Solvates of trametinib

Abstract

The present invention relates to solvates of compound of formula (1) and processes for preparation thereof.

Description

[0001] SOLVATES OF TRAMETINIB

[0002] This invention relates to solvates of trametinib, compound of the formula (1), and to improved processes making of complexes of trametinib, compound of formula (1):

[0003] BACKGROUND OF THE PRESENT INVENTION

[0004] Trametinib, N-(3-{3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo- 3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-l(2H)-yl}phenyl)acetamide , is an oral inhibitor of mitogen- activated protein kinase kinase 1 (MEK1) and of mitogen-activated protein kinase kinase 2 (MEK2). Trametinib is used in therapy of unresectable or metastatic melanoma with a BRAF V600 mutation and in therapy of advanced non-small cell lung cancer with a BRAF V600 mutation.

[0005] W02005121142 discloses trametinib compound as well as complexes with common organic solvents including dimethyl sulfoxide. No particular examples of the form of solvent complexes are disclosed in the application.

[0006] WO2015081566 discloses a method for preparation of particular forms of trametinib solvent complexes utilizing ultrasound.

[0007] WO2016169532 and US20150152100 discloses a particular crystalline form and method of preparation of dimethyl sulfoxide complex of trametinib.

[0008] WO2020161654 discloses a particular crystalline form and method of preparation of acetic acid complex of trametinib.

[0009] IN5116 / CHE / 2014 discloses trametinib benzyl alcohol and ethyl acetate complexes prepared by a conventional method. WO2012088033 discloses solid oral pharmaceutical dosage forms comprising micronized trametinib dimethyl sulfoxide complex.

[0010] WO2015128298 discloses pharmaceutical composition comprising trametinib embedded in a carrier matrix.

[0011] US20170020880 discloses pharmaceutical composition comprising trametinib, trametinib salt, or trametinib solvent complex and a solubility enhancer.

[0012] WO2014085371 discloses pharmaceutical composition comprising trametinib dimethyl sulfoxide complex and a solubilizer.

[0013] The prior art discloses solvates of trametinib with limited industrial usability as medicaments. The disclosed solvates are both chemically and physically unstable and manifest low aqueous solubility.

[0014] The prior art discloses solvates of trametinib with limited industrial usability as medicaments. The disclosed solvates are prepared by processes, which utilize physical methods with rather limited industrial scalability and with negative environmental impact.

[0015] Moreover, the preparation of trametinib solvates is carried out in solutions at very high dilution levels due to a very low solubility of trametinib in most of organic solvents. The low solubility in organic solvents provides for a high environmental burden in the form of high amounts of organic solvent waste obtained after isolation of a desired solid form of trametinib solvate.

[0016] It would be desirable to provide an efficient processes for manufacture of trametinib solvates with a high purity and in a high yield, which are suitable for scale up and industrial production with minimized environmental burden.

[0017] Trametinib, as well as a solvate forms of trametinib exhibit unique properties, which render the use of trametinib or the solvated forms of trametinib in providing for a medicament, suitable for a treatment of life threatening conditions, cumbersome and not straightforward, particularly on a commercial scale. The properties include but are not limited to a low aqueous solubility of trametinib and the instability of the solvate forms of trametinib typically when heated or in the presence of water or light. Trametinib is practically insoluble in water in free desolvated form. The poor water solubility of biologically active substance may lead to a slow absorption and to inadequate and variable bioavailability. The solubility of the active substance is suitably increased by solvation providing for solvate complexes of the active substance with improved and robust bioavailability.

[0018] Trametinib was found to interact with a variety of solvents to form the solvates. The solvate is formed when trametinib is brought in contact with a solvent. Suitably, trametinib is miscible with the solvent. Suitably, trametinib dissolves in the solvent. Trametinib was found to be nearly immiscible with a variety of the solvents. Thus, an excessive amount of the solvent is needed to be contacted with trametinib for successful preparation of a desired solvate. Such excessive amount then leads to an environmentally unacceptable amounts of waste once the desired molecular complex is separated from the contacted mixture on industrial scale.

[0019] The present inventors have surprisingly found that a desired solvate of trametinib and a solvent can be prepared with a high yield and with a high chemical purity from a mixture of solvents in a way the overall amount of solvents is dramatically reduced. Thus, the reduction in the overall amount of solvents diminishes the environmental impact of the process compared to a single solvent process.

[0020] The solvate complexes are suitably prepared in a solid form. Advantageously, the bioavailability of the solvate of the active substance is further increased by a reduction of a particle size of the solid form. The reduction of particle size is typically achieved for example by milling, bashing and / or grinding, to significantly reduce particle size over those produced naturally during chemical synthesis.

[0021] Since the solvate complexes are complexes wherein the individual complex entities are attracted by weak intermolecular forces, the solvated complexes tend to dissociate typically upon exposure to heat during handling. Thus dissociation of solvate complex of the active substance can take place during manufacture of a medicament on a commercial scale. The dissociation of trametinib active substance solvate can lead to the formation of the de solvated trametinib with a disadvantageous solubility characteristics with a negative impact on pharmacodynamics of trametinib medicament.

[0022] It would be desirable to provide the efficient processes of manufacture of particles trametinib solvates with significantly reduced size, which do not comprise excessive heat transfer and / or strong mechanical forces imposed on processed material, and which are suitable for scale up and industrial production.

