Hydrated crystalline form of lazertinib methanesulfonate and methods of making and uses thereof

Abstract

The application relates to the field of pharmaceutical chemistry. The application relates to a hydrate crystal form of lazertinib monomethanesulfonate and a preparation method and application thereof. The hydrate crystal form of lazertinib monomethanesulfonate provided by the application has at least one of the following advantages: good stability, good solubility, good dissolution, low hygroscopicity, uniform particle size distribution, good morphology, good fluidity, good crystallinity, stable storage, avoidance of degradation, impurity increase, appearance change and crystal transformation during development and storage, simple and reliable preparation method, and great development value.

Description

[0001] Citation of relevant applications

[0002] This application claims the full benefits of patent application No. 202110608943.2 filed with the State Intellectual Property Office of the People's Republic of China on June 1, 2021, the entire contents of which are incorporated herein by reference. Technical Field

[0003] This application relates to the field of medicinal chemistry. Specifically, this application relates to a hydrated crystal form of lazertinib methanesulfonate, its preparation method, and its uses. Background Technology

[0004] Polymorphism or polycrystalline phenomena are unique properties of certain molecules and molecular compositions. The same molecules may form different crystals due to different arrangements, and these crystals have different crystal structures and physical properties, such as solubility, stability, thermal properties, mechanical properties, purification ability, X-ray diffraction patterns, infrared absorption patterns, Raman spectroscopy, and solid-state NMR.

[0005] Discovering new crystal forms of pharmaceutical active ingredients (including anhydrous forms, hydrates, solvates, etc.) may result in substances with greater processing advantages or better physicochemical properties, such as better bioavailability, storage stability, ease of processing, ease of purification, or as intermediate crystal forms that promote conversion to other crystal forms. Certain specific crystal forms of compounds used as pharmaceutical active ingredients can also help improve drug performance. This expands the range of raw material options available in formulations, for example, by improving dissolution, extending shelf life, and facilitating processing.

[0006] Lazertinib (trade name LECLAZA) is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) developed by Yuhan Pharmaceuticals in South Korea. It targets the T790M mutation and activates EGFR mutations while preserving wild-type EGFR. This compound can be used as a drug to inhibit the activity of protein kinase-mediated disease, especially EGFR with one or more mutations compared to wild-type EGFR. Its IUPAC name is N-[5-[[4-[4-[(dimethylamino)methyl]-3-phenylpyrazol-1-yl]pyrimidin-2-yl]amino]-4-methoxy-2-morpholin-4-ylphenyl]prop-2-enamide, and its structural formula is shown in formula (I). Clinically, it is mainly used to treat metastatic non-small cell lung cancer, and is administered as a monomethylsulfonate salt of the compound of formula (I).

[0007]

[0008] The solid form of small molecule chemical drugs, i.e., different crystal forms, can result in different solubilities and stability, thereby affecting drug absorption and bioavailability, and even leading to differences in clinical efficacy. CN110869367A reports the crystalline form (I) of lazertinib monomethylsulfonate (hereinafter referred to as: crystal form I). The applicant prepared it according to the method of Example 1 of the patent application and found that the material could not react completely. After improving the preparation method, although crystal form I was successfully obtained, the sample of crystal form I changed color, impurities increased, and the stability was poor during accelerated stability studies, making it unsuitable for long-term storage.

[0009] Therefore, there is still a need in the field for a new crystal form of lazertinib monomethylsulfonate that is highly soluble, stable, and suitable for storage, in order to facilitate the development, production, and storage of lazertinib. Summary of the Invention

[0010] The purpose of this application is to provide the hydrate crystal form of lazertinib monomethanesulfonate (hereinafter referred to as lazertinib methanesulfonate), its preparation method, and its uses. The hydrate crystal form of lazertinib methanesulfonate of this application has at least one of the following advantages: good stability, good solubility, good dissolution rate, low hygroscopicity, uniform particle size distribution, good morphology, good flowability, good crystallinity, stable storage, and avoidance of degradation, increased impurities, changes in appearance, and crystal transformation during drug development and storage. The preparation method is simple and reliable, and it has significant development value.

[0011] One aspect of this application is to provide a hydrate crystal form A (hereinafter referred to as crystal form A) of lazertinib methanesulfonate with the structure shown in formula (I):

[0012]

[0013] Using Cu-Kα radiation, the X-ray powder diffraction (XRPD) pattern of crystal form A, expressed in 2θ angles, has characteristic peaks at at least three of the following: 5.68°±0.2°, 11.74±0.2°, 15.60°±0.2°, 21.61°±0.2°, and 22.71°±0.2°.

