Sau / 1,2 Hu Rong 1 Hol drum Nruas Nkauj Xuzhi ua ntej 1 ncig saib Jinsong 1 - Tus tshiab 1, 2
【Cov Lus Qhia】 Borosilicate iav yog cov khoom ntim khoom siv dav siv thiab cov thawv ntim tshuaj hauv kev lag luam tshuaj.Txawm hais tias nws muaj cov yam ntxwv ntawm kev ua haujlwm siab, xws li du, corrosion kuj thiab hnav tsis kam, cov hlau ions thiab silanol pawg muaj nyob hauv borosilicate iav tseem tuaj yeem cuam tshuam nrog cov tshuaj.Hauv kev tshuaj xyuas cov tshuaj tshuaj los ntawm kev ua haujlwm siab ua kua chromatography (HPLC), cov tshuaj txhaj tshuaj yog borosilicate iav.Los ntawm kev soj ntsuam cov nyhuv ntawm HPLC iav vials ntawm peb hom ntawm kev ruaj ntseg ntawm solifenacin succinate uas yog ib qho tsis muaj zog alkaline compound, nws tau pom tias cov adsorption rau cov tshuaj alkaline muaj nyob hauv cov iav vials uas tsim los ntawm cov tuam txhab sib txawv.Cov adsorption feem ntau yog tshwm sim los ntawm kev sib cuam tshuam ntawm protonated amino thiab dissociative silanol pawg, thiab muaj cov succinate txhawb nws.Qhov sib ntxiv ntawm hydrochloric acid tuaj yeem desorb cov tshuaj los yog ntxiv qhov tsim nyog ntawm cov kuab tshuaj organic tuaj yeem tiv thaiv adsorption.Lub hom phiaj ntawm daim ntawv no yog kom nco ntsoov cov tshuaj ntsuam xyuas cov tuam txhab kom xyuam xim rau kev sib cuam tshuam ntawm cov tshuaj alkaline thiab iav, thiab txo cov ntaub ntawv sib txawv thiab kev tshawb nrhiav kev sib txawv los ntawm qhov tsis muaj kev paub txog cov yam ntxwv adsorption ntawm iav fwj hauv cov txheej txheem ntawm kev tshuaj xyuas tshuaj.
Cov lus tseem ceeb: Solifenacin succinate, amino pawg, HPLC iav vials, adsorb
iav raws li cov khoom ntim khoom muaj qhov zoo ntawm smoothness, yooj yim tshem tawm thiab corrosion kuj.Corrosion, hnav tsis kam, ntim stability thiab lwm yam zoo, yog li nws yog dav siv nyob rau hauv daim ntawv thov tshuaj.Cov iav tshuaj yog muab faib ua sodium calcium glass thiab borosilicate iav, raws li cov khoom sib txawv nws muaj.Ntawm lawv, soda txiv qaub iav muaj 71% ~ 75% SiO2, 12% ~ 15% Na2O, 10% ~ 15% CaO;borosilicate iav muaj 70% ~ 80% SiO2, 7% ~ 13% B2O3, 4% ~ 6% Na2O thiab K2O thiab 2% ~ 4% Al2O3.Borosilicate iav muaj cov tshuaj tiv thaiv zoo heev vim yog siv B2O3 es tsis txhob ntawm Na2O thiab CaO feem ntau.
