TAP CHf Y Dl/QC HQC CXN THg

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TAP CHf Y Dl/QC HQC CXN THg - SO 13-14/2018 TAI L I E U T H A M K H A O

1. AOAC (2012). requirements for single laboratoiy validation of chemical methods.

2. Ebbo Schnaith (2009), "Determination of the pepsin activity in human gastric juice, using defined oligopeptides as substrates". Clinical Biochemistry Journal, 22 (2), pp. 91-98.

3. Food and Drug Administration, Centre for Drug Evaluation and Research (2001), Guidance for industry, Bioemalytical Method Validation.

4. Gomes, N., Gonfalves, C , Garcia (2011), "Optimization of a colorimetric assay for yeast lipase activity in complex systems". Analytical Methods, 3(4), pp. 1008-1013.

5. Hasan, F., Shah, A. A., & Hameed, A. (2009), "Methods for detection and characterization of lipases: a comprehensive review". Biotechnology advances, 27(6), pp. 782-798.

6. Rodrigo, Andreia, Daurin F., Louis J., Valderma H. (2003), "A fluorimeti-ic method for the determination ofpepsin activity", ^na/3'«"ca/5/ocftem«/rv, 316 (l),pp.l 1-14.

7. UUa-Maja Bailey,Chamindie P, Justin J., Cooper-White(2012), "Analysis of the extreme diversity of salivary alpha-amylase isoforms generated by physiological proteolysis using liquid chromatography-tandem mass spectrometry". Journal of Chromatography B, 911, pp. 26-29.

8. European Union (2002), Commission decision of 12 August 2002 implementing Council Directive 96/23/EC concerning the performcmce of cmalytical methods and the interpretation of results.

(Ngdy nhdn bdi: 19/11/2017 - Ngdy duyjt ddng: 09/01/2018)

N G H I E N C i r u T O N G H O P TAP CHAT LIEN QUAN N - B U T Y R Y L - N - { [ 2 ' - ( 1 H - T E T R A Z 6 L - 5 - Y L ) B I P H E N Y L - 4 - Y L ] M E T H Y L } -

L - V A H N CUA VALSARTAN

Trdn Quoc Phd'" Trmmg Trin Trang+ Nguyin Mgnh Quan^, Nguyen Biic Tuan , Do Chau Minh Vinh Thg

1. Cdng ty cd phdn Dugc Hdu Giang 2. Cdng ty co phdn Dugc phdm COu Long 3. Trudng Dgi hgc YDugc Cdn Tha 4. Truang Dgi hgc YDugc TP HCM

*Email: [email protected]

TOM TAT

Bgt vin de: tgp B (N-butyryl-N-{[2'-(lH-tetrazol-5-yl)-biphenyl-4-yl]methyl}-L-valin), phdt sinh trong qud trinh tdng hgp valsartan, cd the dnh hudng den hiju qud dieu tij vd tinh em todn khi sudung valsartan. BP 2014 vd USP 39 yiu cdu phdi kiim tratgp chdt trong nguyen liju valsartcm cUng nhu trong thudc thdnh phdm tuang dng. Tuy nhiin, hijn nay ngudn tgp B chudn khd tdn kem vd chua cd cdng trinh nghien ciru vi tdng hgp tgp B dugc cdng bd. Muc tiiu nghiin ciiu: tdng hgp tgp B cua valsartan vd xdc dinh do tinh khiet bdng phucmg phdp HPLC. Boi tugng vd phuang phdp nghiin cuu: (S)-3-metl^l-2-((2'-(lH-tetiazol-5-yl)-biphenyl-4-yl methyl)- aminoj-butyric acid (DOP) dugc tdng hgp bdng cdch dun hdi luu valsartan trong HCl Them butyryl clorid, pyridin vd acetonitril vdo hdn dich DOP trong acetonitril a -5°C. Them methanol vd nude vdo hdn hgp a nhijt dg phdng. Chinh vi pH = 7,5 bdng Na2COs 10%, cd quay, them

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TAP CHI Y Dl/gC HQC CAN THg - SO 13-14/2018

cloroform, chinh ve pH = 2 bdng HCl Tdch lay dich chiet cloroform, co quay dugc dgng nhdy.

