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E L S E V I E R

Internationa l Journa l of Pharm aceutics 116 (1995) 159-168

i n t e r n t i o n l

j o u r n l o f

p h r m c e u t i c s

M atrix swe l ling A s imp le m od e l descr ib ing ex tent o f swe l l ing o f

H P M C m a t ric es

L u c y S a i C h e o n g W a n * , P a u l W a n S i a H e n g , L e e F u n W o n g

Department of Pharmacy National University of Singapore Singapore Singapore

Rec eived 13 May 1994; accepted 20 Augu st 1994

A b s t r a c t

The swel l ing of HPMC mat r i ces was measured by de te rmining the ve r t i ca l d i sp lacement wi th t ime us ing a d ia l

indica tor . Curve f i t t i ng of the da ta of swe l l ing was ca r r i ed out by us ing the coupled Case I -Case I I mode l . The

th ickness of the swol l en l ayer formed a round the mat r ix core was grea te r in HPMC compac t s of h igher v i scos i ty

grade . Th e ra t es of C ase I (a~ co ef f i c i en t ) and Case I I ( /3 S coef f i c i en t ) swe ll ing mech ani sms inc reased wi th

c o n c e n t r a t io n a n d / o r v i sc o s it y g r a d e o f H P M C .

Keywords: Hyd roxyprop ylmethylce l lu lose ; Swell ing; Case I d i f fus ion; Case I I re l axa t ion; C oupled Case I ; Case I I

mo de l ; V i scos i ty

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

S w e ll in g m e a s u r e m e n t s o f ce l lu l o se a n d t h e

r e l a t i o n b e t w e e n t h e r h e o l o g i c a l a n d s w e l l i n g

p r o p e r t i e s o f c e l lu l o s e w e r e e x t e n s iv e l y d is c u s s e d

b y W e s t m a n a n d L i n d s t r o m ( 1 98 1 a ,b ,c ,d ) . T h e

s w e l li n g o f c e l l u lo s e w a s f o u n d t o b e i n f l u e n c e d

b y c r o s s -l i n k in g , h e a t t r e a t m e n t a n d p H o f t h e

l iq u i d u s e d . T h e s w e l li n g o f c o r e t a b l e t s d u r i n g

a q u e o u s c o a t i n g a n d a m o d e l d e s c r i b i n g t h e e x -

t e n t o f sw e l l in g a n d w a t e r p e n e t r a t i o n f o r in s o l u -

* Corresponding au thor. N ational University of Singapore,

Dept of Pharm acy, 10 Ken t Ridge Crescent, 0511 Singapore,

Singapore.

b l e t a b l e t s c o n t a i n i n g a s u p e r - d i s i n t e g r a n t w a s

d e m o n s t r a t e d b y F a r o o n g s a r n g a n d P e c k ( 19 9 1,

1 9 9 2 ). M i t c h e l l e t a l. ( 1 9 9 1 ) s h o w e d t h a t t h e

s w e l li n g b e h a v i o u r o f c e l lu l o s e e t h e r m a t r i c e s

c o n t a i n i n g H P M C d e p e n d s o n t h e t e m p e r a t u r e ,

d r u g a n d p o l y m e r s u b s ti t u ti o n t y p e .

T h e s w e ll in g o f H P M C - i b u p r o f e n m a t r i c e s

c o u l d b e d e s c r i b e d b y a f i r s t - o r d e r k i n e ti c s ( W a n

e t a l ., 1 9 9 3 a ) . M a t r i x s w e l l i n g w a s a f f e c t e d b y t h e

c o n c e n t r a t i o n a n d v i s c o s it y g r a d e o f t h e p o l y m e r .

O n f u r t h e r e x a m i n a t i o n , i t w a s f o u n d t h a t m a t r i x

s w e ll in g o f H P M C - p r o p r a n o l o l m a t r i c e s d e v i at e s

s i g n i f i c a n t l y f r o m t h i s ~ / t i m e r e l a t i o n s h i p . I n t h i s

s t u dy , t h e k i n e t ic s o f m a t r i x s w e l li n g w a s e x a m -

i n e d u s i n g t h e c o u p l e d C a s e I - C a s e I I e q u a t i o n a s

w a s u s e d f o r l i q u i d u p t a k e i n t o t h e s e m a t r i c e s

( W a n e t a l . , 1 9 9 3 b , c ) .

0378-5173/95/$09.50 1995 Elsevier Science B.V. All rights reserved

SSDI

0 3 7 8 - 5 1 7 3 ( 9 4 ) 0 0 2 8 5 - 1

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160 L.S . Cheong W an e t aL / I n t ernat ional Journa l o f Pharmaceu t i cs 116 1995) 159-1 68

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

2 1 Ma ter ia l s

P r o p r a n o l o l h y d r o c h l o r i d e ( U S P X X I I ) a n d

i b u p r o f e n ( p h a r m a c e u t i c a l g r a d e , I ta l y ) w e r e c h o -

s e n a s m o d e l d r u g s t o r e p r e s e n t w a t e r - s o l u b l e

a n d p o o r l y w a t e r - s o l u b l e d r u g s , r e s p e c t iv e l y .

H y d r o x y p r o p y l m e t h y l c e l l u l o s e s , H P M C ( S h i n -

E t s u C h e m i c a l C o . , J a p a n ) o f d i f f e r e n t v i s co s i ty

g r a d e s : 4 0 0 0 ( K 4 ) , 1 5 0 0 0 ( K 1 5 ) , 3 0 0 0 0 ( K 3 0 ) ,

5 0 0 0 0 ( K 5 0 ) a n d 1 0 0 0 0 0 ( K 1 0 0 ) c p s w e r e u s e d a s

m a t r i x p o l y m e r s . T h e a p p a r e n t v i s c o s i t i e s o f 2 %

( w / v ) a q u e o u s s o l ut io n s o f t h e H P M C w e r e 4 3 80 ,

1 8 2 0 0 , 3 5 8 0 0 , 4 4 4 0 0 a n d 1 0 0 0 0 0 c p s , r e s p e c -

t iv e ly . T h e v i s c o si t y w a s d e t e r m i n e d b y t h e U S P

X X I I m e t h o d .

d e v i a t i o n o f t h e i n c r e a s e i n t h ic k n e s s o f t h r e e

m a t r i c e s w e r e d e t e r m i n e d .

2 2 3 T r ea t m en t o f da t a

A l l c a l c u l a t i o n w a s p e r f o r m e d u s i n g SA S TM

s o f t w a r e o n a p e r s o n a l c o m p u t e r .

