t Nghien CIFU - Ky thuat
Pho IR cua HBBCD
Ket lu^n
Da xdy dyng vd tii u'u hoa quy trinh tong hpp 2- hydroxybutyl-beta-cyclodextrin. Dy bdo cdc yeu (6 anh hydng din phdn u-ng cua phin mem Box Behnken kieu thiet ke be mgt dap ling du'ac xac djnh: vgn toc khuay: 817,22 vong/phut, nhlet dS:
35,59''C, thdi gian: 21,67 gid phii hpp vdi kit qua ttiLFC nghidm. Da thyc hien nang cd 16 kg dO s l lii?ng phgc vg cong tac nghien ciru phat triin thuoc. San pham tong hap dat yeu cau v l cdu fruc hoa hpc, dp the va dp tmh khilt.
Summary
The synthesis of hydroxybutyl-^-eyelodextrin was optimized for the parameters of yield and substitutbn degree. Reaction factors including sSrring speed, temperature, time were optimized by the software Box-Behnken type response surface design. The optimal conditions for the reaction were defined: Stirring speed - 817.22 cpm; temperature - 35.59°C, time duration - 21.67 iTours. The obtained yield and substitution degree at the optimal set of conditions were 77.89% and 5.351. respectively. The stmctural data by IR.
Pho MS cua HBBCD
NMR, MS of the synthesized products consistently complied with the expected chemical stmeture.
Tai lieu t l i a m Iciiao 1. Ming-gang Zhao, Ai-you Hao, Jian Li, Yun-he Wei, Peng Guo (2005), "New cyclomaltoheptaose (p- cyclodexlrin) derivative 2-0-{2-hydroxybutyi) cyclomaltoheptaose: preparation and its application for the separation of enantiomers of dmgs by capillary electrophoresis", Carbohydrate Research, Volume 340, Issues, pp. 1563-1565.
2. Xiuli Lin, Chenfu Zhu, Aiyou Hao (2005),
"Enantioseparation in capillary electrophoresis using 2-0-{2-hydroxybutyl)- p -CD as a chiral selector".
Electrophoresis, 26, pp. 3890-3896.
3. Takako Ishiguro, Eri Morishita, Daisuke lohara, et al. (2011), "Some pharmaceutical and indusionproperties of 2-hydroxybutyl-p-cyclodextrin derivative'. International Joumal of Pharmaceutics, Volume419, Issues 1-2 , pp. 161-169.
4. Takako Ishiguro, Fumitoshi Hirayamaa, Daisuke loharaa, Hidetoshi Arimab, Kaneto Uekama, (2010), "Crystallization and polymorphic transitions of chlorpropamide in aqueous 2-hydroxybutyl-p- cyclodextrin solution", European Journal of Pharmaceut'icai Sciences, 39. pp 248-255.
Nghien cuu kha nang tao phii'c cua desloratadin va beta-cyclodextrin
0?t van de
Desloratadin la thuoc khdng histamin the hp
" tdc dyng kdo ddi dung chong dj dng. du'Q'c chi
•^nh Idm gidm cdc tripu chdng vidm mui dj dng
T4P CHi DUQC HQC - 10/2012 (S6 438 NAM 52)
Pham Thuy Trang, Trircnig Ngpc Tuyen Khoa Duac - Dai hgc Y-Duac TP. Ho Chi Minh
theo mua, viem mui dj dng quanh nam nhu' hdt hai so mui, ngda, nghpt mui, ... va c6 the dung cho tre em td 6 thdng tuoi. Ddy Id logi thulc khdng histamin diing pho bien hign nay.
# Nghien CCFU - Ky thuat
Desloratadin co thi bdo chl dwd\ dang S\TO dio tre em, vien nen, tuy nhien do kem tan nen da gay kho khan cho viec bao che cdc chl pham chda desloratadin. Dd co nhilu nghien cdu ve vide ket hgp gida hoat chat vdi beta-cydodextrin de cdi thign dp tan cua hogt chit. Chfnh dieu ndy da khuyin khich nghien cdu kha nang tao phdc gida desloratadin vdi beta-cyclodextrin nham muc didi' cdi thidn do tan cua desloratadin giup d i dang bao che cdc dang thuoc chda desloratadin.