[0014] In the preferred embodiment of this application, the XRPD spectrum of crystal form A also has a characteristic peak at at least one of 8.62±0.2°, 10.50°±0.2°, 14.50±0.2°, 16.57°±0.2° and 17.21±0.2°2θ.

[0015] In the preferred embodiment of this application, the XRPD spectrum of crystal form A also has a characteristic peak at at least one of 11.24°±0.2°, 13.30±0.2°, 18.17±0.2°, 20.03±0.2°, 24.63°±0.2° and 28.53±0.2°2θ.

[0016] In the preferred embodiment of this application, the XRPD pattern of crystal form A has diffraction peaks at the positions shown in the table below for 2θ values:

[0017] 2θ±0.2° 5.68 8.62 10.50 11.24 11.74 13.30 14.51 15.60 16.57 17.21 17.91 18.17 19.55 20.03

[0018] 20.99 21.61 22.71 23.45 24.63 25.61 25.91 26.57 27.41 28.53 29.61

[0019] Non-limiting, the crystal form A has essentially the following characteristics: Figure 1 The XRPD map shown.

[0020] In another aspect of this application, the TGA spectrum of crystal form A may have a two-stage weight loss, but this application is not limited to this.

[0021] Non-limiting, in one specific embodiment, the TGA pattern of crystal form A is substantially as follows: Figure 2 As shown. Without limitation, in one specific embodiment, the DSC spectrum of crystal form A is substantially as follows. Figure 3 As shown. In the preferred embodiment of this application, the FT-IR (Fourier Transform Infrared) spectrum of crystal form A is at 760.06 cm⁻¹. -1 ±2cm -1 1151.59cm -1 ±2cm -1 2487.87cm -1 ±2cm -1 3291.47cm -1 ±2cm -1 At least one of the bands is present.

[0022] In the preferred embodiment of this application, the FT-IR spectrum of crystal form A is still at 1669.10 cm⁻¹. -1 ±2cm -1 1361.34cm -1 ±2cm -1 1225.88cm -1 ±2cm -1 1194.47cm -1 ±2cm -1 110.26±2cm -1 1037.52cm -1 ±2cm -1 808.41cm -1 ±2cm-1 771.53cm -1 ±2cm - At least one of the bands is present.

[0023] Non-limiting, the FT-IR spectrum of crystal form A is substantially as follows: Figure 4 As shown.

[0024] Without limitation, the DVS pattern of crystal form A is substantially as follows: Figure 5 As shown.

[0025] Another aspect of this application is to provide a method for preparing a hydrate crystal form A of lazertinib methanesulfonate, the method comprising any one of the following methods:

[0026] 1) Lazertinib and methanesulfonic acid are respectively dissolved in dichloromethane to form a lazertinib solution and a methanesulfonic acid solution. The two solutions are mixed, a solid is precipitated, centrifuged, and dried to obtain the hydrate crystal form A of lazertinib methanesulfonate. The lazertinib solution is dissolved at high temperature, and the molar ratio of lazertinib to methanesulfonic acid is 1:1-1.2.

[0027] Preferably, the high temperature is above 60°C; more preferably, it is 65-85°C.

[0028] Preferably, the solution is mixed by adding the methanesulfonic acid solution to the lazertinib solution.

[0029] Preferably, the drying is performed by vacuum drying at room temperature.

[0030] 2) Lazertinib methanesulfonate crystal form B is placed in solvent 1 to form solution 1. Then, solution 1 is added to solvent 2, stirred, and a solid is precipitated. After centrifugation and drying, lazertinib methanesulfonate hydrate crystal form A is obtained. The solvents 1 and 2 are miscible solvents.

[0031] Preferably, the crystal form B has essentially the following characteristics: Figure 7 The XRPD map shown.

[0032] Preferably, solvent 1 is selected from trichloromethane.

[0033] Preferably, the solvent 2 is selected from diethyl ether and acetonitrile.

[0034] Preferably, the volume ratio of solvent 1 to solvent 2 is <1:5; more preferably <1:7.

[0035] Preferably, the drying is performed by air drying at room temperature.

[0036] 3) Dry lazertinib methanesulfonate crystal form B at 40-90℃ to obtain lazertinib methanesulfonate hydrate crystal form A.

[0037] Preferably, the drying temperature is 40-50°C.

[0038] The hydrate crystal form A of lazertinib methanesulfonate described in this application has the following beneficial effects:

[0039] 1) Good stability. The lazertinib methanesulfonate hydrate crystal form A of this application is stable for at least one month under accelerated closed-top conditions (40°C, 75% RH, and 5mL vials in self-sealing bags), with no significant changes in crystal form, melting point, content, and color before and after storage. Under accelerated open-top conditions (40°C, 75% RH, open-top), it is stable for at least 21 days, with no significant changes in crystal form, content, and color before and after storage. In contrast, the lazertinib methanesulfonate crystal form I of the prior art shows a significant decrease in content, an increase in impurities, and a change in color from yellow to pink after 21 days of accelerated open-top conditions (40°C, 75% RH, open-top).

