[go: up one dir, main page]

EP4262983A1 - Formes solides de baloxavir, sels de baloxavir et co-cristaux de baloxavir - Google Patents

Formes solides de baloxavir, sels de baloxavir et co-cristaux de baloxavir

Info

Publication number
EP4262983A1
EP4262983A1 EP21835303.5A EP21835303A EP4262983A1 EP 4262983 A1 EP4262983 A1 EP 4262983A1 EP 21835303 A EP21835303 A EP 21835303A EP 4262983 A1 EP4262983 A1 EP 4262983A1
Authority
EP
European Patent Office
Prior art keywords
baloxavir
solid
theta
degrees
xrpd pattern
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP21835303.5A
Other languages
German (de)
English (en)
Inventor
Michal HEGEDUS
Nicolas Tesson
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Synthon BV
Original Assignee
Synthon BV
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Synthon BV filed Critical Synthon BV
Publication of EP4262983A1 publication Critical patent/EP4262983A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • 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
    • C07D498/02—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 two hetero rings
    • C07D498/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses

Definitions

  • the invention relates to solid forms of Baloxavir, salts thereof and cocrystals thereof and solid forms of Baloxavir, salts thereof and cocrystals thereof.
  • This invention relates to solid forms Baloxavir, compound of formula (1), solvates thereof and solid forms of the solvates.
  • This invention further relates to salts of Baloxavir and solid forms thereof.
  • This invention also relates to cocrystals of Baloxavir and solid forms thereof.
  • the invention also relates to process for preparation of the solid forms.
  • [l,2,4]triazine-6,8-dione, is an anti-influenza virus drug.
  • Baloxavir was disclosed in WO2016175224 application.
  • WO2017221869 application discloses a solid form of Baloxavir. There are no Baloxavir salts or cocrystals disclosed in prior art.
  • Crystalline form of an active substance plays an important role in final drug product.
  • the crystallinity and stability of the polymorphic form might affect the solubility of the product.
  • Solubility of API or its salt or its cocrystal plays a major role for final dosage forms like parenteral or oral formulations.
  • Solubility is one of the important parameters to achieve desired concentration of drug in systemic circulation for achieving required pharmacological response. Any drug to be absorbed must be present in the form of an aqueous solution at the site of absorption.
  • solubility is the most important one rate limiting parameter to achieve their desired concentration in systemic circulation for pharmacological response. It is therefore advantageous to develop Baloxavir solid forms or solid forms of Baloxavir salts or solid forms of Baloxavir cocrystals having improved crystallinity, solubility, purity or stability.
  • the presented invention relates to sodium, potassium and meglumin salts of Baloxavir and solid forms thereof.
  • the presented invention further relates to solid forms of Baloxavir and solvates thereof.
  • the presented invention also relates to co-crystals of Baloxavir with oxalic acid, propyl gallate and L-lactic acid and solid forms thereof.
  • Figure 1 depicts the X-Ray Powder Diffractogram (XRPD) of cocrystal of Baloxavir with propyl gallate, Form I, prepared according to Example 1.
  • XRPD X-Ray Powder Diffractogram
  • Figure 2 depicts the DSC pattern of cocrystal of Baloxavir with propyl gallate, Form I, prepared according to Example 1.
  • Figure 3 depicts NMR pattern of cocrystal of Baloxavir with propyl gallate, Form I, prepared according to Example 1.
  • Figure 4 depicts the X-Ray Powder Diffractogram (XRPD) of cocrystal of Baloxavir with oxalic acid, ethyl acetate solvate, Form II, prepared according to Example 2.
  • Figure 5 depicts the DSC pattern of cocrystal of Baloxavir with oxalic acid, ethyl acetate solvate, Form II, prepared according to Example 2.
  • XRPD X-Ray Powder Diffractogram
  • Figure 6 depicts NMR pattern of cocrystal of Baloxavir with oxalic acid, ethyl acetate solvate, Form II, prepared according to Example 2.
  • Figure 7 depicts the X-Ray Powder Diffractogram (XRPD) of cocrystal of Baloxavir with oxalic acid, ethyl acetate solvate, Form lib, prepared according to Example 2.
  • XRPD X-Ray Powder Diffractogram
  • Figure 8 depicts NMR pattern of cocrystal of Baloxavir with oxalic acid, ethyl acetate solvate, Form lib, prepared according to Example 2.