[0023] The present inventors have surprisingly found that a desired solvate of trametinib and a solvent with a reduced particle size of the solid form of the desired solvate can be produced with a high yield and with a high chemical purity by a chemical process without a need to use of mechanical particle size reducing means. Thus, the particles of trametinib solvate providing for an acceptable solubility and bioavailability are provided for.

[0024] The present inventors have also found that anisol, butan-l-ol, cyclohexanol, and methanol solvents provide for the solvates of trametinib, which are stable and can be advantageously used in a manufacture of a medicament on a commercial scale. Thus, the stable solvates of trametinib provide for the medicaments with desired and robust bioavailability.

[0025] BRIEF DESCRIPTION OF THE INVENTION

[0026] The present invention is directed to a solvate comprising trametinib and a solvent selected from a group consisting of anisole, butan-l-ol, cyclohexanol, and methanol.

[0027] The present invention further relates to a process for preparation of a solvate of trametinib and a first solvent comprising: a) Dissolving trametinib in a second solvent; b) Freeze drying the solution obtained in the step a); c) Mixing a solid obtained in the step b) with the first solvent; d) Separating a solid form of the solvate from the mixture; and e) Drying the solid form of the complex.

[0028] The present invention also discloses a process for preparation of a solvate of trametinib and a solvent comprising: a) Mixing trametinib with the solvent and the solvate seed; b) Separating a solid form of the solvate from the mixture; and c) Drying the solid form of the complex. The present invention also relates to a process for preparation of a solvate of trametinib and a first solvent comprising: a) Dissolving trametinib in a second solvent; b) Mixing a solution obtained in step a) with the first solvent; c) Separating a solid form of the solvate from the mixture; and d) Drying the solid form.

[0029] It would be desirable to provide the efficient processes of manufacture of particles of trametinib solvates with significantly reduced size, which are suitable for scale up and industrial production, and provide for an acceptable solubility and bioavailability of trametinib.

[0030] It would be desirable to provide an efficient processes for manufacture of trametinib solvates with a high purity and in a high yield, which are suitable for scale up and industrial production with minimized environmental burden.

[0031] BRIEF DESCRIPTION OF THE DRAWINGS

[0032] Figure 1 depicts the X-Ray Powder Diffractogram (XRPD) of trametinib anisole solvate prepared according to the Example 1.

[0033] Figure 2 depicts the differential scanning calorimetry (DSC) curve of trametinib anisole solvate prepared according to the Example 1.

[0034] Figure 3 depicts the thermogravimetric analysis (TGA) curve of trametinib anisole solvate prepared according to the Example 1.

[0035] Figure 4 depicts the X-Ray Powder Diffractogram (XRPD) of trametinib butan-l-ol solvate prepared according to the Example 2.

[0036] Figure 5 depicts the differential scanning calorimetry (DSC) curve of trametinib butan-l-ol solvate prepared according to the Example 2.

[0037] Figure 6 depicts the thermogravimetric analysis (TGA) curve of trametinib butan-l-ol solvate prepared according to the Example 2. Figure 7 depicts the X-Ray Powder Diffractogram (XRPD) of trametinib cyclohexanol solvate prepared according to the Example 3.

[0038] Figure 8 depicts the differential scanning calorimetry (DSC) curve of trametinib cyclohexanol solvate prepared according to the Example 3.

[0039] Figure 9 depicts the thermogravimetric analysis (TGA) curve of trametinib cyclohexanol solvate prepared according to the Example 3.

[0040] Figure 10 depicts the X-Ray Powder Diffractogram (XRPD) of trametinib methanol solvate prepared according to the Example 4.

[0041] Figure 11 depicts the differential scanning calorimetry (DSC) curve of trametinib methanol solvate prepared according to the Example 4.

[0042] Figure 12 depicts the thermogravimetric analysis (TGA) curve of trametinib methanol solvate prepared according to the Example 4.

[0043] Figure 13 depicts scanning electron microscope (SEM) image of trametinib methanol solvate prepared according to Example 7.

[0044] Figure 14 depicts scanning electron microscope (SEM) image of trametinib ethanol solvate prepared according to Example 8.

[0045] Figure 15 depicts scanning electron microscope (SEM) image of trametinib propan-2 -ol solvate prepared according to Example 9.

[0046] Figure 16 depicts scanning electron microscope (SEM) image of trametinib ethanol solvate prepared according to Example 10.

[0047] Figure 17 depicts scanning electron microscope (SEM) image of trametinib propan-2 -ol solvate prepared according to Example 11.

[0048] Figure 18 depicts scanning electron microscope (SEM) image of trametinib methanol solvate prepared according to Example 12.

[0049] Figure 19 depicts scanning electron microscope (SEM) image of trametinib ethanol solvate prepared according to Example 13.

[0050] Figure 20 depicts scanning electron microscope (SEM) image of trametinib propan-2 -ol solvate prepared according to Example 14. DETAILED DESCRIPTION OF THE INVENTION

[0051] The present invention is directed to a solvate comprising trametinib and a solvent selected from a group consisting of anisole, butan-l-ol, cyclohexanol, and methanol.

[0052] The present invention relates to a solvate comprising trametinib and a solvent selected from a group consisting of anisole, butan-l-ol, cyclohexanol, and methanol.

[0053] In one embodiment, the solvate is solid.

