Toolerutinib amorphous form as well as preparation method and application thereof
By preparing tolebrutinib in Form 1, Form 2, and amorphous forms, the stability and solubility issues of tolebrutinib in drug development were resolved, enabling its effective application in pharmaceuticals, particularly for the treatment of cancer, autoimmune diseases, and thromboembolic diseases.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- SOLIPHARMA
- Filing Date
- 2022-04-22
- Publication Date
- 2026-05-19
AI Technical Summary
The crystal form of tolebrutinib is not disclosed in the existing technology, which leads to problems such as poor stability, high hygroscopicity, and insufficient solubility in drug development, thus limiting its medicinal value.
Methods for preparing Form 1 and Form 2 of tolebrutinib are provided, as well as an amorphous form of tolebrutinib with good stability and solubility, prepared by crystal and amorphous processes under specific solvents and conditions to ensure its stability and solubility during pharmaceutical use.
Tolebrutinib Form 1 and Form 2 exhibit good stability and solubility, making them suitable for the industrial production and storage of pharmaceutical formulations. This improves the bioavailability of the drug and the stability of the formulation, making them suitable for the treatment of cancer, autoimmune diseases, and thromboembolic diseases.
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Figure CN122059957A_ABST
Abstract
Description
[0001] Citation of relevant applications This application claims the full benefits of patent application No. 202110440752.X filed with the State Intellectual Property Office of the People's Republic of China on April 23, 2021, and patent application No. 202110479686.7 filed with the State Intellectual Property Office of the People's Republic of China on April 30, 2021, the entire contents of which are incorporated herein by reference. Technical Field
[0002] This application relates to the field of medicinal chemistry. Specifically, this application relates to the crystal form, amorphous form, preparation method, and uses of tolebrutinib. Background Technology
[0003] 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.
[0004] 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.
[0005] Tolebrutinib (development code SAR442168), developed by Principia and later acquired by Sanofi, is a BTK inhibitor used to treat cancer, autoimmune diseases such as multiple sclerosis and myasthenia gravis, inflammatory diseases, and thromboembolic diseases. Its structural formula is as follows:
[0006] Currently, there are no publicly available reports regarding the crystal forms of this compound. Therefore, it is necessary to conduct a comprehensive and systematic polymorphic screening of tolebrutinib to select crystal forms with beneficial properties for tolebrutinib product development.
[0007] The inventors of this application made a surprising discovery during their research: two crystal forms of tolebrutinib. The crystal forms of tolebrutinib provided in this application have at least one of the following advantages: good stability, low hygroscopicity, uniform particle size distribution, solubility meeting pharmaceutical requirements, stable storage, prevention of crystal transformation during development and storage, reliable preparation method, and significant development value.
[0008] Furthermore, the inventors of this application have made a surprising discovery of an amorphous form of tolebrutinib. It is well known that solid powders exist in two physical states: amorphous and crystalline. Amorphous solids typically exhibit lower stability and higher hygroscopicity, limiting their medicinal value. However, the amorphous tolebrutinib discovered by the applicant possesses better solubility than the crystalline form of tolebrutinib while maintaining good storage stability and acceptable hygroscopicity, thus exhibiting high medicinal value. Summary of the Invention
[0009] In view of the shortcomings of the prior art, the purpose of this application is to provide the crystal form, amorphous form of tolebrutinib, its preparation method and uses.
[0010] One object of this application is to provide a tolebrutinib Form 1 (hereinafter referred to as Form 1) whose XRPD spectrum has characteristic peaks at at least four of the following four 2θ values: 10.4°±0.2°, 11.4°±0.2°, 20.6°±0.2°, 16.7°±0.2°, and 22.7°±0.2°.
[0011] Furthermore, the XRPD spectrum of the tolebrutinib Form 1 also has characteristic peaks at one or more of the following 2θ values: 4.2°±0.2°, 15.8°±0.2°, 17.9°±0.2°, 20.8±0.2°, and 24.8°±0.2°, or / and its XRPD spectrum also has characteristic peaks at one or more of the following 2θ values: 10.9°±0.2°, 21.3°±0.2°, 23.5±0.2°, 25.3±0.2°, and 25.7±0.2°.
[0012] Furthermore, the XRPD spectrum of tolebrutinib Form 1 shows diffraction peaks at the positions indicated in the table below for 2θ values:
[0013] In the preferred embodiment of this application, the XRPD pattern of tolebrutinib Form 1 is basically as follows: Figure 7 As shown.
[0014] In the preferred embodiment of this application, the TGA spectrum of tolebrutinib Form 1 is basically as follows: Figure 8 As shown.
[0015] In the preferred embodiment of this application, the DSC spectrum of tolebrutinib Form 1 begins to show an endothermic peak at around 126°C.
[0016] In the preferred embodiment of this application, the DSC spectrum of tolebrutinib Form 1 is basically as follows: Figure 9 As shown.
[0017] In the preferred embodiment of this application, the FT-IR (Fourier Transform Infrared) spectrum of tolebrutinib Form 1 is at 840.7 ± 2 cm⁻¹. -1 978.3±2 cm -1 1472.3±2 cm -1 1492.5±2 cm -1 There is a musical band here.
[0018] Preferably, the FT-IR spectrum of tolebrutinib Form 1 is still at 748.5±2 cm⁻¹. -1 1230.6±2cm -1 1396.8±2 cm -1 1447.4±2 cm -1 1508.9±2 cm -1 1588.1±2 cm -1 1638.1±2 cm -1 and 1698.4±2 cm -1 There are spectral bands in one or two or more locations.
[0019] In the preferred embodiment of this application, the FT-IR spectrum of tolebrutinib Form 1 is basically as follows: Figure 13 As shown.
[0020] In the preferred embodiment of this application, the tolebrutinib Form 1 is an anhydrous form.
[0021] One of the objectives of this application is to provide a method for preparing tolebrutinib Form 1, said method being selected from any of the following methods: 1) Dissolve tolebrutinib in solvent 1 to form a solution, evaporate, crystallize, separate, and dry to obtain Form 1.
[0022] Solvent 1 is acetone.
[0023] Preferably, the dissolution step is performed at room temperature.
[0024] Preferably, the volatilization occurs at room temperature.
[0025] 2) Dissolve tolebrutinib in a good solvent to form a solution, stir (1), add an antisolvent, stir (2), crystallize, separate, and dry to obtain Form 1.
[0026] The good solvent is selected from single or mixed solvents of ethanol, acetone and tetrahydrofuran; the antisolvent is selected from single or mixed solvents of water, n-heptane and n-hexane, preferably a mixed solvent containing water.
