Solid [(4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carbonyl)amino] acetic acid

Abstract

The present application relates to solid [(4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carbonyl)amino] acetic acid of having a unimodal particle size distribution of D90 of about 21 µm to 29 µm; a D50 of about 12 µm to 17 µm; and a D10 of about 6 µm to 10 µm, and pharmaceutical compositions thereof. Preparation of the solid [(4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carbonyl)amino] acetic acid of the particular particle size distribution, and use of same for the treatment of anemia is also described.

Description

SOLID [(4-HYDROXY-1-METHYL-7-PHENOXYISOQUINOLINE-3- CARBONYL)AMINO]ACETIC ACIDFIELD OF THE INVENTION

[0001] The present application relates to solid [(4-hydroxy-l-methyl-7- phenoxyisoquinoline-3-carbonyl)amino]acetic acid of particular particle size distribution, the preparation of the same and use of same for the treatment of anemia.BACKGROUND

[0002] The particle size distribution (PSD) of compounds is an important aspect of drug development because the PSD can affect the dissolution properties of the compound and can impact the bioavailability and / or efficacy of the active pharmaceutical ingredient and / or pharmaceutical composition. Furthermore, PSD can impact the flowability and manufacturing process of compounds and pharmaceutical compositions.

[0003] Roxadustat, a hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitor, promotes coordinated erythropoiesis through increasing endogenous erythropoietin, improving iron availability, and reducing hepcidin. Administration of roxadustat has been shown to increase red blood cell production while maintaining plasma erythropoietin levels within or near normal physiologic range in multiple subpopulations of chronic kidney disease (CKD) patients, including in the presence of inflammation, and without a need for supplemental intravenous iron.

[0004] Roxadustat is approved in China, Europe, Japan, and numerous other countries for the treatment of anemia in CKD patients on dialysis and patients not on dialysis. Roxadustat is in clinical development for anemia of myelodysplastic syndromes (MDS), and for treatment of chemotherapy-induced anemia (CIA).

[0005] Therefore, ensuring that the particle size of the roxadustat active pharmaceutical ingredient and pharmaceutical compositions containing said roxadustat have good dissolution and bioavailabilty is critical for the effective treatment of patients.SUMMARY

[0006] Disclosed herein is a solid compound of Formula (I):wherein the solid compound has a particle size of D90 < 43 pm and the particle size distribution is unimodal. In some embodiments the solid compound has a unimodal particle size distribution with a D90 of about 13 pm to 43 pm. In some embodiments the solid compound has a unimodal particle size distribution with a D90 of about 21 pm to 29 pm. In some embodiments the solid compound has a unimodal particle size distribution with a D90 of about 21 pm to 29 pm; a D50 of about 12 pm to 17 pm; and a DIO of about 6 pm to 10 pm. In some embodiments the compound has a particle size distribution of D90 of about 21.9 pm to 28.5 pm; a D50 of about 12.28 pm to 16.03; and a DIO of about 6.66 pm to 9.13 pm. In some embodiments the compound has a particle size distribution of

[0007] Also disclosed herein is an oral pharmaceutical composition comprising a therapeutically effective amount of a solid compound of Formula (I):wherein the solid compound has a unimodal particle size distribution with a D90 < 43 pm; and at least one pharmaceutically acceptable excipient, provided the excipient is not a cyclodextrin derivative and polacrilin potassium. In some embodiments the solid compound has a unimodal particle size distribution with a D90 of about 13 pm to 43 pm. In some embodiments the solid compound has a unimodal particle size distribution with a D90 of about 21 pm to 29 pm. In some embodiments the solid compound has a unimodal particle size distribution of D90 of about 21 pm to 29 pm; a D50 of about 12 pm to 17 pm; and a DIO of about 6 pm to 10 pm. In some embodiments the compound has a particle size distribution of D90 of about 21.9 pm to 28.5 pm; a D50 of about 12.28 pm to 16.03; and a D10 of about 6.66 pm to 9.13 pm. In some embodiments the compound has a particle size distribution ofIn some embodiments the excipient is selected from the group consisting of a diluent, a binder, a disintegrant, and a lubricant or combinations thereof. In some embodiments the diluent is selected from starch, saccharides, disaccharides, sucrose, polysaccharides, cellulose, cellulose ethers, hydroxypropyl cellulose, sugar alcohols, xylitol, sorbitol, maltitol, microcrystalline cellulose, calcium or sodium carbonate, lactose, lactose monohydrate, dicalcium phosphate, compressible sugars, dibasic calcium phosphate dehydrate, mannitol, and tribasic calcium phosphate or a combination thereof. In some embodiments the diluent is selected from microcrystalline cellulose or lactose monohydrate or a combination thereof. In some embodiments the binder is selected from hydroxypropylcellulose, hydroxypropylmethylcellulose, povidone, and ethyl cellulose or a combination thereof. In some embodiments the binder is povidone. In some embodiments the disintegrant is selected from maize starch, sodium starch glycolate, croscarmellose sodium, crospovidone, microcrystalline cellulose, modified com starch, sodium carboxymethyl starch, povidone, pregelatinized starch, and alginic acid or a combination thereof. In some embodiments the disintegrant is croscarmellose sodium. In some embodiments the lubricant is selected from magnesium stearate, stearic acid, silica, fats, calcium stearate, polyethylene glycol, sodiumstearyl fumarate, talc, and fatty acids. In some embodiments the lubricant is magnesium stearate. In some embodiments the pharmaceutically acceptable excipient comprises microcrystalline cellulose, lactose monohydrate, povidone, croscarmellose sodium and magnesium stearate. In some embodiments the pharmaceutical composition further comprises a photostabilizer. In some embodiments the photostabilizer comprises Allura Red AC, titanium dioxide and iron oxide yellow. In some embodiments the photostabilizer comprises titanium dioxide and iron oxide yellow. In some embodiments the pharmaceutical composition is a capsule or a tablet. In some embodiments the pharmaceutical composition is a capsule. In some embodiments the pharmaceutical composition comprises 20 mg or 50 mg of the compound.

[0008] Some embodiments describe a capsule comprising: a capsule fill comprising a pharmaceutical composition according to any embodiment described herein, and a capsule shell. In some embodiments the capsule shell comprises a photostabilizer. In some embodiments the photostabilizer comprises Allura Red AC, titanium dioxide and iron oxide yellow. In some embodiments the photostabilizer comprises titanium dioxide and iron oxide yellow.

[0009] Some embodiments describe a capsule comprising a capsule fill and a capsule shell; wherein the capsule fill comprises 20 mg of a solid compound of Formula (I):wherein the solid compound has a unimodal particle size distribution with a D90 < 43 pm; and at least one pharmaceutically acceptable excipient, provided the excipient is not a cyclodextrin derivative and polacrilin potassium. In some embodiments the solid compound has a unimodal particle size distribution with a D90 of about 13 pm to 43 pm. In some embodiments the solid compound has a unimodal particle size distribution with a D90 of about 21 pm to 29 pm. In some embodiments the solid compound has a unimodal particle size distribution of D90 of about 21 pm to 29 pm; a D50 of about 12 pm to 17 pm; and a D10 of about 6 pm to 10 pm;and a pharmaceutically acceptable excipient comprising lactose monohydrate, microcrystalline cellulose, povidone, croscarmellose sodium and magnesium stearate, provided the excipient does not also contain a cyclodextrin derivative and polacrilin potassium; and the capsule shell is a gelatin shell comprising titanium dioxide, iron yellow oxide and gelatin. In some embodiments the capsule fill comprises lactose monohydrate (310), microcrystalline cellulose PH101, povidone K30, croscarmellose sodium and magnesium stearate. In some embodiments the capsule fill comprises 101.84 mg of lactose monohydrate (310), 9.36 mg of microcrystalline cellulose PH101, 6.48 mg of povidone K30, 5.76 mg of croscarmellose sodium and 0.56 mg of magnesium stearate. In some embodiments the titanium dioxide, and iron yellow oxide comprise 3% by weight of the capsule shell. In some embodiments the titanium dioxide is 1%, by weight of the capsule shell and the iron yellow oxide is 2% by weight of the capsule shell.

[0010] Some embodiments describe a capsule comprising a capsule fill and a capsule shell; wherein the capsule fill comprises 50 mg of a solid compound of Formula (I):wherein the solid compound has a unimodal particle size distribution with a D90 < 43 pm; and at least one pharmaceutically acceptable excipient, provided the excipient is not a cyclodextrin derivative and polacrilin potassium. In some embodiments the solid compound has a unimodal particle size distribution with a D90 of about 13 pm to 43 pm. In some embodiments the solid compound has a unimodal particle size distribution with a D90 of about 21 pm to 29 pm. In some embodiments the solid compound has a unimodal particle size distribution of D90 of about 21 pm to 29 pm; a D50 of about 12 pm to 17 pm; and a DIO of about 6 pm to 10 pm; and the pharmaceutically acceptable excipient comprising lactose monohydrate, microcrystalline cellulose, povidone, croscarmellose sodium and magnesium stearate, provided the excipient does not also contain a cyclodextrin derivative and polacrilin potassium; and the capsule shell is a gelatin shell comprising Allura red AC, titanium dioxide, iron yellow oxide and gelatin. In some embodiments the capsule fill comprises lactose monohydrate (310), microcrystalline cellulose PH101, povidone K30, croscarmellose sodium and magnesiumstearate. In some embodiments the capsule fill comprises 254.6 mg of lactose monohydrate (310), 23.4 mg of microcrystalline cellulose PH101, 16.20 mg of povidone K30, 14.40 mg of croscarmellose sodium and 1.4 mg of magnesium stearate. In some embodiments the Allura red AC, titanium dioxide, and iron yellow oxide comprise 3% by weight of the capsule shell. In some embodiments the Allura red AC is 1% by weight of the capsule shell, the titanium dioxide is 1%, by weight of the capsule shell and the iron yellow oxide is 1% by weight of the capsule shell.

[0011] Some embodiments describe a solid compound of Formula (I):wherein the solid compound has a unimodal particle size distribution of D90 of about 21 pm to 29 pm; a D50 of about 12 pm to 17 pm; and a D10 of about 6 pm to 10 pm, prepared by a process comprising:(i.) preparing an aqueous sodium hydroxide solution (Solution 1) by dissolving sodium hydroxide (0.135-0.145 times the weight of technical grade roxadustat) in water (3.3- 3.5 times the weight of technical grade roxadustat);(ii.) preparing an aqueous acetic acid (45-55%) solution (Solution 2) by dissolving acetic acid (0.41-0.45 times the weight of technical grade roxadustat) in water (0.40-0.45 times the weight of technical grade roxadustat);(iii.) mixing technical grade roxadustat and water (9.5-10.5 times the weight of technical grade roxadustat) into a reactor (Rl) with stirring to form a mixture;(iv.) slowly, adding all of the aqueous sodium hydroxide (solution 1) into the mixture of step (iii.) in the reactor (Rl) to form another mixture and stirring at 15-35°C until all the solid is dissolved, provided the stirring is for at least 45 minutes;(v.) transferring the solution of step (iv.) through a cartridge of activated carbon into a new reactor (R2) and washing the cartridge with water (1.9-2.1 times the weight oftechnical grade roxadustat) and then adjusting the solution temperature in the reactor (R2) to 60-80°C;(vi.) adjusting the solution of step (v.) to a pH of 6.0-6.8 by adding aqueous acetic acid (solution 2) into the reactor (R2) at 60-80°C in three parts as follows:(a) first part: Solution 2 (0.060-0.068 times the weight of technical grade roxadustat) is added to reactor 2 (R2);(b) second part: Solution 2 (0.019-0.027 times the weight of technical grade roxadustat) is added to reactor (R2) in portions (0.0005-0.0020 times the weight of technical grade roxadustat) to achieve pH 6.0-6.8;(c) micronized seed roxadustat (0.045-0.055 times the weight of technical grade roxadustat, D90 8 pm -11 pm) is added to the solution in reactor (R2) followed by stirring at 60-80°C for 10-20 minutes;(d) Third part: Solution 2 (0.57-0.64 times the weight of technical grade roxadustat) is added to reactor (R2) and the mixture is stirred at 60-80°C for at least 1 hour; wherein the total acetic acid solution added to reactor (R2) is 0.66-0.72 times the weight of technical grade roxadustat;(vii.) filtering the mixture from step (vi.) at 60-80°C and washing the solid obtained three times with water; wherein the total water used for washing is 4.4-5.6 times the weight of technical grade roxadustat;(viii.) measuring the pH of the filtrate and if the pH of the filtrate is not 6-7 further washing the solid with water until the filtrate reaches pH 6-7;(ix.) drying the solid under vacuum with minimum agitation at < 70°C until residual acetic acid is < 1500 ppm and residual water content is < 0.1% to obtain the compound of Formula (I).In some embodiments the compound has a particle size distribution of D90 of about 21.9 pm to 28.5 pm; a D50 of about 12.28 pm to 16.03; and a D10 of about 6.66 pm to 9.13 pm. In some embodiments the compound has a particle size distribution ofIn some embodiments the solid compound is prepared on a kilogram scale or higher. In some embodiments the technical grade roxadustat is at least 98% pure area by HPLC. In some embodiments the technical grade roxadustat is > 99% pure area by HPLC.

[0012] Some embodiments describe the use of a compound or pharmaceutical composition according to any of the embodiments described herein for the treatment, of anemia. In some embodiments the anemia is anemia of chronic kidney disease (CKD). In some embodiments the anemia is anemia of chronic kidney disease in patients on dialysis. In some embodiments the anemia is anemia of chronic kidney disease in non-dialysis dependent patients. In some embodiments the anemia is chemotherapy-induced anemia (CIA). In some embodiments the anemia is anemia of myelodysplastic syndromes (MDS).

[0013] Some embodiments describe the use of a compound or pharmaceutical composition according to any embodiment described herein for treating a condition mediated by hypoxia inducible factor (HIF).

[0014] Some embodiments describe the use of a compound or pharmaceutical composition according to any embodiment described herein for treating a condition mediated by erythropoietin (EPO).

[0015] Some embodiments describe the use of a compound or pharmaceutical composition according to any embodiment described herein for the manufacture of a medicament.

[0016] Some embodiments describe a process for preparing a solid compound Formula (I):wherein the solid compound has a unimodal particle size distribution of D90 of about 21 pm to 29 pm; a D50 of about 12 pm to 17 pm; and a D10 of about 6 pm to 10 pm, comprising:(i.) preparing an aqueous sodium hydroxide solution (Solution 1) by dissolving sodium hydroxide (0.135-0.145 times the weight of technical grade roxadustat) in water (3.3- 3.5 times the weight of technical grade roxadustat);(ii.) preparing an aqueous acetic acid (45-55%) solution (Solution 2) by dissolving acetic acid (0.41-0.45 times the weight of technical grade roxadustat) in water (0.40-0.45 times the weight of technical grade roxadustat);(iii.) mixing technical grade roxadustat and water (9.5-10.5 times the weight of technical grade roxadustat) into a reactor (Rl) with stirring to form a mixture;(iv.) slowly, adding all of the aqueous sodium hydroxide (solution 1) into the mixture of step (iii.) in the reactor (Rl) to form another mixture and stirring at 15-35°C until all the solid is dissolved, provided the stirring is for at least 45 minutes;(v.) transferring the solution of step (iv.) through a cartridge of activated carbon into a new reactor (R2) and washing the cartridge with water (1.9-2.1 times the weight of technical grade roxadustat) and then adjusting the solution temperature in the reactor (R2) to 60-80°C;(vi.) adjusting the solution of step (v.) to a pH of 6.0-6.8 by adding aqueous acetic acid (solution 2) into the reactor (R2) at 60-80°C in three parts as follows:(a) first part: Solution 2 (0.060-0.068 times the weight of technical grade roxadustat) is added to reactor 2 (R2);(b) second part: Solution 2 (0.019-0.027 times the weight of technical grade roxadustat) is added to reactor (R2) in portions (0.0005-0.0020 times the weight of technical grade roxadustat) to achieve pH 6.0-6.8;(c) micronized seed roxadustat (0.045-0.055 times the weight of technical grade roxadustat, D90 8 pm -11 pm) is added to the solution in reactor (R2) followed by stirring at 60-80°C for 10-20 minutes;(d) Third part: Solution 2 (0.57-0.64 times the weight of technical grade roxadustat) is added to reactor (R2) and the mixture is stirred at 60-80°C for at least 1 hour; wherein the total acetic acid solution added to reactor (R2) is 0.66-0.72 times the weight of technical grade roxadustat;(vii.) filtering the mixture from step (vi.) at 60-80°C and washing the solid obtained three times with water; wherein the total water used for washing is 4.4-5.6 times the weight of technical grade roxadustat;(viii.) measuring the pH of the filtrate and if the pH of the filtrate is not 6-7 further washing the solid with water until the filtrate reaches pH 6-7;(ix.) drying the solid under vacuum, with minimum agitation at < 70°C until residual acetic acid is < 1500 ppm and residual water content is < 0.1% to obtain the compound of Formula (I).In some embodiments the compound has a particle size distribution of D90 of about 21.9 pm to 28.5 pm; a D50 of about 12.28 pm to 16.03; and a DIO of about 6.66 pm to 9.13 pm. In some embodiments the compound has a particle size distribution ofIn some embodiments the so id compound is prepared on a kilogram scale or higher. In some embodiments the technical grade roxadustat is at least 98% pure area by HPLC. In some embodiments the technical grade roxadustat is > 99% pure area by HPLC.BRIEF DESCRIPTION OF THE DRAWINGS

[0017] FIG. 1 is a Graph showing particle size distribution percentile comparison of the solid compounds described in Table 1. The diamonds represent D50 and the Squares represent the DIO. The solid line is a linear distribution for D50 and the dashed line is a linear distribution of the DIO.

[0018] FIG. 2 is a Graph showing dissolution of 150 mg tablets at varying PSD. Q Value is represented by the dashed horizontal line ( ). The small square with solid line (-•--) represents tablets wherein the compound of Formula (I) has a particle size of D90 / D50 / D10 of 93 pm / 54 pm / 30 pm respectively. The diamond with alternating dash and two dot line (—*-•) represents tablets wherein the compound of Formula (I) has a particle size of D90 / D50 / D10 of 70 pm / 40 pm / 21 pm respectively. The large X with solid line (— ) represents tablets wherein the compound of Formula (I) has a particle size of D90 / D50 / D10 of 58 pm / 34 pm / 18 pm respectively. The diamond with dash line (-•*- ) represents tablets wherein the compound of Formula (I) has a particle size of D90 / D50 / D10 of 45 pm / 27 pm / 15 pm respectively. The square with small dash line ( --*-) represents tablets wherein the compound of Formula (I) has a particle size of D90 / D50 / D10 of 22 pm / 13 pm / 7.7 respectively. The circle with small dash line (-■*••-) represents tablets wherein the compound of Formula (I) has a particle size of D90 / D50 / D10 of 13 pm / 6.4, 6.3 pm / 2.1, 1.9 pm respectively.

[0019] FIG. 3 is a Graph showing dissolution of 100 mg tablets at varying PSD. Q Value is represented by the dashed horizontal line ( -). The small square with solid line (-•—) represents tablets wherein the compound of Formula (I) has a particle size of D90 / D50 / D10 of 93 pm / 54 pm / 30 pm respectively. The diamond with alternating dash and two dot line (—♦• •) represents tablets wherein the compound of Formula (I) has a particle size of D90 / D50 / D10 of 70 pm / 40 pm / 21 pm respectively. The large X with solid line (-*— ) represents tablets wherein the compound of Formula (I) has a particle size of D90 / D50 / D10 of 58 pm / 34 pm / 18 pm respectively. The diamond with dash line (~ ) represents tablets wherein the compound ofFormula (I) has a particle size of D90 / D50 / D10 of 45 pm / 27 pm / 15 pm respectively. The circle with alternating dash and dot line (-*■) represents tablets wherein the compound of Formula (I) has a particle size of D90 / D50 / D10 of 22 pm / 13 pm / 7.7 pm respectively. The square with small dash line ( --»-) represents tablets wherein the compound of Formula (I) has a particle size of D90 / D50 / D10 of 13 pm / 6.4, 6.3 pm / 2.1, 1.9 pm respectively.

[0020] FIG. 4 is a Graph showing dissolution of 20 mg tablets at varying PSD. Q Value is represented by the dashed horizontal line ( ). The small square with solid line (— *— )represents tablets wherein the compound of Formula (I) has a particle size of D90 / D50 / D10 of 93 pm / 54 pm / 30 pm respectively. The diamond with alternating dash and two dot line (-*• ■) represents tablets wherein the compound of Formula (I) has a particle size of D90 / D50 / D10 of 70 pm / 40 pm / 21 pm respectively. The large X with solid line (~ ~ ) represents tablets wherein the compound of Formula (I) has a particle size of D90 / D50 / D10 of 58 pm / 34 pm / 18 pm respectively. The diamond with dash line (~) represents tablets wherein the compound ofFormula (I) has a particle size of D90 / D50 / D10 of 45 pm / 27 pm / 15 pm respectively. The circle with alternating dash and dot line (— *•) represents tablets wherein the compound of Formula (I) has a particle size of D90 / D50 / D10 of 22 pm / 13 / 7.7 pm respectively. The square with small dash linerepresents tablets wherein the compound of Formula (I) has a particle size of D90 / D50 / D10 of 13 pm / 6.4, 6.3 pm / 2.1, 1.9 pm respectively.

[0021] FIG. 5 shows the unimodal particle size distribution for a compound of Formula (I) having particle size distribution of D90 of about 21 pm to 29 pm; a D50 of about 12 pm to 17 pm; and a DIO of about 6 pm to 10 pm produced by the method of Example 1.

[0022] FIG. 6 shows the consistency of the process of Example 1 over multiple runs to produce the compound of Formula (I) having particle size distribution of D90 of about 21 pm to 29 pm; a D50 of about 12 pm to 17 pm; and a D10 of about 6 pm to 10 pm produced by the method.DETAILED DESCRIPTIONDEFINITIONS

[0023] Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods, devices, and materials are now described. All publications cited herein are incorporated herein by reference in their entirety for the purpose of describing and disclosing the methodologies, reagents, and tools reported in the publications that might be used in connection with the invention. Nothing herein is to be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior invention.

[0024] The articles "a" and "an" as used herein mean "one or more" or "at least one," unless otherwise indicated. That is, reference to any element of the present invention by the indefinite article "a" or "an" does not exclude the possibility that more than one of the elements is present.

[0025] The term “about” when used before a numerical designation, e.g., temperature, time, amount, and concentration, including a range, indicates approximations which may vary by ±10%, ±5% or ±l%.

[0026] “Administration” refers to introducing an agent into a patient. A therapeutic amount can be administered, which can be determined by the treating physician or the like. An oral route of administration is preferred for compounds of the present invention. The related terms and phrases “administering” and “administration of’, when used in connection with a compound or pharmaceutical formulation (and grammatical equivalents) refer both to direct administration, which may be administration to a patient by a medical professional or by selfadministration by the patient, and / or to indirect administration, which may be the act of prescribing a drug. For example, a physician who instructs a patient to self-administer a drug and / or provides a patient with a prescription for a drug is administering the drug to the patient. In any event, administration entails delivery of the drug to the patient.

[0027] The term “anemia” as used herein refers to any abnormality in hemoglobin or erythrocytes that leads to reduced oxygen levels in the blood. Anemia can be associated with abnormal production, processing, or performance of erythrocytes and / or hemoglobin. The term anemia refers to any reduction in the number of red blood cells and / or level of hemoglobin in blood relative to normal blood levels. Anemia can arise due to conditions such as acute or chronic kidney disease, infections, inflammation, cancer, irradiation, toxins, diabetes, and surgery. Infections may be due to, e.g., virus, bacteria, and / or parasites, etc. Inflammation may be due to infection, autoimmune disorders, such as rheumatoid arthritis, etc. Anemia can also be associated with blood loss due to, e.g., stomach ulcer, duodenal ulcer, hemorrhoids, cancer of the stomach or large intestine, trauma, injury, surgical procedures, etc. Anemia is further associated with radiation therapy, chemotherapy, and kidney dialysis. Anemia is also associated with HIV-infected patients undergoing treatment with azidothymidine (zidovudine) or other reverse transcriptase inhibitors, and can develop in cancer patients undergoing chemotherapy, e.g., with cyclic cisplatin- or non-cisplatin-containing chemotherapeutics. Aplastic anemia and myelodysplastic syndromes are diseases associated with bone marrowfailure that result in decreased production of erythrocytes. Further, anemia can result from defective or abnormal hemoglobin or erythrocytes, such as in disorders including microcytic anemia, hypochromic anemia, etc. Anemia can result from disorders in iron transport, processing, and utilization, see, e.g., sideroblastic anemia, etc.

[0028] The term “API” is the abbreviation for “active pharmaceutical ingredient.” As used herein, API refers to a compound of Formula (I), also known as roxadustat or [(4-hydroxy-l- methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic acid.

[0029] “Binder” refers to any pharmaceutically acceptable substance which can be used to bind the active and inert components together to maintain cohesive and discrete portions. Non-limiting examples of binders include hydroxypropylcellulose, hydroxypropylmethylcellulose, povidone, and ethyl cellulose.

[0030] “Diluent or filler” refers to substances that are used to dilute the active pharmaceutical ingredient prior to delivery. Diluents can also serve as stabilizers. Non-limiting examples of diluents include starch, saccharides, disaccharides, sucrose, polysaccharides, cellulose, cellulose ethers, hydroxypropyl cellulose, sugar alcohols, xylitol, sorbitol, maltitol, microcrystalline cellulose, calcium or sodium carbonate, lactose, lactose monohydrate, dicalcium phosphate, compressible sugars, dibasic calcium phosphate dehydrate, mannitol, and tribasic calcium phosphate.

[0031] “Disintegrant or disintegrating agents” refers to a substance which, upon addition to a solid preparation, facilitates its break-up or disintegration after administration and permits the release of an active ingredient as efficiently as possible to allow for its rapid dissolution. Non-limiting examples of disintegrants include maize starch, sodium starch glycolate, croscarmellose sodium, crospovidone, microcrystalline cellulose, modified com starch, sodium carboxymethyl starch, povidone, pregelatinized starch, and alginic acid.

[0032] The terms “disorders,” “diseases,” and “conditions” are used inclusively herein and refer to any condition deviating from normal.

[0033] The term “erythropoietin” refers to any recombinant or naturally occurring erythropoietin including, e.g., human erythropoietin (GenBank Accession No. AAA52400; Lin et al. (1985) Proc Natl Acad Sci USA 82:7580-7584), EPOETIN human recombinant erythropoietin (Amgen, Inc., Thousand Oaks CA), ARANESP human recombinanterythropoietin (Amgen), PROCRIT human recombinant erythropoietin (Ortho Biotech Products, L.P., Raritan NJ), etc.

[0034] The term “excipient” or “pharmaceutically acceptable excipient” refers to pharmacologically inactive substances that are added to a pharmaceutical preparation in addition to the active pharmaceutical ingredient. Excipients may take the function of vehicle, diluent, release, disintegration or dissolution modifying agent, absorption enhancer, stabilizer or a manufacturing aid among others. Excipients may include fillers (diluents), binders, disintegrating agents, lubricants, and glidants.

[0035] The “fit factors” are used to compare dissolution profiles and can be expressed by two approaches: f (the difference factor) and / 2 (the similarity factor). Two dissolution profiles to be considered similar and bioequivalent, / I should be between 0 and 15 whereas fl should be between 50 and 100.

[0036] “Glidant” as used herein is intended to mean agents used in tablet and capsule formulations to improve flow-properties during tablet compression and to produce an anticaking effect. Non-limiting examples of glidants include colloidal silicon dioxide, talc, fumed silica, starch, starch derivatives, and bentonite.

[0037] Hypoxia inducible factor (HIF) is a basic helix-loop-helix (bHLH) PAS (Per / Amt / Sim) transcriptional activator that mediates changes in gene expression in response to changes in cellular oxygen concentration. HIF is a heterodimer containing an oxygen- regulated a-subunit (HIFa), and a constitutively expressed -subunit (HIF / ARNT). In oxygenated (normoxic) cells, HIFa subunits are rapidly degraded by a mechanism that involves ubiquitination by the von Hippel-Lindau tumor suppressor (pVHL) E3 ligase complex. Under hypoxic conditions, HIFa is not degraded, and an active HIFa / complex accumulates in the nucleus and activates the expression of several genes including glycolytic enzymes, glucose transporters, erythropoietin (EPO), and vascular endothelial growth factor (VEGF). (Jiang et al. (1996) J Biol. C / zem. 271:17771-17778; Iliopoulus et al. (1996) Proc. Natl. Acad. Sci. USA, 93:10595-10599; Maxwell et al. (1999) Nature 399:271-275; Sutter et al. (2000) Proc. Natl. Acad. Sci. USA 97:4748-4753; Cockman et al. (2000) J Biol. Chem. 275:25733-25741; and Tanimoto et al. (2000) EMBOJ. 19:4298-4309.)

[0038] The terms “HIF -associated conditions” and “conditions mediated at least in part byHIF” are used inclusively and refer to any condition that can be associated with below normal,abnormal, or inappropriate modulation of HIF. HIF-associated conditions include any condition wherein an increase in HIF level would provide therapeutic benefit. HIF-associated conditions include anemic conditions and tissue damage, or disorders associated with ischemic or hypoxic conditions.

