WO2024062344A1 - Solid state forms of mesdopetam and salts therof - Google Patents
Solid state forms of mesdopetam and salts therof Download PDFInfo
- Publication number
- WO2024062344A1 WO2024062344A1 PCT/IB2023/059085 IB2023059085W WO2024062344A1 WO 2024062344 A1 WO2024062344 A1 WO 2024062344A1 IB 2023059085 W IB2023059085 W IB 2023059085W WO 2024062344 A1 WO2024062344 A1 WO 2024062344A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- mesdopetam
- theta
- degrees
- crystalline
- ray powder
- Prior art date
Links
- OSBPYFBXSLJHCR-UHFFFAOYSA-N n-[2-(3-fluoro-5-methylsulfonylphenoxy)ethyl]propan-1-amine Chemical compound CCCNCCOC1=CC(F)=CC(S(C)(=O)=O)=C1 OSBPYFBXSLJHCR-UHFFFAOYSA-N 0.000 title claims abstract description 451
- 229940015186 mesdopetam Drugs 0.000 title claims abstract description 401
- 150000003839 salts Chemical class 0.000 title claims abstract description 50
- 239000007787 solid Substances 0.000 title abstract description 80
- 238000000034 method Methods 0.000 claims abstract description 120
- 230000008569 process Effects 0.000 claims abstract description 82
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 44
- 238000002360 preparation method Methods 0.000 claims abstract description 19
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 128
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 114
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 claims description 76
- 229940049920 malate Drugs 0.000 claims description 73
- 150000001875 compounds Chemical class 0.000 claims description 23
- 239000013078 crystal Substances 0.000 claims description 23
- 208000012661 Dyskinesia Diseases 0.000 claims description 21
- 208000018737 Parkinson disease Diseases 0.000 claims description 20
- 238000009472 formulation Methods 0.000 claims description 19
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 18
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 13
- WTDRDQBEARUVNC-LURJTMIESA-N L-DOPA Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-LURJTMIESA-N 0.000 claims description 12
- WTDRDQBEARUVNC-UHFFFAOYSA-N L-Dopa Natural products OC(=O)C(N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-UHFFFAOYSA-N 0.000 claims description 12
- 229960004502 levodopa Drugs 0.000 claims description 12
- 208000028017 Psychotic disease Diseases 0.000 claims description 10
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 8
- 229940092714 benzenesulfonic acid Drugs 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 7
- 239000002775 capsule Substances 0.000 claims description 6
- 239000003826 tablet Substances 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 4
- 239000001630 malic acid Substances 0.000 claims description 3
- 238000000746 purification Methods 0.000 claims description 2
- 239000007909 solid dosage form Substances 0.000 claims description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 79
- 239000000203 mixture Substances 0.000 description 78
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 69
- 239000002904 solvent Substances 0.000 description 67
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 54
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 51
- 235000002639 sodium chloride Nutrition 0.000 description 48
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 45
- 239000000243 solution Substances 0.000 description 44
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 28
- 238000003756 stirring Methods 0.000 description 26
- 238000002425 crystallisation Methods 0.000 description 21
- 239000000725 suspension Substances 0.000 description 21
- 238000001816 cooling Methods 0.000 description 18
- 230000008025 crystallization Effects 0.000 description 16
- 238000001914 filtration Methods 0.000 description 14
- 239000011541 reaction mixture Substances 0.000 description 14
- 239000002552 dosage form Substances 0.000 description 13
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- -1 Mesdopetam salts Chemical class 0.000 description 11
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 11
- 239000007788 liquid Substances 0.000 description 11
- 239000000463 material Substances 0.000 description 9
- 238000001556 precipitation Methods 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 8
- 239000008187 granular material Substances 0.000 description 8
- 238000010908 decantation Methods 0.000 description 7
- 238000004090 dissolution Methods 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 239000004480 active ingredient Substances 0.000 description 6
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 229940116298 l- malic acid Drugs 0.000 description 6
- 235000011090 malic acid Nutrition 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
- 239000012453 solvate Substances 0.000 description 6
- 229920002472 Starch Polymers 0.000 description 5
- 238000004458 analytical method Methods 0.000 description 5
- 238000007907 direct compression Methods 0.000 description 5
- 238000012545 processing Methods 0.000 description 5
- 239000008107 starch Substances 0.000 description 5
- 235000019698 starch Nutrition 0.000 description 5
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical class OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 4
- 108010010803 Gelatin Proteins 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 4
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 4
- 229920002125 Sokalan® Polymers 0.000 description 4
- 239000001913 cellulose Substances 0.000 description 4
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- 230000008020 evaporation Effects 0.000 description 4
- 229920000159 gelatin Polymers 0.000 description 4
- 239000008273 gelatin Substances 0.000 description 4
- 229940014259 gelatin Drugs 0.000 description 4
- 235000019322 gelatine Nutrition 0.000 description 4
- 235000011852 gelatine desserts Nutrition 0.000 description 4
- 238000000227 grinding Methods 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 229920000609 methyl cellulose Polymers 0.000 description 4
- 235000010981 methylcellulose Nutrition 0.000 description 4
- 239000001923 methylcellulose Substances 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 239000008247 solid mixture Substances 0.000 description 4
- 229940032147 starch Drugs 0.000 description 4
- 238000003860 storage Methods 0.000 description 4
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 3
- 241000220479 Acacia Species 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 3
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 3
- 229920002907 Guar gum Polymers 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 3
- 239000005913 Maltodextrin Substances 0.000 description 3
- 229920002774 Maltodextrin Polymers 0.000 description 3
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 3
- 229920000881 Modified starch Polymers 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 3
- 239000008186 active pharmaceutical agent Substances 0.000 description 3
- 235000010443 alginic acid Nutrition 0.000 description 3
- 229920000615 alginic acid Polymers 0.000 description 3
- 239000000783 alginic acid Substances 0.000 description 3
- 229960001126 alginic acid Drugs 0.000 description 3
- 150000004781 alginic acids Chemical class 0.000 description 3
- 150000001335 aliphatic alkanes Chemical class 0.000 description 3
- 239000012296 anti-solvent Substances 0.000 description 3
- 229960001631 carbomer Drugs 0.000 description 3
- 229940063834 carboxymethylcellulose sodium Drugs 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 238000007906 compression Methods 0.000 description 3
- 230000006835 compression Effects 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 235000010417 guar gum Nutrition 0.000 description 3
- 239000000665 guar gum Substances 0.000 description 3
- 229960002154 guar gum Drugs 0.000 description 3
- 239000000314 lubricant Substances 0.000 description 3
- 229940035034 maltodextrin Drugs 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 229960002900 methylcellulose Drugs 0.000 description 3
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 3
- 239000008108 microcrystalline cellulose Substances 0.000 description 3
- 229940016286 microcrystalline cellulose Drugs 0.000 description 3
- 239000012454 non-polar solvent Substances 0.000 description 3
- 239000000825 pharmaceutical preparation Substances 0.000 description 3
- 229940127557 pharmaceutical product Drugs 0.000 description 3
- 229920003124 powdered cellulose Polymers 0.000 description 3
- 235000019814 powdered cellulose Nutrition 0.000 description 3
- 235000010413 sodium alginate Nutrition 0.000 description 3
- 239000000661 sodium alginate Substances 0.000 description 3
- 229940005550 sodium alginate Drugs 0.000 description 3
- 239000000600 sorbitol Substances 0.000 description 3
- 235000010356 sorbitol Nutrition 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 239000000454 talc Substances 0.000 description 3
- 229910052623 talc Inorganic materials 0.000 description 3
- 229940033134 talc Drugs 0.000 description 3
- 235000012222 talc Nutrition 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- XPCTZQVDEJYUGT-UHFFFAOYSA-N 3-hydroxy-2-methyl-4-pyrone Chemical compound CC=1OC=CC(=O)C=1O XPCTZQVDEJYUGT-UHFFFAOYSA-N 0.000 description 2
- 241000416162 Astragalus gummifer Species 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- 229920001353 Dextrin Polymers 0.000 description 2
- 239000004375 Dextrin Substances 0.000 description 2
- 208000032131 Diabetic Neuropathies Diseases 0.000 description 2
- 239000004097 EU approved flavor enhancer Substances 0.000 description 2
- 239000001856 Ethyl cellulose Substances 0.000 description 2
- 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 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 2
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 206010036376 Postherpetic Neuralgia Diseases 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 229920001615 Tragacanth Polymers 0.000 description 2
- SNAAJJQQZSMGQD-UHFFFAOYSA-N aluminum magnesium Chemical compound [Mg].[Al] SNAAJJQQZSMGQD-UHFFFAOYSA-N 0.000 description 2
- SESFRYSPDFLNCH-UHFFFAOYSA-N benzyl benzoate Chemical compound C=1C=CC=CC=1C(=O)OCC1=CC=CC=C1 SESFRYSPDFLNCH-UHFFFAOYSA-N 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- 229920003123 carboxymethyl cellulose sodium Polymers 0.000 description 2
- 229940084030 carboxymethylcellulose calcium Drugs 0.000 description 2
- 239000004359 castor oil Substances 0.000 description 2
- 235000019438 castor oil Nutrition 0.000 description 2
- 229940082500 cetostearyl alcohol Drugs 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 235000015165 citric acid Nutrition 0.000 description 2
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 2
- 239000003086 colorant Substances 0.000 description 2
- 239000010949 copper Substances 0.000 description 2
- 235000019425 dextrin Nutrition 0.000 description 2
- RBLGLDWTCZMLRW-UHFFFAOYSA-K dicalcium;phosphate;dihydrate Chemical compound O.O.[Ca+2].[Ca+2].[O-]P([O-])([O-])=O RBLGLDWTCZMLRW-UHFFFAOYSA-K 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 239000007884 disintegrant Substances 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 2
- 235000019325 ethyl cellulose Nutrition 0.000 description 2
- 229920001249 ethyl cellulose Polymers 0.000 description 2
- CBOQJANXLMLOSS-UHFFFAOYSA-N ethyl vanillin Chemical group CCOC1=CC(C=O)=CC=C1O CBOQJANXLMLOSS-UHFFFAOYSA-N 0.000 description 2
- 238000011049 filling Methods 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 235000013355 food flavoring agent Nutrition 0.000 description 2
- 235000019264 food flavour enhancer Nutrition 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 2
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000008172 hydrogenated vegetable oil Substances 0.000 description 2
- 229940071826 hydroxyethyl cellulose Drugs 0.000 description 2
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 2
- 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 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 229940099690 malic acid Drugs 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 239000004570 mortar (masonry) Substances 0.000 description 2
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- 229920000191 poly(N-vinyl pyrrolidone) Polymers 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 229920000193 polymethacrylate Polymers 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 229940069328 povidone Drugs 0.000 description 2
- 230000005855 radiation Effects 0.000 description 2
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 2
- 239000004299 sodium benzoate Substances 0.000 description 2
- 235000010234 sodium benzoate Nutrition 0.000 description 2
- 229920003109 sodium starch glycolate Polymers 0.000 description 2
- 239000008109 sodium starch glycolate Substances 0.000 description 2
- 229940079832 sodium starch glycolate Drugs 0.000 description 2
- OULAJFUGPPVRBK-UHFFFAOYSA-N tetratriacontyl alcohol Natural products CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCO OULAJFUGPPVRBK-UHFFFAOYSA-N 0.000 description 2
- 235000010487 tragacanth Nutrition 0.000 description 2
- 239000000196 tragacanth Substances 0.000 description 2
- 229940116362 tragacanth Drugs 0.000 description 2
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 2
- 235000019731 tricalcium phosphate Nutrition 0.000 description 2
- 238000005550 wet granulation Methods 0.000 description 2
- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 description 1
- 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 description 1
- AEQDJSLRWYMAQI-UHFFFAOYSA-N 2,3,9,10-tetramethoxy-6,8,13,13a-tetrahydro-5H-isoquinolino[2,1-b]isoquinoline Chemical compound C1CN2CC(C(=C(OC)C=C3)OC)=C3CC2C2=C1C=C(OC)C(OC)=C2 AEQDJSLRWYMAQI-UHFFFAOYSA-N 0.000 description 1
- CYDQOEWLBCCFJZ-UHFFFAOYSA-N 4-(4-fluorophenyl)oxane-4-carboxylic acid Chemical compound C=1C=C(F)C=CC=1C1(C(=O)O)CCOCC1 CYDQOEWLBCCFJZ-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- 108010011485 Aspartame Proteins 0.000 description 1
- 239000004255 Butylated hydroxyanisole Substances 0.000 description 1
- 108010076119 Caseins Proteins 0.000 description 1
- PTHCMJGKKRQCBF-UHFFFAOYSA-N Cellulose, microcrystalline Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC)C(CO)O1 PTHCMJGKKRQCBF-UHFFFAOYSA-N 0.000 description 1
- 241000206576 Chondrus Species 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 102000002322 Egg Proteins Human genes 0.000 description 1
- 108010000912 Egg Proteins Proteins 0.000 description 1
- YIKYNHJUKRTCJL-UHFFFAOYSA-N Ethyl maltol Chemical compound CCC=1OC=CC(=O)C=1O YIKYNHJUKRTCJL-UHFFFAOYSA-N 0.000 description 1
- 229920003134 Eudragit® polymer Polymers 0.000 description 1
- 229930091371 Fructose Natural products 0.000 description 1
- 239000005715 Fructose Substances 0.000 description 1
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- HYMLWHLQFGRFIY-UHFFFAOYSA-N Maltol Natural products CC1OC=CC(=O)C1=O HYMLWHLQFGRFIY-UHFFFAOYSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 229920003091 Methocel™ Polymers 0.000 description 1
- 241000238367 Mya arenaria Species 0.000 description 1
- 229920003072 Plasdone™ povidone Polymers 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- HDSBZMRLPLPFLQ-UHFFFAOYSA-N Propylene glycol alginate Chemical compound OC1C(O)C(OC)OC(C(O)=O)C1OC1C(O)C(O)C(C)C(C(=O)OCC(C)O)O1 HDSBZMRLPLPFLQ-UHFFFAOYSA-N 0.000 description 1
- WINXNKPZLFISPD-UHFFFAOYSA-M Saccharin sodium Chemical compound [Na+].C1=CC=C2C(=O)[N-]S(=O)(=O)C2=C1 WINXNKPZLFISPD-UHFFFAOYSA-M 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 239000012615 aggregate Substances 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000000605 aspartame Substances 0.000 description 1
- 235000010357 aspartame Nutrition 0.000 description 1
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 description 1
- 229960003438 aspartame Drugs 0.000 description 1
- 230000006399 behavior Effects 0.000 description 1
- 239000000440 bentonite Substances 0.000 description 1
- 229910000278 bentonite Inorganic materials 0.000 description 1
- 229940092782 bentonite Drugs 0.000 description 1
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 229960002903 benzyl benzoate Drugs 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 235000019282 butylated hydroxyanisole Nutrition 0.000 description 1
- 229940043253 butylated hydroxyanisole Drugs 0.000 description 1
- CZBZUDVBLSSABA-UHFFFAOYSA-N butylated hydroxyanisole Chemical compound COC1=CC=C(O)C(C(C)(C)C)=C1.COC1=CC=C(O)C=C1C(C)(C)C CZBZUDVBLSSABA-UHFFFAOYSA-N 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- XAAHAAMILDNBPS-UHFFFAOYSA-L calcium hydrogenphosphate dihydrate Chemical compound O.O.[Ca+2].OP([O-])([O-])=O XAAHAAMILDNBPS-UHFFFAOYSA-L 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 229940078456 calcium stearate Drugs 0.000 description 1
- 239000005018 casein Substances 0.000 description 1
- BECPQYXYKAMYBN-UHFFFAOYSA-N casein, tech. Chemical compound NCCCCC(C(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(CC(C)C)N=C(O)C(CCC(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(C(C)O)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(COP(O)(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(N)CC1=CC=CC=C1 BECPQYXYKAMYBN-UHFFFAOYSA-N 0.000 description 1
- 235000021240 caseins Nutrition 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 229960000541 cetyl alcohol Drugs 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 238000001311 chemical methods and process Methods 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 229960004106 citric acid Drugs 0.000 description 1
- 239000008119 colloidal silica Substances 0.000 description 1
- 238000005056 compaction Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 229960001681 croscarmellose sodium Drugs 0.000 description 1
- 229960000913 crospovidone Drugs 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 239000013058 crude material Substances 0.000 description 1
- 239000002178 crystalline material Substances 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 229940096516 dextrates Drugs 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 238000000113 differential scanning calorimetry Methods 0.000 description 1
- GXGAKHNRMVGRPK-UHFFFAOYSA-N dimagnesium;dioxido-bis[[oxido(oxo)silyl]oxy]silane Chemical compound [Mg+2].[Mg+2].[O-][Si](=O)O[Si]([O-])([O-])O[Si]([O-])=O GXGAKHNRMVGRPK-UHFFFAOYSA-N 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 238000007908 dry granulation Methods 0.000 description 1
- 235000013345 egg yolk Nutrition 0.000 description 1
- 210000002969 egg yolk Anatomy 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 description 1
- 229960004667 ethyl cellulose Drugs 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 229940093503 ethyl maltol Drugs 0.000 description 1
- 229940073505 ethyl vanillin Drugs 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 229960002737 fructose Drugs 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 229960002598 fumaric acid Drugs 0.000 description 1
- 239000003517 fume Substances 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- FETSQPAGYOVAQU-UHFFFAOYSA-N glyceryl palmitostearate Chemical compound OCC(O)CO.CCCCCCCCCCCCCCCC(O)=O.CCCCCCCCCCCCCCCCCC(O)=O FETSQPAGYOVAQU-UHFFFAOYSA-N 0.000 description 1
- 229940046813 glyceryl palmitostearate Drugs 0.000 description 1
- 229940071676 hydroxypropylcellulose Drugs 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 229960004903 invert sugar Drugs 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000006193 liquid solution Substances 0.000 description 1
- 239000006194 liquid suspension Substances 0.000 description 1
- 238000000786 liquid-assisted grinding Methods 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 235000014380 magnesium carbonate Nutrition 0.000 description 1
- 239000000395 magnesium oxide Substances 0.000 description 1
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 1
- 235000012245 magnesium oxide Nutrition 0.000 description 1
- 239000000391 magnesium silicate Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229940057948 magnesium stearate Drugs 0.000 description 1
- 229940099273 magnesium trisilicate Drugs 0.000 description 1
- 235000019793 magnesium trisilicate Nutrition 0.000 description 1
- 229910000386 magnesium trisilicate Inorganic materials 0.000 description 1
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 description 1
- 229940043353 maltol Drugs 0.000 description 1
- 229960001855 mannitol Drugs 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
- 229940041616 menthol Drugs 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 229960000292 pectin Drugs 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 229960000540 polacrilin potassium Drugs 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- WVWZXTJUCNEUAE-UHFFFAOYSA-M potassium;1,2-bis(ethenyl)benzene;2-methylprop-2-enoate Chemical compound [K+].CC(=C)C([O-])=O.C=CC1=CC=CC=C1C=C WVWZXTJUCNEUAE-UHFFFAOYSA-M 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 235000010409 propane-1,2-diol alginate Nutrition 0.000 description 1
- 239000000770 propane-1,2-diol alginate Substances 0.000 description 1
- RUOJZAUFBMNUDX-UHFFFAOYSA-N propylene carbonate Chemical compound CC1COC(=O)O1 RUOJZAUFBMNUDX-UHFFFAOYSA-N 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 239000011863 silicon-based powder Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 235000011083 sodium citrates Nutrition 0.000 description 1
- 239000000176 sodium gluconate Substances 0.000 description 1
- 235000012207 sodium gluconate Nutrition 0.000 description 1
- 229940005574 sodium gluconate Drugs 0.000 description 1
- 239000001540 sodium lactate Substances 0.000 description 1
- 235000011088 sodium lactate Nutrition 0.000 description 1
- 229940005581 sodium lactate Drugs 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 229940080313 sodium starch Drugs 0.000 description 1
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 1
- 239000012439 solid excipient Substances 0.000 description 1
- 238000000279 solid-state nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 229960004274 stearic acid Drugs 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 229960004793 sucrose Drugs 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- 238000002411 thermogravimetry Methods 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 description 1
- 229940057977 zinc stearate Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
- C07C317/16—Sulfones; Sulfoxides having sulfone or sulfoxide groups and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C317/22—Sulfones; Sulfoxides having sulfone or sulfoxide groups and singly-bound oxygen atoms bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Definitions
- the present disclosure encompasses Mesdopetam salts, solid state forms of Mesdopetam and salts thereof, in embodiments processes for preparation thereof and pharmaceutical compositions thereof.
- Mesdopetam is developed for the treatment of levodopa-induced dyskinesias commonly occurring in Parkinson's disease. Mesdopetam is also being investigated for the treatment or Parkinson’s disease psychosis.
- Different salts and solid state forms (including solvated forms) of an active pharmaceutical ingredient may possess different properties. Such variations in the properties of different salts and solid state forms and solvates may provide a basis for improving formulation, for example, by facilitating better processing or handling characteristics, changing the dissolution profile in a favorable direction, or improving stability (polymorph as well as chemical stability) and shelf-life. These variations in the properties of different salts and solid state forms may also offer improvements to the final dosage form, for instance, if they serve to improve bioavailability. Different salts and solid state forms and solvates of an active pharmaceutical ingredient may also give rise to a variety of polymorphs or crystalline forms, which may in turn provide additional opportunities to assess variations in the properties and characteristics of a solid active pharmaceutical ingredient.
- New solid state forms of a pharmaceutically useful compound can also provide an opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for formulation optimization, for example by providing a product with different properties, including a different crystal habit, higher crystallinity, or polymorphic stability, which may offer better processing or handling characteristics, improved dissolution profile, or improved shelf-life (chemical/physical stability). For at least these reasons, there is a need for additional solid state forms (including solvated forms) of Mesdopetam.
