FIELD OF THE INVENTION
The present invention relates to crystalline solvates of lifitegrast. The present invention further provide processes for preparation of various solvates of lifitegrast.

Moreover, the present invention relates to a composition comprising a crystalline solvate of lifitegrast along with at least one pharmaceutical acceptable excipients 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 and is represented as Formula I.

Formula-I

Lifitegrast, known by the trade name Xiidra, is a drug for the treatment of keratoconjunctivitis sicca (dry eye syndrome) and is generically disclosed in US 7,314,938. Further, US 8,080,562 discloses various crystalline polymorphic forms such as Forms A, B, C, D, and E of Lifitegrast. US 9,085,553 discloses process of preparation and purification of Lifitegrast and polymorphs thereof. This patent further provides process for the preparation of Form II of lifitergrast.

Although there are certain known polymorphic forms of Lifitegrast in the prior publications, however the development of new solvates and polymorphic forms of a pharmaceutically useful compound provides a new opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the range of materials that a formulation scientist can use for designing pharmaceutical formulation having desired characteristics.

The crystalline solvates of the present invention have advantages in the preparation of pharmaceutical compositions of the lifitegrast, such as ease of processing, handling, and dosing. In particular, they exhibit improved physicochemical properties, such as solubility, stability to stress, and rate of dissolution, rendering them particularly suitable for the manufacture of various pharmaceutical dosage forms.

OBJECT OF THE INVENTION
The main object of the present invention is to provide various solvates of lifitegrast and polymorph thereof.

Another object of the present invention is to provide crystalline solvates of lifitegrast and process of preparation thereof.

One another object of the present invention is to provide a composition comprising crystalline solvate(s) of lifitegrast or its pharmaceutical acceptable salts along with atleast one pharmaceutical acceptable excipients.

SUMMARY OF THE INVENTION
The present invention encompasses crystalline solvates of lifitegrast. In particular, the present invention provides crystalline ethanol solvate of lifitegrast described and characterized herein as Form I.

Accordingly, in the main aspect, the present invention provides a crystalline ethanol solvate of lifitegrast represented as Form-I wherein said Form-I is characterized by X-ray powder diffraction pattern having peaks at a reflection angle 2? of about 10.55, 14.95, 15.94, 19.61, 22.34, 24.19, 25.34, 28.70±0.2°?.

In another aspect, the present invention provides a process for preparation of crystalline solvate of lifitegrast, wherein said process comprising the steps of:
a) preparing a slurry of lifitegrast in solvent(s); and
b) stirring followed by filtration to get crystalline lifitegrast solvate.

In another aspect, the present invention provides a process for preparation of crystalline ethanol solvate of lifitegrast wherein said process comprising the steps of:
a) preparing a slurry of lifitegrast in ethanol;
b) stirring for 1-8h; and
c) filtering to get crystalline ethanol solvate of lifitegrast.

DETAILED DESCRIPTION
Description of Drawings:
The invention is illustrated by reference to the accompanying drawings described below:
Fig. 1 shows a graphical representation of the XRPD pattern of crystalline Form-I of the ethanol solvate of lifitegrast for three batches.
Fig. 2 shows a graphical representation of the DSC pattern of crystalline Form I of the ethanol solvate of lifitegrast for three batches.
Fig. 3 shows a graphical representation of the TGA pattern of crystalline Form I of the ethanol solvate of lifitegrast for three batches.
Fig. 4 shows a graphical representation of the 1HNMR of crystalline Form I of the ethanol solvate of lifitegrast.

Definitions:
The names used herein to characterize a specific form, e.g. “Form-I”, should not be considered limiting with respect to any other substance possessing similar or identical physical and chemical characteristics, but rather it should be understood that these designations are mere identifiers that should be interpreted according to the characterization information presented in the present invention.

As used herein, “solvate” means a physical association of a compound with one or more solvent molecules, whether organic or inorganic. The solvate may comprise either a stoichiometric or nonstoichiometric amount of the solvent molecules. “Solvate” encompasses both solution-phase and isolable solvates.

As used herein, “substantially pure,” when used in reference to a crystalline form, means a compound having a purity greater than 90 weight %, including greater than 90, 91, 92, 93, 94, 95, 96, 97, 98 and 99 weight %, and also including equal to and greater than about 99.99 weight % of the compound, based on the weight of the compound. The remaining material comprises other form(s) of the compound, and/or reaction impurities and/or processing impurities arising from its preparation.

The crystalline forms may be prepared by a variety of methods, including methods other than the methods disclosed in the present invention, for example, crystallization or recrystallization from a suitable solvent, sublimation, growth from a melt, solid state transformation from another phase, crystallization from a supercritical fluid, and jet spraying. Techniques for crystallization or recrystallization of crystalline forms from a solvent mixture includes, for example, evaporation of the solvent, decreasing the temperature of the solvent mixture, crystal seeding a supersaturated solvent mixture of the molecule and/or salt, freeze drying the solvent mixture, and addition of antisolvents (counter solvents) to the solvent mixture.

