EP3256477A1 - Solid forms of dolutegravir salts and a method of their preparation - Google Patents

Solid forms of dolutegravir salts and a method of their preparation

Info

Publication number
EP3256477A1
EP3256477A1 EP16712715.8A EP16712715A EP3256477A1 EP 3256477 A1 EP3256477 A1 EP 3256477A1 EP 16712715 A EP16712715 A EP 16712715A EP 3256477 A1 EP3256477 A1 EP 3256477A1
Authority
EP
European Patent Office
Prior art keywords
dolutegravir
salt
amine
potassium
magnesium
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP16712715.8A
Other languages
German (de)
French (fr)
Inventor
Iva OBADALOVA
Ondrej Dammer
Lukas KREJCIK
Jaroslava SVOBODOVA
Jaroslav Havlicek
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.)
Zentiva KS
Original Assignee
Zentiva KS
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Zentiva KS filed Critical Zentiva KS
Publication of EP3256477A1 publication Critical patent/EP3256477A1/en
Withdrawn legal-status Critical Current

Links

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 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.
  • 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:
  • 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 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. 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.

Landscapes

  • Engineering & Computer Science (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Engineering & Computer Science (AREA)
  • Mechanical Engineering (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Combustion & Propulsion (AREA)
  • Virology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Oncology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Communicable Diseases (AREA)
  • Molecular Biology (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • AIDS & HIV (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

The invention relates to solid forms of salts of dolutegravir of formula I, (4R,12aS)-N-(2,4-difluorobenzyl)-7-hydroxy-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxamide, a method of their preparation and their use in a dosage form. For example, solid forms of dolutegravir with amines (e.g.diethylamine, N,N'-dibenzylethylenediamine, meglumine, ethanolamine, diethanolamine, tromethamine, tert-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.

