Polymer Bulletin 32, 509-515 (1994)
Polymer Bullelin 9 Springer-Verlag 1994
Incorporation of salicylates into poly(L-lactide) H. Super, D. W. Grijpma, and A. J. Pennings* Department of Polymer Chemistry, University of Groningen, Nijenborg 4, 9747 AG Groningen, The Netherlands Summary Recent studies have indicated that complications like swelling and i n f l a m m a t i o n of t h e s u r r o u n d i n g t i s s u e m a y o c c u r in t h e l a t e s t a g e o f t h e tn vtvo degradation of s e m i - c r y s t a l l i n e PLLA bone f i x a t i o n devices. Incorporation of an a n t i - i n f l a m m a t o r y d r u g , like a s a l i c y l a t e , in t h e p o l y ( L - l a c t i d e ) c h a i n m i g h t be a r o u t e to p r e v e n t t h e s e c o m p l i c a t i o n s . In t h i s s t u d y , it h a s been s h o w n t h a t it is p o s s i b l e to c o p o l y m e r i z e L - I a c t i d e w i t h d i - a n d t r i s a l i c y l i d e and to u s e s a l i c y l i c acid as an i n i t i a t o r f o r t h e L - l a e t i d e p o l y m e r i z a t i o n or t h e L - l a e t i d e / c - e a p r o l a c t o n e e o p o l y m e r i z a tion. Furthermore, PLLA w a s blended with poly(salicylic acid) and Z n ( s a l i c y l a t e ) 2 w a s s y n t h e s i z e d a n d t u r n e d o u t to be a c a t a l y s t f o r t h e r i n g o p e n i n g p o l y m e r i z a t i o n of L - l a c t i d e . The b i n a r y p o l y ( L - l a c t i d e ) / o - a c e t y l s a l i c y l i c acid s y s t e m h a s an e u t e c t i c c o m p o s i t i o n f o r 52 7, w / w of p o l y ( L - l a c t i d e ) in t h e m i x t u r e . Its e u t e e t i c m e l t i n g t e m p e r a t u r e is 119 ~
Introduction Among several biodegradable polymers, poly(L-lactide) (PLLA), a s e m i c r y s t a l l i n e p o l y e s t e r , is widely u s e d in biomedical a p p l i c a t i o n s s u c h a s d r u g r e l e a s e s y s t e m s (1), s u r g i c a l s u t u r e s (2) and i m p l a n t s f o r f i x a t i o n of bone f r a c t u r e s (3,4}. T h i s is due to t h e proven s t r e n g t h , b i o e o m p a t l b i l i t y a n d d e g r a d a b i l i t y by h y d r o l y s i s of PLLA. The u s e of h i g h m o l e c u l a r w e i g h t PLLA a s a f r a c t u r e f i x a t i o n device in oral a n d m a x i l l o f a c i a l s u r g e r y i n i t i a l l y gave good r e s u l t s , h e a l i n g of t h e bone f r a c t u r e w i t h o u t clinically d e t e c t a b l e c o m p l i c a t i o n s took place. A s e r i o u s p r o b l e m , h o w e v e r , w a s t h e slow d e g r a d a t i o n r a t e of PLLA a n d c o m p l i c a t i o n s s u c h as i n f l a m m a t o r y r e a c t i o n s and swelling, w h i c h s h o w e d up in t h e l a t e s t a g e of t h e d e g r a d a t i o n a f t e r an i m p l a n t a t i o n period of 3 y e a r s o f t h e device (5). In o r d e r to l o w e r t h e c r y s t a l l i n i t y of PLLA a n d to p r e v e n t or inhibit t h e s e unwanted reactions, incorporation of a biologically active drug with a n t i - i n f l a m m a t o r y p r o p e r t i e s in t h e PLLA device m i g h t be a s o l u t i o n to t h i s p r o b l e m . Upon d e g r a d a t i o n of t h e PLLA t h e active c o m p o n e n t will be r e l e a s e d . R e c e n t s t u d i e s s h o w e d t h a t a d e c r e a s e in t h e c r y s t a l