Umbhali / 1,2 Hu Rong 1 Hol isigubhu Isigubhu Ingoma Xuezhi ngaphambi kohambo olu-1 Jinsong 1 – The new 1, 2
【Abstract】Ingilazi ye-Borosilicate iyimpahla yokupakisha esetshenziswa kakhulu nesiqukathi sesixazululo embonini yezemithi.Nakuba inezici zokumelana okuphezulu, njengokushelela, ukumelana nokugqwala nokumelana nokugqoka, ama-ion ensimbi namaqembu e-silanol aqukethwe engilazini ye-borosilicate asengasebenzisana nezidakamizwa.Ekuhlaziyweni kwezidakamizwa zamakhemikhali nge-high performance liquid chromatography (HPLC), ibhodlela lomjovo elijwayelekile ingilazi ye-borosilicate.Ngokuphenya umphumela wezitsha zengilazi ze-HPLC zemikhiqizo emithathu ekuzinzeni kwe-solifenacin succinate okuyinhlanganisela ye-alkaline ebuthakathaka, kwatholakala ukuthi ukufakwa kwezidakamizwa ze-alkali kukhona ezitsheni zengilazi ezikhiqizwa abakhiqizi abahlukene.I-adsorption yayibangelwa ikakhulukazi ukusebenzisana kwe-protonated amino neqembu le-dissociative silanol, futhi ukuba khona kwe-succinate kwakukhuthaza.Ukwengezwa kwe-hydrochloric acid kungaqeda umuthi noma kwengeze ingxenye efanele yezinyibilikisi zemvelo kungavimbela ukukhangisa.Inhloso yaleli phepha ukukhumbuza amabhizinisi okuhlola izidakamizwa ukuthi anake ukusebenzisana phakathi kwezidakamizwa ezine-alkaline nengilazi, nokunciphisa ukuchezuka kwedatha nomsebenzi wophenyo wokuchezuka okubangelwa ukuntula ulwazi lwezimpawu ze-adsorption zamabhodlela engilazi inqubo yokuhlaziywa kwezidakamizwa.
Amagama angukhiye: Solifenacin succinate, amino group, HPLC glass vials, adsorb
I-Glass njengento yokupakisha inezinzuzo zokushelela, ukuqedwa kalula kanye nokumelana nokugqwala.I-Corrosion, ukumelana nokugqoka, ukuzinza kwevolumu kanye nezinye izinzuzo, ngakho-ke isetshenziswa kabanzi ekusetshenzisweni kwemithi.Ingilazi yokwelapha ihlukaniswe ingilazi ye-sodium calcium kanye nengilazi ye-borosilicate, ngokusho kwezingxenye ezihlukene eziqukethe.Phakathi kwazo, ingilazi ye-soda lime iqukethe 71% ~ 75%SiO2, 12% ~ 15% Na2O, 10% ~ 15% CaO;ingilazi ye-borosilicate iqukethe 70%~80% SiO2, 7%~13%B2O3, 4%~6% Na2O kanye ne-K2O kanye ne-2%~4% Al2O3.Ingilazi ye-Borosilicate inokumelana okuhle kakhulu namakhemikhali ngenxa yokusetshenziswa kwe-B2O3 esikhundleni seningi le-Na2O ne-CaO.
Ngenxa yemvelo yayo yesayensi, yakhethwa njengesiqukathi esikhulu somuthi owuketshezi.Kodwa-ke, ingilazi ye-boronSilicone, noma inokumelana kwayo okuphezulu, isengasebenzisana nezidakamizwa, Kunezindlela ezine ezijwayelekile zokusabela ngale ndlela elandelayo [1]:
1)I-ion exchange: Na+, K+, Ba2+, Ca2+ engilazini ishintshana nge-ion nge-H3O+ esixazululweni, futhi kukhona ukusabela phakathi kwama-ion ashintshiwe nomuthi;
I-2) Ukuchithwa kwengilazi: I-Phosphate, i-oxalate, i-Citrate kanye ne-tartrates izosheshisa ukuqedwa kwengilazi futhi kubangele ama-silicides.futhi i-Al3+ ikhishwa ibe yisixazululo;
3)Ukugqwala: I-EDTA ekhona esixazululweni sesidakamizwa (EDTA) ingase ibe yinkimbinkimbi ngama-ion ahlukene noma ama-ion a-trivalent engilazini.
