Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
  • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
  • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents

Definitions

• the invention relates to solid forms of 4-[3-chloro-4-(cyclopropylcarbamoylamino)phenoxy]- 7-methoxy-quinoline-6-carboxamide (CAS No. 417716-92-8) of formula I, known as lenvatinib, methods of their preparation and use in a drug form.
• the drug with the name Lenvima which contains lenvatinib mesylate, has been approved by the Food and Drug Administration (FDA) for the treatment of locally recurrent or metastatic, progressive thyroid cancer, resistant to radioactive iodine.
• FDA Food and Drug Administration
• the patent application WO 2006/137474 describes preparation and characterization methods of amorphous forms of lenvatinib esylate and lenvatinib mesylate.
• the patent application WO 2014/098176 describes preparation and characterization methods of an amorphous form of lenvatinib free base.
• Pharmaceutical compositions containing lenvatinib or its salts are disclosed in the patent applications WO 2006/030826 and WO 2011/021597.
• Many pharmaceutical solid compounds can form salts or cocrystals with suitable counterions and thus exist in various crystalline forms that have different crystal units and thus different physicochemical properties as the melting point, solubility, dissolution rate as well as biological availability.
• several solid- state analytic methods can be used, e.g. X-ray powder diffraction, solid-state NMR, Raman spectroscopy as well as thermoanalytic methods.
• the object of the invention are pharmaceutically acceptable salts of lenvatinib and methods of their preparation.
• These solid forms of lenvatinib are prepared through a reaction of lenvatinib free base with suitable inorganic or organic acids in a suitable solvent or mixtures of solvents.
• the prepared solid forms have suitable physicochemical characteristics for use in the pharmaceutical industry and formulation of new drug forms.
• An object of this invention is the salt of lenvatinib with phosphoric acid, tartaric acid, citric acid, camphorsulfonic acid, isethionic acid and naphthalenedisulfonic acid.
• Another object of the invention is the salt of lenvatinib with phosphoric acid, exhibiting the characteristic reflections in the X-ray powder pattern with the use of CuKa radiation: 8.1; 11.3; 20.3; 21.5 and 25.8 ⁇ 0,2° 2-theta.
• the salt of lenvatinib with phosphoric acid is further characterized by the differential scanning calorimetry curve with the melting point at 178°C.
• Another object of the invention is a preparation method of the salt of lenvatinib with phosphoric acid wherein the free base of lenvatinib is dissolved in a suitable solvent and phosphoric acid is added subsequently.
• a suitable solvent is a solvent selected from the group consisting of aliphatic C1-C4 alcohols, ketones, esters, nitriles, water or their mixtures, preferably from acetone, ethyl acetate, acetonitrile, methanol, ethanol, water or their mixtures.
• Another object of the invention is the salt of lenvatinib with tartaric acid, exhibiting the characteristic reflections in the X-ray powder pattern with the use of CuKa radiation: 4.0; 11.1; 15.2; 20.2 and 22.4 ⁇ 0.2° 2-theta.
• the salt of lenvatinib with tartaric acid is further characterized by the differential scanning calorimetry curve with the melting point at 169°C.
• Another object of the invention is the salt of lenvatinib with citric acid, exhibiting the characteristic reflections in the X-ray powder pattern with the use of CuKa radiation: 8.0; 12.0; 13.9; 20.0 and 24.3 ⁇ 0.2° 2-theta.
• the salt of lenvatinib with citric acid is further characterized by the differential scanning calorimetry curve with the melting point at 148°C.
• Another object of the invention is the salt of lenvatinib with camphorsulfonic acid, exhibiting the characteristic reflections in the X-ray powder pattern with the use of CuKa radiation: 4.6; 12.8; 14.4; 16.4; 18.1; 18.5; 20.1 and 25.8 ⁇ 0.2° 2-theta.
• the salt of lenvatinib with camphorsulfonic acid is further characterized by the differential scanning calorimetry curve with the melting point at 211°C.
• Another object of the invention is the salt of lenvatinib with isethionic acid, exhibiting the characteristic reflections in the X-ray powder pattern with the use of CuKa radiation: 5.1; 9.4; 14.6; 17.3; 20.1 and 25.4 ⁇ 0.2° 2-theta.
• the salt of lenvatinib with isethionic acid is further characterized by the differential scanning calorimetry curve with the melting point at 144°C.
