HRP20030442A2 - Atorvastatin hemi-calcium form vii - Google Patents
Atorvastatin hemi-calcium form vii Download PDFInfo
- Publication number
- HRP20030442A2 HRP20030442A2 HR20030442A HRP20030442A HRP20030442A2 HR P20030442 A2 HRP20030442 A2 HR P20030442A2 HR 20030442 A HR20030442 A HR 20030442A HR P20030442 A HRP20030442 A HR P20030442A HR P20030442 A2 HRP20030442 A2 HR P20030442A2
- Authority
- HR
- Croatia
- Prior art keywords
- atorvastatin hemicalcium
- form vii
- atorvastatin
- hydrates
- vii
- Prior art date
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- FQCKMBLVYCEXJB-MNSAWQCASA-L atorvastatin calcium Chemical group [Ca+2].C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC([O-])=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1.C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC([O-])=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 FQCKMBLVYCEXJB-MNSAWQCASA-L 0.000 title claims description 47
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Description
Reference srodnih prijava
Ova prijava poziva se na privremenu prijavu broj Serial Number 60/245,897, predano 3.11.2000. koja je ovdje uključena putem reference.
Područje izuma
Predmetni izum odnosi se na kristalne polimorfne forme atorvastatin hemikalcija i nove postupke za preparaciju kristalnih krutina.
Pozadina izuma
Atorvastatin, ([R-(R*,R*)]-2-(4-fluorfenil)-p,6-dihidroksi-5-(1-metiletil)-3-fenil-4-[(fenilamino)karbonil]-1H-pirol-1-heptanska kiselina), prikazan u laktonskom obliku u formuli (I), i trihidrat njegove kalcijeve soli formule (II) poznati su u struci i opisani US 4,681,893,5,273,995', te u oubičajeno pridruženom, pripadnom USSN 60/166,153, predano 17. 11. 2000., koje su sve uključene putem reference.
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Atorvastatin je član klase lijekova koji se zovu statini. Statinski lijekovi su trenutačno terapeutski efikasni lijekovi na raspolaganju za snižavanje koncentracije čestica lipoproteina niske gustoće (LDL) u krvotoku pacijenata sa rizikom kardiovaskularne bolesti. Visoka razina LDL u krvotoku povezana je s nastajanjem koronarnih ozljeda koje ometaju protok krvi i može doći do kidanja te potiču trombozu. Goodman and Gilman, The Pharmacological Basis of Therapeutics 879 (9th ed. 1996) . Snižavanje razina LDL u plazmi pokazano je da smanjuje rizik kliničkih stanja kod pacijenata s kardiovaskularnom bolesti i koji kardiovaskularne bolesti ali koji imaju hiperkolesterolemiju. Scandinavian Simvastatin Survival Study Group, 1994; Lipid Research Clinics Program, 1984a, 1984b.
Mehanizam djelovanja statinskih lijekova razrađen je nešto detaljnije. Oni se miješaju u sintezu kolesterola i drugih sterola u jetri tako što kompetitivno inhibiraju enzim 3-hidroksi-3-metil-glutaril-koenzim A reduktaza ("HMG-CoA reduktaza"). HMG-CoA reduktaza katalizira pretvaranje HMG u mevalonat što je korak koji određuje brzinu u biosintezi kolesterola i tako njegova inhibicija dovodi do smanjivanja koncentracije kolesterola u jetri, Lipoprotein vrlo niske gustoće (VLDL) je biološko sredstvo za transport kolesterola i triglicerida iz jetre do perifernih stanica. VLDL se katabolizira u perifernim stanicama što oslobađa masne kiseline koje se mogu spremiti u adopocitima ili oksidirati u mišićima. VLDL se pretvara u lipoprotein srednje (prijelazne) gustoće(IDL) koji se ili uklanja putem LDL receptora ili se pretvara u LDL. Smanjena proizvodnja kolesterola dovodi do povećanja broja LDL receptora i odgovarajućeg smanjenja u proizvodnji LDL česticama putem metabolizma IDL.