[0040] 2) Excellent solubility. Compared with the prior art lazertinib mesylate hydrate crystal form A, the hydrate crystal form A of this application exhibits unexpectedly superior solubility. The equilibrium solubility of crystal form A in pH 4.0 buffer, water, and pH 1.2 buffer is greater than 60 mg / mL. In contrast, under the same test method, the solubility of crystal form I in pH 4.0 buffer, water, and pH 1.2 buffer in Test Example 1 of CN110869367A is 20.9 mg / mL, 21.6 mg / mL, and 14.9 mg / mL, respectively, which is far lower than the solubility of crystal form A of this application. In addition, crystal form A of this application also exhibits unexpectedly good instantaneous solubility. Its instantaneous solubility in pH 4.0 buffer and water is greater than 50 mg / mL, and its instantaneous solubility in pH 1.2 buffer is greater than 80 mg / mL, which is beneficial for achieving ideal drug bioavailability and efficacy, and meeting pharmaceutical requirements.

[0041] 3) Good dissolution. The tablets made from the hydrate crystal form A of lazertinib mesylate of this application have a dissolution rate that meets pharmaceutical requirements. Under the same experimental conditions, the dissolution rate of both the tablets made from crystal form A and the tablets made from crystal form I can reach 100% in a pH 1.2 solution within 10 minutes. Therefore, the dissolution rate of the tablets made from crystal form A is comparable to that of the tablets made from crystal form I reported in the patent.

[0042] 4) The method for preparing the hydrate crystal form A of lazertinib methanesulfonate in this application is simple, highly reproducible, and has industrialization potential.

[0043] In another aspect of this application, a pharmaceutical composition of lazertinib is provided, the composition comprising lazertinib mesylate hydrate crystal form A, and at least one pharmaceutically acceptable carrier.

[0044] Another aspect of this application is to provide a formulation prepared from the above-mentioned lazertinib pharmaceutical composition, wherein the formulation form includes, but is not limited to, oral solid dosage form, topical dosage form, and injection.

[0045] In the preferred embodiment of this application, the formulation is in the form of tablets, capsules, pills, suppositories, granules, fine granules, powders / powders, sustained-release formulations, immediate-release formulations, solutions, suspensions, elixirs, aerosols, etc.

[0046] In the preferred embodiment of this application, the formulation is a tablet.

[0047] The pharmaceutically acceptable carrier is an excipient commonly used in formulations in the art, including but not limited to any one or a mixture of two or more of the following: adhesives, surfactants, diluents, anti-adhesion agents, hydrophilic or hydrophobic polymers, stabilizers or disintegrants, antioxidants, defoamers, fillers, flow aids / lubricants, adsorbents, preservatives, plasticizers, and sweeteners.

[0048] In the preferred embodiment of this application, when the formulation is an oral solid dosage form, the filler or diluent is selected from any one or a combination of lactose, D-mannitol, microcrystalline cellulose, starch, pregelatinized starch, calcium sulfate, calcium hydrogen phosphate, and calcium carbonate; the disintegrant is selected from any one or a combination of sodium carboxymethyl starch, croscarmellose sodium, low-substituted hydroxypropyl cellulose, and croscarmellose; and the lubricant / flow aid is selected from any one or a combination of magnesium stearate, talc, and micronized silica gel.

[0049] In a preferred embodiment of this application, the pharmaceutical composition may further comprise one or more pH adjusters or buffers, for example: acids, such as any one or a combination of acetic acid, boric acid, citric acid, fumaric acid, maleic acid, tartaric acid, malic acid, lactic acid, phosphoric acid, and hydrochloric acid; or bases, such as any one or a combination of sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate, and tris(hydroxymethyl)aminomethane; or buffers, such as citrate / glucose, sodium bicarbonate, ammonium chloride, and the like. Such buffers used as bases may have balancing ions other than sodium, such as potassium, magnesium, calcium, ammonium, and other balancing ions; and other amounts necessary to maintain the pH of the components within an acceptable range, in solutions or solids comprising such acids, bases, and buffers.

[0050] Another aspect of this application is to provide a hydrate crystal form A of lazertinib mesylate or the pharmaceutical composition thereof in the preparation of a medicament for treating protein kinase-mediated diseases.

[0051] Preferably, the disease mediated by the protein kinase is cancer.

[0052] Preferably, the cancer is non-small cell lung cancer, metastatic non-small cell lung cancer, brain metastatic non-small cell lung cancer, EGFR-positive non-small cell lung cancer, or non-squamous non-small cell lung cancer.

