Crystal, pharmaceutical composition, preparation method therefor, and use 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 significance for improving the production and quality control of drugs, solid oral formulation development prospects, etc.

Description

Crystal, pharmaceutical composition, preparation method and application thereof Technical Field

[0001] The present invention belongs to the technical field of medicinal chemistry, and particularly relates to a crystal form of a compound used as a kinase inhibitor, a preparation method and an application thereof. Background Art

[0002] The tropomyosin receptor kinase (TRK) family belongs to the transmembrane receptor tyrosine kinase (RTK) family and is involved in regulating synaptic growth and maintenance in the mammalian nervous system, the development of memory, and protecting neurons from damage. TRK kinases are a class of nerve growth factor receptors. The TRK family consists of the highly homologous tropomyosin-related kinase A (TRKA), tropomyosin-related kinase B (TRKB), and tropomyosin-related kinase C (TRKC), encoded by the NTRK1, NTRK2, and NTRK3 genes, respectively. The complete TRK kinase consists of three regions: an extracellular domain, a transmembrane domain, and an intracellular domain. Like other RTKs, the extracellular domain of a TRK kinase forms a dimer upon ligand binding. This dimerization triggers autophosphorylation of the intracellular domain of the TRK kinase, activating its own kinase activity and further activating downstream signal transduction pathways. TRK kinases influence cell proliferation, differentiation, metabolism, and apoptosis through downstream pathways such as Ras / MAPK, PI3K / AKT, and PLCγ. When NTRKs genes undergo fusion or mutation, the extracellular domain receptor is altered or eliminated (Greco, A. et al., Mol. Cell. Biol. 1995, 15, 6118; Oncogene 1998, 16, 809). The fused or mutated TRK protein maintains a highly activated kinase activity state without the need for ligand binding, thereby continuously activating downstream signal transduction pathways. This can lead to dysregulation of TRK kinase downstream signaling pathways, inducing cell proliferation and promoting tumor development and progression. 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 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 fusions is relatively low, approximately 1%-3%. However, in rare cancers, such as infantile fibrosarcoma and secretory breast carcinoma, the incidence can reach over 90%. The TPM3-TRKA fusion protein was first discovered in colon cancer cells. Subsequently, more NTRK fusion proteins, such as CD74-NTRKA, MPRIP-NTEKA, QKI-NTRKB, ETV6-NTRKC, and BTB1-NTRKC, have been discovered in various clinical tumor 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 a promising anti-cancer target and a hot topic in anti-cancer drug development.With the further in-depth understanding of TRK kinases in recent years, more TRK fusion protein types 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 to develop new NTRK inhibitors with better activity and broader effects in clinical practice 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 humans. It is located on chromosome 6q22.1 and belongs to the tyrosine kinase insulin receptor gene. It consists of an intracellular tyrosine kinase active domain, a transmembrane domain, and an extracellular domain, encoding a chimeric protein with tyrosine kinase activity. The 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). Rearrangements in the ROS1 gene result in the loss of the extracellular domain, while retaining the transmembrane and intracellular tyrosine kinase domains. The rearrangement occurs primarily in exons 32-36 of the ROS1 gene. ROS1 gene mutations occur predominantly in 1%-2% of lung cancer patients. In NSCLC, the ROS1 gene primarily 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, leading to tumorigenesis. Numerous studies and clinical trials have demonstrated that inhibiting the activity of mutant ROS1 kinases can treat diseases caused by ROS1 overactivation, particularly cancer. Currently available treatments for ROS1-positive NSCLC include crizotinib and entrectinib, both first-generation small molecule ROS1 inhibitors. However, drug resistance and disease progression can develop around 15 months after treatment with crizotinib or entrectinib. Among patients who develop drug resistance, the most common resistance mutation is solvent-front mutations such as G2032R. Currently, no treatment options are available for these patients. Therefore, there is an urgent need to develop new inhibitors against ROS1, especially new ROS1 inhibitors for clinical treatment of patients who have developed resistance to first-generation ROS1 inhibitors such as crizotinib or entrectinib.

[0004] 2-5% of NSCLC cases harbor anaplastic lymphoma kinase (ALK) rearrangements. ALK is a receptor-type protein tyrosine kinase of the insulin receptor superfamily. ALK was initially discovered as an activated fusion oncogene in anaplastic large cell lymphoma. Subsequent studies have revealed ALK fusions in various cancers, including systemic dysplasia, inflammatory myofibroblastic carcinoma, and non-small cell lung cancer. ALK mutations and aberrant activity in various cancers have made it a drug target for treating ALK-positive cancers. Currently, several ALK kinase inhibitors are available. With the clinical use of these drugs, patients often develop resistance mutations. Resistance mutations, such as G1202R, can render these drugs ineffective.

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

[0006] Patent document CN112867717A discloses a kinase inhibitor that can simultaneously act on oncogenic proteins such as NTRK, ALK, and / or ROS1 - compound TY-2136b shown in the following formula I. 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] Drugs need to be in solution to be absorbed, but such precipitation can affect the extent and rate of drug absorption. Compounds with pH-dependent solubility, particularly basic compounds, can exhibit undesirable pharmacokinetic properties, such as poor absorption or low bioavailability, which can lead to significant inter- and intra-patient variability. Therefore, there is a need to discover improved TY-2136b dosage forms with favorable dissolution and pharmacokinetic profiles and exhibit good storage stability.

[0008] There are no reports on the preparation of formulations for the compound of Formula I. To deliver the therapeutic benefits of TY-2136b to patients in need, TY-2136b needs to be formulated into a pharmaceutical composition, particularly a solid dosage form suitable for oral administration. Therefore, there is a need for a pharmaceutical formulation of TY-2136b with good in vivo dissolution, high bioavailability, and excellent storage and accelerated stability, which is consistent in quality.

[0009] Furthermore, no literature has been found reporting on the preparation of crystalline forms of the compound of Formula I. Those skilled in the art understand that discovering compound forms that facilitate the purification and quality control of pharmaceutical compounds is crucial for improving pharmaceutical production, quality control, and the development prospects of solid oral dosage forms. Because different drug crystalline forms can affect the drug's formulation properties, bioavailability, and efficacy, research on drug crystalline forms is of great significance. Therefore, since the performance of TY-2136b, such as stability, flowability, and other aspects of formulation properties, quality control, and bioavailability, still requires improvement, it is necessary to develop suitable forms of the compound and methods for their preparation.

[0010] Summary of the Invention

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

[0012] Crystalline Form A of the Monohydrate of the Compound of Formula I

[0013] and pharmaceutically acceptable carriers, excipients or vehicles;

[0014] The crystalline 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 angles.

[0015] In one or more embodiments, the crystalline form A 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 angles.

[0016] In one or more embodiments, the Form A has an X-ray powder diffraction pattern substantially as shown in FIG5 .

[0017] In one or more embodiments, the pharmaceutical composition is prepared as an oral formulation.

