ZA200309586B - Stable polymorph of flibanserin technical process for its preparation and the use thereof for preparing medicaments - Google Patents
Stable polymorph of flibanserin technical process for its preparation and the use thereof for preparing medicaments Download PDFInfo
- Publication number
- ZA200309586B ZA200309586B ZA2003/09586A ZA200309586A ZA200309586B ZA 200309586 B ZA200309586 B ZA 200309586B ZA 2003/09586 A ZA2003/09586 A ZA 2003/09586A ZA 200309586 A ZA200309586 A ZA 200309586A ZA 200309586 B ZA200309586 B ZA 200309586B
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- South Africa
- Prior art keywords
- flibanserin
- polymorph
- medicament
- water
- preferred
- Prior art date
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- PPRRDFIXUUSXRA-UHFFFAOYSA-N flibanserin Chemical compound FC(F)(F)C1=CC=CC(N2CCN(CCN3C(NC4=CC=CC=C43)=O)CC2)=C1 PPRRDFIXUUSXRA-UHFFFAOYSA-N 0.000 title claims description 40
- 229960002053 flibanserin Drugs 0.000 title claims description 39
- 239000003814 drug Substances 0.000 title claims description 24
- 238000000034 method Methods 0.000 title claims description 18
- 230000008569 process Effects 0.000 title claims description 15
- 238000002360 preparation method Methods 0.000 title claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 23
- 239000000203 mixture Substances 0.000 claims description 16
- 239000008194 pharmaceutical composition Substances 0.000 claims description 14
- 239000002904 solvent Substances 0.000 claims description 11
- 238000006243 chemical reaction Methods 0.000 claims description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 9
- 125000006239 protecting group Chemical group 0.000 claims description 8
- 150000001298 alcohols Chemical class 0.000 claims description 6
- 150000001875 compounds Chemical class 0.000 claims description 5
- 201000010099 disease Diseases 0.000 claims description 5
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- 239000004480 active ingredient Substances 0.000 claims description 4
- 230000008901 benefit Effects 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- 230000001225 therapeutic effect Effects 0.000 claims description 4
- 208000019901 Anxiety disease Diseases 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 3
- 230000036506 anxiety Effects 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 3
- 206010027175 memory impairment Diseases 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 208000020016 psychiatric disease Diseases 0.000 claims description 3
- 201000000980 schizophrenia Diseases 0.000 claims description 3
- 208000012201 sexual and gender identity disease Diseases 0.000 claims description 3
- 208000015891 sexual disease Diseases 0.000 claims description 3
- 230000001568 sexual effect Effects 0.000 claims description 3
- 208000019116 sleep disease Diseases 0.000 claims description 3
- 208000022925 sleep disturbance Diseases 0.000 claims description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-M Methanesulfonate Chemical compound CS([O-])(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 claims description 2
- MYONAGGJKCJOBT-UHFFFAOYSA-N benzimidazol-2-one Chemical compound C1=CC=CC2=NC(=O)N=C21 MYONAGGJKCJOBT-UHFFFAOYSA-N 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 239000008024 pharmaceutical diluent Substances 0.000 claims description 2
- 239000003880 polar aprotic solvent Substances 0.000 claims description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 claims description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 claims description 2
- 238000002076 thermal analysis method Methods 0.000 claims 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 36
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 18
- -1 1,1-diphenylmethyl Chemical group 0.000 description 17
- 239000013543 active substance Substances 0.000 description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 16
- 230000035946 sexual desire Effects 0.000 description 10
- 229960004592 isopropanol Drugs 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- 238000000227 grinding Methods 0.000 description 6
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 208000006262 Psychological Sexual Dysfunctions Diseases 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 208000035475 disorder Diseases 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 239000011877 solvent mixture Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- 206010024419 Libido decreased Diseases 0.000 description 3
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 3
- 208000017020 hypoactive sexual desire disease Diseases 0.000 description 3
- 229910052744 lithium Inorganic materials 0.000 description 3
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 125000006678 phenoxycarbonyl group Chemical group 0.000 description 3
- 239000011591 potassium Substances 0.000 description 3
- 229910052700 potassium Inorganic materials 0.000 description 3
- 238000000634 powder X-ray diffraction Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 150000001805 chlorine compounds Chemical class 0.000 description 2
