DRUG DEVELOPMENT AND INDUSTRIAL PHARMACY, 16(6), 951-962 (1990)
`
`ROLE OF SURFACTANT ON DRUG RELEASE FROM TABLIES
`
`Paul W S Heng, Lucy S C Wan and T e r e s a S H Ang
`Department OF Pharmacy, National U n i v e r s i t y of Singapore
`10 Kent Ridge Crescent, Singapore 0511
`
`ABSTRACT
`
`The a d d i t i o n of a s u r f a c t a n t i n t o a t a b l e t formulation a p p e a r s t o
`t o improve t h e drug release rate. The
`be an a t t r a c t i v e method
`rate i s o f t e n a s s o c i a t e d w i t h t h e e f f e c t of
`improved release
`s u r f a c t a n t i n c r e a s i n g t h e h y d r o p h i l i c i t y of t h e d o s a g e f o r m
`t h e r e b y p r o m o t i n g d r u g d i s s o l u t i o n . The f i n d i n g s o f
`t h i s
`i n v e s t i g a t i o n showed t h a t t h e presence of s u r f a c t a n t i n f l u e n c e d
`t h e t a b l e t d i s i n t e g r a t i o n rate, producing a f i n e r d i s p e r s i o n of
`d i s i n t e g r a t e d p a r t i c l e s . It f o l l o w s t h a t t h e a c t i o n of s u r f a c t a n t
`improving drug d i s s o l u t i o n from t a b l e t s may be a t t r i b u t e d t o t h e
`a c t i o n of s u r f a c t a n t producing f i n e d i s i n t e g r a t e d p a r t i c l e s w i t h
`correspondingly l a r g e r surface area f o r d r u g d i s s o l u t i o n . It w a s
`a l s o d e m o n s t r a t e d
`t h a t u p o n
`t a b l e t d i s i n t e g r a t i o n t h e
`d i s i n t e g r a t e d p a r t i c l e s have a tri-modal frequency d i s t r i b u t i o n .
`
`I n t h e e v a l u a t i o n of compressed t a b l e t s , t h e d i s i n t e g r a t i o n time
`of t a b l e t s i s t h e t i m e f o r t h e complete passage of deaggregated
`
`Copyright 0 1990 by Marcel Dekker, Inc.
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`951
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`952
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`HENG, WAN, AND ANG
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`t h e d i s i n t e g r a t i o n t e s t ,
`t h r o u g h a mesh d u r i n g
`p a r t i c l e s
`according t o t h e o f f i c i a l pharmacopoeia. The mesh s i z e s p e c i f i e d
`i s r a t h e r l a r g e , u s u a l l y a b o u t 1 m m . F i n e n e s s o f
`t h e
`d i s i n t e g r a t e d p a r t i c l e s i s n o t taken i n t o c o n s i d e r a t i o n . Roland
`t h e s i z e of
`t h e s i g n i f i c a n c e o f
`t h e
`[ l ] had d e m o n s t r a t e d
`d i s i n t e g r a t e d p a r t i c l e s on t h e drug release rate. It w a s proposed
`t h a t d i s i n t e g r a t e d p a r t i c l e s may be g r o u p e d i n t o t h r e e main
`c a t e g o r i e s : marcogranular, microgranular and micronised.
`I n t h e
`s t u d i e s on deaggregation of compressed t a b l e t s , Rubinstein e t a l .
`[2-31 determined t h e s u r f a c e area of
`t a b l e t s generated through
`t h e p r o c e s s o f d i s i n t e g r a t i o n and showed
`t h a t t h e s u r f a c e
`generated c o r r e l a t e d with t h e d i s s o l u t i o n rate.
`
`T a b l e t formulations c o n t a i n i n g s u r f a c t a n t have been r e p o r t e d t o
`produce t a b l e t s with good d i s s o l u t i o n rate [4-61. It w a s however,
`found t h a t d i s i n t e g r a t i o n time does n o t necessary improve i n t h e
`p r e s e n c e of a s u r f a c t a n t . T a b l e t s c o n t a i n i n g s t a r c h a s a
`d i s i n t e g r a n t [ 4 ] showed prolonged d i s i n t e g r a t i o n i n t h e presence
`of a s u r f a c t a n t although t h e d i s s o l u t i o n rate w a s improved. The
`t h e s t u d y on t h e role of
`p r e s e n t paper r e p o r t s t h e f i n d i n g s of
`s u r f a c t a n t i n improving t a b l e t d i s s o l u t i o n .