- the present disclosure provides Mesdopetam salts, or crystalline polymorphs of Mesdopetam and salts thereof, processes for preparation thereof and pharmaceutical composition thereof. Any one of the crystalline forms can be used to prepare other solid state forms of Mesdopetam and Mesdopetam salts and solid state forms thereof.
- the present disclosure also provides uses of said Mesdopetam salts, or solid state forms of Mesdopetam or salts thereof in the preparation of other solid state forms of Mesdopetam or salts thereof.
- the present disclosure provides said Mesdopetam salts, or crystalline forms of Mesdopetam and salts thereof for use in medicine, including for the treatment of patients with Parkinson's Disease Dyskinesia, levodopa-induced dyskinesias, or Parkinson’s disease Psychosis.
- the present disclosure also encompasses the use of said Mesdopetam salts, or crystalline polymorphs of Mesdopetam and salts thereof for the preparation of pharmaceutical compositions and/or formulations.
- the present disclosure provides pharmaceutical compositions comprising said Mesdopetam salts, or crystalline polymorphs of Mesdopetam or salts thereof according to the present disclosure.
- the present disclosure includes processes for preparing the above mentioned pharmaceutical compositions.
- the processes include combining any one or a combination of the Mesdopetam salts, or crystalline polymorphs of Mesdopetam or salts thereof with at least one pharmaceutically acceptable excipient.
- the crystalline polymorphs of Mesdopetam or salts thereof as defined herein and the pharmaceutical compositions or formulations of the Mesdopetam salts, or crystalline polymorphs of Mesdopetam or salts thereof may be used as medicaments, such as for the treatment of patients with Parkinson's Disease Dyskinesia, levodopa-induced dyskinesias, or Parkinson’s disease Psychosis.
- the present disclosure also provides methods for the treatment of patients with levodopa-induced dyskinesias by administering a therapeutically effective amount of said Mesdopetam salts, or crystalline polymorphs of Mesdopetam or salts thereof of the present disclosure, or at least one of the above pharmaceutical compositions, to a subject suffering from Parkinson's Disease Dyskinesia, levodopa-induced dyskinesia, or Parkinson’s disease Psychosis or otherwise in need of the treatment.
- the present disclosure also provides uses of said Mesdopetam salts, or crystalline polymorphs of Mesdopetam or salts thereof of the present disclosure, or at least one of the above pharmaceutical compositions, for the manufacture of medicaments for treating e.g., patients with Parkinson's Disease Dyskinesia, levodopa-induced dyskinesia, or Parkinson’s disease Psychosis.
- Parkinson's Disease Dyskinesia e.g., levodopa-induced dyskinesia, or Parkinson’s disease Psychosis.
- Figure 1 shows a characteristic X-ray powder diffraction pattern (XRPD) of Mesdopetam Form Bl.
- Figure 2 shows the X-ray powder diffraction pattern (XRPD) of Mesdopetam Form B3 prepared according to Example 2.
- Figure 3 shows the X-ray powder diffraction pattern (XRPD) of Mesdopetam Form B4 prepared according to Example 3.
- Figure 4 shows the X-ray powder diffraction pattern (XRPD) of Mesdopetam mesylate Form MSI prepared according to Example 4.
- Figure 5 shows the X-ray powder diffraction pattern (XRPD) of Mesdopetam mesylate Form MS2 prepared according to Example 5, procedure A.
- Figure 6 shows the X-ray powder diffraction pattern (XRPD) of Mesdopetam besylate Form BS1 prepared according to Example 6.
- Figure 7 shows the X-ray powder diffraction pattern (XRPD) of Mesdopetam (L)- malate Form Ml prepared according to Example 7.
- Figure 8 shows the X-ray powder diffraction pattern (XRPD) of Mesdopetam hemi- (A)-malate Form HM1 prepared according to Example 8.
- the present disclosure encompasses Mesdopetam salts, or crystalline forms of Mesdopetam and salts thereof, processes for preparation thereof, and pharmaceutical compositions thereof.
- Solid state properties of Mesdopetam or salts thereof and crystalline polymorphs thereof can be influenced by controlling the conditions under which Mesdopetam and crystalline polymorphs thereof are obtained in solid form.
- Solid state forms of Mesdopetam e.g. Mesdopetam, Mesdopetam salts
- Mesdopetam salts e.g. Mesdopetam, Mesdopetam salts
- a solid state form may be referred to herein as polymorphically pure or as substantially free of any other solid state (or polymorphic) forms.
- the expression “substantially free of any other forms” will be understood to mean that the solid state form contains about 20% (w/w) or less, about 10% (w/w) or less, about 5% (w/w) or less, about 2% (w/w) or less, about 1% (w/w) or less, or about 0% of any other forms of the subject compound as measured, for example, by XRPD.
- polymorphically pure Mesdopetam form Bl means that the solid state form is substantially free of other solid state forms of Mesdopetam.
- a crystalline polymorph of Mesdopetam or salts thereof described herein as substantially free of any other solid state forms would be understood to contain greater than about 80% (w/w), greater than about 90% (w/w), greater than about 95% (w/w), greater than about 98% (w/w), greater than about 99% (w/w), or about 100% of the subject crystalline polymorph of Mesdopetam or salts thereof.
- the described crystalline polymorph of Mesdopetam, salt or cocrystal may contain from about 1% to about 20% (w/w), from about 5% to about 20% (w/w), or from about 5% to about 10% (w/w) of one or more other crystalline polymorph of the same Mesdopetam.
- the crystalline polymorphs of Mesdopetam or salts thereof of the present disclosure may have advantageous properties selected from at least one of the following: chemical purity, flowability, solubility, dissolution rate, morphology or crystal habit, stability, such as chemical stability as well as thermal and mechanical stability with respect to polymorphic conversion, stability towards dehydration and/or storage stability, low content of residual solvent, a lower degree of hygroscopicity, flowability, and advantageous processing and handling characteristics such as compressibility and bulk density.
- a solid state form such as a crystal form or an amorphous form, may be referred to herein as being characterized by graphical data “as depicted in” or “as substantially depicted in” a Figure.
- Such data include, for example, powder X-ray diffractograms and solid state NMR spectra.
- the graphical data potentially provides additional technical information to further define the respective solid state form (a so-called “fingerprint”) which cannot necessarily be described by reference to numerical values or peak positions alone.
- a crystal form of Mesdopetam referred to herein as being characterized by graphical data “as depicted in” or “as substantially depicted in” a Figure will thus be understood to include any crystal forms of Mesdopetam characterized with the graphical data having such small variations, as are well known to the skilled person, in comparison with the Figure.
- anhydrous in relation to crystalline forms of Mesdopetam relates to a crystalline form of Mesdopetam which does not include any crystalline water (or other solvents) in a defined, stoichiometric amount within the crystal. Moreover, an “anhydrous” form would generally not contain more than 1% (w/w), of either water or organic solvents as measured for example by TGA.
- solvate refers to a crystal form that incorporates a solvent in the crystal structure.
- the solvent is water, the solvate is often referred to as a "hydrate.”
- the solvent in a solvate may be present in either a stoichiometric or in a non-stoichiometric amount.
- the term "isolated" in reference to crystalline polymorph of Mesdopetam of the present disclosure corresponds to a crystalline polymorph of Mesdopetam that is physically separated from the reaction mixture in which it is formed.
- the XRPD measurements are taken using copper K a radiation wavelength 1.54184 A.
- a thing e.g., a reaction mixture
- room temperature or “ambient temperature,” often abbreviated as “RT.” This means that the temperature of the thing is close to, or the same as, that of the space, e.g., the room or fume hood, in which the thing is located.
- room temperature is from about 20°C to about 30°C, or about 22°C to about 27°C, or about 25°C.
- the amount of solvent employed in a chemical process may be referred to herein as a number of “volumes” or “vol” or “V.”
- a material may be referred to as being suspended in 10 volumes (or 10 vol or 10V) of a solvent.
- this expression would be understood to mean milliliters of the solvent per gram of the material being suspended, such that suspending a 5 grams of a material in 10 volumes of a solvent means that the solvent is used in an amount of 10 milliliters of the solvent per gram of the material that is being suspended or, in this example, 50 mb of the solvent.
- v/v may be used to indicate the number of volumes of a solvent that are added to a liquid mixture based on the volume of that mixture. For example, adding solvent X (1.5 v/v) to a 100 ml reaction mixture would indicate that 150 mL of solvent X was added.
- a process or step may be referred to herein as being carried out “overnight.” This refers to a time interval, e.g., for the process or step, that spans the time during the night, when that process or step may not be actively observed. This time interval is from about 8 to about 20 hours, or about 10-18 hours, in some cases about 16 hours.
- reduced pressure refers to a pressure that is less than atmospheric pressure.
- reduced pressure is about 10 mbar to about 50 mbar.
- ambient conditions refer to atmospheric pressure and a temperature of 22-24°C.
- the Mesdopetam salts, or solid state form of Mesdopetam e.g. Mesdopetam, Mesdopetam salts
- Mesdopetam salts as described in any aspect or embodiment of the present disclosure may be chemically pure, or substantially free of any other compounds.
- a compound may be referred to herein as chemically pure or purified compound or as substantially free of any other compounds.
- chemically pure or purified or “substantially free of any other compounds” refer to a compound that is substantially free of any impurities including enantiomers of the subject compound, diastereomers or other isomers.
- a chemically pure or purified compound or a compound that is substantially free of any other compound will be understood to mean that it contains about 10% (w/w) or less, about 5% (w/w) or less, about 4% (w/w) or less, about 3% (w/w) or less, about 2% (w/w) or less, about 1.5% (w/w) or less, about 1% (w/w) or less, about 0.8% (w/w) or less, about 0.6% (w/w) or less, about 0.4% (w/w) or less, about 0.2% (w/w) or less, about 0.1% (w/w) or less, or about 0% of any other compound as measured, for example, by HPLC.
- a chemically pure or purified compound or a compound that is substantially free of any other compound will be understood to mean that it contains about 10% area percent or less, about 5% area percent or less, about 4% area percent or less, about 3% area percent or less, about 2% area percent or less, about 1.5% area percent or less, about 1% area percent or less, about 0.8% area percent or less, about 0.6% area percent or less, about 0.4% area percent or less, about 0.2% area percent or less, about 0.1% area percent or less, or about 0% of any other compound as measured by HPLC.
- pure or purified Mesdopetam or salts thereof described herein as substantially free of any compounds would be understood to contain greater than about 90% (w/w), greater than about 95% (w/w), greater than about 96% (w/w), greater than about 97% (w/w), greater than about 98% (w/w), greater than about 98.5% (w/w), greater than about 99% (w/w), greater than about 99.2% (w/w), greater than about 99.4% (w/w), greater than about 99.6% (w/w), greater than about 99.8% (w/w), greater than about 99.9% (w/w), or about 100% of the subject Mesdopetam or salts thereof.
- pure or purified Mesdopetam or salts thereof, described herein as substantially free of any compounds would be understood to contain greater than about 90% area percent, greater than about 95% area percent, greater than about 96% area percent, greater than about 97% area percent, greater than about 98% area percent, greater than about 98.5% area percent, greater than about 99% area percent, greater than about 99.2% area percent, greater than about 99.4% area percent, greater than about 99.6% area percent, greater than about 99.8% area percent, greater than about 99.9% area percent, or about 100% of the subject Mesdopetam or salts thereof.
- the present disclosure includes a crystalline polymorph Mesdopetam designated Form Bl.
- the crystalline Form Bl of Mesdopetam may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 1; an X-ray powder diffraction pattern having peaks at 5.5, 11.1, 16.6 and 22.2 degrees 2- theta ⁇ 0.2 degrees 2-theta; and combinations of these data.
- Crystalline Form Bl of Mesdopetam may be further characterized by an X-ray powder diffraction pattern having peaks at 5.5, 11.1, 16.6 and 22.2 degrees 2-theta ⁇ 0.2 degrees 2-theta, and also having any one, two, three, four or five additional peaks selected from 12.8, 14.7, 19.3 and 27.8 degrees 2-theta ⁇ 0.2 degrees 2-theta.
- Crystalline Form Bl of Mesdopetam may be alternatively characterized by an X-ray powder diffraction pattern having peaks at 5.5, 11.1, 12.8, 14.7, 16.6, 19.3, 22.2 and 27.8 degrees 2-theta ⁇ 0.2 degrees 2-theta.
- crystalline Form Bl of Mesdopetam may be isolated.
- crystalline Form Bl of Mesdopetam according to any aspect or embodiment of the disclosure may be isolated.
- crystalline form Bl may be chemically pure.
- crystalline Form Bl of Mesdopetam may be polymorphically pure.
- crystalline Form Bl of Mesdopetam may be anhydrous.
- Crystalline Form Bl of Mesdopetam may be characterized by each of the above characteristics alone/or by all possible combinations, e.g., an XRPD pattern having peaks at 5.5, 11.1, 16.6 and 22.2 degrees 2-theta ⁇ 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 1, and combinations thereof.
- the present disclosure includes a crystalline polymorph Mesdopetam designated Form B3.
- the crystalline Form B3 of Mesdopetam may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 2; an X-ray powder diffraction pattern having peaks at 12.0, 13.5, 14.2 and 18.4 degrees 2-theta ⁇ 0.2 degrees 2-theta; and combinations of these data.
- Crystalline Form B3 of Mesdopetam may be further characterized by an X-ray powder diffraction pattern having peaks at 12.0, 13.5, 14.2 and 18.4 degrees 2-theta ⁇ 0.2 degrees 2-theta, and also having any one, two, three or four additional peaks selected from 17.4, 23.3, 25.3 and 27.1 degrees 2-theta ⁇ 0.2 degrees 2-theta.
- Crystalline Form B3 of Mesdopetam may be alternatively characterized by an X-ray powder diffraction pattern having peaks at 12.0, 13.5, 14.2, 17.4, 18.4, 23.3, 25.3 and 27.1 degrees 2-theta ⁇ 0.2 degrees 2-theta.
- crystalline Form B3 of Mesdopetam may be isolated.
- crystalline Form B3 of Mesdopetam according to any aspect or embodiment of the disclosure may be isolated.
- crystalline form B3 may be chemically pure.
- crystalline Form B3 of Mesdopetam may be polymorphically pure.
- Crystalline Form B3 of Mesdopetam may be characterized by each of the above characteristics alone/or by all possible combinations, e.g., an XRPD pattern having peaks at 12.0, 13.5, 14.2 and 18.4 degrees 2-theta ⁇ 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 2, and combinations thereof.
- the present disclosure includes a crystalline polymorph Mesdopetam designated Form B4.
- the crystalline Form B4 of Mesdopetam may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 3; an X-ray powder diffraction pattern having peaks at 9.9, 16.4, 21.8, 23.4 and 26.0 degrees 2-theta ⁇ 0.2 degrees 2-theta; and combinations of these data.
- Crystalline Form B4 of Mesdopetam may be further characterized by an X-ray powder diffraction pattern having peaks at 9.9, 16.4, 21.8, 23.4 and 26.0 degrees 2-theta ⁇ 0.2 degrees 2-theta, and also having any one, two, three or four additional peaks selected from 7.1, 14.3, 17.9, 19.9 and 22.5 degrees 2-theta ⁇ 0.2 degrees 2-theta.
- Crystalline Form B4 of Mesdopetam may be alternatively characterized by an X-ray powder diffraction pattern having peaks at 7.1, 9.9, 14.3, 16.4, 17.9, 19.9, 21.8, 22.5, 23.4 and 26.0 degrees 2-theta ⁇ 0.2 degrees 2-theta.
- crystalline Form B4 of Mesdopetam may be isolated.
- crystalline Form B4 of Mesdopetam according to any aspect or embodiment of the disclosure may be isolated.
- crystalline form B4 may be chemically pure.
- crystalline Form B4 of Mesdopetam may be polymorphically pure.
- Crystalline Form B4 of Mesdopetam may be characterized by each of the above characteristics alone/or by all possible combinations, e.g., an XRPD pattern having peaks at 9.9, 16.4, 21.8, 23.4 and 26.0 degrees 2-theta ⁇ 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 3, and combinations thereof.
- the present disclosure encompasses Mesdopetam mesylate.
- the Mesdopetam mesylate is preferably in a solid form, and more preferably the Mesdopetam mesylate is crystalline.
- Mesdopetam mesylate may be isolated.
- Mesdopetam mesylate according to any aspect or embodiment may be chemically pure.
- Crystalline Mesdopetam mesylate according to any aspect or embodiment may be polymorphically pure (i.e.
- Mesdopetam mesylate containing a single crystalline form of Mesdopetam mesylate), preferably containing about 20% (w/w) or less, about 10% (w/w) or less, about 5% (w/w) or less, about 2% (w/w) or less, about 1% (w/w) or less, or about 0% of any other crystalline form of Mesdopetam mesylate, as measured, for example, by XRPD.
- Mesdopetam mesylate may be anhydrous.
- the present disclosure includes a crystalline polymorph Mesdopetam mesylate designated Form MSI.
- the crystalline Form MSI of Mesdopetam mesylate may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 4; an X-ray powder diffraction pattern having peaks at
- Crystalline Form MSI of Mesdopetam mesylate may be further characterized by an X-ray powder diffraction pattern having peaks at 8.7, 13.7, 16.8, 19.9 and 22.3 degrees 2-theta ⁇ 0.2 degrees 2-theta, and also having any one, two, three, four or five additional peaks selected from 12.6, 13.0, 15.9, 17.6 and 26.1 degrees 2-theta ⁇ 0.2 degrees 2-theta.
- Crystalline Form MSI of Mesdopetam mesylate may be alternatively characterized by an X-ray powder diffraction pattern having peaks at 8.7, 12.6, 13.0, 13.7, 15.9, 16.8, 17.6, 19.9, 22.3 and 26.1 degrees 2-theta ⁇ 0.2 degrees 2-theta.
- crystalline Form MSI of Mesdopetam mesylate may be isolated.
- crystalline Form MSI of Mesdopetam mesylate according to any aspect or embodiment of the disclosure may be isolated.
- crystalline form MSI of Mesdopetam mesylate may be chemically pure.
- crystalline Form MSI of Mesdopetam mesylate may be polymorphically pure.
- crystalline Form MSI of Mesdopetam mesylate may be anhydrous.
- Crystalline Form MSI of Mesdopetam mesylate may be characterized by each of the above characteristics alone/or by all possible combinations, e.g., an XRPD pattern having peaks at 8.7, 13.7, 16.8, 19.9 and 22.3 degrees 2-theta ⁇ 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 4, and combinations thereof.
- the present disclosure includes a crystalline polymorph Mesdopetam mesylate designated Form MS2.
- the crystalline Form MS2 of Mesdopetam mesylate may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 5; an X-ray powder diffraction pattern having peaks at
- Crystalline Form MS2 of Mesdopetam mesylate may be further characterized by an X-ray powder diffraction pattern having peaks at 7.8, 15.2, 19.6, 23.5 and 25.0 degrees 2-theta ⁇ 0.2 degrees 2-theta, and also having any one, two, three, four or five additional peaks selected from 15.7, 17.2, 18.2, 20.2 and 20.9 degrees 2-theta ⁇ 0.2 degrees 2-theta.
- Crystalline Form MS2 of Mesdopetam mesylate may be alternatively characterized by an X-ray powder diffraction pattern having peaks at 7.8, 15.2, 15.7, 17.2, 18.2, 19.6, 20.2, 23.5 and 25.0 degrees 2-theta ⁇ 0.2 degrees 2-theta.
- Crystalline Form MS2 of Mesdopetam mesylate may be alternatively characterized by an X-ray powder diffraction pattern having peaks at 7.8, 15.2, 15.7, 17.2, 18.2, 19.6, 20.2, 20.9, 23.5 and 25.0 degrees 2-theta ⁇ 0.2 degrees 2-theta.
- crystalline Form MS2 of Mesdopetam mesylate may be isolated.
- crystalline Form MS2 of Mesdopetam mesylate according to any aspect or embodiment of the disclosure may be isolated.
- crystalline form MS2 of Mesdopetam mesylate may be chemically pure.
- crystalline Form MS2 of Mesdopetam mesylate may be polymorphically pure.
- crystalline Form MS2 of Mesdopetam mesylate may be anhydrous.
- Crystalline Form MS2 of Mesdopetam mesylate may be characterized by each of the above characteristics alone/or by all possible combinations, e.g., an XRPD pattern having peaks at 7.8, 15.2, 19.6, 23.5 and 25.0 degrees 2-theta ⁇ 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 5, and combinations thereof.
- Mesdopetam Mesylate may be prepared by reacting Mesdopetam with methane sulfonic acid in any suitable solvent.
- the solvent is preferably selected at least enable dissolution of Mesdopetam and methanesulfonic acid, and optionally enables precipitation of the resulting Mesdopetam Mesylate (e.g. through cooling and/or evaporation). If the solvent does not readily enable precipitation of Mesdopetam Mesylate, an antisolvent for Mesdopetam Mesylate, for example a non-polar solvent such as an alkane, or a solvent selected from n-heptane, dichloromethane, acetone or tetrahydrofuran, may be added to facilitate precipitation.
- a non-polar solvent such as an alkane
- a solvent selected from n-heptane, dichloromethane, acetone or tetrahydrofuran may be added to facilitate precipitation.
- Crystalline form MS2 of Mesdopetam Mesylate may be prepared by crystallisation of Mesdopetam Mesylate from a solvent comprising isopropanol, acetonitrile, ethanol, methanol, or mixture thereof.
- the process may comprise:
- the solution in step (a) may be prepared by combining Mesdopetam mesylate with the solvent.
- the solution in step (a) may be at elevated temperature, preferably, at a temperature of about 35°C to about 75°C, about 40°C to about 70°C, or about 45°C to about 65°C.
