DESC:Field of the invention
The present invention relates to novel solid state forms of 2-((5-bromo-4-(4­cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-yl)thio)acetic acid of formula (I) and its process for preparation thereof. The compound of formula (I) is represented by the following structural formula.

Formula (I)

Background of the invention
2-((5-Bromo-4-(4­cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-yl)thio)acetic acid is known as “Lesinurad” which is approved by USFDA as ZURAMPIC® on December 22, 2015 and it is available with dosage form of 200 mg tablet for oral administration. Further, Lesinurad is also approved in combination with Allopurinol which is xanthine oxidase inhibitor as DUZALLO® on August 18, 2017 with two dosage forms: 300 mg of Allopurinol and 200 mg of Lesinurad; 200 mg of Allopurinol and 200 mg of Lesinurad.
ZURAMPIC® is a URAT1 inhibitor indicated in combination with a xanthine oxidase inhibitor for the treatment of hyperuricemia associated with gout in patients who have not achieved target serum uric acid levels with a xanthine oxidase inhibitor alone.
US Patent 8003681 B2 discloses Lesinurad product and its methods for the preparation thereof.
US Patent 8524754 B2 discloses crystalline Form A, Form B, Form B', Form C, Form D Form E, Mesophase 1, Mesophase 2, Mesophase 3 and amorphous form of Lesinurad sodium salt and their methods for the preparation thereof.
US patent 8546436 B2 discloses amorphous, crystalline Form 1 and Form 2 of Lesinurad.
PCT Publication WO 2015/075561 A2 discloses crystalline Form III, Form IV, Form V and Form VI of Lesinurad and Form a, Form ß, Form ?, Form d of crystalline sodium salt and process for its preparation thereof.
Chinese patent application CN 104557748 A discloses Lesinurad Form-??and Form-? and its process for preparation thereof.
PCT Publication WO 2015/095703 discloses L-proline and glycolic acid co-crystals of Lesinurad.
PCT Publication WO 2016/203436 discloses amorphous and solid dispersion of Lesinurad and their preparation.
Indian patent application IN 201621039313 discloses methanol solvate of Lesinurad Form L1, L2, L3, ethanol solvate of Lesinurad Form L1, an amorphous form of Lesinurad and pharmaceutical compositions comprising any one of the Form L1, L2, L3 and L4 of Lesinurad or mixture thereof.
Indian patent application IN 201641039752 discloses Lesinurad crystalline Form S1, S2, S3, RB6, RB7, RB8, RB9, RB5, RB10, RB11, RB12 and Lesinurad and nicotinamide co-crystal, Urea cocrystal Form LU of Lesinurad and pure DMSO solvate of Lesinurad.
PCT Publication WO 2017/036884 A1 discloses crystalline Lesinurad free form / ethyl ester co-crystal and process for their preparation thereof.
PCT Publication WO 2018/085932 discloses Lesinurad Forms APO-I, a hemimethanolate, APO-II, a hemiethanolate, and APO-III, a co-crystal of Lesinurad and nicotinamide.
Polymorphism, the occurrence of different crystal forms, is a property of some molecules and molecular complexes. A single molecule, may give rise to a variety of crystalline forms having distinct crystal structures and physical properties like melting point, X-ray diffraction pattern, infrared absorption fingerprint, and solid state NMR spectrum, thermogravimetric analysis ('TGA'), and differential scanning calorimetry ('DSC') which have been used to distinguish polymorphic forms.
The difference in the physical properties of different crystalline forms results from the orientation and intermolecular interactions of adjacent molecules or complexes in the bulk solid. Accordingly, polymorphs are distinct solids sharing the same molecular formula yet having distinct advantageous physical properties compared to other crystalline forms of the same compound or complex.
The discovery of new solid state or crystalline or polymorphic forms of a pharmaceutical compound always provides a new opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for designing, for example, a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristic.
Hence, there is a significant need in the art to develop novel solid state forms or crystalline forms of Lesinurad which improves the performance characteristics of a pharmaceutical product.
Inventors of the present invention surprisingly found two novel crystalline forms of Lesinurad and novel co-crystal comprising Lesinurad and L-proline and also process for their preparation thereof.
Brief description of the invention
In first embodiment, the present invention provides novel crystalline form of Lesinurad (hereinafter designated as “Form-M5”).
In second embodiment, the present invention provides a process for preparation of Form-M5 of Lesinurad.
In third embodiment, the present invention provides novel crystalline of Lesinurad (hereinafter designated as “Form-M6”).
In fourth embodiment, the present invention provides a process for preparation of Form-M6 of Lesinurad.
In fifth embodiment, the present invention provides novel co-crystal of Lesinurad and L-proline characterized by differential scanning calorimetry (DSC) having endothermic transition at 161±3°C.
In sixth embodiment, the present invention provides a process for the preparation of co-crystal of Lesinurad and L-proline characterized by differential scanning calorimetry (DSC) having endothermic transition at 161±3°C.