[0039] The terms “HIF prolyl hydroxylase”, “PHD”, “EGLN”, and “HIF PH” refer to any enzyme that modifies the alpha subunit of HIF protein by hydroxylation of one or more proline residues. HIF PH includes members of the Egl-Nine (EGLN) gene family described by Taylor (2001, Gene 275:125-132), and characterized by Aravind and Koonin (2001, Genome Biol 2: RESEARCH 0007), Epstein et al. (2001, Cell 107:43-54), and Bruick and McKnight (2001, Science 294:1337-1340). HIF PH2, as used in exemplary assays described herein (infra), may be any HIF PH2, also referred to as PHD2, e.g., human EGLN1 (GenBank Accession No. AAG33965; Dupuy et al. (2000) Genomics 69:348-54), mouse EGLN1 (GenBank Accession No. CAC42515), rat EGLN1 (GenBank Accession No. P59722), etc. Alternatively, another HIF PH may be used in the assay. Such HIF PH enzymes include, but are not limited to HIF PHI, also referred to as PHD1, e.g., human EGLN2 isoform 1 (GenBank Accession No. CAC42510; Taylor, supra), human EGLN2 isoform 3 (GenBank Accession No. NP 542770), mouse EGLN2 (GenBank Accession No. CAC42516), and rat EGLN2 (GenBank Accession No. AA046039), etc.; and any HIF PH3, also referred to as PDH3, e.g. human EGLN3 (GenBank Accession No. CAC42511; Taylor, supra), mouse EGLN3 (GenBank Accession No. CAC42517), and rat EGLN3 (SM-20) (GenBank Accession No. AAA19321). In other embodiments of the present disclosure, EGLN may include Caenorhabditis elegans EGL-9 (GenBank Accession No. AAD56365) and Drosophila melanogaster CGI 114 gene product (GenBank Accession No. AAF52050).

[0040] “Lubricant” refers to an excipient which is added to a powder blend to prevent the compacted powder mass from sticking to the equipment during the tableting or encapsulation process. It aids the ejection of the tablet form and can improve powder flow. Non-limiting examples of lubricants include magnesium stearate, stearic acid, silica, fats, calcium stearate, polyethylene glycol, sodium stearyl fumarate, talc, or fatty acids including lauric acid, oleic acid, and Cs / Cio fatty acid.

[0041] “Particle Size Distribution” (PSD) is a measurement that describes the variation of particles of a compound according to their size. D90 means 90% of the particles in the distribution are smaller than this value, on a volume basis. D50 is the median particle size;50% of the particles are above this value and 50% of the particles fall below this value, on a volume basis. DIO indicates that 10% of the particles in the distribution are smaller than this value, on a volume basis. Methods for measuring particle size distribution are known to those of skill in the art. In some embodiments the particle size distribution is measured by laser diffraction, after suspending the compound in a liquid. In some embodiments the particle size distribution is measured by a Malvern Panalytical Mastersizer 3000 particle size analyzer or Microtrac model S3500. In preferred embodiments, the PSD is measured according to the procedure described in Example 5. It will be understood by one of skill in the art that the value for a particular PSD encompasses the PSD numeric value + 20%, unless otherwise recited in an embodiment. In some embodiments the PSD is the PSD numeric value + 20%. In some embodiments the PSD is the PSD numeric value + 19%. In some embodiments the PSD is the PSD numeric value + 18%. In some embodiments the PSD is the PSD numeric value + 17%. In some embodiments the PSD is the PSD numeric value + 16%. In some embodiments the PSD is the PSD numeric value + 15%. In some embodiments the PSD is the PSD numeric value + 14%. In some embodiments the PSD is the PSD numeric value + 13%. In some embodiments the PSD is the PSD numeric value + 12%. In some embodiments the PSD is the PSD numeric value + 11%. In some embodiments the PSD is the PSD numeric value + 10%. %. In some embodiments the PSD is the PSD numeric value + 9%. In some embodiments the PSD is the PSD numeric value + 8%. In some embodiments the PSD is the PSD numeric value + 7%. In some embodiments the PSD is the PSD numeric value + 6%. In some embodiments the PSD is the PSD numeric value + 5%. In some embodiments the PSD is the PSD numeric value + 4%. In some embodiments the PSD is the PSD numeric value + 3%. In some embodiments the PSD is the PSD numeric value + 2%. In some embodiments the PSD is the PSD numeric value + 1%. It will be understood that the term “+ X%” means a range of X% below to X% above of a given value. For example, a particle size of 10 + 20% means a range of 8-12.

[0042] The term “pharmaceutically acceptable” indicates that the material does not have properties that would cause one of skill in the art to avoid administration of the material to a patient, taking into consideration the disease or conditions to be treated and the respective route of administration. Further, the material is considered to be safe for administration in humans or animals.

[0043] “Q” or “Q value” is the amount of dissolved compound or API expressed as a percentage of label claim dissolved at a particular time for that compound. For immediate release dosage forms the acceptance criteria in the USP are based upon 12 samples, otherwise seen as n=12. In the acceptance tables, this is Stage 2. In stage 2, you will see that your average release is equal to Q. Stage 1 is essentially a shortcut based on statistics where you can pass the test with only 6 samples, or n=6, using a tighter set of acceptance criteria.

[0044] The terms "subject," “individual” or “patient” are used interchangeably and as used herein are intended to include human and non-human animals. Non-human animals include all vertebrates, e.g., mammals and non-mammals, such as non-human primates, sheep, dogs, cats, cows, horses, chickens, amphibians, and reptiles, although mammals are preferred, such as non-human primates, sheep, dogs, cats, cows, and horses. The methods are particularly suitable for treating human patients having a disease or disorder described herein.

[0045] “Strength of roxadustat”, “strength of API” or “strength” refer to the amount of roxadustat (compound of Formula (I)) in a particular formulation. It will also be understood that when referring to an “x mg tablet” or “x mg capsule”, x is the amount of roxadustat in the tablet or capsule. For example, a 20 mg capsule means that there is 20 mg of roxadustat in the capsule formulation.

[0046] The term "tablet" refers to a solid dosage form of a pharmaceutical formulation in which the API is blended with one or more pharmaceutically acceptable excipient(s) and compressed into a single solid final dosage form. Tablets can be produced in a wide variety of sizes, shapes, and surface markings. Tablets may be uncoated or coated by a variety of techniques that are well known in the art. Typically, a tablet comprises a tablet core and a coating.

[0047] The term "tablet core" refers to the inner part of a tablet containing the API and one or more pharmaceutically acceptable excipient(s) compressed into the desired shape butnot including the coating. The amount of API in the tablet core can be expressed as a percent of API by weight based on the total weight of the tablet core, % w / w.

[0048] The term "coating" refers to an outer part of a tablet. For tablets as described herein, the coating is applied to the outer surface of the tablet core and typically adheres thereto. The coating may provide one or more of the following properties: taste masking, protecting the API(s) from photodegradation, ease of administration, release modification of the API(s), dust protection, or unique appearance (colors), among other things. Non-limiting examples of coating materials include polyvinylalcohol-based compounds, hydroxyethylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose sodium, polyethylene glycol 4000 and cellulose acetate phthalate. In one embodiment, the coating is a polyvinylalcohol-based coating. The amount of coating that is applied over the outer surface of tablet core can be expressed as a percent of coating by weight based on the weight of the tablet core (% w / w). In one embodiment, the coating may comprise a photostabilizing agent such as a dye. The amount of dye within a coating can be expressed as a percent of dye weight based on the weight of the coating (% w / w). Alternatively, the amount of dye within a coating can be expressed as the amount of the dye applied per surface area unit of the tablet core (mg / cm2).

[0049] “Technical grade roxadustat” refers to crude roxadustat, wherein the purity of the roxadustat is at least 94% pure area by HPLC. In some embodiments the purity of the roxadustat is at least 95% pure area by HPLC. In some embodiments the purity of the roxadustat is at least 96% pure area by HPLC. In some embodiments the purity of the roxadustat is at least 97% pure area by HPLC. In some embodiments the purity of the roxadustat is at least 98% pure area by HPLC. In some embodiments the purity of the roxadustat is at least 99% pure area by HPLC. In some embodiments the purity of the roxadustat is > 94% pure area by HPLC. In some embodiments the purity of the roxadustat is> 95% pure area by HPLC. In some embodiments the purity of the roxadustat is > 96% pure area by HPLC. In some embodiments the purity of the roxadustat is > 97% pure area by HPLC. In some embodiments the purity of the roxadustat is >_98% pure area by HPLC. In some embodiments the purity of the roxadustat is > 99% pure area by HPLC. In some embodiments the purity of the roxadustat is 94% pure area by HPLC. In some embodiments the purity of the roxadustat is 95% pure area by HPLC. In some embodiments the purity of the roxadustat is 96% pure area by HPLC. In some embodiments the purity of the roxadustat is 97% pure area by HPLC. In some embodiments the purity of the roxadustat is 98% pure area by HPLC. Insome embodiments the purity of the roxadustat is 99% pure area by HPLC. The technical grade roxadustat can be prepared by any process known in the art, for example the methods described in WO2014 / 014834 and WO2014 / 014835.

[0050] ‘Treatment”, “treating”, and “treat” are defined as acting upon a disease, disorder, or condition with an agent to reduce or ameliorate the harmful or any other undesired effects of the disease, disorder, or condition and / or its symptoms. Treatment, as used herein, covers the treatment of a human patient, and includes: (a) reducing the risk of occurrence of the condition in a patient determined to be predisposed to the disease but not yet diagnosed as having the condition, (b) impeding the development of the condition, and / or (c) relieving the condition, i.e. , causing regression of the condition and / or relieving one or more symptoms of the condition.COMPOUNDS

[0051] The particle size distribution (PSD) of compounds is an important aspect of drug development because the PSD can affect the dissolution properties of the compound and can impact the bioavailability and / or efficacy of the active pharmaceutical ingredient and / or pharmaceutical composition. Furthermore, PSD can impact the flowability and manufacturing process of compounds and pharmaceutical compositions.

[0052] Roxadustat, a hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitor, promotes coordinated erythropoiesis through increasing endogenous erythropoietin, improving iron availability, and reducing hepcidin. Administration of roxadustat has been shown to increase red blood cell production while maintaining plasma erythropoietin levels within or near normal physiologic range in multiple subpopulations of chronic kidney disease (CKD) patients, including in the presence of inflammation, and without a need for supplemental intravenous iron.

[0053] Roxadustat is approved in China, Europe, Japan, and numerous other countries for the treatment of anemia in CKD patients on dialysis and patients not on dialysis. Roxadustat is in clinical development for anemia of myelodysplastic syndromes (MDS), and for treatment of chemotherapy-induced anemia (CIA).

[0054] Therefore, ensuring that the particle size of the roxadustat active pharmaceutical ingredient and pharmaceutical compositions containing said roxadustat have good dissolution and bioavailabilty is critical for the effective treatment of patients.

[0055] Roxadustat is a compound of Formula (I):also known as [(4-hydroxy-l-methyl-7-phenoxyisoquinoline-3-carbonyl)amino] acetic acid. The present invention describes solid compounds of Formula (I), wherein the compound has a particle size distribution that provides for suitable dissolution and good bioavailability of the compound and / or pharmaceutical compositions containing the compound.

[0056] Applicant has discovered that roxadustat of a particle size distribution of greater than D90 of 58 pm; a D50 of 34 pm; and a DIO of 18 pm has an impact on roxadustat dissolution and is expected to have an impact on pharmacokinetics. Furthermore, Applicant has surprisingly found that the process for preparing the roxadustat of the present invention results in a reproducible, uni-modal, tight distribution of particle size across D90, D50, DIO which provides unexpected advantages such as, but not limited to: a) rapid and comparable in vitro dissolution over the claimed PSD range; b) no need for milling of the API; excellent blending with excipients, resulting in homogenous API distribution (as confirmed through content uniformity testing); c) the ability for granulation using a fixed water amount and granulation conditions over the claimed PSD range; d) ease of API filtration process; e) ease and thoroughness of rinsing (washing) of API particles; f) simple API drying process; andg) convenience in handling-this solid powder flows better, so it is easier to charge into a storage drum and to discharge when using it to make formulation.

[0057] In embodiments described herein the solid compound of Formula (I) has a particle size distribution of D90 of about 6 pm + 10% to 58 pm + 10%; a D50 of about 3.2 pm + 10% to 34 pm + 10%; and a D10 of about 1.1+ 10% pm to 18 pm + 10%. In embodiments described herein the solid compound of Formula (I) has a particle size distribution of D90 of about 6 pm + 5% to 58 pm + 5%; a D50 of about 3.2 pm + 5% to 34 pm + 5%; and a D10 of about 1.1+ 5% pm to 18 pm + 5%. In embodiments described herein the solid compound of Formula (I) has a particle size distribution of D90 of about 6 pm + 2% to 58 pm + 2%; a D50 of about 3.2 pm + 2% to 34 pm + 2%; and a D10 of about 1.1+ 2% pm to 18 pm + 2%. In embodiments described herein the solid compound of Formula (I) has a particle size distribution of D90 of about 6 pm to 58 pm; a D50 of about 3.2 pm to 34 pm; and a D10 of about 1.1 pm to 18 pm. In some embodiments the compound has a particle size distribution of D90 of about 6.8 pm to 43 pm; a D50 of about 3.2 pm to 24 pm; and a D10 of about 1.1 pm to 12 pm. In some embodiments the compound has a particle size distribution of D90 of about 13 pm to 58 pm; a D50 of about 6.3 pm to 34 pm; and a D10 of about 1.9 pm to 18 pm. In some embodiments the solid compound has a particle size distribution of D90 of about 58 pm; a D50 of about 34 pm; and a D10 of about 18 pm. In some embodiments the solid compound has a particle size distribution of D90 of about 45 pm; a D50 of about 27 pm; and a D10 of about 15 pm. In some embodiments the solid compound has a particle size distribution of D90 of about 22 pm; a D50 of about 13 pm; and a D10 of about 7.7 pm. In some embodiments the solid compound has a particle size distribution of D90 of about 13 pm; a D50 of about 6.3 pm; and a D10 of about 1.9 pm. In some embodiments the solid compound has a particle size distribution of D90 of about 6.8 pm; a D50 of about 3.2 pm; and a D10 of about 1.1 pm. In some embodiments the solid compound has a particle size distribution of D90 of about 43 pm; a D50 of about 24 pm; and a D10 of about 12 pm. In some embodiments the solid compound has a particle size distribution of D90 of about 29 pm; a D50 of about 15 pm; and a D10 of about 7.2 pm. In some embodiments the solid compound has a particle size distribution of D90 of about 25 pm; a D50 of about 13 pm; and a D10 of about 6.2 pm. In some embodiments the solid compound has a particle size distribution of D90 of about 19 pm; a D50 of about 11 pm; and a D10 of about 5.6 pm. In some embodiments the solid compound has a particle size distribution of D90 of about 23 pm; a D50 of about 12 pm; and a D10 of about 6.5 pm. In some embodiments the solid compound has a particle size distribution of D90 of about 22 pm; a D50 of about 12 pm;and a DIO of about 6.5 pm. In some embodiments the solid compound has a particle size distribution of D90 of about 22 pm; a D50 of about 12 pm; and a DIO of about 5.6 pm. In some embodiments the solid compound has a particle size distribution of D90 of about 36 pm; a D50 of about 17 pm; and a DIO of about 4.1 pm. In some embodiments the solid compound has a particle size distribution of D90 of about 12 pm; a D50 of about 6.4 pm; and a DIO of about 2.1 pm. In some embodiments the solid compound has a particle size distribution of D90 of about 12 pm; a D50 of about 6 pm; and a DIO of about 3 pm. In some embodiments the solid compound has a particle size distribution of D90 of about 25 pm; a D50 of about 14 pm; and a DIO of about 7.7 pm.

[0058] Some embodiments describe a solid compound of Formula (I):wherein the compound has a unimodal particle size distribution with a D90 < 43 pm. In some embodiments the compound has unimodal particle size distribution with a D90 of 13 pm to 43 pm.

[0059] Some embodiments describe a solid compound of Formula (I):wherein the solid compound has particle size distribution of D90 of 43 pm + 20 %, a D50 of 24 pm + 20 %; and a D10 of 12 pm + 20 %. In some embodiments the particle size distribution is D90 of 43 pm + 10 %, a D50 of 24 pm + 10 %; and a D10 of 12 pm + 10 %. In some embodiments the particle size distribution is D90 of 43 pm + 5 %, a D50 of 24 pm + 5 %; and a D10 of 12 pm + 5 %. In some embodiments the particle size distribution is D90 of 43 pm + 2 %, a D50 of 24 pm + 2 %; and a D10 of 12 pm + 2 %. In some embodiments the particle size distribution is D90 of 43 pm, a D50 of 24 pm and a D10 of 12 pm.

[0060] Some embodiments describe a solid compound of Formula (I):wherein the solid compound has a unimodal particle size distribution of D90 of about 21 pm to 29 pm; a D50 of about 12 pm to 17 pm; and a DIO of about 6 pm to 10 pm. In some embodiments the compound has a unimodal particle size distribution of D90 of about 21.9 pm to 28.5 pm; a D50 of about 12.28 pm to 16.03; and a DIO of about 6.66 pm to 9.13 pm. In some embodiments the solid compound has a unimodal particle size distribution selected from:

[0061] In some embodiments, the solid compound according to any embodiment described herein may be an amorphous solid, an anhydrous polymorph, a solvate, a hydrate or a hemihydrate. In some embodiments the solid is amorphous solid, crystalline form A, crystalline form B, crystalline form C or crystalline form D, as described in WO2014 / 014835, herein incorporated by reference in its entirety. In some embodiments the solid is amorphous solid, crystalline form A, or crystalline form B.In Vitro Particle Size Dissolution Rates

[0062] To investigate the effect of compound particle size on pharmaceutical composition dissolution rates several particle size challenge studies were conducted and exemplar samples are discussed below. The results indicate that dissolution of roxadustat is impacted when the compound has a particle size distribution outside of those described in the embodiments herein.

[0063] In one study, solid roxadustat with varying PSDs, were prepared for the particle size challenge and a dissolution evaluation was performed on 100 mg tablets of varying particle size distributions as shown in Table 1.

[0064] Table 1: Dissolution Evaluation of Particle Size Distribution in 100 mgTablets of Roxadustat with various PSDQ=80; S1=A11 > Q+5; S2=Ave > Q & > Q-15

[0065] Results of this particle size distribution challenge indicated that at a 100 mg strength of roxadustat API, tablets containing the API with a particle size of D90 >12 pm and <65 pm exhibited excellent dissolution rates at 30 minutes. Tablets containing roxadustat with a particle size of D90=65 pm and 112 pm did not meet the SI or S2 criteria at 30 minutes indicating that the compound of Formula (I) of these particle size distributions, would be expected to have an impact on pharmacokinetics in vivo.

[0066] To assess how different pharmaceutical formulations of varying amounts of the active ingredient (strength of compound of Formula (I)) would impact dissolution, a variety of tablets was prepared with similar particle size and the dissolution of the tablets was measured. As shown in Table 2, strengths of 20 to 100 mg reached the dissolution specification of Q=80 at 30 minutes and the 150 mg strength reached the dissolution specification of Q=80 at 45 minutes.

[0067] Table 2: Tablet Dissolution Evaluation of Roxadustat with similar PSD

[0068] A particle size challenge study was also conducted to include different tablet strengths of roxadustat with various PSD. Roxadustat samples having the particle size distribution shown in Table 3, were prepared.

[0069] Table 3: Particle Size Distribution of Roxadustat API

[0070] These compounds were then formulated into 20 mg, 100 mg and 150 mg tablets and their dissolution (See Figs. 2 through 4 and Tables 4-6) and fit factors were measured.

[0071] Table 4: Dissolution Evaluation of 20 mg tablets

[0072] Table 5: Dissolution Evaluation of 100 mg tablets

[0073] Table 6: Dissolution Evaluation of 150 mg tablets

[0074] These results indicate that PSD of D90 / D50 / D10 of 93 pm / 54 pm / 30 pm failed stage 1 and stage 2 at 150 mg and 100 mg strength and failed stage 1 for 20 mg strength. D90 / D50 / D10 of 70 pm / 40 pm / 21 pm failed stage 1 for 150 and 100 mg strength. D90 / D50 / D10 of 58 pm / 34 pm / 18 m passed stage 1 for all doses. Furthermore, D90 / D50 / D10 of 70 pm / 40 pm / 21 pm and 93 pm / 54 pm / 30 pm failed f2 for 150 mg, 100 mg, and 20 mg strength. Importantly, all tablets (20 mg, 100 mg, or 150 mg) that contained roxadustat with a D90 / D50 / D10 of 70 pm / 40 pm / 21 pm or 93 pm / 54 pm / 30 pm failed fl / f2 comparison (when compared to a typical clinical batch). Thus, capsules and tablets containing roxadustat with a particle size of D90 > 58 pm have poor performance in dissolution studies and would be expected to have an impact on pharmacokinetics in vivo.

[0075] An additional particle size distribution challenge was conducted on 50 mg tablets and capsules and 100 and 150 mg tablets containing roxadustat of various PSD as the active ingredient, as shown in Table 7 and Table 8. These dissolution data suggest that a D90 particle size as low as 6.8 would not be expected to have an impact on pharmacokinetics.

[0076] Table 7: Dissolution Evaluation of 50 mg tablets and capsules at various PSD

[0077] Table 8: Dissolution Evaluation of 50 mg, 100 mg and 150 mg tablets at various PSD* Presumed average particles size from combining T 100-02 and T 100-03

[0078] A dose of the compound of Formula (I) could be administered either as a single tablet or capsule of a one strength, or as multiple capsules or tablets of different / same strengths. For example, if a 100 mg dose is needed, a single 100 mg tablet or capsule can be administered, or two 50 mg tablets / capsules could be administered to achieve the desired dose. Therefore, dissolution studies were performed to assess the dissolution of two combined strengths versus a single strength at doses of 70 mg and 150 mg as described in Table 9.

[0079] Table 9: Dissolution of 20 mg tablet plus 50 mg tablet compared with dissolution of 70 mg tablet and dissolution of 100 mg tablet plus a 50 mg tablet, compared with a 150 mg tabletNote: Underline indicated data used for calculation of / 2 value

[0080] These results support that dissolution of a combination of tablets / capsules of lower strength to achieve a particular dose is similar to a single strength tablet / capsule of the same dose. This was further supported in in vivo bioequivalence studies (vide infra). These findings further support that roxadustat of PSD of greater than D90 of 58 pm; a D50 of 34 pm; and a DIO of 18 pm have an impact on roxadustat dissolution and could have an impact on PK, especially at doses at or greater than 50 mg (whether the dose is achieved through administration of a single tablet / capsule or through administration of multiple tablets / capsules).

[0081] The various in vitro particle size distribution studies indicate that roxadustat of PSD of greater than D90 of 58 pm; a D50 of 34 pm; and a D10 of 18 pm have an impact on roxadustat dissolution and could impact on PK. Furthermore, these results also indicate that roxadustat of a PSD of D90 of 6 pm; a D50 of 3.2 pm; and a DlO oft 1.1 pm did not have an impact on roxadustat dissolution and are predicted not to have an impact on PK.

[0082] The particle size distribution of the solid compounds of the present embodiments shows a strong correlation between the D90 and the D50 and DIO as shown in Table 3 and Fig.1.In Vivo Pharmacokinetics and Predicted Pharmacokinetics

[0083] Different dosage forms of various strengths were developed and used in clinical studies. Biopharmaceutical studies were conducted to evaluate the relative bioavailability / bioequivalence of different capsules and tablets used in clinical trials.

[0084] One study was an open-label, randomized, single oral dose, three-way crossover study to assess the relative bioavailability of gelatin capsules versus HPMC capsules (n=24) and tablets (n=12) after a single-dose of 50 mg roxadustat to healthy volunteers under fasting conditions. The capsules and tablets used in the study are described in Table 10.

[0085] Table 10: PSD of Formulations Used in 50 mg Capsule / T ablet Bioequivalence Study

[0086] The statistical comparison of roxadustat pharmacokinetic parameters is summarized in Table 11 and Table 12. The 90% CI for the geometric mean ratio of the Formulation A capsules to the Formulation D capsules fell within the NMPA’s bioequivalence criteria for AUCiast, AUCmf (80%-125%), and Cmax(70%-143%) under fasting conditions, demonstrating the bioequivalence of the two formulations.

[0087] Table 11. Statistical Comparison of Plasma Roxadustat Pharmacokinetic Parameters: Formulation A versus Formulation Dsingle oral 50 mg

[0088] Table 12. Statistical Comparison of Plasma Roxadustat PharmacokineticParameters: Formulation B versus Formulation Dsingle oral 50 mg

[0089] In Part 2 of Study, the gelatin capsules and the HPMC capsules were also compared to tablets of the same dose. The 90% CI for the geometric mean ratio of the A capsules to the tablets and the B capsules to the tablets fell within the NMPA’s bioequivalence criteria for AUCiast, AUCinf(80%-125%), and Cmax(70%-143%) under fasting conditions (Table 13, Table 14, and Table 15).

[0090] These trials demonstrated the bioequivalence of HPMC capsules with gelatin capsules and with tablets of the same strength.

[0091] Table 13. Statistical Comparison of Plasma Roxadustst Pharmacokinetic Parameters: Formulation A versus Formulation Esingle oral 50 mg

[0092] Table 14. Statistical Comparison of Plasma Roxadustat PharmacokineticParameters: Formulation B versus Formulation Esingle oral 50 mg

[0093] Table 15. Statistical Comparison of Plasma Roxadustat Pharmacokinetic Parameters (Formulation D versus Formulation E)single oral 50 mg

[0094] A second study was conducted to evaluate the difference between a 150 mg dose administered as a 100 mg tablet plus a 50 mg tablet, compared with a 150 mg dose administered as a 150 mg tablet. (Table 16)

[0095] Table 16: PSD of Formulations Used in 150 mg Bioequivalence Study

[0096] This was an open-label, randomized, 2-period, 2-sequence crossover study in 24 healthy male and female subjects, 18 to 55 years of age with a body mass index (BMI) of 18.5 to 29.9 kg / m2, inclusive. Subjects received single 150-mg doses of roxadustat tablets as 1 tablet of 100 mg plus 1 tablet of 50 mg or 1 tablet of 150 mg under fasting conditions in randomorder. Doses were separated by a minimum 7-day washout. Blood samples were collected for determination of plasma concentrations of roxadustat prior to and up to 96 h after each dose.

[0097] As shown in Table 17, one tablet of 150 mg was bioequivalent to a 150 mg dose administered as a 100 mg tablet plus a 50 mg tablet. All 90% confidence intervals [Cis] for the geometric mean ratios [GMRs] of roxadustat AUCiast, AUCinf and Cmaxlie within the bioequivalence limits of 80% and 125%. Median tmaxof roxadustat was obtained at 2.5 h post-dose for the 150 mg dose administered as a 100 mg tablet plus a 50 mg tablet and 2.0 h post-dose for the 150 mg tablet. Thus a 150 mg dose administered as a 150 mg tablet is bioequivalent to a 150 mg dose administered as a 100 mg tablet plus a 50 mg tablet.

[0098] Table 17: Bioequivalence of Roxadustat 150 mg dose administered as a 100 mg tablet plus a 50 mg tablet, compared with a 150 mg dose administered as a 150 mg tabletCI: confidence interval; CV: coefficient of variation; GMR: geometric mean ratio; PK: pharmacokinetic. f The exponentiated value of the geometric least squares mean based on natural log-transformed data. Ratios (test / reference) and confidence limits are transformed back to raw units by exponentiating and expressed as a percent. Results based on an analysis of variance with fixed effect for sequence, period and treatment condition and subject as a random effect.

[0099] A physiological based biopharmaceutics model (PBBM) for roxadustat was developed to establish an in vitro-in vivo correlation based on the derivation from in vitro dissolution data and to assess the impact of drug substance particle size and in vitro dissolution rate on the in vivo exposure of roxadustat immediate-release pharmaceutical formulations and to confirm the dissolution specification limits for the immediate release pharmaceutical formulations.

[0100] The model was verified by human pharmacokinetic data from several studies including formulations with different particle sizes to be able to predict the effect of differentdrug substance particle sizes (D90 of about 6.8 pm to 43 pm; a D50 of about 3.2 pm to 24 pm; and a DIO of about 1.1 pm to 12 pm), doses and drug products. Clear linear correlation between the predicted and observed mean Cmax, AUCo-inf, and AUCo-t and all predicted plasma concentration-time profiles were within clinical variability. The model verification demonstrated that the predicted performance of the developed model was highly accurate.

[0101] The model supported pharmaceutical compositions of roxadustat with a PSD of an upper limit of D90 / D50 / D10 of 58 pm / 34 pm / 18 pm, since above this PSD the bioavailability was predicted to be decreased.

[0102] The data above shows that at a roxadustat PSD less than or equal to D90 / D50 / D10 of 58 pm / 34 pm / 18 pm would have good bioavailability.PHARMACEUTICAL COMPOSITIONS

[0103] The roxadustat of the present disclosure can be delivered directly or in pharmaceutical compositions along with suitable excipients, as is well known in the art.

[0104] While it is possible that a compound as described in any embodiment herein, may be administered as the bulk substance, it is preferable to present the compound in a pharmaceutical formulation, e.g., wherein the active agent is in an admixture with a pharmaceutically acceptable carrier selected with regard to the intended route of administration and standard pharmaceutical practice.

[0105] Some embodiments describe a pharmaceutical composition comprising roxadustat according to any embodiment described herein and a pharmaceutically acceptable excipient. The pharmaceutical compositions can be prepared in a manner well known in the pharmaceutical arts.

[0106] In particular, the disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of roxadustat according to any embodiment described herein, and optionally, a pharmaceutically acceptable excipient.

[0107] In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a solid compound of Formula (I):wherein the solid compound has a unimodal particle size distribution with a D90 < 43 pm; and at least one pharmaceutically acceptable excipient, provided the excipient is not a cyclodextrin derivative and polacrilin potassium. In some embodiments the solid compound has a unimodal particle size distribution with a D90 of about 13 pm to 43 pm. In some embodiments the solid compound has a unimodal particle size distribution with a D90 of about 21 pm to 29 pm; a D50 of about 12 pm to 17 pm; and a DIO of about 6 pm to 10 pm. In some embodiments the compound has a particle size distribution of D90 of about 21.9 pm to 28.5 pm; a D50 of about 12.28 pm to 16.03; and a DIO of about 6.66 pm to 9.13 pm. In some embodiments the compound has a particle size distribution of

[0108] In the present disclosure, the roxadustat according to any embodiment herein is prepared in a formulation intended for oral administration. For oral administration, it can be formulated readily by combining the roxadustat according to any embodiment herein with pharmaceutically acceptable excipients well known in the art. Such excipients enable the roxadustat according to any embodiment herein, to be formulated as tablets, pills, dragees, and capsules, for oral ingestion by a subject.