- the solution in step (a) may be prepared by combining Mesdopetam mesylate with the heated solvent, or by combining Mesdopetam mesylate with the solvent at ambient temperature, and heating the mixture to provide a solution.
- step (b) may comprise: cooling the mixture (preferably to about 5°C to about 30°C, or about 10°C to about 25°C or about 20°C to about 25°C).
- the solution in step (a) is heated to a temperature of about 40°C to about 70°C (preferably about 45°C to about 65 °C)
- step (b) comprises cooling the mixture in step (a) to a temperature of: about 5°C to about 35°C, about 10°C to about 30°C, or room temperature.
- the cooling may be active or passive, preferably passive (i.e. the mixture is allowed to cool under ambient conditions).
- the cooling is preferably conducted without stirring.
- step (c) may comprise isolating the solid by any suitable method such as by decantation, centrifuge or by filtration, preferably by filtration.
- the Mesdopetam mesylate Form MS2 may optionally be dried, for example under reduced pressure, and optionally elevated temperature, preferably at reduced pressure and at a temperature of: about 40°C to about 90°C, about 55°C to about 85°C, or about 60°C to about 80°C.
- the process may comprise:
- step a) when the solvent is acetonitrile, step a) may be performed at a temperature of about 40°C to about 80°C, about 50°C to about 70°C or about 55°C to about 65°C; when the solvent is ethanol, step a) may be performed at a temperature of about 40°C to about 70°C, about 45°C to about 60°C or about 50°C to about 60°C; and when the solvent is methanol, step a) may be performed at a temperature of times be dried, for example under reduced pressure, and optionally elevated temperature, preferably at reduced pressure and at a temperature of: about 40°C to about 90°C, about 55°C to about 85°C, or about 60°C to about 80°C.
- Mesdopetam mesylate form MS2 may be prepared by a process comprising stirring a suspension of Mesdopetam mesylate in isopropanol.
- the suspension of Mesdopetam mesylate in isopropanol is prepared by combining Mesdopetam (preferably form Bl), methanesulfonic acid, and isopropanol. More particularly, the process comprises:
- step (iii) optionally isolating crystalline form MS2 of Mesdopetam Mesylate from the mixture.
- the isopropanol may be present in an amount of: about 5 to about 20 ml per gram of Mesdopetam, about 7 to about 15 ml per gram of Mesdopetam, or about 7 to about 12 ml per gram of Mesdopetam.
- the molar ratio of methanesulfonic acid to Mesdopetam may be: about 1 to about 1.5 molar equivalents, about 1 to about 1.3 molar equivalents, about 1.0 to about 1.2 molar equivalents, about 1.1 molar equivalents, or about 1.0 molar equivalents.
- the mixture in step (i) is preferably at room temperature.
- step (ii) comprises stirring the mixture for a sufficient time to prepare Mesdopetam mesylate form MS2, preferably about 8 hours to about 4 days, about 12 hours to about 72 hours, about 20 hours to about 60 hours, or about 24 hours to about 48 hours.
- step (iii) comprises isolating the Mesdopetam mesylate Form MS2 by any suitable method such as by decantation, centrifuge or filtration, preferably filtration.
- the Mesdopetam mesylate Form MS2 may optionally be dried, for example under reduced pressure, and optionally elevated temperature, preferably at reduced pressure and at a temperature of: about 40°C to about 90°C, about 55°C to about 85°C, or about 60°C to about 80°C; optionally, the drying can be conducted for a sufficient time to obtain a dried solid, preferably about 1 hour to about 10 hours, about 2 hours to about 8 hours, about 3 hours to about 6 hours, or about 4 hours to about 6 hours.
- Crystalline form MS2 of Mesdopetam Mesylate may alternatively be prepared by crystallisation of Mesdopetam Mesylate from water.
- the process may comprise:
- the solution in step (a) may be prepared by combining Mesdopetam (preferably form Bl), methanesulfonic acid, and water.
- the water in step (a), may be present in an amount of: about 5 to about 20 ml per gram of Mesdopetam, about 10 to about 18 ml per gram of Mesdopetam, about 12 to about 16 ml per gram of Mesdopetam or about 13 to about 14 ml per gram of Mesdopetam.
- the molar ratio of methanesulfonic acid to Mesdopetam may be: about 1 to about 1.5 molar equivalents, about 1 to about 1.3 molar equivalents, about 1.0 to about 1.2 molar equivalents, about 1.1 molar equivalents, or about 1.0 molar equivalents.
- the solution in step (a) is preferably at room temperature.
- step (b) comprises stirring the mixture, preferably about 1 to about 60 minutes, about 2 to about 30 minutes, about 2 to about 10 minutes, or about 5 minutes.
- step (c) comprises partial or complete evaporation of the water, preferably by exposure to room temperature.
- step (c) comprises allowing the water to evaporate over a period of about 1 to about 10 days, about 2 to about 8 days, about 3 to about 6 days, or about 4 days.
- the Mesdopetam mesylate may optionally be isolated by any suitable process if the water is partially evaporated, preferably by decantation, centrifuge or filtration, preferably filtration.
- the Mesdopetam mesylate Form MS2 may optionally be dried, for example under reduced pressure, and optionally elevated temperature, preferably at reduced pressure and at a temperature of: about 40°C to about 90°C, about 55°C to about 85°C, or about 60°C to about 80°C.
- the present disclosure encompasses Mesdopetam besylate.
- the Mesdopetam besylate is preferably in a solid form, and more preferably the Mesdopetam besylate is crystalline. In any aspect or embodiment of the present disclosure, Mesdopetam besylate may be isolated.
- Mesdopetam besylate may be chemically pure.
- Crystalline Mesdopetam besylate according to any aspect or embodiment may be polymorphically pure (i.e. containing a single crystalline form of Mesdopetam besylate), preferably containing about 20% (w/w) or less, about 10% (w/w) or less, about 5% (w/w) or less, about 2% (w/w) or less, about 1% (w/w) or less, or about 0% of any other crystalline form of Mesdopetam besylate, as measured, for example, by XRPD.
- Mesdopetam besylate may be anhydrous.
- the present disclosure includes a crystalline polymorph Mesdopetam besylate designated Form BS1.
- the crystalline Form BS1 of Mesdopetam besylate may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 6; an X-ray powder diffraction pattern having peaks at 8.0, 15.0, 16.1, 18.2 and 22.6 degrees 2-theta ⁇ 0.2 degrees 2-theta; and combinations of these data.
- Crystalline Form BS1 of Mesdopetam besylate may be further characterized by an X- ray powder diffraction pattern having peaks at 8.0, 15.0, 16.1, 18.2 and 22.6 degrees 2-theta ⁇ 0.2 degrees 2-theta, and also having any one, two, three or four additional peaks selected from 16.7, 17.7, 20.5 and 23.4 degrees 2-theta ⁇ 0.2 degrees 2-theta.
- Crystalline Form BS1 of Mesdopetam besylate may be alternatively characterized by an X-ray powder diffraction pattern having peaks at 8.0, 15.0, 16.1, 16.7, 17.7, 18.2, 20.5, 22.6 and 23.4 degrees 2-theta ⁇ 0.2 degrees 2-theta.
- crystalline Form BS1 of Mesdopetam besylate may be isolated.
- crystalline Form BS1 of Mesdopetam besylate according to any aspect or embodiment of the disclosure may be isolated.
- crystalline form BS1 of Mesdopetam besylate may be chemically pure.
- crystalline Form BS1 of Mesdopetam besylate may be polymorphically pure.
- crystalline Form BS1 of Mesdopetam besylate may be anhydrous.
- Crystalline Form BS1 of Mesdopetam besylate may be characterized by each of the above characteristics alone/or by all possible combinations, e.g., an XRPD pattern having peaks at 8.0, 15.0, 16.1, 18.2 and 22.6 degrees 2-theta ⁇ 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 6, and combinations thereof.
- Mesdopetam Besylate may be prepared by reacting Mesdopetam with benzenesulfonic acid in any suitable solvent.
- the solvent is preferably selected at least enable dissolution of Mesdopetam and benzenesulfonic acid, and optionally enables precipitation of the resulting Mesdopetam Besylate (e.g. by cooling or evaporation).
- an antisolvent for Mesdopetam Besylate for example a non-polar solvent such as an alkane, or a solvent selected from n-heptane, dichloromethane, acetone or tetrahydrofuran, may be added to facilitate precipitation.
- Crystalline form BS1 of Mesdopetam Besylate may be prepared by crystallisation from a mixture comprising Mesdopetam Besylate and a solvent comprising isopropanol, water, acetonitrile, ethanol, methanol, or mixture thereof.
- the process comprises:
- step (c) optionally isolating crystalline form BS1 of Mesdopetam Besylate from the mixture.
- the solution in step (a) may be prepared by combining Mesdopetam besylate with the solvent.
- the solvent may be isopropanol, water, acetonitrile, ethanol (optionally 96% ethanol/water or absolute ethanol), or methanol, or a mixture of acetonitrile and water.
- the solvent in step (a), may be present in an amount of: about 2 ml to about 40 ml per gram of Mesdopetam Besylate, about 4 ml to about 35 ml per gram of Mesdopetam Besylate, or about 5 to about 30 ml per gram of Mesdopetam Besylate.
- the solution in step (a) may be at elevated temperature, preferably, at a temperature of about 15°C to about 70°C, about 18°C to about 65°C, about 20°C to about 60°C, or about 22°C to about 58°C.
- the solution in step (a) may be prepared by combining Mesdopetam besylate with the heated solvent, or by combining Mesdopetam besylate with the solvent at ambient temperature, and optionally heating the mixture to provide a solution.
- step (b) may comprise: cooling the mixture, preferably to about 5°C to about 30°C, or about 10°C to about 25°C or about 20°C to about 25°C.
- step (b) comprises cooling the mixture in step (a) to a temperature of: about 5°C to about 35°C, about 10°C to about 30°C, or room temperature.
- the cooling may be active or passive, preferably passive (i.e. the mixture is allowed to cool under ambient conditions).
- the cooling is preferably conducted without stirring.
- step (c) may comprise isolating the solid by any suitable method such as by decantation, centrifuge or by filtration, preferably by filtration.
- the Mesdopetam Besylate Form BS1 may optionally be dried, for example under reduced pressure, and optionally elevated temperature, preferably at reduced pressure and at a temperature of: about 40°C to about 90°C, about 55°C to about 85°C, or about 60°C to about 80°C.
- the solution in step a) may be at a temperature of about 30°C to about 70°C, about 40°C to about 60°C, about 45°C to about 55°C, or about 45°C to about 50°C; and/or the acetonitrile is used in an amount of about 10 ml to about 30 ml, about 15 ml to 25 ml, or about 20 ml per gram of Mesdopetam Besylate.
- step a) when the solvent is ethanol, step a) may be performed at a temperature of about 40°C to about 70°C, about 45°C to about 60°C, about 50°C to about 60°C or about 55°C to about 60°; and/or the ethanol is used in an amount of about 15 ml to 25 ml, or about 20 ml per gram of Mesdopetam Besylate.
- step a) when the solvent is methanol, step a) may be performed at a temperature of about 18°C to about 35°C, about 18°C to about 30°C, about 20°C to about 25°C or at room temperature; and/or the methanol is used in an amount of about 5 ml to 20 ml, about 8 to about 15 ml, or about 10 ml per gram of Mesdopetam Besylate.
- step a) when the solvent is isopropanol, step a) may be performed at a temperature of about 30°C to about 70°C, about 40°C to about 60°C, about 45°C to about 55°C, or about 48°C to about 54°C; and/or the isopropanol is used in an amount of about 15 ml to 50 ml, about 20 ml to about 40 ml, about 25 ml to about 35 ml, or about 30 ml per gram of Mesdopetam Besylate.
- step a) when the solvent a mixture of acetonitrile and water, step a) may be performed at a temperature of about 18°C to about 35°C, about 18°C to about 30°C, about 20°C to about 25°C or at room temperature; and/or the combined amount of acetonitrile/water used is: about 2 ml to 15 ml, about 2 ml to about 10 ml, about 2 ml to about 8 ml, 4 ml to about 7 ml, or about 5 ml per gram of Mesdopetam Besylate.
- the ratio (vol/vol) of acetonitrile to water is: about 3: 1 to about 1:3; about 2: 1 to about 1:2, about 1.5: 1 to about 1: 1.5, about 1.2:1 to about 1 : 1.2, or about 1:1.
- Mesdopetam Besylate Form BS1 may be prepared by a process comprising stirring a suspension of Mesdopetam Besylate in isopropanol.
- the suspension of Mesdopetam Besylate in isopropanol is prepared by combining Mesdopetam (preferably form Bl), benzenesulfonic acid, and isopropanol. More particularly, the process comprises:
- the isopropanol may be present in an amount of: about 5 to about 25 ml per gram of Mesdopetam, about 8 to about 20 ml per gram of Mesdopetam, about 10 to about 15 ml per gram of Mesdopetam, or about 11 ml to about 17 ml per gram of Mesdopetam.
- the molar ratio of benzenesulfonic acid to Mesdopetam may be: about 1 to about 1.5 molar equivalents, about 1 to about 1.3 molar equivalents, about 1.0 to about 1.2 molar equivalents, about 1.0 to about 1.1 molar equivalents, or about 1.0 molar equivalents.
- the mixture in step (i) is preferably at room temperature.
- step (ii) comprises stirring the mixture for a sufficient time to prepare Mesdopetam besylate form BS1, preferably about 4 hours to about 72 hours, about 8 hours to about 48 hours, about 16 hours to about 36 hours, about 20 hours to about 30 hours, or about 24 hours.
- step (iii) comprises isolating the Mesdopetam besylate Form BS1 by any suitable method such as by decantation, centrifuge or filtration, preferably filtration.
- the Mesdopetam besylate Form BS1 may optionally be dried, for example under reduced pressure, and optionally elevated temperature, preferably at reduced pressure and at a temperature of: about 40°C to about 90°C, about 55°C to about 80°C, or about 60°C to about 75°C; optionally, the drying can be conducted for a sufficient time to obtain a dried solid, preferably about 1 hour to about 10 hours, about 2 hours to about 8 hours, about 3 hours to about 6 hours, or about 4 hours to about 6 hours.
- the present disclosure encompasses Mesdopetam (L)-malate.
- the Mesdopetam (L)- malate is preferably in a solid form, and more preferably the Mesdopetam (L)-malate is crystalline.
- Mesdopetam (L)-malate may be isolated.
- Mesdopetam (L)-malate according to any aspect or embodiment may be chemically pure.
- Crystalline Mesdopetam (L)-malate according to any aspect or embodiment may be polymorphically pure (i.e.
- Mesdopetam (L)-malate containing a single crystalline form of Mesdopetam (L)- malate), preferably containing about 20% (w/w) or less, about 10% (w/w) or less, about 5% (w/w) or less, about 2% (w/w) or less, about 1% (w/w) or less, or about 0% of any other crystalline form of Mesdopetam (L)-malate, as measured, for example, by XRPD.
- Mesdopetam (L)-malate may be anhydrous.
- the present disclosure includes a crystalline polymorph Mesdopetam (L)-malate designated Form Ml.
- the crystalline Form Ml of Mesdopetam (L)-malate may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 7; an X-ray powder diffraction pattern having peaks at 5.0, 14.9, 16.2, 22.8 and 24.9 degrees 2-theta ⁇ 0.2 degrees 2-theta; and combinations of these data.
- Crystalline Form Ml of Mesdopetam (L)-malate may be further characterized by an X-ray powder diffraction pattern having peaks at 5.0, 14.9, 16.2, 22.8 and 24.9 degrees 2-theta ⁇ 0.2 degrees 2-theta, and also having any one, two, three or four additional peaks selected from 17.5, 18.3, 19.7 and 23.4 degrees 2-theta ⁇ 0.2 degrees 2-theta.
- Crystalline Form Ml of Mesdopetam (L)-malate may be alternatively characterized by an X-ray powder diffraction pattern having peaks at 5.0, 14.9, 16.2, 17.5, 18.3, 19.7, 22.8, 23.4 and 24.9 degrees 2-theta ⁇ 0.2 degrees 2-theta.
- crystalline Form Ml of Mesdopetam (L)-malate may be isolated.
- crystalline Form Ml of Mesdopetam (L)- malate according to any aspect or embodiment of the disclosure may be isolated.
- crystalline form Ml of Mesdopetam (L)-malate may be chemically pure.
- crystalline Form Ml of Mesdopetam (L)-malate may be polymorphically pure.
- crystalline Form Ml of Mesdopetam (L)-malate may be anhydrous.
- Crystalline Form Ml of Mesdopetam (L)-malate may be characterized by each of the above characteristics alone/or by all possible combinations, e.g., an XRPD pattern having peaks at 5.0, 14.9, 16.2, 22.8 and 24.9 degrees 2-theta ⁇ 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 7, and combinations thereof.
- the present disclosure encompasses Mesdopetam hemi-(L)-malate.
- the Mesdopetam hemi-(L)-malate is preferably in a solid form, and more preferably the Mesdopetam-hemi (L)- malate is crystalline.
- Mesdopetam hemi- (L)-malate may be isolated.
- Mesdopetam hemi-(L)-malate according to any aspect or embodiment may be chemically pure.
- Crystalline Mesdopetam hemi-(L)-malate according to any aspect or embodiment may be polymorphically pure (i.e.
- Mesdopetam-hemi (L)-malate containing a single crystalline form of Mesdopetam hemi-(A)-malate), preferably containing about 20% (w/w) or less, about 10% (w/w) or less, about 5% (w/w) or less, about 2% (w/w) or less, about 1% (w/w) or less, or about 0% of any other crystalline form of Mesdopetam hemi-(/.)-malate, as measured, for example, by XRPD.
- Mesdopetam-hemi (L)-malate may be anhydrous.
- the present disclosure includes a crystalline polymorph Mesdopetam hemi-(L)- malate designated Form HM1.
- the crystalline Form HM1 of Mesdopetam hemi-(/.)-malate may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 8; an X-ray powder diffraction pattern having peaks at
- Crystalline Form HM1 of Mesdopetam hemi-(/.)-malate may be further characterized by an X-ray powder diffraction pattern having peaks at 14.5, 15.5, 20.5, 21.3 and 23.3 degrees 2- theta ⁇ 0.2 degrees 2-theta, and also having any one, two, three, four or five additional peaks selected from 11.6, 13.2, 19.1, 22.4 and 26.5 degrees 2-theta ⁇ 0.2 degrees 2-theta.
- Crystalline Form HM1 of Mesdopetam hemi-(/.)-malate may be alternatively characterized by an X-ray powder diffraction pattern having peaks at 11.6, 13.2, 14.5, 15.5, 19.1,
- crystalline Form HM1 of Mesdopetam hemi-(L)-malate may be isolated.
- crystalline Form HM1 of Mesdopetam hemi-(L)-malate according to any aspect or embodiment of the disclosure may be isolated.
- crystalline form HM1 of Mesdopetam hemi-(L)-malate may be chemically pure.
- crystalline Form HM1 of Mesdopetam hemi-(L)-malate may be polymorphically pure.
- crystalline Form HM1 of Mesdopetam hemi-(L)-malate may be anhydrous.
- Crystalline Form HM1 of Mesdopetam hemi-(L)-malate may be characterized by each of the above characteristics alone/or by all possible combinations, e.g., an XRPD pattern having peaks at 14.5, 15.5, 20.5, 21.3 and 23.3 degrees 2-theta ⁇ 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 8, and combinations thereof.
- Crystalline form HM1 of Mesdopetam hemi-(L)-malate may be prepared by crystallisation from a mixture comprising Mesdopetam hemi-(L)-malate and a solvent comprising, acetonitrile, ethanol, methanol, acetone, or mixture thereof.
- Mesdopetam hemi-(L)-malate may be prepared by reacting Mesdopetam with L-malic acid in any suitable solvent.
- the solvent is preferably selected at least enable dissolution of Mesdopetam and L-malic acid, and optionally enables precipitation of the resulting Mesdopetam hemi-(L)-malate (e.g. by cooling or evaporation).
- an antisolvent for Mesdopetam hemi-(L)-malate for example a non-polar solvent such as an alkane, or a solvent selected from n-heptane, dichloromethane, acetone, or tetrahydrofuran, may be added to facilitate precipitation.
- a non-polar solvent such as an alkane, or a solvent selected from n-heptane, dichloromethane, acetone, or tetrahydrofuran
- Crystalline form HM1 of Mesdopetam hemi-(L)-malate may be prepared by crystallisation from a mixture comprising Mesdopetam hemi-(L)-malate and a solvent comprising acetonitrile, ethanol (96% ethanol/water or absolute ethanol), methanol, or mixture thereof.
- the process may comprise:
- the solution in step (a) may be prepared by combining Mesdopetam hemi-(L)-malate with the solvent.
- the solvent may be present in an amount of: about 5 to about 40 ml per gram of Mesdopetam hemi-(L)-malate, about 5 ml to about 35 ml per gram of Mesdopetam hemi-(L)-malate, about 7 to about 32 ml per gram of Mesdopetam hemi-(L)-malate, or about 10 to about 30 ml per gram of Mesdopetam hemi-(L)-malate.
- the solution in step (a) may be at elevated temperature, preferably, at a temperature of: about 15°C to about the reflux temperature, about 15°C to about 100°C, about 18°C to about 100°C, about 20°C to about 98°C, or about 22°C to about 98°C.
- the solution in step (a) may be prepared by combining Mesdopetam hemi-(L)-malate with the heated solvent, or by combining Mesdopetam hemi-(L)-malate with the solvent at ambient temperature, and optionally heating the mixture to provide a solution.
- step (b) may comprise: cooling the mixture, preferably to about 5°C to about 30°C, or about 10°C to about 25°C or about 20°C to about 25°C.
- the solution in step (a) is heated to a temperature of about 18°C to about 60°C (preferably about 22°C to about 60°C)
- step (b) comprises cooling the mixture in step (a) to a temperature of: about 5°C to about 35°C, about 10°C to about 30°C, or room temperature.