- 238000003776 cleavage reaction Methods 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000008030 elimination Effects 0.000 description 2
- 238000003379 elimination reaction Methods 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 230000007017 scission Effects 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000009827 uniform distribution Methods 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 208000021663 Female sexual arousal disease Diseases 0.000 description 1
- 206010057671 Female sexual dysfunction Diseases 0.000 description 1
- 239000001828 Gelatine Substances 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
- 206010024870 Loss of libido Diseases 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000001785 acacia senegal l. willd gum Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910000272 alkali metal oxide Inorganic materials 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
- 239000012670 alkaline solution Substances 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical class OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 229960001760 dimethyl sulfoxide Drugs 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 description 1
- 229910052808 lithium carbonate Inorganic materials 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 239000007922 nasal spray Substances 0.000 description 1
- 229940097496 nasal spray Drugs 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000000646 scanning calorimetry Methods 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 125000004417 unsaturated alkyl group Chemical group 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Stable polymorph of flibanserin, technical process for its preparation and the use thereof for preparing medicaments - The invention relates to the polymorph A of flibanserin, to a technical process for the : 5 preparation thereof, as well as to the use thereof for preparing medicaments.
The compound 1-[2-(4-(3-trifluoromethyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H- benzimidazol-2-one (flibanserin) is disclosed in form of its hydrochlorid in European
Patent Application EP-A-526434 and has the following chemical structure: . 0) nA CF, /N\
JEN . \_/ 4 x HCI ) Flibanserin shows affinity for the 5-HT 1a and 5-HT,-receptor. lt is therefore a promising therapeutic agent for the treatment of a variety of diseases, for instance depression, schizophrenia, Parkinson, anxiety, sleep disturbances, sexual and mental disorders and age associated memory impairment.
A certain phamaceutical activity is of course the basic prerequisite to be fulfilled by a pharmaceutically active agent before same is approved as a medicament on the market. However, there are a variety of additional requirements a pharmaceutically active agent has to comply with. These requirements are based on various parameters which are connected with the nature of the active substance itself.
Without being restrictive, examples of these parameters are the stability of the active agent under various environmental conditions, its stability during production of the pharmaceutical formulation and the stability of the active agent in the final medicament compositions. The pharmaceutically active substance used for . preparing the pharmaceutical compositions should be as pure as possible and its stability in long-term storage must be guaranteed under various environmental . 30 conditions. This is absolutely essential to prevent the use of pharmaceutical compositions which contain, in addition to the actual active substance, breakdown products thereof, for example. In such cases the content of active substance in the medicament might be less than that specified.
Uniform distribution of the medicament in the formulation is a critical factor, particularly when the medicament has to be given in low doses. To ensure uniform distribution, the particle size of the active substance can be reduced to a suitable on level, e.g. by grinding. Since breakdown of the pharmaceutically active substance as a side effect of the grinding (or micronising) has to be avoided as far as possible, in ’ spite of the hard conditions required during the process, it is absolutely essential that the active substance should be highly stable throughout the grinding process. Only if the active substance is sufficiently stable during the grinding process is it possible to produce a homogeneous pharmaceutical formulation which always contains the specified amount of active substance in reproducible manner.
Another problem which may arise in the grinding process for preparing the desired pharmaceutical formulation is the input of energy caused by this process and the stress on the surface of the crystals. This may in certain circumstances lead to polymorphous changes, to a change in the amorphous configuration or to a change in the crystal lattice. Since the pharmaceutical quality of a pharmaceutical formulation requires that the active substance should always have the same crystalline morphology, the stability and properties of the crystalline active substance are subject to stringent requirements from this point of view as well.