[0018] In one or more embodiments, the crystalline Form A has a thermogravimetric analysis spectrum and a differential scanning calorimetry spectrum substantially as shown in FIG6 .

[0019] In one or more embodiments, the crystal form A is a monoclinic system, a P2(1) space group, and a unit cell parameter of α=γ=90°β=93.349(8)°, deviation factor R1=0.0562, Z=4.

[0020] In one or more embodiments,

[0021] The pharmaceutical composition comprises the following components in parts by weight:

[0022] In one or more embodiments, the D90 of the crystalline form A is 17-523 μm, for example 17-191 μm;

[0023] In one or more embodiments, the first diluent is selected from mannitol, lactose, anhydrous calcium hydrogen phosphate, or a combination thereof.

[0024] In one or more embodiments, the second diluent is microcrystalline cellulose.

[0025] In one or more embodiments, the glidant is colloidal silicon dioxide.

[0026] In one or more embodiments, the disintegrant is selected from sodium starch glycolate, croscarmellose sodium, crospovidone, or a combination thereof.

[0027] In one or more embodiments, the lubricant is selected from sodium stearyl fumarate, magnesium stearate, or a combination thereof.

[0028] 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, and yellow iron oxide, and the polymer is selected from at least one of polyvinyl alcohol and polyethylene glycol.

[0029] In one or more embodiments, the pharmaceutical composition has one or more of the following characteristics:

[0030] 1) Under conditions of pH 6.0-7.6 and 0.2% SDS, within 15 minutes, the dissolution rate of Form A in the pharmaceutical composition is ≥70%;

[0031] 2) Under conditions of pH 6.0-7.6 and 0.2% SDS, within 45 minutes, the dissolution rate of Form A in the pharmaceutical composition is ≥85%;

[0032] 3) Under conditions of pH 6.0-7.6 and 0.2% SDS, the dissolution rate of Form A in the pharmaceutical composition is ≥95% within 60 minutes;

[0033] 4) The pharmaceutical composition is stored at 25±2°C and 60%±5% RH for 18 months, and the dissolution rate of Form A in the pharmaceutical composition is ≥85% within 45 minutes;

[0034] 5) The pharmaceutical composition is stored at 40±2° C. and 75%±5% RH for 6 months, and within 45 minutes, the dissolution rate of Form A in the pharmaceutical composition is ≥85%.

[0035] One or more embodiments of the present application provide a method for preparing the pharmaceutical composition of the present application, comprising:

[0036] The following materials in parts by weight are provided as raw materials and the raw materials are prepared into a composition:

[0037] In one or more embodiments,

[0038] In one or more embodiments, the D90 of the crystalline form A is 17-523 μm, for example, 17-191 μm.

[0039] In one or more embodiments, the first diluent is selected from mannitol, lactose, anhydrous calcium hydrogen phosphate, or a combination thereof.

[0040] In one or more embodiments, the second diluent is microcrystalline cellulose.

[0041] In one or more embodiments, the glidant is colloidal silicon dioxide.

[0042] In one or more embodiments, the disintegrant is selected from sodium starch glycolate, croscarmellose sodium, crospovidone, or a combination thereof.

[0043] In one or more embodiments, the lubricant is selected from sodium stearyl fumarate, magnesium stearate, or a combination thereof.

[0044] 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, and yellow iron oxide, and the polymer is selected from at least one of polyvinyl alcohol and polyethylene glycol.

[0045] In one or more embodiments, the preparation method of the crystalline form A is to slurry the compound of formula I using a mixed solvent of acetonitrile and water.

[0046] In one or more embodiments, the preparation method of the crystalline form A is to slurry the compound of formula I using a mixed solvent of acetonitrile and water for 1-4 days, and collect the crystalline powder solid by centrifugation.

[0047] One or more embodiments of the present application provide use of the pharmaceutical composition of the present application in preparing a drug for treating and / or preventing anti-cancer or anti-tumor.

[0048] In one or more embodiments, the cancer or tumor targeted by the 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, papilloma, leukemia, lymphoma, myeloma and thyroid tumor.

[0049] One or more embodiments of the present application provide 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.

[0050] In one or more embodiments, the ROS1, NTRK, ALK-mediated disease is selected from cancer, sarcoma, and pain.

[0051] One or more embodiments of the present application provide a pharmaceutical composition comprising the following components:

[0052] Component 1) Compound represented by formula I

[0053] or a pharmaceutically acceptable hydrate, solvate or salt thereof, as an active ingredient; and

[0054] Component 2) a pharmaceutically acceptable carrier.

[0055] In one or more embodiments, the pharmaceutical composition comprises the following components in parts by weight:

[0056] In one or more embodiments, the pharmaceutical composition has one or more characteristics selected from the following:

[0057] 1) Under conditions of pH 6.0-7.6, 0.2% SDS (e.g., pH 6.2-7.4 or pH 6.5-7.2), within 15 minutes, the solubility of the active ingredient in the pharmaceutical composition is ≥70% (e.g., ≥75%, ≥80%, ≥85%);

[0058] 2) Under conditions of pH 6.0-7.6, 0.2% SDS (e.g., pH 6.2-7.4 or pH 6.5-7.2), within 45 minutes, the solubility of the active ingredient in the pharmaceutical composition is ≥85% (e.g., ≥90%, ≥95%);

[0059] 3) Under conditions of pH 6.0-7.6, 0.2% SDS (e.g., pH 6.2-7.4, pH 6.5-7.2), within 60 minutes, the solubility of the active ingredient in the pharmaceutical composition is ≥95% (e.g., ≥98%, ≥100%);

[0060] 4) After storage at 25±2°C 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;

[0061] 5) After storage at 40±2°C 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.

[0062] In one or more embodiments, the pharmaceutically acceptable compound is a monohydrate.

[0063] In one or more embodiments, the pharmaceutical composition is an oral formulation.

[0064] In one or more embodiments, the pharmaceutical composition is in a solid dosage form.

[0065] In one or more embodiments, the pharmaceutical composition is a tablet.

[0066] In one or more embodiments, the pharmaceutical composition further comprises a coating material.

[0067] In one or more embodiments, the weight of the coating material is 1.5-10%, such as 1.8-8%, or 2-6%, of the total weight of component 1) and component 2).

[0068] One or more embodiments of the present application provide a method for preparing the pharmaceutical composition of the present application, comprising:

[0069] 1) Provide the following materials as raw materials;

[0070] 2) The above materials are prepared into a pharmaceutical composition.

[0071] In one or more embodiments, step 2) includes the following steps:

[0072] 2-1) premixing the active ingredient, the first diluent, the second diluent, the glidant, the disintegrant, and the lubricant to obtain a premix;

[0073] 2-2) dry granulation;

[0074] 2-3) mixing the product obtained in step 2-2) with a second lubricant to obtain a mixture;

[0075] 2-4) tabletting to obtain plain tablets, i.e., the pharmaceutical composition.

[0076] In one or more embodiments, the hardness of the plain tablet is 40-150N, such as 70-130N, 80-120N.