l i n i t y of PLLA r e s u l t e d in a n a c c e l e r a t i o n of t h e d e g r a d a t i o n (6). F u r t h e r m o r e , m u c h research h a s been done on t h e s y n t h e s i s a n d b e h a v i o u r of a s p i r i n , d e r i v a t i v e s o f s a l i c y l i c acid m o d i f i e d p o l y m e r i c s y s t e m s , w h i c h is b e c a u s e of t h e know a n a l g e s i c s a n d a n t i - i n f l a m m a t o r y p r o p e r t i e s of t h e s a l i c y l a t e s (7). In m a n y of t h e s e s y s t e m s t h e d r u g is a t t a c h e d by m e a n s of a h y d r o l y t i c a l l y d e g r a d a b l e bond to t h e m a i n c h a i n of a polymer, as a m e a n s of i n c r e a s i n g t h e d u r a t i o n of i t s a c t i v i t y (8-11). L e s s r e s e a r c h h a s been
*Correspondingauthor
510 done upon the incorporation of salicylates in the main chain of polymers which are to be used in the biomedical field (12-13}. The aim of t h i s s t u d y is to investigate t h e possibility of incorporation of s a l i c y l a t e s into PLLA by means of blending PLLA with poly(salicylic acid), poly(o-oxybenzoyl), copolymerization of L-lactide with the cyclic e s t e r disalicylide (di-benzo1,5-dioxocin6,12-dion) and trisalicylide (tri-benzo-l,5,9-trioxacydodecin-6,12,18- trion), Figure 1, and by polym e r i z a t i o n of L-laetide, and copolymerization of L - l a c t i d e / e - c a p r o l a c t o n (50/50), initiated by the hydroxyl group of salicylic acid. Also Zn(salicylate)2 has been synthesized, and used as a c a t a l y s t in the r i n g opening polymerization of L-lactide. F u r t h e r m o r e the solidification and the melting behaviour of the g u a s i - b i n a r y s y s t e m formed by poly(L-lactide) and the diluent v-acetylsalicylic acid h a s been investigated. It is know t h a t e u t e e t i c solidification of polymers may lead to porous m a t e r i a l s . This can be an i m p o r t a n t f a c t o r if the polymer is to be used as a surgical implant, as porosity determines t i s s u e ingrowth (14-16).
,
o_c%
.
~C
#0
o..,c..O
Vo~C-O-" v
Figure 1: Structural formula~ o f dtsattcyttde (I) and trtsaltcyttde (II). Experimental
(Co)polymerizations:
Aspirin, o-acetylsalicylic acid (Janssen Chimica; Belgium), w a s used without f u r t h e r p u r i f i c a t i o n and slowly heated above i t s melting point (ca. i37 ~ at 21 mm Hg p r e s s u r e in order to p r e p a r e poly salicylic acid. Acetic acid w a s distilled o f f under N2 f o r one hour. Next t h e t e m p e r a t u r e w a s slowly increased to 190 ~ and maintained f o r two hours. The distillation took place until no more acetic acid was formed. Depolymerization of the polycondensate poly(o-oxybenzoyl) was c a r r i e d out a t 330 ~ (15 mm Hg p r e s s u r e ) in a heated tube-oven. P u r i f i c a t i o n of the s u b l i m a t e and isolation of the di- and trisalicylide occurred by means of r e f l u x i n g in chloroform (3 hours) and r e c r y s t a l l i z a t i o n (-15 ~ f r o m pure chloroform and acetone. Copolymers of L-lactide with di- and trisalicylide were prepared by dissolving the salicylate in the lactide melt, and using s t a n n o u s octoate Sn(Oct)z a s a r i n g opening catalyst. The polymerizations were c a r r i e d out in silanized polymerization vessels under N2 at 110 ~ f o r V days. The copolymers were purified by precipitation using chloroform as the solvent and methanol as the precipitant. L - l a c t i d e (Purac Biochem; The Netherlands) was r e c r y s t a l l i z e d f r o m sodium dried toluene. ~-caprolactone (Janssen Chimica, Belgium) was p u r i f i e d by drying over Calla and distillation under reduced nitrogen atmosphere. The
