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Ho ithuta ka adsorption ea motsoako o fokolang oa motheo ho linkho tsa khalase

Author / 1,2 Hu Rong 1 Hol drum Drum Song Xuezhi before the 1 tour Jinsong 1 – The new 1, 2

【Abstract】 Khalase ea Borosilicate ke sesebelisoa sa ho paka se sebelisoang haholo le sejana sa tharollo indastering ea meriana.Le hoja e na le litšoaneleho tsa ho hanyetsa ho phahameng, tse kang boreleli, ho hanyetsa ho bola le ho roala, li-ion tsa tšepe le lihlopha tsa silanol tse nang le khalase ea borosilicate li ntse li ka sebelisana le lithethefatsi.Ha ho hlahlojoa lithethefatsi tsa lik'hemik'hale ka "high performance liquid chromatography" (HPLC), vial e tloaelehileng ea ente ke khalase ea borosilicate.Ka ho batlisisa phello ea likhalase tsa khalase tsa HPLC tsa lihlahisoa tse tharo ka botsitso ba solifenacin succinate e leng motsoako o fokolang oa alkaline, ho ile ha fumanoa hore ho kenngoa ha lithethefatsi tsa alkaline ho ne ho e-na le likhalase tsa khalase tse hlahisoang ke bahlahisi ba fapaneng.Phatlalatso e ne e bakoa haholo-holo ke tšebelisano ea protonated amino le sehlopha sa dissociative silanol, 'me boteng ba succinate bo ile ba bo khothalletsa.Ho eketsoa ha hydrochloric acid ho ka senya sethethefatsi sena kapa ho eketsa karolo e nepahetseng ea metsoako ea tlhaho ho ka thibela ho ata.Sepheo sa pampiri ena ke ho hopotsa likhoebo tse hlahlobang lithethefatsi ho ela hloko tšebelisano pakeng tsa lithethefatsi tsa alkaline le khalase, le ho fokotsa ho kheloha ha data le mosebetsi oa lipatlisiso oa ho kheloha o bakoang ke ho hloka tsebo ea litšobotsi tsa adsorption tsa libotlolo tsa khalase. mokhoa oa ho hlahloba lithethefatsi.
Mantsoe a bohlokoa: Solifenacin succinate, sehlopha sa amino, HPLC likhalase tsa khalase, adsorb

Khalase e le thepa ea liphutheloana e na le melemo ea ho boreleli, ho felisa habonolo le ho hanyetsa ho bola.Ho senya, ho hanyetsa ho roala, botsitso ba molumo le melemo e meng, kahoo e sebelisoa haholo ho sebelisoa ha meriana.Khalase ea meriana e arotsoe ka khalase ea sodium calcium le khalase ea borosilicate, ho latela likarolo tse fapaneng tse nang le eona.Har'a tsona, khalase ea soda ea lime e na le 71% ~ 75%SiO2, 12% ~ 15% Na2O, 10% ~ 15% CaO;khalase ea borosilicate e na le 70% ~ 80% SiO2, 7% ~ 13%B2O3, 4% ~ 6% Na2O le K2O le 2% ~ 4% Al2O3.Khalase ea borosilicate e na le khanyetso e ntle ea lik'hemik'hale ka lebaka la ts'ebeliso ea B2O3 sebakeng sa boholo ba Na2O le CaO.
Ka lebaka la tlhaho ea eona ea saense, e ile ea khethoa e le sejana se seholo sa meriana ea metsi.Leha ho le joalo, khalase ea boronSilicone, leha e na le khanyetso e phahameng, e ntse e ka sebelisana le lithethefatsi, Ho na le mekhoa e mene e tloaelehileng ea karabelo ka tsela e latelang [1]:
1) Phapanyetsano ea Ion: Na+, K+, Ba2+, Ca2+ ka khalase e sebelisa phapanyetsano ea ion le H3O + ka tharollo, 'me ho na le karabelo pakeng tsa li-ion tse fapanyetsanoang le lithethefatsi;
2) Ho qhibiliha ha khalase: Phosphate, oxalate, Citrate le tartrates li tla potlakisa ho qhibiliha ha khalase le ho baka li-silicides.'me Al3+ e lokolloa hore e be tharollo;
3) Corrosion: EDTA e teng ka tharollo ea lithethefatsi (EDTA) e ka 'na ea rarahana ka li-ion tsa divalent kapa li-ion tse tharo ka khalase.
4) Adsorption: Ho na le tlamo ea Si-O e robehileng holim'a khalase, e ka bapatsang H+

