• l^ghien ciJu - Ky thuat
Nghien cmi xac dinh bo dich chuyen Raman co*
cua sildenafil, ibuprofen va lamivudin de sang loc nhanh thuoc gia
Dang Thi Ngoc Lan', Boan Cao Son^, Thai Nguyin Hung Thu'*
'D-trdng Bgi hoc Dugc Ha Npi - yien Kiim nghiim thudc Tmng uang 'E-mail, [email protected] Summary
in conSnuabon of our previous studies, ^bask:Fiaman^ifisof3APIs, induding sildenafil, ibuprofenand lamiwjdine. were built. The basic Raman sh/ft has been af^ied to test some products on the market and hx positive result. The basic Raman shift of the resea/cfted APIs had already contributed significanSy to /gpjtf screening of counterfeit dmgs on the market Furffier studies are required to detect substendard dmgs and insufficient API in formulas.
Keywords: Fiaman, sildenafil, ibupn^ten, lamivudin, counterfeit dmgs.
Dat van d@
Quang ph6 Raman \d m^t phirong phdp phSn Hch c6 nhi^u inj dilm, g^n dSy dang diroc tei &iln khai d i i>ng dgng trong nhieu ITnh vi/c. frong 36 c6 ngSnh Di/gc i^^. Vd'i kha nSng phSn tEch nhanh, kh6ng phS huy mau, thu 6in^ ph6 qua bao bl trong suot qua chai Ip thuy tinh.... ph6 Raman d i o tiiiy nhiiu tiim nSng trang kiem tra, gidm s&t di^t lifp'ng thuoc •*'.
Phuung phSp pho Raman da bdt dSu iJifiyc tnin Wiai a Vi$t Nam, cho thay Itha nSng ung dgng 16'n trong vi§c sdng Ipc thuic gia P'. Quang p h i Raman Id mOt trong ba loai p h i n^m trong khuin khi a i t i Nghj i^nh thu- v&i Hoa Ky do Viin Kilm nghi$m thuic Tmng uung chu tri thyx: hi§n. Nh&ng nghifin cini birttc diu cua i>ng dgng quang p h i Raman trong phSn tich difp'c phim dd 6w<?c triln khai 1^. O l xay dyng tiiu- vifin p h i chuin, nhim phgc vg cho c6ng tSc phSn tJdi phat ht§n thuic gia tgi Vifit Nam, siWenafil, ibuprofen va lamrvudin la cac hoat chit duvc Hip tgc triin khai nghifin ciiu.
Nguyen lieu va phuwig phap nghien ciru Nguyfin lidu
- Chit chuin; Sildenafil, ibuprofen, lamivudin (Chuin Vi6n Kiim nghidm Hiuic Trung trong).
- iWOt s6 c h i phim c6 chiJa du^yc c h i t Siklenafil, ibuprofen, lamivudin.
- Thilt bj nghi6n ctru: May quang p h i Raman d l ban hang Renishaw (Phdng Quang p h i Vi^n vat iy - Kf thudt Tnr6ng Bgi hpc Bdch khoa Hd Nii), da dutrc kiim t^nh.
cac m l u nghifin CIPU C^c vi§n chira sildenafil
- Viagra 100 mg ci3a Pfizer, 16 121483352, k?
h i ^ u S n .
- Adagrin 50 mg cOa ICA, 16 010613, ky hi$ij SI2.
- Caverta 100 mg cua Ranbaxy, lfl 2428179, kj hi^u SIS.
- Sildenafil 100 mg cua SAVA, 16 4230C, ky hi$u SI4.
- Sildenafil 50 mg cOa Badinh, 16 010114, k^
hi$u SI5.
CAc vf$n chOB ibuprofen
- Ibuprofen STADA400 nng cua STADA-VN, 16 0709131c? hifiu IBI.
- Ibuprofen 400 mg cOa TV Phama, Ifl 01082015, k? hifiu IB2.
- Mofen 400 cua Medopharm India, 16 3934, ky hifiu IB3.
- Ibuflam 400 cua Axon drugs PVT, lfl B13JFM0, ky hifiu IB4.
