B GIO DC V O TO

B Y T

TRNG I HC DC H NI

TRN MINH C

NGHIN CU BIN PHP CI THIN

HA TAN CA
PARACETAMOL V IBUPROFEN
TRONG VIN NN PHI HP
LUN VN THC S DC HC

H NI 2013

B GIO DC V O TO

B Y T

TRNG I HC DC H NI

TRN MINH C

NGHIN CU BIN PHP CI THIN

HA TAN CA
PARACETAMOL V IBUPROFEN
TRONG VIN NN PHI HP
LUN VN THC S DC HC
CHUYN NGNH CNG NGH DC PHM V BO CH
M S: 60720402

Ngi hng dn khoa hc: TS. NGUYN NGC CHIN

H NI 2013

LI CM N

Lun vn ny c thc hin v hon thnh ti cc b mn phn tch, bo ch

- b mn Cng nghip dc. Trong qu trnh thc hin kha lun tt nghip ti
nhn c s gip tn tnh ca thy hng dn, cc ging vin ca b
mn Cng nghip dc.
u tin ti xin c by t s cm n su sc ti:

TIN S NGUYN NGC CHIN

L ngi thy trc tip hng dn, du dt ch bo v a ra nhng kin
qu bu trong sut qu trnh thc hin lun vn.
Ti xin chn thnh cm n s gip ca cc thy c, cc k thut vin b
mn Cng nghip dc to iu kin tt nht tt hon thnh lun vn ny.
Ti xin chn thnh cm n s quan tm ca ban gim hiu, phng o to v
cc thy c truyn t kin thc cho ti trong sut thi gian hc tp v thc
hin lun vn.
Ti v cng bit n gia nh, bn b v nhng ngi lun st cnh, ng vin
v gip ti c iu kin tt nht tp trung vo ti.
H Ni, thng 10 nm 2013
Hc vin
Trn Minh c

MC LC
T VN ....................................................................................................... 1
Chng 1. TNG QUAN ..................................................................................... 3
1.1 Paracetamol ................................................................................................ 3
1.1.1

Cng thc cu to ............................................................................... 3

1.1.2

Tnh cht ............................................................................................. 3

1.1.3

Dc ng hc ................................................................................... 3

1.1.4

Cng dng........................................................................................... 4

1.1.5

Tc dng khng mong mun .............................................................. 4

1.1.6

Tng tc thuc .................................................................................. 4

1.1.7

Chng ch nh.................................................................................... 5

1.2 Ibuprofen .................................................................................................... 5

1.2.1

Cng thc ha hc .............................................................................. 5

1.2.2

Tnh cht ............................................................................................. 5

1.2.3

Dc ng hc ................................................................................... 5

1.2.4

Cng dng........................................................................................... 5

1.2.5

Tc dng khng mong mun .............................................................. 6

1.2.6

Tng tc thuc .................................................................................. 6

1.2.7

Chng ch nh.................................................................................... 7

1.3 Mt s yu t nh hng n ha tan ca vin nn ............................. 8

1.3.1

Qu trnh gii phng dc cht t vin nn ....................................... 8

1.3.2

Cc yu t thuc phm vi xy dng cng thc dp vin ................... 9

1.3.3

Cc yu t thuc phng php quy trnh dp vin........................ 11

1.4 Cc phng php ci thin ha tan ca dc cht t tan .................... 12

1.4.1

Phng php ch to h phn tn rn ............................................... 12

1.4.2

Phng php s dng cc cht thn nc c cu to vng.............. 12

1.4.3

Phng php phun ng t ............................................................... 13

1.4.4

Phng php s dng cht din hot................................................ 13

1.4.5

K thut tc ng vo mi trng ha tan ....................................... 14

1.4.6

Phng php s dng t dc siu r .............................................. 16

1.5 Mt s nghin cu gn y v PAR v IBU............................................ 17

1.5.1

Paracetamol ...................................................................................... 17

1.5.2

Ibuprofen .......................................................................................... 18

1.5.3

Paracetamol v ibuprofen ................................................................. 19

1.6 Phng php nh lng ng thi paracetamol v ibuprofen bng quang

ph o hm t i ........................................................................................... 20
1.6.1

C s ca phng php quang ph o hm t i ......................... 20

1.6.2

Phng php ph o hm t i ..................................................... 21

Chng 2. I TNG V PHNG PHP NGHIN CU ...................... 23

2.1 Nguyn liu v thit b nghin cu .......................................................... 23
2.1.1

Nguyn liu v ha cht ................................................................... 23

2.1.2

Thit b .............................................................................................. 24

2.2 Ni dung nghin cu ................................................................................ 24

2.3 Phng php nghin cu ......................................................................... 25
2.3.1

Phng php bo ch vin nn hn hp........................................... 25

2.3.2

Phng php bo ch vin nn n thnh phn ............................... 27

2.3.3

Phng php nh lng bng quang ph o hm t i............... 28

2.3.4

Phng php th ha tan ............................................................. 29

2.3.5

Phng php xc nh tan trong dung mi kim ........................ 30

2.3.6

Phng php nh gi mt s ch tiu ca vin nn v ht ............. 31

2.3.7

Phng php nh gi tng quan gia hai th gii phng ........ 31

Chng 3. KT QU NGHIN CU ............................................................... 33

3.1 Xy dng phng php nh lng ng thi PAR v IBU bng phng
php quang ph o hm t i. ...................................................................... 33
3.1.1

Kho st khong tuyn tnh .............................................................. 33

3.2 Kt qu kho st ha tan ca vin i chiu ....................................... 34

3.3 Kt qu kho st nh hng ca cc thnh phn trong cng thc ti

ha tan ca cc dc cht ................................................................................ 35
3.3.1

Kt qu kho st nh hng ca mt s cht din hot ................... 35

3.3.2

Kt qu kho st nh hng ca mt s t dc siu r .................. 41

3.3.3

Kt qu kho st nh hng ca kch thc tiu phn dc cht .... 44

3.3.4

Kt qu kho st nh hng ca t l HPMC E15 ........................... 47

3.3.5
cht

Kt qu kho st nh hng ca t dc kim ti ha tan dc

...48

3.4 xut mt s ch tiu ca vin bo ch c ....................................... 52

Chng 4. BN LUN ...................................................................................... 53
4.1 nh hng ca cht din hot n ha tan ca dc cht trong cng
thc ..53
4.2 nh hng ca t dc siu r n ha tan ca dc cht trong cng
thc . ................................................................................................................. 53
4.3 nh hng ca kch thc tiu phn dc cht n ha tan ca dc
cht trong cng thc ......................................................................................... 55
4.4 nh hng ca t dc kim n ha tan ca dc cht trong cng
thc .55
4.5 V phng php nh lng vin nn phi hp paracetamol v ibuprofen
..56
KT LUN V KIN NGH............................................................................. 57
TI LIU THAM KHO ................................................................................... 59
PH LC ............................................................................................................ 64

DANH MC CC CH VIT TT
CCS

Natri Croscarmellose

CDH

Cht din hot

DC

Dc cht

DVN

Dc in Vit Nam

HPLC

Sc k lng hiu nng cao

HPMC

Hydroxypropyl methylcellulose

HPTR

H phn tn rn

IBU

Ibuprofen

LSD

Lactose phun sy

NaLS

Natri laurylsulfat

PAR

Paracetamol

PHT

Ph o hm t i

PEG

Polyethylen glycol

PVP

Polyvinyl pyrollidon

SSG

Natri starch glycolat

TD

T dc

TDSR

T dc siu r

DANH MC CC BNG
Bng 2.1. Nguyn liu s dng ....................................................................... 23
Bng 2.2. Cc thit b s dng ........................................................................ 24
Bng 3.1. Mi tng quan gia nng v gi tr PHT ........................... 33
Bng 3.2. T l phn trm ha tan DC t vin Alaxan ................................... 35
Bng 3.3. Cc tnh cht vin nn n thnh phn........................................... 36
Bng 3.4. T l phn trm DC ha tan vi cc CDH khc nhau .................... 36
Bng 3.5. Cng thc vin vi thnh phn, t l CDH khc nhau ................... 37
Bng 3.6. Cc tnh cht vin s dng cc CDH khc nhau ............................ 37
Bng 3.7. T l phn trm DC ha tan t vin c CDH khc nhau, t l 3% 38
Bng 3.8. T l phn trm DC ha tan t vin c CDH khc nhau, t l 5% 38
Bng 3.9. Cng thc vin nn s dng cc TDSR khc nhau ........................ 41
Bng 3.10. Cc tnh cht vin s dng cc TDSR khc nhau ........................ 42
Bng 3.11. T l phn trm DC ha tan t vin c thnh phn TDSR khc
nhau ................................................................................................................. 42
Bng 3.12. Cng thc vin nn s dng kch thc tiu phn dc cht khc
nhau ................................................................................................................. 44
Bng 3.13. Cc tnh cht vin s dng kch thc tiu phn khc nhau ........ 45
Bng 3.14. T l phn trm dc cht ha tan khi s dng ry khc nhau .... 45
Bng 3.15. Cng thc vin nn s dng t l HPMC E15 khc nhau ............ 47
Bng 3.16. tan sau 8 ln siu m ca IBU v PAR trong cc dung dch
khc nhau iu kin phng th nghim ........................................................ 48
Bng 3.17. Cng thc vin nn vi cc t l t dc kim khc nhau ........... 49
Bng 3.18. Cc tnh cht vin s dng t dc kim t l khc nhau ............ 49
Bng 3.19. T l phn trm PAR v IBU ha tan trong CT12, CT17 v CT18
......................................................................................................................... 50
Bng 3.20. xut tiu chun ca vin nn phi hp PAR v IBU .............. 52

DANH MC CC HNH, TH
Hnh 2.1. S bo ch vin nn phi hp .................................................... 26
Hnh 3.1. Mi tng quan gia gi tr PHT v nng PAR .................. 33
Hnh 3.2. Mi tng quan gia gi tr PHT v nng IBU. .................. 34
Hnh 3.3. T l phn trm PAR ha tan t vin nn vi cc CDH khc nhau 39
Hnh 3.4. T l phn trm IBU ha tan t vin nn vi cc CDH khc nhau 39
Hnh 3.5. T l phn trm PAR ha tan t vin nn vi cc TDSR khc nhau
......................................................................................................................... 43
Hnh 3.6. T l phn trm IBU ha tan t vin nn vi cc TDSR khc nhau
......................................................................................................................... 43
Hnh 3.7. T l phn trm PAR ha tan trong vin qua ry 125 v qua ry 180
......................................................................................................................... 46
Hnh 3.8. T l phn trm IBU ha tan trong vin qua ry 125 v qua ry 180
......................................................................................................................... 46
Hnh 3.9. T l phn trm PAR ha tan vi TD kim v khng dng TD kim
......................................................................................................................... 51
Hnh 3.10. T l phn trm IBU ha tan vi TD kim v khng dng TD kim
......................................................................................................................... 51

T VN
Hin nay, vin nn l dng thuc c s dng nhiu nht trong iu tr do
nhiu u im nh: tin s dng, d sn xut...nhng sinh kh dng thng
khng n nh c bit vi cc dc cht t tan trong nc. Do vy, vic
nghin cu bin php lm tng tc v mc ha tan dc cht t tan t
vin nn ang l hng nghin cu c nhiu nh khoa hc quan tm.
Vin nn cha ibuprofen v paracetamol l s kt hp tc dng gim au,
khng vim v h st. S kt hp ca ibuprofen v paracetamol liu iu tr
thp nht khi s dng s an ton hn khi s dng hai vin ring r m vn cho
hiu qu iu tr cao hn.
Vin nn phi hp ibuprofen v paracetamol ch yu c dng trong iu
tr bnh au c khp do chn thng, thp khp, vim thn kinh, au sau
phu thut, iu tr cm st, nhc u, au rng, au bng kinh.
Tuy nhin, theo h thng phn loi sinh dc hc, paracetamol c xp
vo nhm I cn ibuprofen c xp vo nhm II. V vy, khi s dng theo
ng ung, tc hp thu ca ibuprofen b hn ch bi tc ha tan dc
cht t dng thuc v sinh kh dng i khi khng t theo mong mun.
Gn y, cc nc tin tin bo ch vin nn cha ibuprofen v
paracetamol gii phng nhanh nhm nng cao sinh kh dng ca thuc.
trong nc, c tc gi nghin cu bo ch vin nn phi hp
ibuprofen v paracetamol gii phng nhanh dc cht. Kt qu ban u cho
thy tc v mc ha tan ca paracetamol v ibuprofen c ci thin
mt cch ng k [15].
Nhm tip tc hng nghin cu bo ch vin nn phi hp cha
paracetamol v ibuprofen, chng ti thc hin ti: Nghin cu bin php
ci thin ha tan ca paracetamol v ibuprofen trong vin nn phi hp
vi mc tiu:

1. nh gi c nh hng ca cc t dc n ha tan
dc cht t vin nn phi hp cha 325 mg paracetamol
v 200 mg ibuprofen.
2. Bo ch c vin nn phi hp cha 325 mg paracetamol
v 200 mg ibuprofen c ha tan 2 dc cht trn 90%
sau 30 pht.

