TWI912013B - Crystals, pharmaceutical compositions, their preparation methods and applications - Google Patents

Abstract

This invention relates to a pharmaceutical composition of compound A of formula I, which exhibits excellent storage stability and dissolution properties, and crystal form A possesses good stability, reduced hygroscopicity, and good bioavailability. This pharmaceutical composition and crystal form A are of great significance for improving drug production, quality control, and the prospects for developing solid oral formulations.

Description

Crystals, pharmaceutical compositions, their preparation methods and applications

This invention belongs to the field of pharmaceutical chemistry technology, and specifically relates to the crystal form of compounds used as kinase inhibitors, their preparation methods, and applications.

The tropomyosin receptor kinase (TRK) family belongs to the transmembrane receptor tyrosine kinase (RTK) family and is involved in regulating synaptic growth and functional maintenance, memory development, and protecting neurons from damage in the mammalian nervous system. TRK kinases are a class of neurogrowth 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. A complete TRK kinase consists of three parts: an extracellular region, a transmembrane region, and an intracellular region. Like other RTKs, the extracellular region of a TRK kinase binds to its corresponding ligand to form a dimer, which can induce autophosphorylation of the intracellular region of the TRK kinase, thereby initiating its own kinase activity and further activating downstream signal transduction pathways. TRK kinases affect cell proliferation, differentiation, metabolism, and apoptosis through downstream pathways such as Ras/MAPK, PI3K/AKT, and PLCγ. When NTRK genes fuse or mutate, they alter or eliminate extracellular receptors (Greco, A. et al, Mol. Cell. Biol. 1995, 15, 6118; Oncogene 1998, 16, 809). The fused or mutated TRK protein, without ligand binding, remains in a highly activated kinase state, continuously activating downstream signaling pathways. This can lead to dysregulation of TRK kinase downstream signaling pathways, inducing cell proliferation and promoting tumor development and progression. NTRK gene fusions are found in various solid tumors in adults and children, including breast cancer, colorectal cancer, non-small cell lung cancer, papillary thyroid carcinoma, Spitz-like melanoma, glioma, and various sarcomas. In common cancers, such as non-small cell lung cancer and colorectal cancer, the incidence of NTRK gene fusion is relatively low, approximately 1%-3%. However, in some rare cancers, such as fibrosarcoma of infantile naïve and secretory carcinoma of the breast, the incidence of NTRK gene fusion can reach over 90%. The earliest TPM3-TRKA fusion protein was discovered in colon cancer cells. Later, more types of NTRK fusion proteins, such as CD74-NTRKA, MPRIP-NTEKA, QKI-NTRKB, ETV6-NTRKC, and BTB1-NTRKC, were discovered in various clinical tumor patient samples, including breast cancer, non-small cell lung cancer, papillary thyroid carcinoma, Spitz-like melanoma, and glioma. Therefore, in recent years, NTRK fusion proteins have become an effective anti-cancer target and a hot topic in anti-cancer drug development. With the deepening understanding of TRK kinases in recent years, more types of TRK fusion proteins and mutations 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 clinical need to develop novel NTRK inhibitors with better activity and broader effects to solve the treatment problems of tumors caused by these NTRK protein fusions or mutations.

ROS1 (c-ros oncogene 1 receptor kinase) is a tyrosine protein kinase encoded by the ROS1 proto-oncogene in the human body. Located on chromosome 6q22.1, it belongs to the tyrosine kinase insulin receptor gene family and consists of three parts: an intracellular tyrosine kinase active domain, a transmembrane domain, and an extracellular domain. It encodes a chimeric protein with tyrosine kinase activity. Its basic structure comprises an extracellular N-terminal ligand-binding domain (amino acids 1-1861), a transmembrane domain (amino acids 1862-1882), and an intracellular C-terminal 464-amino acid tyrosine kinase active domain (amino acids 1883-2347). During ROS1 gene rearrangements, the extracellular domain is lost, while the transmembrane domain and the intracellular tyrosine kinase domain are retained. Rearrangement sites primarily occur in exons 32-36 of the ROS1 gene. ROS1 gene mutations primarily occur in lung cancer patients, accounting for 1%-2% of cases. In NSCLC, the ROS1 gene mainly fuses with SLC34A2 and CD74, continuously activating the ROS1 tyrosine kinase domain and downstream signaling pathways such as JAK/STAT, PI3K/AKT, and RAS/MAPK, thereby leading to tumorigenesis. Extensive literature and clinical studies have confirmed that inhibiting the activity of mutated ROS1 kinases can treat diseases caused by ROS1 overactivation, especially cancer. Currently marketed drugs for treating ROS1-positive non-small cell lung cancer include crizotinib and entrectinib, both of which are first-generation small-molecule ROS1 inhibitors. However, during treatment with crizotinib or entrectinib, resistance typically develops around 15 months, leading to disease progression. The most common resistance mutation in resistant patients is the solvent front mutation, such as G2032R. Currently, there are no treatments available for these resistant patients. Therefore, there is an urgent need to develop new ROS1 inhibitors, especially new ROS1 inhibitors targeting resistance to first-generation ROS1 inhibitors like crizotinib or entrectinib, for clinical treatment.

In NSCLC, 2-5% of cases are anaplastic lymphoma kinase (ALK) rearrangements. ALK is a receptor-type protein tyrosine phosphokinase belonging to the insulin receptor superfamily. ALK was initially discovered in anaplastic large cell lymphoma as a fusion oncogene. Subsequent studies have identified fusion forms of ALK in various cancers, including systemic histiocytosis, inflammatory myofibroblastic carcinoma, and non-small cell lung cancer. The mutations and aberrant activities of ALK in various cancers have made it a potential drug target for treating ALK-positive cancers. Currently, several ALK kinase inhibitors are on the market. With the clinical application of these drugs, patients will develop drug resistance mutations. If drug resistance mutations such as G1202R occur, these drugs will lose their efficacy.

With a deeper understanding of kinases such as ROS1, NTRK, and ALK in recent years, and the increasing number of drug-resistant patients in clinical practice, there is an urgent need to develop new tyrosine kinase inhibitors with better activity and broader effects to solve the treatment problems of tumors caused by the fusion or mutation of kinase proteins such as ROS1, NTRK, and ALK.

Patent document CN112867717A discloses a kinase inhibitor that can simultaneously act on oncogenic proteins such as NTRK, ALK, and/or ROS1—compound TY-2136b as shown in Formula I below, whose free base has the chemical name (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]pyrimidine-5-amine: . Formula I

Drugs need to be present in solution for absorption, but such precipitation can affect the extent and rate of absorption. Compounds with pH-dependent solubility (especially alkaline compounds) can exhibit undesirable pharmacokinetic properties, such as poor absorption or low bioavailability, leading to significant inter-patient and intra-patient variability. Therefore, there is a need to discover an improved formulation of TY-2136b with favorable dissolution and pharmacokinetic profiles and good storage stability.

No formulations for preparing the compound of Formula I have been reported. To deliver the therapeutic benefits of TY-2136b to patients in need, it is necessary to formulate TY-2136b into a pharmaceutical compound, particularly a solid dosage form suitable for oral administration. Therefore, a stable TY-2136b pharmaceutical formulation with good in vivo dissolution, high bioavailability, good storage stability, and good acceleration stability is required.

Furthermore, no literature has been found reporting on the preparation of the crystal form of the compound of Formula I. Those skilled in the art understand that discovering compound morphologies favorable for drug purification and quality control is of great significance for improving drug production, quality control, and the prospects for developing solid oral formulations. Since different drug crystal forms affect drug formulation properties, bioavailability, and efficacy, research on drug crystal forms is of great importance. Therefore, because the properties of TY-2136b, such as stability, flowability, drug formulation properties, quality control, and bioavailability, still need improvement, it is necessary to develop suitable forms of the above-mentioned compound and their preparation methods.

One or more embodiments of the present invention provide a pharmaceutical composition comprising: crystal form A of a monohydrate of compound of formula I. Formula I and pharmaceutically acceptable carriers, excipients or formulations; wherein the crystal form A has characteristic peaks at one or more of the following locations in an X-ray powder diffraction pattern expressed in 2θ angles: 9.35±0.2°, 11.42±0.2°, 12.06±0.2°, 18.71±0.2° and 21.16±0.2°.

In one or more embodiments, the crystal form A also has characteristic peaks at one or more of the following locations in the X-ray powder diffraction pattern expressed in 2θ angles: 9.97±0.2°, 13.16±0.2°, 19.15±0.2°, 19.97±0.2°, and 21.00±0.2°.

In one or more embodiments, the crystal form A has an X-ray powder diffraction pattern substantially as shown in Figure 5.

In one or more embodiments, the pharmaceutical composition is prepared as an oral formulation.

In one or more embodiments, the crystal form A has a thermogravimetric analysis spectrum and a differential scanning calorimetry spectrum, which are basically as shown in Figure 6.

In one or more embodiments, the crystal form A is a monoclinic crystal system, space group P2(1), with cell parameters a=10.2499(10) Å, b=17.9931(16) Å, c=11.2407(8) Å, α=γ=90°, β=93.349(8)°, deviation factor _R1 =0.0562, and Z=4.

In one or more embodiments, the pharmaceutical composition comprises the following components in parts by weight: Components weight Crystal form A 2.5-40 First dilution 10-70 Second diluent 10-70 Flow aid 0.5-5 Disintegrant 1-15 Lubricant 0.2-10 Coating material 1-10 .