`
`Materials - Sulfanilamide and s u l f a g u a n i d i n e (B.P. grade) were
`u s e d w i t h o u t p u r i f i c a t i o n . The s u r f a c t a n t , p o l y o x y e t h y l e n e
`s o r b i t a n m o n o o l e a t e ( p o l y s o r b a t e 80, H o n e y w i l l - A t l a s L t d . ,
`I.C.I., England) and s t a r c h (maize, Corn Brand, Holland) were
`a l s o included i n t h e formulations.
`
`Preparation of Tablets - Granules c o n t a i n i n g
`t h e drug and 5%
`s t a r c h were prepared by w e t massing and s c r e e n i n g through a 1.0
`mm mesh sieve, oven d r i e d a t 60°C f o r 6h and r e g r a n u l a t e d through
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`ROLE OF SURFACTANT ON DRUG RELEASE FROM TABLETS
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`t h e same s i e v e . The s u r f a c t a n t , when used, was i n c o r p o r a t e d w i t h
`t h e g r a n u l a t i n g f l u i d , water. The g r a n u l e s r e t a i n e d on a 0.375 mm
`(Model F3, Manesty, England)
`mesh s i e v e were compressed
`i n t o
`t a b l e t s c o n t a i n i n g 250 mg drug and having a p o r o s i t y of 0.13 2
`0.01.
`
`Evaluation of T a b l e t s - T a b l e t hardness was t h e mean of 10 d e t e r -
`minations u s i n g an automated hardness tester (Erweka, Model TBH).
`D i s i n t e g r a t i o n time (Pharma T e s t , PTZ 3) was determined according
`t o t h e BP method. The d i s i n t e g r a t i o n time i s d e f i n e d as t h e t i m e
`f o r a l l r e s i d u e (from s i x t a b l e t s ) t o p a s s through t h e s c r e e n of
`t h r e e d e t e r m i n a t i o n s w a s
`t h e d i s i n t e g r a t i o n baskets. A mean of
`taken as t h e d i s i n t e g r a t i o n t i m e . The d i s s o l u t i o n test w a s i n
`1°C u s i n g t h e r o t a t i n g b a s k e t a p p a r a t u s
`d i s t i l l e d water a t 31"
`(Hanson Research Gorp., 72RL E a s i - l i f t ) w i t h a b a s k e t speed of
`100 rpm. P r o g r e s s of t h e d i s s o l u t i o n was monitored continuously
`using flow cells i n a spectrophotometer (LKB U l t r o s p e c , 4052 TDS)
`c o n t r o l l e d v i a a microcomputer (Apple I1 w i t h LKB d i s s o l u t i o n
`software). The r e s u l t s from f i v e t a b l e t s were averaged.
`
`D e t e r m i n a t i o n of Particle Size of Disintegrated T a b l e t
`-
`Immediately a f t e r t a b l e t d i s i n t e g r a t i o n , t h e s i z e d i s t r i b u t i o n of
`t h e d i s i n t e g r a t e d p a r t i c l e s c a n be very l a r g e . Larger p a r t i c l e s
`t e n d t o s e t t l e v e r y r a p i d l y . Any a t t e m p t t o r e s u s p e n d t h e s e
`p a r t i c l e s r e q u i r e s i g n i f i c a n t a g i t a t i o n which can be s e v e r e f o r
`two methods of size
`t h e f r e s h l y d i s i n t e g r a t e d p a r t i c l e s . Thus,
`a n a l y s i s were employed f o r t h e s i z i n g o f
`t h e d i s i n t e g r a t e d
`p a r t i c l e s : w e t s i e v i n g and C o u l t e r C o u n t e r method ( C o u l t e r
`E l e c t r o n i c s , TA 11). ( i ) S i e v i n g Method - I m m e d i a t e l y a f t e r
`d i s i n t e g r a t i o n (40 s o r s l i g h t l y more f o r t a b l e t s w i t h a l o n g e r
`d i s i n t e g r a t i o n time) as d e s c r i b e d above f o r s i x weighed t a b l e t s ,
`t h e d i s i n t e g r a t i o n medium was poured o n t o a s i e v e . The weight
`gained by t h e s i e v e a f t e r oven d r y i n g f o r h a l f a n hour a t 120"C,
`was
`taken as t h e weight of p a r t i c l e s r e t a i n e d . S i e v e s of 250,
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`9 54
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`HENG, WAN, AND ANG
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`TABLE 1
`
`Effect of Polysorbate 80 on the Hardness and Disintegration Time
`of Sulfanilamide and Sulfaguanidine Tablet Formulations.