4) I-Adsorption: Kunebhondi ye-Si-O ephukile endaweni engilazi, engakhanga i-H+
Ukwakheka kwe-OH- kungenza izibopho ze-hydrogen namaqembu athile emthini, okuholela ekutheni umuthi ukhangiswe endaweni yengilazi.
Amakhemikhali amaningi aqukethe amaqembu e-amine ayisisekelo abuthakathaka, Lapho kuhlaziywa izidakamizwa zamakhemikhali ezine-high performance liquid chromatography (HPLC), i-HPLC autosampler vial evame ukusetshenziswa eyenziwe ngengilazi ye-borosilicate, kanye nokuba khona kwe-SiO- endaweni engilazi kuzosebenzisana neqembu le-amine eline-protonated. , okuvumela ukuminyana kwezidakamizwa kwehle, imiphumela yokuhlaziya izobe inganembile, kanye ne-OOS yaselabhorethri (Ingaphandle Kokucaciswa).Kulo mbiko, isisekelo esibuthakathaka (i-pKa yi-8.88[2]) yesidakamizwa i-solifenacin succinate (ifomula yesakhiwo iboniswa kuMdwebo 1) isetshenziswa njengento yocwaningo, kanye nomthelela wezitsha zengilazi ezimbalwa ze-amber borosilicate zokujova emakethe ekuhlaziyweni kwezidakamizwa. kuyaphenywa., futhi kusukela ekubukeni kokuhlaziya ukuthola isixazululo ekukhangisweni kwezidakamizwa ezinjalo engilazini.
1.Ingxenye yokuhlola
1.1Izisetshenziswa namathuluzi okuhlolwa
1.1.1 Izisetshenziswa: I-Agilent High Kahle Enomtshina we-UV
I-chromatography ewuketshezi
1.1.2 Izinto zokuhlola: I-Solifenacin succinate API yakhiqizwa ngu-Alembic
I-Pharmaceuticals Ltd. (India).Izinga le-Solifenacin (ubumsulwa obungama-99.9%) lathengwa kwa-USP.I-ARgrade potassium dihydrogen phosphate, triethylamine, ne-phosphoric acid ithengwe kwa-China Xilong Technology Co., Ltd. I-Methanol ne-acetonitrile (zombili izinga le-HPLC) zathengwa kumabhodlela e-Sibaiquan Chemical Co., Ltd. Polypropylene (PP) athengwe kwa-ThermoScientific (US) , kanye namabhodlela engilazi e-amber HPLC angu-2ml athengwe kwa-Agilent Technologies(China) Co., Ltd., Dongguan Pubiao Laboratory Equipment Technology Co., Ltd., kanye ne-Zhejiang Hamag Technology Co., Ltd. (A, B, C isetshenziswa ngezansi ukumela imithombo ehlukene yezitsha zengilazi, ngokulandelana).
1.2Indlela yokuhlaziya yeHPLC
1.2.1I-Solifenacin succinate nesisekelo samahhala se-solifenacin: ikholomu ye-chromatographic isphenomenex luna®C18 (2), 4.6 mm × 100 mm, 3 µm.Nge-phosphate buffer (isisindo esingu-4.1 g se-potassium dihydrogen phosphate, nesisindo esingu-2 ml we-triethylamine, yengeze ku-1 Litha lamanzi ahlanzekile, ugovuze ukuze uncibilike, usephosphoric acid(pH yalungiswa yaba ngu-2.5) -acetonitrile-methanol (40:30:30) njengesigaba seselula,
Umfanekiso 1 Ifomula yesakhiwo ye-solifenacin succinate
Umfanekiso 2 Ukuqhathaniswa kwezindawo eziphakeme kakhulu zesisombululo esifanayo se-solifenacin succinate ezitsheni ze-PP nezitsha zengilazi ezivela kubakhiqizi abathathu A, B, no-C.
izinga lokushisa lekholomu lalingu-30°C, izinga lokugeleza lalingu-1.0 mL/min, futhi umthamo womjovo wawungu-50 mL, Ubude bokutholwa bungu-220 nm.
