Xây dựng phương pháp định tính, định lượng nguyên liệu tạp chất C của terazosin

B YT

B YT IH

I

IH

I

N T T NGHI

C

N T T NGHI ng d n: Th Thanh Th y c hi n: B

I - 2019

I - 2019

c

M CL C L IC DANH M

VI T T T

DANH M

NG

DANH M

TH

TV Th Thanh Th y - gi N

i th y tr c ti

c

NG 1. T NG QUAN .................................................................................... 2

t th i gian qua,

1.1. Terazosin ............................................................................................................ 2

ih c

ng d

b

1.1.1. M t s

t qua nh

c nghi

............................................................................................................ 1

1.1.2. Ch

ni

nh c a terazosin .................................................................................. 2

1.1.3. M t s ch ph m ch a terazosin .................................................................. 3

khoa h c. h

k thu

ih

i

1.2. T p ch t C c a terazosin .................................................................................. 4

ab

1.2.1. M t s

u ki

t p C c a terazosin ............................................ 4 nh v gi i h n t p ch t C c

th c hi

ph m ch a terazosin ............................................................................................... 4

Cu anh, ch

u khoa h c t i b

c

n

nh ICT b ng TLC ......................................................... 5

n

nh gi i h n t p ch t C .................................................. 5

n t t nghi

Ti n tr ng s

terazosin ............................................................ 2

c at tc m

ng h p t p ch t C c a terazosin .......................................... 7

i.

1.3. T ng quan v 1.3.1. P

d

u .... 7

........................................................................................ 7 ..................................................................................... 8 c ........................... 9

1.4. Th p h th ng s

.................................................................... 9

c hi u................................................................................................. 10 ............................................................................................... 10 tuy

nh.............................................................. 10 ...................................................................................................... 11 nh c a dung d t l p t p chu t l p t p chu

........................................................... 11 gi i .......................... 11 gi i ................................................. 11

t l p t p chu n t i Vi t Nam ................................................ 12

T LI U, THI T B , N U ............................................................................................ 13

ACDQ

u, thi t b ......................................................................................... 13

dimethoxyquinazolin

t, ch t chu n .................................................................................. 13

ACN

2.1.2. Thi t b ....................................................................................................... 14 2.2. N

4-Amino-2-cloro-6,7-

Acetonitril

BP (British Pharmacopoeia)

u........................................................................................ 15

DOX

ng TLC ...................................... 15

Doxazosin

EP

ng ICT b ng HPLC ............... 15 2.2.3.

HL

ng d ng c

HLNT

li u ICT ................................................................................................................ 15 2.3.

HPLC (High performance liquid chromatography) IAT (Impurity A of terazosin)

u ................................................................................ 15 ...................................................................................... 15 ................................................................................... 16

2.3.3. Th

ICT (Impurity C of terazosin)

............................................................ 16

2.3.4. M t s

th

d

C NGHI M, K T QU 3.1. Th c nghi

KP (Korean Pharmacopoeia)

....................... 17

PA (Pure Analysis)

N ............................ 18

MeOH

t qu .................................................................................. 18

Methanol

RSD (Relative standard deviation)

ng TLC ...................................... 18 ng ICT b ng HPLC ............... 21 3.1.3.

TB

ng d

li u ICT ................................................................................................................ 35

TEA

Triethylamin

n ............................................................................................................ 37

TEZ

Terazosin

u ICT b ng TLC .................................. 37

TLC (Thin layer chromatography)

u ICT b ng HPLC ............ 37 3.2.3.

ng d

TLTK u

USP (United State Pharmacopoeia)

ICT ....................................................................................................................... 38 K T LU

N NGH ................................................................................ 40 U THAM KH O

PH L C

UV (Ultraviolet) VIS (Visible) VKNTTW

G B ng 1.1. M t s ch ph m ch B ng 1.2.

ng ...........................................3

nh v gi i h n t p ch t C c

c c u t o c a terazosin .....................................................................2

nh

M t s bi

c ch

ng ...........................................4

ph m ch a terazosin ........................................................................................................5

c c u t o t p ch t C c a terazosin theo USP ....................................4

B ng 1.3.

nh ICT b ng TLC ...........................................................5

Ph n ng t ng h p ICT...................................................................................7

B ng 1.4.

nh gi i h n t p C c a terazosin ......................................6

T p chu n C c a terazosin c a H

B ng 2.1. Danh m c ch t chu

d

u.....................................13 ng c

B ng 2.2.

B ng 2.3. M t s

th

d

B ng 3.1. K t qu kh B ng 3.2. S

ng c

h nh

19

ic ng c

B ng 3.3.

