Qoraaga / 1,2 Hu Rong 1 Hol drum Drum Song Xuezhi ka hor 1 dalxiiska Jinsong 1 - Kan cusub 1, 2
【Abstract】 Muraayada Borosilicate waa shay baakad ah oo si weyn loo isticmaalo iyo weelka xal ee warshadaha dawooyinka.Inkasta oo ay leedahay sifooyinka iska caabbinta sare, sida siman, caabbinta daxalka iyo xidhashada caabbinta, ions birta iyo kooxaha silanol ee ku jira galaaska borosilicate weli laga yaabaa in ay la falgalaan daroogada.Falanqaynta daawooyinka kiimikada ee waxqabadka sare ee chromatography dareeraha (HPLC), fiilada caadiga ah ee duritaanka waa muraayad borosilicate ah.Iyadoo la baarayo saamaynta dhalooyinka dhalada ee HPLC ee saddexda nooc ee xasiloonida solifenacin succinate taas oo ah xarun alkaline ah oo daciif ah, waxaa la ogaaday in adsorption ee daawooyinka alkaline ay ku jiraan dhalooyinka dhalada ee ay soo saaraan warshado kala duwan.Xayeysiintu waxay inta badan sababtay isdhexgalka amino-protonated iyo kooxda silanol dissociative, iyo joogitaanka succinate ayaa kor u qaaday.Ku darida hydrochloric acid waxay qurxin kartaa daawada ama ku darista saamiga ku habboon ee dareerayaasha organic waxay ka hortagi kartaa xajinta.Ujeedada warqadani waa in la xasuusiyo shirkadaha tijaabinta daroogada in ay fiiro gaar ah u yeeshaan isdhexgalka ka dhexeeya daawooyinka alkaline iyo dhalooyinka, iyo in la yareeyo leexinta xogta iyo shaqada baarista ee leexinta ee ay sababtay aqoon la'aanta sifooyinka xayeysiinta dhalooyinka dhalooyinka habka falanqaynta daroogada.
Erayada muhiimka ah: Solifenacin succinate, kooxda amino, HPLC dhalooyinka dhalooyinka, adsorb
Muraayadaha sida alaabada baakadaha ayaa leh faa'iidooyinka jilicsanaanta, baabi'inta fudud iyo iska caabinta daxalkaMuraayadaha daawada waxa loo qaybiyaa galaas kalsiyum sodium iyo galaas borosilicate, marka loo eego qaybaha kala duwan ee ay ka kooban tahay.iyaga ka mid ah, galaaska lime soodhaha ka kooban 71% ~ 75% SiO2, 12% ~ 15% Na2O, 10% ~ 15% CaO;galaas borosilicate ka kooban 70% ~ 80% SiO2, 7% ~ 13% B2O3, 4% ~ 6% Na2O iyo K2O iyo 2% ~ 4% Al2O3 .Dhalada Borosilicate waxay leedahay iska caabin kiimiko oo heer sare ah iyadoo ay ugu wacan tahay isticmaalka B2O3 halkii laga isticmaali lahaa inta badan Na2O iyo CaO
Sababtoo ah dabeecadda sayniska, waxaa loo doortay sida weelka ugu muhiimsan ee daawada dareeraha ah.Si kastaba ha ahaatee, galaas boronSilicone, xitaa iyada oo iska caabintiisa sare, ayaa laga yaabaa inay weli la falgasho daawooyinka, Waxaa jira afar hab oo falcelin caadi ah sida soo socota [1]:
1) Beddelka Ion: Na+ , K+ , Ba2+, Ca2+ ee galaaska dhex mara ion beddelka H3O
2) Kala dirida galaaska: Phosphate, oxalate, citrates iyo tartrates waxay dardar galin doonaan kala dirida dhalada waxayna keenaan silicides.iyo Al3+ waxaa lagu sii daayay xal;
3) Daxalka: EDTA ee ku jirta xalka dawada
4) Adsorption: Waxaa jira dammaanad Si-O ah oo jabay oogada muraayadda, kaas oo xajin kara H +
Samaynta OH- waxay samayn kartaa bonds haydarojiin kooxo gaar ah oo daroogada ah, taasoo keentay in dawada lagu dhejiyo dusha muraayadda.