LL Co
The stability of a pharmaceutically active substance is also important in pharmaceutical compositions for determining the shelf life of the particular medicament; the shelf life is the length of time during which the medicament can be administered without any risk. High stability of a medicament in the abovementioned pharmaceutical compositions under various storage conditions is therefore an additional advantage for both the patient and the manufacturer.
Apart from the requirements indicated above, it should be generally borne in mind that any change to the solid state of a pharmaceutical composition which is capable of improving its physical and chemical stability gives a significant advantage over less stable forms of the same medicament.
The aim of the invention is thus to provide a new, stable crystalline form of the . compound flibanserin which meets the stringent requirements imposed on pharmaceutically active substances as mentioned above.
Surprisingly, it has been found that the free base of flibanserin in a specific polymophic form fulfils the requirements mentioned hereinbefore.
Moreover it has been found that, depending on the choice of conditions which can be applied during the synthesis of flibanserin the free base occurs in different crystalline o modifications, polymorphs A and B. ’ It has been found that these different modifications can be deliberately produced by a suitable choice of the process conditions used in the manufacturing process.
Surprisingly, it has been found that polymorph A, which can be obtained in crystalline form by choosing specific reaction conditions, meets the stringent requirements mentioned above and thus solves the problem on which the present invention is based. Accordingly the present invention relates to polymorph A of flibanserin.
Polymorph A of flibanserin is characterised by a melting point of about 161°C (determined via DSC; heating rate 10 K/min).
Polymorph B, the less stable modification of flibanserin displays a melting point of about 120°C (determined via DSC; heating rate 10 K/min). Whereas polymorph B shows little stability under the effects of for instance mechanical stress produced by grinding, polymorph A turned out to fulfill the aforementioned stability requirements.
According to another aspect, the present invention relates to a process for the manufacture of polymorph A of flibanserin in technical scale. The process according to the inventon is illustrated in diagram 1.
H CF,
N X
Lr OS —
N \_/
R
2 3
O
HN A CF,
OO
__/
Diagram 1:
The benzimidazolone 2 is reacted with the piperazine-derivative 3 under basic reaction conditions in a suitable solvent to lead to 1. In 2 the group R denotes an amino protecting group. The protecting group used may be any of the groups commonly used to protect the amino function. Examples include groups selected from alkyl, substituted alkyl, heterosubstituted alkyl, unsaturated alkyl, alkyl substituted heteroatoms, substituted or unsubstituted phenyl, substituted or a unsubstituted benzyl, alkyloxycarbonyl groups and aryloxycarbonyl groups. Preferred protecting groups are selected from butyl, 1,1-diphenylmethyl, methoxymethyl, ’ benzyloxymethyl, trichloroethoxymethyl, pyrrolidinomethyl, cyanomethyl, pivaloyloxymethyl, allyl, 2-propenyl, t-butyldimethylsilyl, methoxy, thiomethyl, 4- methoxyphenyl, benzyl, 4-methoxybenzyl, 2,4-dimethoxybenzyl, 2-nitrobenzyl, t- butoxycarbonyl, benzyloxycarbonyl, phenoxy carbonyl, 4-chloro-phenoxycarbonyl, 4- nitro-phenoxycarbonyl, methoxycarbonyl and ethoxycarbonyl. Among them the preferred protecting groups are selected from t-butoxycarbonyl, ethoxycarbonyl, methoxycarbonyl, benzyloxycarbonyl, phenoxycarbonyl and 2-propenyl, the latter being most preferred. X in 3 represents a leaving group selected from chlorine, bromine, iodine, methanesulphonate, trifluoromethanesulphonate or para- toluenesulphonate. Preferably X denotes chlorine, bromine or iodine, chlorine being most preferred. Suitable solvents are selected from water, alcohols and mixtures of water with alcohols, polar aprotic solvents and mixtures thereof with water. CL
