EP2776406A2 - Erlotinib salts - Google Patents
Erlotinib saltsInfo
- Publication number
- EP2776406A2 EP2776406A2 EP12826647.5A EP12826647A EP2776406A2 EP 2776406 A2 EP2776406 A2 EP 2776406A2 EP 12826647 A EP12826647 A EP 12826647A EP 2776406 A2 EP2776406 A2 EP 2776406A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- erlotinib
- acid salt
- ray powder
- powder diffraction
- diffraction peaks
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 150000004923 Erlotinib derivatives Chemical class 0.000 title claims abstract description 29
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical class OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 claims abstract description 33
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical class OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 claims abstract description 19
- IWYDHOAUDWTVEP-ZETCQYMHSA-N (S)-mandelic acid Chemical compound OC(=O)[C@@H](O)C1=CC=CC=C1 IWYDHOAUDWTVEP-ZETCQYMHSA-N 0.000 claims abstract description 10
- ODHCTXKNWHHXJC-VKHMYHEASA-N 5-oxo-L-proline Chemical class OC(=O)[C@@H]1CCC(=O)N1 ODHCTXKNWHHXJC-VKHMYHEASA-N 0.000 claims abstract description 8
- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims abstract description 5
- 239000012453 solvate Substances 0.000 claims abstract description 5
- 238000011282 treatment Methods 0.000 claims abstract description 5
- 238000011321 prophylaxis Methods 0.000 claims abstract description 4
- SJJCQDRGABAVBB-UHFFFAOYSA-N 1-hydroxy-2-naphthoic acid Chemical class C1=CC=CC2=C(O)C(C(=O)O)=CC=C21 SJJCQDRGABAVBB-UHFFFAOYSA-N 0.000 claims abstract description 3
- 150000004677 hydrates Chemical class 0.000 claims abstract description 3
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical class O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 claims abstract 2
- 239000005551 L01XE03 - Erlotinib Substances 0.000 claims description 92
- 229960001433 erlotinib Drugs 0.000 claims description 91
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 73
- AAKJLRGGTJKAMG-UHFFFAOYSA-N erlotinib Chemical compound C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 AAKJLRGGTJKAMG-UHFFFAOYSA-N 0.000 claims description 66
- 150000003839 salts Chemical class 0.000 claims description 45
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 37
- -1 Erlotinib adipinic acid salt Chemical class 0.000 claims description 33
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 33
- 239000000203 mixture Substances 0.000 claims description 30
- 238000002360 preparation method Methods 0.000 claims description 30
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 27
- 238000000034 method Methods 0.000 claims description 20
- 239000002904 solvent Substances 0.000 claims description 18
- 239000008194 pharmaceutical composition Substances 0.000 claims description 17
- XTEGVFVZDVNBPF-UHFFFAOYSA-N naphthalene-1,5-disulfonic acid Chemical class C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1S(O)(=O)=O XTEGVFVZDVNBPF-UHFFFAOYSA-N 0.000 claims description 13
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 claims description 13
- 229960004889 salicylic acid Drugs 0.000 claims description 13
- HAFWELDDNUXLCK-ODZAUARKSA-N (z)-but-2-enedioic acid;hydrate Chemical compound O.OC(=O)\C=C/C(O)=O HAFWELDDNUXLCK-ODZAUARKSA-N 0.000 claims description 12
- 239000002253 acid Substances 0.000 claims description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 10
- 239000003960 organic solvent Substances 0.000 claims description 10
- 238000009835 boiling Methods 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- 238000006243 chemical reaction Methods 0.000 claims description 5
- 239000012752 auxiliary agent Substances 0.000 claims description 4
- 150000007524 organic acids Chemical class 0.000 claims description 4
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 3
- 150000002148 esters Chemical class 0.000 claims description 3
- 208000021045 exocrine pancreatic carcinoma Diseases 0.000 claims description 3
- 239000000010 aprotic solvent Substances 0.000 claims description 2
- AUALQMFGWLZREY-UHFFFAOYSA-N acetonitrile;methanol Chemical compound OC.CC#N AUALQMFGWLZREY-UHFFFAOYSA-N 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 150000002689 maleic acids Chemical class 0.000 claims 1
- 150000004682 monohydrates Chemical class 0.000 claims 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims 1
- 238000002560 therapeutic procedure Methods 0.000 abstract description 2
- 150000002688 maleic acid derivatives Chemical class 0.000 abstract 1
- 210000000496 pancreas Anatomy 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 42
- 239000000047 product Substances 0.000 description 40
- 238000003756 stirring Methods 0.000 description 33
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical class Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 25
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- 239000011541 reaction mixture Substances 0.000 description 23
- 239000000843 powder Substances 0.000 description 22
- 239000013078 crystal Substances 0.000 description 19
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 18
- 239000002585 base Substances 0.000 description 16
- 150000001875 compounds Chemical class 0.000 description 14
- 238000001556 precipitation Methods 0.000 description 11
- 239000012043 crude product Substances 0.000 description 10
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 9
- 239000004480 active ingredient Substances 0.000 description 9
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 9
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 9
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 8
- 238000004458 analytical method Methods 0.000 description 8
- GTTBEUCJPZQMDZ-UHFFFAOYSA-N erlotinib hydrochloride Chemical compound [H+].[Cl-].C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 GTTBEUCJPZQMDZ-UHFFFAOYSA-N 0.000 description 8
- 239000011976 maleic acid Substances 0.000 description 8
- 238000010992 reflux Methods 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- 238000005481 NMR spectroscopy Methods 0.000 description 7
- 229960000250 adipic acid Drugs 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- ODHCTXKNWHHXJC-UHFFFAOYSA-N acide pyroglutamique Natural products OC(=O)C1CCC(=O)N1 ODHCTXKNWHHXJC-UHFFFAOYSA-N 0.000 description 6
- 239000002244 precipitate Substances 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 5
- 239000002775 capsule Substances 0.000 description 5
- 229960005073 erlotinib hydrochloride Drugs 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- IWYDHOAUDWTVEP-UHFFFAOYSA-N mandelic acid Chemical compound OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- 239000012071 phase Substances 0.000 description 4
- 238000003860 storage Methods 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical class CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000007937 lozenge Substances 0.000 description 3
- 239000000523 sample Substances 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 239000012736 aqueous medium Substances 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 238000011109 contamination Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 230000029087 digestion Effects 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 238000009472 formulation Methods 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
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- NNKQLUVBPJEUOR-UHFFFAOYSA-N 3-ethynylaniline Chemical compound NC1=CC=CC(C#C)=C1 NNKQLUVBPJEUOR-UHFFFAOYSA-N 0.000 description 1
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 229920001353 Dextrin Polymers 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
- 108010010803 Gelatin Proteins 0.000 description 1
- JVTAAEKCZFNVCJ-REOHCLBHSA-N L-lactic acid Chemical compound C[C@H](O)C(O)=O JVTAAEKCZFNVCJ-REOHCLBHSA-N 0.000 description 1
- 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 1
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-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
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 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 1
- 150000008043 acidic salts Chemical class 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 239000012059 conventional drug carrier Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 239000002274 desiccant Substances 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- CJYQQUPRURWLOW-YDLUHMIOSA-M dmsc Chemical compound [Na+].OP(=O)=O.OP(=O)=O.OP(=O)=O.[O-]P(=O)=O.O=C1C2=C(O)C=CC=C2[C@H](C)[C@@H]2C1=C(O)[C@]1(O)C(=O)C(C(N)=O)=C(O)[C@@H](N(C)C)[C@@H]1[C@H]2O CJYQQUPRURWLOW-YDLUHMIOSA-M 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 230000009931 harmful effect Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 229940030980 inova Drugs 0.000 description 1
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 1
- YOBAEOGBNPPUQV-UHFFFAOYSA-N iron;trihydrate Chemical compound O.O.O.[Fe].[Fe] YOBAEOGBNPPUQV-UHFFFAOYSA-N 0.000 description 1
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 229940116871 l-lactate Drugs 0.000 description 1
- 239000008101 lactose 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
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- OIXMUQLVDNPHNS-UHFFFAOYSA-N methanesulfonic acid;hydrate Chemical compound O.CS(O)(=O)=O OIXMUQLVDNPHNS-UHFFFAOYSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000010899 nucleation Methods 0.000 description 1
- 239000008203 oral pharmaceutical composition Substances 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 239000003880 polar aprotic solvent Substances 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 239000013074 reference sample Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229940120982 tarceva Drugs 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 230000008646 thermal stress Effects 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
- 150000004917 tyrosine kinase inhibitor derivatives Chemical class 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
- C07D239/94—Nitrogen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Definitions
- the invention relates to new erlotinib salts, anhydrous forms, hydrates and solvates thereof, a process for the preparation thereof, pharmaceutical compositions containing the same and use of said pharmaceutical compositions in therapy.
- [6,7-bis-(2-methoxyethoxy)-4-chinazolinyl](3-ethynyl-phenyl) amine of the Formula 1 is a pharmaceutical active ingredient acting by the tyrosine kinase inhibitor mechanism having the INN erlotinib and which can be preferably used for the treatment of non-small cell lung carcinoma and pancreas cancer.
- the erlotinib of the Formula 1 was first described in EP 817,775. In this patent the synthesis of the erlotinib hydrochloric acid salt is disclosed and the product is characterized by the melting point.
- EP 1,076,652 relates to the mesylate hydrate of erlotinib and the anhydrous forms (A, B and C) thereof. According to the patent the solubility of the mesylate salt is low.
- a process is set forth for the preparation of erlotinib salts and the conversion of the erlotinib salts into the base.
- the acidic conditions cover the following disclosed acids: HC1, HBr, H 2 S0 4 , p-toluenesulfonic acid, benzoic acid, citric acid, succinic acid, oxalic acid, benzenesulfonic acid, tartaric acid, methanesulfonic acid, phosphoric acid and mixtures thereof.
- Particularly the preparation of the hydrochloric acid salt from the base by using aqueous hydrochloric acid or a solvent containing hydrochloric acid is described.
- the object of the present invention is to provide a process for the preparation of morphologically pure new erlotinib salts of high purity which possess more favourable physical-chemical properties than the known salts and have at least as high chemical stability as the known salts and can be prepared in a reproducible manner suitable fore industrial scale manufacture.
- Erlotinib hydrochloride is poorly soluble in aqueous medium which restricts the bioavailability thereof.
- the low solubility also limits the route of administration thereof and the finishing of the active ingredient into solid pharmaceutical compositions.
- the above object is solved according to the present invention by the preparation of the new salts of erlotinib, namely by salts formed with maleic acid, salicylic acid, L-mandelic acid, adipinic acid, 1,5-naphthalene-disulfonic acid, L-pyroglutamic acid, 1 -hydroxys- naphthoic acid and DL-mandelic acid.
- the common inventive idea of the present invention resides in the preparation of new erlotinib salts which are more soluble in aqueous medium than the erlotinib hydrochloride salt.
- the invention relates to normal or acidic salts of erlotinib and the hydrate and solvate forms thereof.
- the invention relates to the Ml polymorph /Form 1/ of the crystalline erlotinib maleate monohydrate salt of the Formula 2 which has the following characteristic X-ray powder diffraction peaks: 2 ⁇ ( ⁇ 0.2° 2 ⁇ ): 6.870; 8.190; 8.880; 12.760; 13.740; 16.080; 19.430; 20.850; 21.710; 25.030; 25.740; 26.920; 28.450.
