Shaanxi BLOOM Tech Co., Ltd. yog ib qho ntawm cov tuam ntxhab thiab cov muag khoom ntawm itraconazole 500mg hauv Suav teb. Txais tos rau cov lag luam wholesale bulk zoo siab itraconazole 500mg rau muag ntawm no los ntawm peb lub hoobkas. Kev pabcuam zoo thiab tus nqi tsim nyog muaj.
Itraconazole 500 mgnrog rau qhov tshwj xeeb ntawm 500mg, txheeb xyuas los ntawm CAS naj npawb 84625-61-6 thiab cov mis mos molecular C₃₅H₃₈Cl₂N₈O₄, yog cov tshuaj hluavtaws triazole antifungal uas muaj lub cev thiab tshuaj lom neeg. Nyob rau hauv tus txheej txheem ntawm chav tsev kub (20-25 degree) thiab atmospheric siab tej yam kev mob, cov compound no tshwm sim raws li ib tug greyish-dawb mus rau daj ntseg daj crystalline hmoov, uas yog visually characterized los ntawm ib tug zoo, uniform particle zoo nkauj yam tsis pom tseeb agglomeration nyob rau hauv nws pib qhuav lub xeev. Olfactorily, nws tsis muaj ntxhiab los yog emits ib tug faint, tshwj xeeb tsw uas tsis pungent thiab yog muaj nyob rau hauv nws cov qauv tshuaj, ua rau nws txawv los ntawm lwm yam zoo li antifungal hmoov.
Hais txog cov khoom siv hmoov, itraconazole nthuav tawm cov dej ntws zoo thaum khaws cia hauv qhov chaw qhuav, ib qho tseem ceeb uas pab txhawb kev ua haujlwm xws li hnyav, hloov pauv, thiab pib sib xyaw thaum lub sijhawm tsim tshuaj. Qhov dej ntws zoo no yog ntaus nqi rau cov qauv crystalline tsis tu ncua ntawm nws cov khoom thiab qhov qis adhesion ntawm cov khoom qhuav. Txawm li cas los xij, cov hmoov yog hygroscopic heev, txhais tau tias nws muaj lub siab nyiam nqus dej los ntawm cov huab cua ib puag ncig. Thaum raug rau ib puag ncig nrog cov av noo ntau tshaj 60%, qhov saum npoo ntawm cov khoom yuav maj mam nqus cov dej molecules, ua rau kom cov viscosity nce ntxiv thiab inter-particle cohesion. Qhov no thaum kawg ua rau clumping, caking, los yog agglomeration mus rau hauv me me lumps, uas hnyav heev impairs nws processability. Yog li ntawd, kev cia khoom nruj yog qhov yuav tsum tau ua: nws yuav tsum tau khaws cia rau hauv lub thawv ntim khoom uas ua los ntawm cov dej noo- cov ntaub ntawv pov thawj (xws li txhuas- cov khoom ntim yas lossis iav fwj nrog cov roj hmab stoppers) thiab khaws cia rau hauv lub tsev muag khoom qhuav nrog cov av noo tswj (cov av noo tsawg dua lossis sib npaug li 50%) thiab kom tsis txhob muaj cov dej noo ncaj qha ntawm lub xeev.
Cov ntaub ntawv ntxiv ntawm chemical compound:
Peb cov khoom tsim
Itraconazole COA
Lub solubility ntawm itraconazole yog ib qho ntawm nws cov khoom tseem ceeb tshaj plaws ntawm lub cev, uas ncaj qha txiav txim siab cov tshuaj nqus tau zoo thiab cov qauv tsim qauv.
Solubility
Solubility dej tsis zoo:
Nyob rau hauv nruab nrab pH tej yam kev mob, lub saturated solubility ntawmitraconazole 500 mgHauv cov kua dej aqueous tsawg dua 1ng / mL, thiab nws yuav luag insoluble hauv dej. Cov yam ntxwv no yog vim muaj cov pab pawg muaj zog hydrophobic hauv nws cov qauv molecular, xws li dichlorophenyl, triazole nplhaib, thiab piperazine nplhaib, uas ua rau nws nyuaj rau cov tshuaj yaj thiab nqus hauv plab hnyuv.
