SI21616A - New crystal forms of carvedilol - Google Patents
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- SI21616A SI21616A SI200300218A SI200300218A SI21616A SI 21616 A SI21616 A SI 21616A SI 200300218 A SI200300218 A SI 200300218A SI 200300218 A SI200300218 A SI 200300218A SI 21616 A SI21616 A SI 21616A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/56—Ring systems containing three or more rings
- C07D209/80—[b, c]- or [b, d]-condensed
- C07D209/82—Carbazoles; Hydrogenated carbazoles
- C07D209/88—Carbazoles; Hydrogenated carbazoles 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 to carbon atoms of the ring system
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Abstract
Description
NOVE KRISTALNE OBLIKE KARVEDILOLANEW CRYSTAL FORMS OF CARVEDILOL
Področje tehnike, v katero spada izumFIELD OF THE INVENTION
Izum se nanaša na področje fizikalne in sintezne organske kemije. Nanaša se na postopek za kristalizacijo nove trdne kristalne modifikacije karvedilola ali njegovega solvata, ki ima odlično učinkovitost kot zdravilo.The invention relates to the field of physical and synthetic organic chemistry. It relates to a process for crystallization of a new solid crystalline modification of carvedilol or a solvate thereof, which has excellent efficacy as a drug.
Stanje tehnikeThe state of the art
Karvedilol, (±)-l-(9//-karbazolil-4-oksi)-3-[[2-(2-metoksifenoksi)etil]amino]-2propanol, je neselektiven β-adrenergični blokator z αΐ-blokirajočo aktivnostjo. Trdne zdravilne formulacije so uporabne pri zdravljenju hipertenzije, kongestivne srčne napake in angine. Uporablja se v farmacevtskih sestavkih kot racemna zmes obeh enantiomerov, ki ima strukturno formulo:Carvedilol, (±) -1- (9H-carbazolyl-4-oxy) -3 - [[2- (2-methoxyphenoxy) ethyl] amino] -2propanol, is a non-selective β-adrenergic blocker with αΐ-blocking activity. Solid drug formulations are useful in the treatment of hypertension, congestive heart failure and angina. It is used in pharmaceutical compositions as a racemic mixture of both enantiomers, having the structural formula:
Karvedilol ima izrazito polimorfno lastnost. Odvisno od postopka izolacije so identificirali številne različne trdne kristalne modifikacije. Različne stabilne modifikacije in nekatere stabilne in polstabilne hidrate, solvate in soli učinkovine so odkrile mnoge razvojne skupine. Trdni polimorfi, psevdopolimorfi, hidrati, solvati in soli so dobro analitično okarakterizirani. Materiale je mogoče uspešno razlikovati na osnovi njihovih tališč ter IR, Ramanovih, XRPD, DSC spektrov ali NMR spektrov trdne faze.Carvedilol has a distinct polymorphic property. Depending on the insulation process, many different solid crystalline modifications have been identified. Various stable modifications and some stable and semi-stable hydrates, solvates and salts of the active substance have been identified by many development groups. Solid polymorphs, pseudopolymorphs, hydrates, solvates and salts are well analytically characterized. The materials can be successfully distinguished based on their melting points and IR, Raman, XRPD, DSC spectra or solid phase NMR spectra.
Sinteza karvedilola je sestavljena iz več zaporednih sinteznih stopenj. Stabilna trdna oblika, uporabljena za oralne farmacevtske formulacije, je izolirana iz etil acetata. Postopki za sintezo in izolacijo so opisani v EP 0 004 920 BI.Carvedilol synthesis consists of several successive synthesis steps. The stable solid form used for oral pharmaceutical formulations is isolated from ethyl acetate. The synthesis and isolation procedures are described in EP 0 004 920 BI.
EP 0 004 920 BI opisuje izolacijo karvedilola iz etil acetata. Po postopku je izolirana čista in stabilna modifikacija II karvedilola in okarakterizirana s tališčem.EP 0 004 920 BI describes the isolation of carvedilol from ethyl acetate. Following the process, pure and stable modification of carvedilol II is isolated and characterized by melting point.
EP 0 893 440 Al opisuje kristalizacijo karvedilola iz metanola. Izolirana je termodinamično bolj stabilna modifikacija I.EP 0 893 440 Al describes the crystallization of carvedilol from methanol. A thermodynamically more stable modification I is isolated.
WO 02/00216 in WO 03/005970 opisujeta stabilno modifikacijo III karvedilola. Skladno z eksperimenti, opisanimi v navedenih prijavah, je možno pripraviti polimorfWO 02/00216 and WO 03/005970 describe stable modification of carvedilol III. According to the experiments described in these applications, it is possible to prepare a polymorph
III s kristalizacijo iz vode ali z obarjanjem iz organskega topila z dodatkom vode, uporabljene kot protitopilo.III by crystallization from water or by precipitation from an organic solvent with the addition of water used as an antituber.
WO 02/00216 opisuje tudi nove trdne modifikacije karvedilola, označene kot oblikiWO 02/00216 also describes the novel solid formulations of carvedilol
IV in V, ki jih je mogoče pripraviti z izolacijo iz organskih topil z obarjanjem z dodatkom cikloheksana ali heksana.IV and V, which can be prepared by isolation from organic solvents by precipitation with the addition of cyclohexane or hexane.
WO 03/029214 Al opisuje novo modifikacijo karvedilola, ki je semihidrat in je pripravljen z raztapljanjem materiala s sledečo izolacijo z razprševanjem raztopine v vodi ali metanolu/vodi kot kristalizacij skih medijih.WO 03/029214 Al describes a new modification of carvedilol, which is a semihydrate and is prepared by dissolving the material by the following isolation by dispersing the solution in water or methanol / water as crystallization media.
