DESC:AMORPHOUS ELAGOLIX SODIUM, SOLID DISPERSION AND PROCESS THEREOF

INTRODUCTION
The present invention provides processes for preparation of amorphous Elagolix sodium and solid dispersion thereof.
BACKGROUND OF THE INVENTION
Elagolix sodium is a non-peptide antagonist of the gonadotropin-releasing hormone receptor and chemically known as sodium;4-[[(1R)-2-[5-(2-fluoro-3-methoxyphenyl)-3-[[2-fluoro-6-(trifluoromethyl)phenyl]methyl]-4-methyl-2,6-dioxopyrimidin-1-yl]-1-phenylethyl]amino]butanoate as below .

The US patent number 7056927 B2 discloses, elagolix sodium salt as a white solid and process for its preparation in Example-1; Step-1H.
The US patent number 8765948 B2 discloses a process for preparation of amorphous elagolix sodium by spray drying method and solid dispersion of amorphous elagolix sodium with a polymer.

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 Elagolix sodium in a solid form, wherein the physicochemical stability and the dissolution characteristics of the solid form is improved, and wherein Elagolix sodium is rendered more suitable for use in a pharmaceutical composition.
SUMMARY
In an aspect, the present invention provides process for the preparation of amorphous Elagolix sodium, amorphous solid dispersion of Elagolix sodium and solid dispersion comprising amorphous Elagolix sodium and one or more pharmaceutically acceptable carriers.
In a second aspect, the present invention provides a process for the preparation of amorphous Elagolix sodium, comprising the steps;
a) providing a solution of Elagolix sodium in a solvent or mixture of solvents; and
b) isolating amorphous Elagolix sodium.
In a third aspect, the present invention provides a process for the preparation of amorphous Elagolix sodium, comprising the step;
a) ball milling Elagolix sodium under suitable milling conditions.
In a fourth aspect, the present invention provides a process for the preparation of amorphous solid dispersion of Elagolix sodium comprising the steps:
a) providing a solution comprising Elagolix sodium and one or more pharmaceutically acceptable carriers in a solvent,
b) removing the solvent from the solution obtained in step (a) and,
c) recovering amorphous solid dispersion of Elagolix sodium.
In a fifth aspect, the present invention provides a process for the preparation of solid dispersion comprising amorphous Elagolix sodium and one or more pharmaceutically acceptable carriers, comprising the steps:
a) providing a solution comprising Elagolix sodium 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 amorphous Elagolix sodium and one or more pharmaceutically acceptable carriers.
In a sixth aspect, the present invention provides a process for the preparation of amorphous solid dispersion of Elagolix sodium comprising the steps;
a) grinding Elagolix sodium and one or more pharmaceutically acceptable carriers and
b) recovering amorphous solid dispersion of Elagolix sodium.
BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1 illustrates the PXRD pattern of amorphous Elagolix sodium, obtained by the procedure of Example 1.
Fig. 2 illustrates the PXRD pattern of amorphous Elagolix sodium, obtained by the procedure of Example 2.
Fig. 3 illustrates the PXRD pattern of amorphous Elagolix sodium, obtained by the procedure of Example 3.
Fig. 4 illustrates the PXRD pattern of amorphous Elagolix sodium, obtained by the procedure of Example 4.
Fig. 5 illustrates the PXRD pattern of amorphous Elagolix sodium, obtained by the procedure of Example 5.
Fig. 6 illustrates the PXRD pattern of amorphous solid dispersion of Elagolix sodium, obtained by the procedure of Example 6.
Fig. 7 illustrates the PXRD pattern of amorphous solid dispersion of Elagolix sodium, obtained by the procedure of Example 7.
Fig. 8 illustrates the PXRD pattern of solid dispersion comprising amorphous Elagolix sodium with PEG-8000 obtained by the procedure of Example 8.
Fig. 8(i) illustrates the PXRD pattern of PEG-8000 used in the procedure of Example 8.
Fig. 9 illustrates the PXRD pattern of amorphous solid dispersion of Elagolix sodium, obtained by the procedure of Example 9.
Fig. 10 illustrates the PXRD pattern of amorphous solid dispersion of Elagolix sodium, obtained by the procedure of Example 10.
DETAILED DESCRIPTION
In an aspect, the present invention provides process for the preparation of amorphous Elagolix sodium, amorphous solid dispersion of Elagolix sodium and solid dispersion comprising amorphous Elagolix sodium and one or more pharmaceutically acceptable carriers.
