Ibrutinib monolauryl sulfate, preparation method and application

Abstract

The invention discloses an ibrutinib monolaurinol sulfate crystal compound, a preparation method and application, the structural formula of the ibrutinib monolaurinol sulfate crystal compound is shown as a formula II, the ibrutinib monolaurinol sulfate crystal compound is a crystal compound or an amorphous compound, and the crystal compound exists in an anhydrous and solvent-free form. According to the crystal compound, good druggability of the ibrutinib is ensured, the bioavailability of oral absorption is remarkably improved, and meanwhile, the difference between preprandial and postprandial of the ibrutinib is reduced, so that gastrointestinal reaction and potential toxic and side effects can be reduced.

Description

Technical Field

[0001] This invention relates to the field of ibrutinib medicinal chemistry, specifically to an ibrutinib monolaurate sulfate, its preparation method, and its application. Background Technology

[0002] Ibrutinib, also known as ibrutinib, is the first small-molecule BTK (Bruton's tyrosine kinase) inhibitor. BTK is expressed at the pre-B cell to mature B cell stages of B lymphocytes. It can regulate B cell development and differentiation by activating positive cell cycle regulators and differentiation factors, and simultaneously regulate B cell survival and proliferation by modulating the expression of pro-apoptotic and anti-apoptotic proteins. BTK is a potential therapeutic target for B cell-related malignancies, including chronic lymphocytic leukemia (CLL), non-Hodgkin's lymphoma (NHL), and mantle cell lymphoma (MCL). Furthermore, BTK inhibitors hold promise as the first disease-modifying therapy targeting the origin of brain injury in multiple sclerosis (MS) patients with brain penetration and selectivity; and as a drug for the treatment of systemic lupus erythematosus (SLE).

[0003] Ibrutinib was developed and manufactured by Catalent CTS LLC / Johnson & Johnson / AbbVie. It was approved by the US FDA in 2013, the European EMA in 2014, the Japanese PMDA in 2016, and the China CFDA in 2017. It was also included in the National Reimbursement Drug List (NRDL) under the brand name [Brand Name Missing]. The chemical name is: 1-{(3R)-3-[4-amino-3-(4-phenoxyphenol)-1H-pyrazol[3,4-d]pyrimidin-1-yl]piperidin-1-yl}prop-2-en-1-one, and the molecular formula is: C 25 H 24 N6O2, structural formula (Ⅰ) is as follows:

[0004]

[0005] Ibrutinib forms a covalent bond with cysteine ​​residues at the active site of BTK, thereby inhibiting the enzymatic activity of BTK. BTK is a signaling molecule in the B cell antigen receptor (BCR) 41 / 45 and cytokine receptor pathways. BTK activates pathways essential for B cell migration, chemotaxis, and adhesion via B cell surface receptor signaling. Non-clinical studies have shown that ibrutinib inhibits the in vivo proliferation and survival of malignant B cells, as well as in vitro cell migration and basal adhesion.

[0006] Clinically, ibrutinib has shown good efficacy against various malignant tumors. However, ibrutinib is a drug with low solubility and high permeability, belonging to BCS class II, and is almost insoluble in water. The original manufacturer used micronization of the ibrutinib API and added the surfactant sodium dodecyl sulfate to increase the drug's solubility, thereby improving the bioavailability of ibrutinib capsules and tablets. However, the effect was not ideal; the absolute bioavailability of ibrutinib taken orally in an empty stomach was only 2.9%, while absorption doubled after eating.

[0007] Therefore, ibrutinib is used in clinical practice at relatively high single-dose doses. For example, the dose for treating mantle cell lymphoma and marginal zone lymphoma is 560 mg once daily; for treating chronic lymphocytic leukemia and small lymphocytic lymphoma, the dose is 420 mg once daily until disease progression or intolerable toxicity. The higher doses lead to a higher incidence of gastrointestinal adverse reactions (constipation, abdominal pain, diarrhea, nausea, vomiting, etc.). Diarrhea is the most common adverse reaction associated with ibrutinib. The RESONATE phase III study showed that at 9 months follow-up, the overall incidence of diarrhea was 47.7%, and the incidence of grade ≥3 diarrhea was 4.1%. Other common side effects of ibrutinib include bleeding, infection, myelosuppression, nephrotoxicity, second primary malignancy, and embryo-fetal toxicity. The ibrutinib package insert clearly states that 5% of patients with mantle cell lymphoma experience grade 3 or higher bleeding events (subdural hematoma, gastrointestinal bleeding, and hematuria). For these patients, severe side effects not only significantly impact their quality of life but may also affect their confidence in and choice of treatment, thus affecting the overall prognosis of the disease. Statistics show that approximately 20% of patients have to discontinue treatment due to these side effects. Therefore, improving the bioavailability of ibrutinib in clinical practice helps to reduce gastrointestinal adverse reactions and toxic side effects, thereby improving patient adherence.

[0008] To address this, researchers have attempted to improve the bioavailability of formulations through multiple approaches. These include modifying the API (pipeline), such as preparing specific crystal forms of ibrutinib salts and special cocrystal compounds; preparing special dosage forms, such as soft capsules, emulsions, enteric-coated formulations, nano-formulations; and improving excipient formulations or processes. These efforts have yielded some improvements. For example, WO2013184572A1 discloses the pharmaceutical crystal form A of ibrutinib, along with amorphous, crystal forms B, C, D, and F, as well as pharmaceutically acceptable salt forms. CN109776543A discloses a new crystal form obtained by salting ibrutinib with HCl, HBr, or benzoic acid. CN113135917A and CN105622614B disclose corresponding amorphous ibrutinib formulations. WO2016079216A1 discloses an amorphous form of ibrutinib and its solvate crystal forms with anisole, chlorobenzene, 1,4-dioxane, and pyridine, respectively. However, modified APIs or formulations still suffer from factors such as the introduction of new impurities, decreased long-term quality stability, and difficulties in commercial production. Therefore, it is necessary to develop a modified formulation that is stable in quality, cost-controllable, easy to commercialize, and has better efficacy.

