Ketnooi.

com chia se

NGUYN TH HNG H

Nghin cu bo ch v sinh kh dng

vin nn paracetamol gii phng nhanh

LUN N TIN S DC HC

H NI 2011

B GIO DC V O TO

B Y T

TRNG I HC DC H NI

NGUYN TH HNG H

Nghin cu bo ch v sinh kh dng

vin nn paracetamol gii phng nhanh

LUN N TIN S DC HC
CHUYN NGNH BO CH
M S: 62730105
Ngi hng dn khoa hc: PGS.TS. Nguyn ng Ho
PGS.TS. Nguyn Vn Long

H NI 2011

LI CAM OAN
Ti xin cam oan y l cng trnh nghin cu ca ring ti. Cc s liu,
kt qu nu trong lun n l trung thc v cha tng c ai cng b trong bt
k cng trnh no khc.
Nguyn Th Hng H

LI CM N
Ti xin by t lng bit n su sc ti PGS.TS. Nguyn ng Ho v
PGS.TS. Nguyn Vn Long, nhng ngi thy tn tnh hng dn v to iu
kin gip ti hon thnh bn lun n ny.
Ti cng xin chn thnh cm n GS.TS. V Xun Minh, PGS,TS. Phm
Th Minh Hu, TS. Nguyn Th Kiu Anh, TS. Nguyn Ngc Chin, TS.
Nguyn Trn Linh v ton th cc thy c gio, k thut vin B mn Bo Ch,
B mn Cng Nghip Dc, Phng Th Nghim Trung Tm, B mn Dc
Lm Sng, Phng Sau i hc - Trng i Hc Dc H Ni to iu kin
thun li v gip ti trong qu trnh thc hin lun n.
Ti xin cm n cc cn b, nhn vin cng ty Dc Khoa, cng ty CPDP
Sao Kim v Trung tm tng ng sinh hc - Vin Kim nghim thuc Trung
ng tn tnh h tr ti trong qu trnh nghin cu.
Ti cng xin chn thnh cm n Ban Gim c, Ban lnh o Khoa Dc
cng ton th cc anh, ch, em v cc bn ng nghip cng tc ti Bnh Vin
Nhi Trung ng to iu kin thun li, ng vin v gip ti trong sut
qu trnh nghin cu ti.
Ti cng xin gi ti gia nh v bn b li cm n chn thnh v dnh
cho ti thi gian, tnh cm, s gip v nhng li ng vin khch l gip ti
hon thnh lun n ny.
H Ni, ngy

thng

nm 2010

Nguyn Th Hng H

ii

MC LC
Trang ph ba
Li cam oan
Li cm n
Mc lc
Danh mc cc ch ci vit tt
Danh mc cc bng
Danh mc cc hnh
T VN
Chng 1: TNG QUAN
1.1. Vin nn gii phng nhanh
1.1.1. Khi nim
1.1.2. u nhc im ca vin nn gii phng nhanh
1.1.3. Mt s k thut v phng php bo ch vin gii phng nhanh
1.1.3.1
Mt s k thut tc ng vo dc cht
1.1.3.2. S dng t dc siu r
1.1.3.3. S dng h t dc si bt
1.1.3.4. Phng php ng kh
1.1.3.5. Phng php khun
1.1.3.6. Phng php thng hoa
1.1.3.7. K thut rn lng
1.1.3.8. K thut ko bng
1.1.3.9. K thut in phun ba chiu
1.1.3.10. Phng php x l sau khi dp vin
1.1.4. Phng php nh gi cht lng vin nn gii phng nhanh
1.2. Tng quan v paracetamol
1.2.1. Cng thc, tnh cht
1.2.2. Tc dng dc l
1.2.3. Dc ng hc
1.2.4. Ch nh, chng ch nh, tc dng khng mong mun
1.2.5. Mt s nghin cu v vin paracetamol gii phng nhanh
1.2.6. Phng php nh lng paracetamol
1.2.6.1. nh lng paracetamol nguyn liu v ch phm
1.2.6.2. nh lng paracetamol trong dch sinh hc
1.3. Nghin cu sinh kh dng v tng ng sinh hc

iii

i
ii
iii
vii
viii
xii
1
3
3
3
4
5
6
8
10
10
11
12
13
14
14
15
16
18
18
19
20
20
21
23
23
27
31

1.3.1. nh gi ho tan in vitro

1.3.2. nh gi sinh kh dng in vivo v tng ng sinh hc
Chng 2: NGUYN VT LIU, THIT B V PHNG PHP NGHIN CU
2.1. Nguyn vt liu v thit b nghin cu
2.1.1 Nguyn vt liu
2.1.2 Thit b, phng tin
2.1.3 i tng nghin cu
2.1.4 a im nghin cu
2.2. Phng php nghin cu
2.2.1 Phng php bo ch vin nn paracetamol gii phng nhanh
2.2.1.1. Phng php s dng t dc thng hoa
2.2.1.2. Phng php ch to ht rn-lng
2.2.1.3. Phng php bo ch vin si ni
2.2.2 Phng php hon thin v thm nh qui trnh sn xut
2.2.2.1. Chun b trc thm nh
2.2.2.2. Tin hnh thm nh
2.2.2.3. Kim sot qui trnh bng phng php thng k
2.2.3 Phng php nh gi v tiu chun ho cht lng bn thnh
phm v thnh phm vin nn paracetamol gii phng nhanh.
2.2.4 Phng php nghin cu n nh
2.2.5 Phng php nh gi sinh kh dng v tng ng sinh hc
2.2.5.1. Xy dng v thm nh phng php nh lng
paracetamol trong huyt tng
2.2.5.2. Phng php nghin cu sinh kh dng v tng ng
sinh hc
2.2.7 X l kt qu nghin cu
Chng 3: KT QU NGHIN CU
3.1. Bo ch vin paracetamol gii phng nhanh
3.1.1 S dng k thut thng hoa
3.1.2 Bo ch vin s dng k thut to ht rn lng
3.1.3 Bo ch vin si ni
3.1.3.1. Kt qu kho st cc yu t thnh phn cng thc
3.1.3.2. Kt qu nh gi nh hng ca mt s thng s k thut
n thi gian r v ho tan paracetamol t vin
3.2. Xy dng tiu chun cht lng vin nn paracetamol gii phng nhanh.
3.2.1. Kho st ch tiu cht lng
3.2.2. xut tiu chun vin nn paracetamol gii phng nhanh
3.3. Nghin cu n nh

iv

31
32
37
37
38
39
39
40
40
40
41
42
46
46
46
47
49
51
51
51
52
54
55
55
55
59
62
62
71
77
77
81
83

3.3.1 nh gi n nh
3.3.2 Xc nh tui th ca thuc
3.4. Hon thin v thm nh qui trnh sn xut vin nn paracetmol gii phng
nhanh
3.4.1 Hon hin qui trnh sn xut vin nn paracetamol gii phng
nhanh
3.4.1.1. Nhng thay i chnh khi nng c l
3.4.1.2. Cng thc vin
3.4.1.3. Tm tt quy trnh sn xut
3.4.1.4. S quy trnh sn xut
3.4.2 Thm nh quy trnh sn xut vin nn paracetamol gii phng
nhanh.
3.4.2.1. nh gi nguy c gy mt n nh quy trnh sn xut
3.4.2.2. La chn cc thng s thm nh
3.4.2.3. K hoch ly mu trong qu trnh thm nh
3.4.2.4. Giai on trn bt kh
3.4.2.5. Giai on nho m
3.4.2.6. Giai on sy
3.4.2.7. Giai on sa ht
3.4.2.8. Giai on trn hon tt
3.4.2.9. Giai on dp vin
3.4.2.10. Kt qu thm nh thng s kim sot
3.5. Nghin cu sinh kh dng vin nn paracetamol gii phng nhanh
3.5.1. Xy dng v thm nh phng php nh lng paracetamol
trong huyt tng
3.5.1.1. Xy dng phng php nh lng
3.5.1.2. Thm nh phng php phn tch
3.5.2. Kt qu nghin cu sinh kh dng
Chng 4: BN LUN
4.1. V la chn phng php bo ch vin paracetamol gii phng nhanh
4.2 V nghin cu xy dng cng thc bo ch vin
4.2.1. La chn kch thc tiu phn dc cht
4.2.2. La chn t l natri bicarbonat
4.2.3. La chn t dc dnh
4.2.4. La chn t dc r
4.2.5. La chn t dc trn
4.2.6. La chn thi gian nho m
4.2.7. La chn lc gy v vin

83
88
90
90
90
92
93
93
95
95
96
98
99
101
103
104
105
106
108
117
117
117
120
128
134
134
137
137
138
139
139
140
140
140

4.2.8. La chn k thut to ht

4.3. V xy dng tiu chun cht lng vin nn paracetamol gii phng
nhanh
4.4. V n nh ca ch phm
4.4.1. Theo di n nh
4.4.2. D tnh tui th ca ch phm nghin cu
4.5. V hon thin v thm nh qui trnh sn xut
4.6. V nghin cu sinh kh dng vin nn paracetamol gii phng nhanh
4.6.1. Xy dng v thm nh phng php nh lng paracetamol
trong huyt tng
4.6.2. Nghin cu sinh kh dng vin nn v tng ng sinh hc vin
nn paracetamol gii phng nhanh trn ngi tnh nguyn
KT LUN V XUT
DANH MC CC BI BO C LIN QUAN N LUN N
TI LIU THAM KHO
PH LC

vi

141
141
142
142
143
144
146
146
148
150
152
153

DANH MC CC K HIU, CC CH VIT TT

ASEAN : Hip hi cc nc ng Nam (Association of Sounth East Asia Nations)
AUC
: Din tch di ng cong (Area under the curve)
BCS
: H thng phn loi sinh dc hc (Biopharmaceutics Classification
System)
BP
: Dc in Anh (Bristish Pharmacopoeia)
CE
: in di mao qun (Capillary electrophoresis)
: Nng thuc cc i trong huyt tng
Cmax
CS
: Cng s
DVN : Dc in Vit Nam
FDA
: Cc qun l thuc v thc phm (Food and Drug Administration)
FPIA
: Phn tch min dch hunh quang phn cc (Fluorescence Polarization
Immunoassay)
HPLC
: Sc k lng hiu nng cao (High performance liquid chomatography)
HPMC
Hydroxypropyl methylcellulose
IVIVC
: Mi tng quan in vitro in vivo (In vitro - in vivo correlation)
NaCMC : Natri carboxymethyl cellulose
NBC
Natri bicarbonat
PEG
: Polyethylen glycol
PG
: Propylen glycol
PVP
: Polyvinyl pyrolidon
SKD
: Sinh kh dng
: Thi gian bn thi (Time terminal half-life)
t1/2
: Thi gian thuc t nng cc i trong huyt tng
Tmax
USP
: Dc in M (United State Pharmacopoeia)
UV
: T ngoi (Ultra violet)
Vis
: Kh kin (Visible)

vii

DANH MC CC BNG
Bng 2.1.

Cc nguyn liu, ho cht s dng trong nghin cu

37

Bng 2.2.

Cc thit b v phng tin s dng trong nghin cu

38

Bng 3.3

Cng thc cc mu vin gii phng nhanh ng dng k thut

thng hoa.

55

T trng v trn chy ca cc mu ht paracetamol bo ch

bng k thut thng hoa sau khi trn hon tt (n=5)

56

bn c hc, r v bin thin khi lng cc mu vin

thc nghim bo ch bng phng php thng hoa (gi tr
trung bnh SD, n=6)

57

T l paracetamol ho tan t cc mu vin iu ch bng k

thut thng hoa trong mi trng HCl 0,1 N (n=6)

58

Cng thc bo ch mt s mu vin kho st ng dng h rn

lng

59

Bng 3.8

T trng biu kin ca ht rn lng paracetamol-PG

59

Bng 3.9

r trung bnh ca cc mu vin rn- lng trong mi trng

nc v acid HCl 0,1N

60

T l paracetamol ho tan t cc mu vin rn lng trong mi

trng HCl 0,1N (n=6)

61

Bng 3.11

Thnh phn cng thc cc mu vin kho st trong nghin cu

(Mi cng thc 500 g paracetamol )

63

Bng 3.12

Phn trm paracetamol ho tan t cc mu vin c t l natri

bicarbonat khc nhau (n=6)

65

ho tan paracetamol t cc mu vin c thnh phn t dc

r khc nhau

67

Phn trm paracetamol ho tan t cc mu vin c t l t dc

r khc nhau (n=6)

68

Phn trm paracetamol ho tan t cc mu vin c thnh phn

t dc trn khc nhau(n=6)

70

Bng 3.16

Thi gian r ca cc mu vin c thi gian nho m khc nhau

72

Bng 3.17

Thi gian r trung bnh ca cc mu vin c cng khc

nhau

73

Tc gii phng paracetamol t cc mu vin c cng

khc nhau

74

Bng 3.4
Bng 3.5

Bng 3.6
Bng 3.7

Bng 3.10

Bng 3.13
Bng 3.14
Bng 3.15

Bng 3.18

viii

Bng 3.19

ho tan paracetamol t cc mu vin bo ch theo qui trnh

khc nhau

75

Bng 3.20

Kt qu kho st ha tan ca vin nn paracetamol

78

Bng 3.21

Kt qu kho st ng u khi lng vin paracetamol

79

Bng 3.22

Kt qu nh lng paracetamol trong vin nn ca 3 l kho

st ch tiu cht lng

81

Phn trm paracetamol ho tan t cc mu vin sau 5 pht khi

bo qun iu kin lo ha cp tc (n=6, P=0,95)

84

Phn trm paracetamol ho tan t cc mu vin sau 5 pht khi

bo qun iu kin thng (n=6, P=0,95)

86

Hm lng 4-aminophenol (%) trong cc mu vin khi

boqun iu kin thng (n=3)

86

Bng 3.23
Bng 3.24
Bng 3.25
Bng 3.26

Hm lng 4-aminophenol (%) trong mu vin khi bo qun

iu kin lo ha cp tc (n=3)

85

Hm lng (%) paracetamol trong vin nn gii phng nhanh

bo qun iu kin thc

87

Hm lng (%) paracetamol trong vin nn gii phng nhanh

bo qun iu kin lo ha cp tc

88

T l paracetamol trong vin thc nghim cn li so vi ban

u khi bo qun trong v nhm-nhm iu kin thng

89

Phng trnh hi qui tuyn tnh gim hm lng paracetamol

theo thi gian bo qun trong iu kin thc v d tnh tui th
thuc.

89

Bng 3.31

So snh ht paracetamol sy tnh v sy tng si

91

Bng 3.32

Cng thc sn xut l 30.000 vin

92

Bng 3.33

nh gi nguy c nh hng n n nh ca quy trnh sn

xut

95

Bng 3.34

Cc thng s trng yu cn thm nh

97

Bng 3.35

K hoch ly mu trong qu trnh thm nh

98

Bng 3.36

phn tn hm lng paracetamol l P1, giai on trn bt

kh.

99

Bng 3.27
Bng 3.28
Bng 3.29
Bng 3.30

Bng 3.37

phn tn hm lng paracetamol cc l P2 v P3, giai

on trn bt kh.

ix

100

Bng 3.38

phn tn hm lng natri bicarbonat l P1, giai on trn

bt kh.

100

phn tn hm lng natri bicarbonat cc l P2 v P3, giai

on trn bt kh.

101

phn tn hm lng paracetamol cc l P1, P2 v P3 khi

nho m

102

phn tn hm lng natri bicarbonat cc l P1, P2 v P3

khi nho m

103

Bng 3.42

m cm paracetamol sau khi sy

104

Bng 3.43

m cm natri bicarbonat sau khi sy

104

Bng 3.44

Kt qu xc nh hm lng paracetamol (%) trong cc mu

ca l P1

105

Bng 3.45

phn tn hm lng paracetamol cc l P2 v P3

106

Bng 3.46

Tm tt kt qu thm nh cc thng s trng yu

107

Bng 3.47

Khi lng vin ca l P1

108

Bng 3.48

Khi lng vin ca l P2

109

Bng 3.49

Khi lng vin ca l P3

Bng 3.39
Bng 3.40
Bng 3.41

110
X

Bng 3.50

Kt qu kho st biu Shewhart X

114

Bng 3.51

Kt qu kho st biu Shewhart R

114

Bng 3.52

Kt qu kho st ch bo hiu nng

116

Bng 3.53

Kt qu kho st tnh ph hp ca h thng sc k (n=6)

120

Bng 3.54

Kt qu kho st khong nng tuyn tnh ca paracetamol

trong huyt tng

122

Bng 3.55

Kt qu kho st chnh xc ca phng php phn tch

123

Bng 3.56

Kt qu kho st ng ca phng php (n=5)

124

Bng 3.57

tm li ca phng php x l mu huyt tng bng

acetonitril (n = 5)

125

Bng 3.58

Kt qu kho st gii hn nh lng ca phng php (n = 5).

126

Bng 3.59

n nh ca paracetamol trong thi gian phn tch (n=3)

126

Bng 3.60

n nh ca paracetamol trong iu kin bo qun (n = 5)

127

Bng 3.61

Nng paracetamol trong huyt tng tng ngi tnh

nguyn sau khi ung vin nghin cu Paracetamol FR 500 mg

129

Bng 3.62
Bng 3.63
Bng 3.64

Bng 3.65

Nng paracetamol trong huyt tng tng ngi tnh

nguyn sau khi ung vin i chiu Panadil actifast 500 mg

130

Nng paracetamol trong huyt tng tng ngi tnh

nguyn sau khi ung vin nghin cu Panadol 500 mg

131

Gi tr trung bnh v khong tin cy 95% cc thng s dc

ng hc ca paracetamol sau khi ung vin PF, PA hoc P
(n=18)

132

So snh Cmax, Tmax , AUC0- v khong tin cy 90%

132

xi

DANH MC CC HNH V, TH

Hnh 1.1.

S biu din qu trnh ho tan v hp thu dc cht t vin nn

Hnh 2.2

S cc bc bo ch vin paracetamol gii phng nhanh bng

phng php s dng t dc thng hoa.

41

S cc bc bo ch vin paracetamol gii phng nhanh s

dng h rn lng.

43

S cc giai on bo ch vin paracetamol bng phng php

xt ht chung paracetamol vi natri bicarbonat

44

S cc giai on bo ch vin paracetamol bng phng php

to ht paracetamol v ht natri bicarbonat ring bit

45

th ho tan paracetamol t cc mu vin bo ch bng k thut

thng hoa trong mi trng HCl 0,1N

58

th ho tan paracetamol t cc mu vin bo ch p dng k

thut rn lng trong mi trng HCl 0,1N

61

th tc ho tan paracetamol t vin c KTTP dc cht khc

nhau

64

th ho tan paracetamol t cc mu vin c t l natri

bicarbonat khc nhau

65

th ho tan dc cht t vin s dng mt s loi t dc r

khc nhau

67

th ho tan paracetamol t cc mu vin c t l t dc r khc

nhau

69

th ho tan paracetamol t cc mu vin c thnh phn t dc

trn khc nhau

71

th ho tan paracetamol t cc mu vin c thi gian nho m

khc nhau

72

Hnh 3.14

th ho tan paracetamol t cc mu vin c cng khc nhau

74

Hnh 3.15

So snh th ho tan paracetamol t cc mu vin c cng cng

thc nhng vi qui trnh to ht chung v to ht ring

76

Hnh 3.16

Sc mu chun 4-aminophenol

80

Hnh 3.17

Sc nh lng 4-aminophenol trong mu vin

80

Hnh 2.3
Hnh 2.4
Hnh 2.5
Hnh 3.6
Hnh 3.7
Hnh 3.8
Hnh 3.9
Hnh 3.10
Hnh 3.11
Hnh 3.12
Hnh 3.13

xii

Hnh 3.18

ng hi quy gi tr trung bnh v cn di 95% d on hm

lng paracetamol trong vin ca 3 l cn li so vi ban u trong
iu kin bo qun thc (n=5, P=0,95).

90

Hnh 3.19

S qui trnh sn xut vin nn paracetamol gii phng nhanh

94

Hnh 2.20

S ly mu thm nh d phn tn hm lng

98

Hnh 3.21

Biu Shewhart X / R v khi lng vin ca l P1: (a)

Biu R, (b) Biu X

111

Biu Shewhart X / R v khi lng vin ca l P2: (a)

Biu R, (b) Biu X

112

Biu Shewhart X / R v khi lng vin ca l P3: (a)

Biu R, (b) Biu X

113

Hnh 3.24

Biu cusum l P1

115

Hnh 3.25

Biu cusum l P2

115

Hnh 3.26

Biu cusum l P3

116

Hnh 3.27

Ph hp th t ngoi ca paracetamol

119

Hnh 3.28

Sc k mu huyt tng trng

121

Hnh 3.29

Sc mu huyt tng trng thm paracetamol

121

Hnh 3.30

Sc mu huyt tng ngi tnh nguyn 15 pht sau khi ung

500 mg paracetamol

122

Hnh 3.31

ng chun nh lng paracetamol trong huyt tng

123

Hnh 3.32

S bin thin gi tr trung bnh ca nng paracetamol trong

huyt tng theo thi gian sau khi ung PF, PA v P

128

Hnh 3.22
Hnh 3.23

xiii

T VN
Paracetamol hay cn gi l acetaminophen c bit n vi tn khoa hc l Nacetyl-p- aminophenol, l mt dc cht c tc dng gim au v h st. K t ln u
tin c a ra th trng cho ti nay hn 50 nm, paracetamol vn lun l thuc
gim au h st thng dng nht. C ch tc dng ca paracetamol hin nay cng cha
thc s r rng. Tuy nhin, mt s nghin cu cho thy tc dung np thuc l yu
t quan trng. Tng tc hp thu paracetamol c th em li tc dng gim au, h
st nhanh v hiu qu hn sau khi ung [79].
Ti nhiu nc trn th gii, paracetamol c lu hnh m khng cn k n
vi cc dng bo ch phong ph nh: dung dch ung, thuc n, vin nang, vin nn.
Tc hp thu ca dng thuc thng c nh gi qua cc thng s dc ng hc
nh nng nh v thi gian t c nng nh trong huyt tng sau khi ung
thuc (Cmax v Tmax). Mc hp thu c nh gi bng gi tr din tch di ng
cong ca th nng thuc trong mu (AUC). Tmax ngn ng ngha vi hp thu
nhanh. c rt nhiu n lc trong nghin cu dng bo ch mi c kh nng hp thu
nhm xut hin tc dng nhanh, in hnh l dng vin nn ho tan nh mt s ch
phm vi bit dc Efferalgan, Panadol si bt trn th trng. Cc ch phm ny c
tc hp thu nhanh v do t hiu qu gim au nhanh hn so vi vin nn qui
c [71],[83]. Tuy nhin, vin nn ho tan khng c thun tin khi s dng v phi
ho tan vo nc trc khi ung v dung dch ho tan c hng v kh ung. Khc
phc nhc im trn l s ra i ca ch phm vin nn paracetamol hp thu nhanh
dng nut, hin ang lu hnh ti mt s nc pht trin.
p ng nhu cu iu tr v nghin cu, pht trin nn sn xut trong nc,
ti Nghin cu bo ch v sinh kh dng vin nn paracetamol gii phng
nhanh c thc hin nhm mc tiu sau:
1- Xy dng c cng thc v qui trnh sn xut vin nn paracetamol
gii phng nhanh m bo n nh.
2- So snh c sinh kh dng ca ch phm nghin cu vi sn phm
nhp ngoi c uy tn c c s ng dng vo sn xut trong nc.

Nhm t c mc tiu t ra, ti c thit k vi m hnh nghin cu

ton din, bao gm cc ni dung sau:
- Xy dng cng thc v qui trnh bo ch vin nn paracetamol 500 mg gii
phng nhanh
- Xy dng tiu chun cht lng vin
- Nghin cu n nh ca vin
- Nng cp qui m v thm nh qui trnh sn xut vin
- Nghin cu sinh kh dng ca vin, so snh vi thuc i chiu l Panadol
actifast v mt ch phm vin nn qui c Panadol 500 mg.

Chng 1: TNG QUAN

1.1. Vin nn gii phng nhanh
1.1.1. Khi nim
Vin nn gii phng nhanh l dng thuc rn phn liu c kh nng r v ho
tan dc cht trong mt thi gian ngn. Vin gii phng nhanh cn c bit n vi
nhiu tn gi khc nhau: vin nn r nhanh, vin ha tan nhanh, vin tan trong ming,
vin ng kh, vin hp thu nhanh, vin phn tn nhanh, ...
Nm 2008, FDA ca M thng qua hng dn v vin nn r trong ming
(Orally Disintegrating Tablets). Trong nh ngha: Vin nn r trong ming l
dng bo ch thuc rn dng ng ung, r nhanh trong khoang ming trong vng 30
giy khi th r theo hng dn th r in vivo ca USP [99].
Theo Allen LV., vin nn ho tan nhanh (hoc r nhanh) c b o ch vi mc
tiu khi a vo ming, vin c th r nhanh chng trong khong 10 60 giy [14].
Tng t nh vy, Dc in chu u cng a ra khi nim vin nn phn tn
trong ming (orodispersible tablets), khi a vo ming s phn tn v r nhanh chng
trc khi nut [34]
Pfister WR. nh ngha: Vin nn r trong ming l mt dng thuc rn r v
ho tan ti khoang ming trong vng 60 giy m khng cn nhai hoc dng thm
nc [75].
Mc d c gi bng rt nhiu tn khc nhau, tu theo v tr r v ho tan, vin
nn gii phng nhanh c th phn loi tng i thnh ba dng chnh: vin nn r
trong ming, vin nn r nhanh trong ng tiu ho v vin nn ho tan.
Vin nn r trong ming: l dng vin nn phn liu cha dc cht, r nhanh
trong vng vi chc giy khi t ln li m khng cn nc. Dc cht do s
c gii phng, ho tan hoc phn tn trong nc bt ri c nut xung v hp thu
theo ng tiu ho.
Vin nn r nhanh trong ng tiu ho: Vin r v ho tan nhanh dc cht
ngay sau khi nut vo ng tiu ho. Theo phn loi BCS, mt ch phm thuc rn
dng ng ung c coi l ho tan nhanh khi khng di 85% lng dc cht

c ho tan trong vng 30 pht trong 900 ml mi trng (acid hydrocloric 0,1N ,
dung dch m pH 4,5 hoc dung dch m pH 6,8) vi thit b cnh khuy 50
vng/pht hoc gi quay 100 vng/pht [96].
Vin nn ho tan: Vin c ho tan nhanh thnh dng dung dch trc khi
ung. Phn ln cc ch phm vin ho tan theo c ch si bt. Thc cht, thuc c
hp thu t dng dung dch ung nn kh nng hp thu c ci thin.
1.1.2. u nhc im ca vin gii phng nhanh

u im:
Vin nn gii phng nhanh c mt s u im ni bt sau y [17]:
- Khng cn nc cng c th s dng c thuc, thun tin cho bnh nhn

trong trng hp ang di chuyn hoc khng sn nc ung.

- t y cc u im ca dng bo ch lng mc d l dng vin nn.
- Thuc c ho tan v hp thu nhanh chng em li hiu qu tc dng nhanh
- Mt s ch phm c hp thu ngay ming, hng, thc qun trn ng
xung d dy nn c th lm tng sinh kh dng ca thuc. Trn c s , mt s
thuc c th gim c liu v do tc dng ph ca thuc cng gim theo.

Hn ch:
Bn cnh nhng u im ni bt, vin gii phng nhanh c mt s mt hn ch

sau y:
- Mi v ca dc cht: Hu ht cc thuc u c mi v khng d chu nn
khi bo ch cc dng thuc ung, cc nh khoa hc cng phi quan tm ti vic che
du mi v. Vn ny cng ng lu tm hn i vi cc ch phm vin nn r ngay
t trong khoang ming, khi tip xc vi c quan v gic l li. Do , che du mi v
l mt trong nhng yu cu ca vin r trong ming [23],[77].
- cng ca vin: Vin nn gii phng nhanh cn phi c xp thch hp
gip d thm v phi c dp vi lc nn cng thp cng tt. Vin c cu trc xp
thng b v d v, i hi vn chuyn rt kht khe v yu cu bao b c bit lm
tng gi thnh sn phm. Ch c rt t k thut bo ch p ng c yu cu ny, vin

t cng v cho php c th ng gi trong l nh hai ch phm Wowtab ca

Yamanouchi-Shaklee v Durasolv ca CIMA labs [16],[44].
- Tnh ht m: Mt s ch phm c tnh ht m do cc thnh phn trong cng
thc bo ch, khng bn vng khi bo qun iu kin m v nhit thng.
Hn na, vin nn gii phng nhanh thng c cu trc xp nn d b ht m. m
ca vin thay i s nh hng ti cht lng thuc. Bin php khc phc l phi ng
gi trong bao b chng ht m c bit [43].
- Hm lng dc cht: Mt s k thut bo ch vin gii phng nhanh phi
hn ch v hm lng dc cht trong vin. V d i vi phng php ng kh,
hm lng dc cht khng qu 400 mg vi cc dc cht kh tan v khng qu 60
mg i vi dc cht d tan. Thng s ny a vo ch tiu ca vin ng kh
[23],[39].
- Kch thc vin: Nhiu kt qu kho st cho thy, vin c kch thc 7 8
mm tr xung c coi l d nut. Vin nn cng d s dng nu kch thc cng nh
trong khi vin nn gii phng nhanh thng xp nn c kch thc ln hn so vi vin
nn qui c c cng khi lng. V vy, bo ch vin nn gii phng nhanh c hm
lng dc cht cao cng l mt thch thc vi cc nh bo ch [88].
1.1.3. Mt s k thut v phng php bo ch vin nn gii phng nhanh
Theo Wagner, qu trnh ho tan v hp thu dc cht t vin nn xy ra nh
sau:
R ln 1

R ln 2

Vin nn

Ht

Tiu phn

Ho tan rt hn ch

Ho tan hn ch

Ho tan ti u

Dc cht ho tan
Hp thu
Dc cht trong mu
Hnh 1.1: S biu din qu trnh ho tan v hp thu dc cht t vin nn

S trn cho thy r v ho tan l hai qu trnh lin quan cht ch vi nhau.
Qu trnh ho tan v hp thu dc cht ph thuc vo thi gian r ca vin nn, c
tnh l, ho ca dc cht v mi trng ho tan [1],[2]. Do vy, cc phng php bo
ch vin nn gii phng nhanh thng nhm xoay quanh hai mc tiu: Gim thi gian
r v tng tc , mc ho tan ca dc cht t vin nn.
1.1.3.1. Mt s k thut tc ng vo dc cht

Gim kch thc tiu phn dc cht

Theo phng trnh Noyes Whitney, tc ho tan dc cht ph thuc vo

tan v din tch b mt tip xc ca n vi mi trng ho tan. Nu kch thc tiu

phn gim, din tch b mt tip xc s tng v do , dc cht s ho tan nhanh hn.
K thut thng dng lm gim kch thc tiu phn dc cht l nghin c
hc. Phng php ny n gin, gi thnh thp, tit kim thi gian v d p dng qui
m cng nghip. Tuy nhin, cn lu l qu trnh nghin c th lm v mng li tinh
th to ra cu trc v nh hnh c kh nng d ho tan hn nhng li khng bn vng
vi mt s dc cht. Cc tiu phn sau khi nghin mn c xu hng kt t vi nhau
lm gim din tch b mt tip xc.
Gn y, cc nh khoa hc ng dng mt s phng php mi lm gim
kch thc tiu phn dc cht nh k thut phun sy, ng kh, kt ta Cc k
thut ny c u im l c th kim sot c kch thc v c tnh ca tiu phn
dc cht. Nhc im l qui trnh phc tp, mt thi gian, kh khn khi p dng trn
qui m cng nghip.
Phun sy l phng php nhanh v kinh t loi dung mi, to ra bt c
xp v mn cao. Allen v CS ch to h ct bo ch vin ho tan nhanh bng
k thut phun sy. Thnh phn ca ct bao gm hai polypeptid vi hm lng bng
nhau (thng dng gelatin khng thu phn v gelatin thu phn), t dc n
(manitol) v mt dung mi bay hi. Hn hp c phun sy to ra bt xp. Vin
bo ch t bt phun sy r di 20 giy. Bng cch kt hp vi dung mi bay hi
(thng dng ethanol), sc cng b mt ca cc git dch nh trong qu trnh phun sy
gim i nhiu, to ra nhiu l xp v nhiu ng mao dn trong cu trc ht. gip

vin n nh trong qu trnh s dng, c th bao ngoi bng mt lp mng polyme

mng. Dc cht c th dng di dng vi nang che du mi v [14] .
S.M. Wong s dng k thut phun sy lm gim kch thc tiu phn
griseofulvin. Kt qu cho thy, tiu phn phun sy c kch thc siu mn (8,51 m) ,
tc ho tan griseofulvin c ci thin ng k. Sau 15 pht, 18% dc cht c
ho tan so vi 7% t mu dc cht khng tc ng khi th trong mi trng m pH
6,8 [107]. Trong mt nghin cu khc, tc gi s dng k thut khuch tn dung
mi kt hp vi ng kh gim kch thc tiu phn griseofulvin. Tiu phn ng
kh c kch thc nh hn 6 ln so vi ban u (2,18 m so vi 12,61 m) [108].
H phn tn rn lm tng kh nng ho tan ca cc dc cht t tan vi s c
mt ca cht mang lm tng tan. Nh , dc cht di dng h phn tn rn c
kh nng ho tan tt hn nhiu so vi dng dc cht ban u. Kt qu nghin cu ca
Garekani v cng s cho thy rng tan ca acetaminophen trong nc tng ln
nhiu vi s c mt ca PVP. Quang ph hng ngoi ch ra tng tc gia
acetaminophen v PVP l qua lin kt hydro khng bn vng, l mt tng tc vt
l thun nghch. Thy c s tng quan gia tan ca acetaminophen v nng
PVP. Trn c s , tc gi ch h phn tn rn acetaminophen/PVP (1:2) [37].
Vin nn glyburid ha tan nhanh bng cch ch to h phn tn rn vi PEG
cho vin nn bn vng, r nhanh trong vng 10 pht v ho tan 50% dc cht ch sau
5 pht, nhanh hn gp nhiu ln so vi so vi vin nn thng thng (60 pht) [102].

Thay i cu trc tiu phn dc cht

M.S. Roberts v CS ch to thnh cng dng paracetamol ho tan nhanh

bng phng php kt tinh. Paracetamol c ho tan trong ethanol, un nng 70 oC

ri cho kt tinh li trong dung dch PVP 1%. Tinh th to thnh cha 3 - 6% PVP,
c lc ri lm kh chn khng 40oC ti m khong 1%. Kt qu nghin cu
cho thy cc mu vin bo ch t dng paracetamol ho tan nhanh gii phng trn
90% paracetamol trong vng 90 giy, nhanh hn r rt so vi vin bo ch t
paracetamol siu mn (84%) [79].

1.1.3.2. S dng t dc siu r

Trong bo ch vin nn gii phng nhanh, k thut dp thng hoc xt ht c
s dng nhiu v n gin, d thc hin v chi ph thp hn so vi cc k thut khc.
T dc r l thnh phn khng th thiu trong vin nn bo ch bng k thut dp
thng hoc xt ht, c tc dng lm cho vin r nhanh khi tip xc vi mi trng ho
tan. Trong thi gian gn y, cc nh nghin cu s dng t dc siu r (super
disintegrants) bo ch vin nn gii phng nhanh da vo kh nng trng n rt
mnh ca chng khi tip xc vi mi trng ho tan (c th trng n gp 300 ln th
tch), nhanh chng ph v cu trc ca vin.
u im ca k thut s dng t dc siu r trong bo ch vin nn gii phng
nhanh l chi ph sn xut thp, d thc hin, ch cn cc trang thit b thng thng,
vin c bn c hc cao. T dc siu r l nhng t dc c s dng trong cng
thc vi mt t l nh (2 - 5%) nhng vn cho hiu qu r cao. So vi cc t dc r
thng thng (nh tinh bt), ngoi hiu qu r nhanh, t dc siu r t nh hng n
kh nng trn chy, kh nng chu nn ca khi bt khi dp vin.
Nhc im ca vin nn gii phng nhanh cha t dc siu r l khi vin r
ti khoang ming s gy ra s kh chu cho ngi s dng do b kch thch nim mc
ming. Nguyn nhn l do t dc siu r khng tan trong nc.
Da vo cu trc ha hc, t dc siu r c chia thnh 3 nhm chnh nh
sau:

Tinh bt bin tnh

Thng dng nht trong nhm tinh bt bin tnh l

natri starch glycolat (SSG)

c sn xut t tinh bt bng bin i ha hc. Nhm carboxymethyl lm tng tnh

thn nc. SSG dng bt trng hoc gn trng, khng mi khng v. Tiu phn c
dng hnh cu do trn chy tt. Khi phn tn trong nc (3,3%) SSG to pH t 3
n 5 hoc t 5,5 n 7,5. SSG t tan trong ethanol, khng tan trong nc nhng phn
tn trong nc to gel. Trng n trong nc gp ti 300 ln th tch. SSG c s
dng lm t dc r trong vin nn dp thng hoc xt ht t v trong nang cng.
Hm lng s dng lm t dc r trong vin nn l 2-8 %, tt nht l 4%. Kh nng
r ca SSG t b nh hng ca cc t dc trn s nc nh magnesi stearat.

Takeuchi v CS. bo ch vin indomethacin ha tan nhanh s dng

hydroxypropyl cellulose v tinh bt bin tnh lm t dc r. T l ha tan
indomethacin t vin s dng t dc r trong 5 pht (34,1%) cao hn hn vin khng
s dng t dc r (19,1%) [90].

Cellulose bin tnh

Cellulose bin tnh c s dng nhiu trong bo ch thuc l natri

croscarmellose, l

dng polyme c lin kt cho ca natri carboxymethylcellulose.

Croscamellose khng tan trong nc c th trng n gp 4 n 8 ln khi tip xc vi

nc, c s dng lm t dc r trong vin nang v vin nn, thch hp vi c xt ht
t v dp thng. Hm lng croscamellose c th dng ti 5% nhng thng thng l
2% vi dp thng v 3% vi xt ht t. Croscamellose tng i n nh, t nh hng
ti kh nng ho tan ca dc cht trong qu trnh bo qun, do kh ht m nn c th
nh hng ti nhng dc cht d b thu phn. Nhng cht ht m lm gim hiu qu
r ca croscarmellose. Croscarmellose c tng k vi acid mnh, mui tan ca st,
nhm, thu ngn...[38],[81].

Polyvinylpyrolidon lin kt cho

Cht in hnh l crospovidon, cu to gm nhiu tiu phn nh ni li vi nhau

to khi dng hnh cu, nn c xp rt cao. C dng bt siu mn tng ng
u, r theo c ch trng n v c s dng lm t dc r trong vin nn, vin nang
hay pellet vi hm lng 1 - 3%. Crospovidon tng i n nh v t tng k. Kh
nng ht m ca t dc siu r ni chung l cao v cao nht l crospovidon.
Mt vn hay gp i vi nhm t dc trng n l chng to lp gel dnh
cn tr s ph v vin v s ht nc vo lng vin trong qu trnh r. Do khng
nn s dng hm lng ln t dc siu r v nhm ny c kh nng trng n rt cao.
Malke v CS. bo ch vin ho tan nhanh cha oxcarbazepin bng phng php
xt ht t s dng Avicel PH 102 lm t dc n v Ac-Di-Sol (natri croscamellose)
lm t dc siu r. Cng thc cha 12% Ac-Di-Sol, 25% Avicel PH 102 v 8,5% tinh
bt lm t dc dnh c cng 4-4,5 kg/cm2, thi gian r 28 5 giy, khng di
90% lng dc cht gii phng trong 30 pht [67].

1.1.3.3. S dng h t dc si bt
H t dc si bt bao gm mt acid (acid hu c, anhydrid, mui acid) v mt
mui kim (natri bicarbonat, natri carbonat, kali carbonat, kali bicarbonat, natri glycin
carbonat...). Trong mi trng nc, hai thnh phn ny tham gia phn ng ha hc,
gii phng ra kh CO2, ph v cu trc vin gip vin r rt nhanh. Trc khi s dng,
ch cn ha tan vin vo mt cc nc, vin s r v ho tan nhanh trong vng v i pht
nn rt thch hp cho nhng bnh nhn kh nut, ng thi lm gim kch ng d dy.
H si bt c ng dng nhiu trong cc ch phm paracetamol vin nn hay
cm si bt lu hnh trn th trng (Efferalgan) v cc ch phm vitamin C,
multivitamin... u im ca vin si bt l thch hp vi nhng ngi kh nut vin
nn, lm gim kch ng nim mc ca mt s dc cht do c pha long trc khi
ung, lm tng sinh kh dng ca thuc. Mt khc, kh CO2 to ra c tc dng che du
mi v kh chu ca mt s dc cht, kch thch nhu ng rut, lm gim thi gian
lu thuc d dy nn lm tng hp thu dc cht.
Hn ch ca ch phm si bt l n nh thp do tc ng ca nhit v
m nn phi c bo ch trong iu kin mi trng kh hu c kim sot, c bit l
m tng i < 40% (l tng l 25%) v phi ng gi trong bao b c kh nng
chng m cao, t tin. Nu nhit v m cao, phn ng si bt c th xy ra
ngay trong qu trnh bo ch.
Gn y, cc nghin cu s dng t dc si ni c quan tm nhiu. Thay v
s dng h si bt, vin si ni ch s dng thnh phn mui carbonat kim loi kim.
Khi vo ng tiu ha, acid dch v l tc nhn gy si ph v cu trc vin. K
thut ny lm tng n nh ca vin so vi vin ho tan si bt v gim c nguy
c xy ra phn ng si bt trong qu trnh bo ch v bo qun. Nhiu nghin cu s
dng t dc si ni cho vin nn paracetamol thu c nhng kt qu rt kh quan.
Trn th gii c mt s ch phm u tin ca dng bo ch ny nh Panadol
actifast, Panodil Zapp vi dc cht paracetamol [57],[80].
1.1.3.4. Phng php ng kh
ng kh l qu trnh loi dung mi ra khi dung dch, hn dch hoc nh
tng trng thi ng lnh. Qu trnh ng kh to ra cu trc v nh hnh, vin nh

10

v xp, lm tng tc ho tan. Ton b qu trnh ng kh c thc hin nhit

thp, do hn ch c nh hng bt li n n nh ca thuc. Khi bo qun
iu kin kh ro, dng thuc ng kh t gp phi vn v n nh. Tuy nhin,
phng php ng kh c chi ph sn xut tng i cao v sn phm km n nh
di tc ng ca nhit v m.
K thut bo ch vin ng kh c nghin cu p dng cho mt s dc
cht. Ahmed I. S. v cng s bo ch thnh cng vin ketoprofen tan nhanh trong
ming. Th in vitro, tan ca ketoprofen t vin ng kh cao gp 3 ln, tc

ha tan ban u cao gp 10 ln so vi vin thng thng. Ketoprofen dng bo

ch ny trong vng 5 pht ho tan c 95% cn vin thng thng trong 60
pht ch ho tan c 45% do ketoprofen chuyn trng thi kt tinh thnh dng
v nh hnh v kch thc tiu phn gim. So snh in vivo, tc hp thu thuc t
vin ng kh cao hn vin thng thng (Cmax cao hn 50% v Tmax sm hn 15
pht) trong khi mc hp thu cng cao hn. Sinh kh dng tng i bng 168%
so vi vin i chiu [12].
Trong k thut b o ch vin Zydis, dc cht c ho tan hoc phn tn vo
dung dch nc ca cc t dc to cu trc (hai t dc to cu trc vin thng dng
nht l gelatin v manitol, mt s t dc to cu trc khc cng c s dng tu
thuc vo tnh cht ca dc cht). Dung dch hoc hn dch sau c chuyn vo
khoang v ri lm ng lnh. Dung mi trng thi ng lnh c loi i, to ra cu
trc xp. Vin Zydis c th r m trn 65%, do vin s hng ngay nu bao b b
rch, h. Sn phm thu c nh v d v nn mt lp mng c bit c s dng
ng gi [57].
1.1.3.5. Phng php khun
Bo ch vin bng phng php khun c hai cch: dng dung mi hoc s
dng nhit. Phng php dung mi lm m hn hp dc cht v t dc bng cc
hydro alcol (thng l ethanol), sau khi bt m c khun to thnh vin.
Dung mi c loi trong qu trnh lm kh vin. Vin bo ch theo cch ny khng
phi chu lc nn nn c cu trc xp, d b thm t v do vy, ho tan nhanh hn.