Nguyen lieu va p i i u - c n g phiap nghiien CLPU
Nguyen lieu hod chat
Desloratadin. tete-cyclodextrin 03-CD) dat tieu chuan du'ac dung, cac hod chit tinh khiet dung cho HPLC, cdc dung moi nhu- ethanol, aceton dat tieu chuan phdng thi nghiem.
Phu'ang phap thirc nghiem Nghien cdn sw tao thinh phwc hap Nghien cwu sw biin dii do tan ^^-'^^
Nghien cdu nham muc dich chdng minh desloratadin cd kha nang tao phdc vd sy tao phdc gida desloratadin-^CD giup cai thien dp tan, cung qua do xac djnh tT Id tao phdc cua desloratadin-^CD. Diing lu'png du" desloratadin (100 mg) thdm vdo 50 ml nu'dc cat co chda nong dp tang dan j6-CD (1-20 mg/ml) trcing binh non co nut mdi, dem lac d nhidt do 37 ± 0,5 "C trong 7 ngay vdi may lac rung kilm sodt nhidt. Sau 7 ngay, lpc bo tua, lay djch lpc thu dwac do dp hap thu UV d budc song 240 nm vdi mSu trang id dung djch chda ning 66 ^-CD tuang dng. Mli mlu do 3 ldn vd ldy tmng binh. Ve do thj bien dli dp tan vdi true tung la dp tan cua hoat chat; true hoanh la nong dp ^-CD tuang dng.
Nghiin cCru quang phd L/V™
Nham muc dieh xac dinh ea chl tao phde dya tren do thj moi tuang quan gida nong dp, dp hap thu va budc song cyc dai. Hoa tan mpt luang desloratadin cd nong dp 1,5 mg/ ml trong ethanol va hoa tan )3-CD trong nudc elt vdi nong dp tang dan tu 5-15 mg/ ml. Cho hai dung djch vdo binh djnh mdc 50 ml, b l sung nude cat vda du. Lac rung trong 2 gid, sau dd Ipc bo tOa.
Dung djch thu duac dem qudt pho UV budc sdng td 200 nm din 400 nm, mau trang Id ning dp j8-CD tuang ung. So sanh pho thu duac vdi pho hap thu cua hoat chat
Dieu chi phwc hgp ™ Phwang phip t^o bot nhao
Can 3,40 g (0,003 md) J3-CD cho vao c6i sd nghiin mjn, thdm 1 ml nudc d t , nghien trpn thanh khii nhao. Thdm td tu 0,93 g (0,003 moi) de^oratadin va tilp tgc nghiin trpn trong 30-60 phut, them khoang 3 ml lup'ng nudc de bao dam hon hpp d?ng khoi nhao. Sly Wio d 50 "C din khoi lup'ng khong dli. Can va bao quan chong am.
Phwang phap dong kit tua « 6 hd tta eda dung moi huv ca *
Hoa tan 3,40 g (0,003mol) jS-CD trong mpt lup'ng nude eat toi thilu, nang nhi§t dd Idn 50°C de p-CD tan hoan toan. Hoa tan 0,93 g (0,003 moi) desloratadin trong mgt \wang toi thilu dung mdi thich hap (aeeton, clorofomi, diclorometan, ethanol, ethyl aeetat hogc methanol). Cho dung djch hoat ehat tu tu vao dung djeh ^-CD, Ipc bd tua niu CO, khuay trpn trong dieu kien thdi gian vd nhidt do thfch hp'p cho din khi phdc hpp hinh thanh dudi dang tua mjn. Lpe lly tua va sly khd.
Phwang phap dong bay hoi
Hoa tan 0,31 g (0,001 moi) desloratadin trong lup'ng dung mfii toi thilu (aceton, clorofonn, diclorometan, ethanol, ethyl acetat hoac methanol) va 1,14 g (0,001 moi) )S-CD dup'c hoa tan trong nudc d t . Cho dung djch ^ CD vdo dung djch desloratadin, neu c6 tOa Ipc bo tua. Djch thu dupc khuay d nhidt dd phdng trong 2 gid. Boc hai dung moi. Chit ran thu duo'c thu'dng Id hon hp'p hoat ehat, /3-CD, vd phuc hp'p hinh thanh.