[0077] In one or more embodiments, the hardness of the plain tablet is 30-100N, such as 40-90N, 50-80N.

[0078] One or more embodiments of the present application provide use of the pharmaceutical composition of the present application in the preparation of anti-tumor drugs.

[0079] 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, papilloma, leukemia, lymphoma, myeloma, and thyroid tumor.

[0080] One or more embodiments of the present application provide a crystalline form A of a monohydrate of a compound of formula I, 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 an X-ray powder diffraction pattern expressed in 2θ angles, wherein the chemical structure of the compound of formula I is as follows:

[0081] In one or more embodiments, the crystalline form A 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 angles.

[0082] In one or more embodiments, the X-ray powder diffraction of the crystalline form A expressed in 2θ angle has an absorption peak at the following position,

[0083] In one or more embodiments, the Form A has an X-ray powder diffraction pattern substantially as shown in FIG5 .

[0084] In one or more embodiments, the thermogravimetric analysis (TGA) spectrum of Form A shows a weight loss of 4.216% between room temperature (about 25° C.) and 130° C.

[0085] In one or more embodiments, the crystalline Form A has a thermogravimetric analysis spectrum substantially as shown in FIG6 .

[0086] In one or more embodiments, the differential scanning calorimetry (DSC) spectrum of the crystalline form A has endothermic peaks at approximately 87.11° C. and 142.34° C.

[0087] In one or more embodiments, the Form A has a differential scanning calorimetry spectrum substantially as shown in FIG6 .

[0088] In one or more embodiments, the crystal form A is a block crystal with a size of 20-100 μm.

[0089] In one or more embodiments, the crystalline Form A has a morphology substantially as shown in FIG. 7 .

[0090] In one or more embodiments, the crystal form A is a monoclinic system, a P2(1) space group, and a unit cell parameter of α=γ=90°β=93.349(8)°, deviation factor R1=0.0562, Z=4.

[0091] One or more embodiments of the present application provide a method for preparing Form A, comprising: slurrying the compound of Formula I using a mixed solvent of acetonitrile and water.

[0092] In one or more embodiments, the volume ratio of acetonitrile to water is 1:(1-3), for example 1:1 or 1:2.

[0093] In one or more embodiments, beating is performed at room temperature.

[0094] In one or more embodiments, the crystalline form A is prepared by the following method: taking the compound of formula I, adding a mixed solvent of acetonitrile and water to perform a slurrying test, and after slurrying for 1-4 days, centrifuging to collect the crystalline powder solid.

[0095] One or more embodiments of the present application provide an amorphous form of the compound of Formula I having an X-ray powder diffraction pattern substantially as shown in FIG. 8 .

[0096] One or more embodiments of the present application provide Form B of the compound of Formula I, which has an X-ray powder diffraction pattern substantially as shown in FIG. 17 .

[0097] One or more embodiments of the present application provide Form C of the compound of Formula I, which has an X-ray powder diffraction pattern substantially as shown in FIG. 18 .

[0098] One or more embodiments of the present application provide Form D of the compound of Formula I, which has an X-ray powder diffraction pattern substantially as shown in FIG. 20 .

[0099] One or more embodiments of the present application provide Form E of the compound of Formula I, which has an X-ray powder diffraction pattern substantially as shown in FIG. 9 .

[0100] One or more embodiments of the present application provide the use of Form A of the compound of Formula I in preparing a pharmaceutical composition.

[0101] One or more embodiments of the present application provide the use of Form A of the compound of Formula I in the preparation of a medicament for preventing and / or treating diseases with pathological characteristics mediated by ROS1, NTRK, ALK, etc.

[0102] In one or more embodiments, the diseases with pathological characteristics mediated by ROS1, NTRK, ALK, etc. include cancer, sarcoma and pain.

[0103] 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, papilloma, leukemia, lymphoma, myeloma, and thyroid tumor.

[0104] In one or more embodiments, Form A of the compound of Formula I is used to prevent and / or treat the following diseases: inflammation, cancer, cardiovascular disease, infection, immune disease, metabolic disease.

[0105] One or more embodiments of the present application provide a treatment method, which includes the steps of administering Form A of the compound of Formula I described in the present invention to a subject in need of treatment, for selectively inhibiting fusion mutations and drug-resistant mutations of ROS1, NTRK, ALK, etc.

[0106] In one or more embodiments, Form A is of great significance for improving the production, quality control and development prospects of solid oral dosage forms of drugs.

[0107] In one or more embodiments, the results of the physicochemical stability evaluation show that Form A is a monohydrate and does not lose water or have hygroscopicity under normal conditions.

[0108] In one or more embodiments, the stability under high temperature, high humidity, accelerated test and light irradiation test is significantly better than that of the amorphous form and crystalline form E.

[0109] In one or more embodiments, Form A has better flowability than Form E and the amorphous form.

[0110] In one or more embodiments, the bioavailability of Form A is significantly higher than that of the amorphous form.

[0111] In one or more embodiments, based on the good physicochemical stability, fluidity and bioavailability of Form A, it has great potential in subsequent development and production.

[0112] One or more embodiments of the present application provide the composition of the present application or the crystalline form A of the compound of formula I, which is used for treating and / or preventing a disease.

[0113] One or more embodiments of the present application provide the composition of the present application or the crystalline form A of the compound of formula I, which is used to treat and / or prevent cancer or tumors.

[0114] One or more embodiments of the present application provide a composition of the present application or a crystalline form A of a compound of formula I, which is used to treat and / or prevent 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, melanomas, gliomas, glioblastomas, head and neck cancers, papillary nephroma, leukemia, lymphoma, myeloma or thyroid tumor.

[0115] One or more embodiments of the present application provide the composition of the present application or the crystalline form A of the compound of formula I, which is used to treat and / or prevent diseases mediated by ROS1, NTRK, or ALK.

[0116] One or more embodiments of the present application provide a method for treating and / or preventing a disease, comprising administering the composition of the present application or Form A of the compound of Formula I to a subject in need thereof.

[0117] One or more embodiments of the present application provide a method for treating and / or preventing cancer or tumors, comprising administering the composition of the present application or Form A of the compound of Formula I to a subject in need thereof.

[0118] One or more embodiments of the present application provide a method for treating and / or preventing 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 nephroma, leukemia, lymphoma, myeloma or thyroid tumor, which comprises administering a composition of the present application or Form A of the compound of Formula I to a subject in need thereof.

[0119] One or more embodiments of the present application provide a method for treating and / or preventing diseases mediated by ROS1, NTRK, or ALK, comprising administering the composition of the present application or Form A of the compound of Formula I to a subject in need thereof.

[0120] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features described in detail below can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be listed here one by one. BRIEF DESCRIPTION OF THE DRAWINGS

[0121] FIG1 is a dissolution curve of Tablet 1 obtained in Composition Example 1.

[0122] FIG2 is a dissolution curve of Tablet 2 obtained in Composition Example 2.

[0123] FIG3 shows the dissolution curves of tablets 3 and 4 obtained from Examples 3 and 4 of the composition.