- the cooling may be active or passive, preferably passive (i.e. the mixture is allowed to cool under ambient conditions).
- the cooling is preferably conducted without stirring.
- step (c) may comprise isolating the solid by any suitable method such as by decantation, centrifuge or by filtration, preferably by filtration.
- the Mesdopetam hemi-(L)-malate form HM1 may optionally be dried, for example under reduced pressure, and optionally elevated temperature, preferably at reduced pressure and at a temperature of: about 40°C to about 90°C, about 55°C to about 85°C, or about 60°C to about 80°C; optionally, the drying can be conducted for a sufficient time to obtain a dried solid, preferably about 1 hour to about 10 hours, about 2 hours to about 8 hours, about 3 hours to about 6 hours, or about 4 hours to about 6 hours.
- the solution in step a) may be at a temperature of about 50°C to about the reflux temperature, about 80°C about 100°C, about 90°C to about 100°C, or about the reflux temperature; and/or the acetonitrile is used in an amount of about 4 ml to about 20 ml, about 6 ml to 15 ml, about 8 ml to about 12 ml, or about 10 ml per gram of Mesdopetam Hemi-(L)-malate.
- step a) when the solvent is ethanol, step a) may be performed at a temperature of about 50°C to about 80°C, about 60°C to about 75°C, or about 65°C to about 70°C; and/or the ethanol is used in an amount of: about 15 ml to 35 ml, about 18 ml to about 32 ml, or about 20 ml to about 30 ml per gram of Mesdopetam Hemi-(L)-malate.
- step a) when the solvent is methanol, step a) may be performed at a temperature of about 18°C to about 35°C, about 18°C to about 30°C, about 20°C to about 25°C or at room temperature; and/or the methanol is used in an amount of about 5 ml to 20 ml, about 8 to about 15 ml, or about 10 ml per gram of Mesdopetam Hemi-(L) -malate.
- Mesdopetam Hemi-(L)-malate Form HM1 may be prepared by a process comprising stirring a suspension of Mesdopetam Hemi-(L)-malate in acetone.
- the suspension of Mesdopetam Hemi-(L)-malate in acetone is prepared by combining Mesdopetam (preferably form Bl), L-malic acid, and acetone. More particularly, the process comprises:
- the acetone in step (i), may be present in an amount of: about 5 to about 20 ml per gram of Mesdopetam, about 7 to about 18 ml per gram of Mesdopetam, about 10 to about 15 ml, or about 11 to about 13 ml per gram of Mesdopetam.
- the amount of (L)-malic acid to Mesdopetam may be: about 0.5 mole equivalents.
- the mixture in step (i) is preferably at room temperature.
- step (ii) comprises stirring the mixture for a sufficient time to prepare Mesdopetam hemi-(L)-malate form HM1 , preferably about 4 hours to about 72 hours, about 8 hours to about 60 hours, about 18 hours to about 50 hours, about or about 24 hours to about 48 hours.
- step (iii) comprises isolating the Mesdopetam hemi-(L) -malate Form HM1 by any suitable method such as by decantation, centrifuge or filtration, preferably filtration.
- the Mesdopetam hemi-(L)-malate Form HM1 may optionally be dried, for example under reduced pressure, and optionally elevated temperature, preferably at reduced pressure and at a temperature of: about 40°C to about 90°C, about 55°C to about 80°C, or about 60°C to about 75°C; optionally, the drying can be conducted for a sufficient time to obtain a dried solid, preferably about 1 hour to about 10 hours, about 2 hours to about 8 hours, about 3 hours to about 6 hours, or about 4 hours to about 6 hours.
- the present disclosure encompasses a process for preparing solid state forms of Mesdopetam, Mesdopetam salts and solid state forms thereof.
- the process includes preparing any one of the Mesdopetam salts, or solid state forms of Mesdopetam or salts thereof by the processes of the present disclosure, and converting that form to a different form of Mesdopetam or salts thereof.
- the conversion can be done, for example, by a process comprising acidifying any one of the above described forms of Mesdopetam to prepare the corresponding salt.
- the solid state form of Mesdopetam of the present disclosure may be prepared from Mesdopetam salts.
- This conversion can be done, for example, by a process comprising basifying a Mesdopetam salt.
- the process may include preparing any one of the solid state forms of Mesdopetam salts of the present disclosure by the processes of the present disclosure, and converting it to said other form of Mesdopetam or Mesdopetam salt.
- the conversion can be done for example by a process comprising basifying any one of the above described forms of Mesdopetam salts and reacting the obtained Mesdopetam with an appropriate acid, to obtain the corresponding salt.
- the conversion can be done by salt switching, i.e., reacting any one of the forms of the Mesdopetam salts of the present disclosure with an acid having a pKa which is lower than that of the acid of the original salt.
- the Mesdopetam salts and crystalline polymorphs of Mesdopetam or salts thereof as defined herein and the pharmaceutical compositions or formulations of the Mesdopetam salts, or crystalline polymorphs of Mesdopetam or salts thereof may be used as medicaments, such as for the treatment of patients with Parkinson's Disease Dyskinesia, levodopa-induced dyskinesias, or Parkinson’s disease Psychosis.
- the present disclosure also provides methods for the treatment of patients with levodopa-induced dyskinesias by administering a therapeutically effective amount of said Mesdopetam salts, or crystalline polymorphs of Mesdopetam or salts thereof of the present disclosure, or at least one of the above pharmaceutical compositions, to a subject suffering from Parkinson's Disease Dyskinesia, levodopa-induced dyskinesia, or Parkinson’s disease Psychosis or otherwise in need of the treatment.
- the present disclosure also provides uses of Mesdopetam salts, or crystalline polymorphs of Mesdopetam or salts thereof of the present disclosure, or at least one of the above pharmaceutical compositions, for the manufacture of medicaments for treating e.g., patients with Parkinson's Disease Dyskinesia, levodopa-induced dyskinesia, or Parkinson’s disease Psychosis.
- the present disclosure provides the above described Mesdopetam salts, or crystalline polymorphs of Mesdopetam or salts thereof for use in the preparation of pharmaceutical compositions comprising Mesdopetam or salts thereof and/or solid state forms thereof.
- the present disclosure also encompasses the use of Mesdopetam salts, or crystalline polymorphs of Mesdopetam or salts thereof of the present disclosure for the preparation of pharmaceutical compositions of crystalline polymorph Mesdopetam or salts thereof and/or solid state forms thereof.
- the present disclosure includes processes for preparing the above mentioned pharmaceutical compositions.
- the processes include combining any one or a combination of the Mesdopetam salts, or crystalline polymorphs of Mesdopetam or salts thereof of the present disclosure with at least one pharmaceutically acceptable excipient.
- Pharmaceutical combinations or formulations of the present disclosure contain any one or a combination of the Mesdopetam salts, or solid state form of Mesdopetam or salts thereof of the present disclosure.
- the pharmaceutical formulations of the present disclosure can contain one or more excipients. Excipients are added to the formulation for a variety of purposes.
- Diluents increase the bulk of a solid pharmaceutical composition, and can make a pharmaceutical dosage form containing the composition easier for the patient and caregiver to handle.
- Diluents for solid compositions include, for example, microcrystalline cellulose (e.g., Avicel®), microfine cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates (e.g., Eudragit®), potassium chloride, powdered cellulose, sodium chloride, sorbitol, and talc.
- microcrystalline cellulose e.g., Avicel®
- microfine cellulose lactose
- starch pregelatinized starch
- calcium carbonate calcium sulfate
- sugar dextrates
- Solid pharmaceutical compositions that are compacted into a dosage form, such as a tablet can include excipients whose functions include helping to bind the active ingredient and other excipients together after compression.
- Binders for solid pharmaceutical compositions include acacia, alginic acid, carbomer (e.g. carbopol), carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxy ethyl cellulose, hydroxypropyl cellulose (e.g. Klucel®), hydroxypropyl methyl cellulose (e.g.
- Methocel® liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates, povidone (e.g. Kollidon®, Plasdone®), pregelatinized starch, sodium alginate, and starch.
- povidone e.g. Kollidon®, Plasdone®
- pregelatinized starch sodium alginate, and starch.
- Disintegrants include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g., Ac- Di-Sol®, Primellose®), colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g., Kollidon®, Polyplasdone®), guar gum, magnesium aluminum silicate, methyl cellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (e.g., Explotab®), and starch.
- alginic acid e.g., Ac- Di-Sol®, Primellose®
- colloidal silicon dioxide e.g., croscarmellose sodium
- crospovidone e.g., Kollidon®, Polyplasdone®
- guar gum e.g., magnesium aluminum silicate
- methyl cellulose e.g., microcrystalline cellulose
- polacrilin potassium ed
- Glidants can be added to improve the flowability of a non-compacted solid composition and to improve the accuracy of dosing.
- Excipients that can function as glidants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc, and tribasic calcium phosphate.
- a dosage form such as a tablet is made by the compaction of a powdered composition
- the composition is subjected to pressure from a punch and dye.
- Some excipients and active ingredients have a tendency to adhere to the surfaces of the punch and dye, which can cause the product to have pitting and other surface irregularities.
- a lubricant can be added to the composition to reduce adhesion and ease the release of the product from the dye.
- Lubricants include magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, and zinc stearate.
- Flavoring agents and flavor enhancers make the dosage form more palatable to the patient. Common flavoring agents and flavor enhancers for pharmaceutical products that can be included in the composition of the present disclosure include maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol, and tartaric acid.
- Solid and liquid compositions can also be dyed using any pharmaceutically acceptable colorant to improve their appearance and/or facilitate patient identification of the product and unit dosage level.
- liquid pharmaceutical compositions of the present invention Mesdopetam or salts thereof and any other solid excipients can be dissolved or suspended in a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol, or glycerin.
- a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol, or glycerin.
- Liquid pharmaceutical compositions can contain emulsifying agents to disperse uniformly throughout the composition an active ingredient or other excipient that is not soluble in the liquid carrier.
- Emulsifying agents that can be useful in liquid compositions of the present invention include, for example, gelatin, egg yolk, casein, cholesterol, acacia, tragacanth, chondrus, pectin, methyl cellulose, carbomer, cetostearyl alcohol, and cetyl alcohol.
- Liquid pharmaceutical compositions of the present invention can also contain a viscosity enhancing agent to improve the mouth-feel of the product and/or coat the lining of the gastrointestinal tract.
- a viscosity enhancing agent include acacia, alginic acid bentonite, carbomer, carboxymethylcellulose calcium or sodium, cetostearyl alcohol, methyl cellulose, ethylcellulose, gelatin guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, maltodextrin, polyvinyl alcohol, povidone, propylene carbonate, propylene glycol alginate, sodium alginate, sodium starch glycolate, starch tragacanth, xanthan gum and combinations thereof.
- Sweetening agents such as sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol, and invert sugar can be added to improve the taste.
- Preservatives and chelating agents such as alcohol, sodium benzoate, butylated hydroxyl toluene, butylated hydroxyanisole, and ethylenediamine tetraacetic acid can be added at levels safe for ingestion to improve storage stability.
- a liquid composition can also contain a buffer such as gluconic acid, lactic acid, citric acid, or acetic acid, sodium gluconate, sodium lactate, sodium citrate, or sodium acetate. Selection of excipients and the amounts used can be readily determined by the formulation scientist based upon experience and consideration of standard procedures and reference works in the field.
- a buffer such as gluconic acid, lactic acid, citric acid, or acetic acid, sodium gluconate, sodium lactate, sodium citrate, or sodium acetate.
- the solid compositions of the present disclosure include powders, granulates, aggregates, and compacted compositions.
- the dosages include dosages suitable for oral, buccal, rectal, parenteral (including subcutaneous, intramuscular, and intravenous), inhalant, and ophthalmic administration. Although the most suitable administration in any given case will depend on the nature and severity of the condition being treated, in embodiments the route of administration is oral.
- the dosages can be conveniently presented in unit dosage form and prepared by any of the methods well-known in the pharmaceutical arts.
- Dosage forms include solid dosage forms like tablets, powders, capsules, suppositories, sachets, troches, and lozenges, as well as liquid syrups, suspensions, and elixirs.
- the dosage form of the present disclosure can be a capsule containing the composition, such as a powdered or granulated solid composition of the disclosure, within either a hard or soft shell.
- the shell can be made from gelatin and optionally contain a plasticizer such as glycerin and/or sorbitol, an opacifying agent and/or colorant.
- compositions and dosage forms can be formulated into compositions and dosage forms according to methods known in the art.
- a composition for tableting or capsule filling can be prepared by wet granulation.
- wet granulation some or all of the active ingredients and excipients in powder form are blended and then further mixed in the presence of a liquid, typically water that causes the powders to clump into granules.
- the granulate is screened and/or milled, dried, and then screened and/or milled to the desired particle size.
- the granulate can then be tableted, or other excipients can be added prior to tableting, such as a glidant and/or a lubricant.
- a tableting composition can be prepared conventionally by dry blending.
- the blended composition of the actives and excipients can be compacted into a slug or a sheet and then comminuted into compacted granules. The compacted granules can subsequently be compressed into a tablet.
- a blended composition can be compressed directly into a compacted dosage form using direct compression techniques.
- Direct compression produces a more uniform tablet without granules.
- Excipients that are particularly well suited for direct compression tableting include microcrystalline cellulose, spray dried lactose, dicalcium phosphate dihydrate, and colloidal silica. The proper use of these and other excipients in direct compression tableting is known to those in the art with experience and skill in particular formulation challenges of direct compression tableting.
- a capsule filling of the present disclosure can include any of the aforementioned blends and granulates that were described with reference to tableting, but they are not subjected to a final tableting step.
- a pharmaceutical formulation of Mesdopetam can be administered.
- Mesdopetam may be formulated for administration to a mammal, in embodiments to a human, by injection.
- Mesdopetam can be formulated, for example, as a viscous liquid solution or suspension, such as a clear solution, for injection.
- the formulation can contain one or more solvents.
- a suitable solvent can be selected by considering the solvent's physical and chemical stability at various pH levels, viscosity (which would allow for syringeability), fluidity, boiling point, miscibility, and purity.
- Suitable solvents include alcohol USP, benzyl alcohol NF, benzyl benzoate USP, and Castor oil USP. Additional substances can be added to the formulation such as buffers, solubilizers, and antioxidants, among others.
- Ansel et al. Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th ed.
- the Mesdopetam salts, and crystalline polymorph of Mesdopetam salts and the pharmaceutical compositions and/or formulations of Mesdopetam or Mesdopetam salts of the present disclosure can be used as medicaments, in embodiments for the treatment of patients with Diabetic Peripheral Neuropathic pain and/or Post-Herpetic Neuralgia.
- the present disclosure also provides methods of treating of patients with Diabetic Peripheral Neuropathic pain and/or Post-Herpetic Neuralgia by administering a therapeutically effective amount of any one or a combination of the Mesdopetam salts, or crystalline polymorphs of Mesdopetam of the present disclosure, or at least one of the above pharmaceutical compositions and/or formulations, to a subject in need of the treatment.
- Sample is powdered in a mortar and pestle and applied directly on a silicon plate holder.
- Mesdopetam hemitartrate can be prepared according to methods known from the literature, for example according to the disclosure in International Publication No. WO 2020/239568.
- Mesdopetam hemitartrate may also be prepared according to the following procedure: 2.0 grams of Mesdopetam hemitartrate crude material was dissolved in 4 ml of solvent mixture ethanol/water (ratio 1: 1) at 65 °C. The solution was allowed to cool and crystallization occurred at 30 °C. The suspension was allowed to cool to room temperature and vacuum filtered at room temperature. The solid was vacuum dried at 80 °C for 6 hours.
Abstract
The present disclosure encompasses Mesdopetam salts, solid state forms of Mesdopetam and salts thereof, in embodiments processes for preparation thereof and pharmaceutical compositions thereof.
Description
SOLID STATE FORMS OF MESDOPETAM AND SALTS THEROF
FIELD OF THE DISCLOSURE
[0001] The present disclosure encompasses Mesdopetam salts, solid state forms of Mesdopetam and salts thereof, in embodiments processes for preparation thereof and pharmaceutical compositions thereof.
BACKGROUND OF THE DISCLOSURE
[0002] Mesdopetam, N-[2-(3-fhroro-5-methylsulfonylphenoxy)ethyl]propan-l-amine, has the following chemical structure:
[0003] Mesdopetam is developed for the treatment of levodopa-induced dyskinesias commonly occurring in Parkinson's disease. Mesdopetam is also being investigated for the treatment or Parkinson’s disease psychosis.
[0004] The compound is described in International Publication No. WO 2012/143337 [0005] Mesdopetam salts are described in International Publication No. WO 2020/239568. [0006] Polymorphism, the occurrence of different crystalline forms, is a property of some molecules and molecular complexes. A single molecule may give rise to a variety of polymorphs having distinct crystal structures and physical properties like melting point, thermal behaviors (e.g., measured by thermogravimetric analysis (“TGA”), or differential scanning calorimetry (“DSC”)), X-ray diffraction (XRD) pattern, infrared absorption fingerprint, and solid state (13C) NMR spectrum. One or more of these techniques may be used to distinguish different polymorphic forms of a compound.
[0007] Different salts and solid state forms (including solvated forms) of an active pharmaceutical ingredient may possess different properties. Such variations in the properties of
different salts and solid state forms and solvates may provide a basis for improving formulation, for example, by facilitating better processing or handling characteristics, changing the dissolution profile in a favorable direction, or improving stability (polymorph as well as chemical stability) and shelf-life. These variations in the properties of different salts and solid state forms may also offer improvements to the final dosage form, for instance, if they serve to improve bioavailability. Different salts and solid state forms and solvates of an active pharmaceutical ingredient may also give rise to a variety of polymorphs or crystalline forms, which may in turn provide additional opportunities to assess variations in the properties and characteristics of a solid active pharmaceutical ingredient.
[0008] Discovering new salts and solid state forms and solvates of a pharmaceutical product may yield materials having desirable processing properties, such as ease of handling, ease of processing, storage stability, and ease of purification or as desirable intermediate crystal forms that facilitate conversion to other polymorphic forms. New solid state forms of a pharmaceutically useful compound can also provide an opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for formulation optimization, for example by providing a product with different properties, including a different crystal habit, higher crystallinity, or polymorphic stability, which may offer better processing or handling characteristics, improved dissolution profile, or improved shelf-life (chemical/physical stability). For at least these reasons, there is a need for additional solid state forms (including solvated forms) of Mesdopetam.
SUMMARY OF THE DISCLOSURE
[0009] The present disclosure provides Mesdopetam salts, or crystalline polymorphs of Mesdopetam and salts thereof, processes for preparation thereof and pharmaceutical composition thereof. Any one of the crystalline forms can be used to prepare other solid state forms of Mesdopetam and Mesdopetam salts and solid state forms thereof.
[0010] The present disclosure also provides uses of said Mesdopetam salts, or solid state forms of Mesdopetam or salts thereof in the preparation of other solid state forms of Mesdopetam or salts thereof.
[0011] The present disclosure provides said Mesdopetam salts, or crystalline forms of Mesdopetam and salts thereof for use in medicine, including for the treatment of patients with
Parkinson's Disease Dyskinesia, levodopa-induced dyskinesias, or Parkinson’s disease Psychosis.
[0012] The present disclosure also encompasses the use of said Mesdopetam salts, or crystalline polymorphs of Mesdopetam and salts thereof for the preparation of pharmaceutical compositions and/or formulations.
[0013] In another aspect, the present disclosure provides pharmaceutical compositions comprising said Mesdopetam salts, or crystalline polymorphs of Mesdopetam or salts thereof according to the present disclosure.
[0014] The present disclosure includes processes for preparing the above mentioned pharmaceutical compositions. The processes include combining any one or a combination of the Mesdopetam salts, or crystalline polymorphs of Mesdopetam or salts thereof with at least one pharmaceutically acceptable excipient.
[0015] The crystalline polymorphs of Mesdopetam or salts thereof as defined herein and the pharmaceutical compositions or formulations of the Mesdopetam salts, or crystalline polymorphs of Mesdopetam or salts thereof may be used as medicaments, such as for the treatment of patients with Parkinson's Disease Dyskinesia, levodopa-induced dyskinesias, or Parkinson’s disease Psychosis.
[0016] The present disclosure also provides methods for the treatment of patients with levodopa-induced dyskinesias by administering a therapeutically effective amount of said Mesdopetam salts, or crystalline polymorphs of Mesdopetam or salts thereof of the present disclosure, or at least one of the above pharmaceutical compositions, to a subject suffering from Parkinson's Disease Dyskinesia, levodopa-induced dyskinesia, or Parkinson’s disease Psychosis or otherwise in need of the treatment.
[0017] The present disclosure also provides uses of said Mesdopetam salts, or crystalline polymorphs of Mesdopetam or salts thereof of the present disclosure, or at least one of the above pharmaceutical compositions, for the manufacture of medicaments for treating e.g., patients with Parkinson's Disease Dyskinesia, levodopa-induced dyskinesia, or Parkinson’s disease Psychosis. BRIEF DESCRIPTION OF THE DRAWINGS
[0018] Figure 1 shows a characteristic X-ray powder diffraction pattern (XRPD) of Mesdopetam Form Bl.
[0019] Figure 2 shows the X-ray powder diffraction pattern (XRPD) of Mesdopetam Form B3 prepared according to Example 2.
[0020] Figure 3 shows the X-ray powder diffraction pattern (XRPD) of Mesdopetam Form B4 prepared according to Example 3.
[0021] Figure 4 shows the X-ray powder diffraction pattern (XRPD) of Mesdopetam mesylate Form MSI prepared according to Example 4.
[0022] Figure 5 shows the X-ray powder diffraction pattern (XRPD) of Mesdopetam mesylate Form MS2 prepared according to Example 5, procedure A.