[0109] In some embodiments the excipient of the oral pharmaceutical composition according to any embodiment described herein, is selected from the group consisting of a diluent, a binder, a disintegrant, and a lubricant or combinations thereof.

[0110] In some embodiments the diluent of the oral pharmaceutical composition according to any embodiment described herein, is selected from one or more of starch, saccharides, disaccharides, sucrose, polysaccharides, cellulose, cellulose ethers, hydroxypropyl cellulose, sugar alcohols, xylitol, sorbitol, maltitol, microcrystalline cellulose, calcium or sodium carbonate, lactose, lactose monohydrate, dicalcium phosphate, compressible sugars, dibasic calcium phosphate dehydrate, mannitol, and tribasic calcium phosphate. In some embodiments the diluent is selected from microcrystalline cellulose or lactose monohydrate or a combination thereof.[OHl] In some embodiments the binder of the oral pharmaceutical composition according to any embodiment described herein, is selected from one or more of hydroxypropylcellulose, hydroxypropylmethylcellulose, povidone, and ethyl cellulose or a combination thereof. In some embodiments the binder is povidone.

[0112] In some embodiments the disintegrant of the oral pharmaceutical composition according to any embodiment described herein, is selected from one or more of maize starch, sodium starch glycolate, croscarmellose sodium, crospovidone, microcrystalline cellulose,modified com starch, sodium carboxymethyl starch, povidone, pregelatinized starch, and alginic acid or a combination thereof. In some embodiments the disintegrant is croscarmellose sodium.

[0113] In some embodiments the lubricant of the oral pharmaceutical composition according to any embodiment described herein, is selected from one or more of magnesium stearate, stearic acid, silica, fats, calcium stearate, polyethylene glycol, sodium stearyl fumarate, talc, and fatty acids. In some embodiments the lubricant is magnesium stearate.

[0114] In some embodiments the excipient of the oral pharmaceutical composition according to any embodiment described herein, comprises microcrystalline cellulose, lactose monohydrate, povidone, croscarmellose sodium and magnesium stearate.

[0115] Pharmaceutical preparations for oral use can be obtained using solid excipients, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients are, for example, diluents, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, microcrystalline cellulose and / or polyvinylpyrrolidone (PVP or povidone). If desired, disintegrants may be added, such as the cross-linked polyvinyl pyrrolidone, agar, croscarmellose sodium or alginic acid or a salt thereof such as sodium alginate. In some embodiments the disintegrant is selected from maize starch, sodium starch glycolate, croscarmellose sodium, crospovidone, microcrystalline cellulose, modified com starch, sodium carboxymethyl starch, povidone, pregelatinized starch, and alginic acid or a combination thereof. In some embodiments the disintegrant is croscarmellose sodium Also, wetting agents such as sodium dodecyl sulfate or lubricants such as magnesium stearate may be included. In some embodiments the excipient is selected from the group consisting of one or more of a diluent, a binder a disintegrant and a lubricant or combinations thereof. In some embodiments the roxadustat according to any embodiment described herein may be formulated for oral delivery according to any formulation described in WO2014 / 197660.

[0116] In some embodiments the pharmaceutical composition of any of any embodiment described herein further comprises a photostabilizer. In some embodiments the photostabilizer is selected from one or more of Allura Red AC, Allura Red AC Aluminum Lake, titaniumdioxide and iron oxide yellow. In some embodiments the photostabilizer comprises titanium dioxide and iron oxide yellow. In some embodiments the photostabilizer comprises Allura Red AC, titanium dioxide and iron oxide yellow. In some embodiments the photostabilizer comprises titanium dioxide and Allura Red AC or Allura Red AC aluminum lake.

[0117] Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active doses.

[0118] Pharmaceutical preparations for oral administration include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol (capsule shell). In some embodiments the capsule shell further comprises a photostabilizer. In some embodiments the photostabilizer is selected from one or more of Allura Red AC, titanium dioxide and iron oxide yellow. In some embodiments the photostabilizer comprises titanium dioxide and iron oxide yellow. In some embodiments the photostabilizer comprises Allura Red AC, titanium dioxide and iron oxide yellow. The push- fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and / or lubricants such as talc or magnesium stearate and, optionally, stabilizers (capsule fill). In soft capsules, the roxadustat may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. In some embodiments the roxadustat according to any embodiment described herein may be formulated for oral delivery according to any capsule formulation described in WO2014 / 197660.

[0119] Pharmaceutical preparations for oral administration include tablets. In some embodiments the tablet comprises a tablet core and a coating. In some embodiments the tablet coating further comprises a photostabilizer. In some embodiments the photostabilizer is selected from one or more of iron oxide red, iron oxide yellow, Allura Red AC, Allura Red AC in aluminum lake, and titanium dioxide. In some embodiments the photostabilizer is Allura Red AC in aluminum lake and titanium dioxide. In some embodiments the photostabilizer is selected from one or more of Allura Red AC in aluminum lake 38-42%, Allura Red AC in aluminum lake 15-17% and titanium dioxide. In some embodiments the photostabilizer comprises Allura Red AC in aluminum lake 38-42%, Allura Red AC in aluminum lake 15-17% and titanium dioxide. In some embodiments the photostabilizer comprises titanium dioxide, iron oxide red and iron oxide yellow. In some embodiments the tablet can contain the active ingredients (i.e. roxadustat according to any embodiment described herein) in admixture with fillers such as lactose, binders such as starches, and / or lubricants such as talc or magnesium stearate and, optionally, stabilizers (tablet core). In some embodiments the roxadustat according to any embodiment described herein may be formulated for oral delivery according to any tablet formulation described in WO2014 / 197660.

[0120] In some embodiments the oral formulation is a tablet or a capsule. In some embodiments the oral formulation is a capsule. In some embodiments the pharmaceutical composition is a capsule comprising 20 mg of roxadustat according to any embodiment described herein, and at least one appropriate excipient for oral capsule delivery. In some embodiments the pharmaceutical composition is a capsule comprising 50 mg of roxadustat according to any embodiment described herein, and at least one appropriate excipient for oral capsule delivery.

[0121] Some embodiments describe a capsule comprising a capsule fill and a capsule shell; wherein the capsule fill comprises 20 mg of a solid compound of Formula (I):wherein the solid compound has a unimodal particle size distribution with a D90 < 43 pm; and a pharmaceutically acceptable excipient comprising lactose monohydrate, microcrystalline cellulose, povidone, croscarmellose sodium and magnesium stearate, provided the excipient does not also contain a cyclodextrin derivative and polacrilin potassium; and the capsule shell is a gelatin shell comprising titanium dioxide, iron yellow oxide and gelatin. In some embodiments the solid compound has a unimodal particle size distribution with a D90 of about 13 pm to 43 pm. In some embodiments the solid compound has a unimodal particle size distribution with a D90 of about 21 pm to 29 pm; a D50 of about 12 pm to 17 pm; and a D10 of about 6 pm to 10 pm. In some embodiments the capsule fill comprises lactose monohydrate(310), microcrystalline cellulose PH101, povidone K30, croscarmellose sodium and magnesium stearate. In some embodiments the capsule fill comprises 101.84 mg of lactose monohydrate (310), 9.36 mg of microcrystalline cellulose PH101, 6.48 mg of povidone K30, 5.76 mg of croscarmellose sodium and 0.56 mg of magnesium stearate. In some embodiments the titanium dioxide, and iron yellow oxide comprise 3% by weight of the capsule shell. In some embodiments the titanium dioxide is 1%, by weight of the capsule shell and the iron yellow oxide is 2% by weight of the capsule shell.

[0122] Some embodiments describe a capsule comprising a capsule fill and a capsule shell; wherein the capsule fill comprises 50 mg of a solid compound of Formula (I):wherein the solid compound has a unimodal particle size distribution with a D90 < 43 pm; and a pharmaceutically acceptable excipient comprising lactose monohydrate, microcrystalline cellulose, povidone, croscarmellose sodium and magnesium stearate, provided the excipient does not also contain a cyclodextrin derivative and polacrilin potassium; and the capsule shell is a gelatin shell comprising titanium dioxide, iron yellow oxide and gelatin. In some embodiments the solid compound has a unimodal particle size distribution with a D90 of about 13 pm to 43 pm. In some embodiments the solid compound has a unimodal particle size distribution with a D90 of about 21 pm to 29 pm; a D50 of about 12 pm to 17 pm; and a DIO of about 6 pm to 10 pm. In some embodiments the capsule fill comprises lactose monohydrate (310), microcrystalline cellulose PH101, povidone K30, croscarmellose sodium and magnesium stearate. In some embodiments the capsule fill comprises 254.6 mg of lactose monohydrate (310), 23.4 mg of microcrystalline cellulose PH101, 16.20 mg of povidone K30, 14.40 mg of croscarmellose sodium and 1.4 mg of magnesium stearate. In some embodiments the Allura red AC, titanium dioxide, and iron yellow oxide comprise 3% by weight of the capsule shell. In some embodiments the Allura red AC is 1% by weight of the capsule shell, the titanium dioxide is 1%, by weight of the capsule shell and the iron yellow oxide is 1% by weight of the capsule shell.

[0123] In some embodiments the oral formulation is a tablet. In some embodiments the pharmaceutical composition is a tablet comprising 20 to 150 mg of roxadustat according to any embodiment described herein, and at least one appropriate excipient for oral tablet delivery. In some embodiments the pharmaceutical composition is a tablet comprising 20mg, 50 mg, 70 mg, 100 mg, 150 mg of roxadustat according to any embodiment described herein, and at least one appropriate excipient for oral tablet delivery. In some embodiments the pharmaceutical composition is a tablet comprising 20 mg of roxadustat according to any embodiment described herein, and at least one appropriate excipient for oral tablet delivery. In some embodiments the pharmaceutical composition is a tablet comprising 50 mg of roxadustat according to any embodiment described herein, and at least one appropriate excipient for oral tablet delivery. In some embodiments the pharmaceutical composition is a tablet comprising 70 mg of roxadustat according to any embodiment described herein, and at least one appropriate excipient for oral tablet delivery. In some embodiments the pharmaceutical composition is a tablet comprising 100 mg of roxadustat according to any embodiment described herein, and at least one appropriate excipient for oral tablet delivery. In some embodiments the pharmaceutical composition is a tablet comprising 150 mg of roxadustat according to any embodiment described herein, and at least one appropriate excipient for oral tablet delivery.

[0124] In some embodiments the pharmaceutical composition is a min-tablet comprising 5 mg of roxadustat according to any embodiment described herein, and at least one appropriate excipient for oral tablet delivery.

[0125] Some embodiments describe a tablet comprising a tablet core and a coating; wherein the tablet core comprises 20 mg of a solid compound of Formula (I):wherein the solid compound has a unimodal particle size distribution with a D90 < 43 pm; and a pharmaceutically acceptable excipient comprising lactose monohydrate, microcrystalline cellulose, povidone, croscarmellose sodium and magnesium stearate, provided the excipient does not also contain a cyclodextrin derivative and polacrilin potassium; and the coatingcomprises titanium dioxide, and Allura red AC in aluminum lake. In some embodiments the solid compound has a unimodal particle size distribution with a D90 of about 13 pm to 43 pm. In some embodiments the solid compound has a unimodal particle size distribution with a D90 of about 21 pm to 29 pm; a D50 of about 12 pm to 17 pm; and a DIO of about 6 pm to 10 pm. In some embodiments the povidone is povidone K30. In some embodiments the tablet core comprises 42.6 mg of lactose monohydrate, 9.12 mg of microcrystalline cellulose, 3.6 mg of povidone K30, 4.0 mg of croscarmellose sodium and 0.68 mg of magnesium stearate. In some embodiments the coating comprises poly vinyl alcohol, talc, macrogol 3350, Allura Red AC in aluminum lake, titanium dioxide and lecithin. In some embodiments the coating comprises 0.1 to 0.4 mg / cm2titanium dioxide, and 0.1 -0.4 mg / cm2Allura Red AC in aluminum lake, based on the surface area of the tablet. In some embodiments the coating comprises 0.293 mg / cm2titanium dioxide, and 0.286 mg / cm2Allura Red AC in aluminum lake, based on the surface area of the tablet. In some embodiments the surface area of the tablet is 0.894 cm2. In some embodiments the coating comprises 0.293 mg / cm2titanium dioxide, and 0.286 mg / cm2Allura Red AC in aluminum lake, based on the surface area of the tablet and the surface area of the tablet is 0.894 cm2. In some embodiments the coating comprises poly vinyl alcohol, talc, macrogol 3350, 0.293 mg / cm2titanium dioxide based on surface area of the tablet, 0.286 mg / cm2Allura Red AC in aluminum lake based on surface are of the tablet, and lecithin; and the surface area of the tablet is 0.894 cm2. In some embodiments the coating comprises 2.64 mg poly vinyl alcohol, 1.20 mg talc, 0.74 mg macrogol 3350, 0.28 mg titanium dioxide, 0.58 mg Allura Red AC in aluminum lake 38-42%, 0.34 mg Allura Red AC in aluminum lake 15- 17% and 0.21 mg lecithin. In some embodiments the tablet core comprises 42.6 mg of lactose monohydrate, 9.12 mg of microcrystalline cellulose, 3.6 mg of povidone K30, 4.0 mg of croscarmellose sodium and 0.68 mg of magnesium stearate and the coating comprises 2.64 mg poly vinyl alcohol, 1.20 mg talc, 0.74 mg macrogol 3350, 0.28 mg titanium dioxide, 0.58 mg Allura Red AC in aluminum lake 38-42%, 0.34 mg Allura Red AC in aluminum lake 15-17% and 0.21 mg lecithin.

[0126] Some embodiments describe a tablet comprising a tablet core and a coating; wherein the tablet core comprises 20 mg of a solid compound of Formula I according to any embodiment described herein, and a pharmaceutically acceptable excipient comprising 42.6 mg of lactose monohydrate, 9.12 mg of microcrystalline cellulose, 3.6 mg of povidone K30, 4.0 mg of croscarmellose sodium and 0.68 mg of magnesium stearate provided the excipient does not also contain a cyclodextrin derivative and polacrilin potassium; and the coatingcomprising 2.64 mg poly vinyl alcohol, 1.20 mg talc, 0.74 mg macrogol 3350, 0.28 mg titanium dioxide, 0.58 mg Allura Red AC in aluminum lake 38-42%, 0.34 mg Allura Red AC in aluminum lake 15-17% and 0.21 mg lecithin.

[0127] Some embodiments describe a tablet comprising a tablet core and a coating; wherein the tablet core comprises 50 mg of a solid compound of Formula (I):wherein the solid compound has a unimodal particle size distribution with a D90 < 43 pm; and a pharmaceutically acceptable excipient comprising lactose monohydrate, microcrystalline cellulose, povidone, croscarmellose sodium and magnesium stearate, provided the excipient does not also contain a cyclodextrin derivative and polacrilin potassium; and the coating comprises titanium dioxide, and Allura red AC in aluminum lake. In some embodiments the solid compound has a unimodal particle size distribution with a D90 of about 13 pm to 43 pm. In some embodiments the solid compound has a unimodal particle size distribution with a D90 of about 21 pm to 29 pm; a D50 of about 12 pm to 17 pm; and a DIO of about 6 pm to 10 pm. In some embodiments the povidone is povidone K30. In some embodiments the tablet core comprises 106.5 mg of lactose monohydrate, 22.8 mg of microcrystalline cellulose, 9.0 mg of povidone K30, 10 mg of croscarmellose sodium and 1.7 mg of magnesium stearate. In some embodiments the coating comprises poly vinyl alcohol, talc, macrogol 3350, Allura Red AC in aluminum lake, titanium dioxide and lecithin. In some embodiments the coating comprises 0.1 to 0.4 mg / cm2titanium dioxide, and 0.1 -0.4 mg / cm2Allura Red AC in aluminum lake based, on the surface area of the tablet. In some embodiments the coating comprises 0.285 mg / cm2titanium dioxide, and 0.278 mg / cm2Allura Red AC in aluminum lake, based on the surface area of the tablet. In some embodiments the surface area of the tablet is 1.638 cm2. In some embodiments the coating comprises 0.285 mg / cm2titanium dioxide, and 0.278 mg / cm2Allura Red AC in aluminum lake, based on the surface area of the tablet and the surface area of the tablet is 1.638 cm2. In some embodiments the coating comprises poly vinyl alcohol, talc,macrogol 3350, 0.285 mg / cm2titanium dioxide based on surface area of the tablet, 0.278 mg / cm2Allura Red AC in aluminum lake based on surface are of the tablet, and lecithin; and the surface area of the tablet is 1.638 cm2. In some embodiments the coating comprises 4.84 mg poly vinyl alcohol, 2.20 mg talc, 1.36 mg macrogol 3350, 0.51 mg titanium dioxide, 1.07 mg Allura Red AC in aluminum lake 38-42%, 0.63 mg Allura Red AC in aluminum lake 15- 17% and 0.39 mg lecithin. In some embodiments the tablet core comprises 106.5 mg of lactose monohydrate, 22.8 mg of microcrystalline cellulose, 9.0 mg of povidone K30, 10 mg of croscarmellose sodium and 1.7 mg of magnesium stearate and the coating comprises 4.84 mg poly vinyl alcohol, 2.20 mg talc, 1.36 mg macrogol 3350, 0.51 mg titanium dioxide, 1.07 mg Allura Red AC in aluminum lake 38-42%, 0.63 mg Allura Red AC in aluminum lake 15-17% and 0.39 mg lecithin.

[0128] Some embodiments describe a tablet comprising a tablet core and a coating; wherein the tablet core comprises 50 mg of a solid compound of Formula I according to any embodiment described herein, and a pharmaceutically acceptable excipient comprising 106.5 mg of lactose monohydrate, 22.8 mg of microcrystalline cellulose, 9.0 mg of povidone K30, 10 mg of croscarmellose sodium and 1.7 mg of magnesium stearate provided the excipient does not also contain a cyclodextrin derivative and polacrilin potassium; and the coating comprising 4.84 mg poly vinyl alcohol, 2.20 mg talc, 1.36 mg macrogol 3350, 0.51 mg titanium dioxide, 1.07 mg Allura Red AC in aluminum lake 38-42%, 0.63 mg Allura Red AC in aluminum lake 15-17% and 0.39 mg lecithin.

[0129] Some embodiments describe a tablet comprising a tablet core and a coating; wherein the tablet core comprises 70 mg of a solid compound of Formula (I):wherein the solid compound has a unimodal particle size distribution with a D90 < 43 pm; and a pharmaceutically acceptable excipient comprising lactose monohydrate, microcrystalline cellulose, povidone, croscarmellose sodium and magnesium stearate, provided the excipient does not also contain a cyclodextrin derivative and polacrilin potassium; and the coatingcomprises titanium dioxide, and Allura red AC in aluminum lake. In some embodiments the solid compound has a unimodal particle size distribution with a D90 of about 13 pm to 43 pm. In some embodiments the solid compound has a unimodal particle size distribution with a D90 of about 21 pm to 29 pm; a D50 of about 12 pm to 17 pm; and a DIO of about 6 pm to 10 pm. In some embodiments the povidone is povidone K30. In some embodiments the tablet core comprises 149.1 mg of lactose monohydrate, 31.92 mg of microcrystalline cellulose, 12.6 mg of povidone K30, 14 mg of croscarmellose sodium and 2.38 mg of magnesium stearate. In some embodiments the coating comprises poly vinyl alcohol, talc, macrogol 3350, Allura Red AC in aluminum lake, titanium dioxide and lecithin. In some embodiments the coating comprises 0.1 to 0.4 mg / cm2titanium dioxide, and 0.1-0.4 mg / cm2Allura Red AC in aluminum lake based, on the surface area of the tablet. In some embodiments the coating comprises 0.295 mg / cm2titanium dioxide, and 0.288 mg / cm2Allura Red AC in aluminum lake, based on the surface area of the tablet. In some embodiments the surface area of the tablet is 1.885 cm2. In some embodiments the coating comprises 0.295 mg / cm2titanium dioxide, and 0.288 mg / cm2Allura Red AC in aluminum lake, based on the surface area of the tablet and the surface area of the tablet is 1.638 cm2. In some embodiments the coating comprises poly vinyl alcohol, talc, macrogol 3350, 0.295 mg / cm2titanium dioxide based on surface area of the tablet, 0.288 mg / cm2Allura Red AC in aluminum lake based on surface are of the tablet, and lecithin; and the surface area of the tablet is 1.885 cm2. In some embodiments the coating comprises 5.85 mg poly vinyl alcohol, 2.66 mg talc, 1.64 mg macrogol 3350, 0.62 mg titanium dioxide, 1.30 mg Allura Red AC in aluminum lake 38-42%, 0.76 mg Allura Red AC in aluminum lake 15- 17% and 0.47 mg lecithin. In some embodiments the tablet core comprises 149.1 mg of lactose monohydrate, 31.92 mg of microcrystalline cellulose, 12.6 mg of povidone K30, 14 mg of croscarmellose sodium and 2.38 mg of magnesium stearate and the coating comprises 5.85 mg poly vinyl alcohol, 2.66 mg talc, 1.64 mg macrogol 3350, 0.62 mg titanium dioxide, 1.30 mg Allura Red AC in aluminum lake 38-42%, 0.76 mg Allura Red AC in aluminum lake 15-17% and 0.47 mg lecithin.

[0130] Some embodiments describe a tablet comprising a tablet core and a coating; wherein the tablet core comprises 70 mg of a solid compound of Formula I according to any embodiment described herein, and a pharmaceutically acceptable excipient comprising 149.1 mg of lactose monohydrate, 31.92 mg of microcrystalline cellulose, 12.6 mg of povidone K30, 14 mg of croscarmellose sodium and 2.38 mg of magnesium stearate provided the excipient does not also contain a cyclodextrin derivative and polacrilin potassium; and thecoating comprising 5.85 mg poly vinyl alcohol, 2.66 mg talc, 1.64 mg macrogol 3350, 0.62 mgtitanium dioxide, 1.30 mg Allura Red AC in aluminum lake 38-42%, 0.76 mg Allura Red AC in aluminum lake 15-17% and 0.47 mg lecithin.

[0131] Some embodiments describe a tablet comprising a tablet core and a coating; wherein the tablet core comprises 100 mg of a solid compound of Formula (I):wherein the solid compound has a unimodal particle size distribution with a D90 < 43 pm; and a pharmaceutically acceptable excipient comprising lactose monohydrate, microcrystalline cellulose, povidone, croscarmellose sodium and magnesium stearate, provided the excipient does not also contain a cyclodextrin derivative and polacrilin potassium; and the coating comprises titanium dioxide, and Allura red AC in aluminum lake. In some embodiments the solid compound has a unimodal particle size distribution with a D90 of about 13 pm to 43 pm. In some embodiments the solid compound has a unimodal particle size distribution with a D90 of about 21 pm to 29 pm; a D50 of about 12 pm to 17 pm; and a DIO of about 6 pm to 10 pm. In some embodiments the povidone is povidone K30. In some embodiments the tablet core comprises 213.0 mg of lactose monohydrate, 45.6 mg of microcrystalline cellulose, 18.0 mg of povidone K30, 20 mg of croscarmellose sodium and 3.4 mg of magnesium stearate. In some embodiments the coating comprises poly vinyl alcohol, talc, macrogol 3350, Allura Red AC in aluminum lake, titanium dioxide and lecithin. In some embodiments the coating comprises 0.1 to 0.4 mg / cm2titanium dioxide, and 0.1 -0.4 mg / cm2Allura Red AC in aluminum lake based, on the surface area of the tablet. In some embodiments the coating comprises 0.295 mg / cm2titanium dioxide, and 0.288 mg / cm2Allura Red AC in aluminum lake, based on the surface area of the tablet. In some embodiments the surface area of the tablet is 2.535 cm2. In some embodiments the coating comprises 0.295 mg / cm2titanium dioxide, and 0.288 mg / cm2Allura Red AC in aluminum lake, based on the surface area of the tablet and the surface area of the tablet is 2.535 cm2. In some embodiments the coating comprises poly vinyl alcohol, talc, macrogol 3350, 0.295 mg / cm2titanium dioxide based on surface area of the tablet, 0.288 mg / cm2Allura Red AC in aluminum lake based on surface are of the tablet, and lecithin; andthe surface area of the tablet is 2.535 cm2. In some embodiments the coating comprises 7.92 mg poly vinyl alcohol, 3.6 mg talc, 2.22 mg macrogol 3350, 0.84 mgtitanium dioxide, 1.75 mg Allura Red AC in aluminum lake 38-42%, 1.03 mg Allura Red AC in aluminum lake 15-17% and 0.63 mg lecithin. In some embodiments the tablet core comprises 213.0 mg of lactose monohydrate, 45.6 mg of microcrystalline cellulose, 18.0 mg of povidone K30, 20 mg of croscarmellose sodium and 3.4 mg of magnesium stearate and the coating comprises 7.92 mg poly vinyl alcohol, 3.6 mg talc, 2.22 mg macrogol 3350, 0.84 mg titanium dioxide, 1.75 mg Allura Red AC in aluminum lake 38-42%, 1.03 mg Allura Red AC in aluminum lake 15-17% and 0.63 mg lecithin.

[0132] Some embodiments describe a tablet comprising a tablet core and a coating; wherein the tablet core comprises 100 mg of a solid compound of Formula I according to any embodiment described herein, and a pharmaceutically acceptable excipient comprising 213.0 mg of lactose monohydrate, 45.6 mg of microcrystalline cellulose, 18.0 mg of povidone K30, 20 mg of croscarmellose sodium and 3.4 mg of magnesium stearate provided the excipient does not also contain a cyclodextrin derivative and polacrilin potassium; and the coating comprising 7.92 mg poly vinyl alcohol, 3.6 mg talc, 2.22 mg macrogol 3350, 0.84 mg titanium dioxide, 1.75 mg Allura Red AC in aluminum lake 38-42%, 1.03 mg Allura Red AC in aluminum lake 15-17% and 0.63 mg lecithin.

[0133] Some embodiments describe a tablet comprising a tablet core and a coating; wherein the tablet core comprises 150 mg of a solid compound of Formula (I):wherein the solid compound has a unimodal particle size distribution with a D90 < 43 pm; and a pharmaceutically acceptable excipient comprising lactose monohydrate, microcrystalline cellulose, povidone, croscarmellose sodium and magnesium stearate, provided the excipient does not also contain a cyclodextrin derivative and polacrilin potassium; and the coating comprises titanium dioxide, and Allura red AC in aluminum lake. In some embodiments the solid compound has a unimodal particle size distribution with a D90 of about 13 pm to 43 pm.In some embodiments the solid compound has a unimodal particle size distribution with a D90 of about 21 pm to 29 pm; a D50 of about 12 pm to 17 pm; and a DIO of about 6 pm to 10 pm. In some embodiments the povidone is povidone K30. In some embodiments the tablet core comprises 319.5 mg of lactose monohydrate, 68.4 mg of microcrystalline cellulose, 27.0 mg of povidone K30, 30 mg of croscarmellose sodium and 5.1 mg of magnesium stearate. In some embodiments the coating comprises poly vinyl alcohol, talc, macrogol 3350, Allura Red AC in aluminum lake, titanium dioxide and lecithin. In some embodiments the coating comprises 0.1 to 0.4 mg / cm2titanium dioxide, and 0.1-0.4 mg / cm2Allura Red AC in aluminum lake based, on the surface area of the tablet. In some embodiments the coating comprises 0.311 mg / cm2titanium dioxide, and 0.304 mg / cm2Allura Red AC in aluminum lake, based on the surface area of the tablet. In some embodiments the surface area of the tablet is 3.156 cm2. In some embodiments the coating comprises 0.311 mg / cm2titanium dioxide, and 0.304 mg / cm2Allura Red AC in aluminum lake, based on the surface area of the tablet and the surface area of the tablet is 3.156 cm2. In some embodiments the coating comprises poly vinyl alcohol, talc, macrogol 3350, 0.311 mg / cm2titanium dioxide based on surface area of the tablet, 0.304 mg / cm2Allura Red AC in aluminum lake based on surface are of the tablet, and lecithin; and the surface area of the tablet is 3.156 cm2. In some embodiments the coating comprises 10.56 mg poly vinyl alcohol, 4.8 mg talc, 2.96 mg macrogol 3350, 1.12 mgtitanium dioxide, 2.34 mg Allura Red AC in aluminum lake 38-42%, 1.38 mg Allura Red AC in aluminum lake 15-17% and 0.84 mg lecithin. In some embodiments the tablet core comprises 319.5 mg of lactose monohydrate, 68.4 mg of microcrystalline cellulose, 27.0 mg of povidone K30, 30 mg of croscarmellose sodium and 5.1 mg of magnesium stearate and the coating comprises 10.56 mg poly vinyl alcohol, 4.8 mg talc, 2.96 mg macrogol 3350, 1.12 mg titanium dioxide, 2.34 mg Allura Red AC in aluminum lake 38-42%, 1.38 mg Allura Red AC in aluminum lake 15-17% and 0.84 mg lecithin.

[0134] Some embodiments describe a tablet comprising a tablet core and a coating; wherein the tablet core comprises 150 mg of a solid compound of Formula I according to any embodiment described herein, and a pharmaceutically acceptable excipient comprising 319.5 mg of lactose monohydrate, 68.4 mg of microcrystalline cellulose, 27.0 mg of povidone K30, 30 mg of croscarmellose sodium and 5.1 mg of magnesium stearate provided the excipient does not also contain a cyclodextrin derivative and polacrilin potassium; and the coating comprising 10.56 mg poly vinyl alcohol, 4.8 mg talc, 2.96 mg macrogol 3350, 1.12 mgtitanium dioxide, 2.34 mg Allura Red AC in aluminum lake 38-42%, 1.38 mg Allura Red AC in aluminum lake 15-17% and 0.84 mg lecithin.

