HRP20010904A2 - Polymorphs of a crystalline azabicyclo[2,2,2]octan-3-amine citrate and their pharmaceutical compositions - Google Patents
Polymorphs of a crystalline azabicyclo[2,2,2]octan-3-amine citrate and their pharmaceutical compositions Download PDFInfo
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- HRP20010904A2 HRP20010904A2 HR20010904A HRP20010904A HRP20010904A2 HR P20010904 A2 HRP20010904 A2 HR P20010904A2 HR 20010904 A HR20010904 A HR 20010904A HR P20010904 A HRP20010904 A HR P20010904A HR P20010904 A2 HRP20010904 A2 HR P20010904A2
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- Croatia
- Prior art keywords
- polymorphic form
- approximately
- citrate
- crystalline
- hours
- Prior art date
Links
- JASMWYNKLTULAN-UHFFFAOYSA-N octan-3-amine Chemical compound CCCCCC(N)CC JASMWYNKLTULAN-UHFFFAOYSA-N 0.000 title claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 title description 3
- YASYEJJMZJALEJ-UHFFFAOYSA-N Citric acid monohydrate Chemical compound O.OC(=O)CC(O)(C(O)=O)CC(O)=O YASYEJJMZJALEJ-UHFFFAOYSA-N 0.000 claims description 17
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 6
- 206010047700 Vomiting Diseases 0.000 claims description 6
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 5
- 150000001875 compounds Chemical class 0.000 claims description 5
- 239000013078 crystal Substances 0.000 claims description 5
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 5
- 102000002002 Neurokinin-1 Receptors Human genes 0.000 claims description 4
- 108010040718 Neurokinin-1 Receptors Proteins 0.000 claims description 4
- 238000001914 filtration Methods 0.000 claims description 4
- 239000012458 free base Substances 0.000 claims description 4
- 239000007787 solid Substances 0.000 claims description 4
- 239000000725 suspension Substances 0.000 claims description 4
- 238000007664 blowing Methods 0.000 claims description 3
- 238000002425 crystallisation Methods 0.000 claims description 3
- 230000008025 crystallization Effects 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- 230000008673 vomiting Effects 0.000 claims description 3
- 239000005557 antagonist Substances 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims description 2
- 238000002844 melting Methods 0.000 claims description 2
- 230000008018 melting Effects 0.000 claims description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims 3
- 238000005469 granulation Methods 0.000 claims 2
- 230000003179 granulation Effects 0.000 claims 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims 1
- 239000002585 base Substances 0.000 claims 1
- 230000000694 effects Effects 0.000 claims 1
- 230000007613 environmental effect Effects 0.000 claims 1
- 150000004682 monohydrates Chemical class 0.000 description 6
- 229960004106 citric acid Drugs 0.000 description 2
- 238000000921 elemental analysis Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 239000002464 receptor antagonist Substances 0.000 description 2
- 229940044551 receptor antagonist Drugs 0.000 description 2
- 238000001159 Fisher's combined probability test Methods 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical group CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 229960004543 anhydrous citric acid Drugs 0.000 description 1
- -1 benzoate Chemical class 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000000113 differential scanning calorimetry Methods 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 239000002895 emetic Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 238000001907 polarising light microscopy Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
- C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
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- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Otolaryngology (AREA)
- Hospice & Palliative Care (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
Pozadina izuma
Ovaj izum se odnosi na bezvodni monohidrat citratne soli (2S,3S)-N-(metoksi-5-t-butilfenilmetil-2-difenilmetil-1-azobiciklo[2,2,2]oktan-3-amina, njegov pojedinačni kristalni polimorfni oblik A i farmaceutski pripravak koji ga sadrži. Ovaj izum se također odnosi na antagonist NK-1 receptora aktivnog u CNS za liječenje povraćanja kod sisavaca, uključujući i ljude. Kao što je ovdje definirano, pod liječenjem se podrazumijeva i sprječavanje i liječenje.
[image]
US patent br. 5.393.762 i US patentna prijava br. 08/816,016, oboje ovdje uključeni kao referenca, opisuju farmaceutske pripravke i liječenje povraćanja upotrebom antagonista NK-1 receptora. Citrat monohidrat ima značajno povećanu stabilnost u odnosu na druge oblike soli, kao što je benzoat, koji je nestabilan već na 5 °C. Mesilatni oblik je topiv.
Bit izuma
Ovaj izum se odnosi na monohidrat citrata (2S,3S)-N-(metoksi-5-t-butilfenilmetil-2-difenilmetil-1-azobiciklo[2,2,2]oktan-3-amina. U jednoj realizaciji izuma, citrat monohidrat je kristalan, stabilan, nehigroskopan, pojedinačni oblik. Kristalna struktura su pločice, a karakteristike su određene niže navedenim uzorkom defrakcije X zraka na prahu:
Citrat monohidrat
[image]
Kristalna monohidratna citratna sol nije higroskopna i karakterizira se gubitkom vode (isparivanje) na približno 116 °C, a početak taljenja je na približno 152,7 °C. Bezvodni citrat prevodi se u monohidrat u vodi.
