NOV E L C OC RY STA L O F L E SINURA D AN D PR OC E SS FOR T H E

PR E PA RAT ION T H E R E O F

F ield of the Invention:

The present invention relates to co-crystals of lesinurad with nicotinamide, urea, and caffeine; methods for thei r preparation, pharmaceutical compositions and method of use thereof.

Background of the Invention:

Lesinurad is chemically known as 2-((5-bromo-4-(4- cyclopropylnaphthalen-l-yl)-4H- 1 , 2,4-tri azol - 3-y I )thi o) aceti c acid, having the structural formula:

Lesinurad is a urate transporter inhibitor for treating hyperuricemia associated with gout in patients who have not achieved target serum uric acid levels with a xanthine oxidase inhi bitor alone. It has been approved by FDA on December 22, 2015. Lesinurad is marketed i n U S A and E urope under the trade name of Z urampi c ^÷ .

Lesinurad is used for decreasing uric acid levels i n one or more tissues or organs, blood, serum, urine, or combinations thereof. It is also used for reducing uric acid production, increasing uric acid excretion or both in an individual and for treati ng an individual suffering from a condition characterized by abnormal tissue levels of uric acid.

Different polymorphic forms of Lesinurad are known in the literature, which differ from, each other in terms of stability, physical properties and pharmacokinetics. The reported polymorphs of lesinurad are incorporated here by the way of reference.

PCT publication W 02012092395 describes crystalline Form I and II of lesinurad. PCT publication WO 2015075561 describes crystalline forms III, IV, V and VI of I esinurad.

PCT publication W 02015095703 describes crystalline form of lesinurad namely a I esinurad- proline co-crystal and a lesinurad-glycol ic acid co-crystal.

¾ PCT publication W 02017036884 descri bes a lesinurad cocrystal comprising lesinurad free form and lesinurad ethyl ester.

Polymorphs often improve physical and biological characteristics of mother compounds without modifying primary pharmacological activity, based on mechanism of action. Thus there is a continuing need to obtain new polymorphs of lesinurad having improved 3a physical and/or chemical properties.

Summary of the Invention:

In one aspect, the present invention provides a co-crystal comprising lesinurad and a co- crystal former wherein the co-crystal former is selected from nicotinamide, urea and caffeine and the I ike.

¾ In another aspect the invention provides a I esinurad- nicotinamide co-crystal designated as Form L5 and process for the preparation thereof.

In another aspect the invention provides a lesinurad-urea co-crystal designated as Form L 6 and process for the preparati on thereof.

In another aspect, the invention provides a lesinurad-caffeine co-crystal designated as , Form L7 and process for the preparation thereof.

In another aspect the invention provides for pharmaceutical composition of Form L5, L6 and L7 of lesinurad or mixture thereof.

Description of the drawings:

Figure 1: Illustrates X -ray powder diffraction pattern of I esinurad- nicotinamide co-crystal t& (Form L 5).

Figure 2: Illustrates Differential Scanning Calorimetry thermogram of Form L5 of L esi nurad. Figure 3: Illustrates Thermogravi metric analysis curve of Form L5 of Lesi nurad.

Figure 4: Illustrate IR spectrum for Form L5 of Lesinurad.

Figure 5: Illustrates X -ray powder diffraction pattern of lesinurad- urea co-crystal (Form L6).

¾ Figure 6: Illustrates Differential Scanning Calorimetry thermogram of Form L6 of L esi nurad.

Figure 7: Illustrates Thermogravi metric analysis curve of Form L6 of Lesinurad.

Figure 8: Illustrate IR spectrum for Form L6 of Lesinurad.

Figure 9: Illustrates X -ray powder diffraction pattern of I esi nurad- urea co-crystal (Form 3a L7).

Figure 10: Illustrates Differential Scanning Calorimetry thermogram of Form L7 of L esi nurad.

Figure 11 : Illustrates Thermogravi metric analysis curve of Form L7 of Lesinurad.

Figure 12: Illustrate IR spectrumfor Form L7 of Lesinurad.

¾ Figure 13: The ORT E Ps of (a) Lesinurad- nicotinamide (1 :1) and (b) Lesinurad-caffeine (1 : 1) co-crystals with 50% thermal ellipsoid

Detail Description of the Invention:

The present invention provides novel solid state forms of Lesinurad, which comprises lesinurad co-crystals with nicotinamide, urea or caffeine. T hese solid state forms can be , used to prepare pharmaceutical compositions comprising the crystalline lesinurad co- crystal forms of the present invention and a pharmaceutical ly acceptable carrier and their use in treating conditions and disorders for which lesinurad is therapeutically effective.