- Nurofen 400 mg cOa Reckitt Benckiser, 16166, l<y hifiu IB5.
C4c vien chira lamivudin
- Lamivudin STADA100 mg cua STADA-VN, Ifl 010313, ky hifiu LAI.
- Zeffix 100 mg cua GlaxoSmith Kline, lfl R655179, ky hifiu LA2.
- Lamivir HBV 100 mg cua Cipla. 16 A00328. lc?
hifiu LA3.
T ^ CHi D i r o c H p c - 7/2016 ( S 6 483 N A M 56)
• Nghien ciJu - Ky thuat
-Lamivudine HBV 100 mg cua Alpha, 1665015 k> hi^u L M .
- Mevudine 100 mg cda Medipharco. 16100113 kf hi^u LA5.
Phiromg phdp nghign ciru
CQng giong nhip nghign ci>u tni-^^ ^, phuang ph^p nghl6n ci>u 3 hoat chat n^y dirac thirc hign qua cdc budc.
- CSc m i u vign nen va vign nang dui?c nghign oi>u vi c h l tao b4i Khoa Nghign o i u vd phat triin, Vign Kiem nghigm thuSc Tnjng i/ong dtra tign ham lm?ng thi/c t4 cua mSi duoc chSt v*l cSc nen ta ducc CO ban. M6i loai vign du'oc c h i tao tign 5 ngn ta du'oc Ishac nhau c6 chi>a dipoc chit (vign tu' bao chi) va khgng chiia dugc chit (vign placebo).
T i t ca cac vign nay d i u dat chat luvng ve dinh tinh va dinh lu'ong sau khi da kiem tra bJng dc phuang phap phgn tich khac.
^ f r xac djnh b6 djch chuyen Raman co ban cua Krng ho9t chit
- Kiem tra bd djch chuyen Raman ca ban di k i t lugn o H&i viSI 5 m l u c h i phim c6 tign thi truing cho moi hoat chat
Viec xac ainh ba dich chuyin Raman co ban du'oc t i n hanh qua cac but^c sau:
- Do pho cua chit chuin d i xac dmh bg d|ch chuyin Raman: v| tri cac dinh va ty lg cuong d6 so vd'i ^ n h tham chiiu.
- 0 0 pho Raman cua cac vien placebo d i loai cac dich chuyin Raman cua duoc chit b| anh huong cua ta d u o c
- Bo pho Raman cua cgc vign ngn vg vign nang tu bao c h i de c6 k i t lugn ve b6 djch chuyin Raman co ban cua tiing duoc chit nghien ciiu.
- Anh huong cua hgm luong duac chit tiong vign ducc xac dinh bing so sanh p h i cua vign c6 ham luong 50% vol pho cOa vign eg du ham luang tuong ling.
K i t qua nghien CLPU
Bd dfch chuyen Raman ca ban cua sildenafil
Hinh 1; Ph6 Raman cda sildenafil chuin TU p h i Raman cua sildenafll chuin vign placebo va vign tu bao chl, xac djnh duoc oae dJnh dgc tnjng va ty Ig cu^ng dg Raman o
600 TOO BOD eOQ 1
Hinh 2: Phd Raman cOa vi§n nang sildenafil c^c dinh d0c tm-ng cua chat chuin v^ c^c iogi vifin nhu- bang 1. Trong 66, dinh 1238 c m ' du-gc chpn ISm dinh quy chiiu.
., , o - f • '"-'-UII w rail I uiiiM i^uy u t m u .
^^''S^-CicmdictningviltKcudngddRamanddcm^lnjiigdphdslUenafilchuin vide mill viin tu bio chi Raman shift (cnri) "
UK
Oai i»iMiiiWWiB<vili eic lofl van OaodjniivitrKilolvtiicickiflvHn
I W 0,54
1't85 0,37 ' t l 156312 1529±1 1238±2 I w t 2 1.tfc?
