WO2023174390A1 - 尼罗司他二氢溴酸盐的晶型及其制备方法和用途 - Google Patents

尼罗司他二氢溴酸盐的晶型及其制备方法和用途 Download PDF

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WO2023174390A1
WO2023174390A1 PCT/CN2023/082030 CN2023082030W WO2023174390A1 WO 2023174390 A1 WO2023174390 A1 WO 2023174390A1 CN 2023082030 W CN2023082030 W CN 2023082030W WO 2023174390 A1 WO2023174390 A1 WO 2023174390A1
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Prior art keywords
crystal form
csii
dihydrobromide
compound
csiii
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PCT/CN2023/082030
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English (en)
French (fr)
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沈艺楠
史佳明
孟丽苹
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苏州科睿思制药有限公司
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Publication of WO2023174390A1 publication Critical patent/WO2023174390A1/zh

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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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • 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
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/88—Nitrogen atoms, e.g. allantoin

Definitions

  • the present invention relates to the field of crystal chemistry. Specifically, it relates to the crystal form of nirostat dihydrobromide and its preparation method and use.
  • Desmoid tumors also known as invasive fibromatosis, are rare, locally aggressive, slow-growing soft tissue tumors. Although desmoid tumors do not metastasize and are considered benign tumors, they can cause serious complications and occasionally death in patients, necessitating the urgent need for drugs.
  • Nirogacestat the gamma secretase inhibitor Nirogacestat developed by Spring Works Therapeutics has obtained breakthrough therapy and fast track designations from the FDA, and has obtained orphan drug designations from the FDA and EMA. It is being studied for the treatment of desmoid tumors with positive clinical results. Nirostat can bind to ⁇ -secretase and block the hydrolytic activation of Notch receptors. Existing clinical research data indicate that Notch signaling plays an important role in cancer development. Therefore, inhibiting Notch signaling is an important strategy for the treatment of desmoid tumors.
  • nirostat is (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetralin-2-yl)amine)-N-( 1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide (hereinafter referred to as "Compound I”), Compound I dihydrobromide
  • Compound I Compound I dihydrobromide
  • a crystal is a solid in which compound molecules are arranged in a three-dimensional order in a microstructure to form a crystal lattice.
  • Polymorphism refers to the phenomenon that a compound exists in multiple crystal forms.
  • a compound may exist in one or more crystalline forms, but its existence and properties cannot be specifically predicted.
  • Different crystal forms of raw materials have different physical and chemical properties, which may lead to different dissolution and absorption of the drug in the body, thus affecting the clinical efficacy of the drug to a certain extent.
  • the crystal form is crucial to product performance.
  • the physical and chemical properties of the crystal form are crucial to the production process. Therefore, polymorphism is an important part of drug research and drug quality control.
  • solubility of crystalline form A is low. According to the definition standards of drug solubility in the Chinese Pharmacopoeia and the United States Pharmacopoeia, the solubility of crystalline form A in water is only slightly soluble. Crystalline form A has low solubility in water, which is not conducive to the absorption of the drug in the human body, thereby affecting the bioavailability of the drug.
  • the inventor of the present application prepared crystal form A according to the method disclosed in the prior art WO2021029854A1. Further research found that the particle size distribution of crystal form A was uneven and easy to agglomerate.
  • the inventor of the present application unexpectedly discovered the anhydrous form of the dihydrobromide salt of Compound I according to the present invention through an unconventional crystallization method in an unconventional organic solvent, trifluoroethanol.
  • purification effect, stability, adhesion, compressibility, fluidity, dissolution in vivo and in vitro, biological effectiveness, etc. have advantages in at least one aspect, especially high solubility, more uniform particle size distribution, not easy to agglomerate, and no solvent residue , good fluidity, high density, good compressibility, good stability of raw materials and preparations, which solves the problems existing in the existing technology and is of great significance to the development of drugs containing compound I dihydrobromide.
  • the present invention provides a new crystal form of compound I dihydrobromide, a preparation method thereof, and a pharmaceutical composition containing the new crystal form.
  • the present invention provides the crystalline form CSII of Compound I dihydrobromide (hereinafter referred to as "crystalline form CSII").
  • the X-ray powder diffraction pattern of the crystal form CSII has characteristic peaks at diffraction angle 2 ⁇ values of 7.6° ⁇ 0.2°, 8.4° ⁇ 0.2°, and 12.0° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal form CSII has a diffraction angle 2 ⁇ value of 18.5° ⁇ 0.2°, 19.5° ⁇ 0.2°, 20.5° ⁇ 0.2° at 1, or 2 , or 3 has characteristic peaks; preferably, the X-ray powder diffraction pattern of the crystal form CSII has characteristic peaks at diffraction angle 2 ⁇ values of 18.5° ⁇ 0.2°, 19.5° ⁇ 0.2°, and 20.5° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form CSII at diffraction angle 2 ⁇ has values of 7.6° ⁇ 0.2°, 8.4° ⁇ 0.2°, 12.0° ⁇ 0.2°, and 18.5° ⁇ 0.2°. , 19.5° ⁇ 0.2°, 20.5° ⁇ 0.2°, 15.3° ⁇ 0.2°, 16.9° ⁇ 0.2°, 24.1° ⁇ 0.2°, 27.1 ⁇ 0.2° at any 3 places, or 4 places, or 5 places, or 6 places place, There are characteristic peaks at 7, 8, 9, or 10 places.
  • the X-ray powder diffraction pattern of crystal form CSII is substantially as shown in Figure 1.
  • thermogravimetric analysis diagram of crystalline form CSII is substantially as shown in Figure 2, with a weight loss of approximately 1.0% when heated to 100°C.
  • Form CSII is anhydrous.
  • the present invention also provides a preparation method of the crystal form CSII, and the preparation method includes:
  • Compound I dihydrobromide solid is dissolved in trifluoroethanol and volatilized to obtain a solid.
  • the obtained solid is heated at a certain temperature for a period of time to obtain a crystalline solid.
  • the heating temperature is preferably 120-200°C, further, 150°C is preferred; the heating time is preferably 0.5-60 minutes.
  • the present invention provides the crystalline form CSIII of Compound I dihydrobromide (hereinafter referred to as "crystalline form CSIII").
  • the X-ray powder diffraction pattern of the crystal form CSIII has characteristic peaks at diffraction angle 2 ⁇ values of 8.4° ⁇ 0.2°, 8.8° ⁇ 0.2°, and 16.3° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal form CSIII has a diffraction angle 2 ⁇ value of 1, or 2 of 12.7 ⁇ 0.2°, 14.1° ⁇ 0.2°, 20.8° ⁇ 0.2°. , or 3 has characteristic peaks; preferably, the X-ray powder diffraction pattern of the crystal form CSIII has characteristic peaks at diffraction angle 2 ⁇ values of 12.7 ⁇ 0.2°, 14.1° ⁇ 0.2°, and 20.8° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal form CSIII has a characteristic peak at one or two of the diffraction angle 2 ⁇ values of 21.7 ⁇ 0.2°, 22.2° ⁇ 0.2°; preferably , the X-ray powder diffraction pattern of the crystal form CSIII has characteristic peaks at diffraction angle 2 ⁇ values of 21.7 ⁇ 0.2° and 22.2° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal form CSIII at diffraction angle 2 ⁇ has values of 8.4° ⁇ 0.2°, 8.8° ⁇ 0.2°, 16.3° ⁇ 0.2°, 12.7 ⁇ 0.2°, There are characteristic peaks at any 3, or 4, or 5, or 6, or 7, or 8 places among 14.1° ⁇ 0.2°, 20.8° ⁇ 0.2°, 21.7 ⁇ 0.2°, and 22.2° ⁇ 0.2°. .
  • the X-ray powder diffraction pattern of Form CSIII is substantially as shown in Figure 3 using Cu-K ⁇ radiation.
  • thermogravimetric analysis diagram of Form CSIII is substantially as shown in Figure 5, with a weight loss of approximately 0.8% when heated to 100°C.
  • Form CSIII is anhydrous.
  • the present invention also provides a preparation method of the crystal form CSIII, and the preparation method includes:
  • Compound I dihydrobromide solid is dissolved in trifluoroethanol and volatilized to obtain a solid.
  • the obtained solid is heated to a certain temperature at a certain heating rate to obtain a crystalline solid.
  • the heating rate is preferably 1-5°C/min, and further preferably 2°C/min; the certain temperature is preferably 201-205°C, and further preferably 202°C.
  • the present invention provides the use of crystal form CSII, crystal form CSIII or any mixture of the above two crystal forms for preparing other crystal forms or salts or co-crystals of Compound I.
  • the present invention provides a pharmaceutical composition, which contains an effective therapeutic amount of crystal form CSII, crystal form CSIII, or any mixture of the above two crystal forms and pharmaceutically acceptable excipients.
  • the present invention provides the use of crystal form CSII, crystal form CSIII or any mixture of the above two crystal forms in the preparation of ⁇ -secretase inhibitor drugs.
  • the present invention provides the use of crystal form CSII, crystal form CSIII or any mixture of the above two crystal forms in the preparation of drugs for the treatment of desmoid tumors.
  • the technical problem solved by the present invention is to provide a new crystal form that is different from the crystal form in the prior art.
  • this crystal form On the basis of excellent stability, this crystal form has higher solubility and better stability than the crystal form A in the prior art.
  • Uniform particle size distribution, smaller particle size, better fluidity, greater density, better compressibility, no solvent residue and difficulty in agglomeration solve the problems existing in the existing technology.