Atorvastatin hemikalcijeva sol trihidrat prodaje Warner-Lambert Co. pod imenom LIPITOR. Atorvastatin je prvo prikazan javnosti i prijavljen u U.S. Patent No. 4,681,893. Hemikalcijeva sol prikazana u formuli (II) opisana je u U.S. Patent No. 5,273,995. '995 patent podučava da se hemikalcijeva sol dobije kristalizacijom iz slane otopine koja nastaje tako da CaCl2 zamijeni natrijevu sol i dalje se pročisti prekristalizacijom iz 5 : 3 smjese etil a-cetata i heksana.
Predmetni izum pruža novi kristalni oblik atorvastatin hemikalcija. Pojava različitih kristalnih formi (polimorfizam) je svojstvo nekih molekula i molekulskih kompleksa. Pojedinačna molekula, kao atorvastatin u formuli (I) ili kompleksna sol formule (II), može dovesti do raznolikih krutina koje imaju različita fizikalna svojstva kao talište, rendgenski difraktogram, otisak prsta infracrvene apsorpcije i NMR spektar. Razlike u fizilkalnim svojstvima polimorfa dolaze uslijed orijentacija i intermolekulskih interakcija susjednih molekula (kompleksa) u cjelini krutine. U skladu s tim, polimorfi su međusobno različite krutine koje imaju istu molekulsku formulu ali imaju različita fizikalna svojstva kao prednost i/ili kao nedostatak u usporedbi s drugim formama u porodici polimorfa. Jedno od najvažnijih fizikalnih svojstava farmaceutskih polimorfa je njihova topljivost u vodenoj otopini, naročito njihova topljivost u gastričkim sokovima pacijenta. Na primjer, kada je apsorpcija kroz gastrointestinalni trakt polagana, često je poželjno da se lijek koji je nestabilan u uvjetima pacijentovog želuca ili crijeva otapa polagano tako da se ne nakuplja u štetnoj sredini. S druge strane, kada je efikasnost lijeka u skladu s vršnim razinama lijeka u krvotoku, svojstvo koje dijele statinski lijekovi, i pod uvjetom da se lijek brzo apsorbira u GI sistemu, onda je vjerojatno da će forma koja se brzo otapa pokazivati povećanu efikasnost od usporedive količine forme koja se otapa sporije.
Kristalne forme I, II, III i IV atorvastatin hemi-kalcija su predmet u U.S. Patentima Nos. 5,959,156 i 6,121,461 pripisanima Warner-Lambert i kristalna atorvastatin hemi-kalcij forma V je iznesena u zajedničkoj pridruženoj prijavi serijskog broja 09/714,351. U '156 patentu postoji tvrdnja da forma I ima povoljnije karakteristike filtriranja isušenja nego poznata amorfna forma atorvastatin hemi-kalcija. Iako forma I popravlja neke nedostatke amorfne tvari u smislu mogućnosti proizvodnje, ostaje potreba za još daljnjim poboljšanjem ovih svojstava kao i poboljšanjem drugih svojstava kao što je protočnost, nepropusnost za pare i topljivost. Otkriće nove kristalne polimorfne forme lijeka povećava izbor materijala koje znanstvenik pri formuliranju ima s kojima može projektirati farmaceutsku formu lijeka sa ciljanim profilom otpuštanja ili drugom željenom karakteristikom.
Kratak opis crteža
Slika 1 je karakteristični rendgensko difraktogram praškastog uzorka atorvastatin hemikalcij forme VII.
Sažetak izuma
Predmetni izum pruža novi kristalni oblik atorvastatin hemikalcija označen forma VII, njegove hidrate i nove postupke za njegovu preparaciju.
U jednom drugom aspektu, izum pruža kompozicije i forme doziranja koje obuhvaćaju atorvastatin hemi-kalcij formu VII.
