WO2019134455A1 - Acalabrutinib的新晶型及其制备方法和用途 - Google Patents
Acalabrutinib的新晶型及其制备方法和用途 Download PDFInfo
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- WO2019134455A1 WO2019134455A1 PCT/CN2018/116288 CN2018116288W WO2019134455A1 WO 2019134455 A1 WO2019134455 A1 WO 2019134455A1 CN 2018116288 W CN2018116288 W CN 2018116288W WO 2019134455 A1 WO2019134455 A1 WO 2019134455A1
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- crystal form
- propanediol
- solvate
- ray powder
- acalabrutinib
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- WDENQIQQYWYTPO-IBGZPJMESA-N CC#CC(N(CCC1)[C@@H]1c1nc(-c(cc2)ccc2C(Nc2ccccn2)=O)c2[n]1ccnc2N)=O Chemical compound CC#CC(N(CCC1)[C@@H]1c1nc(-c(cc2)ccc2C(Nc2ccccn2)=O)c2[n]1ccnc2N)=O WDENQIQQYWYTPO-IBGZPJMESA-N 0.000 description 1
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- 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
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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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Definitions
- the invention relates to the field of medicinal chemistry.
- it relates to the crystalline form of Acalabrutinib and its preparation and use.
- Mantle Cell Lymphoma is one of the non-Hodgkin's lymphomas and is a difficult to cure lymphoma.
- 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 activation and survival of mature B cells. BTK has been reported to play a role in apoptosis, and thus BTK inhibitors are useful in the treatment of certain B-cell lymphomas and leukemias.
- Acalabrutinib is a second-generation BTK inhibitor with higher drug selectivity and lower side effects than the first-generation BTK inhibitor, Ibrutinib.
- the availability of Acalabrutinib provides a new treatment option for patients with relapsed drug-resistant mantle cell lymphoma.
- Acalabrutinib was developed by Acerta and launched in the US in October 2017.
- the crystal form is a different solid form formed by different arrangement of compound molecules in the lattice space.
- the drug polymorph refers to the presence of two or more different crystal forms of the drug.
- crystal forms of the drug may affect its dissolution and absorption in the body, it may affect the clinical efficacy and safety of the drug to some extent; especially for poorly soluble oral drugs, the effect of crystal form will be greater. Therefore, in the development of solid oral formulations, the study of crystalline forms facilitates the selection of a crystalline form that is clinically therapeutically meaningful and stable and controllable.
- the drug crystal form must be an important part of drug research, detection and supervision, and an important part of drug quality control.
- Patent WO2017002095A1 discloses eight crystal forms of Acalabrutinib, in which the crystal form I is an anhydrate; the crystal form II is a trihydrate, the flowability is poor, the particle size is not uniform, the water content is different under different conditions, and the highest water content can be Up to 10%; Form III is dihydrate, crystal form is unstable, water content is different under different conditions, the highest water content can reach 8%; Form IV, Form V is anhydrate, unstable, respectively Form II is obtained by dehydration and heat dehydration under low moisture conditions; Form VI, Form VII is a methanol solvate; and Form VIII is an acetic acid solvate. Therefore, it is necessary to perform polymorph screening to find crystal forms that can be used in pharmaceutical preparations, making the developed crystal form more suitable for industrial production.
- the present invention provides L-lactide ethyl ester solvate crystal form A of Acalabrutinib, glycerol solvate crystal form D, (S)-1,2-propanediol solvate crystal form F, (R)-1, 2 - Propylene glycol solvate Form G, (R)-1,2-propanediol solvate Form CS15, which is stable, melting point, solubility, in vitro and in vivo dissolution, wettability, bioavailability, adhesion, compressibility
- sex ethyl ester solvate crystal form A of Acalabrutinib, glycerol solvate crystal form D
- (S)-1,2-propanediol solvate crystal form F (R)-1, 2 - Propylene glycol solvate Form G
- (R)-1,2-propanediol solvate Form CS15 which is stable, melting point, solubility, in vitr
- the solvent used has low toxicity, simple preparation method, good repeatability, remarkable purification effect, high dissolution rate, good wettability, fluidity, compressibility and adhesion, and provides a new and better preparation for pharmaceutical preparations containing Acalabrutinib. Good choices are very important.
- the main object of the present invention is to provide a novel crystalline form of Acalabrutinib and a process for its preparation and use.
- the present invention provides L-lactate ethyl ester solvate crystal form A (hereinafter referred to as "crystal form A”) of the compound (I).
- the X-ray powder diffraction of the crystal form A has a characteristic peak at a diffraction angle 2 ⁇ of 5.7° ⁇ 0.2°, 17.4° ⁇ 0.2°, and 18.2° ⁇ 0.2°.
- the X-ray powder diffraction of the Form A has a characteristic peak at one, or two, or three of the diffraction angles 2 ⁇ of 8.5° ⁇ 0.2°, 13.9° ⁇ 0.2°, and 24.8° ⁇ 0.2°.
- the X-ray powder diffraction of the Form A has a characteristic peak at a diffraction angle 2 ⁇ of 8.5° ⁇ 0.2°, 13.9° ⁇ 0.2°, and 24.8° ⁇ 0.2°.
- the X-ray powder diffraction of the Form A has a characteristic peak at one, or two, or three of the diffraction angles 2 ⁇ of 19.2° ⁇ 0.2°, 22.9° ⁇ 0.2°, and 15.1° ⁇ 0.2°.
- the X-ray powder diffraction of the Form A has a characteristic peak at a diffraction angle 2 ⁇ of 19.2° ⁇ 0.2°, 22.9° ⁇ 0.2°, and 15.1° ⁇ 0.2°.
- the X-ray powder diffraction of the crystal form A is 5.7° ⁇ 0.2°, 17.4° ⁇ 0.2°, 18.2° ⁇ 0.2°, 8.5° ⁇ 0.2°, 13.9 at the diffraction angle 2 ⁇ . Any 3, or 4, or 5, or 6, or 7 of ° ⁇ 0.2 °, 24.8 ° ⁇ 0.2 °, 19.2 ° ⁇ 0.2 °, 22.9 ° ⁇ 0.2 °, 15.1 ° ⁇ 0.2 °, Or there are characteristic peaks at 8 or 9 places.
- the X-ray powder diffraction pattern of Form A is substantially as shown in FIG.
- the present invention also provides a process for preparing the crystal form A, which comprises: placing Acalabrutinib free base in an L-ethyl lactate solvent or a solvent containing L-ethyl lactate, and placing The reaction was carried out at 5-60 ° C for 1-3 days to give a solid.
- the temperature of the reaction is preferably 40-50 ° C;
- the time of the reaction is preferably 24 hours.
- the crystal form A provided by the present invention has good physical stability. After being placed at 25 ° C / 60% Relative Humidity (RH) and 25 ° C / 60% RH closed, the crystal form A did not change for at least 2 months, and the purity remained basically unchanged during storage. It is indicated that the crystalline form A drug substance has good long-term stability and is beneficial for drug storage. At the same time, it was placed under the condition of 40 ° C / 75% RH open and 40 ° C / 75% RH closed, and the crystal form A did not change for at least 2 months. It shows that the crystalline form A drug substance has better acceleration stability and is beneficial for the drug to be stored under special environmental conditions, such as the tropics.
- Form A has good physical stability, ensuring consistent controllable quality of the drug substance and preparation, and maximally reducing the toxicity of the drug due to crystal form change, ensuring the efficacy of the drug.
- the crystal form A of the present invention has a superior dissolution rate as compared with the prior art.
- the intrinsic dissolution rate of the Form A API is 1.2 times that of the prior art WO2017002095A1 Form I in a pH 2.5 HCl/NaCl solution.
- Different crystal forms may lead to different dissolution rates of the preparation in the body, which directly affect the absorption, distribution, excretion and metabolism of the preparation in the body, and finally the difference in clinical efficacy due to different bioavailability.
- the dissolution rate is an important prerequisite for the absorption of the drug.
- the high dissolution rate allows the drug to reach the highest concentration in the plasma quickly after administration, thereby ensuring rapid drug action.
- the crystal form A of the present invention has a good purification effect.
- the purity is significantly improved after the preparation of the raw material from the raw material.
- the purity of the raw material used in the present invention is 98.93%. After the preparation of the crystalline form A, the purity is increased to 99.63%, and the purity is improved by 0.70%.
- the chemical purity of the drug is of great significance for ensuring the efficacy and safety of the drug and preventing the occurrence of adverse drug reactions.
- Impurities in drugs are the main factors affecting purity. For example, if the drug contains more than a limited amount of impurities, it may change the physical and chemical constants, the appearance traits will mutate, and affect the stability of the drug. The increase of impurities also makes the drug content significantly lower or The activity is reduced and the side effects are significantly increased.
- the crystal form with good purification effect can exhibit extremely strong impurity elimination ability in the crystallization process, so that the raw material medicine with higher purity can be obtained by crystallization, and the drug stability with low drug purity is low, and the curative effect is poor. , high toxicity and other shortcomings.
- the crystal form A of the present invention has a low wettability.
- the test results show that the crystal form A of the present invention has a wettability weight gain of 0.99% under the condition of 80% RH, which is slightly wetted.
- Humidity affects the stability of the drug, fluidity and uniformity during processing, and ultimately affects the quality of the drug formulation. Humidity affects the preparation, post-treatment and storage of the drug.
- the low wettability crystal form requires less stringent storage conditions, reduces material storage and quality control costs, and has high economic value.
- crystal form A provided by the present invention has the following beneficial effects:
- the crystal form A provided by the present invention has superior compressibility.
- the good compressibility of the crystal form A can effectively improve the hardness/friability degree, cracking and the like in the tableting process, and make the preparation process more controllable, improve the appearance of the product, and improve the product quality.