- this product can be characterized by the following characteristic X-ray powder diffraction peaks: 2 ⁇ ( ⁇ 0.2° 2 ⁇ ): 6.870; 8.190; 8.880; 10.690; 12.760; 13.740; 16.080; 17.700; 18.490; 19.110; 19.430; 20.850; 21.170. 21.710; 24.750; 25.030; 25.740; 26.920; 27.720; 28.450; 32.230.
- the characteristic X-ray powder diffractogram of the product is shown on Figure 1 and the signals having an intensity larger than 6 % are summarized in Table 1
- the present invention is also concerned with the M2 polymorph /Form 21 of the crystalline erlotinib maleate monohydrate of the Formula 2 which has the following characteristic X-ray powder diffraction peaks: 2 ⁇ ( ⁇ 0.2° 2 ⁇ ): 6.710; 8.018; 8.702; 12.552; 12.951 ; 13.533; 18.224; 18.859; 19.142; 21.385; 24.395; 25.960.
- this product can be characterized by the following characteristic X-ray powder diffraction peaks: 2 ⁇ ( ⁇ 0.2° 2 ⁇ ): 6.710; 8.018; 8.702; 10.494; 10.891 ; 12.552; 12.951 ; 13.533; 17.510; 18.224; 18.859; 19.142; 20.454; 20.843; 21.385; 22.806; 24.395; 25.316; 25.960; 28.979; 30.413; 31.194; 34.408.
- the characteristic X-ray powder diffractogram of this product is shown on Figure 2 and the signals having an intensity larger than 1 % are summarized in Table 2:
- the crystalline erlotinib salicylic acid /1 : 1/ salt of the Formula 3 which has the following characteristic X-ray powder diffraction peaks: 2 ⁇ ( ⁇ 0.2° 2 ⁇ ): 5.830; 6.990; 16.060; 23.490; 26.000. More particularly this product can be characterized by the following X-ray powder diffraction peaks: 2 ⁇ ( ⁇ 0.2° 2 ⁇ ): 5.830; 6.990; 16.060; 20.220; 22.740; 23.490; 24.930; 26.000.
- the characteristic X-ray powder diffractogram of this product is shown on Figure 3 and the signals having an intensity larger than 10 % are summarized in Table 3:
- the invention also relates to the crystalline erlotinib L-mandelic acid salt / 1 :1/ of the Formula 4 which has the following characteristic X-ray powder diffraction peaks 2 ⁇ ( ⁇ 0.2°. 2 ⁇ ): 6.040; 12.190; 16.200; 17.090; 18.270; 19.230; 20.030; 23.250; 24.870. 26.170. More particularly this product can be characterized by the following X-ray powder diffraction peaks: 2 ⁇ ( ⁇ 0.2° 2 ⁇ ): 6.040; 8.010; 12.190; 16.200; 18.270; 19.230; 20.030; 21.170; 21.780; 22.630; 23.250; 24.870; 26.170.
- the characteristic X-ray powder diffractogram of this product is shown on Figure 4 and the signals having an intensity larger than 6 % are summarized in Table 4:
- the invention also relates to the crystalline erlotinib adipinic acid salt /1 : 1/ of the Formula 5 which has the following characteristic X-ray powder diffraction peaks: 2 ⁇ ( ⁇ 0.2° 2 ⁇ ): 6.400; 7.050; 8.990; 12.920; 18.740; 21.820; 22.660; 28.830. More particularly this product can be characterized by the following X-ray powder diffraction peaks: 2 ⁇ ( ⁇ 0.2° 2 ⁇ ): 6.400; 7.050; 8.990; 12.920; 16.860; 17.350; 18.740; 20.430; 21.240; 21.820; 22.660; 23.370; 28.830.
- the characteristic X-ray powder diffractogram of this product is shown on Figure 5 and the signals having an intensity larger than 7 % are summarized in Table 5:
- this product can be characterized by the following X-ray powder diffraction peaks: 2 ⁇ ( ⁇ 0.2° 2 ⁇ ): 6.310; 12.540; 13.660; 14.330; 17.430; 18.750; 19.070; 19.940; 21.690; 22.640; 23.230; 25.220; 25.770; 27.490; 28.250; 28.860; 29.630; 32.820; 33.400.
- the characteristic X-ray powder diffractogram of this product is shown on Figure 6 and the signals having an intensity larger than 6 % are summarized in Table 6:
- the crystalline erlotinib L- pyroglutamic acid /1 : 1/ salt of the Formula 7 which has the following characteristic X-ray powder diffraction peaks: 2 ⁇ ( ⁇ 0.2°. 2 ⁇ ): 7.180; 13.310; 14.920. 19.590; 20.850; 22.160; 23.100; 24.170; 26.500.
- this product can be characterized by the following X-ray powder diffraction peaks: 2 ⁇ ( ⁇ 0.2° 2 ⁇ ): 5.180; 7.180; 13.310; 14.920; 16.260; 16.610; 18.460; 19.060; 19.590; 20.080; 20.850; 22.160; 23.100; 24.170; 24.580; 25.070; 26.500; 27.360; 28.290; 28.670.
- the X-ray powder diffractogram of this product is shown on Figure 7 and the signals having an intensity larger than 5% are summarized in table 7:
- the invention also relates to the crystalline erlotinib l-hydroxy-2-naphthoic acid /1 : 1/ salt of the Formula 8 which has the following characteristic X-ray powder diffraction peaks: 2 ⁇ ( ⁇ 0.2° 2 ⁇ ): 4.300; 1 1.630; 14.340; 17.470; 19.140; 19.850; 22.800; 26.200. More particularly this product can be characterized by the following X-ray powder diffraction peaks: 2 ⁇ ( ⁇ 0.2° 2 ⁇ ): 4.300; 6.760; 1 1.630; 13.120; 13.750; 14.340; 16.860; 17.470; 18.540; 19.140; 19.850; 21.030; 22.800; 23.660; 24.540; 26.200; 28.580.
- the characteristic X-ray powder diffractogram of this product is shown on Figure 8 and the signals having an intensity larger than 6 % are summarized in Table 8:
- the invention also relates to the crystalline erlotinib DL-mandelic acid salt of the Formula 9 , which has the following characteristic X-ray powder diffraction peaks: 2 ⁇ ( ⁇ 0.2° 2 ⁇ ): 5.400; 9.160; 14.530; 18.140; 21.700; 23.010. More particularly this product can be characterized by the following X-ray powder diffraction peaks. 2 ⁇ ( ⁇ 0.2° 2 ⁇ ): 5.400; 9.160; 14.530; 15.490; 17.040; 17.360; 18.140; 18.370; 20.190; 21.180; 21.700; 23.010; 23.800; 24.700; 25.230; 25.960; 27.030.
- the characteristic X-ray powder diffractogram of this product is shown on Figure 9 and the signals having an intensity larger than 3 % are summarized in Table 9:
- the salts according to the present invention can be prepared by reacting erlotinib free base of the Formula 1 in an organic solvent with the desired acid, separating the crystallized salt and if desired washing with organic solvent.
- the salts according to the present invention can also be prepared by reacting the free erlotinib base of the Formula 1 without isolation in an organic solvent with the desired acid, separating the crystallized salt and if desired washing it with an organic solvent.
- the salt can be separated by known methods of pharmaceutical industry suitable for the separation of a solid phase and a liquid, such as filtration which is optionally carried out under atmospheric pressure or in vacuo or under pressure or by using a centrifuge.
- mono-or polybasic organic or inorganic acids can be used, such as maleic acid, salicylic acid, L-mandelic acid, adipinic acid, 1,5-naphthalene-disulfonic acid, L-pyroglutamic acid ,l-hydroxy-2-naphthoic acid or DL-mandelic acid.
- the process can be carried out in an organic solvent, e.g. C aliphatic alcohols, ethers, esters or mixtures thereof. It is preferred to use as organic solvent a C ether, ester or alcohol or a dipolar-aprotic solvent, particularly tetrahydrofurane, diethyl ether, ethyl acetate, acetonitrile, methanol, ethanol or 2-propanol or mixtures thereof.
- organic solvent e.g. C aliphatic alcohols, ethers, esters or mixtures thereof. It is preferred to use as organic solvent a C ether, ester or alcohol or a dipolar-aprotic solvent, particularly tetrahydrofurane, diethyl ether, ethyl acetate, acetonitrile, methanol, ethanol or 2-propanol or mixtures thereof.
- the salt forming acid is preferably applied in a 0.3-3.0 molar equivalent amount related to the amount of the erlotinib of the Formula 1.
- One may proceed preferably by using the solution of the organic acid and carrying out the reaction at a temperature between 0°C and the boiling point of the solvent,
- One may particularly preferably proceed by reacting the ethanolic solution of erlotinib of the Formula 1 with a solution containing a 0.3-3.0 molar equivalent of the acid at a temperature near to the boiling point of the solvent.
- the precipitated product is separated by filtration.
- the precipitated product is separated by filtration.
- the new erlotinib salts of the present invention can be prepared by dissolving erlotinib base of the Formula 1 in a suitable solvent, preferably a Ci -6 alcohol, particularly ethanol, methanol or isopropanol and adding a 0.5-3.0, preferably a 0.5-1.0 molar equivalent amount of an acid in solid form or as a solution. If the salt precipitates at the temperature of the addition or under cooling it is filtered, if desired purified by digestion or recrystallization and finally filtered, washed and dried. If the precipitation does not spontaneously take place, the solvent is removed in vacuo and the residue is crystallized by adding a suitable solvent or solvent mixture, if desired purified by digestion or recrystallization and finally filtered, washed and dried.
- a suitable solvent preferably a Ci -6 alcohol, particularly ethanol, methanol or isopropanol
- a 0.5-3.0 preferably a 0.5-1.0 molar equivalent amount of an acid in solid form
- the erlotinib maleic acid salt of the Formula 2 is preferably prepared by stirring the solution of the formed erlotinib base of the Formula 1 with an alcohol type solvent, preferably ethanol and adding the ethanolic solution of maleic acid at a temperature between 0°C and the boiling point of the solvent, preferably at a temperature between 0°C and 80°C, more preferably at 70°C. If necessary the reaction mixture is cooled to 5-25°C, the precipitated crystals are filtered, optionally washed and dried. The product is recrystallized from an alcohol type solvent or a mixture thereof formed with water, preferably from methanol, if necessary. From the erlotinib maleic acid /1 : 1/ salt of the Formula 2 thus obtained the anhydrous erlotinib maleic acid salt can be prepared by known methods e.g. by drying.
- the erlotinib salicylic acid /1 :1/ salt of the Formula 3 can be preferably prepared by stirring the erlotinib free base of the Formula 1 in an alcohol type solvent, preferably methanol, adding to the mixture solid crystalline salicylic acid at a temperature between 0°C and the boiling point of the solvent, preferably at a temperature between 0°C and 80°C. more preferably at 70°C.
- the reaction mixture is cooled to 5-25°C, the precipitated crystals are dried, optionally washed and dried. If desired the product is crystallized from an alcohol type solvent, preferably 2-propanol.
- the erlotinib L-mandelic acid /1 : 1/ salt of the Formula 4 is prepared in an analogous manner to the preparation of the salicylic acid salt except that salicylic acid is replaced by L- mandelic acid.
