Ibrutinib monododecyl sulfate, and preparation method therefor and use thereof

Abstract

Disclosed in the present invention are a crystalline compound of ibrutinib monododecyl sulfate, and a preparation method therefor and the use thereof. The structural formula of the crystalline compound is as represented by formula II. Ibrutinib monododecyl sulfate is a crystalline compound or an amorphous compound, and the crystalline compound is present in an anhydrous and solvent-free form. The crystalline compound ensures a good druggability of ibrutinib and also significantly improves the bioavailability thereof during oral absorption; moreover, the crystalline compound is also conducive to reducing the difference in the effect of ibrutinib before and after meals, thereby reducing gastrointestinal reactions and potential toxicity and side effects.

Description

Ibrutinib monolauryl sulfate, preparation method and application TECHNICAL FIELD

[0001] The present application relates to the field of ibrutinib pharmaceutical chemistry, in particular to ibrutinib monolauryl sulfate, a preparation method and application thereof. BACKGROUND

[0002] Ibrutinib, also known as Ibrutinib, is the first small molecule BTK (Bruton's tyrosine kinase) inhibitor. BTK is expressed in B lymphocytes from pre-B cells to B cell maturation stage, which can regulate the development and differentiation of B cells by activating cell cycle positive regulators and differentiation factors, and regulate the survival and proliferation of B cells by regulating 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) etc.; at the same time, BTK inhibitors are expected to become the first disease-modifying treatment drug with brain penetration and selectivity targeting brain damage in multiple sclerosis (MS) patients; and a drug for the treatment of systemic lupus erythematosus (SLE).

[0003] Ibrutinib is developed and produced by Catalent CTS LLC / Johnson & Johnson / AbbVie, approved for marketing by the US FDA in 2013, approved for marketing by the European EMA in 2014, approved for marketing by the Japanese PMDA in 2016, and approved for marketing by the Chinese CFDA in 2017 and included in the medical insurance class B, with the trade name The chemical name is: 1-{(3R)-3-[4-amino-3-(4-phenoxyphenol)-1H-pyrazole[3,4-d]pyrimidine-1-yl]piperidin-1-yl}prop-2-en-1-one, the molecular formula is: C 25 H 24 N6O2, the structural formula (I) is as follows:

[0004] Ibrutinib forms a covalent bond with the cysteine residue of the active site of BTK, thereby inhibiting the enzyme activity of BTK. BTK is a signal molecule of B cell antigen receptor (BCR) 41 / 45 and cytokine receptor pathway. BTK activates the pathway necessary for B cell migration, chemotaxis and adhesion through B cell surface receptor signal. Non-clinical research results show that ibrutinib inhibits the in vivo proliferation and survival of malignant B cells and in vitro cell migration and basal adhesion.

[0005] Ibrutinib has good clinical efficacy on various malignant tumors, but it is a drug with low solubility and high permeability, belonging to BCS II, almost insoluble in water. The original research company adopts micronization treatment of ibrutinib API, and adds surfactant sodium dodecyl sulfate to increase the solubility of the drug, so as to improve the bioavailability of ibrutinib capsules and tablets. However, the effect is not very ideal, and the absolute bioavailability of patients in the fasting state is only 2.9%, and the absorption in the fed state doubles.

[0006] Therefore, the single dose of ibrutinib in clinical practice is large, for example, the dosage for treating mantle cell lymphoma and marginal zone lymphoma is 560 mg, once a day; for treating chronic lymphocytic leukemia and small lymphocytic lymphoma, the dosage is 420 mg once a day until disease progression or intolerable toxicity. Higher drug dosage leads to a higher incidence of gastrointestinal adverse reactions (constipation, abdominal pain, diarrhea, nausea, vomiting, etc.). Among them, diarrhea is the highest incidence of adverse reactions of ibrutinib. The results of phase III study of RESONATE showed that the total incidence of diarrhea was 47.7% at 9 months of follow-up, and the incidence of diarrhea ≥3 was 4.1%. In addition, the common side effects of ibrutinib include: bleeding, infection, myelosuppression, nephrotoxicity, second primary malignancy, embryo-fetal toxicity. The instructions of ibrutinib clearly indicates that 5% of mantle cell lymphoma patients have grade 3 or higher bleeding events (subdural hematoma, gastrointestinal bleeding and hematuria). For these patients, serious side effects not only seriously affect the quality of life, but also may affect the patient's confidence and treatment choice, thereby affecting the prognosis of the overall disease treatment. Statistics show that about 20% of patients have to stop treatment due to these side effects. Therefore, improving the bioavailability of ibrutinib in clinical practice can help to improve gastrointestinal adverse reactions and side effects, thereby improving the patient's medication compliance.

