B Y T

TRNG I HC DC H NI

NGUYN TH TRANG
M SINH VIN: 1101535

NGHIN CU BO CH VIN NN
CLOPIDOGREL 300MG
KHA LUN TT NGHIP DC S

H NI - 2016

B Y T
TRNG I HC DC H NI

NGUYN TH TRANG
M SINH VIN: 1101535

NGHIN CU BO CH VIN NN
CLOPIDOGREL 300MG
KHA LUN TT NGHIP DC S

Ngi hng dn:

1. Ths. Bi Th Lan Phng
2. DSCKI. Nguyn Th Huyn

Ni thc hin:
1. Vin Cng ngh Dc phm Quc gia
2. B mn Cng nghip Dc

H NI - 2016

LI CM N
Li u tin ti xin by t lng bit n chn thnh v su sc ti ThS.Bi Th
Lan Phng, DSCKI.Nguyn Th Huyn- nhng ngi nhit tnh hng dn,
gip , gii p nhng kh khn, thc mc m ti gp phi trong sut thi gian
thc hin kha lun.
Ti xin chn thnh cm n PGS.TS.Nguyn Ngc Chin- ngi truyn la
tnh yu khoa hc, tn tnh ch bo v a ra nhng li khuyn qu bu trong qu
trnh lm nghin cu khoa hc hon thnh kha lun tt nghip ny.
Ti cng xin gi li cm n ti ThS.Nguyn Th Thy Trang, ThS.Ng Quang
Trung, cc anh ch Vin Cng Ngh Dc phm Quc gia- nhngngi lun
gip , du dt ti t nhng ngy u lm nghin cu khoa hc, to iu kin
thun li cho ti trong qu trnh lm thc nghim v hon thnh kha lun.
Ti cng xin cm n Ban gim hiu, cc phng ban, cc thy c gio v cn
b nhn vin trng i hc Dc H Ni- nhng ngi dy bo, truyn t
nhng kin thc qu bu, tnh yu ngh nghip, lun gip ti trong sut 5 nm
hc tp ti y.
Cui cng, ti xin by t lng bit n su sc ti gia nh v bn b lun
bn ng vin khch l v gip ti trong sut thi gian qua.
H Ni, ngy 02 thng 05 nm 2016
Sinh vin

Nguyn Th Trang

MC LC
DANH MC CC K HIU V CH VIT TT
DANH MC CC BNG BIU
DANH MC CC TH, HNH V
T VN ................................................................................................................. 1
CHNG 1: TNG QUAN.......................................................................................... 2
1.1. i nt v clopidogrel bisulfat ......................................................................... 2
1.1.1. c im ca clopidogrel bisulfat ............................................................ 2
1.1.2. c im dc ng hc .......................................................................... 5
1.1.3. Ch nh ..................................................................................................... 5
1.2. Cc yu t nh hng v bin php ci thin tan, ha tan dc
cht trong vin nn .................................................................................................. 6
1.2.1. Cc yu t nh hng n tan v ha tan dc cht ca vin
nn ....................................................................................................................... 6
1.2.2. Mt s bin php lm tng tan v ha tan dc cht t tan ......... 10
1.3. n nh v mt s yu t nh hng n n nh ca dc cht.... 11
1.3.1. n nh ............................................................................................... 11
1.3.2. Cc yu t nh hng n tc phn hy dc cht ........................... 11
1.4. Mt s hng nghin cu ci thin kh nng ha tan v n nh ca
ch phm cha clopidogrel trn th gii ............................................................. 12
CHNG 2:I TNG V PHNG PHP NGHIN CU ......................... 14
2.1.Nguyn liu, thit b ......................................................................................... 14
2.1.1. Nguyn liu ............................................................................................. 14
2.1.2. Thit b nghin cu ................................................................................. 15
2.2.Ni dung............................................................................................................ 15
2.3.i tng nghin cu ...................................................................................... 15
2.4. Phng php nghin cu ............................................................................... 15
2.4.1. Phng php bo ch vin...................................................................... 15
2.4.2. Phng php th ha tan ....................................................................... 17

2.4.3. Phng php nh lng clopidogrel bisulfat t vin nn clopidogrel ........ 19

2.4.4. Phng php th n nh vin nn clopidogrel sau khi bo ch ...... 21
CHNG 3: THC NGHIM, KT QU V BN LUN ................................. 22
3.1. Kt qu thm nh mt s ch tiu ca phng php nh lng o
quang ph hp th ................................................................................................. 22
3.2. Kho st cng thc s b clopidogrel ........................................................... 23
3.3. Kho st nh hng t dc n nh, t dc dnh.................................... 25
3.3.1. Kho st nh hng ca t dc n nh ............................................... 25
3.3.2. Kho st nh hng ca nng t dc dnh ...................................... 26
3.4. Kho st t dc chng oxy ha ................................................................... 27
3.5. Kho st nh hng ca mng bao ln n nh ca dc cht ............ 29
3.6. Kho st s nh hng ca cht din hot ln ha tan ......................... 30
3.7. Kho st nh hng ca t dc siu r ln kh nng gii phng dc
cht .......................................................................................................................... 32
KT LUN V KIN NGH ..................................................................................... 37
TI LIU THAM KHO
PH LC

DANH MC CC K HIU V CH VIT TT

ADP

Adenosin diphosphat

BHT

Butylated hydroxy toluen

CDT

Cc dng bo ch thng thng

CT

Cng thc

CV

Coefficient of variation (H s phn tn)

EDTA

Acid ethylendiamintetraacetic

HPLC

High performance liquid chromatography (Sc k lng hiu

nng cao)

HPMC

Hydroxy propyl methyl cellulose

HQC

Higher quality control(Mu kim chng nng cao)

LHCT

Lo ha cp tc

LOQQC

Limit of quantification quality control (Gii hn nh lng ca

mu kim chng)

LQC

Lower quality control (Mu kim chng nng thp)

LS

Ht rn lng (Liquidsolid system)

MQC

Medium quality control (Mu kim chng nng trung bnh)

PEG

Polyethylen glycol

PVP

Polyvinyl pyrrolidon

SD

lch chun (Standard deviation)

SSG

Sodium starch glycolat

DANH MC CC BNG BIU

Tn bng

Trang

Bng 1.1

tan ca clopidogrel bisulfat trong mi trng nc

Bng 1.2

tan ca clopidogrel bisulfat trong mt s dung mi

Bng 2.1

Cc nguyn liu s dng trong qu trnh thc nghim

14

Bng 2.2

Thnh phn cng thc mng bao

16

Bng 3.1. Kt qu thm nh mt s ch tiu ca phng php nh lng

22

o quang ph hp th
Bng 3.2

Cng thc s b vin nn clopidogrel

24

Bng 3.3

Thnh phn cng thc c t l t dc n nh khc nhau

25

Bng 3.4

Thnh phn cng thc c t l t dc dnh khc nhau

26

Bng 3.5

Thnh phn cng thc c loi t dc chng oxy ha khc nhau

28

Bng 3.6

Hm lng dc cht gii phng sau khi bao

30

Bng 3.7

Thnh phn cng thc c loi cht din hot khc nhau

31

Bng 3.8

Thnh phn cng thc c t l t dc r khc nhau

33

Bng 4.1

Thnh phn cng thc tt nht

37

DANH MC CC TH, HNH V

Tn hnh
Hnh 3.1
Hnh 3.2
Hnh 3.3
Hnh 3.4
Hnh 3.5
Hnh 3.6

Trang

Biu th hin phn trm dc cht gii phng gim sau khi
th LHCT 1 thng
th biu din phn trm gii phng ca clopidogrel khi bao

28

nh hng ca cht din hot ln kh nng gii phng hot

cht
nh hng ca t dc siu r n kh nng gii phng hot
cht
Kt qu th ha tan sau khi th lo ha cp tc 1 thng

32

th biu din s thay i hm lng dc cht sau khi th

LHCT

35

29

34
35

T VN
Cc bnh tim mch ang l mi e da ln i vi sc khe ca nhn loi,
trong cc bnh v huyt khi nh: x va ng mch, nhi mu c tim,...chim
t l cao v gy ra nhng hu qu nghim trng. V vy, liu php khng kt tp tiu
cu ng vai tr thit yu trong iu tr v d phng huyt khi.
Clopidogrel c bit n l thuc t hiu qu cao trong iu tr bnh l v
huyt khi, thuc phn nhm II theo phn loi sinh dc hc, c tan km, sinh
kh dng rt thp (khong 50%), km n nh trong qu trnh bo ch v bo qun
do kh nng ht m mnh. Nhng c im trn gy kh khn ln trong qu trnh
bo ch vin nn clopidogrel.
Trn th trng, Plavix (Sanofi-Aventis) l bit dc ni ting cha
clopidogrel bisulfat em li hiu qu iu tr cao.Tuy nhin, gi thnh cao gy
tr ngi cho vic tip cn loi thuc ny n vi ngi dn.Gn y thi hn bo h
c quyn v sn phm cha clopidogrel ht hiu lc nn vic nghin cu sn
xut thuc generic l v cng cp thit, c ngha to ln v mt kinh t v chm
sc sc khe ca nhn dn.
Vi thc t nh trn kt hp vi kh khn khi sn xut vin nn cha
clopidogrel v n nh v ha tan, chng ti tin hnh ti Nghin cu
bo ch vin nn clopidogrel 300mg vi mc tiu nh sau:
1. Bo ch c vin nn clopidogrel n nh v mt hnh thc v hm lng
trong iu kin lo ha cp tc t nht 1 thng.
2. Bo ch c vin nn clopidogrel c ha tan t t nht 80% sau 30
pht.