Them methanol di tgo dung djch trong, them nuac de chuyin sang dgng hdn dich. Cd quay 5(fC din khi thu dugc bgt mau trdng. Dg tinh khiit cua sdn phdm dugc xdc dinh sa bg bdng sdc ky lap mdng, sau do bdng HPLC/PDA. Cdu tiuc cua hgp chat dugc xdc dinh bdng IR MS vd NMR Ket qud: tdng hgp thdnh cdng tgp B cda valsartan bdng phdn dng acyl hda giira DOP vd butyryl clorid. D0 tinh khiet tien 99% vd hiju sudt dgt khodng 75.37%.Kit lu^n: tgp B ciia valsartcm co the dugc tdng hgp bdng phucmg phdp de xudt, dan gidn vd cd tinh kinh te, dii dieu kijn de thiit lgp chudn doi chieu.

Tir khda: tgp B ciia valsartan. N-butyryl-N-{[2'-(lH-tetrazol-5-yl)-biphenyl-4-yl]methyl}- L-valin.

ABSTRACT

SYNTHESIS A N D PURITY DETERMINATION OF N-BUTYRYL-N-{[2'-(lH-TETRAZOLE-5-YL)-BIFHENYL-4- YL1METHYL}-L-VALINE A S R E L A T E D V A L S A R T A N IMPURITY

Phu Tran Quoc, Trang Truong Tran, Quan Nguyen Manh, Tho Do Chau Minh Vinh, Tuan Nguyen Due Background: valsartan impurity B (N-butyryl-N-{[2'-(lH-tetrazole-5-yl)-biphenyl-4- yl]methyl}-L-valine), arising from synthesis, may influence the treatment efricacy and safety oj valsartan. The BP 2014 and USP 39 require conducting the impurity test in valsartan pharmaceutical substcmce as well as corresponding finished products. However, the mentioned impurity reference stemdard is costly and there have been no published local studies on chemical synthesis of valsartan related compound B so far. Objectives: the aim of this study was to synthesize valsartan impurity B and determine its purity by HPLC method. Materials and method:

firstly, (S)-3-methyl-2-((2'-(lH-tetiazol-5-yl)-biphenyl-4-yl methyl)-amino)-butyric acid (DOP) was synthesized by refluxing valsartan in HCl. Butyryl chloride and mixture of pyridine and acetonitrile were added to DOP suspension in acetonitiile at -5°C. Methanol cmd water were added to the mixture at room temperature. The resultant mixture was adjusted to pH = 7.5 by Na^COj 10%, evaporated, added into by chloroform, and adjusted to pH = 2 by HCL The chloroform extract was separated cmd evaporated to mucus form. Methemol was added to make clear solution, then water was added to form suspension. The suspension was evaporated at 50°C in vacua until the white solid was formed. The purity of the synthesized product was preliminarily determined by TLC, and then was determined by HPLC/PDA. The structure of synthesized compound was elucidated by IR MS and NMR data. Results: valsartan impurity B was successfully synthesized by acylating DOP with butyryl chloride. The purity was more than 99%

and yield approximately 75.37%. Conclusion: valsartan impurity B could be synthesized by the proposed method, which is simple and cost-effective. The impurity conforms jiilly to establish reference stemdard for impurity testing in pharmaceuticals.

Keywords: valsartan impurity B, N-butyryl-N-{[2'-(lH-tetrazole-5-yl)-biphenyl-4- ylJmethyl}-L-valine.

I. D ^ T V A N Bt

T^p B cua valsartan (N-butyryl-N-{[2'-(IH-tetrazol-5-yl)biphenyl-4-yl]methyI}-L- valin) la tap 0-ong qud ti-mh tdng hop nen c6 thi xudt hien tirong nguyen li^u va thanh pham CO chua valsartan, d6ng thai co dpc tinh m^mh, gdy ra cdc tac dung phu khong mong muon va dnh huong nhiSu din hieu qua diSu tri. Voi nguyen li^u valsartan, USP 39 [13]

va BP 2014 [2] dlu co quy dinh 3 tap chat liSn quan A, B, C bdt bu^c phai duac kiim soat. C6n d6i vai thudc thanh phdm, USP 39 [13] co quy dinh phdi kidm sodt tap B. Tuy 316

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TifllP CHfY Dl/QC HQC C X N THg - SO 13-14/2018

nhien, chat chuan tzip B ciia valsartan khdng co san a Viet Nam, ngudn chudn ngoai nhap 1^ dang dupe cung ung vdi gid rdt cao. Hien nay, van chua co cdng trinh nghien cihi tdng hpp tap B cua valsartan dupe cdng bd a Viet Nam va tren the gidi. Xudt phdt tu nhitng ly do tren, chung tdi tiin hdnh nghien cuu tdng hpp tap chat lien quan N-butyryl-N-{[2'-(lH- tetrazol-5-yl)biphenyl-4-yl]methyl}-L-valin cua valsartan.