WO 03/059807 A2 opisuje kristalno trdno snov karvedilol solvata, označeno kot oblika VI.WO 03/059807 A2 describes the crystalline solid of carvedilol solvate, designated Form VI.
Tehnični problemA technical problem
Pojav organskih spojin v različnih trdnih modifikacijah je predmet izziva v farmacevtski industriji. Sintezni postopki, uporabljeni za proizvodnjo, posebno izolacijske stopnje in industrijski farmacevtski postopki so področja, ki jih v industriji intenzivno raziskujejo. Izdelani in uveljavljeni so kvalitativni in kvantitativni fizikalni parametri teh stopenj.The appearance of organic compounds in various solid modifications is a challenge in the pharmaceutical industry. Synthesis processes used for production, especially insulation rates and industrial pharmaceutical processes are areas of intense research in the industry. The qualitative and quantitative physical parameters of these degrees are elaborated and implemented.
Različne trdne modifikacije iste spojine navadno kažejo različne fizikalne lastnosti in različne lastnosti raztapljanja, kar ima znaten učinek na postopek formuliranja trdnega zdravila in končno lahko vpliva na biorazpoložljivost zdravila. Aktivne farmacevtske sestavine, izolirane v postopkih za sintezo in uporabljene v formulacijah, morajo biti v definiranih kristalnih modifikacijah in navadno z uveljavljenimi fizikalnimi lastnostmi, kot so velikost delcev in specifična površina.Different solid modifications of the same compound typically exhibit different physical properties and different dissolution properties, which has a significant effect on the solid drug formulation process and ultimately may affect the bioavailability of the drug. The active pharmaceutical ingredients isolated in the synthesis processes and used in the formulations must be in defined crystalline modifications and usually with established physical properties such as particle size and specific surface area.
Kratka vsebina izumaSUMMARY OF THE INVENTION
Pri naših raziskavah izolacijske stopnje za pripravo karvedilola z uporabo etil acetata kot topila smo presenetljivo ugotovili nove kristalne oblike karvedilola. Izolirali smo različne trdne kristalne modifikacije karvedilola tako, da smo modificirali koncentracijo učinkovine v etil acetatni raztopim in koncentracijo vode v etil acetatu, v katerem smo učinkovino raztopili in kristalizirali.In our studies of the isolation rate for the preparation of carvedilol using ethyl acetate as a solvent, we surprisingly identified novel crystalline forms of carvedilol. Various solid crystalline modifications of carvedilol were isolated by modifying the concentration of the active substance in ethyl acetate soluble and the water concentration in ethyl acetate in which the active ingredient was dissolved and crystallized.
Kratek opis slikShort description of the pictures
Slika 1: FT-IR-spekter kristalne oblike VII.Figure 1: FT-IR spectrum of crystalline form VII.
Slika 2: DSC-krivulja kristalne oblike VII.Figure 2: DSC curve of crystalline form VII.
Slika 3: XRPD-vzorec kristalne oblike VII.Figure 3: XRPD-pattern of crystalline form VII.
Slika 4: FT-IR-spekter kristalne oblike IX.Figure 4: FT-IR spectrum of crystalline Form IX.
Slika 5: DSC-krivulja kristalne oblike IX.Figure 5: DSC curve of crystalline Form IX.
Slika 6: XRPD-vzorec kristalne oblike IX.Figure 6: XRPD pattern of crystalline Form IX.
Metode merjenjaMeasurement methods
FT-IR-spektre v KBr-peletih smo posneli v območju valovnih števil od 4000 cm'1 do 400 cm'1 s spektrometrom Paragon 1000 Perkin Elmer pri ločljivosti 4 cm'1.FT-IR spectra in KBr pellets were recorded in the wavenumber range from 4000 cm -1 to 400 cm -1 using a Paragon 1000 Perkin Elmer spectrometer at a resolution of 4 cm -1 .
DSC-skene smo posneli na skening kalorimetru Perkin Elmer DSC 7. Vzorce z zatehto približno 3 mg smo skenirali med 30 °C in 130 °C pri hitrosti segrevanja 10 °C/min v atmosferi dušika v aluminijastih DSC odprtih pladnjih.DSC scans were recorded on a Perkin Elmer DSC 7 scanning calorimeter. Samples weighing approximately 3 mg were scanned between 30 ° C and 130 ° C at a heating rate of 10 ° C / min under nitrogen atmosphere in aluminum DSC open trays.
Rentgenske praškaste difrakcijske diagrame smo dobili z diffaktometrom Phillips PW3040/60 X'Pert PRO, opremljenim z detektorjem X'Celerator; CuK« sevanje 0,1541874 nm. Področje 2 Oje bilo 4-30° in velikost stopnje je bila 0,0167 °.X-ray powder diffraction patterns were obtained with a Phillips PW3040 / 60 X'Pert PRO diffractometer equipped with an X'Celerator detector; CuK «radiation 0.1541874 nm. Area 2 It was 4-30 ° and its magnitude was 0.0167 °.
Podroben opis izumaDETAILED DESCRIPTION OF THE INVENTION
V skladu s predloženim izumom izvedemo postopek za pripravo kristalnega karvedilola v etil acetatu kot kristalizacijskem topilu ali etil acetatu z dodano vodo v količinah, v katerih se voda še meša z etil acetatom, kot kristalizacijskem topilu.According to the present invention, a process for the preparation of crystalline carvedilol in ethyl acetate as a crystallization solvent or ethyl acetate with added water is carried out in amounts in which water is still miscible with ethyl acetate as a crystallization solvent.
