LLM T

K

TR

NGHTNG

KHA

NG

CHU

HIN G CA

LUN

H

B Y I H

U QUN

CU TAN

FELO

N TT N

H NI

T C D

NH AN

BINN V ODIP

NGHI

2013

C H N

H

N PH H

PIN

P D

NI

P HA T

C S

TAN

B Y T TRNG I HC DC H NI

********

CHU QUNH ANH

NGHIN CU BIN PHP LM TNG TAN V HA TAN

CA FELODIPIN

KHA LUN TT NGHIP DC S

Ngi hng dn: 1. TS. Nguyn Th Thanh Duyn 2. ThS. Hong Vn c Ni thc hin: B mn Cng nghip Dc

H NI 2013

LI CM N Vi lng knh trng v bit n su sc, ti xin gi li cm n ti:

TS. Nguyn Th Thanh Duyn

ThS. Hong Vn c

Nhng ngi thy tn tnh hng dn v gip ti trong sut qu trnh

thc hin kha lun ny.

Ti xin chn thnh cm n cc thy c gio v cc anh ch k thut vin B

mn Cng nghip, c bit l DS. Nguyn Vn Thng to iu kin gip ti

trong qu trnh lm thc nghim.

Ti cng xin gi li cm n ti Ban gim hiu, cc phng ban Trng i hc

Dc H Ni cng ton th cc thy c gio trong trng dy ti nhng kin

thc qu bu trong sut qu trnh hc tp ti trng.

Cui cng, ti xin gi li cm n su sc ti gia nh v bn b lun bn

cnh ng vin ti trong qu trnh thc hin kha lun ny.

H Ni, ngy 10 thng 5 nm 2013

Chu Qunh Anh

MC LC Li cm n

Mc lc

Danh mc k hiu v cc ch vit tt

Danh mc cc bng

Danh mc cc hnh v, th

T VN ......................................................................................................... 1

CHNG I: TNG QUAN .................................................................................. 2

1.1. Vi nt v felodipin ........................................................................................ 2 1.1.1. Cng thc .................................................................................................. 2

1.1.2. Tnh cht l ha v kim nghim.............................................................. 2

1.1.3. Dc ng hc, tc dng v ch nh ....................................................... 3

1.1.4. Mt s bit dc cha felodipin trn th trng ....................................... 3

1.2. Mt s bin php lm tng tan ca dc cht t tan .............................. 4 1.2.1. Lm gim kch thc tiu phn ................................................................ 4

1.2.2. iu chnh pH ........................................................................................... 4

1.2.3. S dng ng dung mi ............................................................................ 4

1.2.4. To phc d tan ......................................................................................... 5

1.2.5. S dng h phn tn rn............................................................................ 5

1.2.6. Cc phng php khc .............................................................................. 5

1.3. H phn tn rn ..................................................................................... 5 1.3.1. Khi nim ................................................................................................ 5

1.3.2. Phn loi .................................................................................................. 5

1.3.3. Mt s phng php bo ch h phn tn rn ......................................... 7

1.3.4. C ch lm tng tan v tc ha tan dc cht trong h phn

tn rn ...................................................................................................... 9

1.3.5. u nhc im ca h phn tn rn ........................................................ 9

1.3.6. Mt s cht mang thng c dng trong h phn tn rn ................... 10

1.3.7. Cc phng php nh gi c tnh ca h phn tn rn ........................ 13

1.3.8. Mt s nghin cu v h phn tn rn cha felodipin ............................ 14

CHNG II: NGUYN LIU, THIT B V PHNG PHP NGHIN

CU .................................................................................................................. 17

2.1. Nguyn liu v thit b 17 1.1.1. Nguyn liu ............................................................................................. 17

1.1.2. Thit b ..................................................................................................... 17

2.2. Ni dung nghin cu ....................................................................................... 18 2.3. Phng php thc nghim ............................................................................. 18

2.3.1. Cc phng php bo ch ...................................................................... 18

2.3.2. Cc phng php nh gi mt s ch tiu ca h phn tn rn ............ 19

2.3.3. Cc phng php khc ........................................................................... 23 CHNG III: THC NGHIM, KT QU V BN LUN ........................ 25

3.1. Kho st li mt s tiu ch trong nh gi cht lng ca h phn tn

rn.. ................................................................................................................. 25

3.1.1. Phng php nh lng felodipin trong h phn tn rn v trong dch

th ha tan cc mu th cha felodipin bng phng php o quang .. 25

3.1.2. Phng php nh lng felodipin trong nh gi tan ca felodipin

nguyn liu v trong h phn tn rn .................................................... 26

3.1.3. Phng php nh lng felodipin bng phng php HPLC ............... 27

3.2. nh hng ca mt s cht mang ti tan v ha tan ca felodipin t

h phn tn rn .............................................................................................. 30

3.2.1. H phn tn rn vi cht mang l PVP K30 ........................................... 30

3.2.2. H phn tn rn vi cht mang l HPMC E5 LV ................................... 32

3.2.3. H phn tn rn vi cht mang l PEG ................................................... 33

3.3. nh hng poloxamer ti tan v ha tan ca felodipin t h phn

tn rn ............................................................................................................. 37

3.3.1. H phn tn rn vi cht mang l PVP K30 kt hp vi poloxamer ...... 37

3.3.2. H phn tn rn vi cht mang l PEG 4000 kt hp vi poloxamer.39

3.3.3. H phn tn rn vi cht mang l PEG 6000 kt hp vi poloxamer.41

3.4. Bn lun chung ................................................................................................ 44

3.4.1. V iu ch h phn tn rn ca felodipin vi cht mang l cc polyme

thn nc ................................................................................................ 44

3.4.2. V iu ch h phn tn rn ca felodipin vi cht mang l cc polyme

thn nc kt hp vi cht din hot ..................................................... 46

KT LUN V XUT ................................................................................... 49

Ti liu tham kho

Ph lc

DANH MC CC K HIU V CH VIT TT BP : Dc in Anh (Bristish pharmacopoeia)

CD : Cyclodextrin

DVN : Dc in Vit Nam

DSC : Phn tch nhit vi sai (Differential Scanning Calorimetry)

FDP : Felodipin

HHVL : Hn hp vt l

HPMC : Hydroxypropylmethylcellulose

Kl/kl : Khi lng/ khi lng

HPTR : H phn tn rn

NaLS : Natri laurylsulfat

PEG : Polyethylenglycol

PLX : Poloxamer

PVP : Polyvinylpyrolidon

SCF : Cht lng siu ti hn (Supercritical Fluid)

SEM : Knh hin vi in t qut (Scanning Electron Microscope)

USP : Dc in M (The United States pharmacopoeia)

v/p/p : Vng/pht/pht

DANH MC CC BNG Trang Bng 1.1 Mt s bit dc cha felodipin c trn th trng 3 Bng 1.2 Phn loi cc cht mang s dng trong h phn tn rn 11 Bng 2.1 Cc nguyn liu s dng trong nghin cu 17 Bng 3.1 hp th quang ca cc mu chun bc sng = 363,5 nm 25 Bng 3.2 hp th quang ca cc mu chun bc sng = 361,5 nm 26 Bng 3.3 Thi gian lu v din tch pic ca cc mu xc nh c

hiu ca phng php 27

Bng 3.4 Thi gian lu v din tch pic ca cc mu xc nh khong tuyn tnh ca phng php

28

Bng 3.5 Thi gian lu v din tch pic ca cc mu xc nh chnh xc ca phng php

29

Bng 3.6 Thi gian lu v din tch pic ca cc mu xc nh ng ca phng php

29

Bng 3.7 tan ca felodipin nguyn liu v trong HPTR vi PVP K30 trong dung dch poloxamer 1% trong nc

30

Bng 3.8 T l FDP ha tan t mu th vi PVP K30 (n=3) 31 Bng 3.9 tan ca felodipin nguyn liu v trong HPTR vi HPMC

E5 LV trong dung dch poloxamer 1% trong nc 32

Bng 3.10 T l FDP ha tan t mu th vi HPMC E5 LV (n=3) 33 Bng 3.11 tan ca felodipin nguyn liu v trong HPTR vi PEG

trong dung dch poloxamer 1% trong nc 34

Bng 3.12 T l FDP ha tan t mu th vi PEG 4000 (n=3) 35 Bng 3.13 T l FDP ha tan t mu th vi PEG 6000 (n=3) 36 Bng 3.14 tan ca felodipin nguyn liu v trong HPTR vi PVP K30,

poloxamer trong dung dch poloxamer 1% trong nc 37

Bng 3.15 T l FDP ha tan t mu th vi PVP K30, poloxamer (n=3) 38 Bng 3.16 tan ca felodipin nguyn liu v trong HPTR vi PEG

4000, poloxamer trong dung dch poloxamer 1% trong nc 40

Bng 3.17 T l FDP gii phng t HPTR, HHVL vi PEG 4000, poloxamer trong mi trng ha tan trong 5 gi (n=3)

40

Bng 3.18 tan ca felodipin nguyn liu v trong HPTR vi PEG 6000, poloxamer trong dung dch poloxamer 1% trong nc

42

Bng 3.19 T l FDP ha tan t mu th vi PEG 6000, poloxamer (n=3) 42

DANH MC CC HNH V, TH Trang Hnh 2.1 M hnh thit b th ha tan felodipin t h phn tn rn 21

Hnh 3.1 ng chun biu din mi tng quan gia nng felodipin ban u trong dung dch 1% natri laurylsulfat trong m phosphat pH 6,5 vi hp th quang

25

Hnh 3.2 ng chun biu din mi tng quan gia nng felodipin trong dung dch poloxamer 1% vi hp th quang

26

Hnh 3.3 ng chun biu din mi tng quan gia nng felodipin trong dung dch vi din tch pic p ng

28

Hnh 3.4 th ha tan ca felodipin trong mu th vi PVP K30 31 Hnh 3.5 th biu din ha tan ca felodipin trong HHVLv

HPTR vi cht mang HPMC E5 LV 33

Hnh 3.6 th ha tan ca felodipin trong mu th vi PEG 4000 35 Hnh 3.7 th ha tan ca felodipin trong mu th vi PEG 6000 36 Hnh 3.8 th ha tan ca felodipin trong mu th vi PVP K30,

poloxamer 39

Hnh 3.9 th ha tan ca felodipin trong mu th vi PEG 4000, poloxamer

41

Hnh 3.10 th ha tan ca felodipin trong mu th vi PEG 6000, poloxamer

43

1

T VN

Hin nay, s ngi trn ton th gii c chn on tng huyt p ang ngy

cng tng nhanh. Tng huyt p l yu t nguy c quan trng nht lin quan n

cc bnh mch vnh, suy tim, bnh mch mu no v bnh thn mn tnh. Nm

2005, trong s 17,5 triu ngi t vong do cc bnh tim mch th tng huyt p l

nguyn nhn trc tip gy t vong ca 7,1 triu ngi. Do vy, iu tr tng huyt

p tr thnh nhu cu thng xuyn v lu di ca ngi bnh.

Trong cc thuc iu tr tng huyt p hin nay, felodipin l thuc thuc nhm

chn knh calci c s dng kh ph bin. Tuy nhin, felodipin l dc cht thuc

nhm II trong h thng phn loi sinh dc hc, c kh nng thm tt nhng tan

hn ch lm cho qu trnh hp thu dc cht gim, nh hng ti sinh kh dng ca

thuc. V vy, chng ti tin hnh thc hin ti: Nghin cu bin php lm

tng tan v ha tan ca felodipin vi mc tiu sau:

- Nghin cu nh hng ca mt s cht mang thn nc n tan v ha

tan ca felodipin trong h phn tn rn.

2

CHNG I: TNG QUAN 1.1. Vi nt v felodipin

1.1.1. Cng thc:

Cng thc ha hc:

[20]

Cng thc phn t: C18H19Cl2NO4.

Phn t lng: 384,26 vC.

Tn khoa hc: Ethyl methyl (4RS)-4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-

dihydropyridin-3,5-dicarboxylat [8], [20], [26].

1.1.2. Tnh cht l ha v kim nghim

- Tinh th trng hoc vng nht [8], nhit nng chy 145C [20].

- Thc t khng tan trong nc, d tan trong aceton, ethanol khan, methanol v

dichloromethan [8].

- Felodipin khng bn vi nh sng, cn bo qun ni kh ro, nhit phng,

trnh nh sng.

- nh tnh: dung dch FDP 15 g/ml trong methanol c cc i hp th 238 nm

v 361 nm trong A361 / A238 = 0,34 0,36 [8].

- nh lng:

+ Phng php o ceri: da vo tnh kh ca felodipin, chun vi dung dch ceri

sulfat 0,1 M, ch th feroin sulfat [8].

+ Phng php HPLC vi detector UV bc sng 254 nm, pha ng gm dung

dch m phosphat: acetonitril: methanol= 40:40:20, ct C18-4,6 mm x 15 cm nhi

pha tnh 5 m vi tc dng 1,0 ml/ pht [26].

HN

O CH3H3CO

O

CH3H3C

OCl

Cl

3

1.1.3. Dc ng hc, tc dng v ch nh

Felodipin hp thu gn nh hon ton qua ng ung nhng chuyn ha bc

u qua gan chm vi sinh kh dng t 10-25%, t nng ti a trong huyt

tng sau khong 3-5 gi vi t l lin kt vi protein huyt tng (ch yu l

albumin) ln n 99%. Felodipin chuyn ha c gan v rut thnh dng chuyn

ha khng cn hat tnh, bi tit khong 70% qua thn v 30% qua phn. Thi gian

bn thi t 11-25 gi. Felodipin gn c hiu trn t bo c tim v c trn thnh

mch, phong ta knh calci khng cho Ca++ i vo trong t bo nn lm gin c, c

ch nucleotid phosphodiesterase vng t bo c trn, lm tng nucleotid vng gy

gin c trn mch mu lm gim huyt p. Felodipin v cc thuc thuc nhm dn

cht 1,4-dihydropyridin tc dng ch yu u tin trn mch, lm gin mch ngoi

vi, mch vnh v mch no. liu iu tr, felodipin khng gy h huyt p th

ng, t gy nhp tim nhanh do phn x [2], [3], [4], [25].