Chng 1. TNG QUAN

1.1 Paracetamol
1.1.1 Cng thc cu to

C8H9NO2

P.t.l: 151,2

1.1.2 Tnh cht

Bt kt tinh mu trng, khng mi. Hi tan trong nc, rt kh tan trong
cloroform, ether, methylen clorid, d tan trong dung dch kim, ethanol 96 %
[3].
1.1.3 Dc ng hc
-

Hp thu: paracetamol c hp thu nhanh chng v hu nh hon ton

qua ng tiu ha c. Thc n c th lm vin nn gii phng ko
di paracetamol chm c hp thu mt phn v thc n giu carbon
hydrat lm gim t l hp thu ca paracetamol. Nng nh trong
huyt tng t trong vng 30 n 60 pht sau khi ung vi liu iu
tr.

Phn b: paracetamol phn b nhanh v ng u trong phn ln cc

m ca c th. Khong 25% paracetamol lin kt vi protein huyt
tng.

Thi tr: na i huyt tng ca paracetamol l 1,25 - 3 gi, c th

ko di vi liu gy c hoc ngi bnh c thng tn gan [4].

1.1.4 Cng dng

Paracetamol (acetaminophen hay N - acetyl - p - aminophenol) l cht
chuyn ha c hot tnh ca phenacetin, l thuc gim au - h st hu hiu
c th thay th aspirin; tuy vy, khc vi aspirin, paracetamol khng c hiu
qu iu tr vim. Vi liu ngang nhau tnh theo gam, paracetamol c tc
dng gim au v h st tng t nh aspirin.
Paracetamol lm gim thn nhit ngi bnh st, nhng him khi lm
gim thn nhit ngi bnh thng. Thuc tc ng ln vng di i gy
h nhit, ta nhit tng do gin mch v tng lu lng mu ngoi bin [4].
1.1.5 Tc dng khng mong mun
Ban da v nhng phn ng d ng khc thnh thong xy ra. Thng l ban
hoc my ay, nhng i khi nng hn v c th km theo st do thuc v
thng tn nim mc. Ngi bnh mn cm vi salicylat him mn cm vi
paracetamol v nhng thuc c lin quan. Trong mt s t trng hp ring
l, paracetamol gy gim bch cu trung tnh, gim tiu cu v gim ton
th huyt cu [4].
1.1.6 Tng tc thuc
Ung di ngy liu cao paracetamol lm tng nh tc dng chng ng ca
coumarin v dn cht indandion. Tc dng ny c v t hoc khng quan
trng v lm sng, nn paracetamol c a dng hn salicylat khi cn gim
au nh hoc h st cho ngi bnh ang dng coumarin hoc dn cht
indandion.
Cn phi ch n kh nng gy h st nghim trng ngi bnh dng
ng thi phenothiazin v liu php h nhit.
Ung ru qu nhiu v di ngy c th lm tng nguy c paracetamol gy
c cho gan [4].

1.1.7 Chng ch nh
Ngi bnh c bnh tim, phi, thn hoc gan.
Ngi bnh qu mn vi paracetamol.
Ngi bnh thiu ht glucose - 6 - phosphat dehydro-genase [4].
1.2 Ibuprofen
1.2.1 Cng thc ha hc

C13H18O2

P.t.l: 206,3

1.2.2 Tnh cht

Bt kt tinh mu trng hay tinh th khng mu, thc t khng tan trong
nc, d tan trong aceton, dicloromethan, methanol v ether. Tan trong cc
dung dch hydroxyd kim long v carbonat kim [3].
1.2.3 Dc ng hc
Ibuprofen hp thu tt ng tiu ha. Nng ti a ca thuc trong huyt
tng t c sau khi ung t 1 n 2 gi. Thuc lin kt mnh vi protein
huyt tng. Na i ca thuc khong 2 gi. Ibuprofen o thi rt nhanh
qua nc tiu (1% di dng khng i, 14% di dng lin hp) [4].
1.2.4 Cng dng
Ibuprofen l thuc chng vim khng steroid, dn xut t acid propionic.
Ging nh cc thuc chng vim khng steroid khc, ibuprofen c tc dng
gim au, h st v chng vim. C ch tc dng ca thuc l c ch
prostaglandin synthetase v do ngn to ra prostaglandin, thromboxan v

cc sn phm khc ca cyclooxygenase. Ibuprofen cng c ch tng hp

prostacyclin thn v c th gy nguy c nc do lm gim dng mu ti
thn. Cn phi n iu ny i vi cc ngi bnh b suy thn, suy tim,
suy gan v cc bnh c ri lon v th tch huyt tng.
Tc dng chng vim ca ibuprofen xut hin sau hai ngy iu tr.
Ibuprofen c tc dng h st mnh hn aspirin, nhng km indomethacin.
Thuc c tc dng chng vim tt v c tc dng gim au tt trong iu tr
vim khp dng thp thiu nin.
Ibuprofen l thuc an ton nht trong cc thuc chng vim khng steroid
[4].
1.2.5 Tc dng khng mong mun
5 - 15% ngi bnh c tc dng ph v tiu ha: chng bng, bun
nn, nn, au bng, chy mu d dy - rut, lm lot d dy tin
trin.
Ton thn: St, mi mt, phn ng d ng (c bit co tht ph qun
ngi bnh b hen), vim mi, ni my ay.
Thn kinh trung ng: Nhc u, hoa mt chng mt, bn chn.
Mt: Ri lon th gic
Tai: Thnh lc gim.
Mu: Thi gian mu chy ko di [4].
1.2.6 Tng tc thuc
Ibuprofen v cc thuc chng vim khng steroid khc lm tng tc
dng ph ca cc khng sinh nhm quinolon ln h thn kinh trung
ng v c th dn n co git.

 Magnesi hydroxyd lm tng s hp thu ban u ca ibuprofen;

nhng nu nhm hydroxyd cng c mt th li khng c tc dng
ny.
Vi cc thuc chng vim khng steroid khc: Tng nguy c chy
mu v gy lot.
Methotrexat: Ibuprofen lm tng c tnh ca methotrexat.
Furosemid: Ibuprofen c th lm gim tc dng bi xut natri niu
ca furosemid v cc thuc li tiu.
Digoxin: Ibuprofen c th lm tng nng digoxin huyt tng [4].
1.2.7 Chng ch nh
Mn cm vi ibuprofen.
Lot d dy t trng tin trin.
Qu mn vi aspirin hay vi cc thuc chng vim khng steroid khc
(hen, vim mi, ni my ay sau khi dng aspirin).
Ngi bnh b hen hay b co tht ph qun, ri lon chy mu, bnh tim
mch, tin s lot d dy t trng, suy gan hoc suy thn (lu lng lc
cu thn di 30 ml/pht).
Ngi bnh ang c iu tr bng thuc chng ng coumarin.
Ngi bnh b suy tim sung huyt, b gim khi lng tun hon do
thuc li niu hoc b suy thn (tng nguy c ri lon chc nng thn).
Ngi bnh b bnh to keo (c nguy c b vim mng no v khun.
Cn ch l tt c cc ngi bnh b vim mng no v khun u
c tin s mc mt bnh t min).
Ba thng cui ca thai k [4].

1.3 Mt s yu t nh hng n ha tan ca vin nn

Hin nay vin nn l dng thuc c s dng rng ri nht, chim khong
60-70% tt c cc thuc lu hnh trn th trng, l do c nhiu u im nh:
D sn xut ln, nht l vi nhng my dp vin hin i, cng sut ln.
Hot cht n nh, hn dng di.
c chia liu mt ln tng i chnh xc.
Th tch gn nh, d vn chuyn, tin dng.
S dng linh hot do c nhin dng nh: ung, ngm, t di li, cy
di da, pha thnh dung dch, c tc dng ko di.
Phi hp c nhiu dc cht k c dc cht tng k.
Che du c mi v kh chu ca dc cht, trnh c s phn hy
ca dc cht dch v (bao tan rut), kim sot c tc dng ca
thuc (vin tc dng ko di).
Tuy nhin, vn sinh kh dng (SKD) ca vin nn ang c nhiu nh
nghin cu quan tm. Sau khi dp thnh vin, din tch b mt tip xc ca
dc cht vi mi trng ha tan b gim rt nhiu, do vi dc cht t tan
nu bo ch vin nn khng tt, sinh kh dng ca thuc c th b gim kh
nhiu. Sinh kh dng vin nn thay i tht thng do trong qu trnh bo
ch, c rt nhiu yu t tc ng n n nh ca dc cht v kh nng
gii phng dc cht t vin. V vy, vn t ra vi nh bo ch l phi
nm r cc yu t nh hng ti SKD ca vin nn cng nh cc phng
php nh gi cht lng ca dng thuc ny.
1.3.1 Qu trnh gii phng dc cht t vin nn
Nhc im c bn ca vin nn v mt SKD l sau khi nn, din tch b
mt tip xc ca dc cht vi mi trng ha tan gim nhiu, do nh
hng rt ln n tc ha tan v hp thu ca thuc, c bit vi nhng
dc cht t tan.
8

R v ha tan l hai qu trnh lin quan cht ch vi nhau. Thc ra, qu

trnh ha tan xy ra ngay t khi vin cha r v ngay t ht, nhng phi n
khi din tch b mt tip xc ca dc cht vi mi trng ha tan tng mnh
th tc ha tan mi tng.
C th ni ng hc ca qu trnh gii phng dc cht t vin nn l qu
trnh r v ha tan dc cht vng hp thu dc cht ti u trong ng
tiu ha.
Ngoi ra, c nhiu yu t thuc v dc cht nh hng ti sinh kh dng
ca vin nn nh: tan v tc ha tan ca dc cht, trng thi kt tinh
hay v nh hnh, hin tng a hnh, hin tng hydrat ha, kch thc tiu
phn, h s phn b du/nc ca dc cht s ion ha ca dc cht
1.3.2 Cc yu t thuc phm vi xy dng cng thc dp vin
C mt s dc cht c cu trc tinh th u n c th dp thnh vin m
khng cn cho thm t dc, tuy nhin s dc cht ny khng nhiu.Vi a
s dc cht cn li, mun dp thnh vin nn, ngi ta phi cho thm t
dc. Vic la chn t dc xy dng cng thc dp vin l mt khu
quan trng trong qu trnh sn xut vin nn, v theo quan dim sinh dc
hc, t dc nh hng trc tip n sinh kh dng va vin nn. Khi la
chn t dc cn xem xt c th cc yu t sau:
Mc ch s dng ca vin
Tnh cht ca dc cht
Tnh cht ca t dc
Phng php dp vin
C 4 nhm t dc chnh sau:

a) T dc n
Nhm t dc ny thng chim t l ln so vi dc cht nn c th gy
ra nhiu tng tc nh hng n kh nng gii phng dc cht.
Nhm bt mn v c: lm vin d r, nhng nhiu cht trong nhm
ny c kh nng hp ph dc cht.
Nhm bt ng lactose: c xu hng ko di thi gian r ca vin
lm chm s gii phng dc cht. Hin nay thng dng lactose
phun sy (LSD) c trn chy tt.
Nhm tinh bt: bin dc cht s nc thnh thn nc lm vin d
r.
Nhm t dc dp thng: LSD, Avicel, tinh bt bin tnhm bo
chc v d r, trn chy tt, m bo sai s khi lng vin [1,
5].
b) T dc dnh
Bn cht l cc t dc keo thn nc, d ha tan trong nc to dung dch
c nht cao, cho nn c xu hng ko di thi gian r v lm chm s ha
tan dc cht. Vi dc cht s nc, vic dng t dc dnh lng xt ht
c th lm tng tc ha tan ca dc cht. Cc t dc ny to thnh mt
mng thn nc, do d ha tan hn. Trong s cc t dc dnh th
polyvinylpyrolidon (PVP) v h tinh bt t nh hng nht n ha tan ca
dc cht. PVP thng c s dng nng 3-15%. Xt ht bng PVP
ht nhanh kh v c kh nng nn tt [19].
c) T dc r
Mc ch ca t dc r l thc y qu trnh lm v vin sau khi ung.
Nguyn nhn lm r trc y c cho l ch yu do s trng n ca t