Inta badan kiimikooyinka waxaa ku jira kooxo aamin ah oo daciif ah, Marka la falanqeynayo daawooyinka kiimikada leh chromatography dareeraha waxqabadka sare leh (HPLC), fiilada HPLC autosampler ee sida caadiga ah loo isticmaalo taas oo ka samaysan muraayad borosilicate ah, iyo joogitaanka SiO- oogada muraayadda waxay la falgali doontaa kooxda amine protonated. , Oggolaanshaha cufnaanta maandooriyaha hoos u dhaca, natiijooyinka falanqaynta waxay noqon doonaan kuwo aan sax ahayn, iyo shaybaarka OOS (Out of Specification).Warbixintan, aasaaska daciifka ah (pKa waa 8.88 [2]) daroogada solifenacin succinate (qaabdhismeedka qaabdhismeedka ayaa lagu muujiyey Jaantuska 1) waxaa loo isticmaalaa shayga cilmi-baarista, iyo saameynta dhowr fijaan oo dhalada borosilicate amber ah oo suuqa ku leh falanqaynta daroogada waa la baarayaa., iyo marka laga eego dhinaca falanqaynta si loo helo xal u adsorption ee daroogada sida muraayadda.
1.Qaybta tijaabada
1.1 Qalabka iyo qalabka tijaabada
1.1.1 Qalabka: Waxtarka sare ee firfircoon oo leh UV Detector
chromatography dareere ah
1.1.2 Qalabka tijaabada: Solifenacin succinate API waxaa soo saaray Alembic
Pharmaceuticals Ltd. (Hindiya).Heerka Solifenacin (99.9% daahirnimada) ayaa laga soo iibsaday USP.ARgrade potassium dihydrogen phosphate, triethylamine, iyo phosphoric acid ayaa laga soo iibsaday China Xilong Technology Co., Ltd. Methanol iyo acetonitrile (labadaba darajada HPLC) waxaa laga soo iibsaday Sibaiquan Chemical Co., Ltd. Polypropylene (PP) dhalooyinka waxaa laga soo iibsaday ThermoScientific (US). , iyo 2ml amber dhalada HPLC ah ayaa laga soo iibsaday Agilent Technologies (Shiinaha) Co., Ltd., Dongguan Pubiao Laboratory Equipment Technology Co., Ltd., iyo Zhejiang Hamag Technology Co., Ltd. (A, B, C ayaa hoos loo isticmaalaa si ay u matalaan ilo kala duwan oo dhalooyin ah, siday u kala horreeyaan).
1.2HPLC habka falanqaynta
1.2.1Solifenacin succinate iyo saldhiga bilaashka ah ee solifenacin: tiirka chromatographic isphenomenex luna®C18 (2), 4.6 mm × 100 mm, 3 µm.Iyada oo leh fosfooraska fosfooraska (miisaanka 4.1 g ofpotassium dihydrogen phosphate, miisaan 2 ml oo triethylamine ah, ku dar 1 L oo biyo ah ultrapure, walaaq si ay u milaan, usephosphoric acid (pH waxaa lagu hagaajiyay 2.5) -acetonitrile-methanol (40:30:30) sida marxaladda mobilada,
Jaantuska 1 Qaacidada qaab dhismeedka ee solifenacin succinate
Jaantuska 2 Isbarbardhigga aagagga ugu sarreeya ee isku midka ah ee solifenacin succinate ee fijaannada PP iyo dhalooyinka dhalada ah ee saddexda warshadood ee A, B, iyo C
Heerkulka tiirka wuxuu ahaa 30 ° C, qulqulka qulqulka wuxuu ahaa 1.0 mL / min, mugga duritaanka wuxuu ahaa 50 mL, hirarka dhererka la ogaado waa 220 nm.
1.2.2 Succinic acid muunad: iyadoo la isticmaalayo YMC-PACK ODS-A 4.6 mm × 150 mm, 3 µm column, 0.03 mol/L fosfooraska buffer (oo lagu hagaajiyay pH 3.2 leh fosfooraska acid) -methanol (92: 8) sida wajiga wareega, socodka heerka 1.0 mL/daqiiqo, heerkulka tiirka 55 °C, mugga duritaankana wuxuu ahaa 90 ml.Chromatograms waxaa lagu helay 204 nm.
1.3 Habka falanqaynta ICP-MS
Qodobbada ku jira xalka ayaa lagu falanqeeyay iyadoo la adeegsanayo nidaamka Agilent 7800 ICP-MS, qaabka falanqaynta wuxuu ahaa qaab He (4.3mL / min), awoodda RF waxay ahayd 1550W, heerka gaaska plasma wuxuu ahaa 15L / min, iyo heerka socodka gaaska side wuxuu ahaa 1.07ml/min.Heerkulka qolka ceeryaanta wuxuu ahaa 2°C, xawaaraha qaadista/dejinta bamka peristaltic wuxuu ahaa 0.3/0.1 rps, wakhtiga muunadku xasilintu waxay ahayd 35 s, wakhtiga qaadista muunadu waxay ahayd 45 s, qoto dheerna ururintu waxay ahayd 8 mm.
