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    E L S E V I E R Journa l o f Con t ro l led Release 33 ( 1995 ) 143-152

    j o u r n a l o fc o n t r o l l e d

    r e l e a s e

    S t ru c tu r e a n d b e h a v i o u r i n h y d r o p h i l ic m a t r ix su s t a i n e d r e l e a sed o sa g e f o r m s: 3 . T h e i n f l u e n c e o f p H o n t h e su s t a i n e d - r e l e a se

    per formance and interna l ge l s t ruc ture o f sod ium a lg ina te matr icesA l i s o n C . H o d s d o n a, J o h n R . M i t c h e l lb, M a r t y n C . D a v i e s a, C o l i n D . M e l i a a '*

    aDepartment of Pharmaceutical Sciences, Nottingham University, Nottingham NG7 2RD, UK"Department of Applied Biochemistry and Food Science, Nottingham University, UniversityPark, Nottingham NG7 2RD, UK

    Receiv ed 4 Janua ry 1994; accepted 6 July 1994

    A b s t r a c t

    The effec t of pH and drug solubi li ty on the re lease kine tics o f sodium a lgina te m atrices has been studied. R elease of a highlysoluble model drug, chlorpheniramine maleate, was significantly faster in simulated gastric fluid (SGF) than in simulatedintestinal f lu id (S IF ) , whereas the oppo si te e ffec t was ob served for hydrochlorothiaz ide , a drug o f poor solubi li ty . These resul tscould be exp la ined in te rms o f the interna l micro scopic st ruc ture of the hydra ted surface layer form ed on matr ix hydra t ion andby the di f ferent hydra t ion kine t ics of the polym er in these tw o media . Cryo genic e lec t ron micro scop y revealed the hydra tedsurface layer formed by a lgina te matr ices in SGF to be par t icula te and porous in na ture , in cont rast to the highly hydra tedcont inuou s ge l layer formed in S IF. Dru g re lease m echanism s were discussed wi th respect to drug solubi li ty and the st ruc tureand propert ies of the surface layers form ed by a lgina te matr ices when hy dra ted in di f ferent pH media .Keywords: Sodium a lg ina te ; Hydrophi l ic m at r ixes ; Sus ta ined re lease ; Table t; Cryogenic scanning e lec t ron microscopy; Hydra t ion ; pH

    1 . I n t r o d u c t i o n

    S o d i u m a l g i n a t e is a n a tu r a l h y d r o p h i l i c p o l y s a c c h a -r i d e d e r i v e d f r o m s e a w e e d . T h e a b i l it y o f t h is p o l y m e rt o r a p i d l y f o r m v i s c o u s s o l u t i o n s a n d g e l s o n c o n t a c tw i t h a q u e o u s m e d i a h a s b e e n e x p l o i t e d b y t h e p h a r -m a c e u t i c a l i n d u s t r y , i n i t s w i d e a p p l i c a t i o n a s a c a r r i e ri n h y d r o p h i l i c m a t r i x c o n t r o l l e d r e l e a s e o r a l d o s a g ef o r m s . M a t r i c e s i n c o r p o r a t i n g e i t h e r a s i n g l e a l g i n a t es a lt o r a c o m b i n a t i o n o f s al ts h a v e b e e n e m p l o y e d t os u c c e s s f u l l y s u s t a i n r e l e a s e o f m a n y d r u g s i n v it r o a n di n v i v o [ 1 - 4 ] .

    D r u g r e l e a s e f r o m h y d r o p h i l i c m a t r i x t ab l e ts i s c o n -t r o ll e d b y t h e f o r m a t i o n o f a h y d r a t e d v i s c o u s l a y e r* Correspon ding au thor .

    016 8-36 59/95 /$09 .50 1995 Elsev ie r Sc ience B.V. Al l r igh ts reservedSSDIOI68-3659(94)OOO76-X

    a r o u n d t h e t a bl e t, a f t e r i n g e s t io n o f t h e d o s a g e f o r m[ 5 , 6 ] . T h e s u r f a c e l a y e r a c ts a s a b a r ri e r t o d r u g r e l e a s eb y o p p o s i n g p e n e t r a t i o n o f w a t e r i n t o t h e t a b le t a n da l so t h e m o v e m e n t o f d i s s o l v ed s o l u te s o u t o f th em a t r i x [ 7 ] . W a t e r - s o l u b l e d r u g s a r e r e l e a s e d p r i m a r i l yb y d i f f u s i o n o f d i s s o l v e d d r u g m o l e c u l e s a c r o s s t h e g e ll a y e r , w h i l s t p o o r l y w a t e r - s o l u b l e d r u g s a r e r e l e a s e dp r e d o m i n a n t l y b y e r o s io n m e c h a n i s m s [ 8 ] . T h e c o n -t r ib u t i o n o f e a c h r e l e a s e m e c h a n i s m t o t h e o v e r a l l d r u gr e l e a s e p r o c e s s i s i n f l u e n c e d b o t h b y d r u g s o l u b i l i t ya n d a l s o b y t h e p h y s i c a l a n d m e c h a n i c a l p r o p e r ti e s o ft h e g e l b a r r i e r t h a t f o r m s a r o u n d t h e t a b l e t .