511
s a l i c y l i c acid (Merck; Germany) i n i t i a t e d p o l y m e r i z a t i o n of L - l a c t i d e a n d L-lactide/e-caprolactone (50/50) in bulk took place by r i n g opening w i t h Sn(0ct)2 as a c a t a l y s t a c c o r d i n g to s t a n d a r d p r o c e d u r e s (17). The m o l e c u l a r w e i g h t of t h e s a l i c y l i c acid i n i t i a t e d p o l y m e r s w a s d e t e r m i n e d by m e a n s of titration with KOH solution. Polymerization of L-lactide with Z n ( s a l i c y l a t e ) 2 as a c a t a l y s t o c c u r r e d also a c c o r d i n g to t h e s e s t a n d a r d procedures. Blends and Zn(saltcylate)2 catalyst: Blends of poly(L-lactide) and p o l y ( o - o x y b e n z o y l ) w e r e p r e p a r e d by d i s s o l v i n g t h e two p o l y m e r s (ca. 7 g) in c h l o r o f o r m (160 ml) f o l l o w e d by p r e c i p i t a t i o n in m e t h a n o l and d r y i n g in a vacuum oven. Zn(salicylate)z was prepared by reaction of ZnO (0.064 mole) with salicylic a c i d (0.128 mole) in w a t e r (250 ml) a t (90 ~ ~ h o u r s ) f o l l o w e d by f i l t r a t i o n a n d c r y s t a l l i s a t i o n a t - 15 ~ Eutecttc solidification: Poly(L-lactide) was precipitated according to s t a n d a r d p r o c e d u r e s a n d h a d a Mw/Mn r a t i o of 2.0. The v i s c o s i t y - a v e r a g e m o l e c u l a r w e i g h t of t h e p o l y m e r w a s 4 * i0 s , and i t s m e l t i n g peak 189.i ~ A s p i r i n e w a s r e c r y s t a l l i s e d t w i c e f r o m o - x y l e n e . Its m e l t i n g t e m p e r a t u r e w a s 138.2 ~ D i - c h l o r o m e t h a n e w a s u s e d to dissolve a n d m i x t h e p r o p e r a m o u n t s of p o l y ( L - l a c t i d e ) and a s p i r i n e , afterwards the solvent was evaporated. For f u r t h e r homogenization the mixtures were kept at a t e m p e r a t u r e 10 ~ h i g h e r t h a n t h e m e l t i n g t e m p e r t u r e of t h e h i g h e s t m e l t i n g c o m p o n e n t f o r 15 m i n u t e s . The s a m p l e s w e r e t h e n q u e n c h e d to r o o m t e m p e r a t u r e . Melting c h a r a c t e r i s t i c s w e r e o b t a i n e d w i t h a Perkin E l m e r DSC-7 a p p a r a t u s u s i n g 6 m g s a m p l e s a n d a s c a n s p e e d of 10 ~ Compression Moulding and Characterization: (Co)polymer c o n v e r s i o n s a n d c o m p o s i t i o n s w e r e d e t e r m i n e d by 3 0 0 MHz 1H NMR of s o l u t i o n s in d e u t e r a t e d c h l o r o f o r m . T h e r m a l p r o p e r t i e s w e r e m e a s u r e d on a P e r k i n - E l m e r DSC-7 a t a h e a t i n g r a t e of 10 ~ p e r m i n u t e . T e n s i l e t e s t i n g s p e c i m e n s w e r e m o u l d e d to 6*50*2 m m a t 2 0 0 ~ and r a p i d l y cooled to r o o m t e m p e r a t u r e . The s t r e s s - s t r a i n b e h a v i o u r w a s e x a m i n e d at r o o m t e m p e r a t u r e w i t h an I n s t r o n 4301 t e n s i l e t e s t e r , a t a c r o s s h e a d speed of 10 m m p e r m i n u t e .
