or more embodiments, the second diluent is microcrystalline cellulose.

[0027] In one or more embodiments, the glidant is colloidal silicon dioxide.

[0028] In one or more embodiments, the disintegrant is selected from sodium carboxymethyl starch, croscarmellose sodium, crospovidone, or a combination thereof.

[0029] In one or more embodiments, the lubricant is selected from sodium stearyl fumarate, magnesium stearate, or a combination thereof.

[0030] In one or more embodiments, the coating material comprises a stabilizing substance and a polymer, wherein the stabilizing substance is selected from at least one of titanium dioxide, talc powder, and yellow iron oxide, and the polymer is selected from at least one of polyvinyl alcohol and polyethylene glycol.

[0031] In one or more embodiments, the pharmaceutical composition has one or more of the following characteristics:

[0032] 1) Under the conditions of pH 6.0 - 7.6 and 0.2% SDS, within 15 min, the dissolution rate of the crystalline form A in the pharmaceutical composition is ≥ 70%;

[0033] 2) Under the conditions of pH 6.0 - 7.6 and 0.2% SDS, within 45 min, the dissolution rate of the crystalline form A in the pharmaceutical composition is ≥ 85%;

[0034] 3) Under the conditions of pH 6.0 - 7.6 and 0.2% SDS, within 60 min, the dissolution rate of the crystalline form A in the pharmaceutical composition is ≥ 95%;

[0035] 4) The drug composition is stored at 25 ± 2 °C and 60% ± 5% RH for 18 months, and within 45 minutes, the dissolution rate of crystalline form A in the drug composition is ≥ 85%;

[0036] 5) The drug composition is stored at 40 ± 2 °C and 75% ± 5% RH for 6 months, and within 45 minutes, the dissolution rate of crystalline form A in the drug composition is ≥ 85%.

[0037] One or more embodiments of the present application provide a preparation method of the drug composition of the present application, which includes:

[0038] Providing the following materials in parts by weight as raw materials and preparing the raw materials into a composition:

[0039] Component Parts by weight Crystal form A 2.5-40 First diluent 10-70 Second diluent 10-70 Glidant 0.5-5 Disintegrant 1-15 Lubricant 0.2-10 Coating material 1-10 。

[0040] In one or more embodiments,

[0041] Component Parts by weight Crystal form A 4-30 First diluent 20-60 Second diluent 20-60 Glidant 1-4 Disintegrant 2-12 Lubricant 0.5-10 Coating material 1.5-8 。

[0042] In one or more embodiments, the D90 of crystalline form A is 17 - 523 μm, for example, 17 - 191 μm.

[0043] In one or more embodiments, the first diluent is selected from mannitol, lactose, anhydrous calcium hydrogen phosphate, or a combination thereof.

[0044] In one or more embodiments, the second diluent is microcrystalline cellulose.

[0045] In one or more embodiments, the glidant is colloidal silica.

[0046] In one or more embodiments, the disintegrant is selected from sodium carboxymethyl starch, croscarmellose sodium, crospovidone, or a combination thereof.

[0047] In one or more embodiments, the lubricant is selected from sodium stearyl fumarate, magnesium stearate, or a combination thereof.

[0048] In one or more embodiments, the coating material contains a stabilizing substance and a polymer, wherein the stabilizing substance is selected from at least one of titanium dioxide, talcum powder, and yellow iron oxide, and the polymer is selected from at least one of polyvinyl alcohol and polyethylene glycol.

[0049] In one or more embodiments, the preparation method of crystalline form A is to slurry the compound of formula I using a mixed solvent of acetonitrile and water.

[0050] In one or more embodiments, the method for preparing Form A is to slurry the compound of Formula I in a mixed solvent of acetonitrile and water for 1 - 4 days, and collect the crystalline powder solid by centrifugation.

[0051] One or more embodiments of the present application provide the use of the pharmaceutical composition of the present application in the preparation of a medicament for treating and / or preventing anti-cancer or anti-tumor drugs.

[0052] In one or more embodiments, the cancers or tumors targeted by the anti-cancer or anti-tumor drugs are selected from breast cancer, cervical cancer, colon cancer, lung cancer, gastric 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 multiforme, head and neck cancer, papillary renal tumor, leukemia, lymphoma, myeloma, and thyroid tumor.

[0053] One or more embodiments of the present application provide the use of the pharmaceutical composition of the present application in the preparation of a medicament for treating and / or preventing diseases mediated by ROS1, NTRK, or ALK.

[0054] In one or more embodiments, the diseases mediated by ROS1, NTRK, or ALK are selected from cancer, sarcoma, and pain.

[0055] One or more embodiments of the present application provide a pharmaceutical composition, which comprises the following components:

[0056] Component 1) The compound shown in Formula I

[0057]

[0058] or its pharmaceutically acceptable hydrate, solvate, or salt, as the active ingredient; and

[0059] Component 2) A pharmaceutically acceptable carrier.

[0060] In one or more embodiments, the pharmaceutical composition comprises the following components in parts by weight:

[0061] Composition Parts by weight Parts by weight Parts by weight Parts by weight Active ingredient 2.5-40 4-30 5-20 7.5-15 First diluent 10-70 20-60 25-55 30-50 Second diluent 10-70 20-60 25-55 30-50 Glidant 0.5-5 1-4 1-3 1.5-3 Disintegrant 1-15 2-12 3-10 4-9 Lubricant 0.2-10 0.5-5 0.5-3 0.5-2 Coating weight gain 1-10 1.5-8 2-7 2-6

[0062] In one or more embodiments, the pharmaceutical composition has one or more of the following characteristics:

[0063] 1) Under the conditions of pH 6.0 - 7.6 and 0.2% SDS (for example, pH 6.2 - 7.4 or pH 6.5 - 7.2), within 15 minutes, the dissolution rate of the active ingredient in the pharmaceutical composition is ≥70% (for example, ≥75%, ≥80%, ≥85%);

[0064] 2) Under the conditions of pH 6.0 - 7.6 and 0.2% SDS (such as pH 6.2 - 7.4 or pH 6.5 - 7.2), within 45 minutes, the dissolution rate of the active ingredient in the pharmaceutical composition is ≥ 85% (such as ≥ 90%, ≥ 95%);

[0065] 3) Under the conditions of pH 6.0 - 7.6 and 0.2% SDS (such as pH 6.2 - 7.4, pH 6.5 - 7.2), within 60 minutes, the dissolution rate of the active ingredient in the pharmaceutical composition is ≥ 95% (such as ≥ 98%, > 100%);

[0066] 4) When stored at 25 ± 2 °C and 60% ± 5% RH for 18 months, within 45 minutes, the dissolution rate of the active ingredient in the pharmaceutical composition is ≥ 85% (such as ≥ 90%, ≥ 95%);

[0067] 5) When stored at 40 ± 2 °C and 75% ± 5% RH for 6 months, within 45 minutes, the dissolution rate of the active ingredient in the pharmaceutical composition is ≥ 85% (such as ≥ 90%, ≥ 95%).

[0068] In one or more embodiments, the pharmaceutically acceptable compound is a monohydrate.

[0069] In one or more embodiments, the pharmaceutical composition is an oral preparation.

[0070] In one or more embodiments, the pharmaceutical composition is in a solid dosage form.

[0071] In one or more embodiments, the pharmaceutical composition is a tablet.

[0072] In one or more embodiments, the pharmaceutical composition further comprises a coating material.

[0073] In one or more embodiments, the weight of the coating material is 1.5 - 10% of the total weight of component 1) and component 2), such as 1.8 - 8%, 2 - 6%.