11

Phng php dng nhit bo ch mt hn dch bao gm dc cht, thch v ng

(manitol hoc lactose). Hn dch to thnh c rt vo v khun. Vin s rn li nh
thnh phn thch nhit 30oC trong iu kin chn khng.
Mt phng php khun khc ging nh ng kh nhng lm kh vin
iu kin p sut thng (non-vacuum lyophilization). Vin nn khun c
Pebley v CS bo ch thnh cng bng cch cho bay hi dung mi t hn hp ng
kh bao gm: mt loi gm, mt loi bt ng (dextrose, lactose, maltose, manitol
hoc maltodextrin) v dung mi [74].
Bi v CS. s dng lactose c kch thc ht khc nhau phi hp vi dc
cht nho m v p thnh vin di lc nn thp. Vin to ra c lm kh trong l
tun hon kh. bn c hc v thi gian r ca vin ph thuc vo lng cu ni rn
gia cc ht lactose. Bng cch ti u cc thng s nh lc p, kch thc ht lactose
v m ca ht, l nhng thng s c th nh hng n s hnh thnh cu ni rn,
c th to ra vin c cng trn 0,5 Mpa v thi gian r di 15 giy [19].
bn c hc v r ca vin khun c th c ci thin bng cch s
dng cc thit b c bit nhng cn u t ln v trang thit b. So vi phng php
ng kh, bo ch vin theo phng php khun n gin hn, d nng c l vo
sn xut, tuy nhin thi gian r ca vin li ko di hn [16].
1.1.3.6. Phng php thng hoa
Mt trong nhng cha kho to ra vin r nhanh l s tn ti ca cu trc xp
bn trong vin. Dng vin quy c thng kh r nhanh do xp thp. Cc t dc
rn d bay hi (amoni bicarbonat, amoni carbonat, acid benzoic, camphor, naphthalen,
anhydrid phthalic, ure v urethan) c phi hp vi dc cht v t dc ri em to
ht hoc dp thng thnh vin, sau c loi i nh qu trnh thng hoa, to ra vin
c cu trc xp.
Vin salbutamol tan trong ming c Suresh v CS bo ch bng phng
php xt ht t s dng t dc thng hoa l camphor v amoni bicarbonat. Vin sau
khi dp c sy 50oC lm bay hi cc t dc thng hoa n khi lng khng
i. Thi gian r ca vin thnh phm khng qu 40 giy [95].

12

Ht cha nimesulid, camphor, crospovidone v lactose c bo ch bng

phng php st ht t Camphor thng hoa qua qu trnh lm kh ht trong iu kin
chn khng. Vin sau khi bo ch c xp cao (khong 30%) v ho tan nhanh sau
15 giy trong nc bt [60].
Vin ho tan trong ming fenofibrat cng c Kumar R. v CS bo ch thnh
cng bng cch p dng k thut thng hoa. Vi t l camphor 12,5% khi lng, vin
to thnh d bo ch theo phng php dp thng hay st ht t u c tc ho tan
dc cht nhanh hn r rt so vi mu vin thng thng v r trong vng 20 -24 giy
[63].
1.1.3.7. Phng php to ht rn lng
Dc cht t tan c phn tn trong t dc lng khng bay hi ri trn vi
hn hp cht mang v cht bao. Hn hp thu c c th em dp thng hoc to ht
ri dp thnh vin.
T dc lng s dng trong k thut to ht rn-lng phi khng c hi, khng
bay hi. PEG 200, PEG 400 v Tween 80 l nhng polyme thn nc thng c cc
nh nghin cu la chn lm t dc lng cho cc vin gii phng nhanh. T l thng
thng l khong 1:1, 1:2 hoc 1:4 (dc cht : t dc lng).
Cc hn hp cht mang/cht bao thng dng l Eudragit hoc cellulose vi tinh
th vi silica hoc HPMC vi t l 20:1 hoc 15:1. m bo tnh trn chy v chu
nn ca hn hp bt em dp vin, lng cht mang v cht bao thng chim t l ln
v c c trng bi h s t dc lng (Lf) c tnh theo cng thc sau:

L
Trong :

W
Q

(1)

W l khi lng ca dch lng thuc (thuc + t dc lng)

Q l lng cht mang.

K thut ny thng ch p dng vi vin c hm lng dc cht thp v cn

phi thm lng cht mang ln. i vi cc thuc cn c hm lng dc cht cao
hn, cc nh khoa hc nghin cu gim t l cht mang bng cch hoc la chn
cc t dc lng c nht cao hoc thm cc cht h tr nhm tng nht ca t

13

dc lng. Khi nghin cu mt s h rn lng ca naproxen, Tiong N. nhn thy t

dc lng c nht cng cao th h s Lf cng ln. Lf thp (0,168) vi t dc lng
PEG 400 nhng c th ln ti 0,9 khi s dng Synperonic lm t dc lng [91].
Javadzadeh v CS ch to h rn lng ca carbamazepin bng cch ho tan
carbamazepin vo mt dung mi thn nc ri hp ph dung dch ln b mt silica.
lm gim lng cht mang, ngi ta cho thm mt s cht nh PVP K30, HPMC v
PEG 35000 vi t l 10% so vi lng cht mang. Kt qu l h s Lf tng t 0,25 ln
0,47, gim ng k lng cht mang. H rn lng cha PVP ho tan nhanh hn ng
k so vi ht compact ch to theo phng php dp thng [53].
Tc v mc ho tan ca cc dc cht t tan nh piroxicam [52],
carbamazepin [84], propranolol [54] v indomethacin [109] c ci thin r rt
bng cch ng dng k thut to ht rn lng.
1.1.3.8. K thut Ko bng
Cc nghin cu ca hng Fuisz Technologies to ra ct Shearform (ging nh
ko bng) c cha bt ng bng phng php x l nhit nhanh. Ct Shearform c
thnh phn l cc loi ng (thng dng saccarose, sorbitol v xylitol) c a vo
mt my quay trn c bit ly tm v gia nhit ng thi, tc quay trn khong
3000 4000 vng/pht v nhit khong 180 250oC. Khi bt chy ra u
quay trn c kt tinh mt phn nh cc cht lm tng hoc thay i kt tinh (thng
dng cht din hot) to ra dng si c kh nng trn chy tt. Si c trn vi cc
thnh phn khc ri dp vin bng thit b quy c, to ra vin r nhanh trong vng 30
giy [18]. K thut ko bng c th p dng c vi nhng thuc c hm lng dc
cht ln. Tuy nhin, hn ch ca phng php ny l i hi nhit cao trong qui
trnh bo ch.
1.1.3.9. K thut in phun ba chiu (Three-dimensional Printing, 3DP)
K thut in phun ba chiu (3DP) l mt k thut mi, c kh nng to thnh
nhng lp c bit rt nhanh t dc cht v dung dch t dc dnh. Vin nn c
bo ch bng k thut ny c c im l xp, lin kt lng lo nn nhanh chng b r
v gii phng dc cht khi tip xc vi nc. Da trn m hnh thit k c h tr
bi phn mm my tnh, vin nn gii phng nhanh acetaminophen c bo ch t

14

ng bng h thng 3DP. Vin t cng 54,5 N/cm2 v ch mt 0,92% khi lng
khi th b ca vin. r ca vin l 21,8 giy v kt qu th nghim ho tan cho
thy 97,7% acetaminophen c ho tan sau 2 pht [111].
1.1.3.10. Phng php x l sau khi dp vin
X l m
Nghin cu cho thy khi mt ng v nh hnh c x l m ri lm kh s
chuyn thnh dng tinh th. S bin i ny lm tng cng ca vin [70].
Liu v CS. ch to vin ho tan nhanh bng cch x l m. Qu trnh gm 4
bc: (1) dung dch polyme tan trong nc c dng lm t dc dnh to ht cha
dc cht v t dc; (2) ht c dp thnh vin; (3) vin c lm m m 50100%; (4) lm kh vin. cng ca vin thu c khong 0,5-12,0 kP v thi gian r
in vivo khong 1-40 giy [66].
X l nhit
Yoshio bo ch vin r nhanh bng phng php chuyn pha alcol ng.
Hn hp mt alcol ng c im chy cao l erythritol (im chy: 122oC) v mt
alcol ng c im chy thp l xylitol (im chy: 93 95oC) c dp vin di
lc nn thp. Vin sau khi bo ch c sy trong l vi sng 93oC trong 15 pht, sau
c gi iu kin nhit 25oC v m 65% trong 4 gi. Vin nn thu c c
cng gp 4 ln so vi vin trc khi x l nhit v thi gian r di 30 giy. iu
ny c gii thch l do khi sy vin im chy ca xylitol, xylitol chuyn t pha
rn sang pha lng v bao quanh cc ht erythritol. Khi iu kin nhit thp,
xylitol ha rn tr li to ra lin kt bn vng hn trn b mt ht erythritol, lm tng
cng ca vin. Mt khc, xylitol tan tt trong nc nn gip vin r nhanh [110].
Lagoviyer v CS. th nghim lm tng cng ca vin bng cch bo ch vin
s dng t dc dnh l polyme tan trong nc nh PEG (nhit nng chy t 5090oC) vi hm lng 0,5-25% khi lng vin. Vin c sy 50-100oC trong 3-45
pht lm tan chy thnh phn t dc dnh ri ngui n nhit mi trng.
Vin to ra c bn c hc tt v r nhanh trong 3-60 giy [64].

15

1.1.4. Phng php nh gi cht lng vin nn gii phng nhanh

Vin nn gii phng nhanh phi m bo t cc ch tiu ca vin nn qui c,
ng thi phi p ng c mt s php th sau:

Thi gian thm t v ch s hp thu nc

Kh nng thm t lin quan cht ch ti r ca vin. Thi gian thm ngn
chng t vin s r nhanh. Thi gian thm t ca vin c xc nh nh sau: Cho
10 ml nc vo mt ci a petri nh (ng knh 10 cm), vin nn c t cn thn
vo gia a, ghi li thi gian vin r hon ton.
Ch s hp thu nc (water absorption ratio) R c tnh theo cng thc sau :
R = 100 (Wa-Wb) / Wb

(2)

Trong : Wa l khi lng vin sau khi thm t, Wb l khi lng vin trc
khi thm t [73]

Phng php th r vin nn gii phng nhanh rt a dng, tu thuc vo

loi vin gii phng nhanh v c ch r ca vin. i vi vin nn ho tan, vin nn
phn tn trong nc v vin nn phn tn trong ming, r c th theo chuyn
lun vin nn thng thng, vin phi r hon ton trong vng 3 pht. i vi vin si
bt, r c xc nh bng cch th vin vo cc cha 200 ml nc tinh khit 15
25oC, vin phi to ra nhiu bt v thi gian r ca vin c tnh cho ti khi phn
ng si bt kt thc, vin r hoc phn tn hon ton, khng cn ht kt vn v thi
gian r khng c qu 5 pht [4],[22].
Vic p dng cc phng php th r thng thng b hn ch v khng ph
hp vi cc ch phm c thi gian r qu nhanh. Theo nh cc khi nim v vin gii
phng nhanh, mt s yu cu vin nn gii phng nhanh phi r trong vng mt pht,
thc t c nhiu ch phm t r ch trong khong 5 30 giy. Do , phng php
th r p dng cho cc vin r nhanh cn phi c thay i cho thch hp.
Bi Y. v cng s nghin cu phng php th r vin gii phng nhanh
nh sau: vin c t trong dng c gi quay nhng trong 900 ml mi trng nc

16

37oC, quay vi tc 100 vng/pht. r c xc nh l thi gian vin r hon

ton v khuch tn ht ra khi gi [19].
i vi vin tan trong ming, r ca vin c th c th trc tip trn
ngi tnh nguyn. r c xc nh bng gi tr trung bnh thi gian thuc r hon
ton trong ming ca 6 ngi tnh nguyn [87].

Th nghim ho tan

Hu ht cc vin gii phng nhanh u c xp cao v chu lc km. Nhm

t tng quan sinh hc, th nghim ho tan p dng cho dng vin ho tan nhanh
thng c thc hin theo chuyn lun ca USP vi mi trng ho tan l acid HCl
0,1N hay cc h m pH 4,5 v 6,8. Thit b cnh khuy thch hp nht v thng
c la chn nhiu hn so vi thit b gi quay bi c tnh c l ca vin nn. Tc
khuy thng c la chn trong khong 25 75 vng/pht. Thc t cho thy
dng c cnh khuy vi tc 50 rpm l thch hp v c la chn ph bin nht.
Khi vin ho tan qu nhanh, c th gim tc khuy v tc khuy c th tng ln
khi th ho tan nhng vin c khi lng trn 1 gam [59].

Nghin cu tnh ht m

Nghin cu hp ph hi m cn c tin hnh xc nh r tnh n nh ca

thuc bi c mt s t dc v dc cht c tnh ht m. Mi vin thuc c t
pha trn calci clorid trong t sy 37oC trong 24 gi. Sau , vin c cn ri t
trong iu kin m cao (RH 75%) v nhit phng trong hai tun. Cc vin th
c cn ri tnh t l % tng khi lng vin [87].

Nghin cu sinh kh dng in vivo

Nghin cu in vivo vin gii phng nhanh nhm tm hiu tc ng ca thuc ra

sao khi qua ming v thc qun, nghin cu dc ng hc, hiu qu iu tr v kh
nng chp nhn c ca dng bo ch. Vin Zydis t hiu qu iu tr tt v d s
dng cho bnh nhn, c bit vi i tng tr em hay bnh nhn cn gim au nhanh.
Tt c cc thuc bo ch theo k thut Zydis u c hp thu ngay t khoang ming
v mng nhy thc qun, do sinh kh dng ca thuc tng ng thi gim c cc

17

tc dng ph. iu ny c bit c ngha vi nhng dc cht b chuyn ho qua gan

ln u .
Vin gii phng nhanh cng c chng minh l c ci thin v c tnh
dc ng hc so vi cc dng bo ch rn phn liu khc. Trng hp vin
acetaminophen Flashtab t tc hp thu nhanh hn r rt so vi vin thng thng
mc d c sinh kh dng tng ng [24]. Vin gii phng nhanh Panadol Actifast
c nghin cu bng phng php dng cht pht quang. Kt qu nghin cu cho
thy vin Panadol Actifast lm tng tc tho rng d dy c trong hai trng hp
NTN nhn n hoc n no, nhanh hn nhiu so vi vin Panadol thng. cng chnh
l yu t gip vin Panadol Actifast t c nng nh cao v nhanh hn [58]

cng ca vin

cng ca vin nn c xc nh l lc gy v vin p theo ng knh

(vin trn) hoc chiu di (vin hnh tr). Vin nn gii phng nhanh thng xp v
km chu lc. Tuy nhin, thc t i hi vin phi m bo cng nht nh trnh
b st m, b mi mn hay v trong qu trnh vn chuyn v bo qun thuc [87].
1.2. Tng quan v paracetamol
1.2.1. Cng thc, tnh cht
- Cng thc ho hc

Cng thc phn t:

C8H9NO2

Phn t lng:

151,2

Tn khoa hc:

N- (4-hydroxyphenyl) acetamid

Tn khc:

Acetaminophen

- Tnh cht vt l

18

Paracetamol tn ti di dng bt kt tinh mu trng, khng mi, v hi ng.

Paracetamol rt km chu nn. Nhit nng chy nm trong khong 168-172oC.
Dung dch bo ho ca paracetamol trong nc c pH khong 5,3-6,8. tan ca
paracetamol: 1/70 trong nc lnh 25oC, 1/20 trong nc nng. Paracetamol tan trong
methanol, dimethylformmamid, ethylen diclorid, ethyl acetat, PEG v trong dung dch
kim, t tan trong ete v cloroform [3].
- Tnh cht ho hc
Paracetamol th hin tnh cht ho hc ca nhn thm v nhm hydroxy
phenol. Paracetamol cn th hin tnh cht c trng ca nhm chc amid l phn ng
thu phn khi c mt xc tc acid hay base to ra 4-aminophenol (4-AP). Cht ny d
b oxy ho tip to thnh p-benzoquinonimin c mu. Gii hn 4-AP c xc nh
bng HPLC, sc k lp mng hay bng php o nitrit [3].
Paracetamol c th nh lng bng php o nitrit hoc o hp th t ngoi
trong mi trng methanol hoc mi trng kim. Phng php nh lng
paracetamol bng HPLC cng c s dng ph bin nh lng paracetamol trong
ch phm v dch sinh hc cng nh phn tch v nh lng cc tp cht phn hu
ca paracetamol [98].
- n nh
n nh ca paracetamol trong nc ch yu lin quan n phn ng thu
phn khi c mt xc tc acid hay base. Tc thu phn ph thuc trc tip vo nng
paracetamol v khng ph thuc nng ion. Trong dung dch, paracetamol n
nh nht pH t 5-7. nh sng, nhit v cc cht oxy ho cng l tc nhn thc
y phn ng thu phn paracetamol. Paracetamol t hp thu hi m trong khng kh,
k c khi m ln ti 90% 25oC [105].
1.2.2. Tc dng dc l
Paracetamol l thuc gim au v h st hu hiu, nhng khng c tc dng
chng vim nh cc thuc gim au chng vim khng steroid khc. Paracetamol l
thuc gim au tc ng ngoi vi do c ch sinh tng hp prostaglandin h thn kinh
trung ng. Paracetamol lm gim thn nhit ca ngi bnh st, nhng him khi lm

19

gim thn nhit ngi bnh thng. Thuc tc ng ln vng di i gy h nhit,

to nhit tng do gin mch v tng lu lng mu ngoi bin [5].
1.2.3. Dc ng hc
Paracetamol c th c s dng di dng ung, tim hoc t trc trng.
liu bnh thng, paracetamol dung np tt theo ng ung, sinh kh dng tuyt i
trong khong 62 89% [56]. Nng nh trong huyt tng t trong vng 10 n
60 pht sau khi ung. Thuc phn b nhanh v ng u trong phn ln cc m ca c
th. Khong 25% paracetamol trong mu kt hp vi protein huyt tng. Paracetamol
b chuyn ha rt nhanh ch yu qua gan thnh sn phm lin hp vi glucuronid v
sulphat (paracetamol glucuronid v paracetamol sulfat). Mt phn nh b N-hydroxyl
ho bi cytochrom P450 to nn N-acetyl-benzoquinonimin (NAPQI). Paracetamol thi
tr ch yu qua nc tiu. Thi gian bn thi ca paracetamol l 1,25 - 3gi [5].
Khong nng thuc trong huyt tng t c hiu qu tc dng gim au
l 5 20 g/ml v h st l 10 20 g/ml. Khi dng qu liu paracetamol (trn 159
mg/kg cn nng hoc 10 g), NAPQI tch t gy ph hu t bo gan, dn n suy gan
nng v c th gy hoi t ng thn. Mt s nghin cu cho thy, ng c gan bt u
khi nng paracetamol trong huyt tng ln ti 120 g/ml sau 4 gi ung thuc v
gan b ph hu nhanh chng nu nng thuc ti 200 g/ml [79].
Cc thng s dc ng hc ca paracetamol rt c ngha trong vic la chn
phng php nh lng paracetamol phc v nghin cu v cng tc iu tr. Trng
hp chn on ng c cp, phng php la chn phi c gii hn nh lng cao.
Ngc li, phng php c la chn trong cc nghin cu dc ng hc yu cu
phi c gii hn nh lng thp ng thi c khong nng tuyn tnh thch hp
c th hoch nh c chng trnh ly mu mu
1.2.4. Ch nh, chng ch nh, tc dng khng mong mun
- Ch nh v liu dng
Paracetamol c s dng rng ri trong iu tr cc chng st v au nh hoc
au va nh: au u, au rng, au dy thn kinh, au do chn thng, thp khp...
- Ngi ln: 200-500 mg/ln x 2-3 ln/ngy. Ti a: 1g/ln; 3g/24 gi.

20

- Tr em: 60-325 mg/ln x 3-4 ln/ngy tu theo tui [5]

1.2.5. Mt s nghin cu v vin paracetamol gii phng nhanh

Nghin cu bo ch v dc ng hc

- Trn th gii:
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. Hong Wen v CS. 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 tng ln ng k [48]. Nghin cu ca Abdelbary
v CS s dng t dc dnh thn nc (Superpolystate, PEG-6-stearate) va gip vin
paracetamol r nhanh (40 2 giy), va m bo cng ca vin (47,9 2,5 N) [9].
Mizumoto v CS bo ch vin nn r nhanh vi paracetamol lm dc cht.
Tc gi s dng hai loi bt ng: mt loi c kh nng chu nn tt nhng r chm
(mannitol, lactose) c s dng di dng dung dch cha mm tinh th lm t dc
dnh, mt loi c kh nng chu nn km nhng r nhanh (maltose). Vin sau khi dp
c c cng thp (1,7 kp) nhng thi gian r rt nhanh (khong 20 giy). Khi
trong iu kin nhit 25oC v m 70% trong 18 gi, cng ca vin tng ln
5,8 kP trong khi thi gian r vn khng qu 20 giy [70].
Cilurzo v CS nghin cu v nh gi tnh cht ca mng ho tan nhanh
cha dc cht paracetamol bo ch bng k thut n nng chy s dng ct
maltodextrin. Trong mi trng m phosphat pH 5,8, hn 50% lng paracetamol
c ho tan sau 5 pht v ho tan hon ton sau 10 pht. Kt qu nh gi in vivo cho
thy mng paracetamol r trong vng 1 pht. Cc gi tr AUC v Cmax ca mng ny
u cao hn so vi dng siro [29].
ho tan ca vin paracetamol (hm lng 500 mg) do hng
GlaxoSmithKline sn xut, s dng natri bicarbonat lm t dc si ni c
Rostami-Hodjegan v CS. so snh vi cc dng vin paracetamol quy c khc. Kt
qu cho thy vin cha natri bicarbonat ho tan nhanh hn hn so vi vin
paracetamol quy c v t ph thuc vo tc khuy. ng thi, sinh kh dng ca

21

vin nghin cu cng cao hn vin quy c, th hin gi tr Tmax ngn hn (45 pht
so vi 120 pht nhm ngi n v 25 pht so vi 55 pht nhm ngi nhn n) v
Cmax cao hn (24 g/ml so vi 18 g/ml) [60]. Kt qu tng t cng thu c trong
cc nghin cu ca Kelly [58] v Ibnez [49].
Grattan v CS so snh sinh kh dng ca paracetamol t hai ch phm vin nn
paracetamol (hm lng 500 mg) quy c v ba ch phm paracetamol (500 mg) ln
lt cha 400 mg , 630 mg v 375 mg natri bicarbonat. Kt qu cho thy cng thc
cha 630 mg natri bicarbonat c tc hp thu paracetamol nhanh hn so vi c vin
nn quy c v vin paracetamol si bt. Cng thc cha 400 mg natri bicarbonat
cng gip tng tc hp thu paracetamol so vi vin quy c, nhng khng c s
khc bit so vi vin paracetamol si bt. Cng thc cha 375 mg natri bicarbonat c
tc hp thu dc cht tng ng so vi vin nn quy c [71], [83]. Tc hp
thu dc cht t cc mu vin cha natri bicarbonat tng ln c th do tng tc tho
rng d dy, gip dc cht di chuyn nhanh hn ti v tr hp thu l rut non [40].
Burnett v CS s dng vin paracetamol (hm lng 500 mg) cha 630 mg
natri bicarbonat gim au cho bnh nhn vim hng cp v nhn thy tc dng
gim au t c khong 15 pht sau khi ung. Khng c s khc bit khi ung lc
no v i. Tc dng gim au sau 6 gi tt hn hn so vi nhm chng [25].
Vi liu ung mt vin nn 500 mg, paracetamol t nng nh trong huyt
tng Cmax = 9,47 4,18 g/ml sau thi gian Tmax = 35,6 27,7 pht [82]. Grattan v
CS nghin cu sinh kh dng trn hai bit dc vin nn paracetamol vi liu 1000
mg paracetamol, kt qu cho thy Tmax = 110 28 pht v Cmax = 20,4 3,2 g/ml i
vi vin Paralen, cn Panadol th cho Cmax = 17,02 6,04 g/ml sau thi gian Tmax
khong 35 77 pht [40]
Gn y, mt nghin cu dc ng hc paracetamol trn ngi Nht cng
cho kt qu tng t (Tmax = 0,5 0,1 gi v Cmax = 17,7 3,3 g/ml) [85].
- Trong nc:
L nh Quang v CS nghin cu bo ch vin nn gii phng nhanh cha
paracetamol v ibuprofen. Cc tc gi tm cch ci thin tan ca nguyn liu

22

bng cch phn tn paracetamol trong propylen glycol 25% v ng kt ta ibuprofen

vi PEG v sorbitol, sau s dng nguyn liu c tc ng bo ch vin
nn. Bng cch s dng phi hp cc t dc siu r l natri starch glycolat v
croscarmellose, cc tc gi bo ch c vin nn gii phng 93,9% lng
paracetamol v 86,5% lng ibuprofen sau 3 pht [8].
Tuy nhin, cc nghin cu trn mi ch dng li kho st bc u, cha ng
dng c a vo sn xut v lu thng trn th trng. Cho ti nay, Vit Nam
cng cha c nghin cu no v dc ng hc ca paracetamol.
1.2.6. Phng php nh lng paracetamol
1.2.6.1. nh lng paracetamol nguyn liu v ch phm
Phng php chun
Paracetamol c nh lng bng phng php chun trong nhiu nm
trc khi ra i ca cc phng php o quang hay HPLC. Cho ti nay, hu ht cc
dc in vn hng dn qui trnh nh lng paracetamol nguyn liu theo phng
php chun bng dung dch amoni ceri (IV) sulfat vi thuc th feroin . Nguyn tc
ca phng php l thu phn paracetamol trong mi trng acid sulfuric to paminophenol, sn phm thu phn ny c chun bng dung dch amoni ceri (IV)
sulfat vi ch th mu l feroin. Lng paracetamol c tnh cn c vo th tch dung
dch amoni ceri (IV) sulfat s dng.
Phng php chun nu trn cng c p dng nh lng paracetamol
trong chuyn lun vin n paracetamol ghi trong DVN IV, BP 2009.
Phng php so mu
Nhiu phng php so mu nh lng paracetamol c nghin cu,
thng da trn phn ng thu phn paracetamol thnh p-aminophenol, cht ny s
chuyn thnh hp cht c mu qua mt phn ng thch hp. C in l cc phng
php dng phn ng to indophenol, to base Shiff, nitro ho ri to phc chelat vi
cobalt (II) v ng (II), oxy ho, phn ng diazo ho hay phn ng thay i pH [33].
Tuy nhin, hu ht cc phng php ny u phc tp, mt thi gian do phi thc hin

23

bc thu phn paracetamol to sn phm p-aminophenol bng cch un nng vi

acid v c trong khong 2 gi, sau p dng cc bc o tiu chun vi amin thm.
Verma v CS nghin cu ra phng php o nhanh v n gin hn, da trn
phn ng paracetamol vi 2-iodylbenzoat trong mi trng acid long, ch trong thi
gian cha y mt pht, phn ng to ra hp cht mu vng cam c hp thu cc i
444 nm [103].
Cekic S.D v CS s dng kim thu phn paracetamol thnh p-aminophenol
v oxy ho tip thnh benzoquinoneimin, cht ny phn ng vi tiron to phc hp
indophenol xanh l cy. Phc hp thu c s bn vng nu thm dung dch ng ho
tr II v c hp th cc i bc sng 601 nm trong mi trng kim [27].
Gn y, H. Filik v CS xut mt thuc th mi c tn khoa hc l 2,2-(1,4phenylenedivinylene)bis-8- hydroxyquinoline, cht ny phn ng vi p-aminophenol
to thnh phc hp c mu xanh lam [36]. Cc phng php so mu phc tp, mang
tnh th cng v chnh xc thng khng cao. Nhc im ca cc phng php
ny l phn ng thu phn i hi nhit cao. Phn ng phi c b tr trong mt
bnh lm nng hoc l vi sng. Cc cht sau khi phn ng li phi qua mt b phn
lm lnh v nhit phng.
Phng php so mu nh lng paracetamol rt phong ph. Tuy nhin kh
nng ng dng cha cao bi qui trnh thc hin phc tp, i hi phi c thuc th
chun v chnh xc khng cao. Hn na, phng php so mu ch p dng c
vi cc mu n thnh phn.

Phng php quang ph hp th t ngoi

Phng php quang ph hp th t ngoi da trn kh nng hp th tia t ngoi

ca paracetamol trong cc dung dch nc (trung tnh, kim hay acid) hay trong cc
dung mi hu c. Hp th cc i ca paracetamol ti cc bc sng khc nhau tu
thuc vo dung mi, thng giao ng trong khong 200 300 nm. nh lng
paracetamol bng phng php o hp th t ngoi trc tip c a vo Dc
in. Nht XV hng dn nh lng paracetamol nguyn liu bng phng php o
quang dung dch paracetamol trong nc bc sng 244 nm [51]. Dc in Vit

24

Nam IV v BP 2009 hng dn nh lng paracetamol trong vin nn bng cch o

quang ph hp th ca dung dch paracetamol trong mi trng kim NaOH 0,01M
bc sng 257 nm. Paracetamol c ho tan trong NaOH 0,1 M ri pha long vi
nc c dung dch c nng khong 75 g/ml v mu trng l dung dch
NaOH 0,01M [3], [22].
Phng php quang ph hp th t ngoi n gin v d thc hin, c ng
dng rng ri nh lng paracetamol trong nguyn liu cng nh cc ch phm
n cht. o quang ph t ngoi cng l k thut ph bin nht c s dng kt hp
vi cc k thut tch chit khc nh lng paracetamol trong cc ch phm a
thnh phn cng nh trong cc mu dch sinh hc.
Phng php quang ph hunh quang
Bn cht paracetamol trong dung dch nc l khng pht quang. Tuy nhin,
khi cho phn ng vi mt s thuc th oxy ho s to thnh dn xut c kh nng pht
quang. Trn c s , paracetamol c nh lng bng phng php o quang
ph hunh quang vi gii hn nh lng thp. Ce(IV) c s dng lm thuc th
oxy ho v nh lng paracetamol thng qua xc nh lng Ce(II) to thnh t
Ce(IV). Cc thuc th oxy ho khc thng c s dng l: fluorescamin [13],
dansyl chloride , 1-Nitroso-2-naphthol, v natri hexacyano Fe(III) [76].
Gn y, mt s th nghim ban u cho thy paracetamol c pht quang th
rn. iu ny rt thun li, thc t l paracetamol c th nh lng trc tip bng
phng php o quang ph hunh quang trong khong bc sng 333 382 nm
dng bt ln vi cc t dc (lactose, tinh bt, PVP, talc hay acid stearic) m khng
cn phi qua bt k phn ng ho hc no [31].
Phng php quang ho
Cc php phn tch quang ho o quang ph nh sng pht ra bng phn ng
ho hc ca cht phn tch vi thuc th ho pht quang. K thut quang ho c
bit n nhiu l cc phn ng luminol, peroxyoxalat v lucigenin v ch yu p dng
vi cc mu phn tch l hp cht v c nn phm vi ng dng trong dc phm rt
hn ch. Trong thi gian gn y c mt s dc phm nh lng c bng k

25

thut quang ho dng chy lin tc v rt c trin vng. Alapont A.G. v CS cng
b phng php nh lng gin tip paracetamol s dng h luminol-H2O2-Fe(CN)6
3

. Thuc th tris(2,2-bipyridyl)Ru(II) cng c s dng da trn c s phn ng

oxy ho thnh phc hp Ru(III) [13]. Tuy nhin, gii hn pht hin ca nhng phng
php ny khng cao (1,0 and 2,5 g/ml) v c nhiu n lc trong nghin cu nhm
tng nhy. Kt qu l s ra i ca mt phng php nh lng paracetamol n
gin, da trn phn ng ho pht quang ca paracetamol trong h luminol-KMnO4,
cng nh sng pht ra c khuych i nh s c mt ca Mn(II) [31].
Phng php sc k
Sc k l k thut phn tch khai thc s khc bit trong phn b gia pha ng
v pha tnh tch cc thnh phn trong hn hp. Cc thnh phn ca hn hp c th
tng tc vi pha tnh da trn in tch, tan tng i v tnh hp ph. K thut
sc k c ng dng nhiu nht trong phn tch nh lng hin nay l sc k lng
hiu nng cao (HPLC).
HPLC c la chn trong nh lng paracetamol trong cc ch phm, c
bit l cc ch phm phi hp do c tnh c hiu cao v kh nng phn tch cc cht
rt tt. Tt c cc chuyn lun v cc ch phm phi hp trong cc dc in u
hng dn nh lng paracetamol bng phng php HPLC. Dc in M 30 c ti
22 chuyn lun cc ch phm paracetamol bao gm cc dng bo ch n hoc a
thnh phn, tt c u qui nh p dng HPLC trong nh lng paracetamol [100].
Phng php in di mao qun
Nguyn l ca php phn tch in di mao qun (CE) l da trn kh nng di
chuyn ca cc ht mang in tch trong mt ng mao qun di tc dng ca in
trng. CE l mt k thut phn tch mi, cho php phn tch cc phn t sinh hc m
HPLC khng thc hin c.
Paracetamol cng c nh lng phn tch ng thi vi cc dc cht khc
nh pseudoephedrin v dextromethorphan cng c trong cc ch phm iu tr cm
cm. CE c thc hin trong dung dch m natri phosphat 20 mmol/l (pH 7), ba

26

thnh phn c phn tch trong vng 5 pht v c o bc sng UV 200 nm

[86].
1.2.6.2. nh lng paracetamol trong dch sinh hc
Paracetamol c hp thu nhanh sau khi ung v c phn b khp hu ht
cc dch trong c th. Hai sn phm chuyn ho ch yu l dng sulfat v glucuronat.
Khong 90% liu iu tr c thi tr qua ng nc tiu trong vng 24 gi, ch c
1 - 4% c thi tr di dng khng i.
Cc phng php phn tch c dng ph bin nh lng paracetamol
trong dch sinh hc l phng php sc k lng hiu nng cao. HPLC c kh nng pht
hin dc cht ln trong cc cht ni sinh c trong dch sinh hc.
Dch sinh hc thng c ly lm mu phn tch nh lng thuc a phn l
huyt tng, huyt thanh hoc nc tiu c ln rt nhiu tp cht hu c. V vy, mu
phi c x l trc khi em nh lng.

X l mu

Mc ch ca bc x l mu gm gii phng thuc khi dng lin hp vi

protein huyt tng v tch thuc khi protein v cc cht cn tr c trong dch sinh
hc.
Acid hoc kim c thng c s dng tch thuc ra khi dng lin hp
vi protein. Mt s khng bn trong mi trng kim hoc acid c th c thu phn
bng cc enzym thch hp.
+ X l mu bng ta protein
Protein trong dch sinh hc c th c ta bng mt s acid nh acid
tricloacetic, acid percloric, acid tungstic hoc bng dung mi hu c nh: methanol,
acetonitril

hoc s dng bin php siu lc. Sau khi ta protein, hn hp c ly tm

tc cao (khong 8.000 12.000 vng/pht), gn ly dch trong, lc qua mng lc

0,45 mcm ri tin hnh phn tch.
Phng php x l mu bng ta protein c u im l n gin, d thc hin,
khng i hi nhiu my mc, thit b, tit kim thi gian, chi ph v thng c hiu
sut cao. Tuy nhin, ta protein bng acid mnh c th ph hu cu trc ca mt s

27

dc cht. Phng php ta protein bng dung mi hu c (methanol, acetonitril )

khng ph hp khi nng thuc trong dch sinh hc qu thp cn lm giu v lng
dung mi hu c s dng thng ln gp nhiu ln so vi th tch mu dn n nng
dc cht b pha long.
Mt s nh nghin cu x l mu paracetamol trong huyt tng bng
phng php ta protein vi acid percloric [55] vi nng 30% .
Cng trnh nghin cu ca Schwenzer v

Kathryn S. chng minh rng mu

huyt thanh hay huyt tng sau khi c x l bng 1,4 2 ln th tch acetonitril,
propionitrile, tetrahydrofuran hay hn hp ca chng l thu c dch ni trong, p
ng cho vic phn tch cc thuc [69].
+ X l mu bng phng php chit lng

lng

Chit lng lng l phng php tch cc cht t mt hn hp da trn s

phn b ca cht tan trong 2 dung mi khng ng tan vi nhau, thng l nc v
dung mi hu c (c gi l pha nc v pha du). Cht tan s chuyn t dung mi
ny sang dung mi khc cho n khi t trng thi cn bng. chit ht lng dc
cht trong mu, qu trnh chit c th c thc hin hai hoc nhiu ln trn mt mu.
Dch chit s c c ti cn ri pha li bng dung mi thch hp nh lng. u
im ca phng php chit lng lng l d thc hin, chi ph thp. Nng mu
nh lng c th tng ln tu thuc vo lng dung mi pha li mu trc khi nh
lng. Kh khn thng gp khi chit lng lng l qu trnh tch lp i khi din ra
rt chm v km, c hin tng nh ho b mt tip xc. Ngi ta x l bng cch
nhit thp hoc s dng my ly tm. Giai on bay hi dung mi hu c cn c
thit b thi kh nit trnh qu trnh oxy ho dc cht.
+ X l mu bng phng php chit pha rn
Chit pha rn l mt k thut x l mu tin tin, s dng mt pha rn v mt
pha lng tch mt hay nhiu cht cn phn tch t mt dung dch. u im ca
phng php chit pha rn l hiu qu hn so vi chit lng lng, tinh khit ca
dch chit cao, c th chit vi th tch mu nh c 0,5 ml. Chit pha rn gii quyt
c nhiu kh khn m phng php chit lng lng thng gp nh s tch lp
khng hon ton, hiu sut thp, phi s dng nhiu dng c thu tinh t tin, b i

28

lng ln dung mi hu c. Nhc im ca phng php chit pha rn l c gi thnh

cao, cha ph hp vi iu kin thc t cc nc ang pht trin nh Vit Nam.

Phn tch nh lng

Sau khi c x l loi thnh phn protein, c th p dng hu ht cc

phng php nh lng ch phm xc nh paracetamol trong mu phn tch.
- Cc phng php o quang
Mt s phng php so mu cng c nghin cu thnh cng nh
lng paracetamol trong mu huyt tng, huyt thanh v nc tiu. Phng php
phn tch paracetamol trong mu huyt thanh kh ph bin trong th k 19 l da trn
phn ng nitrat ho. Paracetamol c phn ng vi acid nitric to 2-nitro 4acetamidophenol, cht ny trong mi trng kim c ph hp th cc i bc sng
430 nm [21].
Paracetamol cng c nh lng trong mu nc tiu bng phng php
so mu. Mu nc tiu c x l bng cch thu phn bng acid hoc enzym thnh
p-aminophenol, sau cho tc dng vi o-cresol trong mi trng kim thnh dn
xut c mu , o c bc sng 620 nm. Thi gian thc hin qui trnh phn tch
b ko di ch yu bi phn ng thu phn v ln ti 30 pht mi mu. Mt nhc
im na ca phng php ny l nguy c b nhiu do N-acetylcystein (thuc gii c
paracetamol) v c th dn ti kt qu sai hoc m tnh khi phn tch mu nc tiu.
Mc tiu t ra l pht trin cc phng php mi khc phc c hai nhc im
chnh nu trn: thi gian phn ng thu phn v nhiu bi N-acetylcystein [104].
o quang ph hp th t ngoi vn l phng php c s dng ch yu
nh lng paracetamol trong cc mu sau khi c x l.
- Cc phng php sc k
Phng php c a dng nht trong phn tch nng paracetamol trong
huyt tng l HPLC. Bn cnh mt s phng php ch thch hp vi cc ch phm
bo ch th c rt nhiu phng php nh lng paracetamol trong cc dch sinh hc.
Tuy nhin, a s cc phng php l p dng cho mc nng gy c, theo di nng

29

 iu tr. Ch c mt s phng php c nhy c th xc nh c cc

mc nng thp theo yu cu ca cc nghin cu v dc ng hc.
Cc qui trnh nh lng thng i hi t nht 1 ml huyt tng. iu ny
khng thun li i vi cc nghin cu dc ng hc cc ch phm phi hp v i
hi phi ly mt lng mu ln, gy phin phc cho ngi tham gia nghin cu. V
vy, xu hng nghin cu l tm ra nhng k thut c nhy cao v khng tn nhiu
mu.
M.A. Campanero v CS cng b mt phng php sc k lng nhanh v n
gin nh lng paracetamol trong huyt tng. p-Propionamidophenol c s dng
lm cht chun ni. Paracetamol c chit t mu huyt tng bng ethyl acetat. Pha
ng bao gm acetonitril v dung dch KH2PO4 0,005M v pht hin bc sng 242
nm. Phng php c gii hn nh lng di thp (0,05 g/ml) v ch cn 0,1 ml
huyt tng [26].
Mt s phng php HPLC vi detector UV khng ch nh lng c
paracetamol m cn c th nh lng c ng thi mt s thnh phn khc c
trong mu huyt tng nh cc cht chuyn ho ca paracetamol trong c th hoc cc
dc cht khc khi bnh nhn ung thuc hn hp nhiu thnh phn.
- Phng php in di mao qun
CE u vit hn sc l lng bi thi gian phn tch nhanh hn, khng nhim
bi dung mi v chi ph thp hn. CE c ng dng rng ri trong phn tch nh
lng cc thuc. Paracetamol v cc cht chuyn ho ca n trong c th c theo
di bng phng php CE, o c nng paracetamol trong khong 0,5 100g/ml
[20]. Tng t nh vy, paracetamol v cc cht chuyn ho trong mu nc tiu
c nh lng bng h thng CE-UV vi dung dch m borat 50 nM (pH 9,4) [45].
- Phng php phn tch min dch
Phn tch min dch c s dng pht hin hoc nh lng cc cht trong
mu hoc cc mu dch sinh hc da trn phn ng min dch. T nm 1984, Hepler
v CS nghin cu k thut phn tch min dch enzym ng nht v ng dng nh
lng paracetamol trong mu huyt thanh trong khong nng 10 200 g/ml [46].