- Better compressibility also increases the tableting speed and thus the production efficiency, while reducing the cost of the excipients used to improve the compressibility.
- the crystal form A of the present invention has better adhesion than the prior art.
- the results of the adhesion evaluation showed that the adsorption amount of the crystal form A was lower than that of the prior art crystal form.
- the low adhesion of the crystal form A can effectively improve or avoid the phenomenon of sticking and sticking caused by dry granulation and tablet tableting, and is beneficial to improving the appearance and weight difference of the product.
- the low adhesion of Form A can effectively reduce the agglomeration of raw materials, reduce the adsorption between materials and utensils, facilitate the dispersion of raw materials and mixing with other excipients, increase the mixing uniformity of materials and the final product. Content uniformity.
- the crystal form A of the present invention has good fluidity. Good fluidity can effectively improve the production speed of tableting and filling, and improve production efficiency; the good flowability of crystal form A ensures the mixing uniformity and content uniformity of the preparation, reduces the weight difference of the dosage form, and improves the product quality.
- the present invention provides a glycerol solvate crystal form D (hereinafter referred to as "crystal form D”) of the compound (I).
- the X-ray powder diffraction of the crystal form D has a characteristic peak at a diffraction angle 2 ⁇ of 14.2° ⁇ 0.2°, 6.7° ⁇ 0.2°, 13.4° ⁇ 0.2°.
- the X-ray powder diffraction of the crystal form D has a characteristic peak at one, or two, or three of the diffraction angles 2 ⁇ of 16.2° ⁇ 0.2°, 11.0° ⁇ 0.2°, and 9.6° ⁇ 0.2°.
- the X-ray powder diffraction of the crystal form D has a characteristic peak at a diffraction angle 2 ⁇ of 16.2° ⁇ 0.2°, 11.0° ⁇ 0.2°, and 9.6° ⁇ 0.2°.
- the X-ray powder diffraction of the crystal form D has a characteristic peak at one, or two, or three of the diffraction angles 2 ⁇ of 8.1° ⁇ 0.2°, 24.3° ⁇ 0.2°, and 20.3° ⁇ 0.2°.
- the X-ray powder diffraction of the crystal form D has a characteristic peak at a diffraction angle 2 ⁇ of 8.1° ⁇ 0.2°, 24.3° ⁇ 0.2°, and 20.3° ⁇ 0.2°.
- the X-ray powder diffraction of the crystal form D is 14.2° ⁇ 0.2°, 6.7° ⁇ 0.2°, 13.4° ⁇ 0.2°, 16.2° ⁇ 0.2°, 11.0 at the diffraction angle 2 ⁇ . Any three, or four, or five, or six, or seven of ° ⁇ 0.2 °, 9.6 ° ⁇ 0.2 °, 8.1 ° ⁇ 0.2 °, 24.3 ° ⁇ 0.2 °, 20.3 ° ⁇ 0.2 °, Or there are characteristic peaks at 8 or 9 places.
- the X-ray powder diffraction pattern of Form D is substantially as shown in FIG.
- the present invention also provides a process for preparing the crystal form D, which comprises: placing Acalabrutinib free base in a glycerol solvent or a solvent containing glycerin at 20-80 ° C The reaction was carried out for 10-72 hours to give a solid.
- the temperature of the reaction is preferably from 50 to 60 ° C;
- the time of the reaction is preferably 24 hours.
- the crystal form D provided by the present invention has good physical stability. Under the condition of 25 ° C / 60% RH open, 25 ° C / 60% RH closed, the crystal form D did not change for at least 2 months, and the purity remained basically unchanged during storage. It is indicated that the crystalline form D drug substance has good long-term stability and is beneficial for drug storage. At the same time, it was placed under 40 ° C / 75% RH closed conditions, and the crystal form D did not change for at least 2 months. It shows that the crystalline D drug substance has better acceleration stability and is beneficial for the drug to be stored under special environmental conditions, such as in the tropics.
- Form D has good physical stability, ensuring consistent controllable quality of the drug substance and preparation, and maximally reducing the toxicity of the drug due to crystal form change, ensuring the efficacy of the drug.
- the crystal form D of the present invention has a good purification effect.
- the purity is significantly improved after the preparation of the raw material from the raw material.
- the purity of the raw material used in the present invention is 98.93%. After the preparation of the crystalline form D, the purity is increased to 99.49%, and the purity is improved by 0.56%.
- the chemical purity of the drug is of great significance for ensuring the efficacy and safety of the drug and preventing the occurrence of adverse drug reactions.
- Impurities in drugs are the main factors affecting purity. For example, if the drug contains more than a limited amount of impurities, it may change the physical and chemical constants, the appearance traits will mutate, and affect the stability of the drug. The increase of impurities also makes the drug content significantly lower or The activity is reduced and the side effects are significantly increased.
- the crystal form with good purification effect can exhibit extremely strong impurity elimination ability in the crystallization process, so that the raw material medicine with higher purity can be obtained by crystallization, and the drug stability with low drug purity is low, and the curative effect is poor. , high toxicity and other shortcomings.
- the crystal form D of the present invention has a superior dissolution rate as compared with the prior art.
- the intrinsic dissolution rate of the Form D drug substance in the pH 2.5 HCl/NaCl solution was 1.1 times that of the prior art WO2017002095A1 Form I.
- Different crystal forms may lead to different dissolution rates of the preparation in the body, which directly affect the absorption, distribution, excretion and metabolism of the preparation in the body, and finally the difference in clinical efficacy due to different bioavailability.
- the dissolution rate is an important prerequisite for the absorption of the drug.
- the high dissolution rate allows the drug to reach the highest concentration in the plasma quickly after administration, thereby ensuring rapid drug action.
- crystal form D provided by the present invention has the following beneficial effects:
- the crystal form D provided by the present invention has better compressibility.
- the good pressureability of the crystal form D can effectively improve the hardness/friability degree, cracking and the like in the tableting process, so that the preparation process is more stable, the appearance of the product is improved, and the product quality is improved.
- Better compressibility also increases the tableting speed and thus the production efficiency, while reducing the cost of the excipients used to improve the compressibility.
- Form F (S)-1,2-propanediol solvate Form F (hereinafter referred to as "Form F”) of Compound (I).
- the X-ray powder diffraction of the Form F has characteristic peaks at diffraction angles 2 ⁇ of 16.1° ⁇ 0.2°, 24.3° ⁇ 0.2°, and 12.4° ⁇ 0.2°.
- the X-ray powder diffraction of the Form F has a characteristic peak at one, or two, or three of the diffraction angles 2 ⁇ of 10.0° ⁇ 0.2°, 18.0° ⁇ 0.2°, and 13.2° ⁇ 0.2°.
- the X-ray powder diffraction of the Form F has a characteristic peak at a diffraction angle 2 ⁇ of 10.0° ⁇ 0.2°, 18.0° ⁇ 0.2°, and 13.2° ⁇ 0.2°.
- the X-ray powder diffraction of the Form F has a characteristic peak at one, or two, or three of the diffraction angles 2 ⁇ of 8.1° ⁇ 0.2°, 14.5° ⁇ 0.2°, and 18.9° ⁇ 0.2°.
- the X-ray powder diffraction of the Form F has a characteristic peak at a diffraction angle 2 ⁇ of 8.1° ⁇ 0.2°, 14.5° ⁇ 0.2°, and 18.9° ⁇ 0.2°.
- the X-ray powder diffraction of the form F is 16.1° ⁇ 0.2°, 24.3° ⁇ 0.2°, 12.4° ⁇ 0.2°, 10.0° ⁇ 0.2°, 18.0 at the diffraction angle 2 ⁇ .
- the X-ray powder diffraction pattern of Form F is substantially as shown in FIG.
- the present invention also provides a method for preparing the crystalline form F, which comprises: placing Acalabrutinib free base in a solvent of (S)-1,2-propanediol at 5 to 60 ° C, The reaction was carried out for 10-72 hours to give a solid.
- the temperature of the reaction is preferably room temperature -50 ° C;
- the time of the reaction is preferably 24 hours.
- the crystal form F provided by the present invention has good physical stability. Under the conditions of 25 ° C / 60% RH open, 25 ° C / 60% RH closed mouth, the form F did not change for at least 2 months, and the purity remained basically unchanged during storage. It is indicated that the crystalline form F drug substance has good long-term stability and is beneficial for drug storage. At the same time, it was placed under the condition of 40 ° C / 75% RH open and 40 ° C / 75% RH closed, and the crystal form F did not change for at least 2 months.
- the physical stability of the drug substance is critical to the drug. From bulk drugs to drugs, they need to go through storage, transportation, and formulation processes. These processes often encounter harsh conditions, most often high temperatures and high humidity. Such as the collision of raw materials in storage and transportation, the wet granulation process in the production of the preparation, the seasonal and regional climate differences, and weather factors.
- the prior art solids are partially converted to a crystalline form after being placed under high temperature and high humidity conditions, while the crystalline form of the present invention is not converted.
- Form F has good physical stability, ensuring consistent controllable quality of the drug substance and preparation, and maximally reducing the toxicity of the drug due to crystal form change, and ensuring the efficacy of the drug.
- the crystalline form F of the present invention has a superior dissolution rate as compared with the prior art.
- the intrinsic dissolution rate of the Form F drug substance in the pH 2.5 HCl/NaCl solution was 1.3 times that of the prior art WO2017002095A1 Form I.
- Different crystal forms may lead to different dissolution rates of the preparation in the body, which directly affect the absorption, distribution, excretion and metabolism of the preparation in the body, and finally the difference in clinical efficacy due to different bioavailability.
- the dissolution rate is an important prerequisite for the absorption of the drug.
- the high dissolution rate allows the drug to reach the highest concentration in the plasma quickly after administration, thereby ensuring rapid drug action.