  • Figure 9 depicts the X-Ray Powder Diffractogram (XRPD) of cocrystal of Baloxavir with L-lactic acid, Form III, prepared according to Example 4.
  • XRPD X-Ray Powder Diffractogram
  • Figure 10 depicts the DSC pattern of cocrystal of Baloxavir with L-Lactid acid, Form III, prepared according to Example 4.
  • Figure 11 depicts NMR pattern of cocrystal of Baloxavir with L-Lactid acid, Form III, prepared according to Example 4.
  • Figure 12 depicts the X-Ray Powder Diffractogram (XRPD) of cocrystal of Baloxavir with oxalic acid, methylacetate solvent, Form M, prepared according to Example 3.
  • XRPD X-Ray Powder Diffractogram
  • Figure 13 depicts the DSC pattern of cocrystal of Baloxavir with oxalic acid, methylacetate solvent, Form M, prepared according to Example 3.
  • Figure 14 depicts the TGA pattern of cocrystal of Baloxavir with oxalic acid, methylacetate solvent, Form M, prepared according to Example 3.
  • Figure 15 depicts the X-Ray Powder Diffractogram (XRPD) of sodium salt of Baloxavir, Form 1, prepared according to Example 5.
  • XRPD X-Ray Powder Diffractogram
  • Figure 16 depicts the DSC pattern of sodium salt of Baloxavir, Form 1, prepared according to Example 5.
  • Figure 17 depicts the X-Ray Powder Diffractogram (XRPD) of potassium salt of Baloxavir, Form 2, prepared according to Example 6.
  • XRPD X-Ray Powder Diffractogram
  • Figure 18 depicts the DSC pattern of potassium salt of Baloxavir, Form 2, prepared according to Example 6.
  • Figure 19 depicts the X-Ray Powder Diffractogram (XRPD) of meglumine salt of Baloxavir, Form 1, prepared according to Example 7.
  • Figure 20 depicts the DSC pattern of meglumine salt of Baloxavir, Form 1, prepared according to Example 7.
  • Figure 21 depicts the X-Ray Powder Diffractogram (XRPD) of Baloxavir Form 2, prepared according to Example 11.
  • Figure 22 depicts the DSC pattern of Baloxavir Form 2, prepared according to Example 11.
  • Figure 23 depicts the X-Ray Powder Diffractogram (XRPD) of Baloxavir Form 5, prepared according to Example 12.
  • Figure 24 depicts the DSC pattern of Baloxavir Form 5, prepared according to Example 12.
  • Figure 25 depicts the X-Ray Powder Diffractogram (XRPD) of Baloxavir Form 8, prepared according to Example 15.
  • Figure 26 depicts the DSC pattern of Baloxavir Form 8, prepared according to Example 15.
  • Figure 27 depicts the X-Ray Powder Diffractogram (XRPD) of Baloxavir Form 6, prepared according to Example 13.
  • Figure 28 depicts the DSC pattern of Baloxavir Form 6, prepared according to Example
  • Figure 29 depicts the X-Ray Powder Diffractogram (XRPD) of Baloxavir Form 9, prepared according to Example 10.
  • Figure 30 depicts the DSC pattern of Baloxavir Form 9, prepared according to Example 10.
  • Figure 31 depicts TGA pattern of Baloxavir Form 6, prepared according to Example 13.
  • Figure 32 depicts TGA pattern of Baloxavir Form 9, prepared according to Example 10.
  • the presented invention relates to sodium, potassium and meglumine salt of Baloxavir, solid forms thereof and processes for preparation thereof.
  • the presented invention also relates to solid forms of Baloxavir and solvates thereof.
  • the presented invention further relates to Baloxavir cocrystals with propyl gallate or oxalic acid or L-lactic acid, solid forms thereof and processes for preparation thereof.
  • Cocrystals can be defined as a binary compound where two components (co-formers) are in a solid state connected via non-ionic intermolecular bonds.
  • the invention further to Baloxavir sodium, potassium and meglumine salts, solid forms thereof and processes for preparation thereof.
  • the solid form of Baloxavir sodium salt, Form 1 can be characterized by XRPD pattern having 20 values 3.8°, 4.3° and 10.1° degrees 2 theta ( ⁇ 0.2 degrees 2 theta).
  • the solid Form 1 can be also characterized by XRPD pattern having 20 values 3.8°, 4.3°, 5.3°, 9.7° and 10.1° degrees 2 theta ( ⁇ 0.2 degrees 2 theta).
  • the solid form can be further characterized by XRPD pattern described in the following table:
  • the solid Form 1 can be further characterized by XRPD pattern depicted in Figure 15 and DSC pattern depicted in Figure 16.
  • the Form 1 can be prepared by a process comprising: a. Mixing Baloxavir and sodium base in methanol or ethanol; b. Heating the mixture; c. Cooling the mixture; d. Isolating Baloxavir sodium salt, Form 1.
  • Sodium base can be selected from for example sodium hydroxide or sodium hydride or sodium methoxide.