Banh gia phwc hop Phan tich nhiet vl sai (DSC)
DSC dwac dOng d l xac ^nh muc dd tinh khilt eiJa cdc dup'c ehit. Phuang phdp nay dya trdn sy gidm cu'dng dd dinh npi nhidt vd gidm nhiet dp ndng chay cua cdc chat. Theo ly thuyit, khi dieu che phdc hp'p, trong phuc co 3 thanh phin: hoat chit trong phuc, hogt chit ty do vd J3- CD. Xem hogt ehit trong phdc Id tgp chit, chit ndy Idm giam nhidt dp ndng chdy oua hogt chit dgng ty do vd md rdng dinh nOi nhipt.
Phan tich phi hong ngo^i
Phan tfch vd danh gia sy thay d ^ eua cdc dinh dgc hipu cQa hogt chat dgng nguydn lipu so vdi cac dinh eOa hogt chat chda trong phdc.
T ^ CHf DirgiC HQC - 10/2012 (SO 438 N A M 52)
» Nghidn ci>u - Ky thuat
Phin tidi pho cdng hwdng ti>'^
Tiln hdnh phan tfch phi cpng hudng tu proton cho mau desloratadin dgng phuc bao vd
^ D . So sdnh sy djch chuyin hoa hoe cOa H(C3), H(C5) cda ^CD gida 2 pho do.
" ThQ'ttghi^ do hda tan Thilt bj: Mdy lie mng on nhipt.
M6i trudng: nude d t . Tic dO lie: 200 vong/phiit.
Nhi0t dO: 37 ± 0,5°C.
Cho chfnh xac 100 mg desloratadin hode phdc hpp desloratadin-^CD vdo mpt t h i tieh xdc Q\nt\ nudc d t (100 ml). Lie mng vd lly mlu sau 15, 30, 45, 60, 90 phCit. Lpc bo nhung phin khdng tan, pha loang thich hp'p vd do dp hap thu UV d budc sdng 240 nm. Tfnh phan tram dO tan tgi tdng thdi diem.
Cdng thde tfnh dp hda tan cua hogt chat d ti>ng thdi dilm:
Dt (%) = -(SOOCt + 10 ^ C() 1=1
Trong dd:
D,: d^ tan cda hoat chit (%) t^i then diim liy miut
a: Iw^g ho^t chit cho vio (mg) CI: ning dd hoat chit (pg/ml) t^i thdi diim t Q: ning d^ hoat ehit (pg/ml) tai thoi diem i Dfnh Iwgng hoat chit toin phin Phuang phdp dinh lupng: HPLC.
Thilt bj: Mdy sac ky Idng cao dp cot: CIS (25 cm X 4,6 mm, 5 ^m) Pha di^ng: Methanol : natri heptansulphonat 0,03 M : add acetic bang (70 : 30 : 4), trdn diu, IQC qua mdng Ipe 0,45 pm, sidu dm 5 phut.
Tic dO ddng: 1,0 ml/phtit.
Detector: 247 nm.
Thi tfch tiem: 20 pi.
Dung djch ttid: Hda tan chfnh xdc khoang 25 mg phdc hg'p ttong pha ddng, sau do pha loang thSnh 100 ml, lac diu, lpc qua mdng Ipe 0,45 fim.
Dung djch chuan: Hda tan chfnh xac khoang 25 mg desloratadin ehuan trong pha dpng, sau 46 pha lodng thdnh 100 ml, lie deu, Ipc qua mdng [pc 0,45 pm.
Tidm 6 l l n dung djch ehuln vd 2 l l n dung djch ttid.
T*P CHf DlTQC H O C - 1 0 / 2 0 1 2 ( S 6 438 NAIVI 52)
Ham lup'ng desloratadin dupc tinh theo cong thde:
S^xM,x(lOO~N) Trang do:
Si: Diin tich pic desloratadin tmng phdc hop cua dung djeh thw
Sc: Diin tich pic desloratadin eOa dung djch chuin
M,: Khoi IwQfng phwc hop (mg) Mc: Lwqng cin desloratadin chuin (mg) C%: Him Iwgng desloratadin ehuin N (%): Ham IwQfng nwde eOa phdc hpp.
Ket qud va ban lu^n
Ket qua nghien cdu SLP bien doi dp tan
Hi n h 1: D6 thi bien doi di tan eua desloratadin
Do thj biin ddi dd tan cCia desloratadin la mpt dudng cong hudng ngang, do thj c6 dgng AN, dieu nay chdng td ning dd desloratadin tan kdm khi cdng tdng ning dp j6-CD.
