DESC:The following specification particularly describes the invention and the manner in which it is to be performed:
FILED OF INVENTION
An aspect of the present application provides amorphous solid dispersions of Vadadustat together with at least one pharmaceutically acceptable excipient, process for its preparation and pharmaceutical composition thereof. Another aspect of the present application provides co-crystals of Vadadustat and Nicotinamide, process for its preparation and pharmaceutical composition comprising said co-crystal of Vadadustat.
BACKGROUND OF THE INVENTION
Vadadustat is a hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitor and has the function of treating or preventing anemia. The drug compound having the adopted name “Vadadustat” has chemical name: [5-(3-chlorophenyl)-3-hydroxypyridine-2-carboxamido]acetic acid represented by the following chemical structure;

The new drug application for Vadadustat is already submitted in Japan for the treatment of anemia due to chronic kidney disease and it is currently under Phase 3 clinical trials in US, Europe and other countries.
WO 2015073779A1 discloses crystalline Form A, Form B and Form C of Vadadustat. WO 2018108101A1 discloses Crystal form CS1, crystal form CS2 and crystal form CS8. IP.Com (2018), 18(8A), 1-2, discloses amorphous form of Vadadustat.
There remains a need for alternate polymorphic forms of Vadadustat and preparative processes thereof.
SUMMARY OF THE INVENTION
In the first aspect, the present application provides amorphous solid dispersion of Vadadustat together with at least one pharmaceutically acceptable excipient.
In the second aspect, the present application provides a process for the preparation of amorphous solid dispersion of Vadadustat, comprising the steps of:
a) providing a solution of Vadadustat and at least one pharmaceutically acceptable excipient in a suitable solvent or a mixture thereof;
b) removing the solvent from the solution obtained in step a); and
c) isolating the amorphous solid dispersion of Vadadustat;
In the third aspect, the present application provides a pharmaceutical composition comprising amorphous solid dispersion of Vadadustat together with at least one pharmaceutically acceptable excipient.
In the fourth aspect, the present application provides a co-crystal of Vadadustat and Nicotinamide, process for its preparation and pharmaceutical composition comprising the said co-crystal and one or more pharmaceutically acceptable excipients. Preferably, the pharmaceutical composition is in the form of a solid dosage form. Most preferably, the pharmaceutical composition is a tablet.
BRIEF DESCRIPTION OF THE DRAWING
Figure 1 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of Vadadustat with Syloid prepared by the method of Example No 1.
Figure 2 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of Vadadustat with Copovidone prepared by the method of Example No 2.
Figure 3 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of Vadadustat with Polyvinylpyrrolidone K-30 prepared by the method of Example No 3.
Figure 4 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of Vadadustat with HPC and Syloid prepared by the method of Example No 4.
Figure 5 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of Vadadustat with HPMC and Syloid prepared by the method of Example No 5.
Figure 6 is an illustrative X-ray powder diffraction pattern of co-crystal of Vadadustat and Nicotinamide.
DETAILED DESCRIPTION OF THE INVENTION
In the first aspect, the present application provides amorphous solid dispersion of Vadadustat together with at least one pharmaceutically acceptable excipient.
In the second aspect, the present application provides a process for the preparation of amorphous solid dispersion of Vadadustat, comprising the steps of:
a) providing a solution of Vadadustat and at least one pharmaceutically acceptable excipient in a suitable solvent or a mixture thereof;
b) removing the solvent from the solution obtained in step a); and
c) isolating the amorphous solid dispersion of Vadadustat;

In an embodiment, suitable solvent at step a) may be selected from halogenated hydrocarbons, C1-C6 alcohols, C3-C6 ketones, C5-C8 aliphatic or aromatic hydrocarbons, C3-C6 esters, C2-C6 aliphatic or cyclic ethers, C2-C6 nitriles, water or mixtures thereof.
In preferred embodiment, the suitable solvent may be selected from the group consisting of dichloromethane, methanol, ethanol, 2-propanol, 1-butanol, 2-butanol, 1-pentanol, 2-pentanol, 3-pentanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl acetate, ethyl acetate, isopropyl acetate, tetrahydrofuran, 1,4-dioxane, water or any mixtures of two or more thereof.