[0074] One or more embodiments of the present application provide a method for preparing the pharmaceutical composition of the present application, comprising:

[0075] 1) Providing the following materials as raw materials;

[0076] Composition Parts by weight Parts by weight Parts by weight Parts by weight Active ingredient 2.5-40 4-30 5-20 7.5-15 First diluent 10-70 20-60 25-55 30-50 Second diluent 10-70 20-60 25-55 30-50 Glidant 0.5-5 1-4 1-3 1.5-3 Disintegrant 1-15 2-12 3-10 4-9 Lubricant 0.2-10 0.5-5 0.5-3 0.5-2 Coating material 1-10 1.5-8 2-7 2-6

[0077] 2) Preparing the above materials into a pharmaceutical composition.

[0078] In one or more embodiments, step 2) comprises the following steps:

[0079] 2-1) Premix the active ingredient, the first diluent, the second diluent, the glidant, the disintegrant, and the lubricant to obtain a premix;

[0080] 2-2) Perform dry granulation;

[0081] 2-3) Total mix the product obtained in step 2-2) with the second lubricant to obtain a total mix;

[0082] 2-4) Compress the tablets to obtain the plain tablets, i.e., the pharmaceutical composition.

[0083] In one or more embodiments, the hardness of the plain tablets is 40-150 N, such as 70-130 N, 80-120 N.

[0084] In one or more embodiments, the hardness of the plain tablets is 30-100 N, such as 40-90 N, 50-80 N.

[0085] One or more embodiments of the present application provide the use of the pharmaceutical composition of the present application in the preparation of anti-tumor drugs.

[0086] In one or more embodiments, the tumor is any one of breast cancer, cervical cancer, colon cancer, lung cancer, gastric 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 multiforme, head and neck cancer, papillary renal tumor, leukemia, lymphoma, myeloma, thyroid tumor.

[0087] One or more embodiments of the present application provide polymorph A of the compound of formula I monohydrate, which has characteristic peaks at one or more of 9.35±0.2°, 11.42±0.2°, 12.06±0.2°, 18.71±0.2°, and 21.16±0.2° in the X-ray powder diffraction pattern expressed in 2θ angle, wherein the chemical structural formula of the compound of formula I is as follows:

[0088]

[0089] In one or more embodiments, the polymorph A also has characteristic peaks at one or more of 9.97±0.2°, 13.16±0.2°, 19.15±0.2°, 19.97±0.2°, and 21.00±0.2° in the X-ray powder diffraction pattern expressed in 2θ angle.

[0090] In one or more embodiments, the X-ray powder diffraction of the polymorph A expressed in 2θ angle has absorption peaks at the following positions,

[0091]

[0092]

[0093] In one or more embodiments, the crystalline form A has an X-ray powder diffraction pattern substantially as Figure 5 shown.

[0094] In one or more embodiments, the thermogravimetric analysis spectrum (TGA) of the crystalline form A has a weight loss of 4.216% between room temperature (about 25 °C) and 130 °C.

[0095] In one or more embodiments, the crystalline form A has a thermogravimetric analysis spectrum substantially as Figure 6 shown.

[0096] In one or more embodiments, the differential scanning calorimetry spectrum (DSC) of the crystalline form A has endothermic peaks at about 87.11 °C and 142.34 °C.

[0097] In one or more embodiments, the crystalline form A has a differential scanning calorimetry spectrum substantially as Figure 6 shown.

[0098] In one or more embodiments, the crystalline form A is a massive crystal with a size of 20 - 100 μm.

[0099] In one or more embodiments, the crystalline form A has a morphology substantially as Figure 7 shown.

[0100] In one or more embodiments, the crystalline form A belongs to the monoclinic system, space group P2(1), and the unit cell parameters are a = γ = 90° β = 93.349(8)°, the deviation factor R 1 = 0.0562, Z = 4.

[0101] One or more embodiments of the present application provide a method for preparing crystalline form A, comprising: pulping the compound of formula I using a mixed solvent of acetonitrile and water.

[0102] In one or more embodiments, the volume ratio of acetonitrile to water is 1∶(1 - 3), such as 1∶1 or 1∶2.

[0103] In one or more embodiments, the pulping is carried out at room temperature.

[0104] In one or more embodiments, crystalline form A is prepared by the following method: taking the compound of formula I, adding a mixed solvent of acetonitrile and water for pulping test, and after pulping for 1 - 4 days, centrifuging to collect the crystalline powder solid.

[0105] One or more embodiments of the present application provide an amorphous form of the compound of formula I, which has substantially asFigure 8 The X-ray powder diffraction pattern shown

[0106] One or more embodiments of the present application provide polymorph B of the compound of formula I, which has substantially the same X-ray powder diffraction pattern as that Figure 17 shown

[0107] One or more embodiments of the present application provide polymorph C of the compound of formula I, which has substantially the same X-ray powder diffraction pattern as that Figure 18 shown

[0108] One or more embodiments of the present application provide polymorph D of the compound of formula I, which has substantially the same X-ray powder diffraction pattern as that Figure 20 shown

[0109] One or more embodiments of the present application provide polymorph E of the compound of formula I, which has substantially the same X-ray powder diffraction pattern as that Figure 9 shown

[0110] One or more embodiments of the present application provide the use of polymorph A of the compound of formula I in the preparation of a pharmaceutical composition

[0111] One or more embodiments of the present application provide the use of polymorph A of the compound of formula I in the preparation of a medicament for preventing and / or treating diseases mediated by ROS1, NTRK, ALK, etc. with pathological features

[0112] In one or more embodiments, the diseases mediated by ROS1, NTRK, ALK, etc. with pathological features include cancer, sarcoma, and pain

[0113] In one or more embodiments, the cancer is any one of breast cancer, cervical cancer, colon cancer, lung cancer, gastric 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 multiforme, head and neck cancer, papillary renal tumor, leukemia, lymphoma, myeloma, thyroid tumor

[0114] In one or more embodiments, polymorph A of the compound of formula I is used for preventing and / or treating the following diseases: inflammation, cancer, cardiovascular diseases, infections, immune diseases, metabolic diseases

[0115] One or more embodiments of the present application provide a treatment method, which includes the step of administering polymorph A of the compound of formula I described in the present invention to a subject in need of treatment for selectively inhibiting the fusion mutations and drug-resistant mutations of ROS1, NTRK, ALK, etc

[0116] In one or more embodiments, polymorph A is very important for improving properties such as drug production, quality control, and the development prospects of solid oral preparations.

[0117] In one or more embodiments, the results of the physicochemical stability assessment show that polymorph A is a monohydrate and does not lose water or have hygroscopicity under conventional conditions.

[0118] In one or more embodiments, its stability is significantly better than that of the amorphous form and polymorph E under high temperature, high humidity, accelerated testing, and light exposure testing.

[0119] In one or more embodiments, the flowability of polymorph A is better than that of polymorph E and the amorphous form.

[0120] In one or more embodiments, the bioavailability of polymorph A is significantly higher than that of the amorphous form.

[0121] In one or more embodiments, based on the good physicochemical stability, flowability, and bioavailability of polymorph A, it has great potential in subsequent development and production.

[0122] It should be understood that within the scope of the present invention, the above technical features of the present invention and the technical features specifically described below can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be elaborated one by one here. BRIEF DESCRIPTION OF THE DRAWINGS

[0123] Figure 1 It is the dissolution curve of tablet 1 obtained in Composition Example 1.

[0124] Figure 2 It is the dissolution curve of tablet 2 obtained in Composition Example 2.

[0125] Figure 3 It is the dissolution curves of tablets 3 and 4 obtained in Composition Examples 3 and 4.

[0126] Figure 4 It is the dissolution curves of tablets 5 - 6 obtained in Composition Examples 5 - 6.

[0127] Figure 5 It is the XRD pattern of polymorph A.

