FIELD OF THE INVENTION
The present invention relates to a solid form of lifitegrast of Formula I and process for
the preparation thereof

BACKGROUND OF THE INVENTION
Lifitegrast, chemically known as (S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl) propanoic acid, approved by the USFDA under the brand name Xiidra for the treatment of dry eye disease (DED). Lifitegrast is generically disclosed in US 7,314,938.

US patent no. 8,080,562 discloses various crystalline Forms A-E as well as amorphous form of lifitegrast and their process of preparation. US’562 discloses preparation of Form A from suspension of compound in an organic solvent i.e. acetonitrile, methyl ethyl ketone or water.

US 8,367,701 discloses process of recrystallization of lifitegrast by slurring lifitegrast in methyl ethyl ketone or acetonitrile followed by filtering and washing with water. US’701 discloses process for preparation of Form A by suspending amorphous form in acetonitrile and exposing to ultrasonic radiation. Form A is alternatively prepared by dissolving amorphous form in methyl ethyl ketone or water. It further discloses process for preparing crystalline Form B by suspending crystalline Form A in ethyl acetate or in tert-butyl methyl ether. Moreover, crystalline Form C is prepared by suspending crystalline Form A in ethanol. Crystalline Form D is prepared by suspending crystalline Form A in water followed by stirring for four days. Crystalline Form E is prepared by stirring crystalline Form A in acetonitrile and isolating wet material. It further discloses preparation of amorphous form from ethyl acetate extract.

US 9,085,553 and US 9,708,303, discloses a process of recrystallization of lifitegrast from solution comprising acetone, preferably aqueous acetone.

Although, certain published references provides various crystalline forms and amorphous form of lifitegrast however, present invention is focussed towards the development of a novel solid form of lifitegrast which is stable and can be easily formulated.

OBJECT OF THE INVENTION
The main object of the present invention is to provide a novel solid form of lifitegrast of Formula-I and process of preparation thereof.

Formula I

Another object of the present invention is to provide a composition comprising the novel solid form along with pharmaceutical acceptable excipients.

SUMMARY OF THE INVENTION
In one aspect, the present invention provides a solid form of lifitegrast of Formula I characterized by X-Ray powder diffraction pattern having peak at about 31.68 ±0.2o2?,

Formula I .

In another aspect, the present invention provides a solid form of lifitegrast of Formula I wherein said solid form is characterized by Differential Scanning Calorimetry (DSC) plot comprising an endothermic peak at about 131.55oC.

In another aspect, the present invention provides a process for the preparation of a solid form of lifitegrast of Formula I,

Formula I
wherein said process comprises the steps of:
(a) adding lifitegrast to water followed by addition of suitable base;
(b) adjusting the pH to acidic; and
(c) filtering and washing with water to get solid form of lifitegrast.

In another aspect, the present invention provides a process for the preparation of a solid form of lifitegrast of Formula I,

Formula I
wherein said process comprises the steps of:
(a) adding lifitegrast to a solvent system comprising one or more solvent;
(b) heating at a temperature in the range of 40-130oC;
(c) filtering and washing with organic solvent to get a wet mass;
(d) adding the wet mass to water followed by addition of suitable base;
(e) adjusting the pH to acidic; and
(f) filtering and washing with water to get solid form of lifitegrast.

DETAILED DESCRIPTION
Drawings:
Fig. 1 represents X-Ray Powder Diffraction Pattern (XRPD) of solid form of lifitegrast
Fig. 2 represents Differential Scanning Calorimetry (DSC) of solid form of lifitegrast
Fig. 3 represents Thermal Gravimetric Analysis (TGA) of solid form of lifitegrast.
Fig. 4 represents X-Ray Powder Diffraction Pattern (XRPD) of solid form of lifitegrast after one month.

