Shaanxi BLOOM Tech Co., Ltd. yog ib qho ntawm cov tuam ntxhab thiab cov muag khoom ntawm posaconazole hmoov hauv Suav teb. Txais tos rau cov lag luam wholesale bulk zoo posaconazole hmoov muag ntawm no los ntawm peb lub hoobkas. Kev pabcuam zoo thiab tus nqi tsim nyog muaj.
Posaconazole hmoov, tshuaj lub npe 4- [4- [4- [4- [4-] [[(3R, 5R) -5- (2,4-difluorophenyl) -5- (1,2,4-triazol-1-ylmethyl) oxazol-3-yl] methoxy] phenyl] piperazin-1-yl] phenyl] -2-3 [S2-3] 1,2,4-triazol-3-one, molecular mis C37H42F2N8O4, CAS 171228-49-2, meej molecular hnyav 700.77700. Nws cov qauv molecular muaj ib lub nplhaib triazole, uas qhia txog fluorine atoms los hloov cov tshuaj chlorine atoms los ntawm sab saw txuas ntxiv, thiab qhia txog hydroxylated sab chains. Cov qauv kev hloov kho no ua rau muaj kev sib raug zoo ntawm cov tshuaj thiab 14 - demethylase (CYP51) nyob ntawm cov kab mob fungal cytochrome P450, thaum txo nws txoj kev cuam tshuam rau tib neeg cytochrome P450 enzymes, tshwm sim tsuas yog CYP3A4 inhibitors. Tsis tas li ntawd, cov qauv ntawm cov saw ntev ntev txo qhov kev sib txuas ntawm cov tshuaj mus rau transmembrane transporters (efflux twj) thiab txo qhov kev pheej hmoo ntawm cov tshuaj tiv thaiv.
Triazole ring core: Raws li ib qho qauv ntawm cov tshuaj tua kab mob triazole, lub nplhaib triazole khi rau cov kab mob fungal cytochrome P450 nyob ntawm 14 - demethylase (CYP51) los ntawm nitrogen atom, inhibiting synthesis ntawm ergosterol.
Fluorine atom hloov pauv: Cov tshuaj chlorine atom hauv lub nplhaib benzene yog hloov los ntawm fluorine atom, txhim khu kev sib raug zoo ntawm cov tshuaj thiab fungal CYP51, thaum txo qhov cuam tshuam rau tib neeg cytochrome P450 enzymes.
Hydroxylated side chains: Taw qhia (2S, 3S) -2-hydroxypent-3-yl side chains tsub kom cov tshuaj polarity, txhim kho cov dej solubility, thiab txo kev khi rau transmembrane transporters (efflux twj), yog li txo qhov kev pheej hmoo ntawm kev siv tshuaj tiv thaiv.
Cov ntaub ntawv ntxiv ntawm chemical compound:
Peb Cov Khoom
Posaconazole hmoov COA
Solubility thiab pH dependence
Lub solubility nthuav tawm qhov tseem ceeb pH dependence, uas yog lub hauv paus tseem ceeb rau kev tsim ntawm nws cov txheej txheej enteric:
Acid ib puag ncig (gastric acid, pH 1-3):
Lub solubility hauv gastric acid yog tsawg heev, tab sis enteric txheej muaj peev xwm tiv thaiv tag nrho cov yeeb yam tseem ceeb thiab tsis txhob degradation los ntawm gastric acid.
Alkaline ib puag ncig (lub plab, pH 6-8):
Lub txheej dissolves nyob rau hauv alkaline tej yam kev mob nyob rau hauv lub plab, tso cov tshuaj core. Lub solubility hauv dimethyl sulfoxide (DMSO) yog 50mg / mL, tab sis cov solubility hauv dej yog tsawg heev (<0.1mg/mL). This characteristic requires clinical medication to be taken together with a high-fat diet or acidic carbonated beverages to promote emulsification and absorption of the drug in the intestine. Research has shown that co administration with high-fat foods can increase the systemic exposure (AUC) of posaconazole by 4 times, while co administration with skimmed foods increases it by 2.6 times.
Chemical Overview thiab Basic Information
Posaconazole hmoovyog triazole-raws li dav-spectrum tshuaj tiv thaiv kab mob. Nws lub npe tshuaj yog 4-[4-[4-[[(3R,5R)-5-(2,4-difluorophenyl)-5-(1,2,4-triazole-1-ylmethyl)oxazepane-3-yl methoxy)phenyl]piperazine-1-yl]phenyl]-2-[(2S,3S)-2-hydroxypent-3-yl]-1,2,4-triazole-3-ib. Cov mis mos molecular yog C₃₇H₄₂F₂N₈O₄, thiab qhov hnyav molecular yog 700.78. Nws zoo nkaus li cov hmoov dawb los yog dawb crystalline hmoov, nrog lub melting point ntawm 170-172 degree. Nws yuav luag insoluble hauv dej, tab sis soluble nyob rau hauv cov organic solvents xws li chloroform thiab methanol.