[0009] Meanwhile, in terms of formulation innovation, inventors have developed various solutions to increase the bioavailability of formulations, such as optimizing formulations and processes, and using other dosage forms. They have explored different dosage form approaches to improve bioavailability. CN114681459B discloses an ibrutinib pharmaceutical composition, its preparation method, and its application. CN109010844B discloses an ibrutinib phospholipid complex and its preparation method. CN113440481B discloses a preparation method and use of an ibrutinib self-microemulsion composition. CN111973570B discloses an ibrutinib nanocomposite modified with sialic acid derivatives and its preparation method. However, even with improvements in new formulations, processes, and dosage forms, problems such as the introduction of new impurities, high long-term stability risks, or difficulties in commercialization still exist. Therefore, it is necessary to develop a solid dosage form that can improve bioavailability, reduce the instability risks caused by component compatibility, ensure quality stability, and facilitate commercial scale-up.

[0010] Therefore, this patent application is filed. Summary of the Invention

[0011] The purpose of this invention is to provide ibrutinib monolaurate sulfate, as well as its preparation method and application, to solve the technical problems of low bioavailability, poor long-term quality stability, and low commercial feasibility of ibrutinib in the prior art.

[0012] This invention utilizes ibrutinib to form a salt with sodium lauryl sulfate, an excipient in the original formulation, reducing the risks associated with component compatibility. Furthermore, the drug composition of the developed formulation is essentially consistent with the original, lowering the stability risk of the finished product. The significantly improved oral bioavailability allows for a reduction in the total dosage, minimizing gastrointestinal reactions and potential toxic side effects. Moreover, the ibrutinib monolauryl sulfate crystallizer exhibits better drug-like properties, a simpler preparation process, suitability for large-scale production, and stable product quality.

[0013] To achieve the above objectives, the present invention provides the following technical solution:

[0014] The first objective of this invention is to provide ibrutinib monolaurate sulfate.

[0015]

[0016] It is a crystalline compound or an amorphous compound, wherein the crystalline compound exists in an anhydrous and solvent-free form.

[0017] In an optional embodiment, the crystallized compound is subjected to Cu-Kα radiation, and the X-ray diffraction pattern, expressed in 2θ, has characteristic peaks at 5.38±0.2°, 18.66±0.2°, 20.97±0.2°, 21.36±0.2°, 21.62±0.2°, and 22.06±0.2°.

[0018] The amorphous compound, when subjected to Cu-Kα radiation, exhibits no sharp diffraction peaks in its X-ray diffraction pattern represented by 2θ.

[0019] In an optional embodiment, the crystallized compound is subjected to Cu-Kα radiation, and the X-ray diffraction pattern, expressed in 2θ, has characteristic peaks at 5.38±0.2°, 10.39±0.2°, 12.03±0.2°, 13.28±0.2°, 15.76±0.2°, 16.30±0.2°, 18.02±0.2°, 18.66±0.2°, 19.41±0.2°, 20.14±0.2°, 20.97±0.2°, 21.36±0.2°, 21.62±0.2°, 22.06±0.2°, 23.16±0.2°, 26.23±0.2°, and 28.57±0.2°.

[0020] In an optional embodiment, the X-ray diffraction pattern of the crystallizer is as follows: Figure 1As shown, the diffraction angles 2θ are represented at 5.38±0.2°, 10.39±0.2°, 10.74±0.2°, 12.03±0.2°, 12.83±0.2°, 13.28±0.2°, 13.72±0.2°, 15.30±0.2°, 15.76±0.2°, 16.30±0.2°, 16.91±0.2°, 18.02±0.2°, 18.66±0.2°, and 19.41±0.2°. Characteristic peaks are observed at 20.14±0.2°, 20.97±0.2°, 21.36±0.2°, 21.62±0.2°, 22.06±0.2°, 22.60±0.2°, 23.16±0.2°, 24.25±0.2°, 25.25±0.2°, 26.23±0.2°, 27.11±0.2°, and 28.57±0.2°, with the characteristic peak at 21.0±0.2° having a relative intensity of 100%.

[0021] Specifically, the X-ray powder diffraction (PXRD) pattern, expressed in 2θ angles, shows characteristic peaks and relative intensities at the following locations:

[0022]

[0023]

[0024] The X-ray diffraction pattern of the amorphous compound is as follows: Figure 6 or Figure 7 As shown, there is no obvious peak shape. The XRPD spectra of the solids obtained by different preparation methods are different, and they are respectively denoted as amorphous compound I. Figure 6 ), amorphous compound II ( Figure 7 ).

[0025] In an optional embodiment, the differential scanning calorimetry (DSC) curve of the crystallizer shows a characteristic endothermic peak at 74–101 °C and a characteristic exothermic peak at 146–169 °C; the thermogravimetric analysis (TGA) curve of the crystallizer shows a weight loss of 32.9 ± 1.0% at 200–320 °C and a weight loss of 51.9 ± 1.0% at 320–500 °C.

[0026] In an optional embodiment, the molar ratio of ibrutinib to monolauryl sulfate is 1:0.5 to 1.5, preferably 1:0.9 to 1.1, and more preferably 1:1.

