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 ~., , i ~ ..:~

E L S E V I E R International Journal of Pharmaceutics 119 (1995) 165-171

i n t e r n t i o n l

j o u m l o f

p h r m c e u t i c s

a l c u l a t i o n o f th e b l o o d l e v e l o f a d r u g ta k e n o r a ll y

w i t h a d i f f u s i o n c o n t r o l l e d d o s a g e f o r m

B . N i a , E . M O u r i e m c h i , J.M . V e r g n a u d

Faculty of Sciences University of St Etienne 23 Dr. P. Michelon 42023 St Etienne France

Rece ived 4 Augu st 1994; revised 24 October 1994; accepted 27 O ctober 1994

A b s t r a c t

Ora l dosage forms wi th cont ro l l ed re l ease a re genera l ly inves t iga ted e i the r by in v i t ro or in v ivo t e s t s and the

problem of cor re l a t ing these resu l t s appears . A numer ica l mode l i s bui l t , t ak ing in to account the charac te r i s t i c s of

drug re l ease out of the dosage form a long the gas t ro in tes t ina l t rac t , t he s t ages of absorp t ion in the b lood

c o m p a r t m e n t a n d o f e l im i n a t i o n . T h e d o s a g e f o r m i s o b t a i n e d b y d i s p e r si n g t h e o p h y l li n e a s a d r u g i n E u d r a g i t R S

playing the ro le of a polymer mat r ix . The proces s of drug re l ease i s cont ro l l ed by d i f fus ion , wi th a cons tant

d if fus iv i ty . T he fo l lowing resu l ts a re o bta ined: the k ine t i c s of re l ease o f the drug out o f the dosag e form, the k ine t i c s

o f t h e d r u g i n t h e b l o o d c o m p a r t m e n t , a n d t h e k i n e t ic s o f d r u g e li m i n a ti o n .

Keywords: Drug re l ease ; Cont ro l l ed re l ease ; Kine t i c s

1 I n t r o d u c t i o n

V a r i o u s o r a l d o s a g e f o r m s w i t h c o n t r o l le d r e -

l e a se o f t h e d r u g a r e p r e p a r e d b y d i sp e r s in g t h e

d r u g i n a p o l y m e r a n d c o m p r e s s i n g th e d r y m i x -

t u r e i n t o t a b l e t s o r p r e s s i n g t h e h u m i d p a s t e i n t o

b e a d s a n d d r y in g t h e m ( V e r g n a u d , 1 9 92 ). W h e n

t h e s e m o n o l i t h i c d e v i c e s a r e i n c o n t a c t w i t h a

l iq u i d , t h e l i q u i d e n t e r s t h e p o l y m e r , d i s s o lv e s t h e

d r u g a n d e n a b l e s t h e d r u g t o l e a v e t h e d e v i c e .

T h e p o l y m e r m a t r ix m a y b e e r o d e d o r n o t, a n d

t h e t w o m a i n m e c h a n i s m s ( F e ij e n , 1 9 8 4 ) c o n t r o l -

l in g d r u g r e l e a s e a p p e a r w i t h e r o s i o n o f t h e p o l y -

m e r ( H e l l e r , 1 98 4 ; B i d a h a n d V e r g n a u d , 1 9 9 0) o r

* Corresponding author.

d i f f u s io n t h r o u g h t h e p o l y m e r ( V e r g n a u d , 1 9 9 3 ).

A s a r e s u lt , t h e d r u g i s r e l e a s e d f r o m t h e d o s a g e

f o r m o v e r a l o n g p e r i o d o f t im e . W h e n t h e p r o -

c e s s is c o n t r o l l e d b y d i f f u s io n , t h e r a t e o f d r u g

r e l e a s e d e c r e a s e s e x p o n e n t i a l l y w i t h t im e . T h e s e

d e v i c e s a r e e v a l u a t e d u s i n g i n v it r o t e s ts b y d e t e r -

m i n i n g t h e k i n e t i cs o f d r u g r e l e a s e i n a s y n t h e t i c

g a s t r i c l i q u i d a t 3 7 ° C a t a g i v e n r a t e o f s t ir r i n g ,

a n d t h e p a r a m e t e r s o f i n t e r e s t a r e , in th e c a s e o f

a d i f f u s i o n a l p r o c e s s , t h e d i f f u s iv i t y , t h e p a r t i t i o n -

i n g f a c t o r a n d t h e c o e f f i c i e n t o f m a s s t r a n s f e r o n

t h e s u r f a c e ( B a k h o u y a e t a l . , 1 9 9 4 ) .