B ng 3.4. K t qu kh

10 s

ng c

S

th

c hi u c

...........27

S

kh

ng USP 40 m u ICT C 2

S

kh

.............................................................32

S

kh

.................................33

S

th

ng tuy l pl ic

B ng 3.8. K t qu th B ng 3.9. K t qu th

.............................21

c - acetonitril - methanol (60:30:10) ........................................................22 ng USP 40 v

u MeOH ..........23 u MeOH...............23

c hi u c

..........................30

..........33

K t qu

tinh khi t pic ICT chu n ..............................................30

...................................34

K t qu

tinh khi t pic ICT th ..................................................30

.........................................................34 u t ng h

............................................. 18

........................25

.........................................31

B ng 3.7. K t qu th

B ng 3.11.

XPE26 (d = 0,001 mg) ......................15

tuy

B ng 3.6. K t qu kh

n M ......................................13

.

..........................................28

ch th

nh c a ch

Ch t chu n terazosin c a H

p h th ng s

B ng 3.5.

B ng 3.10. S li

T p chu n A c a terazosin c a VKNTTW ...................................................13

...........16 .........................17

n M ............................. 13

K t qu ch ng ph UV pic t p C chu

c .....................................36

th bi u di n s ph thu c gi a n

p C th ............................31 a pic ICT .......32

S

u ICT b ng TLC .........................................35

.S

u ICT b ng HPLC ......................................35

1.1. Terazosin g cao khi

70.

N

1.1.1. M t s

terazosin

.M

n

c:

-

-

1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-(tetrahydro-2-

furoyl)piperazin monohydroclorid.

-

: C19H25N5O4.HCl cc ut

1.1.

[31], [38].

1 - adrenergic tuy

[24], [33], [46] [32], [43], [44], [45] 1,4-bis(4-amino-

6,7-dimethoxy-2-quinazolinyl)piperazin dihydroclorid)

th

-

,

i [9].

C19H25N5O4.HCl C19H25N5O4.HCl.2H2

[43].

cloroform c th c hi n v i 3 m c

u t p ch t C c

1.

23,89 ng 459,92

-

ICT trong .

n-hexan [26], [32], [43].

1.1.2. Ch

nh c a terazosin

u ICT b ng TLC ng nguy

2.

3.

c c u t o c a terazosin

1.

d ng h p

d ng

nh

nh

li u ICT b ng HPLC ng

-

u ICT t ng

-

c.

[2], [25], [42].

-

nh. Terazosin trong

[22],

[37], [46]. phosphoglycerat kinase 1

1

2

[27] [29]

[34]

[33], [36] -

[23], [28], [39].

1.1.3. M t s ch ph m ch a terazosin 2. M t s bi

c ch

ng

1.2.

[47]

H

1.2.1. M t s

).

B ng 1.1. M t s ch ph m ch

Apo-terazosin

2, 5

Apotex

2

Hytrin

1, 2, 5, 10

Abbott

4 5 6 7

Terazosin Accord Terazosin hydrochlorid Vicard-T Terazosin 1A - Pharma Terazosin HCl dihydrate

2, 5 2

1,4-bis(4-amino-6,7-dimethoxy-2-quinazolinyl)piperazin dihydroclorid

-

1

3

-

ng

HL (mg)

TT

t p C c a terazosin

Accord Healthcare Geneva Pharmaceuticals

2

Abbott

2, 5

1A - Pharma

1, 2, 5, 10

Sandoz

Canada, New Zealand, Singapore M , Australia, Trung Qu c, Philipin, n

-

C24H28N8O4.2HCl cc ut

C c c u t o t p ch t C c a terazosin theo USP

3.

-

ng: 565,45

- Nhi c M

y: 305 C [49].

- T p ch t C c a terazosin theo 9.0, t p III theo KP X 1.2.2.

ng v i t p ch t E theo BP 2017

ng th

m t t p ch t c a doxazosin [45].

nh v gi i h n t p ch t C c

m

ch a terazosin u terazosin

ph m ch

v gi i h n t p ch

3

ng 1.2.

4

B ng 1.2.

nh v gi i h n t p ch t C c ph m ch a terazosin n u terazosin u terazosin

Gi i h n t p ch t C 0,4% 0,5% 0,4% 0,4%

1.2.3.