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

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

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

In one or more embodiments, the flow aid is colloidal silicon dioxide.

In one or more embodiments, the disintegrant is selected from sodium carboxymethyl cellulose, sodium cross-linked carboxymethyl cellulose, cross-linked povidone, or combinations thereof.

In one or more embodiments, the lubricant is selected from sodium stearate, magnesium stearate, or a combination thereof.

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

In one or more embodiments, the pharmaceutical composition has one or more of the following characteristics: 1) Under conditions of pH 6.0-7.6 and 0.2% SDS, the dissolution rate of crystal form A in the pharmaceutical composition is ≥70% within 15 min; 2) Under conditions of pH 6.0-7.6 and 0.2% SDS, the dissolution rate of crystal form A in the pharmaceutical composition is ≥85% within 45 min; 3) Under conditions of pH 6.0-7.6 and 0.2% SDS, the dissolution rate of crystal form A in the pharmaceutical composition is ≥95% within 60 min; 4) After storage at 25±2℃ and 60%±5%RH for 18 months, the dissolution rate of crystal form A in the pharmaceutical composition is ≥85% within 45 min; 5) When the drug composition is stored at 40±2℃ and 75%±5%RH for 6 months, the dissolution rate of crystal form A in the drug composition is ≥85% within 45 minutes.

One or more embodiments of the present invention provide a method for preparing a pharmaceutical composition of the present invention, comprising: providing the following materials in parts by weight as raw materials and preparing the raw materials into a composition: Components weight Crystal form A 2.5-40 First dilution 10-70 Second diluent 10-70 Flow aid 0.5-5 Disintegrant 1-15 Lubricant 0.2-10 Coating material 1-10 .

In one or more implementation methods, Components weight Crystal form A 4-30 First dilution 20-60 Second diluent 20-60 Flow aid 1-4 Disintegrant 2-12 Lubricant 0.5-10 Coating material 1.5-8 .

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

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

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

In one or more embodiments, the flow aid is colloidal silicon dioxide.

In one or more embodiments, the disintegrant is selected from sodium carboxymethyl cellulose, sodium cross-linked carboxymethyl cellulose, cross-linked povidone, or combinations thereof.

In one or more embodiments, the lubricant is selected from sodium stearate, magnesium stearate, or a combination thereof.

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

In one or more embodiments, the method for preparing crystal form A is to pulp the compound of formula I using a mixed solvent of acetonitrile and water.

In one or more embodiments, the method for preparing crystal form A is to slurry the compound of formula I using a mixed solvent of acetonitrile and water for 1-4 days, and then centrifuge to collect the crystalline powder solid.

One or more embodiments of the present invention provide the use of a pharmaceutical composition of the present invention in the preparation of a drug for the treatment and/or prevention of cancer or tumors.

In one or more embodiments, the cancer or tumor targeted by the said anticancer or antitumor 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, head and neck cancer, papillary renal tumor, leukemia, lymphoma, myeloma, and thyroidoma.

One or more embodiments of the present invention provide the use of the pharmaceutical composition of the present invention in the preparation of a medicament for the treatment and/or prevention of ROS1, NTRK, ALK-mediated diseases.

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

One or more embodiments of the present invention provide a pharmaceutical composition comprising the following components: Component 1) Compound represented by Formula I Formula I or its pharmaceutically acceptable hydrate, solvent or salt, as the active ingredient; and component 2) a pharmaceutically acceptable carrier.

In one or more embodiments, the pharmaceutical composition comprises the following components in parts by weight: Composition weight weight weight weight Active ingredients 2.5-40 4-30 5-20 7.5-15 First dilution 10-70 20-60 25-55 30-50 Second diluent 10-70 20-60 25-55 30-50 Flow aid 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 for weight gain 1-10 1.5-8 2-7 2-6

In one or more embodiments, the pharmaceutical composition has one or more of the following characteristics: 1) Under conditions of pH 6.0-7.6 and 0.2% SDS (e.g., pH 6.2-7.4 or pH 6.5-7.2), the dissolution rate of the active ingredient in the pharmaceutical composition is ≥70% (e.g., ≥75%, ≥80%, ≥85%) within 15 min; 2) Under conditions of pH 6.0-7.6 and 0.2% SDS (e.g., pH 6.2-7.4 or pH 6.5-7.2), the dissolution rate of the active ingredient in the pharmaceutical composition is ≥85% (e.g., ≥90%, ≥95%) within 45 min; 3) Under conditions of pH 6.0-7.6 and 0.2% SDS (e.g., pH 6.2-7.4, pH 6.5-7.2), the dissolution rate of the active ingredient is ≥85% (e.g., ≥90%, ≥95%) within 60 min. Within 45 minutes, the dissolution rate of the active ingredient in the pharmaceutical composition is ≥95% (e.g., ≥98%, ≥100%); 4) After storage at 25±2℃ and 60%±5%RH for 18 months, the dissolution rate of the active ingredient in the pharmaceutical composition is ≥85% (e.g., ≥90%, ≥95%) within 45 minutes; 5) After storage at 40±2℃ and 75%±5%RH for 6 months, the dissolution rate of the active ingredient in the pharmaceutical composition is ≥85% (e.g., ≥90%, ≥95%) within 45 minutes.

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

In one or more embodiments, the pharmaceutical composition is an oral formulation.

In one or more embodiments, the pharmaceutical composition is a solid dosage form.

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

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

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), for example 1.8-8% or 2-6%.

One or more embodiments of the present invention provide a method for preparing a pharmaceutical composition of the present invention, comprising: 1) providing the following materials as raw materials; Composition weight weight weight weight Active ingredients 2.5-40 4-30 5-20 7.5-15 First dilution 10-70 20-60 25-55 30-50 Second diluent 10-70 20-60 25-55 30-50 Flow aid 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 2) Prepare the above materials into a pharmaceutical composition.

In one or more embodiments, step 2) includes the following steps: 2-1) Premixing the active ingredient, a first diluent, a second diluent, a gliding agent, a disintegrant, and a lubricant to obtain a premix; 2-2) Dry granulation; 2-3) Mixing the product obtained in step 2-2) with a second lubricant to obtain a total mixture; 2-4) Tableting to obtain unmixed tablets, i.e., the pharmaceutical composition.

In one or more embodiments, the hardness of the raw sheet is 40-150N, for example 70-130N or 80-120N.

In one or more embodiments, the hardness of the raw sheet is 30-100N, for example 40-90N or 50-80N.

One or more embodiments of the present invention provide the use of the pharmaceutical composition of the present invention in the preparation of an antitumor drug.

In one or more embodiments, the tumor is any one of 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.

One or more embodiments of the present invention provide a crystal form A of a monohydrate of formula I, which has characteristic peaks at one or more of the following locations in its X-ray powder diffraction pattern expressed in 2θ angles: 9.35±0.2°, 11.42±0.2°, 12.06±0.2°, 18.71±0.2°, and 21.16±0.2°. The chemical structure of the compound of formula I is shown below: . Formula I

In one or more embodiments, the crystal form A also has characteristic peaks at one or more of the following locations in the X-ray powder diffraction pattern expressed in 2θ angles: 9.97±0.2°, 13.16±0.2°, 19.15±0.2°, 19.97±0.2°, and 21.00±0.2°.

In one or more embodiments, the X-ray powder diffraction of crystal form A, expressed at an angle of 2θ, shows absorption peaks at the following positions: Peak position [°2θ] Relative strength [%] 9.35±0.2° 15.42 9.97±0.2° 11.93 11.42±0.2° 100.00 12.06±0.2° 90.08 12.70±0.2° 4.31 13.16±0.2° 7.07 15.12±0.2° 3.38 16.67±0.2° 1.90 17.37±0.2° 2.22 18.05±0.2° 2.57 18.71±0.2° 28.76 19.15±0.2° 12.71 19.35±0.2° 6.53 19.97±0.2° 12.26 21.00±0.2° 12.55 21.16±0.2° 18.92 21.76±0.2° 2.76 22.89±0.2° 3.20 23.14±0.2° 3.98 23.46±0.2° 2.20 23.83±0.2° 2.24 27.35±0.2° 1.79 27.78±0.2° 3.64 28.72±0.2° 1.55 30.01±0.2° 0.99

In one or more embodiments, the crystal form A has an X-ray powder diffraction pattern substantially as shown in Figure 5.

In one or more embodiments, the thermogravimetric analysis (TGA) spectrum of crystal form A shows a weight loss of 4.216% between room temperature (approximately 25°C) and 130°C.

In one or more embodiments, the crystal form A has a thermogravimetric analysis spectrum as shown in Figure 6.

In one or more embodiments, the differential scanning calorimetry (DSC) of crystal form A has endothermic peaks at approximately 87.11 °C and 142.34 °C.

In one or more embodiments, the crystal form A has a differential scan calorimeter as shown in FIG6.

In one or more embodiments, the crystal form A is a bulk crystal of 20-100 μm.

In one or more embodiments, the crystal form A has a morphology that is substantially as shown in FIG7.

In one or more embodiments, the crystal form A is a monoclinic crystal system, space group P2(1), with cell parameters a=10.2499(10) Å, b=17.9931(16) Å, c=11.2407(8) Å, α=γ=90°, β=93.349(8)°, deviation factor _R1 =0.0562, and Z=4.

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

In one or more embodiments, the volume ratio of acetonitrile to water is 1:(1~3), for example 1:1 or 1:2.

In one or more implementation methods, slurrying is carried out at room temperature.