D o s a g e f o r m s w i th c o n t r o l l e d r e l e a s e a r e e v a l -

u a t e d u s i n g i n v iv o te s t s w i t h h e a l t l y v o l u n t e r s

p e r f o r m e d u n d e r g i v e n c o n d i ti o n s ( S k e l l y e t a l. ,

1 9 90 ). O f c o u r s e , i n v i v o te s t s n e c e s s i t a t e g r e a t e r

i n v e s t m e n t t h a n i n v i t r o t e s ts , a n d a t t e m p t s h a v e

0378-5173/95//$09.50 © 1995 Elsevier Science B.V. All rights reserved

SSDI 0 3 7 8 - 5 1 7 3 ( 9 4 ) 0 0 3 8 5 - 8

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166

B . N i a e t aL / 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 ic s 1 1 9 1 9 95 ) 1 6 5 - 1 7 l

lossary

Symbol Meaning

~ln

/3rn

c

D

h

2 L

M,,M~

R

R1, Rr

X

Y

Z

r~ Z

positive roots of Eq 4

positive roots of Eq 6

concentration of the drug in the dosage

form

diffusivity cm~/s)

coefficientof mass transfer on the surface

cm/s)

height of the cylinder,

amoun t of drug released out of the dosage

form after tim e t, after infinite time

radius of the cylinder

dimensionless num bers

amoun t of drug in the gastrointestinal ract

amoun t of drug in the blood compartment

amoun t of drug eliminated

radial, longitudinal coordin ates for the cylind er

b e e n m a d e i n o r d e r t o f in d c o r r e la t i o n s b e t w e e n

i n v i t r o a n d i n v i v o t e s t s . T h e k i n e t i c s o f d r u g

r e l e a s e o b t a i n e d w i t h i n v i t r o t e s t s w e r e t h u s

c o m p a r e d t o t h e i n p u t f u n c t i o n r e s u l t i n g f r o m

d e c o n v o l u t i o n o f t h e d r u g l e v e l - t i m e h i s t o r y i n

t h e b l o o d c o m p a r t m e n t A o k i e t a l., 19 9 2; K o c h ,

1 9 9 2 ) . I n o r d e r t o o b t a i n a n a c c e p t a b l e c o r r e l a -

t i o n b e t w e e n t h e s e c u r v e s , t h e o p e r a t i o n a l c o n d i -

t i o n s f o r t h e i n v i t r o t e s t w e r e s o m e t i m e s m o d i -

f i e d A l y S a s a n d M e g w a , 1 9 8 9) . S o m e p a r a m e -

t e r s w e r e f o u n d t o b e o f in t e r e s t: t h e r a t e o f

s t i r ri n g s e l e c t e d f o r t h e i n v i t r o t e s t N i c k l a s s o n ,

1 9 90 ); t h e r e s i d e n c e t i m e o f t h e d o s a g e f o r m

a l o n g t h e g a s t r o i n t e s t i n a l t r a c t S o u r n a c e t a l. ,

1 9 8 8 ) . I n v i t r o a n d i n v i v o e v a l u a t i o n w a s p e r -

f o r m e d w i t h o r a l s u s t a i n e d r e l e a s e f l o a t i n g d o s a g e

f o r m s m a d e o f v a r i o u s h y d r o p h i l i c p o l y m e r s H i l -

t o n a n d D e a s y , 1 9 9 2) . T h e n a t u r e o f t h e f o o d i n

t h e s t o m a c h w a s a l s o c o n s i d e r e d a s a p a r a m e t e r

f o r t h e r e l e a s e w i t h i n v i v o t e s t s V e r h o e v e n e t

a l ., 1 9 8 9 ; J u n j i n g e r e t a l. , 1 9 9 0 ) . V e r y o f t e n , im-

p o r t a n t d e v i a t i o n s w e r e s h o w n b e t w e e n i n v i t r o

a n d i n v i v o c u r v e s F i n n e a n d U r t t i , 1 9 9 2) . I n

f a c t , t h e p r o c e s s o f d r u g t r a n s p o r t i s d i f f e r e n t