[0124] FIG4 is a dissolution curve of tablet 5-6 obtained from composition example 5-6.

[0125] FIG5 is the XRD spectrum of Form A.

[0126] FIG6 is a thermogravimetric analysis and differential scanning calorimetry (TGA-DSC) diagram of Form A.

[0127] FIG7 is a partial light microscope (PLM) spectrum of Form A.

[0128] Figure 8 is the XRD spectrum of amorphous.

[0129] FIG9 is an XRD spectrum of Form E.

[0130] FIG10 is the DVS test results of Form A.

[0131] FIG11 shows the DVS test results of Form E.

[0132] Figure 12 shows the DVS test results of the amorphous sample.

[0133] FIG13 shows the flowability results of Form A, Form E, and amorphous samples.

[0134] Figure 14 is a blood concentration-time curve of rats administered 10 mg / kg of the compound of formula I (Form A).

[0135] Figure 15 is a blood concentration-time curve of the compound of formula I (amorphous form) administered at 10 mg / kg to rats.

[0136] Figure 16 is a single crystal structure diagram of Form A of the compound of Formula I (Figure 16 is a modified unit, containing 2 molecules of compound and 1 molecule of crystalline water, wherein C7C7' are both R configurations, and the FLACK parameter is 0.26 (12)).

[0137] FIG17 is an XRD spectrum of Form B.

[0138] FIG18 is an XRD spectrum of Form C.

[0139] FIG19 is a thermogravimetric analysis and differential scanning calorimetry (TGA-DSC) diagram of Form C.

[0140] FIG20 is an XRD spectrum of Form D.

[0141] FIG21 is a thermogravimetric analysis and differential scanning calorimetry (TGA-DSC) diagram of Form D.

[0142] Figure 22 is the XRD spectrum of Form D after closed storage at room temperature for two days.

[0143] FIG23 is an XRD spectrum of Form D heated to 120° C. and cooled to room temperature.

[0144] Figures 24 and 25 are XRD patterns of Forms A / C / D after suspension competition at different water activities at room temperature. DETAILED DESCRIPTION

[0145] The technical solutions of the present invention will be described in further detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanations of the present invention and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are encompassed within the scope of protection that the present invention is intended to protect.

[0146] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0147] After long and in-depth research, the inventors have obtained a pharmaceutical composition with excellent dissolution performance, pharmacokinetic performance and storage stability by optimizing the composition. On this basis, the inventors have completed the present invention.

[0148] Following oral administration, drugs can be absorbed at numerous different sites along the gastrointestinal tract (including via the stomach, duodenum, jejunum, ileum, and colon). As the pH varies significantly between the stomach (pH 1-3.5) and the small intestine (pH 4-8), the pH varies at each absorption site. Studies conducted in this application have shown that the solubility of TY-2136b is pH-dependent, increasing with increasing pH but remaining relatively low overall. Dissolution studies have shown that sink conditions can be met in a pH 6.8 medium supplemented with SDS.

[0149] One or more embodiments of the present application provide pharmaceutical compositions suitable for oral administration, and more specifically, pharmaceutical compositions (e.g., pharmaceutical tablets) comprising TY-2136b or a pharmaceutically acceptable hydrate, solvate, or salt thereof. Furthermore, the solid dosage form of the composition of the present application exhibits excellent storage stability.

[0150] In one or more embodiments, the pharmaceutical compositions of the present application can be formed into tablets that exhibit improved dissolution properties under physiologically relevant conditions and / or higher total release of the agent on physiologically relevant parameters.

[0151] Typically, crystallization produces solvates of the compounds of the present invention. As used herein, the term "solvate" refers to an aggregate comprising 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. Alternatively, the solvent can be an organic solvent. Thus, the compounds of the present invention can exist as hydrates, including monohydrates, dihydrates, hemihydrates, sesquihydrates, trihydrates, tetrahydrates, and the like, as well as the corresponding solvated forms.

[0152] "Pharmaceutical composition" refers to a preparation of a compound of the present invention and a medium generally accepted in the art for delivering the biologically active compound to a mammal, such as a human. Such a medium includes all pharmaceutically acceptable carriers, diluents or excipients.

[0153] "Pharmaceutically acceptable carrier, diluent or excipient" includes, but is not limited to, any acceptable adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier approved by the U.S. Food and Drug Administration for use in humans or domestic animals.

[0154] As used herein, the term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention formed with an acid or base that is suitable for pharmaceutical use. Pharmaceutically acceptable salts include inorganic salts and organic salts. A preferred class of salts are salts formed with a compound of the present invention and an acid. Suitable acids for forming salts include, but are not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, and phosphoric acid; 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, and naphthalenesulfonic acid; and amino acids such as proline, phenylalanine, aspartic acid, and glutamic acid.

[0155] Another preferred salt is a salt of the compound of the present invention formed with a base, such as an alkali metal salt (e.g., sodium salt or potassium salt), an alkaline earth metal salt (e.g., magnesium salt or calcium salt), an ammonium salt (e.g., lower alkanolammonium salt and other pharmaceutically acceptable amine salts), for example, methylamine salt, ethylamine salt, propylamine salt, dimethylamine salt, trimethylamine salt, diethylamine salt, triethylamine salt, tert-butylamine salt, ethylenediamine salt, hydroxyethylamine salt, dihydroxyethylamine salt, trihydroxyethylamine salt, and amine salts formed from morpholine, piperazine, and lysine, respectively.

[0156] Since TY-2136b has excellent anti-tumor activity, the pharmaceutical composition containing TY-2136b as the main active ingredient can be used to treat, prevent and alleviate tumor-related diseases.

[0157] The pharmaceutical composition of the present application comprises a safe and effective amount of a compound of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier. "Safe and effective amount" means an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Typically, 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, "one dose" is one capsule or tablet.

[0158] "Pharmaceutically acceptable carriers" refer to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed 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 include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0159] The pharmaceutical composition of the present application is in the form of an injection, capsule, tablet, pill, powder or granule.

[0160] There is no particular limitation on the administration of the compound or pharmaceutical composition of the present invention. Representative administration routes include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

[0161] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0162] Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials 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 certain portion of the digestive tract. Examples of useful encapsulating components are polymeric substances and waxes. If desired, the active compound can also be microencapsulated with one or more of the above-mentioned excipients.

[0163] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide and oils, in particular cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.

[0164] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0165] Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0166] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0167] Dosage forms for topical administration of the compounds of this invention 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.

[0168] The composition of the present invention can be administered alone or in combination with other pharmaceutically acceptable compositions (such as anti-tumor drugs).

[0169] The treatment method of the present invention can be used alone or in combination with other treatment methods or therapeutic drugs.

[0170] When using a pharmaceutical composition, a safe and effective amount of the compound of the present invention is administered to a mammal (e.g., a human) in need of treatment, wherein the dosage is a pharmaceutically effective dosage. For a 60 kg human, the daily dosage is generally 1-2000 mg, preferably 50-1000 mg. The specific dosage will also take into account factors such as the route of administration and the patient's health condition, all of which are within the skill of a skilled physician.

