Classifications

• • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
  • F02—COMBUSTION ENGINES; HOT-GAS OR COMBUSTION-PRODUCT ENGINE PLANTS
  • F02C—GAS-TURBINE PLANTS; AIR INTAKES FOR JET-PROPULSION PLANTS; CONTROLLING FUEL SUPPLY IN AIR-BREATHING JET-PROPULSION PLANTS
  • F02C3/00—Gas-turbine plants characterised by the use of combustion products as the working fluid
  • F02C3/20—Gas-turbine plants characterised by the use of combustion products as the working fluid using a special fuel, oxidant, or dilution fluid to generate the combustion products
  • F02C3/22—Gas-turbine plants characterised by the use of combustion products as the working fluid using a special fuel, oxidant, or dilution fluid to generate the combustion products the fuel or oxidant being gaseous at standard temperature and pressure
• • 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
  • A61P31/18—Antivirals for RNA viruses for HIV
• • 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
• • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
  • F02—COMBUSTION ENGINES; HOT-GAS OR COMBUSTION-PRODUCT ENGINE PLANTS
  • F02C—GAS-TURBINE PLANTS; AIR INTAKES FOR JET-PROPULSION PLANTS; CONTROLLING FUEL SUPPLY IN AIR-BREATHING JET-PROPULSION PLANTS
  • F02C3/00—Gas-turbine plants characterised by the use of combustion products as the working fluid
  • F02C3/04—Gas-turbine plants characterised by the use of combustion products as the working fluid having a turbine driving a compressor
  • F02C3/10—Gas-turbine plants characterised by the use of combustion products as the working fluid having a turbine driving a compressor with another turbine driving an output shaft but not driving the compressor
• • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
  • F02—COMBUSTION ENGINES; HOT-GAS OR COMBUSTION-PRODUCT ENGINE PLANTS
  • F02C—GAS-TURBINE PLANTS; AIR INTAKES FOR JET-PROPULSION PLANTS; CONTROLLING FUEL SUPPLY IN AIR-BREATHING JET-PROPULSION PLANTS
  • F02C6/00—Plural gas-turbine plants; Combinations of gas-turbine plants with other apparatus; Adaptations of gas- turbine plants for special use
  • F02C6/04—Gas-turbine plants providing heated or pressurised working fluid for other apparatus, e.g. without mechanical power output

Definitions

• the invention relates to new solid forms of salts of dolutegravir (I), (4-i J 12a5)-N-(2,4-difluorobenzyl)-7-hydroxy-4-methyl-6 5 8-dioxo-3,4,6 ! 8,12,12a-hexahydro- 2H-pyrido[r,2':4 5 5]pyrazino[2,l-i)][l,3]oxazine-9-carboxamide, a method of their preparation and their use in a dosage form.
• solid forms of dolutegravir with amines e.g.
• diethylamine, N,N r -dibenzylethylenediamine, meglumine, emanolamine, diethanolamine, tromethamine, ie ⁇ butylamine), potassium, magnesium and calcium are well usable. These salts can be conveniently used to increase purity of dolutegravir and its stabilization in terms of chemical as well as polymorphic purity.
• Dolutegravir is indicated, in combination with other retroviral medications, for the treatment of adult and adolescent patients over 12 years of age infected by the human immunodeficiency virus (HIV).
• Dolutegravir inhibits HIV integrase by binding to the active site of the integrase and by blocking the transfer processes of integration of retroviral deoxyribonucleic acid (DNA), which is important for the replication cycle of HIV.
• DNA retroviral deoxyribonucleic acid
• Dolutegravir very readily forms salts with amines, e.g. with diethylamine, N.iV'-dibenzylethylenediamine, meglumine, tromethamine, ethanolamine, diethanolamine, ieri-butylamine and amino acids.
• the amine binds to dolutegravir in the molar ratio of the amine to dolutegravir of 2:1 to 1:4, however ideally in the molar ratios of 1 :1 or 1:2.
• the potassium, magnesium and calcium salts of dolutegravir have been prepared, which can be further used for the development and production of a particular dosage form and a particular medicinal product.
• Dolutegravir forms salts with aliphatic and aromatic amines as well as potassium, magnesium and calcium salts.
