Onkọwe / 1,2 Hu Rong 1 Hol drum Drum Song Xuezhi ṣaaju irin-ajo 1 Jinsong 1 – Tuntun 1, 2
【Abstract】 Borosilicate gilasi jẹ ohun elo iṣakojọpọ ti a lo pupọ ati eiyan ojutu ni ile-iṣẹ elegbogi.Botilẹjẹpe o ni awọn abuda ti resistance giga, bii didan, resistance ipata ati yiya resistance, awọn ions irin ati awọn ẹgbẹ silanol ti o wa ninu gilasi borosilicate le tun ṣe ajọṣepọ pẹlu awọn oogun.Ninu itupalẹ awọn oogun kemikali nipasẹ kiromatografi omi iṣẹ giga (HPLC), vial abẹrẹ aṣoju jẹ gilasi borosilicate.Nipa ṣiṣewadii ipa ti awọn lẹgbẹrun gilasi HPLC ti awọn ami iyasọtọ mẹta lori iduroṣinṣin ti solifenacin succinate eyiti o jẹ apopọ alkaline ti ko lagbara, a rii pe ipolowo si awọn oogun alkali wa ninu awọn lẹgbẹ gilasi ti a ṣe nipasẹ awọn aṣelọpọ oriṣiriṣi.Adsorption jẹ pataki nitori ibaraenisepo ti amino protonated ati ẹgbẹ silanol dissociative, ati wiwa succinate ni igbega.Afikun hydrochloric acid le desorb oogun naa tabi ṣafikun ipin ti o yẹ ti awọn nkan ti ara le ṣe idiwọ adsorption.Idi ti iwe yii ni lati leti awọn ile-iṣẹ idanwo oogun lati san ifojusi si ibaraenisepo laarin awọn oogun ipilẹ ati gilasi, ati lati dinku iyapa data ati iṣẹ iwadii ti iyapa ti o ṣẹlẹ nipasẹ aini imọ ti awọn abuda adsorption ti awọn igo gilasi ni awọn ilana ti oògùn onínọmbà.
Awọn ọrọ pataki: Solifenacin succinate, ẹgbẹ amino, HPLC gilasi lẹgbẹrun, adsorb
Gilasi bi ohun elo apoti ni awọn anfani ti didan, imukuro irọrun ati ipata ibajẹ.Gilaasi oogun ti pin si iṣuu soda kalisiomu gilasi ati gilasi borosilicate, ni ibamu si awọn paati oriṣiriṣi ti o ni.Lara wọn, gilasi orombo soda ni 71% ~ 75% SiO2, 12% ~ 15% Na2O, 10% ~ 15% CaO;gilasi borosilicate ni 70% ~ 80% SiO2, 7% ~ 13% B2O3, 4% ~ 6% Na2O ati K2O ati 2% ~ 4% Al2O3.Borosilicate gilasi ni o ni o tayọ kemikali resistance nitori awọn lilo ti B2O3 dipo ti julọ ti Na2O ati CaO
Nitori ẹda onimọ-jinlẹ rẹ, o yan bi apoti akọkọ fun oogun olomi.Bibẹẹkọ, gilasi boronSilicone, paapaa pẹlu resistance giga rẹ, tun le ṣe ajọṣepọ pẹlu awọn oogun, Awọn ilana ifasẹpọ mẹrin lo wa bi atẹle [1]:
1) Ion paṣipaarọ: Na + , K+ , Ba2 +, Ca2 + ni gilasi faragba ion paṣipaarọ pẹlu H3O + inthe ojutu, ati nibẹ ni a lenu laarin awọn pasipaaro ions ati awọn oògùn;
2) Itu gilasi: Phosphate, oxalate, Citrates ati tartrates yoo mu itujade gilasi pọ si ati fa awọn silicides.ati Al3 + ti wa ni idasilẹ sinu ojutu;
3) Ipata: EDTA ti o wa ninu ojutu oogun (EDTA) le ṣe eka pẹlu awọn ions divalent tabi awọn ions trivalent ninu gilasi
4) Adsorption: iwe adehun Si-O ti bajẹ lori dada gilasi, eyiti o le adsorb H +
Ipilẹṣẹ ti OH- le ṣe awọn ifunmọ hydrogen pẹlu awọn ẹgbẹ kan ninu oogun naa, ti o mu ki oogun naa jẹ adsorbed si dada gilasi.