[0171] The specific examples of the present invention specifically describe methods for preparing the pharmaceutical compositions of the present invention, but these specific methods do not limit the present invention in any way. The pharmaceutical compositions of the present invention can also be conveniently prepared by optionally combining various preparation methods described in this specification or known in the art. Such combinations can be easily performed by those skilled in the art.

[0172] Typically, the raw materials and reagents used in the process for preparing the pharmaceutical composition of the present invention can be purchased through commercial channels unless otherwise specified.

[0173] In one or more embodiments, the pharmaceutical composition of the present application has one or more of the following beneficial effects:

[0174] (1) The pharmaceutical composition has excellent dissolution performance, pharmacokinetic properties and storage stability;

[0175] (2) The pharmaceutical composition has stable quality;

[0176] (3) The preparation process of the pharmaceutical composition is simple and easy to implement, and is convenient for industrial production;

[0177] (4) The pharmaceutical composition is easy to administer, safe and reliable to use, easily accepted by patients, and has high social and economic value.

[0178] Example

[0179] The present invention will be further described below with reference to specific examples. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit the scope of the present invention. The experimental procedures in the following examples, for which specific conditions are not specified, were generally performed 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.

[0180] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those familiar to those skilled in the art. Furthermore, any methods and materials similar or equivalent to those described herein can be applied to the methods of the present invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0181] Examples of compositions

[0182] General raw materials

[0183] General Methods

[0184] Dissolution performance

[0185] Dissolution rate refers to the rate and extent of drug dissolution from solid dosage forms, such as tablets, in a specified solvent. Dissolution rate is a key indicator for tablet quality control, and poorly soluble drugs are generally subject to dissolution testing. The dissolution test involves placing a specific amount of a solid dosage form in the rotating basket (or dissolution cup) of a dissolution apparatus. Operating the apparatus at a constant temperature of 37°C ± 0.5°C, at a specified rotational speed and in a specified dissolution medium, the apparatus then samples the solution within a specified time period and measures the amount dissolved.

[0186] The dissolution test conditions are as follows:

[0187] Dissolution medium: pH 6.8 phosphate buffer + 0.2% SDS

[0188] Dissolution medium volume: 900ml

[0189] Speed: 50rpm (60-75min is the ultimate speed, the speed is 250rpm)

[0190] Water bath temperature: 37±0.5℃

[0191] Sampling time points: 5, 15, 30, 45, 60, 75 minutes

[0192] Composition Example 1 Tablet 1 and its preparation (prescription composition (40 mg))

[0193] Note: The TY-2136b used contains one molecule of water. 41.85 mg of hydrate is equivalent to 40 mg of TY-2136b free base.

[0194] Tablet 1 was manufactured using a dry blending / compacting process using the materials listed in the table above. TY-2136b, colloidal silicon dioxide, croscarmellose sodium, and microcrystalline cellulose were each sieved through a 40-mesh screen and added sequentially to a mixing hopper at a mixing speed of 20 rpm for 25 minutes. Magnesium stearate (added internally) was added to the mixing hopper at a mixing speed of 20 rpm for 5 minutes to obtain a premix. The premix was added to a dry granulator for dry granulation at a feed 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 granulation speed of 120-180 rpm (specifically 150 rpm) to obtain dry granulated granules. The granules collected after dry granulation and the sieved magnesium stearate (added externally) were added to a mixing hopper at a speed of 20 rpm for 5 minutes (i.e., the total mixing time). The mixture was tableted and a plain tablet 1 (hardness 81-115 N) was pressed using a punch.

[0195] The film coating premix (12 mg / tablet) was prepared into a 12% (w / w) coating suspension, and the plain tablet 1 was coated with 3% of the weight of the plain tablet to form tablet 1.

[0196] The dissolution results of the obtained tablet 1 are shown in Table 1 below.

[0197] Table 1

[0198] FIG1 is a dissolution curve of Tablet 1 obtained in Example 1.

[0199] As shown in FIG1 and Table 1 above, Tablet 1 was able to completely dissolve under the above dissolution conditions, and the dissolution rate reached 97% of the labeled amount at 45 minutes, meeting the standard.

[0200] Composition Example 2 Tablet 2 and its preparation (prescription composition (10 mg))

[0201] Note: The TY-2136b used contains one molecule of water. 10.46 mg of hydrate is equivalent to 10 mg of TY-2136b free base.

[0202] Tablet 2 was manufactured using a dry mixing / rolling process using the materials listed in the table above. TY-2136b, colloidal silicon dioxide, croscarmellose sodium, and microcrystalline cellulose were each sieved through a 40-mesh sieve and added sequentially to a mixing hopper at a mixing speed of 20 rpm for 25 minutes. Magnesium stearate (added internally) was added to the mixing hopper at a mixing speed of 20 rpm for 5 minutes to obtain a premix. The premix was added to a dry granulator for dry granulation at a feed 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 granulation speed of 120-180 rpm (specifically 150 rpm) to obtain dry granulated granules. The granules collected after dry granulation and the sieved magnesium stearate (added externally) were added to a mixing hopper at a speed of 20 rpm for 5 minutes (i.e., total mixing time). The mixture was tableted and pressed into plain tablets 2 (hardness 53-78N) using a punch.

[0203] The film coating premix (3 mg / tablet) was prepared into a 12% (w / w) coating suspension, and the plain tablet 2 was coated with 3% of the weight of the plain tablet to form tablet 2.

[0204] Table 2

[0205] FIG2 is a dissolution curve of Tablet 2 obtained in Example 2.

[0206] As shown in FIG. 2 and Table 2 above, Tablet 2 was able to completely dissolve under the above dissolution conditions, and the dissolution rate reached 97% of the labeled amount at 45 minutes, meeting the standard.

[0207] Composition Examples 3-4 Tablets 3 and 4

[0208] The same as Example 1, the main difference is the different amount of disintegrant used, as shown in Table 3 below, and the dissolution results are shown in Table 4 below.

[0209] Table 3 Prescription composition of different disintegrant dosages

[0210] Table 4 Effect of different disintegrant dosages on dissolution rate

[0211] As shown in FIG3 and Table 4 above, Tablet 4 was able to completely dissolve under the above dissolution conditions, and the dissolution rate reached 84% of the labeled amount at 45 minutes, meeting the standard.

[0212] Composition Example 5-6 Tablet 5-6

[0213] The same as Example 3, except that the particle size of TY-2136b in the formula is different, the process adopts powder direct compression, the details are shown in Table 5 below, and the solubility is shown in Table 6 below.

[0214] Table 5 Formulation composition of different API particle sizes

[0215] Table 6 Effect of different API particle sizes on dissolution rate

[0216] As shown in Table 6 of FIG4 , tablets 5-6 were completely dissolved under the above dissolution conditions, and the dissolution rate reached more than 80% of the labeled amount at 45 minutes, meeting the standard.