Brief description of the drawings:

Figure 1: Illustrates characteristic Powdered X-Ray Diffraction (PXRD) pattern of Lesinurad crystalline Form-M5.
Figure 2: Illustrates characteristic PXRD pattern of Lesinurad crystalline Form-M6.
Figure 3: Illustrates characteristic differential scanning calorimetry (DSC) of co-crystal of Lesinurad and L-proline (1:2).
Figure 4: Illustrates characteristic PXRD pattern of co-crystal of Lesinurad and L-proline (1:2).

Detailed description of the invention
The term "suitable solvent" used in the present invention refers to "hydrocarbon solvents" such as n-hexane, n-heptane, cyclohexane, petroleum ether, benzene, toluene, xylene and the like; "ether solvents" such as dimethyl ether, diisopropyl ether, diethyl ether, methyl tert-butyl ether, 1 ,2-dimethbxy ethane, tetrahydrofuran, 1,4-dioxane and the like; "ester solvents" such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate and the like; "polar-aprotic solvents such as dimethylacetamide, dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone (NMP) and the like; "chloro solvents" such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride and the like; "ketone solvents" such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; "nitrile solvents" such as acetonitrile, propionitrile, isobutyronitrile and the like; "alcoholic solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol, 2-methylpropan-1-ol, 2-butanol, t-butanol and the like; "polar solvents" such as water or mixtures thereof.
As used herein, the term "anti-solvent" refers to a solvent which is used to precipitate the solid from a solution and the suitable anti-solvent used herein the present invention is selected from hydrocarbon solvents.
In first embodiment, the present invention provides crystalline Form-M5 of Lesinurad.
Crystalline Form-M5 of the present invention is characterized by its Powder X-Ray Diffraction (PXRD) pattern having peaks at about 6.0, 9.0, 12.4, 17.1, 17.4, 21.9 24.3 and 28.6 ± 0.2 degrees two-theta. Crystalline Form-M5 of the present invention further characterized by its X-Ray powder diffraction pattern having additional peaks at about 15.1, 15.9, 18.2, 23.1, 21.9, 25.1, 27.3 and 30.0 ± 0.2 degrees two-theta. The crystalline Form-M5 of Lesinurad is further characterized by the PXRD pattern as illustrated in figure-1.
In second embodiment, the present invention provides a process for the preparation of crystalline Form-M5 of Lesinurad, comprising:
a) dissolving Lesinurad in 2-butanol,
b) combining the mixture obtained in step-a) with anti-solvent,
c) isolating crystalline Form-M5 of Lesinurad.
wherein in step-a) the dissolving is carried out at a suitable temperature ranging between 25ºC to reflux temperature of 2-butanol; in step-b), the anti-solvent is selected from hydrocarbon solvents such as n-heptane, n-hexane, xylene, toluene and the like; in step-b) combining refers to addition of the mixture obtained in step-a) to anti-solvent or addition of an anti-solvent to the mixture obtained in step-a); in step-c), the term "isolating" refers to the removal of solvent by filtration or distillation or decantation from the mixture.
An aspect of the second embodiment provides a process for the preparation of crystalline Form-M5 of Lesinurad, comprising:
a) dissolving Lesinurad in 2-butanol;
b) adding the mixture obtained in step-a) to n-heptane;
c) isolating crystalline Form-M5 of Lesinurad.