[0007] For this purpose, scientific researchers have tried to improve the bioavailability of the preparation from multiple channels, such as improving the API, including preparing special crystal forms of ibrutinib salt, special co-crystal compounds, etc., preparing special dosage forms, including making soft capsules, emulsions, enteric agents, nano-preparations, or improving the formulation of excipients or the process, etc., and some improvement effects have been achieved. For example, WO2013184572A1 discloses a pharmaceutical crystal form A of ibrutinib, and also discloses amorphous, crystal form B, crystal form C, crystal form D, crystal form and crystal form F, and pharmaceutically acceptable salt forms. CN109776543A discloses a new crystal form of ibrutinib salt with HCl, HBr or benzoic acid, respectively. CN113135917A and CN105622614B disclose corresponding amorphous ibrutinib, respectively. WO2016079216A1 discloses an amorphous ibrutinib and a solvate crystal form formed with anisole, chlorobenzene, 1,4-dioxane, pyridine, respectively. However, the modified API or preparation still has the problems of introducing new impurities, poor long-term quality stability, and difficulty in commercial production, and it is necessary to develop an improved preparation with stable quality, controllable cost, easy commercial production and better efficacy.

[0008] At the same time, in the innovation of the preparation, the inventors have developed various solutions to increase the bioavailability of the preparation, such as optimizing the prescription, process, and using other dosage forms, and exploring different dosage forms to improve the bioavailability. CN114681459B discloses an ibrutinib pharmaceutical composition, a preparation method and application thereof. CN109010844B discloses an ibrutinib phospholipid complex and a preparation method thereof. CN113440481B discloses a preparation method and use of an ibrutinib self-microemulsion composition. CN111973570B discloses a sialic acid derivative modified ibrutinib nano-complex and a preparation method thereof. However, after some new prescriptions, new processes and new dosage forms are improved, there are still problems such as introduction of new impurities, high risk of long-term stability or difficulty in commercialization. Therefore, it is necessary to develop a solid preparation that can improve bioavailability and reduce instability risk due to component compatibility, thereby ensuring stable quality and facilitating commercialization.

[0009] In view of this, the present patent application is proposed. SUMMARY

[0010] The purpose of the present application is to provide an ibrutinib monolaurin sulfate, and a preparation method and application thereof, to solve the technical problems of low bioavailability, poor long-term stability and low commercial feasibility of ibrutinib in the prior art.

[0011] The present application adopts ibrutinib to form a salt with lauryl alcohol sodium sulfate in the auxiliary material in the original preparation, reduces the risk of component compatibility, and the pharmaceutical composition developed in the preparation is basically consistent with the original preparation, thereby reducing the stability risk of the finished preparation. The significant improvement of oral absorption bioavailability can reduce the total amount of administration, reduce gastrointestinal reactions and potential toxic side effects. Moreover, the ibrutinib lauryl alcohol sulfate crystalline compound has better drug property, simple preparation process, suitable for large-scale production, and stable product quality.

[0012] To achieve the above object, the present application provides the following technical solutions.

[0013] The first object of the present application is to provide a ibrutinib lauryl alcohol sulfate,

[0014] which is a crystalline compound or an amorphous compound, wherein the crystalline compound exists in the form of anhydrous and solvent-free.

[0015] In an optional embodiment, the crystalline compound has characteristic peaks at 5.38±0.2°, 18.66±0.2°, 20.97±0.2°, 21.36±0.2°, 21.62±0.2°, 22.06±0.2° in the X-ray diffraction spectrum expressed in 2θ using Cu-Kα radiation.

[0016] The amorphous compound has no sharp diffraction peak in the X-ray diffraction spectrum expressed in 2θ using Cu-Kα radiation.

[0017] In an optional embodiment, the crystalline compound 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°, 28.57±0.2° in the X-ray diffraction spectrum expressed in 2θ using Cu-Kα radiation.

[0018] In an alternative embodiment, the X-ray diffraction spectrum of the crystalline compound is shown in Figure 1, and has characteristic peaks at diffraction angles 2θ of 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°, 19.41±0.2°, 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°, 28.57±0.2°, wherein the relative intensity of the characteristic peak at 21.0±0.2° is 100%.

[0019] Specifically, the X-ray powder diffraction (PXRD) pattern in terms of 2θ angle shows characteristic peaks and relative intensities at the following positions:

[0020] The X-ray diffraction spectrum of the amorphous compound is shown in Figure 6 or Figure 7, and has no obvious peak pattern, and the XRPD patterns of the solids obtained by different preparation methods are different, and are denoted as amorphous I compound (Figure 6) and amorphous II compound (Figure 7), respectively.

[0021] In an alternative embodiment, the differential scanning calorimetry curve of the crystalline compound shows a characteristic endothermic peak at 74-101℃, and a characteristic exothermic peak at 146-169℃; the thermogravimetric analysis curve of the crystalline compound shows a weight loss of 32.9±1.0% at 200-320℃, and a weight loss of 51.9±1.0% at 320-500℃.