[0053] Another aspect of this application is to provide a hydrate crystal form A of lazertinib mesylate or the pharmaceutical composition thereof for use in the preparation of a medicament for inhibiting the activity of EGFR having at least one mutation compared to wild-type EGFR.

[0054] Another aspect of this application is to provide a method for treating a protein kinase-mediated disease, comprising administering to a patient an effective amount of a hydrate crystal form A of lazertinib mesylate or the pharmaceutical composition thereof.

[0055] Preferably, the disease mediated by the protein kinase is cancer.

[0056] Preferably, the cancer is non-small cell lung cancer, metastatic non-small cell lung cancer, brain metastatic non-small cell lung cancer, EGFR-positive non-small cell lung cancer, or non-squamous non-small cell lung cancer.

[0057] Another aspect of this application is to provide a method for inhibiting the activity of EGFR having at least one mutation compared to wild-type EGFR, comprising administering to a patient an effective amount of a hydrate crystal form A of lazertinib mesylate or the pharmaceutical composition thereof.

[0058] Preferably, the effective amount of the lazertinib mesylate hydrate crystal form A of this application is 0.001-10 mg / kg, more preferably 0.005-5 mg / kg.

[0059] Preferably, the method may involve administering the medication once, twice, three times, or more times a day; a single dose may be 0.1 mg to 500 mg / kg / day, and the specific dose will be determined according to the patient's actual condition.

[0060] Preferably, the method involves administering the medication once daily.

[0061] Preferably, the single dose is 10, 20, 40, 60, 80, 100, 160, 240, 320 or 400 mg of a hydrate crystal form A of lazertinib mesylate; more preferably, it is 240 mg.

[0062] Another aspect of this application is to provide a hydrate crystal form A of lazertinib mesylate or a pharmaceutical composition thereof for use in combination with other drugs.

[0063] Preferably, the other drugs are selected from midazolam, rosuvastatin, metformin, amitraz, itraconazole, rifampin, gefitinib, pemetrexed, carboplatin, Ami-HC-CF, and Ami-HC.

[0064] The term "channel hydrate" can be used to describe stoichiometric or nonstoichiometric hydrates that have water-filled one-dimensional channels or two-dimensional planes in a crystal structure. The amount of water in the lattice of a nonstoichiometric hydrate can vary with the water pressure and temperature in the surrounding atmosphere.

[0065] Unless otherwise specified:

[0066] The experimental operating temperature generally refers to room temperature, which is a temperature of 10℃ to 30℃.

[0067] When considered by those skilled in the art, the term “about” means a value that falls within an acceptable standard of average error.

[0068] XRD, TGA results, and water adsorption behavior of Lazertinib methanesulfonate hydrate crystal form A indicate that this crystal form can gradually adsorb and desorb different amounts of water relative to changes in humidity. These water characteristics are typical of channel (variable) hydrates. In some cases, crystal form A may be referred to as a non-stoichiometric hydrate or a non-stoichiometric channel hydrate. Furthermore, this crystal form undergoes a transformation after the removal of another portion of water at high temperatures (approximately 150°C).

[0069] "Stirring" can be carried out using conventional methods in the field, such as magnetic stirring or mechanical stirring, with a stirring speed of 50 to 1800 rpm, preferably 300 to 900 rpm.

[0070] "Separation" can be performed using conventional methods in the art, such as centrifugation or filtration. Reduced pressure filtration is preferred, typically using a pressure less than atmospheric pressure, preferably less than 0.09 MPa.

[0071] "Drying" can be accomplished using conventional techniques in the field, such as room temperature drying, forced-air drying, or vacuum drying; it can be carried out under reduced or normal pressure, preferably less than 0.09 MPa. The drying apparatus and methods are not limited and can include fume hoods, forced-air ovens, spray dryers, fluidized bed dryers, or vacuum ovens; it can be carried out under reduced or no pressure, preferably less than 0.09 MPa.