CHNG 1:TNG QUAN

1.1.i nt v clopidogrel bisulfat
1.1.1.c im ca clopidogrel bisulfat
a.Cng thc cu to, tnh cht vt l

Cng thc phn t: C16H16ClNO2S.H2SO4

Tn khoa hc:
+

Methyl

(S)-2-chlorophenyl(4,5,6,7-tetrahydrothieno[3,2-c]pyridin-5-yl)

acetat bisulphat
+ Methyl (+)-(S)--(o-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)acetat sulphat
-

Khi lng phn t: 419,90g/mol

Tnh cht l ha: Bt hoc tinh th mu trng, tan trong nc, methanol
(1,891mol/l methanol), khng tan trong ether.

im nng chy: 184C

Gc quay cc: []D20= +55,10 (1,891mol/l methanol) [27].

b. tan ca clopidogrel bisulfat

Theo nghin cu v tng kt nh gi mi trng ca vin nn Plavix 75mg
ca C quan qun l Thuc v Dc phm M a ra tan ca clopidogrel
bisulfat trong mt s mi trng nh sau[40]:
Bng 1.1: tan ca clopidogrel bisulfat trong mi trng nc [40]
Mi trng

tan (g/100ml) 25oC

m pH 2,6

0,68

m pH 3

0,30

m pH 4

0,005

m pH 6

0,001

m pH 8

0,001

Bng 1.2: tan ca clopidogrel bisulfat trong mt s dung mi [40]

Dung mi

tan (g/100ml) 20oC

Methanol

45,9

Ethanol

5,2

Methylen Clorid

1,5

Dioxan

0,24

Ethyl ether

0,001

c.Cc dng mui v th hnh

Clopidogrel dng base khng c s dng trong cc ch phm thng mi do
gp kh khn trong vic tinh ch dc cht trong pha du. Clopidogrel bisulfat l
dng mui c s dng chnh trong cc ch phm thng mi bi v n tn ti
di dng tinh th v kh nng ci thin tan tt vi 90mg/ml [12], [13].
Clopidogrel bisulfat c 6 dng a hnh khc nhau nhng ch c dng a hnh I
v II c s dng trong thng mi [23], hai dng ny c sinh kh dng gn
nh l tng ng[26]. Dng v nh hnh ca thuc c sinh kh dng thp hn
hai dng a hnh I v II [38].
Vi 2 dng a hnh I, II cc nghin cu chi tit v s sp xp phn t trong
khng gian ca mi dng ch ra s khc nhau trong vic sp xp cc anion sulfat
trong 2 dng tinh th, do c tnh chu nn ca 2 dng l khc nhau. So vi dng
II th dng I c cu trc cng nhc, c c tnh chu nn km, d b bin dng khi
chu p lc nn. Tuy nhin nh bn lin kt cao dng I c kh nng to ht v to
vin tt hn dng a hnh II [21].
d. n nh ca clopidogrel bisulfat
Hin nay c rt nhiu nghin cu trn th gii ghi nhn clopidogrel bisulfat
l mt cht km n nh di iu kin m v nhit cao, to ra lng ln cc
sn phm phn hy ca dc cht [15], [38], [44]. Cc c ch phn hy c th xy
ra l thy phn este, phn ng kh carboxyl, hydroxyl ha, kh ha v dime ha
[38]. iu kin lo ha cp tc (nhit 40oC, m 75%), mui clopidogrel

bisulfat b thy phn to cc sn phm khng c hot tnh, ngoi ra n c th c

chuyn i dng ng phn to cc sn phm racemic v c hot tnh km hn [28],
[29].
Mt s sn phm phn hy ca clopidogrel bisulfat l:
+ [(+)-(S)-(o-clorophenyl)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-acetic acid]
+ [methyl ()-(o-clorophenyl)-4,5-dihydrothienol[2,3-c]pyridin-6(7H)-acetat,
hydrogen sulfat]
+

[methyl-(R)-o-clorophenyl-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-acetate,

hydrogen sulfat][47].
Theo nghin cu ca Raijada Dhara Kv cng s cho thy trong iu kin th
nghim lo ha cp tc (nhit 40oC, m 75%), c hai dng th hnh I, II v
dng v nh hnh ca clopidogrel bisulfat sau 3 thng th nghim trong vi mi
trng acid (acid oxalic), base (natri carbonat) v iu kin thng u c s thay
i mu sc r rt (t trng ng sang mu nu), tt c cc mu tr nn vn cc v
nng dc cht gim xung di 60% [38].
e. Mt vi phng php nh lng vin nn clopidogrel
Hin nay, dc in M s dng phng php sc k lng hiu nng cao
(HPLC) nh lng clopidogrel bisulfat trong vin nn, tuy nhin, trn th gii
c rt nhiu nghin cu s dng phng php o quang ph hp th UV nh
lng clopidogrel bisulfat vi u im n gin, nhanh chng m vn m bo
c ng, chnh xc, nhy cao.
+ Phng php HPLC: Vi u im v tnh chnh xc v c hiu, HPLC
l phng php c nhiu tc gi la chn nh lng clopidogrel bisulfat
trong qu trnh nghin cu sng lc cng thc, trong cc dng bo ch cng nh
trong cc ch phm phi hp khc [34], [36], [39], [20].iu kin sc k c quy
nh trong dc in M USP 36 nh sau: ct L57 (4,6mm x 15 mm). Tc dng
1,0 ml/pht. Detector: 220nm. T l pha ng m phosphat : acetonitril = 75 : 25
(Theo t l th tch) [47].

+ Phng php o quang ph hp th: Vi u th v tnh n gin, tit kim,

nhanh chng, phng php o quang cng c mt s tc gi nghin cu nh gi
v thm nh [11], [37]. Ngoi ra phng php quang ph o hm cng c
nghin cu nh lng clopidogrel bisulfat trong cc dng bo ch [30].
Cholke Pravin v cng s tin hnh nghin cu phng php o quang
nh lng clopidogrel bisulfat dng nguyn liu v trong cc ch phm vin nn
bao phim. Nhm nghin cu xc nh hm lng clopidogrel bisulfat trong mi
trng dung dch m pH 1 bng phng php o quang ph hp th ti bc sng
220nm. Nghin cu ch ra c mi tng quan tuyn tnh gia gi tr mt
quang vi nng clopidogrel trong dung dch (khong nng tuyn tnh 40-70
g/ml) (vi R2 = 1). Khi nghin cu phn tch vi vin nn Plavix 75mg (SanofiAventis) ch ra kt qu % hm lng dc cht thc t tm thy l 99,62% (SD =
0,224), % hm lng dc cht phc hi l 99,64% (SD = 0,236). Tin hnh xc
nh ng nng 80%, 100%, 120% so vi nng ca dc cht trong mu
chun (100 g/ml), ng trung bnh tng ghi nhn c l 98,87% (SD = 0,975).
Tin hnh xc nh chnh xc trong ngy t 4,5%, chnh xc khc ngy
khong 5,5-10,2%. Nhm nghin cu i n kt lun nh lng clopidogrel
bisulfat bng phng php o quang ph hp th n gin hiu qu vi ng,
chnh xc v lp li cao [11].
1.1.2. c im dc ng hc
Theo phn loi sinh dc hc, clopidogrelbisulfat thuc nhm II (kh nng
thm tt nhng kh nng ha tan km).
Clopidogrel bisulfat c hp thu nhanh chng nhng khng hon ton qua
ng ung, sinh kh dng rt thp vi t l hp thu t khong 50% do kh nng
ha tan km v thoi ha nhanh chng trong chuyn ha bc mt[18], [9].
Clopidogrelbisulfat l mt tin thuc v c chuyn ha mnh gan, c
gn kt mnh vi protein huyt tng sau c bi tit qua nc tiu (khong
50%) v qua phn (46%)[45].

Cc cht chuyn ha c hot tnh ca clopidogrel bisulfat c ch chn lc s

gn kt ca adenosin diphosphat (ADP) ln th th P2Y12 trn tiu cu, sau kch
hot ADP qua trung gian cc phc hp glycoprotein GPIIb/IIIa, do c ch kt
tp tiu cu [42].
1.1.3. Ch nh
Clopidogrel c s dng thay th cho aspirin bnh nhn x va ng
mch v nhng ngi c nguy c ri lon huyt khi tc mch nh nhi mu c
tim, bnh ng mch ngoi bin, v t qu[45].
Ngoi ra, clopidogrel c s dng phi hp vi aspirin trong hi chng
mch vnh cp tnh, bao gm nhi mu c tim cp tnh v au tht ngc khng n
nh, v t stent ng mch vnh[45].
1.2. Cc yu t nh hng v bin php ci thin tan, ha tan dc cht
trong vin nn
1.2.1. Cc yu t nh hng n tan v ha tan dc cht ca vin nn
a.Cc yu t thuc v dc cht
tan v ha tan ca dc cht ph thuc cc yu t sau:
+ Kch thc tiu phn dc cht: tan ca dc cht tng ln khi kch
thc tiu phn gim, do nng lng t do trn b mt tip xc tng ln. Nh vy
vic nghin mn dc cht rn s lm tng tan mt mc no [2.
+ Dng mui: Cc dc cht thng l acid yu v base yu t phn li, do t
ha tan v t c hp thu trong ng tiu ha. tng cng sinh kh dng ca
cc dc cht ngi ta thng dng dng mui d ion ha, c phn ly ln
hn. V d clopidogrel c bn cht l base yu, c tan rt km trong nc, khi
to mui vi ion sulfat s lm tng tan ln ti 90mg/ml [12], [13].
+ Dng kt tinh, hin tng a hnh: Mt dc cht c th kt tinh di nhiu
dng tinh th khc nhau, ty theo iu kin kt tinh. Cc dng kt tinh khc nhau c
cu trc tinh th bn vng mc khc nhau, t tan khc nhau. Dng kt
tinh c cu trc tinh th bn vng nn thng kh tan hn dng v nh hnh [2]

