Water in Polymers - ACS Publications

20 Solute Permeation Through Hydrogel Membranes Hydrophilic vs. Hydrophobic Solutes

Downloaded by UNIV OF MICHIGAN ANN ARBOR on February 18, 2015 | http://pubs.acs.org Publication Date: August 19, 1980 | doi: 10.1021/bk-1980-0127.ch020

S. W. KIM, J. R. CARDINAL, S. WISNIEWSKI, and G. M. ZENTNER Department of Pharmaceutics, University of Utah, Salt Lake City, UT 84112

P o l y ( 2 - h y d r o x y e t h y l m e t h a c r y l a t e ) (p-HEMA) i s a h y d r o p h i l i c m e t h a c r y l a t e p o l y m e r w h i c h was f i r s t p r e p a r e d b y W i c h t e r l e and L i m OJ. T h i s p o l y m e r , a n d many o t h e r s y n t h e t i c h y d r o g e l s , has been e x t e n s i v e l y examined f o r p o t e n t i a l b i o m e d i c a l a p p l i c a t i o n s (2J. A l t h o u g h many s t u d i e s have f o c u s e d on t h e p h y s i c o c h e m i c a l n a t u r e o f t h e s e h y d r o g e l s , many q u e s t i o n s r e m a i n u n a n s w e r e d . Among t h e s e a r e t h e n a t u r e , o r g a n i z a t i o n , and r o l e o f w a t e r i n d e t e r m i n i n g s u c h p r o p e r t i e s a s i n t e r f a c i a l a n d t r a n s p o r t phenom ena. Problems which deal w i t h t h e presence o f water and t h e s t r u c t u r e o f water a t t h e m o l e c u l a r l e v e l a r e o f t e n complex. F o r h y d r o g e l s , i t h a s been p r o p o s e d ( 3 ) t h a t w a t e r c a n be t r e a t e d i n terms o f a t h r e e s t a t e m o d e l . These i n c l u d e : bound, i n t e r f a c i a l , and " b u l k - l i k e " w a t e r . Bound w a t e r i s s t r o n g l y a s s o c i a t e d w i t h the polymer, probably as water h y d r a t i n g t h e h y d r o p h i l i c groups of t h e polymer. I n t e r f a c i a l water i s probably associated with h y d r o p h o b i c i n t e r a c t i o n s between t h e p o l y m e r s e g m e n t s . Finally, " b u l k - l i k e " water i s t h a t w i t h p r o p e r t i e s which a r e s i m i l a r t o t h a t o f b u l k w a t e r i n aqueous s o l u t i o n . S e v e r a l s t u d i e s have been d e s i g n e d i n an e f f o r t t o v e r i f y t h i s m o d e l . The t o t a l g e l w a t e r c o n t e n t was e s t i m a t e d s e m i q u a n t i t a t i v e ^ u s i n g NMR (4,_5). Simi l a r a p p r o a c h e s were made t o i n v e s t i g a t e t h e s t a t e o f " w a t e r i n p HEMA g e l s u s i n g t h e t e c h n i q u e s o f d i l a t o m e t r y , s p e c i f i c c o n d u c t i v i t y and d i f f e r e n t i a l s c a n n i n g c a l o r i m e t r y ( 6 ) . R e c e n t l y , we have examined s o l u t e p e r m e a t i o n t h r o u g h h y d r o g e l membranes i n a n e f f o r t t o d e v e l o p m o d e l s w h i c h d e s c r i b e i n d e t a i l t h e t r a n s p o r t phenomena w i t h p a r t i c u l a r e m p h a s i s on t h e r o l e o f water i n t h i s process. These s t u d i e s have u t i l i z e d p HEMA a n d i t s c o p o l y m e r s , and b o t h h y d r o p h o b i c a n d h y d r o p h i l i c solutes (7*8,9). I t was d e t e r m i n e d t h a t p-HEMA a n d i t s c o p o l y mers a r e p e r m e a b l e t o b o t h h y d r o p h o b i c a n d h y d r o p h i l i c s o l u t e s . The f a c t o r s w h i c h i n f l u e n c e t h e p e r m e a b i l i t i e s i n c l u d e t h e n a t u r e and p e r c e n t o f c r o s s l i n k e r s a n d t h e w a t e r c o n t e n t o f t h e h y d r o gel . In t h i s m a n u s c r i p t , t h e p e r m e a b i l i t i e s o f w a t e r s o l u b l e n o n -

Ameriean Chemical

In Water in Polymers; Rowland, S.; Washington, D. C. 20036 ACS Symposium Series; American Chemical Society: Washington, DC, 1980.