30

Tip n l phng php phn tch min dch hunh quang (FPIA) ca Koizumi v
CS, nh lng paracetamol trong mu huyt tng [61] .
u im ni bt ca cc phng php phn tch min dch l rt nhanh, d thc
hin, kt qu thu c c c hiu v nhy cao, khng b nhiu bi cc cht
khc v c bit l khng phi x l mu trc khi phn tch. FPIA c th phn tch
paracetamol trong khong nng 15 333 g/ml [32]. Vic ng dng phng php
FPIA nh lng paracetamol trong dch sinh hc thng c tin hnh cc c s
iu tr sn c my sinh ho, phc v cho vic chun on khn cp nhng ca ng c
paracetamol v theo di nng thuc trong mu. Phng php ny khng thch hp
vi cc nghin cu dc ng hc v nhy thp v gi thnh cao.
1.3. Nghin cu sinh kh dng v tng ng sinh hc
1.3.1. nh gi ho tan in vitro
ho tan in vitro nh gi qu trnh ha tan gii phng dc cht t dng
thuc. Cc dc in ca nhiu nc (M, Anh) qui nh th ha tan dc
cht thnh mt tiu chun cht lng ca cc dng thuc rn. Mc d php th ha
tan c m phng mt s iu kin sinh hc nhng vn cn khc xa so vi thc t. V
vy, ho tan in vitro cha phi l SKD thc s do cha nh gi y hiu qu
lm sng ca ch phm. Tuy nhin, ho tan in vitro l cng c quan trng sng
lc, nh hng cho nh gi SKD in vivo gim chi ph nghin cu. ho tan in
vitro ch c dng thay th SKD in vivo trong cc trng hp chng minh c
s tng quan cht gia ho tan in vitro v SKD in vivo.
ho tan in vitro ca thuc c nh gi bng thit b v mi trng thch
hp tu theo tng ch phm bo ch. Vi dng vin nn, th nghim c tin hnh
trn 12 vin, phn trm dc cht ho tan c xc nh bng phng php phn tch
thch hp.
nh gi mc tng ng ho tan in vitro ca thuc th so vi thuc i
chiu c da trn h s ging nhau f2 (similarity factor).

31

 0 .5
n

2
100
f 2 50 log 1 (1 / n ) ( R t Tt )
t 1

(3)

Hai ch phm c th ho tan ging nhau nu f2 nhn gi tr khong 50-100

[30]
1.3.2. nh gi sinh kh dng in vivo v tng ng sinh hc
C nhiu phng php nh gi SKD in vivo v TSH, nhng phng php
dc ng hc l ph bin nht FDA ca M c hng dn c th v cch nh gi
SKD v TSH bng phng php dc ng hc [97].

Thuc i chiu:

Ch phm i chiu tu thuc vo mc ch nghin cu [95],[97].

Nu nh gi SKD, thuc i chiu c th l dung dch, hn dch thuc ung
hoc dung dch thuc tim tnh mch. Cc s liu v nng dc cht trong mu
hoc trong huyt tng hoc tng lng dc cht dng khng bin i thi tr
qua nc tiu sau khi dng thuc nghin cu c so snh vi cc s liu tng ng
thu c sau khi dng thuc i chiu.
nh gi tng ng sinh hc gia cc ch phm tng ng bo ch
nhng c ngun gc khc nhau th dng thuc gc ca nh pht minh hoc thuc ca
nh sn xut c uy tn trn th trng l thuc chun so snh.

Thuc nghin cu:

Thuc nghin cu phi l thuc c sn xut trn dy chuyn thc hnh tt

sn xut, c l sn xut . Nu l ch phm ca l sn xut th (pilot) th l ny khng
c di 10% c l sn xut chun. Hm lng hot cht ca hai ch phm khng
khc nhau qu 5%. Nu khc nhau qu 5% th phi hiu chnh cc thng s ph thuc
liu so snh nh gi kt qu [97].

i tng th thuc

- Th thuc trn ng vt

32

Cc thuc mi, thuc ang nghin cu thng c th s b trn ng vt

trc khi th trn ngi. Trng hp nng thuc trong mu qu thp khng th
nh lng c th c th tng liu gp 10-20 ln liu dng cho ngi v khi nng
thuc trong mu ln nh lng c bng phng php phn tch thch hp.
Tuy nhin, gia ngi v ng vt c s khc nhau rt ln v chuyn ha thuc trong
c th [5]. Cc loi ng vt c th dng nghin cu SKD ca thuc: ch, kh, th,
chut
- Th trn ngi tnh nguyn
Phi tun th y v quy ch th thuc trn ngi tnh nguyn m bo
an ton ti a cho ngi th thuc. Ngi tnh nguyn thng l nam gii khe mnh,
tui t 20 n 40, khng c tin s v bnh ng tiu ha, gan, thn. Trc khi tham
gia th thuc, ngi tnh nguyn thng c kim tra v cc hng s huyt hc, men
gan, nc tiu loi b nhng trng hp bt thng. gim bt giao ng lin c
th, nn chn nhng ngi c ngoi hnh tng i ging nhau (ch s c th BMI
tng t nhau), cn nng c th khng chnh lch qu 10% so vi khi lng tiu
chun.

M hnh th thuc

Thng nh gi TSH theo m hnh th cho ngu nhin, cc i tng th

u phi ung c thuc nghin cu v thuc i chiu theo th t ngu nhin, nhm
gim bt sai s c th. Trng hp nh gi mt ch phm nghin cu so vi ch
phm i chiu th b tr th 2 t theo phng php cho i. Trng hp cn nh
gi nhiu ch phm th, b tr th nghim theo phng php vung latin gim bt
s ngi tnh nguyn. Thi gian gia cc ln th thuc phi thuc dng ln
trc thi tr ht khi c th, thng l gp 10 ln thi gian bn thi ca thuc [93].

Chn dch sinh hc xc nh sinh kh dng

+ Dch sinh hc c th l mu, c dng trong trng hp dc cht c

p ng sinh hc ph thuc vo nng dc cht trong mu. S mu cn ly phi

xc nh c pha hp thu v pha thi tr ca dc cht trong c th, ng thi xc

33

nh c gi tr nng dc cht t cao nht trong mu (Cmax). Thng ly khong

10-15 mu. Khong thi gian ly mu cn ko di t 3-4 ln thi gian bn thi ca
thuc hoc ly mu cho ti khi nng dc cht gim xung cn 5-10% gi tr ca
Cmax. Vi thuc tim tnh mch, ly mu sau khi tim 5 pht, khong 10-15 pht ly
mu mt ln cho n khi hon thin th [97]. Mu sau khi ly phi c bo qun
nhit < -200C cho ti khi phn tch.
+ Dch sinh hc c th l nc tiu xc nh tng lng dc cht
hoc cht chuyn ha ca n c bi tit qua nc tiu sau khi ung thuc.
+ Dch sinh hc c th l nc bt khi dc cht bi tit qua nc bt v
phng php phn tch nhy, nng dc cht trong mu v trong nc bt ng
bin vi nhau.

Vai tr ca phng php nh lng trong nghin cu SKD

Phng php nh lng nng dc cht hoc cht chuyn ha ca n trong

dch sinh hc c ngha ht sc quan trng. V cc thng s dc ng hc v SKD
ca thuc u c tnh ton da trn nng dc cht xc nh c. Do
phng php phn tch phi c chn lc cao, phn bit c dc cht vi cht
chuyn ha ca n v nhiu thnh phn cn tr khc c sn trong dch sinh hc.
Phng php phn tch phi c nhy cao c th o c nng dc cht c
g hay ng trong 1 ml mu. Cc phng php phn tch c dng ph bin trong
nghin cu SKD l phng php sc k lng hiu nng cao (HPLC), sc k lp mng
hiu nng cao (HPTLC).

Thm nh phng php phn tch trong dch sinh hc

nh gi SKD da trn phn tch nng thuc trong mu l cch thng c

s dng. Mu sinh hc thng c cha nhiu tp cht, lng mu t v nng cht
phn tch thng rt thp. Do vy, phng php phn tch sinh hc phi c thm
nh trc khi p dng vo phn tch mu. Ni dung thm nh phng php c
hng dn trong cc ti liu v phn tch v c quy nh trong cc Dc in, bao
gm cc tiu ch sau:

34

- Tnh chn lc c hiu

Tnh chn lc, hay tnh c hiu l kh nng nh gi mt cch r rng cht cn
phn tch khi c mt cc thnh phn khc c th l tp cht hoc cc thnh phn cn
tr khc. Kt qu trn sc thu c t mu trng, mu th v mu chun pha trong
mu trng cht cn phn tch phn tch hon ton vi cc pic tp.
- Xy dng ng chun v xc nh khong tuyn tnh
ng chun biu din mi quan h gia p ng ca pic (din tch hay chiu
cao) v nng thuc trong dch sinh hc. Mi quan h ny phi c nh gi bng
phng trnh hi quy, thu c t phng php phn tch hi quy.
Khong tuyn tnh l khong nng t thp nht n cao nht trong mt
ng chun c p ng tuyn tnh. ng chun phi c t nht 5 mc nng ca
cht chun pha trong cng mt mu dch sinh hc. Khong tuyn tnh phi bao gm
ton b nng ca cc mu cn phn tch. Trong khong nng cn kho st,
ng chun phi tuyn tnh v c h s R2 0,98 v phi p ng cc iu kin sau:
lch so vi gi tr thc ca cc nng phi 15%, tr im gn gi tr
nh lng di c chp nhn 20%.
C t nht 4/6 im trong dy chun t c tiu chun trn, bao gm c gii
hn nh lng di v nng cao nht.
- Gii hn nh lng di (LLOQ)
Mu chun c nng thp nht trn ng chun c chp nhn l LLOQ
nu tha mn:
+ p ng nng ny t nht bng 5 ln p ng ca mu trng.
+ Pic ca cht cn phn tch c th nhn bit, nm tch ring v c th
ti lp vi ng t 80 120%
- ng - lp li
ng: gi tr phn nh st gn ca kt qu phn tch vi gi tr thc ca
mu bit. Gi tr ny phi nm trong khong 85-115%, nhng c th l 80 120%
i vi im gn gii hn nh lng di.

35

 lp li: mc thng nht gia cc kt qu ring bit khi lp li quy trnh

phn tch nhiu ln trn cng mt mu th ng nht trong ngy v khc ngy.
- Hiu sut chit / tm li
T l thu hi hot cht sau khi mu c chit tch theo quy trnh chn so
vi cng nng khng c x l qua chit tch.
Hiu sut chit / tm li khng vt qu 110% v khng nn qu thp.
- n nh
Qu trnh phn tch nh gi SKD v TSH thng ko di v s lng mu
ln. Do vy, cn nghin cu n nh ca hot cht trong dch sinh hc. n nh
ca mu phn tch trong dch sinh hc cn c nh gi trong lc x l v bo qun
mu. Mu phn tch phi m bo n nh trong thi gian d kin cho phn tch ht
mu

36

Chng 2 - NGUYN VT LIU, THIT B V PHNG PHP

NGHIN CU
2.1. Nguyn vt liu, thit b v i tng nghin cu
2.1.1. Nguyn vt liu
Cc nguyn liu, ho cht chnh c s dng trong cc ni dung nghin cu
ca ti c trnh by bng 2.1.
Bng 2.1. Cc nguyn liu, ho cht s dng trong nghin cu
Tn nguyn liu

Ngun gc

Tiu chun

Paracetamol (Hn SD: 6/2011)

Trung Quc

BP 2007

Natri bicarbonat

Trung Quc

BP 2007

PVP K30

Trung Quc

BP 2007

Ethanol 96o

Vit Nam

DVN III

Tinh bt m

Php

BP 2007

Disolcel

Trung Quc

USP 28

Comprecel

Trung Quc

USP 28

Vit Nam

DVN III

Trung Quc

DVN III

Nht

USP 28

Acid hydrocloric

Trung Quc

Tinh khit ha hc

Natri hydroxyd

Trung Quc

Tinh khit ha hc

Natri bicarbonat

Trung Quc

Tinh khit ha hc

Prolabo - Php

Dng cho HPLC

Natri butansulfonat

Merck c

Dng cho HPLC

Acetonitril

Merck c

Dng cho HPLC

Acid Phosphoric

Merck c

Dng cho HPLC

Prolabo - Php

Dng cho HPLC

Cht chun paracetamol

Vin kim nghim thuc TW

SKS: 0195019

Cht chun 4-aminophenol

Vin kim nghim thuc TW

SKS: 0199052

Talc
Magnesi stearat
Aerosil

Methanol

Acid formic

37

2.1.2. Thit b, phng tin

Qu trnh nghin cu v sn xut s dng cc thit b chnh c lit k trong bng
2.2.
Bng 2.2. Cc thit b v phng tin s dng trong nghin cu
Tn thit b

Hng - Model

Xut x

My trn hp lp phng

ERWEKA

My nho sigma

ERWEKA

My xt ht

ERWEKA

My dp vin tm sai

ERWEKA

My nho trn cao tc

Cng ty Hong Anh

Vit Nam

My sy tng si

KYBACO 2000

Vit Nam

My xt ht

KYBACO 2000

Vit Nam

My trn lp phng

KYBACO 2000

Vit Nam

RIMEK

Memmert

CLIMACEL

H thng HPLC

Thermo Finnigan

My th ha tan

VANKEL-VARIAN

My th ha tan

ERWEKA

U-1800 HITACHI

Nht Bn

ERWEKA

ERWEKA TBH 200

My o t trng biu kin

ERWEKA SVM

My o trn chy

ERWEKA GWF

Sartorius

Sartorius MA 30

LC 60H

My dp vin quay trn

T sy tnh
T vi kh hu
Cc thit b kim nghim chnh

My quang ph UV-VIS
My th r
My o cng

Cn phn tch
Cn xc nh hm m nhanh
My siu m

38

2.1.3. i tng nghin cu

Thuc th

- Thuc th l ch phm nghin cu, sn xut trn dy chuyn thc hnh tt sn

xut thuc , vi qui m 30000 vin.

Thuc i chiu

- Vin nn Panadol Actifast 500 mg (l XLF162, HD:08/2010), sn xut bi

GlaxoSmithKline Malaysia.
Thnh phn: paracetamol, natri bicarbonate, tinh bt ng, tinh bt h ho, natri
sorbat, cellulose vi tinh th,

povidon, magne stearat, Carnauba wax, talc,

polydextrose, Hypromellose, glycerol triacetat, polyethylen glycol.

c im: vin nn hnh tr, bao phim
Tui th thuc: 24 thng
- Vin nn Panadol 500 mg (l 0812143, HD:12/2011), sn xut ti cng ty c
phn dc

phm

Sanofi-Synthelabo Vit Nam theo nhng quyn ca

GlaxoSmithKline.
Thnh phn: tinh bt ng, natri sorbat, talc, acid stearic, tinh bt h ho,
promellose, triacetin.
c im: vin nn hnh tr
Tui th thuc: 48 thng
2.1.4. a im nghin cu
- Trng i hc Dc H Ni (Nghin cu bo ch)
- Cng ty Dc khoa Trng H Dc H Ni (Hon thin v thm nh qui
trnh sn xut)
- Cng ty CP Dc phm Sao Kim (p v)
- Vin kim nghim thuc trung ng (nghin cu SKD v TSH)

39

2.2. Phng php nghin cu

2.2.1. Phng php bo ch vin nn paracetamol gii phng nhanh
Ba phng php bo ch vin gii phng nhanh c la chn lm thc nghim
l: (1) S dng t dc thng hoa, (2) S dng h rn lng v (3) Bo ch vin si ni.
Tin hnh kho st cc yu t nh hng nh: t l cht thng hoa, t dc
lng, cht mang - cht bao, t dc m, t dc r, t dc trn cng nh cc k
thut bo ch ti kh nng gii phng paracetamol ca vin.
Da vo cc kt qu thc nghim v nh gi cht lng ht cng nh cht
lng vin trong tng phng php, la chn phng php bo ch thch hp v xy
dng cng thc cho vin nn paracetamol gii phng nhanh t mc tiu ra.
2.2.1.1. Phng php s dng t dc thng hoa
T dc thng hoa camphor c s dng vi t l khc nhau (5, 10 v 15%)
nhm kho st nh hng ca t l camphor ti xp, tc r v ha tan ca vin.
Vai tr ca t dc r cng c kho st bao gm loi thng thng (tinh bt) v t
dc siu r (crospovidon, croscamellose).
Cc mu vin c bo ch bng phng php xt ht t T dc dnh s
dng to ht l dung dch PVP 15% trong ethanol. Camphor c ho tan trong
dung dch t dc dnh trong qu trnh to ht. Sau , ht c sy nhit thp
cho camphor thng hoa. m bo trn chy ca bt khi dp vin, talc v Aerosil
c s dng lm t dc trn v chng dnh.
Cc mu vin s dng t dc thng hoa c bo ch theo cc bc trong
hnh 2.2. Mu vin S0 c bo ch theo phng php xt ht t thng thng khng
thm t dc thng hoa, nhm so snh kh nng ci thin tc ho tan ca cc mu
vin c s dng t dc thng hoa.

40

Paracetamol
Tinh bt (r trong)
Camphor / Dung dch
PVP 15% trong ethanol

Trn bt kp

My trn lp
phng

Nho m

My nho

Ry 1 mm

Xt ht

Sy ht / thng hoa

T sy
45oC / 8 -10gi)
Ry 1 mm

Sa ht
T dc r ngoi,
t dc trn

My trn lp
phng

Trn hon tt

Dp vin

Sy vin / thng hoa

My dp vin
Caplet
(21,0 x 9,5 mm)
5 10 Kp
T sy
45 C / 4 6 gi
o

Hnh 2.2 : S cc bc bo ch vin paracetamol gii phng nhanh bng

phng php s dng t dc thng hoa.
2.2.1.2. Phng php ch to ht rn lng
Cc mu vin rn lng c bo ch bng k thut ch to ht rn lng
paracetamol PG. Qui trnh bo ch c trnh by theo s hnh 2.3.

41

Comprecel c la chn lm cht mang, trong khi cht bao c kho st l

Aerosil. Paracetamol c phn tn vo t dc lng (PG) vi cc t l 5:1 ; 5:1,5 v
5:2 nhm nh gi nh hng ca t l t dc lng ti tc ho tan paracetamol.
Dch lng thuc to thnh c phi hp vi Comprecel, cht bao c thm vo cht
mang vi t l 1:20 v 1:15 so vi lng cht mang ht ht lng t dc lng d
trong hn hp bt.
PVP c thm vo vi t l 10% lng dch lng thuc nhm tng nht
ca t dc lng v do , lm gim t l cht mang. Hn hp cht mang v cht bao
c s dng trong kho st ny l Comprecel v Aerosil vi t l 20:1 hoc 15:1.
Hn hp bt thuc to thnh c xt ht c ry 1 mm. Sy ht qua m 45oC ri
trn vi t dc trn chng dnh (talc 2%). Hn hp trn hon tt c em dp vin
caplet c cng khong 17 21 Kp.
2.2.1.3. Phng php bo ch vin si ni
Cn c vo cc kt qu thc nghim s b, vin paracetamol gii phng nhanh
theo c ch si ni bc u c la chn vi cc thnh phn nh sau:
Paracetamol

500 mg

Natri bicarbonat

thay i theo nghin cu

T dc r trong

thay i theo nghin cu

PVP K30 *

va

Talc

thay i theo nghin cu

Aerosil

thay i theo nghin cu

T dc r ngoi

thay i theo nghin cu

Cc thnh phn trong cng thc c thay i v chng loi cng nh t l,

nhm tm ra cng thc thch hp cho vin nn paracetamol gii phng nhanh, da trn
kt qu th nghim ho tan trong mi trng acid hydrocloric 0,1N.
Cc mu vin c bo ch theo phng php xt ht t theo trnh t phi
hp cc thnh phn nh m t trong s cc hnh 2.4 hoc 2.5, mi cng thc 500
mg paracetamol.

42

Paracetamol
PVP/T dc lng (PG)

Phn tn dc cht
trong t dc lng

My nho
trn

Hn hp
(cht mang + cht bao)

Trn u

My nho
trn

Xt ht

Ry 1 mm

Sy ht

T sy
45 C/ 4-6 gi

Sa ht

Ry 1 mm

Trn hon tt

My trn lp
phng

T dc r ngoi,
t dc trn

Dp vin

My dp vin
Caplet
17 21 Kp

Hnh 2.3 : S cc bc bo ch vin paracetamol gii phng nhanh s dng h

rn lng

43

Paracetamol
Natri bicarbonat
T dc r trong

Trn u

My nho
trn

Nho m

My nho
trn

Xt ht

Ry 1 mm

Sy se

45 -50oC
15 pht

Xt li ht

Ry 1 mm

Sy kh

45 - 50oC
hm m 2-3%

Chn ht

Ry 1 mm

Trn u

My trn
lp phng

Dung dch PVP 15%

T dc trn

T dc r ngoi

Qua ry 0,125 mm
Bt mn

Dp vin

My dp vin
cng
13-18 kP

Hnh 2.4. S cc giai on bo ch vin paracetamol bng phng php

xt ht chung paracetamol vi natri bicarbonat
44

Natri hydrocarbonat
T dc r

Paracetamol
T dc r

Trn u

My nho
trn

Trn u

Dung dch PVP 15%

Nho m

My nho
trn

Nho m

Xt ht

Ry 1 mm

Xt ht

Sy se

45 -50oC
15 pht

Sy se

Xt li ht

Ry 1 mm

Xt li ht

Sy kh

45 - 50oC
hm m 2-3%

Sy kh

Chn ht

Ry 1 mm

Chn ht

T dc trn
T dc r ngoi

Trn hon
tt
Dp vin

My trn
lp phng
My dp
vin
cng
13-18 kP

Hnh 2.5. S cc giai on bo ch vin paracetamol bng phng php

to ht paracetamol v ht natri bicarbonat ring bit

45

2.2.2. Phng php hon thin v thm nh qui trnh sn xut

Trn c s qui trnh bo ch la chn, thit k cng thc cho l 30000 vin.
2.2.2.1. Chun b trc thm nh
Son tho ti liu thm nh
- Cc ti liu cn son tho bao gm: cng thm nh tin lng QTSX,
bo co thm nh v phiu thm nh thng s.
- Phn tch cc thng s v son cc phiu thm nh thng s da theo cc th
nghim ca Dc in, cc ti liu v c kt t thc t nghin cu.

Chn thng s trng yu

nhn dng c cc thng s trng yu trong mi giai on ca qu trnh

sn xut cn:
- V lu QTSX phn tch cc giai on trng yu
- Lp bng lit k cc thng s trng yu phi kim sot hay thm nh cho mi
cng on sn xut v ch ra cc ch tiu nh gi tng ng.
- Lp bng phn tch mc nh hng ca mi thng s quy trnh n cc
tnh cht ph thuc tng ng
2.2.2.2. Tin hnh thm nh
- Thm nh bng phng php thc nghim v phn tch kt qu bng thng
k, phng php phn tch phng sai.
- K hoch sn xut l 3 l lin tc, mi l 30 000 vin. Thm nh quy trnh
sn xut vin nn paracetamol gii phng nhanh theo phng php tin lng
chng minh tnh n nh ca quy trnh sn xut.
- nh gi cc thng s trng yu theo tiu ch a ra trong phiu thm nh
(nh km vi cng thm nh).

46

2.2.2.3. Kim sot qui trnh bng phng php thng k

Biu Shewhart [6],[7],[28]
Nguyn tc ca biu Shewhart da trn s trnh by bng th so snh
khi lng trung bnh vin thc t vi khi lng vin l thuyt, t cho php theo
di s bin thin khi lng trung bnh ca cc mu vin v pht hin s dch chuyn
gi tr trung bnh ca khi lng vin.
Biu Shewhart theo di bin thin khi lng vin c thit lp bao gm:
- ng trung tm th hin gi tr khi lng trung bnh vin
- ng gii hn kim sot trn v di l cc ng bin xc nh khong gi
tr c chp nhn ca khi lng vin
ng gii hn kim sot c xc nh sao cho khi QTSX ang trong gii hn
kim sot th xc sut mt vin c khi lng nm ngoi gii hn kim sot l rt
nh. Thng thng, ng gii hn c la chn v tr 3 ln lch chun so vi
ng trung tm v gi l gii hn kim sot 3 sigma (3).
Hai loi biu Shewhart c s dng ng thi l biu Shewhart

(kim

sot gi tr trung bnh) v biu Shewhart R (kim sot phm vi quan st).
Biu Cusum [6],[7],[28]
Biu Shewhart d s dng v nhy vi nhng thay i 2, nht l nhng
bin thin t ngt nn cho php nhn dng nhanh nhng bin thin ny, t kp thi
a ra cc bin php khc phc. Nhc im ca biu Shewhart l kh nhn dng
nhng bin thin nh hn 2.
Biu Cusum (cumulative sum chart) nhy vi nhng bin thin chm v
thng xuyn c bin dao ng nh, t 0,5 n 2, iu ny thch hp vi vic
theo di QTSX theo thi gian v cho php a ra nhng can thip c tnh phng nga.
Biu cusum c hiu qu khi theo di cc gi tr n trong khi biu Shewhart t
hiu qu trong trng hp ny.

47

Loi biu Cusum c s dng l biu Cusum thut ton. Nguyn tc ca

biu cusum thut ton l biu din trn th cc tng gi tr tch ly (trn v di)
ca cc lch chun gia gi tr quan st vi gi tr trung tm.
Ch bo hiu nng [7],[28]
Mt QTSX tt phi cho ra sn phm c tnh lp li v khng lch tm (gi tr
trung bnh gn bng gi tr mong mun). Hiu nng ca qui trnh c th c din t
bng cc ch bo hiu nng.
- Ch bo hiu nng tng qut (Cp)

H L
6

(4)

- Ch bo hiu nng ti hn (Cpk)

H X X L
,
Min

3
3

pk

(5)

- Ch bo hiu nng iu chnh (Rr)

C
C

pk

100%

(6)

- Ch bo tnh trng lch tm (Cpm)

pm

C
X X
1
p

C
1 9C C
p

pk

(7)

- Ch bo hiu nng tc thi hay ch bo hiu nng ca thit b (Cm)

H L
6

(8)

- Ch bo mc n nh (Rs)

C
C

100%

(9)

Trong :
H: Gii hn trn

48

L: Gii hn di
: lch chun tng th
: lch chun c tnh

: l gi tr trung bnh ca dn s mu
0

: Gi tr mong i ca mu

2.2.3. Phng php nh gi v tiu chun ho cht lng bn thnh phm v

thnh phm vin nn paracetamol gii phng nhanh.
ng u khi lng
Tin hnh theo ch dn ca DVN III, ph lc 8.3.
r ca vin
Tin hnh theo ch dn ca DVN III, Ph lc 8.6. Th r trong 2 mi
trng l nc ct v dung dch HCl 0,1N.
Kt qu l gi tr trung bnh thi gian r ca 6 vin.
ha tan
Tin hnh theo ch dn ca DVN III, Ph lc 8.4.
Thit b

: cnh khuy

Mi trng ho tan

: 900 ml dung dch acid hydrocloric 0,1N

Nhit

: 37 0,50C

Tc khuy

: 50 vng/pht.

Sau mi pht, ly mu 5 ml, lc, pha long 50 ln v o mt quang ca dung

dch bc sng 242 nm. Song song tin hnh o mt quang ca mu chun trong
cng iu kin. Lng paracetamol gii phng c tnh ton da trn mt quang
ca mu chun.
S liu c x l trn my tnh vi s tr gip ca phn mm Excel. Kt qu
l gi tr trung bnh tnh trn 3 ln thc nghim.

49

 nh lng paracetamol trong vin

nh lng paracetamol trong vin bng phng php quang ph hp th t
ngoi theo DVN III, ph lc 3.1. Kt qu c tnh ton trn c s so snh vi nng
ca mu chun (n=5).
nh lng natri bicarbonat
Hm lng natri bicarbonat c nh lng theo phng php chun acidbase (DVN III) bng dung dch HCl 1M, ch th da cam methyl vi cht chun l
Na2CO3 tinh khit (99,8%).
Kt qu l gi tr trung bnh tnh trn 3 ln thc nghim.
nh lng tp cht 4-aminophenol
Th theo DVN III, chuyn lun Vin nn paracetamol, mc 4aminophenol.
Tp cht lin quan
Th theo DVN III, chuyn lun Vin nn paracetamol, mc Tp cht lin
quan.
o mi mn ca vin
Th theo hng dn ca dc in Anh (BP 2009), chuyn lun th mi
mn ca vin nn khng bao (Friability of uncoated tablets).
Xc nh trn chy
o trn my ERWEKA GWF vi ng knh l phu 9 mm. Xc nh khi
lng ht chy qua phu trong mt n v thi gian (g/giy)
Xc nh khi lng ring biu kin
o trn my ERWEKA SVM v tnh kt qu theo quy nh chung
Xc nh mt khi lng do sy kh
Thc hin trn cn xc nh hm m nhanh Sartorius MA 30.

50

Xy dng tiu chun cht lng vin

Tiu chun cht lng vin nn paracetamol gii phng nhanh c xy dng

da trn mt s ch tiu cht lng ca 3 l thuc nghin cu, c bo ch theo cng

thc v qui trnh la chn. Cc ch tiu bao gm: hnh thc, ng u hm
lng, nh tnh, tp cht lin quan, nh lng v ho tan dc cht trong mi
trng HCl 0,1 N.
2.2.4. Phng php nghin cu n nh
Vic kho st n nh ca thuc c thc hin da theo quy nh ca
ASEAN v WHO. Tui th ca thuc c d tnh bng phng php ngoi suy qu
trnh bo qun trong iu kin thc [2],[15],[50],[106].
-

i tng th: Thuc t 3 l thc nghim c ng trong bao b thch hp.

iu kin bo qun v chu k ly mu kim tra:

Nhit (toC)

m (RH%)

iu kin thc (K phng th nghim )

18 - 30oC

40 80%

Lo ha cp tc

40 2oC

75 5%

iu kin th nghim

- Cc tiu chun kho st:

+ nh k kho st hnh thc, ha tan, hm lng tp cht 4-aminophenol v
hm lng paracetamol.
+ Ti thi im bt u v khi kt thc bo qun, kim tra tt c cc ch tiu ca
tiu chun sn phm. Vi sn phm bo qun iu kin thng, kim tra tt c cc
tiu chun sn phm sau 6 thng, 12 thng, 18 thng, 24 thng v cc ln ly mu tip
theo.
2.2.5. Phng php nh gi sinh kh dng v tng ng sinh hc
2.2.5.1. Xy dng v thm nh phng php nh lng paracetamol trong
huyt tng
Xy dng phng php phn tch

51

Bng thc nghim tm ra iu kin sc k cho php tch paracetamol c

tt nht, tin hnh thu thp s liu v x l thng k nh gi kt qu.
Xy dng chng trnh sc k nh lng paracetamol trong huyt tng bao
gm:
- Chn ct sc k.
- Chn pha ng (thnh phn, t l).
- Detector UV, chn bc sng o.
- Tc dng.
- Th tch tim.
- Cch x l mu.
Thm nh phng php phn tch
Tin hnh theo cc tiu ch c hng dn ca FDA gm c: tnh chn lc,
khong nng tuyn tnh, chnh xc, ng, n nh, gii hn nh lng,
tm li.
2.2.5.2. Phng php nghin cu sinh kh dng v tng ng sinh hc
Thit k nghin cu
Nghin cu c thit k theo m hnh cho 3, ngu nhin, liu n mt vin thuc
th (A) hoc thuc i chiu (B, C), 6 trnh t. 18 ngi tnh nguyn c chia ngu
nhin thnh 6 nhm v m ha (1, 2, 3, 4, 5, 6), ba giai on (I, II, III).
Nhm
1
2
3
4
5
6

Trong :

Thuc ung giai on

I
II
III
A
B
C
A
C
B
B
A
C
B
C
A
C
C

A
B

A: 01 vin thuc th (cp nghin cu)

B: 01 vin Panadol Actfast 500mg
C: 01 vin Panadol 500mg

B
A

i tng th
Ngi tnh nguyn (NTN): Nam gii khe mnh, tui t 18 40, ch s BMI
trong khong 18,5 22,9 kg/m2, khng mc bnh mn tnh, khng c tin s mc bnh
ng tiu ha.

52

NTN c kim tra sc kho trc khi vo nghin cu: Khm tng qut, huyt
p, nhp tim, chc nng gan, thn, cng thc mu, HIV. Sau khi kt thc nghin cu,
NTN c khm tng qut, huyt p, nhp tim..
NTN khng c dng thuc, ru hay bt c loi thuc g trc khi th 30
ngy v cho ti khi php th hon tt.
NTN c thng tin y v qu trnh nghin cu, mc ch ca nghin cu,
quyn li v trch nhim khi tham gia nghin cu., tc dng dc l ca thuc v
nhng ri ro c th gp phi khi s dng thuc, khi ly mu mu. NTN t nguyn
tham gia nghin cu v k vo Bn cam kt tnh nguyn tham gia nghin cu . Cc
thng tin v nghi tnh nguyn c gi b mt trong h s nghin cu.
Ni dung nghin cu trn NTN phi c Hi ng o c ca Trng i
hc Dc H Ni thng qua.
Ngi tnh nguyn khng n g k t 22 gi hm trc mi ngy nghin cu.
Khong 7 8 gi sng, mi ngi c ung mt vin thuc theo thit k nghin cu
vi 240 ml nc tinh khit. Sau khi ung thuc 4 gi c th n ba tra theo qui nh,
sau 10 gi c th n ti. NTN khng c dng cc loi thc ung c cha cn, cafein
48 gi trc khi ung thuc, khng c ung bt c loi thuc g trong thi gian
nghin cu.
Theo thit k nghin cu c 3 giai on th thuc, khong cch gia hai giai
on t nht l 7 ngy.
Phng php ly mu, x l v bo qun
Mu mu c ly 2 ml vo cc thi im sau: ngay trc khi ung thuc; sau
khi ung thuc 5; 10; 15; 20; 25; 30; 35; 45; 60; 90 pht v 2; 6, 10 gi. Qu trnh ly
mu c thc hin trong iu kin c chm sc y t, c bc s lm sng theo di.
Nu c phn ng bt li, cn phi c x tr kp thi.
Mu mu c ly tm tch ly huyt tng ri bo qun trong t lnh su -35oC, ch
phn tch.

53

 Phn tch mu huyt tng

nh lng paracetamol trong huyt tng bng phng php HPLC sau khi
thm nh t cc tiu ch theo qui nh ca FDA.

Xc nh cc thng s dc ng hc
Cc thng s dc ng hc ca thuc c tnh ton khng theo m hnh ngn

vi s h tr ca phn mm my tnh Kinetica 5.0 v Winonlin 5.2..

-

Cmax v Tmax c xc nh trc tip t s liu thc nghim

AUC0-t : xc nh bng phng php hnh thang:

n 1

[AUC]0t (Ci Ci 1 ).
t 0

(ti 1 ti )
2

AUC0- = AUC0-t + Cn/ z

n 1

[AUC]0 (Ci Ci 1 ).
t 0

(10)
(11)

(ti 1 ti ) Cn

z
2

(12)

2.2.7. X l kt qu nghin cu
Cc s liu nghin cu u c x l theo phng php thng k trnh by
tng phng php. S dng tr gip ca mt s phn mm tnh ton nh: Excel
2003, Kinetica 5.0, Winonlin 5.2, S-Plus 6.1, Stab for R v 0.1.3.

54

Chng 3 - KT QU NGHIN CU
3.1. Nghin cu bo ch vin paracetamol gii phng nhanh
3.1.1. S dng k thut thng hoa
- Nghin cu bo ch vin
Bo ch vin nn paracetamol gii phng nhanh ng dng k thut thng hoa
(cc mu S1 S7) s dng t dc thng hoa camphor, c kho st vi cc t l
5%, 10% v 15% so vi lng dc cht theo nh mt s kt qu kho st cng b
trc [60],[89]. Crospovidon, croscamellose l cc t dc siu r, c s dng
lm tng tc r ca vin vi t l ln lt l khong 2% v 5%. T dc dnh s
dng to ht l PVP, c ho tan trong ethanol thnh dung dch t dc dnh
to ht. m bo trn chy ca bt khi dp vin, talc v Aerosil c s dng
lm t dc trn v chng dnh. Thnh phn cng thc ca cc mu vin kho st
c trnh by trong bng 3.3 vi mi cng thc 500 gam paracetamol. Bo ch cc
mu vin theo cc bc m t hnh 2.2, mc 2.2.1.1.
Bng 3.3: Cng thc cc mu vin gii phng nhanh ng dng k thut thng hoa.
Thnh phn

n v

S0

S1

S2

S3

S4

S5

S6

S7

Paracetamol

mg

500 500 500 500 500 500 500 500

Tinh bt m (r trong)

mg

25

25

25

25

25

25

25

25

Camphor *

mg

25

50

50

50

75

75

75

PVP K30

mg

15

15

15

15

15

15

15

15

Ethanol *

ml

10

10

10

10

10

10

10

10

Tinh bt m (r ngoi)

mg

25

25

25

Crospovidon (r ngoi)

mg

10

10

Croscamellose (r ngoi)

mg

25

25

Talc (2%)

mg

10

10

10

10

10

10

10

10

Khi lng vin

mg

575 575 575 560 575 575 560 575

25

Ghi ch: (*) bay hi trong qu trnh bo ch vin

55

Mu vin S0 c bo ch theo phng php xt ht t thng thng khng

thm t dc thng hoa v ch s dng t dc r thng thng l tinh bt nhm so
snh kh nng ci thin tc ho tan khi s dng t dc thng hoa v t dc siu
r..
Camphor dng tinh th, khi nghin nh th bt dnh nn rt kh phi hp vi
bt thuc. Bin php kh thi l ho tan camphor trong dung dch t dc dnh,
camphor s c trn ln vi bt thuc trong qu trnh nho m v to ht. Ht to
thnh em sy 45oC trong 8 - 10 gi (sy qua m). Camphor thng hoa ng thi
ht s kh dn trong qu trnh sy.
- nh gi s b cht lng ht paracetamol
Hn hp bt trn hon tt em dp vin ca tng mu c nh gi s b v
t trng v kh nng trn chy qua cc thng s: t trng ht v trn chy (Bng
3.4).
T trng ht thp, kh nng trn chy km nn phi tng t l t dc trn
m bo ng u khi lng khi dp vin. Khi trn hon tt, cc mu ht trn t
dc ngoi l crospovidon (S3 v S6) rt nhanh b ht m v tr nn bt dnh, khng
dp c vin.
Bng 3.4: T trng v trn chy ca cc mu ht paracetamol bo ch
bng k thut thng hoa sau khi trn hon tt (n=5)
Mu
T trng (g/cm3)
trn chy (g/s)

S0

S1

S2

S3

S4

S5

S6

S7

0,67

0,42

0,33

0,31

0,29

0,22

0,23

0,22

3,98

3,75

2,84

2,92

Ghi ch: (-) Khng o c

xp ca ht paracetamol tng ln theo t l camphor. Cc mu ht s dng

15% camphor (S5, S6, S7) c t trng thp hn c (khong 0,22 g/ml) so vi cc mu
10% camphor (khong 0,3 g/ml) v mu 5% camphor (0,42 g/ml).

56

- nh gi cht lng vin

Bng 3.5: bn c hc, r v bin thin khi lng cc mu vin thc nghim
bo ch bng phng php thng hoa (gi tr trung bnh SD, n=6)
Mu vin

cng
(kP)

mi mn
(%)

r trong nc
(giy)

Bin thin khi lng

vin (mg)

S0

12,1 1,4

0,33 0,1

100,4 7,5

578 11

S1

6,1 0,8

0,32 0,11

60,4 5,9

569 78

S2

6,4 0,9

0,62 0,09

50,4 4,6

580 62

S4

5,9 0,3

0,54 0,14

35,2 4,4

573 37

S5

5,4 1,0

45,0 4,7

564 45

S7

5,0 0.8

32,0 2,9

572 44

Cc mu vin S5 v S7 s dng 15% camphor khng bn v mt c hc, s

vin b v v bong mt chim t l cao (40%) sau khi th mi mn. Bin thin khi
lng vin rt ln.
Vai tr ca t dc siu r trong trng hp ny khng r rt. Mu vin S4 c
cng t l camphor vi S2 nhng s dng t dc siu r croscamelose c tc ho
tan khng nhanh hn mu vin S2 s dng t dc r thng thng, thm ch cn
chm hn trong nhng pht u.
Cc mu vin s dng t dc thng hoa th hin tc ho tan paracetamol
nhanh hn r rt so vi mu vin khng s dng t dc thng hoa (Hnh 3.6). Ti
thi im 6 pht, lng paracetamol trong vin S0 ch ho tan c 24,6% trong khi
cc mu vin s dng t dc thng hoa u t trn 90%.
Qu trnh thc nghim cho thy, vin paracetamol gii phng nhanh hon ton
c th bo ch bng phng php s dng t dc thng hoa nu chng ta x l tt
vn trn chy ca ht. Tuy nhin, qu trnh lm thc nghim cho thy rt kh kim
sot qu trnh thng hoa cng nh tn d tp cht trong vin nu a vo sn xut.