Predloženi izum nadalje zagotavlja postopke za kristalizacijo, ki obsegajo raztapljanje karvedilola pri koncentracijah 1-40 mas./mas. % v segretih topilih, kot etil acetatu ali etil acetat/vodnih zmeseh, in ohlajevanje kristalizacijskih zmesi na nižje temperature, kot je vrelišče kristalizacijskih zmesi, da izzovemo kristalizacijo karvedilolnih trdnih kristalnih modifikacij.The present invention further provides crystallization processes comprising dissolving carvedilol at concentrations of 1-40 w / w. % in heated solvents such as ethyl acetate or ethyl acetate / aqueous mixtures, and cooling the crystallization mixtures to lower temperatures, such as the boiling point of the crystallization mixtures, to induce crystallization of carvedilol solid crystalline modifications.
Karvedilol lahko uspešno kristaliziramo iz etil acetata z uporabo razlike v topnosti učinkovine, ki je višja v toplem ali vrelem etil acetatu in nižja v ohlajenem etil acetatu, pri čemer je pri temperaturi, nižji od 9 °C, topnost karvedilola nižja od 0,5 mas./mas. %.Carvedilol can be successfully crystallized from ethyl acetate using a difference in the solubility of the active ingredient, which is higher in warm or hot ethyl acetate and lower in chilled ethyl acetate, with a carvedilol solubility lower than 0.5 wt. ./mas. %.
S hlajenjem bistrih karvedilolnih raztopin v etil acetatu na nižje temperature, kot je vrelišče etil acetata, lahko opazimo kristalizacijo trdnega materiala.By cooling the clear carvedilol solutions in ethyl acetate to lower temperatures than the boiling point of ethyl acetate, crystallization of the solid material can be observed.
Kristalizacija trdnega kristalnega zdravila iz raztopin, ki vsebujejo 25-30 mas./mas. % karvedilola, se začne pri temperaturah, višjih od 60 °C.Crystallization of solid crystalline drug from solutions containing 25-30% w / w % carvedilol begins at temperatures above 60 ° C.
Kristalizacija trdne kristalne učinkovine iz raztopin, ki vsebujejo 2-10 mas./mas. % karvedilola, se začne pri temperaturah 20-40 °C.Crystallization of a solid crystalline substance from solutions containing 2-10% w / w % carvedilol begins at temperatures of 20-40 ° C.
Kristalizacija trdnega kristalnega zdravila iz raztopin s koncentracijami od 10-25 mas.mas.% se dokazano zgodi v temperaturnem intervalu 40-60 °C.The crystallization of a solid crystalline drug from solutions with concentrations of 10-25% by weight has been demonstrated to occur at a temperature range of 40-60 ° C.
Če uporabimo postopek priprave karvedilola s kristalizacijo zdravila iz raztopin, ki vsebujejo 3-30 mas./mas. % karvedilola v etil acetatu, tvorimo in izoliramo čisti karvedilol, modifikacijo II, vendar pa lahko v nekaterih posebnih razmerah zaznamo nastanek karvedilol-solvatov.If a carvedilol preparation process is used by crystallizing the drug from solutions containing 3-30 wt./mass. % carvedilol in ethyl acetate, form and isolate pure carvedilol, modification II, but the formation of carvedilol solvates can be detected in some special conditions.
Z zniževanjem koncentracije karvedilola v etil acetatu prednostno nastanejo etil acetatni solvati karvedilola.By reducing the concentration of carvedilol in ethyl acetate, ethyl acetate solvates of carvedilol are preferably formed.
Pri kristalizaciji karvedilola iz etil acetatnih raztopin pri koncentracijah v etil acetatu, nižjih od 10 mas./mas. %, prednostno 5 mas./mas. %, najbolj prednostno 3 mas./mas. %, je predominantna tvorba karvedilol solvatov.On crystallization of carvedilol from ethyl acetate solutions at concentrations in ethyl acetate lower than 10 wt./wt. %, preferably 5 wt./wt. %, most preferably 3 wt./wt. %, is the predominant formation of carvedilol solvates.
Karvedilol, pripravljen s kristalizacijo iz 2 mas./mas. % karvedilol etil acetatne raztopine, vsebuje 12 mas./mas. % vključenega etil acetata v kristalno mrežo trdnega materiala.Carvedilol prepared by crystallization from 2% w / w % carvedilol ethyl acetate solution, contains 12% w / w % of ethyl acetate incorporated into the crystalline solid network.
Solvatirana oblika je dobro stabilna v suspenziji, prav tako dobro pa jo lahko tudi izoliramo in okarakteriziramo. Pri sobni temperaturi je le začasno stabilna in v enem tednu prekristalizira v bolj stabilne trdne modifikacije.The solvated form is well stable in suspension and can also be isolated and characterized. At room temperature, it is only temporarily stable and recrystallizes to more stable solid modifications within a week.
Z uporabo sušilnih temperatur, višjih od 50 °C, prednostno 55 °C, najbolj prednostno 60 °C, med sušilnim postopkom in pri uporabljenem normalnem ali znižanem tlaku se metastabilna solvatirana oblika transformira v modifikacijo II, III ali v zmes obeh modifikacij.By using drying temperatures higher than 50 ° C, preferably 55 ° C, most preferably 60 ° C, during the drying process and at normal or reduced pressure, the metastable solvated form is transformed into modification II, III or a mixture of both modifications.