[0022] In an alternative embodiment, the molar ratio of ibrutinib to monolaurin sulfate is 1:0.5-1.5, preferably 1:0.9-1.1, and more preferably 1:1.

[0023] The second object of the present application is to provide a preparation method of ibrutinib monolaurin sulfate, and the preparation process of the crystalline compound comprises:

[0024] Obtaining ibrutinib monolaurin sulfate;

[0025] Dissolving ibrutinib monolaurin sulfate in a first good solvent, and adding a first non-good solvent to filter and crystallize after complete dissolution to obtain the crystalline compound.

[0026] The preparation process of the amorphous compound comprises:

[0027] The ibrutinib monolaurate sulfate is dissolved in a second good solvent, and then mixed with water, filtered, and the filter cake is dried to obtain an amorphous solid without solvent or a corresponding solventate;

[0028] The first and second good solvents are organic solvents with high solubility for ibrutinib monolaurate sulfate, and the non-good solvent is an organic solvent or water with almost no solubility for ibrutinib monolaurate sulfate.

[0029] In an optional embodiment, in the preparation process of the crystalline compound, the mass-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; wherein the mass is measured in grams and the volume is measured in milliliters.

[0030] More preferably, in the preparation process of the crystalline compound, after ibrutinib monolaurate sulfate is added to the first good solvent, the solution is dissolved by moderate heating, then filtered, and the first non-good solvent is added dropwise to the filtrate, and slowly cooled to 0-35°C, and then stirred to crystallize to obtain high-purity ibrutinib monolaurate sulfate crystals.

[0031] Alternatively, ibrutinib monolaurate sulfate is dissolved in a second good solvent, then mixed with water, filtered, and the filter cake is dried to obtain an amorphous solid without solvent or a corresponding solventate. In addition, the amorphous ibrutinib monolaurate sulfate can be mixed with a pharmaceutically acceptable functional excipient during the preparation process, such as after the completion of wet granulation, and then dried to obtain the corresponding intermediate solid, at which time the ibrutinib monolaurate sulfate may exist in an amorphous form.

[0032] 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, isopropyl alcohol, ethanol, methanol, acetone, and butanone;

[0033] 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;

[0034] Preferably, the second good solvent is any one or a mixture of two or more of methanol, ethanol, isopropyl alcohol, acetone, butanone, isobutyl ketone, tetrahydrofuran, N-methyl pyrrolidone, pyridine, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and the like.

[0035] A third object of the present application is to provide the ibrutinib monolaurate sulfate salt as an active ingredient for the preparation of an anticancer drug for the same indications as ibrutinib, according to any one of the above or obtained by the preparation method according to any one of the above;

[0036] Preferably, the indications of the anticancer drug include chronic graft versus host disease (cGVHD), chronic lymphocytic leukemia, acute B lymphocytic leukemia, B lymphoma, central nervous system tumor, 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, follicle center lymphoma, prostate tumor, respiratory distress syndrome, T-cell lymphoma, transitional lymphoid cancer, lymphoplasmacytic lymphoma, mantle cell lymphoma, marginal zone B-cell lymphoma, etc.

[0037] A fourth object of the present application is to provide a pharmaceutical composition or a pharmaceutical preparation comprising the ibrutinib monolaurate sulfate salt according to any one of the above or obtained by the preparation method according to any one of the above, and a pharmaceutically acceptable excipient, which is at least one of a carrier, an excipient, a diluent, and the pharmaceutical preparation is any one of a hard capsule, a soft capsule, a tablet, a pill, a powder, a granule, a suspension.

[0038] In particular, the present application provides a composition or a dosage form of ibrutinib monolaurate sulfate salt and at least one pharmaceutically acceptable excipient, which is preferably administered to an individual via oral administration.

[0039] The present application further encompasses a method of reducing the total daily oral dosage of ibrutinib. More particularly, the present application encompasses oral administration of a composition and / or dosage form prepared according to the present application, wherein the total daily amount of ibrutinib administered is reduced by 10%, 20%, 30%, 40%, 50%, 60%, 70% or more than 80% compared to the total daily amount approved by the U.S. Food and Drug Administration (FDA), thereby reducing the side effects associated therewith and enhancing patient compliance.

[0040] In one embodiment of the present application, the composition and / or dosage form for oral administration is a hard capsule, a tablet or a suspension comprising ibrutinib monolaurate sulfate salt and at least one additional ingredient of a pharmaceutically acceptable carrier, diluent and excipient. In certain aspects of this embodiment, the hard or soft capsule can be a gelatin-based or non-gelatin-based capsule. In some embodiments, the pharmaceutical composition comprises crystalline ibrutinib monolaurate sulfate salt. In some embodiments, the pharmaceutical composition comprises amorphous ibrutinib monolaurate sulfate salt.