`
`Fo rmu 1 at i on
`
`Hardness
`(N)
`
`Disintegration
`Time ( s )
`
`Sulfanilamide
`+ 5% starch only
`+ 5% starch and 0.2% P80
`
`Sulfaguanidine
`+ 5% starch only
`+ 5% starch and 0.02% P80
`+ 5% starch and 0.2% P80
`
`14.8 - + 4.4
`12.3
`2.7
`
`27.2 - + 4.6
`24.3 2 3.0
`22.0 2 3.2
`
`29.6
`33.6
`
`37.0
`38.3
`44.0
`
`150, 105 and 75 um mesh size were used. (ii) Coulter Counter
`Method - Disintegrated particles not retained by 75 urn mesh sieve
`were sized using the Coulter Counter.
`
`RESULTS AND DISCUSSION
`
`The effect of polysorbate 80 on hardness and disintegration of
`sulfanilamide and sulfaguanidine tablets containing 5% starch are
`given in Table 1 . Tablets containing the surfactant showed
`reduced hardness but had prolonged disintegration times.
`Polysorbate 80 had been reported previously to reduce the
`disintegration efficiency of starch [ 41.
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`ROLE OF SURFACTANT ON DRUG RELEASE FROM TABLETS
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`955
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`0
`
`5
`
`10
`
`15
`
`Tim ( 5 )
`
`FIGURE 1
`D i s s o l u t i o n p r o f i l e s of s u l f a g u a n i d i n e t a b l e t s c o n t a i n i n g 5%
`s t a r c h (open c i r c l e s ) and corresponding t a b l e t s c o n t a i n i n g 0.2%
`polysorbate 80 ( c l o s e d circles).
`
`Despite t h e prolonged d i s i n t e g r a t i o n time of t a b l e t s c o n t a i n i n g
`t h e d i s s o l u t i o n rates of
`these t a b l e t s
`s t a r c h and s u r f a c t a n t ,
`( c o n t a i n i n g 0.2% p o l y s o r b a t e 80) were f a s t e r t h a n t h a t from
`similar t a b l e t s w i t h o u t p o l y s o r b a t e 80 ( F i g . 1 ) . I n o t h e r
`i n v e s t i g a t i o n s i n t o t h e r o l e of s u r f a c t a n t i n t a b l e t f o r m u l a t i o n s
`c o n t a i n i n g d i s i n t e g r a n t s such as m i c r o c r y s t a l l i n e c e l l u l o s e and
`t h e presence of s u r f a c t a n t was a l s o
`calcium sodium a l g i n a t e ,
`shown
`t o produce
`improved d i s s o l u t i o n rate [4-61.
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`956
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`HENG, WAN, AND ANG
`
`From Figure 1, i t can be seen t h a t during t h e f i r s t minute, t h e
`d i s s o l u t i o n r a t e f o r t a b l e t s c o n t a i n i n g p o l y s o r b a t e 80 was
`t h a t f o r t a b l e t s without p o l y s o r b a t e 80 was
`45.6 % s-l w h i l s t
`For d i s s o l u t i o n from drug s u r f a c e s , considered as
`18.0 % s-'.
`t h e Noyes-Whitney e q u a t i o n [ 7 ] may b e
`d i f f u s i o n - c o n t r o l l e d ,
`w r i t t e n as:
`
`dm/dt = k.A.(S-C)
`
`t h a t h a s d i s s o l v e d from a
`where m is t h e amount of material
`is t h e s u r f a c e area, S is t h e s a t u r a t i o n s o l u b i l i t y , C
`s o l i d , A
`is t h e s o l u t e c o n c e n t r a t i o n and k is t h e rate c o n s t a n t p e r u n i t
`area. The rate c o n s t a n t , k f o r a p a r t i c u l a r drug i s t h e q u o t i e n t
`of t h e d i f f u s i o n c o e f f i c i e n t , D, d i v i d e d by t h e t h i c k n e s s of t h e
`d i f f u s i o n layer, h.