In one or more embodiments, crystal form A is prepared by the following method: Take a compound of formula I, add a mixed solvent of acetonitrile and water to conduct a slurry test, and after slurrying for 1-4 days, collect the crystalline powder solid by centrifugation.

One or more embodiments of the present invention provide an amorphous form of a compound of formula I having an X-ray powder diffraction pattern substantially as shown in Figure 8.

One or more embodiments of the present invention provide a crystal form B of a compound of formula I having an X-ray powder diffraction pattern substantially as shown in Figure 17.

One or more embodiments of the present invention provide a crystal form C of a compound of formula I, having an X-ray powder diffraction pattern substantially as shown in Figure 18.

One or more embodiments of the present invention provide a crystal form D of a compound of formula I having an X-ray powder diffraction pattern substantially as shown in Figure 20.

One or more embodiments of the present invention provide a crystal form E of a compound of formula I having an X-ray powder diffraction pattern substantially as shown in Figure 9.

One or more embodiments of the present invention provide the use of crystal form A of a compound of formula I in the preparation of a pharmaceutical composition.

One or more embodiments of the present invention provide the use of a crystal form A of a compound of formula I in the preparation of a medicament for the prevention and/or treatment of diseases mediated by ROS1, NTRK, ALK, etc.

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

In one or more embodiments, the cancer is any one of 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.

In one or more embodiments, the crystal form A of the compound of formula I is used for the prevention and/or treatment of the following diseases: inflammation, cancer, cardiovascular disease, infection, immune disease, metabolic disease.

One or more embodiments of the present invention provide a treatment method comprising the steps of: applying crystal form A of a compound of formula I described in the present invention to the object to be treated for selectively inhibiting fusion mutations and drug resistance mutations of ROS1, NTRK, ALK, etc.

In one or more embodiments, crystal form A is of great significance for improving the properties of drug production, quality control, and the prospects for development of solid oral formulations.

In one or more embodiments, the physicochemical stability assessment results show that crystal form A is a monohydrate that does not lose water or exhibit hygroscopicity under normal conditions.

In one or more embodiments, the stability under high temperature, high humidity, accelerated testing and light exposure is significantly better than that of amorphous and crystalline E.

In one or more embodiments, crystal form A exhibits better flowability than crystal form E and amorphous form.

In one or more embodiments, the bioavailability of crystal form A is significantly higher than that of amorphous form.

In one or more embodiments, crystal form A has great potential for further development and production due to its good physicochemical stability, fluidity and bioavailability.

One or more embodiments of the present invention provide a combination of the present invention or a crystal form A of a compound of formula I for the treatment and/or prevention of disease.

One or more embodiments of the present invention provide a combination of the present invention or a crystal form A of a compound of formula I for the treatment and/or prevention of cancer or tumors.

One or more embodiments of the present invention provide a combination of the present invention or a crystal form A of a compound of formula I for the treatment and/or prevention 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 tumors, peritoneal tumors, melanoma, glioma, glioblastoma, head and neck cancer, papillary renal tumor, leukemia, lymphoma, myeloma, or thyroidoma.

One or more embodiments of the present invention provide a combination of the present invention or a crystal form A of a compound of formula I for the treatment and/or prevention of ROS1, NTRK, ALK mediated diseases.

One or more embodiments of the present invention provide a method for treating and/or preventing disease, comprising giving an object in need an assembly of the present invention or a crystal form A of a compound of formula I.

One or more embodiments of the present invention provide a method for treating and/or preventing cancer or tumors, comprising giving an object in need an assembly of the present invention or a crystal form A of a compound of formula I.

One or more embodiments of the present invention provide a method for treating and/or preventing 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, or thyroidoma, comprising giving an object in need of the combination of the present invention or crystal form A of a compound of formula I.

One or more embodiments of the present invention provide a method for treating and/or preventing ROS1, NTRK, ALK-mediated diseases, comprising giving an object in need of the composition of the present invention or crystal form A of a compound of formula I.

It should be understood that, within the scope of this invention, the aforementioned technical features of this 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 described in detail here.

The invention is further described below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and not for limiting the scope of the invention. Experimental methods in the following embodiments, unless specific conditions are specified, are generally performed according to standard conditions as described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or according to the manufacturer's recommendations. Unless otherwise stated, percentages and parts are by weight.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as are familiar to one of skill in the art. Furthermore, any methods and materials similar 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. Examples of embodiments of the composition are provided below.

General raw materials Material Name Model TY-2136b N/A Lactose Tablettose80 Microcrystalline cellulose 102 Colloidal silicon dioxide 200 Magnesium stearate LIGAMED MF-2-V Film-coated premix (gastric-soluble) Obad® 85F620077

General Method

Dissolution performance

Dissolution rate refers to the rate and extent to which a drug dissolves from a solid preparation such as tablets in a specified solvent. Dissolution rate is an important indicator for tablet quality control, and it should generally be tested for poorly soluble drugs. The dissolution test method involves placing a certain amount of a solid preparation into the rotating basket (or dissolution vessel) of a dissolution tester, operating at a constant temperature of 37℃±0.5℃, at a specified rotation speed and in a specified dissolution medium, and taking samples within a specified time to determine the amount dissolved.

The dissolution test conditions are as follows:

Dissolution medium: pH 6.8 phosphate buffer + 0.2% SDS

Dissolution medium volume: 900ml

Rotation speed: 50 rpm (60~75 min is the final rotation speed, which is 250 rpm)

Water bath temperature: 37±0.5℃

Sampling time points: 5, 15, 30, 45, 60, 75 min. Example 1: Tablet 1 and its preparation ( Prescription composition ( 40 mg ) ). Raw and auxiliary material names Specific gravity % (w/w) mg/ tablet Function TY-2136b (D90 17.00 μm) 10.46 41.85 pharmaceutical substances lactose 39.77 159.08 diluent Microcrystalline cellulose 39.77 159.08 diluent Colloidal silicon dioxide 2.00 8.00 Flow aid Crosslinked carboxymethyl cellulose sodium 7.00 28.00 Disintegrant Magnesium stearate (added internally) 0.50 2.00 Lubricant Magnesium stearate (added) 0.50 2.00 Lubricant Total of uncut films 100.00 400.00 Film-coated premix (gastric-soluble) 3.00 12.00 Coating Total number of coated sheets 103.00 412.00 Note: The TY-2136b used contains one molecule of water, and 41.85 mg of hydrate is equivalent to 40 mg of TY-2136b free base.

Tablet 1 was manufactured using a dry mixing/milling process and the materials listed in the table above. TY-2136b, colloidal silica, cross-linked carboxymethyl cellulose sodium, and microcrystalline cellulose were each sieved through a 40-mesh sieve and then added sequentially to the mixing hopper. The mixing speed was set to 20 rpm, and the mixture was mixed for 25 min. Magnesium stearate (added internally) was added to the mixing hopper, and the mixing speed was set to 20 rpm, and the mixture was mixed for 5 min to obtain the premix. The premix is added to a dry granulator for dry granulation. The feed speed is 20-30 rpm, the forming pressure is 25-35 bar (specifically 30 bar), the roller speed is 10-20 rpm (specifically 15 rpm), and the pelletizing speed is 120-180 rpm (specifically 150 rpm) to obtain dry granulated particles. The collected particles after dry granulation and the sieved magnesium stearate (added externally) are added to a mixing hopper. The speed is set to 20 rpm, and the mixing time is 5 minutes (i.e., total mixing time). This mixture is used to compress tablets, and tablet 1 (hardness 81-115 N) is formed using a stud.

The film-coating premix (12 mg/tablet) was prepared into a 12% (w/w) coating suspension, and the unprocessed tablet 1 was coated with 3% of the unprocessed tablet weight to form tablet 1.

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

Table 1 time(min) 0 5 15 30 45 60 75 Dissolution rate (%) 0 41 83 93 97 99 102

Figure 1 shows the dissolution curve of tablet 1 obtained in Example 1.

As shown in Figure 1 and Table 1 above, tablet 1 can be completely dissolved under the above dissolution conditions, and the dissolution rate reaches 97% of the labeled amount after 45 minutes, which meets the standard. Example 2 : Tablet 2 and its preparation ( Prescription composition ( 10 mg ) ) Raw and auxiliary material names Specific gravity % (w/w) mg/ tablet Function TY-2136b (D90 17.00 μm) 10.46 10.46 pharmaceutical substances lactose 39.77 39.77 diluent Microcrystalline cellulose 39.77 39.77 diluent Colloidal silicon dioxide 2.00 2.00 Flow aid Crosslinked carboxymethyl cellulose sodium 7.00 7.00 Disintegrant Magnesium stearate (added internally) 0.50 0.50 Lubricant Magnesium stearate (added) 0.50 0.50 Lubricant Total of uncut films 100.00 100.00 Film-coated premix (gastric-soluble) 3.00 3.00 Coating Total number of coated sheets 103.00 103 Note: The TY-2136b used contains one molecule of water, and 10.46 mg of hydrate is equivalent to 10 mg of TY-2136b free base.