    S o d i u m a l g i n at e i s t h e s o d i u m s a l t o f a l g i n ic a c i d[ 9 ] , a h i g h m o l e c u l a r w e i g h t l i n ea r r a n d o m c o p o l y m e rc o n s i s t i n g o f b l o c k s o f 1 --->4 , l i n k e d D - m a n n u r o n i c

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    2 .2. M a t r i x p r e par a t i onc id (M M ) and L-gu lu ron ic ac id r e s idues (G G ) , inadd i t ion to r eg ions in w h ich the tw o u ron ic ac id r e s i-dues a l te rna te [10 -13 ] . By v i r tue o f the ca rboxy lg roups on the co mp onen t u ron ic ac id r e s idues , the pKaof a lg in ic ac id r anges be tw een 3 .4 and 4 .4 , depend ingon the type of a lg inate and the sa l ts present in themix tu re [ 14 ] . There fo re , changes in pH over the r eg iono f pH 3 to 4 , f rom more neu t r a l pH va lues, in f luencepo lymer hyd ra t ion and a lg ina te ge l rheo logy , due tothe r eady in te r conver s ion o f ca rboxy la te an ions( s od ium a lg ina te ) to f r ee ca rboxy l g roups ( a lg in icac id ) , a s the concen t r a t ion o f hyd rog en ions inc reas es[ 15 ,16 ] . A t neu t r a l pH s od ium a lg ina te i s s o lub le andhydra tes to fo rm v i s cous s o lu t ions , bu t be low pH 3 ,a lg in ic acid , water swel lable but insoluble , i s rapid lyfo rmed . S ince the hy d ra t ion cha rac te r is t i cs o f the po l -ymer and the s ubs equen t phys ica l p roper t i e s o f thehydra ted ge l l aye r m ay c r i t ica l ly in fluence d rug r e lease[17 ] , any change in the p roper t i e s o f the hyd ra teds u r f ace l aye r caus ed by a change in pH , i s l ike ly toin f luence the pe r fo rm ance o f s od ium a lg ina te as a s us -ta ined re lease car r ier .

    Th i s paper s tud ies the e f f ec t o f pH on the r e leas e o ftw o d rugs o f d i f f e r ing w a te r - s o lub i l i ty f rom s od iumalg ina te ma t r i ces. C ryo gen ic s cann ing e lec t ron mic ros -copy ( c ryo -S EM ) and l iqu id up take s tud ies w ereemployed to exp la in the pH -dependen t d i f f e r encesobserve d in drug re lease , in terms of the in ternal micro-s cop ic s t ruc tu re o f the ge l l aye r and the hyd ra t ion k ine t -i c s o f the po lymer .

    100-

    a 0 -

    6 O -

    .~ 4O

    .L.2O -

    O01

    Tab le t s w ere p repa red co n ta in ing 49% s od ium a lg in -a te , 20% d rug , 30 .25% lac to s e and 0 .75% w /w mag-nes ium s tea ra te , by mix ing the pow der s fo r 15 minwitho ut lubr icant and for a fur ther 5 m in af ter addi t iono f m agnes ium s tea ra te . The b lends w ere d i r ec t ly com-pres sed on a M anes ty F 3 s ing le punch t ab le t ingmach ine u s ing 11 m m d iamete r f l a t - faced punches , toa w eight o f 350 m g an d a c om press ion force o f 40___ 2kN (6 -7 kg t ab le t ha rdnes s ) . P u re po lym er tab le ts w erea l s o manufac tu red , to a compres s ion fo rce o f 15 + 0 .5kN , eq uiva len t to a tab let poro sity o f 34.5 ___ 1% (6 .8 -

    8 0 '

    60 "=,

    ._~ 40"Sm

    O. 2O"

    V S1F ( pH 7.5 )

    T i m e ( H o u r s )

    F i g . 1 . E f f e c t o f p H o n t h e r e l e a s e o f c h l o r p h e n i r a m i n e m a l e a t e f r o ms o d i u m a lg i n a te m a t r ic e s ( m e a n ( n = 6 ) + 1 SD ; f o r S G F re s u l ts , a l lS D < 2 % ) .

    2 . M a t e r i a l s a n d m e t h o d s

    2.1 . Mater ia l sS o d i u m a l g i n a t e ( K e l t o n e H V TM, K elco , D iv i s ion

    o f M erck , S an D iego , CA ) w as u s ed as s uppl i ed. Ch lo r -phen i r amine ma lea te (S igm a Chem ica l Co . , S t. Lou i s ,M O ) , h y d r o c h l o r o t h i a z i d e ( L a n c a s t e r R e s e a r c hChemica l s , M orecambe , U K ) , l ac to s e f a s t - r io U S P( Z e p a r o x , L a c t o c h e m , C h e s t e r, U K ) a n d m a g n e s i u ms tea rate BP (BD H , P oo le , U K ) w ere u s ed in the pa r -t i c le s ize r ange 125 -180 /xm, ob ta ined by s i ev ing . S im-u la ted gas tr i c f lu id U S P (S G F ) and s imu la ted in te s tina lf lu id U S P (S IF ) w i thou t enzym es , w ere u s ed in thehydra t ion s tud ies and as the d i s s o lu t ion med ia .