WATER IN P O L Y M E R S


348

e l e c t r o l y t e s and h y d r o p h o b i c s o l u t e s i n p-HEMA and c r o s s l i n k e d pHEMA a r e examined f r o m a m e c h a n i s t i c p o i n t o f v i e w . For hydro p h i l i c s o l u t e s , i t was f o u n d t h a t p e r m e a t i o n p r o b a b l y o c c u r s v i a the " b u l k - l i k e " water regions of the hydrogels. For hydrophobic s o l u t e s , analyses of permeation data i n d i c a t e t h a t solutes d i f f u s e p r e d o m i n a n t l y v i a a " p o r e " t y p e mechanism i n p-HEMA and v i a a " p a r t i t i o n " mechanism i n p-HEMA h i g h l y c r o s s l i n k e d w i t h e t h y l ene g l y c o l d i m e t h a c r y l a t e (EGDMA). The a n a l y s e s o f p e r m e a t i o n d a t a was based on t h e a s s u m p t i o n t h a t t h e p o r o u s f l u x o f a s o l u t e i s a s s o c i a t e d w i t h the " b u l k - l i k e " water r e g i o n s o f the hydrogels and t h e p a r t i t i o n f l u x w i t h t h e p o l y m e r m a t r i x , " i n t e r f a c i a l " and "bound" water regions o f the hydrogels. M a t e r i a l s and Methods Materials. HEMA was a h i g h l y p u r i f i e d sample ( g i f t o f Hydron L a b o r a t o r i e s , New B r u n s w i c k , N . J . ) c o n t a i n i n g t h e f o l l o w i n g l e v e l s of i m p u r i t i e s : m e t h a c r y l i c a c i d 0.06%, e t h y l e n e g l y c o l dimetha c r y l a t e 0 . 0 2 4 % , and d i e t h y l e n e g l y c o l m e t h a c r y l a t e 0 . 2 4 % . EGDMA (Monomer P o l y m e r L a b o r a t o r i e s , P h i l a d e l p h i a , PA) was p u r i f i e d by b a s e e x t r a c t i o n and d i s t i l l a t i o n . The i n i t i a t o r , a z o b i s ( m e t h y l i s o b u t y r a t e ) was p r e p a r e d by t h e method o f M o r t i m e r ( 1 0 ) . PolyHEMA f i l m s and f i l m s c o n t a i n i n g 1 mole % EGDMA were s y n t h e s i z e d i n the presence of t h e i r e q u i l i b r i u m water contents. F i l m s w i t h 5.25 m o l e % EGDMA were s y n t h e s i z e d i n 40% ( v / v ) e t h a n o l as t h e s o l v e n t . A l l f i l m s were e q u i l i b r a t e d i n w a t e r (changed r e p e a t e d l y ) f o r t h r e e t o f o u r weeks p r i o r t o u s e . A l l s o l u t e s were u s e d as r e c e i v e d . A l l s t e r o i d s p r o d u c e d a s i n g l e s p o t f r o m TLC. R a d i o l a b e l e d s t e r o i d s had t h e same Rf v a l u e s as t h e u n l a b e l e d m a t e r i a l s w i t h >95% o f t h e d e t e c t a b l e a c t i v i t y a s s o c i a t e d w i t h the primary spot. Methods. The d i f f u s i o n e x p e r i m e n t s were p e r f o r m e d a t room t e m p e r a t u r e (23°C) u t i l i z i n g a g l a s s d i f f u s i o n c e l l c o n s i s t i n g o f two c o m p a r t m e n t s e a c h w i t h a volume o f 175 m l . Each chamber was s t i r r e d a t a c o n s t a n t r a t e t o reduce boundary l a y e r e f f e c t s . So l u t e c o n c e n t r a t i o n s were m o n i t o r e d by H o r * C t r a c e r s , r e f r a c t i v e i n d e x , o r U.V. s p e c t r o s c o p y . P a r t i t i o n c o e f f i c i e n t s , defined as t h e r a t i o o f t h e c o n c e n t r a t i o n s i n t h e membrane and i n t h e b u l k aqueous phase were d e t e r m i n e d by s o l u t i o n d e p l e t i o n t e c h n i q u e . The t h i c k n e s s o f w a t e r s w o l l e n membranes were measured u s i n g a l i g h t w a v e m i c r o m e t e r (Van Kueren C o . , W a t e r t o w n , MA). P e r m e a t i o n c o e f f i c i e n t s f o r h y d r o p h i l i c s o l u t e s were o b t a i n e d t h r o u g h t h e use o f t h e f o l l o w i n g e q u a t i o n {]}): 3

lnO-2

C /C ) = t

0

-0/ν

α

k

+ 1/V ) 2

AUt

Eq. 1

where C t = c o n c e n t r a t i o n a t t i m e t ; Co = i n i t i a l c o n c e n t r a t i o n ; = V = compartment volume (175 m l ) ; A = membrane a r e a ( 1 4 . 9 c m ) ; U = p e r m e a b i l i t y ( c m / s e c ) ; and t = t i m e ( s e c o n d s ) . D i f f u s i o n 2

2

In Water in Polymers; Rowland, S.; ACS Symposium Series; American Chemical Society: Washington, DC, 1980.

20.

K I M ET A L .

