DESC:The following specification describes the invention and the manner in which it is to be performed:
SOLID DISPERSION OF AMORPHOUS ROXADUSTAT

INTRODUCTION
The present invention provides amorphous solid dispersion of Roxadustat and its processes for preparation.
BACKGROUND OF THE INVENTION
Roxadustat (I) or FG-4592 is chemically known as [(4-Hydroxy-1-methyl-7-phenoxy-iso quinoline-3-carbonyl)-amino]-acetic acid. It is an oral small molecule inhibitor of HIF prolyl hydroxylases, or HIF-PHs, in Phase 3 clinical development for treating and preventing disorders associated with HIF, including anemia in chronic kidney disease, or CKD, ischemia, and hypoxia.

(I)
The US patent number 7323475 B2, Example D-81 (e), by referring Example D-78 (d), discloses a process for isolation of roxadustat by concentration of organic phases (EtOAc/Methanol) in vacuo.
The US patent number 8883823 B2 discloses amorphous, different polymorphic Forms, solvates and salts of roxadustat.
The US patent number 9206134 B2 discloses different crystalline Forms of roxadustat.
The discovery of further solid forms of an active pharmaceutical ingredient (API) can offer an opportunity to improve the performance profile of a pharmaceutical composition comprising the said API.
Processability of the API during manufacture of the pharmaceutical composition and characteristics of the finished dosage form, such as storage stability under difficult environmental conditions, such as high relative humidity and/or high temperature, can still be improved or optimized. The presence of the high energy form of the API in a pharmaceutical composition (amorphous form) usually improves the dissolution rate.
An object of the present invention is to provide a pharmaceutical composition comprising amorphous solid dispersion of roxadustat wherein the physicochemical stability and the dissolution characteristics of the solid form is improved, and wherein roxadustat is rendered more suitable for use in a pharmaceutical composition.
SUMMARY
In a first aspect, the present invention provides a solid dispersion comprising amorphous roxadustat and one or more pharmaceutically acceptable carriers.
In a second aspect, the present invention provides a process for the preparation of solid dispersion comprising amorphous roxadustat and one or more pharmaceutically acceptable carriers, comprising the steps:
a) providing a solution comprising roxadustat and one or more pharmaceutically acceptable carriers in a solvent,
b) removing the solvent from the solution obtained in step (a) and,
c) recovering a solid dispersion comprising roxadustat and one or more pharmaceutically acceptable carriers.
BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1 illustrates the PXRD pattern of amorphous roxadustat, obtained by the procedure of Example 1.
Fig. 2 illustrates the PXRD pattern of solid dispersion comprising amorphous roxadustat with PVPK-30 excipient, obtained by the procedure of Example 2.
Fig. 3 illustrates the PXRD pattern of solid dispersion comprising amorphous roxadustat with PVPK-30 & syloid excipients, obtained by the procedure of Example 2.
Fig. 4 illustrates the PXRD pattern of solid dispersion comprising amorphous roxadustat with Copovidone, obtained by the procedure of Example 3.
Fig. 5 illustrates the PXRD pattern of solid dispersion comprising amorphous roxadustat with Copovidone and syloid excipients obtained by the procedure of Example 3.
Fig.6 illustrates the PXRD pattern of solid dispersion comprising amorphous roxadustat with HPMC-AS, obtained by the procedure of Example 4.
DETAILED DESCRIPTION
In a first aspect, the present invention provides a solid dispersion comprising amorphous roxadustat and one or more pharmaceutically acceptable carriers.
The term "solid dispersion" defines a system in a solid state wherein one component is dispersed more or less evenly throughout the other component or components, e.g. in the context of the present invention amorphous roxadustat within the polymer.
The absence of peaks on the X-ray powder diffractogram of the solid dispersion of the invention, suggests that the solid dispersion of the present invention is amorphous.
The absence of peaks on the X-ray powder diffractogram of the solid dispersion of the invention suggests that, in the solid dispersion of the present invention roxadustat is in amorphous form.