In a second aspect, the present invention provides a process for the preparation of amorphous Elagolix sodium, comprising the steps;
a) providing a solution of Elagolix sodium in a solvent or mixture of solvents and,
b) isolating amorphous Elagolix sodium.
Providing a solution of Elagolix sodium in step a) includes:
i) direct use of a reaction mixture containing Elagolix sodium that is obtained in the course of its synthesis; or
ii) dissolving Elagolix sodium in a solvent.
Any physical form of Elagolix sodium may be utilized for providing the solution of Elagolix sodium in step a). The dissolution temperatures may range from about 0 °C to about the reflux temperature of the solvent, or less than about 70°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 Elagolix sodium is obtained without affecting its quality. The solution may optionally be treated with carbon, flux-calcined diatomaceous earth (Hyflow) or any other suitable material to remove color, insoluble materials, improve clarity of the solution, and/or remove impurities adsorbable on such material. Optionally, the solution obtained above may be filtered to remove any insoluble particles. The insoluble particles may be removed suitably by filtration, centrifugation, decantation, or any other suitable techniques under pressure or under reduced pressure. The solution may be filtered by passing through paper, glass fiber, cloth or other membrane material, or a bed of a clarifying agent such as Celite® or Hyflow. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature crystallization.
In embodiments, Elagolix sodium can be dissolved in the following solvents. Examples of the solvents comprises alcohols, such as methanol, ethanol, 1-propanol, 2-propanol (isopropyl alcohol), 2-methoxyethanol, 1-butanol, 2-butanol, iso-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, cyclohexanol, glycerol, 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; or any mixtures of two or more solvents thereof. In a more preferred embodiment solvents such as alcohols, chlorohydrocarbons or mixture thereof are used.
The quantity of solvent used for dissolution depends on the solvent and the dissolution temperature adopted.
Step b) involves isolating amorphous Elagolix sodium from the solution obtained in step a). Isolation of amorphous Elagolix sodium in step b) may involve methods including removal of solvent, 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, rotary vacuum paddle dryer, adding anti-solvent or the like. Stirring or other alternate methods such as shaking, agitation, or the like, may also be employed for the isolation. The amorphous Elagolix sodium 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.
Suitable temperatures for isolation may be less than about 60°C, less than about 40°C, less than about 30°C, less than about 20°C, less than about 10°C, less than about 0°C, less than about -10°C, less than about -40°C or any other suitable temperatures.
Optionally isolation of amorphous Elagolix sodium may also be effected by combining a suitable anti-solvent with the solution obtained in step a). Anti-solvent as used herein refers to a liquid in which Elagolix sodium is less soluble or poorly soluble. An inert anti-solvent has no adverse effect on the reaction and it can assist in the solidification or precipitation of the dissolved starting material. Suitable anti-solvents that may be used include, but are not limited to: saturated or unsaturated, linear or branched, cyclic or acyclic, C1 to C10 hydrocarbons, such as heptanes, cyclohexane, or methylcyclohexane; water; or any mixtures thereof.
The recovered solid 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 Elagolix sodium 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.
In a third aspect, the present invention provides a process for the preparation of amorphous Elagolix sodium, comprising the step;
a) ball milling Elagolix sodium under suitable milling conditions.
Any solid forms, either crystalline or amorphous form of Elagolix sodium can be used to mill it with one or more pharmaceutically acceptable carriers.
In a fourth aspect, the present invention provides a process for the preparation of amorphous solid dispersion of Elagolix sodium comprising the steps:
a) providing a solution comprising Elagolix sodium and one or more pharmaceutically acceptable carriers in a solvent,
b) removing the solvent from the solution obtained in step (a) and,
c) recovering amorphous solid dispersion of Elagolix sodium.
Step a) involves providing a solution of Elagolix sodium and at least one pharmaceutically acceptable carrier in a solvent;
Step a) may involve forming a solution of Elagolix sodium 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 Elagolix sodium that is obtained in the course of its manufacture, if desired, after addition of one or more pharmaceutically acceptable carriers; or
ii) dissolution of Elagolix sodium 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.