[0027] The stirring (1) step is optional.
[0028] The stirring (2) step is optional and is particularly suitable for embodiments where no solid precipitates immediately after the addition of the antisolvent; this step can be omitted for embodiments where a solid precipitates immediately after the addition of the antisolvent.
[0029] Preferably, the volume ratio of the antisolvent to the good solvent is ≥0.1:1, more preferably 1:1-8:1.
[0030] Preferably, the dissolution step is performed at room temperature.
[0031] Preferably, the stirring is carried out at a certain temperature, wherein the certain temperature is ≤30℃; and the stirring time is ≥30min.
[0032] 3) Form a suspension of tolebrutinib in solvent 2, stir at room temperature, separate, and dry to obtain Form 1.
[0033] Solvent 2 is selected from one or a mixture of ethanol and ethyl acetate. Preferably, the solvent is ethanol. The mass-to-volume ratio (mg / mL) of tolebrutinib to solvent 2 is 20:1-100:1.
[0034] Preferably, the mass-to-volume ratio (mg / mL) of tolebrutinib to solvent 2 is 25:1-50:1.
[0035] The tolebrutinib Form 1 of this application has the following beneficial effects: 1) Tolebrutinib Form 1 exhibits good stability, which is beneficial for sample storage and formulation stability. The crystal form of Tolebrutinib Form 1 remained unchanged after 10 months of long-term and accelerated storage, and its chemical purity remained essentially unchanged before and after storage. Furthermore, after Tolebrutinib Form 1 was mixed with excipients to form a pharmaceutical formulation, its crystal form remained unchanged after at least 14 days of storage at 25°C / 60%RH, indicating that both the Tolebrutinib Form 1 active pharmaceutical ingredient and the formulation prepared using Form 1 of this application have good stability under harsh conditions.
[0036] 2) Tolebrutinib Form 1 has low hygroscopicity and does not have special requirements for the humidity of the production and storage environment, making it suitable for industrial production and beneficial for the storage of the compound and its formulation products.
[0037] 3) Tolebrutinib Form 1 has good solubility, with a solubility of about 20 mg / mL in a solvent with a pH similar to that of the human stomach, which is conducive to achieving ideal drug bioavailability and efficacy and meeting pharmaceutical requirements.
[0038] 4) Tolebrutinib Form 1 has good compressibility, which is beneficial to the formulation process, improves the product appearance, and enhances the product quality.
[0039] 5) Tolebrutinib Form 1 has a good appearance, is a solid powder with fine particles, which is beneficial to improving flowability.
[0040] 6) The preparation method of Tolebrutinib Form 1 is mild and highly reproducible, and has the potential for industrialization.
[0041] 7) Tolebrutinib Form 1 exhibits very high chemical purity. The Form 1 sample obtained in this application without any special purification process already possesses a purity of 99.8%, indicating that high purity is an inherent beneficial property of the Form 1 crystal form itself. Even after stability testing, as shown in Table 2, it still retains a purity of 99.5% after being left exposed at 40°C / 75%RH for 10 months, demonstrating that Form 1 maintains high chemical purity while also possessing high chemical stability.
[0042] In summary, tolebrutinib Form 1 has good physicochemical properties, is easy to prepare into formulations, better ensures the quality of the compound and formulations, and is conducive to the efficacy of tolebrutinib.
[0043] Another objective of this application is to provide a tolebrutinib Form 2 (hereinafter referred to as Form 2) whose XRPD spectrum has characteristic peaks at at least four of the following four 2θ values: 7.8°±0.2°, 12.0°±0.2°, 18.5°±0.2°, 18.8°±0.2°, and 22.9°±0.2°.
[0044] Furthermore, the XRPD spectrum of the tolebrutinib Form 2 also has characteristic peaks at one or more of the following 2θ values: 11.1°±0.2°, 13.7°±0.2°, 16.2±0.2°, 23.9°±0.2°, and 24.9°±0.2°, or / and its XRPD spectrum also has characteristic peaks at one or more of the following 2θ values: 13.3°±0.2°, 14.1°±0.2°, 20.3±0.2°, and 21.7±0.2°.
[0045] Furthermore, the XRPD pattern of tolebrutinib Form 2 shows diffraction peaks at the positions indicated in the table below for 2θ values:
[0046] In the preferred embodiment of this application, the XRPD pattern of tolebrutinib Form 2 is basically as follows: Figure 14 As shown.
[0047] In the preferred embodiment of this application, the TGA spectrum of tolebrutinib Form 2 is basically as follows: Figure 15 As shown.
[0048] In the preferred embodiment of this application, the DSC spectrum of tolebrutinib Form 2 begins to show an endothermic peak at 160-164℃.
[0049] In the preferred embodiment of this application, the DSC spectrum of tolebrutinib Form 2 is basically as follows: Figure 16 As shown.
[0050] In the preferred embodiment of this application, the FT-IR spectrum of tolebrutinib Form 2 is at 1699±2 cm⁻¹. -1 1229±2 cm -1 1486 cm -1 1507±2 cm -1 There is a musical band here.
[0051] Preferably, the FT-IR spectrum of tolebrutinib Form 2 is still at 693±2 cm⁻¹.-1 1395±2 cm -1 1507±2 cm -1 and 1626±2 cm -1 There are spectral bands in one or two or more locations.
[0052] In the preferred embodiment of this application, the FT-IR spectrum of tolebrutinib Form 2 is basically as follows: Figure 19 As shown.
[0053] In the preferred embodiment of this application, the tolebrutinib Form 2 is an anhydrous product.
[0054] One of the objectives of this application is to provide a method for preparing tolebrutinib Form 2, said method being selected from any of the following methods: 1) Disperse tolebrutinib in solvent 3 into a suspension, stir at a constant temperature, separate the solid, and dry to obtain Form 2; The constant temperature stirring time is ≥12 hours, preferably 1-5 days; the constant temperature stirring temperature is ≥30℃, preferably 30-80℃, and more preferably 40-70℃.
[0055] The solvent 3 is selected from single or mixed solvents such as methyl tert-butyl ether, n-heptane, butanone, water, n-butyl acetate, isopropyl ether, sec-butanol, methyl tert-butyl ether, dichloromethane, and 1,4-dioxane.
[0056] Preferably, the solvent 3 is selected from a mixed solvent of butanone and water, with a mixing volume ratio of 1:1 to 1:10; or, it is selected from a mixed solvent of n-butyl acetate and dichloromethane, with a mixing volume ratio of 1:1 to 1:10.
