3P M E C H A N I S M S OF INSTABILITY IN W/O/W
MULTIPLE EMULSIONS
.
D Whitehill and A . r. F l o r e n c e , D e p a r t m e n t of P h a r m a c e u t i c s University of Strathclyde, Glasgow G1 1xw.
,
Water-in-oil-in-water (W/O/W) multiple e m u l s i o n s have shown p r o m i s e as druq d e l i v e r y s y s t e m s . Additives s u c h as d r u g s c a n m a r k e d l y u p s e t t h e delicate b a l a n c e of f a c t o r s which maintain stability. If t h e p r o c e s s e s of instability of t h e s e s y s t e m s w e r e b e t t e r understood, it should b e p o s s i b l e t o f o r m u l a t e s t a b l e s y s t e m s with many biopharmaceutical advantages. The stability of t h e s e s y s t e m s composed of two e m u l s i o n s is difficult to study and t h e r e is little published work on the s u b j e c t . Davis et a1 (1976 ) have used f r e e z e - f r a c t u r e techniques ; Kita & -(1977a,b) have m e a s u r e d m i g r a t i o n of i o n s f r o m t h e i n t e r n a l p h a s e and a viscom e t r i c technique to follow breakdown of multiple e m u l s i o n s . T h r e e different s y s t e m s of water/isopropyl m y r i s t a t e (IPM ) / w a t e r w e r e p r e p a r e d The p r i m a r y W/O s y s t e m c o m p r i s e d i n all using v a r i o u s nonionic s u r f a c t a n t s . The multiple e m u l s i o n w a s cases IPM, Span 80 ( 2 . 5 ~ ~and ) w a t e r (5oy0). p r e p a r e d by emulsifying t h e p r i m a r y s y s t e m i n a n equal volume of w a t e r containTriton X-165 ( s y s t e m B ) and Span 80: ing 270 s u r f a c t a n t : 3 r i j 30 ( s y s t e m A ), Tween 8 0 3:l ( s y s t e m C ) . S y s t e m A had s m a l l multiple ( o i l ) d r o p s ( m e a n d i a m e t e r 8 . 6 p m ) , 82y0of which contained only one i n t e r n a l aqueous d r o p l e t . S y s t e m 3 had somewhat l a r g e r multiple d r o p s ( m e a n s i z e 19pm) with s e v e r a l s m a l l e r internal aqueous d r o p s . System C c o m p r i s i n g much l a r g e r multiple d r o p s than A or B ( m e a n size 25pm) contairec' l a r g e n u m b e r s of i n t e r n a l d r o p s which w e r e i m p o s s i b l e to r e s o l v e . Using conventional photomicrography, t h e d e c r e a s e i n t h e r a t i o of filled/empty multiple d r o p s and i n t h e n u m b e r of i n t e r n a l d r o p l e t s i n s i d e t h e multiple d r o p s w a s o b s e r v e d . The i n t e r n a l d r o p l e t s of e m u l s i o n s A and B showed little chanqe i n d i a m e t e r o v e r a p e r i o d of twenty w e e k s , and only slight c h a n g e s i n t h e m e a n size of t h e multiple d r o p s w e r e noted. Although t h e s e m e t h o d s are tedious, they d o provide s o m e information on multiple d r o p stability. W e h a v e also used a modified time-lapse c i n e m i c r o g r a p h y technique d e s c r i b e d by Dawson (1963) t o study d r o p l e t m o v e m e n t s for p e r i o d s of up t o twenty four h o u r s , i n t h e p r e s e n c e and a b s e n c e of e l e c t r o l y t e i n t h e i n t e r n a l and e x t e r n a l aqueous p h a s e s . This h a s shown t h e i n t e r n a l d r o p l e t s to be f a i r l y s t a b l e in t h e e a r l y s t a g e s of t h e life of t h e emulsion. They a p p e a r to collide frequently but d o not coalesce. Normal and high-speed c i n e m i c r o g r a p h y have a l s o been used. In t h e p r e s e n c e of e l e c t r o l y t e in t h e e x t e r n a l p h a s e , d r o p s of e m u l s i o n A r u p t u r e , r e l e a s i n g the i n t e r n a l aqueous d r o p l e t s . D r o p s of e m u l s i o n R, however, coalesce, behaving l i k e a n o r m a l O/W e m u l s i o n , leaving t h e i n t e r n a l d r o p l e t s i n t a c t . The main f a c t o r s likely t o influence c o a l e s c e n c e i n t h e c o n s t r a i n e d e n v i r o n m e n t of t h e d i s p e r s e d oil p h a s e are t h e v i s c o s i t y of t h e oil p h a s e , i n t e r a c t i o n s between t h e interfacial f i l m s and Brownian movement.
,
D . d. i s supported by t h e Science Research Council. h e r help with time-lapse c i n e m i c r o g r a p h y .
We thank D r . Cawson f o r
C a v i s , S. S. Purewal ,T. S., 3 u r b a g e , A . S. (1976), J.Pharni . P h a r m a c .
28 :60
Dawson, P.1. (1963), J. Royal Mic. SOC. 8 2 : 1-16 %ita, Y Matsumoto, S., Yonezawa, D. (1977a), Nippon Kagaku Kaishi, 6:748-751 K i t a , ' J . , $latsumoto, S . , Yonezawa, D. (1977b), J . Colloid I n t e r f a c e Sci. 6 2 : 87-94
.,
MULTIPLE EMULSIONS
.