The solid dispersion of the present invention is obtainable as a solid dispersion that is stable and pure with regard to the physical form of amorphous roxadustat therein, and that is obtainable in an easy and reliable manner, e.g. even in large scale.
The present invention further describes processes for the preparation of the solid dispersion.
In a second aspect, the present invention provides a process for the preparation of solid dispersion comprising amorphous roxadustat and one or more pharmaceutically acceptable carriers, comprising the steps:
a) providing a solution comprising roxadustat and one or more pharmaceutically acceptable carriers in a solvent
b) removing the solvent from the solution obtained in step (a) and
c) recovering the solid dispersion comprising amorphous roxadustat and one or more pharmaceutically acceptable carriers.
Step a) involves providing a solution of roxadustat and at least one pharmaceutically acceptable carrier in a solvent;
Step a) may involve forming a solution of roxadustat and one or more pharmaceutically acceptable carriers. In embodiments, the carrier enhances stability of the amorphous solid upon removal of solvent.
Providing the solution in step a) includes:
i) direct use of a reaction mixture containing roxadustat that is obtained in the course of its manufacture, if desired, after addition of one or more pharmaceutically acceptable carriers; or
ii) dissolution of roxadustat in a solvent, either alone or in combination with one or more pharmaceutically acceptable carriers.
The quantity of solvent used for dissolution depends on the solvent and the dissolution temperature adopted. The concentration of roxadustat in the solution may generally range from about 0.1 to about 10 g/ml in the solvent.
Any physical form of roxadustat, such as crystalline, amorphous or their mixtures may be utilized for providing a solution in step a).
Pharmaceutically acceptable carriers that may be used in step a) include, but are not limited to: diluents such as starches, pregelatinized starches, lactose, powdered celluloses, microcrystalline celluloses, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar, or the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidones (PVP), PVPK-30, copovidone, hydroxypropyl celluloses, hydroxypropyl methyl celluloses, pregelatinized starches, or the like; disintegrants such as starches, sodium starch glycolate, pregelatinized starches, crospovidones, croscarmellose sodium, colloidal silicon dioxide, or the like; lubricants such as stearic acid, magnesium stearate, zinc stearate, or the like; glidants such as colloidal silicon dioxide or the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants; complex forming agents such as various grades of cyclodextrins or resins; release rate controlling agents such as hydroxypropyl celluloses (HPC), hydroxymethyl celluloses, hydroxyethylcellulose, hydroxyethylmethylcellulose (HEMC), carboxymethylcellulose (CMC), carboxymethylhydroxyethylcellulose (CMHEC), hydroxyethylcarboxymethylcellulose (HECMC), sodium carboxymethylcellulose, cellulose acetate phthalate (CAP), hydroxypropyl methylcelluloses (HPMC), hydroxypropylmethylcellulose acetate (HPMCA), hydroxypropylmethylcellulose phthalate (HPMCP), hydroxypropyl methyl cellulose acetate succinate (HPMC-AS), ethylcelluloses, methylcelluloses, propylcellulose, hydroxyethyl methyl cellulose, hydroxyethyl cellulose acetate, hydroxyethyl ethyl cellulose, syloid cellulose, various grades of methyl methacrylates, poly(meth)acrylates (EUDRAGIT®), waxes, or the like. Other pharmaceutically acceptable excipients that are of use include, but are not limited to, film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants, or the like.
Roxadustat and the pharmaceutically acceptable carrier may be dissolved either in the same solvent or they may be dissolved in different solvents and then combined to form a mixture. In embodiments, the solid dispersion described herein comprises amorphous roxadustat and the carrier present in weight ratios ranging from about 5:95 to about 95:5. An example of a ratio is about 50:50.