[0057] 2) Dissolve tolebrutinib in solvent 4 to form a solution, allow it to evaporate in an open container, and then dry it.
[0058] Solvent 4 is selected from toluene and methylcyclohexane or a mixture thereof.
[0059] Preferably, solvent 4 is a mixed solvent of toluene and methylcyclohexane, with a solvent mixing ratio of 5:1 to 1:2.
[0060] 3) Place tolebrutinib in a sealed solvent container for ≥1 day and dry to obtain Form 2.
[0061] Solvent 5 is acetonitrile.
[0062] The tolebrutinib Form 2 of this application has the following beneficial effects: 1) Tolebrutinib Form 2 has a high melting point, which is very beneficial for high-temperature processes such as hot melt extrusion.
[0063] 2) Tolebrutinib Form 2 has very low hygroscopicity, with only 0.3% moisture absorption at 0-80%RH, making it more suitable for industrial production and storage.
[0064] 3) Tolebrutinib Form 2 exhibits good physical and chemical stability, which is beneficial for sample storage and formulation stability. The crystal form of Tolebrutinib Form 2 remained unchanged after 10 months of long-term and accelerated storage conditions, and its chemical purity remained essentially unchanged before and after storage. Furthermore, after mixing Tolebrutinib Form 2 with excipients to form a pharmaceutical formulation, the crystal form remained unchanged after at least 14 days of storage at 25°C / 60%RH. This indicates that both the active pharmaceutical ingredient of Tolebrutinib Form 2 and the formulation prepared using Tolebrutinib Form 2 exhibit good stability under harsh conditions, making them suitable for formulation production and storage.
[0065] 4) Competitive slurry tests showed that Tolebrutinib Form 2 is a thermodynamically stable crystal form at temperatures of 30°C and above.
[0066] 5) Tolebrutinib Form 2 has good solubility, which is conducive to achieving ideal drug bioavailability and efficacy, and meeting pharmaceutical requirements.
[0067] 6) Tolebrutinib Form 2 has good compressibility, which is beneficial to the formulation process, improves product appearance, and enhances product quality.
[0068] 7) Tolebrutinib Form 2 has a good appearance, is a solid powder with fine particles, uniform distribution, and good flowability.
[0069] 8) The preparation method of Tolebrutinib Form 2 is mild and highly reproducible, and has the potential for industrialization.
[0070] One of the objectives of this application is to provide an amorphous solid form of tolebrutinib, wherein the 2θ value of the amorphous XRPD pattern does not have a diffraction peak in the range of 3-40°.
[0071] Preferably, the 2θ value of the amorphous XRPD pattern has a diffuse packet in the range of 10-40°.
[0072] In the preferred embodiment of this application, the amorphous XRPD pattern is basically as follows: Figure 1 As shown.
[0073] In the preferred embodiment of this application, the amorphous TGA spectrum is basically as follows: Figure 2 As shown.
[0074] In the preferred embodiment of this application, the amorphous mDSC spectrum is basically as follows: Figure 3 As shown.
[0075] In the preferred embodiment of this application, the amorphous FT-IR spectrum is located at 1703±2 cm⁻¹. -1 1440±2 cm -1 788 cm -1 and 753±2 cm -1 There is a musical band here.
[0076] In the preferred embodiment of this application, the amorphous FT-IR spectrum is still at 693±2 cm⁻¹. -1 950±2 cm -1 1227±2 cm -1 1391±2 cm -1 1487±2 cm -1 1487±2 cm -1 1588±2 cm -1 and 1625±2 cm -1 There are spectral bands in one or two or more locations.
[0077] In the preferred embodiment of this application, the amorphous FT-IR spectrum is basically as follows: Figure 6 As shown.
[0078] One of the objectives of this application is to provide a method for preparing tolebrutinib amorphous form, said method being selected from any of the following methods: 1) Dissolve tolebrutinib in a good solvent, then add an anti-solvent, stir, precipitate the solid, separate, and dry.
[0079] The good solvent is one of dimethyl sulfoxide and toluene or a mixture thereof; the antisolvent is selected from one of water and diethyl ether or a mixture thereof.
[0080] Preferably, the good solvent is dimethyl sulfoxide; the antisolvent is water.
[0081] Preferably, the volume ratio of the good solvent to the antisolvent is 10:1 to 1:10, more preferably 1:1.
[0082] 2) Dissolve tolebrutinib in solvent 6 at high temperature, filter, stir at low temperature, separate, and dry.
[0083] The solvent 6 is selected from one or more of the following mixed solvents: trifluoroethanol / water, isopropyl acetate / water, tetrahydrofuran / water, 1,4-dioxane / water, acetonitrile / water, and chloroform / water.
[0084] Preferably, the solvent 6 is a mixed solvent of trifluoroethanol and water.
[0085] Preferably, the high temperature is 40-80℃.
[0086] Preferably, the low temperature is ≤10℃.
[0087] Surprisingly, the amorphous solid form of tolebrutinib in this application has the following unexpected combined beneficial effects: 1) The tolebrutinib amorphous form of this application exhibits good stability, which is beneficial for sample storage and formulation stability. The tolebrutinib amorphous form remained unchanged after 10 months of long-term and accelerated storage, and its chemical purity remained essentially unchanged before and after storage. The amorphous sample did not undergo crystallization after at least 14 days of storage under light and oxidation conditions, and its chemical purity remained essentially unchanged before and after storage. Furthermore, after the amorphous form was mixed with excipients to form a pharmaceutical formulation, it remained unchanged after at least 14 days of storage at 25°C / 60%RH. This demonstrates that the tolebrutinib amorphous active pharmaceutical ingredient and the formulation prepared using the amorphous form of this application exhibit good stability under harsh conditions.
[0088] 2) The tolebrutinib in this application has a high amorphous chemical purity of ≥98.9%. Moreover, its purity remains unchanged after 10 months of long-term open storage, and it still has a purity of 98.0% after 10 months of open storage under accelerated conditions.
[0089] 3) Tolebrutinib amorphous form has good solubility, which is higher than that of Tolebrutinib Form 1 and Form 2, which is conducive to achieving ideal drug bioavailability and efficacy and meeting pharmaceutical requirements.
[0090] 4) Tolebrutinib has low hygroscopicity due to its amorphous form, with a weight gain of only about 1.9% between 20%RH and 80%RH, making it suitable for industrial production.
[0091] 5) Tolebrutinib amorphous form has good compressibility, which is beneficial to formulation process, improves product appearance, and enhances product quality.
[0092] One of the objectives of this application is to provide a pharmaceutical composition of tolebrutinib, said composition comprising one or more tolebrutinib Form 1, or tolebrutinib Form 2, or tolebrutinib amorphous solid form, or any combination thereof, and at least one pharmaceutically acceptable carrier.