w i t h i n v i t r o a n d i n v i v o t e s t s O u r i e m c h i e t a l .,

1 9 9 5 ) . W i t h t h e i n v i t r o t e s t , t h e s y s t e m i s c l o s e d ,

w h i l e i t is o p e n w i t h t h e i n v i v o t e s t , t h e d r u g

b e i n g c o n s t a n t l y tr a n s f e r r e d o u t o f t h e d o s a g e

f o r m i n t o t h e b l o o d c o m p a r t m e n t a n d t h e n e l im i -

n a t e d . M o r e o v e r , t w o k i n d s o f d o s a g e f o r m s w i t h

a p o l y m e r m a t r i x a r e o n t h e m a r k e t , t h a t i n w h i c h

t h e r e l e a s e i s c o n t r o l l e d b y d i f f u s i o n a n d t h e

o t h e r w h e r e t h e p r o c e s s i s c o n t r o l l e d b y e r o s i o n

V e r g n a u d , 1 9 9 3 ; B a k h o u y a e t a l . , 1 9 9 4 )

T h e f i r s t p u r p o s e i n t h i s s t u d y i s t o b u i l d a

n u m e r i c a l m o d e l a b l e t o d e s c r i b e t h e p r o c e s s o f

d r u g t r a n s f e r i n v i v o , b y c o n s i d e r i n g a d o s a g e

f o r m w i t h d r u g r e l e a s e c o n t r o l l e d b y d i f fu s i o n .

T h e m o d e l t a k e s a ll t h e k n o w n f a c t s i n t o a c c o u n t :

t h e k i n e t i c s o f d r u g r e l e a s e o b t a i n e d w i t h i n v i tr o

t e s t s a n d t h e t w o m a i n c h a r a c t e r i s t i c s w i t h t h e

d i f f u si v i t y a n d t h e c o e f f i c i e n t o f m a s s t r a n s f e r a t

t h e s u r f a c e ; t h e r a t e c o n s t a n t s o f a b s o r p t i o n i n

t h e b l o o d c o m p a r t m e n t a n d o f e l im i n a t io n , a n d

t h e v o l u m e o f th e b l o o d c o m p a r t m e n t . T h e c a s e

o f a d o s a g e f o r m c y l i n d r i c a l i n s h a p e i s s e l e c t e d ,

a s it is w i d e l y u s e d . T h e r e s i d e n c e t i m e o f t h e

d o s a g e f o r m a l o n g t h e g a s t r o i n t e s t i n a l t r a c t i s

a l s o c o n s i d e r e d .

T h e s e c o n d o b j e c t i v e i s t o u s e t h e m o d e l f o r

c a l c u l a t i n g v a r i o u s k i n e t i c s o f i n t e r e s t i n t h e c a s e

o f t h e o p h y l l i n e : n o t o n l y t h e k i n e t ic s o f r e l e a s e o f

t h e d r u g o u t o f th e d o s a g e f o r m o b t a i n e d w i t h in

v i t r o t e s t s a t v a r i o u s p H v a l u e s , b u t a l s o t h e

k i n e t ic s o f t h e d r u g i n th e b l o o d c o m p a r t m e n t

a n d e l i m i n a t i o n a r e e v a l u a t e d . A m a t h e m a t i c a l

t r e a t m e n t i s c o n s i d e r e d f o r t h e d i f f u s i o n o f t h e

d r u g t h r o u g h t h e p o l y m e r d e v ic e w i t h a c o n s t a n t

d i f f u s iv i ty . A s t h i s d i f f u s iv i t y v a r i e s s l i g h t l y w i th

t h e p H , a m e a n v a l u e f o r t h e d i f f u s i v it y i s d e t e r -

m i n e d b y c o n s i d e r i n g t h e r e s i d e n c e t i m e s i n t h e

v a r i o u s p a r t s o f t h e g a s t r o i n t e st i n e S o u r n a c e t

a l. , 1 9 88 ) . B y u s i n g t h e d a t a a s s o c i a t e d w i t h t h e

p h a r m a c o k i n e t i c s o f t h e o p h y l l i n e , i t i s t h u s a l s o

p o s s i b l e t o d e t e r m i n e t h e d r u g l e v e l i n t h e b l o o d

c o m p a r t m e n t .