Hydro gel

Membranes

349


c o e f f i c i e n t s a r e g i v e n by Dm = Ud/Ko where d = wet membrane t h i c k n e s s and Ko i s t h e p a r t i t i o n c o e f f i c i e n t . Under t h e c o n d i t i o n s o f t h e e x p e r i m e n t s used i n o u r l a b o r a t o r i e s , E q . 1 i s n o t v a l i d f o r h y d r o p h o b i c s o l u t e s due t o h i g h p a r t i t i o n i n g o f t h e s e s p e c i e s i n t o t h e membrane. In a p r e v i o u s p u b l i c a t i o n ( 8 ) , i t was shown t h a t t h e f o l l o w i n g e q u a t i o n i s v a l i d f o r the hydrophobic s o l u t e s : l

n , n

(CiV (CiV -

(2V + Kp/Vm) C t ) _ 2 UA ( t - t ) (2V + KD/Vm) Co) " " V 0

Eq. 2

where C i = i n i t i a l c o n c e n t r a t i o n i n compartment I; Co = c o n c e n t r a t i o n i n compartment II a t t h e o n s e t o f s t e a d y s t a t e ( t o ) , C t = c o n c e n t r a t i o n i n compartment II a t any t i m e t w h i c h i s g r e a t e r t h a n t o ; V = membrane v o l u m e , and V = compartment volume (175 ml). In t h e l i m i t t h a t Kp i s s m a l l , E q . 2 r e d u c e s t o E q . 1. m

Results

and

Discussion

1) Hydrophilic Solutes. The mechanisms o f p e r m e a t i o n o f h y d r o p h i l i c s o l u t e s i n h y d r o g e l f i l m s has been c o n s i d e r e d p r e v i o u s l y by Yasuda e t a l . ( 1 2 J . These a u t h o r s u t i l i z e d t h e " f r e e v o l u m e " model f o r s o l u t e p e r m e a t i o n i n h y d r o g e l f i l m s i n w h i c h i t was assumed t h a t : i ) t h e e f f e c t i v e f r e e volume f o r s o l u t e d i f f u s i o n c o r r e s p o n d s t o t h e f r e e volume o f t h e aqueous p h a s e ; i i ) t h e s o l u t e d i f f u s e s t h r o u g h " f l u c t u a t i n g p o r e s " by s u c c e s s i v e jumps through " h o l e s " which are l a r g e r than the s o l u t e ; i i i ) the s o l u t e p e r m e a t e s o n l y t h r o u g h aqueous r e g i o n s and s o l u t e - p o l y m e r i n t e r a c t i o n s a r e m i n i m a l . Based on t h i s m o d e l , t h e d i f f u s i o n c o e f f i c i e n t , Dm, i n t h e h y d r a t e d membrane i s g i v e n b y :

Do

Vf

IH

/

t

q

'

0

where B q i s p r o p o r t i o n a l t o s o l u t e c r o s s s e c t i o n a l a r e a ( n r ) , D i s the d i f f u s i o n c o e f f i c i e n t f o r the s o l u t e i n water, Vf i s the f r e e v o l u m e , and H i s t h e volume f r a c t i o n o f w a t e r i n t h e h y d r a t e d membrane. From E q . 3 i t i s a p p a r e n t t h a t Dm s h o u l d be d e p e n d e n t upon b o t h t h e c r o s s s e c t i o n a l r a d i u s o f t h e d i f f u s i n g s o l u t e s and t h e membrane h y d r a t i o n . V a l u e s o f Dm f o r t h e h y d r o p h i l i c s o l u t e s i n p-HEMA and p-HEMA c r o s s l i n k e d w i t h 1 m o l e % EGDMA a r e shown i n T a b l e s I and I I . It i s e v i d e n t t h a t t h e Dm v a l u e s i n t h e c r o s s l i n k e d membrane a r e s m a l l e r t h a n i n p-HEMA. P l o t s o f t h e s e v a l u e s a c c o r d i n g t o E q . 3 a r e shown i n F i g . 1. A s e m i e m p e r i c a l e q u a t i o n d e v e l o p e d by W i l k e and Chang (13) was u t i l i z e d t o c a l c u l a t e Do. The m o l a r volume o f t h e s o l u t e was e s t i m a t e d f r o m a t o m i c c o n t r i b u t i o n s a c c o r d i n g t o LeBas ( 1 4 J . The m o l e c u l a r r a d i i , r , g i v e n i n T a b l e I were c a l c u l a t e d a s s u m i n g t h a t t h e s o l u t e s were s p h e r i c a l ( 1 5 ) . 2

2

0

0


WATER IN P O L Y M E R S

350

TABLE

I

Transport Parameters of H y d r o p h i l i c Solutes

D x 10 (cm /sec)

D

Dm χ Ι Ο " (cn^/sec)

5. 57 0. 23 0. 22 0. 20 0. 23 1. 27 0. 14 0. 53

1.95 4.96 3.28 17.4 26.0 97.0 1.81 149.