Tablet 2 was manufactured using a dry mixing/milling process and the materials listed in the table above. TY-2136b, colloidal silica, cross-linked carboxymethyl cellulose sodium, and microcrystalline cellulose were each sieved through a 40-mesh sieve and then added sequentially to the mixing hopper. The mixing speed was set to 20 rpm, and the mixture was mixed for 25 min. Magnesium stearate (added internally) was added to the mixing hopper, and the mixing speed was set to 20 rpm, and the mixture was mixed for 5 min to obtain the premix. The premix is added to a dry granulator for dry granulation. The feed speed is 20-30 rpm, the forming pressure is 25-35 bar (specifically 30 bar), the roller speed is 10-20 rpm (specifically 15 rpm), and the granulation speed is 120-180 rpm (specifically 150 rpm) to obtain dry granulated particles. The collected particles after dry granulation and the sieved magnesium stearate (added externally) are added to a mixing hopper. The speed is set to 20 rpm, and the mixing time is 5 minutes (i.e., total mixing time). This mixture is used to compress tablets, and tablets 2 (hardness 53-78 N) are formed using a pin press.

The film-coating premix (3 mg/tablet) was prepared into a 12% (w/w) coating suspension, and the unprocessed tablet 2 was coated with 3% of the unprocessed tablet weight to form tablet 2.

Table 2 time(min) 0 5 15 30 45 60 75 Dissolution rate (%) 0 59 82 93 97 98 99

Figure 2 shows the dissolution curve of tablet 2 obtained in Example 2.

As shown in Figure 2 and Table 2 above, tablet 2 can be completely dissolved under the above dissolution conditions, and the dissolution rate reaches 97% of the labeled amount after 45 minutes, which meets the standard. Examples of Compositions 3-4: Tablets 3 and 4

Similar to Example 1, the main difference lies in the amount of disintegrant used, as shown in Table 3 below, and the dissolution results are shown in Table 4 below.

Table 3. Prescription composition with different amounts of disintegrant Implementation Example 3 Implementation Example 4 Raw and auxiliary material names Specific gravity % (w/w) mg/tablet Specific gravity % (w/w) mg/tablet TY-2136b (D90 17 μm) 10.46 41.85 10.46 41.85 lactose 41.77 167.08 40.77 163.08 Microcrystalline cellulose 41.77 167.08 40.77 163.08 Colloidal silicon dioxide 2.00 8.00 2.00 8.00 Crosslinked carboxymethyl cellulose sodium 3.00 12.00 5.00 20.00 Magnesium stearate (added internally) 0.50 2.00 0.50 2.00 Magnesium stearate (added) 0.50 2.00 0.50 2.00 Total of uncut films 100.00 400.00 100.00 400.00 Film-coated premix (gastric-soluble) 3.00 12.00 3.00 12.00 Total number of coated sheets 103.00 412.00 103.00 412.00

Table 4. Effect of different disintegrant dosages on dissolution rate Disintegrant dosage pH 6.8 + 0.5% SDS, osmosis at 50 rpm, 900 mL Dissolution rate (%, n=3) 5 min 15 min 30 min 45 min 60 min 75 min Implementation Example 3 3% 38 57 68 72 75 93 Implementation Example 4 5% 51 69 79 84 86 99

As shown in Figure 3 and Table 4 above, tablet 4 can be completely dissolved under the above dissolution conditions, and the dissolution rate reaches 84% of the labeled amount after 45 minutes, which meets the standard. Example of Composition 5-6 Tablet 5-6

Similar to Example 3, the difference lies in the particle size of TY-2136b in the formula, the manufacturing process using direct powder compression, as shown in Table 5 below, and the dissolution rate as shown in Table 6 below.

Table 5. Prescription composition for different API particle sizes Implementation Example 5 Implementation Example 6 Manufacturing process Powder Direct Press Powder Direct Press Particle size distribution of active pharmaceutical ingredient D90 124 μm D90 191 μm Composition w/w % mg/ tablet w/w % mg/ tablet TY-2136b 10.46 41.85 10.46 41.85 lactose 42.77 171.08 42.77 171.08 Microcrystalline cellulose 102 42.77 171.08 42.77 171.08 Crosslinked carboxymethyl cellulose sodium 3.00 12.00 3.00 12.00 Magnesium stearate 1.00 4.00 1.00 4.00 Total 100.00 400.00 100.00 400.00 Film-coated premix (gastric-soluble) 3.00 12.00 3.00 12.00 Total number of coated sheets 103.00 412.00 103.00 412.00

Table 6. Effect of different particle sizes of API on dissolution rate Prescription number API PSD pH 6.8 + 0.2% SDS , osmotic method, 50 rpm , 900 mL Dissolution rate ( % ), n= 3 5 min 15 min 30 min 45 min 60 min 75 min Implementation Example 5 D90 124 μm 43 71 82 88 90 98 Implementation Example 6 D90 191 μm 33 61 76 84 89 97

As shown in Figure 4 and Table 6 above, tablets 5-6 can be completely dissolved under the above dissolution conditions. The dissolution rate reaches over 80% of the labeled amount after 45 minutes, meeting the standard. Example 7 of the composition.

The inventors produced tablet 1 (40 mg) and tablet 2 (10 mg) according to the prescriptions in Examples 1 and 2. The above samples were placed at 40°C/75% RH (open), 40°C/75% RH (closed), and 40°C/75% RH (closed + 1 g desiccant) respectively to investigate dissolution and related substances. The results are shown in Tables 7 and 8 below.

Table 7 shows the dissolution results of the samples in the stability study.

Table 7 Batch number condition Dissolution rate ( % ), n= 3 5 min 15 min 30 min 45 min 60 min 75 min 2 tablets (10 mg) 0 days 59 82 93 97 98 99 40℃/75% RH (open) 10 days 62 82 92 96 97 99 30 days 65 86 95 98 99 101 40℃/75% RH (closed + 1g desiccant) 10 days 66 88 97 101 104 106 30 days 67 86 95 98 99 100 1 tablet (40 mg) 0 days 41 83 93 97 99 102 40℃/75% RH (open) 10 days 66 83 92 96 97 99 30 days 65 84 93 98 100 101 40℃/75% RH (closed + 1g desiccant) 10 days 64 85 94 98 99 100 30 days 66 84 93 96 97 99

Table 8 shows the results of the stability study on the relevant substances in the samples.

Table 8 Specifications condition time Impurities (% ) Simple Mixture (RRT ) General 0.56 0.66/0.67/0.69/0.70 0.71/0.72/0.73/0.74 0.91 1.02 1.05/1.06 1.07/1.08 1.14 raw material drug ^*1 N/A <0.05 0.22 0.18 <0.05 0.27 0.07 0.18 <0.05 0.92 Raw material drug ^*2 N/A <0.05 0.22 0.19 <0.05 0.32 0.07 0.19 <0.05 0.99 2 tablets (10 mg) T0 <0.05 0.21 0.19 <0.05 0.29 0.09 0.19 0.06 1.03 40℃/75% RH (open) 10 days <0.05 0.22 0.23 <0.05 0.26 <0.05 0.18 <0.05 0.89 30 days <0.05 0.23 0.25 <0.05 0.17 ND 0.25 <0.05 0.90 40℃/75% RH (closed) 10 days <0.05 0.22 0.21 <0.05 0.25 0.08 0.18 <0.05 0.94 30 days <0.05 0.22 0.21 <0.05 0.17 0.05 0.24 <0.05 0.89 40℃/75% RH (closed + 1g desiccant) 10 days <0.05 0.21 0.19 <0.05 0.18 0.05 0.20 <0.05 0.83 30 days <0.05 0.23 0.20 <0.05 0.35 0.06 0.21 <0.05 1.05 1 tablet (40 mg) T0 <0.05 0.22 0.18 <0.05 0.27 0.08 0.19 <0.05 0.94 40℃/75% RH (open) 10 days <0.05 0.22 0.24 <0.05 0.24 <0.05 0.18 <0.05 0.88 30 days <0.05 0.22 0.25 <0.05 0.16 ND 0.24 <0.05 0.87 40℃/75% RH (closed) 10 days <0.05 0.21 0.20 <0.05 0.19 0.07 0.17 <0.05 0.84 30 days <0.05 0.21 0.20 <0.05 0.17 0.05 0.23 <0.05 0.86 40℃/75% RH (closed + 1g desiccant) 10 days <0.05 0.21 0.20 <0.05 0.17 0.05 0.21 <0.05 0.84 30 days <0.05 0.22 0.21 <0.05 0.35 0.05 0.21 <0.05 1.04 Note: *1. The results for the active pharmaceutical ingredient in this row are issued according to the same sequence as the results for both specifications at T0, 40℃/75% RH (open) for 10 days and 40℃/75% RH (closed) for 10 days. *2. The results for the active pharmaceutical ingredient in this row are issued according to the same sequence as the results for both specifications at 40℃/75% RH (closed + 1g desiccant) for 30 days.

As shown in Table 7, the dissolution rate of tablet 1 (40 mg) and tablet 2 (10 mg) did not change significantly after being placed at 40℃/75%RH (open) and (closed + 1g desiccant) for 30 days, which is in line with the Chinese Pharmacopoeia.

Table 8 shows that when tablet 1 (40 mg) and tablet 2 (10 mg) were stored for 30 days under the conditions of 40℃/75%RH (open), 40℃/75%RH (closed), and 40℃/75%RH (closed + 1 g desiccant), the individual impurities fluctuated within acceptable ranges. Regarding the examples of crystal forms: Example 1: Preparation of crystal form A

15.3 mg of compound I was placed in a 1.5 mL HPLC flask, and 0.2 mL of ACN/ _H₂O (1:1, v:v) was added for slurry preparation at room temperature. After slurry preparation for approximately 4 days, the crystalline powder solid was collected by centrifugation, which was crystal form A. Its XRD pattern is shown in Figure 5. Thermogravimetric analysis and differential scanning calorimetry (TGA-DSC) are shown in Figure 6. The polarized light microscope (PLM) spectrum is shown in Figure 7.

