the effect of particle size and viscosity grade on the compaction propertis of hpmc
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8/10/2019 The Effect of Particle Size and Viscosity Grade on the Compaction Propertis of HPMC
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E L S E V I E R
International Journal of Pharmaceutics 126 (1995) 189-197
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
T h e
ef fect of part ic le s i ze and v i scos i ty grade on the compact ion
propert i e s o f hydroxypropy lmet hy lce l lu los e 22 8
A . N o k h o d c h i , M . H . R u b i n s t e in , J . L . F o r d *
School of Pharmacy Liverpool John Moores University Byrom Street Liverpool L3 3AF UK
Received 22 D ecember 1994; revised 3 May 1995; accepted 22 M ay 1995
A b s t r a c t
T he i n f lue nc e o f pa r ti c l e s iz e a nd v i s c os it y g r a de o f hyd r ox ypr opy l me t hy l c e l l u l o s e 2208 ( H P M C ) on t he t e ns il e
s t r e ng t h , c ompr e s s i b il i ty , e ne r g ie s i nvo l ve d du r i ng c o ns o l i da t i on , m e a n y i e l d p re s s u r e a nd e l as t ic r e c ove r y o f H P M C
c om pa c t s ha ve be e n de t e r mi ne d . T h e r e l a t i ons h i p be t w e e n pa r t ic l e s iz e, t e n si le s t r e ng t h a nd t he v i s c os i ty g r a de o f
H P M C w a s c ompl e x . A t s ma l le r pa rt i c le s iz es ( < 45 a nd 4 5 - 1 25 ~ m) , a n i nc re a s e i n t he v i sc os i ty g r a de o f H P M C
r e s u lt e d i n a r e du c t i on i n t he t ens il e s t r e ng t h o f i ts c omp a c t s . H ow e ve r , a t l a r ge r pa r ti c l e si ze s (125 - 180 , 180 - 250 o r
2 5 0 - 3 5 0 / ~ m ) , t h e te n si le s t r e n g th o f H P M C c o m p a c t s d e cr e a se d w i t h a n i n c re a se i n v is c o si ty g ra d e u p t o H P M C
K 1 5M , bu t f o r H P M C K 1 00M t he r e w a s a sma l l inc r e a se i n t e nsi le s t re ng t h . T he c ompr e s s i b i l i ty ind i c es o f H P M C
K 1 0 0 , H P M C K 4 M , H P M C K 1 5 M a n d H P M C K 1 0 0 M i n c re a s ed 5 8% , 74 % , 4 9 % a n d 7 0% , re sp e c ti ve ly , a s t h e
pa r t ic l e si ze w a s r e duc e d f r o m 25 0- 35 0 / t m t o < 45 / ~ m. T h i s ind i c a te s t ha t t he in t e r pa r ti c l e f ri c t iona l a nd c ohe s i ve
forces inc reased w i th decreas ing pa r t i c l e si ze . The t ens i l e s t rength o f com pac t s mad e o f the smal les t pa r t i c l e si ze ( < 45
/ t m) f r a c t i on a t e a c h v i s c os it y g r a de w e r e a t l e a st t h r e e t ime s m or e t ha n t he t e ns il e s t re ng t hs o f c om pa c t s m a de o f
25 0 - 3 50 / ~ m . P a r t i cl e s iz e w a s the s i ng le mos t i m por t a n t f a c t o r i n c on t r o l l i ng t he t ens il e s tr e ng t hs o f H P M C t a b le t s.
T he me a n y i e l d p r es s u r e t o i nduc e p l a s t i c de f o r m a t i on c a l c u l a te d f r o m t he s l ope s o f H e c ke l p l o t s w a s t he l ow e s t f o r
H P M C K I 00 , I nc r e a s e in pa r t i cl e s iz e r e su l t ed i n a n i nc r ea s e i n e la s ti c r e c ove r y , p r e s um a b l y due t o a r e d uc t i on i n t he
num be r o f pa r ti c l e- pa r t ic l e i n t e r a c t i on p o i n t s du r i ng c om pa c t i on , a nd i n a r e duc t i on o f t he p l a st i c e ne r gy f o r al l t he
samples . Th e v i scos i ty grad e of HP M C had no e f fec t on the e l as ti c energy. Par t ic l e s ize , how ever , d id s igni f i cant ly
a f fe c t t h e el as ti c e n e r g y o f H P M C K 4 M a n d H P M C K 1 0 0 M .
Keywords:
H yd r oxyp r opy l m e t hy l c e l l u l o s e ; V i s c os i ty g r a de ; T e ns il e s t r e ng t h ; P a r t ic l e s iz e; C om pa c t i o n e ne r gy ; C o m-
press ib i l i ty index
1 . I n t r o d u c t i o n
* Corresponding author.