10

dc v s ha tan cc thnh phn trong vin. Gn y, c ch vi mao qun

m i din l tinh bt c nhc n nhiu.
Hin nay, xu hng chung l dng t dc r trong v t dc r ngoi. T
dc r ngoi gip vin r nhanh hn nhng c th gy hin tng phn lp
khi ht.
Cc t dc r thng dng l: tinh bt, dn cht cellulose,Avicel lm
cho vin r nhanh do kh nng ht nc v trng n mnh, l t dc r rt
tt t l khong 5-10% so vi khi lng vin, kt hp c va r va
dnh [1, 5].
d) T dc trn
T dc trn c tc dng iu ha s chy ca ht, gim lc ma st, lc b
mt, lc tnh in ca tiu phn, m bo s ng nht v khi lng trong
vin nn. 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 v nh hng n
s ha tan dc cht trong vin. V d: magnesi stearat, calci stearat V
vy, cn chn t dc trn nh th no :

Cho php ht chy tt v phn phi lc nn ng nht trong vin.

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

trong vin.
Aerosil l t dc trn c dng ph bin hin nay. Vi t l dng thp
(0,1% 0,5%).
1.3.3 Cc yu t thuc phng php quy trnh dp vin

Phng php to ht nh hng n bn c hc ca ht, kh nng

lin kt v r ca vin, n nh ha hc ca dc cht.

11

Kch thc ht, trn chy v m ca ht nh hng n kh nng

lin kt ca vin, n s ng nht v khi lng vin v hm lng
dc cht trong vin.

Lc nn lin quan n xp ca vin, do nh hng n r v

kh nng gii phng dc cht ca vin.

Cc loi thit b nghin, trn, my dp vin u c nh hng mc

nht nh n kh nng gii phng dc cht ca vin.

1.4 Cc phng php ci thin ha tan ca dc cht t tan

1.4.1 Phng php ch to h phn tn rn
H phn tn rn (HPTR- Solid dispersion system) c nh ngha: l mt
hn hp ng nht th rn trong d dc cht phn tn trong cht mang
hoc ct tr v dc l, c iu ch bng phng php thch hp [7, 8, 19,
20, 33].
S dng h phn tn rn l mt bin php v ang c p dng lm
tng tan v tc tan ca nhiu loi dc cht t tan, trn c s lm
tng sinh kh dng ca thuc.
1.4.2 Phng php s dng cc cht thn nc c cu to vng
Phng php ny p dng cho cc dc cht m trong phn t c cu to t
vng benzen. Cc cht thn nc lm tng ha tan ca dc cht cng
phi c cu to t vng benzen. Trong mi trng nc, mt phng vng ca
dc cht tng tc vi cc cht thn nc lm tng tan ca dc cht.
S lng vng trong phn t cc cht thn nc cng nh hng nhiu ti
kh nng ha tan ca dc cht. M.P. Evstigneev nghin cu nh hng
ca hn hp cafein v nicotinamid n tan ca vitamin B2 trong mi
trng nc. Kt qu cho thy, khi a cafein v nicotinamid vo trong dung
dch c cha vitamin B2, tan ca vitamin B2 tng ln ng k [21].

12

1.4.3 Phng php phun ng t

Nguyn l chung ca phng php ny l dc cht c ha tan rt km,
c ha tan vo mt dung mi thch hp. Sau c phun qua mt u
phun c kch thc khong 100 200 m vo mt dung mi khc c
lm lnh. Bc hi ngay dung dch ny bng my ng kh thch hp thu c
bt kh. Loi bt ny c cu trc siu mn v dng v nh hnh, do vy
ci thin ng k tnh thm v din tch b mt ca dc cht.
Hu J. s dng phng php ny ci thin tan ca danazol. Kt qu
cho thy: sau 2 pht th ha tan, nguyn liu c ci thin bng phng
php ng t gii phng 95% dc cht trong khi bt nguyn liu ch ha tan
c 30% dc cht. Mt nghin cu khc ca Hu J. (2004) trn hn hp bt
gm carbamazepin/ PVP K-15 / Poloxame 407 c x l bng phng php
trn cng cho kt qu tng t. Carbamazepin sau khi phun ng t, ha
tan l 92% ch trong 10 pht, trong khi nguyn liu ban u ch ha tan 5%
sau 20 pht [25].
1.4.4 Phng php s dng cht din hot
Mt yu t nh hng n tan ca cc cht tan l kh nng thm t b
mt. iu ny lin quan n sc cng b mt gia cht tan v dung mi. Sc
cng b mt cng cao th cc cht cng kh tan. V vy lm tng tan ca
cc cht kh tan, nhiu tc gi s dng cc cht din hot, dng hn hp dung
mi ng tan vi nc hoc phi hp c 2 phng php trn.
Cht din hot l mt nhm cc hp 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,
ng thi gim s kt tp ca cc tiu phn dc cht, do lm tng din
tch b mt tip xc ca cc tiu phn dc cht vi mi trng ha tan.
13

nng cao, cc cht din hot c kh nng hnh thnh cc phc dng keo
trong dung dch (c gi l cc micell). Nng cc cht din hot m
xut hin cc micelle c gi l nng micelle ti hn. Cc micelle c kh
nng ha tan c cht thn nc, thn du v lng tnh. Do vy, ha tan
ca dc cht t tan tng mnh trong cc dung dch micelle cht din hot.
Nhc im ca cc cht din hot l c th gy c cho c th. Bn cnh
, cc cht din hot thng trng thi lng hoc bn rn nn kh to ra
th cht ph hp cho dng thuc rn.
Phn loi: theo cu trc phn t cht din hot dng trong dc phm c
chia thnh 4 nhm:
Cht din hot anion: natri laurylsulfat
Cht din hot cation: benzalkonium clorid
Cht din hot lng tnh: N-dodecyl betain, N-dimethyl betain
Cht din hot khng ion ha: polysorbat 80, Labrasol
Nm 2011, nghin cu ci thin ha tan ca ibuprofen trong vin nn,
tc gi Seng Dueane Leuang Kham Ma [12] so snh kh nng lm tng
ha tan ca cc cht din hot khc nhau kt qu cho thy rng vic s dng
Labrasol lm tng ng k tan ca dc cht.
1.4.5 K thut tc ng vo 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 hot base
yu thay i mnh khi pH mi trng thay i. Cc cht c kh nng to vi
mi trng c gi l t dc m [35].
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
14

thun li cho s ha tan cc dc cht c bn cht l acid hoc base yu. T

dc m c th chia lm 2 loi t dc kim v t dc acid [5].
Cc t dc to vi mi trng c pH acid: bao gm cc acid hu c nh
acid malic, acid citric, acid tartaric v.v thng c dng trong cc cng
thc thuc cha dc cht l cc base yu. Chng thng c s dng vi
t l bng hoc ln hn t l dc cht trong cng thc.
Cc t dc to vi mi trng c pH base: c chia lm 2 loi:
T dc m base hu c: Thng l cc base amin hu c nh 2amino-2-methyl-1,3-propanediol. u im ca loi t dc ny l an
ton, t nh hng n n nh ca dc cht. Nhc im ca
chng l kh nng iu chnh pH yu, phi dng vi t l ln mi c
tc dng.
T dc m base v c: l cc mui kim v c nh natri borat,
natri citrat, dinatri phosphat, trinatri phosphat. u im ca loi t
dc ny l kh nng iu chnh pH mnh, ch dng vi nng
thp c nh hng ln n kh nng ha tan ca dc cht.
Nhc im ca chng l nh hng n n nh ca thuc.
Tc gi Nguyn Hu M (2007) [13], s dng t dc m lm tng
tc v mc ha tan ibuprofen t vin nn. Kt qu cho thy vi t l s
dng l 3%, t dc m natri citrat lm gim ng k thi gian r v lm
tng tc , mc mc ha tan ibuprofen t vin nn. Sau 6 pht trong
mi trng m phosphat pH 6,8 v 30 pht trong mi trng HCl 0,1N t l
IBU ha tan t vin nn cha natri citrat cao hn khong 1,5 ln so vi vin
khng cha t dc m.

15

1.4.6 Phng php s dng t dc siu r

T dc siu r c s dng trong vin nn gii phng nhanh da vo kh
nng trng n rt mnh ca chng khi tip xc vi mi trng ha tan,
nhanh chng ph v cu trc ca vin.
T dc siu r l cc t dc r s dng vi t l thp (1-8%) trong thnh
phn ca vin nn, vin nang, cm thuc, nhng vn t hiu qu r nhanh,
t dc siu r t nh hng n kh nng trn chy, kh nng chu nn ca
khi bt dp vin. Bn cnh vic s dng t dc siu r cng em li li
ch kinh t do chi ph sn xut thp, n gin v d p dng [1]. Cc t dc
siu r c th s dng r trong, r ngoi hoc kt hp c r trong v r ngoi.
Phn loi: t dc siu r phn loi thnh ba nhm da vo cu trc ha
hc:
Natri starch glycolat (SSG): c sn xut t tinh bt khoai ty bng
bin i ha hc, to cc lin kt cho v carboxymethyl ha, tiu
phn c dng hnh cu, kh nng trn chy, chu nn tt. Trn th
trng c mt s sn phm thng mi nh Primojel, Explotab
Natri croscarmellose: l polyme c lin kt cho ca natri
carboxymethyl cellulose (NaCMC). Tiu phn dng th c cu trc
si xon vi di khc nhau, trn chy rt km. V vy, trc
khi s dng cn xay nghin nhit thp lm gy cc si polyme
ci thin trn chy. Mt s sn phm thng mi sn c nh
Ac-Di-Sol, Disolcel.
Crospovidon: c to ra bi lin kt cho ca cc monome Nvinyl-2-pyrrolidon, tiu phn c dng hnh cu, xp cao, chu nn
tt v kh nng trng n mnh. Mt vi sn phm thng mi l
Kollidon, Polyplasdon.

16

Cng trong nghin cu ca tc gi Nguyn Hu M nm 2007 [13]. Kt

qu cho thy, vi t l s dng l 4% SSG lm gim mnh thi gian r,
lm ci thin tc , mc ha tan ca ibuprofen t vin nn trong mi
trng m pH 6,8 so vi t dc thng thng. Sau 6 pht, t l dc cht
c ha tan t vin nn cha SSG cao gp gn 2 ln so vi vin khng cha
t dc siu r.
Trong nghin cu ca tc gi Seng Dueane Leuang Kham Ma nm 2011
[12], so snh nh hng ca 3 t dc siu r khc nhau l SSG, CCS v
Crospovidon. Kt qu cho thy sau 15 pht c trn 90% ibuprofen c ha
tan t vin nn khi s dng t dc siu r.
1.5 Mt s nghin cu gn y v PAR v IBU
1.5.1 Paracetamol
Paracetamol l dc cht t tan trong nc, v vy c nhiu nghin cu
nhm ci thin tan v tc ha tan vi mc ch lm tng sinh kh dng
ca thuc.
a) Trong n c
c nghin cu kho st nh hng ca cc loi t dc ln kh
nng chu nn, thi gian r v ha tan paracetamol ra khi vin nn
s dng t dc si ni natri bicarbonat. Kt qu cho thy dung dch
PVP 15%, Croscarmellose, Aerosil l nhng t dc ph hp vi
mc ch gii phng nhanh ca vin.
Nguyn Thu Hng nghin cu bo ch thuc n paracetamol gii
phng ko di. Kt qu cho thy hn hp acid stearic, suppocire c
nhit nng chy n nh, gn nhit c th, ph hp bo ch
thuc n v s b nh gi n nh ca thuc n paracetamol bng
phng php HPLC [7].

