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WO2021135346A1 - Nouvelle forme cristalline de l'acalabrutinib, son procédé de préparation et son utilisation - Google Patents

Nouvelle forme cristalline de l'acalabrutinib, son procédé de préparation et son utilisation Download PDF

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Publication number
WO2021135346A1
WO2021135346A1 PCT/CN2020/113424 CN2020113424W WO2021135346A1 WO 2021135346 A1 WO2021135346 A1 WO 2021135346A1 CN 2020113424 W CN2020113424 W CN 2020113424W WO 2021135346 A1 WO2021135346 A1 WO 2021135346A1
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Prior art keywords
crystal form
preparation
present
acalabrutinib
drug
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PCT/CN2020/113424
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English (en)
Chinese (zh)
Inventor
陈敏华
李英杰
钱佳乐
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Crystal Pharmaceutical Suzhou Co Ltd
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Crystal Pharmaceutical Suzhou Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the invention relates to the technical field of drug crystals. Specifically, it relates to the crystal form of Acalabrutinib and its preparation method and use.
  • Mantle Cell Lymphoma is a type of non-Hodgkin's lymphoma.
  • MCL is a lymphoproliferative disorder derived from a subpopulation of naive germinal center cells located in the primary follicle or in the mantle area of the secondary follicle.
  • MCL is characterized by specific chromosomal translocations.
  • MCL is a type of lymphoma that is difficult to cure.
  • CHOP cyclophosphamide + doxorubicin + vincristine + prednisone
  • BTK is a member of the Tec family of tyrosine kinases and has been shown to be a key regulator of early B cell development and mature B cell activation and survival. Functional mutations in human BTK lead to X-linked gammaglobulinemia (XLA). These patients are immunocompromised and show impaired B cell maturation, reduced immunoglobulin and peripheral B cell levels. In addition, BTK has been reported to play a role in cell apoptosis, and therefore BTK inhibitors can be used to treat certain B-cell lymphomas and leukemias.
  • XLA X-linked gammaglobulinemia
  • Acalabrutinib was developed by Acerta and was launched in the United States in October 2017. The marketing of Acalabrutinib provides a new treatment option for patients with relapsed drug-resistant mantle cell lymphoma.
  • Acalabrutinib is a second-generation BTK inhibitor. Compared with the first-generation BTK inhibitor Ibrutinib, Acalabrutinib has higher drug selectivity and lower side effects. In previous clinical trials, Acalabrutinib has achieved a very high remission rate.
  • Compound I The chemical name of Acalabrutinib is: (S)-4-(8-amino-3-(1-but-2-ynylpyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl )-N-(pyridin-2-yl)benzamide (hereinafter referred to as "Compound I”), its structural formula is shown in the figure below:
  • the crystal form is a solid in which compound molecules are arranged in a three-dimensional order in the microstructure to form a crystal lattice.
  • the phenomenon of drug polymorphism refers to the existence of two or more different crystal forms of the drug. Because of the different physical and chemical properties, different crystal forms of the drug may have different dissolution and absorption in the body, which will affect the clinical efficacy and safety of the drug to a certain extent. Especially for poorly soluble solid drugs, the crystal form will have a greater impact. Therefore, the crystal form of a drug must be an important content of drug research and an important content of drug quality control.
  • the inventor of the present application unexpectedly discovered that the compound I crystal form K3 provided by the present invention has advantages in physical and chemical properties, preparation processing properties, and bioavailability, such as melting point, solubility, and solubility.
  • advantages in at least one aspect of wetness, purification, stability, adhesion, compressibility, fluidity, in vivo and in vitro dissolution, bioavailability, etc. especially (specifically achieved beneficial effects), which contains Acalabrutinib
  • the drug development of China provides new and better options, which is of great significance.
  • the main purpose of the present invention is to provide a new crystal form of Acalabrutinib and its preparation method and application.
  • the present invention provides a crystalline form K3 of Acalabrutinib (hereinafter referred to as "crystalline form K3").
  • the X-ray powder diffraction of the crystal form K3 has characteristic peaks at diffraction angle 2 ⁇ values of 7.8° ⁇ 0.2°, 15.6° ⁇ 0.2°, and 17.3° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form K3 has characteristic peaks at one or more of the diffraction angle 2 ⁇ values of 20.6° ⁇ 0.2°, 16.6° ⁇ 0.2°, 18.2° ⁇ 0.2°; preferably, The X-ray powder diffraction of the crystal form K3 has characteristic peaks at the diffraction angle 2 ⁇ values of 20.6° ⁇ 0.2°, 16.6° ⁇ 0.2°, and 18.2° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form K3 has characteristic peaks at one or more of the diffraction angle 2 ⁇ values of 14.4° ⁇ 0.2°, 9.3° ⁇ 0.2°, 11.0° ⁇ 0.2°; preferably, The X-ray powder diffraction of the crystal form K3 has characteristic peaks at the diffraction angle 2 ⁇ values of 14.4° ⁇ 0.2°, 9.3° ⁇ 0.2°, and 11.0° ⁇ 0.2°.