[0217] Composition Example 7

[0218] The present inventors produced Tablet 1 (40 mg) and Tablet 2 (10 mg) according to the prescriptions in Example 1 and Example 2. The 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.

[0219] Table 7 shows the dissolution results of the stability study samples.

[0220] Table 7

[0221] Table 8 shows the results of related substances in the stability study samples.

[0222] Table 8 Note: *1. The API results for this row are issued in the same sequence as the results for the two strengths T0, 40°C / 75% RH (open) 10 days, and 40°C / 75% RH (closed) 10 days. *2. The API results for this row are issued in the same sequence as the results for the two strengths 40°C / 75% RH (closed + 1g desiccant) 30 days.

[0223] As shown in Table 7, the dissolution rates of Tablet 1 (40 mg) and Tablet 2 (10 mg) did not change significantly after being placed under 40°C / 75% RH (open) and (closed + 1 g desiccant) conditions for 30 days, which is in compliance with the Chinese Pharmacopoeia.

[0224] As shown in Table 8, the individual impurities in Tablets 1 (40 mg) and 2 (10 mg) were kept within acceptable limits for 30 days at 40°C / 75% RH (open), 40°C / 75% RH (closed), and 40°C / 75% RH (closed + 1 g desiccant).

[0225] Examples of Crystal Forms

[0226] Crystal Example 1 Preparation of Crystal Form A

[0227] 15.3 mg of the compound of Formula I was placed in a 1.5 mL HPLC vial and 0.2 mL of ACN / H₂O (1:1, v:v) was added for a room temperature slurry test. After approximately 4 days of slurrying, a crystalline powder solid was collected by centrifugation, representing Form A. Its XRD pattern is shown in Figure 5 . Thermogravimetric analysis and differential scanning calorimetry (TGA-DSC) are shown in Figure 6 . The partial light microscopy (PLM) spectrum is shown in Figure 7 .

[0228] Table 9 XRPD test parameters

[0229] The single crystal structure of Form A is shown in Figure 16. The single crystal data are: monoclinic system, P2(1) space group, unit cell parameters are α=γ=90°β=93.349(8)°, deviation factor R1=0.0562, Z=4.

[0230] Preparation of Crystal Example 2 Amorphous

[0231] 400 mg of the Form A sample prepared in Example 1 was weighed and dissolved in 20 mL of dichloromethane at room temperature. After filtration, the filtrate was quickly freed of solvent by rotary evaporation. The resulting solid sample was subjected to corresponding characterization tests, and its XRD spectrum is shown in Figure 8. After the amorphous sample was left overnight under ambient conditions (room temperature, >20% RH), the PLM was again observed, revealing that some of the sample had transformed into crystals. After the sample was left under the same conditions for two more days, XRD results showed that the crystal form of the transformed sample was essentially identical to Form A. These results indicate that the amorphous sample is unstable under ambient conditions and recrystallizes into Form A upon hygroscopic absorption.

[0232] Crystal Form Example 3 Preparation of Crystal Form E

[0233] A Form E sample 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. XRD results, shown in Figure 9, indicate that the Form E sample transformed into Form A after approximately one day of open drying at room temperature. Based on this, Form E is presumed to be a metastable form.

[0234] Preparation of Crystal Form Example 4 Crystal Form B

[0235] Form B was obtained from the starting Form A sample after purging under nitrogen (approximately 5% RH) for 2 hours. The XRD results are shown in Figure 17. Because the sample rapidly transformed to Form C under room humidity conditions (17.3% RH) on the same day, it is presumed to be a metastable form.

[0236] Preparation of Crystal Form Example 5 Crystal Form C

[0237] Form C was obtained by purging the starting Form A sample under nitrogen (about 5% RH) for 2 hours and then placing it in room humidity (17.3% RH) for 2 hours. Its XRD results are shown in Figure 18. The TGA / DSC results are shown in Figure 19, which 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 temperature). The 1H NMR spectrum of Form C was tested in DMSO-d6 and no obvious solvent residue was found. Since Form C was obtained by increasing the humidity of Form B, combined with the obvious step-like weight loss in the TGA curve and the endothermic signal in the DSC curve, it was preliminarily speculated that Form C was a hydrate. Form C was prepared repeatedly, but no pure Form C sample was obtained.

[0238] Preparation of Crystal Form Example 6 Crystal Form D

[0239] The Form D sample was obtained by slowly volatilizing the starting sample Form A in methanol solvent. Its XRD results are shown in Figure 20. The TGA / DSC results are shown in Figure 21. The results show that the sample loses 2.6% of its weight when heated from room temperature to 150°C, and there is an endothermic peak at 83.4°C (peak temperature). 1 H NMR spectra obtained in DMSO-d6 revealed no significant residual solvent. As shown in Figure 22, after two days of closed-cup storage at room temperature, the crystallinity of Form D decreased significantly. As shown in Figure 23, after heating to 120°C and cooling to room temperature, the sample transformed into an amorphous state. Combined with the sample NMR data and the heating test results, Form D is presumed to be a hydrated crystalline form.

[0240] Crystal form test example 1 Crystal form solubility and hygroscopicity evaluation

[0241] The approximate solubility of Form A in different organic solvents at room temperature is as follows:

[0242] Dynamic Vapor Sorption (DVS) was used to study the hygroscopicity of different crystalline APIs.

[0243] Determination method:

[0244] Instrument: dynamic water vapor adsorption instrument; temperature: 25°C; protective gas and flow rate: N2, 200 mL / min;

[0245] dm / dt: 0.002% / min; RH range: 0%RH-100%RH; cycle: 1 complete cycle.

[0246] Experimental results:

[0247] The DVS test results for Form A are shown in Figure 10. As can be seen, at 0% humidity, the Form A sample loses approximately 3-4% weight, a weight loss comparable to the mass of the water of crystallization. Significant weight gain occurs from 0% to 20% humidity, while almost no water gain occurs from 20% to 80%. Significant moisture absorption occurs above 90%. Continued weight loss occurs from 100% to 0%, with the adsorption and desorption weight changes completely overlapping.

[0248] The DVS test results for Form E are shown in Figure 11. As shown, Form E loses weight continuously as the humidity increases from 0% to 90%. From 0% to 30% humidity, the sample loses approximately 2%, and from 40% to 50% humidity, the weight loss suddenly increases. From 90% to 100% humidity, the sample absorbs moisture and gains approximately 4%. From 100% to 90% humidity, the sample loses approximately 2%, with the weight gain exceeding the weight loss. Below 20% humidity, the sample experiences a significant weight loss of 3%. The adsorption and desorption weight change trajectories do not overlap.

[0249] The DVS experimental results for the amorphous sample are shown in Figure 12. As can be seen, the amorphous sample continues to gain weight as the humidity increases from 0% to 100%. From 0% to 80% humidity, the weight gain is uniform, while from 80% to 100% humidity, the weight gain is abrupt. From 90% to 100% humidity, the weight gain is approximately 3.5%. From 100% to 0% humidity, the amorphous sample continues to lose weight. From 100% to 90% humidity, the weight loss is rapid, approximately 1.5%, which is less than the weight gain. From 90% to 0% humidity, the weight loss is uniform. The adsorption and desorption weight change trajectories do not overlap at all.

