WO2017076356A1 - Nouvelle forme cristalline de la flibansérine et son procédé de préparation - Google Patents
Nouvelle forme cristalline de la flibansérine et son procédé de préparation Download PDFInfo
- Publication number
- WO2017076356A1 WO2017076356A1 PCT/CN2016/104735 CN2016104735W WO2017076356A1 WO 2017076356 A1 WO2017076356 A1 WO 2017076356A1 CN 2016104735 W CN2016104735 W CN 2016104735W WO 2017076356 A1 WO2017076356 A1 WO 2017076356A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- crystal form
- ray powder
- powder diffraction
- diffraction pattern
- crystal
- Prior art date
Links
- 239000013078 crystal Substances 0.000 title claims abstract description 86
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- XGAGFLQFMFCIHZ-UHFFFAOYSA-N 3-[2-[4-[3-(trifluoromethyl)phenyl]piperazin-1-yl]ethyl]-1h-benzimidazol-2-one;hydrochloride Chemical compound Cl.FC(F)(F)C1=CC=CC(N2CCN(CCN3C(NC4=CC=CC=C43)=O)CC2)=C1 XGAGFLQFMFCIHZ-UHFFFAOYSA-N 0.000 title abstract 3
- 239000000825 pharmaceutical preparation Substances 0.000 claims abstract description 7
- 208000019901 Anxiety disease Diseases 0.000 claims abstract description 4
- 208000026139 Memory disease Diseases 0.000 claims abstract description 4
- 208000020016 psychiatric disease Diseases 0.000 claims abstract description 4
- 201000000980 schizophrenia Diseases 0.000 claims abstract description 4
- 208000012201 sexual and gender identity disease Diseases 0.000 claims abstract description 4
- 208000015891 sexual disease Diseases 0.000 claims abstract description 4
- 230000001568 sexual effect Effects 0.000 claims abstract description 4
- 208000019116 sleep disease Diseases 0.000 claims abstract description 4
- 239000000203 mixture Substances 0.000 claims abstract description 3
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 52
- 238000000034 method Methods 0.000 claims description 25
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 22
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical group CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 16
- 239000007787 solid Substances 0.000 claims description 15
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical group COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- 229910001868 water Inorganic materials 0.000 claims description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 8
- 230000005855 radiation Effects 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- 239000012046 mixed solvent Substances 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 6
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 4
- 150000004292 cyclic ethers Chemical class 0.000 claims description 4
- 230000036506 anxiety Effects 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims 2
- 208000020401 Depressive disease Diseases 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- 206010024419 Libido decreased Diseases 0.000 abstract 2
- 208000006262 Psychological Sexual Dysfunctions Diseases 0.000 abstract 2
- 208000017020 hypoactive sexual desire disease Diseases 0.000 abstract 2
- 238000012360 testing method Methods 0.000 description 13
- 238000002411 thermogravimetry Methods 0.000 description 12
- 238000000227 grinding Methods 0.000 description 11
- 238000004128 high performance liquid chromatography Methods 0.000 description 11
- 238000000113 differential scanning calorimetry Methods 0.000 description 10
- 239000002245 particle Substances 0.000 description 10
- 238000010586 diagram Methods 0.000 description 9
- 238000009826 distribution Methods 0.000 description 8
- 239000003814 drug Substances 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 238000005481 NMR spectroscopy Methods 0.000 description 6
- 230000004584 weight gain Effects 0.000 description 5
- 235000019786 weight gain Nutrition 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 239000012458 free base Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 238000003860 storage Methods 0.000 description 4
- 238000009736 wetting Methods 0.000 description 4
- 239000013543 active substance Substances 0.000 description 3
- 238000009509 drug development Methods 0.000 description 3
- 230000007774 longterm Effects 0.000 description 3
- 238000005498 polishing Methods 0.000 description 3
- 238000001179 sorption measurement Methods 0.000 description 3
- 229910005429 FeSSIF Inorganic materials 0.000 description 2
- 208000030047 Sexual desire disease Diseases 0.000 description 2
- 238000002441 X-ray diffraction Methods 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000005312 bioglass Substances 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 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 description 2
- 235000011389 fruit/vegetable juice Nutrition 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 230000000968 intestinal effect Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 230000001681 protective effect Effects 0.000 description 2
- 238000013112 stability test Methods 0.000 description 2
- 230000004580 weight loss Effects 0.000 description 2
- CNPVJWYWYZMPDS-UHFFFAOYSA-N 2-methyldecane Chemical group CCCCCCCCC(C)C CNPVJWYWYZMPDS-UHFFFAOYSA-N 0.000 description 1
- 102000049773 5-HT2A Serotonin Receptor Human genes 0.000 description 1
- 108010072564 5-HT2A Serotonin Receptor Proteins 0.000 description 1
- 102100022738 5-hydroxytryptamine receptor 1A Human genes 0.000 description 1
- 101710138638 5-hydroxytryptamine receptor 1A Proteins 0.000 description 1
- YZCXKBFJMOSVOX-UHFFFAOYSA-N FC(C=1C=C(C=CC=1)N1CCN(CC1)CCN1CNC2=C1C=CC=C2)(F)F Chemical group FC(C=1C=C(C=CC=1)N1CCN(CC1)CCN1CNC2=C1C=CC=C2)(F)F YZCXKBFJMOSVOX-UHFFFAOYSA-N 0.000 description 1
- 229910016860 FaSSIF Inorganic materials 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 229940036329 addyi Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000012159 carrier gas Substances 0.000 description 1
- 239000013626 chemical specie Substances 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000002612 dispersion medium Substances 0.000 description 1
- 229940088679 drug related substance Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 229960002053 flibanserin Drugs 0.000 description 1
- 238000007654 immersion Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000004570 mortar (masonry) Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000004441 surface measurement Methods 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
- C07D235/26—Oxygen atoms
Definitions
- the patent CN1288147C discloses two crystal forms of Fluboxerin, Form A and Form B.