Organic hnyav solubility:
Itraconazole yog soluble hauv cov kuab tshuaj organic xws li chloroform (50mg / mL), dimethyl sulfoxide (DMSO), thiab N, N-dimethylformamide (DMF), tsim cov tshuaj pob tshab. Cov yam ntxwv no yog siv rau hauv kev tshuaj xyuas tshuaj kom yaj cov qauv rau kev txiav txim siab cov ntsiab lus lossis kev txheeb xyuas cov qauv.
PH-dependent dissolution:
Nyob rau hauv ib puag ncig acidic xws li gastric acid, solubility ntawm itraconazole me ntsis nce, tab sis nws tseem tsis txaus los txhawb nws qhov ncauj nqus. Yog li ntawd, cyclodextrin inclusion technology (xws li tsim ib qho 1: 1 inclusion complex nrog hydroxypropyl - - cyclodextrin) los yog nanocrystal technology feem ntau yog siv nyob rau hauv formulations kom cov tshuaj solubility mus rau 5-10mg / mL, yog li no ho txhim kho bioavailability.
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Melting point thiab boiling point
Melting point:
Lub melting point range ntawm itraconazole yog 165-169 degree, uas yog qhov tseem ceeb hauv kev kuaj tshuaj purity. Itraconazole nrog ntau dua purity nthuav qhia cov ntsiab lus ntawm qhov sib txawv ntawm qhov sib txawv scanning calorimetry (DSC), thaum lub xub ntiag ntawm impurities tuaj yeem ua rau txo qis hauv melting point lossis widening ntawm melting ntau.
Boiling point:
Qhov ntsuas kub tau kwv yees yog 850 ± 75 degree, tab sis hauv kev tshawb fawb tiag tiag, nws raug ntsuas ncaj qha vim qhov pheej hmoo ntawm decomposition tsawg. Cov yam ntxwv kub kub kub qhia tau hais tias itraconazole ruaj khov nyob rau hauv cov pa distillation tej yam kev mob, tab sis yuav tsum tau saib xyuas kom tsis txhob oxidative degradation los ntawm kub kub.
Qhov ceev thiab kev sib hloov tshwj xeeb
Ceev:
Qhov ceev ntawm itraconazole yog 1.27g / cm ³ (qee cov ntaub ntawv qhia nws li 1.4g / cm ³), uas yog siv nyob rau hauv cov ntsiav tshuaj compression txheej txheem los xam lub ntim thiab qhov hnyav ntawm cov ntsiav tshuaj thiab xyuas kom meej npaum li cas.
Kev sib hloov tshwj xeeb:
Hauv cov tshuaj dichloromethane (concentration 10mg / mL, 20 degree), qhov tshwj xeeb kev sib hloov ntawm itraconazole yog -0.1℃rau +0.1 degree, qhia txog qhov siab symmetry ntawm chiral center nyob rau hauv nws cov qauv molecular thiab ib tug racemic ratio ze rau 1: 1. Cov yam ntxwv no yuav tsum muaj kev tswj hwm nruj ntawm stereoselectivity hauv cov tshuaj synthesis kom tsis txhob muaj kev hloov pauv tau los ntawm qhov sib txawv hauv kev ua enantiomeric.
Itraconazole 500 mgyog ib qho dav -spectrum triazole antifungal tshuaj, thiab nws cov txheej txheem synthesis koom nrog ntau yam tshuaj tiv thaiv, xav tau kev tswj xyuas meej ntawm cov tshuaj tiv thaiv kom ua tiav kev npaj cov khoom lag luam. Cov hauv qab no yog cov lus piav qhia ntxaws txog nws txoj kev sib xyaw ua ke:
Classic multi-txoj kev synthesis txheej txheem
Pib los ntawm m-dichlorobenzene, ib tug tseem ceeb niam core thiab sab saw qauv tau tsim los ntawm ntau yam - cov kauj ruam cov tshuaj tiv thaiv. Txoj kev no siv cov qauv tsim los faib cov molecules nyuaj rau hauv ob ntu: niam txiv nucleus (Ia) thiab sab saw (Ib), uas tau muab sib xyaw sib cais thiab docked kom txo tau cov tshuaj tiv thaiv nyuaj.
Cov tshuaj tiv thaiv condensation: m-dichlorobenzene yog condensed nrog 1H-1,2,4-triazole nyob rau hauv alkaline tej yam kev mob (xws li catalyzed los ntawm poov tshuaj carbonate) los ua intermediate IIa.