Table 9 XRPD Test Parameters Instrument Model X' Pert3 ( transmission ) Empyrean ( reflection ) X-rays Cu, kα; Kα1 (Å: 1.540598, Kα2 (Å: 1.544426), Intensity ratio Kα2/Kα1: 0.50 Cu, kα; Kα1 (Å: 1.540598, Kα2 (Å: 1.544426), Intensity ratio Kα2/Kα1: 0.50 X-ray tube settings 45 kV, 40 mA 45 kV, 40 mA Diverging Narrow Seam 1/2° Automatic Scan mode Continuous Continuous Scan range (°2TH) 3~40 3~40 Scan step size (°2TH) 0.0131 0.0263 Scanning time per step (s) 33.15 49.73 Scanning time (s) 7 min 03 s 5 min 16 s

The single-crystal structure of crystal form A is shown in Figure 16. The single-crystal data are: monoclinic system, space group P2(1), cell parameters a=10.2499(10) Å, b=17.9931(16) Å, c=11.2407(8) Å, α=γ=90° β=93.349(8)°, deviation factor _R1 = 0.0562, Z=4. Crystal form embodiment 2 Preparation of amorphous crystals

400 mg of the crystal form A sample prepared in Example 1 was weighed and dissolved in 20 mL of dichloromethane at room temperature. After filtration, the solvent was quickly removed from the filtrate by rotary evaporation. The resulting solid sample underwent corresponding characterization tests, and its XRD pattern is shown in Figure 8. After the amorphous sample was left overnight under environmental conditions (room temperature, >20% RH), PLM was observed again, revealing that some of the sample had transformed into crystals. After leaving the sample under the same conditions for two more days, the XRD results showed that the crystal form of the transformed sample was essentially consistent with crystal form A. The above results indicate that the amorphous sample is unstable under environmental conditions and recrystallizes into crystal form A upon hygroscopic absorption. Example 3 : Preparation of crystal form E

Crystal form 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 shown in Figure 9. The results indicate that crystal form E transforms into crystal form A after being air-dried at room temperature for approximately one day. Based on this, it is inferred that crystal form E is a metastable crystal form. Preparation of crystal form B in Example 4

Crystal form B was obtained by purging the initial crystal form A sample under nitrogen (approximately 5% RH) for 2 hours. The XRD results are shown in Figure 17. Since the sample rapidly transformed into crystal form C under the ambient humidity conditions (17.3% RH) on the same day, it is presumed to be a metastable crystal form. Example 5 : Preparation of crystal form C

Crystal form C was obtained by purging the initial crystal form A sample under nitrogen (approximately 5% RH) for 2 hours and then placing it at room temperature (17.3% RH) for 2 hours. Its XRD results are shown in Figure 18. The TGA/DSC results are shown in Figure 19, indicating that the sample lost 3.2% of its weight when heated from room temperature to 150ºC, with endothermic peaks at 57.5ºC, 94.5ºC, and 138.4ºC (peak temperature). The ^1H NMR spectrum of crystal form C was obtained by testing in DMSO-d6, and no significant solvent residue was observed. Since crystal form C was obtained by increasing the humidity of crystal form B, combined with the relatively obvious stepwise weight loss in the TGA curve and the endothermic signal in the DSC curve, it is preliminarily inferred that crystal form C is a hydrate. Crystal form C was prepared repeatedly, but a pure crystal form C sample could not be obtained. Example 6 : Preparation of crystal form D

Crystal form D was obtained by slowly evaporating the starting sample, crystal form A, in methanol solvent. Its XRD results are shown in Figure 20. The TGA/DSC results, shown in Figure 21, indicate that the sample lost 2.6% of its weight when heated from room temperature to 150ºC, and exhibited an endothermic peak at 83.4ºC (peak temperature). The ^1H NMR spectrum of crystal form D was obtained in DMSO-d6, showing no significant solvent residue. As shown in Figure 22, after two days of closed storage at room temperature, the crystallinity of crystal form D decreased significantly; as shown in Figure 23, after heating to 120ºC and cooling to room temperature, the sample transformed into an amorphous form. Based on the NMR data and heating test results, crystal form D is presumed to be a hydrate crystal form. Crystal form testing example 1: Evaluation of crystal form solubility and hygroscopicity

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

The hygroscopicity of different crystalline drug substances was studied using dynamic vapor sorption (DVS) analysis.

Measurement method:

Instrument: Dynamic water vapor adsorption instrument; Temperature: 25℃; Protective gas and flow rate: _N2 , 200 mL/min;

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

Experimental results:

The DVS experimental results for crystal form A are shown in Figure 10. As can be seen from Figure 10, at 0% humidity, the sample of crystal form A loses approximately 3-4% of its weight, a result comparable to that of crystal water. Significant weight gain occurs from 0% to 20% humidity, almost no weight gain from 20% to 80% humidity, and significant moisture absorption occurs above 90% humidity. Weight loss continues as humidity decreases from 100% to 0%, and the adsorption and desorption weight change trajectories completely overlap.

The DVS experimental results for crystal form E are shown in Figure 11. As can be seen from Figure 11, the crystal form E sample exhibits continuous weight loss as humidity increases from 0% to 90%: approximately 2% weight loss from 0% to 30% humidity, and a sudden weight loss from 40% to 50% humidity. From 90% to 100% humidity, weight gain from moisture absorption is approximately 4%; from 100% to 90% humidity, weight loss is approximately 2%, with the weight gain from moisture absorption exceeding the weight loss. At humidity below 20%, the weight loss is significantly higher, reaching 3%. The adsorption and desorption weight change trajectories are essentially non-overlapping.

The results of the DVS experiment for amorphous samples are shown in Figure 12. As can be seen from Figure 12, the amorphous sample continuously gains weight as humidity increases from 0% to 100%: the weight gain rate is uniform from 0% to 80%, and abrupt from 80% to 100%. The weight gain from 90% to 100% is approximately 3.5%. Conversely, the amorphous sample continuously loses weight as humidity decreases from 100% to 0%. The weight loss rate is rapid from 100% to 90%, approximately 1.5%, which is less than the weight gain; the weight loss rate from 90% to 0% is uniform. The adsorption and desorption weight change trajectories do not overlap at all.

In summary, crystal form A is a monohydrate, which does not lose water and is not hygroscopic under normal conditions; crystal form E is a solvent, which will lose its solvent under normal environmental humidity changes and is hygroscopic; the amorphous form is hygroscopic. Therefore, crystal form A exhibits significantly better stability than crystal form E and the amorphous form under normal storage and production conditions. Example 2: Evaluation of Crystal Form Transformation Relationship

For the relatively stable crystal forms A/C/D at room temperature, the transformation relationship between crystal forms was studied through a competition suspension test at different water activities at room temperature. The initial crystal form A sample was vacuum dried at room temperature and used to prepare saturated solutions of different water activities in an acetone/water system. After pre-equilibration for 8 to 24 hours, the solution was filtered through a PTFE membrane with a pore size of 0.45 μm. The filtrate was transferred to HPLC vials containing crystal forms A, C, and D. After stirring and suspending at room temperature, the solid wet samples were separated and XRD (coating test) was performed. The results are summarized in Table 10, and the XRD patterns are shown in Figures 24 and 25. The results show that crystal form A was obtained in all systems.

Table 10 Competition Test Table for Suspension Between Crystal Forms A/C/D Initial crystal form Number Solvent (v/v) temperature Suspended Time result Crystal form A/C/D A1 acetone room temperature 4 days Crystal form A A2 Acetone/water (984/16, aw~0.2) 3 days Crystal form A A3 Acetone/water (948/52, aw~0.4) 3 days Crystal form A A4 Acetone/water (857/143, aw~0.6) 4 days Crystal form A A5 Acetone/water (60/40, aw~0.8) 5 days Crystal form A A6 water 6 days Crystal form A Example 3: Physicochemical Stability Assessment ( Crystal Form Test )

To verify the stability of crystal form A, crystal form E, and amorphous form, high temperature, high humidity, accelerated testing, and light exposure experiments were also conducted. The specific test methods and results are shown below.

3.1 High-temperature test

The high-temperature test methods are shown in Table 11 below.

Table 11 Formula I compound active pharmaceutical ingredient Crystal form A Crystal form E amorphous Quantity stored (mg) 502.00 129.98 501.07 Storage conditions 50℃±2℃ Actual inspection time point 0 days, 5 days, 11 days, 32 days Packaging Weighing bottle (open)

3.2 The high humidity test method is shown in Table 12 below.

Table 12 Formula I compound active pharmaceutical ingredient Crystal form A Crystal form E amorphous Quantity stored (mg) 504.79 131.39 508.32 Storage conditions 90%RH±5%RH Actual inspection time point 0 days, 5 days, 11 days, 32 days Packaging Weighing bottle (open)

3.3 Illumination Experiment

The methods for conducting light exposure experiments are shown in Table 13 below.

Table 13 Formula I compound active pharmaceutical ingredient Crystal form A Crystal form E amorphous Quantity stored (mg) 500.53 131.34 500.91 Storage conditions 4500lx±500lx Actual inspection time point 0 days, 5 days, 11 days, 32 days Packaging Weighing bottle (open)

3.4 Accelerated Testing

The accelerated testing methods are shown in Table 14 below.