T h e p a r t i c l e s i ze o f a m a t e r i a l is o n e o f t h e m o s t
i m p o r t a n t f a c t o r s a f fe c t in g t a b le t s t r e n g t h
( S h e i k h - S a l e m a n d F e ll , 1 9 8 2 ). I t h a s b e e n
c l a i m e d t h a t w h e n t h e i n t e r p a r ti c u l a te b o n d s i n a
0378-5173/95/$09.50 1995 Elsevier Science B.V. All rights reserved
SSDI
0 3 7 8 -5 1 7 3 ( 9 5 ) 0 4 1 2 2 - Q
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8/10/2019 The Effect of Particle Size and Viscosity Grade on the Compaction Propertis of HPMC
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19
A . N o k h o d c h i 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 ] P h a r m a c e u t i c s 1 2 6 1 9 9 5 ) 1 8 9 - 1 9 7
c om pa c t a re we a k e .g . fo r l a c tose ) the i n i ti a l
pa r t i c l e s i z e i s no t e xpe c t e d t o i n f l ue nc e t a b l e t
s t re n g t h S h o t t o n a n d G a n d e r t o n , 1 9 6 1 ) . H o w -
e ve r , Vr om a ns e t a l . 1985) fou nd t ha t a de c re a se
in par t ic le s ize of l ac tose resu l ted in an increa se in
t e ns il e s t r e ng t h o f t he t a b l e ts . W he n t he i n t e rpa r -
t i c u l a t e b o n d s a r e s t r o n g , h o w e v e r , f r a c t u r e o c -
c u r s a c r o s s t h e g r a i n s o f c r y s ta l s a n d t h e s t r e n g t h s
of t he re su l t a n t t a b l e t s a re a func t i o n o f t he i n it i a l
pa r t i c l e s i z e . Ge ne ra l l y , sma l l e r pa r t i c l e s g i ve
s t r o n g e r t a b le t s H i i t t e n r a u c h , 1 9 7 7 ). S m a l l e r p a r -
t i c l e s t e n d t o a g g r e g a t e u n d e r c o m p a c t i o n ,
w h e r e a s l a r g e r p a r t i c l e s a r e f r a c t u r e d . A n u m b e r
o f s t u d i e s c o n f i r m t h a t t h e f r a g m e n t a t i o n p r o p e n -
s i t y o f a subs t a nc e unde r l oa d i nc re a se s wi t h i t s
pa r t i c l e s iz e He rse y e t a l ., 197 3; M c K e n na a n d
M c C a f f e r t y , 1 9 8 2 ; A l d e r b o r n e t a l. , 1 9 8 5 ) . F o r
t h i s r e a s o n a c h a n g e i n m e a n p a r t i c l e s i z e m a y
a l te r t h e p r e d o m i n a n t c o n s o l i d a ti o n m e c h a n is m .
Al d e rb orn e t a l. 1988) c a t e gor i se d t he e f fe c t s o f
pa r t i c l e s i z e on t he ba s i s o f t he me c ha ni sms i n -
v o l v e d d u r i n g c o m p a c t i o n . F o r m a t e r i a l s w i t h a
h i g h t e n d e n c y t o f r a g m e n t , t h e o r i g i n a l p a r t i c l e
s iz e is o f le ss i mp or t a n c e t h a n fo r p l a s t i c ma t e r i a l s
a n d t h e t a b l e t s tr e n g t h i s g e n e r a l ly i n d e p e n d e n t o f
pa r t i c l e s i z e . For ma t e r i a l s wi t h i n t e rme di a t e t e n-
d e n c y t o f r a g m e n t , t h e t a b l e t s t r e n g t h i s i n c re a s e d
wi t h re duc i ng pa r t i c l e s i z e . For ma t e r i a l s wi t h a
l o w t e n d e n c y t o f r a g m e n t , t h e s i t u a t i o n i s c o m -
pl e x . R e duc t i on i n pa r t i c l e s i z e c a n g i ve a n i n -
c r e a s e i n t a b l e t s t r e n g t h , p r o b a b l y d u e t o t h e
i n c re a s ed n u m b e r o f p o i n t s o f c o n t a c t b e t w e e n
part ic les .
C o m p a c t i o n s p e e d p l a y s a n i m p o r t a n t r o l e i n
de t e rmi n i ng t he e f fe c t o f i n i t i a l pa r t i c l e s i z e on
t e ns i l e s t r e ng t h . Di f fe re nc e s i n t he s t r e ng t hs o f
t a b l e t s o b t a i n e d f r o m d i f f e r e n t s i e v e f r a c t i o n s o f
l a c to s e b e c a m e n e g l i g ib l e as t h e c o m p a c t i o n s p e ed
wa s i nc re a se d Al p a r e t a l ., 19 70) . Th i s i nc re a se
c a u s e d a g r e a t e r f r a g m e n t a t i o n o f t h e s t a r t in g
m a t e r i a l w h i c h e l i m i n a t e d a n y d i f f e r en c e s b e tw e e n
the ini t ial sizes.
F o r t h e p l a s t i c a l l y d e f o r m i n g m a t e r i a l s , s o d i u m
c h l o r i d e a n d p o t a s s i u m c h l o r i d e , H e r s e y e t a l .
1 9 73 ) a n d H u m b e r t - D r o z e t a l. 1 9 82 ) r e p o r t e d
t h a t y i e l d p r e s s u r e s w e r e i n d e p e n d e n t o f p a r t i c l e
s i z e . H o w e v e r , f o r m a t e r i a l s w h i c h d e f o r m b y
p a r t ic l e f r a g m e n t a t i o n l a c to s e a n d c a l ci u m c a r-
bon a t e ) He rse y e t a l . 1973) a nd Yo rk 1978)
f o u n d t h a t t h e y i e l d p r e s s u r e o f c o m p a c t s i n -
c re a se d wi t h a r e duc t i on i n pa r t i c l e s i z e .