Felodipin c ch nh trong iu tr tng huyt p v au tht ngc. Trong iu

tr tng huyt p, liu khi u thng thng l 5 mg, liu duy tr t 2,5-10 mg mi

ngy. Trong iu tr au tht ngc, liu thng thng l 5 mg, c th tng ln 10 mg

nu cn. Hiu chnh liu vi bnh nhn suy gan v ngi cao tui [25].

1.1.4. Mt s bit dc cha felodipin c trn th trng:

Bng 1.1: Mt s bit dc cha felodipin c trn th trng

Tn bit dc

Dng thuc Hm lng

felodipin Nh sn xut

Plendil Vin nn gii phng ko di (GPKD)

2,5 mg

5,0 mg AstraZeneca

Felodipin

Stada 5mg

retard

Vin nn GPKD 5,0 mg Stada - VN

Logimax Vin nn GPKD

5,0 mg felodipin /

47,5 mg

metoprolol

succinat

AstraZeneca

Flodicar 5mg

MR Vin nn GPKD 5,0 mg Pymepharco

Felutam Vin nn GPKD 5,0 mg Vellpharm VN

Enfelo-5 Vin nn GPKD 5,0 mg Aegis., Ltd

4

1.2. Mt s bin php lm tng tan ca dc cht t tan:

Sinh kh dng ca mt dng thuc thng lin quan ti kh nng tan trong nc

ca dc cht . Tng tan cho cc dc cht t tan trong nc l mt bin php

cn thit ci thin sinh kh dng ca chng.

1.2.1. Lm gim kch thc tiu phn:

Theo phng trnh Noey Whitneys, din tch b mt tip xc ca cht tan v

dung mi nh hng ti tan ca cht tan. Khi kch thc tiu phn cht tan gim,

tng din tch tip xc v mc tng tc gia dung mi v cht tan gip tng

tan. Cc phng php c th s dng gim kch thc tiu phn dc cht nh

phng php xay, nghin, micronization v nano nh tng. Mi phng php c

nguyn tc v s dng thit b gim kch thc tiu phn khc nhau.

Micronization c p dng vi griseofulvin, progesteron, spironolacton,

diosmin v fenofibrat. Cn nano nh tng c p dng cho mt s dc cht

nh tarazepid, paclitaxel, bupravaquon atovaquon v amphotericin B [9], [19].

1.2.2. iu chnh pH:

Khi s dng cc t dc iu chnh pH trong cng thc bo ch, cc thuc t

tan trong nc c th cho hoc nhn proton chuyn thnh dng c th ha tan.

iu chnh pH c th p dng cho c thuc dng ng tiu ha v ngoi ng

tiu ha, c thuc dng lng v dng rn (to vi mi trng) [9].

1.2.3. S dng ng dung mi:

Trong phng php ny, nc v mt dung mi ng tan vi nc c trn ln

to thnh mt h dung mi c kh nng lm tng tan ca dc cht do lm thay

i hng s in mi ca dung mi ban u. ng dung mi thng c kt hp

vi iu chnh pH ci thin tan ca dc cht trong dng bo ch lng dng

ng tiu ha v ngoi ng tiu ha [21]. Mt s dung mi c s dng to

ng dung mi nh PEG 300, PEG 600, polyglycol, ethanol, dimethyl sulfoxid

(DMSO), dimethyl acetoamid (DMA),

5

1.2.4. To phc d tan:

Phc hp dc cht thn du-cyclodextrin (CD) c s dng kh ph bin

ci thin mc v tc tan ca cc dc cht t tan cng nh tng sinh kh dng

ca cc dng thuc [9]. Cc CD l cc phn t hnh nhn, b mt ngoi thn nc,

phn thn du l cc l rng ng knh 5-8 A, y chnh l khoang cha cc dc

cht thn du khi phc hnh thnh [17].

1.2.5. S dng h phn tn rn:

Dc cht c phn tn trong mt hay nhiu cht mang hoc h ct bng

phng php thch hp c th lm tng tan ca dc cht t tan trong nc.

Nhiu dc cht t tan trong nc c ci thin tan trong cc ch phm bng

phng php ny: griseofluvin-PEG, itraconazol-HPMC, nifedipin-PVP [10].

1.2.6. Cc phng php khc:

- To mui, to tin thuc.

- S dng cht din hot lm tng tan.

- To vi nh tng, nano nh tng.

1.3. H phn tn rn:

1.3.1. Khi nim:

H phn tn rn (HPTR) l h mt pha rn trong mt hay nhiu dc cht

c phn tn trong mt hay nhiu cht mang (carriers) hoc ct (matrix) tr v

mt tc dng dc l, c iu ch bng phng php thch hp [5].

H phn tn rn ci thin tan ca dc cht t tan, lm tng din tch tip xc

gia dc cht vi mi trng ha tan sau khi cht mang c ha tan. Chnh v

vy tc gii phng v ha tan dc cht cng tng ln, iu ny rt quan trng

trong vn ci thin sinh kh dng ca dc cht [5].

1.3.2. Phn loi:

Da vo cu trc ha l ca h phn tn rn, ngi ta c th phn chia h phn

tn rn thnh cc loi sau [21], [23]:

- Hn hp eutecti: mt hn hp eutecti n gin bao gm hai thnh phn c th trn

ln hon ton trng thi lng nhng ch trn ln rt hn ch khi trng thi rn.

6

H phn tn rn c cu trc hn hp eutecti c to ra bng cch lm ng rn

nhanh dng chy ng nht hai thnh phn c tnh cht nh trn.

- S kt ta dng v nh hnh trong ct dng tinh th: tng t nh hn hp eutecti

nhng dc cht tn ti dng v nh hnh.

- Dung dch v hn dch thy tinh: dung dch thu tinh l h ng th, trong cht

tan tan trong cht mang thy tinh. Hn dch thy tinh l h trong cc ht kt ta

l lng trong dung mi thy tinh. Nng lng mng li trong dung dch v hn

dch thy tinh thng thp.

- Dung dch rn: dung dch rn c th xem nh dung dch lng, ch bao gm mt

pha, khng phn bit s lng cc thnh phn. i vi dung dch rn, kch thc

cc tiu phn dc cht c gim n mc ti thiu tuyt i ca n (kch

thc phn t) v mc gii phng dc cht c xc nh bng mc gii

phng cht mang. C th phn loi cc dung dch rn theo s trn ln ca cc thnh

phn (dung dch rn ng th hay khng lin tc) hoc theo cch thc m cc phn

t ha tan c phn b trong dung mi rn (dung dch rn thay th, k hay v nh

hnh):

+ Dung dch rn lin tc: trong mt dung dch rn lin tc, cc thnh phn c th

trn ln tt c cc t l. V mt l thuyt, iu ny c ngha l bn lin kt gia

hai thnh phn ln hn lc lin kt gia cc phn t ca mi thnh phn ring l.

Cc dung dch rn thuc loi ny cha c ng dng trong dc phm.

+ Dung dch rn khng lin tc: trong cc dung dch rn khng lin tc, ha tan

ca mi thnh phn trong cc thnh phn khc hn ch. Da trn nhng nghin cu

thc t, Goldberg v cc cng s xut rng dung dch rn khng lin tc ch nn

c p dng khi tan ca hai thnh phn mc trn 5%.

+ H dung dch rn thay th: c kch thc ca cc phn t cht tan ln hn 15%

kch thc phn t dung mi. Cc dung dch rn c in c cu trc tinh th, trong

cc phn t cht tan c th hoc thay th cho cc phn t dung mi trong mng

tinh th hoc va vi cc khe h gia cc phn t dung mi.

7

+ H dung dch rn k: trong cc dung dch rn k, cc phn t cht tan chim

khng gian k gia cc phn t dung mi trong mng tinh th. ng knh phn t

cht tan nh hn 5% so vi ng knh phn t dung mi.

1.3.3. Mt s phng php ch to h phn tn rn:

HPTR c th c ch to bng cc phng php sau y [5], [10], [21], [23] :

Phng php un chy:

- Nguyn tc chung: un chy cht mang ri phi hp dc cht vo cht mang

un chy nhit thch hp, khuy trn ti khi thu c dung dch trong sut,

lm lnh nhanh ng thi vn khuy trn ti khi h ng rn li. Sn phm c

nghin nh v ry ly cc ht c kch thc nht nh.

- Phm vi p dng: dc cht bn vi nhit, cht mang c nhit nng chy tng

i thp, linh ng ca cht mang khi trng thi nng chy thay i s

kt hp cc phn t dc cht.

- Cc phng php:

+ Phng php n nng chy (Hot stage extrusion): phng php ny bao gm

qu trnh n dc cht v cht mang c trn trc vi tc n rt ln

nhit nng chy trong mt khong thi gian ngn. Sn phm thu c em lm

ngui nhit phng v nghin nh.

+ Phng php un chy ng t (Melt agglomeration): nung nng mt hn hp

ca dc cht, cht mang v t dc nhit ln hn hoc bng nhit nng

chy ca cht mang, sau lm ngui v nghin nh.

Phng php dung mi:

- Nguyn tc chung: ha tan dc cht v cc cht mang trong mt dung mi d bay

hi sau bc hi dung mi. Trong phng php ny, c th hn ch s phn hy

dc cht v cht mang do nhit v qu trnh bc hi dung mi hu c xy ra

nhit thp. Cc bc c bn ca qu trnh iu ch HPTR theo phng php ny

bao gm ha tan dc cht v cht mang (thng l polyme) trong mt dung mi

hoc mt hn hp cc dung mi. Loi b dung mi, sn phm thu c em nghin

thnh bt.

8

- Phm vi p dng: dc cht v cht mang khng bn vi nhit. C dung mi thch

hp ha tan c dc cht v cht mang hoc cc dung mi khc nhau nhng c kh

nng trn ln (nu dc cht v cht mang khng ng tan trong mt dung mi).

- bay hi dung mi, ngi ta c th s dng cc bin php sau:

+ Bay hi dung mi nhit phng, kt hp thi kh gip dung mi bay hi

nhanh hn.

+ Bc hi dung mi trn ni cch thy, lm kh trong bnh ht m.

+ Bc hi dung mi di p sut gim bng my ct quay hoc thit b sy chn

khng nhit thp.

+ K thut phun sy: dc cht c ha tan hoc phn tn vo cht mang sau

c phun vo mt dng kh nng loi b dung mi. Vi k thut ny, dung mi

bay hi nhanh, hn ch hin tng tch pha khi HPTR hnh thnh, c th kim sot

kch thc tiu phn rn. Vi k thut phun sy, dc cht tn ti dng v nh

hnh thng chim t l cao hn [12].

+ K thut ng kh: gm 3 giai on l giai on lnh ng, giai on thng hoa

m v giai on bc hi m lin kt cn li. u im ca phng php ny l ci

thin ha tan do lm thay i trng thi kt tinh, to cc l xp do dung mi bay

hi, do lm tng kh nng ht nc, trnh phn hy dc cht [1].

+ K thut phun ng t: dung dch c phun qua nit lng hoc khng kh lnh

kh v nh git lnh ng kh. K thut ny cng hn ch s phn tch pha, c

th kim sot kch thc tiu phn rn.

+ K thut s dng cht lng siu ti hn (SCF): ha tan dc cht v cht mang

trong mt dung mi thch hp, dung dch c qua mt ming vi cng vi SCF

tch ring dung mi. K thut ny c th gip to ra ht dc cht nm trong

khong gii hn kch thc 5 2000 nm.

Phng php ng kt ta: nh t t dung mi vo dung dch cha dc cht v

cht mang km theo khuy lin tc. Trong qu trnh thm dung mi, dc cht v

cht mang s ng kt ta to thnh cc vi ht. Ht c lc, sy kh trong chn

9

khng nhit phng v gi bn trong lng p (37C) trong 12 gi, sau c

a qua ry la chn kch thc ph hp.

Ngoi ra, HPTR cn c th bo ch bng phng php ng nghin, dung mi

thm t v chiu x vi sng [19].

1.3.4. C ch lm tng tan v tc ha tan dc cht trong h phn tn rn:

i vi cc dc cht c tan di 1 mg/ml v tc ha tan di 0,1 mg.cm-

2pht

-1 trong mi trng pH t 1-8, nhit 37C, thng c vn v sinh kh

dng do qu trnh hp thu dc cht t ng tiu ha b gii hn bi tan v tc

ha tan ca dc cht [5]. a dc cht t tan vo HPTR l mt trong cc

phng php vt l lm tng tan ca dc cht, ci thin sinh kh dng ca

thuc. HPTR lm tng c tan v tc tan ca dc cht, mc tng cc tiu

ch ny ph thuc vo loi cht mang s dng, vo t l gia dc cht v cht

mang, vo phng php to HPTR. S tng tan v tc ha tan ca dc cht

trong HPTR c th theo mt s c ch sau y [5], [23]:

- Lm thay i trng thi kt tinh ca dc cht, hoc chuyn t dng kt tinh sang

dng v nh hnh c kh nng ha tan tt hn (khng i hi nng lng ph v

mng tinh th).

- Lm gim kch thc ca tiu phn dc cht: dc cht c phn tn mc

cc k mn, thm ch mc phn t nu h c cu trc dung dch rn. S gim

kch thc ny khng mc phi hin tng kt t cc tiu phn mn di tc ng

ca lc Van der Waals do s c mt ca cht mang bao quanh tiu phn dc cht,

to ra din tch b mt ha tan ln hn sau khi cht mang c ha tan.

- Lm tng mc thm t mi trng ha tan ca dc cht do c mt ca cht

mang thn nc, c bit l khi trong HPTR c mt cht din hot.

- Lm gim nng lng ca s ha tan.

- To phc d tan.

1.3.5. u nhc im ca h phn tn rn:

HPTR thng c s dng ci thin tan v ha tan ca cc dc cht

t tan do s gim kch thc tiu phn dc cht, tng kh nng thm t v ci

10

thin xp ca dc cht, cng nh hn ch dng tinh th, tng dng v nh hnh

ca tiu phn dc cht. Ngoi ra, a dc cht vo HPTR cn gip che du mi

v ca dc cht, d dng ng dng trong dng bo ch cc dng vin nn gii

phng nhanh hay ko di [18].

