EP4262983A1 - Solid forms of baloxavir, salts of baloxavir and cocrystals of baloxavir - Google Patents

Solid forms of baloxavir, salts of baloxavir and cocrystals of baloxavir

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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.)
Pending
Application number
EP21835303.5A
Other languages
German (de)
French (fr)
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
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Filing date
Publication date
Application filed by Synthon BV filed Critical Synthon BV
Publication of EP4262983A1 publication Critical patent/EP4262983A1/en
Pending legal-status Critical Current

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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.

Abstract

The presented invention relates to Baloxavir, salts of Baloxavir, cocrystals of Baloxavir, to solid forms of thereof and to processes for preparation thereof.

Description

SOLID FORMS OF BALOXAVIR, SALTS OF BALOXAVIR AND
COCRYSTALS OF BALOXAVIR
The invention relates to solid forms of Baloxavir, salts thereof and cocrystals thereof and solid forms of Baloxavir, salts thereof and cocrystals thereof.
BACKGROUND OF THE PRESENT INVENTION
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.
Baloxavir,
(12aR)-12-[(l lS)-7,8-Difluoro-6,ll-dihydrodibenzo[b,e]thiepin-ll-yl]-7-hydroxy- 3,4,12,12a-tetrahydro-lH-[l,4]oxazino[3,4-c]pyrido[2,l-f|[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. For orally administered drugs 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.
BRIEF DESCRIPTION OF THE INVENTION
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.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 depicts the X-Ray Powder Diffractogram (XRPD) of cocrystal of Baloxavir with propyl gallate, Form I, prepared according to Example 1.
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.
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.
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.
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.
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.
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.
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
13. 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.
DETAILED DESCRIPTION OF THE INVENTION
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. The 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
20 values 3.8°, 4.3°, 5.3°, 9.9° and 12.4° 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 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. To the mixture an antisolvent (i.e. solvent in which solubility of potassium salt of Baloxavir is low) such as an ether (for example diisopropyl ether or diethyl ether) is added. 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. The 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
DSC pattern depicted in Figure 2 or NMR pattern depicted in Figure 3.
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. The concentration of Baloxavir in the ethyl acetate can be between 0.05 g/ml and 0.15 g/ml.
To the mixture of Baloxavir and oxalic acid ethyl 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. When the solid Form II of cocrystal of Baloxavir with oxalic acid is exposed to a temperature between 45°C and 55°C for between 3 to 10 days in vacuum (100 mbar), 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.
The invention will be further described with reference to the following examples.
EXAMPLES
NMR pattern were obtained using following measurement conditions:
1H Nuclear magnetic resonance analyses were recorded in CDC13 in a Varian Mercury 400 MHz spectrometer, equipped with a broadband probe ATB 1H/19F/X of 5 mm. Spectra were acquired dissolving 5-10 mg of sample in 0.7 mL of deuterated solvent.
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.
XRPD patterns depicted in Figures 1, 4, 7 and 9 were obtained using following measurement conditions:
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;
Starting Baloxavir was prepared by a process disclosed in WO2016175224 application. Example 1: Baloxavir cocrystals with propyl gallate, Form I
50 mg of Baloxavir was mixed with 66 mg of propyl gallate and 0.25 ml of acetone.
The resulting suspension was stirred at room temperature for 15 hours. Then, the suspension was filtered, dried under vacuum at 25°C overnight. 34 mg (54% yield) of Baloxavir cocrystal with propyl gallate, Form I, was obtained. XRPD pattern of obtained solid corresponds to XRPD pattern depicted in Figure 1, DSC pattern of obtained solid corresponds to DSC pattern depicted in Figure 2, NMR pattern of obtained solid corresponds to NMR pattern depicted in Figure 3.
Example 2: Baloxavir cocrystal with oxalic acid, Forms II and lib
50 mg of Baloxavir and 19 mg of oxalic acid were mixed with 0.5 ml of ethyl acetate. The resulting suspension was stirred at room temperature for 15 hours. Then, the suspension was filtered, washed with ethyl acetate (3 x 0.1 ml), dried under vacuum at 25°C overnight. 32.2 mg (89% yield) of Form II was obtained.
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. According to 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.
Example 3: Baloxavir cocrystal with oxalic acid, Form M
100 mg of Baloxavir were mixed with 38 mg of oxalic acid and 1 ml of methyl acetate. The resulting suspension was stirred at 25°C for 15 hours. Then, the suspension was filtered, washed with 3 x 0.1 ml acetate, dried at 25°C, atmospheric pressure overnight.
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. According to
TGA pattern, Form M is a solvated form. Example 4: Baloxavir cocrystal with L-lactate, Form III
200 mg of Baloxavir were mixed with 187 mg of L-Lactic acid and 2 ml of heptane. The resulting mixture was stirred at 25°C for 15 hours. Then, the solid was isolated by filtration and washed with 3x0.8 ml of heptane. Solid was dried under vacuum at 25°C overnight and at 50 °C for 3 hours. 31 mg (89% yield) of Baloxavir cocrystal with L-lactate was obtained.