M ts

u tham kh o [44], [45] [32], [43] [45] [45]

(%) C8 (250 x

nh ICT b ng TLC u tham kh

nh ICT b ng TLC v i nhi u

h

c

nh gi i h n t p C c a terazosin

B ng 1.4.

c khai tri

n m ng

P - acetonitril citrat pH 3,2 (2 : 350 : TEZ.HCl 1650) [32] : T [43] T : Detector: UV 245 nm

): 5 mg ICT

0,5

B, C, E, K, J, M, L

silica gel 60 F254 (B ng 1.3). nh ICT b ng TLC

B ng 1.3. i ng m u li u TEZ [26] li u TEZ [26]

li u ICT [10]

Nguy li u ICT [10]

li u ICT [10] 1.2.4.

P

ng Cloroform - toluen methanol (9 : 1 : 6) Methylen chlorid - ethyl acetat - acid acetic (19 : 1 : 0,2) Ethyl acetat - TEA dung d ch amoniac 25% chi t l h (21: 6 : 7) Dicloromethan - TEA dung d ch amoniac 25% - methanol, chi t l y h (25 : 7 : 12 : 1) n-butanol - TEA - dung d ch amoniac 25% (20 : 4 : 1)

N

ICT

nv t ICT

c p

n

Ch

c

t pc a terazosin

P 3,2 - acetonitril (1685: 315) TEZ.HCl T : [44] : [45] Detector: UV 254 nm N : 1,7

TEZ 0,5 mg/ml ICT 2

0,4

TEZ, IAT, IBT, ICT

c Phun xeri sulfatc p amoni molipdat

i 0,05 mg/ml 2 nm, 312 nm.

i 0,05 mg/ml 2

i 0,05 mg/ml 2

-

t pc a terazosin IAT ACDQ ICT

ICT th ICT chu n

ICT th ICT chu n

acetonitril - methanol O theo EP, t

TEZ.HCl [35]

5

u tham kh o

B, C, E, J, K, L, M, N, O

QDa mass o

N DOX mesylat [45]

o

C

C18 (250 x 4 mm, 5 ng: gradient n P g m dung d ch acid phosphoric (5g/100ml) acetonitril c /;lnl; ml ICT 1,5 T Detector: 210 nm Nhi c Th

nh gi i h n t p ch t C nh gi i h n ICT trong m t s

0,5

:

6

IAT, ICT, 0,25 doxazosin

1.2.5.

1.3.1.2.

ng h p t p ch t C c a terazosin

terazosin.

n

Rf

Rf = terazosi

4 [9]:

[1], [3], [20].

f

1.3.1.3.

ng d ng trong ki m nghi m

-

trong

f

-

4. Ph n ng t ng h p ICT T

ng h p ICT ng

, u t p ch t C c a terazosin c

gi i ch

[3], [20].

1.3.2.

1.3.2.1.

c

T

terazosin.

1.3.

1.3.1.

1.3.1.1.

c

[1], [20].

1.3.2.2.

-

(tR): l

i gian c n thi

r a gi i m t ch t, t

t

n detector [1], [3].

- Di

ion

-S

t [30]. t (N): s

t bi u th hi

c a c t)

[1], [3].

7

8

a c t (hay hi u l c bi u ki n

)2 ho c N = 16 ( )2

N= 5,54 ( W: chi u r

pic

W1/2: chi u r -

n a chi u cao pic [1], [4], [20].

1.4.2.

i gi a hai pic c a hai ch

i (Rs): RS =

c hi u

c sau:

c hi

h ch c ch n ch t trong m u, ch ng h

ho c

t

p ch

n ph m suy

...[21]. tRB, tRA: t

(A

nh:

WA, WB

-

W1/2A, W1/2B

t ch

nha -H s

t ch

[1], [20].

(T) (h s

i x ng AS):

[1], [30]. c sau:

n gi ng ch t

n -

ng: ch ng minh k t qu

1.4.3.

l pl

nh

ng b

ut

T= :c

l p l i di n t

d: k

am

trong m

nghi m trong m t kho ng th i gian ng n v

[1], [3], [4].

1.3.2.3.

trung gian

b.C

ng d ng trong ki m nghi m

l pl ib ng

3n

nh t i thi

(3 n

m c t i thi

-

t thi t

nh

n trong ph m

nl pl ic am in 100% n

) ho c s d ng

th nghi m.

hi n s

cv

, thi t b

m [21], [45].

1.4.4.

[4].

-

tuy

nh

tuy

[3], [20]. v in

1.4.

tuy

-

am (trong kho ng nh

di n t k t qu nh) c a ch

h gi

m

1.4.1.

ng, kho

p h th ng s p c a h th

p [1].

9

mb

i c a ch

tuy

nh

nh t i thi

n 120% n

nh: chu n b

thi u c a m

m b o h th ng s

in c kh

(x) trong kho ng

i quy y = ax + b, h s

Kho [21], [45].

u th hay s ph thu c ch t c

nh, bi u th b

-

ct l

th . n X1 - Xn (t i thi u 5 m c

n

n th

10

c

ng Y1 - Yn. T

s

n

1.5.2.

t l p t p chu n t i Vi t Nam

.

trong ,

: %Y

c

[30].