[0135] In one embodiment, the pharmaceutical composition further comprises an additional therapeutic agent selected from the group consisting of vitamin Bl 2, folic acid, ferrous sulfate, recombinant human erythropoietin, and an erythropoiesis stimulating agent (ESA). In another embodiment, the pharmaceutical composition is formulated for oral delivery. In another embodiment, the pharmaceutical composition is formulated as a tablet or a capsule. In another embodiment the pharmaceutical composition is formulated as a capsule.

[0136] All formulations for oral administration should be in dosages suitable for such administration. It will be understood by one of skill in the art that more than one roxadustat pharmaceutical composition may be administered to a subject. For example, if the subject requires a dose of 70 mg, this can be achieved by administration of a 20 mg capsule or tablet and a 50 mg capsule or tablet taken concurrently or a dose of 70 mg can be achieved by administration of a single 70 mg tablet or capsule. A 100 mg dose can be achieved by administration of two 50 mg capsules or tablets taken concurrently or a dose of 100 mg can be achieved by administration of a single 100 mg tablet or capsule. A 120 mg dose can be achieved for example, by administration of a 70 mg tablet or capsule and a 50 mg tablet or capsule; by administration of six, 20 mg tablets or capsules; or by administration or two, 50 mg tablets or capsules and one, 20 mg tablets or capsules. A 150 mg dose can be achieved for example, by administration of one 150 mg tablet or capsule; by administration of three 50 mg tablets or capsules; by administration of a 100 mg tablet or capsule and a 50 mg tablet or capsule; or by administration of a 50 mg tablet or capsule and five 20 mg tablets or capsules.

[0137] For any composition used in the various treatments embodied herein, a therapeutically effective dose can be estimated initially using a variety of techniques well known in the art. For example, in a cell culture assay, a dose can be formulated in animal models to achieve a circulating concentration range that includes the ICso as determined in cell culture. Dosage ranges appropriate for human subjects can be determined, for example, using data obtained from cell culture assays and non-human animal studies. In some embodiments the dose is 70 mg to 150 mg. In some embodiments the dosage is 70 mg to 120 mg. In some embodiments the dosage is 70 mg to 100 mg. In some embodiments the dosage is 100 mg to 120 mg. In some embodiments the dose is 120 mgto 150 mg. In some embodiments the dosage is 70 mg. In some embodiments the dosage is 100 mg. In some embodiments the dosage is120 mg. In some embodiments the dose is 150 mg. In some embodiments the dose is 70 mg to 150 mg three times a week. In some embodiments the dosage is 70 mg to 120 mg three times a week. In some embodiments the dosage is 70 mg to 100 mg three times a week. In some embodiments the dosage is 100 mg to 120 mg three times a week. In some embodiments the dosage is 120 mg to 150 mg three times a week. In some embodiments the dosage is 70 mg three times a week. In some embodiments the dosage is 100 mg three times a week. In some embodiments the dosage is 120 mg three times a week. In some embodiments the dose is 150 mg three times a week. In some embodiments the dose is 70 mg to 150 mg two times a week. In some embodiments the dosage is 70 mg to 120 mg two times a week. In some embodiments the dosage is 70 mg to 100 mg two times a week. In some embodiments the dosage is 100 mg to 120 mg two times a week. In some embodiments the dosage is 120 mg to150 mg two times a week. In some embodiments the dosage is 70 mg two times a week. In some embodiments the dosage is 100 mg two times a week. In some embodiments the dosage is 120 mg two times a week. In some embodiments the dose is 150 mg two times a week. In some embodiments the dosage is 70 mg to 150 mg three times a week administered orally. In some embodiments the dosage is 70 mg to 120 mg three times a week administered orally. In some embodiments the dosage is 70 mg to 100 mg three times a week administered orally. In some embodiments the dosage is 100 mg to 120 mg three times a week administered orally. In some embodiments the dosage is 120 mg to 150 mg three times a week administered orally. In some embodiments the dosage is 70 mg three times a week administered orally. In some embodiments the dosage is 100 mg three times a week administered orally. In some embodiments the dosage is 120 mg three times a week administered orally. In some embodiments the dosage is 150 mg three times a week administered orally. In some embodiments the dosage is 70 mg to 150 mg two times a week administered orally. In some embodiments the dosage is 70 mg to 120 mg two times a week administered orally. In some embodiments the dosage is 70 mg to 100 mg two times a week administered orally. In some embodiments the dosage is 100 mg to 120 mg two times a week administered orally. In some embodiments the dosage is 120 mg to 150 mg two times a week administered orally. In some embodiments the dosage is 70 mg two times a week administered orally. In some embodiments the dosage is 100 mg two times a week administered orally. In some embodiments the dosage is 120 mg two times a week administered orally. In some embodiments the dosage is 150 mg two times a week administered orally. In some embodiments the dosage is 3.5 mg / kg or 400 mg, whichever is lower. In some embodiments the dosage is 3.5 mg / kg or 400 mg, whichever is lower, three times a week. In some embodiments the dosage is 3.5 mg / kg or 400 mg,whichever is lower, two times a week. In some embodiments the dosage is 3.5 mg / kg or 400 mg, whichever is lower, three times a week, administered orally. In some embodiments the dosage is 3.5 mg / kg or 400 mg, whichever is lower, two times a week, administered orally. Various formulations and drug delivery systems are available in the art (see, e.g., Gennaro, A. R., ed. (1995) Remington's Pharmaceutical Sciences).

[0138] A therapeutically effective dose of a compound refers to that amount of the compound that results in amelioration of symptoms or a prolongation of survival in a subject. Toxicity and therapeutic efficacy of such molecules can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., by determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio of toxic to therapeutic effects is the therapeutic index, which can be expressed as the ratio LD50 / ED50. Compounds that exhibit high therapeutic indices are preferred.

[0139] Dosages preferably fall within a range of circulating concentrations that includes the EDsowith little or no toxicity. Dosages may vary within this range depending upon the dosage form employed and the route of administration utilized. The exact formulation, route of administration, and dosage should be chosen, according to methods known in the art, in view of the specifics of a subject's condition.

[0140] Dosage amount and interval may be adjusted individually to provide plasma levels of the active moiety that are sufficient to modulate a desired parameter, e.g., endogenous erythropoietin plasma levels, i.e., minimal effective concentration (MEC). The MEC will vary for each compound but can be estimated from, for example, in vitro data. Dosages necessary to achieve the MEC will depend on individual characteristics. Compounds or compositions thereof should be administered using a regimen which maintains plasma levels above the MEC for about 10-90% of the duration of treatment, preferably about 30-90% of the duration of treatment, and most preferably between 50-90%. Alternatively, modulation of a desired parameter, e.g., stimulation of endogenous erythropoietin, may be achieved by 1) administering a loading dose followed by a maintenance dose, 2) administering an induction dose to rapidly achieve the desired parameter, e.g., erythropoietin levels, within a target range, followed by a lower maintenance dose to maintain, e.g., hematocrit, within a desired target range, or 3) repeated intermittent dosing.

[0141] The amount of compound or composition administered will, of course, be dependent on a variety of factors, including the sex, age, and weight of the subj ect being treated, the severity of the affliction, the manner of administration, and the judgment of the prescribing physician.

[0142] The present compositions may, if desired, be presented in a pack or dispenser device containing one or more unit dosage forms containing the active ingredient. Such a pack or device may, for example, comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. Compositions comprising roxadustat according to any embodiment described herein formulated in a compatible pharmaceutical excipient may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition. Suitable conditions indicated on the label may include treatment of conditions, disorders, or diseases in which anemia is a major indication.METHODS OF USE

[0143] One aspect of the disclosure provides for use of roxadustat according to any embodiment described herein or a pharmaceutical composition according to any embodiment described herein for use in treating various conditions or disorders as described herein. It also provides methods of using roxadustat according to any embodiment described herein or a pharmaceutical composition according to any embodiment described herein, to treat, pretreat, or delay progression or onset of various conditions or disorders as described herein.

[0144] Various treatments embodied herein can comprise administration of an effective amount of roxadustat according to any embodiment herein to a subject in need, e.g., a subject having or at risk for anemia due to, e.g., chronic renal failure, diabetes, cancer, AIDS, radiation therapy, chemotherapy, kidney dialysis, or surgery. In one embodiment, the subject is a mammalian subject, and in one embodiment, the subject is a human subject. Various treatments embodied herein can comprise administration of an effective amount of roxadustat according to any embodiment herein to a subject in need thereof, e.g., a subject having or at risk for anemia of chronic kidney disease in non-dialysis dependent patients; chronic kidney disease in patients on dialysis; chemotherapy-induced anemia or myelodysplastic syndromes.

[0145] The roxadustat according to any embodiment described herein or a pharmaceutical composition according to any embodiment described herein can be used to modulate the stability and / or activity of HIF, and thereby activate HIF-regulated gene expression. The roxadustat according to any embodiment described herein or a pharmaceutical composition according to any embodiment described herein, can be used in methods to treat, pretreat, or delay progression or onset of conditions associated with HIF including, but not limited to, anemic, ischemic, and hypoxic conditions. In various embodiments, the roxadustat according to any embodiment described herein or a pharmaceutical composition according to any embodiment described herein, is administered immediately following a condition producing acute ischemia, e.g., myocardial infarction, pulmonary embolism, intestinal infarction, ischemic stroke, and renal ischemic-reperfusion injury. In another embodiment, the roxadustat according to any embodiment described herein or a pharmaceutical composition according to any embodiment described herein, is administered to a patient diagnosed with a condition associated with the development of chronic ischemia, e.g., cardiac cirrhosis, macular degeneration, pulmonary embolism, acute respiratory failure, neonatal respiratory distress syndrome, and congestive heart failure. In yet another embodiment, roxadustat according to any embodiment described herein or a pharmaceutical composition according to any embodiment described herein, is administered immediately after a trauma or injury. In other embodiments, the roxadustat according to any embodiment described herein or a pharmaceutical composition according to any embodiment described herein, can be administered to a subject based on predisposing conditions, e.g., hypertension, diabetes, occlusive arterial disease, chronic venous insufficiency, Raynaud's disease, chronic skin ulcers, cirrhosis, congestive heart failure, and systemic sclerosis. In still other embodiments, the roxadustat according to any embodiment described herein or a pharmaceutical composition according to any embodiment described herein, may be administered to pretreat a subject to decrease or prevent the development of tissue damage associated with ischemia or hypoxia.

[0146] The roxadustat according to any embodiment described herein or a pharmaceutical composition according to any embodiment described herein, can also be used to increase endogenous erythropoietin (EPO). The roxadustat according to any embodiment described herein or a pharmaceutical composition according to any embodiment described herein, can be administered to prevent, pretreat, or treat EPO-associated conditions, including, e.g., conditions associated with anemia and neurological disorders. Conditions associated with anemia include disorders such as acute or chronic kidney disease, diabetes, cancer, ulcers,infection with virus, e.g., HIV, bacteria, or parasites, inflammation, etc. Anemic conditions can further include those associated with procedures or treatments including, e.g., radiation therapy, chemotherapy, dialysis, and surgery. Disorders associated with anemia additionally include abnormal hemoglobin and / or erythrocytes, such as found in disorders such as microcytic anemia, hypochromic anemia, aplastic anemia, etc. In some embodiments the roxadustat according to any embodiment described herein or a pharmaceutical composition according to any embodiment described herein is used for the treatment of anemia in CKD patients on dialysis and patients not on dialysis. In some embodiments the roxadustat according to any embodiment described herein or a pharmaceutical composition according to any embodiment described herein is used to treat anemia of myelodysplastic syndromes or chemotherapy-induced anemia.

[0147] The disclosure is also directed to use of the roxadustat according to any embodiment described herein or a pharmaceutical composition according to any embodiment described herein to treat, pretreat, or delay onset of a condition associated with a disorder selected from the group consisting of anemic disorders; neurological disorders and / or injuries including cases of stroke, trauma, epilepsy, and neurodegenerative disease; cardiac ischemia including, but not limited to, myocardial infarction and congestive heart failure; liver ischemia including, but not limited to, cardiac cirrhosis; renal ischemia including, but not limited to, acute kidney failure and chronic kidney failure; peripheral vascular disorders, ulcers, bums, and chronic wounds; pulmonary embolism; and ischemic-reperfusion injury.

[0148] The disclosure is also directed to a method of inhibiting the activity of at least one hydroxylase enzyme which modifies the alpha subunit of hypoxia inducible factor. The HIF hydroxylase enzyme may be a prolyl hydroxylase including, but not limited to, the group consisting of EGLN1, EGLN2, and EGLN3 (also known as PHD2, PHD1 and PHD3, respectively), described by Taylor (2001, Gene 275:125-132), and characterized by Aravind and Koonin (2001, Genome Biol 2:RESEARCH0007), Epstein et al. (2001, Cell 107:43-54), and Bruick and McKnight (2001, Science 294:1337-1340). The method comprises contacting the enzyme with an inhibiting effective amount of the roxadustat according to any embodiment described herein. In some embodiments, the HIF hydroxylase enzyme is an asparaginyl hydroxylase or a prolyl hydroxylase. In other embodiments, the HIF hydroxylase enzyme is a human Factor Inhibiting HIF (FIH), EGLN1, EGLN2, or EGLN3.

[0149] Some embodiments describe the use of an oral pharmaceutical composition comprising a therapeutically effective amount of a solid compound of Formula (I):wherein the solid compound has a unimodal particle size distribution with a D90 < 43 pm; and at least one pharmaceutically acceptable excipient, provided the excipient is not a cyclodextrin derivative and polacrilin potassium; for the treatment of anemia. In some embodiments the solid compound has a unimodal particle size distribution with a D90 of about 13 pm to 43 pm. In some embodiments the solid compound has a unimodal particle size distribution with a D90 of about 21 pm to 29 pm; a D50 of about 12 pm to 17 pm; and a DIO of about 6 pm to 10 pm. In some embodiments the solid compound of the pharmaceutical composition has a particle size distribution of D90 of about 21.9 pm to 28.5 pm; a D50 of about 12.28 pm to 16.03; and a DIO of about 6.66 pm to 9.13 pm. In some embodiments the solid compound of the pharmaceutical composition has a particle size distribution selected fromIn some embodiments the pharmaceutically acceptable excipient of the pharmaceutical composition, comprises microcrystalline cellulose, lactose monohydrate, povidone, croscarmellose sodium and magnesium stearate. In some embodiments the pharmaceutical composition the pharmaceutical composition further comprises a photostabilizer selected from one or more of Allura Red AC, titanium dioxide and iron oxide yellow. In some embodiments the pharmaceutical composition is a capsule. In some embodiments the anemia is anemia of chronic kidney disease in non-dialysis dependent patients. In some embodiments the anemia is anemia of chronic kidney disease in patients on dialysis. In some embodiments the anemia is chemotherapy-induced anemia. In some embodiments the anemia is anemia of myelodysplastic syndrome.

[0150] Some embodiments describe the use of a capsule comprising: a capsule fill comprising an oral pharmaceutical composition comprising 20 mg of a solid compound Formula (I):wherein the solid compound has a unimodal particle size distribution with a D90 < 43 pm; and a pharmaceutically acceptable excipient comprising lactose monohydrate, microcrystalline cellulose, povidone, croscarmellose sodium and magnesium stearate, provided the excipient does not also contain a cyclodextrin derivative and polacrilin potassium; and a gelatin capsule shell comprising titanium dioxide, iron yellow oxide and gelatin; for the treatment, of anemia.In some embodiments the solid compound has a unimodal particle size distribution with a D90 of about 13 pm to 43 pm. In some embodiments the solid compound has a unimodal particle size distribution with a D90 of about 21 pm to 29 pm; a D50 of about 12 pm to 17 pm; and a DIO of about 6 pm to 10 pm. In some embodiments the solid compound of the pharmaceutical composition has a particle size distribution of D90 of about 21.9 pm to 28.5 pm; a D50 of about 12.28 pm to 16.03; and a DIO of about 6.66 pm to 9.13 pm. In some embodiments the solid compound of the pharmaceutical composition has a particle size distribution selected fromIn some embodiments the anemia is anemia of chronic kidney disease in non-dialysis dependent patients. In some embodiments the anemia is anemia of chronic kidney disease inpatients on dialysis. In some embodiments the anemia is chemotherapy-induced anemia. In some embodiments the anemia is anemia of myelodysplastic syndrome.

[0151] Some embodiments describe the use of capsule comprising: a capsule fill comprising an oral pharmaceutical composition comprising 50 mg of a solid compound of Formula (I):wherein the solid compound has a unimodal particle size distribution with a D90 < 43 pm; and a pharmaceutically acceptable excipient comprising lactose monohydrate, microcrystalline cellulose, povidone, croscarmellose sodium and magnesium stearate, provided the excipient does not also contain a cyclodextrin derivative and polacrilin potassium; and a gelatin capsule shell comprising Allura red AC, titanium dioxide, iron yellow oxide and gelatin; for the treatment, of anemia. In some embodiments the solid compound has a unimodal particle size distribution with a D90 of about 13 pm to 43 pm. In some embodiments the solid compound has a unimodal particle size distribution with a D90 of about 21 pm to 29 pm; a D50 of about 12 pm to 17 pm; and a DIO of about 6 pm to 10 pm. In some embodiments the solid compound of the pharmaceutical composition has a particle size distribution of D90 of about 21.9 pm to 28.5 pm; a D50 of about 12.28 pm to 16.03; and a DIO of about 6.66 pm to 9.13 pm. In some embodiments the solid compound of the pharmaceutical composition has a particle size distribution selected fromIn some embodiments the anemia is anemia of chronic kidney disease in non-dialysis dependent patients. In some embodiments the anemia is anemia of chronic kidney disease in patients on dialysis. In some embodiments the anemia is chemotherapy-induced anemia. In some embodiments the anemia is anemia of myelodysplastic syndrome.PROCESS FOR PREPARATION OF ROXADUSTAT OF EMBODIMENTS HEREIN

[0152] General Procedure

[0153] The compounds of the present invention can be prepared by a general process as follows.

[0154] 1. Technical grade roxadustat and solvent are charged into a reactor (Rl) with stirring. Slowly, a base is charged into the mixture in reactor (Rl), to obtain a pH of about 7. The mixture is stirred at 15-35°C until all the solid is dissolved.

[0155] In some embodiments the base is an inorganic base. In some embodiments the base is an organic base. In some embodiments the base is selected from the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide, triethylamine, morpholine, imidazole, and pyridine. In some embodiments the base is aqueous sodium hydroxide. In some embodiments the amount of base is 0.135-0.145 times the weight of technical grade roxadustat. In some embodiments the solvent is water. In some embodiments the solvent is a cosolvent with water and the co solvent is selected from the group consisting of methanol, ethanol, isopropanol and acetone. In some embodiments the solvent is 9.5-10.5 times the weight of technical grade roxadustat. In some embodiments the solvent is water, and the base is aqueous sodium hydroxide.

[0156] 2. The solution is optionally transferred through activated carbon into a new reactor(R2). The activated carbon is washed with solvent (1.9-2.1 times the weight of technical grade roxadustat). The solution in the reactor (R2) is heated. In some embodiments the activated carbon is a cartridge. In some embodiments the cartridge is a CUNO cartridge. In some embodiments the solution in the reactor (R2) is adjusted to 60-80°C.

[0157] 3. The pH of the solution in step 2. is adjusted to 6.2-6.7 by slowly adding acid into the reactor (R2) at 60-80°C. In some embodiments the pH is 6.3-6.6. In some embodiments the pH is 6.2-6.4. In some embodiments the temperature is about 70 °C. Seed, micronized roxadustat (about 5% by weight of technical grade roxadustat, D90 8 pm -13 pm), is added to the solution in the reactor (R2). The size of the seed is dependent on the size of the final PSD desired. Generally, the final PSD will be about 2x the seed PSD if the crystallization is carried out at a pH of 6.3. At pH above 6.5, smaller particles in the seed will dissolve before being involved in any recrystallization, leading to higher PSD than would be expected based on seed PSD. The mixture is maintained at 60-80°C during crystallization. In some embodiments the temperature is maintained at 70°C. Additional aqueous acid solution is added to reactor (R2) to maintain the pH during crystallization. In some embodiments the acid is an inorganic acid. In some embodiments the acid is an organic acid. In some embodiments the acid is selected from the group consisting of acetic acid, formic acid, citric acid, lactic acid, tartaric acid, propionic acid, sulfuric acid, nitric acid, hydrobromic acid, and boric acid. In some embodiments the acid is aqueous acetic acid. In some embodiments the seed micronized roxadustat D90 is <13 pm. In some embodiments the seed micronized roxadustat D90 is 8 pm -13 pm. In some embodiments the seed micronized roxadustat is 8 pm -11 pm. In some embodiments the seed microcrystalline roxadustat has a particle size distribution of 8 pm to 11 pm; a D50 of about 2 pm to 6 pm; and a D10 of about 1 pm to 2 pm. In some embodiments the seed microcrystalline roxadustat has a particle size distribution of D90 of 8.39 to 10.7 pm;a D50 of 2.67 pm to 5.11; and a DIO of 0.74 pm to 1.7 pm. In some embodiments the seed micronized roxadustat has a particle size distribution of

[0158] 4. The solid is then isolated at 60-80°C. In some embodiments the solid is isolated by filtration at about 70°C. In some embodiments the solid is isolated by centrifugation at 70°C.

[0159] 5. The roxadustat crystals are dried. In some embodiments the roxadustat is dried under vacuum. In some embodiments the roxadustat is dried under vacuum with minimum agitation. In some embodiments the roxadustat is dried under vacuum with minimum agitation at < 70°C. In some embodiments the roxadustat is dried under vacuum with minimum agitation at < 70°C until residual acid is < 1500 ppm and residual water content is < 0.1%.

[0160] In some embodiments, the process produces a compound of Formula (I), having a unimodal particle size distribution of D90 of about 21 pm to 29 pm; a D50 of about 12 pm to 17 pm; and a D10 of about 6 pm to 10 pm. In some embodiments the process produces a compound of Formula (I) having a unimodal particle size distribution of D90 of about 21.9 pm to 28.5 pm; a D50 of about 12.28 pm to 16.03; and a D10 of about 6.66 pm to 9.13 pm. In some embodiments the process produces a compound of Formula (I) having a unimodal particle size distribution selected from:

[0161] The seed micronized roxadustat of step 3., according to any embodiment described herein, is prepared by jet milling roxadustat until micronized roxadustat of D90 of 8 pm -13 pm is achieved. In some embodiments, seed micronized roxadustat of step 3., is prepared by jet milling roxadustat until micronized roxadustat of D90 of 8 pm -11 pm is achieved. In some embodiments the roxadustat that is jet milled is a roxadustat according to any embodiment described herein. In some embodiments, the seed micronized roxadustat is prepared by jet milling roxadustat that has a unimodal particle size distribution of D90 of about 21 pm to 29 pm; a D50 of about 12 pm to 17 pm; and a DIO of about 6 pm to 10 pm.

[0162] An exemplary process comprises:

[0163] Preparation of Solution 1 : Aqueous sodium hydroxide

[0164] Aqueous sodium hydroxide was prepared by dissolving sodium hydroxide (0.135- 0.145 times the weight of technical grade roxadustat) in water (3.3-3.5 times the weight of technical grade roxadustat).

[0165] Preparation of Solution 2: Aqueous acetic acid (45-55%)

[0166] Aqueous acetic acid (45-55%), was prepared by dissolving acetic acid (0.41-0.45 times the weight of technical grade roxadustat) in water (0.40-0.45 times the weight of technical grade roxadustat).

[0167] Process

[0168] Technical grade roxadustat and water (9.5-10.5 times the weight of technical grade roxadustat) were charged into reactor (Rl) with stirring. Slowly, all of the aqueous sodiumhydroxide (solution 1), was charged into the mixture in reactor (Rl). The mixture was stirred at 15-35°C for at least 45 min., until all the solid was dissolved.

[0169] The solution was transferred through a cartridge of activated carbon (CUNO) into anew reactor (R2). The cartridge was washed with water (1.9-2.1 times the weight of technical grade roxadustat). The solution temperature in the reactor (R2) was then adjusted to 60-80°C.

[0170] The solution pH was adjusted to 6.0-6.8 by adding aqueous acetic acid (solution 2) into reactor (R2) at 60-80°C in three parts as follows: The first part: Solution 2 (0.060-0.068 times the weight of technical grade roxadustat) was added to reactor (R2). The second part: Solution 2 (0.019-0.027 times the weight of technical grade roxadustat) was added to reactor (R2) in portions (0.0005-0.0020 times the weight of technical grade roxadustat) to achieve pH 6.0-6.8. Seed, micronized roxadustat (0.045-0.055 times the weight of technical grade roxadustat, D90 8 pm -13 pm), was added to the solution in reactor (R2). The mixture was stirred at 60-80°C for 10-20 min. Third part: Solution 2 (0.57-0.64 times the weight of technical grade roxadustat) was added to reactor (R2). The mixture was stirred at 60-80°C for at least 1 hour. [Note: The total acetic acid solution charged is 0.66-0.72 times the weight of technical grade roxadustat],

[0171] The mixture was filtered at 60-80°C. Solid was washed three times with water; (total water used for wash was 4.4-5.6 times the weight of technical grade roxadustat). Water wash was continued until the filtrate reached pH 6-7.

[0172] The roxadustat crystals were dried under vacuum (with minimum agitation) at < 70°C until residual acetic acid was < 1500 ppm and residual water content was < 0.1%.

[0173] The yield was > 90%.

[0174] Some embodiments provide for a compound of Formula (I), according to any embodiment described herein, prepared by a process comprising(i.) preparing an aqueous sodium hydroxide solution (Solution 1), by dissolving sodium hydroxide (0.135-0.145 times the weight of technical grade roxadustat) in water (3.3- 3.5 times the weight of technical grade roxadustat);(ii.) preparing an aqueous acetic acid (45-55%) solution (Solution 2), by dissolving acetic acid (0.41-0.45 times the weight of technical grade roxadustat) in water (0.40-0.45 times the weight of technical grade roxadustat);(iii.) mixing technical grade roxadustat and water (9.5-10.5 times the weight of technical grade roxadustat) into a reactor (Rl) with stirring to form a mixture;(iv.) slowly, adding all of the aqueous sodium hydroxide (solution 1), into the mixture of step (iii.) in the reactor (Rl) to form another mixture and stirring at 15-35°C until all the solid is dissolved, provided the stirring is for at least 45 minutes;(v.) transferring the solution of step (iv.) through a cartridge of activated carbon into a new reactor (R2) and washing the cartridge with water (1.9-2.1 times the weight of technical grade roxadustat) and then adjusting the solution temperature in the reactor (R2) to 60-80°C;(vi.) adjusting the solution of step (v.) to a pH of 6.0-6.8 by adding aqueous acetic acid (solution 2) into the reactor (R2) at 60-80°C in three parts as follows:(a) first part: Solution 2 (0.060-0.068 times the weight technical grade roxadustat) is added to reactor 2 (R2);(b) second part: Solution 2 (0.019-0.027 times the weight of technical grade roxadustat) is added to reactor (R2) in portions (0.0005-0.0020 times the weight of technical grade roxadustat) to achieve pH 6.0-6.8;(c) micronized seed roxadustat (0.045-0.055 times the weight of technical grade roxadustat D90 8 pm -13 pm), is added to the solution in reactor (R2) followed by stirring at 60-80°C for 10-20 minutes;(d) Third part: Solution 2 (0.57-0.64 times the weight of technical grade roxadustat) is added to reactor (R2) and the mixture is stirred at 60-80°C for at least 1 hour; wherein the total acetic acid solution added to reactor (R2) is 0.66-0.72 times the weight of technical grade roxadustat;(vii.) filtering the mixture from step (vii.) at 60-80°C and washing the solid obtained three times with water; wherein the total water used for washing is 4.4-5.6 times the weight of technical grade roxadustat;(viii.) measuring the pH of the filtrate and if the pH of the filtrate is not 6-7, further washing the solid with water until the filtrate reaches pH 6-7;(ix.) drying the solid under vacuum, with minimum agitation at < 70°C until residual acetic acid is < 1500 ppm and residual water content is < 0.1% to obtain the compound of Formula (I).EXAMPLES

[0175] Example 1 : Preparation of Roxadustat of PSD having a unimodal particle size distribution of D90 of about 21 pm to 29 pm; a D50 of about 12 pm to 17 pm; and a DIO of about 6 pm to 10 pm

[0176] Preparation of Solution 1 : Aqueous sodium hydroxide

[0177] Aqueous sodium hydroxide was prepared by dissolving 50.6-54.4 kg of sodium hydroxide (0.135-0.145 times the weight of technical grade roxadustat) in 1237-1313 kg water (3.3 -3.5 times the weight of technical grade roxadustat).

[0178] Preparation of Solution 2: Aqueous acetic acid (45-55%)

[0179] Aqueous acetic acid (45-55%), was prepared by dissolving 154-169 kg of acetic acid (0.41-0.45 times the weight of technical grade roxadustat) in 150-169 kg water (0.40-0.45 times the weight of technical grade roxadustat).

[0180] Process

[0181] Technical grade roxadustat (> 98.9% by HPLC, 371-379 kg) and water 3563-3938 kg (9.5-10.5 times the weight of technical grade roxadustat) were charged into reactor (Rl) with stirring. Slowly, all of the aqueous sodium hydroxide (solution 1) was charged into the mixture in reactor (Rl). The mixture was stirred at 15-35°C for at least 45 min. Stirring was continued until all the solid was dissolved.

[0182] The solution was transferred through a cartridge of activated carbon (CUNO) into a new reactor (R2). The cartridge was washed with 712-788 kg water (1.9-2.1 times the weight of technical grade roxadustat). The solution temperature in the reactor (R2) was then adjusted to 60-80°C.