Results and discussion
Polymerization o f L-tacttde with di- and trisallcyltde: P o l y c o n d e n s a t i o n of a s p i r i n (ca. 63.5 g) gave, a s p r e v i o u s l y w a s s h o w n (18,19), a yellow, b r i t t l e t r a n s p a r e n t , a m o r p h o u s poly(o-oxybenzoyl) a n d a c e t i c acid (19.3 g). The g l a s s t r a n s i t i o n t e m p e r a t u r e of t h e p o l y c o n d e n s a t e w a s f o u n d to be Tg = 76.8 ~ D e p o l y m e r i z a t i o n of t h i s p o l y c o n d e n s a t e on h e a t i n g in vacuo yielded a white semi-crystalline sublimate, from which diand t r i s a l i c y l i d e could be isolated. An a m o u n t of 7 g of t h e s u b l i m a t e w a s d i s s o l v e d in boiling c h l o r o f o r m a n d a f t e r c r y s t a l l i z a t i o n upon cooling 2.4 g (16.8 %), disalicylide w a s o b t a i n e d a s c o l o u r l e s s , t w i n n e d r h o m b s m.p. 232.6 ~ (Found: C, 69.2 Z; H, 3.4 %: Calc. f o r C14H804: C, 7 0 . 0 Z; H 3,4 %); 1H NMR (CDCI3): 7.4 - 8.0 ppm (m, 8H, ClzHs). R e c r y s t a l l i z a t i o n of t h e c h l o r o f o r m r e s i d u e a f t e r a c e t o n e a d d i t i o n gave 1.9 g (13.3 %) t r i s a l i c y l i d e a s c o l o u r l e s s n e e d l e s m.p. 198.4~ (Found: C, 7 0 . 0 %; H, 3.3 %: Calc. f o r C2IH1206: C, 7 0 . 0 Z; H 3.4 Z); IH NMR (CDCI3): 7.4 - 8 . 0 p p m (m, 12H, C18H12). Two c o p o l y m e r i z a t i o n s a t 110 ~ of h - l a c t i d e w i t h t h e cyclic e s t e r s d i - a n d t r i s a l i c y l i d e by m e a n s of r i n g o p e n i n a w i t h Sn(Oct)2 gave s l i g h t l y - y e l l o w , crystalline copolymers. The t h e r m a l properties of t h e as-polymerized c o p o l y m e r s a r e g i v e n in Table 1.
512
Table 1
Thermal p r o p e r t i e s o f as-poL y m e r t z e d co p o l y m e r s o f L - l a c t t d e and c y c l i c sat tcyl ides. comonomer
moz 1e
t r i s a l i c y l i d e [i disalicylide I
0.0 1.6 4.9
AH (J/g)
(~
72.1 50.9 41.1
192.4 169.0 164.2
Tg (~
Tm
57 58
A decrease in the orystallinity and the melting temperature of the PLLA is observed upon copolymerization with cyclic salicylides. The incorporation of o-oxybenzoyl groups from di- or trisalicylide was checked with "H NMR. Figure 2 shows the NMR spectrum of the poly(L-laetide/trisalicytide) copolymer a f t e r precipitation. Obviously trisalicylide (and disalicylide, spectrum not shown) has been incorporated into PLLA chains, giving four peaks at 7.3 to 8.0 ppm which can be assigned to the aromatic protons of the o-oxybenzoyl groups. The peaks at 5.1 and at 1.55 ppm respectively correspond to methyne and methyl protons of the lactide units.
f
8.1
7.9
l
9
l
7,7
l
I
8
I
7.3
7.5
I
P
7
I
P
6
f
T
5
I
I
I
4
chemical shift (oprn)
I
P
P
3
2
I
~.