+ Dng solvat ha: Tc ha tan ca dng khan nhanh hn dng ngm nc.
V d, ampicillin khan c tan ln hn ampicillin trihydrat [2].
Ngoi ra cc yu t nh kch thc tiu phn, h s phn b du nc, s ion
ha ca dc cht, to tin cht d tan cng nh hng ti ha tan ca dc cht
[2].
b.Cc yu t thuc v t dc
Mt s t dc s dng trong vin nn c nh hng ti tan ca dc cht:
+ T dc n: Do nhm t dc ny chim t l ln trong vin nn c th gy
ra nhiu tng tc nh hng n ha tan ca vin, i khi lm gim thi gian r
ca vin t lm tng tc ha tan ca dc cht.
+ T dc dnh: Vi bn cht l nhng cht keo thn nc, t dc dnh lm
tng lin kt tiu phn, to bn c hc cho vin, do dn n xu hng ko di
thi gian r ca vin. Cc t dc polyvinylpyrrolidon (PVP) v h tinh bt t nh
hng nht n kh nng r v gii phng dc cht ca vin.PVP thng c s
dng nng 3-15% trong ethanol hoc hn hp ethanol- nc. Xt ht bng
PVP cho ht nhanh kh v c kh nng nn tt [10]. Chng hn, meloxicam thuc
nhm II trong h thng phn loi sinh dc hc, c tan km, thi gian r ca
vin tng dn khi to ht t vi cc t dc dnh ln lt theo th t: h tinh bt
10% < dung dch PVP 10%/nc < dung dch PVP 10%/ ethanol 96% < hn hp h
tinh bt 10% v gelatin 2% [4].
+ T dc siu r: Tinh bt t lu c s dng trong vin nn nh l t
dc r r tin, d kim, nhng cn dng vi lng ln nn nh hng ng k n
trn chy cng nh tnh chu nn ca khi bt. Gn y, vi s ra i nhm t
dc siu r, ch cn dng vi lng nh (2-8%) trong cng thc lm gim thi
gian r m t nh hng n trn chy, tnh chu nn ca khi bt[6], [8].
Mt s loi t dc siu r thng dng:

Sodium starch glycolat (SSG):

Loi tinh bt bin tnh dng lm t dc siu r l loi gn thm nhm -CH2COONa vo mch tinh bt.Dng bt trng n gn trng, khng mi, khng v, trn
chy tt.
SSG thng c s dng lm t dc r trong vin nn vi phng php dp
thng hoc xt ht t vi c ch r l ht nc trng n.
Mt s tn thng mi ca SSG: Explotab (Edward Mendell Co.), Primojel
(Generichem Corp.), Tablo (Blanver, Brazil)[8].

Cellulose bin tnh (natri croscarmellose):

Loi cellulose bin tnh dng lm t dc siu r l loi c to thnh t cc

lin kt cho ca natri carboxymethylcellulose.Dng bt trng, khng mi.Khc vi
SSG, natri croscarmellose c dng cu trc si xon nn trn chy km. khc
phc nhc im ny cn xay, nghin natri croscarmellose lm cho cc si
polyme tr nn ngn hn.
Natri croscarmellose c s dng l t dc r trong vin nang, vin nn v
ht. T l c s dng c th ln ti 5%, trong vin nn dp thng thng dng
2%, trong vin nn bo ch bng phng php xt ht t thng s dng 3%.
Mt s tn thng mi ca natri croscarmellose: Ac-Di-Sol (FMC Corp),
Nymcel ZSX (Nyma, Metherlands), Primellose (Avebe, Netherlands), Solutab
(Blanver, Brazil) [8].

Crospovidon (PVP lin kt cho):

L sn phm tng hp t monome N-vinyl-2-pyrrolidon bi qu trnh polyme

ha mch nhnh to thnh cc lin kt cho khng tan trong nc. Crospovidon c
hot tnh mao dn cao v d dng b hydrat ha to gel.
T l thng c s dng 2-5% trong vin, c th dng trong quy trnh bo
ch vin nn bng phng php dp thng, xt ht kh cng nh xt ht t.
Mt s tn thng mi: Polyplasdone XL, Polyplasdone Xl-10, Kollidon CL,
Kollidon CLM, Crospovidone. Trong Polyplasdone XL-10 l dng siu mn ca
Polyplasdone XL, Crospovidone M l dng siu mn ca Kollidon CL, Kollidon
CLM l dng siu mn ca Crospovidone M[8].

+ T dc trn: T dc trn c tc dng iu ha tc chy ca ht, gim lc

ma st, lc b mt, lc tnh in ca cc tiu phn, m bo s ng nht v khi
lng trong vin nn. Phn ln t dc trn c bn cht s nc,to thnh mt
mng bao quanh tiu phn, lm gim s thm nc, do lm vin kh r, nh
hng n s ha tan dc cht trong vin. V d: magnesi stearat, calci stearat,
talc, Aerosil V vy cn chn t dc trn ph hp :

m bo s trn chy ca ht v phn phi lc nn ng u trong

Khng to s s nc qu ln lm hn ch tc ha tan dc cht

vin.

trong vin.
Aerosil l mt t dc trn hay c s dng vi t l 0,1-0,5%. Ngoi mc
ch l t dc trn, Aerosil cn c s dng lm t dc trong sn xut vin nn
vi nhiu mc ch khc nhau nh: tng cng ca vin nn lc dp thp hn,
hot ng nh mt cht kh tnh in, d dng chuyn dng bo ch t dng lng
sang dng bt trn chy tt, l cht mang hiu qu vi cc cht vn chuyn baselipid hoc cc du c hot tnh.
c. Yu t thuc v dung mi
La chn dung mi, hn hp dung mi c tnh cht tng t hot cht v
phn cc, cu trc ha hc, nhm ha chc t lm thay i hng s in mi,
phn cc ca hn hp dung mi lm thay i kh nng ha tan ca dc cht.
d. Yu t thuc v mi trng ha tan
Cc nh nghin cu c th lm tng kh nng ha tan ca dc cht t tan
bng cch thay i pH mi trng ha tan hoc to vi mi trng xung quanh tiu
phn dc cht. tan ca cc dc cht c bn cht acid yu hoc base yu thay
i mnh khi pH mi trng thay i. Cc cht c kh nng to vi mi trng c
gi l cc t dc m.
T dc m l nhng cht c tnh kim hoc acid d tan trong mi trng
ha tan. Khi a thuc vo mi trng ha tan cc t dc ny s tan trc to ra
xung quanh cc vi tiu phn thuc mt vi mi trng pH ring, to thun li cho s

10

ha tan dc cht c bn cht acid hoc base yu. C 2 loi t dc m l t dc

kim v t dc acid.
Cc t dc to vi mi trng c pH acid: cc acid hu c nh acid malic,
acid citric, acid tartaric,thng c dng trong cng thc thuc cha dc cht
l cc base yu. Chng thng s dng vi t l ln hn hoc bng t l dc cht
trong cng thc.
Cc t dc to vi mi trng pH basec 2 loi l:
+ T dc m base hu c chng hn nh 2-amino-2-methyl-1,3-propanodiol,
u im l an ton, t nh hng n n nh ca dc cht, nhc im l kh
nng iu chnh pH yu, cn dng lng ln th mi pht huy tc dng.
+ T dc m base v c l cc mui kim v c nh: natri borat, natri citrat,
dinatri hydrophosphat, trinatri phosphat. u im ca loi t dc ny l: kh nng
iu chnh pH mnh, ch dng vi nng thp c nh hng n kh nng ha
tan ca dc cht. Nhc im l nh hng n n nh ca thuc [7],[35].
1.2.2. Mt s bin php lm tng tan v ha tan dc cht t tan
a. S dng hn hp dung mi
La chn dung mi thch hp vi t l thch hp t lm cho hn hp dung
mi c phn cc gn vi phn cc ca dc cht kh tan, thay i hng s
in mi t lm thay i tan ca dc cht. Mt s hn hp dung mi hay
dng: nc-alcol, glycerin- alcol- nc, ethanol- glycerin- nc,. Tuy nhin cn
lu trong qu trnh pha long m thay i mi trng phn tn dc cht c th b
kt ta tr li [2].
b. To mui d tan
Cc dc cht l acid yu hay base yu t phn li, do t ha tan, tng
tan ngi ta thng dng dng mui d ion ha. Vic la chn dng mui s dng
ph thuc vo pKa ca dc cht, ng dng v dng thuc bo ch. Mt s ion
to mui thng dng l: SO42-, Cl-, HCl, Na+, K+, Ca2+.[2].
c. S dng cht din hot

11

Mt trong nhng yu t nh hng n tan ca dc cht t tan l kh

nng thm t b mt, iu ny lin quan n sc cng b mt ca cht tan v dung
mi. Sc cng b mt cng cao th cc cht cng kh ha tan, do vy ngi ta
thng s dng thm cht din hot tng tan ca dc cht t tan.
Cht din hot l mt nhm cc hot cht ha hc m trong phn t cha cc
phn thn du v thn nc c kh nng hp ph ln b mt dc cht hay b mt
phn cch pha lm thay i bn cht ca b mt ny. C ch lm tng ha tan
dc cht ca cc cht din hot l do ci thin tnh thm v ng thi lm gim s
kt tp ca cc tiu phn dc cht do lm tng din tch tip xc ca tiu phn
vi mi trng ha tan [2].
1.3. n nh v mt s yu t nh hng n n nh ca dc cht
1.3.1. n nh
a.Khi nim
n nh ca thuc l kh nng ca thuc (nguyn liu hoc thnh phm)
bo qun trong iu kin xc nh gi c nhng c tnh vn c v vt l, ha
hc, vi sinh, tc dng dc l v c tnh trong thi hn quy nh ca tiu chun
cht lng thuc[1], [3].
b.S lin quan gia tui th ca nguyn liu v thnh phm thuc
n nh, tui th ca nguyn liu dc cht c lin quan, nh hng n
n nh, tui th ca thnh phm bo ch. i t nguyn liu dc cht c n
nh cao vi mt quy trnh sn xut chc chn thu c thnh phm bo ch c
n nh cao hn khi s dng nguyn liu c n nh thp. Tuy nhin, tui th
ca nguyn liu v thnh phm bo ch l cc ti liu c lp thu c t kt qu
nghin cu sn xut c th[1], [3].
1.3.2. Cc yu t nh hng n tc phn hy dc cht
a. Nhit
Da vo thc nghim, Vant Hoff nu ra nguyn tc gn ng v nh
hng ca nhit n tc phn ng nh sau: tc ca phn ng ng th
thng tng t 2 n 3 ln khi nhit tng thm 10oC.