  • the characteristic peaks of the crystal form K3 include X-ray powder diffraction at diffraction angle 2 ⁇ values of 7.8° ⁇ 0.2°, 15.6° ⁇ 0.2°, 17.3° ⁇ 0.2°, 20.6° ⁇ 0.2°, 16.6° ⁇ 0.2°, 18.2° ⁇ 0.2°, 14.4° ⁇ 0.2°, 9.3° ⁇ 0.2°, 11.0° ⁇ 0.2°Any 3 locations, or 4 locations, or 5 locations, or 6 locations , Or 7, or 8, or 9 have characteristic peaks.
  • the crystal form K3 is a hemiacetonitrile solvate.
  • the present invention also provides a preparation method of the crystal form K3, characterized in that the preparation method includes:
  • the other solvent may be a solvent miscible with acetonitrile.
  • the other solvents may be alcohols and alkanes.
  • the stirring temperature is 4°C-90°C, more preferably 50°C.
  • crystalline or “polymorphic” refers to those confirmed by X-ray powder diffraction pattern characterization.
  • X-ray powder diffraction pattern characterization Those skilled in the art can understand that the physical and chemical properties discussed here can be characterized, and the experimental error depends on the condition of the instrument, the preparation of the sample, and the purity of the sample.
  • the X-ray powder diffraction pattern usually changes with the different instrument conditions.
  • the relative intensity of diffraction peaks in X-ray powder diffraction patterns may also change with changes in experimental conditions, so the order of diffraction peak intensities cannot be the only or decisive factor.
  • the relative intensity of the diffraction peaks in the X-ray powder diffraction pattern is related to the preferred orientation of the crystals.
  • the intensity of the diffraction peaks shown in this article are illustrative rather than for absolute comparison.
  • the experimental error of the position of the diffraction peak is usually 5% or less, and the error of these positions should also be taken into account, and an error of ⁇ 0.2° is usually allowed.
  • the overall angle of the diffraction peak will be shifted, and a certain shift is usually allowed.
  • the X-ray powder diffraction pattern of a crystal form in the present invention does not have to be exactly the same as the X-ray powder diffraction pattern in the embodiment referred to here, and any characteristic peaks in these patterns.
  • the crystal forms of the same or similar X-ray powder diffraction patterns fall within the scope of the present invention.
  • Those skilled in the art can compare the X-ray powder diffraction pattern listed in the present invention with the X-ray powder diffraction pattern of an unknown crystal form to confirm whether the two sets of images reflect the same or different crystal forms.
  • the crystal form K3 of the present invention is pure, and substantially no other crystal forms are mixed.
  • substantially no when used to refer to a new crystal form means that this crystal form contains less than 20% by weight of other crystal forms, especially less than 10% by weight of other crystal forms, and even less. Other crystal forms that are less than 5% by weight, and even other crystal forms that are less than 1% by weight.
  • the term "about”, when used to refer to a measurable value, such as the mass, time, temperature, etc. of the compound and preparation, means that there can be a certain range of fluctuations around the specific value, and the range may be ⁇ 10% , ⁇ 5%, ⁇ 1%, ⁇ 0.5%, or ⁇ 0.1%.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of the crystal form K3 of the present invention and a pharmaceutically acceptable carrier, diluent or excipient.
  • the present invention provides the use of crystal form K3 in the preparation of Bruton's tyrosine kinase inhibitor drugs.
  • the present invention provides the use of crystal form K3 in the preparation of a medicine for treating mantle cell lymphoma.
  • the present invention provides the use of crystal form K3 for preparing crystal form K1.
  • crystal form K1 is the crystal form described in WO2019205812A1.
  • the present invention relates to crystal form K3 of Acalabrutinib which has advantages in at least one aspect of solubility, melting point, stability, dissolution, hygroscopicity, adhesion, fluidity, bioavailability, processing performance, formulation production, etc.
  • the preparation of Acalabrutinib's pharmaceutical preparations provides a new and better choice, which is of great significance for drug development.
  • the X-ray powder diffraction pattern of the present invention is collected on a Bruker D2 PHASER X-ray powder diffractometer.
  • the parameters of the X-ray powder diffraction method of the present invention are as follows:
  • Scan range: from 3.0 to 40.0 degrees
  • the differential scanning calorimetry (DSC) chart of the present invention was collected on TA Q2000.
