A comparison of the physical properties and absorption rates of compressed tablets made from microcrystalline and regular sulfadiazine

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A COMPARISON OF THE PHYSICAL PROPERTIES AND ABSORPTION RATES OF COMPRESSED TABLETS MADE FROM MICROCRYSTALLINE AND REGULAR SULFADIAZINE

,iby Jam es Di M cK in ley , J r *

T h e s is s u b m itte d t o th e F a c u lty o f t h e G ra d u a te S ch o o l o f t h e U n i v e r s i t y o f M ary lan d i n p a r t i a l f u l f i l l m e n t o f t h e r e q u ir e m e n ts f o r th e d e g re e o f M a s te r o f S c ie n c e

1950

UMI Number: DP70133

All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a complete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion.

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ACKNOWLEDGEMENTS

I t i s a p l e a s u r e t o ack n o w led g e t h e a s s i s t a n c e an d g u id a n c e I h a v e r e c e iv e d i n th e p r e p a r a t i o n o f t h i s t h e s i s *

Of s p e c i a l h e l p was

Dr* 0* W* Chapman, who b o th d i r e c t e d an d a s s i s t e d me w ith t h e c o m p a ri­ s o n o f t h e a b s o r p t i o n r a t e s o f s u l f a d i a z i n e i n dogs*

I a l s o w is h t o

th a n k Dr* N oel E . F o ss f o r h i s h e l p i n th e w r i t i n g o f t h i s p a p e r , Dr* W. A r th u r Purdum f o r h i s p e r m is s i o n t o u s e th e f a c i l i t i e s o f The J o h n s H op k in s H o s p i t a l P harm acy t o m a n u fa c tu re th e t a b l e t s u s e d i n t h e ex ­ p e r im e n t, and my w ife f o r h e r a s s i s t a n c e . Jam es D* M cK in ley , J r * B a l tim o r e , M ary lan d

TABLE OF CONTENTS Page INTRODUCTION..............................................

1

HISTORICAL BACKGROUND.........................................................................................

2

EXPERIMENTAL.................................................................................................................................... 6

M anufacture o f T a b l e t s ......................................

6

P h y s ic a l P r o p e r tie s o f T a b le ts ........................................................................

7

A b so rp tio n Rate o f S u lfa d ia z in e i n D o g s .................................................... 6 D i s c u s s i o n ............................................................................................................................. 11 CONCLUSIONS....................................................................................................................................... 15 BIBLIOGRAPHY.................................................................................................................................. l 4

APPENDIX............................................................................................................................. 16

INTRODUCTION

There a re s e v e ra l re fe re n c e s i n th e l i t e r a t u r e (2 ,4 ,9 » H > l4 ) p o in t­ in g o u t t h a t many su b sta n c es become more a c tiv e p h y s io lo g ic a lly when t h e i r p a r t i c l e s iz e i s reduced to m icro sco p ic dim ensions*

J* G* R ein g o ld , F. J*

P h i l l i p s , and H* F* F lip p in r e p o r t: M ic ro c ry s ta llin e sulfonam ides have shown d if fe re n c e s from o rd in a ry sulfonam ides i n b o th pharmacodynamic b eh av io r and th e r a p e u tic a c tiv ity * In g e n e r a l, such d if f e r e n c e s sug­ g e s t t h a t in m ic r o c r y s ta llin e form th e a c t i v i t y i s enhanced, b u t th e in fo rm a tio n a v a ila b le i s lim ite d , and i t i s d e s ira b le t h a t f u r t h e r in v e s tig a tio n s be made* ( 11) T hese m i c r o c r y s t a l l i n e d ru g s h av e b e e n shown t o be more a c t i v e when t a k e n i n t e r n a l l y a s a s u s p e n s i o n , ( 4 ,1 1 ) when a p p l i e d l o c a l l y a s a pow­ d e r (6 ) o r o in tm e n t, (9 ) o r when i n h a le d a s a p o w d e r, (8 ) t h a n th e r e g u l a r l y u s e d c r y s t a l l i n e form*

H ow ever, t h e r e i s no m e n tio n i n th e

l i t e r a t u r e o f an y co m p ressed t a b l e t s b e in g made from m i c r o c r y s t a l l i n e d ru g s*

S in c e c o m p ressed t a b l e t s p ro v id e one o f t h e moBt e c o n o m ic a l,

s t a b l e , and s a t i s f a c t o r y fo rm s o f m e d ic a t io n , i t was c o n s id e r e d w o rth ­ w h ile t o i n v e s t i g a t e th e p o s s i b i l i t i e s o f m aking t a b l e t s from m ic ro ­ c r y s ta llin e d ru g s.

S u l f a d i a z i n e was s e l e c t e d f o r th e e x p e r im e n t s in c e

i t i s r e a d i l y a v a i l a b l e i n b o th m i c r o c r y s t a l l i n e and m a c r o c r y s t a l l i n e fo r m s , i t i s w id e ly u s e d i n th e form o f t a b l e t s , and i t s r a t e o f a b s o r p ­ t i o n from th e g a s t r o i n t e s t i n a l t r a c t c a n be fo llo w e d by w e ll e s t a b l i s h e d m e th o d s f o r d e te r m in in g i t s

c o n c e n t r a t i o n i n th e blo o d *

HISTORICAL BACKGROUND The u s e o f m i c r o c r y s t a l l i n e d ru g s an d c h e m ic a ls i s r e l a t i v e l y new b e c a u s e o n ly i n r e c e n t y e a r s h a s i t b e e n p o s s i b l e t o p ro d u c e a pow der w ith a maximum p a r t i c l e s i z e o f l e s s t h a n t e n m ic r o n s .

S e v e r a l m a c h in e s

a r e i n u s e to d a y w h ich w i l l re d u c e th e p a r t i c l e s i z e o f a pow der t o th e m ic ro c r y s t a l l i n e and s e m i - m i c r o c r y s t a l l i n e s t a t e .

In 1

M. A. L i s s -

man (1 0 ) d e s c r ib e d a m a c h in e , th e ’’M ic r o n iz e r 11, w h ich i s a j e t i n d u c t i o n m i l l d e v e lo p in g i t s p u l v e r i z i n g p r o p e r t i e s from j e t s o f co m p re sse d g a s o r s u p e r h e a te d s te a m .