Description

Solid forms of dolutegravir salts and a method of their preparation
Technical Field The invention relates to new solid forms of salts of dolutegravir (I), (4-iJ12a5)-N-(2,4-difluorobenzyl)-7-hydroxy-4-methyl-658-dioxo-3,4,6!8,12,12a-hexahydro- 2H-pyrido[r,2':455]pyrazino[2,l-i)][l,3]oxazine-9-carboxamide, a method of their preparation and their use in a dosage form. For example, solid forms of dolutegravir with amines (e.g. diethylamine, N,Nr-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.
(I)
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.
Background Art Dolutegravir has first been mentioned in the patent application WO20061 16764, which does not mention any details of the character of the solid form of the product. On the other hand, the patent application WO2010068253 describes crystalline sodium salts of dolutegravir, the anhydrous salt and the monohydrate. There, these salts are characterized with the use XRPD and IR. The anhydrous sodium salt in a crystalline form is also included in the original medicinal product Tivicay. The last known solid form, i.e. the amorphous sodium salt of dolutegravir, is described in the patent application WO2013038407, using the XRPD, DSC, TGA, I and Raman spectroscopy methods. Preparation of other salts has not been published yet.
Disclosure of Invention
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. Further, 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.
Detailed description of the invention
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 benefits of using the salts of dolutegravir with amines consist in the possibility to increase the chemical purity during crystallization and possible re-crystallizations. Thus, dolutegravir gets stabilized in terms of chemical as well as polymorphic purity. Table 1 summarizes the chemical purity values of the starting dolutegravir and of the prepared salts of dolutegravir with amines after the first crystallization.
Table 1: Chemical purity of dolutegravir and its salts with amines
chemical purity (HPLC) dolutegravir (starting) 98.2 % diethylamine salt of dolutegravir 98.7 %
N,N'-dibenzylethylenediamine salt of dolutegravir 99.7 %
ethanolamine salt of dolutegravir 98.9 % tromethamine salt of dolutegravir 99.5 % lysine salt of dolutegravir 99.0 %
The salts of dolutegravir with amines were also studied with the use of load tests and subsequent verification of their chemical purity. The results of these tests are summarized in Table 2. The tests have concentrated on amines used in pharmacy, i.e. Ν,Ν'- dibenzylethylenediamine (benzathine), ethanolamine (olamine) and tromethamine.
Table 2: Chemical purity (HPLC) of salts of dolutegravir with amines before and after the load tests
Formation of salts of dolutegravir with amines was confirmed with the use of analytic methods, X-ray powder diffraction, differential scanning calorimetry and by means of the solid-state nuclear magnetic resonance. The X-ray powder diffraction (XRPD) pattern of various salts of dolutegravir - with diethylamine (fig. 5), with N,N -dibenzylethylenediamine (fig. 8), with ethanolamine (fig. 11), with tromethamine (fig. 15) and with lysine (fig. 18) differ from the XRPD pattern of dolutegravir (fig. 2). Similarly, 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. 6), dolutegravir salt with N,N -dibenzylethylenediamine 155.7°C (fig. 9), dolutegravir salt with ethanolamine 188.4°C (fig. 12), dolutegravir salt with tromethamine 169.5°C (fig. 16) and dolutegravir salt with lysine 196.5°C (fig. 19).
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. The anhydrous form of dolutegravir with emanolarriine contains 1% of water and 16% of emanolamine. According to TGA, the salt of dolutegravir with diethylamine contains 1% of water and 14% of diethylamine. According to TGA, the salt of dolutegravir with N,N-dibenzylethylenediamine contains 2% of water. According to TGA, 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:
a/ dissolution and/or dispersion of a mixture of dolutegravir and an amine in a solvent or mixture of solvents;
b/ removal of the solvents from the mixture from step a .
Preparation of a salt of dolutegravir with an amine according to variant B comprises the following steps:
a dissolution and/or dispersion of dolutegravir in a solvent or a mixture of solvents; hi addition of an amine in the solid form or in the form of a solution;
c/ removal of the solvents from the mixture from step hi.
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. In 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. Besides dolutegravir itself and the excipients, 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. Thus, 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.
Table 3: Diffraction peaks of the salt of dolutegravir with diethyiamine
Interplanar spacing [A = 0.1
Position [°2Th.] nm] Rel. intensity (%)
5.55 15.925 38.0
7.39 11.951 4.2
10.32 8.563 31.2
11.15 7.927 100.0
11.97 7.386 10.2
14.27 6.203 49.7
14.80 5.980 8.3
15.81 5.602 7.4
16.78 5.279 29.3
19.14 4.634 70.5
20.58 4.312 8.1
21.05 4.218 19.5 21.95 4.047 17.9
22.84 3.891 5.4
23.30 3.814 8.5
24.40 3.645 21.1
25.64 3.472 12.1
28.08 3.175 10.2
28.84 3.093 5.1
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.
Table 4: Diffraction peaks of the salt of dolutegravir withN,N'-diben2ylethylenediamine
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 characteristic peaks of the hydrated form of the salt of dolutegravir with ethanolamine are 6.9; 11.5; 19.7 and 22.2 ± 0.2 °2-theta; its diffraction peaks with a relative intensity higher than 15% are presented in Table 6.
Table 5: Diffraction peaks of the anhydrous salt of dolutegravir with ethanolamine
Table 6: Diffraction peaks of the hydrated form of the salt of dolutegravir with ethanolamine
Interplanar spacing [A = 0.1
Position [°2Th.l nm] Rel. intensity (%)
6.90 12.798 100.0
7.76 11.388 8.3
11.52 7.674 35.6
13.16 6.721 3.6
14.86 5.957 3.1
17.52 5.058 4.7
18.54 4.782 5.9
19.41 4.570 10.8
19.67 4.510 13.6
20.44 4.341 3.4
22.19 4.002 8.5 23.50 3.783 5.1
24.77 3.591 3.9
26.15 3.406 2.8
26.56 3.354 2.9
27.91 3.194 2.7
28.35 3.146 2.9
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.
Table 7: Diffraction peaks of the salt of dolutegravir with tromethamine
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
Table 9: Diffraction peaks of the potassium salt of dolutegravir
Interplanar spacing [A = 0.1
Position [°2Th.] run] Rel. intensity (%)
5.22 16.921 88.9
6.47 13.642 10.1
7.98 11.077 54.1
9.00 9.817 100.0 9.85 8.973 16.2
11.16 7.920 15.8
12.74 6.945 11.1
13.38 6.611 9.1
13.98 6.331 13.2
14.93 5.928 11.2
16.05 5.519 23.1
18.10 4.898 14.5
