WO2022100395A1 - Forme cristalline d de baloxavir marboxil et son procédé de préparation - Google Patents

Forme cristalline d de baloxavir marboxil et son procédé de préparation Download PDF

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Publication number
WO2022100395A1
WO2022100395A1 PCT/CN2021/125344 CN2021125344W WO2022100395A1 WO 2022100395 A1 WO2022100395 A1 WO 2022100395A1 CN 2021125344 W CN2021125344 W CN 2021125344W WO 2022100395 A1 WO2022100395 A1 WO 2022100395A1
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WIPO (PCT)
Prior art keywords
crystal form
baloxavir
dipivoxil
crystal
solvent
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PCT/CN2021/125344
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English (en)
Chinese (zh)
Inventor
赵楠
胡文军
刘晓雨
魏俊杰
Original Assignee
上海迪赛诺生物医药有限公司
上海迪赛诺药业股份有限公司
上海迪赛诺化学制药有限公司
江苏普信制药有限公司
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Publication of WO2022100395A1 publication Critical patent/WO2022100395A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/14—Ortho-condensed systems
    • 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 a baloxavir dipivoxil crystal form D and a preparation method thereof, belonging to the technical field of medicinal chemistry.
  • Baloxavir Marboxil is a new anti-influenza drug developed by Shionogi, Japan, and its trade name is Xofluza.
  • Xofluza is an innovative Cap-dependent endonuclease inhibitor and one of the few new oral drugs in the world that can inhibit the proliferation of influenza virus. It can target the key link of influenza virus replication and inhibit it from obtaining the 5' end of host mRNA from host cells.
  • CAP structure thereby inhibiting the transcription of the influenza virus's own mRNA, the drug was approved by Japan in February 2018 for the treatment of adult and pediatric patients with influenza A and B, and was approved by the FDA in October 2018 for the treatment of Uncomplicated acute influenza patients 12 years of age and older within 48 hours.
  • Baloxavir dipivoxil is a prodrug, which is hydrolyzed into the active substance baloxavir in the body, and their chemical structural formula is as follows:
  • baloxavir dipivoxil is a polymorphic compound, such as: three crystal forms of Form I, Form II and Form III of baloxavir dipivoxil are disclosed in patent WO2018030463, wherein the Form I crystal form It is prepared in a mixed solution of dimethyl sulfoxide and water (see Example 10 therein), and the Form II crystal form is first dissolved in a mixed solution of acetonitrile (50 mL) and water (5 mL), and then replenished.
  • Form II crystal form and Form III crystal form are unstable, and are easily converted into Form I crystal form during the crystallization process;
  • the Form A and Form B crystal forms of Wei Dipivoxil have good stability under high temperature, high humidity and light conditions.
  • the Form A crystal form is the Form I crystal form published in the patent WO2018030463, and
  • the thermogravimetric analysis of Form B shows that it has a weight loss of about 0.5%. According to the patent, it is anhydrous, so this part of the weight loss indicates that Form B is a mixed crystal form mixed with solvates.
  • Form B is obtained by volatilization and crystallization from the acetonitrile system, and acetonitrile belongs to the second-class solvent stipulated by ICH, the limit is lower, and on the other hand, mixed crystal will also affect the dissolution of the preparation, so the Form B in the form of acetonitrile solvate is It is impossible to be used as a medicine, and the preparation of Form B crystal form requires the natural volatilization of acetonitrile solution at room temperature for 3 to 4 days, which is definitely not possible in industrial production, and a large amount of acetonitrile solvent is volatilized into the air.
  • the raw material used for oral preparations is still Form I crystal form (the same crystal form as Form A crystal form), but the crystal habit of the existing Form I crystal form is flaky, and the flaky crystal, in During the drying process, it is easy to wrap the solvent and agglomerate, which makes the material hard after drying, and the solvent residue is easy to exceed the standard.
  • the object of the present invention is to provide a baloxavir dipivoxil crystal form D that is superior to the existing crystal form in terms of stability, solubility, fluidity, etc. Industrial production requirements for oral formulations of loxavir dipivoxil.