[0054] In one embodiment, the solvate wherein the solvent is anisole is solid form A-l. The solid form A-l can be characterized by XRPD pattern having 20 values 13.7, 17.4, 18.2, and 23.5 degrees 2 theta (± 0.2 degrees 2 theta), when measured with CuKal radiation (X = 1.54060 A). The solid form A-l can be also characterized by XRPD pattern having 20 values 10.2, 10.4, 11.2, 13.7, 17.4, 18.2, and 23.5 degrees 2 theta (± 0.2 degrees 2 theta), when measured with CuKal radiation (X = 1.54060 A). The solid form A-l can be further characterized by XRPD pattern describe in the following table: The solid A-l can be also characterized by XRPD pattern depicted in Figure 1. The solid can be further characterized by DSC curve depicted in Figure 2 and by TGA curve depicted in Figure 3.

[0055] In another embodiment, the solvate wherein the solvent is butan-l-ol is solid form B-l. The solid form B-l can be characterized by XRPD pattern having 20 values 6.7, 7.7, 11.0, and 18.1 degrees 2 theta (± 0.2 degrees 2 theta), when measured with CuKal radiation (X = 1.54060 A). The solid form B-l can be also characterized by XRPD pattern having 20 values 3.6, 5.0, 6.7, 7.7, 11.0, 13.7, and 18.1 degrees 2 theta (± 0.2 degrees 2 theta), when measured with CuKal radiation (X = 1.54060 A). The solid form B-l can be further characterized by XRPD pattern describe in the following table: The solid form B-l can be also characterized by XRPD pattern depicted in Figure 4. The solid can be further characterized by DSC curve depicted in Figure 5 and by TGA curve depicted in Figure.

[0056] In another embodiment, the solvate wherein the solvent is cyclohexanol is solid form CX-1.

[0057] The solid form CX-1 can be characterized by XRPD pattern having 20 values 9.1, 16.7, 18.5, and 19.8 degrees 2 theta (± 0.2 degrees 2 theta), when measured with CuKal radiation (X = 1.54060 A). The solid form CX-1 can be also characterized by XRPD pattern having 20 values 9.1, 10.6, 13.6, 17.1, 18.2, 16.7, 18.5, 19.8, and 24.8 degrees 2 theta (± 0.2 degrees 2 theta), when measured with CuKal radiation (X = 1.54060 A). The solid form CX-1 can be further characterized by XRPD pattern describe in the following table:

[0058]

[0059] The solid CX-1 can be also characterized by XRPD pattern depicted in Figure 7. The solid can be further characterized by DSC curve depicted in Figure 8 and by TGA curve depicted in Figure 9.

[0060] In another embodiment, the solvate wherein the solvent is methanol is solid form M-l. The solid form M-l can be characterized by XRPD pattern having 20 values 5.4, 10.6, 12.7, and 21.3 degrees 2 theta (± 0.2 degrees 2 theta), when measured with CuKal radiation (X = 1.54060 A). The solid form M-l can be also characterized by XRPD pattern having 20 values 5.4, 9.5, 10.2, 10.6, 12.1, 12.7, 20.4, 21.3, and 24.3 degrees 2 theta (± 0.2 degrees 2 theta), when measured with CuKal radiation (X = 1.54060 A). The solid form M-l can be further characterized by XRPD pattern describe in the following table :

[0061] The solid M-l can be also characterized by XRPD pattern depicted in Figure 10. The solid can be further characterized by DSC curve depicted in Figure 11 and by TGA curve depicted in Figure 12.

[0062] The solvates of trametinib according to presented invention can be prepared by a process comprising contacting trametinib with a solvent selected from group consisting of anisole, butan-l-ol, cyclohexanol and methanol. The solvates od the presented invention can be formulated into pharmaceutical composition comprising the solvate and one or more excipients.

[0063] The present invention also relates to a process for preparation of a solvate of trametinib and a first solvent comprising: a) Dissolving trametinib in a second solvent; b) Freeze drying the solution obtained in the step a); c) Mixing the solid obtained in the step b) with the first solvent; d) Separating a solid form of the solvate from the mixture; and e) Drying the solid form of the complex.

[0064] In one embodiment, trametinib is dissolving in the second solvent in the process of the present invention. The suitable second solvent can be selected from 1,1,1 -trichloroethane, 1,1,2-trichloro- ethene, 1,1 -dichloroethene, 1,1 -diethoxypropane, 1,1 -dimethoxymethane, 1,2-dichloroethane, 1,2- dichloroethene, 1,2-dimethoxyethane, 1,4-dioxane, 1 -butanol, 1 -pentanol, 1 -propanol, 2,2-dimethoxy- propane, 2-butanol, 2-ethoxyethanol, 2-methoxyethanol, 2 -methyl- 1 -propanol, 2-methyltetrahydro- furan, 2-propanol, 3 -methyl- 1 -butanol, acetic acid, acetone, acetonitrile, anisole, benzene, butyl acetate, carbon tetrachloride, chlorobenzene, chloroform, cumene, cyclohexane, cyclopentyl methyl ether, dichloromethane, dimethyl sulfoxide, ethanol, ethyl acetate, ethyl ether, ethyl formate, ethyleneglycol, formamide, formic acid, heptane, hexane, isobutyl acetate, isooctane, isopropyl acetate, isopropyl ether, methanol, methyl acetate, methyl butyl ketone, methylcyclohexane, methylethyl ketone, methylisobutylketone, methylisopropyl ketone, '. '-dimcthylacctamidc. '. '-dimcthyl- formamide, nitromethane, N-methylpyrrolidone, pentane, petroleum ether, propyl acetate, pyridine, sulfolane, tert-butylmethyl ether, tert-butyl alcohol, tetrahydrofuran, tetralin, toluene, trichloroacetic acid, triethylamine, trifluoroacetic acid, xylene, or a mixture thereof. Preferably, 1,4-dioxane is used.