[0093] One of the objectives of this application is to provide a formulation prepared from the above-mentioned tolebrutinib pharmaceutical composition, wherein the formulation form includes, but is not limited to, oral solid dosage form, topical dosage form, and injection.
[0094] 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.
[0095] In the preferred embodiment of this application, the formulation is a tablet.
[0096] 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.
[0097] 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, microcrystalline cellulose, starch, pregelatinized starch, calcium sulfate, dicalcium 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.
[0098] Furthermore, the pharmaceutical composition may also contain 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 required to maintain the pH of the components within an acceptable range, in solutions or solids containing such acids, bases, and buffers.
[0099] One of the purposes of this application is to provide the use of one or more tolebrutinib Form 1, or tolebrutinib Form 2, or tolebrutinib in amorphous solid form, or any combination thereof, or the pharmaceutical composition thereof, in the preparation of a medicament for treating BTK-mediated diseases.
[0100] One of the purposes of this application is to provide the use of one or more tolebrutinib Form 1, or tolebrutinib Form 2, or tolebrutinib in amorphous solid form, or any combination thereof, or the pharmaceutical composition thereof, in the preparation of a medicament for treating cancer, autoimmune diseases, inflammatory diseases, and thromboembolic diseases.
[0101] One of the objectives of this application is to provide a method for treating BTK-mediated conditions, comprising administering to a patient an effective amount of one or more tolebrutinib Form 1, or tolebrutinib Form 2, or tolebrutinib in amorphous solid form, or any combination thereof, or the pharmaceutical composition thereof.
[0102] One of the purposes of this application is to provide a method for treating cancer, autoimmune diseases, inflammatory diseases, and thromboembolic diseases, said method comprising administering to a patient in need a therapeutically effective amount of one or more of the tolebrutinib Form 1, or tolebrutinib Form 2, or tolebrutinib in amorphous solid form, or any combination thereof, or said pharmaceutical composition thereof.
[0103] Preferably, the effective amount of one or more tolebrutinib Form 1, or tolebrutinib Form 2, or tolebrutinib amorphous solid form, or any combination thereof, is 0.001-10 mg / kg, more preferably 0.005-5 mg / kg.
[0104] Preferably, the method may involve administration once, twice, three times, or more times a day. A single dose may range from 0.1 mg to 500 mg / kg / day, with the specific dose determined based on the patient's actual condition.
[0105] Preferably, the method is to administer once daily, with a single dose being 10, 30, 60, 90, 120, 150, 180, 210, 300, 450 or 500 mg of one or more tolebrutinib Form 1, or tolebrutinib Form 2, or tolebrutinib amorphous solid form, or any combination thereof; more preferably 60 or 120 mg.
[0106] In the preferred embodiment of this application, the diseases include, but are not limited to, acute hemorrhagic necrotizing leukoencephalitis, acute disseminated encephalomyelitis, Addison's disease, agammaglobulinemia, alopecia areata, alopecia universalis, amyloidosis, ankylosing spondylitis, anti-GBM / anti-TBM nephritis, antiphospholipid syndrome (APS), antiphospholipid antibody syndrome, aplastic anemia, arthritis, autoimmune angioedema, autoimmune familial autonomic dysfunction, autoimmune hepatitis, autoimmune hyperlipidemia, autoimmune inner ear disease (AIED), autoimmune myocarditis, autoimmune oophoritis, autoimmune pancreatitis, autoimmune retinopathy, autoimmune thrombocytopenic purpura (ATP), autoimmune thyroid disease, autoimmune urticaria, autoimmune hemolytic anemia, axonal and neuronal neuropathy, Balo disease, and Behcet's disease. Diseases including bullous pemphigoid, cardiomyopathy, Castleman disease, celiac disease, Chagas disease, chronic fatigue syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic relapsing multifocal osteomyelitis (CRMO), allergic granulomatous vasculitis (Churg-Strauss syndrome), cicatricial pemphigoid / benign mucosal pemphigoid, celiac disease, Cogans syndrome, cold agglutinin disease, congenital heart block, coxsackie myocarditis, CREST disease, Crohn's disease, demyelinating neuropathy, herpetic dermatitis, dermatomyositis, Devic's disease (neuromyelitis optica), diabetes, discoid lupus, and Dressler's syndrome. Syndrome, dry eye disease, familial autonomic dysfunction, endometriosis, eosinophilic esophagitis, eosinophilic fasciitis, erythema nodosum, spontaneous mixed cryoglobulinemia, Evans syndrome, experimental allergic encephalomyelitis, fibromyalgia, fibrotic alveolitis, giant cell arteritis (temporal arteritis), giant cell myocarditis, glomerulonephritis, Goodpasture's syndrome, granulomatous polyangiitis (GPA) (formerly known as Wegener's granulomatosis), Graves' disease, Guillain-Barré syndrome.Kawasaki syndrome, Hashimoto's thyroiditis, hemolytic anemia, Henoch-Schonlein purpura, herpes gestationis, hypogammaglobulinemia, idiopathic pulmonary fibrosis, idiopathic thrombocytopenic purpura (ITP), IgA nephropathy, IgG4-related sclerotic diseases, immunomodulatory lipoproteins, inclusion body myositis, inflammatory bowel disease, interstitial cystitis, juvenile arthritis, juvenile diabetes mellitus (type 1 diabetes), juvenile myositis, Kawasaki syndrome, Lambert-Eaton syndrome, leukocytoclastic vasculitis, lichen planus, lichen sclerosus, woody conjunctivitis, linear IgA disease (LAD), lupus (SLE), lupus including lupus nephritis, Lyme disease, chronic diseases, Meniere's disease Disease), microscopic polyangiitis, mixed connective tissue disease (MCTD), keratodermal ulcer, Mucha-Habermann's disease, mucosal pemphigoid, multiple sclerosis, myasthenia gravis, myositis, narcolepsy, neuromuscular rigidity, neutropenia, ocular cicatricial pemphigoid, oculoclonus-myoclonus syndrome, optic neuritis, Ord's thyroiditis, osteoarthritis, relapsing rheumatoid arthritis, PANDAS (streptococcal-associated childhood autoimmune neuropsychiatric disorder), paraneoplastic cerebellar degeneration, paroxysmal nocturnal hemoglobinuria (PNH), Parry Romberg syndrome, periclival plaque inflammation (peripheral uveitis), Parsonnage-Turner syndrome, peripheral neuropathy, perivenous encephalomyelitis, pernicious anemia, pemphigus (e.g., pemphigus vulgaris, pemphigus foliaceus), POEMS syndrome, polyarteritis nodosa, polymyalgia rheumatica, polymyositis, post-myocardial infarction syndrome, post-pericardiotomy syndrome, primary biliary cirrhosis, primary sclerosing cholangitis, primary biliary cirrhosis, progesterone dermatitis, psoriasis, psoriatic arthritis, psoriatic arthritis, pure red cell aplasia, pyoderma gangrenosum, Raynaud's phenomenon, reactive arthritis, reflex sympathetic dystrophy, Reiter's syndrome, relapsing polychondritis, restless legs syndrome, retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis, sarcoidosis, Schmidt syndrome Sjogren's syndrome, scleritis, scleroderma, sperm and testicular autoimmunity, stiff-person syndrome, Still's diseaseDisease), subacute bacterial endocarditis (SBE), Susac syndrome, sympathetic ophthalmia, Takayasu's arteritis, temporal arteritis / giant cell arteritis, thrombocytopenic purpura (TTP), Tolosa-Hunt syndrome, transverse myelitis, class I, II and III autoimmune polyglandular syndromes, ulcerative colitis, undifferentiated connective tissue disease (UCTD), uveitis, vasculitis, bullous dermatitis, vitiligo, vulvar pain or lupus, multiple sclerosis (MS).
