DESC:CROSS-REFERENCE TO RELATED APPLICATIONS
This application, in its entirety, claims the benefit of earlier Indian provisional patent applications No. 5116/CHE/2014 filed on Oct 10, 2014 and 714/CHE/2015 filed Feb 13, 2015.
FIELD OF THE INVENTION
The present invention relates to the field of pharmaceutical sciences and more specifically to a Trametinib benzyl alcohol solvate, Trametinib ethyl acetate solvate and Trametinib anhydrous form. And also relates to process for the preparation of the same.
BACKGROUND OF THE INVENTION
Trametinib dimethyl sulfoxide, chemically known as acetamide, N-[3-[3­ cyclopropyl-5-[(2-fluoro-4- iodophenyl)amino]-3,4,6,7-tetrahydro-6,8-dimethyl- 2,4,7­ trioxopyrido[4,3-d]pyrimidin-1(2H)-yl]phenyl]-, compound with 1,1’-sulfinylbis[methane] and structurally represented as formula-I. Trametinib dimethyl sulphoxide is approved under the trade name MEKINIST by the United States Food and Drug Administration (USFDA). MEKINIST is a kinase inhibitor indicated for the treatment of BRAF V600E or V600K mutation-positive unresectable or metastatic melanoma.

Trametinib is disclosed in US patent number 7,378,423. This patent also discloses the Trametinib solvate forms such as acetic acid solvate, dimethylsulfoxide solvate, ethanol solvate, nitromethane solvate, chlorobenzene solvate, 1-pentanol solvate, isopropyl alcohol solvate, ethylene glycol solvate and 3-methylbutanol solvate.
The present invention relates to Trametinib benzyl alcohol solvate, Trametinib ethyl acetate solvate and Trametinib anhydrous form. And also relates to process for the preparation of the same.
OBJECT AND SUMMARY OF THE INVENTION
Principle object of the present invention is to provide Trametinib benzyl alcohol.
Another object of the present invention is to provide Trametinib ethyl acetate solvate.
One more object of the present invention provides Trametinib anhydrous form.
Another aspect of the present invention is to provide process for the preparation of Trametinib benzyl alcohol solvate comprising the steps of:
a) adding benzyl alcohol to the Trametinib,
b) adding ethereal solvent to the reaction mass, and
c) isolating Trametinib benzyl alcohol solvate.
Another aspect of the present invention is to provide process for the preparation of Trametinib ethyl acetate solvate comprising the steps of:
a) adding ethyl acetate to the Trametinib,
b) heating the reaction mass at 35-80°C,
c) cooling the reaction mass, and
d) isolating Trametinib ethyl acetate solvate.
Another aspect of the present invention provide process for the preparation of Trametinib anhydrous from comprising the steps of:
a) heating Trametinib benzyl alcohol solvate, and
b) isolating Trametinib anhydrous form.
BRIEF DESCRIPTION OF THE DRAWINGS
Further objects of the present invention together with additional features contributing thereto and advantages accruing there from will be apparent from the following description of preferred embodiments of the invention which are shown in the accompanying drawing figures wherein:
Figure 1: illustrates the powder X-ray diffraction pattern of Trametinib benzyl alcohol solvate.
Figure 2: shows a powder X-ray diffraction pattern of Trametinib ethyl acetate solvate.
Figure 3: Shows a differential Scanning Calorimetry pattern of Trametinib ethyl acetate solvate.
Figure 4: shows a thermo gravimetric analysis pattern of Trametinib ethyl acetate.
Figure 5: illustrates the powder X-ray diffraction pattern of Trametinib anhydrous form.

DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to Trametinib benzyl alcohol solvate, Trametinib ethyl acetate solvate and Tarmetinib anhydrous form. And also relates to process for the preparation of the same.
Instrumentation
Powder X-ray Diffraction (PXRD)
The said polymorph of the present invention is characterized by their X-ray powder diffraction pattern. Thus, the X-ray diffraction patterns of said polymorphs of the invention were measured on BRUKER D-8Discover powder diffractometer equipped with goniometer of ?/2? configuration and Lynx Eye detector. The Cu-anode X-ray tube was operated at 40kV and 40mA. The experiments were conducted over the 2? range of 2.0°-50.0°, 0.030° step size and around 0.8 seconds step time.
Differential Scanning Calorimetry (DSC)
The DSC measurements were carried out on TA Q1000 of TA instruments. The experiments were performed at a heating rate of 20.0 °C/min over a temperature range of 30°C-330°C purging with nitrogen at a flow rate of 50ml/min. Standard aluminum crucibles covered by lids with pin holes were used.
Thermo gravimetric Analysis (TGA)
TGA/DTA was recorded using the instrument TA Q5000 IR of TA instruments. The experiments were performed at a heating rate of 10.0 °C/min over a temperature range of 30°C-350°C purging with nitrogen at a flow rate of 25ml/min.
The main aspect of the present invention is to provide Trametinib benzyl alcohol solvate.