The term “slurry,” as used herein, means a saturated solution of the compound, which may contain an additional amount of the compound to afford a heterogeneous mixture of the compound and a solvent at a given temperature.

In main embodiment, the present invention provides a crystalline ethanol solvate of lifitegrast represented as Form I wherein said Form-I is characterized by X-ray powder diffraction pattern having peaks at a reflection angle 2? of about 10.55, 14.95, 15.94, 19.61, 22.34, 24.19, 25.34, 28.70±0.2°?.

The present invention provides a crystalline ethanol solvate of lifitegrast represented as crystalline Form I, which can be identified by one or more analytical methods. The X-ray powder diffraction pattern of Form I is provided in Fig. 1.

In another embodiment, the crystalline ethanol solvate of lifitegrast (Form I) characterized by X-ray powder diffraction pattern having characteristic peaks at a reflection angle 2? of about 7.85, 8.97, 9.74, 10.55, 12.28, 12.87, 14.07, 14.95, 15.15, 15.94, 17.18, 18.90, 19.61, 20.86, 21.77, 22.34, 23.09, 24.19, 25.34, 25.92, 27.06, 28.70, 29.46, 30.83, 31.09, 32.31, 33.38, 33.62, 34.88, 36.01, 36.35, 37.93, 38.15, 38.78, 40.21, 43.66, 44.50, 45.43, 45.68, 46.01±0.2°?.

In another embodiment, the crystalline ethanol solvate of lifitegrast (Form I) is characterized with peak endotherm at about 153.10°C and with peak onset at about 142.26°C.

In other embodiment, the crystalline ethanol solvate of lifitegrast (Form I) is produced by isolating from a slurry of the lifitegrast in ethanol.

In another embodiment, the present invention provides a crystalline solvates of lifitegrast wherein said solvates are prepared by crystallization from suitable solvent(s) selected from polar aprotic solvents, polar protic solvents, non-polar solvents, water and mixture thereof.

Suitable polar aprotic solvents include, but not limited to, dichloromethane (CH2Cl2 or DCM), chloroform, tetrahydrofuran (THF), methyl-tetrahydrofuran, acetone, methyl ethyl ketone (MEK), methyl isobutyl ketone (MIBK), butanone, dimethylformamide (DMF), dimethylacetamide (DMAc), 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU), 1,3-dimethyl-2-imidazolidinone (DMI), N-methylpyrrolidinone (NMP), formamide, N-methylacetamide, N-methylformamide, acetonitrile (ACN or MeCN), dimethylsulfoxide (DMSO), propionitrile, ethyl formate, methyl acetate (MeOAc), ethyl acetate (EtOAc), isopropyl acetate (IpOAc), butyl acetate (BuOAc), t-butyl acetate, hexachloroacetone, dioxane, sulfolane, N,N-dimethylpropionamide, nitromethane, nitrobenzene and hexamethylphosphoramide.

Suitable polar protic solvents include, but not limited to, alcohols and glycols, methanol, ethanol, 1-propanol, 2-propanol, isopropanol (IPA), 1-butanol (1-BuOH), 2-butanol (2-BuOH), i-butyl alcohol, t-butyl alcohol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 2-methoxyethanol, 2-ethoxyethanol, diethylene glycol, propylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, glycerol and methyl t-butyl ether (MTBE).

Suitable non-polar solvents include, but not limited to, ethyl acetate, isopropyl acetate, isopropene acetate, butyl acetate, t-butyl acetate, cyclohexanone, heptane, hexane and the like.

Preferably, the suitable solvents are selected from ethanol, cyclohexanone, propylene glycol, butanone, chloroform, ethyl acetate and mixture thereof.

In another embodiment, the present invention provides a crystalline cyclohexanone solvate of lifitegrast characterized by X-ray powder diffraction pattern having peaks at a reflection angle 2? of about 12.84, 18.81, 19.33, 19.67, 21.35, 25.21, 25.54, 26.74, 29.59, 30.94, 33.30, 35.32, 35.58, 37.09, 38.24, 39.62, 39.98, 40.62, 40.69, 41.90, 42.36, 46.97, 48.35±0.2°?.

In another embodiment, the crystalline cyclohexanone solvate of lifitegrast undergoes a predominant endotherm at about 140.60°C with onset peak as about 130.16°C

In another embodiment, the present invention provides a process for preparation of crystalline solvate of lifitegrast, wherein said process comprising the steps of:
a) preparing a slurry of lifitegrast in solvent(s); and
b) stirring followed by filtration to get crystalline lifitegrast solvate.