II. DOI TU"glNG VA PHU'ONG PHAP NGHIEN ClTU 2.1. Doi tu-^ng nghiSn cuii

Ddi tuang nghiin ciiu: tap chat lien quan N-butyryl-N-{[2'-(lH-tetrazol-5- yl)biphenyl-4-yl]methyl}-L-valin (tap B) ciia valsartan.

Hda chdt: acetonitril (ACN), acid acetic, acid hydroclorid, n-butanol, butyryl clorid (BTC), cloroform, cyclohexan, ethyl aeetat, methanol (MeOH), natri bicarbonat, natri hydroxyd, pyridin (PYR), valsartan (VAL).

Thiit bi: dung cu dun hdi luu, may khuay tir gia nhiet, bp lpc dp sudt giam, may khudy tir, may do pH, may cd quay, binh trien khai sac ky, den UV 254nm & 365nm, hS thdng mdy HPLC/PDA, may do hdng ngoai Bruker Alpha - T, may do khdi phd Waters Xevo TQD, mdy do NMR Brucker Avance III.

2.2. Phiromg phap nghien cihi

2.2.1. Tong hpp san ph^m trung gian desoxopentyl valsartan (DOP) DOP dupe tdng hprp theo sa dd duai day [4], [10], [12]-.

H'C, ,CH, H,C XH- HN. ,.N .^,, ,., J., ,0H

VAL ^"'- DOP

Hinh 2.1. Phan ling thuy phSn valsartan trong moi tmong acid 2.2.2. T6ng hffp t^p B

Tap B duoc tong hpptheo so d6 duoi day [1], [3], [5], [8], [11];

H,C CH, ^^^ H.C C„,

- • J ^°H x - ^ c i ""Y" f^f-'Y'*

DOP T a p B CHj

Hinh 2.2. Phan ung acyl hoa giOa DOP va BTC 2.2.3. Thu- tinh khilt cua DOP va tap B

sdc k^ lefp mongtsu dung 3 he dtmg moi co do phan cue khac nhau.

SSc kf ling hifu nang cao: do tinh khiSt cua DOP va tap B dugc tinh toan bSng phuong phap quy ve 100% dien tich pic.

2.2.4. Xac dinh c^u triic DOP v4 t?p B: bang cac phuong phap ph6 nghiem: UV, IR, MS, NMR.

rai. KET QUA NGHIEN C t t I

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T»P CHI Y DirpC HQC CAN THg - SO 13-14/2018 3.1. Tong hffp DOP

3.1.1. Ket qua tdng hpp DOP

Cho 2g VAL vao 150mL dung dich HCl 3M. Dun hdi Imi a 90°C cho din khi VAL tan hoan todn. De ngudi dung dich 6 nhiet dp phong, tinh the xuat hien. Lpc, rua cdn vdi nuac cdt (4 mL/ldn x 3 lan). Sdy khd d6 thu duac DOP la tinh the Mnh kim mdu trdng, ndng chay d 177-1SCC. Hieu suat phan ung tdng hpp DOP trung binh la 83,71%.

3.1.2. Thu-tinh khiet p o p

Sac ky ldp mdng: kit qua khai trien sdc ky mau thii DOP 4000ppm trong MeOH tr€n 3 he dung mdi c6 dd phdn cue khac nhau: CHCU-MeOH-CHaCOOH (8:2:0,5); n- C4H9OH-H2O-CH3COOH (4:1:1); CHiCb-MeOH-CHaCOOH (2:6:0,5) dlu cho 1 vlt duy nhdt.

sdc ky long hiju nang cao: dieu kien sac ky tdi uu: cot Thermo C16 (250mm x 4,6mm; 5pm); nhiet dp cot: 25°C; tdc dp ddng: l,0mL/phut; the tich tiem: lOpL; pha ddng A: ACN, pha ddng B: nuac H3PO4 pH = 2,5, chuang trinh gradient dung mdi pha ddng nhu bang 3.1; dung mdi pha mdu: A - B (50:50); mau thu: DOP 400ppm trong dung mdi pha mau; ddu do: UV 225nm, PDA.