1.2.2 Isampula ye-Succinic acid: kusetshenziswa i-YMC-PACK ODS-A 4.6 mm × 150 mm, ikholomu engu-3 µm, 0.03 mol/L i-phosphate buffer (eshintshwe yaba pH 3.2 ngephosphoric acid) -methanol (92:8) njengesigaba seselula, ukugeleza isilinganiso esingu-1.0 mL/min, izinga lokushisa lekholomu lingu-55 °C, futhi umthamo womjovo wawungu-90 mL.Ama-Chromatograms atholwe ku-204 nm.
1.3 Indlela yokuhlaziya ye-ICP-MS
Izinto ezisesixazululweni zahlaziywa kusetshenziswa uhlelo lwe-Agilent 7800 ICP-MS, imodi yokuhlaziya bekuyimodi ethi He (4.3mL/min), amandla e-RF ayengu-1550W, izinga lokugeleza kwegesi ye-plasma lalingu-15L/min, kanye nezinga lokugeleza kwegesi yenkampani yenethiwekhi. ibingu-1.07mL/min.Izinga lokushisa legumbi lenkungu lalingu-2°C, ijubane lokuphakamisa/lokuqinisa iphampu ye-peristaltic lalingu-0.3/0.1 rps, isikhathi sokuzinza sesampula sasingu-35 s, isikhathi sokuphakamisa isampula sasingu-45 s, futhi ukujula kweqoqo kube ngu-8 mm.
Ukulungiselela isampula
Isixazululo se-Solifenacin succinate: silungiselelwe ngamanzi acwebile, ukugxiliswa kwe-0.011 mg/mL.
1.4.2 Isixazululo se-Succinic acid: esilungiselelwe ngamanzi ahlanzekile, ukugxila ku-1mg/mL.
1.4.3 Isixazululo se-Solifenacin: ncibilikisa i-solifenacin succinate emanzini, i-sodium carbonate yanezelwa, futhi ngemva kokuba ikhambi lishintshile lisuka ku-tomilky white elingenambala, kwenezelwa i-ethyl acetate.Ungqimba lwe-ethyl acetate lwabe seluhlukaniswa futhi i-thesolvent yahwamuka ukuze inikeze i-solifenacin.Chaza inani elifanele le-inethanol ye-solifenacin (i-ethanol yenza ama-m 5% esixazululweni sokugcina), bese uyixuba ngamanzi ukuze ulungise isixazululo ngokuhlangana kwe-solifenacin engu-0.008 mg/mL (nesixazululo se-solifenacin succinate esiqukethwe kwisixazululo esifana ne-solifenacin. ukugxila).
Imiphumela nengxoxo
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2.1 Umthamo we-Adsorption wezitsha ze-HPLC zemikhiqizo ehlukene
Nikeza isixazululo samanzi esifanayo se-solifenacin succinate ezitsheni ze-PP kanye nezinhlobo ezi-3 ze-autosampler vials zajovwa ngezikhathi ezithile endaweni efanayo, futhi indawo ephakeme kakhulu yesiqongo esikhulu yarekhodwa.Kusukela emiphumeleni ku-Figure 2, kungabonakala ukuthi indawo ephakeme yezitsha ze-PP izinzile, futhi cishe akukho shintsho ngemva kwamahora angu-44. Ngenkathi izindawo eziphakeme zezinhlobo ezintathu zezitsha zeglasi ku-0 h zazincane kunebhodlela le-PP. , futhi indawo ephakeme kakhulu iyaqhubeka nokuncipha ngesikhathi sokugcina.
Umfanekiso wesi-3 Ushintsho ezindaweni eziphakeme kakhulu ze-solifenacin, i-succinic acid, ne-solifenacin zifaka izixazululo ezinamanzi ezigcinwe ezitsheni zengilazi nezitsha ze-PP.