The dissolution temperatures may range from about 0°C to about the reflux temperature of the solvent, or less than about 60°C, less than about 50°C, less than about 40°C, less than about 30°C, less than about 20°C, less than about 10°C, or any other suitable temperatures, as long as a clear solution of roxadustat is obtained without affecting its quality. The solution may optionally be treated with carbon, flux-calcined diatomaceous earth (Hyflow) or any other suitable material to remove color, insoluble materials, improve clarity of the solution, and/or remove impurities adsorbable on such material. Optionally, the solution obtained above may be filtered to remove any insoluble particles. The insoluble particles may be removed suitably by filtration, centrifugation, decantation, or any other suitable techniques under pressure or under reduced pressure. The solution may be filtered by passing through paper, glass fiber, cloth or other membrane material, or a bed of a clarifying agent such as Celite® or Hyflow. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature crystallization.
The solvents that may be used in step a) include but are not limited to: alcohols, such as methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, ethylene glycol, 1-propanol, 2-propanol (isopropyl alcohol), 2-methoxyethanol, 1-butanol, 2-butanol, iso-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, cyclohexanol, or C1-C6 alcohols and the like; nitriles, such as acetonitrile or propionitrile; amides, such as formamide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, or hexamethyl phosphoric triamide and the like; sulfoxides, such as dimethylsulfoxide and the like; ketone, such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like.
Step b) involves removal of the solvent from the solution comprising roxadustat and one or more pharmaceutically acceptable carriers. The solvent can be removed using the techniques such as evaporation, spray drying and other conventional techniques.
Step c) involves recovering the solid dispersion comprising amorphous roxadustat and one or more pharmaceutically acceptable carriers.
A solid dispersion comprising amorphous roxadustat and one or more pharmaceutically acceptable carriers may be isolated from a solution comprising roxadustat and one or more pharmaceutically acceptable carriers in a solvent by using the conventional methods. The methods includes but not limited to cooling, crash cooling, concentrating the mass, evaporation, flash evaporation, simple evaporation, fast solvent evaporation, rotational drying, spray drying, thin-film drying, agitated thin-film drying, agitated nutsche filter drying, pressure nutsche filter drying, freeze-drying or the like. Stirring or other alternate methods such as shaking, agitation, or the like, may also be employed for the isolation. The amorphous roxadustat as isolated may carry some amount of occluded mother liquor and may have higher than desired levels of impurities. If desired, this amorphous form may be washed with a solvent or a mixture of solvents to wash out the impurities.
The recovered solid dispersion may optionally be dried. Drying may be carried out in a tray dryer, vacuum oven, air oven, cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at temperatures less than about 100°C, less than about 80°C, less than about 60°C, less than about 50°C, less than about 30°C, or any other suitable temperatures, at atmospheric pressure or under a reduced pressure, as long as the roxadustat is not degraded in quality. The drying may be carried out for any desired times until the required product quality is achieved. The dried product may optionally be subjected to a size reduction procedure to produce desired particle sizes. Milling or micronization may be performed before drying, or after the completion of drying of the product. Techniques that may be used for particle size reduction include, without limitation, ball, roller or hammer milling; or jet milling; or bead milling.
Hygroscopic stability, chemical stability and polymorphic stability of the solid dispersion comprising roxadustat and the pharmaceutically acceptable carrier at various conditions are given below in table-1.
Table-1: Stability details
S.
No Solid Dispersion Stability Conditions Testing Intervals Water Content %(w/w) Total Impurity (%) by HPLC PXRD
1 Roxadustat Amorphous Solid Dispersion With Co-Povidone

25°C±2°C 65%RH± 5RH Initial 1.5 1.6 Amorphous
3rd month 1.5 1.9 Amorphous
2 40°C±2°C 75%RH± 5RH Initial 1.5 1.6 Amorphous
3rd month 1.2 2.2 Amorphous
3
2 to 8°C Initial 1.5 1.6 Amorphous
3rd month 1.4 1.8 Amorphous

The present invention also provides a pharmaceutical composition comprising the solid dispersion as described above.