- the crystalline form F of the present invention has a good purification effect.
- the purity is significantly improved after the preparation of the raw material from the raw material.
- the purity of the raw material used in the present invention is 98.93%. After the preparation of the crystalline form F, the purity is increased to 99.80%, and the purity is improved by 0.87%.
- the chemical purity of the drug is of great significance for ensuring the efficacy and safety of the drug and preventing the occurrence of adverse drug reactions.
- Impurities in drugs are the main factors affecting purity. For example, if the drug contains more than a limited amount of impurities, it may change the physical and chemical constants, the appearance traits will mutate, and affect the stability of the drug. The increase of impurities also makes the drug content significantly lower or The activity is reduced and the side effects are significantly increased.
- the crystal form with good purification effect can exhibit extremely strong impurity elimination ability in the crystallization process, so that the raw material medicine with higher purity can be obtained by crystallization, and the drug stability with low drug purity is low, and the curative effect is poor. , high toxicity and other shortcomings.
- the crystalline form F of the present invention has a low wettability.
- the test results show that the crystal form F of the present invention has a wet weight gain of 0.09% under the condition of 80% RH, and has no or almost no wettability.
- Humidity affects the stability of the drug, fluidity and uniformity during processing, and ultimately affects the quality of the drug formulation. Humidity affects the preparation, post-treatment and storage of the drug.
- the low wettability crystal form requires less stringent storage conditions, reduces material storage and quality control costs, and has high economic value.
- crystal form F provided by the present invention has the following beneficial effects:
- the crystal form F provided by the present invention has superior compressibility as compared with the prior art.
- the good pressability of the crystal form F can effectively improve the hardness/friability degree, cracking and the like in the tableting process, and make the preparation process more stable, improve the appearance of the product, and improve the product quality.
- Better compressibility also increases the tableting speed and thus the production efficiency, while reducing the cost of the excipients used to improve the compressibility.
- the crystalline form F of the present invention has superior adhesion.
- the results of adhesion evaluation showed that the adsorption amount of Form F was lower than that of the prior art crystal form.
- the low adhesion of the crystalline form F can effectively improve or avoid the phenomenon of sticking and sticking caused by dry granulation and tablet tableting, and is beneficial to improving the appearance and weight difference of the product.
- the low adhesion of Form F can effectively reduce the agglomeration of raw materials, reduce the adsorption between materials and utensils, facilitate the dispersion of raw materials and mixing with other excipients, increase the mixing uniformity of materials and the final product. Content uniformity.
- the crystal form F of the present invention has good fluidity. Good fluidity can effectively improve the production speed of tableting and filling, and improve production efficiency; the good flowability of crystal form F ensures the mixing uniformity and content uniformity of the preparation, reduces the weight difference of the dosage form, and improves the product quality.
- crystal form G (R)-1,2-propanediol solvate crystal form G (hereinafter referred to as "crystal form G") of the compound (I).
- the X-ray powder diffraction of the Form G has characteristic peaks at diffraction angles 2 ⁇ of 5.1° ⁇ 0.2°, 12.2° ⁇ 0.2°, and 13.5° ⁇ 0.2°.
- the X-ray powder diffraction of the crystal form G has a characteristic peak at one, or two, or three of the diffraction angles 2 ⁇ of 15.6° ⁇ 0.2°, 17.0° ⁇ 0.2°, and 6.6° ⁇ 0.2°.
- the X-ray powder diffraction of the Form G has a characteristic peak at a diffraction angle 2 ⁇ of 15.6° ⁇ 0.2°, 17.0° ⁇ 0.2°, and 6.6° ⁇ 0.2°.
- the X-ray powder diffraction of the Form G has a characteristic peak at one, or two, or three of the diffraction angles 2 ⁇ of 23.0° ⁇ 0.2°, 17.7° ⁇ 0.2°, and 21.3° ⁇ 0.2°.
- the X-ray powder diffraction of the Form G has a characteristic peak at a diffraction angle 2 ⁇ of 23.0° ⁇ 0.2°, 17.7° ⁇ 0.2°, and 21.3° ⁇ 0.2°.
- the X-ray powder diffraction of the crystal form G is 5.1° ⁇ 0.2°, 12.2° ⁇ 0.2°, 13.5° ⁇ 0.2°, 15.6° ⁇ 0.2°, 17.0 at the diffraction angle 2 ⁇ . Any 3, or 4, or 5, or 6 or 7 of ° ⁇ 0.2 °, 6.6 ° ⁇ 0.2 °, 23.0 ° ⁇ 0.2 °, 17.7 ° ⁇ 0.2 °, 21.3 ° ⁇ 0.2 °, Or there are characteristic peaks at 8 or 9 places.
- the X-ray powder diffraction pattern of Form G is substantially as shown in FIG.
- the present invention also provides a process for preparing the crystalline form G, which comprises: placing Acalabrutinib free base in a solvent of (R)-1,2-propanediol at 5 to 60 ° C, The reaction was carried out for 10-48 hours to give a solid.
- the temperature of the reaction is preferably room temperature
- the time of the reaction is preferably 24 hours.
- the crystal form G provided by the present invention has good physical stability. When placed under the condition of 25 ° C / 60% RH closed mouth, the crystal form G did not change for at least 2 months, and the purity remained basically unchanged during storage. It shows that the crystalline G drug substance has good long-term stability and is beneficial for drug storage.
- Form G has good physical stability, ensuring consistent controllable quality of the drug substance and preparation, and maximally reducing the toxicity of the drug due to crystal form change, and ensuring the efficacy of the drug.
- the crystal form G of the present invention has a superior dissolution rate as compared with the prior art.
- the intrinsic dissolution rate of the Form G drug substance in the pH 2.5 HCl/NaCl solution was 1.2 times that of the prior art WO2017002095A1 Form I.
- Different crystal forms may lead to different dissolution rates of the preparation in the body, which directly affect the absorption, distribution, excretion and metabolism of the preparation in the body, and finally the difference in clinical efficacy due to different bioavailability.
- the dissolution rate is an important prerequisite for the absorption of the drug.
- the high dissolution rate allows the drug to reach the highest concentration in the plasma quickly after administration, thereby ensuring rapid drug action.
- the crystal form G of the present invention has a good purification effect.
- the purity is significantly improved after the preparation of the raw material from the raw material.
- the purity of the raw material used in the present invention is 98.93%.
- the purity is increased to 99.86%, and the purity is improved by 0.93%.
- the chemical purity of the drug is of great significance for ensuring the efficacy and safety of the drug and preventing the occurrence of adverse drug reactions.
- Impurities in drugs are the main factors affecting purity. For example, if the drug contains more than a limited amount of impurities, it may change the physical and chemical constants, the appearance traits will mutate, and affect the stability of the drug. The increase of impurities also makes the drug content significantly lower or The activity is reduced and the side effects are significantly increased.
- the crystal form with good purification effect can exhibit extremely strong impurity elimination ability in the crystallization process, so that the raw material medicine with higher purity can be obtained by crystallization, and the drug stability with low drug purity is low, and the curative effect is poor. , high toxicity and other shortcomings.
- crystal form G provided by the present invention has the following beneficial effects:
- the crystal form G provided by the present invention has superior compressibility.
- the good pressure property of the crystal form G can effectively improve the hardness/friability degree, cracking and the like in the tableting process, so that the preparation process is more stable, the appearance of the product is improved, and the product quality is improved.
- Better compressibility also increases the tableting speed and thus the production efficiency, while reducing the cost of the excipients used to improve the compressibility.
- the crystal form G of the present invention has superior adhesion as compared with the prior art.
- the results of the adhesion evaluation showed that the adsorption amount of the crystal form G was lower than that of the prior art crystal form.
- the low adhesion of the crystal form G can effectively improve or avoid the phenomenon of sticking and sticking caused by dry granulation and tablet tableting, and is beneficial to improving the appearance and weight difference of the product.
- the low adhesion of Form G can effectively reduce the agglomeration of raw materials, reduce the adsorption between materials and utensils, facilitate the dispersion of raw materials and mixing with other excipients, increase the mixing uniformity of materials and the final product. Content uniformity.
- the crystal form G of the present invention has good fluidity. Good fluidity can effectively improve the production speed of tableting and filling, and improve production efficiency; the good flowability of crystal form G ensures the uniformity of mixing and content uniformity of the preparation, reduces the weight difference of the dosage form, and improves the product quality.
- crystal form CS15 (R)-1,2-propanediol solvate crystal form CS15 (hereinafter referred to as "crystal form CS15") of the compound (I).
- the X-ray powder diffraction of the crystal form CS15 has a characteristic peak at a diffraction angle 2 ⁇ of 8.6° ⁇ 0.2°, 9.3° ⁇ 0.2°, and 13.6° ⁇ 0.2°.
- the X-ray powder diffraction of the crystal form CS15 is at one or two of the diffraction angles 2 ⁇ of 8.0° ⁇ 0.2°, 14.3° ⁇ 0.2°, 17.4° ⁇ 0.2°, and 19.2° ⁇ 0.2°. Or a characteristic peak at 3 or 4; preferably, the X-ray powder diffraction of the crystalline form CS15 is 8.0° ⁇ 0.2°, 14.3° ⁇ 0.2°, 17.4° ⁇ 0.2°, 19.2° ⁇ at a diffraction angle 2 ⁇ There is a characteristic peak at 0.2°.
- the X-ray powder diffraction of the crystal form CS15 is 8.6° ⁇ 0.2°, 9.3° ⁇ 0.2°, 13.6° ⁇ 0.2°, 8.0° ⁇ 0.2°, 14.3 at the diffraction angle 2 ⁇ . Any 3, or 4, or 5, or 6 of ° ⁇ 0.2 °, 17.4 ° ⁇ 0.2 °, 19.2 ° ⁇ 0.2 °, 20.2 ° ⁇ 0.2 °, 22.2 ° ⁇ 0.2 °, 22.9 ° ⁇ 0.2 ° There are characteristic peaks at, or at 7, or 8, or at 9, or at 10.