12

Da vo phng trnh Arrhenius, bng thc nghim lo ha cp tc ngi ta

c th tham kho d on chnh xc hn v tui th ca thuc trn c s xc
nh mc suy gim hm lng dc cht trong qu trnh vn chuyn v bo
qun[1].
b. m
m khng kh cao to iu kin cho nm mc pht trin, hn na m
cao cn thc y nhanh s phn hy do phn ng thy phn, phn ng si bt v
lm thay i tnh cht l hc ca dc cht.
c. nh sng
Mt s hot cht b phn hy di tc dng ca nh sng.
d. bao gi
Cht lng ca nguyn liu v ch phm c th b nh hng bi kim ca
thy tinh, bao gi kim loi, nt cao su, thm m v kh ca vt liu bao gi.
1.4.Mt s hng nghin cu ci thin kh nng ha tan v n nh ca ch
phm cha clopidogrel trn th gii
Gupta Vrm v cng s tin hnh nghin cu bo ch vin r nhanh trong
ming ci thin sinh kh dng ca vin nn clopidogrel.Nghin cu ch ra vi
vic s dng lng ln t dc siu r natri croscarmellose v crospovidon gip
vin gii phng c 99% hot cht so vi vin nn Plavix (Sanofi-Aventis) trong
vng 30 pht. V vn n nh nghin cu tin hnh bao phim Opadry bo
v dc cht khi nh sng v m mi trng. n nh c theo di di
iu kin nhit 40oC, m 75% trong vng 3 thng [16].
Kim Yong-Il.v cng s cng tin hnh nghin cu bo ch vin nn
clopidogrel vi vic s dng dng mui clopidogrel napadisilat trong h phn tn
rn. Nghin cu ch s dng mui clopidogrel napadisilat khng gip lm tng
tan cng nh n nh so vi clopidogrel bisulfat, tuy nhin khi to h phn
tn rn gm clopidogrel napadisilat, HPMC v silic dioxid dng keo khan vi t l
khi lng 11,069/3/3,5 ci thin tan 6,5 ln so vi clopidogrel napadisilat.

13

c bit, nghin cu ch ra h phn tn rn trn ci thin ng k n nh v

sinh kh dng so vi clopidogrel bisulfat [22].
Nghin cu caSahitya G v cng s a ra kt qu h phn tn rn gm
clopidogrel bisulfat vi cht mang l polyethylen glycol (PEG) 6000 gip ci thin
kh nng gii phng dc cht clopidogrel trong vin nn. Kho st loi vnng
t dc siu r nh crospovidon, natri croscarmellose, SSG, tin hnh th n
nh 40oC, m 75%. Kt qu ch ra rng cng thc s dng vi 10%
crospovidon l cng thc ti u vi kh nng gii phng dc cht t 99% sau 60
pht [41].
Ngoi ra,Liversidge Gv cng s tin hnh nghin cu bo ch tiu phn
nano clopidogrel gip tng cng kh nng ha tan dc cht, tng sinh kh dng,
gim liu v kch thc vin nn [25].

14

CHNG 2:
I TNG V PHNG PHP NGHIN CU
2.1.Nguyn liu, thit b
2.1.1.Nguyn liu
Bng 2.1: Cc nguyn liu s dng trong qu trnh thc nghim
STT

Nguyn liu

Ngun gc

Tiu chun

USP 36

Clopidogrel bisulfat

Natribisulfit

Trung Quc

TCCS

Poloxamer 407

Trung Quc

TCCS

Aerosil 200

Php

BP 2008

Avicel PH101

i Loan

USP 29

Crospovidon

Trung Quc

TCCS

Manitol

Trung Quc

TCCS

Polyvinyl pyrrolidon (PVP) K30

Trung Quc

USP 29

Natri laurylsulfat

Trung Quc

BP 2008

10

Tween 80

Trung Quc

USP 29

11

Butylated hydroxytoluen (BHT)

Trung Quc

USP 29

Trung Quc

TCCS

Trung Quc

USP 29

12

Acid ethylenediamintetraacetic
(EDTA)

13

Kolliwax HCO

14

HPMC E15

Colorcon M

USP 29

15

PEG 6000

Vit Nam

DVN IV

16

Acid stearic

Trung Quc

TCCS

17

Talc

Vit Nam

DVN IV

18

Ethanol 96%

Vit Nam

DVN IV

19

Nc ct

Vit Nam

DVN IV

20

Methanol

Trung Quc

Tinh khit ha
hc

15

2.1.2. Thit b nghin cu

- My dp vin quay trn 8 chy (n ).
- Cn k thut Sartorius TE3102S (c).
- Cn phn tch Sartorius TE3102S (c).
- My o cng PTB 511E (c).
- My th ha tan PHARMATEST (c).
- My o pH Sartorius Mettle Toledo (M).
- My bao phim mini Caleva (Anh).
- My quang ph UV-Vis Optima SP-3000 nano (Nht Bn).
- Chu siu m Ultrasonic LC 60H (M).
- Bnh nh mc, ry, pipet, chy, ci s, cc loi dng c thy tinh khc.
2.2.Ni dung
Kho st nh hng ca cc loi t dc n n nh v kh nng gii
phng dc cht ca vin nn clopidogrel bo ch c.
2.3.i tng nghin cu
-Vin nn clopidogrel 300mg.
-Vin i chiu :
Vin nn bao phim Plavix 300mg (Sanofi- Aventis)
L sn xut : 3A003
Nh sn xut: Sanofi winthrop industrie
Nhp khu bi: Cng ty TNHH MTV Dc Si Gn (Sapharco)
Ngy sn xut: 10/2013
Hn s dng: 01/09/2016
2.4. Phng php nghin cu
2.4.1. Phng php bo ch vin
a. Phng php dp vin nn
Vin nn clopidogrel c bo ch vi cc bc sau:
- Chun b t dc dnh: Ha tan PVP K30 trong ethanol 96% sau phi hp
Poloxamer 407 vo dung dch trn n khi tan hon ton.

16

- Ry tng loi nguyn liu chun b (clopidogrel bisulfat, natri bisulfit, t

dc n nh) qua ry 0,150mm sau trn u khi bt theo nguyn tc ng
lng.
- To ht t: Thm t t t dc dnh vo khi bt, dng chy tc ng lc
vo thnh ci gip phn tn u t dc dnh khp khi bt (thm ethanol nu cn).
- Xt ht qua ry 1mm, sy se 40oC/ 5-10 pht.
- Sa ht qua ry 0,8mm sau sy 40oC n t hm m 2-3%.
- Chun b t dc trn ngoi bao gm manitol, Avicel PH101, crospovidon.
Ry nguyn liu qua ry 0,150mm sau trn u theo nguyn tc ng lng.
- Phi hp t dc trn ngoi vi ht t hm m trn.
- Trn t dc trn: T dc trn c ry qua ry 0,125mm trn u vi
khi ht trn trong khong 3 pht.
- Dp vin: s dng chy ci 19mm x 9mm.
Dp vin quy m 100 vin/m. Kim sot khi lng vin theo so vi khi
lng l thuyt l 900mg 5%. Trong qu trnh nghin cu, c nh khi lng
vin, qu trnh kho st ch thay i t l khi lng cc t dc trong cng thc.
b. Phng php bao vin
Vin nn clopidogrel c tin hnh bao nhm mc ch tng cng n
nh ca dc cht trnh m v nh sng ngoi mi trng. Tham kho cng
thc v quy trnh bao chng m theo nghin cu ca Phm Hin Giang [5].
Cng thc mng bao:
Bng 2.2: Thnh phn cng thc mng bao
Thnh phn

T l

Khi lng

HPMC E15

4,5%

5g

PEG 6000

0,675%

0,75g

Acid stearic

0,45%

0,5g

Talc

0,675%

0,75g

Ethanol 96%

60g

m pH 2

30g

17

Chun b dch bao

+ Ngm trng n HPMC E15trong hn hp dung mi ethanol 96% : m pH
2 (t l 1:1, s dng 50% ethanol 96% v 100% lng m c trong cng thc),
phihp PEG 6000 t t trn my khuy t thu c dch A.
+ Ha tan acid stearic vo lng ethanol cn li thu c dung dch B.
+ Nghin mn talc, ry qua ry 0,125 mm, dng dung dch B ko dn talc vo
dung dch A, khuy cho n khi thu c dch ng nht, lc hn hp qua ry
0,150mm thu c dch bao.
Thng s bao
Vin trn c bao trong my bao phim Caleva vi quy m 20 vin, cc thng
s sau:
+Nhit kh vo: 38-40oC
+ Nhit kh ra: 28-30oC
+ng knh vi phun: 1,2 mm
+Tc phun dch: 0,9 ml/pht
+Tc rung: 40%
+p sut kh phun: 1bar
+Khng kh thi vo bung bao: 100%
Sau khi dng phun dch bao tip tc cho thit b chy vi cc thng s trn
trong khong 15 pht sy kh vin, sau cn xc nh khi lng mng bao v
n nh vin trong 24h iu kin thng trc khi tin hnh nh gi kh nng
gii phng ha tan dc cht.
2.4.2. Phng php th ha tan
Phng php c tham kho theo chuyn lun vin nn clopidogrel ca dc
in M USP 36 [4].
Cch tin hnh: Cn chnh xc khi lng tng vin v th ha tan (n=6)
trn my th ha tan Pharmatest vi cc thng s sau:
- Thit b: cnh khuy.

18

- Tc khuy: 50 1 vng/ pht.