[0072] Unless otherwise specified, the ratios mentioned in this application, when referring to liquids and solids, are mass-to-volume ratios, and when referring to liquids with each other, are volume ratios. Attached Figure Description

[0073] Figure 1 XRPD pattern of sample 1-1 (hydrate form A of lazertinib methanesulfonate);

[0074] Figure 2 TGA spectra of the sample in Example 1-1;

[0075] Figure 3 DSC spectrum of sample in Example 1-1;

[0076] Figure 4 FT-IR spectra of the sample in Example 1-1;

[0077] Figure 5 DVS spectrum of sample in Example 1-1;

[0078] Figure 6 XRPD pattern of sample from Preparation Example 1 (lazertinib methanesulfonate crystal form I);

[0079] Figure 7 XRPD pattern of sample in Preparation Example 2 (lazertinib methanesulfonate crystal form B);

[0080] Figure 8 XRPD patterns of samples from Examples 1-2 (crystal form A of lazertinib methanesulfonate hydrate);

[0081] Figure 9 TGA spectra of samples from Examples 1-2;

[0082] Figure 10 XRPD spectra of samples from Examples 1-3 (crystal form A of lazertinib methanesulfonate hydrate);

[0083] Figure 11 TGA spectra of samples from Examples 1-3;

[0084] Figure 12 XRPD overlay images of lazertinib methanesulfonate hydrate crystal form A before and after placement under accelerated closed-cell conditions;

[0085] Figure 13 XRPD overlay images of lazertinib methanesulfonate hydrate crystal form A before and after placement under accelerated open conditions;

[0086] Figure 14 Color comparison of lazertinib mesylate crystal form I before and after placement under accelerated open conditions. Detailed Implementation

[0087] The technical solutions of this application will be described in detail below with reference to the accompanying drawings and embodiments, but this does not limit the application to the scope of the embodiments described.

[0088] In this application, X-ray powder diffraction (XRPD) data were acquired using a Bruker D8 Advanced Fractometer; parameters are as follows: Cu target; wavelength: Current and voltage: 40KV, 40mA; Angle range: 3~40°2θ.

[0089] In this application, thermogravimetric analysis (TGA) data were acquired from a TA Instruments Q500 TGA; the parameters are as follows: mode: high resolution mode; heating rate: 10℃ / min; protective gas: N2; sample pan: platinum crucible.

[0090] In this application, the differential thermal analysis (DSC) data were acquired from a TA Instruments Q200 DSC; the parameters are as follows: heating rate: 10℃ / min; protective gas: N2; sample tray: covered aluminum crucible.

[0091] In this application, dynamic moisture adsorption analysis (DVS) data and isothermal adsorption analysis data were obtained from TA Instruments Q5000 TGA; the parameters are as follows: temperature: 25℃; relative humidity range: 0%RH-80%RH; dm / dt=0.001% / min; equilibration time: 90min; protective gas: N2; sample tray: platinum crucible.

[0092] In this application, Fourier transform infrared (FT-IR) spectroscopy data were acquired using a Bruker Tensor 27; the parameters are as follows: ATR method, acquisition range 600 cm⁻¹. -1 -4000cm -1 4cm resolution -1 .

[0093] In this application, 1H NMR data ( 1 H NMR was collected using a Bruker Ascend 500 MHz nuclear magnetic resonance spectrometer. An appropriate amount of sample was weighed and dissolved in approximately 0.5 mL of deuterated dimethyl sulfoxide reagent into the NMR sample tube for detection.

[0094] In this application, the high-performance liquid chromatography (HPLC) detection parameters for content, solubility, and dissolution data are as follows:

[0095]

[0096] Experimental methods in the following examples that do not specify specific conditions should be performed according to conventional methods and conditions, or according to the product instructions. Unless otherwise specified, all reagents and raw materials used in this application are commercially available.

[0097] In this application, the starting material, free lazertinib, can be obtained commercially or prepared using existing techniques, such as the method mentioned in WO2016060443A2.

[0098] Preparation Example 1: Preparation of lazertinib methanesulfonate crystal form I

[0099] Approximately 5 g of free lazertinib sample was taken and added to 35 mL of tetrahydrofuran. The mixture was stirred at 70 °C to form a lazertinib solution. Approximately 1472 mg of methanesulfonic acid was taken and added to 10 mL of tetrahydrofuran. The mixture was stirred to form a methanesulfonic acid solution. 6.8 mL of the methanesulfonic acid solution was added to the lazertinib solution. The mixture was stirred at room temperature for 2 hours, and a solid precipitated. Then, 35 mL of n-heptane was added and stirring continued. The solid was collected and dried under vacuum at 30 °C overnight to obtain lazertinib methanesulfonate crystal form I. Its XRPD pattern is shown below. Figure 6 As shown.

[0100] Preparation Example 2: Preparation of lazertinib methanesulfonate crystal form B

[0101] Approximately 50 mg of lazertinib methanesulfonate crystal form I obtained in Preparation Example 1 was added to 1 mL of dichloromethane. The crystal slurry was stirred overnight at room temperature, centrifuged, and air-dried at room temperature to obtain lazertinib methanesulfonate crystal form B. Its XRPD pattern is shown below. Figure 7 As shown.