`I n t h e i n i t i a l s t a g e s ,
`
`S >> C; (S-C) -->S and t h u s
`
`dm/dt = k.A.S
`
`( i i )
`
`e q u a t i o n ( i i ) t o t h e drug
`t h e modified Noyes-Whitney
`Applying
`d i s s o l u t i o n from a t a b l e t i n t h e d i s s o l u t i o n a p p a r a t u s , t h e h i g h
`i n i t i a l d i s s o l u t i o n rate from t h e t a b l e t c o n t a i n i n g s u r f a c t a n t
`(Fig. 1) must be a t t r i b u t e d t o e i t h e r t h e e f f e c t of s u r f a c t a n t on
`t h e r a t e c o n s t a n t , k , o r t h e s u r f a c t a n t e f f e c t i n g a l a r g e
`i n c r e a s e i n t h e a v a i l a b l e s u r f a c e , A , f o r drug d i s s o l u t i o n . The
`s a t u r a t i o n s o l u b i l i t y , S, i s l i k e l y t o be almost c o n s t a n t , s i n c e
`t h e u s u a l s u r f a c t a n t c o n t e n t of a t a b l e t , when d i s s o l v e d i n t o t h e
`d i s s o l u t i o n media, have n e g l i g i b l e e f f e c t on S.
`
`From t h e s t u d i e s o f d r u g release [ 4 , 81,
`t h e i n c l u s i o n of
`s u r f a c t a n t i n t a b l e t s and g r a n u l e s c o n t a i n i n g s u l f a n i l a m i d e and
`no o t h e r e x c i p i e n t f a i l e d t o e l i c i t any s i g n i f i c a n t enhancement
`i n d r u g release. T h u s , i t i s u n l i k e l y t h a t t h e s u r f a c t a n t
`improves drug release per se although t h e w e t t i n g p o t e n t i a l of
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`ROLE OF SURFACTANT ON DRUG RELEASE FROM TABLETS
`
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`t h e s u r f a c t a n t may act t o i n c r e a s e t h e ' e f f e c t i v e s u r f a c e ' [ 9 ] but
`t h e i n f l u e n c e of t h i s e f f e c t on t h e o v e r a l l t a b l e t d i s s o l u t i o n i s
`n o t l i k e l y t o be dominant.
`I n f a c t , from t h e s t u d i e s on drug
`release from g r a n u l e s ,
`t h e a d d i t i o n of s u r f a c t a n t [8] r e t a r d e d
`drug release. Using a r o t a t i n g d i s k method, I t a i e t a l . [lo] also
`demonstrated t h a t t h e presence of t h e s u r f a c t a n t , p o l y s o r b a t e 80
`t h e c r i t i c a l micelle c o n c e n t r a t i o n
`beyond
`i n t h e d i s s o l u t i o n
`media decreased
`t h e d i s s o l u t i o n
`rate c o n s t a n t of
`flufenamic
`a c i d .
`
`Thus i t a p p e a r s t h a t t h e a c t i o n of s u r f a c t a n t i n promoting drug
`d i s s o l u t i o n from t a b l e t s c o n t a i n i n g t h e s u r f a c t a n t i s l i k e l y t o
`be brought about by t h e a c t i o n of t h e s u r f a c t a n t i n f l u e n c i n g t h e
`t a b l e t d i s i n t e g r a t i o n p r o c e s s r a t h e r t h a n t h e a c t i o n of
`s u r f a c t a n t i m p r o v i n g w e t t a b i l i t y per E. The m o s t
`l i k e l y
`parameter a f f e c t i n g t h e d i s s o l u t i o n rate i s probably t h e area (A)
`generated f o r drug release upon t a b l e t d i s i n t e g r a t i o n .
`
`The s u r f a c e area generated by a d i s i n t e g r a t i n g
`t a b l e t may be
`equated t o t h e degree of
`fragmentation. S i z e a n a l y s i s of
`t h e
`t a b l e t p a r t i c l e s upon d i s i n t e g r a t i o n can r e f l e c t the e x t e n t of
`new s u r f a c e generated. It i s however, d i f f i c u l t t o o b t a i n
`t h e
`e x a c t s i z e d i s t r i b u t i o n of t h e d i s i n t e g r a t e d p a r t i c l e s due t o t h e
`i n s t a b i l i t y and t r a n s i e n t n a t u r e of t h e i n t e r m e d i a t e p a r t i c l e s .