[48], [50]. i

1.4.5. p c a k t qu th c nghi m so v m nghi

th c.

iv im

u

- T ng h p t p chu n A c a terazosin [12], [17] - T ng h p t p chu n B c a terazosin [14]

s d

- T p chu n C c a terazosin [9]

i c a chu n.

d

nh l

Ph i th c hi

t

3n

(trong ph

ng c a m ch t chu n. ng), m i n

t3l n

- T p chu n A c a clopidogrel [5], [18] - T p chu n 4-aminophenol c a paracetamol [8] -T

l p l i. s

t qu c

ng

trong

1.4.6.

c a c

n ho c

th m

a gliclazid [6]

- T p (2-clorophenyl)diphenylmethanol c a clotrimazol [7] - T p A c a gabapentin [10]

nh [30].

- T p A c a metronidazol [11]

nh c a dung d

-T

a nifedipin [13]

- T p captopril disulfit c a captopril [15]

[30].

- T p 2-amino-1-(4-nitrophenyl)propan-1,3-diol c a chloramphenicol [16]

1.5.

1.5.1.

t l p t p chu

H i ngh qu c t v c ph c v im

th t

c ph

n hi u qu ng nh . Nh n d

p ch t a thu

nh c b

[40], [41]

,

u tr ngay .

i trong thu

u

- T p B c a valsartan [19].

gi i

m b o ch

c

ng thu c gi i h u h t

nh vi c ki m tra t p ch

th gi

u t p chu n c

C c a terazosin

cH

t ch

c thi t l p.

n M , Sigma

Research Chemicals thi t l p

ng h

t p chu n

Aldrich (Merck), Toronto c

.

11

12

2.1.1.2.

CT): -

2.1.

2.1.1.

-

t, ch t chu n

:

- Acid citric khan PA

2.1.1.1. Ch t chu n

- Acetonitril PA

1.

B ng 2.1. Danh m c ch t chu

d

- Acetonitril HPLC

u

- n-butanol PA - Cloroform PA HLNT H0M084

terazosin (H

- Ethyl acetat PA

95,0%

C

terazosin

- Diclomethan

WS.0117344.01

)

- Isopropanol

97,26%

- Methanol PA G0F290

)

- Methanol HPLC

91,9%

- Natri citrat PA

2-cloro-6,7dimethoxyquinazolin-4- Sigma-Aldrich amino (ACDQ) PA

- Tetrahydrofuran PA STBC3541V

99,7%

- Triethylamin PA 2.1.2. Thi t b -

.

254

-

.

-VIS V

-

.

-

. .

-

-VIS Hitachi U-

.

1. T p chu n C c a terazosin c a H i nM

2. T p chu n A c a terazosin c a VKNTTW

-VIS SPD-

3. Ch t chu n ng terazosin c a H nM

-

m gradient LCCTO-10AS VP, b

DAD SPD-M20A

-

13

ch METTLER TOLEDO XPE26 (d = 0,001 mg)

14

).

-

Cloroform - tetrahydrofuran - methanol (6 : 3 : 1).

-

Dicloromethan - acetonitril - methanol (4 : 4 : 1).

2.3.2.

LC

-

.

-P dihydrat

8,63g acid citric khan

(d = 0,001 mg)

4.

00 ml

ml triethylamin

2.2.

B

2.2.1.

ng TLC

ng c

B ng 2.2.

ACN 92

8

83

17

ng ICT b ng HPLC

2.2.2.

Gradient

Gradient 2.2.3.

ng d ng c

92

li u ICT

-

: 1,0 ml

2.3.

-

: 40 C.

2.3.1.

-

:

gel 60 F254

8

.

.

2.3.3. Th 2.3.3.1. Th

n

: -

- triethylamin -

(21 : 6 : 7)

2.3.3.2. Th

.

-

- triethylamin -

: 1) -

- methanol (25 : 7 : 12 .

n-butanol - triethylamin -

p l i nhi u l n dung d ch chu s th i g

(20 : 4 :1).

- triethylamin - triethylamin -

tR, di

S, s

t N, h s

-

- cloroform - n-hexan - methanol (9 : 8 : 2 : 2).

- methanol -

15

; R

, .

.

i

.

form - ethyl acetat - methanol - triethylamin (7 : 3 : 2 : 1).

i x ng As,

Rs. .

-

-

:

-

tuy

nh:

16

t

50% -

+ b,

3.1.