Table 14 Formula I compound active pharmaceutical ingredient Crystal form A Crystal form E amorphous Quantity stored (mg) 503.60 132.12 508.32 Storage conditions 40℃±2℃, 75%RH±5%RH Actual inspection time point 0 days, 5 days, 11 days, 32 days Packaging Weighing bottle (open)

The results of the relevant substances in each crystal form under high temperature conditions (50℃±2℃) are shown in Table 15.

HPLC detection results of relevant substances under high temperature conditions:

Table 15 Components Impurity content (%) in crystal form A Impurity content (%) in crystal form E 0 days 5 days 11 days 32 days 0 days 5 days 11 days 32 days RRT0.55 0.03 0.03 0.03 0.05 0.04 0.03 0.04 0.04 RRT0.66 0.18 0.19 0.19 0.20 0.21 0.22 0.22 0.26 RRT0.71 0.15 0.16 0.16 0.17 0.14 0.15 0.13 0.14 RRT0.94 0.04 0.04 0.03 0.05 0.03 0.03 0.03 0.05 RRT1.02 0.28 0.31 0.30 0.30 0.21 0.27 0.30 0.40 RRT1.06 0.07 0.08 0.08 0.08 0.07 0.05 0.06 0.05 RRT1.08 0.16 0.19 0.22 0.21 0.17 0.24 0.29 0.40 RRT1.15 0.03 0.03 0.03 0.05 0.03 0.03 0.03 0.05 Total miscellaneous (%) 0.95 1.03 1.04 1.11 0.89 1.03 1.10 1.40

After being placed under high-temperature conditions (50℃±2℃) for 32 days, the content of specific impurity RRT0.66 showed no significant change (increase ≤0.02%) in crystal form A with prolonged high-temperature time, while the content increased by 0.05% in crystal form E. The content of specific impurity RRT0.71 showed no significant change in either crystal form with prolonged high-temperature time. Specific impurity RRT1.02 showed no significant change in crystal form A, but increased by 0.19% in crystal form E. Specific impurity RRT1.08 increased by 0.05% in crystal form A and 0.23% in crystal form E. The contents of other non-specific impurities were all less than 0.10%. The total impurities increased by 0.16% and 0.51% in crystal form A and crystal form E, respectively, and the total impurity content was less than 2.0% in both crystal forms. In summary, under high-temperature conditions, crystal form A exhibits superior stability compared to crystal form E.

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

The HPLC detection results of relevant substances under high humidity conditions are shown below:

Table 16 Components Impurity content (%) in crystal form A Impurity content (%) in crystal form E Impurity content in amorphous materials (%) 0 days 5 days 11 days 32 days 0 days 5 days 11 days 32 days 0 days 5 days 11 days 32 days RRT0.55 0.03 0.03 0.03 0.03 0.04 0.03 0.04 0.04 0.03 0.03 0.03 0.03 RRT0.66 0.18 0.20 0.20 0.18 0.21 0.21 0.21 0.22 0.20 0.21 0.20 0.20 RRT0.71 0.15 0.16 0.16 0.16 0.14 0.15 0.14 0.15 0.16 0.17 0.16 0.18 RRT0.94 0.04 0.03 0.03 0.05 0.03 0.03 0.02 0.05 0.04 0.03 0.03 0.04 RRT1.02 0.28 0.31 0.30 0.26 0.21 0.21 0.20 0.19 0.29 0.31 0.31 0.31 RRT1.06 0.07 0.09 0.08 0.06 0.07 0.05 0.05 0.04 0.07 0.09 0.09 0.06 RRT1.08 0.16 0.21 0.21 0.18 0.17 0.18 0.21 0.21 0.18 0.19 0.25 0.23 RRT1.15 0.03 0.04 0.03 0.05 0.03 0.03 0.03 0.04 0.04 0.04 0.03 0.05 Total miscellaneous (%) 0.95 1.07 1.05 0.98 0.89 0.89 0.89 0.94 1.01 1.07 1.11 1.11

After being placed under high humidity conditions (90%RH±5%RH) for 32 days, the contents of specific impurities RRT0.66 and RRT0.71 remained essentially unchanged in all three crystal forms (increase ≤0.02%). Specific impurity RRT1.02 remained essentially unchanged in crystal forms A and E, but increased by 0.03% in the amorphous form. Specific impurity RRT1.08 remained essentially unchanged in crystal form A, but 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 less than 0.10%, and the total impurities increased by 0.03%, 0.05%, and 0.10% in crystal forms A, E, and the amorphous form, respectively, with the total impurity content not exceeding 2.0% in all cases. In summary, under high humidity conditions, the stability of crystal form A is better than that of crystal form E and amorphous form.

The results of the relevant substances in each crystal form under illumination conditions (4500 lx ± 500 lx) are shown in Table 17.

The HPLC detection results of relevant substances under illumination are shown below:

Table 17 Components Impurity content (%) in crystal form A Impurity content (%) in crystal form E Impurity content in amorphous materials (%) 0 days 5 days 11 days 32 days 0 days 5 days 11 days 32 days 0 days 5 days 11 days 32 days RRT0.55 0.03 0.03 0.03 0.03 0.04 0.03 0.04 0.03 0.03 0.04 0.03 0.05 RRT0.66 0.18 0.21 0.22 0.27 0.21 0.22 0.22 0.25 0.20 0.20 0.21 0.23 RRT0.71 0.15 0.14 0.15 0.10 0.14 0.14 0.14 0.13 0.16 0.17 0.17 0.21 RRT0.92 ND ND 0.03 ND ND RRT0.94 0.04 0.04 0.03 0.07 0.03 0.02 0.03 0.08 0.04 0.03 0.03 0.06 RRT1.02 0.28 0.30 0.31 0.28 0.21 0.22 0.20 0.20 0.29 0.32 0.33 0.35 RRT1.06 0.07 0.08 0.07 0.06 0.07 0.05 0.04 0.04 0.07 0.08 0.09 0.07 RRT1.08 0.16 0.20 0.22 0.25 0.17 0.20 0.24 0.25 0.18 0.21 0.28 0.37 RRT1.15 0.03 0.04 0.04 0.02 0.03 0.04 0.03 0.04 0.04 0.04 0.03 0.05 Total miscellaneous (%) 0.95 1.03 1.08 1.08 0.89 0.92 0.98 1.02 1.01 1.09 1.17 1.38 Note: ND indicates not detected.

After 32 days of exposure to light (4500 lx ± 500 lx), the content of specific impurity RRT0.66 increased in crystalline form A, crystalline form E, and amorphous forms, increasing by 0.09%, 0.04%, and 0.03%, respectively. Specific impurities RRT0.71 and RRT1.02 showed no increase in crystalline form A and crystalline form E, but increased by 0.05% and 0.06%, respectively, in amorphous forms. Specific impurity RRT1.08 increased by 0.09%, 0.08%, and 0.19%, respectively, in crystalline form A, crystalline form E, and amorphous forms. The content of other non-specific impurities was not greater than 0.10%, and the total impurities increased by 0.13%, 0.13%, and 0.37% in crystalline form A, crystalline form E, and amorphous forms, respectively, with the total impurity content not exceeding 2.0% in any of these forms. In summary, under illumination, the stability of crystal forms A and E is better than that of the amorphous form.

The results of material changes in each crystal form under accelerated conditions (40℃±2℃, 75%RH±5%RH) are shown in Table 18.

The HPLC detection results of relevant substances under accelerated conditions are shown below:

Table 18 Components Impurity content (%) in crystal form A Impurity content (%) in crystal form E Impurity content in amorphous materials (%) 0 days 5 days 11 days 32 days 0 days 5 days 11 days 32 days 0 days 5 days 11 days 32 days RRT0.55 0.03 0.03 0.04 0.04 0.04 0.04 0.04 0.04 0.03 0.04 0.03 0.04 RRT0.66 0.18 0.20 0.20 0.20 0.21 0.21 0.21 0.21 0.20 0.20 0.20 0.20 RRT0.71 0.15 0.16 0.17 0.16 0.14 0.15 0.15 0.16 0.16 0.17 0.17 0.18 RRT0.94 0.04 0.04 0.03 0.04 0.03 0.03 0.02 0.04 0.04 0.03 0.03 0.04 RRT1.02 0.28 0.30 0.33 0.27 0.21 0.21 0.21 0.20 0.29 0.32 0.31 0.29 RRT1.06 0.07 0.08 0.09 0.07 0.07 0.05 0.05 0.04 0.07 0.08 0.08 0.06 RRT1.08 0.16 0.18 0.25 0.20 0.17 0.18 0.21 0.20 0.18 0.22 0.24 0.21 RRT1.15 0.03 0.03 0.04 0.06 0.03 0.03 0.03 0.05 0.04 0.04 0.03 0.03 Total miscellaneous (%) 0.95 1.02 1.14 1.03 0.89 0.89 0.94 0.95 1.01 1.09 1.10 1.05

After 32 days of accelerated storage (40℃±2℃, 75%RH±5%RH), the specific impurities RRT0.66, RRT0.71, and RRT1.02 showed no significant changes (increase ≤0.02%) in the three crystal forms. The specific impurity RRT1.08 increased by 0.04%, 0.03%, and 0.03% in crystal forms A, E, and amorphous, respectively, with comparable increases. The contents of other non-specific impurities were all no greater than 0.10%, and the total impurities were all no greater than 2.0%. This indicates that the stability of the three crystal forms is comparable under accelerated storage conditions.