Vim nws txoj kev tshawb fawb, nws tau raug xaiv los ua lub thawv loj rau cov tshuaj ua kua.Txawm li cas los xij, boronSilicone iav, txawm tias nws muaj kev tiv thaiv siab, tseem tuaj yeem cuam tshuam nrog cov tshuaj, Muaj plaub hom tshuaj tiv thaiv raws li hauv qab no [1]:
1) Ion txauv: Na + , K + , Ba2 + , Ca2 + nyob rau hauv lub khob muab ion pauv nrog H3O + hauv cov tshuaj, thiab muaj cov tshuaj tiv thaiv ntawm cov ions sib pauv thiab cov tshuaj;
2) Cov iav tawg: Phosphate, oxalate, Citrates thiab tartrates yuav ua rau kom cov iav tawg thiab ua rau silicides.thiab Al3+ raug tso tawm rau hauv kev daws teeb meem;
3) Corrosion: EDTA tam sim no nyob rau hauv cov tshuaj tov (EDTA) yuav complex nrog divalent ions los yog trivalent ions nyob rau hauv lub khob
4) Adsorption: Muaj qhov tawg Si-O daim ntawv cog lus ntawm lub iav nto, uas tuaj yeem adsorb H +
Kev tsim ntawm OH- tuaj yeem tsim cov ntawv cog lus hydrogen nrog qee cov pab pawg hauv cov tshuaj, uas ua rau cov tshuaj raug adsorbed rau iav nto.
Feem ntau cov tshuaj muaj cov pab pawg amine tsis muaj zog, Thaum tshuaj xyuas cov tshuaj siv tshuaj nrog kev ua haujlwm siab ua kua chromatography (HPLC), feem ntau siv HPLC autosampler vial uas yog ua los ntawm borosilicate iav, thiab muaj SiO- ntawm lub iav nto yuav cuam tshuam nrog pawg amine protonated. , tso cai rau cov tshuaj density txo, qhov kev soj ntsuam cov txiaj ntsig yuav tsis raug, thiab kuaj OOS (Tawm ntawm Specification).Hauv tsab ntawv ceeb toom no, qhov tsis muaj zog hauv paus (pKa yog 8.88 [2]) tshuaj solifenacin succinate (cov qauv qauv qhia hauv daim duab 1) yog siv los ua cov khoom tshawb fawb, thiab kev cuam tshuam ntawm ob peb amber borosilicate iav txhaj tshuaj vials ntawm kev lag luam ntawm kev tshuaj xyuas tshuaj. yog soj ntsuam., thiab los ntawm kev txheeb xyuas qhov pom los nrhiav kev daws teeb meem rau adsorption ntawm cov tshuaj no ntawm iav.
1.Test part
1.1 Cov khoom siv thiab cov khoom siv rau kev sim
1.1.1 Khoom siv: Agilent High Efficiency nrog UV Ntes
Ua kua chromatography
1.1.2 Cov ntaub ntawv sim: Solifenacin succinate API yog tsim los ntawm Alembic
Pharmaceuticals Ltd. (India).Solifenacin tus qauv (99.9% purity) tau yuav los ntawm USP.ARgrade potassium dihydrogen phosphate, triethylamine, thiab phosphoric acid tau yuav los ntawm Tuam Tshoj Xilong Technology Co., Ltd. Methanol thiab acetonitrile (ob qib HPLC) tau yuav los ntawm Sibaiquan Chemical Co., Ltd. Polypropylene (PP) fwj tau yuav los ntawm ThermoScientific (US) , thiab 2ml amber HPLC iav fwj tau yuav los ntawm Agilent Technologies (China) Co., Ltd., Dongguan Pubiao Laboratory Equipment Technology Co., Ltd., thiab Zhejiang Hamag Technology Co., Ltd. (A, B, C yog siv hauv qab no los sawv cev sib txawv ntawm cov iav vials, ntsig txog).