[0183] The solution pH was adjusted to 6.0-6.8 by adding aqueous acetic acid (solution 2) into reactor (R2) at 60-80°C in three parts as follows: The first part: 22.5-25.7 kg of Solution 2 (0.060-0.068 times the weight of technical grade roxadustat) was added to reactor (R2). The second part: 7-10 kg of Solution 2 (0.019-0.027 times the weight of technical grade roxadustat) was added to reactor (R2) in 0.2-0.8 kg portions (0.0005-0.0020 times the weight of technical grade roxadustat) to achieve pH 6.0-6.8. Seed (16.9-20.6 kg), micronized roxadustat (0.045- 0.055 times the weight of technical grade roxadustat, D90 8 pm -11 pm, prepared by passing roxadustat through a jet mill to achieve D908 pm -13 pm), was added to the solution in reactor (R2). The mixture was stirred at 60-80°C for 10-20 min. Third part: 212.3-240.5 kg of Solution 2 (0.57-0.64 times the weight of technical grade roxadustat) was added to reactor (R2). The mixture was stirred at 60-80°C for at least 1 hour. The total acetic acid solution charged is 248- 270 kg (0.66-0.72 times the weight of technical grade roxadustat).

[0184] The mixture was filtered at 60-80°C. Solid was washed three times with water; total water used for wash was 1650-2100 kg (4.4-5.6 times the weight of technical grade roxadustat). (Note: Water wash was continued until the filtrate reached pH 6-7).

[0185] The roxadustat crystals having a unimodal particle size distribution of D90 of about21 pm to 29 pm; a D50 of about 12 pm to 17 pm; and a D10 of about 6 pm to 10 pm; were dried under vacuum (with minimum agitation) at < 70°C until residual acetic acid was < 1500 ppm and residual water content was < 0.1%.

[0186] FIG. 5 shows the unimodal particle size distribution for a compound of Formula (I) having particle size distribution of D90 of about 21 pm to 29 pm; a D50 of about 12 pm to 17 pm; and a D10 of about 6 pm to 10 pm produced by this method.

[0187] FIG. 6 shows the consistency of the process over multiple runs to produce the compound of Formula (I) having particle size distribution of D90 of about 21 pm to 29 pm; a D50 of about 12 pm to 17 pm; and a D10 of about 6 pm to 10 pm produced by this method

[0188] Example 2: Preparation of Roxadustat of PSD D90 / D50 / D10 of about 6.8 lim / 3.2 iim / 1.1 pm

[0189] Technical grade roxadustat (1.55 kg) and water (15.0 kg) were charged into reactor(Rl) with stirring. Slowly, aqueous sodium hydroxide (prepared from 0.22 kg of sodium hydroxide and 5.4 kg of water) was charged into the mixture in reactor (Rl), while maintaining the temperature below 25°C. The mixture was stirred until all the solid was dissolved.

[0190] An aqueous active carbon mixture (prepared from 0.016 kg of carbon and 1.5 kg of water) was charged into Rl and the contents of Rl were stirred for approximately 2 hours, and then filtered. The solids were washed with water (2 x 3.1 kg) and the filtrate was transferred to reactor (R2).

[0191] While maintaining the temperature at 18-22°C, an aqueous acetic acid solution (prepared from 0.55 kg of water and 0.80 kg of acetic acid) was added very slowly to R2 and the contents of R2 were stirred at 18-22°C for 6 to 8 hrs. The mixture was then filtered, and the filter cake was washed with water (4 x 4-5 kg). The solid was dried under vacuum at 40- 45°C.

[0192] The solid was sieved through a 20-mesh sieve to yield roxadustat (1.2 kg PSD D90 / D50 / D10= 6.8 pm / 3.2 prn / 1.1 pm)

[0193] Example 3: Preparation of Roxadustat of PSD D90 / D50 / D10 of about 36 pm / 17 pm / 4.1 pm

[0194] Technical grade roxadustat (111.4 kg) and water (1017.6 kg) were charged into reactor (Rl) with stirring. Into Rl water was charged (97.7 kg). Slowly, aqueous sodium hydroxide (prepared from 31.5 kg of 50% aqueous sodium hydroxide and 3777.7 kg of water), was charged into the mixture in reactor (Rl). The mixture was stirred until all the solid was dissolved.

[0195] While maintaining the temperature at 20-30°C, an aqueous acetic acid solution (prepared from 74.4 kg of water and 38.4 kg of acetic acid) was added very slowly to Rl. Water (56.3 kg) was charged into Rl and the contents of Rl were stirred at 20-30°C for over 1 hr. The mixture was then filtered, and the filter cake was washed with water (565.0 kg). Thesolid was dried under vacuum at 45°C to yield roxadustat (98.0 kg PSD D90 / D50 / D10= 36 pm / 17 pm / 4.1 m).

[0196] Example 4: Preparation of Roxadustat of PSD D90 / D50 / D10 of about 43 um / 24 pm / 12 pm

[0197] Technical grade roxadustat (104.2 kg) and water (1039.4 kg) were charged into reactor (Rl) with stirring. Slowly, aqueous sodium hydroxide (prepared from 14.6 kg of sodium hydroxide and 349.4 kg of water), was charged into the mixture in reactor (Rl). The mixture was stirred until all the solid was dissolved.

[0198] An aqueous active carbon mixture (prepared from 0.016 kg of carbon and 1.5 kg of water) was charged into Rl and the contents of Rl were stirred for approximately 2 hours, and then filtered. The solids were washed with water (209.8 kg) and the filtrate was transferred to reactor (R2).

[0199] While maintaining the temperature at 32-38°C, an aqueous acetic acid solution (prepared from 34.3 kg of water and 37.4 kg of acetic acid) was added very slowly to R2 and the contents of R2 were stirred at 32-38°C for over 7 hrs. The mixture was then filtered, and the filter cake was washed with water (4 times 210 kg). The solid was dried under vacuum at 45°C to yield roxadustat (100.8 kg PSD D90 / D50 / D10= 43 pm / 24 pm / 12 pm).

[0200] Example 5: Roxadustat Particle Size Distribution Measurement

[0201] The particle size distribution of roxadustat was determined by a customized wetdispersion laser diffraction technique.

[0202] A one gram roxadustat aliquot was subjected to orbital shaking in the presence of 5 mL of pre-dispersion media, to create a fully wetted slurry. The pre-dispersion media contained water, 2% w / w sodium 1 -octanesulfonate, and 12 mM oxalic acid. The surfactant sodium 1 -octanesulfonate was chosen to facilitate particle wetting and to inhibit reagglomeration. The mixture was acidified to approximately pH 2 using pre-dispersion media to prevent roxadustat dissolution. The resulting slurry was diluted with additional 250 mL pre- dispersion media. Continuous magnetic stirring was initiated. A uniform, disagglomerated roxadustat sample was obtained by applying energy with an ultrasonic probe.

[0203] A portion of the roxadustat sample was transferred to a laser diffraction instrument, Microtrac model S3500 (Microtrac MRB, York PA), filled with dispersion media. The dispersion media contained water, 25 ppm oleth-7 (polyethylene glycol monooleyl ether, containing an average of approximately 7 oxyethylene units), and 12 mM oxalic acid. The laser diffraction instrument contained fluid pumps that circulated the roxadustat sample repeatedly past the lasers and optics, where the particle size distribution was measured.

[0204] Three independently prepared roxadustat samples were tested for each roxadustat lot. Mean results were reported for the 10th, 50th, and 90th percentiles of particle size (DvlO, Dv50 and Dv90).

[0205] A more detailed process follows:

[0206] The following abbreviations are used in this process:

[0207] The following reagents were used in this process

[0208] Equivalent reagents may be used where appropriate, provided supporting data is available (e.g., Certificates of Analysis, comparability studies).

[0209] Solution Preparation

[0210] Pre-Dispersion Media

[0211] PD Step 1: A polypropylene pitcher was tared and for each liter of media, was added 1,000 ± 10 g water. For each liter, 10.8 ± 0.5 mL 10% oxalic acid solution was added. The container was placed on a stir plate and a T-handle magnet was added into the solution. The solution was stirred at a speed which created a vortex without splashing.

[0212] PD Step 2: A weigh boat was tared, and for each liter 20.0 ± 1.0 g sodium 1- octanesulfonate was added. The sodium 1 -octanesulfonate was added to the stirring oxalic acid solution. The media was stirred until a clear solution was obtained. The final composition of the media was water, 2% w / w sodium 1 -octanesulfonate, and 12 mM oxalic acid.

[0213] Dispersion Media

[0214] DM Step 1 : A polypropylene pitcher was tared and for each liter of media, was added 1,000 ± 10 g water. For each liter, 10.8 ± 0.5 mL 10% oxalic acid solution was added. The container was placed on a stir plate and a T-handle magnet was added into the solution. The solution was stirred at a speed which created a vortex without splashing.

[0215] DM Step 2: A small weigh boat was tared, and for each liter 25 ± 2 mg oleth-7 was added. The weigh boat was added to the stirring oxalic acid solution and the vortex was allowed to submerge the weigh boat and wash the oleth-7 into solution. Stirring was continued until the weigh boat, upon removal and inspection, exhibited no visible remaining oleth-7, and until all oleth-7 had dissolved into the media, yielding a clear solution. The final composition of the media was water, 25 ppm oleth-7, and 12 mM oxalic acid.

[0216] Set up laser diffraction system: Microtrac model S3500

[0217] Set up the Microtrac system for wet dispersion testing, using the parameters shown in Table below.

[0218] Test overview for roxadustat control material (for system suitability evaluation).

[0219] Three independently prepared replicates of roxadustat control material were tested in a pre-dispersion preparation procedure, an optimal load determination procedure, and the test procedure.

[0220] Test overview for roxadustat samples

[0221] When aliquotting roxadustat, the primary container was briefly tumbled by hand, then a stainless-steel spatula was used to dig past surface layers to take the aliquot from the approximate center of the material mass.

[0222] A pre-dispersion preparation procedure, an optimal load determination procedure, and the test procedure were used to create and analyze one dispersion for each roxadustat sample.

[0223] Pre-dispersion preparation procedure

[0224] Static on the roxadustat (control material or sample) solid was discharged using an anti-static gun. Roxadustat (0.90 to 1.10 g) was added using a stainless-steel spatula to a 600- mL glass beaker and the beaker mouth was sealed with Parafilm to prevent particles from becoming airborne. For roxadustat control material, three samples were prepared in this manner.

[0225] The Parafilm of each beaker was partially opened and 5 mL Pre-Dispersion Media was added via use a pipettor and the Parafilm was closed

[0226] Each beaker was placed in a clamp on an orbital shaker platform (3 / 4-inch orbit, digital speed control, digital auto-off timer, with clamps to fit 600-mL beakers) and shaken at 350 RPM (with a 3 / 4-inch orbit) with the shaker’s count-down (auto-off) timer set to stop at 2 minutes. This process yielded beakers each containing approximately 5 mL of wetted roxadustat slurry. The wetted roxadustat slurry in each beaker was inspected. If dry (nonwetted) material remained floating on the surface of the slurry the 350-RPM, 2-minute shake cycle was repeated.

[0227] The Parafilm on a single first beaker was opened and a 7.9 mm x 31.8 mm Circulus stir bar was added to the beaker followed by addition of 250 mL of Pre -Dispersion Solution. The Parafilm was closed to prevent escape of aerosolized roxadustat during the next step.

[0228] The beaker was placed on the digitally controlled magnetic stir plate and the solution was stirred on medium low and 250 RPM.

[0229] A small slit was made in the center of the Parafilm covering the beaker, and an ultrasonicator probe (1 / 2-inch, 76-pm to 78-pm maximum amplitude, Sonics & Materials P / N 630-0560 (equivalent to Qsonica P / N 4560)) was lowered through it into the liquid so that it entered the liquid surface at approximately the center of the beaker. The Parafilm closed around the probe, preventing aerosolized roxadustat from escaping into the noise enclosure during ultrasonication.

[0230] The ultrasonicator (Ultrasonicator, 125 Watt, 20 kHz, microprocessor-controlled (with Qsonica converter P / N CL- 18), Qsonica model QI 25 A (VWR P / N 89184-816)) was programed to generate 50% amplitude, and sonication was started. The material was sonicated until a total of 6.0 ± 0.2 kJ had been delivered.

[0231] 250 RPM stirring was maintained during and after the sonication process. The final suspended concentration of roxadustat particles in the pre-dispersion was 4 mg / mL.

[0232] The optimal load was immediately determined, and the pre-dispersion tested. The formal test of the pre-dispersion was conducted within 30 minutes from the end of ultrasonication. The other pre-dispersions were prepared and tested as described above and in the test procedure below.

[0233] The probe (Sonics & Materials P / N 630-0560) has maximum possible amplitude of 76 pm to 78 pm. Taking into account the 50% setting, the probe while operating in the pre- dispersion had an actual amplitude of approximately 38 pm to 39 pm, which is one-half the maximum possible amplitude.

[0234] The term “pre-dispersion” is used to describe roxadustat particles prepared at relatively high concentration (4 mg / mL) in a beaker. A portion of the pre-dispersion is transferred to the Microtrac, undergoing dilution by Dispersion Media circulating through the instrument, and creating the final “dispersion”, which undergoes laser diffraction measurement.

[0235] Procedure for determining optimal load

[0236] Analysis of each roxadustat sample lot entailed preparing and testing a pre- dispersion. The pre-dispersion was used both to determine the optimal sample load for that roxadustat lot (i.e., the volume of pre-dispersion which must be added to the Microtrac in order to obtain an acceptable level of laser light transmission) and to prepare a dispersion which served for formal testing of that roxadustat lot.

[0237] The Microtrac flow was started (after rinsing the system and degassing the Dispersion Media) and a manual setzero was performed. The software sample loading interface was opened manually and when the first roxadustat sample pre-dispersion was ready, it was immediately used to prepare a “trial dispersion” in the Microtrac, as follows:

[0238] The Parafilm covering the beaker containing the pre-dispersion was pulled away so the pipettor tip could be lowered into the liquid. A small aliquot (e.g., 0.5 mL) was drawn up from the pre-dispersion into a pipettor and added to the SDC sample bowl. The softwaresample loading interface was watched to observe the change in the level of laser light transmission.

[0239] The addition process was continued (using several aliquots, if necessary, by refilling the pipettor from the pre-dispersion beaker, and by adjusting the pipettor volume setting as needed) until an acceptable dispersion concentration was obtained, as indicated by the FLEX software sample loading interface having the red bar fall in the green zone. Ensuring the red bar was in green zone was the primary software loading requirement. As a secondary objective, the loading was adjusted to a transmission target of 0.92. Achieving a 0.92 transmission target was not required as long as the primary loading criterion has been satisfied (i.e. , the red bar lies in the green zone).

[0240] During the optimal load determination process, the additions and corresponding volume setting(s) on the pipettor were counted. This information was used to keep track of the total volume of pre-dispersion added to the SDC sample bowl to achieve an acceptable dispersion concentration. This summed volume defined the optimal pre-dispersion load for the particular roxadustat lot being evaluated. For example, if three aliquots, 0.50 mL each, and one 0.25 mL aliquot, were needed to achieve suitable laser light transmission, then the optimal load volume for that roxadustat lot is (3 x 0.50 mL + 0.25 mL) = 1.75 mL.

[0241] Once the optimal pre-dispersion volume was established, that volume was used when performing the formal testing for the pre-dispersion for that roxadustat lot, as described in below.

[0242] When the optimal load determination process was complete, the software sample loading interface screen was closed, and a rinse was initiated manually to remove the trial dispersion from the system.

[0243] Formal analysis of the pre-dispersion immediately followed, as described below

[0244] The trial dispersion is intended only to gauge light transmission, for determining the optimal pre-dispersion aliquot volume to be dispensed as a bolus as described in below

[0245] The optimal pre-dispersion volume may vary from one roxadustat drug substance lot to another, depending on each lot’s particle size distribution. Roxadustat lots consisting of relatively small particles (e.g., milled material) contain a high number of crystals per unitweight. These lots therefore require a relatively small volume of pre-dispersion to obtain adequate loading, because each milliliter contains many small, light-diffracting crystals. Conversely, pre-dispersions prepared from roxadustat lots consisting of larger particles contain fewer crystals per milliliter, and therefore require an increased volume of pre-dispersion to obtain adequate loading.

[0246] When more than one roxadustat lot was to be tested, the optimal sample load for each lot was determined.

[0247] Pre-dispersion test procedure

[0248] After rinsing the system and degassing the Dispersion Media the Microtrac software was used to start an automated run sequence

[0249] The Parafilm covering the beaker containing the pre-dispersion was pulled away so that a pipettor tip could be lowered into the liquid, avoiding tip contact with the spinning stir bar. The aliquot was slowly drawn up into the pipettor.

[0250] The aliquot was dispensed into the SDC sample bowl with the point of the pipettor tip positioned approximately 5 mm below the liquid surface in the SDC sample bowl.

[0251] The automated Microtrac run routine confirmed acceptable laser transmission. Followed by a 60-second pause while the dispersion recirculated to become homogeneous. Then the instrument automatically made three, 30-second laser diffraction measurements of the dispersion.

[0252] The system then automatically drained, rinsed, and deaerated. The SDC ultrasound was manually started to degas the Dispersion Media. The next pre-dispersion was prepared and the automated run sequence started in preparation for analysis. System preparation, aliquot addition, and testing was repeated for all additional pre-dispersions.

[0253] An Average Record Report for each control material dispersion and for each roxadustat sample dispersion was generated. Each Average Record Report summarized the measurements from three, 30-second readings. There were a total of three Average Record Reports from the control material tests, and one Average Record Report from each roxadustat sample lot.

[0254] Example 6: Roxadustat Dissolution

[0255] Dissolution testing of the roxadustat tablets was performed using a USP apparatus II at 50 rpm paddle speed with 900 mL of 0.05 M Potassium Phosphate Buffer media pH 6.5, USP, maintained at 37°C. Samples were collected at 7 (or 5), 10, 15, 20, 30, 45 and 60 min, using automated sampling. After 60 minutes, the paddle speed was increased to 250 rpm and an infinity sample was collected at 75 min. Roxadustat dissolution sample concentration was determined by HPLC using area normalization and external reference standard.

[0256] Dissolution testing on the roxadustat gelatin capsules was performed using a USP apparatus II at 75 rpm paddle speed with 900 mL of 0.05 M Potassium Phosphate Buffer media pH 6.8 USP, maintained at 37°C. Samples were collected at 5, 10, 15, 20, 30, 45 and 60 min, using automated sampling. After 60 minutes, the paddle speed was increased to 250 rpm and an infinity sample was collected at 75 min. Roxadustat dissolution sample concentration was determined by HPLC using area normalization and external reference standard.

[0257] The yield was > 90%.ADDITIONAL EMBODIMENTS

[0258] Embodiments include the following

[0259] Embodiment 1: A solid compound of Formula (I):wherein the compound has a particle size distribution of D90 of about 6 pm to 58 pm; a D50 of about 3.2 pm to 34 pm; and a D10 of about 1.1 pm to 18 pm.

[0260] Embodiment 2: The solid compound of Embodiment 1, wherein the solid compound is selected from, an amorphous solid, crystalline form A, crystalline form B, crystalline form C, or crystalline form D.

[0261] Embodiment 3: The solid compound of Embodiment 2, selected from, an amorphous solid, crystalline form A, or crystalline form B.

[0262] Embodiment 4: The solid compound of any of Embodiments 1 to 3, wherein the compound has a particle size distribution of D90 of about 6.8 pm to 43 pm; a D50 of about 3.2 pm to 24 pm; and a DIO of about 1.1 pm to 12 pm.

[0263] Embodiment 5: The solid compound of any of Embodiments 1 to 3, wherein the compound has a particle size distribution of D90 of about 13 pm to 58 pm; a D50 of about 6.3 pm to 34 pm; and a DIO of about 1.9 pm to 18 pm.

[0264] Embodiment 6: The solid compound of any of Embodiments 1 to 3, wherein the compound has a particle size distribution of D90 of about 58 pm; a D50 of about 34 pm; and a DIO of about 18 pm.

[0265] Embodiment 7: The solid compound of any of Embodiments 1 to 3, wherein the compound has a particle size distribution of D90 of about 45 pm; a D50 of about 27 pm; and a D10 of about 15 pm.

[0266] Embodiment 8: The solid compound of any of Embodiments 1 to 3, wherein the compound has a particle size distribution of D90 of about 22 pm; a D50 of about 13 pm; and a D10 of about 7.7 pm.

[0267] Embodiment 9: The solid compound of any of Embodiments 1 to 3, wherein the compound has a particle size distribution of D90 of about 13 pm; a D50 of about 6.3 pm; and a D10 of about 1.9 pm.

[0268] Embodiment 10: The solid compound of any of Embodiments 1 to 3, wherein the compound has a particle size distribution of D90 of about 6.8 pm; a D50 of about 3.2 pm; and a D10 of about 1.1 pm.

[0269] Embodiment 11 The solid compound of any of Embodiments 1 to 3, wherein the compound has a particle size distribution of D90 of about 43 pm; a D50 of about 24 pm; and a D10 of about 12 pm.

[0270] Embodiment 12. The solid compound of any of Embodiments 1 to 3, wherein the compound has a particle size distribution of D90 of about 29 pm; a D50 of about 15 pm; and a DIO of about 7.2 pm.

[0271] Embodiment 13: The solid compound of any of Embodiments 1 to 3, wherein the compound has a particle size distribution of D90 of about 25 pm; a D50 of about 13 pm; and a DIO of about 6.2 pm.

[0272] Embodiment 14: The solid compound of any of Embodiments 1 to 3, wherein the compound has a particle size distribution of D90 of about 19 pm; a D50 of about 11 pm; and a DIO of about 5.6 pm.

[0273] Embodiment 15: The solid compound of any of Embodiments 1 to 3, wherein the compound has a particle size distribution of D90 of about 23 pm; a D50 of about 12 pm; and a D10 of about 6.5 pm.

[0274] Embodiment 16: The solid compound of any of Embodiments 1 to 3, wherein the compound has a particle size distribution of D90 of about 12 pm; a D50 of about 6 pm; and a D10 of about 3 pm.

[0275] Embodiment 17: The solid compound of any of Embodiments 1 to 3, wherein the compound has a particle size distribution of D90 of about 25 pm; a D50 of about 14 pm; and a D10 of about 7.7 pm.

[0276] Embodiment 18: The solid compound of any of Embodiments 1 to 3, wherein the compound has a particle size distribution of D90 of about 54 pm; a D50 of about 33 pm; and a D10 of about 17 pm.

[0277] Embodiment 19: The solid compound of any of Embodiments 1 to 3, wherein the compound has a particle size distribution of D90 of about 22 pm; a D50 of about 12 pm; and a D10 of about 6.5 pm.

[0278] Embodiment 20: The solid compound of any of Embodiments 1 to 3, wherein the compound has a particle size distribution of D90 of about 12 pm; a D50 of about 6.4 pm; and a D10 of about 2.1 pm.

[0279] Embodiment 21: The solid compound of any of Embodiments 1 to 3, wherein the compound has a particle size distribution of D90 of about 36 pm; a D50 of about 17 pm; and a DIO of about 4.1 pm.

[0280] Embodiment 22: A solid compound of Formula (I):wherein the compound has a particle size of D90 < 43 pm and the particle size distribution is unimodal.

[0281] Embodiment 23: A solid compound of Formula (I):wherein the compound has a particle size distribution of D90 of 43 pm + 20 %, a D50 of 24 pm + 20 %; and a D10 of 12 pm + 20 %.

[0282] Embodiment 24: The solid compound of Embodiment 21, wherein the compound has a particle size distribution of D90 of 43 pm + 10 %, a D50 of 24 pm + 10 %; and a D10 of 12 pm + 10 %.

[0283] Embodiment 25 : The solid compound of Embodiment 21 wherein the compound has a particle size distribution of D90 of 43 pm + 5 %, a D50 of 24 pm + 5 %; and a D10 of 12 pm + 5 %.

[0284] Embodiment 26: The solid compound of Embodiment 21, wherein the compound has a particle size distribution of D90 of 43 pm + 2 %, a D50 of 24 pm + 2 %; and a D10 of 12 pm + 2 %.

[0285] Embodiment 27: A solid compound of Formula (I):wherein the compound has a particle size distribution of about 6 pm to 58 pm; a D50 of about 3.2 pm to 34 pm; and a DIO of about 1.1 pm to 18 pm, prepared by a process comprising(i.) preparing an aqueous sodium hydroxide solution (Solution 1), by dissolving sodium hydroxide (0.135-0.145 times the weight of technical grade roxadustat) in water (3.3- 3.5 times the weight of technical grade roxadustat);(ii.) preparing an aqueous acetic acid (45-55%) solution (Solution 2), by dissolving acetic acid (0.41-0.45 times the weight of technical grade roxadustat) in water (0.40-0.45 times the weight of technical grade roxadustat);(iii.) mixing technical grade roxadustat and water (9.5-10.5 times the weight of technical grade roxadustat) into a reactor (Rl) with stirring to form a mixture;(iv.) slowly, adding all of the aqueous sodium hydroxide (solution 1), into the mixture of step (iii.) in the reactor (Rl) to form another mixture and stirring at 15-35°C until all the solid is dissolved, provided the stirring is for at least 45 minutes;(v.) transferring the solution of step (iv.) through a cartridge of activated carbon (CUNO) into a new reactor (R2) and washing the cartridge with water (1.9-2.1 times the weight of technical grade roxadustat) and then adjusting the solution temperature in the reactor (R2) to 60-80°C;(vi.) adjusting the solution of step (v.) to a pH of 6.0-6.8 by adding aqueous acetic acid (solution 2) into the reactor (R2) at 60-80°C in three parts as follows:(a) first part: Solution 2 (0.060-0.068 times the weight technical grade roxadustat) is added to reactor 2 (R2);(b) second part: Solution 2 (0.019-0.027 times the weight of technical grade roxadustat) is added to reactor (R2) in portions (0.0005-0020 times the weight of technical grade roxadustat) to achieve pH 6.0-6.8;(c) micronized seed roxadustat (0.045-0.055 times the weight of technical grade roxadustat, D90 8 pm -13 pm), is added to the solution in reactor (R2) followed by stirring at 60-80°C for 10-20 minutes;(d) Third part: Solution 2 (0.57-0.64 times the weight of technical grade roxadustat) is added to reactor (R2) and the mixture is stirred at 60-80°C for at least 1 hour; wherein the total acetic acid solution added to reactor (R2) is 0.66-0.72 times the weight of technical grade roxadustat;(vii.) filtering the mixture from step (vi.) at 60-80°C and washing the solid obtained three times with water; wherein the total water used for washing is 4.4-5.6 times the weight of technical grade roxadustat;(viii.) measuring the pH of the filtrate and if the pH of the filtrate is not 6-7 further washing the solid with water until the filtrate reaches pH 6-7;(ix.) drying the solid under vacuum with minimum agitation at < 70°C until residual acetic acid is < 1500 ppm and residual water content is < 0.1% to obtain the compound of Formula (I).

[0286] Embodiment 28: The solid compound of Embodiment 27: wherein the solid compound is selected from an amorphous solid, crystalline form A, crystalline form B, crystalline form C, or crystalline form D.

[0287] Embodiment 29: The solid compound of Embodiment 28 wherein the solid compound is selected from an amorphous solid, crystalline form A, or crystalline form B.

[0288] Embodiment 30: The solid compound of any of Embodiments 27 to 29, wherein the compound has a particle size distribution of D90 of about 6.8 pm to 43 pm; a D50 of about 3.2 pm to 24 pm; and a D10 of about 1.1 pm to 12 pm.

[0289] Embodiment 31: The solid compound of any of Embodiments 27 to 29, wherein the compound has a particle size distribution of D90 of about 13 pm to 58 pm; a D50 of about 6.3 pm to 34 pm; and a DIO of about 1.9 pm to 18 pm.

[0290] Embodiment 32: The solid compound of any of Embodiments 27 to 29, wherein the compound has a particle size distribution of D90 of about 58 pm; a D50 of about 34 pm; and a DIO of about 18 pm.

[0291] Embodiment 33: The solid compound of any of Embodiments 27 to 29, wherein the compound has a particle size distribution of D90 of about 45 pm; a D50 of about 27 pm; and a DIO of about 15 pm.

[0292] Embodiment 34: The solid compound of any of Embodiments 27 to 29, wherein the compound has a particle size distribution of D90 of about 22 pm; a D50 of about 13 pm; and a D10 of about 7.7 pm.

[0293] Embodiment 35: The solid compound of any of Embodiments 27 to 29, wherein the compound has a particle size distribution of D90 of about 13 pm; a D50 of about 6.3 pm; and a D10 of about 1.9 pm.

[0294] Embodiment 36: The solid compound of any of Embodiments 27 to 29, wherein the compound has a particle size distribution of D90 of about 6.8 pm; a D50 of about 3.2 pm; and a D10 of about 1.1 pm.

[0295] Embodiment 37: The solid compound of any of Embodiments 27 to 29, wherein the compound has a particle size distribution of D90 of about 43 pm; a D50 of about 24 pm; and a D10 of about 12 pm.

[0296] Embodiment 38: The solid compound of any of Embodiments 27 to 29, wherein the compound has a particle size distribution of D90 of about 29 pm; a D50 of about 15 pm; and a D10 of about 7.2 pm.

[0297] Embodiment 39: The solid compound of any of Embodiments 27 to 29, wherein the compound has a particle size distribution of D90 of about 25 pm; a D50 of about 13 pm; and a D10 of about 6.2 pm.

[0298] Embodiment 40: The solid compound of any of Embodiments 27 to 29, wherein the compound has a particle size distribution of D90 of about 19 pm; a D50 of about 11 pm; and a DIO of about 5.6 pm.

[0299] Embodiment 41: The solid compound of any of Embodiments 27 to 29, wherein the compound has a particle size distribution of D90 of about 23 pm; a D50 of about 12 pm; and a DIO of about 6.5 pm.

[0300] Embodiment 42: The solid compound of any of Embodiments 27 to 29, wherein the compound has a particle size distribution of D90 of about 12 pm; a D50 of about 6 pm; and a D10 of about 3 pm.