[0128] Figure 6 It is the thermogravimetric analysis and differential scanning calorimetry (TGA - DSC) of polymorph A.

[0129] Figure 7 It is the polarized light microscopy (PLM) pattern of polymorph A.

[0130] Figure 8 It is the XRD pattern of the amorphous form.

[0131] Figure 9 It is the XRD pattern of crystal form E.

[0132] Figure 10 It is the DVS test result of crystal form A.

[0133] Figure 11 It is the DVS test result of crystal form E.

[0134] Figure 12 It is the DVS test result of the amorphous sample.

[0135] Figure 13 It is the flowability results of crystal form A, crystal form E and the amorphous sample.

[0136] Figure 14 It is the plasma concentration-time curve of rats administered with 10 mg / kg of Compound I (crystal form A).

[0137] Figure 15 It is the plasma concentration-time curve of rats administered with 10 mg / kg of Compound I (amorphous).

[0138] Figure 16 It is the single crystal structure diagram of crystal form A of Compound I ( Figure 16 is the correction unit, containing 2 molecules of the compound and 1 molecule of crystal water, where C7 and C7’ are both in the R configuration, and the FLACK parameter is 0.26(12)).

[0139] Figure 17 It is the XRD pattern of crystal form B.

[0140] Figure 18 It is the XRD pattern of crystal form C.

[0141] Figure 19 It is the thermogravimetric analysis and differential scanning calorimetry (TGA-DSC) of crystal form C.

[0142] Figure 20 It is the XRD pattern of crystal form D.

[0143] Figure 21 It is the thermogravimetric analysis and differential scanning calorimetry (TGA-DSC) of crystal form D.

[0144] Figure 22 It is the XRD pattern of crystal form D after being stored at room temperature in a closed container for two days.

[0145] Figure 23 It is the XRD pattern of crystal form D after being heated to 120 °C and cooled to room temperature.

[0146] Figure 24 and Figure 25XRD patterns after suspension competition of crystal forms A / C / D at different water activities at room temperature. Detailed implementation manners

[0147] The technical solutions of the present invention will be further described in detail below in conjunction with specific embodiments. It should be understood that the following embodiments are only used to illustrate and explain the present invention exemplarily, and should not be construed as limiting the protection scope of the present invention. All technologies implemented based on the above content of the present invention are covered within the scope of protection of the present invention.

[0148] Unless otherwise specified, the raw materials and reagents used in the following embodiments are all commercially available products, or can be prepared by known methods.

[0149] Through long-term and in-depth research, the inventor of the present invention has obtained a pharmaceutical composition with excellent dissolution performance, pharmacokinetic performance and storage stability by optimizing the composition. On this basis, the inventor has completed the present invention.

[0150] Drugs can be absorbed at many different sites along the gastrointestinal tract (including via the stomach, duodenum, jejunum, ileum and colon) after oral administration. With a significant change in pH between the stomach (pH 1 - 3.5) and the small intestine (pH 4 - 8), the pH is different at each absorption site. According to the research findings of the present application, the solubility of TY-2136b is pH-dependent and increases with increasing pH, but is generally low. It was found in the dissolution study that the sink conditions can be met in the pH 6.8 medium with the addition of SDS.

[0151] One or more embodiments of the present application provide pharmaceutical compositions suitable for oral administration, and more specifically relate to pharmaceutical compositions (such as pharmaceutical tablets) containing TY-2136b or its pharmaceutically acceptable hydrates, solvates or salts. At the same time, the solid dosage forms of the compositions of the present application show excellent storage stability.

[0152] In one or more embodiments, the pharmaceutical compositions of the present application can be formed into tablets, which exhibit improved dissolution characteristics under physiologically relevant conditions and / or a higher total release of the agent in physiologically relevant indicators.

[0153] Generally, crystallization will produce solvates of the compounds of the present invention. As used herein, the term "solvate" refers to an aggregate including one or more molecules of TY-2136b and one or more solvent molecules. The solvent can be water, in which case the solvate can be a hydrate. Optionally, the solvent can be an organic solvent. Therefore, the compounds of the present invention can exist in the form of hydrates, including monohydrates, dihydrates, hemihydrates, sesquihydrates, trihydrates, tetrahydrates, etc., and the corresponding solvated forms.

[0154] "Pharmaceutical composition" refers to a preparation of the compounds of the present invention and a medium generally acceptable in the art, for delivering a bioactive compound to a mammal, such as a human. Such media include all pharmaceutically acceptable carriers, diluents or excipients.

[0155] "Pharmaceutically acceptable carrier, diluent or excipient" includes, but is not limited to, any acceptable adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye / colorant, flavoring agent, surfactant, wetting agent, dispersing agent, suspending agent, stabilizing agent, isotonic agent, solvent, or emulsifying agent approved by the US Food and Drug Administration for use in humans or domestic animals.

[0156] As used herein, the term "pharmaceutically acceptable salt" refers to a salt formed by a compound of the present invention and an acid or a base that is suitable for use as a drug. Pharmaceutically acceptable salts include inorganic salts and organic salts. A preferred class of salts is the salts formed by the compounds of the present invention and acids. Acids suitable for forming salts include, but are not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, etc.; organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid, etc.; and amino acids such as proline, phenylalanine, aspartic acid, glutamic acid, etc.

[0157] Another preferred class of salts is the salts formed by the compounds of the present invention and bases, such as alkali metal salts (e.g., sodium salts or potassium salts), alkaline earth metal salts (e.g., magnesium salts or calcium salts), ammonium salts (such as lower alkanolammonium salts and other pharmaceutically acceptable amine salts), such as methylamine salts, ethylamine salts, propylamine salts, dimethylamine salts, trimethylamine salts, diethylamine salts, triethylamine salts, tert-butylamine salts, ethylenediamine salts, hydroxyethylamine salts, dihydroxyethylamine salts, trihydroxyethylamine salts, and amine salts formed by morpholine, piperazine, and lysine, respectively.

[0158] Since TY-2136b has excellent anti-tumor activity, a pharmaceutical composition containing TY-2136b as the main active ingredient can be used for the treatment, prevention, and alleviation of diseases related to tumors.

[0159] The pharmaceutical composition of the present application contains a compound of the present invention or a pharmaceutically acceptable salt thereof within a safe and effective amount range and a pharmaceutically acceptable excipient or carrier. The "safe and effective amount" herein refers to: an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Generally, the pharmaceutical composition contains 1 - 2000 mg of the compound of the present invention per dose, more preferably, 10 - 1000 mg of the compound of the present invention per dose. Preferably, the "per dose" is a capsule or a tablet.

[0160] "Pharmaceutically acceptable carrier" refers to one or more compatible solid or liquid fillers or gel substances that are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" herein means that the components in the composition can be admixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds. Some examples of pharmaceutically acceptable carriers are 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, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0161] The pharmaceutical compositions of the present application are injection solutions, capsules, tablets, pills, powders or granules.

[0162] There is no particular limitation on the mode of administration of the compounds or pharmaceutical compositions of the present invention. Representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

[0163] Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is admixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dibasic calcium phosphate, or admixed with the following components: (a) fillers or bulking agents, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxypropylmethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin wax; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glycerol monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage form may also contain buffering agents.

[0164] Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared with coatings and casings, such as enteric coatings and other materials well known in the art. They may contain opacifying agents, and the release of the active compound or compounds in such compositions can be delayed in a manner such that they are released in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and wax-like substances. If necessary, the active compound can also be in the form of microcapsules with one or more of the above excipients.

[0165] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3 - butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances, etc.

[0166] In addition to these inert diluents, the compositions may also contain adjuvants, such as wetting agents, emulsifying agents and suspending agents, sweetening agents, flavoring agents and fragrances.