19.00 4.666 8.5
20.45 4.340 23.0
21.45 4.139 30.6
21.74 4.084 28.7
22.50 3.948 19.4
24.09 3.692 14.2
24.66 3.607 22.7
25.70 3.464 20.8
26.34 3.381 9.1
28.26 3.156 45.3
29.93 2.983 7.6
30.41 2.937 11.6
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 (Mg2+) or calcium (Ca2+) cations. This preparation may be done separately, e.g. during crystallization, or later in the formulation process, e.g. during wet granulation. When the salt is produced during the formulation process, dolutegravir together with a reagent containing potassium (K+), magnesium (Mg2+) or calcium (Ca2+) cations are charged into a homogenizer besides the excipients.
If preparation of the said salts is conducted separately, in a solution, preferably during crystallization, it comprises the following steps:
a dissolution and/or dispersion of dolutegravir in a solvent or a mixture of solvents; b/ addition of a reagent containing potassium (K+), magnesium (Mg2+) or calcium (Ca2+) cations, in a solid form or in the form of a solution;
c/ removal of the solvents from the mixture from step b/.
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. In step b/ 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. 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.
Brief Description of Drawings
Fig. 1: ssNMR record of dolutegravir
Fig. 2 : XRPD pattern of dolutegravir
Fig.3: DSC record 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. 6: DSC record 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
Examples
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. 1H NMR (500 MHz, dmso-i/d): δ 1.33 (d, J = 7.0 Hz, 3H); 1.54 (m, 1H); 2.00 (m, 1H); 3.89 (m, 1H); 4.03 (m, 1H); 4.35 (dd5 J = 13.8 Hz, J= 5.9 Hz, 1H); 4.54 (d, J= 6.1 Hz, 2H); 4.56 (dd, J= 13.8 Hz, J= 4.0 Hz, 1H); 4.79 (m, 1H); 5.45 (dd, J= 5.7 Hz, J= 4.2 Hz, 1H); 7.06 (td, J= 8.6 Hz, J= 2.5 Hz, 1H); 7.24 (td, J= 10.3 Hz, J = 2.5 Hz, 1H); 7.38 (m, 1H); 8.50 (s, 1H); 10.36 (t, J = 5.9 Hz); 12.51 (s, 1H). 13C NMR (125.8 MHz, dmso-i¾): δ 15.4; 29.3; 35.9; 44.9; 51.3; 62.2; 76.3; 104.0; 111.6; 115.6; 117.0; 122.6; 130.9; 140.9; 154.8; 160.3; 161.7; 162.5; 163.9; 170.5 (some of the signals are split due to C-F interactions).
Example 1
Preparation of the salt of dolutegravir with diethylamine
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.
Example 2
Preparation of the salt of dolutegravir with Ayv -dibenzylethylenediamiiie
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.
Example 3
Preparation of the salt of dolutegravir with ethanolamine
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 (Ή 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).
Example 4
Preparation of the salt of dolutegravir with tromethamine
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 (LH NMR) was obtained.
Example 5
Preparation of the salt of dolutegravir with fer/-butylamine
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.
Example 6
Preparation of the salt of dolutegravir with lysine
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 (LH NMR) was obtained. Exam le 7
Preparation of the potassium salt of dolutegravir
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.
Example 8
Preparation of the magnesium salt of dolutegravir
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.
Example 9
Preparation of the calcium salt of dolutegravir
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.
Example 10
Preparation of the salt of dolutegravir with N,N -dibenzylethylenediamine during wet granulation
The following ingredients were placed into a homogenizer: dolutegravir (5.2 g), Ν,Ν'- dibenzylethylenediamine (1.6 g), mannitol (14.6 g), microcrystalline cellulose (5.8 mg) and povidone (1.5 mg). The mixture was homogenized at 20 rpm for 60 min. Finally, sodium stearyl fumarate (1.0 mg) was added and the mixture was homogenized at 20 rpm for another 10 min.
Example 11
Preparation of the salt of dolutegravir with ethanolamine during wet granulation
The following ingredients were placed into a homogenizer: dolutegravir (5.2 g), ethanolamine (0.4 g), mannitol (14.6 g), microcrystalline cellulose (5.8 mg) and povidone (1.5 mg). The mixture was homogenized at 20 rpm for 60 min. Finally, sodium stearyl fumarate (1.0 mg) was added and the mixture was homogenized at 20 rpm for another 10 min. Example 12
Preparation of the salt of dolutegravir with tromethamine during wet granulation
The following ingredients were placed into a homogenizer: dolutegravir (5.2 g), tromethamine (0.8 g), mannitol (14.6 g), microcrystalline cellulose (5.8 mg) and povidone (1.5 mg). The mixture was homogenized at 20 rpm for 60 min. Finally, sodium stearyl fumarate (1.0 mg) was added and the mixture was homogenized at 20 rpm for another 10 min.
Example 13
Pharmaceutical composition of the product - core
The following ingredients were charged into a homogenizer: dolutegravir olamine, mannitol, microcrystalline cellulose and povidone. The mixture was homogenized at 20 rpm for 15 min. Finally, sodium stearyl fumarate was added and the mixture was homogenized at 20 rpm for another 3 min. The tabletting matter produced in the above mentioned way was compressed in a rotary tabletting machine and used for the production of cores with the approximate weight of310 mg.
Overview of analytic methods
Measurement parameters of XRPD: The diffraction patterns were measured using an X'PERT PRO MPD PANalytical diffractometer, used radiation CuKa (λ=1.542 A), excitation voltage: 45 kV, anode current: 40 mA, measured range: 2 - 40° 2Θ, increment: 0,01° 2Θ, the measurement was carried out on a flat powder sample that was applied on a Si plate. Programmable divergence slits with the irradiated area of the sample of 10 mm, 0.02 rad S oiler slits and a ¼° 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 Ή spectra were measured at the frequency of 500.13 MHz, l3C 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 N2 at the flow rate of 20 ml min was used as the carrier gas.
The records of the thermogravimetric analysis (TGA) were measured using a 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 N2 at the flow rate of 20 ml/min was used as the carrier gas.
Chemical purity was measured with the use of liquid chromatography (HPLC):
Device: Waters Acquity UPLC, PDA detection
Sample preparation: Dissolve 4.0 mg of the tested sample in 10.0 ml of 40% acetonitrile Column: - dimension: 1 = 0.10 m, 0 = 2.1 mm
- stationary phase : Acquity BEH phenyl, 1.7 μπι particles
- column temperature: 30°C. Mobile phase: A: 10 mM phosphate buffer at pH 2.5
B methanol
Gradient elution:
Detection: spectrophotometer 258
Injected quantity: 1 μΐ
Sample temperature: 20°C
Sample concentration: 0.4 mg / ml