The pharmaceutical composition of the present invention may be formulated in accordance with conventional methods, and may be prepared in the form of oral formulations such as tablets, pills, powders, capsules, syrups, emulsions, micro emulsions, and others, or formulation for parenteral injection, e.g., intramuscular, intravenous, or subcutaneous administration. The pharmaceutical composition of the present invention may comprise the inventive solid dispersion, and any possible carrier and excipient
EXAMPLES
Example 1: Preparation of amorphous roxadustat
0.5 g of roxadustat was taken in a glass vial at 25oC and placed on hot plate at 40°C. Temperature of the hot plate was increased to 235°C. The glass vial was kept in 25°C suddenly to obtain the title compound.
Example 2: Preparation of solid dispersion of roxadustat
To the mixture of 1.0 g of roxadustat and 1.0 g of PVPK-30, 50 mL of methanol/50 mL of acetone mixture was added at 25°C. The contents were stirred at 40°C to get the clear solution. The solution was spray dried at 35°C to get the solid dispersion comprising amorphous roxadustat with PVPK-30 excipient. The obtained solid dispersion was blended with 1.0 g of syloid.

Example 3: Preparation of solid dispersion of roxadustat
To the mixture of 1.0 g of roxadustat and 1.0 g of Copovidone, 100 mL of methanol/100 mL of acetone mixture was added at 25°C. The contents were stirred at 40°C to get the clear solution. The solution was spray dried at 60°C to get the solid dispersion comprising amorphous roxadustat with Copovidone. The obtained solid dispersion was blended with 1.0 g of syloid.
Example 4: Preparation of solid dispersion of roxadustat
To the mixture of 1.0 g of roxadustat and 1.0 g of HPMC-AS, 100 mL of methanol/100 mL of acetone mixture was added at 25°C. The contents were stirred at 40°C to get the clear solution. The solution was spray dried at 60°C to get the solid dispersion comprising amorphous roxadustat with HPMC-AS.
,CLAIMS:1. An amorphous solid dispersion comprising roxadustat and pharmaceutically acceptable carrier.
2. The solid dispersion as claimed in claim 1, wherein the carrier is selected from starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar, acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidones (PVP), PVPK-30, copovidone, hydroxypropyl celluloses, hydroxypropyl methyl celluloses, sodium starch glycolate, crospovidone, croscarmellose sodium, colloidal silicon dioxide, stearic acid, magnesium stearate, zinc stearate, colloidal silicon dioxide, hydroxymethylcelluloses, hydroxyethylcellulose, hydroxyl ethylmethylcellulose(HEMC),carboxymethylcellulose(CMC), carboxymethyl hydroxyethylcellulose(CMHEC), hydroxyethylcarboxy methylcellulose (HECMC), sodium carboxymethylcellulose, cellulose acetate phthalate (CAP), hydroxypropylmethylcelluloseacetate(HPMCA), hydroxypropylmethyl cellulose phthalate (HPMCP), hydroxypropyl methyl cellulose acetate succinate (HPMC-AS), ethylcelluloses, methylcelluloses, propylcellulose, hydroxyethyl methyl cellulose, hydroxyethyl cellulose acetate, hydroxyethyl ethyl cellulose, syloid cellulose, methyl methacrylates, poly(meth)acrylates (EUDRAGIT®) and waxes.
3. The solid dispersion as claimed in claim 2, wherein the carrier is selected from (Polyvinylpyrrolidone) K-30, copovidone, syloid and hydroxypropyl methyl cellulose acetate succinate (HPMC-AS).
4. The solid dispersion as claimed in claim 3, wherein the carrier is Copovidone.
5. The solid dispersion as claimed in claim 2, wherein the carrier is mixture of (Polyvinylpyrrolidone) K-30 and syloid.
6. The solid dispersion as claimed in claim 2, wherein the carrier is mixture of Copovidone and syloid.
7. A process for preparation of solid dispersion comprising roxadustat and pharmaceutically acceptable carrier, comprising;
a) providing a solution of roxadustat and one or more pharmaceutically acceptable carrier in solvent
b) isolating the solid dispersion comprising amorphous roxadustat and one or more pharmaceutically acceptable carriers.
8. The process as claimed 7, wherein the solvent is selected from alcohol and ketone or a mixture thereof.
9. The process as claimed in 8, wherein the solvent is mixture of methanol and acetone.