    0 ~ "

    " -- '11-- SIF (pHT .5)

    1 2 3

    1 4 4 A . C . H o d s d o n e t a l . / J o u r n a l o f C o n t r o l l e d R e l e a s e 3 3 ( 1 9 9 5 ) 1 4 3 - 1 5 2

    0. sS q u a r e r o o t o f t i m e ( H o u r s )

    F i g . 2 . R e l e a s e o f c h l o r p h e n i r a m i n e m a l e a t e , p l o tt e d a s a f u n c t i o n o ft h e s q u a re r o ot o f t i m e ( m e a n ( n - - - 6 ) + 1 S D ) .

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    A.C. Hodsdon et al. / Journal of Controlled Release 33 (1995) 143-152 1457 . 3 k g t a b l e t h a r d n e s s ) , f o r c r y o - SE M a n d l i q u i dup take s tud ies .2.3. Dissolution studies

    D r u g r e l e a s e w a s m e a s u r e d u s i n g t h e r o ta t i n g b a s k e td i s s o lh t i o n me t h o d ( U SP d i s s o l u t io n a p p a r a t u s 1 ) a t ab a s k e t r o t a ti o n s p e e d o f 1 0 0 r e v mi n - 1, i n 9 0 0 m l SG F( p H 1 .2 ) o r S I F ( p H 7 . 5 ) , a t 3 7 C . C h l o r p h e n ir a m i n em a l e a t e c o n c e n t r a t i o n w a s m e a s u r e d s p e c t r o p h o t o -me t r i c a l l y a t 2 6 4 n m a n d 2 6 1 n m i n SG F a n d S I Fr e s p e c t i v e l y , a n d h y d r o c h l o r o t h i a z i d e c o n c e n t r a t i o n a t2 71 n m, i n b o th me d i a . R e s u l t s a re s h o w n a s a me a n + 1SD of s ix t ab le t s .2.4. Cryogenic scanning electron microscopy (cryo-SEM)

    T a b l e t s w e r e h y d r a t e d i n SG F o r S I F a t 3 7 C u s i n gt h e d i s s o lu t i o n a p p a r a t u s . A f t e r 1 h , s a mp l e s w e r e c a r e -f u l l y r e mo v e d f r o m t h e b a s k e t s a n d s e c t i o n e d t h r o u g ha n u n d i s t u r b e d p o r t i o n o f th e g e l f o r me d f r o m t h e f i a t

    f a c e o f t h e t ab l e t. T h e s p e c i m e n w a s t h e n p o s i t i o n e do n t h e s a m p l e h o l d e r, s o a s t o p r e s e n t a c r o s s - s e c t i o no f t h e t a b l e t t o t h e mi c r o s c o p e . T h e s a mp l e w a s t h e nr a p id l y f r o z e n i n n i tr o g e n sl u sh ( - 2 1 0 C ) , f r e e z e -f r a c t u r e d w i t h a c o l d k n i f e , e t c h e d u n d e r v a c u u m( - 8 0 C ) a n d g o l d - co a t e d . I m a g e s w e r e o b t a in e d a t2 5 k e V o n a Ph i li p s 5 0 5 s c a n n i n g e l e c t r o n mi c r o s c o p ee q u i p p e d w i t h a H e x l a n d C T I 0 0 0 c r y o s t a t i o n , m a i n -t a in ing the spec ime n a t - 180C th roughou t .

    2.5. Liquid uptake studies

    T a b l e t h y d r a t i o n k i n e t i c s w e r e i n v e s t i g a t e d u s i n g t h el iq u i d v o l u m e u p t a k e me t h o d o f W a n e t a l. [ 1 8 ] . T h eappara tus cons i s t ed o f a s in te red g lass f i l t e r over l a idw i t h w e t f i l te r p a p e r a n d c o n n e c t e d t o a h o r i z o n t a lg r a d u a t e d c a p i l l a r y c o n t a i n i n g e i t h e r SG F o r S I F . T h ew h o l e a s s e mb l y w a s e q u i l i b r a t e d a n d ma i n t a i n e d a t3 7 C a n d c o v e r e d t o p r e v e n t e v a p o r a t i o n . S i n g l e t a b l e t sw e r e p l a c e d c e n t r a l l y o n t h e f i l t e r a n d t h e v o l u me o fl iqu id t aken up in to the s ing le face o f the t ab le t in

    Fig. 3. Micrographof the outer 1 mm o f the surface hydrated layer of a sodiumalginate ablet, hydrated for 1 h in S F ( X 101 ).

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    146 A.C. H odsdon et al. / Journal of Controlled Release 33 (1995 ) 143-152c o n t a c t w i t h t h e f i l t e r , w a s mo n i t o r e d o v e r o n e h o u r .Re s u l t s a r e s h o w n a s a m e a n _ 1 SD o f f iv e t a b le t s .