Sildenaf I c6 cgc tin higu djc trung tgi lap quanh ego dich chuyin Raman chlnh oiJa chit chuin Nin ta duoc 4nh huong khgng dgng k i d i n vi tii ego dinh age tn/ng ma ch! lam thay d i i euftng da Raman 6 ego dinh do su can t i * hogc cgng hop cudng dg. nhung lam Ihay d i i rit it 9 ig euftng do Raman cac dinh dgc tning 66. Trang ag dinh 1485 cm-' ft p h i chuin bj nln tg duoc Igm giam
TAP CHl D t (JC HQC - 7/2016 (S6 483 NJM sij
1,65.2,20 0.97-1,31 0.95-1.19 0,51-0,61 0,24-0.39 euftng ag Raman dang k l ngn khgng c6n lg dinh aac tnrng d l nhgn biit hoat chit nay trong vign.
Anh huftng cua hgm luong duoc chit vfti bg dich chuyin Raman co ban khgng nhiiu. P h i Raman cua cac vign c h l tao ch*a 50% sildenafil aiu cho cac dinh age trung trting vfti dinh dgc tn/ng cua pho chuin nhung ti lg euftng dg
• Nghien ciru - Ky thuat
Raman a ^ n h 1404 ± 2 cnr^ n i m ngoai gidi han da xac djnh (bang 2).
Bang 2: Cac dinh ddc tmng vdSI§ cudng dQ Raman
^cdc^h^ tnmg cda f^cdci^n che tao c^iJa 50% sikienani KamansAW fcnr'J 1580 himluvng 2.08 Raman sfift (oir'J 15B0 n/pflS/rofvMnirtnSWfiam
1564 1,12 15R4 1,06
IfiW 1,12 1520 1,07
im 1.00
m
1405 0,59
0,48
Tuy nhign sai igch ngy khfing nhilu (0,48 so v 4 0,51) ngn cft t h i mft rang khoang gifti hgn cho dlnl]
nay la 0,48-0.61.
Nhu vgy, p h i Raman cua cgc thuic chiia h o j chat sildenafil c6 b6 dich chuyin Raman co b nhu bang 3.
Bang 3: Bg dich chuyin Raman cabin cda si/de/aj
^ ~ '±2 1529tl (23812 I m g
disss'
Bamanshiftfcwr'J ISSOtI n / ! 1.85^23) 0.97-1.31 0.95-1
Hinh 3: PhS Raman cda ibupiofen chu4n T!r p h i c h u i n IbuproliBn, pho vign placebo v g pho ciia vign t u bao c h i . xac dinh d u y c cgc ainh age tn/ng vg t f ig euftng a g Raman ft cgc ainh
~ i " 9 * TI^':udng^Rsmanddcmhi^tmnacilaph6Ibupmlen
^ ^ ^ ^ 834 im m ^sm ^ Hinh 4 : Phd Raman oda vHn nin ibupmfen age tn/ng nhu bang 4 Oinh 1607 c m ' duoc chon Igm quy chilu
Raman sliiftlm^f
na.
DaoSjmivevltilaavdiciiitnfinfy, 0«)i»TO»iH)fiiaro<delij»ai~0.70 746 0,64
j s 4
lM7t2 ll82tl 120at2 mtl 5«7T 0.44'_:j looait K i i ' n ^ " " * ' ' ^ " " ^ 9 " " W Chit Ibuprofen
bang 50% so vfti hgm luong cua cac m i u vign thuc t i va eft cUng khii luftng vign, p h i Raman cua Chung cho cgc dinh trdng vfti «nh age tnrng Ti,, " f t . ™ "^ "SOU gifti ban aa xac ainh (bang 5). Tuy nhign sal Igch ngy khcng n h i i u (0 54
*:naX52!:'9r''"'*'*^^^^*
B 4 n g & ^'^ dinh vi tiii cudng dd Raman ddc dinh
• f p tmng cua phd dc yiin cd 50% him luvng ibupmfen
J,«>1,54 (,W 0,i6-,99 0.55-76 n4«.,76 0.47-.70 fiai-tf D o VSy cft t h l xgc ainh bft dich c h u y i n Raman CO ban cua ibuprofen n h u ft bang 6.