The term ^" co-crystal _ means a crystalline material comprised of two or more unique solids at room temperature, each containing distinctive physical characteristics, such as i¾ structure, melting point and heats of fusion. In the context of the present invention, the term ^" co-crystal _ means a crystalline material comprised of lesinurad and a second solid molecule designated as ^" co-crystal former _, . In one preferred embodiment the co-crystal former is nicotinamide. In another preferred embodiment the co-crystal former is urea. In yet another preferred embodiment the co-crystal former is caffeine. The stoichiometry of each component in the co-crystal can vary. In some embodiments, the stoichiometry of the complex is 1 :1, i.e., one molecule of lesinurad co-crystal lized with one molecule of nicotinamide or urea. In other embodiments, one molecule of lesinurad co-crystallizes

¾ with more than one molecule of nicotinamide, urea or caffeine, such that the stoichiometry between the two molecules is, e.g., 1:2, 1 :3, 1:4 etc. lesinurad- nicotinamide/urea/caffeine. In other embodiments, one molecule of lesinurad co- crystallizes with less than one molecule of nicotinamide/urea/caffeine, such that the stoichiometry between the two molecules is, e.g., 4:1, 3:1, 2:1 etc. lesinurad-

3a nicotinamide/urea/caffeine. T he term ^" co-crystal _ does not include a physical mixture of lesinurad with nicotinamide/urea/caffeine. Also included in the present invention are solvates and hydrates (e.g., monohydrate, di hydrate etc.) as well as anhydrous and various polymorphic forms of the co-crystals of the present invention. Co-crystals have the dual advantages of improved solubility and stabil ity than the corresponding salts and solvates

¾ or hydrates.

In one embodiment, the invention provides a lesinurad- nicotinamide co-crystal (Form L5).

The lesinurad- nicotinamide co-crystal (Form L5) is characterized by X -ray powder diffraction (X RPD) pattern, which comprises of peaks expressed as 2 : at 6.3, 7.66, 10.39, tin 13.26, 14.17, 15.4, 19.99, 22.86, 23.45, 25.56 and 26.62 e 0.2 degrees. The X RPD of Form L5 is depicted in figure 1.

The lesinurad- nicotinamide co-crystal (Form L5) is further characterised by differential scanning calorimetry (DSC), thermal gravimetric analysis (TGA), Infra-Red spectroscopy and Single crystal data. i¾ The DSC thermogram of lesinurad- nicotinamide co-crystal is as set forth in Figure 2 with an endotherm havi ng an onset at about 176 eC and a peak at about 179 eC.

The thermo-gravi metric analysis (TGA) thermogram of lesinurad-nicotinamide co-crystal is as set forth in Figure 3. The Infrared (IR) spectrum of I esinurad- nicotinamide co-crystal is as set forth in Figure 4 with peaks at about 3355, 3172, 1909, 1889, 1718, 1666, 1592, 1555, 1412 and 1198 cmB1.

The I esinurad- nicotinamide co-crystal is characterized by single-crystal x-ray data as ¾ provided in Table-1. The unit cell parameters of the I esinurad- nicotinamide co-crystal comprises of the foil owing cell dimensions: a= 14.083(19) i ; b=6.958(9) \ ; c= 23.11(3) i ; =90e ;<f =95.555(17)e; =90e , "space Group = P-21/c and crystal lattice = monoclinic.

In another embodiment the invention provides a L esinurad- nicotinamide co-crystal (Form L5) that has at least one of the following properties:

3a (a) an X -Ray powder diffraction (X RPD) pattern as shown in Figure 1;

(b) an X -ray powder diffraction (X RPD) pattern comprising of characteristic peaks expressed as 2 : :at 6.30, 7.66, 10.39, 13.26, 14.17, 15.39, 19.99, 22.86, 23.45, 25.56 and 26.62 e0.2 degrees;

(c) a DSC thermogram as set forth in Figure 2;

¾ (d) a thermo-gravi metric analysis (TGA) thermogram as setforth in Figure 3;

(e) a DSC thermogram with an endotherm having an onset at about 176 eC and a peak at about 179 eC;