17

b) Ngoi nc
Wen H. v cng s nghin cu tng tc gia PVP vi
paracetamol v nhn thy: PVP to lin kt hydro lm thay i b
mt tinh th ca paracetamol, gip dc cht tr nn thn nc hn
v tan ca paracetamol tng ln ng k [41].
Mizumoto v cng s bo ch vin nn r nhanh vi paracetamol.
Trong nghin cu, tc gi to ra mt nguyn liu ph hp cho
vin nn r nhanh bng cch kt hp hai loi bt ng: mt loi c
kh nng chu nn thp (mannitol, lactose) v mt loi c kh nng
chu nn cao (maltose) da trn tnh cht ha l ca ng saccharid.
Thm na, tc gi s dng s thay i ca tinh th maltose lm
cho vin ng thi t c cng v s r mong mun. Vin sau
khi dp c cng thp (1,7 kP) nhng thi gian r rt nhanh
(khong 20 giy). Khi trong iu kin nhit 250C v m
70% trong 18 gi, cng ca vin tng ln 5,8 kP trong khi thi
gian r vn khng qu 20 giy [31].
1.5.2 Ibuprofen
Ibuprofen l mt cht kh tan trong nc. c rt nhiu nghin cu trong
v ngoi nc vi mc ch lm ci thin ha tan ca ibuprofen bng
nhiu phng php khc nhau.
a) Trong n c
V Ngc Ph (2006) nghin cu bo ch vin nn IBU 200mg s
dng natri starch glycolat phi hp vo vin vi t l r trong v r
ngoi bng nhau, s dng t dc m v cht din hot vo thnh
phn vin lm gim thi gian r ca vin. Sau thi gian 6 pht gii
phng dc cht c 84,64 % trong mi trng m pH 6,8 [14].

18

 Nguyn Th Liu (2006) nghin cu bo ch pellet IBU bng phng

php n to cu, xy dng cng thc bo ch IBU vi t l IBU l
80%, Avicel 20%, Aerosil 1,5%, t dc dnh lng l HPMC 3%
trong nc v cc thng s khc cho qu trnh bo ch pellet IBU
bng phng php n to cu [10].
b) Ngoi n c
Gupta v cng s (2011) nghin cu ci thin ha tan ca
ibuprofen dng h phn tn rn vi urea bng phng php dung mi
v un chy cc t l ibuprofen: cht mang l 1:1; 1:3; 1:5. Kt qu
cho thy, iu kin 370C 0,5 v pH 7,2 sau 90 pht, s ha tan
ca ibuprofen v cht mang vi t l 1:5 l 88,33% (phng php
dung mi); 82,31% (phng php un chy) cao hn ng k so vi
ha tan ca ibuprofen khng c tc ng 37,08% [24].
Madhuri Newa (2008) nghin cu lm tng ha tan ca
ibuprofen trong h phn tn rn s dng cht mang PEG 20000 cng
cho thy s ci thin tan v s hp thu ng ung chut ca
ibuprofen. Kt qu ca nghin cu cng ch ra rng h phn tn rn
ca ibuprofen s dng cht mang PEG 20000 l mt phng php
ci thin tan, t l ha tan v hp thu ca IBU [33].
1.5.3 Paracetamol v ibuprofen
a) Trong n c
Nm 2007, tc gi L nh Quang nghin cu bo ch vin nn
gii phng nhanh t mu nguyn liu c tc ng bi k thut
to ht rn lng vi paracetamol v phng php ng kt ta vi
ibuprofen. Kt qu nghin cu cho thy, ha tan ca paracetamol
trong 3 pht u t trn 94% v ibuprofen l trn 97%. Trong khi

19

 ha tan ca paracetamol l 53,3% v ibuprofen l 50,4 % t vin

nn Alaxan i chiu. ha tan ca ibuprofen b nh hng bi s
thay i t l ca PEG 6000 v sorbitol [15].
b) Ngoi n c
Pawar s dng phng php kt t ng thi PAR v IBU cng
vi mt s t dc bng phng php dung mi thu c h phn
tn rn. Kt qu th ha tan cho thy: vi h tt nht, sau 5 pht
PAR gii phng gn 90% v IBU gii phng c 80% [34].
Nghin cu in vivo nh hng ca pH ti kh nng khuych tn ca
PAR v IBU trong mng nhy d dy, Shaw L. ch ra rng: mng
nhy d dy ngn cn ng k mc khuych tn ca PAR v IBU.
Thay i pH khng nh hng ti kh nng khuych tn PAR nhng
nh hng ng k ti IBU: pH d dy tng, mc khuych tn ca
IBU tng. Kt qu ny khng nh s dng cc t dc c tnh kim
bo ch thuc ng ung cho IBU [36].
1.6 Phng php nh lng ng thi paracetamol v ibuprofen bng
quang ph o hm t i
1.6.1 C s ca phng php quang ph o hm t i
Theo nh lut Lambert Beer ta c:
hp th:
A= . l. C
Trong : A l hp th
l h s hp th
C l nng cht tan trong dung dch (mol/l)
L l b dy ca lp dung dch (cm)
Nu nng C tnh theo phn trm (kl/tt) v l tnh theo centimet th:

20

c gi l h s hp th ring.
C th ly o hm bc 1, bc 2 hoc bc cao hn i vi hp th A ti
bc sng , ta c:

dy ca l lun lun khng i v ti mt bc sng nht nh th o

hm ca

l mt hng s, nn gi tr A ch cn ph thuc tuyn tnh vi

nng C ca dung dch.

1.6.2 Phng php ph o hm t i
Gi s c ph hp th UV-VIS (quang ph hp thu kh kin) ca mt dung
dch cht X c nng Cx v mt dung dch cht Y c nng C0. Ti mi
bc sng ta c mt gi tr ca t s hp th ca X vi hp th ca Y
nng C0.
ng biu din mi lin h gia cc gi tr ny vi bc sng nh sng l
ph t i ca X so vi Y nng C0 v o hm ca ph t i ny c
gi l ph o hm t i ca dung dch X so vi dung dch Y nng C0.
Ph t i ca cht Y nng Cy so vi Y nng C0 theo l thuyt l
mt ng thng song song vi trc ca bc sng do o hm ca n
lun lun bng 0.

Trong k y,I l hp th ca cht Y ti bc sng i

21

Nu dung dch kho st cha 2 cht: X c nng Cx v Y c nng Cy

th o hm ph t i ca n so vi ph ca Y nng C0 c tnh nh
sau:

Cng thc ny cho thy gi tr ph o hm t i ti bt k bc sng no

cng ch ph thuc vo nng ca X v nng C0 ca cht Y. iu ny
cho php khi C0 bit th c th xc nh c X cn c vo gi tr o hm
o c ti mt bc sng c chn thch hp (phi c gi tr khc 0) [16].

22

Chng 2. I TNG V PHNG PHP NGHIN CU

2.1 Nguyn liu v thit b nghin cu
2.1.1 Nguyn liu v ha cht
Bng 2.1. Nguyn liu s dng
Nguyn liu

Ngun gc

Tiu chu n

Aerosil

Trung Quc

TCCS

Avicel PH101

i Loan

USP 29

Cremophor

Trung Quc

TCCS

Croscarmellose

Trung Quc

TCCS

Crospovidon

Trung Quc

TCCS

Gelucire 50/13

Php

Nh sn xut

HPMC E15

Trung Quc

TCCS

Ibuprofen

Trung Quc

BP 98

Kali dihydrophosphat

Trung Quc

Tinh khit ha hc

Labrasol

Php

Nh sn xut

Lactose monohydrat

TCCS

Magnesi stearat

Trung Quc

TCCS

Natri carbonat

Trung Quc

TCCS

Natri hydroxid

Trung Quc

Tinh khit ha hc

Natri laurylsulfat

Trung Quc

BP 2008

Paracetamol

Trung Quc

BP 98

Natri starch glycolat

Trung Quc

TCCS

Vin nn Alaxan cha 325mg

paracetamol v 200mg ibuprofen

S l: 503371
United Pharma

S ng k:VNB-0525-00
Hn dng: 8/2014

23

2.1.2 Thit b
Bng 2.2. Cc thit b s dng
Tn my

Ngun gc

Cn phn tch METTLER TOLEDO

Thy S

T sy MEMMERT

My dp vin PYE UNICAM

My dp vin tm sai KORSCH

My o cng ERWEKA

My o mi mn ERWEKA

My o t trng biu kin ERWEKA

My quang ph UV-VIS SHIMADZU

Nht bn

My siu m ULTRASONIC LC 60H

My th ha tan ERWEKA DT6000

My th r ERWEKA

Cc, a thy tinh, chy, ci s, b ry...

2.2 Ni dung nghin cu

Xy phng php nh lng ng thi paracetamol v ibuprofen trong
ch phm.
nh gi nh hng ca mt s t dc ti ha tan ca paracetamol
v ibuprofen trong vin nn hn hp v vin nn n thnh phn.

24

2.3 Phng php nghin cu

2.3.1 Phng php bo ch vin nn hn hp
Vin nn hn hp PAR v IBU c bo ch da trn c s nghin cu
nh hng ca cc t dc ti ha tan dc cht t vin nn. Bo ch vin
nn theo phng php xt ht t.
Cng thc gm cc thnh phn:
1. Paracetamol

325 mg

2. Ibuprofen

200 mg

3. Lactose

Thay i theo mc ch nghin cu

4. Avicel PH101

Thay i theo mc ch nghin cu

5. T dc siu r

Thay i theo mc ch nghin cu

6. Cht din hot

Thay i theo mc ch nghin cu

7. Aerosil

Thay i theo mc ch nghin cu

8. Magnesi stearate

Thay i theo mc ch nghin cu

9. HPMC E15 5%

5 ml

Phng php bo ch theo s

25

Hnh 2.1. S bo ch vin nn phi hp

M t :
Cn, ry dc cht v t dc qua ry 180.
Trn u PAR, IBU, Avicel PH 101, lactose, cht din hot, t dc
r trong theo nguyn tc ng lng.
Pha dung dch t dc dnh HPMC E15 5% trong nc.
Nho trn khi bt vi t dc dnh thnh khi m.
Xt ht qua ry 1000.
Sy ht nhit 45-500C n hm m 2-3%.
Sa ht qua ry 1000.
Trn t dc r ngoi, t dc trn.
Dp vin khi lng 730 mg vi chy lm ng knh 12 mm.