5


0

Solute

(&)

Na M e t h o t r e x a t e Sucrose Lactose Inositol Glucose Thiourea Raffinose Urea

27.7 27.4 18.1 18.1 8.8 35.7 8.1

2

0.38 0.41 0.41 0.64 0.64 1.30 0.31 1.39

TABLE

i n p-HEMA

K

Dm χ 1 0 (cnf/sec) 8

Solute Na M e t h o t r e x a t e Sucrose Lactose Inositol Glucose Thiourea Raffinose Urea

D

5.84 0.25 0.21 0.18 0.24 1.14 0.12 0.48

I n Pja Do -5. -4. -4. -3. -3. -2. -5. -2.

27 41 75 61 47 59 14 23

II

Transport Parameters of H y d r o p h i l i c Solutes p-HEMA w i t h 1 M o l e % EGDMA

K

8

1.09 3.53 2.45 13.1 15.6 88.0 1.31 128

in

"ft -5.85 -4.75 -5.12 -3.89 -3.71 -2.70 -5.47 -2.39

From t h e p l o t s shown i n F i g . 1, i t i s e v i d e n t t h a t Eq. 3 i s v a l i d f o r t h e h y d r o p h i l i c s o l u t e s examined i n t h e p r e s e n t s t u d y . The d e p e n d e n c e o f Dm on c r o s s s e c t i o n a l r a d i u s i s e v i d e n t f r o m t h e l i n e a r i t y of the p l o t s . The w a t e r c o n t e n t s o f p-HEMA and p-HEMA c r o s s l i n k e d w i t h 1 m o l e % EGDMA a r e 42% (w) and 37% (w) r e s p e c t ively. T h i s e f f e c t o f membrane h y d r a t i o n i s c o n t a i n e d i n t h e s l o p e o f t h e p l o t s g i v e n i n F i g . 1. I t i s a p p a r e n t t h a t as t h e membrane h y d r a t i o n i s i n c r e a s e d , Dm i s l e s s s e n s i t i v e t o c h a n g e s i n the s i z e o f the permeating s o l u t e . From t h e s e r e s u l t s , i t may be c o n c l u d e d t h a t h y d r o p h i l i c s o l u t e s p e r m e a t e p-HEMA and p-HEMA c r o s s l i n k e d w i t h 1 mole % EGDMA p r i m a r i l y v i a the water f i l l e d channels or "pores" w i t h i n the h y d r o g e l f i l m s . T h i s c o n c l u s i o n d o e s n o t a p p e a r t o be v a l i d ,



KIM ET A L .

Hydrogel

Membranes

35

Figure 1. Dependence of diffusion coefficients of hydrophilic solutes on molecular size in (—) p-HEMA and (---) p-HEMA crosslinked with 1 mol % EGDMA: (1) urea; (2) thiourea; (3) glucose; (4) inositol; (5) sucrose; (6) lactose; (7) raffinose.



352

WATER IN POLYMERS

h o w e v e r , f o r p-HEMA c o n t a i n i n g h i g h e r c o n c e n t r a t i o n s o f t h e c r o s s l i n k e r EGDMA. F o r e x a m p l e , i n f i l m s c o n t a i n i n g 2.5 m o l e % EGDMA d e v i a t i o n s f r o m l i n e a r i t y i n p l o t s o f t h e t y p e shown i n F i g . 1 were n o t e d . F o r f i l m s p r e p a r e d f r o m 5 m o l e % EGDMA, no d e t e c t a b l e d i f f u s i o n was f o u n d a f t e r two weeks f o r t h e s o l u t e s r a f f i n o s e and inositol. From t h e d a t a shown i n T a b l e s I and I I , and t h a t g i v e n i n a t h e s i s by Sung ( 5 ) , i t i s p o s s i b l e t o f u r t h e r d e f i n e t h e model f o r h y d r o p h i l i c s o l u t e p e r m e a t i o n i n h y d r o g e l f i l m s v i a an a n a l y s i s o f t h e KD v a l u e s . The p a r t i t i o n c o e f f i c i e n t s f o r w a t e r i n p-HEMA and p-HEMA c r o s s l i n k e d w i t h 1 m o l e % EGDMA a r e 0.52 and 0.51 r e s p e c t i v e l y . However, f r o m S u n g ' s d a t a ( 5 ) , i t i s p o s s i b l e t o d e f i n e p a r t i t i o n c o e f f i c i e n t s f o r water i n t o the various subclasses of water i n the h y d r o g e l membranes. F o r p-HEMA, t h e s e v a l u e s o f KD a r e : bulk w a t e r 0 . 3 0 , b u l k + i n t e r m e d i a t e w a t e r 0 . 4 1 , and b u l k + i n t e r m e d i a t e + bound w a t e r 0 . 5 2 . F o r p-HEMA w i t h 1 m o l e % EGDMA, t h e v a l u e s a r e : b u l k w a t e r 0 . 2 1 , b u l k + i n t e r m e d i a t e w a t e r 0 . 3 6 , and b u l k + i n t e r m e d i a t e + bound w a t e r 0 . 5 0 . A comparison o f these v a l u e s w i t h t h e e x p e r i m e n t a l v a l u e s f o u n d i n T a b l e s I and II i n d i c a t e s t h a t the sugars p a r t i t i o n p r i m a r i l y i n t o bulk water of b o t h membranes a n d , t h e r e f o r e , t h a t t h e d i f f u s i o n o f t h e s e s o l u t e s o c c u r s p r i m a r i l y i n t h e b u l k w a t e r o f t h e membranes. This r e s u l t i s c o n s i s t e n t w i t h the observed very low p e r m e a b i l i t y o f i n o s i t o l and r a f f i n o s e i n p-HEMA w i t h 5 mole % EGDMA. These membranes have l i t t l e o r no b u l k w a t e r ( 5 ) . T h i o u r e a and Na m e t h o t r e x a t e show l a r g e d e v i a t i o n s f o r Kp f r o m v a l u e s e x p e c t e d based on p a r t i t i o n s o l e l y i n t o t h e w a t e r f r a c t i o n o f t h e membrane. T h i s phenomena may be due t o s p e c i f i c i n t e r a c t i o n s of the s o l u t e s w i t h the macromolecular chains. The i n c r e a s e i n p o l a r i z a b i l i t y i n g o i n g f r o m u r e a t o t h i o u r e a and t h e p r e s e n c e o f p o l a r i z a b l e a r o m a t i c g r o u p s i n Na m e t h o t r e x a t e i n d i c a t e s t h a t t h i s i n t e r a c t i o n may be d i s p e r s i v e i n n a t u r e . From t h e s e r e s u l t s , i t may be i n f e r r e d a l s o t h a t some p o r t i o n o f t h e t o t a l t r a n s p o r t o f t h e s e s o l u t e s may o c c u r i n r e g i o n s o t h e r t h a n t h e b u l k w a t e r r e g i o n s o f t h e h y d r o g e l membranes. It is i n t e r e s t i n g t o n o t e t h a t t h e t o t a l volume f r a c t i o n o f H 0 i n p-HEMA and p-HEMA w i t h 1 mole % EGDMA may be a v a i l a b l e f o r t h e t r a n s p o r t of urea. 2