- the erlotinib 1 ,5-naphthalene-disulfonic acid I2: ⁇ l salt of the Formula 6 can be preferably prepared by stirring erlotinib free base 111 in an alcohol type solvent, preferably ethanol, adding to the solution solid 1 ,5-naphthalene-disulfonic acid at a temperature between 0°C and the boiling point of the solvent, preferably between room temperature and 80°C, more preferably at 70°C, then stirring the mixture, preferably at room temperature overnight.
- the precipitated crystals are filtered, optionally washed and dried.
- the product is recrystallized from a polar-aprotic solvent, preferably from dimethyl sulfoxide.
- the erlotinib L-pyroglutamic acid /1 : 1/ salt of the Formula 7 can be prepared in an analogous manner to the preparation of the salicylic acid salt except that salicylic acid is replaced by crystalline L-pyroglutamic acid.
- the erlotinib l-hydroxy-2-naphthoic acid /1 : 1/ of the Formula 8 can be prepared in an analogous manner to the preparation of the salicylic acid salt except that salicylic acid is replaced by crystalline 1 -hydroxy-2-naphthoic acid.
- the erlotinib DL-mandelic acid /1 : 1/ salt of the Formula 9 can be prepared in an analogous manner to the preparation of the salicylic acid salt except that salicylic acid is replaced by crystalline DL-mandelic acid.
- the erlotinib salts of the present invention show a higher stability than the salts known from prior art in the storage tests carried out under various conditions. It has been found that from the new salts of the present invention the maleic acid monohydrate and the adipinic acid salts proved to be particularly stable. Said salts are particularly useful in the preparation of pharmaceutical compositions.
- the solubility of the new erlotinib salts of the invention was tested in a 0.1 M hydrochloric acid solution.
- the solubility was tested in said 0.1 M hydrochloric acid solution because the pH of this solution is 1.0 which is suitably similar to the pH value of 0.8-1.5 of the gastric fluid. It has been found in a surprising manner that the new erlotinib salts of the present invention show a better solubility than the hydrochloride salt known from prior art in the 0.1 M hydrochloric acid solution modeling the physiological conditions.
- compositions comprising a therapeutically effective amount of an erlotinib salt of the present invention and if desired a pharmaceutically active carrier.
- compositions of the invention can be administered preferably orally.
- Such oral compositions may be e.g. tablets, capsules, dragees, solutions, elixirs, suspensions or emulsions.
- the pharmaceutical compositions according to the present invention may contain conventional pharmaceutical carriers and/or auxiliary agents.
- carrier e.g. magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, low melting wax, PEG, cocoa butter etc.
- carrier often serves as the capsule wall material so that no additional carrier is required.
- Chartula and lozenge are further oral pharmaceutical compositions. Particularly preferred oral administration forms are the powders, pirules, chartula and lozenges.
- the tablets are prepared by admixing the active ingredient with suitable carriers in an appropriate ratio and from this mixture tablets of desired shape and size are pressed.
- the powders are prepared by admixing the finely powdered active ingredient with the carriers.
- the liquid compositions may be solutions, suspensions and emulsions which can also be sustained release compositions.
- Aqueous solutions and aqueous propylene glycol solutions proved to be advantageous.
- Compositions suitable for parenteral administration can be prepared preferably in the form of aqueous polyethylene glycol solutions.
- compositions of the invention can be preferably prepared in the form of dosage units which contain the desired amount of the active ingredient.
- the dosage units can be put on the market in the form of packages comprising separated amounts of the compositions e.g. packed tablets, capsules, vials or ampoules which contain the powder.
- the term "dosage unit" relates to the capsules, chartula, lozenge and also to the package comprising a suitable amount of dosage units.
- a process for the preparation of the above pharmaceutical compositions which comprises admixing an erlotinib salt of the Formula 2, 3, 4, 5, 6, 7, 8 or 9 or a mixture thereof with pharmaceutically acceptable solid or liquid diluents and/or auxiliary agents and bringing the mixture to a galenic composition.
- compositions of the present invention can be prepared by conventional methods of pharmaceutical industry.
- the pharmaceutical compositions of the present invention may contain further pharmaceutical active ingredients which are compatible with the new salts of the Formula 2, 3, 4, 5, 6, 7, 8 or 9 or mixtures thereof.
- the advantage of the present invention is that the compounds of the Formulae 2, 3, 4, 5, 6, 7, 8 and 9 are substances of uniform morphology and have an advantageous crystal form.
- the salts of the present invention possess preferable and reproducible properties, such as dissolving velocity, bioavailability, chemical stability and processing characteristics e.g. filtration, drying and tabletting properties.
- the active ingredients of the Formulae 2, 3, 4, 5, 6, 7, 8 and 9 can be prepared by procedures readily suitable for industrial scale manufacture.
- Figure 2 shows the X-ray powder diffractogram of the M2 polymorph /Form 21 of the erlotinib maleic acid monohydrate salt of the Formula 2.
- Figure 3 shows the X-ray powder diffractogram of the erlotinib salicylic acid salt of the Formula 3.
- Figure 4 shows the X-ray powder diffractogram of the erlotinib L-mandelic acid salt of the Formula 4.
- Figure 5 shows the X-ray powder diffractogram of the erlotinib adipinic acid salt of the Formula 5.
- Figure 6 shows the X-ray powder diffractogram of the erlotinib 1,5-naphthalene-disulfonic acid salt of the Formula 6.
- Figure 7 shows the X-ray powder diffractogram of the erlotinib L-pyroglutamic acid salt of the Formula 7.
- Figure 8 shows the X-ray powder diffractogram of the erlotinib l-hydroxy-2 -naphthoic acid salt of the Formula 8.
- Figure 9 shows the X-ray powder diffractogram of the erlotinib DL-mandelic acid salt of the Formula 9.
- the erlotinib base used in the following Examples is prepared from erlotinib hydrochloride by methods well-known for the person skilled in the art.
- the erlotinib hydrochloride was obtained from the firm Zheijang Jiuzhou /China/.
- the X-ray powder diffraction data of all prepared products are obtained under the following measuring conditions:
- Orifices 1,25° (divergence, scattered); 0,3 mm (receiving)
- a) are recrystallized from 90 ml of a 80:20 mixture of methanol and water whereupon the reaction mixture is cooled to 20-25°C within an hour under stirring.
- the precipitate is filtered and washed with a 80:20 mixture of methanol and water.
- the wet solid is dried at room temperature in vacuo until constant weight.
- 1,06 g of the crude product thus obtained are recrystallized from 20 ml of dimethyl sulfoxide.
- the precipitate is filtered, washed with a small amount of cold dimethyl sulfoxide and tertiary butyl methyl ether.
- the crude product thus obtained is recrystallized from 10 ml of isopropanol.
- the suspension obtained is allowed to stand in a refrigerator, filtered and washed with a small amount of cold isopropanol and thereafter with tertiary butyl methyl ether.
- Erlotinib maleate monohydrate salt 10 mg of erlotinib maleate monohydrate are weighed in a 25 ml round-bottomed flask whereupon a 0.1 M hydrochloric acid solution /exact titre/ is added under continuous stirring /Heidolph 3001 mixer, 1000 rpm/ After addition of 10 ml of the hydrochloric acid solution immediately a clear solution is obtained.
- Erlotinib adipinate salt 10 mg of erlotinib adipinate are weighed in a 25 ml round-bottomed flask whereupon a 0.1 M hydrochloric acid solution /exact titre/ is added under continuous stirring /Heidolph 3001 mixer. 1000 rpm/. After addition of 2 ml of the hydrochloric acid solution immediately a clear solution is obtained.
- Erlotinib hydrochloride 10 mg of erlotinib hydrochloride salt are weighed into a 50 ml round- bottomed flask whereupon a 0.1 M hydrochloric acid solution /exact titre/ is added under continuous stirring. After addition of 50 ml of the hydrochloric acid solution no clear solution is obtained even after stirring for two hours /according to visual observation the mixture still contains insoluble particles/.
- the further advantage of the above salt formation procedures is that as a result of the aqueous washing steps the precipitated salt contains no residual inorganic contaminations /e.g. sodium chloride/ contrary e.g. to the precipitation of the base carried out from an alcoholic solution with sodium acetate.
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Abstract
The invention relates to erlotinib salts selected from the group consisting of the maleic acid salt, salicylic acid salt. L-mandelic acid alt. adipinic acid salt. 1.5-naphthalene-disulfonic acid salt. L-pyroglutamic acid salt. 1 -hydroxy-2-naphthoic acid salt, and mandelic acid salt and amorphous and crystalline forms, hydrates and solvates thereof. The erlotinib salts of the present invention are useful in therapy, particularly for the treatment or prophylaxis of non- small cell lung carcinoma and pancreas rarcinoma.
Description
ERLOTINIB SALTS
Subject matter of the invention
The invention relates to new erlotinib salts, anhydrous forms, hydrates and solvates thereof, a process for the preparation thereof, pharmaceutical compositions containing the same and use of said pharmaceutical compositions in therapy.
The state of the art
It is known that [6,7-bis-(2-methoxyethoxy)-4-chinazolinyl](3-ethynyl-phenyl) amine of the Formula 1 is a pharmaceutical active ingredient acting by the tyrosine kinase inhibitor mechanism having the INN erlotinib and which can be preferably used for the treatment of non-small cell lung carcinoma and pancreas cancer. The erlotinib of the Formula 1 was first described in EP 817,775. In this patent the synthesis of the erlotinib hydrochloric acid salt is disclosed and the product is characterized by the melting point.
EP 1,076,652 relates to the mesylate hydrate of erlotinib and the anhydrous forms (A, B and C) thereof. According to the patent the solubility of the mesylate salt is low.
In WO 2008/122,776 a process is set forth for the preparation of erlotinib salts and the conversion of the erlotinib salts into the base. The acidic conditions cover the following disclosed acids: HC1, HBr, H2S04, p-toluenesulfonic acid, benzoic acid, citric acid, succinic acid, oxalic acid, benzenesulfonic acid, tartaric acid, methanesulfonic acid, phosphoric acid and mixtures thereof. Particularly the preparation of the hydrochloric acid salt from the base by using aqueous hydrochloric acid or a solvent containing hydrochloric acid is described.
In WO 2011/068403 the preparation of new erlotinib salts is described. Namely that of the following salts: ethanesulfonate, isethionate, hydrobromide, malonate, L-lactate and succinate.
The object of the invention
Recently serious demand has occurred in pharmaceutical industry on the reproducible manufacture of morphologically uniform products. This is a fundamental-condition for active ingredients needed to meet the requirements of the formulation of medicines. It is well-known that various salts and polymorphs differ from each other in important properties such as solubility, chemical stability, polymorph stability, bioavailability, filtration, drying and tabletting properties etc.
From the point of view of the economy of the manufacturing process it is highly important that the product should be prepared by a process suitable for industrial scale manufacture in a reproducible manner to provide a morphologically uniform salt free of contaminations.
The object of the present invention is to provide a process for the preparation of morphologically pure new erlotinib salts of high purity which possess more favourable physical-chemical properties than the known salts and have at least as high chemical stability as the known salts and can be prepared in a reproducible manner suitable fore industrial scale manufacture.
Erlotinib hydrochloride is poorly soluble in aqueous medium which restricts the bioavailability thereof. The low solubility also limits the route of administration thereof and the finishing of the active ingredient into solid pharmaceutical compositions.
The above object is solved according to the present invention by the preparation of the new salts of erlotinib, namely by salts formed with maleic acid, salicylic acid, L-mandelic acid, adipinic acid, 1,5-naphthalene-disulfonic acid, L-pyroglutamic acid, 1 -hydroxys- naphthoic acid and DL-mandelic acid.