26

 Mi cng thc dp 30 vin (tr cng thc CT18 dp 100 vin) trn
my dp vin PYE UNICAM.
Bo qun vin trong l kn. Vin c n nh t nht 24 gi ri
mi em nh gi cc ch tiu cht lng.
2.3.2 Phng php bo ch vin nn n thnh phn
a) i v i dc cht paracetamol
Paracetamol

325 mg

Avicel PH 101

43,5 mg

Natri starch glycolat

29,2 mg

Natri laurylsulfat

Thay i (1%, 2% , 3% so vi khi lng

vin)

Aerosil

1,46 mg

Magnesi stearat

7,3 mg

Lactose

Cho va 530 mg

HPMC E15 5%

5 ml

b) i v i dc cht ibuprofen
Ibuprofen

200 mg

Avicel PH 101

43,5 mg

Natri starch glycolat

29,2 mg

Natri laurylsulfat

Thay i (1%, 2%, 3% so vi khi

lng vin)

Aerosil

1,46 mg

Magnesi stearat

7,3 mg

Lactose

Cho va 405 mg

HPMC E15 5%

5 ml

27

Quy trnh bo ch tng t vin nn hn hp PAR v IBU. Dp vin khi

lng chy lm ng knh 12 mm, lc nn 2 tn.
2.3.3 Phng php nh lng bng quang ph o hm t i
a)

hu n

dung

i:

S dng dung mi l dung dch m phosphat pH 7,2 c pha theo Dc

in Vit Nam IV nh sau: ha trn 250 ml dung dch kali dihydrophosphat
0,2 M vi 175 ml dung dch natri hydroxid 0,2 M v thm nc va 1000
ml [3].
b) Chu n b dung d ch chu n v dung d ch th
Dung dch chun PAR: cn chnh xc 500 mg PAR nguyn liu, pha
vi dung dch m phosphat pH 7,2 trong bnh nh mc 100 ml. Ht
chnh xc 10 ml cho vo bnh nh mc 100 ml, b sung bng dung
dch m pH 7,2 c dung dch gc PAR 500 mg/l. Pha dung dch
chun PAR 32,5 mg/l.
Dung dch chun IBU: cn chnh xc 200 mg IBU nguyn liu, pha
vi dung dch m phosphat pH 7,2 trong bnh nh mc 100 ml. Ht
chnh xc 10 ml cho vo bnh nh mc 100 ml, b sung bng dung
dch m pH 7,2 c dung dch gc IBU 200 mg/l. Pha dung dch
chun IBU 20 mg/l.
Dung dch chun hn hp PAR (thay i) + IBU (c nh): pha dung
dch chun paracetamol c nng thay i trong khong t 24- 40
mg/l (20, 24, 28, 32, 36, 40), cn nng ca ibuprofen lun c nh
khong 20 mg/l.
Dung dch chun hn hp PAR (c nh) + IBU (thay i): pha dung
dch chun ibuprofen c nng thay i trong khong t 12- 28

28

mg/l (12, 16, 20, 24, 28, 32) cn nng paracetamol lun c nh
khong: 32,5 mg/l.
Vi dung dch th: cn lng cm tng ng khong 10 vin,
nghin mn. Cn chnh xc mt lng bt thuc tng ng vi 32,5
mg PAR v 20,0 mg IBU, cho vo bnh nh mc 100 ml, thm dung
dch m phosphat pH 7,2, lc, siu m khong 20 pht v thm m
cho va 100ml. Lc, loi b 20 30 ml dch lc u. Ly 10 ml
dch lc, cho vo bnh nh mc 100 ml, thm dung dch m cho
va ri lc u.
c) Phng php ph o h t i
Vi PAR: ly ph hp th ca dung dch chun hn hp v ch phm
th chia cho ph hp th ca dung dch chun IBU 20 mg/l, c
ph t i. Tin hnh ly o hm bc 1 ca ph t i.
Vi IBU: ly ph hp th ca dung dch hn hp v ch phm th
chia cho ph hp th ca dung dch chun PAR 32,5 mg/l, c ph
t i. Tin hnh ly o hm bc 1 ca ph t i [16].
2.3.4 Phng php th ha tan
a) Vin hai thnh phn:
iu kin th ha tan:
Mi trng: 900 ml dung dch m phosphat pH 7,2.
Thit b kiu cnh khuy.
Tc quay: 50 vng/ pht.
Tin hnh:
t nhit ca nc trong b 370,50C v duy tr nhit
trong sut qu trnh th.
Cho 900 ml dung dch m phosphat pH 7,2 vo 6 cc th.

29

 mi trng n nh nhit .
Cho mi vin vo mi cc, chy my ha tan.
Ht ly 5 ml dch ha tan cc thi im thch hp mi
cc (b sung dung mi sau mi ln ht mu).
Dung dch ti cc thi im ht dch c pha ti nng
thch hp v nh lng bng phng php quang ph o
hm t i.
b) i vi vin n thnh phn:
Phng php th ha tan tng t nh vin hai thnh phn, dung dch
ti cc thi im ht dch c pha ti nng thch hp, em o mt
quang bc sng 257 nm i vi PAR v 221 nm i vi IBU, so snh vi
dung dch chun tng ng xc nh nng cc dc cht.
2.3.5 Phng php xc nh tan trong dung mi kim
Dung dch th: pha dung dch Na2CO3 1% v Na2HPO4 1%. Cho mi
trng cn th tan vo ng thy tinh. Cho mt lng d dc
cht vo trong ng thy tinh c mi trng cn th tan. em
mu thu c siu m trong 8 ln, mi ln 10 pht, ngh gia mi ln
5 pht. Dung dch thu c em lc, b 2 ml dch lc u ri pha
long n nng thch hp trc khi o quang.
Dung dch chun: pha dung dch PAR 20 g/L v IBU 20 g/L lm
dung dch chun.
o hp th ca cc dung dch trn ti bc sng 257 nm i vi
PAR v 221 nm i vi IBU, so snh vi dung dch chun tng ng
xc nh nng cc dc cht.

30

2.3.6 Phng php nh gi mt s ch tiu ca vin nn v ht

a) Phng php nh gi cng ca vin
Xc nh bng my o cng ERWEKA, mi cng thc 3 vin. Nguyn
tc: tc ng mt lc qua ng knh ca vin cho n lc vin b v. Xc
nh lc gy v vin. Lc ny ph thuc vo tc tc ng, vo ng knh
vin.
b) Phng php o r ca vin
Tin hnh trn my th r ERWEKA DT 600 theo DVN IV. Mi th
nghim lm vi 6 vin. Mi trng th 900 ml nc ct, nhit 370,50C.
c) Phng php o i n ca vin
Tin hnh trn my o mi mn ERWEKA. Cn mt lng tng ng
khong 6,5g vo trng quay (10 vin). Quay vin 100 vng trong my o
mi mn. Ly vin ra sng sch bt, cn li khi lng. Tnh mi mn
(phn trm khi lng vin b mt).
mi mn khng c qu 1%.
d) Phng php ki tra trn chy ca khi ht v t
trn chy ca bt c xc nh bng cch o thi gian chy ca 50 g
bt qua phu o tiu chun.
Phu o c cu to bng thp khng g, c ng knh trong ca chui
phu l 9 mm gn thng ng vi thit b rung, o ba ln ly kt qu trung
bnh.
2.3.7 Phng php nh gi tng quan gia hai th gii phng
ha tan ca mu c so snh vi vin i chiu Alaxan (United
International Pharma) da trn th ha tan s dng h s f2 (similarity

31

factor) c quy nh bi c quan qun l dc phm v thc phm M

FDA. Ch s ny c tnh theo cng thc sau:

Trong : n: s im ly mu.
Rt: phn trm dc cht gii phng thi im t ca mu chng.
Tt: phn trm dc cht gii phng thi im t ca mu th.
Hai th c coi l tng ng nu f2 50.

32

Chng 3. KT QU NGHIN CU
3.1 Xy dng phng php nh lng ng thi PAR v IBU bng
phng php quang ph o hm t i.
Qua kho st nhiu bc sng, tin hnh chn bc sng nh lng
PAR trong ch phm l 237,3 nm, vi IBU l 224 nm.
3.1.1 Kho st khong tuyn tnh
Kho st khong tuyn tnh gia PHT v nng ca cc dc cht
nhm tm ra c khong nng thch hp cho tng dc cht dng trong
nh lng. Mi quan h gia nng ca PAR, IBU vi gi tr PHT ti
cc bc sng nh lng c biu din trong bng 3.1:
Bng 3.1. Mi tng quan gia nng v gi tr PHT

IBU

Nng (mg/l)

20

24

28

32

36

40

Gi tr PHT

0,955

1,176

1,423

1,643

1,779

2,008

Nng (mg/l)

12

16

20

24

28

32

Gi tr PHT

-0,027

-0,036

-0,049

-0,059

-0,066

-0,084

Gi tr PHT

PAR

2,5
2
1,5
1
0,5
0
-0,5 0

20

ng chu n PAR
y = 0,0715x - 0,7172
R = 0,959
ng chun
PAR
Linear (ng
chun PAR)
40
60

Nng (mg/L)

Hnh 3.1. Mi tng quan gia gi tr PHT v nng PAR

33

Gi tr PHT

ng chu n IBU
0
-0,02

20

40

60

y = -0,002x + 0,0036
R = 0,9111

-0,04

ng chun
IBU
Linear (ng
chun IBU)

-0,06
-0,08
-0,1

Nng (mg/L)

Hnh 3.2. Mi tng quan gia gi tr PHT v nng IBU.

Nhn xt,
T bng 3.1, hnh 3.1 v hnh 3.2 cho thy: trong khong nng kho st
c s tng quan tuyn tnh gia gi tr PHT vi nng paracetamol v
ibuprofen ti bc sng kho st vi h s tng quan R2 tng ng bng
0,959 v 0,911. Nh vy, c th s dng phng php PHT ti bc sng
237,3 nm i vi paracetamol v ti bc sng 224 nm i vi ibuprofen
xc nh hm lng dc cht trong vin nn cng nh trong php th ha
tan.
Cc cng thc tip theo trong nghin cu c tin hnh th ha tan v
nh lng cc DC theo phng php PHT ti bc sng 237,3 nm i
vi paracetamol v ti bc sng 224 nm i vi ibuprofen. Kt qu kho st
ha tan ca vin i chiu
lm c s so snh, chng ti tin hnh kho st ha tan vin Alaxan,
thnh phn nh sau:
Paracetamol 325 mg.
Ibuprofen 200 mg.
T dc: lactose, tinh bt bp, natri starch glycolat, magnesi stearat.
Tin hnh th ha tan theo mc 2.3.3 v 2.3.4, kt qu c trnh by
bng 3.2:

34

Bng 3.2. T l phn trm ha tan DC t vin Alaxan

Thi gian
(pht)

Vin Alaxan (n=3)

PAR (%)

IBU (%)

54,23

62,52

10

71,56

73,77

15

82,89

78,44

20

87,35

89,69

30

95,52

94,05

45

98,35

95,33

60

99,24

99,34

Nhn xt,
Vin Alaxan c t l phn trm ha tan ca cc dc cht tt, sau 5 pht
ha tan trn 50%. Sau 60 pht, gn 100% hai dc cht ha tan.
3.2 Kt qu kho st nh hng ca cc thnh phn trong cng thc ti
ha tan ca cc dc cht
3.2.1 Kt qu kho st nh hng ca mt s cht din hot
Tin hnh bo ch v nh gi tnh cht vin, kho st ha tan vin n
thnh phn theo mc 2.3.2, 2.3.4, 2.3.6 v 2.3.7, thu c kt qu theo bng
3.3 v bng 3.4 nh sau:

35

Bng 3.3. Cc tnh cht vin nn n thnh phn

Cc

tnh

cht

NaLS 1%

NaLS 2%

NaLS 3%

PAR

IBU

PAR

IBU

PAR

IBU

cng(N)

54

53

55

52

55

54

r (pht)

Hm lng

99,8%

99,5%

100,4%

99,8%

101,8% 100,5%

Bng 3.4. T l phn trm DC ha tan vi cc CDH khc nhau

Thi gian NaLS 1%

NaLS 2%

NaLS 3%

(pht)

PAR

IBU

PAR

IBU

PAR

IBU

13,51

16,68

19,19

20,97

27,7

19,72

10

26,43

29,89

39,08

38,35

47,94

39,39

15

46,39

47,18

50,01

58,58

68,26

58,81

30

67,39

66,54

74,03

82,9

89,43

71,39

45

80,94

86,1

85,48

93,25

92,48

89,12

60

89,22

91,12

90,24

97,51

95,01

94,47

T bng trn, nhn thy: vin n IBU c ha tan tt vi t l 2, 3%

CDH cn vin n PAR c ha tan tt vi t l 3% CDH. V vy tin hnh
kho st vi CDH vi t l 3% trong cng thc vin nn phi hp.
Bo ch cc mu vin theo phng php nh trong mc 2.3.1 vi cc thnh
phn cng thc c ghi trong bng 3.5:

36

Bng 3.5. Cng thc vin vi thnh phn, t l CDH khc nhau
Thnh phn (mg)