Posaconazole exerts nws antifungal nyhuv los ntawm inhibiting lub biosynthesis ntawm ergosterol nyob rau hauv lub fungal cell daim nyias nyias, yog li ua rau kev ncaj ncees ntawm lub cell membrane. Nws muaj zog inhibitory kev ua si tawm tsam ntau yam nyuaj- rau- kho cov kab mob xws li Candida hom, Cryptococcus hom, thiab Aspergillus hom. Nws yog tshwj xeeb tshaj yog haum rau kev kho mob ntawm invasive fungal kab mob uas resistant mus rau lwm yam tshuaj antifungal.
Kev tsim khoom thiab kev sib txuas lus
Kev tsim cov posaconazole suav nrog ntau yam kev sib xyaw ua ke ntawm cov organic thiab yuav tsum muaj kev tswj xyuas meej ntawm cov tshuaj tiv thaiv kom tau txais cov khoom siab tshaj -purity. Cov hauv qab no yog ib qho kev piav qhia ntawm cov txheej txheem synthesis:
Kev xaiv cov khoom pib
Cov khoom pib muaj xws li 2'-chloro-2,4-difluorobenzoic acid lossis meta-difluorobenzene. Tus qub siv cov txheej txheem npaj reagent los hloov cov tshuaj tiv thaiv Wittig, nrog cov txheej txheem luv dua tab sis cov ntsiab lus isomer siab dua, xav tau ntau yam purifications; lub tom kawg yog synthesized los ntawm cov kauj ruam xws li Friedel-Crafts acylation, Wittig cov tshuaj tiv thaiv, thiab condensation amide, tab sis nws yog nquag mus tsim intramolecular nplhaib-forming impurities, uas cuam tshuam rau yield.
Synthesis ntawm tseem ceeb intermediates
Threeazole rings thiab oxacyclopentane cov qauv yog tsim los ntawm ntau yam kev cuam tshuam. Piv txwv li:
Siv 2,4-difluorobenzene ua cov khoom siv raw, ib pawg carbonyl tau qhia los ntawm Friedel-Crafts acylation, thiab tom qab ntawd ob daim ntawv cog lus yog tsim los ntawm Wittig cov tshuaj tiv thaiv. Tom qab ntawd, cov tshuaj tiv thaiv epoxidation yog nqa tawm los tsim lub nplhaib oxazepane.
Thaum qhia txog pawg 1,2,4-triazole, cov tshuaj tiv thaiv yuav tsum tau tswj kom tsis txhob tsim los ntawm- cov khoom. Feem ntau, kev hloov pauv nucleophilic lossis hlau-catalyzed coupling tshwm sim tau txais yuav.
Side chain modification thiab coupling
Lub hydroxyl pentyl sab saw txuas nrog lub nplhaib triazole los ntawm alkylation lossis acylation cov tshuaj tiv thaiv los tsim cov txheej txheem molecular kawg. Cov kauj ruam no yuav tsum muaj kev tswj xyuas qhov kub thiab txias thiab xaiv cov kuab tshuaj kom paub meej qhov chaw ntawm cov saw hlau sab.
Purification thiab crystallization
Cov khoom siv hluavtaws yuav tsum tau ua kom huv los ntawm kab chromatography, recrystallization, los yog npaj siab -kev ua tau zoo kua chromatography (HPLC) kom tshem tawm isomers thiab impurities. Cov txheej txheem crystallization (xws li hnyav, qhov kub thiab txias, thiab pH tus nqi) muaj qhov cuam tshuam loj rau purity thiab crystal daim ntawv ntawm cov khoom, thiab yuav tsum tau ua kom zoo kom tau cov hmoov crystalline uas ua tau raws li cov qauv ntawm cov tshuaj pharmacopoeia.
Kev Tswj Xyuas Zoo thiab Cov Qauv
Qhov zoo ntawm posaconazole hmoov yuav tsum ua raws li cov lus qhia tseem ceeb hauv qab no:
Purity
Los ntawm kev kuaj HPLC, tag nrho cov ntsiab lus impurity yuav tsum tsawg dua lossis sib npaug li 1.0%, thiab txhua tus neeg tsis huv yuav tsum tsawg dua lossis sib npaug li 0.2%. Rau siab -cov khoom purity (Ntau dua lossis sib npaug li 99.5%), cov txheej txheem purification yuav tsum nruj dua xws li ntau yam recrystallizations lossis chromatographic sib cais.