U još jednom drugom aspektu, izum pruža postupak za snižavanje razine lipoprotein niske gustoće u plazmi kod pacijenta koji pati ili je podložan hiperkolesterolemiji davanjem pacijentu farmaceutske forme doziranja koja sadrži atorvastatin hemikalcij formu VII.
Detaljan opis preferiranih izvedbi
Predmetni izum pruža novi kristalni polimorfni oblik atorvastatina označen kao forma VII u skladu s ustanovljenom nomenklaturom za ovu organsku sol. Atorvastatin hemikalcij forma VII je karakterizirana i može se razlikovati od drugih formi pomoću rendgenskog difraktograma praškastog uzorka (sl. 1) koji ima dva široka maksimuma u rasponu 18.5 - 21.8 i 21-. 8 - 25.0 stupnjeva 2θ te druge široke maksimume na 4.7, 7.8, 9.3, 12.0, 17.1, 18.2 ± 0.2 stupnjeva 2θ. Uzorci forme VII mogu sadržavati do 12% vode. Forma VII se lako razlikuje od poznate forme atorvastatin hemikalcija pomoću širokih maksimuma na 7.8 i 9.30.2 stupnjeva 2θ. Na primjer, forma I ima maksimume na 9.2, 9.5, 10.3, 10.6, 11.0 i 12.2 stupnjeva 2θ prema informaciji pruženoj u U.S. Patent No. 5,969,156. U ovom području forma II ima dva oštra maksimuma na 8.5 i 9.0 stupnjeva 2θ i forma IV ima jedan jaki maksimum na 8.0 stupnjeva 20. Drugi široki maksimumi u području 15 - 25 stupnjeva 2θ razlikuju formu VII od svih drugih formi. Forme I, III i IV sve imaju oštre maksimume u ovom području. Podaci rendgenske difrakcije praškastog uzorka ("PXRD") dobiveni su postupcima poznatim u struci pomoću SCINTAG rendgenskog difraktometra za praškasti uzorak model X'TRA A opremljenog s detektorom čvrstog stanja. Upotrijebljeno je bakreno zračenje λ = 1.5418 Å.
Atorvastatin hemikalcij forma VII može se prirediti obrađivanjem atorvastatin hemikalcij forme I ili V etanolom, preferirano apsolutnim etanolom, pri sobnoj temperaturi do temperature refluksa kroz period od oko 1 h do oko 24 h, preferirano 2,5 - 16 h. Brzina prelaska forme I ili V u formu VII ovisi o temperaturi. Preferirani raspon radne temperature je od oko 20°C do oko 78°C. Kompletni prijelaz je opažen u tako kratkom periodu kao što je oko 2.5 h u suspenziji u EtOH pri refluksu. Ako se postupak provodi pri sobnoj temperaturi, potreban je dulji period. Nakon što je konverzija potpuna, kristali forme VII mogu se izolirati konvencionalno, kao što je filtriranjem, i osušiti. Temperatura od oko 65°C, atmosferski tlak i 24 sata sušenja su pogodni uvjeti za sušenje kristala.
Polazna tvar atorvastatin hemikalcij forma I može se prirediti prema postupku u primjeru 1 patenta U.S. Patent No. 5,969,156 koji je ovdje uključen putem reference u svojoj potpunosti. Prema jednom postupku, smjesa atorvastatin laktona preparirana prema postupku opisanom u U.S. Patent No. 5,273,995, koji je ovdje također uključen putem reference u svojoj potpunosti, metil tercijarnibutil eter (MTBE) i metanol reagiraju s vodenom otopinom natrijevog hidroksida pri 48 - 5°C 40 do 60 minuta da nastane natrijeva sol atorvastatin slobodne kiseline. Nakon hlađenja na 25 - 35°C, organski sloj se odbaci i vodeni sloj se ponovo ekstrahira pomoću MTBE. Organski sloj se odbaci i vodena otopina natrijeve soli zasićena s MTBE je zagrijana na 47 - 52°C. U ovu otopinu se dodaje otopina; kalcijevog acetat hemihidrata otopljenog u vodi kroz najmanje 30 minuta. U smjesu se doda muljevita kristalna forma I atorvastatina ubrzo nakon dodavanja otopine 'kalcijevog acetata. Smjesa se onda zagrijava na 51 - 57°C najmanje 10 minuta i onda ohladi na 15 - 40°C. Smjesa se filtrira, ispere otopinom vode i metanola nakon čega slijedi voda. Krutina se suši na 60 - 70°C u vakuumu 3 do 4 dana da se dobije kristalna forma I atorvastatina.