[0027] A second objective of this invention is to provide a method for preparing ibrutinib monolaurate sulfate, wherein the preparation process of the crystalline compound includes:

[0028] Obtain ibrutinib monolaurate sulfate;

[0029] Ibrutinib monolaurate sulfate is dissolved in a first good solvent. After complete dissolution, a first non-good solvent is added, and the mixture is filtered and crystallized to obtain the product.

[0030] The preparation process of the amorphous compound includes:

[0031] Ibrutinib monolaurate sulfate was dissolved in a second good solvent, then mixed with water and filtered. The filter cake was dried to obtain a solvent-free or corresponding solvate amorphous solid.

[0032] The first and second good solvents are organic solvents with high solubility for ibrutinib monolauryl sulfate, and the non-good solvents are organic solvents or water that are almost insoluble in ibrutinib monolauryl sulfate.

[0033] In an optional embodiment, during the preparation of the crystallized compound, the mass-to-volume ratio of ibrutinib monolaurate sulfate to the first good solvent is 1:0.5 to 20; the volume ratio of the first good solvent to the non-good solvent is 1:0.5 to 20; wherein the mass is in g and the volume is in ml.

[0034] Better still, in the preparation of the crystallized compound, ibrutinib monolauryl sulfate is added to the first good solvent, heated appropriately to dissolve and then filtered. The first non-good solvent is added dropwise to the filtrate, the temperature is slowly lowered to 0-35℃, and the mixture is stirred to crystallize, thus obtaining the high-purity ibrutinib monolauryl sulfate crystal form.

[0035] Alternatively, ibrutinib monolauryl sulfate is dissolved in a second good solvent, then thoroughly mixed with water and filtered. The filter cake is dried to obtain a solvent-free or corresponding solvate amorphous solid. Simultaneously, the amorphous ibrutinib monolauryl sulfate can be mixed with pharmaceutically acceptable functional excipients during formulation, for example, after wet granulation and drying to obtain the corresponding intermediate solid, in which ibrutinib monolauryl sulfate may exist in an amorphous form.

[0036] Preferably, the first good solvent is any one or a mixture of two or more of acetonitrile, ethyl acetate, propyl acetate, butyl acetate, n-butanol, isopropanol, ethanol, methanol, acetone, and butanone;

[0037] The first non-good solvent is any one or a mixture of two or more of cyclohexane, n-hexane, n-heptane, and methyl tert-butyl ether;

[0038] Preferably, the second good solvent is any one or a mixture of two or more solvents selected from methanol, ethanol, isopropanol, acetone, butanone, isobutyl ketone, tetrahydrofuran, N-methylpyrrolidone, pyridine, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, etc.

[0039] The third objective of this invention is to provide ibrutinib monolaurate sulfate, obtained by any of the above-described methods or by any of the above-described methods, as an active ingredient for the preparation of anticancer drugs to treat the same indications as ibrutinib.

[0040] Preferably, the indications for the anticancer drugs include: chronic graft-versus-host disease (cGVHD), chronic lymphocytic leukemia, acute B-lymphocytic leukemia, B-lymphocytic tumors, central nervous system tumors, hairy cell leukemia, lymphoma, non-Hodgkin's lymphoma (NHL), metastatic colon cancer, metastatic renal cell carcinoma, metastatic gastric cancer, primary mediastinal large B-cell lymphoma, follicular center lymphoma, prostate tumors, acute respiratory distress syndrome, T-cell lymphoma, transitional lymphoma, lymphoplasmacytic lymphoma, mantle cell lymphoma, marginal zone B-cell lymphoma, etc.

[0041] A fourth object of the present invention is to provide a pharmaceutical composition or pharmaceutical preparation comprising ibrutinib monolaurate sulfate as described in any of the preceding claims or prepared by any of the preceding claims, and pharmaceutically acceptable excipients, wherein the excipients are at least one of a carrier, an excipient, and a diluent, and the pharmaceutical preparation is any one of a hard capsule, a soft capsule, a tablet, a pill, a powder, a granule, or a suspension.

[0042] Specifically, the composition or dosage form of ibrutinib monolaurate sulfate and at least one pharmaceutically acceptable excipient provided by the present invention is preferably administered orally to an individual.

[0043] This invention further covers methods for reducing the total daily oral dose of ibrutinib. More specifically, this invention covers the oral administration of compositions and / or dosage forms prepared according to this invention, wherein the total daily dose of ibrutinib is reduced by more than 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% compared to the currently approved total daily dose by the U.S. Food and Drug Administration (FDA), thereby reducing the resulting side effects and improving patient adherence.

[0044] In one embodiment of the invention, the composition and / or dosage form for oral administration is a hard capsule, tablet, or suspension comprising ibrutinib monolauryl sulfate and at least one additional component of a pharmaceutically acceptable carrier, diluent, and excipient. In some aspects of this embodiment, the hard or soft capsule may be a gelatin-based or non-gelatin-based capsule. In some embodiment schemes, the pharmaceutical composition comprises crystalline ibrutinib monolauryl sulfate. In some embodiments, the pharmaceutical composition comprises amorphous ibrutinib monolauryl sulfate.

[0045] In an optional embodiment, the diluent includes, but is not limited to, any one or a combination of two or more of the following: lactose, sucrose, dextrose, glucose binder, maltodextrin, mannitol, xylitol, sorbitol, cyclodextrin, calcium phosphate, calcium sulfate, starch, modified starch, microcrystalline cellulose, microcellulose, and talc.