• Another object of the invention is the salt of lenvatinib with naphthalenedisulfonic acid, exhibiting the characteristic reflections in the X-ray powder pattern with the use of CuKa radiation: 5.8; 10.2; 13.5; 15.6; 19.9 and 23.3 ⁇ 0.2° 2-theta.
• the salt of lenvatinib with naphthalenedisulfonic acid is further characterized by the differential scanning calorimetry curve with the melting point at 155°C.
• Another object of the invention is a preparation method of a salt of lenvatinib with an acid in accordance with the present invention wherein the free base of lenvatinib is dissolved in a suitable solvent together with an acid that is selected from the group consisting of tartaric acid, citric acid, camphorsulfonic acid, isethionic acid and naphthalenedisulfonic acid.
• a suitable solvent is a solvent selected from the group consisting of aliphatic C1-C4 alcohols, ketones, esters, nitriles, water or their mixtures, preferably from acetone, ethyl acetate, acetonitrile, methanol, ethanol, water or their mixtures.
• Another object of the invention is the use of a solid form of a salt of lenvatinib with an acid in accordance with the present invention for the preparation of a pharmaceutical composition.
• Another object of the invention is a pharmaceutical composition comprising a solid form of a salt of lenvatinib with an acid in accordance with the present invention and at least one pharmaceutically acceptable excipient.
• Figure 1 X-ray powder pattern of lenvatinib phosphate
• This invention provides several crystalline salts of lenvatinib, the obtained crystalline forms exhibiting a lower melting point than the crystalline lenvatinib mesylate used in the drug Lenvima.
• the invention prefers crystalline forms of salts of lenvatinib with counterfoils of acids whose salts are physiologically common, or they represent intermediates of metabolites in biochemical processes. These compounds comprise phosphoric acid, citric acid and tartaric acid.
• An object of this invention are solid forms of lenvatinib with phosphoric acid, tartaric acid, naphthalenedisulfonic acid, citric acid, camphorsulfonic acid and isethionic acid in various molar ratios. Within the invention, 1 :1 molar ratios are preferred.
• Solid forms of lenvatinib with these acids can be prepared in adequate ratios and yields with high chemical purity in a crystalline or amorphous form.
• solid forms can be both anhydrous and/or non-solvated, and they can have the form of hydrates/solvates of the respective solvents.
• the prepared solid forms of lenvatinib may have various internal arrangements (polymorphism) with different physicochemical properties depending on the conditions of their preparation. For this reason, the invention relates to individual crystals or their mixtures in any ratio.
• the preparation of the solid forms of lenvatinib in accordance with the present invention is carried out through a reaction of levantinib base with phosphoric acid, tartaric acid, naphthalenedisulfonic acid, citric acid, camphorsulfonic acid and isethionic acid.
• the reaction is conducted in a suitable solvent, which can be ketones, esters, ethers, amides, nitriles or organic acids, alcohols, aliphatic and aromatic hydrocarbons, chlorinated hydrocarbons, water or their mixtures. Aliphatic C1-C4 alcohols, ketones, esters, nitriles or their mixtures are preferred.
• the most commonly used solvents are acetone, ethyl acetate, acetonitrile, methanol, ethanol, water or their mixtures.
• the final product is typically precipitated or crystallized at temperatures in the range of - 30 C to the boiling point of the solvent.
• Lenvatinib free base (form B) was prepared in accordance with the process disclosed in the patent application WO 2004/101526. Differential scanning calorimetry (DSC) was applied to measure the melting point of crystalline form B of lenvatinib free base of 204°C. Crystalline salt of lenvatinib with methanesulfonic acid (form C) was prepared according to the process disclosed in the patent application WO 2005/063713. Differential scanning calorimetry (DSC) was applied to measure the melting point of the crystalline salt of lenvatinib with methanesulfonic acid (form C) of 238°C.
• the crystalline form of lenvatinib phosphate (prepared according to Example 1) is Characterized by the reflections presented in Table 1.
• Table 1 includes reflections whose relative intensity value is higher than 1%.
• Characteristic diffraction peaks of the crystalline form of lenvatinib phosphate in accordance with the present invention with the use of CuKa radiation are: 8.1; 11.3; 20.3; 21.5 and 25.8 ⁇ 0,2° 2-theta.
• the X-ray powder pattern is shown in Fig. 1.