Lub cev muaj zog
Melting point: 170 - 172 degree, txheeb xyuas qhov sib txawv scanning calorimetry (DSC).
Kev sib hloov tshwj xeeb: -28.0℃rau -34.0 degree, cuam tshuam qhov purity ntawm chiral center.
Cov ntsiab lus dej: Tsawg dua lossis sib npaug li 2.0%, txiav txim siab los ntawm Karl Fischer txoj kev.
Cov kuab tshuaj residual thiab cov hlau hnyav
Raws li ICH cov lus qhia, cov kuab tshuaj residual (xws li methanol, ethanol, dichloromethane) yuav tsum tau tswj nyob rau hauv kev txwv tsis pub dhau; Cov ntsiab lus ntawm cov hlau hnyav (xws li txhuas, arsenic) yuav tsum tsawg dua lossis sib npaug li 10 ppm.
Microbial txwv
Ua raws li cov cai tswj hwm microbial contamination ntawm cov tshuaj pharmacopoeia rau cov khoom tsis yog -sterile raw cov ntaub ntawv, xws li tag nrho cov kab mob aerobic suav tsawg dua lossis sib npaug li 1000 CFU/g, pwm thiab cov poov xab suav tsawg dua lossis sib npaug li 100 CFU/g..
Txheej txheem Optimization thiab Innovation
Nyob rau hauv xyoo tas los no, kev tsim cov txheej txheem ntawm posaconazole tau ua kom zoo dua qub los txo cov nqi thiab txhim kho ib puag ncig tus phooj ywg:
Green Chemistry Application
Siv dej raws li cov kuab tshuaj los yog qis dua - cov kuab tshuaj lom neeg cov kuab tshuaj (xws li ethyl acetate), txo kev siv cov pa phem heev xws li roj av ether. Qee cov kauj ruam tshuaj tiv thaiv yog hloov los ntawm catalytic hydrogenation es tsis txhob siv cov tshuaj txo cov tshuaj (xws li sodium borohydride), yog li txo cov khoom pov tseg.
Nruam Flow Reaction Technology
Qhia microreactors lossis cov khoom siv tas mus li kom ua tiav kev tswj xyuas cov xwm txheej ntawm cov tshuaj tiv thaiv, txhim kho cov tshuaj tiv thaiv kev xaiv thiab tawm los, thiab ua kom lub voj voog ntau lawm.
Chiral Synthesis Technology
Tsim cov chiral catalysts tshiab los yog asymmetric synthesis txoj hauv kev kom tau ncaj qha mus rau optically ntshiab intermediates, txo cov kauj ruam ntawm isomer sib cais thiab txo nqi ntau lawm.
Txheej txheem Scaling thiab Stability Studies
Txheeb xyuas qhov ua tau ntawm cov txheej txheem los ntawm kev sim- ntsuas ntsuas thiab ua qhov ntev- cov kev tshawb fawb ruaj khov (xws li kev sim nrawm thiab ntev- kev sim ntsuas) kom ntseeg tau tias cov khoom ruaj khov zoo thaum khaws cia.
Ntim thiab Cia
Posaconazole hmoov yuav tsum tau muab cia rau hauv qhov chaw qhuav thiab tsaus, kaw, tiv thaiv kom tsis txhob ya raws thiab degradation. Cov ntaub ntawv ntim khoom pom zoo yog cov hnab aluminium foil los yog siab -cov khoom ntim polyethylene (HDPE) fwj, lined nrog desiccants. Qhov ntsuas kub tau pom zoo yog 2-8℃. Qee cov khoom tuaj yeem khaws cia hauv chav sov (tsawg dua lossis sib npaug li 25 degree) rau lub sijhawm luv. Thaum lub sij hawm kev thauj mus los, tsis txhob muaj kev vibrations hnyav thiab ib puag ncig kub.
Daim Ntawv Thov thiab Kev Ua Lag Luam Zoo
Posaconazole hmoov tsuas yog siv rau kev npaj ntawm qhov ncauj tshem tawm, ntsiav tshuaj lossis txhaj tshuaj. Nws yog siv nyob rau hauv kev kho mob rau kev tiv thaiv thiab kev kho mob ntawm invasive fungal kab mob nyob rau hauv cov neeg mob uas tsis muaj zog tiv thaiv kab mob. Nrog rau kev loj hlob ntawm kev lag luam tshuaj tua kab mob, qhov kev thov rau posaconazole tseem nce ntxiv. Cov neeg tsim khoom yuav tsum tau them sai sai rau cov qauv hauv qab no:
Kev loj hlob tshuaj ntsuab
Tom qab patent tas sij hawm, cov tuam txhab tshuaj generic yuav nkag mus rau hauv kev ua lag luam, tsav cov nqi qis thiab nce kev nkag mus tau yooj yim.