In one embodiment, Trametinib benzyl alcohol solvate is characterized by the powder X-ray diffraction having characteristic peak at about 19.5, 19.9, 22.3 and 26.0 (±) 0.2° 2-theta.
The Trametinib benzyl alcohol is further characterized by the powder X-ray diffraction as depicted in Figure 1.
Another aspect of the present invention provide process for the preparation of Trametinib benzyl alcohol solvate comprising the steps of:
a) adding benzyl alcohol to the Trametinib,
b) adding ethereal solvent to the reaction mass, and
c) isolating the Trametinib benzyl alcohol solvate.
In one embodiment of the present invention, ethereal solvent used in step b is selected from isopropyl ether, dimethyl ether, diethyl ether, ethyl methyl ether and methyl tertiary butyl ether, preferably isopropyl ether.
As per the present invention, benzyl alcohol is added to Trametinib and the reaction mixture is heated to 45 °C to 105 °C, preferably 55 °C to 100 °C. Reaction mixture is optionally cooled and ethereal solvent such as isopropyl ether is added, stirred the reaction mixture and solid is filtered and washed, followed by drying to yield Trametinib benzyl alcohol solvate.
Another aspect of the present invention is to provide Trametinib ethyl acetate solvate.
In one embodiment of the present invention, Trametinib ethyl acetate solvate is Trametinib hemi ethyl acetate solvate.
In one embodiment, Trametinib ethyl acetate solvate is characterized by the powder X-ray diffraction having characteristic peak at about 5.06, 7.71, 11.0, 13.8, 17.3, 19.9 and 24.4 (±) 0.2° 2-theta.
The Trametinib ethyl acetate is further characterized by the powder X-ray diffraction as depicted in Figure 2.
The Trametinib ethyl acetate is further characterized by the Differential Scanning Calorimetry pattern as depicted in Figure 3.
The Trametinib ethyl acetate is further characterized by the thermo gravimetric analysis pattern as depicted in Figure 4.
Another aspect of the present invention is to provide process for the preparation of Trametinib ethyl acetate solvate comprising the steps of:
a) adding ethyl acetate to the Trametinib,
b) heating the reaction mass at 35-80°C,
c) cooling the reaction mass, and
d) isolating Trametinib ethyl acetate solvate.
In one embodiment of the present invention, Trametinib is taken in an ethyl acetate solvent and heated to 35-80°C, preferably 75-85°C and stirred for 0-5 hours, preferably 1-2 hours. The reaction mixture is cooled and solid is filtered to get Trametinib ethyl acetate solvate.
In one embodiment of the present invention, Trametinib ethyl acetate solvate is further converted into Trametinib dimethyl sulphoxide solvate by using dimethyl sulphoxide.
Another aspect of the present invention is to provide Trametinib anhydrous form.
In one embodiment, Trametinib anhydrous is characterized by the powder X-ray diffraction having characteristic peak at about 3.6, 18.3, 19.3 and 21.9 (±) 0.2° 2-theta.
In another embodiment, Trametinib anhydrous is further characterized by the powder X-ray diffraction having characteristic peak at about 3.6, 9.1, 14.5, 18.3, 19.3, 20.4 and 21.9 (±) 0.2° 2-theta.
The Trametinib anhydrous is further characterized by the powder X-ray diffraction as depicted in Figure 5.
Another aspect of the present invention provide process for the preparation of Trametinib anhydrous form comprising the steps of:
a) heating Trametinib benzyl alcohol solvate, and
b) isolating Trametinib anhydrous form.
As per the present invention, Trametinib benzyl alcohol solvate is heated to 170-180 °C, preferably 175 °C and dried atmospherically for 1-3 hours at 170 -185 °C, preferably 175 -180 °C to isolate Trametinib anhydrous form.
The trametinib disclosed herein may be incorporated into oral dosage forms, for example, a tablet. Within the context of the present invention, trametinib may be incorporated into dosage forms with a variety of excipients well known in the art. Suitable excipients include, for example, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, povidone, and colloidal silicon dioxide. Coatings of formulations in tablet form may contain ferric oxide red, ferric oxide yellow, lecithin, polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide. Within the context of the present invention, dosage forms may have about 0.5 milligram, 1 milligram and 2 milligram of trametinib.
One of skill in the art will be familiar with a variety of excipients and formulations that may be used to prepare desirable dosage forms with desired release characteristics and pharmacokinetic properties without undue experimentation.
When administered to human and non-human patients, formulations of Trametinib may be adjusted to compensate for the age, weight, and physical condition of the patient. Trametinib may be administered over a wide dosage range from about 0.5 to 2 milligrams per day.
All patents and patent applications cited herein by reference should be considered in their entirety. The following examples are provided to illustrate the process of the present invention. They, are however, not intended to limiting the scope of the present invention in any way and several variants of these examples would be evident to person ordinarily skilled in the art.

Experimental procedure:
Example: 1
Process for the preparation of Trametinib benzyl alcohol solvate.