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

T a k i n g a a s t h e o r i g i n a l th i c k n e s s o f th e d r y

m a t r i x , s a s t h e t h i c k n e s s o f t h e s w o l l e n m a t r i x ,

t h e n o r m a l i s e d i n c r e a s e i n t h e m a t r i x t h i c k n e s s ,

e x p r e s s e d a s a p e r c e n t a g e , ~ , c a n b e u s e d a s a

s w e l l i n g i n d e x w h e r e :

s - - a

6 = 1 0 0 % ( 1 )

a

2 2 M e t h o d s

2 2 1 Prepa rat ion o f ma t rices

T h e d r u g a nd H P M C w e r e t h o ro u g h l y m i x ed

i n a m i x i n g b a g f o r 1 0 m i n . A w e i g h e d a m o u n t o f

t h e m i x t u r e w a s f e d m a n u a l l y i n t o t h e d i e o f a

s i n g l e - p u n c h t a b l e t t i n g m a c h i n e ( M a n e s t y F 3 ,

U K ) t o p r o d u c e a m a t r i x t a b l e t o f 6 0 0 m g a n d

p o r o s i t y o f 0 . 1 0 + 0. 0 1 u s i n g f i a t p u n c h e s o f d i -

a m e t e r 1 4 m m f o r H P M C - i b u p r o f e n m a t ri c es ,

a n d 3 0 0 m g a n d p o r o s i t y o f 0 . 15 + 0. 01 u s i n g f i a t

p u n c h e s o f d i a m e t e r 9 .5 m m f o r H P M C - p r o -

p r a n o l o l m a t r i c e s . M a t r i c e s w e r e p r e p a r e d u s i n g

t h e v a r i o u s v is c o si ty g r a d e s o f H P M C a n d w i t h

d i f f e r e n t c o n c e n t r a t i o n s o f t h e d r u g .

2 2 2 Swel l ing s tudies

I n a c i r c u l a r d i s h m e a s u r i n g 6 . 5 c m i n d i a m e -

t e r a n d 3 . 4 c m d e e p , t h e m a t r i x w a s m o u n t e d

b e t w e e n t w o f i l te r p a p e r s ( W h a t m a n 5 4 ) a n d a

g la s s c o v e r sl ip w a s p l a c e d b e t w e e n t h e t i p o f t h e

d i a l a n d t h e u p p e r f i l t e r p a p e r ( W a n e t a l ., 1 9 9 3 a ).

T h e w h o l e a s s e m b l y w a s p l a c e d i n a w a t e r - b a t h

t h e r m o s t a t i c a l l y m a i n t a i n e d a t 3 7 + 0 . 5 C . A f i x e d

v o l u m e ( 5 0 m l) o f th e l i qu i d , p r e - e q u i l i b r a t e d a t

3 7 _+ 0 . 5 C , w a s p o u r e d i n t o t h e d i s h . T h e v e r t i c a l

i n c r e a s e i n t h e m a t r i x t h i c k n e s s w a s r e c o r d e d

w i t h a d i a l i n d i c a t o r ( M i t u t o y o , 2 1 1 8 - 5 0 , J a p a n ) .

F o r e a c h f o r m u l a t i o n , t h e m e a n a n d s t a n d a r d

3 1 K i ne t i c mode l s o f t he s w e l li ng me chan i s m s

T h e d y n a m i c s w e l l in g o f th e m a t r ix , r e p r e -

s e n t e d b y 3 , as a f u n c t i o n o f ti m e , t , w a s a n a l y z e d

a c c o r d i n g t o :

l o g 6 = n s l o g t + e 2 ( 2 )

w h e r e 3 i s t h e s w e l l i n g i n d e x d e f i n e d i n E q . 1 , n S

i s t h e e x p o n e n t d e s c r i b i n g F i c k i a n o r a n o m a l o u s

s w e l l in g m e c h a n i s m a n d c 2 is a c o n s t a n t . T h e

v a l u e s o f c 2 a n d e x p o n e n t s n s f o r t h e v a r i o u s

f o r m u l a t i o n s a n a l y z e d a r e g i v e n i n T a b l e s 1 a n d

2.

T h e s w el li ng m e c h a n i s m o f H P M C - i b u p r o f e n

m a t r i c e s i n p H 7 . 2 b u f f e r s o l u t i o n w a s a p p r o x i -

m a t e l y C a s e I ( F i c k i a n ) w i t h n s c l u s t e r i n g a r o u n d

0 .5 ( T a b l e 1 ). A t v e r y lo w H P M C c o n c e n t r a t i o n

( 5 - 1 0 % ) , t h e e s t i m a t i o n o f n s w a s l e s s a c c u r a t e ,

p r o b a b l y d u e t o t h e l i m i t e d n u m b e r o f d a t a p o i n t s

c o l l e c t e d f o r t h e s e m a t r i c e s , i n c o m p a r i s o n w i t h

o t h e r s . T h i s w a s a l so t r u e f o r n ~ v a l u e s o b s e r v e d

i n H P M C - p r o p r a n o l o l m a t r i c e s c o n t a i n i n g s i m i l a r

a m o u n t o f H P M C ( T a b l e 2 ). T h is w as b e c a u s e

t h e a m o u n t o f i n c r e a s e i n m a t r i x sw e l li n g in t h e s e

m a t r i c e s w e r e v e r y l ow a n d i n s o m e i n s t an c e s , t h e

m a t r i c e s c o l l a p s e d a f t e r a m a x i m u m i n c r e a s e i n

t h i c k n e s s w a s a t t a i n e d . F o r H P M C - p r o p r a n o l o l

m a t r i c e s , t h e s w e l l i n g m e c h a n i s m i n w a t e r b e -

c a m e n o n - F i c k i a n w i t h i n c r e a si n g a m o u n t s o f

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L.S .

Cheong Wan et a l ~ In terna t iona l Journ a l o f Pharmaceut i cs

116 1995) 159 -168

161

T a b l e 1

V a l u e s o f k i n e t i c e x p o n e n t (ns ) , c 2 and c or r e lat ion c oe f f i c ie nt

(r 2) fo l lowing l ine ar r e gr e s s ion analys i s of data f r om swe l l ing