[0301] Embodiment 43: The solid compound of any of Embodiments 27 to 29, wherein the compound has a particle size distribution of D90 of about 25 pm; a D50 of about 14 pm; and a D10 of about 7.7 pm.

[0302] Embodiment 44: The solid compound of any of Embodiments 27 to 29, wherein the compound has a particle size distribution of D90 of about 54 pm; a D50 of about 33 pm; and a D10 of about 17 pm.

[0303] Embodiment 45: The solid compound of any of Embodiments 27 to 29, wherein the compound has a particle size distribution of D90 of about 22 pm; a D50 of about 12 pm; and a D10 of about 6.5 pm.

[0304] Embodiment 46: The solid compound of any of Embodiments 27 to 29, wherein the compound has a particle size distribution of D90 of about 12 pm; a D50 of about 6.4 pm; and a D10 of about 2.1 pm.

[0305] Embodiment 47: The solid compound of any of Embodiments 27 to 29, wherein the compound has a particle size distribution of D90 of about 36 pm; a D50 of about 17 pm; and a D10 of about 4.1 pm.

[0306] Embodiment 48: A solid compound of Formula (I):according to any of Embodiments 20 to 24, prepared by a process comprising:(i.) preparing an aqueous sodium hydroxide solution (Solution 1), by dissolving sodium hydroxide (0.135-0.145 times the weight of technical grade roxadustat) in water (3.3- 3.5 times the weight of technical grade roxadustat);(ii.) preparing an aqueous acetic acid (45-55%) solution (Solution 2), by dissolving acetic acid (0.41-0.45 times the weight of technical grade roxadustat) in water (0.40-0.45 times the weight of technical grade roxadustat);(iii.) mixing technical grade roxadustat and water (9.5-10.5 times the weight of technical grade roxadustat) into a reactor (Rl) with stirring to form a mixture;(iv.) slowly, adding all of the aqueous sodium hydroxide (solution 1), into the mixture of step (iii.) in the reactor (Rl) to form another mixture and stirring at 15-35°C until all the solid is dissolved, provided the stirring is for at least 45 minutes;(v.) transferring the solution of step (iv.) through a cartridge of activated carbon (CUNO) into a new reactor (R2) and washing the cartridge with water (1.9-2.1 times the weight of technical grade roxadustat) and then adjusting the solution temperature in the reactor (R2) to 60-80°C;(vi.) adjusting the solution of step (v.) to a pH of 6.0-6.8 by adding aqueous acetic acid (solution 2) into the reactor (R2) at 60-80°C in three parts as follows:(a) first part: Solution 2 (0.060-0.068 times the weight of technical grade roxadustat) is added to reactor 2 (R2);(b) second part: Solution 2 (0.019-0.027 times the weight of technical grade roxadustat) is added to reactor (R2) in portions (0.0005-0020 times the weight of technical grade roxadustat) to achieve pH 6.0-6.8;(c) micronized seed roxadustat (0.045-0.055 times the weight of technical grade roxadustat, D90 8 -13 pm), is added to the solution in reactor (R2) followed by stirring at 60-80°C for 10-20 minutes;(d) Third part: Solution 2 (0.57-0.64 times the weight of technical grade roxadustat) is added to reactor (R2) and the mixture is stirred at 60-80°C for at least 1 hour; wherein the total acetic acid solution added to reactor (R2) is 0.66-0.72 times the weight of technical grade roxadustat;(vii.) filtering the mixture from step (vi.) at 60-80°C and washing the solid obtained three times with water; wherein the total water used for washing is 4.4-5.6 times the weight of technical grade roxadustat;(viii.) measuring the pH of the filtrate and if the pH of the filtrate is not 6-7 further washing the solid with water until the filtrate reaches pH 6-7;(ix.) drying the solid under vacuum, with minimum agitation at < 70°C until residual acetic acid is < 1500 ppm and residual water content is < 0.1% to obtain the compound of Formula (I).

[0307] Embodiment 49: The solid compound of any of Embodiments 1 to 48, wherein the compound is prepared on a kilogram scale or higher.

[0308] Embodiment 50: The solid compound of any one of Embodiments 27 to 48, wherein the technical grade roxadustat is at least 98% pure area by HPLC.

[0309] Embodiment 51: The solid compound of any one of Embodiments 27 to 48, wherein the technical grade roxadustat is > 99% pure area by HPLC.

[0310] Embodiment 52: A pharmaceutical composition comprising a therapeutically effective amount of the solid compound of any of Embodiments 1 to 51 ; and a pharmaceutically acceptable excipient, provided the excipient is not a cyclodextrin derivative and polacrilin potassium.

[0311] Embodiment 53: The pharmaceutical composition of Embodiment 52, wherein the excipient is selected from the group consisting of a diluent, a binder a disintegrant and a lubricant or combinations thereof.

[0312] Embodiment 54: The pharmaceutical composition according to Embodiment 52- 53, for oral administration.

[0313] Embodiment 55: The pharmaceutical composition of Embodiments 52 to 54, wherein the pharmaceutical composition is a tablet or a capsule.

[0314] Embodiment 56: The pharmaceutical composition of Embodiment 55, wherein the pharmaceutical composition is a capsule.

[0315] Embodiment 57: An oral capsule pharmaceutical composition comprising a compound of Formula (I):wherein the compound has a particle size of D90 < 43 pm; and a pharmaceutically acceptable excipient, provided the excipient is not a cyclodextrin derivative and polacrilin potassium.

[0316] Embodiment 58: An oral capsule pharmaceutical composition comprising a compound of Formula (I):wherein the compound has a particle size distribution of D90 of 43 pm + 20 %, a D50 of 24 pm + 20 %; and a DIO of 12 pm + 20 %; and a pharmaceutically acceptable excipient, provided the excipient is not a cyclodextrin derivative and polacrilin potassium.

[0317] Embodiment 59: The pharmaceutical composition of Embodiment 58, wherein the compound has a particle size distribution of D90 of 43 pm + 10 %, a D50 of 24 pm + 10 %; and a D10 of 12 pm + 10 %.

[0318] Embodiment 60: The pharmaceutical composition of Embodiment 58, wherein the compound has a particle size distribution of D90 of 43 pm + 5 %, a D50 of 24 pm + 5 %; and a DIO of 12 pm + 5 %.

[0319] Embodiment 61: The pharmaceutical composition of Embodiment 58, wherein the compound has a particle size distribution of D90 of 43 pm + 2 %, a D50 of 24 pm + 2 %; and a DIO of 12 pm + 2 %.

[0320] Embodiment 62: The pharmaceutical composition of Embodiment 58, wherein the compound has a particle size distribution of D90 of 43 pm, a D50 of 24 pm; and a D10 of 12 pm.

[0321] Embodiment 63: The pharmaceutical composition of any one of Embodiments 52 to 62 wherein the capsule comprises 20 mg or 50 mg of the compound.

[0322] Embodiment 64: Use of a compound of any of Embodiments 1 to 51, or a pharmaceutical composition according any one of Embodiments 52 to 63, for the treatment, of anemia.

[0323] Embodiment 65 : The use of Embodiment 64, wherein the anemia is anemia of chronic kidney disease (CKD).

[0324] Embodiment 66: The use of Embodiment 64 or 65, wherein the anemia is anemia of chronic kidney disease in patients on dialysis.

[0325] Embodiment 67: The use of Embodiment 64 or 65, wherein the anemia is anemia of chronic kidney disease in non-dialysis dependent patients.

[0326] Embodiment 68: The use of Embodiment 64, wherein the anemia is chemotherapy- induced anemia (CIA).

[0327] Embodiment 69: The use of Embodiment 64, wherein the anemia is anemia of myelodysplastic syndromes (MDS).

[0328] Embodiment 70: Use of a compound of any of Embodiments 1 to 51, or a pharmaceutical composition according any one of Embodiments 52 to 63 for treating a condition mediated by hypoxia inducible factor (HIF).

[0329] Embodiment 71: Use of a compound of any of Embodiments 1 to 51, or a pharmaceutical composition according any one of Embodiments 52 to 63 for treating a condition mediated by erythropoietin (EPO).

[0330] Embodiment 72: Use of a compound of any of Embodiments 1 to 51, for the manufacture of a medicament.

[0331] Embodiment 73: A process for preparing a solid compound of Formula (I):according to any of Embodiments 1-26, comprising:(i.) preparing an aqueous sodium hydroxide solution (Solution 1), by dissolving sodium hydroxide (0.135-0.145 times the weight of technical grade roxadustat) in water (3.3- 3.5 times the weight of technical grade roxadustat);(ii.) preparing an aqueous acetic acid (45-55%) solution (Solution 2), by dissolving acetic acid (0.41-0.45 times the weight of technical grade roxadustat) in water (0.40-0.45 times the weight of technical grade roxadustat);(iii.) mixing technical grade roxadustat and water (9.5-10.5 times the weight of technical grade roxadustat) into a reactor (Rl) with stirring to form a mixture;(iv.) slowly, adding all of the aqueous sodium hydroxide (solution 1), into the mixture of step (iii.) in the reactor (Rl) to form another mixture and stirring at 15-35°C until all the solid is dissolved, provided the stirring is for at least 45 minutes;(v.) transferring the solution of step (iv.) through a cartridge of activated carbon (CUNO) into a new reactor (R2) and washing the cartridge with water (1.9-2.1 times the weight of technical grade roxadustat) and then adjusting the solution temperature in the reactor (R2) to 60-80°C;(vi.) adjusting the solution of step (v.) to a pH of 6.0-6.8 by adding aqueous acetic acid (solution 2) into the reactor (R2) at 60-80°C in three parts as follows:(a) first part: Solution 2 (0.060-0.068 times the weight of technical grade roxadustat) is added to reactor 2 (R2);(b) second part: Solution 2 (0.019-0.027 times the weight of technical grade roxadustat) is added to reactor (R2) in portions (0.0005-0020 times the weight of technical grade roxadustat) to achieve pH 6.0-6.8;(c) micronized seed roxadustat (0.045-0.055 times the weight of technical grade roxadustat, D90 8 pm -13 pm), is added to the solution in reactor (R2) followed by stirring at 60-80°C for 10-20 minutes;(d) Third part: Solution 2 (0.57-0.64 times the weight of technical grade roxadustat) is added to reactor (R2) and the mixture is stirred at 60-80°C for at least 1 hour; wherein the total acetic acid solution added to reactor (R2) is 0.66-0.72 times the weight of technical grade roxadustat;(vii.) filtering the mixture from step (vi.) at 60-80°C and washing the solid obtained three times with water; wherein the total water used for washing is 4.4-5.6 times the weight of technical grade roxadustat;(viii.) measuring the pH of the filtrate and if the pH of the filtrate is not 6-7 further washing the solid with water until the filtrate reaches pH 6-7;(ix) drying the solid under vacuum, with minimum agitation at < 70°C until residual acetic acid is < 1500 ppm and residual water content is < 0.1% to obtain the compound of Formula (I).

[0332] Embodiment Al: A solid compound of Formula (I):wherein the solid compound has a unimodal particle size distribution of D90 of about 21 pm to 29 pm; a D50 of about 12 pm to 17 pm; and a DIO of about 6 pm to 10 pm.

[0333] Embodiment A2: The solid compound of Embodiment 1, wherein the compound has a particle size distribution of D90 of about 21.9 pm to 28.5 pm; a D50 of about 12.28 pm to 16.03; and a DIO of about 6.66 pm to 9.13 pm.

[0334] Embodiment A3: The solid compound of Embodiment 1, wherein the compound has a particle size distribution selected from:

[0335] Embodiment Bl: An oral pharmaceutical composition comprising a therapeutically effective amount of a solid compound of Formula (I):wherein the solid compound has a unimodal particle size distribution of D90 of about 21 pm to 29 pm; a D50 of about 12 pm to 17 pm; and a DIO of about 6 pm to 10 pm; and at least one pharmaceutically acceptable excipient, provided the excipient is not a cyclodextrin derivative and polacrilin potassium.

[0336] Embodiment B2 : The pharmaceutical composition of Embodiment B 1 , wherein the solid compound has a particle size distribution of D90 of about 21.9 pm to 28.5 pm; a D50 of about 12.28 pm to 16.03; and a DIO of about 6.66 pm to 9.13 pm.

[0337] Embodiment B3: The pharmaceutical composition of either of Embodiments Bl or B2, wherein the solid compound has a particle size distribution selected from:

[0338] Embodiment B4: The pharmaceutical composition of any one of Embodiments Bl to B3, wherein the excipient is selected from the group consisting of a diluent, a binder a disintegrant and a lubricant or combinations thereof.

[0339] Embodiment B5 : The pharmaceutical composition of Embodiment B4, wherein the diluent is selected from starch, saccharides, disaccharides, sucrose, polysaccharides, cellulose, cellulose ethers, hydroxypropyl cellulose, sugar alcohols, xylitol, sorbitol, maltitol, microcrystalline cellulose, calcium or sodium carbonate, lactose, lactose monohydrate, dicalcium phosphate, compressible sugars, dibasic calcium phosphate dehydrate, mannitol, and tribasic calcium phosphate or a combination thereof.

[0340] Embodiment B6: The pharmaceutical composition of either of Embodiments B4 or B5 wherein the diluent is selected from microcrystalline cellulose or lactose monohydrate or a combination thereof.

[0341] Embodiment B7: The pharmaceutical composition of any one of Embodiments B4 to B6 wherein the binder is selected from hydroxypropylcellulose, hydroxypropylmethylcellulose, povidone, and ethyl cellulose or a combination thereof.

[0342] Embodiment B8: The pharmaceutical composition of any one of Embodiments B4 to B7 wherein the binder is povidone.

[0343] Embodiment B9: The pharmaceutical composition of any one of Embodiments B4 to B8 wherein the disintegrant is selected from maize starch, sodium starch glycolate, croscarmellose sodium, crospovidone, microcrystalline cellulose, modified com starch, sodiumcarboxymethyl starch, povidone, pregelatinized starch, and alginic acid or a combination thereof.

[0344] Embodiment BIO: The pharmaceutical composition of any one of Embodiments B4 to B9 wherein the disintegrant is croscarmellose sodium.

[0345] Embodiment Bll: The pharmaceutical composition of any one of Embodiments B4 to BIO wherein the lubricant is selected from magnesium stearate, stearic acid, silica, fats, calcium stearate, polyethylene glycol, sodium stearyl fumarate, talc, and fatty acids.

[0346] Embodiment B12: The pharmaceutical composition of any one of Embodiments B4 to B 11 , wherein the lubricant is magnesium stearate.

[0347] Embodiment B13: The pharmaceutical composition of any one of Embodiments B4 to B12, wherein the pharmaceutically acceptable excipient comprises microcrystalline cellulose, lactose monohydrate, povidone, croscarmellose sodium and magnesium stearate.

[0348] Embodiment B14: The pharmaceutical composition of any one of Embodiments Bl to B 13, wherein the pharmaceutical composition further comprises a photostabilizer.

[0349] Embodiment B 15: The pharmaceutical composition of Embodiment Bl 4, wherein the photostabilizer comprises Allura Red AC, titanium dioxide and iron oxide yellow.

[0350] Embodiment Bl 6: The pharmaceutical composition of Embodiment Bl 4, wherein the photostabilizer comprises titanium dioxide and iron oxide yellow.

[0351] Embodiment B17: The pharmaceutical composition of any one of Embodiments Bl to Bl 6, wherein the pharmaceutical composition is a capsule or a tablet.

[0352] Embodiment Bl 8: The pharmaceutical composition of any one of Embodiments Bl to Bl 7, wherein the pharmaceutical composition is a capsule.

[0353] Embodiment B19: The pharmaceutical composition of any one of Embodiments Bl to Bl 8, wherein the pharmaceutical composition comprises 20 mg or 50 mg of the compound.

[0354] Embodiment B20: A capsule comprising: a capsule fill comprising a pharmaceutical composition according to any one of Embodiments B 1 to B 16, and a capsule shell.

[0355] Embodiment B21: The capsule of Embodiment B20, wherein the capsule shell comprises a photostabilizer.

[0356] Embodiment B22: The capsule of Embodiment B21, wherein the photostabilizer comprises Allura Red AC, titanium dioxide and iron oxide yellow.

[0357] Embodiment B23: The capsule of Embodiment B21, wherein the photostabilizer comprises titanium dioxide and iron oxide yellow.

[0358] Embodiment B24: A capsule comprising a capsule fill and a capsule shell; wherein the capsule fill comprises 20 mg of a solid compound of Formula (I):wherein the solid compound has a unimodal particle size distribution of D90 of about 21 pm to 29 pm; a D50 of about 12 pm to 17 pm; and a D10 of about 6 pm to 10 pm; and a pharmaceutically acceptable excipient comprising lactose monohydrate, microcrystalline cellulose, povidone, croscarmellose sodium and magnesium stearate, provided the excipient does not also contain a cyclodextrin derivative and polacrilin potassium; and the capsule shell is a gelatin shell comprising titanium dioxide, iron yellow oxide and gelatin.

[0359] Embodiment B25: The capsule of Embodiment B24 wherein the capsule fill comprises lactose monohydrate (310), microcrystalline cellulose PH101, povidone K30, croscarmellose sodium and magnesium stearate.

[0360] Embodiment B26: The capsule of either of Embodiments B24 or B25, wherein the capsule fill comprises 101.84 mg of lactose monohydrate (310), 9.36 mg of microcrystallinecellulose PH101, 6.48 mg of povidone K30, 5.76 mg of croscarmellose sodium and 0.56 mg of magnesium stearate.

[0361] Embodiment B27: The capsule of any one of Embodiments B24 to B26, wherein the titanium dioxide, and iron yellow oxide comprise 3% by weight of the capsule shell.

[0362] Embodiment B28: The capsule of any one of Embodiments B24 to B27, wherein the titanium dioxide is 1%, by weight of the capsule shell and the iron yellow oxide is 2% by weight of the capsule shell.

[0363] Embodiment B29: A capsule comprising a capsule fill and a capsule shell; wherein the capsule fill comprises 50 mg of a solid compound of Formula (I):wherein the solid compound has a unimodal particle size distribution of D90 of about 21 pm to 29 pm; a D50 of about 12 pm to 17 pm; and a D10 of about 6 pm to 10 pm; and the pharmaceutically acceptable excipient comprising lactose monohydrate, microcrystalline cellulose, povidone, croscarmellose sodium and magnesium stearate, provided the excipient does not also contain a cyclodextrin derivative and polacrilin potassium; and the capsule shell is a gelatin shell comprising Allura red AC, titanium dioxide, iron yellow oxide and gelatin.

[0364] Embodiment B30: The capsule of Embodiment B29 wherein the capsule fill comprises lactose monohydrate (310), microcrystalline cellulose PH101, povidone K30, croscarmellose sodium and magnesium stearate.

[0365] Embodiment B31 : The capsule of either of Embodiments B29 or B30, wherein the capsule fill comprises 254.6 mg of lactose monohydrate (310), 23.4 mg of microcrystalline cellulose PH101, 16.20 mg of povidone K30, 14.40 mg of croscarmellose sodium and 1.4 mg of magnesium stearate.

[0366] Embodiment B32: The capsule of any one of Embodiments B29 to B31, wherein the Allura red AC, titanium dioxide, and iron yellow oxide comprise 3% by weight of the capsule shell.

[0367] Embodiment B33: The capsule of any one of Embodiments B29 to B32, wherein the Allura red AC is 1% by weight of the capsule shell, the titanium dioxide is 1%, by weight of the capsule shell and the iron yellow oxide is 1 % by weight of the capsule shell.

[0368] Embodiment Cl: Use of an oral pharmaceutical composition comprising a therapeutically effective amount of a solid compound of Formula (I):wherein the solid compound has a unimodal particle size distribution of D90 of about 21 pm to 29 pm; a D50 of about 12 pm to 17 pm; and a D10 of about 6 pm to 10 pm; and at least one pharmaceutically acceptable excipient, provided the excipient is not a cyclodextrin derivative and polacrilin potassium; for the treatment of anemia.

[0369] Embodiment C2: The use of claim Embodiment Cl, wherein the solid compound of the pharmaceutical composition has a particle size distribution of D90 of about 21.9 pm to 28.5 pm; a D50 of about 12.28 pm to 16.03; and a DIO of about 6.66 pm to 9.13 pm.

[0370] Embodiment C3: The use either of Embodiments Cl or C2, wherein the solid compound of the pharmaceutical composition has a particle size distribution selected from

[0371] Embodiment C4: The use of any one of Embodiments Cl to C3, wherein the excipient of the pharmaceutical composition of is selected from the group consisting of a diluent, a binder a disintegrant and a lubricant or combinations thereof.

[0372] Embodiment C5: The use of Embodiment C4 wherein the diluent of the pharmaceutical composition is selected from starch, saccharides, disaccharides, sucrose, polysaccharides, cellulose, cellulose ethers, hydroxypropyl cellulose, sugar alcohols, xylitol, sorbitol, maltitol, microcrystalline cellulose, calcium or sodium carbonate, lactose, lactose monohydrate, dicalcium phosphate, compressible sugars, dibasic calcium phosphate dehydrate, mannitol, and tribasic calcium phosphate or a combination thereof.

[0373] Embodiment C6: The use of either of Embodiments C4 or C5, wherein the diluent of the pharmaceutical composition is selected from microcrystalline cellulose or lactose monohydrate or a combination thereof.

[0374] Embodiment C7: The use of any one of Embodiments C4 to C6, wherein the binder of the pharmaceutical composition is selected from hydroxypropylcellulose, hydroxypropylmethylcellulose, povidone, and ethyl cellulose or a combination thereof.

[0375] Embodiment C8: The use of any one of Embodiments C4 to C7, wherein the binder of the pharmaceutical composition is povidone.

[0376] Embodiment C9: The use of any one of Embodiments C4 to C8, wherein the disintegrant of the pharmaceutical composition is selected from maize starch, sodium starch glycolate, croscarmellose sodium, crospovidone, microcrystalline cellulose, modified com starch, sodium carboxymethyl starch, povidone, pregelatinized starch, and alginic acid or a combination thereof.

[0377] Embodiment CIO: The use of any one of Embodiments C4 to C9, wherein the disintegrant of the pharmaceutical composition is croscarmellose sodium.

[0378] Embodiment C 11 : The use of any one of Embodiments C4 to C 10, herein the lubricant of the pharmaceutical composition is selected from magnesium stearate, stearic acid, silica, fats, calcium stearate, polyethylene glycol, sodium stearyl fumarate, talc, and fatty acids.

[0379] Embodiment Cl 2: The use of any one of Embodiments C4 to Cl 1, wherein the lubricant of the pharmaceutical composition is magnesium stearate.

[0380] Embodiment Cl 3: The use of any one of Embodiments C4 to Cl 2, wherein the pharmaceutically acceptable excipient of the pharmaceutical composition, comprises microcrystalline cellulose, lactose monohydrate, povidone, croscarmellose sodium and magnesium stearate.

[0381] Embodiment C14: The use of any one of Embodiments Cl to C13, wherein the pharmaceutical composition further comprises a photostabilizer.

[0382] Embodiment C15: The use of Embodiment Cl 4, wherein the photostabilizer comprises Allura Red AC, titanium dioxide and iron oxide yellow.

[0383] Embodiment C16: The use of Embodiment Cl 4, wherein the photostabilizer comprises titanium dioxide and iron oxide yellow.

[0384] Embodiment Cl 7: The use of any one of Embodiments Cl. to Cl 6, wherein the pharmaceutical composition is a capsule or a tablet.

[0385] Embodiment C18: The use of any one of Embodiments Cl to C17, wherein the pharmaceutical composition is a capsule.

[0386] Embodiment Cl 9: The use of any one of Embodiments Cl to Cl 8, wherein the pharmaceutical composition comprises 20 mg or 50 mg of the compound.

[0387] Embodiment C20: Use of capsule comprising: a capsule fill comprising an oral pharmaceutical composition comprising a therapeutically effective amount of a solid compound of Formula (I):wherein the solid compound has a unimodal particle size distribution of D90 of about 21 pm to 29 pm; a D50 of about 12 pm to 17 pm; and a DIO of about 6 pm to 10 pm; and at least one pharmaceutically acceptable excipient; and a gelatin capsule shell; for the treatment of anemia.

[0388] Embodiment C21: The use of Embodiment C20, wherein the compound of the pharmaceutical composition of the capsule fill of the capsule, has a particle size distribution of D90 of about 21.9 pm to 28.5 pm; a D50 of about 12.28 pm to 16.03; and a D10 of about 6.66 pm to 9.13 pm.

[0389] Embodiment C22: The use of claim either of Embodiments C20 or C21, wherein the compound of the pharmaceutical composition of the capsule fill of the capsule, has a particle size distribution selected from

[0390] Embodiment C23: The use of any one of Embodiments C20 to C22, wherein the capsule shell comprises a photostabilizer.

[0391] Embodiment C24: The use of Embodiment C23, wherein the photostabilizer comprises Allura Red AC, titanium dioxide and iron oxide yellow.

[0392] Embodiment C25: The use of Embodiment C24, wherein the photostabilizer comprises titanium dioxide and iron oxide yellow.

[0393] Embodiment C26: Use of a capsule comprising: a capsule fill comprising an oral pharmaceutical composition comprising 20 mg of a solid compound of Formula (I):wherein the solid compound has a unimodal particle size distribution of D90 of about 21 pm to 29 pm; a D50 of about 12 pm to 17 pm; and a DIO of about 6 pm to 10 pm; and a pharmaceutically acceptable excipient comprising lactose monohydrate, microcrystalline cellulose, povidone, croscarmellose sodium and magnesium stearate, provided the excipient does not also contain a cyclodextrin derivative and polacrilin potassium; and a gelatin capsule shell comprising titanium dioxide, iron yellow oxide and gelatin; for the treatment of anemia.

[0394] Embodiment C27: The use of Embodiment C26, wherein the capsule fill of the capsule, comprises lactose monohydrate (310), microcrystalline cellulose PH101, povidone K30, croscarmellose sodium and magnesium stearate.

[0395] Embodiment C28: The use of either of Embodiments C26 or C27, wherein the excipient of the capsule fill, comprises 101.84 mg of lactose monohydrate (310), 9.36 mg of microcrystalline cellulose PH101, 6.48 mg of povidone K30, 5.76 mg of croscarmellose sodium and 0.56 mg of magnesium stearate.

[0396] Embodiment C29: The use of any one of Embodiments C26 to C28, wherein the titanium dioxide, and iron yellow oxide comprise 3% by weight of the capsule shell.

[0397] Embodiment C30: The use of any one of Embodiments C26 to C29, wherein the titanium dioxide is 1%, by weight of the capsule shell and the iron yellow oxide is 2% by weight of the capsule shell.

[0398] Embodiment C31: Use of a capsule comprising: a capsule fill comprising an oral pharmaceutical composition comprising 50 mg of a solid compound of Formula (I):wherein the solid compound has a unimodal particle size distribution of D90 of about 21 pm to 29 pm; a D50 of about 12 pm to 17 pm; and a D10 of about 6 pm to 10 pm; and a pharmaceutically acceptable excipient comprising lactose monohydrate, microcrystalline cellulose, povidone, croscarmellose sodium and magnesium stearate, provided the excipient does not also contain a cyclodextrin derivative and polacrilin potassium; and a gelatin capsule shell comprising Allura red AC, titanium dioxide, iron yellow oxide and gelatin; for the treatment of anemia.

[0399] Embodiment C32: The use of Embodiment C31, wherein the capsule fill of the capsule, comprises lactose monohydrate (310), microcrystalline cellulose PH101, povidone K30, croscarmellose sodium and magnesium stearate.

[0400] Embodiment C33: The use of either of Embodiments C31 or C32, wherein the excipient of the capsule fill, 254.6 mg of lactose monohydrate (310), 23.4 mg of microcrystalline cellulose PH101, 16.20 mg of povidone K30, 14.40 mg of croscarmellose sodium and 1.4 mg of magnesium stearate.

[0401] Embodiment C34: The use of any one of Embodiments C31 to C33, wherein the Allura red AC, titanium dioxide, and iron yellow oxide comprise 3% by weight of the capsule shell.

[0402] Embodiment C35.: The use of any one of Embodiments C31 to C34, wherein the Allura red AC is 1% by weight of the capsule shell, the titanium dioxide is 1% by weight of the capsule shell, and the iron yellow oxide is 1% by weight of the capsule shell.

[0403] Embodiment C36: The use of any one of Embodiments Cl to C35, wherein the anemia is anemia of chronic kidney disease in patients on dialysis.

[0404] Embodiment C37: The use of any one of Embodiments Cl to C35, wherein the anemia is anemia of chronic kidney disease in non-dialysis dependent patients.

[0405] Embodiment C38: The use any one of Embodiments Cl to C35, wherein the anemia is chemotherapy-induced anemia (CIA).

[0406] Embodiment C39: The use of any one of Embodiments Cl to C35, wherein the anemia is anemia of myelodysplastic syndromes (MDS).

[0407] Embodiment C40: Use of an oral pharmaceutical composition comprising a therapeutically effective amount of a solid compound of Formula (I):wherein the solid compound has a unimodal particle size distribution of D90 of about 21 pm to 29 pm; a D50 of about 12 pm to 17 pm; and a DIO of about 6 pm to 10 pm; and at least one pharmaceutically acceptable excipient, provided the excipient is not a cyclodextrin derivative and polacrilin potassium; for treating a condition mediated by hypoxia inducible factor.

[0408] Embodiment C41: Use of an oral pharmaceutical composition comprising a therapeutically effective amount of a solid compound of Formula (I):wherein the solid compound has a unimodal particle size distribution of D90 of about 21 pm to 29 pm; a D50 of about 12 pm to 17 pm; and a DIO of about 6 pm to 10 pm; and at least one pharmaceutically acceptable excipient, provided the excipient is not a cyclodextrin derivative and polacrilin potassium; for treating a condition mediated by erythropoietin.