CT1

CT2

CT3

CT4

CT5

CT6

CT7

CT8

PAR

325

325

325

325

325

325

325

325

IBU

200

200

200

200

200

200

200

200

Lactose

101,6 101,6 101,6 101,6

91,38

91,38

91,38

91,38

Avicel PH101

43,54 43,54 43,54 43,54

39,61

39,61

39,61

39,61

SSG

29,2

29,2

29,2

29,2

29,2

29,2

29,2

29,2

NaLS

21,9

36,5

Labrasol

21,9

36,5

Cremophor

21,9

36,5

Gelucire

21,9

36,5

Aerosil

1,46

1,46

1,46

1,46

1,46

1,46

1,46

1,46

Magnesi stearat

7,3

7,3

7,3

7,3

7,3

7,3

7,3

7,3

Tin hnh bo ch v nh gi tnh cht vin, kho st ha tan vin theo

mc 2.3.2, 2.3.4, 2.3.6 v 2.3.7, thu c kt qu theo bng 3.6, bng 3.7,
bng 3.8 v hnh 3.3, hnh 3.4 nh sau:
Bng 3.6. Cc tnh cht vin s dng cc CDH khc nhau
Cc tnh
cht

cng (N) r (pht)

Hm lng
PAR(%)

IBU(%)

CT1

51

101,0

100,5

CT2

52

99,8

100,1

CT3

55

102,0

100,7

CT4

54

100,4

99,5

CT5

57

101,5

101,5

CT6

52

99,5

102,0

CT7

55

100,6

100,4

CT8

54

100,7

98,8

37

Bng 3.7. T l phn trm DC ha tan t vin c CDH khc nhau, t l 3%

% ha tan dc cht (n=3)

Thi
gian
(pht)

CT1
PAR

CT2
IBU

PAR

CT3
IBU

PAR

CT4
IBU

PAR

IBU

10,45

16,02

21,65

21,46

20,62

23,22

9,21

10,57

10

39,07

39,74

51,17

50,07

41,82

64,26

26,35

28,15

15

45,78

61,92

74,37

66,39

65,23

75,56

45,71

41,35

20

67,34

82,54

86,53

81,09

77,87

77,08

62,26

62,72

30

74,34

87,35

89,05

83,46

81,24

81,71

84,14

81,41

45

85,62

92,48

93,38

89,89

86,6

87,81

89,28

89,04

60

93,35

94,15

97,94

92,92

90,72

89,82

95,34

92,45

Bng 3.8. T l phn trm DC ha tan t vin c CDH khc nhau, t l 5%

% ha tan dc cht (n=3)

Thi
gian
(pht)

CT5
PAR

CT6
IBU

PAR

CT7
IBU

PAR

CT8
IBU

PAR

IBU

14,28

12,65

25,02

20,04

21,76

20,56

12,42

14,89

10

31,42

36,76

45,09

53,45

57,69

52,34

28,37

27,05

15

49,05

50,05

70,57

68,03

75,6

65,6

40,07

36,62

20

68,45

77,52

78,54

75,53

83,89

75,23

52,91

53,02

30

79,09

85,19

85,86

83,42

88,18

77,08

70,04

74,76

45

86,72

91,54

93,75

91,24

89,76

79,47

79,28

80,48

60

95,83

95,04

96,32

94,02

93,05

88,23

90,52

87,47

38

% PAR ha tan

120

NaLS 3%
Labrasol 3%
Cremophor 3%
Gelucire 3%
Alaxan

100
80
60
40
20
0
0

20

40

60

80

Thi gian (pht)

Hnh 3.3. T l phn trm PAR ha tan t vin nn vi cc CDH khc nhau

% IBU ha tan

120

NaLS 3%
Labrasol 3%
Cremophor 3%
Gelucire 3%
Alaxan

100
80
60
40
20
0
0

20

40

60

80

Thi gian (pht)

Hnh 3.4. T l phn trm IBU ha tan t vin nn vi cc CDH khc nhau
Nhn xt,
So snh v t l ca cng mt cht din hot dng:

NaLS 3% v NaLS 5% (CT1 v CT5)

Khi t l NaLS tng t 3% ti 5%, ha tan ca hai dc cht thay i

khng ng k, v d nh thi im 60 pht, % ha tan PAR v IBU CT1
l 93,35% v 94,15% th CT5 tng ng l 95,89% v 95,04%.

39

 Labrasol 3% v Labrasol 5% (CT2 v CT6)

T l cht din hot Labrasol tng t 3% ti 5%, ha tan ca PAR v
IBU c xu hng gim trong 20 pht u v t thay i cc thi im sau
(v d thi im 20 pht, % ha tan PAR v IBU ca CT2 l 86,53% v
81,09% cn CT6 l 78,54% v 75,53%)
Cremophor 3% v Cremophor 5% (CT3 v CT7)
Khi t l Cremophor tng t 3% ti 5%, ha tan trong 15 pht u ca
PAR c xu hng tng, ca IBU c xu hng gim v d nh thi im 15
pht, % ha tan PAR ca CT3 l 65,23% cn CT7 l 75,60%; cn IBU ca
CT3 l 75,56% cn CT7 l 65,60%).
Gelucire 3% v Gelucire 5% (CT4 v CT8)
T l cht din hot Gelucire tng t 3% ti 5%, ha tan ca PAR v
IBU c xu hng gim t thi im 20 pht n 60 pht v d thi im 60
pht, % PAR v IBU CT 4 l 95,34% v 92,45% cn CT8 tng ng l
90,52% v 87,47%.
Nh vy vi c bn cht din hot s dng th t l cht din hot 5% c
phn trm ha tan dc cht khng cao hn nhiu so vi t l 3%, mt s
trng hp cn c ha tan thp hn so vi t l 3%.
Kt qu so snh bn cht din hot vi t l 3% cho thy t l % ha tan
cc dc cht khi dng Labrasol (CT2) cao hn khi s dng NaLS c thi
im ban u v thi im cui cng, cao hn Gelucire thi im ban u
v Cremophor thi im cui cng. C th % ha tan PAR v IBU thi
im ban u khi dng Labrasol tng ng l 21,65% v 21,46% cn khi
dng NaLS l 10,45% v 16,02%, Gelucire l 9,21% v 10,57%. Thi im
cui cng khi dng Labrasol % PAR v IBU ha tan tng ng l 97,94% v
92,92%, cn ca Cremophor l 90,72% v 89,82%, ca Gelucire l 95,34% v
92,45%. Hn na, ti thi im 20 pht, % ha tan PAR v IBU khi s dng
Labrasol t trn 80%.
40

Nh vy chng ti quyt nh la chn cht din hot Labrasol vi t l 3%

trong cc cng thc vin nn phi hp tip theo.
So snh vi ha tan ca vin Alaxan thy rng thi im 5 pht, dc
cht trong vin Alaxan gii phng nhiu hn 2 ln so vi cng thc s dng
Labrasol 3%. Sau 30 pht, c 2 dc cht trong vin Alaxan ha tan trn
90% trong khi cng thc s dng Labrasol 3% c ha tan ca PAR v IBU
ln lt l 89,05% v 83,46%. V vy, chng ti tip tc tin hnh kho st
nh hng ca t dc siu r ti ha tan ca dc cht trong cng thc
bo ch vin.
3.2.2 Kt qu kho st nh hng ca mt s t dc siu r
Bo ch cc mu vin theo phng php nh trong mc 2.3.1 vi cc thnh
phn cng thc c ghi trong bng 3.9 :
Bng 3.9. Cng thc vin nn s dng cc TDSR khc nhau
Thnh phn (mg)

CT9 (CT2)

CT10

CT11

PAR

325

325

325

IBU

200

200

200

Lactose

101,6

101,6

101,6

Avicel PH101

43,54

43,54

43,54

Labrasol

21,9

21,9

21,9

SSG

29,2

Croscarmellose

29,2

Crospovidon

29,2

Aerosil

1,46

1,46

1,46

Magnesi stearat

7,3

7,3

7,3

Cc tnh cht v vin c tin hnh theo mc 2.3.6 v 2.3.7, kt qu c

th hin trong bng 3.10 nh sau:

41

Bng 3.10. Cc tnh cht vin s dng cc TDSR khc nhau

Cc tnh

Hm lng

cng (N) r (pht)

cht

PAR(%)

IBU(%)

CT9 (CT2)

52

99,8

100,1

CT10

53

101,7

100,8

CT11

25

102,3

101,5

nh gi kh nng ha tan dc cht theo mc 2.3.2 v 2.3.3 thu c kt

qu nh biu din bng th hnh 3.5, 3.6 v bng 3.11:
Bng 3.11. T l phn trm DC ha tan t vin c thnh phn TDSR khc
nhau
% ha tan dc cht (n=3)

Thi
gian
(pht)

CT2
PAR

IBU

CT10
PAR

IBU

CT11
PAR

IBU

21,65

21,46

23,45

19,01

34,1

31,38

10

51,17

50,07

34,45

25,92

62,42

61,45

15

74,37

66,39

49,51

44,25

74,61

64,26

20

86,53

81,09

66,99

64,42

84,91

74,37

30

89,05

83,46

75,91

68,96

89,63

78,33

45

93,38

89,89

82,31

73,91

90,15

80,06

60

97,94

92,92

84,97

81,19

92,49

86,17

Nhn xt,
Trong 3 cng thc s dng 3 TDSR khc nhau t l 4% th ha tan
ca hai dc cht CT2 (dng SSG) v CT11 (dng CrosPVP) cao hn
CT10 (dng Croscarmellose) t thi im 15 pht, v d thi im 15 pht
th % ha tan PAR v IBU CT2 tng ng l 74,37% v 66,39%, CT11 l
74,61% v 64,26% cao hn CT10 l 49,51% v 44,25%. Tuy nhin khi so
snh vi vin Alaxan v % ha tan dc cht vn c s khc bit ng k
thi im ban u 5 pht v 10 pht. Sau 60 pht nhn thy CT2 cho ha
42

tan ca 2 dc cht l tt nht, khi so snh vi % ha tan dc cht trong

vin Alaxan nhn thy % ha tan IBU ti thi im 60 pht ca vin CT2 vn
thp hn so vi vin Alaxan (92,92% trong CT2 so vi 99,34% trong
Alaxan).

% PAR ha tan

120
100
80

SSG 4%
60

CCS 4%

40

CrosPVP 4%

20

Alaxan

0
0

20

40

60

80

Thi gian (pht)

Hnh 3.5. T l phn trm PAR ha tan t vin nn vi cc TDSR khc nhau
120
100

% IBU ha tan

80

SSG 4%
60

CCS 4%

40

CrosPVP 4%

20

Alaxan

0
0

20

40

60

80

Thi gian (pht)

Hnh 3.6. T l phn trm IBU ha tan t vin nn vi cc TDSR khc nhau
Trong qu trnh thc nghim tin hnh vi cng thc c s dng CrosPVP
nhn thy ht to ra m, xp, kh chu nn. Do vy vin nn to ra mm b
nn khi cho vo mi trng ha tan th chng nhanh r ra. Nhng vin nn

43

cng thc c s dng CrosPVP khng t ch tiu v cng v b nn

c loi b.
Cng thc c s dng SSG t b hn, cng ca vin cao hn nhng vn
cn thp. Do vy, tin hnh thay ton b lactose trong cng thc bng Avicel
PH101. Kt qu cho thy mu vin bo ch thu c c cng t, hnh
thc vin p v ha tan tt. Ngoi ra Avicel PH101 cng lm cho vin r
nhanh hn do kh nng ht nc v trng n.
V vy, trong cc cng thc tip theo chng ti s dng t dc n hon
ton l Avicel PH101.
3.2.3 Kt qu kho st nh hng ca kch thc tiu phn dc cht
Bo ch vin theo cng thc nh bng sau:
Bng 3.12. Cng thc vin nn s dng kch thc tiu phn dc cht khc
nhau
Thnh phn (mg)

CT12

CT13

PAR

325 (qua ry 125)

325 (qua ry 180)

IBU

200 (qua ry 125)

200 (qua ry 180)

Labrasol

21,9

21,9

Avicel PH101

145

145

SSG

29,2

29,2

Aerosil

1,46

1,46

Magnesi stearat

7,3

7,3

Cc tnh cht v vin c tin hnh theo mc 2.3.6 v 2.3.7, kt qu c

th hin trong bng 3.13 nh sau:

44

Bng 3.13. Cc tnh cht vin s dng kch thc tiu phn khc nhau
Cc tnh

cng (N) r (pht)

cht

Hm lng
PAR(%)

IBU(%)

CT12

55

99,7

100,5

CT13

56

100,5

99,4

nh gi kh nng ha tan ca dc cht thu c kt qu biu din bng

hnh 3.7, hnh 3.8 v bng 3.14 sau:
Bng 3.14. T l phn trm dc cht ha tan khi s dng ry khc nhau
% ha tan dc cht (n=3)
Thi gian (pht)

CT12

CT13

PAR

IBU

PAR

IBU

31,24

38,96

25,53

24,48

10

54,1

70,91

52,18

51,32

15

85,09

77,18

78,74

65,93

20

94,32

78,8

89,95

70,45

30

96,53

79,91

91,42

74,81

45

98,12

82,13

93,45

78,53

60

99,34

84,57

94,67

83,79

Nhn xt,
Phn trm ha tan IBU trong 2 cng thc thi im cui cng l gn
nh nhau, thi im 5 pht v 10 pht th IBU trong cng thc CT12 ha
tan nhiu hn so vi IBU trong cng thc CT13 (38,96% so vi 24,48% ti 5
pht v 70,91% so vi 51,32% ti thi im 10 pht).
Vin c bo ch theo cng thc CT12 c ha tan ca PAR ti cc
thi im l tt hn so vi cng thc CT13. Ngay t thi im 20 pht, PAR
trong cng thc CT12 ha tan ti 94,32%. thi im 5 pht l 31,24%

45

cao hn so vi cng thc CT13 thi im 5 pht l 25,53%. 60 pht,

PAR trong cng thc CT13 cng ch ha tan ht 94,67%. Nh vy, kch
thc tiu phn c nh hng ti % ha tan dc cht trong vin nn phi
hp. Nhn thy rng, trong cng thc CT12 % ha tan PAR t trn 90%
t pht th 20 gn tng ng nh trong vin Alaxan, tuy nhin % ha tan
IBU cn t hn tng i so vi vin Alaxan, thi im 60 pht l 84,57%
trong CT12 cn ca vin Alaxan l 99,34%.
120

% PAR ha tan

100
80

Qua ry 125

60

Qua ry 180

40

Alaxan
20
0
0

20

40

60

80

Thi gian (pht)

Hnh 3.7. T l phn trm PAR ha tan trong vin qua ry 125 v qua ry 180

% IBU ha tan

120
100
80
60

Qua ry 125

40

Qua ry 180

20

Alaxan

0
0

20

40

60

80

Thi gian (pht)

Hnh 3.8. T l phn trm IBU ha tan trong vin qua ry 125 v qua ry 180
46

V vy cc cng thc tip theo chng ti tin hnh bo ch vin vi dc

cht c ry qua ry 125.
3.2.4 Kt qu kho st nh hng ca t l HPMC E15
tng tan v tc tan, t l polyme thn nc (HPMC E15) c
tng ln trong cng thc v thay i phng php to ht nh sau: Dc cht
c nghin vi HPMC E15 trong cn vi t l 9:1, sy kh, nghin qua ry
240, sau to ht nh phn 2.3.1.
Vin c bo ch theo cng thc nh bng 3.15 sau:
Bng 3.15. Cng thc vin nn s dng t l HPMC E15 khc nhau
Thnh phn (mg)

CT14

CT15

CT16

PAR

325

325

325

IBU

200

200

200

HPMC E15

33

66

132

Avicel PH101

112,14

79,14

13,14

SSG

29,2

29,2

29,2

Labrasol

21,9

21,9

21,9

Aerosil

1,46

1,46

1,46

Magnesi stearat

7,3

7,3

7,3

Nhn xt,
Khi nghin dc cht vi HPMC E15 trc khi bo ch, qu trnh nho m,
trn t dc dnh kh thc hin hn, CT15 v CT16 tng ng vi t l
HPMC:DC l 1:8 v 1:4 c vin dp c khng t yu cu v cng v
b. V vy chng ti ch tin hnh th ha tan ca vin CT14 vi t l
HPMC: DC l 1:16. Tuy nhin, trong khi thc nghim, chng ti quan st
thy vin r km. Phn trm ha tan ca dc cht thp khi so snh vi CT12

47

(ph lc 1). V vy, cc cng thc tng t l HPMC E15 v phi trn vi
dc cht trc khng c kho st tip.
3.2.5 Kt qu kho st nh hng ca t dc kim ti ha tan dc cht
a) nh hng ca loi t dc kim
nh gi nh hng ca t dc kim n tan ca 2 dc cht
nghin cu, tin hnh xc nh tan sau 8 ln siu m ca PAR v IBU
trong dung dch Na2CO3 1%, dung dch Na2HPO4 1% v nc ct theo mc
2.3.4. tan ca 2 DC c th hin trong bng 3.16 nh sau:
Bng 3.16. tan sau 8 ln siu m ca IBU v PAR trong cc dung dch
khc nhau iu kin phng th nghim
IBU (mg/L)

PAR (mg/L)

Dung dch Na2CO3 1%

189,00

112,28

Dung dch NaH2PO4 1%.

86,18

31,03

Nc ct

5,35

25,63

Nh vy, trong dung dch Na2CO3 1% tan PAR v IBU sau 8 ln siu
m 10 pht cao hn so vi trong dung dch NaH2PO4 1% v nc ct tng
ng. Do t dc kim l natri carbonat c s dng trong cc nghin cu
tip theo.
b) nh gi nh hng ca t l t dc kim t i ha tan ca
dc cht.
Tin hnh nh gi nh hng ca t l t dc kim ti ha tan ca
dc cht. Bo ch vin vi cc cng thc nh bng 3.17 sau:

48

Bng 3.17. Cng thc vin nn vi cc t l t dc kim khc nhau

Thnh phn (mg)

CT17

CT18

CT19

CT20

CT21

PAR

325

325

325

325

325

IBU

200

200

200

200

200

Natri carbonat

1,8

3,65

7,3

14,6

21,9

Labrasol

21,9

21,9

21,9

21,9

21,9

Natri starch glycolat

29,2

29,2

29,2

29,2

29,2

Avicel PH101

110,44

112,29

115,94

148,5

123,24

Aerosil

1,46

1,46

1,46

1,46

1,46

Magnesi stearat

7,3

7,3

7,3

7,3

7,3

Khi bo ch vin theo cc cng thc CT19, CT20 v CT21, nhn thy rng
khi bt m, rt kh sy kh v dp vin. Nguyn nhn c th do c tnh ht
m ca t dc natri carbonat.
Cc tnh cht v vin ca vin trong cng thc CT17 v CT18 c tin
hnh theo mc 2.3.6 v 2.3.7, kt qu c th hin trong bng 3.18 nh sau:
Bng 3.18. Cc tnh cht vin s dng t dc kim t l khc nhau
Cc tnh
cht

cng (N) r (pht)

Hm lng
PAR(%)

IBU(%)

CT17

55

101,5

100,7

CT18

54

101,5

101,5

Phn trm ha tan dc cht trong vin bo ch theo cng thc CT17 v
CT18 c th hin trong bng sau:

49

Bng 3.19. T l phn trm PAR v IBU ha tan trong CT12, CT17 v CT18
% ha tan dc cht (n=3)

Thi
gian

CT17

CT18

CT12

(pht)

PAR

IBU

PAR

IBU

PAR

IBU

31,94

35,18

43,67

50,63

31,24

38,96

10

61,37

60,16

66,25

65,96

54,1

70,91

15

80,14

73,95

96,1

83,45

85,09

77,18

20

85,47

80,23

96,97

90,36

94,32

78,8

30

88,92

87,12

97,18

92,86

96,53

79,91

45

90,51

89,56

98,94

95,02

98,12

82,13

60

93,37

91,37

99,8

95,87

99,34

84,57

Nhn xt,
Kt qu cho thy, khi s dng t dc kim trong cng thc, ha tan ca
dc cht c ci thin mt cch r rt so vi cng thc khng dng t dc
kim (CT12). Ti thi im 10 pht, phn trm paracetamol ha tan CT17
v CT18 tng ng l 61,37% v 65,25% trong khi CT12 ch t 54,10%.
Tuy nhin cc thi im sau, vin CT17 c % PAR ha tan thp hn vin
CT12 (ti thi im 20 pht, CT12 c % PAR ha tan trn 90% trong khi
pht th 30, vin CT17 c t l % PAR ha tan cha t 90%). i vi
% IBU ha tan, kt qu cho thy hai cng thc s dng t dc kim cho %
IBU ha tan cao hn ng k so vi cng thc khng s dng TD kim
(CT12). Ti thi im 15 pht, c hai CT17 v CT18 u c % IBU ha tan
trn 85% trong khi vin CT12 n pht 60 vn cha t 85%.
c bit, khi so snh hai cng thc vi t l t dc kim khc nhau, vin
s dng t dc kim t l 0,5% (CT18) c ha tan ca dc cht c
ci thin nhiu hn so vi khi s dng t dc kim t l 0,25% (CT17).
thi im 20 pht, c 2 dc cht u ha tan trn 90% vi cng thc CT18,

50

trong khi cng thc CT17 l 85,47% v 80,23% tng ng ca PAR v

IBU.

% PAR ha tan

120
100

TD kim 0,5%

80

TD kim 0,25%

60

Khng dng TD
kim
Alaxan

40
20
0
0

20

40

60

80

Thi gian (pht)

Hnh 3.9. T l phn trm PAR ha tan vi TD kim v khng dng TD kim
120

TD kim 0,5%
% BU ha tan

100

TD kim 0,25%

80
60

Khng dng TD
kim
Alaxan

40
20
0
0

20

40

60

80

Thi gian (pht)

Hnh 3.10. T l phn trm IBU ha tan vi TD kim v khng dng TD
kim
Khi so snh vi vin i chiu Alaxan, tuy ha tan thi im 5 pht
ca c hai dc cht t CT18 vn thp hn vin i chiu, nhng ch s f2
c tnh theo mc 2.3.7 bng 56 (i vi PAR) v 55 (i vi IBU), th hin
s tng ng gia hai th ha tan ca CT18 v vin i chiu Alaxan.
PHT ca cng thc CT18 ti cc thi im ca 2 dc cht c th
hin ph lc 2 v ph lc 3.
51

T cc kt qu thu c, nhn thy rng, vin nn bo ch theo cng thc

CT18 cho ha tan ca 2 dc cht tt nht.
3.3 xut mt s ch tiu ca vin bo ch c
Tin hnh bo ch vin nn phi hp theo CT18, lm hai m: m 1v m 2.
Mi m tng ng vi 100 vin, dp vin bng my dp vin tm sai v tin
hnh kho st mt s ch tiu ca bt cm v vin bo ch c. Chng ti s
b xut mt s tiu chun cho vin nn cha paracetamol v ibuprofen bo
ch theo cng thc CT18 nh sau:
Bng 3.20. xut tiu chun ca vin nn phi hp PAR v IBU
Tiu chun