T h e a i m s o f t h i s s t u d y w e r e t o d e t e r m i n e t h e
e f fe c t o f d i f fe re n t pa r t i c l e s i z e s o f HPMC 2208 of
d i f f e r e n t v i s c o s i t y g r a d e s o n c o m p r e s s i o n p r o p e r -
t ie s. M a l a m a t a r i s e t a l . 1994) pa r t l y re se a rc he d
t h e e f f e c t o f p a r t i c l e s i z e o f H P M C o n i t s c o m -
p r e s s io n b e h a v i o u r b u t o n l y u s e d th e < 1 2 0 , 1 2 0 -
3 20 , a n d > 3 20 /~ m f r a c t i o n s o f H P M C K 4 M ,
H P M C K 1 5 M a n d H P M C K 1 0 0 M . S i m i l a r l y ,
M a l a m a t a r i s a n d K a r i d a s 1 99 4) e x a m i n e d t h e
t e n si le s tr e n g t h o f H P M C m a t r i c e s b u t n e i t h e r
s t u d y f u ll y e x a m i n e d t h e c o m p a c t i o n b e h a v i o u r o f
H P M C i n th e a b s en c e o f a d s o r b e d m o i s tu r e .
2 M a ter i a l s an d meth od s
D i f f e r e n t v i s c o s i t y g r a d e s o f h y d r o x y p r o p y l -
m e t h y lc e ll u lo s e 2 20 8 H P M C K I 0 0 , H P M C
K 4 M , H P M C K 1 5 M a n d H P M C K 1 0 0M m a n u -
f a c t u r e d , r e s p e c t i v e l y , a s M e t h o c e l K 1 0 0 L V ,
M e t h o c e l K 4 M , M e t h o c e l K 1 5 M a n d M e t h o c e l
K I 0 0 M b y D o w C h e m i c a l s , U S A ) w e r e u s e d .
P a r t ic l e s iz e f r a c t i o n s < 4 5 , 4 5 - 1 2 5 , 1 2 5 - 1 8 0 ,
1 8 0 -2 5 0 , a n d 2 5 0 - 3 5 0 / ~ m ) o f e a ch H P M C w e re
o b t a i n e d b y s i e v i n g t h e m a t e r i a l s t h r o u g h t e s t
s ie ve s E n d e c o t t s L t d . , L o n d o n , U K ) o n a m e -
c h a n i c a l v i b r a t o r P a s c a l E n g i n e e r i n g , S u s s ex ,
U K ) . T h e s i e v e d f r a c t i o n s w e r e d r i e d a t 7 0 C f o r
5 d a y s p r i o r t o u s e .
2 1 Determination o f pack ing properties
Th e c ompre ss i b i l i t y i nde x C a r r , 1965) i s a me a -
s u r e o f t h e p r o p e n s i t y o f a p o w d e r t o c o n s o l i d a t e .
T h e t r u e d e n s i t y p g) , b u l k d e n s i t y P b ) a n d t a p
de n s i t y P t) o f d i f fe re n t pa r t i c l e s iz e f ra c t i ons o f
d i f f e r e n t v i s c o s i t y g r a d e s o f H P M C w e r e d e t e r -
m i n e d . T r u e d e n s i t i e s w e r e d e t e r m i n e d u s i n g a
B e c k m a n a ir c o m p a r i s o n p y c n o m e t e r m o d e l 9 3 0
C A , U S A ) . T h e b u l k d e n s i t y w a s d e t e r m i n e d f o r
e a c h p o l y m e r f r o m a w e i g h e d 1 0 g s a m p l e , c a r e -
f u l ly p o u r e d i n t o a 5 0 m l c y li n d e r . T h e n t h e
s a m p l e s w e r e t a p p e d 1 00 ti m e s to o b t a i n c o n s t a n t
v o l u m e . C h a n g e s o c c u r r i n g i n p a c k i n g a r r a n g e -
m e n t d u r i n g t h e t a p p i n g p r o c e d u r e a r e e x p r e s s e d
a s t he c ompre ss i b i l i t y i nde x , Eq . 1 .
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A. N okho dehi e t al . / In ternat iona l Journ al o f Pharm aeeut ics 126 1995) 189 197
191
Compressibility index = [ P t -
Pb /Pt]
X 100 (1)
2.2. Compress ion
Compressions were carried out using a High
Speed Compaction Simulator (ESH Testing Ltd
Brierley Hill, UK), as modified at the Liverpool
School of Pharmacy, fitted with 12.5 mm fiat-
faced punches. The details of the compaction
simulator have been published elsewhere
(Nokhodchi et al., 1995a, b). Four tablets were
produced for each particle size of each viscosity
grade of HPMC. A constant weight of 400 mg
was maintained for all the samples and each tablet
was compressed, by a compaction force of 10 kN.
During compression, upper punch load and
punch separation were monitored to an accuracy
of +0.05 kN and + 12 /~ m, respectively
(Bateman, 1988). Before each compaction, the die
wall was cleaned with acetone and prelubricated
with 4 w/w magnesium stearate in acetone.
2.3. M easu rem ent o f plas t ic an d elas tic energies
The manipulation of compression data has been
described previously (Nokhodchi et al., 1995b).
For a system where both punches are mobile, the
punch separation may be plotted against upper
punch force. The area under this curve will be the
work done or energy (joules). The plastic and
elastic energy of compaction of the H PMC tablets
were measured using energy analysis on the force-
punch separation plot. Gross, plastic and elastic
energies were determined for each compaction.
Fig. 1 illustrates a typical force-punch separa-
tion plot, where A is the punch separation at the
first measurable force, B is the force at the mini-
mum punch separation D, and C is the decom-
pression force. The area under the curve A B D
gives the gross energy, whilst that under curve
C B D corresponds to the decompression energy or
elastic energy. The net compaction energy or plas-
tic energy was determined from the difference
between area
A B D
and area
C B D .