[0041] In an optional embodiment, the diluent includes, but is not limited to, any one or a combination of two or more of lactose, sucrose, dextrose, dextrates, maltodextrin, mannitol, xylitol, sorbitol, cyclodextrin, calcium phosphate, calcium sulfate, starch, modified starch, microcrystalline cellulose, microcellulose, talc, and any one or a combination of two or more of the above.

[0042] The excipient includes a disintegrant and / or a lubricant, the disintegrant including, but not limited to, any one or a combination of two or more of 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 cross-linked carboxymethyl cellulose, cross-linked starch such as sodium starch glycolate, cross-linked polymer such as crospovidone, cross-linked polyvinylpyrrolidone, sodium alginate, clay, gum, and any one or a combination of two or more of the above.

[0043] The lubricant includes, but is not limited to, any one or a combination of two or more of calcium hydroxide, talc, corn starch, sodium stearyl fumarate, stearic acid, sodium stearate, magnesium stearate, zinc stearate, wax, and any one or a combination of two or more of the above.

[0044] The advantages and benefits of the present application include, but are not limited to:

[0045] (1) The present application provides a compound containing ibrutinib monolaurin sulfate, the active substance solid is a crystalline compound, which is easy to process into a medicine, and is beneficial to the long-term quality stability of the finished product.

[0046] (2) The present application provides a compound containing ibrutinib monolaurin sulfate, which greatly improves the bioavailability of ibrutinib, reduces the total daily intake, and achieves the same effect as the original research; thereby, reducing the gastrointestinal side effects caused by the patient after taking the medicine.

[0047] (3) The present application provides a compound containing ibrutinib monolaurin sulfate, the obtained composition is a hard capsule or tablet containing ibrutinib monolaurin sulfate, the obtained composition is rapidly absorbed, and is beneficial to rapid drug efficacy.

[0048] (4) The present application provides a preparation method of a compound containing ibrutinib monolaurin sulfate, which is simple in preparation process. BRIEF DESCRIPTION OF DRAWINGS

[0049] In order to more clearly illustrate the technical solutions of the embodiments of the present application, the following will briefly introduce the drawings needed to be used in the embodiment description. Obviously, the drawings in the following description are only some structural verification data examples of the present application, and other drawings can also be obtained according to these drawings without creative labor for those skilled in the art.

[0050] Figure 1 is an X-ray powder diffraction pattern of the crystalline compound of Example 1 of the present application;

[0051] Figure 2 is a HNMR spectrum of the crystalline compound of Example 1 of the present application; 1 HNMR spectrum;

[0052] Figure 3 is a DSC spectrum of the crystalline compound of Example 1 of the present application;

[0053] Figure 4 is a TGA spectrum of the crystalline compound of Example 1 of the present application;

[0054] Figure 5 is a FTIR spectrum of the crystalline compound of Example 1 of the present application;

[0055] Figure 6 is an X-ray powder diffraction pattern of the amorphous Form I compound of the present application;

[0056] Figure 7 is an X-ray powder diffraction pattern of the amorphous Form II compound of the present application;

[0057] Figure 8 is a TGA spectrum of the amorphous Form I compound of the present application;

[0058] Figure 9 is a DSC spectrum of the amorphous Form I compound of the present application;

[0059] Figure 10 is a TGA spectrum of the amorphous Form II compound of the present application;

[0060] Figure 11 is a DSC spectrum of the amorphous Form II compound of the present application. DETAILED DESCRIPTION

[0061] The embodiments of the present application will be further described in the following examples. The following examples are provided to illustrate the principles of the present application and should not be considered limiting of the scope of the application, as this application is not limited to the examples described. Unless otherwise indicated, all parts and percentages are on a weight basis.

[0062] 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.

[0063] Unless otherwise specified, all embodiments and optional embodiments of this application can be combined to form new technical solutions.

[0064] Unless otherwise specified, all technical features and optional technical features of this application may be combined to form new technical solutions.

[0065] 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.

[0066] 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.

[0067] The term "or" is inclusive in this application, unless otherwise indicated. So, for example, a phrase A or B means A, B, or both A and B. More specifically, any of the following satisfy the condition A or B: A is true (or present) and B is false (or not present); A is false (or not present) and B is true (or present); or both A and B are true (or present).

[0068] The term "Cmax" means the highest blood drug concentration obtained during the dosing interval, unless otherwise indicated.

[0069] The term "Tmax" means the time to reach the highest blood drug concentration (Cmax), unless otherwise indicated.

[0070] The term "AUC" means the area under the drug concentration-time curve within a specified time interval calculated using the linear trapezoidal summation, unless otherwise indicated. 0-24 refers to the area under the drug concentration-time curve from the time of dosing until 24 hours after dosing;

[0071] The determination of the pharmacokinetic parameters described herein is generally according to methods known and understood by those skilled in the art and generally described in publications.

[0072] The term "effective therapeutic dose" as described herein, unless otherwise defined, refers to the amount of ibrutinib free base effective to treat a disease or condition described herein.