Druga pogodna polazna tvar, atorvastatin hemikalcij forma V, može se preparirati kristalizacijom iz smjese tetrahidrofurana, metanola ili etanola s vodom. Na primjer, atorvastatin hemikalcij može se otopiti u metanolu (npr. pri 0.025 - 0.050 g/ml). Otopina se može zagrijati do oko 60°C i onda se doda otprilike podjednaki volumen ili manje vode. Otopina se onda ohladi što, u kombinaciji s dodanom vodom, potiče kristalizaciju atorvastatin hemikalcija u polimorfnoj formi V. Etanol i THF mogu jednostavno nadomjestiti metanol u ovom postupku iako, kada se koristi THF, preferirano je da se doda suvišak volumena vode.
Atorvastatin hemikalcij forma VII je korisna za snižavanje razine lipoproteina niske gustoće u plazmi kod pacijenta koji pati ili je podložan hiperkolesterolemiji. Za ovu svrhu tipično će se davati humanim pacijentima u jediničnoj dozi od oko 0.5 mg do oko 100 mg. Za većinu pacijenata, doza od oko 2.5 do oko 80 mg na dan, određenije od oko 2.5 do oko 20 mg na dan, uzrokuje snižavanje razine lipoproteina niske gustoće u plazmi kod humanih pacijenata. Da li je takvo snižavanje dovoljno i da li se doza ili učestalost davanja treba povećati, je odluka koja je u domeni razine stručnosti odgovarajuće uvježbanog medicinskog osoblja.
Daljnji aspekt predmetnog izuma je farmaceutska kompozicija i forma doziranja koja sadrži novu formu atorvastatin hemikalcija koja se može davati u praksi postupaka izuma.
Kompozicije izuma uključuju praškove, granulate, agregate i druge čvrste kompozicije koje obuhvaćaju novu formu VII atorvastatin hemikalcija. Dodatno, forma VII kompozicije koje promišljen predmetni izum mogu dalje uključivati razrjeđivače, kao što su tvari izvedene iz celuloze kao celuloza u prahu, mikrokristalinična celuloza, mikrofina celuloza, metil celuloza, etil celuloza, hidroksietil celuloza, hidroksipropil celuloza, hidroksipropilmetil celuloza, karboksimeti l celuloza soli i druge supstituirane i nesupstituirane celuloze; škrob; predželatinizirani škrob; anorganska otapala kao kalcijev karbonat i kalcijev difosfat te drugi razrjeđivači poznati u farmaceutskoj industriji. Još drugi pogodni razrjeđivači uključuju voskove, šećere i šećerne alkohole kao manitol i sorbitol, akrilatne polimere i kopolimere, kao i pektin, dekstrin te želatinu.
Daljnji ekscipijenti koji su unutar promišljanja predmetnog izuma uključuju veziva, kao što je akacija guma, predželatinizirani škrob, natrijev alginat, glukoza i druga veziva koja se koriste u vlažnoj i suhoj granulaciji te u postupcima tabletiranja direktnim prešanjem.