(f) Infrared (IR) spectrum as set forth i n Figure 4;

(g) Infrared (IR) spectrum with peaks at about 3355, 3172, 1909, 1889, 1718, 1666, 1592, tin 1555, 1412, and 1198 cmE1; or

(h) combinations thereof

The present i nvention further provides a process for preparation of I esinurad- nicotinamide co-crystal (Form L5), which comprises the steps of: (a) dissolving lesinurad and nicotinamide in a mixture of solvent selected from alcohol, ketone, nitrile and water;

(b) cool i ng the sol ution obtai ned i n step (a); and

(c) isolating lesinurad- nicotinamide co-crystal (Form L5).

¾ The dissolution of lesinurad and nicotinamide in step (a) is carried out at a temperature of 35 to 80eC, preferably at 45 to 70eC, more preferably at 40 to 45eC, 50 to 55eC and 65 to 70eC.

The isolation of lesi nurad- nicotinamide co-crystal (Form L5) of step (c) is done by conventional techniques known in the art such as concentration, filtration, centrifugation 3a and drying etc. Combination of more than one conventional technique can be used for the isolation of desired product

The mixture of solvent employed in step (a) is selected from but not li mited to lower alky I alcohols such as methanol, ethanol, isopropyl alcohol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, and t-butyl alcohol; ketones such as acetone, ethyl methyl ketone, diethyl ¾ ketone, and methyl isobutyl ketone; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform and carbon tetrachloride; esters such as ethyl acetate, n- propyl acetate, n-butyl acetate and t-butyl acetate; ethers such as diethyl ether, dimethyl ether, di isopropyl ether, methyl t-butyl ether and 1,4-dioxane; nitriles such as acetonitrile and propionitrile; water; and mixtures thereof.

More preferably the mixture of solvent employed in step (a) is selected from but not limited to ketone such as acetone, ethyl methyl ketone and diethyl ketone, alcohol such as methanol and ethanol, nitrile such as acetonitrile and water and mixtures thereof. i¾ In a further embodiment the invention provides a lesinurad- urea co-crystal (Form L6).

The lesinurad- urea co-crystal (Form L6) is characterized by X -ray powder diffraction (X R PD) pattern, which comprises of peaks expressed as 2 : :at 7.34, 8.19, 11.73, 13.0, 14.69, 15.36, 16.18, 19.12, 20.94, 23.61, 24.47 and 31.22 e 0.2 degrees. The X RPD of Form L6 is depicted in figure 5. The lesinurad urea co-crystal (Form L6) is further characterised by differential scanning calorimetry (DSC), thermal gravimetric analysis (TGA) and Infra-Red spectroscopy.

The DSC thermogram of lesinurad-urea co-crystal is as set forth in Figure 6 with an endotherm havi ng an onset at about 158 eC and a peak at about 159 eC .

¾ The thermo-gravi metric analysis (TGA) thermogram of lesinurad-urea co-crystal is as set forth in Figure 7.

The Infrared (IR) spectrum of lesi nurad-urea co-crystal is as set forth in Figure 8 with peaks at about 3459, 3005, 2420, 1903,1633,1697,1456, 1420 and 1298 cmB1.

In yet another embodiment the invention provides a Lesinurad-urea co-crystal (Form L6) 3a that has at I east one of the f ol I owi ng properti es:

(a) an X -Ray powder diffraction (X RPD) pattern as shown in Figure 5;

(b) an X -ray powder diffraction (X RPD) pattern comprising of characteristic peaks expressed as 2 : :at 7.34, 8.19, 11.73, 12.99, 14.69, 15.36, 16.18, 19.12, 20.94, 23.61, 24.47 and 31.22 e0.2 degrees;

¾ ( c) a D S C thermogram as set forth i n F i gure 6;

(d) a thermo-gravi metric analysis (TGA) thermogram as setforth in Figure 7;

(e) a DSC thermogram with an endotherm having an onset at about 158 eC and a peak at about 159 eC;

(f) Infrared (IR) spectrum as set forth in Figure 8; tft (g) Infrared (IR) spectrum with peaks at about 3459, 3005, 2420, 1903,1633,1697,1456, 1420 and 1298 cmB1; or

(h) combinations thereof.