[0073] The technical solutions in the embodiments of the present application will be described clearly and completely in combination with the drawings in the embodiments of the present application. Obviously, the described embodiments are only some of the embodiments of the present application, not all the embodiments.

[0074] I. Crystalline Compound

[0075] Example 1: Preparation of ibrutinib monolauryl sulfate anhydrous crystalline compound

[0076] (1) Preparation of ibrutinib monolauryl sulfate:

[0077] Weigh 20.0 g of ibrutinib and dissolve it in 2000 ml of dilute hydrochloric acid with a concentration of 0.1 N, and take 13.1 g of sodium monolauryl sulfate and dissolve it in 100 ml of dilute hydrochloric acid with a concentration of 0.1 N, and after dissolving, respectively, standby. Mix the above two solutions well, and stand for 24 hours. Remove the upper liquid, and then wash the precipitate with deionized water until it is neutral. Dry at 40°C for 24 hours to obtain ibrutinib monolauryl sulfate precipitate.

[0078] (2) Take 1.0 g of ibrutinib monolaurate sulfate salt precipitate, dissolve in 10 ml of acetonitrile at 50 °C, slowly add 60 ml of n-heptane at this temperature. After mixing well, cool to 0-5 °C at 0.1 °C / min, incubate and maintain stirring overnight to crystallize. Filter the solid and dry at 40 °C, collect 0.82 g of anhydrous crystalline compound, HPLC purity 98.8%, chiral purity 98.5%.

[0079] Example 2: Preparation of anhydrous crystalline compound of ibrutinib monolaurate sulfate salt

[0080] (1) Preparation of ibrutinib monolaurate sulfate salt: same as Example 1.

[0081] (2) Take 1.0 g of ibrutinib monolaurate sulfate salt precipitate, dissolve in 10 ml of acetonitrile at 50 °C, slowly add 60 ml of n-heptane at this temperature. After mixing well, cool to 0-5 °C at 0.1 °C / min, incubate and maintain stirring overnight to crystallize. Filter the solid and dry at 40 °C, collect 0.82 g of anhydrous crystalline compound, HPLC purity 98.8%, chiral purity 98.5%.

[0082] Example 3: Preparation of anhydrous crystalline compound of ibrutinib monolaurate sulfate salt

[0083] (1) Preparation of ibrutinib monolaurate sulfate salt: same as Example 1.

[0084] (2) Take 1.0 g of ibrutinib monolaurate sulfate salt precipitate, dissolve in 10 ml of acetonitrile at 50 °C, slowly add 60 ml of n-heptane at this temperature. After mixing well, cool to 0-5 °C at 0.1 °C / min, incubate and maintain stirring overnight to crystallize. Filter the solid and dry at 40 °C, collect 0.82 g of anhydrous crystalline compound, HPLC purity 98.8%, chiral purity 98.5%.

[0085] Example 4: Preparation of anhydrous crystalline compound of ibrutinib monolaurate sulfate salt

[0086] (1) Preparation of ibrutinib monolaurate sulfate salt: same as Example 1.

[0087] (2) Take 1.0 g of ibrutinib monolaurate sulfate salt precipitate, dissolve in 10 ml of acetonitrile at 50 °C, slowly add 60 ml of n-heptane at this temperature. After mixing well, cool to 0-5 °C at 0.1 °C / min, incubate and maintain stirring overnight to crystallize. Filter the solid and dry at 40 °C, collect 0.82 g of anhydrous crystalline compound, HPLC purity 98.8%, chiral purity 98.5%.

[0088] II. Amorphous compound

[0089] Example 5: Preparation of Ibrutinib monolaurate sulfate amorphous

[0090] (1) Preparation of Ibrutinib monolaurate sulfate: same as Example 1.

[0091] (2) Take 1.0 g Ibrutinib monolaurate sulfate precipitate, dissolve in 5 ml ethanol, and slowly add 30 ml deionized water. After mixing evenly, stand and cool to 0-5°C at 0.1°C / min, and incubate overnight. Filter the solid and dry at 40°C, and collect 0.93 g of amorphous compound with HPLC purity of 98.1% and chiral purity of 98.5%. Marked as amorphous I compound.

[0092] Example 6: Preparation of Ibrutinib monolaurate sulfate amorphous

[0093] (1) Preparation of Ibrutinib monolaurate sulfate: same as Example 1.

[0094] (2) Take 1.0 g Ibrutinib monolaurate sulfate precipitate, dissolve in 5 ml ethanol, and slowly add 30 ml deionized water. After mixing evenly, stand and cool to 0-5°C at 0.1°C / min, and incubate overnight. Filter the solid and dry at 40°C, and collect 0.93 g of amorphous compound with HPLC purity of 98.1% and chiral purity of 98.5%. Marked as amorphous I compound.

[0095] Example 7: Preparation of Ibrutinib monolaurate sulfate amorphous

[0096] (1) Preparation of Ibrutinib monolaurate sulfate: same as Example 1.