57

Bng 3.6. T l paracetamol ho tan t cc mu vin iu ch bng k thut thng

hoa trong mi trng HCl 0,1 N (n=6)
% Paracetamol ho tan

Thi gian (pht)

S1

S2

S4

S7

S0

0.0

17,6

22,5

16,0

27,6

0,1

71,1

86,2

77,3

89,6

2,1

90,5

102,5

94,4

99,2

24,6

98,5

107,2

100,7

102,9

62,6

10

102,3

108,8

103,6

104,7

80,6

12

104,4

109,1

104,7

105,2

86,5

14

105,1

109,6

106,3

105,6

88,7

16

105,6

109,6

106,7

105,5

90,5

18

106,5

110,1

107,4

105,6

91,5

20

106,7

110,1

107,6

106,0

92,2

120

% paracetamol ho tan

100
80
60
S1
S2

40

S4
S7

20

S0

0
0

10

12

14

16

18

20

22

Thi gian (pht)

Hnh 3.6. th ho tan paracetamol t cc mu vin bo ch bng k thut

thng hoa trong mi trng HCl 0,1N

58

3.1.2. Bo ch vin s dng k thut to ht rn lng

Cc mu vin nn paracetamol gii phng nhanh s dng k thut to ht rn
lng c cng thc ghi trong bng 3.7 v c bo ch theo phng php m t s
hnh 2.3, mc 2.2.1.2. Mi cng thc 500 gam paracetamol tng ng vi 1000 vin.
Bng 3.7: Cng thc bo ch mt s mu vin kho st ng dng h rn lng
Thnh phn

P0

LS1

LS2

LS3

LS4

500

500

500

500

500

200

150

100

150

PVP K30 (mg)

31

70

65

60

65

Comprecel (mg)

500

500

500

500

500

Aerosil (mg)

25

25

25

25

33

Croscamellose (mg)

50

50

50

50

50

Talc (mg)

26

26

26

26

26

Khi lng vin

1132

1371

1316

1261

1324

T l cht mang - cht bao

20:1

20:1

20:1

15:1

Lf

1,54

1,43

1,32

1,43

Paracetamol (mg)
Propylen glycol (mg)

Kt qu nh gi ht rn lng paracetamol thu c v t trng c trnh by

bng 3.8.
Bng 3.8. T trng biu kin ht rn lng paracetamol -PG
Ht rn lng

T trng
(g/cm3)
0,67

P0
LS2
LS3
LS4

0,30
0,29
0,33

59

Nhn xt:
Mu ht LS1 vi t l t dc lng cao, khi trn vi hn hp cht mang v
cht bao to thnh hn hp bt bt dnh. V vy mu LS1 khng th em dp thnh
vin c. Cc mu cn li sau khi sy thu c ht c th cht ti xp, t trng thp,
kh nng trn chy km.
nh gi cht lng vin thu c cc kt qu ghi bng 3.9, 3.10 v hnh 3.7.
Bng 3.9. r trung bnh ca cc mu vin rn lng trong mi trng nc v
acid HCl 0,1N
Mu vin

r trong mi

r trong mi trng

rn lng

trng nc (giy)

HCl 0,1N (giy)

LS2

90

55

LS3

120

72

LS4

96

60

Nhn xt:
- Vi lc nn trong khong 17 21 kP, cc mu vin to thnh m bo v
bn c hc ( mi mn < 1%)
- Tc ho tan paracetamol ra khi cc vin LS c ci thin r rt so
vi vin khng s dng h rn lng (mu P0). Sau 5 pht, mu P0 ch ho tan
20% lng paracetamol trong vin , thp hn nhiu so vi cc mu LS (hnh 3.7)
- Tc ho tan paracetamol ca cc mu LS2 v LS4 nhanh hn cc mu LS3
trong 6 pht u tin. Nh vy, t l t dc lng c nh hng ti tc ho tan
dc cht, lng t dc lng cao gip vin ho tan nhanh hn.
Kt qu thc nghim cho thy, vic ch to ht rn lng bo ch vin
paracetamol c tc dng lm tng tc ho tan ca dc cht ra khi vin. Tuy
nhin, trn chy ca ht cha t yu cu do lng cht mang kho st cha
ht ht lng t dc lng mc d t dc lng kho st mc ti thiu ng thi

60

dng bin php lm tng nht ca t dc lng nhm gim thiu lng cht bao.
Chnh v vy, vic nghin cu trin khai vo sn xut l rt kh kh thi.
Bng 3.10: T l paracetamol ho tan t cc mu vin rn lng trong mi trng
HCl 0,1N (n=6)
% Paracetamol gii phng
LS4
LS3
0,0
0,0

Thi gian
(pht)
0,0

LS2
0,0

2,0

18,5

15,3

8,1

0,1

4,0

77,0

72,3

61,1

2,2

6,0

89,9

85,5

90,7

26,1

8,0

95,6

90,4

95,5

66,5

10,0

98,3

93,7

98,4

85,5

12,0

100,9

96,3

100,8

91,8

14,0

102,0

98,2

101,9

94,2

16,0

102,5

99,1

103,2

96,1

P0
0,0

120

% paracetamol ho tan

100
80
60

LS2
LS3

40

LS4
P0

20
0
0

10

12

14

16

18

Thi gian (pht)

Hnh 3.7: th ho tan paracetamol t cc mu vin bo ch bng phng php

ch to ht rn lng trong mi trng HCl 0,1N

61

3.1.3.. Bo ch vin si ni
nh gi cc yu t nh hng ti mc v tc gii phng paracetamol
ra khi vin, trn 25 cng thc bo ch c nghin cu thc nghim (trnh by
bng 3.11). Cc mu vin c bo ch theo phng php m t trong mc 2.2.1.3. ,
mi cng thc 500 gam paracetamol tng ng vi 1000 vin. Cc thnh phn c
thay i tu theo mc ch kho st.
3.1.3.1. Kt qu kho st cc yu t thnh phn cng thc

nh hng ca kch thc tiu phn paracetamol

Xt theo l thuyt, kch thc tiu phn dc cht cng nh th qu trnh gii

phng v ho tan dc cht s nhanh hn do tng din tch b mt tip xc vi mi

trng ho tan ln hn. Quan st nguyn liu paracetamol cho thy th cht bt xp,
cu trc tinh th ln bt mn vi kch thc tiu phn c xc nh bng cch ry
nguyn liu qua cc c ry khc nhau (n = 3), kt qu thu c nh sau:
Kch thc mt sng (mm)

T l bt

< 0,076

62,20 %

0,076 0,098

13,45 %

0,098 0,125

24,33 %

> 0,125

0,02 %

kho st nh hng ca kch thc tiu phn (KTTP) dc cht n ho

tan, tin hnh bo ch vin theo cng thc M1.1 M1.4 (bng 3.11) theo quy trnh
hnh 2.4 t nguyn liu paracetamol vi kch thc nh sau:
Mu vin

KTTP paracetamol

M1.1

< 0,076 mm

M1.2

0,076 0,098 mm

M1.3

0,098 0,125 mm

M1.4

Nguyn liu ban u

nh gi ho tan paracetamol t cc mu vin, kt qu thu c trnh by

hnh 3.8.

62

Bng 3.11: Thnh phn cng thc cc mu vin kho st trong nghin cu (Mi cng thc 500 g paracetamol )
Mu
M1.1 - M1.4
M2
M3
M4
M5
M6
M7
M8
M9
M10
M11
M12
M13
M14
M15
M16
M17
M18
M19
M20
M21.1 M21.4
M22
M23
M24
M25

Paracetamol
(mg)
500
500
500
500
500
500
500
500
500
500
500
500
500
500
500
500
500
500
500
500
500
500
500
500
500

NBC
(mg)
630
630
470
315
63
630
630
630
630
630
630
630
630
630
630
630
630
630
630
630
630
630
630
630
630

Td r trong (%)
A C
D
5
_
_
5
_
_
5
_
_
5
_
_
5
_
_
_
5
_
_
_
4
5
_
_
5
_
_
5
_
_
5
_
_
5
_
_
5
_
_
1
_
_
3
_
_
7
_
_
_
_
4
_
_
4
_
_
4
_
_
4
_
_
4
_
_
4
5
_
_
_
_
4
5
_
_

Td r ngoi (%)
A C
D
_
_
4
_
_
4
_
_
4
_
_
4
_
_
4
_
_
4
_
_
4
_
_
4
_
5
_
5
_
_
1
_
_
3
_
_
7
_
_
5
_
_
5
_
_
5
_
_
_
_
4
_
_
4
_
_
4
_
_
4
_
_
4
_
_
4
_
_
4
_
_
4
_
_
4

PVP K30
(%)
3,05
3,0
3,1
3,1
3,7
3,1
3,1
3,1
3,1
3,1
3,1
3,1
3,1
3,1
3,1
3,1
3,1
3,1
3,1
3,1
3,1
3,1
3,1
3,1
3,1

Aerosil
(%)
0,50
0,50
0,50
0,50
0,50
0,50
0,50
0,50
0,50
0,50
0,50
0,50
0,50
0,50
0,50
0,50
0,50
0,50
0,50
0,50
0,50
0,50
0,50
0,50
0,50

Talc
(%)
2,00
2,00
2,00
2,00
2,00
1,25
1,25
1,25
1,25
1,25
1,25
1,25
1,25
1,25
1,25
1,25
1,25
1,25
1,00
1,00
1,00
1,00
1,00
1,00
1,00

MS (%)

NL (%)

_
_
_
_
_
1,25
1,25
1,25
1,25
1,25
1,25
1,25
1,25
1,25
1,25
1,25
1,25
1,25
1,50
1,00
1,00
1,00
1,00
1,00
1,00

_
_
_
_
_
_
_
_
_
_
_
_
_
_
_
_
_
1,00
1,00
1,00
1,00
1,00
1,00
1,00
1,00

(NBC) natri bicarbonat, (A) Tinh bt m, (C) Cellulose vi tinh th, (D) Croscamellose, (MS) Magnesi stearat, (NL) natri lauryl sulfat

63

120%

% paracetamol gii phng

100%
80%
60%
40%

M1.1

20%

M1.2
M1.3
M1.4

0%
0

4
Thi gian (pht)

Hnh 3.8. th tc ho tan paracetamol t cc mu vin c KTTP dc cht

khc nhau.
Nhn xt:
Kt qu cho thy sau 5 pht, trn 90% dc cht c gii phng t tt c
cc mu vin. Tc ha tan c 4 mu vin khc nhau khng ng k. iu c
ngha l KTTP dc cht trong vin khng nh hng nhiu n tc ha tan dc
cht t vin trong trng hp ny. V vy, cc nghin cu tip theo khng tc ng vo
KTTP ca nguyn liu paracetamol m s dng ton b nguyn liu ban u c kch
thc tiu phn dc cht nh nh sn xut cung cp.
nh hng ca t l natri bicarbonat
kho st nh hng ca t l natri bicarbonat trong cng thc n ho tan
dc cht, tin hnh bo ch cc mu vin theo cng thc M2 M5 vi t l natri
bicarbonat khc nhau (bng 3.11) theo quy trnh bo ch hnh 2.4. Th r trong mi
trng acid v nh gi kh nng ho tan dc cht theo mc 2.2.3, thu c kt qu
th hin bng 3.12 v hnh 3.9.
64

Bng 3.12. Phn trm paracetamol ho tan t cc mu vin c t l natri

bicarbonat khc nhau (n=6)
Thi gian

T l dc cht ho tan (%)

(pht)

M2

M3

M4

M5

46,3

41,6

38,0

19,4

79,4

69,3

72,7

60,2

91,4

86,3

89,7

79,6

97,8

97,0

92,6

85,4

98,4

97,0

94,5

91,3

98,0

97,0

94,9

93,4

99,0

97,0

94,0

92,3

120.0

% paracetamol ho tan

100.0
80.0
60.0

M2 (T l 1 : 1,26)
M3 ( T l 1 : 0,95)

40.0

M4 (T l 1 ; 0,63)
M5 (T l 1 :0,13)

20.0
0.0
0

4
Thi gian (pht)

Hnh 3.9. th ho tan paracetamol t cc mu vin c t l

natri bicarbonat khc nhau

65

Nhn xt
Kt qu th r trong mi trng acid cho thy khng c s khc bit ng k
v thi gian r 3 mu vin M2, M3, M4 (thi gian r t 2-3 pht), ring mu M5 c
t l natri bicarbonat thp nht ( 1:0,13), thi gian r ko di hn (3,65 pht).
Kt qu tng t i vi php th ho tan. Mc d khng c s khc bit ng
k v tc v mc ho tan paracetamol cc mu vin M2, M3 v M4, nhng kt
qu cho thy mu M2 vi 630 mg natri bicarbonat th hin tc ho tan paracetamol
nhanh hn c. Tc ho tan chm dn khi lng natri bicarbonat gim, c bit mu
M5 th hin tc ho tan chm hn hn trong nhng pht u. Tuy nhin sau 5 pht,
lng paracetamol ho tan u t mc trn 90% tt c cc mu vin kho st.
Hn na, c nghin cu chng minh rng: t l gia paracetamol v natri
bicarbonat c nh hng n kh nng hp thu dc cht v vi t l 1:1,26 ,
paracetamol c hp thu tt nht [41]. Do , t l 1:1,26 (tng ng vi lng
natribicarbonat l 630 mg/ vin) c la chn trong cc nghin cu tip theo.
nh hng ca loi t dc r
i vi dng vin nn gii phng nhanh, t dc r ng vai tr rt quan trng
i vi qu trnh r v ho tan dc cht. Trn quan im s dng t dc siu r
nhm tng tc ho tan dc cht, mt s cng thc c tin hnh kho st
vai tr ca cc loi t dc r celulose vi tinh th (Comprecel), croscamellose
(Disolcel) v tinh bt m (Amidon) n tc ho tan dc cht. V vin bo ch c
khi lng ln nn lng t dc r c kho st vi t l ti thiu l 5%. Ring
Disolcel la chn t l ti u theo kt qu kho sts b trc l 4%.
Cc mu vin M6 M10 vi thnh phn ghi trong bng 3.11 c bo ch theo
s hnh 2.4. nh gi ho tan dc cht trong mi trng HCl 0,1N theo mc
2.2.3. Kt qu c trnh by bng 3.13 v hnh 3.10.

66

Bng 3.13. ho tan paracetamol t cc mu vin vi thnh phn t dc r

khc nhau
Thi gian

T l dc cht ho tan (%)

(pht)

M6

M7

M8

M9

M10

44,3

49,5

30,9

32,7

41,2

80,0

76,6

72,5

66,1

74,4

91,5

92,6

86,9

89,3

84,4

98,4

96,0

92,7

95,5

89,6

102,0

98,1

98,2

95,5

101,6

102,0

99,9,0

98,2

96,4

98,7

102,1

100,0

98,3

94,5

99,2

102,0

100,0

98,3

100,1

100,1

120%

% paracetamol ho tan

100%
80%
60%
M6 (CtDn)

40%

M7(DtDn)
M8(AtDn)

20%

M9(AtCn)
M10(AtAn)

0%
0

Thi gian (pht)

Ghi ch: (C)Comprecel, (D) Disolcel, (A) Amidon, (t) r trong, (n) r ngoi.

Hnh 3.10 : th ho tan paracetamol t cc mu vin s dng mt s loi t

dc r khc nhau

67

Nhn xt
Kt qu kho st khng hon ton nh gi thit ban u, cc mu vin s dng
tinh bt lm t dc r ch th hin tc r chm hn trong pht u tin. S khc
bit ny khng cn c ngha trong nhng pht sau . Sau 5 pht, lng paracetamol
ho tan t vin u t trn 90% vi tt c cc mu. Tc ho tan dc cht t vin
nn khng b nh hng ng k bi loi t dc r trong v r ngoi. Vai tr ca t
dc siu r trong trng hp ny khng pht huy tc dng do b ln t bi c ch ho
tan si bt ca natri bicarbonat trong vin trong mi trng acid.
Do vy, vi u im sn c v chi ph thp, tinh bt m (Amidon) c la chn
lm t dc r cho vin nghin cu.
nh hng ca t l tinh bt m lm t dc r
nh gi nh hng ca t l t dc r trong cng thc n kh nng ho
tan dc cht, cc mu vin M10 M16 (Bng 3.11) c bo ch vi thnh phn c
bn ging nhau nhng thay i t l t dc r trong v ngoi (1, 3, 5 v 7%). Kt qu
th ha tan cc mu vin c trnh by bng 3.14 v hnh 3.11.
Bng 3.14: Phn trm paracetamol ho tan t cc mu vin c t l t dc r
khc nhau (n=6).
Thi gian

% paracetamol ho tan

(pht)

M11

M12

M10

M13

M14

M15

M16

7,9

23,6

35,9

32,7

30,2

33,4

35,6

32,4

45,2

52,3

66,1

51,4

53,9

57,5

46,3

61,5

76,4

84,3

72,4

75,5

81,3

58,4

72,1

91,7

93,9

84,3

85,1

93,4

69,4

84,2

94,6

95,5

87,5

91,1

96,5

84,1

100,2

99,8

97,4

92,1

92,5

96,7

92,7

100,5

100,2

98,2

95,4

97,7

98,9

96,5

100,1

101,4

100,1

98,2

100,4

99,2

68

120

% paracetmaol ho tan

100
80
M11
M12
M10
M13
M14
M15
M16

60
40
20
0
0

Thi gian (pht)

Hnh 3.11. th ho tan paracetamol t cc mu vin c t l t dc r khc

nhau
Nhn xt:
T l t dc r ngoi c nh hng r rt ti tc ho tan paracetamol. Th
hin trn th hai mu vin M11 v M12 s dng tinh bt m lm t dc r vi t l
thp (1 v 3%) c tc ho tan chm hn hn so vi cc mu cn li. Mu M10 (5%)
v M13 (7%) c tc ho tan paracetamol khc nhau khng ng k.
Trong khi , d liu ho tan khng th hin c nh hng ca t l t dc
r trong i vi tc ho tan paracetamol. Cc mu M10, M14, M15 v M16 s dng
t l tinh bt r trong khc nhau nhng cho kt qu ho tan tng t nh nhau.
Trn c s cc kt qu nghin cu, tinh bt m vi t l 5% c la chn lm
t dc r trong cng nh r ngoi cho cng thc vin nghin cu.
nh hng ca t dc trn
Cc mu vin c s dng t dc trn khc nhau M17 M20 (bng 3.11) c
bo ch theo quy trnh ghi trong s hnh 2.4. nh gi ho tan dc cht theo
mc 2.2.3. Kt qu c th hin trong bng 3.15 v hnh 3.12.

69

Bng 3.15: Phn trm paracetamol ho tan t cc mu vin c thnh phn t

dc trn khc nhau(n=6)
Thi
gian

T l paracetamol ho tan (%)

M17

M18

M19

M20

(pht)

{T(1,25%) M(1,25%)}

{T(1,25%)
M(1,25%)N(1%)}

{T(1%)M(1,5%)N(1%)}

{T(1%)M(1%)
N(1%)}

30,23

40,15

48,33

46,15

68,58

74,45

70,67

80,25

85,62

88,31

90,82

92,73

95,84

92,68

100,83

94,44

98,03

97,03

102,34

94,68

100,34

98,62

102,56

96,06

99,63

97,83

102,93

96,35

100,73

97,67

102,33

98,78

(T) Talc, ( M) Magnesi stearat, ( N) Natri lauryl sulfat.

Aerosil c s dng c nh vi t l khong 0,5% trong khi t l talc v

magnesi stearat thay i nhm tm ra t l t dc trn v chng dnh thch hp cho
vin nghin cu. Vai tr ca cht din hot ti tc ho tan paracetamol t vin c
kho st thng qua vic s dng natri lauryl sulfat 1% trong cng thc cc mu vin
M18, M19 v M20.
Nhn xt
S c mt ca natri lauryl sulphat trong cng thc lm vin ho tan nhanh hn
trong pht u tin, nhng ti pht th hai tr i, hu nh khng cn s khc bit v
tc ho tan gia cc mu vin. Tc ny t b nh hng khi thay i t l
magnesi stearat v talc k c khi dng vi t l cao (1,5% mi loi). Kt qu thc
nghim cho thy sau 5 pht, c 4 mu vin u ho tan c trn 90% lng
paracetamol trong vin. Nh vy, vai tr ca natri lauryl sulfat l khng thc s cn

70

thit v t l t dc trn la chn ch cn ph thuc vo kh nng trn chy ca ht

khi dp vin, m bo ng u hm lng v hnh thc vin.

% paracetamol ho tan

120

100

80

60

M17 {T(1,25%) M(1,25%)}

M18 {T(1,25%) M(1,25%)N(1%)}

40

M19 {T(1%)M(1,5%)N(1%)}
M20 {T(1%)M(1%) N(1%)}

20

0
0

Thi gian (pht)

Hnh 3.12: th ho tan paracetamol t cc mu vin c thnh phn t dc

trn khc nhau
3.1.3.2. Kt qu nh gi nh hng ca mt s thng s k thut n thi gian r
v ho tan paracetamol t vin
nh hng ca thi gian nho m
nh gi nh hng ca thi gian nho m n tc ho tan dc cht, cc
mu vin c cng thc M21.1 M21.4 (hnh 3.11), bo ch theo s hnh 2.4, mi l
500 gam paracetamol, vi thi gian nho m ln lt l 5, 10, 15, 20 pht. Kt qu th
r v ho tan c th hin bng 3.16 v hnh 3.13.
Nhn xt:
r c phn tng ln khi ko di thi gian nho m. Tuy nhin, tc ho tan
paracetamol t cc mu vin khc nhau khng ng k.

71

Bng 3.16: Thi gian r ca cc mu vin c thi gian nho m khc nhau
Mi trng
Nc
HCl 0,1N

Thi gian r (pht)

M21.2
M21.3
(Nho 10 pht) (Nho 15 pht)
1,08
1,26

M21.1
(nho 5 pht)
1,18
2,10

2,43

M21.4
(Nho 20 pht)
1,39

2,38

2,55

120%
100%

% paracetamol ho tan

80%
60%
40%

M21.1 (Nho 5 pht)

M21.2 (Nho 10 pht)
M21.3 (Nho 15 pht)

20%

M.21.4 (Nho 20 pht)

0%
0

Thi gian (pht)

Hnh 3.13: th ha tan paracetamol t cc mu vin c thi gian nho m khc

nhau
Cc mu vin u ho tan tt paracetamol. Nh vy, thi gian nho m trong
qu trnh to ht khng nh hng ng k n mc v tc ho tan paracetamol
t vin. Thc t cho thy, thi gian nho 5 - 10 pht, khi dp vin d b bong mt v
kt chy, c th l do thi gian nho m ngn nn ht khng chc v t l bt mn sau
khi sy cao. Ngc li, khi thi gian nho m ko di, khi m d b dnh bt vo nhau
v vo thit b, kh to ht. V vy, thi gian nho m hp l c la chn l 15
pht, va m bo cht lng ht ng thi khng nh hng ti tc ho tan dc
cht.

72

 nh hng ca lc dp vin
nh gi nh hng ca lc dp vin (thng qua lc gy v vin) n ho
tan dc cht, vin c bo ch theo cng thc M22 v M23 (bng 3.11) theo quy
trnh hnh 2.4. Thay i lc dp vin thu c cc mu vin c lc gy v vin
trong cc khong 9-12 kP, 12-15 kP, 15-18 kP v 18-21 kP. Kt qu kho st nh
hng ca lc gy v vin n kh nng r v ho tan paracetamol t vin c th
hin bng 3.17, 3.18 v hnh 3.14.
Bng 3.17: Thi gian r trung bnh ca cc mu vin c cng khc nhau (n=6)
Thi gian r ca cc mu vin (kP)
(9 12)

(12 15)

(15 18)

(18 21)

Thi gian r trong nc (pht)

1,21

1,91

2,26

2,58

Thi gian r trong acid (pht)

2,14

2,25

2,27

2,34

Bng 3.18: Phn trm paracetamol ho tan t cc mu vin c cng khc nhau
T l paracetamol ho tan (%)

Thi gian
(pht)

(9 12 kP)

(12 15 kP)

(15 18 kP)

(18 21kP)

9,85

23,66

28,94

32,75

34,71

45,28

52,36

62,16

52,82

64,94

76,47

83,45

77,44

81,72

91,72

93,93

92,16

92,03

94,68

95,50

94,54

100,21

99,81

97,40

97,23

100,54

100,20

98,24

96,58

100,16

101,43

100,11

73

120

% paracetmaol ho tan

100
80

18 21kP

60

15 18 kP

40

12 15 kP
9 12kP

20
0
0

4
Thi gian (pht)

Hnh 3.14: th ho tan paracetamol t cc mu vin c cng khc nhau

Nhn xt:
Thi gian r ca vin nn tng ln theo lc gy v vin c hai mi trng
nc v acid. Trong 4 pht u tin, ho tan dc cht gn nh t l nghch vi lc
gy v vin, lc gy v vin tng lm gim tc ho tan paracetamol mt cch r rt.
Tuy nhin, n thi im 5 pht, mc ho tan dc cht t tt c cc mu vin u
trn 90% lng paracetamol v khng cn s khc bit ng k gia cc mu vin
c dp vi lc nn khc nhau. V vy, lc nn dp vin c la chn da trn c s
bn c hc ca vin. Qu trnh thc nghim cho thy, vin m bo bn c hc
v qu trnh dp vin n nh khi lc gy v vin nm trong khong 13 18 kP
nh hng ca k thut to ht
c th hn ch tng k gia paracetamol v natri bicarbonat, tin hnh
kho st quy trnh to ht ring tng loi nhm hn ch tip xc gia paracetamol v
natri bicarbonat di tc ng ca m v nhit trong qu trnh bo ch ht dp vin.
Cc mu vin M24 v M25 (bng 3.11) c bo ch theo qui trnh to ht ring (hnh
74

2.5), mc 2.2.2.1. Paracetamol v natri bicarbonat c trn ring vi t dc r trong

vi t l trong cng thc, nho m bng dung dch PVP 15% ri em xt ht. Cc mu
vin M24 v M25 c em so snh vi ln lt cc mu M22 v M23 c cng cng
thc nhng bo ch theo qui trnh to ht chung v mc nh hng ti tc ho
tan dc cht.
Bng 3.19: Phn trm paracetamol ho tan t cc mu vin bo ch theo qui trnh
khc nhau
T l paracetamol ho tan (%)

Thi gian
(pht)

To ht ring

To ht chung

M24

M25

M22

M23

55,8

47,1

39,9

38,0

96,2

92,4

67,5

64,7

100,2

97,0

83,4

87,8

100,5

100,3

90,0

95,0

100,7

100,3

93,6

95,4

100,7

100,5

98,0

96,0

100,7

100,6

98,6

96,5

Kt qu kho st cho thy, cc mu vin c bo ch theo qui trnh to ht

ring th hin tnh u vit hn v tc ho tan so vi cc mu vin bo ch theo qui
trnh to ht chung. Vin ho tan paracetamol nhanh hn, cc mu vin M24 v M25
ho tan trn 90% dc cht ch trong 2 pht trong khi M22 v M23 phi mt 4 pht
(Bng 3.19 v hnh 3.15)
Nh vy, vic p dng qui trnh to ht ring khng nhng hn ch c tng
k gia paracetamol v natri bicarbonat m cn gip vin ho tan nhanh hn so vi qui
trnh to ht chung

75

120%
% paracetamol ho tan

% Paracecetamol hotan

120%
100%
80%
60%
M24 To ht ring

40%

M22: To ht chung

20%

100%
80%
60%

M25: To ht ring

40%

M23: To ht chung

20%
0%

0%
1

Thi gian (pht)

Thi gian (pht)

Hnh 3.15: So snh th ho tan paracetamol t cc mu vin cng cng thc

bo ch nhng vi qui trnh to ht chung v to ht ring.
T cc kt qu nghin cu thc nghim thu c nh trnh by trn,
phng php bo ch vin nn gii phng nhanh paracetamol 500 mg c la chn l
s dng h si ni vi cng thc bo ch vin nh sau:

Thnh phn nguyn liu

1 vin

Paracetamol

500 mg

Natri bicarbonat

630 mg

Tinh bt m

115 mg

PVP K30 *

36 mg

Aerosil

6 mg

Talc

12 mg

Magnesi stearat

12 mg

Khi lng vin

1311 mg

Ghi ch: (*) PVP c pha thnh dung dch t dc dnh 15% trong ethanol.

76

Vin c bo ch theo qui trnh m t trong s hnh 2.5. Hai thnh phn:
paracetamol v natri bicarbonat c to ht ring bit ri phi hp vi cc t dc
dp vin.
3.2. Xy dng tiu chun cht lng vin nn paracetamol gii phng nhanh
3.2.1. Kho st ch tiu cht lng
Tin hnh bo ch 3 l theo cng thc v qui trnh la chn trn, mi l tng
ng vi 2000 vin kho st cc ch tiu cht lng vin.
nh tnh
nh tnh cc mu vin theo DVN III, chuyn lun Vin nn paracetamol
u cho kt qu dng tnh.
ng u khi lng
Kt qu kho st ng u khi lng vin c trnh by bng 3.20.
Nhn xt: Khi lng ca cc vin t chnh lch nhau v chnh lch so vi khi
lng trung bnh vin u di 5% cho thy ch phm t yu cu v ng u
khi lng theo quy nh ca DVN III.
ha tan
Tin hnh th ha tan cc mu vin theo mc 2.2.3. Kt qu c trnh by
bng 3.21.
Kt qu cho thy ch phm t tiu chun v ha tan (tt c cc vin u ho
tan trn 90% lng dc cht sau 5 pht) v chnh lch v ha tan gia cc vin
thp.
4-aminophenol
S dng phng php HPLC, vi iu kin sc k nh sau:
-

H thng sc k lng hiu nng cao Thermo Finigan

77

Ct Apollo C18 (4,6250 mm, 5m)

Pha ng: dung dch natri butansulfonat 0,01M trong hn hp acid formic :
methanol : nc (0,4 : 15 : 85).

Tc dng

: 2 ml/pht

Th tch tim mu : 20 l

Detector t ngoi vi bc sng : 272 nm

Kt qu sc k cho thy dung dch chun 4-aminophenol cho pic chnh vi thi

gian lu 4,4 pht, trong khi cc mu vin khng thy xut hin pic ti thi im ny,
ngha l hm lng 4-aminophenol trong cc mu vin u nh hn 0,01%. (Hnh
3.17).
Tp cht lin quan
Tin hnh sc k lp mng theo DVN III, chuyn lun Vin nn
paracetamol. Hnh nh sc k cho thy dung dch th cho 2 vt tch r rng, vt
tng ng vi 4-cloroacetanilid c gi tr Rf cao hn, khng c vt no tng ng vi
vt ca 4-cloroacetanilid trn sc k ca dung dch th m hn vt trn sc k
ca dung dch i chiu, cng nh khng c vt no c Rf thp hn Rf ca 4cloroacetanilid m hn vt trn sc k ca dung dch i chiu.
Bng 3.20. Kt qu kho st ha tan ca vin nn paracetamol
Vin s

Lng paracetamol ho tan sau 5 pht (%)

L 1

L 2

L 3

98,35

96,56

96,12

99,99

97,52

98,42

98,36

98,92

97,24

95,24

99,61

98,36

99,31

96,41

95,24

97,12

95,54

97,30

98,06 1,69

97,43 1,57

97,11 1,25

SD (%)

78

Bng 3.21. Kt qu kho st ng u khi lng vin paracetamol

Vin
th

Khi lng

Chnh lch so vi

vin (mg)

KLTB vin (%)

L 1

L 2

L 3

L 1

L 2

L 3

1318,7

1282,3

1293,6

0,48

-1,66

-0,52

1322,6

1290,3

1285,8

0,78

-1,05

-1,12

1299,2

1300,0

1286,4

-1,01

-0,31

-1,08

1299,6

1320,7

1326,5

-0,98

1,28

2,01

1304,3

1316,5

1320,3

-0,62

0,96

1,53

1313,5

1320,6

1326,5

0,08

1,27

2,01

1287,3

1303,9

1302,4

-1,91

-0,01

0,15

1322,4

1300,2

1315,6

0,76

-0,29

1,17

1337,8

1322,6

1312,2

1,94

1,43

0,91

10

1319,7

1312,0

1280,2

0,56

0,61

-1,55

11

1321,4

1315,1

1292,5

0,69

0,85

-0,61

12

1313,6

1326,6

1306,6

0,09

1,73

0,48

13

1326,8

1282,4

1263,8

1,10

-1,66

-2,81

14

1310,5

1293,7

1275,2

-0,14

-0,79

-1,94

15

1302,0

1276,6

1293,4

-0,79

-2,10

-0,54

16

1315,9

1305,2

1313,9

0,27

0,09

1,04

17

1313,2

1280,3

1285,4

0,06

-1,82

-1,15

18

1301,5

1293,4

1327,2

-0,83

-0,81

2,06

19

1299,2

1306,9

1293,3

-1,01

0,22

-0,55

20

1319,2

1330,5

1306,8

0,52

2,03

0,49

KLTB vin (mg)

1312,4

1304,0

1300,4

11,7

16,0

17,8

79

Hnh 3.16: Sc mu chun 4-aminophenol

Hnh 3.17: Sc nh lng 4-aminophenol trong vin paracetamol

80

 nh lng paracetamol
nh lng bng phng php quang ph hp th t ngoi theo ch dn ca
DVN III. Kt qu nh c c trnh by trong bng 3.22.
Kt qu thc nghim cho thy c 3 l u t yu cu v hm lng dc cht
t 95% n 105% so vi hm lng ghi trn nhn.
Bng 3.22. Kt qu nh lng paracetamol trong vin nn ca 3 l kho st
ch tiu cht lng .
Ln

Hm lng paracetamol trong vin (%)

L 1

L 2

L 3

99,39

99,57

99,85

99,43

99,65

100,34

99,80

100,96

100,22

99,66 0,23

99,90 0,78

100,01 0,26

SD (%)

3.2.2. xut tiu chun vin nn paracetamol gii phng nhanh

Da vo kt qu kho st thu c nh trnh by trong mc 3.2.1, tiu chun c
s ca vin nn paracetamol gii phng nhanh c xut nh sau:
3.2.2.1. Yu cu k thut
Cng thc bo ch: Cho 1 vin nn.
- Paracetamol:

500mg

- T dc:

v 1 vin

(Natri bicarbonat, PVP K30, Ethanol, Amidon, Talc, Magnesi stearat, Aerosil, nc
tinh khit)
Nguyn liu:
- Paracetamol:

t tiu chun DVN III.

- Natri bicarbonat:

t tiu chun BP 2007.

- PVP K30:

t tiu chun BP 2007.

81

- Ethanol:

t tiu chun DVN III.

- Amidon:

t tiu chun BP 2007.

- Talc:

t tiu chun DVN III.

- Magnesi stearat:

t tiu chun DVN III.

- Aerosil:

t tiu chun USP 30 - NF 25.

- Nc tinh khit:
Cht lng thnh phm:

t tiu chun DVN III.

- Hnh thc: Vin nn hnh caplet, mu trng, mt mt c vch ngang, khng

st v.
- nh tnh: Ch phm phi cho php th nh tnh paracetamol.
- ng u khi lng: Khi lng trung bnh vin 5,0%.
- ha tan: Khng di 90,0% lng paracetamol (C8H9NO2), so vi lng
ghi trn nhn, c ha tan trong 5 pht.
- 4-Aminophenol: Khng qu 0,01%.
- Tp cht lin quan: Phi t theo quy nh ca DVN III chuyn lun Vin
nn paracetamol mc Tp cht lin quan.
- nh lng: Hm lng paracetamol (C8H9NO2) phi t 95,0% n 105,0%,
so vi lng ghi trn nhn.
3.2.2.2. Phng php th
Hnh thc: Bng cm quan, ch phm phi t cc yu cu nu.
nh tnh: Th theo DVN III chuyn lun Vin nn paracetamol mc nh
tnh
ng u khi lng: Th theo DVN III - Ph lc 8.3.
ho tan: Th theo DVN III - Ph lc 8.4.
Thuc th: Theo DVN III.
iu kin ha tan:
- Mi trng ha tan: Dung dch acid hydrocloric 0,1N (TT): 900ml,
- Thit b: Cnh khuy,
- Tc : 50 vng/pht,
82

- Thi gian: 5 pht.

nh lng paracetamol (C8H9NO2) ha tan: (Phng php quang ph UVVIS). Th theo DVN III - Ph lc 3.1.
Dung dch chun: Cn chnh xc khong 27,7mg paracetamol chun vo bnh
nh mc dung tch 50ml. Ha tan v pha long bng dung dch acid hydrocloric 0,1N
(TT) va n vch, trn u. Ht chnh xc 2,0ml dung dch trn vo bnh nh mc
dung tch 100ml v pha long bng dung dch acid hydrocloric 0,1N (TT) va n
vch, trn u.
Dung dch th: Sau thi gian th quy nh, ht 50ml mi trng, lc qua giy
lc v b 20ml dch lc u. Ht chnh xc 2,0ml dch lc vo bnh nh mc dung tch
100ml v pha long bng dung dch acid hydrocloric 0,1N (TT) va n vch, trn
u.
Tin hnh: o hp th ca cc dung dch th v dung dch chun bc
sng cc i khong 242nm, cc o dy 1cm, mu trng l dung dch acid hydrocloric
0,1N (TT).
Tnh kt qu: Da vo hp th ca dung dch th v dung dch chun, hm
lng cht chun; tnh hm lng (%) paracetamol (C8H9NO2), so vi lng ghi trn
nhn, c ha tan trong 5 pht.
4-Aminophenol: Th theo DVN III chuyn lun Vin nn paracetamol mc
4-Aminophenol.
Tp cht lin quan: Th theo DVN III chuyn lun Vin nn paracetamol
mc Tp cht lin quan.
nh lng: Th theo DVN III chuyn lun Vin nn paracetamol mc
nh lng.
Tiu chun c Vin kim nghim thuc trung ng thm nh v nht tr
vi tiu chun xut (Ph lc 2).
3. 3. Nghin cu n nh
3.3.1. nh gi n nh

83

Cc mu vin paracetamol ca 3 l (2000 vin) khc nhau bo ch thng

02/2008 theo quy trnh ghi ph lc 1 c ng gi trong 2 loi bao b l v PVCnhm v nhm-nhm ri bo qun cc iu kin nh nu trong mc 2.2.4. Cc ch
tiu cht lng c nh gi nh nu trong xut tiu chun vin nn paracetamol
gii phng nhanh. Kt qu kho st cc ch tiu cht lng ca vin nh sau:
Hnh thc
So vi vin mi bo ch, cc mu vin ng gi trong c bao b v PVC-nhm
v v nhm-nhm khi bo qun iu kin thng sau 24 thng u khng c s thay
i ng k v mt hnh thc. Tuy nhin, iu kin lo ha cp tc, ch c cc mu
vin ng gi trong v nhm-nhm l gi c hnh thc khng thay i so vi ban
u, cn cc mu ng gi trong bao b v PVC-nhm bt u c s thay i ng k
v mt hnh thc t thng th 3: b mt vin khng cn trng, bng m tr nn sm
mu hn v x x. iu ny cho thy vin ng gi trong bao b v PVC-nhm ht
m v tr nn km n nh, cht liu PVC c kh nng chng m km hn nhm.
Bng 3.23. Phn trm paracetamol ho tan sau 5 pht t cc mu vin bo qun
iu kin lo ha cp tc (n=6, P=0,95)
Thi gian
bo qun
(thng)

L 1
98,36
0
3,17
96,72
1
2,82
94, 33
3
2,74
91,17
6
3,08
ha tan

% paracetamol ho tan
V PVC-nhm
V nhm-nhm
L 2
99,31
2,58
97,07
2,69
95,15
2,24
90,76
3,27

L 3
97,12
2,92
95,75
2,87
93,18
2,66
91,03
2,54

L 1
98,35
3,28
97,27
3,24
96,42
2,84
95,08
2,61

L 2
99,92
3,24
98,48
2,97
97,26
2,63
95,94
3,01

L 3
97,40
3,47
96,19
2,72
95,84
2,53
94,50
2,61

Kt qu kho st ha tan dc cht t vin nn gii phng nhanh trong cc

iu kin bo qun lo ho cp tc v iu kin thc c trnh by bng 3.23 v
3.24.