T hese j e t s a r e s e t a t a n a n g le i n t o a c y l i n d r i c a l

s t r u c t u r e w ith a n a p e r t u r e i n th e c e n t e r f o r w ith d ra w in g th e f i n e l y g ro u n d p o w d e r.

The f o r c e o f t h e co m p re sse d g a s c a u s e s a w h i r l i n g m o tio n

i n t o w h ich th e s u b s ta n c e t o be g ro u n d i s in tr o d u c e d .

The g r i n d i n g a c t i o n

comes from th e p a r t i c l e s c o l l i d i n g w ith e a c h o t h e r a t g r e a t s p e e d .

One

a d v a n ta g e o f t h e j e t i n d u c t i o n m i l l i s t h a t th e su d d en e x p a n s io n o f th e gaB es upon e n t e r i n g th e g r i n d i n g cham ber c a u s e s a r e f r i g e r a t i n g e f f e c t w h ich h o ld s t o a minimum th e h e a t g e n e r a te d by f r i c t i o n .

In 1946, 0 . S .

B e r ry ( l ) d e s c r ib e d s e v e r a l d i f f e r e n t m a c h in e s , b o th r o t o r and j e t i n ­ d u c t i o n t y p e s , w hich a r e u s e d i n th e p r o d u c ti o n o f m i c r o c r y s t a l l i n e p ro d u c ts .

The r o t o r ty p e m i l l d i f f e r s from th e j e t i n d u c t i o n ty p e i n

t h a t th e p u l v e r i z i n g a c t i o n comes from th e g r in d i n g o f th e m a t e r i a l b e tw e e n a r o t a t i n g w heel known a s a r o t o r and a s t a t i o n a r y a b r a s i v e su rfa c e . Pow dered i n s e c t i c i d e s w ere among t h e f i r s t r e l a t i v e l y i n s o l u b l e s u b s ta n c e s i n v e s t i g a t e d w ith t h e p u rp o se o f d e te r m in in g th e s p e c i f i c e f f e c t o f m ic ro c ry s ta llin e p a r tic le s iz e .

I n 1 9 4 1 , L. M. B e r t h o l f and

J . S . P i l s o n (2 ) e x p e rim e n te d w ith th e t o x i c i t y o f le a d a r s e n a t e on th e

5 h o n e y b e e , A p is m e l l i f e r a *

They com pared th e t o x i c i t y o f t h i s p o is o n i n

r e l a t i o n t o i t s p a r t i c l e s i z e an d fo u n d t h a t th e m e d ia n l e t h a l d o se o f t h e l e a d a r s e n a t e w ith a p a r t i c l e s i z e o f e i g h t e e n m ic ro n s was one h u n d re d an d e i g h t y - f i v e m ic ro g ra m s p e r b e e , w h ile t h a t o f l e a d a r s e n a t e **ith a p a r t i c l e

s i z e o f two m ic ro n s was o n ly f i v e m icro g ram s*

T hese men

c o n c lu d e d t h a t ,

"When m a t e r i a l s o f d i f f e r e n t p a r t i c l e s i z e w ere u s e d , th e

f i n e f r a c t i o n s w ere on th e w hole m ore t o x i c t h a n t h e c o a r s e *11 (2 ) 0 . M. S m ith a n d L . D* Goodhue (1 4 ) re v ie w e d t h e l i t e r a t u r e

In 1942,

c o n c e rn in g t h e

e f f e c t i v e n e s s o f pow dered i n s e c t i c i d e s an d c o n c lu d e d t h a t th e s m a l le r th e p a r t i c l e s i z e , t h e m ore e f f e c t i v e th e i n s e c t i c i d e .

L* A. Chambers, T. H. H a r r is , F. Schuman, and L. K. Ferguson (6) re p o rte d i n 1942 t h a t m ic r o c r y s ta llin e s u lf a th ia z o le had been used advan­ ta g e o u s ly i n traum a and m inor su rg e ry .

They found t h a t a more ra p id

s o lu tio n and a b s o rp tio n was o b tain ed w ith m ic r o c r y s ta llin e s u lf a th ia z o le th a n was o b ta in e d w ith th e re g u la r c ry s ta ls *

They a ls o re p o rte d t h a t th e

m icro c r y s t a l l i n e s u lf a th ia z o le was much l e s s l i k e l y to clump when p u t in to a su sp en sio n o r s p rin k le d on a wound*

L. E. S ilc o x and H. P.

S ch en ck (1 5 ) u s e d m i c r o c r y s t a l l i n e s u l f a t h i a z o l e i n 1942 i n c a s e s o f a c u te u p p e r r e s p i r a t o r y i n f e c t i o n s , a c u te and c h r o n ic s i n u s i t i s , and c h r o n ic s u p p u r a tiv e o t i t i s m e d ia .

T hese men r e p o r t :

The drug ( s u l f a t h i a z o l e ) i s f i n e l y d iv id ed and i s in d i r e c t c o n ta c t w ith in f e c te d t i s s u e s over a la r g e su rfa ce a r e a ................... The m i c r o c r y s t a l s a r e removed c o m p le te ly from s in u s c a v i t i e s w i t h i n f o u r o r f i v e d a y s , e i t h e r by c i l i a r y m ovement o r by a b s o r p t i o n , and a r e fo u n d e x p e r i ­ m e n ta lly t o be d i f f u s e d o v e r th e s u r f a c e o f th e membrane r a t h e r t h a n d e p o s it e d i n one a r e a a s a p o w d er. ( 15 )

They a ls o re p o rte d t h a t th e m ic r o c r y s ta llin e drug gave b e t t e r r e s u l t s , l e s s t o x i c r e a c t i o n s , and t h a t l e s s c o m p lic a tio n s r e s u l t e d i n th o s e c a s e s t r e a t e d w ith m i c r o c r y s t a l l i n e s u l f a t h i a z o l e th a n i n th o s e

4 t r e a t e d w ith th e u s u a l t h e r a p e u t i c m e asu re I n 1945® T . N . H a r r i s , H. S* Sommer, and 0 . 0 . O happle ( 8 ) u s e d m ic ro ­ c r y s t a l l i n e s u l f a t h i a z o l e e x p e r i m e n t a l l y i n m ice a s a n i n h a l a n t .

