WO2016203436A1 - Dispersions amorphes et solides amorphes de lesinurad et leur préparation - Google Patents
Dispersions amorphes et solides amorphes de lesinurad et leur préparation Download PDFInfo
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- WO2016203436A1 WO2016203436A1 PCT/IB2016/053605 IB2016053605W WO2016203436A1 WO 2016203436 A1 WO2016203436 A1 WO 2016203436A1 IB 2016053605 W IB2016053605 W IB 2016053605W WO 2016203436 A1 WO2016203436 A1 WO 2016203436A1
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- WIPO (PCT)
- Prior art keywords
- lesinurad
- amorphous
- solid dispersion
- mixture
- solvent
- Prior art date
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- FGQFOYHRJSUHMR-UHFFFAOYSA-N lesinurad Chemical compound OC(=O)CSC1=NN=C(Br)N1C(C1=CC=CC=C11)=CC=C1C1CC1 FGQFOYHRJSUHMR-UHFFFAOYSA-N 0.000 title claims abstract description 128
- 229960003838 lesinurad Drugs 0.000 title claims abstract description 126
- 239000007962 solid dispersion Substances 0.000 title claims abstract description 55
- 238000002360 preparation method Methods 0.000 title claims abstract description 25
- 238000000034 method Methods 0.000 claims abstract description 49
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 29
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 8
- 239000003937 drug carrier Substances 0.000 claims abstract description 7
- 239000000203 mixture Substances 0.000 claims description 52
- 239000002904 solvent Substances 0.000 claims description 42
- 238000001035 drying Methods 0.000 claims description 22
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 21
- 239000007787 solid Substances 0.000 claims description 19
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 18
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 12
- 238000001914 filtration Methods 0.000 claims description 12
- 239000002245 particle Substances 0.000 claims description 12
- 238000002156 mixing Methods 0.000 claims description 11
- FVYMVLTWIBGEMC-UHFFFAOYSA-M sodium;2-[[5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-1,2,4-triazol-3-yl]sulfanyl]acetate Chemical compound [Na+].[O-]C(=O)CSC1=NN=C(Br)N1C(C1=CC=CC=C11)=CC=C1C1CC1 FVYMVLTWIBGEMC-UHFFFAOYSA-M 0.000 claims description 10
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 9
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 8
- 150000008282 halocarbons Chemical class 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- 150000001298 alcohols Chemical class 0.000 claims description 6
- 150000002576 ketones Chemical class 0.000 claims description 6
- 150000002148 esters Chemical class 0.000 claims description 5
- 150000002170 ethers Chemical class 0.000 claims description 5
- -1 miglyols Polymers 0.000 claims description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- 229960001760 dimethyl sulfoxide Drugs 0.000 claims description 4
- 150000002825 nitriles Chemical class 0.000 claims description 4
- 239000000377 silicon dioxide Substances 0.000 claims description 4
- 235000012239 silicon dioxide Nutrition 0.000 claims description 4
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 claims description 3
- 229920002307 Dextran Polymers 0.000 claims description 3
- 239000001856 Ethyl cellulose Substances 0.000 claims description 3
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 claims description 3
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 3
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 claims description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical class CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 3
- 229920001531 copovidone Polymers 0.000 claims description 3
- HDERJYVLTPVNRI-UHFFFAOYSA-N ethene;ethenyl acetate Chemical class C=C.CC(=O)OC=C HDERJYVLTPVNRI-UHFFFAOYSA-N 0.000 claims description 3
- 235000019325 ethyl cellulose Nutrition 0.000 claims description 3
- 229920001249 ethyl cellulose Polymers 0.000 claims description 3
- 150000004676 glycans Chemical class 0.000 claims description 3
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 3
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 3
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 3
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims description 3
- 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 claims description 3
- 229940031704 hydroxypropyl methylcellulose phthalate Drugs 0.000 claims description 3
- 229920000639 hydroxypropylmethylcellulose acetate succinate Polymers 0.000 claims description 3
- 239000000787 lecithin Substances 0.000 claims description 3
- 235000010445 lecithin Nutrition 0.000 claims description 3
- 229920000609 methyl cellulose Polymers 0.000 claims description 3
- 239000001923 methylcellulose Substances 0.000 claims description 3
- 235000010981 methylcellulose Nutrition 0.000 claims description 3
- 239000001814 pectin Substances 0.000 claims description 3
- 235000010987 pectin Nutrition 0.000 claims description 3
- 229920001277 pectin Polymers 0.000 claims description 3
- 150000008105 phosphatidylcholines Chemical class 0.000 claims description 3