[0065] In another embodiment, trametinib is dissolved in the second solvent at an elevated temperature in the process of the present invention. Trametinib is dissolved at a temperature from 40 °C to 180 °C, preferably at temperature from 60 °C to 140 °C, or more preferably at temperature from 80 °C to 100

[0066] C. In another embodiment, the solution of trametinib in the second solvent prepared in the process of the present invention contains from 0.5 % to 5 % of trametinib by weight based on the total weight of the solution. Preferably, the solution contains from 1 % to 4.5 %, more preferably 2 % to 3.5 %, of trametinib by weight based on the total weight of the solution.

[0067] In one embodiment, a solution of trametinib in the second solvent is freeze-dried at a diminished pressure in the process of the present invention. Preferably, the solution is freeze-dried at the pressure from 0.5 mTorrto 100 mTorr, more preferably at the pressure from 1 mTorr to 75 mTorr.

[0068] In another embodiment, the solution of trametinib in the second solvent is freeze dried at a diminished temperature in the process of the present invention. Preferably, the solution is freeze-dried at the temperature from -25 °C to 25 °C, more preferably at the temperature from -10 °C to 10 °C.

[0069] In one embodiment, a material produced by free-drying is mixed with the first solvent in the process of the present invention. The first solvent can be selected from 1,1,1 -trichloroethane, 1,1,2- trichloroethene, 1,1 -dichloroethene, 1,1 -diethoxypropane, 1,1 -dimethoxymethane, 1,2-dichloroethane, 1,2-dichloroethene, 1,2-dimethoxyethane, 1,4-dioxane, 1 -butanol, 1 -pentanol, 1 -propanol, 2,2- dimethoxypropane, 2-butanol, 2-ethoxyethanol, 2-methoxyethanol, 2 -methyl- 1 -propanol, 2 -methyl - tetrahydrofuran, 2-propanol, 3 -methyl- 1 -butanol, acetic acid, acetone, acetonitrile, anisole, benzene, butyl acetate, carbon tetrachloride, chlorobenzene, chloroform, cumene, cyclohexane, cyclopentyl methyl ether, dichloromethane, dimethyl sulfoxide, ethanol, ethyl acetate, ethyl ether, ethyl formate, ethyleneglycol, formamide, formic acid, heptane, hexane, isobutyl acetate, isooctane, isopropyl acetate, isopropyl ether, methanol, methyl acetate, methyl butyl ketone, methylcyclohexane, methylethyl ketone, methylisobutylketone, methylisopropyl ketone, '. '-dimcthylacctamidc. '. '-dimcthyl- formamide, nitromethane, N-methylpyrrolidone, pentane, petroleum ether, propyl acetate, pyridine, sulfolane, tert-butylmethyl ether, tert-butyl alcohol, tetrahydrofuran, tetralin, toluene, trichloroacetic acid, triethylamine, trifluoroacetic acid, or xylene. Preferably, methanol, ethanol, propan-2-ol, propan- I-ol, anisol, or cyclohexanol is used. More preferably, methanol, ethanol, propan-2 -ol, or propan- l-ol is used.

[0070] In another embodiment, the mixing of the freeze-dried material and the first solvent is performed at ambient temperature in the process of the present invention. Preferably, the mixing is performed at a temperature from 10 °C to 30 °C. More preferably, the mixing is performed at a temperature from 15 °C to 25 °C.

[0071] In one embodiment, a solid form of the solvate of trametinib and the first solvent is separated by filtration in the process of the present invention.

[0072] In one embodiment, an isolated solid form of the solvate of trametinib and the first solvent is dried in the process of the present invention. The drying of the solid form can be performed at a pressure equal to, lower than, or higher than the atmospheric pressure. Preferably, the solvate is at pressure lower than or equal to the atmospheric pressure.

[0073] In another embodiment, the solid form of the solvate of trametinib and the first solvent is heated when dried in the process of the present invention. Preferably, the solid form is heated to a temperature lower than or equal to 100 °C. More preferably, the solid form is heated to a temperature lower than or equal to 80 °C.

[0074] The present invention further relates to a process for preparation of a solvate of trametinib and a solvent comprising: a) Mixing trametinib with the solvent and the solvate seed; b) Separating a solid form of the solvate from the mixture; and c) Drying the solid form of the complex.

[0075] In one embodiment, trametinib and a seed of trametinib solvate with a solvent is mixed with the solvent in the process of the present invention. The solvent can be selected from 1,1,1 -trichloroethane, 1,1,2-trichloroethene, 1,1 -dichloroethene, 1,1 -diethoxypropane, 1,1 -dimethoxymethane, 1,2-dichloro- ethane, 1,2-dichloroethene, 1,2-dimethoxyethane, 1,4-dioxane, 1 -butanol, 1 -pentanol, 1 -propanol, 2,2- dimethoxypropane, 2-butanol, 2-ethoxyethanol, 2-methoxyethanol, 2 -methyl- 1 -propanol, 2 -methyl - tetrahydrofuran, 2-propanol, 3 -methyl- 1 -butanol, acetic acid, acetone, acetonitrile, anisole, benzene, butyl acetate, carbon tetrachloride, chlorobenzene, chloroform, cumene, cyclohexane, cyclopentyl methyl ether, dichloromethane, dimethyl sulfoxide, ethanol, ethyl acetate, ethyl ether, ethyl formate, ethyleneglycol, formamide, formic acid, heptane, hexane, isobutyl acetate, isooctane, isopropyl acetate, isopropyl ether, methanol, methyl acetate, methyl butyl ketone, methylcyclohexane, methylethyl ketone, methylisobutylketone, methylisopropyl ketone, '. '-dimcthylacctamidc. '. '-dimcthyl- formamide, nitromethane, N-methylpyrrolidone, pentane, petroleum ether, propyl acetate, pyridine, sulfolane, tert-butylmethyl ether, tert-butyl alcohol, tetrahydrofuran, tetralin, toluene, trichloroacetic acid, triethylamine, trifluoroacetic acid, or xylene. Preferably, methanol, ethanol, propan-2-ol, propan- l-ol, anisol, or cyclohexanol is used. More preferably, methanol, ethanol, propan-2 -ol, or propan- l-ol is used.