2) Hydrophobic S o l u t e s . The v a l u e s o f D , Kp, Dm and In Djp/D f o r s e v e r a l h y d r o p h o b i c s o l u t e s i n p-HEMA and p-HEMA c r o s s l i n k e d w i t h 5.25 mole % EGDMA a r e g i v e n i n T a b l e s I I I and IV. 0

0


20.

κίΜ

ET AL.

Hydrogel

Membranes

TABLE

III

Transport Parameters o f Hydrophobic Solutes

D x 10 (cm /sec)

D

Dm x 1 0 (cm /sec)

48 70 129 83 177 27

18.8 13.5 7.04 10.6 5.48 8.86

9

6

0


Solute

2

6.04 5.83 5.59 5.56 6.41 5.55

Testosterone Norethindrone Progesterone 17-Hydroxy progesterone Estradiol Cortisol

TABLE

i n p-HEMA

K

In

2

Dm Do

-5.78 -6.06 -6.68 -6.27 -7.07 -6.44

IV

Transport Parameters o f Hydrophobic S o l u t e s i n p-HEMA C r o s s l i n k e d w i t h 5.25 M o l e % EGDMA

Dm x 1 0 (cn^/sec) 9

D

l

n

l

n

Dm Do"

Solute

K


89 131 232 132

2.70 1.16 1.12 1.53

-7.71 -7.91 -8.52 -8.20

235 20

1.21 1.78

-8.57 -8.04

By c o m p a r i s o n o f Dm v a l u e s g i v e n i n T a b l e s I I I and IV w i t h t h o s e f o u n d i n T a b l e s I and I I , i t may be n o t e d t h a t Dm v a l u e s f o r h y d r o p h o b i c s o l u t e s a r e a p p r o x i m a t e l y two o r d e r s o f m a g n i t u d e l e s s than f o r the h y d r o p h i l i c s o l u t e s . C o n v e r s e l y , Kp v a l u e s a r e a b o u t two o r d e r s o f m a g n i t u d e g r e a t e r f o r t h e h y d r o p h o b i c s o l u t e s i n d i c a t i n g t h a t v e r y s t r o n g i n t e r a c t i o n s o c c u r between t h e s e h y d r o p h o b i c s o l u t e s and t h e m a c r o m o l e c u l a r segments o f t h e h y d r o g e l membranes. In a p r e v i o u s p u b l i c a t i o n (7.) i t was c o n c l u d e d t h a t h y d r o p h o b i c s o l u t e s , s u c h as p r o g e s t e r o n e , p e r m e a t e p-HEMA p r i m a r i l y v i a t h e " p o r e " mechanism. However, f o r p r o g e s t e r o n e i n p-HEMA w i t h 5.25 m o l e % EGDMA, i t was f o u n d t h a t t h e " p a r t i t i o n " m e c h a n ism d o m i n a t e s p e r m e a t i o n . In t h i s m e c h a n i s m , i t i s presumed t h a t t h e s o l u t e s p e r m e a t e by d i s s o l u t i o n and d i f f u s i o n w i t h i n t h e m a c r o m o l e c u l a r segments o f t h e p o l y m e r b a c k b o n e . In t h e " p o r e " mechanism v a l u e s a r e e x p e c t e d t o be l e s s t h a n one and r e f l e c t