Pupọ julọ awọn kemikali ni awọn ẹgbẹ amine ipilẹ ti ko lagbara, Nigbati o ba n ṣe itupalẹ awọn oogun kemikali pẹlu chromatography omi iṣẹ giga (HPLC), vial HPLC autosampler ti a lo nigbagbogbo eyiti o jẹ gilasi borosilicate, ati wiwa SiO- lori dada gilasi yoo ṣe ajọṣepọ pẹlu ẹgbẹ amine protonated. , gbigba iwuwo oogun dinku, awọn abajade itupalẹ yoo jẹ aiṣedeede, ati OOS yàrá (Jade ti Specification).Ninu ijabọ yii, ipilẹ ti ko lagbara (pKa jẹ 8.88 [2]) oogun solifenacin succinate (agbekalẹ agbekalẹ ti a fihan ni Nọmba 1) ni a lo bi nkan iwadii, ati ipa ti ọpọlọpọ awọn abẹrẹ gilasi amber borosilicate lori ọja lori itupalẹ oogun. ti wa ni iwadi., ati lati oju-ọna itupalẹ lati wa ojutu kan si adsorption ti iru awọn oogun lori gilasi.
1.Test apakan
1.1 Awọn ohun elo ati ẹrọ fun awọn adanwo
1.1.1 Awọn ohun elo: Agilent High Efficiency with UV Detector
Kiromatogirafi olomi
1.1.2 Awọn ohun elo idanwo: Solifenacin succinate API jẹ iṣelọpọ nipasẹ Alembic
Pharmaceuticals Ltd. (India).Idiwọn Solifenacin (99.9% mimọ) ti ra lati USP.ARgrade potasiomu dihydrogen fosifeti, triethylamine, ati phosphoric acid ni a ra lati China Xilong Technology Co., Ltd. Methanol ati acetonitrile (mejeeji ipele HPLC) ni a ra lati ọdọ Sibaiquan Chemical Co., Ltd. Polypropylene (PP) igo ti a ra lati ThermoScientific (US) , ati 2ml amber HPLC gilasi igo ti a ra lati Agilent Technologies (China) Co., Ltd., Dongguan Pubiao Laboratory Equipment Technology Co., Ltd., ati Zhejiang Hamag Technology Co., Ltd. (A, B, C ti wa ni lilo ni isalẹ). lati ṣe aṣoju awọn orisun oriṣiriṣi ti awọn lẹgbẹrun gilasi, lẹsẹsẹ).
1.2HPLC onínọmbà ọna
1.2.1Solifenacin succinate ati ipilẹ ọfẹ solifenacin: ọwọn chromatographic isphenomenex luna®C18 (2), 4.6 mm × 100 mm, 3µm.Pẹlu ifasilẹ fosifeti (ṣe iwọn 4.1 g ofpotassium dihydrogen fosifeti, ṣe iwọn 2 milimita ti triethylamine, fi sii si 1 L ti omi ultrapure, aruwo lati tu, usephosphoric acid (pH ti ṣatunṣe si 2.5) -acetonitrile-methanol (40:30:30) bi ipele alagbeka,
Ṣe nọmba 1 agbekalẹ igbekale ti solifenacin succinate
Nọmba 2 Ifiwera ti awọn agbegbe ti o ga julọ ti ojutu kanna ti solifenacin succinate ni awọn lẹgbẹrun PP ati awọn agbọn gilasi lati ọdọ awọn olupese mẹta A, B, ati C.
Iwọn otutu ti ọwọn jẹ 30 ° C, iwọn sisan jẹ 1.0 milimita / min, ati iwọn abẹrẹ jẹ 50 milimita, Iwo gigun wiwa jẹ 220 nm.
1.2.2 Succinic acid ayẹwo: lilo YMC-PACK ODS-A 4.6 mm × 150 mm, 3 µm iwe, 0.03 mol / L fosifeti buffer (ti a ṣatunṣe si pH 3.2 withphosphoric acid) -methanol (92: 8) bi alakoso alagbeka, ṣiṣan oṣuwọn 1.0 milimita / min, iwọn otutu ọwọn 55 °C, ati iwọn abẹrẹ jẹ 90 milimita.Awọn chromatograms ni a gba ni 204 nm.