s t u d i es o f H P M C i b u p r o f e n m a t r i ce s a t

pH 7.2

Visc os i ty Pe r c e nt Log 6 = n s log t + c 2

gr ade

H P M C H s C 2 r 2

K4 5 0.12_+0.01 -2 .45 0.8511

10 0.30 _+ 0.00 - 1.54 0.985 3

20 0.40 _+ 0.01 - 0.88 0.972 5

30 0.41 -+0.01 -0. 76 0.9867

40 0.48 _+ 0.00 - 0.99 0.99 68

50 0.50 _+ 0.00 - 0.89 0.99 68

100 0.56_+0.01 -1 .44 0.9952

K15 5 0.16_+0.01 -4 .36 0.8473

10 0.32 + 0.01 - 1.86 0.96 64

20 0.42 _+ 0.01 - 0.89 0.98 34

30 0.43 _+ 0.01 - 0.82 0.98 76

40 0.47 _+ 0.00 - 0.82 0.99 70

50 0.50 _+ 0.00 - 1.05 0.998 5

100 0.58 _+ 0.00 - 1.60 0.99 77

K30 5 0.22 _+ 0.01 - 2.25 0.96 75

10 0.37_+0.01 -2 .20 0.9535

20 0.47 _+ 0.00 - 1.28 0.99 40

30 0.45 _+ 0.00 - 0.88 0.99 44

40 0.47 -+ 0.00 - 0.70 0.99 84

50 0.48 + 0.00 - 0.79 0.9992

100 0.58 -+ 0.00 - 1.45 0.99 80

K50 5 0.52 -+ 0.02 - 3.82 0.943 5

10 0.44 _+ 0.01 - 2.47 0.98 84

20 0.42 + 0.00 - 0.88 0.9942

30 0.43 _+ 0.00 - 0.69 0.99 33

40 0.47 _+ 0.00 - 0.82 0.99 70

50 0.48 -+ 0.00 - 0.72 0.99 58

100 0.60_+0.01 - 1.46 0.9956

H P M C ( T a b l e 2 ) . T h i s in d i c a t e d t h e i n c r e a s i n g

i m p o r t a n c e o f C a s e I I r e l a x at i o n al m e c h a n i s m t o

o v e r a l l m a t r i x s w e l l i n g .

I n o r d e r t o a s c e r t a i n t h e i m p o r t a n c e o f t h e

t w o s w e l l in g m e c h a n i s m s t o o v e r a ll m a t r ix

s w e l l in g , t h e k i n e t i c s o f s w e l l i n g w a s r e - e v a l u a t e d

b y c o n s i d e r i n g t h a t t h e s w e l l i n g o f m a t r i c e s d e -

p e n d s o n t w o p r o c e s s e s : l i q u i d d i ff u s i o n i n t o th e

m a t r i x a n d p o l y m e r s w e l l i n g d u e t o t h e p e n e -

t r a nt . C a l c u l a t i o n o f th e a p p r o x i m a t e c o n t r i b u -

t i o n s o f t h e t w o m e c h a n i s m s t o o v e r a ll s w e l l in g

p r o c e s s w a s c a r r ie d o u t b y f it t in g t h e d a t a t o t h e

s e c o n d o r d e r e q u a t i o n a n a l o g o u s t o t h a t p r o -

p o s e d b y P e p p a s a n d S a h l i n ( 1 9 8 9 ) f o r r e l e a s e

f r o m s w e l l a b l e m a t r i c e s. T h e e q u a t i o n o f t h e

m o d e l i s :

t~ = a s tl /2 + i s t c 3 (3)

w h e r e t h e f i r s t t e r m o n t h e r i g h t - h a n d s i d e r e p r e -

s e n t s C a s e I ( F i c k i a n ) c o n t r i b u t i o n a n d t h e s e c -

o n d t e r m i s t h e C a s e I I ( r e l a x a t i o n a l ) c o n t r i b u -

t i o n , ~5 i s t h e s w e l l i n g i n d e x o f m a t r i x , a n d f ls

c o r r e s p o n d t o s w e l l in g r a t e s o f t h e C a s e I a n d

C a s e I I m e c h a n i s m s r e s p e c t iv e l y , c 3 i s a c o n s t a n t

a n d t i s t im e . T h e g o o d n e s s - o f - f i t o f t h e s w e l l in g

d a t a w a s a l s o t e s t e d a c c o r d i n g t o t w o o t h e r m o d -

e l s r e p r e s e n t i n g C a s e I I a l o n e ( E q . 4 ) a n d C a s e I

a l o n e ( E q . 5 ) :

= / ~ ' s t + C 4 ( 4 )

= a , s t 1 / 2 + c s ( 5 )

T a b l e 2

V a l u e s o f k i n e t ic e x p o n e n t (ns) c 2 and correlat ion coeff ic ient

(r 2) fo l lowing l ine ar r e gr e s s ion analys i s of data f r om swe l l ing

s tudie s of HPMC pr opr anolol matr ic e s in wate r

Visc os i ty Pe r c e nt Log t5 = n s log t + c.

g r ade H P M C

/ /s C2

K4 5 0.25 _+ 0.03 0.43 0.773 9

10 0.06 + 0.01 1.28 0.650 2

25 0.79 _+ 0.03 - 3.78 0.934 4

50 0.64_+0.02 - 1.96 0.9_+49

75 1.58 _+ 0.08 - 8.74 0.903 6

K15 5 0.69_+0.18 -3 .19 0.4999

10 0.50 _+ 0.02 - 2.16 0.932 7

25 0.39 -+ 0.00 - 0.55 (I.9948

50 0.89 _+ 0.03 - 3.77 0.950 2

75 0.89 +_ 0.02 - 3.37 0.978 7

K30 5 0.11_+0.04 0.57 0.2716

10 0.16_+0.00 0.74 0.9518

25 0.36-+0.00 -0 .17 0.9898

50 0.52 -+ 0.00 - 0.81 0.9955

75 0.63 + 0.00 - 1.45 0.9993

K50 5 0.63 -+ 0.00 - 1.45 0.9993

10 0.40 -+ 0.05 - 0.58 0.6735

25 0.32 + 0.00 - 0.22 0.9977

50 0.52 _+ 0.00 - 0.73 0.9981

75 1.80_+0.0 7 - 10.21 0.925 8

K100 5 1.16_+0.12 -3 .80 0.8807

10 0.4 4 _+ 0.05 - 1.05 0.62 91

25 0.29 _+ 0.00 0.51 0.996 9

50 1.17 _+ 0.03 - 5.53 0.952 8

75 1.10 + 0.03 - 4.73 0.964 7

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162 L . S .

Cheong Wan et a l I n te rn a t i ona l Jou rna l o f Pha rmaceu t i c s

1 1 6 1 9 9 5 ) 1 5 9 - 1 6 8

w h e r e / 3 S a n d a a r e th e r a t e c o n s t a n t s o f C a s e I I

a n d C a s e I t r a n s p o r t , r e s p e c t i v e l y , a n d c 4 a n d c 5

a r e c o n s t a n t s .

T a b l e s 3 a n d 4 g i v e t h e g o o d n e s s - o f - f i t o f t h e

t h r e e m o d e l s b a s e d o n E q . 3 - 5 . A s c a n b e s e e n

f r o m t h e s q u a r e o f t h e c o r r e l a t i o n c o e f f i c i e n t s ,

t h e C a s e I m o d e l ( E q . 5 ) g e n e r a l l y fi ts t h e s w e l l in g

d a t a b e t t e r t h a n t h e C a s e I I m o d e l ( E q . 4 ) . H o w -

e v e r , o n f u r t h e r e x a m i n a t i o n u s i n g t h e p o l y n o -

m i a l m o d e l ( E q . 3 ) , t h e s e c o n d - o r d e r p o l y n o m i a l

e q u a t i o n g a v e t h e b e s t d a t a f i t . A s a n e x a m p l e o f

t h e d a t a o b t a i n e d , p l o t t i n g t h e s w e l l i n g d a t a a s a

f u n c t i o n o f t i m e ( F i g . 1 ) a g o o d f i t o f t h e p o l y n o -

m i a l m o d e l t o t h e a c t u a l d a t a c o l l e c t e d . T y p i c a l l y ,

t h e C a s e I m o d e l t e n d s t o o v e r e s t i m a t e t h e

s w e l l i n g i n d e x i n t h e e a r l y st a g e a n d t o u n d e r e s t i -

m a t e t h e s w e l l i n g i n d e x a t a m u c h l a t e r s t a g e o f

t h e s t u d y . T h e c o n v e r s e i s t r u e f o r t h e C a s e I I

n l o d e l . B a s e d o n t h e s e r e s u lt s , E q . 3 is u s e d

s u b s e q u e n t l y f o r t h e a n a l y s is o f a l l d a t a o n m a t r i x

s w e l l i n g .