[0107] In the preferred embodiment of this application, the multiple sclerosis includes, but is not limited to, relapsing multiple sclerosis (RMS), primary progressive multiple sclerosis (PPMS), and secondary progressive multiple sclerosis (SPMS).
[0108] One of the purposes of this application is to provide one or more tolebrutinib Form 1, or tolebrutinib Form 2, or tolebrutinib in amorphous solid form, or any combination thereof, or the combination of such pharmaceutical compositions with other pharmaceuticals.
[0109] The other drugs include, but are not limited to, any one or more of the following: anticancer drugs, corticosteroids, non-corticosteroids, immunosuppressants, and anti-inflammatory drugs, or combinations thereof.
[0110] Preferably, the other drugs are selected from ibrutinib, acalabrutinib, zanubrutinib, Velexbru, and orelabrutinib.
[0111] Unless otherwise specified: The experimental operating temperature generally refers to room temperature, which is a temperature of 10℃ to 30℃.
[0112] "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.
[0113] "Separation" can be performed using conventional methods in the art, such as centrifugation or filtration. Preferred method is vacuum filtration, typically performed at a pressure less than atmospheric pressure, preferably less than 0.09 MPa.
[0114] "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.
[0115] 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
[0116] Figure 1 XRPD spectrum of sample 1-1 (tolebrutinib amorphous); Figure 2 TGA image of sample 1-1 in Example 1; Figure 3 mDSC chromatogram of sample 1-1 in Example 1; Figure 4 DVS of Sample 1-1 in Example Figure 1 ; Figure 5 DVS of Sample 1-1 in Example Figure 2 ; Figure 6 FT-IR image of sample 1-1 in Example 1; Figure 7 XRPD spectrum of sample 2-1 (tolebrutinib Form 1); Figure 8 TGA image of sample 2-1; Figure 9 DSC chart of sample 2-1; Figure 10 DVS of Sample 2-1 in Example Figure 1 ; Figure 11 DVS of Sample 2-1 Figure 2 ; Figure 12 PLM diagram of sample in Example 2-1; Figure 13 FT-IR image of sample in Example 2-1; Figure 14 XRPD spectrum of sample 3-1 (tolebrutinib Form 2); Figure 15 TGA image of sample 3-1 in Example 3-1; Figure 16DSC chart of sample 3-1 in Example 3-1; Figure 17 DVS diagram of sample 3-1 in Example 3-1; Figure 18 PLM diagram of sample 3-1 in Example 3-1; Figure 19 FT-IR image of sample 3-1 in Example 3-1; Figure 20 Example 1-1 XRPD overlay of a sample (amorphous) placed under long-term (25℃ / 60%RH / open) and accelerated (40℃ / 75%RH / open) conditions for 10 months; Figure 21 Example 2-1 XRPD overlay of sample (Form 1) after 10 months of long-term (25°C / 60%RH / open) and accelerated (40°C / 75%RH / open) conditions; Figure 22 Example 3-1 XRPD stacked image of sample (Form 2) after 10 months of long-term (25℃ / 60%RH / open) and accelerated (40℃ / 75%RH / open) conditions; Figure 23 Example 1-1 XRPD overlay images of the sample (amorphous) before and after formulation; Figure 24 Example 2-1 XRPD overlay images of the sample (Form 1) before and after formulation; Figure 25 Example 3-1 XRPD overlay images of the sample (Form 2) before and after formulation; Figure 26 Example 1-1 XRPD overlay image of stability of sample (amorphous) tablets; Figure 27 XRPD overlay image of the stability of sample (Form 1) tablets in Example 2-1; Figure 28 XRPD overlay image of the stability of sample (Form 2) tablets in Example 3-1; Figure 29 XRPD spectra of samples from Examples 1-2 (tolebrutinib amorphous); Figure 30 These are the XRPD spectra (tolebrutinib Form 1) of samples from Examples 2-4. Figure 31 This is the XRPD spectrum (tolebrutinib Form 2) of the sample from Example 3-2. Figure 32 These are the DSC images of samples from Examples 3-6. Detailed Implementation
[0117] 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.
[0118] In this application, X-ray powder diffraction (XRPD) data were obtained from a Bruker D8 Advancediffractometer; the parameters are as follows: Cu target; wavelength 1.54 Å; current and voltage: 40 KV, 40 mA; angle range: 3~40˚2θ.
[0119] 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.
[0120] 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.
[0121] In this application, the mDSC data were acquired from a TA Instruments Q200 DSC; the parameters are as follows: amplitude: ±0.048℃, period: 60s, heating rate: 2℃ / min, protective gas: N2; sample tray: covered aluminum crucible.
[0122] 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: 90 min; protective gas: N2; sample pan: platinum crucible.
[0123] In this application, Fourier transform infrared (FT-IR) spectroscopy data were acquired using a Bruker Tensor 27; parameters are as follows: ATR method, acquisition range 600 cm⁻¹. -1 -4000 cm -1 4 cm resolution -1 .
[0124] In this application, the polarization microscopy (PLM) images were obtained from the XPV~990E polarization microscopy; a small amount of powder sample was placed on a glass slide, a small amount of mineral oil was added to disperse the sample, a coverslip was placed on the stage for observation and photography.
