DRUG DEVELOPMENT AND INDUSTRIAL PHARMACY, 10(7), 1085-1096 (1984)

EFFECT OF PARTICLE SIZE AND EXCIPIENTS ON

THE DISSOLUTION RATE OF METRONIDAZOLE
FROM SOLID DOSAGE FORMS: I1
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J. A. K. LAW0
Department of Pharmaceutics
and Pharmaceutical Wcrobiology
Ahmadu Bello University
Zaria, Nigeria.
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ABSTRACT
In-vitro d i s s o l u t i o n tests were c a r r i e d out with
t a b l e t s prepared from d i f f e r e n t p a r t i c l e s i z e ranges
o f metronidazole. Influence of t a b l e t binding agents
(Methylcellulose, polyvinyl pyrrolidone - (FVP) ,
potato starch and g e l a t i n ) on the drug release were
i n v e s t i g a t e d under s i m i l a r conditions, Comprimates
containing PVP and drug with p a r t i c l e size 1.75 lun ( i n
l a c t o s e mixture) gave optimum r e s u l t s These findings
mY open new Ways of formulating a metronidazole
t a b l e t e x h i b i t i n g improved drug - liberation, subse-
quently with a better b i o a v a i l a b i l i t y than the K L X d -
Tablet manufactured i n Hungary,
1085
Copyright 0 1984 by Marcel Dekker, Inc. 0363-90451841 1007-1085 $3.5010
 1086 LAUWO

INTRODUCTION

The influence of formulation on drug action has

been carefully reviewed by Munzel (1) and Blanchard (2).
Among formulation factors found to exert much effect
on bioavailability of solid dosage forms e.g. tablets
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are t h e ones attributed to dissolution rate such

as particle size, granule size (31, carriers e.g.
lactose (4, 5), binding agents and their concentra-
tions (6).

In the first part of these investigations, t h e

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effects of drug particle size and lactose on t h e

--
in-vitro dissolution of metronidazole were reported.
Particle size reduction plus the application of
lactose as a carrier were found to increase dissolu-
tion rate.

In this paper, t h e effects of particle size,

lactose and some tablet binders on the in-vitro
release of the same drug (Metronidazole) from
tablets are presented.

EXPERIMENTAL
Materials
Me tronidazole (Richter-Budapes t) USP- standard,
potato starch, corn starch (Agena Austria),
Gelatina Alba (Rousselot - Paris), Polyvinyl
 EFFECT OF PARTICLE SIZE. I1 1087

pyrrolidone (CAAF- Cooperation, FRG) , Methylcellulose

400cp. (Fluka AG), Lactose spray d r i e d (HMS - Holland)
A l l materials used were of a n a l y t i c a l grade.

Methods:

Tablet - Formulatioe
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A l l t a b l e t s formulated and tested contained

equivalent amounts o f t h e same vehicles. The t a b l e t
composition given i n table 1 was used with d i f f e r e n t
sizes of metronidazole named, 1.75p1, 125 - 200-
and 400 - 500 -0
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Tablet binders (Gelatin, Methylcellulose, Starch and

Polyvinyl pyrrolidone (PVP)), were used a t a weight
range of 2% (w/w) of the formula. Wet granulation

TABLE 1: M e t r o u a z o l e Tab1e t ComDositiop

Ingredient Quantity per

t a b l e t (mg)

Metronidazole 250.0
Aerosil 1.5
Magn. s t e a r . 1.5
Tablet binder 7.5
Talc 10.0
Corn s t a r c h 79.5

Weight of Tablet 350.0 (mg)

 1088 LAW0

was applied and the amount of moisture i n t h e

granules p r i o r t o t a b l e t t i n g was found t o be 3.11 + -
0,1% S.E? f o r formulations w i t h 1.75 wn metronidazole
( i n metronidazole: l a c t o s e mixture), and 2.07 2 0.08%
S.E? f o r granules containing l a r g e r c r y s t a l s of t h e
drug (i.e. d = 125 - 200- and d P 400 - 5Oo~m).
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From every granulate, comprimates of 10 m i n diameter,

weighing 350 mg each were prepared using a s i n g l e
,
punch t a b l e t t i n g machine 1 and a constant f o r c e of
7.5 kg w t . (The t a b l e t hardness was found t o vary
from 4.5 t o 5,6 ERWEKA kg w t ) .
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Pisso&tion Rate S t ud'l e g

A n i n - v i t r o d i s s o l u t i o n method r e l a t e d t o that o f

Needham e t a 1 (7) was adopted. Tablets were placed

in a USP Basket h e l d s t a t i o n a r y i n d i s t i l l e d water
(500 ml) a t 37 f 0
.
5
'. Agitation of the d i s s o l u t i o n
medium was f a c i l i t a t e d by a magnet s t i r r e r ( 2 . 9 x
0.85 cm) operated 2.5 cm under the basket a t a speed
of I50 r.p.m. Samples were withdrawnat s p e c i f i e d
i n t e r v a l s of time and were immediately f i l t e r e d
using 0.45pn S a r t o r i u s F i l t e r Membranes.
Replacement of We sample volume by water a t t h e
same temperature (37') was done.

'Wittenberg Type KP - 2 (GDR); 2S.E. = Standard Error

 EFFECT OF PARTICLE SIZE. I1 1089

A f t e r an appropriate d i l u t i o n , concentration was

determined from absorbance a t 320 nm, using
SPECTROMOPJ: - 204, W-Spectroghotometer (Hungary),

I n order t o study t h e r e p r o d u c i b i l i t y of the

method, 9 t a b l e t s from the same batch were i n d i v i -
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d u a l l y t e s t e d f o r d i s s o l u t i o n and t h e results were

s t a t i s t i c a l l y analysed.On t h e basis of t h e obtained
narrow standard e r r o r s , t h e method was considered
r e l i a b l e and the r e s t of t h e t e s t s were repeated a t
l e a s t t h r e e times.