In addition to the pharmaceutically acceptable excipients provided in the examples described in this application, any other suitable excipient can also be used for preparation of amorphous solid dispersion.
In an embodiment, the other suitable pharmaceutically acceptable excipient of this aspect may be selected from the group consisting of polyvinylpyrrolidone, polyvinylpyrrolidone K-30, polyvinylpyrrolidone K-90, povidone K-60, copovidone, hydroxypropyl cellulose (HPC), hydroxypropyl cellulose SSL (HPC-SSL), hydroxypropyl cellulose SL (HPC-SL), hydroxypropyl cellulose L (HPC-L), hydroxypropylmethyl cellulose (HPMC), methyl cellulose 15 cps, prosolv HD 40, syloid, syloid 244 NF, polyvinylpyrrolidone vinylacetate, polyvinylacetal diethylaminoacetate (AEA®), polyvinyl acetate phthalate, polysorbate 80, polyoxyethylene–polyoxypropylene copolymers (Poloxamer® 188), polyoxyethylene (40) stearate, polyethyene glycol monomethyl ether, polyethyene glycol, poloxamer 188, pluronic F-68, methylcellulose, Soluplus® (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (PCL-PVAc-PEG)), gelucire 44/14, D-alpha-tocopheryl polyethylene glycol 1000 succinate, cellulose acetate phthalate, carboxymethylethyl cellulose and the like; cyclodextrins, gelatins, hypromellose phthalates, sugars, polyhydric alcohols, and the like; water soluble sugar excipients, preferably having low hygroscopicity, which include, but are not limited to, mannitol, lactose, fructose, sorbitol, xylitol, maltodextrin, dextrates, dextrins, lactitol and the like; polyethylene oxides, polyoxyethylene derivatives, polyvinyl alcohols, propylene glycol derivatives and the like; homopolymers and copolymers of N-vinyl lactams, cellulose esters, cellulose ethers, high molecular weight polyalkylene oxides, polyacrylamides, vinyl acetate polymers, graft copolymers of polyethylene glycol, polyvinyl caprolactam and polyvinyl acetate, oligo- and polysaccharides and mixtures thereof organic amines such as alkyl amines (primary, secondary, and tertiary), aromatic amines, alicyclic amines, cyclic amines, aralkyl amines, hydroxylamine or its derivatives, hydrazine or its derivatives, and guanidine or its derivatives, or any other excipient at any aspect of present application. The use of mixtures of more than one of the pharmaceutical excipients to provide desired release profiles or for the enhancement of stability is within the scope of this invention. Also, all viscosity grades, molecular weights, commercially available products, their copolymers, and mixtures are all within the scope of this invention without limitation.
In an embodiment, providing a solution at step a) may be carried out by taking the reaction mixture containing Vadadustat directly or by dissolving Vadadustat and at least one pharmaceutically acceptable excipient in a suitable solvent simultaneously or by dissolving components in a suitable solvent separately to form individual solutions and combining those solutions later.
In an embodiment, a solution of Vadadustat and the excipient may be prepared at any suitable temperatures, such as about 0°C to about the reflux temperature of the solvent used. Stirring and heating may be used to reduce the time required for the dissolution process.
In an embodiment, a solution of Vadadustat and the excipient may be filtered to make it clear, free of unwanted particles. In embodiments, the obtained solution may be optionally treated with an adsorbent material, such as carbon and/or hydrose, to remove colored components, etc., before filtration.
In an embodiment, removal of solvent at step b) may be carried out by methods known in the art or any procedure disclosed in the present application. In preferred embodiments, removal of solvent may include, but not limited to: solvent evaporation under atmospheric pressure or reduced pressure / vacuum such as a rotational distillation using buchi rotavapor, spray drying, freeze drying, agitated thin film drying, filtration and the like.
In preferred embodiment, the solvent may be removed under reduced pressures, at temperatures of less than about 100°C, less than about 60°C, less than about 40°C, or any other suitable temperatures.
