DESC:POLYMORPHS AND CO-CRYSTALS OF LESINURAD
FIELD OF THE INVENTION
The present invention provides crystalline forms, solvates and co-crystals of Lesinurad, process for their preparation and pharmaceutical compositions thereof.
BACKGROUND OF THE INVENTION
Lesinurad is a selective uric acid re-absorption inhibitor (SURI). Lesinurad or its salt is used for reducing serum uric acid level and for the treatment of gout and hyperurecemia. Lesinurad is chemically known as 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetic acid and has following structural formula (I):

I
US8546436B2 discloses crystalline Forms 1 and 2 of Lesinurad and their processes for preparation. Similarly, US8524754B2 discloses crystalline forms A, B, B’, C, D and E of Lesinurad sodium and their processes for preparation.
WO2015075561A1 assigned to Crystal Pharmatech Co Ltd & Suzhou pengxu Pharmatech co. ltd., discloses crystalline forms III, IV, V, and VI of Lesinurad and their process for preparation.
CN104557748 A assigned to Guangdong East Sunshine Pharmaceutical Co., Ltd., discloses crystalline forms a, ß of Lesinurad and their process for preparation.
WO2015095703 A1 assigned to Crystal Pharmatech Co Ltd & Suzhou pengxu Pharmatech co. ltd., discloses co-crystal of Lesinurad and proline, cocrystal of Lesinurad and glycolic acid.
WO2017036884 A1 assigned to Sandoz, discloses a co-crystal of Lesinurad and Lesinurad ethyl ester and its process.
In general, polymorphism refers to the ability of a substance to exist as two or more crystalline phases that have different spatial arrangements and/or conformations of molecules in their crystal lattices. Thus, “polymorphs” refer to different crystalline forms of the same pure substance in which the molecules have different spatial arrangements of the molecules, atoms, and/or ions forming the crystal. Different polymorphs may have different physical properties such as melting points, solubilities, powder properties, etc. The variation in solid forms may appreciably influence the pharmaceutical properties, such as bioavailability, handling properties, dissolution rate, and stability, and in turn such properties can significantly influence the processing, shelf life, and commercial acceptance of a polymorphic form. For these reasons, regulatory authorities require drug manufacturing companies to put efforts into identifying all polymorphic forms, e.g., crystalline, amorphous, solvates, stable dispersions with a pharmaceutically acceptable carriers, etc., of new drug substances.
The existence and possible numbers of polymorphic forms for a given compound cannot be predicted, and there are no “standard” procedures that can be used to prepare polymorphic forms of a substance. This is well-known in the art, as reported, for example, by A. Goho, “Tricky Business,” Science News, Vol. 166(8), August 2004.
Hence, there remains a need for alternate solid forms, particularly, need for alternate crystalline forms of Lesinurad, which are stable, reproducible and can be prepared through an industrially viable process.
SUMMARY OF THE INVENTION
In a first embodiment of the present invention provides a crystalline Form S1 of Lesinurad, characterized by a PXRD comprising the peaks at about 8.24, 15.73, 16.46, 17.67, 28.92 and 39.29 ± 0.2° 2?.
In a second embodiment of the present invention provides a process for the preparation of crystalline form S1 of Lesinurad, comprising:
a) providing a solution or suspension of Lesinurad in a solvent comprising methanol;
b) optionally, heating the solution or suspension obtained in step a);
c) isolating the crystalline Form S1 of Lesinurad.
In a third embodiment of the present invention provides a crystalline Form S2 of Lesinurad, characterized by a PXRD comprising the peaks at about 17.90, 29.15, 33.27, 34.61 and 39.10 ± 0.2° 2?.
In a fourth embodiment of the present invention provides a process for the preparation of crystalline Form S2 of Lesinurad, comprising the step of drying crystalline Form S1 of Lesinurad.
In a fifth embodiment of the present invention provides a crystalline Form S3 of Lesinurad, characterized by a PXRD comprising the peaks at about 15.48, 21.28, 23.27, 23.60 and 38.68 ± 0.2° 2?.
In a sixth embodiment, the present invention provides a process for the preparation of crystalline Form S3 of Lesinurad, comprising the step of exposing crystalline Form S1 of Lesinurad to open atmosphere at 25-28°C.
In a seventh embodiment of the present invention provides a crystalline Form RB6 of Lesinurad, characterized by a PXRD comprising the peaks at about 8.79, 14.34, 14.53, 14.90, 15.10, 15.64, 17.61, 28.88 and 32.81 ± 0.2° 2? and also having additional peaks at about 8.18,18.38, 19.76, 20.36, 21.96, 22.71 and 23.41 ± 0.2° 2?.
In an eighth embodiment of the present invention provides a process for the preparation of crystalline Form RB6 of Lesinurad, comprising:
a) providing a solution or suspension of Lesinurad in a solvent comprising ethanol;
b) optionally, heating the solution or suspension obtained in step a);
c) isolating the crystalline Form RB6 of Lesinurad.
In a ninth embodiment of the present invention provides a crystalline Form RB7 of Lesinurad, characterized by a PXRD comprising the peaks at about 11.56, 14.27, 17.04, 21.14, 22.11, 24.34, 26.90 and 32.29 ± 0.2° 2?. In an embodiment, the invention provides crystalline Form RB7 of Lesinurad, characterized by a PXRD having additional peaks at about 7.78, 9.73, 13.90, 15.93, 18.34, 20.02, 20.21, 20.85, 22.73 and 23.22 ± 0.2° 2?.
In a tenth embodiment of the present invention provides a process for the preparation of crystalline Form RB7 of Lesinurad comprising recrystallization from methanol.
In a eleventh embodiment of the present invention provides a crystalline DMSO solvate Form RB8 of Lesinurad, characterized by a PXRD comprising the peaks at about 7.40, 12.15, 15.58, 16.73 and 23.43 ± 0.2° 2?. In an embodiment, the invention provides crystalline Form RB8 of Lesinurad, characterized by a PXRD having additional peaks at about 15.25, 18.57, 20.26, 21.70, 22.22, 22.49, 25.04, 25.47 and 28.54 ± 0.2° 2?.
In a twelfth embodiment of the present invention provides a process for the preparation of crystalline DMSO solvate Form RB8 of Lesinurad comprising:
a) slurrying Lesinurad in methyl tertiary butyl ether;
b) optionally, heating the solution of step a);
c) adding dimethyl sulfoxide to the solution of Lesinurad; or adding solution of Lesinurad to dimethyl sulfoxide;
d) isolating the solid of crystalline Form RB8 of Lesinurad;
e) optionally, drying the product at suitable temperature.
In a thirteenth embodiment of the present invention provides a crystalline Form RB9 of Lesinurad, characterized by a PXRD substantially as shown in figure 7.
In a fourteenth embodiment of the present invention provides a process for the preparation of crystalline Form RB9 of Lesinurad comprising humidification of crystalline Form RB5 of Lesinurad at 40°C and relative humidity of 75%.
In a fifteenth embodiment of the present invention provides nicotinamide co-crystal of Lesinurad, designated as Form LN characterized by X-ray powder diffraction pattern having peaks at about 6.33, 13.32, 14.22, 15.42 and 29.08± 0.2° 2?. In an embodiment, the invention provides co-crystal Form LN of Lesinurad, characterized by a PXRD having additional peaks at about 7.69, 10.41, 20.04, 21.20, 25.64, 25.91 and 26.68 ± 0.2° 2?.
In a sixteenth embodiment of the present invention provides a process for the preparation of nicotinamide co-crystal of Lesinurad (Form LN), which comprises:
a) dissolving Lesinurad in solvent;
b) optionally, heating the solution of step a);
c) adding nicotinamide to the solution of step b);
d) isolating the nicotinamide co-crystal of Lesinurad.