3 2 Swell ing o f HPM C

H P M C i s a h y d r o p h i l ic p o ly m e r . I t s w e l ls o n

c o n t a c t w i t h w a t e r. T h e s w e l li n g o f H P M C c o m -

p a c t s o f d i ff e r e n t v i s c o si t y g r a d e w e r e d e t e r m i n e d

i n p H 7 . 2. T h e t h i c k n e s s o f s w o l l e n l a y e r fo r m e d

a r o u n d t h e m a t r ix c o r e w a s g r e a t e r i n m a t r ic e s

c o n t a i n i n g H P M C o f h i g h e r v i sc o s it y g r a d e. T h e

h y d r o d y n a m i c v o l u m e o c c u p i e d b y th e h y d r a t e d

p o l y m e r c h a i n s i s l a r g e r i n h i g h v i s c o s i t y g r a d e

p o l y m e r . C o n s e q u e n t l y , g r e a t e r s w o l l e n m a s s o f

t h e m a t r i c e s w a s f o r m e d ( T a b l e 5 ) .

T a b l e 3

V a l u e s o f c o r r e la t i o n c o e f f i c i e n t r 2 ) fo l l o w i n g l in e a r r e g r e s s io n a n a l y si s o f d a t a f r o m s w e l l in g s t u d i e s o f H P M C - i b u p r o f e n m a t r i c e s

a t p H 7 . 2 u s i n g E q . 3-5

V i s c o s i t y P e r c e n t 6 = f l ~ t + c 4 ~ = a ~ t 1 / 2 + c 5 ~ = as tl /2 + f i s t + c 3

g ra de HPMC

K4 5 0.3344 0.5535 0.8202

10 0.9079 0.9875 0.9879

20 0.9491 0.9940 0.9967

30 0.9505 0.9963 0.9988

40 0.9439 0.9987 0.9998

50 0.9442 0.9985 0.9996

100 0.9794 0.9831 0.9996

K15 5 0.4434 0.6712 0.8828

10 0.9509 0.9863 0.9910

20 0.9431 0.9974 0.9985

30 0.9420 0.9985 0.9993

40 0.9400 0.9992 0.9998

50 0.9472 0.9983 0.9999

100 0.9785 0.9841 0.9997

K30 5 0.8582 0.9683 0.9747

10 0.9747 0.9776 0.9944

20 0.9453 0.9983 0.9996

30 0.9878 0.9976 0.9993

40 0.9312 0.9998 0.9999

50 0.9367 0.9996 0.9999

100 0.9727 0.9887 0.9999

K50 5 0.7435 0.9242 0.9809

10 0.9375 0.9977 0.9982

20 0.9377 0.9989 0.9993

30 0.9295 0.9987 0.9988

40 0.9414 0.9989 0.9997

50 0.9606 0.9936 0.9991

100 0.9863 0.9749 0.9993

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L . S . C h e o n g W a n e t a l. / I n t e r n a t i o n a l J o u r n a l o f P h a r m a c e u t i c s 1 1 6 1 9 9 5 ) 1 5 9 - 1 6 8

163

ab l e 4

V a l u e s o f c o r r e l a t i o n c o e f f i c i e n t ( r 2 ) f ol l o w in g l i n e a r r e g r e s s i o n

m a t r i c e s i n d is t il l e d w a t e r u s i n g E q . 3 - 5

V i s c o s i t y P e r c e n t 8 = / 3 ' s t + c 4

g r a d e H P M C

a n a l y s is o f d a t a f r o m s w e l l in g s tu d i e s o f H P M C - p r o p r a n o l o l

6 = a ~ t 1 / ~ + c s 6 = a s t I / 2 + ~ s t + c 3

K 4 5 0 . 4 4 1 6 0 . 6 8 7 0 0 . 9 8 2 2

1 0 0 .1 3 7 7 0 .2 8 9 7 0 .5 9 2 1

2 5 0 .8 5 2 3 0 .9 8 1 5 0 .9 9 8 1

5 0 0 .8 8 1 2 0 .9 9 1 2 0 .9 8 6 7

7 5 0 .9 7 8 2 0 .9 5 5 5 0 .9 8 6 7

K 1 5 5 0 .3 7 5 9 0 .5 8 6 9 0 .7 9 2 1

1 0 0 .7 9 8 4 0 .9 4 4 4 0 .9 8 9 4

2 5 0 .8 1 4 6 0 .9 6 9 6 0 .9 9 9 1

5 0 0 .8 9 2 3 0 .9 8 2 1 0 .9 8 3 5

7 5 0 .9 5 3 6 0 .9 9 1 7 0 .9 9 5 8

K 3 0 5 0 .1 1 6 5 0 .3 2 5 3 0 .9 0 0 4

1 0 0 .5 3 8 2 0 .7 2 5 3 0 .9 1 3 5

2 5 0 .7 6 2 3 0 .9 4 3 3 0 .9 9 7 8

5 0 0 .8 7 6 8 0 .9 9 1 9 0 .9 9 9 3

7 5 0 .9 5 3 5 0 .9 9 4 4 0 .9 9 7 9

K 5 0 5 0 .8 1 7 1 0 .8 8 1 9 0 .8 8 2 0

1 0 0 .4 7 1 9 0 .6 9 2 8 0 .9 3 7 2

2 5 0 .8 0 9 1 0 .9 6 5 9 0 .9 9 7 0

5 0 0 .9 0 5 9 0 .9 9 5 9 0 .9 9 8 1

7 5 0 .9 8 6 6 0 .9 9 6 7 0 .9 9 0 3

K 1 0 0 5 0 . 7 8 0 9 0 . 8 6 9 6 0 . 8 7 l l

1 0 0 .5 5 5 0 0 .7 6 4 0 0 .9 4 5 1

2 5 0 .7 9 2 3 0 .9 5 5 9 0 .9 9 3 3

5 0 0 .9 3 1 4 0 .9 8 9 1 0 .9 8 9 8

7 5 0 .9 6 5 4 0 .9 8 7 0 0 .9 9 6 0

T h e swe l l i n g p r o f i l e s o f HPM C c om p ac ts c ou l d

b e ac c u r ate l y d e sc r i b e d b y th e p o l yn om i a l m od e l

Eq. 3) , as shown by the resul ts of l inear regres-

s i on an a l ys i s o f HPM C c om p ac ts i n T ab l e 4 . T h e

c oe f f i c i e n ts o f th e Case I an d Case I I m e c h a-

n i sm s on th e H PM C c om p ac ts o f vari ou s v i s cos i ty

gr ad e s sh owe d th at th e c oe f f i c i e n ts o f th e Case I

m e c h an i sm we r e r a th e r s i m i l ar wh i l e th a t o f th e

C a s e I I m e c h a n i s m w a s s l i g h tl y l a r g e r f o r t h e

H P M C K 5 0 c o m p a c t .