The c r y s ­

t a l s w ere s u sp e n d e d i n a f i n e m i s t , an d a s t h e w a te r e v a p o r a te d , a "smoke" w as p ro d u c e d .

The m ice showed a h i g h b lo o d l e v e l o f th e d ru g v e r y soon

a f t e r in h a lin g t h i s

"sm oke", an d i t s u s e i n pneum onia seem ed i n d i c a t e d .

A lso i n 194^ j T . H. H a r r i s (7 ) u s e d m i c r o c r y s t a l l i n e s u l f a t h i a z o l e i n c a s e s o f Im p e tig o c o n t a g i o s a .

He r e p o r t e d a much b e t t e r r e s u l t from th e

u s e o f t h e m i c r o c r y s t a l l i n e d ru g th a n w ith t h e o r d i n a r y pow dered d r u g .

In

h i s r e p o r t , H a r r i s s e t s f o r t h h i s b e l i e f s a s t o why th e m i c r o c r y s t a l l i n e s u l f a t h i a z o l e i s b e t t e r th a n th e r e g u l a r l y u s e d p o w d er. The im proved r e s u l t s i n t h e t r e a t m e n t o f im p e tig o r e ­ p o r te d h e r e a r e due o n ly t o th e p h y s ic a l form o f t h e a g e n t and i t s c h e m ic a l s i m p l i c i t y . O rd in a ry s u lfo n a m id e p o w d ers cak e on l e s i o n s o f im p e tig o f o r th e same r e a s o n t h a t th e y cake i n p u re a q u eo u s s u s p e n s io n , p re s u m a b ly b e c a u s e t h e g r a i n s o f pow der a r e n o t n a t u r a l l y c r y s t a l l i n e i n s h a p e . The m ic ro ­ c r y s t a l l i n e d ru g m a in ta in s th e s e p a r a t i o n o f th e c r y s t a l s , a s s u r i n g a much g r e a t e r s u r f a c e f o r s o l u t i o n i n t o l o c a l t i s s u e f l u i d s and a c o n tin u e d d i s t r i b u t i o n o v e r th e l e s i o n . (7 ) J . Yf. B ig g e r and G. A. H odgson ( 5 ) c o r r o b o r a t e d t h i s r e p o r t i n 1 9 4 4 , s t a t i n g t h a t m i c r o c r y s t a l l i n e s u l f a t h i a z o l e c a u se d a m ore r a p i d h e a l i n g th a n t h e r e g u l a r c r y s t a l l i n e form i n a l l c a s e s o f Im p e tig o c o n t a g i o s a t h a t th e y h ad t r e a t e d . I n 1 9 4 5 9 J* G* R e in g o ld , F . J . P h i l l i p s , and H. F. F l i p p i n (1 1 ) r e p o r t e d t h a t t h e y h a d c o n d u c te d c l i n i c a l e x p e r im e n ts on th e a b s o r p t i o n r a t e o f r e g u l a r and m i c r o c r y s t a l l i n e s u l f a d i a z i n e when t a k e n i n t e r n a l l y i n t h e form o f a s u s p e n s io n .

They s t a t e ;

1. P a t i e n t s r e c e i v i n g by m outh s u s p e n s io n s o f m ic ro ­ c r y s t a l l i n e s u l f a d i a z i n e (5 gm.) showed s i g n i f i c a n t l y h i g h e r c o n c e n t r a t i o n s o f s u l f a d i a z i n e i n serum d u r in g th e f i r s t s i x h o u rs f o llo w in g i t s i n g e s t i o n th a n d id th o s e who r e c e iv e d o r d in a r y s u l f a d i a z i n e .

5 2 . The e x c r e t i o n o f s u l f a d i a z i n e i n t h e u r i n e o f th o s e r e c e i v i n g m i c r o c r y s t a l l i n e m a t e r i a l was l i k e w i s e s i g n i f i c a n t ­ l y h i g h e r d u r in g t h i s p e r i o d . T hese o b s e r v a t i o n s i n d i c a t e t h a t m i c r o c r y s t a l l i n e s u l f a d i a z i n e i s a b s o r b e d m ore r a p i d l y th a n i s o rd in a ry s u lf a d ia z in e , ( l l )

In 1947, E. M, Boyd and R* W, Dingwall (4) d u p lic a te d t h i s e x p e ri­ m ent u sin g a fo u r gram d o se, and o b ta in e d a p p ro x im ately th e same r e s u l t s . However, th e y a ls o found t h a t when th e dosage was c o n tin u e d , th e r e was no s i g n i f i c a n t d iffe r e n c e i n th e blood l e v e ls which were m ain tain ed by th e m ic r o c r y s ta llin e and th e re g u la r drug a f t e r th e f i r s t s ix h o u rs . I n 1 9 4 9 j B, Levy and 0 , L , Huyck (1 2 ) r e p o r t e d t h a t t h e r e was a f a s t e r d i f f u s i o n r a t e from o in tm e n t b a s e s o f th e m i c r o c r y s t a l l i n e s u l f a ­ d i a z i n e th a n t h e r e g u l a r c r y s t a l l i n e fo rm .

F o r t h i s t e s t th e o in tm e n t

w as p la c e d on a k% a g a r g e l c o n t a i n i n g E h r lic h * s A ldehyde R e a g e n t, w h ic h t u r n s y e llo w when i n c o n t a c t w ith s u l f a d i a z i n e .

The r a t e o f

d i f f u s i o n was t h e n d e te r m in e d by th e d e p th o f c o l o r f o r m a tio n i n th e g e l i n a s p e c i f i e d p e r i o d o f tim e .

EXPERIMENTAL M a n u fa c tu re o f T a b l e t s The t a b l e t s u s e d i n t h i s e x p e r im e n t w ere made by t h e w et g r a n u la ­ t i o n m e th o d .