- the X-ray powder diffraction pattern of Form CS15 is substantially as shown in FIG.
- the present invention also provides a method for preparing the crystalline form CS15, which comprises: placing Acalabrutinib free base in a solvent of (R)-1,2-propanediol at 5 to 60 ° C, The reaction is carried out for 10 to 48 hours, and the obtained sample is placed in a nitrile solvent and stirred at -20 to 5 ° C for 1 to 7 days to obtain a solid;
- Acalabrutinib free base is placed in a mixed solvent of (R)-1,2-propanediol solvent and a nitrile solvent, and placed at 5-60 ° C for 10 to 48 hours to obtain a solid.
- the temperature of the reaction is preferably room temperature
- the time of the reaction is preferably 24 hours.
- the crystal form CS15 provided by the present invention has the following beneficial effects:
- the crystal form CS15 provided by the present invention has good physical stability. Under the condition of 25 ° C / 60% RH open, 25 ° C / 60% RH closed, the crystalline form of CS15 did not change for at least 2 months, and the purity remained basically unchanged during storage. It shows that the crystalline CS15 drug substance has good long-term stability and is beneficial for drug storage.
- the transformation of the crystal form causes a change in the absorption of the drug, causing toxic side effects of the drug.
- the crystalline form CS15 has good physical stability, ensuring consistent controllable quality of the drug substance and the preparation, and maximally reducing the toxicity of the drug due to the change of the crystal form, and ensuring the therapeutic effect of the drug.
- the crystal form CS15 of the present invention has a superior dissolution rate as compared with the prior art.
- the intrinsic dissolution rate of the Form CS15 drug substance in the pH 2.5 HCl/NaCl solution was 1.6 times that of the prior art WO2017002095A1 Form I.
- Different crystal forms may lead to different dissolution rates of the preparation in the body, which directly affect the absorption, distribution, excretion and metabolism of the preparation in the body, and finally the difference in clinical efficacy due to different bioavailability.
- the dissolution rate is an important prerequisite for the absorption of the drug.
- the high dissolution rate allows the drug to reach the highest concentration in the plasma quickly after administration, thereby ensuring rapid drug action.
- the crystal form CS15 of the present invention has a good purification effect.
- the purity is significantly improved after the preparation of the raw material from the raw material.
- the purity of the raw material used in the present invention is 99.20%.
- the purity is increased to 99.83%, and the purity is improved by 0.63%.
- the chemical purity of the drug is of great significance for ensuring the efficacy and safety of the drug and preventing the occurrence of adverse drug reactions.
- Impurities in drugs are the main factors affecting purity. For example, if the drug contains more than a limited amount of impurities, it may change the physical and chemical constants, the appearance traits will mutate, and affect the stability of the drug. The increase of impurities also makes the drug content significantly lower or The activity is reduced and the side effects are significantly increased.
- the crystal form with good purification effect can exhibit extremely strong impurity elimination ability in the crystallization process, so that the raw material medicine with higher purity can be obtained by crystallization, and the drug stability with low drug purity is low, and the curative effect is poor. , high toxicity and other shortcomings.
- the crystal form CS15 of the present invention has a low wettability.
- the test results show that the wettability weight gain of the crystalline form CS15 of the present invention is 1.78% under the condition of 80% RH, which is slightly wetted.
- Humidity affects the stability of the drug, fluidity and uniformity during processing, and ultimately affects the quality of the drug formulation. Humidity affects the preparation, post-treatment and storage of the drug.
- the low wettability crystal form requires less stringent storage conditions, reduces material storage and quality control costs, and has high economic value.
- crystal form CS15 provided by the present invention has the following beneficial effects:
- the present invention provides the crystalline form CS15 with superior compressibility.
- the good compressibility of the crystal form CS15 can effectively improve the hardness/friability degree, cracking and the like in the tableting process, making the preparation process more stable, improving the appearance of the product and improving the product quality.
- Better compressibility also increases the tableting speed and thus the production efficiency, while reducing the cost of the excipients used to improve the compressibility.
- the present invention provides an ethylene glycol solvate Form B of Acalabrutinib (hereinafter referred to as "Form B").
- the X-ray powder diffraction of the Form B is 7.1° ⁇ 0.2°, 5.1° ⁇ 0.2°, 14.1° ⁇ 0.2°, 13.3° ⁇ 0.2°, 11.8° ⁇ 0.2° at the diffraction angle 2 ⁇ . There are characteristic peaks at one or more of 21.6° ⁇ 0.2°, 18.1° ⁇ 0.2°, 11.3° ⁇ 0.2°, and 8.0° ⁇ 0.2°.
- the present invention also provides a preparation method of the crystal form B, which comprises dissolving Acalabrutinib free base in ethylene glycol, and placing it in a sealed atmosphere of an ester solvent, and reacting at 5 to 40 ° C. 2 to 5 days, a solid was obtained.
- the ester solvent is preferably isopropyl acetate
- the reaction temperature is preferably room temperature
- the reaction time is preferably 3 days.
- the present invention also provides a pharmaceutical composition
- a pharmaceutical composition comprising a therapeutically effective amount of Form A, Form D, Form F, Form G, Form CS15 or any combination thereof And a pharmaceutically acceptable carrier, diluent or excipient.
- the use of the crystalline form A, the crystalline form D, the crystalline form F, the crystalline form G, the crystalline form CS15 or any combination thereof of the present invention for the preparation of a Bruton's tyrosine kinase inhibitor drug.
- the use of the crystalline form A, the crystalline form D, the crystalline form F, the crystalline form G, the crystalline form CS15 or any combination thereof provided by the present invention for the preparation of a medicament for treating a mantle cell lymphoma.
- the "room temperature” is not an accurate temperature value and means a temperature range of 10-30 °C.
- crystal or “polymorph” means confirmed by X-ray powder diffraction pattern characterization.
- X-ray powder diffraction pattern characterization Those skilled in the art will appreciate that the physicochemical properties discussed herein can be characterized, with experimental error depending on the conditions of the instrument, the preparation of the sample, and the purity of the sample.
- the X-ray diffraction pattern will generally vary with the conditions of the instrument. It is particularly important to note that the relative intensity of the X-ray powder diffraction pattern may also vary with experimental conditions, so the order of peak intensities cannot be the sole or decisive factor. In fact, the relative intensity of the diffraction peaks in the XRPD pattern is related to the preferred orientation of the crystal.
- the peak intensities shown here are illustrative and not for absolute comparison.
- the experimental error of the peak angle is usually 5% or less, and the error of these angles should also be taken into account, and an error of ⁇ 0.2° is usually allowed.
- the overall offset of the peak angle is caused, and a certain offset is usually allowed.
- Any crystal form having a map identical or similar to the characteristic peaks in these maps is within the scope of the present invention.
- One skilled in the art will be able to compare the maps listed herein with a map of an unknown crystal form to verify whether the two sets of maps reflect the same or different crystal forms.
- Form A, Form D, Form F, Form G, Form CS15 of the present invention are pure, unitary, and substantially free of any other crystalline form.
- substantially free when used to refer to a new crystalline form means that the crystalline form contains less than 20% by weight of other crystalline forms, especially less than 10% by weight of other crystalline forms, more Other crystal forms of 5% by weight, more preferably less than 1% by weight of other crystal forms.
- Figure 2 is a DSC chart of L-lactate ethyl ester solvate crystal form A obtained in Example 1.
- Figure 3 is a TGA diagram of Form L of L-lactate solvate obtained in Example 1.
- Figure 1 is a 1 H NMR chart of L-lactate ethyl ester solvate crystal form A obtained in Example 1.
- Figure 5 is an XRPD pattern of the ethylene glycol solvate crystal form B obtained in Example 40.
- Figure 6 is a DSC chart of the ethylene glycol solvate crystal form B obtained in Example 40.
- Figure 7 is a TGA diagram of the ethylene glycol solvate crystal form B obtained in Example 40.
- Figure 1 is a 1 H NMR chart of the ethylene glycol solvate crystal form B obtained in Example 40
- Figure 9 is an XRPD pattern of the glycerol solvate crystal form D obtained in Example 10.
- Figure 10 is a DSC chart of the glycerol solvate crystal form D obtained in Example 10.
- Figure 11 is a TGA diagram of the glycerol solvate crystal form D obtained in Example 10.
- Figure 12 is a 1 H NMR chart of the glycerol solvate crystal form D obtained in Example 10.
- Figure 13 is an XRPD pattern of the crystalline form F of (S)-1,2-propanediol solvate obtained in Example 16.
- Figure 14 is a DSC chart of the crystalline form F of (S)-1,2-propanediol solvate obtained in Example 16.
- Figure 15 is a TGA diagram of the crystalline form F of (S)-1,2-propanediol solvate obtained in Example 16.
- Figure 16 is a 1 H NMR chart of (S)-1,2-propanediol solvate Form F obtained in Example 16.
- Figure 17 is an XRPD pattern of (R)-1,2-propanediol solvate crystal form G obtained in Example 25.
- Figure 18 is a DSC chart of the (R)-1,2-propanediol solvate crystal form G obtained in Example 25.
- Figure 19 is a TGA diagram of the (R)-1,2-propanediol solvate crystal form G obtained in Example 25.
- Figure 20 is a 1 H NMR chart of the (R)-1,2-propanediol solvate crystal form G obtained in Example 25.
- Figure 22 is a DSC chart of the (R)-1,2-propanediol solvate crystal form CS15 obtained in Example 34.