84

Sau 24 thng bo qun iu kin thng v 6 thng bo qun iu kin lo ha cp

tc, khng nhn thy s thay i ng k v mc v tc ha tan dc cht cc
mu vin ng gi trong bao b v nhm-nhm.
Trn 90% lng paracetamol ho tan tt c cc mu vin. Mt s mu vin
ng gi trong bao b v PVC-nhm t thng th 6 trong iu kin lo ha cp tc v
t thng th 15 trong iu kin thng c t l phn trm dc cht ho tan gim ng
k, nhng vn t yu cu v ch tiu ho tan.
Bng 3.24. Phn trm paracetamol ho tan sau 5 pht t cc mu vin bo qun
iu kin thng (n=6, P=0,95)
Thi gian
bo qun
(thng)
0
1
3
6
9
12
15
18
24

% paracetamol ho tan
V PVC-nhm
V nhm-nhm
L 1
98,36
2,28
98,22
3,06
98,03
2,13
97,41
2,92
96,25
1,99
95,43
2,25
94,84
2,34
92,18
2,47

L 2
99,31
3,34
99,07
2,42
98,24
2,27
97,71
3,42
96,03
1,38
95,32
3,15
93,26
2,53
91,72
2,91

L 3
97,12
2,84
96,81
3,18
96,13
2,96
95,37
2,92
94,82
3,13
93,12
3,20
92,41
3,06
91,17
2,85

L 1
98,35
2,38
98,30
2,26
98,12
3,17
97,75
2,73
97,42
2,67
97,16
2,52
96,94
2,48
96,17
3,30
96,11
2,45

L 2
99,92
3,26
99,57
2,53
99,12
2,42
98,74
2,16
98,22
2,88
97,53
2,27
97,04
2,92
96,32
3,29
95,76
3,05

L 3
97,40
2,78
97,15
2,84
96,87
3,17
96,22
3,43
95,38
2,52
95,00
2,44
94,41
3,30
94,11
3,35
92,89
3,14

4-aminophenol
Kt qu nh lng tp cht 4-aminophenol cho thy cc mu vin ng gi
trong bao b v nhm-nhm u t yu cu v hm lng 4-aminophenol (< 0,1%) khi
bo qun c trong iu kin thc v lo ha cp tc.
85

Bng 3.25. Hm lng 4-aminophenol (%) trong cc mu vin bo qun

iu kin thng (n=3, P=0,95)
Thi gian
bo qun
(thng)
0
1
3
6
9
12
15
18
24

T l 4-aminophenol trong vin (%)

V PVC-nhm
V nhm-nhm
L 1
0,0034
0,00013
0,0052
0,00021
0,0096
0,00025
0,0163
0,00038
0,0277
0,00032
0,0358
0,00029
0,0375
0,00030
0,0536
0,00037

L 2
0,0036
0,00024
0,0049
0,00027
0,0073
0,00029
0,0181
0,00017
0,0249
0,00023
0,0384
0,00037
0,0398
0,00034
0,0512
0,00021

L 3
0,0037
0,00018
0,0069
0,00025
0,0093
0,00013
0,0154
0,00029
0,0278
0,00031
0,0396
0,00032
0,0425
0,00030
0,0525
0,00024

L 1
0,0032
0,00014
0,0036
0,00012
0,0063
0,00010
0,0138
0,00025
0,0212
0,00018
0,0284
0,00025
0,0363
0,00028
0,0451
0,00026
0,0541
0,00030

L 2
0,0035
0,00020
0,0048
0,00015
0,0066
0,00024
0,0121
0,00017
0,0197
0,00024
0,0251
0,00019
0,0326
0,00015
0,0402
0,00022
0,0537
0,00027

L 3
0,0035
0,00017
0,0043
0,00018
0,0082
0,00023
0,00184
0,00018
0,0245
0,00021
0,0313
0,00023
0,0382
0,00024
0,0507
0,00019
0,0555
0,00024

Bng 3.26. Hm lng 4-aminophenol (%) trong mu vin khi bo qun

iu kin lo ha cp tc (n=3)
Thi gian
bo qun
(thng)
0
1
3
6

T l 4-aminophenol trong vin (%)

V PVC-nhm
L 1
0,0034
0,00013
0,0231
0,00032
0,0782
0,00025
0,0994
0,00027

L 2
0,0036
0,00024
0,0265
0,00037
0,0841
0,00026
0,125
0,00013

V nhm-nhm
L 3
0,0037
0,00018
0,0351
0,00025
0,0824
0,00030
0,109
0,00034

86

L 1
0,0032
0,0014
0,0174
0,00021
0,0486
0,00027
0,0792
0,00029

L 2
0,0035
0,00020
0,0214
0,00018
0,0533
0,0015
0,0854
0,00025

L 3
0,0035
0,00017
0,0199
0,00033
0,0515
0,00031
0,0820
0,00030

Vin ng gi trong v PVC-nhm vn t yu cu v hm lng 4aminophenol sau 18 thng bo qun iu kin thng, nhng khng t yu cu sau
6 thng bo qun iu kin lo ha cp tc (hm lng 4-aminophenol > 0,1%).
(Bng 3.25 v 3.26)
Hm lng dc cht
S thay i hm lng dc cht ca cc mu vin trong qu trnh bo qun
c trnh by cc bng 3.27 v bng 3.28.
Bng 3.27. Hm lng (%) paracetamol trong vin nn gii phng nhanh bo qun
iu kin thc (n=3, P=0,95)
Thi gian bo qun
(thng)

% paracetamol trong vin

V PVC-nhm
V nhm-nhm
L 1

L 2

L 3

L 1

L 2

L 3

100,75
1,28
100,64
1,35
100,31
1,04
99,90
0,95
98,63
0,86
97,75
1,07
96,29
1,13
95,15
0,91

100,25
0,94
100,04
1,18
99,78
1,22
98,93
0,89
98,20
0,95
96,59
1,28
96,42
1,43
95,72
1,21

101,33
1,23
100,41
1,18
99,42
0,96
98,51
0,92
97,25
1,13
96,30
1,20
95,87
1,06
95,05
0,85

21

24

100,69
1,22
100,54
1,26
100,32
1,15
99,93
0,97
99,67
0,92
99,40
1,18
98,85
1,24
98,54
1,07
98,46
1,21
98,09
0,87

101,18
0,87
100,94
1,23
100,72
1,18
100,35
0,95
99,93
0,88
99,52
1,14
99,27
1,25
99,00
1,09
98,72
0,87
98,40
0,89

101,32
1,15
101,07
0,97
100,93
1,24
100,66
1,16
100,32
0,78
99,86
0,58
99,64
1,22
99,24
0,74
99,07
1,11
98,83
0,98

0
1
3
6
9
12
15
18

87

Kt qu thy vin c ng gi trong v nhm-nhm c hm lng

paracetamol t thay i sau khi bo qun iu kin thng 24 thng v iu kin lo
ha cp tc 6 thng.
Bng 3.28. Hm lng (%) paracetamol trong vin nn gii phng nhanh bo qun
iu kin lo ha cp tc(n=3, P=0,95)
% paracetamol trong vin

Thi gian
bo qun
(thng)
0

V PVC-nhm

V nhm-nhm

L 1

L 2

L 3

L 1

L 2

L 3

100,29

100,33

101,35

100,57

100,41

101,28

1,52

0,96

1,36

1,42

0,98

1,50

98,05

97,05

98,97

100,23

100,23

100,65

1,19

0,87

1,33

1,26

1,40

1,38

96,34

95,98

96,52

99,54

99,84

100,03

1,24

1,25

1,29

1,37

0,94

1,29

94,83

94,04

95,18

98,84

98,20

99,74

1,36

1,42

1,34

1,28

0,99

1,10

3.3.2. Xc nh tui th ca thuc

Vic tnh ton, d on s thay i hm lng paracetamol trong ch phm cn
c vo s liu thu c trong qu trnh bo qun thuc iu kin thc c thc hin
theo cc quy nh, hng dn ca ASEAN v ICH [15],[50].
Xc nh tui th ca thuc c xc nh cho vin c p trong dng v
nhm-nhm. V khng c s thay i mc c ngha i vi cc mu vin ng gi
trong v nhm-nhm bo qun iu kin lo ha cp tc nn c th dng s liu bo
qun iu kin thc xc nh tui th ca thuc bng php phn tch hi quy v
ngoi suy.
88

T cc s liu trong bng 3.27, tnh c t l phn trm dc cht cn li trong

ch phm so vi ban u nh ghi trong bng 3.29.
Bng 3.29. T l paracetamol trong vin thc nghim cn li so vi ban u khi bo
qun trong v nhm-nhm iu kin thng
Thi gian bo qun

T l % paracetamol cn li so vi ban u

(thng)

L 1

L 2

L 3

100,00 1,21

100,00 0,98

100,00 1,13

99,85 1,25

99,76 1,05

99,75 0,99

99,63 1,15

99,55 1,17

99,62 1,23

99,25 0,97

99,18 0,85

99,35 1,15

98,99 0,92

98,77 0,89

99,01 0,78

12

98,73 1,17

98,36 1,16

98,56 0,58

15

98,17 1,25

98,12 1,23

98,34 1,22

18

97,86 1,09

97,85 1,07

97,95 0,73

21

97,79 0,98

97,57 0,79

97,78 1,00

24

97,42 0,80

97,25 0,82

97,54 0,91

Trong qu trnh bo qun, hm lng paracetamol ch gim m khng th tng,

nn xc nh tui th ca thuc i vi tiu ch ny, ch cn xem xt gi tr trung
bnh v ng gii hn di vi P=0,95 l c. Kt qu c trnh by bng 3.30
v hnh 3.18.
Bng 3.30: Phng trnh hi qui tuyn tnh gim hm lng paracetamol theo thi
gian bo qun trong iu kin thc v d tnh tui th thuc.
L

Phng trnh tuyn tnh

Tui th d tnh (thng)

Y = 98,8216 +( -0,1098721 ) X

32,7

Y = 99,14538 +( -0,1211358 ) X

32,2

Y = 98,993 +( -0,1070643 ) X

34,1

89

L 1
L 2
L 3

Hnh 3.18. ng hi quy gi tr trung bnh v cn di 95% d on

hm lng paracetamol trong vin ca 3 l cn li so vi ban u trong iu kin
bo qun thc (n=5, P=0,95)
Nhn xt:
Nu gi thit ng hc phn hy paracetamol trong vin nn khng thay i
trong qu trnh bo qun v nu thi gian theo di, c th ly gi tr thp nht ca
X trong 3 l (X = 32,2 thng) l tui th ca ch phm nghin cu i vi tiu chun
v hm lng dc cht. Thi gian bo qun c 24 thng nn i chiu vi tiu
chun ny ti thi im hin ti, c th d on tui th ca ch phm nghin cu l 32
thng.
3.4.. Hon thin v thm nh qui trnh sn xut vin nn paracetamol gii phng
nhanh
3.4.1. Hon thin qui trnh sn xut vin nn paracetamol gii phng nhanh
3.4.1.1. Nhng thay i chnh khi nng c l
90

Cng thc v qui trnh sn xut vin nn paracetamol gii phng nhanh c bn
da trn cng thc v qui trnh bo ch vin xy dng. Tuy nhin, khi trin khai sn
xut ti cng ty Dc Khoa, mt s thit b mi thay i bao gm: my nho trn cao
tc, my xt ht, my sy tng si (sy ht) v my dp vin quay trn 8 chy.
m bo cht lng ch phm nghin cu, tin hnh kho st qui trnh to
ht v dp vin trn h thng thit b sn xut vi qui m bng cng sut ti thiu ca
my nho trn cao tc, tng ng vi 5000 g paracetamol. Trn c s hiu chnh
cng thc cng nh cc thng s k thut ca cc bc trong qui trnh sn xut cho
ph hp. Kt qu kho st c trnh by tm tt bng 3.31.
Bng 3.31: So snh cc thng s khi thay i thit b sy v my dp vin
Thng s
Dung mi ho tan PVP

L thc nghim

L SX kho st

Ethanol 96o

Nc (ht paracetamol)
Ethanol 60o (ht NBC)

Thi gian sy

4 5 gi

30 pht

< 0,2

5,0 %

22,7 %

0,2 0,4

10,5 %

23,5 %

0,4 0,6

18,5 %

13,5 %

0,6 0,8

20,3 %

12,3 %

0,8 1,0

34,1 %

11,7 %

> 1,0

11,6 %

16,3 %

Ht paracetamol

0,68

0,64

Ht natri bicarbonat

1,12

1,08

Aerosil

0,5 %

0,3 %

Talc

1,0 %

1,25 %

Magnesi stearat

1,0 %

0,2 %

10,3 g/s

10,2 g/s

Phn b kch thc ht paracetamol

T trng ht

T dc trn

trn chy (sau trn hon tt)

91

 Thay i thit b sy
Thi gian sy ht bng my sy tng si nhanh hn nhiu, m ca hai loi
ht t yu cu (hm m 2 3%) ch sau 20 - 30 pht.
Ht paracetamol v natri bicarbonat sau khi sy b v vn, to rt nhiu bt mn.
Xc nh kh nng do ethanol bay hi nhanh ng thi ht b va p mnh trong qu
trnh sy v s kt dnh gia cc tiu phn km. Bin php khc phc l thm nc vo
dung mi pha PVP lm v lm nh kch thc tiu phn dc cht. Thc t kt qu
kho st cho thy phi p dng c hai bin php nu trn, ht paracetamol v natri
bicarbonat thu c mi t yu cu. C th l s dng ethanol 60o pha dung dch t
dc dnh PVP 15% v xay mn paracetamol v natri bicarbonat qua ry 0,25 mm.
Thay i my dp vin
Cc mu vin kho st xy dng cng thc bo ch c dp bng my dp
vin tm sai. Xt v mt l thuyt, so vi my dp vin quay trn, kh nng phn phi
bt ca my tm sai km m bo tnh ng nht v th tch hn nn vin cn t l cao
t dc trn v chng dnh. Tuy phn b kch thc ht khng ng u, khc nhiu so
vi sy tnh, ht sau sy tng si vn c trn chy tt hn, ngay c khi gim tng
lng t dc trn so vi la chn ban u (t 2,5 % xung cn 1,75 %)
3.4.1.2. Cng thc vin
T kt qu nghin cu trn, cng thc l sn xut 30000 vin c iu chnh
nh ghi bng 3.32.
Bng 3.32. Cng thc sn xut l 30.000 vin
Thnh phn nguyn liu

Tnh cho 1 vin

L 30.000 vin

Paracetamol

500 mg

15,00 kg

Natri bicarbonat

630 mg

18,90 kg

Tinh bt m (r trong)

54 mg

1,62 kg

PVP K30

36 mg

1,08 kg

Nc tinh khit *

0,10 ml

3,00 l

Ethanol 60o *

0,13 ml

3,78 l

92

Tinh bt m (r ngoi)

61 mg

1,83 kg

Aerosil

3,7 mg

0,111 kg

Talc

16,3 mg

0,489 kg

Magnesi stearat

2,5 mg

0,075 kg

1303 mg

39,09 kg

Tng khi lng

Ghi ch: (*) bay hi trong qu trnh sn xut

3.4.1.3. Tm tt quy trnh sn xut

Quy trnh sn xut gm cc giai on chnh sau y:
Chun b nguyn liu: xay paracetamol v natri bicarbonat 2 ln bng my xay
inh, tt c cc tiu phn paracetamol v natri bicarbonat u phi i qua ry c
kch thc mt ry l 0,25 mm.
Trn bt kh:
- To ht paracetamol: trn paracetamol v tinh bt m
- To ht natri bicarbonat: trn natri bicarbonat v tinh bt m
Nho m: nho m v to ht vi dung dch PVP 15% trong ethanol 60o
Sy: sy ht 45-50oC n m 2-3%
Sa ht: sa ht qua ry c kch thc mt ry 1 mm
Trn hon tt: trn ht paracetamol v ht natri bicarbonat vi talc, magnesi
stearat, aerosil v tinh bt m r ngoi.
Dp vin caplet, lc gy v vin trong khong 13-18 kP, khi lng 1,303 g
3.4.1.4. S quy trnh sn xut
Qui trnh sn xut vin nn paracetamol gii phng nhanh c trnh by tm
tt theo s hnh 3.19.

93

Kim sot trong qu trnh sn xut:

Paracetamol
Tinh bt m

Trn bt kh

Natri bicarbonat
Tinh bt m
My nho trn
cao tc

Trn bt kh

ng nguyn liu
Khi lng nguyn liu
mn
Thi gian trn
phn tn hm lng

Dung dch PVP 15%

Lng t dc dnh
Nho m

Nho m

My nho trn
cao tc

To ht

Sy kh

Sa ht

Talc
Magnesi stearat
Aerosil

Thi gian nho m

To ht
My sy
tng si
45 - 50oC
m 2-3%
My xt ht
Ry 1 mm
Trn hon tt

Sa ht

C ry
Phn b kch thc ht
T trng biu kin

My trn
lp phng

Dp vin
Hnh 3.19. S qui trnh sn xut vin nn
paracetamol gii phng nhanh

Sy kh

Nhit sy
Thi gian sy
m cm

94

My dp vin
quay trn
cng

13-18 kP

Thi gian trn

phn tn hm lng
trn chy
Hm lng
phn tn khi lng trung bnh
ng u khi lng
cng
ha tan

3.4.2. Thm nh quy trnh sn xut vin nn paracetamol gii phng nhanh
3.4.2.1. nh gi nguy c gy mt n nh quy trnh sn xut
Phn tch tng giai on ca quy trnh bo ch nh gi cc nguy c nh
hng v c th lm cho quy trnh sn xut khng n nh (bng 3.33). T xut
bin php x l cng nh cc thng s cn thm nh hn ch cc nguy c ny.
Bng 3.33. nh gi nguy c nh hng n n nh ca quy trnh sn xut
Giai on
(1)

Nguy c d kin
(2)

Trn bt

Hm lng

kh

khng ng u

Tn
sut
nguy
c
(3)
Thp

nh
hng
(4)

Nhiu

Kh
nng
pht
hin
(5)

Bin php x l
(6)

Kh

Kim sot thi gian trn,

tc trn, lng bt
em trn
Thm nh phn tn
hm lng
Kim sot thi gian nho,
tc nho

Hm lng
Nho m
Xt ht

khng ng u
Th cht ht khng

Thp
Thp

Nhiu
Trung

ng nht

m khng t

Kh
D

bnh

Thp

Trung

Sy
Thp

Nhiu

Thm nh phn tn
hm lng
Thm nh hnh thc ca
ht

Kim sot thi gian sy,

nhit sy, lng ht
em sy, nhit vo/ra,
lu lng gi vo/ra

Kh

Kim sot n nh ca
dc cht

bnh
nh hng n
n nh ca dc
cht

Kim sot lng t dc

dnh

Thm nh m ca ht
Lng tp cht

95

Sa ht

Phn b kch thc

ht thay i

Trung

Trung

bnh

bnh

T trng biu kin

thay i

Trung

Trung

bnh

bnh

Thm nh t trng biu

kin

Thp

Nhiu

Kh

Kim sot thi gian trn,

vn tc trn, khi lng
ht

Trung

Trung

Kh

bnh

bnh

Hm lng khng
ng u

Trn
hon tt

Kim sot c ry, vn tc

xt ht, lng ht em xt

trn chy thay

i

Thm nh phn b
D

kch thc ht

Thm nh phn tn
hm lng
Thm nh trn chy
ca ht

Khi lng vin

khng ng u
cng khng t
Dp vin

Kim sot tc dp
Trung

Nhiu

Thm nh phn tn
khi lng vin

Trung

Thm nh cng

bnh
Thp

Thm nh ha tan

bnh
ha tan khng
t

Thp

Nhiu

Kh

3.4.2.2. La chn cc thng s thm nh

Qua nh gi nguy c nh trn, chng ti la chn cc thng s cn thm nh
nh sau: (bng 3.34)
- Thng s trng yu:

96

Bng 3.34. Cc thng s trng yu cn thm nh

STT

Thng s

Yu cu

Giai on trn bt kh
1
phn tn hm CV 2%
lng
Giai on nho m
2
phn tn hm CV 2%
lng
Giai on sy ht
3
m
2,0 3,0%
Sa ht
4
Phn b kch thc Cc gi tr phi
ht
ng nht gia 3 l
5
T trng biu kin
Cc gi tr phi
ng nht gia 3 l
Trn hon tt
6
phn tn hm CV 2%
lng
7
trn chy
Cc gi tr phi
ng nht gia 3 l
8
T trng ht
Cc gi tr phi
ng nht gia 3 l
Giai on dp vin
9
ng u khi lng Khi lng trung
bnh vin 5%
10
11

cng
ha tan

13-18 kP
90% sau 5 pht

Phng php
Thc nghim

Thc nghim

Thc nghim
Thc nghim
Mc 2.2.3

Thc nghim
Mc 2.2.3
Mc 2.2.3

Theo DVN III,

Ph lc 8.3
Thc nghim
Theo DVN III,
Ph lc 8.4

- Thng s kim sot:

Khi lng vin c la chn lm thng s kim sot quy trnh v y l mt
thng s quan trng m GMP khuyn co phi kim sot trong sut qu trnh dp vin.

97

3.4.2.3. K hoch ly mu trong qu trnh thm nh

Tin hnh ly mu nh ghi bng 3.35 ri nh gi cht lng mu bng
phng php thch hp.
Bng 3.35. K hoch ly mu trong qu trnh thm nh
Giai on

S lng mu

Thng s thm nh

Trn bt kh

5 mu (theo s )

phn tn hm lng

Nho m

5 mu (theo s )

phn tn hm lng

Sy ht

3 mu (ngu nhin)

m ht

Sa ht

100 g x 2 mu (ngu nhin)

Phn b kch thc ht

100 g x 2 mu (ngu nhin)

T trng biu kin

5 mu (theo s )

phn tn hm lng

100 g x 3 mu (ngu nhin)

trn chy

100 g x 2 mu (ngu nhin)

T trng biu kin

20 vin x 4 ln/l

ng u khi lng vin

10 vin x 4 ln/l

cng

6 vin x 1 ln/l

ha tan

10 vin mi 30 pht

Khi lng (trung bnh)

Trn hon tt

Dp vin

Cc mu thm nh phn tn hm lng c ly theo s hnh 3.20

1
1

2
3
3

4
4

5
My nho trn cao tc

Hp trn lp phng

Hnh 3.20. S ly mu thm nh d phn tn hm lng

98

3.4.2.4. Giai on trn bt kh

Trn paracetamol v tinh bt m
nh gi ng nht ca khi bt trn c da trn kt qu phn tch phn
tn hm lng paracetamol. Kt qu c trnh by bng 3.36 v 3.37.
Bng 3.36. phn tn hm lng paracetamol l P1, giai on trn bt kh.
V tr

Hm lng paracetamol (%)

3 pht

4 pht

5 pht

7 pht

97,56

96,45

96,78

98,76

98,24

99,72

99,65

98,52

94,15

100,05

98,76

95,84

101,64

98,34

100,02

96,20

97,51

96,72

96,85

97,76

Gi tr trung bnh

97,82

98,26

98,41

97,42

lch chun

2,66

1,66

1,53

1,33

H s phn tn CV (%)

2,72

1,69

1,55

1,37

l P1 tin hnh ly mu ti cc thi im 3, 4, 5 v 7 pht trong qu trnh trn

paracetamol v tinh bt m. Da vo kt qu nh gi phn tn hm lng ca l P1
la chn thi gian trn bt kh thch hp cho l P2 v P3.
Kt qu cho thy pht th 4, phn tn hm lng ca hn hp bt kh < 2%,
chng t qu trnh trn bt kh ng nht. Tuy nhin, m bo ng nht cao
trong qu trnh trn, chng ti la chn thi gian trn bt kh to ht paracetamol
thch hp l 5 pht cho cc l P2 v P3. Vi thi gian trn l 5 pht, c 2 l P2 v P3
u t yu cu v phn tn hm lng vi gi tr CV < 2%.

99

Bng 3.37. phn tn hm lng paracetamol trong l P2 v P3, giai on trn

bt kh
Hm lng paracetamol (%)

V tr

L P2

L P3

98,65

96,80

99,10

95,70

96,84

97,24

97,20

98,40

96,40

99,00

Gi tr trung bnh

97,64

97,43

lch chun

1,18

1,31

H s phn tn CV (%)

1,20

1,34

Trn natri bicarbonat v tinh bt m

phn tn hm lng natri bicarbonat khi trn bt kh c trnh by bng
3.38 v 3.39.
l P1 tin hnh ly mu ti cc thi im 3, 4, 5 v 7 pht trong qu trnh trn
natri bicarbonat v tinh bt m ri nh lng natri bicarbonat theo mc 2.2.3. Da
Bng 3.38. phn tn hm lng natri bicarbonat l P1, giai on trn bt kh.
V tr

Hm lng natri bicarbonat (%)

3 pht

4 pht

5 pht

7 pht

99,30

98,43

99,21

98,42

98,96

96,59

97,45

96,14

95,24

98,24

98,54

97,20

99,24

95,92

96,92

96,16

95,82

98,88

96,34

98,05

Gi tr trung bnh

97,71

97,61

97,69

97,19

lch chun

2,01

1,28

1,17

1,05

H s phn tn CV (%)

2,05

1,31

1,20

1,08

100

vo kt qu nh gi phn tn hm lng ca l P1 la chn thi gian trn bt

kh thch hp cho l P2 v P3.
Kt qu cho thy t sau 4 pht, phn tn hm lng ca hn hp bt kh <
2%, chng t qu trnh trn bt kh ng nht. Ko di thi gian trn kh cng khng
lm tng ng k ng nht. Do , chng ti la chn thi gian trn bt kh thch
hp to ht natri bicarbonat l 4 pht cho cc l P2 v P3. Vi thi gian trn l 4
pht, c 2 l P2 v P3 u t yu cu v phn tn hm lng vi gi tr CV < 2%.
Bng 3.39. phn tn hm lng natri bicarbonat l P2 v P3, giai on trn bt
kh
V tr

Hm lng natri bicarbonat (%)

L P2

L P3

97,87

98,14

96,11

96,25

98,88

95,87

97,12

97,63

96,03

99,16

Gi tr trung bnh

97,20

97,41

lch chun

1,21

1,36

H s phn tn CV (%)

1,24

1,39

3.4.2.5. Giai on nho m

To ht paracetamol
Trong qu trnh nghin cu xy dng quy trnh bo ch vin nn paracetamol
gii phng nhanh, ht paracetamol c to thnh bng cch nho trn 15 pht hn
101

hp paracetamol v t dc r vi dung dch PVP 15% trong ethanol 96o trn thit b
nho trn ERWEKA. V vy, khi chuyn sang s dng my nho trn cao tc, cn phi
tin hnh thm nh li thi gian nho m.
Theo nh gi bng cm quan, thi gian nho m thch hp trong thit b nho
trn cao tc l 10 pht, ht to ra ti, chc, t l bt mn thp, t b dnh bt v m bo
ng u hm lng. Khi thi gian nho m qu ngn, ht to ra khng chc, t l
bt mn cao. Ngc li, khi thi gian nho ko di hn 10 pht, cc ht c xu hng
dnh bt li vi nhau v vo thit b nho.
Vi thi gian nho m l 10 pht, c 3 l u m bo phn tn hm lng
(CV<2%). Kt qu nh gi phn tn hm lng paracetamol khi nho m c
trnh by bng 3.40.
Bng 3.40. phn tn hm lng paracetamol cc l P1, P2 v P3 khi nho m
Hm lng paracetamol (%)

V tr
L P1

L P2

L P3

98,27

97,32

97,82

97,94

95,21

96,46

96,31

96,27

97,22

95,99

97,98

95,11

98,79

98,01

98,25

Gi tr trung bnh

97,46

96,96

96,97

lch chun

1,24

1,21

1,24

H s phn tn CV (%)

1,27

1,24

1,28

102

 To ht natri bicarbonat
Bng 3.41. phn tn hm lng natri bicarbonat cc l P1, P2 v P3 khi nho m.

V tr

Hm lng natri bicarbonat (%)

L P1

L P2

L P3

98,24

99,46

100,04

97,54

96,41

98,64

99,14

97,72

97,45

95,87

97,01

98,41

96,22

96,45

96,89

Gi tr trung bnh

97,40

97,41

98,29

lch chun

1,37

1,26

1,21

H s phn tn CV (%)

1,40

1,30

1,23

Tin hnh thm nh tng t nh i vi ht paracetamol, t la chn c

thi gian nho m thch hp m bo ng nht v chc ca ht natri bicarbonat
l 8 pht. Vi thi gian nho m ny, c 3 l u to ra ht ti, chc, t l bt mn thp,
t b dnh bt v m bo phn tn hm lng (CV<2%) (bng 3.41).
3.4.2.6. Giai on sy
Trong qu trnh xy dng cng thc v qui trnh bo ch vin nghin cu, ht
to thnh c sy bng t sy tnh, trong khi thit b sn xut l my sy tng si. Vi
thit b sn xut l my sy tng si, kt qu kho st cho thy thi gian sy kh nhanh
hn nhiu so vi sy tnh. Nghin cu xy dng quy trnh bo ch cho thy nu sy ht
qu kh, khi dp vin d b bong mt, ngc li, nu ht qu m, trn chy ca ht
km, vin d b dnh chy ci. m cng l yu t nh hng ln n n nh ca
vin. Do , ht sau khi sy c kim sot m trong khong 2-3%.
103

Ly 3 mu ti 3 v tr khc nhau trong thuyn sy, xc nh m ca ht bng

cn xc nh hm m nhanh (mc 2.2.3). Kt qu cho thy c ht paracetamol v ht
natri bicarbonat 3 l P1, P2, P3 u t yu cu v m (bng 3.42 v 3.43).
Bng 3.42. m ht paracetamol sau khi sy
m (%)

L
V tr 1

V tr 2

V tr 3

Trung bnh

P1

1,92

2,50

2,14

2,19

P2

2,05

2,31

1,92

2,09

P3

2,17

2,64

2,41

2,41

Bng 3.43. m ht natri bicarbonat sau khi sy

m (%)

L
V tr 1

V tr 2

V tr 3

Trung bnh

P1

2,01

2,60

2,14

2,25

P2

2,53

2,01

1,92

2,15

P3

2,07

2,40

2,10

2,19

3.4.2.7. Giai on sa ht
Ht paracetamol : Ry 100 g ht qua cc ry c kch thc mt ry khc nhau:
0,2 mm; 0,4 mm; 0,6 mm; 0,8 mm v 1,0 mm phn loi kch thc ht. Cn lng
ht cn li trn mi loi ry tng ng.
Tin hnh phn tch phng sai so snh phn b kch thc ht gia 3 l. Kt
qu (Ph lc 4.1) cho thy kch thc ht v t trng biu kin ca cc mu trong 3 l
l ng nht (P>0,05)
104

 Ht natri bicarbonat
Tin hnh nh gi phn b kch thc ht v o t trng biu kin tng t
nh i vi ht paracetamol. Kt qu (Ph lc 4.2) cho thy c s ng u v phn b
kch thc ht v t trng biu kin gia 3 l (P>0,05).
3.4.2.8. Giai on trn hon tt
phn tn hm lng
Do t trng gia ht paracetamol v natri bicarbonat c s chnh lch ng k
nn cn thm nh thi gian trn hon tt m bo ng u hm lng.
Tin hnh trn ht paracetamol, ht natri bicarbonat vi t dc trn v t dc
r ngoi, ly mu ti cc thi im 8 pht, 9 pht, 10 pht, 11 pht l P1. Da vo
kt qu nh gi phn tn hm lng ca l P1 la chn thi gian trn hon tt
thch hp cho l P2 v P3.
Bng 3.44. Kt qu xc nh hm lng paracetamol trong vin gii phng nhanh
l P1
V tr
1
2
3
4
5
Gi tr trung bnh
lch chun
H s phn tn CV (%)

Hm lng paracetamol (%)

8 pht
9 pht 10 pht 11 pht
97,46
98,50
99,80
99,40
99,56
100,60 97,45 100,25
102,10
96,14
98,75
97,89
92,80
94,80
96,80
96,80
94,80
96,80
95,90
97,50
97,34
97,37
97,74
98,37
3,70
2,24
1,55
1,42
3,80
2,31
1,59
1,44

Kt qu trnh by bng 3.44 cho thy t pht th 10, phn tn hm lng

ca hn hp bt trn hon tt < 2%, chng t qu trnh trn hon tt m bo ng
nht. T , chng ti la chn thi gian trn hon tt thch hp l 10 pht cho cc l
P2 v P3.

105

Vi thi gian trn hon tt l 10 pht, c 3 l u t yu cu v phn tn

hm lng vi gi tr CV < 2% (Bng 3.45).
Bng 3.45. phn tn hm lng paracetamol cc l P2 v P3
V tr

Hm lng paracetamol (%)

L P3

L P2
100,21

2
3
4
5
Gi tr trung bnh
lch chun
H s phn tn CV (%)

97,24
96,48
95,53
95,04
97,62
1,84
1,89

96,18
97,24
95,98
98,42
98,02
0,98
1,00

97,63

T trng ht: o t trng biu kin ca ht trn hon tt theo mc 2.2.3. Kt

qu phn tch phng sai (Ph lc 4.5) cho thy t trng biu kin ca ht trn hon
tt gia cc l l ng nht (P>0,05).
trn chy ca ht: Tin hnh o chy ca ht 3 l theo mc 2.2.3. Kt
qu phn tch phng sai (Ph lc 4.6) cho thy trn chy ca ht 3 l l ng
nht (P>0,05).
3.4.2.9. Giai on dp vin
ng u khi lng vin: nh gi ng u khi lng vin theo DVN
III, ph lc 8.3. Kt qu (Ph lc 4.7) cho thy tt c cc mu vin u t yu cu v
ng u khi lng.
cng: Kt qu nh gi cng ca vin (Ph lc 4.8) cho thy tt c cc
mu vin u t yu cu v cng.
ha tan: Kt qu nh gi ha tan ca vin (Ph lc 4.9) cho thy tt c
cc mu vin u t yu cu v ha tan.

106

Bng 3.46. Tm tt kt qu thm nh cc thng s trng yu

STT
1

2
3
4

Giai on
Trn bt
kh
Nho m
Sy ht
Sa ht

Trn hon
tt

Dp vin

Thng s

Yu cu

L P1

L P2

L P3

1,55

1,20

1,34

1,31

1,24

1,39

CV 2%

phn tn hm lng natri bicarbonat

CV 2%

phn tn hm lng paracetamol

CV 2%

1,27

1,24

1,28

phn tn hm lng natri bicarbonat

CV 2%

1,40

1,30

1,23

m ht paracetamol

2,0 3,0%

2,19

2,09

2,41

m ht natri bicarbonat

2,0 3,0%

2,25

2,15

2,19

Phn b kch thc ht

Khng khc nhau gia 3 l

T trng biu kin ht paracetamol

Khng khc nhau gia 3 l

0,65

0,64

0,66

T trng biu kin ht nabica

Khng khc nhau gia 3 l

1,081

1,083

1,083

CV 2%

1,59

1,9

1,10

trn chy

Khng khc nhau gia 3 l

11,13

10,97

11,07

T trng ht

Khng khc nhau gia 3 l

0,95

0,95

0,94

KLTB 5%

1303,7

1312,9

1305,9

13-18 kP

15,93

16,06

16,14

90% sau 5 pht

98,06

96,61

98,89

Biu Shewhart X /R

Theo quy nh

Biu cusum

Theo quy nh

phn tn hm lng

ng u khi lng
ha tan

Kim sot

Kt lun

phn tn hm lng paracetamol

cng
7

Gi tr trung bnh

107

3.4.2.10. Kt qu thm nh thng s kim sot

Dao ng khi lng vin trong qu trnh dp vin c theo di bng cch ly
mu nh k (10 vin sau mi 30 pht) nh gi. Kt qu thu c 20 ln ly mu
nh c trnh by bng 3.47, 3.48 v 3.49.
Bng 3.47. Khi lng vin ca l P1
Khi lng vin (mg)

Ln
ly

Vin

Vin

Vin

Vin

Vin

Vin

Vin

Vin

Vin

Vin

mu

s 1

s 2

s 3

s 4

s 5

s 6

s 7

s 8

s 9

s 10

1306,2

1301,6

1305,5

1302,4

1319,0

1290,1

1285,3

1302,6 1305,4 1315,4 1303,4

1310,8

1327,0

1275,2

1310,5

1296,7

1275,5

1326,4

1300,2 1332,7 1295,0 1305,0

1296,6

1306,4

1296,9

1315

1287,6

1316,1

1306,0

1316,6 1303,4 1305,3 1305,0

1285,4

1296,2

1315,4

1316,8

1302,6

1287,2

1335,2

1297,3 1295,2 1299,2 1303,1

1316,2

1296,5

1285,6

1286,6

1305,4

1312,2

1297,3

1326,5 1300,1 1312,8 1303,9

1285,7

1294,4

1330,4

1282,9

1302,9

1297,5

1315,4

1300,1 1281,2 1302,8 1299,3

1310,5

1296,7

1305,5

1296,4

1285,6

1306,6

1310,8

1300,7 1312,4 1316,8 1304,2

1315,0

1287,6

1316,1

1306,0

1315,4

1312,9

1296,6

1306,4 1285,6 1315,6 1305,7

1316,8

1302,6

1287,2

1296,2

1275,5

1326,4

1285,4

1296,2 1305,5 1302,4 1299,4

10

1286,6

1305,4

1312,2

1297,3

1309,1

1306,0

1316,2

1296,5 1275,2 1310,5 1301,5

11

1315,4

1316,8

1302,6

1287,2

1296,2

1310,8

1287,4

1315,4 1296,9 1315,0 1304,4

12

1285,6

1286,6

1305,4

1296,9

1315,0

1327,0

1275,5

1306,4 1315,4 1316,8 1303,1

13

1315,4

1312,9

1302,9

1315,4

1316,8

1306,4

1316,1

1306,0 1285,6 1286,6 1306,4

14

1275,5

1344,4

1285,6

1285,6

1286,6

1296,2

1287,2

1296,2 1315,4 1341,9 1301,5

15

1316,1

1306,0

1315,4

1315,4

1312,9

1288,5

1325,7

1294,4 1275,5 1296,4 1304,6

16

1290,1

1302,8

1296,7

1275,5

1326,4

1294,4

1316,1

1306,0 1286,1 1306,0 1300,0

17

1337,5

1316,8

1302,9

1315,4

1287,6

1305,3

1287,2

1296,2 1295,5 1314,4 1305,9

18

1316,1

1296,6

1296,7

1295,0

1302,6

1299,2

1312,2

1297,3 1296,1 1306,0 1301,8

19

1287,2

1302,4

1303,4

1305,3

1305,4

1312,8

1317,5

1315,4 1297,2 1296,2 1304,3

20

1315,6

1296,6

1310,8

1300,5

1316,8

1302,8

1266,6

1310,8 1312,2 1297,3

108

TB

1303

Bng 3.48. Khi lng vin ca l P2

Khi lng vin (mg)

Ln
ly

Vin

Vin

Vin

Vin

Vin

Vin

Vin

Vin

Vin

Vin

mu

s 1

s 2

s 3

s 4

s 5

s 6

s 7

s 8

s 9

s 10

1316,4

1285,6

1286,6

1310,8

1327,0

1316,8

1302,6

1287,2

1335,2

1316,8

1308,5

1326,0

1315,4

1312,9

1296,6

1306,4

1286,6

1305,4

1312,2

1297,3

1286,6

1304,5

1276,2

1275,5

1326,4

1285,4

1296,2

1312,9

1302,9

1317,5

1295,4

1312,9

1300,1

1287,3

1329,1

1306,0

1316,2

1296,5

1326,4

1285,6

1286,6

1310,8

1306,4

1305,1

1307,2

1296,2

1280,8

1294,0

1315,4

1286,0

1315,4

1312,9

1306,6

1306,0

1302,1

1266,9

1315,0

1327,0

1275,5

1326,4

1296,2

1275,5

1326,4

1285,4

1296,2

1299,1

1265,4

1316,8

1306,4

1316,1

1306,0

1297,3

1319,1

1306,0

1316,2

1297,3

1304,7

1275,6

1286,6

1296,2

1287,2

1296,2

1287,2

1296,2

1310,8

1327,0

1287,2

1295,0

1310,2

1332,7

1285,0

1305,0

1300,2

1296,9

1315,0

1317,0

1275,5

1296,9

1303,4

10

1286,6

1303,4

1305,3

1305,0

1286,2

1335,4

1316,8

1306,4

1316,1

1325,4

1308,7

11

1267,5

1285,2

1299,2

1308,1

1297,6

1305,4

1296,9

1315,0

1317,0

1305,5

1299,7

12

1306,5

1300,1

1312,8

1303,9

1316,5

1302,9

1315,4

1296,8

1306,4

1316,1

1307,7

13

1280,1

1281,2

1302,8

1310,3

1300,1

1285,6

1285,6

1316,6

1296,2

1287,2

1294,6

14

1287,0

1342,4

1316,8

1287,8

1287,4

1315,4

1315,4

1312,9

1328,5

1325,7

1311,9

15

1266,4

1325,6

1295,6

1317,7

1306,4

1296,7

1275,5

1286,4

1294,4

1316,1

1298,1

16

1326,2

1305,5

1302,4

1299,4

1296,2

1302,9

1315,4

1287,6

1305,3

1317,2

1305,8

17

1301,1

1275,2

1310,5

1304,5

1296,5

1276,7

1295,0

1302,6

1299,2

1312,2

1297,4

18

1295,4

1306,9

1315,0

1308,3

1315,4

1305,4

1296,9

1315,0

1297,7

1275,5

1303,2

19

1316,4

1315,4

1316,8

1265,1

1306,4

1302,9

1315,4

1316,8

1306,4

1316,1

1307,8

20

1280,2

1312,7

1295,0

1305,0

1300,2

1285,6

1285,6

1286,6

1256,2

1287,2

1289,4

109

TB

Bng 3.49. Khi lng vin (mg) ca l P3

Khi lng vin (mg)

Ln
ly

Vin

Vin

Vin

Vin

Vin

Vin

Vin

Vin

Vin

Vin

mu

s 1

s 2

s 3

s 4

s 5

s 6

s 7

s 8

s 9

s 10

1296,2

1287,2

1296,2

1310,8

1296,2

1326,5

1300,1

1312,8

1303,9

1326,5

1305,6

1300,2

1296,9

1315,0

1327,0

1300,2

1320,1

1281,2

1320,8

1308,3

1320,1

1309,0

1316,6

1315,4

1316,8

1306,4

1316,6

1290,4

1303,4

1276,8

1307,8

1300,6

1305,1

1287,2

1305,4

1316,9

1315,0

1280,8

1306,4

1285,6

1315,5

1307,7

1306,4

1302,7

1300,6

1302,9

1315,4

1316,8

1306,5

1296,2

1275,5

1302,4

1294,4

1296,2

1300,7

1316,4

1338,1

1285,6

1286,6

1260,1

1296,5

1275,2

1310,5

1304,5

1296,5

1297,0

1287,7

1315,4

1315,4

1312,9

1293,9

1315,4

1296,9

1300,4

1298,3

1305,4

1304,2

1315,0

1327,0

1275,5

1296,9

1315,2

1315,6

1287,2

1295,2

1277,3

1315,2

1302,0

1310,1

1306,4

1316,1

1315,4

1299,4

1305,4

1312,2

1297,3

1326,5

1300,1

1308,9

10

1296,9

1285,4

1287,2

1275,5

1305,4

1302,9

1317,5

1315,4

1300,1

1271,2

1295,8

11

1315,4

1316,8

1306,4

1316,1

1302,9

1265,7

1286,6

1310,8

1280,7

1312,3

1301,4

12

1285,6

1286,6

1296,2

1327,2

1285,6

1315,4

1312,9

1296,6

1306,4

1285,6

1299,8

13

1315,4

1312,9

1298,1

1285,7

1315,4

1275,5

1326,4

1285,4

1296,2

1305,5

1301,7

14

1275,5

1326,4

1294,4

1316,1

1332,1

1339,1

1302,5

1316,2

1296,5

1272,2

1307,1

15

1315,4

1287,6

1305,3

1287,2

1302,9

1296,2

1310,8

1327,0

1325,4

1296,9

1305,5

16

1295,6

1302,6

1299,2

1312,2

1276,7

1315,0

1300,4

1275,5

1326,4

1315,4

1301,9

17

1296,9

1315,0

1327,0

1275,5

1305,4

1316,8

1306,4

1316,1

1306,0

1285,6

1305,1

18

1315,4

1266,8

1306,4

1316,1

1302,9

1286,6

1296,2

1287,2

1296,2

1315,4

1298,9

19

1313,8

1317,0

1305,5

1296,9

1315,0

1312,9

1336,2

1325,7

1294,4

1275,5

1309,3

20

1305,4

1306,4

1316,1

1315,4

1288,7

1302,6

1297,2

1305,2

1277,3

1315,2

1303,0

110

TB

 Kho st biu Shewhart X /R:

Kt qu kho st biu Shewhart X /R v khi lng vin ca 3 l c trnh
by cc hnh 3.21 (a, b), 3.22 (a, b), v 3.23 (a, b) v bng 3.50

(a)

(b)
Hnh 3.20. Biu Shewhart X / R v khi lng vin ca l P1:
(a) Biu R, (b) Biu X

111

(a)

(b)
Hnh 3.22. Biu Shewhart X /R v khi lng vin ca l P2:
(a) Biu R, (b) Biu X

112

(a)

(b)
Hnh 3.23: Biu Shewhart X /R v khi lng vin ca l P3:
(a) Biu R, (b) Biu X

113

Bng 3.50. Kt qu kho st biu Shewhart X

Kt qu
Quy tc

Yu cu (khng c)

P1

P2

P3

Gii hn +3

1 im ngoi gii hn +3

t t

Gii hn -3

1 im ngoi gii hn -3

t t

Vng gi tr cao

Lin tip 6, 7, 8, 9 im nm trn X

t t

Vng gi tr thp

Lin tip 6, 7, 8, 9 im nm di X

t t

i ln

Lin tip 6, 7, 8, 9 im i ln

t t

i xung

Lin tip 6, 7, 8, 9 im i xung

t t

t t

t t

Gii hn +3
Gii hn -3

2 trn 3 trong vng +A, 3 trn 7 trong vng +A

4 trn 10 trong vng +A, 4 trn 5 trong vng +B
2 trn 3 trong vng -A, 3 trn 7 trong vng -A
4 trn 10 trong vng -A, 4 trn 5 trong vng -B
Bng 3.51. Kt qu kho st biu Shewhart R

Kt qu
Quy tc

Yu cu (khng c)

P1

P2

P3

Gii hn +3

1 im ngoi gii hn +3

t t

Vng gi tr cao

Lin tip 6, 7, 8, 9 im nm trn R

t t

i ln

Lin tip 6, 7, 8, 9 im i ln

t t

t t

Gii hn +3

2 trn 3 trong vng +A, 3 trn 7 trong vng +A

4 trn 10 trong vng +A, 4 trn 5 trong vng +B

Nh vy, c 3 l u c biu Shewhart X v R t yu cu, chng t QTSX

n nh.

114

 Kho st biu cusum:

Kt qu kho st biu cusum v khi lng vin ca 3 l P1, P2 v P3 c
trnh by cc hnh 3.24 3.26.