354

WATER IN POLYMERS

t h e d i s t r i b u t i o n o f s o l u t e between membrane s o l v e n t and b u l k s o l v ent. In t h e " p a r t i t i o n " mechanism p o l y m e r s e g m e n t / s o l u t e i n t e r a c t i o n i s h i g h w h i c h l e a d s t o w i d e r a n g e o f Kp v a l u e s w h i c h a r e much g r e a t e r t h a n o n e . From t h e d a t a g i v e n i n T a b l e s I I I and I V , i t i s a p p a r e n t t h a t Kp v a l u e s f o r b o t h membranes a r e much g r e a t e r t h a n o n e . These h i g h KD v a l u e s f o r p-HEMA a p p e a r t o be i n c o n s i s t e n t w i t h t h e " p o r e " mechanism f o r s o l u t e t r a n s p o r t . T h i s c o n t r a d i c t i o n c a n be s o l v e d a s s u m i n g t h a t KD i s d o m i n a t e d by t h e h i g h s o l u b i l i t y o f t h e hydrophobic s o l u t e w i t h i n the hydrophobic region of the hydrogel, w h e r e a s , p e r m e a t i o n i s c a r r i e d by d i f f u s i o n w i t h i n " f l u c t u a t i n g p o r e s " as d e s c r i b e d i n h y d r o p h i l i c s o l u t e p e r m e a t i o n . It i s , t h e r e f o r e , i m p o r t a n t t o s e p a r a t e " p o r e " and " p a r t i t i o n " c o n t r i b u t i o n s t o the t o t a l permeation i n o r d e r t o determine the dominant mechanisms f o r h y d r o p h o b i c s o l u t e s i n p-HEMA. As n o t e d i n p r e v i o u s s e c t i o n s o f t h i s m a n u s c r i p t , i t has been proposed t h a t t h r e e types o f water e x i s t w i t h i n hydrogel f i l m s , n a m e l y , b o u n d , i n t e r m e d i a t e , and b u l k w a t e r . From t h i s m o d e l , i t i s p r o p o s e d t h a t h y d r o g e l membranes p r e p a r e d w i t h o u t c r o s s l i n k e r a r e composed o f two domains d e s i g n a t e d A and Β ( 8 ) . Domain A c o n s i s t s o f p o l y m e r s e g m e n t s , bound w a t e r and i n t e r f a c i a l w a t e r . Domain Β i s c o n s i d e r e d t o be b u l k w a t e r w h i c h f o r m s t h e " f l u c t u a ting pores." P-HEMA w i t h 5 . 2 5 mole % EGDMA, h a v i n g no " b u l k - l i k e " w a t e r , i s assumed t o be composed e n t i r e l y o f A t y p e d o m a i n s . T r a n s p o r t i n t h e A domains o f t h e h y d r o g e l o c c u r s t h r o u g h t h e bound and i n t e r f a c i a l w a t e r a n d / o r t h r o u g h t h e h y d r o p h o b i c p o l y meric regions. T h e r e f o r e , p e r m e a t i o n i n t h e A domains w i l l o c c u r v i a t h e " p a r t i t i o n " mechanism as p r e v i o u s l y d e s c r i b e d . KD v a l u e s f o r t r a n s p o r t i n A domains v a r y w i d e l y d e p e n d i n g on t h e s o l u t e solubilities. T r a n s p o r t i n t h e Β domains o c c u r s by d i f f u s i o n o f the s o l u t e i n " b u l k - l i k e " water. KD v a l u e s a r e i d e a l l y one i n t h i s case s i n c e the s o l u t e i s s i m p l y p a r t i t i o n i n g from bulk water i n t o hydro'gel domains o f " b u l k - l i k e " w a t e r . D i f f u s i o n composed e x c l u s i v e l y o f A - t y p e d o m a i n s , as p o s t u l a t e d i n p-HEMA w i t h 5 . 2 5 m o l e % EGDMA, o c c u r s o n l y by t h e p a r t i t i o n mechanism w h i c h has no " b u l k - l i k e " water. T h i s model was s u c c e s s f u l l y a p p l i e d t o e s t i mate t h e c o n t r i b u t i o n o f e a c h domain t o t h e t o t a l p e r m e a b i l i t i e s o f s t e r o i d s i n h y d r o g e l membranes. I t c a n be shown t h a t p-HEMA c o n t a i n s 2 2 . 8 % " b u l k - l i k e " w a t e r ( 8 ) . As n o t e d , KD f o r p a r t i t i o n i n t o t h i s w a t e r must be 1 . 0 . W i t h t h i s i n f o r m a t i o n , t h e r a t i o o f s o l u t e d i f f u s i o n due t o Β domains t o t o t a l s o l u t e p e r m e a b i l i t y , DB/PT> w h i c h r e p r e s e n t s t h e f r a c t i o n o f " p o r e - t y p e " p e r m e a t i o n i n p-HEMA membranes, can be d e t e r m i n e d ( 8 ) . These v a l u e s a r e g i v e n i n T a b l e V. I t may be n o t e d t h a t t h e v a l u e s o f D B / Ρ Τ a r e a l l approximately 0 . 8 0 except C o r t i s o l which i s 0 . 8 8 . This i n d i c a t e s t h a t t h e " p o r e " c o n t r i b u t i o n t o t r a n s p o r t i n p-HEMA i s s i m i l a r f o r a l l hydrophobic s t e r o i d s except the r e l a t i v e l y water s o l u b l e s t e r o i d , C o r t i s o l , w h i c h p e r m e a t e s by " p o r e s " t o a g r e a t e r e x t e n t .