[0076] In another embodiment, the mixture of trametinib and the seed is cooled in the process of the present invention. Preferably, the mixing is performed at a temperature from -5 °C to 25 °C. More preferably, the mixing is performed at a temperature from 0 °C to 15 °C.

[0077] In one embodiment, a solid form of the solvate of trametinib and the solvent is separated by filtration in the process of the present invention.

[0078] In one embodiment, an isolated solid form of the solvate of trametinib and the solvent is dried in the process of the present invention. The drying of the solid form can be performed at a pressure equal to, lower than, or higher than the atmospheric pressure. Preferably, the solvate is at pressure lower than or equal to the atmospheric pressure.

[0079] In another embodiment, the solid form of the solvate of trametinib and the solvent is heated when dried in the process of the present invention. Preferably, the solid form is heated to a temperature lower than or equal to 100 °C. More preferably, the solid form is heated to a temperature lower than or equal to 80 °C.

[0080] The present invention also relates to a process for preparation of a solvate of trametinib and a first solvent comprising: a) Dissolving trametinib in a second solvent; b) Mixing a solution obtained in step a) with the first solvent; c) Separating a solid form of the solvate from the mixture; and d) Drying the solid form. In one embodiment, trametinib is dissolving in the second solvent in the process of the present invention. The suitable second solvent can be selected from 1,1,1 -trichloroethane, 1,1,2-trichloro- ethene, 1,1 -dichloroethene, 1,1 -diethoxypropane, 1,1 -dimethoxymethane, 1,2-dichloroethane, 1,2- dichloroethene, 1,2-dimethoxyethane, 1,4-dioxane, 1 -butanol, 1 -pentanol, 1 -propanol, 2,2-dimethoxy- propane, 2-butanol, 2-ethoxyethanol, 2-methoxyethanol, 2 -methyl- 1 -propanol, 2-methyltetrahydro- furan, 2-propanol, 3 -methyl- 1 -butanol, acetic acid, acetone, acetonitrile, anisole, benzene, butyl acetate, carbon tetrachloride, chlorobenzene, chloroform, cumene, cyclohexane, cyclopentyl methyl ether, dichloromethane, dimethyl sulfoxide, ethanol, ethyl acetate, ethyl ether, ethyl formate, ethyleneglycol, formamide, formic acid, heptane, hexane, isobutyl acetate, isooctane, isopropyl acetate, isopropyl ether, methanol, methyl acetate, methylbutyl ketone, methylcyclohexane, methylethyl ketone, methylisobutylketone, methylisopropyl ketone, '. '-dimcthylacctamidc. '. '-dimcthyl- formamide, nitromethane, N-methylpyrrolidone, pentane, petroleum ether, propyl acetate, pyridine, sulfolane, tert-butylmethyl ether, tert-butyl alcohol, tetrahydrofuran, tetralin, toluene, trichloroacetic acid, triethylamine, trifluoroacetic acid, xylene, or a mixture thereof. Preferably, dimethyl sulfoxide, formamide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, sulfolane, or a mixture thereof is used. More preferably, N,N-dimethylformamide is used.

[0081] In another embodiment, trametinib is dissolved at an elevated temperature in the process of the present invention. Trametinib is dissolved at a temperature from 40 °C to 180 °C, preferably at temperature from 60 °C to 140 °C, or more preferably at temperature from 80 °C to 100 °C.

[0082] In one embodiment, trametinib solution is mixed with the first solvent in the process of the present invention. The first solvent can be selected from 1,1,1 -trichloroethane, 1,1,2-trichloroethene, 1,1 -dichloroethene, 1,1 -diethoxypropane, 1,1 -dimethoxymethane, 1,2-dichloroethane, 1,2-dichloro- ethene, 1,2-dimethoxyethane, 1,4-dioxane, 1 -butanol, 1 -pentanol, 1 -propanol, 2,2-dimethoxypropane, 2-butanol, 2-ethoxyethanol, 2-methoxyethanol, 2 -methyl- 1 -propanol, 2-methyltetrahydrofuran, 2- propanol, 3 -methyl- 1 -butanol, acetic acid, acetone, acetonitrile, anisole, benzene, butyl acetate, carbon tetrachloride, chlorobenzene, chloroform, cumene, cyclohexane, cyclopentyl methyl ether, dichloromethane, dimethyl sulfoxide, ethanol, ethyl acetate, ethyl ether, ethyl formate, ethyleneglycol, formamide, formic acid, heptane, hexane, isobutyl acetate, isooctane, isopropyl acetate, isopropyl ether, methanol, methyl acetate, methylbutyl ketone, methylcyclohexane, methylethyl ketone, methylisobutylketone, methylisopropyl ketone, '. '-dimcthylacctamidc. '. '-dimcthylfonnamidc. nitromethane, N-methylpyrrolidone, pentane, petroleum ether, propyl acetate, pyridine, sulfolane, tert- butylmethyl ether, tert-butyl alcohol, tetrahydrofuran, tetralin, toluene, trichloroacetic acid, triethylamine, trifluoroacetic acid, or xylene. Preferably, methanol, ethanol, propan-2 -ol, propan- l-ol, anisol, or cyclohexanol is used. More preferably, methanol, ethanol, propan-2 -ol, or propan- l-ol is used.