  • the method parameters of the differential scanning calorimetry (DSC) of the present invention are as follows:
  • thermogravimetric analysis (TGA) graph of the present invention is collected on TA Q500.
  • the method parameters of the thermogravimetric analysis (TGA) of the present invention are as follows:
  • the Acalabrutinib and/or its salt as a raw material includes, but is not limited to, solid form (crystalline or amorphous), oily, liquid form and solution.
  • the compound I and/or its salt as a raw material are in solid form.
  • the Acalabrutinib free base solid used in the following examples can be prepared according to the prior art, for example, according to the method described in the WO2017002095A1 document.
  • the obtained crystalline solid is the crystal form K3 of the present invention, and its X-ray powder diffraction pattern is shown in Figure 1, and the XRPD data is shown in Table 1.
  • TGA is shown in Figure 2. When heated to 100°C, it has a mass loss of 0.8%, corresponding to the removal of adsorbed water or solvent on the surface; heating from 100°C to 200°C, has a mass loss of 4.1%, corresponding to the crystal form Removal of acetonitrile solvent in K3 lattice.
  • Solubility is one of the key properties of drugs, which directly affects the absorption of drugs in the human body.
  • the solubility of different crystalline drugs may be significantly different, and the absorption dynamics in the body will also change, resulting in differences in bioavailability, and ultimately affecting the clinical safety and efficacy of the drugs.
  • improving the solubility is more important.
  • the increase in solubility will help to increase the bioavailability of the drug, thereby improving the drug's drug-making properties.
  • the improvement of solubility also reduces the difficulty of formulation process development. Crystal forms with sufficiently high solubility can be developed using traditional formulation processes. For crystal forms with lower solubility, in order to achieve the desired bioavailability, more advanced methods are required. Complex preparation process.
  • the increased solubility can reduce the dose of the drug while ensuring the efficacy of the drug, thereby reducing the side effects of the drug and improving the safety of the drug.
  • the present invention is equipped with a solvent system with 4 pH values ranging from 1.2 to 7.5. Specifically: SGF (simulated gastric juice) with a pH of 1.8, FeSSIF (artificial intestinal fluid under simulated feeding state) with pH of 5.0, FaSSIF (artificial intestinal fluid simulated under fasting state) with pH 6.5, and water.
  • SGF simulated gastric juice
  • FeSSIF artificial intestinal fluid under simulated feeding state
  • FaSSIF artificial intestinal fluid simulated under fasting state
  • the stability of the drug is very important, especially during the effective period of the market, maintaining good stability can reduce the risk of changes in the dissolution rate and bioavailability of the drug due to changes in the crystal form of the drug, which is important for ensuring the efficacy and safety of the drug and preventing The occurrence of adverse drug reactions is of great significance.
  • the more stable crystal form is more controllable during the crystallization process, and mixed crystals are not easy to appear, and it is not easy to transform into other crystal forms during the preparation process and storage process, so as to ensure that the quality of the sample is consistent and controllable, and to ensure the preparation of the product
  • the dissolution profile will not change with the storage time.
  • Influencing factor experiment accurately weigh 5 mg of the crystal form K3 prepared by the present invention, and place them under the conditions of 25°C/60% relative humidity, 40°C/75% relative humidity, and 60°C/75% relative humidity, and sample after a period of time , Using HPLC and XRPD methods to determine the changes in crystal form and purity.
  • the above-mentioned crystal form K3 of the present invention was placed under 40°C/75% relative humidity conditions, and the changes in crystal form and purity at 2 weeks, 2 months, 3 months, and 6 months were determined by HPLC and XRPD methods.
  • the above-mentioned crystal form was placed under the condition of 60° C./75% relative humidity, and the changes in crystal form and purity were determined by HPLC and XRPD methods after acceleration for 2 weeks.
  • the crystal form with good pressure stability can effectively improve the hardness/fragility unqualified during processing and reduce the requirements for the previous processing (such as raw material crushing particle size control, drying moisture control, Particle size and particle size distribution control) to make the process more robust, improve product appearance, and enhance product quality.
  • the previous processing such as raw material crushing particle size control, drying moisture control, Particle size and particle size distribution control
  • Hygroscopicity is one of the key properties of the drug crystal form.