Bang 3.1. Chuong trinh gradient Thoi gian (phut)

0 ^ 5 6 - . 2 0 2 1 ^ 3 5

Pha dgns A (%) 27

50 27

Plia46neB(%) 73 50 73 Dd ddc h

Hinh 3.1. Dp dac hieu d 225nm Sdc ^ dd 1: dung mdi pha mliu.

Sdc ky dd 2: DOP 400ppm.

3.1.3. Xac dinh cau true cua DOP

Hhih 3.2. Dp dac hi6u a Maxplot Sdc ky dd 3: DOP 4obppm va VAL 450ppm.

sdc ky dd 4: VAL 450ppm.

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TiJP CHf Y DLTOC HQC CAN THff - s 6 13-14/2018

\

^ / • \

-C-H(Q

\:

i

/-i

/

/ - C O O H Q

iiitAVf

il

WIVIN

I I I III

Hinh 3.3. Ph6 UV-Vis I M + H Q V ' ~

Hmh 3.4. Pho IR

^' ' '.

a'^..X)

•;t.... "%'...

Hinh 3.5. Phd MS' Hinh 3.6. Pho MS - daughter product ion Bang 3.2. Ket qua bien giai phd NMR cua DOP:

Vj tn

10 24 18 12 15 22 2(1 19 16

Loai carbon

-COOH

>C=

tetrazol)

>C=

-CH=

•SH (ppm)

7,71 d 7,691 7,55 d 7,53 d

Sc (ppm) 168,91 Khong tin hieu 140,9 140,1 Khong

tin hieu 130,66 131,04 130,66 130,37

Vi tri 14 21 17 13 23 6 11 7 9 8

Loai carbon -CH=

-CH=

>C=

>CH- -CH2-

>CH- -CHj -CH3

SH (ppm) 7,51 d 7,59 m 7,18 s 7,16 s 3,70 d

,17 d;

4,13 d 2,40-2,45 m 1,04 d 0,95 d

' " 0 .

Sc (ppm) 130,37 130,45 128,95 128,9 127,97 64,02 49,43 28,13 19,61 16,9 3.2. T6Dg h(rp tap B

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T^P CHI Y Dl/QC HQC CXN THg - s 6 13-14/2018 3.2.1. Ket qua tong hgrp t^p B

Cho khodng 1,12g DOP vdo 20mL ACN dupe lam lanh -5-0°C. Th6m vao khodng ImL BTC, ImL PYR vd lOmL ACN. Hon hpp dupe khudy d nhiet dp lanh nay trong 1 gio. ThSm ti8p hdn hpp gdm 3mL methanol yd lOmL nuac vao va khudy 6 nhiet dp phdng khoang 1 gid. Dung dich dupe dieu chinh ve pH = 7,5 bdng dung dich NaiCOs 10%, sau dd cd quay loai dung mdi huu ca d 50''C. Them vao dung dich nuac sau cd quay khodng 40mL cloroform rdi dieu chinh pH cd hai pha ve 2 bdng dung dich HCl IM. Tach lay lap cloroform rdi cd quay loai dung mdi d 50'*C den khi thu dupe lop dich nhdy trong sudt.

Hieu sudt trung binh cua 3 lan tdng hop la 73,32%.

3.2.2. Ket tinh t^p B

Phirang phdp 7:h6a tan khoang Ig tap B tho vao 20mL methanol. Them tiep 40mL nude nuac vao, ldc dSu. Cd quay chdn khdng d 50°C trong 2 gid thu dupe tap B dang bpt ran, dem say chan khdng d 50°C trong 8 gid. Hieu sudt sau 3 ldn ket tinh Id 95,80%.

Phuang phdp 2:h6a tan khoang Ig tap B thd vao lOmL ethyl aeetat. Dun each thuy d 50°C den khi cdn khoang 5mL rdi cho vao dng nghiSm, them tir tii 5mL cyclohexan dpc theo thdnh dng. De d nhi8t dp phdng khodng 8 gid, xuat Men tinh thS t^p B hinh kim mau trang. Lpc ldy tinh the, sdy chdn khdng d 50'^C trong 8 gid. Hieu sudt sau 3 Idn kat tinh la 70,22%.