1.3 ICP-MS onínọmbà ọna
Awọn eroja ti o wa ninu ojutu ni a ṣe atupale nipa lilo eto Agilent 7800 ICP-MS, ipo itupalẹ jẹ ipo He (4.3mL / min), agbara RF jẹ 1550W, oṣuwọn gaasi pilasima jẹ 15L/min, ati iwọn sisan gaasi ti ngbe je 1.07mL / min.Iwọn otutu yara kurukuru jẹ 2 ° C, iyara fifa soke / iyara imuduro jẹ 0.3 / 0.1 rps, akoko imuduro ayẹwo jẹ 35 s, akoko gbigbe ayẹwo jẹ 45 s, ati ijinle gbigba jẹ 8 mm.
Apeere igbaradi
Solifenacin succinate ojutu: ti a pese sile pẹlu omi ultrapure, ifọkansi jẹ 0.011 mg / milimita.
1.4.2 Succinic acid ojutu: pese sile pẹlu ultrapure omi, ifọkansi jẹ 1mg/mL.
1.4.3 Solifenacin ojutu: tu solifenacin succinate ninu omi, iṣuu soda carbonate ti wa ni afikun, ati lẹhin ti ojutu ti yipada lati funfun tomilky ti ko ni awọ, ethyl acetate ti wa ni afikun.Layer acetate ethyl ni a yapa lẹhinna a ti tu sosita kuro lati fun solifenacin.Tu iye ti o yẹ ti solifenacin inethanol (awọn akọọlẹ ethanol fun m 5% ni ojutu ikẹhin), ati lẹhinna dilute pẹlu omi lati mura ojutu kan pẹlu ifọkansi ti 0.008 mg/mL solifenacin (pẹlu ojutu solifenacin succinate ti o wa ninu ojutu kanna bi solifenacin). fojusi).
Awọn abajade ati ijiroro
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2.1 Adsorption agbara ti HPLC lẹgbẹrun ti o yatọ si burandi
Pin ojutu olomi kanna ti solifenacin succinate sinu awọn lẹgbẹrun PP ati awọn ami iyasọtọ 3 ti awọn lẹgbẹrun autosampler ni abẹrẹ ni awọn aaye arin ni agbegbe kanna, ati pe agbegbe tente oke ti tente oke akọkọ ti gbasilẹ.Lati awọn esi ti o wa ni Nọmba 2, o le rii pe agbegbe ti o ga julọ ti awọn ọpa PP jẹ iduroṣinṣin, ati pe ko fẹrẹ si iyipada lẹhin 44 h. Lakoko ti awọn agbegbe ti o ga julọ ti awọn ami mẹta ti awọn gilasi gilasi ni 0 h kere ju igo PP lọ. , ati agbegbe ti o ga julọ tẹsiwaju lati dinku lakoko ipamọ.
Ṣe nọmba 3 Awọn iyipada ni awọn agbegbe oke ti solifenacin, succinic acid, ati solifenacin succinate awọn ojutu olomi ti o fipamọ sinu awọn agbọn gilasi ati awọn abọ PP.
Lati ṣe iwadi siwaju sii lasan yii, solifenacin, succinate acid, awọn solusan olomi ti solifenacin acid ati succinate ni awọn agbọn gilasi ti awọn igo Band PP lati ṣe iwadii iyipada ti agbegbe oke pẹlu akoko, ati ni akoko kanna gilasi naa.
Awọn ojutu mẹta ninu awọn lẹgbẹrun ni a ti so pọ pọ pẹlu lilo Agilent 7800 ICP-MSPlasma mass spectrometer fun itupalẹ ipilẹ.Awọn data ti o wa ni Nọmba 3 fihan pe awọn abọ gilasi ni agbedemeji olomi ko ṣe adsorb succinic acid, ṣugbọn ipilẹ solifenacinFree ti a polowo ati solifenacin succinate.Gilasi lẹgbẹrun adsorb succinate.Iwọn linacin lagbara ju ti ipilẹ ọfẹ solifenacin, ni akoko ibẹrẹ Solifenacin succinate ati ipilẹ ọfẹ solifenacin ni awọn ago gilasi.Awọn ipin ti awọn agbegbe ti o ga julọ ti awọn ojutu ti o wa ninu awọn igo PP jẹ 0.94 ati 0.98, lẹsẹsẹ.