The common inventive idea of the present invention resides in the preparation of new erlotinib salts which are more soluble in aqueous medium than the erlotinib hydrochloride salt.
Detailed description of the invention
The invention relates to normal or acidic salts of erlotinib and the hydrate and solvate forms thereof.
According to the present invention there is provided the erlotinib maleic acid monohydrate salt of the Formula 2
the L-erlotinib salicylic acid salts of the Formula 3
the L-mandelic acid salt of the Formula 4
the erlotinib adipinic acid salt of the Formula 5
the erlotinib 1 ,5-naphthalene-disulfonic acid salt of the Formula 6
and the erlotinib DL-mandelic acid salt of the Formula 9
More particularly the invention relates to the Ml polymorph /Form 1/ of the crystalline erlotinib maleate monohydrate salt of the Formula 2 which has the following characteristic X-ray powder diffraction peaks: 2 Θ (±0.2° 2 Θ): 6.870; 8.190; 8.880; 12.760; 13.740; 16.080; 19.430; 20.850; 21.710; 25.030; 25.740; 26.920; 28.450. More particularly this product can be characterized by the following characteristic X-ray powder diffraction peaks: 2 Θ (±0.2° 2 Θ): 6.870; 8.190; 8.880; 10.690; 12.760; 13.740; 16.080; 17.700; 18.490; 19.110; 19.430; 20.850; 21.170. 21.710; 24.750; 25.030; 25.740; 26.920; 27.720; 28.450; 32.230. The characteristic X-ray powder diffractogram of the product is shown on Figure 1 and the signals having an intensity larger than 6 % are summarized in Table 1
Table 1 /relative intensity >6 %/
13 19.1 10 4.6404 18
14 19.430 4.5647 61
15 20.340 4.3625 8
16 20.850 4.2569 36
17 21.170 4.1933 20
18 21.710 4.0902 43
19 22.550 3.9397 1 1
20 23.340 3.8081 8
21 23.810 3.7340 7
22 24.750 3.5943 20
23 25.030 3.5547 32
24 25.740 3.4582 32
25 26.280 3.3884 8
26 26.920 3.3092 19
27 27.720 3.2155 13
28 28.450 3.1347 18
29 31.590 2.8299 7
30 32.230 2.7751 10
The present invention is also concerned with the M2 polymorph /Form 21 of the crystalline erlotinib maleate monohydrate of the Formula 2 which has the following characteristic X-ray powder diffraction peaks: 2 Θ (±0.2° 2 Θ): 6.710; 8.018; 8.702; 12.552; 12.951 ; 13.533; 18.224; 18.859; 19.142; 21.385; 24.395; 25.960. More particularly this product can be characterized by the following characteristic X-ray powder diffraction peaks: 2 Θ (±0.2° 2 Θ): 6.710; 8.018; 8.702; 10.494; 10.891 ; 12.552; 12.951 ; 13.533; 17.510; 18.224; 18.859; 19.142; 20.454; 20.843; 21.385; 22.806; 24.395; 25.316; 25.960; 28.979; 30.413; 31.194; 34.408. The characteristic X-ray powder diffractogram of this product is shown on Figure 2 and the signals having an intensity larger than 1 % are summarized in Table 2:
Table 2 /relative signals >1 %/
Peak 2 Θ d (A) Intensity
1 6.710 13.1627 100
2 8.018 11.0179 64
3 8.702 10.1528 29
4 10.494 8.4231 19
5 10.891 8.1168 10
6 12.552 7.0463 17
7 12.951 6.8301 18
8 13.533 6.5376 25
9 13.860 6.3844 7
10 14.180 6.2409 2
11 15.810 5.6008 5
12 16.157 5.4814 4
13 16.505 5.3668 2
14 17.510 5.0607 27
15 18.224 4.8640 37
16 18.859 4.7016 15
17 19.142 4.6329 47
18 20.454 4.3385 14
19 20.843 4.2584 20
20 21.385 4.1517 57
21 21.715 4.0893 11
22 22.806 3.8961 23
23 23.579 3.7701 13
24 24.395 3.6459 32
25 24.765 3.5922 11
26 25.316 3.5152 23
27 25.960 3.4295 29
28 26.524 3.3578 4
29 26.890 3.3130 9
30 28.070 3.1764 8
31 28.609 3.1 177 9
32 28.979 3.0787 15
33 29.870 2.9888 3
34 30.413 2.9368 17
35 31.194 2.8650 16
36 31.885 2.8044 4
37 32.809 2.7275 4
38 33.455 2.6764 5
39 33.817 2.6485 3
40 34.408 2.6044 10
41 34.720 2.5817 5
42 35.185 2.5486 4
43 35.400 2.5336 4
44 35.700 2.5130 2
45 36.080 2.4874 2
46 36.675 2.4484 2
47 37.131 2.4193 3
48 37.514 2.3955 4
49 38.262 2.3504 4
50 38.856 2.3158 3
51 39.623 2.2728 4
According to the present invention there is also provided the crystalline erlotinib salicylic acid /1 : 1/ salt of the Formula 3 which has the following characteristic X-ray powder diffraction peaks: 2 Θ (±0.2° 2 Θ): 5.830; 6.990; 16.060; 23.490; 26.000. More particularly this product can be characterized by the following X-ray powder diffraction peaks: 2 Θ (±0.2° 2 Θ): 5.830; 6.990; 16.060; 20.220; 22.740; 23.490; 24.930; 26.000. The characteristic X-ray powder diffractogram of this product is shown on Figure 3 and the signals having an intensity larger than 10 % are summarized in Table 3:
Table 3 /relative intensities >10 %/
Peak 2 Θ d (A) Intensity
1 5.830 15.1468 100
2 6.990 12.6355 95
3 16.060 5.5142 42
4 20.220 4.3881 39
5 22.740 3.9072 44
6 23.490 3.7841 46
7 24.930 3.5687 43
8 26.000 3.4242 43
The invention also relates to the crystalline erlotinib L-mandelic acid salt / 1 :1/ of the Formula 4 which has the following characteristic X-ray powder diffraction peaks 2 Θ (±0.2°. 2 Θ): 6.040; 12.190; 16.200; 17.090; 18.270; 19.230; 20.030; 23.250; 24.870. 26.170. More particularly this product can be characterized by the following X-ray powder diffraction peaks: 2 Θ (±0.2° 2 Θ): 6.040; 8.010; 12.190; 16.200; 18.270; 19.230; 20.030; 21.170; 21.780; 22.630; 23.250; 24.870; 26.170. The characteristic X-ray powder diffractogram of this product is shown on Figure 4 and the signals having an intensity larger than 6 % are summarized in Table 4:
Table 4 /relative intensities >6 %/
13 26.170 3.4024 21
14 28.280 3.1531 8
The invention also relates to the crystalline erlotinib adipinic acid salt /1 : 1/ of the Formula 5 which has the following characteristic X-ray powder diffraction peaks: 2 Θ (±0.2° 2 Θ): 6.400; 7.050; 8.990; 12.920; 18.740; 21.820; 22.660; 28.830. More particularly this product can be characterized by the following X-ray powder diffraction peaks: 2 Θ (±0.2° 2 Θ): 6.400; 7.050; 8.990; 12.920; 16.860; 17.350; 18.740; 20.430; 21.240; 21.820; 22.660; 23.370; 28.830. The characteristic X-ray powder diffractogram of this product is shown on Figure 5 and the signals having an intensity larger than 7 % are summarized in Table 5:
Table 5 /relative intensities >7 %/
The invention also relates to the crystalline erlotinib 1,5-naphthalene-disulfonic acid /2:1/ salt of the Formula 6 which has the following characteristic X-ray powder diffraction peaks: 2 Θ (±0.2° 2 Θ): 6.310; 12.540; 14.330; 18.750; 19.940; 21.690; 23.230; 25.220. More particularly this product can be characterized by the following X-ray powder diffraction peaks: 2 Θ (±0.2° 2 Θ): 6.310; 12.540; 13.660; 14.330; 17.430; 18.750; 19.070; 19.940;
21.690; 22.640; 23.230; 25.220; 25.770; 27.490; 28.250; 28.860; 29.630; 32.820; 33.400. The characteristic X-ray powder diffractogram of this product is shown on Figure 6 and the signals having an intensity larger than 6 % are summarized in Table 6:
Table 6 /relative intensities >6 %/
According to the present invention there is also provided the crystalline erlotinib L- pyroglutamic acid /1 : 1/ salt of the Formula 7 which has the following characteristic X-ray powder diffraction peaks: 2 Θ (±0.2°. 2 Θ): 7.180; 13.310; 14.920. 19.590; 20.850; 22.160; 23.100; 24.170; 26.500. More particularly this product can be characterized by the following X-ray powder diffraction peaks: 2 Θ (±0.2° 2 Θ): 5.180; 7.180; 13.310; 14.920; 16.260;
16.610; 18.460; 19.060; 19.590; 20.080; 20.850; 22.160; 23.100; 24.170; 24.580; 25.070; 26.500; 27.360; 28.290; 28.670. The X-ray powder diffractogram of this product is shown on Figure 7 and the signals having an intensity larger than 5% are summarized in table 7:
Table 7 /relative intensities >5 %/
The invention also relates to the crystalline erlotinib l-hydroxy-2-naphthoic acid /1 : 1/ salt of the Formula 8 which has the following characteristic X-ray powder diffraction peaks: 2 Θ (±0.2° 2 Θ): 4.300; 1 1.630; 14.340; 17.470; 19.140; 19.850; 22.800; 26.200. More particularly this product can be characterized by the following X-ray powder diffraction peaks: 2 Θ (±0.2° 2 Θ): 4.300; 6.760; 1 1.630; 13.120; 13.750; 14.340; 16.860; 17.470;
18.540; 19.140; 19.850; 21.030; 22.800; 23.660; 24.540; 26.200; 28.580. The characteristic X-ray powder diffractogram of this product is shown on Figure 8 and the signals having an intensity larger than 6 % are summarized in Table 8:
Table 8 /relative intensities >6 %/
The invention also relates to the crystalline erlotinib DL-mandelic acid salt of the Formula 9 , which has the following characteristic X-ray powder diffraction peaks: 2 Θ (±0.2° 2 Θ): 5.400; 9.160; 14.530; 18.140; 21.700; 23.010. More particularly this product can be characterized by the following X-ray powder diffraction peaks. 2 Θ (±0.2° 2 Θ): 5.400; 9.160; 14.530; 15.490; 17.040; 17.360; 18.140; 18.370; 20.190; 21.180; 21.700; 23.010; 23.800; 24.700; 25.230; 25.960; 27.030. The characteristic X-ray powder diffractogram of this
product is shown on Figure 9 and the signals having an intensity larger than 3 % are summarized in Table 9:
Table 9 /relative intensities >3 %/
According to a further aspect of the present invention there is provided a process for the preparation of erlotinib salts which comprises reacting an amorphous or crystalline form of erlotinib of the Formula 1 or an anhydrous form, hydrate or solvate thereof in a suitable organic solvent with the desired acid and separating the erlotinib salt formed.
The salts according to the present invention can be prepared by reacting erlotinib free base of the Formula 1 in an organic solvent with the desired acid, separating the crystallized salt and if desired washing with organic solvent.