  • the crystal form CSII provided by the present invention has higher solubility.
  • the solubility in water is 3-5 times that of crystal form A; in simulated in vivo medium FeSSIF and FaSSIF solutions, the solubility is 1.5 times that of crystal form A in the prior art.
  • the crystal form CSII provided by the present invention has higher solubility, which is beneficial to improving the absorption of drugs in the human body and improving bioavailability; in addition, higher solubility can reduce the dosage of drugs while ensuring the efficacy of the drugs, thereby reducing the cost of drugs. side effects and improve drug safety.
  • the crystal form CSII provided by the present invention does not agglomerate, has smaller particle size, and has a more uniform particle size distribution. Uniform particle size helps reduce solvent enrichment, improve product purity, reduce product dissolved residues, ensure content uniformity of pharmaceutical preparations, and reduce variability in in vitro dissolution. Smaller particle size helps improve drug solubility and bioavailability.
  • the crystal form CSII provided by the present invention has a greater density.
  • Experimental results show that the bulk density and tap density of the crystal form CSII of the present invention are significantly better than those of the prior art crystal form A.
  • the high density of crystal form CSII is conducive to large-scale production. The greater density can reduce dust and reduce occupational hazards.
  • the crystal form CSII provided by the present invention has better fluidity. Better fluidity can avoid clogging production equipment and improve production efficiency; ensure the content uniformity of preparations, reduce weight differences, and improve product quality.
  • the crystal form CSII provided by the present invention has better compressibility.
  • the good compressibility of crystal form CSII can effectively improve problems such as unqualified hardness/friability and fragmentation in the tableting process, making the preparation process more reliable, improving product appearance, and improving product quality and production efficiency.
  • the crystal form CSII provided by the present invention has no dissolved residue. Residual solvents will not only affect the safety of the drug, but also affect the quality and stability of the drug. Residual solvents may cause crystallization or the formation of impurities during the production and storage of drugs, resulting in changes in drug bioavailability and toxic and side effects.
  • the crystal form CSII provided by the present invention has no solvent residue and effectively overcomes the shortcomings of low drug stability, poor efficacy, and high toxicity caused by low drug purity or high solvent residue.
  • the crystal form CSII provided by the present invention has good physical stability under the action of mechanical force. Crystal form The crystal form of CSII API remains unchanged after the formulation process. APIs often need to be ground or pulverized during preparation processing. Good physical stability can reduce the risk of reduced crystallinity and crystallization of APIs during preparation processing. In addition, under a pressure of 5kN, the crystal form CSII API has good physical stability, which is conducive to maintaining the stability of the crystal form during the tableting process.
  • Both the crystalline CSII raw materials and preparations provided by the present invention have good stability.
  • the crystal form of CSII API has not changed for at least 9 months when placed at 25°C/60% RH, and the purity remains basically unchanged during storage.
  • the crystal form of CSII API has not changed after being placed at 40°C/75% RH for at least 6 months, and the purity remains basically unchanged during storage.
  • the crystal form CSII is mixed with excipients to make a pharmaceutical preparation, it is placed under the conditions of 40°C/75%RH and 60°C/75%RH, and the crystal form does not change for at least 1 month.
  • crystalline CSII raw materials and preparations have good stability under accelerated conditions and more stringent conditions. High temperature and high humidity conditions caused by seasonal differences, climate differences in different regions and environmental factors will affect the storage, transportation and production of APIs and preparations. Therefore, the stability of drug substances and formulations under accelerated conditions and more severe conditions is critical to drugs. Crystalline CSII raw materials and preparations have better stability under harsh conditions, which is helpful to avoid the impact on drug quality due to crystallization or purity loss during drug storage.
  • Crystal form CSII has good physical and chemical stability, ensuring consistent and controllable quality of raw materials and preparations, and reducing changes in drug quality, bioavailability, and toxic and side effects caused by changes in crystal form or generation of impurities.
  • the crystal form CSIII provided by the present invention has higher solubility.
  • the solubility is 1.5 times that of the prior art crystal form A; in FaSSIF, the solubility is 1.3 times that of the prior art crystal form A.
  • the crystal form CSIII provided by the present invention has higher solubility, which is beneficial to improving the absorption of drugs in the human body and improving bioavailability; in addition, higher solubility can reduce the dosage of drugs while ensuring the efficacy of drugs, thereby reducing the cost of drugs. side effects and improve drug safety.
  • the crystal form CSIII provided by the present invention does not agglomerate and has a more uniform particle size distribution. Uniform particle size helps reduce solvent enrichment, improve product purity, reduce product dissolved residues, ensure content uniformity of pharmaceutical preparations, and reduce variability in in vitro dissolution.
  • the crystal form CSIII provided by the present invention has no dissolved residue. Residual solvents will not only affect the safety of the drug, but also affect the quality and stability of the drug. Residual solvents may cause crystallization or the formation of impurities during the production and storage of drugs, resulting in changes in drug bioavailability and toxic and side effects.
  • the crystal form CSIII provided by the present invention has no solvent residue and effectively overcomes the shortcomings of low drug stability, poor efficacy, and high toxicity caused by low drug purity or high solvent residue.
  • the crystal form CSIII raw material provided by the present invention has good stability.
  • the crystalline form CSIII API has not changed when placed at 25°C/60%RH for at least 3 months.
  • Crystal form CSIII API has not changed after being placed at 40°C/75%RH for at least 3 months, and the crystalline form has not changed after being placed at 60°C/75%RH for at least 2 months.
  • Description of crystal form CSIII original The drug substance has good stability under accelerated conditions and more severe conditions. High temperature and high humidity conditions caused by seasonal differences, climate differences in different regions and environmental factors will affect the storage, transportation and production of APIs and preparations. Therefore, the stability of drug substances and formulations under accelerated conditions and more severe conditions is critical to drugs. Crystalline form CSIII API has better stability under harsh conditions, which is helpful to avoid the impact on drug quality due to crystallization or purity loss during drug storage.
  • Crystal form CSIII has good physical and chemical stability, ensuring consistent and controllable quality of raw materials and preparations, and reducing changes in drug quality, bioavailability, and toxic and side effects caused by changes in crystal form or generation of impurities.
  • Figure 1 shows the XRPD pattern of crystal form CSII
  • Figure 2 is the TGA diagram of crystal form CSII
  • Figure 3 shows the XRPD pattern of crystal form CSIII.
  • Figure 4 shows the XRPD pattern of crystal form CSIII.
  • Figure 5 is the TGA diagram of crystal form CSIII.
  • Figure 6 is a PLM diagram of crystal form CSII and prior art crystal form A (top: prior art crystal form A, bottom: crystal form CSII)
  • Figure 7 is a particle size distribution diagram of the prior art crystal form A before and after ultrasound (top: before ultrasound, bottom: after ultrasound)
  • Figure 8 Particle size distribution diagram of crystal form CSII before and after ultrasound (top: before ultrasound, bottom: after ultrasound)
  • Figure 9 shows the XRPD overlay of crystalline CSII before and after tableting (from bottom to top, before and after tableting)
  • Figure 10 is the XRPD comparison chart of crystal form CSII before and after being placed under different conditions (from bottom to top: before placement, after being sealed at 25°C/60%RH (adding desiccant and antioxidant) for 9 months, after being placed at 40 °C/75%RH sealed (add desiccant and antioxidant) after 6 months)
  • Figure 11 is the XRPD overlay of crystal form CSII before and after formulation formulation (from bottom to top: crystal form CSII raw material, crystal form CSII after formulation process, and blank powder mixing formulation process)
  • Figure 12 is the XRPD comparison chart of the crystalline CSII preparation before and after being placed under different conditions (from bottom to top: before placement, after being sealed at 40°C/75%RH (adding desiccant and antioxidant) for 1 month, Sealed at 60°C/75%RH (adding desiccant and antioxidant) after 1 month)
  • Figure 13 is a PLM diagram of crystal form CSIII and prior art crystal form A (top: prior art crystal form A, bottom: crystal form CSII)
  • Figure 14 is the XRPD comparison chart of crystal form CSIII before and after being placed under different conditions (from bottom to top: before placement, after being sealed at 25°C/60%RH (adding desiccant and antioxidant) for 3 months, after being placed at 40 °C/75%RH sealed (added desiccant and antioxidant) after 3 months, sealed at 60°C/75%RH (added desiccant and antioxidant) left for 2 months)