Z uporabo vakuumskega sušenja etil acetatnih solvatov pri temperaturah, nižjih od 50 °C, lahko izoliramo tudi nesolvatirano karvedilolno modifikacijo VII. Modifikacija je stabilna pri temperaturah, nižjih od 50 °C, vendar le-ta prekristalizira v trdni obliki v bolj stabilno modifikacijo II ali v zmes modifikacij II in III pri višjih temperaturah in/ali pri daljših časih shranjevanja. S sušenjem etil acetatnih solvatov ali kristalne karvedilolne oblike VII pri temperaturah 60-100 °C lahko izoliramo stabilno modifikacijo II. Prednostno temperaturno območje je 70-80 °C.Using vacuum drying of ethyl acetate solvates at temperatures below 50 ° C, unsolvated carvedilol modification VII can also be isolated. The modification is stable at temperatures below 50 ° C but recrystallizes in solid form to a more stable modification II or to a mixture of modifications II and III at higher temperatures and / or for longer storage times. By drying ethyl acetate solvates or crystalline carvedilol form VII at temperatures of 60-100 ° C, stable modification II can be isolated. The preferred temperature range is 70-80 ° C.
Predloženi izum nadalje zagotavlja novo trdno kristalno modifikacijo karvedilola, nesolvatirano obliko, označeno kot oblika VILThe present invention further provides a new solid crystalline modification of carvedilol, an unsolvated form, designated VIL form
Nesolvatirana kristalna oblika Vlije označena s tališčem 68,8-72,4 °C.The unsolvated crystalline form of Vlija indicated by a melting point of 68.8-72.4 ° C.
Oblika VII ima IR-spekter, slika 1, s karakterističnimi absorpcijskimi trakovi pri:Form VII has an IR spectrum, Figure 1, with characteristic absorption bands at:
3469,2 cm1, 3393,5 cm'1, 3345,5 cm'1, 3278,1 cm'1, 3054,5 cm'1, 3009,0 cm'1, 2909,8 cm'1, 2871,2 cm1, 2836,5 cm4, 1736,2 cm4, 1625,8 cm'1, 1606,3 cm1, 1589,1 cm'1,3469,2 cm 1 , 3393,5 cm 1 , 3345,5 cm 1 , 3278,1 cm 1 , 3054,5 cm 1 , 3009,0 cm 1 , 2909,8 cm 1 , 2871, 2 cm 1 , 2836.5 cm 4 , 1736.2 cm 4 , 1625.8 cm 1 , 1606.3 cm 1 , 1589.1 cm 1 ,
1507.6 cm'1, 1452,7 cm4, 1441,4 cm'1, 1383,1 cm4, 1347,5 cm'1, 1332,7 cm'1, 1305,0 cm1, 1284,5 cm'1, 1255,6 cm1, 1226,9 cm4, 1215,0 cm'1, 1178,8 cm1, 1151,6 cm'1,1507.6 cm 1 , 1452.7 cm 4 , 1441.4 cm 1 , 1383.1 cm 4 , 1347.5 cm 1 , 1332.7 cm 1 , 1305.0 cm 1 , 1284.5 cm 1 , 1255,6 cm 1 , 1226,9 cm 4 , 1215,0 cm 1 , 1178,8 cm 1 , 1151,6 cm 1 ,
1123.6 cm1, 1095,8 cm'1, 1040,0 cm'1, 1020,9 cm'1, 992,6 cm4, 957,1 cm1,1123.6 cm 1 , 1095,8 cm 1 , 1040,0 cm 1 , 1020,9 cm 1 , 992,6 cm 4 , 957,1 cm 1 ,
938,4 cm'1, 907,0 cm'1, 848,1 cm'1, 798,1 cm'1, 784,1 cm'1, 745,0 cm'1, 722,9 cm'1,938.4 cm 1 , 907.0 cm 1 , 848.1 cm 1 , 798.1 cm 1 , 784.1 cm 1 , 745.0 cm 1 , 722.9 cm 1 ,
621,6 cm'1, 611,4 cm'1, 575,9 cm1, 538,4 cm'1, 483,0 cm'1, 434,1 cm1.621.6 cm 1 , 611.4 cm 1 , 575.9 cm 1 , 538.4 cm 1 , 483.0 cm 1 , 434.1 cm 1 .
Najbolj značilni absorpcijski trakovi oblike VII so pri: 3469,2 cm'1, 3278,1 cm'1,The most characteristic absorption bands of Form VII are: 3469.2 cm -1 , 3278.1 cm -1 ,
2871,2 cm'1, 1123,6 cm'1, 1095,8 cm'1, 745,0 cm'1, 722,9 cm1.2871,2 cm 1 , 1123,6 cm 1 , 1095,8 cm 1 , 745,0 cm 1 , 722,9 cm 1 .
Oblika VII je nadalje okarakterizirana z DSC-analizo, slika 2. DSC-krivulja kaže dve endotermi; prvo endotermo s temperaturnim vrhom pri približno 73 °C in drugo s temperaturnim vrhom pri približno 114 °C. Prva endoterma je zaradi polimorfnega prehoda iz oblike VII v bolj stabilno obliko II, druga endoterma predstavlja taljenje oblike II.Form VII is further characterized by DSC analysis, Figure 2. The DSC curve shows two endotherms; a first endotherm with a temperature peak at about 73 ° C and a second endotherm with a temperature peak at about 114 ° C. The first endotherm is due to the polymorphic transition from Form VII to more stable Form II, the second endotherm represents Form II melting.
Kristalna oblika VII je nadalje identificirana z XRPD-analizo, slika 3. Rentgenski praškasti difrakcijski diagram oblike VII kaže karakteristične vrednosti dve theta pri: 6,42, 6,78, 10,94, 11,58, 12,90, 13,62, 16,79, 17,51, 17,90, 18,81, 19,42, 20,83, 21,19, 21,93, 23,30, 24,49, 25,27, 26,09, 27,20, 29,21 ± 0,1.Crystal Form VII is further identified by XRPD analysis, Figure 3. The X-ray powder diffraction pattern of Form VII shows the characteristic values of two theta at: 6.42, 6.78, 10.94, 11.58, 12.90, 13.62 , 16.79, 17.51, 17.90, 18.81, 19.42, 20.83, 21.19, 21.93, 23.30, 24.49, 25.27, 26.09, 27 , 20, 29.21 ± 0.1.