Tusaalaha diyaarinta
Solifenacin succinate: oo lagu diyaariyey biyo ultrapure ah, xooga saarista waa 0.011 mg / mL.
1.4.2 Succinic acid xal: lagu diyaariyey biyo ultrapure ah, xooga saaridu waa 1mg/mL.
1.4.3 Xalka Solifenacin: ku milmi solifenacin succinate oo biyo ah, sodium carbonate ayaa lagu daray, ka dib markii xalku ka bedelay tomilky cad oo aan midab lahayn, ethyl acetate ayaa lagu daray.Lakabka ethyl acetate ayaa markaa la kala saaray oo miraha ayaa la soo saaray si loo siiyo solifenacin.Kala dir qaddarka ku habboon ee solifenacin inethanol (ethanol wuxuu xisaabiyaa m 5% ee xalka ugu dambeeya), ka dibna ku qas biyo si aad u diyaarisid xal leh 0.008 mg/mL solifenacin (oo leh xal solifenacin succinate ah oo ku jira xalka si la mid ah solifenacin). fiirsashada).
Natiijooyinka iyo dood
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2.1 Awoodda adsorption ee fiilooyinka HPLC ee noocyada kala duwan
U dir isla xal aqueous ah ee solifenacin succinate galay fijaannada PP iyo 3 nooc oo fijaanno autosampler ah ayaa lagu duray waqtiyo isku mid ah isla deegaanka, iyo aagga ugu sarreeya ee ugu sarreeya waa la duubay.Laga soo bilaabo natiijooyinka Jaantuska 2, waxaa la arki karaa in aagga ugu sarreeya ee fiilooyinka PP ay xasilloon yihiin, oo aysan jirin wax isbeddel ah ka dib saacadaha 44. Halka meelaha ugu sarreeya ee saddexda nooc ee dhalooyinka dhalada ah ee 0 h ay ka yaraayeen dhalada PP. , iyo aagga ugu sarreeya ayaa weli sii yaraanaya inta lagu jiro kaydinta.
Jaantuska 3 Isbeddelka meelaha ugu sarreeya ee solifenacin, succinic acid, iyo solifenacin succinate xalal aqueous ah oo lagu kaydiyay dhalooyinka dhalooyinka iyo fijaannada PP
Si aad u sii barato dhacdadan, solifenacin, succinate acid, xalalka aqueous ee solifenacin acid iyo succinate ee fiilooyinka galaaska ee saaraha Band PP dhalooyinka si loo baaro isbeddelka aagga ugu sarreeya ee waqti, iyo isla mar ahaantaana muraayadda
Saddex xal oo fijaanno ku jira ayaa si firfircooni leh loogu lamaanay iyadoo la isticmaalayo Agilent 7800 ICP-MSPlasma mass spectrometer ee falanqaynta aasaasiga ah.Xogta ku jirta Jaantuska 3 waxa ay tuseysaa in dhalooyinka galaaska ee dhex dhexaadinta aqueous aanay soo saarin succinic acid, balse ay xidheen salfenacinFree base iyo solifenacin succinate.Fijaannada galaasku waxay u adkeystaan succinate.Baaxadda linacin way ka xoog badan tahay kan saldhigga xorta ah ee solifenacin, wakhtiga ugu horreeya ee Solifenacin succinate iyo saldhigga bilaashka ah ee solifenacin ee fijaannada galaaska ah.Saamiyada meelaha ugu sarreeya ee xalalka ku jira dhalooyinka PP waxay ahaayeen 0.94 iyo 0.98, siday u kala horreeyaan.
Waxaa guud ahaan la aaminsan yahay in dusha sare ee muraayadda silicate ay nuugi karto biyaha qaar, kuwaas oo biyaha qaarkood ay ku daraan Si4 + qaabka kooxaha OH si ay u sameeyaan kooxo silanol ah oo ka kooban galaas oksaydh ah, ions polyvalent si dhib leh uma dhaqaaqi karaan, laakiin birta alkali (sida. Na + ) iyo ion birta dhulka alkaline (sida Ca2+) waxay dhaqaaqi karaan marka xaaladuhu oggolaadaan, gaar ahaan ions birta alkali waa sahlan tahay qulqulka, waxay ku beddelan karaan H + oo lagu dhejiyay dusha muraayadda oo u gudbi dusha muraayadda si ay u sameeyaan kooxo silanol ah [3-4].Sidaa darteed, xoojinta H + ee kororka waxay kor u qaadi kartaa is-weydaarsiga ion si loo kordhiyo kooxaha silanol ee dusha muraayadda.Marka la eego shaxda 1 waxay muujineysaa in nuxurka B, Na, iyo Ca ee xalka ay ku kala duwan yihiin sare ilaa hoose.waa succinic acid, solifenacin succinate iyo solifenacin.