Ekscipijenti koji također mogu biti prisutni u čvrstoj kompoziciji forme VII atorvastatin hemikalcija dalje uključuju sredstva za razgradnju kao natrijev škrob glikolat, krospovidon, niskosupstituiranu hidroksipropil celulozu i druga. Dodatno, ekscipijenti mogu uključivati mazila za tabletiranje kao magnezijev i kalcijev stearat te natrijev stearil fumarat; arome; zaslađivače; konzervanse; farmaceutski prihvatljive boje i sredstva za klizanje glidants kao što je silicijev dioksid.
Doze uključuju doze pogodne za oralno, bukalno, rektalno, parenteralno (uključujući subkutano, intramuskularno i intravenozno), putem inhalacija i oftalmološke davanje. Iako će najpogodniji put davanja u bilo kojem slučaju ovisiti o prirodi i težini stanja koje se liječi, najviše preferirani put davanja predmetnog izuma je oralno. Doze se mogu prikladno predstaviti kao jedinične forme doziranja i prirediti na bilo koji način dobro poznat u farmaceutskoj struci.
Forme doziranja uključuju čvrste forme doziranja kao tablete, praškove, kapsule, supozitorije, sašete, trošeje i lozenge kao i tekuće suspenzije i napitke. Dok opis nije namijenjen da bude ograničavajući, izum također nije namijenjen da bude vezan na stvarne otopine atorvastatin hemikalcija gdje se svojstva koja razlikuju čvrste forme atorvastatin hemikalcija gube. Međutim, upotreba nove forme za pripremu takvih otopina (npr. da bi se dostavio, dodatno uz atorvastatin, solvat u navedenu otopinu u određenom omjeru sa solvatom) smatra se da je unutar promišljanja izuma.
Doze u kapsulama, naravno, će sadržavati čvrstu kompoziciju unutar kapsule koja može biti napravljena od želatine ili drugog uobičajenog sredstva za kapsuliranje. Tablete i prašci mogu biti presvučeni. Tablete i prašci mogu biti presvučeni enteričkom presvlakom. Praskaste forme presvučene enteričkom presvlakom mogu imati presvlake koje obuhvaćaju ftalna kiselina celuloza acetat, hidroksipropilmetilceluloza ftalat, polivinil alkohol ftalat,. karboksimetiletilcelulozu, kopolimer stirena i maleinske kiseline, kopolimer metakrilne kiseline i metil metakrilat te slične materijale i, ako se želi, mogu biti opremljeni prikladnim plastifikatorima i/ili produžujućim sredstvima. Presvučena tableta može imati presvlaku na površine tablete ili može biti tableta koja obuhvaća prašak ili granule s enteričkom presvlakom.
Kako je ovako opisan izum s obzirom na određene preferirane izvedbe, sljedeći primjeri dani su za daljnju ilustraciju izuma. Nisu namijenjeni da budu ograničavajući na bilo koji način.
PRIMJERI
Općenito
Apsolutni etanol koji sadrži manje od 0.2 % vode kupljen je kod Biolab®. Drugi reagensi bili su p.a. i upotrijebljeni su kako su dobiveni.
Primjer 1
Atorvastatin hemikalcij forma V (1.00 g) miješana je u apsolutnom EtOH (400 ml) pri sobnoj temperaturi 16 h. Krutina je sakupljena filtriranjem i sušena na 65°C 24 h da se dobije atorvastatin hemikalcij forma VII (40 mg, 40%).
Primjer 2
Atorvastatin hemikalcij forma I (75 mg) miješana je u apsolutnom EtOH (30 ml) pri sobnoj temperaturi 16 h. Krutina je sakupljena filtriranjem i sušena na 65°C 24 h da se dobije atorvastatin hemikalcij forma VII (0.60 g, 80%).
Kako je ovako opisan izum s obzirom na određene preferirane izvedbe i ilustriran pomoću primjera, stručnjaci u području će prihvatiti modifikacije izuma kako je opisan i ilustriran koje ne odstupaju od duha i dometa izuma kako je definirano patentnim zahtjevima koji slijede.
Claims (17)
1. Atorvastatin hemikalcij forma VII i njegovi hidrati naznačen time da ima rendgenski difraktogram praškastog uzorka značajno kao na slici 1.