- Figure 23 is a TGA diagram of (R)-1,2-propanediol solvate crystal form CS15 obtained in Example 34.
- Figure 1 is a 1 H NMR chart of (R)-1,2-propanediol solvate crystal form CS15 obtained in Example 33.
- Figure 25 XRPD comparison chart of crystal form A stability study (from top to bottom: initial crystal form A, 25 ° C / 60% RH closed condition for 2 months, 25 ° C / 60% RH open condition Place for 2 months, place at 40 °C / 75% RH for 2 months, and place at 40 °C / 75% RH for 2 months)
- Figure 29 XRPD comparison chart of crystal form D stability study (from top to bottom: initial crystal form D, 25 ° C / 60% RH closed condition for 2 months, 25 ° C / 60% RH open condition Placed for 2 months, placed at 40 ° C / 75% RH closed for 2 months)
- Figure 30 XRPD comparison chart of crystal form F stability study (from top to bottom: initial crystal form F, 25 ° C / 60% RH closed condition for 2 months, 25 ° C / 60% RH open condition Place for 2 months, place at 40 °C / 75% RH for 2 months, and place at 40 °C / 75% RH for 2 months)
- Figure 34 XRPD comparison chart of crystal form G stability study (from top to bottom: initial crystal form G, 25 ° C / 60% RH closed condition for 2 months)
- Figure 36 XRPD comparison chart of crystal form CS15 stability study (from top to bottom: initial crystal form CS15, 25 ° C / 60% RH closed condition for 2 months, 25 ° C / 60% RH open condition Placed for 2 months)
- the parameter description of the test instrument involved in the embodiment is performed.
- the X-ray powder diffraction pattern of the present invention was collected on a Bruker D2 PHASER X-ray powder diffractometer.
- the method parameters of the X-ray powder diffraction described in the present invention are as follows:
- Scan range: from 3.0 to 40.0 degrees
- the differential scanning calorimetry (DSC) map of the present invention was acquired on a TA Q2000.
- the method parameters of the differential scanning calorimetry (DSC) described in the present invention are as follows:
- thermogravimetric analysis (TGA) map of the present invention was taken on a TA Q500.
- the method parameters of the thermogravimetric analysis (TGA) described in the present invention are as follows:
- Nuclear magnetic resonance spectroscopy data ( 1 H NMR) were taken from a Bruker Avance II DMX 400M HZ NMR spectrometer. A sample of 1-5 mg was weighed and dissolved in 0.5 mL of deuterated dimethyl sulfoxide to prepare a solution of 2-10 mg/mL.
- HPLC high performance liquid chromatography
- the elution gradient is as follows:
- the Acalabrutinib and/or its salt as a raw material means a solid (crystalline or amorphous), semi-solid, wax or oil form.
- the compound (I) and/or its salt as a raw material is in the form of a solid powder.
- Acalabrutinib free base solids used in the following examples can be prepared according to the prior art, for example, according to the method described in WO2017002095A1.
- the TGA pattern is as shown in Figure 3, with a mass loss of about 20.1% when heated to 180 °C.
- the liquid nuclear magnetic hydrogen spectrum is as shown in Fig. 4.
- the L-lactate ethyl ester solvate crystal form A contains about 1 mole of L-lactic acid ethyl ester, and the nuclear magnetic resonance peak near 1.25, 4.09 and 5.34 is L- Characteristic peak of ethyl lactate.
- a sample of 1.23 g of Acalabrutinib free base was weighed into a 20 mL glass vial and 12.0 mL of L-ethyl lactate/ethyl acetate (1:1, v/v) was added. After magnetic stirring at 50 ° C for 3 days, it was separated and dried to give 1.34 g of a solid.
- the obtained solid was the crystalline form A of the present invention, and its XRPD data is shown in Table 2.
- the crystal form A obtained in this example has the same or similar XRPD pattern as the crystal form A in Example 1, which is the same crystal form and has the same properties.
- the purity of the free base solid and the L-lactate ethyl ester solvate Form A of the present invention was measured by HPLC, and the change in purity was calculated.
- the HPLC purity test results show that the L-lactate ethyl ester solvate crystal form A of the present invention has a remarkable purification effect.
- the purity of the free base solid was 98.93%, and the purity of the L-lactate ethyl ester solvate crystal form A of the present invention was 99.63%, and the purity was increased by 0.70%.
- Form A can be stable for at least 2 months at 25 ° C / 60% RH open, 25 ° C / 60% RH closed, 40 ° C / 75% RH open, 40 ° C / 75% RH closed condition.
- Form A maintains good stability under both long-term and accelerated conditions.
- Form A and WO2017002095A1 Form I were weighed separately, poured into an intrinsic dissolution mold, and kept at a pressure of 10 kN for 1 min to prepare a sheet having a surface area of 0.5 cm 2 , and the whole tablet was transferred to a dissolution apparatus to test the intrinsic dissolution rate.
- the test conditions are shown in Table 4, the measured dissolution profile is shown in Fig. 26, and the dissolution data is shown in Table 5.
- the slope was calculated from the measurement points between 0 and 45 min, and the intrinsic dissolution rate (IDR) was further calculated from the slope in mg/min, expressed in mg/min/cm 2 , and the IDR results are shown in Table 6.
- the wetting weight gain is not less than 15.0%
- Humidity Wet weight gain is less than 15.0% but not less than 2.0%
- wet weight gain is less than 2.0% but not less than 0.2%
- wetting gain is less than 0.2%
- the tensile strength of the powder under hardness. Under a certain pressure, the greater the tensile strength, the better the compressibility, and the experimental results are shown in Table 7.
- Form A and WO2017002095A1 Form I were respectively added to an 8 mm circular flat punch, and subjected to a tableting treatment at a pressure of 10 kN, and left to stand for about half a minute after tableting, and the amount of powder adsorbed by the punch was weighed. After continuous pressing twice by this method, the cumulative amount of final adhesion and the average amount of adhesion of the punches were recorded. The specific experimental results are shown in Table 8.
- the compressibility index or the Carr Index is usually used to evaluate the fluidity of the powder or the intermediate particles by measuring a certain amount of the powder into the measuring cylinder.
- the fluidity evaluation results of the crystal form A are shown in Table 10, and the results show that the fluidity of the crystal form A is good.
- Crystal form Bulk density ( ⁇ 0 , g/mL) Tap density ( ⁇ f , g/mL) Compressibility index fluidity Crystal form A 0.269 0.303 11% it is good
- the TGA pattern is as shown in Figure 11, with a mass loss of about 4.5% when heated to 180 °C.
- the liquid nuclear magnetic hydrogen spectrum is as shown in Fig. 12.
- the crystal form D contains about 1 mole of glycerin, wherein the nuclear magnetic resonance peak near 4.38 and 4.47 and the nuclear magnetic resonance peak overlapping with the water peak 3.33 are glycerol. Characteristic peaks.
- a sample of 1.24 g of Acalabrutinib free base was weighed into a 20 mL glass vial and 12.0 mL of glycerol/isopropanol (1:2, v/v) was added. After magnetic stirring at 50 ° C for 3 days, it was separated and dried to give 1.36 g of a solid. Upon examination, the obtained solid was the crystalline form D of the present invention, and its XRPD data is shown in Table 12.
- the crystal form D obtained in this example has the same or similar XRPD pattern as the crystal form D in Example 10, and is the same crystal form and has the same properties.
- the purity of the free base solids and the glycerol solvate Form D of the present invention was determined by HPLC, and the change in purity was calculated.
- the HPLC purity test results show that the glycerol solvate crystal form D of the present invention has a remarkable purification effect.
- the purity of the free base solid was 98.93%, and the purity of the glycerin solvate form D of the present invention was 99.49%, and the purity was increased by 0.56%.
- Form D and WO2017002095A1 Form I were weighed separately, poured into an intrinsic dissolution mold, and kept at a pressure of 10 kN for 1 min to prepare a sheet having a surface area of 0.5 cm 2 , and the whole tablet was transferred to a dissolution apparatus to test the intrinsic dissolution rate.
- the test conditions are shown in Table 14, the measured dissolution profile is shown in Figure 40, and the dissolution data is shown in Table 15.
- the slope was calculated from the measurement points between 0 and 45 min, expressed in mg/mL, and the intrinsic dissolution rate (IDR) was further calculated from the slope, expressed in mg/min/cm 2 , and the IDR results are shown in Table 16.
- the tensile strength of the powder under hardness. Under a certain pressure, the greater the tensile strength, the better the compressibility, and the experimental results are shown in Table 17.
- the liquid nuclear magnetic hydrogen spectrum is as shown in Fig. 16.
- the form F contains about 1 mole of (S)-1,2-propanediol, and the nuclear magnetic peaks near 1.00, 3.16, 3.24, 3.56, 4.39 and 4.46 are Characteristic peak of (S)-1,2-propanediol.
- the HPLC purity test results showed that the (S)-1,2-propanediol solvate crystal form F of the present invention has a remarkable purification effect.
- the purity of the free base solid was 98.93%, and the purity of the (S)-1,2-propanediol solvate Form F of the present invention was 99.80%, and the purity was increased by 0.87%.
- Form F can be stabilized for at least 2 months at 25 ° C / 60% RH open, 25 ° C / 60% RH closed, 40 ° C / 75% RH open, 40 ° C / 75% RH closed condition.
- Form F maintains good stability under both long-term and accelerated conditions.
- Form F and WO2017002095A1 Form I were weighed separately, poured into an intrinsic dissolution mold, and kept at a pressure of 10 kN for 1 min to prepare a sheet having a surface area of 0.5 cm 2 , and the whole tablet was transferred to a dissolution apparatus to test the intrinsic dissolution rate.
- the test conditions are shown in Table 21, the measured dissolution profile is shown in Fig. 31, and the dissolution data is shown in Table 22.