An a t t e m p t was made t o m a n u fa c tu r e t h e t a b l e t s by t h e

d r y g r a n u l a t i o n m e th o d , b u t t h i s was fo u n d t o be i m p r a c t i c a l on th e s m a ll m ach in e a v a i l a b l e s in c e th e f i n e pow der w ould n o t flo w sm o o th ly i n t o t h e d ie t o make th e " s l u g s ”.

S e v e r a l fo r m u la s u s i n g d i f f e r e n t

b i n d e r s w ere t r i e d t o d e te r m in e w h ich fo rm u la w ould make th e m o s t s a t i s ­ fa c to ry t a b l e t . g r a tin g a g e n t.

I n e a c h fo rm u la 2^/£ c o r n s t a r c h was u s e d a s a d i s i n t e ­ B in d e rs o f s t a r c h p a s t e , l i g h t s y r u p , a c a c i a , an d

s u c r o s e w ere t r i e d .

The fo rm u la w h ich seem ed t o make th e b e s t t a b l e t s

w ith t h e m o st s a t i s f a c t o r y d i s i n t e g r a t i o n an d h a r d n e s s i s g iv e n b e lo w . S u l f a d i a z i n e , USP C orn S t a r c h , USP A c a c ia P o w d er, USP M agnesium S t e a r a t e , M e d ic in a l

70?? 255? 2??

3%

Mix t h e s u l f a d i a z i n e , c o rn s t a r c h , and a c a c i a th o r o u g h ly and g r a n u l a t e by m o is te n in g w ith w a te r an d f o r c i n g th e m ass th r o u g h a # 1 2 s e i v e . Dry th e g r a n u l a t i o n i n a h o t a i r o v e n , p a s s a g a i n th r o u g h t h e # 1 2 s e iv e an d m ix l i g h t l y w ith th e m agnesium s t e a r a t e , w h ich a c t s a s a l u b r i c a n t . Com press i n ­ t o t a b l e t s u s i n g a 5/8>n d i e . The above f o r a u l a and p ro c e d u re w ere fo llo w e d i n m aking b o th th e t a b l e t s o f th e m i c r o c r y s t a l l i n e s u l f a d i a z i n e and th o s e o f th e r e g u l a r s u lfa d ia z in e .

The m ic ro c r y s t a l l in e s u l f a d i a z i n e u s e d was o b ta in e d from

t h e C alco C hem ical Company, w h ile th e r e g u l a r s u l f a d i a z i n e u s e d was o b ta in e d from A b b o tt L a b o r a t o r i e s . The p a r t i c l e s i z e o f b o th ty p e s o f s u lf a d ia z i n e waB d eterm in ed w ith th e a id o f a m ic r o s c o p ic red b lo o d c e l l c o u n tin g chamber.

I t was

found t h a t th e p a r t i c l e s i z e o f th e r e g u la r s u lf a d ia z in e was f i f t e e n t o

7 t h i r t y m ic ro n s i n l e n g t h a n d f i v e m ic ro n s i n w id t h , w h ile th e p a r t i c l e s i z e o f th e m i c r o c r y s t a l l i n e s u l f a d i a z i n e was two t o f o u r m ic ro n s i n l e n g t h an d one an d o n e - h a l f m ic ro n s i n w id th . T h ree h u n d re d t a b l e t s w ere made from e a c h ty p e o f s u l f a d i a z i n e , e a c h t a b l e t c o n t a i n i n g 0 . 265 gram s o f s u l f a d i a z i n e .

I t was n o t p o s s i b l e

t o co m p ress b o th ty p e s o f s u l f a d i a z i n e w ith th e same p r e s s u r e s e t t i n g on th e t a b l e t m a ch in e s in c e t h e m ic ro c r y s t a l l in e p r o d u c t i s v e r y l i g h t an d gram f o r gram o c c u p ie s c o n s i d e r a b ly m ore sp a c e t h a n d o e s t h e r e g u l a r p ro d u c t.

The t a b l e t s w ere made on a ty p e nP" s i n g l e punch S to k e s t a b l e t

m ach in e* P h y s ic a l P r o p e r t i e s o f T a b l e t s Some d i f f e r e n c e s w ere n o te d i n t h e p h y s i c a l p r o p e r t i e s o f t h e t a b ­ l e t s made from t h e r e g u l a r an d from t h e m i c r o c r y s t a l l i n e s u l f a d i a z i n e . The t a b l e t s o f m i c r o c r y s t a l l i n e s u l f a d i a z i n e w ere m ore g l o s s y i n a p p e a r ­ a n c e , h a d a m ore b r i t t l e

f r a c t u r e w ith a c l e a n b r e a k an d l i t t l e

crum­

b l i n g , and h a d l e s s te n d e n c y t o b r e a k when d ro p p e d o r h a n d le d r o u g h ly th a n h a d t h e t a b l e t s made from th e r e g u l a r s u l f a d i a z i n e . I t was a l s o n o te d t h a t th e t a b l e t s made from th e m i c r o c r y s t a l l i n e s u l f a d i a z i n e d i s i n t e g r a t e d i n w a te r m ore r a p i d l y t h a n d id t h e o t h e r g ro u p .

To t e s t t h e d i s i n t e g r a t i o n t i m e , th e t a b l e t was l a i d a c r o s s two

w ir e s w h ich w ere a b o u t 1 /8 " a p a r t .

A n o th e r w ire i n t h e form o f a l a r g e

h o o k w ith a w e ig h t su sp e n d e d from i t was p la c e d o v e r th e t a b l e t i n su ch a way t h a t when th e t a b l e t d i s i n t e g r a t e d th e w e ig h t w ould f a l l t o th e b o tto m o f th e c o n t a i n e r h o ld in g t h e a p p a r a t u s .

To tim e th e d i s i n t e ­

g r a t i o n o f a t a b l e t , th e a p p a r a t u s w ith th e t a b l e t i n p la c e was lo w e re d i n t o th e w a te r an d th e tim e r e c o r d e d from th e moment th e t a b l e t came i n c o n t a c t w ith th e w a te r u n t i l th e w e ig h t d ro p p e d .