The salts according to the present invention can also be prepared by reacting the free erlotinib base of the Formula 1 without isolation in an organic solvent with the desired acid, separating the crystallized salt and if desired washing it with an organic solvent.
The salt can be separated by known methods of pharmaceutical industry suitable for the separation of a solid phase and a liquid, such as filtration which is optionally carried out under atmospheric pressure or in vacuo or under pressure or by using a centrifuge.
For the salt formation according to the present invention mono-or polybasic organic or inorganic acids can be used, such as maleic acid, salicylic acid, L-mandelic acid, adipinic acid, 1,5-naphthalene-disulfonic acid, L-pyroglutamic acid ,l-hydroxy-2-naphthoic acid or DL-mandelic acid.
The process can be carried out in an organic solvent, e.g. C aliphatic alcohols, ethers, esters or mixtures thereof. It is preferred to use as organic solvent a C ether, ester or alcohol or a dipolar-aprotic solvent, particularly tetrahydrofurane, diethyl ether, ethyl acetate, acetonitrile, methanol, ethanol or 2-propanol or mixtures thereof.
The salt forming acid is preferably applied in a 0.3-3.0 molar equivalent amount related to the amount of the erlotinib of the Formula 1. One may proceed preferably by using the solution of the organic acid and carrying out the reaction at a temperature between 0°C and the boiling point of the solvent,
One may particularly preferably proceed by reacting the ethanolic solution of erlotinib of the Formula 1 with a solution containing a 0.3-3.0 molar equivalent of the acid at a temperature near to the boiling point of the solvent. The precipitated product is separated by filtration.
One may also proceed by using the acid in solid crystalline form and performing the reaction at a temperature between 0°C and the boiling point of the mixture or at the boiling point of the solvent.
One may proceed particularly preferably by reacting the ethanolic solution of erlotinib of the Formula 1 with a 0.3-3.0 molar equivalent amount of the solid organic acid at a
temperature near to the boiling point of the solvent. The precipitated product is separated by filtration.
The new erlotinib salts of the present invention can be prepared by dissolving erlotinib base of the Formula 1 in a suitable solvent, preferably a Ci-6 alcohol, particularly ethanol, methanol or isopropanol and adding a 0.5-3.0, preferably a 0.5-1.0 molar equivalent amount of an acid in solid form or as a solution. If the salt precipitates at the temperature of the addition or under cooling it is filtered, if desired purified by digestion or recrystallization and finally filtered, washed and dried. If the precipitation does not spontaneously take place, the solvent is removed in vacuo and the residue is crystallized by adding a suitable solvent or solvent mixture, if desired purified by digestion or recrystallization and finally filtered, washed and dried.
The erlotinib maleic acid salt of the Formula 2 is preferably prepared by stirring the solution of the formed erlotinib base of the Formula 1 with an alcohol type solvent, preferably ethanol and adding the ethanolic solution of maleic acid at a temperature between 0°C and the boiling point of the solvent, preferably at a temperature between 0°C and 80°C, more preferably at 70°C. If necessary the reaction mixture is cooled to 5-25°C, the precipitated crystals are filtered, optionally washed and dried. The product is recrystallized from an alcohol type solvent or a mixture thereof formed with water, preferably from methanol, if necessary. From the erlotinib maleic acid /1 : 1/ salt of the Formula 2 thus obtained the anhydrous erlotinib maleic acid salt can be prepared by known methods e.g. by drying.
The erlotinib salicylic acid /1 :1/ salt of the Formula 3 can be preferably prepared by stirring the erlotinib free base of the Formula 1 in an alcohol type solvent, preferably methanol, adding to the mixture solid crystalline salicylic acid at a temperature between 0°C and the boiling point of the solvent, preferably at a temperature between 0°C and 80°C. more preferably at 70°C. The reaction mixture is cooled to 5-25°C, the precipitated crystals are dried, optionally washed and dried. If desired the product is crystallized from an alcohol type solvent, preferably 2-propanol.
The erlotinib L-mandelic acid /1 : 1/ salt of the Formula 4 is prepared in an analogous manner to the preparation of the salicylic acid salt except that salicylic acid is replaced by L- mandelic acid.
The erlotinib adipinic acid l\ A I salt of the Formula 5 can be prepared in an analogous manner to the preparation of the salicylic acid salt except that salicylic acid is replaced by an ethanolic solution of adipinic acid.
The erlotinib 1 ,5-naphthalene-disulfonic acid I2: \l salt of the Formula 6 can be preferably prepared by stirring erlotinib free base 111 in an alcohol type solvent, preferably ethanol, adding to the solution solid 1 ,5-naphthalene-disulfonic acid at a temperature between 0°C and the boiling point of the solvent, preferably between room temperature and 80°C, more preferably at 70°C, then stirring the mixture, preferably at room temperature overnight. The precipitated crystals are filtered, optionally washed and dried. The product is recrystallized from a polar-aprotic solvent, preferably from dimethyl sulfoxide.
The erlotinib L-pyroglutamic acid /1 : 1/ salt of the Formula 7 can be prepared in an analogous manner to the preparation of the salicylic acid salt except that salicylic acid is replaced by crystalline L-pyroglutamic acid.
The erlotinib l-hydroxy-2-naphthoic acid /1 : 1/ of the Formula 8 can be prepared in an analogous manner to the preparation of the salicylic acid salt except that salicylic acid is replaced by crystalline 1 -hydroxy-2-naphthoic acid.
The erlotinib DL-mandelic acid /1 : 1/ salt of the Formula 9 can be prepared in an analogous manner to the preparation of the salicylic acid salt except that salicylic acid is replaced by crystalline DL-mandelic acid.
In course of the thermal stress test and the forced stability test the decompositions in a pharmaceutical composition occurring during storage are constructed essentially in an accelerated manner. The results of these tests have predicted that under normal storage conditions the new erlotinib salts of the present invention would be more stable than the salts used in the marketed pharmaceutical conditions and those known from the prior art. The advantageous properties of the new erlotinib salts of the present invention are significant from
the point of view of the formulation of pharmaceutical compositions, the storage and the minimalization of the harmful effects exerted in the human body.
The stability of the new erlotinib salts of the present invention was subjected to detailed tests. As referent product the Form B erlotinib hydrochloride salt contained in the TarcevaR medicine of the originator was used.
It has been surprisingly found that the erlotinib salts of the present invention show a higher stability than the salts known from prior art in the storage tests carried out under various conditions. It has been found that from the new salts of the present invention the maleic acid monohydrate and the adipinic acid salts proved to be particularly stable. Said salts are particularly useful in the preparation of pharmaceutical compositions.
The solubility of the new erlotinib salts of the invention was tested in a 0.1 M hydrochloric acid solution. The solubility was tested in said 0.1 M hydrochloric acid solution because the pH of this solution is 1.0 which is suitably similar to the pH value of 0.8-1.5 of the gastric fluid. It has been found in a surprising manner that the new erlotinib salts of the present invention show a better solubility than the hydrochloride salt known from prior art in the 0.1 M hydrochloric acid solution modeling the physiological conditions.
According to a further aspect of the present invention there are provided pharmaceutical compositions comprising a therapeutically effective amount of an erlotinib salt of the present invention and if desired a pharmaceutically active carrier.
According to a further aspect of the present invention there is provided the use of the erlotinib salts of the present invention for the preparation of pharmaceutical compositions.
The pharmaceutical compositions of the invention can be administered preferably orally. Such oral compositions may be e.g. tablets, capsules, dragees, solutions, elixirs, suspensions or emulsions.
The pharmaceutical compositions according to the present invention may contain conventional pharmaceutical carriers and/or auxiliary agents. As carrier e.g. magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth,
methyl cellulose, sodium carboxymethyl cellulose, low melting wax, PEG, cocoa butter etc. can be used. In case of capsules the carrier often serves as the capsule wall material so that no additional carrier is required. Chartula and lozenge are further oral pharmaceutical compositions. Particularly preferred oral administration forms are the powders, pirules, chartula and lozenges.
The tablets are prepared by admixing the active ingredient with suitable carriers in an appropriate ratio and from this mixture tablets of desired shape and size are pressed.
The powders are prepared by admixing the finely powdered active ingredient with the carriers. The liquid compositions may be solutions, suspensions and emulsions which can also be sustained release compositions. Aqueous solutions and aqueous propylene glycol solutions proved to be advantageous. Compositions suitable for parenteral administration can be prepared preferably in the form of aqueous polyethylene glycol solutions.
The pharmaceutical compositions of the invention can be preferably prepared in the form of dosage units which contain the desired amount of the active ingredient. The dosage units can be put on the market in the form of packages comprising separated amounts of the compositions e.g. packed tablets, capsules, vials or ampoules which contain the powder. The term "dosage unit" relates to the capsules, chartula, lozenge and also to the package comprising a suitable amount of dosage units.
According to a further aspect of the present invention there is provided a process for the preparation of the above pharmaceutical compositions which comprises admixing an erlotinib salt of the Formula 2, 3, 4, 5, 6, 7, 8 or 9 or a mixture thereof with pharmaceutically acceptable solid or liquid diluents and/or auxiliary agents and bringing the mixture to a galenic composition.
The pharmaceutical compositions of the present invention can be prepared by conventional methods of pharmaceutical industry. The pharmaceutical compositions of the present invention may contain further pharmaceutical active ingredients which are compatible with the new salts of the Formula 2, 3, 4, 5, 6, 7, 8 or 9 or mixtures thereof.
According to a further aspect of the present invention there is provided the use of the compounds of the Formula 2, 3, 4, 5, 6, 7, 8 or 9 as pharmaceutical active ingredient.
According to a further aspect of the present invention there is provided the use of the erlotinib salts of the present invention for the preparation of pharmaceutical compositions for the treatment or prophylaxis of non-small cell lung carcinoma or pancreas carcinoma.
According to a further aspect of the present invention there is provided the use of the salts of the present invention for the treatment or prophylaxis of non-small cell lung carcinoma and pancreas carcinoma.
The advantage of the present invention is that the compounds of the Formulae 2, 3, 4, 5, 6, 7, 8 and 9 are substances of uniform morphology and have an advantageous crystal form. For this reason the salts of the present invention possess preferable and reproducible properties, such as dissolving velocity, bioavailability, chemical stability and processing characteristics e.g. filtration, drying and tabletting properties.
The active ingredients of the Formulae 2, 3, 4, 5, 6, 7, 8 and 9 can be prepared by procedures readily suitable for industrial scale manufacture.
Short description of the Figures
Figure 1 shows the X-ray powder diffractogram of the Ml polymorph /Form 1/ of the erlotinib maleic acid monohydrate of the Formula 2.
Figure 2 shows the X-ray powder diffractogram of the M2 polymorph /Form 21 of the erlotinib maleic acid monohydrate salt of the Formula 2.
Figure 3 shows the X-ray powder diffractogram of the erlotinib salicylic acid salt of the Formula 3.
Figure 4 shows the X-ray powder diffractogram of the erlotinib L-mandelic acid salt of the Formula 4.
Figure 5 shows the X-ray powder diffractogram of the erlotinib adipinic acid salt of the Formula 5.
Figure 6 shows the X-ray powder diffractogram of the erlotinib 1,5-naphthalene-disulfonic acid salt of the Formula 6.
Figure 7 shows the X-ray powder diffractogram of the erlotinib L-pyroglutamic acid salt of the Formula 7.
Figure 8 shows the X-ray powder diffractogram of the erlotinib l-hydroxy-2 -naphthoic acid salt of the Formula 8.