- the slope was calculated from the measurement points between 0 and 45 min, expressed in mg/mL, and the intrinsic dissolution rate (IDR) was further calculated from the slope, expressed in mg/min/cm 2 , and the IDR results are shown in Table 23.
- the crystal form F of the present invention was weighed to about 10 mg, and its wettability was measured by a dynamic moisture adsorption (DVS) instrument, and it was cycled once at 0-95%-0 relative humidity and 25 °C ⁇ 1 °C, and the quality under each humidity was recorded.
- the change, the DVS result is shown in Figure 32, and the XRPD comparison chart before and after DVS is shown in Figure 33.
- the wetting weight gain is not less than 15.0%
- Humidity Wet weight gain is less than 15.0% but not less than 2.0%
- wet weight gain is less than 2.0% but not less than 0.2%
- wetting gain is less than 0.2%
- the tensile strength of the powder under hardness. Under a certain pressure, the greater the tensile strength, the better the compressibility, and the experimental results are shown in Table 24.
- Form F and WO2017002095A1 Form I were respectively added to an 8 mm circular flush, and the sheet was treated with a pressure of 10 kN, and left to stand for about half a minute after tableting, and the amount of powder adsorbed by the punch was weighed. After continuous pressing twice by this method, the cumulative amount of final adhesion and the average amount of adhesion of the punches were recorded. The specific experimental results are shown in Table 25.
- the compressibility index or the Carr Index is usually used to evaluate the fluidity of the powder or the intermediate particles by measuring a certain amount of the powder into the measuring cylinder.
- the crystal form G obtained in this example has the same or similar XRPD pattern as the crystal form G in Example 25, and is the same crystal form and has the same properties.
- the HPLC purity test results showed that the (R)-1,2-propanediol solvate crystal form G of the present invention has a remarkable purification effect.
- the purity of the free base solid was 98.93%, and the purity of the (R)-1,2-propanediol solvate crystal form G of the present invention was 99.86%, and the purity was increased by 0.93%.
- One part of the crystalline form G of the present invention about 10 mg, was weighed and placed under the conditions of 25 ° C / 60% RH closed, and the crystal form change was measured by the XRPD method. The results are shown in Table 30, and the XRPD comparison chart is shown in FIG.
- Placement condition Placement time Crystal form Start —— Form G 25°C/60% RH closed 2 months Form G
- Form G and WO2017002095A1 Form I were weighed separately, poured into an intrinsic dissolution mold, and kept at a pressure of 10 kN for 1 min to prepare a sheet having a surface area of 0.5 cm 2 , and the whole tablet was transferred to a dissolution apparatus to test the intrinsic dissolution rate.
- the test conditions are shown in Table 31, the measured dissolution profile is shown in Fig. 35, and the dissolution data is shown in Table 32.
- the slope was calculated from the measurement points between 0 and 45 min, expressed in mg/mL, and the intrinsic dissolution rate (IDR) was further calculated from the slope, expressed in mg/min/cm 2 , and the IDR results are shown in Table 33.
- the tensile strength of the powder under hardness. Under a certain pressure, the greater the tensile strength, the better the compressibility, and the experimental results are shown in Table 34.
- the compressibility index or the Carr Index is usually used to evaluate the fluidity of the powder or the intermediate particles by measuring a certain amount of the powder into the measuring cylinder.
- the fluidity evaluation results of the crystal form G are shown in Table 37, and the results show that the fluidity of the crystal form G is good.
- the crystalline form CS15 obtained in this example has the same or similar XRPD pattern as the crystalline form CS15 in Example 33, and is the same crystalline form and has the same properties.
- the purity of the free base solid and the (R)-1,2-propanediol solvate form CS15 of the present invention was determined by HPLC, and the change in purity was calculated.
- the HPLC purity test results showed that the (R)-1,2-propanediol solvate crystal form CS15 of the present invention has a remarkable purification effect.
- the purity of the free base solid was 99.20%, and the purity of the (R)-1,2-propanediol solvate crystal form CS15 of the present invention was 99.83%, and the purity was increased by 0.63%.
- Placement condition Placement time Crystal form Start —— Crystal form CS15 25°C/60% RH closed 2 months Crystal form CS15 25°C/60% RH exposure 2 months Crystal form CS15
- the results show that the crystalline form CS15 can be stabilized for at least 2 months under the conditions of 25 ° C / 60% RH open and 25 ° C / 60% RH closed. It can be seen that the crystalline form CS15 can maintain good stability under long-term conditions.
- the wetting weight gain is not less than 15.0%
- Humidity Wet weight gain is less than 15.0% but not less than 2.0%
- wet weight gain is less than 2.0% but not less than 0.2%
- wetting gain is less than 0.2%
- the weight gain of the crystalline form CS15 at 80% relative humidity was measured to be 1.78%, which was slightly wetted.
- the tensile strength of the powder under hardness. Under a certain pressure, the greater the tensile strength, the better the compressibility, and the experimental results are shown in Table 44.
- the first endothermic peak appears near the temperature of 109 °C, which is the desolvation endothermic peak. Its TGA pattern is as shown in Figure 7, with a mass loss of about 18.3% when heated to 180 °C.