Ukuqhubeka nokutadisha lesi simo, i-solifenacin, i-succinate acid, izixazululo ezinamanzi ze-solifenacin acid kanye ne-succinate ezitsheni zengilazi zomkhiqizi wamabhodlela e-Band PP ukuze uphenye ngokushintsha kwendawo ephakeme ngesikhathi, futhi ngesikhathi esifanayo ingilazi.
Izisombululo ezintathu kumabhodlela zahlanganiswa kusetshenziswa i-Agilent 7800 ICP-MSPlasma mass spectrometer yokuhlaziya okuyisisekelo.Idatha ekuMfanekiso 3 ibonisa ukuthi izitsha zengilazi endaweni enamanzi azizange zikhangise i-succinic acid, kodwa i-adsorbed solifenacinFree base kanye ne-solifenacin succinate.Izitsha zengilazi zikhanga i-succinate.Izinga le-linacin linamandla kunesisekelo samahhala se-solifenacin, ngesikhathi sokuqala i-Solifenacin succinate kanye nesisekelo samahhala se-solifenacin ezitsheni zengilazi.Izilinganiso zezindawo eziphakeme kakhulu zezixazululo eziqukethwe emabhodleleni e-PP zazingu-0.94 no-0.98, ngokulandelana.
Ngokuvamile kunenkolelo yokuthi indawo yengilazi ye-silicate ingakwazi ukumunca amanzi athile, okuthi amanye amanzi ahlanganiswe ne-Si4+ ngendlela yamaqembu e-OH ukuze akhe amaqembu e-silanol Ekubunjweni kwengilazi ye-oxide, i-ion polyvalent ayikwazi ukunyakaza, kodwa insimbi ye-alkali (njenge I-Na+ ) kanye nama-ion ensimbi yomhlaba ane-alkali (njenge-Ca2+) anganyakaza lapho izimo zivuma, ikakhulukazi ama-ion ensimbi e-alkali kulula ukugeleza, angashintshaniswa ne-H+ ekhangisiwe endaweni yengilazi futhiDlulisele endaweni engilazi ukuze kwakhe amaqembu e-silanol [3-4].Ngakho-ke, ukuhlushwa kwe-H+ kokunyuka kungakhuthaza ukushintshaniswa kwe-ion ukwandisa amaqembu e-silanol endaweni yengilazi.ngethebula1 libonisa ukuthi okuqukethwe kuka-B, Na, no-Ca esixazululweni kuyahluka ukusuka kokuphezulu kuye kokuphansi.i-succinic acid, i-solifenacin succinate ne-solifenacin.
isampula B (μg/L) Na(μg/L) Ca(μg/L) Al(μg/L) Si(μg/L) Fe(μg/L)
amanzi 2150 3260 20 Akukho Ukutholwa 1280 4520
Isixazululo se-Succinic acid 3380 5570 400 429 1450 139720
I-Solifenacin Succinate Solution 2656 5130 380 Akukho Ukutholwa 2250 2010
isixazululo solifenacin 1834 2860 200 Akukho Ukutholwa 2460 Akukho Ukutholwa
Ithebula 1 Ukugxila kwe-elemental kwe-solifenacin succinate, i-solifenacin kanye ne-succinic acid ye-aqueous solutions egcinwe ezitsheni zengilazi izinsuku ezingu-8.