Tw enty t a b l e t s w ere

8

p ic k e d a t random from e a c h g ro u p o f t a b l e t s and w ere t e s t e d i n t h e above m anner*

l b was fo u n d t h a t t h e a v e r a g e d i s i n t e g r a t i o n tim e o f t h e m ic ro ­

c r y s t a l l i n e t a b l e t s was 46*1 s e c o n d s , w h ile t h e tim e f o r t h e r e g u l a r t a b ­ l e t s was 57*5 s e c o n d s .

T h is r e p r e s e n t s a d e c r e a s e o f a p p r o x im a te ly 20%

i n th e d i s i n t e g r a t i o n tim e o f t h e t a b l e t s made from th e m i c r o c r y s t a l l i n e s u l f a d i a z i n e o v e r th o s e o f t h e r e g u l a r s u l f a d i a z i n e .

S in c e b o th t y p e s o f

t a b l e t s d i s i n t e g r a t e d i n l e s s t h a n one m in u te , t h i s f a c t o r d o e s n o t seem s ig n ific a n t.

F ig u r e I r e p r e s e n t s a breakdow n o f t h e d i s i n t e g r a t i o n tim e s

o f th e in d iv id u a l t a b l e t s .

A b s o r p tio n H ate o f S u l f a d i a z i n e i n Doge The m ethod u s e d f o r d e te r m in in g t h e b lo o d l e v e l o f th e s u l f a d i a z i n e an d th e r e b y show ing th e a b s o r p t i o n r a t e o f th e d ru g was th e m ethod d e v e l­ oped by M a r s h a ll and B r a tto n (5 ) and d e s c r i b e d b e lo w . R e a g e n ts : 1. t r i c h l o r a c e t i c a c id 2 . 1 :1 0 0 0 sodium n i t r i t e O.J% ammonium s u lf a m a te 4 . 1 :1 0 0 n - ( l - n a p h t h y l ) e t h y l e n e d i a m i n e d i h y d r o c h lo r i d e M ethod: 1 . F o r s e t t i n g up s ta n d a r d c u r v e : a . Make known d i l u t i o n s o f s u l f a d i a z i n e c o v e r in g t h e e x p e c te d ra n g e o f b lo o d l e v e l s . b . To 2 cc o f e a c h known d i l u t i o n , add 8 cc o f th e t r i c h l o r a c e t i c a c i d s o l u t i o n and JO cc o f d i s ­ t i l l e d w a t e r . T h is m akes a 1 :2 0 d i l u t i o n . c . To a 10 cc a l i q u o t o f e a c h d i l u t i o n p r e p a r e d above add 1 cc o f th e sodium n i t r i t e s o l u t i o n . L e t s ta n d f o r J m in u te s . d . Add 1 cc o f th e ammonium e u lfe m a te s o l u t i o n . L e t s ta n d f o r 2 m in u te s . e . Add 1 cc o f t h e n - ( l - n a p h t h y l ) e t h y l e n e d i a m i n e d ih y d r o c h lo r i d e s o l u t i o n . L e t s ta n d f o r a b o u t t e n m in u te s f o r optimum c o l o r f o r m a ti o n , and r e a d th e p e r c e n t t r a n s m i s s i o n o f l i g h t on a s p e c tro p h o to m e te r* P l o t th e r e s u l t s on se m il o g a r i t h m i c g ra p h p a p e r .

9 2 . F o r d e te r m in in g th e s u l f a d i a z i n e l e v e l i n b lo o d : a . Lake 2 cc o f t h e b lo o d w ith JO cc d i s t i l l e d w a te r and add 8 cc o f t h e t r i c h l o r a c e t i c a c i d s o l u t i o n . L e t s ta n d f o r a b o u t 1^ m in u te s and filte r. b . Take a 10 cc a l i q u o t an d add 1 cc o f th e sodium n i t r i t e s o lu tio n * L e t s ta n d f o r J m in u te s . c . Add 1 cc o f t h e ammonium B u lfam ate s o l u t i o n . L e t s ta n d f o r 2 m i n u te s . d . Add 1 cc o f t h e n - ( l - n a p h t h y l ) e t h y l e n e d i a m i n e d ih y d r o c h lo r i d e s o l u t i o n . L e t s ta n d f o r a b o u t 10 m in u te s f o r optim um c o l o r f o r m a tio n . e . Read t h e p e r c e n t t r a n s m i s s i o n on a s p e c tro p h o to m ­ e t e r an d com pare w ith t h e s ta n d a r d c u rv e f o r m i l l i ­ gram s o f s u l f a d i a z i n e p e r 100 cc w hole b lo o d . f . I f t h e e x p e c te d b lo o d l e v e l i s v e r y h ig h o r e x ­ tr e m e ly lo w , t h e d i l u t i o n c a n be made s t r o n g e r o r w eak er th a n t h e 1 :2 0 d e s c r ib e d a b o v e . ThiB d i l u t i o n i s t h e n com pared th e same a s th o s e ab o v e w ith a s ta n d a r d c u rv e made from th e same d i l u t i o n . A s ta n d a r d c u rv e was s e t up f o r t h i s e x p e r im e n t by p r e p a r i n g known s t a n d a r d s o f o n e , tw o , t h r e e , f o u r , and f i v e m ill i g r a m s o f s u l f a d i a z i n e t o e a c h one h u n d re d c u b ic c e n ti m e t e r s o f s o l u t i o n .

T hese known d i l u t i o n s

w ere t r e a t e d a s d e s c r ib e d a b o v e , and r e a d in g s w ere ta k e n from a C e n t r a l S c i e n t i f i c Company S p e c tro p h o to m e te r u s i n g a g r e e n f i l t e r .

On f o u r

d i f f e r e n t o c c a s io n s th e s ta n d a r d d i l u t i o n s w ere p r e p a r e d an d t h e r e s u l t s re c o rd e d .

T hese r e s u l t s w ere t h e n a v e r a g e d , and th e f i n a l r e s u l t was

p l o t t e d on s e m i - lo g a r ith m ic g ra p h p a p e r ( F ig u r e I I ) . To t e s t t h e a c c u r a c y o f t h i s m ethod i n r e c o v e r i n g th e s u l f a d i a z i n e from b lo o d , f i v e sam p les o f b e e f b lo o d c o n ta i n in g v a r y in g known am ounts o f s u l f a d i a z i n e w ere p r e p a r e d .