[0046] The excipients include disintegrants and / or lubricants, wherein the disintegrants include, but are not limited to, any one or a combination of two or more of the following: natural starch, pregelatinized starch, sodium starch, methyl crystalline cellulose, methyl cellulose, cross-linked carboxymethyl cellulose, sodium cross-linked carboxymethyl cellulose, cross-linked carboxymethyl cellulose, cross-linked starch such as sodium glycolate starch, cross-linked polymers such as crosspovidone, cross-linked polyvinylpyrrolidone, sodium alginate, clay, and gum.

[0047] The lubricant includes, but is not limited to, any one or a combination of two or more of the following: calcium hydroxide, talc, corn starch, sodium stearoyl fumarate, stearic acid, sodium stearate, magnesium stearate, zinc stearate, and wax.

[0048] The advantages and beneficial effects of this invention include, but are not limited to:

[0049] (1) The present invention provides a compound containing ibrutinib monolauryl sulfate, wherein the active substance solid is a crystalline compound, which is easy to process into a drug and is conducive to the long-term quality stability of the finished product.

[0050] (2) The present invention provides an ibrutinib monolaurate sulfate compound, which greatly improves the bioavailability of ibrutinib, reduces the total daily intake, and achieves the same effect as the original drug; thereby reducing gastrointestinal and other side effects caused by patients after taking it.

[0051] (3) The present invention provides a compound containing ibrutinib monolauryl sulfate, and the obtained composition is a hard capsule or tablet containing ibrutinib monolauryl sulfate. The obtained composition is rapidly absorbed, which is conducive to the rapid exertion of the drug effect.

[0052] (4) The preparation method of ibrutinib monolauryl sulfate compound provided by the present invention is simple. Attached Figure Description

[0053] To more clearly illustrate the technical solutions of the embodiments of the present invention, the accompanying drawings used in the description of the embodiments will be briefly introduced below. Obviously, the accompanying drawings described below are only some examples of structural verification and testing data of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0054] Figure 1The X-ray powder diffraction pattern of the crystallized compound of Example 1 of the present invention is shown below.

[0055] Figure 2 The crystallized compound of Example 1 of the present invention 1 HNMR spectrum;

[0056] Figure 3 The DSC spectrum of the crystalline compound of Example 1 of the present invention;

[0057] Figure 4 The TGA spectrum of the crystalline compound of Example 1 of this invention;

[0058] Figure 5 The FTIR spectrum of the crystalline compound of Example 1 of this invention;

[0059] Figure 6 This is the X-ray powder diffraction pattern of the amorphous compound I of the present invention;

[0060] Figure 7 This is the X-ray powder diffraction pattern of the amorphous compound II of the present invention;

[0061] Figure 8 The TGA spectrum of the amorphous I compound of this invention;

[0062] Figure 9 This is the DSC spectrum of the amorphous I compound of the present invention;

[0063] Figure 10 The TGA spectrum of the amorphous compound II of this invention;

[0064] Figure 11 This is the DSC spectrum of the amorphous compound II of the present invention. Detailed Implementation

[0065] The embodiments of this application will be described in further detail below with reference to the examples. The detailed description of the following embodiments is used to illustrate the principles of this application, but should not be used to limit the scope of this application, that is, this application is not limited to the described embodiments.

[0066] The "range" disclosed in this application is defined by a lower limit and an upper limit. A given range is defined by selecting a lower limit and an upper limit, which define the boundaries of a particular range. Ranges defined in this way can include or exclude endpoints and can be arbitrarily combined; that is, any lower limit can be combined with any upper limit to form a range. For example, if ranges of 60–120 and 80–110 are listed for a specific parameter, it is understood that ranges of 60–110 and 80–120 are also expected. Furthermore, if minimum range values ​​of 1 and 2 are listed, and if maximum range values ​​of 3, 4, and 5 are listed, then the following ranges are all expected: 1–3, 1–4, 1–5, 2–3, 2–4, and 2–5. In this application, unless otherwise stated, the numerical range "a–b" represents a shortened representation of any combination of real numbers between a and b, where a and b are real numbers. For example, the numerical range "0~5" indicates that all real numbers between "0~5" have been listed in this article; "0~5" is simply a shortened representation of these numerical combinations. Furthermore, when a parameter is stated as an integer ≥2, it is equivalent to disclosing that the parameter is, for example, an integer such as 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, etc.

[0067] Unless otherwise specified, all embodiments and optional embodiments of this application can be combined to form new technical solutions.

[0068] Unless otherwise specified, all technical features and optional technical features of this application may be combined to form new technical solutions.

[0069] Unless otherwise specified, all steps in this application may be performed sequentially or randomly, preferably sequentially. For example, the method includes steps (a) and (b), indicating that the method may include steps (a) and (b) performed sequentially, or it may include steps (b) and (a) performed sequentially. For example, the mention that the method may also include step (c) indicates that step (c) may be added to the method in any order. For example, the method may include steps (a), (b), and (c), or it may include steps (a), (c), and (b), or it may include steps (c), (a), and (b), etc.

[0070] Unless otherwise specified, the terms "comprising" and "including" as used in this application can be open-ended or closed-ended. For example, "comprising" and "including" can mean that other components not listed may also be included, or that only the listed components may be included.

[0071] Unless otherwise specified, the term "or" is inclusive in this application. For example, the phrase "A or B" means "A, B, or both A and B". More specifically, the condition "A or B" is satisfied by any of the following conditions: A is true (or exists) and B is false (or does not exist); A is false (or does not exist) and B is true (or exists); or both A and B are true (or exist).

[0072] Unless otherwise specified, in this application, the term "Cmax" refers to the highest blood concentration achieved during the dosing interval.

[0073] Unless otherwise specified, in this application, the term "Tmax" refers to the time to reach the peak plasma concentration (Cmax).