Preferred solvents are selected from the group consisting of dimethylformamid, dimethylsulfoxid, acetonitrile, tetrahydrofurane, dioxane, methanol, ethanol Co isopropanaol and mixtures of one or several of the aformenetioned solvents with - water. Preferred solvents are those being readily miscible with water. Preferably, a mixture of water with one of the alcohols methanol, ethanol or isopropanol is used as the solvent. In a preferred embodiment a mixture of water and isopropanol is used as the solvent. The base used may be an alkali metal- or alkaline earth metal carbonate of lithium, sodium, potassium, calcium such as sodium carbonate, lithium carbonate, potassium carbonate, calcium carbonate and preferably potassium carbonate. It is also possible to use the hydrogen carbonates of lithium, sodium and potassium. Preferably, the alkali metal- or alkaline earth metal hydroxides of lithium, sodium, potassium, magnesium, calcium, but preferably sodium hydroxide, potassium hydroxide, lithium hydroxide and calcium hydroxide in alcohols or water may also be used. Most preferred base is sodium hydroxide. The base is preferably ‘ added in form of its aqueous solution, preferably in form of concentrated aqueous solutions, for example in concentrations between 30 - 50% weight/volume. In a . preferred embodiment aqueous sodium hydroxide solution in a concentration of about 45% weight/volume is used.
The compounds 2 and 3 are introduced into the reaction in a molar ratio of between 1:1 to 1:2, preferably in a molar ratio of between 1:1.1 to 1:1.5.
As mentioned hereinbefore a mixture of water and isopropanol is used as a preferred solvent mixture for the conduction of the process according to the invention. In this solvent mixture the weight-ratio of water to isopropanol in the preferred solvent mixture is between 10:1 and 1:1, more preferred between 8:1 and 3:1, particular 5 preferred between 7:1 and 5:1. Per mol of compound 2 about 2 - 10 kg, preferably ) 3 - 8 kg, more preferred 4 - 7 kg of the aforementioned solvent mixture are used. In a preferred embodiement the reaction is conducted using aqueous sodium hydroxide solution in a concentration of about 45% weight/volume as the base. Per mol of 2 about 0.1 - 1.5 kg, preferably 0.2 - 1.0 kg, particularly preferred 0.3 - 0.6 kg of the aforementioned sodium hydroxide solution are used. The reaction mixture containing 2, 3 and the base in the aforementioned suitable solvent is preferably heated to at least 50°C. In a preferred embodiment the reaction temperature is in a range of between 60°C to the boiling point of the solvent. Particularly preferred is a temperature between 70 - 90°C. The reaction mixture is heated at the aformentioned temperature for about 10 minutes to about 12 hours, preferably for about 15 minutes to about 6 hours, more preferably for about 30 minutes to about 3 hours. The reaction mixture is preferably heated at the aformentioned temperature for. about 45 to 60 minutes. no oo
Subsequently the protective group R is cleaved. The cleaving conditions depend on the choice of group R. If R denotes for instance benzyl, cleavage is conducted via hydrogenation in acetic acid in the presence of an appropriate catalyst (e.g. Pd on charcoal) or it can be cleaved in aqueous HBr. In case R is methoxycarbonyl, ethoxycarbonyl, phenoxy carbonyl, 4-nitrophenoxycarbonyl it can be cleaved for example by using aqueous alkaline solutions such as NaOH (aq) or KOH(aq). In case R is t-butoxycarbonyl it can be cleaved for instance in aqueous HCl or HBr. In case R denotes 2-propenyl, the particularly preferred protective group according to the invention, cleavage of R is effected via acidic reaction conditions. In a particularly preferred process according to the invention the 2-propenyl group is cleaved by using a strong mineral acid, preferably an acid selected from the group consisting of hydrobromic acid, hydrochloric acid and sulfuric acid, more preferably hydrochloric . acid. Hydrochloric acid can be added in gaseous form or in form of its aqueous solutions, the addition of aqueous solutions being preferred. Particularly preferred is ‘ the addition of hydrochloric acid in form of its concentrated solution (about 36% weight/volume). Per mol 2 at least one mol of hydrochloric acid is to be added.