In a seventeenth embodiment of the present invention provides a crystalline DMSO solvate Form RB10 of Lesinurad, characterized by a PXRD comprising the peaks at about 7.38, 11.51, 14.77, 16.69 and 31.07 ± 0.2° 2?. In an embodiment, the invention provides crystalline DMSO solvate Form RB10 of Lesinurad, characterized by a PXRD having additional peaks at about 7.96, 12.71, 19.54, 21.65, 23.97 and 27.86 ± 0.2° 2?.
In a eighteenth embodiment of the present invention provides a process for the preparation of crystalline DMSO solvate Form RB10 of Lesinurad comprising:
a) slurrying Lesinurad in methyl tertiary butyl ether;
b) optionally, heating the solution of step a);
c) adding dimethyl sulfoxide to the suspension of Lesinurad; or adding suspension of Lesinurad to dimethyl sulfoxide;
d) isolating the crystalline Form RB10 of Lesinurad;
e) optionally, drying the product at suitable temperature.
In a nineteenth embodiment of the present invention provides a crystalline Form RB11 of Lesinurad, characterized by a PXRD comprising the peaks at about 14.28, 16.99, 24.82 and 25.54 ± 0.2° 2?. In an embodiment, the invention provides crystalline Form RB11 of Lesinurad, characterized by a PXRD having additional peaks at about 9.85, 23.66, 26.50, 27.30 and 30.32 ± 0.2° 2?.
In a twentieth embodiment of the present invention provides a process for the preparation of crystalline Form RB11 of Lesinurad comprising:
a) dissolving Lesinurad in isopropyl alcohol;
b) optionally, heating the solution of step a);
c) adding n-heptane to the solution of Lesinurad; or adding solution of Lesinurad to n-heptane;
d) isolating the crystalline Form RB11 of Lesinurad.
e) optionally, drying the product at suitable temperature.
In twenty first embodiment of the present invention provides a process for the preparation of crystalline Form RB11 of Lesinurad comprising:
a) dissolving/slurrying Lesinurad in isopropyl alcohol;
b) optionally, heating the solution of step a);
c) optionally, cooling the solution of step b);
d) isolating the crystalline Form RB11 of Lesinurad.
In a twenty second embodiment of the present invention provides a crystalline Form RB12 of Lesinurad, characterized by a PXRD comprising the peaks at about 8.22, 9.11, 16.44 and 22.17 ± 0.2° 2?. In an embodiment, the invention provides crystalline Form RB12 of Lesinurad, characterized by a PXRD having additional peaks at about 6.88, 19.36, 26.00 and 28.72 ± 0.2° 2?.
In a twenty third embodiment of the present invention provides a process for the preparation of crystalline Form RB12 of Lesinurad comprising:
a) dissolving Lesinurad in formic acid;
b) optionally, heating the solution of step a);
c) adding cyclohexane to the solution of Lesinurad; or adding solution of Lesinurad to cyclohexane;
d) isolating the solid of crystalline Form RB12 of Lesinurad;
e) optionally, drying the product at suitable temperature.
In a twenty fourth embodiment of the present invention provides a urea co-crystal of Lesinurad.
In a twenty fifth embodiment of the present invention provides urea co-crystal of Lesinurad, designated as Form LU of Lesinurad, characterized by X-ray powder diffraction pattern having peaks at about 7.21, 13.62, 16.94, 19.32, 21.86, 22.74, 24.46 and 28.82 ± 0.2° 2?. In an embodiment, the invention provides co-crystal Form LU of Lesinurad, characterized by a PXRD having additional peaks at about 18.59 and 24.80 ± 0.2° 2?.
In a twenty sixth embodiment of the present invention provides a process for the preparation of co-crystal Form LU of Lesinurad comprising:
a) grinding or contacting in solution the Lesinurad with urea;
b) optionally drying; and,
c) isolating co-crystal of Lesinurad (Form LU).
In a twenty seventh embodiment of the present invention provides a process for the preparation of co-crystal Form LU of Lesinurad comprising Lesinurad and Urea, which comprises:
a) dissolving or slurring Urea in a solvent;
b) optionally, heating the solution of step a);
c) adding Lesinurad to the solution of step b); or adding solution of urea to Lesinurad;
d) Isolating the co-crystal of Lesinurad (Form LU).
In a twenty eighth embodiment of the present invention provides a pure crystalline DMSO solvate of Lesinurad characterized by a PXRD comprising the peaks at about 7.45, 11.57, 14.84 and 16.75 ± 0.2° 2?. In an embodiment, the invention provides a pure crystalline DMSO solvate of Lesinurad, characterized by a PXRD having additional peaks at about 8.01, 12.76, 13.58, 13.91, 15.28, 15.94, 16.23, 18.46, 19.60, 21.70, 22.29 and 26.67 ± 0.2° 2?.
In a twenty ninth embodiment of the present invention provides a process for the preparation of pure crystalline DMSO solvate of Lesinurad comprising:
a) suspending Lesinurad in a solvent;
b) optionally, heating the solution of step a);
c) adding DMSO to the slurry of Lesinurad; or adding slurry of Lesinurad to DMSO;
d) isolating pure crystalline DMSO solvate of Lesinurad;
e) Optionally, drying the product at suitable temperature.
In a thirtieth embodiment of the present invention provides a pharmaceutical composition comprising crystalline forms of Lesinurad selected from the group comprising Form S1, Form S2, Form S3, Form RB6, Form RB7, Form RB8 (DMSO solvate), Form RB9, Form LN, Form RB10 (DMSO solvate), Form RB11, Form RB12, Form LU and Form SP (pure DMSO solvate) or mixtures thereof together with at least one pharmaceutically acceptable excipient.
BRIEF DESCRIPTION OF THE DRAWING
Figure 1 is an illustrative X-ray powder diffraction of crystalline Form S1 of Lesinurad prepared by the method of Example-1.
Figure 2 is an illustrative X-ray powder diffraction of crystalline Form S2 of Lesinurad prepared by the method of Example-2.
Figure 3 is an illustrative X-ray powder diffraction of crystalline Form S3 of Lesinurad prepared by the method of Example-3.
Figure 4 is an illustrative X-ray powder diffraction of crystalline Form RB6 of Lesinurad prepared by the method of Example-4.
Figure 5 is an illustrative X-ray powder diffraction of crystalline Form RB7 of Lesinurad prepared by the method of Example-6.
Figure 6 is an illustrative X-ray powder diffraction of crystalline Form RB8 of Lesinurad prepared by the method of Example-7.
Figure 7 is an illustrative X-ray powder diffraction of crystalline Form RB9 of Lesinurad prepared by the method of Example-8.
Figure 8 is an illustrative X-ray powder diffraction of Lesinurad nicotinamide co-crystal Form LN prepared by the method of Example-9.
Figure 9 is an illustrative X-ray powder diffraction of crystalline Form RB10 of Lesinurad prepared by the method of Example-11.
Figure 10 is an illustrative X-ray powder diffraction of crystalline Form RB11 of Lesinurad prepared by the method of Example-13.
Figure 11 is an illustrative X-ray powder diffraction of crystalline Form RB12 of Lesinurad prepared by the method of Example-15.
Figure 12 is an illustrative X-ray powder diffraction of Lesinurad urea 1:1 co-crystal Form LU prepared by the method of Example-17.
Figure 13 is an illustrative X-ray powder diffraction of pure crystalline DMSO solvate of Lesinurad prepared by the method of Example-18.