1.2 HPLC txoj kev tsom xam
1.2.1Solifenacin succinate thiab solifenacin dawb puag: chromatographic kem isphenomenex luna®C18 (2), 4.6 mm × 100 mm, 3 µm.Nrog phosphate buffer (hnyav 4.1 g ntawm poov tshuaj dihydrogen phosphate, hnyav 2 ml ntawm triethylamine, ntxiv rau 1 L ntawm ultrapure dej, do kom yaj, siv phosphoric acid (pH raug kho rau 2.5)-acetonitrile-methanol (40:30:30) raws li lub sijhawm mobile,
Daim duab 1 Cov qauv qauv ntawm solifenacin succinate
Daim duab 2 Kev sib piv ntawm thaj chaw ncov ntawm tib txoj kev daws teeb meem ntawm solifenacin succinate hauv PP vials thiab iav vials los ntawm peb lub tuam txhab A, B, thiab C
Qhov ntsuas kub yog 30 ° C, tus nqi ntws yog 1.0 mL / min, thiab qhov ntim ntim yog 50 mL, qhov ntsuas qhov ntev yog 220 nm.
1.2.2 Succinic acid qauv: siv YMC-PACK ODS-A 4.6 mm × 150 mm, 3 µm kem, 0.03 mol/L phosphate tsis (hloov rau pH 3.2 withphosphoric acid)-methanol (92:8) raws li theem mobile, ntws tus nqi 1.0 mL / min, kem kub 55 ° C, thiab qhov ntim ntim yog 90 mL.Chromatograms tau txais ntawm 204 nm.
1.3 ICP-MS txoj kev tsom xam
Cov ntsiab lus hauv kev daws teeb meem tau txheeb xyuas siv Agilent 7800 ICP-MS system, kev tshuaj ntsuam hom yog Nws hom (4.3mL / min), RF lub zog yog 1550W, plasma gasflow tus nqi yog 15L / min, thiab cov cab kuj gas flow rate. yog 1.07 mL/min.Cov huab cua kub yog 2 ° C, lub twj tso kua mis peristaltic lifting / stabilizing ceev yog 0.3 / 0.1 rps, cov qauv stabilizationtime yog 35 s, cov qauv nqa lub sij hawm yog 45 s, thiab qhov tob sau yog 8 hli.
Kev npaj ua qauv
Solifenacin succinate tov: npaj nrog dej ultrapure, qhov concentration yog 0.011 mg / mL.
1.4.2 Succinic acid tov: npaj nrog dej ultrapure, qhov concentration yog 1mg / mL.
1.4.3 Solifenacin tov: yaj solifenacin succinate hauv dej, sodium carbonate tau ntxiv, thiab tom qab cov tshuaj hloov los ntawm cov xim tsis muaj xim tomilky dawb, ethyl acetate tau ntxiv.Tom qab ntawd cov txheej txheem ethyl acetate tau sib cais thiab cov kuab tshuaj tau evaporated los muab solifenacin.Solifenacin inethanol uas tsim nyog (ethanol account rau m 5% hauv cov tshuaj kawg), thiab tom qab ntawd dilute nrog dej los npaj cov tshuaj nrog ib qho concentration ntawm 0.008 mg / mL solifenacin (nrog rau cov tshuaj solifenacin succinate muaj nyob rau hauv cov tshuaj tib yam li solifenacin. concentration).
Cov txiaj ntsig thiab kev sib tham
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2.1 Adsorption muaj peev xwm ntawm HPLC vials ntawm ntau hom
Dispense tib cov tshuaj aqueous ntawm solifenacin succinate rau hauv PP vials thiab 3 hom autosampler vials raug txhaj rau ib ntus hauv tib qhov chaw, thiab thaj chaw ncov ntawm lub ncov loj tau sau tseg.Los ntawm cov txiaj ntsig hauv daim duab 2, nws tuaj yeem pom tias thaj chaw ncov ntawm PP vials yog qhov ruaj khov, thiab yuav luag tsis muaj kev hloov pauv tom qab 44 h.Thaum lub ncov thaj chaw ntawm peb hom iav vials ntawm 0 h me dua PP lub raj mis. , thiab thaj chaw ncov tseem txo qis thaum lub sijhawm khaws cia.