[0074] Unless otherwise specified, in this application, the term "AUC" refers to the area under the drug concentration-time curve calculated using a linear trapezoidal summation over a specific time interval, such as AUC. 0-24 It refers to the area under the drug concentration-time curve from the moment of administration to 24 hours after administration;

[0075] The determination of pharmacokinetic parameters described herein is generally based on methods known and understood by those skilled in the art and commonly documented in publications.

[0076] Unless otherwise defined, the term "effective therapeutic dose" refers to the amount of ibrutinib free base that is effective in treating the disease or condition described herein.

[0077] The technical solutions of the present invention will be clearly and completely described below with reference to the accompanying drawings of the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments.

[0078] I. Crystallized Compounds

[0079] Example 1: Preparation of anhydrous ibrutinib monolaurate sulfate crystals

[0080] (1) Preparation of ibrutinib monolaurate sulfate:

[0081] Weigh 20.0 g of ibrutinib and dissolve it in 2000 ml of 0.1 N dilute hydrochloric acid. Separately, dissolve 13.1 g of sodium lauryl sulfate in 100 ml of 0.1 N dilute hydrochloric acid, and set aside after dissolving each solution. Mix the two solutions thoroughly and let stand for 24 hours. Remove the supernatant, and wash the precipitate with an appropriate amount of deionized water until neutral. Dry at 40°C for 24 hours to obtain ibrutinib monolauryl sulfate precipitate.

[0082] (2) Dissolve 1.0 g of ibrutinib monolaurate sulfate precipitate in 10 ml of acetonitrile at 50 °C. Then, slowly add 60 ml of n-heptane at the same temperature. After mixing thoroughly, cool to 0-5 °C at 0.1 °C / min, maintain the temperature and stir overnight to allow crystallization. Filter the solid and dry at 40 °C to obtain 0.82 g of anhydrous crystals with an HPLC purity of 98.8% and a chiral purity of 98.5%.

[0083] Example 2: Preparation of anhydrous ibrutinib monolaurate sulfate crystals

[0084] (1) Preparation of ibrutinib monolaurate sulfate: Same as in Example 1.

[0085] (2) Dissolve 1.0 g of ibrutinib monolaurate sulfate precipitate in 10 ml of acetonitrile at 50 °C. At this temperature, slowly add 80 ml of methyl tert-butyl ether. After mixing thoroughly, cool to 0-5 °C at 0.1 °C / min, maintain the temperature, and continue stirring to allow crystallization. Filter the solid and dry at 40 °C to obtain 0.75 g of anhydrous crystals with an HPLC purity of 99.3% and a chiral purity of 99.0%.

[0086] Example 3: Preparation of anhydrous ibrutinib monolaurate sulfate crystals

[0087] (1) Preparation of ibrutinib monolaurate sulfate: Same as in Example 1.

[0088] (2) Dissolve 1.0 g of ibrutinib monolaurate sulfate precipitate in 8 ml of n-butanol at 50 °C. Then, slowly add 90 ml of methyl tert-butyl ether at the same temperature. After mixing thoroughly, cool to 0-5 °C at 0.1 °C / min, maintain the temperature, and continue stirring to allow crystals to crystallize. Filter the solid and dry at 40 °C to obtain 0.68 g of anhydrous crystals with an HPLC purity of 99.9% and a chiral purity of 99.5%.

[0089] Example 4: Preparation of anhydrous ibrutinib monolaurate sulfate crystals

[0090] (1) Preparation of ibrutinib monolaurate sulfate: Same as in Example 1.

[0091] (2) Dissolve 1.0 g of ibrutinib monolaurate sulfate precipitate in 10 ml of butanone at 50 °C by heating. Then, slowly add 100 ml of n-heptane at this temperature. After mixing thoroughly, cool to 0-5 °C at 0.1 °C / min, maintain the temperature, and continue stirring to allow crystals to crystallize. Filter the solid and dry at 40 °C to obtain 0.91 g of anhydrous crystals with an HPLC purity of 99.1% and a chiral purity of 98.8%.

[0092] II. Amorphous Compounds

[0093] Example 5: Preparation of amorphous ibrutinib monolaurate sulfate

[0094] (1) Preparation of ibrutinib monolaurate sulfate: Same as in Example 1.

[0095] (2) Dissolve 1.0 g of ibrutinib monolaurate sulfate precipitate in 5 ml of ethanol by heating, and slowly add 30 ml of deionized water. After mixing thoroughly, let stand, cool to 0-5 °C at 0.1 °C / min, and keep warm overnight. Filter the solid and dry at 40 °C to collect 0.93 g of amorphous compound with HPLC purity of 98.1% and chiral purity of 98.5%. This is designated as amorphous compound I.

[0096] Example 6: Preparation of amorphous ibrutinib monolaurate sulfate

[0097] (1) Preparation of ibrutinib monolaurate sulfate: Same as in Example 1.

[0098] (2) Dissolve 1.0 g of ibrutinib monolaurate sulfate precipitate in 4 ml of 1,4-dioxane by heating, and slowly add 32 ml of deionized water. After mixing thoroughly, let stand, cool to 0-5 °C at 0.1 °C / min, and keep warm overnight. Filter the solid and dry at 40 °C to collect 0.91 g of the amorphous compound, with an HPLC purity of 97.9% and a chiral purity of 98.5%. This is designated as amorphous compound II.

[0099] Example 7: Preparation of amorphous ibrutinib monolaurate sulfate

[0100] (1) Preparation of ibrutinib monolaurate sulfate: Same as in Example 1.