Najbolj značilne difrakcije oblike VII so pri: 6,42, 6,78, 10,94, 11,58, 12,90, 13,62, 16,79, 17,51, 17,90, 23,30 in 27,20 ±0,1 stopinjah dve theta.The most characteristic diffractions of Form VII are: 6.42, 6.78, 10.94, 11.58, 12.90, 13.62, 16.79, 17.51, 17.90, 23.30 and 27, 20 ± 0.1 degrees two theta.
Naša nadaljnja raziskava je bila uporaba zmesi etil acetata in vode kot topilnega sistema za prekristalizacijo karvedilola. Opazili smo nekatere dodatne zanimive morfološke lastnosti karvedilola.Our further study was the use of a mixture of ethyl acetate and water as a solvent system for recrystallizing carvedilol. Some additional interesting morphological properties of carvedilol have been observed.
Na splošno, če uporabimo raztopine etil acetata in vode v razmeijih, pri katerih se voda še topi v etil acetatu, za kristalizacijo karvedilola, se tvorijo modifikacija II, modifikacija III in nova modifikacija IX v čisti obliki ali v zmeseh.Generally, when ethyl acetate and water solutions are used in the conditions at which water still dissolves in ethyl acetate, for crystallization of carvedilol, modification II, modification III and new modification IX are obtained in pure form or in mixtures.
Z etil acetatom, ki ne vsebuje vode ali vsebuje količino vode, manjšo od 0,8 mas./mas. %, prednostno 0,6 mas./mas. %, izoliramo modifikacijo II v čisti kristalni morfološki obliki.With ethyl acetate not containing water or containing less than 0.8% w / w water %, preferably 0.6 wt./wt. %, isolate modification II in pure crystalline morphological form.
Če uporabimo etil acetat z vsebnostjo vode 0,8-1,5 mas./mas. % za kristalizacijo karvedilola, se tvori modifikacija III v čisti obliki ali v zmeseh z modifikacijo II.If ethyl acetate with a water content of 0.8-1.5 w / w is used. % for carvedilol crystallization, modification III is obtained in pure form or in mixtures with modification II.
Zmesi modifikacije III in nove polimorfne modifikacije IX lahko izoliramo z etil acetatom z 2-3 mas./mas. % vode za prekristalizacijo karvedilola.Mixtures of modification III and novel polymorphic modifications IX can be isolated with ethyl acetate of 2-3 wt./wt. % water for recrystallization of carvedilol.
Čisto novo polimorfno modifikacijo IX karvedilola pripravimo z uporabo raztopine etil acetata in vode v razmeijih, pri katerih se voda še meša z etil acetatom, kot topilu za kristalizacijo. Raztopina etil acetata in vode v razmerjih, pri katerih se voda še topi v etil acetatu, vsebuje prednostno več kot 3 mas./mas. % vode in najbolj prednostno več kot 4 mas./mas. % vode.A brand new polymorphic modification of IX carvedilol is prepared using a solution of ethyl acetate and water under conditions in which water is still miscible with ethyl acetate as the solvent for crystallization. A solution of ethyl acetate and water, in proportions at which the water still dissolves in ethyl acetate, preferably contains more than 3% by weight. % water and most preferably more than 4% w / w % water.
Prednostna koncentracija karvedilola je 8-25 mas./mas. %.The preferred concentration of carvedilol is 8-25 w / w. %.
Predloženi izum nadalje zagotavlja novo kristalno trdno modifikacijo karvedilola, označeno kot oblika IX.The present invention further provides a new crystalline solid modification of carvedilol, designated Form IX.
Oblika IX je označena s tališčem 94,5-96,2 °C.Form IX is indicated by a melting point of 94.5-96.2 ° C.
Oblika IX ima IR-spekter, slika 4, s karakterističnimi absorpcijskimi trakovi pri: 3568,0 cm1, 3339,1 cm1, 3287,9 cm1, 3201,4 cm'1, 3052,8 cm'1, 2976,3 cm'1, 2942,9 cm1, 2924,3 cm'1, 2896,1 cm1, 2881,7 cm'1, 2860,0 cm'1, 2841,4 cm'1, 2714,0 cm'1,Form IX has the IR spectrum of Figure 4, with characteristic absorption bands at: 3568.0 cm 1 , 3339.1 cm 1 , 3287.9 cm 1 , 3201.4 cm 1 , 3052.8 cm 1 , 2976, 3 cm ' 1 , 2942,9 cm 1 , 2924,3 cm' 1 , 2896,1 cm 1 , 2881,7 cm ' 1 , 2860,0 cm' 1 , 2841,4 cm ' 1 , 2714,0 cm' 1 ,