Daim duab 3 Kev hloov pauv hauv thaj chaw ncov ntawm solifenacin, succinic acid, thiab solifenacin succinate aqueous daws khaws cia hauv iav vials thiab PP vials
Txhawm rau kawm ntxiv txog qhov tshwm sim no, solifenacin, succinate acid, Aqueous daws ntawm solifenacin acid thiab succinate hauv iav vials ntawm cov chaw tsim khoom Band PP fwj los tshawb xyuas qhov kev hloov pauv ntawm thaj chaw ncov nrog lub sijhawm, thiab tib lub sijhawm ntawm lub khob
Peb cov kev daws teeb meem hauv vials tau sib txuas ua ke siv Agilent 7800 ICP-MSPlasma huab hwm coj spectrometer rau kev tsom xam.Cov ntaub ntawv hauv daim duab 3 qhia tias hauv iav vials hauv nruab nrab aqueous tsis adsorb succinic acid, tab sis adsorbed solifenacinFree puag thiab solifenacin succinate.Cov iav vials adsorb succinate.Qhov twg ntawm linacin muaj zog dua li ntawm solifenacin dawb puag, thaum pib lub sijhawm Solifenacin succinate thiab solifenacin dawb puag hauv iav vials.Qhov sib piv ntawm thaj chaw ncov ntawm cov kev daws teeb meem muaj nyob rau hauv PP fwj yog 0.94 thiab 0.98, raws li.
Nws yog feem ntau ntseeg hais tias qhov saum npoo ntawm silicate iav tuaj yeem nqus tau qee cov dej, uas qee cov dej sib xyaw nrog Si4 + hauv daim ntawv ntawm OH pawg los tsim cov pab pawg silanol Hauv cov muaj pes tsawg leeg ntawm oxide iav, polyvalent ions tsis tuaj yeem txav mus, tab sis alkali hlau (xws li. Na + ) thiab alkaline ntiaj teb hlau ions (xws li Ca2+) tuaj yeem txav tau thaum muaj xwm txheej tso cai, tshwj xeeb tshaj yog alkali hlau ions yooj yim rau ntws, tuaj yeem pauv nrog H + adsorbed rau ntawm iav nto thiab Hloov mus rau iav nto los ua silanol pawg [3-4].Yog li, H + concentration ntawm qhov nce tuaj yeem txhawb kev sib pauv ion kom nce cov silanol pawg ntawm cov iav nto.los ntawm table1 qhia tau hais tias cov ntsiab lus ntawm B, Na, thiab Ca hauv cov tshuaj sib txawv ntawm qhov siab mus rau qis.yog succinic acid, solifenacin succinate thiab solifenacin.
Qauv B (μg/L) Na(μg/L) Ca(μg/L) Al(μg/L) Si(μg/L) Fe(μg/L)
dej 2150 3260 20 Tsis paub 1280 4520
Succinic acid 3380 5570 400 429 1450 139720
Solifenacin Succinate Solution 2656 5130 380 Tsis Tshawb Pom 2250 2010
Solifenacin daws 1834 2860 200 Tsis Tshawb Pom 2460 Tsis Pom
Table 1 Elemental concentrations of solifenacin succinate, solifenacin thiab succinic acid aqueous solutions khaws cia hauv iav vials rau 8 hnub
Tsis tas li ntawd, nws tuaj yeem pom los ntawm cov ntaub ntawv hauv Table 2 tias tom qab tso rau hauv cov iav fwj rau 24 teev, cov dej yaj cov pH ntawm cov kua tau nce.Qhov tshwm sim no yog ze rau qhov kev xav saum toj no
Vial No. Tus nqi rov qab tom qab cia hauv iav rau 71 teev
(%) Tus nqi rov qab tom qab kho PH
Vial 1 97.07 100.35
Vial 2 98.03 100.87
Vial 3 87.98 101.12
Vial 4 96.96 100.82
Vial 5 98.86 100.57
Vial 6 92.52 100.88
Vial 7 96.97 100.76
Vial 8 98.22 101.37
Vial 9 97.78 101.31
Table 3 Desorption teeb meem ntawm solifenacin succinate tom qab ntxiv kua qaub
Txij li Si-OH ntawm lub iav nto tuaj yeem sib cais rau hauv SiO-[5] ntawm pH 2 ~ 12, thaum solifenacin tshwm sim N nyob rau hauv ib puag ncig acidic Protonation ( ntsuas pH ntawm aqueous tov ntawm solifenacin succinate yog 5.34, pH tus nqi ntawm solifenacin. kev daws yog 5.80), thiab qhov sib txawv ntawm ob qhov kev sib cuam tshuam ntawm Hydrophilic ua rau cov tshuaj adsorption ntawm iav nto (Fig. 3), solifenacin tau adsorbed ntau thiab ntau lub sij hawm.