[0125] In this application, the detection parameters for chemical stability and solubility are as follows:
[0126] 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.
[0127] Preparation Example
[0128] Following the synthetic route in Example 3 of WO2016196840A1, crude tolebrutinib was obtained.
[0129] The crude product mentioned above can also be obtained through other synthetic routes or by purchasing.
[0130] Example 1-1: Preparation of amorphous tolebrutinib Approximately 20 mg of crude tolebrutinib product was dissolved in 1.0 mL of dimethyl sulfoxide. After adding 1.0 mL of water, a solid precipitated out. After stirring for two hours, the mixture was centrifuged and dried under vacuum at room temperature for 24 hours to obtain sample 1-1.
[0131] The XRPD spectrum of sample 1-1 is attached. Figure 1 As shown; The TGA characterization data for sample 1-1 showed a weight loss of 1.5% before reaching 100℃, and a decomposition temperature of 359℃, as shown in the attached figure. Figure 2 As shown; The mDSC characterization data for sample 1-1 shows a Tg temperature of 80.5℃, as shown in the attached figure. Figure 3 As shown; The DVS characterization data for sample 1-1 showed a weight gain of approximately 1.9% between 20%RH and 80%RH at 25℃. (See attached data.) Figure 4-5 As shown; The FT-IR spectrum of sample 1-1 is attached. Figure 6 As shown.
[0132] Examples 1-2: Preparation of amorphous tolebrutinib Approximately 20 mg of crude tolebrutinib product was dissolved in 1.5 mL of toluene. After adding 4.0 mL of diethyl ether, a solid precipitated out. After stirring for two hours, the mixture was centrifuged and dried under vacuum at room temperature for 24 hours to obtain amorphous samples 1-2.
[0133] Examples 1-3: Preparation of amorphous tolebrutinib Take about 30 mg of crude tolebrutinib product, dissolve it in trifluoroethanol / water (0.3 / 0.4 ml) at 60°C, filter, stir at 4°C for 2 days, separate, and dry to obtain the amorphous product.
[0134] Examples 1-4: Preparation of amorphous tolebrutinib Following the methods described in Examples 1-3, the sample was dissolved in isopropyl acetate / water (0.1 / 0.3 ml), tetrahydrofuran / water (0.1 / 0.4 ml), 1,4-dioxane / water (0.05 / 0.2 ml), acetonitrile / water (0.05 / 0.2 ml), and chloroform / water (0.4 / 0.2 ml), respectively, under the same conditions, and amorphous forms were obtained in all cases.
[0135] Example 2-1: Preparation of tolebrutinib Form 1 Approximately 20 mg of crude tolebrutinib was dissolved in 0.5 mL of ethyl acetate at room temperature. After stirring at room temperature for 1 day, the clarified solution was cooled to 5°C and stirred for 4 days. Then, 0.6 mL of purified water was added dropwise to the clarified solution, and a solid precipitated out. The solid was centrifuged and dried under vacuum at room temperature to obtain tolebrutinib Form 1 sample 2-1.
[0136] The XRPD data for sample 2-1 are shown in the table below:
[0137] The XRPD spectrum of sample 2-1 is attached. Figure 7 As shown.
[0138] The TGA characterization data for sample 2-1 were determined; it was an anhydrous sample (1.4% weight loss before 100℃), with a decomposition temperature of 346℃, as shown in the attached figure. Figure 8 As shown.
[0139] The DSC characterization data for sample 2-1 were determined; the melting point (expressed as onset value) was 126℃, and the peak value was 133℃, as shown in the attached figure. Figure 9 As shown, when heated to 126°C, an endothermic peak begins to appear.
[0140] The DVS characterization data of sample 2-1 were determined. It exhibits slight hygroscopicity, with a weight gain of approximately 0.46% between 0% and 80% RH. (See attached...) Figure 10-11 As shown.
[0141] The PLM characterization data of sample 2-1 were determined. The particles are fine, uniformly distributed, and ≤10 micrometers in diameter. (See attached image) Figure 12 As shown.
[0142] The FT-IR spectrum of sample 2-1 is attached. Figure 13 As shown.
[0143] Example 2-2: Preparation of tolebrutinib Form 1 Approximately 20 mg of tolebrutinib amorphous solution was dissolved in 0.5 mL of acetone at room temperature, filtered, and allowed to evaporate at room temperature for 1 day to obtain tolebrutinib Form 1 sample.
[0144] Examples 2-3: Preparation of tolebrutinib Form 1 Approximately 20 mg of tolebrutinib amorphous solution was dissolved in 0.5 mL of tetrahydrofuran, filtered, and 1.2 mL of water was added to produce oily droplets. After stirring at room temperature for one day, the solution was transferred to 4°C and stirred. After 7 days, the suspension was centrifuged and vacuum dried overnight at room temperature to obtain tolebrutinib Form 1 sample.
[0145] Examples 2-4: Preparation of tolebrutinib Form 1 Approximately 20 mg of tolebrutinib amorphous solution was dissolved in 1.5 mL of acetone at room temperature, filtered, and 4.0 mL of n-heptane was added to obtain a clear solution. The solution was stirred at room temperature for one day, then cooled to 4°C and stirred again. After 7 days, the suspension was centrifuged and dried under vacuum at room temperature to obtain tolebrutinib Form 1 sample.
[0146] Its XRPD data is shown in the table below:
[0147] Its XRPD spectrum is attached. Figure 30 As shown.
[0148] Examples 2-5: Preparation of tolebrutinib Form 1 Take about 20 mg of tolebrutinib amorphous solution and dissolve it in 0.5 mL of acetone at room temperature. Add 4.0 mL of n-heptane to obtain a clear solution. Stir at room temperature for one day, then cool to 4°C and stir. After 7 days, centrifuge the suspension and dry it under vacuum at room temperature to obtain tolebrutinib Form 1 sample.
[0149] Examples 2-6: Preparation of tolebrutinib Form 1 Take about 50 mg of tolebrutinib amorphous, add 1 mL of ethanol, stir at room temperature for 1 day, separate, and vacuum dry at room temperature to obtain tolebrutinib Form 1 sample.
[0150] Examples 2-7: Preparation of tolebrutinib Form 1 Take about 50 mg of tolebrutinib amorphous, add 1 mL of ethyl acetate, stir for 2 days, separate, and vacuum dry at room temperature to obtain tolebrutinib Form 1 sample.