2660,6 cm'1, 1911,7 cm1, 1882,4 cm'1, 1664,1 cm1, 1629,7 cm'1, 1607,2 cm'1,1593,5 cm'1, 1506,9 cm'1, 1488,0 cm'1, 1470,1 cm1, 1455,5 cm'1, 1443,8 cm'1, 1406,1 cm'1,2660,6 cm 1 , 1911,7 cm 1 , 1882,4 cm 1 , 1664,1 cm 1 , 1629,7 cm 1 , 1607,2 cm 1 , 1593,5 cm 1 , 1506,9 cm ' 1 , 1488,0 cm' 1 , 1470,1 cm 1 , 1455,5 cm ' 1 , 1443,8 cm' 1 , 1406,1 cm ' 1 ,
1386,4 cm'1, 1349,9 cm1, 1334,9 cm'1, 1307,9 cm'1, 1288,4 cm'1, 1254,0 cm'1, 1227,9 cm'1, 1182,8 cm'1, 1148,4 cm'1, 1125,4 cm'1, 1104,0 cm'1, 1091,2 cm1, 1051,7 cm'1,1386.4 cm 1 , 1349.9 cm 1 , 1334.9 cm 1 , 1307.9 cm 1 , 1288.4 cm 1 , 1254.0 cm 1 , 1227.9 cm 1 , 1182, 8 cm ' 1 , 1148,4 cm' 1 , 1125,4 cm ' 1 , 1104,0 cm' 1 , 1091,2 cm 1 , 1051,7 cm ' 1 ,
1018,6 cm1, 997,2 cm1, 930,9 cm'1, 906,1 cm'1, 851,5 cm'1, 838,3 cm'1, 816,7 cm'1,1018.6 cm 1 , 997.2 cm 1 , 930.9 cm 1 , 906.1 cm 1 , 851.5 cm 1 , 838.3 cm 1 , 816.7 cm 1 ,
798,3 cm'1, 782,7 cm'1, 771,5 cm'1, 751,9 cm'1, 748,0 cm'1, 737,1 cm1, 721,4 cm'1,798.3 cm 1 , 782.7 cm 1 , 771.5 cm 1 , 751.9 cm 1 , 748.0 cm 1 , 737.1 cm 1 , 721.4 cm 1 ,
657.1 cm'1, 626,6 cm'1, 612,9 cm'1, 586,9 cm'1, 567,9 cm'1, 546,6 cm'1, 526,5 cm'1,657.1 cm 1 , 626.6 cm 1 , 612.9 cm 1 , 586.9 cm 1 , 567.9 cm 1 , 546.6 cm 1 , 526.5 cm 1 ,
464.2 cm'1, 449,6 cm'1, 435,8 cm'1, 415,8 cm'1.464.2 cm 1 , 449.6 cm 1 , 435.8 cm 1 , 415.8 cm 1 .
Najbolj karakteristični absorpcijski trakovi oblike IX so pri: 3568,0 cm'1, 3339,1 cm'1, 3287,9 cm'1, 2942,9 cm'1, 2896,1 cm'1, 1349,9 cm'1, 1307,9 cm'1, 1288,4 cm'1, 1104,0 cm'1, 997,2 cm'1, 737,1 cm1.The most characteristic absorption bands of Form IX are at: 3568,0 cm ' 1 , 3339,1 cm' 1 , 3287,9 cm ' 1 , 2942,9 cm' 1 , 2896,1 cm ' 1 , 1349,9 cm' 1 , 1307.9 cm 1 , 1288.4 cm 1 , 1104.0 cm 1 , 997.2 cm 1 , 737.1 cm 1 .
Oblika IX je nadalje označena tudi z DSC-analizo.Form IX is further indicated by DSC analysis.
DSC-krivulja v obliki IX (slika 5) kaže manjšo endotermo pri temperaturnem vrhu približno 80 °C in večjo endotermo pri temperaturnem vrhu približno 99 °C in Tonset pri približno 95 °C.The DSC curve in Form IX (Figure 5) shows a smaller endotherm at a temperature peak of about 80 ° C and a larger endotherm at a temperature peak of about 99 ° C and a T onset at about 95 ° C.
Semihidratirana modifikacija IX sprošča vodo iz kristalne mreže pri temperaturah, višjih od 60 °C (prva endoterma, razvidna iz DSC-krivulje), in tako se tvori nehidratirana modifikacija, ki je označena z drugo DSC-endotermo. Nehidratiran material ohrani do tališča enako kristalno mrežo. Z izpostavitvijo nehidratirane modifikacije normalnemu ambientnemu okolju in temperaturam, nižjim od 60 °C, pride do reverzibilne hidratacije brezvodne oblike in dobimo semihidratirano modifikacijo.Semihydrated modification IX releases water from the crystal lattice at temperatures higher than 60 ° C (first endotherm, as shown in the DSC curve), thus forming a non-hydrated modification indicated by the second DSC endotherm. The non-hydrated material retains the same crystal lattice to the melting point. Exposure to a non-hydrated modification to a normal ambient environment and temperatures below 60 ° C results in reversible hydration of the anhydrous form and a semihydrated modification is obtained.
Obliko IX analiziramo tudi z XRPD-analizo, slika 6. Rentgenski praškasti difrakcijski diagram oblike IX prikazuje karakteristične vrednosti dve theta pri: 6,16, 6,46, 8,39, 10,88, 11,39, 12,35, 12,98, 13,62, 14,72, 16,86, 17,42, 18,26, 19,28, 19,58, 21,88,Form IX is also analyzed by XRPD analysis, Figure 6. The X-ray powder diffraction pattern of Form IX shows the characteristic values of two theta at: 6.16, 6.46, 8.39, 10.88, 11.39, 12.35, 12 , 98, 13.62, 14.72, 16.86, 17.42, 18.26, 19.28, 19.58, 21.88,
23,15, 24,61, 25,58, 26,06, 27,40, 27,63, 29,01, 29,55 ± 0,1.23.15, 24.61, 25.58, 26.06, 27.40, 27.63, 29.01, 29.55 ± 0.1.
Najbolj značilne difrakcije oblike IX so pri 6,16, 6,46, 11,39, 12,35, 13,62, 14,72, 16,86, 19,28, 19,58 in 23,15 ±0,1 stopinjah dve theta.The most characteristic diffractions of Form IX are at 6.16, 6.46, 11.39, 12.35, 13.62, 14.72, 16.86, 19.28, 19.58 and 23.15 ± 0.1 degrees two theta.
Naslednje Primeri ponazarjajo izum, ne da bi ga omejevali.The following Examples illustrate the invention without limiting it.