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.
Example 5: Baloxavir, sodium salt, Form 1
1 g of Baloxavir was mixed with 20 ml of methanol. The mixture was heated to 50 °C and 83 mg of sodium hydroxide in a solid form was added. The mixture was stirred at 50°C for about 30 minutes. Then the heating was turned off and the solution was left freely cool down to 25°C. The suspension was stirred for 12 hours and then the solid was filtered off and let freely dry for 72 hours at 25 °C and 40-45%RH to provide 0.960 g of Baloxavir, sodium salt, Form 1. XRPD pattern of obtained solid corresponds to XRPD pattern depicted in Figure 15. DSC pattern of obtained solid corresponds to DSC pattern depicted in Figure 16.
Example 6: Baloxavir, potassium salt, Form 2
1 g of Baloxavir was mixed with 20 ml of methanol. The mixture was heated to 50 °C and 128 mg of solid potassium hydroxide was added. The mixture was stirred at 50°C for 15 minutes. Then the heating was turned off and the mixture was cooled to room temperature. To the mixture 100 ml of diisopropylether was added. The mixture was cooled down to 6 °C and left at this temperature for 24 hours. The solid was then isolated by vacuum filtration and dried at 40 °C for 24 hours in vacuum to provide 1.070 g of Baloxavir, potassium salt, Form 2. XRPD patern of obtained solid corresponds to XRPD patern depicted in Figure 17. DSC patern of obtained solid corresponds to DSC patern depicted in Figure 18.
Example 7: Baloxavir, meglumine salt, Form 1
200 mg of Baloxavir was mixed with 16 ml of methanol. The mixture was heated to 50 °C and to the mixture 162 mg of solid meglumine was added. The mixture was stirred and heated to 60 °C till dissolution of solids. Then the mixture was freely cooled down to 25 °C and the mixture was placed into refridgerator at 6 °C for 2 hours. Obtained solid was filtered off and dried for 50 hours at 25 °C 30-40%RH to provide Baloxavir, meglumine salt, Form 1 in 65% yield. XRPD patern of obtained solid corresponds to XRPD patern depicted in Figure 19. DSC patern of obtained solid corresponds to DSC patern depicted in Figure 20.
Example 8: Purification of Baloxavir via Baloxavir potassium salt, Form 2
100 mg of Baloxavir (purity 90%, HPLC) was mixed with 2 ml of methanol. 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.
Example 9: Purification of Baloxavir via Baloxavir meglumine salt, Form 1
100 mg of Baloxavir (the amount of impurities was 10%, HPLC) was mixed with 8 ml of methanol (MeOH). The mixture was heated to 50 °C and to the suspension 40.4 mg of solid meglumine was added. The mixture was stirred and heated to 60 °C till dissolution of solids. Then the mixture was freely cooled down to 25 °C and placed into refrigerator at 6 °C for 2 hours. The solid was filtered off and washed by small amount (0.4 ml) of chilled (0°C) diisopropylether (DIPE)ZMeOH mixture 10:1. The amount of impurities was 2.5% (HPLC).
Obtained meglumine salt is further transformed to Baloxavir by contacting with an acid.
Example 10: Solid Form of Baloxavir, Form 9, dioxane solvate
3 g of Baloxavir was dissolved in 100 ml of acetonitrile at 25°C. 300 ml of water was added rapidly (during 1 minute). The suspension was left without stirring for 1 hour at 25°C. The solid was filtered off and dried freely in air for 5 hours. 1 g of obtained solid was mixed with 6.6 ml of dioxane. The suspension was stirred at 25 °C for 90 min. The solid was then filtered off and dried in vacuum (nitrogen bleed) at 25 °C for 6 hours to provide 1.070 g Baloxavir Form 9 (yield: 90%). XRPD pattern of obtained solid corresponds to XRPD pattern depicted in Figure 29 and DSC pattern of obtained solid corresponds to DSC pattern depicted in Figure 30. According to TGA analysis, Form 9 is a solvate.
Example 11: Solid form of Baloxavir, Form 2
1 g of 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.
Example 12: Solid form of Baloxavir, Form 5
1 g of Baloxavir was dissolved in 130 ml of methanol at 45 °C. Then, the solution was rapidly poured into 2000 ml of cooled (10°C) water. The suspension was stirred for another 4 hours and 25 °C. Obtained solid was filtered off and dried for 24 hours at 60 °C under vacuum (nitrogen bleed) to obtain 846 mg of Baloxavir Form 5 (yield: 84.6%). XRPD pattern of obtained solid corresponds to XRPD pattern depicted in Figure 23 and
DSC pattern of obtained solid corresponds to DSC pattern depicted in Figure 24.
Example 13: Solid form of Baloxavir, Form 6, acetonitrile solvate
1 g of solid Form 9 of Baloxavir prepared according to Example 10 was mixed with 10 ml of acetonitrile. The suspension was stirred at 25 °C for 90 min. Obtained solid was then filtered off and dried in vacuum (nitrogen bleed) at 25 °C for 6 hours to provide 0.87 g (87% yield) of Baloxavir Form 6.
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. According to TGA analysis, Form 6 is a solvate.
Example 14: Solid form of Baloxavir, Form 6, acetonitrile solvate
100 mg of Baloxavir was dissolved in 10 mL of acetonitrile upon heating to 50 °C. Obtained solution was vacuum evaporated at 50 °C and 150 mbar to obtain solid Form 6 of Baloxavir in quantitative yield.
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.
Example 15: Solid form of Baloxavir, Form 8
500 mg of Baloxavir was dissolved in acetonitrile to give 10 mg/mL solution. The solution was slowly evaporated over the course of 5 days resulting in the formation of single crystals, which were dried freely in air for one week. Solid Form 8 was obtained in quantitative yield.
XRPD pattern of obtained solid corresponds to XRPD pattern depicted in Figure 25 and DSC pattern of obtained solid corresponds to DSC pattern depicted in Figure 26. Example 16: Solid form of Baloxavir, Form 8
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.