  • Figure 15 is the XRPD pattern of crystal form Type K13
  • Figure 16 shows the XRPD pattern of crystal form Type K13
  • Figure 17 is the XRPD pattern of crystal form Type K13
  • PLM Polarized Light Microscope
  • PSD particle size distribution
  • FeSSIF artificial intestinal fluid in the fed state
  • FaSSIF artificial intestinal fluid in the fasting state
  • HDPE high density polyethylene
  • the X-ray powder diffraction pattern of the present invention is collected on a Bruker X-ray powder diffractometer.
  • the method parameters of X-ray powder diffraction according to the present invention are as follows:
  • thermogravimetric analysis (TGA) chart described in the present invention was collected on TA Q500.
  • the method parameters of the thermogravimetric analysis (TGA) according to the present invention are as follows:
  • Hydrogen nuclear magnetic resonance spectrum data ( 1 H NMR) were collected from a Bruker Avance II DMX 400M HZ nuclear magnetic resonance spectrometer. Weigh 1-5 mg of sample, dissolve it in 0.5 mL of deuterated dimethyl sulfoxide, and prepare a solution of 2-10 mg/mL.
  • the polarizing light microscope (PLM) picture described in the present invention was collected on a Sunny CX40P polarizing microscope.
  • the parameters of the PLM diagram method described in the present invention are as follows:
  • the particle size distribution results described in the present invention were collected on the Mastersizer 3000 laser particle size analyzer of Malvern Company. This test adopts the wet method.
  • the wet method uses the Hydro MV dispersion device and the test dispersion medium is Isopar G.
  • the method parameters of the laser particle size analyzer are as follows:
  • the testing method of dynamic solubility according to the present invention is shown in Table 2.
  • the "volatilization” is accomplished by conventional methods in this field, such as slow volatilization or rapid volatilization.
  • Slow evaporation means sealing the container with a sealing film, punching holes, and leaving it to evaporate; rapid evaporation means leaving the container open to evaporate.
  • room temperature is not a specific temperature value, but refers to the temperature range of 10-30°C.
  • the “characteristic peak” refers to the representative diffraction peak used to identify crystals.
  • the peak position can usually have an error of ⁇ 0.2°.
  • anhydrous substance refers to a solid substance that does not contain crystal water or crystallization solvent.
  • the "isomorphous solvate” means that the chemical composition is similar or similar, and under the same thermodynamic conditions, crystals with the same structure are formed.
  • the XRPD patterns of the crystal forms are the same or similar.
  • crystal or “crystal form” can be characterized by X-ray powder diffraction.
  • X-ray powder diffraction patterns are affected by instrument conditions, sample preparation and sample purity.
  • the relative intensity of the diffraction peaks in the X-ray powder diffraction pattern may also change with changes in experimental conditions, so the intensity of the diffraction peaks cannot be used as the only or decisive factor in determining the crystal form.
  • the relative intensity of the diffraction peaks in the X-ray powder diffraction pattern is related to the preferred orientation of the crystal.
  • the intensity of the diffraction peaks shown in the present invention is illustrative and not used for absolute comparison.
  • the X-ray powder diffraction pattern of the protected crystalline form of the present invention does not have to be completely consistent with the X-ray powder diffraction pattern in the embodiments referred to here. Any characteristic peaks with the same characteristics in these patterns Crystal forms with 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 patterns reflect the same or different crystal forms.
  • the crystalline forms CSII and CSIII of the present invention are pure, with substantially no admixture of any other crystalline forms.
  • substantially no when used to refer to a new crystal form means that the crystal form contains less than 20% (weight) of other crystal forms, especially less than 10% (weight) of other crystal forms, and even less Less than 5% (weight) of other crystalline forms refers to less than 1% (weight) of other crystalline forms.
  • the compound I as a starting material includes, but is not limited to, solid forms (crystalline or amorphous), oils, liquid forms and solutions.
  • compound I as starting material is in solid form.
  • Compound I used in the following examples can be prepared according to the existing technology, for example, according to the method described in WO2021029854A1.
  • sample 1 is the crystal form CSII of the present invention. Its X-ray powder diffraction pattern is shown in Figure 1, and the X-ray powder diffraction data is shown in Table 3.
  • TGA of sample 1 is shown in Figure 2, which has a weight loss of approximately 1.0% when heated to 100°C.
  • sample 2 is the crystal form CSII of the present invention, and its X-ray powder diffraction data is shown in Table 4.
  • the obtained crystalline solid is the crystal form CSIII of the present invention. Its X-ray powder diffraction pattern is shown in Figure 3, and the X-ray powder diffraction data is shown in Table 5.
  • the obtained crystalline solid is the crystal form CSIII of the present invention, and its X-ray powder diffraction pattern is shown in Figure 4, X-ray powder diffraction data are shown in Table 6.
  • TGA of crystal form CSIII is shown in Figure 5 and has a weight loss of approximately 0.8% when heated to 100°C.
  • FaSSIF sinulating intestinal fluid in a fasted state
  • FeSSIF sinulating intestinal fluid in a fed state
  • Example 7 Particle size distribution of crystal form CSII
  • Crystal form A before and after ultrasound in the prior art is shown in Figure 7, and the particle size distribution diagram of crystal form CSII before and after ultrasound is shown in Figure 8.
  • the results show that there is almost no change in the particle size distribution of crystalline form A in the prior art before and after built-in ultrasound, indicating that the particle size distribution of crystalline form A cannot be optimized even under the action of external force.
  • Crystal form CSII has a narrow particle size distribution and a uniform particle size distribution. Compared with crystal form A, the particle size of crystal form CSII is smaller and the particle size distribution is more uniform.
  • the degree of compression also known as the compressibility index (Compressibility index) or Carr index (Carr index)
  • Compressibility index Compressibility index
  • Carr index Carr index
  • the density and fluidity evaluation results of the crystal form CSII and the prior art crystal form A are shown in Table 10. The results show that the density and fluidity of the crystal form CSII are significantly better than the prior art crystal form A.
  • Crystal form CSII Take an appropriate amount of crystal form CSII, package it using the corresponding packaging conditions in Table 11, and place it under conditions of 25°C/60%RH and 40°C/75%RH respectively.
  • the results are shown in Table 11, and the XRPD comparison chart is shown in Figure 10.
  • the results show that the crystal form CSII is stable for at least 9 months under the condition of 25°C/60%RH sealing (adding desiccant and antioxidant), and at least 9 months under the condition of 40°C/75%RH sealing (adding desiccant and antioxidant). It is stable for 6 months. It can be seen that the crystal form CSII can maintain good stability under long-term and accelerated conditions.
  • Sealing Place the sample in a glass vial, cover the bottle mouth with a layer of aluminum foil and make holes in the aluminum foil.
  • the glass bottle containing the sample is mixed with 2g silica gel desiccant and 2.2g antioxidant Seal together in an aluminum foil bag.
  • the preparation prescription and blank powder mixing prescription of crystal form CSII are shown in Table 12 and Table 13, and the preparation process is shown in Table 14.
  • FaSSIF sinulating intestinal fluid in a fasted state
  • FeSSIF sinulating intestinal fluid in a fed state
  • Crystal form CSIII prepared by the present invention, package it using the corresponding packaging conditions in Table 16 and place it under the conditions of 25°C/60%RH, 40°C/75%RH and 60°C/75%RH respectively, and use XRPD to measure the crystal. type.
  • the results are shown in Table 16, and the XRPD comparison chart is shown in Figure 14.
  • the results show that crystal form CSIII can be stable for at least 3 months under the conditions of 25°C/60%RH sealing (adding desiccant and antioxidant) and 40°C/75%RH sealing (adding desiccant and antioxidant). It can be stable for at least 2 months under sealed conditions of /75% RH (adding desiccant and antioxidant). It can be seen that crystal form CSIII can maintain good physical stability under long-term, accelerated and even more stringent conditions.
  • Sealing Place the sample in a glass vial, cover the bottle mouth with a layer of aluminum foil and make holes in the aluminum foil.
  • the glass bottle containing the sample is mixed with 2g silica gel desiccant and 2.2g antioxidant Seal together in an aluminum foil bag.
  • Type K13 is isomorphous and can be toluene solvate, anisole solvate, trifluoroethanol solvate, methyl isobutyl ketone solvate, cosolvate of toluene and anisole, Cosolvates of methyl tert-butyl ether and anisole, cosolvates of toluene and trifluoroethanol, and cosolvates of toluene and methyl tert-butyl ether.
  • the X-ray powder diffraction pattern of Type K13 is shown in Figure 15, and the X-ray powder diffraction data is shown in Table 18.
  • the X-ray powder diffraction pattern of Type K13 is shown in Figure 16, and the X-ray powder diffraction data is shown in Table 19.
  • the X-ray powder diffraction pattern of Type K13 is shown in Figure 17, and the X-ray powder diffraction data is shown in Table 20.