  • concentration of Baloxavir in the solvent can be between 30 mg/ml and 80 mg/ml.
  • the molar ratio between Baloxavir and the sodium base can be between 1 :0.8 and 1 : 1.3.
  • the mixture of Baloxavir in methanol or ethanol is heated to a temperature between 45°C and 65°C and to the mixture sodium base is added.
  • the base can be added in a solid form or in a form of a solution is a suitable solvent, for example the solvent used in step a. The mixture is stirred at the elevated temperature for between 20 and 120 minutes.
  • the mixture is cooled to a temperature between 20°C and 25°C and resulting suspension is stirred at this temperature for between 6 and 12 hours.
  • the solid Form 1 can be isolated by any suitable technique, for example using filtration or centrifuge. Obtained solid can be optionally dried.
  • the presented invention also relates to a solid form of Baloxavir potassium salt, Form 2, that can be characterized by XRPD pattern having 20 values 3.8°, 4.3° and 9.9° degrees 2 theta ( ⁇ 0.2 degrees 2 theta).
  • the solid Form 2 can be also characterized by XRPD pattern having
  • the solid form can be further characterized by XRPD pattern described in the following table:
  • the solid Form 2 can be further characterized by XRPD pattern depicted in Figure 17 and DSC pattern depicted in Figure 18.
  • the Form 2 can be prepared by a process comprising: a. Mixing Baloxavir and a potassium base in methanol or ethanol or propanol; b. Heating the mixture; c. Cooling the mixture; d. Adding an anti-solvent; e. Isolating Baloxavir potassium salt, Form 2.
  • the concentration of Baloxavir in the solvent can be between 40 mg/ml and 60 mg/ml.
  • the potassium base can be selected for example from potassium hydroxide or potassium hydride or potassium methoxide.
  • the molar ratio between Baloxavir and potassium base can be between 1:0.8 and 1:1.3.
  • the mixture is heated to a temperature between 45°C and the reflux temperature of used solvent and stirred at this temperature for between 10 to 120 minutes.
  • the mixture is then cooled for example to a temperature between 20°C and 30°C, preferably to a temperature between 20°C and 25°C.
  • an antisolvent i.e. solvent in which solubility of potassium salt of Baloxavir is low
  • an ether for example diisopropyl ether or diethyl ether
  • the volume ration between used solvent and antisolvent can be between 2.3:1 and 2.7:1, preferably it is between 2.4:1 and 2.6:1.
  • the mixture is then cooled to a temperature between (-10°C) and 10°C and stirred at this temperature for between 5 and 24 hours.
  • the solid form can be isolated by any suitable technique, for example using filtration or centrifuge. Obtained solid can be optionally dried.
  • the presented invention further relates to meglumine ((2R,3R,4R,5S)-6- (Methylamino)hexane-l,2,3,4,5-pentol) salt of Baloxavir, a solid form thereof and a process for preparation thereof.
  • the solid form, Form 1 can be characterized by XRPD pattern having 20 values 10.5°, 11.4° and 13.5° degrees 2 theta ( ⁇ 0.2 degrees 2 theta).
  • the solid Form 1 can be also characterized by XRPD pattern having 20 values 9.8°, 10.5°, 11.4°, 13.5° and 21.4° degrees 2 theta ( ⁇ 0.2 degrees 2 theta).
  • the solid form can be further characterized by XRPD pattern described in the following table:
  • the solid Form 1 can be further characterized by XRPD pattern depicted in Figure 19 and DSC pattern depicted in Figure 20.
  • the solid Form 1 can be prepared by a process comprising: a. Contacting Baloxavir and meglumine in methanol or ethanol or propanol; b. Dissolving the mixture; c. Cooling the mixture.
  • the molar ration between Baloxavir and meglumine can be between 1 :2 and 1:2.3.
  • the mixture can be optionally heated in step b. to form a solution.
  • the mixture can be heated to a temperature between 50°C and the reflux temperature of used solvent. After forming a solution, the mixture is cooled to a temperature between 0°C and 5°C.
  • the mixture can be optionally seeded with Baloxavir meglumine salt, Form 1, crystals. The mixture is left at this temperature for between 2 and 10 hours.
  • the solid form can be isolated by any suitable technique, for example using filtration or centrifuge. Obtained solid can be optionally dried.
  • the presented crystalline Baloxavir salts can be used for purification of Baloxavir from impurities for example by using processes disclosed in Examples 8 or 9.
  • the presented invention also relates to solid forms of Baloxavir and processes for preparation thereof.