Figure 9 shows the X-ray powder diffractogram of the erlotinib DL-mandelic acid salt of the Formula 9.
Further details of the present invention are to be found in the following Examples without limiting the scope of protection to said Examples which serve the purpose of illustration only.
EXAMPLES
The erlotinib base used in the following Examples is prepared from erlotinib hydrochloride by methods well-known for the person skilled in the art. The erlotinib hydrochloride was obtained from the firm Zheijang Jiuzhou /China/.
The NMR spectra of the new salts according to the present invention is registered by use of the following apparatus: VARIAN INOVA 500 /500 MHz/, BRUKER AVANCE III 400/400 MHz/.
The X-ray powder diffraction data of all prepared products are obtained under the following measuring conditions:
Apparatus: Rigaku Corporation, Miniflex II. powder diffracto -meter Radiation: CuKccl (λ=1.54059 A)
Accelerating voltage: 30 kV
Anode current: 15 mA
Uptake velocity: 1.5 "/minute
Step interval: 0.02 0
Measuring range: 3.0-40.0° 2Θ (continuous Θ-Θ, reflexion)
Sample holder: zero background, Si one-crystal
Rotation speed of the sample holder: 1 rotation sec
Type of detector: MiniFlex2
Soller: 2,5°
Orifices: 1,25° (divergence, scattered); 0,3 mm (receiving)
Preparatory process of the sample: without powdering at room temperature
Reference sample: RSRP-43275 Si plate
Example 1
Preparation of the polymorphs Ml and M2 of the erlotinib maleic acid 11:11
monohydrate salts Form 1 and Form 2 (compound of the Formula 2). a) Into an apparatus 10 ml of ethanol are weighed in whereupon 0.496 g /l .26 millimoles/ of erlotinib base is dissolved therein under intensive stirring and under reflux. To the reaction mixture a solution of 0.146 g /L26 millimoles/ of maleic acid is added at this temperature under stirring. After some seconds the precipitation of crystals begins. Stirring is continued until the reaction mixture cools to room temperature. The precipitated crystalline product is filtered and washed with tertiary butyl methyl ether. The crude product is dried at 50°C under a pressure of 160 mbar for 10 hours.
Yield: 0.63 g (98 %)
Mp.: 164.5-167°C b) 0.48 g of the crude product thus obtained is recrystallized from 27 ml of methanol. The mixture is allowed to stand in a refrigerator overnight, the precipitated product is filtered, washed with a small amount of cold methanol and tertiary butyl methyl ether.
Thus 0.41 g (85 %) of the Ml polymorph /Form Ml/ are obtained as white crystals.
Mp.: 169.4-173°C.
Analysis for the Formula C22H23N304 · C4H404 · H20 (527,53):
Calc: C: 59.20 H: 5.54 N: 7.97
Found: C: 60.01 H: 5.67 N: 7.93
Water content ( F method) 3.79 %.
IR (KBr, cm'1): 3275, 1584, 1524, 1447, 1039.
Ή-NMR (DMSO-^6, 500 MHz): 10.1 1 (b, 1H), 8.66 (s, 1H), 7.93 (m, 1H), 7.92 (s, 1H),7.82 (m, lH), 7.46 (m, 1H), 7.32 (m, 1H), 7.22 (s, 1H), 6.19 (s, 2H), 4,30 (m, 4H), 4.17 (s, 1H), 3.80 (m, 2H), 3.77 (m, 2H), 3.37 (s, 3H), 3.37 (s, 3H).
13C-NMR (DMSO-i/6, 125 MHz) 167.07, 157.11, 154.80, 151.20, 148.90, 141.96, 138.74, 132.80, 129.21, 127.90, 126.15, 123.84, 122.11, 108.26, 105.03, 103.84, 83.35, 81.02, 70.1 1, 68.71, 68.57, 58.55. c) 3.0 g (5.9 millimoles) of the crude product obtained according to par. a) are recrystallized from 90 ml of a 80:20 mixture of methanol and water whereupon the reaction mixture is cooled to 20-25°C within an hour under stirring. The precipitate is filtered and washed with a 80:20 mixture of methanol and water. The wet solid is dried at room temperature in vacuo until constant weight.
Yield: 2.67 g (89%), A pale fluffy precipitate of the M2 polymorph /Form M2/.
Mp. 167.9-171.5°C.
The Ή-NMR and 13C-NMR data of the product are identical with the values disclosed in point b).
Example 2
Preparation of the erlotinib salicylic acid salt /1:1/ /compound of the Formula 3/
Into an apparatus 25 ml of ethanol are weighed in whereupon 1.3 g (3.3 millimoles) of erlotinib base are dissolved therein under stirring and reflux. To the reaction mixture at this temperature 0.454 g (3.3 millimoles) of salicylic acid are added under stirring; the colour of the solution becomes yellow. The reaction mixture is allowed to cool to room temperature while the precipitation of crystals begins. The precipitated crystalline product is filtered, washed with tert.butyl methyl ether and washed on the air at room temperature for a day. Yield: 1.51 g (86 %).
The crude product thus obtained is recrystallized from 30 ml of isopropanol. The precipitate is filtered and washed with a small amount of cold isopropanol and tertiary butyl methyl ether. Yield :0.85 g (57 %), a pale yellow substance.
Mp.: 138.8-142.4°C.
Analysis for the Formula C22H23N304 ■ C7H603 (531.57):
Calc: C: 65.53 H: 5.50 N: 7.90
Found: C: 64.47 H: 5.72 N: 7.70
IR (KBr, cm4): 3266, 3063, 1642, 1588, 1459, 1127.
1H-NMR (DMSO-i¾, 500 MHz): 9.66 (b, 1H), 8.56 (s, 1H), 8.00 (m, 1H), 7.90 (m, 1H), 7.89 (s, 1H), 7.81 (m, 1H), 7.48 (m, 1H), 7.42 (m, 1H), 7.25 (s, 1H), 6.93 (m, 1H), 6.90 (m, 1H), 4.30 (m, 4H), 4.19 (s, 1H), 3.79 (m, 2H), 3.77 (m, 2H), 3.39 (s, 3H), 3.37 (s, 3H).
13C-NMR (DMSO-d6, 125 MHz) 172.13, 161.43, 156.50, 154.10, 152.44, 148.46, 145.76, 139.66, 135.28, 130.39, 129.03, 126.83, 125.22, 122.98, 121.95, 1 18.97, 1 17.07, 113.90, 108.88, 107.50, 103.55, 83.58, 80.69, 70.19, 68.60, 68.30, 58.50.
Example 3
Preparation of the erlotinib L-mandelic acid salt/1 :1/ /compound of the Formula 4/
Into an apparatus 10 ml of ethanol are weighed in under intensive stirring, whereupon 0.537 g /l .36 millimoles/ of erlotinib base are dissolved therein under intensive stirring and reflux. To the reaction mixture at this temperature 0.207 g /1.36 millimoles/ of L-mandelic acid are added, whereby the colour of the solution becomes yellow. The reaction mixture is allowed to stand overnight at room temperature under stirring whereby the slow precipitation of crystals begins. The reaction mixture is allowed to stand at room temperature overnight. The precipitated crystalline product is filtered and washed with a small amount of ethanol and tertiary butyl methyl ether.
Yield 0.54 g (72% ).
0.325 g of the crude product thus obtained is recrystallized from 25 ml of isopropanol. The suspension is allowed to stand overnight, then filtered and washed with a small amount of cold isopropanol and tertiary butyl methyl ether.
Yield: 0.29 g (89 %).
Mp.: 140.4-141.1°C.
Analysis for the Formula a C22H23N304 · C8H803 (545.60):
Calc: C: 66.04 H: 5.73 N: 7.70
Found: C: 66.26 H: 5.72 N: 7.65
IR (KBr, cm ): 3231, 2927, 1636, 1583, 1515, 1448, 1365, 1327, 1278.
Ή-NMR (DMSC 500 MHz): 9.48 (b, 1H), 8.02 (m, 1H), 7.92 (m, 1H), 7.87 (s, 1H), 7.42
(m, 2H), 7.41 (m, 1H), 7.35 (m, 2H), 7.29 (m, 1H), 7.24 (s, 1H), 7.23 (m, 1H), 5.05 (s, 1H),
4.30 (m, 4H), 4.18 (s, 1H), 3.80 (m, 2H), 3.76 (m, 2H), 3.39 (s, 3H), 3.36 (s, 3H).
13C-NMR (DMSO- 6, 125 MHz) 174.26, 156.32, 153.90, 152.90, 148.34, 147.05, 140.43,
139.97, 129.03, 128.26, 127.77, 126.79, 126.53, 124.95, 122.74, 121.93, 109.10, 108.33,
103.46, 83.68, 80.62, 72.60, 70.30, 70.23, 68.60, 68.24, 58.56.
Example 4
Preparation of the erlotinib adipinic acid salt /1:1/ /compound of the Formula 5/
Into an apparatus 10 ml of ethanol are weighed in under intensive stirring whereupon 0.604 g /l .54 millimoles/ of erlotinib base are dissolved therein under reflux. To the reaction mixture at this temperature a solution of 0.225 g l\ .54 millimoles/ of adipinic acid in 5 ml of ethanol is added under stirring. The reaction mixture is allowed to cool to room temperature under stirring while the precipitation of crystals begins already in the warm solution, The precipitated product is filtered and washed with tertiary butyl methyl ether. The product is dried at room temperature on the air for a day.
Yield: 0.70 g (84 %).
The crude product thus obtained is recrystallized from 25 ml of isopropanol. The precipitate is filtered and washed with a small amount of cold isopropanol and tertiary butyl methyl ether. Thus 0.55 g (78 %) of a white crystalline product is obtained.
Mp.: 150.3-154.0°C
Analysis for the Formula C22H23N304 · C6Hi0N3O4 (539.59):
Calc: C: 62.33 H: 6.16 N: 7.79
Found: C: 62.63 H: 6.29 N: 7.69
IR (KBr, cm-1): 3254, 2929, 2456, 1606, 1574, 1515, 1446, 1327, 1286, 1128, 1073, 1035. Ή-NMR
400 MHz): 12.00 (b, 2H), 9.46 (b, 1H), 8.51 (s, 1H), 8.01 (m, 1H), 7.92 (m, 1H), 7.87 (s, 1H), 7.41 (m, 1H), 7,23 (s, 1H), 7.22 (m, 1H), 4.30 (m, 4H), 3.80 (m, 2H), 3.76 (m, 2H), 3.39 (s, 3H), 3.37 (s, 3H), 2.21 (m, 4H), 1.52 (m, 4H).
,3C-NMR (DMSO- , 100 MHz): 174.46, 156.29, 153.88, 152.93, 148.33, 147.17, 139.98, 129.02, 126.49, 124.91, 122.70, 121.92, 109.1 1, 108.40, 103.45, 83.67, 80.61, 70.31, 70.24, 68.59, 68.23, 58.56, 33.56, 24.21.
Example 5
Preparation of the erlotinib 1,5-naphthalene-disulfonic acid salt Ι2ΛΙ /compound of the
Formula 6/
Into an apparatus 10 ml of ethanol are weighed in under vigorous stirring whereupon 0.730 g /l .86 millimoles/ of erlotinib base are dissolved therein under stirring and reflux. To the reaction mixture 0.335 g /0.93 millimoles/ of 1 ,5-naphthalene-disulfonic acid is added under stirring and the reaction mixture is stirred overnight without heating. The precipitated crystalline product is filtered, washed with a small amount of cold ethanol and tert.butyl methyl ether.