- 229920001983 poloxamer Polymers 0.000 claims description 3
- 229920001987 poloxamine Polymers 0.000 claims description 3
- 229920001200 poly(ethylene-vinyl acetate) Polymers 0.000 claims description 3
- 229920000747 poly(lactic acid) Polymers 0.000 claims description 3
- 229920001223 polyethylene glycol Polymers 0.000 claims description 3
- 239000004626 polylactic acid Substances 0.000 claims description 3
- 229920001282 polysaccharide Polymers 0.000 claims description 3
- 239000005017 polysaccharide Substances 0.000 claims description 3
- 229920002689 polyvinyl acetate Polymers 0.000 claims description 3
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 3
- 235000019422 polyvinyl alcohol Nutrition 0.000 claims description 3
- 235000013772 propylene glycol Nutrition 0.000 claims description 3
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 2
- 229910017604 nitric acid Inorganic materials 0.000 claims description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 27
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- 150000001875 compounds Chemical class 0.000 description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 11
- 238000001144 powder X-ray diffraction data Methods 0.000 description 11
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- 238000004519 manufacturing process Methods 0.000 description 8
- 238000002955 isolation Methods 0.000 description 7
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 238000004108 freeze drying Methods 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 238000000605 extraction Methods 0.000 description 4
- 238000010951 particle size reduction Methods 0.000 description 4
- 238000000638 solvent extraction Methods 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 3
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- 238000005119 centrifugation Methods 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 239000006185 dispersion Substances 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 3
- 229940011051 isopropyl acetate Drugs 0.000 description 3
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 3
- 238000007670 refining Methods 0.000 description 3
- 238000007790 scraping Methods 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 238000001694 spray drying Methods 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- 239000010409 thin film Substances 0.000 description 3
- 238000012546 transfer Methods 0.000 description 3
- YNQLUTRBYVCPMQ-UHFFFAOYSA-N Ethylbenzene Chemical compound CCC1=CC=CC=C1 YNQLUTRBYVCPMQ-UHFFFAOYSA-N 0.000 description 2
- LEHOTFFKMJEONL-UHFFFAOYSA-N Uric Acid Chemical compound N1C(=O)NC(=O)C2=C1NC(=O)N2 LEHOTFFKMJEONL-UHFFFAOYSA-N 0.000 description 2
- TVWHNULVHGKJHS-UHFFFAOYSA-N Uric acid Natural products N1C(=O)NC(=O)C2NC(=O)NC21 TVWHNULVHGKJHS-UHFFFAOYSA-N 0.000 description 2
- 229920001577 copolymer Polymers 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229940088679 drug related substance Drugs 0.000 description 2
- 230000002209 hydrophobic effect Effects 0.000 description 2
- 239000012729 immediate-release (IR) formulation Substances 0.000 description 2
- 239000011159 matrix material Substances 0.000 description 2
- 238000003801 milling Methods 0.000 description 2
- 239000004570 mortar (masonry) Substances 0.000 description 2
- 239000006186 oral dosage form Substances 0.000 description 2
- 238000002464 physical blending Methods 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 229940116269 uric acid Drugs 0.000 description 2
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 201000005569 Gout Diseases 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 238000007905 drug manufacturing Methods 0.000 description 1
- 238000007908 dry granulation Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000001125 extrusion Methods 0.000 description 1
- 239000010408 film Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 238000005563 spheronization Methods 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
- C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D249/12—Oxygen or sulfur atoms
Definitions
- Present application relates to process for preparation of amorphous form of lesinurad. Another aspect of the present invention is directed to amorphous lesinurad characterized by X-ray diffractogram. Another aspect of the present application is directed to amorphous solid dispersion of lesinurad. Still another aspect of the present application relates to process for the preparation of amorphous solid dispersion of lesinurad.
- Lesinurad is a selective uric acid re-absorption inhibitor (SURI). Lesinurad or its salt is used for reducing serum uric acid level and for the treatment of gout and hyperurecemia. Lesinurad is chemically known as 2-(5-bromo-4-(4-cyclopropyl naphthalen-1 -yl)-4H-1 ,2,4-triazol-3-ylthio)acetic acid and has following structural formula (I):
- US8546436B2 discloses crystalline Forms I and 2 of lesinurad and their processes for preparation. Similarly, US8524754B2 discloses crystalline forms A, B, B', C, D and E of lesinurad sodium and their processes for preparation.