  • the solid form, Form 2 can be characterized by XRPD pattern having 20 values 6.5°, 9.7° and 11.4° degrees 2 theta ( ⁇ 0.2 degrees 2 theta).
  • the solid Form 2 can be also characterized by XRPD pattern having 20 values 6.5°, 9.7°, 11.4°, 14.6° and 15.7° degrees 2 theta ( ⁇ 0.2 degrees 2 theta).
  • the solid form can be further characterized by XRPD pattern described in the following table:
  • the solid Form 2 can be also characterized by XRPD pattern depicted in Figure 21.
  • the solid form can be further characterized by DSC pattern depicted in Figure 22.
  • the solid Form 2 can be prepared by a process comprising suspending Baloxavir dioxane solvate (Form 9) in water.
  • the concentration of Baloxavir Form 9 in water can be between 70 mg/ml and 1500 mg/ml.
  • the suspension is stirred for between 18 and 30 hours at a temperature between 20°C and 30°C.
  • the solid form can be isolated by any suitable technique, for example using filtration or centrifuge. Obtained solid can be optionally dried, for example freely in air for between 10 and 30 hours.
  • Baloxavir Form 2 can be also prepared by a process comprising wet milling of a solid form of Baloxavir in MeOH or water for 15 minutes at 25 Hz.
  • the concentration of Baloxavir in the solvent is 100 mg/ml.
  • the presented invention further relates to Baloxavir solid Form 5 and processes for preparation thereof.
  • the solid Form 5, can be characterized by XRPD pattern having 20 values 8.8°, 12.5° and 15.2° degrees 2 theta ( ⁇ 0.2 degrees 2 theta).
  • the solid Form 5 can be also characterized by XRPD pattern having 20 values 8.8°, 11.3°, 12.5°, 13.5° and 15.2° degrees 2 theta ( ⁇ 0.2 degrees 2 theta).
  • the solid form can be further characterized by XRPD pattern described in the following table:
  • the solid Form 5 can be further characterized by XRPD pattern depicted in Figure 23 and DSC pattern depicted in Figure 24.
  • the solid Form 5 can be prepared by a process comprising: a. Dissolving of Baloxavir in an alcohol; b. Contacting the solution with water at a temperature between 0°C and 10°C.
  • the alcohol can be selected for example from methanol or ethanol or propanol or isopropanol.
  • concentration of Baloxavir in the alcohol can be between 6 mg/ml and 10 g/ml.
  • Baloxavir can be dissolved while heating the mixture, for example to a temperature between 40°C and the reflux temperature of the alcohol.
  • Contacting of the solution with water can be done for example by pouring the solution into water or adding water in the solution.
  • the volume ration between the alcohol and water 1: 10 and 1:20, preferably between 1 : 13 and 1: 17.
  • Obtained suspension is stirred at a temperature between 20°C and 30°C for between 2 and 6 hours.
  • the solid form can be isolated by any suitable technique, for example using filtration or centrifuge. Obtained solid can be optionally dried, for example at a temperature between 50°C and 70°C for between 10 and 30 hours.
  • the invention further relates to solid form of Baloxavir, Form 8, and processes for preparation thereof.
  • the solid Form 8 can be characterized by XRPD pattern having 20 values 11.7°, 12.9° and 18.9° degrees 2 theta ( ⁇ 0.2 degrees 2 theta).
  • the solid Form 8 can be also characterized by XRPD pattern having 20 values 10.0°, 11.7°, 12.1° 12.9° and 18.9° degrees 2 theta ( ⁇ 0.2 degrees 2 theta).
  • the solid form can be further characterized by XRPD pattern described in the following table:
  • the solid Form 8 can be further characterized by XRPD pattern depicted in Figure 25 and DSC pattern depicted in Figure 26.
  • the solid Form 8 can be prepared by a process comprising: a. Dissolving Baloxavir in acetonitrile; b. Slow evaporating of the solvent.
  • the concentration of Baloxavir in acetonitrile can be between 6 mg/ml and 12 mg/ml. Slow evaporating was done at a temperature between 20°C and 35°C for between 4 and 6 days. All solvent was evaporated, obtained solid was dried, for example on air for between 5 and 10 days.
  • the solid Form 8 can be also obtained by a process comprising drying of solid Form 6 of Baloxavir at a temperature between 55°C and 70°C for between 18 and 30 hours under vacuum (for example 100 mbar) under a protective atmosphere, for example nitrogen or argon.
  • the presented invention further relates to Baloxavir acetonitrile solvate, a solid form thereof and processes for preparation thereof.
  • the solid form, Form 6 can be characterized by XRPD pattern having 20 values 8.7°, 11.0° and 12.6° degrees 2 theta ( ⁇ 0.2 degrees 2 theta).