3.2.3. Thir tinh khiet tgp B

Sac kj) ldp tndng:ket qua khai trien sac ky mau thii tap B 4000ppm trong MeOH tren 3 he dung mdi cd dd phdn cue khac nhau: CHCla-cyclohexan-CHaCOOH (13:5:2);

EtOAc-cyclohexan-CHjCOOH (7:7:2); n-C4H90H-H20- CH3COOH (9:1:1) deu cho 1 vet duy nhdt.

Sac ftjJ long hiiu nang cao: dieu kiSn sdc k^ tdi uu: cdt Thermo CI6 (250Tnm x 4,6mm; 5pm); nhiet dp cdt: 25°C; tdc dp ddng; l,OmL/phut; thS tich tiem: lOpL; pha dpng A: ACN, pha ddng B: nude H3PO4 pH ^ 2,5, chuang trinh gradient dung mdi pha ddng nhu bdng 3.3; dung mdi pha mdu: A - B (50:50); mdu thu: tap B 450ppm tirong dung mdi pha mau; dau dd: UV 225nm, PDA.

Bang 3.3. Chuang trinh gradient Tbcri sian (phdt)

0 - . 5 6->45 4 6 ^ 6 0

PhadOnBA(%) 27

50 27

Pha done B(%) 73

SO 73 Bang 3.4. K^t qua tuong thich he thSng

XTB RSD%

Che do UV22Snm

Max plot UV225nm Max plot

tR (phUt) 14,62 14,62 0,02 0,02

S 53551231 89601408 0,53 0,28

As 0,97 0,98 0,99 0,98

Rs 28,96 28,90 1,38 1,63

N 28207 21218 0,76 0,94

k' 13,62 13,62 0,03 0,03

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TAP CHf Y Dt/iyc HQC CAN THO - S6 13-14/2018 f d dac hieu

p o p TapB TapB

l i ^

-XJ.-

ITinh 3.7. Do dac hieu o 225mn Sac ky do 1: dung moi pha mau.

sic ky S 2: hon hop DOP 320ppm - tap B 450ppm - VAL 450ppm.

Bang 3.5. Ttnh tuyen tinh Ban, R=

F„

IA tfi

0.9995 7500,1460 4

86,6034 0,6954

> 0,995

> F„.„5(l,4) = 7,709

> to,„,(4) = 2,776

< to,os(4) = 2,776 Phirong trinh tny^n tinh:

_y=116467x

Khoang tnyen tinh:l 12,5 - 675ppm

Hinh 3.8. Dp dac hieu 6 Maxplot sic ky m 3: VAL 450ppm.

sic ky m 4: tap B 450ppm.

sic tj! ai 5: DOP 320ppm 3.6. Do lap lai va do chinh xac trung gian

3.2.4. Xac dinh cau true tap B

Bo lap lai

B6 cbinh

xic trung

gian

Gia tri (%) Dg tinh khiet trung binh RSD%

Khoang tin cay Dp tinh khifit trung binh RSD%

Khoang tin cay 1"

UV 225nm 99,35 0,03 99,31- 99,39 99,34 0,07 99,31- 99,37

Max plot 99,06 0,05 99,01- 99,11 99,07 0,06 99,04- 99,10

Hinh 3.9. Ph6 UV-Vis Hinh 3.10. Pho IR

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T»P CHI Y DL/tyC HpC CAN THO - s6 13-14/2018

O

^|M+Na|'

^{^ ^}

•Y^>^:

o

I M + H T

O cni^ o o

Hinh 3.11. Phd MS' Hinh 3.12. Phd MS"'- I 3.7. Ket qua bien giai phd NMR cua tap B (tin hieu chinh)

daughter production

Vi tri

5 10 24 18 12 15 22 20 19 16 14 21 17

Lo^i carbon

>c=o

-COOH

>C=

(tetiazol

)

>C-

>C=

-CH=

-CH- -CH=

-CH=

6„

(ppm)

7,68 m 7,63 m 7,54 d 7,06 d 7,06 d 7,57 m 7,20 d

Sc (ppm)

**(*)**

173,4 171,9 155,1 141,2 137,8 137,7 131,0 130,6 130,5 128,8 128,8 127,7 126,3

Sc (ppm)

(")

173,3 171,8 Khong tin hieu 141,2 137,7 137,7 130,9 130,5 130,5 128,7 128,7 127,7 126,3

Vi tri

13 23 6 11 4 7 3 2 9 8 1

Loai carbon

-CH=

>C=

>CH- -CHj- -CH2-

>CH- -CH2- -CH2- -CHj -CH3 -CHj

"•?• '^

SH

(ppm) 7,20 d 4,44 d 4,62 s 2,01 m;