[0102] Example 1-1: Preparation of hydrate crystal form A of lazertinib methanesulfonate

[0103] Take approximately 110 mg of free lazertinib and dissolve it in 0.4 mL of dichloromethane at 80 °C to form a lazertinib solution. Take 149.48 mg of methanesulfonic acid and dissolve it in 1 mL of dichloromethane solution to form a methanesulfonic acid solution. Take 0.14 mL of the methanesulfonic acid solution and add it to the lazertinib solution. The solid precipitates at room temperature. Centrifuge and dry under vacuum at room temperature to obtain the hydrate crystal form A of lazertinib methanesulfonate.

[0104] Its XRPD data is shown in the table below:

[0105] 2θ° I％ 5.68 86.9 8.62 27.4 10.50 25.6 11.24 11.0 11.74 70.6 13.30 17.7 14.51 34.9 15.60 55.4 16.57 29.5 17.21 48.4 17.91 12.5 18.17 40.3 19.55 19.2 20.03 58.5

[0106] 20.99 5.0 21.61 100 22.71 74.5 23.45 3.0 24.63 34.7 25.61 11.7 25.91 19.0 26.57 8.9 27.41 10.2 28.53 19.5 29.61 9.8

[0107] Its XRPD map is as follows Figure 1 As shown.

[0108] Based on the NMR data, the molar ratio of mesylate to lazertinib was calculated to be 1:1.

[0109] Its TGA spectrum is as follows Figure 2 As shown, it is a hydrate.

[0110] Its DSC spectrum is as follows Figure 3 As shown.

[0111] Its FT-IR spectrum is as follows Figure 4 As shown.

[0112] Its DVS map is as follows Figure 5 As shown.

[0113] Its hot-stage XRPD shows that it maintains its crystal form even when heated to about 100°C.

[0114] Examples 1-2: Preparation of hydrate crystal form A of lazertinib methanesulfonate

[0115] Take about 150 mg of lazertinib methanesulfonate crystal form B from Preparation Example 2 and dry it under vacuum at 50°C to obtain lazertinib methanesulfonate hydrate crystal form A.

[0116] Its XRPD data is shown in the table below:

[0117] 2θ° I％ 5.62 50.6 8.57 17.5 10.47 10.6 11.20 9.5 11.69 26.1 13.26 13.3

[0118] 14.46 25.6 15.53 31.3 16.53 19.8 17.16 38.7 17.85 7.5 18.13 19.7 18.98 5.3 19.51 16.6 19.97 44.9 20.82 5.9 21.53 100 22.67 79.8 23.41 4.0 24.55 29.7 25.49 12.6 25.85 16.1 26.51 7.4 27.37 10.1 28.51 20.7 29.55 11.7

[0119] Its XRPD map is as follows Figure 8 As shown.

[0120] Its TGA spectrum is as follows Figure 9 As shown.

[0121] Examples 1-3: Preparation of hydrate crystal form A of lazertinib methanesulfonate

[0122] Take about 30 mg of lazertinib methanesulfonate crystal form B from Preparation Example 2, add 0.4 mL of chloroform to dissolve it, and form a methanesulfonate solution; add the methanesulfonate solution to 3 mL of diethyl ether, stir, and a solid will precipitate immediately. Centrifuge and air dry at room temperature to obtain lazertinib methanesulfonate hydrate crystal form A.

[0123] Its XRPD data is shown in the table below:

[0124] 2θ° I％ 5.64 19.8 8.59 15.2 10.48 6.8 11.19 5.3 11.70 13.9 13.24 5.4 14.49 18.4 15.57 19.4 16.55 14.3 17.19 37.0 17.88 5.2 18.14 8.0 19.51 6.4 20.03 19.3 20.81 8.3 21.59 100 22.65 80.0 23.42 2.9 24.61 25.2 25.57 11.3 25.91 10.4 26.55 5.8 27.45 5.4 28.53 20.6 29.61 14

[0125] Its XRPD map is as follows Figure 10 As shown.

[0126] Its TGA spectrum is as follows Figure 11 As shown.

[0127] Examples 1-4: Preparation of hydrate crystal form A of lazertinib methanesulfonate

[0128] By replacing the diethyl ether with acetonitrile in Examples 1-3, and keeping other conditions unchanged, the hydrate crystal form A of lazertinib methanesulfonate was prepared.

[0129] Experimental Example 1: Accelerated Study of Closure Stability

[0130] Following the method described in Example 3 of CN110869367A, an appropriate amount of lazertinib methanesulfonate hydrate crystal form A sample prepared in Examples 1-1 of this application was taken and placed under accelerated closed-top conditions (40°C, 75% RH, and 5mL vials placed in a self-sealing bag) to test the stability of crystal form A. The results showed that crystal form A remained unchanged before and after placement. Figure 12 The color remains unchanged before and after placement, always white, and the content remains essentially unchanged, demonstrating good stability.