[0151] Examples 2-8: Preparation of tolebrutinib Form 1 Approximately 20 mg of crude tolebrutinib was dissolved in 0.5 mL of ethanol at room temperature. After stirring at room temperature for 1 day, the clarified solution was cooled to 5°C and stirred for 4 days. Then, 4.0 mL of n-heptane was added dropwise to the clarified solution, and a solid precipitated out. The solid was centrifuged and dried under vacuum at room temperature to obtain the tolebrutinib Form 1 sample.
[0152] Example 3-1: Preparation of tolebrutinib Form 2 Approximately 20 mg of tolebrutinib amorphous was used to form a suspension in methyl tert-butyl ether (0.5 mL). After crystallization at a constant temperature of 40 °C for 4 days, the mixture was centrifuged and dried at room temperature overnight to obtain Form 2 sample 3-1.
[0153] The XRPD data for sample 3-1 are shown in the table below:
[0154] The XRPD spectrum of sample 3-1 is shown in the attached figure. Figure 14 As shown.
[0155] The TGA characterization data for sample 3-1, being anhydrous, showed a weight loss of 0.6% before reaching 100℃, and a decomposition temperature of 342℃, as shown in the attached figure. Figure 15 As shown.
[0156] The DSC characterization data for sample 3-1 were determined; the melting point (expressed as onset value) was 160℃, and the peak value was 167℃, as shown in the attached figure. Figure 16 As shown, an endothermic peak appears when heated to 160℃.
[0157] The DVS characterization data for sample 3-1 showed a weight gain of approximately 0.34% between 0%RH and 80%RH, as shown in the attached figure. Figure 17 As shown.
[0158] The PLM characterization data of sample 3-1 were determined. The particles are fine, uniformly distributed, and ≤10 micrometers in diameter. (See attached image) Figure 18 As shown.
[0159] The FT-IR spectrum of sample 3-1 is attached. Figure 19 As shown.
[0160] Example 3-2: Preparation of tolebrutinib Form 2 Approximately 20 mg of crude tolebrutinib was taken and a suspension was formed in butanone / water (0.1 / 0.5 mL). After stirring at a constant temperature of 70°C for 3 days, the suspension was centrifuged and dried at room temperature overnight to obtain the Form 2 sample.
[0161] Its XRPD data is shown in the table below:
[0162] Its XRPD spectrum is attached. Figure 31 As shown.
[0163] Example 3-3: Preparation of tolebrutinib Form 2 Approximately 20 mg of tolebrutinib amorphous was taken and a suspension was formed in n-heptane (0.5 mL). After stirring at a constant temperature of 50 °C for 5 days, the suspension was centrifuged and dried at room temperature overnight to obtain the Form 2 sample.
[0164] Examples 3-4: Preparation of tolebrutinib Form 2 Approximately 20 mg of tolebrutinib amorphous was taken and a suspension was formed in butyl acetate / dichloromethane (0.2 / 1.2 mL). After stirring at a constant temperature of 40 °C for 5 days, the suspension was centrifuged and dried at room temperature overnight to obtain the Form 2 sample.
[0165] Examples 3-5: Preparation of tolebrutinib Form 2 Approximately 20 mg of crude tolebrutinib was placed in an acetonitrile atmosphere for 4 days, and then vacuum dried overnight at room temperature to obtain Form 2 sample.
[0166] Examples 3-6: Preparation of tolebrutinib Form 2 Approximately 30 mg of crude tolebrutinib was added to a toluene / methylcyclohexane system (0.55 / 0.2 mL), dissolved at 60 °C, stirred at 5 °C for one day, and then the clear solution was transferred to an open container at 40 °C for 2 days of evaporation to obtain Form 2 samples 3-6.
[0167] DSC characterization data for samples 3-6 were determined; the melting point (expressed as onset value) was 164℃, and the peak value was 170℃, as shown in the attached figure. Figure 32 As shown, an endothermic peak appears when heated to 164℃.
[0168] Examples 3-7: Preparation of tolebrutinib Form 2 Following the method in Example 3-1, approximately 20 mg of tolebrutinib amorphous was taken and suspended in isopropyl ether (0.5 mL), methanol / isopropyl ether (0.1 / 0.6 mL), sec-butanol / n-heptane (0.6 / 0.6 mL), 1,4-dioxane / isopropyl ether (0.2 / 0.6 mL), and methyl tert-butyl ether / n-butyl acetate (0.1 / 1.8 mL), respectively, with other conditions remaining unchanged, to obtain Form 2 samples.
[0169] Example 4: Stability study of tolebrutinib amorphous, tolebrutinib Form 1 and tolebrutinib Form 2 Take appropriate amounts of tolebrutinib amorphous samples prepared in Examples 1-1 of this application, and place them under long-term (25℃ / 60%RH / open) and accelerated (40℃ / 75%RH / open) conditions, respectively. HPLC and XRPD are measured periodically, and the results are shown in Table 1 and [Table data missing]. Figure 20 As shown.
[0170] Table 1. Stability of tolebrutinib amorphous form
[0171] Experimental results show that tolebrutinib amorphous form can be stable for at least 10 months under long-term (25℃ / 60%RH / open) and accelerated (40℃ / 75%RH / open) conditions, respectively, and the chemical purity of the amorphous form remains essentially unchanged before and after storage. In addition, the amorphous sample can also be stable for at least 14 days under light (25℃ / 4500lx / closed) and oxidation (in a urea peroxide atmosphere) conditions, respectively, and the chemical purity of the amorphous form remains essentially unchanged before and after storage.
[0172] An appropriate amount of tolebrutinib Form 1 sample prepared in Example 2-1 of this application was placed under long-term (25℃ / 60%RH / open) and accelerated (40℃ / 75%RH / open) conditions, respectively. HPLC and XRPD were periodically analyzed, and the results are shown in Table 2 and... Figure 21 As shown.
[0173] Table 2. Stability of tolebrutinib Form 1
[0174] Experimental results show that tolebrutinib Form 1 can be stable for at least 10 months under long-term (25℃ / 60%RH / open) and accelerated (40℃ / 75%RH / open) conditions, and the chemical purity of Form 1 remains essentially unchanged before and after the conditions. In addition, the Form 1 sample can also be stable for at least 14 days under light (25℃ / 4500lx / closed) and oxidation (in a urea peroxide atmosphere) conditions, and the chemical purity of Form 1 remains essentially unchanged before and after the conditions.
[0175] The tolebrutinib Form 2 sample prepared in Example 3-1 of this application was weighed and placed under long-term (25℃ / 60%RH / open) and accelerated (40℃ / 75%RH / open) conditions, respectively. XRPD and HPLC were measured periodically, and the results are shown in Table 3. Figure 22 As shown.