Tuy nhin, HPTR cng c mt s nhc im sau:

- n nh: qu trnh phn tch pha v kt tinh li lm cho HPTR km n nh v

mt vt l. Qu trnh ny c th lm gim kh nng gii phng dc cht ca

HPTR.

- Cc tnh cht ha l ca h ph thuc vo nhiu yu t: vi phng php un

chy, nhit nung nng, thi gian nung nng, phng php lm lnh, phng

php v cch thc to thnh bt t HPTR u c th nh hng n tnh cht ca

HPTR. i vi phng php s dng dung mi, t l dc cht/dung mi hoc

dc cht/cht mang, k thut lm bay hi dung mi cng c nh hng ng k

n cc tnh cht ha l ca h.

- Phng php bo ch: i hi nhit cao (phng php un chy) hoc s dng

cc dung mi hu c c hi (phng php bay hi dung mi).

- Pht trin dng bo ch: cc tiu phn ca HPTR nh, d dnh s gy kh khn

trong qu trnh nghin, ry, trn v dp vin. Nhc im ny c th lm gim kh

nng a cc dc cht phn b trong HPTR vo mt dng bo ch thch hp.

- Kh nng m rng qui m sn xut: tnh cht ha l v s n nh ca HPTR c

th b nh hng khi m rng qui m sn xut [7].

1.3.6. Mt s cht mang thng s dng trong h phn tn rn:

Cc cht mang s dng trong HPTR cn d tan trong nc hay cc dung mi hu

c thng thng, c nhit chuyn ha thy tinh cao, nhit nng chy thp,

bn vng v mt nhit ng, d loi dung mi ngay c khi dung dch c nht

cao, khng c tc dng dc l ring, khng c vi c th v to c HPTR c

n nh cao trong qu trnh bo qun [5].

- Phn loi:

11

Bng 1.2: Phn loi cc cht mang s dng trong h phn tn rn [27]

Th h 1: cht mang dng tinh th

Ure, cc loi ng, cc acid hu c

Th h 2: cht mang v nh hnh

Polyethylenglycol (PEG), polyvinylpyrolidon

(PVP), polyvinylacetate (PVA), polymethacrylat,

cc dn xut ca cellulose

Th h 3: cht mang hot ng b mt t nh ha

Poloxamer 408, Tween 80, Gelucire 44/14

- c im ca mt s cht mang thng dng:

+ Polyvinylpyrolidon (PVP): PVP l sn phm trng hp ca vinylpyrolidon, c

trng lng phn t t 2500 n 3000000. Nhit chuyn ha thy tinh ca mt

loi PVP khng ch ph thuc vo khi lng phn t ca n m cn vo ph thuc

vo m. Ni chung, nhit chuyn ha thy tinh ca cc PVP cao nn PVP

thch hp hn khi iu ch bng phng php dung mi. Kh nng tan trong nc

ca PVP kh tt nn c th ci thin kh nng ha tan v tnh thm ca dc cht.

Khi tng chiu di phn t PVP th kh nng tan trong nc ca chng gim trong

khi nht ca dung dch tng ln. T l gia dc cht v PVP trong HPTR cng

nh hng ti kh nng ha tan v gii phng dc cht t h, kh nng ny c xu

hng tng theo t l PVP trong h.

V d: HPTR piroxicam/PVP c t l gii phng dc cht tng cng vi s tng

t l cht mang. T l gii phng cao nht khi t l cht mang/dc cht l 4/1.

Nhng nu tip tc tng t l cht mang ln 5/1 v 9/1 th t l gii phng dc cht

li gim [21].

+ Polyethylenglycol (PEG): l cc polyme ca ethylene oxyd, c khi lng phn

t trong khong 200 300000. nht ca PEG tng theo khi lng phn t ca

n. Cc PEG c khi lng phn t t 4000-6000 thng xuyn c s dng

iu ch HPTR, bi v trong khong khi lng phn t ny, kh nng tan trong

nc kh cao v vic xc nh hm m khng phi l mt vn ln v im nng

chy vt qu 50C. u im ca PEG khi iu ch HPTR l kh nng ha tan

trong nhiu loi dung mi hu c khc nhau, nhit nng chy thng thp (di

65C), ph hp trong vic iu ch HPTR c theo phng php un chy [23]. Nu

12

s dng PEG c khi lng phn t thp, ch phm thay i mc ng nht,

dnh cng l mt yu t gy kh khn khi to HPTR. Cc PEG vi khi lng phn

t cao hn cng c s dng thnh cng tng tan v ha tan ca dc

cht trong HPTR, ch phm c cha PEG 8000 v 10000 tng tan so vi dc

cht tinh khit. Khi to thnh HPTR vi cc PEG, nu t l dc cht qu cao, kh

nng dc cht s tn ti dng tinh th nh trong HPTR nhiu hn l phn tn

dng phn t. Nhng nu t l cht mang qu cao c th lm cho dc cht tn ti

hon ton dng v nh hnh, do gy tng qu mc s ha tan v gii phng

dc cht [7], [23], [21].

V d: T l gliclazid gii phng tng khi a vo HPTR trong PEG 4000, 6000

hoc 8000 [13].

+ Cc dn xut ca cellulose: cellulose l polysaccharid t nhin, thng gp trong

thc vt. Phn t l cc chui khng phn nhnh, trong cc n v saccharid lin

kt vi nhau bng lin kt -1,4-glycosid. Bng qu trnh alkyl ha hoc ester ha,

ngi ta to ra cc dn xut ca cellulose nh methylcellulose (MC),

hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC),

celluloseacetatphthalat (CAP)HPMC l hn hp cc ether ca cellulose trong

c 16,5-30% l sn phm methyl ha nhm hydroxyl v 4-32% l sn phm

hydroxypropyl ha. Trng lng phn t HPMC nm trong khong 10000-

1500000. HPMC tan trong nc, hn hp ethanol: dichloromethan, methanol:

dichloromethan [21]. HPMC E5 LV c t l nhm methoxy t 28-30%, nhm

hydroxypropyl t 7-12%, nht ca dung dch 2% trong nc (khi lng/th

tch) 20C l 5 mPa s [22], [28].

+ Cht din hot: l cc cht m nng thp hp th ln cc b mt lm thay i

tnh cht ca b mt hoc lm gim nng lng t do gia cc b mt tip xc nhau.

Cc cht din hot c cu trc c trng gm mt u a nc v mt u k nc.

Vi cc c im nh vy, cht din hot c kh nng lm thay i c tnh nhit

ng hc, mc tan r, khuch tn, ha tan v gii phng dc cht. Cht din

hot t khi c dng n c lm cht mang m thng c dng phi hp vi

13

cc cht mang khc [5]. Poloxamer l mt nhm cht din hot khng ion ha c

dng lm cht gy phn tn, cht nh ha, cht tng tan, lm t dc trn cho

vin nn, tc nhn gy thm. Poloxamer l tn gi chung ca mt nhm cc ng

polyme ca propylen oxid v ethylen oxid, phn t c u k nc l

polypropylenoxid v phn thn nc l polyethyleneoxid. Cc poloxamer c th

phn loi theo khi lng phn t v t l ethylen oxid trong phn t. Poloxamer

407 c khi lng phn t trung bnh khong 9840-14600, trong polyoxyethylen

chim khong 70-75% khi lng phn t, cn li l polyoxypropylen. Poloxamer

407 tan tt trong nc v ethanol, ch s HLB 18-23 [22].

+ Ngoi ra, cc cht mang thng c s dng khc l polyacrylat v

polymethacrylat, polyvinylalcohol (PVA), crospovidon (PVP-CL),

polvinylpyrolidon-polyvinylacetat copolyme (PVP-PVA), ure, ng, polyol v cc

polyme ca chng (chitosan v mui chitosanglutamat), cc acid hu c (acid

succinic, acid citric,) [21].

1.3.7. Cc phng php nh gi c tnh ca h phn tn rn

- Knh hin vi in t qut (Scanning Electron Microscope - SEM): nh gi kch

thc tiu phn, c im hnh thi b mt ca dc cht v cht mang, cu trc a

hnh ca dc cht, s phn tn ng u ca cc tiu phn dc cht trong ct

[18].

- nh gi tan v ha tan: so snh ha tan ca dc cht, hn hp vt l

ca dc chtcht mang v HPTR dc cht- cht mang c th cho bit c ch ca

vic ci thin kh nng gii phng dc cht ( tan/ thm t/ gim kch thc

ht) [18].

- Phn tch nhit vi sai (Differential Scanning Calorimetry - DSC): nghin cu s

thay i trng thi vt l ca HPTR c th xy ra trong qu trnh un chy do s c

mt ca cc polyme c th nh hng n qu trnh nng chy ca dc cht. Kt

qu thu c cn c kim nh li bng mt phng php khc. Nhn chung, khi

t l tinh th di 2% s kh c th pht hin c [18].

14

- Nhiu x tia X: gip nh gi trng thi kt tinh trong h. Nhiu x tia X l hin

tng cc chm tia X nhiu x trn b mt tinh th ca cht rn do tnh cht tun

hon ca cu trc tinh th to nn cc cc i v cc tiu nhiu x khi tha mn

iu kin Bragg: 2d.sin = n.

d - khong cch gia cc mt nguyn t phn x

- gc phn x

bc sng tia X

n s bc phn x [6]

Phn kt tinh to ra cc nh nhiu x nhn v hp, phn v nh hnh li cho

mt nh rt rng. T l gia cc cng c th c s dng tnh ton s

lng tinh th trong h [23].

1.3.8. Mt s nghin cu v h phn tn rn cha felodipin:

Kim J. v cng s tin hnh nghin cu ch to HPTR ca felodipin vi cc

cht mang PVP K30, HPMC 2910, poloxamer 407 bng phng php dung mi.

Felodipin c ha tan trong dung mi ethanol vi lng thch hp (ty theo cht

mang), dung dch ny c nh git vo cht mang. Qu trnh bc hi dung mi

c tin hnh trong chn khng nhit phng, HPTR thu c em nghin nh

vi chy ci. Kt qu thu c cho thy, vi cht mang PVP K30, t l FDP: PVP

K30 l 1:10 v 1:15, ha tan tng i nh nhau v t khong 63% ngay trong

1 gi u. i vi cht mang l HPMC 2910, ha tan cao nht t khong 70%

t l 1:10 nhng qu trnh ha tan xy ra chm hn. Cn i vi cht mang l

poloxamer 407, ha tan cao nht t khong 80% sau 1 gi u t l 1:10 gia

dc cht v cht mang [15].

Won D. v cng s nghin cu lm tng c tnh ha l ca ht phn tn rn

bng k thut phun cht lng siu ti hn. HPTR ca FDP c to ra vi cht

mang HPMC v cht din hot bng phng php bay hi dung mi thng thng

v phng php s dng cht lng siu ti hn. Cc nguyn liu dng l FDP,

HPMC 2910, poloxamer 188, poloxamer 407, polyoxyethylen (60), du thu du

hydro ha (HCO-60), CO2 tinh khit.

15

- Phng php bc hi dung mi thng thng: FDP v HPMC c ha tan v

phn tn trong ethanol, sau thm cc cht din hot vo, loi ethanol bng mt

thit b ct quay p sut gim 450C v 45 vng/pht trong 12 gi, h phn tn rn

c co ra bng tha v lm kh trong iu kin chn khng 370C trong 24 gi,

HPTR thu c em nghin thnh bt v bo qun trong bnh ht m nhit

phng.

- Phng php s dng cht lng siu ti hn (SCF): u tin FDP, HPMC, cht

din hot c ha tan v phn tn vo hn hp ethanol: methylen clorid = 5,5:4,5

(kl/kl). CO2 c a vo b cha t p sut v nhit t cn bng (100 bar

v 450C), dung dch FDP/polyme c np vo b vi tc 0,5 ml/pht qua vi

phun cng vi CO2 vi tc CO2 l 30 ml/pht. Sau qu trnh chit dung mi

bng CO2, dung mi v CO2 c loi b, HPTR bm trn thnh v y ca b

c thu li.

Kt qu cho thy: Kch thc ht ca HPTR l t 200 250 nm. Kch thc ht

duy tr c 1 gi theo phng php s dng SCF, v duy tr c trn 6 gi i

vi phng php bc hi dung mi thng thng trong nc ct. Da vo d liu

phn tch nhit vi sai v nhiu x tia X xc nhn s chuyn th hnh ca FDP t

dng tinh th sang dng v nh hnh trong HPTR theo c hai phng php trn.

tan ca HPTR iu ch theo phng php s dng cht lng siu ti hn l 1,5-20

g/ml, trong khi tan ti a l 35-110 g/ml, ha tan l 90% sau 2 gi [29].

Suknuntha K. v cng s nghin cu c tnh ca HPTR dng mng phim ca

FDP vi PVP v nh gi tc ng ca dung mi ti c tnh ca h. Hn hp dung

mi dichloromethan v ethanol c phi hp cc t l 9/1, 7/3, 5/5, 3/7 v 1/9 v

khi lng. Mng phim PVP K90 vi 10% FDP c bo ch bng cch ha tan

0,9 g PVP K90 v 0,1 g FDP trong 10 ml hn hp dung mi trong bnh nn 50 ml,

lc cho tan hon ton. Mt lng dung dch 10 ml c a ln khun kch thc 8

cm x 8 cm, khun c gi c nh trn mt b mt, kim sot qu trnh bay hi

dung mi din ra t t iu kin nhit phng. H tip tc c thm 12 gi

nhit phng m bo loi b tt c lng dung mi cn li. HPTR c

16

nh gi dy ca mng phim, trng thi kt tinh vi phng php phn tch DSC

v nhiu x tia X. Kt qu cho thy, vi dung mi ethanol, tan ca HPTR l cao

nht. Tuy nhin, t l 5/5 gia hai dung mi trong hn hp, FDP trng thi v

nh hnh trong cht mang v gi n nh c trng thi ny trong 2 thng [24].