Figure 14 is an illustrative FT-IR Spectra of Lesinurad urea 1:1 co-crystal Form LU.
Figure 15 is an illustrative DSC-TGA overlay of Lesinurad urea 1:1 co-crystal Form-LU.
DETAILED DESCRIPTION OF THE INVENTION
Based on a chemical structure, one cannot predict with any degree of certainty whether a compound will crystallize, under what conditions it will crystallize, how many crystalline solid forms of the compound might exist, or the solid-state structure of any of those forms.
The present invention results from the surprising discoveries of the solid forms of Lesinurad. The present invention also provides novel co-crystals of Lesinurad.
DEFINITIONS
The following definitions are used in connection with the present invention unless the context indicates otherwise.
“Hydrate” refers to a complex formed by the combining of Lesinurad and water. The term includes stoichiometric as well as non-stoichiometric hydrates.
“Solvate” refers to a complex formed by the combining of Lesinurad and a solvent.
"Co-crystal" as used herein is defined as a crystalline material comprising two or more compounds of which at least two are held together, wherein at least one of the compounds is a co-crystal former. "Co-crystal-former" as used herein is defined as a component with which Lesinurad is able to form co-crystals. The co-crystal former is part of the crystal lattice.
The terms "about," "general, ‘generally," and the like are to be construed as modifying a term or value such that it is not an absolute. Such terms will be defined by the circumstances and the terms that they modify as those terms are understood by those of skill in the art. This includes, at very least, the degree of expected experimental error, technique error and instrument error for a given technique used to measure a value.
The term “crystalline form" indicates that the Lesinurad is present in substantially crystalline Form. "Substantially" crystalline denotes that at least 80 %, preferably 90 % or 95 %, more preferably all of the Lesinurad is crystalline form. In other words, "crystalline form" of Lesinurad denotes Lesinurad, which does not contain substantial amounts, preferably does not contain noticeable amounts, of any other crystalline portions of Lesinurad e.g. measurable upon X-ray powder diffraction analysis.
The term “optional” or “optionally” is taken to mean that the event or circumstance described in the specification may or may not occur, and that the description includes instances where the event occurs and instances where it does not.
SOLID FORMS OF LESINURAD
Lesinurad can adopt a variety of solid forms, including, Form S1, Form S2, Form S3, Form RB6, Form RB7, Form RB8 (DMSO solvate), Form RB9, Form RB10 (DMSO solvate), Form RB11, Form RB12, and Form SP (pure DMSO solvate). Lesinurad can form a mixture of two or more crystalline forms, or form a single crystalline form substantially free of other crystalline forms.
Lesinurad forms stable co-crystal with nicotinamide (Form LN) and urea (Form LU).
In a first embodiment of the present invention provides a crystalline Form S1 of Lesinurad, characterized by a PXRD comprising the peaks at about 8.24, 15.73, 16.46, 17.67, 28.92 and 39.29 ± 0.2° 2?.
In an embodiment, the present invention provides crystalline Form S1 of Lesinurad, characterized by a PXRD substantially as shown in figure 1.
In a second embodiment of the present invention provides a process for the preparation of crystalline Form S1 of Lesinurad, comprising:
a) providing a solution or suspension of Lesinurad in a solvent comprising methanol;
b) optionally, heating the solution or suspension obtained in step a);
c) isolating the crystalline Form S1 of Lesinurad.
Providing a solution or suspension in step a) includes:
i) direct use of a reaction mixture containing Lesinurad that is obtained in the course of its synthesis; or
ii) dissolving Lesinurad in methanol; or
iii) providing a suspension by adding methanol to the Lesinurad.
Any physical form of Lesinurad may be utilized for providing the solution or suspension of Lesinurad in step a). Optionally, when a hydrate of Lesinurad is used, before or after step a) a water reduction or removal step may be carried out by the techniques known in the art such as distillation, heating, slurring in a suitable solvent and the like.
In embodiments, Lesinurad obtained in the course of its synthesis may be dissolved or in methanol. The dissolution temperatures may range from about 0 °C to about the reflux temperature of the methanol, or less than about 60°C or less than about 55 °C, less than about 40 °C, or less than about 30 °C, less than about 20 °C, less than about 10 °C, or any other suitable temperatures, as long as a clear solution of Lesinurad is obtained without affecting its quality.
The solution may optionally be treated with carbon, flux-calcined diatomaceous earth (Hyflow) or any other suitable material to remove color, insoluble materials, improve clarity of the solution, and/or remove impurities adsorbable on such material. Optionally, the solution obtained above may be filtered to remove any insoluble particles. The insoluble particles may be removed suitably by filtration, centrifugation, decantation, or any other suitable techniques under pressure or under reduced pressure. The solution may be filtered by passing through paper, glass fiber, cloth or other membrane material, or a bed of a clarifying agent such as Celite® or Hyflow. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature crystallization.
In an embodiment, crystallization of Lesinurad Form S1 may be carried out according to any methods known in the art for the reduction of solubility of Lesinurad such as lowering the temperature (i.e., cooling crystallization) of the solution; vapour diffusion; adding anti-solvent to the solution; slow evaporating the solvent from the solution; or the combinations thereof.
Isolation of crystalline Form S1 of Lesinurad may be carried out by any methods known in the art or procedures described in the present invention. In an embodiment, crystalline Form S1 may be isolated by employing any of the techniques, but not limited to: precipitation, decantation, filtration by gravity or suction, centrifugation, extraction, acid-base treatment, conventional isolation, adding solvent to make slurry followed by filtration, or other techniques specific to the equipment used and the like, and optionally washing with a solvent.
In a third embodiment of the present invention provides a crystalline Form S2 of Lesinurad, characterized by a PXRD comprising the peaks at about 17.90, 29.15, 33.27, 34.61 and 39.10 ± 0.2° 2?.
In an embodiment, the present invention provides crystalline Form S2 of Lesinurad, characterized by a PXRD substantially as shown in figure 2.
In a fourth embodiment of the present invention provides a process for the preparation of crystalline Form S2 of Lesinurad, comprising the step of drying crystalline Form S1 of Lesinurad.
In an embodiment, drying crystalline Form S1 of Lesinurad may be carried out in suitable drying equipment such as a tray drier optionally under reduced pressure or other drying conditions known in the art such as Buchi rotavapour vacuum drying, rotatory cone vacuum drying; fluid bed drying optionally under nitrogen atmosphere, thin film drying; or the like.
In an embodiment, drying crystalline Form S1 of Lesinurad may be carried out at suitable temperatures of about 25°C and above, optionally under reduced pressure. In an embodiment, drying may be carried out at about 60°C and above.
In an embodiment, drying crystalline Form S1 of Lesinurad may be carried out for sufficient time to complete its conversion to crystalline Form S2 of Lesinurad. Drying can be carried out at temperatures and times sufficient to achieve desired quality of product. Drying may be carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to 10 hours or longer.
In a fifth embodiment of the present invention provides a crystalline Form S3 of Lesinurad, characterized by a PXRD comprising the peaks at about 15.48, 21.28, 23.27, 23.60 and 38.68 ± 0.2° 2?.
In an embodiment, the present invention provides crystalline form S3 of Lesinurad, characterized by a PXRD substantially as shown in figure 3.
In a sixth embodiment of the present invention provides a process for the preparation of crystalline Form S3 of Lesinurad, comprising the step of exposing crystalline Form S1 of Lesinurad to open atmosphere at 25-28°C.
In an embodiment, exposing crystalline Form S1 of Lesinurad to open atmosphere may be carried out at suitable temperatures of about room temperature and above, optionally under reduced pressure.