muunada B (μg/L) Na(μg/L) Ca(μg/L) Al(μg/L) Si(μg/L) Fe(μg/L)
biyaha 2150 3260 20 Wax ogaansho ah 1280 4520
Xalka succinic acid 3380 5570 400 429 1450 139720
Solifenacin Succinate Solution 2656 5130 380 Wax ogaansho ah ma jiro 2250 2010
xal solifenacin 1834 2860 200 Wax la ogaado
Shaxda 1 Qaybaha curiye ee solifenacin succinate, solifenacin iyo succinic acid xalal aqueous ah oo lagu kaydiyay fijaanada galaaska muddo 8 maalmood ah.
Intaa waxaa dheer, waxaa laga arki karaa xogta ku jirta Jadwalka 2 in ka dib markii lagu kaydiyo dhalooyinka galaaska ee saacadaha 24, kala diri pH ee dareeraha ayaa kor u kacay.Dhacdadani waxay aad ugu dhowdahay aragtida kore
Vial No. Heerka soo kabashada ka dib kaydinta galaaska 71 saacadood
(%) Heerka soo kabashada kadib PH la hagaajiyay
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
Shaxda 3 Xaaladda xaalufinta ee solifenacin succinate ka dib marka lagu daro aashitada
Maaddaama Si-OH ee dusha muraayadda loo kala qaybin karo SiO-[5] inta u dhaxaysa pH 2 ~ 12, halka solifenacin ay ku dhacdo N jawi acidic Protonation (pH oo lagu qiyaaso xal aqueous of solifenacin succinate waa 5.34, pH qiimaha solifenacin xalku waa 5.80), iyo farqiga u dhexeeya labada isdhexgalka Hydrophilic waxay keenaysaa xayeysiinta daroogada ee dusha muraayadda (Jaantus. 3), solifenacin ayaa lagu dhajiyay waqti badan iyo in ka badan.
Intaa waxaa dheer, Bacon iyo Raggon [6] waxay sidoo kale ogaadeen in xal dhexdhexaad ah, asiidhyada hydroxy acids oo leh koox hydroxyl ah oo ku yaal booska marka loo eego kooxda karboksylka Xalalka milixdu waxay soo saari karaan silicion oksaydh ah.Qaab dhismeedka molecular ee solifenacin succinate, waxaa jira koox hydroxyl ah marka loo eego booska karboxylate, kaas oo weerari doona galaaska, SiO2 waa la soosaaray oo galaasku wuu baaba'ay.Sidaa darteed, ka dib samaynta cusbada leh succinic acid, adsorption ee solifenacin ee biyaha ayaa xitaa aad u cad.
2.2 Hababka looga fogaado xayeysiiska
Waqtiga kaydinta pH
0h 5.50
24h 6.29
48h 6.24
Jadwalka 2 isbeddellada pH ee xalalka aqueous ee solifenacin succinate ee dhalooyinka dhalooyinka
Inkasta oo fijaannada PP-ga aysan ku dhicin solifenacin succinate, Laakiin inta lagu jiro kaydinta xalka ee fiilada PP, meelaha ugu sarreeya ee wasakhda ah ayaa la soo saaraa iyo Kordhinta wakhtiga kaydinta waxay si tartiib tartiib ah u kordhisaa aagga ugu sarreeya ee wasakhda, taas oo keentay faragelin lagu ogaanayo heerka ugu sarreeya. .
Sidaa darteed, waxaa lagama maarmaan ah in la sahamiyo hab ka hortagi kara xayeysiinta muraayadaha.
Qaado 1.5 mL oo solifenacin succinate aqueous aqueous vial galaas ah.Ka dib markii lagu meeleeyay xalka saacadaha 71, heerarka soo kabashada dhamaantood way hooseeyaan.Ku dar 0.1M hydrochloric acid, hagaajin pH ilaa 2.3, laga soo bilaabo xogta ku jirta Jadwalka 3. Waxaa la arki karaa in heerarka soo kabashada oo dhan ay ku soo noqdeen heerar caadi ah, taas oo muujinaysa in falcelinta kaydinta xayeysiinta lagu xakameyn karo pH hoose.