Hydrolysis thiab deacetylation: IIa yog hydrolyzed nrog sodium hydroxide kom tshem tawm cov acetyl tiv thaiv pawg, ua rau IIIa.
Methanesulfonate esterification: IIIa reacts nrog methylsulfonyl chloride ntawm qhov kub thiab txias (5 degree) los tsim methanesulfonate Ia, uas muab cov chaw ua haujlwm rau kev sib txuas txuas ntxiv tom ntej.
Cov ntsiab lus tseem ceeb tswj:
Cov tshuaj tiv thaiv condensation yuav tsum tau tswj qhov kub thiab txias (130 degree) kom tsis txhob muaj kev cuam tshuam sab nraud;
Methanesulfonic acid esterification yuav tsum tau qis - kub ua haujlwm los tiv thaiv ester bond hydrolysis, thiab cov txiaj ntsig tuaj yeem ncav cuag 85%.
Nitration thiab Txo: Siv 1- (4-methoxyphenyl) piperazine hydrobromide ua raw khoom, nws yog condensed nrog p-chloronitrobenzene rau daim IIb, uas yog txo mus rau IIIb los ntawm hydrogenation catalyzed los ntawm active nickel (yield 81.3%).
Chloroformate acylation: IIIb reacts nrog triphosgene los tsim chloroformate IVb, uas ces cyclizes nrog hydrazine hydrate rau Vb (yield 67.4%).
Alkylation thiab deprotection: Vb yog alkylated nrog 2-bromobutane los tsim VIb, uas yog ces deprotected nyob rau hauv hydrobromic acid tej yam kev mob kom tau ib sab saw Ib (yield 82%).
Cov ntsiab lus tseem ceeb tswj:
Nitro txo yuav tsum tswj hwm hydrogen siab kom tsis txhob txo qis ntau dhau;
Cov tshuaj tiv thaiv alkylation xav tau qhov sib ntxiv ntawm alkali thiab halogenated hydrocarbons hauv cov khoom siv txhawm rau txhawm rau tiv thaiv sab.
Nyob rau hauv alkaline tej yam kev mob (xws li KOH / DMF system), Ia thiab Ib condense rau crude itraconazole, uas yog purified los ntawm toluene recrystallization kom tau ib tug dawb hmoov produts (tag nrho yield 22.28%).
Qhov zoo:
Modular tsim txhim kho cov tshuaj tiv thaiv kev tswj;
Cov txiaj ntsig ntawm txhua kauj ruam yog qhov ruaj khov thiab tsim nyog rau kev tsim khoom lag luam.
txwv:
Siv cov kuab tshuaj lom xws li chloroform thiab dioxane;
Qee cov kauj ruam yuav tsum muaj cov catalysts kim (xws li triphosgene).
Convergent synthesis optimization txoj kev
Txais yuav "kev sib koom ua ke" los ua kom sib koom ua ke npaj cov niam txiv tub ntxhais thiab cov saw hlau sab, ua kom lub voj voog tag nrho cov tshuaj tiv thaiv luv luv. Piv txwv li:
Niam nucleus synthesis: Siv 2,4-dichloroacetophenone ua raw khoom, Ia yog tsim los ntawm 6 kauj ruam ntawm cov tshuaj tiv thaiv (condensation, hydrolysis, esterification, thiab lwm yam);
Side saw synthesis: Pib los ntawm 1- (4-methoxyphenyl) piperazine, Ib yog generated los ntawm 7 kauj ruam ntawm cov tshuaj tiv thaiv (nitration, txo, cyclization, thiab lwm yam).
Optimization point:
Txhim kho kev ua haujlwm ntawm nitration cov tshuaj tiv thaiv los ntawm theem hloov catalysis (xws li TEBA);
Siv DMSO / DMF cov kuab tshuaj sib xyaw kom txo tau cov kuab tshuaj hloov pauv.
Nyob rau hauv cov xwm txheej alkaline (pH 12-14), Ia thiab Ib tau condensed ntawm 80℃rau 5 teev. Tom qab tshem tawm cov kuab tshuaj los ntawm lub tshuab nqus tsev distillation, cov khoom tau muab rho tawm nrog chloroform thiab purified los ntawm recrystallization los ntawm toluene (yield 80.3%).