• Useful salts with amines may include diethylamine, N,N-diben2ylethylenediamine, meglumine, tromethamine, ethanolamine, diethanolamine, ferf-butylamine and the whole group of amino acids.
• Advantages of the salts of dolutegravir with amines consist in their easy preparation and high proneness to crystallization. Dolutegravir very readily forms salts with amines and the resulting salts have, unlike the magnesium or calcium salt, a crystalline character.
• the solid-state nuclear magnetic resonance (ssNMR) spectrum of various salts of dolutegravir - with diethylamine (fig. 4), with N,N -dibenzylethylenediamine (fig. 7), with ethanolamine (fig. 10), with tromethamine (fig. 14) and with lysine (fig. 17) differs from the ssNMR spectra of dolutegravir (fig. 1).
• the following melting points were measured with the use of the differential scanning calorimetry (DSC), dolutegravir 189.5°C (fig. 3), dolutegravir salt with diethylamine 186.3°C (fig.
• the salt of dolutegravir with ethanolamine can also exist in a hydrated form; XRPD in fig. 13. This form was confirmed by the thermogravimetric analysis (TGA), according to which it contains 17% of water and 14% of ethanolamine.
• TGA thermogravimetric analysis
• the anhydrous form of dolutegravir with emanolarriine contains 1% of water and 16% of emanolamine.
• the salt of dolutegravir with diethylamine contains 1% of water and 14% of diethylamine.
• the salt of dolutegravir with N,N-dibenzylethylenediamine contains 2% of water.
• the salt of dolutegravir with tromethamine contains 1% of water and the salt with lysine contains 4% of water.
• Preparation of a salt of dolutegravir with an amine according to variant A comprises the following steps:
• Preparation of a salt of dolutegravir with an amine according to variant B comprises the following steps:
• the dissolution or dispersion according to the preparation variants A and B may be carried out in an organic solvent selected from CI to C8 hydrocarbons (aliphatic or aromatic), CI to C4 alcohols, CI to C8 esters, CI to C8 ketones, CI to C6 ethers (acyclic or cyclic), CI to C4 nitriles, water or their mixtures in the range from 20°C to the boiling point of the solvent or solvents. It is preferably carried out in methanol, ethanol, 1-propanol, 2-propanol, acetone, tetrahydrofuran or their mixtures.
• an organic solvent selected from CI to C8 hydrocarbons (aliphatic or aromatic), CI to C4 alcohols, CI to C8 esters, CI to C8 ketones, CI to C6 ethers (acyclic or cyclic), CI to C4 nitriles, water or their mixtures in the range from 20°C to the boiling point of the solvent or solvent
• step hi of the preparation variant B the amine can be added in a solid form or in the form of a solution; the salt with dolutegravir is formed equally readily in both the cases. Subsequently, the mixture is usually cooled down, preferably to the range of 20°C to 30°C and left to crystallize.
• the salt can be isolated either directly by filtration, or concentration of the mixture, or evaporation of the solvents may follow. Preparation of a salt of dolutegravir with an amine according to variant C is directly carried out during the formulation process, preferably directly during the wet granulation.
• the respective equivalent part of the amine - diethyiamine, N.N'-dibenzylethylenediamine, meglumine, tromethamine, ethanolamine, diethanolamine, tefi-butylamine or lysine are charged into a homogenizer.
• the salt is formed during wet granulation.
• Dolutegravir forms salts with amines in the molar ratios of the amine to dolutegravir in the range of 2: 1 to 1 :4, but ideally 1 : 1 to 1 :2.
• a salt of dolutegravir and an amine is generally produced in an 80% yield, preferably 90% yield, while the chemical purity, measured by HPLC, is not lower than that of the input dolutegravir. On the contrary, what often happens is that the chemical purity of the salt is considerably higher than the purity of the input dolutegravir.
• a salt of dolutegravir with an amine can be advantageously used for purification of crude dolutegravir.
• the salt of dolutegravir with diethyiamine exhibits a crystalline character.
• the X-ray powder pattern of this salt is shown in Fig. 5.
• the characteristic peaks are: 5.5; 11.2; 14.3; 16.8; 19.1 and 24.4 ⁇ 0.2 °2-theta.