  • the baloxavir dipivoxil crystal form D of the present invention is an anhydrous anhydrous ansolvate crystal form of baloxavir dipivoxil, and under X-ray powder diffraction, the diffraction angle 2 ⁇ is 4.5°, 8.8°, 10.8°, There are characteristic diffraction peaks at 13.2°, 14.3°, 14.8° and 16.2°, and the test error is ⁇ 0.2°.
  • the baloxavir dipivoxil crystal form D of the present invention under X-ray powder diffraction, has diffraction angles 2 ⁇ of 4.5°, 8.8°, 9.8°, 10.8°, 11.7°, 13.2°, 14.3° , 14.8°, 15.8°, 16.2°, 16.5°, 17.3°, 17.5°, 17.8°, 18.8°, 20.2°, 21.6°, 21.9°, 22.3°, 24.2°, 24.4°, 26.5°, 28.0°, 28.3 There are characteristic diffraction peaks at °, 29.7° and 31.5°, and the test error is ⁇ 0.2°.
  • the X-ray powder diffraction spectrum of the baloxavir dipivoxil crystal form D of the present invention is basically consistent with FIG. 4 .
  • the DSC spectrum of the baloxavir dipivoxil crystal form D of the present invention is basically consistent with FIG. 5 .
  • thermogravimetric analysis spectrum of baloxavir dipivoxil crystal form D according to the present invention is basically consistent with FIG. 6 .
  • a method for preparing baloxavir dipivoxil crystal form D of the present invention comprising the following steps:
  • the baloxavir dipivoxil raw material is dissolved in the mixed solvent formed by methylene chloride and the ester solvent by volume ratio of 1.0: (0.5 ⁇ 2.5), obtains a clear solution;
  • step c) The crystals obtained in step c) are vacuum-dried at 50-100° C. for 6-15 hours to obtain baloxavir dipivoxil crystal form D.
  • the dissolving temperature is preferably 20-40°C, and preferably 25-35°C.
  • the type of the baloxavir dipivoxil raw material is not limited, and it can be amorphous or any known crystal form or a mixture thereof.
  • the mass volume ratio of the baloxavir dipivoxil raw material and the mixed solvent is 1 gram: (8 ⁇ 15) milliliters, preferably 1 gram: (8 ⁇ 12) milliliters, and 1 gram: (8 ⁇ 12) milliliters. Grams: 10ml is optimal.
  • the volume ratio of the dichloromethane to the ester solvent in the mixed solvent is preferably 1.0:(0.8-1.2), and is the best at 1.0:1.0.
  • step a) described ester solvent is selected from at least one in methyl benzoate, ethyl benzoate, methyl formate, ethyl formate, isopropyl formate, butyl formate, butyl acetate, with Any one selected from methyl benzoate, methyl formate and ethyl formate is the best.
  • step b) the ratio of the volume of n-heptane used to the volume of the mixed solvent used in step a) is (1-1.2):1, with 1:1 being the best.
  • the vacuum drying conditions are preferably drying at 70-90°C for 6-10 hours, and optimally drying at 60-80°C for 6-8 hours.
  • the present invention has the following significant beneficial effects:
  • the research results of the present invention show that the crystal form D of baloxavir dipivoxil described in the present invention is an anhydrous and solvent-free crystal form, the crystal habit of the crystal form is a slender needle-like crystal, and the solvent is easily removed by vacuum drying.
  • the baloxavir dipivoxil crystal form D of the present invention has better solubility than the existing crystal form in the pH environment simulating gastric and intestinal juice, which is very beneficial to the absorption and utilization of oral preparations;
  • the loxavir dipivoxil crystal form D has various excellent properties that are more suitable for oral preparations, and has produced significant progress and unexpected technical effects compared with the prior art.
  • Fig. 1 is the X-ray powder diffraction pattern (XRPD) of the crystal form C described in Example 1;
  • Fig. 2 is the differential scanning calorimetry analysis spectrum (DSC) of crystal form C described in embodiment 1;
  • Fig. 3 is the thermogravimetric analysis data (TGA) of crystal form C described in embodiment 1;
  • Figure 4 is the X-ray powder diffraction pattern (XRPD) of Form D described in Example 1;
  • DSC differential scanning calorimetry
  • Fig. 6 is the thermogravimetric analysis data (TGA) of crystal form D described in Example 1;
  • Fig. 7 is the X-ray powder diffraction pattern (XRPD) of known crystal form I;
  • Fig. 8 is the XRPD contrast spectrum of the stability experiment of crystal form D described in Example 4.