“Pharmaceutically acceptable excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Supplementary active ingredients can also be incorporated into the compositions. In context of the present invention, the excipients are selected from the group comprising buffers, tonicity agents, preservatives, chelating agents, antioxidants, surfactants, co-solvents, viscosity modifying agent, vehicles, pH adjusting agents and/ or combinations thereof.

The present invention will now be explained in details. While the invention is susceptible to various modifications and alternative forms, specific embodiment thereof will be described in detail below. It should be understood, however that it is not intended to limit the invention to the particular forms disclosed, but on the contrary, the invention is to cover all modifications, equivalents, and alternative falling within the scope of the invention as defined by the appended claims.

The steps of a method may be providing more details that are pertinent to understanding the embodiments of the present invention and so as not to obscure the disclosure with details that will be readily apparent to those of ordinary skill in the art having benefit of the description herein.

Further characteristics and advantages of the process according to the invention will result from the description herein below of preferred exemplary embodiments, which are given as indicative and non-limiting examples.

Accordingly, in one embodiment, the present invention provides a solid form of lifitegrast of Formula I characterized by X-Ray powder diffraction pattern having peak at about 31.68 ±0.2o2?,

Formula I .

In a preferred embodiment, the solid form of lifitegrast of the present invention is stable at room temperature as depicted by the XRD pattern of said solid form taken after one month time period.

In another embodiment, the present invention provides a solid form of lifitegrast characterized by X-Ray powder diffraction pattern as represented in Fig. 1.

The said solid form of lifitegrast of the present invention is characterized by various analytical techniques such as X-Ray powder diffraction pattern (XRPD), Differential Scanning Calorimetry (DSC) and Thermal Gravimetric Analysis (TGA).

In one another embodiment, the solid form of lifitegrast of the present invention is characterized by atleast one of the techniques comprising of:
(a) X-Ray powder diffraction pattern (XRPD) having peak at about 31.68 ±0.2o2?; and
(b) Differential Scanning Calorimetry (DSC) plot comprising an endothermic peak at about 131.55oC.

In a preferred embodiment, the present invention provides a solid form of lifitegrast of Formula I wherein said solid form is characterized by Differential Scanning Calorimetry (DSC) plot comprising an endothermic peak at about 131.55oC.

In another embodiment, the present invention provides a process for the preparation of a solid form of lifitegrast of Formula I,

Formula I
wherein said process comprises the steps of:
(a) adding lifitegrast to water followed by addition of suitable base;
(b) adjusting the pH to acidic; and
(c) filtering and washing with water to get solid form of lifitegrast.

In one another embodiment, the pH of the solution containing lifitegrast and suitable base in water, is adjusted to acidic pH, preferably = 2.0 for precipitating the pure lifitegrast which is characterized by X-Ray powder diffraction pattern (XRPD) having peak at about 31.68 ±0.2o2?.

In another embodiment, the present invention provides a process for the preparation of a solid form of lifitegrast of Formula-I,

Formula I
wherein said process comprises the steps of:
(a) adding lifitegrast to a solvent system comprising one or more solvent;
(b) heating to 40-130oC;
(c) filtering and washing with organic solvent to get wet mass;
(d) adding the wet mass to water followed by addition of suitable base;
(e) adjusting the pH to acidic; and
(f) filtering and washing with water to get solid form of lifitegrast.

In another embodiment, the solvent used for crystallization of lifitegrast is selected from the group comprising of halogenated solvents such as dichloromethane (DCM), dichlorobenzene, dichloroethane, carbon tetrachloride; esters such as ethyl acetate (EtOAc), n-butyl acetate, isopropyl acetate, n-propyl acetate, propenyl acetate, pentyl acetate; ethers such as diethyl ether, tetrahydrofuran (THF), dioxane, methyl tetrahydrofuran (Me-THF), methyl ethyl ether; ketones such as methyl ethyl ketone, methyl t-butyl ketone, acetone; alcohols such as methanol, ethanol, n-propanol, t-butanol, glycols; nitriles such as acetonitrile, propionitrile; hydrocarbon solvent such as xylene, toluene; polar solvent such as water; and mixture thereof. Preferably the solvent used for crystallization of lifitegrast is acetonitrile and water.