Ho thehoa ha OH- ho ka theha likamano tsa haedrojene le lihlopha tse itseng tsa lithethefatsi, ho fella ka hore moriana o phahamisoe holim'a khalase.
Lik'hemik'hale tse ngata li na le lihlopha tse fokolang tsa amine, Ha ho hlahlojoa lithethefatsi tsa lik'hemik'hale tse nang le high performance liquid chromatography (HPLC), HPLC autosampler vial e sebelisoang hangata e entsoeng ka khalase ea borosilicate, 'me boteng ba SiO holim'a khalase bo tla kopana le sehlopha sa protonated amine. , ho lumella ho fokotseha ha lithethefatsi ho fokotseha, liphetho tsa tlhahlobo e tla ba tse sa nepahaleng, le laboratori ea OOS (Out of Specification).Tlalehong ena, motheo o fokolang (pKa ke 8.88[2]) oa lithethefatsi solifenacin succinate (formula ea sebopeho e bonts'itsoe setšoantšong sa 1) e sebelisoa e le ntho ea lipatlisiso, le tšusumetso ea linkho tse ngata tsa ente ea khalase ea amber borosilicate 'marakeng mabapi le tlhahlobo ea lithethefatsi. e batlisisoa., 'me ho tloha ponong ea ho hlahloba ho fumana tharollo ho adsorption ea lithethefatsi tse joalo ka khalase.

1.Karolo ea teko
1.1 Lisebelisoa le lisebelisoa tsa liteko
1.1.1 Thepa: Ho sebetsa ka Bokhabane bo Phahameng ka ho Fetisisa ka Mohloli oa UV
Chromatography ea metsi
1.1.2 Lisebelisoa tsa liteko: Solifenacin succinate API e hlahisitsoe ke Alembic
Pharmaceuticals Ltd. (India).Tekanyetso ea Solifenacin (bohloeki ba 99.9%) e rekiloe ho USP.ARgrade potassium dihydrogen phosphate, triethylamine, le phosphoric acid li ile tsa rekoa ho tsoa China Xilong Technology Co., Ltd. Methanol le acetonitrile (bobeli ba sehlopha sa HPLC) li rekiloe ho tloha libotlolong tsa Sibaiquan Chemical Co., Ltd. Polypropylene (PP) li rekiloe ho ThermoScientific (US) , le 2ml amber HPLC libotlolo tsa khalase li ile tsa rekoa ho Agilent Technologies(China) Co., Ltd., Dongguan Pubiao Laboratory Equipment Technology Co., Ltd., le Zhejiang Hamag Technology Co., Ltd. (A, B, C li sebelisoa ka tlase ho emela mehloli e fapaneng ea linkho tsa khalase, ka ho latellana).

1.2HPLC mokhoa oa ho hlahloba
1.2.1Solifenacin succinate and solifenacin free base: the chromatographic column isphenomenex luna®C18 (2), 4.6 mm × 100 mm, 3 µm.Ka phosphate buffer (ka boima ba 4.1 g ea potassium dihydrogen phosphate, boima ba 2 ml ea triethylamine, e kenye ho 1 L ea metsi a ultrapure, hlohlelletsa ho qhibiliha, usephosphoric acid (pH e fetotsoe ho 2.5) -acetonitrile-methanol (40:30:30) joalo ka karolo ea mobile,

Setšoantšo sa 1 Sebopeho sa sebopeho sa solifenacin succinate

Setšoantšo sa 2 Papiso ea libaka tse phahameng tsa tharollo e tšoanang ea solifenacin succinate ka linkho tsa PP le likhalase tse tsoang ho baetsi ba bararo ba A, B, le C.

mocheso oa kholomo e ne e le 30 ° C, sekhahla sa phallo e ne e le 1.0 mL / min, 'me molumo oa ente e ne e le 50 mL, Leqhubu la ho lemoha ke 220 nm.
1.2.2 Mohlala oa asiti ea succinic: ho sebelisoa YMC-PACK ODS-A 4.6 mm × 150 mm, kholomo ea 3 µm, 0.03 mol/L phosphate buffer (e fetotsoeng ho pH 3.2 withphosphoric acid) -methanol (92:8) joalo ka mohato o tsamaeang sekhahla 1.0 mL/min, kholomo mocheso 55 °C, 'me bophahamo ba ente e ne e le 90 mL.Li-chromatogram li ile tsa fumanoa ka 204 nm.
1.3 Mokhoa oa ho hlahloba ICP-MS
Likarolo tsa tharollo li ile tsa hlahlojoa ho sebelisoa sistimi ea Agilent 7800 ICP-MS, mokhoa oa tlhahlobo e ne e le He mode (4.3mL / min), matla a RF e ne e le 1550W, sekhahla sa phallo ea khase ea plasma e ne e le 15L / min, le sekhahla sa phallo ea khase ea sephethephethe. e ne e le 1.07mL/min.Thempereichara ea kamore ea moholi e ne e le 2 ° C, lebelo la ho phahamisa pompo ea peristaltic / stabilizing e ne e le 0.3 / 0.1 rps, nako ea ho tsitsa ea sampole e ne e le 35 s, nako ea ho phahamisa sampole e ne e le 45 s, 'me botebo ba pokello e ne e le 8 mm.