    3 . R e s u l t s a n d d i s c u s s i o n

    3 . 1 . E f f e c t o f p H o n t h e r e l e a s e o f a h i g h l y w a t e r -s o l u b le d r u g f r o m a l g i n a te m a t r i c e s

    T h e r e l e a s e p r o f i l e s o f c h l o r p h e n i r a mi n e ma l e a t ef r o m s o d i u m a l g i n a t e ma t r i c e s , i n to SG F ( p H 1 .2 ) a n dSIF (pH 7 .5 ) a re shown in F ig . 1 . Bo th the in i t i a l ra t eo f d r u g r e l e a s e , a n d t h e o v e r a l l s h a p e o f t h e r e l e a s ep r o f i le s d i f fe r e d m a r k e d l y i n t h e t w o d i f f e r e n t me d i a .T h e d i f f e r e n c e s w e r e ma n i f e s t i mme d i a t e l y , w i t h d r u gr e l e a s e b e i n g s i g n i f ic a n t l y mo r e r a p i d i n t o SG F w i t hi nt h e f ir s t h o u r o f d i s s o l u t io n ( M a n n - W h i t n e y U t e s t;P < 0 .01 ) . The r e l ease p ro f i l e a t pH 7 .5 was l inear wi tht i me u p t o 4 h , w h e r e a s a t p H 1 . 2 , d r u g r e l e a s e w a sl i n e a r w i t h t h e s q u a r e r o o t o f t i me ( F i g . 2 ) u p t o 8 0 %drug re l ease . Th i s l as t f ind ing sugges t s tha t in ac id pH

    t h e r e le a s e me c h a n i s m i s p r e d o m i n a n t l y d i f f u s i o n - c o n -t r o l l e d [ 1 9 , 2 0 ] , w h e r e a s a t p H 7 . 5 , d e v i a t i o n f r o ml inear i ty o f the roo t t ime p lo t , i nd ica tes s ign i f i can t con-t r ib u t io n f r o m o t h e r r e l e a s e me c h a n i s m s , s u c h a s e r o -s i o n [ 2 1 ] .

    Drug so lub i l i ty s tud ies conf i rmed tha t ch lo rphen i -r a mi n e m a l e a t e r e ma i n e d h i g h l y s o l u b l e i n b o t h b u f f e r s(de te rm ined to be 225 g 1 - ~ in SGF and 201 g 1 -1 inS I F , 3 7 C) , me a n i n g d r u g d i s s o lu t i o n w a s u n l i k e l y t ob e r a t e - l i m i t in g i n e i th e r me d i u m [ 7 ] . H e n c e , a l t h o u g ht h e s e e f f e c t s ma y h a v e b e e n p a r t l y d u e t o d i f f e r e n c e sin d rug so lub i l i ty , c ryo-SEM resu l t s ind ica te tha t thed i f f e r e n c e s o b s e r v e d ma y b e mo r e a r e s u lt o f a c h a n g ein the qua l i ty and in teg r i ty o f the ge l bar r i e r fo rm edu n d e r a c i d c o n d i t io n s . T h e c o n v e r s i o n o f s o d i u m a l g i n -a t e t o a lg i n i c a c id a t l o w p H i s k n o w n t o d i r e c t l y a f f e c tp o l y m e r s o l u b i l i t y a n d r h e o l o g y . C r y o - S E M m i c r o -g r a p h s o f t h e i nt e r n al m o r p h o l o g y o f s o d i u m a l g i n a t et a b l e ts a f t e r 1 h o u r h y d r a t i o n i n SG F a n d S I F a r e s h o w nin Figs . 3 - -6 . The se i l lu s t ra t e the micro scop ic s t ruc tu re

    Fig. 4. Micrograph at higher m agnificationof the inner hydrated regions of a sodium alginate ablet, hydrated for 1 h in S IF ( 40 6).

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    A . C . H o d s d o n e t a l. / J o u r n a l o f C o n t r o l l e d R e l e a s e 3 3 ( 1 9 9 5 ) 1 4 3 - 1 5 2 147

    Fig. 5. M icrograph of the o uter 1 m m of the surfac e hydrated layer on an alginate ablet, hydrated for 1 h in SG F ( X 101 ).o f d i f f e r e n t r e g i o n s o f t h e t a b l e t g e l l a y e r u n d e r d i f f e r -e n t c o n d i t io n s o f p H .

    F i g . 3 i s a l o w m a g n i f i c a t i o n mi c r o g r a p h o f t h e o u t e r1 m m o f t h e s u r f a c e g e l l a y e r o f a s o d i u m a l g i n a t e t a b le th y d r a t e d i n S I F . T h e r e i s e x t e n s i v e i c e c r y s t a l f o r ma -t i o n , r e p r e s e n t i n g a h i g h l e v e l o f h y d r a t i o n , a t t h ep e r i p h e r y o f t h e o u t e r g e l s u r f a c e . A t h i g h e r ma g n i f i -c a t i o n s , t h e i n n e r g e l r e g i o n s s h o w l e s s e x t e n s i v e a n dl e s s h o m o g e n e o u s h y d r a t i o n ( F i g . 4 ) . T h i s o v e r a l ls t r u c tu r e o f t h e g e l l a y e r i s t y p i c a l i n a p p e a r a n c e o f t h ec o n t i n u o u s , v i s c o u s s u r f a c e g e l l a y e r f o r m e d f r o m p a r -t i c l e s t h a t a r e h y d r a t i n g a n d c o a l e s c i n g , a s o b s e r v e dp r e v i o u s l y i n o t h e r h y d r o p h i l i c m a t r i x s y s t e m s [ 2 2 ] .