• DSC Differential scanning calorimetry
• the crystalline form of lenvatinib tartrate (prepared according to Example 2) is characterized by the reflections presented in Table 2.
• Table 2 includes reflections whose relative intensity value is higher than 1%.
• Characteristic diffraction peaks of the crystalline form of lenvatinib tartrate in accordance with the present invention with the use of CuK radiation are: 4.0; 11.1; 15.2; 20.2 and 22.4 ⁇ 0.2° 2-theta.
• the X-ray powder pattern is shown in Fig. 2.
• DSC Differential scanning calorimetry
• the crystalline form of lenvatinib tartrate (prepared according to Example 3) is characterized by the reflections presented in Table 3.
• Table 3 includes reflections whose relative intensity value is higher than 1%.
• Characteristic diffraction peaks of the crystalline form of lenvatinib citrate in accordance with the present invention with the use of CuKa radiation are: 8.0; 12.0; 13.9; 20.0 and 24.3 ⁇ 0.2° 2-theta.
• the X-ray powder pattern is shown in Fig. 3.
• DSC Differential scanning calorimetry
• the crystalline form of lenvatinib camphorsulfonate (prepared according to Example 4) is characterized by the reflections presented in Table 4.
• Table 4 includes reflections whose relative intensity value is higher than 1%.
• Characteristic diffraction peaks of the crystalline form of lenvatinib camphorsulfonate in accordance with the present invention with the use of CuKa radiation are: 4.6; 12.8; 14.4; 16.4; 18.1; 18.5; 20.1 and 25.8 ⁇ 0.2° 2-theta.
• the X-ray powder pattern is shown in Fig. 4.
• DSC Differential scanning calorimetry
• the crystalline form of lenvatinib isethionate (prepared according to Example 5) is characterized by the reflections presented in Table 5.
• Table 5 includes reflections whose relative intensity value is higher than 1%. Characteristic diffraction peaks of the crystalline form of lenvatinib isethionate in accordance with the present invention with the use of CuKa radiation are: 5.1; 9.4; 14.6; 17.3; 20.1 and 25.4 ⁇ 0.2° 2-theta.
• the X-ray powder pattern is shown in Fig. 5. Table 5
• DSC Differential scanning calorimetry
• the crystalline form of lenvatinib naphthalenedisulfonate (prepared according to Example 6) is characterized by the reflections presented in Table 6.
• Table 6 includes reflections whose relative intensity value is higher than 1%. Characteristic diffraction peaks of the crystalline form of lenvatinib naphthalenedisulfonate in accordance with the present invention with the use of CuKa radiation are: 5.8; 10.2; 13.5; 15.6; 19.9 and 23.3 ⁇ 0.2° 2-theta.
• the X-ray powder pattern is shown in Fig. 6. Table 6
• DSC Differential scanning calorimetry
• the solid forms of the salts of lenvatinib prepared in accordance with the present invention can be used for the preparation of pharmaceutical compositions, especially solid drug forms, e.g. tablets or capsules.
• Such pharmaceutical compositions can contain at least one excipient from the group of fillers (e.g. lactose), binders (e.g. microcrystalline cellulose), disintegrants (e.g. sodium salt of croscarmellose), lubricants (e.g. magnesium stearate), surfactants etc.
• a salt of lenvatinib can be mixed with the above mentioned excipients, screened through a sieve and the resulting mixture can be tabletted or filled into capsules.
• the tablets can be further coated with common coating compounds, e.g. polyvinyl alcohol or polyethylene glycol.
• the diffractograms were obtained using an X'PERT PRO MPD PANalytical powder diffractometer, used radiation CuKa ( ⁇ -01542 nm (1.542 A)), excitation voltage: 45 kV, anode current: 40 mA, measured range: 2 - 40° 2 ⁇ , increment: 0.01° 2 ⁇ at the dwell time at a reflection of 0.5 s, the measurement was carried out with a flat sample with the area/thickness of 10/0.5 mm.
• a 10mm mask and a 1/4° fixed anti-dispersion slit were used.
• the irradiated area of the sample is 10 mm, programmable divergence slits were used.
• Impurities were separated from the prepared salts of lenvatinib on an Ascentis Express CI 8 column, 2.7 um, 4.6 x 100 mm with the use of the mobile phase gradient:
• the amount of 10.0 mg of the tested substance is dissolved in 100% methanol. It is put in an ultrasonic bath for 5 min and after cooling to the laboratory temperature it is diluted with the same solvent to 10.0 ml.

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Citations (7)

• 2016
  • 2016-04-27 CZ CZ2016-240A patent/CZ2016240A3/cs unknown
• 2017
  • 2017-04-27 WO PCT/CZ2017/000030 patent/WO2017186197A1/en active Application Filing

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