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Abstract

本发明涉及尼罗司他（以下称为"化合物I"）二氢溴酸盐的新晶型及其制备方法，含有该晶型的药物组合物，以及该晶型在制备γ分泌酶抑制剂药物和治疗硬纤维瘤药物中的用途。本发明提供的化合物I二氢溴酸盐的晶型比现有技术具有一种或多种改进的性质，解决了现有技术存在的问题，对未来该药物的优化和开发具有重要价值。

Description

尼罗司他二氢溴酸盐的晶型及其制备方法和用途 技术领域
本发明涉及晶体化学领域。具体而言，涉及尼罗司他二氢溴酸盐的晶型及其制备方法和用途。
背景技术
硬纤维瘤，也称为侵袭性纤维瘤病，是一种罕见的局部侵袭性、生长缓慢的软组织肿瘤。尽管硬纤维瘤无法转移而被认为是良性肿瘤，但仍会导致患者出现严重的并发症，偶尔还会导致患者死亡，因此急需药物。
令人惊喜的是，由Spring Works Therapeutics研发的γ分泌酶抑制剂尼罗司他(Nirogacestat)，获得了FDA授予的突破性疗法和快速通道资格，并获得了FDA和EMA授予的孤儿药资格，正在被用于治疗硬纤维瘤的研究，且临床结果积极。尼罗司他能够结合γ分泌酶，阻断Notch受体的水解激活。已有的临床研究数据表明，Notch信号在癌症发展中起着重要作用。因此，抑制Notch信号是治疗硬纤维瘤的重要策略。
尼罗司他的化学名称为(S)-2-(((S)-6,8-二氟-1,2,3,4-四氢萘-2-基)胺基)-N-(1-(2-甲基-1-(新戊基胺基)丙-2-基)-1H-咪唑-4-基)戊酰胺(以下称为“化合物I”)，化合物I二氢溴酸盐的结构式如下：
本领域公知，在小分子药物开发中，药物多晶型是药物研发中的常见现象，是影响药物质量的重要因素。晶体是化合物分子在微观结构中三维有序排列而形成晶格的固体。多晶型是指一种化合物存在多种晶体形式的现象。化合物可能以一种或多种晶型存在，但是无法具体预期其存在与特性。不同晶型的原料药有不同的理化性质，可能导致药物在体内有不同的溶出、吸收，进而在一定程度上影响药物的临床疗效。特别是一些难溶性口服固体或半固体制剂，晶型对产品性能至关重要。除此之外，晶型的理化性质对生产过程至关重要。因此，多晶型是药物研究和药物质量控制的重要内容。
因此，为了得到具备可接受的理化性质，包括化学稳定性、热稳定性、溶解性、吸湿性和/或粒子大小；可制造性，包括产率、结晶期间的杂质排除、过滤性质、干燥性质和碾磨性质以及配制可行性，包括压片期间的相对于压力或压缩力的稳定性的晶型，需要对化合物I二氢溴酸盐的结晶行为进行全面的研究，以得 到满足化合物I药用需求的晶型。
目前，仅发现现有技术WO2021029854A1公开了多个化合物I二氢溴酸盐的晶型。然而，根据该专利文本公开的XRPD图可以看出，晶型B、晶型G、晶型H、晶型H’、晶型K、晶型M和晶型N的结晶度差，含有较大量的无定形，无定形含量高会极大的影响原料药的稳定性、工艺、存储、吸湿以及成药后的溶出速度，不适合药用。进一步深入研究WO2021029854A1后获知，晶型A是该现有技术公开的结晶度较好的优选晶型。然而，晶型A溶解度低，根据中国药典和美国药典对于药物溶解度的界定标准，晶型A在水中的溶解度仅属于微溶。晶型A在水中溶解度低，不利于药物在人体内的吸收，继而影响药物的生物利用度。此外，经本申请发明人依据现有技术WO2021029854A1公开的方法制备得到晶型A，进一步研究发现，晶型A粒度分布不均匀，易团聚。
为克服现有技术的缺点，仍然需要一种符合药用标准的新晶型，以用于含化合物I二氢溴酸盐药物的开发。然而，在现有技术WO2021029854A1已经公开了多个化合物I二氢溴酸盐的晶型的基础上，一种既可以克服现有技术晶型存在的问题，又符合药用标准的新晶型是不易获得的。本申请发明人规避现有技术已使用的结晶方法，设计了近千个实验，尝试了挥发、搅拌、气液扩散、气固扩散、降温结晶及湿度诱导等多种实验方法，均未获得新晶型。最终，本申请发明人在非常规有机溶剂三氟乙醇中，通过非常规的结晶方法，意外的发现了本发明所述的化合物I二氢溴酸盐的无水晶型，其在溶解度、引湿性、提纯效果、稳定性、黏附性、可压性、流动性、体内外溶出、生物有效性等方面中的至少一方面存在优势，特别是溶解度高、粒度分布更均一，不易团聚、无溶剂残留、流动性好、密度大、可压性好、原料药和制剂稳定性好，解决了现有技术存在的问题，对含化合物I二氢溴酸盐的药物开发具有非常重要的意义。
发明内容
本发明提供化合物I二氢溴酸盐的新晶型及其制备方法以及包含该新晶型的药物组合物。
根据本发明的目的，本发明提供化合物I二氢溴酸盐的晶型CSII(以下称作“晶型CSII”)。
一方面，使用Cu-Kα辐射，所述晶型CSII的X射线粉末衍射图在衍射角2θ值为7.6°±0.2°、8.4°±0.2°、12.0°±0.2°处具有特征峰。
进一步地，使用Cu-Kα辐射，所述晶型CSII的X射线粉末衍射图在衍射角2θ值为18.5±0.2°、19.5°±0.2°、20.5°±0.2°中的1处、或2处、或3处具有特征峰；优选地，所述晶型CSII的X射线粉末衍射图在衍射角2θ值为18.5±0.2°、19.5°±0.2°、20.5°±0.2°处有特征峰。
另一方面，使用Cu-Kα辐射，所述晶型CSII的X射线粉末衍射图在衍射角2θ值为中7.6°±0.2°、8.4°±0.2°、12.0°±0.2°、18.5±0.2°、19.5°±0.2°、20.5°±0.2°、15.3°±0.2°、16.9°±0.2°、24.1°±0.2°、27.1±0.2°的任意3处，或4处，或5处，或6处， 或7处，或8处，或9处，或10处有特征峰。
非限制性地，使用Cu-Kα辐射，晶型CSII的X射线粉末衍射图基本如图1所示。
非限制性地，晶型CSII热重分析图基本如图2所示，加热至100℃具有约1.0％的失重。
非限制性地，晶型CSII为无水物。
根据本发明的目的，本发明还提供所述晶型CSII的制备方法，所述制备方法包括：