Claims

1. Sodium salt of Baloxavir.
2. A solid form of the compound according to claim 1, Form 1, characterized by XRPD pattern having 20 values 3.8°, 4.3° and 10.1° degrees 2 theta (± 0.2 degrees 2 theta).
3. Potassium salt of Baloxavir.
4. A solid form of compound according to claim 3 be characterized by XRPD pattern having 20 values 3.8°, 4.3° and 9.9° degrees 2 theta (± 0.2 degrees 2 theta).
5. Meglumine salt of Baloxavir.
6. A solid form of the compound according to claim 5, Form 1, characterized by XRPD pattern having 20 values 10.5°, 11.4° and 13.5° degrees 2 theta (± 0.2 degrees 2 theta).
7. Use of the compound according to claims 1 to 6 for purification of Baloxavir.
8. A solid form of Baloxavir, Form 2, characterized by XRPD pattern having 20 values 6.5°, 9.7° and 11.4° degrees 2 theta (± 0.2 degrees 2 theta).
9. A solid form of Baloxavir, Form 5, characterized by XRPD pattern having 20 values 8.8°, 12.5°and 15.2° degrees 2 theta (± 0.2 degrees 2 theta).
10. A solid form of Baloxavir, Form 8, characterized by XRPD pattern having 20 values 11.7°, 12.9° and 18.9° degrees 2 theta (± 0.2 degrees 2 theta).
11. Baloxavir cocrystal with propyl gallate.
12. A solid form of compound according to claim 11, Form I, characterized by XRPD pattern having 20 values 6.3°, 12.4° and 13.5° degrees 2 theta (± 0.2 degrees 2 theta).
13. Baloxavir cocrystal with oxalic acid.
14. A solid form of the compound according to claim 13, Form II, characterized by XRPD pattern having 20 values 6.7°, 18.3° and 21.5° degrees 2 theta (± 0.2 degrees 2 theta).
15. A solid form of the compound according to claim 13, Form M, characterized by XRPD pattern having 20 values 6.7°, 18.5° and 21.4° degrees 2 theta (± 0.2 degrees 2 theta). Baloxavir cocrystal with L-lactic acid. A solid form of compound according to claim 17, Form III, characterized by XRPD pattern having 20 values 6.1°, 12.3° and 16.3° degrees 2 theta (± 0.2 degrees 2 theta). A pharmaceutical composition comprising the compound according to anyone of claims 1 to 17.
EP21835303.5A 2020-12-15 2021-12-13 Solid forms of baloxavir, salts of baloxavir and cocrystals of baloxavir Pending EP4262983A1 (en)

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