3.1.1.

ng TLC

3.1.1.1. Kh

%Y

ng

Vi c kh -

trung gian:

ng

ICT b

10 h

c th c hi n

c 2.3.1 v

sau:

- S d ng b n m ng silica gel 60 F254.

- Ch

nm

t dung d

ung d ch ICT n

0,05 mg/ml, dung d ch IAT 0,1 mg/ml,

dung d ch chu n TEZ 0,05 mg/ml -

:

t pha trong

ch ACDQ 0,05 mg/ml, dung d ch h n h p

ICT, IAT, TEZ, ACDQ v i n 3

-P

nv ts

-

-

th

M ts

n

c l a ch

ng n

- K t qu kh

:

2.3.4. M t s

a ch n: c

s

100

b ng h

ts c th hi

t p.

ng 3.1

d

th

cs d

u th hi n trong

B ng 2.3.

B ng 2.3. M t s

th

d

th

c : g

= l ch chu n

l ch chu Sai s chu n

3.1a)

1 3.1b)

2 3.1c)

3 3.1d)

4 3.1e)

3.1f)

6 3.1g)

7 3.1h)

8 3.1i)

9 3.1k)

5

S= i

RSD = Sx = i X=

.Sx

17

Sx: sai s chu n

H

1. 10 s

ng c

18

10

B ng 3.1. K t qu kh

ng c -

: silica gel 60 F254 (Merck).

f`

ICT 1

2

IAT TEZ ACDQ

0,41 0,11 0,57

0,37 0,30 0,74

0,64

0,80

ml trong methanol.

-

d

-

4

:d

0,68 0,31 0,75

0,8

4

0,71 0,49 0,76

0,73

5

0,49 0,43 0,51

0,57

mg/ml trong methanol.

ICT 0,05 mg/ml; IAT 0,1 mg/ml, TEZ 0,05

mg/ml, ACDQ 0,05 mg/ml trong methanol.

-

4

ethyl acetat - triethylamin -

ch amoniac 25% (21 : 6 : 7), .

V -

3

ICT

c

4 V

.

3.1.1.2. Th

nhau.

c hi u

- Chu n b f

ch ch m s : methanol.

. :h

6

0,59 0,16 0,73

0,70

4

Dung d

ml methanol. :h

.

ICT

ml methanol.

:h

0 ml methanol. : h

tan

7

0,00 0,00 0,18

0,74

8

0,89 0,50 0,86

0,92

9

0,00 0,00 0,53

0,74

c a USP

10

0,00 0,00 0,57

0,81

mg/ml IAT; 0,05 mg/ml TEZ

ml

methanol. :h

nhau.

5 mg ACDQ trong 100 ml methanol. :h

- Ti

ng t p chu n ICT, IAT c a USP, ch t chu n TEZ c dung d

0,05 mg/ml ICT; 0,1

0,05 mg/ml ACDQ.

ch m

ng

n m ng.

Tri n khai s c

n v t. :d Rf =

Rf ICT, IAT,

TEZ (Rf = 0,57), ACDQ (Rf = 0,64) (

TEZ, ACDQ t n-

19

20

Rf = 0,11), 3.2).

c pic

a) Kh

u ki n s

-

u theo USP 40 c kh

:

- acetonitril -

: 30 : 10)

m citrat pH 3,2 - acetonitril t l 1685

: 1,0 ml : 30 C : 20 : 254 nm Dung d 2. S

th

:h

(t l

c hi u c

ICT trong

c - acetonitril - methanol

c dung d

2 g/ml

USP 40

nh.

:H

ng ICT b ng HPLC

3.1.2.

3.1.2.1. Kh

u

Ti

u nh m m

tan t t nh h nh

c th c hi c - acetonitril - methanol (t l 60 : 30 : 10)

triethylamin - acetonitril -

m citrat (t l 2 : 350 : 1650) v

K t qu kh

u ki n nhi M

t nh t trong methanol (5mg ICT/100 ml

3. S

kh

ng USP 40 m u ICT C 2 ml c - acetonitril - methanol (60:30:10)

-

. c pha m

v i t l ph c t 3.1.2.2. Kh

nh p m acetat ch a 6 g/l

n nhi a ch

t

Kh

v ip

s cn

u.

i

a ICT trong dung

d ch:

ng

methanol h ml ml ACDQ.

21

22

ml ICT,

ml

u ki n ch y s

.S

:

c) Kh

ng

Q

u tham kh

y

i nh ng k t qu s c uc am

u ti l

i theo th i gian.

C 3.4b) H n h

3.4a) M u tr ng 4. S

kh o s

ng USP 40 v

i u MeOH

Nh n th y, chi

. : 1,0 ml

N

.