  • the drug crystal form with high hygroscopicity absorbs more water and changes its weight, which makes it difficult to determine the content of the raw material crystal form component.
  • the crystal form of the drug substance is easy to absorb water and agglomerate due to its high hygroscopicity, which affects the particle size distribution of the sample during the preparation process and the uniformity of the drug substance in the preparation, thereby affecting the dissolution and bioavailability of the sample.
  • APIs with high hygroscopicity have strict requirements on packaging and storage conditions, leading to increased production costs of drugs. Therefore, the preparation of drug crystal forms with low hygroscopicity is essential for drug production.
  • the hygroscopicity study of the crystal form K3 of the present invention is as follows:
  • the general rule 9103 of the Chinese Pharmacopoeia describes the characteristics of moisture absorption and the definition of weight gain:
  • Deliquescence Absorb enough water to form a liquid.
  • moisture-absorbing weight gain is not less than 15%.
  • moisture absorption weight gain is less than 15% but not less than 2%.
  • moisture absorption weight gain is less than 2% but not less than 0.2%.
  • the weight gain is less than 0.2%.
  • XRPD was used to test the crystal form K3 of the present invention to determine the crystal form and crystallinity of the sample in the initial state.
  • the crystal form K3 of the present invention was respectively placed in a mortar, manually ground for 5 minutes, and XRPD was used to test the crystal form after grinding.
  • Crystalline drugs with good mechanical stability have low requirements on crystallization equipment, do not require special post-processing conditions, are more stable in the preparation process, can significantly reduce drug development costs, improve drug quality, and have strong economic value.
  • Different crystal forms may exhibit different compressibility, bulk density, fluidity, and stability to grinding, pressure, and pulverization due to their different particle properties, thereby affecting the process in the formulation.
  • a narrower particle size distribution can improve the uniformity of the drug substance components in the preparation, and at the same time make the difference between different batches of preparations smaller, such as more uniform dissolution; smaller crystal size can increase the specific surface area of the drug , Improve the dissolution rate of the drug, which is conducive to the absorption of the drug, thereby increasing the bioavailability.
  • Large agglomerates of crystals are usually easy to encapsulate residual solvents or other impurities.
  • the bulk crystal powder cannot be uniformly dispersed, and it is difficult to mix uniformly with the auxiliary materials, which is not conducive to the preparation of the preparation.
  • the compressibility coefficient is calculated according to the following formula.
  • Compressibility coefficient (%) (tap density-bulk density)/tap density ⁇ 100%
  • the crystal form with good fluidity can effectively increase the production speed of tableting and filling, and improve production efficiency; there is no need to use some expensive special auxiliary materials to improve fluidity and reduce the cost of auxiliary materials; in addition, It can improve the feasibility of direct compression and direct powder filling, greatly simplify the production process and reduce production costs.
  • a crystal form with good fluidity can ensure the uniformity and content uniformity of the preparation, reduce the weight difference of the dosage form, and improve the quality of the product.
  • the low-adhesive crystal form can effectively improve or avoid sticky wheels and sticking caused by dry granulation and tablet compression. It is beneficial to improve the appearance, weight difference, etc. product quality.
  • the low-adhesive crystal form can effectively reduce the agglomeration of raw materials, reduce the adsorption between materials and utensils, facilitate the dispersion of raw materials and the mixing with other auxiliary materials, and increase the uniformity of the mixing of materials and the content of the final product. Evenness.
  • the physical and chemical stability is good, which is convenient for industrial production; the dissolution in vitro is good, which is beneficial to improve the bioavailability of the drug.
  • the stability is excellent, which is conducive to the production, packaging, storage and transportation of medicines and guarantees the quality of the products.
  • the present invention provides a crystalline form K3 of Acalabrutinib, which has advantages in at least one aspect of solubility, melting point, stability, dissolution, hygroscopicity, adhesion, fluidity, bioavailability, processing performance, preparation production, etc., It provides a new and better choice for the preparation of pharmaceutical preparations containing Acalabrutinib, which is of great significance for drug development.