Preferably the amount of added concentrated hydrochloric acid (36% weight/volume) per mol 2 is between 50 - 500g, more preferred between 80 - 250g. Particularly preferred about 120 - 160 g of concentrated (36% w/v) aqueous hydrochloric acid are added per mol 2 used. Additional water can be optionally added. At a temperature of about 70 - 90°C about 30 - 70%, preferably about 35 - 60% of the solvent is removed via distillation. At a temperature of about 60 - 80°C the pH of the remaining residue is adjusted to about 5 - 9, preferably to about 6 - 8 by addition of aqueous sodium hydroxide (45% wiv). At a temperature of about 40 - 55°C the pH is adjusted to about 8 - 9 by addition of aqueous sodium hydroxide (45% w/v).
Subsequently the mixture is cooled to about 20-40°C, preferably about 30-35°C and centrifuged. The residue thus obtained is washed with about 100 to 750 ml water per mol introduced 2, preferably with about 200 to 500, particularily preffered with about 300 to 400 ml water per mol introduced 2 and isopropanol (about 50 to 250 g per mol 2, preferably about 100 to 200 g per mol 2) and then with water until chlorides elimination. Optionally the product thus obtained can be subjected to another purification step. Preferably, said purification is conducted via crystallization of 1 from fror instance acetone.
One aspect of the present invention relates to flibanserin polymorph A obtainable via the method described above.
The following example of synthesis serves to illustrate a method of preparing polymorph A of flibanserin. It is to be regarded only as a possible method described by way of example, without restricting the invention to its contents. : . -.
Example: 375 kg of 1-[(3-trifluoromethyl)phenyl]-4-(2-cloroethyl)piperazin are charged in a reactor with 2500 kg of water and 200 kg of aqueous Sodium Hydroxide 45%.
Under stirring 169.2 kg of 1-(2-propenyl)-1,3-dihydro-benzimidazol-2H-one, 780 kg of isopropanol, 2000 kg of water and 220 kg of aqueous Sodium Hydroxide 45% are added. The reaction mixture is heated to 75-85°C and 160 kg of concentrated hydrochloric acid and 200 kg of water are added. The reaction mixture is stirred at constant temperature for about 45 minutes. After distillation of a mixture of water and Isopropanol (about 3000 kg) the remaining residue is cooled to about 65-75°C and the pH is adjusted to 6.5 — 7.5 by addition of 125 . kg of aqueous Sodium Hydroxide 45%. After cooling to a temperature of 45- 50°C, the pH value is adjusted to 8-9 by addition of about 4 kg of aqueous ; Sodium Hydroxide 45%. Subsequently the mixture is cooled to 30-35°C and centrifuged. The residue thus obtained is washed with 340 | of water and 126 | of isopropanol and then with water until chlorides elimination. The wet product is dried under vacuum at a temperature of about 45-55°C which leads to 358 kg of crude flibanserin polymorph A. The crude product thus obtained is loaded in a reactor with 1750 kg of Acetone and the resulting mixture is heated under stirring until reflux. The obtained solution is filtered and the filtrate is concentrated by distillation. The temperature is maintained for about 1 hour 0-5°C, then the precipitate solid is isolated by filtration and dried at 55°C for at least 12 hours.
The final yield is 280 kg of pure flibanserin polymorph A. . As mentioned hereinbefore flibanserin polymorph A was characterised by DSC (Differantial Scanning Calorimetry). The peak temperature determined for polymorph
A is about 161°C. For the characterization via DSC a Mettler TA 3000 System equipped with TC 10-A processor and DSC 20 cell was applied. The heating rate was 10 K/min.