Farmaceutski pripravak, koji ima djelovanje antagonista NK-1 receptora aktivnog u CNSu, uključuje polimorfni oblik A, u količini djelotvornoj u liječenju povraćanja, i farmaceutski prihvatljivu podlogu. Postupak liječenja povraćanja uključuje primjenu na pacijentu kome je potrebno liječenje neke emetički djelotvorne količine polimorfnog oblika spoja.
Postupak dobivanja polimorfnog oblika A monohidrata citratne soli (2S,3S)-N-(metoksi-5-t-butilfenilmetil-2-difenilmetil-1-azobiciklo[2,2,2]oktan-3-amina sastoji se u dodavanju limunske kiseline u otopinu slobodne baze u acetonu. Krutina se otopi za približno 2 sata. Bistru otopinu se filtrira i miješa tijekom noći. U otopinu se doda profiltrirani izopropileter, a zatim profiltrirana voda. Dobivenu mješavinu se miješa na sobnoj temperaturi, do početka kristalizacije i granulira se približno 16 sati. Bijeli kristalni oblik skuplja se filtracijom i suši na približno 45 °C pod vakuumom, uz ispuhivanje dušikom, tijekom 24 sata.
Detaljni opis izuma
Postupak dobivanja kristalnog citrat monohidrata, polimorfnog oblika A, sastoji se u dodavanju 353,9 g, 1,1 ekvivalenta limunske kiseline (bezvodna, 99,5+ %) u otopinu slobodne baze, 785 g u acetonu, 7,85 l. Poslije otapanja krutine tijekom približno 2 sata, bistru otopinu se filtrira, miješa tijekom noći, te se doda 7,85 l filtriranog izopropiletera, poslije čega se dodaje 334 ml filtrirane vode. Dobivenu smjesu se miješa na sobnoj temperaturi, do početka kristalizacije, te se granulira dodatnih 16 sati. Bijeli kristalni oblik skuplja se filtracijom i suši na 45 °C, pod vakuumom, uz ispuhivanje dušikom tijekom 24 sata, kako bi se dobilo 992 g (89,9 % prinos). Karakteristike dobivenog polimorfnog oblika monohidrata citratne soli određuju se preko PLM, difrakcijom X zraka na prahu, protonskim NMR, Karl Fisherovim postupkom, DSC i elementarnom analizom. Difrakcija X zraka na prahu i PLM otkriva da je u pitanju kristal. Uočena kristalna struktura su pločice. Najsnažnije refleksije, D razmaci, dobiveni difrakcijom X zraka na prahu, su: 13,280, 7,702, 7,446, 6,337, 5,332, 5,057 i 4,398 Å. Kristali pokazuju gubitak vode (isparavanje) na 116 °C i počinju se taliti na 152,7 °C, uz razgradnju. Mjerenje higroskopnosti pokazuje da je apsorbirano 2,52 % vode, težinski, pri 90 % relativne vlage. Karl Fisher-ova analiza ukazuje na prisustvo 2,7 % vode (2,66 % teoretski), potvrđujući da je dobiven monohidrat. Elementarna analiza potvrđuje čistoću dobivene soli.
Miješanjem bezvodnog citrata u vodi dobiva se kristalni monohidrat, koji ne gubi vodu tijekom sušenja, npr. na 45 °C, pod vakuumom.
Djelotvorna doza za farmaceutski pripravak citrat monohidrata ovisi o traženom načinu primjene, indikatoru, indikaciji koju se liječi i drugim činiteljima, kao što su dob i težina pacijenta. U slijedećim rasponima doza, izraz ''mg A'' odnosi se na miligrame monohidrata. Preporučljiva doza za oralnu primjenu je 5-300 mg A dnevno, po mogućnosti 40-200 mg A dnevno, a najpoželjnije 40-80 mg A dnevno, u pojedinačnoj ili podijeljenim dozama. Preporučljiva doza za oralnu primjenu u oblicima za oralnu primjenu, poput pilula ili tableta, je 2,5 mg A dnevno, do 160 mg A dnevno, a po mogućnosti je 5-80 mg A dnevno. Spoj se također može primijeniti intravenski.
Slijedeći primjeri ilustriraju postupke i spojeve iz ovog izuma. Međutim, podrazumijeva se da izum nije ograničen samo na te specifične primjere.