In third embodiment, the present invention provides crystalline Form-M6 of Lesinurad.

Crystalline Form-M6 of the present invention is characterized by its Powder X-Ray Diffraction (PXRD) pattern having peaks at about 6.0, 8.9, 12.3, 17.2 and 20.7 ± 0.2 degrees two-theta. Crystalline Form-M6 of the present invention further characterized by its X-Ray powder diffraction pattern having additional peaks at about 15.0, 15.8, 17.7, 19.5, 24.3 and 28.1 ± 0.2 degrees two-theta. The crystalline Form-M6 of Lesinurad of formula (I) is further characterized by the PXRD pattern as illustrated in figure-2.
In fourth embodiment, the present invention provides a process for the preparation of crystalline Form-M6 of Lesinurad of formula (I), comprising:
a) dissolving Lesinurad in 2-methylpropan-1-ol,
b) combining mixture obtained in step-a) with an anti-solvent,
c) isolating crystalline Form-M6 of Lesinurad.
wherein in step-a) the dissolving is carried out at suitable temperature ranging between 25ºC to the reflux temperature of 2-methylpropan-1-ol; in step-b), an anti-solvent is selected from hydrocarbon solvents such as n-heptane, n-hexane and the like; in step-c), the term "isolating" refers to the removal of solvent by filtration or distillation or decantation from the reaction mixture.
In one aspect of fourth embodiment, the present invention provides a process for the preparation of crystalline Form-M6 of Lesinurad, comprising:
a) dissolving Lesinurad in 2-methylpropan-1-ol,
b) combining the mixture obtained in step-a) with n-heptane at 0-5°C,
c) optionally seeding with 10% Lesinurad Form-M4 to the mixture obtained in step-b),
d) isolating crystalline Form-M6 of Lesinurad.
In fifth embodiment, the present invention provides co-crystal of Lesinurad and L-proline (1:2) characterized by:
1) differential scanning calorimetry (DSC) having endothermic transition at 161°C,
2) powdered X-Ray Diffraction (PXRD) pattern as illustrated by figure-4.
In sixth embodiment, the present invention provides a process for the preparation of co-crystal of Lesinurad and L-proline (1:2), comprising:
a) providing a mixture of Lesinurad and L-proline in a solvent,
b) isolating co-crystal of Lesinurad and L-proline (1:2).
wherein in step-a) the solvent is selected from nitrile solvents such as acetonitrile, propionitrile, isobutyronitrile, hydrocarbon solvents such as n-hexane, n-heptane, cyclohexane, petroleum ether, benzene, toluene, xylene and the like; ether solvents such as dimethyl ether, diisopropyl ether, diethyl ether, methyl tert-butyl ether, 1,2-dimethbxy ethane, tetrahydrofuran, 1,4-dioxane and the like; ester solvents such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate and the like; polar-aprotic solvents such as dimethylacetamide, dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone (NMP) and the like; chloro solvents such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride and the like; ketone solvents such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; alcoholic solvents such as methanol, ethanol, n-propanol, isopropanol, n-butanol, 2-methylpropan-ol, 2-butanol, t-butanol and the like; polar solvents such as water or mixtures thereof; in step-a) the dissolving is carried out at temperature ranging between 30ºC to reflux temperature of the solvent used; in step-b), the term "isolating" refers to the removal of solvent by filtration or distillation or decantation from the reaction mixture.
In an aspect of sixth embodiment, the present invention provides a process for the preparation of co-crystal of Lesinurad and L-proline, comprising:
a) providing a mixture of Lesinurad and L-proline in acetonitrile at 45-50°C,
b) isolating co-crystal of Lesinurad and L-proline.
It should be kept in mind that slight variations in observed two-theta angle values are expected based on the specific diffractometer employed the analyst and the sample preparation technique. More variation is expected for the relative peak intensities. Identification of the exact crystalline form of a compound should be based primarily on observed two-theta angles with lesser importance attributed to relative peak intensities. The peaks reported herein are listed in order of their peak intensities. Thus, the first listed peak has stronger intensity than the second listed peak in the pattern. Two-theta diffraction angles and corresponding d-spacing values account for positions of various peaks in the X-ray powder diffraction pattern. D-spacing values are calculated with observed two theta angles and copper K(?1) wavelength using the Bragg’s equation known to those of skill in the art.
The starting material “Lesinurad” was prepared by a process described in our pending patent application 201841020700 filed on June 01, 2018 or it can be prepared by the methods known in the art. The seed material Lesinurad crystalline Form-M4 was described in our pending patent application 201741017442 filed on May 18, 2017.
PXRD analysis of the crystalline forms and co-crystal of the present invention were carried out using BRUKER/AXS X-Ray diffractometer using Cu-Ka radiation of wavelength 1.5406 A° and at continuous scan speed of 0.03°/min.
The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention:
Examples
Example 1: Preparation of crystalline Form-M5 of Lesinurad.
Lesinurad (2 gm) was dissolved in 2-butanol (60 ml) at 45-50ºC. The obtained mixture was added to pre-cooled n-heptane (120 ml) at 0-5°C and stirred for about 1 hour. Filtered the precipitated solid and then dried to afford the title compound. (Yield: 1.4 gm).