• Diffraction peaks with a higher relative intensity than 15% are shown in Table 3.
• the salt of dolutegravir with N,N'-dibenzylethylenediamine exhibits a crystalline character.
• the X-ray powder pattern of this salt is shown in Fig. 8.
• the characteristic peaks are: 7.2; 11.2; 16.6; 18.0; 21.8 and 23.6 ⁇ 0.2 °2-theta.
• Diffraction peaks with a higher relative intensity than 15% are shown in Table 4.
• the salt of dolutegravir with ethanolamine exhibits a crystalline character and can exist in an anhydrous or hydrated form.
• the X-ray powder pattern of the anhydrous form of this salt is shown in fig. 11 and that of the hydrated form in fig. 13.
• the characteristic peaks of the anhydrous form of the salt of dolutegravir with ethanolamine are 7.2; 12.5; 18.3; 19.6 and 23.4 ⁇ 0.2 °2-theta; its diffraction peaks with a relative intensity higher than 15% are presented in Table 5.
• the salt of dolutegravir with tromethamine exhibits a crystalline character.
• the X-ray powder pattern of this salt is shown in Fig. 15.
• the characteristic peaks are: 7.9; 15.6; 20.7; 22.4; 2.8; 26.0 and 26.8 ⁇ 0.2 °2-theta.
• Diffraction peaks with a higher relative intensity than 15% are shown in Table 7.
• the salt of dolutegravir with lysine exhibits a crystalline character.
• the X-ray powder pattern of this salt is shown in Fig. 18.
• the characteristic peaks are 7.3; 9.6; 13.8; 17.2; 2.8; 23.0 and 25.4° 2theta.
• Diffraction peaks with a higher relative intensity than 15% are shown in Table 8.
• Table 8 Diffraction peaks of the salt of dol tegravir with lysine
• Dolutegravir also forms salts with alkali metals and alkaline earth metals, in particular the potassium, magnesium and calcium salt, wherein the potassium salt exhibits a crystalline character and the magnesium and calcium salts exhibit an amorphous character.
• Differential scanning calorimetry (DSC) was applied to obtain the melting point of the potassium salt of dolutegravir of 318.6°C.
• the potassium salt of dolutegravir exhibits a crystalline character.
• the X-ray powder pattern of this salt is shown in Fig. 20.
• the characteristic peaks are: 5.2; 9.0; 16.1; 21.5 and 28.3 ⁇ 0.2° 2-theta.
• Diffraction peaks with a higher relative intensity than 15% are shown in Table
• the magnesium and calcium salt of dolutegravir exhibit an amorphous character.
• the X-ray powder pattern of the magnesium salt is shown in Fig. 21.
• the potassium, magnesium and calcium salt can be prepared by mixing of dolutegravir with a reagent containing potassium (K + ), magnesium (Mg 2+ ) or calcium (Ca 2+ ) cations. This preparation may be done separately, e.g. during crystallization, or later in the formulation process, e.g. during wet granulation.
• dolutegravir together with a reagent containing potassium (K + ), magnesium (Mg 2+ ) or calcium (Ca 2+ ) cations are charged into a homogenizer besides the excipients.
• a dissolution and/or dispersion of dolutegravir in a solvent or a mixture of solvents b/ addition of a reagent containing potassium (K + ), magnesium (Mg 2+ ) or calcium (Ca 2+ ) cations, in a solid form or in the form of a solution;
• the dissolution or dispersion may be carried out in an organic solvent selected from CI to C8 hydrocarbons (aliphatic or aromatic), CI to C4 alcohols, CI to C8 esters, CI to C8 ketones, CI to C6 ethers (acyclic or cyclic), CI to C4 nitrites, water or their mixtures in the range from 20°C to the boiling point of the solvent or solvents. It is preferably carried out in methanol, ethanol, l-propanol, 2-propanol, acetone, water, or their mixtures.
• the reagent can be added in the solid form or in the form of a solution; the salt with dolutegravir is formed equally readily in both the cases.
• the mixture is usually cooled down, preferably to the range of -20°C to 30°C, and left to crystallize.
• the salt can be isolated either directly by filtration, or concentration of the mixture, or evaporation of the solvents may follow.