: 40 C.

ic

:

.

i nhau (Rs = 1,081). b) Kh

u ki

.

ng theo BP 2017

c kh

:

m citrat (6 g/l natri citrat

) - acetonitril

Methanol.

- triethylamin (1650 : 350 : 2) u ki

n5 :

ml methanol.

nh c a BP 2017:

ml methanol.

.

T

ml

.

ml IAT, 20

n: UV 245 nm.

Nhi

c

m citrat: h .

at

8,63g acid citric khan

ml

:

ng: h n h

0,25 ml triethylamin.

m citrat - acetonitril v i t l

methanol.

i theo th i gian ch y s (Ph l c 1). K t qu th hi n B ng

h

trong MeOH

3.2.

ml IAT. K t qu s

ml

ml ACDQ.

.

Th

ml

: pic IAT

(H

)

3.5b) M u IAT

3.5a) M u tr ng 5. S kh

u MeOH

23

24

B ng 3.2. S TT

h nh

ic

S c

radient H s

Nh 7

l n, pic ICT lao xu

c ng

n n.

i 1

i gi

nhau Rs = 0,182. . i

8

2

nhau Rs = 1,257.

i nhau Rs = 0,810.

Pic ICT v

9

3

Rs = 1,530.

i nhau Rs = 1,469.

10

Rs = 1,562.

i 4

nhau Rs = 1,554.

C

u b ch

u.

11 RS = 2,573.

5

i nhau Rs = 1,017.

12 6

Rs = 1,745.

Rs = 1,489.

Nh v it l

ng khi b xa kh i nhau. H s ph

citrat gi a

25

m

(Rs1 = 0,182; Rs2 = 0,810; Rs3 = 1,469).

26

i

n 12 v i t l ph m citrat

ng b t

-

ACN, ch s

h

i nhau

i gi

nh t,

ch t chu n TEZ trong

c dung d

m

ml IAT,

ml ICT,

ml TEZ

ml ACDQ.

us d

HPLC.

-

3.1.2.3.

p

HPLC

: : -

C

.

m citrat: h

at

8,63g acid citric khan

ml -

ng: H n h

0,25 ml triethylamin.

m citrat

it l

- aceto

ng:

t l ng c

B ng 3.3.

3.1.2.3. Th

92

8 Gradient

83

92 : 1,0 ml

-

:

-

trong 250 ml methanol.

3.1.2.3. p

HPLC .

B ng 3.4. K t qu kh

8

.

TT

:

. . : ethanol.

-

1

34,257

2815182

17621

1,987

2

34,299

2787085

18114

1,859

3

34,343

2838798

18431

1,971

4

34,045

2798924

19170

1,837

5

33,930

2828841

16831

1,699 1,677

6

ml methanol.

-

RSD (%)

ml methanol.

27

p h th ng s

(mAU.min)

C.

-

-

tan

17 Gradient

-

PLC

a)

ACN

33,874

2791039

16765

34,125

2809978

17822

0,59

0,75

1,81

28

4 0,59 %

0,75 %

(

).

trong

b) 6. S

: MeOH. ICT ICT

:h

3.6d).

ICT

3.6c).

:

th

ICT

c hi u c

ml MeOH.

:

R=

ml MeOH. ml MeOH. :

34,174

R = 34,257

(methanol)

mg ch t chu n terazosin c a USP trong 250 ml

MeOH. Dung d ch ACDQ

mg ACDQ trong 250 ml MeOH.

ICT, t

7, 3.8)

ml MeOH.

.

7. K t qu pic ICT chu n 3.6b).

3.6a).

8. K t qu khi t pic ICT th

K 0,9924

29

tinh khi t

3.9)

30

tinh

B ng 3.6. K t qu kh

ng tuy

50%

80%

100%

120%

150%

10,011

16,018

20,022

24,027

30,033

1580699

2469091

ml)

3147939 3809052 4775829

y = 160646,5790x - 59975,9338 R = 0,9997 1,91% 9. K t qu ch ng ph UV pic t p C chu

p C th y = 160646,5790x - 59975,9338

c)

120%, 150% (Co)

Co

5,269

100 100% (C100)

d ng 2 dung d ch C100, C150 v

c th hi n ch th

B ng 3.5.

50%

4 ml Co

B ng 3.5.

tuy

th bi u di n s ph thu c gi a n

10.

20ml

kho ng n ch pic ICT

80%

4 ml C100

5ml

100%

8 ml Co

20ml

d)

120%

4 ml C150

5ml

-

150%

12 ml Co

20ml

R = 0,9997.

trung gian d .

K

.