The obtained Form-M5 is characterized by the PXRD pattern as illustrated in figure-1.

Example 2: Preparation of crystalline Form-M6 of Lesinurad.
Lesinurad (5 gm) was dissolved in 2-methylpropan-ol (150 ml) at 45-50°C. The obtained mixture was added to pre-cooled n-heptane (300 ml) at 0-5°C which is mixed with seeds of 10% Lesinurad crystalline Form-M4 and stirred for 2 hours at 0-5°C. Filtered the precipitated solid and then dried to afford the title compound. (Yield: 4.0 gm).

The obtained Form-M6 is characterized by PXRD pattern as illustrated in figure-2.

Example 3: Preparation of co-crystal of Lesinurad and L-proline (1:2).
Lesinurad (10 gm) and L-proline (2.84 gm) were added to acetonitrile (200 ml) at 25-30°C. Raised the temperature of the mixture to 45-50°C and stirred for about 30 min at same temperature. Cooled the mixture to 25-30ºC and stirred for 25 min at same temperature. Filtered the obtained solid and then dried under reduced pressure to provide the title compound. (Yield: 6.5 gm).
The obtained co-crystal was characterized by diffraction scanning calorimetry (DSC) having endotherm transition at 161°C and same diffractogram was illustrated in figure-3.
The obtained co-crystal was also characterized by PXRD pattern as illustrated in figure-4.
,CLAIMS:We Claim:

1. A crystalline form of Lesinurad, wherein the crystalline form is:
i) Crystalline Form-M5 of Lesinurad characterized by:
a) powdered X-Ray Diffraction (PXRD) pattern having peaks at about 6.0, 9.0, 12.4, 17.1, 17.4, 21.9 24.3 and 28.6 ± 0.2 degrees two-theta,
b) powdered X-Ray powder diffraction pattern as illustrated in figure-1 (or)
ii) Crystalline Form-M6 of Lesinurad characterized by:
a) powdered X-Ray Diffraction (PXRD) pattern having peaks at about 6.0, 8.9, 12.3, 17.2 and 20.7 ± 0.2 degrees two-theta,
b) powdered X-Ray powder diffraction pattern as illustrated in figure-2.