- Form B exhibits lower stability under the influence of mechanical stress caused by grinding, and only Form A is a crystal form that meets the requirements for polishing stability. Therefore, it is necessary to develop a new crystalline form of flurbinerine suitable for storage and industrial production, providing more and better choices for the subsequent development of drugs.
- the inventors of the present invention found that there are two other crystal forms which have better properties, and the two crystal forms have higher stability, higher solubility than the existing crystal forms, and higher bioavailability.
- the invented crystal form has an unexpected technical effect and is of great significance for future drug development.
- the crystalline form I provided by the present invention has a weight loss gradient of about 3.2% when heated to 98 ° C, and the thermogravimetric analysis chart is shown in FIG.
- the X-ray powder diffraction pattern of Form II also has a diffraction peak at a 2theta value of 15.3 ° ⁇ 0.2 °, 20.0 ° ⁇ 0.2 °, 23.0 ° ⁇ 0.2 °.
- Form II its X-ray powder diffraction pattern (CuK ⁇ radiation) at 25 ° C has a characteristic peak at a value of 16.2 ° ⁇ 0.2 °, 8.8 ° ⁇ 0.2 °, 12.8 ° ⁇ 0.2 ° at 17.4 °.
- ⁇ 0.2°, 19.0° ⁇ 0.2°, 9.6° ⁇ 0.2°, 15.3° ⁇ 0.2°, 20.0° ⁇ 0.2°, and 23.0° ⁇ 0.2° have diffraction peaks.
- D90 indicates the particle size distribution (volume distribution) accounts for 90% of the particle size
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
La présente invention concerne une nouvelle forme cristalline de la flibansérine et son procédé de préparation. La nouvelle forme cristalline de la flibansérine de la présente invention consiste en une forme cristalline I et une forme cristalline II. Par rapport à une forme cristalline existante, la nouvelle forme cristalline présente une stabilité, une solubilité et une biodisponibilité élevées. La forme cristalline I, la forme cristalline II, ou un mélange de la forme cristalline I et de la forme cristalline II de la présente invention peuvent être utilisés pour l'élaboration de préparations pharmaceutiques destinées au traitement de la dépression, de la schizophrénie, de troubles de l'anxiété, de troubles du sommeil, ds troubles mentaux et sexuels et de troubles de la mémoire liés à l'âge; en particulier, elles peuvent être utilisées pour l'élaboration de préparations pharmaceutiques destinées au traitement d'une baisse du désir sexuel (HSDD).