    I n t h e c a s e o f h y d r a t i o n o f a s o d i u m a l g i n a t e t a b l e ti n SG F , o n r e t r i e v a l o f t h i s t y p e o f t a b l e t f r o m t h ed i s s o l u t i o n v e s s e l , t h e o u t e r h y d r a t e d s u r f a c e l a y e rf o r me d a r o u n d t h e t a b l e t c o u l d b e s e e n , b y e y e , t op o s s e s s a v e r y d i f f e r e n t c o n s i s t e n c y t o t h a t f o r me da r o u n d s o d i u m a l g i n a t e t a b l e t s w h i c h w e r e h y d r a t e d i nS I F . T h e S G F - h y d r a t e d l a y e r w a s n o t v i s c o u s a n d a d h e -s i v e in n a t u r e , b u t p o s s e s s e d a t o u g h a n d r u b b e r y t e x -

    t u r e . T h e o u t e r mo s t g e l f o r me d a t o u g h ' r i n d ' w h i c ha l w a y s s e p a r a t e d f r o m t h e g e l b u l k o n c r y o - s e c t i o n i n g .

    Figs . 5 and 6 show the in te rna l s t ruc tu re o f theh y d r a t e d s u r f a c e l a y e r o f a s o d i u m a l g i n a t e t a b l e t ,h y d r a t ed i n S G F . L o w m a g n i f ic a t io n m i c r o g r a p h s o ft h e o u t e r 1 m m r e g i o n o f t hi s la y e r ( F i g . 5 ) s h o w e d i tt o b e c o m p o s e d o f a ma t r i x o f f i b r o u s a l g in a t e p a r t i c le sa n d h i g h e r m a g n i f i c a t i o n s r e v e a l e d t h e p r e s e n c e o f i cec r y s t a l s i n t e r s p e r s e d b e t w e e n d i s c r e t e , r e c o g n i s a b l ep o l y m e r f ib r e s. T h i s s t r u c tu r e w a s a p p a r e n t t h r o u g h o u tt h e g e l ; F i g . 6 c l e a r l y s h o w s h o w p a r t i c le s o f p o o r l yh y d r a t e d p o l y me r a r e b o u n d e d b y a r e a s o f i c e c r y s t a lg r o w t h , w h i c h r e p r e s e n t a h i g h l y h y d r a t e d ( d i l u t e ) g e l .T h e p r e s e n c e o f t h is d i l ut e g e l i n d i c a t e s t h a t e v e n u n d e ra c i d c o n d i ti o n s , s o m e o f th e p o l y m e r h a s d i s s o l v e d a n da p p e a r s t o f o r m a n i n te r s ti ti a l ' g l u e ' b e t w e e n t h e p o o r l yh y d r a t e d r e g i o n s . T h i s s t r u c t u r e e x p l a i n s w h y p u r ea l g i n a te t a b l e t s f o r me d a c o h e r e n t s u r f a c e b a r r i e r l a y e rw h i c h h e l d t o g e t h e r , i n a n e n v i r o n me n t i n w h i c h d i s -i n t e g r a ti o n w o u l d o t h e r w i s e b e e x p e c t e d .

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    148 A . C . H o d s d o n e t a l. / J o u r n a l o f C o n t r o l l e d R e l e a s e 3 3 ( 1 9 9 5 ) 1 4 3 - 1 5 2

    Fig. 6. M icrograph of inner hydrated regions of an alginate ablet, hydrated for 1 h in SG F ( 20 3).A t p H 1 . 2 , s o d i u m a l g i n a t e i s r a p i d l y c o n v e r t e d t o