Thc nghim (CT18)

xut tiu chun

Tiu chun ca khi bt

m
T trng
biu kin
trn chy

1,35%

1%-2%

0,39 g/ml

0,35-0,45 g/ml

45,8 giy

42-48 giy

Tiu chun vin nn

Vin nn mu trng,

Hnh thc

Vin nn mu trng,

thnh v cnh vin lnh thnh v cnh vin lnh

cm quan

ln

Hm lng

ln

PAR: 101,50%
IBU: 101,50%

95%-105% vi mi DC

mi mn

0,63%

1%

cng

553N

50-60N

ha tan trong mi trng m phosphat pH 7,2

ha tan

2 dc cht ha tan trn

90% sau 20 pht

2 dc cht ha tan trn

90% sau 30 pht

52

Chng 4. BN LUN
4.1 nh hng ca cht din hot n ha tan ca dc cht trong
cng thc
Trong nghin cu, chng ti s dng 4 cht din hot l: Labrasol, natri
laurylsulfat, Cremophor, Gelucire. Kt qu cho thy, cng thc s dng natri
laurylsulfat c ha tan dc cht thp v Labrasol cho t l ha tan dc
cht cao nht.
Labrasol, hp cht ca glycerid, l polyethylenglycol v mono, di acid bo
trong acid bo ch yu l acid caprylic v acid capric, c tng hp do
phn ng ester ha chui triglycerid t du da vi PEG 400. Labrasol c
coi nh l mt cht din hot khng ion ha. N lm ci thin tnh thm ca
dc cht to ra cc micel c kch thc nh gip nh hng dc cht bm
trn b mt vng thn nc ca micel t ci thin ha tan ca dc cht
[27]. Labrasol l t dc khng tan trong nc nhng thn nc, kh nng
chu nn km. Labrasol l cht din hot th lng nn khi phi hp vo
cng thc vin s c phn tn trong t dc dnh trc.
Kt qu ny ph hp vi kt qu nghin cu ca tc gi Seng Dueane
Leuang Kham Ma nm 2011. Vin nn ibuprofen s dng cht din hot
Labrasol cho phn trm gii phng ca dc cht cao gp 2 ln so vi cng
thc s dng cht din hot natri laurylsulfat [12].
4.2 nh hng ca t dc siu r n ha tan ca dc cht trong
cng thc
Ibuprofen l dc cht d tan trong hydroxyd kim long v carbonat kim.
Trong mi trng m phosphat pH 6,8 tc ha tan ibuprofen nguyn liu
cao hn rt nhiu so vi trong mi trng acid HCl 0,1N. Sau 20 pht, t l
ibuprofen ha tan trong mi trng m cao gp khong 25 ln so vi trong
mi trng acid [13]. Trong mt s nghin cu khc, kt qu cng cho thy
53

rng tan ca ibuprofen tng khi pH mi trng tng. Kt qu ny cho thy

ha tan ca ibuprofen trong vin nn chu nh hng nhiu bi thi gian r
trong mi trng c pH cao.
Trong nghin cu, chng ti s dng 3 t dc siu r tc ng vo
ha tan ca dc cht l: SSG, Croscarmellose, Crospovidon. Kt qu cho
thy thi im 5 pht, 10 pht, vin s dng Crospovidon c ha tan
dc cht tt hn. Tuy nhin cng thc s dng Crospovidon ht to ra m,
xp, kh chu nn. Do vy vin nn to ra khng t yu cu v cng nn
chng ti loi ra. Nguyn nhn l do trong thnh phn cng thc vin nn c
t dc ht m nh CrosPVP. Hn na, Labrasol l mt cht din hot khng
ion ha c bn cht l ester ca triglyceride dng lng, kh nng chu nn
km. Trong qu trnh lm ht, cc phn t Labrasol bm ln cc b mt tiu
phn dc cht to thnh mt lp mng trn, lm cc tiu phn trt ln nhau
v kh nn khi tc dng lc. Mt khc, kh nng trng n ca Crospovidon
b nh hng bi k thut xt ht t, kh nng ht nc b gim, dn ti
gim s lng cc vi mao qun, kh nng ci thin r vin gim.
Vin nn s dng SSG v Croscarmellose c ha tan dc cht thi
im sau 5 pht l tng ng nhau: 21,65% vi PAR v 21,46% vi IBU
cng thc s dng SSG v 23,45% vi PAR v 19,01% vi IBU cng thc
s dng Croscarmellose. Tuy nhin thi im 60 pht, c 2 dc cht u
ha tan trn 90% trong cng thc s dng SSG cn trong cng thc s dng
Croscarmellose, ha tan ca PAR v IBU ln lt l 84,97% v 81,19%
nn chng ti s dng SSG lm t dc siu r nhm lm tng ha tan ca
PAR v IBU trong vin nn phi hp.

54

4.3 nh hng ca kch thc tiu phn dc cht n ha tan ca

dc cht trong cng thc
Kch thc tiu phn th hin nghin mn v c ry dng ry. Khi
kch thc tiu phn gim din tch b mt tip xc ca dc cht vi mi
trng ha tan tng, do tc ha tan tng theo phng trnh NoyesWithney [1]:
= K. S. (Cs-C)
Trong :

S: din tch b mt.

Cs: nng bo ha ca dc cht.
C: nng cht tan ti thi im t.

Trong nghin cu ny, chng ti thy r s khc bit v tc ha tan ca

hai cng thc qua ry 125 v ry 180. Khi s dng cng thc c dc cht
dc ry qua ry 125 thy vin c t l % dc cht ha tan ti cc thi im
tt hn so vi vin c dc cht c ry qua ry 180. Nh vy, kch thc
tiu phn dc cht c nh hng n ha tan ca dc cht trong vin
nn phi hp paracetamol v ibuprofen.
4.4 nh hng ca t dc kim n ha tan ca dc cht trong
cng thc
Khi s dng t dc kim natri carbonat trong cng thc thy ha tan
ca dc cht c ci thin ng k. Nguyn nhn c th do khi tip xc vi
mi trng ha tan, natri carbonat rt d tan nn s tan trc v to ra xung
quanh tiu phn dc cht mt vi mi trng c pH cao hn so vi mi
trng ha tan [18, 26]. Dc cht d ha tan trong vi mi trng to thnh
bi natri carbonat v do tc ha tan dc cht t vin nn c ci
thin.
Tuy nhin, khi s dng vi t l ln, t dc kim c th nh hng n
tui th ca thuc do phn ng vi dc cht v y nhanh qu trnh phn
55

hy ca dc cht trong qu trnh bo qun di tc ng ca nhit v

m. Mt khc, khi s dng natri carbonat t l cao ht to thnh kh sy kh
v khi dp vin c cng khng t. Nguyn nhn c th do c tnh ht m
ca t dc kim.
Vi kt qu thu c v m bo cho cng ca vin chng ti la
chn t l natri carbonat trong cng thc l 0,5%.
4.5 V phng php nh lng vin nn phi hp paracetamol v
ibuprofen
nh lng vin cha 2 thnh phn tr ln, n gin nht ngi ta
thng tin hnh chit tch ring cc thnh phn ri tin hnh nh lng
[16]. Tuy nhin phng php PHT v phng php HPLC cho php nh
lng ng thi v trc tip paracetamol v ibuprofen m khng cn thc
hin giai on chit tch. Trong , phng php PHT cn l mt phng
php d tin hnh, tit kim v t c hi hn so vi cc phng php khc
nh HPLC.
i vi phng php PHT, vic la chn nng cht chun ly t
i cng nh hng ti chnh xc ca kt qu. Qua kho st nng PAR
32,5 mg/L v IBU 20 mg/L c la chn.
Mc d phng php PHT cho khong tuyn tnh khng cao bng
HPLC, c bit b nh hng bi mt s yu t trong qu trnh thao tc nh
lng: vic la chn bc sng thch hp ca PAR v IBU, khong nng
PAR v IBU xy dng ng chun v s dng trong php chia t i.
Tuy nhin theo thng k vi tin cy 95% khng c s khc bit v gi tr
trung bnh v phng sai so phng php HPLC [16].

56

KT LUN V KIN NGH

T nhng kt ca nghin cu, chng ti thu c kt lun nh sau:
1.

nh gi c nh hng ca cc yu t cng thc ln ha tan

ca 2 dc cht t vin:
S dng cht din hot Labrasol 3% lm tng ng k ha
tan ca dc cht trong vin nn kt hp IBU v PAR trong
mi trng ha tan m pH 7,2. Cht din hot natri
laurylsulfat ci thin khng ng k ha tan ca dc cht
trong mi trng kim.
S dng t dc siu r SSG 4% lm gim thi gian r ca
vin qua lm tng tc v mc ha tan ca dc cht.
Cng thc s dng dc cht ry qua ry 125 c ha tan
dc cht ti cc thi im ln hn cng thc s dng dc
cht ry qua ry 180.
Vin nn s dng t dc kim natri carbonat t l 0,5% c
cng t, hnh thc vin p v lm tng ha tan dc
cht ti cc thi im.

2.

xy dng c cng thc vin nn phi hp cha PAR v IBU,

cng thc cho 1 vin nh sau:
Paracetamol

325 mg

Ibuprofen

200 mg

Natri carbonat

3,65 mg

Natri starch glycolat

29,2 mg

Labrasol

21,9 mg

Avicel PH101

141,5 mg

Aerosil

1,46 mg

Magnesi stearat

7,3 mg

57

HPMC E15 5%

5 ml

Kin ngh v xut

Qua qu trnh nghin cu, chng ti ch nghin cu v thu c nhng kt
qu nh trn. tip tc pht trin v hon thin ti, chng ti xin xut
thm ni dung: s dng m hnh ton hc a ra bi phn mm ti u ha
xy dng cng thc quy trnh bo ch c cng thc vin nn phi hp
paracetamol 325mg v ibuprofen 200mg c ha tan ti u.

58

TI LIU THAM KHO

TI LIU TING VIT
1. B mn bo ch (2006), K thut o ch v sinh dc hc ca dng
thuc, tp 2, NXB Y hc, trang 152-192.
2. B mn ha phn tch (2004), Ha phn tch 2, Trng i hc Dc H
Ni, trang 41-69.
3. B y t (2009), Dc in Vit Nam IV, NXB Y hc.
4. B y t (2009), Dc th quc gia Vit Nam, NXB Y hc, trang 17691774; 2564-2572.
5. V Th Nh H (2000), Nghin cu mt s yu t nh hng n ha
tan v n nh ca vin nn ciprofloxacin,Lun vn thc s dc hc,
Trng i hc Dc H Ni.
6. Nguyn Thu Hng (2011), Nghin cu o ch thuc n paraceta o
gii phng k o di Kha lun tt nghip Dc s, trng i hc Dc
H ni.
7. Nguyn ng Ha (2000), Nghin cu h phn tn rn ca Arte isinin v
ng dng vo t s dng thuc, Lun n tin s dc hc, trng i hc
Dc H Ni.
8. Phm Th Minh Hu (2003), Nghin cu o ch vin n n nifedipin tc
dng k o di Lun n tin s Dc hc, trng i hc Dc H Ni.
9. ng Th Ngc Lan (2010), So snh v phi hp mt s phng php nh
lng trc tip dung dch hai thnh phn bng quang ph, Lun vn thc s
dc hc, trng i hc Dc H Ni.
10.Nguyn Th Liu (2006), Nghin cu o ch Pellet ibuprofen gii phng
nhanh, Lun vn thc s dc hc, Trng i hc Dc H Ni.
11.ng Th H Ly (2010), nh lng ng thi v th ha ha tan
paracetamol v ibuprofen trong vin nn bng phng php hi qui a

59

bin quang ph, Kha lun tt nghip Dc s, Trng i hc Dc H

ni.
12.Seng Dueane Leuang Kham Ma (2011), Nghin cu bin php

tng

ha tan ca ibuprofen t vin n n, Kha lun tt nghip Dc s,

trng i hc Dc H ni.
13.Nguyn Hu M (2007), Nghin cu o ch v sinh kh dng vin n n
ibuprofen, Lun n Tin s Dc hc, Hc vin qun y.
14.V Ngc Ph (2006), Nghin cu o ch vin n n i uprofen gii phng
nhanh, Kha lun tt nghip Dc s, trng i hc Dc H ni.
15.L nh Quang (2006), Nghin cu o ch vin n n gii phng nhanh
cha paraceta o v i uprofen Lun vn thc s dc hc, Trng i
hc Dc H Ni.
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63

PH LC
Ph lc 1. T l phn trm DC ha tan theo CT12 v CT14
% ha tan dc cht (n=3)

Thi
gian
(pht)

CT12

CT14

PAR

IBU

PAR

IBU

31,24

38,96

15,61

13,45

10

54,10

70,91

47,84

37,53

15

85,09

77,18

50,91

41,60

20

94,32

78,80

78,63

64,31

30

96,53

79,91

85,32

72,33

45

98,12

82,13

92,03

75,40

60

99,34

84,57

97,29

78,80

64

Ph lc 2: PHT ca paracetamol trong cng thc CT18

Ph lc 3: PHT ca ibuprofen trong cng thc CT18

65