[0101] (2) Dissolve 1.0 g of ibrutinib monolaurate sulfate precipitate in 3 ml of N,N-dimethylformamide, and slowly add 36 ml of deionized water. After mixing thoroughly, let stand and cool to 0-5 °C at 0.1 °C / min, and keep warm overnight. Filter the solid and dry at 40 °C to collect 0.81 g of amorphous compound with HPLC purity of 98.4% and chiral purity of 98.6%.

[0102] III. Measurement

[0103] 1. Crystalline compounds

[0104] (1) X-ray powder diffraction (XRPD)

[0105] Test conditions: X-ray powder diffraction patterns were acquired using a PANalytical (model: EMPYREAN) diffractometer. Cu Kα rays Voltage: 40kV, Current: 1mA, Step size: 0.01°, Scan rate: 20° / min, Scan range: 5.0~40.0°. Take 10-20mg of sample and spread it evenly in the center of the single crystal silicon sample plate. Press the sample to keep its surface flat and its thickness uniform before testing.

[0106] The anhydrous crystals obtained in Example 1 were measured. Figure 1 X-ray powder diffraction of the anhydrous crystalline compound of Example 1 is shown. Characteristic peaks include 5.4±0.2°, 10.4±0.2°, 12.0±0.2°, 13.3±0.2°, 15.8±0.2°, 16.3±0.2°, 18.0±0.2°, 18.6±0.2°, 19.4±0.2°, 20.1±0.2°, 21.0±0.2°, 21.4±0.2°, 21.6±0.2°, 22.0±0.2°, 23.2±0.2°, 26.2±0.2°, and 28.6±0.2°. The relative intensity of the characteristic peak at 21.0±0.2° is 100%.

[0107] Specifically, the X-ray powder diffraction (PXRD) patterns expressed in 2θ angles show characteristic peaks and their relative intensities at the following locations, as shown in Table 1:

[0108] Table 1

[0109]

[0110]

[0111] The X-ray powder diffraction patterns of the anhydrous crystals obtained in Examples 2-4 are similar to those in Example 1, and will not be described here.

[0112] (2) 1 HNMR test

[0113] The anhydrous crystallized compound obtained in Example 1 was subjected to 1H NMR spectroscopy, and the results are as follows: Figure 2 As shown in the figure, the hydrogen ratio of the corresponding molecule is basically consistent with the theory, and the molecular formula is C. 25 H 24 N6O2·C 12 H 26 O4S.

[0114] (3) Fourier Transform-Infrared (FTIR)

[0115] Test conditions: Instrument: Bruker Vertex 70 Fourier transform infrared spectrometer. A suitable amount of dried sample and dried potassium bromide were ground evenly. Using a Specac GS01190 tablet press and mold, tablets were formed under a pressure of 1.0t for 30s. Wavelength range: 4000–500cm. -1 Resolution: 0.2cm -1 .

[0116] Figure 5 The infrared spectrum of the anhydrous crystallizer obtained in Example 1 is shown. Figure 5 Among the observed characteristic peaks, one is 2921 cm⁻¹. -1 2852cm -1 1612cm -1 1587cm -1 1519cm -1 1488cm -1 1442cm -1 1230cm -1 1166cm -1 971cm -1 854cm -1 and 586cm -1 The results showed that the structure (Ⅱ) was prepared in Example 1.

[0117] (4) Differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA)

[0118] Instrument model: Mettler Toledo TGA / DSC2 differential calorimeter, sample weight: 5-10 mg, crucible material: Al, atmosphere: N2, heating rate: 10℃ / min, test temperature range: 30℃ to decomposition temperature.

[0119] Figure 3 and Figure 4 DSC and TGA thermograms of the crystallized compound from Example 1 are shown. No weight loss was observed, confirming that the material is anhydrous.

[0120] Based on the above tests, it is proven that the anhydrous ibrutinib monolaurate sulfate crystalline compound was obtained according to the preparation method of the present invention.

[0121] (5) Determination of chemical purity

[0122] Instrument model: SHIMADZU LC-2030C 3D; Column: Gemini-NX C18 column (4.6mm × 150mm, 3μm); UV detection wavelength for REG: 260nm; Mobile phase composition: two-phase gradient elution of 0.1% trifluoroacetic acid acetonitrile and 0.1% trifluoroacetic acid aqueous solution; Column temperature required for detection: 40℃; Flow rate for detection: 1.5mL / min; Injection volume per sample: 100μL. Results are shown in the respective examples.

[0123] (6) Determination of chiral purity

[0124] Instrument model: SHIMADZU LC-2030C 3D; Column: Lux Cellulose-1 hand column (4.6mm×250mm, 5μm); UV detection wavelength for REG: 260nm; Mobile phase composition: 20% isopropanol, 80% n-hexane; Column temperature required for detection: room temperature; Flow rate for detection: 1.0mL / min; Injection volume per injection: 100μL.

[0125] The content of the R enantiomer was determined by normalizing the peak area of ​​the enantiomer peak and expressed as a weight / weight percentage. In some embodiments, the ibrutinib sample contained less than 5.0%, less than 4.0%, less than 3.0%, less than 2.0%, or less than 1.0% of the (S)-isomer. This indicates that the crystallization process of the crystalline compound in the embodiments of the present invention is conducive to reducing the S-isomer content.

[0126] 2. Amorphous compounds

[0127] X-ray powder diffraction (XRPD): The products obtained in Examples 5 and 6 were measured separately, such as... Figure 6 , Figure 7 As shown in the image. Figure 6 , 7 None of them have obvious characteristic peak shapes. They are amorphous.