In an embodiment, exposing crystalline Form S1 of Lesinurad to open atmosphere may be carried out for sufficient time to complete its conversion to crystalline Form S3 of Lesinurad. Exposing can be carried out at temperatures and times sufficient to achieve desired quality of product. Exposing may be carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to 10 hours or longer.
In a seventh embodiment of the present invention provides a crystalline Form RB6 of Lesinurad, characterized by a PXRD comprising the peaks at about 8.79, 14.34, 14.53, 14.90, 15.10, 15.64, 17.61, 28.88 and 32.81 ± 0.2° 2? and also having additional peaks at about 8.18,18.38, 19.76, 20.36, 21.96, 22.71 and 23.41 ± 0.2° 2?.
In an embodiment, the present invention provides crystalline Form RB6 of Lesinurad, characterized by a PXRD substantially as shown in figure 4.
In an eighth embodiment of the present invention provides a process for the preparation of crystalline Form RB6 of Lesinurad, comprising:
a) providing a solution or suspension of Lesinurad in a solvent comprising ethanol;
b) optionally, heating the solution or suspension obtained in step a);
c) isolating the crystalline Form RB6 of Lesinurad.
Providing a solution or suspension in step a) includes:
i) direct use of a reaction mixture containing Lesinurad that is obtained in the course of its synthesis; or
ii) dissolving Lesinurad in ethanol; or
iii) providing a suspension by adding ethanol to the Lesinurad.
In embodiments, Lesinurad obtained in the course of its synthesis may be dissolved or suspended in ethanol.
The dissolution temperatures may range from about 0°C to about the reflux temperature of the ethanol, or less than about 70°C or less than about 65 °C, less than about 60 °C, less than about 55 °C, less than about 40 °C, or less than about 30 °C, less than about 20 °C, less than about 10 °C, or any other suitable temperatures, as long as a clear solution of Lesinurad is obtained without affecting its quality.
The solution may optionally be treated with carbon, flux-calcined diatomaceous earth (Hyflow) or any other suitable material to remove color, insoluble materials, improve clarity of the solution, and/or remove impurities adsorbable on such material. Optionally, the solution obtained above may be filtered to remove any insoluble particles. The insoluble particles may be removed suitably by filtration, centrifugation, decantation, or any other suitable techniques at atmospheric pressure or under reduced pressure. The solution may be filtered by passing through paper, glass fiber, cloth or other membrane material, or a bed of a clarifying agent such as Celite® or Hyflow. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature crystallization.
In an embodiment, crystallization of Lesinurad form RB6 may be carried out according to any methods known in the art for the reduction of solubility of Lesinurad such as lowering the temperature (i.e., cooling crystallization) of the solution; adding anti-solvent to the solution; slowly evaporating the solvent from the solution; or the combinations thereof.
Isolation of crystalline Form RB6 of Lesinurad may be carried out by any methods known in the art or procedures described in the present invention. In an embodiment, crystalline Form RB6 may be isolated by employing any of the techniques, but not limited to: precipitation, decantation, filtration by gravity or suction, centrifugation, extraction, acid-base treatment, conventional isolation, adding solvent to make slurry followed by filtration, or other techniques specific to the equipment used and the like, and optionally washing with a solvent.
In a ninth embodiment of the present invention provides a crystalline Form RB7 of Lesinurad, characterized by a PXRD comprising the peaks at about 11.56, 14.27, 17.04, 21.14, 22.11, 24.34, 26.90 and 32.29 ± 0.2° 2?. In an embodiment, the invention provides crystalline form RB7 of Lesinurad, characterized by a PXRD having additional peaks at about, 7.78, 9.73, 13.90, 15.93, 18.34, 20.02, 20.21, 20.85, 22.73 and 23.22 ± 0.2° 2?.
In an embodiment, the present invention provides crystalline Form RB7 of Lesinurad, characterized by a PXRD substantially as shown in figure 5.
In tenth embodiment of the present invention provides a process for the preparation of crystalline Form RB7 of Lesinurad comprising recrystallization from methanol.
In an embodiment, solution comprising Lesinurad and methanol may obtained by dissolving Lesinurad in a solvent or mixture of solvents comprising methanol, optionally by heating.
In an embodiment, dissolution of Lesinurad may be carried out by optionally heating a mixture of Lesinurad and a solvent or mixture of solvents comprising methanol at about 60°C to reflux temperature of the solvent. The solution may be made particle free by filtering the solution, optionally the solution may be treated with carbon, hydrose or any decolorizing agent before filtration.
In an embodiment, crystallization of Lesinurad Form RB7 may be carried out according to any methods known in the art for the reduction of solubility of Lesinurad such as lowering the temperature (i.e., cooling crystallization) of the solution; adding anti-solvent to the solution; slow evaporating the solvent from the solution; or the combinations thereof.
Isolation of crystalline Form RB7 of Lesinurad may be carried out by any methods known in the art or procedures described in the present invention. In an embodiment, crystalline Form RB7 may be isolated by employing any of the techniques, but not limited to: decantation, filtration by gravity or suction, centrifugation, adding solvent to make slurry followed by filtration, or other techniques specific to the equipment used and the like, and optionally washing with a solvent.
In a eleventh embodiment of the present invention provides a crystalline DMSO solvate Form RB8 of Lesinurad, characterized by a PXRD comprising the peaks at about 7.40, 12.15, 15.58, 16.73 and 23.43 ± 0.2° 2?. In an embodiment, the invention provides crystalline DMSO solvate Form RB8 of Lesinurad, characterized by a PXRD having additional peaks at about, 15.25, 18.57, 20.26, 21.70, 22.22, 22.49, 25.04, 25.47 and 28.54 ± 0.2° 2?.
In an embodiment, the present invention provides crystalline DMSO solvate Form RB8 of Lesinurad, characterized by a PXRD substantially as shown in figure 6.
In a twelfth embodiment of the present invention provides a process for the preparation of crystalline Form RB8 of Lesinurad comprising:
a) slurrying Lesinurad in methyl tertiary butyl ether;
b) optionally, heating the solution of step a);
c) adding dimethyl sulfoxide to the solution of Lesinurad; or adding solution of Lesinurad to dimethyl sulfoxide;
d) isolating the solid of crystalline Form RB8 of Lesinurad;
e) optionally, drying the product at suitable temperature.
In embodiments of step a) involves the solution may optionally be treated with carbon, flux-calcined diatomaceous earth (Hyflow), or any other suitable material to remove color and/or to clarify the solution.
Optionally, the solution obtained above may be filtered to remove any insoluble particles. The insoluble particles may be removed suitably by filtration, centrifugation, decantation, or any other suitable techniques. The solution may be filtered by passing thorough paper, glass fiber, or other membrane material, or a bed of a clarifying agent such as celite or hyflow. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature crystallization.
In embodiments of step c) involves adding dimethyl sulfoxide to the suspension obtained in step b), or adding the suspension obtained in step b) to the dimethyl sulfoxide, wherein the suspension is made in step b) with methyl tertiary butyl ether. After adding dimethyl sulfoxide, the reaction mass may be maintained from 15 minutes to 24 hours.
The temperature at which the above steps may be carried out in between about 20 °C and about 100 °C, preferably at about 25°C and about 75°C.
The isolation of step d) can be effected, if desired, by any suitable separation methods such as precipitation, filtration, centrifugation, extraction, acid-base treatment, by scraping, or by shaking the container conventional isolation and refining means such as concentration, concentration under reduced pressure or by a combination of these procedures.
In a thirteenth embodiment of the present invention provides a crystalline Form RB9 of Lesinurad, characterized by a PXRD substantially as shown in figure 7.
