The Effect of Particle Size and Viscosity Grade on the Compaction Propertis of HPMC

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


2/9

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 .


3/9

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 .


4/9

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 .


5/9

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 -


6/9

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.


7/9

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 (


8/9

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


9/9

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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