20.

K I M ET AL.

Hydrogel

Membranes

355

TABLE V


Transport Parameters o f S t e r o i d s i n p-HEMA by M o d e l i s t i c A n a l y s i s

D i f f u s i o n C o e f f i c i e n t (Dg) i n " B u l k - l i k e " Water (cm /sec)

Solute

2


7.20 7.29 5.59 5.56

χ χ χ χ

10" 10" 10 10"

6.41 5.95

χ x

10" 10'

7

7

- 7

7

7

7

-5.78 -6.06 -6.68 -6.27

0.80 0.77 0.76 0.82

0.54 0.54 0.56 0.63

-7.07 -6.44

0.77 0.88

0.75 1.35

The r e l a t i v e l y h i g h f r a c t i o n s o f D B / P T f o r a l l s t e r o i d s s u g g e s t t h a t p e r m e a t i o n t h r o u g h p-HEMA membrane i s d o m i n a t e d by t h e " p o r e " mechanism. The h i g h KD v a l u e s a r e c o n s i s t e n t w i t h t h e p r o posed m o d e l . A c c o r d i n g t o t h e model and d a t a o b t a i n e d i n t h e p-HEMA membrane, p a r t i t i o n i n g o f h y d r o p h o b i c s o l u t e s i s g o v e r n e d p r e d o m i n a n t l y by A t y p e d o m a i n s . S o l u t e w i t h i n t h e s e domains makes a s m a l l c o n t r i b u t i o n t o p e r m e a b i l i t y . S o l u t e p e r m e a t i o n i s d o m i n a t e d by t h e " p o r e " m e c h a n i s m . The a s s u m p t i o n made i n t h e model i s t h a t A domains a r e o f t h e same n a t u r e i n b o t h p-HEMA and c r o s s l i n k e d p-HEMA. If t h i s is s t r i c t l y t r u e , t h e p a r t i t i o n c o e f f i c i e n t s w h i c h a r e d o m i n a t e d by A t y p e domains i n p-HEMA s h o u l d be r e l a t e d t o p a r t i t i o n c o e f f i c i e n t s i n p-HEMA w i t h 5.25 mole % EGDMA a c c o r d i n g t o t h e volume f r a c t i o n o f A t y p e domains p r e s e n t i n p-HEMA. ( T h i s volume f r a c t i o n i s 0.772 s i n c e " b u l k - l i k e " w a t e r i s 2 2 . 8 % i n p-HEMA.) These v a l u e s a r e g i v e n i n T a b l e V as t h e r a t i o K p ( I ) / K p ( I I ) . K D ( H and K D C I I ) a r e p a r t i t i o n c o e f f i c i e n t s o f s t e r o i d s i n p-HEMA and p HEMA w i t h 5.25 m o l e % EGDMA r e s p e c t i v e l y . The e s t r a d i o l v a l u e o f 0.75 i s i n c l o s e agreement w i t h t h e p r e d i c t e d v a l u e o f 0 . 7 7 2 . However, t h i s r a t i o f o r t h e o t h e r s t e r o i d s e x c e p t C o r t i s o l i s a p p r o x i m a t e l y 0.54 t o 0 . 6 3 . Though t h e q u a n t i t a t i v e a g r e e m e n t i s not good, q u a l i t a t i v e agreement w i t h t h e p r e d i c t e d v a l u e i s o b tained. T h i s i n d i c a t e s t h a t d i f f e r e n c e s e x i s t between t h e A domains i n p-HEMA and p-HEMA c r o s s l i n k e d w i t h EGDMA. I t was d i s c u s s e d p r e v i o u s l y t h a t d i f f u s i o n c o e f f i c i e n t s o f h y d r o p h i l i c s o l u t e s i n p-HEMA a c c o r d i n g t o E q . 3 showed a s t r a i g h t l i n e c o r r e l a t i o n p r o v i d e d t h e f r e e volumes a c c e s s i b l e t o t h e v a r i ous s o l u t e s a r e e q u a l . D i f f u s i o n c o e f f i c i e n t s of these s t e r o i d s (from Table I I I ) are p l o t t e d i n F i g . 2 using the r v a l u e o f 11.45 % (16). E x p e r i m e n t a l v a l u e s o f I n Dm/Do f o r t h e s e s t e r o i d s d e v i a t e s u b s t a n t i a l l y from the l i n e a r l i n e o b t a i n e d from hydro2

2



356

W A T E R IN

POLYMERS

Figure 2. Dependence of diffusion coefficients on solute molecular size in p-HEMA: (—) correlation of steroid diffusion in Β-type domains with water-soluble solutes; (—) experimental values of steroid diffusion



20.