In one another embodiment, the heating in step (b) is performed at a temperature in the range of 40-130oC, preferably at 60-90oC, and most preferably at 70-85oC.

In another embodiment, the pH in step (e) is adjusted by treating with a suitable acid selected from organic and inorganic acid, such as acid selected from, but not limited to, hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid and mixture thereof.

In another embodiment, the base used during purification of lifitegrast is an aqueous solution of inorganic base selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, and calcium hydroxide.

In a preferred embodiment, the present invention provides a process for the preparation of a solid form of lifitegrast of Formula I,

Formula I
wherein said process comprises the steps of:
(a) adding lifitegrast to a solvent system comprising one or more solvent wherein atleast one solvent is water;
(b) heating at a temperature in the range of 40-90oC;
(c) filtering and washing with organic solvent to get wet mass;
(d) adding the wet mass to water followed by addition of 10% caustic solution;
(e) adjusting the pH to 2.0 or less; and
(f) filtering and washing with water to get solid form of lifitegrast.

In another embodiment, the solvent used for crystallization of lifitegrast is selected from the group comprising of halogenated solvents such as dichloromethane (DCM), dichlorobenzene, dichloroethane, carbon tetrachloride; esters such as ethyl acetate (EtOAc), n-butyl acetate, isopropyl acetate, n-propyl acetate, propenyl acetate, pentyl acetate; ethers such as diethyl ether, tetrahydrofuran (THF), dioxane, methyl tetrahydrofuran (Me-THF), methyl ethyl ether; ketones such as methyl ethyl ketone, methyl t-butyl ketone, acetone; alcohols such as methanol, ethanol, n-propanol, t-butanol, glycols; nitriles such as acetonitrile, propionitrile; hydrocarbon solvent such as xylene, toluene; polar solvent such as water; and mixture thereof. Preferably the solvent used for crystallization of lifitegrast is acetonitrile and water.

Further, the washings in step (c) is performed by organic solvent selected from dichloromethane (DCM), dichlorobenzene, dichloroethane, ethyl acetate (EtOAc), n-butyl acetate, isopropyl acetate, n-propyl acetate, propenyl acetate, pentyl acetate, diethyl ether, tetrahydrofuran (THF), dioxane, methyl tetrahydrofuran (Me-THF), methyl ethyl ether, methyl ethyl ketone, acetonitrile, xylene, toluene, or mixture thereof. Preferably, the solvent used for washing in step (c) is acetonitrile.

In one another embodiment, the said solid form of lifitegrast of the present invention is prepared by suspending crude lifitegrast in a mixture of organic solvent and water wherein organic solvent is acetonitrile. The suspension was then heated to form a solution which is then stirred for few hours of 0.5 to 3 hrs, filtered and rinsed with acetonitrile to get a wet mass which is then suspended in water. The slurry is then treated with 10% caustic soda to get a solution. Stirred for few hours of 0.5 to 3 hrs, which is then allowed to precipitate by treatment with concentrated hydrochloric acid. Precipitates filtered, rinsed with water and finally dried under vaccum.

Accordingly, in a preferred embodiment, the present invention provides a process for the preparation of a solid form of lifitegrast characterized by X-Ray powder diffraction pattern (XRPD) having peak at about 31.68±0.2o2?, wherein said process comprises the steps of:
(a) adding crude lifitegrast to a mixture of acetonitrile and water;
(b) heating at a temperature in the range of 70-85oC;
(c) filtering and washing with acetonitrile to get a wet mass;
(d) adding the wet mass of step (c) to water followed by addition of 10% caustic solution;
(e) adjusting the pH to 1.5 or less; and
(f) filtering and washing with water to get solid form of lifitegrast.

In another embodiment, the lifitegrast can be prepared by any process known from the prior published references.