RESULTS AND DISCUSSION

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The amounts of metronidazole dissolved i n water

a t d i f f e r e n t time i n t e r v a l s from t a b l e t s prepared
from various p a r t i c l e s i z e ranges of the drug applying
different tablet - binding agents are reported i n
figures 1 - 4, A n increase i n Dissolution Rate with
decreasing p a r t i c l e size was observed, Formulations
containing drug - p a r t i c l e s i z e of 1.75 u n (in-the
l a c t o s e mixture) released the drug a t the f a s t e s t
rate, It is almost c e r t a i n t h a t , a p a r t from the small
p a r t i c l e size of rnetronidazole, l a c t o s e , being e a s i l y
water soluble should have played a p o s i t i v e r o l e i n
t h e increased rate of d i s s o l u t i o n o f t h e drug.
From these s e r i e s of tests, it was a l s o experienced
t h a t t h e comprimates containing Polyvinyl Pyrrolidone
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-s m -
0
3
a
0

0
w

I
5 15 30 120 150
DISSOLUTION TIME Imin)

FIGURE 1
E f f e c t o f Particle Size on t h e Dissolution Rate o f Metronidozole from
Tablets w i t h.- Key: A = 400-500 urn; B = 125-20wm;
C = 1.75um. Vertical lines represent Rel. S.Dev. for 9 similar
experiments.
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m
H
N
M

H
H

5 15 30 60 90 120 I50
DISSOLUTIQN TIME Imin)

FIGURE 2
. .
E f f e c t of Particle Size on the Dissolution Rate o f Metronidazole from
Tablets w i t h 2% Methylcellulose Binder. Key: A = 400-5OOum;
-
f: = 125-2OOurn; C = 1.75um.
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V
5 15 30 90 I20 150

FIGURE 3
E f f e c t o f Particle Size on r o l u t i o n Rate of bhtronidazole
from T a b l e t s w i t h 24’. Potato Starch Binder. Key: A = hOe5wurn;
-
B = 125-200 urn; C = 1.75 Mm.
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H
9
m
H
N
M
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H
H

5 15 30 60 90 120 150
DISSO\UTION TIME Imn)

-
FIGURE 4
E f f e c t o f Particle Size on t h e Dissolution Rate o f M s t r o n i d a z o l e from
Tablets w i t h 2% PVP 0Binder. Key: A = 400-500 urn; I3 s 125-200um;
C = 1.75 ym.
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5 1s r, 60 sb 120 150
DISSOLUTION TIME lminl

FIGURE 5
Comparative Influence o f Binders on the Release o f Metronidazole
from Tablets, Key: A = Methylcellulose B = Potato Starch;
C = Gelatin; D = PVP. Content of Each Binder was 2% (W/W),
Particle Size o f Metronidazole was 1.75um i n each o f t h e Formulafions.
 EFFECT OF PARTICLE S I Z E . I1 1095

(FVP), liberated t h e drug r e l a t i v e l y f a s t e r than those

prepared from o t h e r binding materials ( f i g u r e 5).
Such binders e,g. potato s t a r c h g e l , methyl c e l l u l o s e
and g e l a t i n tend t o swell in water and r e l e a s e t h e drug
more slowly. However, W p d i s s o l v e s i n water more
r a p i d l y and d i s p e r s e s the drug p a r t i c l e s in the disso-
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l u t i o n medium more evenly. This could explain t h e

s u p e r i o r i t y o f W P t o t h e o t h e r binders i n the
l i b e r a t i o n of the a c t i v e drug from t a b l e t s .

These findings may provide new ways of formula-

t i n g a metronidazole - tablet which exhibits b e t t e r
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d i s s o l u t i o n and absorption properties, than the

KLION - Tablet, c u r r e n t l y manufactured i n Hungary,

ACKNOWLEDGEMENTS
Thanks t o t h e Chemical Works of Cedeon Richter
Ltd., Budapest f o r supplying m a t e r i a l s and equipment.
Grateful thanks t o the l a t e Prof, G q w r m a t i , L, (+),
Faculty of Pharm, Sci., University o f Medicine,
Budapest, D r . H, Gyozo and t o D r , I. Kolbe f o r t h e i r
f r i e n d l y encouragement and advice i n t h i s work. Many
thanks t o M r s . J. Brzezina, Dept. of C i v i l Eng., A,B.U,
Zaria, f o r designing t h e f i g u r e s ,

REFERENCES
1. K, Munzel, Pharm. Acta Helv., 46, 513-538 (1971.
 1096 LAW0

2, J , Blanchard, Am, J. Pharrn,, 150, (51, 132-151

(1978).

3. G. Levy, J. Ed, Antkowiak, J, A, Procknal and

D, C, White; J, Pharm. S c i . , 52, 1047-1051
(1963)

4, C. Ampolsuk, J. V, Mauro, A. A. Nyhuis, N, Shah

and C. I. Jarowski; J, Pharm. Sci,, 6J, 11'7-
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118 (1974).

5* N, Shah, R, Pytelewski, H. Eisen and C, I, Jarowski

J, Pharm. Sci., 63, 339-344 (1974).

6, J, T. Jacob, and E, M, Plein, J. fiarmo S c i , , z,

802-805 (1968),

7* T. E. Needham, R, E, Sheperd and L. A. Luzzi

J. Pharrn. S c i . , &, (31, 470-472 (1972).
For personal use only.