    a lg in ic ac id , wh ich has the ab i l i ty to swel l on hydra t ionbu t which i s v i r tua l ly inso lub le . The genera t ion o fswel l ing fo rces wi thou t su r face s t i ck iness i s the bas i sfo r the use o f a lg in ic ac id as a t ab le t d i s in teg ran t . Ino r d e r t o f o r m t h e d i l u t e g e l s e e n i n t h e mi c r o g r a p h ,s o m e d i ss o l ut io n o f t h e p o l y m e r m u s t h a v e o c c u r re dand i t i s pos tu la t ed tha t th i s may be the resu l t o f at e mp o r a r i l y r a i s e d p H w i t h i n t h e h y d r a t in g m a t r i x a s ar e s u l t o f t h e i n t r i n s i c b u f f e r i n g c a p a c i t y o f s o d i u malg ina te [ 23 ] . T he overa l l resu l t i s an in tac t , bu t re l a -t i v e l y p o r o u s , c o m p o s i t e h y d r a t e d l a y e r , i n w h i c h m u c ho f t h e p o l y m e r i s u n d i s s o l v e d a n d d o e s n o t c o n t r i b u t et o t h e d i f f u s i o n a l b a r r i e r . T h e f a s t e r d r u g r e l e a s eo b s e r v e d a t p H 1 .2 i s t h e r e f o r e a l mo s t c e r t a i n l y a re f l e c-t io n o f t h e i n f e r i o r b a r r i e r p r o p e r t i e s o f t h is c o mp o s i t el a y e r , r e la t i v e t o t h o s e o f t h e c o n t i n u o u s g e l l a y e rf o r me d a t p H 7 . 5 . T h i s p r o p o s a l i s r e i n f o r c e d b y t h ef a c t t h a t a l g i n a t e ma t r i c e s in SG F r e l e a s e d CPM mo r er a p i d l y t h a n t h e y d i d i n S I F , e v e n t h o u g h t h e y w e r ec o m p e t i n g a g a i n s t s i g n i f ic a n t l y f a s te r - e r o d i n g s y s t e m s

    i n S I F , a n d f u r t h e r s u p p o r t in g e v i d e n c e i s p r o v i d e d b ythe l iqu id up take s tud ies .

    T h e g e l l a y e r a l s o p r o v i d e s a b a r r i e r to t h e i n g r e s s o fhydra ted l iqu id in to the co re . F ig . 7 shows how ac id ic

    3O

    2 0

    1 0 . - - - - O - - S G F ( p H { 2 )~.

    2' ,'o e'oT i m e ( M i n u t e s )

    Fig. 7 . E f f e c t o f p H on liquid uptake into sodium alginate tablets( m e a n ( n = 5 ) 1 S D ; f or S G F re s ul ts , a l l S D < 3 % f r om 1 0 ~ 0r a i n ) .

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    A.C. H odsdon et al. / Journal o f Controlled Release 33 (1995) 143-152 149

    F i g . 8 . M i c r o g r a p h o f the outer surface hydrated layer o f a chlorpheniraminemaleate-containingalginate matrix, hydrated for 1 h i n S G F( X 406).m e d i u m w a s a b s o r b e d s i g n i fi c a n tl y m o r e q u i c k l y( M a n n - W h i t n e y U t e st ; P < 0 .0 1 , a t 1 0 - 6 0 m i n ) , i n t os od i um a l g i na t e t ab l e t s t han i t s neu t r a l coun t e rpa r t ,wh i ch s ubs t an t i a t e s t he p ropos a l t ha t a m ore po rous ,l e s s r e t a rd i ng ba r r i e r l aye r i s fo rm ed a round a l g i na t et ab l e t s hyd ra t ed a t pH 1 .2 .

    W h i l s t p u r e p o l y m e r c o m p a c t s m a y b e u s e d t o il lu s -t r at e t h e b e h a v i o u r o f t h e p o l y m e r i n a m a t r ix u n d e r -go i ng hyd ra t i on , t he a l g i na t e m a t r i ces u s ed i n t hed i s s o l u t i on s t ud i es a l s o con t a i ned d rug and t ab l e t i ngexc i p i en t s who s e p res en ce m a y a l s o i n f luence the t ab l e thyd ra t i on ch a rac t e r i s t i c s and t he p roper t i e s o f t he s u r -f ace ge l l aye r . Th ere fo re , t he i n t e rna l s truc t u re o f t heg e l f o r m e d a r o u n d t h e s e m a t r ic e s , w h i c h c o n t a i n e d n o to n l y p o l y m e r b u t a l s o c h l o r p h e n i r a m i n e m a l e a t e , l ac -t o s e an d m a g n e s i u m s t ea r a te , w a s e x a m i n e d w i th t h ea i m o f con f i rm i ng t ha t s od i um a l g i na t e behave s s i m i -l a r ly , i n m ore r ea l i s t i c , com pl ex hy d roph i l i c m a t r i x fo r -m u l a t i ons .

    S E M m i c r o g r a p h s s h o w e d t h a t t h e se t a b le t s ex h i b -i t ed s im i l a r ge l m i c ros t ruc t u res t o thos e s e en p rev i ous l y

    i n t he pu re po l ym er m a t r ices , exce p t t ha t t he ge l l aye rfo rm ed i n ac i d , pa r t icu l a r l y the ou t e r s u r face , was r a t he rl e s s pa r t i cu l a t e i n na t u re t han t he ge l fo rm ed by p u rea l g i na t e tab l e ts . F i g . 8 and 9 s how t yp i ca l exam pl es o ft h e c o m p o s i t e g e l l a y e r f o rm e d i n S G F a n d t h e c o n t in -uous ge l l aye r fo rm ed i n S IF , r e s pec t i ve l y , a f t e r 1 hhyd ra t i on o f t hes e t ab l e ts .