In an embodiment, the isolation of an amorphous solid dispersion of Vadadustat and excipient at step c) involves recovering the solid obtained in step b). The solid obtained from step b) may be recovered using techniques such as by scraping, or by shaking the container, or adding solvent to make slurry followed by filtration, or other techniques specific to the equipment used.
In an embodiment, amorphous solid dispersion of Vadadustat may be combined with additional excipient using a technique known in art or by the procedures disclosed in the present application.
In preferred embodiment, amorphous solid dispersion of the present application may be combined with additional excipient either by physical blending of both the solid components or by suspending both the components in a suitable solvent and conditions, such that both the components remain unaffected. Blending may be carried out using techniques known in art such as rotatory cone dryer, fluidized bed dryer or the like optionally under reduced pressure / vacuum or inert atmosphere such nitrogen at suitable temperature and sufficient time to obtain uniform composition of amorphous solid dispersion of Vadadustat with pharmaceutically acceptable excipient and at least one additional pharmaceutically acceptable excipient.
In an embodiment, amorphous solid dispersion of Vadadustat may be combined with additional excipient using a technique known in art or by the procedures disclosed in the present application.
In an embodiment, amorphous solid dispersion of the present application may be combined with additional excipient by evaporating the suspension or solution of amorphous solid dispersion of Vadadustat and additional excipient.
In an embodiment, pharmaceutically acceptable additional excipient may be same or different from the excipient used in the preparation of amorphous solid dispersion of Vadadustat. Additional excipient may include, but not limited to an inorganic oxide such as SiO2, TiO2, ZnO2, ZnO, Al2O3 and zeolite; a water insoluble polymer is selected from the group consisting of cross- polyvinyl pyrrolidinone, cross-linked cellulose acetate phthalate, cross-linked hydroxypropyl methyl cellulose acetate succinate, microcrystalline cellulose, polyethylene/polyvinyl alcohol copolymer, polyethylene/polyvinyl pyrrolidinone copolymer, cross-linked carboxymethyl cellulose, sodium starch glycolat, and cross-linked styrene divinyl benzene or any other excipient at any aspect of present application.
Amorphous solid dispersion of Vadadustat isolated at step c) may be dried in a suitable drying equipment such as tray dryer, vacuum oven, rotatory cone dryer, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at atmospheric pressure or under reduced pressures at temperatures of less than about 100°C, less than about 60°C, or any other suitable temperatures. The 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 the third embodiment, the present application provides a pharmaceutical composition comprising amorphous solid dispersion of Vadadustat together with at least one pharmaceutically acceptable excipient.
In embodiments, the present application provides adsorbates, wherein Vadadustat is associated with a suitable substrate. Suitable substrate may be a particulate and/or porous substrate, wherein this substrate has an outer and/or inner surface onto which the API may be adsorbed. This means that if the substrate has pores, these pores are filled by the Vadadustat and the substrate remains unaffected, it does not, at least not essentially, change during and / or after the adsorption. In embodiments, the suitable substrate is selected from the excipients provided in the present application.
Amorphous solid dispersion of Vadadustat may be obtained alternatively either by employing a melt-extrusion technique.
In the fourth aspect, the present application provides co-crystal of Vadadustat and Nicotinamide, process for its preparation and pharmaceutical composition comprising said co-crystal and one or more pharmaceutically acceptable excipients. Preferably, the pharmaceutical composition is in the form of a solid dosage form. Most preferably, the pharmaceutical composition is a tablet.
In an aspect, the co-crystal of Vadadustat and Nicotinamide characterized by a PXRD pattern having X-ray powder diffraction peaks selected from the following at about 8.1° and 20.9°± 0.2° 2? and it may be further characterized by X-ray powder diffraction peaks at about 6.1, 12.1° and 14.5° ± 0.2° 2?. It is a 1:1 stoichiometric anhydrous co-crystal.
In another aspect, the application provides co-crystal of Vadadustat and Nicotinamide, characterized by an X-ray powder diffraction pattern as illustrated in Figure 6.
In another aspect, the present application provides process for the preparation of co-crystal of Vadadustat and Nicotinamide by dissolving Vadadustat and Nicotinamide in a suitable solvent.