[0167] In addition to the active compound, the suspension may contain suspending agents, for example, ethoxylated isooctadecanol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum monostearate and agar or mixtures of these substances, etc.

[0168] Compositions for parenteral injection may contain physiologically acceptable sterile aqueous or non - aqueous 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.

[0169] Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required if necessary.

[0170] The compositions of the present invention can be administered alone, or in combination with other pharmaceutically acceptable compositions (such as anti - tumor drugs).

[0171] The treatment methods of the present invention can be administered alone, or in combination with other treatment means or therapeutic drugs.

[0172] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to a mammal in need of treatment (such as a human), wherein the dosage administered is an effective dosage considered pharmaceutically. For a human with a body weight of 60 kg, the daily dosage is usually 1 - 2000 mg, preferably 50 - 1000 mg. The specific dosage should also consider factors such as the route of administration and the health status of the patient, which are all within the scope of the skills of a skilled physician.

[0173] The specific embodiments of the present invention specifically describe the preparation method of the pharmaceutical composition of the present invention, but these specific methods do not constitute any limitation to the present invention. The pharmaceutical composition of the present invention can also be conveniently prepared by optionally combining various preparation methods described in this specification or known in the art, and such combinations can be easily carried out by those skilled in the art to which the present invention pertains.

[0174] Typically, the raw materials and reagents used in the preparation process flow of the pharmaceutical composition of the present invention can be purchased through commercial channels without special instructions.

[0175] In one or more embodiments, the pharmaceutical composition of the present application has one or more of the following beneficial effects:

[0176] (1) The pharmaceutical composition has excellent dissolution performance, pharmacokinetic performance and storage stability;

[0177] (2) The quality of the pharmaceutical composition is stable;

[0178] (3) The preparation process of the pharmaceutical composition is simple and easy to implement, facilitating the connection of industrial production;

[0179] (4) The pharmaceutical composition is convenient for administration, safe and reliable to use, easy for patients to accept, and has high social and economic value.

[0180] Examples

[0181] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and not to limit the scope of the present invention. The experimental methods without specific conditions noted in the following examples are generally carried out under conventional conditions such as those described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or according to the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0182] Unless otherwise defined, all professional and scientific terms used herein have the same meaning as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to those described herein can be applied to the method of the present invention. The preferred implementation methods and materials described herein are for illustrative purposes only.

[0183] Examples of the composition

[0184] General raw materials

[0185]

[0186]

[0187] General method

[0188] Dissolution performance

[0189] Dissolution refers to the rate and extent of drug dissolution from solid preparations such as tablets in a specified solvent. Dissolution is an important indicator for tablet quality control, and dissolution tests are generally required for poorly soluble drugs. The dissolution test method is to place a certain amount of a solid preparation in the rotating basket (or dissolution cup) of a dissolution tester, and under a constant temperature of 37°C ± 0.5°C, operate according to the specified rotation speed and dissolution medium, and sample and determine the dissolution amount within the specified time.

[0190] The dissolution test conditions are as follows:

[0191] Dissolution medium: pH 6.8 phosphate buffer + 0.2% SDS

[0192] Volume of dissolution medium: 900 ml

[0193] Rotation speed: 50 rpm (the ultimate rotation speed is 250 rpm from 60 - 75 min)

[0194] Water bath temperature: 37 ± 0.5°C

[0195] Sampling time points: 5, 15, 30, 45, 60, 75 min

[0196] Tablet 1 of Composition Example 1 and its preparation (prescription composition (40 mg))

[0197] Name of raw and auxiliary materials Specific gravity % (w / w) mg / tablet Function TY-2136b (D90 17.00μm) 10.46 41.85 Drug substance Lactose 39.77 159.08 Diluent Microcrystalline cellulose 39.77 159.08 Diluent Colloidal silicon dioxide 2.00 8.00 Glidant Croscarmellose sodium 7.00 28.00 Disintegrant Magnesium stearate (added internally) 0.50 2.00 Lubricant Magnesium stearate (added externally) 0.50 2.00 Lubricant Total of plain tablets 100.00 400.00 Film coating premix (gastric-soluble type) 3.00 12.00 Coating Total of coated tablets 103.00 412.00

[0198] Note: The TY - 2136b used contains one molecule of water, and 41.85 mg of the hydrate is equivalent to 40 mg of TY - 2136b free base.

[0199] Tablet 1 was manufactured using a dry mixing / rolling process with the materials listed in the table above. After passing TY-2136b, colloidal silicon dioxide, croscarmellose sodium, and microcrystalline cellulose through a 40-mesh sieve respectively, they were sequentially added into the mixing hopper. The mixing rotation speed was set at 20 rpm and mixed for 25 min. Magnesium stearate (added internally) was added into the mixing hopper, the mixing rotation speed was set at 20 rpm and mixed for 5 min to obtain a premix. The premix was added into a dry granulator for dry granulation, with the rotary feeding speed (20 - 30 rpm), the forming pressure 25 - 35 bar (specifically 30 bar), the roller speed 10 - 20 rpm (specifically 15 rpm), and the sizing speed 120 - 180 rpm (specifically 150 rpm) to obtain dry granulation particles. The particles collected after dry granulation and the sieved magnesium stearate (added externally) were added into the mixing hopper, the rotation speed was set at 20 rpm, and the mixing time was 5 minutes (i.e., the total mixing time). Tablets were pressed using this mixture, and plain tablets 1 (hardness 81 - 115 N) were pressed using punch nails.

[0200] The film coating premix (12 mg / tablet) was formulated into a 12% (w / w) coating suspension, and plain tablet 1 was coated at 3% of the plain tablet weight to form tablet 1.

[0201] The dissolution results of the obtained tablet 1 are shown in Table 1 below.

[0202] Table 1

[0203] Time (min) 0 5 15 30 45 60 75 Dissolution (%) 0 41 83 93 97 99 102

[0204] Figure 1 It is the dissolution curve of tablet 1 obtained in Example 1.

[0205] As Figure 1 shown in the above and Table 1, tablet 1 can be completely dissolved under the above dissolution conditions, and the dissolution degree has reached 97% of the labeled amount at 45 minutes, meeting the standard.

[0206] Composition Example 2, Tablet 2 and Its Preparation (Prescription Composition (10 mg))

[0207] Name of raw and auxiliary materials Specific gravity % (w / w) mg / tablet Function TY-2136b (D90 17.00μm) 10.46 10.46 Drug substance Lactose 39.77 39.77 Diluent Microcrystalline cellulose 39.77 39.77 Diluent Colloidal silicon dioxide 2.00 2.00 Glidant Croscarmellose sodium 7.00 7.00 Disintegrant Magnesium stearate (added internally) 0.50 0.50 Lubricant Magnesium stearate (added externally) 0.50 0.50 Lubricant Total of plain tablets 100.00 100.00 Film coating premix (gastric-soluble type) 3.00 3.00 Coating Total of coated tablets 103.00 103

[0208] Note: The TY-2136b used contains one molecule of water, and 10.46 mg of the hydrate is equivalent to 10 mg of the TY-2136b free base.

[0209] Tablet 2 was manufactured using a dry mixing / rolling process with the materials listed in the table above. After passing TY-2136b, colloidal silicon dioxide, croscarmellose sodium, and microcrystalline cellulose through a 40-mesh sieve respectively, they were sequentially added to the mixing hopper. The mixing rotation speed was set at 20 rpm and mixed for 25 min. Magnesium stearate (added internally) was added to the mixing hopper, the mixing rotation speed was set at 20 rpm, and mixed for 5 min to obtain a premix. The premix was added to a dry granulator for dry granulation, with a rotary feeding speed of (20 - 30 rpm), a forming pressure of 25 - 35 bar (specifically 30 bar), a roller speed of 10 - 20 rpm (specifically 15 rpm), and a sizing speed of 120 - 180 rpm (specifically 150 rpm) to obtain dry granulation particles. The particles collected after dry granulation and the sieved magnesium stearate (added externally) were added to the mixing hopper, the rotation speed was set at 20 rpm, and the mixing time was 5 minutes (i.e., the total mixing time). The mixture was used for tableting, and plain tablets 2 (hardness 53 - 78 N) were pressed using punch nails.