- polymorphism refers to the ability of a substance to exist as two or more crystalline phases that have different spatial arrangements and/or conformations of molecules in their crystal lattices.
- polymorphs refer to different crystalline forms of the same pure substance in which the molecules have different spatial arrangements of the molecules, atoms, and/or ions forming the crystal. Different polymorphs may have different physical properties such as melting points, solubilities, X-ray diffraction patterns, etc.
- the variation in solid forms may appreciably influence the pharmaceutical properties, such as bioavailability, handling properties, dissolution rate, and stability, and in turn such properties can significantly influence the processing, shelf life, and commercial acceptance of a polymorphic form.
- pharmaceutical properties such as bioavailability, handling properties, dissolution rate, and stability
- regulatory authorities require drug manufacturing companies to put efforts into identifying all polymorphic forms, e.g., crystalline, amorphous, solvates, stable dispersions with a pharmaceutically acceptable carriers, etc., of new drug substances.
- amorphous form and amorphous solid dispersion form of a drug may exhibit a higher bioavailability than its crystalline counterparts, which leads to the selection of the amorphous or its solid dispersion form as the final drug substance for pharmaceutical dosage form development.
- the solubility of crystalline form is lower than its amorphous or amorphous solid dispersion in some instances, particularly aqueous solubility, which may result in the difference in their in-vivo bioavailability. Therefore, it is desirable to have amorphous or amorphous solid dispersion form of a drug to meet the needs of drug development and also a reproducible process for their preparation. Hence, it is desirable to provide amorphous or amorphous solid dispersion of lesinurad.
- the present application relates to amorphous form of lesinurad which may be characterized by a PXRD pattern substantially as illustrated in figure-1 .
- the present application relates to process for preparing amorphous form of lesinurad comprising:
- the present application relates to process for preparing amorphous form of lesinurad comprising:
- the present application relates to amorphous solid dispersion of lesinurad together with at least one pharmaceutically acceptable excipient.
- the present application relates to amorphous solid dispersion of lesinurad together with HPMC which may be characterized by X-ray diffractogram as shown in figure-3.
- the present application relates to amorphous solid dispersion of lesinurad together with PVP K-30.
- the present application relates to process for preparing amorphous solid dispersion of lesinurad comprising: a) dissolving lesinurad and one or more pharmaceutically acceptable excipients in a suitable solvent or mixture thereof;
- the present application relates to process for preparing amorphous solid dispersion of lesinurad comprising blending of lesinurad with one or more pharmaceutically acceptable excipients.
- the present application provides pharmaceutical formulations comprising amorphous form of lesinurad, together with one or more pharmaceutically acceptable carrier, diluents and excipients.
- the present application provides pharmaceutical composition comprising amorphous solid dispersion of lesinurad with a pharmaceutically acceptable excipient, together with one or more pharmaceutically acceptable excipients.
- Figure 1 is an illustration of a PXRD pattern of amorphous form of lesinurad obtained by the example 1 .
- Figure 2 is an illustration of a PXRD pattern of amorphous form of lesinurad obtained by the example 2.
- Figure 3 is an illustration of a PXRD pattern of amorphous form of solid dispersion of lesinurad obtained by the example 5.
- Figure 4 is an illustration of a PXRD pattern of amorphous form of solid dispersion of lesinurad obtained by the example 7.
- Figure 5 is an illustration of a PXRD pattern of amorphous form of solid dispersion of lesinurad obtained by the example 8.
- Figure 6 is an illustration of a PXRD pattern of amorphous form of solid dispersion of lesinurad obtained by the example 9.
- Figure 7 is an illustration of a PXRD pattern of amorphous form of solid dispersion of lesinurad obtained by the example 10.
- the present application relates to amorphous form of lesinurad which may be characterized by a PXRD pattern substantially as illustrated in Figure 1 .
- the present application relates to process for preparing amorphous form of lesinurad comprising:
- Any crystalline form or amorphous form of lesinurad sodium or mixture thereof may be used as starting material for preparing amorphous form of lesinurad.
- Lesinurad sodium may be prepared by methods known in the art.