[0023] Figure 6 shows the X-ray powder diffraction pattern (XRPD) of Mesdopetam besylate Form BS1 prepared according to Example 6.
[0024] Figure 7 shows the X-ray powder diffraction pattern (XRPD) of Mesdopetam (L)- malate Form Ml prepared according to Example 7.
[0025] Figure 8 shows the X-ray powder diffraction pattern (XRPD) of Mesdopetam hemi- (A)-malate Form HM1 prepared according to Example 8.
DETAILED DESCRIPTION OF THE DISCLOSURE
[0026] The present disclosure encompasses Mesdopetam salts, or crystalline forms of Mesdopetam and salts thereof, processes for preparation thereof, and pharmaceutical compositions thereof.
[0027] Solid state properties of Mesdopetam or salts thereof and crystalline polymorphs thereof can be influenced by controlling the conditions under which Mesdopetam and crystalline polymorphs thereof are obtained in solid form.
[0028] The solid state forms of Mesdopetam (e.g. Mesdopetam, Mesdopetam salts) as described in any aspect or embodiment of the present disclosure may be polymorphically pure, or substantially free of any other solid state (or polymorphic) forms.
[0029] A solid state form (or polymorph) may be referred to herein as polymorphically pure or as substantially free of any other solid state (or polymorphic) forms. As used herein in this context, the expression "substantially free of any other forms" will be understood to mean that the solid state form contains about 20% (w/w) or less, about 10% (w/w) or less, about 5% (w/w) or less, about 2% (w/w) or less, about 1% (w/w) or less, or about 0% of any other forms of the subject compound as measured, for example, by XRPD. For example, polymorphically pure
Mesdopetam form Bl means that the solid state form is substantially free of other solid state forms of Mesdopetam. Thus, a crystalline polymorph of Mesdopetam or salts thereof described herein as substantially free of any other solid state forms would be understood to contain greater than about 80% (w/w), greater than about 90% (w/w), greater than about 95% (w/w), greater than about 98% (w/w), greater than about 99% (w/w), or about 100% of the subject crystalline polymorph of Mesdopetam or salts thereof. In some embodiments of the disclosure, the described crystalline polymorph of Mesdopetam, salt or cocrystal may contain from about 1% to about 20% (w/w), from about 5% to about 20% (w/w), or from about 5% to about 10% (w/w) of one or more other crystalline polymorph of the same Mesdopetam.
[0030] Depending on which other crystalline polymorphs a comparison is made, the crystalline polymorphs of Mesdopetam or salts thereof of the present disclosure may have advantageous properties selected from at least one of the following: chemical purity, flowability, solubility, dissolution rate, morphology or crystal habit, stability, such as chemical stability as well as thermal and mechanical stability with respect to polymorphic conversion, stability towards dehydration and/or storage stability, low content of residual solvent, a lower degree of hygroscopicity, flowability, and advantageous processing and handling characteristics such as compressibility and bulk density.
[0031] A solid state form, such as a crystal form or an amorphous form, may be referred to herein as being characterized by graphical data “as depicted in” or “as substantially depicted in” a Figure. Such data include, for example, powder X-ray diffractograms and solid state NMR spectra. As is well-known in the art, the graphical data potentially provides additional technical information to further define the respective solid state form (a so-called “fingerprint”) which cannot necessarily be described by reference to numerical values or peak positions alone. In any event, the skilled person will understand that such graphical representations of data may be subject to small variations, e.g., in peak relative intensities and peak positions due to certain factors such as, but not limited to, variations in instrument response and variations in sample concentration and purity, which are well known to the skilled person. Nonetheless, the skilled person would readily be capable of comparing the graphical data in the Figures herein with graphical data generated for an unknown crystal form and confirm whether the two sets of graphical data are characterizing the same crystal form or two different crystal forms. A crystal form of Mesdopetam referred to herein as being characterized by graphical data “as depicted in”
or “as substantially depicted in” a Figure will thus be understood to include any crystal forms of Mesdopetam characterized with the graphical data having such small variations, as are well known to the skilled person, in comparison with the Figure.
[0032] As used herein, and unless stated otherwise, the term “anhydrous” in relation to crystalline forms of Mesdopetam relates to a crystalline form of Mesdopetam which does not include any crystalline water (or other solvents) in a defined, stoichiometric amount within the crystal. Moreover, an “anhydrous” form would generally not contain more than 1% (w/w), of either water or organic solvents as measured for example by TGA.
[0033] The term "solvate," as used herein and unless indicated otherwise, refers to a crystal form that incorporates a solvent in the crystal structure. When the solvent is water, the solvate is often referred to as a "hydrate." The solvent in a solvate may be present in either a stoichiometric or in a non-stoichiometric amount.
[0034] As used herein, the term "isolated" in reference to crystalline polymorph of Mesdopetam of the present disclosure corresponds to a crystalline polymorph of Mesdopetam that is physically separated from the reaction mixture in which it is formed.
[0035] As used herein, unless stated otherwise, the XRPD measurements are taken using copper K a radiation wavelength 1.54184 A. XRPD peaks reported herein are optionally measured using CuK a radiation, X = 1.54184 A, typically at a temperature of 25 ± 3°C.
[0036] A thing, e.g., a reaction mixture, may be characterized herein as being at, or allowed to come to “room temperature” or “ambient temperature,” often abbreviated as “RT.” This means that the temperature of the thing is close to, or the same as, that of the space, e.g., the room or fume hood, in which the thing is located. Typically, room temperature is from about 20°C to about 30°C, or about 22°C to about 27°C, or about 25°C.
[0037] The amount of solvent employed in a chemical process, e.g., a reaction or crystallization, may be referred to herein as a number of “volumes” or “vol” or “V.” For example, a material may be referred to as being suspended in 10 volumes (or 10 vol or 10V) of a solvent. In this context, this expression would be understood to mean milliliters of the solvent per gram of the material being suspended, such that suspending a 5 grams of a material in 10 volumes of a solvent means that the solvent is used in an amount of 10 milliliters of the solvent per gram of the material that is being suspended or, in this example, 50 mb of the solvent. In another context, the term "v/v" may be used to indicate the number of volumes of a solvent that
are added to a liquid mixture based on the volume of that mixture. For example, adding solvent X (1.5 v/v) to a 100 ml reaction mixture would indicate that 150 mL of solvent X was added. [0038] A process or step may be referred to herein as being carried out "overnight." This refers to a time interval, e.g., for the process or step, that spans the time during the night, when that process or step may not be actively observed. This time interval is from about 8 to about 20 hours, or about 10-18 hours, in some cases about 16 hours.
[0039] As used herein, the term “reduced pressure” refers to a pressure that is less than atmospheric pressure. For example, reduced pressure is about 10 mbar to about 50 mbar.
[0040] As used herein and unless indicated otherwise, the term "ambient conditions" refer to atmospheric pressure and a temperature of 22-24°C.
[0041] The Mesdopetam salts, or solid state form of Mesdopetam (e.g. Mesdopetam, Mesdopetam salts) as described in any aspect or embodiment of the present disclosure may be chemically pure, or substantially free of any other compounds.
[0042] A compound may be referred to herein as chemically pure or purified compound or as substantially free of any other compounds. As used herein, the terms "chemically pure" or "purified" or "substantially free of any other compounds" refer to a compound that is substantially free of any impurities including enantiomers of the subject compound, diastereomers or other isomers. A chemically pure or purified compound or a compound that is substantially free of any other compound will be understood to mean that it contains about 10% (w/w) or less, about 5% (w/w) or less, about 4% (w/w) or less, about 3% (w/w) or less, about 2% (w/w) or less, about 1.5% (w/w) or less, about 1% (w/w) or less, about 0.8% (w/w) or less, about 0.6% (w/w) or less, about 0.4% (w/w) or less, about 0.2% (w/w) or less, about 0.1% (w/w) or less, or about 0% of any other compound as measured, for example, by HPLC. Alternatively, A chemically pure or purified compound or a compound that is substantially free of any other compound will be understood to mean that it contains about 10% area percent or less, about 5% area percent or less, about 4% area percent or less, about 3% area percent or less, about 2% area percent or less, about 1.5% area percent or less, about 1% area percent or less, about 0.8% area percent or less, about 0.6% area percent or less, about 0.4% area percent or less, about 0.2% area percent or less, about 0.1% area percent or less, or about 0% of any other compound as measured by HPLC. Thus, pure or purified Mesdopetam or salts thereof described herein as substantially free of any compounds would be understood to contain greater than about 90% (w/w), greater
than about 95% (w/w), greater than about 96% (w/w), greater than about 97% (w/w), greater than about 98% (w/w), greater than about 98.5% (w/w), greater than about 99% (w/w), greater than about 99.2% (w/w), greater than about 99.4% (w/w), greater than about 99.6% (w/w), greater than about 99.8% (w/w), greater than about 99.9% (w/w), or about 100% of the subject Mesdopetam or salts thereof. Alternatively, pure or purified Mesdopetam or salts thereof, described herein as substantially free of any compounds would be understood to contain greater than about 90% area percent, greater than about 95% area percent, greater than about 96% area percent, greater than about 97% area percent, greater than about 98% area percent, greater than about 98.5% area percent, greater than about 99% area percent, greater than about 99.2% area percent, greater than about 99.4% area percent, greater than about 99.6% area percent, greater than about 99.8% area percent, greater than about 99.9% area percent, or about 100% of the subject Mesdopetam or salts thereof.
[0043] The present disclosure includes a crystalline polymorph Mesdopetam designated Form Bl. The crystalline Form Bl of Mesdopetam may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 1; an X-ray powder diffraction pattern having peaks at 5.5, 11.1, 16.6 and 22.2 degrees 2- theta ± 0.2 degrees 2-theta; and combinations of these data.
[0044] Crystalline Form Bl of Mesdopetam may be further characterized by an X-ray powder diffraction pattern having peaks at 5.5, 11.1, 16.6 and 22.2 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, three, four or five additional peaks selected from 12.8, 14.7, 19.3 and 27.8 degrees 2-theta ± 0.2 degrees 2-theta.
[0045] Crystalline Form Bl of Mesdopetam may be alternatively characterized by an X-ray powder diffraction pattern having peaks at 5.5, 11.1, 12.8, 14.7, 16.6, 19.3, 22.2 and 27.8 degrees 2-theta ± 0.2 degrees 2-theta.
[0046] In any aspect or embodiment of the present disclosure, crystalline Form Bl of Mesdopetam may be isolated. Particularly, crystalline Form Bl of Mesdopetam according to any aspect or embodiment of the disclosure may be isolated.
[0047] In any aspect or embodiment crystalline form Bl may be chemically pure. [0048] In any aspect or embodiment crystalline Form Bl of Mesdopetam may be polymorphically pure.
[0049] In any aspect or embodiment of the present disclosure, crystalline Form Bl of Mesdopetam may be anhydrous.
[0050] Crystalline Form Bl of Mesdopetam may be characterized by each of the above characteristics alone/or by all possible combinations, e.g., an XRPD pattern having peaks at 5.5, 11.1, 16.6 and 22.2 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 1, and combinations thereof.
[0051] The present disclosure includes a crystalline polymorph Mesdopetam designated Form B3. The crystalline Form B3 of Mesdopetam may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 2; an X-ray powder diffraction pattern having peaks at 12.0, 13.5, 14.2 and 18.4 degrees 2-theta ± 0.2 degrees 2-theta; and combinations of these data.
[0052] Crystalline Form B3 of Mesdopetam may be further characterized by an X-ray powder diffraction pattern having peaks at 12.0, 13.5, 14.2 and 18.4 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, three or four additional peaks selected from 17.4, 23.3, 25.3 and 27.1 degrees 2-theta ± 0.2 degrees 2-theta.
[0053] Crystalline Form B3 of Mesdopetam may be alternatively characterized by an X-ray powder diffraction pattern having peaks at 12.0, 13.5, 14.2, 17.4, 18.4, 23.3, 25.3 and 27.1 degrees 2-theta ± 0.2 degrees 2-theta.
[0054] In any aspect or embodiment of the present disclosure, crystalline Form B3 of Mesdopetam may be isolated. Particularly, crystalline Form B3 of Mesdopetam according to any aspect or embodiment of the disclosure may be isolated.
[0055] In any aspect or embodiment crystalline form B3 may be chemically pure.
[0056] In any aspect or embodiment crystalline Form B3 of Mesdopetam may be polymorphically pure.
[0057] Crystalline Form B3 of Mesdopetam may be characterized by each of the above characteristics alone/or by all possible combinations, e.g., an XRPD pattern having peaks at 12.0, 13.5, 14.2 and 18.4 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 2, and combinations thereof.
[0058] The present disclosure includes a crystalline polymorph Mesdopetam designated Form B4. The crystalline Form B4 of Mesdopetam may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in
Figure 3; an X-ray powder diffraction pattern having peaks at 9.9, 16.4, 21.8, 23.4 and 26.0 degrees 2-theta ± 0.2 degrees 2-theta; and combinations of these data.
[0059] Crystalline Form B4 of Mesdopetam may be further characterized by an X-ray powder diffraction pattern having peaks at 9.9, 16.4, 21.8, 23.4 and 26.0 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, three or four additional peaks selected from 7.1, 14.3, 17.9, 19.9 and 22.5 degrees 2-theta ± 0.2 degrees 2-theta.
[0060] Crystalline Form B4 of Mesdopetam may be alternatively characterized by an X-ray powder diffraction pattern having peaks at 7.1, 9.9, 14.3, 16.4, 17.9, 19.9, 21.8, 22.5, 23.4 and 26.0 degrees 2-theta ± 0.2 degrees 2-theta.
[0061] In any aspect or embodiment of the present disclosure, crystalline Form B4 of Mesdopetam may be isolated. Particularly, crystalline Form B4 of Mesdopetam according to any aspect or embodiment of the disclosure may be isolated.
[0062] In any aspect or embodiment crystalline form B4 may be chemically pure.
[0063] In any aspect or embodiment crystalline Form B4 of Mesdopetam may be polymorphically pure.
[0064] Crystalline Form B4 of Mesdopetam may be characterized by each of the above characteristics alone/or by all possible combinations, e.g., an XRPD pattern having peaks at 9.9, 16.4, 21.8, 23.4 and 26.0 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 3, and combinations thereof.
[0065] The present disclosure encompasses Mesdopetam mesylate. The Mesdopetam mesylate is preferably in a solid form, and more preferably the Mesdopetam mesylate is crystalline. In any aspect or embodiment of the present disclosure, Mesdopetam mesylate may be isolated. Particularly, Mesdopetam mesylate according to any aspect or embodiment may be chemically pure. Crystalline Mesdopetam mesylate according to any aspect or embodiment may be polymorphically pure (i.e. containing a single crystalline form of Mesdopetam mesylate), preferably containing about 20% (w/w) or less, about 10% (w/w) or less, about 5% (w/w) or less, about 2% (w/w) or less, about 1% (w/w) or less, or about 0% of any other crystalline form of Mesdopetam mesylate, as measured, for example, by XRPD. In any aspect or embodiment of the present disclosure, Mesdopetam mesylate may be anhydrous.
[0066] The present disclosure includes a crystalline polymorph Mesdopetam mesylate designated Form MSI. The crystalline Form MSI of Mesdopetam mesylate may be
characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 4; an X-ray powder diffraction pattern having peaks at
8.7, 13.7, 16.8, 19.9 and 22.3 degrees 2-theta ± 0.2 degrees 2-theta; and combinations of these data.
[0067] Crystalline Form MSI of Mesdopetam mesylate may be further characterized by an X-ray powder diffraction pattern having peaks at 8.7, 13.7, 16.8, 19.9 and 22.3 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, three, four or five additional peaks selected from 12.6, 13.0, 15.9, 17.6 and 26.1 degrees 2-theta ± 0.2 degrees 2-theta.
[0068] Crystalline Form MSI of Mesdopetam mesylate may be alternatively characterized by an X-ray powder diffraction pattern having peaks at 8.7, 12.6, 13.0, 13.7, 15.9, 16.8, 17.6, 19.9, 22.3 and 26.1 degrees 2-theta ± 0.2 degrees 2-theta.
[0069] In any aspect or embodiment of the present disclosure, crystalline Form MSI of Mesdopetam mesylate may be isolated. Particularly, crystalline Form MSI of Mesdopetam mesylate according to any aspect or embodiment of the disclosure may be isolated.
[0070] In any aspect or embodiment crystalline form MSI of Mesdopetam mesylate may be chemically pure.
[0071] In any aspect or embodiment crystalline Form MSI of Mesdopetam mesylate may be polymorphically pure.
[0072] In any aspect or embodiment of the present disclosure, crystalline Form MSI of Mesdopetam mesylate may be anhydrous.
[0073] Crystalline Form MSI of Mesdopetam mesylate may be characterized by each of the above characteristics alone/or by all possible combinations, e.g., an XRPD pattern having peaks at 8.7, 13.7, 16.8, 19.9 and 22.3 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 4, and combinations thereof.
[0074] The present disclosure includes a crystalline polymorph Mesdopetam mesylate designated Form MS2. The crystalline Form MS2 of Mesdopetam mesylate may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 5; an X-ray powder diffraction pattern having peaks at
7.8, 15.2, 19.6, 23.5 and 25.0 degrees 2-theta ± 0.2 degrees 2-theta; and combinations of these data.
[0075] Crystalline Form MS2 of Mesdopetam mesylate may be further characterized by an X-ray powder diffraction pattern having peaks at 7.8, 15.2, 19.6, 23.5 and 25.0 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, three, four or five additional peaks selected from 15.7, 17.2, 18.2, 20.2 and 20.9 degrees 2-theta ± 0.2 degrees 2-theta.
[0076] Crystalline Form MS2 of Mesdopetam mesylate may be alternatively characterized by an X-ray powder diffraction pattern having peaks at 7.8, 15.2, 15.7, 17.2, 18.2, 19.6, 20.2, 23.5 and 25.0 degrees 2-theta ± 0.2 degrees 2-theta.
[0077] Crystalline Form MS2 of Mesdopetam mesylate may be alternatively characterized by an X-ray powder diffraction pattern having peaks at 7.8, 15.2, 15.7, 17.2, 18.2, 19.6, 20.2, 20.9, 23.5 and 25.0 degrees 2-theta ± 0.2 degrees 2-theta.
[0078] In any aspect or embodiment of the present disclosure, crystalline Form MS2 of Mesdopetam mesylate may be isolated. Particularly, crystalline Form MS2 of Mesdopetam mesylate according to any aspect or embodiment of the disclosure may be isolated.
[0079] In any aspect or embodiment crystalline form MS2 of Mesdopetam mesylate may be chemically pure.
[0080] In any aspect or embodiment crystalline Form MS2 of Mesdopetam mesylate may be polymorphically pure.
[0081] In any aspect or embodiment of the present disclosure, crystalline Form MS2 of Mesdopetam mesylate may be anhydrous.
[0082] Crystalline Form MS2 of Mesdopetam mesylate may be characterized by each of the above characteristics alone/or by all possible combinations, e.g., an XRPD pattern having peaks at 7.8, 15.2, 19.6, 23.5 and 25.0 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 5, and combinations thereof.
[0083] Mesdopetam Mesylate may be prepared by reacting Mesdopetam with methane sulfonic acid in any suitable solvent. The solvent is preferably selected at least enable dissolution of Mesdopetam and methanesulfonic acid, and optionally enables precipitation of the resulting Mesdopetam Mesylate (e.g. through cooling and/or evaporation). If the solvent does not readily enable precipitation of Mesdopetam Mesylate, an antisolvent for Mesdopetam Mesylate, for example a non-polar solvent such as an alkane, or a solvent selected from n-heptane, dichloromethane, acetone or tetrahydrofuran, may be added to facilitate precipitation.
[0084] Crystalline form MS2 of Mesdopetam Mesylate may be prepared by crystallisation of Mesdopetam Mesylate from a solvent comprising isopropanol, acetonitrile, ethanol, methanol, or mixture thereof. In any embodiment, the process may comprise:
(a) providing a solution of Mesdopetam Mesylate in a solvent, preferably wherein the solvent comprises acetonitrile, ethanol, methanol, or mixtures thereof;
(b) crystallising Mesdopetam Mesylate Form MS2; and
(c) optionally isolating crystalline form MS2 of Mesdopetam Mesylate from the mixture. [0085] In any embodiment of this process, the solution in step (a) may be prepared by combining Mesdopetam mesylate with the solvent. In any embodiment of the process, the solution in step (a) may be at elevated temperature, preferably, at a temperature of about 35°C to about 75°C, about 40°C to about 70°C, or about 45°C to about 65°C. In any embodiment, the solution in step (a) may be prepared by combining Mesdopetam mesylate with the heated solvent, or by combining Mesdopetam mesylate with the solvent at ambient temperature, and heating the mixture to provide a solution. In any embodiment of the process, step (b) may comprise: cooling the mixture (preferably to about 5°C to about 30°C, or about 10°C to about 25°C or about 20°C to about 25°C). Preferably, in any embodiment of this process, the solution in step (a) is heated to a temperature of about 40°C to about 70°C (preferably about 45°C to about 65 °C), and step (b) comprises cooling the mixture in step (a) to a temperature of: about 5°C to about 35°C, about 10°C to about 30°C, or room temperature. In any embodiment, the cooling may be active or passive, preferably passive (i.e. the mixture is allowed to cool under ambient conditions). In any embodiment of this process, the cooling is preferably conducted without stirring. In any embodiment of this process, step (c) may comprise isolating the solid by any suitable method such as by decantation, centrifuge or by filtration, preferably by filtration. The Mesdopetam mesylate Form MS2 may optionally be dried, for example under reduced pressure, and optionally elevated temperature, preferably at reduced pressure and at a temperature of: about 40°C to about 90°C, about 55°C to about 85°C, or about 60°C to about 80°C.