In a fourteenth embodiment of the present invention provides a process for the preparation of crystalline Form RB9 of Lesinurad comprising humidification of crystalline Form RB5 of Lesinurad at 40°C and relative humidity of 75%.
The crystalline Form RB9 of Lesinurad material obtained in the present invention is subjected to humidification studies at different temperature conditions with different relative humidity percentages. In a particular example, the humidification studies were carried out on crystalline Form RB5 (Formamide solvate) of present invention at about 40°C and relative humidity of 75%.
Crystalline Form RB5 of Lesinurad used in the above aspect may be prepared by the step of crystallizing Lesinurad from solvent or solvent mixtures comprising formamide.
In a fifteenth embodiment of the present invention provides co-crystal of Lesinurad, comprising Lesinurad and Nicotinamide, designated as Form LN of Lesinurad, characterized by X-ray powder diffraction pattern having peaks at about 6.33, 13.32, 14.22, 15.42 and 29.08± 0.2° 2?. In an embodiment, the invention provides Form LN of Lesinurad, characterized by a PXRD having additional peaks at about, 7.69, 10.41, 20.04, 21.20, 25.64, 25.91 and 26.68 ± 0.2° 2?.
In an embodiment, the present invention provides co-crystal Form LN of Lesinurad, characterized by a PXRD substantially as shown in figure 8.
In a sixteenth embodiment of the present invention provides a process for the preparation of co-crystal Form LN of Lesinurad, which comprises:
a) dissolving Lesinurad in solvent;
b) optionally, heating the solution of step a);
c) adding nicotnamide to the solution of step b);
d) isolating the co-crystals of Lesinurad comprising Lesinurad and nicotinamide.
Step (a) may be carried out in one or more suitable solvents. Suitable solvent that may be used in step (a) include, but are not limited to alcohol solvents, such as, for example, methanol, ethanol, isopropanol or the like; ketone solvents, such as, for example, acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, C3-C6 ketones or the like; ester solvents, such as, for example, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, or the like; ether solvents, such as, for example, diethyl ether, diisopropyl ether, tert-butyl methyl ether, dibutyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 2-methoxyethanol, 2-ethoxyethanol, anisole, 1, 4-dioxane, or the like; aromatic hydrocarbon solvents, such as, for example, toluene, xylene, chlorobenzene, tetralin, or the like; chlorinated hydrocarbon solvents, such as chloroform, dichloromethane or the like and mixtures thereof.
The temperature at which the above steps may be carried out in between about 20 °C and about 100 °C, preferably at about 25°C and about 75°C.
Co-crystals exhibit different properties than free acid or base and salts. The solid form influences relevant physico-chemical parameters such as solubility, dissolution rate of the drug, chemical stability, melting point, and hygroscopicity, which can result in solids with modulated properties.
Co-crystals herein can be anhydrous; can also exist as co-crystal hydrates or solvates thereof.
In a seventeenth embodiment of the present invention provides a crystalline DMSO solvate Form RB10 of Lesinurad, characterized by a PXRD comprising the peaks at about 7.38, 11.51, 14.77, 16.69 and 31.07 ± 0.2° 2?. In an embodiment, the invention provides crystalline form RB10 of Lesinurad, characterized by a PXRD having additional peaks at about, 7.96, 12.71, 19.54, 21.65, 23.97 and 27.86 ± 0.2° 2?.
In an embodiment, the present invention provides crystalline Form RB10 of Lesinurad, characterized by a PXRD substantially as shown in figure 9.
In a eighteenth embodiment of the present invention provides a process for the preparation of crystalline Form RB10 of Lesinurad comprising:
a) slurrying Lesinurad in methyl tertiary butyl ether;
b) optionally, heating the solution of step a);
c) adding dimethyl sulfoxide to the suspension of Lesinurad; or adding suspension of Lesinurad to dimethyl sulfoxide;
d) isolating the crystalline Form RB10 of Lesinurad;
e) optionally, drying the product at suitable temperature.
In embodiments of step a) involves the solution may optionally be treated with carbon, flux-calcined diatomaceous earth (Hyflow), or any other suitable material to remove color and/or to clarify the solution.
Optionally, the solution obtained above may be filtered to remove any insoluble particles. The insoluble particles may be removed suitably by filtration, centrifugation, decantation, or any other suitable techniques. The solution may be filtered by passing thorough paper, glass fiber, or other membrane material, or a bed of a clarifying agent such as celite or hyflow. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature crystallization.
In embodiments of step c) involves adding dimethyl sulfoxide to the suspension obtained in step b), or adding the suspension obtained in step b) to the dimethyl sulfoxide, wherein the suspension is made in step b) with methyl tertiary butyl ether. After adding dimethyl sulfoxide, the reaction mass may be maintained from 15 minutes to 24 hours.
The temperature at which the above steps may be carried out in between about 20 °C and about 100 °C, preferably at about 25°C and about 75°C.
The isolation of step d) can be effected, if desired, by any suitable separation methods such as precipitation, filtration, centrifugation, extraction, acid-base treatment, by scraping, or by shaking the container conventional isolation and refining means such as concentration, concentration under reduced pressure or by a combination of these procedures.
In a nineteenth embodiment of the present invention provides a crystalline Form RB11 of Lesinurad, characterized by a PXRD comprising the peaks at about 14.28, 16.99, 24.82 and 25.54 ± 0.2° 2?. In an embodiment, the invention provides crystalline Form RB11 of Lesinurad, characterized by a PXRD having additional peaks at about, 9.85, 23.66, 26.50, 27.30 and 30.32 ± 0.2° 2?.
In an embodiment, the present invention provides crystalline Form RB11 of Lesinurad, characterized by a PXRD substantially as shown in figure 10.
In a twentieth embodiment of the present invention provides a process for the preparation of crystalline Form RB11 of Lesinurad comprising:
a) dissolving Lesinurad in isopropyl alcohol;
b) optionally, heating the solution of step a);
c) adding n-heptane to the solution of Lesinurad; or adding solution of Lesinurad to n-heptane;
d) isolating the crystalline Form RB11 of Lesinurad.
e) optionally, drying the product at suitable temperature.
In embodiments of step a) involves the solution may optionally be treated with carbon, flux-calcined diatomaceous earth (Hyflow), or any other suitable material to remove color and/or to clarify the solution.
Optionally, the solution obtained above may be filtered to remove any insoluble particles. The insoluble particles may be removed suitably by filtration, centrifugation, decantation, or any other suitable techniques. The solution may be filtered by passing thorough paper, glass fiber, or other membrane material, or a bed of a clarifying agent such as celite or hyflow. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature crystallization.
In embodiments of step c) involves adding n-heptane to the solution obtained in step b), or adding the solution obtained in step b) to the n-heptane, wherein the solution is made in step b) with isopropyl alcohol. After adding isopropyl alcohol, the reaction mass may be maintained from 15 minutes to 24 hours.
The temperature at which the above steps may be carried out in between about -15 °C and about 100 °C, preferably at about -15°C and about 25°C.
The isolation of step d) can be effected, if desired, by any suitable separation methods such as precipitation, filtration, centrifugation, extraction, acid-base treatment, by scraping, or by shaking the container conventional isolation and refining means such as concentration, concentration under reduced pressure or by a combination of these procedures.
In a twenty first embodiment of the present invention provides a process for the preparation of crystalline Form RB11 of Lesinurad comprising:
a) dissolving/slurrying Lesinurad in isopropyl alcohol;
b) optionally, heating the solution of step a);
c) optionally, cooling the solution of step b);
d) isolating the crystalline Form RB11 of Lesinurad
In embodiments of step a) involves the solution may optionally be treated with carbon, flux-calcined diatomaceous earth (Hyflow), or any other suitable material to remove color and/or to clarify the solution.