- Suitable solvents of step a) for dissolving lesinurad sodium include, but are not limited to water, dimethylformamide; dimethylacetamide; dimethyl sulphoxide; nitriles such as acetonitrile, propionitrile and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone; ethers such as tetrahydrofuran, dioxane; esters such as ethyl acetate, isopropyl acetate; halogenated hydrocarbons such as chloroform, dichloromethane; alcohols such as methanol, ethanol, propanol, isopropanol; and mixtures thereof.
- Suitable acid of step c) include, but are not limited to hydrochloric acid, sulfuric acid, nitric acid, acetic acid, hydrobromic acid and the like.
- the isolation of the crude compound after the step (c) may be carried out by solvent extraction.
- suitable solvents that may be used for extraction include, but are not limited to, ethers such as tetrahydrofuran, dioxane; esters such as ethyl acetate, isopropyl acetate; aromatic hydrocarbons such as toluene, xylene, ethylbenzene; halogenated hydrocarbons such as chloroform, dichloromethane and the like.
- Suitable techniques that may be used for the removal of solvent include but are not limited to rotational distillation using a device such as Buchi Rotavapor, spray drying, agitated thin film drying (“ATFD”), freeze drying (lyophilization) and the like, optionally under reduced pressure.
- a device such as Buchi Rotavapor, spray drying, agitated thin film drying (“ATFD”), freeze drying (lyophilization) and the like, optionally under reduced pressure.
- ATFD agitated thin film drying
- freeze drying lyophilization
- the isolation and purification can be effected, if desired, by any suitable separation or purification procedure such as, for example, filtration, centrifugation, extraction, acid-base treatment, conventional isolation and refining means such as concentration, concentration under reduced pressure, solvent-extraction, crystallization, phase-transfer chromatography, column chromatography, or by a combination of these procedures.
- suitable separation or purification procedure such as, for example, filtration, centrifugation, extraction, acid-base treatment, conventional isolation and refining means such as concentration, concentration under reduced pressure, solvent-extraction, crystallization, phase-transfer chromatography, column chromatography, or by a combination of these procedures.
- the resulting solid may be collected by using techniques such as by scraping, or by shaking the container or other techniques specific to the equipment used.
- the isolated solid may be optionally further dried to afford amorphous form of lesinurad.
- Drying in the embodiments of the present invention may be suitably carried out by using any of an air tray dryer, vacuum tray dryer, fluidized bed dryer, spin flash dryer, flash dryer, and the like.
- the drying may be carried out at atmospheric pressure or above, or under reduced pressures, specifically at temperatures less than about 80 °C and more specifically less than about 60 °C.
- the drying may be carried out for any time period required for obtaining a desired product quality, such as from about 30 minutes to about 24 hours, or longer.
- the steps of the above embodiment may be performed at a temperature of about 0°C to about the boiling point of the solvent.
- lesinurad sodium may be dissolved in a suitable solvent at a temperature of about 0°C to about 70°C.
- the dried product may optionally be subjected to a particle size reduction procedure to produce desired particle sizes and distributions. Milling or micronization may be performed before drying, or after the completion of drying of the product.
- Equipment that may be used for particle size reduction includes but not limited to ball mill, roller mill, hammer mill, and jet mill.
- the amorphous form of lesinurad of the present invention is substantially free of any crystalline form of lesinurad.
- Amorphous form of lesinurad of the present invention does not contain more than about 10 % of any crystalline form of lesinurad.
- amorphous form of lesinurad does not contain more than about 5 % of any crystalline form of lesinurad.
- amorphous form of lesinurad does not contain more than about 3 % of any crystalline form of lesinurad.
- amorphous form of lesinurad does not contain more than about 1 % of any crystalline form of lesinurad.
- Fig. 1 illustrate PXRD pattern of amorphous lesinurad obtained by process of example 1 .
- the amorphous form of lesinurad is stable and has excellent physico-chemical properties.
- the amorphous form of lesinurad of the present application may be easily formulated into a pharmaceutical composition along with suitable pharmaceutically acceptable excipients.
- the amorphous form of lesinurad obtained in the present invention may be converted to either crystalline or amorphous form of lesinurad sodium by following the methods known in the art.