O gbagbọ ni gbogbogbo pe oju ti gilasi silicate le fa diẹ ninu omi, eyiti omi kan darapọ pẹlu Si4 + ni irisi awọn ẹgbẹ OH lati ṣẹda awọn ẹgbẹ silanol Ninu akopọ ti gilasi oxide, awọn ions polyvalent ko le gbe, ṣugbọn irin alkali (gẹgẹbi Na + ) ati awọn ions irin ilẹ alkaline (gẹgẹbi Ca2 +) le gbe nigbati awọn ipo ba gba laaye, paapaa awọn ions irin alkali jẹ irọrun ṣiṣan, le ṣe paṣipaarọ pẹlu H + adsorbed lori gilasi gilasi ati Gbigbe lọ si aaye gilasi lati dagba awọn ẹgbẹ silanol [3-4].Nitorinaa, ifọkansi H + ti ilosoke le ṣe igbelaruge paṣipaarọ ion lati mu awọn ẹgbẹ silanol pọ si lori dada gilasi.nipasẹ table1 fihan pe akoonu ti B, Na, ati Ca ninu ojutu yatọ lati giga si kekere.jẹ succinic acid, solifenacin succinate ati solifenacin.
ayẹwo B (μg/L) Na (μg/L) Ca (μg/L) Al (μg/L) Si (μg/L) Fe (μg/L)
omi 2150 3260 20 Ko si Iwari 1280 4520
Succinic acid ojutu 3380 5570 400 429 1450 139720
Solifenacin Succinate Solusan 2656 5130 380 Ko si Iwari 2250 2010
Solifenacin ojutu 1834 2860 200 Ko si Iwari 2460 Ko si wiwa
Tabili 1 Awọn ifọkansi eroja ti solifenacin succinate, solifenacin ati awọn ojutu olomi succinic acid ti a fipamọ sinu awọn ago gilasi fun awọn ọjọ 8
Ni afikun, o le rii lati data ti o wa ninu tabili 2 pe lẹhin ibi ipamọ ninu awọn igo gilasi fun awọn wakati 24, tituka pH ti omi bibajẹ ti jinde.Iyatọ yii jẹ isunmọ pupọ si imọran ti o wa loke
Vial No. Oṣuwọn imularada lẹhin ipamọ ni gilasi fun 71 h
(%) Oṣuwọn imularada lẹhin atunṣe 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
Tabili 3 Ipo iparun ti solifenacin succinate lẹhin afikun acid
Niwọn igba ti Si-OH lori dada gilasi le ti pin si SiO-[5] laarin pH 2 ~ 12, lakoko ti solifenacin waye N ni agbegbe ekikan Protonation (iwọn pH ti ojutu olomi ti solifenacin succinate jẹ 5.34, pH iye ti solifenacin). ojutu jẹ 5.80), ati iyatọ laarin awọn ibaraẹnisọrọ Hydrophilic meji ti o yorisi adsorption oogun lori dada gilasi (Fig 3), solifenacin ti wa ni ipolowo siwaju ati siwaju sii ni akoko pupọ.
Ni afikun, Bacon ati Raggon [6] tun rii pe ni ojutu didoju, awọn acids hydroxy pẹlu ẹgbẹ hydroxyl ni ipo ti o ni ibatan si ẹgbẹ carboxyl Awọn solusan Iyọ le jade siliki oxidized.Ninu eto molikula ti solifenacin succinate, ẹgbẹ hydroxyl kan wa ti o ni ibatan si ipo ti carboxylate, eyiti yoo kọlu gilasi naa, SiO2 ti fa jade ati gilasi ti bajẹ.Nitorinaa, lẹhin iṣelọpọ iyọ pẹlu acid succinic, adsorption ti solifenacin ninu omi paapaa han diẹ sii.
2.2 Awọn ọna lati yago fun adsorption
pH akoko ipamọ
0h 5.50
24h 6.29
48h 6.24
Awọn iyipada pH 2 ti awọn ojutu olomi ti solifenacin succinate ninu awọn igo gilasi
Botilẹjẹpe awọn lẹgbẹrun PP ko ṣe adsorb solifenacin succinate, Ṣugbọn lakoko ibi ipamọ ti ojutu ni vial PP, awọn oke alaimọ miiran ti wa ni ipilẹṣẹ ati gigun ti akoko ibi-itọju maa n pọ si agbegbe tente oke aimọ, eyiti o fa kikọlu si wiwa ti tente oke akọkọ. .
Nitorina, o jẹ dandan lati ṣawari ọna ti o le ṣe idiwọ adsorption gilasi.
Mu 1.5 milimita ti solifenacin succinate ojutu olomi ninu vial gilasi kan.Lẹhin ti a gbe sinu ojutu fun awọn wakati 71, awọn oṣuwọn imularada jẹ gbogbo kekere.Fi 0.1M hydrochloric acid kun, ṣatunṣe pH si nipa 2.3, lati inu data ti o wa ninu Table 3. O le rii pe awọn oṣuwọn imularada gbogbo pada si awọn ipele deede, ti o nfihan pe iṣeduro akoko ipamọ adsorption le ni idinamọ ni pH kekere.