[0131] Experimental Example 2: Accelerated Opening Stability Study

[0132] Take appropriate amounts of lazertinib methanesulfonate hydrate crystal form A prepared in Example 1-1 of this application and lazertinib methanesulfonate crystal form I prepared in Preparation Example 1, respectively, and place them under accelerated open conditions (40°C, 75% RH, open) to test their stability. The results are shown in the table below.

[0133] Table 1. Stability of accelerated openings for crystal form A and crystal form I.

[0134]

[0135] The results showed that the hydrate form A of lazertinib methanesulfonate remained stable for at least 21 days under accelerated open conditions (40°C, 75% RH, open). The crystal form before and after this period remained stable. Figure 13 The content and color of the yellow lazertinib mesylate crystal form I remained unchanged after 21 days; however, the content of the lazertinib mesylate crystal form I decreased significantly, the impurities increased, and the color changed from yellow to pink. Figure 14 ).

[0136] Experimental Example 3: Solubility Study of Crystal Form A

[0137] Solubility test parameters were used in Test Example 1 of CN110869367A to test the solubility of the hydrate crystal form A of lazertinib methanesulfonate of this application. The results are shown in the table below:

[0138] Table 2 Solubility of Crystal Form A

[0139]

[0140] The results showed that the equilibrium solubility of the hydrated form A of lazertinib mesylate in pH 4.0 buffer, water, and pH 1.2 buffer met pharmaceutical requirements. Form A of this application exhibits unexpectedly good solubility, with concentrations greater than 60 mg / mL in pH 4.0 buffer, water, and pH 1.2 buffer, which is beneficial for achieving ideal drug bioavailability and efficacy, thus meeting pharmaceutical requirements.

[0141] Experimental Example 4: Study on the instantaneous solubility of crystal form A

[0142] 50 mg and 80 mg of the hydrate crystal form A of lazertinib mesylate of this application were taken sequentially and added to 1 ml of different systems (pH 4.0 buffer, water, and pH 1.2 buffer prepared according to the method of Test Example 1 in CN110869367A), briefly sonicated, and the clarity of the solution was immediately observed. The results are shown in the table below:

[0143] Table 3 Instantaneous solubility of crystal form A

[0144]

[0145] The results showed that the instantaneous solubility of the hydrated form A of lazertinib mesylate in this application in pH 4.0 buffer, water, and pH 1.2 buffer met pharmaceutical requirements. Form A of this application exhibits unexpectedly good instantaneous solubility, with instantaneous solubility greater than 50 mg / mL in both pH 4.0 buffer and water, and greater than 80 mg / mL in pH 1.2 buffer. This is beneficial for achieving ideal drug bioavailability and efficacy, thus meeting pharmaceutical requirements.

[0146] Examples 1-5: Preparation of Tablets

[0147] According to the formulation in the table below, the API (crystal form A prepared in Example 1-1), additives and disintegrants are mixed using a stirrer, and then a lubricant is added. After compression, tablets are obtained.

[0148] Table 4 Tablet Formulation

[0149]

[0150] Experimental Example 5: Dissolution of Tablets

[0151] Take tablet 2 prepared in Examples 1-5 and perform dissolution testing according to a method basically consistent with the dissolution test (1) of test example 2 of CN113015521A - tablets, under the following conditions:

[0152] Dissolution apparatus: RC12AD type Tianda Tianfa dissolution apparatus

[0153] Dissolution medium: pH 1.2 solution

[0154] Media volume: 900mL

[0155] Dissolution method: Slurry method

[0156] Medium temperature: 37℃

[0157] Speed: 100 rpm

[0158] Sample collection time: 5 minutes, 10 minutes, 15 minutes, 30 minutes

[0159] The dissolution results are shown in Table 5 below.

[0160] Table 5 Dissolution results of crystal form A tablets

[0161] Time (min) Dissolution 5 34％ 10 100％ 15 100％ 30 100％

[0162] The results showed that the tablets made from the hydrate crystal form A of lazertinib mesylate of this application had a dissolution rate of 100% in a pH 1.2 solution after 10 minutes; under the same experimental conditions, the tablets made from crystal form I had a dissolution rate of 100% in a pH 1.2 solution after 5 minutes (CN 113015521 A Test Example 2 - Dissolution Test of Tablets (1)). The dissolution rate of the tablets made from crystal form A was comparable to that of the tablets made from crystal form I.

[0163] The above embodiments are preferred embodiments of this application, but the implementation of this application is not limited to the above embodiments. Any changes, modifications, substitutions, combinations, or simplifications made without departing from the spirit and principle of this application shall be considered equivalent substitutions and shall be included within the protection scope of this application.