[0086] In any embodiment, the process may comprise:
(a) providing a solution of Mesdopetam Mesylate in a solvent comprising, acetonitrile, ethanol, methanol, or mixtures thereof at elevated temperature, preferably at a temperature of about 40°C to about 70°C or preferably about 45°C to about 65°C;
(b) cooling the mixture to about 30°C, or room temperature (preferably by allowing to cool); and
(c) optionally isolating crystalline form MS2 of Mesdopetam Mesylate from the mixture. Preferably, according to any aspect or embodiment of the processes, when the solvent is acetonitrile, step a) may be performed at a temperature of about 40°C to about 80°C, about 50°C to about 70°C or about 55°C to about 65°C; when the solvent is ethanol, step a) may be performed at a temperature of about 40°C to about 70°C, about 45°C to about 60°C or about 50°C to about 60°C; and when the solvent is methanol, step a) may be performed at a temperature of times be dried, for example under reduced pressure, and optionally elevated temperature, preferably at reduced pressure and at a temperature of: about 40°C to about 90°C, about 55°C to about 85°C, or about 60°C to about 80°C.
[0087] Alternatively, Mesdopetam mesylate form MS2 may be prepared by a process comprising stirring a suspension of Mesdopetam mesylate in isopropanol. Preferably, the suspension of Mesdopetam mesylate in isopropanol is prepared by combining Mesdopetam (preferably form Bl), methanesulfonic acid, and isopropanol. More particularly, the process comprises:
(i) providing a mixture of Mesdopetam, preferably form Bl, and methanesulfonic acid in isopropanol;
(ii) optionally stirring the mixture; and
(iii) optionally isolating crystalline form MS2 of Mesdopetam Mesylate from the mixture. [0088] In any aspect or embodiment of this process, in step (i), the isopropanol may be present in an amount of: about 5 to about 20 ml per gram of Mesdopetam, about 7 to about 15 ml per gram of Mesdopetam, or about 7 to about 12 ml per gram of Mesdopetam. In any embodiment of this process, the molar ratio of methanesulfonic acid to Mesdopetam may be: about 1 to about 1.5 molar equivalents, about 1 to about 1.3 molar equivalents, about 1.0 to about 1.2 molar equivalents, about 1.1 molar equivalents, or about 1.0 molar equivalents. In any embodiment of this process, the mixture in step (i) is preferably at room temperature. In any embodiment of this process, step (ii) comprises stirring the mixture for a sufficient time to prepare Mesdopetam mesylate form MS2, preferably about 8 hours to about 4 days, about 12 hours to about 72 hours, about 20 hours to about 60 hours, or about 24 hours to about 48 hours. In any embodiment of this process, step (iii) comprises isolating the Mesdopetam mesylate Form
MS2 by any suitable method such as by decantation, centrifuge or filtration, preferably filtration. The Mesdopetam mesylate Form MS2 may optionally be dried, for example under reduced pressure, and optionally elevated temperature, preferably at reduced pressure and at a temperature of: about 40°C to about 90°C, about 55°C to about 85°C, or about 60°C to about 80°C; optionally, the drying can be conducted for a sufficient time to obtain a dried solid, preferably about 1 hour to about 10 hours, about 2 hours to about 8 hours, about 3 hours to about 6 hours, or about 4 hours to about 6 hours.
[0089] Crystalline form MS2 of Mesdopetam Mesylate may alternatively be prepared by crystallisation of Mesdopetam Mesylate from water. In any embodiment, the process may comprise:
(a) providing a solution comprising Mesdopetam Mesylate in water;
(b) crystallising Mesdopetam Mesylate Form MS2 from the solution; and
(c) optionally isolating crystalline form MS2 of Mesdopetam Mesylate.
[0090] In any embodiment of this process, the solution in step (a) may be prepared by combining Mesdopetam (preferably form Bl), methanesulfonic acid, and water. In any embodiment of this process, in step (a), the water may be present in an amount of: about 5 to about 20 ml per gram of Mesdopetam, about 10 to about 18 ml per gram of Mesdopetam, about 12 to about 16 ml per gram of Mesdopetam or about 13 to about 14 ml per gram of Mesdopetam. In any embodiment of this process, the molar ratio of methanesulfonic acid to Mesdopetam may be: about 1 to about 1.5 molar equivalents, about 1 to about 1.3 molar equivalents, about 1.0 to about 1.2 molar equivalents, about 1.1 molar equivalents, or about 1.0 molar equivalents. In any embodiment of this process, the solution in step (a) is preferably at room temperature. In any embodiment of this process, step (b) comprises stirring the mixture, preferably about 1 to about 60 minutes, about 2 to about 30 minutes, about 2 to about 10 minutes, or about 5 minutes. In any embodiment of this process, step (c) comprises partial or complete evaporation of the water, preferably by exposure to room temperature. Preferably, in any embodiment of this process, step (c) comprises allowing the water to evaporate over a period of about 1 to about 10 days, about 2 to about 8 days, about 3 to about 6 days, or about 4 days. The Mesdopetam mesylate may optionally be isolated by any suitable process if the water is partially evaporated, preferably by decantation, centrifuge or filtration, preferably filtration. The Mesdopetam mesylate Form MS2 may optionally be dried, for example under reduced pressure, and optionally elevated
temperature, preferably at reduced pressure and at a temperature of: about 40°C to about 90°C, about 55°C to about 85°C, or about 60°C to about 80°C.
[0091] The present disclosure encompasses Mesdopetam besylate. The Mesdopetam besylate is preferably in a solid form, and more preferably the Mesdopetam besylate is crystalline. In any aspect or embodiment of the present disclosure, Mesdopetam besylate may be isolated.
Particularly, Mesdopetam besylate according to any aspect or embodiment may be chemically pure. Crystalline Mesdopetam besylate according to any aspect or embodiment may be polymorphically pure (i.e. containing a single crystalline form of Mesdopetam besylate), preferably containing about 20% (w/w) or less, about 10% (w/w) or less, about 5% (w/w) or less, about 2% (w/w) or less, about 1% (w/w) or less, or about 0% of any other crystalline form of Mesdopetam besylate, as measured, for example, by XRPD. In any aspect or embodiment of the present disclosure, Mesdopetam besylate may be anhydrous.
[0092] The present disclosure includes a crystalline polymorph Mesdopetam besylate designated Form BS1. The crystalline Form BS1 of Mesdopetam besylate may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 6; an X-ray powder diffraction pattern having peaks at 8.0, 15.0, 16.1, 18.2 and 22.6 degrees 2-theta ± 0.2 degrees 2-theta; and combinations of these data. [0093] Crystalline Form BS1 of Mesdopetam besylate may be further characterized by an X- ray powder diffraction pattern having peaks at 8.0, 15.0, 16.1, 18.2 and 22.6 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, three or four additional peaks selected from 16.7, 17.7, 20.5 and 23.4 degrees 2-theta ± 0.2 degrees 2-theta.
[0094] Crystalline Form BS1 of Mesdopetam besylate may be alternatively characterized by an X-ray powder diffraction pattern having peaks at 8.0, 15.0, 16.1, 16.7, 17.7, 18.2, 20.5, 22.6 and 23.4 degrees 2-theta ± 0.2 degrees 2-theta.
[0095] In any aspect or embodiment of the present disclosure, crystalline Form BS1 of Mesdopetam besylate may be isolated. Particularly, crystalline Form BS1 of Mesdopetam besylate according to any aspect or embodiment of the disclosure may be isolated.
[0096] In any aspect or embodiment crystalline form BS1 of Mesdopetam besylate may be chemically pure.
[0097] In any aspect or embodiment crystalline Form BS1 of Mesdopetam besylate may be polymorphically pure.
[0098] In any aspect or embodiment of the present disclosure, crystalline Form BS1 of Mesdopetam besylate may be anhydrous.
[0099] Crystalline Form BS1 of Mesdopetam besylate may be characterized by each of the above characteristics alone/or by all possible combinations, e.g., an XRPD pattern having peaks at 8.0, 15.0, 16.1, 18.2 and 22.6 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 6, and combinations thereof.
[00100] Mesdopetam Besylate may be prepared by reacting Mesdopetam with benzenesulfonic acid in any suitable solvent. The solvent is preferably selected at least enable dissolution of Mesdopetam and benzenesulfonic acid, and optionally enables precipitation of the resulting Mesdopetam Besylate (e.g. by cooling or evaporation). If the solvent does not readily enable precipitation of Mesdopetam Besylate, an antisolvent for Mesdopetam Besylate, for example a non-polar solvent such as an alkane, or a solvent selected from n-heptane, dichloromethane, acetone or tetrahydrofuran, may be added to facilitate precipitation.
[00101] Crystalline form BS1 of Mesdopetam Besylate may be prepared by crystallisation from a mixture comprising Mesdopetam Besylate and a solvent comprising isopropanol, water, acetonitrile, ethanol, methanol, or mixture thereof. In embodiments, the process comprises:
(a) providing a solution of Mesdopetam Besylate in a solvent comprising acetonitrile, ethanol, methanol, isopropanol, water or mixtures thereof;
(b) cooling the mixture; and
(c) optionally isolating crystalline form BS1 of Mesdopetam Besylate from the mixture. [00102] In any embodiment of this process, the solution in step (a) may be prepared by combining Mesdopetam besylate with the solvent. In any embodiment, the solvent may be isopropanol, water, acetonitrile, ethanol (optionally 96% ethanol/water or absolute ethanol), or methanol, or a mixture of acetonitrile and water. According to any embodiment, in step (a), the solvent may be present in an amount of: about 2 ml to about 40 ml per gram of Mesdopetam Besylate, about 4 ml to about 35 ml per gram of Mesdopetam Besylate, or about 5 to about 30 ml per gram of Mesdopetam Besylate. In any embodiment of the process, the solution in step (a) may be at elevated temperature, preferably, at a temperature of about 15°C to about 70°C, about 18°C to about 65°C, about 20°C to about 60°C, or about 22°C to about 58°C. In any embodiment, the solution in step (a) may be prepared by combining Mesdopetam besylate with the heated solvent, or by combining Mesdopetam besylate with the solvent at ambient
temperature, and optionally heating the mixture to provide a solution. In any embodiment of the process, step (b) may comprise: cooling the mixture, preferably to about 5°C to about 30°C, or about 10°C to about 25°C or about 20°C to about 25°C. Preferably, in any embodiment of this process, the solution in step (a) is heated to a temperature of about 18°C to about 60°C (preferably about 22°C to about 60°C), and step (b) comprises cooling the mixture in step (a) to a temperature of: about 5°C to about 35°C, about 10°C to about 30°C, or room temperature. In any embodiment, the cooling may be active or passive, preferably passive (i.e. the mixture is allowed to cool under ambient conditions). In any embodiment of this process, the cooling is preferably conducted without stirring. In any embodiment of this process, step (c) may comprise isolating the solid by any suitable method such as by decantation, centrifuge or by filtration, preferably by filtration. The Mesdopetam Besylate Form BS1 may optionally be dried, for example under reduced pressure, and optionally elevated temperature, preferably at reduced pressure and at a temperature of: about 40°C to about 90°C, about 55°C to about 85°C, or about 60°C to about 80°C. According to any embodiment of the process, when the solvent is acetonitrile, the solution in step a) may be at a temperature of about 30°C to about 70°C, about 40°C to about 60°C, about 45°C to about 55°C, or about 45°C to about 50°C; and/or the acetonitrile is used in an amount of about 10 ml to about 30 ml, about 15 ml to 25 ml, or about 20 ml per gram of Mesdopetam Besylate. According to any embodiment of the process, when the solvent is ethanol, step a) may be performed at a temperature of about 40°C to about 70°C, about 45°C to about 60°C, about 50°C to about 60°C or about 55°C to about 60°; and/or the ethanol is used in an amount of about 15 ml to 25 ml, or about 20 ml per gram of Mesdopetam Besylate. According to any embodiment of the process, when the solvent is methanol, step a) may be performed at a temperature of about 18°C to about 35°C, about 18°C to about 30°C, about 20°C to about 25°C or at room temperature; and/or the methanol is used in an amount of about 5 ml to 20 ml, about 8 to about 15 ml, or about 10 ml per gram of Mesdopetam Besylate. According to any embodiment of the process, when the solvent is isopropanol, step a) may be performed at a temperature of about 30°C to about 70°C, about 40°C to about 60°C, about 45°C to about 55°C, or about 48°C to about 54°C; and/or the isopropanol is used in an amount of about 15 ml to 50 ml, about 20 ml to about 40 ml, about 25 ml to about 35 ml, or about 30 ml per gram of Mesdopetam Besylate. According to any embodiment of the process, when the solvent a mixture of acetonitrile and water, step a) may be performed at a temperature of about 18°C to about 35°C, about 18°C to
about 30°C, about 20°C to about 25°C or at room temperature; and/or the combined amount of acetonitrile/water used is: about 2 ml to 15 ml, about 2 ml to about 10 ml, about 2 ml to about 8 ml, 4 ml to about 7 ml, or about 5 ml per gram of Mesdopetam Besylate. Preferably, in any embodiment of the process wherein a mixture of acetonitrile and water are used, the ratio (vol/vol) of acetonitrile to water is: about 3: 1 to about 1:3; about 2: 1 to about 1:2, about 1.5: 1 to about 1: 1.5, about 1.2:1 to about 1 : 1.2, or about 1:1.
[00103] Alternatively, Mesdopetam Besylate Form BS1 may be prepared by a process comprising stirring a suspension of Mesdopetam Besylate in isopropanol. Preferably, the suspension of Mesdopetam Besylate in isopropanol is prepared by combining Mesdopetam (preferably form Bl), benzenesulfonic acid, and isopropanol. More particularly, the process comprises:
(i) providing a mixture of Mesdopetam, preferably form Bl, and benzenesulfonic acid in isopropanol;
(ii) optionally stirring the mixture; and
(iii) optionally isolating crystalline form BS1 of Mesdopetam Besylate from the mixture. [00104] In any aspect or embodiment of this process, in in step (i), the isopropanol may be present in an amount of: about 5 to about 25 ml per gram of Mesdopetam, about 8 to about 20 ml per gram of Mesdopetam, about 10 to about 15 ml per gram of Mesdopetam, or about 11 ml to about 17 ml per gram of Mesdopetam. In any embodiment of this process, the molar ratio of benzenesulfonic acid to Mesdopetam may be: about 1 to about 1.5 molar equivalents, about 1 to about 1.3 molar equivalents, about 1.0 to about 1.2 molar equivalents, about 1.0 to about 1.1 molar equivalents, or about 1.0 molar equivalents. In any embodiment of this process, the mixture in step (i) is preferably at room temperature. In any embodiment of this process, step (ii) comprises stirring the mixture for a sufficient time to prepare Mesdopetam besylate form BS1, preferably about 4 hours to about 72 hours, about 8 hours to about 48 hours, about 16 hours to about 36 hours, about 20 hours to about 30 hours, or about 24 hours. In any embodiment of this process, step (iii) comprises isolating the Mesdopetam besylate Form BS1 by any suitable method such as by decantation, centrifuge or filtration, preferably filtration. The Mesdopetam besylate Form BS1 may optionally be dried, for example under reduced pressure, and optionally elevated temperature, preferably at reduced pressure and at a temperature of: about 40°C to about 90°C, about 55°C to about 80°C, or about 60°C to about 75°C; optionally, the drying can be
conducted for a sufficient time to obtain a dried solid, preferably about 1 hour to about 10 hours, about 2 hours to about 8 hours, about 3 hours to about 6 hours, or about 4 hours to about 6 hours. [00105] The present disclosure encompasses Mesdopetam (L)-malate. The Mesdopetam (L)- malate is preferably in a solid form, and more preferably the Mesdopetam (L)-malate is crystalline. In any aspect or embodiment of the present disclosure, Mesdopetam (L)-malate may be isolated. Particularly, Mesdopetam (L)-malate according to any aspect or embodiment may be chemically pure. Crystalline Mesdopetam (L)-malate according to any aspect or embodiment may be polymorphically pure (i.e. containing a single crystalline form of Mesdopetam (L)- malate), preferably containing about 20% (w/w) or less, about 10% (w/w) or less, about 5% (w/w) or less, about 2% (w/w) or less, about 1% (w/w) or less, or about 0% of any other crystalline form of Mesdopetam (L)-malate, as measured, for example, by XRPD. In any aspect or embodiment of the present disclosure, Mesdopetam (L)-malate may be anhydrous.
[00106] The present disclosure includes a crystalline polymorph Mesdopetam (L)-malate designated Form Ml. The crystalline Form Ml of Mesdopetam (L)-malate may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 7; an X-ray powder diffraction pattern having peaks at 5.0, 14.9, 16.2, 22.8 and 24.9 degrees 2-theta ± 0.2 degrees 2-theta; and combinations of these data. [00107] Crystalline Form Ml of Mesdopetam (L)-malate may be further characterized by an X-ray powder diffraction pattern having peaks at 5.0, 14.9, 16.2, 22.8 and 24.9 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, three or four additional peaks selected from 17.5, 18.3, 19.7 and 23.4 degrees 2-theta ± 0.2 degrees 2-theta.
[00108] Crystalline Form Ml of Mesdopetam (L)-malate may be alternatively characterized by an X-ray powder diffraction pattern having peaks at 5.0, 14.9, 16.2, 17.5, 18.3, 19.7, 22.8, 23.4 and 24.9 degrees 2-theta ± 0.2 degrees 2-theta.
[00109] In any aspect or embodiment of the present disclosure, crystalline Form Ml of Mesdopetam (L)-malate may be isolated. Particularly, crystalline Form Ml of Mesdopetam (L)- malate according to any aspect or embodiment of the disclosure may be isolated.
[00110] In any aspect or embodiment crystalline form Ml of Mesdopetam (L)-malate may be chemically pure.
[00111] In any aspect or embodiment crystalline Form Ml of Mesdopetam (L)-malate may be polymorphically pure.
[00112] In any aspect or embodiment of the present disclosure, crystalline Form Ml of Mesdopetam (L)-malate may be anhydrous.
[00113] Crystalline Form Ml of Mesdopetam (L)-malate may be characterized by each of the above characteristics alone/or by all possible combinations, e.g., an XRPD pattern having peaks at 5.0, 14.9, 16.2, 22.8 and 24.9 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 7, and combinations thereof.
[00114] The present disclosure encompasses Mesdopetam hemi-(L)-malate. The Mesdopetam hemi-(L)-malate is preferably in a solid form, and more preferably the Mesdopetam-hemi (L)- malate is crystalline. In any aspect or embodiment of the present disclosure, Mesdopetam hemi- (L)-malate may be isolated. Particularly, Mesdopetam hemi-(L)-malate according to any aspect or embodiment may be chemically pure. Crystalline Mesdopetam hemi-(L)-malate according to any aspect or embodiment may be polymorphically pure (i.e. containing a single crystalline form of Mesdopetam hemi-(A)-malate), preferably containing about 20% (w/w) or less, about 10% (w/w) or less, about 5% (w/w) or less, about 2% (w/w) or less, about 1% (w/w) or less, or about 0% of any other crystalline form of Mesdopetam hemi-(/.)-malate, as measured, for example, by XRPD. In any aspect or embodiment of the present disclosure, Mesdopetam-hemi (L)-malate may be anhydrous.
[00115] The present disclosure includes a crystalline polymorph Mesdopetam hemi-(L)- malate designated Form HM1. The crystalline Form HM1 of Mesdopetam hemi-(/.)-malate may be characterized by data selected from one or more of the following: an X-ray powder diffraction pattern substantially as depicted in Figure 8; an X-ray powder diffraction pattern having peaks at
14.5, 15.5, 20.5, 21.3 and 23.3 degrees 2-theta ± 0.2 degrees 2-theta; and combinations of these data.
[00116] Crystalline Form HM1 of Mesdopetam hemi-(/.)-malate may be further characterized by an X-ray powder diffraction pattern having peaks at 14.5, 15.5, 20.5, 21.3 and 23.3 degrees 2- theta ± 0.2 degrees 2-theta, and also having any one, two, three, four or five additional peaks selected from 11.6, 13.2, 19.1, 22.4 and 26.5 degrees 2-theta ± 0.2 degrees 2-theta.
[00117] Crystalline Form HM1 of Mesdopetam hemi-(/.)-malate may be alternatively characterized by an X-ray powder diffraction pattern having peaks at 11.6, 13.2, 14.5, 15.5, 19.1,
20.5, 21.3, 22.4, 23.3, and 26.5 degrees 2-theta ± 0.2 degrees 2-theta.
[00118] In any aspect or embodiment of the present disclosure, crystalline Form HM1 of Mesdopetam hemi-(L)-malate may be isolated. Particularly, crystalline Form HM1 of Mesdopetam hemi-(L)-malate according to any aspect or embodiment of the disclosure may be isolated.
[00119] In any aspect or embodiment crystalline form HM1 of Mesdopetam hemi-(L)-malate may be chemically pure.
[00120] In any aspect or embodiment crystalline Form HM1 of Mesdopetam hemi-(L)-malate may be polymorphically pure.
[00121] In any aspect or embodiment of the present disclosure, crystalline Form HM1 of Mesdopetam hemi-(L)-malate may be anhydrous.
[00122] Crystalline Form HM1 of Mesdopetam hemi-(L)-malate may be characterized by each of the above characteristics alone/or by all possible combinations, e.g., an XRPD pattern having peaks at 14.5, 15.5, 20.5, 21.3 and 23.3 degrees 2-theta ± 0.2 degrees 2-theta; an XRPD pattern as depicted in Figure 8, and combinations thereof.
[00123] Crystalline form HM1 of Mesdopetam hemi-(L)-malate may be prepared by crystallisation from a mixture comprising Mesdopetam hemi-(L)-malate and a solvent comprising, acetonitrile, ethanol, methanol, acetone, or mixture thereof.