Kev txhim kho tseem ceeb:
Qhia theem hloov pauv catalysts (TEBA) kom nrawm cov tshuaj tiv thaiv;
Kev siv lub tswv yim stepwise alkali ntxiv los tswj cov tshuaj tiv thaiv tus nqi.
Lwm yam tshuaj lom cov kuab tshuaj: Hloov benzene nrog toluene thiab dioxane nrog THF;
Cov kuab tshuaj rov qab: DMF thiab DMSO tau rov qab los ntawm lub tshuab nqus tsev distillation, nrog tus nqi rov ua dua ntawm 85%.
Environmental txiaj ntsig:
Txo cov hluav taws xob tsis zoo (VOC) emissions;
Txo cov nqi tsim khoom (cov nqi hnyav txo los ntawm 30%).
Pharmacokinetics: qhov ncauj nqus thiab faib cov ntaub so ntswg
Cov yam ntxwv ntawm pharmacokinetic ntawmItraconazole 500 mgcapsules ncaj qha cuam tshuam rau lawv cov kev ua tau zoo thiab kev nyab xeeb, thiab nkag siab txog lawv qhov nqus, faib, metabolism, thiab cov txheej txheem excretion yog qhov tseem ceeb rau kev kho mob tshuaj.
- Absorb:
Kev tswj hwm tom qab noj mov: Itraconazole yog cov tshuaj muaj roj soluble uas tuaj yeem noj tam sim tom qab noj mov kom txhawb nqa cov kua tsib, ua kom cov tshuaj solubility, thiab nqus tau los ntawm kev siv cov roj hauv cov zaub mov. Kev tshawb fawb tau pom tias bioavailability ntawm cov tshuaj postprandial tuaj yeem ncav cuag 55%, thaum yoo mov tsuas yog tsawg dua 30%.
Lub sijhawm ncov: Tom qab kev tswj hwm qhov ncauj ntawm 200mg, cov ntshav tshuaj concentration nce mus txog qhov siab kawg ntawm 4.6 ± 1.3 teev (Cmax yog 0.32 ± 0.16 μ g / ml).
Dose dependence: Nyob rau hauv ntau npaum li cas ntawm 100-400mg, muaj ib tug linear kev sib raug zoo ntawm cov ntshav cov tshuaj concentration thiab koob tshuaj; Thaum nws ntau dua 400mg / hnub, qhov nqus tau tuaj yeem ua kom txaus, ua rau txo qis hauv bioavailability.
- Kev faib tawm:
Plasma protein binding tus nqi: mus txog 99.8%, feem ntau khi rau albumin, nrog tsis tshua muaj tshuaj dawb concentration, tab sis txaus los tiv thaiv cov kab mob.
Kev nkag mus rau hauv lub koom haum: Cov tshuaj concentration hauv lub cev xws li lub ntsws, lub raum, thiab daim siab yog 2-3 npaug ntawm cov ntshav plasma, thiab cov tawv nqaij concentration siab dua 4 npaug ntawm cov ntshav. Cov tshuaj concentration hauv cov ntsia hlau cuticle tuaj yeem khaws cia rau 6-9 lub hlis, ua rau nws tsim nyog rau kev kho mob ntev xws li onychomycosis.
Kev faib tawm tshwj xeeb: Hauv cov ntaub so ntswg qhov chaw mos, cov tshuaj concentration tuaj yeem kav ntev li 2 hnub tom qab kev kho mob nrog 0.2g ib hnub ib zaug rau 3 hnub; Kev kho mob 0.2g ob zaug hauv ib hnub rau 1 hnub tuaj yeem siv sijhawm li 3 hnub, muab lub hauv paus rau luv luv -kev kho mob ntawm vulvovaginal candidiasis.
- Metabolism:
Lub ntsiab metabolic enzymes: Metabolized los ntawm daim siab CYP3A4 enzyme rau hydroxylated itraconazole, nws cov tshuaj tiv thaiv kab mob sib npaug rau cov tshuaj qub. Qib ntawm cov tshuaj tiv thaiv kab mob uas ntsuas los ntawm kev tshuaj lom neeg yog kwv yees li peb npaug ntawm cov tshuaj thawj zaug tshuaj ntsuam xyuas los ntawm siab -siab kua chromatography.