[0128] Differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA): The products obtained in Examples 5 and 6 were measured respectively. The TGA and DSC thermograms of the amorphous I compounds are shown below. Figure 8 , 9 As shown in the figure, the TGA and DSC thermograms of the amorphous compound are as follows: Figure 10 , 11 As shown in the figure. The data indicate that the amorphous compounds have relatively lower melting points and more complex phase transitions during heating; suggesting that they are slightly less stable than the crystalline compounds.

[0129] Chemical purity determination:

[0130] Instrument model: SHIMADZU LC-2030C 3D; Column: Gemini-NX C18 column (4.6mm×150mm, 3μm); UV detection wavelength for REG: 260nm; Mobile phase composition: two-phase gradient elution of 0.1% trifluoroacetic acid acetonitrile and 0.1% trifluoroacetic acid aqueous solution; Column temperature required for detection: 40℃; Flow rate for detection: 1.5mL / min; Injection volume per injection: 100μL.

[0131] The results are shown in the various embodiments.

[0132] IV. Pharmacokinetic Studies

[0133] Pharmacokinetic study of a composition containing ibrutinib monolaurate sulfate provided by this invention in beagle dogs:

[0134] The formulations of compositions containing ibrutinib monolaurate sulfate are shown in Table 2:

[0135] Table 2

[0136]

[0137]

[0138] Prepare capsules from the above formula by weighing the components shown in the table above, mixing them together, adding them to capsules of appropriate size, and then sealing the capsules.

[0139] Study Objective: To determine the plasma concentration of ibrutinib capsules RF (reference preparation) and ibrutinib monolaurate sulfate crystallized capsules prepared according to this patent application (i.e., Table 1 numbers P1 and P2) in dogs, and to investigate its pharmacokinetic characteristics in dogs.

[0140] Methods: Three beagle dogs were selected and administered a single dose over three cycles. The dogs were fasted for at least 12 hours before each administration, and given approximately 40 ml of water immediately after each capsule administration. They were also kept fasted and deprived of water for 4 hours after administration, with a 14-day cleansing period.

[0141] During each administration cycle, approximately 0.6 mL (0.5–0.7 mL) of whole blood was collected from the canine forelimb vein at 0 h before administration and at 0.5 h, 1 h, 1.5 h, 2 h, 3 h, 4 h, 6 h, 8 h, 10 h, 24 h, and 30 h after administration. The blood was anticoagulated with heparin and centrifuged at 6000 rpm for 5 min at 4°C to obtain plasma, which was temporarily stored at -80°C in the animal testing laboratory. After all samples were collected, they were transported at low temperature to the pharmacokinetics laboratory for storage at -80°C, where drug concentration was measured.

[0142] The LC-MS / MS method established in our laboratory was used to detect the ibrutinib content in the plasma of reference dogs, calculate the main pharmacokinetic parameters, and compare the relative bioavailability of the self-made ibrutinib monolaurate sulfate capsules and the reference capsules in dogs. The test results are shown in Table 3.

[0143] Table 3. Pharmacokinetic data in beagle dogs

[0144]

[0145] Note: Reference RF dog 101 data is not included in the statistics.

[0146] The results in Table 3 show that the two formulations of ibrutinib monolaurate sulfate provided by this invention are capsules (P1 60 mg / dose and P2 90 mg / dose). The Cmax and AUC of the P2 formulation are significantly higher than those of the reference formulation (RF 140 mg / dose). This indicates that the same effect as the reference formulation can be achieved when the total daily intake is reduced. Moreover, it is rapidly absorbed after administration, which is conducive to rapid efficacy and has better pharmacokinetic properties.

[0147] This invention utilizes ibrutinib to form a salt with sodium lauryl sulfate, an excipient in the original formulation, providing a pharmaceutical composition of ibrutinib monolaurate sulfate, its preparation method, and its application. This pharmaceutical composition ensures the stability of the finished formulation to the greatest extent possible while significantly improving the bioavailability of oral absorption. Theoretically, it also helps reduce the difference in ibrutinib dosage before and after meals. Due to the significantly reduced dosage, gastrointestinal reactions and potential toxic side effects can be reduced. The ibrutinib monolaurate sulfate crystallizer exhibits better drug-like properties, and the preparation process of this composition is simple, suitable for large-scale production, and produces stable product quality.

[0148] It will be apparent to those skilled in the art that the present invention is not limited to the details of the exemplary embodiments described above, and that the invention can be implemented in other specific forms without departing from the spirit or essential characteristics of the invention. Therefore, the embodiments should be considered exemplary and non-limiting in all respects, and the scope of the invention is defined by the appended claims rather than the foregoing description. Thus, all variations falling within the meaning and scope of equivalents of the claims are intended to be included within the present invention. No reference numerals in the claims should be construed as limiting the scope of the claims. The above detailed embodiments further illustrate the purpose, technical solution, and beneficial effects of the present invention. It should be understood that the above are merely specific embodiments of the present invention and are not intended to limit the scope of protection of the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. An ibrutinib monolaurate sulfate, characterized in that, Its structural formula is shown in Formula II: It is a crystalline compound or an amorphous compound, wherein the crystalline compound exists in an anhydrous and solvent-free form.

2. The ibrutinib monolaurate sulfate according to claim 1, characterized in that, The crystallized compound, when subjected to Cu-Kα radiation, exhibits characteristic peaks in its X-ray diffraction pattern (denoted as 2θ) at 5.38±0.2°, 18.66±0.2°, 20.97±0.2°, 21.36±0.2°, 21.62±0.2°, and 22.06±0.2°. The amorphous compound, when subjected to Cu-Kα radiation, exhibits no sharp diffraction peaks in its X-ray diffraction pattern represented by 2θ.