Primjer 1
Dobivanje kristalnog citrat monohidrata
47 grama slobodne baze suspendira se u 470 ml izopropiletera pod uobičajenim uvjetima okoliša. U dobivenu rijetku, bijelu, suspenziju doda se 21,42 g bezvodne limunske kiseline, na sobnoj temperaturi. Ovu suspenziju se zatim upotrebljava u prevođenju u monohidrat, njenim suspendiranjem u 150 ml vode, tijekom 18 sati. Suspenziju se filtrira kako bi se dobilo bijelu, kristalnu krutinu. Konfiguracija Xzraka potvrđuje da je spoj citrat monohidrat.
Claims (10)
1. Kristalni oblik citrata (2S,3S)-N-(metoksi-5-t-butilfenilmetil-2-difenilmetil-1-azobiciklo[2,2,2]oktan-3-amina formule
[image]
,
naznačen time što je spomenuti kristalni oblik stabilni polimorfni oblik A, što pokazuje uzorak difrakcije X zraka na prahu
[image]
2. Polimorfni oblik citrat monohidrata prema zahtjevu 1, naznačen time što njegova kristalna struktura su pločice.
3. Polimorfni oblik citrat monohidrata prema zahtjevu 1, naznačen time što citrat monohidrat nije higroskopan.
4. Polimorfni oblik citrat monohidrata prema zahtjevu 1, naznačen time što isparava na približno 116 °C.
5. Polimorfni oblik citrat monohidrata prema zahtjevu 1, naznačen time što taljenje počinje na približno 152,7 °C.
6. Farmaceutski pripravak koji ima aktivnost antagonista NK-1 receptora aktivnog u CNSu, naznačen time što sadrži polimorfni oblik prema zahtjevu 1, u količini djelotvornoj u liječenju povraćanja, i farmaceutski prihvatljivu podlogu.
7. Postupak liječenja povraćanja, naznačen time što se sastoji u primjeni na pacijentu, kojem je potrebno liječenje, antiemetički djelotvorne količine polimorfnog oblika A spoja prema zahtjevu 1.
8. Postupak dobivanja kristalnog polimorfnog oblika monohidrata citratne soli (2S,3S)-N-(metoksi-5-t-butilfenilmetil-2-difenilmetil-1-azobiciklo[2,2,2]oktan-3-amina, naznačen time što se sastoji u:
dodavanju limunske kiseline u otopinu slobodne baze u acetonu; otapanju krutine tijekom 2 sata; filtriranju i miješanju bistre otopine preko noći; dodavanju filtriranog izopropiletera, a zatim dodavanju filtrirane vode; miješanju dobivene smjese na sobnoj temperaturi do početka kristalizacije i granulacije tijekom približno 16 sati; te prikupljanju bijele, kristalne soli, nastale filtracijom i sušenjem na približno 45 °C, pod vakuumom, uz ispuhivanje dušikom tijekom približno 24 sata.
9. Postupak prema zahtjevu 8, naznačen time što se suspendiranje provodi pod uvjetima okoliša, u trajanju od približno 1,572 sata, granulacija u izopropileteru, izopropilalkoholu i vodi.
10. Postupak prema zahtjevu 8, naznačen time što je limunska kiselina bezvodna > 99,5 %.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US13699299P | 1999-06-01 | 1999-06-01 | |
PCT/IB2000/000665 WO2000073304A1 (en) | 1999-06-01 | 2000-05-18 | Polymorphs of a crystalline azabicyclo (2,2,2) octan-3-amine citrate and their pharmaceutical compositions |
Publications (1)
Publication Number | Publication Date |
---|---|
HRP20010904A2 true HRP20010904A2 (en) | 2003-02-28 |
Family
ID=22475338
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
HR20010904A HRP20010904A2 (en) | 1999-06-01 | 2001-12-04 | Polymorphs of a crystalline azabicyclo[2,2,2]octan-3-amine citrate and their pharmaceutical compositions |
Country Status (49)
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU2005216707A1 (en) * | 2004-01-30 | 2005-09-09 | Pfizer Products Inc. | Pharmaceutical compositions of neurokinin receptor antagonists and cyclodextrin and methods for improved injection site toleration |
US8183230B2 (en) * | 2004-01-30 | 2012-05-22 | Pfizer Inc. | Antimicrobial preservatives to achieve multi-dose formulation using beta-cyclodextrins for liquid dosage forms |
MXPA06007964A (es) * | 2004-01-30 | 2007-01-26 | Pfizer Prod Inc | Antagonistas del receptor nk-1 para mejorar la recuperacion de anestesia. |
DE602005003791T2 (de) * | 2004-02-02 | 2008-05-29 | Pfizer Products Inc., Groton | Verfahren zur herstellung von 1-(2s,3s)-2-benzhydril-n-(5-tert.-butyl-2-methoxybenzyl)chinuklidin-3-amin |