Hnh 3.24. Biu cusum l P1

Hnh 3.25. Biu cusum l P2

115

Hnh 3.26. Biu cusum l P3

Kt qu kho st biu cusum khng pht hin thy khuynh hng bin thin
no ng k v khi lng vin trong qu trnh dp vin. Nh vy, QTSX c tnh n
nh cao.
Kho st ch bo hiu nng
Bng 3.52. Kt qu kho st ch bo hiu nng
Mong
mun

Loi ch bo

ngha

Hiu nng tng

qut Cp

Bin thin tng qut xung quanh

gi tr trung bnh
Tng quan gia gii hn cho
php v gii hn kim sot, gia
gi tr trung bnh vi gi tr mong
mun
Tnh trng lch tm qua mi tng
quan gia Cpk vi Cp
Tnh trng hng tm v phn
tn ca QTSX

Hiu nng ti
hn Cpk

Hiu nng iu
chnh Rr
Tnh trng lch
tm Cpm
Hiu nng tc
thi (hiu nng phn tn tc thi ca mu
thit b) Cm
Mc n nh Mc n nh ca QTSX qua
mi tng quan gia Cp v Cm
Rs

116

Kt qu
L P1 L P2 L P3

1,33

1,54

1,40

1,39

1,33

1,54

1,39

1,39

100%

100% 99,3% 100%

1,33

1,59

1,38

1,42

1,58

1,40

1,39

75%

97,5

100%

100%

3.5. Nghin cu sinh kh dng vin nn paracetamol gii phng nhanh

3.5.1. Xy dng v thm nh phng php nh lng paracetamol trong huyt
tng
3.5.1.1. Xy dng phng php nh lng
Kho st phng php x l mu huyt tng
Da vo cc ti liu tham kho v iu kin th nghim, tin hnh kho st
phng php x l mu, chit tch paracetamol t huyt tng trn cc mu chun
paracetamol ho tan trong pha ng, mu huyt tng trng v cc mu paracetamol
chun ho tan trong huyt tng ba mc nng khc nhau: 0,5 ; 5 v 20 g/ml.
Cc phng php c kho st bao gm:
- Phng php chit lng-lng bng dung mi hu c
Trong mt ng nghim c np, ly 1ml mu, thm 20 mcl acid acetic, 5 ml
ethyl acetate, lc xoy 5 pht, ly tm. Tch ring phn dch ni, c cho ti kh bng
cch thi kh nit qua b mt. Cn thu c em ho tan trong pha ng, lc qua mng
0.45 m ri em phn tch.
- Phng php ta protein
+ Ta bng acid percloric: Vi 1 ml mu, thm 0,5 ml acid percloric, lc, ly
tm. Tch dch, lc 0,45 m, tim sc k.
+ Ta bng dung mi acetonitril: Vi 1 ml mu, thm 20 l acid acetic, 2 ml
acetonitril, lc xoy, ly tm, ly dch, lc 0,45 m, tim sc k.
Tin hnh x l mu theo qui trnh. Dch chit tch sau khi lc c em chy
HPLC : ct Hypersil (250 x 4,6 mm, 5m), pha ng gm acetonitril v dung dch kali
dihydrophosphat (pH3; 0,005 M), t l 15:85 . Pha ng c lc qua mng 0,45 m,
tc dng 1ml/pht. Lm 6 ln mi mu v so snh kt qu thu c vi kt qu nh
lng mu paracetamol chun pha trong pha ng c cng nng .

117

Thc nghim chit bng ethyl acetat cho thy th tch dch chit khng th thu
c bng so vi dung mi ban u do mt phn b nh ho, hiu sut chit thp. Nh
vy, mun c c kt qu chnh xc th cn phi c dung dch chun ni. Mt khc,
chit lng lng phi qua cng on bay hi dung mi rt mt thi gian v phc tp,
dung mi bay hi c hi. Phng php ta protein bng acid percloric khng sch,
li nhiu pic tp ln vi pic ca paracetamol. Phng php ta protein bng acetonitril
thc hin n gin, n nh v t tp, c la chn tin hnh x l cc mu trong
nghin cu.
Kho st la chn iu kin sc k
Ct sc k: qua kho st trn cc ct Alltech C18 (4,6150 mm; 5 m), Inertsil ODS3 (4,6150 mm; 5 m), Zorbax SB- C18 (4,6150 mm; 5 m); Hypersil ODS (250
4,6 mm; 5 m) chng ti thy ct Hypersil ODS (250 4,6 mm; 5 m) l ph hp, c
kh nng tch tt v chn lc paracetamol ra khi mu phn tch.
Pha ng: kho st kh nng tch paracetamol trong huyt tng vi nhng h pha
ng sau:
-

Acetonitril - m phosphat 0,06M iu chnh pH 2,7 bng H3PO4 25%

(48:52).

Acetonitril acid acetic - H2O - triethylamin vi cc t l ln lt l 800:1:

200:0,75 ; 850:1:150:0,75 v 900:1: 100:0,75.

Acetonitril kali dihydrophosphat 10 mM pH 3,0 vi cc t l ln lt l

49:51, 50:50, 60:40, 40: 60.

Acetonitril Methanol - m phosphat 10mM iu chnh v pH 3

(50:30:110).

Kt qu cho thy h dung mi Acetonitril kali dihydrophosphat 10 mM pH

3,0 (49:51) c kh nng tch tt nht, pic sc nt, chn pic gn, cc pic tch ri nhau
v thi gian phn tch hp l. Do chng ti chn h dung mi ny lm pha ng.

118

 Bc sng: Ly ph UV ti thi gian lu ca paracetamol trn sc trong khong

200 350 nm. Chn c bc sng thch hp max = 245 nm. (hnh 3.27).
Tc dng: kt qu kho st s thay i tc dng 0,6; 0,8-1,0; 1,2 ml/pht cho
thy tc dng 0,8 ml/pht tt nht, va tch ring c cht phn tch va c thi
gian phn tch hp l.
La chn th tch tim mu: kho st th tch tim mu l 10; 20; 50; 100 l cho thy
th tch tim mu 20 l thch hp nht.

Hnh 3.27: Ph hp th t ngoi ca paracetamol

T cc kt qu nghin cu trn la chn c chng trnh HPLC nh
lng paracetamol trong huyt tng nh sau:
-

Ct sc k

: Hypersil ODS (250 4,6 mm; 5 m),

ct bo v

: ODS (12,5 4,6 mm; 5 m)

Pha ng

: Acetonitryl - KH2PO4 10 mM pH 3,0 (49:51).

Bc sng

: 245 nm.

Lu lng

: 0,8 ml/pht.

Th tch tim

: 20 l.

Nhit phn tch

: nhit phng

119

 Xc nh tnh ph hp ca h thng sc k
Chun b mt mu huyt tng trng, thm paracetamol chun nng
khong 5 g/ml. X l mu v tim sc k lp li 6 ln.
Xc nh cc thng s sau mi ln tim mu: thi gian lu ca paracetamol
(tR), din tch pic (SPA). Kt qu thc nghim c trnh by trong bng 3.53. lch
chun tng i ca cc thng s phn tch u di 2%, iu chng t h thng
sc k c tnh ph hp cao, c th ng dng phn tch mu trong thc t.
Bng 3.53. Kt qu kho st tnh ph hp ca h thng sc k (n=6)
Ln tim

Thi gian lu ca paracetamol

Din tch pic ca paracetamol

(pht)

(mAU.s)

3,637

480457

3,602

485800

3,625

481268

3,638

486742

3,612

478825

3,628

480016

Trung bnh

3,624

482185

RSD%

0,392

0,679

3.5.1.2 Thm nh phng php phn tch

Pha dung dch chun
Cn chnh xc cht chun paracetamol ha tan trong acetonitril c dung
dch gc c nng paracetamol l 1 mg/ml. T dung dch gc pha long bng
acetonitril thnh cc dung dch chun th cp c nng paracetamol ln lt l 200;
100; 25; 5 g/ml.

120

 Kho st tnh chn lc ca phng php

Chun b 6 mu huyt tng khng c thuc (mu trng) v 6 mu huyt tng c
paracetamol nng 0,5 g/ml (mu chun). So snh sc k mu trng khng c
paracetamol (Hnh 3.28) vi sc k mu chun c paracetamol (Hnh 3.29).

Hnh 3.28. Sc k mu huyt tng trng

Hnh 3.29. Sc mu huyt tng trng thm paracetamol

Mu chun cho pic ca paracetamol ti thi im khong 3,6 pht, pic cn i
v sc nt, tch ring bit. Trn sc k mu trng, ti v tr tng ng vi thi gian
lu ca paracetamol (t = 3 - 4 pht) khng xut hin pic. Sc k mu huyt tng
ngi tnh nguyn (mu th) cng c pic trng vi thi im ca pic paracetamol ca
mu chun (hnh 3.30). Vy phng php phn tch c tnh chn lc cao.

121

UV6K-245nm
1500

Retention Time
Area

1250

3.577 4076092

mAU

1000

750

500

250

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5
Minutes

4.0

4.5

5.0

5.5

6.0

6.5

7.0

Hnh 3.30: Sc mu huyt tng ngi tnh nguyn 15 pht sau khi ung
500mg paracetamol
Xc nh khong nng tuyn tnh:
Chun b 1 thang nng chun ca paracetamol trong huyt tng trng vi nng
40 20 10 5 1 0,5 0,2 g/ mL g/ml. X l mu v tin hnh chy sc k.
Tnh phng trnh hi quy v h s tng quang R2. (Bng 3.54 v hnh 3.31).
Bng 3.54. Kt qu kho st khong nng tuyn tnh ca paracetamol trong
huyt tng
Nng (g/ml)

Din tch pic (mAU.giy)

40

4588455

H s tng quan: R2 = 0,9995

20

2217774

Phng trnh hi quy:

10

1239419

545133

98558

0,5

47127

0,2

22050

y = 114452 x - 2855

122

Kt qu cho thy, ng hi quy c dng ng thng v h s tng quan ln

hn 0,999 chng t p ng phn tch v nng paracetamol c mi lin h tuyn
tnh trong khong nng kho st v ng hi quy c th tnh ton kt qu nh
lng vi tin cy cao.
5000000
Din tch pic (mAU.giy)

4500000
4000000
3500000
3000000
2500000
2000000
1500000
1000000
500000
0
0

10

20

30

40

50

Nng (mcg/mL)

Hnh 3.31: ng chun nh lng paracetamol trong huyt tng

Kho st chnh xc ca phng php
chnh xc c nh gi bng lp li trong ngy v khc ngy ca
phng php phn tch (Bng 3.55).
Bng 3.55. Kt qu kho st chnh xc ca phng php phn tch
Nng paracetamol (g/mL)
Lp li trong ngy

STT

Lp li khc ngy

0,5g/ml

5 g/ml

20 g/ml

0,5g/ml

5 g/ml

20 g/ml

0,435

4,88

20,38

0,514

5,10

20,77

0,398

5,06

17,70

0,483

4,65

20,15

0,461

4,55

19,58

0,464

4,99

18,91

0,461

4,44

19,94

0,449

4,65

20,34

0,428

5,01

19,41

0,469

4,70

19,18

TB

0,437

4,79

19,40

0,476

4,82

19,87

RSD %

6,02

5,77

5,26

5,12

4,36

3,98

123

Xc nh lp li trong ngy v khc ngy phn tch bng cch thm chnh
xc paracetamol vo huyt tng trng c cc nng khong 0,5; 5 v 20
g/ml. Mi nng lm song song 5 mu. X l mu v tin hnh chy sc k. Xc
nh lch chun tng i (RSD%) mi nng .
lch chun tng i t 3,98% n 6,02% (< 15%) vi n = 5. Vy php th
t yu cu v lp li trong ngy v khc ngy phn tch theo quy nh v phn tch
thuc trong dch sinh hc.
Kho st ng ca phng php
ng c nh gi bng cch so snh nng paracetamol nh lng
c v nng thc. Thm chnh xc lng paracetamol vo huyt tng trng
c cc nng 0,5; 5 v 20 g/ml. Mi nng lm 5 mu. X l mu v tin hnh
chy sc k, kt qu thu c bng 3.56.
Bng 3.56: Kt qu kho st ng ca phng php (n=5)
0,5g/ml
STT

5 g/ml

20 g/ml

Nng o

ng

Nng o

ng

Nng o

ng

c (g/ml)

(%)

c (g/ml)

(%)

c (g/ml)

(%)

0,435

86,96

4,88

97,61

20,38

101,91

0,398

79,63

5,06

101,21

17,7

88,51

0,461

92,30

4,55

91,03

19,58

97,90

0,461

92,19

4,44

88,84

19,94

99,69

0,428

85,65

5,01

100,10

19,41

97,04

Kt qu

87,35%

95,76%

97,01%

ng ca phng php nm trong khong 85 115%, t yu cu v phn

tch thuc trong dch sinh hc.

124

 Kho st kh nng tm li
Chun b cc mu cha paracetamol vi cc nng khong 0,5; 5 v 20 g/ml
trong huyt tng trng v trong nc ct. Mi nng tin hnh lm 5 mu song
song.
X l mu v tin hnh phn tch. tm li c xc nh bng phn trm gia
p ng ca cht phn tch trong huyt tng so vi p ng ca cht phn tch trong
nc. Kt qu kho st kh nng tm li c trnh by bng 3.57.
Bng 3.57. Kh nng tm li ca phng php x l mu huyt tng bng
acetonitril (n = 5)
Din tch pic (mAU.s)
Nng (g/ml)

Kh nng tm li

Mu th/nc

Mu th/ HT

0,5

54400

53074

97,6

5,0

614560

583628

95,0

20,0

2640986

2443095

92,5

(%)

Kh nng tm li ca cht phn tch khng di 30% v khng trn 110% c

chp nhn i vi phng php phn tch sinh hc.
T kt qu thu c, chng ti a ra quy trnh x l mu huyt tng nh
sau: Ly 500l huyt tng (mu chun hoc mu th), thm 10l acid acetic. Lc 1
pht. Sau thm 1 ml acetonitril. Lc xoy trong 5 pht, ly tm 5000 vng/pht
trong 15 pht. Lc dch ni trn qua mng lc 0,45 m.
Xc nh gii hn nh lng ca phng php
Chun b cc mu cha paracetamol trong huyt tng trng vi cc nng 0,1
0,05 0,02 g/ml. Mi nng tin hnh lm 5 mu song song. X l mu v tin
hnh chy sc k. Tnh RSD (%) mi nng ca kt qu din tch pic. (Bng 3.58)

125

Bng 3.58: Kt qu kho st gii hn nh lng ca phng php (n = 5).

Din tch pic cc nng (mAU.giy)
STT

0,10 g/ml

0,05 g/ml

0,025 g/ml

15595

10602

7617

16268

8717

8958

18588

9132

6228

16193

10045

7405

18478

8526

9448

RSD%

9,45%

16,24%

19,66%

Ti nng paracetamol 0,025 g/ml cho gi tr RSD 20% , c la chn l

gii hn nh lng ca phng php.
Kho st n nh ca paracetamol trong huyt tng iu kin phn
tch:
Chun b 3 mu paracetamol trong huyt tng trng nng 0,5 g/ml. X
l mu ri tin hnh sc k ngay v tip tc c mi gi tim mu 1 ln trong vng 5
gi iu kin nhit phng. Kt qu c trnh by bng 3.59.
Bng 3.59: n nh ca paracetamol trong thi gian phn tch (n=3)
Nng
paracetamol /HT

% paracetamol tnh
theo mu phn tch

(g/ml)

u tin

0,500

100,0

0,502

100,4

+0,40

0,496

99,20

-0,80

0,495

99,00

-1,00

0,491

98,20

-1,80

0,488

97,60

-2,40

Thi gian (gi)

126

Lng paracetamol
thay i (%)

Kt qu kho st cho thy lng paracetamol thay i trong vng 4 gi phn

tch bin ng di 2%. Vy cht phn tch n nh trong thi gian ngn sau khi x
l mu (4 gi) nhit phng.
Kho st n nh ca paracetamol trong iu kin bo qun
Chun b cc mu paracetamol trong HT trng vi cc nng ln lt l 0,5;
5 v 20 g/ml. Mi nng lm 5 mu song song. Cc mu c ng trong ng
nha PE dung tch 10 ml nt xoy, bo qun -350C trong khong thi gian 30 ngy.
Ngay sau khi chun b mu v sau 10; 20; 30 ngy ly mu huyt tng ra r ng.
Tin hnh x l mu v phn tch. Song song tin hnh cng vi mu va chun b.
Tnh kt qu theo phng php so snh.
Xc nh hm lng tng thuc thay i theo thi gian bo qun bng cch so
snh nng cht phn tch sau khong thi gian bo qun vi mu c phn tch
ngay sau khi chun b.
Kt qu nghin cu ( Bng 3.60) cho thy, paracetamol n nh trong iu kin
bo qun -350C trong vng 30 ngy (Yu cu: Lng paracetamol gim khng qu
5%).
Bng 3.60: n nh ca paracetamol trong iu kin bo qun (n = 5)
Ngy u

Sau 10 ngy

Sau 20 ngy

Sau 30 ngy

(g/ml)

Nng
cn li
(g/ml)

Hm
lng
thay i
so vi ban
u (%)

Nng
cn li
(g/ml)

Hm
lng
thay i
so vi ban
u (%)

Nng
cn li
(g/ml)

Hm
lng
thay i
so vi ban
u (%)

0,50

0,488

-2,40

0,485

-3,00

0,477

-4,60

5,0

4,89

-2,20

4,88

-2,40

4,81

-3,80

20

19,82

-0,90

19,61

-1,95

19,48

-2,60

Nng

127

Kt qu thm nh c hiu chn lc, ng, lp li, khong tuyn

tnh, gii hn nh lng di, hiu sut chit, tm li v n nh cho thy
phng php xy dng p ng cc yu cu ca mt phng php phn tnh dch
sinh hc, c th p dng nh lng paracetamol trong huyt tng trong cc
nghin cu sinh kh dng v tng ng sinh hc cc ch phm cha paracetamol.
3.5.2. Kt qu nghin cu sinh kh dng
18 ngi tnh nguyn hon thnh y ba giai on nghin cu. C ba ch

Nng paracetamol trong huyt tng

(mcg/ml)

phm u c dung np tt. Khng trng hp no xy ra phn ng bt li.

35
Paracetamol FR

30

Panadol Actifast
Panadol

25
20
15
10
5
0
0

30

60

90

120

Thi gian (pht)

Hnh 3.32: S bin thin gi tr trung bnh ca nng paracetamol trong huyt
tng theo thi gian sau khi ung PF, PA v P
T kt qu phn tch (bng 3.61-3.63), s bin thin gi tr trung bnh ca nng
paracetamol trong huyt tng ca 18 ngi tnh nguyn khi ung vin thc
nghim Paracetamol FR 500 (PF) v hai ch phm i chiu l Panadol actifast (PA)
v Panadol (P) c biu din hnh 3.32. T kt qu nh lng paracetamol trong
mu ngi tnh nguyn, xc nh c cc thng s DH ca cc thuc (chi tit xem
ph lc 5). Gi tr trung bnh v khong tin cy ca cc thng s dc ng hc c
trnh by trong bng 3.64. Kt qu so snh cc thng s dc ng hc gia ch phm
thc nghim v ch phm i chiu c th hin trong bng 3.65 (chi tit xem cc
phn ph lc 7.1 7.4).

128

Bng 3.61: Nng paracetamol trong huyt tng tng ngi tnh nguyn sau khi ung vin nghin cu paracetamol FR 500
Nng paracetamol trong huyt tng (g/ml)
Thi
gian NTN1 NTN2 NTN3 NTN4 NTN5 NTN6 NTN7 NTN8 NTN9 NTN10 NTN11 NTN12 NTN13 NTN14 NTN15 NTN16 NTN17 NTN18
(pht) (CBA) (ABC) (BCA) (CAB) (CBA) (CAB) (ACB) (BCA) (ACB) (BAC) (CBA) (BCA) (ABC) (BCA) (ABC) (BAC) (CAB) (ACB)
0

0,00

0,00

0,00

0,00

0,00

0,00

0,00

0,00

0,00

0,00

0,00

0,00

0,00

0,00

0,00

0,00

0,00

0,00

0,00

0,49

3,18

6,05

3,31

1,71

1,83

10,68

0,00

3,23

0,52

0,25

11,36

10,15

27,04

11,31

3,15

3,45

10

16,81

15,22

14,50

45,33

29,21

21,41

10,03

43,94

2,25

17,30

1,37

1,04

35,10

31,26

43,62

61,25

40,31

23,23

15

18,24

28,43

25,33

45,51

44,34

29,77

16,92

44,76

2,43

21,95

7,87

1,73

26,12

24,01

32,88

46,68

33,04

27,13

20

26,15

19,97

19,99

38,63

24,41

37,59

19,80

41,09

2,82

17,35

19,23

2,50

18,92

20,35

25,06

33,66

21,35

21,95

25

17,48

18,83

17,36

34,23

22,78

28,61

19,97

26,48

5,44

14,30

19,30

5,91

17,57

15,63

19,65

27,29

17,11

17,51

30

17,13

18,24

17,20

28,80

19,61

26,20

19,90

23,15

13,40

13,19

18,16

8,96

15,15

14,12

17,67

26,79

14,74

15,54

35

12,72

17,88

16,53

28,63

18,61

25,77

18,83

20,90

16,63

12,23

14,90

10,96

13,73

14,03

17,14

23,06

12,61

13,87

45

10,15

14,93

16,27

21,40

18,70

25,27

15,94

20,42

20,59

10,45

14,31

15,39

13,32

13,87

15,34

20,53

12,22

13,73

60

9,79

11,85

14,75

20,13

16,27

24,59

13,01

19,58

20,89

9,35

14,30

8,84

11,19

11,72

13,58

17,61

12,01

12,37

90

7,96

10,06

12,92

19,33

15,39

13,95

14,17

18,02

20,55

8,47

8,72

6,84

10,21

9,89

10,83

15,78

11,19

8,27

120

6,38

8,98

11,28

18,18

10,34

11,52

11,73

17,41

14,43

7,40

7,35

6,17

8,90

8,91

10,63

11,03

9,25

7,57

360

1,86

2,56

4,27

7,06

2,82

4,06

2,74

8,22

5,29

1,71

2,26

1,65

3,68

1,29

2,51

2,36

2,44

2,33

600

0,86

0,58

1,78

3,03

1,36

2,02

0,53

4,63

1,59

0,42

1,48

0,53

1,45

0,64

0,91

1,11

0,87

0,81

129

Bng 3.62: Nng paracetamol trong huyt tng tng ngi tnh nguyn sau khi ung vin Panadol ActiFast 500 mg
Nng paracetamol trong huyt tng (g/ml)
Thi
NTN1
gian
(pht) (CBA)
0,00
0

NTN2

NTN3

NTN4

NTN5

NTN6

NTN7

NTN8

NTN9

NTN10 NTN11 NTN12 NTN13 NTN14 NTN15 NTN16 NTN17 NTN18

(ABC)
0,00

(BCA)
0,00

(CAB)
0,00

(CBA)
0,00

(CAB)
0,00

(ACB)
0,00

(BCA)
0,00

(ACB)
0,00

(BAC)
0,00

(CBA)
0,00

(BCA)
0,00

(ABC)
0,00

(BCA)
0,00

(ABC)
0,00

(BAC)
0,00

(CAB)
0,00

(ACB)
0,00

0,00

0,78

0,00

0,10

0,25

0,27

0,42

0,95

0,26

0,00

0,47

0,81

0,13

0,11

0,36

0,13

0,00

0,00

10

12,88

13,29

29,49

16,67

10,81

0,46

9,48

15,63

13,98

3,96

6,00

9,23

22,25

6,53

2,15

33,27

15,12

2,07

15

26,07

36,58

34,79

30,67

33,86

1,29

10,54

33,47

29,02

25,25

27,76

29,31

29,84

14,39

6,01

37,71

43,45

14,67

20

20,94

26,26

19,21

37,36

26,73

6,28

11,24

32,32

30,24

33,07

23,94

27,56

22,76

34,69

10,11

41,52

33,13

15,91

25

18,31

24,70

18,89

32,32

22,49

9,20

11,72

25,19

27,37

23,73

18,13

21,26

16,86

28,62

21,13

26,73

22,36

17,05

30

17,59

17,61

17,09

29,92

20,07

11,85

13,04

24,30

24,56

17,38

16,70

16,29

15,65

21,03

25,57

24,77

19,25

16,13

35

11,53

13,77

15,20

26,68

18,17

20,71

14,18

23,84

23,12

12,76

14,65

15,78

15,46

20,62

21,41

24,52

16,73

14,90

45

10,64

10,85

15,07

24,95

17,85

48,87

14,80

20,20

20,38

12,66

14,12

13,12

15,32

16,38

16,20

22,76

16,60

14,62

60

10,37

10,27

11,14

21,97

16,32

35,23

10,80

19,38

16,88

11,85

13,27

12,17

11,86

14,59

12,20

22,38

12,95

12,57

90

9,79

9,79

10,29

21,00

13,26

24,26

10,49

18,75

15,38

9,38

11,44

9,22

9,24

12,32

11,66

16,63

11,97

12,45

120

8,50

6,93

9,28

19,99

11,58

18,23

4,85

18,31

13,89

7,71

8,59

7,86

9,12

9,68

9,92

13,19

10,54

8,78

360

1,74

2,80

2,41

7,61

4,88

6,10

4,56

7,78

4,23

1,84

1,05

2,26

4,16

1,75

2,99

2,93

3,41

2,57

600

0,79

1,78

1,53

3,08

1,10

2,73

0,19

4,09

2,19

0,71

0,21

1,14

1,35

0,51

0,96

0,14

1,41

0,54

130

Bng 3.63: Nng paracetamol trong huyt tng tng ngi tnh nguyn sau khi ung vin Panadol 500 mg
Nng paracetamol trong huyt tng (g/ml)
Thi
NTN1 NTN2 NTN3 NTN4 NTN5 NTN6 NTN7 NTN8 NTN9 NTN10 NTN11 NTN12 NTN13 NTN14 NTN15 NTN16 NTN17 NTN18
gian
(pht) (CBA) (ABC) (BCA) (CAB) (CBA) (CAB) (ACB) (BCA) (ACB) (BAC) (CBA) (BCA) (ABC) (BCA) (ABC) (BAC) (CAB) (ACB)
0

0,00

0,00

0,00

0,00

0,00

0,00

0,00

0,00

0,00

0,00

0,00

0,00

0,00

0,00

0,00

0,00

0,00

0,00

0,00

0,23

0,00

0,37

0,49

0,36

0,33

0,00

0,00

1,35

0,65

0,63

0,23

0,00

0,55

0,00

0,00

0,00

10

0,00

2,22

0,00

2,05

0,55

3,02

2,65

0,24

0,00

28,57

7,21

0,73

0,26

0,12

3,94

0,16

17,11

0,00

15

9,95

9,25

2,24

9,98

13,66

22,88

6,28

3,21

0,31

27,74

11,96

1,26

11,23

0,97

19,66

6,74

38,65

0,13

20

10,36

10,17

13,53

19,22

37,99

30,02

8,87

14,92

4,36

21,91

26,70

3,79

21,19

13,21

33,99

30,83

30,14

1,16

25

15,72

12,07

23,16

21,92

30,71

33,53

12,73

21,60

6,74

21,81

23,96

10,32

19,41

13,35

27,51

37,64

20,47

3,50

30

17,76

18,62

23,82

24,63

26,14

37,00

13,18

31,17

9,69

18,86

20,77

25,69

14,63

14,70

19,09

33,03

16,86

3,85

35

22,45

13,40

22,49

27,48

21,96

31,17

14,72

29,90

20,66

18,38

20,30

16,69

14,31

15,40

18,58

25,63

15,39

8,58

45

15,73

12,85

16,76

22,68

20,52

30,30

20,89

25,99

27,94

14,21

18,56

14,37

14,01

18,85

14,98

18,91

13,68

8,90

60

11,26

11,75

13,04

20,56

15,56

28,70

17,25

23,14

21,90

10,34

15,69

12,62

13,58

18,14

14,20

16,71

12,85

10,01

90

9,21

9,49

10,47

20,57

13,43

18,31

13,18

16,35

18,39

9,36

11,17

8,06

11,12

12,37

10,24

14,75

11,35

11,96

120

5,82

7,26

8,66

18,33

12,94

16,40

12,34

14,32

13,94

7,70

11,15

6,12

9,18

10,11

7,67

12,97

9,83

11,75

360

1,50

2,97

3,47

6,07

5,01

6,66

1,18

7,09

4,85

3,26

3,98

2,28

2,76

2,79

3,69

1,83

3,47

3,03

600

1,45

0,24

1,44

3,36

2,16

1,43

0,17

3,09

2,15

0,32

1,59

1,07

1,24

0,41

1,08

1,03

1,36

0,70

131

Bng 3.64. Gi tr trung bnh v khong tin cy 95% cc thng s dc ng hc

ca paracetamol sau khi ung vin PF, PA hoc P (n=18)
Thng s DH

PF

PA

P_value

Cmax (g/ml)

32,7 12,1

32,1 8,4

27,3 7,7

0,057

AUC0-600 (g/ml*pht)

3767 1391

3893 1431

3770 1200

0,647

AUC0- (g./ml*pht)

4110 1731

4218 1712

4093 1418

0,763

Tmax (pht)

19 13

21 10

32 18

0,002

Bng 3.65. So snh Cmax, Tmax v AUC0- v khong tin cy 90%

So snh

T s gi tr trung bnh (%)

cp

lch gi tr trung bnh

Cmax

AUC 0-

Tmax

PF / PA

99,0 ( 87,1 ; 112,5)

96,9 (90,3 ; 104,1)

-5 (-7,5 ; 5,5)

PF/ P

117,1 (103,1 ; 133,1)

98,5 (91,7 ; 105,8)

-12,5 (-17,5 ; -5)

Nhn xt:
Cc bng phn tch phng sai vi bin ph thuc l Ln(Cmax), Ln(AUC0-t) v
Ln(AUC0-) cho gi tr P_value u > 0,05 (phn ph lc), chng t nh hng ca s
khc nhau gia cc giai on th thuc, nhng ngi tnh ngun, cc mu th hay
gia cc phn nhm NTN (trnh t th thuc) l khng c ngha thng k .
ng biu din nng thuc theo thi gian ca PF c hnh dng gn nh
trng kht ln ng biu din ca PA. Kt qu phn tch cho thy khng c s khc
nhau c ngha thng k gia PF v PA v cc gi tr Cmax, Tmax, AUC0-t v AUC0-
trong khong tin cy 90%. C th, gi tr Cmax trung bnh ca PF (32,7 12,1 g/ml)

132

tng t nh PA ( 32,1 8,4 g /ml), Tmax cng xp x nhau (p>0,05). So vi P, ch

phm thc nghim PF t Cmax cao hn, Tmax trung bnh ca PF l 19 13 pht,
nhanh hn r rt so vi 32 18 pht ca P (p<0,05; khong tin cy vt ra ngoi
khong quy nh 80-125%).
Kt qu th nghim trn ngi tnh nguyn cho thy ch phm thc nghim
Paracetamol FR500 c sinh kh dng tng ng vi ch phm i chiu l vin nn
hp thu nhanh Panadol Actifast. Mt s thng s dc ng hc (Cmax, Tmax, AUC0-t
v AUC0- ) khc nhau khng ng k. Tc hp thu vin paracetamol FR 500
nhanh hn r rt so vi vin paracetamol thng thng.

133

Chng 4: BN LUN
4.1. V la chn phng php bo ch vin paracetamol gii phng nhanh
Cho ti nay c nhiu phng php bo ch vin nn gii phng nhanh
c cng b. Mt s phng php c cp bng ca Cc sng ch M v cho ra
th trng nhng ch phm c cht lng tt.
Phng php ng kh bo ch vin gii phng nhanh c nghin cu v ng
dng nhiu. Tuy nhin, rt kh c th p dng cho vin paracetamol gii phng nhanh
vi hm lng dc cht cao (500 mg). xp ca vin tng ng ngha vi tng
kch thc vin, kh khn cho qu trnh bo ch cng nh s dng.
Mt s phng php khc yu cu k thut c bit nh phng php phun sy,
k thut Ko bng, in phun ba chiu ... i hi cc thit b c bit, khng ph hp
vi thc t. Nhng phng php i hi nhit cao hay x l m cng khng p
dng c trong trng hp ny do paracetamol khng bn vng bi nhit v m.
Cn c vo c tnh ca dc cht, kh nng p dng ca cc phng php v
iu kin hin c, ba phng php chnh c la chn lm thc nghim bo ch
vin paracetamol gii phng nhanh bao gm: s dng cht thng hoa, s dng h rn
lng v ng dng h si ni ng thi phi hp vi t dc siu r.
Phng php s dng t dc thng hoa
Qu trnh thng hoa c th c thc hin giai on to ht [68] hoc sau khi
dp thng thnh vin [62]. Phng php dp thng cng vi t dc thng hoa to
ra vin c xp cao hn v do r v ho tan dc cht nhanh hn [754]. Tuy
nhin, thc t cc t dc thng hoa kho st nh camphor hay menthol rt kh nghin
mn nn kh c th phi hp ng u vi dc cht. Hn na, khng th p dng
phng php dp thng c v paracetamol nguyn liu c th cht ti xp v rt
km chu nn. Bin php kh thi l bo ch vin bng phng php xt ht t,
camphor c ho trong dung dch t dc dnh ri phi hp vi dc cht v t dc.
Vin bo ch bng phng php ny c u im l kch thc nh gn, khi
lng vin khng cao (< 1 gam). Tc gii phng paracetamol tng ln r rt khi s

134

dng t dc thng hoa. T l paracetamol gii phng ca cc mu kho st u t

trn 90% sau 5 pht, t tiu chun t ra ban u v cao hn nhiu so vi mu vin
khng s dng t dc thng hoa.
Tuy nhin, qu trnh bo ch cn gp phi mt s kh khn, c bit l qu
trnh dp vin v bn c hc ca vin. Ht paracetamol to thnh rt xp (t trng
khong 0,3 g/ml), tt c cc mu sau khi trn t dc trn v r ngoi u khng t
yu cu v trn chy. Thc t cc mu vin c khi lng vin khng ng u
(bin thin khi lng vin ln). Mt s mu vin khng t tiu chun v mi mn
v c t l bong mt cao. Kh nng do t trng ca ht qu thp nn km chu nn,
ng thi qu trnh sy ht thng hoa ko di lm ht c hm m thp.
Hn na, mt vn cn phi lu l vic kim sot qu trnh thng hoa nhm
m bo ch phm bo ch khng cn tn d cht thng hoa. Nu sy ht ti khi
lng khng i, ht s c hm m qu thp gy kh khn cho qu trnh dp vin. Nu
khng kim sot tt qu trnh thng hoa, cht thng hoa v tp cht tn d nu cn li
trong ch phm c th gy ra nhng phn ng ph, nh hng n tc dng ca thuc
v sc kho ngi bnh.
Nh vy, kt qu thc nghim cho thy vic p dng k thut dng t dc
thng hoa trong bo ch vin nn c nh hng r rt ti tc gii phng dc cht.
Trin vng p dng phng php ny bo ch dng vin nn gii phng nhanh l
hon ton c cn c, v c bit u im hn so vi mt s phng php khc l c
th p dng cho nhng vin c hm lng dc cht cao. Tuy nhin, mt s hn ch
lin quan n k thut bo ch v kim sot cht lng thuc nu trn cho thy cha
th p dng phng php ny vo sn xut. V vy chng ti khng la chn phng
php ny bo ch vin thc nghim.
Phng php s dng h rn lng
Vin bo ch theo phng php s dng h rn lng c khi lng ln do phi
s dng lng cht mang ht ht lng t dc lng d trong hn hp. Kt qu
thc nghim cho thy bin php s dng h rn lng gp phn lm tng ng k

135

ho tan paracetamol. T l t dc lng s dng trong vin c nh hng ti ho

tan dc cht trong nhng pht u. Tuy nhin, tng t l t dc lng ng ngha vi
lng cht mang tng v do , khi lng vin s rt ln. Mc d s dng bin
php thm cht ph tr (10% PVP) lm tng nht ca t dc lng nhm gim
thiu lng cht mang, khi lng vin vn ln ti khong 1300 - 1500 mg.
Hn na, hn hp bt sau khi trn hon tt u khng t yu cu v trn
chy mc d tng t l t dc trn v chng dnh. Kh nng trn chy km l do h
s t dc lng ca cc mu vn qu ln (Lf = 1,32 1,54), cao hn a phn cc h s
Lf ca cc h rn lng trong cc nghin cu cng b [42],[52],[53],[54],[91],[109].
Kt qu thc nghim cho thy, k thut s dng h rn lng l mt phng
php c trin vng tt trong bo ch vin nn gii phng nhanh, nhng thch hp hn
vi vin c hm lng dc cht thp. i vi nhng vin c hm lng dc cht
cao, khi bt em dp vin c trn chy tt, lng cht mang v cht bao cn
phi thm vi t l cao, vin s c khi lng ln. Do vy, phng php s dng h
rn lng cng khng c la chn bo ch vin nghin cu.
Phng php bo ch vin si ni
Qu trnh lm thc nghim cho thy phng php bo ch vin si ni
paracetamol gii phng nhanh thc nghim c cc u im sau:
- Qui trnh bo ch n gin v d kim sot: vin c bo ch theo phng
php xt ht t thng thng, c bn c hc tt
- Tt c cc mu vin thc nghim gii phng paracetamol nhanh ngay t pht
u tin v t l dc cht ho tan u t trn 90% sau 5 pht.
- Nguyn liu sn c, chi ph thp.
- Qui trnh bo ch khng i hi thit b c bit, d dng trin khai qui m
sn xut
Vai tr ca natri bicarbonat trong vin c khng nh qua mt s nghin
cu khc. Robert M.S. v cng s gi natri bicarbonat l cht iu chnh pH [79].

136

Natri bicarbonat c tnh kim, khi gp mi trng acid s phn ng to CO2, tc nhn
gy phn ng to bt khi gp mi trng acid dch v. Phn ng si bt ph v cu
trc vin gip vin r nhanh v ho tan dc cht.
Kelly v CS nghin cu theo di bng hnh nh d dy sau khi ung thuc cho
thy natri bicarbonat c tc dng lm tng tc tho rng d dy [58]. Thm vo ,
quan st qu trnh si to rt nhiu bt, lm tng din tch b mt tip xc v nh
dc cht c ho tan nhanh v nhiu hn.
Tuy nhin, vin bo ch theo phng php s dng h si ni phi i mt vi
c mt s th thch cn phi khc phc. Th nht, trong thnh phn c lng natri
tng i ln, cn phi lu khi s dng, c bit i vi ngi b bnh thn. Mt
vn na cn phi lu l n nh ca vin. Natri bicarbonat c tnh kim yu, d
b phn hu bi nhit v m, nu b phn hu s nh hng n dc cht
paracetamol.
Trn c s cc u im v cng thc v k thut bo ch vin n gin, tnh
kh thi trong sn xut v cc kt qu nghin cu cng b v vai tr lm tng hp
thu paracetamol ca natri bicarbonat [40], phng php s dng h si ni c la
chn bo ch vin paracetamol gii phng nhanh nghin cu.
4.2. V nghin cu xy dng cng thc bo ch vin paracetamol gii phng
nhanh
4.2.1. La chn kch thc tiu phn dc cht
Kch thc tiu phn dc cht l mt trong nhng yu t quan trng nh
hng ti tc ho tan ca dc cht. V mt l thuyt, tiu phn c kch thc nh
hn s ho tan nhanh hn do c b mt tip xc ln hn. Kt qu kho st cho thy:
hai mu vin s dng nguyn liu c kch thc tiu phn nh hn 0,098 mm cho tc
ho tan c phn nhanh hn trong pht u tin so vi hai mu cn li. Tuy nhin, t
pht th ba tr i, tc ho tan paracetamol ca bn mu khc nhau khng ng k
v sau 5 pht, trn 90% paracetamol c ho tan t tt c vin kho st. Nh vy,
trong trng hp ny, kch thc nguyn liu khng nh hng n kh nng ha tan

137

dc cht v qu trnh ny ph thuc vo nng lc gii phng CO2 trong mi trng

acid ca natri bicarbonat.
Tuy nhin, khi p dng vo thc t sn xut cho thy kch thc nguyn liu
nh hng rt ln n giai on to ht v giai on sy. Nu s dng ngay nguyn
liu ban u vo sn xut, kh nng kt dnh km ng ngha vi vic t l bt mn rt
cao. Thit b sy l my sy tng si nn i hi ht sau khi to ht t phi c
chc gim t l v vn do va p mnh trong qu trnh sy. Thc t cho thy khi
gim kch thc nguyn liu, lng PVP s dng t hn v ng thi ht thu c sau
khi to ht t rt u v chc. Khi th nghim ha tan vin nn cho thy, t l dc
cht ho tan trong 5 pht khong 93 - 98%, ln hn so vi cc mu vin kho st ban
u. V vy, kch thc nguyn liu i vi c natri bicarbonat v paracetamol, yu
cu phi qua ry 0,125 mm.
4.2.2. La chn t l natri bicarbonat
Trong nghin cu ny, lng natribicarbonat trong vin c kho st l t 63
n 630 mg, tng ng vi t l natribicarbonat so vi hm lng paracetamol l t
0,13 n 1,26. Kt qu thc nghim cho vin c t l natri bicarbonat thp (t l 0,13)
ho tan paracetamol chm hn hn so vi cc mu khc. ng cong ho tan ca cc
mu vin cn li khc nhau khng ng k. Tuy nhin, khi quan st k thy c s khc
bit trong 2 pht u tin, vin c t l natribicarbonat cao hn gip vin ho tan
paracetamol nhanh hn. Kt qu ny cng ph hp vi nghin cu ca Grattan v CS ,
tc gi c nhn xt: t c mc ch ho tan nhanh, t l natribicarbonat t nht
phi l 0,8 , thch hp hn l 1 v thch hp hn na l 1,26. Tc gi cn kt lun t l
natri bicarbonat c nh hng ti s hp thu paracetamol, vin cha 630 mg natri
bicarbonat t Cmax v AUC(0-20) cao nht, cao hn c vin ho tan si bt [41].
Cng ging nh vin i chiu Panadol actifast, so vi vin si bt ho tan trn
th trng hin nay, lng natri bicarbonat trong vin gim i c rt nhiu. Hm
lng natri trong vin nghin cu ch cn 172,5 mg cha bng mt na so vi vin
ho tan si bt Efferalgan 500 mg (lng natri trong vin l 412,4 mg).