- the present application relates to process for preparing amorphous form of lesinurad comprising:
- Suitable solvents of step a) for dissolving lesinurad include, but are not limited to ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone; alcohols such as methanol, ethanol, propanol, isopropanol; halogenated hydrocarbons such as chloroform, dichloromethane; and mixtures thereof.
- Suitable techniques that may be used for the removal of solvent in step c) include but are not limited to rotational distillation using a device such as Buchi Rotavapor, spray drying, agitated thin film drying (“ATFD”), freeze drying (lyophilization) and the like, optionally under reduced pressure.
- a device such as Buchi Rotavapor, spray drying, agitated thin film drying (“ATFD”), freeze drying (lyophilization) and the like, optionally under reduced pressure.
- the isolation and purification can be effected, if desired, by any suitable separation or purification procedure such as, for example, filtration, centrifugation, extraction, acid-base treatment, conventional isolation and refining means such as concentration, concentration under reduced pressure, solvent-extraction, crystallization, phase-transfer chromatography, column chromatography, or by a combination of these procedures.
- the resulting solid may be collected by using techniques such as by scraping, or by shaking the container or other techniques specific to the equipment used.
- the isolated solid may be optionally further dried to afford amorphous form of lesinurad.
- the steps of the above embodiment may be performed at a temperature of about 0°C to about the boiling point of the solvent. Specifically, lesinurad may be dissolved in a suitable solvent at a temperature of about 0°C to about 1 10°C.
- the present application relates to amorphous solid dispersion of lesinurad together with at least one pharmaceutically acceptable excipient.
- the pharmaceutically acceptable excipient may include but not limited to methyl cellulose, ethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl cellulose, polysaccharides, heteropolysaccharides (pectins), poloxamers, poloxamines, ethylene vinyl acetates, polyethylene glycols, dextrans, polyvinylalcohols, propylene glycols, polyvinylacetates, phosphatidylcholines (lecithins), miglyols, polylactic acid, polyhydroxybutyric acid, polyvinylpyrrolidones (PVP), copovidone, methacrylic acid, silicon dioxide, mixtures of two or more thereof, copolymers thereof and derivatives thereof.
- PVP polyvinylpyrrolidones
- the present application relates to amorphous solid dispersion of Lesinurad with polyvinylpyrrolidones (PVP). More specifically, the present application relates to amorphous solid dispersion of lesinurad with PVP K-30 or HPMC.
- PVP polyvinylpyrrolidones
- the weight/weight ratio of lesinurad and pharmaceutically acceptable excipient in amorphous solid dispersion may be about 5:95, or about 10:90, or about 15:85, or about 20:80, or about 25:75, or about 30:70, or about 35:65, or about 40:60, or about 45:55, or about 50:50 and vice versa.
- the present application relates to amorphous solid dispersion of lesinurad together with HPMC which may be characterized by X-ray diffractogram as shown in figure-3.
- the present application relates to amorphous solid dispersion of lesinurad together with PVP K-30.
- the present application relates to process for preparing amorphous solid dispersion of lesinurad comprising:
- Suitable solvents of step a) for dissolving lesinurad include, but are not limited to water, dimethylformamide; dimethylacetamide; dimethyl sulphoxide; nitriles such as acetonitrile, propionitrile and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone; alcohols such as methanol, ethanol, propanol, isopropanol; halogenated hydrocarbons such as chloroform, dichloromethane; ethers such as tetrahydrofuran, dioxane; esters such as ethyl acetate, isopropyl acetate; and mixtures thereof.
- the pharmaceutically acceptable excipient of step a) may include but not limited to methyl cellulose, ethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl cellulose, polysaccharides, heteropolysaccharides (pectins), poloxamers, poloxamines, ethylene vinyl acetates, polyethylene glycols, dextrans, polyvinylalcohols, propylene glycols, polyvinylacetates, phosphatidylcholines (lecithins), miglyols, polylactic acid, polyhydroxybutyric acid, polyvinylpyrrolidones (PVP), copovidone, methacrylic acid, silicon dioxide, mixtures of two or more thereof, copolymers thereof and derivatives thereof.
- PVP polyvinylpyrrolidones
- the present application relates to amorphous solid dispersion of Lesinurad with polyvinylpyrrolidones (PVP). More specifically, the present application relates to amorphous solid dispersion of lesinurad with PVP K-30 or HPMC.