P B ^ n Y _[D/CD]_ Slope _ CD (1-Slope) Cl-0.140')
D : C D = 1 : ( U ^ ) = 1 7,25
Nhu vdy trung binh cd 7 phan td /3-CD tan trong nude se cd 1 phan td j8-CD kit hpp vdi phdn td hoat chit kdm tan de hinh thdnh phde hap cachlt/CD tiid 1:1.
Ket qua nghidn cdu quang pho UV Khi tang ning dp cCia jS-CD thi dO hap thu eOa desloratadin tdng theo nhung khdng ed sy ehuyln djch budc sdng cyc dgi Amax. nhu vdy chdng to sy hinh thdnh phde hp'p vdi J3-CD theo ca che ehCi thi-khdch thi.
• Nghien CIFU - Ky thuat
Hinh 2: Pho hip thu UV cda desloratadin thay doi theo nong do ctia /3-CD
Dieu c h l phdc chat gida desloratadin va p-CD
Phwong phap tao bdt nhao
San phim sau khi d y d 50*'C din khdi iug'ng khdng doi thu dupc bpt mdu trang hdng, cd nhidt dO ndng ehay 250-253**C.
Phwong phap dong kit tOa c6 h6 trqr cua dung mdi hwu cc
Trong cdc dung mdi duac chpn thd nghiem gom aeeton, eloroform, diclorometan, ethanol, ethyl acetat hode methanol thi ethanol la dung mdt cho sdn phim tua nhleu nhit. Sau khi Ipe dudi ap suat giam, d y san pham d 50°C den khoi lupng khdng doi. San pham la bpt mau trang, nhi^ dd ndng ehay 250-253°C.
Phwong phap dong bay hoi
Sau khi boc hai logi dung mdi, sdn pham thu dupc dgng bpt mjn, mau hong nhgt, nhiet dp ndng chdy 25(i-253°C.
Cac san pham nay dup'c dem chdng minh sy tgo phde bdng cac ehi tieu dudi day.
Danh gia sir hinh thanh phdc hgp Kit qua phan tich nhiet vi sai
Hinh 3: Giin do nhiit vi sai ciJa desloratadin, 0-CD, phOc desloratadin- fiCD
Td gidn do nhidt vi sai cOa desloratadin, j8- CD vd phdc desloratadin- j8CD cho thay pho phdn tieh nhipt cda desloratadin ed mOt dinh npi nhi#t d 158,25°C tuang dng vdi nhiet dp nong chay cua desloratadin. Phi phdn tich nhidt cua
^ C D cd vCing dinh npi nhi^t td 68°C den 140,1°C tuang ung vdi qua trinh dehydrat hda (khoang 12%). Pho phdn tfch nhiet cua phue hpp khong cdn thay dinh n0i nhidt cua desloratadin nda va dinh npi ntiiet cua ^CD cung gidm ve cudng dp va nhidt dO rit nhilu.
Kit qud thu dup'c cho thay cd sy tuang tdc gida desloratadin vd 0-CD: phdn td desloratadin bj bat giu trong khoang rong cOa p-CD vd tao thdnh phde bao desloratadln-^-CD.
Kit qua phan tich pho hing ngo^i So sdnh pho eua desloratadin va phdc desloratadin-/3-CD ta thiy phin Idn cae dinh cua desloratadin trong phde hp'p bj che lip bdi ^CD vd cd sy djch chuyen cung nhu gidm cudng dp cda ede dinh dgc trung cho desloratadin.
Bdng 1: Sw thay doi mgt so dinh die tnmg cOa desloratadin khi tao phOv
NhdmchUc N-H C=C C=N Desloratadin 2802.4 1635,5 1585,4
OCI 779,2 Desloratadin-pCD 2854,5 1652,9
Kit qua phan tich ph6 c^ng hwdng fd So sanh pho ^H-NMR cua phdc desloratadin-
^CD vd /3-CD chuan.
Kit qua pho ^H-NMR cho thiy dp chuyen djch hda hpc cua H(C3) vd H(C5) bj thay doi ve phfa vCing tu trudng thlp han chdng to H(C3), H(C5) da bj gidm chin, nhu vgy cd sy slp x i p Igi ve cau trde khdng gian eua cdc nguyen tu trong khoang ciia J3-CD, tu dd cho thiy cd sy hinh thdnh phdc hp^p giua desloratadin vd j6-CD.
Trdn phi con thay mpt s l dinh cua desloratadin nhu vdy mpt phin phan td desloratadin da di vao khoang cOa /3-CD.