    Even wi t h t he r e l a t i ve l y h i gh am oun t s o f s o l ub l eexc i p i en t s p res en t , t he s t ruc t u re and i n t eg r i t y o f t he ge ll aye r fo rm ed by a l g i na t e m a t r i ces appea r s t o d i f f e rg rea t l y in d i f f e ren t pH m ed i a , an d i n t hes e exam pl es i ti s p redom i nan t l y t he hyd ra t i on cha rac t e r i s t i c s o f t heh y d r o p h i li c p o l y m e r w i th i n a m a t r ix d o s a g e f o r m , t h a td i c t a t e s the s t ruc t u re o f t he hyd ra t ed l aye r .3 .2 . E f f e c t o f p H o n t h e r e l e a s e o f a p o o r l y w a t e r -s o l u b l e d r u g f r o m a l g i n a t e m a t r i c e s

    The s e s t ud i es have exp l a i ne d t he f a s t e r r e l eas e o f ah i gh l y wa t e r - s o l ub l e m ode l d rug i n t o ac i d m ed i umm ai n l y on t he bas i s o f an i nc reas ed po ros i t y o f t he

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    150 A , C . H o d s d o n e t al . / J o u r n a l o f C o n t r o l l e d R e l e a s e 3 3 ( 1 9 9 5 ) 1 4 3 - 1 5 2

    Fig. 9. Micrographof he outer surface hydrated ayerof a chlorpheniraminemaleate-containingalginate matrix,hydrated for 1 h in S1F ( X406).h y d r a t e d l a y e r , a t t h i s p H , e n a b l i n g f a s t e r s o l u t e o u t -g r e s s . H o w e v e r , t h e p o r o u s h y d r a t e d s t r u c t u r e f o r me da t p H 1 .2 a l so p o s s e s s e d m a r k e d l y d i f f e r e n t me c h a n i c a lp r o p e r t i e s to t h o s e p r o d u c e d a t n e u tr a l p H . A t o u g h a n dr u b b e r y ' r i n d ' w a s p r o d u c e d i n c o n t r a s t t o t h e v i s c o u s ,g e l a t i n o u s l a y e r f o r me d a r o u n d t h e t a b l e t a t p H 7 . 5 .T h i s d i f f e r e n c e i n g e l b a r r i e r i n t e g r i ty m a n i f e s t s i t s e lfa s d i f f e r e n c e s i n t h e s u s c e p t i b i l i ty o f t h e h y d r a t e d l a y -ers to e ros ion , on ag i t a t ion o f the t ab le t and i s therefo rel i k e l y t o i n f l u e n c e t h e r e l e a s e r a t e o f p o o r l y - s o l u b l ed r u g s w h i c h d e p e n d p r e d o mi n a n t l y o n s u r f a c e e r o s i o nfo r the i r re l ease [ 7 ] .

    F i g . 1 0 s h o w s h o w t h e r e l e a s e p r o f i le s o f h y d r o c h -l o r o t h i a z i d e f r o m a l g i n a t e ma t r i c e s d i f f e r i n SG F a n dSIF. Al though the so lub i l i ty o f th i s d rug i s s l igh t lyh i g h e r i n a c i d p H ( d e t e r m i n e d a s 1 .1 8 g l - l , 3 7 C)t h a n i n p H 7 . 5 b u f f e r ( d e t e r mi n e d a s 1 .1 4 g 1 - l, 3 7 o c ) ,d r u g r e l e a s e w a s d r a m a t i c a l l y f a s t e r i n S I F , t h e o p p o s i t es c e n a r i o a s s e e n f o r CPM . 8 3 % o f h y d r o c h l o r o t h i a z i d ew a s r e l e a s e d i n t o S I F a f t e r 4 h , c o mp a r e d w i t h o n l y1 5 % i n t o SG F . V i s u a l o b s e r v a t i o n o f t h e ma t r i c e s d ur -

    ing d i s so lu t ion t es t ing , revea led tha t those hydra ted inS I F h a d e r o d e d s i g n if i c a n tl y a f t e r o n l y 3 0 mi n , w h e r e a si n SG F , t h e r e w a s n o v i s i b le e v i d e n c e o f ma t r i x e r o s i o n

    100- I = -- =

    ----O--- SGF ( pH 1.2 )

    ~ 20-

    0 2 4 6 8 10 12T i m e ( H o u r s )

    Fig. 10, Effe ct of pH o n the release of hydrochlorothiazide fromsodium alginate matrices (m ean (n= 6) +S D ; all SD

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    A . C . H o d s d o n e t a l . / J o u r n a l o f C o n t r o l l e d R e l e a s e 3 3 ( 1 9 9 5 ) 1 4 3 - 1 5 2 151

    a f t e r 12 h d i s s o l u t i on t e s t i ng , a t t he end o f wh i ch as t ro n g r u b b e r y m a t r i x r e m a i n e d .