Ngaphezu kwalokho, kungabonakala kudatha ekuThebula 2 ukuthi ngemva kokugcinwa emabhodleleni engilazi amahora angu-24, okuncibilikisiwe I-pH yoketshezi ikhuphukile.Lesi simo sisondelene kakhulu nethiyori engenhla
I-Vial No. Izinga lokubuyisela ngemva kokugcinwa engilazini amahora angu-71
(%) Izinga lokutakula ngemva kokulungiswa kwe-PH
Ibhodlela 1 97.07 100.35
I-Vial 2 98.03 100.87
I-Vial 3 87.98 101.12
I-Vial 4 96.96 100.82
I-Vial 5 98.86 100.57
I-Vial 6 92.52 100.88
I-Vial 7 96.97 100.76
I-Vial 8 98.22 101.37
IVial 9 97.78 101.31
Ithebula 3 Isimo sokuncibilika kwe-solifenacin succinate ngemuva kokufakwa kwe-asidi
Njengoba i-Si-OH endaweni engilazi ingahlukaniswa ibe yi-SiO-[5] phakathi kwe-pH 2~12, kuyilapho i-solifenacin yenzeka N endaweni ene-asidi I-Protonation (i-pH elinganisiwe yesisombululo esinamanzi se-solifenacin succinate ingu-5.34, inani le-pH le-solifenacin isisombululo singu-5.80), kanti umehluko phakathi kokusebenzelana okubili kwe-Hydrophilic kuholela ekukhangisweni kwezidakamizwa endaweni yengilazi (Fig. 3), i-solifenacin yakhangiswa kakhulu ngokuhamba kwesikhathi.
Ngaphezu kwalokho, i-Bacon ne-Raggon [6] iphinde yathola ukuthi kusisombululo esingathathi hlangothi, ama-hydroxy acid aneqembu le-hydroxyl endaweni ehlobene neqembu le-carboxyl Izisombululo zikasawoti zingakhipha i-silicion ene-oxidized.Esakhiweni samangqamuzana e-solifenacin succinate, kuneqembu le-hydroxyl elihlobene nendawo ye-carboxylate, elizohlasela engilazini, i-SiO2 iyakhishwa futhi ingilazi iyaguguleka.Ngakho-ke, ngemva kokwakhiwa kukasawoti nge-succinic acid, i-adsorption ye-solifenacin emanzini ibonakala nakakhulu.
2.2 Izindlela zokugwema i-adsorption
Isikhathi sokugcina i-pH
0h 5.50
24h 6.29
48h 6.24
Ithebula le-2 pH lishintsha izixazululo ezinamanzi ze-solifenacin zifakela emabhodleleni engilazi
Nakuba izitsha ze-PP zingakhangisi i-solifenacin succinate, Kodwa ngesikhathi sokugcinwa kwesisombululo ku-vial ye-PP, ezinye iziqongo zokungcola ziyakhiqizwa futhi Ukwelulwa kwesikhathi sokugcina kukhulisa kancane kancane indawo ephakeme yokungcola, okubangele ukuphazamiseka ekubonweni kwenani eliphakeme kakhulu. .
Ngakho-ke, kuyadingeka ukuhlola indlela engavimbela i-glass adsorption.
Thatha u-1.5 mL we-solifenacin succinate isixazululo samanzi ebhodleleni lengilazi.Ngemva kokufakwa esixazululweni samahora angu-71, amanani okuthola kabusha abephansi wonke.Engeza i-0.1M hydrochloric acid, lungisa i-pH iye cishe ku-2.3, kusukela kudatha ekuThebula 3. Kungabonwa ukuthi amanani okuthola kabusha wonke abuyele kumazinga avamile, okubonisa ukuthi ukusabela kwesikhathi sokulondoloza i-adsorption kungavinjelwa ku-pH ephansi.
Enye indlela ukunciphisa i-adsorption ngokungeza ama-organic solvents.Yenza u-10%, u-20%, u-30%, u-50% we-methanol, i-ethanol, i-isopropanol, i-acetonitrile ilungiselelwe ekuhlanganiseni kuka-0.01 mg/mL ku-Solifenacin succinate liquid.Izixazululo ezingenhla zafakwa ezitsheni zengilazi kanye nezitsha ze-PP, ngokulandelana.Emazingeni okushisa asekamelweni Ukuzinza kwawo kwafundwa imibukiso.Uphenyo lwathola ukuthi i-solvent encane kakhulu ye-organic ayikwazanga ukuvimbela i-adsorption, kuyilapho i-solvent ephilayo kakhulu izoholela ekumiseni okungavamile kwesiqongo esiphezulu ngenxa yomphumela we-solvent.Izinyibilikisi eziphilayo ezimaphakathi kuphela ezingengezwa ukuze kuvinjwe ngempumelelo i-succinic acid I-Solifenacin ikhangiswa engilazini, engeza i-methanol engu-50% noma i-ethanol noma i-30% ~50% i-acetonitrile inganqoba ukusebenzisana okubuthakathaka phakathi komuthi nobuso bebhodlela.