将化合物I二氢溴酸盐固体溶解于三氟乙醇中，挥发得到固体，所得固体在一定温度加热一段时间，得到结晶固体。
进一步地，所述加热温度优选120-200℃，更进一步，优选150℃；所述加热时间优选0.5-60分钟。
根据本发明的目的，本发明提供化合物I二氢溴酸盐的晶型CSIII(以下称作“晶型CSIII”)。
一方面，使用Cu-Kα辐射，所述晶型CSIII的X射线粉末衍射图在衍射角2θ值为8.4°±0.2°、8.8°±0.2°、16.3°±0.2°处具有特征峰。
进一步地，使用Cu-Kα辐射，所述晶型CSIII的X射线粉末衍射图在衍射角2θ值为12.7±0.2°、14.1°±0.2°、20.8°±0.2°中的1处、或2处、或3处具有特征峰；优选地，所述晶型CSIII的X射线粉末衍射图在衍射角2θ值为12.7±0.2°、14.1°±0.2°、20.8°±0.2°处有特征峰。
进一步地，使用Cu-Kα辐射，所述晶型CSIII的X射线粉末衍射图在衍射角2θ值为21.7±0.2°、22.2°±0.2°中的1处、或2处具有特征峰；优选地，所述晶型CSIII的X射线粉末衍射图在衍射角2θ值为21.7±0.2°、22.2°±0.2°处有特征峰。
另一方面，使用Cu-Kα辐射，所述晶型CSIII的X射线粉末衍射图在衍射角2θ值为8.4°±0.2°、8.8°±0.2°、16.3°±0.2°、12.7±0.2°、14.1°±0.2°、20.8°±0.2°、21.7±0.2°、22.2°±0.2°中的任意3处，或4处，或5处，或6处，或7处，或8处有特征峰。
非限制性地，使用Cu-Kα辐射，晶型CSIII的X射线粉末衍射图基本如图3所示。
非限制性地，晶型CSIII热重分析图基本如图5所示，加热至100℃具有约0.8％的失重。
非限制性地，晶型CSIII为无水物。
根据本发明的目的，本发明还提供所述晶型CSIII的制备方法，所述制备方法包括：
将化合物I二氢溴酸盐固体溶解于三氟乙醇中，挥发得到固体，将所得固体以一定加热速率加热到一定温度，得到结晶固体。
进一步地，所述加热速率优选1-5℃/min，更进一步优选2℃/min；所述一定温度优选201-205℃，更进一步优选202℃。
根据本发明的目的，本发明提供晶型CSII、晶型CSIII或以上两中晶型的任意混合用于制备化合物I其他晶型或盐或共晶的用途。
根据本发明的目的，本发明提供一种药物组合物，所述药物组合物包含有效治疗量的晶型CSII、晶型CSIII或以上两中晶型的任意混合及药学上可接受的辅料。
根据本发明的目的，本发明提供晶型CSII、晶型CSIII或以上两种晶型的任意混合在制备γ分泌酶抑制剂药物中的用途。
根据本发明的目的，本发明提供晶型CSII、晶型CSIII或以上两种晶型的任意混合在制备治疗硬纤维瘤药物中的用途。
有益效果及本发明解决的技术问题
本发明解决的技术问题是提供了不同于现有技术晶型的新晶型，该晶型在兼具优异的稳定性基础上，相比于现有技术晶型A具有更高的溶解度、更均一的粒度分布、更小的粒径、更好的流动性、更大密度，更优的可压性，无溶剂残留和不易团聚，解决了现有技术存在的问题。
本发明提供的晶型CSII具有以下有益效果：
(1)与现有技术晶型A相比，本发明提供的晶型CSII具有更高的溶解度。特别是在水中溶解度是晶型A的3-5倍；在模拟体内介质FeSSIF和FaSSIF溶液中，溶解度均是现有技术晶型A的1.5倍。本发明提供的晶型CSII有更高的溶解度，有利于提高药物在人体内的吸收，提高生物利用度；另外，更高的溶解度能够在保证药物疗效的同时，降低药品的剂量，从而降低药品的副作用并提高药品的安全性。
(2)与现有技术晶型A相比，本发明提供的晶型CSII不团聚，粒径更小，具有更均一的粒度分布。均匀的粒径有助于减少溶剂富集，提高产品纯度，降低产品溶残，保证药物制剂含量均匀度，降低体外溶出度的变异性。更小的粒径，有助于提高药物的溶解度和生物利用度。
(3)与现有技术晶型A相比，本发明提供的晶型CSII具有更大的密度。实验结果表明：本发明晶型CSII的松密度与振实密度均明显优于现有技术晶型A。晶型CSII的密度大，有利于大规模生产，更大的密度可减少粉尘，降低职业危害。
(4)与现有技术晶型A相比，本发明提供的晶型CSII具有更好的流动性。更好的流动性可以避免堵塞生产设备，提升生产效率；保证制剂的含量均匀度、降低重量差异，提升产品质量。
(5)与现有技术晶型A相比，本发明提供的晶型CSII具有更优的可压性。晶型CSII好的可压性可以有效改善压片工艺中的硬度/脆碎度不合格、裂片等问题，使制剂工艺更为可靠，改善产品外观，提升产品质量和生产效率。
(6)本发明提供的晶型CSII无溶残。残留溶剂不仅会影响药物的安全性，还会对药物质量和稳定性产生影响。残留溶剂可能会导致药物在生产和储存的过程中发生转晶或者杂质生成，从而引起药物生物利用度变化和毒副作用。本发明提供的晶型CSII无溶剂残留，有效地克服了药物纯度低或溶剂残留高带来的药物稳定性低、疗效差、毒性高等缺点。
(7)本发明提供的晶型CSII在机械力作用下具有良好的物理稳定性。晶型 CSII原料药在制剂处方工艺后晶型保持不变。制剂加工过程中常需要将原料药研磨或粉碎，良好的物理稳定性能够降低制剂加工过程中原料药结晶度降低和转晶的风险。此外，在5kN压力下，晶型CSII原料药具有良好的物理稳定性，有利于在制剂压片工艺中保持晶型稳定。
(8)本发明提供的晶型CSII原料药和制剂均具有良好的稳定性。晶型CSII原料药在25℃/60％RH条件下放置，至少9个月晶型未发生变化，且储存过程中纯度基本保持不变。
同时，晶型CSII原料药在40℃/75％RH条件下放置至少6个月晶型未发生变化，且储存过程中纯度基本保持不变。晶型CSII与辅料混合做成药物制剂后，在40℃/75％RH和60℃/75％RH条件下放置，至少1个月晶型未发生变化。说明晶型CSII原料药和制剂在加速条件及更严苛的条件下，具有较好的稳定性。季节差异、不同地区气候差异和环境因素等带来的高温和高湿条件会影响原料药和制剂的储存、运输、生产。因此，原料药和制剂在加速条件及更严苛的条件下的稳定性对于药物至关重要。晶型CSII原料药和制剂在苛刻的条件下具有更好的稳定性，有利于避免药物储存过程中因转晶或纯度下降对药物质量产生影响。