Dasgupta A. nghin cu ci thin tan ca FDP bng cch s dng HPTR vi

cc cht mang PEG cc t l dc cht/PEG l 1/1-1/2-1/3-1/4, PVP K30 cc t

l dc cht/PVP K30 l 1/1-1/2-1/3-1/4, hydroxyl -cyclodextrin cc t l dc

cht/HCD l 1/1-1/2 v cyclodextrin t l 1/1 so vi dc cht. HPTR c

bo ch bng phng php dung mi vi dung mi c dng l ethanol, thi gian

trn trong 30 pht. Kt qu cho thy tan tt nht ca FDP l 14,68 v 10,08

g/ml khi to HPTR vi cht mang PEG v PVP K30 t l 1/2 [11].

Konno H. v cng s nghin cu nh hng ca loi polyme n c tnh gii

phng FDP t HPTR v nh hnh cha FDP. FDP c ha tan trong ethanol v

thm vo cc polyme khc nhau bao gm PVP K30, HPMC v HPMCAS. Dung

mi c bay hi chn khng nhit phng trong 8 gi, sau sn phm thu

c em nung n 160C trong vi giy m bo rng HPTR dng v nh

hnh. Kt qu cho thy, s gii phng FDP t HPTR vi cc cht mang u cao hn

trng thi cn bng v tan ca FDP dng tinh th, ngoi tr HPTR cha t 10-

15% PVP v khi lng. Mt khc, t l FDP gii phng c s khc nhau gia cc

HPTR cha cc cht mang khc nhau. T l gii phng cao nht t c trong

vng 60 pht vi h cha PVP trong khi thi gian ny l t 180 n 240 pht vi

cc h cha HPMC. Cc polyme u c tc dng trong vic c ch s ti kt tinh

ca FDP trong HPTR trong hiu qu nht l PVP K30 [16].

17

Chng 2: NGUYN LIU, THIT B V PHNG PHP

NGHIN CU

2.1. Nguyn liu v thit b

1.1.1. Nguyn liu:

Bng 2.1: Cc nguyn liu s dng trong nghin cu

STT Tn nguyn liu Ngun gc Tiu chun

1 Felodipin Supor (Trung Quc) EP 7.0

2 PVP K30 Trung Quc BP 2008

3 HPMC E5 Dow (M) Nh sn xut

4 PEG 4000 Singapore Nh sn xut

5 PEG 6000 Trung Quc Nh sn xut

6 Poloxamer Sigmaaldric (Singapore) Nh sn xut

7 Dinatri hydrophosphat

dodecahydrat Trung Quc

Tinh khit ha hc

8 Natri dihydrophosphat

dihydrat Trung Quc

Tinh khit ha hc

9 Natri laurylsulfat Singapore Nh sn xut

10 Natri hydroxid Trung Quc Tinh khit ha hc

11 Ethanol tuyt i Vit Nam DVN IV

12 Methanol Baker (M) PA (dng cho

HPLC)

13 Acetonitril Baker (M) PA (dng cho

HPLC)

14 Acid phosphoric Merck PA (dng cho

HPLC)

15 Nc ct Vit Nam DVN IV

1.1.2. Thit b:

- Cn k thut SARTORIUS TE412 c

18

- Cn phn tch SARTORIUS TE214S c

- My khuy t IKAC-MAG HS-4 c

- My o pH EUTECH Instrument Thy in

- My siu m ng nht WiseClean Hn Quc

- B iu nhit Wisecircu Fuzzy Control System c

- My th ha tan ERWEKA DT600 c

- My ly tm Rotina 46 c

- Cn xc nh hm m Precisa XM60 Thy in

- My o quang UV VIS HITACHI U-1900 Nht Bn

- My o ph nhiu x tia X D8 Advance, Brucker c

- My phn tch nhit vi sai DSC 1 Mettler Toledo Thy S

- My sc k lng hiu nng cao Shimadzu CLASS-VP 5.03- Nht Bn

1.2. Ni dung nghin cu:

1.2.1. Kho st nh hng ca cc cht mang PVP K30, HPMC E5 LV, PEG 4000,

PEG 6000 n tan v ha tan ca felodipin trong HPTR.

1.2.2. Kho st nh hng ca poloxamer n tan v ha tan ca felodipin

trong HPTR vi cc cht mang PVP K30, PEG 4000, PEG 6000.

1.3. Phng php thc nghim:

1.3.1. Cc phng php bo ch:

Phng php bo ch h phn tn rn:

- Cn cc thnh phn theo t l thit k trong cng thc.

- Ha tan FDP v poloxamer (PLX) (nu c) trong lng ethanol tuyt i thch

hp, thm cht mang vo dung dch dc cht trong ethanol, khuy lin tc trn

my khuy t trong khi dung mi bay hi, 48 gi trong bnh ht m loi dung

mi cn li.

- Nghin nh HPTR thu c vi chy ci, ry qua ry 250, xc nh hm m

nhanh vi cn xc nh hm m (tr HPTR cha PEG), ng l, bo qun trong

bnh ht m.

19

Phng php ch to hn hp vt l:

- Cn cc dc cht v cht mang theo t l thit k ging thnh phn ca HPTR.

- Trn dc cht v cht mang thnh hn hp bt kp theo nguyn tc trn ng

lng. Ry hn hp bt qua ry 250 thu c hn hp bt ng nht.

1.3.2. Cc phng php nh gi mt s ch tiu ca h phn tn rn:

1.3.2.1. Phng php nh lng felodipin c trong h phn tn rn, hn hp vt l

- Phng php o quang:

+ Dung dch 1% natri laurylsulfat (NaLS) trong m phosphat pH 6,5: cn 6,42 g

natri dihydrophosphat dihydrat v 7,01 g dinatri hydrophosphat dodecahydrat ha

tan trong khong 900 ml nc ct, thm 10,0 g NaLS, siu m cho tan hon ton,

iu chnh pH n 6,5, chuyn vo bnh nh mc 1000 ml, b sung th tch va

n vch bng nc ct.

+ Dung dch chun gc CG: cn chnh xc khong 125,0 mg FDP vo bnh nh

mc 50 ml, ha tan vi khong 30 ml methanol, siu m 5 pht cho tan hon ton,

b sung th tch va n vch bng methanol.

+ Dung dch chun thm CT: ht chnh xc 1,0 ml dung dch chun gc vo bnh

nh mc 25 ml, b sung th tch va n vch bng dung dch 1% NaLS trong

m phosphat pH 6,5.

+ Mu chun: ht chnh xc 1,0 ml dung dch chun thm CT vo bnh nh mc 10

ml, b sung va th tch bng dung dch chun 10,0 g/ml pha t dung dch

chun gc.

+ Mu th: Cn chnh xc mt lng HPTR tng ng 5,0 mg FDP cho vo bnh

nh mc 25 ml, ha tan trong khong 15 ml methanol, siu m 5 pht cho tan hon

ton, b sung th tch n vch bng methanol. Ht chnh xc 5,0 ml dung dch trn

vo bnh nh mc 100 ml, b sung th tch n vch bng dung dch 1% NaLS

trong m phosphat pH 6,5. Ht chnh xc 1,0 ml dung dch chun thm CT vo

bnh nh mc 10 ml, b sung va th tch bng dung dch va pha. Ly tm 5000

v/p/10p. Thu ly dch trong, o hp th bc sng 361,5 nm, mu trng l

dung dch 1% NaLS trong m phosphat pH 6,5.

20

+ Xc nh hm lng ca FDP theo cng thc:

% FDP = x 100 (%)

C : nng dung dch chun (g/ml)

Dt, Dc: hp th quang ca mu th v mu chun

m: khi lng mu th (g)

- Phng php sc k lng hiu nng cao:

+ Pha ng: Acetonitril: H2O= 80:20

+ Detector: UV 234 nm

+ Ct: C18 Phenomenex (4,6 mm x 25 cm; 5m)

+ Tc dng: 1 ml/pht

+ Th tch tim: 20 l

+Dung dch chun: pha dung dch chun gc 2,0 mg/ml FDP chun trong methanol.

Pha cc dung dch chun th cp 0,5; 1,0; 2,0; 4,0; 8,0; 12,0; 16,0; 20,0 g/ml vi

dung mi pha long l pha ng.

+ Dung dch th: cn chnh xc mt lng mu th (HPTR, HHVL) tng ng

vi 5,0 mg FDP vo bnh nh mc 50 ml, ha tan trong khong 30 ml pha ng,

siu m 5 pht cho tan hon ton, b sung th tch va bng pha ng. Ht chnh

xc 5,0 ml dung dch trn vo bnh nh mc 50 ml, b sung th tch n vch bng

pha ng.

+ Tnh ton kt qu: % FDP = x 100 (%)

Cc : nng dung dch chun (10,0 g/ml) (g/ml)

St, Sc: din tch pic dung dch th v dung dch chun 10,0 g/ml (mAU)

m: khi lng mu th (g)

1.3.2.2. Phng php nh gi tan ca felodipin nguyn liu v trong h phn

tn rn trong dung dch poloxamer 1%

Pha dung dch PLX 1% trong nc. Cn mt lng HPTR hoc FDP nguyn

liu tng ng khong 30 mg FDP (lng d) vo ng nghim c nt. Thm vo

21

mi ng nghim chnh xc 10,0 ml dung dch PLX 1%, y kn nt, gi n nh

nhit 37C trong 24 gi trong b iu nhit, khuy trn trong qu trnh. Sau 24

gi, ly cc dung dch em ly tm 5000 v/p/20 p( cn ly mu c thi im sau

kim tra s bo ha dc cht). Thu ly dch trong, pha long bng dung dch PLX

1% n nng khong 20,0 g/ml. Ly tm dung dch thu c 5000 v/p/10p, thu

ly dch trong, o hp th = 361,5 nm. Hoc pha long bng pha ng n

nng khong 10,0 g/ml nh lng bng phng php HPLC. Pha dung dch

FDP 20,0 g/ml trong dung dch PLX 1% t dung dch chun gc CG lm chun, o

hp th = 361,5 nm.

+ Tnh ton kt qu: tan = (g/ml)

C: nng dung dch chun (g/ml)

Dt, Dc: hp th quang ca dung dch th v dung dch chun.

K: h s pha long

T kt qu ny ta c th tnh ton s gam FDP tan trong 100 g dung mi.

1.3.2.3. Phng php nh gi kh nng ha tan felodipin t h phn tn rn, hn

hp vt l

- iu kin

+ Thit b cnh khuy gi tnh theo USP 30. Mu th (HPTR, HHVL) tng ng

5,0 mg FDP c t trong mt ti lc trong gi.

+ 500ml dung dch 1% NaLS trong m phosphat pH 6,5.

+ Nhit 37 0,50C.

+ Tc khuy: 50 vng/pht.

+ Thi im ly mu: 0,5h, 1h, 2h, 3h, 4h, 5h

Hnh 2.1: M hnh thit b th ha tan felodipin t h phn tn rn

22

- Dung dch 1% NaLS trong m phosphate pH 6,5, dung dch chun gc CG, dung

dch chun thm CT, dung dch chun 10,0 g/ml: chun b nh trong mc 2.3.2.1.

- Dung dch th: Ti cc thi im quy nh rt 12,0 ml dch ha tan, b sung 12,0

ml mi trng.

- Tin hnh:

+ Mu trng: dung dch 1% NaLS ly tm 5000 v/p/10p.

+ Mu th: ly tm 5000 v/p/10p dch ha tan. Ht 1,0 ml dung dch chun thm vo

bnh nh mc 10 ml, b sung va th tch bng dch ha tan tng ng ly

tm.

+ Mu chun: ht 1,0 ml dung dch chun thm vo bnh nh mc 10 ml, b sung

va th tch bng dung dch chun 10,0 g/ml.

+ o hp th ca mu th v mu chun = 363,5 nm.

- Tnh ton kt qu:

+ Nng FDP cha hiu chnh ln ht th n Cn0:

Cn0 =

Cn0: nng FDP cha hiu chnh ca ln ht th n (g/ml)

Cc: nng FDP trong mu chun (g/ml)

Dt, Dc: hp th quang ca mu th v mu chun

+ Nng FDP sau khi hiu chnh ln ht th n c tnh theo cng thc sau:

Cn = Cn0 + Cn-1

Cn: nng FDP hiu chnh ca ln ht th n (g/ml)

Cn0: nng FDP cha hiu chnh ca ln ht th n (g/ml)

Cn-1: nng FDP hiu chnh ca ln ht th n-1(g/ml)

V0: th tch ca dch ha tan ht (V0= 12 ml)

V: th tch mi trng th ha tan (V= 500 ml)

+ Phn trm FDP ha tan ti thi im t c tnh theo cng thc:

% FDP = x100 (%)

23

Cn: nng FDP hiu chnh ln ht th n (g/ml)

m: khi lng FDP trong mu (g)

Mi mu th 3 ln ly kt qu trung bnh. Kt qu c bo co l kt qu trung

bnh.

lch chun gia cc mu: SD =

: phn trm gii phng trung bnh ca cc mu ti mt thi im (%)

= (%)

xi: phn trm gii phng ca mi mu ti mt thi im (%)

n: c mu (n=3)

1.3.2.4. Phng php nhiu x tia X nh gi mc kt tinh trong h phn tn

rn

Mu phn tch c nghin mn, nhiu x tia X c ghi vi gc qut 5 ti 50

(2) tc qut 0,030/ pht v nhit 25C.

1.3.2.5. Phn tch nhit vi sai (DSC)

Mu phn tch c nghin mn, khi lng mi mu trn a nhm khong 5,0

mg, phn tch nhit vi sai trn gii nhit t 30-200C vi tc gia nhit 10C/

pht, tc dng kh nit 20 ml/pht.

2.3.3. Cc phng php khc:

2.3.3.1. Phng php xy dng ng chun ca felodipin trong dung dch

poloxamer 1%

Pha dung dch PLX 1% vi dung mi nc.