  • the solid Form 6 can be also characterized by XRPD pattern having 20 values 7.7°, 8.7°, 11.0°, 12.6° and 21.2° degrees 2 theta ( ⁇ 0.2 degrees 2 theta).
  • the solid form can be further characterized by XRPD pattern described in the following table:
  • the solid Form 6 can be further characterized by XRPD pattern depicted in Figure 27 and DSC pattern depicted in Figure 28.
  • the solid Form 6 can be prepared by a process comprising suspending Baloxavir Form 9 in acetonitrile.
  • the concentration of Baloxavir in acetonitrile can be between 80 mg/ml and 120 mg/ml.
  • the suspension is stirred at a temperature between 20°C and 30 °C for between 4 and 10 hours.
  • the solid form can be isolated by any suitable technique, for example using filtration or centrifuge. Obtained solid can be optionally dried, for example at a temperature between 20°C and 25°C for between 4 and 10 hours.
  • Solid Form 6 can be also prepared by a process comprising: a. Dissolving Baloxavir in acetonitrile; b. Evaporating the solvent.
  • the concentration of Baloxavir in acetonitrile can be between can be between 8 mg/ml and 12 mg/ml.
  • Baloxavir can be dissolved at an elevated temperature, for example between 45°C and 60°C. Evaporating the solvent can be done for example using vacuum and an elevated temperature.
  • the presented invention further relates to Baloxavide dioxane solvate, a solid form thereof and a process for preparation thereof.
  • the solid form, Form 9 can be characterized by XRPD pattern having 20 values 8.2°, 12.0° and 12.6° degrees 2 theta ( ⁇ 0.2 degrees 2 theta).
  • the solid Form 9 can be also characterized by XRPD pattern having 20 values 7.5°, 8.2°, 12.0°, 12.6° and 14.7° degrees 2 theta ( ⁇ 0.2 degrees 2 theta).
  • the solid form can be further characterized by XRPD pattern described in the following table:
  • the solid Form 9 can be further characterized by XRPD pattern depicted in Figure 29 and DSC pattern depicted in Figure 30.
  • Form 9 can be prepared by a process comprising: a. Dissolving solid Baloxavir in acetonitrile; b. Adding water to obtain a suspension; c. Isolating solid Baloxavir; d. Suspending the isolated Baloxavir in dioxane.
  • the concentration of Baloxavir in acetonitrile can be between 8 mg/ml and 12 mg/ml.
  • the volume ratio between acetonitrile and water can be between 1:2.5 and 1:4. Obtained suspension is left at 20°C to 25°C for between 1 and 5 hours.
  • the solid form can be isolated by any suitable technique, for example using filtration or centrifuge. Obtained solid is suspending in dioxane.
  • the concentration of Baloxavir in dioxane can be between 50 mg/ml and 200 mg/ml.
  • the suspension is stirred at between 25°C and 30°C for between 0.5 to 12 hours.
  • the solid form can be isolated by any suitable technique, for example using filtration or centrifuge. Obtained solid can be optionally dried.
  • the solid form of cocrystals of Baloxavir propyl gallate, Form I can be characterized by XRPD pattern having 20 values 6.3°, 12.4° and 13.5° degrees 2 theta ( ⁇ 0.2 degrees 2 theta).
  • the solid Form I can be also characterized by XRPD pattern having 20 values 6.3°, 7.7°, 12.4°, 13.5° and 18.5° degrees 2 theta ( ⁇ 0.2 degrees 2 theta).
  • the solid form can be further characterized by XRPD pattern described in the following table:
  • the solid Form I can be further characterized by XRPD pattern depicted in Figure 1 or
  • the solid Form I can be prepared by a process comprising: a. Contacting Baloxavir and propyl gallate with acetone; b. Isolating the Form I.
  • the molar ratio between Baloxavir and propyl gallate can be between 1:2.9 and 1:3.2.
  • the concentration of Baloxavir in acetone can be between 0.15 g/ml and 0.25 g/ml.
  • Acetone is added to the mixture of Baloxavir and propyl gallate. The resulting mixture is stirred at a temperature between 20°C and 30°C for between 10 and 20 hours.
  • the solid form can be isolated by any suitable technique, for example using filtration or centrifuge. Obtained solid can be optionally dried.
  • the presented invention also relates to a cocrystal of Baloxavir with oxalic acid, ethylacetate solvate, solid forms thereof and processes for preparation thereof.
  • the solid form, Form II can be characterized by XRPD pattern having 20 values 6.7°, 18.3° and 21.5° degrees 2 theta ( ⁇ 0.2 degrees 2 theta).
  • the solid Form II can be also characterized by XRPD pattern having 20 values 6.7°, 12.4°, 15.1°, 18.3° and 21.5° degrees 2 theta ( ⁇ 0.2 degrees 2 theta).