In one another embodiment, the solid form of lifitegrast prepared as per the process of the present invention is isolated with moisture content of 2.0% w/w, which is characterized by Thermal Gravimetric Analysis (TGA) as represented in Fig. 3.

Moreover, the solid form of lifitegrast of Formula I prepared as per the process of the present invention is characterized by purity of 95% and more by HPLC; preferably 99% and more by HPLC; and most preferably 99.9% and more by HPLC.

In further embodiment, the present invention further relates to a composition comprising solid form of lifitegrast of the present invention along with at least one pharmaceutically acceptable excipients thereof.

In one more embodiment, present invention provides use of solid form of lifitegrast of the present invention, as a LFA-1 inhibitor and for the treatment of dry eye disease.

In another embodiment, the solid form of lifitegrast of the present invention is characterized by particle size distribution wherein, d90 is 0.1µm to 200µm.

In a preferred embodiment, the solid form of lifitegrast of the present invention is characterized by particle size distribution wherein, d90 is 2.0 µm to 150µm.

The present invention is explained below by way of examples. However, the examples are provided as one of the possible way to practice the invention and should not be considered as limitation of the scope of the invention.

EXAMPLES:

EXAMPLE 1: Preparation of tert-butyl (R)-5,7-dichloro-6-((1-methoxy-3-(3-(methylsulfonyl)phenyl)-1-oxopropan-2-yl)carbamoyl)-3,4-dihydro isoquinoline-2(1H)-carboxylate
Charged 50.0 ml of DMF to 20.0 g of 2-(tert-butoxycarbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid followed by addition of 37.2 g (5.0 mole equivalent) of diisopropyl ethyl amine (DIPEA), 27.4 g (1.25 mole equivalent) of HATU and stirred for 30 min at room temperature. Added 17.6 g (1.05 mole equivalent) of methyl (S)-2-amino-3-(3-(methylsulfonyl)phenyl)propanoate hydrochloride and stirred for 1-2hrs at 100°C. After reaction completion cooled the reaction mass to 30-35°C and charged reaction mass in the mixture of ethylacetate (200ml) and water (200ml). Stirred for 15-30 min at 30-35°C and separated the ethylacetate layer, washed the organic layer with acidic water (200ml water + 18ml conc. HCl) followed by washing with water (200ml). Distilled and degassed the ethyl acetate layer under vacuum at 45-50°C to get 36.0 g of tert-butyl (R)-5,7-dichloro-6-((1-methoxy-3-(3-(methylsulfonyl)phenyl)-1-oxopropan-2-yl) carbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate.

EXAMPLE 2: Preparation of methyl (S)-2-(5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl) propanoate hydrochloride
Added 100 ml of dioxane and 100 ml of Dioxane. HCl to 36.0 g of tert-butyl (R)-5,7-dichloro-6-((1-methoxy-3-(3-(methylsulfonyl)phenyl)-1-oxopropan-2-yl) carbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate at 25-30°C and stirred for 4-10 hrs at 25-30°C. After reaction completion, charged 300 ml of MIBK (Methyl isobutyl ketone) at 25-30°C. Stirred for 3-4hr at 25-30°C and filtered the material and washed with 50 ml MIBK. The wet material so obtained is used as such in next step.

EXAMPLE 3: Preparation of (S)-2-(5,7-dichloro-1,2,3,4-tetrahydro isoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl) propanoic acid
Charged 80 ml of water to wet material obtained in Example 2 at 20-25°C and added 20 ml (12.7g NaOH in 20 ml water) of sodium hydroxide solution at 20-25°C. Stirred for 10-15 hrs at 20-25°C and after completion of reaction distilled out the reaction mass completely under vacuum at 38-42°C. Stripped out with 50 ml acetonitrile and added 100 ml of water and stirred till clear solution is obtained at 20-25°C. Charged 100 ml methylene dichloride (MDC) and stirred followed by layer separation. Washed the aqueous layer by 100 ml MDC. Adjusted the pH of aqueous layer to 3 to 5 by conc. HCl. Stirred the crystallized material for 2-3hr at 20-25°C, filtered the solid material and washed with water. Dried the solid material at 50°C under vacuum to get 16.0 g of (S)-2-(5,7-dichloro-1,2,3,4-tetrahydro isoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl) propanoic acid.