2. A process for the preparation of crystalline Form-M5 of Lesinurad, comprising:
a) dissolving Lesinurad in 2-butanol,
b) combining the mixture obtained in step-a) with an anti-solvent,
c) isolating crystalline Form-M5 of Lesinurad

wherein in step-a) dissolving is carried out at a suitable temperature ranging between 25ºC to reflux temperature of 2-butanol; in step-b), the anti-solvent is selected from hydrocarbon solvents such as n-heptane, n-hexane, xylene, toluene and the like; in step-b) combining refers to addition of the mixture obtained in step-a) to anti-solvent or addition of an anti-solvent to the mixture obtained in step-a); in step-c), the term "isolating" refers to the removal of solvent by filtration or distillation or decantation from the mixture.

3. A process for the preparation of crystalline Form-M5 of Lesinurad, comprising:
a) dissolving Lesinurad in 2-butanol;
b) adding the mixture obtained in step-a) to n-heptane;
c) isolating crystalline Form-M5 of Lesinurad.

4. A process for the preparation of crystalline Form-M6 of Lesinurad, comprising:
a) dissolving Lesinurad in 2-methylpropan-1-ol,
b) combining mixture obtained in step-a) with an anti-solvent,
c) isolating crystalline Form-M6 of Lesinurad

wherein in step-a) dissolving is carried out at a suitable temperature ranging between 25ºC to the reflux temperature of 2-methylpropan-1-ol; in step-b), the anti-solvent is selected from hydrocarbon solvents such as n-heptane, n-hexane and the like; in step-c), the term "isolating" refers to the removal of solvent by filtration or distillation or decantation from the reaction mixture.

5. A process for the preparation of crystalline Form-M6 of Lesinurad, comprising:
a) dissolving Lesinurad in 2-methylpropan-1-ol,
b) combining the mixture obtained in step-a) with n-heptane at 0-5°C,
c) optionally seeding with 10% Lesinurad Form-M4 to the mixture obtained in step-b),
d) isolating crystalline Form-M6 of Lesinurad.

6. Lesinurad co-crystal with L-proline (1:2) characterized by differential scanning calorimetry (DSC) having endothermic transition at 161°C.

7. Lesinurad co-crystal with L-proline according to claim 6, is characterized by powdered X-Ray Diffraction (PXRD) pattern as illustrated by figure-4.

8. A process for the preparation of co-crystal of Lesinurad and L-proline (1:2), comprising:
a) providing a mixture of Lesinurad and L-proline in solvent,
b) isolating co-crystal of Lesinurad and L-proline (1:2)

wherein in step-a) the solvent is selected from nitrile solvents such as acetonitrile, propionitrile, isobutyronitrile, hydrocarbon solvents such as n-hexane, n-heptane, cyclohexane, petroleum ether, benzene, toluene, xylene and the like; ether solvents such as dimethyl ether, diisopropyl ether, diethyl ether, methyl tert-butyl ether, 1,2-dimethbxy ethane, tetrahydrofuran, 1,4-dioxane and the like; ester solvents such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate and the like; polar-aprotic solvents such as dimethylacetamide, dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone (NMP) and the like; chloro solvents such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride and the like; ketone solvents such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; alcoholic solvents such as methanol, ethanol, n-propanol, isopropanol, n-butanol, 2-methylpropan-ol, 2-butanol, t-butanol and the like; polar solvents such as water or mixtures thereof; in step-b), the term "isolating" refers to the removal of solvent by filtration or distillation or decantation from the reaction mixture.

9. A process for the preparation of co-crystal of Lesinurad and L-proline, comprising:
a) providing a mixture of Lesinurad and L-proline in acetonitrile at 45-50°C,
b) isolating co-crystal of Lesinurad and L-proline.