The flibanserin polymorph A was additionally characterised by powder x-ray diffractometry. The x-ray powder diffraction pattern for polymorph A was obtained according to the following conditions:
Equipment: Philips PW 1800/10 diffractometer equipped with a digital microvax 2000.
Setting parameters: X-ray
Type tube: Cu (long fine focus)
Wavelenghts (A): Kg = 1.54060 A
Kg2 = 1.54439 A
Intensity ratio (a2/ a1): 0.500
Start angle [°20]: 2.000
End angle [°20]: 60.000
Step size [°20]: 0.020
Maximum intensity[s]: 7310.250
Type of scan: continuous ) Minimum peak tip width: 0.00 ’
Maximum peak tip width: 1.00 . Peak base width: 2.00
Minimum significance: 0.75
Number of peaks: 69
Generator: high voltage: 50 KV tube current: 30 mA
The powder x-ray diffraction pattern obtained for polymorph A is illustrated in figure 1. The appropiate values are collected in table 1.
Table 1: ‘ Angle d-value d-value Peak width Peakint Back.int Rel. int Signif.
[20] al [Al a 2A] [°20] [counts] [counts] [%] 5.195 16.9967 17.0390 0.960 8 69 0.1 1.05 0.045 9.7689 9.7931 0.100 92 96 1.3 0.97 9.335 9.4660 9.4896 0.080 114 98 1.6 0.88 10.025 8.8160 8.8379 0.140 400 100 5.5 7.18 10.595 8.3430 8.3637 0.140 204 102 2.8 3.46 11.280 7.8309 7.8503 0.140 467 104 6.4 6.91 13.225 6.6891 6.7058 0.180 548 112 7.5 13.10 14.595 6.0642 6.0793 0.180 404 121 55 9.17 16.460 5.7268 5.7410 0,140 4186 125 57.3 23.20 16.655 5.3185 5.3317 0.200 515 130 7.0 12.38 17.085 5.1856 5.1985 0.100 1347 132 18.4 2.78 17.285 5.1260 5.1388 0.060 1399 135 19.1 2.26 ©. 17.420 5.0866 5.0992 0.100 1204 135 16.5. 4.71 18.140 4.8863 4.8984 0.180 1043 139 14.3 13.14 18.650 4.7538 4.7656 0.120 1063 142 14.5 0.91 19.140 4.6332 4.6447 0.140 7310 144 100.0 32.77 19.820 4.4757 4.4869 0.160 3624 146 49.6 9.02 20.080 4.4184 4.4294 0.140 5402 149 73.9 21.06 20.385 4.3530 4.3638 0.160 2652 149 36.3 23.25 21.215 4.1845 4.1949 0.160 369 154 5.0 5.78 21.800 4.0570 4.0670 0.200 773 156 10.6 3.09 22.630 3.9259 3.9357 0.280 4277 161 58.5 74.66 23.210 3.8291 3.8386 0.120 484 164 6.6 3.33 24.355 3.6516 3.6607 0.060 2725 169 37.3 1.16 24610 3.6144 3.6234 0.140 3540 172 48.4 17.08 24.995 3.5596 3.5684 0.100 529 174 7.2 1.01 . 25.260 3.5228 3.5316 0.120 557 174 7.6 3.02 26.575 3.3514 3.3597 0.240 2421 182 33.1 42.58 27.455 3.2811 3.2893 0.140 676 185 9.2 1.32 27.310 3.2629 3.2710 0.100 767 185 10.5 2.75 27.865 3.1991 3.2071 0.120 420 188 5.7 1.08 28.210 3.1608 3.1686 0.100 1467 190 20.1 0.79
28.325 3.1482 3.1560 0.140 1789 190 245 4.41 28.650 3.1132 3.1210 0.180 1204 190 165 11.65 20.520 3.0234 3.0309 0.220 1011 196 13.8 15.74
: 30.250 29521 2.9594 0.120 159 199 22 1.22 31.105 2.8729 2.8800 0.360 282 204 39 8.14
31.905 2.8026 2.809 0.100 339 207 46 096 32.350 2.7651 2.7720 0.120 237 210 32 3.01
33.300 2.6884 2.6950 0.180 1347 216 184 14.06
33.640 2.6620 2.6686 0.100 404 216 55 1.45
34.880 25701 2.5765 0.200 202 222 28 1.04
35.275 2.5422 2.5486 0.240 299 225 41 484
36.055 2.4890 2.4952 0.280 202 228 28 3.78
36.910 24333 2.4393 0.320 169 234 23 0.90
37.160 2.4175 2.4235 0.120 216 234 3.0 214
37.680 2.3853 2.3912 0.240 240 237 33 158