F i g u r e 2: tH 300 MHz s p e c t r u m o f the p u r i f i e d p o l y ( L - l a c t t d e / t r t s a l i c y L L d e ) copolymer.
513 The h y d r o l y t i c d e g r a d a t i o n of t h e s e d e g r a d a b l e c o p o l y m e r s by c l e a v a g e of t h e e s t e r b o n d s yields t h e r e l e a s e of l a c t i c acid a n d s a l i c y l i c acid. B e c a u s e of the release of salicylic acid and its anti-inflammatory p r o p e r t i e s , u n w a n t e d i n f l a m m a t o r y r e a c t i o n s (ref. 5) m i g h t be p r e v e n t e d . T h e s e c o p o l y m e r s m i g h t also be a r o u t e to c o n t r o l t h e r a t e of r e l e a s e o f s a l i c y l i c acid and could t h e r e f o r e be u s e d as a c o n t r o l l e d d r u g r e l e a s e system. Unfortunally incorporation of o-oxybenzoyl grou~s by means of a t r a n s e s t e r i f i c a t i o n r e a c t i o n of PLLA (Mn = 4 * 10 ) w i t h o - a c e t y l s a l i c y l i c acid u s i n g d i f f e r e n t t y p e s of c a t a l y s t s did n o t succeed. No i n c o r p o r a t i o n took place. Blends o f PLLA with Poly(o-oxybenzoyl): Two blends of h i g h m o l e c u l a r w e i g h t PLLA (My = 5 * 10 s) and poly(o-oxybenzoyl) (Mn = 2050) w e r e m a d e by d i s s o l v i n g t h e p o l y m e r s in c h l o r o f o r m , giving a s l i g t h l y pink s o l u t i o n . After precipitation and compression moulding, the blends showed a marble-like structure. This can presumably be attributed to some d e g r a d a t i o n of PLLA as a r e s u l t of t h e p r e s e n c e of t h e c a r b o x y l i e end g r o u p s of p o l y ( o - o x y b e n z o y l ) . The r e s u l t s of t h e m e c h a n i c a l t e s t i n g of t h e b l e n d s a r e g i v e n in T a b l e 2. Table
2
Mechantcal properties of
poly
po l y ( L - l a c t t d e ) / p o l y ( o - o x y b e n z o y l )
We i g h t Y. (o-oxyben.) 0.0 17.3 28.1
blends.
(y
(MPa)
(Z)
72.3 53.2 36.6
7.1 4.4 5.7
It shows that a negative effect on the tensile increase in the amount of poly(o-oxybenzoyll. This stiff o-oxybenzoyl units and the degradation optimization of processing conditions and increase of the poly(o-oxybenzoyl) is expected to improve of these blends.
strength occurs with an can be attributed to the of the PLLA. Further of the molecular weight the mechanical properties
Salicylic acid initiated PLLA polymerization and Z n ( s a l t c y l a t e ) z as a catalyst: T h e p o l y m e r i z a t i o n of L - l a c t i d e in t h e p r e s e n c e of Sn(0ct)z p r o c e e d s v i a a c o o r d i n a t e d i n s e r t i o n m e c h a n i s m (17,20), s m a l l a m o u n t s of Hz0 or h y d r o l y z e d m o n o m e r s c a n n o t c o m p l e t e l y be e x c l u d e d a n d m i g h t be t h e t r u e i n i t i a t o r of t h e p o l y m e r i z a t i o n (21,22}. It is g e n e r a l l y a c c e p t e d t h a t t h e r i n g opening r e a c t i o n of l a c t i d e c a n be i n i t i a t e d by a l c o h o l s (23). A s m a l l q u a n t i t y of alcohol a c t s as a m o l e c u l a r w e i g h t c o n t r o l a g e n t . U s i n g s a l i c y l i c acid in t h e r i n g opening p o l y m e r i z a t i o n of L - l a c t i d e , i n i t i a t i o n will