Ho lokisetsa mohlala

Solifenacin succinate solution: e lokiselitsoeng ka metsi a mangata haholo, khatello ea maikutlo ke 0.011 mg/mL.
1.4.2 Tharollo ea Succinic acid: e lokiselitsoeng ka metsi a ultrapure, mahloriso ke 1mg / mL.
1.4.3 Tharollo ea Solifenacin: qhibiliha solifenacin succinate ka metsing, sodium carbonate e ile ea eketsoa, ​​​​'me ka mor'a hore tharollo e fetohe ho tloha ho tomilky white e se nang mebala, ethyl acetate e ile ea eketsoa.Ka mor'a moo, ethyl acetate layer e ile ea aroloa 'me thesolvent ea fetoha mouoane ho fana ka solifenacin.Qhibiliha palo e loketseng ea solifenacin inethanol (ethanol e nka 5% tharollong ea ho qetela), ebe e hlapolla ka metsi ho lokisa tharollo ka motsoako oa 0.008 mg/mL solifenacin (ka solifenacin succinate solution e fumanehang ka har'a tharollo e tšoanang le solifenacin. mahloriso).

Liphetho le puisano
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2.1 Matla a Adsorption a linkho tsa HPLC tsa mefuta e fapaneng
Fana ka tharollo e ts'oanang ea metsi ea solifenacin succinate ka har'a linkho tsa PP 'me mefuta e 3 ea linkho tsa li-autosampler li ile tsa kenngoa ka linako tse fapaneng tikolohong e le' ngoe, 'me sebaka sa tlhoro ea tlhoro e kholo se tlalehiloe.Ho tsoa ho liphetho ho Setšoantšo sa 2, ho ka bonoa hore sebaka sa tlhōrō ea li-vials tsa PP se tsitsitse, 'me ho batla ho se na phetoho ka mor'a lihora tse 44. , 'me sebaka sa tlhōrō se tsoela pele ho fokotseha nakong ea polokelo.

Setšoantšo sa 3 Liphetoho libakeng tse phahameng tsa solifenacin, succinic acid, le solifenacin succinate litharollo tsa metsi tse bolokiloeng ka lijaneng tsa khalase le linkho tsa PP.

Ho tsoela pele ho ithuta ketsahalo ena, solifenacin, succinate acid, Aqueous solutions of solifenacin acid le succinate ka linkho tsa khalase tsa moetsi oa libotlolo tsa Band PP ho hlahloba phetoho ea sebaka se phahameng ka nako, 'me ka nako e ts'oanang khalase.
Litharollo tse tharo ka har'a linkho li ile tsa kopanngoa ka mokhoa o ts'oanang ho sebelisoa spectrometer ea boima ba Agilent 7800 ICP-MSPlasma bakeng sa tlhahlobo ea mantlha.Lintlha tse ho Setšoantšo sa 3 li bontša hore linkho tsaGlass tse sebakeng se nang le metsi a mangata ha lia ka tsa hlahisa succinic acid, empa li ne li adsorbed solifenacinFree base le solifenacin succinate.Linkho tsa khalase li adsorb succinate.Tekanyo ea linacin e matla ho feta ea solifenacin free base, qalong ea Solifenacin succinate le solifenacin free base in the glasses.Likarolo tsa libaka tse phahameng tsa tharollo tse ka har'a libotlolo tsa PP e ne e le 0.94 le 0.98, ka ho latellana.
Ka kakaretso ho lumeloa hore bokaholimo ba khalase ea silicate e ka monya metsi a mang, ao metsi a mang a a kopanyang le Si4 + ka sebopeho sa lihlopha tsa OH ho theha lihlopha tsa silanol Ka sebopeho sa khalase ea oxide, li-ion tse nang le polyvalent ha li khone ho sisinyeha, empa tšepe ea alkali (joalo ka ha ho lumeloa hore khalase ea silicate e ka monya metsi a mang, ao metsi a mang a kopanang le Si4 + ka sebopeho sa lihlopha tsa OH ho theha lihlopha tsa silanol. Na + ) le alkaline lefatše tšepe ion (tse kang Ca2 +) ka tsamaea ha maemo a lumella, haholo-holo alkali tšepe ion ba bonolo ho phalla, ka fapanyetsana le H+ adsorbed holim'a khalase holim'a khalase holim'a khalase ho theha lihlopha tsa silanol [3-4].Ka hona, khatello ea H + ea Keketseho e ka khothaletsa phapanyetsano ea ion ho eketsa lihlopha tsa silanol holim'a khalase.ka tafole1 e bontša hore litaba tsa B, Na, le Ca ka tharollo li fapana ho tloha holimo ho ea tlaase.ke succinic acid, solifenacin succinate le solifenacin.