In embodiments optionally an anti-solvent is added to the solution to increase the yield of the product.
In another aspect, the present application provides process for the preparation of co-crystal of Vadadustat and Nicotinamide by
a) dissolving Vadadustat and Nicotinamide in a suitable solvent;
b) optionally adding anti-solvent;
c) isolating co-crystal of Vadadustat and Nicotinamide.
In embodiments any suitable solvent can be used for preparing solution. The suitable solvents can be selected from ketones, alcohols, esters, nitriles, chlorinated hydrocarbons, ethers, organic acids, aprotic polar solvents such as DMF, DMAc, DMSO, NMP or the like or their mixtures.
In embodiment, anti-solvent is added to solution. In embodiments the anti-solvent can be selected from ethers, alkanes, cycloalkanes or mixtures thereof. In embodiments preferably the anti-solvent is hexane. In embodiments the ratio of solvent to anti-solvents can be in the range of 1:5 to 1:100 or preferably 1:5 to 1: 50 or any suitable combination.
In embodiments the solution of Vadadustat and Nicotinamide may be obtained by heating and stirring at suitable temperature. In embodiments the solution of Vadadustat and Nicotinamide may be filtered to get particle free solution. In embodiments the seed of co-crystals of Vadadustat and Nicotinamide may also be used for preparing product. The solution may be cooled to get precipitation at a temperature about -10 to 30°C, preferably about 0 to 25°C. The precipitated product may be isolated by filtration and dried at suitable temperature.
In embodiments the seed of co-crystals of Vadadustat and Nicotinamide may also be used for preparing product.
In another aspect, the present application provides a pharmaceutical composition comprising the co-crystals of Vadadustat and Nicotinamide as described in the present application together with at least one pharmaceutically acceptable excipient. Preferably, the pharmaceutical composition is a solid dosage form suitable for oral administration, such as a capsule, tablet, pill, powder or granulate. Most preferably, the pharmaceutical composition is a tablet.
Suitable pharmaceutically acceptable excipients are preferably inert with respect to the co-crystal of Vadadustat and Nicotinamide of the present invention, and may include, for example, one or more excipients selected from binders such as lactose, starches, modified starches, sugars, gum acacia, gum tragacanth, guar gum, pectin, wax binders, microcrystalline cellulose, methylcellulose, carboxymethylcellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, copolyvidone, gelatin, polyvinylpyrollidone (PVP) and sodium alginate; fillers or diluents such as lactose, sugar, starches, modified starches, mannitol, sorbitol, inorganic salts, cellulose derivatives (e.g., microcrystalline cellulose, cellulose), calcium sulphate, xylitol and lactitol; disintegrants such as croscarmellose sodium, crospovidone, polyvinylpyrrolidone, sodium starch glycollate, corn starch, microcrystalline cellulose, hydroxypropyl methylcellulose and hydroxypropyl cellulose; lubricants such as magnesium stearate, magnesium lauryl stearate, sodium stearyl fumarate, stearic acid, calcium stearate, zinc stearate, potassium benzoate, sodium benzoate, myristic acid, palmitic acid, mineral oil, hydrogenated castor oil, medium-chain triglycerides, poloxamer, polyethylene glycol and talc; and dispersants or solubility enhancing agents, such cyclodextrins, glyceryl monostearate, hypromellose, meglumine, Poloxamer, polyoxyethylene castor oil derivatives, polyoxyethylene stearates, polyoxylglycerides, povidone, and stearic acid. Other excipients including preservatives, stabilisers, anti-oxidants, silica flow conditioners, antiadherents or glidants may be added as required. Other suitable excipients and the preparation of solid oral dosage forms is well known to person of skill in the art, and is described generally, for example, in Remington The Science and Practice of Pharmacy 21st Edition (Lippincott Williams & Wilkins: Philadelphia; 2006; Chapter 45).
Optionally, when the pharmaceutical compositions are solid dosage forms, the solid dosage forms may be prepared with coatings, such as enteric coatings and extended release coatings, using standard pharmaceutical coatings. Such coatings, and their application, are well known to persons skilled in the art, and are described, for example, in Remington The Science and Practice of Pharmacy 21st Edition (Lippincott Williams & Wilkins: Philadelphia; 2006; Chapter 47).