30435 202831 2.2888 0.280 449 246 6.1 2.67
30.675 2.2698 2.2755 0.080 396 246 54 0.82
40.325 2.2347 2.2403 0.160 520 250 71 095 40.930 2.2031 2.2086 0.120 480 253 6.6 266 41.445 21769 2.1823 0240 © 372 256 51 265 41.990 2.1499 2.1552 0.120 538 259 74 1.31
42.670 2.1172 2.4225 0.160 428 262 59 145
43.145 2.0050 2.1002 0.120 433 266 59 1.50
44.190 2.0478 2.0529 0.160 376 269 51 0.89
46.095 1.9675 1.9724 0.160 279 279 3.8 0.86
46.510 1.9509 1.9558 0.240 310 282 42 087
48.305 1.8826 1.8872 0.200 506 292 6.9 2.06
48.900 1.8610 1.8657 0.240 615 206. 84 167
50.330 1.8115 1.8160 0.160 437 303 6.0 1.73
51.035 1.7881 1.7925 0.080 416 306 57 093
53.550 1.7099 1.7141 0.480 177 317 24 284 54.500 1.6823 1.6865 0.400 130 324 1.8 1.37 55.420 1.6565 1.6606 0.320 130 328 1.8 1.72 . 56.220 1.6348 1.6389 0.320 121 331 1.7 0.87 56.770 1.6203 1.6243 0.240 142 335 1.9 159 57.405 1.6039 1.6079 0.240 112 339 15 1.19 58.500 1.5764 1.5804 0.240 67 342 0.9 157 in the light of the pharmaceutical efficacy of flibanserin, the present invention furthermore relates to the use of flibanserin polymorph A as a medicament.
A further aspect of the present invention relates to the use of flibanserin polymorph A - 5 for preparing a pharmaceutical composition for treating diseases in which the use of ’ compounds displaying affinity for the 5-HT1a and 5-HT,-receptor may have a therapeutic benefit.
A further aspect of the present invention relates to the use of flibanserin polymorph A 10 for preparing a pharmaceutical composition for treating a disease seleceted from depression, schizophrenia, Parkinson, anxiety, sleep disturbances, sexual and mental disorders and age associated memory impairment.
In particular, the instant invention relates to the use of flibanserin polymorph A for the preparation of a medicament for the treatment of disorders of sexual desire.
In a preferred embodiment the invention relates to the use of flibanserin polymorph A for the preparation of a medicament for the treatment of disorders selected from the group consisting of Hypoactive Sexual Desire Disorder, loss of sexual desire, lack of sexual desire, decreased sexual desire, inhibited sexual desire, loss of libido, libido disturbance, and frigidity.
Particular preferred according to the invention is the use of flibanserin polymorph A for the preparation of a medicament for the treatment of disorders selected from the group consiting of Hypoactive Sexual Desire Disorder, loss of sexual desire, lack of sexual desire, decreased sexual desire, inhibited sexual desire.
In a particularily preferred embodiment the invention relates to the use of flibanserin polymorph A for the preparation of a medicament for the treatment of disorders selected from the group of Hypoactive Sexual Desire Disorder and loss of sexual desire. / The aforementioned therapeutic effects of flibanserin polymorph A can be achieved in men and women. However, according to a further aspect of the invention the use . of flibanserin polymorph A for the preparation of a medicament for the treatment of female sexual dysfunction is preferred.