[00124] Mesdopetam hemi-(L)-malate may be prepared by reacting Mesdopetam with L-malic acid in any suitable solvent. The solvent is preferably selected at least enable dissolution of Mesdopetam and L-malic acid, and optionally enables precipitation of the resulting Mesdopetam hemi-(L)-malate (e.g. by cooling or evaporation). If the solvent does not readily enable precipitation of Mesdopetam hemi-(L)-malate, an antisolvent for Mesdopetam hemi-(L)-malate, for example a non-polar solvent such as an alkane, or a solvent selected from n-heptane, dichloromethane, acetone, or tetrahydrofuran, may be added to facilitate precipitation.
[00125] Crystalline form HM1 of Mesdopetam hemi-(L)-malate may be prepared by crystallisation from a mixture comprising Mesdopetam hemi-(L)-malate and a solvent comprising acetonitrile, ethanol (96% ethanol/water or absolute ethanol), methanol, or mixture thereof. In any embodiment, the process may comprise:
(a) providing a solution of Mesdopetam hemi-(L)-malate in a solvent comprising acetonitrile, ethanol, methanol or mixtures thereof;
(b) optionally cooling the mixture; and 1
(c) optionally isolating crystalline form HM1 of Mesdopetam hemi-(L)-malate from the mixture.
[00126] In any embodiment of this process, the solution in step (a) may be prepared by combining Mesdopetam hemi-(L)-malate with the solvent. In any embodiment of this process, the solution in step (a), the solvent may be present in an amount of: about 5 to about 40 ml per gram of Mesdopetam hemi-(L)-malate, about 5 ml to about 35 ml per gram of Mesdopetam hemi-(L)-malate, about 7 to about 32 ml per gram of Mesdopetam hemi-(L)-malate, or about 10 to about 30 ml per gram of Mesdopetam hemi-(L)-malate. In any embodiment of the process, the solution in step (a) may be at elevated temperature, preferably, at a temperature of: about 15°C to about the reflux temperature, about 15°C to about 100°C, about 18°C to about 100°C, about 20°C to about 98°C, or about 22°C to about 98°C. In any embodiment, the solution in step (a) may be prepared by combining Mesdopetam hemi-(L)-malate with the heated solvent, or by combining Mesdopetam hemi-(L)-malate with the solvent at ambient temperature, and optionally heating the mixture to provide a solution. In any embodiment of the process, step (b) may comprise: cooling the mixture, preferably to about 5°C to about 30°C, or about 10°C to about 25°C or about 20°C to about 25°C. Preferably, in any embodiment of this process, the solution in step (a) is heated to a temperature of about 18°C to about 60°C (preferably about 22°C to about 60°C), and step (b) comprises cooling the mixture in step (a) to a temperature of: about 5°C to about 35°C, about 10°C to about 30°C, or room temperature. In any embodiment, the cooling may be active or passive, preferably passive (i.e. the mixture is allowed to cool under ambient conditions). In any embodiment of this process, the cooling is preferably conducted without stirring. In any embodiment of this process, step (c) may comprise isolating the solid by any suitable method such as by decantation, centrifuge or by filtration, preferably by filtration. The Mesdopetam hemi-(L)-malate form HM1 may optionally be dried, for example under reduced pressure, and optionally elevated temperature, preferably at reduced pressure and at a temperature of: about 40°C to about 90°C, about 55°C to about 85°C, or about 60°C to about 80°C; optionally, the drying can be conducted for a sufficient time to obtain a dried solid, preferably about 1 hour to about 10 hours, about 2 hours to about 8 hours, about 3 hours to about 6 hours, or about 4 hours to about 6 hours.
[00127] According to any embodiment of the process, when the solvent is acetonitrile, the solution in step a) may be at a temperature of about 50°C to about the reflux temperature, about
80°C about 100°C, about 90°C to about 100°C, or about the reflux temperature; and/or the acetonitrile is used in an amount of about 4 ml to about 20 ml, about 6 ml to 15 ml, about 8 ml to about 12 ml, or about 10 ml per gram of Mesdopetam Hemi-(L)-malate. According to any embodiment of the process, when the solvent is ethanol, step a) may be performed at a temperature of about 50°C to about 80°C, about 60°C to about 75°C, or about 65°C to about 70°C; and/or the ethanol is used in an amount of: about 15 ml to 35 ml, about 18 ml to about 32 ml, or about 20 ml to about 30 ml per gram of Mesdopetam Hemi-(L)-malate. According to any embodiment of the process, when the solvent is methanol, step a) may be performed at a temperature of about 18°C to about 35°C, about 18°C to about 30°C, about 20°C to about 25°C or at room temperature; and/or the methanol is used in an amount of about 5 ml to 20 ml, about 8 to about 15 ml, or about 10 ml per gram of Mesdopetam Hemi-(L) -malate.
[00128] Alternatively, Mesdopetam Hemi-(L)-malate Form HM1 may be prepared by a process comprising stirring a suspension of Mesdopetam Hemi-(L)-malate in acetone.
Preferably, the suspension of Mesdopetam Hemi-(L)-malate in acetone is prepared by combining Mesdopetam (preferably form Bl), L-malic acid, and acetone. More particularly, the process comprises:
(i) providing a mixture of Mesdopetam, preferably form Bl, and (L)-malic acid in acetone;
(ii) optionally stirring the mixture; and
(iii) optionally isolating crystalline form HM1 of Mesdopetam hemi-(L)-malate from the mixture.
[00129] In any aspect or embodiment of this process, in step (i), the acetone may be present in an amount of: about 5 to about 20 ml per gram of Mesdopetam, about 7 to about 18 ml per gram of Mesdopetam, about 10 to about 15 ml, or about 11 to about 13 ml per gram of Mesdopetam. In any embodiment of this process, the amount of (L)-malic acid to Mesdopetam may be: about 0.5 mole equivalents. In any embodiment of this process, the mixture in step (i) is preferably at room temperature. In any embodiment of this process, step (ii) comprises stirring the mixture for a sufficient time to prepare Mesdopetam hemi-(L)-malate form HM1 , preferably about 4 hours to about 72 hours, about 8 hours to about 60 hours, about 18 hours to about 50 hours, about or about 24 hours to about 48 hours. In any embodiment of this process, step (iii) comprises isolating the Mesdopetam hemi-(L) -malate Form HM1 by any suitable method such as by
decantation, centrifuge or filtration, preferably filtration. The Mesdopetam hemi-(L)-malate Form HM1 may optionally be dried, for example under reduced pressure, and optionally elevated temperature, preferably at reduced pressure and at a temperature of: about 40°C to about 90°C, about 55°C to about 80°C, or about 60°C to about 75°C; optionally, the drying can be conducted for a sufficient time to obtain a dried solid, preferably about 1 hour to about 10 hours, about 2 hours to about 8 hours, about 3 hours to about 6 hours, or about 4 hours to about 6 hours.
[00130] The present disclosure encompasses a process for preparing solid state forms of Mesdopetam, Mesdopetam salts and solid state forms thereof. The process includes preparing any one of the Mesdopetam salts, or solid state forms of Mesdopetam or salts thereof by the processes of the present disclosure, and converting that form to a different form of Mesdopetam or salts thereof. For example, the conversion can be done, for example, by a process comprising acidifying any one of the above described forms of Mesdopetam to prepare the corresponding salt. Alternatively, the solid state form of Mesdopetam of the present disclosure may be prepared from Mesdopetam salts. This conversion can be done, for example, by a process comprising basifying a Mesdopetam salt. In yet another example, the process may include preparing any one of the solid state forms of Mesdopetam salts of the present disclosure by the processes of the present disclosure, and converting it to said other form of Mesdopetam or Mesdopetam salt. The conversion can be done for example by a process comprising basifying any one of the above described forms of Mesdopetam salts and reacting the obtained Mesdopetam with an appropriate acid, to obtain the corresponding salt. Alternatively, the conversion can be done by salt switching, i.e., reacting any one of the forms of the Mesdopetam salts of the present disclosure with an acid having a pKa which is lower than that of the acid of the original salt.
[00131] The Mesdopetam salts and crystalline polymorphs of Mesdopetam or salts thereof as defined herein and the pharmaceutical compositions or formulations of the Mesdopetam salts, or crystalline polymorphs of Mesdopetam or salts thereof may be used as medicaments, such as for the treatment of patients with Parkinson's Disease Dyskinesia, levodopa-induced dyskinesias, or Parkinson’s disease Psychosis.
[00132] The present disclosure also provides methods for the treatment of patients with levodopa-induced dyskinesias by administering a therapeutically effective amount of said Mesdopetam salts, or crystalline polymorphs of Mesdopetam or salts thereof of the present disclosure, or at least one of the above pharmaceutical compositions, to a subject suffering from
Parkinson's Disease Dyskinesia, levodopa-induced dyskinesia, or Parkinson’s disease Psychosis or otherwise in need of the treatment.
[00133] The present disclosure also provides uses of Mesdopetam salts, or crystalline polymorphs of Mesdopetam or salts thereof of the present disclosure, or at least one of the above pharmaceutical compositions, for the manufacture of medicaments for treating e.g., patients with Parkinson's Disease Dyskinesia, levodopa-induced dyskinesia, or Parkinson’s disease Psychosis. [00134] The present disclosure provides the above described Mesdopetam salts, or crystalline polymorphs of Mesdopetam or salts thereof for use in the preparation of pharmaceutical compositions comprising Mesdopetam or salts thereof and/or solid state forms thereof.
[00135] The present disclosure also encompasses the use of Mesdopetam salts, or crystalline polymorphs of Mesdopetam or salts thereof of the present disclosure for the preparation of pharmaceutical compositions of crystalline polymorph Mesdopetam or salts thereof and/or solid state forms thereof.
[00136] The present disclosure includes processes for preparing the above mentioned pharmaceutical compositions. The processes include combining any one or a combination of the Mesdopetam salts, or crystalline polymorphs of Mesdopetam or salts thereof of the present disclosure with at least one pharmaceutically acceptable excipient.
[00137] Pharmaceutical combinations or formulations of the present disclosure contain any one or a combination of the Mesdopetam salts, or solid state form of Mesdopetam or salts thereof of the present disclosure. In addition to the active ingredient, the pharmaceutical formulations of the present disclosure can contain one or more excipients. Excipients are added to the formulation for a variety of purposes.
[00138] Diluents increase the bulk of a solid pharmaceutical composition, and can make a pharmaceutical dosage form containing the composition easier for the patient and caregiver to handle. Diluents for solid compositions include, for example, microcrystalline cellulose (e.g., Avicel®), microfine cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates (e.g., Eudragit®), potassium chloride, powdered cellulose, sodium chloride, sorbitol, and talc.
[00139] Solid pharmaceutical compositions that are compacted into a dosage form, such as a tablet, can include excipients whose functions include helping to bind the active ingredient and other excipients together after compression. Binders for solid pharmaceutical compositions include acacia, alginic acid, carbomer (e.g. carbopol), carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxy ethyl cellulose, hydroxypropyl cellulose (e.g. Klucel®), hydroxypropyl methyl cellulose (e.g. Methocel®), liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates, povidone (e.g. Kollidon®, Plasdone®), pregelatinized starch, sodium alginate, and starch. [00140] The dissolution rate of a compacted solid pharmaceutical composition in the patient's stomach can be increased by the addition of a disintegrant to the composition. Disintegrants include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g., Ac- Di-Sol®, Primellose®), colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g., Kollidon®, Polyplasdone®), guar gum, magnesium aluminum silicate, methyl cellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (e.g., Explotab®), and starch.
[00141] Glidants can be added to improve the flowability of a non-compacted solid composition and to improve the accuracy of dosing. Excipients that can function as glidants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc, and tribasic calcium phosphate.
[00142] When a dosage form such as a tablet is made by the compaction of a powdered composition, the composition is subjected to pressure from a punch and dye. Some excipients and active ingredients have a tendency to adhere to the surfaces of the punch and dye, which can cause the product to have pitting and other surface irregularities. A lubricant can be added to the composition to reduce adhesion and ease the release of the product from the dye. Lubricants include magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, and zinc stearate. [00143] Flavoring agents and flavor enhancers make the dosage form more palatable to the patient. Common flavoring agents and flavor enhancers for pharmaceutical products that can be included in the composition of the present disclosure include maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol, and tartaric acid.
[00144] Solid and liquid compositions can also be dyed using any pharmaceutically acceptable colorant to improve their appearance and/or facilitate patient identification of the product and unit dosage level.
[00145] In liquid pharmaceutical compositions of the present invention, Mesdopetam or salts thereof and any other solid excipients can be dissolved or suspended in a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol, or glycerin.
[00146] Liquid pharmaceutical compositions can contain emulsifying agents to disperse uniformly throughout the composition an active ingredient or other excipient that is not soluble in the liquid carrier. Emulsifying agents that can be useful in liquid compositions of the present invention include, for example, gelatin, egg yolk, casein, cholesterol, acacia, tragacanth, chondrus, pectin, methyl cellulose, carbomer, cetostearyl alcohol, and cetyl alcohol.
[00147] Liquid pharmaceutical compositions of the present invention can also contain a viscosity enhancing agent to improve the mouth-feel of the product and/or coat the lining of the gastrointestinal tract. Such agents include acacia, alginic acid bentonite, carbomer, carboxymethylcellulose calcium or sodium, cetostearyl alcohol, methyl cellulose, ethylcellulose, gelatin guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, maltodextrin, polyvinyl alcohol, povidone, propylene carbonate, propylene glycol alginate, sodium alginate, sodium starch glycolate, starch tragacanth, xanthan gum and combinations thereof.
[00148] Sweetening agents such as sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol, and invert sugar can be added to improve the taste.
[00149] Preservatives and chelating agents such as alcohol, sodium benzoate, butylated hydroxyl toluene, butylated hydroxyanisole, and ethylenediamine tetraacetic acid can be added at levels safe for ingestion to improve storage stability.
[00150] According to the present disclosure, a liquid composition can also contain a buffer such as gluconic acid, lactic acid, citric acid, or acetic acid, sodium gluconate, sodium lactate, sodium citrate, or sodium acetate. Selection of excipients and the amounts used can be readily determined by the formulation scientist based upon experience and consideration of standard procedures and reference works in the field.
[00151] The solid compositions of the present disclosure include powders, granulates, aggregates, and compacted compositions. The dosages include dosages suitable for oral, buccal,
rectal, parenteral (including subcutaneous, intramuscular, and intravenous), inhalant, and ophthalmic administration. Although the most suitable administration in any given case will depend on the nature and severity of the condition being treated, in embodiments the route of administration is oral. The dosages can be conveniently presented in unit dosage form and prepared by any of the methods well-known in the pharmaceutical arts.
[00152] Dosage forms include solid dosage forms like tablets, powders, capsules, suppositories, sachets, troches, and lozenges, as well as liquid syrups, suspensions, and elixirs. [00153] The dosage form of the present disclosure can be a capsule containing the composition, such as a powdered or granulated solid composition of the disclosure, within either a hard or soft shell. The shell can be made from gelatin and optionally contain a plasticizer such as glycerin and/or sorbitol, an opacifying agent and/or colorant.
[00154] The active ingredient and excipients can be formulated into compositions and dosage forms according to methods known in the art.
[00155] A composition for tableting or capsule filling can be prepared by wet granulation. In wet granulation, some or all of the active ingredients and excipients in powder form are blended and then further mixed in the presence of a liquid, typically water that causes the powders to clump into granules. The granulate is screened and/or milled, dried, and then screened and/or milled to the desired particle size. The granulate can then be tableted, or other excipients can be added prior to tableting, such as a glidant and/or a lubricant.
[00156] A tableting composition can be prepared conventionally by dry blending. For example, the blended composition of the actives and excipients can be compacted into a slug or a sheet and then comminuted into compacted granules. The compacted granules can subsequently be compressed into a tablet.
[00157] As an alternative to dry granulation, a blended composition can be compressed directly into a compacted dosage form using direct compression techniques. Direct compression produces a more uniform tablet without granules. Excipients that are particularly well suited for direct compression tableting include microcrystalline cellulose, spray dried lactose, dicalcium phosphate dihydrate, and colloidal silica. The proper use of these and other excipients in direct compression tableting is known to those in the art with experience and skill in particular formulation challenges of direct compression tableting.
[00158] A capsule filling of the present disclosure can include any of the aforementioned blends and granulates that were described with reference to tableting, but they are not subjected to a final tableting step.
[00159] A pharmaceutical formulation of Mesdopetam can be administered. Mesdopetam may be formulated for administration to a mammal, in embodiments to a human, by injection. Mesdopetam can be formulated, for example, as a viscous liquid solution or suspension, such as a clear solution, for injection. The formulation can contain one or more solvents. A suitable solvent can be selected by considering the solvent's physical and chemical stability at various pH levels, viscosity (which would allow for syringeability), fluidity, boiling point, miscibility, and purity. Suitable solvents include alcohol USP, benzyl alcohol NF, benzyl benzoate USP, and Castor oil USP. Additional substances can be added to the formulation such as buffers, solubilizers, and antioxidants, among others. Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th ed.
[00160] The Mesdopetam salts, and crystalline polymorph of Mesdopetam salts and the pharmaceutical compositions and/or formulations of Mesdopetam or Mesdopetam salts of the present disclosure can be used as medicaments, in embodiments for the treatment of patients with Diabetic Peripheral Neuropathic pain and/or Post-Herpetic Neuralgia.
[00161] The present disclosure also provides methods of treating of patients with Diabetic Peripheral Neuropathic pain and/or Post-Herpetic Neuralgia by administering a therapeutically effective amount of any one or a combination of the Mesdopetam salts, or crystalline polymorphs of Mesdopetam of the present disclosure, or at least one of the above pharmaceutical compositions and/or formulations, to a subject in need of the treatment.
[00162] Having thus described the disclosure with reference to particular preferred embodiments and illustrative examples, those in the art can appreciate modifications to the disclosure as described and illustrated that do not depart from the spirit and scope of the disclosure as disclosed in the specification. The Examples are set forth to aid in understanding the disclosure but are not intended to, and should not be construed to limit its scope in any way.
[00163] Sample is powdered in a mortar and pestle and applied directly on a silicon plate holder. The X-ray powder diffraction pattern was measured with Philips X'Pert PRO X-ray powder diffractometer, equipped with Cu irradiation source =1.54184 A (Angstrom),
X’Celerator (2.022° 20) detector. Scanning parameters: angle range: 3-40 deg., step size 0.0167, time per step 37 s, continuous scan.
[00164] The described peak positions were determined without using silicon powder as an internal standard in an admixture with the sample measured.
EXAMPLES
Preparation of starting materials
[00165] Mesdopetam hemitartrate can be prepared according to methods known from the literature, for example according to the disclosure in International Publication No. WO 2020/239568.
[00166] Mesdopetam hemitartrate may also be prepared according to the following procedure: 2.0 grams of Mesdopetam hemitartrate crude material was dissolved in 4 ml of solvent mixture ethanol/water (ratio 1: 1) at 65 °C. The solution was allowed to cool and crystallization occurred at 30 °C. The suspension was allowed to cool to room temperature and vacuum filtered at room temperature. The solid was vacuum dried at 80 °C for 6 hours.
Example 1: Preparation of Mesdopetam crystal Form Bl
[00167] 1000 mg of Mesdopetam hemitartrate was dissolved in 5 ml of water at room temperature. Aqueous solution of sodium hydroxide (1 M) was added dropwise until pH of 11.7 was reached. The solution was extracted with 20 ml of dichloromethane and the organic layer was evaporated on rotavapour to obtain an oil. 3 ml of heptane was added to the oil and a suspension was observed after 20 minutes of mixing. The suspension was mixed for additional 5 hours and vacuum filtered. Obtained solid was analyzed and characterized by X-ray powder diffraction as Mesdopetam Form Bl. The XRPD pattern is presented in Figure 1.
Example 2: Preparation of Mesdopetam crystal Form B3
[00168] Mesdopetam form Bl (200 mg) was dissolved in cyclohexanone (1.5 mL) at room temperature. Solution was put into ice bath and crystallization occurred after 10 minutes of mixing. Suspension was additionally stirred for 3 hours and filtered. Obtained solid was dried in a vacuum oven at 80°C for 12 hours. The obtained product was analyzed by XRPD and characterized as Mesdopetam form B3. The XRPD pattern is presented in Figure 2.
Example 3: Preparation of Mesdopetam crystal Form B4
[00169] Mesdopetam form Bl (20 mg) was dissolved in cyclohexanone (0.2 mL) at room temperature. Prepared solution was left open at room conditions for solvent to evaporate. After crystallization occurred, crystals were filtrated off, analyzed by XRPD and characterized as Mesdopetam form B4. The XRPD pattern is presented in Figure 3.
Example 4: Preparation of Mesdopetam mesylate crystal Form MSI
[00170] 70 mg of Mesdopetam form Bl and 20 pL of methanesulfonic acid were suspended in 1 ml of acetone at room temperature. Suspension was mixed for 4 days and vacuum filtered. Obtained solid was analyzed by XRPD and characterized as Mesdopetam mesylate form MSI. The XRPD pattern is presented in Figure 4.
Example 5: Preparation of Mesdopetam mesylate crystal Form MS2
Procedure A
[00171] 455 mg of Mesdopetam form Bl and 1.05 mL of methanesulfonic acid were suspended in 5 ml of 2-propanol at room temperature. Suspension was mixed for 2 days, vacuum filtered and vacuum dried at 60 °C for 4 hours. Obtained solid was analyzed by XRPD and characterized as Mesdopetam mesylate form MS2. The XRPD pattern is presented in Figure 5.
Procedure B
[00172] 70 mg of Mesdopetam form Bl and 20 pL of methanesulfonic acid were suspended in 1 ml of water at room temperature. Solution was obtained after stirring for 5 minutes and it was left to evaporate. After 4 days solid was obtained. Obtained solid was analyzed by XRPD and identified as Mesdopetam mesylate form MS2.