[0097] (2) Take 1.0 g Ibrutinib monolaurate sulfate precipitate, dissolve in 5 ml ethanol, and slowly add 30 ml deionized water. After mixing evenly, stand and cool to 0-5°C at 0.1°C / min, and incubate overnight. Filter the solid and dry at 40°C, and collect 0.93 g of amorphous compound with HPLC purity of 98.1% and chiral purity of 98.5%. Marked as amorphous I compound.

[0098] III. Determination

[0099] 1. Crystalline compound

[0100] (1) X-ray powder diffraction (XRPD)

[0101] Test conditions: X-ray powder diffraction pattern was collected on a PANalytical (Model: EMPYREAN) diffractometer. Cu Kα ray Voltage: 40 kV, current: 1 mA, step: 0.01°, scan speed: 20° / min, scan range: 5.0-40.0°. 10-20 mg sample was evenly spread in the center of a single crystal silicon sample plate, the sample was pressed to keep the surface flat and the thickness uniform, and then tested.

[0102] The anhydrous crystalline compound obtained in Example 1 was measured, and Figure 1 shows the X-ray powder diffraction of the anhydrous crystalline compound of Example 1. 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%.

[0103] Specifically, the X-ray powder diffraction (PXRD) pattern expressed in terms of 2θ angle shows characteristic peaks and relative intensities at the following positions as shown in Table 1:

[0104] Table 1

[0105] The X-ray powder diffraction pattern of the anhydrous crystalline compound obtained in Examples 2-4 is similar to that of Example 1, and is not described here.

[0106] (2) 1 HNMR test

[0107] The anhydrous crystalline compound obtained in Example 1 was measured by nuclear magnetic resonance hydrogen spectrum, and the results are shown in Figure 2. It can be seen that the hydrogen quantity 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.

[0108] (3) Fourier transform-infrared (FTIR)

[0109] Test conditions: instrument: Bruker Vertex 70 Fourier transform infrared spectrometer. An appropriate amount of dried sample and dried potassium bromide were ground uniformly, and a tablet was pressed under a pressure of 1.0 t for 30 s using a tablet press and a mold of GS01190 type of Specac Company, UK. Wavelength range: 4000-500 cm -1 , resolution: 0.2 cm -1 .

[0110] Figure 5 shows the infrared spectrum of the anhydrous crystalline compound obtained in Example 1. In Figure 5, the characteristic peaks observed include 2921 cm -1 , 2852 cm -1 , 1612 cm -1 , 1587 cm -1 , 1519 cm -1 , 1488 cm -1 , 1442 cm -1 , 1230 cm -1 , 1166 cm -1 , 971 cm -1 , 854 cm -1 and 586 cm -1 . The results show that the preparation of Example 1 has obtained a compound having the structural formula as (II).

[0111] (4) Differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA)

[0112] Instrument model: Mettler-Toledo TGA / DSC 2 type differential calorimeter, sample weight: 5-10 mg, crucible material: Al, atmosphere: N2, heating rate: 10°C / min, temperature range tested: 30°C to decomposition temperature.

[0113] Figures 3 and 4 show the DSC and TGA thermograms of the crystalline compound of Example 1, respectively. No weight loss was observed. This proves that the material is anhydrous.

[0114] In summary, the above tests prove that, according to the preparation method of the present application, an anhydrous crystalline compound of ibrutinib monolaurate sulfate salt is obtained.

[0115] (5) Chemical purity determination

[0116] Instrument model: SHIMADZU LC-2030C 3D; chromatographic column: Gemini-NX C18 column (4.6 mm x 150 mm, 3 μm); UV detection wavelength of REG: 260 nm; composition of mobile phase: 0.1% trifluoroacetic acid acetonitrile, 0.1% trifluoroacetic acid aqueous solution two-phase gradient elution; required column temperature for detection: 40°C; flow rate for detection: 1.5 mL / min; sample size: 100 μL. The results are shown in each example.

[0117] (6) Chiral purity determination

[0118] Instrument model: SHIMADZU LC-2030C 3D; chromatographic column: Lux Cellulose-1 hand column (4.6 mm x 250 mm, 5 μm); UV detection wavelength of REG: 260 nm; composition of mobile phase: 20% isopropyl alcohol, 80% n-hexane; required column temperature for detection: room temperature; flow rate for detection: 1.0 mL / min; sample injection amount: 100 μL each time.

[0119] The content of R enantiomer was determined by normalizing the peak area of the enantiomer peak and expressed as a weight / weight percentage. In some embodiments, the sample of ibrutinib contains 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. The crystallization process of the crystalline compound in the embodiments of the present application is conducive to the reduction of the content of S-isomer.

[0120] 2. Amorphous compound

[0121] X-ray powder diffraction (XRPD): The products obtained from Examples 5, 6 were respectively determined, as shown in Figures 6, 7. There is no obvious characteristic peak type in Figures 6, 7. It is amorphous.