p r e f e r e n t i a l l y t a k e p l a c e a t t h e h y d r o x y g r o u p a t t a c h e d to t h e aromatic ring, although initiation by the carboxylic group cannot c o m p l e t e l y be e x c l u d e d (24,25). U s i n g t h i s concept, a n a m o r p h o u s low m o l e c u l a r w e i g h t PLLA (Tg = 46 ~ was s y n t h e s i z e d u s i n g 5.2 mole Z salicylic acid a s t h e i n i t i a t o r . The m o l e c u l a r w e i g h t of t h e p o l y m e r d__etermined by m e a n s of t i t r a t i o n w i t h a KOH s o l u t i o n w a s Mn = 2609 (calc. Mn = 2769). Evenso an a m o r p h o u s w a x y low m o l e c u l a r w e i g h t c o p o l y m e r of L - l a c t i d e a n d e - c a p r o l a c t o n e ( 5 0 / 5 0 ) w a s s y n t h e s i z e d
514
(Mn = 2544) u s i n g 5.2 mol 7. salicylic acid. Obviously, it is p o s s i b l e to incorporate salicylic acid endgroups into poly(L-lactide) (co)polymers. P o l y m e r s o f t h e s e kind m i g h t be u s e d f o r t h e c o n t r o l l e d r e l e a s e o f s a l i c y l i c acid as t h e s a l i c y l i c acid initiator will be r e l e a s e d upon hydrolysis. Although Sn(Oct)z is a suitable and often used catalyst for the p o l y m e r i z a t i o n o f L - l a c t i d e (it is also FDA approved), u s e of a zink c o n t a i n i n g c a t a l y s t i n s t e a d of t i n m i g h t prove to be l e s s t o x i c in t h e h u m a n body. Z n ( s a l i c y l a t e ) z w a s s y n t h e s i z e d by r e a c t i o n of ZnO and s a l i c y l i c acid to f o r m a Z n - s a l t (25). R e a c t i o n of ZnO w i t h s a l i c y l i c acid r e s u l t e d in l a r g e b r o w n c r y s t a l s (Found: Zn, 17.2 7.; C, 49.5 7.; H 3.8 7.: Calc. f o r Zn(CTHsOa)z: Zn, 19,3 7.; C, 49.5 7.; H, 2.9 70. The Z n - s a l i c y l a t e s h o w e d c a t a l y t i c a c t i v i t y . P o l y m e r i z a t i o n of L - l a c t i d e w i t h 1.0 mole 7o Zn(salicylate)z yielded a brittle, crystalline, low molecular weight p o l y m e r w i t h a m e l t i n g t e m p e r a t u r e of 153.0 ~ and a h e a t of f u s i o n of 39.i J / g . C o n v e r s i o n of t h e m o n o m e r s m e a s u r e d by IH NMR w a s 97.09 7..
Eutecttc solidification of system: F i g u r e 2 s h o w s t h e
the
pol.y(L-tacttde)/o-acetylsal.tcyltc
phase
diagram
for
acid
poiy(L-tactide)/o-acetyi-
s a l i c y l i c acid m i x t u r e s .
200
i
180
160 I.140
120
: . . . . . . . .
@ . . . . . . . . . . . . . . . . .
O 100
--
0
_Q
. . . . . . . . . . . . . . . . .
O ~
P
'
r
20
40
60
80
100
Weight fraction PLLA (% w/w)
Figure
3: Phase diagram f o r the p o l y ( L - l a c t i d e ) / o - a c e t y L s a l t c y l t c
acid
system. The m i x t u r e s f o r m e d an e u t e c t i c c o m p o s i t i o n f o r 52 7. w / w of p o l y ( L - l a c t i d e ) w i t h an e u t e c t i c m e l t i n g t e m p e r a t u r e of 119 ~ However a s o - a c e t y l s a l i c y l i c acid p o l y m e r i z e s q u i t e easily, it is n o t p o s s i b l e to d i s t i n g u i s h if t h e m i n i m u m in t h e c u r v e f o r t h e p o l y ( L - l a c t i d e ) / o - a c e t y l - s a l i c y l i c acid s y s t e m is due e x c l u s i v e l y to e u t e c t i c c r y s t a l l i z a t i o n .