The beneficial effects of flibanserin polymorph A can be observed regardless of whether the disturbance existed lifelong or was acquired, and independent of etiologic origin (organic - both, physically and drug induced-, psychogen, a combination of organic - both, physically and drug induced-, and psychogen, or unknown).
As a further feature of the present invention there are provided pharmaceutical compositions comprising as an active ingredient flibanserin polymorph A in addition ’ with one or more pharmaceutical carrier, diluents or excipients. For pharmaceutical administration flibanserin polymorph A may be incorporated into the conventional pharmaceutical preparation in solid, liquid or spray form. The composition may, for example, be presented in a form suitable for oral, rectal, parenteral administration or for nasal inhalation: preferred forms includes for example, capsules, tablets, coated tablets, ampoules, suppositories and nasal spray.
The active ingredient may be incorporated in excipients or carriers conventionally used in pharmaceutical compositions such as, for example, talc, arabic gum, lactose, gelatine, magnesium stearate, corn starch, acqueous or non acqueous vehicles, polyvynil pyrrolidone, semisynthetic glicerides of fatty acids, benzalconium chloride, sodium phosphate , EDTA, polysorbate 80. The compositions are advantageously formulated in dosage units, each dosage unit being adapted to supply a single dose of the active ingredient. Each-dosage unit may conveniently contain from 0,01 mg to 100 mg, preferably from 0,1 to 50 mg.
Claims (10)
- Patent Claims 1) Crystalline polymorph A (form A) of flibanserin 1, 0 /N\ Cy N\_/1 having an endothermic maximum at 161°C which occurs during thermal analysis using DSC.
- 2) Flibanserin 1 comprising form A according to claim 1. 3) Process for the technical preparation of flibanserin 1 according to claim 1 or 2, To : 0) nA CFs ANNAN \_/ 1 characterized in that in a first reaction step a benzimidazolone 2 H N =o N \ R 2 wherein R denotes a suitable amino protecting group is reacted with a piperazine 3 CF, X —\ » \ / 3 wherein X is a leaving group selected from chlorine, bromine, iodine, methanesulphonate, trifluoromethanesulphonate and para-toluenesulphonate.
- in a suitable solvent selected from water, alcohols, mixtures of water with alcohols, polar aprotic solvents and mixtures thereof with water in presence of a suitable base and that in a second reaction step the amino protecting group R is cleaved under suitable cleaving conditions.
- 4) Process according to claim 3, charcterized in that the reaction of 2 with 3 is conducted at a temperature of at least 50°C.
- 5) Process according to claim 4, characterized in that heating is conducted for about 10 minutes to about 12 hours.
- 6) Polymorph A of flibanserin 1 obtainable according to one of claims 3 to 5.
- 7) Polymorph A of flibanserin 1 according to one of claims 1, 2 or 6 for use as a medicament.
- 8) Use of polymorph A of flibanserin 1 according to one of claims 1, 2 or 6 for preparing a medicament for treating diseases in which the use of therapeutic. effective amounts of compounds displaying affinity for the 5-HT1a and 5-HT.-receptor display a therapeutic benefit.Ce
- 9) Use of polymorph A of flibanserin 1 according to one of claims 1, 2 or 6 for preparing a medicament for treating a disease seleceted from depression, schizophrenia, Parkinson, anxiety, sleep disturbances, sexual and mental disorders and age associated memory impairment.
- 10) Pharmaceutical compositions comprising as an active ingredient polymorph A of flibanserin 1 according to one of claims 1, 2 or 6 optionally in admixture with one or more pharmaceutical carriers, diluents or excipients.>
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PCT/EP2002/008466 WO2003014079A1 (en) | 2001-08-02 | 2002-07-30 | Stable polymorph of flibanserin, technical process for its preparation and the use thereof for preparing medicaments |
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