  • the solid form can be further characterized by XRPD pattern described in the following table:
  • the solid Form II can be further characterized by XRPD pattern depicted in Figure 4 or DSC pattern depicted in Figure 5 or NMR pattern depicted in Figure 6.
  • the solid Form II can be prepared by a process comprising: a. Contacting Baloxavir and oxalic acid with ethylacetate; b. Isolating the Form II.
  • the molar ration between Baloxavir and oxalic acid can be between 1:1.9 and 1:2.2.
  • concentration of Baloxavir in the ethyl acetate can be between 0.05 g/ml and 0.15 g/ml.
  • the solid form can be isolated by any suitable technique, for example using filtration or centrifuge. Obtained solid can be optionally dried.
  • a solid Form lib is prepared.
  • the Form lib can be characterized by XRPD pattern having 20 values 8.6°, 12.5° and 15.3° degrees 2 theta ( ⁇ 0.2 degrees 2 theta).
  • the solid Form lib can be also characterized by XRPD pattern having 20 values 8.6°, 12.5°, 15.3°, 17.6° and 18.0° degrees 2 theta ( ⁇ 0.2 degrees 2 theta).
  • the solid form can be further characterized by XRPD pattern described in the following table:
  • the solid Form lib can be further characterized by XRPD pattern depicted in Figure 7 or NMR pattern depicted in Figure 8.
  • the presented invention further relates to a cocrystal of Baloxavir with oxalic acid, methylacetate solvate, solid form thereof and process for preparation thereof.
  • the solid form, Form M can be characterized by XRPD pattern having 20 values 6.7°, 18.5° and 21.4° degrees 2 theta ( ⁇ 0.2 degrees 2 theta).
  • the solid Form M can be also characterized by XRPD pattern having 20 values 6.7°, 9.0°, 12.5°, 13.1°, 18.5° and 21.4° degrees 2 theta ( ⁇ 0.2 degrees 2 theta).
  • the solid form can be further characterized by XRPD pattern described in the following table:
  • the solid Form M can be further characterized by XRPD pattern depicted in Figure 12 DSC pattern depicted in Figure 13 or TGA pattern depicted in Figure 14.
  • the solid Form M can be prepared by a process comprising: a. Contacting Baloxavir and oxalic acid with methyl acetate; b. Isolating the Form M.
  • the molar ratio between Baloxavir and oxalic acid can be between 1:1.9 and 1:2.2.
  • the concentration of Baloxavir in methyl acetate can be between 50 mg/ml and 150 mg/ml.
  • To the mixture of Baloxavir and oxalic acid methyl acetate is added. The resulting mixture is stirred at a temperature between 20°C and 30°C for between 10 and 20 hours.
  • the solid form can be isolated by any suitable technique, for example using filtration or centrifuge. Obtained solid can be optionally dried.
  • the presented invention also relates to a cocrystal of Baloxavir with L-lactic acid, a solid form thereof and a process for preparation thereof.
  • the solid form, Form III can be characterized by XRPD pattern having 20 values 6.1°, 12.3° and 16.3° degrees 2 theta ( ⁇ 0.2 degrees 2 theta).
  • the solid Form III can be also characterized by XRPD pattern having 20 values 6.1°, 12.3°, 16.3°, 19.5° and 22.3° degrees 2 theta ( ⁇ 0.2 degrees 2 theta).
  • the solid form can be further characterized by XRPD pattern described in the following table:
  • the solid Form III can be further characterized by XRPD pattern depicted in Figure 9 or DSC pattern depicted in Figure 10 or NMR pattern depicted in Figure 11.
  • the Form III can be prepared by a process comprising: a. Contacting Baloxavir and L-lactic acid with heptane; b. Isolating the Form III.
  • the molar ration between Baloxavir and L-Lactic acid can be between 1 :4.8 and 1 :5.3.
  • the concentration of Baloxavir in heptane can be between 0.05 g/ml and 0.15 g/ml.
  • To the mixture of Baloxavir and L-lactic acid heptane is added. The resulting mixture is stirred at a temperature between 20°C and 30°C for between 10 and 20 hours.
  • the solid form can be isolated by any suitable technique, for example using filtration or centrifuge. Obtained solid is dried for example at a temperature between 40°C and 60°C for between 2 and 10 hours.
  • the solid forms of Baloxavir or the Baloxavir salts or the Baloxavir cocrystals of presented invention can be used in a pharmaceutical composition for the treatment of conditions treatable by Baloxavir.
  • DSC patterns depicted in Figures 2, 5, 10, 16, 18, 20, 22, 24, 26, 28 and 30 were obtained using following measurement conditions: 10°C/min -> 300°C.
  • DSC pattern depicted in Figure 13 was obtained using following measurement conditions: 10°C/min -> 250°C.