PrimeriExamples
Primer 1Example 1
Priprava kristalnega karvedilol etil acetatnega solvata g karvedilolne morfološke oblike II raztopimo v 740 ml etil acetata z manj kot 0,1 mas./mas. % vode. Zmes segrevamo do temperature vrelišča ali dokler se trdna snov ne raztopi in dobimo bistro reakcijsko raztopino. Po končanem segrevanju reakcijsko zmes ohladimo na približno 25 °C. Trdni produkt se začne obarjati iz kristalizacijske zmesi. Kristalizacijsko zmes nadalje ohladimo na 0-5 °C in po približno 1 uri trden material odfiltriramo. Trden material sušimo pri sobni temperaturi 20-25 °C 6-12 ur in izoliramo 16,7 g etil acetatnega solvata karvedilola s tališčem 66-70 °C. V skladu s TGA-analizo in *H NMR vsebuje proizvod 12-13 mas./mas. % etil acetata.Preparation of the crystalline carvedilol ethyl acetate solvate g of carvedilol morphological form II is dissolved in 740 ml of ethyl acetate with less than 0.1% w / w. % water. The mixture was heated to boiling point or until the solid dissolved to give a clear reaction solution. After heating is complete, the reaction mixture is cooled to about 25 ° C. The solid product begins to precipitate from the crystallization mixture. The crystallization mixture was further cooled to 0-5 [deg.] C. and the solid material was filtered off after about 1 hour. The solid material was dried at room temperature 20-25 ° C for 6-12 hours and 16.7 g of ethyl acetate solvate of carvedilol were isolated at a melting point of 66-70 ° C. According to TGA analysis and * H NMR, the product contains 12-13 w / w. % ethyl acetate.
Ta Primer ponovimo z uporabo karvedilolne morfološke oblike III, zmesi karvedilolnih oblik II in III ali amorfnega karvedilola namesto karvedilolne oblike II. Proizvodi so vsi identični proizvodu, pridobljenemu s karvedilolno obliko II.This Example is repeated using carvedilol morphological form III, a mixture of carvedilol forms II and III, or amorphous carvedilol instead of carvedilol form II. The products are all identical to the product obtained with carvedilol form II.
Primer 2Example 2
Priprava kristalne karvedilolne oblike VIIPreparation of crystalline carvedilol form VII
Karvedilol etil acetatni solvat sušimo pri znižanem tlaku 13,3 · 10 -26,6 - 10 Pa pn največ 50 °C, da uparimo topilo, in po izgubi mase za 12 % do 15 % v 6-8 urah izoliramo nesolvatiran karvedilol morfološke oblike VII s tališčem 68,8-72,4 °C.The carvedilol ethyl acetate solvate is dried under reduced pressure at 13.3 · 10 -26.6 - 10 Pa p at a maximum of 50 ° C to evaporate the solvent and, after losing weight by 12% to 15%, isolate the unsolvated carvedilol morphologically in 6-8 hours VII with a melting point of 68.8-72.4 ° C.
Primer 3Example 3
Priprava kristalne karvedilolne oblike IIPreparation of crystalline carvedilol form II
Kristalno karvedilolno obliko II dobimo s sušenjem karvedilolne oblike VII pri temperaturah 70-80 °C, 6-8 ur.Crystalline carvedilol form II is obtained by drying carvedilol form VII at temperatures of 70-80 ° C for 6-8 hours.
Primer 4Example 4
Priprava kristalne karvedilolne oblike IX g karvedilolne morfološke oblike II raztopimo v 26,6 ml etil acetata s 4 mas./mas. % vode. Zmes segrevamo do temperature vrelišča ali dokler se trdna snov ne raztopi in dobimo bistro reakcijsko raztopino. Po končanem segrevanju reakcijsko zmes ohladimo na 40-45 °C. Trdni produkt se začne obarjati iz kristalizacijske zmesi in segrevanje pri tej temperaturi vzdržujemo 0,5-1,5 ure. Potem reakcijsko zmes postopno ohladimo na 20-25 °C in nadalje na 0-5 °C. Pri 0-5 °C kristalizacijsko zmes mešamo približno 1 uro in odfiltriramo trdni produkt. Trdni produkt sušimo pri sobni temperaturi 20-25 °C 12 ur. Dobimo 3,7 g karvedilola. Proizvod sušimo do konstantne mase približno 2-4 ure pri 50-60 °C in znižanem tlaku 0,3 · 102-39,9 · 102 Pa.Preparation of crystalline carvedilol form IX g of carvedilol morphological form II is dissolved in 26.6 ml of ethyl acetate with 4 wt./wt. % water. The mixture was heated to boiling point or until the solid dissolved to give a clear reaction solution. After heating is complete, the reaction mixture is cooled to 40-45 ° C. The solid product begins to precipitate from the crystallization mixture and is maintained at this temperature for 0.5-1.5 hours. The reaction mixture was then gradually cooled to 20-25 ° C and further to 0-5 ° C. At 0-5 ° C, the crystallization mixture was stirred for about 1 hour and the solid product was filtered off. The solid was dried at room temperature 20-25 ° C for 12 hours. 3.7 g of carvedilol are obtained. The product is dried to constant weight for about 2-4 hours at 50-60 ° C and reduced pressure 0.3 · 10 2 -39.9 · 10 2 Pa.
Dobimo 3,56 g, 91 % proizvoda s tališčem 94,5-96,2 °C.3.56 g, 91% of the product are obtained with a melting point of 94.5-96.2 ° C.