138

4.2.3. La chn t dc dnh

Lng PVP thch hp trong vin nghin cu c la chn l 36 mg, khc vi
cc cng thc thc nghim ca Grattan, PVP ch ng vai tr l t dc dnh th yu
(2 mg / vin), ch yu l h tinh bt (pregelatinesed starch) vi lng 50 mg/vin.
PVP c kh nng kt dnh tt hn nn ph hp hn vi loi dc cht c th cht xp
v km chu nn nh paracetamol. Hn na, PVP c tnh thn nc v c kh nng
lm tng tan ca paracetamol do to thnh mi lin kt hydro khng bn vng vi
paracetamol [40]. Cng khc vi cch phi hp ca Grattan, PVP c ho tan trong
nc loi ion hoc ethanol thnh dng dung dch ri mi phi hp vi hn hp
dc cht v t dc to ht. Kt qu kho st s b cho thy phi s dng dung
dch t dc dnh PVP ti nng 15% mi t hiu qu kt dnh . Nh vy, la chn
PVP lm t dc dnh l hp l, lng t dc dnh s dng t hn ng thi ci thin
tt tnh km chu nn v lm tng tan ca paracetamol.
Khi tin hnh bo ch vin nn paracetamol gii phng nhanh qui m phng
th nghim vi nhng l nh l, ht c sy trong t sy tnh, s dng dung dch PVP
15% trong ethanol l la chn thch hp v tit kim c thi gian sy do ethanol d
bay hi, ng thi vn m bo chc ca ht. Thc t cho thy, khi chuyn sang
sy my sy tng si, thi gian sy nhanh hn, c hai loi ht u b v vn v to t
l bt mn cao. L do c th l ht kh nhanh do ethanol bay hi nhanh ng thi ht
b va p nhiu trong qu trnh sy lm gim s kt dnh. Bin php khc phc c
la chn sau khi kho st s b l s dng nc loi ion lm dung mi pha dung
dch PVP 15% to ht paracetamol, cn vi ht natri bicarbonat s dng ethanol 60o
lm dung mi pha t dc dnh. Kt qu hai loi ht thu c m bo v phn b
kch thc ht cng nh trn chy.
4.2.4. La chn t dc r
V mt l thuyt, s dng t dc siu r croscamellose hay cellulose vi tinh
th s gip vin r nhanh hn so vi s dng tinh bt. Grattan s dng
croscamellose (Acdisol) vi t l 2 3% trong cc cng thc kho st vin
paracetamol si ni [41]. Kt qu kho st thc t cho thy khng c s khc bit ng

139

k v r ca cc mu vin khi s dng t dc siu r (croscamellose,

microcrystalline cellulose) v t dc r thng thng (tinh bt). iu ny c th l
gii bi vin r theo c ch si bt, ln t cc c ch r ca t dc siu r.
Tuy nhin, kt qu thc nghim cng cho thy vai tr ca tinh bt lm t dc
r trong trng hp ny vn cn thit, nu t l t dc r thp (1 -3%) th cng nh
hng ti tc r ca vin. V vy, tinh bt m, l nguyn li sn c, chi ph thp
vi t l 5% r trong cng nh r ngoi l la chn thch hp cho vin thc nghim.
4.2.5. La chn t dc trn
c tnh chung ca cc t dc trn l s nc. V vy, natri lauryl sunfat (NL)
c a vo thnh phn kho st vi mc ch hn ch nh hng ca t dc trn
ti tc ho tan dc cht. Kt qu thc nghim cho thy 1% NL thm vo cng
thc gip vin ho tan nhanh hn trong pht u nhng khc bit khng ng k trong
thi gian sau . Xt thy vai tr NL khng nh hng ng k ti tc ho tan
paracetamol ra khi vin, cng thc sn xut khng c thnh phn NL.
Khi chuyn sang qui m sn xut vi qui trnh dp vin bng my quay trn,
tng t l t dc trn gim c ng k.so vi cng thc xy dng ban u trong
khi vin vn m bo ng u v bng p.
4.2.6. La chn thi gian nho m
Thi gian nho m khng nh hng ng k n kh nng gii phng
paracetamol t vin. Nhng thc t cho thy cc vin dp t ht c thi gian nho m 5
10 pht c t l bong mt cao v d gy kt chy khi dp. Nguyn nhn l do ht
khng chc, d b v to t l bt min cao trong qu trnh sy v sa ht. Ngc li,
khi thi gian nho m ko di, khi m d b dnh bt vo nhau v vo thit b, kh to
ht. V vy, thi gian nho m hp l c la chn l 15 pht, va m bo cht
lng ht ng thi khng nh hng ti tc ho tan dc cht.
4.2.7. La chn lc gy v vin
Kt qu th ho tan c th hin cho thy lc dp ln lm gim tc ho
tan dc cht trong nhng pht u tin, nhng sau 5 pht th khng cn s khc nhau

140

v lng paracetamol ho tan trn tt c cc mu vin nghin cu.. C th gii thch l

do khi lc nn tng, xp ca vin gim, kh nng thm ht mi trng ha tan km
hn. Nhng khi thm ht dung dch acid, phn ng sinh CO2 din ra mnh ph v
cu trc vin, gip vin ho tan rt nhanh. Thc t cho thy qu trnh dp vin n nh,
to ra vin m bo bn c hc khi vin c cng nm trong khong t 13 18
kP.
4.2.8. La chn k thut to ht
Phng php to ht paracetamol v natri bicarbonat ring bit ri phi hp
vi nhau dp vin c la chn c nhiu u im hn c.
Trc tin l to ht ring hn ch c tng k do hn ch tip xc gia
paracetamol v natri bicarbonat, m bo n nh ca vin do paracetamol l dc
cht d b thy phn khi c mt natri bicarbonat c tnh kim. Kt qu thc nghim
cho thy ch phm nghin cu c cht lng n nh, vi tui th d tnh cao.
Th hai l kt qu thc nghim cho thy cc mu vin bo ch theo qui trnh
to ht ring th hin tnh u vit hn so vi qui trnh to ht chung v tc ho tan
dc cht. C th vin r nhanh hn (1,5 so vi 2,2 pht) ng thi ho tan
paracetamol cng nhanh hn (90% trong 2 pht so vi 4 pht).
4.3. V xy dng tiu chun cht lng vin nn paracetamol gii phng nhanh
Hai mc tiu t ra khi xy dng tiu chun vin nn paracetamol gii phng
nhanh l: t cc tiu chun c bn ca vin nn paracetamol, ng thi phi t ch
tiu gii phng nhanh. Nh vy, ch phm nghin cu trc tin phi p ng cc
tiu chun v hnh thc, nh tnh, ng u khi lng, 4-aminophenol, tp cht
lin quan v nh lng nh vin nn paracetamol. Cc tiu chun ny c th theo
ng qui nh chuyn lun Vin nn paracetamol trong DVN III.
Ch tiu quan trng nhm p ng mc tiu gii phng nhanh chnh l tiu
chun v th ho tan ca vin. Phn ln cc nh ngha v vin gii phng nhanh yu
cu qu trnh r ca vin phi xy ra ngay trong khoang ming v phi r hon ton
trong vng 60 giy [14],[75]. Tuy nhin, ch phm thc nghim c khi lng vin

141

ln ng thi c ch r ch o ca vin l si bt trong mi trng acid d dy.

t mc tiu trn, phng php th ho tan nn phn nh tng i chnh xc mi
trng trong d dy. V vy, mi trng th ho tan n gin v thch hp nht l
dung dch acid HCl 0,1 N, c pH tng t vi dch v lc i. Dng c cnh khuy vi
tc 50 vng/pht cng c coi l ph hp vi ng hc d dy lc i. Vi tiu
ch gii phng nhanh th ch tiu t ra l khng di 90% lng paracetamol ho tan
sau 5 pht.
Tiu chun cht lng vin nn paracetamol gii phng nhanh c xy dng
trn c s kho st cc ch tiu cht lng n nh trn 3 l sn phm v c Vin
kim nghim thuc Trung ng thm nh.
4.4. V n nh ca ch phm
4.4.1. Theo di n nh
n nh ca paracetamol ch yu lin quan n phn ng thu phn vi xc
tc l acid hoc base trong mi trng m. Ngoi ra, nh sng, nhit cao v cc cht
oxy ho cng l tc nhn thc y phn ng thu phn paracetamol. Ch phm thc
nghim c cha mt lng ln natri bicarbonat c tnh kim yu, l mt yu t c
nguy c nh hng ti tnh bn vng ca paracetamol. V vy, n nh ca vin
thc nghim l vn rt cn c quan tm. Bin php to ht paracetamol v natri
bicarbonat ring bit trong qui trnh bo ch vin phn no hn ch c b mt
tip xc gia hai thnh phn ny. Bo qun trong v nhm-nhm cng l mt bin
php hu hiu hn ch ht m, xc tc cho phn ng phn hu paracetamol.
Theo di n nh ca ch phm nghin cu c tin hnh trn 3 l thc
nghim, c ng gi bng hai loi bao b: v PVP-nhm v v nhm-nhm. Hm
lng paracetamol ca vin p v PVC-nhm gim ng k sau 18 thng bo qun
iu kin thng v sau 6 thng iu kin lo ho cp tc. Trong khi , vin p v
nhm-nhm tng i n nh trong c hai iu kin bo qun, c bit n nh trong
24 thng iu kin thng. Nh vy, cc vt liu ch to bao b c nh hng ng
k ti n nh ca vin paracetamol gii phng nhanh thc nghim. Kt qu nghin

142

cu cng ph hp vi kt lun ca Amad I. v Shaikh RH. khi kho st kh nng ht

m ca vin nn paracetamol trong mi trng m tng i 75%. Vin
paracetamol ng trong v nhm-nhm t b ht m hn hn so vi cc mu vin ng
trong mt s mng polyme thng thng (PVC/ PVDC-nhm) [10].
Nh vy, la chn v nhm-nhm c lm bao b ng gi ch phm vin nn
paracetamol gii phng nhanh l ph hp bi kh nng chng ht m tt, m bo duy
tr cht lng vin qua cc qu trnh vn chuyn v bo qun thuc, c bit trong iu
kin kh hu nhit i nng m Vit nam.
Theo qui nh hin hnh, vic theo di n nh ca ch phm thuc phi
c thc hin trn c l qui m sn xut. Tuy nhin, trong khun kh hn ch v thi
gian nghin cu i vi nghin cu sinh, chng ti mi ch nh gi c n nh
ca thuc qui m thc nghim.
Tuy nhin, cc mu vin nghin cu qui m sn xut c gi i kim
nghim ti Vin kim nghim thuc trung ng ngay sau khi sn xut v sau mt nm
bo qun iu kin thng. Kt qu cho thy ch phm nghin cu vn m bo y
cc yu cu trong tiu chun cht lng c s xy dng v thm nh (ph lc
8). Ch phm nghin cu s c tip tc theo di n nh c kt lun chc chn
v tui th ca thuc.
4.4.2. V d tnh tui th ca ch phm nghin cu
V khng c s thay i mc c ngha i vi cc mu vin ng gi trong
bao b v nhm bo qun iu kin lo ha cp tc nn c th dng s liu bo qun
iu kin thng xc nh tui th ca thuc bng php phn tch hi quy v
ngoi suy [50] theo ICH.
Theo ng nh kt qu phn tch ngoi suy, tui th trung bnh ca ch phm
nghin cu Paracetamol FR 500 t 32 thng. Nh vy, ch phm nghin cu c tnh
n nh cao. Kt qu ny l rt kh quan i vi ch phm paracetamol, c bit i
vi trng hp c thnh phn natri bicarbonat trong vin. Theo nh thng tin ca nh
sn xut, Panadol actifast c tui th l 24 thng. Nghin cu ca Ahmad v Shaikh

143

cho thy vin nn paracetamol qui c bo qun trong v polyme-nhm ch bn vng

trong vng 19 - 23 thng trong iu kin 25oC v m 75% [11]. u im v tnh n
nh ca ch phm nghin cu c th l kt qu ca vic la chn qui trnh to ht
ring hai thnh phn paracetamol v natri bicarbonat, ng thi do la chn bao b bo
qun v nhm-nhm.
4.5. V hon thin v thm nh qui trnh sn xut
Trn c s cng thc bo ch nn paracetamol gii phng nhanh c
nghin cu, xut trc c ng dng a vo sn xut trn quy m ln hn
v tin hnh thm nh tin lng quy trnh sn xut. Qu trnh nghin cu cng thc
cung cp nhng thng tin c bn v hot cht, dng bo ch, v tc ng ca nguyn
liu cng nh t dc c trong sn phm. Tuy nhin cc trang thit b s dng trong
nghin cu cng thc khc so vi trang thit b sn xut, thm nh quy trnh nn trong
qu trnh nghin cu thm nh quy trnh chng ti c nhng ci tin nht nh cho
ph hp vi quy m sn xut:
V phi hp t dc dnh:
Dung dch t dc dnh s dng to ht natri bicarbonat: dung mi s dng
pha t dc dnh l ethanol 600. Cc nghin cu vi cn khc nhau cho thy, vi
cn cao hn dung dch PVP c kh nng dnh km hn, do bn cht qu ti ca natri
bicarbonat, ht t sau khi to ht thu c khng chc, lng t dc dnh s dng
nhiu hn, ht sau khi sy tng si b v vn, t l bt mn sau khi sy cao, ht sau khi
sy d b ht m. Cn vi cn thp hn 600, ht thu c rt cng nh hng rt ln
n qu trnh ha tan dc cht. C th do cn thp hn, t l nc nhiu hn, natri
bicarbonat b tan mt phn to nn cu ni rn gia cc phn t dn n qu trnh ha
tan trong mi trng ha tan gim. i vi vic to ht paracetamol dung mi s dng
pha t dc dnh l nc thm thu. Khi s dng dung mi ny dung dch t dc dnh
thu c c dnh tt hn khi s dng ethanol 960. Mt khc, vi dung mi l
ethanol 600 th chi ph nguyn liu gim i v an ton, khng c nguy c chy n
trong qu trnh sn xut nh khi s dng ethanol 960.

144

 Qu trnh to ht t: y l mt giai on quan trng, nh hng n chc ca

ht, cng, ha tan ca vin sau ny. Nht l vi qu trnh to ht paracetamol.
Thi gian trn thp ht thu c khng chc cn thi gian trn lu hn ht c xu
hng kt t li vi kch thc rt ln. Vi thi gian nho trn nghin cu v thc
nghim thc t cho thy thi gian to ht t ca paracetamol l 10 pht v thi gian
to ht natri bicarbonat l 8 pht m bo ht sau khi sy kh chc, ht u.
Phn b kch thc ht: l mt thng s quan trng, nh hng n nn ca
vin, cng, dy, r, ha tan, s thay i v khi lng v ng u
hm lng. Phn b kch thc ht chu nh hng trc tip ca qu trnh to ht t.
V vy, thng s thi gian to ht t cn c kim sot cht ch. Kt qu thc
nghim cho thy phn b kch thc ht ca ht sau khi sy kh ng nht gia 3 l.
m ht sau khi sy: m ht phi nm trong gii hn 2-3%. Nu ht qu kh
vin kh kt dnh, s b tch lp, bong mt. Ht c m ln hn 3%, qu trnh dp
vin s xy ra hin tng dnh chy, ci. V vy, m ht cn c kim sot cht
ch trong qu trnh sn xut.
Trn ng nht: qu trnh trn xy ra nhiu ln trong quy trnh, t trn bt kh n
trn hon tt trc khi dp vin. giai on trn nguyn liu paracetamol v tinh bt
m, thi gian trn nh hng trc tip n phn tn hm lng dc cht. Thi gian
trn c la chn l 5 pht v kt qa c 3 l cho thy vi thi gian ny phn
tn hm lng c 3 l u < 2%. Cn vi thi gian thp hn nguy c khng ng
u hm lng dc cht xy ra s l nguyn nhn dn n khng ng u hm
lng ca vin. giai on trn hon tt, do t trng ht natri bicarbonat gp khong
1,5 ln ht paracetamol qu chnh lch nn thi gian trn hon tt m bo phn
tn hm lng <2% nm trong mt khong hp. Thi gian trn hon tt nh hng n
ng u hm lng cng nh ng u khi lng ca quy trnh. V vy cn
kim sot cht ch trnh tnh trng phn lp xy ra do thi gian trn qu lu hay
thi gian trn qu nhanh ht cha t c tnh trng ng nht.
Giai on dp vin: hai yu t nh hng n hiu sut quy trnh l tc dp vin
v lc dp vin. Tc dp vin qu nhanh, vin khng m bo chc, d b tch

145

lp, trn mi thit b dp vin khc nhau cn kim sot li thng s ny cho ph hp
vi iu kin sn xut thc t. Lc dp vin i vi vin nn paracetamol gii phng
nhanh c la chn t 13 18 Kp. Nu lc dp vin nh hn vin b, d v, khng
m bo cho qu trnh ng gi, vn chuyn. Lc dp vin ln, vin khng m bo
r, ha tan dc cht.
Vi quy trnh sn xut vin paracetamol gii phng nhanh c thm nh, kt qu
chng minh c quy trnh sn xut n nh, vin to ra t tiu chun c s
xut.
4.6. V nghin cu sinh kh dng vin nn paracetamol gii phng nhanh
4.6.1. Xy dng v thm nh phng php nh lng paracetamol trong huyt
tng
La chn phng php x l mu huyt tng
Qua kho st thc nghim c ba phng php x l mu huyt tng cho thy
chit hot cht bng ethyl acetat, th tch dch chit khng th thu c bng so vi
dung mi ban u do mt phn b nh ho, hiu sut chit thp. Nh vy, mun c
c kt qu chnh xc th cn phi c cht chun ni. Mt khc, chit lng lng phi
qua cng on bay hi dung mi rt mt thi gian v phc tp, dung mi bay hi c
hi, gy nhim mi trng.
Phng php ta protein huyt tng bng acid percloric c u im l mu
khng b pha long nhng kt qu sc k cho thy cn li nhiu pic tp ln vi
paracetamol.
Phng php ta protein bng acetonitril n gin, d thc hin. Dch lc thu
c trong, cho kt qu sc k phn tch r pic ca paracetamol. Tuy mu huyt tng
b pha long nhng do nng paracetamol trong huyt tng cao nn vn m bo
c th pht hin v nh lng c vi kt qu chnh xc cao. Phng php ta
protein bng acetonitril c la chn trong nghin cu l kt qu ca thc nghim
kho st v cng rt ph hp vi cng b ca cc sng ch M v phng php ta
protein huyt tng bng dung mi hu c. Theo kt qu nghin cu ca Schwenzer,
lng acetonitril s dng ch cn vi t l 1,4 ln so vi huyt tng l thu c dch

146

ni trong. Tuy nhin, chng ti la chn t l 2:1 nhm m bo ta hon ton protein
trong mu huyt tng [69].
La chn iu kin sc k
Tuy c nhiu ti liu tham kho phng php nh lng paracetamol trong
huyt tng nhng trong thc t khng th p dng hon ton cc iu kin sc k
cng b.
Nh a phn cc nghin cu khc [26],[65], chng ti la chn ct ODS vi
kch thc (250 4,6 mm; 5 m) phn tch mu huyt tng paracetamol. Qua qu
trnh kho st phn tch th, ct Hypersil c nhiu u im hn c, kh nng phn tch
tt v chn lc paracetamol ra khi mu phn tch.
Tng t nh vy, thc t kho st l da trn c s mt s cc phng php
cng b nhng thay i cc iu kin nh: t l pha ng, lu lng dng, th tch
tim mu v bc sng pht hin ti u. Kt qu l h thng sc k la chn c
lch chun tng i ca cc thng s phn tch u di 2%, t tiu chun theo
hng dn ca FDA [94], iu chng t h thng sc k c tnh ph hp cao, c th
ng dng phn tch mu trong thc t.
Thm nh phng php nh lng paracetamol trong huyt tng
Phng php nh lng nh hng rt ln n kt qu nghin cu nh gi sinh
kh dng ca thuc. V vy phng php nh lng phi t chnh xc cao trong
phm vi chp nhn ca FDA [94]. Theo quy nh ca FDA khi xy dng mt phng
php phn tch sinh hc phi thm nh phng php . Thm nh y gm: xc
nh tnh chn lc, kho st s tng quan gia nng v din tch pic, xc nh tnh
chnh xc, tnh ng, n nh v gii hn nh lng ca phng php. phc v
cho nghin cu ti, mt phng php nh lng paracetamol trong huyt tng
c xy dng v thm nh t cc yu cu trn theo quy nh ca FDA.
Phng php xy dng vi iu kin sc k khng qu phc tp, thi gian lu t
= 3-4 pht, thi gian sc k khng di, cho php nh lng nhiu mu mt ngy,
thun li trin khai nghin cu SKD v TSH.

147

Thc t qu trnh nghin cu SKD v TSH c ti gn 800 mu huyt tng NTN

c phn tch lin tc v cho kt qu ng tin cy mt ln na khng nh tnh
ng n v ph hp ca phng php nh lng paracetamol trong huyt tng
c xy dng v la chn trong nghin cu sinh kh dng.
4.6.2. Nghin cu sinh kh dng v tng ng sinh hc vin nn paracetamol
gii phng nhanh trn ngi tnh nguyn
- Nghin cu sinh kh dng vin thc nghim c i chng c thit k theo
m hnh cho ba, ngu nhin, ba thuc, liu n, ba giai on c thc hin thnh
cng trn 18 ngi tnh nguyn. Nghin cu c thit k v tun th theo hng
dn ca FDA [97] v c chp thun bi Hi ng o c - Trng H Dc H
Ni. Kt qu phn tch phng sai cho thy nh hng ca s khc nhau gia cc giai
on th thuc, gia nhng ngi tnh nguyn v trnh t th thuc l khng c
ngha thng k.
- V tc hp thu dc cht: Vin gii phng nhanh thc nghim Paracetamol
FR500 t gi tr trung bnh Tmax = 19 pht, tc hp thu c th so snh ngang bng
vi dng dung dch ung (Tmax = 20 pht) theo nh kt qu nghin cu gn y ca
Farre v CS [35] Tc hp thu paracetamol ca ch phm nghin cu Paracetamol
FR500 nh vy c ci thin rt tt. Trong khi vin nn paracetamol thng thng
t nng nh lu v dao ng hn nhiu : 35,6 pht [82], 35 77 pht thm ch c
th ln ti 1,82 gi [40]. Tc hp thu ca c hai mu paracetamol trong trng hp
ny nhanh hn r rt so vi kt qu nghin cu ca Rostami-Hodjegan v CS (Tmax
ca vin hp thu nhanh l 25 pht v vin thng thng l 55 pht) [80]..
- V nng nh trong huyt tng: Ch phm thc nghim v Panadol actifast
t nng nh trong huyt tng l nh nhau ( khong 32,7 g/ml) v cao hn so
vi vin nn thng thng (27 g/ml). iu ng ngc nhin l nng nh trong
nghin cu ny (liu ung tng ng 500 mg paracetamol) ca tt c cc mu u cao
hn nhiu so vi kt qu nghin cu ca Rostami-Hodjegan v CS khi cho NTN ung
liu 1000 mg ( 24 g/ml vi vin hp thu nhanh v 18 g/ml vi vin thng thng).
Nhn xt ny cng tng t khi so snh vi mt s cc nghin cu khc. iu ny c

148

th l gii do cn nng trung bnh ca ngi Vit Nam thp hn nhiu so vi cc nc

khc. Tuy nhin cng c th do c s khc bit v cc thng s dc ng hc trn
ngi Vit Nam.
- V mc hp thu: cc d liu AUC0-600 v AUC0- cho thy mc hp thu
ca vin thc nghim v ca c hai vin i chiu khc nhau khng ng k, chng t
sinh kh dng ton phn ca cc mu vin gii phng nhanh khng ci thin hn so
vi vin nn thng thng. Cng tng t nh cc thng s dc ng hc trn, cc
gi tr AUC ca cc mu vin trong nghin cu ny (khong 4100 g./ml*pht) cao
hn nhiu so vi kt qu ca cc nghin cu cng b trc (khong 3100 3200
g/ml*pht) [41],[58].
- So snh vi mu i chiu gii phng nhanh Panadol Actifast, ch phm
nghin cu Paracetamol FR500 c cc gi tr Tmax , Cmax v AUC khc nhau khng
ng k. Hai ch phm ny l tng ng v mt sinh hc.
- So vi vin nn thng thng (Panadol 500 mg), ch phm nghin cu
Paracetamol FR500 u vit hn hn v tc hp thu, biu hin r trn gi tr Tmax
ngn v Cmax cao hn hn so vi vin nn Panadol. Cc kt qu ny tng i ph hp
vi cc d liu nghin cu trc ca Grattan v Rostami-Hodjegan trn cc ch
phm paracetamol si ni tng t. Tc gi l gii kh nng hp thu nhanh l do
thnh phn natri bicarbonat lm tng tc tho rng d dy, do gip vn chuyn
paracetamol xung rut non nhanh hn [75].

149

KT LUN V XUT
Kt lun
1- Cng trnh nghin cu xy dng c cng thc v qui trnh sn xut
vin nn paracetamol gii phng nhanh (ch phm Paracetamol FR) theo c ch si
ni qui m 30.000 vin/l. Ch phm nghin cu c tiu chun ho p ng
y cc ch tiu cht lng i vi vin gii phng nhanh. Tiu chun ny c
Vin kim nghim thuc trung ng thm nh v nht tr, p dng nh gi cht
lng ch phm nghin cu. Ch phm nghin cu m bo n nh 24 thng theo
thi gian theo di c v tui th d tnh l 32 thng.
Cng thc v qui trnh sn xut vin nn paracetamol gii phng nhanh theo c
ch si ni n gin, d trin khai v c th p dng pht trin cc sn phm vin gii
phng nhanh i vi cc dc cht khc m hiu qu iu tr ph thuc vo tc gii
phng dc cht t vin.
2- ti nh gi c sinh kh dng ca ch phm nghin cu, so snh
vi thuc i chiu da trn thng s dc ng hc thu c t 18 ngi tnh nguyn
kho mnh, c th theo m hnh cho ba, ngu nhin, vi phng php nh lng
paracetamol trong huyt tng c thm nh y theo cc hng dn hin
hnh.
Kt qu nh gi sinh kh dng cho thy ch phm nghin cu Paracetamol FR
c sinh kh dng tng ng vi vin hp thu nhanh Panadol actifast ca nh sn
xut GlaxoSmithKline. Tc hp thu dc cht ca vin Paracetamol FR nhanh hn
r rt so vi vin nn qui c Panadol cng hm lng dc cht. Cc s liu v sinh
kh dng in vivo chng t vin Paracetamol FR l vin gii phng nhanh v hp
thu nhanh.
xut
T nhng kt qu nghin cu trn, chng ti xut mt s kin sau:

150

- Trin khai quy trnh sn xut vin nn paracetamol gii phng nhanh vo thc
t sn xut cng nghip, lu hnh trn th trng mt ch phm vin nn paracetamol
gii phng nhanh va thun tin trong s dng, va t sinh kh dng cao.
- M rng nghin cu p dng m hnh bo ch vin nn gii phng nhanh
dng vin s dng t dc si ni cho cc dc cht khc cn c tc dng nhanh trong
iu tr.

151

DANH MC CC BI BO C LIN QUAN N LUN N

1. Nguyn Th Hng H, Nguyn ng Ho, Nguyn Vn Long, Nguyn Th Hi
Yn, Dng Vn T, (2009), Kho st nh hng ca mt s yu t cng thc v k
thut bo ch ti tc ho tan paracetamol ra khi vin nn gii phng nhanh, Tp
ch Dc hc, 402, tr. 13-16 .
2. Nguyn Th Hng H, Nguyn ng Ho, Nguyn Vn Long, Dng Vn T,
(2010), nh gi sinh kh dng vin nn paracetamol FR 500, Tp ch Dc Hc,
408, tr. 4 - 7.

152

TI LIU THAM KHO

Ting Vit
1 B mn Bo ch (2005), Mt s chuyn v bo ch hin i, NXB Y hc, tr.
210-239.
2 B mn bo ch (2006), Sinh dc hc bo ch, Trng i hc Dc H Ni
3 B Y t (2002), Dc in Vit Nam III, NXB Y hc, H Ni, tr. 769-772.
4 B Y t (2009), Dc in Vit nam IV, NXB Y hc.
5 B Y t (2003), Dc th quc gia Vit Nam, Nh xut bn Y hc, H Ni, tr.
207-10.
6 ng Vn Gip , (2002), Kim sot qu trnh sn xut: vi tnh ng dng, i
hc y dc TP HCM, tr.100-104; 167-175.
7 Hunh Vn Ha (2005), Xy dng mt s m hnh thm nh quy trnh sn xut
thuc Vit Nam, Lun n tin s dc hc, Trng i hc Y Dc TP. H
Ch Minh.
8 L nh Quang (2006), Nghin cu bo ch vin nn gii phng nhanh cha
paracetamol v ibuprofen, Lun vn thc s dc hc, Trng i hc Dc H
Ni.

Ting Anh
9 Abdelbary G. et al. (2004), The preparation of orally disintegrating tablets using
a hydrophilic waxy binder, Int. J. Pharm., 278, 2, pp. 423-433.
10 Ahmad I. and Shaikh R.H. (2003), Effect of moisture on the stability of
packaged paracetamol tablet formulations, Pak. J. Pharm. Sci., 16, 2, pp.13-16.
11 Ahmad I. and Shaikh R.H., (1993), Stability of paracetamol in packaged tablet
formulayion Pak. J. Pharm. Sci., 6, 2, pp.37-45.
12 Ahmed, I. S. et al. (2006), Formulation of a Fast-Dissolving Ketoprofen Tablet
Using Freeze-Drying Blisters Technique, Drug Dev. , 32 (4), pp. 437-442.
13 Alapont A.G., (1999) , Indirect determination of paracetamol in pharmaceutical
formulations by inhibition of the system luminol-H2O2-Fe(CN)6/3chemiluminescence, J. Pharm. Biomedi. Anal., 21, 2, pp. 311-317.
14 Allen L. V., (2003), Rapid-dissolve technology, Int. J. pharm. compounding, 7,
6, pp. 449-450.
15 ASEAN Guideline 2005), Stability study of drug product, 9th CCQ-PPWG
Meeting Philipines.
16 Aurora J, Pathak V., (2005), Oral disintegrating technologies: Oral disintegrating
dosage forms: An overview. Drug Del. Technol, 5, 3, pp.50-54.
17 Bhaskaran, S., and Narmada, G.V., (2002), Rapid dissolving tablet A novel
dosage form, Ind. Pharmacist, 1, 2, pp.9-12.

153

18 Bhowmik D et al., (2009), Fast Dissolving Tablet: An Overview, J. Chem.

Pharm. Res., 1, 1, pp.163-177.
19 Bi Y. et al. (1999), Rapidly disintegrating tablets prepared by the wet
compression method: mechanism and optimization, J. Pharm. Sci., 88(10),
pp.1004-1010.
20 Bohnenstengel F. et al., (1999), In vitro cleavage of paracetamol glucuronide by
human liver and kidney -glucuronidase: determination of paracetamol by
capillary electrophoresis, J. Chromatogr. B , 721, pp. 295299.
21 Bosch M.E., (2006), Determination of paracetamol: Historical evolution, Journal
of Pharmaceutical and Biomedical Analysis, J Pharm Biomed Anal., 42, 3,
pp.291-321.
22 British Pharmacopoeia 2009.
23 Brown D., (2001), Orally disintegrating tablets: Taste over speed. Drug Del.
Technol., 3., 6, pp. 58-61.
24 Bruna E, et al., (1998), Acetaminophen flashtab formulation: fast disintegration
and optimal absorption of the active ingredient, Proc. Intl. Symp. Control. Rel.
Bioact. Mater., 25, pp.938939.
25 Burnett I. et at. (2006), Onset of analgesia of a paracetamol tablet containing
sodium bicarbonate: A double-blind, placebo-controlled study in adult patients
with acute sore throat, Clin. Therap., 28, 9, pp.1273-1278.
26 Campanero MA. et al., (1999), Rapid liquid chromatographic assay for the
determination
of
acetaminophen
in
plasma
after
propacetamol
administrationapplication to pharmacokinetic studies, J. Pharm. Biomed.
Anal, 20, pp.327-34.
27 Cekic S.D. et al., (2005), Simultaneous spectrophotometric determination of
paracetamol and p-aminophenol in pharmaceutical products with tiron using
dissolved oxygen as oxidant, J. Anal. Chem., 60, 11, pp.1019-1023.
28 Cheng, P.H. & Dutt, J.E (1993), Analysis of retrospective production data using
qualility control charts, Pharmaceutical proccess validation, Marcel Deckk Inc.,
New York, p.532-540.
29 Cilurzo F. et al., (2008), Fast dissolving films made of maltodextrin, Eur. J.
Pharm. Biopharm., 70, 3, pp.895900.
30 Dressman J., Kramer J. (2005), Pharmaceutical dissolution testing, Taylor &
Francis Group, LLC, New York, pp.81-96.
31 Easwaramoorthy D. et al., (2001), Chemiluminescence detection of paracetamol
by a luminol-permanganate based reaction, Anal. Chim. Acta, 439, 1, pp. 95100.
32 Edinboro L.E. et al., (1991), Determination Of Serum Acetaminophen In
Emergency Toxicology: Evaluation Of Newer Methods: Abbott Tdx and Second
Derivative Ultraviolet Spectrophotometry, Clinical Toxicology, 29, 2, pp.241-255

154

33 Elsayed M.A.H. et al., (1997), Spectrophotometric determination of

acetaminophen, salicylamide and codeine phosphate in tablets, Analyst, 104, pp.
620625.
34 European Pharmacopoeia 5.0 (2005), pp.628.
35 Farre. et al. (2008), Study of paracetamol 1g oral solution bioavailability,
Methods Find. Exp. Clin. Pharmacol., 30, 1, pp.37-41
36 Filik H. et al., (2005), Sequential spectrophotometric determination of
paracetamol and p-aminophenol with 2,2-(1,4-phenylenedivinylene) bis-8hydroxyquinoline as a novel coupling reagent after microwave assisted
hydrolysis, Anal. Chim. Act., 535 , 2, pp.177-182.
37 Garekani H. A. et al (2003), Increasing the aqueous Solubility of Acetaminophen
in Presence of Polyvinylpirolidone and Investigation of the mechanisms
involved, Drug Dev.Ind. Pharm., 29, 2, pp.173-179.
38 Genanaro A. R., (2000), Remington: The science and practical of pharmacy, 20th
edition, pp. 862
39 Ghosh TK. Et al. (2005), Quick dissolving oral dosage forms: Scientific and
regulatory considerations from a clinical pharmacology and biopharmaceutical
perspective, USA: CRC Press., pp. 337-356.
40 Grattan T. et al. (2000), A five-way crossover human volunteer study to compare
the pharmacokinetics of paracetamol following oral administration of two
commercially available paracetamol tablets and three development tablets
containing paracetamol in combination with sodium bicarbonate or calcium
carbonate, Eur. J. Pharm. Biopharm., 49, 3, pp. 225229.
41 Grattan T. et al. (2001), Swallow tablet comprising paracetamol, US Patent
Aplication No. 6316025 B1
42 Gubbi S. and Jarag R. (2009), Liquisolid technique for enhancement of
dissolution properties of bromhexine hydrochloride, Research J. Pharm. and
Tech., 2, 2, pp.382-386
43 Habib W. et al., (2000), Fast dissolving drug delivery systems. Crt Rev Ther
Drug Carrier Syst, 17, 1, pp. 61-72.
44 Hamilton EL, Luts EM., (2005), Advanced Orally disintegrating tablets bring
significant benefits to patients and product life cycle, Drug Del. Technol., 5, 1,
pp. 34-37.
45 Heitmeier S. et al., (1999), Direct assay of nonopioid analgesics and their
metabolites in human urine by capillary electrophoresis and capillary
electrophoresis-mass spectrometry, J. Chromatog. B, 721, 1, pp.109-125.
46 Hepler B. et al., (1984), Homogeneous enzyme immunoassay of acetaminophen
in serum. Am. J. Clin. Pathol., 81, 5, pp.602-610.
47 Hirani J., (2009), Orally Disintegrating Tablets: A Review, Trop J Pharm Res, 8,
2, pp.161-172
48 Hong W. et al. (2005), Study on the interactions between polyvinylpyrrolidone
(PVP) and acetaminophen crystals: Partial dissolution pattern change, J. Pharm.
Sci., 94, 10, pp. 2166-2174.

155

49 Ibnez Y. et al. (2006), A pharmacokinetic study investigating the rate of

absorption of a 500 mg dose of a rapidly absorbed paracetamol tablet and a
standard paracetamol tablet, Curr. Med. Res. Opin., 22, 10, pp. 1893-1897.
50 ICH harmonised tripartite guideline (2003), Evaluation for stability data Q1E,
Current Step 4 version, International conference on harmonisation of technical
requirements for registration of pharmaceutical for human use.
51 Japanese Pharmacopoeia XV (2007), pp.267-268.
52 Javadzadeh Y. et al., (2007), An Investigation of Physicochemical Properties of
Piroxicam Liquisolid Compacts, Pharm. Dev. Technol., 12, pp.337343.
53 Javadzadeh Y. et al., (2007), Liquisolid technique for dissolution rate
enhancement of a high dose water-insoluble drug (carbamazepine), Int. J.
Pharm., 341, pp. 2634
54 Javadzadeh Y. et al., (2008), Liquisolid technique as a new approach to sustain
propranolol hydrochloride release from tablet matrices, Int. J. Pharm., 362, pp.
102108.
55 Jensen L.S. et al. (2004), The quantification of paracetamol, paracetamol
glucuronide and paracetamol sulphate in plasma and urine using a single highperformance liquid chromatography assay, J. Pharm. Biomed. Anal. ,34 , pp.
585593
56 Kalantzi L. et al., (2006), Biowaiver monographs for immediate release solid oral
dosage forms: Acetaminophen (Paracetamol), J. Pharm. Sci., 95, 1, pp. 414.
57 Kearney P., (2003), The zydis oral fast dissolving dosage form, Modified
release drug delivery technology. New York , Marcel Dekker, pp.192-194.
58 Kelly K. et al. (2003), Comparison of the rates of disintegration, gastric
emptying, and drug absorption following administration of a new and a
conventional paracetamol formulation, using scintigraphy, Pharm. Res., 20, 10,
pp.1668-1673.
59 Klancke J., (2003), Dissolution testing of orally disintegrating tablets,
Dissolution Technol., 10, 2, pp. 6-8.
60 Koizumi K.I. et al. (1997), New method for preparing high-porosity rapid
saliva-soluble compressed tablets using mannitol with camphor a subliming
material, Int. J. Pharm., 152, pp.127-131.
61 Koizumi, F. et al., (1988), Plasma paracetamol concentrations measured by
fluorescence polarization immunoassay and gastric emptying time, Tohoku J.
exp. Med., 155, 2, pp.159-164.
62 Kumar R. et al., (2009), Formulation evaluation of mouth dissolving tablets of
fenofibrate using sublimation technique, Int. J. Chem. Res.,1, 4, pp. 840-850,
63 Kumar R. et al., (2009), Formulation Evaluation of Mouth Dissolving Tablets of
Fenofibrate Using Sublimation Technique, Int.J. ChemTech Res., 1, 4, pp.840850.
64 Lagoviyer Y. (2002), Means for creating a mass having structural integrity, US
Patent 6465010.

156

65 Lau G.S.N. et al., (1994), The estimation of paracetamol and its major
metabolites in both plasma and urine by a single high-performance liquid
chromatography assay, J. Pharm. Biomed. Anal., 12, pp.15631572.
66 Liu F. et al. (2002), Water solube polymer-based rapidly dissolving tablets and
production processes thereof, US Patent 6465009.
67 Malke S. et al. (2007), Formulation and evaluation of oxcarbazepine fast dissolve
tablets, Ind. J. Pharm. Sci., 69, 2, pp.211-214.
68 Masareddy R.S. et al., (2008), Delopment of mouth dissolving tablets of
clozapine using two different techniques, Ind. J. Pharm. Sci., 70, pp. 526-528.
69 Mathies J.C. , Austin M.A., (1980), Modified acetonitrile protein- precipitation
method of sample preparationfor drug assay by liquid chromatography, Clin.
Chem., 26, 12, pp.1760.
70 Mizumoto T. et al. (2005), Formulation design of a novel fast-disintegrating
tablet, Int. J. Pharm., 306, pp. 83-90.
71 Moeller P. L. et al. (2000), Time to onset of analgesia and analgesic efficacy of
effervescent acetaminophen 1000 mg compared to tablet acetaminophen 1000
mg in postoperative dental pain: A single-dose, double-blind, randomized,
placebo-controlled study. J. Clin. Pharm., 40, pp. 370-378.
72 Moore, J.W. and Flanner, H.H. (1996), Mathematical comparison of dissolution
profiles, Pharm. Tech, 20, 6), pp. 64-74.
73 Morita Y., (2002), Evaluation of the disintegration time of rapidly disintegrating
tablets via a novel method utilizing a CCD camera, Chem. Pharm. Bull., 50, 9,
p.1181-1186.
74 Pebley W.S. et al. (1994), Rapidly disintegrating tablet, US Patent 5, 298, 261.
75 Pfister W. R. et al., (2006), Orally disintegrating tablets: Products, technologies,
and development issues, Pharm. Tech. Asia, pp. 28-33.
76 Pulgarin J.A.M. et al., (1996), Flow-injection stopped-flow spectrofluorimetric
kinetic determination of paracetamol based on its oxidation reaction by
hexacyanoferrate(III), Anal. Chim. Acta, 333, 1-2, pp. 59-69.
77 Reddy LH, Ghosh BR., (2002), Fast dissolving drug delivery systems: A review
of the literature, Ind J Pharm Sci, 64, 4, pp. 331-336.
78 Rifino C.B. (2003), Process Validation and Quality Assurance, Pharmaceutical
Process Validation, 3rd Ed, Marcel Dekker, Inc, Newyork, pp. 750-792.
79 Roberts M.S. et al., (2007), Oral delivery system, US Patent application
publication No.: US 20070141144 A1
80 Rostami-Hodjegan A. et al. (2002), A new rapidly absorbed paracetamol tablet
containing sodium bicarbonate. I. A four-way crossover study to compare the
concentration-time profile of paracetamol from the new paracetamol/sodium
bicarbonate tablet and a conventional paracetamol tablet in fed and fasted
volunteers, Drug Dev. Ind. Pharm., 28. 5, pp.523-531.
81 Rowe R C. et al. (2005), Handbook of Pharmaceutical Excipients, 5th edition,
Pharmaceutical Press.