  • TGA pattern was obtained using following measurement conditions: 10°C/min -> 250°C.
  • Diffraction measurements of the starting material and the samples from the screening were performed at ambient conditions on a PANalytical X'Pert PRO 0-0 diffractometer of 240 mm of radius in reflection geometry, equipped with Cu Ka radiation and a PIXcel detector, operated at 45 kV and 40 mA. Each sample was mounted on a zero-background silicon holder and allowed to spin at 0.25 rev/s during the data collection. The measurement angular range was 3.0-40.0° (20) with a step size of 0.013°. The scanning speed was 0.328°/s (10.20 s/step) for the samples from the screening and 0.082 (40.80 s/step) for the references.
  • XRPD patterns depicted in Figures 12, 15, 17, 19, 21, 23, 25, 27 and 29 were obtained using following measurement conditions: Panalytical Empyrean diffractometer with 0/20 geometry (transmition mode), equipped with a PixCell 3D detector;
  • Example 2 Baloxavir cocrystal with oxalic acid, Forms II and lib
  • XRPD pattern of obtained solid corresponds to XRPD pattern depicted in Figure 4
  • DSC pattern of obtained solid corresponds to DSC pattern depicted in Figure 5
  • NMR pattern of obtained solid corresponds to NMR pattern depicted in Figure 6.
  • TGA pattern Form II is a solvated form.
  • Solid Form II was dried at 50°C under vacuum for 4 days and Baloxavir cocrystal with oxalic acid, Form lib, was obtained.
  • XRPD pattern of obtained solid corresponds to XRPD pattern depicted in Figure 7
  • NMR pattern of obtained solid corresponds to NMR pattern depicted in Figure 8.
  • XRPD pattern of obtained solid corresponds to XRPD pattern depicted in Figure 12
  • DSC pattern of obtained solid corresponds to DSC pattern depicted in Figure 13
  • TGA pattern of obtained solid corresponds to TGA pattern depicted in Figure 14.
  • XRPD pattern of obtained solid corresponds to XRPD pattern depicted in Figure 9
  • DSC pattern of obtained solid corresponds to DSC pattern depicted in Figure 10
  • NMR pattern of obtained solid corresponds to NMR pattern depicted in Figure 11.
  • Baloxavir purity 90%, HPLC
  • 100 mg of Baloxavir purity 90%, HPLC
  • the mixture was heated to 50 °C and to the suspension 12.76 mg of potassium hydroxide was added.
  • the mixture was stirred at reflux for 20 minutes. The heating was turned off and cooled to 25°C.
  • To the mixture 10 ml of diisopropylether was added.
  • the suspension was placed into a refrigerator for 5 hours. The solid was filtrated off and washed by small amount (0.4 ml) of chilled (0°C) mixture of diisopropylether/methanol mixture (10:1).
  • the purity of obtained Baloxavir potassium salt was 99.8% (HPLC).
  • Obtained potassium salt is further transformed to Baloxavir by contacting with an acid.
  • Obtained meglumine salt is further transformed to Baloxavir by contacting with an acid.
  • Example 10 Solid Form of Baloxavir, Form 9, dioxane solvate
  • Baloxavir Form 9 prepared according to Example 10 was mixed with 10 ml of water and the suspension was stirred for 24 hours at 25 °C. Obtained solid was filtered off and dried freely in air for 24 hours. Baloxavir, Form 2, was obtained in 100% yield.
  • Baloxavir, Form 2 can be also prepared by wet milling of Baloxavir Form 9, prepared according to Example 10, in MeOH or distilled water at concentration 100 mg/mL, for 15 minutes, at 25 Hz (three balls) in quantitative yield.
  • XRPD pattern of obtained solid corresponds to XRPD pattern depicted in Figure 21 and DSC pattern of obtained solid corresponds to DSC pattern depicted in Figure 22.
  • DSC pattern of obtained solid corresponds to DSC pattern depicted in Figure 24.
  • Example 13 Solid form of Baloxavir, Form 6, acetonitrile solvate
  • XRPD pattern of obtained solid corresponds to XRPD pattern depicted in Figure 27 and DSC pattern of obtained solid corresponds to DSC pattern depicted in Figure 28.
  • Form 6 is a solvate.
  • Example 14 Solid form of Baloxavir, Form 6, acetonitrile solvate
  • XRPD pattern of obtained solid corresponds to XRPD pattern depicted in Figure 27 and DSC pattern of obtained solid corresponds to DSC pattern depicted in Figure 28.
  • Baloxavir, Form 6 was vacuum dried (nitrogen bleed) at 60 °C for 24 hours to provide Baloxavir Form 8 in quantitative yield.
  • XRPD patern of obtained solid corresponds to XRPD patern depicted in Figure 25 and DSC patern of obtained solid corresponds to DSC patern depicted in Figure 26.