In another embodiment, the solvent used for preparing slurry of lifitegrast is selected from polar aprotic solvents, polar protic solvents, non-polar solvents, water and mixture thereof.

In preferred embodiment, the polar aprotic solvents include, but not limited to, dichloromethane (CH2Cl2 or DCM), chloroform, tetrahydrofuran (THF), methyl-tetrahydrofuran, acetone, methyl ethyl ketone (MEK), methyl isobutyl ketone (MIBK), butanone, dimethylformamide (DMF), dimethylacetamide (DMAC), 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU), 1,3-dimethyl-2-imidazolidinone (DMI), N-methylpyrrolidinone (NMP), formamide, N-methylacetamide, N-methylformamide, acetonitrile (ACN or MeCN), dimethylsulfoxide (DMSO), propionitrile, ethyl formate, methyl acetate (MeOAc), ethyl acetate (EtOAc), isopropyl acetate (IpOAc), butyl acetate (BuOAc), t-butyl acetate, hexachloroacetone, dioxane, sulfolane, N,N-dimethylpropionamide, nitromethane, nitrobenzene and hexamethylphosphoramide. The polar protic solvents include, but not limited to, alcohols and glycols, methanol, ethanol, 1-propanol, 2-propanol, isopropanol (IPA), 1-butanol (1-BuOH), 2-butanol (2-BuOH), i-butyl alcohol, t-butyl alcohol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 2-methoxyethanol, 2-ethoxyethanol, diethylene glycol, propylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, glycerol and methyl t-butyl ether (MTBE). The non-polar solvents include, but not limited to, ethyl acetate, isopropyl acetate, isopropene acetate, butyl acetate, t-butyl acetate, cyclohexanone, heptane, hexane and the like.

In another embodiment, the lifitegrast can be prepared by any method known in the prior published references or can be procured from any commercial resource.

In another embodiment, the present invention provides a process for preparation of crystalline ethanol solvate of lifitegrast, wherein said process comprising the steps of:
a) preparing a slurry of lifitegrast in ethanol;
b) stirring for 1-8h; and
c) filtering the crystalline ethanol solvate of lifitegrast.

In another embodiment, the lifitegrast can be prepared by any method known in the prior published references or can be procured from any commercial resource.

In another embodiment, the lifitegrast free acid or its pharmaceutical acceptable salts can be used for preparing various crystalline solvates.

In one another embodiment, the process of preparing crystalline ethanol solvate of lifitegrast further includes a process of drying of the crystalline polymorph of ethanol solvate of lifitegrast wherein said process of drying can be performed by any known methods including heating, heating under vacuum, under vacuum at room temperature, freeze drying, lyophilisation, spray drying, centrifugation and the like.

In another embodiment, the invention, provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a crystalline solvate of lifitegrast, or its pharmaceutically acceptable salts.

In another embodiments, the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients.

In one another embodiment, the pharmaceutical composition comprising a pharmaceutically acceptable carrier and a crystalline solvate of lifitegrast, or its pharmaceutically acceptable salts, which may further comprise at least one additional therapeutic agent.

Preferably, the solvates such as ethanolates of lifitegrast can be used as pharmaceutical active agents in a pharmaceutical composition with at least one pharmaceutically acceptable excipient.

In further embodiment, the present invention provides crystalline solvates of lifitegrast with solvent content in between 2-15%w/w.

In further embodiment, the present invention provides crystalline ethanol solvate of lifitegrast with ethanol content in between 2-15%w/w.

In further embodiment, the present invention provides a substantially pure crystalline solvate of lifitegrast having purity greater than about 99.0%.

In a preferred embodiment, the present invention provides a substantially pure crystalline solvate of lifitegrast having purity greater than about 99.9%.

In another preferred embodiment, the present invention provides a substantially pure crystalline solvate of lifitegrast having purity greater than about 99.9% with each impurity less than about 0.05% w/w.

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

In a preferred embodiment, the present invention provides crystalline solvate of lifitegrast 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 crystalline ethanol solvate of lifitegrast
To 500 mg of lifitegrast was added 10 ml of ethanol and kept slurry crystallization on magnetic stirrer for 4 hours. The slurry was then filtered and dried over night at room temperature. The resulting solvate was then examined by PXRD, DSC, 1HNMR and TGA.

EXAMPLE 2: Preparation of crystalline ethyl acetate solvate of lifitegrast
To 500 mg of lifitegrast was added 10 ml of ethyl acetate and kept slurry crystallization on magnetic stirrer for 3 hours. The slurry was filtered and dried over night at RT to get crsystalline ethyl acetate solvate of lifitegrast.

EXAMPLE 3: Preparation of crystalline chloroform solvate of lifitegrast
To 300 mg of lifitegrast was added 10 ml of CHCl3 and kept slurry crystallization on magnetic stirrer for 3 hours. The slurry was filtered and dried over night at RT to get desired crystalline chloroform solvate of lifitegrast.