2,23 d 2,18ni 1,50 t;

1,43 m 0,93 d 0,76 m 0,76 m

6c (ppm)

**(*)**

126,3 123,6 62,9 48,7 34,6 27,5 18,1 20,1 18,8 13,6

6c (ppm)

(")

126,3 123,5 62,9 48,7 34,6 27,5 18,0 20,1 18,8 13,5 Bang 3.8. Ket qud bien giai phd NMR cua tap B (tin hi^u phu)

Vi tri

5 10

Loai carbon

>C=0 COOH

XSP^"A°

8H

(ppm) 6c (ppm)

(•)

173,4 171,6

6c (ppm)

()**

173,3 171,6

V|

tri

17 13 23

Lo^i carbon

-CH=

-CH-

>C=

6H

(ppm) 7,10d 7,10 d

Sc (ppm)

(•)

_126,9

126,9 123,5

6c (ppm)

**(*•)**

126,9 126,9 123,5

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T»P CHt Y D\JQC HQC CAN THO - S6 13-14/2018 24

18 15 12 22 20 19 16 14 21

>C=

tetrazol)

>C=

> C - -CH=

-CH=

7,68 m 7,63 m 7,51s 6,97 d 6,97 d 7,57 m

155,1 141,3 137,1 138,2 131,0 130,6 130,5 128,3 128,3 127,6

Khong tin hieu 141,3 137,1 138,2 130,9 130,5 130,5 128,2 128,2 127,5

6 11 4 7 3 2 9 8 1

>CH- -CH2- -CH,-

>CH- -CH2- -CH2- -CH]

-CHJ -CHj

4,06 m 4,49 d 2,45 m 2,14s 1,58 dd 0,93 d 0,70 d 0,88 m

65,7 45,5 34,8 27,6 18,1 19,4 18,5 13,7

65,7 45,4 34,7 27,6 18,2 19,4 18,4 13,7

(*)• (**): phd C-NMR cua tgp B kit tinh bdng phucmg phdp 1 vd phucmg phdp 2.

IV. BAN LUAN Tong h9p t^p B

Khdo sdt ty li moi BTC:DOP (hinh 4.1):tii:n hanh theo cac didu kien: ty le moi PYR:DOP Id 4:1, thai gian phdn iing la I gid, pH = 2. Thay ddi thd tich BTC (mL).

Nhdn xet: ty le moi BTC:DOP = 3:1 cho kdt qua tdt nhdt.

Khdo sdt ty li moi PYR:DOP (hinh ^.2>.*tien hanh theo cac dieu kien: ty le moi BTC:DOP la 3:1, thdi gian phdn iing la 1 gid, pH = 2. Thay ddi thd tich PYR (mL).

Nhan x^t: ty le moi PYR:DOP = 4:1 cho kgt cjud tdt nhdt.

Khdo sdt thoi gian phdn irng (hinh 4.3): tien hdnh theo cac dieu kien: ty le moi BTC:DOP la 3:1, ty Ie moi PYR:DOP la 4:1, pH = 2. Thay ddi thdi gian phan ung: 15 phut, 30 phut, I gid, 2 gia, 4 gid, 6 gid, 8 gid.

N h ^ xet: thdi gian I gid cho ket qud tdt nhat.

Khdo sdtpH (hinh 4.4):tiin hdnh theo cdc di6u kien: ty le moi BTC:DOP la 3:1, ty Ie moi PYR:D0Pla4:I,thdi gian phan ung lai gid. Thay doi pH: 1,2,3,4,5.

Nhan x6X: pH = 2 cho kdt qud tdt nhat.

^ 80

i 60

u 4 0

•S 2 0 3

I . 0 4

iitli

K 1:1 2:1 3:1 4:1 5:1 6:1 T^ If moi gifhi BTC \k DOP

Hmh 4.1. Anh hudng cua ty 1? moi BTC va DOP ddn hifu sudt

^ O CO O I

Ty H moi Riita P V l i va D O P

Hmh 4.2. Anh hudng cua ty 1^ moi PYR vd DOP den hieu sudt

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T»P CHI Y DircyC HOC CAN THP - SO 13-14/2018

ThM fdnn phan img (gicr)

Hinh 4.3. Anh huong cua thai gian phan iing Hinh 4.4. Anh huong ciia pH den hieu

dkn hieu suat suat

V. KET LUAN

Da xay dung quy trinh tong hpp tap B bang phan ling acyl hoa giira DOP va BTC vdi xiic tac la pyridm. Kdt tinh du<?c tap B voi 2 phuong phap khac nhau. Tap B tong hop duoc CO dp tilth {chi8t > 99,0%. KSt qua cua cac phuofng phap pho nghiem cho thSy san phdm t6ng hop dugc co cau tnic phu hop vcri cau true tap B.