RU2696582C2 (ru) * | 2013-03-15 | 2019-08-05 | Перл Терапьютикс, Инк. | Способы и системы кондиционирования дисперсных кристаллических материалов |
CN110577522B (zh) * | 2018-06-07 | 2022-12-27 | 东莞市东阳光动物保健药品有限公司 | 马罗匹坦柠檬酸盐新晶型及其制备方法 |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
PL171379B1 (en) * | 1991-05-31 | 1997-04-30 | Pfizer | Method of obtaining novel derivatives of quinuclidine |
US5393762A (en) * | 1993-06-04 | 1995-02-28 | Pfizer Inc. | Pharmaceutical agents for treatment of emesis |
US5576317A (en) * | 1994-12-09 | 1996-11-19 | Pfizer Inc. | NK-1 receptor antagonists and 5HT3 receptor antagonists for the treatment of emesis |
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2000
- 2000-05-08 US US09/566,307 patent/US6255320B1/en not_active Expired - Lifetime
- 2000-05-17 HN HN2000000077A patent/HN2000000077A/es unknown
- 2000-05-18 MX MXPA01012325A patent/MXPA01012325A/es unknown
- 2000-05-18 WO PCT/IB2000/000665 patent/WO2000073304A1/en active IP Right Grant
- 2000-05-18 IL IL14640600A patent/IL146406A0/xx not_active IP Right Cessation
- 2000-05-18 EP EP00925528A patent/EP1181290B1/en not_active Expired - Lifetime
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- 2000-05-18 AP APAP/P/2001/002349A patent/AP2001002349A0/en unknown
- 2000-05-18 ES ES00925528T patent/ES2199825T3/es not_active Expired - Lifetime
- 2000-05-18 CN CNB008082782A patent/CN1146565C/zh not_active Expired - Lifetime
- 2000-05-18 KR KR10-2001-7015494A patent/KR100476606B1/ko not_active IP Right Cessation
- 2000-05-18 PL PL00352716A patent/PL196046B1/pl not_active IP Right Cessation
- 2000-05-18 YU YU81101A patent/YU81101A/sh unknown
- 2000-05-18 OA OA1200100318A patent/OA11956A/en unknown
- 2000-05-18 EA EA200101108A patent/EA003731B1/ru active Protection Beyond IP Right Term
- 2000-05-18 TR TR2001/03473T patent/TR200103473T2/xx unknown
- 2000-05-18 PT PT00925528T patent/PT1181290E/pt unknown
- 2000-05-18 AT AT00925528T patent/ATE244239T1/de not_active IP Right Cessation
- 2000-05-18 SI SI200030161T patent/SI1181290T1/xx unknown
- 2000-05-18 DK DK00925528T patent/DK1181290T3/da active
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- 2000-05-18 CZ CZ20014269A patent/CZ295819B6/cs not_active IP Right Cessation
- 2000-05-18 UA UA2001118214A patent/UA66925C2/uk unknown
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- 2000-05-18 BR BR0011094-9A patent/BR0011094A/pt not_active Application Discontinuation
- 2000-05-18 HU HU0201301A patent/HUP0201301A3/hu unknown
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- 2000-05-18 DE DE60003679T patent/DE60003679T2/de not_active Expired - Lifetime
- 2000-05-18 JP JP2001500629A patent/JP3830816B2/ja not_active Expired - Lifetime
- 2000-05-23 PA PA20008496101A patent/PA8496101A1/es unknown
- 2000-05-26 CO CO00039195A patent/CO5170463A1/es not_active Application Discontinuation
- 2000-05-26 TW TW089110206A patent/TWI285204B/zh not_active IP Right Cessation
- 2000-05-29 UY UY26176A patent/UY26176A1/es not_active Application Discontinuation
- 2000-05-30 AR ARP000102663A patent/AR033331A1/es active IP Right Grant
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- 2000-05-31 DZ DZ000101A patent/DZ3050A1/xx active
- 2000-05-31 MA MA25997A patent/MA26742A1/fr unknown
- 2000-05-31 SV SV2000000093A patent/SV2001000093A/es unknown
- 2000-06-01 EC EC2000003508A patent/ECSP003508A/es unknown
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2001
- 2001-11-28 ZA ZA200109775A patent/ZA200109775B/en unknown
- 2001-11-30 NO NO20015848A patent/NO20015848L/no not_active Application Discontinuation
- 2001-12-04 HR HR20010904A patent/HRP20010904A2/hr not_active Application Discontinuation
- 2001-12-10 BG BG106204A patent/BG65240B1/bg unknown
-
2002
- 2002-10-30 HK HK02107879A patent/HK1046284A1/xx not_active IP Right Cessation
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2007
- 2007-03-27 CY CY2007011C patent/CY2007011I1/el unknown
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