Optionally, the solution/slurry obtained above may be filtered to remove any insoluble particles. The insoluble particles may be removed suitably by filtration, centrifugation, decantation, or any other suitable techniques. The solution may be filtered by passing thorough paper, glass fiber, or other membrane material, or a bed of a clarifying agent such as celite or hyflow. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature crystallization.
The temperature at which the above steps may be carried out in between about 0 °C and about 100 °C, preferably at about 0°C and about 25°C.
Isolation of crystalline Form RB11 of Lesinurad may be carried out by any methods known in the art or procedures described in the present invention. In an embodiment, crystalline Form RB11 may be isolated by employing any of the techniques, but not limited to: decantation, filtration by gravity or suction, centrifugation, adding solvent to make slurry followed by filtration, or other techniques specific to the equipment used and the like, and optionally washing with a solvent.
In a twenty second embodiment of the present invention provides a crystalline Form RB12 of Lesinurad, characterized by a PXRD comprising the peaks at about 8.22, 9.11, 16.44 and 22.17 ± 0.2° 2?. In an embodiment, the invention provides crystalline Form RB12 of Lesinurad, characterized by a PXRD having additional peaks at about 6.88, 19.36, 26.00 and 28.72 ± 0.2° 2?.
In an embodiment, the present invention provides crystalline Form RB12 of Lesinurad, characterized by a PXRD substantially as shown in figure 11.
In twenty third embodiment of the present invention provides a process for the preparation of crystalline Form RB12 of Lesinurad comprising:
a) Dissolving Lesinurad in formic acid;
b) optionally, heating the solution of step a);
c) adding cyclohexane to the solution of Lesinurad; or adding solution of Lesinurad to cyclohexane;
d) isolating the solid of crystalline Form RB12 of Lesinurad;
e) optionally, drying the product at suitable temperature.
In embodiments of step a) involves the solution may optionally be treated with carbon, flux-calcined diatomaceous earth (Hyflow), or any other suitable material to remove color and/or to clarify the solution.
Optionally, the solution obtained above may be filtered to remove any insoluble particles. The insoluble particles may be removed suitably by filtration, centrifugation, decantation, or any other suitable techniques. The solution may be filtered by passing thorough paper, glass fiber, or other membrane material, or a bed of a clarifying agent such as celite or hyflow. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature crystallization.
In embodiments of step c) involves adding cyclohexane to the solution obtained in step b), or adding the solution obtained in step b) to the cyclohexane, wherein the solution is made in step b) with only formic acid. After adding cyclohexane, the reaction mass may be maintained from 15 minutes to 24 hours.
The temperature at which the above steps may be carried out in between about 8 °C and about 100 °C, preferably at about 10°C and about 80°C.
The isolation of step d) can be effected, if desired, by any suitable separation methods such as precipitation, filtration, centrifugation, extraction, acid-base treatment, by scraping, or by shaking the container conventional isolation and refining means such as concentration, concentration under reduced pressure or by a combination of these procedures.
In a twenty fourth embodiment of the present invention provides a co-crystal of Lesinurad with Urea.
In a twenty fifth embodiment of the present invention provides co-crystal of Lesinurad, comprising Lesinurad and Urea, designated as Form LU of Lesinurad, characterized by X-ray powder diffraction pattern having peaks at about 7.21, 13.62, 16.94, 19.32, 21.86, 22.74, 24.46 and 28.82 ± 0.2° 2?. In an embodiment, the invention provides crystalline form LU of Lesinurad, characterized by a PXRD having additional peaks at about, 18.59 and 24.80 ± 0.2° 2?.
In an embodiment, the present invention provides Form LU of Lesinurad, characterized by a PXRD substantially as shown in figure 12.
Theoretical assay of Lesinurad in 1:1 Lesinurad-Urea co-crystal is 87.06 % as measured by HPLC.
In a twenty sixth embodiment of the present invention provides a process for the preparation of co-crystal Form LU of Lesinurad comprising:
a) grinding or contacting in solution the Lesinurad with urea;
b) optionally drying; and
c) isolating co-crystal Form LU of Lesinurad.
The grinding process comprises dry grinding or wet grinding of Lesinurad with urea. In dry grinding process, Lesinurad and urea are ground in a mortar, a grinder or a mill to obtain a co-crystal. Grinding in a mortar involves physical grinding of Lesinurad and urea. In wet grinding process, Lesinurad and urea are ground in a mortar, a grinder or a mill with the solvent or mixture of solvents followed by drying to obtain the co-crystal. The solvent for wet grinding process includes but are not limited to: alcohol solvents such as methanol, ethanol, 1-propanol, 2-propanol, n-butanol, 2-butanol or the like.
The amount of solvent used for wet grinding is in the range of up to about 40 % by weight (w/w). For example, a weight percent of less than or equal to about 1, 2, 3, 4, 5, 10, 15, 20, 25, 30 and 35 may be used.
Drying can be carried out at reduced pressures. Drying can be suitably carried out in a tray dryer, vacuum oven, air oven, or using a fluidized bed drier, spin flash dryer, flash dryer, atmospheric drying and the like.
For isolation to occur, the reaction mass may be maintained further at temperatures lower than the dissolution temperatures such as for example below about 10° C. to about 25° C., for a period of time as required for complete isolation of the product. The exact cooling temperature and time required for complete crystallization can be readily determined by a person skilled in the art and will also depend on parameters such as concentration and temperature of the solution or slurry.
Optionally, the obtained product is further dried. Drying can be carried out at reduced pressures. Drying can be suitably carried out in a tray dryer, vacuum oven, air oven, or using a fluidized bed drier, spin flash dryer, flash dryer and the like.
In a twenty seventh embodiment of the present invention provides a process for the preparation of co-crystal Form LU of Lesinurad, which comprises:
a) dissolving or slurring Urea in solvent;
b) optionally, heating the solution of step a);
c) adding Lesinurad to the solution of step b); or adding solution of urea to Lesinurad;
d) isolating the co-crystal Form LU of Lesinurad.
Step (a) may be carried out in one or more suitable solvents. Suitable solvent that may be used in step (a) include, but are not limited to alcohol solvents, such as, for example, methanol, ethanol, 1-propanol, isopropanol, n-butanol, 2-butanol or the like; ketone solvents, such as, for example, acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, C3-C6 ketones or the like; ester solvents, such as, for example, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, or the like; ether solvents, such as, for example, diethyl ether, diisopropyl ether, tert-butyl methyl ether, dibutyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 2-methoxyethanol, 2-ethoxyethanol, anisole, 1, 4-dioxane, or the like; aromatic hydrocarbon solvents, such as, for example, toluene, xylene, chlorobenzene, tetralin, or the like; chlorinated hydrocarbon solvents, such as chloroform, dichloromethane or the like and mixtures thereof.
The temperature at which the above steps may be carried out in between about 10 °C and about 100 °C, preferably at about 25°C and about 75°C.
Co-crystals exhibit different properties than free acid or base and salts. The solid form influences relevant physico-chemical parameters such as solubility, dissolution rate of the drug, chemical stability, melting point, and hygroscopicity, which can result in solids with modulated properties.
Co-crystals herein can be anhydrous; can also exist as co-crystal hydrates or solvates thereof.
In a twenty eighth embodiment of the present invention provides a pure crystalline DMSO solvate of Lesinurad characterized by a PXRD comprising the peaks at about 7.45, 11.57, 14.84 and 16.75 ± 0.2° 2?. In an embodiment, the invention provides a pure crystalline DMSO solvate of Lesinurad, characterized by a PXRD having additional peaks at about 8.01, 12.76, 13.58, 13.91, 15.28, 15.94, 16.23, 18.46, 19.60, 21.70, 22.29 and 26.67 ± 0.2° 2?.