Dung dch chun gc CG c nng FDP 2500,0 g/ml trong methanol pha nh

trong mc 2.3.2.1. T dung dch chun gc pha long thnh cc dung dch chun

th cp c nng 5,0; 7,5; 10,0; 12,5; 15,0; 17,5; 20,0; 22,5; 25,0 g/ml. Ly tm

dung dch PLX 1% 5000 v/p/10p lm mu trng. Ly tm cc dung dch chun

5000 v/p/10p.

24

Qut ph hp th ca FDP trong dung dch PLX 1% vi mu trng l dung dch

PLX 1% trong khong 200-500 nm xc nh bc sng hp th cc i. o

hp th ca cc dung dch chun bc sng hp th cc i. Xy dng mi tng

quan gia hp th bc sng hp th cc i vi nng FDP trong dung

dch.

2.3.3.2. Phng php xy dng ng chun ca felodipin trong dung dch 1%

natri laurylsulfat trong m phosphat pH 6,5

Chun b cc dung dch 1% NaLS trong m phosphat pH 6,5, dung dch chun

gc CG, dung dch chun thm CT nh trn. T dung dch chun gc, pha cc dung

dch chun th cp c nng 0,5; 1,0; 4,0; 6,0; 8,0; 10,0; 12,0 g/ml. Mu trng l

dung dch 1% NaLS trong m phosphat pH 6,5 ly tm 5000 v/p/10p. Ly tm cc

dung dch chun 5000 v/p/10p, ht 1,0 ml dung dch chun thm vo bnh nh mc

10 ml, b sung th tch n vch bng cc dung dch chun th cp ly tm lm

mu chun.

Qut ph hp th ca FDP trong dung dch 1% NaLS trong m phosphat pH

6,5 trong khong 200-500 nm xc nh bc sng hp th cc i. o hp th

ca cc dung dch chun bc sng hp th cc i. Xy dng mi tng quan

gia hp th ca FDP bc sng hp th cc i vi nng FDP trong dung

dch.

25

Chng III: THC NGHIM, KT QU V BN LUN

3.1. Kho st li mt s tiu ch trong nh gi cht lng ca h phn tn rn

3.1.1. Phng php nh lng felodipin trong h phn tn rn v trong dch th

ha tan cc mu th cha felodipin bng phng php o quang:

Qut ph hp th UV ca FDP trong dung dch 1% NaLS trong m phosphat

pH 6,5 vi = 200 500 nm, ta thu c hai v tr bc sng m ti hp th

quang ca FDP t cc i l 1 = 239 nm v 2 = 363,5 nm.

Xy dng ng chun biu din s ph thuc ca nng FDP trong dung

dch 1% NaLS trong m phosphat pH 6,5 vi hp th quang theo phng php

trnh by mc 2.3.3. hp th quang ca cc mu chun bc sng hp th

cc i = 363,5 nm c trnh by trong bng v hnh sau:

Bng 3.1: hp th quang ca cc mu chun bc sng = 363,5 nm

C chun ban u (g/ml)

0 0,5 1,0 4,0 6,0 8,0 10,0 12,0

C chun sau thm (g/ml)

10,0 10,45 10,9 13,6 15,4 17,2 19,0 20,8

hp th 0,185 0,200 0,214 0,252 0,283 0,318 0,341 0,381

Hnh 3.1: ng chun biu din mi tng quan gia nng felodipin ban u

trong dung dch 1% natri laurylsulfat trong m phosphat pH 6,5 vi hp th

quang

y = 0.0157x + 0.1898

R = 0.9969

0

0.05

0.1

0.15

0.2

0.25

0.3

0.35

0.4

0.45

0 1 2 3 4 5 6 7 8 9 10 11 12

h

p t

h

C (g/ml)

26

Nhn xt: vi ng chun thu c c R2= 0,9969, ta c th s dng phng

php o quang nh lng FDP trong HPTR v trong dch th ha tan cc mu

th cha FDP.

3.1.2. Phng php nh lng felodipin trong nh gi tan ca felodipin

nguyn liu v trong h phn tn rn:

Qut ph hp th UV ca FDP trong dung dch PLX 1% vi = 200 500 nm,

ta thu c hai v tr bc sng m ti hp th quang ca FDP t cc i l

1 = 238 nm v 2 = 361,5 nm.

kho st mi tng quan gia nng ca FDP trong dung dch PLX 1%

vi hp th quang, tin hnh xy dng ng chun ca FDP trong dung dch

PLX 1% theo phng php trnh by mc 2.3.3. hp th quang ca cc

mu chun bc sng hp th cc i = 361,5 nm c trnh by trong bng v

hnh sau:

Bng 3.2: hp th quang ca cc mu chun bc sng = 361,5 nm

C

(g/ml) 5,0 7,5 10,0 12,5 15,0 17,5 20,0 22,5 25,0

hp th

0,09 0,123 0,164 0,203 0,246 0,290 0,329 0,371 0,403

Hnh 3.2: ng chun biu din mi tng quan gia nng felodipin trong

dung dch PLX 1% vi hp th quang

y = 0.0161x + 0.0053

R = 0.9991

0

0.05

0.1

0.15

0.2

0.25

0.3

0.35

0.4

0.45

0 2.5 5 7.5 10 12.5 15 17.5 20 22.5 25

h

p t

h

C (g/ml)

27

Nhn xt: vi ng chun thu c c R2= 0,9991, ta c th s dng phng

php o quang nh lng FDP trong nh gi tan ca FDP nguyn liu v

trong HPTR.

3.1.3. Phng php nh lng felodipin bng phng php HPLC:

Phng php nh lng FDP bng HPLC c tin hnh theo phng php

trnh by mc 2.3.2. Tin hnh thm nh mt s ch tiu ca phng php ny.

Xc nh c hiu ca phng php nh lng (specificity)

- Chun b mu trng, mu chun v mu th:

- Mu trng: pha ng

- Mu chun: dung dch FDP chun c nng 10,0 g/ml

- Mu th: dung dch c pha t mu HPTR nng FDP khong 10,0 g/ml

- Tim ln lt cc mu: mu trng, mu chun, mu th

Bng 3.3: Thi gian lu v din tch pic ca cc mu xc nh c hiu ca

phng php

Mu Thi gian lu (pht) Din tch pic (mAU)

Mu trng - -

Mu chun 5,56 630314

Mu th 5,60 680417

Nhn xt: khng xut hin pic trn sc k ca mu trng. Mu chun v mu

th cho thi gian lu tng ng ging nhau (ph lc 4). Chng t rng phng

php nh lng FDP bng h thng HPLC t yu cu v c hiu.

Xc nh khong tuyn tnh

- Chy sc k ln lt cc mu chun c nng FDP t 0,5 20,0 g/ml. Kt qu

c trnh by trong bng sau:

28

Bng 3.4: Thi gian lu v din tch pic ca cc mu xc nh khong tuyn

tnh ca phng php

Hnh 3.3: ng chun biu din mi tng quan gia nng felodipin trong

dung dch vi din tch pic p ng

Nhn xt: phng trnh hi qui vi R2= 0,9991 > 0,98 chng t c s tng

quan cht ch gia nng FDP v din tch pic p ng trong khong nng t

0,5 20,0 g/ml.

Xc nh chnh xc

- Ly mu chun vi nng 0,5 v 10,0 g/ml (tng ng vi nng FDP

trong mi trng ha tan khi gii phng 100%), tim 6 ln vi mi nng , xc

nh thi gian lu, din tch pic, tnh RSD ca cc mu ti mi nng . Kt qu

c trnh by bng sau:

y = 61538x + 9864.7 R = 0.9991

0

100000

200000

300000

400000

500000

600000

700000

800000

0 2 4 6 8 10 12 14

mA

U

C (g/ml)

C

(g/ml) 0,5 1,0 2,0 4,0 6,0 8,0 10,0 12,0

tR (pht) 5,55 5,54 5,55 5,55 5,56 5,56 5,56 5,60

Din tch pic

(mAU)

50507 68709 130285 252958 381713 486146 630314 754664

29

Bng 3.5: Thi gian lu v din tch pic ca cc mu xc nh chnh xc ca

phng php

Ln o

Nng 0,5 g/ml Nng 10,0 g/ml

Thi gian lu (pht)

Din tch pic (mAU)

Thi gian lu (pht)

Din tch pic (mAU)

1 5,54 49177 5,56 624548

2 5,53 49793 5,56 630314

3 5,55 50296 5,56 633620

4 5,53 50628 5,56 626706

5 5,55 50312 5,58 630987

6 5,55 50507 5,58 629188

Gi tr trung bnh 50119

628050

lch chun 542,6 2504,0

RSD (%) 1,08 0,40

Nhn xt: ti cc nng 0,5 v 10,0 g/ml u cho lp li tt, th hin

RSD < 2%. Phng php t yu cu v chnh xc.

Xc nh ng

- Ly mu chun nng 10,0 g/ml, tim 6 ln, xc nh nng thu c thng

qua phng trnh hi quy xc nh ti mc Xc nh khong tuyn tnh. So

snh gi tr thu c vi kt qu theo l thuyt (10,0 g/ml). Kt qu c trnh by

trong bng sau :

Bng 3.6: Thi gian lu v din tch pic ca cc mu xc nh ng ca

phng php

Ln o Din tch pic (mAU) Nng thu hi

(g/ml) thu hi (%)

1 624548 9,962 99,62

2 630314 10,056 100,56

3 626556 9,995 99,95

4 626706 9,997 99,97

5 630987 10,067 100,67

6 629188 10,038 100,38

Nhn xt: nng 10,0 g/ml, thu hi nm t 99,62 100,67% chng t

rng phng php t yu cu v ng.

30

Phng php nh lng FDP bng HPLC t cc yu cu v c hiu,

chnh xc v ng, do , trong khong tuyn tnh kho st, ta c th nh

lng FDP trong cc nghin cu theo phng php ny.

3.2. nh hng ca mt s cht mang thn nc ti tan v ha tan ca

felodipin t h phn tn rn.

nh gi nh hng ca t l cht mang ti tan ca FDP t HPTR, tin

hnh xc nh tan ca FDP nguyn liu v trong HPTR vi dung mi ha tan l

dung dch PLX 1% theo phng php ghi mc 2.3.2. Cc mu HPTR sau khi tin

hnh nh gi tan s c nh gi ha tan v so vi cc mu HHVL vi t l

tng ng theo phng php ghi mc 2.3.2.

3.2.1. H phn tn rn vi cht mang l PVP K30

HPTR ca FDP vi PVP K30 c iu ch theo phng php ghi mc 2.3.1

vi cc t l dc cht: cht mang l 1:4, 1:9, 1:14, 1:19 (kl/kl). HPTR sau qu trnh

nghin v ry la chn kch thc c dng bt mn, mu trng hi vng. Cc HPTR

ny c em xc nh hm m nhanh v nh lng theo phng php ghi mc

2.3.2. Kt qu c trnh by trong ph lc 13.

nh gi tan:

Tin hnh xc nh tan ca FDP nguyn liu v trong cc HPTR vi cht

mang PVP K30 iu ch. Kt qu c trnh by trong bng 3.7.

Bng 3.7: tan ca felodipin nguyn liu v trong HPTR vi PVP K30 trong

dung dch poloxamer 1% trong nc

Mu th Felodipin FDP:PVP

K30 =1:4

FDP:PVP

K30 =1:9

FDP:PVP

K30 =1:14

FDP:PVP

K30 =1:19

tan (g/ml) 241,9 259,4 404,7 281,3 285,9

n* 1,0 1,1 1,7 1,2 1,2

(n*: mc tng tan ca HPTR so vi nguyn liu)

Nhn xt: khi phi hp vi PVP K30 trong HPTR, tan ca FDP u c ci

thin so vi FDP nguyn liu. Trong , tan ca FDP tng tt nht (gp 1,7 ln

nguyn liu) khi phi hp t l 1:9 vi PVP K30. C ch lm tng tan ca PVP

K30 l do kh nng tng thm t FDP ca PVP K30, s to thnh lin kt hydro

gia nhm carbonyl ca PVP K30 vi nhm amino ca FDP gy phn tn FDP

31

trong mi trng ha tan v s thay i trng thi kt tinh ca FDP t kt tinh sang

dng v nh hnh ( c chng minh trong kt qu ph nhiu x tia X ca HPTR

t l 1:9 (hnh ph lc 6).

nh gi ha tan:

Cc mu HPTR v HHVL vi 4 t l nh trn c nh gi ha tan theo

phng php ghi mc 2.3.2. Kt qu c trnh by trong bng 3.8 v hnh 3.4.

Bng 3.8: T l FDP ha tan t mu th vi PVP K30 (n=3)

Thi gian

(gi)

T l 1:4 T l 1:9 T l 1:14 T l 1:19

HHVL HPTR HHVL HPTR HHVL HPTR HHVL HPTR

0,5 0,0 6,9 0,0 10,9 5,6 13,0 8,8 18,0

1 8,1 25,9 10,1 32,8 11,8 34,2 17,9 47,1

2 14,3 40,7 15,7 41,9 27,8 47,9 34,9 57,8

3 18,3 51,7 23,7 53,5 30,2 57,0 40,8 71,5

4 21,3 55,9 26,2 58,6 38,6 62,9 49,7 79,2

5 21,6 56,7 26,7 59,2 43,2 64,0 50,2 79,8

Hnh 3.4: th ha tan ca FDP trong mu th vi PVP K30

Nhn xt: Vi cht mang PVP K30, ha tan FDP trong cc HPTR vi cc t

l khc nhau u tng so vi HHVL t l tng ng. thi im 5 gi, lng

FDP ha tan t HPTR vi t l 1:4 tng 2,6 ln so HHVL tng ng. ha tan ca

FDP tng khi tng t l cht mang PVP K30 trong HPTR. Sau 5 gi, t l 1:4,

dc cht ha tan 56,74%. Cn t l 1:19, ha tan ti thi im l 79,83%. Ta

thy rng mc tng ha tan ny l khng ng k so vi s tng t l PVP.