[0122] Differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA): The products obtained from Examples 5, 6 were respectively determined, and the TGA and DSC thermograms of the amorphous I compound are shown in Figures 8, 9, respectively, and the TGA and DSC thermograms of the amorphous II compound are shown in Figures 10, 11, respectively. The data show that the melting point of the amorphous compound is relatively lower, and the phase transition during heating is more complex; indicating that the stability is slightly worse than that of the crystalline compound.

[0123] Chemical purity determination:

[0124] Instrument model: SHIMADZU LC-2030C 3D; chromatographic column: Gemini-NX C18 column (4.6 mm x 150 mm, 3 μm); UV detection wavelength of REG: 260 nm; composition of mobile phase: 0.1% trifluoroacetic acid acetonitrile, 0.1% trifluoroacetic acid aqueous solution two-phase gradient elution; required column temperature for detection: 40°C; flow rate for detection: 1.5 mL / min; sample injection amount: 100 μL each time.

[0125] The results are shown in each of the embodiments.

[0126] Four, pharmacokinetic study

[0127] Pharmacokinetic study of a composition containing ibrutinib monolaurin sulfate provided by the present application in beagle dogs:

[0128] The composition containing ibrutinib monolaurate sulfate is formulated as shown in Table 2:

[0129] Table 2

[0130] The above formulations are made into capsules, specifically, the components shown in the above table are weighed and mixed together, and added to capsules of appropriate size, and the capsules are closed.

[0131] Purpose of the study: orally administer ibrutinib capsules RF (reference formulation) to beagle dogs as a comparison, and ibrutinib monolaurate sulfate crystalline compound capsules (i.e. Table 1 Nos. P1, P2) prepared according to the present patent application to beagle dogs, respectively, to determine the plasma concentration in dogs and investigate the pharmacokinetic characteristics in dogs.

[0132] Method of the study: three beagle dogs were selected, and single dose, three cycles of administration were used. The dogs were fasted for at least 12 hours before each administration, and water was given immediately after each administration of the capsules, about 40 ml, and the dogs were fasted and watered within 4 hours after administration, and the washout period was 14 days.

[0133] When each cycle of administration was given, about 0.6 mL (0.5-0.7 mL) of whole blood was collected from the forelimb vein of the dogs at 0 h before administration and 0.5 h, 1 h, 1.5 h, 2 h, 3 h, 4 h, 6 h, 8 h, 10 h, 24 h, 30 h after administration, respectively, and heparin was used for anticoagulation, and the plasma was obtained by centrifugation at 6000 rpm for 5 min at 4°C, and was temporarily stored in the animal test laboratory at -80°C. After all the samples were collected, they were transported to the pharmacokinetic laboratory at -80°C for storage, and the drug concentration was detected.

[0134] The content of ibrutinib in the plasma of beagle dogs was detected by the LC-MS / MS method established in the laboratory, the main pharmacokinetic parameters were calculated, and the relative bioavailability of ibrutinib monolaurate sulfate capsules and capsule reference in dogs was compared. The test results are shown in Table 3.

[0135] Table 3 Pharmacokinetic data in beagle dogs

[0136] Note: The reference RF dog 101 data is not statistically analyzed.

[0137] From the results in Table 3, it can be seen that the two formulations of the ibrutinib monolaurate sulfate composition provided by the present application are capsules (P1 60 mg / dose and P2 90 mg / dose), wherein the Cmax and AUC of the P2 scheme are significantly improved compared with the reference formulation (RF 140 mg / dose), and the same effect as the reference formulation can be achieved when the total daily intake is reduced, and it is rapidly absorbed after administration, which is beneficial to rapid drug efficacy and has better pharmacokinetic properties.

[0138] The present application adopts ibrutinib and the auxiliary material sodium lauryl sulfate in the original preparation to form a salt, and provides an ibrutinib monolaurate sulfate pharmaceutical composition, a preparation method and application thereof. The pharmaceutical composition can maximize the stability of the finished product, and significantly improve the oral absorption bioavailability. At the same time, it is theoretically beneficial to reduce the difference between pre-meal and post-meal ibrutinib. Due to the significant reduction in the dosage, gastrointestinal reactions and potential side effects can be reduced. The ibrutinib monolaurate sulfate crystalline compound has better drug properties, and the preparation process is simple, suitable for large-scale production, and the product quality is stable.

[0139] It is apparent for those skilled in the art that the present application is not limited to the details of the above exemplary embodiments, and can be implemented in other specific forms without departing from the spirit or essential characteristics of the present application. Therefore, the embodiments should be regarded as exemplary and non-limiting, and the scope of the present application is defined by the appended claims rather than the above description, and it is intended to encompass all changes falling within the meaning and scope of the equivalent elements of the claims. Any reference signs in the claims should not be regarded as limiting the claims involved. The above detailed description further illustrates the purposes, technical solutions and beneficial effects of the present application, and it should be understood that the above is only a specific embodiment of the present application and is not used to limit the protection scope of the present application, and any modification, equivalent replacement, improvement, etc. within the spirit and principles of the present application should be included in the protection scope of the present application.