2.4. Heckel analys is
The data were also analysed using Eq. 2
(Heckel, 1961a, b):
ln[1/(1 - O)] =
K P + A
(2)
where D is the relative density of the tablet at
pressure P and K denotes a material constant
which is the slope of the straight line portion of
the Heckel plot (for example, Fig. 2), the recipro-
cal of which is the mean yield pressure. A is the
value of the intercept of the straight line and is a
function of the initial bulk volume. Regression
analyses were carried out on the Heckel plots for
data between 20 and 75 MPa and the mean yield
pressures from each set of data. All data were
therefore the means of four determinations. The
relative densities of the powders (Do), at the point
when a measurable force is applied, and the rela-
tive density, D~, predicted from the intercept of
the Heckel plot (Fig. 2), were also calculated.
2.5. Dete rmin ation o f elastic recover ,
The percentage elastic recovery of each com-
pact was determined using Eq. 3 (Armstrong and
Haines-Nutt, 1972; Malamataris et al., 1984);
E R = [(Ht- Hm /Hm] x 100 (3)
o
t3
u c r u a e h s p m u ~ [ ] A
F i g . 1. T y p i c a l f o rc e - p u n c h s e p a r a t i o n p l o t f o r H P M C K 4 M
o b t a i n e d a t a c o m p r e s s i o n s p e e d o f 1 5 m m / s .
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192
A . N o k h o d c h i e t a l . ,' I n t e r n a t i o n a l J o u r n a l ~ P h a r m a c e u t i c s 1 2 6 ( 1 9 9 5 ) 1 8 9 1 9 7
-4
]}l
Db= D a DO
i
O
m CompressionP r es m r e [ l ~ ]
F i g. 2 . T y p i c a l H e c k e l p l o t [ o r H P M C K 4 M o b t a i n e d a t a
c o m p r e s s i o n s p e e d o f 1 5 m m / s .
w h e r e H m i s t h e h e i g h t o f t h e t a b l e t a t m a x i m u m
c o m p r e s s i o n f o r c e a n d / 4 1 is th e t a b l e t h e i g h t 2 4 h
a f t e r e j e c t i on .
2 6 T e n s i l e s t r e n g t h
T e n s i l e s t r e n g t h s w e r e d e t e r m i n e d f r o m t h e
f o r c e r e q u i r e d t o f r a c t u r e t a b l e t s b y d i a m e t r a l
c o m p r e s s i o n o n a m o t o r i s e d t a b l e t h a r d n e s s t e s t e r
(mode l 2E , Sc h l e un i ge r , Zur i c h , Swi t z e r l a nd) . The
t e n s i l e s t r e n g t h s w e r e c a l c u l a t e d a c c o r d i n g t o E q .
4 (Fe l l a nd Ne wt on , 1970) :
T = 2 P / ~ r D H
(4)
whe re T i s t he t e ns i l e s t r e ng t h , P i s t he a pp l i e d
l o a d , D a n d H a r e t a b l e t d i a m e t e r a n d t h i c k n e s s ,
respec t ive ly.
2 7 S t a t i s t i c a l a n a l y s i s
A l l d a t a w e r e s t a t i s t i c a l l y a n a l y s e d b y t w o - w a y
a n a ly s i s o f v a r i a n c e a n d T u k e y s m u l t ip l e c o m -
pa r i son t e s t . R e su l t s a re quo t e d a s s i gn i f i c a n t
where P < 0.05.
3 R e s u l t s a n d d i s c u s s i o n
T a b l e 1 g i v es d a t a i n d i c a t i n g t h e e f f ec t s o f
v i s c o si ty g r a d e a n d p a r t ic l e siz e o f H P M C o n t h e
t e n si le s t r e n g t h o f it s c o m p a c t s . T w o - w a y a n a l y s i s
o f v a r i a n c e c o n f i r m e d t h a t t h e r e w e r e s i g n i f i c a n t
d i f fe re nc e s i n t e ns i l e s t r e ng t h be t we e n t he va r i ous
v i s c o si ty g r a d e s . T u k e y s t e s t s h o w e d t h a t t e n s il e
s t r e n g t h d e c r e a s e d a s t h e v i s c o si t y g r a d e i n c r e a s ed
f r o m H P M C K 1 0 0 , t h r o u g h H P M C K 4 M t o
H P M C K 1 5 M f o r a l l p a r t i c l e s i z e s . H o w e v e r ,
w i t h th e e x c e p t io n o f t h e 2 5 0 - 3 5 0 p m f r a c t io n s ,
t he re we re no s t a t i s t i c a l d i f f e re nc e s be t we e n t he
d a t a f o r H P M C K 1 5 M a n d f o r H P M C K 1 0 0 M .
T w o - w a y a n a ly s i s o f v a r ia n c e a l s o s h o w e d t h a t
t he re wa s i n t e ra c t i on be t we e n pa r t i c l e s i z e a nd
v i sc o s it y g r a d e o f H P M C .