[0210] The film coating premix (3 mg / tablet) was formulated into a 12% (w / w) coating suspension, and plain tablet 2 was coated at 3% of the plain tablet weight to form tablet 2.

[0211] Table 2

[0212] Time (min) 0 5 15 30 45 60 75 Dissolution (%) 0 59 82 93 97 98 99

[0213] Figure 2 It is the dissolution curve of tablet 2 obtained in Example 2.

[0214] As Figure 2 shown in the above and Table 2, tablet 2 can be completely dissolved under the above dissolution conditions, and the dissolution rate has reached 97% of the labeled amount at 45 minutes, meeting the standard.

[0215] Composition Examples 3 - 4 Tablets 3 and 4

[0216] Same as Example 1, the main difference is the dosage of the disintegrant, as shown in Table 3 below, and the dissolution results are shown in Table 4 below.

[0217] Table 3 Prescription Composition with Different Dosages of Disintegrant

[0218]

[0219]

[0220] Table 4 Effect of Different Dosages of Disintegrant on Dissolution Rate

[0221]

[0222] As Figure 3As shown in Table 4 above, tablet 4 can be completely dissolved under the above dissolution conditions, and the dissolution rate has reached 84% of the labeled amount at 45 minutes, meeting the standard.

[0223] Composition Example 5 - 6, Tablets 5 - 6

[0224] Same as Example 3, with the difference that the particle size of TY - 2136b in the formula is different, and the powder direct compression process is adopted. Specifically, as shown in Table 5 below, the dissolution rates are shown in Table 6 below.

[0225] Table 5 Prescription Composition of Different API Particle Sizes

[0226]

[0227] Table 6 Influence of Different Particle Size APIs on Dissolution Rate

[0228]

[0229] As Figure 4 shown in Table 6 above, tablets 5 - 6 can be completely dissolved under the above dissolution conditions, and the dissolution rate has reached more than 80% of the labeled amount at 45 minutes, meeting the standard.

[0230] Composition Example 7

[0231] Tablets 1 (40mg) and Tablets 2 (10mg) produced by the present inventor according to the prescriptions in Example 1 and Example 2 were placed in 40°C / 75%RH (open), 40°C / 75%RH (closed), and 40°C / 75%RH (closed + 1g desiccant) respectively to investigate dissolution and related substances. The results are shown in Table 7 and Table 8 below.

[0232] Table 7 shows the dissolution results of the stability study samples.

[0233] Table 7

[0234]

[0235] Table 8 shows the related substance results of the stability study samples.

[0236] Table 8

[0237]

[0238] Note: *1. The results of the active pharmaceutical ingredient in this row are presented in the same sequence as the results of two specifications at T0, 40°C / 75%RH (open) for 10 days and 40°C / 75%RH (closed) for 10 days.

[0239] *2. The results of the active pharmaceutical ingredient in this row are presented in the same sequence as the results of two specifications at 40°C / 75%RH (closed + 1g desiccant) for 30 days.

[0240] As can be seen from Table 7, the dissolution rates of Tablet 1 (40 mg) and Tablet 2 (10 mg) showed no significant change after being placed at 40°C / 75% RH (open) and (closed + 1 g desiccant) for 30 days, meeting the requirements of the Chinese Pharmacopoeia.

[0241] As can be seen from Table 8, for Tablet 1 (40 mg) and Tablet 2 (10 mg) placed at 40°C / 75% RH (open), 40°C / 75% RH (closed), and 40°C / 75% RH (closed + 1 g desiccant) for 30 days, the individual impurities fluctuated within the acceptable range.

[0242] Examples of crystal forms

[0243] Preparation of Crystal Form A in Crystal Form Example 1

[0244] Take 15.3 mg of the compound of Formula I in a 1.5 mL HPLC vial, add 0.2 mL of ACN / H 2 O (1:1, v:v) and conduct a slurry test at room temperature. After about 4 days of slurrying, centrifuge to collect the crystalline powder solid, which is Crystal Form A. Its XRD pattern is as Figure 5 shown. The thermogravimetric analysis and differential scanning calorimetry (TGA-DSC) are as Figure 6 shown. The polarized light microscopy spectrum (PLM) is as Figure 7 shown.

[0245] Table 9 XRPD test parameters

[0246]

[0247] The single crystal structure diagram of Crystal Form A is as Figure 16 shown. The single crystal data are as follows: monoclinic system, space group P2(1), cell parameters are α = γ = 90°, β = 93.349(8)°, the deviation factor R 1 = 0.0562, Z = 4.

[0248] Preparation of Amorphous in Crystal Form Example 2

[0249] Weigh 400 mg of the Crystal Form A sample prepared in Example 1, dissolve it in 20 mL of dichloromethane at room temperature, filter the solution, and quickly remove the solvent by rotary evaporation. The obtained solid sample is subjected to corresponding characterization tests, and its XRD pattern is as Figure 8 shown. After the amorphous sample was placed overnight under ambient conditions (room temperature, > 20% RH) and the PLM was observed again, it was found that part of the sample had transformed into crystals. After the sample was placed under the same conditions for another two days, the XRD results showed that the crystal form of the sample after crystal transformation was basically the same as that of Crystal Form A. From the above results, it can be seen that the amorphous sample is unstable under ambient conditions and absorbs moisture and recrystallizes into Crystal Form A.

[0250] Preparation of Polymorph Example 3, Polymorph E

[0251] The sample of polymorph E was obtained by suspending and stirring the amorphous sample prepared in Example 2 in a 1,4-dioxane / n-heptane solvent system at room temperature. The XRD results are as Figure 9 shown. The results indicate that the sample of polymorph E transformed into polymorph A after being air-dried at room temperature for about 1 day. Based on this, it is speculated that polymorph E is a metastable polymorph.

[0252] Preparation of Polymorph Example 4, Polymorph B

[0253] Polymorph B was obtained by purging the starting polymorph A sample with nitrogen (about 5% RH) for 2 hours. The XRD results are shown in Figure 17 . Since the sample rapidly underwent polymorphic transformation into polymorph C under the room humidity conditions (17.3% RH) on the same day, it is speculated that it is a metastable polymorph.

[0254] Preparation of Polymorph Example 5, Polymorph C

[0255] Polymorph C was obtained by purging the starting polymorph A sample with nitrogen (about 5% RH) for 2 hours and then placing it at room humidity (17.3% RH) for 2 hours. The XRD results are shown in Figure 18 . The TGA / DSC results are as Figure 19 shown. The results show that the sample lost 3.2% of its weight when heated from room temperature to 150 °C, and had endothermic peaks at 57.5 °C, 94.5 °C, and 138.4 °C (peak temperatures). The 1 1H NMR spectrum of polymorph C was measured in DMSO-d6, and no obvious solvent residue was observed. Since polymorph C was obtained by increasing the humidity of polymorph B, combined with the obvious step-like weight loss in the TGA curve and the endothermic signal in the DSC curve, it is preliminarily speculated that polymorph C is a hydrate. Polymorph C was prepared repeatedly for many times, but a pure sample of polymorph C could not be obtained.