0

20

40

60

80

100

0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5

% F

DP

h

a ta

n

Thi gian (gi)

FDP :PVP K30 HHVL 1:4 HHVL 1:9 HHVL 1:14 HHVL 1:19

HPTR 1:4 HPTR 1:9 HPTR 1:14 HPTR 1:19

32

Mt khc, khi t l cht mang trong HPTR cng ln, qu trnh bo ch HPTR bng

phng php dung mi gp kh khn, do dung mi chm bay hi khi dung dch c

nht cao, HPTR kh kh v kh nghin mn, d b ht m trong qu trnh bo

qun. Do , chng ti la chn t l FDP: PVP K30 l 1:9 thc hin cc nghin

cu tip theo.

3.2.2. H phn tn rn vi cht mang HPMC E5 LV

HPTR ca FDP vi HPMC E5LV c iu ch cc t l FDP: HPMC ln

lt l 1:4, 1:9, 1:14 (kl/kl). Xc nh hm m ca h v hm lng FDP trong h,

kt qu c trnh by trong ph lc 13.

nh gi tan:

Tin hnh xc nh tan ca FDP nguyn liu v trong HPTR nghin cu. Kt

qu c trnh by trong bng 3.9.

Bng 3.9: tan ca felodipin nguyn liu v trong HPTR vi HPMC E5 LV

trong dung dch poloxamer 1% trong nc

Mu th Felodipin FDP:HPMC

E5 LV=1:4

FDP:HPMC

E5 LV=1:9

FDP:HPMC

E5 LV=1:14

tan (g/ml) 241,9 736,3 724,7 952,8

n* 1,0 3,2 3,1 3,9

(n*: mc tng tan ca HPTR so vi nguyn liu)

Nhn xt: khi c mt HPMC E5 LV, tan ca FDP tng ln ng k so vi

FDP nguyn liu. Trong , tan ca FDP tng tt nht, gp 4 ln nguyn liu khi

phi hp t l 1:14 trong HPTR. tan ca FDP trong HPTR vi HPMC tng so

vi nguyn liu c th do lin kt hydro to thnh gia cc nhm hydroxyl ca

HPMC vi nhm amino ca FDP gy phn tn FDP, tng t nh vi PVP.

nh gi ha tan:

Cc mu HPTR v HHVL vi 3 t l nh trn c nh gi ha tan theo

phng php ghi mc 2.3.2. Kt qu c trnh by trong bng 3.10 v hnh 3.5.

33

Bng 3.10: T l FDP ha tan t mu th vi HPMC E5 (n=3)

Thi gian (gi)

T l 1:4 T l 1:9 T l 1:14

HHVL HPTR HHVL HPTR HHVL HPTR

0,5 0,0 0,0 0,0 0,0 0,0 0,0

1 0,0 0,7 0,0 2,6 1,5 8,3

2 7,3 9,9 2,4 11,0 9,2 20,2

3 13,0 21,3 7,4 12,7 31,6 21,9

4 16,1 24,1 9,6 13,8 38,0 33,6

5 26,8 32,7 10,7 17,8 45,5 42,7

Hnh 3.5: th ha tan ca FDP t mu th vi HPMC E5 LV

Nhn xt: HPTR cha cht mang HPMC E5 LV c ha tan FDP khng khc

bit so vi HHVL t l tng ng. t l 1:4 v 1:9, ha tan FDP thi im

5 gi ca HPTR cao hn HHVL tng ng nhng khng ng k. Khi tng t l ln

1:14 th ha tan li thp hn. Kt qu ny c th do HPMC trong HPTR to

thnh lp gel cn tr qu trnh ha tan FDP ra khi HPTR. Ta cng thy rng, gia

cc mu th ca cng mt HPTR, ha tan FDP ti cng mt thi im c s dao

ng tng i r rt. S dao ng ny l do HPTR vi cht mang HPMC to thnh

dng mng cng, gy kh khn trong qu trnh nghin, cc tiu phn HPTR khng

ng u nhau nn qu trnh ha tan FDP khng n nh gia cc mu khc nhau.

HPTR ca FDP vi cht mang HPMC E5 LV tuy ci thin c tan ca FDP

nhng ko di thi gian ha tan FDP trong mi trng ha tan. Mt khc, HPTR

0

5

10

15

20

25

30

35

40

45

50

0.5 1.5 2.5 3.5 4.5 5.5

% F

DP

h

a ta

n

Thi gian (gi)

FDP : HPMC E5 LV

HHVL 1:4 HHVL 1:9 HHVL 1:14

HPTR 1:4 HPTR 1:9 HPTR 1:14

34

ny gp kh khn trong qu trnh bo ch do HPMC trong dung mi ethanol to

dung dch c nht cao, kh phn tn u dc cht, kh loi dung mi, th cht

to thnh kh ng dng trong cc dng bo ch thng thng.

3.2.3. H phn tn rn vi cht mang PEG

HPTR ca FDP vi cht mang PEG 4000 v 6000 c iu ch cc t l 1:4,

1:9, 1:14 v 1:19 (kl/kl) theo phng php ghi mc 2.3.1. H thu c dng bt

mn, mu trng, d dnh. Cc HPTR vi PEG d b chy lng di tc dng ca

nhit do nhit nng chy ca cc PEG thng thp, v vy khng th xc nh

nhanh hm m ca HPTR bng cn xc nh hm m nhanh. Hm lng FDP c

tnh trn khi lng ton h v c th hin trong ph lc 13.

nh gi tan:

Tin hnh xc nh tan ca FDP nguyn liu v cc HPTR theo phng php

ghi mc 2.3.3. Kt qu c trnh by trong bng 3.11.

Bng 3.11: tan ca felodipin nguyn liu v trong HPTR vi PEG trong

dung dch poloxamer 1% trong nc

Mu th

Felodipin

T l 1:4 (kl/kl) T l 1:9 (kl/kl)

T l 1:14 (kl/kl)

T l 1:19 (kl/kl)

PEG 4000

PEG 6000

PEG 4000

PEG 6000

PEG 4000

PEG 6000

PEG 4000

PEG 6000

tan (g/ml)

241,9 641,9 342,7 546,1 541,6 560,6 605,5 505,6 570,6

n* 1,0 2,7 1,4 2,3 2,2 2,3 2,5 2,1 2,4

(n*: mc tng tan ca HPTR so vi nguyn liu)

Nhn xt: Kt qu nh gi tan ca cc HPTR cha FDP v PEG cho thy,

vi cht mang PEG 4000, kh nng tan ca FDP trong dung dch PLX 1% t h c

t l 1:4 gia FDP v cht mang l ln nht (gp 2,7 ln FDP nguyn liu), vi cc

h cn li ca cht mang ny, tan ny hu nh khng c s chnh lch ng k.

Cn i vi cht mang PEG 6000, tan tng ln khi t l cht mang:dc cht

tng dn t 4:1, 9:1, 14:1, tan khng tng so vi t l 14:1 khi i khi tng t l

ln 19:1. Kh nng lm tng tan FDP ca cc HPTR cha PEG c th do s tng

kh nng thm t, to ng dung mi ha tan dc cht v gy phn tn dc cht

ca cc PEG. cng t l kt hp 1:4 v 1:9, tan ca FDP t HPTR vi cht

35

mang PEG 4000 cao hn vi cht mang PEG 6000. Ngc li, cc t l 1:14 v

1:19, tan ca FDP t HPTR vi cht mang PEG 4000 li thp hn vi cht mang

PEG 6000 tng ng. iu ny cho thy rng, chiu di phn t PEG cng c nh

hng n mc tng tc gia dc cht v cht mang trong HPTR.

nh gi ha tan:

Cc mu HPTR v HHVL vi 4 t l nh trn c nh gi ha tan theo

phng php ghi mc 2.3.2. Kt qu ha tan ca HPTR vi cc cht mang

PEG 4000, PEG 6000 c trnh by bng v hnh sau:

Bng 3.12: T l FDP ha tan t mu th vi PEG (n=3)

Thi gian

(gi)

T l 1:4 T l 1:9 T l 1:14 T l 1:19

HHVL HPTR HHVL HPTR HHVL HPTR HHVL HPTR

0,5 0,0 21,4 0,0 11,2 1,0 35,0 0,0 39,0

1 0,0 47,6 0,0 41,0 2,0 52,2 1,2 52,2

2 0,0 56,3 0,0 51,7 2,7 65,2 1,7 60,5

3 1,4 58,3 1,7 53,0 5,5 66,2 6,4 62,3

4 1,7 59,7 9,3 53,2 6,9 67,0 11,1 62,3

5 2,7 61,0 9,8 54,0 8,7 67,0 17,8 62,3

Hnh 3.6: th ha tan ca FDP trong HHVL v HPTR vi PEG 4000

0

10

20

30

40

50

60

70

80

90

0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5

% F

DP

h

a ta

n

Thi gian (gi)

FDP: PEG 4000

HHVL 1:4 HHVL 1:9 HHVL 1:14 HHVL 1:19

HPTR 1:4 HPTR 1:9 HPTR 1:14 HPTR 1:19

36

Bng 3.13: T l FDP ha tan t mu th vi PEG 6000 (n=3)

Thi gian

(gi)

T l 1:4 T l 1:9 T l 1:14 T l 1:19

HHVL HPTR HHVL HPTR HHVL HPTR HHVL HPTR

0,5 0,0 53,8 0,0 51,5 0,3 41,0 3,2 28,9

1 0,0 57,0 0,0 64,3 0,6 69,6 3,2 67,8

2 0,0 63,0 2,3 69,5 1,2 83,3 6,7 82,6

3 1,2 65,2 4,4 73,7 3,8 83,3 11,9 82,6

4 10,8 73,1 4,6 77,3 3,8 83,3 12,8 82,9

5 20,6 78,5 31,4 85,1 4,1 83,3 21,2 82,9

Hnh 3.7: th ha tan ca FDP trong mu th vi PEG 6000

Nhn xt: Kt qu nh gi ha tan ch ra rng, t l FDP ha tan t cc

HPTR vi PEG u cao hn ng k so vi t HHVL tng ng. Vi cht mang

PEG 4000, vi t l 1:14, thi im 5 gi, t l FDP ha tan cao nht t 67%,

trong khi t l ny l 8,7% i vi HHVL tng ng. th biu din qu trnh ha

tan FDP t cc HPTR vi PEG 4000 cho thy, qu trnh ha tan trong 5 gi u ca

HPTR t l 1:14 l cao nht, t l 1:9 l thp nht. Vi cht mang PEG 6000,

cng vi t l kt hp 1:14, t l FDP ha tan cao nht t 83,3% cng thi im.

Kh nng ha tan FDP tng ln cng vi lng cht mang, tuy nhin, khng c s

khc bit r rt khi t l cht mang tng t 14:1 ln 19:1. c bit, vi c hai cht

mang ny, t l ha tan 0,5 gi u t trn 25% v trn 50% sau 1 gi.

0

10

20

30

40

50

60

70

80

90

0.5 1.5 2.5 3.5 4.5 5.5

% F

DP

h

a ta

n

Thi gian (gi)

FDP: PEG 6000 HHVL 1:4 HHVL 1:9 HHVL 1:14 HHVL 1:19HPTR 1:4 HPTR 1:9 HPTR 1:14 HPTR 1:19

37

Cc HPTR vi cht mang PEG u c u im v th cht v thun li bo ch,

do vi kt qu thu c, chng ti s dng HPTR FDP: PEG 4000 t l 1:4 v

FDP: PEG 6000 t l 1:9 thc hin cc nghin cu tip theo.

3.3. nh hng ca poloxamer ti tan v ha tan ca felodipin t h

phn tn rn

Tin hnh iu ch HPTR ca FDP vi ln lt cc cht mang PVP K30, PEG

4000, PEG 6000, s dng PLX nh mt cht din hot theo phng php ghi mc

2.3.1. Cc t l tin hnh kho st nh sau:

- Vi PVP K30, t l phi hp l FDP: PVP K30: PLX = 1:9:1 (kl/kl) v 1:9:1,5

(kl/kl).

- Vi PEG 4000, t l phi hp l FDP: PEG 4000: PLX = 1:4:1 (kl/kl) v 1:4:1,5

(kl/kl).

- Vi PEG 4000 t l phi hp l FDP: PEG 6000: PLX = 1:9:1 (kl/kl) v 1:9:1,5

(kl/kl).

3.3.1. H phn tn rn vi cht mang l PVP K30 kt hp vi poloxamer:

Sau khi iu ch, HPTR thu c c dng bt mn, mu hi vng, d ht m.

Tin hnh xc nh hm m v nh lng FDP c trong cc h, kt qu c trnh

by trong ph lc 13.

nh gi tan:

Tin hnh xc nh tan ca cc HPTR iu ch trong dung dch PLX 1%,

so snh vi tan ca FDP nguyn liu v HPTR ch cha PVP K30 t l tng

ng. Kt qu c trnh by trong bng 3.14.

Bng 3.14: tan ca felodipin nguyn liu v trong HPTR vi PVP K30,

poloxamer trong dung dch poloxamer 1% trong nc

Mu th Felodipin FDP:PVP K30

=1:9

FDP:PVP K30 :PLX

=1:9:1

FDP:PVP K30

:PLX =1:9:1,5

tan (g/ml)

241,9 404,7 558,9 851,9

n* 1,0 1,7 2,3 3,5

(n*: mc tng tan ca HPTR so vi nguyn liu)

38

Nhn xt: khi c mt PLX trong HPTR, tan ca FDP trong h tng ln ng

k so vi nguyn liu v h khng c PLX. Vi s c mt ca PLX t l 1:1 vi

dc cht, tan gp 2,3 ln so vi nguyn liu v t l 1:1,5 l 3,5 ln, trong khi

ch l 1,7 ln vi HPTR khng cha PLX. Nh vy, c th thy rng, tan ca

FDP ph thuc vo lng PLX c trong HPTR. PLX l mt cht din hot khng

ion ha, kh nng ci thin tan cho HPTR ca cht ny l do tng kh nng thm

t cho dc cht, to lp o thn nc bao quanh dc cht, hn ch qu trnh ti

kt tinh dc cht trong dung dch bo ha, khi lng PLX tng s lm tng kh

nng tan trong nc cho dc cht. Kt qu nhiu x tia X (hnh ph lc 7) v kt

qu phn tch DSC (hnh ph lc 12) cng cho thy, FDP tn ti phn ln dng v

nh hnh trong HPTR.

nh gi ha tan:

Tin hnh xc nh ha tan FDP t cc HPTR iu ch, so snh vi

HHVL v HPTR ch cha PVP K30 tng ng. Kt qu c trnh by trong bng

3.15 v hnh 3.8.