Procedure C
[00173] 667 mg of Mesdopetam form Bl and 0.16 ml (1 eq) of methanesulfonic acid were suspended in 5 ml of 2-propanol at room temperature. Suspension was mixed for 1 day and vacuum filtered and dried at 80 °C for 6 hours in vacuum dryer. Obtained solid was analyzed by XRPD and identified as Mesdopetam mesylate form MS2. The material was vacuum dried at 80°C for 6 hours, analyzed by XRPD and identified as Mesdopetam mesylate form MS2.
Procedure D
[00174] 50 mg of Mesdopetam mesylate was dissolved in 1 ml of Acetonitrile at 64°C.
Solution was left to cool (without stirring) and crystallization occurred. The reaction mixture was vacuum filtered. Obtained solid was analyzed by XRPD and identified as Mesdopetam mesylate form MS2.
Procedure E
[00175] 50 mg of Mesdopetam mesylate was dissolved in 1 ml of Ethanol, 96% (or absolute) at 56 °C (70 °C with abs EtOH). Solution was left to cool (without stirring) and crystallization occurred. The reaction mixture was vacuum filtered. Obtained solid was analyzed by XRPD and identified as Mesdopetam mesylate form MS2.
Procedure F
[00176] 50 mg of Mesdopetam mesylate was dissolved in 0.5 ml of methanol at 45 °C.
Solution was left to cool (without stirring) and crystallization occurred. The reaction mixture was vacuum filtered. Obtained solid was analyzed by XRPD and identified as Mesdopetam mesylate form MS2.
Procedure G
[00177] 455 mg of Mesdopetam form Bl and 0.105 mL of methanesulfonic acid were suspended in 5 ml of 2-propanol at room temperature. Suspension was mixed for 2 days, vacuum filtered and vacuum dried at 60 °C for 4 hours. Obtained solid was analyzed by XRPD and characterized as Mesdopetam mesylate form MS2. The XRPD pattern is presented in Figure 5.
Example 6: Preparation of Mesdopetam besylate crystal Form BS1
Procedure A
[00178] 59 mg of Mesdopetam form Bl and 49 mg of benzenesulfonic acid were suspended in
1 ml of 2-propanol at room temperature. Suspension was mixed for 1 day, vacuum filtered and vacuum dried at 60 °C for 4 hours. Obtained solid was analyzed by XRPD and characterized as Mesdopetam besylate form BS1. The XRPD pattern is presented in Figure 6.
Procedure B
[00179] 813 mg of Mesdopetam form Bl and 468 mg (1 eq) of benzenesulfonic acid were suspended in 9 ml of 2-propanol at room temperature. Suspension was mixed for 1 day and vacuum filtered. Obtained solid was analyzed by XRPD and identified as Mesdopetam besylate form BS1. The material was vacuum dried at 75°C for 5 hours, analyzed by XRPD and identified as Mesdopetam besylate form BS1.
Procedure C
[00180] 50 mg of Mesdopetam besylate was dissolved in 1 ml of acetonitrile at 48 °C. Solution was left to cool (without stirring) and crystallization occurred. The reaction mixture was vacuum filtered. Obtained solid was analyzed by XRPD and identified as Mesdopetam besylate form BS1.
Procedure D
[00181] 50 mg of Mesdopetam besylate was dissolved in 1 ml of ethanol, 96% at 57 °C (in ethanol, absolute at 59 °C). Solution was left to cool (without stirring) and crystallization occurred. The reaction mixture was vacuum filtered. Obtained solid was analyzed by XRPD and identified as Mesdopetam besylate form BS1.
Procedure E
[00182] 50 mg of Mesdopetam besylate was dissolved in 0.5 ml of methanol at room temperature. Solution was left to cool (without stirring) and crystallization occurred. The reaction mixture was vacuum filtered. Obtained solid was analyzed by XRPD and identified as Mesdopetam besylate form BS1.
Procedure F
[00183] 50 mg of Mesdopetam besylate was dissolved in 1.5 ml of 2-propanol at 51 °C.
Solution was left to cool (without stirring) and crystallization occurred. The reaction mixture was vacuum filtered. Obtained solid was analyzed by XRPD and identified as Mesdopetam besylate form BS1.
Procedure G
[00184] 50 mg of Mesdopetam besylate was dissolved in 0.25 ml of acetonitrile/water (1: 1) at room temperature. Solution was left to cool (without stirring) and crystallization occurred. Obtained solid was analyzed by XRPD and identified as Mesdopetam besylate form BS1.
Example 7: Preparation of Mesdopetam (Z)-malate crystal Form Ml
[00185] 63 mg Mesdopetam form Bl and 37 mg of L-malic acid were suspended in 1 ml of acetone at room temperature. Suspension was dissolved after 5 minutes of mixing and it was put to ice bath for 1 day. Suspension was obtained after 1 day, vacuum filtered and vacuum dried at 60 °C for 4 hours. Obtained solid was analyzed by XRPD and characterized as Mesdopetam malate form Ml . The XRPD pattern is presented in Figure 7.
Example 8: Preparation of Mesdopetam hemi-(Z)-malate crystal Form HM1
Procedure A
[00186] 80 mg of Mesdopetam form Bl and 20 mg of L-malic acid were suspended in 1 ml of acetone at room temperature. Suspension was mixed for 2 days, vacuum filtered and vacuum dried at 60 °C for 4 hours. Obtained solid was analyzed by XRPD and characterized as Mesdopetam hemi-L-malate form HM1. The XRPD pattern is presented in Figure 8.
Procedure B
[00187] 483 mg of Mesdopetam base and 117 mg of L-malic acid (0.5 eq) were suspended in
6 ml of acetone at room temperature. Suspension was mixed for 1 day and vacuum filtered. Obtained solid was analyzed by XPRD and identified as Mesdopetam hemi-L-malate form HM1. Material was vacuum dried at 80 °C for 6 hours and analyzed by XRPD and identified as Mesdopetam hemi-L-malate form HM1.
Procedure C
[00188] 50 mg of Mesdopetam hemimalate was dissolved in 0.5 ml of acetonitrile at reflux temperature. Solution was left to cool (without stirring) and crystallization occurred. The reaction mixture was vacuum filtered. Obtained solid was analyzed by XRPD and identified as Mesdopetam hemi-L-malate form HM1.
Procedure D
[00189] 50 mg of Mesdopetam hemiamalate was dissolved in 1.5 ml of ethanol, absolute at 70
°C. Solution was left to cool (without stirring) and crystallization occurred. The reaction mixture was vacuum filtered. Obtained solid was analyzed by XRPD and identified as Mesdopetam hemi-L-malate form HM1.
Procedure E
[00190] 50 mg of Mesdopetam hemimalate was dissolved in 1 ml of ethanol, 96% at 65 °C.
Solution was left to cool (without stirring) and crystallization occurred. The reaction mixture was vacuum filtered. Obtained solid was analyzed by XRPD and identified as Mesdopetam hemi-L- malate form HM1.
Procedure F
[00191] 50 mg of Mesdopetam hemimalate was dissolved in 0.5 ml of methanol at room temperature. Solution was left to cool (without stirring) and crystallization occurred. The reaction mixture was vacuum filtered. Obtained solid was analyzed by XRPD and identified as
Mesdopetam hemi-L-malate form HM1.
Example 9
[00192] Stability of Mesdopetam Mesylate, Mesdopetam Besylate and Mesdopetam Hemi- (Z)-Malate.
Storage stability at different relative humidities at ambient temperature
[00193] Samples of Mesdopetam Mesylate Form MS2, Mesdopetam Besylate Form BS1 and Mesdopetam Hemi-(Z)-Malate form HM1 were subjected to conditions of different relative humidities at ambient temperature. XRPD analysis was performed on the samples after 7 days. The results are shown in Table 1 below.
Table 1
[00194] These results demonstrate that Mesdopetam Mesylate, Mesdopetam Besylate and Mesdopetam Hemi-(Z)-Malate are especially stable to high and low relative humidity conditions and is particularly suitable for use in pharmaceutical dosage forms.
Grinding experiments
[00195] Samples of Mesdopetam Mesylate Form MS2, Mesdopetam Besylate Form BS1 and Mesdopetam Hemi-(Z)-Malate form HM1 were subjected to strong grinding, and to solvent drop grinding in water, ethanol, ethyl acetate, isopropanol and acetone. In these experiments, about 20
mg of the sample is placed in a mortar and ground with a pestle for 5 minutes. The solvent, when used, as added to the crystalline material before grinding, in a volume of 10 microliters. XRPD analysis performed on each of the samples after the grinding experiment, confirmed no change in the starting material (Table 2):
Table 2
[00196] The results demonstrate that Mesdopetam Mesylate, Mesdopetam Besylate and Mesdopetam Hemi-(Z)-Malate are resistant to polymorphic changes and are highly suitable for preparing pharmaceutical formulations.
Thermal stability
[00197] Samples of Mesdopetam Mesylate Form MS2, Mesdopetam Besylate Form BS1 and Mesdopetam Hemi-(Z)-Malate form HM1 were subjected to heating up to 100°C for 30 minutes. XRPD analysis of the samples confirmed no change in the starting material (Table 3):
Table 3
[00198] The above data shows that Mesdopetam Mesylate, Mesdopetam Besylate and Mesdopetam Hemi-(Z)-Malate are highly stable, showing no polymorphic conversion when heated to 100°C for 30 minutes.
Stability to compression
[00199] Samples of Mesdopetam Mesylate Form MS2, Mesdopetam Besylate Form BS1 and Mesdopetam Hemi-(Z)-Malate form HM1 were subjected to a pressure of 1000 kg and 2000 kg (Atlas® Autopress hydraulic press, set to 1 or 2 tons). XRPD analysis was performed on the samples after 1-5 minutes. The results are shown in Table 4 below:
Table 4
[00200] The results demonstrate the high stability of Mesdopetam Mesylate Mesdopetam Besylate and Mesdopetam Hemi-(Z)-Malate to compression, and further confirm the suitability of these salts for preparing pharmaceutical dosage forms.
Stability to solvent vapours
[00201] Samples of Mesdopetam Mesylate Form MS2, Mesdopetam Besylate Form BS1 and Mesdopetam Hemi-(Z)-Malate form HM1 were exposed to solvent vapours of acetone, ethanol, isopropanol, water and ethyl acetate at 25°C. XRPD analysis was performed on the samples after 7 days and after 30 days. The results are shown in Table 5 below:
Table 5
[00202] The above data further confirms the excellent stability of Mesdopetam Mesylate, Mesdopetam Besylate and Mesdopetam Hemi-(L)-Malate.
Claims
1. A salt of Mesdopetam with an acid selected from methanesulfonic acid, benzenesulfonic acid, or (L)-malic acid.
2. A salt according to Claim 1, which is selected from Mesdopetam mesylate. Mesdopetam besylate, or Mesdopetam hemi-(L)-malate, optionally wherein the salt is crystalline.
3. A crystalline form of Mesdopetam mesylate according to Claim 1 or Claim 2, designated form MS2, which is characterized by data selected from:
(a) an X-ray powder diffraction pattern having peaks at 7.8, 15.2, 19.6, 23.5 and 25.0 degrees 2-theta ± 0.2 degrees 2-theta;
(b) an X-ray powder diffraction pattern substantially as depicted in Figure 5; and
(c) a combination of (a) and (b).
4. A crystalline form of Mesdopetam mesylate according to Claim 3, which is characterized by an X-ray powder diffraction pattern having peaks at 7.8, 15.2, 19.6, 23.5 and 25.0 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, three, four or five additional peaks selected from 15.7, 17.2, 18.2, 20.2 and 20.9 degrees 2-theta ± 0.2 degrees 2-theta.
5. A crystalline form of Mesdopetam mesylate according to claim 3 or claim 4, which is characterized by an X-ray powder diffraction pattern having peaks at 7.8, 15.2, 15.7, 17.2, 18.2, 19.6, 20.2, 23.5 and 25.0 degrees 2-theta ± 0.2 degrees 2-theta.
6. A crystalline form of Mesdopetam mesylate according to any one of claims 3, 4 or 5, which is characterized by an X-ray powder diffraction pattern having peaks at 7.8, 15.2, 15.7, 17.2, 18.2, 19.6, 20.2, 20.9, 23.5 and 25.0 degrees 2-theta ± 0.2 degrees 2-theta.
7. A crystalline form of Mesdopetam Besylate according to Claim 1 or Claim 2, designated form BS1, which is characterized by data selected from:
(a) an X-ray powder diffraction pattern having peaks at 8.0, 15.0, 16.1, 18.2 and 22.6 degrees 2-theta ± 0.2 degrees 2-theta;
(b) an X-ray powder diffraction pattern substantially as depicted in Figure 6; and
(c) a combination of (a) and (b).
A crystalline form of Mesdopetam Besylate according to Claim 7, which is characterized by an X-ray powder diffraction pattern having peaks at 8.0, 15.0, 16.1, 18.2 and 22.6 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, three or four additional peaks selected from 16.7, 17.7, 20.5 and 23.4 degrees 2-theta ± 0.2 degrees 2-theta. A crystalline form of Mesdopetam Besylate according to Claim 7 or Claim 8, which is characterized by an X-ray powder diffraction pattern having peaks at 8.0, 15.0, 16.1, 16.7, 17.7, 18.2, 20.5, 22.6 and 23.4 degrees 2-theta ± 0.2 degrees 2-theta. A crystalline form of Mesdopetam hemi-(L)-malate according to Claim 1 or Claim 2, designated Form HM1, which is characterized by data selected from:
(a) an X-ray powder diffraction pattern having peaks at 14.5, 15.5, 20.5, 21.3 and 23.3 degrees 2-theta ± 0.2 degrees 2-theta;
(b) an X-ray powder diffraction pattern substantially as depicted in Figure 8; and
(c) a combination of (a) and (b). A crystalline form of Mesdopetam hemi-(L)-malate according Claim 10, which is characterized by an X-ray powder diffraction pattern having peaks at 14.5, 15.5, 20.5, 21.3 and 23.3 degrees 2-theta ± 0.2 degrees 2-theta, and also having any one, two, three, four or five additional peaks selected from 11.6, 13.2, 19.1, 22.4 and 26.5 degrees 2-theta ± 0.2 degrees 2-theta. A crystalline form of Mesdopetam hemi-(L)-malate according to Claim 10 or Claim 11, which is characterized by an X-ray powder diffraction pattern having peaks at 11.6, 13.2, 14.5, 15.5, 19.1, 20.5, 21.3, 22.4, 23.3, and 26.5 degrees 2-theta ± 0.2 degrees 2-theta. A product according to any of Claims 1 to 12, which is anhydrous. A product according to any of Claims 1 to 13, which is isolated. A crystalline product according to any of Claims 2 to 14 which is polymorphically pure; preferably wherein the crystalline product contains: about 20% (w/w) or less, about 10% (w/w) or less, about 5% (w/w) or less, about 2% (w/w) or less, about 1% (w/w) or less, or about 0% of any other crystalline forms of the same compound, and/or wherein the crystalline product contains: about 20% (w/w) or less, about 10% (w/w) or less, about 5%
(w/w) or less, about 2% (w/w) or less, about 1% (w/w) or less, or about 0% of any amorphous forms of the same compound. Use of product according to any preceding claim for the preparation of other crystalline polymorphs of Mesdopetam, Mesdopetam salts, or Mesdopetam co-crystals; or as an intermediate for the purification of Mesdopetam, Mesdopetam salts, or Mesdopetam cocrystals. Use of product according to any of claims 1 to 15, for the preparation of pharmaceutical compositions comprising Mesdopetam or Mesdopetam salts, or Mesdopetam cocrystals and/or crystalline polymorphs thereof. A pharmaceutical composition or formulation comprising a product according to any of Claims 1 to 15, and at least one pharmaceutically acceptable excipient, optionally in the form of a solid dosage form, particularly a capsule or tablet, and more preferably a capsule. A process preparing a pharmaceutical composition or formulation according to Claim 18, comprising combining a product according to any of Claims 1 to 15 with at least one pharmaceutically acceptable excipient. A product to any of Claims 1 to 15, or a pharmaceutical composition or formulation according to Claim 18, for use as a medicament. A product according to any of Claims 1 to 15, or a pharmaceutical composition or formulation according to Claim 15, for use in the treatment of Parkinson's Disease Dyskinesia, levodopa-induced dyskinesia, or Parkinson’s disease Psychosis. A method of treating Parkinson's Disease Dyskinesia, levodopa-induced dyskinesia, or Parkinson’s disease Psychosis, comprising administering a therapeutically effective amount of any one or a combination of a product according to any of Claims 1 to 15, or a pharmaceutical composition or formulation according to Claim 18, to a subject in need of the treatment.
Applications Claiming Priority (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US202263408516P | 2022-09-21 | 2022-09-21 | |
US63/408,516 | 2022-09-21 | ||
US202263422047P | 2022-11-03 | 2022-11-03 | |
US202263422056P | 2022-11-03 | 2022-11-03 | |
US63/422,047 | 2022-11-03 | ||
US63/422,056 | 2022-11-03 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2024062344A1 true WO2024062344A1 (en) | 2024-03-28 |
Family
ID=88146855
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/IB2023/059085 WO2024062344A1 (en) | 2022-09-21 | 2023-09-13 | Solid state forms of mesdopetam and salts therof |
Country Status (1)
Country | Link |
---|---|
WO (1) | WO2024062344A1 (en) |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2012143337A1 (en) | 2011-04-19 | 2012-10-26 | Neurosearch A/S | Novel modulators of cortical dopaminergic- and nmda-receptor-mediated glutamatergic neurotransmission |
WO2020239568A1 (en) | 2019-05-24 | 2020-12-03 | Integrative Research Laboratories Sweden Ab | Pharmaceutically acceptable salts of [2-(3-fluoro-5-methane-sulfonylphenoxy)ethyl](propyl)amine and uses thereof |
WO2021191417A1 (en) * | 2020-03-27 | 2021-09-30 | Som Innovation Biotech, S.A. | Compounds for use in the treatment of synucleinopathies |
WO2022101227A1 (en) * | 2020-11-10 | 2022-05-19 | Integrative Research Laboratories Sweden Ab | [2-(3-fluoro-5-methanesulfonylphenoxy)ethyl](propyl)amine (mesdopetam) for use in the prevention or reduction of sensitization to a pharmaceutical drug for parkinson's disease, in particular l-dopa induced dyskinesias |
-
2023
- 2023-09-13 WO PCT/IB2023/059085 patent/WO2024062344A1/en unknown
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2012143337A1 (en) | 2011-04-19 | 2012-10-26 | Neurosearch A/S | Novel modulators of cortical dopaminergic- and nmda-receptor-mediated glutamatergic neurotransmission |
WO2020239568A1 (en) | 2019-05-24 | 2020-12-03 | Integrative Research Laboratories Sweden Ab | Pharmaceutically acceptable salts of [2-(3-fluoro-5-methane-sulfonylphenoxy)ethyl](propyl)amine and uses thereof |
WO2021191417A1 (en) * | 2020-03-27 | 2021-09-30 | Som Innovation Biotech, S.A. | Compounds for use in the treatment of synucleinopathies |
WO2022101227A1 (en) * | 2020-11-10 | 2022-05-19 | Integrative Research Laboratories Sweden Ab | [2-(3-fluoro-5-methanesulfonylphenoxy)ethyl](propyl)amine (mesdopetam) for use in the prevention or reduction of sensitization to a pharmaceutical drug for parkinson's disease, in particular l-dopa induced dyskinesias |
Non-Patent Citations (1)
Title |
---|
ANSEL ET AL.: "Pharmaceutical Dosage Forms and Drug Delivery Systems" |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US20210387952A1 (en) | Solid state forms of daprodustat and process for preparation thereof | |
WO2021154904A1 (en) | Solid state forms of mavacamten and process for preparation thereof | |
US11427533B2 (en) | Crystalline polymorphs of bardoxolone methyl | |
US20230167090A1 (en) | Solid state forms of aprocitentan and process for preparation thereof | |
US20230058102A1 (en) | Solid state forms of blarcamesine salts | |
WO2022261410A1 (en) | Solid state forms of lanifibranor and process for preparation thereof | |
EP4214212A1 (en) | Solid state forms of sep-363856 and process for preparation thereof | |
EP4182318A1 (en) | Solid state forms of rucaparib salts | |
EP3990113A1 (en) | Solid state forms of roluperidone and salts thereof | |
EP3947386A1 (en) | Solid state forms of acalabrutinib | |
WO2024062344A1 (en) | Solid state forms of mesdopetam and salts therof | |
US20240051964A1 (en) | Solid state forms of capivasertib and process for preparation thereof | |
US20230097240A1 (en) | Solid state forms of asciminib and processes for the preparation thereof | |
WO2023199258A1 (en) | Solid state forms of mavacamten and process for preparation thereof | |
US20230357163A1 (en) | Solid state forms of gefapixant and process for preparation thereof | |
WO2024069574A1 (en) | Solid state forms of denifanstat | |
WO2023223205A1 (en) | Solid state forms of mirdametinib and process for preparation thereof | |
EP4347564A1 (en) | Solid state form of centanafadine hcl and process for preparation thereof | |
WO2021133811A1 (en) | Solid state forms of cenicriviroc and process for preparation thereof | |
WO2023107660A1 (en) | Solid state forms of lotilaner and process for preparation thereof | |
WO2021216628A1 (en) | Solid state forms of trifarotene and process for preparation thereof | |
WO2023163964A1 (en) | Solid state forms of seltorexant | |
WO2023287938A1 (en) | Solid state forms of amcenestrant | |
WO2023238112A1 (en) | Solid state forms of paltusotine and process for preparation thereof | |
WO2024074986A1 (en) | Solid state form of ecopipam hydrobromide salt |