515 Conclusions
The r e s u l t s p r e s e n t e d in t h i s study show t h a t along d i f f e r e n t ways it is possible to incorporate salicylates into PLLA. These polymers might be used as b o n e - f r a c t u r e f i x a t i o n devices. The whole polymeric s y s t e m is expected to eventually degrade and release lacticand salicylic acid upon d e g r a d a t i o n (hydrolytic or enzymmatic). Besides load bearing devices, the modified PLLA polymers might probably also be used as a controlled r e l e a s e s y s t e m f o r salicylic acid. For t h i s purpose, also copolymers of L-lactide and other lactones can be used. F u r t h e r m o r e the poly(L-lactide)/o-acetylsaIicylic acid s y s t e m f o r m e d an e u t e c t i e composition f o r 52 % w / w of poly(L-iactide) with an e u t e e t i e m e l t i n g t e m p e r a t u r e of 119 ~
References
1. 2. 3. 4. 5.
6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26.
P i t t CG, Schindler A (1984), in Controlled Drug Delivery, Basic Concepts ((Bruek SD), ed), CRC Press, 1: 53-80. Leenslag JW, Gogolewski S, Pennings AJ (1984), J. Appl. Polm. Set., 29: 2829. Tune D (1990), US Patent to Johnson and Johnson, 4905680. Bos RRM, Boering G, Rozema FR, Leenslag JW, Pennings AJ and Verwey AB (1987), J. Oral. Maxillofac. Surg., 45: 751. Bergsma JE, Rozema FR, Bos RRM and Bruin de WC (1993), J. Oral. Maxillofae. Surg., 51: 666. Rozema FR (1991), PhD Thesis, University of Groningen, The Netherlands. Vion JM, J~r6me R, Teyssi6 P (1986), Maeromoleeules, 19: 1828. Rainsford KD (1984), Aspirin and the salieylates, Butterworth & Co., London. S~nchez-Chaves M, Arranz F, Diaz C (1989), Makromol. Chem., 190: 2391. Roman JS and Levenfeld B (1990), Macromolecules, 23: 423. Weiner BZ and Zilkha A (1973), Isr. J. Chem., 11: 567. Baranovsky V, Petrova T, Rashkov I (1991), Eur. Polym. J., 27: 1045. Schneider KA (1954), US P a t e n t 2,696,481. Shalaby et al. (1992), US Patent 5,082,925. Smith P (1976), PhD Thesis, University of Groningen, The Netherlands. Wittman JC, Manley R (1977), J. Polym. Sci. Polym. Phys., 15: 1089. Zwiers RJM, Gogolewski S, Pennings AJ (1983), Polymer, 24: 167. Leenslag JW, Pennings AJ (1987), Macromol. Chem., 188: 1809. Baker W, OIiis WD, Zealley TS (1951), J. Chem. Soe.: 201. Ansehtitz R (1919), Bet., 52: 1875. Krieheldorf HR, Dunsing R (1986), Maeromol. Chem., 187: 1611. Schindler A, Hibionada YM, Pitt CG (1982), J. Polym. Sei. Polym. Chem. Ed, 20: 319. Nijenhuis AJ, Grijpma DW and Pennings AJ (1992), Macromolecules, 25: 6419. F r a z z a EJ, Sehmitt EE (1971), J. Biomed. Mater. Res., 1: 43. Bassi MB, Padias AB, Hall HK [1990), Polym. Bull. 24: 227. Bixler KJ, Calhoun GC, Scholsky KM, Stackman RW (1990), Polym. Prep., 31: 494. Matsuda H, Takeehi S (1990), J. Polym. Sci. Pol. Chem. Ed, 28: 1895.
A c c e p t e d March 25, 1994
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