D Whitehill and A . r. F l o r e n c e , D e p a r t m e n t of P h a r m a c e u t i c s University of Strathclyde, Glasgow G1 1xw.
,
Water-in-oil-in-water (W/O/W) multiple e m u l s i o n s have shown p r o m i s e as druq d e l i v e r y s y s t e m s . Additives s u c h as d r u g s c a n m a r k e d l y u p s e t t h e delicate b a l a n c e of f a c t o r s which maintain stability. If t h e p r o c e s s e s of instability of t h e s e s y s t e m s w e r e b e t t e r understood, it should b e p o s s i b l e t o f o r m u l a t e s t a b l e s y s t e m s with many biopharmaceutical advantages. The stability of t h e s e s y s t e m s composed of two e m u l s i o n s is difficult to study and t h e r e is little published work on the s u b j e c t . Davis et a1 (1976 ) have used f r e e z e - f r a c t u r e techniques ; Kita & -(1977a,b) have m e a s u r e d m i g r a t i o n of i o n s f r o m t h e i n t e r n a l p h a s e and a viscom e t r i c technique to follow breakdown of multiple e m u l s i o n s . T h r e e different s y s t e m s of water/isopropyl m y r i s t a t e (IPM ) / w a t e r w e r e p r e p a r e d The p r i m a r y W/O s y s t e m c o m p r i s e d i n all using v a r i o u s nonionic s u r f a c t a n t s . The multiple e m u l s i o n w a s cases IPM, Span 80 ( 2 . 5 ~ ~and ) w a t e r (5oy0). p r e p a r e d by emulsifying t h e p r i m a r y s y s t e m i n a n equal volume of w a t e r containTriton X-165 ( s y s t e m B ) and Span 80: ing 270 s u r f a c t a n t : 3 r i j 30 ( s y s t e m A ), Tween 8 0 3:l ( s y s t e m C ) . S y s t e m A had s m a l l multiple ( o i l ) d r o p s ( m e a n d i a m e t e r 8 . 6 p m ) , 82y0of which contained only one i n t e r n a l aqueous d r o p l e t . S y s t e m 3 had somewhat l a r g e r multiple d r o p s ( m e a n s i z e 19pm) with s e v e r a l s m a l l e r internal aqueous d r o p s . System C c o m p r i s i n g much l a r g e r multiple d r o p s than A or B ( m e a n size 25pm) contairec' l a r g e n u m b e r s of i n t e r n a l d r o p s which w e r e i m p o s s i b l e to r e s o l v e . Using conventional photomicrography, t h e d e c r e a s e i n t h e r a t i o of filled/empty multiple d r o p s and i n t h e n u m b e r of i n t e r n a l d r o p l e t s i n s i d e t h e multiple d r o p s w a s o b s e r v e d . The i n t e r n a l d r o p l e t s of e m u l s i o n s A and B showed little chanqe i n d i a m e t e r o v e r a p e r i o d of twenty w e e k s , and only slight c h a n g e s i n t h e m e a n size of t h e multiple d r o p s w e r e noted. Although t h e s e m e t h o d s are tedious, they d o provide s o m e information on multiple d r o p stability. W e h a v e also used a modified time-lapse c i n e m i c r o g r a p h y technique d e s c r i b e d by Dawson (1963) t o study d r o p l e t m o v e m e n t s for p e r i o d s of up t o twenty four h o u r s , i n t h e p r e s e n c e and a b s e n c e of e l e c t r o l y t e i n t h e i n t e r n a l and e x t e r n a l aqueous p h a s e s . This h a s shown t h e i n t e r n a l d r o p l e t s to be f a i r l y s t a b l e in t h e e a r l y s t a g e s of t h e life of t h e emulsion. They a p p e a r to collide frequently but d o not coalesce. Normal and high-speed c i n e m i c r o g r a p h y have a l s o been used. In t h e p r e s e n c e of e l e c t r o l y t e in t h e e x t e r n a l p h a s e , d r o p s of e m u l s i o n A r u p t u r e , r e l e a s i n g the i n t e r n a l aqueous d r o p l e t s . D r o p s of e m u l s i o n R, however, coalesce, behaving l i k e a n o r m a l O/W e m u l s i o n , leaving t h e i n t e r n a l d r o p l e t s i n t a c t . The main f a c t o r s likely t o influence c o a l e s c e n c e i n t h e c o n s t r a i n e d e n v i r o n m e n t of t h e d i s p e r s e d oil p h a s e are t h e v i s c o s i t y of t h e oil p h a s e , i n t e r a c t i o n s between t h e interfacial f i l m s and Brownian movement.
,
D . d. i s supported by t h e Science Research Council. h e r help with time-lapse c i n e m i c r o g r a p h y .
We thank D r . Cawson f o r
C a v i s , S. S. Purewal ,T. S., 3 u r b a g e , A . S. (1976), J.Pharni . P h a r m a c .
28 :60
Dawson, P.1. (1963), J. Royal Mic. SOC. 8 2 : 1-16 %ita, Y Matsumoto, S., Yonezawa, D. (1977a), Nippon Kagaku Kaishi, 6:748-751 K i t a , ' J . , $latsumoto, S . , Yonezawa, D. (1977b), J . Colloid I n t e r f a c e Sci. 6 2 : 87-94
.,
![W) emulsions using a radiotracer technique [proceedings].](/assets/img/hold.png)