Certain specific aspects and embodiments of the present application 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 application in any manner. Variations of the described procedures, as will be apparent to those skilled in the art, are intended to be within the scope of the present application.

Definitions
The term "about" when used in the present application preceding a number and referring to it, is meant to designate any value which lies within the range of ±10%, preferably within a range of ±5%, more preferably within a range of ±2%, still more preferably within a range of ±1 % of its value. For example "about 10" should be construed as meaning within the range of 9 to 11, preferably within the range of 9.5 to 10.5, more preferably within the range of 9.8 to 10.2, and still more preferably within the range of 9.9 to 10.1.
The term "solid dispersion" when used in the present application, denotes a state where most of the Vadadustat, preferably 90%, 95% or all of the Vadadustat of the solid dispersion, is homogeneously molecularly dispersed in a solid polymer matrix. Preferably solid dispersion, relates to a molecular dispersion where the API (active pharmaceutical ingredient) and polymer molecules are uniformly but irregularly dispersed in a non-ordered way. In other words, in a solid dispersion, the two components (polymer and API) form a homogeneous one-phase system, where the particle size of the API in the solid dispersion is reduced to its molecular size. In a preferred embodiment, in the solid dispersion according to the present invention no chemical bonds can be detected between the API and the polymer. In order to arrive at such a solid dispersion, preferably solid solution, it is required to have a substantial amount of API dissolved in a suitable solvent at least at one time point during preparation of said solid dispersion.
The term "adsorbate" when used in the present application, specifies that the Vadadustat is, preferably evenly, and preferably homogeneously, distributed on the inner and/or outer surface of the particulate substrate.
General description of the PXRD equipment
All PXRD data reported herein are obtained using a PANalytical X-ray Diffractometer, with copper Ka radiation.
Instrumental parameters.
Model & Detector
Model PANalytical & X’Pert PRO
Detector X’Celerator
Instrument Setting
Goniometer Theta/Theta
Mode of Collection Reflection
Measuring circle 240 mm
Radiation Cu K-alpha (Wave length = 1.5406 Å)
Scan Parameters
Voltage (kV) and Current (mA) 45 kV and 40 mA
Scan range (°2?) 3-40
Step size (°2?) 0.017
Scan Step Time (s) 64.77
Run Time (min) 20 min
Scan mode Continuous
Divergent slit (°) 0.5
Anti-scattering slit (mm) 5.5 mm
Rotation/min On

EXAMPLES
Example-1: Preparation of amorphous solid dispersion of Vadadustat with Syloid.
Vadadustat (250 mg), 1,4-dioxane (5 mL) and water (5 mL) were charged into a flask, stirred and filtered to a get clear solution. The solution was frozen for 1 h and further lyophilized for 16 h. 100 mg of the obtained solid was ground with Syloid 244 FP (100 mg) in a mortar and pestle.
Yield: 230 mg
The PXRD pattern of the premix of the isolated material and Syloid is represented as Figure-1.
Example-2: Preparation of amorphous solid dispersion of Vadadustat with Copovidone.
Vadadustat (250 mg), Copovidone (250 mg) and acetone (15 mL) were added into a flask and stirred for complete dissolution. The clear solution was evaporated under reduced pressure at 45 °C and the obtained solid product dried under vacuum. The product was obtained was amorphous.
Yield: 430 mg
The PXRD pattern of the isolated material is represented as Figure-2.
Example-3: Preparation of amorphous solid dispersion of Vadadustat with Polyvinylpyrrolidone K-30
Vadadustat (250 mg), Polyvinylpyrrolidone K-30 (250 mg), dichloromethane (5 mL) and Acetone (10 mL) were charged into a flask and stirred to get a clear solution. The clear solution was evaporated using rotavapor at 45°C. The product obtained was amorphous.
Yield: 470 mg
The PXRD pattern of the isolated material is represented as Figure-3.