6

31

a pic ICT

32

B ng 3.7. K t qu th

l pl ic

B ng 3.9. K t qu th

ap

TT TT

pic (mAU.s)

(mg)

gian (mg)

pic (mAU.s)

HL (%)

1

34,257

2815182

4,461 34,174

2787450

99,39

2

34,299

2787085

5,272 34,267

3287698

99,20

34,343

2838798

5,167 34,227

3218931

99,10

34,045

2798924

5,248 34,225

3288048

99,66

5

33,930

2828841

4,857 33,811

3025529

99,09

6

33,874

2791039

5,299 33,794

3300120

99,06

4,705

3

(HL: 95,0%)

4

TB

2809978

1

80%

4,014

3,974

99,00

2

80%

3,988

3,928

98,50

3

80%

4,025

3,949

98,11

4

100%

5,017

5,060

100,86

5

100%

5,152

5,104

99,07

6

100%

5,029

5,100

101,41

7

120%

6,137

6,200

101,03

8

120%

6,159

6,239

101,30

9

120%

6,032

6,152

101,99

99,25

RSD (%)

t B

0,24

9

98,11 %

n 101,99 %

f) K

ng

.

ICT

B ng 3.8. K t qu th TT 1 2 3 4 5 6

HL (%) 99,39 99,20 99,10 99,66 99,09 99,06

TT 7 8 9 10 11 12

HL (%) 99,03 98,99 99,85 99,51 99,39 99,58

TB (n = 12) = 99,32 % RSD (n = 12) = 0,29 % k p e) ICT , .

.

33

B

.

B ng 3.10. S li

nh c a ch

(mAU.s)

(mAU.s)

0

34,453

3194004

34,106

3201108

1

34,535

3191628

33,972

3225145

2

34,520

3184074

34,005

3239525

6

34,519

3180868

34,052

3232994

12

34,372

3199112

33,976

3198621

24

34,416

3192271

34,080

3229496

TB

34,469

3190326

34,032

3221148

RSD (%)

0,19

0,21

0,16

0,53

34

K t qu : s .N

3.1.3.

th i g

c a pic ICT trong dung d ch chu n.

3.1.3.3.

ng d

dung d ch th

ng d

u ICT

li u ICT 3.1.3.1.

ng d

u ICT

3.1.2.3.

p

HPLC . D

hu sau: ng ICT (%) = 3.11 u t ng h

B ng 3.11.

ICT (mg) 11. S

u ICT b ng TLC

s Rf = 0,41

3.1.3.2.

ng d

u ICT

(mAU.s)

c

(%)

5,243

3666246

95,0

5,200

3631551

95,0

4,985

3662574

99,82

4,857

3558162

99,53

4,886

3583131

99,63

4,968

3628082

99,34

5,092

3723404

99,47

5,057

3690114

12)

99,26 99,51

S

0,20

Sx

0,08

RSD (%)

0,20

X

0,21 99,51

h

99,51

3.12b)

3.12a) 12. S

u ICT b ng HPLC

35

36

0,21%.

0,21

3.2.

3.2.1.

.

u ICT b ng TLC -

a terazosin, m C

40 C trong m

u tham kh

IA

[35], nhi

a ch n m c nhi l

c

40 C,

hai m c nhi 35

20 C,

i v i doxazosin.

nhi

ts

u

t t.

u ICT b ng HPLC

3.2.2.

t .

-

[21], [45]

-

:p

terazosin

i gi : methanol

-

s

: 30 : 10

40

BP 2017,

c a dung d

24 gi t

i. Dung d

u ki n thu n l

ng t ch gi a n

kh :

-

l pl

HPLC cho k t qu ml

i v i dung

c hi n

d pv -

n

m

ml,

3.2.3.

y.

ng d

u

ICT

ng.

hi u l d

:k 0,25 ml/1l .C 3.1.2.3.

ng th

ng n ng

ng nh

u

u ICT. H

HPLC

c th m

nh

ng quy k thu t

thi t l p t p ch n C c p

nM

n Ki m nghi m thu c

(Ph l c 4).

Trong vi c ng d

u ICT,

u ICT cho k t qu

Rf

Rf nhau

37

ng

38

TLC

,

ng 99,51

%.

1. a terazosin

u ICT b ng TLC: u ki n s

n m ng silica gel 60 F254 (Merck), h

g m ethyl acetat - triethylamin n

ng

(21 : 6 : 7),

.

, th

i nv ts c

254 nm.

-

c th

uv

c hi u.