Yield 0.83 g (78 %) white crystals.
1,06 g of the crude product thus obtained are recrystallized from 20 ml of dimethyl sulfoxide. The precipitate is filtered, washed with a small amount of cold dimethyl sulfoxide and tertiary butyl methyl ether.
Yield: 0.85 g (80 %), ochre colored substance.
Mp.: >290°C (decomposition)
Analysis for the Formula (C22H23N304)2 · C10H8S2O6 (1075.59):
Calc: C: 60.32 H: 5.06 N: 7.82 S: 5.96
Found: C: 59.96 H: 4.96 N: 7.82 S: 5.89
IR (KBr, cm-1): 3269, 1637, 1575, 1451, 1165, 1029, 607.
Ή-NMR (DMSO- g, 500 MHz): 14.53 (b), 8.88 (m, 1H), 8.86 (s, 1H), 8.06 (s, 1H), 7.95 (m, 1H), 7.83 (m, 1H), 7.71 (m, 1H), 7.51 (m, 1H), 7.43 (m, 1H), 7.39 (m, 1H), 7.29 (s, 1H), 4.31 (m, 4H), 4.27 (s, 1H), 3.76 (m, 2H), 3.36 (s, 3H), 3.35 (s, 3H).
13C-NMR (DMSO-£¾, 125 MHz): 158.26, 156.01, 149.66, 149.25, 143.95, 137.26, 135.81, 129.66, 129.63, 129.50, 129.16, 127.69, 125.27, 124.15, 123.98, 122.35, 107.34, 104.56, 101.12, 82.94, 81.57, 69.98, 69.96, 69.01, 68.92, 58.56.
Example 6
Preparation of the erlotinib L-pyroglutamic acid salt /1:1/ /compound of the Formula 11
Into an apparatus 20 ml of ethanol are weighed in under intensive stirring whereupon 1.000 g (2.54 millimoles) of erlotinib base are dissolved therein under stirring and reflux. To the reaction mixture at this temperature 0.328 g /2.54 millimoles/ of L-pyroglutamic acid is added under stirring. The reaction mixture is allowed to cool to room temperature under stirring whereby the slow precipitation of crystals begins. The reaction mixture is allowed to stand at room temperature for an hour, the precipitated crystalline product is filtered and washed with a small amount of cold ethanol and thereafter with tertiary butyl methyl ether.
Yield 0.87 g (65 %)
0.717 g of the crude product is recrystallized from 25 ml of isopropanol. The suspension obtained is allowed to stand in a refrigerator overnight, filtered and washed with a small amount of cold isopropanol and thereafter with tertiary butyl methyl ether.
Yield: 0.51 g (72 %).
Mp.: 158.3-160.7°C.
Analysis for the Formula C22H23N304 · C5H7N03 (522.56):
Calc: C: 62.06 H: 5.79 N: 10.72
Found: C: 60.97 H: 6.08 N: 10.65
IR (KBr, cm"1): 3319, 1691, 1628, 1520, 1447, 1279, 1 129.
1H-NMR (DMSO-i/e, 500 MHz): 12.74 (b), 9.47 (b, 1H), 8.35 (s, 1H), 8.01 (m, 1H), 7.92 (m, 1H), 7.90 (b, 1H), 7.87 (s, 1H), 7.41 (m, 1H), 7.23 (s, 1H), 7.22 (m, 1H), 4.30 (m, 4H), 4.18 (s, 1H), 4.09 (m, 1H), 3.80 (m, 2H), 3.76 (m, 2H), 3.39 (s, 3H), 3.38 (s, 3H), 2.34 (m, 1H), 2.14 (m, 2H), 1.99 (m, 1H).
13C-NMR (DMSO-<¾, 125 MHz) 177.1 1, 174.57, 156.29, 153.88, 152.91, 148.32, 147.12, 139.97, 129.02, 126.50, 124.92, 122.70, 121.91, 109.10, 108.37, 103.44, 83.67, 80.62, 70.31 , 70.23, 68.59, 68,23, 58.56, 58.50, 54.93, 29.22, 24.77.
Example 7
Preparation of erlotinib l-hydroxy-2-naphthoicc acid salt /1:1/ /compound of the
Formula 8/
Into an apparatus 15 ml of ethanol are weighed in under vigorous stirring, whereupon 0.704 g /l .79 millimoles/ of erlotinib base are dissolved therein under stirring and reflux. To the reaction mixture at this temperature 0.336 g /l .79 millimoles/ of l-hydroxy-2 -naphthoic acid are added under stirring. A dark yellow solution is obtained. The reaction mixture is allowed to cool to room temperature under stirring whereby a slow precipitation of crystals can begin. The reaction mixture is allowed to stand in a refrigerator overnight the precipitated product is filtered and washed with a small amount of cold ethanol and thereafter with tertiary butyl methyl ether.
Yield: 0.77 g (74 %)
0.700 g of the crude product thus obtained is recrystallized from 10 ml of ethanol. The suspension obtained is allowed to stand in a refrigerator overnight and washed with a small amount of cold isopropanol and thereafter with tertiary butyl methyl ether.
Yield: 0.47 g (67 %)
Mp.:144.2-147°C.
Analysis for the Formula C22H23N304 ■ CuH803 (581.63):
Calc: C: 68.15 H: 5.37 N: 7.22
Found: C: 67.39 H: 5.46 N: 7.22
IR (KBr, cm"1): 3258, 1648, 1583, 1439, 1403, 775.
Ή-NMR (DMSO-</6, 500 MHz): 12-10 (b), 9.74 (b, 1H), 8.58 (s, 1H), 8.29 (m, 1H), 8.00 (m, 1H), 7.89 (m, 3H), 7.78 (d, J=8.7 Hz, 1H), 7.65 (m, 1H9, 7.56 (m, 1H), 7.43 (m, 1H), 7.34 (d, J=8.7 Hz, 1H), 7.27 (m, lH), 7.25 (s, 1H), 4.30 (m, 4H), 4.21 (s, 1H), 3.78 (m, 4H), 3.39 (s, 2H), 3.37 (s,3H).
13C-NMR (DMSO- e, 125 MHz) 173.06, 160.68, 156.54, 154.14, 152.36, 148.49, 145.53, 139.60, 129.22, 129.05, 127.69, 126.91 , 125.80, 125.28, 125.23, 124.43, 123.22, 123.04, 121.96, 117.88, 108.84, 107.35, 106.93, 103.57, 83.56, 80.73, 70.24, 70.18, 68.60, 68.31 , 58.53, 58.49.
Example 8
Preparation of erlotinib DL-mandelic acid salt /1:1/ /compound of the Formula 9/
Into an apparatus 20 ml of ethanol are weighed in whereupon 1.00 g /2.54 millimoles/ of erlotinib base are dissolved therein under intensive stirring and reflux. To the reaction mixture at this temperature 0.387 g /2.54 millimoles/ of DL-mandelic acid are added. The colour of the solution becomes yellow. The reaction mixture is allowed to cool to room temperature whereby a slow precipitation of crystals begins on rubbing. The reaction mixture is allowed to stand at room temperature overnight the precipitated product is filtered and washed with a small amount of cold ethanol and tertiary butyl methyl ether.
Yield.: 0.80 g (80 %)
The crude product thus obtained is recrystallized from 10 ml of isopropanol. The suspension obtained is allowed to stand in a refrigerator, filtered and washed with a small amount of cold isopropanol and thereafter with tertiary butyl methyl ether.
Yield: 0.60 g (75 %)
Mp.: 138.6-140.9°C.
Analysis for the Formula C22H23N304 ■ C8H803 (545.60):
Calc: C: 66.04 H: 5.73 N: 7.70
Found: C: 65.24 H: 5.73 N: 7.73
IR (KBr, cm'1): 3284, 2933, 1583, 1513, 1448, 1 128, 946, 861, 731 , 699.
Ή-NMR (DMSO-i/6, 500 MHz): 9.48 (b, 1H), 8.02 (m, 1H), 7.92 (m, 1H), 7.87 (s, 1H), 7.42
(m, 2H), 7.41 (m, 1H), 7.35 (m, 2H), 7.29 (m, 1H), 7.24 (s, 1H), 7.23 (m, 1H), 5.05 (s, 1H),
4.30 (m, 4H), 4.18 (s, 1H), 3.80 (m, 2H), 3.76 (m, 2H), 3.39 (s, 3H), 3.36 (s, 3H).
13C-NMR (DMS0-i 125 MHz) 174.26, 156.32, 153.90, 152.90, 148.34, 147.05, 140.43,
139.97, 129.03, 128.26, 127.77, 126.79, 126.53, 124.95, 122.74, 121.93, 109.10, 108.33,
103.46, 83.68, 80.62, 72.60, 70.30, 70.23, 68.60, 68.24, 58.56.
Example 9
Determination of the solubility of erlotinib maleate and erlotinib adipinate salts in 0.1 M hydrochloric acid solution
Erlotinib maleate monohydrate salt: 10 mg of erlotinib maleate monohydrate are weighed in a 25 ml round-bottomed flask whereupon a 0.1 M hydrochloric acid solution /exact titre/ is added under continuous stirring /Heidolph 3001 mixer, 1000 rpm/ After addition of 10 ml of the hydrochloric acid solution immediately a clear solution is obtained.
Erlotinib adipinate salt: 10 mg of erlotinib adipinate are weighed in a 25 ml round-bottomed flask whereupon a 0.1 M hydrochloric acid solution /exact titre/ is added under continuous stirring /Heidolph 3001 mixer. 1000 rpm/. After addition of 2 ml of the hydrochloric acid solution immediately a clear solution is obtained.
Erlotinib hydrochloride: 10 mg of erlotinib hydrochloride salt are weighed into a 50 ml round- bottomed flask whereupon a 0.1 M hydrochloric acid solution /exact titre/ is added under continuous stirring. After addition of 50 ml of the hydrochloric acid solution no clear solution is obtained even after stirring for two hours /according to visual observation the mixture still contains insoluble particles/.
Example 10
Preparation of erlotinib maleate monohydrate /compound of the Formula 21 and erlotinib adipinate /compound of the Formula 5/ without isolating the erlotinib base
3.0 g 16.9 millimoles/ of erlotinib hydrochloride are intensively stirred in the mixture of 100 ml of ethyl acetate, 60 ml of water and 30 ml of a concentrated ammonium hydroxide solution
for 30 minutes /Heidolph MR 3001 , 1000 rpm/ at 50°C. The phases are separated and the strongly alkaline aqueous layer is washed twice with 80 ml of ethyl acetate each and thereafter with 50 ml ethyl acetate at 50°C the solution layers are well separated and are completely clear. The united ethyl acetate phases are washed four times with 100 ml of water each at the above temperature /the duration of each washing step is 15 minutes/. After each washing step clear well-separated phases are obtained. Finally the ethyl acetate phase is washed with 100 ml of a saturated sodium chloride solution, which is then dried over sodium sulfate and the drying agent is filtered off. Thus 310 ml /total volume/ of a solution are obtained which can be used in the salt forming reactions. a) Salt formation with maleic acid /preparation of the compound of the Formula 2/
To the 310 ml of the ethyl acetate solution thus obtained a solution of 0.81 g (6.98 millimoles) of maleic acid and 10 ml of ethanol is added under intensive stirring /Heidolph MR 3001 , 1000 rpm/ at room temperature. The precipitation of crystals begins, whereupon the mixture is stirred for a further period of 24 hours, the precipitated crystals are filtered, washed with 20 ml of tert. butyl methyl ether and dried at 50°C under a pressure of 160 mbar for 20 hours. Yield: 3.17 g (89 %). b) Salt formation with adipinic acid /preparation of the compound of the Formula 5/
One proceeds according to point a) except that to the ethyl acetate solution 1.02 g (6.98 millimoles) of adipinic acid in 20 ml of ethanol is added. Crystallization is started by using a seeding crystals and external ice-water cooling. After the beginning of the crystal precipitation the mixture is stirred for a further period of 24 hours. The precipitated crystals are filtered, washed with 20 ml of tert. butyl methyl ether and dried at 50°C under a pressure of 160 mbar for 20 hours.