2. Atorvastatin hemikalcij forma VII i njegovi hidrati naznačen time da je karakteriziran rendgenskim difraktogramom praškastog uzorka koji ima široke maksimume u rasponu od 18.5 - 21.8 i 21.8 - 25.0 stupnjeva dva theta.
3. Atorvastatin hemikalcij forma VII i njegovi hidrati prema zahtjevu 2 naznačen time da je dalje karakteriziran širokim maksimumima na 4.7, 7.8, 9.3, 12.0, 17.1, 18.2 ± 0.2 stupnjeva 2θ u svom rendgenskom difraktogramu praškastog uzorka.
4. Atorvastatin hemikalcij forma VII i njegovi hidrati prema zahtjevu 2 naznačen time da sadrži do 12% vode.
5. Atorvastatin hemikalcij forma VII i njegovi hidrati prema zahtjevu 2 naznačen time da sadrži od oko jedan do oko osam molova vode po molekuli atorvastatin hemikalcija
6. Atorvastatin hemikalcij forma VII i njegovi hidrati prema zahtjevu 2 naznačen time da ima usku raspodjelu veličine čestica
7. Atorvastatin hemikalcij forma VII i njegovi hidrati prema zahtjevu 6 naznačen time da sve čestice imaju dijametar 100 mikrona ili manje.
8. Atorvastatin hemikalcij forma VII i njegovi hidrati prema zahtjevu 7 naznačen time da sve čestice imaju dijametar 50 mikrona ili manje.
9. Postupak za preparaciju atorvastatin hemikalcij forme VII naznačen time da obuhvaća korake:
a) suspendiranje atorvastatin hemikalcija u etanolu kroz vremenski period dovoljan da ga se prevede u formu VII i
b) izoliranje forme VII iz suspenzije.
10. Postupak za preparaciju atorvastatin hemikalcij forme VII prema zahtjevu 9 naznačen time da se suspenzija održava na temperaturi u rasponu od oko 20°C do oko 78°C kroz vremenski period u kojem se atorvastatin hemikalcij prevede u formu VII.
11. Postupak prema zahtjevu 9 naznačen time da atorvastatin hemikalcij je forma I ili forma V.
12. Postupak prema zahtjevu 9 naznačen time da etanol sadrži manje od oko 0.5% vode
13. Postupak prema zahtjevu 12 naznačen time da etanol sadrži manje od oko 0.2% vode
14. Farmaceutska kompozicija naznačena time da obuhvaća atorvastatin hemikalcij formu VII i njegove hidrate prema zahtjevu 2.
15. Farmaceutska forma doziranja naznačena time da obuhvaća farmaceutsku kompoziciju atorvastatin hemikalcij forme VII prema zahtjevu 14.
16. Postupak za snižavanje razine lipoproteina niske gustoće u plazmi kod pacijenta koji pati ili je podložan hiperkolesterolemij i naznačen time da se daje pacijentu farmaceutska forma doziranja prema zahtjevu 15.