In an embodiment, the present invention provides a pure crystalline DMSO solvate of Lesinurad, characterized by a PXRD substantially as shown in figure 13.
In another embodiment of the present invention provides a pure crystalline DMSO solvate of Lesinurad, also designated as Form SP.
In a twenty ninth embodiment of the present invention provides a process for the preparation of pure crystalline DMSO solvate of Lesinurad comprising:
a) suspending Lesinurad in a solvent;
b) optionally, heating the solution of step a);
c) adding DMSO to the slurry of Lesinurad; or adding slurry of Lesinurad to DMSO;
d) isolating pure crystalline DMSO solvate of Lesinurad;
e) optionally, drying the product at suitable temperature.
Suitable solvent that may be used in step (a) include, but are not limited to alcohol solvents, such as, for example, methanol, ethanol, 1-propanol, isopropanol, n-butanol, 2-butanol or the like; ester solvents, such as, for example, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, isopropyl acetate, isobutyl acetate, or the like; ketone solvents, such as, for example acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, C3-C6 ketones or the like; ether solvents, such as, for example, diethyl ether, diisopropyl ether, methyl tert-butyl ether, dibutyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 2-methoxyethanol, 2-ethoxyethanol, anisole, 1, 4-dioxane, or the like; aromatic hydrocarbon solvents, such as, for example, toluene, xylene, chlorobenzene, tetralin, or the like; chlorinated hydrocarbon solvents, such as chloroform, dichloromethane or the like and mixtures thereof.
In embodiments of step a) involves the solution may optionally be treated with carbon, flux-calcined diatomaceous earth (Hyflow), or any other suitable material to remove color and/or to clarify the solution.
Optionally, the solution obtained above may be filtered to remove any insoluble particles. The insoluble particles may be removed suitably by filtration, centrifugation, decantation, or any other suitable techniques. The solution may be filtered by passing thorough paper, glass fiber, or other membrane material, or a bed of a clarifying agent such as celite or hyflow. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature crystallization.
In embodiments of step c) involves adding DMSO to the slurry obtained in step b), or adding the slurry obtained in step b) to the DMSO. After adding DMSO, the reaction mass may be maintained from 15 minutes to 24 hours.
The temperature at which the above steps may be carried out in between about 8 °C and about 100 °C, preferably at about 10°C and about 80°C, more preferably at about 5°C and about 60°C.
The isolation of step d) can be effected, if desired, by any suitable separation methods such as precipitation, filtration, centrifugation, extraction, acid-base treatment, by scraping, or by shaking the container conventional isolation and refining means such as concentration, concentration under reduced pressure or by a combination of these procedures.
In thirtieth embodiment of the present invention provides a pharmaceutical composition comprising crystalline form of Lesinurad selected from the group comprising Form S1, Form S2, Form S3, Form RB6, Form RB7, Form RB8, Form RB9, Form LN, Form RB10, Form RB11, Form RB12, Form LU and Form SP (pure DMSO solvate) or mixtures thereof together with at least one pharmaceutically acceptable excipient.
In another embodiment of the present invention provides crystalline forms of Lesinurad or their pharmaceutical compositions comprising Lesinurad having a chemical purity of at least 99% by HPLC or at least 99.5% by HPLC or at least 99.9% by HPLC.
Lesinurad that is used as starting material for the preparation of any of the solid forms of present invention may be purified before using employing any of the purification techniques known in the art such as recrystallization, slurrying or chromatography or according to the procedures described or exemplified in the instant invention.
Starting material may be either in a crystalline or amorphous state. In embodiments, crystalline form of Lesinurad that may be used may include but not limited to crystalline Form 1 or crystalline Form 2 or Form a or Form ß of Lesinurad or an alternate crystalline form of Lesinurad known in the art.
Drying in the all embodiments of the present invention may be suitably carried out by using any of an air tray dryer, vacuum tray dryer, fluidized bed dryer, spin flash dryer, flash dryer, and the like. The drying may be carried out at atmospheric pressure or above, or under reduced pressures, specifically at temperatures less than about 80 °C and more specifically less than about 60 °C. The drying may be carried out for any time period required for obtaining a desired product quality, such as from about 30 minutes to about 24 hours, or longer.
The PXRD data reported herein are obtained using a PANalytical X-ray Diffractometer and Bruker D8 advance X-ray Diffractometer, with copper Ka radiation.
Certain specific aspects and embodiments of the present invention will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the disclosure in any manner.
EXAMPLES
Example 1: Preparation of crystalline Form S1 of Lesinurad.
Lesinurad a form (1 g) was taken in Buchner funnel to make a uniform bed. Methanol (45 mL) was taken in a conical flask and Buchner funnel kept on conical flask for vapour diffusion at 25°C.The reaction mixture was allowed to vapour diffusion to obtain the title compound.
Example-2: Preparation of crystalline Form S2 of Lesinurad.
Crystalline form S1 of Lesinurad obtained in example-1 was dried under vacuum at 60°C for 2 hours to obtain the title compound.
Example-3: Preparation of crystalline Form S3 of Lesinurad.
Lesinurad a form (2.7 g) was taken in Buchner funnel to make a uniform bed. Methanol (100 mL) was taken in a conical flask and Buchner funnel kept on conical flask for vapour diffusion at 25°C.The reaction mixture was allowed to vapour diffusion to obtain crystalline form S1 of Lesinurad. Exposing of obtained crystalline form S1 of Lesinurad to open atmosphere at 25°C to obtain the title compound.
Example-4: Preparation of crystalline Form RB6 of Lesinurad.
Lesinurad (1.501 g) was dissolved in ethanol (10 mL) at 68°C and rapidly cooled to 30°C. The reaction mixture was then allowed to attain 26°C and stirred for 80- 90 minutes. The reaction mass was filtered under vacuum to obtain the title compound. Yield: 1.15 g
Example-5: Preparation of crystalline Form RB6 of Lesinurad.
Lesinurad (1.504 g) was dissolved in ethanol (10 mL) at 68°C and rapidly cooled to 30°C. The reaction mixture was then allowed to attain 26°C and stirred for 80- 90 minutes. The solid was filtered and dried under vacuum for 2 hours to obtain the title compound.

Example-6: Preparation of crystalline Form RB7 of Lesinurad.
Lesinurad (5.014 g) was dissolved in methanol (20 mL) at 60°C. The reaction mixture was cooled to 28°C and stirred for two hours. The solid was filtered and washed with methanol to obtain the title compound.
Example-7: Preparation of crystalline Form RB8 of Lesinurad.
Lesinurad (0.505 g) was dissolved in methyl tertiary butyl ether (8 mL) at 25°C and stirred for 5-10 minutes. Dimethyl sulfoxide (0.087 mL) was added to the reaction mass and stirred for 5-6 hours. The solid was filtered through hyflow bed to obtain the title compound.
Example-8: Preparation of crystalline Form RB9 of Lesinurad.
Crystalline form RB5 of Lesinurad (0.250 g) was kept in a humidification chamber at 40 ºC and 75% relative humidity for 100 hours and found that the crystalline form RB9 is retained as such by X-ray diffractogram.
Example-9: Preparation of Lesinurad and nicotinamide co-crystal.
Lesinurad (0.50 g) was dissolved in methanol (4 mL) at 60°C. The reaction mixture was cooled to 28°C. Nicotinamide (150 mg) was added to the reaction mass at 28°C and stirred for 60-120 minutes. The solid was filtered and washed with methanol to obtain the title compound. Yield: 0.510 g
Example-10: Preparation of crystalline Form RB5 of Lesinurad.