Benzyl alcohol (5.0 ml) was added to the Trametinb (1.0 g) and the reaction temperature was raised to 50-100 °C. The reaction mixture was stirred and cooled to 20-30 °C. To this isopropyl ether (10 ml) was added and stirred the reaction mixture. The resulted solid was filtered, washed with isopropyl ether and dried to yield Trametinib benzyl alcohol solvate (0.8 g).

Example: 2
Process for the preparation of Trametinib ethyl acetate solvate.
Ethyl acetate (25.0 ml) was added to the Trametinb (1.0 g). Reaction temperature was raised to 40-45°C and maintained for 1-2 hours. The reaction mixture was cooled to 20-30°C. Solid was filtered and dried to yield Trametinib ethyl acetate solvate (0.8 g).
Example: 3
Process for the preparation of 1-(3-Aminophenyl)-3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidine.
In a flask 3-Cyclopropyl-5-(2-fluoro-4-iodo-phenylamino)-6, 8-dimethyl-1- (3-nitro-phenyl)-1H, 6H-pyrido [4, 3-d] pyrimidine-2, 4, 7-trione (100 g) was taken. To this Ethanol (1000 ml) and stannous chloride dihydrate (149.7 g) were added. Reaction temperature was raised to 75-85°C, stirred the reaction mass at same temperature for 4 hours. After completion of the reaction, dichloromethane (4000 ml) and water (1000 ml) were added and reaction mass was cooled to 0-3°C.pH of the reaction mas was adjusted to 12 ± 1 by using 10% sodium hydroxide solution. Reaction temperature was raised to room temperature and layers were separated. Aqueous layer was extracted with dichloromethane. Combined organic layer was washed with water followed by concentration. To the residue ethyl acetate (1000 ml) was added and temperature was raised to 75-80°C and maintained for 1-2 hours. Reaction mass was cooled to 20-30°C. The resulted solid was filtered and dried to get 1-(3-Aminophenyl)-3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8- dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidine.
Example-4
Process for the preparation of Preparation of N-{3-[3-cyclopropyl-5-(2-fluoro-4-iodophenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}acetamide.
In a flask 1-(3-Aminophenyl)-3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8- dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidine (100 g) was taken. To this dichloromethane (1000 ml), pyridine (1000 ml) and acetic anhydride (20 ml) were added at 20-30°C and stirred the reaction mass at same temperature for 2 hours. After completion of the reaction, dichloromethane (3000 ml) and water (300 ml) were added and reaction mass was cooled to 5-15°C. pH of the reaction mass was adjusted to 3.0 ± 1.0 by using aqueous hydrochloric acid solution. Reaction temperature was raised to 20-30°C, stirred the reaction mass at same temperature for 10-30 min. Layers were separated. Organic layer was washed with brine solution followed by concentration. To the residue ethyl acetate (25.0 ml) was added and the reaction temperature was raised to 75-80°C and maintained for 1-2 hours. Reaction mass was cooled to 20-30°C. Solid was filtered and dried to get N-{3-[3-cyclopropyl-5-(2-fluoro-4-iodophenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl] phenyl}acetamide (0.8 g).
Example-5
Process for the preparation of Trametinib anhydrous form.
Trametinib benzyl alcohol solvate (0.35 g) was heated to 175 °C and dried atmospherically for 1-3 hours at 175-180 °C to isolate Trametinib anhydrous form (0.3 g).
,CLAIMS:1. Trametinib benzyl alcohol solvate.
2. The Trametinib benzyl alcohol solvate according to claim 1, characterized by the X- ray diffraction having peaks at about 19.5, 19.9, 22.3 and 26.0 (±) 0.2° values.
3. A process for the preparation of Trametinib benzyl alcohol solvate comprising the steps of:
a) adding benzyl alcohol to the Trametinib,
b) adding ethereal solvent to the reaction mass, and
c) isolating the Trametinib benzyl alcohol solvate.
4. The process according to claim 3, wherein the ethereal solvent selected from isopropyl ether, dimethyl ether, diethyl ether, ethyl methyl ether and methyl tertiary butyl ether.
5. Trametinib ethyl acetate solvate.
6. The Trametinib ethyl acetate solvate according to claim 5, characterized by the X- ray diffraction having peaks at about 5.06, 7.71, 11.0, 13.8, 17.3, 19.9 and 24.4 (±) 0.2° values.
7. A process for the preparation of Trametinib ethyl acetate solvate comprising the steps of:
a) adding ethyl acetate to the Trametinib,
b) heating the reaction mass at 35-80°C,
c) cooling the reaction mass, and
d) isolating Trametinib ethyl acetate solvate.
8. The Trametinib anhydrous form, characterized by the X- ray diffraction having peaks at about 3.6, 18.3, 19.3 and 21.9 (±) 0.2° values.
9. A process for the preparation of Trametinib anhydrous form comprising the steps of:
a) heating Trametinib benzyl alcohol solvate, and
b) isolating Trametinib anhydrous form.
10. The process according to claim 9, wherein the Trametinib benzyl alcohol solvate is heated at a temperature of about 170-180 °C.