[0250] In summary, Form A is a monohydrate that does not lose water or exhibit hygroscopicity under normal conditions; Form E is a solvate that loses its solvent when humidity fluctuates and exhibits hygroscopicity; and the amorphous form is hygroscopic. In summary, Form A exhibits significantly better stability than Form E and the amorphous form under normal storage and production conditions.

[0251] Crystal form test example 2 Crystal form transformation relationship evaluation

[0252] For the more stable Form A / C / D samples at room temperature, the conversion relationship between the crystal forms was studied by suspension competition tests under different water activities at room temperature. The starting 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 using a PTFE filter membrane with a pore size of 0.45 microns. The filtrate was transferred to an HPLC vial containing Form A, Form C, and Form D samples. After suspension and stirring at room temperature, the solid wet sample was separated for XRD testing (film coating test). The results are summarized in Table 10, and the XRD patterns are shown in Figures 24 and 25. The results show that Form A was obtained in all systems.

[0253] Table 10 Suspension competition test between crystal forms A / C / D

[0254] Crystal form test example 3 physical and chemical stability evaluation

[0255] In order to verify the stability of Form A, Form E and amorphous form, high temperature, high humidity, accelerated tests and light experiments were also carried out. The specific test methods and results are shown below.

[0256] 3.1 High temperature test

[0257] The high temperature test inspection method is shown in Table 11 below.

[0258] Table 11

[0259] 3.2 The high humidity test inspection method is shown in Table 12 below.

[0260] Table 12

[0261] 3.3 Lighting test

[0262] The illumination test investigation method is shown in Table 13 below.

[0263] Table 13

[0264] 3.4 Accelerated testing

[0265] The accelerated test investigation method is shown in Table 14 below.

[0266] Table 14

[0267] The results of related substances in each crystal form under high temperature conditions (50℃±2℃) are shown in Table 15.

[0268] HPLC test results of related substances under high temperature conditions:

[0269] Table 15

[0270] After being placed under high temperature conditions (50℃±2℃) for 32 days, the content of specific impurity RRT0.66 in crystal form A did not change significantly with the extension of high temperature time (increase ≤0.02%), and the content in crystal form E increased by 0.05%. The content of specific impurity RRT0.71 did not change significantly in both crystal forms with the extension of high temperature time. The specific impurity RRT1.02 did not change significantly in crystal form A, but increased by 0.19% in crystal form E. The specific impurity RRT1.08 increased by 0.05% and 0.23% in crystal form A and crystal form E, respectively. The content of other non-specific impurities was no more 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 no more than 2.0%. In summary, under high temperature conditions, crystal form A is more stable than crystal form E.

[0271] The results of related substances in each crystal form under high humidity conditions (90% RH ± 5% RH) are shown in Table 16.

[0272] The HPLC test results of related substances under high humidity conditions are as follows:

[0273] Table 16

[0274] After being placed under high humidity conditions (90% RH ± 5% RH) for 32 days, the contents of specific impurities RRT0.66 and RRT0.71 in the three crystal forms were basically unchanged (increase ≤ 0.02%). The specific impurity RRT1.02 was basically unchanged in both crystal form A and crystal form E, and increased by 0.03% in the amorphous form. The specific impurity RRT1.08 was basically unchanged in crystal form A, and increased by 0.04% and 0.05% in crystal form E and amorphous form, respectively. The contents of other non-specific impurities were no 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 amorphous form, respectively, and the total impurity content was no more than 2.0%. In summary, the stability of crystal form A under high humidity conditions is better than that of crystal form E and amorphous form.

[0275] The results of related substances in each crystal form under lighting conditions (4500lx±500lx) are shown in Table 17.

[0276] The HPLC test results of related substances under illumination conditions are as follows:

[0277] Table 17

[0278] Note: ND means not detected.

[0279] After being placed under light conditions (4500lx±500lx) for 32 days, the content of the specific impurity RRT0.66 in Form A, Form E and amorphous form increased by 0.09%, 0.04% and 0.03%, respectively. The specific impurities RRT0.71 and RRT1.02 did not increase in Form A and Form E, but increased by 0.05% and 0.06% in the amorphous form, respectively. The specific impurity RRT1.08 increased by 0.09%, 0.08% and 0.19% in Form A, Form E and amorphous form, respectively. The content of other non-specific impurities was no more than 0.10%, and the total impurity content increased by 0.13%, 0.13% and 0.37% in Form A, Form E and amorphous form, respectively, and the total impurity content was no more than 2.0%. In summary, the stability of Form A and Form E under light conditions is better than that of the amorphous form.

[0280] The results of the changes in related substances in each crystal form under accelerated conditions (40°C±2°C, 75%RH±5%RH) are shown in Table 18.

[0281] The HPLC test results of related substances under accelerated conditions are as follows:

[0282] Table 18

[0283] After 32 days of storage under accelerated conditions (40°C ± 2°C, 75% ± 5% RH), the specific impurities RRT0.66, RRT0.71, and RRT1.02 showed no significant change in the three crystalline forms (increase ≤ 0.02%). The specific impurity RRT1.08 increased by 0.04%, 0.03%, and 0.03% in Form A, Form E, and the amorphous form, respectively, with comparable increases. The contents of other non-specific impurities were all less than 0.10%, and the total impurities were all less than 2.0%. This indicates that the three crystalline forms are equally stable under accelerated conditions.

[0284] Under high temperature (50°C ± 2°C) and high humidity (90% RH ± 5% RH), Form A showed superior stability to Form E and the amorphous form, respectively. Under illumination (4500 lx ± 500 lx), both Form A and Form E showed superior stability to the amorphous form. Under accelerated conditions (40°C ± 2°C, 75% RH ± 5% RH), the three forms showed comparable stability. Compared to other conditions, the stability of the three forms was poor under illumination (4500 lx ± 500 lx), suggesting that they should be stored away from light.

[0285] In summary, compared with Form E and amorphous form, Form A is the most stable form and most suitable for subsequent processing and development.

[0286] Crystal form test example 4 flowability test

[0287] The flowability determination method is as follows: the angle of repose is determined using a device consisting of 2 to 3 funnels staggered in series. The drug powder flows slowly and evenly through the funnel onto 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 funnel height must be maintained within a range of 2 to 4 cm from the top of the powder pile. The cone height h is measured, and the angle of repose tanθ = h / (d / 2) is calculated.

[0288] Experimental results: The powder flowability test results of the three crystalline APIs are shown in Figure 13.

[0289] After testing, the angle of repose of the crystal form A sample is about 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 about 37.5°.

[0290] Since the smaller the angle of repose of the powder, the better the fluidity, the fluidity of the crystal form A is better than that of the crystal form E and the amorphous form.