Claims

1. The potassium, magnesium or calcium salt of dolutegravir or a salt of dolutegravir with an amine, or their solvate.
2. A salt of dolutegravir with an amine or its solvate according to claim 1.
3. A salt of dolutegravir with an amine according to claim 2, wherein the amine is of formula R1-NH2, R^NH or R1NH-C¾CH2-NHR2, wherein R1, R2 is a CI to C8 aliphatic and/or aromatic substituent, substituted in any manner by hydroxyl or carboxyl groups, or its solvate.
4. A salt of dolutegravir with an amine according to claim 3, characterized in that the amine is selected from the group comprising diethylamine, NN'-dibenzylemylenediamine, ethanolamine, tromeraamine, teri-butylamine and lysine.
5. The salt of dolutegravir with diemylamine according to claim 4, exhibiting the following characteristic reflections in the X-ray powder pattern with the use of CuKa radiation: 5.5; 11.2; 14.3; 16.8; 19.1 and 24.4 ± 0.2 °2-theta.
6. The salt of dolutegravir with N,N'-dibenzylethylenediamine according to claim 4, exhibiting the following characteristic reflections in the X-ray powder pattern with the use of CuKa radiation: 7.2; 11.2; 16.6; 18.0; 21.8 and 23.6 ± 0.2 °2-theta.
7. The salt of dolutegravir with ethanolamine according to claim 4, exhibiting the following characteristic reflections in the X-ray powder pattern with the use of CuKa radiation: 7.2; 12.5; 18.3; 19.6 and 23.4 ± 0.2 °2-theta.
8. A hydrated form of the salt of dolutegravir with ethanolamine according to claim 4, exhibiting the following characteristic reflections in the X-ray powder pattern with the use of CuKa radiation: 6.9; 11.5; 19.7 and 22.2 ± 0.2 °2-theta.
9. The salt of dolutegravir with tromethamine according to claim 4, exhibiting the following characteristic reflections in the X-ray powder pattern with the use of Cu a radiation: 7.9; 15.6; 20.7; 22.4; 26.0 and 26.8 + 0.2 °2-theta.
10. The salt of dolutegravir with lysine according to claim 4, exhibiting the following characteristic reflections in the X-ray powder pattern with the use of CuKa radiation: 7.3; 9.6; 13.8; 17.2; 23.0 and 25.4° 2theta.
11. A salt of dolutegravir with an amine according to claims 1 to 9, characterized in that the molar ratio of the amine to dolutegravir is in the range of 2: 1 to 1 :4.
12. A salt of dolutegravir with an amine according to claim 10, characterized in that the molar ratio of the amine to dolutegravir is 1:1 to 1:2.
13. The potassium salt of dolutegravir or its solvate according to claim 1.
14. The potassium salt of dolutegravir according to claim 13, in a crystalline form.
15. The potassium salt of dolutegravir according to claim 14, exhibiting the following characteristic reflections in the X-ray powder pattern with the use of CuKa radiation: 5.2; 9.0; 16.1; 21.5 and 28.3 + 0.2° 2-theta.
16. The magnesium salt of dolutegravir or its solvate according to claim 1.
17. The magnesium salt of dolutegravir according to claim 16, in an amorphous form.
18. The magnesium salt of dolutegravir according to claim 17, which is characterized by the glass transition temperature in the range of 231 to 234°C.
19. A process of preparing a salt of dolutegravir with an amine according to claims 1 to 12, comprising the following steps:
a) dissolution and/or dispersion of a mixture of dolutegravir and an amine in a solvent or mixture of solvents; b) removal of the solvents from the mixture from step a).
20. A process of preparing a salt of dolutegravir with an amine according to claims 1 to 12, comprising the following steps:
a) dissolution and/or dispersion of dolutegravir in a solvent or a mixture of solvents; b) addition of an amine in the solid form or in the form of a solution;
c) removal of the solvents from the mixture from step b).
21. The process according to claim 19 or 20, characterized in that the dissolution or dispersion is carried out in an organic solvent selected from CI to C4 alcohols, CI to C6 esters, CI to C6 ketones, CI to C6 ethers (acyclic or cyclic) or in their mixtures, preferably in methanol, ethanol, 1-propanol or 2-propanol, tetrahydrofuran or in their mixtures.
22. The process according to claim 21, characterized in that the removal of the solvents from the mixture is carried by lyophilization, spray drying or filtration.
23. The process according to claim 22, characterized in that the amine is selected from the group comprising diethylamine, N,N'-diberizylemylenediamine5 ethanolamine, diethanolamine, meglumine, tromethamine, ie t-butylamine and lysine.
24. A process of preparing the potassium, magnesium or calcium salt of dolutegravir according to claims 1, 13 to 18, comprising the following steps:
a) dissolution and/or dispersion of dolutegravir in a solvent or a mixture of solvents; b) addition of a reagent containing potassium ( +), magnesium (Mg2+) or calcium (Ca2+) cations, in a solid form or in the form of a solution;
c) removal of the solvents from the mixture from step b).
25. The process according to claim 24, characterized in that the dissolution or dispersion is 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, in water or in their mixtures, preferably in methanol, ethanol, 1-propanol, 2-propanol, acetone, water, or in their mixtures.
26. The process according to claim 25, characterized in that the removal of the solvents from the mixture is carried by lyophilization, spray drying or filtration.
27. The process according to claim 26, characterized in that said reagent containing potassium (K*), magnesium (Mg2+) or calcium (Ca2+) cations is potassium hydroxide, magnesium hydroxide or calcium hydroxide.
28. A pharmaceutical composition, characterized in that it contains the potassium, calcium, magnesium salt of dolutegravir and/or a salt of dolutegravir with an amine or their solvate.
29. The pharmaceutical composition according to claim 28, containing the potassium salt of dolutegravir and at least one pharmaceutically acceptable excipient.
30. The pharmaceutical composition according to claim 28, contaimng the calcium salt of dolutegravir and at least one pharmaceutically acceptable excipient.
31. The pharmaceutical composition according to claim 28, containing the magnesium salt of dolutegravir and at least one pharmaceutically acceptable excipient.
32. The pharmaceutical composition according to claim 28, containing a salt of dolutegravir with an amine and at least one pharmaceutically acceptable excipient.
33. The pharmaceutical composition according to claim 32, characterized in that the amine is selected from the group comprising diethylamine, N,N'-dibenzylethylenediamines ethanolamine, diemanolaniine, Ixomethamine, te^butylamine and lysine.
34. The pharmaceutical composition according to any one of claims 28 to 33, characterized in that it has the form of a tablet.
35. The pharmaceutical composition according to any one of claims 28 to 34, for the use for the treatment of a retroviral infection.
36. The pharmaceutical composition according to claim 35, characterized in that the retroviral infection is the human immunodeficiency virus (HIV).
37. A process of preparing the pharmaceutical composition according to any of claims 28 to 36, characterized in that dolutegravir or its solvate is mixed with an amine, producing the salt of dolutegravir with the respective amine in-situ.
38. The process according to claim 37, characterized in that said amine is of formula R1- NH2, R^NH or R1NH-CH2CH2-NHR2 5 where R1, R2 is a CI to C8 aliphatic and/or aromatic substituent, substituted in any manner by hydroxyl or carboxyl groups, or its solvate.
39. The process according to claim 38, characterized in that said amine is selected from the group comprising diemylamine, N,N'-diberizylemylenediamine, ethanolainine, tromethamine, fert-butylamine and lysine.
40. The process of preparing the pharmaceutical composition according to any one of claims 28 to 36, characterized in that dolutegravir or its salt is mixed with a suitable compound containing potassium (K ), magnesium (Mg2+) or calcium (Ca2+) cations, producing the potassium, calcium or magnesium salt of dolutegravir in-situ.
41. The process according to claim 40, characterized in that said reagent containing potassium (K+), magnesium (Mg2+) or calcium (Ca2+) cations is potassium hydroxide, magnesium hydroxide or calcium hydroxide.
42. The process according to any one of claims 37 to 41, characterized in that said composition is prepared by wet granulation.
43. The potassium, calcium or magnesium salt of dolutegravir and/or a salt of dolutegravir with an amine according to any one of claims 1 to 18: for the use for the treatment of a retroviral infection.
44. The potassium, calcium or magnesium salt of dolutegravir and/or a salt of dolutegravir with an amine according to claim 43, wherein the said retroviral infection is the human immunodeficiency virus (HIV).
45. Use of the potassium, calcium or magnesium salt of dolutegravir and/or a salt of dolutegravir with an amine according to claims 1 to 18, in a process of preparing dolutegravir of a high chemical purity of at least 99.85% according to HPLC.
EP16712715.8A 2015-02-13 2016-02-12 Solid forms of dolutegravir salts and a method of their preparation Withdrawn EP3256477A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CZ2015-99A CZ201599A3 (en) 2015-02-13 2015-02-13 Solid forms of dolutegravir salts and process for preparing thereof
PCT/CZ2016/000019 WO2016127965A1 (en) 2015-02-13 2016-02-12 Solid forms of dolutegravir salts and a method of their preparation