Ta Primer ponovimo z uporabo karvedilolne morfološke oblike III, zmesi karvedilolnih oblik II in III ali amorfnega karvedilola namesto karvedilolne oblike II. Proizvodi so vsi identični proizvodu, pridobljenemu s karvedilolno obliko II.This Example is repeated using carvedilol morphological form III, a mixture of carvedilol forms II and III, or amorphous carvedilol instead of carvedilol form II. The products are all identical to the product obtained with carvedilol form II.
Primer 5Example 5
Priprava kristalne karvedilolne oblike IX g karvedilolne morfološke oblike II raztopimo v 32,1 ml etil acetata s 6,8 mas./mas. % vode. Zmes segrevamo do temperature vrelišča ali dokler se trdna snov ne raztopi in dobimo bistro reakcijsko zmes. Po končanem segrevanju reakcijsko zmes ohladimo. Proizvod se začne obaijati iz kristalizacijske zmesi pri 25-30 °C. Kristalizacijsko zmes postopno ohladimo na 0-5 °C in po približno 1 uri kristalizacijsko zmes odfiltriramo. Trdno snov sušimo pri sobni temperaturi 20-25 °C ur. Proizvod sušimo do konstantne mase približno 2-4 ure pri 50—60 °C in znižanem tlaku 0,3 102-39,9 · 102 Pa.Preparation of crystalline carvedilol form IX g of carvedilol morphological form II is dissolved in 32.1 ml of ethyl acetate with 6.8% w / w. % water. The mixture was heated to boiling point or until the solid dissolved and a clear reaction mixture was obtained. After heating is complete, the reaction mixture is cooled. The product begins to be suspended from the crystallization mixture at 25-30 ° C. The crystallization mixture was gradually cooled to 0-5 ° C and after about 1 hour the crystallization mixture was filtered off. The solid was dried at room temperature 20-25 ° C for hours. The product is dried to constant weight for approximately 2-4 hours at 50-60 ° C and reduced pressure 0.3 10 2 -39.9 · 10 2 Pa.
Dobimo 4,74 g, 94,8 % polimorfa IX s tališčem 94,5-97,3 °C.4.74 g, 94.8% of polymorph IX are obtained with a melting point of 94.5-97.3 ° C.
Ta Primer ponovimo z uporabo karvedilolne morfološke oblike III, zmesi karvedilolnih oblik II in III ali amorfnega karvedilola namesto karvedilolne oblike II. Proizvodi so vsi identični proizvodu, pridobljenemu s karvedilolno obliko II.This Example is repeated using carvedilol morphological form III, a mixture of carvedilol forms II and III, or amorphous carvedilol instead of carvedilol form II. The products are all identical to the product obtained with carvedilol form II.
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| SI200300218A SI21616A (en) | 2003-09-02 | 2003-09-02 | New crystal forms of carvedilol |
| EP04775682A EP1660451A2 (en) | 2003-09-02 | 2004-09-01 | New crystalline forms of carvedilol |
| PCT/SI2004/000029 WO2005021504A2 (en) | 2003-09-02 | 2004-09-01 | New crystalline forms of carvedilol |
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| HUP0301802A3 (en) | 2000-06-28 | 2009-04-28 | Teva Pharma | Process for producing carvedilol, crystalline carvedilol, process for producing it and pharmaceutical composition containing it |
| CA2472377A1 (en) | 2002-01-15 | 2003-07-24 | Teva Pharmaceutical Industries Ltd. | Crystalline solids of carvedilol and processes for their preparation |
| EP1781611A1 (en) * | 2005-06-09 | 2007-05-09 | Teva Pharmaceutical Industries Ltd. | Crystalline forms of carvedilol and processes for their preparation |
| WO2007043938A1 (en) * | 2005-10-07 | 2007-04-19 | Astrazeneca Ab | NOVEL CRYSTALLINE FORM OF 3,5-DIBROMO-N- [ (2S) -2- (-4- FLUOROPHENYL) -4- (3-MORPHOLIN-4-YLAZTIDIN-l-YL) BUTYL] -N METHYLBENZAMIDE, MODIFICATION B |
| WO2008002683A2 (en) | 2006-06-28 | 2008-01-03 | Teva Pharmaceutical Industries Ltd. | Polymorphous forms of carvedilol phosphate |
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| EP0893440A1 (en) * | 1997-07-22 | 1999-01-27 | Roche Diagnostics GmbH | Thermodynamically stable modification of 1-(4-carbazolyloxy)-3-[2-(2-methoxyphenoxy)ethylamino]-2-propanole, process for its preparation and pharmaceutical compositions containing it |
| HUP0301802A3 (en) * | 2000-06-28 | 2009-04-28 | Teva Pharma | Process for producing carvedilol, crystalline carvedilol, process for producing it and pharmaceutical composition containing it |
| JP2004534840A (en) * | 2001-07-13 | 2004-11-18 | スミスクライン・ビーチャム・コーポレイション | Carvedilol polymorphism |
| CA2460486A1 (en) * | 2001-09-28 | 2003-04-10 | F. Hoffmann-La Roche Ag | Pseudopolymorphic forms of carvedilol |
| CA2472377A1 (en) * | 2002-01-15 | 2003-07-24 | Teva Pharmaceutical Industries Ltd. | Crystalline solids of carvedilol and processes for their preparation |
| SK285547B6 (en) * | 2002-11-08 | 2007-03-01 | Zentiva, A. S. | Preparation process of Carvedilol |
| US20040151772A1 (en) * | 2002-11-08 | 2004-08-05 | Egalet A/S | Controlled release carvedilol compositions |
| WO2004113296A1 (en) * | 2003-06-20 | 2004-12-29 | Sun Pharmaceutical Industries Limited | A process for preparation of 1-[9h-carbazol-4-yloxy]- 3-[{2-(2-(-(methoxy)phenoxy)-ethyl}-amino]-propan-2-ol |
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