Bng 3.15: T l FDP ha tan t mu th vi PVP K30 (n=3)

Thi gian

(gi)

T l 1:9 T l 1:9:1 T l 1:9:1,5

HHVL HPTR HHVL HPTR HHVL HPTR

0,5 0,0 10,9 9,4 35,7 23,2 35,9

1 10,1 32,8 18,8 54,5 27,1 55,1

2 15,7 41,9 19,3 68,6 34,4 66,2

3 23,7 53,5 27,5 82,0 45,0 75,1

4 26,2 58,6 28,1 87,2 45,0 81,8

5 26,7 59,2 29,9 87,2 45,3 82,1

39

Hnh 3.8: th ha tan ca FDP trong mu th vi PVP K30, poloxamer

Nhn xt: qu trnh ha tan FDP vo mi trng ha tan trong 5 gi u c s

khc bit ng k gia cc mu th c mt PLX v khng c mt PLX. Sau 5 gi,

t l FDP ha tan cc mu th HHVL v HPTR khng cha PLX u thp hn

cc mu th tng ng c PLX. Nh vy, PLX thc y qu trnh ha tan FDP

vi vai tr nh mt cht din hot tng tan. Ta cng thy rng, t l FDP ha tan

t hai HHVL so vi hai HPTR cha PLX tng ng cng c s khc bit ng k.

C th cho rng PLX trong HPTR c phn tn c phn tn ng u cng vi

dc cht di tc dng ca qu trnh ha tan c dc cht v PLX trong dung mi

trc khi phi hp vo cht mang, trong khi HHVL, qu trnh phn tn ny ch do

s nghin trn thng thng. Khi so snh hai HPTR vi lng PLX khc nhau, kt

qu cho thy, mc d tan ca h cha PLX t l 1:1,5 so vi dc cht cao hn

h cn li nhng % FDP ha tan ti cc thi im trong 5 gi u li thp hn. iu

ny c th lin quan ti s thay i t l gia hai trng thi kt tinh ca FDP trong

HPTR khi thay i t l PLX. Trong , trng thi kt tinh i hi nhiu nng lng

hn trong qu trnh ha tan.

3.3.2. H phn tn rn vi cht mang l PEG 4000 kt hp vi poloxamer

HPTR vi cht mang PEG 4000 v PLX sau khi iu ch c dng bt mn, mu

trng, d dnh. Phn trm FDP so vi khi lng ton h trong hai HPTR c trnh

by trong ph lc 13.

0

20

40

60

80

100

0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5

% F

DP

h

a ta

n

Thi gian (gi)

FDP: PVP K30: Poloxamer

HHVL 1:9 HHVL 1:9:1 HHVL 1:9:1,5

40

nh gi tan:

Tin hnh xc nh tan ca cc HPTR iu ch theo phng php ghi

mc 2.3.2. Kt qu c trnh by trong bng 3.16.

Bng 3.16: tan ca felodipin nguyn liu v trong HPTR vi PEG 4000,

poloxamer trong dung dch poloxamer 1% trong nc

Mu th Felodipin FDP:PEG 4000

=1:4

FDP:PEG 4000

:PLX =1:4:1

FDP:PEG 4000

:PLX =1:4:1,5

tan (g/ml)

241,9 641,9 734,5 837,5

n* 1,0 2,7 3,0 3,5

(n*: mc tng tan ca HPTR so vi nguyn liu)

Nhn xt: tan ca FDP trong HPTR c mt PLX vi cht mang PEG 4000

tng ng k so vi nguyn liu nhng khng tng nhiu so vi h khng c mt

PLX. Khi tng t l PLX t 1:1 ln 1,5:1 so vi dc cht th tan ca FDP khng

tng nhiu. Da vo kt qu v tan v ha tan ca HPTR ch cha FDP v

cht mang PEG 4000 cho thy, c th FDP phn tn a s dng phn t trong

cht mang, v vy, s c mt PLX khng lm tng kh nng tan ca FDP t HPTR

r rt nh vi cht mang PVP K30.

nh gi ha tan:

Tin hnh xc nh ha tan FDP t cc HPTR iu ch trong 5 gi u so

snh vi HHVL v HPTR ch cha PEG 4000 tng ng. Kt qu c trnh by

trong bng 3.17 v hnh 3.9.

Bng 3.17: T l FDP ha tan t mu th vi PEG 4000, poloxamer (n=3)

Thi gian

(gi)

T l 1:4 T l 1:4:1 T l 1:4:1,5

HHVL HPTR HHVL HPTR HHVL HPTR

0,5 0,0 21,4 15,0 55,9 26,7 73,9

1 0,0 47,6 18,1 76,3 35,9 87,1

2 0,0 56,3 30,5 91,4 48,2 96,8

3 1,4 58,3 37,4 95,0 50,5 98,1

4 1,7 59,7 42,0 96,9 52,9 98,6

5 2,7 61,0 45,8 96,9 56,6 98,6

41

Hnh 3.9: th ha tan ca FDP trong mu th vi PEG 4000, poloxamer

Nhn xt: qu trnh ha tan FDP t cc mu th (HHVL, HPTR) c PLX tng

ng k so vi cc mu th tng ng khng cha PLX. i vi cc HHVL, lng

FDP gii phng sau 5 gi u i vi hn hp khng c mt PLX l 2,7%, trong

khi lng ny ln lt l 45,8% v 56,6% khi c mt PLX t l 1:1 v 1,5:1 vi

dc cht. i vi cc HPTR, thi im cui cng kho st, lng FDP gii

phng ln lt l 61,0%, 96,9% v 98,6% vi h khng c PLX, h c PLX cc t

l 1:4:1 v 1:4:1,5. Nh vy, s c mt PLX thc y qu trnh ha tan FDP,

gip FDP ha tan nhanh v gn nh hon ton (i vi cc HPTR) vo lng mi

trng ha tan trong php th (t l ha tan > 95%).

3.3.3. H phn tn rn vi cht mang PEG 6000 kt hp vi poloxamer

HPTR vi cht mang PEG 6000 v PLX sau khi iu ch c th cht tng t

khi s dng cht mang PEG 4000. Phn trm FDP so vi khi lng ton h trong

hai HPTR c trnh by trong ph lc 13.

nh gi tan:

Tin hnh xc nh tan ca cc HPTR iu ch trong dung dch poloxamer

1%, so snh vi tan ca FDP nguyn liu v HPTR ch cha PEG 6000 t l

tng ng. Kt qu c trnh by trong bng 3.18.

0

20

40

60

80

100

0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5

% F

DP

h

a ta

n

Thi gian (gi)

FDP: PEG 4000: Poloxamer HHVL 1:4 HHVL 1:4:1 HHVL 1:4:1,5HPTR 1:4 HPTR 1:4:1 HPTR 1:4:1,5

42

Bng 3.18: tan ca felodipin nguyn liu v trong HPTR vi PEG 6000,

poloxamer trong dung dch poloxamer 1% trong nc

Mu th Felodipin FDP:PEG 6000

=1:9

FDP:PEG 6000

:PLX =1:9:1

FDP:PEG 6000

:PLX =1:9:1,5

tan (g/ml)

241,9 541,6 753,7 684,4

n* 1,0 2,2 3,1 2,8

(n*: mc tng tan ca HPTR so vi nguyn liu)

Nhn xt: tan ca FDP trong HPTR c mt PLX vi cht mang PEG 6000

tng ng k so vi nguyn liu nhng khng tng nhiu so vi h khng c mt

PLX. Ta thy rng, khi tng lng PLX t 1 ln 1,5 ln (so vi dc cht) th tan

li c xu hng gim mc d khng nhiu.

nh gi ha tan:

Tin hnh xc nh ha tan FDP t cc HPTR iu ch trong 5 gi u so

snh vi HHVL v HPTR ch cha PEG 6000 tng ng. Kt qu c trnh by

trong bng 3.19 v hnh 3.10.

Bng 3.19: T l FDP ha tan t mu th vi PEG 6000, poloxamer (n=3)

Thi gian

(gi)

T l 1:9 T l 1:9:1 T l 1:9:1,5

HHVL HPTR HHVL HPTR HHVL HPTR

0,5 0,0 51,5 0,0 58,8 0,0 62,5

1 0,0 64,3 0,3 62,8 0,5 70,3

2 2,3 67,4 2,8 69,2 3,8 74,8

3 4,3 73,7 3,7 78,5 5,1 81,2

4 4,6 77,3 6,2 87,7 7,6 89,0

5 31,4 85,1 37,4 88,2 40,5 89,5

43

Hnh 3.10: th ha tan ca FDP trong mu th vi PEG 6000, poloxamer

Nhn xt: qu trnh ha tan FDP t cc mu th (HHVL, HPTR) c PLX khng

c s khc bit ng k so vi cc mu th tng ng khng cha PLX. i vi

cc HHVL, lng FDP gii phng sau 4 gi u i vi hn hp khng c mt

PLX l 4,6%, trong khi lng ny ln lt l 6,2% v 7,6% khi c mt PLX t l

1:1 v 1,5:1 so vi dc cht.

i vi cc HPTR, thi im cui cng kho st, lng FDP gii phng ln

lt l 85,1%, 88,2% v 89,5% vi h khng c PLX, h c PLX cc t l 1:4:1

v 1:4:1,5. Nh vy, c th thy rng, s c mt ca PLX trong HPTR khng nh

hng nhiu n qu trnh ha tan FDP t h nh i vi PVP K30. Tuy nhin, cc

mu th ca HHVL u c hin tng tng nhanh tc ha tan sau thi im 4

gi v u t t 30-40% ti thi im 5 gi trong khi cc HPTR li khng c hin

tng ny. iu ny c th lin quan ti s khc nhau v mc ng u ca s

phn tn dc cht v cht mang trong HHVL v HPTR. Trong HHVL, cht mang

ch c nghin trn thng thng cng vi dc cht nn mc ng u trong

phn tn cng nh ng u vi kch thc tiu phn dc cht hn ch, do ,

cc thi im u, ch yu l s ha tan cht mang l polyme thn nc hn l

0

10

20

30

40

50

60

70

80

90

100

0.5 1.5 2.5 3.5 4.5 5.5

% F

DP

h

a ta

n

Thi gian (gi)

FDP: PEG 6000: Poloxamer

HHVL 1:9 HHVL 1:9:1 HHVL 1:9:1.5

HPTR 1:9 HPTR 1:9:1 HPTR 1:9:1,5

44

dc cht s nc. Cn i vi HPTR, mc ng u ny tng cao do c trng

thi c dc cht v cht mang (v cht din hot) ng tan trong dung mi.

3.4. Bn lun chung

3.4.1. V iu ch h phn tn rn ca felodipin vi cht mang l cc polyme thn

nc:

HPTR ca felodipin vi cht mang l cc polyme thn nc c iu ch bng

phng php dung mi vi mc tiu ci thin tan v ha tan cho dc cht.

Kh nng ci thin tan v ha tan cho dc cht ca HPTR iu ch theo

phng php ny ph thuc vo cc yu t: loi polyme c s dng lm cht

mang, t l polyme s dng trong HPTR, phng php lm bay hi dung mi.

Trong kha lun tt nghip ny, chng ti kho st hai thng s lin quan n

polyme gm loi v t l polyme c s dng lm cht mang:

Nghin cu v loi polyme c s dng lm cht mang: tin hnh nghin cu

vi PVP K30, HPMC E5 LV, PEG 4000, PEG 6000

- Nhng thun li v kh khn trong iu ch HPTR: cc polyme s dng trong

nghin cu u d tan trong dung mi s dng l ethanol tuyt i. Do , lng

dung mi cn s dng khng nhiu, dung mi ny d bay hi, t gy nhim mi

trng trong qu trnh bay hi v lng dung mi tn d trong HPTR sau khi bay

hi hu nh khng c. Vi cc cht mang l PVP K30, PEG 4000, PEG 6000,

HPTR c u im v tnh thun li khi iu ch, d loi dung mi ngay c khi t l

cht mang ln, th cht HPTR to thnh d nghin thnh dng bt mn, c th kim

sot cc yu t v kch thc tiu phn, trn chy, kh nng chu nn ng

dng vo vin nn GPKD. Cn vi cht mang l HPMC E5 LV, qu trnh loi b

dung mi gp kh khn khi nht ca dung dch tng cao, HPTR to thnh dng

mng cng, kh nghin mn v kim sot phn b kch thc tiu phn ca HPTR.

- V kh nng ci thin tan v ha tan cho dc cht: c ba loi polyme thn

nc c s dng lm cht mang trong HPTR u gip ci thin tan v

ha tan cho dc cht trong h mc khc nhau. Trong , tan tng thp

nht l 1,1 ln i vi HPTR vi PVP K30 t l 1:9, cao nht i vi HPTR t l

45

1:14 vi cht mang HPMC E5 LV. Kh nng ci thin ha tan cho dc cht ca

cc polyme khc nhau cng c s khc nhau. Vi cht mang l PEG, qu trnh ha

tan dc cht c y nhanh ngay ti cc thi im u, c bit l vi PEG 6000.

Trong khi vi cht mang HPMC E5 LV, qu trnh ny li chm hn rt nhiu do

cht mang to thnh lp gel bao quanh dc cht, cn tr qu trnh ha tan. C ch

lm tng tan v ha tan cho dc cht trong cc HPTR c th do s tng kh

nng thm t dc cht ca cc cht mang, s ha tan cht mang thn nc ko

theo s ha tan dc cht, gim kch thc tiu phn dc cht hay thay i trng

thi kt tinh ca dc cht t dng tinh th sang dng v nh hnh. iu ny c th

thy trn kt qu ph nhiu x tia X (hnh ph lc 6) v kt qu DSC (hnh ph lc

11) ca HPTR gia FDP vi cht mang PVP K30 t l 1:9, th hin bng s bin

mt ca cc nh nhiu x hp v nhn quan st thy trn ph nhiu x ca nguyn

liu FDP v HHVL tng ng hay nh ni nhit 146,35C ca FDP. Nh vy,

trong HPTR ca FDP vi cht mang PVP K30 t l ny, dc cht c phn

tn trong h trng thi v nh hnh, d dng ha tan trong mi trng ha tan hn

trng thi tinh th do khng cn nng lng ph v cu trc mng tinh th.