Under high temperature (50℃±2℃) and high humidity (90%RH±5%RH) conditions, crystal form A exhibits better stability than crystal form E and the amorphous form, respectively. Under illumination (4500lx±500lx), both crystal forms A and E show better stability than the amorphous form. Under accelerated conditions (40℃±2℃, 75%RH±5%RH), the stability of the three crystal forms is comparable. Compared to other conditions, the stability of all three crystal forms is poorer under illumination (4500lx±500lx), suggesting that they should be stored away from light.

In conclusion, compared to crystal form E and amorphous crystals, crystal form A is the most stable and most suitable for subsequent processing and development. Crystal form test example 4: Flowability test.

The flowability test method is as follows: Use a device with 2 to 3 funnels connected in staggered series to measure the angle of repose. The drug powder flows slowly and evenly through the funnels to a stationary base with a diameter of d, forming a symmetrical powder pile with a single layer of powder at the bottom. During the formation of the powder pile, the height of the funnels must be maintained within 2 to 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).

Experimental results: The experimental results of powder flowability of the three crystal forms of active pharmaceutical ingredients are shown in Figure 13.

The tests showed that the angle of repose for crystal form A was approximately 32.7°, for crystal form E it was 37.9°, and for the amorphous sample it was approximately 37.5°.

Since a smaller angle of repose in powders results in better flowability, crystal form A exhibits superior flowability compared to crystal form E and amorphous powders. Example 5 : Pharmacokinetic Testing of Crystal Forms.

This test case compared the pharmacokinetic processes of crystalline A and amorphous forms in SD rats, and compared their pharmacokinetic characteristics in SD rats.

Experimental methods and materials

Compound Information

test substance

Name: Compound of Formula I (Crystal Form A)

Name: Compound of Formula I (Amorphous)

Internal Standard

Name: Verapamil

Experimental animals: Six healthy adult male SD rats, divided into two groups of three, aged 6-8 weeks, weighing approximately 200-300 grams. The animals were housed in rat cages and fasted (for at least 10 hours) but allowed free access to water. On the day of the experiment, each rat was weighed and marked on its tail. Blank blood samples were collected before drug administration. Blood was collected via tail vein. Administration method: Post-oral administration (p.o.): Drug suspension was administered via gavage. Preparation of the drug suspension: Approximately 10 mg of the test sample was accurately weighed, dissolved in 5% DMSO (converted to 5%), and vortexed with 10% Solutol HS-15 and 85% Saline to obtain a suspension with a concentration of 1.0 mg/mL. The suspension was freshly prepared before use.

Sample collection: Rats were administered 10 mg/kg orally by gavage. Timing began immediately after administration, and blood samples were collected at 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-administration. 0.1 ml of whole blood was collected into EDTA- _Na2 anticoagulant tubes, inverted 3-4 times to mix thoroughly, and centrifuged at 10000 g for 5 min at 4°C to separate the plasma. The plasma was then stored at -80°C for later analysis. Blood was collected via the tail vein.

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

Analytical conditions: Liquid chromatography: Shimadzu Nexera X2; Column: Agilent ZORBAX XDB-C18 3.5 (2.1 × 50 mm); Column temperature: 35℃; Mobile phase: A-5% acetonitrile (0.1% formic acid aqueous solution), B-95% acetonitrile (0.1% formic acid aqueous solution); Injection volume: 3 µL;

Flow rate: 0.5 mL/min. Gradient elution was used, and the elution program is shown in the table below.

Table 19 time(min) 0.01 0.2 1.7 2.0 2.0 2.5 % B 10 10 100 100 10 10

Mass spectrometry conditions: Electrospray ion source ESI was used for mass spectrometry analysis in positive ion and multiple reaction monitoring (MRM) mode. The mass spectrometry ion source parameters and compound detection parameters are shown in the table below.

Mass spectrometry ion source parameters

Table 20 Instruments Triple Quad™ 6500+AB Mass Spectrometer, Made in Canada Ion source mode ESI Scan mode MRM Curtain 20 L/min atomizing gas 50 L/min Auxiliary Qi 50 L/min Ion source temperature 300°C Ion spray voltage +5500 v (positive MRM)

The main scan parameters for the analytes and internal standards are shown in the table below.

Table 21 Compound Name Q1 (m/z) Q3 (m/z) DP (v) EP (v) CE (v) CXP (v) Formula I compound 391.1 159.1 135 10 50 15 IS (verapamil) 455.3 165.2 135 10 35 15

PK parameter processing: Based on the blood 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 blood drug concentration using a non-compartmental model. (1) The PK parameters used to evaluate pharmacokinetics include: Cmax, AUC0-t, AUC0-∞, Tmax, and t1/2.

(2) Used for bioequivalence assessment: Cmax, AUC0-t, and AUC0-∞ are used for bioequivalence assessment.

Cmax: The maximum blood drug concentration measured within a specified time period, which is the measured value.

Tmax: The time to peak plasma concentration, measured as a real value. If the maximum value occurs at more than one time point, Tmax is defined as the first time point with that value.

AUC0-t: Blood drug concentration from 0 to the last time point t - the area under the time curve.

AUC0-∞: The area under the plasma concentration time curve from zero to infinity. Ct is the concentration measured last, and λz is the terminal phase elimination rate constant. t1/2: Elimination or terminal half-life, via ln2/ z estimate.

Results: The linear range of compound I was 2-2000 ng/ml. The plasma concentrations of compound I (crystalline form A) and compound I (amorphous form) in rats after administration of 10 mg/kg over time are shown in Tables 22 and 23, and Figures 14 and 15, respectively. The main pharmacokinetic parameters in rats are shown in Tables 24 and 25.

Table 22: Blood concentration-time data of rats administered 10 mg/kg of compound I (crystal form A) Blood drug concentration (ng/ml) Time (h) No. mean SD CV (%) 1 2 3 0.5 220 168 285 224 58.6 26.1 1 170 257 474 300 157 52.1 2 448 453 470 457 11.5 2.52 4 652 459 623 578 104 18.0 6 307 277 602 395 180 45.4 8 240 238 459 312 127 40.7 12 88.3 47.2 146 93.8 49.6 52.9 twenty four 11.6 5.25 21.3 12.7 8.08 63.6

Table 23: Plasma concentration-time data of rats administered 10 mg/kg of compound I (amorphous). Blood drug concentration (ng/ml) Time (h) No. mean SD CV (%) 1 2 3 0.5 44.5 49.0 29.4 41.0 10.3 25.1 1 20.8 21.5 25.3 22.5 2.42 10.7 2 64.1 71.2 33.2 56.2 20.2 36.0 4 71.7 307 47.9 142 143 101 6 72.4 128 58.3 86.2 36.9 42.7 8 87.1 84.3 34.7 68.7 29.5 42.9 12 18.6 40.6 14.0 24.4 14.2 58.3 twenty four 10.2 52.2 NA 31.2 29.7 95

Table 24. Partial pharmacokinetic parameters of rats after gavage administration of compound I (crystal form A) at 10 mg/kg. No. Tmax (h) Cmax (ng/ml) AUClast (h*ng/ml) AUCinf (h*ng/ml) HL_ (h) MRTlast (h) 1 4.00 652 4324 4386 3.76 6.09 2 4.00 459 3551 3575 3.07 5.52 3 4.00 623 6326 6440 3.70 6.66 Mean 4.00 578 4734 4800 3.51 6.09 SD 0.00 104 1432 1477 0.38 0.57 CV (%) 0.00 18.0 30.3 30.8 10.9 9.41

Table 25. Partial pharmacokinetic parameters of rats after gavage administration of compound I (amorphous) at 10 mg/kg. No. Tmax (h) Cmax (ng/ml) AUClast (h*ng/ml) AUCinf (h*ng/ml) HL_ (h) MRTlast (h) 1 8.00 87.1 894 982 6.05 7.84 2 4.00 307 1908 3203 17.2 9.26 3 6.00 58.3 428 487 2.93 5.56 Mean 6.00 151 1077 1558 8.72 7.55 SD 2.00 136 757 1446 7.50 1.87 CV (%) 33.3 90.2 70.3 92.9 85.9 24.8

After oral administration of the same dose of compound I (crystalline form A) or compound I (amorphous form) to rats, the Cmax was 578 ng/ml and 151 ng/ml, respectively; the AUClast was 4734 h*ng/ml and 1077 h*ng/ml, respectively. 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 amorphous form.

The embodiments of this invention have been described above. However, this invention is not limited to the above embodiments. Any modifications, equivalent substitutions, or improvements made within the spirit and principles of this invention shall be included within the scope of protection of this invention. All documents mentioned in this invention are cited in this invention as if each document were cited separately. Furthermore, it should be understood that after reading the above teachings of this invention, those skilled in the art can make various modifications or alterations to this invention, and these equivalent forms also fall within the scope defined by the claims attached to this invention.

without

Figure 1 shows the dissolution curve of tablet 1 obtained from composition example 1.

Figure 2 shows the dissolution curve of tablet 2 obtained from composition example 2.

Figure 3 shows the dissolution curves of tablets 3 and 4 obtained from actual compositions 3 and 4.

Figure 4 shows the dissolution curves of tablets 5-6 obtained from composition example 5-6.

Figure 5 shows the XRD pattern of crystal form A.

Figure 6 shows the thermogravimetric analysis and differential scanning calorimetry (TGA-DSC) of crystal form A.