Tsis tas li ntawd, Bacon thiab Raggon [6] kuj pom tias nyob rau hauv nruab nrab tov, hydroxy acids nrog ib pab pawg neeg hydroxyl nyob rau hauv txoj hauj lwm txheeb ze rau carboxyl pab pawg neeg ntsev tov tau extract oxidized silicion.Nyob rau hauv cov qauv molecular ntawm solifenacin succinate, muaj ib pab pawg neeg hydroxyl txheeb ze rau txoj hauj lwm ntawm carboxylate, uas yuav tawm tsam ntawm lub khob, SiO2 raug rho tawm thiab iav yog eroded.Yog li ntawd, tom qab ntsev tsim nrog succinic acid, qhov adsorption ntawm solifenacin hauv dej yog qhov pom tseeb dua.
2.2 Cov txheej txheem kom tsis txhob adsorption
Lub sijhawm khaws cia pH
0h5.50 ua
24.29 Nws 6
48h 6.24 ib
Table 2 pH hloov ntawm aqueous daws ntawm solifenacin succinate hauv iav fwj
Txawm hais tias PP vials tsis adsorb solifenacin succinate, Tab sis thaum lub sij hawm cia cov tshuaj nyob rau hauv PP vial, lwm yam impurity peaks yog generated thiab ncua sij hawm cia lub sij hawm maj mam nce lub impurity ncov cheeb tsam, uas ua rau cuam tshuam rau kev tshawb nrhiav ntawm lub ntsiab ncov. .
Yog li ntawd, nws yog ib qho tsim nyog los tshawb nrhiav ib txoj hauv kev uas tuaj yeem tiv thaiv iav adsorption.
Noj 1.5 mL ntawm solifenacin succinate aqueous tov nyob rau hauv ib khob vial.Tom qab muab tso rau hauv cov tshuaj rau 71 h, tus nqi rov qab tau qis dua.Ntxiv 0.1M hydrochloric acid, kho cov pH txog li 2.3, los ntawm cov ntaub ntawv hauv Table 3. Nws tuaj yeem pom tias cov nqi rov qab tag nrho rov qab mus rau qib qub, qhia tias cov tshuaj adsorption storagetime tuaj yeem inhibited ntawm qis pH.
Lwm txoj hauv kev yog txo cov adsorption los ntawm kev ntxiv cov kuab tshuaj organic.Ua 10%, 20%, 30%, 50% methanol, ethanol, isopropanol, acetonitrile tau npaj ntawm qhov concentration ntawm 0.01 mg / mL hauv Solifenacin succinate kua.Cov kev daws teeb meem saum toj no tau muab tso rau hauv iav vials thiab PP vials, feem.Nyob rau hauv chav tsev kub nws stability tau kawm qhia.Kev tshawb nrhiav pom tias cov kuab tshuaj organic tsawg dhau los tsis tuaj yeem tiv thaiv adsorption, thaum cov kuab tshuaj organic ntau dhau yuav ua rau lub cev tsis zoo ntawm lub ncov loj vim hnyav hnyav.Tsuas yog cov kuab tshuaj nruab nrab tuaj yeem muab ntxiv kom zoo tiv thaiv succinic acid Solifenacin yog adsorbed ntawm iav, ntxiv 50% methanol lossis ethanol lossis 30% ~ 50% acetonitrile tuaj yeem kov yeej qhov kev cuam tshuam tsis muaj zog ntawm cov tshuaj thiab qhov chaw ntawm lub vial.