[0409] Embodiment C42: Use of an oral pharmaceutical composition comprising a therapeutically effective amount of a solid compound Formula (I):wherein the solid compound has a unimodal particle size distribution of D90 of about 21 pm to 29 pm; a D50 of about 12 pm to 17 pm; and a DIO of about 6 pm to 10 pm; and at least one pharmaceutically acceptable excipient, provided the excipient is not a cyclodextrin derivative and polacrilin potassium; for the manufacture of a medicament.

[0410] Embodiment DI: A solid compound of Formula (I):wherein the solid compound has a unimodal particle size distribution of D90 of about 21 pm to 29 pm; a D50 of about 12 pm to 17 pm; and a D10 of about 6 pm to 10 pm, prepared by a process comprising:(i.) preparing an aqueous sodium hydroxide solution (Solution 1), by dissolving sodium hydroxide (0.135-0.145 times the weight of technical grade roxadustat) in water (3.3-3.5 times the weight of technical grade roxadustat);(ii.) preparing an aqueous acetic acid (45-55%) solution (Solution 2), by dissolving acetic acid (0.41-0.45 times the weight of technical grade roxadustat) in water (0.40-0.45 times the weight of technical grade roxadustat);(iii.) mixing technical grade roxadustat and water (9.5-10.5 times the weight of technical grade roxadustat) into a reactor (Rl) with stirring to form a mixture;(iv.) slowly, adding all of the aqueous sodium hydroxide (solution 1), into the mixture of step (iii.) in the reactor (Rl) to form another mixture and stirring at 15-35°C until all the solid is dissolved, provided the stirring is for at least 45 minutes;(v.) transferring the solution of step (iv.) through a cartridge of activated carbon into a new reactor (R2) and washing the cartridge with water (1.9-2.1 times the weight of technical grade roxadustat) and then adjusting the solution temperature in the reactor (R2) to 60-80°C;(vi.) adjusting the solution of step (v.) to a pH of 6.0-6.8 by adding aqueous acetic acid (solution 2) into the reactor (R2) at 60-80°C in three parts as follows:(a) first part: Solution 2 (0.060-0.068 times the weight of technical grade roxadustat) is added to reactor 2 (R2);(b) second part: Solution 2 (0.019-0.027 times the weight of technical grade roxadustat) is added to reactor (R2) in portions (0.0005-0.0020 times the weight of technical grade roxadustat) to achieve pH 6.0-6.8;(c) micronized seed roxadustat (0.045-0.055 times the weight of technical grade roxadustat, D90 8 pm -11 pm), is added to the solution in reactor (R2) followed by stirring at 60-80°C for 10-20 minutes;(d) third part: Solution 2 (0.57-0.64 times the weight of technical grade roxadustat) is added to reactor (R2) and the mixture is stirred at 60-80°C for at least 1 hour; wherein the total acetic acid solution added to reactor (R2) is 0.66-0.72 times the weight of technical grade roxadustat;(vii.) filtering the mixture from step (vi.) at 60-80°C and washing the solid obtained three times with water; wherein the total water used for washing is 4.4-5.6 times the weight of technical grade roxadustat;(viii.) measuring the pH of the filtrate and if the pH of the filtrate is not 6-7 further washing the solid with water until the filtrate reaches pH 6-7;(ix.) drying the solid under vacuum, with minimum agitation at < 70°C until residual acetic acid is < 1500 ppm and residual water content is < 0.1% to obtain the solid compound of Formula (I).

[0411] Embodiment D2: The solid compound of Embodiment D 1 , wherein the compound has a particle size distribution of D90 of about 21.9 pm to 28.5 pm; a D50 of about 12.28 pm to 16.03; and a DIO of about 6.66 pm to 9.13 pm.

[0412] Embodiment D3: The solid compound of Embodiment D 1 , wherein the compound has a particle size distribution selected from:

[0413] Embodiment D4: The solid compound of any one of Embodiments DI to D3, wherein the microcrystalline seed roxadustat has a particle size distribution of D90 of about 8 pm to 11 pm; a D50 of about 2 pm to 6; and a DIO of about 1 pm to 2 pm.

[0414] Embodiment D5: The solid compound of any one of Embodiments DI to D4, wherein the microcrystalline seed roxadustat has a particle size distribution of D90 of 8.39 to 10.7 pm; a D50 of 2.67 pm to 5.11; and a DIO of 0.74 pm to 1.7 pm.

[0415] Embodiment D6: The solid compound of any one of Embodiments DI to D5, wherein the microcrystalline seed roxadustat has a particle size

[0416] Embodiment D7 : The solid compound of any one of Embodiments D 1 to D6, wherein the compound is prepared on a kilogram scale or higher.

[0417] Embodiment D8: The solid compound of any one of Embodiments DI to D7, wherein the technical grade roxadustat is at least 98% pure area by HPLC.

[0418] Embodiment D9: The solid compound of any one of Embodiments DI to D8, wherein the technical grade roxadustat is > 99% pure area by HPLC.

[0419] Embodiment El : A process for preparing a solid compound of Formula (I):wherein the solid compound has a unimodal particle size distribution of D90 of about 21 pm to 29 pm; a D50 of about 12 pm to 17 pm; and a DIO of about 6 pm to 10 pm, comprising:(i.) preparing an aqueous sodium hydroxide solution (Solution 1), by dissolving sodium hydroxide (0.135-0.145 times the weight of technical grade roxadustat) in water (3.3-3.5 times the weight of technical grade roxadustat);(ii.) preparing an aqueous acetic acid (45-55%) solution (Solution 2), by dissolving acetic acid (0.41-0.45 times the weight of technical grade roxadustat) in water (0.40-0.45 times the weight of technical grade roxadustat);(iii.) mixing technical grade roxadustat and water (9.5-10.5 times the weight of technical grade roxadustat) into a reactor (Rl) with stirring to form a mixture;(iv.) slowly, adding all of the aqueous sodium hydroxide (solution 1), into the mixture of step (iii.) in the reactor (Rl) to form another mixture and stirring at 15-35°C until all the solid is dissolved, provided the stirring is for at least 45 minutes;(v.) transferring the solution of step (iv.) through a cartridge of activated carbon into a new reactor (R2) and washing the cartridge with water (1.9-2.1 times the weight of technical grade roxadustat) and then adjusting the solution temperature in the reactor (R2) to 60-80°C;(vi.) adjusting the solution of step (v.) to a pH of 6.0-6.8 by adding aqueous acetic acid (solution 2) into the reactor (R2) at 60-80°C in three parts as follows:(a) first part: Solution 2 (0.060-0.068 times the weight of technical grade roxadustat) is added to reactor 2 (R2);(b) second part: Solution 2 (0.019-0.027 times the weight of technical grade roxadustat) is added to reactor (R2) in portions (0.0005-0.0020 times the weight of technical grade roxadustat) to achieve pH 6.0-6.8;(c) micronized seed roxadustat (0.045-0.055 times the weight of technical grade roxadustat, D90 8 pm -11 pm), is added to the solution in reactor (R2) followed by stirring at 60-80°C for 10-20 minutes;(d) third part: Solution 2 (0.57-0.64 times the weight of technical grade roxadustat) is added to reactor (R2) and the mixture is stirred at 60-80°C for at least 1 hour; wherein the total acetic acid solution added to reactor (R2) is 0.66-0.72 times the weight of technical grade roxadustat;(vii.) filtering the mixture from step (vi.) at 60-80°C and washing the solid obtained three times with water; wherein the total water used for washing is 4.4-5.6 times the weight of technical grade roxadustat;(viii.) measuring the pH of the filtrate and if the pH of the filtrate is not 6-7 further washing the solid with water until the filtrate reaches pH 6-7;(ix.) drying the solid under vacuum, with minimum agitation at < 70°C until residual acetic acid is < 1500 ppm and residual water content is < 0.1% to obtain the solid compound of Formula (I).

[0420] Embodiment E2: The process of Embodiment El, wherein the compound has a particle size distribution of D90 of about 21.9 pm to 28.5 pm; a D50 of about 12.28 pm to 16.03; and a D10 of about 6.66 pm to 9.13 pm.

[0421] Embodiment E3: The process of Embodiment El, wherein the compound has a particle size distribution selected from:

[0422] Embodiment E4: The process of any one of Embodiments El to E3, wherein the microcrystalline seed roxadustat has a particle size distribution of D90 of about 8 pm to 11 pm; a D50 of about 2 pm to 6; and a DIO of about 1 pm to 2 pm.

[0423] Embodiment E5: The process of any one of Embodiments El to E4, wherein the microcrystalline seed roxadustathas a particle size distribution of D90 of 8.39 to 10.7 pm; a D50 of 2.67 pm to 5.11; and a DIO of 0.74 pm to 1.7 pm.

[0424] Embodiment E6: The process of any one of Embodiments El to E5, wherein the microcrystalline seed roxadustat has a particle size

[0425] Embodiment E7 : The process of any one of Embodiments E 1 to E6, wherein the solid compound is prepared on a kilogram scale or higher.

[0426] Embodiment E8: The process of any one of Embodiments El to E7, wherein the technical grade roxadustat is at least 98% pure area by HPLC.

[0427] Embodiment E9: The process of any one of Embodiments El to E8, wherein the technical grade roxadustat is > 99% pure area by HPLC.

[0428] Embodiment Fl. A solid compound of Formula: (I)wherein the compound has a particle size of D90 < 43 pm and the particle size distribution is unimodal.

[0429] Embodiment F2. The solid compound of Embodiment Fl, wherein the compound has a particle size of D90 of 6.8 pm to 43 pm.

[0430] Embodiment F3. The solid compound of Embodiment Fl or F2 wherein the compound has a particle size D90 of 13 to 43 pm.

[0431] Embodiment F4. The solid compound of Embodiment Fl, wherein the compound has a particle size of D90 of 21 pm to 29 pm.

[0432] Embodiment F5. The solid compound of any one of Embodiments Fl to F3, wherein the compound has a particle size of D50 of 6.2 pm to 24 pm.

[0433] Embodiment F6. The solid compound of any one of Embodiments Fl to F3, wherein the compound has a particle size of D50 of 12 pm to 17 pm.

[0434] Embodiment F7. The solid compound of any one of Embodiments Fl to F5, wherein the compound has a particle size of D 10 of 1.1 pm to 18 pm.

[0435] Embodiment F8. The solid compound of any one of Embodiments Fl to F5, wherein the compound has a particle size of DIO of about 6.0 pm to 10 pm.Embodiment F9. The solid compound of Embodiment F 1 , wherein the compound has a particle size distribution selected from the group consisting of:

[0436] Embodiment Fl 0. The solid compound of Embodiment Fl, wherein the compound has a particle size distribution ofD90 of 21 pm to 29 pm; a D50 of 12 pm to 17 pm; and a D10 of 6 pm to 10 pm.

[0437] Embodiment Fl l. The solid compound of Embodiment F10, wherein the compound has a particle size distribution of D90 of 21.9 pm to 28.5 pm; a D50 of 12.28 pm to 16.03; and a D10 of 6.66 pm to 9.13 pm.

[0438] Embodiment Fl 2. The solid compound of Embodiment F10 or Fl 1, wherein the compound has a particle size distribution selected from:

[0439] Embodiment Fl 3. An oral pharmaceutical composition comprising a therapeutically effective amount of a solid compound of any one of Embodiments Fl to F12; and at least one pharmaceutically acceptable excipient, provided the excipient is not a cyclodextrin derivative and polacrilin potassium.

[0440] Embodiment F14. The pharmaceutical composition of Embodiment Fl 3, wherein the excipient is selected from the group consisting of a diluent, a binder, a disintegrant and a lubricant or combinations thereof.

[0441] Embodiment F15. The pharmaceutical composition of Embodiment Fl 4, wherein the diluent is selected from saccharides, cellulose ethers, sugar alcohols, calcium or sodium carbonate, dicalcium phosphate, dibasic calcium phosphate dehydrate, tribasic calcium phosphate or a combination thereof.

[0442] Embodiment F16. The pharmaceutical composition of Embodiment F15, wherein the saccharides is selected from disaccharides, polysaccharides or a combination thereof.

[0443] Embodiment F17. The pharmaceutical composition of Embodiment F14, wherein the diluent is selected from starch, sucrose, hydroxypropyl cellulose, xylitol, sorbitol, maltitol, microcrystalline cellulose, calcium or sodium carbonate, lactose, lactose monohydrate, dicalcium phosphate, dibasic calcium phosphate dehydrate, mannitol, and tribasic calcium phosphate or a combination thereof.

[0444] Embodiment Fl 8. The pharmaceutical composition of Embodiment Fl 7, wherein the diluent is selected from microcrystalline cellulose or lactose monohydrate or a combination thereof.

[0445] Embodiment F19. The pharmaceutical composition of Embodiment F14, wherein the binder is selected from hydroxypropylcellulose, hydroxypropylmethylcellulose, povidone, and ethyl cellulose or a combination thereof.

[0446] Embodiment F20. The pharmaceutical composition of Embodiment Fl 9, wherein the binder is povidone.

[0447] Embodiment F21. The pharmaceutical composition of Embodiment Fl 4, wherein the disintegrant is selected from maize starch, croscarmellose sodium, crospovidone, microcrystalline cellulose, modified com starch, sodium carboxymethyl starch, povidone, pregelatinized starch, and alginic acid or a combination thereof.

[0448] Embodiment F22. The pharmaceutical composition of Embodiment F21, wherein the disintegrant is croscarmellose sodium.

[0449] Embodiment F23. The pharmaceutical composition of Embodiment Fl 4, wherein the lubricant is selected from magnesium stearate, stearic acid, silica, fats, calcium stearate, polyethylene glycol, sodium stearyl fumarate, talc, and fatty acids.

[0450] Embodiment F24. The pharmaceutical composition of Embodiment F23, wherein the lubricant is magnesium stearate.

[0451] Embodiment F25. The pharmaceutical composition of Embodiment Fl 4, wherein the pharmaceutically acceptable excipient comprises microcrystalline cellulose, lactose monohydrate, povidone, croscarmellose sodium and magnesium stearate.

[0452] Embodiment F26. The pharmaceutical composition of any one of Embodiments F14 to F25, wherein the pharmaceutical composition further comprises a photostabilizer.

[0453] Embodiment F27. The pharmaceutical composition of Embodiment F26, wherein the photostabilizer is selected from the group consisting of Allura Red AC, Allura Red AC in aluminum lake, titanium dioxide, iron oxide red, iron oxide yellow, and combinations thereof.

[0454] Embodiment F28. The pharmaceutical composition of Embodiment F31, wherein the photostabilizer comprises Allura Red AC, titanium dioxide, and iron oxide yellow.

[0455] Embodiment F29. The pharmaceutical composition of Embodiment F27, wherein the photostabilizer comprises titanium dioxide, and Allura Red AC in aluminum lake.

[0456] Embodiment F30. The pharmaceutical composition of Embodiment F27, wherein the photostabilizer comprises titanium dioxide, iron oxide red, and iron oxide yellow.

[0457] Embodiment F31. The pharmaceutical composition of Embodiment F26, wherein the photostabilizer comprises titanium dioxide and iron oxide yellow.

[0458] Embodiment F32. The pharmaceutical composition of any one of Embodiments F13 to F31, wherein the pharmaceutical composition is a capsule or a tablet.

[0459] Embodiment F33. The pharmaceutical composition of Embodiment F32, wherein the pharmaceutical composition is a capsule.

[0460] Embodiment F34. The pharmaceutical composition of Embodiment F32, wherein the pharmaceutical composition is a tablet.

[0461] Embodiment F35. The pharmaceutical composition of any one of Embodiments Fl 3 to F34, wherein the pharmaceutical composition comprises 20 mg, 50 mg, 70 mg, 100 mg, or 150 mg of the compound.

[0462] Embodiment F36. The pharmaceutical composition of any one of Embodiments F13 to F34, wherein the pharmaceutical composition comprises 20 mg or 50 mg of the compound.

[0463] Embodiment F37. A capsule comprising: a capsule fill comprising a pharmaceutical composition according to any one of Embodiments Fl 3 to F35, and a capsule shell.

[0464] Embodiment F38. The capsule of Embodiment F37, wherein the capsule shell comprises a photostabilizer.

[0465] Embodiment F39. The capsule of Embodiment F38, wherein the photostabilizer comprises Allura Red AC, titanium dioxide, and iron oxide yellow.

[0466] Embodiment F40. The capsule of Embodiment F38, wherein the photostabilizer comprises titanium dioxide and iron oxide yellow.

[0467] Embodiment F41. A capsule comprising a capsule fill and a capsule shell, wherein the capsule fill comprises 20 mg of a solid compound of any one of Embodiments Fl to F13; and a pharmaceutically acceptable excipient comprising lactose monohydrate, microcrystalline cellulose, povidone, croscarmellose sodium and magnesium stearate, provided the excipient does not also contain a cyclodextrin derivative and polacrilin potassium; and the capsule shell is a gelatin shell comprising titanium dioxide, iron yellow oxide, and gelatin.

[0468] Embodiment F42. The capsule of Embodiment F41, wherein the solid compound has a particle size distribution ofD90 of 21 pm to 29 pm; a D50 of 12 pm to 17 pm; and a D10 of 6 pm to 10 pm.

[0469] Embodiment F43. The capsule of Embodiment F41 or F42, wherein the pharmaceutical excipient in the capsule fill comprises lactose monohydrate 310, microcrystalline cellulose PH101, povidone K30, croscarmellose sodium and magnesium stearate.

[0470] Embodiment F44. The capsule of any one of Embodiments F41 to F33, wherein the pharmaceutical excipient in the capsule fill comprises 101.84 mg of lactose monohydrate 310, 9.36 mg of microcrystalline cellulose PH101, 6.48 mg of povidone K30, 5.76 mg of croscarmellose sodium and 0.56 mg of magnesium stearate.

[0471] Embodiment F45. The capsule of Embodiment F44, wherein the titanium dioxide, and iron yellow oxide comprise 3% by weight of the capsule shell.

[0472] Embodiment F46. The capsule of Embodiment F44, wherein the titanium dioxide is 1%, by weight of the capsule shell and the iron yellow oxide is 2% by weight of the capsule shell.

[0473] Embodiment F47. A capsule comprising a capsule fill and a capsule shell, wherein the capsule fill comprises 50 mg of a solid compound of any one of Embodiments Fl to F13; and the pharmaceutically acceptable excipient comprising lactose monohydrate, microcrystalline cellulose, povidone, croscarmellose sodium and magnesium stearate, provided the excipient does not also contain a cyclodextrin derivative and polacrilin potassium; and the capsule shell is a gelatin shell comprising Allura red AC, titanium dioxide, iron yellow oxide and gelatin.

[0474] Embodiment F48. The capsule of Embodiment F47, wherein the solid compound has a particle size distribution ofD90 of 21 pm to 29 pm; a D50 of 12 pm to 17 pm; and a D10 of 6 pm to 10 pm.

[0475] Embodiment F49. The capsule of Embodiment F47 or Embodiment F48, wherein the pharmaceutical excipient in the capsule fill comprises lactose monohydrate 310, microcrystalline cellulose PH101, povidone K30, croscarmellose sodium and magnesium stearate.

[0476] Embodiment F50. The capsule of Embodiment F47 or Embodiment F49, wherein the pharmaceutical excipient in the capsule fill comprises 254.6 mg of lactose monohydrate 310, 23.4 mg of microcrystalline cellulose PH101, 16.20 mg of povidone K30, 14.40 mg of croscarmellose sodium and 1.4 mg of magnesium stearate.

[0477] Embodiment F51. The capsule of any one of Embodiments F47 to F50, wherein the Allura red AC, titanium dioxide, and iron yellow oxide comprise 3% by weight of the capsule shell.

[0478] Embodiment F52. The capsule of any one of Embodiments F47 to F50, wherein the Allura red AC is 1% by weight of the capsule shell, the titanium dioxide is 1%, by weight of the capsule shell and the iron yellow oxide is 1 % by weight of the capsule shell.

[0479] Embodiment F53. A tablet comprising a tablet core and a coating, wherein the tablet core comprises 20 mg, 50 mg. 70 mg, 100 mg or 150 mg of a solid compound of any one of Embodiments Fl to F13; and a pharmaceutically acceptable excipient comprising lactose monohydrate, microcrystalline cellulose, povidone, croscarmellose sodium and magnesium stearate, provided the excipient does not also contain a cyclodextrin derivative and polacrilin potassium; and the coating comprises titanium dioxide and Allura red AC in aluminum lake.

[0480] Embodiment F54. The tablet of Embodiment F53, wherein the solid compound has a particle size distribution of D90 of 21 pm to 29 pm; a D50 of 12 pm to 17 pm; and a D10 of 6 pm to 10 pm.

[0481] Embodiment F55. The tablet of Embodiment F53 or F54, wherein the coating comprises 0.1 to 0.4 mg / cm2of the titanium dioxide, and 0.1 to 0.4 mg / cm2of the Allura Red AC in aluminum lake, based on the surface area of the tablet.

[0482] Embodiment F56. The tablet of any one of Embodiment F53 to F55, wherein the tablet core comprises 20 mg of the compound, 42.6 mg of the lactose monohydrate, 9.12 mg of the microcrystalline cellulose, 3.6 mg of the povidone K30, 4.0 mg of the croscarmellose sodium and 0.68 mg of the magnesium stearate.

[0483] Embodiment F57. The tablet of Embodiment 56, wherein the coating comprises 0.293 mg / cm2of the titanium dioxide, and 0.286 mg / cm2of the Allura Red AC in aluminum lake, based on the surface area of the tablet.

[0484] Embodiment F58. The tablet of Embodiment F57, wherein the surface area of the tablet is 0.894 cm2.

[0485] Embodiment F59. The tablet of any one of Embodiment F53 to F55, wherein the tablet core comprises 50 mg of the compound, 106.5 mg of the lactose monohydrate, 22.8 mg of the microcrystalline cellulose, 9.0 mg of the povidone K30, 10.0 mg of the croscarmellose sodium and 1.7 mg of the magnesium stearate.

[0486] Embodiment F60. The tablet of Embodiment F59, wherein the coating comprises 0.285 mg / cm2of the titanium dioxide, and 0.278 mg / cm2of the Allura Red AC in aluminum lake, based on the surface area of the tablet.

[0487] Embodiment F61. The tablet of Embodiment F60, wherein the surface area of the tablet is 1.638 cm2.

[0488] Embodiment F62. The tablet of any one of Embodiment F53 to F55, wherein the tablet core comprises 70 mg ofthe compound, 149.1 mg ofthe lactose monohydrate, 31.92 mg of the microcrystalline cellulose, 12.6 mg of the povidone K30, 14 mg of the croscarmellose sodium and 2.38 mg ofthe magnesium stearate.

[0489] Embodiment F63. The tablet of Embodiment F62, wherein the coating comprises 0. 295 mg / cm2of the titanium dioxide, and 0. 288 mg / cm2of the Allura Red AC in aluminum lake, based on the surface area of the tablet.

[0490] Embodiment F64. The tablet of Embodiment F63, wherein the surface area of the tablet is 1.885 cm2.

[0491] Embodiment F65. The tablet of claim any one of Embodiments F53 to F55, wherein the tablet core comprises 100 mg of the compound, 213.0 mg of the lactose monohydrate, 45.6 mg of the microcrystalline cellulose, 18.0 mg of the povidone K30, 20 mg of the croscarmellose sodium and 3.4 mg of the magnesium stearate.

[0492] Embodiment F66. The tablet of Embodiment F65, wherein the coating comprises 0. 295 mg / cm2of the titanium dioxide, and 0. 288 mg / cm2of the Allura Red AC in aluminum lake, based on the surface area of the tablet.

[0493] Embodiment F67. The tablet of Embodiment F66, wherein the surface area of the tablet is 2.535 cm2.

[0494] Embodiment F68. The tablet of any one of Embodiments F53 to F55, wherein the tablet core comprises 150 mg ofthe compound, 319.5 mg ofthe lactose monohydrate, 68.4 mg of the microcrystalline cellulose, 27.0 mg of the povidone K30, 30 mg of croscarmellose sodium and 5.1 mg ofthe magnesium stearate.

[0495] Embodiment F69. The tablet of Embodiment F68, wherein the coating comprises 0.311 mg / cm2of the titanium dioxide, and 0.304 mg / cm2of the Allura Red AC in aluminum lake, based on the surface area of the tablet.

[0496] Embodiment F70. The tablet of Embodiment F69, wherein the surface area of the tablet is 3.156 cm2.

[0497] Embodiment F71. A tablet comprising a tablet core and a coating, wherein the tablet core comprises 100 mg of a solid compound of any one of Embodiments Fl to F13; and a pharmaceutically acceptable excipient comprising lactose monohydrate, microcrystalline cellulose, povidone, croscarmellose sodium and magnesium stearate, provided the excipient does not also contain a cyclodextrin derivative and polacrilin potassium; and the coating comprises titanium dioxide iron oxide red and iron oxide yellow.

[0498] Embodiment F72. The tablet of Embodiment F71 , wherein the solid compound has a particle size distribution of D90 of 21 pm to 29 pm; a D50 of 12 pm to 17 pm; and a D10 of 6 pm to 10 pm.618.

[0499] Embodiment F73. The tablet of Embodiment F72 or claim F73, wherein the tablet core comprises 213.0 mg of the lactose monohydrate, 45.6 mg of the microcrystalline cellulose, 18.0 mg of the povidone, 20 mg of the croscarmellose sodium and 3.4 mg of the magnesium stearate.

[0500] Embodiment F74. A method of treating anemia in a subject in need thereof, comprising administering to the subject a solid compound of any one of Embodiments Fl to F13, an oral pharmaceutical composition of any one of Embodiments F14 to F34, a capsule of any one of Embodiments F37 to F53 or a tablet of any one of Embodiments F53 to F73.

[0501] Embodiment F75. The method of Embodiment F74, wherein the anemia is anemia of chronic kidney disease in patients on dialysis.

[0502] Embodiment F76. The method of Embodiment F74, wherein the anemia is anemia of chronic kidney disease in non-dialysis dependent patients.

[0503] Embodiment F77. The method of Embodiment F74, wherein the anemia is chemotherapy-induced anemia (CIA).

[0504] Embodiment F78. The method of Embodiment F74, wherein the anemia is anemia of myelodysplastic syndromes (MDS).

[0505] Embodiment F79. A method of treating a condition mediated by hypoxia inducible factor or by erythropoietin in a subject in need thereof, comprising administering to the subject a solid compound of any one of Embodiments Fl to Fl 3, an oral pharmaceutical composition of any one of Embodiments F14 to F34, a capsule of any one of Embodiments F37 to F53 or a tablet of any one of Embodiments F53 to F73.

[0506] Embodiment F80. Use of the solid compound of any one of Embodiments Fl to F13, or an oral pharmaceutical composition of any one of Embodiments F14 to F36, in the manufacture of a medicament for the treatment of anemia.

[0507] Embodiment F81. The use of Embodiment F80, wherein the anemia is anemia of chronic kidney disease in patients on dialysis.

[0508] Embodiment F82. The use of Embodiment F80, wherein the anemia is anemia of chronic kidney disease in non-dialysis dependent patients.

[0509] Embodiment F83. The use of Embodiment F80, wherein the anemia is chemotherapy-induced anemia (CIA).

[0510] Embodiment F84. The use of Embodiment F80, wherein the anemia is anemia of myelodysplastic syndromes (MDS).

[0511] Embodiment F85. Use of the solid compound of any one of Embodiments Fl to F13, or an oral pharmaceutical composition of any one of Embodiments F14 to F36, in the manufacture of a medicament for treating a condition mediated by hypoxia inducible factor or by erythropoietin.

[0512] Embodiment F86. A solid compound of Formula:wherein the solid compound has a unimodal particle size distribution of distribution of D90 of 21 pm to 29 pm; a D50 of 12 pm to 17 pm; and a D10 of 6 pm to 10 pm;prepared by a process comprising:(i.) preparing an aqueous sodium hydroxide solution (Solution 1), by dissolving sodium hydroxide in water; wherein the sodium hydroxide is 0.135-0.145 times the weight of technical grade roxadustat, the water is 3.3-3.5 times the weight of technical grade roxadustat;(ii.) preparing an 45-55% aqueous acetic acid solution (Solution 2), by dissolving acetic acid in water; wherein the acetic acid is 0.41-0.45 times the weight of technical grade roxadustat, the water is 0.40-0.45 times the weight of technical grade roxadustat;(iii.) mixing technical grade roxadustat and water into a reactor (Rl) with stirring to form a mixture; wherein the water is 9.5-10.5 times the weight of technical grade roxadustat;(iv.) slowly, adding all of the aqueous sodium hydroxide (solution 1), into the mixture of step (iii.) in the reactor (Rl) to form another mixture and stirring at 15-35°C until all the solid is dissolved, provided the stirring is for at least 45 minutes;(v.) transferring the solution of step (iv.) through a cartridge of activated carbon into a new reactor (R2) and washing the cartridge with water and then adjusting the solution temperature in the reactor (R2) to 60-80°C; wherein the water used for washing is 1.9-2.1 times the weight of technical grade roxadustat;(vi.) adjusting the solution of step (v.) to a pH of 6.0-6.8 by adding aqueous acetic acid (solution 2) into the reactor (R2) at 60-80°C in three parts as follows:(a) first part: Solution 2 is added to reactor 2 (R2); wherein the Solution 2 in first part is 0.060-0.068 times the weight technical grade roxadustat;(b) second part: Solution 2 is added to reactor (R2) in portions to achieve pH 6.0-6.8; wherein the Solution 2 in second part is 0.019-0.027 times the weight of technical grade roxadustat, the each portion is 0.0005-0.0020 times the weight of technical grade roxadustat;(c) micronized seed roxadustat is added to the solution in reactor (R2) followed by stirring at 60-80°C for 10-20 minutes; wherein the micronized seed roxadustat is 0.045-0.055 times the weight of technical grade roxadustat and the D90 of micronized seed roxadustat is 8 pm - 11 pm;(d) third part: Solution 2 is added to reactor (R2) and the mixture is stirred at 60-80°C for at least 1 hour; wherein the total acetic acid solution added to reactor (R2) is 0.66-0.72 times the weight of technical grade roxadustat; wherein the Solution 2 in third part is 0.57-0.64 times the weight of technical grade roxadustat;(vii.) filtering the mixture from step (vi.) at 60-80°C and washing the solid obtained three times with water; wherein the total water used for washing is 4.4-5.6 times the weight of technical grade roxadustat;(viii.) measuring the pH of the filtrate and if the pH of the filtrate is not 6-7 further washing the solid with water until the filtrate reaches pH 6-7;(ix.) drying the solid under vacuum, with minimum agitation at < 70°C until residual acetic acid is < 1500 ppm and residual water content is < 0.1% to obtain the solid compound of Formula (I).