  • Fig. 9 is the crystal habit photo of crystal form D described in this application.
  • Figure 10 is a photograph of the crystal habit of the known Form I.
  • test method is usually carried out under conventional conditions or conditions suggested by the manufacturer, and the indicated raw materials and reagents can be obtained by commercially available methods.
  • X-ray powder diffractometer Brucker D8 advance X-ray powder diffractometer
  • Step size 0.020°
  • Measurement time per step 0.1 sec/step
  • DSC Differential scanning calorimetry
  • DSC Differential Scanning Calorimetry
  • Temperature range room temperature ⁇ 250°C;
  • TGA Thermogravimetric analysis
  • Thermogravimetric analysis (TGA) instrument TGA55 type;
  • Temperature range room temperature ⁇ 300°C;
  • the 2 ⁇ of the X-ray powder diffraction pattern of the crystal form C is at 4.0 ⁇ 0.2°, 8.0 ⁇ 0.2°, 11.1 ⁇ 0.2°, 11.4 ⁇ 0.2°, 12.0 ⁇ 0.2°, 13.2 ⁇ 0.2°, 13.6 ⁇ 0.2°, 14.1 ⁇ 0.2°, 14.3 ⁇ 0.2°, 16.1 ⁇ 0.2°, 16.3 ⁇ Featured at 0.2°, 17.9 ⁇ 0.2°, 20.2 ⁇ 0.2°, 20.8 ⁇ 0.2°, 23.9 ⁇ 0.2°, 24.3 ⁇ 0.2°, 24.5 ⁇ 0.2°, 25.6 ⁇ 0.2°, 28.5 ⁇ 0.2° and 32.6 ⁇ 0.2° peak.
  • Fig. 2 is a differential scanning calorimetry spectrum of the crystal form C, and it can be seen from Fig. 2 that the crystal form C has endothermic peaks at 90-100°C and 235°C.
  • Fig. 3 is the thermogravimetric analysis spectrum of the crystal form C. It can be seen from Fig. 3 that the crystal form C has a weight loss of 8.0-11.0% at 90-100°C, indicating that the crystal form C is baloxavir dipivoxil The solvate of methyl benzoate, wherein the content of methyl benzoate is 8.0-11.0%.
  • the obtained crystal form C was dried in a vacuum drying oven at 80 ° C for 6 hours to obtain 9.2 g of solid.
  • Its XRPD spectrum is shown in Figure 4, that is: the diffraction angles 2 ⁇ are 4.5°, 8.8°, 9.8° °, 10.8°, 11.7°, 13.2°, 14.3°, 14.8°, 15.8°, 16.2°, 16.5°, 17.3°, 17.5°, 17.8°, 18.8°, 20.2°, 21.6°, 21.9°, 22.3°, There are characteristic diffraction peaks at 24.2°, 24.4°, 26.5°, 28.0°, 28.3°, 29.7° and 31.5°, and the test error is ⁇ 0.2°.
  • the application records the crystal form obtained after drying as crystal form D.
  • Fig. 5 is the differential scanning calorimetry spectrum of the crystal form D, as can be seen from Fig. 5: the crystal form D has an endothermic peak at 235°C;
  • Fig. 6 is the thermogravimetric analysis spectrum of the crystal form D , it can be seen from Figure 6 that the crystal form D is an anhydrous and solvent-free crystal form.
  • baloxavir dipivoxil was dissolved in a mixed solvent of 50 mL of dichloromethane and 50 mL of ethyl formate, then 100 mL of n-heptane was added dropwise, stirred and crystallized for 1 hour, filtered, and the filter cake was washed with n-heptane. Rinse with heptane, and then vacuum dry at 60 °C for 8 hours to obtain 9.6 g of solid.
  • Its XRPD spectrum is basically consistent with Figure 4
  • its differential scanning calorimetry spectrum is basically consistent with Figure 5
  • thermogravimetric analysis spectrum The figure is basically consistent with FIG. 6, which is the crystal form D described in this application.