Landscapes

  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Virology (AREA)
  • Oncology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Communicable Diseases (AREA)
  • Pulmonology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne le baloxavir, des sels de baloxavir, des co-cristaux de baloxavir, des formes solides associées et des procédés de préparation associés.
EP21835303.5A 2020-12-15 2021-12-13 Formes solides de baloxavir, sels de baloxavir et co-cristaux de baloxavir Withdrawn EP4262983A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
EP20214207 2020-12-15
EP20214209 2020-12-15
EP20214212 2020-12-15
PCT/EP2021/085526 WO2022128934A1 (fr) 2020-12-15 2021-12-13 Formes solides de baloxavir, sels de baloxavir et co-cristaux de baloxavir

Publications (1)

Publication Number Publication Date
EP4262983A1 true EP4262983A1 (fr) 2023-10-25

Family

ID=79170662

Family Applications (1)

Application Number Title Priority Date Filing Date
EP21835303.5A Withdrawn EP4262983A1 (fr) 2020-12-15 2021-12-13 Formes solides de baloxavir, sels de baloxavir et co-cristaux de baloxavir

Country Status (2)

Country Link
EP (1) EP4262983A1 (fr)
WO (1) WO2022128934A1 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116969970A (zh) * 2023-06-21 2023-10-31 山东大学 巴洛沙韦酯晶型b1及其制备方法

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016175224A1 (fr) 2015-04-28 2016-11-03 塩野義製薬株式会社 Dérivé de pyridone polycyclique substitué et promédicaments de celui-ci
IL263812B2 (en) 2016-06-20 2023-09-01 Shionogi & Co A process for the preparation of a polycyclic derivative of a modified pyridone and a hymane crystal
CN108440564B (zh) * 2018-04-11 2019-08-06 安帝康（无锡）生物科技有限公司 被取代的多环氨基甲酰基吡啶酮衍生物及其前药
CN109504721B (zh) * 2018-12-26 2021-07-09 杭州科巢生物科技有限公司 一种抗流感药物的合成方法
US12234246B2 (en) * 2019-03-05 2025-02-25 Assia Chemical Industries Ltd. Solid state forms of baloxavir marboxil

Also Published As

Publication number Publication date
WO2022128934A1 (fr) 2022-06-23

Similar Documents

Publication Publication Date Title
RU2557237C2 (ru) Соль конденсированного гетероциклического производного и его кристаллы
EP3506896A1 (fr) Formes solides de mésylate de cenicriviroc et procédés de fabrication de formes solides de mésylate de cenicriviroc
WO2017202351A1 (fr) Nouvelle forme cristalline d'un médicament inhibiteur des cotransporteurs de sodium-glucose, son procédé de préparation et son utilisation
AU2021277593A1 (en) Solid forms of [(1 S)-1 -[(2S,4R,5R)-5-(5-amino-2-oxo-thiazolo[4,5-d]pyrimidin-3-yl)-4-hydroxy-te trahydrofuran-2-yl]propyl] acetate
CN116139080B (zh) 卡利拉嗪药物组合物、制备方法及应用
EP2524921A1 (fr) Nouveaux sels cristallins d'asénapine
EP4262983A1 (fr) Formes solides de baloxavir, sels de baloxavir et co-cristaux de baloxavir
EP2524919A1 (fr) Nouveaux sels cristallins d'asénapine avec des di-acides et des tri-acides cristallins
CA3108007C (fr) Forme d1 de sel de monoethanolamine eltrombopag cristalline hautement stable
EP4177257B1 (fr) Succinate de composé octahydrothiénoquinoline et cristaux de celui-ci
US12012420B2 (en) Solid forms of [(1S)-1-[(2S,4R,5R)-5-(5-amino-2-oxo-thiazolo[4,5-d]pyrimidin-3-yl)-4-hydroxy-tetrahydrofuran-2-yl]propyl] acetate
US12012421B2 (en) Solid forms of [(1S)-1-[(2S,4R,5R)-5-(5-amino-2-oxo-thiazolo[4,5-d]pyrimidin-3-yl)-4-hydroxy-tetrahydrofuran-2-yl]propyl] acetate
CA3108134C (fr) Forme d de sel de monoethanolamine d'eltrombopag cristalline
TW202248189A (zh) 芬戈莫德藥用鹽、製備方法、含其的藥物組合物及應用
EP2507250A1 (fr) Formes solides du sel de calcium du fosamprénavir et leur procédé de synthèse
CN107868058B (zh) 一种喹唑啉衍生物的盐、其制备方法及应用

Legal Events

Date Code Title Description
STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: UNKNOWN

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE INTERNATIONAL PUBLICATION HAS BEEN MADE

PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: REQUEST FOR EXAMINATION WAS MADE

17P Request for examination filed

Effective date: 20230717

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

DAV Request for validation of the european patent (deleted)
DAX Request for extension of the european patent (deleted)
STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20240206