[0256] Preparation of Polymorph Example 6, Polymorph D

[0257] The sample of polymorph D was obtained by slow evaporation of the starting sample polymorph A in a methanol solvent. The XRD results are shown in Figure 20 . The TGA / DSC results are as Figure 21 shown. The results show that the sample lost 2.6% of its weight when heated from room temperature to 150 °C, and had an endothermic peak at 83.4 °C (peak temperature). The 1 1H NMR spectrum of polymorph D was measured in DMSO-d6, and no obvious solvent residue was observed. As Figure 22 shown, after being stored in a closed container at room temperature for two days, the crystallinity of the sample of polymorph D decreased significantly; as Figure 23As shown, after heating to 120 °C and cooling to room temperature, the sample transformed into an amorphous form. Combining the NMR data of the sample and the results of the heating test, it is speculated that crystal form D is a hydrate crystal form.

[0258] Crystal form test example 1 Crystal form solubility and hygroscopicity evaluation

[0259] The approximate solubility of crystal form A in different organic solvents at room temperature is as follows:

[0260] Solvent Solubility (mg / mL) Methanol S＞36.0 Ethanol S＞38.0 Isopropanol S＞42.0 Dichloromethane S＞40.0 Chloroform S＞44.0 Acetonitrile S＞44.0 Acetone S＞40.0 Methyl isobutyl ketone S＞40.0 Ethyl acetate S＞44.0 Isopropyl acetate S＞38.0

[0261] The hygroscopicity of different crystal forms of the API was studied using the Dynamic Vapor Sorption (DVS) method.

[0262] Determination method:

[0263] Instrument: Dynamic vapor sorption instrument; Temperature: 25 °C; Protective gas and flow rate: N 2 , 200 mL / min;

[0264] dm / dt: 0.002% / min; RH range: 0% RH - 100% RH; Cycle: 1 complete cycle.

[0265] Experimental results:

[0266] The DVS experimental results of crystal form A are shown in Figure 10 . From Figure 10 it can be seen that when the humidity is 0%, the weight loss of the crystal form A sample is about 3 - 4%, and the weight loss result is equivalent to the mass of the crystal water. The weight gain is obvious when the humidity increases from 0% to 20%, and there is almost no water absorption and weight gain when the humidity is from 20% to 80%. The hygroscopicity is obvious when the humidity is above 90%. When the humidity decreases from 100% to 0%, the weight loss continues, and the weight change trajectories of adsorption and desorption can completely coincide.

[0267] The DVS experimental results of crystal form E are shown in Figure 11 . From Figure 11 it can be seen that when the humidity increases from 0% to 90%, the crystal form E sample continuously loses weight: the weight loss is about 2% when the humidity increases from 0 to 30%, and there is a sudden weight loss when the humidity is from 40% to 50%. The weight gain is about 4% when the humidity increases from 90% to 100%; the weight loss is about 2% when the humidity decreases from 100% to 90%, and the weight gain due to hygroscopicity is greater than the weight loss. The weight loss is obvious and reaches 3% when the humidity is below 20%. The weight change trajectories of adsorption and desorption basically do not coincide.

[0268] The DVS experimental results of the amorphous form are shown in Figure 12 . From Figure 12It can be seen that the amorphous sample continuously gains weight as the humidity increases from 0% to 100%. The weight gain rate is uniform when the humidity increases from 0 to 80%, and there is a sudden weight gain when the humidity increases from 80% to 100%. The weight gain is about 3.5% when the humidity increases from 90% to 100%. When the humidity decreases from 100% to 0%, the amorphous sample continuously loses weight. The weight loss rate is fast when the humidity decreases from 100% to 90%, with a weight loss of about 1.5%, and the weight loss is less than the weight gain. The weight loss rate is uniform when the humidity decreases from 90% to 0%. The weight change trajectories of adsorption and desorption do not coincide at all.

[0269] In summary, crystal form A is a monohydrate, which will not lose water and does not have hygroscopicity under conventional conditions; crystal form E is a solvate, which will cause the loss of the carried solvent and has hygroscopicity when the ambient humidity changes normally; the amorphous form has hygroscopicity. In summary, the stability of crystal form A under normal storage and production conditions is significantly better than that of crystal form E and the amorphous form.

[0270] Crystal Form Test Example 2 Evaluation of Crystal Form Transformation Relationship

[0271] For the relatively stable crystal form A / C / D samples at room temperature, the transformation relationship between crystal forms was studied through a suspension competition test at different water activities at room temperature. The starting crystal form A samples were dried under vacuum at room temperature and used to prepare saturated solutions with different water activities in an acetone / water system. After pre-equilibrating for 8 to 24 hours, the solutions were filtered using a PTFE membrane with a pore size of 0.45 microns. The filtrate was transferred to HPLC vials containing crystal form A, crystal form C, and crystal form D samples, and the solid wet samples were separated after suspension stirring at room temperature and tested by XRD (film-covered test). The results are summarized in Table 10, and the XRD patterns are shown in Figure 24 and Figure 25 . The results show that crystal form A was obtained in all systems.

[0272] Table 10 Suspension Competition Test Table between Crystal Forms A / C / D

[0273]

[0274] Crystal Form Test Example 3 Physicochemical Stability Evaluation

[0275] To verify the stability of crystal form A, crystal form E, and the amorphous form, high-temperature, high-humidity, accelerated, and light experiments were also carried out. The specific test methods and results are as follows.

[0276] 3.1 High-Temperature Test

[0277] The method for the high-temperature test is shown in Table 11 below.

[0278] Table 11

[0279]

[0280] 3.2 The method for the high-humidity test is shown in Table 12 below.

[0281] Table 12

[0282]

[0283] 3.3 Light Exposure Test

[0284] The investigation method for the light exposure test is shown in Table 13 below.

[0285] Table 13

[0286]

[0287] 3.4 Accelerated Test

[0288] The investigation method for the accelerated test is shown in Table 14 below.

[0289] Table 14

[0290]

[0291]

[0292] The results of related substances in each crystal form under high temperature conditions (50°C ± 2°C) are shown in Table 15.

[0293] HPLC detection results of related substances under high temperature conditions:[[]]

[0294] Table 15

[0295]

[0296] After being placed at high temperature conditions (50°C ± 2°C) for 32 days, the content of specific impurity RRT 0.66 showed no obvious change (increase ≤ 0.02%) with the extension of high temperature time in crystal form A, and increased by 0.05% in crystal form E. The content of specific impurity RRT 0.71 showed no obvious change with the extension of high temperature time in both crystal forms. The content of specific impurity RRT 1.02 showed no obvious change in crystal form A and increased by 0.19% in crystal form E. The content of specific impurity RRT 1.08 increased by 0.05% and 0.23% in crystal forms A and E respectively. The content of other non-specific impurities was not more than 0.10%. The total impurities increased by 0.16% and 0.51% in crystal forms A and E respectively, and the total impurity content was not more than 2.0%. In summary, under high temperature conditions, the stability of crystal form A is better than that of crystal form E.

[0297] The results of related substances in each crystal form under high humidity conditions (90% RH ± 5% RH) are shown in Table 16.

[0298] The HPLC detection results of related substances under high humidity conditions are as follows:[[]]

[0299] Table 16

[0300]

[0301] Stored for 32 days under high humidity conditions (90% RH ± 5% RH), the contents of specific impurities RRT 0.66 and RRT 0.71 showed basically no change (increase ≤ 0.02%) in all three crystal forms. Specific impurity RRT 1.02 showed basically no change in both crystal form A and crystal form E, and increased by 0.03% in the amorphous form. Specific impurity RRT 1.08 showed basically no change in crystal form A, and increased by 0.04% and 0.05% in crystal form E and the amorphous form, respectively. The contents of other non-specific impurities were all not more than 0.10%, and the total impurities increased by 0.03%, 0.05%, and 0.10% in crystal form A, crystal form E, and the amorphous form, respectively, and the total impurity contents were all not more than 2.0%. In summary, under high humidity conditions, the stability of crystal form A is better than that of crystal form E and the amorphous form.