Any physical form of Elagolix sodium, 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, Neusilin® (Magnesium Alumino-metasilicate), polyvinylpyrrolidones (PVP), Polyvinylpyrrolidone K 30 (PVPK-30), Polyethylene glycol, 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 (HPMCAS), Low-Substituted Hydroxypropyl Cellulose (HPC-L), ethylcelluloses, methylcelluloses, propylcellulose, hydroxyethyl methyl cellulose, hydroxyethyl cellulose acetate, hydroxyethyl ethyl cellulose, Syloid®, various grades of methyl methacrylates, poly(meth)acrylates (EUDRAGIT®), waxes, Soluplus® 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.
Elagolix sodium and the pharmaceutically acceptable carriers 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 Elagolix sodium 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. In some embodiments, the solid dispersion described herein comprises one or more pharmaceutically acceptable excipients, preferably two excipients.
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 Elagolix sodium 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;
Step b) involves removal of the solvent from the solution comprising Elagolix sodium 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 amorphous solid dispersion comprising Elagolix sodium and one or more pharmaceutically acceptable carriers.
A solid amorphous dispersion comprising Elagolix sodium and one or more pharmaceutically acceptable carriers may be isolated from a solution comprising Elagolix sodium 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 Elagolix sodium 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 Elagolix sodium 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.
In a fifth aspect, the present invention provides a process for the preparation of solid dispersion comprising amorphous Elagolix sodium and one or more pharmaceutically acceptable carriers, comprising the steps:
a) providing a solution comprising Elagolix sodium 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 amorphous Elagolix sodium and one or more pharmaceutically acceptable carriers.
Step a) involves providing a solution of Elagolix sodium and at least one pharmaceutically acceptable carrier in a solvent;
Step a) may involve forming a solution of Elagolix sodium 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 Elagolix sodium that is obtained in the course of its manufacture, if desired, after addition of one or more pharmaceutically acceptable carriers; or
ii) dissolution of Elagolix sodium 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 Elagolix sodium in the solution may generally range from about 0.1 to about 10 g/ml in the solvent.
Any physical form of Elagolix sodium, 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, Neusilin® (Magnesium Alumino-metasilicate), polyvinylpyrrolidones (PVP), Polyvinylpyrrolidone K 30 (PVPK-30), Polyethylene glycol, 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 (HPMCAS), Low-Substituted Hydroxypropyl Cellulose (HPC-L), ethylcelluloses, methylcelluloses, propylcellulose, hydroxyethyl methyl cellulose, hydroxyethyl cellulose acetate, hydroxyethyl ethyl cellulose, Syloid®, various grades of methyl methacrylates, poly(meth)acrylates (EUDRAGIT®), waxes, Soluplus® 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.
Elagolix sodium and the pharmaceutically acceptable carriers 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 Elagolix sodium and the carrier present in weight ratios ranging from about 5:95 to about 95:5 by weight. An example of a ratio is about 50:50 by weight. In some embodiments, the solid dispersion described herein comprises one or more pharmaceutically acceptable excipients, preferably two excipients.
The dissolution temperatures may range from about 0°C to about the reflux temperature of the solvent, or less than about 45°C, less than about 45°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 Elagolix sodium 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;
Step b) involves removal of the solvent from the solution comprising Elagolix sodium 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 Elagolix sodium and one or more pharmaceutically acceptable carriers.
A solid dispersion comprising amorphous Elagolix sodium and one or more pharmaceutically acceptable carriers may be isolated from a solution comprising Elagolix sodium 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 Elagolix sodium 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 Elagolix sodium 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.
In a sixth aspect, the present invention further provides a process for preparation of solid dispersion comprising amorphous Elagolix sodium and one or more pharmaceutically acceptable carriers, comprising the steps of:
a) grinding Elagolix sodium and one or more pharmaceutically acceptable carriers and
b) recovering a solid dispersion comprising amorphous Elagolix sodium and one or more pharmaceutically acceptable carriers.
Any solid forms, either crystalline or amorphous form of Elagolix sodium can be used to grind it with one or more pharmaceutically acceptable carriers.
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 Elagolix sodium
1g of Elagolix sodium and 20 mL of methanol were charged into a round bottom flask at 30oC. The contents were stirred for dissolution and filtered. The filtrate was distilled at 65oC to afford the title compound.
Example 2: Preparation of amorphous Elagolix sodium
1g of Elagolix sodium and 20 mL of methanol & Dichloromethane mixture (1:4) were charged into a round bottom flask at 28oC. The contents were stirred for dissolution and filtered. The filtrate was distilled at 45oC to afford the title compound.