The present i nvention further provides a process for preparation of lesinurad-urea co- i¾ crystal (Form L6), which comprises the steps of: (a) dissolving lesinurad and urea in a solvent selected from ketone;

(b) cool i ng the sol ution obtai ned i n step (a); and

(c) isolating lesinurad urea co-crystal (Form L6).

The dissolution of lesinurad and urea in step (a) is carried out at a temperature of 35 to ¾ 70eC, more preferably at 45 to 50eC .

The isolation of lesi nurad-urea co-crystal of step (c) is done by conventional techniques known in the art such as concentration, filtration, centrifugation and drying etc. Combination of more than one conventional technique can be used for the isolation of desi red product

3a The solvent employed in step (a) is selected from but not li mited to ketone such as acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone and mixtures thereof.

In another embodiment the invention provides a lesinurad-caffeine co-crystal (Form L7).

¾ The lesinurad-caffeine co-crystal (Form L7) is characterized by X -ray powder diffraction (X R PD) pattern, which comprises of peaks expressed as 2 : :at 5.91, 8.16, 9.94, 11.83, 12.47, 14.83, 16.09, 17.50, 19.95, 20.34, 23.43, 25.89 and 29.70 e 0.2 degrees. The X R PD of Form L6 is depicted in figure 9.

The lesinurad-caffeine co-crystal (Form L7) is further characterised by differential , scanning calorimetry (DSC), thermal gravimetric analysis (TGA), Infra-Red spectroscopy and Single crystal data.

The DSC thermogram of lesinurad-caffeine co-crystal is as set forth in Figure 10 with an endotherm havi ng an onset at about 146 eC and a peak at about 147 eC .

The TGA thermogram of lesinurad-caffeine co- crystal is as setforth in Figure H . i¾ The Infrared (IR) spectrum of lesinurad-caffeine co-crystal is as set forth in Figure 12 with peaks at about 3418, 3120, 3059, 2950, 2781, 2497, 1911, 1702, 1660, 1597, 1552, 1455 and 1426 cmB1. The lesinurad-caffeine co-crystal is characterized by single-crystal x-ray data as provided in Table-1. The unit cell parameters of the lesinurad-caffei ne co-crystal comprises of the following cell dimensions: a=15.201(7) i , b=6.796(3) \ , c= 26.002(11) \ , =90e , =101.392(7)e, =90¾ space group = P-21/c and crystal lattice is monoclinic.

¾ In yet another embodiment the invention provides a Lesinurad-caffeine co-crystal (Form L 7) that has at I east one of the f ol I owi ng properti es:

(a) an X -Ray powder diffraction (X RPD) pattern as shown in Figure 9;

(b) an X -ray powder diffraction (X RPD) pattern comprising of characteristic peaks expressed as 2 : :at 5.91, 8.16, 9.94, 11.83, 12.47, 14.83, 16.09, 17.50, 19.95, 20.34,

3 25.89 and 39.70 e0.2 degrees;

(c) a DSC thermogram as set forth in Figure 10;

(d) a thermo-gravi metric analysis (TGA) thermogram as setforth in Figure 11;

(e) a DSC thermogram with an endotherm having an onset at about 146 eC and a peak at about 147 eC;

¾ (f) Infrared (IR) spectrum as set forth in Figure 12;

(g) Infrared (IR) spectrum weak peaks at about 3418, 3120, 3059, 2950, 2781, 2497, 1911, 1702, 1660, 1597, 1552, 1455 and 1426 cmB1 ; or

(h) combinations thereof. tin, The present invention further provides a process for preparation of lesinurad-caffeine co- crystal (Form L7), which comprises the steps of:

(a) dissolving lesinurad and caffeine in a solvent selected from ester;

(b) cool i ng the sol ution obtai ned i n step (a); and

(c) isolating lesinurad-caffeine co-crystal (Form L7). The dissol ution of lesinurad and caffeine in step (a) is carried out at a temperature of 35 to 80eC, more preferably at 65 to 80eC.

The isolation of lesinurad-caffeine cocrystal (Form L7) of step (c) is done by conventional techniques known in the art such as concentration, filtration, centrifugation ¾ and drying etc. Combination of more than one conventional technique can be used for the isolation of the desired product

The solvent employed in step (a) is selected from but not limited to esters such as ethyl acetate, n-propyl acetate, n-butyl acetate and t- butyl acetate and mixtures thereof.