2 T h e o r e t i c a l

2 1 Assum ptions

T h e f o l lo w i n g a s s u m p t i o n s a r e m a d e :

i ) T h e o r a l d o s a g e f o r m i s c y l i n d r i c a l i n s h a p e

a n d t h e d r u g c o n c e n t r a t i o n is in i ti a ll y u n i f o r m .

i i) T h e p r o c e s s o f r e l e a s e o f t h e d r u g o u t o f

t h e d o s a g e f o r m i s c o n t r o l l e d b y d i f f u s i o n , a s

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1 6 8 B. Nia e t a l. / I n t erna t ional Journal o f Pharmaceu t i cs 119 1995) 165 -171

C y l i n d e r

D i f f u s i o n

G a s t r o i n t e s t i n e

k a

> Y - -

B l o o d V b

F i g . 1 . S c h e m e o f t h e p r o c e s s .

ke

> Z

E x t e r i o r

Th e mix tu re i s thus p re s s ed in to cy l inde r s w i th

the fo l low ing cha rac te r i s t i c s : 500 mg ; d iamete r ,

1 .15 cm; height , 0 .44 cm. The hardness is 8 .9

m e a n i n g t h a t b r e a k i n g r u p t u r e i s a t t a i n e d f o r 8 9

N ) . T h e a p p a r a t u s i s a n e x c e n t r i c t a b l e t m a c h i n e

A M 28 .50 F rogera i s ) .

3 2 In vitro tests

A cy l inde r i s p laced in a f l a s k w i th 200 ml o f

l iqu id , ma in ta ined a t 37°C und er a s t ir r ing a t 250

rpm. T he pH va lues o f the l iqu ids a r e 1 .2 , 4 , 6

and 8 , respect ively .

A t in te rva l s , 0 .5 ml o f liqu id i s ex t r ac ted and

a n a l y z e d u s in g a U V s p e c t r o m e t e r H i t a c h i U

1.100) cal ibra ted a t 271 nm.

4 R e s u l t s

Th ree k inds o f r e s u l t s a r e cons ide red : the f i r s t

ob ta ined w i th the in v i t ro t e s t s l ead ing to the

p a r a m e t e r s o f d if f u si o n o f th e d r u g o u t o f t h e

dos age fo rms , the s econd w i th the ca lcu la t ion o f

the k ine t i c s o f the d rug t r ans fe r r e d th rou gh the

body , and es pec ia l ly w i th the d rug l eve l in the

b l o o d c o m p a r t m e n t ; t h e l a s t w i t h t h e e f f e c t o f t h e

d imens ions o f the dos age fo rms .

4 1 In vitro tests

T h e k i n e t i c s o f r e l e a s e o f t h e d r u g o u t o f t h e

dos age fo rms ob ta ined w i th in v i t ro t e s t s a r e

con t ro l l ed by t r ans ien t d i f fu sion , a s s how n in F ig .

2 . T h e k i n e ti c s o b t a i n e d e i t h e r b y e x p e r i m e n t s o r

by ca lcu la t ion u s ing Eq . 1 a r e w e l l s upe r imp os ed .

M o reover , the d i f fu s iv ity i s cons tan t a nd th e coe f -

100

8 0

6 0

4 0

2 0

0 ~

M t / M i n

' ' ~ . - I ' ~

0 5 10 15 20 25 30 35

T I M E ( h )

F i g . 2 . I n v i t r o t e s t s . K i n e t i c s o f r e l e a s e o f t h e d r u g o u t o f t h e d o s a g e f o r m . ( 1 ) p H 1 .2 ; ( 2) p H 8 .

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B. Nia et al . / International Journal of Pharmaceutics 119 1995) 165-1 71 169

T a b l e 1

C h a r a c t e r i s t i c s o f t h e r e l e a s e o f t h e d r u g

p H

1.2 4 6 8

D ( × 1 0 7) ( c m 2 / s ) 5 . 3 7 8 1 5

h ( × 10S ) ( cm Z/s ) 2 2 2 2

T a b l e 2

C h a r a c t e r i s t i c s f o r t h e o p h y l l i n e

k a = 6 . 0 3 / h k e = 0 . 0 8 9 / h

Vb = 26.41

T i m e , 1 5 m i n ( s t o m a c h ) ; 1 0 5 r a i n ( d u o d e n a l - c e c a l ) ; 4 6 0 r a i n

( g a s t r o - c e c a l ) .

ficient of mass transfer on the surface is finite, as

the tangent at the origin of time is not vertical.