Izitsha ze-PP Izitsha zengilazi Izitsha zengilazi Izitsha zengilazi Izitsha zengilazi
Isikhathi sokugcina 0h 0h 9.5h 17h 48h
30% i-acetonitrile 823.6 822.5 822 822.6 823.6
50% i-acetonitrile 822.1 826.6 828.9 830.9 838.5
30% isopropanol 829.2 823.1 821.2 820 806.9
50% i-ethanol 828.6 825.6 831.4 832.7 830.4
50% methanol 835.8 825 825.6 825.8 823.1
Ithebula 4 Imithelela yezinyibilikisi ezihlukene zemvelo ekukhangisweni kwamabhodlela engilazi
ukuthi i-solifenacin succinate igcinwa njengesixazululo.Ithebula 4 izinombolo
Kuye kwaboniswa ukuthi uma i-solifenacin succinate igcinwa ezitsheni zengilazi, sebenzisa
Ngemuva kokuthi isixazululo se-organic solvent salesi sibonelo esingenhla sihlanjululwe, i-succinate ezitsheni zeglasi.Indawo ephakeme ye-linacin phakathi kwamahora angu-48 iyafana nendawo ephakeme ye-PP vial ngo-0h.Phakathi kuka-0.98 no-1.02, idatha izinzile.
3.0 isiphetho:
Izinhlobo ezahlukene zezitsha zengilazi zesisekelo esibuthakathaka i-succinic acid I-Solifenacin izokhiqiza amazinga ahlukene e-adsorption, i-adsorption ibangelwa ikakhulukazi ukusebenzisana kwamaqembu e-protonated amine namaqembu amahhala e-silanol.Ngakho-ke, lesi sihloko sikhumbuza izinkampani ezihlola izidakamizwa ukuthi ngesikhathi sokugcinwa koketshezi noma ukuhlaziya, qiniseka ukuthi unaka ukulahleka komuthi, i-pH exutshiwe efanelekile noma i-pH encibilikisiwe efanele ingaphenywa kusenesikhathi.Isibonelo salokho kumakhemikhali e-ogani ukuze kugwenywe ukusebenzisana phakathi kwezidakamizwa eziyisisekelo nengilazi, ukuze kuncishiswe ukuchema kwedatha phakathi nokuhlaziywa kwezidakamizwa kanye nomphumela wokuchema ophenyweni.
[1] Nema S, Ludwig JD.Amafomu omthamo wemithi - imithi yomzali: umthamo 3: imithethonqubo, ukuqinisekiswa kanye nekusasa.3rd ed.Crc Press;2011.
[2] https://go.drugbank.com/drugs/DB01591
[3] El-Shamy TM.Ukuqina kwamakhemikhali kwezibuko ze-K2O-CaO-MgO-SiO2, i-Phys Chem Glass 1973;14:1-5.
[4] El-Shamy TM.Isinyathelo sokunquma izinga ekwenziweni kwezibuko ze-silicateglass.
I-Phys Chem Glass 1973;14:18-19.
[5] Mathes J, Friess W. Umthelela we-pH namandla e-ionic kuma-tovials e-IgG adsorption.
I-Eur J Pharm Biopharm 2011, 78(2):239-
[6] Bacon FR, Raggon FC.Ukuphromothwa kwe-Attack on Glass ne-Silica ngu-Citrateand
Amanye ama-Anions ku-Neutral Solution.J AM
Umfanekiso 4. Ukusebenzisana phakathi kweqembu le-protonated amino le-solifenacin namaqembu e-silanol ahlukanisiwe endaweni yengilazi.
Isikhathi sokuthumela: May-26-2022