[0513] Embodiment F87. The process of Embodiment F86, wherein the particle size distribution is selected from:

[0514] Embodiment F88. The solid compound of Embodiment F86, wherein the microcrystalline seed roxadustat has a particle size distribution of D90 of 8 pm to 11 pm; a D50 of 2 pm to 6; and a D 10 of 1 pm to 2 pm.

[0515] Embodiment F89. The solid compound of Embodiment F86, wherein the microcrystalline seed roxadustat has a particle size distribution of D90 of 8.39 to 10.7 pm; a D50 of 2.67 pm to 5.11; and a DIO of 0.74 pm to 1.7 pm.

[0516] Embodiment F90. The solid compound of Embodiment F86, wherein the microcrystalline seed roxadustat has a particle size

[0517] Embodiment F91. The solid compound of any one of Embodiments F86 to F90, wherein the compound is prepared on a kilogram scale or higher.

[0518] Embodiment F92. The solid compound of any one of Embodiments F86 to F90, wherein the technical grade roxadustat is at least 98% pure area by HPLC.

[0519] Embodiment F93. The solid compound of any one of Embodiments F86 to F90, wherein the technical grade roxadustat is > 99% pure area by HPLC.

[0520] Embodiment F94. A process for preparing a solid compound of Formula:wherein the solid compound has a unimodal particle size distribution of D90 of 21 pm to 29 pm; a D50 of 12 pm to 17 pm; and a DIO of 6 pm to 10 pm. prepared by a process comprising:(i.) preparing an aqueous sodium hydroxide solution (Solution 1), by dissolving sodium hydroxide in water; wherein the sodium hydroxide is 0.135-0.145 times the weight of technical grade roxadustat, the water is 3.3-3.5 times the weight of technical grade roxadustat;(ii.) preparing an 45-55% aqueous acetic acid solution (Solution 2), by dissolving acetic acid in water; wherein the acetic acid is 0.41-0.45 times the weight of technical grade roxadustat, the water is 0.40-0.45 times the weight of technical grade roxadustat;(iii.) mixing technical grade roxadustat and water into a reactor (Rl) with stirring to form a mixture; wherein the water is 9.5-10.5 times the weight of technical grade roxadustat;(iv.) slowly, adding all of the aqueous sodium hydroxide (solution 1), into the mixture of step (iii.) in the reactor (Rl) to form another mixture and stirring at 15-35°C until all the solid is dissolved, provided the stirring is for at least 45 minutes;(v.) transferring the solution of step (iv.) through a cartridge of activated carbon into a new reactor (R2) and washing the cartridge with water and then adjusting the solution temperature in the reactor (R2) to 60-80°C; wherein the water used for washing is 1.9-2.1 times the weight of technical grade roxadustat;(vi.) adjusting the solution of step (v.) to a pH of 6.0-6.8 by adding aqueous acetic acid (solution 2) into the reactor (R2) at 60-80°C in three parts as follows:(a) first part: Solution 2 is added to reactor 2 (R2); wherein the Solution 2 in first part is 0.060-0.068 times the weight technical grade roxadustat;(b) second part: Solution 2 is added to reactor (R2) in portions to achieve pH 6.0-6.8; wherein the Solution 2 in second part is 0.019-0.027 times the weight of technical grade roxadustat, the each portion is 0.0005-0.0020 times the weight of technical grade roxadustat;(c) micronized seed roxadustat is added to the solution in reactor (R2) followed by stirring at 60-80°C for 10-20 minutes; wherein the micronized seed roxadustat is 0.045-0.055 times the weight of technical grade roxadustat and the D90 of micronized seed roxadustat is 8 pm - 11 pm;(d) third part: Solution 2 is added to reactor (R2) and the mixture is stirred at 60-80°C for at least 1 hour; wherein the total acetic acid solution added to reactor (R2) is 0.66-0.72 times the weight of technical grade roxadustat; wherein the Solution 2 in third part is 0.57-0.64 times the weight of technical grade roxadustat;(vii.) filtering the mixture from step (vi.) at 60-80°C and washing the solid obtained three times with water; wherein the total water used for washing is 4.4-5.6 times the weight of technical grade roxadustat;(viii.) measuring the pH of the filtrate and if the pH of the filtrate is not 6-7 further washing the solid with water until the filtrate reaches pH 6-7;(ix.) drying the solid under vacuum, with minimum agitation at < 70°C until residual acetic acid is < 1500 ppm and residual water content is < 0.1% to obtain the solid compound of Formula (I).

[0521] Embodiment F95. The process of Embodiment F94, wherein the particle size distribution is selected from:

[0522] Embodiment F96. The process of Embodiment F94, wherein the microcrystalline seed roxadustat has a particle size distribution of D90 of 8 pm to 11 pm; a D50 of 2 pm to 6; and a DIO of 1 pm to 2 pm.

[0523] Embodiment F97. The process of Embodiment F94, wherein the microcrystalline seed roxadustat has a particle size distribution of D90 of 8.39 to 10.7 pm; a D50 of 2.67 pm to 5.11; and a DIO of 0.74 pm to 1.7 pm.

[0524] Embodiment F98. The process of Embodiment F94, wherein the microcrystalline seed roxadustat has a particle size selected from the group consisting of

[0525] Embodiment F99. The process of any one of Embodiments F94 to F98, wherein the compound is prepared on a kilogram scale or higher.

[0526] Embodiment F100. The process of any one of Embodiments F94 to F98, wherein the technical grade roxadustat is at least 98% pure area by HPLC.

[0527] Embodiment F101. The process of any one of Embodiment F94 to F98, wherein the technical grade roxadustat is > 99% pure area by HPLC.

Claims

CLAIMS1. A solid compound of Formula:wherein the compound has a particle size of D90 < 43 pm and the particle size distribution is unimodal.

2. The solid compound of claim 1 , wherein the compound has a particle size of D90 of 6.8 pm to 43 pm.

3. The solid compound of claim 1 or 2 wherein the compound has a particle size D90 of 13 to < 43 pm.

4. The solid compound of claim 1 , wherein the compound has a particle size of D90 of 21 pm to 29 pm.

5. The solid compound of any one of claims 1 to 3, wherein the compound has a particle size of D50 of 3.2 pm to 24 pm.

6. The solid compound of any one of claims 1 to 3, wherein the compound has a particle size of D50 of 12 pm to 17 pm.

7. The solid compound of any one of claims 1 to 5, wherein the compound has a particle size of DIO of 1.1 pm to 18 pm.

8. The solid compound of any one of claims 1 to 5, wherein the compound has a particle size of DIO of about 6.0 pm to 10 pm.

9. The solid compound of claim 1, wherein the compound has a particle size distribution selected from the group consisting of:

10. The solid compound of claim 1, wherein the compound has a particle size distribution of D90 of 21 pm to 29 pm; a D50 of 12 pm to 17 pm; and a DIO of 6 pm to 10 pm.

11. The solid compound of claim 10, wherein the compound has a particle size distribution ofD90 of21.9 pm to 28.5 pm; a D50 of 12.28 pm to 16.03; and a D10 of 6.66 pm to 9.13 pm.

12. The solid compound of claim 10 or 11, wherein the compound has a particle size distribution selected from:

13. An oral pharmaceutical composition comprising a therapeutically effective amount of a solid compound of any one of claims 1 to 12; and at least one pharmaceutically acceptable excipient, provided the excipient is not a cyclodextrin derivative and polacrilin potassium.

14. The pharmaceutical composition of claim 13, wherein the excipient is selected from the group consisting of a diluent, a binder, a disintegrant and a lubricant or combinations thereof.

15. The pharmaceutical composition of claim 14, wherein the diluent is selected from saccharides, cellulose ethers, sugar alcohols, calcium or sodium carbonate, dicalcium phosphate, dibasic calcium phosphate dehydrate, tribasic calcium phosphate or a combination thereof.

16. The pharmaceutical composition of claim 15, wherein the saccharides is selected from disaccharides, polysaccharides or a combination thereof.

17. The pharmaceutical composition of claim 14, wherein the diluent is selected from starch, sucrose, hydroxypropyl cellulose, xylitol, sorbitol, maltitol, microcrystalline cellulose, calcium or sodium carbonate, lactose, lactose monohydrate, dicalcium phosphate, dibasic calcium phosphate dehydrate, mannitol, and tribasic calcium phosphate or a combination thereof.

18. The pharmaceutical composition of claim 17, wherein the diluent is selected from microcrystalline cellulose or lactose monohydrate or a combination thereof.

19. The pharmaceutical composition of claim 14, wherein the binder is selected from hydroxypropylcellulose, hydroxypropylmethylcellulose, povidone, and ethyl cellulose or a combination thereof.

20. The pharmaceutical composition of claim 19, wherein the binder is povidone.

21. The pharmaceutical composition of claim 14, wherein the disintegrant is selected from maize starch, croscarmellose sodium, crospovidone, microcrystalline cellulose, modified com starch, sodium carboxymethyl starch, povidone, pregelatinized starch, and alginic acid or a combination thereof.

22. The pharmaceutical composition of claim 21, wherein the disintegrant is croscarmellose sodium.

23. The pharmaceutical composition of claim 14, wherein the lubricant is selected from magnesium stearate, stearic acid, silica, fats, calcium stearate, polyethylene glycol, sodium stearyl fumarate, talc, and fatty acids.

24. The pharmaceutical composition of claim 23, wherein the lubricant is magnesium stearate.

25. The pharmaceutical composition of claim 14, wherein the pharmaceutically acceptable excipient comprises microcrystalline cellulose, lactose monohydrate, povidone, croscarmellose sodium and magnesium stearate.

26. The pharmaceutical composition of any one of claims 14 to 25, wherein the pharmaceutical composition further comprises a photostabilizer.

27. The pharmaceutical composition of claim 26, wherein the photostabilizer is selected from the group consisting of Allura Red AC, Allura Red AC in aluminum lake, titanium dioxide, iron oxide red, iron oxide yellow, and combinations thereof.

28. The pharmaceutical composition of claim 31, wherein the photostabilizer comprises Allura Red AC, titanium dioxide, and iron oxide yellow.

29. The pharmaceutical composition of claim 27, wherein the photostabilizer comprises titanium dioxide and Allura Red AC in aluminum lake.

30. The pharmaceutical composition of claim 27, wherein the photostabilizer comprises titanium dioxide, iron oxide red, and iron oxide yellow.

31. The pharmaceutical composition of claim 26, wherein the photostabilizer comprises titanium dioxide and iron oxide yellow.

32. The pharmaceutical composition of any one of claims 13 to 31, wherein the pharmaceutical composition is a capsule or a tablet.

33. The pharmaceutical composition of claim 32, wherein the pharmaceutical composition is a capsule.

34. The pharmaceutical composition of claim 32, wherein the pharmaceutical composition is a tablet.

35. The pharmaceutical composition of any one of claims 13 to 34, wherein the pharmaceutical composition comprises 20 mg, 50 mg, 70 mg, 100 mg, or 150 mg of the compound.

36. The pharmaceutical composition of any one of claims 13 to 34, wherein the pharmaceutical composition comprises 20 mg or 50 mg of the compound.

37. A capsule comprising: a capsule fill comprising a pharmaceutical composition according to any one of claims 13 to 35, and a capsule shell.

38. The capsule of claim 37, wherein the capsule shell comprises a photostabilizer.

39. The capsule of claim 38, wherein the photostabilizer comprises Allura Red AC, titanium dioxide and iron oxide yellow.

40. The capsule of claim 38, wherein the photostabilizer comprises titanium dioxide and iron oxide yellow.

41. A capsule comprising a capsule fill and a capsule shell, wherein the capsule fill comprises 20 mg of a solid compound of any one of claims 1 to 13; and a pharmaceutically acceptable excipient comprising lactose monohydrate, microcrystalline cellulose, povidone, croscarmellose sodium and magnesium stearate, provided the excipient does not also contain acyclodextrin derivative and polacrilin potassium; and the capsule shell is a gelatin shell comprising titanium dioxide, iron yellow oxide and gelatin.

42. The capsule of claim 41, wherein the solid compound has a particle size distribution of D90 of 21 pm to 29 pm; a D50 of 12 pm to 17 pm; and a DIO of 6 pm to 10 pm.

43. The capsule of claim 41 or 42, wherein the pharmaceutical excipient in the capsule fill comprises lactose monohydrate 310, microcrystalline cellulose PH101, povidone K30, croscarmellose sodium and magnesium stearate.

44. The capsule of any one of claims 41 to 33, wherein the pharmaceutical excipient in the capsule fill comprises 101.84 mg of lactose monohydrate 310, 9.36 mg of microcrystalline cellulose PH101, 6.48 mg of povidone K30, 5.76 mg of croscarmellose sodium and 0.56 mg of magnesium stearate.

45. The capsule of claim 44, wherein the titanium dioxide, and iron yellow oxide comprise 3% by weight of the capsule shell.

46. The capsule of claim 44, wherein the titanium dioxide is 1%, by weight of the capsule shell and the iron yellow oxide is 2% by weight of the capsule shell.

47. A capsule comprising a capsule fill and a capsule shell, wherein the capsule fill comprises 50 mg of a solid compound of any one of claims 1 to 13; and the pharmaceutically acceptable excipient comprising lactose monohydrate, microcrystalline cellulose, povidone, croscarmellose sodium and magnesium stearate, provided the excipient does not also contain a cyclodextrin derivative and polacrilin potassium; and the capsule shell is a gelatin shell comprising Allura red AC, titanium dioxide, iron yellow oxide and gelatin.

48. The capsule of claim 47, wherein the solid compound has a particle size distribution of D90 of 21 pm to 29 pm; a D50 of 12 pm to 17 pm; and a D10 of 6 pm to 10 pm.

49. The capsule of claim 47 or claim 48, wherein the pharmaceutical excipient in the capsule fill comprises lactose monohydrate 310, microcrystalline cellulose PHI 01, povidone K30, croscarmellose sodium and magnesium stearate.

50. The capsule of claim 47 or claim 49, wherein the pharmaceutical excipient in the capsule fill comprises 254.6 mg of lactose monohydrate 310, 23.4 mg of microcrystallinecellulose PH101, 16.20 mg of povidone K30, 14.40 mg of croscarmellose sodium and 1.4 mg of magnesium stearate.

51. The capsule of any one of claims 47 to 50, wherein the Allura red AC, titanium dioxide, and iron yellow oxide comprise 3% by weight of the capsule shell.

52. The capsule of any one of claims 47 to 50, wherein the Allura red AC is 1% by weight of the capsule shell, the titanium dioxide is 1%, by weight of the capsule shell and the iron yellow oxide is 1% by weight of the capsule shell.

53. A tablet comprising a tablet core and a coating, wherein the tablet core comprises 20 mg, 50 mg. 70 mg, 100 mg or 150 mg of a solid compound of any one of claims 1 to 13; and a pharmaceutically acceptable excipient comprising lactose monohydrate, microcrystalline cellulose, povidone, croscarmellose sodium and magnesium stearate, provided the excipient does not also contain a cyclodextrin derivative and polacrilin potassium; and the coating comprises titanium dioxide, and Allura red AC in aluminum lake.

54. The tablet of claim 53, wherein the solid compound has a particle size distribution of D90 of 21 pm to 29 pm; a D50 of 12 pm to 17 pm; and a D10 of 6 pm to 10 pm.

55. The tablet of claim 53 or 54, wherein the coating comprises 0.1 to 0.4 mg / cm2of the titanium dioxide, and 0.1 to 0.4 mg / cm2of the Allura Red AC in aluminum lake, based on the surface area of the tablet.

56. The tablet of any one of claim 53 to 55, wherein the tablet core comprises 20 mg of the compound, 42.6 mg of the lactose monohydrate, 9.12 mg of the microcrystalline cellulose, 3.6 mg of the povidone K30, 4.0 mg of the croscarmellose sodium and 0.68 mg of the magnesium stearate.

57. The tablet of claim 56, wherein the coating comprises 0.293 mg / cm2of the titanium dioxide, and 0.286 mg / cm2of the Allura Red AC in aluminum lake, based on the surface area of the tablet.

58. The tablet of claim 57, wherein the surface area of the tablet is 0.894 cm2.

59. The tablet of any one of claim 53 to 55, wherein the tablet core comprises 50 mg of the compound, 106.5 mg of the lactose monohydrate, 22.8 mg of the microcrystalline cellulose,9.0 mg of the povidone K30, 10.0 mg of the croscarmellose sodium and 1.7 mg of the magnesium stearate.

60. The tablet of claim 59, wherein the coating comprises 0.285 mg / cm2of the titanium dioxide, and 0.278 mg / cm2ofthe Allura Red AC in aluminum lake, based on the surface area of the tablet.

61. The tablet of claims 60, wherein the surface area of the tablet is 1.638 cm2.

62. The tablet of any one of claim 53 to 55, wherein the tablet core comprises 70 mg of the compound, 149.1 mg of the lactose monohydrate, 31.92 mg of the microcrystalline cellulose, 12.6 mg of the povidone K30, 14 mg of the croscarmellose sodium and 2.38 mg of the magnesium stearate.

63. The tablet of claim 62, wherein the coating comprises 0. 295 mg / cm2ofthe titanium dioxide, and 0. 288 mg / cm2ofthe Allura Red AC in aluminum lake, based on the surface area of the tablet.

64. The tablet of claim 63, wherein the surface area of the tablet is 1.885 cm2.

65. The tablet of claim any one of claims 53 to 55, wherein the tablet core comprises 100 mg of the compound, 213.0 mg of the lactose monohydrate, 45.6 mg of the microcrystalline cellulose, 18.0 mg of the povidone K30, 20 mg of the croscarmellose sodium and 3.4 mg of the magnesium stearate.

66. The tablet of claim 65, wherein the coating comprises 0. 295 mg / cm2ofthe titanium dioxide, and 0. 288 mg / cm2ofthe Allura Red AC in aluminum lake, based on the surface area of the tablet.

67. The tablet of claim 66, wherein the surface area of the tablet is 2.535 cm2.

68. The tablet of any one of claims 53 to 55, wherein the tablet core comprises 150 mg of the compound, 319.5 mg ofthe lactose monohydrate, 68.4 mg ofthe microcrystalline cellulose, 27.0 mg ofthe povidone K30, 30 mg of croscarmellose sodium and 5.1 mg ofthe magnesium stearate.

69. The tablet of claim 68, wherein the coating comprises 0.311 mg / cm2of the titanium dioxide, and 0.304 mg / cm2ofthe Allura Red AC in aluminum lake, based on the surface area of the tablet.

70. The tablet of claim 69, wherein the surface area of the tablet is 3.156 cm2.

71. A tablet comprising a tablet core and a coating, wherein the tablet core comprises 100 mg of a solid compound of any one of claims 1 to 13; and a pharmaceutically acceptable excipient comprising lactose monohydrate, microcrystalline cellulose, povidone, croscarmellose sodium and magnesium stearate, provided the excipient does not also contain a cyclodextrin derivative and polacrilin potassium; and the coating comprises titanium dioxide iron oxide red and iron oxide yellow.

72. The tablet of claim 71, wherein the solid compound has a particle size distribution of D90 of 21 pm to 29 pm; a D50 of 12 pm to 17 pm; and a D10 of 6 pm to 10 pm.618.

73. The tablet of claim 72 or claim 73, wherein the tablet core comprises 213.0 mg of the lactose monohydrate, 45.6 mg of the microcrystalline cellulose, 18.0 mg of the povidone, 20 mg of the croscarmellose sodium and 3.4 mg of the magnesium stearate.

74. A method of treating anemia in a subject in need thereof, comprising administering to the subject a solid compound of any one of claims 1 to 13, an oral pharmaceutical composition of any one of claims 14 to 34, a tablet of any one of claims 37 to 53 or a tablet of any one of claims 53 to 73.

75. The method of claim 74, wherein the anemia is anemia of chronic kidney disease in patients on dialysis.

76. The method of claim 74, wherein the anemia is anemia of chronic kidney disease in non-dialysis dependent patients.

77. The method of claim 74, wherein the anemia is chemotherapy-induced anemia (CIA).

78. The method of claim 74, wherein the anemia is anemia of myelodysplastic syndromes (MDS).

79. A method of treating a condition mediated by hypoxia inducible factor or by erythropoietin in a subject in need thereof, comprising administering to the subject a solidcompound of any one of claims 1 to 13, an oral pharmaceutical composition of any one of claims 14 to 34, a capsule of any one of claims 37 to 53 or a tablet of any one of claims 53 to 73.

80. Use of the solid compound of any one of claims 1 to 13, or an oral pharmaceutical composition of any one of claims 14 to 36, in the manufacture of a medicament for the treatment of anemia.

81. The use of claim 80, wherein the anemia is anemia of chronic kidney disease in patients on dialysis.

82. The use of claim 80, wherein the anemia is anemia of chronic kidney disease in nondialysis dependent patients.

83. The use of claim 80, wherein the anemia is chemotherapy-induced anemia (CIA).

84. The use of claim 80, wherein the anemia is anemia of myelodysplastic syndromes (MDS).

85. Use of the solid compound of any one of claims 1 to 13, or an oral pharmaceutical composition of any one of claims 14 to 36, in the manufacture of a medicament for treating a condition mediated by hypoxia inducible factor or by erythropoietin.

86. A solid compound of Formula:wherein the solid compound has a unimodal particle size distribution of distribution of D90 of 21 pm to 29 pm; a D50 of 12 pm to 17 pm; and a D10 of 6 pm to 10 pm; prepared by a process comprising:(i.) preparing an aqueous sodium hydroxide solution (Solution 1), by dissolving sodium hydroxide in water; wherein the sodium hydroxide is 0.135-0.145 times the weight of technical grade roxadustat, the water is 3.3-3.5 times the weight of technical grade roxadustat;(ii.) preparing an 45-55% aqueous acetic acid solution (Solution 2), by dissolving acetic acid in water; wherein the acetic acid is 0.41-0.45 times the weight of technical grade roxadustat, the water is 0.40-0.45 times the weight of technical grade roxadustat;(iii.) mixing technical grade roxadustat and water into a reactor (Rl) with stirring to form a mixture; wherein the water is 9.5-10.5 times the weight of technical grade roxadustat;(iv.) slowly, adding all of the aqueous sodium hydroxide (solution 1), into the mixture of step (iii.) in the reactor (Rl) to form another mixture and stirring at 15-35°C until all the solid is dissolved, provided the stirring is for at least 45 minutes;(v.) transferring the solution of step (iv.) through a cartridge of activated carbon into a new reactor (R2) and washing the cartridge with water and then adjusting the solution temperature in the reactor (R2) to 60-80°C; wherein the water used for washing is 1.9-2.1 times the weight of technical grade roxadustat;(vi.) adjusting the solution of step (v.) to a pH of 6.0-6.8 by adding aqueous acetic acid (solution 2) into the reactor (R2) at 60-80°C in three parts as follows:(a) first part: Solution 2 is added to reactor 2 (R2); wherein the Solution 2 in first part is 0.060-0.068 times the weight technical grade roxadustat;(b) second part: Solution 2 is added to reactor (R2) in portions to achieve pH 6.0-6.8; wherein the Solution 2 in second part is 0.019-0.027 times the weight of technical grade roxadustat, the each portion is 0.0005-0.0020 times the weight of technical grade roxadustat;(c) micronized seed roxadustat is added to the solution in reactor (R2) followed by stirring at 60-80°C for 10-20 minutes; wherein the micronized seed roxadustat is 0.045-0.055 times the weight of technical grade roxadustat and the D90 of micronized seed roxadustat is 8 pm - 11 pm;(d) third part: Solution 2 is added to reactor (R2) and the mixture is stirred at 60-80°C for at least 1 hour; wherein the total acetic acid solution added to reactor (R2) is 0.66-0.72 times the weight of technical grade roxadustat; wherein the Solution 2 in third part is 0.57-0.64 times the weight of technical grade roxadustat;(vii.) filtering the mixture from step (vi.) at 60-80°C and washing the solid obtained three times with water; wherein the total water used for washing is 4.4-5.6 times the weight of technical grade roxadustat;(viii.) measuring the pH of the filtrate and if the pH of the filtrate is not 6-7 further washing the solid with water until the filtrate reaches pH 6-7;(ix.) drying the solid under vacuum, with minimum agitation at < 70°C until residual acetic acid is < 1500 ppm and residual water content is < 0.1% to obtain the solid compound of Formula (I).

87. The process of claim 86, wherein the particle size distribution is selected from:

88. The solid compound of claim 86, wherein the microcrystalline seed roxadustat has a particle size distribution of D90 of 8 pm to 11 pm; a D50 of 2 pm to 6; and a DIO of 1 pm to 2 pm.

89. The solid compound of claim 86, wherein the microcrystalline seed roxadustat has a particle size distribution of D90 of 8.39 to 10.7 pm; a D50 of 2.67 pm to 5.11; and a D10 of 0.74 pm to 1.7 pm.

90. The solid compound of claim 86, wherein the microcrystalline seed roxadustat has a particle size91. The solid compound of any one of claims 86 to 90, wherein the compound is prepared on a kilogram scale or higher.

92. The solid compound of any one of claims 86 to 90, wherein the technical grade roxadustat is at least 98% pure area by HPLC.

93. The solid compound of any one of claims 86 to 90, wherein the technical grade roxadustat is > 99% pure area by HPLC.

94. A process for preparing a solid compound of Formula:wherein the solid compound has a unimodal particle size distribution of D90 of 21 pm to 29 pm; a D50 of 12 pm to 17 pm; and a DIO of 6 pm to 10 pm. prepared by a process comprising:(i.) preparing an aqueous sodium hydroxide solution (Solution 1), by dissolving sodium hydroxide in water; wherein the sodium hydroxide is 0.135-0.145 times the weight of technical grade roxadustat, the water is 3.3-3.5 times the weight of technical grade roxadustat;(ii.) preparing an 45-55% aqueous acetic acid solution (Solution 2), by dissolving acetic acid in water; wherein the acetic acid is 0.41-0.45 times the weight of technical grade roxadustat, the water is 0.40-0.45 times the weight of technical grade roxadustat;(iii.) mixing technical grade roxadustat and water into a reactor (Rl) with stirring to form a mixture; wherein the water is 9.5-10.5 times the weight of technical grade roxadustat;(iv.) slowly, adding all of the aqueous sodium hydroxide (solution 1), into the mixture of step (iii.) in the reactor (Rl) to form another mixture and stirring at 15-35°C until all the solid is dissolved, provided the stirring is for at least 45 minutes;(v.) transferring the solution of step (iv.) through a cartridge of activated carbon into a new reactor (R2) and washing the cartridge with water and then adjusting the solution temperature in the reactor (R2) to 60-80°C; wherein the water used for washing is 1.9-2.1 times the weight of technical grade roxadustat;(vi.) adjusting the solution of step (v.) to a pH of 6.0-6.8 by adding aqueous acetic acid (solution 2) into the reactor (R2) at 60-80°C in three parts as follows:(a) first part: Solution 2 is added to reactor 2 (R2); wherein the Solution 2 in first part is 0.060-0.068 times the weight technical grade roxadustat;(b) second part: Solution 2 is added to reactor (R2) in portions to achieve pH 6.0-6.8; wherein the Solution 2 in second part is 0.019-0.027 times the weight of technical grade roxadustat, the each portion is 0.0005-0.0020 times the weight of technical grade roxadustat;(c) micronized seed roxadustat is added to the solution in reactor (R2) followed by stirring at 60-80°C for 10-20 minutes; wherein the micronized seed roxadustat is 0.045-0.055 times the weight of technical grade roxadustat and the D90 of micronized seed roxadustat is 8 pm - 11 pm;(d) third part: Solution 2 is added to reactor (R2) and the mixture is stirred at 60-80°C for at least 1 hour; wherein the total acetic acid solution added to reactor (R2) is 0.66-0.72 times the weight of technical grade roxadustat; wherein the Solution 2 in third part is 0.57-0.64 times the weight of technical grade roxadustat;(vii.) filtering the mixture from step (vi.) at 60-80°C and washing the solid obtained three times with water; wherein the total water used for washing is 4.4-5.6 times the weight of technical grade roxadustat;(viii.) measuring the pH of the filtrate and if the pH of the filtrate is not 6-7 further washing the solid with water until the filtrate reaches pH 6-7;(ix.) drying the solid under vacuum, with minimum agitation at < 70°C until residual acetic acid is < 1500 ppm and residual water content is < 0.1% to obtain the solid compound of Formula (I).

95. The process of claims 94, wherein the particle size distribution is selected from:

96. The process of claim 94, wherein the microcrystalline seed roxadustat has a particle size distribution of D90 of 8 pm to 11 pm; a D50 of 2 pm to 6; and a DIO of 1 pm to 2 pm.

97. The process of claim 94, wherein the microcrystalline seed roxadustat has a particle size distribution of D90 of 8.39 to 10.7 pm; a D50 of 2.67 pm to 5.11; and a D10 of 0.74 pm to 1.7 pm.

98. The process of claim 94, wherein the microcrystalline seed roxadustat has a particle size selected from the group consisting of99. The process of any one of claims 94 to 98, wherein the compound is prepared on a kilogram scale or higher.

100. The process of any one of claims 94 to 98, wherein the technical grade roxadustat is at least 98% pure area by HPLC.

101. The process of any one of claims 94 to 98, wherein the technical grade roxadustat is > 99% pure area by HPLC.

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