B i n g 6: Bj) dich chuySn Raman cabin cOa lbiipit*ti Raman
« « «33i1 ( » 7 i l 118212 120812 13941 74641 m i l lair}
- " ' ' ''"S-IM f,l» 0,54.,89 0,5I^,76 D,46.,76 0,47-,70 DJOIM Ba dich chuyin Raman c c M n ciia lamivudin
C * '•" '•" '" » »•« '^ 0.37
Hinh 5; PhS Raman cQa lamivudin chuin
T 4 P CHi Dlf(fC H p c - 7/2016 ( S 6 483 NAM 56)
• Nghien CLFU - Ky thuat
Phan tich p h i chuan cua lamivudin, p h i cua vien placetxD va p h i cua cac vien ty bao che, xAc tSnh duuc cac dinh dgc tnjng vdty l& cu^ng 66 Raman a cSc dinh dac tru-ng cua cSc loai vien nhy t)ang7.
W-'-w" '-Vf'vW'
iLu
!\*MHinh 6: Phd Raman cda viin nang lamivudin dhim luang giim 50%
Bing 7: V!trlvit}l$ cudng m Raman ddc anh die tnmg ctia lamivudin
"^ ?»' 1243 m m ffli m
Raman shut Icmi)
774 798
2,30 2.27
1243 1258 2,13 Mvivitila6iv6lcach^viSn 79810 78011 124341 " j j a i T Oifl4lllgil8i»aeaeliial»iai 1,67-2,35 1.61-2.61 1,62-2,30 OSiUt
1.01 tm
1612 1522 SMlf 120242 161241 152212 9861 0,68-1,09 >,l» D,73<.95 0.660,85 0,^7^1.e4 0.4H1.67 Tign vign eft hgm luftng duoe chit lamivudin
bang 50% so vfti ham luong cua cac m i u vign t h i r i te va eg cCing khii luong vign, pho Raman cua chiing cho cac dtnh tning vfti dinh age tiung cua p h i chuin nhung ti Ig euftng ag Raman ^ , „ .
Bang 8: Bg d M chuyin Raman cabin cda hoat chil lamivudin tmng viin
~^ii^ 'n:^ ^^- j ^ j
o ainh 1613 c m ' n i m ngoai gifti han da xgc ainh. CQng tu'ong tu nhu vfti ibuprofen, mft rgng khoang gifti ban ty lg euftng dg cua dinh 1613 c m ' thgnh 0,64-0,85 a i han c h l gm tinh
Raman shift (curl)
10 11
1243
1 1 41 1288 ± 0
1202 1612
" I j l,5fr2.45 1,61-2.67 1.62-2.30 0.61-1.19 O.BB-l Khgo sat trgn cgc chg p h i m
Tiln hanh khao sgt thuc t i tign 6 m i u vign chiia sildenafil (SI1-SI5). 5 mau vign
1522
± 2 41
1,00 0.72-0.95 0,64^,95 0,45<l.89 0,41-0.67 ehCra ibupiolen (IB1-IB5) vg 5 m i u vien chiia lamivudin (IA1-LA5) cft trgn th| tn/ftng. k i t qua thu duoc nhu o bang 9.10 vg 11
Raman shift(cnr'l
cm
Bangs: Kit qui do phi Raman da chi phim khio sil n ) chda siklenafil '^^•^-^- 156342
sn
( 1 . 8 5 . 2 a 1560(1.941(0.97-1.311 1561 (2.111
1561 (0.971 152911 (0.95-1.19)
123842 140442
1580(2.03
8(1.141
1529(0.961
1560(2.201 1563(1.1:
1529(1.081
1238(1.00)
(0.46-0.611 1403(0.551
1580(2.171
1563(1.191
1529(1.(61 1238(1.001 140410.601 g (1.131
1529(1.111 1236(1.001 1404(0,551 1529(1.061 1238(1.001 1403(0.621