Example 3: Preparation of amorphous Elagolix sodium
1.25g of Elagolix sodium and 25 mL of Tetrahydrofuran were charged into a round bottom flask at 28oC. The contents were stirred for dissolution and filtered. The filtrate was distilled at 65oC to afford the title compound.
Example 4: Preparation of amorphous Elagolix sodium
1.0g of Elagolix sodium was charged into a ball milling chamber at 28oC and milled for about 2hours to afford the title compound.
Example 5: Preparation of amorphous Elagolix sodium
1.5g of Elagolix sodium and 150 mL of N,N-Dimethyl Formamide were charged into a round bottom flask at 28oC. The contents were stirred for dissolution and filtered. The filtrate was spray dried at 130oC to afford the title compound.
Example 6: Preparation of amorphous solid dispersion of Elagolix sodium
0.2 g of Elagolix sodium and 0.2 g of Syloid® were added into Mortar and pestle. The contents were grinded for five minutes to get the title compound.
Example 7: Preparation of amorphous solid dispersion of Elagolix sodium
0.5 g of Elagolix sodium and 0.5 g of Soluplus® were added to 20 mL of methanol&Dicholromethane mixture (1:4) at 28°C. The contents were stirred for dissolution and filtered. The filtrate was distilled under reduced pressure at 45oC to afford the title compound.
Example 8: Preparation of amorphous solid dispersion of Elagolix sodium
0.5 g of Elagolix sodium and 0.5 g of PEG-8000 were added to 20 mL of methanol & dichloromethane mixture (1:4) at 28°C. The contents were stirred for dissolution and filtered. The filtrate was distilled under reduced pressure at 45oC to afford the title compound.
Example 9: Preparation of amorphous solid dispersion of Elagolix sodium
0.25g of solid dispersion of Elagolix sodium obtained from the above example 7 and 0.125g of Neusilin® ULF2 were added into Mortar and pestle. The contents were grinded for ten minutes to get the title compound.
Example 10: Preparation of amorphous solid dispersion of Elagolix sodium
0.25 g of Elagolix sodium and 0.25 g of Neusilin® were added into Mortar and pestle. The contents were grinded for five minutes to get the title compound. ,CLAIMS:We Claim:
1. A process for the preparation of amorphous Elagolix sodium, comprising the steps of:
a) providing a solution of Elagolix sodium in a solvent or mixture of solvents; and
b) isolating amorphous Elagolix sodium.
2. Amorphous solid dispersion of Elagolix sodium, wherein the Elagolix sodium is dispersed with one or more pharmaceutically acceptable carriers selected from Polyethylene glycol, Syloid®, Soluplus®,and Neusilin®
3. A process for the preparation of amorphous solid dispersion of Elagolix sodium comprising the steps of:
a) providing a solution comprising Elagolix sodium and one or more pharmaceutically acceptable carriers in a solvent,
b) removing the solvent from the solution obtained in step (a) and,
c) recovering amorphous solid dispersion of Elagolix sodium.
4. A solid dispersion comprising amorphous Elagolix sodium and one or more pharmaceutically acceptable carriers wherein pharmaceutically acceptable carrier is selected from Polyethylene glycol, Syloid®, Soluplus®,and Neusilin®.
5. A process for the preparation of solid dispersion comprising amorphous Elagolix sodium and one or more pharmaceutically acceptable carriers, comprising the steps of:
a) providing a solution comprising Elagolix sodium 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 amorphous Elagolix sodium and one or more pharmaceutically acceptable carriers.
6. A process for preparation of solid dispersion comprising amorphous Elagolix sodium and one or more pharmaceutically acceptable carriers, comprising the steps of:
a) grinding Elagolix sodium and one or more pharmaceutically acceptable carriers and;
b) recovering a solid dispersion comprising amorphous Elagolix sodium and one or more pharmaceutically acceptable carriers.
7. The pharmaceutically acceptable carrier according to claim 3, 5 & 7, is selected from Polyethylene glycol, Syloid®, Soluplus® and Neusilin®.
8. A pharmaceutical composition comprising amorphous Elagolix sodium.
9. A pharmaceutical composition comprising amorphous solid dispersion of Elagolix sodium.
10. A method for preparing a pharmaceutical composition, the method comprising combining the Elagolix sodium of claim 1- 9 and at least one pharmaceutically acceptable excipient.