- Nhit th: 37 0,5oC.
- Mi trng th: 1000ml dung dch m pH 2 (USP 36).
Tin hnh ly mu th (5ml mi ln) ti cc thi im: 5, 10, 15, 20, 30, 45,
60 pht. Sau mi ln ly mu, tin hnh b sung 5ml mi trng vo mi cc th
ha tan. Mu th c lc qua mng 0,45m, pha long 10 ln bng dung dch m
pH 2, o quang bc sng 240nm.
Mu chun: Cn chnh xc khong 30,0mg clopidogrel (tng ng vi khong
39,2mg clopidogrel sulfat) ho tan trong khong 10ml methanol trong bnh nh
mc 20ml, b sung methanol va thu c dung dch X (1500g/ml). Ht chnh
xc 2ml dung dch X vo bnh nh mc 10ml, b sung m pH 2 va thu c
dung dch Y (300g/ml). Pha long dung dch Y 10 ln bng m pH 2, tin hnh
o quang ti bc sng 240nm.
Tnh kt qu:
T kt qu mt quang o c ca mu chun v mu th, tnh ton c
lng dc cht gii phng ha tan cc thi im. Nng dc cht trong thi
im th n c tnh theocng thc:
Cn= Cchx

(g/ml)

% Dc cht gii phng ti thi im th n: Hn=

x 100%

Trong :
Cn: nng dc cht trong dch ha tan rt ra ti thi im n (g/ml)
Cch: nng dc cht trong mu chun (g/ml)
An: hp th quang ca mu th thi im n
Ach: hp th quang ca mu chun
Hn: hm lng % dc cht c gii phng ti thi im n (%)
So snh hai th gii phng dc cht da vo ch s tng ng f2 v c
tnh theocng thc sau:

19

= 50

1+

100

Trong : n l s im ly mu th, Ri,Ti l phn trm dc cht gii phng

ti thi im t ca mu i chiu, mu th.
Nu 0 f1 15 v 50 f2 100 th hai th c coi l tng ng.
Nu f2 = 100 thhai th c coi l ging nhau hon ton.
Nu f2 = 50 thhai th c s sai khc trung bnh ti mi thi im l 10%
[30].
2.4.3. Phng php nh lng clopidogrel bisulfat t vin nn clopidogrel
S dng phng php o quang ti bc sng 240nm, so snh mt quang
ca mu th v mu chun tnh hm lng clopidogrel bisulfat trong vin nn.
Tin hnh
Mu th: Cn 20 vin nn clopidogrel bo ch, tnh khi lng trung bnh
vin, nghin vin thnh bt mn. Cn chnh xc mt lng bt (mt) tng ng
khong 300,0 mg clopidogrel cho vo bnh nh mc 100 ml, thm 20 ml dung dch
methanol, lctan hon ton. B sung dung dch m HCl pH 2 va v lc qua
mng lc 0,45 m, b 20 ml dch lc u. Ht chnh xc 10,0 ml dch lc cho vo
bnh nh mc 100 ml, thm dung dch m HCl pH 2 n vch, lc u. Ht chnh
xc 5,0 ml dch ny cho vo bnh nh mc 25 ml, thm dung dch m HCl pH 2
n vch, lc u.
Mu chun: Cn chnh xc mt lng khong 300,0 mg clopidogrel (mc) cho
vo bnh nh mc 100 ml,thm 20 ml dung dch methanol, lc cho tan hon ton.
Tin hnh tip tng t mu chun.
Mu trng: dung dch m HCl pH 2.
Hm lng dc cht trong mu th c tnh bng cch so snh vi mu
chun c nng bit theo cng thc:
%R =

Dt x mc
x 100%
Dc x mt

20

Trong :
Dt: mt quang ca mu th

mt: khi lng bt vin bo ch (mg)

Dc: mt quang ca mu chun

mc: khi lng ca cht chun (mg)

Thm nh mt s ch tiu xc nh lng dc cht s dng phng php

o quang ph hp th
c hiu
Chun b mu chun: Pha tng t mu chun trong phng php nh lng
theo mc 2.4.3.
Chun b dung dch mu nn cha t dc:
Chun b vin mu nn bo ch vi cc t dc chnh trong cng thc t
l trung bnh trong khong kho st (thnh phn xem ph lc 1) sau tin hnh
bao vin theo mc 2.4.1.
Tin hnh pha mu trng cha t dc tng t mu th trong phng php
nh lng theo mc 2.4.3.
Chun b mu th:Tin hnh chun b nh dung dch mu trng cha t dc
nhng thm 391,4 mg clopidogrel bisulfat (tng ng khong 300,0 mg
clopidogrel).
thch hp ca h thng
o quang ti bc sng 240 nm dung dch chun (chun b theo mc 2.4.3)
lp li lin tip 6 ln.nh gi da trn h s phn tn (CV).
tuyn tnh
Chun b dy dung dch chun c nng ln lt l 2,25; 6,00; 15,00; 24,00;
30,00; 36,00; 45,00 g/ml.
Xc nh mi lin h gia bin mt quang ca dung dch v nng dung
dch clopidogrel bisulfat.
ng
Tin hnh vi cc nng 3, 15, 30, 36 g/ml (tng ng 10%, 50%, 100%,
120% so vi nng nh lng), mi nng tin hnh 3 mu pha t 3 dung dch
chun gc khc nhau.

21

Tnh phn trm clopidogrel bisulfat tm thy so vi lng clopidogrel bisulfat

ban u cho ta thng tin v % tm thy trn lng hot cht.
ng(%):
ng (%) =

Nng tm thy
x 100%
Nng thc

chnh xc
Tin hnh nh lng hm lng clopidogrel bisulfat trong cc mu th c
lp ca 6 vin bo ch v 6 vin Plavix.
n nh ca dung dch
Thc hin pha mu th v mu chun, sau lu nhit phng sau 24h
tin hnh nh lng li dc cht xc nh thi gian s dng ca dung dch mu
th v mu chun sau khi pha.
2.4.4. Phng php th n nh vin nn clopidogrel sau khi bo ch
Tin hnh th n nh vin nn clopidogrel bo ch trong ti trong sut
c kha ko kn 30 vin nn clopidogrel, t trong t vi kh hu iu kin lo ha
cp tc (LHCT) (nhit 40oC, m 75%). Sau thi gian th nghim tin hnh
quan st cm quan (s thay i mu sc) v nh lng li dc cht theo mc
2.4.3.

22

CHNG 3:THC NGHIM, KT QU V BN LUN

3.1. Kt qu thm nh mt s ch tiu ca phng php nh lng o quang
ph hp th
Sau khi tin hnh thm nh mt s ch tiu ca phng php nh lng o
quang ph hp th thu c kt qu nh sau(kt qu chi tit xem ph lc 1):
Bng 3.1:Kt qu thm nh mt s ch tiu phng php nh lng o quang ph
hp th
Yu cu

Kt qu

Ch tiu thm nh
Tnh c hiu

XTB 2,0%

thch hp h thng

CV 2,0% (n = 6)

ng (t l thu hi)

95,0% 105,0% mc nng t yu cu

LQC, MQC, HQC.
90,0% 101,0% mc nng
LOQQC.

t yu cu (XTB- nn =
1,44%; XTB-mu th =
1,87%)
t yu cu (0,07%)

chnh xc
lp li

CV 2,0% (n = 6)

t yu cu (0,83%;
0,38%)
t yu cu

tuyn tnh
H s tng quan

r 0,998

r = 0.9999

H s gc

a = 0,0200

H s chn

b = 0,0024

% H s chn so vi p %Y 2%
ng pic nng 100%
(%Y)
n nh dung dch
Chun
98102%

%Y = 0,40%

Th
Khong xc nh

t yu cu
100,28%

Khng khc nhau v thng k

T 10 % n 120%

Ch thch: LQC: mu kim chng nng thp

HQC: mu kim chng nng cao
MQC: mu kim chng nng trung bnh CV: h s phn tn
LOQQC: gii hn nh lng ca mu kim chng

23

Nhn xt:
c hiu: Ti bc sng 240nm t dc khng nh hng n kh nng
hp th UV ca clopidogrel bisulfat (kt qu nh hng ca t dc nh hn 2%).
Do vy, c th tin hnh o quang ti bc sng 240nm nh lng hm lng
clopidogrel bisulfat trong cc mu nh lng.
thch hp ca h thng: Phng php xy dng c lch chun tng
i v hp th ca dung dch chun clopidogrel bisulfat: CV = 0,07% tho mn
yu cu chung v lch chun tng i khi nh lng bng quang ph UV vi
CV 2%. Nh vy phng php t yu cu v tnh thch hp h thng.
tuyn tnh: Kt qu thc nghim cho thy mt quang c mi quan h
tuyn tnh vi nng dung dch clopidogrel bisulfat trong dung dch m HCl pH
2 trong khong nng t 2,25 mg/ml n 45mg/ml vi R2 = 0,9999.
ng: T kt qu cho thy vi tt c cc nng u c t l phc hi
trung bnh nm trong khong 95,0-105,0%, vi mu LOQQC t 90-110% (CV =
1,69%).
lp li: Kt qu kho st cho thy phng php c lp li kh tt. Tt
c cc nng u c CV thp (nh hn 1%).
n nh: Nhn thy t l tm li ca mu th nm trong khong 98-102%.
Khng c s khc nhau v kt qu hm lng dc cht gia hai ngy v mt thng
k.
Khong xc nh:T kt qu tuyn tnh, ng v chnh xc ta c
khong xc nh ca phng php t 10% n 120%.
Kt lun:Phng php phn tch nh lng bng o quang ph hp th ti
bc sng 240 nm t cc yu cu ra v tnh c hiu, n nh, thch hp
h thng, tuyn tnh, ng, chnh xc, khong xc nh nn c th p dng
nh lng ha tan hot cht clopidogrel trong vin nn Plavix 300 mg v
vin clopidogrel nghin cu 300mg.
3.2. Kho st cng thc s b clopidogrel