Publications (1)

Publication Number Publication Date
EP3256477A1 true EP3256477A1 (en) 2017-12-20

Family

ID=55642195

Family Applications (1)

Application Number Title Priority Date Filing Date
EP16712715.8A Withdrawn EP3256477A1 (en) 2015-02-13 2016-02-12 Solid forms of dolutegravir salts and a method of their preparation

Country Status (3)

Country Link
EP (1) EP3256477A1 (en)
CZ (1) CZ201599A3 (en)
WO (1) WO2016127965A1 (en)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108250215B (en) * 2016-12-28 2022-04-19 华创合成制药股份有限公司 Novel anti-HIV medicine, preparation method and application thereof

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006116764A1 (en) 2005-04-28 2006-11-02 Smithkline Beecham Corporation Polycyclic carbamoylpyridone derivative having hiv integrase inhibitory activity
MX2011006241A (en) 2008-12-11 2011-06-28 Shionogi & Co Synthesis of carbamoylpyridone hiv integrase inhibitors and intermediates.
US9206197B2 (en) 2011-09-14 2015-12-08 Mapi Pharma Ltd. Amorphous form of dolutegravir
EP3022209B1 (en) * 2013-07-17 2018-03-07 ratiopharm GmbH Dolutegravir potassium salt
EP3096763B1 (en) * 2014-01-21 2019-12-25 Laurus Labs Limited Novel process for the preparation of dolutegravir and pharmaceutically acceptable salts thereof
ZA201503540B (en) * 2014-05-20 2016-10-26 Cipla Ltd Process for preparing polycyclic carbamoyl pyridone derivatives