17. Primjena atorvastatin hemikalcij forme VII i njenih hidrata prema zahtjevu 2 naznačena time da je za pripremu farmaceutske forme doziranja.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US24589700P | 2000-11-03 | 2000-11-03 | |
| PCT/US2001/043947 WO2002041834A2 (en) | 2000-11-03 | 2001-11-05 | Atorvastatin hemi-calcium form vii |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| HRP20030442A2 true HRP20030442A2 (en) | 2005-06-30 |
Family
ID=22928549
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| HR20030442A HRP20030442A2 (en) | 2000-11-03 | 2003-06-02 | Atorvastatin hemi-calcium form vii |
Country Status (18)
| Country | Link |
|---|---|
| US (1) | US6605636B2 (hr) |
| EP (1) | EP1332130A4 (hr) |
| JP (1) | JP2004513956A (hr) |
| KR (1) | KR100704213B1 (hr) |
| CN (1) | CN1535139A (hr) |
| AU (1) | AU4150602A (hr) |
| CA (1) | CA2426632C (hr) |
| CZ (1) | CZ20031495A3 (hr) |
| HR (1) | HRP20030442A2 (hr) |
| HU (1) | HUP0303765A2 (hr) |
| IL (2) | IL155734A0 (hr) |
| IS (1) | IS6798A (hr) |
| MX (1) | MXPA03003900A (hr) |
| NO (1) | NO20031986L (hr) |
| PL (1) | PL362472A1 (hr) |
| SK (1) | SK6592003A3 (hr) |
| WO (1) | WO2002041834A2 (hr) |
| ZA (1) | ZA200303972B (hr) |
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| US7074818B2 (en) | 2001-07-30 | 2006-07-11 | Dr. Reddy's Laboratories Limited | Crystalline forms VI and VII of Atorvastatin calcium |
| WO2003011826A1 (en) * | 2001-07-30 | 2003-02-13 | Dr. Reddy's Laboratories Ltd. | Crystalline forms vi and vii of atorvastatin calcium |
| US20060020137A1 (en) * | 2001-11-29 | 2006-01-26 | Limor Tessler | Novel crystal forms of atorvastatin hemi-calcium and processes for their preparation as well as novel processes for preparing other forms |
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| WO2003070665A2 (en) * | 2002-02-19 | 2003-08-28 | Teva Pharmaceutical Industries Ltd. | Desolvating solvates of atorvastatin hemi-calcium |
| AU2003297594A1 (en) * | 2002-11-28 | 2004-06-23 | Teva Pharmaceutical Industries Ltd. | Crystalline form f of atorvastatin hemi-calcium salt |
| EP1424324A1 (en) * | 2002-11-28 | 2004-06-02 | Teva Pharmaceutical Industries Limited | Crystalline form F of Atorvastatin hemi-calcium salt |
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| CA2573969C (en) * | 2004-07-16 | 2014-02-04 | Lek Pharmaceuticals D.D. | Oxidative degradation products of atorvastatin calcium |
| CA2701710C (en) | 2004-07-20 | 2013-08-27 | Warner-Lambert Company Llc | Novel forms of [r-(r*,r*)]-2-(4-fluorophenyl)-.beta.,.delta.-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1h-pyrrole-1-heptanoic acid calcium salt (2:1) |
| MX2007003652A (es) * | 2004-09-28 | 2009-02-16 | Teva Pharma | Proceso para preparar formas de calcio de atorvastatina sustancialmente libre de impurezas. |
| KR20070054730A (ko) * | 2004-10-18 | 2007-05-29 | 테바 파마슈티컬 인더스트리즈 리미티드 | 알콜 및 케톤 및/또는 에스테르의 혼합물인 유기 용매에아토르바스타틴 헤미-칼슘 염을 용해시키고 용매를제거하여 비결정형 아토르바스타틴 헤미-칼슘을 제조하는방법 |
| RU2007115543A (ru) | 2004-10-28 | 2008-12-10 | Уорнер-Ламберт Компани Эл-Эл-Си (US) | Способ получения аморфного аторвастатина |
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| CZ2007772A3 (cs) * | 2005-04-08 | 2008-02-27 | EGIS GYOGYSZERGYÁR Nyilvánosan Müködö Részvénytársaság | Nová krystalická polymorfní forma hemivápenaté soli atorvastatinu |
| CA2547216A1 (en) | 2005-09-21 | 2007-03-21 | Renuka D. Reddy | Process for annealing amorphous atorvastatin |