Example-4: Preparation of amorphous solid dispersion of Vadadustat with HPC and Syloid
Vadadustat (250 mg), HPC (250 mg), dichloromethane (20 mL) and methanol (10 mL) were charged into a flask and stirred to get a clear solution. The clear solution was evaporated using rotavapor at 45°C. 100 mg of the obtained product was ground grinded with Syloid 244 FP (100 mg) in a mortar and pestle. The obtained product was amorphous.
Yield: 465 mg
The PXRD pattern of the premix of the isolated material and Syloid is represented as Figure-4.
Example-5: Preparation of amorphous solid dispersion of Vadadustat with HPMC and Syloid
Vadadustat (250 mg), HPMC (250 mg), dichloromethane (10 mL) and THF (10 mL) were charged into a flask and stirred to get clear solution. The clear solution was evaporated using rotavapor at 45°C. The obtained product was grinded with Syloid 244 FP (100 mg) in a mortar and pestle. The obtained product was amorphous.
Yield: 468 mg
The PXRD pattern of the premix of the isolated material and Syloid is represented as Figure-5.
Example 6: Preparation of co-crystal of Vadadustat and Nicotinamide
Vadadustat (1 g), Nicotinamide (398 mg) and acetone (18 mL) were added into a flask and stirred for 2 minutes at room temperature to obtain a transiently clear solution that rapidly turns into a milky white suspension. Hexane (50 mL) was added to the suspension and stirred for 15 minutes. The solid was obtained by filtration and dried under vacuum at 27°C for 2 h.
Yield: 1.05 g, Yield (%): 75.1 %

The PXRD pattern of the isolated material is represented as Figure-6.
,CLAIMS:WE CLAIM:
1. An amorphous solid dispersion of Vadadustat together with at least one pharmaceutically acceptable excipient.
2. The amorphous solid dispersion of Vadadustat as claimed in claim-1, wherein the pharmaceutically acceptable excipient is selected from group consisting of syloid, copovidone, polyvinylpyrrolidone, polyvinylpyrrolidone K-30, hydroxypropyl cellulose (HPC), hydroxypropylmethyl cellulose (HPMC) or the mixture thereof.
3. A process for the preparation of amorphous solid dispersion of Vadadustat, comprising the steps of:
a) providing a solution of Vadadustat and at least one pharmaceutically acceptable excipient in a solvent or a mixture thereof;
b) removing the solvent from the solution obtained in step a); and
c) isolating the amorphous solid dispersion of Vadadustat.
4. The process as claimed in claim-3 wherein, the pharmaceutically acceptable excipient is selected from group consisting of syloid, copovidone, polyvinylpyrrolidone, polyvinylpyrrolidone K-30, hydroxypropyl cellulose (HPC), hydroxypropylmethyl cellulose (HPMC) or the mixture thereof.
5. The process as claimed in claim-3 wherein, solvent is selected from group consisting of dichloromethane, methanol, ethanol, 2-propanol, 1-butanol, 2-butanol, 1-pentanol, 2-pentanol, 3-pentanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl acetate, ethyl acetate, isopropyl acetate, tetrahydrofuran, 1,4-dioxane, water or any mixtures of two or more thereof.
6. A pharmaceutical composition comprising amorphous solid dispersion of Vadadustat together with at least one pharmaceutically acceptable excipient.
7. A process for the preparation of co-crystal of Vadadustat and Nicotinamide by
a) dissolving Vadadustat and Nicotinamide in a suitable solvent;
b) optionally adding anti-solvent;
c) isolating co-crystal of Vadadustat and Nicotinamide.
8. The process as claimed in claim-7, wherein the co-crystal of Vadadustat and Nicotinamide is characterized by a PXRD pattern having X-ray powder diffraction peaks at about 6.1°, 8.1°, 12.1°, 14.5° and 20.9°± 0.2° 2?.
9. The process as claimed in claim-7 wherein the solvent is selected from group consisting of ketones, alcohols, esters, nitriles, chlorinated hydrocarbons, ethers, organic acids, aprotic polar solvents or mixture thereof.
10. The process as claimed in claim-7, wherein the anti-solvent is selected from ethers, alkanes, cycloalkanes or mixtures thereof.