Also Published As

Publication number Publication date
WO2016127965A1 (en) 2016-08-18
CZ201599A3 (en) 2016-08-24

Similar Documents

Publication Publication Date Title
WO2017008773A1 (en) Crystalline forms of obeticholic acid
JP6110817B2 (en) Solid forms of macrocyclic kinase inhibitors
JP6349435B2 (en) 7-{(3S, 4S) -3-[(cyclopropylamino) methyl] -4-fluoropyrrolidin-1-yl} -6-fluoro-1- (2-fluoroethyl) -8-methoxy-4-oxo Of 1,4-dihydroquinoline-3-carboxylic acid
AU2018259089B2 (en) Polymorphs and solid forms of (s)-2-((2-((s)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo(ƒ)imidazo(1,2-d)(1,4)oxazepin-9-yl)amino)propanamide, and methods of production
JP2018520205A (en) Novel crystal form of lenvatinib mesylate and process for producing the same
JP2018501289A (en) Novel crystal form of neratinib maleate and process for producing the same
AU2020276695A1 (en) New crystalline forms of N-(3-(2-(2-hydroxyethoxy)-6-morpholinopyridin-4-yl)-4-methvlphenyl)-2 (trifluoromethyl)isonicotinamide as Raf inhibitors for the treatment of cancer
CZ2015110A3 (en) Empagliflozin solid forms
WO2019236889A1 (en) Novel salts and crystals
NO331272B1 (en) Acid addition salts of polysure basic compounds as well as processes for their preparation
WO2018148961A1 (en) Crystal form of acp-196 salt and preparation method, pharmaceutical composition, and use thereof
WO2007109799A2 (en) Polymorphs of eszopiclone malate
AU2021277593A1 (en) Solid forms of [(1 S)-1 -[(2S,4R,5R)-5-(5-amino-2-oxo-thiazolo[4,5-d]pyrimidin-3-yl)-4-hydroxy-te trahydrofuran-2-yl]propyl] acetate
CN111819174A (en) Polymorphs and solid forms of pyrimidinylamino-pyrazole compounds and methods of preparation
EP3256477A1 (en) Solid forms of dolutegravir salts and a method of their preparation
EP3830091A1 (en) Novel polymorphs of acalabrutinib, a bruton's tyrosine kinase inhibitor
CA3034535C (en) Novel salt of (r)-(1-methylpyrrolidine-3-yl)methyl(3'-chloro-4'-fluoro-[1,1'-biphenyl]-2-yl)carbamate and a crystal form thereof
CN107868059B (en) Salt of quinazoline derivative, preparation method and application thereof
WO2023187762A1 (en) Co-crystals of vortioxetine hydrobromide
CZ2016222A3 (en) Solid forms of the salts of the obeticholic acid
CN114981266A (en) GABAA positive allosteric modulator compounds, preparation method and use thereof
JP2021531329A (en) Maleate of benzothiophene compound, its crystalline form and its use
KR20190005679A (en) Novel 1-[2-(2,4-Dimethylphenylsulfanyl)phenyl]piperazine salt and method for preparing the same
EP2154137A1 (en) Crystalline form of moxifloxacin base
KR20160042107A (en) Form 2 crystalline polymorph of a salt of n-[1-6-(ethynyl-3-oxo-hexahydro-furo[3,2-b]pyrrole-4-carbonyl)-3-methyl-butyl]-4-[5-fluoro-2-(4-methyl-piperazinyl)thiazol-4-yl]-benzamide useful as cysteine protease inhibitor

Legal Events

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

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20170913

AK Designated contracting states

Kind code of ref document: A1

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

AX Request for extension of the european patent

Extension state: BA ME

DAV Request for validation of the european patent (deleted)
17Q First examination report despatched

Effective date: 20180814

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

INTG Intention to grant announced

Effective date: 20191007

GRAJ Information related to disapproval of communication of intention to grant by the applicant or resumption of examination proceedings by the epo deleted

Free format text: ORIGINAL CODE: EPIDOSDIGR1

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

GRAS Grant fee paid

Free format text: ORIGINAL CODE: EPIDOSNIGR3

INTC Intention to grant announced (deleted)
INTG Intention to grant announced

Effective date: 20191127

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

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

18D Application deemed to be withdrawn

Effective date: 20200603