Metabolites: Ntxiv nrog rau hydroxylation produts, me me ntawm demethylation, oxidation, thiab khi metabolites kuj tsim, tab sis cov tshuaj tiv thaiv kab mob tsis muaj zog.
- Tshem tawm:
Prototype drug excretion: Prototype drug excreted los ntawm feces account rau li 3-18% ntawm cov koob tshuaj siv, thaum prototype tshuaj tawm los ntawm ob lub raum account rau tsawg tshaj li 0.03%.
Metabolite excretion: Kwv yees li 35% ntawm cov metabolites raug tso tawm hauv cov zis hauv ib lub lis piam, thaum tus so yog tawm los ntawm cov kua tsib thiab quav.
Terminal ib nrab-lub neej: 23.8 ± 4.7 teev, txhawb nqa ib zaug lossis ob zaug kev noj tshuaj txhua hnub.
Nqe lus piav qhia
Nyob rau hauv cov ntsiab lus, itraconazole, raws li ib tug dav -spectrum triazole antifungal tshuaj, muaj cov yam ntxwv physicochemical zog, nrog rau cov yam ntxwv solubility thiab zoo-txhais melting thiab boiling cov ntsiab lus, uas nteg lub hauv paus ruaj khov rau nws cov kws kho mob kev loj hlob thiab formulation tsim. Nws cov synthesis suav nrog ntau yam tshuaj lom neeg cov tshuaj tiv thaiv uas xav tau kev tswj xyuas nruj ntawm cov tshuaj tiv thaiv, thiab cov txheej txheem kev sib xyaw ua ke zoo tshaj plaws tau txhim kho qhov ua tau zoo, tawm los, thiab purity ntawm nws cov kev npaj, muab kev txhawb zog rau kev lag luam loj -. Los ntawm qhov kev xav ntawm pharmacokinetics, nws qhov ncauj nqus cov yam ntxwv thiab cov qauv kev faib cov ntaub so ntswg txiav txim siab nws cov kev siv tshuaj kho mob thiab kev siv tshuaj kho mob, ua rau nws siv tshuaj tua kab mob hauv cov ntaub so ntswg thiab dhau los ua qhov kev xaiv txhim khu kev qha rau kev kho ntau yam kab mob fungal.
Saib ua ntej, txoj kev loj hlob ntawm itraconazole tuav cov zeem muag dav. Nrog rau kev sib zog ntawm kev tshawb fawb tshuaj, kev siv zog yuav raug tsom rau kev txhim kho nws cov solubility thiab bioavailability kom kov yeej cov kev txwv ntawm qhov ncauj tsis zoo thiab nthuav dav nws cov kev siv tshuaj kho mob. Nyob rau hauv cov nqe lus ntawm synthesis, ntxiv optimization ntawm convergent synthesis txheej txheem thiab kev tshawb fawb ntawm greener, tus nqi ntau dua -cov tshuaj tiv thaiv zoo yuav yog cov lus qhia tseem ceeb, aiming kom txo tau tej yam ib puag ncig thiab cov nqi ntau lawm thaum ua kom cov khoom zoo. Tsis tas li ntawd, nrog kev tshwm sim tsis tu ncua ntawm cov tshuaj- cov kab mob tiv thaiv kab mob, kev tshawb fawb ntawm kev sib txuas ntawm itraconazole nrog rau lwm cov tshuaj tiv thaiv kab mob lossis hloov kho nws cov qauv los txhim kho nws cov kev ua ub no tiv thaiv yeeb tshuaj- cov kab mob resistant yuav dhau los ua qhov kev tshawb fawb hotspot. Tsis tas li ntawd, kev tshawb nrhiav txog nws cov txiaj ntsig kho mob tshaj li kev ua haujlwm ntawm cov tshuaj tiv thaiv kab mob tuaj yeem qhib cov ntawv thov tshiab. Zuag qhia tag nrho, itraconazole yuav txuas ntxiv mus ua lub luag haujlwm tseem ceeb hauv kev kho tshuaj tiv thaiv kab mob, thiab kev siv thev naus laus zis txuas ntxiv yuav ua rau nws ua tau raws li qhov xav tau kev kho mob ntau dua yav tom ntej.
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