3. The ibrutinib monolaurate sulfate crystal compound according to claim 1, characterized in that, The crystalline compound, when subjected to Cu-Kα radiation, exhibits characteristic peaks in its 2θ X-ray diffraction pattern at 5.38±0.2°, 10.39±0.2°, 12.03±0.2°, 13.28±0.2°, 15.76±0.2°, 16.30±0.2°, 18.02±0.2°, 18.66±0.2°, 19.41±0.2°, 20.14±0.2°, 20.97±0.2°, 21.36±0.2°, 21.62±0.2°, 22.06±0.2°, 23.16±0.2°, 26.23±0.2°, and 28.57±0.2°.

4. The ibrutinib monolaurate sulfate crystal compound according to claim 1, characterized in that, The X-ray diffraction pattern of the crystallized compound is shown in Figure 1; The X-ray diffraction pattern of the amorphous compound is shown in Figure 6 or Figure 7.

5. An ibrutinib monolaurate sulfate according to claim 1, characterized in that, The differential scanning calorimetry (DSC) curve of the crystallizer shows a characteristic endothermic peak at 74–101 °C and a characteristic exothermic peak at 146–169 °C. The thermogravimetric analysis (TGA) curve of the crystallizer shows a weight loss of 32.9 ± 1.0% at 200–320 °C and a weight loss of 51.9 ± 1.0% at 320–500 °C.

6. The ibrutinib monolaurate sulfate according to claim 1, characterized in that, For the crystalline compound, the molar ratio of ibrutinib to monolauryl sulfate is 1:0.5 to 1.5, preferably 1:0.9 to 1.1; more preferably 1:

1.

7. The method for preparing ibrutinib monolaurate sulfate according to claim 1, characterized in that, The preparation process of the crystallized compound includes: Obtain ibrutinib monolaurate sulfate; Ibrutinib monolaurate sulfate is dissolved in a first good solvent. After complete dissolution, a first non-good solvent is added, and the mixture is filtered and crystallized to obtain the product. The preparation process of the amorphous compound includes: Ibrutinib monolaurate sulfate was dissolved in a second good solvent, then mixed with water and filtered. The filter cake was dried to obtain a solvent-free or corresponding solvate amorphous solid.

8. The method for preparing ibrutinib monolaurate sulfate according to claim 7, characterized in that, In the preparation of the crystallized compound, the mass-to-volume ratio of ibrutinib monolaurate sulfate to the first good solvent is 1:0.5-20; the volume ratio of the first good solvent to the non-good solvent is 1:0.5-20; where mass is expressed in g and volume in ml. Preferably, the first good solvent is any one or a mixture of two or more of acetonitrile, ethyl acetate, propyl acetate, butyl acetate, n-butanol, isopropanol, ethanol, methanol, acetone, and butanone; The first non-good solvent is any one or a mixture of two or more of cyclohexane, n-hexane, n-heptane, and methyl tert-butyl ether; Preferably, the second good solvent is any one or a mixture of two or more solvents selected from methanol, ethanol, isopropanol, acetone, butanone, isobutyl ketone, tetrahydrofuran, N-methylpyrrolidone, pyridine, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, etc.

9. Ibrutinib monolaurate sulfate, obtained according to any one of claims 1 to 6 or by the preparation method according to any one of claims 7 to 8, is used as an active ingredient in the preparation of an anticancer drug for the treatment of the same indications as ibrutinib; Preferably, the indications for anticancer drugs include: Chronic graft-versus-host disease (cGVHD), chronic lymphocytic leukemia, acute B-lymphocytic leukemia, B-lymphocytic tumor, central nervous system tumors, hairy cell leukemia, lymphoma, non-Hodgkin's lymphoma (NHL), metastatic colon cancer, metastatic renal cell carcinoma, metastatic gastric cancer, primary mediastinal large B-cell lymphoma, follicular center lymphoma, prostate tumors, acute respiratory distress syndrome, T-cell lymphoma, transitional lymphoma, lymphoplasmacytic lymphoma, mantle cell lymphoma, marginal zone B-cell lymphoma.

10. A pharmaceutical composition or pharmaceutical preparation, characterized in that, The pharmaceutical preparation comprises ibrutinib monolaurate sulfate as described in any one of claims 1 to 6, or prepared by any one of claims 7 to 8, and pharmaceutically acceptable excipients, wherein the excipients are at least one of carriers, excipients, and diluents, and the pharmaceutical preparation is any one of hard capsules, soft capsules, tablets, pills, powders, granules, and suspensions.

11. A pharmaceutical composition or pharmaceutical preparation according to claim 10, characterized in that, The diluent is selected from any one or a combination of two or more of the following: lactose, sucrose, dextrose, glucose binder, maltodextrin, mannitol, xylitol, sorbitol, cyclodextrin, calcium phosphate, calcium sulfate, starch, modified starch, microcrystalline cellulose, microcellulose, and talc. The excipients include disintegrants and / or lubricants, wherein the disintegrants are selected from any one or a combination of two or more of the following: natural starch, pregelatinized starch, sodium starch, methyl crystalline cellulose, methyl cellulose, cross-linked carboxymethyl cellulose, sodium cross-linked carboxymethyl cellulose, cross-linked carboxymethyl cellulose, cross-linked starch such as sodium glycolate starch, cross-linked polymers such as crosspovidone, cross-linked polyvinylpyrrolidone, sodium alginate, clay, and gum. The lubricant is selected from any one or a combination of two or more of the following: calcium hydroxide, talc, corn starch, sodium stearoyl fumarate, stearic acid, sodium stearate, magnesium stearate, zinc stearate, and wax.

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