T h e t e n si le s t r e n g t h s o f t a b le t s c o n t a i n i n g t h e
s m a l l e r p a r t ic l e s iz es ( < 4 5 a n d 4 5 - 1 2 5 /~ m ) o f
H P M C K 1 0 0 o r H P M C K 4 M w e r e s t a t i s t i c a l l y
s i mi l a r (Tuk e y s t e s t) bu t we re s i gn i f i c a n t ly h i gh e r
( T u k e y s t e st ) th a n f o r t a b l e t s c o n t a i n i n g t h e s a m e
size f r ac t io n o f H P M C K 1 5 M o r H P M C K 1 0 0 M
whi c h we re a l so s t a t i s t i c a l l y i nd i s t i ngu i sha b l e
f r o m e a c h o t h e r ( T u k e y s t es t) . T h e t e n si le
s t r e ng t hs o f ma t r i c e s c on t a i n i n g 125 180 or 180
2 50 p m H P M C K 1 0 0 w e r e s ig n i fi c an t ly h i g h e r
( T u k e y s t e s t) t h a n t h e t e n s il e s t r e n g t h s o f t a b le t s
c o n t ai n in g s im i la rl y s iz ed H P M C K 4 M , H P M C
K 1 5 M o r H P M C K 1 0 0 M w h i c h w e r e a l s o i n d i s -
t i n g u i s h a b l e b y T u k e y s t e s t f r o m e a c h o t h e r
(Ta b l e 1 ). Pa ra d oxi c a l l y , the s t r e ng t hs o f ta b l e t s
c o n ta in i ng 2 5 0 - 3 50 p m H P M C K 1 0 0 o r H P M C
K 1 0 0 M w e r e s t a t i s t i c a l l y h i g h e r t h a n t h o s e o f
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 s i z e d f r a c t i o n s o f
H P M C K 4 M o r H P M C K 1 5M .
F o r e a c h p a r t i c l e s i z e , c o m p a c t s m a d e f r o m t h e
l o w e st v is c o si ty g r ad e ( H P M C K 1 0 0 ) h a d t h e
h i ghe s t t e ns i l e s t r e ng t hs a nd t he l owe s t t e ns i l e
s t r e n g t h s w e r e f o u n d f o r c o m p a c t s c o m p o s e d o f
e it he r H P M C K 1 5 M o r H P M C K 1 0 0 M ( T ab l e 1).
The se re su l t s i nd i c a t e t ha t de ns i f i c a t i on o f t he
po l yme r be c a me l e s s d i f f i c u l t a s t he v i sc os i t y
g r a d e o f H P M C d e c re a se d . T h e s u b s e q u e n t in -
crease in t ens i le s t rength a t l a rger par t i c le s izes
w a s p r o b a b l y d u e t o a n i n c r e a s e i n p l a s t i c f l o w ,
w h i c h w o u l d c a u s e a r e s i s t a n c e t o f r a c t u r e d u r i n g
t h e d i a m e t r a l c o m p r e s s i o n .
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A . N o k h o d c h i e t a l. / I n t e rn 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 ic s 1 2 6 1 9 9 5 ) 1 8 9 - 1 9 7 193
T a b l e 1
T h e e f f e c t o f p a r t ic l e si z e o n t h e t e n s i l e s t r e n g t h s M P a ) o f H P M C c o m p a c t s o f d i f f e r e n t v i s c o s it y g r a d e s p r e p a r e d a t a c o m p r e s s i o n
s p e e d o f 1 5 m m / s a n d c o m p r e s s i o n f o r ce o f 1 0 k N r e su l ts a r e t h e m e a n s a n d s t a n d a r d d e v i a t i o n s o f f o u r d e t e r m i n a t io n s )
P a r t i c l e s i z e / ~m ) T e n s i l e s t r e n g t h M P a S D
H P M C K 10 0 H P M C K 4 M H P M C K I 5 M H P M C K 1 00 M
< 45 2.03 _+ 0.1 0 2.02 _+ 0.06 1.73 0.41 1.67 _+ 0.0 6
45 -12 5 1.47 _+ 0.23 1.33 -+ 0.02 0.85 0.06 0.88 _+ 0.03
125 180 1.01 _+0.04 0.70_+ 0.06 0.64_ +0.07 0.74_+0.06
180 -250 0.82 _+ 0.07 0.64 _+ 0.02 0.60 _+ 0.04 0.64 _+ 0.04
25 0-3 50 0.57 -+ 0.04 0.48 _+ 0.03 0.45 _+ 0.01 0.57 _+ 0.05
Pa r t i c l e s iz e ha d a m a rk e d e f fe c t on t h e t e ns i le
s t r e n g th o f t h e H P M C c o m p a c t s ( T a b le 1 ). A
de c re a se i n t he pa r t i c l e s i z e re su l t e d i n a n i nc re a se
i n t e n s il e s t r e n g t h o f c o m p a c t s a t a l l v is c o s i ty
g r a d e s o f H P M C . P a r ti c le s iz e is o n e o f t h e m o s t
i m p o r t a n t f a c t o r s w h i c h c o n t r o l s t h e t e n s i l e
s t r e n g t h o f c o m p r e s s e d t a b l e t s. B o t h t h e d i r e c t i o n
a n d m a g n i t u d e o f t h e e f f e c t o f p a r t i c l e s i z e o n
t a b l e t s t r e n g t h v a r y b e t w e e n s u b s t a n c e s a n d a r e
r e la t e d t o t h e f r a g m e n t a t i o n p r o p e n s i t y o f th e
m a t e r i a l s . F o r a h i g h l y f r a g m e n t i n g m a t e r i a l , su c h
a s d i c a l c i u m p h o s p h a t e ( D e B o e r e t a l . , 1 9 7 8 ) t h e
or i g i na l pa r t i c l e s i z e i s o f l e s s i mpor t a nc e t ha n fo r
p l a s t i c ma t e r i a l s a nd t he t a b l e t s t r e ng t h i s ge ne r -
a l ly i n d e p e n d e n t o f p a r t i c le s iz e. F o r m a t e r i a l s
whi c h f ra gme nt t o a l e s se r e x t e n t , e . g . l a c t ose
(C ol e e t a l . , 1975) s i gn i f i c a n t c ha n ge s i n t a b l e t
s t r e n g t h d u e t o c h a n g e s i n p a r t i c l e s i z e o r s h a p e
h a v e b e e n o b s e r v e d . I n m a t e r i a l s u n d e r g o i n g e x -
t e n s i v e f r a g m e n t a t i o n , n e w c l e a n s u r f a c e s a r e c r e -
a t e d d u r i n g t h e c o m p r e s s i o n a n d t h e r e f o r e t h e
pa r t i c l e s i z e o f t he o r i g i na l ma t e r i a l e xe r t s a
s m a l l e r e f f e c t c o m p a r e d w i t h t h o s e m a t e r i a l s
w h i c h a r e l e s s p r o n e t o f r a g m e n t a t i o n .