原料药晶型良好的物理和化学稳定性可以确保药物在生产和存储的过程中不会发生转晶且基本没有杂质产生。晶型CSII具有良好的物理化学稳定性，保证原料药和制剂质量一致可控，减少由于晶型改变或杂质产生引起的药物质量变化，生物利用度变化，和毒副作用。
本发明提供的晶型CSIII具有以下有益效果：
(1)与现有技术晶型A相比，本发明提供的晶型CSIII具有更高的溶解度。特别是在FeSSIF中，溶解度是现有技术晶型A的1.5倍；在FaSSIF中，溶解度是现有技术晶型A的1.3倍。本发明提供的晶型CSIII有更高的溶解度，有利于提高药物在人体内的吸收，提高生物利用度；另外，更高的溶解度能够在保证药物疗效的同时，降低药品的剂量，从而降低药品的副作用并提高药品的安全性。
(2)与现有技术晶型A相比，本发明提供的晶型CSIII不团聚，具有更均一的粒度分布。均匀的粒径有助于减少溶剂富集，提高产品纯度，降低产品溶残，保证药物制剂含量均匀度，降低体外溶出度的变异性。
(3)本发明提供的晶型CSIII无溶残。残留溶剂不仅会影响药物的安全性，还会对药物质量和稳定性产生影响。残留溶剂可能会导致药物在生产和储存的过程中发生转晶或者杂质生成，从而引起药物生物利用度变化和毒副作用。本发明提供的晶型CSIII无溶剂残留，有效地克服了药物纯度低或溶剂残留高带来的药物稳定性低、疗效差、毒性高等缺点。
(4)本发明提供的晶型CSIII原料药具有良好的稳定性。晶型CSIII原料药在25℃/60％RH条件下放置，至少3个月晶型未发生变化。
同时，晶型CSIII原料药在40℃/75％RH条件下放置至少3个月晶型未发生变化，在60℃/75％RH条件下放置，至少2个月晶型未发生变化。说明晶型CSIII原 料药在加速条件及更严苛的条件下，具有较好的稳定性。季节差异、不同地区气候差异和环境因素等带来的高温和高湿条件会影响原料药和制剂的储存、运输、生产。因此，原料药和制剂在加速条件及更严苛的条件下的稳定性对于药物至关重要。晶型CSIII原料药在苛刻的条件下具有更好的稳定性，有利于避免药物储存过程中因转晶或纯度下降对药物质量产生影响。
原料药晶型良好的物理和化学稳定性可以确保药物在生产和存储的过程中不会发生转晶且基本没有杂质产生。晶型CSIII具有良好的物理化学稳定性，保证原料药和制剂质量一致可控，减少由于晶型改变或杂质产生引起的药物质量变化，生物利用度变化，和毒副作用。
附图说明
图1为晶型CSII的XRPD图
图2为晶型CSII的TGA图
图3为晶型CSIII的XRPD图
图4为晶型CSIII的XRPD图
图5为晶型CSIII的TGA图
图6为晶型CSII和现有技术晶型A的PLM图(上：现有技术晶型A，下：晶型CSII)
图7为现有技术晶型A超声前后的粒度分布图(上：超声前，下：超声后)
图8晶型CSII超声前后的粒度分布图(上：超声前，下：超声后)
图9为晶型CSII压片前后的XRPD叠图(从下至上依次为压片前，压片后)
图10为晶型CSII在不同条件下放置前后的XRPD对比图(从下至上依次为：放置前，在25℃/60％RH密封(加干燥剂和抗氧化剂)放置9个月后，在40℃/75％RH密封(加干燥剂和抗氧化剂)放置6个月后)
图11为晶型CSII在制剂处方前后的XRPD叠图(从下到上依次为：晶型CSII原料药，晶型CSII制剂工艺后，空白混粉制剂工艺后)
图12为晶型CSII制剂在不同条件下放置前后的XRPD对比图(从下到上依次为：放置前，在40℃/75％RH密封(加干燥剂和抗氧化剂)放置1个月后，在60℃/75％RH密封(加干燥剂和抗氧化剂)放置1个月后)
图13为晶型CSIII和现有技术晶型A的PLM图(上：现有技术晶型A，下：晶型CSII)
图14为晶型CSIII在不同条件下放置前后的XRPD对比图(从下至上依次为：放置前，在25℃/60％RH密封(加干燥剂和抗氧化剂)放置3个月后，在40℃/75％RH密封(加干燥剂和抗氧化剂)放置3个月后，在60℃/75％RH密封(加干燥剂和抗氧化剂)放置2个月后)
图15为晶型Type K13的XRPD图
图16为晶型Type K13的XRPD图
图17为晶型Type K13的XRPD图
具体实施方式
结合以下实施例对本发明做详细说明，所述实施例详细描述本发明的晶型的制备和使用方法。对本领域技术人员显而易见的是，对于材料和方法两者的许多改变可在不脱离本发明范围的情况下实施。
本发明中所用到的缩写的解释如下：
XRPD：X射线粉末衍射
TGA：热重分析
PLM：偏光显微镜
PSD：粒度分布
1H NMR：液态核磁氢谱
HPLC：高效液相色谱
UPLC：超高效液相色谱
FeSSIF：进食状态下人工肠液
FaSSIF：空腹状态下人工肠液
RH：相对湿度
HDPE：高密度聚乙烯
LDPE：低密度聚乙烯
采集数据所用的仪器及方法：
本发明所述的X射线粉末衍射图在Bruker X射线粉末衍射仪上采集。本发明所述的X射线粉末衍射的方法参数如下：
X射线光源：Cu,Kα
Kα2/Kα1强度比例：0.50
本发明所述的热重分析(TGA)图在TA Q500上采集。本发明所述的热重分析(TGA)的方法参数如下：
扫描速率：10℃/min
保护气体：N2
核磁共振氢谱数据(1H NMR)采自于Bruker Avance II DMX 400M HZ核磁共振波谱仪。称量1-5mg样品，用0.5mL氘代二甲亚砜溶解，配成2-10mg/mL的溶液。
本发明所述的偏光显微镜(PLM)图在舜宇CX40P偏光显微镜上采集。本发明所述的PLM图方法参数如下：
放大倍数100倍
本发明中所述的粒径分布结果是在Malvern公司的Mastersizer 3000型激光粒度分析仪上采集。本测试采用湿法，湿法测试使用Hydro MV分散装置，测试分散介质为Isopar G。所述的激光粒度分析仪的方法参数如下：