Kev tshawb nrhiav kev tsim kho tshiab
Kev xa khoom tshiab xws li nanocrystals thiab liposomes tuaj yeem txhim kho bioavailability thiab txo cov kev mob tshwm sim.
Ntiaj teb no kev lag luam expansion
Kev thov rau siab -cov tshuaj tiv thaiv kab mob siab kawg hauv cov lag luam tawm tshiab (xws li Asia-Pacific thiab Latin America) tab tom loj hlob, muab sijhawm rau cov tuam txhab lag luam.
Kev sib cuam tshuam ntawm cov tshuaj thiab contraindications
CYP3A4 substrate:
Muaj zog inhibitor:Posaconazole hmoovyog ib tug muaj zog CYP3A4 inhibitor. Thaum siv ua ke nrog sirolimus thiab tacrolimus, tom kawg cov ntshav siab tuaj yeem nce 9 zaug, thiab qhov ntau npaum li cas yuav tsum tau kho thiab saib xyuas kom zoo.
Substrate contraindications: Tsis txhob siv ua ke nrog ergot alkaloids (xws li ergotamine), pimozide, thiab quinidine, vim nws tuaj yeem ua rau mob hnyav lossis ergot lom.
Lwm yam kev sib tham
Cyclosporine: Thaum siv ua ke, qhov ntau npaum ntawm cyclosporine yuav tsum tau hloov kho thiab cov trough concentration ntawm tag nrho cov ntshav yuav tsum tau saib xyuas kom tsis txhob muaj nephrotoxicity thiab cov kab mob dawb.
Changchun alkaloids: Kev siv sib xyaw ua ke tuaj yeem txhim kho neurotoxicity, thiab qhov kev pheej hmoo rov qab yuav tsum tau ua tib zoo soj ntsuam.
HMG CoA reductase inhibitors
Thaum ua ke nrog atorvastatin, lovastatin, thiab simvastatin, qhov nce hauv cov ntshav siab tom kawg tuaj yeem ua rau rhabdomyolysis, thiab yuav tsum tau zam lossis hloov nrog statins uas tsis tshua muaj nyob ntawm CYP3A4 (xws li pravastatin).
Contraindication
Nws yog contraindicated rau cov tib neeg tsis haum rau posaconazole los yog lwm yam tshuaj triazole.
Cov neeg mob uas muaj mob hnyav arrhythmia lossis congenital QT interval prolongation syndrome yog contraindicated.
FAQ
1. Solubility ntawm hmoov thiab cia cov lus pom zoo
Posaconazole hmoov yog soluble hauv dimethyl sulfoxide (DMSO) hauv kev sim hauv vitro. Nws tuaj yeem yaj ntawm qhov ntau ntawm 100 mg / mL lossis 140 mg / mL, tab sis yog insoluble hauv dej thiab ethanol. Txhawm rau tswj nws txoj kev ruaj ntseg, cov hmoov yuav tsum tau khaws cia ntawm qhov kub thiab txias: nws raug nquahu kom khaws cia rau hauv lub teeb - pov thawj, ntim ntim ntawm 2-8 degree, lossis ntawm -20 degree, qhov twg nws tuaj yeem ruaj khov mus txog 3 xyoos.
2. Kev siv cov hmoov nplej yog dab tsi?
Posaconazole yog ib qho dav -spectrum triazole tshuaj tiv thaiv kab mob. Hauv kev tshawb fawb, nws feem ntau yog siv los ua tus neeg sawv cev kho mob, feem ntau yog sterol C14 demethylase inhibitor, los ntawm inhibiting cov synthesis ntawm ergosterol nyob rau hauv fungi kom puas cov fungal cell membrane thiab exert antifungal teebmeem. Nws yog feem ntau siv los kawm txog nws cov haujlwm inhibitory tiv thaiv ntau yam fungi (xws li Candida, Aspergillus).
3. Yuav npaj li cas hauv vivo formulations rau kev sim tsiaj?
Thaum ua nyob rau hauv vivo tsiaj thwmsim, posaconazole feem ntau yog muab raws li ib tug uniform ncua kev kawm ntawv. Ib txoj hauv kev zoo tshaj plaws yog kom tawg cov hmoov hauv cov tshuaj sodium carboxymethyl cellulose (CMC-Na), piv txwv li, npaj ib qho kev ncua ntawm 5 mg / mL rau kev siv qhov ncauj. Nws yuav tsum tau muab sau tseg tias muaj cov zaub mov (tshwj xeeb tshaj yog siab- cov zaub mov muaj roj) ua rau kom muaj bioavailability ntawm posaconazole hauv lub cev.
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