157

82 Rumble R. H. et al., (1991), Effects of Posture and Sleep on the

Pharmacokinetics of Paracetamol (Acetaminophen) and Its Metabolites, Clin.
Pharmacokinet, 20, 2, pp.167-173
83 Rygnestad T. et al. (2000), Absorption of effervescent paracetamol tablets
relative to ordinary paracetamol tablets in healthy volunteers, Eur. J. Clin.
Pharm., 56, pp. 141 - 143.
84 Saadia A. et al., (2008), Improvement of dissolution properties of Carbamazepine
through application of the liquisolid tablet technique, Eur. J. Pharm.Biopharm.,
69, pp. 342347.
85 Shinoda S. et al., (2007), Pharmacokinetics/Pharmacodynamics of
Acetaminophen Analgesia in Japanese Patients with Chronic Pain, Biol. Pharm.
Bull. 30, 1, pp.157161.
86 Shulin Zhao et al., (2006), Detection of paracetamol by capillary electrophoresis
with chemiluminescence detection, Anal. Chim. Acta 559, pp.195199.
87 Siddiqui M. N., (2010), Fast dissolving tablets: preparation, characterization and
evaluation: an review, Int. J. Pharm. Sci. Rev. Res., 4, 2, pp.87-96
88 Sugihara M. et al., (1986), Discriminatory features of dosage form and package.
Jpn. J. Hosp. Pharm., 12, p.322-328.
89 Suresh S. et al. (2007), Preparation and evaluation of mouth dissolution tablets of
salbutamol sulphate, Indian J. Pharm. Sci., 69, 3, pp.467-469.
90 Takeuchi H. et al. (2005), Tabletting of solid dispersion particles consisting of
indomethacin and porous silica particles, Chem. Pharm. Bull., 53, 5, pp.487-491.
91 Tayel S.A. et al. (2008), Improvement of dissolution properties of carbamazepine
through application of the liquisolid tablet technique, Eur. J. Pharm. Biopharm.,
69, pp.342347
92 Tiong N. et al. , (2009), Effects of liquisolid formulations on dissolution of
naproxen, Eur. J. Pharm. Biopharm., 73, pp.373384
93 U.S. Food and Drug administration; CDER (2003), Bioavailability and
bioequivalance studies for orally administered drug products
General
considerations.
94 U.S. Food and Drug administration; CDER, (1994), Reviewer Guidance
Validation of Chromatographic Methods.
95 U.S. Food and Drug administration; CDER, (1997), Guidance for industry,
extended release oral dosage forms: development, evaluation and application of
an in vitro/in vivo correlation. U.S. Department of Health and Human Services.
96 U.S. Food and Drug administration; CDER, (2000), Guidance for Industry
(2000): Waiver of In Vitro Bioavailability and Bioequivalence Studies for
Immediate-Release Solid Oral Dosage Forms Based on a Biopharmaceutics
Classification System.

158

97 U.S. Food and Drug administration; CDER, (2003), Guidance for Industry
Bioavailability and Bioequivalence Studies for Orally Administered Drug
Products
General Considerations, U.S. Department of Health and Human
Services.
98 U.S. Food and Drug administration; CDER, (2008), Guidance for industry: Drug
stability guidelines,U.S. Department of Health and Human Services.
99 U.S. Food and Drug administration; CDER, (2008), Guidance for Industry:
Orally Disintegrating Tablets , U.S. Department of Health and Human Services.
100 United States Pharmacopoeia 30 (2007). In vitro and In vivo Evaluations of
Dosage Forms, 27th edition, Revision, Mack Publishing Co., Easton, PA.
101 US. Food and Drug Administration (2001), Guidance for Industry Q1A(R2)
Stability Testing of New Drug Substances and Products.
102 Valleri M. et al. (2004), Development and evaluation of glyburide fast dissolving
tablets using solid dispersion technique. Drug Dev. Ind. Pharm., 30 (5), pp. 525534.
103 Verma K.K. et al., (1984), Spectrophotometric determination of paracetamol in
drug formulations with 2-iodylbenzoate, Analyst, 109, 6, pp. 735-737.
104 Vilchez J.L. et al., (1995), Spectrofluorimetric determination of paracetamol
pharmaceuticals and biological fluids, J. Pharm. Biomed. Anal., 13, 9, pp. 11191125.
105 Walter L. (1994), The pharmaceutical codex, The pharmaceutical press, 908910, 987-994.
106 WHO (2006), Stability: global challlenges to harmonization, 12th International
Conference of Drug Regulatory Autorities Proceedings, pp. 61-63.
107 Wong S.M. et al. (2006), Enhancement the dissolution rate and oral absorption
of a poorly water sol by formation of surfactants-containing microparticles, Int.
J. Pharm., 317, pp.61-68
108 Wong S.M. et al. (2006), Fast-dissolving microparticles fail to show improved
oral bioavailability, J. Pharm. Pharmacol., 58, pp.1319-1326
109 Yadav V.B. et al., (2009), Improvement of Solubility and Dissolution of
Indomethacin by Liquisolid and Compaction Granulation Technique, J. Pharm.
Sci. & Res.,1, 2, pp. 44-51.
110 Yoshio Kuno (2005), Evaluation of rapidly disintegrating tablets manufactured
by phase transition of sugar alcohols, J. Control Rel., 105, 16-22.
111 Yu D.G. et al., (2008), Oral Fast-Dissolving DDD Fabricated Using 3DP,
Bioinformatics and Biomedical Engineering 2008, pp.1602 1605.

159

PH LC
Ph lc 1

QUY TRNH SN XUT VIN NN PARACETAMOL GII

PHNG NHANH

Ph lc 2

TIU CHUN CHT LNG VIN NN PARACETAMOL GII

PHONG NHANH
KT QU THM NH QUY TRNH SN XUT VIN NN
PARACETAMOL GII PHNG NHANH

Ph lc 3

Ph lc 4

D LIU THM NH QUY TRNH SN XUT VIN NN

PARACETAMOL GII PHNG NHANH

Ph lc 5

THNG S DC NG HC CA THUC NGHIN CU V

THUC I CHIU

Ph lc 6

SC MT S MU HUYT TNG CA NGI TNH

NGUYN

Ph lc 7

KT QU PHN TCH DC NG HC
PHIU KIM NGHIM CA CH PHM NGHIN CU:
KT QU XC NH BC SNG HP TH CC I CA
DUNG DCH PARACETAMOL TRONG HCl O,1N V MI
TNG QUAN TUYN TNH GIA NNG PARACETAMOL
VI MT QUANG
CC VN BN LIN QUAN KHC

Ph lc 8
Ph lc 9

Ph lc 10

Ph lc 1
QUY TRNH SN XUT VIN NN PARACETAMOL GII PHNG NHANH
TRNG I HC DC H NI

QUY TRNH SN XUT VIN NN

CNG TY DC KHOA

PARACETAMOL GII PHNG NHANH

I. C IM THNH PHM
1. Cng thc cho mt vin nn:
Paracetamol

Nm trm miligam

500 mg

T dc

v 1 vin

(Natri bicarbonat, PVP K30, Amidon, Talc, Magnesi stearat, Ethanol 60o, Nc tinh
khit)
2. Tnh cht thnh phm:
Vin nn hnh caplet, mu trng, mt mt c vch ngang, khng st v
3. Cng dng:
iu tr cc chng au v st t nh n va.
4. Liu dng, cch dng:
Ung 1 vin, 4-6 gi mt ln khi cn thit.
5. Trnh by:
V 6 vin, hp 4 v.
6. Bo qun:
Ni kh mt, trnh nh sng.
II. C IM NGUYN PH LIU
- Paracetamol:
- Natri bicarbonat:
- PVP K30:
- Ethanol:
- Amidon:
- Talc:
- Magnesi stearat:
- Natri lauryl sulfat:
- Nc tinh khit:

t tiu chun DVN III

t tiu chun BP 2007
t tiu chun BP 2007
t tiu chun DVN III
t tiu chun BP 2007
t tiu chun DVN III
t tiu chun DVN III
t tiu chun BP 2007
t tiu chun DVN III

II. S CC GIAI ON SN XUT

IV. C IM TRANG THIT B DNG TRONG QU TRNH SN XUT

Tn thit b

Hng - Model

Xut x

Cc thit b ch yu s dng trong sn xut

My nho trn cao tc

Cng ty Hong Anh

Vit Nam

My sy tng si

Vin c hc ng dng

Vit Nam

My xt ht

Vin c hc ng dng

Vit Nam

My trn lp phng

Vin c hc ng dng

Vit Nam

Cng ty Tin Tun CP-250

Vit Nam

RIMEK Mini Press II

My p v
My dp vin quay trn

V. M T QU TRNH SN XUT
Qu trnh sn xut c chia lm 3 giai on:
(1) Chun b nguyn ph liu, phng pha ch
(2) Pha ch
(3) p v, b hp, ng thng, nhp kho
5.1. Chun b
Kim tra nguyn, ph liu:
Nguyn liu c kim tra cht lng trc khi a vo sn xut theo tiu
chun ghi trong mc II.
Chun b phng pha ch:
Phng sn xut phi t yu cu v sinh i vi pha ch thuc ung: lau sch
sn nh, bn pha ch bng nc my, sau lau bng ethanol 70%, bt n t ngoi
trong 30 pht trc khi pha ch.
5.2. Pha ch
5.2.1. Cn, ong nguyn ph liu theo cng thc sau:

TT

Tn nguyn liu

S lng cho 30.000 vin

Paracetamol

15,00 kg

Natri bicarbonat

18,90 kg

Amidon (r trong)

1,62 kg

PVP K30

1,08 kg

Nc ct

3,00 L

Ethanol 60o

3,78 L

Amidon (r ngoi)

1,83 kg

Talc

0,489 kg

Magnesi stearat

0,075 kg

5.2.2. Pha ch:

- Xay paracetamol v natri bicarbonat 2 ln bng my xay inh. Ry
paracetamol, natri bicarbonat v amidon qua ry c kch thc mt ry l 0,25 mm.
Ry aerosil, talc v magnesi stearat qua ry 180.
- Trn paracetamol v amidon thnh bt kp trong my nho cao tc trong 5
pht. Thm dung dch PVP 15% trong nc ri nho m trong 10 pht. Xt ht qua ry
c kch thc mt ry 1 mm ri em sy nhit khong 50oC n khi m t 23%.
- Trn natri bicarbonat v amidon thnh bt kp trong my nho cao tc trong 4
pht. Thm dung dch PVP 15% trong ethanol 96o ri nho m trong 12 pht. Xt ht
qua ry 1 mm ri em sy nhit khong 50oC n khi m t 2-3%.
- Trn ht paracetamol v ht natri bicarbonat vi aerosil, talc, magnesi stearat
v amidon r ngoi trong my trn lp phng trong 10 pht.
- Dp vin caplet c khi lng 1,303 g v cng 13-18 kP.
5.3. ng gi
Vin nn paracetamol c ng trong v nhm, mi v 6 vin ri cho vo hp
carton, mi hp 4 v.

VI. CH V SINH V TRNG

Theo ng quy nh ca GMP.
1. V sinh c nhn:
Ngi tham gia sn xut phi khe mnh, khng mc bnh truyn nhim hoc
ang au m, phi ra tay trc khi lm vic.
Qun o, m, khu trang phi sch. Trong khi sn xut phi tun theo ng cc
quy trnh thao tc chun.
2. V sinh bung pha ch:
Bung pha ch (tng, sn, trn, bn, my mc, thit b) phi c lau ra
sch. Sau khi pha ch phi thu dn v lau li bng nc sch.
3. V sinh cc phng tin khc:
Cc thit b dng trong sn xut phi c v sinh theo ng quy nh ca thc
hnh tt sn xut thuc.
VII. K THUT AN TON LAO NG
1. Trong qu trnh sn xut, ngi lao ng phi mc o cng tc, i m trm tc v
eo khu trang.
2. Thc hin ng cc quy trnh, ni quy vn hnh my v thit b dng trong sn xut.
VIII. PHNG PHP KIM SOT, KIM NGHIM
TT
1
2
3
4
5

Cc giai on cn
KS-KN

Ni dung
KS-KN
nh tnh
Kim nghim nguyn
nh lng
liu
Th tinh khit
Cn, ong nguyn
Cng thc
liu
Cn v qu cn
Trnh t
Pha ch
Kim sot cc
thng s
Kim nghim bn
nh lng
thnh phm
Hm m
nh tnh
KN thnh phm
ng u khi
lng

Yu cu

Ngi thc
hin

Theo tiu chun

ghi trong mc II

Phng KN

ng

KSV, ngi
sn xut

ng

KSV, ngi
sn xut

ng
t TCCS

KSV
Phng KN
KSV, ngi
SX

ng gi

ha tan
4-aminophenol
Tp cht lin quan
nh lng
S lng

ng

IX. D PHM, PH PHM

1. Nhng vin khng t v hnh thc c thu hi v gp vo m sau
2. Khng c ph phm

KSV, t trng

Ph lc 2
TIU CHUN CHT LNG
VIN NN PARACETAMOL GII PHNG NHANH

Ph lc 3
KT QU THM NH QUY TRNH SN XUT VIN NN
PARACETAMOL GII PHNG NHANH
BO CO THM NH

M s:

QUY TRNH SN XUT

VIN NN PARACETAMOL FR 500 mg
1. MC CH YU CU
Bo co v cng vic v kt qu thm nh QTSX vin nn Paracetamol FR 500 mg
gii phng nhanh thuc k hoch:
X Thm nh trc (QTSX mi)
Thm nh lui (QTSX trin khai n nh)
Thm nh li (khi thay i nguyn liu hay thit b)
2. CHUN B TRC THM NH
2.1. Thm nh thit b
- Ti liu v h s thm nh thit b sn xut
- Ti liu v h s thm nh thit b kim nghim
2.2. Bin son v ban hnh ti liu
- QTSX vin nn Paracetamol FR 500 mg
- cng thm nh QTSX
- Phiu thm nh: phn tn hm lng, m, phn b kch thc ht, t trng
biu kin, trn chy, ng u khi lng, cng, ha tan, khi lng trung
bnh vin.
- Mu bo co QTSX
- SOP vn hnh: my nho cao tc, my sy tng si, my dp vin, cn in t, my
quang ph, my th ha tan
2.3. Tp hun nhn s thm nh
- K hoch o to v Phiu o to c nhn

3. PHNG PHP TIN HNH

- Thc nghim: theo QTSX, cng thm nh, cc phiu thm nh ca vin nn
paracetamol gii phng nhanh v cc SOP vn hnh thit b nu mc 2.
- Phn tch d liu bng cc phng php thng k ton hc
4. KT QU THM NH
STT Thng s
Giai on trn bt kh
1
phn tn hm
lng paracetamol
phn tn hm
lng natri
bicarbonat
Giai on nho m
2
phn tn hm
lng paracetamol
phn tn hm
lng natri
bicarbonat
Giai on sy ht
3
m ht
paracetamol
4
m ht natri
bicarbonat
Sa ht
5
Phn b kch thc
ht
6
T trng biu kin
ht paracetamol
7
T trng biu kin
ht natri bicarbonat
Trn hon tt
8
phn tn hm
lng
9
trn chy
10

T trng cm

Yu cu

Kt qu
L P1 L P2 L P3

CV 2%

1,55

1,20

1,34

CV 2%

1,31

1,24

1,39

CV 2%

1,27

1,24

1,28

CV 2%

1,40

1,30

1,23

2,0 3,0%

2,19

2,09

2,41

2,0 3,0%

2,25

2,15

2,19

Khng khc nhau gia 3

l
Khng khc nhau gia 3
l
Khng khc nhau gia 3
l

0,65

0,64

0,66

1,081

1,083

1,083

CV 2%

1,59

1,89

1,00

Cc gi tr phi
ng nht gia 3 l
Cc gi tr phi
ng nht gia 3 l

11,13

10,97

11,07

0,95

0,95

0,94

Giai on dp vin
11
ng u khi lng
12
13

cng
ha tan

Khi lng trung bnh

vin 5%
13-18 kP
90% sau 5 pht

1303,7 1312,9 1305,9

15,93
98,06

16,06
96,61

16,14
98,89

5. NHN XT V NH GI
Kt qu thm nh:
X t X Khng t

6. KT LUN V NGH
QTSX vin nn paracetamol gii phng nhanh c chng minh l cho sn phm
t yu cu cht lng v c kim sot v mt thng k. Do QTSX vin nn
paracetamol gii phng nhanh c php trin khai sn xut theo s ng k.

Ph lc 4
D LIU THM NH QUY TRNH SN XUT VIN NN
PARACETAMOL GII PHNG NHANH

Ph lc 4.1. phn b kch thc ht ca cm paracetamol

Khi lng cm cn li trn ry (g) (gi tr trung bnh)

L
1
2
3

< 0,2 mm Ry 0,2 mm

6,90
9,60
8,10
6,10
9,70
8,80

Ry 0,4 mm
24,3
25,6
19,3

Ry 0,6 mm Ry 0,8 mm
21,2
36,0
26,0
31,9
21,8
37,0

Ry 1,0 mm
2,0
2,3
1,2

Phn tch ANOVA

Ngun bin
thin

Tng bnh
phng
(SS)

Gia cc l
Trong tng l
Sai s
Tng

0,537778
2337,811
61,19556
2399,544

Bc
t
do
(df)
2
5
10
17

Trung bnh
bnh phng
(MS)
0,268889
467,5622
6,119556

0,043939
76,4046

0,957196
1,23E-07

Ph lc 4.2. T trng biu kin ca cm paracetamol

L
L P1
L P2
L P3

T trng biu kin (g/ml)

(gi tr trung bnh)
V tr 1
V tr 2
V tr 3
0,67
0,63
0,66
0,66
0,67
0,61
0,68
0,65
0,65

Trung
bnh
0,65
0,64
0,66

Phn tch ANOVA

Ngun bin
thin

Tng bnh
phng
(SS)

Gia cc l
Trong tng l
Sai s
Tng

0,000267
0,0014
0,002133
0,0038

Bc
t
do
(df)
2
2
4
8

Trung bnh
bnh phng
(MS)
0,000133
0,0007
0,000533

0,25
1,3125

0,790123
0,364543

Ph lc 4.3. phn b kch thc ht ca cm natri bicarbonat

L
1
2
3

Khi lng cm cn li trn ry (g) (gi tr trung bnh)

< 0,2 mm Ry 0,2 mm
10,0
18,1
12,20
14,2
9,80
14,5

Ry 0,4 mm
41,2
38,4
43,1

Ry 0,6 mm Ry 0,8 mm
15,5
15,2
17,2
16,0
16,3
14,8

Ry 1,0 mm
0,0
2,0
1,5

Phn tch ANOVA

Ngun bin
thin
Gia cc l
Trong tng l
Sai s
Tng

Tng bnh
phng
(SS)
0
2599,593
28,50667
2628,1

Bc t
do
(df)
2
5
10
17

Trung bnh
bnh phng
(MS)
0
519,9187
2,850667

0
182,3849

1
1,74E-09

Ph lc 4.4. T trng biu kin ca cm natri bicarbonat

L
L P1
L P2
L P3

T trng biu kin (g/ml)

(gi tr trung bnh)
V tr 1
V tr 2
V tr 3
1,087
1,081
1,075
1,075
1,087
1,087
1,081
1,075
1,093

Trung
bnh
1,081
1,083
1,083

Phn tch ANOVA

Ngun bin
thin
Gia cc l
Trong tng l
Sai s
Tng

Tng bnh
phng
(SS)
8E-06
3,2E-05
0,000304
0,000344

Bc t
do
(df)
2
2
4
8

Trung bnh
bnh phng
(MS)
4E-06
1,6E-05
7,6E-05

0,052632
0,210526

0,949375
0,818594

Ph lc 4.5. T trng biu kin ca cm trn hon tt

L
L P1
L P2
L P3

T trng biu kin (g/ml)

(gi tr trung bnh)
V tr 1
V tr 2
V tr 3
0,95
0,96
0,94
0,96
0,93
0,95
0,94
0,95
0,93

Trung
bnh
0,95
0,95
0,94

Phn tch ANOVA

Ngun bin
thin

Tng bnh
phng
(SS)

Gia cc l
Trong tng l
Sai s
Tng

0,000156
0,000156
0,000711
0,001022

Bc
t
do
(df)
2
2
4
8

Trung bnh
bnh phng
(MS)
7,78E-05
7,78E-05
0,000178

0,4375
0,4375

0,673241
0,673241

Ph lc 4.6. trn chy ca cm trn hon tt

L
L P1
L P2
L P3

trn chy (giy/100 g cm)

(gi tr trung bnh)
V tr 1
V tr 2
V tr 3
11,10
10,60
11,70
10,80
11,40
10,70
10,90
11,30
11,00

Trung
bnh
11,13
10,97
11,07

Phn tch ANOVA

Ngun bin
thin
Gia cc l
Trong tng l
Sai s
Tng

Tng bnh
phng
(SS)
0,042222
0,068889
0,911111
1,022222

Bc t do
(df)
2
2
4
8

Trung bnh
bnh phng
(MS)
0,021111
0,034444
0,227778

0,092683
0,15122

0,913383
0,864352

Ph lc 4.7. ng u khi lng vin

L P1
n
1
2
3
4
5

K.lng
(mg)
1326,2
1317,5
1293,4
1306,0
1304,7

n
6
7
8
9
10

K.lng
(mg)
1296,4
1299,6
1309,1
1297,8
1280,4

n
11
12
13
14
15

K.lng
(mg)
1294,2
1293,6
1320,6
1289,4
1322,7

n
16
17
18
19
20

K.lng
(mg)
1291,4
1317,4
1301,5
1302,7
1309,2

Khi lng vin trung bnh: 1303,7 mg

Khi lng vin trung bnh 5%: 1238,5 mg 1368,9 mg
L P2
n
1
2
3
4
5

K.lng
(mg)
1318,7
1322,4
1302,0
1322,6
1337,8

n
6
7
8
9
10

K.lng
(mg)
1315,9
1299,2
1319,7
1313,2
1299,6

n
11
12
13
14
15

K.lng
(mg)
1321,4
1301,5
1304,3
1313,6
1299,2

Khi lng vin trung bnh: 1312,9 mg

Khi lng vin trung bnh 5%: 1247,3 mg 1378,6 mg

n
16
17
18
19
20

K.lng
(mg)
1313,5
1326,8
1319,2
1297,3
1310,5

L P3
n
1
2
3
4
5

K.lng
(mg)
1292,5
1320,4
1313,2
1307,7
1303,3

n
6
7
8
9
10

K.lng
(mg)
1311,5
1284,2
1325,1
1307,6
1314,3

n
11
12
13
14
15

K.lng
(mg)
1311,5
1284,2
1325,1
1307,6
1314,3

n
16
17
18
19
20

K.lng
(mg)
1305,3
1312,1
1281
1315,6
1302,9

Khi lng vin trung bnh: 1305,9 mg

Khi lng vin trung bnh 5%: 1240,7 mg 1371,3 mg
Ph lc 4.8. cng ca vin
L
P1
P2
P3

cng ca cc vin (kP)

1
2
3
4
5
6
7
8
9
10
TB
15,50 16,00 17,20 14,00 15,40 17,00 16,40 16,30 15,80 15,70 15,93
16,20 17,00 15,60 15,50 14,70 16,20 16,00 16,80 15,60 17,00 16,06
15,20 17,00 16,80 16,30 15,80 17,20 16,50 15,80 15,30 15,50 16,14
Ph lc 4.9. ha tan ca vin

L
P1
P2
P3

T l dc cht (%) gii phng sau 5 pht t cc vin

1
2
3
4
5
6
TB
98,35
99,99
98,36
95,24
99,31
97,12
98,06
99,30
95,10
92,20
96,70
99,40
96,94
96,61
98,90
99,40
99,70
98,50
97,80
99,06
98,89

Ph lc 5
THNG S DC NG HC CA VIN NGHIN CU V THUC I
CHIU
Ph lc5.1: Cc thng s dc ng hc ca vin Paracetamol FR
Cmax

Tmax

AUC0-600

AUC0-

(g/ml)

(pht)

(g.pht/ml)

(g.pht/ml)

26,15

20

2443,00

2609,50

28,43

15

3073,89

3184,38

25,33

15

4116,65

4559,94

45,51

15

6742,24

7552,50

44,34

15

3933,32

4167,84

37,59

20

4780,97

5275,51

19,97

25

3480,75

3566,44

44,76

25

7041,24

8699,81

20,89

20

4820,98

5327,14

10

21,95

15

2385,37

2454,93

11

19,30

25

2786,75

3143,61

12

15,39

30

1926,39

2027,61

13

35,10

10

3571,91

3957,81

14

31,26

10

2716,02

2800,52

15

43,62

10

3663,64

3828,03

16

61,25

15

4236,96

4399,21

17

40,31

10

3227,85

3391,92

18

27,13

15

2866,71

3039,17

32,68

19,44

3767,48

4110,33

12,16

13,16

1391,36

1731,02

NTN

SD

Ph lc 5.2: Cc thng s dc ng hc ca vin Panadol ActiFast 500 mg

Cmax

Tmax

AUC0-600

AUC0-

(g/ml)

(pht)

(g.pht/ml)

(g.pht/ml)

26,07

15

2662,24

2799,89

36,58

15

3091,87

3549,56

34,79

15

3280,12

3574,87

37,36

20

6948,47

7730,9

33,86

15

4335,37

4591,15

48,87

45

6351,95

7009,43

14,80

45

2650,49

2697,70

33,47

15

6692,39

7978,49

30,24

20

4796,39

5280,82

10

33,07

20

2697,62

2816,34

11

27,76

15

2504,37

2528,98

12

29,31

15

2939,68

3159,56

13

29,84

15

3637,20

4015,04

14

34,69

20

3078,30

3150,27

15

25,57

30

3274,80

3468,21

16

41,52

20

4337,13

4360,30

17

43,45

15

3862,98

4183,24

18

17,05

25

2933,43

3030,74

32,13

21,11

3893,04

4218,08

8,42

9,63

1430,82

1712,20

NTN

SD

Ph lc 5.3: Cc thng s dc ng hc ca vin Panadol 500 mg

Cmax

Tmax

AUC0-600

AUC0-

(g/ml)

(pht)

(g.pht/ml)

(g.pht/ml)

22,45

35

2360,80

2590,55

18,62

30

2590,71

2638,70

23,82

30

3340,37

3723,39

27,48

35

5995,53

6848,82

37,99

20

4730,84

5312,35

37,00

30

6084,79

6381,86

20,89

45

2822,76

2841,32

31,17

30

5747,61

6728,16

27,94

45

4719,68

5249,91

10

28,57

10

3085,16

3145,31

11

26,70

20

3986,56

4371,12

12

25,69

30

2443,07

2726,47

13

21,19

20

3129,25

3377,54

14

18,85

45

3149,48

3217,27

15

33,99

20

3399,70

3677,42

16

37,64

25

3678,67

3811,07

17

38,65

15

3682,14

3998,79

18

11,96

90

2904,88

3026,21

27,26

31,94

3769,56

4092,57

7,69

17,67

1199,99

1418,35

NTN

SD

Ph lc 6
SC MT S MU HUYT TNG CA NGI TNH NGUYN
Ph lc 6.1. Sc cc mu huyt tng ca ngi tnh nguyn s 13 ln lt ti
cc thi im 0 pht, 10 pht v 10 gi sau khi ung vin Paracetamol FR 500 mg
UV6K-245nm
Retention Time
Area

2000

mAU

1500

1000

5.363 1695

500

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5
Minutes

4.0

4.5

5.0

5.5

6.0

6.5

7.0

UV6K-245nm
1500

Retention Time
Area

1250

3.577 4076092

mAU

1000

750

500

250

0.0

1400

0.5

1.0

1.5

2.0

2.5

3.0

3.5
Minutes

1.5

2.0

2.5

3.0

3.5
Minutes

4.0

4.5

5.0

4.0

4.5

5.0

5.5

6.0

6.5

7.0

5.5

6.0

6.5

7.0

UV6K-245nm
Retention Time
Area

1200
1000

600
400
200

5.330 4121

3.577 196660

mAU

800

0.0

0.5

1.0

Ph lc 6.2. Sc cc mu huyt tng ca ngi tnh nguyn s 13 ln lt ti

cc thi im 0 pht, 15 pht v 10 gi sau khi ung vin Panadol ActiFast
UV6K-245nm
1500

Retention Time
Area

1250

mAU

1000

750

500

250

4
Minutes

UV6K-245nm
Retention Time
Area

1200
1000

3.717 3470391

mAU

800

600
400
200

4
Minutes

UV6K-245nm
1200

Retention Time
Area

1000

600

400
3.695 185316

mAU

800

200

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5
4.0
Minutes

4.5

5.0

5.5

6.0

6.5

7.0

Ph lc 6.3. Sc cc mu huyt tng ca ngi tnh nguyn s 13 ln lt ti

cc thi im 0 pht, 25 pht v 6 gi sau khi ung vin Panadol 500 mg
UV6K-245nm
1500

Retention Time
Area

1250

mAU

1000

750

500

250

0
1400

4
Minutes

UV6K-245nm
Retention Time
Area

1200
1000

600
400

5.348 4031

3.587 2267213

mAU

800

200
0

1200

4
Minutes

UV6K-245nm
Retention Time
Area

1000

600

400

200

5.397 499

3.632 347959

mAU

800

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5
4.0
Minutes

4.5

5.0

5.5

6.0

6.5

7.0

Ph lc 6.4. Sc cc mu huyt tng ca ngi tnh nguyn s 14 ln lt ti

cc thi im 0 pht, 20 pht v 10 gi sau khi ung vin Panadol ActiFast
1400

UV6K-245nm
Retention Time
Area

1200
1000

mAU

800
600
400
200
0

0.0

1200

0.5

1.0

1.5

2.0

2.5

3.0

3.5
Minutes

4.0

4.5

5.0

5.5

6.0

6.5

7.0

UV6K-245nm
Retention Time
Area

1000

3.598 4177982

mAU

800

600

400

200

1000

4
Minutes

UV6K-245nm
Retention Time
Area

800

400
3.587 113674

mAU

600

200

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5
Minutes

4.0

4.5

5.0

5.5

6.0

6.5

7.0

Ph lc 6.5. Sc cc mu huyt tng ca ngi tnh nguyn s 14 ln lt ti

cc thi im 0 pht, 10 pht v 10 gi sau khi ung vin Paracetamol FR 500 mg
1000

UV6K-245nm
Retention Time
Area

800

mAU

600

400

200

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5
Minutes

1.5

2.0

2.5

3.0

3.5
Minutes

1.5

2.0

2.5

3.0

3.5
Minutes

4.0

4.5

5.0

5.5

6.0

6.5

7.0

4.0

4.5

5.0

5.5

6.0

6.5

7.0

4.0

4.5

5.0

5.5

6.0

6.5

7.0

UV6K-245nm
1000

Retention Time
Area

3.587 3770014

800

mAU

600

400

0.018 19

200

0.0

0.5

1.0

UV6K-245nm
Retention Time
Area

800

400

3.668 129511

mAU

600

200

0.0

0.5

1.0

Ph lc 6.6. Sc cc mu huyt tng ca ngi tnh nguyn s 14 ln lt ti

cc thi im 0 pht, 45 pht v 10 gi sau khi ung vin Panadol 500 mg
UV6K-245nm
Retention Time
Area

800

mAU

600

400

3.653 8496

200

0.0

1000

0.5

1.0

1.5

2.0

2.5

3.0
3.5
Minutes

4.0

4.5

5.0

5.5

6.0

6.5

UV6K-245nm
Retention Time
Area

800

3.622 2294396

mAU

600

400

200

0.0

1000

0.5

1.0

1.5

2.0

2.5

3.0

3.5
Minutes

1.5

2.0

2.5

3.0

3.5
Minutes

4.0

4.5

5.0

5.5

6.0

6.5

7.0

4.0

4.5

5.0

5.5

6.0

6.5

7.0

UV6K-245nm
Retention Time
Area

800

400
3.645 101664

mAU

600

200

0.0

0.5

1.0

Ph lc 6.7. Sc cc mu huyt tng ca ngi tnh nguyn s 15 ln lt ti

cc thi im 0 pht, 10 pht v 10 gi sau khi ung vin Paracetamol FR 500 mg
1000

UV6K-245nm
Retention Time
Area

800

mAU

600

400

200

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5
Minutes

1.5

2.0

2.5

3.0

3.5
Minutes

4.0

4.5

5.0

5.5

6.0

6.5

7.0

4.0

4.5

5.0

5.5

6.0

6.5

7.0

UV6K-245nm
Retention Time
Area
3.623 4512314

800

mAU

600

400

200

0.0

800

0.5

1.0

UV6K-245nm
Retention Time
Area

400

200

3.637 75310

mAU

600

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5
4.0
Minutes

4.5

5.0

5.5

6.0

6.5

7.0

Ph lc 6.8. Sc cc mu huyt tng ca ngi tnh nguyn s 15 ln lt ti

cc thi im 0 pht, 30 pht v 10 gi sau khi ung vin Panadol ActiFast
UV6K-245nm
Retention Time
Area

800

mAU

600

400

0.017 16

200

4
Minutes

UV6K-245nm
800

Retention Time
Area

3.638 2637173

mAU

600

400

200

0.0

600

0.5

1.0

1.5

2.0

2.5

3.0

3.5
4.0
Minutes

4.5

5.0

5.5

6.0

6.5

7.0

UV6K-245nm
Retention Time
Area

500

300

200
3.660 80389

mAU

400

100

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5
Minutes

4.0

4.5

5.0

5.5

6.0

6.5

7.0

Ph lc 6.9. Sc cc mu huyt tng ca ngi tnh nguyn s 15 ln lt ti

cc thi im 0 pht, 25 pht v 10 gi sau khi ung vin Panadol 500 mg
UV6K-245nm
Retention Time
Area

800

mAU

600

400

200

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5
4.0
Minutes

4.5

5.0

5.5

6.0

6.5

7.0

UV6K-245nm
800

Retention Time
Area

3.633 2838166

mAU

600

400

200

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5
Minutes

4.0

4.5

5.0

5.5

6.0

6.5

UV6K-245nm
Retention Time
Area

600

mAU

400

3.698 93445

200

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5
4.0
Minutes

4.5

5.0

5.5

6.0

6.5

7.0

7.0

Ph lc 6.10. Sc cc mu huyt tng ca ngi tnh nguyn s 16 ln lt ti

cc thi im 0 pht, 25 pht v 10 gi sau khi ung vin Panadol ActiFast 500
mg
UV6K-245nm
Retention Time
Area

800

mAU

600

400

200

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5
Minutes

1.5

2.0

2.5

3.0

3.5
Minutes

2.5

3.0

3.5
Minutes

4.5

5.0

5.5

6.0

6.5

7.0

4.0

4.5

5.0

5.5

6.0

6.5

7.0

UV6K-245nm

800

Retention Time
Area

3.653 3608729

600

mAU

4.0

400

200

0.0

800

0.5

1.0

UV6K-245nm
Retention Time
Area

400

200

3.608 98195

mAU

600

0.0

0.5

1.0

1.5

2.0

4.0

4.5

5.0

5.5

6.0

6.5

7.0

Ph lc 6.11. Sc cc mu huyt tng ca ngi tnh nguyn s 16 ln lt ti

cc thi im 0 pht, 15 pht v 10 gi sau khi ung vin Paracetamol FR 500 mg
UV6K-245nm
Retention Time
Area

800

mAU

600

400

200

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5
Minutes

4.5

5.0

5.5

6.0

6.5

UV6K-245nm

800

3.772 4046333

Retention Time
Area

600

mAU

4.0

400

200

4
Minutes

UV6K-245nm
Retention Time
Area

800

400

3.675 90536

mAU

600

200

4
Minutes

7.0

Ph lc 6.12. Sc cc mu huyt tng ca ngi tnh nguyn s 16 ln lt ti

cc thi im 0 pht, 25 pht v 10 gi sau khi ung vin Panadol 500 mg
UV6K-245nm
Retention Time
Area

1200
1000

mAU

800
600
400
200
0

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5
Minutes

4.0

4.5

5.0

5.5

6.0

6.5

UV6K-245nm
Retention Time
Area

1000

3.688 3279106

800

mAU

600

400

200

4
Minutes

4
Minutes

UV6K-245nm
Retention Time
Area

800

400

3.675 83675

mAU

600

200

7.0

Ph lc 6.13. Sc cc mu huyt tng ca ngi tnh nguyn s 17 ln lt ti

cc thi im 0 pht, 15 pht v 10 gi sau khi ung vin Panadol 500 mg
UV6K-245nm

1750

Retention Time
Area

1500
1250

mAU

1000
750
500
250
0

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5
4.0
Minutes

4.5

4
Minutes

5.0

5.5

6.0

6.5

7.0

UV6K-245nm

1750

Retention Time
Area

1500

3.653 4420431

1250

mAU

1000
750
500
250
0

UV6K-245nm
1500

Retention Time
Area

1250

750

500
3.682 151832

mAU

1000

250

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5
Minutes

4.0

4.5

5.0

5.5

6.0

6.5

7.0

Ph lc 6.14. Sc cc mu huyt tng ca ngi tnh nguyn s 17 ln lt ti

cc thi im 0 pht, 10 pht v 10 gi sau khi ung vin Paracetamol FR 500 mg
UV6K-245nm
1400

Retention Time
Area

1200
1000

mAU

800
600
400
200
0

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5
Minutes

4.0

4.5

5.0

5.5

6.0

6.5

7.0

UV6K-245nm

1500

Retention Time
Area

3.657 4611285

1250

mAU

1000

750

0.017 20

500

250

1000

4
Minutes

UV6K-245nm
Retention Time
Area

800

400
3.717 95880

mAU

600

200

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5
Minutes

4.0

4.5

5.0

5.5

6.0

6.5

7.0

Ph lc 6.15. Sc cc mu huyt tng ca ngi tnh nguyn s 17 ln lt ti

cc thi im 0 pht, 10 pht v 10 gi sau khi ung vin Panadol ActiFast
UV6K-245nm
1400

Retention Time
Area

1200
1000

mAU

800
600
400
200
0

0.0

1400

0.5

1.0

1.5

2.0

2.5

3.0

4.0

4.5

5.0

5.5

6.0

6.5

7.0

UV6K-245nm
Retention Time
Area

3.698 4970171

1200
1000
800
mAU

3.5
Minutes

600
400
200
0

4
Minutes

UV6K-245nm
1000

Retention Time
Area

800

mAU

600

3.738 157605

400

200

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5
Minutes

4.0

4.5

5.0

5.5

6.0

6.5

7.0

Ph lc 6.16. Sc cc mu huyt tng ca ngi tnh nguyn s 18 ln lt ti

cc thi im 0 pht, 15 pht v 10 gi sau khi ung vin Paracetamol FR 500 mg
1400

UV6K-245nm
Retention Time
Area

1200
1000

mAU

800
600
400
200
0

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5
Minutes

4.0

4.5

5.0

5.5

6.0

6.5

7.0

UV6K-245nm
Retention Time
Area

1000

3.613 3144224

800

mAU

600

400

200

800

4
Minutes

UV6K-245nm
Retention Time
Area

400

3.762 64493

mAU

600

200

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5
4.0
Minutes

4.5

5.0

5.5

6.0

6.5

7.0

Ph lc 6.17. Sc cc mu huyt tng ca ngi tnh nguyn s 18 ln lt ti

cc thi im 0 pht, 90 pht v 10 gi sau khi ung vin Panadol 500 mg
UV6K-245nm
Retention Time
Area

800

mAU

600

400

0.017 16

200

4
Minutes

UV6K-245nm
Retention Time
Area

800

3.790 1369049

mAU

600

400

200

Minutes

UV6K-245nm
700

Retention Time
Area

600
500

300

3.753 51897

200
0.017 25

mAU

400

100

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5
4.0
Minutes

4.5

5.0

5.5

6.0

6.5

7.0

Ph lc 6.18. Sc cc mu huyt tng ca ngi tnh nguyn s 18 ln lt ti

cc thi im 0 pht, 25 pht v 10 gi sau khi ung vin Panadol ActiFast.
UV6K-245nm
1500

Retention Time
Area

1250

mAU

1000

750

500

250

Minutes

700

UV6K-245nm
Retention Time
Area

600
500

4.002 1264565

mAU

400
300

0.018 16

200
100

0.0

1000

0.5

1.0

1.5

2.0

2.5

3.0

3.5
4.0
Minutes

4.5

5.0

5.5

6.0

6.5

7.0

UV6K-245nm
Retention Time
Area

800

400

200

5.350 107

3.575 94686

mAU

600

0.0

0.5

1.0

1.5

2.0

2.5

3.0
3.5
Minutes

4.0

4.5

5.0

5.5

6.0

6.5

Ph lc 7
KT QU PHN TCH DC NG HC
Ph lc 7.1. Phn tch phng sai vi bin ph thuc l ln[Cmax]
Bin ph
thuc
Ln(Cmax)
Ln(Cmax)
Ln(Cmax)
Ln(Cmax)

n
v
g/mL
g/mL
g/mL
g/mL

Ngun bin
thin
Tung gc
Trnh t
Mu
Giai on

Bc t do
t s
1
5
2
2

Bc t do
mu s
12,0
12,0
32,0
32,0

F
4480,63
3,00
3,12
1,59

P_value
0,0000
0,0550
0,0576
0,2200

Ph lc 7.2. Phn tch phng sai vi bin ph thuc l ln[AUC0-]

Bin ph
thuc
Ln(AUC0-)
Ln(AUC0-)
Ln(AUC0-)
Ln(AUC0-)

n v
g/mL*pht
g/mL*pht
g/mL*pht
g/mL*pht

Ngun bin
thin
Tung gc
Trnh t
Mu
Giai on

Bc t
do t s
1
5
2
2

Bc t do
F
P_value
mu s
12,0
11179,44 0,0000
12,0
1,09
0,4121
32,0
0,27
0,7637
32,0
2,36
0,1102

Ph lc 7.3. So snh gi tr Tmax ca vin PF v vin PA

theo phng php thng k phi tham s
Php th
Trnh t
Mu
Giai on
Mu v phn d (ng thi)

T
L
95,5
70,5
67
2,80

P_value
0,3661
0,1801
0,0979
0,2464

Ph lc 7.4. So snh gi tr Tmax ca vin PF v vin P

theo phng php thng k phi tham s
Php th
Trnh t
Mu
Giai on
Mu v phn d (ng thi)

T
L
86
57,5
75,5
9,17

P_value
0,9645
0,025
0,3702
0,0102

Ph lc 8
PHIU KIM NGHIM CH PHM NGHIN CU
PARACETAMOL FR 500 MG

Ph lc 9
KT QU XC NH BC SNG HP TH CC I CA DUNG DCH
PARACETAMOL TRONG HCl O,1N V MI TNG QUAN TUYN TNH
GIA NNG PARACETAMOL VI MT QUANG

9.1. Xc nh bc sng hp th cc i
Tin hnh qut ph UV ca dung dch paracetamol nng 10 g/ml trong HCl
0,1N, di sng 200 - 300 nm bng my o quang ph U-1800 (HITACHI). Kt qu
c th hin hnh 9.1.
Hnh nh ph cho thy paracetamol c nh hp th cc i bc sng 242 nm.
Do , chng ti chn bc sng ny kho st tng quan gia nng dung dch
paracetamol v mt quang.

Hnh 9.1. Ph UV ca dung dch paracetamol nng 10 g/ml trong HCl 0,1N.
9.2. Tng quan gia nng v mt quang ca dung dch paracetamol

Pha cc dung dch chun paracetamol nng t 0,511 g/ml. o mt

quang bc sng 242 nm v xy dng ng chun. Kt qu cho thy gia nng
paracetamol v mt quang c s tng quan tuyn tnh trong khong nng
kho st vi h s tng quan l 0,9968 (Hnh 9.2).

V vy, m bo chnh xc ca php o, cc mu th c pha long n

nng paracetamol nm trong khong 0,511 g/ml.
0.8
0.7

R = 0.9968

Mt quang

0.6
0.5
0.4
0.3
0.2
0.1
0
0

10

12

Nng dung dch 4-aminophenol (mcg/ml)

Hnh 9.2. ng chun biu din tng quan gia nng v mt quang
ca dung dch paracetamol trong HCl 0,1 N

Ph lc 10
CC TI LIU LIN QUAN KHC