    The s e r e s u l t s i nd i ca t e tha t hyd ro ch l o ro t h i a z i de r e l i e sp r e d o m i n a n t l y o n m e c h a n i s m s o f e r o si o n f o r re l e a s e ,f r o m a l g in a t e m a t r i c e s. E v i d e n t l y , th e t o u g h m e c h a n i -c a l p r o p e r t i e s o f t h e p a r t ic u l a t e h y d r a t e d l a y e r f o r m e da t ac id pH rend ered t he m a t r i x ve ry r e s i s tan t t o e ro s ion ,a f ac t o r wh i ch w as r e s pons i b l e fo r the g rea t l y r e t a rdeda n d l im i t e d r e l e a s e o f h y d r o c h l o r o t h i a z i d e f r o m a l gi n -a t e m a t r i ces , ove r 12 h , i n t o an ac i d env i ronm en t . InS I F , h o w e v e r , t h e o u t e r m o s t l a y e r o f t he v i s c o u s g e lba r r i e r t ha t was fo rm ed , was m uch l e s s r e s i s t an t t oa t t r i t i on , r e s u l t i ng i n m uch m ore r ap i d r e l eas e o fhyd roch l o ro t h i az i de a t neu t r a l pH, due t o t he m a t r i xp r o g r e s s i v e l y e r o d in g a n d r e l e a si n g t h e d r u g .

    A p l o t o f t h e c u b e r o o t o f t h e w e i g h t o f d r u g r e l e a s e df rom t ab l e t s , a s a func t i on o f t i m e , r evea l ed t ha t t heH i x s o n - C r o w e l l c u b e r o o t e q u a t i o n f o r d i s so l u ti o n c o n -t r ol o f d r u g r e l e a s e [ 2 4 ] , a d e q u a t e l y d e s c r ib e d t h er e l e a s e o f h y d r o c h l o r o t h i a z i d e i n to S I F , o v e r t h e r a n g eo f 1 6 % t o 9 6 % c u m u l a t i v e p e r c e n t d r u g r e le a s e d . T h i sf i nd i ng s uppo r t s t he hypo t hes i s t ha t hyd roch l o ro t h i a -z i d e r e li e s m a i n l y o n e r o s i o n f o r r e l e a se f r o m h y d r o -ph i l i c m a t r i x t ab l e t s . C h l o rp hen i ra m i ne m a l ea t e wh i chas a h i gh l y s o l ub l e d rug i s be l i eved t o r e l y p redom i -nan t l y on d i f fu s i on m echan i s m s fo r r e l eas e , exh i b i t edn o s u c h H i x s o n - C r o w e l l k i n e ti c s.4 . Conclusions

    Th e res u l t s ob t a i ne d i n t h i s s tudy s how t ha t the i n t e r -n a l s t ru c t u r e o f t h e s u r f a c e h y d r a t e d l a y e r f o r m e d b ys o d i u m a l g i n a t e m a t r i c e s i n S G F , d i f f e r s m a r k e d l yf rom t he s t ruc t u re fo rm e d i n S IF . The hy d ra t i on k i ne t-i c s o f s o d i u m a l g i n a t e c o m p a c t s w e r e a l s o f o u n d t od i f f e r in t h e t w o d i f f e r e n t p H m e d i a . T h e s e d i f f e r e n c e si n m a t r ix g e l m o r p h o l o g y a n d p o l y m e r h y d r a ti o n c h a r-ac t e r i s ti c s in t he t wo d i f f e ren t pH m e d i a a re t hough t t ob e a c o n s e q u e n c e o f t h e p H - d e p e n d e n t s o l u b i l i t y o fs o d i u m a l g in a t e . T h i s c o n t r a s t in g b e h a v i o u r o f s o d i u mal g i na t e i n fo rm i ng t he hyd ra t ed s u r face l aye r , onm at r i x hyd ra t i on , i s t houg h t t o be p r i m ar i l y r e s pons i b l ef o r t h e d i f fe r e n c e s o b s e r v e d i n d r u g r e l e a s e b e h a v i o u rf r o m s o d i u m a l g i n a te m a t r ic e s , in S G F a n d S I F .

    D r u g r e l e a s e k i n e t i c s w e r e s e e n t o d e p e n d o n t h es o l ub i l it y o f t he d rug a nd a l s o t he pH o f t he d i s s o lu t i onm ed i um , s ug ges t i ng t ha t fo r a pa r t i cu l a r d rug , changes

    i n t he i n t e rna l st ruc t u re o f t he s u r face hyd ra t ed l aye rm a y a f f e c t t h e e x t e n t to w h i c h d i f f e r e n t m e c h a n i s m s o fd rug r e l eas e con t r i bu t e t owards t he ove ra l l r e l eas ekinet ics .

    AcknowledgementsT h e a u t h o rs w o u l d l ik e t o t h a n k K e l c o D i v i s i o n o f

    M erck an d C o . , Inc . , fo r t he i r fi nanc i a l suppo r t i n fund -i ng t h is work and i n pa r t i cu l a r Mr . G eo rg e C o l eg rov e ,M r . B r i a n L o c k w o o d a n d M r . J o h n F i t z p a t ri c k fo r t h e irs uppo r t and as s i st ance .

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    15 2 A . C . H o d s d o n e t a l . / J o u r n a l o f C o n t r o l l e d R e l e a s e 3 3 ( 1 9 9 5 ) 1 4 3 - 1 5 2

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