• Fig. 1 ssNMR record of dolutegravir
• Fig. 2 XRPD pattern of dolutegravir
• Fig. 4 ssNMR record of the salt of dolutegravir salt with diethylamine
• Fig. 5 XRPD pattern of the salt of dolutegravir with diethylamine
• Fig. 7 ssNMR record of the salt of dolutegravir with N.N'-dibenzylethylenediamine
• Fig. 8 XRPD pattern of the salt of dolutegravir withN,N'-dibenzylethylenediamine
• Fig. 9 DSC record of the salt of dolutegravir with N,N-dibenzylethylenediamine
• Fig. 10 ssNMR record of the anhydrous salt of dolutegravir with ethanolamine
• Fig. 11 XRPD pattern of the anhydrous salt of dolutegravir with ethanolamine
• Fig. 12 DSC record of the anhydrous salt of dolutegravir with ethanolamine
• Fig. 13 XRPD pattern of the hydrated salt of dolutegravir with ethanolamine
• Fig. 14 ssNMR record of the salt of dolutegravir with tromethamine
• Fig. 15 XRPD pattern of the salt of dolutegravir with tromethamine
• Fig. 16 DSC record of the salt of dolutegravir with tromethamine
• Fig. 17 ssNMR record of the salt of dolutegravir with lysine
• Fig. 18 XRPD pattern of the salt of dolutegravir with lysine
• Fig. 19 DSC record of the salt of dolutegravir with lysine
• Fig. 20 XRPD pattern of the potassium salt of dolutegravir
• Fig. 21 XRPD pattern of the magnesium salt of dolutegravir
• Dolutegravir was prepared according to the procedure published in the patent application WO2006116764. The chemical purity of dolutegravir prepared this way was 98.2% (HPLC). The solid-state NMR spectrum (Fig. 1), XRPD pattern (Fig. 2) and DSC record (Fig.3) confirm the structure of dolutegravir.
• Dolutegravir 200 mg, 0.48 mmol is dissolved together with diethylamine (70 mg, 0.95 mmol) in methanol at an elevated temperature. The clear solution is left to slowly cool down to the room temperature and subsequently it is left to evaporate at the room temperature. 190 mg (81% yield) of the crystalline salt of dolutegravir with diethylamine in the molar ratio of 1 :1 (1H NMR) was obtained.
• Dolutegravir (2 g, 4.77 mmol) is dissolved together with N,N-dibenzylethylenediamine (1.2 g, 5.01 mmol) in a mixture of 10 ml of tetrahydrofuran and 25 ml of methanol at an elevated temperature. The clear solution is left to slowly cool down to the room temperature and subsequently it is left to crystallize in a refrigerator overnight. The produced crystals are aspirated and dried. 2.8 g (91% yield) of the crystalline salt of dolutegravir with ⁇ N-dibenzylethylenediamine in the molar ratio of 2:1 (1H NMR) was obtained.
• Dolutegravir (2 g, 4.77 mmol) is dissolved together with ethanolamine (310 mg, 5.01 mmol) in a mixture of tetrahydrofuran and methanol at an elevated temperature. The clear solution is left to slowly cool down to the room temperature and subsequently it is left to crystallize in a refrigerator overnight. The produced crystals are aspirated and dried freely at the room temperature. 2.20 g (94% yield) of a hydrated form of the crystalline salt of dolutegravir with ethanolamine in the molar ratio of 1 :1 ( ⁇ NMR) was obtained. If the crystals are dried in a vacuum drier at 40°C, an anhydrous form of the crystalline salt of dolutegravir with ethanolamine is obtained in the molar ratio of 1 : 1 ( H NMR).
• Dolutegravir (2 g, 4.77 mmol) is dissolved together with tromethamine (610 mg, 5.01 mmol) in methanol at an elevated temperature. The clear solution is left to slowly cool down to the room temperature and subsequently it is left to crystallize in a refrigerator overnight. The produced crystals are aspirated and dried. 2.4 g (92% yield) of the crystalline salt of dolutegravir with tromethamine in the molar ratio of 1:1 ( L H NMR) was obtained.