The s u l f a d i a z i n e was d e te rm in e d by th e

ab o v e m e th o d , and th e r e s u l t s w ere fo u n d to be a c c u r a t e t o w i t h i n o n e h a l f o f a m illi g r a m p e r one h u n d re d c u b ic c e n t i m e t e r s o f b lo o d . I t was f e l t t h a t dogs w ould be th e m o st s a t i s f a c t o r y a n im a l t o u s e i n co m p arin g t h e a b s o r p t i o n r a t e s o f th e two ty p e s o f t a b l e t s .

I t has

b e e n shown t h a t th e a b s o r p t i o n c u rv e o f s u lfo n a m id e s i n dogs i s more r e g u l a r and p r e d i c t a b l e t h a n i s th e c u rv e i n o t h e r a n im a ls su ch a s c a t s

10 o r ra b b its , (l^ )

S in c e s u lfo n a m id e s a r e n o t a c e t y l a t e d i n d o g s a s t h e y

a r e i n m o st a n im a ls , (1 2 ) th e d e t e r m i n a t i o n o f th e b lo o d l e v e l i s sim ­ p lifie d

s in c e i t i s n o t n e c e s s a r y t o h y d r o l i z e t h e a c e t y l a t e d compound

t o t h e s u lfo n a m id e b a s e b e f o r e t e s t i n g .

A n o th e r f a c t o r w h ich made d o g s

a p r a c t i c a l a n im a l f o r t h e p u rp o s e o f t h i s e x p e r im e n t i s t h a t dogs a r e l a r g e enough t o be fe d t h e t a b l e t s o r a l l y w i th o u t d i f f i c u l t y an d a l s o h a v e l a r g e eno u g h v e i n s t o p e r m it th e w ith d ra w a l o f num erous sa m p le s o f b lo o d f o r t h e p u rp o s e o f d e te r m in in g t h e b lo o d l e v e l o f th e s u l f a d i a z i n e w i th o u t s e r i o u s l y i n j u r i n g t h e v e i n . F o r t h i s e x p e r im e n t tw o dogs w ere u s e d , one a m ale a n im a l w e ig h in g tw e lv e and o n e - h a l f k ilo g r a m s (d o g $ l ) , th e o t h e r a fe m a le w e ig h in g f i v e a n d s e v e n - t e n t h s k ilo g r a m s (d o g # 2 ) , I n th e c o m p a riso n o f t h e t a b l e t s p r e p a r e d f o r t h e e x p e rim e n t from t h e m i c r o c r y s t a l l i n e and from th e r e g u l a r s u l f a d i a z i n e , t h e d ogs w ere f e d t h e t a b l e t s o f s u l f a d i a z i n e and b lo o d sam p les w ere ta k e n a t a p p r o x i­ m a te ly o n e - h a l f , o n e , tw o , t h r e e , f o u r , s i x , e i g h t , and tw e n t y - f o u r h o u rs.

S in c e th e b lo o d o f dogs c l o t s v e r y r a p i d l y , ( l ^ ) t h e i n s i d e o f

t h e s y r in g e was w e tte d w ith a 1% s o l u t i o n o f h e p a r in *

T h is p ro c e d u re

made p o s s i b l e th e a c c u r a t e m easu rem en t o f two c u b ic c e n t i m e t e r s o f b lo o d . A p p ro x im a te ly t h r e e c u b ic c e n ti m e te r s o f b lo o d w ere w ith d ra w n f o r e a c h d e t e r m i n a t i o n and p la c e d i n a t e s t t u b e .

Two c u b ic c e n t i m e t e r s o f b lo o d

c o u ld t h e n be a c c u r a t e l y m e a su re d w ith a two c u b ic c e n t i m e t e r p i p e t t e . Food was w ith h e ld from th e a n im a ls f o r t w e n ty - f o u r h o u r s p r i o r t o th e t e s t and w a te r f o r a t l e a s t t h i r t y m in u te s p r i o r t o th e t e s t .

The w a te r

a n d fo o d w ere a l s o w ith h e ld d u r in g t h e f i r s t e i g h t h o u r s a f t e r f e e d in g th e t a b l e t s ,

A r e s t p e r io d o f a t l e a s t t h r e e d a y s was a llo w e d b e tw e e n

e a c h s e r i e s o f t e s t s t o a llo w th e s u l f a d i a z i n e t o be c o m p le te ly e x c r e t e d .

11 The "two 'ty p e s o f s u l f a d i a z i n e " ta b le ts w ere com pared t h r e e s e p a r a t e t i m e s o n t h e s m a ll fe m a le dog an d tw ic e on t h e l a r g e m a le d o g .

In th e

f i r s t tw o c o m p a ris o n s on t h e s m a ll dog an d th e f i r s t c o m p a riso n on th e l a r g e d o g , o n ly w hole t a b l e t s w ere u s e d w ith th e r e s u l t t h a t t h e d o s a g e s w ere n o t e x a c t l y th e same f o r e a c h d o g .

I n th e f i n a l t e s t on b o th d o g s ,

t h e d o sa g e was a d j u s t e d by b r e a k in g a t a b l e t i n su c h a way a s t o h av e b o th dogs r e c e i v e th e same d o se p e r k ilo g r a m o f body w e ig h t. R e s u l t s o f a l l t h e t e s t s a r e p l o t t e d on th e g ra p h s m arked F ig u r e s I I I an d IV .

The r e s u l t s w ere th e n a v e ra g e d i n o r d e r t o g e t a more con­

c i s e p i c t u r e o f t h e d i f f e r e n c e s i n t h e a b s o r p t i o n r a t e s , an d t h i s a v e ra g e i s shown on t h e g ra p h m arked F ig u r e V.

D is c u s s io n I t seem s t h a t t a b l e t s made from m i c r o c r y s t a l l i n e s u l f a d i a z i n e p o s s e s s somewhat b e t t e r p h y s i c a l p r o p e r t i e s t h a n th e t a b l e t s made from th e re g u la r ly u sed s u lf a d ia z in e .