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Abstract

La présente invention concerne une nouvelle forme cristalline de l'acalabrutinib, ainsi qu'un procédé de préparation de celle-ci, une composition pharmaceutique contenant la forme cristalline, et des utilisations de la forme cristalline dans la préparation d'un inhibiteur de la tyrosine kinase de Bruton ainsi qu'une préparation pharmaceutique servant à traiter un lymphome à cellules du manteau. La nouvelle forme cristalline selon la présente invention a des avantages économiques évidents et présente une ou plusieurs propriétés améliorées par rapport à l'état de la technique et est de grande valeur pour l'optimisation et le développement du médicament à l'avenir.
PCT/CN2020/113424 2019-12-31 2020-09-04 Nouvelle forme cristalline de l'acalabrutinib, son procédé de préparation et son utilisation Ceased WO2021135346A1 (fr)

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CN201911411450.9 2019-12-31
CN201911411450 2019-12-31

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114605416A (zh) * 2020-12-08 2022-06-10 奥锐特药业(天津)有限公司 阿卡替尼晶型i的制备方法

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018064797A1 (fr) * 2016-10-05 2018-04-12 杭州领业医药科技有限公司 Forme cristalline d'acp-196, procédé de préparation et composition pharmaceutique associés
CN108349978A (zh) * 2015-07-02 2018-07-31 安塞塔制药公司 (S)-4-(8-氨基-3-(1-(丁-2-炔酰基)吡咯烷-2-基)咪唑并[1,5-a]吡嗪-1-基)-N-(吡啶-2-基)苯甲酰胺的固体形式和制剂
WO2019105359A1 (fr) * 2017-11-30 2019-06-06 苏州科睿思制药有限公司 Forme cristalline de l'acalabrutinib, son procédé de préparation et son application
WO2019159097A1 (fr) * 2018-02-14 2019-08-22 Sun Pharmaceutical Industries Limited Nouvelles formes polymorphes cristallines d'acalabrutinib
WO2019205812A1 (fr) * 2018-04-26 2019-10-31 苏州科睿思制药有限公司 Nouvelle forme cristalline de l'acalabrutinib, son procédé de préparation et son utilisation
WO2020065667A1 (fr) * 2018-09-25 2020-04-02 Cipla Limited Nouveaux polymorphes d'acalabrutinib, un inhibiteur de la tyrosine kinase de bruton

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108349978A (zh) * 2015-07-02 2018-07-31 安塞塔制药公司 (S)-4-(8-氨基-3-(1-(丁-2-炔酰基)吡咯烷-2-基)咪唑并[1,5-a]吡嗪-1-基)-N-(吡啶-2-基)苯甲酰胺的固体形式和制剂
WO2018064797A1 (fr) * 2016-10-05 2018-04-12 杭州领业医药科技有限公司 Forme cristalline d'acp-196, procédé de préparation et composition pharmaceutique associés
WO2019105359A1 (fr) * 2017-11-30 2019-06-06 苏州科睿思制药有限公司 Forme cristalline de l'acalabrutinib, son procédé de préparation et son application
WO2019159097A1 (fr) * 2018-02-14 2019-08-22 Sun Pharmaceutical Industries Limited Nouvelles formes polymorphes cristallines d'acalabrutinib
WO2019205812A1 (fr) * 2018-04-26 2019-10-31 苏州科睿思制药有限公司 Nouvelle forme cristalline de l'acalabrutinib, son procédé de préparation et son utilisation
WO2020065667A1 (fr) * 2018-09-25 2020-04-02 Cipla Limited Nouveaux polymorphes d'acalabrutinib, un inhibiteur de la tyrosine kinase de bruton

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114605416A (zh) * 2020-12-08 2022-06-10 奥锐特药业(天津)有限公司 阿卡替尼晶型i的制备方法
CN114605416B (zh) * 2020-12-08 2023-12-01 奥锐特药业(天津)有限公司 阿卡替尼晶型i的制备方法

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