T h e d e p e n d e n c e o f t a b l e t s t r e n g t h o n p a r t i c l e
s iz e f o r e a c h o f th e H P M C s s u g g e s t s t h a t e x t e n -
s iv e f r a g m e n t a t i o n d i d n o t o c c u r d u r i n g c o m p r e s -
s i o n o f H P M C . G e n e r a l l y , t h e p a r t i c l e s i z e o f
H P M C h a d a s i g n i fi c a n t e f fe c t ( t w o - w a y a n a l y s is
of va r i a nc e ) on t e ns i le s t r e ng t h . Th e t e ns i le
s t r e n g t h s o f e a c h p a r t i c l e s i z e f r a c t i o n o f H P M C
K 1 0 0 c o u l d c l e a r l y b e d i f f e r e n t i a t e d f r o m e a c h
o t h e r ( T u k e y s t es t) . O n t h e o t h e r h a n d , t h e r e
we re no s i gn i f i c a n t d i f fe re nc e s be t w e e n t he 125
1 8 0 / ~ m a n d 1 8 0 - 2 5 0 / ~ m f r a c t i o n s o f H P M C
K 4 M a n d H P M C K 1 5 M ( T u k ey s te st). F o r
H P M C K 1 0 0 M t h e 1 8 0 -2 5 0 a n d 2 5 0 - 3 5 0 /~ m
f r a c ti o n s c o u l d n o t b e d i f fe r e n ti a te d b y T u k e y s
test .
Ta b l e 2 sho ws t he e f fe c t o f pa r t i c l e s iz e a nd
v i s c o s i t y g r a d e o f H P M C o n t h e c o m p r e s s i b i l i t y
i nde x (C I ) . Inc re a se i n pa r t i c l e s i z e re su l t e d i n a
d e c r e a s e i n c o m p r e s s i b i li t y in d e x f o r e a c h g r a d e o f
H P M C . T h i s i n d i c a t e s t h a t t h e r e i s a n i n c r e a s e i n
b o t h t h e i n t e r p a r t i c u l a t e f r i c t i o n a l a n d c o h e s i v e
forc e s wi t h de c re a s i ng pa r t i c l e s i z e . The se fa c t o r s
ma y e xp l a i n t he i nc re a se i n t a b l e t t e ns i l e s t r e ng t h
wi t h de c re a s i ng pa r t i c l e s i z e o f d i f fe re n t v i sc os i t y
g r a d e s o f H P M C ( T a b le 1) a n d t h e C I m a y
i n d i c a t e t h e e a s e w i t h w h i c h p a r t i c l e r e a r r a n g e -
m e n t o c c u r s . T w o - w a y a n a l y s i s o f v a r i a n c e
s h o w e d t h a t b o t h p a r t ic l e s iz e a n d v i s c o s i ty g r a d e
ha d a s i gn i f i c a n t e ffe c t (P < 0 .05) on t he c om -
p r e s s ib i l it y i n d e x o f H P M C s a m p l e s a n d t h e r e
wa s i n t e ra c t i on be t we e n pa r t i c l e s i z e a nd v i sc os i t y
g r a d e o f H P M C . T u k e y s t es t s h o w e d t h a t t h e
c o m p r e s s i b i l i t y i n d i c e s o f H P M C K 1 0 0 a n d
H P M C K 1 0 0 M w e re a f f e c t e d u p to 1 25 1 8 0 / t m .
I n o t h e r w o r d s , t h e r e w a s n o s i g n if i c a n t d i f f er e n c e
b e t w e e n t h e i r 1 8 0 - 2 5 0 a n d 2 5 0 3 5 0
tm
f ra c -
t i o n s . T h e c o m p r e s s i b i l i t y i n d e x o f e a c h p a r t i c l e
s iz e f r a c t io n o f H P M C K 4 M c o u l d c le a rl y b e
d i f f e r e n t i a t e d f r o m e a c h o t h e r ( P < 0 . 0 5 ) w i t h t h e
e x c e p t i o n o f 1 8 0 - 2 5 0 a n d 1 2 5 1 8 0 / z m f r ac t i o n s .
O n t h e o t h e r h a n d , f o r K 1 5 M , t h e r e w a s n o
s i gn i f i c a n t d i f fe re nc e be t w e e n t he 250 350 a nd
1 80 2 5 0 a n d t h e 4 5 - 1 2 5 a n d < 4 5 / z m f r ac t io n s .