3.3 . Swel l ing s tudies o f matr ices contain ing HPMC

an d ibuprofen as a poor ly water soluble drug

The plots of percent increase in matr ix swel l ing

against t for matr ices contain ing ibup rofen and

ab l e 5

h e

s w e ll in g b e h av i o u r o f H P M C c o m p a c t s a t p H 7 .2

V i s c o s i t y g r a d e a S ( 1 0 - l ) ( % / ~ / s )

K 4 2 . 3 4 + 0 . 0 4

K15 2 .30 _+ 0 .30

K3 0 3 .00 _+ 0 .02

K 5 0 2 . 3 0 + 0 . 0 7

/3 s ( 1 0 - 3 ) ( % / s )

3 .6 8 + 0 .0 8

3 .4 2 + 0 .0 6

3 .3 5 + 0 .0 4

5.49 _+ 0 .16

y - i n t e rc ep t c 3 6 3 o min

0 .3 2 1 6 .6 7 + 0 .4 8

0.21 15 .97 + 1 .25

0.03 18 .77 _+/ ).72

0.48 20 .06 _+ 0 .19

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164

L . S . C h e o n g W a n e t al . / I n t e r n a t i o n a l J o u r n a l o f P h a r m a c e u t i c s 11 6 1 9 95 ) 1 5 9 - 1 6 8

d i f f e r e n t a m o u n t o f H P M C o f v a r i o u s v i s co s i ty

g r a d e s a r e p r e s e n t e d i n F i g . 2 . T h e s w e l l i n g o f

m a t r i c e s i n c r e a s e s w i t h t h e c o n c e n t r a t i o n o f p o ly -

m e r . M a t ri c e s c o n t ai n i n g 5 % H P M C d i d n o t h a ve

s u f f ic i e n t p o l y m e r f o r s i g n if i ca n t m e a s u r a b l e

s w e l li n g o f m a t r i c e s t o o c c u r , t h e a m o u n t o f

s w o l l e n l a y e r f o r m e d a t 3 0 m i n ( 6 3 0 min ) b e i n g l e s s

t h a n 1 % o f t h e o r i g i n a l t h i c k n e s s ( T a b l e 6 ) . A

m i n i m u m a m o u n t o f 2 0 % H P M C w a s re q u i re d

f o r t h e m a t r i c e s t o s w e l l to 1 0 % o f t h e i r i n i ti a l

t h i c k n e s s .

T h e s w e l l i n g r a t e s a t t r i b u t e d t o t h e C a s e I

m e c h a n i s m i n c r e a s e d s h ar p ly w h e n t h e H P M C

c o n c e n t r a t i o n w a s v a r ie d f r o m 5 t o 5 0 % o f t h e

t o t a l w e i g h t c o n t e n t ( F i g . 3) . T h e e f f e c t o f H P M C

c o n c e n t r a t i o n o n s w e l l i n g r a t e s w a s l e s s m a r k e d

a t h i g h e r p o l y m e r c o n t e n t ( > 5 0 % H P M C o f h i g h

v i s c o s it y g r a d e ) . A s a t u r a t i o n s t a t e w a s a t t a i n e d

b e y o n d 4 0 % H P M C c o n t e n t o f t h e s e m a t ri c es .

T h i s is b e c a u s e a s th e H P M C b e c o m e s h y d r a t e d

a n d f o r m s a s w o l l e n g e l , d i s s o l u t i o n a n d s u r f a c e

e r o s i o n o f t h i s w a t e r l o g g e d g e l o c c u r s i m u l t a n e -

o u s l y . T h e w a t e r u p t a k e r a t e a l s o s l o w s d o w n i n

v e r y h i g h p o l y m e r c o n c e n t r a t i o n a s t h e s w o l l e n

p o l y m e r c a n i n t u r n a f f e c t t h e w a t e r u p t a k e r a t e .

T h e c o n t r i b u t i o n o f t h e C a s e I I m e c h a n i s m t o

m a t r i x s w e l l i n g w a s r e l a t i v e l y l e s s t h a n t h a t o f t h e

C a s e I m e c h a n i s m ( T a b l e 6 ) . A s o b s e r v e d i n t h e

c a s e o f C a s e I s w e l li n g r a t e s , t h e r a t e s o f s w e l l in g

o f t h e C a s e I I m e c h a n i s m g e n e r a l l y i n c r e a s e d

w i t h H P M C c o n c e n t r a t i o n . I t i s i n t e r e s t i n g t o

n o t e t h a t n e g a t i v e r a t e s w e r e o b t a i n e d f o r m a t r i -

c es c o n t a in i n g 5 % H P M C a n d 1 0 % H P M C K 4 .

T h i s c o u l d b e d u e t o t h e p a r t i a l c o l l a p s e o f m a t r i-

c e s d u r i n g s w e l l i n g m e a s u r e m e n t w h i c h w i l l b e

d i s c u s s e d s h o r t l y .

3.4. Swelling behaviour of matrices containing

HPMC and propranolol as a water soluble drug

T h e s w e l l in g b e h a v i o u r o f m a t r i c e s c o n t a i n i n g

H P M C o f v a r i o u s v i s co s i ty g r a d e a n d p r o p r a n o l o l

Table 6

Effect of varying the amount of HPMC of various viscosity grade on the swelling of HPMC-ibuprofen matrices at pH 7.2

Viscosity grad e Percent HP MC as a ( X 10 -2 ) ( /x/ s) /3 s b ( X 10 -4 ) ( /S ) y-in terc ept c 3 t]30 min