Hab kale ayaa ah in la yareeyo xayaysiinta iyadoo lagu darayo dareerayaasha organic.Samee 10%, 20%, 30%, 50% methanol, ethanol, isopropanol, acetonitrile waxaa lagu diyaariyey xadiga 0.01 mg/mL ee dareeraha Solifenacin succinate.Xalalka kor ku xusan waxaa lagu riday dhalooyin quraarad ah iyo dhalooyin PP, siday u kala horreeyaan.Heerkulka qolka Deganaanshaheeda ayaa la darsay waxay muujinaysaa.Baaritaanka ayaa lagu ogaaday in dareeraha organic aad u yar uusan ka hortagi karin xayeysiiska, halka dareeraha organic aad u badan uu u horseedi doono qaabka ugu sarreeya ee aan caadiga ahayn ee ugu sarreeya sababtoo ah saameynta dareeraha.Keliya dareerayaasha organic dhexdhexaadka ah ayaa lagu dari karaa si wax ku ool ah looga hortago succinic acid Solifenacin waxaa lagu dhajiyaa muraayadda, ku dar 50% methanol ama ethanol ama 30% ~ 50% acetonitrile waxay ka adkaan kartaa isdhexgalka daciifka ah ee ka dhexeeya daroogada iyo dusha fiilada.
Fijaannada PP-ga Dhalada Dhalada Dhalada Fijaannada Dhalada ah
Waqtiga kaydinta 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
Shaxda 4 Saamaynta dareerayaasha dabiiciga ah ee kala duwan ee ku saabsan xayeysiinta dhalooyinka dhalooyinka
in solifenacin succinate si gaar ah loogu hayo xal.Shaxda 4 tirooyinka
Waxaa la muujiyay in marka solifenacin succinate lagu kaydiyo dhalooyin dhalo ah, isticmaal
Ka dib markii xalka dareeraha organic ee tusaalaha kor ku xusan la qaso, succinate ee fijaannada galaaska.Aagga ugu sarreeya ee linacin gudaha 48h waxay la mid tahay aagga ugu sarreeya ee fiilada PP ee 0h.Inta u dhaxaysa 0.98 iyo 1.02, xogtu waa mid deggan.
3.0 gabagabada:
Noocyada kala duwan ee dhalooyinka dhalada ah ee saldhigga daciifka ah ee succinic acid Solifenacin waxay soo saari doontaa heerar kala duwan oo adsorption ah, xayeysiinta waxaa inta badan keena isdhexgalka kooxaha amine-protonated ee kooxaha silanol ee bilaashka ah.Sidaa darteed, maqaalkani wuxuu xasuusinayaa shirkadaha tijaabinta daroogada in inta lagu jiro kaydinta dareeraha ama falanqaynta, hubi inaad fiiro gaar ah u yeelatid luminta daroogada, pH-ka ku habboon ee dareeraha ah ama pH ku habboon ayaa horay loo baari karaa.Tusaale ahaan dareerayaasha oganic si ay uga fogaadaan isdhexgalka ka dhexeeya daawooyinka aasaasiga ah iyo dhalooyinka, si loo yareeyo eexda xogta inta lagu jiro falanqaynta daroogada iyo eexda ka dhalatay baaritaanka.
[1] Nema S, Ludwig JD.Foomamka qiyaasta daawada - daawooyinka waalidnimada: mugga 3: xeerarka, ansixinta iyo mustaqbalka.Qormada 3aad.Crc Press;2011.
[2] https://go.drugbank.com/drugs/DB01591
[3] El-Shamy TM.Waarta kiimikada ee muraayadaha K2O-CaO-MgO-SiO2, Phys Chem Glass 1973;14:1-5.
[4] El-Shamy TM.Talaabada go'aaminta heerka ee macaamilka muraayadaha silicate.
Phys Chem Glass 1973;14: 18-19.
[5] Xisaab J, Friess W. Saamaynta pH iyo xoogga ionic ee tovials adsorption IgG.
Eur J Pharm Biopharm 2011, 78 (2): 239-
[6] Bacon FR, Raggon FC.Kor u qaadida weerarka lagu qaaday dhalooyinka iyo Silica ee Citrateand
Anions kale ee Xalka Dhexdhexaadka ah.J AM
Jaantus 4. Isdhexgalka u dhexeeya kooxda amino-protonated ee solifenacin iyo kooxaha silanol ee la kala gooyay ee dusha muraayadda
Waqtiga boostada: May-26-2022