`The p a r t i c l e s are l i k e l y t o be very f r a g i l e . For l a r g e p a r t i c l e s ,
`and are n o t a v a i l a b l e f o r size a n a l y s i s
`they r a p i d l y s e t t l e
`u s i n g m e t h o d s s u c h a s t e c h n i q u e s e m p l o y i n g t h e t r a n s f e r o f
`p a r t i c l e s t h r o u g h a n a p e r t u r e . T h u s , a c o m b i n a t i o n of
`two
`methods, w e t s i e v i n g f o r l a r g e p a r t i c l e s and C o u l t e r Counter
`s i z i n g for t h e smaller p a r t i c l e s is more a p p r o p r i a t e .
`
`P a r t i c l e s i z e d i s t r i b u t i o n of d i s i n t e g r a t e d p a r t i c l e s using s i e v e
`a n a l y s i s f o r t a b l e t s w i t h and w i t h o u t p o l y s o r b a t e 80 showed t h a t
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`-
`
`I
`
`L
`
`-l
`
`I
`
`FIGURE 2
`S i z e d i s t r i b u t i o n s of d i s i n t e g r a t e d p a r t i c l e s from sulfanilamide
`(a) and sulfaguanidine (b) t a b l e t s without polysorbate 80 ( c l e a r )
`and with 0.2% polysorbate 80 (shaded) .
`
`both sulfanilamide and sulfaguanidine t a b l e t s without polysorbate
`80 produced coarser d i s i n t e g r a t e d p a r t i c l e s than t h e t a b l e t s i n
`which t h e s u r f a c t a n t had been incorporated (Fig. 2 ) .
`
`For a complete s i z e d i s t r i b u t i o n c h a r a c t e r i z a t i o n , a composite
`p l o t of t h e s i z e d i s t r i b u t i o n s obtained using s i e v e a n a l y s i s f o r
`t h e l a r g e p a r t i c l e s ( g r e a t e r than 75 microns) and
`t h e Coulter
`Counter f o r t h e f i n e r p a r t i c l e s , were obtained (Fig. 3a), It can
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`Collegium v. Purdue, PGR2018-00048
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`

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`ROLE OF SURFACTANT ON DRUG RELEASE FROM TABLETS
`
`959
`
`2
`
`3
`
`4
`
`5
`
`10 -
`-
`I 5
`U
`
`c
`
`W
`g5
`c
`0
`4 c
`2
`W
`0,
`n
`
`0
`
`2
`
`3
`
`4
`[Size (un)l
`
`109,
`
`5
`
`FIGURE 3
`C u m u l a t i v e size d i s t r i b u t i o n s (a) and frequency d i s t r i b u t i o n s
`(b) of d i s i n t e g r a t e d p a r t i c l e s of s u l f a n i l a m i d e (squares) and
`0.2% polysorbate 80 (closed) .
`sulfaguanidine ( c i r c l e s ) without polysorbate 80 (open) and with
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`960
`
`HENG, WAN, AND ANG
`
`be seen t h a t t a b l e t s c o n t a i n i n g p o l y s o r b a t e 80 produced a f i n e r
`d i s p e r s i o n of d i s i n t e g r a t e d p a r t i c l e s . I f t-he f r e q u e n c y
`d i s t r i b u t i o n of t h e d i s i n t e g r a t e d p a r t i c l e s is p l o t t e d (Fig. 3b),
`t a b l e t s produced a
`t h e d i s i n t e g r a t e d p a r t i c l e s of s u l f a g u a n i d i n e
`tri-modal d i s t r i b u t i o n w i t h class modes a t approximately 1 4 , 45
`and 90 urn, suggesting t h a t t h e break-down of
`t a b l e t s t a k e s t h e
`c o u r s e of d i s i n t e g r a t i n g f i r s t t o g r a n u l e s
`t h e n t o f i n e r
`aggregates and f i n a l l y deaggregating t o t h e o r i g i n a l p a r t i c u l a t e
`t h e materials which have n o t d i s s o l v e d . S i n c e swollen
`state of
`s t a r c h g r a i n s have a mean s i z e about 14 um, it i s l i k e l y t h a t t h e
`smallest p a r t i c l e s are mainly t h e i n s o l u b l e s t a r c h g r a i n s .