Yield 2.71 g (72 %).
The further advantage of the above salt formation procedures is that as a result of the aqueous washing steps the precipitated salt contains no residual inorganic contaminations /e.g. sodium chloride/ contrary e.g. to the precipitation of the base carried out from an alcoholic solution with sodium acetate.
Claims
1. Erlotinib salt selected from the group consisting of the maleic acid salt, salicylic acid salt, L-mandelic acid salt, adipinic acid salt, 1,5-naphthalene-disulfonic acid salt, L-pyroglutamic acid salt, 1 -hydroxy-2-naphthoic acid salt and (D,L) mandelic acid salt and amorphous and crystalline forms, hydrates and solvates thereof.
2. Ml polymorph /Form Ml/ of erlotinib maleic monohydrate acid salt according to Claim 1 which has the following characteristic X-ray powder diffraction peaks: 2 Θ (±0.2° 2 Θ): 6.870; 8.190; 8.880; 12.760; 13.740; 16.080; 19.430; 20.850; 21.710; 25.030; 25.740; 26.920; 28.450.
3. Ml polymorph /Form Ml/ of erlotinib maleic acid salt monohydrate according to Claim 2 which has the following characteristic X-ray powder diffraction peaks: 2 Θ (±0.2° 2 Θ): 6.870; 8.190; 8.880; 10.690; 12.760; 13.740; 16.080; 17.700; 18.490; 19.1 10; 19.430; 20.850; 21.170. 21.710; 24.750; 25.030; 25.740; 26.920; 27.720; 28.450; 32.230.
4. M2 polymorph /Form M2/ of erlotinib maleic acid salt monohydrate according to Claim 1 which has the following characteristic X-ray powder diffraction peaks: 2 Θ (±0.2° 2 Θ): 6.710; 8.018; 8.702; 12.552; 12.951; 13.533; 18.224; 18.859; 19.142; 21.385; 24.395; 25.960.
5. M2 polymorph /Form M2/ of erlotinib maleic acid salt monohydrate according to Claim 4 which has the following characteristic X-ray powder diffraction peaks: 2 Θ (±0.2° 2 Θ): 6.710; 8.018; 8.702; 10.494; 10.891 ; 12.552; 12.951 ; 13.533; 17.510; 18.224; 18.859; 19.142; 20.454; 20.843; 21.385; 22.806; 24.395; 25.316; 25.960; 28.979; 30.413; 31.194; 34.408.
6. Erlotinib salicylic acid /1 :1/ salt according to Claim 1 which has the following characteristic X-ray powder diffraction peaks: 2 Θ (±0.2° 2 Θ): 5.830; 6.990; 16.060; 23.490; 26.000.
7. Erlotinib salicylic acid 71 : 1/ salt according to Claim 6 which has the following characteristic X-ray powder diffraction peaks: (±0.2° 2 Θ): 5.830; 6.990; 16.060; 20.220; 22.740; 23.490; 24.930; 26.000.
8. Erlotinib L-mandelic acid /1 : 1/ salt according to Claim 1 which has the following characteristic X-ray powder diffraction peaks: 2 Θ (±0.2°. 2 Θ): 6.040; 12.190; 16.200; 17.090; 18.270; 19.230; 20.030; 23.250; 24.870. 26.170.
9. Erlotinib L-mandelic acid /1 : 1/ salt according to Claim 8 which has the following characteristic X-ray powder diffraction peaks: 2 Θ (±0.2° 2 Θ): 6.040; 8.010; 12.190; 16.200; 18.270; 19.230; 20.030; 21.170; 21.780; 22.630; 23.250; 24.870; 26.170.
10. Erlotinib adipinic acid salt according to Claim 1 which has the following characteristic X- ray powder diffraction peaks: 2 Θ (±0.2° 2 Θ): 6.400; 7.050; 8.990; 12.920; 18.740; 21.820; 22.660; 28.830.
11. Erlotinib adipinic acid salt according to Claim 10 which has the following characteristic X-ray powder diffraction peaks: 2 Θ (±0.2° 2 Θ): 6.400; 7.050; 8.990; 12.920; 16.860; 17.350; 18.740; 20.430; 21.240; 21.820; 22.660; 23.370; 28.830.
12. Erlotinib 1.5-naphthalene-disulfonic acid salt according to Claim 1 which has the following characteristic X-ray powder diffraction peaks: 2 Θ (±0.2° 2 Θ): 6.310; 12.540; 14.330; 18.750; 19.940; 21.690; 23.230; 25.220.
13. Erlotinib 1.5-naphthalene-disulfonic acid salt according to Claim 12 which has the following characteristic X-ray powder diffraction peaks: 2 Θ (±0.2° 2 Θ): 6.310; 12.540; 13.660; 14.330; 17.430; 18.750; 19.070; 19.940; 21.690; 22.640; 23.230; 25.220; 25.770; 27.490; 28.250; 28.860; 29.630; 32.820; 33.400.
14. Erlotinib L-pyroglutamic acid salt according to Claim 1 which has the following characteristic X-ray powder diffraction peaks: 2 Θ (±0.2°. 2 Θ): 7.180; 13.310; 14.920. 19.590; 20.850; 22.160; 23.100; 24.170; 26.500.
15. Erlotinib L-pyroglutamic acid salt according to Claim 14 which has the following characteristic X-ray powder diffraction peaks: 2 Θ (±0.2° 2 Θ): 5.180; 7.180; 13.310; 14.920; 16.260; 16.610; 18.460; 19.060; 19.590; 20.080; 20.850; 22.160; 23.100; 24.170; 24.580; 25.070; 26.500; 27.360; 28.290; 28.670.
16. Erlotinib l-hydroxy-2-naphthoic acid salt according to Claim 1 which has the following characteristic X-ray powder diffraction peaks: 2 Θ (±0.2°. 2 Θ): 4.300; 1 1.630; 14.340; 17.470; 19.140; 19.850; 22.800; 26.200.
17. Erlotinib l-hydroxy-2-naphthoic acid salt according to Claim 16 which has the following characteristic X-ray powder diffraction peaks: 2 Θ (±0.2° 2 Θ): 4.300; 6.760; 1 1.630; 13.120; 13.750; 14.340; 16.860; 17.470; 18.540; 19.140; 19.850; 21.030; 22.800; 23.660; 24.540; 26.200; 28.580.
18. Erlotinib DL-mandelic acid salt according to Claim 1 which has the following characteristic X-ray powder diffraction peaks: 2 Θ (±0.2°. 2 Θ): 5.400; 9.160; 14.530; 18.140; 21.700; 23.010.
19. Erlotinib DL-mandelic acid salt according to Claim 18 which has the following characteristic X-ray powder diffraction peaks: 2 Θ (±0.2° 2 Θ): 5.400; 9.160; 14.530; 15.490; 17.040; 17.360; 18.140; 18.370; 20.190; 21.180; 21.700; 23.010; 23.800; 24.700; 25.230; 25.960; 27.030.
20. Process for the preparation of erlotinib salts according to any of Claims 1 to 19, characterized in that it comprises reacting erlotinib base with an organic acid in an organic solvent or a mixture of an organic solvent and water and separating the erlotinib salt formed.
21. Process according to Claim 20 characterized in that it comprises using the acid in a 0.3-3.0 molar equivalent amount, preferably in a 0.5-1.0 molar equivalent amount.
22. Process according to any of Claims 20 and 21 characterized in that the used organic solvent is a C1-4 alcohol, an ether, ester or a dipolar aprotic solvent or a mixture thereof.
23. Process according to Claim 22 which characterized in that used solvent is tetrahydrofurane. diethyl ether, ethyl acetate, acetonitrile. methanol, ethanol. 2-propanol or a mixture thereof.
24. Process according to any of Claims 20 to 23 characterized in that the reaction is carried out at a temperature between 0°C and the boiling point of the solvent, preferably between room temperature and 80°C.
25. Pharmaceutical composition comprising an erlotinib salt according to any of Claims 1 to 19 in an admixture with conventional pharmaceutical auxiliary agents.
26. Process for the preparation of pharmaceutical compositions according to Claim 25 characterized in that it comprises admixing a therapeutically effective amount of an erlotinib salt according to any of Claims 1 to 19 with a pharmaceutically acceptable carrier and optionally with further pharmaceutically acceptable auxiliary agents and bringing the mixture into a galenic form.
27. Erlotinib salts according to any of Claims 1 to 19 for use in medicine.
28. Erlotinib salts according to any of Claims 1 to 19 for use in the treatment or prophylaxis of non-small cell lung carcinoma or pancreas carcinoma.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU1100562A HU230483B1 (en) | 2011-10-10 | 2011-10-10 | Erlotinib salts |
| PCT/HU2012/000102 WO2013054147A2 (en) | 2011-10-10 | 2012-10-10 | Erlotinib salts |
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| EP (1) | EP2776406A2 (en) |
| CN (1) | CN103958483A (en) |
| BR (1) | BR112014008733A2 (en) |
| EA (1) | EA201490773A1 (en) |
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| CN104250230A (en) * | 2014-09-05 | 2014-12-31 | 亿腾药业（泰州）有限公司 | Erlotinib citrate, crystal form and preparation method of two |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| EP3103799B1 (en) | 1995-03-30 | 2018-06-06 | OSI Pharmaceuticals, LLC | Quinazoline derivatives |
| ATE295839T1 (en) | 1998-04-29 | 2005-06-15 | Osi Pharm Inc | N-(3-ETHINYLPHENYLAMINO)-6,7-BIS(2-METHOXYETHOX )-4-CHINAZOLINAMIN MESYLATE ANHYDRATE AND MONOHYDRATE |
| US7960545B2 (en) * | 2005-11-23 | 2011-06-14 | Natco Pharma Limited | Process for the prepartion of erlotinib |
| JP5524041B2 (en) | 2007-04-04 | 2014-06-18 | シプラ・リミテッド | Method for producing erlotinib and pharmaceutically acceptable salts thereof |
| US8440823B2 (en) * | 2009-03-26 | 2013-05-14 | Ranbaxy Laboratories Limited | Process for the preparation of erlotinib or its pharmaceutically acceptable salts thereof |
| WO2011068403A2 (en) * | 2009-12-02 | 2011-06-09 | Ultimorphix Technologies B.V. | Novel n-{3-ethynylphenylamino)-6,7-bis(2-methoxyethoxy)-4-quinazolinamjne salts |
-
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| HU230483B1 (en) | 2016-07-28 |
| CN103958483A (en) | 2014-07-30 |
| EA201490773A1 (en) | 2014-10-30 |
| WO2013054147A2 (en) | 2013-04-18 |
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