They h a v e a h a r d , g l o s s y s u r f a c e w h ich

i s p l e a s i n g t o t h e eye and a h a r d f i n i s h w h ich d o e s n o t c h ip e a s i l y . T h ese t a b l e t s o f m i c r o c r y s t a l l i n e s u l f a d i a z i n e a l s o b r e a k more c l e a n l y w ith a b r i t t l e

fra c tu re .

S c o re d t a b l e t s p r o v id e m ore a c c u r a t e d o sag e

w ith l e s s w a s te o f t a b l e t s w here i t i s n e c e s s a r y t o a d m i n i s t e r o n e - h a l f ta b l e t p e r dose.

The f a c t t h a t t h e r e i s a p p r o x im a te ly a 20% d e c r e a s e i n

d i s i n t e g r a t i o n tim e i n th e m i c r o c r y s t a l l i n e t a b l e t s o v e r th e r e g u l a r d o e s n o t seem t o be o f s i g n i f i c a n t im p o rta n c e s in c e b o th ty p e s o f t a b l e t s d i s ­ in te g r a te in a m a tte r o f seco n d s.

H ow ever, w ith d ru g s w hich form s lo w ly

d i s i n t e g r a t i n g t a b l e t s , t h e u s e o f th e m i c r o c r y s t a l l i n e form m ig h t p ro v e im p o r ta n t i n a s s u r i n g d i s i n t e g r a t i o n i n th e g a s t r o i n t e s t i n a l t r a c t . A c o m p a riso n o f t h e a b s o r p t i o n r a t e s i n th e two dogs d o e s n o t d e f i n i t e l y p ro v e o r d is p r o v e th e p o s s i b i l i t y o f a f a s t e r a n d / o r h i g h e r

12 b lo o d l e v e l by th e a d m i n i s t r a t i o n o f t a b l e t s made from m i c r o c r y s t a l l i n e s u lfa d ia z in e .

I n t h e f i r s t p l a c e , th e r e s u l t s a r e n o t s t a t i s t i c a l l y im­

p o r t a n t s in c e o n ly two dogs w ere a v a i l a b l e f o r th e e x p e r im e n t.

M o re o v e r,

i t i s p o s s i b l e t h a t t h e g r e a t d i f f e r e n c e i n th e w e ig h ts o f th e tw o dogs u s e d may h a v e h a d some in f l u e n c e on t h e a b s o r p t i o n r a t e s . A f t e r e a c h f e e d in g o f t h e t a b l e t s , i t was o b s e rv e d t h a t a t l e a s t a n h o u r l a p s e d b e f o r e t h e r e was a n a p p r e c i a b l e r i s e o f t h e b lo o d l e v e l o f th e s u lf a d ia z in e .

On one o c c a s io n t h e r e was a d e la y o f t h r e e h o u r s

b e f o r e a s i g n i f i c a n t am ount o f s u l f a d i a z i n e a p p e a re d i n th e b lo o d o f e ith e r dog.

I t i s s u s p e c te d , a lth o u g h im p o s s ib le t o p r o v e , t h a t th e

a n im a ls w ere i n a d v e r t e n t l y fe d j u s t p r i o r t o t h e f e e d in g o f th e t a b l e t s on t h a t p a r t i c u l a r d a y . The d i f f e r e n c e i n th e r e a c t i o n s o f th e two dogs was much more n o t i c e a b l e th a n was th e d i f f e r e n c e i n th e a b s o r p t i o n r a t e s o f t h e two ty p e s o f t a b l e t s .

The s m a ll dog (d o g # 2 ) c o n s i s t e n t l y showed a h i g h e r

b lo o d l e v e l w ith th e m ic ro c r y s t a l l i n e s u l f a d i a z i n e th a n w ith a n e q u iv a ­ l e n t d o se o f t h e r e g u l a r d ru g .

H ow ever, th e l a r g e dog (d o g $ l )

showed

no s i g n i f i c a n t d i f f e r e n c e i n th e b lo o d l e v e l o b ta in e d from e i t h e r ty p e ta b le t. The d i f f e r e n t r e a c t i o n s r e c e iv e d from th e two dogs make a d e f i n i t e c o n c lu s io n im p o s s ib le a s t o th e sp e e d o f a b s o r p t i o n o f t h e m i c r o c r y s t a l ­ lin e

s u l f a d i a z i n e a s com pared w ith t h e sp e e d o f a b s o r p t i o n o f t h e re g u ­

l a r s u l f a d i a z i n e ; t h e r e f o r e , m ore e x p e r im e n ta tio n seem s i n d i c a t e d .

CONCLUSIONS 1.

C om pressed t a b l e t s o f m i c r o c r y s t a l l i n e s u l f a d i a z i n e a r e g l o s s i e r ,

m ore e a s i l y d iv id e d a c c u r a t e l y , and f a s t e r d i s i n t e g r a t i n g t h a n a r e com­ p r e s s e d t a b l e t s made from th e r e g u l a r l y u s e d s u l f a d i a z i n e , 2,

T h e re i s enough e v id e n c e t o show a p o s s i b i l i t y t h a t c o m p re sse d

t a b l e t s made from m i c r o c r y s t a l l i n e s u l f a d i a z i n e w i l l p ro d u c e a h i g h e r b lo o d l e v e l o f t h e d ru g i n th e b lo o d o f d o g s , b u t m ore e x t e n s i v e e x p e r i ­ m e n ta tio n i s n e e d e d b e f o r e a d e f i n i t e c o n c lu s io n c a n be d raw n .

BIBLIOGRAPHY 1.

B e r r y , O* E . , ’’M odem M ach in es f o r Dry S iz e R e d u c tio n i n F in e S iz e R an g e ” , I n d u s t r i a l an d E n g , Ohem#, 5 ^ * 6 7 2 -6 7 8 , 1 9 4 6 .

2,

B e r t h o l f , L . M. a n d J . E . P i l s o n , ’’S t u d i e s on T o x i c i t y t o H oneybees o f A c id Lead A r s e n a te , C alciu m A r s e n a te , P h e n o th ia z i n e , and C r y o l i t e ” , J . E c o n . E n to m o l. . 54-524, 1 9 4 1 .