1236(1.001 Raman shift fcm^f
f"W
° ! , " r ?' '^^ ""^ ^ ""^ Raman cila chi phim khio sit cd chua ibupmfen 1206 4 2
160741 (1.05-1.6
634(1.631 1608(10
((,(»
' ' ^ ? 1 •'°.'.™-!? '°-«^.76) ^0.47^1.701 (!>.2M.S» 74641 100811 1182(0.85) 1206(0.70) 140(0.691 745(0.651 ! o ; i 7 » ? S 1180fOS7\ 15nfi/n«!N ixn/ncm ^.^\^^-t. - . - ' ' - ^ :834(1.22) 1608(1.00) 1160(0:571 1206 o k 140 O M834(1 031 IRnfiM (VH non,n„„. :7:;;rb^:^f . . . ' ' 634(1,031 1606(1.001 1160
834(1,071 1608(1 1208(0,54) 140 ( O M 745(ll'.59l 745(0.621 1006(0.401 834(1,481 1607(1.00) 1182(0761 1206 TOM)
-'"T2 !"!°:"! '^'°'"' ' « ' " ^ ' ~ ^ i ^
1007(0.371 KamanshUtlani (Tilt
Bing n: Kit qui do phi Raman cua chi phim khio sited chda lamivudin
•0 78011 124341 12Sat1 1:
138(0.611 745(0CT 1007(0.471
J M " 120242 161211 152212 ' ^ ^ m T : » " • ^ ' - ' • ^ l J g a j » « H g L ( W ) (..,2^1,95) ,0.640.961 ^^^BTl^iiiT^
798(1.92) 78.(2.0.) 1244(1.79) 1259(0.82) 128.,.i2l S i j ^ a T l i o a (0.821 ,613,0.761 l . S ^ n J _ L n g -
T i P C H l D V p c HQC - 7/2016 (S6 483 NAM 56)
• Nghien cipu - Ky thuat
ua 798(2.45) 780(267) 1243 ( 2 a ) 1258(1.19) LA3 798(1.59) 730(171) 1243(1.68) 1259(0.65) IM 798(1.83) 779(1.90) 1243(1.73) 1258(0.82) LAS 798(1.68) 779(1.78) 1243(1.90) 1258(0,84)
1288(1,02) 1288(0,73) 1288(0,93) 1287(0,78)
593(1,00) 593(1,00) S93(f,O0) 593(1,00)
1202(0.82) 1203(0.79) 1203(0.72) 1202(0,82)
1613 J ) K ) 1612(0.80) 1613^1.80) 1612(0.71)
1522(0.89) 1522fll.45) 1521 (0.69) 1522(0.59)
985 ( 0 « | 988(0.44) 986(0.52) 985(0.481 K i t qua cho tiiiy cdc tfnh dac tJung va t' [#
cu*ng dp Raman deu nSm trong gid'i hgn cho ph6p. Nhu- v3y, c^c che pham tr&n c6 c^ua hoat chit (sildenafil hay ibuprofen hole lamivudin) tuwng O'ng.
Ban luan
Thuic tr&n thj tru'd'ng rat da dang, tCJy vdo loai hoat chat vd muc dlch su* dgng, hdm lugng hoat chat trong vi§n se kh^c nhau. Ngay ca vdi cCing mOt hoat chit, cOng lu-gng hoat chat trong vi§n, nhu-ng nhiiu cing ty du-p-c da san xuit ra cdc c h i phim c6 thdnh phin vd hdm luvng {khii lugng/khii lugng) du-gc chit trong vifin khdc nhau. Tuy nhiSn, trong ciing m i t dang bdo c ^ i , chung chi dugc hlnh thdnh boi hoat chit vd mOt so logi td dugc co- b i n , Ching hgn vdi viSn n6n thudng bao g i m hai phin: phin vo vd phin iOi.
Phin vd g i m cdc td du-gc bao vd td dugc mdu, phan ldi g i m dugc chat vd cdc td dugc ddn, rd, dfnh, tran.