T u k e y s te s t s h o w e d t h a t t h e < 45 tz m f r a c t io n o f
H P M C K 4 M h a d s ig n i fi c an t ly t h e h ig h e s t c o m -
p r e s s i b i l i t y i n d e x . A t 4 5 - 1 2 5 / z m t h e c o m p r e s s -
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194
A. N ok hode h i e t a / . / I n t e r na t iona l J our na l o f Phar mac e u t i c s 126 1995) 189 197
T a b l e 2
T h e e f f e c t o f v i s c o s it y g r a d e a n d p a r t i c le s i ze o f H P M C o n t h e c o m p r e s s i b i l it y i n d i c e s r e s u l ts a r e t h e m e a n s a n d s t a n d a r d d e v i a t i o n s
o f f o u r d e t e r m i n a t i o n s )
P a r t i c l e s i z e / L m ) C o m p r e s s i b i l i t y i n d e x
( _ + S D )
H P M C K 1 00 H P M C K 4 M H P M C K 1 5M H P M C K I 0 0M
< 45 35.9 + 1.9 42.6 + 0.5 36.9_+ 0.5 39.3 _+ 0.7
45 125 34.3_+0.8 34.4_+0.9 35.2_+ 1.0 33.1 + 0. 8
125 180 26.3_+3.1 30.7_+ 1.0 31.7_+0.9 25.7_+ 1.7
180 -25 0 23.2 _+ 2.1 29.4 _+ 0.6 26.8 _+ 1.6 24.1 _+ 0.2
250 350 22.7_+ 1.6 24.5_+0.8 24.8_+ 1.0 23.2_+0.9
ibility index was not affected by viscosity grade of
HPMC. The compressibility index appeared to be
independent of the viscosity grade.
The effects of particle size on the mean yield
pressures for the HPMCs are shown in Fig. 3. For
each of the HPMCs, except HPMC K100M, the
mean yield pressures were independent o f the
particle size. For HPMC K100M, the mean yield
pressures decreased with increase in the particle
size. This would be expected for a material that
deforms by the combined mechanisms of particle
fracture and plastic deformation. This conclusion
is supported by the fact that the calculated mean
8
4
3
M I ~ ] ~ c K
1
I ' r ' I ' I ' I ' I ' I
5 1 1 5 2 2 8 ; 3 3 8
P a r t i c l e s i z e [ / ~ m ]
F i g . 3 . T h e e f f e c t s o f p a r t i c l e s i z e a n d v i s c o s i t y g r a d e o f
H P M C o n t h e m e a n y i el d p r es s u re s o f t a b le t s c o m p r e s s e d at
a c o m p r e s s i o n s p e e d o f 1 5 m m / s t o a c o m p r e s s i o n f o r c e o f
1 0 k N r e s u l ts a re t h e m e a n s a n d s t a n d a r d d e v i a t i o n s o f f o u r
d e t e r m i n a t i o n s ) .
yield pressures were unaffected by particle size for
all the HPMCs except KI00M (Fig. 3), indicating
that the deformation properties were unchanged
for HPMC K100, HPMC K4M and HPMC
KI5M by particle size. Thus H PMC K100M per-
forms similarly to lactose, where the yield pressure
increased as its particle size decreased (Roberts
and Rowe, 1986) in contrast to the other grades of
HPMC which performed similarly to microcrys-
talline cellulose (Roberts and Rowe, 1986). Two-
way analysis of variance showed that there was
interaction between particle si ze and viscosity
grade of HPMC (Fig. 3).
The effects of particle size on the elastic recovery
of the HPMCs are shown in Fig. 4. Elastic recov-
ery, in the die, increased with increasing particle
size and was generally independent of the grade o f
HPMC. Indeed, for the 250-350/lm fractions of
HPMC, only HPMC K100M could be differenti-
ated from the other HPMCs by Tukey s test.
Two-way analysis of variance showed that there
was interaction between particle size and viscosity
grade of HPMC (Fig. 4). The effects of particle
size on the plastic energy of different viscosity
grades of HPMC are illustrated in Table 3. Gener-
ally the plastic energies decreased with increase in
particle size but were independent of viscosity
grade and this was confirmed by two-way analysis
of variance. The smaller particle sizes of HPMC
gave thinner tablets (Table 4) which would indi-
cate that the top punch had travelled further
during compression. The corresponding increase
in plastic energy or net compaction energy should
indicate a higher ability of the smaller sized mate-
rial to deform plastically.
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A . N o k h o d c h i 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 2 6 1 9 9 5 ) 1 8 9 - 1 9 7 195
I I I
1 0 0 2 0 0 3 0 0
P t r t l e l e s l z e [ p r o ]
9 I
4 0 0
Fig. 4. The effect of particle size and viscosity grade of
HPM C on the elastic recoveries of compacts compressed at a
compression speed of 15 mm/s to a compression force of 10
kN results are the means and stand ard deviations of four
determinations).
Since particle size had no significant effect on
the plasticity, i.e. mean yield pressure, of the
HPMCs except HPMC K100M (Fig. 3), it may
therefore be assumed that the effect of particle
size on the plastic energy is not due to differences
in the plasticity but is caused by differences in
particle interactions, i.e. the number of contact
points. This interaction may be due to interparti-
cle friction or a different degree of bonding. This
explanation will also apply to the effects of parti-
cle size on tensile strength (Table 1), and elastic
recovery (Fig. 4).
The plastic energy of HPMC K100M was inde-
pendent of the particle size. However, for HPMC
KI00, HPMC K4M and HPMC K15M, the plas-
tic energies significantly decreased (Tukey s test)
as the particle size was increased from < 45 /~m
to 125-180/~m whereas the plastic energies could
not be differentiated for particle size fractions of
125-180, 180 250 and 250 -350/zm.