[0083] In another embodiment, the first solvent is cooled in the process of the present invention. The first solvent is cooled at a temperature from -20 °C to 20 °C, preferably at temperature from -10 °C to 10 °C, or more preferably at temperature from -10 °C to 10 °C.

[0084] In one embodiment, the mixture of a solution of trametinib in the second solvent and the first solvent is optionally seeded with a solvate of trametinib and the fist solvent in the process of the present invention

[0085] In one embodiment, a solid form of the solvate of trametinib and the first solvent is separated by filtration in the process of the present invention.

[0086] In one embodiment, the solid form of the solvate of trametinib and the first solvent is dried in the process of the present invention. The drying of the solid form can be performed at a pressure equal to, lower than, or higher than the atmospheric pressure. Preferably, the solvate is at pressure lower than or equal to the atmospheric pressure.

[0087] In another embodiment, the solid form of the solvate of trametinib and the first solvent is heated when dried in the process of the present invention. Preferably, the solid form is heated to a temperature lower than or equal to 100 °C. More preferably, the solid form is heated to a temperature lower than or equal to 80 °C.

[0088] The invention will be further described with reference to the following examples.

[0089] EXAMPLES

[0090] Nuclear magnetic resonance spectroscopy (NMR) was performed using Avance III 400 MHz

[0091] NMR spectrometer.

[0092] DCS patterns were obtained using the following conditions: 10°C / min -> 350°C TGA paterns were obtained using the following conditions: 10°C / min -> 350°C

[0093] XRPD spectrum was obtained using the following measurement conditions:

[0094] Panalytical Empyrean diffractometer with 0 / 20 geometry (transmition mode), equipped with a

[0095] PixCell 3D detector:

[0096] Start angle (20): 2.0°

[0097] End angle (20): 35.0°

[0098] Step size: 0.026°

[0099] Scan speed: 0.0955 ° / seconds

[0100] Radiation type: Cu

[0101] Radiation wavelengths: 1.5406A (Kai)

[0102] Divergence slit: 1 / 2°

[0103] Antiscater slit: 1 / 2°

[0104] Seller slit: 0.02 rad

[0105] Detector slit: 7.5 mm

[0106] Rotation speed: 30 rpm

[0107] Example 1 Anisole solvate

[0108] 0.3 g of trametinib was dissolved upon constant stirring at 140 °C in 35 ml of anisole. The solution was crash-cooled to 0 °C and stirred for approximately six hours. The solid was isolated by vacuum filtration. The product was washed by acetone and suck dried for 5 minutes. Example 2 Butan-l-ol solvate

[0109] 0. 1 g of trametinib was dissolved upon constant stirring at 115 °C in 20 ml of 1 -butanol. The solution was crash-cooled to 0 °C and stirred for approximately ten hours. The mixture was left to sit for one more hour, filtered, and suck dried for another hour in air to provide trametinib butan-l-ol solvate. Example 3 Cyclohexanol solvate

[0110] 0.2 g of trametinib was dissolved upon constant stirring at 160 °C in 22.5 ml of cyclohexanol. The solution was crash-cooled to -10 °C and stirred for approximately six hours. The mixture was left to sit for four more hours, filtered, and suck dried for another hour in air to provide trametinib cyclohexanol solvate.

[0111] Example 4 Methanol solvate

[0112] 0. 1 g of trametinib was dissolved upon constant stirring at 65 °C in 15 ml of methanol. The solution was crash-cooled to -20 °C and stirred for approximately one hour. The mixture was left to sit for one more hour, filtered, and suck dried for another hour in air to provide trametinib cyclo- hexanol solvate.

[0113] Example 5 Open dish stability

[0114] Around 100 mg of corresponding solvate was placed on a Petri's dish and enclosed in a chamber with set temperature and relative humidity to 55 °C and 90 %RH. The material was sampled and measured by XRPD after 6 hours, 24 hours, 48 hours, and 168 h of storage. Table 1 Example 6 Stability in ALU and LDPE

[0115] The samples (about 50 mg) were packed in ALU, LDPE bags and put into the stability chamber with the relevant temperature and humidity. Materials were analyzed by XRPD after 1 month storage. Table 2

[0116] Example 7 The methanol solvate

[0117] 1.5 g oftrametinib was suspended into 10 ml of N,N-dimethylformamide and yellowish slurry was heated to 90 °C. The resulting solution was kept at 90 °C and filtered through PTFE (0.7 microns) filter into 40 ml of pre-cooled methanol at 0 °C upon constant stirring, during addition temperature was not allowed to exceed 0.5 °C. The mixture was seeded with trametinib methanol complex (1 wt. %) and stirred for two hours at 0 °C. The solids were isolated by vacuum filtration and suck dried in air for 30 minutes (no additional drying was applied). The yield of dried material was 77% of the theoretical value.