K4 5 0.66 + 0.05 - 0.84 + 0.09 0.09 0.20 + 0.08

i0 4.36 + 0.22 0.46 + 0.38 0.37 2.17 + 0.23

20 16.38 + 0.56 6.68 + 0.98 0.67 8.96 + 0.52

30 20.07 + 0.42 7.93 _+ 0.72 0.77 10.82 _+ 1.34

40 29.48 _+ 0.24 7.12 _+ 0.41 0.25 14.13 _+ 1.36

50 36.49 _+ 0.39 9.10 +_ 0.68 0.19 17.36 _+ 1.32

K15 5 0.14 _+ 0.01 -0 .17 _+ 0.02 0.01 0.04 _+ 0.02

10 2.82 _+ 0.17 1.68 _+ 0.30 0.31 1.76 +_ 0.15

20 19.97 _+ 0.42 4.96 _+ 0.74 0.54 10.04 +_ 1.07

30 24.74 _+ 0.34 5.31 _+ 0.60 0.52 12.01 _+ 0.66

40 32.03 +_ 0.26 5.59 _+ 0.45 0.37 15.03 _+ 1.49

50 32.02 _+ 0.15 9.65 +_ 0.26 0.15 15.58 _+ 0.88

K30 5 1.26 _+ 0.08 -0 .52 _+ 0.13 0.16 0.59 +_ 0.14

10 2.41 _+ 0.16 3.87 + 0.29 0.27 2.00 _+ 0.43

20 19.94 _+ 0.42 5.38 _+ 0.37 0.23 9.72 _+ 0.53

30 24.19 +_ 0.35 7.85 +_ 0.61 0.59 12.35 +_ 2.58

40 39.44 _+ 0.21 1.67 _+ 0.37 0.28 17.33 +_ 0.42

50 38.08 _+ 0.18 4.60 + 0.32 0.26 17.10 +_ 1.68

K50 5 4.47 + 0.16 -3 .80 _+ 0.28 -0. 14 1.06 + 0.33

10 4.99 + 0.11 0.79 _+ 0.20 0.11 2.35 + 0.25

20 21.21 + 0.30 3.07 + 0.51 0.57 10.19 + 0.53

30 27.87 + 0.48 0.93 +_ 0.84 0.71 12.71 + 0.42

40 34.53 + 0.32 6.86 + 0.56 0.68 16.49 _+ 0.71

50 31.65 + 0.64 20.73 _+ 1.11 0.79 17.92 + 0.57

p < 0.0001.

h Not significant.

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L.S . C heong W an e t a l . / I n t ernat iona l Journa l o f Pharmaceut i cs 116 1995) 159- 168 165

3 0

2 5

M o d e l

- v - A c t u a l

- - & - C a s e I

I - C a s e I I

c o u p l e d C a s e I - C a s e I I

2 0

1 0

y ,

. A

w , L

~ t A

A .

A v

v

O I I I I

0 1 0 2 0 3 0 4 0 5 0 6 0

T i m e ( r a i n )

Fig. 1. A typical gra ph showing the goodness-of-fit of various

models compared to the actual swelling data of HPMC K4

compact at pH 7.2.

3 0

P e r c e n t H P M C

5 0

0 4 O

2 5

~ 3 0

- ~ - 2 0

+ 1 0

2 0 - * 5

1 5

/

1 0 / ~ e ~ D ~ e

0 1 0 2 0 3 0 4 0 5 0 6 0

T i m e ( m i n )

Fig. 2. Effect of variation of amounts of HPMC K4 on the

swelling of HPMC-ibuprofen matrices at pH 7.2.

Table 7

Swelling profiles of HPMC-propranolol matrices containing varying amounts of HPMC in distilled water

Viscosity grade Percen t HPM C a s

( X 1 0 - 1 ) ( % / ~ / S )

fls ( 10- 2) ( / s ) y-in terc ept c27 ~30 mi~

K4 5 9.68 + 0.38 -4. 79 _+ 0.26 -0 .0 1 0.00 + 0.00

10 1.40 + 0.17 -0 .20 _+ 0.03 3.52 5.56 + 0.89

25 2.47 + 0.04 -0 .14 _+ 0.01 - 1.06 10.14 + 2.28

50 4.59 + 0.10 -0 .17 + 0.02 - 1.25 15.37 +_ 2.35

75 1.97 _+ 0.31 0.66 + 0.06 - 2.06 19.25 +_ 0.89

K15 5 2.38 + 0.42 - 1.36 + 0.34 -0 .28 0.00 _+ 0.00

10 1.84 + 0.07 -0 .32 _+ 0.02 -0 .22 0.91 _+ 1.57

25 3.35 + 0.03 -0. 23 + 0.00 -0 .27 10.14 + 2.28

50 5.05 + 0.28 -0 .1 1 _+ 0.05 -2 .9 1 17.27 + 1.12

75 4.83 + 0.17 0.26 _+ 0.03 -2 .29 23.68 _+ 1.00

K30 5 8.13 _+ 0.72 -5.64 _+ 0.59 0.10 1.87 _+ 1.96

10 3.10 _+ 0.22 -0.60 _+ 0.06 1.81 2.31 +_ 3.83

25 4.28 _+ 0.53 -0. 36 + 0.09 0.52 11.95 +_ 1.78

50 6.56 _+ 0.06 -0. 28 _+ 0.01 -0 .99 21.94 + 0.33

75 4.53 _+ 0.15 0.26 _+ 0.03 - 1.25 27.07 _+ 2.29

K50 5 2.53 _+ 0.95 0.10 + 0.90 -0 .34 0.00 + 0.00

10 5.83 + 0.37 - 1.66 ___0.14 -0 .09 2.31 + 2.73

25 4.22 +_ 0.07 -0 .30 + 0.01 1.38 13.67 + 0.12

50 6.21 _+ 0.11 -0 .13 _+ 0.02 -0. 63 23.51 +_ 0.46

75 1.44 _+ 0.30 0.85 _+ 0.05 - 1.76 20.99 _+ 2.62

K100 5 4.03 _+ 1.33 -0. 49 +_ 1.27 -0 .49 0.00 +_ 0.00

10 4.18 +_ 0.23 -0 .80 _+ 0.07 -0 .16 3.84 _+ 2.34

25 4.50 +_ 0.11 -0 .34 +_ 0.02 2.04 14.57 +_ 0.12

50 4.80 _+ 0.26 0.09 _+ 0.04 -2 .97 19.77 + 0.20

75 4.97 +_ 0.23 0.47 0.04 - 2.88 27.60 + 0.66

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166

L. S. Cheong Wan et al. / International Journal of Pharmaceutics 116 1995) 159-168

[ _ ~ 1 0 0 -

7 5 -

~ s 0 -

2 5 -

1 ~ 1 0 0 .

l s l t y

x l O 3 c p $ )

5 . 0 0

1 0 0 . 0 0

7 6 . 2 5 . -

5 2 . 5 0 .

u

~ . 6 , 5 5

. . . . . . . . . .

- . . . . 3 0 . 7 7

2 8 . 7 5 , ~ - - - - - - - - - - ~ 2 4 . 9 9

. . . . 1 3 .4 ~3 ~ ~ ' ' ' ' ~

. . . .

; . 65

. . . . . . . . . .