TAI LI|U THAM KHAO

1. Tnrong Thi Ky (2006), Hoa hm ca tgp 1, Bp Y ti, Nha xuit ban Y hpc, tr. 68-81; 282;

284.

2. British Pharmacopoeia (2014).

3. Donatienne Denni-Dischert, Hans Hirt, Dan Neville, Gottfried Sedelmeier, Anita Schnyder, Nadine Derrien, Daniel Kaufinann (2004), Process for the manufacture of valsartan. Patent WO 2004026847 Al.

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(Ngdy nhgn bai: 19/11/2017 - Ngdy duyet ddng: 10/01/2018)

NGHIEN C U t J X A Y DlTNG P H l T O N G P H A P D I N H T I N H N H A N H M Q T SO G L U C O C O R T I C O I D N G U Y T A O T R O N G C A C C H E P H A M D O N G DU*(?C D I E U T R I T H A P K H ^ P B A N G K Y T H U A T K H O I P H 6

Hd Anh Xuang^, Ngityin Mqnh Quan^\ Dd Chdu Minh VTnh Tho^

1. Cdng ty cdphdn Duac phdm Hgu Giang 2. Trudng DH YDuac Cdn Tha

* Email:nmquan@ctump. edu. vn T6M TAT

Dat van de: Vi^c phdt tiiin duac phucmg phdp phdn tich dinh tinh nhanh, nhgy, tin cdy ddng thdi 11 glucocorticoid nguy tgo trong ddng duac diiu tri viem, thdp kh&p la mot yeu cdu rdt thiit yiu. Theo dd,phucmg phdp khdi pho vdi chi do tiim mdu tiuc tiip di dinh tinh nhanh cdc chat phdn tich dang rdt dugc quan tdm phdt triin. Muc tiiu nghiin ciru: Xdy cjungyd thdm dinh quy tiinh djnh tinh nhanh ddng thdi 11 glucocorticoid nguy tgo trong cdc che phdm ddng dicgc dimg tiong diiu trj b?nh viim, thdp khdp bdng phuang phdp khdi phd theo hudng ddn cua ICH.

Boi tuang vd phtrang phdp nghiin cd-u: Mdu trdng bao gdm 17 logi dugc liiuQud tiinh chudn bi mdu dugc thuc hiin bdng cdch them chudn vao mdu tidng. Diiu kien Ididiphd bao gdm thdnh phdn dung mdi, acid formic diiu chinh pH, chi dg ion hda dirang hay dm vai cdc: kieu ghi nhdn ion m? vd mdnh con. Su nhdn biit cdc glucocorticoid bdng each so sdnh phd chudn vd mdu thir a cdc chi dg khdi phd. Kit qua: Diiu kien khdi phd toi uu: thi mao qudn 3kV, thi cone 15V. nhiit hoa hen dung mdi 400 °C, tdc dg ddng khi 900Lit/gid. Dung mdi hda tern mdu la hdn hgp MeOH:

nude acid formic 0,1% (70:30). Phuang phdp dugc thdm dinh vdi tinh ddc hieu cao vd gidi hgn phdt hiin (0.0l-0.3ppm), dugc dp dmg diphdn tich 45 mdu chi phdm dong dugc thu thdp tgi dia bdn TP. Cdn Tha vdi kit qud khodng 40% (19/45) mdu cd su nguy tgo glucocorticoid, chu yiu Id dexamethason vd betamethason. Ket ludn: phirang phdp khoi phd kieu phun mdu true tiep vai dg nhgy cao vd thdi giem phdn tich nhanh de djnh tinh ddng thdi 11 glucocorticoid da dugc xdy dung vd thdm djnh thdnh cdng. Phuang phdp cd the dp dung thuc tiin phdt hien cdc glucocorticoid nguy tgo trong cdc chi pham ddng dugc dieu trj viim, thdp khdp.

Tir khda: Khdi phd, glucocorticoid, ddng dugc, nguy tgo.