Bdng 2: Sw djeh chuyin hda hgc ciia H(C3) va HC5) tmng khoang ^-CD
Mu
E)$ djch chuySn h<5a hgc (ppm)
f-CD chuin H(C3) H(CS)
3,32 3,35 Desloratatiln-
P-CD H(C3) H(CS)
3,35 3,37
TAP CHf DiraC HOC -10/2012 (S6 43S NAM 52)
» Nghien ciru - Ky thuat
Kit qua thd nghifm d$ hda tan DO hda tan cua phdc desloratadin- ^CD tdng so vdi desloratadin nguydn lidu d mpi thdi diem, a^c bipt Id thdi dilm cuoi thd nghipm. Dieu nay ctiLPng td sy tao phdc cd khd nang lam tang dp tan cila desloratadin.
Bang 3: 00 hda tan cua desloratadin vi desloratadin trong phwc & tdng thdi diim
BQ hda tan (%) Thai gian (phut)
Desioratadjn Piitjc desloratadin- /}CD
15 1,98 2,29
30 45 60 2,00 2,40 2,50 2,48 2,83 2,97 90 3,19 4,53
' • - P h i l r c DaloiaUulln-p<
Ket qua djnh luvng
Bdng phuang phdp HPLC, xdc ^nh hdm Itrpng desloratadin trong phde tao bdi phuang phap dong ket tua cd hd trp dung mdi hdu ca ethanol la 90,15%.
Kit qua va ban luan
Ti> ede kit qud thu dupe d tren, cd the kit lu|n desloratadin c6 kha nang tgo phdc vdi y3- CD vdi ti le 1 : 1 d ede phuang phdp khde nhau nhu tgo bdt nhao, dong ket tua cd h i trp dung mfii, dong bay hai vd cho phde hpp cd dO tan cSl thi$n han nhieu so vdi desloratadin dgng ty do. Sy cdi thidn dd tan cCia desloratadin thdng qua tgo phdc da dup'c chdng minh bdng thyc nghidm. Va d l dp dgng dupc trong bdo ehl
<l?ng vidn nen hay nang cdng thi phuang phdp tw bdt nhao Id phCi hpp nhit, vi phuang phap i^y cd ttil thye hipn ngay trong giai dogn xdt W^cat mfoc HOC -10/2012 (s6 438 NAIVI 52)
hat udt ma khdng cin them mpt cong dogn nao trong qud trinh bao chl. Cdn doi vdi dgng siro thi cung cd the sd dung phuang phap tgo bpt nhao roi sau dd phan tdn trong dung mdi thfch hap.
Summary
To improve the solubility and stability of the new well-effective anti-allergic desloratadine of undesirable water-insolubility and photo- unstability, an inclusion complex of it was prepared with beta-cyclodextrlne (^-CD) by co- precipitation in distilled water (or other suitable solvents), in form of slurry between desloratadine and beta-cyclodextrlne (p-CD) and evaporating with suitable solvents. By differential scanning calorimetry diagram (DSC), IR, ^H-NMR, quantitative analysis and dissolution tests, the formation of desloratadine-p-CD inclusion complex was proved, changes in solubility after entering p-CD rings was confirmed. These suggested the application of making slurry between desloratadine and P-CD to formulation of anti- allergic film-coated tablets, hard-capsules or symps of desloratadine.
Tai lieu tham khao 1. Allan R. Hedges (1998), "Industrial /Application of Cyclodextrins", Chemical Reviews, 98, 2035-2044.
2. Loflsson T., Brewster M. E. (2007),
"Cyclodextrins as pharmaceutical solubilizers", Advanced dmg delivery reviews. 59, 645-666,
3. Loftsson T, Hreinsdottir D„ Masson M. (2007),
"The complexation efficiency", Journal of Inclusion Phenomena and MacrocycHc Chemistry, volume 57.
4. S. M. Badr-Eldin et at. (2008), "Inclusion complexes of tadalafil with natural and chemically modified /?-cyclodextrin. I: Preparation and in-vitro evaluation", European Journal of Pharmaceutics and Biopharmaceutics. 70.
5 Amber Vyas, Shallendra Saraf, Swarnlata Saraf (2008), "Cyciodextrin based novel drug delivery systems", Joumal of Inclusion Phenomena and Macrocycl'ic Chemistry, 62, 23-42.
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