PP Vials iav Vials iav Vials iav Vials iav Vials
Cia lub sij hawm 0h 0h 9.5h 17h 48h
30% acetonitrile 823.6 822.5 822 822.6 823.6
50% acetonitrile 822.1 826.6 828.9 830.9 838.5
30% isopropanol 829.2 823.1 821.2 820 806.9
50% Ethanol 828.6 825.6 831.4 832.7 830.4
50% methanol 835.8 825 825.6 825.8 823.1
Table 4 Cov teebmeem ntawm cov kuab tshuaj organic sib txawv ntawm qhov adsorption ntawm iav fwj
tias solifenacin succinate yog qhov tshwj xeeb khaws cia hauv kev daws teeb meem.Table 4 tus lej
Nws tau raug pom tias thaum solifenacin succinate khaws cia rau hauv lub khob vials, siv
Tom qab cov organic solvent tov ntawm cov piv txwv saum toj no yog diluted, lub succinate nyob rau hauv lub iav vials.Qhov chaw siab tshaj ntawm linacin hauv 48h yog tib yam li thaj tsam ncov ntawm PP vial ntawm 0h.Ntawm 0.98 thiab 1.02, cov ntaub ntawv ruaj khov.
3.0 xaus:
Ntau hom iav vials rau lub hauv paus tsis muaj zog succinic acid Solifenacin yuav tsim cov qib sib txawv ntawm adsorption, qhov adsorption feem ntau yog tshwm sim los ntawm kev sib cuam tshuam ntawm protonated amine pawg nrog dawb silanol pawg.Yog li ntawd, tsab xov xwm no ceeb toom cov tuam txhab tshuaj ntsuam xyuas tias thaum lub sij hawm ua kua los yog tshuaj ntsuam xyuas, nco ntsoov ua tib zoo saib xyuas cov tshuaj poob, qhov tsim nyog diluent pH los yog haum diluent pH tuaj yeem tshawb xyuas ua ntej.Piv txwv li rau cov kuab tshuaj oganic kom tsis txhob muaj kev sib cuam tshuam ntawm cov tshuaj yooj yim thiab iav, thiaj li txo cov ntaub ntawv tsis ncaj ncees thaum kev tshuaj xyuas tshuaj thiab qhov tshwm sim tsis ncaj ncees ntawm kev tshawb nrhiav.
[1] Nema S, Ludwig JD.Pharmaceutical dosage forms - Cov tshuaj parenteral: ntim 3: cov cai, kev siv tau thiab yav tom ntej.3rd ed.Crc Xovxwm; 2011.
[2] https://go.drugbank.com/drugs/DB01591
[3] El-Shamy TM.Cov tshuaj tiv thaiv ntawm K2O-CaO-MgO-SiO2 tsom iav, Phys Chem Glass 1973;14:1-5.
[4] El-Shamy TM.Tus nqi-txhais kauj ruam hauv dealkalisation ntawm silicateglasses.
Phys Chem iav 1973;14:18-19.
[5] Mathes J, Friess W. Influence of pH thiab ionic zog ntawm IgG adsorption tovials.
Eur J Pharm Biopharm 2011, 78(2:239-
[6] Bacon FR, Raggon FC.Txhawb nqa Kev Tawm Tsam ntawm iav thiab Silica los ntawm Citrateand
Lwm yam Anions hauv Neutral Solution.J AM
Daim duab 4. Kev sib cuam tshuam ntawm cov protonated amino pawg ntawm solifenacin thiab dissociated silanol pawg ntawm iav nto
Post lub sij hawm: May-26-2022