The coefficient of mass transfer on the surface h

is about the same for the various liquids at differ-

ent pH and the diffusivity slightly increases with

the pH, as shown in Table 1.

4 2 I n u i v o c a lc u la t ion

The characteristics for theophylline are given

in the literature Sournac et al., 1988) as well as

the time of the gastrointestinal tractus. Table 2).

It is necessary to have a constant diffusivity

when using Eq. 3.

An average value is determined for the diffu-

sivity of the drug through the dosage form by

considering the time of residence in the various

parts of the gastrointestine at various pH. The

value of 13.4 x 10 -7 cm2/s is thus obtained.

The following kinetics are thus obtained by

calculation, expressing the amount of drug-time

histories in various parts Fig. 3): the kinetics in

the gastrointes tine 1) and in the blood compart-

ment 3); the kinetics of the drug eliminated out

of the blood compartment 4) and of the drug

released out of the dosage form 4).

Moreover, the drug level in the blood compart-

ment is obtained from the kinetics of the amount

of drug in the blood and the volume of liquid in

the blood compartment Fig. 4).

Some conclusions can be drawn from these

c u r v e s .

Mt mg)

250

200

4

150

I O0

50

0

5 I[) 15 20 25 30 3S 40

TIME h)

F i g . 3. I n v iv o c a l c u l a t i o n . K i n e t i c s o f t h e a m o u n t o f d r u g : i n

t h e g a s t r o i n t e s t i n a l t r a c t ( 1 ) ; i n t h e b l o o d c o m p a r t m e n t ( 3 ) ;

e l i m i n a t e d ( 2 ) ; r e l e a s e d o u t o f t h e d o s a g e f o r m ( 4) . D o s a g e

f o r m , 50 0 m g w i t h 5 0 t h e o p h y l l i n e ; c y l i n d e r w i t h r a d i u s 0 .5 7

c m a n d h e i g h t 0 .4 4 c m .

i) The amount of drug located in the gastroin-

testine is rather low at any time.

ii) The kinetics of the drug in the blood com-

partment follows a typical pattern with a rather

flat maximum. The maximum is attained after

around 6 h and the concentration of drug at this

time is 5.2 mg/1. The shape of this drug level-time

history is similar to that obtained from experi-

ment with Theost at tablets Sournac et al., 1988)

exhibiting a maximum at around 6 h 15 min and a

drug level of 6.2 mg/l with a dose of theophylline

of 300 mg.

Concentl ation [rag/] J

6

4

2

I

0 i i i ~ i

5 10 15 20 25 30 ~5 40

T IME

[h

F i g . 4 . D r u g l e v e l ti m e h i s t o r y in t h e b l o o d c o m p a r t m e n t w i t h

t h e d o s a g e f o r m : 5 0 0 m g w i th 5 0 t h e o p h y l l i n e .

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170 B. Nia et al. / International Journal of Pharmaceutics 119 1995) 165-171

(iii) The ratio of the values of the drug level in

the blood compartmen t obtained with the dosage

forms made of cylinders with 250 mg drug and

with the Theostat tablets with 300 mg drug is

about the same.

(iv) Curve 4 in Fig. 3 is of interest, as it shows

clearly the effect of the residence time of the

dosage form along the gastrointes tine tract. About

6 of the drug remains in the dosage form at the

end of the stage in the gastrointestinal tract. In

fact, the same drawback was observed for the

Theostat tablet (Sournac et al., 1988).

(v) As the process of release of the drug out of

the dosage form is controlled by diffusion, it is

possible to determine the effect of the dimension

of the dosage form on the process of drug trans-

fer, and especially on the kinetics of drug release

out of the dosage form.

M t ( m g )

5o

2170 I C ~ I

1 5 0

1 0 0

5 0

0

0 5 t (} 15 2 0 2 5 3 0 3 5 4 0

I I M E ( h )

Fig. 5. In vivo calculations for dosage forms o f various dimen-

sions with the sane amount of drug: in the gastrointestinal

tract 1); in the blood compartment 2); eliminated 3); re-

leased out of the dosage form 4). 1C, one dosage form with

250 mg drug; 2C, two dosage forms with 125 mg drug each;

3C, eight dosage forms with 31.25 mg drug each.