Claims

1. An ibrutinib monolaurate sulfate salt, characterized by, The structural formula is shown as formula II: which is a crystalline compound or an amorphous compound, wherein the crystalline compound exists in the form of anhydrous and solvent-free.

2. The ibrutinib monolaurate sulfate salt of claim 1, wherein, The X-ray diffraction spectrum of the crystalline compound has characteristic peaks at 5.38±0.2°, 18.66±0.2°, 20.97±0.2°, 21.36±0.2°, 21.62±0.2°, 22.06±0.2°, using Cu-Kα radiation. The X-ray diffraction spectrum of the amorphous compound has no sharp diffraction peaks.

3. The crystalline compound of ibrutinib monolaurate sulfate salt according to claim 1, characterized in that, The X-ray diffraction spectrum of the crystalline compound 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°, 28.57±0.2°, using Cu-Kα radiation.

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

5. The ibrutinib monolaurate sulfate salt of claim 1, wherein, The differential scanning calorimetry curve of the crystalline compound shows a characteristic endothermic peak at 74-101℃ and a characteristic exothermic peak at 146-169℃; the thermogravimetric analysis curve of the crystalline compound shows a weight loss of 32.9±1.0% at 200-320℃ and a weight loss of 51.9±1.0% at 320-500℃.

6. The ibrutinib monolaurate sulfate salt of claim 1, wherein, For the crystalline compound, the molar ratio of ibrutinib to monolaurin sulfate is 1:0.5-1.5, preferably 1:0.9-1.1; more preferably 1:

1.

7. A process for the preparation of Ibrutinib monolaurate sulfate salt according to claim 1, characterized in that, The preparation process of the crystalline compound comprises: obtaining ibrutinib monolaurin sulfate; dissolving ibrutinib monolaurin sulfate in a first good solvent, adding a first non-good solvent after complete dissolution, and filtering and crystallizing to obtain the crystalline compound; The preparation process of the amorphous compound comprises: dissolving ibrutinib monolaurin sulfate in a second good solvent, mixing with water after drying, and filtering to obtain the amorphous solid without solvent or corresponding solvent.

8. A process for the preparation of Ibrutinib monolaurate sulfate salt according to claim 7, characterized in that, In the preparation process of the crystalline compound, the mass-volume ratio of ibrutinib monolaurin 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; wherein the mass is measured in grams and the volume is measured in milliliters. 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, isopropyl alcohol, 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 of methanol, ethanol, isopropanol, acetone, butanone, isobutyl ketone, tetrahydrofuran, N-methylpyrrolidone, pyridine, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and the like.

9. A medicament for treating the same indications as Ibrutinib for treating cancer, which comprises Ibrutinib monolaurate sulfate as an active ingredient according to any one of claims 1 to 6, or obtained by the preparation method according to any one of claims 7 to 8. Preferably, the indications for the anticancer drug include: chronic graft versus host disease (cGVHD), chronic lymphocytic leukemia, acute B lymphocytic leukemia, B lymphoma, central nervous system tumor, 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 tumor, respiratory distress syndrome, T-cell lymphoma, transitional lymphocarcinoma, lymphoplasmacytic lymphoma, mantle cell lymphoma, marginal zone B-cell lymphoma.

10. A pharmaceutical composition or pharmaceutical preparation, characterized by, A pharmaceutical preparation comprising Ibrutinib monolaurate sulfate according to any one of claims 1 to 6, or obtained by the preparation method according to any one of claims 7 to 8, and a pharmaceutically acceptable excipient, which is at least one of a carrier, an excipient, a diluent, is any one of a hard capsule, a soft capsule, a tablet, a pill, a powder, a granule, a suspension.

11. A pharmaceutical composition or a pharmaceutical preparation according to claim 10, characterized in that, The diluent is selected from any one or a combination of two or more of lactose, sucrose, dextrose, dextrate, maltodextrin, mannitol, xylitol, sorbitol, cyclodextrin, calcium phosphate, calcium sulfate, starch, modified starch, microcrystalline cellulose, microcellulose, talc; The excipient includes a disintegrant and / or a lubricant, the disintegrant is selected from any one or a combination of two or more of 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 cross-linked carboxymethyl cellulose, cross-linked starch such as sodium starch glycolate, cross-linked polymer such as crospovidone, cross-linked polyvinylpyrrolidone, sodium alginate, clay, gum; The lubricant is selected from any one or a combination of two or more of calcium hydroxide, talc, corn starch, sodium stearyl fumarate, stearic acid, sodium stearate, magnesium stearate, zinc stearate, wax.

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