Claims

1. A hydrate crystal form A of lazertinib methanesulfonate with the structure shown in formula (I), ， (I) Its features are, Using Cu-Kα radiation, the X-ray powder diffraction (XRPD) pattern of crystal form A, expressed in 2θ angles, has characteristic peaks at 5.68°±0.2°, 11.74±0.2°, 15.60°±0.2°, 21.61°±0.2°, and 22.71°±0.2°.

2. The hydrate crystal form A of lazertinib methanesulfonate according to claim 1, characterized in that, The XRPD spectrum of crystal form A also has a characteristic peak at at least one of 8.62±0.2°, 10.50°±0.2°, 14.50±0.2°, 16.57°±0.2° and 17.21±0.2°2θ.

3. The hydrate crystal form A of lazertinib methanesulfonate according to claim 1 or 2, characterized in that, The XRPD spectrum of crystal form A also has a characteristic peak at at least one of the following: 11.24°±0.2°, 13.30±0.2°, 18.17±0.2°, 20.03±0.2°, 24.63°±0.2°, and 28.53±0.2°2θ.

4. The hydrate crystal form A of lazertinib methanesulfonate according to claim 3, characterized in that, The XRPD pattern of crystal form A shows diffraction peaks at the positions indicated in the table below for 2θ values: 。 5. The hydrate crystal form A of lazertinib methanesulfonate according to any one of claims 1-4, characterized in that, The crystal form A has a basic XRPD pattern as shown in Figure 1.

6. The method for preparing lazertinib methanesulfonate hydrate crystal form A according to any one of claims 1-5, characterized in that, The method includes any one of the following methods: 1) Lazertinib and methanesulfonic acid are respectively dissolved in dichloromethane to form a lazertinib solution and a methanesulfonic acid solution. The two solutions are mixed, a solid is precipitated, centrifuged, and dried to obtain the hydrate crystal form A of lazertinib methanesulfonate. The lazertinib solution is dissolved at high temperature, and the molar ratio of lazertinib to methanesulfonic acid is 1:1-1.

2. 2) Lazertinib methanesulfonate crystal form B is prepared into solution 1 in solvent 1. Then, solution 1 is added to solvent 2, stirred, and a solid is precipitated. The solid is centrifuged and dried to obtain hydrate crystal form A of lazertinib methanesulfonate. The solvents 1 and 2 are miscible solvents. 3) Dry lazertinib methanesulfonate crystal form B at 40-90℃ to obtain lazertinib methanesulfonate hydrate crystal form A.

7. The method for preparing lazertinib methanesulfonate hydrate crystal form A according to claim 6, characterized in that, In method 1), the high temperature is above 60°C; The solution is mixed by adding the methanesulfonic acid solution to the lazertinib solution; The drying process is a vacuum drying process at room temperature. In method 2), the crystal form B has an XRPD pattern as shown in Figure 7; Solvent 1 is selected from trichloromethane; Solvent 2 is selected from diethyl ether and acetonitrile; The volume ratio of solvent 1 to solvent 2 is <1:5; The drying process is air drying at room temperature. In method 3), the drying temperature is 40-50℃.

8. The method for preparing lazertinib methanesulfonate hydrate crystal form A according to claim 7, characterized in that, In method 1), the high temperature is 65-85℃; in method 2), the volume ratio of solvent 1 to solvent 2 is <1:

7.

9. A pharmaceutical composition for lazertinib, characterized in that, The composition comprises the hydrate crystal form A of lazertinib mesylate according to any one of claims 1-5, and at least one pharmaceutically acceptable carrier.

10. A formulation prepared from the lazertinib pharmaceutical composition according to claim 9, characterized in that, The formulation is selected from oral solid dosage forms, topical dosage forms, and injections.

11. The formulation according to claim 10, characterized in that, The formulation is in tablet form.

12. Use of the hydrate crystal form A of lazertinib mesylate according to any one of claims 1-5 or the pharmaceutical composition according to claim 9 in the preparation of a medicament for treating EGFR kinase-mediated diseases.

13. Use of the hydrate crystal form A of lazertinib mesylate according to any one of claims 1-5 or the pharmaceutical composition according to claim 9 in the preparation of a medicament for inhibiting the activity of EGFR having at least one mutation compared to wild-type EGFR.

14. The use according to claim 12, characterized in that, The disease mentioned is non-small cell lung cancer or metastatic non-small cell lung cancer.

15. The use according to claim 12, characterized in that, The use also includes combination therapy with other drugs selected from midazolam, rosuvastatin, metformin, amitraz, itraconazole, rifampin, gefitinib, pemetrexed, carboplatin, Ami-HC-CF, and Ami-HC.

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