3a Lesinurad used as starting material for the preparation of novel Lesinurad co- crystals of the present i nvention is purchased from commercial sources or prepared from processes known in the art.

Additionally, any crystalline form or amorphous form of Lesinurad or mixture thereof may be used as starting material for preparing novel Lesinurad co-crystals of the present ¾ invention.

In another embodiment the invention provides pharmaceutical compositions comprising an effective amount of any one of the Form L5, L6 or L7 of lesinurad or mixture thereof.

The Form L5, L 6 or L 7 of lesi nurad prepared according to the present invention can be used in the preparation of pharmaceutical composition for treating hyperuricemia , associated with gout in patients who have not achieved target serum uric acid levels with a xanthine oxidase inhibitor alone. Such pharmaceutical composition can be prepared using one or more pharmaceutically acceptable carriers, excipients or diluents by methods known in the literature.

Pharmaceutical formulations of novel polymorphs of lesinurad co-crystal according to i¾ the present invention comprises of one or more pharmaceutically acceptable carriers or excipients such as diluents, binders, stabil izers, glidants, disintegrates, surfactants, lubricants or combinations thereof and optionally other therapeutic agents. Pharmaceutical formulations containing the active ingredient may be in any form suitable for the intended method of administration. When used for oral use for example, tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs may be prepared.

The diluents, binders, stabilizers, lubricants, glidants, disintegrating agents, surfactants, and other additives that are commonly used in sol id pharmaceutical dosage form ¾ preparati ons i ncl ude as f ol I ows:

Diluents:

Various useful fillers or diluents include but are not limited to starches, lactose, mannitol ( Pearl itolT M SD200), cellulose derivatives, confectioner's sugar and the like. Different grades of lactose i nclude but are not limited to lactose monohydrate, lactose DT (direct

3a tableting), lactose anhydrous, FlowlacT M, PharmatoseT M and others. Different starches include but are not limited to maize starch, potato starch, rice starch, wheat starch, pregelatinized starch and starch 1500, starch 1500 L M grade (low moisture content grade) from Colorcon, fully pregelatinized starch and others. Different cel lulose compounds that can be used include crystalline celluloses and powdered celluloses. Examples of

¾ crystalline cellulose products include but are not limited to CEOL UST M KG801, AvicelT M PH101, PH102, PH301, PH302 and PH-F20, PH112 mi crocrystalline cellulose 114, and mi crocrystalline cellulose 112. Other useful diluents include but are not limited to carmellose, sugar alcohols such as mannitol ( Pearl itolT M SD200), sorbitol and xylitol, calcium carbonate, magnesium carbonate, dibasic calcium phosphate, and tri basic , cal ci um phosphate.

Binders:

Various useful binders incl ude but are not limited to hydroxypropy I celluloses, also called H PC (K lucelT M L F, Klucel EX F) and useful in various grades, hydroxypropyl methyl cell uloses, also called hypromelloses or H PMC (MethocelT M) and useful in i¾ various grades, polyvinylpyrrolidones or povidones (such as grades PV P-K25, PV P-K29, PV P-K30, and PV P-K90), PlasdoneT M S-630 (copovidone), powdered acacia, gelatin, guar gum, carbomers (CarbopolT M), methyl celluloses, polymethacrylates, and starches.

Disintegrants: Various useful di si integrants include but are not limited to carmellose calcium, carboxymethylstarch sodium, croscarmellose sodium, crospovidones, examples of commercial ly available crospovidone products including but not limited to crossl inked povidone, KollidonT M CL, Polypi asdoneT M X L, X I-10, and INF-10 and low-substituted ¾ hydroxypropyl celluloses. Examples of low- substituted hydroxypropyl celluloses include but are not limited to low-substituted hydroxypropyl cellulose L H11, L H21, L H31, L H22, L H32, L H20, L H30, L H32 and L H33. Other useful disintegrants i nclude sodium starch glycolate, colloidal si licon dioxide, and starches.