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B ig g e r , J* W. end G. A. H odgson, 11Im p e tig o C o n ta g io s a T r e a te d w ith M i c r o c r y s t a l l i n e S u l f a t h i a z o l e ” , L a n c e t, 2 4 7 * 7 8 , 1944*

4*

Boyd, E . M. and R. W. D in g w a ll, ’’The A b s o r p tio n and E l i m i n a t i o n o f S u l f a d i a z i n e A d m in is te re d a s T a b l e t s , and a G round (M ic ro n iz e d ) Pow der and a s M i c r o c r y s t a l e ” , Am. J . Med. S c i . , 2 1 8 :5 4 9 -5 5 6 , 1947.

5*

B r a t t o n , A . C. and E . K. M a r s h a ll , J r . , ”A New C o u p lin g Component f o r S u lf a n ila m id e D e te r m in a t io n ” , J . o f B i o l * C hem ., 1 2 8 :5 5 7 , 1959.

6.

C ham bers, L . A ., T . N. H a r r i s , F . Schuman, and L. K. F e rg u s o n , ’’The Use o f M i c r o c r y s t a l s o f S u l f a t h i a z o l e i n S u r g e r y ” , J . Am. Med. A s s i n . , 1 1 9 t5 2 4 , 1 9 4 2 ,

7.

H a r r i s , T . N . , ’’T re a tm e n t o f Im p e tig o C o n ta g io s a w ith a New P h y s ic a l Form o f S u l f a t h i a z o l e ” , J . Am. Med. A s s 'n . . 1 2 1 :4 0 5 , 1945*

8.

H a r r i s , T . N ., R . E . Sommer, and C. C. C h a p p ie , nThe A d m in i s tr a tio n o f S u lfo n a m id e M i c r o c r y s t a l s by I n h a l a t i o n ” , Am. J . Med. S c i . . 2 0 5 : 1- 6 , 1945*

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L evy, B . a n d C. L . H uyck, ”The E f f e c t o f F in e n e s s o f S u l f a d i a z i n e and W e ttin g A g e n ts on D i f f u s io n from O in tm e n t B a s e s ” , J . Am. P h a m . A s s ’ n . , S c i e n t i f i c E d ., 5^ 5611- 6 1 4 , 1949*

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L issm a n , M. A ., ”J e t P u l v e r i z i n g Now P r a c t i c a l ” , Chem. and M et. E ng. . 4 5 *258- 2 5 9 , I 9 5 8 .

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R e in g o ld , J . G ., F . J . P h i l l i p s , H. F . F l i p p i n , “A C om parison o f t h e B e h a v io r o f M i c r o c r y e t a l l i n e S u l f a d i a z i n e w ith t h a t o f O rd in a ry S u l f a d i a z i n e i n Man” , Am. J* Med. S c i . , 2 1 0 :1 4 1 -1 4 7 , 1945*

.

R o b in so n , E . J . and M. L . C r o s s e l y , "The M eta b o lism o f N '- a c y l s u l f a n ila m id e s i n th e Dog” , A rc h . B iochem . . 1 :4 1 5 - 4 2 5 , 1945*

12

15*

S i l c o x , L . E . and H. P . S c h e n ck , ’’Use i n O to la ry n g o lo g y o f M icro ­ c r y s t a l s o f D rugs o f th e S u lf a n ila m id e G roup” , A rc h . O to la r y n ­ g o lo g y . 5 6 *171- 1 8 6 , 1 9 4 2 .

15

14*

S m ith , C. M. an d L* D* G oodhue, " P a r t i c l e S iz e i n R e l a t i o n t o I n s e c t i c i d e E f f i c i e n c y " , I n d u s t r i a l and E n g * C hem ., ^ 4 :4 9 0 - 4 9 4 , 1942.

15»

W elch , M ., 0 . R. S c h r o e d e r , D. F . V roman, L* R e d d in , R* B u r k h a r t, and P . L a n g e r, " F a te and A b s o r p tio n o f a | g r * / l b . Dose o f S u lfo n a m id e s i n A n im a ls " , P r o c * U. £[. L i v e s to c k S a n i t a r y A s s l n . , 4 0 : 215 - 2 ^ 4 , 1 9 4 6 .

16 FIGURE I DISINTEGRATION TIMES OF MICROCRYSTALLINE AND REGULAR SULFADIAZINE TABLETS D i s i n t e g r a t i o n T im es o f T a b l e t s Made From M i c r o c r y s t a l l i n e S u lfa d ia z in e S econds

D i s i n t e g r a t i o n Tim es o f T a b le t s Made From R e g u la r S u lfa d ia z in e Seconds

52

47

55

49

55

49

56

50

59

50

59

50

4o

55

40

55

45

56

45

58

45

59

45

59

46

60

50

60

52

62

56

64

57

75

60

75

67

76

61

90

M edian - 4^

M edian - 58

Mean - 46*1

Mean -» 57*5

17 FIGURE II

STANDARD CURVE FOR DETERMINING BLOO D L E V E L S OF SU LFAD IAZINE

FILTER

PERCENT

TRANSMISSION

GREEN

1

1— . ■

0

1

*---------------------- 1______________ i_______________ I---------------------- 1----------------------- L---------------------

%

3

+

5

6

MILLIGRAMS O F SULFADIAZINE P E R 100 CUBIC C E N T I M E T E R S B L O O D

7

MILLIGRAMS OF SULFADIAZINE PEA 100 CUBIC C E N T I M E T E R S BLOOD

VJ>

r* o o ni ri

T"(a

o Cn

rn

n

o o

OD

MILUGRA/1S

O F S U L F A D I A Z I N E P ER m

CUBIC C E N T ! P I E T E R S

BLOOO

HOURS

M I L L I G R A M S o r S U L F A D I A Z I N E PER loo CUBIC C E N T I M E T E R S

BLOOD

f*

LEVELS

HOURS

s

BLOOD

r~

AVERAGE

r>

OF ALL TESTS

oo