• Dolutegravir (200 mg, 0.48 mmol) is dissolved together with rerr-butylamine (70 mg, 0.95 mmol) in a mixture of methanol and tetrahydrofuran at an elevated temperature. The clear solution is left to slowly cool down to the room temperature and subsequently the product is left to crystallize in a refrigerator. 205 mg (87% yield) of the crystalline salt of dolutegravir with teri-butylamine in the molar ratio of 1 : 1 ('Hi NMR) was obtained.
• Dolutegravir 400 mg, 0.95 mmol is dissolved together with lysine (280 mg, 1.91 mmol) in a mixture of methanol and water (1 :1) at an elevated temperature. The clear solution is left to slowly cool down to the room temperature and subsequently it is left to crystallize in a refrigerator. The produced crystals are aspirated and dried. 470 mg (88% yield) of the crystalline salt of dolutegravir with lysine in the molar ratio of 1 :1 ( L H NMR) was obtained. Exam le 7
• Dolutegravir (5,0 g, 11.92 mmol) is dissolved together with potassium hydroxide (23,8 mmol) in a mixture of methanol and water at an elevated temperature. Subsequently, the mixture is left to cool down and crystallize in a refrigerator. The produced crystals are aspirated and dried. 4.45 g (89% yield) of the potassium salt of dolutegravir was obtained.
• Dolutegravir (500 mg, 1.19 mmol) is stirred up together with magnesium hydroxide (2.38 mmol) in a mixture of methanol and water. This mixture is stirred overnight in a suspension, then it is filtered and the crystals dried. 400 mg (80% yield) of the magnesium salt of dolutegravir was obtained.
• Dolutegravir (500 mg, 1.19 mmol) is stirred up together with calcium hydroxide (2.38 mmol) in a mixture of methanol and water. This mixture is stirred overnight and subsequently left to evaporate. The crystals are dried. 490 mg (98% yield) of the calcium salt of dolutegravir was obtained.
• Programmable divergence slits with the irradiated area of the sample of 10 mm, 0.02 rad S oiler slits and a 1 ⁇ 4° anti-diffusion slit were used for the setting of the primary optical equipment.
• An X'Celerator detector with maximum opening of the detection slot, 0.02 rad Soller slits and a 5.0 mm anti-diffusion slit were used for the setting of the secondary optical equipment.
• the nuclear magnetic resonance (MR) spectra were measured using a Bruker Avance 500 device.
• the ⁇ spectra were measured at the frequency of 500.13 MHz, l3 C at the frequency of 125.8 MHz.
• the sample was measured in a deuterated solvent specified for the particular analysis, normally at 25°C (unless specified otherwise for a particular analysis).
• the chemical shift 5 is expressed as ppm, the interaction constants J are specified in Hz.
• the spectra were normally referenced to the residual solvent content.
• Carbon spectra of solid-state nuclear magnetic resonance (ssNMR) were measured with the use of an Avance 400 WB Bruker device, using the CP/MAS method in a 4mm rotor at the speed of 13 kHz, normally at 25°C.
• the records of the differential scanning calorimetry (DSC) were measured using a DSC Pyris 1 device made by the company Perkin Elmer.
• the sample charge in a standard Al pot (40 ]iL) was between 2-4 mg and the heating rate was 10°C/min.
• the temperature program that was used consists of 1 min stabilization at the temperature of 20°C and then of heating up to 300°C at the heating rate of 10 °C/min. 4.0 N 2 at the flow rate of 20 ml min was used as the carrier gas.
• thermogravimetric analysis TGA 6 device made by the company Perkin Elmer.
• the sample charge in a corundum pot was 4-20 mg and the heatmg rate was 10°C/min.
• the temperature program that was used consists of 1 minute's stabilization at the temperature of 20°C and then of heating up to 250°C at the heating rate of 10°C/min. 4.0 N 2 at the flow rate of 20 ml/min was used as the carrier gas.

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• 2015
  • 2015-02-13 CZ CZ2015-99A patent/CZ201599A3/cs unknown
• 2016
  • 2016-02-12 WO PCT/CZ2016/000019 patent/WO2016127965A1/en active Application Filing
  • 2016-02-12 EP EP16712715.8A patent/EP3256477A1/en not_active Withdrawn

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