Stabilizers:

3a Various useful stabi lizers i nclude basic inorganic salts, such as but not limited to basic inorganic salts of sodium, potassium, magnesium and calcium Examples of basic inorganic salts of sodium are sodi um carbonate, sodi um hydrogen carbonate, sodium hydroxide, and the like. Examples of basic inorganic salts of potassium are potassium carbonate, potassium hydrogen carbonate, potassium hydroxide, and the like. Examples

¾ of basic i norganic salts of magnesium are heavy magnesi um carbonate, magnesium carbonate, magnesi um oxi de, magnesium hydroxide, magnesium metasi I icate aluminate, magnesium silicate, magnesium aluminate, synthetic hydrotalcite [Mg6AI2(OH)16.C03.4H20], aluminum hydroxide- magnesium [Z5MgO.AI203.xH20], and the like. Examples of basic inorganic salts of calci um incl ude precipitated calcium , carbonate, cal ci um hydroxi de, and the I i ke.

Surface-Active A gents:

Useful surface-active agents include non-ionic, cationic and anionic surface-active agents. Useful non-ionic surface-active agents include ethylene glycol stearates, propylene glycol stearates, diethylene glycol stearates, glycerol stearates, sorbitan esters (SPA NT M) and i¾ polyhydroxyethylenically treated sorbitan esters (TWE E NTM), aliphatic alcohols and PEG ethers, phenol and PE G ethers. Useful cationic surface-active agents include quaternary ammonium salts (e.g. cetyltrimethylammonium bromide) and amine salts (e.g. octadecylamine hydrochloride). Useful anionic surface-active agents include sodium stearate, potassium stearate, ammonium stearate, and calcium stearate, triethenol amine

†3a stearate, sodium lauryl sulphate, sodium dioctylsulphosuccinate, and sodium dodecylbenzenesulphonate. Natural surface-active agents may also be used, such as for example phospholipids, e.g. diacyl phosphatidyl glycerols, diacey I phosphatidyl cholines, and diaceyl phosphatide acids, the precursors and derivatives thereof, such as for example soybean I ecithi n and egg yol k.

¾ L ubricants:

An effective amount of any pharmaceutically acceptable tableting l ubricant can be added to assist with compressing tablets. Useful tablet lubricants include magnesium stearate, glyceryl monostearates, palmitic acid, talc, carnauba wax, calcium stearate sodium, sodium or magnesium lauryl sulfate, calcium soaps, zinc stearate, polyoxy ethylene 3a monostearates, calcium silicate, silicon dioxide, hydrogenated vegetable oi ls and fats, stearic acid and combinations thereof.

G lidants:

One or more glidant materials, which improve the flow of powder blends and minimize dosage form weight variations, can be used. Useful glidants include but are not limited to ¾ si I i cone di oxi de, tal c and combi nati ons thereof.

C oloring Agents:

Coloring agents can be used to color code the compositions, for example, to i ndicate the type and dosage of the therapeutic agent therei n. Suitable coloring agents include, without limitation, natural and/or artificial compounds such as FD&C coloring agents, natural , juice concentrates, pigments such as titanium oxide, silicon dioxide, iron oxides, zinc oxide, combi nati ons thereof, and the I i ke.

Useful additives for coatings include but are not limited to plasticizers, anti adherents, opacifiers, solvents, and optionally colorants, lubricants, pigments, antifoam agents, and polishing agents. i¾ Various useful plasticizers include but are not limited to substances such as castor oil, di acetyl ated monoglycerides, di butyl sebacate, diethyl phthalate, glycerin, polyethylene glycol, propylene glycol, triacetin, and triethyl citrate. Also, mixtures of plasticizers may be utilized. The type of plasticizer depends upon the type of coating agent An opacifier like titianium dioxide may also be present typically in an amount ranging from about 10% to about 20% based on the total weight of the coati ng.

The present invention will now be further illustrated by reference to the following examples, which do not limit the scope of the i nventi on any way.

¾ E xamples:

E xample 1 :

Preparation of C rystalline F orm L 5 of L esi nurad co-crystal

1.0 g of Lesinurad and 0.3 g of nicotinamide were dissolved in 15 ml of acetone, 2 ml of methanol and 2 ml of water at 50-55eC. The solution was cooled to 10eC, followed by 3a filtration of the white precipitate formed. The solid obtained was dried under vacuum at 45eC for 15-16 h to give 1.1 g of desi red product

E xample 2:

Preparation of C rystalline F orm L 5 of L esi nurad co-crystal

1.0 g Lesinurad and 0.3g nicotinamide were dissolved in 20 ml EtOH, followed by 5.0 ml ¾ MeOH at 65-70eC. The solution was cooled to 25eC and distil led using rotatory evaporator at 50eC. The sol id obtained was dried at 45eC for 15-16 h to give 1.0 g of desi red product