- the liquid nuclear magnetic hydrogen spectrum is as shown in Fig. 8. According to the nuclear magnetic data, the ethylene glycol solvate crystal form B contains about 2 moles of ethylene glycol, and the nuclear magnetic resonance peak near 3.39 and 4.45 is a characteristic peak of ethylene glycol.
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Abstract
Description
时间(min) | %B |
0.0 | 20 |
9.0 | 34 |
11.0 | 40 |
18.0 | 50 |
22.0 | 70 |
30.0 | 70 |
31.0 | 20 |
40.0 | 20 |
衍射角2θ(±0.2°) | d值 | 强度% |
5.72 | 15.45 | 100.00 |
8.54 | 10.35 | 36.36 |
9.21 | 9.61 | 4.24 |
12.65 | 7.00 | 2.71 |
13.87 | 6.38 | 22.32 |
15.15 | 5.85 | 10.46 |
16.41 | 5.40 | 9.25 |
17.41 | 5.09 | 84.03 |
18.22 | 4.87 | 43.58 |
19.21 | 4.62 | 18.18 |
20.31 | 4.37 | 3.50 |
21.75 | 4.09 | 5.09 |
22.85 | 3.89 | 14.98 |
23.28 | 3.82 | 10.30 |
24.84 | 3.58 | 19.78 |
25.49 | 3.49 | 7.95 |
25.80 | 3.45 | 8.84 |
27.07 | 3.29 | 10.26 |
28.00 | 3.19 | 5.56 |
29.57 | 3.02 | 3.87 |
31.45 | 2.84 | 4.18 |
33.44 | 2.68 | 3.58 |
36.60 | 2.46 | 1.85 |
37.88 | 2.38 | 2.15 |
衍射角2θ(±0.2°) | d值 | 强度% |
5.80 | 15.24 | 33.97 |
8.60 | 10.28 | 100.00 |
9.26 | 9.55 | 8.61 |
12.70 | 6.97 | 13.05 |
12.99 | 6.81 | 7.37 |
13.93 | 6.36 | 14.40 |
14.83 | 5.97 | 12.42 |
15.21 | 5.83 | 38.34 |
15.88 | 5.58 | 2.65 |
16.46 | 5.39 | 20.39 |
17.48 | 5.07 | 22.13 |
18.30 | 4.85 | 18.80 |
18.60 | 4.77 | 6.79 |
19.27 | 4.61 | 6.63 |
19.59 | 4.53 | 13.09 |
19.84 | 4.47 | 4.33 |
20.48 | 4.34 | 2.04 |
21.75 | 4.09 | 9.65 |
22.26 | 3.99 | 4.25 |
22.95 | 3.87 | 15.71 |
23.68 | 3.76 | 12.02 |
24.88 | 3.58 | 34.38 |
25.60 | 3.48 | 17.42 |
25.87 | 3.44 | 10.69 |
27.11 | 3.29 | 5.42 |
28.07 | 3.18 | 8.91 |
溶出仪 | Agilent 708DS |
介质 | pH=2.5盐酸/氯化钠水溶液 |
介质体积 | 500mL |
转速 | 100rpm |
介质温度 | 37℃ |
取样点 | 5,10,15,20,25,30,35,45min |
补充介质 | 不补充(每个时间点取样1.0mL) |
晶型 | IDR(mg/min/cm 2) |
WO2017002095A1晶型I | 0.3656 |
晶型A | 0.4520 |
晶型 | 抗张强度(MPa) |
WO2017002095A1晶型I | 无法压制成片 |
晶型A | 1.35 |
晶型 | 累计的最终黏附量(μg) | 平均黏附量(μg) |
WO2017002095A1晶型I | 90 | 45 |
晶型A | 80 | 40 |
可压性系数(%) | 流动性 |
≦10 | 极好 |
11-15 | 好 |
16-20 | 一般 |
21-25 | 可接受 |
26-31 | 差 |
32-37 | 很差 |
>38 | 极差 |
晶型 | 松密度(ρ 0,g/mL) | 振实密度(ρ f,g/mL) | 可压性指数 | 流动性 |
晶型A | 0.269 | 0.303 | 11% | 好 |
衍射角2θ(±0.2°) | d值 | 强度% |
6.68 | 13.24 | 39.74 |
8.06 | 10.97 | 8.29 |
9.55 | 9.26 | 29.75 |
11.02 | 8.03 | 30.67 |
13.45 | 6.58 | 35.87 |
13.86 | 6.39 | 15.29 |
14.21 | 6.23 | 100.00 |
16.21 | 5.47 | 34.96 |
17.99 | 4.93 | 4.14 |
19.57 | 4.54 | 5.20 |
20.26 | 4.38 | 14.82 |
21.59 | 4.12 | 13.56 |
22.55 | 3.94 | 20.88 |
23.84 | 3.73 | 13.45 |
24.27 | 3.67 | 18.38 |
25.51 | 3.49 | 9.21 |
26.40 | 3.38 | 4.04 |
27.20 | 3.28 | 4.38 |
30.44 | 2.94 | 6.12 |
32.38 | 2.76 | 4.53 |
衍射角2θ(±0.2°) | d值 | 强度% |
6.72 | 13.14 | 37.17 |
8.08 | 10.95 | 9.94 |
9.56 | 9.25 | 38.32 |
11.05 | 8.01 | 32.54 |
13.47 | 6.57 | 35.23 |
13.90 | 6.37 | 19.03 |
14.20 | 6.24 | 100.00 |
16.23 | 5.46 | 39.04 |
17.98 | 4.93 | 10.07 |
18.28 | 4.85 | 10.79 |
20.30 | 4.38 | 16.00 |
20.80 | 4.27 | 3.29 |
21.65 | 4.11 | 15.81 |
22.23 | 4.00 | 18.02 |
22.53 | 3.95 | 23.09 |
23.37 | 3.81 | 10.49 |
23.85 | 3.73 | 11.57 |
24.31 | 3.66 | 18.14 |
25.54 | 3.49 | 10.45 |
26.43 | 3.37 | 3.44 |
27.21 | 3.28 | 6.41 |
30.46 | 2.94 | 8.37 |
32.43 | 2.76 | 5.96 |
溶出仪 | Agilent 708DS |
介质 | pH=2.5盐酸/氯化钠水溶液 |
介质体积 | 500mL |
转速 | 100rpm |
介质温度 | 37℃ |
取样点 | 5,10,15,20,25,30,35,45min |
补充介质 | 不补充(每个时间点取样1.0mL) |
晶型 | IDR(mg/min/cm 2) |
WO2017002095A1晶型I | 0.3656 |
晶型D | 0.4112 |
晶型 | 抗张强度(MPa) |
WO2017002095A1晶型I | 无法压制成片 |
晶型D | 0.83 |
衍射角2θ(±0.2°) | d值 | 强度% |
6.62 | 13.36 | 19.97 |
8.08 | 10.95 | 47.34 |
10.00 | 8.85 | 62.32 |
12.39 | 7.14 | 67.91 |
13.24 | 6.69 | 57.05 |
14.47 | 6.12 | 45.63 |
16.10 | 5.51 | 100.00 |
18.00 | 4.93 | 57.06 |
18.94 | 4.69 | 29.72 |
19.91 | 4.46 | 6.05 |
21.31 | 4.17 | 9.67 |
22.28 | 3.99 | 8.47 |
24.29 | 3.66 | 78.07 |
24.87 | 3.58 | 16.87 |
25.61 | 3.48 | 11.82 |
26.59 | 3.35 | 25.52 |
衍射角2θ(±0.2°) | d间隔 | 强度% |
6.55 | 13.50 | 15.76 |
7.98 | 11.07 | 45.42 |
9.93 | 8.91 | 62.59 |
12.31 | 7.19 | 72.52 |
13.14 | 6.74 | 57.65 |
14.41 | 6.15 | 46.02 |
16.04 | 5.52 | 95.59 |
17.91 | 4.95 | 49.20 |
18.86 | 4.71 | 34.52 |
19.77 | 4.49 | 6.61 |
21.24 | 4.18 | 9.33 |
21.70 | 4.10 | 7.35 |
22.17 | 4.01 | 8.77 |
22.81 | 3.90 | 10.18 |
24.19 | 3.68 | 100.00 |
24.79 | 3.59 | 19.82 |
25.58 | 3.48 | 17.00 |
26.48 | 3.37 | 33.37 |
29.34 | 3.04 | 6.28 |
溶出仪 | Agilent 708DS |
介质 | pH=2.5盐酸/氯化钠水溶液 |
介质体积 | 500mL |
转速 | 100rpm |
介质温度 | 37℃ |
取样点 | 5,10,15,20,25,30,35,45min |
补充介质 | 不补充(每个时间点取样1.0mL) |
晶型 | IDR(mg/min/cm 2) |
WO2017002095A1晶型I | 0.3656 |
晶型F | 0.4898 |
晶型 | 抗张强度(MPa) |
WO2017002095A1晶型I | 无法压制成片 |
晶型F | 1.02 |
晶型 | 累计的最终黏附量(μg) | 平均黏附量(μg) |
WO2017002095A1晶型I | 90 | 45 |
晶型F | 60 | 30 |
可压性系数(%) | 流动性 |
≦10 | 极好 |
11-15 | 好 |
16-20 | 一般 |
21-25 | 可接受 |
26-31 | 差 |
32-37 | 很差 |
>38 | 极差 |
晶型 | 松密度(ρ 0,g/mL) | 振实密度(ρ f,g/mL) | 可压性指数 | 流动性 |
晶型F | 0.185 | 0.216 | 14% | 好 |
衍射角2θ(±0.2°) | d值 | 强度% |
5.11 | 17.31 | 100.00 |
6.62 | 13.35 | 27.17 |
7.70 | 11.48 | 10.59 |
10.72 | 8.25 | 13.38 |
12.15 | 7.28 | 74.10 |
13.47 | 6.57 | 65.32 |
15.57 | 5.69 | 51.38 |
16.97 | 5.22 | 44.26 |
17.72 | 5.01 | 34.77 |
18.57 | 4.78 | 20.62 |
20.64 | 4.30 | 43.04 |
21.29 | 4.17 | 28.78 |
22.99 | 3.87 | 38.30 |
23.71 | 3.75 | 28.27 |
25.87 | 3.44 | 20.97 |
26.41 | 3.37 | 14.65 |
28.98 | 3.08 | 8.43 |
衍射角2θ(±0.2°) | d间隔 | 强度% |
5.24 | 16.88 | 100.00 |
6.71 | 13.17 | 19.59 |
7.81 | 11.32 | 8.53 |
10.76 | 8.22 | 15.55 |
12.39 | 7.14 | 84.94 |
13.30 | 6.66 | 36.96 |
13.64 | 6.49 | 71.90 |
15.92 | 5.57 | 66.87 |
16.29 | 5.44 | 21.98 |
17.24 | 5.14 | 67.05 |
17.90 | 4.96 | 41.47 |
18.79 | 4.72 | 29.86 |
20.38 | 4.36 | 30.57 |
20.99 | 4.23 | 55.18 |
21.39 | 4.15 | 24.76 |
23.15 | 3.84 | 42.69 |
23.92 | 3.72 | 22.60 |
26.08 | 3.42 | 22.69 |