24

Vi c tnh tan km v n nh km trong mi trng nhit v

m cao ca dc cht clopidogrel bisulfat, mt s nghin cu a ra cc gi v
cc t dc s dng trong vin nn cha clopidogrel nh sau:
+Manitol, cellulose vi tinh th c s dng l t dc n,ngoi ra cellulose
vi tinh th cn c s dng lm t dc dnh[31], [43].
+Crospovidon c th c s dng lm t dc siu r vi nng t 0,5 n
10%[43].
+ PEG 6000, Aerosil, talc c s dng lm t dc trn [31], [32], [43].
+ S kt hp clopidogrel bisulfat v magnesi stearat lm gim n nh ca
clopidogrel bisulfat[43].
T cc gi trn, tin hnh bo ch cng thc (CT) 1 bng phng php dp
vin qua to ht tvi cc thnh phn c nu trong bng 3.2.
Bng 3.2: Cng thc s b vin nn clopidogrel 300mg
Thnh phn

CT1 (%)

Clopidogrel bisulfat (300mg)

43,56

Manitol

35,44

Avicel PH101

10

Crospovidon

PVP K30

PEG6000

Aerosil

0,5

Kolliwax HCO

0,5

Talc

Tng

100

Nhn xt: T thc nghim, nhn thy vin bo ch vi CT 1 rt d dnh chy

ci, qu trnh dp din ra kh khn, lin tc dng my do b dnh,b mt vin th
rp, s c trn c Lei Jifeng gii thch do clopidogrel bisulfat ht m t mi
trng trong qu trnh dp vin, do gy dnh mnh vi chy v ci ca my dp
vin, lm b mt sn si, nh hng hnh thc v cht lng ca vin [24]. Ngoi

25

ra,ch mt ngy sau khi dp, vin bo ch c c s thay i mu sc r rt (t

trng ng chuyn sang mu vng) (hnh nh xem ph lc 5). Kt hp vi kt qu
nh gi s b n nh ca nguyn liu clopidogrel bisulfat (ph lc 2) nhn thy
clopidogrel bisulfat rt d b phn hy di iu kin nhit , m cao v nh
sng trc tip.
Kt lun: Vin nn clopidogrel c bo chtheo CT 1 rt d dnh chy ci
khi dp vin, khng n nh trong qu trnh bo qun. Do , cn s dng thm cc
bin php tng n nh ca vin cng nh qu trnh bo ch din ra thun
li.
3.3. Kho st nh hngt dc n nh, t dc dnh
3.3.1. Kho st nh hng ca t dc n nh
Nghin cu thit lp CT vin nn clopidogrel nh bng 3.3 kho st nh
hng ca t dc n nh ln hin tng dnh vin clopidogrel khi dp.
Bng 3.3: Thnh phn cng thcc t l t dc n nh khc nhau
Thnh phn

CT2 (%)

CT3 (%)

CT4 (%)

Clopidogrel bisulfat (300mg)

43,56

43,56

43,56

12

30,44

26,44

23,44

Avicel PH101

10

10

10

Crospovidon

PVP K30

PEG6000

Aerosil

0,5

0,5

0,5

Kolliwax HCO

0,5

0,5

0,5

Talc

Tng

100

100

100

T dc n nh
Manitol

Nhn xt: Lng t dc n nh s dng tng dn theo th t CT2 (5%),

CT3 (9%), CT4 (12%). Kt qu cho thy, vin bo ch CT 2 (s dng 5% t dc
n nh) quan st thy hin tng dnh chy ci ngay sau khi dp vin.Trong khi ,

26

CT 4 (ng vi lng t dc n nh chim 12%) nhn thy rt kh trn u khi

bt do lng t dc n nh qu cao. Vin bo ch theoCT3 nhn thy lng t
dc n nh s dng l hp l hn c (9%), qu trnh trn khi bt din ra thun li
v ci thin c hin tng dnh trong qu trnh dp.C ch khc phc s c dnh
chy ci ca clopidogrel bisulfat khi dp vin bng vic s dng t dc n nh
c gii thch l do t dc n nh c kh nng chng dnh v kch thc tiu
phn nh ph mt lp mng ln b mt dc cht clopidogrel bisulfat, gip c
lp nguyn liu clopidogrel bisulfat khi mi trng xung quanh. T khc phc
c hin tng dnh chy ci trong qu trnh dp vin nn clopidogrel.
Kt lun:Chn CT 3 (tng ng mc t dc n nh l 9%) tip tc
nghin cu.
3.3.2. Kho st nh hng ca nng t dc dnh
ci thin tnh trng dnh chy ci, tin hnh thay i t dc dnh trong
CT, nghin cu thit lp CT vin nn clopidogrel nh bng 3.4.
Bng 3.4: Thnh phn cng thc c t l t dc dnh khc nhau
CT3

CT5

CT6

CT7

CT8

(%)

(%)

(%)

(%)

(%)

43,56

43,56

43,56

43,56

43,56

26,44

27,69

27,99

28,14

28,29

Avicel PH101

10

10

10

10

10

Crospovidon

PVP K30

0,75

0,45

0,3

0,15

Nng t dc dnh (%)

13

Talc

Aerosil

0,5

0,5

0,5

0,5

0,5

Kolliwax HCO

0,5

0,5

0,5

0,5

0,5

100

100

100

100

100

Thnh phn
Clopidogel bisulfat (300mg)
T dc n nh
Manitol

PEG 6000
Tng

27

Nhn xt:CT 3 (nng t dc dnh 13%) v CT 5 (nng t dc dnh

5%) trong qu trnh nho m, khi m kt dnh mnh gy kh khn trong qu trnh
to ht. Trong qu trnh dp vin hin tng dnh chy ci xy ra ngay trong giai
on u.Mt khc,CT 8 c nng t dc dnh thp (1%) ht to ra khng chc
khng u, khi dp vin s dng lc dp ln, nng my khi dp nhng vin to ra
vn khng t cng yu cu.CT 6 v CT 7 c nng t dc dnh ph hp
(tng ng mc 3% v 2%), d dng trong qu trnh to ht v khng b dnh
chy ci trong qu trnh dp vin.Chn nng t dc dnh t 2-3% tip tc
tin hnh nghin cu.
Kt lun: Chn t dc n nh vi nng 9% v t dc dnh t 2-3%
gip khc phc hin tng dnh chy ci tng ng CT 7.
3.4. Kho st t dc chng oxy ha
Nhn thy ngay sau tun u tin khi dp vin bo ch theoCT 7, vin nhanh
chng b phn hy chuyn sang mu vng. Do , cn s dng cc bin php tng
n nh ca sn phm, cc gii php s dng gm s dng t dc chng oxy
ha v s dng mng bao.
Tin hnh bo ch cc CT s dng cc t dc chng oxy ha khc nhau (gm
c: BHT, EDTA, natri bisulfit) nh trong bng 3.5.
Sau khi dp vin, tin hnh nh lng hm lng ca clopidogrel bisulfat
trong vin bo ch c ngay sau khi dp vin v sau 3 tun iu kin LHCT theo
mc 2.4.3, quan st v mt hnh thc v so snh hm lng dc cht trong vin
nn clopidogrel 3 CT b gim thu c hnh 3.1.

28

Bng 3.5: Thnh phn cng thc c loi t dc chng oxy ha khc nhau
Thnh phn

CT9 (%)

CT10 (%)

CT11 (%)

Clopidogrel bisulfat (300mg)

43,56

43,56

43,56

23,14

23,14

23,14

Avicel PH101

10

10

10

Crospovidon

BHT

T dc n nh
Manitol

EDTA

Natribisulfit

PVP K30

0,3

0,3

0,3

PEG6000

Aerosil

0,5

0,5

0,5

Kolliwax HCO

0,5

0,5

0,5

Talc

Tng

100

100

100

120

% Hm lng

100
80
60

Hm lng sau khi

dp xong (%)

40

Hm lng sau 1
thng th LHCT (%)

20
0
CT9

CT10

CT11

Hnh 3.1: Biu th hin phn trm dc cht gii phng gim sau khi th
LHCT 3 tun

29

Kt qu:
V mt hnh thc: Vin clopidogrel c bo ch theo CT 11 khng c s
thay i mu r rt so vi vin ngay sau khi dp v bo qun nhit phng th
nghim. Vin clopidogrel c bo ch theo CT 9 trn b mt bt u xut hin cc
vt mu vng lm tm. Trong khi vin clopidogrel c bo ch theo CT 10 c
s chuyn mu r rt t mu trng ng sang mu vng (hnh nh xem ph lc 5).
V kt qu nh lng: Nhn thy sau 3 tun iu kin lo ha cp tc mc
gim hm lng hot chttheo th t: CT 10 (EDTA) > CT9 (BHT) > CT11
(natri bisulfit). Do , CT 11 vi cht chng oxy ha s dng l natri bisulfit c
la chn cho cc kho st tip theo.
3.5. Kho st nh hng ca mng bao ln n nh ca dc cht
Nhm bo v vin nn khi tc dng ca m mi trng trong qu trnh
vn chuyn v bo qun tin hnh bao vin(CT 11).Vi dch bao v thng s nu
mc 2.4.1, vin c bao vi t l khi lng mng bao so vi vin nhn ln lt
l 3%, 5%.Kt qu kh nng gii phng dc cht t cc CT kho st t l mng
bao c biu din trong hnh 3.2.
120

% Gii phng

100
80
60

Plavix
CT 11 bao 3%

40

CT 11 bao 5%
20
0
0

10

20

30

40
50
Thi gian (Pht)