2.

li u ICT b ng

HPLC: - i u ki n s

t C8 (250 x 4,6 mm;

(0,25 ml triethylamin/ 1 l dung d c

C, th

b

-

c th

s ck

c hi

nh

uv

t

p h th ng

nh. d ng

nh

nh

ng

c:

X

99,51

t qu

%

u

pc .

1. S

2.

39

m citrat

ml

n UV 254 nm.

tuy

p d ng 2 t ng h p

nh

m) - acetonitril, t

40

c h c s 515, xu t b

u ICT

3. S Ti ng Vi t 1.

B y t (2017),

2.

B Y t (2007),

3.

B y t (2016),

n Vi t Nam V

i, ph l c 5.3, 5,4.

ct p2

tb nYh

i, tr. 60.

ng c

tb nYh

N i, tr. 79-82, 84-110, 173-210.

4.

B y t (2011), Ki m nghi

c ph m

tb nYh

i, tr. 84-

110.

5.

Nguy n Kim Chi (2016),

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ng t p ch t A c a clopidogrel

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M ch Kh c Duy, Nguy

c Tu n (2016), "Thi t l p ch

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methylbenzensulfonamid (t p A), 2-nitroso-octahydrocyclopenta[c]pyrrol (t p ng th i t p A, t p B trong ch ph m gliclazid", T 7.

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Nguy n Th Qu nh Giang (2016), Thi t l p ch t chu n (2-clorophenyl) diphenylmethanol, Lu

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trong ki m nghi m

n t t nghi

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22.

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symptoms: evidence and approaches for best case management", Canadian

Tr

i, Nguy

(2016), "Thi t l p ch nifedipin (t

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ph m nifedipin", T 14.

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nh, Nguy

,

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chu n c p nh t:

PH L C 1 ng c

Ph l c 1:

NG C Ph l c 2: M t s s

i di n th

ng ICT

TT

b ng HPLC Ph l c 3: M t s s Ph l c 4: T

i di n

u ICT b ng HPLC

ng quy k thu t thi t l p t p chu n C c a terazosin theo D

nM

1

Ph l c 5: B

2

3

4

5

6

Th 0-7 7 - 15 15 - 29 29 - 30 30 - 40 0-7 7 - 15 15 - 29 29 - 30 30 - 40 0-7 7 - 10 10 - 25 25 - 26 26 - 45 45 - 46 46 - 60 0-7 7 - 15 15 - 35 35 - 36 36 - 60 0-7 7 - 10 10 - 15 15 - 18 18 - 19 19 - 40 40 - 41 41 - 60 0-7 7 - 10 10 - 17 17 - 18 18 - 40 40 - 41 41 - 60

m (%) 90 90 - 82 82 82 - 90 90 90 90 - 83 83 83 - 90 90 90 90 84 84 84 - 82 82 82 - 90 90 92 92 - 82 82 82 - 92 92 92 92 - 90 90 90 - 85 85 - 83 83 83 - 92 92 92 92 - 90 90 90 - 83 83 83 - 92 92

ACN (%) 10 10 - 18 18 18 - 10 10 10 10 - 17 17 17 - 10 10 10 10 - 16 16 16 - 18 18 18 - 10 10 8 8 - 18 18 18 - 8 8 8 8 -10 10 10 -15 15 - 17 17 17 - 8 8 8 8 - 10 10 10 - 17 17 17 - 8 8

Ch Gradient Gradient ng d Gradient Gradient

Gradient Gradient Gradient

Gradient Gradient

Gradient Gradient Gradient Gradient

Gradient Gradient Gradient

7

8

9

10

11

12

0-7 7 - 15 15 - 35 35 - 36 36 - 45 0-7 7-1 10 - 45 45 - 46 46 - 60 0-7 7 - 15 15 - 29 29 - 30 30 - 40 0-7 7 - 15 15 - 30 30 - 31 31 - 40 0-7 7 - 15 15 - 35 35 - 36 36 - 45 0-7 7 - 15 15 - 32 32 - 33 33 - 45

92 92 - 84 84 84 - 92 92 92 92 - 83 83 83 - 92 92 92 92 - 83 83 83 - 92 92 92 92 - 83 83 83 - 92 92 92 92 - 83 83 83 - 92 92 92 92 - 83 83 83 - 92 92

8 8 - 16 16 16 - 8 8 8 8 - 17 17 17 - 8 8 8 8 - 17 17 17 - 8 8 8 8 - 17 17 17 - 8 8 8 8 - 17 17 17 - 8 8 8 8 - 17 17 17 - 8 8

Gradient Gradient

Gradient Gradient

Gradient Gradient

Gradient Gradient

Gradient Gradient

Gradient Gradient g

PH L C 2

PH L C 3

HPLC

PH L C 4

PH L C 5

CAO