本发明所述有关物质的测试方法如表1所示。
表1
本发明所述动态溶解度的测试方法如表2所示。
表2

所述“挥发”，采用本领域的常规方法完成，例如缓慢挥发或快速挥发。缓慢挥发是将容器封上封口膜，扎孔，静置挥发；快速挥发是将容器敞口放置挥发。
所述“室温”不是特定的温度值，是指10-30℃温度范围。
所述“特征峰”是指用于甄别晶体的有代表性的衍射峰，使用Cu-Kα辐射测试时，峰位置通常可以有±0.2°的误差。
所述“无水物”是指不含结晶水或结晶溶剂的固态物质。
所述“类质同晶溶剂合物”是指，是指化学组成相似或相近，在相同的热力学条件下，形成具有相同结构的晶体。表现为晶型的XRPD图相同或相似。
本发明中，“晶体”或“晶型”可以用X射线粉末衍射表征。本领域技术人员能够理解，X射线粉末衍射图受仪器的条件、样品的准备和样品纯度的影响而有所改变。X射线粉末衍射图中衍射峰的相对强度也可能随着实验条件的变化而变化，所以衍射峰强度不能作为判定晶型的唯一或决定性因素。事实上，X射线粉末衍射图中衍射峰的相对强度与晶体的择优取向有关，本发明所示的衍射峰强度为说明性而非用于绝对比较。因而，本领域技术人员可以理解的是，本发明所保护晶型的X射线粉末衍射图不必和这里所指的实施例中的X射线粉末衍射图完全一致，任何具有和这些图谱中的特征峰相同或相似的X射线粉末衍射图的晶型均属于本发明的范畴之内。本领域技术人员能够将本发明所列的X射线粉末衍射图和一个未知晶型的X射线粉末衍射图相比较，以证实这两组图反映的是相同还是不同的晶型。
在一些实施方案中，本发明的晶型CSII和晶型CSIII是纯的，基本没有混合任何其他晶型。本发明中，“基本没有”当用来指新晶型时指这个晶型含有少于20％(重量)的其他晶型，尤其指少于10％(重量)的其他晶型，更指少于5％(重量)的其他晶型，更指少于1％(重量)的其他晶型。
本发明中术语“约”，当用来指可测量的数值时，例如质量、时间、温度等，意味着可围绕具体数值有一定的浮动的范围，该范围可以为±10％、±5％、±1％、±0.5％、或±0.1％。
除非特殊说明，以下实施例均在室温条件下操作。
根据本发明，作为原料的所述化合物I包括但不限于固体形式(结晶或无定形)、油状、液体形式和溶液。优选地，作为原料的化合物I为固体形式。
以下实施例中所使用的化合物I可根据现有技术制备得到，例如根据WO2021029854A1文献所记载的方法制备获得。
实施例1晶型CSII的制备方法
称取201.3mg化合物I二氢溴酸盐固体，加入2.0mL三氟乙醇得到澄清溶液，室温挥发约5天，得到固体，取两份适量所得固体，分别在氮气保护下加热到150℃，恒温5分钟后再回到室温，得到结晶固体，将所得结晶固体分别标记为样品1和样品2。
经检测，样品1为本发明晶型CSII，其X射线粉末衍射图如图1，X射线粉末衍射数据如表3所示。
样品1的TGA如图2所示，将其加热至100℃具有约1.0％的失重。
样品1的1H NMR数据为：1H NMR(400MHz,DMSO-d6)δ11.29(s,1H),9.30(brs,2H),7.93(brs,2H),7.75(s,1H),7.54(s,1H),7.08(td,J＝9.8,2.4Hz,1H),6.90(d,J＝9.3Hz,1H),4.22(s,1H),3.51(s,2H),3.30–3.19(m,2H),3.00–2.88(m,1H),2.87–2.69(m,2H),2.61–2.52(m,2H),2.29–2.14(m,1H),2.04–1.73(m,3H),1.64(d,J＝7.6Hz,6H),1.41–1.25(m,2H),0.91(t,J＝7.3Hz,3H),0.85(s,9H)。核磁数据表明晶型CSII无任何有机溶剂残留。
表3
经检测，样品2为本发明晶型CSII，其X射线粉末衍射数据如表4所示。
表4

实施例2晶型CSIII的制备方法
称取201.3mg化合物I二氢溴酸盐固体，加入2.0mL三氟乙醇得到澄清溶液，室温挥发约5天，得到固体，将所得固体在氮气保护下加热到150℃，恒温5min后回到室温，再在氮气保护下加热到210℃，恒温0.1min后回到室温，得到结晶固体。
经检测，所得结晶固体为本发明晶型CSIII，其X射线粉末衍射图如图3，X射线粉末衍射数据如表5所示。
表5
实施例3晶型CSIII的制备方法
称取400.4mg化合物I二氢溴酸盐固体，加入18.0mL三氟乙醇得到澄清溶液，过滤后取滤液在室温挥发约13天得到固体，将所得固体在氮气保护下以2℃/min加热到202℃，再以20℃/min回到室温，得到结晶固体。
经检测，所得结晶固体为本发明晶型CSIII，其X射线粉末衍射图如图4， X射线粉末衍射数据如表6所示。
晶型CSIII的TGA如图5所示，将其加热至100℃具有约0.8％的失重。
表6
实施例4晶型CSIII的1H NMR
晶型CSIII的1H NMR数据为：1H NMR(400MHz,DMSO-d6)δ11.30(s,1H),9.32(brs,2H),7.95(brs,2H),7.75(s,1H),7.54(s,1H),7.16–7.03(m,1H),6.91(d,J＝9.4Hz,1H),4.22(s,1H),3.51(s,2H),3.32–3.21(m,2H),2.93(d,J＝17.3Hz,1H),2.88–2.63(m,2H),2.63–2.53(m,2H),2.29–2.15(m,1H),1.99–1.74(m,3H),1.63(d,J＝7.8Hz,6H),1.41–1.25(m,2H),0.91(t,J＝7.3Hz,3H),0.85(s,9H)。核磁结果表明晶型CSIII无任何有机溶剂残留。
实施例5晶型CSII的溶解度
水中溶解度测试
取1.9mg晶型CSII至玻璃小瓶中，37℃下逐滴加入水直至固体完全溶解，记录样品在水中的最大不溶体积和最小溶清体积，计算得到晶型CSII在水中的溶解度(mg/mL)。结果如表7所示。结果表明，本发明提供的晶型CSII具有更高的溶解度，在水中溶解度至少是晶型A的3-5倍。
表7
晶型A的溶解度数据引自WO2021029854A1实施例1
生物介质中溶解度测试
进行药物溶解度测试以预测药物体内性能的时候，很重要的一点是尽可能的模拟体内条件。对口服药，用FaSSIF(模拟禁食状态肠液)和FeSSIF(模拟进食状态肠液)可以模拟体内条件并预测进食的影响。在此类介质中测试的溶解度与人体环境中的溶解度更加接近。
取晶型CSII及现有技术晶型A各约15mg于37℃分别分散在4.0mL的FeSSIF和FaSSIF中配制成饱和溶液，平衡1小时后分别用高效液相色谱法测试饱和溶液中样品的含量(mg/mL)，结果如表8所示。结果表明，本发明提供的晶型CSII具有更高的溶解度。在FeSSIF和FaSSIF中，溶解度均是现有技术晶型A的1.5倍。
表8
实施例6晶型CSII的形貌
取约0.5mg晶型CSII和现有技术晶型A至载玻片上，滴加少量浸油使样品分散，覆盖上盖玻片后。采用偏光显微镜分别放大100倍对样品进行形貌进行观察，结果如图6显示。结果表明，晶型CSII为大小均一的片状晶体，现有技术晶型A呈聚团块状。
实施例7晶型CSII的粒度分布
取现有技术晶型A和晶型CSII加入Isopar G(含有0.2％卵磷脂)，将待测样品充分混合均匀后加入Hydro MV分散装置中，使遮光度达到合适范围，开始实验，先直接进行粒度分布的测试，再用内置超声超声60秒后进行粒度分布的测试。从而得到按照体积计算的平均粒径、粒度分布中(体积分布)占10％所对应的粒径(D10)、粒度分布中(体积分布)占50％所对应的粒径(D50)和粒度分布中(体积分布)占90％所对应的粒径(D90)，测试结果如表9所示。现有技术晶型A超声前后的粒度分布图如图7所示，晶型CSII超声前后的粒度分布图如图8所示。结果表明，现有技术晶型A内置超声前后粒度分布几乎无变化，表明在外力作用下也无法优化晶型A的粒度分布。晶型CSII粒度分布窄，具有均一的粒径分布。相比于晶型A，晶型CSII的粒径更小，且粒径分布均一性更好。
表9
实施例8晶型CSII的密度和流动性
将约300-500mg粉体轻轻装入5mL量筒测量体积，后在ZS-2E振实仪上振实1250次，使粉体处于最紧状态，测量振实后体积，计算松密度ρ0与振实密度ρf。
制剂工艺过程中，通常可采用压缩度(c)又称为可压性系数(Compressibility index)或卡尔系数(Carr index)来评价粉体或颗粒的流动性，根据公式c＝(ρf－ρ0)/ρf计算。参考ICH Q4B附录13记载的可压性系数对粉体流动性的界定标准可知，可压性系数越小流动性越好。
晶型CSII和现有技术晶型A的密度和流动性评价结果见表10，结果表明晶型CSII的密度和流动性明显优于现有技术晶型A。
表10