4

1 ~ 8 7

1

. 0 0

4 . 0 1 5 . 5 2 7 . 0 3 1 3 . 5 5 0 . 0

iscosity

( x 1 0 3 c p s )

F i g. 3 . S u r f a c e a n d c o n t o u r p l o t s d e p i c t i n g t h e e f f e c t o f

c o n c e n t r a t i o n a n d v i s c o s it y o f H P M C o n t h e a s c o e f f i c ie n t o f

H P M C i b u p r o f e n m a t r i c e s at p H 7 .2 .

i n d i s t il l e d w a t e r w a s s t u d i e d . S w e l l in g o f m a t r i -

c e s w a s f a s t e r d u r i n g t h e f i r s t f e w m i n u t e s f o r

m a t r i c e s c o n t a i n i n g a l o w p o l y m e r c o n t e n t ( 5 -

1 0 % ) . T h i s w a s d u e t o a f a s t e r h y d r a t i o n o f t h e s e

m a t r i c e s w i t h a b u n d a n t s o l u b le d ru g . W h e n t h e

s w e l l i n g m e a s u r e m e n t w a s a l l o w e d t o e x t e n d o v e r

a l o n g e r p e r i o d , m a t r i c e s c o n t a i n i n g a l o w H P M C

l e v e l s w e l l e d t o a m a x i m u m t h i c k n e s s . T h i s w a s

f o l l o w e d b y a p e r i o d o f c o n s t a n t s w e l li n g r a te

b e f o r e a r e d u c t i o n i n t h e 6 v a l u e s w a s a c h i e v ed .

T h e s w o l l e n m a s s d i m i n i s h e d i n t h i c k n e s s a n d

s lo w l y c o l l a p s e d . T h i s o b s e r v a t i o n w a s o f t e n s e e n

i n m a t r i c e s w i t h p o l y m e r c o n t e n t < 1 0 % a n d c a n

b e a t t r i b u t e d t o d i s s o lu t i o n o f th e w a t e r - s o l u b l e

d r u g . T h e t h i c k n e s s o f t h e s w o l l e n l a y e r a r o u n d

t h e m a t r i x c o r e v a r i e d w i t h t h e p o l y m e r c o n t e n t

o f t h e m a t r i x s y s te m s . T h e p e r c e n t s w e l l in g a t 3 0

min,

8 30 min w a s u s e d t o c o m p a r e t h e i n f l u e n c e o f

H P M C c o n c e n t r a t i o n a n d v i sc o si ty g r a d e o n t h e

s w el li ng b e h a v i o u r o f H P M C - p r o p r a n o l o l m a t r i-

c e s ( Ta b le 7 ) . G e ne r a l l y , 830 m in i nc r e a s e d w i th

t h e c o n c e n t r a t i o n o f p o l y m e r i n t h e f o r m u l a t i o n s .

T h e a m o u n t o f g e l a ti n o u s l a y e r f o r m e d a l s o v a r -

i e d w i t h t h e v i s c o si t y g r a d e o f H P M C u s e d , g e n -

e r a l l y a t h i c k e r l a y e r o f s w o l l e n m a s s w a s o b -

t a i n e d w i t h m a t r i c e s c o n t a i n i n g s i m i l a r H P M C

c o n t e n t o f h i g h e r v i s co s i ty g r a d e .

T h e m e a s u r e m e n t o f m a t r i x sw e l li n g i n v o l v ed

t h e u s e o f a g a u g e t o r e c o r d t h e v e r t i c a l i n c r e a s e

i n t h e t h i c k n e s s o f t h e s w o l l e n m a s s . I n r e s p o n s e

t o t h e s w e l li n g p r e s s u r e o f t h e m a t r i x w i t h t i m e ,

t h e c o m p r e s s i o n o f t h e t i p o f t h e g a u g e w o u l d

r e s u l t i n a c o n s t a n t b a c k p r e s s u r e ( 1 . 4 7 N ) o n t h e

s w e l l in g m a t r i x . I f t h e u p w a r d s w e l l in g f o r c e o f

t h e m a t r i x w e r e l o w , t h e o p p o s i n g b a c k p r e s s u r e

w o u l d r e s u l t i n a l o w e r r e a d i n g . T h i s p r o d u c e d

n e g a t i v e v al u e s o f C a s e I I c o e f f i c ie n t s d u e t o a n

u n d e r e s t i m a t i o n o f t h e e x t e n t o f m a t r ix s w e l li n g.

I n m a t r i c e s w i t h l o w H P M C c o n t e n t , l e a c h i n g o f

d r u g w e a k e n e d t h e s w o l l e n m a s s . A s t h e m a t r i x

s w e l l e d , t h e d r u g - d e p l e t e d s w o l l e n m a s s i n -

c r e a s e d i n v o l u m e a n d t h e s w o l l en s t r u c t u r e

w e a k e n e d . H y d r a t i o n o f t h e p o l y m e r c a u s e d a

v i s c o u s g e l a t i n o u s l a y e r t o b e f o r m e d a r o u n d t h e

m a t r i x . T h i s c o u l d a c t a s a s h i e l d t h a t r e g u l a t e d

l i q u i d e n t r y i n t o t h e m a t r i x . T h e m a t r i x c o r e w a s

n o t w e t t e d a n d r e m a i n e d d r y . T h e s w o l l e n p e -

r i p h e r a l l a y e r a n d t h e i n n e r d r y c o r e w e r e d i s -

t i n ct l y s e p a r a t e u n d e r l ig h t m i c r o s c o p i c e x a m i n a -

t i on .

T w o o p p o s i n g f o r c e s o c c u r i n t h e m a t r i x w h e n

p o l y m e r s w e l l s . T h e a d h e s i v e f o r c e o f H P M C

b i n d s t h e m a t r i x t o g e t h e r . A s t h e p a r t i c l e s w e l l s ,

t h e m a t r i x e x p e r i e n c e s i n t r a m a t r i x s w e l l i n g f o r c e

p r o m o t i n g d i s i n t e g r a t io n . T h e a m o u n t o f g e l - fo r -

m i n g s u b s t a n c e w a s s m a l l i n m a t r i c e s w i t h a l o w

p o l y m e r c o n t e n t ( < 1 0% ) . O n t h e o t h e r h a n d ,

t h e s e m a t r i c e s h a d a l a r g e a m o u n t o f h ig h l y s o lu -

b l e d r u g ( > 9 0 % ) . A c o n t i n u o u s H P M C g e l w a s

n o t f o r m e d a n d p o c k e t s o f p o l y m e r m a s s w e r e

f o u n d w i t h i n t h e m a t r ix . D i s s o l u t i o n o f d r u g c r e -

a t e d v o i d s p a c e s w i t h in t h e s w o l l en p o r t i o n o f t h e

m a t r ix . T h i s f u r t h e r w e a k e n e d t h e g e l s t ru c t u r e .

I n t h e m e a n t i m e , w a t e r c o n t i n u e d t o e n t e r t h e

m a t r i x . W h e n t h e w a t e r - l o g g e d m a t r i x c o u l d n o t

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L.S . Cheong Wan e t a l . / I n t ernat iona l Journa l o f Pharmaceu t i cs 116 1995) 15 9-16 8 167

s u p p o r t t h e a m o u n t o f fl u i d i n th e m a t r i x , th e

s w o l l e n m a s s c o l l a p s e d d u e t o t h e s m a l l b a c k

p r e s s u r e e x e r t e d b y th e g a u g e . T h i s o b s e r v a t i o n

w a s o f t e n s e e n i n m a t r i c e s c o n t a i n i n g t h e s o l u b l e

d r u g, p r o p r a n o l o l o r w i t h lo w H P M C c o n t e n t

( 5 - 1 0 % H P M C in H P M C - i b u p r o f e n m a tr ic es ).