κίΜ E T A L .

Hydrogel

Membranes

357

philic solutes. However, i f t h e c a l c u l a t e d v a l u e s o f I n D B / D O a r e f i t w i t h t h e l i n e a r c o r r e l a t i o n o b t a i n e d from t h e h y d r o p h i l i c s o l u t e s , e x c e l l e n t a g r e e m e n t i s o b t a i n e d ( F i g . 2 ) . These r e s u l t s p r o v i d e f u r t h e r s u b s t a n t i a t i o n o f t h e model p r e s e n t e d a b o v e , i . e . , t h a t h y d r o p h o b i c s o l u t e s p e r m e a t e p-HEMA membranes p r i m a r i l y v i a the " b u l k - l i k e " water r e g i o n s . In c o n c l u s i o n , 1} H y d r o p h i l i c s o l u t e s p e r m e a t e p-HEMA and p-HEMA c r o s s l i n k e d w i t h l o w e r m o l e % EGDMA v i a t h e " p o r e " m e c h a n ism. T h e d i f f u s i o n c o e f f i c i e n t s o f t h e s o l u t e s depend on t h e m o l e c u l a r s i z e a n d may u t i l i z e t h e " b u l k - l i k e " w a t e r i n t h e h y d r o gels. As t h e water content o f hydrogel i n c r e a s e s , t h e s o l u t e p e r meability increases. 2 ) H y d r o p h o b i c s o l u t e s p e r m e a t e p-HEMA and p-HEMA c r o s s l i n k e d w i t h EGDMA v i a e i t h e r t h e " p o r e " o r " p a r t i t i o n " mechanisms. D i f f u s i o n c o e f f i c i e n t s a r e lower than those o f hydro p h i l i c s o l u t e s ; h o w e v e r , s t e r o i d s c a n p e r m e a t e even i n p-HEMA w i t h 5 . 2 5 m o l e % EGDMA d u e t o t h e p r e d o m i n a n t " p a r t i t i o n " m e c h a n i s m f o r h y d r o p h o b i c s o l u t e p e r m e a t i o n i n t h i s membrane. Hydro p h i l i c s o l u t e s f a i l t o permeate t h e high c r o s s l i n k e d h y d r o g e l s . 3) B a s e d on p a r t i t i o n c o e f f i c i e n t d a t a , t h e h y d r o p h i l i c s o l u t e s examined a p p e a r t o p e r m e a t e p-HEMA and p-HEMA w i t h 1 m o l e % EGDMA v i a " b u l k - l i k e " water regions. Partition coefficients of steroids i n p-HEMA a r e d o m i n a t e d by t h e i r h i g h s o l u b i l i t y o f t h e s t e r o i d s i n t h e hydrophobic regions o f t h e hydrogels o r A domains, whereas, p e r m e a t i o n i s d o m i n a t e d by d i f f u s i o n w i t h i n " f l u c t u a t i n g p o r e s . " Acknowledgements S t i m u l a t i n g d i s c u s s i o n s w i t h D r s . J . D. A n d r a d e , D. G. G r e g o n i s , and J . F e i j e n made t h i s work p o s s i b l e . We g r e a t f u l l y a c k n o w l e d g e D r . S. R o n e l , Hydron Med. S c i . , I n c . , f o r h i s g e n e r o u s d o n a t i o n s o f p u r e HEMA. S u p p o r t e d by NIH g r a n t s HD 09791 and HL 13738. Abstract The permeabilities of water soluble nonelectrolytes and sev eral hydrophobic steroids in poly(hydroxyethyl methacrylate) hydrogel films were determined. The effects of crosslinking and variations in equilibrium water content of the films, on the ob served permeabilities, were investigated. For hydrophilic solutes the permeation and partition coefficients are consistent with transport via the "bulk-like" water regions of the hydrogel films. These "bulk-like" water regions probably exist within the porous regions of the film. Decreases in the "bulk-like" water via copolymerization or crosslinking reduce both the partition and per meation coefficients, indicating exclusion of hydrophilic solutes from non "bulk-like" water regions. For hydrophobic solutes, per meability coefficients are smaller and partition coefficients are much larger relative to the hydrophilic solutes. For the hydro phobic solutes modelistic analysis of the permeation and partition


WATER IN POLYMERS

358


data indicate permeation occurs predominantly by a pore-type mechanism in poly(hydroxyethyl methacrylate) and by a partition mechanism in highly crosslinked poly(hydroxyethyl methacrylate) films. The porous flux was associated with the "bulk-like" water regions of the hydrogel films and the partition flux with the collective polymer matrix, "interfacial" and "bound" water region of the films.

O.;

Literature

Cited

Lim, D.

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RECEIVED January 4, 1980.


Salt

Water in Polymers - ACS Publications

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