  • the crystal form D (prepared from Examples 1-3) described in this application and the known crystal form I (prepared with reference to Example 10 in patent WO2018030463) are prepared, and their XRPD spectra are shown in the figure 7, which is basically consistent with Figure 3 in WO2018030463) to conduct experiments on influencing factors, including high temperature test, high humidity test and strong light irradiation test, to investigate the stability conditions affecting its crystal form:
  • High temperature test Take appropriate amount of crystal form D and crystal form I samples respectively, lay them flat in a weighing bottle, and place them in a constant temperature and humidity box at 70°C and RH75% for 10 days. Take about 100 mg of the above samples, and use powder X-ray Its crystal form was tested by powder diffraction (XRPD), and the results are shown in Table 1 and Figure 8;
  • High humidity test Take appropriate amount of crystal form D and crystal form I samples respectively, lay them flat in a weighing bottle, and place them in a constant temperature and humidity box at 25°C and RH 92.5% for 10 days. Take about 100 mg of the above samples and use powder X - XRPD testing its crystal form, the results are shown in Table 1 and Figure 8;
  • Illumination test Take appropriate amount of samples of crystal form D and crystal form I respectively, spread them into weighing bottles, and put them in a constant temperature and humidity box (25°C) with visible light 4500Lux ⁇ 500Lux (VIS) and ultraviolet light 1.7W*h/m2 (UV). °C, RH 60% ⁇ 5%) for 10 days, take about 100 mg of the above sample, use powder X-ray powder diffraction (XRPD) to test its crystal form, the results are shown in Table 1 and Figure 8.
  • XRPD powder X-ray powder diffraction
  • Sample crystal form Form D Form I High temperature (70°C, RH75%, 10 days) still in form D still in form I High humidity (25°C, RH 92.5%, 10 days) still in form D still in form I Light (10 days) still in form D still in form I
  • pH 1.2 solution take 2.0 g of sodium chloride, dissolve it in an appropriate amount of water, add 7 mL of hydrochloric acid, add water to dilute to 1000 mL, and mix well to get it;
  • pH4.0 solution mix 0.05mol/L acetic acid solution and 0.05mol/L sodium acetate solution in a ratio of 16.4:3.6 to obtain;
  • Phosphate buffer at pH 6.8 Take 1.7 g of potassium dihydrogen phosphate and 1.775 g of anhydrous disodium hydrogen phosphate, add water to dissolve and dilute to 1000 mL.
  • the baloxavir dipivoxil crystal form D described in this application has a solubility better than the existing crystal form I in the pH environment of simulating gastrointestinal fluid, which is very beneficial to the absorption and utilization of oral preparations. .
  • Fig. 9 is the crystal habit photo of the crystal form D described in the application, as can be seen from Fig. 9: the crystal habit of the crystal form D described in the present application is a slender needle-like crystal, and the particle dispersibility is good, indicating that it has good fluidity and compressibility, very suitable for use as a raw material for tablets;
  • Fig. 10 is the crystal habit photo of the known crystal form I, as can be seen from Fig. 10: the crystal habit of crystal form I is flaky, and the flaky crystal, in the process of baking the material, is easy to wrap the solvent and agglomerate, resulting in baking After drying, the material is hard, and the solvent residue is easy to exceed the standard. It often takes a long time to dry to reach the solvent limit. If the drying time is too long, it is easy to cause the degradation of impurities to exceed the standard. In addition, after the material is agglomerated, the product has poor fluidity and needs to be physically crushed. Reaching the particle size requirement causes trouble to the production and preparation of tablets, and is not an ideal raw material for tablet preparation.