EXAMPLE 4: Preparation of crystalline propylene glycol solvate of lifitegrast
To 300 mg of lifitegrast was added 10 ml of propylene glycol and kept slurry crystallization on magnetic stirrer for 3 hours. The slurry was filtered and dried overnight at RT.

EXAMPLE 5: Preparation of crystalline cyclohexane solvate of lifitegrast
Dissolved 500 mg of lifitegrast in 5 ml of cyclohexanone and distilled the solvent by rotavapour technique using vacuum, with solvent not evaporated completely. The resulting residue was refrigerated overnight at 3ºC the resultant crystals so obtained were washed with ethyl acetate. Added 5 ml of ethyl acetate distilled to dryness to get cyclohexane solvate of lifitegrast.

EXAMPLE 6: Preparation of crystalline 2-butanone solvate of lifitegrast
To 400 mg of lifitegrast was added 10 ml of 2-butanone (or, methyl ethyl ketone) and kept slurry crystallization on magnetic stirrer for 24 hours. The slurry was then filtered and dried over night at RT.

EXAMPLE 7: Preparation of crystalline cyclohexane: ethylacetate solvate of lifitegrast
To 450 mg of lifitegrast was added mixture of 1ml of cyclohexanone and 2ml of ethyl acetate and kept slurry crystallization on magnetic stirrer for 24 hours. The slurry was filtered and dried over night at room temperature.

We Claim:

1. A crystalline ethanol solvate of lifitegrast characterized by X-ray powder diffraction pattern having peaks at a reflection angle 2? of about 10.55, 14.95, 15.94, 19.61, 22.34, 24.19, 25.34, 28.70±0.2°? and is represented as Form-1.

2. The crystalline ethanol solvate of lifitegrast as claimed in claim 1, wherein said solvate is characterized by peak endotherm at about 153.10°C and with peak onset at about 142.26°C.

3. A process for the preparation of crystalline solvate of lifitegrast, wherein said process comprising the steps of:
a) preparing a slurry of lifitegrast in solvent(s); and
b) stirring followed by filtration to get crystalline lifitegrast solvate.

4. The process as claimed in claim 3, wherein said solvent is selected from the group comprising of dichloromethane (CH2Cl2 or DCM), chloroform, tetrahydrofuran (THF), methyl-tetrahydrofuran, acetone, methyl ethyl ketone (MEK), methyl isobutyl ketone (MIBK), butanone, dimethylformamide (DMF), dimethylacetamide (DMAc), 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU), 1,3-dimethyl-2-imidazolidinone (DMI), N-methylpyrrolidinone (NMP), formamide, N-methylacetamide, N-methylformamide, acetonitrile (ACN or MeCN), dimethylsulfoxide (DMSO), propionitrile, ethyl formate, methyl acetate (MeOAc), ethyl acetate (EtOAc), isopropyl acetate (IpOAc), butyl acetate (BuOAc), t-butyl acetate, hexachloroacetone, dioxane, sulfolane, N,N-dimethylpropionamide, nitromethane, nitrobenzene, cyclohexanone, heptane, hexane, hexamethylphosphoramide, methanol, ethanol, 1-propanol, 2-propanol, isopropanol (IPA), 1-butanol (1-BuOH), 2-butanol (2-BuOH), i-butyl alcohol, t-butyl alcohol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 2-methoxyethanol, 2-ethoxyethanol, diethylene glycol, propylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, glycerol, methyl t-butyl ether (MTBE), water, and mixture thereof.

5. A process for preparation of crystalline ethanol solvate of lifitegrast, wherein said process comprising the steps of:
a) preparing a slurry of lifitegrast in ethanol;
b) stirring for 1-8h; and
c) filtering the crystalline ethanol solvate of lifitegrast.

6. The process as claimed in in claim 3 and 5, wherein said process further includes drying of crystalline solvate of lifitegrast.

7. The process as claimed in claim 6, wherein said drying is carried out by a technique selected from heating, heating under vacuum, under vacuum at room temperature, freeze drying, lyophilisation, spray drying, and centrifugation.

8. A pharmaceutical composition comprising one or more pharmaceutically acceptable excipient (s) and the crystalline ethanol solvate of lifitegrast as claimed in claim 1.

9. The crystalline ethanol solvate of lifitegrast as claimed in claim 1, wherein said solvate have ethanol content in between 2-15%w/w.

10. The crystalline solvate of lifitegrast prepared by the process as claimed in claim 3 comprises of ethyl acetate solvate, chloroform solvate, propylene glycol solvate, cyclohexane solvate, 2-butanone solvate, mixture of cyclohexane and ethyl acetate solvate, ethanol solvate, and methanol solvate of lifitegrast.