[0118] Example 8 The ethanol solvate

[0119] 1.5 g of trametinib was dissolved in 11 ml of N,N-dimethylformamide at 90 °C upon constant stirring (magnetic stirring bar) to provide yellow solution. The resulting solution was kept at 90 °C and fdtered through PTFE (0.7 microns) fdter into 40 ml of pre-cooled ethanol at 0 °C upon constant stirring. The mixture was seeded with trametinib ethanol solvate (1 wt. %) and mechanically stirred for two hours at 0 °C. The solids were isolated by vacuum fdtration and suck dried in air for 30 minutes (no additional drying was applied). The yield of dried material was 80% of the theoretical value

[0120] Example 9 The propan-2-ol solvate

[0121] 1.5 g of trametinib was dissolved in 11 ml of N,N-dimethylformamide at 90 °C upon constant stirring (magnetic stirring bar) to provide yellow solution. The resulting solution was kept at 90 °C and fdtered through PTFE (0.7 microns) fdter into 40 ml of pre-cooled 2-propanol at 0 °C upon constant stirring. The mixture was seeded with trametinib 2-propanol complex (1 wt. %) and mechanically stirred for two hours at 0 °C. The solids were isolated by vacuum fdtration and suck dried in air for 30 minutes (no additional drying was applied). The yield of dried material was 80% of the theoretical value.

[0122] Example 10 The ethanol solvate

[0123] Trametinib was dissolved in 1,4-dioxane at concentration around 3 wt.% at elevated temperature. The solution was freeze dried at 0 °C / 10-50 mTorr for 3 hours followed by secondary drying at 25 °C / 10-50 mTorr. 1g of freeze dried trametinib was suspended at temperature of 25 °C upon constant stirring in 20 mb of ethanol. The resulting slurry was stirred for about two hours at 25 °C. The solids were fdtered off by suction fdtration, suck dried in air for one hour and then at 40 °C / vacuum / nitrogen bleed for 4 hours. The yield: 0.890 g (83 %). Example 11 The propan-2-ol solvate

[0124] Trametinib was dissolved in 1,4-dioxane at concentration around 3 wt.% at elevated temperature. The solution was freeze dried at 0 °C / 10-50 mTorr for 3 hours followed by secondary drying at 25 °C / 10-50 mTorr. 0.87 g of freeze dried trametinib was suspended at temperature of 25 °C upon constant stirring in 20 mL of propan-2-ol. The resulting slurry was stirred for about two hours at 25 °C. The solids were filtered off by suction filtration, suck dried in air for one hour and then at 40 °C / vacuum / nitrogen bleed for 4 hours. The yield: 0.65 g (68 %).

[0125] Example 12 The methanol solvate

[0126] 90 mg of trametinib was mixed with approximately 20 mg of trametinib complex with methanol and 1 mL of methanol was added and the white slurry was stirred at 25 °C for around 18 hours. The solids were isolated by suction filtration and suck dried for 30 minutes.

[0127] Example 13 The ethanol solvate

[0128] 90 mg of trametinib was mixed with approximately 20 mg of trametinib complex with ethanol and 1 ml of ethanol was added and the white slurry was stirred at 25 °C for around 18 hours. The solids were isolated by suction filtration and suck dried for 30 minutes.

[0129] Example 14 The complex with propan-2-ol

[0130] 90 mg of trametinib was mixed with approximately 20 mg of trametinib complex with propan- 2-ol and 1 ml of propan-2-ol was added and the white slurry was stirred at 25 °C for around 18 hours. The solids were isolated by suction filtration and suck dried for 30 minutes.

[0131] Example 15 The cyclohexanol solvate

[0132] 1.5 g of trametinib was dissolved in 11 ml of N,N-dimethylformamide at constant stirring and 90 °C. The resulting solution was kept at 90 °C and filtered through PTFE (0.7 microns) filter into 55 ml of cyclohexanol pre-cooled to 0 °C. The resulting solution was seeded with a slurry of cyclohexanol solvate and stirred 72 hours at -10 °C. The solids were isolated by vacuum filtration and dried overnight in vacuum, ambient temperature to provide cyclohexanol solvate with 62% yield. Example 16 The methanol solvate

[0133] 1.5 g of trametinib was suspended into 10 ml of N,N-dimethylformamide and yellowish slurry was heated to 90 °C. The resulting solution was kept at 90 °C and filtered through PTFE (0.7 microns) filter into 40 ml of pre-cooled methanol at 0 °C upon constant stirring, during addition temperature was not allowed to exceed 0.5 °C. The mixture was seeded with trametinib methanol complex (1 wt. %) and stirred for two hours at 0 °C. The solids were isolated by vacuum filtration and suck dried in air for 30 minutes (no additional drying was applied). The yield of dried material was 77% of the theoretical value.

[0134] Example 17 The ethanol solvate

[0135] 1.5 g of trametinib was dissolved in 11 ml of N,N-dimethylformamide at 90 °C upon constant stirring (magnetic stirring bar) to provide yellow solution. The resulting solution was kept at 90 °C and filtered through PTFE (0.7 microns) filter into 40 ml of pre-cooled ethanol at 0 °C upon constant stirring. The mixture was seeded with trametinib ethanol solvate (1 wt. %) and mechanically stirred for two hours at 0 °C. The solids were isolated by vacuum filtration and suck dried in air for 30 minutes (no additional drying was applied). The yield of dried material was 80% of the theoretical value.