[0291] Crystal form test example 5 pharmacokinetic test

[0292] This test example compared the pharmacokinetic processes of crystal form A and amorphous form in SD rats, and compared their pharmacokinetic characteristics in SD rats.

[0293] Experimental methods and materials

[0294] Compound information

[0295] Test substance

[0296] Name: Compound of Formula I (Form A)

[0297] Name: Compound of Formula I (amorphous form)

[0298] Internal standard

[0299] Name: verapamil

[0300] Experimental animals: 6 healthy adult SD rats, male, divided into two groups, 3 rats in each group, 6-8 weeks old; weighing approximately 200-300 grams. The animals were housed in rat cages and fasted (for at least 10 hours) but not water from the day before the experiment; on the day of the experiment, they were weighed and their tails were marked. Blank blood was collected before administration. Blood was collected from the tail vein. Dosage: Oral gavage (po): The drug suspension was administered orally; preparation of the dosing suspension: accurately weigh approximately 10 mg of the sample to be tested, dissolve it in 5% DMSO, and vortex to mix with 10% solutol HS-15 and 85% saline to obtain a suspension with a concentration of 1.0 mg / mL; freshly prepared before use.

[0301] Sample Collection: Rats were orally administered 10 mg / kg of the drug by gavage. Blood was collected at 0.5, 1, 2, 4, 6, 8, 12, and 24 hours after administration. (0.1 ml) of whole blood was collected in an EDTA-Na2 anticoagulant tube and inverted 3-4 times to mix thoroughly. Plasma was separated by centrifugation at 10,000 g for 5 minutes at 4°C and stored at -80°C until testing. Blood was collected from the tail vein.

[0302] Sample Preparation: 1) Thaw the sample and transfer 15 μL each of the unknown plasma sample, standard solution, single blank, and double blank samples, pre- or post-dose, into a 1.5 mL centrifuge tube. 2) Add 15 μL of protein precipitant (methanol) and 400 μL of internal standard solution (verapamil in methanol, approximately 10 ng / mL) to each sample, vortex mix for 2 minutes, and centrifuge at 12,000 rpm for 10 minutes at 4°C. 3) Prepare the supernatant for LC / MS / MS analysis.

[0303] Analytical 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;

[0304] Flow rate: 0.5 mL / min. Use gradient elution. See the table below for the elution program.

[0305] Table 19

[0306] Mass spectrometry conditions: Mass spectrometry analysis was performed using an electrospray ionization (ESI) source in positive ionization and multiple reaction monitoring (MRM) mode. The mass spectrometry source parameters and compound detection parameters are shown in the table below.

[0307] Mass spectrometry ion source parameters

[0308] Table 20

[0309] The main scanning parameters of analytes and internal standards are shown in the following table

[0310] Table 21

[0311] PK parameter processing: Based on each individual's plasma drug concentration and corresponding sampling time data, the software Phoenix WinNonlin was used to calculate pharmacokinetic (PK) parameters based on the plasma drug concentration using a non-compartmental model. (1) PK parameters used to evaluate pharmacokinetics include: Cmax, AUC0-t, AUC0-∞, Tmax, and t1 / 2.

[0312] (2) For bioequivalence evaluation: Cmax, AUC0-t, and AUC0-∞ are used for bioequivalence evaluation.

[0313] Cmax: The maximum blood drug concentration measured within a specified period of time, which is the actual measured value.

[0314] Tmax: The time to peak plasma concentration is 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.

[0315] AUC0-t: The area under the plasma drug concentration-time curve from point 0 to the last time point t.

[0316] AUC0-∞: The area under the plasma concentration-time curve from zero to infinity. Ct is the last measured concentration, and λz is the terminal phase elimination rate constant.

[0317] t1 / 2: Elimination or terminal half-life, estimated by ln2 / λz.

[0318] Results: The linear range of the compound of Formula I was 2-2000 ng / ml. The plasma concentrations of the compound of Formula I (Form A) and the compound of Formula I (amorphous form) over time in rats administered 10 mg / kg are shown in Tables 22 and 23, and Figures 14 and 15, respectively. Key pharmacokinetic parameters in rats are shown in Tables 24 and 25.

[0319] Table 22: Plasma concentration-time data of the compound of formula I (Form A) administered at 10 mg / kg in rats

[0320] Table 23: Plasma concentration-time data of the compound of formula I (amorphous form) administered at 10 mg / kg in rats

[0321] Table 24 Some pharmacokinetic parameters of rats after oral administration of 10 mg / kg of the compound of formula I (Form A)

[0322] Table 25 Some pharmacokinetic parameters of rats after oral administration of 10 mg / kg of the compound of formula I (amorphous form)

[0323] After oral administration of the same dose of the compound of Formula I (Form A) or the compound of Formula I (amorphous form) to rats, 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, with significant differences (p < 0.05), indicating that the bioavailability of Form A is significantly higher than that of the amorphous form.

[0324] The above describes the embodiments of the present invention. However, the present invention is not limited to the above embodiments. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the scope of protection of the present invention. All documents mentioned in the present invention are cited as references in this application, just as each document is cited as a reference separately. 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 claims attached to 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 the crystalline 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, the crystalline 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°; Preferably, the crystalline form A has an X-ray powder diffraction pattern substantially as shown in Figure 5; More preferably, the pharmaceutical composition is prepared as an oral preparation.

2. The pharmaceutical composition according to claim 1, wherein the crystalline 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)°, 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 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, cross-linked carboxymethyl cellulose sodium, cross-linked povidone, 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.

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 crystalline 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 crystalline 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 crystalline 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 crystalline 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 crystalline form A in the pharmaceutical composition is ≥ 85%.

5. A method for preparing the pharmaceutical composition according to any one of claims 1 - 4, which comprises: Provide the following parts by weight of materials as raw materials and prepare 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, cross-linked sodium carboxymethyl cellulose, cross-linked povidone, 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, and yellow iron oxide, and the polymer is selected from at least one of polyvinyl alcohol and polyethylene glycol; Preferably, the method for preparing Form A is to slurry the compound of formula I with a mixed solvent of acetonitrile and water; more preferably, the method for preparing 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.

6. Crystal Form A of the Monohydrate of the Compound of Formula I and a pharmaceutically acceptable carrier, excipient or vehicle; wherein 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, 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; More preferably, Form A has an X-ray powder diffraction pattern substantially as shown in Figure 5.

7. The method for preparing Form A according to claim 6, which comprises slurrying the compound of formula I with a mixed solvent of acetonitrile and water; more preferably, the method for preparing 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.

8. Use of the pharmaceutical composition according to any one of claims 1 - 5 or Form A according to claim 6 in the preparation of a medicament for treating and / or preventing anti-cancer or anti-tumor drugs; preferably, 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.

9. Use of the pharmaceutical composition according to any one of claims 1 - 5 or Form A according to claim 6 in the preparation of a medicament for treating and / or preventing diseases mediated by ROS1, NTRK, or ALK; preferably, the diseases mediated by ROS1, NTRK, or ALK are selected from cancer, sarcoma, and pain.

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