mohlala oa B (μg/L) Na(μg/L) Ca(μg/L) Al(μg/L) Si(μg/L) Fe(μg/L)
metsi 2150 3260 20 Ha ho Khethollo 1280 4520
Succinic acid solution 3380 5570 400 429 1450 139720
Solifenacin Succinate Solution 2656 5130 380 No Detection 2250 2010
tharollo ea solifenacin 1834 2860 200 Ha e fumanehe 2460 Ha e fumanehe

Letlapa la 1 Likarolo tsa mantlha tsa solifenacin succinate, solifenacin le succinic acid e metsi a bolokiloeng ka linkhong tsa khalase matsatsi a 8.

Ho phaella moo, e ka bonoa ho tswa ho data ho Lethathamo la 2 hore ka mor'a ho boloka ka libotlolong tsa khalase bakeng sa 24 h, e qhibilihisitsoeng The pH ea mokelikeli e tsohile.Ketsahalo ena e haufi haholo le khopolo e ka holimo

Vial No. Sekhahla sa ho hlaphoheloa ka mor'a ho bolokoa ka khalase bakeng sa 71 h
(%) Sekhahla sa ho hlaphoheloa ka mor'a hore PH e lokisoe
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
Letlapa la 3 Boemo ba ho senyeha ha solifenacin ho succinate ka mor'a ho eketsoa ha asiti

Kaha Si-OH holim'a khalase e ka aroloa ho SiO-[5] pakeng tsa pH 2 ~ 12, ha solifenacin e hlaha N sebakeng se nang le asiti Protonation (e lekanyelitsoeng pH ea tharollo e nang le metsi a solifenacin succinate ke 5.34, pH ea boleng ba solifenacin tharollo ke 5.80), 'me phapang pakeng tsa litšebelisano tse peli tsa Hydrophilic e lebisa ho adsorption ea lithethefatsi holim'a khalase (setšoantšo sa 3), solifenacin e ne e adsorbed ho feta le ho feta ha nako e ntse e feta.
Ho phaella moo, Bacon le Raggon [6] ba fumane hape hore ka tharollo e sa nke lehlakore, hydroxy acid e nang le sehlopha sa hydroxyl boemong bo amanang le sehlopha sa carboxyl Litharollo tsa letsoai li ka ntša silika e nang le oxidized.Sebopeho sa limolek'hule tsa solifenacin succinate, ho na le sehlopha sa hydroxyl se amanang le boemo ba carboxylate, se tla hlasela ka khalase, SiO2 e ntšoa 'me khalase ea senyeha.Ka hona, ka mor'a ho thehoa ha letsoai le succinic acid, adsorption ea solifenacin ka metsing e totobetse le ho feta.

2.2 Mekhoa ea ho qoba adsorption
Nako ea ho boloka pH
0h 5.50
24h 6.29
48h 6.24
Tafole ea 2 pH ea liphetoho tsa tharollo ea metsi ea solifenacin e succinate ka libotlolong tsa khalase

Le hoja linkho tsa PP li sa adsorb solifenacin succinate, Empa nakong ea polokelo ea tharollo ka har'a PP vial, ho hlahisoa litlhōrō tse ling tsa ho se hloeke 'me Ho lelefatsa nako ea polokelo butle-butle ho eketsa sebaka sa tlhoro ea litšila, e leng se bakileng ho kena-kenana le ho fumanoa ha tlhoro e kholo. .
Ka hona, hoa hlokahala ho hlahloba mokhoa o ka thibelang adsorption ea khalase.
Nka 1.5 mL ea solifenacin succinate aqueous solution ka vial ea khalase.Ka mor'a ho kenngoa ka tharollo bakeng sa 71 h, litefiso tsa ho hlaphoheloa kaofela li ne li le tlaase.Eketsa 0.1M hydrochloric acid, fetola pH ho hoo e ka bang 2.3, ho tloha ho data ho Lethathamo la 3. Ho ka bonoa hore litekanyetso tsa ho hlaphoheloa kaofela li khutletse maemong a tloaelehileng, e leng se bontšang hore karabelo ea nako ea polokelo ea adsorption e ka thibeloa ka pH e tlaase.