60

70

Hnh 3.2. th biu din phn trm gii phng ca clopidogrel khi bao

30

T thc nghim, nhn thy vin bao cho kh nng gii phng dc cht
gim i ng k, c th, vi mng bao c khi lng t 5% so vi vin nhnphn
trm dc cht gii phng gim ng k v sau 60 pht vn cha gii phng c
hon ton (ch t 91,46%).
Kt qu kho st n nh 2 cng thc vin vi 2 t l mng bao khc nhau
ti iu kin LHCT 1 thng theo mc 2.4.3 c th hin trong bng 3.6.
Bng 3.6: Hm lng dc cht gii phng sau khi bao
CT 11 bao 3%

CT 11 bao 5%

% Hm lng ngay sau khi bao 24h

99,15%

99,46%

% Hm lng sau 1 thng ti iu kin LHCT

99,02%

99,27%

Nhn thy v mt hnh thc, i vi c 2 t l mng bao kho st u c b

mt vin nhn bng v khng c s thay i mu sc r rt sau khi th LHCT (hnh
nh xem ph lc 5). V kt qu nh lng,vin bo ch theo CT 11 sau khi em
bao vi khi lng mng bao t 3% v 5% khi th trong iu kin LHCT 1 thng
c s thay i hm lng khng ng k (cc mu th u c hm lng trn
99%)(SD < 0,2).
Cn nhc gia kh nng bo v ca mng bao vi kh nng gii phng dc
cht, la chn mng bao c khi lng mng bao t 3% so vi khi lng vin
nhn cho cc kho st tip theo.
3.6. Kho st s nh hng ca cht din hot ln ha tan
Sau khi bao kh nng ha tan dc cht ca vin nn clopidogrel CT 11 chm
hn so vi vin i chiu Plavix, kt hp vi kt qu th tan s b ca nguyn
liu clopidogrel bisulfat (ph lc 3) nghin cu tip tc tin hnh thit lp CT nh
bng 3.7 nghin cu nh hng ca cht din hot ln kh nng ha tan
clopidogrel bisulfat trong vin nn clopidogrel.

31

Bng 3.7: Thnh phncng thc c loi cht din hot khc nhau
Thnh phn

CT12 (%)

CT13 (%)

CT14 (%)

Clopidogrel bisulfat (300mg)

43,56

43,56

43,56

Natri bisulfit

T dc n nh

18,14

18,14

18,14

Avicel PH101

10

10

10

Crospovidon

Poloxamer 407

Manitol

Tween 80

Natri laurylsulfat

PVP K30

0,3

0,3

0,3

PEG6000

Aerosil

0,5

0,5

0,5

Kolliwax HCO

0,5

0,5

0,5

Talc

Tng

100

100

100

Sau khi dp vin, tin hnh bao vin CT12, CT13, CT14 nh mc 2.4.1 vi
khi lng mng bao t 3% khi lng vin nhn, nh gi % gii phng dc
cht c tin hnh nh mc 2.4.2, kt qu c trnh by nh hnh 3.3.

32

120

% Gii phng

100
80
Plavix
60

CT 13
CT 12

40

CT 14

20
0
0

10

20

30
40
Thi gian (pht)

50

60

70

Hnh 3.3:nh hng ca cht din hot ln kh nng gii phng hot cht
Nhn xt:
V mt hnh thc, cc vin sau khi dp khng c s khc bit r rt v hnh
thc, cc CT u cho vin nhn, bng, p, mu trng (hnh nh xem ph lc 5).
Kt qu th ha tan cc mu vin sau khi baoso snh vi vin i chiu
Plavix th CT12, CT13, CT14 cho h s f2 gim dn, (c th: 61,98>48,91>48,34),
trong CT 12 (s dng Poloxamer 407)cho f2 cao nht.
C th s b kt lun vic s dng Poloxamer 407gip ci thin kh nng gii
phng ca dc cht, th gii phng ha tan tng t so vi vin i chiu, tuy
nhin vn cha t yu cu v ha tan t t nht 80% sau 30 pht.CT 12 c
chn tip tc nghin cu.
3.7. Kho st nh hng ca t dc siu r ln kh nng gii phng dc cht
Tin hnh thit lp cc CT nh bng 3.8 kho st nng t dc siu r
crospovidon s dng ci thin ha tan ca vin nn clopidogrel:

33

Bng 3.8: Thnh phn cng thc c t l t dc r khc nhau

CT 15

CT16

CT 17

CT12

CT18

(%)

(%)

(%)

(%)

(%)

43,56

43,56

43,56

43,56

43,56

Natribisulfit

T dc n nh

14,14

16,14

17,64

18,14

19,14

Avicel PH101

10

10

10

10

10

Crospovidon

1,5

Poloxamer 407

PVP K30

0,3

0,3

0,3

0,3

0,3

PEG6000

Aerosil

0,5

0,5

0,5

0,5

0,5

Kolliwax HCO

0,5

0,5

0,5

0,5

0,5

Talc

Tng

100

100

100

100

100

Thnh phn
Clopidogrel bisulfat (300mg)

Manitol

Sau khi dp vin, v mt hnh thc tt c cc mu vin u nhn, p c mu

trng ng. Sau tin hnh bao vin cc CT bo ch trn nh mc 2.4.1 vi khi
lng mng bao t 3% khi lng vin nhn, tin hnh th ha tan, nh gi %
gii phng dc cht nh mc 2.4.1, kt qu c biu din trong th gii phng
nh hnh 3.4.

34

% Nng dc cht GP

120
100
80

Vin Plavix
CT 17

60

CT 15
CT 16

40

CT 12
CT 18

20
0
0

10

20

30
40
Thi gian (pht)

50

60

70

Hnh 3.4: nh hng ca t dc siu r n kh nng gii phng hot cht

Nhn xt: Thc nghim cho thy ch c cc cng thc: CT 15, CT 16, CT 17
t c yu cu v ha tan t t nht 80% sau 30 pht, nh vy vic thay i
nng t dc siu r crospovidon c nh hng ng k n s gii phng ca
clopidogrel, c th kh nng gii phng dc cht tng dn theo chiu tng ca
nng crospovidon (CT15> CT16> CT17> CT12> CT18). iu ny c th do
crospovidon c kh nng ht nc mnh, to cc vi mao qun dn nc vo trong
lng vin gip ci thin kh nng r ca vin. Xt v th gii phng ha tan, nhn
thy vin bo ch theo CT 17 (ng vi t l crosspovidon l 1,5%) cho th ging
vi th gii phng ha tan ca vin i chiu Plavix (f2 t 82,2).
Tin hnh theo di n nh ca vin nn clopidogrel bo ch theo CT17
trong iu kin 40oC, m 75% trong vng mt thng. Kt qu th ha tan c
biu din nh hnh 3.5.

35

120

% Gii phng

100
80
60
Vin Plavix
CT 17 sau khi bao
CT 17 LHCT

40
20
0
0

10

20

30

40

50

60

70

Thi gian (pht)

Hnh 3.5: Kt qu th ha tan sau khi th lo ha cp tc 1 thng

Nhn xt: CT 17 sau khi th LHCT sau 1 thng hu nh khng c s thay i
r rt v mt mu sc (hnh nh xem ph lc 5) v v kh nng gii phng ca dc
cht (f2 t 80,06).
Tin hnh nh lng clopidogrel bisulfat trong mu vin c bo ch theo
CT 17 theo mc 2.4.3 trc v sau khi th nghim lo ha cp tc thu c kt qu
nh hnh 3.6.
120

% Hm lng

100
80
60

Hm lng sau khi dp

xong (%)

40

Hm lng sau 1 thng

th LHCT (%)

20
0
Hm lng sau Hm lng sau 1
khi dp xong (%) thng th LHCT
(%)

Hnh 3.6: th biu din s thay i hm lng dc cht sau khi th

LHCT

36

Nhn xt:Sau khi dp vin v bao bo v CT 17, hm lng dc cht nh

lng c trc v sau 1 thng th nghim lo ha cp tc thay i khng ng k
vi hm lng ln lt l 99,74% (SD = 0,115) v 99,01% (SD = 0,204).
Kt lun: Bo ch vin theo CT 17 cho qu trnh bo ch thun li, dc cht
n nh trong t nht 1 thng khi tin hnh th nghim v ng cong gii phng
ha tan dc cht ging vi vin i chiu nht, t tiu chun v ha tan ca
vin nn clopidogrel t t nht 80% sau 30 pht theo dc in M USP 36.

37

KT LUN V KIN NGH

KT LUN:
Sau thi gian tin hnh thc nghim, chng ti thu c mt s kt qu
nh sau:
1. bo ch c vin nn clopidogrel n nh v mt hnh thc v hm
lng trong iu kin lo ha cp tc trong t nht 1 thng.
2. bo ch c vin nn clopidogrel c ha tan t t nht 80% sau 30
pht.
Kt qu kho st nh hng ca cc yu t cho thynh hng cat l t dc
n nh, nng t dc dnh, loi cht chng oxy ha, loi cht din hot, dy
mng bao vt l t dc siu r ln s n nh v ha tan ca vin nn
clopidogrel.
T kt qu trn la chn c CT c % gii phng dc cht gn vi vin
i chiu Plavix nht.
Bng 4.1:Thnh phn cng thc tt nht
Thnh phn
Clopidogrel bisulfat (300mg)

CT 17 (%)
43,56

Natribisulfit

T dc n nh

Manitol

17,64

Avicel PH101

10

Crospovidon

1,5

Poloxamer 407

PVP K30

0,3

PEG6000

Aerosil

0,5

Kolliwax HCO

0,5

Talc

Tng

100

38

KIN NGH:
Do thi gian thc hin ti c hn, nghin cu ch mi trin khai quy
m nh v thu c kt qu ban u kh quan. pht trin v hon thin
ti, chng ti xin a ra mt s kin ngh sau:
-Tin hnh nh gi n nh ca vin nn clopidogrel CT17 trong thi gian
di hn.
- Tin hnh kho st CT ca dch bao tng n nh trong gii phng
dc cht cng nh trong bo qun vin nn clopidogrel.

TI LIU THAM KHO

TING VIT
1.

B mn bo ch- Trng i hc Dc H Ni (2005), Mt s chuyn v

bo ch hin i, tr.210-238 Nh xut bn y hc, H Ni.