实施例9晶型CSII的可压性
采用ENERPAC手动压片机进行压片，压片时，选择Φ6mm圆形平冲，分别加入约60mg晶型CSII和现有技术晶型A，采用3kN的压力压制圆形片剂各3片，室温放置24h，待完全弹性复原后采用片剂硬度测定仪测试其径向破碎力(硬度，H，N)。采用游标卡尺测量片剂的直径(D，mm)和厚度(L，mm)，利用公式T＝2H/πDL计算粉体的抗张强度。结果显示晶型CSII的平均抗张强度为0.68MPa，现有技术晶型A的平均抗张强度为0.37MPa。在一定的压力下，抗张强度越大的，可压性越好。因此，结果表明相比现有技术晶型A，晶型CSII具有更优的可压性。
实施例10晶型CSII在机械力作用下的物理稳定性
取适量晶型CSII，选择Φ6mm圆形平冲，在手动压片机下用5kN的压力压制成片并保持10s，压片前后进行XRPD测试，测试结果如图所示图9。结果表明晶型CSII在压片后晶型保持稳定。
实施例11晶型CSII的稳定性
取适量晶型CSII，采用表11中对应包装条件包装后分别放置在25℃/60％RH和40℃/75％RH条件下，采用HPLC和XRPD测定纯度与晶型。结果如表11所示，XRPD对比图如图10所示。结果表明，晶型CSII在25℃/60％RH密封(加干燥剂和抗氧化剂)条件下至少可稳定9个月，在40℃/75％RH密封(加干燥剂和抗氧化剂)条件下至少可稳定6个月，可见，晶型CSII在长期和加速条件下均可保持良好的稳定性。
表11
密封(加干燥剂和抗氧化剂)：将样品置于玻璃小瓶中，瓶口盖上一层铝箔纸并在铝箔纸上开孔，装有样品的玻璃瓶与2g硅胶干燥剂和2.2g抗氧化剂一起密封于铝箔袋中。
实施例12晶型CSII的制剂制备
晶型CSII的制剂处方和空白混粉处方见表12和表13，制剂工艺见表14。测试空白混粉和制剂处方前后样品的XRPD，结果如图11所示。结果表明，晶型CSII在制剂处方工艺后晶型保持稳定。
表12
表13
表14
实施例13晶型CSII制剂中的稳定性
取适量晶型CSII片剂在40℃/75％RH以及60℃/75％RH闭口条件下，加2g干燥剂和1g抗氧化剂放置1月后，采用XRPD测定晶型，结果如图12所示。结果表明，晶型CSII制剂在40℃/75％RH以及60℃/75％RH条件下可以至少可稳定1个月。
实施例14晶型CSIII的形貌
取约0.5mg晶型CSIII和现有技术晶型A至载玻片上，滴加少量浸油使样品分散，覆盖上盖玻片后。采用偏光显微镜分别放大100倍对样品进行形貌进行观察，结果如图13显示。结果表明，晶型CSIII为大小均一的片状晶体，现有技术晶型A呈聚团块状。
实施例15晶型CSIII的溶解度
进行药物溶解度测试以预测药物体内性能的时候，很重要的一点是尽可能的模拟体内条件。对口服药，用FaSSIF(模拟禁食状态肠液)和FeSSIF(模拟进食状态肠液)可以模拟体内条件并预测进食的影响。在此类介质中测试的溶解度与人体环境中的溶解度更加接近。
取晶型CSIII及现有技术晶型A各约15mg于37℃分别分散在4.0mL的FeSSIF和FaSSIF中配制成饱和溶液，平衡1小时后分别用高效液相色谱法测试饱和溶液中样品的含量(mg/mL)，结果如表15所示。结果表明，本发明提供的晶型CSIII具有更高的溶解度。在FaSSIF中，溶解度是现有技术晶型A的1.3倍，在FeSSIF中，溶解度是现有技术晶型A的1.5倍。
表15
实施例16晶型CSIII的稳定性
取适量本发明制备得到的晶型CSIII，采用表16中对应包装条件包装后分别放置在25℃/60％RH、40℃/75％RH和60℃/75％RH条件下，采用XRPD测定晶型。结果如表16所示，XRPD对比图如图14所示。结果表明，晶型CSIII在25℃/60％RH密封(加干燥剂和抗氧化剂)和40℃/75％RH密封(加干燥剂和抗氧化剂)条件下至少可稳定3个月，在60℃/75％RH密封(加干燥剂和抗氧化剂)条件下至少可稳定2个月，可见，晶型CSIII在长期、加速乃至更严苛的条件下均可保持良好的物理稳定性。
表16
密封(加干燥剂和抗氧化剂)：将样品置于玻璃小瓶中，瓶口盖上一层铝箔纸并在铝箔纸上开孔，装有样品的玻璃瓶与2g硅胶干燥剂和2.2g抗氧化剂一起密封于铝箔袋中。
实施例17溶剂合物Type K13的制备
称取如表17所示质量的化合物I二氢溴酸盐固体，加入0.3mL表17中对应的溶剂，-20℃下振荡3-23h后得到的Type K13。经本申请发明人研究发现 Type K13为类质同晶，可以是甲苯溶剂合物、苯甲醚溶剂合物、三氟乙醇溶剂合物、甲基异丁基酮溶剂合物，甲苯和苯甲醚的共溶剂合物、甲基叔丁基醚和苯甲醚共溶剂合物、甲苯和三氟乙醇的共溶剂合物以及甲苯和甲基叔丁基醚的共溶剂合物。
表17
Type K13的X射线粉末衍射图如图15，X射线粉末衍射数据如表18所示。
表18

Type K13的X射线粉末衍射图如图16，X射线粉末衍射数据如表19所示。
表19

Type K13的X射线粉末衍射图如图17，X射线粉末衍射数据如表20所示。
表20
上述实施例只为说明本发明的技术构思及特点，其目的在于让熟悉此项技术的人士能够了解本发明的内容并据以实施，并不能以此限制本发明的保护范围。凡根据本发明精神实质所作的等效变化或修饰，都应涵盖在本发明的保护范围之内。

Claims (11)

  1. 一种化合物I二氢溴酸盐的晶型CSII，其特征在于，使用Cu-Kα辐射，其X射线粉末衍射图在2θ值为7.6°±0.2°、8.4°±0.2°、12.0°±0.2°处具有特征峰，
  2. 根据权利要求1所述的化合物I二氢溴酸盐的晶型CSII，其特征在于，使用Cu-Kα辐射，其X射线粉末衍射图在2θ值为18.5°±0.2°、19.5°±0.2°、20.5°±0.2°中的1处、或2处、或3处具有特征峰。
  3. 根据权利要求2所述的化合物I二氢溴酸盐的晶型CSII，其特征在于，X射线粉末衍射图基本如图1所示。
  4. 一种化合物I二氢溴酸盐的晶型CSIII，其特征在于，使用Cu-Kα辐射，其X射线粉末衍射图在2θ值为8.4°±0.2°、8.8°±0.2°、16.3°±0.2°处具有特征峰。
  5. 根据权利要求4所述的化合物I二氢溴酸盐的晶型CSIII，其特征在于，使用Cu-Kα辐射，其X射线粉末衍射图在2θ值为12.7°±0.2°、14.1°±0.2°、20.8°±0.2°中的1处、或2处、或3处具有特征峰。
  6. 根据权利要求4所述的化合物I二氢溴酸盐的晶型CSIII，其特征在于，使用Cu-Kα辐射，其X射线粉末衍射图在2θ值为21.7°±0.2°、22.2°±0.2°中的1处、或2处具有特征峰。
  7. 根据权利要求5所述的化合物I二氢溴酸盐的晶型CSIII，其特征在于，使用Cu-Kα辐射，其X射线粉末衍射图在2θ值为21.7°±0.2°、22.2°±0.2°中的1处、或2处具有特征峰。
  8. 根据权利要求4所述的化合物I二氢溴酸盐的晶型CSIII，其特征在于，X射线粉末衍射图基本如图3所示。
  9. 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所述的化合物I二氢溴酸盐的晶型CSII、权利要求4中所述的化合物I二氢溴酸盐的晶型CSIII或以上两种晶型的任意混合及药学上可接受的辅料。
  10. 权利要求1中所述的化合物I二氢溴酸盐的晶型CSII、权利要求4中所述的化合物I二氢溴酸盐的晶型CSIII或以上两种晶型的任意混合在制备γ分泌酶抑制剂药物中的用途。
  11. 权利要求1中所述的化合物I二氢溴酸盐的晶型CSII、权利要求4中所述的化合物I二氢溴酸盐的晶型CSIII或以上两种晶型的任意混合在制备治疗硬纤维瘤药物中的用途。
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