Figure 7 shows the polarimetric light spectrum (PLM) of crystal form A.

Figure 8 shows the XRD pattern of the amorphous material.

Figure 9 shows the XRD pattern of crystal form E.

Figure 10 shows the DVS test results for crystal form A.

Figure 11 shows the DVS test results for crystal form E.

Figure 12 shows the DVS test results of the amorphous sample.

Figure 13 shows the flowability results of crystal form A, crystal form E, and amorphous samples.

Figure 14 shows the plasma concentration-time curve of rats given 10 mg/kg of compound I (crystal form A).

Figure 15 shows the plasma concentration-time curve of rats given 10 mg/kg of compound I (amorphous).

Figure 16 is a single crystal structure diagram of compound A of formula I (Figure 16 is a modified unit containing 2 molecules of compound and 1 molecule of crystal water, where C7 and C7’ are both R configurations and the FLACK parameter is 0.26(12)).

Figure 17 shows the XRD pattern of crystal form B.

Figure 18 shows the XRD pattern of crystal form C.

Figure 19 shows the thermogravimetric analysis and differential scanning calorimetry (TGA-DSC) of crystal form C.

Figure 20 shows the XRD pattern of crystal form D.

Figure 21 shows the thermogravimetric analysis and differential scanning calorimetry (TGA-DSC) of crystal form D.

Figure 22 shows the XRD pattern of crystal form D after being stored at room temperature in a closed container for two days.

Figure 23 shows the XRD pattern of crystal form D heated to 120ºC and cooled to room temperature.

Figures 24 and 25 show the XRD patterns of crystal forms A/C/D after being mixed and suspended at different water activities at room temperature.

Claims (41)

A pharmaceutical composition comprising: crystal form A of the monohydrate of compound I. Formula I and pharmaceutically acceptable carriers, excipients or formulations; wherein the crystal form A has characteristic peaks at one or more of the following locations in an X-ray powder diffraction pattern expressed in 2θ angles: 9.35±0.2°, 11.42±0.2°, 12.06±0.2°, 18.71±0.2° and 21.16±0.2°. According to claim 1, the pharmaceutical composition wherein the crystal form A has characteristic peaks at one or more of the following locations in the X-ray powder diffraction pattern expressed in 2θ angles: 9.97±0.2°, 13.16±0.2°, 19.15±0.2°, 19.97±0.2°, and 21.00±0.2°. The pharmaceutical composition according to claim 1, wherein the crystal form A has an X-ray powder diffraction pattern substantially as shown in Figure 5. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is prepared as an oral formulation. The pharmaceutical composition according to claim 1, wherein the crystal form A has a thermogravimetric analysis spectrum and a differential scanning calorimetry spectrum as shown in Figure 6. The pharmaceutical composition according to claim 1, wherein the crystal form A is a monoclinic crystal system, space group P2(1), with cell parameters a=10.2499(10) Å, b=17.9931(16) Å, c=11.2407(8) Å, α=γ=90° β=93.349(8)°, deviation factor _R1 =0.0562, and Z=4. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition comprises the following components in parts by weight: Components weight Crystal form A 2.5-40 First dilution 10-70 Second diluent 10-70 Flow aid 0.5-5 Disintegrant 1-15 Lubricant 0.2-10 Coating material 1-10 . The pharmaceutical composition according to claim 7, wherein the D90 of crystal form A is 17-523 μm. The pharmaceutical composition according to claim 7, wherein the D90 of crystal form A is 17-191 μm. The pharmaceutical composition according to claim 7, wherein the first diluent is selected from mannitol, lactose, anhydrous calcium hydrogen phosphate, or a combination thereof. The pharmaceutical composition according to claim 7, wherein the second diluent is microcrystalline cellulose. The pharmaceutical composition according to claim 7, wherein the gliding agent is colloidal silica. The pharmaceutical composition according to claim 7, wherein the disintegrant is selected from sodium carboxymethyl cellulose, sodium cross-linked carboxymethyl cellulose, cross-linked povidone, or a combination thereof. The pharmaceutical composition according to claim 7, wherein the lubricant is selected from sodium stearate, magnesium stearate, or a combination thereof. The pharmaceutical composition according to claim 7, wherein the coating material comprises a stabilizer and a polymer, wherein the stabilizer is selected from at least one of titanium dioxide, talc and ferric oxide, and the polymer is selected from at least one of polyvinyl alcohol and polyethylene glycol. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition has one or more of the following characteristics: 1) under pH 6.0-7.6 and 0.2% SDS conditions, the dissolution rate of crystal form A in the pharmaceutical composition is ≥70% within 15 min; 2) under pH 6.0-7.6 and 0.2% SDS conditions, the dissolution rate of crystal form A in the pharmaceutical composition is ≥85% within 45 min; 3) under pH 6.0-7.6 and 0.2% SDS conditions, the dissolution rate of crystal form A in the pharmaceutical composition is ≥95% within 60 min; 4) after storage at 25±2℃ and 60%±5%RH conditions for 18 months, the dissolution rate of crystal form A in the pharmaceutical composition is ≥85% within 45 min; 5) When the drug composition is stored at 40±2℃ and 75%±5%RH for 6 months, the dissolution rate of crystal form A in the drug composition is ≥85% within 45 min. A method for preparing a pharmaceutical composition according to any one of claims 1-16, comprising: providing the following materials in parts by weight as raw materials and preparing the raw materials into a composition: Components weight Crystal form A 2.5-40 First dilution 10-70 Second diluent 10-70 Flow aid 0.5-5 Disintegrant 1-15 Lubricant 0.2-10 Coating material 1-10 . According to the preparation method of claim 17, the following materials in parts by weight are provided as raw materials and said raw materials are prepared into a composition: Components weight Crystal form A 4-30 First dilution 20-60 Second diluent 20-60 Flow aid 1-4 Disintegrant 2-12 Lubricant 0.5-10 Coating material 1.5-8 . According to the preparation method of claim 17, the D90 of the crystal form A is 17-523 μm. According to the preparation method of claim 17, the D90 of the crystal form A is 17-191 μm. The preparation method according to claim 17, wherein the first diluent is selected from mannitol, lactose, anhydrous calcium hydrogen phosphate, or a combination thereof. The preparation method according to claim 17, wherein the second diluent is microcrystalline cellulose. The preparation method according to claim 17, wherein the flow aid is colloidal silica. According to the preparation method of claim 17, the disintegrant is selected from sodium carboxymethyl cellulose, sodium cross-linked carboxymethyl cellulose, cross-linked povidone, or a combination thereof. The preparation method according to claim 17, wherein the lubricant is selected from sodium stearate, magnesium stearate, or a combination thereof. According to the preparation method of claim 17, the coating material comprises a stabilizer and a polymer, wherein the stabilizer is selected from at least one of titanium dioxide, talc and yellow iron oxide, and the polymer is selected from at least one of polyvinyl alcohol and polyethylene glycol. According to the preparation method of claim 17, wherein the preparation method of crystal form A is to pulp the compound of formula I using a mixed solvent of acetonitrile and water. According to the preparation method of claim 27, wherein the preparation method of crystal form A is to slurry the compound of formula I using a mixed solvent of acetonitrile and water for 1-4 days, and centrifuge to collect the crystalline powder solid. Crystal form A of a monohydrate of compound of formula I Formula I states that crystal form A has characteristic peaks at one or more of the following locations in an X-ray powder diffraction pattern expressed in 2θ angles: 9.35±0.2°, 11.42±0.2°, 12.06±0.2°, 18.71±0.2°, and 21.16±0.2°. According to claim 29, the crystal form A has characteristic peaks at one or more of the following locations in the X-ray powder diffraction pattern expressed in 2θ angles: 9.97±0.2°, 13.16±0.2°, 19.15±0.2°, 19.97±0.2°, and 21.00±0.2°. Crystal form A according to claim 29, wherein crystal form A has an X-ray powder diffraction pattern substantially as shown in FIG5. A method for preparing crystal form A as described in any of claims 29-31, comprising pulping a compound of formula I using a mixed solvent of acetonitrile and water. According to the preparation method of claim 32, wherein the preparation method of crystal form A is to slurry the compound of formula I with a mixed solvent of acetonitrile and water for 1-4 days, and centrifuge to collect the crystalline powder solid. Use of a pharmaceutical composition according to any one of claims 1-16 or crystal form A according to any one of claims 29-31 in the preparation of a drug for treating cancer or tumor. According to the use described in claim 34, the cancer or tumor targeted by the anticancer or antitumor drug is selected from breast cancer, cervical cancer, colon cancer, lung cancer, stomach cancer, rectal cancer, pancreatic cancer, brain cancer, skin cancer, prostate cancer, bone cancer, kidney cancer, ovarian cancer, bladder cancer, liver cancer, fallopian tube tumor, peritoneal tumor, head and neck cancer, leukemia, lymphoma, and myeloma. According to the use described in claim 35, the brain cancer is a glioma or a glioblastoma. According to the use described in claim 35, the skin cancer is melanoma. According to the use described in claim 35, the head and neck cancer is oral cancer or thyroid adenoma. According to the use described in claim 35, the kidney cancer is a papillary renal tumor. Use of a pharmaceutical composition according to any one of claims 1-16 or crystal form A according to any one of claims 29-31 in the preparation of a medicament for treating ROS1, NTRK, and ALK-mediated diseases. According to the use described in claim 40, the diseases mediated by ROS1, NTRK, and ALK are selected from cancer, sarcoma, and pain.