26.66 | 3.34 | 11.15 |
27.43 | 3.25 | 10.24 |
28.77 | 3.10 | 9.88 |
29.23 | 3.05 | 13.60 |
放置条件 | 放置时间 | 晶型 |
起始 | —— | 晶型G |
25℃/60%RH闭口 | 2个月 | 晶型G |
溶出仪 | Agilent 708DS |
介质 | pH=2.5盐酸/氯化钠水溶液 |
介质体积 | 500mL |
转速 | 100rpm |
介质温度 | 37℃ |
取样点 | 5,10,15,20,25,30,35,45min |
补充介质 | 不补充(每个时间点取样1.0mL) |
晶型 | IDR(mg/min/cm 2) |
WO2017002095A1晶型I | 0.3656 |
晶型G | 0.4396 |
晶型 | 抗张强度(MPa) |
WO2017002095A1晶型I | 无法压制成片 |
晶型G | 1.62 |
晶型 | 累计的最终黏附量(μg) | 平均黏附量(μg) |
WO2017002095A1晶型I | 90 | 45 |
晶型G | 60 | 30 |
可压性系数(%) | 流动性 |
≦10 | 极好 |
11-15 | 好 |
16-20 | 一般 |
21-25 | 可接受 |
26-31 | 差 |
32-37 | 很差 |
>38 | 极差 |
晶型 | 松密度(ρ 0,g/mL) | 振实密度(ρ f,g/mL) | 可压性指数 | 流动性 |
晶型G | 0.443 | 0.488 | 11% | 好 |
衍射角2θ(±0.2°) | d值 | 强度% |
5.46 | 16.20 | 5.95 |
6.75 | 13.09 | 6.20 |
8.03 | 11.01 | 34.24 |
8.64 | 10.23 | 81.08 |
9.28 | 9.53 | 100.00 |
13.61 | 6.51 | 69.55 |
14.29 | 6.20 | 30.05 |
17.40 | 5.10 | 35.92 |
19.16 | 4.63 | 17.45 |
20.21 | 4.39 | 7.56 |
22.15 | 4.01 | 6.38 |
22.92 | 3.88 | 7.71 |
23.56 | 3.78 | 8.08 |
24.41 | 3.65 | 5.54 |
25.35 | 3.51 | 2.09 |
衍射角2θ(±0.2°) | d值 | 强度% |
6.75 | 13.10 | 2.86 |
8.01 | 11.04 | 18.83 |
8.56 | 10.33 | 74.42 |
9.18 | 9.63 | 100.00 |
13.59 | 6.52 | 35.98 |
14.27 | 6.21 | 19.69 |
16.73 | 5.30 | 7.18 |
17.22 | 5.15 | 62.24 |
19.12 | 4.64 | 15.64 |
20.02 | 4.44 | 20.19 |
21.10 | 4.21 | 5.18 |
22.02 | 4.04 | 15.30 |
22.90 | 3.88 | 28.75 |
23.61 | 3.77 | 20.25 |
23.96 | 3.71 | 7.89 |
24.29 | 3.66 | 12.85 |
25.15 | 3.54 | 22.95 |
26.55 | 3.36 | 9.56 |
26.93 | 3.31 | 12.72 |
28.00 | 3.19 | 4.41 |
29.36 | 3.04 | 6.16 |
放置条件 | 放置时间 | 晶型 |
起始 | —— | 晶型CS15 |
25℃/60%RH闭口 | 2个月 | 晶型CS15 |
25℃/60%RH敞口 | 2个月 | 晶型CS15 |
溶出仪 | Agilent 708DS |
介质 | pH=2.5盐酸/氯化钠水溶液 |
介质体积 | 500mL |
转速 | 100rpm |
介质温度 | 37℃ |
取样点 | 5,10,15,20,25,30,35,45min |
补充介质 | 不补充(每个时间点取样1.0mL) |
晶型 | IDR(mg/min/cm 2) |
WO2017002095A1晶型I | 0.3656 |
晶型CS15 | 0.5778 |
晶型 | 抗张强度(MPa) |
WO2017002095A1晶型I | 无法压制成片 |
晶型CS15 | 1.18 |
衍射角2θ(±0.2°) | d值 | 强度% |
5.14 | 17.18 | 71.66 |
7.06 | 12.52 | 100.00 |
8.01 | 11.04 | 20.33 |
10.32 | 8.57 | 5.55 |
11.26 | 7.86 | 21.71 |
11.82 | 7.49 | 29.32 |
13.01 | 6.80 | 15.73 |
13.32 | 6.65 | 44.55 |
14.14 | 6.26 | 49.92 |
14.65 | 6.05 | 13.55 |
15.08 | 5.87 | 15.37 |
15.52 | 5.71 | 15.23 |
16.06 | 5.52 | 6.79 |
16.68 | 5.32 | 17.72 |
18.14 | 4.89 | 27.46 |
18.48 | 4.80 | 16.69 |
19.22 | 4.62 | 9.74 |
20.21 | 4.39 | 19.34 |
21.06 | 4.22 | 17.57 |
21.64 | 4.11 | 28.96 |
23.09 | 3.85 | 10.35 |
25.21 | 3.53 | 15.79 |
26.05 | 3.42 | 10.91 |
Claims (22)
- 一种Acalabrutinib的L-乳酸乙酯溶剂合物晶型A,其特征在于,使用Cu-Kа辐射,其X射线粉末衍射图在2θ值为5.7°±0.2°、17.4°±0.2°、18.2°±0.2°处具有特征峰。
- 根据权利要求1所述的L-乳酸乙酯溶剂合物晶型A,其特征还在于,使用Cu-Kа辐射,其X射线粉末衍射图在2θ值为8.5°±0.2°、13.9°±0.2°、24.8°±0.2°中的1处、或2处、或3处具有特征峰。
- 根据权利要求1所述的L-乳酸乙酯溶剂合物晶型A,其特征还在于,使用Cu-Kа辐射,其X射线粉末衍射图在2θ值为19.2°±0.2°、22.9°±0.2°、15.1°±0.2°中的1处、或2处、或3处具有特征峰。
- 一种根据权利要求1所述的L-乳酸乙酯溶剂合物晶型A的制备方法,其特征在于:将Acalabrutinib游离碱置于L-乳酸乙酯溶剂或含L-乳酸乙酯的溶剂中,置于5-60℃,反应1-3天,得到固体。
- 一种Acalabrutinib的丙三醇溶剂合物晶型D,其特征在于,使用Cu-Kа辐射,其X射线粉末衍射图在2θ值为14.2°±0.2°、6.7°±0.2°、13.4°±0.2°处具有特征峰。
- 根据权利要求5所述的丙三醇溶剂合物晶型D,其特征还在于,使用Cu-Kа辐射,其X射线粉末衍射图在2θ值为16.2°±0.2°、11.0°±0.2°、9.6°±0.2°中的1处、或2处、或3处具有特征峰。
- 根据权利要求5所述的丙三醇溶剂合物晶型D,其特征还在于,使用Cu-Kа辐射,其X射线粉末衍射图在2θ值为8.1°±0.2°、24.3°±0.2°、20.3°±0.2°中的1处、或2处、或3处具有特征峰。
- 一种根据权利要求5所述的丙三醇溶剂合物晶型D的制备方法,其特征在于:将Acalabrutinib游离碱置于丙三醇溶剂或含丙三醇的溶剂中,置于20-80℃,反应10-72小时,得到固体。
- 一种Acalabrutinib的(S)-1,2-丙二醇溶剂合物晶型F,其特征在于,使用Cu-Kа辐射,其X射线粉末衍射图在2θ值为16.1°±0.2°、24.3°±0.2°、12.4°±0.2°处具有特征峰。
- 根据权利要求9所述的(S)-1,2-丙二醇溶剂合物晶型F,其特征还在于,使用Cu-Kа辐射,其X射线粉末衍射图在2θ值为10.0°±0.2°、18.0°±0.2°、13.2°±0.2°中的1处、或2处或3处具有特征峰。
- 根据权利要求9所述的(S)-1,2-丙二醇溶剂合物晶型F,其特征还在于,使用Cu-Kа辐射,其X射线粉末衍射图在2θ值为8.1°±0.2°、14.5°±0.2°、18.9°±0.2°中的1处、或2处、或3处具有特征峰。
- 一种根据权利要求9所述的(S)-1,2-丙二醇溶剂合物晶型F的制备方法,其特征在于:将Acalabrutinib游离碱置于(S)-1,2-丙二醇溶剂中,置于5-60℃,反应10-72小时,得到固体。
- 一种Acalabrutinib的(R)-1,2-丙二醇溶剂合物晶型G,其特征在于,使用Cu-Kа辐射,其X射线粉末衍射图在2θ值为5.1°±0.2°、12.2°±0.2°、13.5°±0.2°处具有特征峰。
- 根据权利要求13所述的(R)-1,2-丙二醇溶剂合物晶型G,其特征还在于,使用Cu-Kа辐射,其X射线粉末衍射图在2θ值为6.6°±0.2°、23.0°±0.2°、17.7°±0.2°、21.3°±0.2°中的1处、或2处、或3处、或4处具有特征峰。
- 一种权利要求13所述的(R)-1,2-丙二醇溶剂合物晶型G的制备方法,其特征在于:将Acalabrutinib游离碱置于(R)-1,2-丙二醇溶剂中,置于5-60℃,反应10-48小时,得到固体。
- 一种Acalabrutinib的(R)-1,2-丙二醇溶剂合物晶型CS15,其特征在于,使用Cu-Kа辐射,其X射线粉末衍射图在2θ值为8.6°±0.2°、9.3°±0.2°、13.6°±0.2°处具有特征峰。
- 根据权利要求16所述的(R)-1,2-丙二醇溶剂合物晶型CS15,其特征还在于,使用Cu-Kа辐射,其X射线粉末衍射图在2θ值为8.0°±0.2°、14.3°±0.2°、17.4°±0.2°、19.2°±0.2°中的1处、或2处、或3处、或4处具有特征峰。
- 一种根据权利要求16所述的(R)-1,2-丙二醇溶剂合物晶型CS15的制备方法,其特征在于:将Acalabrutinib游离碱置于(R)-1,2-丙二醇溶剂中,置于5-60℃,反应10-48小时,将所得样品置于腈类溶剂中,在-20-5℃下搅拌1-7天,得到固体;或将Acalabrutinib游离碱置于(R)-1,2-丙二醇溶剂与腈类溶剂的混合溶剂中,置于5-60℃,反应10-48小时,得到固体。
- 根据权利要求18所述制备方法,所述腈类溶剂为乙腈。
- 一种药物组合物,所述药物组合物包含有效治疗量的权利要求1中所述的L-乳酸乙酯溶剂合物晶型A、权利要求5所述的丙三醇溶剂合物晶型D、权利要求9所述的(S)-1,2-丙二醇溶剂合物晶型F、权利要求13所述(R)-1,2-丙二醇溶剂合物晶型G、权利要求16所述的(R)-1,2-丙二醇溶剂合物晶型CS15或它们的任意组合及药学上可接受的载体、稀释剂或赋形剂。
- 权利要求1中所述的L-乳酸乙酯溶剂合物晶型A、权利要求5所述的丙三醇溶剂合物晶型D、权利要求9所述的(S)-1,2-丙二醇溶剂合物晶型F、权利要求13所述(R)-1,2-丙二醇溶剂合物晶型G、权利要求16所述的(R)-1,2-丙二醇溶剂合物晶型CS15或它们的任意组合在制备布鲁顿酪氨酸激酶抑制剂药物中的用途。
- 权利要求1中所述的L-乳酸乙酯溶剂合物晶型A、权利要求5所述的丙三醇溶剂合物晶型D、权利要求9所述的(S)-1,2-丙二醇溶剂合物晶型F、权利要求13所述(R)-1,2-丙二醇溶剂合物晶型G、权利要求16所述的(R)-1,2-丙二醇溶剂合物晶型CS15或它们的任意组合在制备治疗套细胞淋巴癌药物中的用途。
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CN107056786B (zh) | 2016-10-14 | 2019-05-07 | 苏州明锐医药科技有限公司 | 阿卡替尼的制备方法 |
CN107522701B (zh) | 2017-09-01 | 2019-11-08 | 苏州富士莱医药股份有限公司 | 一种治疗慢性淋巴细胞白血病的BTK抑制剂Acalabrutinib的合成方法 |
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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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CA3087474A1 (en) | 2019-07-11 |
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KR20200106511A (ko) | 2020-09-14 |
EP3736273A4 (en) | 2021-02-24 |
JP2021510149A (ja) | 2021-04-15 |
CN111527089B (zh) | 2021-03-12 |
EP3736273A1 (en) | 2020-11-11 |
US11091494B2 (en) | 2021-08-17 |
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