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| KR20080079646A (ko) * | 2005-11-21 | 2008-09-01 | 테바 파마슈티컬 인더스트리즈 리미티드 | 아토르바스타틴 제제 |
| TW200745026A (en) | 2005-12-13 | 2007-12-16 | Teva Pharma | Crystal form of atorvastatin hemi-calcium and processes for preparation thereof |
| EP1810667A1 (en) | 2006-01-20 | 2007-07-25 | KRKA, tovarna zdravil, d.d., Novo mesto | Pharmaceutical composition comprising amorphous atorvastatin |
| WO2007103223A1 (en) * | 2006-03-01 | 2007-09-13 | Teva Pharmaceutical Industries Ltd. | Process for preparing a crystalline form of atorvastatin hemi-calcium |
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| US9334266B2 (en) | 2009-09-04 | 2016-05-10 | The University Of Toledo | Catalysts and related processes for producing optically pure beta-lactones from aldehydes and compositions produced thereby |
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| HRP960313B1 (en) | 1995-07-17 | 2002-08-31 | Warner Lambert Co | Form iii crystalline (r- (r*, r*)-2- (4-fluorophenyl) -beta-delta-hydroxy-5-(1-methylethyl) -3-phenyl-4- ((phenylamino) carbonyl -1h-pyrrole-1-heptanoic acid calcium salt (2:1) |
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| CA2450111C (en) * | 2001-06-29 | 2006-02-07 | Warner-Lambert Company Llc | Crystalline forms of [r-(r*,r*)]-2-(4-fluorophenyl)-beta, delta-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[phenylamino)carbonyl]-1h-pyrrole-1-heptanoic acid calcium salt(2:1)(atorvastatin) |
| WO2003011826A1 (en) * | 2001-07-30 | 2003-02-13 | Dr. Reddy's Laboratories Ltd. | Crystalline forms vi and vii of atorvastatin calcium |
-
2001
- 2001-11-05 CA CA 2426632 patent/CA2426632C/en not_active Expired - Fee Related
- 2001-11-05 IL IL15573401A patent/IL155734A0/xx active IP Right Grant
- 2001-11-05 US US09/992,746 patent/US6605636B2/en not_active Expired - Fee Related
- 2001-11-05 MX MXPA03003900A patent/MXPA03003900A/es active IP Right Grant
- 2001-11-05 HU HU0303765A patent/HUP0303765A2/hu unknown
- 2001-11-05 CN CNA018183840A patent/CN1535139A/zh active Pending
- 2001-11-05 EP EP01988174A patent/EP1332130A4/en not_active Withdrawn
- 2001-11-05 JP JP2002544015A patent/JP2004513956A/ja not_active Withdrawn
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- 2001-11-05 AU AU4150602A patent/AU4150602A/xx active Pending
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Also Published As
| Publication number | Publication date |
|---|---|
| JP2004513956A (ja) | 2004-05-13 |
| NO20031986D0 (no) | 2003-05-02 |
| IL155734A0 (en) | 2003-11-23 |
| CN1535139A (zh) | 2004-10-06 |
| PL362472A1 (en) | 2004-11-02 |
| MXPA03003900A (es) | 2005-02-17 |
| IL155734A (en) | 2008-11-26 |
| HUP0303765A2 (hu) | 2004-03-01 |
| EP1332130A2 (en) | 2003-08-06 |
| KR20040005854A (ko) | 2004-01-16 |
| CZ20031495A3 (cs) | 2004-01-14 |
| CA2426632A1 (en) | 2002-05-30 |
| EP1332130A4 (en) | 2004-01-21 |
| CA2426632C (en) | 2008-08-05 |
| AU4150602A (en) | 2002-06-03 |
| KR100704213B1 (ko) | 2007-04-10 |
| US6605636B2 (en) | 2003-08-12 |
| IS6798A (is) | 2003-04-30 |
| WO2002041834A3 (en) | 2002-07-18 |
| ZA200303972B (en) | 2004-08-23 |
| US20020115709A1 (en) | 2002-08-22 |
| SK6592003A3 (en) | 2004-01-08 |
| NO20031986L (no) | 2003-05-02 |
| WO2002041834A8 (en) | 2003-01-03 |
| WO2002041834A2 (en) | 2002-05-30 |
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