[0302] The results of related substances in each crystal form under light conditions (4500 lx ± 500 lx) are shown in Table 17.

[0303] The HPLC detection results of related substances under light conditions are as follows:

[0304] Table 17

[0305]

[0306] Note: N.D. indicates not detected.

[0307] Stored for 32 days under light conditions (4500 lx ± 500 lx), the contents of specific impurity RRT 0.66 increased in crystal form A, crystal form E, and the amorphous form, by 0.09%, 0.04%, and 0.03% respectively. Specific impurities RRT 0.71 and RRT 1.02 showed no increase in crystal form A and crystal form E, and increased by 0.05% and 0.06% respectively in the amorphous form. Specific impurity RRT 1.08 increased by 0.09%, 0.08%, and 0.19% respectively in crystal form A, crystal form E, and the amorphous form. The contents of other non-specific impurities were all not more than 0.10%, and the total impurities increased by 0.13%, 0.13%, and 0.37% respectively in crystal form A, crystal form E, and the amorphous form, and the total impurity contents were all not more than 2.0%. In summary, under light conditions, the stability of crystal form A and crystal form E is better than that of the amorphous form.

[0308] The results of changes in related substances in each crystal form under accelerated conditions (40°C ± 2°C, 75% RH ± 5% RH) are shown in Table 18.

[0309] The HPLC detection results of related substances under accelerated conditions are as follows:

[0310] Table 18

[0311]

[0312] Placed at the accelerated conditions (40°C ± 2°C, 75% RH ± 5% RH) for 32 days, there were no obvious changes (increase ≤ 0.02%) in the specific impurities with RRT 0.66, RRT 0.71, and RRT 1.02 in the three crystal forms. The specific impurity with RRT 1.08 increased by 0.04%, 0.03%, and 0.03% in crystal form A, crystal form E, and amorphous form respectively, and the growth amounts were comparable. The contents of other non-specific impurities were all not more than 0.10%, and the total impurities were all not more than 2.0%. It shows that the stabilities of the three crystal forms are comparable under the accelerated conditions.

[0313] Under the conditions of high temperature (50°C ± 2°C) and high humidity (90% RH ± 5% RH), the stability of crystal form A is superior to that of crystal form E and the amorphous form respectively. Under the light condition (4500 lx ± 500 lx), the stabilities of crystal form A and crystal form E are both superior to that of the amorphous form. Under the accelerated conditions (40°C ± 2°C, 75% RH ± 5% RH), the stabilities of the three crystal forms are comparable. Compared with other conditions, the stabilities of the three crystal forms are relatively poor under the light condition (4500 lx ± 500 lx), suggesting that it should be stored away from light.

[0314] In summary, compared with crystal form E and the amorphous form, crystal form A is the most stable crystal form and is most suitable for subsequent processing and development.

[0315] Crystal form test example 4 Flowability test

[0316] The method for measuring flowability is as follows: The angle of repose is measured using a device with 2 - 3 funnels connected in series in a staggered manner. The drug powder slowly and evenly flows through the funnels onto a stationary base with a diameter of d, forming a symmetric powder pile with a single layer of powder at the bottom. During the formation of the powder pile, the height of the funnel must be maintained within the range of 2 - 4 cm from the top of the powder pile. Measure the height h of the cone and calculate the angle of repose tanθ = h / (d / 2).

[0317] Experimental results: The experimental results of the powder flowability of the three crystal form APIs are shown in Figure 13 。

[0318] After testing, the angle of repose of the crystal form A sample is approximately 32.7°, the angle of repose of the crystal form E sample is 37.9°, and the angle of repose of the amorphous sample is approximately 37.5°.

[0319] Since the smaller the angle of repose of the powder, the better the flowability, the flowability of crystal form A is superior to that of crystal form E and the amorphous form.

[0320] Crystal form test example 5 Pharmacokinetics test

[0321] In this test example, the pharmacokinetic processes of crystal form A and the amorphous form in SD rats were compared and tested to compare their pharmacokinetic characteristics in SD rats.

[0322] Experimental methods and materials

[0323] Compound information

[0324] Test article

[0325] Name: Compound of Formula I (Crystal Form A)

[0326] Name: Compound of Formula I (Amorphous)

[0327] Internal standard

[0328] Name: verapamil

[0329] Test animals: Six healthy adult male Sprague-Dawley (SD) rats, 6 - 8 weeks old, weighing approximately 200 - 300 g, were divided into two groups of three rats each. The animals were housed in rat cages and fasted (for at least 10 h) but not water-deprived starting from the day before the experiment. On the day of the experiment, the rats were weighed and marked on the tail. Blank blood samples were collected from the tail vein before drug administration. Administration method: Oral gavage (p.o.): The drug suspension was administered by gavage. Preparation of the administration suspension: Approximately 10 mg of the test sample was accurately weighed, dissolved in 5% DMSO after conversion, vortexed with 10% solutol HS-15 and 85% saline to obtain a suspension with a concentration of 1.0 mg / mL, and freshly prepared before use.

[0330] Sample collection: The rats were orally administered the drug at a dose of 10 mg / kg. After administration, timing started. Blood samples were collected at 0.5, 1, 2, 4, 6, 8, 12, and 24 h after administration. 0.1 ml of whole blood was collected into an EDTA-Na 2 anticoagulant tube, inverted 3 - 4 times to mix evenly, centrifuged at 10000 g for 5 min at 4°C to separate the plasma, and stored at -80°C for further analysis. Blood samples were collected from the tail vein.

[0331] Sample preparation: 1) Thaw the samples. Take 15 μL each of the unknown plasma samples before or after drug administration, standard series solutions, single blank, and double blank samples into 1.5 ml centrifuge tubes. 2) Add 15 μL of protein precipitant (methanol) and 400 μL of internal standard solution (verapamil prepared in methanol, approximately 10 ng / ml) to each sample in sequence, vortex for 2 min, and then centrifuge at 12000 rpm for 10 min at 4°C. 3) Take the supernatant for LC / MS / MS analysis.

[0332] Analysis conditions: Liquid phase conditions: Liquid phase: Shimadzu Nexera X2; Chromatographic column: Agilent ZORBAX XDB-C18 3.5 (2.1×50 mm); Column temperature: 35 °C; Mobile phase: A - 5% acetonitrile (0.1% formic acid in water), B - 95% acetonitrile (0.1% formic acid in water); Injection volume: 3 μL;

[0333] Flow rate: 0.5 mL / min. Gradient elution was adopted, and the elution program is shown in the following table.

[0334] Table 19

[0335]

[0336] Mass spectrometry conditions: Electrospray ionization source ESI was used, and mass spectrometry analysis was carried out in the positive ion and multiple reaction monitoring (MRM) mode. The mass spectrometry ion source parameters and compound detection parameters are shown in the following table.

[0337] Mass spectrometry ion source parameters

[0338] Table 20

[0339] Instrument Triple QuadTM 6500+AB Mass Spectrometer, Made in Canada Ion source mode ESI Scanning mode MRM Curtain gas 20L / min Nebulizing gas 50L / min Auxiliary gas 50L / min Ion source temperature 300℃ Ion spray voltage +5500v (positive MRM)

[0340] The main scanning parameters of the analyte and internal standard are as follows in the table

[0341] Table 21

[0342] Compound name Q1 (m / z) Q3 (m / z) DP (v) EP (v) CE (v) CXP (v) Compound of Formula I 391.1 159.1 135 10 50 15 IS (verapamil) 455.3 165.2 135 10 35 15

[0343] PK parameter processing: According to the plasma drug concentration and corresponding sampling time data of each individual, the software Phoenix WinNonlin was used to calculate the pharmacokinetic (PK) parameters based on the plasma drug concentration by using a non-compartmental model. (1) The PK parameters used to evaluate pharmacokinetics include: Cmax, AUC0-t, AUC0-∞, Tmax, t1 / 2.