EXAMPLE 4: Preparation of (S)-2-(5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl) propanoic acid
Charged 100 ml of Dioxane and 40 ml conc. HCl to 36g of tert-butyl (R)-5,7-dichloro-6-((1-methoxy-3-(3-(methylsulfonyl)phenyl)-1-oxopropan-2-yl) carbamoyl)-3,4-dihydro isoquinoline-2(1H)-carboxylate at 25-30°C, and then stirred for 4-10 hrs at 25-30°C. After completion of reaction separated the aqueous layer and proceeded in situ to next step. Charged 100 ml (12.7g NaOH in 100 ml water) of sodium hydroxide solution to the aq. layer at 20-25°C, and stirred for 10-15 hrs at 20-25°C. After completion of reaction, added methyl isobutyl ketone (MIBK) (100 ml) and stirred and separated the layers followed by addition of MDC (100 ml). Separated the layers and added 2.0 g of carbon to the MDC layer. Filtered and washed the organic layer with 100 ml of water. Adjusted the pH of aqueous layer to 3 to 7 by conc. HCl. Stirred the material so obtained for 2-3hr at 20-25°C, filtered the solid material and washed with water. Dried the solid material at 50°C under vacuum to get 20 g of desired compound. HPLC Purity NLT 98%.

EXAMPLE 5: Preparation of crude lifitegrast
Method 1: Charged 35 ml of dichloromethane, 3.6 g (1.05 mole equivalent) of 2,3-dihydrobenzofuran-5-carboxylic acid and cooled the solution followed by addition of 3.44g (1.2 mole equivalent) of oxalyl chloride. Stirred for 5-8 hrs at 0-10°C under nitrogen and added the solution to the mixture of 10.0 g of (S)-2-(5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl) phenyl) propanoic acid and 50ml (NaOH 4.24g (5 mole equivalent) + water 50.0ml) of NaOH solution in 50 ml of dichloromethane at a temperature of -5 to 0°C. Stirred the reaction mass for 30-60 min. at -5 to 0°C. After completion of reaction added conc. HCl solution to adjust the pH to 1-2. Stirred for 10-15 minutes and separated the layers. Charged 50 ml of DM water to MDC layer, then stirred for 10-15 minutes and separated the layers. MDC layer seeded with pure lifitegrast and stirred for 30 min. Charged 50 ml of acetonitrile and stirred for 10-15 hr at 20-25°C. Filtered the solid material and washed with 20 ml of acetonitrile to get crude lifitegrast.

Method 2: Charged 35 ml of dichloromethane, 3.6 g (1.05 mole equivalent) of 2,3-dihydrobenzofuran-5-carboxylic acid and cooled the solution followed by addition of 3.44g (1.2 mole equivalent) of oxalyl chloride. Stirred for 5-8 hrs under nitrogen atmosphere and then distilled off the solvents and excess oxalyl chloride under vacuum to get a residue. Added dichloromethane to the residue and added the solution to the mixture of 10.0 g of (S)-2-(5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl) propanoic acid and 50ml (NaOH 4.24g (5 mole equivalent) + water 50.0ml) of sodium hydroxide solution in 50 ml of dichloromethane at a temperature of -5 to 0°C. Stirred the reaction mass for 30-60min. at -5 to 0°C. After completion of reaction added conc. HCl solution to adjust the pH to 1-2. Stirred for 10-15 minutes and separated the layers. Charged 50 ml of DM water in MDC layer, then stirred for 10-15 minutes and separate the layers. Distilled the MDC layer to get residue of crude lifitegrast.