4 3 Ef fec t o f the dimensions o f the dosage forms

As the process is controlled by diffusion, it is

clear that the time necessary for a given ratio of

drug released

M t / M =

is proportional to the

square of the dimensions of the dosage form, by

considering the dimensionless numbers D t / L 2 or

D t / R 2 in Eq. 3.

The process of drug transfer has thus been

studied by considering three types of dosage forms

with the same amount of theophylline and the

same drug/Eudragit ratio. The three dosage

forms have the dimensions shown in Table 3.

The various kinetics of drug transfer are shown

in Fig. 5 as obtained by calculations by keeping

the same values shown in Tables 1 and 2.

The blood level-time histories are also de-

picted in Fig. 6.

The following conclusions can be drawn:

Table 3

Dimensions of the dosage forms

Dosage form Radius Height Drug weight

i) numb er cm) cm) mg)

1 C 17 0.575 0.44 250

2 C 2) 0.456 0.35 250

3 C 8) 0.287 0.22 250

(i) Of course, the smaller the dosage form, the

faster the kinetics of drug release out of the

dosage form.

(ii) This above conclusion is of importance,

because the transit time in the gastrointestinal

tract becomes so long that the whole drug is

extracted from these small dosage forms.

(iii) Of course, as a result of the increase in the

rate of drug release, a higher blood level is at-

tained with the smaller dosage forms. Moreover,

( 7 o n c l n t r ~ i ti O l l { n l ~ / ] )

?

6

4

I

0 5 I 0 I 5 2 0 2 5 3 0 3 5 4 0

T I M E ( 11 )

Fig. 6. In vivo calculation, drug level in the blood compart-

ment: on e dosage form 250 mg drug 1C); two dosage forms

with 125 mg drug each 2C); eigh t dosage forms with 31.25 mg

drug each 3C).

7/21/2019 Calculation of the Blood Level of a Drug Taken Orally With a Diffusion Controlled Dosage Form 1995 International …

http://slidepdf.com/reader/full/calculation-of-the-blood-level-of-a-drug-taken-orally-with-a-diffusion-controlled 7/7

B. Nia et al . ~Interna tional Journal of Pharmaceutics 119 1995) 165-171 171

the maximum of the drug concentration in the

blood is reached at a shorter time.

iv) A compromise has to be made for selecting

the desired dimensions of the dosage forms. Small

dosage forms can lead to the complete release of

the drug along the gastrointestinal tract, but they

are responsible for a higher drug level in the

blood compartment.

5 . Con c l u s i on s

Predic t ion of the k inet ics curves obtained with

in vivo tests i s poss ib le by calculat ion for oral

d osage for m s wi th c on tr o l l e d r e l e ase . T h e c a l c u -

lat ion can be rather s imple by incrementing t ime

during the process when the d i f fus iv i ty of the

d r u g th r ou gh th e d osage for m i s c on s i d e r e d as

c on s tan t wh i l e a n u m e r i c a l m od e l wi th f in i te

di fferenc es i s necessary whe n th e d i f fus iv i ty i s not

constant .

Ca l c u l a t i on h as b e e n p e r for m e d i n th e c ase o f

an oral dosag e form cylindr ical in shape with

theopy l l ine and Eudragi t the re lease of the drug

be ing control led by d i f fus ion . As the d i f fus iv i ty

var ies s light ly wi th the pH an average value of

the d i f fus iv i ty had to be determined by consider-

i n g th e r e s i d e n c e t i m e o f th e d osage for m a l on g

the ga strointest inal tract and the var ious values of

th e p H.

S om e r e su l t s ar e ob ta i n e d e i th e r f r om a th e o -

re t ical or from a pract ical point of v iew. The

kinet ics of the amount of drug transferred in the

blood compartment as we l l as the drug leve l in

the b lood are thus obtained.

Not only the drug leve l - t ime his tory in the

b l ood c om p ar tm e n t i s ob ta i n e d b u t a lso th e

am ou n t o f d r u g r e m ai n in g i n th e d osage for m . B y

using the numerical model i t i s thus poss ib le to

d e te r m i n e th e e f fe c t o f th e d i m e n s i on s o f th e

d osage for m on th e d r u g l e ve l i n th e b l ood c om -

partment as we l l as the amount of drug remain-

ing in the dosage form.

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