Lesinurad (2.004 g), formamide (8 mL) were charged in to the glass vial at 25°C and stirred for 2-3 hours. The solid was filtered and dried under vacuum to obtain the title compound.
Example-11: Preparation of crystalline Form RB10 of Lesinurad.
Lesinurad (18 g) was slurried in methyl tertiary butyl ether (72 mL) at 25 °C. Dimethyl sulfoxide (3 mL) was added to the suspension and stirred for 14 hours. The solid was filtered and kept for drying in vacuum tray dryer at 40 °C for 2 hours to obtain the title compound.
Example-12: Preparation of crystalline Form RB10 of Lesinurad.
Lesinurad (3 g) was slurried in methyl tertiary butyl ether (12 mL) at 25 °C. Dimethyl sulfoxide (0.6 mL) was added to the suspension and stirred for 3 hours. The solid was filtered and kept for drying in vacuum tray dryer at 50 °C for 1 hour to obtain the title compound.
Example-13: Preparation of crystalline Form RB11 of Lesinurad.
Lesinurad (3 g) was dissolved in isopropyl alcohol (30 mL) at 60°C. The above solution was added to n-heptane (100 mL) at -15°C and stirred at -5 °C for 12 hours. Further, the resultant reaction mass was maintained for 3 hours at 25 °C. The solid was filtered and kept for drying in vacuum tray dryer at 40 °C for 90 minutes to obtain the title compound.
Example-14: Preparation of crystalline Form RB11 of Lesinurad.
Lesinurad (10 g) was dissolved in isopropyl alcohol (80 mL) at 75 °C. The above solution was cooled to 0 °C and stirred for 150 minutes at 0 °C. The solid was filtered and kept drying in vacuum tray dryer at 40 °C for 90 minutes to obtain the title compound.
Example-15: Preparation of crystalline Form RB12 of Lesinurad.
Lesinurad (3 g) was dispensed in formic acid (4 mL) at 85°C. The reaction mass was added to cyclohexane (100 mL) at 10°C and maintained under stirring for 20-22 hours. The resultant suspension was filtered and dried in Vacuum Tray Dryer at 50°C to obtain the title compound.
Example-16: Preparation of co-crystal Form LU of Lesinurad.
Lesinurad (0.404 g) and urea (0.060) were taken in a mortar. N-butanol (0.5 mL) was added to the above mixture and ground for 10-15 minutes. The obtained solid was kept for drying in Air Tray Dryer at 45°C to obtain the title compound.
Example-17: Preparation of co-crystal Form LU of Lesinurad.
Urea (0.240 g) was dissolved in n-butanol (12 mL) at 65°C. Lesinurad (1.616 g) was added to the above solution at 65°C and stirred for 10 minutes. The reaction mass was cooled to 30°C under stirring. The resultant suspension was filtered and dried in Vacuum Tray Dryer at 45°C to obtain the title compound.
HPLC assay % of Lesinurad obtained in Form-LU is 87.04 % which conforms to a 1:1 co-crystal of Lesinurad and Urea.

Example-18: Preparation of pure DMSO solvate of Lesinurad.
Lesinurad (5 g) was added in ethyl acetate (20 mL) at 28°C. DMSO (2.5 mL) was added to the reaction mass at 28°C and stirred for 60 minutes. The resultant mass was filtered and dried in Vacuum Tray Dryer at 50°C to obtain the title compound. Purity by HPLC: 99.89%
Example-19: Preparation of pure DMSO solvate of Lesinurad.
Lesinurad (2 g) was added in isopropyl acetate (8 mL) at 25°C. DMSO (0.5 mL) was added to the reaction mass at 25°C and stirred for 80 minutes. The resultant mass was filtered and dried in vacuum tray dryer at 40°C to obtain the title compound. Purity by HPLC: 99.86%
Example-20: Preparation of pure DMSO solvate of Lesinurad.
Lesinurad (2 g) was added in butyl acetate (8 mL) at 25°C. DMSO (0.5 mL) was added to the reaction mass at 25°C and stirred for 2-3 hours. The resultant mass was filtered and washed with butyl acetate (3X 2mL), dried in vacuum tray dryer at 50°C to obtain the title compound.
Purity by HPLC: 99.85%
Example-21: Preparation of pure DMSO solvate of Lesinurad.
Lesinurad (40 g) was added in methyl tertiary butyl ether (160 mL) at 25°C. DMSO (8 mL) was slowly added to the reaction mass at 22°C-25°C for a period of 20 minutes and stirred for 4 hours. The resultant mass was filtered and dried in vacuum tray dryer at 40°C to obtain the title compound. Purity by HPLC: 99.74%
,CLAIMS:1) A crystalline DMSO solvate of Lesinurad.
2) A crystalline DMSO solvate of Lesinurad according to claim 1, characterized by an X-ray diffraction pattern having peaks at 7.45, 11.57, 14.84 and 16.75 ± 0.2° 2?; an X-ray powder diffraction pattern as depicted in figure 13.
3) A crystalline DMSO solvate of Lesinurad according to claim 1, 7.38, 11.51, 14.77, 16.69 and 31.07 ± 0.2° 2?; an X-ray powder diffraction pattern as depicted in figure 9.
4) A crystalline DMSO solvate of Lesinurad according to claim 1, characterized by an X-ray diffraction pattern having peaks at 7.40, 12.15, 15.58, 16.73 and 23.43 ± 0.2° 2?; an X-ray powder diffraction pattern as depicted in figure 6.
5) A process for the preparation of pure crystalline DMSO solvate of Lesinurad comprising:
a) suspending Lesinurad in a solvent;
b) optionally, heating the solution of step a);
c) adding DMSO to the slurry of Lesinurad; or adding slurry of Lesinurad to DMSO;
d) isolating pure crystalline DMSO solvate of Lesinurad;
e) optionally, drying the product at suitable temperature.
6) The process as claimed in claim 5, wherein solvent used in step a) is selected from methanol, ethanol, 1-propanol, isopropanol, n-butanol, 2-butanol, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, isopropyl acetate, isobutyl acetate, acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, C3-C6 ketones, diethyl ether, diisopropyl ether, methyl tert-butyl ether, dibutyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 2-methoxyethanol, 2-ethoxyethanol, anisole, 1,4-dioxane, toluene, xylene, chlorobenzene, chloroform, dichloromethane, water or mixtures thereof.
7) A Urea co-crystal of Lesinurad characterized by X-ray powder diffraction pattern having peaks at about 7.21, 13.62, 16.94, 19.32, 21.86, 22.74, 24.46 and 28.82 ± 0.2° 2?; an X-ray powder diffraction pattern as depicted in figure 12.
8) A Nicotinamide co-crystal of Lesinurad characterized by X-ray powder diffraction pattern having peaks at about 6.33, 13.32, 14.22, 15.42 and 29.08± 0.2° 2?; an X-ray powder diffraction pattern as depicted in figure 8.
9) A crystalline Form RB11 of Lesinurad, characterized by a PXRD comprising the peaks at about 14.28, 16.99, 24.82 and 25.54 ± 0.2° 2?; an X-ray powder diffraction pattern as depicted in figure 10.
10) A crystalline Form RB6 of Lesinurad, characterized by a PXRD comprising the peaks at about 8.79, 14.34, 14.53, 14.90, 15.10, 15.64, 17.61, 28.88 and 32.81 ± 0.2° 2?; an X-ray powder diffraction pattern as depicted in figure 4.