- PVP polyvinylpyrrolidones
- silicon dioxide may be added to the amorphous solid dispersion of lesinurad, prepared by the process of this application, in order to increase the stability and to reduce the hygroscopicity of the amorphous solid dispersion.
- Suitable techniques that may be used for the removal of solvent in step c) include but are not limited to rotational distillation using a device such as Buchi Rotavapor, spray drying, agitated thin film drying (“ATFD”), freeze drying (lyophilization) and the like, optionally under reduced pressure.
- a device such as Buchi Rotavapor, spray drying, agitated thin film drying (“ATFD”), freeze drying (lyophilization) and the like, optionally under reduced pressure.
- step (d) may be same as used in step (a) or mixtures thereof
- the blending may be carried out by known processes in the literature.
- the processes which include but are not limited to physical blending, blending in rotatory equipment such as rotatory cone vacuum drier, mortar-pestle or similar suitable methods or combinations of any of these methods.
- the isolation and purification can be effected, if desired, by any suitable separation or purification procedure such as, for example, filtration, centrifugation, extraction, acid-base treatment, conventional isolation and refining means such as concentration, concentration under reduced pressure, solvent-extraction, crystallization, phase-transfer chromatography, column chromatography, or by a combination of these procedures.
- suitable separation or purification procedure such as, for example, filtration, centrifugation, extraction, acid-base treatment, conventional isolation and refining means such as concentration, concentration under reduced pressure, solvent-extraction, crystallization, phase-transfer chromatography, column chromatography, or by a combination of these procedures.
- the resulting solid may be collected by using techniques such as by scraping, or by shaking the container or other techniques specific to the equipment used.
- the isolated solid may be optionally further dried to afford amorphous form of lesinurad.
- the steps of the above embodiment may be performed at a temperature of about 0°C to about the boiling point of the solvent. Specifically, lesinurad may be dissolved in a suitable solvent at a temperature of about 0°C to about 1 10°C.
- the present application relates to process for preparing amorphous solid dispersion of lesinurad comprising blending of lesinurad with one or more pharmaceutically acceptable excipients.
- the blending may be carried out by known processes in the literature.
- the processes which include but are not limited to physical blending, blending in rotatory equipment such as rotatory cone vacuum drier, mortar-pestle or similar suitable methods or combinations of any of these methods.
- Any crystalline form or amorphous form of lesinurad or mixture thereof may be used as starting material for preparing amorphous form of lesinurad or amorphous solid dispersion of lesinurad.
- Drying in all the embodiments discussed above of the present invention may be suitably carried out by using any of an air tray dryer, vacuum tray dryer, fluidized bed dryer, spin flash dryer, flash dryer, and the like.
- the drying may be carried out at atmospheric pressure or above, or under reduced pressures, specifically at temperatures less than about 80 °C and more specifically less than about 60 °C.
- the drying may be carried out for any time period required for obtaining a desired product quality, such as from about 30 minutes to about 24 hours, or longer.
- the dried product in all the embodiments discussed above may optionally be subjected to a particle size reduction procedure to produce desired particle sizes and distributions. Milling or micronization may be performed before drying, or after the completion of drying of the product.
- Equipment that may be used for particle size reduction includes but not limited to ball mill, roller mill, hammer mill, and jet mill.
- the amorphous solid dispersion of lesinurad of the present invention is substantially free of any crystalline form of lesinurad.
- Amorphous solid dispersion of lesinurad of the present invention does not contain more than about 10 % of any crystalline form of lesinurad.
- amorphous solid dispersion of lesinurad does not contain more than about 5 % of any crystalline form of lesinurad.
- amorphous solid dispersion of lesinurad does not contain more than about 1 % of any crystalline form of lesinurad.
- the solid dispersion of amorphous form of lesinurad is stable and has excellent physico-chemical properties.
- the solid dispersion of amorphous form of lesinurad of the present application may be easily formulated into a pharmaceutical composition along with suitable pharmaceutically acceptable excipients.
- the present application provides pharmaceutical formulations comprising amorphous form of lesinurad, together with one or more pharmaceutically acceptable excipients, carrier and diluents.
- the present application provides pharmaceutical composition comprising amorphous solid dispersion of lesinurad with a pharmaceutically acceptable excipient, together with one or more pharmaceutically acceptable excipients.