Nghin cu v t l polyme c s dng lm cht mang:

- Nhng thun li v kh khn trong iu ch HPTR: khi thay i t l polyme trong

HPTR, th cht ca cc HPTR thu c hu nh khng c s khc bit. Tuy vy,

khi t l cht mang qu ln, qu trnh bay hi dung mi xy ra chm hn do s tng

nht ca cc dung dch cha polyme v dc cht. Mt khc, kh nng ng dng

HPTR vo dng bo ch vin nn GPKD s hn ch nu s dng nhiu cht mang

do s tng ln ca khi lng vin.

- V kh nng ci thin tan v ha tan cho dc cht: ni chung, vi cng

mt loi polyme, t l phi hp trong HPTR ca polyme c nh hng n kh

nng ci thin tan v ha tan cho dc cht ca h. Khi thay i t l PVP

K30 trong cc HPTR khc nhau nh trnh by, chng ti thy rng khi tng

lng polyme th tan v ha tan ca dc cht u tng ln. Trn ph nhiu

x tia X (hnh ph lc 8) v kt qu DSC ca PVP K30 v HPTR FDP: PVP K30

46

(hnh ph lc 11), ta c th thy cht mang ny tn ti ch yu dng v nh hnh

c trong hai mu trn, nh vy, c th cho rng, s tng ln ca lng cht mang

tan trong nc ko theo qu trnh ha tan dc cht cng c tng ln. Trong khi

vi HPMC E5 LV, khi tng t l cht mang ny th tan ca h tng ln nhng qu

trnh ha tan li din ra chm hn do s to thnh lp gel cn tr qu trnh ha tan

ca loi polyme ny. Cn i vi cht mang l cc PEG, tan v ha tan khng

c s khc bit r rt khi thay i cc t l nh trong nghin cu. Vi cht mang

PEG 4000: tan ca cc HPTR vi cc t l cht mang khc nhau tng ln t 2,3-

2,7 ln so vi nguyn liu, ha tan sau 5 gi u t t 55-65% v c s chnh

lch ng k so vi cc HHVL. Vi PEG 6000: tan ca cc HPTR vi cc t l

cht mang khc nhau tng ln t 1,4-2,5 ln so vi nguyn liu, ha tan sau 5 gi

u t t 75-85% v cao hn hn so vi cc HHVL. Nh vy, c th thy rng, c

ch ci thin tan v ha tan ca cc PEG c th khc vi cc cc cht mang

cn li.

3.4.2. V iu ch h phn tn rn ca felodipin vi cht mang l cc polyme thn

nc kt hp vi poloxamer:

Cht din hot PLX c la chn tip tc nghin cu kh nng ci thin

tan v ha tan ca FDP trong HPTR. Khi xem xt v mt thun li ca qu trnh

iu ch, chng ti thy rng, vi cc mu HPTR cha cht din hot vi t l khc

nhau c kho st, qu trnh iu ch v th cht ca h to hnh khng c s

khc bit gia cc h vi h khng c mt cht din hot tng ng.

nh gi cc mu th c mt PLX, bt c t l no kho st no, cc mu

th u lm tng tan v ha tan cho dc cht tt hn so vi cc mu th

khng cha PLX mc d cc mc khc nhau, iu ny xy ra ngay c vi cc

mu th l cc HHVL. Nh vy c th thy rng, PLX ng vai tr nh mt cht

din hot trong qu trnh ha tan FDP t HPTR v HHVL. PLX l mt cht din

hot khng ion ha, vi loi PLX s dng trong nghin cu, t l thnh phn thn

nc (polyoxyethylen) trong phn t ln do kh nng lm tng tan cho cc

dc cht t tan trong nc kh tt. nh hng ca cht din hot ny ti tan v

47

ha tan ca FDP trong c HHVL v HPTR l do s tng kh nng thm t

dc cht, thay i c tnh b mt ca cc tiu phn dc cht. Trn kt qu nh

gi ha tan ca cc HHVL v HPTR c mt PLX, ta cn thy rng tc ha tan

dc cht t HPTR din ra nhanh hn hn so vi HHVL tng ng. Trong HPTR,

PLX c ha tan cng vi FDP trong dung mi trc khi phi hp cht mang to

iu kin cho cht din hot ny phn tn u cng vi dc cht, to lp o thn

nc bao quanh dc cht. Cn i vi HHVL, s tng tc dc cht v PLX ch

din ra thng qua qu trnh nghin trn thng thng. Trn kt qu DSC ca HHVL

gia FDP vi PVP K30 v PLX (hnh ph lc 12), ta c th thy nh ni nhit ca

FDP 145,1C, nh vy, qu trnh nghin trn khi iu ch HHVL khng lm thay

i cu trc tinh th ca FDP. Cn i vi HPTR, c ch lm tng tan v ha

tan cho dc cht khi c mt PLX s lin quan ti s phn tn dc cht mc

cao, s gim kch thc tiu phn dc cht v gim t l dc cht tn ti dng

tinh th trong HPTR. Khi so snh ph nhiu x tia X ca FDP nguyn liu, hn hp

cht mang PVP K30: PLX, HHVL FDP: PVP K30: PLX v HPTR FDP: PVP K30:

PLX (hnh ph lc 10), ta c th thy rng s bin mt cc nh nhiu x nhn v

hp ca FDP trn c ph nhiu x ca HHVL v HPTR, trong , i vi HPTR,

cc nh ny gn nh bin mt hon ton, ch tn ti cc nh nhiu x c cho l

ca PLX. Kt qu trn hon ton ph hp vi kt qu DSC ca cc mu th (hnh

ph lc 12), ta khng quan st thy nh ni nhit ca FDP 146,35C trn kt qu

phn tch mu HPTR. Mt khc, khi ha tan vo mi trng ha tan, cht din hot

cn c vai tr ngn cn qu trnh kt ta li dc cht, do gip cho mc ha

tan dc cht tng ln v n nh hn.

Vi cc HPTR vi t l PLX khc nhau, mc ci thin tan v ha tan

ca FDP cng khc nhau. i vi cht mang PEG 4000 kt hp vi PLX, khi tng

t l PLX th c tan v ha tan u tng ln. Trong khi, vi cht mang PVP

K30 kt hp vi PLX, tan bo ha sau 24 gi tng ln cng vi t l PLX nhng

HPTR li c xu hng ko di thi gian gii phng. Ngc li, vi cht mang PEG

6000 kt hp vi PLX, tan bo ha sau 24 gi gim nh khi tng t l PLX

48

nhng HPTR li c xu hng y nhanh tc gii phng. Kt qu ny c th lin

quan n t l khc nhau gia hai trng thi kt tinh ca FDP (dng tinh th v dng

v nh hnh) trong cc HPTR vi cc cht mang khc nhau t l PLX khc nhau.

49

KT LUN V XUT

Kt lun:

Sau thi gian nghin cu, kt qu t c cc mc tiu ra:

1. nghin cu c nh hng ca mt s cht mang thn nc nh PVP K30,

HPMC E5 LV, PEG 4000, PEG 6000 n tan v ha tan ca FDP trong

HPTR.

- xy dng c phng php bo ch HPTR bng phng php dung mi.

- Vi cht mang l PVP K30: tan v ha tan u c xu hng tng ln cng

vi s tng t l cht mang. t l dc cht: PVP K30 l 1:9, tan tng hn 2,7

ln so vi nguyn liu v t l gii phng t 32,8% sau 1 gi u v sau 5 gi t

59,2%.

- Vi cht mang l HPMC E5 LV: khi tng t l cht mang ny trong HPTR, tan

ca dc cht c xu hng tng cao nhng tc v mc ha tan li gim. t

l dc cht: HPMC E5 LV l 1:14, tan tng hn 3,9 ln so vi nguyn liu v t

l gii phng t 8,3% sau 1 gi v sau 5 gi t 42,7%.

- Vi cht mang l PEG 4000: nhn chung, khi tng t l PEG 4000, tan ca dc

cht khng thay i nhiu, tuy nhin ha tan trong gi u li c xu hng tng.

t l dc cht: PEG 4000 l 1:4, tan tng hn 2,7 ln so vi nguyn liu v t

l gii phng t 47,6% sau 1 gi v sau 5 gi t 61,0%.

- Vi cht mang l PEG 6000: khi tng t l cht mang t 4:1 ln 14:1 so vi dc

cht, tan v ha tan ca dc cht t h cng tng ln, khi t l ny l 19:1 th

hai ch tiu ny li khng thay i so vi t l 14:1. t l dc cht: PEG 4000 l

1:14, tan tng hn 2,7 ln so vi nguyn liu v t l gii phng t 69,6% trong

1 gi u v sau 5 gi t 83,3%.

2. nghin cu c nh hng ca poloxamer kt hp vi cht mang khc n

tan v ha tan ca FDP t HPTR:

- Vi cht mang PVP K30 kt hp poloxamer: tan v ha tan ca FDP t

HPTR u tng ln khi tng t l PLX t 1 ln 1,5 so vi dc cht. t l 1:9:1,5

50

gia FDP: PVP K30: PLX, tan tng 3,5 ln so vi FDP nguyn liu, t l gii

phng t 55,1% sau 1 gi v sau 5 gi t 82,1%.

- Vi cht mang PEG 4000 kt hp poloxamer: tan v ha tan ca FDP t

HPTR u tng ln khi tng t l PLX t 1 ln 1,5 so vi dc cht nhng khng

nhiu, tuy nhin tc gii phng dc cht trong gi u tin li tng mnh. t

l 1:4:1,5 gia FDP: PEG 4000: PLX, tan tng 3,5 ln so vi FDP nguyn liu, t

l gii phng t 73,9% sau 1 gi v sau 5 gi t 98,6%.

- Vi cht mang PEG 6000 kt hp poloxamer: khi tng t l PLX t 1 ln 1,5 do

vi dc cht, tan ca FDP t HPTR c xu hng gim trong khi qu trnh ha

tan sau 5 gi li khng khc bit ng k. t l 1:9:1 gia FDP: PEG 6000: PLX,

tan tng 3,1 ln so vi FDP nguyn liu, t l gii phng t 62,8% sau 1 gi v

sau 5 gi t 88,2%.

xut:

- Tip tc nghin cu n nh ca HPTR bo ch c

- Tip tc nghin cu a ra cng thc HPTR ti u ng dng vo dng thuc

gii phng ko di.

- Tip tc nghin cu cc yu t nh hng n c tnh ca HPTR qui m ln

hn.

- Tin hnh bo ch vi cc phng php khc: phng php un chy, phng

php phun sy, phng php ng kh, so snh. T , ng dng m rng

qui m sn xut.

TI LIU THAM KHO

Ting Vit:

1. B mn Cng nghip Dc (2011), Qu trnh v thit b dc phm, tr.35-40.

2. B Y t (2007), Dc l hc, tp 2, Nh xut bn Y hc, tr.49.

3. B Y t (2007), Ha dc, tp 1, Nh xut bn Y hc, tr.154.

4. B Y t (2002), Dc th quc gia Vit Nam, NXB Y hc, tr.523 525.

5. Nguyn ng Ha (2000), Nghin cu h phn tn rn ca artemisinin v ng

dng mt s dng thuc, Lun n tin s dc hc, Trng i hc Dc H

Ni.

6. Nguyn Th Kim L (2009), Nghin cu bin php ci thin ho tan ca vin

nn Telmisartan 40 mg, Kha lun tt nghip dc s, Trng i hc Dc H

Ni.

Ting Anh:

7. Al- Dhalli S. (2007), Preparation and evaluation of fenofibrat gelucire 44/14

solid dispersion, Thesis for the degree of Master of Science.

8. Bristish pharmacopoeia (2009), Monographs Felodipine, 1, pp.2443-2447.

9. Chaudhary A. et al(2012), Enhancement of solubilization and bioavailability of

poorly soluble drugs by physical and chemical modifications: a recent review,

Journal of Advanced Pharmacy Education & Research, 2 (1), pp. 32-67.

10. Das S. et al (2012), Solid dispersions: an approach to enhance the

bioavailability of poorly water-soluble drugs, International Journal of

Pharmacology and Pharmaceutical Technology , 1 (1), pp.38-46.

11. Dasgupta A. et al (2012), Solubility enhancement of felodipine through solid

dispersion, International Journal of Pharmacology and Pharmaceutical

Technology, 1 (1), pp.51-52.

12. Drihendrad K. et al (2009), Solid dispersion: a review, J. Pharm. Sci., 22 (2),

pp.234-236.

13. Guleria R. et al (2012), PEG based solid dispersions of gliclazide: a

comparative study, International Journal of Pharmacy and Pharmaceutical

Sciences, 4 (1), pp.507-512.

14. Karavase E. et al (2006), Effect of hydrogen bonding interactions on the release

mechanism of felodipine from nanodispersions with polyvinylpyrolidone,

European Journal of Pharmaceutics and Biopharmaceutics, 63, pp.103114.

15. Kim J. et al (2006), Prepation of a solid dispersion of felodipine using a solvent

wetting method, European Journal of Pharmaceutics and Biopharmaceutics,

64, pp.200 -205.

16. Konno H. et al (2008), Effect of polymer type on the dissolution profile of

amorphous solid dispersions containing felodipine, European Journal of

Pharmaceutics and Biopharmaceutics, 70, pp.493499.

17. Kuchekara B. et al (2007), The effect of water soluble polymers on felodipine

aqueous solubility and complexing abilities with natural and modified -

cyclodextrin, Iranian Journal of Pharmaceutical Sciences, 3(4), pp.197-202.

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