[0136] Example 18 The ethanol solvate

[0137] At room temperature, take 10.0 mg of trametinib, add 15.0 mL of ethanol and sonicate at 40 kHz for 5 minutes to obtain a solution. The small hole is subjected to volatile crystallization to obtain the ethanol solvate.

[0138] Example 19 The ethanol solvate

[0139] At room temperature, take 20.0 mg of trametinib amorphous, add 10 mL ethanol, warmed to 75 ° C dissolved 15 ° C per hour cooled to room temperature, crystallization, fdtration, the fdter cake was dried at 30 ° C in vacuo 16 hours to obtain ethanol solvate.

[0140] Example 20 The ethanol solvate

[0141] At room temperature, taking 20.0 mg of trametinib, add 10 mL ethanol, heated to 50° C distillation crystallization, the solvent was distilled off to obtain ethanol solvate. Example 21 The propan-2-ol solvate

[0142] 1.5 g of trametinib was dissolved in 11 ml of N,N-dimethylformamide at 90 °C upon constant stirring (magnetic stirring bar) to provide yellow solution. The resulting solution was kept at 90 °C and fdtered through PTFE (0.7 microns) fdter into 40 ml of pre-cooled 2-propanol at 0 °C upon constant stirring. The mixture was seeded with trametinib 2-propanol complex (1 wt. %) and mechanically stirred for two hours at 0 °C. The solids were isolated by vacuum fdtration and suck dried in air for 30 minutes (no additional drying was applied). The yield of dried material was 80% of the theoretical value.

[0143] Example 22 The purity of solvates The trametinib and trametinib solvate samples were analyzed for a sum of area percent levels of impurities HPLC. The HPLC was performed on Kinetex Phenyl-C6, 150x4.6 mm, dp = 2.6 pm column. The detection with UV light at wavelength of 240 nm was used. The column was eluted, using a gradient method, with aqueous ammonium dihydrogen phosphate (10 mM, pH 6.5) and acetonitrile-methanol (3: 1) at column temperature of 30 °C for 15 min. Table 1 The material purities as detected by HPLC area % by internal normalization for the materials obtained as exemplified above.

Claims

CLAIMS1 . A solvate comprising trametinib with a solvent selected from group consisting of anisole, butan-l-ol, cyclohexanol, and methanol.

2. The solvate according to claim 1 wherein the solvate is solid.

3. The solvate according to claim 1 or 2 wherein the solvent is anisole and the solvate is characterized by XRPD pattern having 20 values 13.7, 17.4, 18.2, and 23.5 degrees 2 theta (± 0.2 degrees 2 theta), when measured with CuKal radiation (X = 1.54060 A).

4. The solvate according to claim 1 or 2 wherein the solvent is butan-l-ol and the solvate is characterized by XRPD pattern having 20 values 6.7, 7.7, 11.0, and 18.1 degrees 2 theta (± 0.2 degrees 2 theta), when measured with CuKal radiation (X = 1.54060 A).

5. The solvate according to claim 1 or 2 wherein the solvent is cyclohexanol and the solvate is characterized by XRPD pattern having 20 values 9.1, 16.7, 18.5, and 19.8 degrees 2 theta (± 0.2 degrees 2 theta), when measured with CuKal radiation (X = 1.54060 A).

6. The solvate according to claim 1 or 2 wherein the solvent is methanol and the complex is characterized by XRPD pattern having 20 values 5.4, 10.6, 12.7, and 21.3 degrees 2 theta (± 0.2 degrees 2 theta), when measured with CuKal radiation (X = 1.54060 A).

7. A process for preparation of a solvate according to the claim 1 wherein trametinib is contacted with a solvent selected from group consisting of anisole, butan-l-ol, cyclohexanol, and methanol.

8. A pharmaceutical composition comprising a solvate according to the claim 1 and one or more excipients.

9. A process for preparation of a solvate of trametinib with a first solvent comprising: a) Dissolving trametinib in a second solvent; b) Freeze drying the solution obtained in the step a); c) Mixing a solid obtained in the step b) with the first solvent; d) Separating a solid form of the solvate from the mixture; and e) Drying the solid form of the solvate.

10. The process according to claim 9 wherein the first solvent is selected from a group consisting of anisole, butan-l-ol, cyclohexanol, and methanol.11 . The process according to claims 9 or 10 wherein the second solvent in step a) is an organic solvent.

12. The process according to any of the claims 9 to 11 wherein the second solvent in step a) is 1,4- dioxane.

13. A process for preparation of a solvate of trametinib and a solvent comprising: a) Mixing trametinib with the solvent and the solvate seed; b) Separating a solid form of the solvate from the mixture; and c) Drying the solid form of the solvate.

14. The process according to the claim 14 wherein the solvent is selected from a group consisting of anisole, butan-l-ol, cyclohexanol, and methanol.

15. A process for preparation of a solvate of trametinib with a first solvent comprising: a) Dissolving trametinib in a second solvent; b) Mixing a solution obtained in step a) with the first solvent; c) Separating a solid form of the solvate from the mixture; and d) Drying the solid form.

16. The process according to the preceding claim wherein the first solvent is selected from a group consisting of anisole, butan-l-ol, cyclohexanol, and methanol.

17. The process according to any of the claims 15 or 16 wherein the second solvent in step a) is an organic solvent.

18. The process according to any of the claims 15 to 17 wherein the second solvent in step a) isN,N- dimethylformamide.

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