[0176] Table 3. Stability of tolebrutinib Form 2
[0177] Experimental results show that tolebrutinib Form 2 can be stable for at least 10 months under long-term (25℃ / 60%RH / open) and accelerated (40℃ / 75%RH / open) conditions, and the chemical purity of Form 2 remains basically unchanged before and after the conditions. In addition, the Form 2 sample can also be stable for at least 14 days under light (25℃ / 4500lx / closed) and oxidation (in a urea peroxide atmosphere) conditions, and the chemical purity of Form 2 remains basically unchanged before and after the conditions.
[0178] Example 5: Solubility study of tolebrutinib amorphous, tolebrutinib Form 1 and tolebrutinib Form 2 The tolebrutinib amorphous, tolebrutinib Form 1, and tolebrutinib Form 2 samples from this application were prepared into supersaturated solutions using pH 1.2 buffer (preparation: weigh 375.90 mg of potassium chloride solid and 1709.47 mg of concentrated hydrochloric acid (37%) into a 100 mL volumetric flask, add approximately 80 mL of pure water, adjust the pH to 1.2 with hydrochloric acid or potassium hydroxide, and dilute to the mark with pure water) and pH 1.2 SGF (preparation: take 765 μL of concentrated hydrochloric acid (37%), add approximately 80 mL of water, 1 g of pepsin, and 200 mg of sodium chloride, shake well, and dilute with water to 100 mL). The sample content in the saturated solutions was determined by high-performance liquid chromatography (HPLC) at fixed time points. The results are shown in Table 4. Table 4. Solubility of amorphous, Form 1, and Form 2 in pH 1.2 buffer and pH 1.2 SGF
[0179] As shown in Table 4, the solubility of tolebrutinib amorphous, tolebrutinib Form 1, and tolebrutinib Form 2 in pH 1.2 buffer and pH 1.2 SGF meets pharmaceutical requirements. The amorphous, Form 1, and Form 2 of this application exhibit ideal solubility, all in the order of approximately 20 mg / mL, which is beneficial for achieving ideal drug bioavailability and efficacy, thus meeting pharmaceutical requirements.
[0180] Example 6: Compressibility Study of Amorphous Tolebrutinib, Tolebrutinib Form 1, and Tolebrutinib Form 2 Tableting was performed using a Tianxiang rotary tablet press. A Φ7.5mm circular die was used, with a filling depth of 17.9mm. A main pressure of 1.8 KN was applied to produce circular tablets. The radial crushing force (hardness, H) was tested using a tablet hardness tester. The diameter (D) and thickness (L) of the tablets were measured using vernier calipers. The tensile strength of the powder was calculated using the formula T=2H / πDL*9.8. The results are shown in Table 5. Table 5 Compressible Forms of Amorphous, Form 1 and Form 2
[0181] The results showed that tolebrutinib amorphous, tolebrutinib Form 1 and tolebrutinib Form 2 all had excellent compressibility, meeting the requirements for pharmaceutical use.
[0182] Example 7: Preparation of tablets According to the prescription in Table 6, API, lactose hydrate, polyvinylpyrrolidone, hydroxypropyl cellulose, microcrystalline cellulose and magnesium stearate are mixed and compressed to obtain a tablet core. The tablet core is then coated with a film-coating aqueous solution / suspension to prepare a tablet.
[0183] Table 6 Tablet Prescriptions
[0184] Tolebrutinib amorphous, tolebrutinib Form 1, and tolebrutinib Form 2 maintained their crystal forms before and after formulation and manufacturing processes. XRPD comparison images are shown below. Figure 23 , Figure 24 and Figure 25 As shown.
[0185] Example 8: Preparation of Capsules According to the prescription in Table 7, the components of each prescription are sieved and mixed, and then filled into hard gelatin capsules to prepare the capsules.
[0186] Table 7 Capsule Prescription
[0187] Example 9: Stability of tolebrutinib amorphous form, tolebrutinib Form 1, and tolebrutinib Form 2 in tablets The prepared amorphous tablets, Form 1 tablets, and Form 2 tablets were placed at 25℃ / 60%RH for 14 days, and XRPD was measured before and after placement. The XRPD comparison images before and after placement are shown below. Figure 26 , Figure 27 and Figure 28 As shown.
[0188] The results showed that amorphous tablets, Form 1 tablets, and Form 2 tablets remained stable for at least 14 days at 25°C / 60%RH.
[0189] 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. The structural formula of tolebrutinib is shown below, representing an amorphous solid form. Its features are, The amorphous XRPD pattern is basically shown in Figure 1.
2. The amorphous solid form of tolebrutinib according to claim 1, characterized in that, The amorphous FT-IR spectrum was at 1703±2 cm⁻¹. -1 1440±2 cm -1 788 cm -1 and 753±2 cm -1 There is a musical band here.
3. The method for preparing tolebrutinib in amorphous solid form according to claim 1 or 2, characterized in that, The preparation method is selected from any one of the following methods: 1) Dissolve tolebrutinib in a good solvent, then add an anti-solvent, stir, precipitate the solid, separate, and dry; The good solvent is one of dimethyl sulfoxide and toluene or a mixture thereof; the antisolvent is selected from one of water and diethyl ether or a mixture thereof.
4. Preferably, the good solvent is dimethyl sulfoxide; the antisolvent is water; Preferably, the volume ratio of the good solvent to the antisolvent is 10:1 to 1:10, more preferably 1:1; 2) Dissolve tolebrutinib in solvent 6 at high temperature, filter, stir at low temperature, separate, and dry; Wherein, solvent 6 is selected from one or more of the following mixed solvents: trifluoroethanol / water, isopropyl acetate / water, tetrahydrofuran / water, 1,4-dioxane / water, acetonitrile / water, and chloroform / water; Preferably, solvent 6 is a mixture of trifluoroethanol and water; Preferably, the high temperature is 40-80℃; Preferably, the low temperature is ≤10℃.
5. A pharmaceutical composition comprising an amorphous solid form of tolebrutinib as described in claim 1 or 2, and at least one pharmaceutically acceptable carrier.
6. Use of the tolebrutinib amorphous solid form as described in claim 1 or 2, or the pharmaceutical composition as described in claim 4, in the preparation of a medicament for treating BTK-mediated diseases.
7. Use of tolebrutinib in an amorphous solid form as described in claim 1 or 2, or the pharmaceutical composition as described in claim 4, in the preparation of a medicament for treating cancer, autoimmune diseases, inflammatory diseases, and thromboembolic diseases.
8. The use of tolebrutinib in an amorphous solid form as described in claim 1 or 2, or in combination with other pharmaceutical products as described in claim 4.