Ona miiran ni lati din adsorption nipa fifi Organic olomi.Ṣe 10%, 20%, 30%, 50% methanol, ethanol, isopropanol, acetonitrile ti pese sile ni ifọkansi ti 0.01 mg/mL ninu omi Solifenacin succinate.Awọn solusan ti o wa loke ni a fi sinu awọn apoti gilasi ati awọn lẹgbẹrun PP, lẹsẹsẹ.Ni iwọn otutu yara Iduroṣinṣin rẹ ti ṣe iwadi awọn ifihan.Iwadi na rii pe epo-ara Organic kekere ko le ṣe idiwọ adsorption, lakoko ti epo epo ti o pọ julọ yoo ja si apẹrẹ tente oke ajeji ti tente oke akọkọ nitori ipa ipalọlọ.Awọn olomi Organic iwọntunwọnsi ni a le ṣafikun lati ṣe idiwọ imunadoko succinic acid Solifenacin ti wa ni ipolowo lori gilasi, ṣafikun 50% methanol tabi ethanol tabi 30% ~ 50% acetonitrile le bori ibaraenisọrọ alailagbara laarin oogun naa ati oju ti vial.
PP lẹgbẹrun Gilasi lẹgbẹrun Gilasi lẹgbẹrun Gilasi lẹgbẹrun Gilasi lẹgbẹrun
Akoko ipamọ 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% kẹmika kẹmika 835.8 825 825.6 825.8 823.1
Table 4 Awọn ipa ti o yatọ si Organic olomi lori awọn adsorption ti gilasi igo
pe solifenacin succinate ti wa ni idaduro ni pataki ni ojutu.Table 4 awọn nọmba
O ti han pe nigbati solifenacin succinate ti wa ni ipamọ ninu awọn lẹgbẹrun gilasi, lo
Lẹhin ojutu olomi Organic ti apẹẹrẹ ti o wa loke ti fomi, succinate ninu awọn lẹgbẹrun gilasi.Agbegbe tente oke ti linacin laarin 48h jẹ kanna bi agbegbe tente oke ti vial PP ni 0h.Laarin 0.98 ati 1.02, data jẹ iduroṣinṣin.
3.0 ipari:
Awọn burandi oriṣiriṣi ti awọn lẹgbẹrun gilasi fun ipilẹ alailagbara succinic acid Solifenacin yoo ṣe agbejade awọn iwọn oriṣiriṣi ti adsorption, adsorption jẹ pataki nipasẹ ibaraenisepo ti awọn ẹgbẹ amine protonated pẹlu awọn ẹgbẹ silanol ọfẹ.Nitorinaa, nkan yii leti awọn ile-iṣẹ idanwo oogun pe lakoko ibi ipamọ omi tabi itupalẹ, rii daju lati fiyesi si pipadanu oogun, pH diluent ti o yẹ tabi pH diluent to dara le ṣe iwadii ni ilosiwaju.Apeere bẹ fun awọn olomi oganic lati yago fun ibaraenisepo laarin awọn oogun ipilẹ ati gilasi, nitorinaa lati dinku aiṣedeede data lakoko itupalẹ oogun ati abajade abajade lori iwadii.
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[2] https://go.drugbank.com/drugs/DB01591
[3] El-Shamy TM.Igbara kemikali ti awọn gilaasi K2O-CaO-MgO-SiO2, Phys Chem Glass 1973;14:1-5 .
[4] El-Shamy TM.Oṣuwọn-ipinnu igbese ni dealkalisation ti silicateglasses.
Phys Chem Gilasi 1973;14: 18-19 .
[5] Mathes J, Friess W. Ipa pH ati agbara ionic lori awọn tovials adsorption IgG.
Eur J Pharm Biopharm 2011, 78 (2): 239-
[6] Bacon FR, Raggon FC.Igbega ti Attack lori Gilasi ati Silica nipasẹ Citrateand
Awọn Anions miiran ni Ojutu Aṣoju.J AM
Ṣe nọmba 4. Ibaraṣepọ laarin ẹgbẹ amino protonated ti solifenacin ati awọn ẹgbẹ silanol ti o ya sọtọ lori oju gilasi
Akoko ifiweranṣẹ: Oṣu Karun-26-2022