Tsela e 'ngoe ke ho fokotsa adsorption ka ho eketsa metsoako ea tlhaho.Etsa 10%, 20%, 30%, 50% methanol, ethanol, isopropanol, acetonitrile e ne e lokiselitsoe ka bongata ba 0.01 mg/mL ho Solifenacin succinate liquid.Litharollo tse ka holimo li kentsoe ka har'a linkho tsa khalase le linkho tsa PP, ka ho latellana.Mocheso oa kamore Botsitso ba eona bo ile ba ithutoa bo bontša.Patlisiso e fumane hore solvent e nyane haholo ea organic ha e khone ho thibela adsorption, athe organic solvent e ngata haholo e tla lebisa sebopehong se sa tloaelehang sa tlhoro e kholo ka lebaka la phello ea solvent.Ke li-solvents tse leka-lekaneng feela tse ka ekeletsoang ho thibela ka katleho asiti ea "succinic" Solifenacin e adsorbed ka khalase, eketsa 50% methanol kapa ethanol kapa 30% ~ 50% acetonitrile e ka hlola tšebelisano e fokolang lipakeng tsa moriana le bokaholimo ba vial.

PP Linkho tsa Khalase Linkho tsa Khalase Linkho tsa Khalase Linkho tsa Khalase Linkho tsa Khalase
Nako ea polokelo 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
Letlapa la 4 Liphello tsa litlhare tse fapaneng tsa organic ho adsorption ea libotlolo tsa khalase

hore solifenacin succinate ke khetho e khethehileng e bolokiloeng ka tharollo.Tafole 4 linomoro
Ho 'nile ha bontšoa hore ha solifenacin succinate e bolokoa ka vials khalase, sebelisa
Ka mor'a hore tharollo ea organic solvent ea mohlala o ka holimo e hlapolloe, succinate ka lijaneng tsa khalase.Sebaka se phahameng sa linacin ka hare ho 48h se tšoana le sebaka se phahameng sa PP vial ka 0h.Pakeng tsa 0.98 le 1.02, data e tsitsitse.

3.0 sephetho:
Mefuta e fapaneng ea linkho tsa khalase bakeng sa motsoako o fokolang oa succinic acid Solifenacin e tla hlahisa likhato tse fapaneng tsa adsorption, adsorption e bakoa haholo ke tšebelisano ea lihlopha tsa protonated amine tse nang le lihlopha tsa mahala tsa silanol.Ka hona, sengoloa sena se hopotsa lik'hamphani tse hlahlobang lithethefatsi hore nakong ea polokelo ea mokelikeli kapa tlhahlobo, etsa bonnete ba hore u ela hloko tahlehelo ea lithethefatsi, pH e nepahetseng ea diluent kapa pH e nepahetseng ea diluent e ka batlisisoa esale pele.Mohlala o joalo bakeng sa lihlapolli tsa oganic ho qoba tšebelisano lipakeng tsa lithethefatsi tsa mantlha le likhalase, e le ho fokotsa leeme la data nakong ea tlhahlobo ea lithethefatsi le leeme le hlahang lipatlisisong.

[1] Nema S, Ludwig JD.Mefuta ea litekanyetso tsa meriana - meriana ea batsoali: bophahamo ba 3: melao, netefatso le bokamoso.3rd ed.Crc Press;2011.
[2] https://go.drugbank.com/drugs/DB01591
[3] El-Shamy TM.Ho tšoarella ha lik'hemik'hale tsa likhalase tsa K2O-CaO-MgO-SiO2, Phys Chem Glass 1973;14:1-5 .
[4] El-Shamy TM.Mohato oa ho khetholla sekhahla oa ho sebetsana le likhalase tsa silicate.
Phys Chem Glass 1973;14:18-19 .
[5] Mathes J, Friess W. Tšusumetso ea pH le matla a ionic ho IgG adsorption tovials.
Eur J Pharm Biopharm 2011, 78(2):239-
[6] Bacon FR, Raggon FC.Khothatso ea Tlhaselo ea Khalase le Silika ka Citrateand
Li-Anions tse ling ho Neutral Solution.J AM

Setšoantšo sa 4. Tšebelisano pakeng tsa sehlopha sa protonated amino sa solifenacin le lihlopha tse arohaneng tsa silanol holim'a khalase.


Nako ea poso: May-26-2022