E xample 3:

Preparation of C rystalline F orm L 5 of L esi nurad co-crystal , 1.0 g Lesinurad and 0.3 g nicotinamide were dissolved in 15 ml acetonitrile and 2 ml EtOH and 1 ml water at 65-70eC. The solution was cooled. The crystallization started at 20eC. The reaction mixture was further cooled to 10eC, followed by filtration of the white precipitate formed. The solid obtained was dried under vacuum at 45eC for 15-16h to give 1.0 g of desired product ¾ E xample 4: Preparation of C rystalline F orm L 5 of L esi nurad co-crystal

Lesinurad (2.0g) and nicotinamide (0.6g) were dissolved in 23 ml MeOH and 4 ml water at 50-55eC. The solution was cooled to 10eC followed by filtration of the white precipitate and dried under vacuum at 45eC for 15-16h to give 1.4 g of the desired ¾ product.

E xample 5:

Preparation of C rystalline F orm L 5 of L esi nurad co-crystal

1.0 g Lesinurad and 0.3 g nicotinamide were dissolved in 10 ml acetone and 2 ml water at room temperature. The clear solution obtained was refluxed at 40-45eC. Crystallization 3a was observed at 40eC. The reaction mixture was cooled to 10eC, filtered the white preci pitate and dried under vacuum at 45eC for 1 h to give 1.0 g of desi red product.

E xample 6:

Preparation of C rystalline F orm L 6 of L esi nurad co-crystal

1.0 g of Lesinurad and 0.15 g of urea were dissolved in 10 ml acetone at 45-50eC. The ¾ solution was cooled to 5eC followed by filtration of the white precipitate formed. The sol id obtai ned was dried under vacuum at 45eC for 2-3 h to give 0.6 g of desi red product

E xample 7:

Preparation of C rystalline F orm L 6 of L esinurad co-crystal

5.0g Lesinurad and 0.8g urea were dissolved in 30 ml acetone at 45-50eC. The , crystallization started at 45eC immediate after dissolution. The reaction mixture was cool ed to 10eC f ol I owed by f i I trati on of the preci pi tated sol i d, dri ed under vacuum at45eC for 15-16h to give 4.8g of the desi red product

E xample 8:

Preparation of C rystalline F orm L 7 of L esi nurad co-crystal 1.0 g of Lesinurad and 0.5 g of caffeine were dissolved in 20 ml ethyl acetate at 65-80eC. T he sol uti on was cool ed to 5eC f ol I owed by f i I trati on of the whi te preci pi tate formed. T he sol id obtai ned was dried under vacuum at 45eC for 2-3 h to give 0.6 g of desi red product

E xample- 9:

¾ Single X-ray crystal structure investigation of L esinurad-nicotinamide and L esi nurad-caff ei ne co-crystal

Single crystals were obtained by dissolving lesinurad co-crystals i n 8V methanol at 45eC, followed by cooling at 25eC and then slow evaporation at ambient conditions. A good qual ity si nge crystal was mounted on a Rigaku Mercury 375/M CCD (XtaLAB mini)

3a diffractometer using graphite monochromated Mo K irradiation at 296 K. The data were processed with Crystal Clear software (Rigaku, 2009). Structure solution and refinements were executed using SH E LX 97 (Sheldrick, 2008) and the WinGX (Farrugia, 1999) suite of programs. Refinement of coordinates and anisotropic displacement parameters of non- H atoms were performed with the full-matrix least-squares method. The H-atom positions

¾ were located from difference Fourier maps or calculated using a riding model.

T able 1 : Crystal data of Lesinurad Co-crystals

C ompounds L esinurad-nicoti nami de L esi nurad-caffei ne

Chemical formula C ₁₇ H ₁₄ BrN302S. C ₆ H ₆ N ₂ 0 Ci7Hi4BrN ₃ 0 ₂ S, C ₈ HioN ₄ 02

Formula Weight 526.41 598.48

Temperature (K) 296(2) 296(2)

Wavelength (j ) 0.71073 0.71073

Crystal lattice Monoclinic Monocli nic

Space group P-21/c P-21/c

a, b, c [j ] 14.083(19), 6.958(9), 23.11(3) 15.201(7), 6.796(3), 26.002(11)

, j, m 90, 95.555(17), 90 90, 101.392(7), 90