The effects of particle size on the elastic energy
of different viscosity grades of HPMC are shown
in Table 5. Two-way analysis of variance showed
tha t an increase in particle size generally increased
elastic energy for all K grades of HPMC. This
was due to a decrease in the number of particle-
particle interaction points. These trends were sup-
ported by the increase in elastic recovery of the
compacts (Fig. 4) with increasing particle size.
Two-way analysis of variance also showed that
the viscosity grade of HPMC had no significant
effect on the elastic energy.
Tukey s tests showed that the particle size had
no significant effect on the elastic energies of
HPMC K100 and HPMC K15M but had a sig-
nificant effect on the elastic energies of HPMC
K4M and HPMC K100M.
The compression studies showed that HPMC
K100 is the easiest of four polymers to compress
and it undergoes more plasticity during compres-
sion. This study also showed that not only viscos-
ity grade but also the particle size of HPMC
affected their compression and compaction prop-
erties. Since the compaction characteristics of
polymers are dominant factors in choosing a poly-
mer for sustained release, the selection of a defin-
ite particle size and viscosity grade of HPMC may
be important in the formulation of a controlled
release drug delivery system.
4 C o n c l u s io n
The results suggest that tensile strength, com-
pressibility index, plastic and elastic energies and
elastic recovery are significantly affected by parti-
cle size of HPMCs. It was found that the smallest
particle size (
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196 A . N o k h o d c h i e t al . / I n t e r n a ti 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 2 6 1 9 9 5 ) 1 8 9 1 9 7
T a b l e 3
T h e e f f e c t o f v i s c o s it y g r a d e a n d p a r t i c le s i z e o f H P M C o n t h e p l a s t i c e n e r g i e s o f t a b l e t s c o m p r e s s e d a t a s p e e d o f 1 5 m m / s t o a
c o m p r e s s i o n fo r c e o f l 0 k N r e su l t s a r e t h e m e a n s a n d s t a n d a r d d e v i a t io n s o f fo u r t a b le t s )
P a r t i c l e s i z e / ~ m ) P l a s t i c e n e r g y J ou l e i SD )
H P M C K I 0 0 H P M C K 4 M H P M C K I 5 M H P M C K 1 00 M
< 4 5 6 . 8 3 + 0 . 3 1 6 . 8 5 - + 0 . 2 0 6 . 8 0 - + 0 . 2 5 6 . 3 3 - + 0 . 1 5
45 125 6 . 64_+0 . 25 6 . 60_+ 0 . 22 6 . 58 _+0 .40 6 , 54_+ 0 . 06
125 -180 6 . 09_+0 . 33 5 . 86_+ 0 . 12 6 . 16_+ 0 . 26 5~88_+0. 22
1 8 0 - 2 5 0 6 . 0 8 _ + 0 . 1 7 5 . 9 3 _ + 0 . 1 4 5 . 9 8 _ + 0 . 1 8 6 , 1 2 _ + 0 . 5 6
25 0-3 50 5.97 -+ 0.23 5.91 -+ 0.07 6.13 _+ 0.11 5,85 _+ 0.43
T a b l e 4
T h e e f f e ct o f p a rt i c l e si z e o f H P M C o n t h e t h i c k n e s s e s o f t a b l e t s i n t h e d i e a n d o b t a i n e d a t a c o m p r e s s i o n f o r c e o f l 0 k N a n d s p e e d
o f 1 5 m m / s r e s ul t s a r e t h e m e a n s a n d s t a n d a r d d e v i a t i o n s o f fo u r t a b le t s )
P a r t ic l e s i ze / ~ m ) T h i c k n e s s o f t a b l e t s m m _ + S D )
H P M C K I 0 0 H P M C K 4 M H P M C K 1 5M H P M C K 1 00 M
< 45 2 . 494 + 0 . 020 2 . 473 _+ 0 . 051 2 . 500 _+ 0 . 023 2 . 501 _+ 0 . 004
45 125 2 . 536_ +0 . 02 9 2 . 526_+ 0 . 027 2 . 549_+ 0 . 021 2 . 551 _+0 .007
125 -180 2 . 548 _+ 0 . 023 2 . 555 _+ 0 . 013 2 . 555 _+0 .006 2 . 55 6-+ 0 . 01 6
180 250 2 . 577 _+ 0 . 032 2 . 552 0 . 004 2 . 572 -+ 0 . 008 2 . 575 + 0 . 013
250 350 2 . 566 0 . 007 2 . 575 -+ 0 . 025 2 . 570 -+ 0 . 009 2 . 580 -+ 0 . 012
T a b l e 5
T h e e f f e c t o f v is c o s i t y g r a d e a n d p a r t i c le s i z e o n t h e e l a s t ic e n e r g i e s o f H P M C c o m p a c t s c o m p r e s s e d a t a c o m p r e s s i o n s p e e d o f 1 5
m m / s t o a c o m p r e s s i o n f o rc e o f 1 0 k N r e s u lt s a r e t h e m e a n s a n d s t a n d a r d d e v i a t i o n s o f f o u r t a b le t s)
P a r t i c l e s i z e / ~ m ) P l a s t i c e n e r g y J o u l e _ + S D )
H P M C K 1 00 H P M C K 4 M H P M C K 1 5 M H P M C K 1 0 0M
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A. N ok hodc h i e t a l . / In t e r na t i ona l J our na l o f Phar mac e u t i c s 126 1995) 189 - 197 197
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