`
`I n t h e case of s u l f a n i l a m i d e t a b l e t s , only one d i s t i n c t peak w a s
`obtained. The d i s i n t e g r a t i o n rate of
`t h e s u l f a n i l a m i d e t a b l e t s
`was extremely r a p i d . The d i s i n t e g r a t e d p a r t i c l e s c o n t a i n i n g t h e
`s u l f a n i l a m i d e i s l i k e l y t o d i s s o l v e much faster.
`more s o l u b l e
`The t a b l e t s are a l s o softer (Table I ) .
`
`t h e s u r f a c t a n t , p o l y s o r b a t e 80 i n t a b l e t
`The i n c l u s i o n of
`f o r m u l a t i o n s c o n t a i n i n g s t a r c h , had e l i c i t e d f a s t e r d r u g
`d i s s o l u t i o n rates d e s p i t e t h e prolonged d i s i n t e g r a t i o n . From s i z e
`a n a l y s i s d a t a of t h e d i s i n t e g r a t e d p a r t i c l e s , i t is e v i d e n t t h a t
`t h e s u r f a c t a n t t o produce a f i n e r d i s p e r s i o n of
`t h e a b i l i t y of
`d i s i n t e g r a t e d p a r t i c l e s had enabled an enhanced drug release
`t h e s u r f a c t a n t may have a role i n
`rate. As a w e t t i n g a g e n t ,
`promoting drug release through improved w e t t a b i l i t y of
`t h e drug
`p a r t i c l e s as suggested by many workers [ll-121 b u t it had been
`shown t h a t t h e improved w e t t i n g by s u r f a c t a n t does n o t necessary
`p r o d u c e t h e e x p e c t e d e n h a n c e m e n t i n release 181. O f g r e a t e r
`importance is t h e size of t h e d i s i n t e g r a t e d p a r t i c l e s .
`
`The s i z e of t h e d i s i n t e g r a t e d p a r t i c l e s have a more s i g n i f i c a n t
`i n f l u e n c e on drug release rate from t a b l e t s . Where t h e e x c i p i e n t
`
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`Collegium v. Purdue, PGR2018-00048
`
`

`

`ROLE OF SURFACTANT ON DRUG RELEASE FROM TABLETS
`
`961
`
`i s a b l e t o produce f i n e r d i s p e r s i o n of d i s i n t e g r a t e d p a r t i c l e s ,
`i t f o l l o w s t h a t i t would e n h a n c e d r u g release t h r o u g h t h e
`i n c r e a s e d s u r f a c e area f o r d i s s o l u t i o n . S u r f a c t a n t i s o f t e n
`c l a i m e d t o p r o d u c e
`improved d r u g release t h r o u g h t h e w e l l
`documented s u r f a c t a n t a c t i o n of w e t t i n g , s o l u b i l i z a t i o n and even
`f l o c c u l a t i o n [13]. However, it appears from t h i s i n v e s t i g a t i o n
`t h a t t h e most l i k e l y effect of t h e s u r f a c t a n t i n enhancing d r u g
`release i s through t h e e f f e c t of
`t h e s u r f a c t a n t i n a l t e r i n g t h e
`i n t e g r i t y of
`t h e t a b l e t . The reduced t a b l e t i n t e g r i t y
`can be
`t h e lower hardness v a l u e s obtained i n t h e presence of
`seen by
`s u r f a c t a n t (Table 1). T a b l e t s c o n t a i n i n g s u r f a c t a n t are known t o
`be softer t h a n similar t a b l e t s without s u r f a c t a n t b u t compressed
`t o t h e same p r e s s u r e o r p o r o s i t y . As t h e t a b l e t s c o n t a i n i n g
`s u r f a c t a n t are softer due
`t o reduced
`i n t e r p a r t i c u l a t e bonding
`[ 1 4 ] , t h e d i s i n t e g r a t e d p a r t i c l e s from such t a b l e t s are l i k e l y t o
`be of a smaller s i z e .
`
`REFERENCES
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`Purdue 2031
`Collegium v. Purdue, PGR2018-00048
`
`