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Est divulguée une forme cristalline D de baloxavir marboxil et son procédé de préparation. La forme cristalline D de baloxavir marboxil est une forme cristalline anhydre et exempte de solvant du baloxavir marboxil, et présente des pics de diffraction caractéristiques à des angles de diffraction 2θ de 4,5°, 8,8°, 10,8°, 13,2°, 14,3°, 14,8° et 16,2° sous diffraction de rayons X sur poudre, l'erreur de test étant de ± 0,2°. Les résultats de la recherche selon la présente invention montrent que l'habitus cristallin de la forme cristalline D de baloxavir marboxil est un cristal de type aiguille allongé. Un solvant est facilement éliminé par séchage sous vide. Après séchage, les particules cristallines présentant une pureté allant jusqu'à 99,5 %, les limites des résidus d'impuretés et du solvant satisfaisant toutes les normes de qualité des principes actifs pharmaceutiques, et une stabilité, une dispersibilité, une fluidité et une compressibilité élevées peuvent être obtenues, les particules cristallines étant appropriées pour une utilisation en tant que matières premières pour produire des comprimés. De plus, la forme cristalline D de baloxavir marboxil présente une meilleure solubilité que les formes cristallines existantes dans des environnements qui simulent le pH de l'estomac et des fluides intestinaux, et est bénéfique pour l'absorption et l'utilisation de préparations orales.
PCT/CN2021/125344 2020-11-12 2021-10-21 Forme cristalline d de baloxavir marboxil et son procédé de préparation WO2022100395A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN117741017A (zh) * 2024-02-21 2024-03-22 湖南科锐斯医药科技有限公司 一种检测化合物a及代谢物巴洛沙韦浓度的生物分析方法

Citations (8)

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Publication number Priority date Publication date Assignee Title
CN107709321A (zh) * 2015-04-28 2018-02-16 盐野义制药株式会社 经取代的多环性吡啶酮衍生物及其前药
CN109504721A (zh) * 2018-12-26 2019-03-22 杭州科巢生物科技有限公司 一种新型抗流感药物的合成方法
WO2020058745A1 (fr) * 2018-09-18 2020-03-26 Shionogi & Co., Ltd. Traitement de la grippe à l'aide de dérivés de pyridone polycycliques substitués et leurs promédicaments
CN111233891A (zh) * 2020-03-04 2020-06-05 江苏柯菲平医药股份有限公司 一种稠环吡啶酮衍生物及其制备方法和用途
WO2020181025A1 (fr) * 2019-03-05 2020-09-10 Assia Chemical Industries Ltd Formes à l'état solide de baloxavir marboxil
CN111647005A (zh) * 2020-06-15 2020-09-11 安徽皓元药业有限公司 巴洛沙韦新晶型及其制备方法
CN111875619A (zh) * 2020-07-30 2020-11-03 深圳市新阳唯康科技有限公司 巴洛沙韦酯的新晶型及其制备方法
WO2021057834A1 (fr) * 2019-09-27 2021-04-01 广东东阳光药业有限公司 Forme cristalline de composé ester et son procédé de préparation

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107709321A (zh) * 2015-04-28 2018-02-16 盐野义制药株式会社 经取代的多环性吡啶酮衍生物及其前药
WO2020058745A1 (fr) * 2018-09-18 2020-03-26 Shionogi & Co., Ltd. Traitement de la grippe à l'aide de dérivés de pyridone polycycliques substitués et leurs promédicaments
CN109504721A (zh) * 2018-12-26 2019-03-22 杭州科巢生物科技有限公司 一种新型抗流感药物的合成方法
WO2020181025A1 (fr) * 2019-03-05 2020-09-10 Assia Chemical Industries Ltd Formes à l'état solide de baloxavir marboxil
WO2021057834A1 (fr) * 2019-09-27 2021-04-01 广东东阳光药业有限公司 Forme cristalline de composé ester et son procédé de préparation
CN111233891A (zh) * 2020-03-04 2020-06-05 江苏柯菲平医药股份有限公司 一种稠环吡啶酮衍生物及其制备方法和用途
CN111647005A (zh) * 2020-06-15 2020-09-11 安徽皓元药业有限公司 巴洛沙韦新晶型及其制备方法
CN111875619A (zh) * 2020-07-30 2020-11-03 深圳市新阳唯康科技有限公司 巴洛沙韦酯的新晶型及其制备方法

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN117741017A (zh) * 2024-02-21 2024-03-22 湖南科锐斯医药科技有限公司 一种检测化合物a及代谢物巴洛沙韦浓度的生物分析方法

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