2.

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sinh dc hc cc dng thuc, NXB Y hc, tp 2, H Ni.

3.

Cc qun l dc (2005), Hng dn ca ASEAN v nghin cu n nh

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4.

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Phm Hin Giang (2015), Thm nh quy trnh bo ch vin nn glipizid gii
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Ph lc 1: Kt qu thm nh mt s ch tiu ca phng php o quang ph

hp th

Thnh phn t dc trong cng thc vin nn

Thnh phn

Khi lng (mg)

Natribisulfit

45

Poloxamer 407

45

T dc n nh

108

Avicel

90

Crosspovidon

81

Manitol

66,96

PVP K30

18

Talc

45

Aerosil

4,5

Kolliwax HCO

4,5

Kt qu kho st c hiu
STT

Mu

mCLO.BI (mg)

Nn 1

Nn 2

Nn 3

Chun

396,4

Th

392,9

ABS
0,010
0,010
0,007
0,007
0,009
0,009
0,601
0,601
0,609
0,609

ABSTB

Kt qu

0,010

1,44%

0,007
0,009
0,601
0,609

1,89%

Kt qu kho st thch hp ca h thng

Ln o

T.bnh

CV %

hp thu

0.602

0.603

0.603

0.603

0.603

0.603

0.603

0,07%

Abs

TH TUYN TNH

y = 0.0200x + 0.0024
R2 = 0.9999

0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
0

10

15

20

25

30

35

40

45

50

Clopidogrel (g/mL)

th biu din mi tng quan nng dung dch clopidogrel bisulfat v mt

quang

Kt qu kho st tuyn tnh

Mu

% Nng

S1

7.5

Nng
Clopidogrel (g/mL)

ABS

ABSTB

D liu thng
k

0,045
2.27

0,045
0,045
0,120

S2

20

6.05

0,120
0,120
0,303

S3

50

15.13

0,303
0,303

b = 0,0024

0,486
S4

80

24.21

0,486
0,486

100

30.26

0,603
0,603
0,731

S6

120

36.31

0,731
0,731
0,909

S7

150

45.39

0,909
0,909

%Y = 0,40%
r = 0.9999

0,603
S5

a = 0,0200

Kt qu kho st ng
mCLO.BI
Mu ban u
(mg)
Chun: 396,4

CCLOP
dd o
b

Mt

Mt

quang chun quang th

(g/ml)

CCLOP

Tm

tm thy

li

(g/ml)

(%)

Thng
k
TB
CV%

30,26
Mu 10% Clopidogrel

42,5

3,244

0,606 0,608 0,068 0,068

3,390

104,50 105,70

42,6

3,252

0,606 0,608 0,068 0,068

3,390

104,25

42,2

3,221

0,606 0,608 0,070 0,070

3,490

108,34

2,17

Mu 50% Clopidogrel
1

201,9

15,411 0,606 0,608 0,316 0,316 15,753 102,22 104,10

202,2

15,433 0,606 0,608 0,327 0,327 16,302 105,62

202,6

15,464 0,606 0,608 0,324 0,324 16,152 104,45

1,66

Mu 100% Clopidogrel
1

392,9

29,989 0,608 0,608 0,616 0,616 30,658 102,23 102,34

393,0

29,997 0,608 0,608 0,616 0,616 30,658 102,20

393,4

30,027 0,608 0,608 0,619 0,619 30,807 102,60

0,21

Mu 120% Clopidogrel
1

469,4

35,828 0,608 0,608 0,746 0,746 37,128 103,63 103,63

470,2

35,889 0,608 0,608 0,749 0,749 37,278 103,87

469,9

35,866 0,608 0,608 0,745 0,745 37,078 103,38

Thng k tng

TB 103,64; CV% 1,69; n = 12

0,24

Kt qu kho st lp li
Mu

mch

Mt quang

Mt quang

Hm

Thng k

(mg)

chun

th

lng (%)

TB
CV%

Chun:

396,4

KLTB

1017,6

1005,5

0,603

0,605

0,599

0,599

101,22

1005,5

0,603

0,605

0,596

0,596

100,72

1004,6

0,603

0,605

0,585

0,585

98,95

1005,8

0,603

0,605

0,594

0,594

100,35

1006,0

0,603

0,605

0,592

0,592

99,99

1005,7

0,603

0,605

0,598

0,598

101,03

KLTB

901,6

901,9

0,605

0,606

0,621

0,622

103,40

901,5

0,605

0,606

0,623

0,623

103,78

901,5

0,605

0,606

0,625

0,625

104,11

901,9

0,605

0,606

0,626

0,626

104,23

901,7

0,605

0,606

0,620

0,620

103,26

902,0

0,605

0,606

0,623

0,622

103,56

Vin Plavix 300

100,38
0,83

Vin th

103,72
0,38

Kt qu kho st n nh ca dung dch

CCLOd
Mu

KL

d o

(mg)

b
g/ml

Chun 392,0 29,92

KLTB 1,017

CCLO

CCLO
tm

Mt

Mt

thy tm

quang

quang

g/m li 1

chun

th

tm
thy
2
g/m

%
tm

Thng k

li 2

l
Ngy 2
Vin Plavix 300

HTB1=100,30

6
1

1005,
5
1005,
5
1004,
6

29,643

29,643

29,617

30,01 101,2 0,59 0,59 0,60 0,60 30,27 102,1

0

29,85 100,7 0,59 0,59 0,59 0,59 29,94 101,0

9
29,30
8

2
98,95

0,59 0,59 0,58 0,58 29,29

7

2
98,91

HTB2=100,68

S1 = 1,193

S2 = 1,631

So

Ftn= 1,870 <19 = Flt(2,2, P = 0,05); ttn = 0,164 <2,776 = tlt (n = n1 + n2 -2 =

snh

4, P= 0,05)

CLO, Th
BI

HTB1=102,34

MQC

30,65 102,2 0,59 0,59 0,61 0,61 30,69 102,3

392,9 29,989

393,0 29,997

393,4 30,027

So

Ftn= 1,203 <19 = Flt(2,2, P = 0,05); ttn = 0,978 <2,776 = tlt (n = n1 + n2 -2 =

snh

4, P= 0,05)

Chun 396,4 30,26

30,65 102,2 0,59 0,59 0,61 0,61 30,72 102,4

8

30,80 102,6 0,59 0,59 0,61 0,61 30,87 102,8

7

HTB2=102,53

S1 = 0,223

S2 = 2,244

0,59 0,59 0,60 0,60 30,34 100,2 98<100,28<1

7

02

Ph lc 2: Hm lng dc cht cn li sau 1 thng khi th n nh s b

nguyn liu

iu kin mi trng

Thay i v hnh

Hm lng (%)

thc
t trong ngn mt t lnh

Mu trng ng, hi

97,61

vn cc
t ngoi ca s (ni tip xc
nh nng)

Mu vng nu, dnh

97,69

bt

t trong t vi kh hu 40oC,

Mu hi vng

98,46

Khng thay i

98,84

Khng thay i

99,35

m 75%
t trong t vi kh hu 30oC,
m 75%
t trong phng ch ti (trnh
nh sng)

Ph lc 3: Lng dung mi (tng i) s dng ha tan 1 g clopidogrel

bisulfat nhit 25oC
Dung mi

Th tch (ml)

Methanol

HCl 0,1N (pH 1,2)

28

m pH 2

190

Nc ct

300

m pH 4,5

m pH 6,8

Ph lc 4: Kt qu phn trm th ha tan ca cc cng thc kho st

CT

5 pht 10 pht

15 pht

20 pht

30 pht

45 pht

60 pht

SD (%)

SD

SD

SD

SD

SD

SD

(%)

(%)

(%)

(%)

(%)

(%)

CT 11

4,86

12,52

17,6

48,6

73,32

92,02

97,15

(Bao

2,14

2,84

3,45

4,15

5,23

2,13

1,07

CT 11

0,85

2,88

11,92

29,29

59,45

73,73

91,46

(Bao

1,10

1,98

2,93

2,04

2,30

3,08

0,89

12,01

24,82

39,79

53,81

71,98

90,15

101,5

1,28

2,45

2,56

2,67

1,78

2,45

1,07

9,09

18,09

37,40

49,07

66,61

79,09

97,09

1,89

1,74

2,78

3,09

2,65

1,56

1,39

8,89

20,52

32,68

45,08

71,36

81,63

89,80

1,90

2,34

2,67

3,79

2,62

3,09

1,89

55,15

72,35

87,24

94,21

99,32

99,33

99,33

5,49

4,56

3,08

1,12

0,24

0,01

0,01

42,54

57,18

68,98

78,09

92,15

99,45

99,45

4,7

3,59

2,63

2,45

1,08

0,05

0,02

11,96

29,02

46,72

64,50

85,62

93,82

99,69

3,14

3,40

2,07

3,58

2,08

1,03

0,51

5,13

11,23

23,34

32,74

42,09

56,14

70,31

0,56

1,34

3,45

3,51

4,1

4,29

3,78

CT17

11,70

29,56

49,02

64,78

83,25

92,78

98,07

(Sau

1,03

2,67

2,54

2,13

1,01

0,51

0,02

11,32

28,66

45,70

61,06

81,67

93,74

99,51

0,26

0,48

0,18

0,37

0,53

0,62

047

3%)

5%)
CT12

CT13

CT14

CT15

CT16

CT17

CT18

LHCT)
Plavix

Ph lc 5: Hnh nh mt s vin bo ch theo cc cng thc khc nhau ti mt

s thi im

CT 1 ngay sau khi dp vin

CT 1 sau 1 ngy bo qun

CT 9, 10, 11 ngay sau khi dp

CT 9, 10, 11 sau 3 tun th LHCT

CT 11 bao 3%, 5%

CT 12, 13, 14 ngay sau khi dp

CT 17 ngay sau khi bao

CT 17 sau khi th LHCT 1 thng