- Amorphous lesinurad or solid dispersion of amorphous lesinurad together with one or more pharmaceutically acceptable excipients, carrier and diluents of the present application may be formulated as: solid oral dosage forms such as, but not limited to, powders, granules, pellets, tablets, and capsules; liquid oral dosage forms such as, but not limited to, syrups, suspensions, dispersions, and emulsions; and injectable preparations such as, but not limited to, solutions, dispersions, and freeze dried compositions.
- Formulations may be in the forms of immediate release, delayed release, or modified release.
- immediate release compositions may be conventional, dispersible, chewable, mouth dissolving, or flash melt preparations; and modified release compositions that may comprise hydrophilic or hydrophobic, or combinations of hydrophilic and hydrophobic release rate controlling substances to form matrix or reservoir or combination of matrix and reservoir systems.
- the compositions may be prepared using any one or more of techniques such as direct blending, dry granulation, wet granulation, extrusion and spheronization.
- Compositions may be presented as uncoated, film coated, sugar coated, powder coated, enteric coated, and modified release coated.
- the PXRD data reported herein are obtained using a PANalytical X-ray Diffractometer, with copper Ka radiation.
- Syloid 250 mg was blended with Lesinurad (250 mg) at 30°C using a mortar pestle to afford the title compound.
- Example 8 Preparation of amorphous solid dispersion of lesinurad
Abstract
La présente invention concerne une forme amorphe de lesinurad, une dispersion solide amorphe de lesinurad et leurs procédés de préparation. La présente invention concerne également une composition pharmaceutique comprenant une dispersion amorphe ou solide amorphe de lesinurad et un ou plusieurs excipients ou supports pharmaceutiquement acceptables.
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP3315494A1 (fr) * | 2017-04-19 | 2018-05-02 | Química Sintética, S.A. | Forme amorphe de lésinurad et ses procédés de préparation |
EP3498697A1 (fr) | 2017-12-12 | 2019-06-19 | Química Sintética, S.A. | Nouveaux sels et polymorphes de lesinurad |
CN111153862A (zh) * | 2020-01-19 | 2020-05-15 | 北京鑫开元医药科技有限公司海南分公司 | 一种雷西纳德的精制方法 |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20090197825A1 (en) * | 2007-11-27 | 2009-08-06 | Ardea Biosciences, Inc. | Novel compounds and compositions and methods of use |
WO2011159732A1 (fr) * | 2010-06-15 | 2011-12-22 | Ardea Biosciences,Inc. | Traitement de la goutte et de l'hyperuricémie |
US20120172405A1 (en) * | 2010-12-30 | 2012-07-05 | Ardea Biosciences Inc. | Polymorphic forms of 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4h-1,2,4-triazol-3-ylthio)acetic acid and uses thereof |
WO2015075561A2 (fr) * | 2013-11-22 | 2015-05-28 | Crystal Pharmatech Co., Ltd. | Formes cristallines de lésinurad et son sel de soude |
-
2016
- 2016-06-17 WO PCT/IB2016/053605 patent/WO2016203436A1/fr active Application Filing
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20090197825A1 (en) * | 2007-11-27 | 2009-08-06 | Ardea Biosciences, Inc. | Novel compounds and compositions and methods of use |
WO2011159732A1 (fr) * | 2010-06-15 | 2011-12-22 | Ardea Biosciences,Inc. | Traitement de la goutte et de l'hyperuricémie |
US20120172405A1 (en) * | 2010-12-30 | 2012-07-05 | Ardea Biosciences Inc. | Polymorphic forms of 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4h-1,2,4-triazol-3-ylthio)acetic acid and uses thereof |
WO2015075561A2 (fr) * | 2013-11-22 | 2015-05-28 | Crystal Pharmatech Co., Ltd. | Formes cristallines de lésinurad et son sel de soude |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP3315494A1 (fr) * | 2017-04-19 | 2018-05-02 | Química Sintética, S.A. | Forme amorphe de lésinurad et ses procédés de préparation |
EP3498697A1 (fr) | 2017-12-12 | 2019-06-19 | Química Sintética, S.A. | Nouveaux sels et polymorphes de lesinurad |
CN111153862A (zh) * | 2020-01-19 | 2020-05-15 | 北京鑫开元医药科技有限公司海南分公司 | 一种雷西纳德的精制方法 |
CN111153862B (zh) * | 2020-01-19 | 2021-07-06 | 北京鑫开元医药科技有限公司海南分公司 | 一种雷西纳德的精制方法 |
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