P h i Raman d$c trung cho cdc dao ddng llSn k i t phdn cue, CCing vdi p h i hing ngogi, nd hS trg cho vt0c phdn tich c i u trOc phdn t u Tuy nhi§n, ngodi cdc dfnh cua cdc IiSn k i t d^c tnjng, khi cd bi>c xg kfch thich chiiu vdo, phdn ti> cdn tdn xg ra cdc bii-c xg Id tuo-ng tdc giOa cdc gic, cdc lign k i t trong phdn t u vdi nhau tgo n^n cdc dinh d^c trung rifing cho m i i phdn tu. Cdc dinh ddc trung ndy cd the su- dyng nhu "diu vdn tay" de so sdnh vd tim ra d i y cd phai id chit khao sdt hay khdng V i n d i Id phai xde djnh thfim vdi bd djch ehuyin Raman xde djnh dugc thi hdm lugng cdc hogt chit trong vifin giam d i n bao nhifiu thl tin hifiu khdng cdn phii hgp mdi thu$n tifin dp dgng vdi cdc logi c h i phim luu hdnh trfin th| trudng.
Khi st> dgng edc thiit bj Raman c i m tay, phfip phdn tich xde djnh hfi so tuang ding p h i (HQI - Hit Quality Index) gilja ehit ehuin vd ehit thu dga ti*n co sd ndy dang dugc mdy tfnh hodc phin m i m tich hgp trfin thiit bj cd tiii tinh todn so sdnh tiieo kieu "diu vdn tay" khd d i ddng
dk eho k i t qua nhanh vd chlnh xde theo cdc mt>c d i yfiu c i u cOa ngudi si> dyng.
Kit lu$n
Tif nhO-ng k i t qua dgt dugc d nghifin ci>u trudc cua chOng tdi, ba hgp chit Id sildenafil, ibuprofen, lamivudin se t i i p tye dugc khao sdt dl xde dinh bO djch ehuyin Raman ca ban. Vdi cSc bfl djch chuyin Raman ca ban ndy ed t h i tiip tyc triin khal cde bi$n phdp sdng Igc nhanh trong Idem tra phdt hi$n thuoc gia trfin thj trudng mk khflng cd hogt chat chinh nhu ghi trfin nhdn. Gin nghifin eO-u thfim d i cd the phdt hiin dugc ca nhOng thuoc kfim chit lugng do khflng du hdm lugng eOa cdc hogt chit.
Tai li^u tiiam khao 1 Assi Sulaf, A. V\fett Roberi, C. Moffat Anthony (2012), "On the quantification of ciprofloxacin in propri- etary ciproxin tablets and generic ciprofloxacin tablets using handheld Raman spectroscopy", Joumal of Ra- man Spectroscopy, 43(8), 1049-1057.
2 DSgardin Klara, Roggo Yves, Margot Pierre (2014), "Understanding and fighting the medicine counterfeit market", Joumal of Pharmaceutical and Bi- omedical Analysis, 87,167-175.
3. Haijou Mustapha, Qin Yanyan, Bradby Sanford, Bempong Daniel, Lukulay Patrick (2013), "Assess- ment of the performance of a handheld Raman device for potential use as a screening tool in evaluating me- dicines quality", Joumal of Phamiaceutical and Biome- dical Analysis, 74, 47-55.
4 Kalantri Pushkar P.. Somani Rakesh R., Makhija Dinesh T. (2010), "Raman spectroscopy: A potenial technique in analysis of phamiaceuticals", Pelagia Research Library, 1(1), 1-12.
5. e$ng Thi Nggc Lan, Nguyin Thi Thiiy Linh, Th*
NguySn Hiing Thu (2016), "Budc diu nghifin cdu (rng dyng ph6 Raman trong vific phat hifin nhanh thu6c ching lao gi^". Tap chl Duvc HQC, 01/2016 (477), 6-11
6. Le TTii Thifin Huo-ng, Dodn Cao Scm, TrSn Vi$t Hiing, Bei Ma, Young Uu. Magdy M. AH (2015),
"Phat hifin nhanh thuic gid (ethambutol hydroelond vd cefuroxim axetil) bSng k? thu^t quang phi Raman cSm tay, c|n hing ngogi cim tay vd hfing ngogi chuyin dgng Fourier xSch tay". Tap chl Duvc hpc, 08/2015 (472), 23-26.
(Ngdy nh$n bdi: 11/05/2016 - Ngdy duy$t <SSng: 05A}7/2016)
T^ CHi Dirge HQC - 7/2OI6 (S6 483 NAM 56)