[0344] (2) For bioequivalence evaluation: Cmax, AUC0-t, and AUC0-∞ were used for bioequivalence evaluation.

[0345] Cmax: The maximum plasma drug concentration measured within the specified period, which is the measured value.

[0346] Tmax: The time to reach the peak plasma concentration measured, which is the measured value. If the maximum value occurs at more than one time point, Tmax is defined as the first time point with this value.

[0347] AUC0-t: The area under the plasma drug concentration-time curve from 0 to the last time point t.

[0348] AUC0-∞: Area under the plasma concentration-time curve from zero to infinity. Ct is the last measured concentration, and λz is the elimination rate constant in the terminal phase.

[0349]

[0350] t1 / 2: Elimination or terminal half-life, estimated by ln2 / λz.

[0351] Results: The linear range of the compound of formula I was 2 - 2000 ng / ml. The plasma concentration-time profiles of rats administered 10 mg / kg of the compound of formula I (crystalline form A) and the compound of formula I (amorphous) are shown in Tables 22 and 23, Figure 14 and Figure 15 . The main pharmacokinetic parameters in rats are shown in Tables 24 and 25.

[0352] Table 22: Plasma Concentration-Time Data of Rats Administered 10 mg / kg of the Compound of Formula I (Crystalline Form A)

[0353]

[0354] Table 23: Plasma Concentration-Time Data of Rats Administered 10 mg / kg of the Compound of Formula I (Amorphous)

[0355]

[0356] Table 24: Partial Pharmacokinetic Parameters of Rats After Oral Administration of 10 mg / kg of the Compound of Formula I (Crystalline Form A)

[0357]

[0358] Table 25: Partial Pharmacokinetic Parameters of Rats After Oral Administration of 10 mg / kg of the Compound of Formula I (Amorphous)

[0359]

[0360] After rats were orally administered the same dose of the compound of formula I (crystalline form A) or the compound of formula I (amorphous), the Cmax values were 578 ng / ml and 151 ng / ml respectively; the AUClast values were 4734 h*ng / ml and 1077 h*ng / ml respectively, and there was a significant difference between the two (p < 0.05), indicating that the bioavailability of crystalline form A was significantly higher than that of the amorphous form.

[0361] The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiments. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principle of the present invention shall be included within the protection scope of the present invention. All documents mentioned in the present invention are cited herein as references, as if each document were individually cited as a reference. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of this application.

Claims

1. A pharmaceutical composition, comprising: Crystal form A of the monohydrate of the compound of formula I and a pharmaceutically acceptable carrier, excipient or vehicle; wherein said crystal form A has characteristic peaks at one or more of 9.35±0.2°, 11.42±0.2°, 12.06±0.2°, 18.71±0.2° and 21.16±0.2° in the X-ray powder diffraction pattern expressed in 2θ angle; Preferably, said crystal form A also has characteristic peaks at one or more of 9.97±0.2°, 13.16±0.2°, 19.15±0.2°, 19.97±0.2° and 21.00±0.2° in the X-ray powder diffraction pattern expressed in 2θ angle; Preferably, said crystal form A has an X-ray powder diffraction pattern substantially as shown in Figure 5; More preferably, said pharmaceutical composition is prepared as an oral preparation.

2. The pharmaceutical composition according to claim 1, wherein said crystal form A has a thermogravimetric analysis spectrum and a differential scanning calorimetry spectrum substantially as shown in Figure 6; Preferably, the crystal form A is monoclinic system, space group P2(1), and the unit cell parameters are α = γ = 90°, β = 93.349(8)°, and the deviation factor R 1 = 0.0562, Z = 4.

3. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition comprises the following components in parts by weight: ； Preferably, the D90 of said crystal form A is 17 - 523 μm, more preferably 17 - 191 μm; Preferably, said first diluent is selected from mannitol, lactose, anhydrous calcium hydrogen phosphate, or a combination thereof; Preferably, said second diluent is microcrystalline cellulose; Preferably, said glidant is colloidal silicon dioxide; Preferably, said disintegrant is selected from sodium carboxymethyl starch, cross-linked carboxymethyl cellulose sodium, cross-linked povidone, or a combination thereof; Preferably, said lubricant is selected from sodium stearyl fumarate, magnesium stearate, or a combination thereof; Preferably, said coating material comprises a stabilizing substance and a polymer, wherein said stabilizing substance is selected from at least one of titanium dioxide, talc powder and yellow iron oxide, and said polymer is selected from at least one of polyvinyl alcohol and polyethylene glycol.

4. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition has one or more of the following characteristics: 1) Under the conditions of pH 6.0 - 7.6 and 0.2% SDS, within 15 min, the dissolution rate of crystal form A in the pharmaceutical composition is ≥70%; 2) Under the conditions of pH 6.0 - 7.6 and 0.2% SDS, within 45 min, the dissolution rate of crystal form A in the pharmaceutical composition is ≥85%; 3) Under the conditions of pH 6.0 - 7.6 and 0.2% SDS, within 60 min, the dissolution rate of crystal form A in the pharmaceutical composition is ≥95%; 4) The pharmaceutical composition is stored at 25±2°C and 60%±5% RH for 18 months, and within 45 min, the dissolution rate of crystal form A in the pharmaceutical composition is ≥85%; 5) The pharmaceutical composition is stored at 40±2°C and 75%±5% RH for 6 months, and within 45 min, the dissolution rate of crystal form A in the pharmaceutical composition is ≥85%.

5. The preparation method of the pharmaceutical composition according to any one of claims 1 - 4, which comprises: providing the following materials in parts by weight as raw materials and preparing the raw materials into a composition: ； Preferably Preferably, the D90 of the crystalline form A is 17 - 523 μm, more preferably 17 - 191 μm; Preferably, the first diluent is selected from mannitol, lactose, anhydrous calcium hydrogen phosphate, or a combination thereof; Preferably, the second diluent is microcrystalline cellulose; Preferably, the glidant is colloidal silicon dioxide; Preferably, the disintegrant is selected from sodium carboxymethyl starch, croscarmellose sodium, crospovidone, or a combination thereof; Preferably, the lubricant is selected from sodium stearyl fumarate, magnesium stearate, or a combination thereof; Preferably, the coating material comprises a stabilizing substance and a polymer, wherein the stabilizing substance is selected from at least one of titanium dioxide, talc powder, and yellow iron oxide, and the polymer is selected from at least one of polyvinyl alcohol and polyethylene glycol; Preferably, the preparation method of the crystalline form A is to slurry the compound of formula I with a mixed solvent of acetonitrile and water; more preferably, the preparation method of the crystalline form A is to slurry the compound of formula I with a mixed solvent of acetonitrile and water for 1 - 4 days, and collect the crystalline powder solid by centrifugation.

6. Use of the pharmaceutical composition according to any one of claims 1 - 5 in the preparation of a medicament for treating and / or preventing anti - cancer or anti - tumor drugs; preferably, the cancer or tumor targeted by the anti - cancer or anti - tumor drug is selected from breast cancer, cervical cancer, colon cancer, lung cancer, gastric 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 multiforme, head and neck cancer, papillary renal tumor, leukemia, lymphoma, myeloma, and thyroid tumor.

7. Use of the pharmaceutical composition according to any one of claims 1 - 5 in the preparation of a medicament for treating and / or preventing diseases mediated by ROS1, NTRK, ALK; preferably, the diseases mediated by ROS1, NTRK, ALK are selected from cancer, sarcoma, and pain.

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