I n t h e i n it ia l s t a g e ( < 5 r a in ) , H P M C - p r o -

p r a n o l o l m a t r i c e s w i t h > 2 5 % p o l y m e r s w e l l e d

s l o w e r t h a n t h o s e w i t h a l o w e r p o l y m e r c o n t e n t .

A h i g h a m o u n t o f p r o p r a n o l o l i m p r o v e d t h e s u r -

f a c e w e t t i n g o f t h e m a t r i x . T h i s d i f f e r e n c e i n t h e

s w e l l i n g p r o f i l e s c a n b e c o n t r a s t e d b y c o m p a r i n g

w i t h t h e s w e l li n g p r o f i l e s o f H P M C - i b u p r o f e n

m a t r i c e s .

[ ~ 2 0 -

o ~ 1 5 -

o

-g

~ 0

~ ; . . ~ 52

5 7 . 5 2 5 V i s c o s i ty ( x 1 0 3 c p s )

4 0 . 0

P e r c e n t H P M 5 ~ 4

f

J

5 7 . 5 -

' 5 , g 3

4 0 . 0 -

2 2 . 5 -

. _ j .

. - ~ ~ ~ ~ , 8 .1 4 j

/ f 9 . 2 9 X _ _ ~ ~

5 0 , - 2 0 s 2 r 6 1 0 0

V i s c o s i t y ( x l O 3 c p s )

Fig. 4. Surface and contour plots depicting the effect of

concentr ation and viscosity of HPM C on the a S coefficient of

HPMC-propranolol matrices.

T h e s w e l l i n g c h a r a c t e r i s t i c s o f H P M C - p r o -

p r a n o l o l m a t r i c e s c o u l d b e d e s c r i b e d b y a p o l y n o -

m i a l e q u a t i o n ( E q . 3 ). T h e c o e f f i c ie n t s o f b o t h

C a s e I a n d C a s e I I m e c h a n i s m s g e n e r a l l y i n -

c r e a s e d w h e n t h e c o n c e n t r a t i o n a n d / o r v i s c o s i t y

g r a d e o f H P M C w e r e i n c r ea s e d ( T a b l e 7 ). U n l ik e

H P M C - i b u p r o f e n m a t r ic e s , t h e c o e ff i c i e n ts o f t h e

C a s e I m e c h a n i s m o f H P M C - p r o p r a n o l o l m a t ri -

c e s d i d n o t i n c r e a s e p r o p o r t i o n a l l y t o t h e H P M C

c o n t e n t b u t e x h i b i t e d a m i n i m u m - m a x i m u m r e l a -

t i o n s h i p ( F i g . 4 ) . T h i s w a s d u e t o t h e d i f f e r e n c e

i n d r u g s o l u b i l it i e s o f t h e m a t r i c e s . T h e s t r u c t u r e

o f th e s w o ll en m a s s o f H P M C - i b u p r o f e n m a t r ic e s

w a s m o r e r i g id a n d f i r m e r th a n t h a t o f H P M C -

p r o p r a n o l o l m a t r i c e s . B e i n g a h i g h l y s o l u b l e d r u g ,

m o r e p r o p r a n o l o l l e a c h e d o u t o f t h e s w o l l e n m a s s

c o m p a r e d t o t h e p o o r l y w a t e r - s o l u b l e d r u g ,

i b u p r o f e n . L e a c h i n g o f d r u g l e f t b e h i n d a h i g hl y

p o r o u s a n d w e a k m a t r i x s t r u c t u r e . T h e b a c k p r e s -

s u r e e x e r t e d b y t h e g a u g e o n t h e s w o l l e n m a s s

c o m p r e s s e d t h e s w o l l e n m a s s . I n t h e c a s e s o f

m a t r i c e s w i t h 5 % p o l y m e r , t h e a m o u n t o f s w o l l e n

m a s s f o r m e d w a s s m a ll . S w e ll in g o f H P M C i n t h e

m a t r i c e s w a s n o t s u m m a t i v e . I s o l a te d H P M C g e l

p o c k e t s f o r m e d a s H P M C s w e l l e d w e r e r e s p o n s i -

b l e f o r t h e v e r y h i g h a S c o e f f i c i e n t s o b t a i n e d ( F i g.

4 ). A r a t h e r l i n e a r p o r t i o n o f t h e g r a p h b e t w e e n

1 0 a n d 2 5 % i n d i c a t e s t h e e f f e c t o f i n c r e a si n g

p o l y m e r c o n t e n t o n t h e C a s e I s w e l l i n g c o e f f i -

c i e nt s . I n m a t r i c e s w i t h h i g h p o l y m e r c o n c e n t r a -

t i o n ( > 2 5 % ) , t h e h i g h l y p o r o u s s w o l l en m a s s w a s

s e v e r e l y c o m p r e s s e d a n d t h e t h i c k n e s s o f t h e

s w o l l e n l a y e r w a s r e d u c e d . T h e t o r t u o s i t y o f t h e

m a t r i x w a s i n c r e a s e d . T h e r a t e o f C a s e I d i f f u s i o n

o f li q u id i n t o t h e m a t r i x w a s t h e r e f o r e r e d u c e d .

4 C o n c l u s i o n s

T h e s w e l l in g c h a ra c t e r is t i c s o f H P M C m a t r i c e s

w e r e d e s c r i b e d b y a p o l y n o m i a l e q u a t i o n . T h e

c o e f f i c ie n t s o f b o t h C a s e I a n d C a s e I I m e c h a -

n i s m s g e n e r a ll y i n c r e a s e d w h e n t h e c o n c e n t r a t i o n

a n d / o r v is c os it y g r a d e o f H P M C w e r e i n c r e a se d .

F o r H P M C - i b u p r o f e n m a t r i c e s , t h e s w e l l i n g r a t e s

a t t r i b u t e d t o t h e C a s e I m e c h a n i s m i n c r e a s e d

s h a rp l y w h e n t h e H P M C c o n c e n t r a t i o n w a s va r-

i e d f r o m 5 to 5 0 % o f t o t a l w e i g h t c o n t e n t . T h e

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168 L.S. Cheong Wa n et al . / International Journal o f Pha rma ceut cs 116 1995) 159-1 68

effect of HPMC concentration on swelling rates

was less marked at higher polymer content (>

50 HPMC of high viscosity grade). A saturation

state was attained beyond 40 HPMC content of

these matrices. Unlike HPMC-ibuprofen matri-

ces, the coefficients of the Case I mechanism of

HPMC-propranolol matrices did not increase in

proportion to HPMC content but exhibited a

minimum-maximum relationship. This was due

the difference in drug solubilities in the matrices.

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