EXAMPLE 6: Purification and recrystallization of lifitegrast
Charged 100 ml of acetonitrile, 4 ml of water to 10 g of crude lifitegrast. Heated to 80-85°C and stirred for 1hr followed by slow cooling to 20-25°C with stirring for 1-4hrs. Filtered the solid material and washed with 20 ml of acetonitrile. The Wet lifitegrast so obtained is added to 150 ml of water. Added 10% caustic solution and stirred for 1hr and then added the concentrated hydrochloric acid solution to adjust the pH ~1.0 at 20-25°C. Stirred for 1-4hrs at 20-25°C, filtered the solid material and washed with 20 ml of water. Dried at 40-50°C under vacuum for 4-8hrs to get pure solid form of lifitegrast.

WE CLAIM

1. A solid form of lifitegrast of Formula I characterized by X-Ray powder diffraction pattern having peak at about 31.68 ±0.2o2?,

Formula I .

2. The solid form of lifitegrast as claimed in claim 1, wherein said solid form is further characterized by Differential Scanning Calorimetry (DSC) plot comprising an endothermic peak at about 131.55oC,

Formula I .

3. A process for the preparation of a solid form of lifitegrast of Formula I,

Formula I
wherein said process comprises the steps of:
(a) adding lifitegrast to water followed by addition of suitable base;
(b) adjusting the pH to acidic; and
(c) filtering and washing with water to get solid form of lifitegrast.

4. The process as claimed in claim 3, wherein said pH is = 2.0.

5. The process as claimed in claim 3, wherein said base is aqueous solution of inorganic base selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, and calcium hydroxide.

6. A process for the preparation of solid form of lifitegrast as claimed in claim 1, comprising the steps of:
(a) adding lifitegrast to a solvent system comprising one or more solvent;
(b) heating to 40-130oC;
(c) filtering and washing with organic solvent to get wet mass;
(d) adding the wet mass to water followed by addition of suitable base;
(e) adjusting the pH to acidic; and
(f) filtering and washing with water to get solid form of lifitegrast.

7. The process as claimed in claim 6, wherein said solvent is selected from the group comprising of dichloromethane (DCM), dichlorobenzene, dichloroethane, carbon tetrachloride, ethyl acetate (EtOAc), n-butyl acetate, isopropyl acetate, n-propyl acetate, propenyl acetate, pentyl acetate, diethyl ether, tetrahydrofuran (THF), dioxane, methyl tetrahydrofuran (Me-THF), methyl ethyl ether, methyl ethyl ketone, methyl t-butyl ketone, acetone, methanol, ethanol, n-propanol, t-butanol, glycols, acetonitrile, propionitrile, xylene, toluene, water, or mixture thereof.

8. The process as claimed in claim 6, wherein said process comprising the steps of:
(a) adding lifitegrast to a solvent system comprising one or more solvent wherein atleast one solvent is water;
(b) heating at a temperature in the range of 40-90oC;
(c) filtering and washing with organic solvent to get wet mass;
(d) adding the wet mass to water followed by addition of 10% caustic solution;
(e) adjusting the pH to 2.0 or less; and
(f) filtering and washing with water to get solid form of lifitegrast.

9. The process as claimed in claim 8, wherein said organic solvent used in step (c) is selected from the group comprising of dichloromethane (DCM), dichlorobenzene, dichloroethane, ethyl acetate (EtOAc), n-butyl acetate, isopropyl acetate, n-propyl acetate, propenyl acetate, pentyl acetate, diethyl ether, tetrahydrofuran (THF), dioxane, methyl tetrahydrofuran (Me-THF), methyl ethyl ether, methyl ethyl ketone, acetonitrile, xylene, toluene, or mixture thereof.

10. The solid form of lifitegrast as claimed in claim 1, wherein said solid form is used in preparation of composition comprising lifitegrast along with atleast one pharmaceutically acceptable excipients.