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510751851.4 | 2015-11-05 | ||
| CN201510751851 | 2015-11-05 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2017076356A1 true WO2017076356A1 (fr) | 2017-05-11 |
Family
ID=58661833
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/CN2016/104735 WO2017076356A1 (fr) | 2015-11-05 | 2016-11-04 | Nouvelle forme cristalline de la flibansérine et son procédé de préparation |
Country Status (1)
| Country | Link |
|---|---|
| WO (1) | WO2017076356A1 (fr) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11492343B2 (en) * | 2016-01-31 | 2022-11-08 | Xiaoming Meng | Polymorph of flibanserin and preparation method thereof and use of same |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0526434A1 (fr) * | 1991-07-30 | 1993-02-03 | BOEHRINGER INGELHEIM ITALIA S.p.A. | Dérivés de benzimidazolone comme antagonistes de 5-HT1A et 5-HT2 |
| CN1551879A (zh) * | 2001-08-02 | 2004-12-01 | ���������ﻯѧ����˾ | 氟立班丝氨(flibanserin)的稳定多晶体,其制备的技术法及其在药物制备的用途 |
| WO2010079045A2 (fr) * | 2008-12-15 | 2010-07-15 | Boehringer Ingelheim International Gmbh | Nouveaux sels |
| WO2010146595A2 (fr) * | 2009-06-16 | 2010-12-23 | Symed Labs Limited | Nouveaux polymorphes d'hydrochlorure de flibansérine |
-
2016
- 2016-11-04 WO PCT/CN2016/104735 patent/WO2017076356A1/fr active Application Filing
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0526434A1 (fr) * | 1991-07-30 | 1993-02-03 | BOEHRINGER INGELHEIM ITALIA S.p.A. | Dérivés de benzimidazolone comme antagonistes de 5-HT1A et 5-HT2 |
| CN1551879A (zh) * | 2001-08-02 | 2004-12-01 | ���������ﻯѧ����˾ | 氟立班丝氨(flibanserin)的稳定多晶体,其制备的技术法及其在药物制备的用途 |
| WO2010079045A2 (fr) * | 2008-12-15 | 2010-07-15 | Boehringer Ingelheim International Gmbh | Nouveaux sels |
| WO2010146595A2 (fr) * | 2009-06-16 | 2010-12-23 | Symed Labs Limited | Nouveaux polymorphes d'hydrochlorure de flibansérine |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11492343B2 (en) * | 2016-01-31 | 2022-11-08 | Xiaoming Meng | Polymorph of flibanserin and preparation method thereof and use of same |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| RU2728827C2 (ru) | Кристаллическая форма ингибитора тирозинкиназы брутона и способ её получения | |
| AU2018219967B2 (en) | Stable crystal form of tipiracil hydrochloride and crystallization method for the same | |
| WO2017215617A1 (fr) | Forme cristalline de l'ozanimod, forme cristalline de son hydrochloride et son procédé de préparation | |
| WO2016165650A1 (fr) | Cocristal d'olaparib et d'urée et son procédé de préparation | |
| WO2017107972A1 (fr) | Nouvelle forme cristalline d'agoniste sélectif du récepteur s1p1 et son procédé de préparation | |
| WO2016110270A1 (fr) | Nouvelle forme cristalline de maléate de nératinib et méthode de préparation de cette dernière | |
| WO2016124149A1 (fr) | Nouvelle forme cristalline d'un médicament anti-androgène destiné à traiter le cancer de la prostate, et procédé de préparation de la nouvelle forme cristalline | |
| WO2016091221A1 (fr) | Sel de composé de pyrrolo[2,3-d]pyrimidine et nouveau polymorphe de sel | |
| WO2018050091A1 (fr) | Forme cristalline du chlorhydrate de l'ozanimod et son procédé de préparation | |
| WO2018033149A1 (fr) | Forme cristalline d'ozanimod et leur procédé de préparation | |
| KR20150036336A (ko) | 타이로신 키나제 억제제 다이말리에이트의 결정형 아이 및 그의 제조 방법 | |
| WO2019019959A1 (fr) | Forme cristalline d'un monosuccinate de ribociclib et procédé de préparation et utilisation de ce dernier | |
| JPWO2018117267A1 (ja) | 置換ピペリジン化合物の塩 | |
| WO2017114446A1 (fr) | Nouvelle forme cristalline d'éluxadoline, et son procédé de préparation | |
| WO2018157803A1 (fr) | Formes cristallines de vénétoclax et leur procédé de préparation | |
| WO2018103726A1 (fr) | Forme cristalline d'un médicament inhibiteur de protéine de bromodomaine, son procédé de préparation et son utilisation | |
| WO2016070697A1 (fr) | Forme cristalline de bisulfate inhibiteur de kinase jak et procédé de préparation correspondant | |
| WO2017025045A1 (fr) | Nouvelle forme cristalline de l'acide 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxole-5-yl)cyclopropane formamido)-3-méthylpyridine-2-yl)benzoïque et son procédé de préparation | |
| WO2017063572A1 (fr) | Nouvelle forme cristalline d'agent induisant l'apoptose de cellules et son procédé de préparation | |
| WO2016127844A1 (fr) | Forme cristalline de l'ipi-145 et son procédé de préparation | |
| WO2018133705A1 (fr) | Forme cristalline de gft-505 et procédé de préparation et d'utilisation de celle-ci | |
| WO2017076356A1 (fr) | Nouvelle forme cristalline de la flibansérine et son procédé de préparation | |
| JP2019523297A5 (fr) | ||
| WO2016131406A1 (fr) | Forme cristalline d'un inhibiteur oral des protéines kinases activées par des signaux mitogènes (mapk) et procédé de préparation de cette dernière | |
| WO2023179069A1 (fr) | Forme cristalline de sulfate de composé d'isoquinoléine, son procédé de préparation et son utilisation |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 16861624 Country of ref document: EP Kind code of ref document: A1 |
|
| NENP | Non-entry into the national phase |
Ref country code: DE |
|
| 122 | Ep: pct application non-entry in european phase |
Ref document number: 16861624 Country of ref document: EP Kind code of ref document: A1 |