The Manufacture of Compressed Hypodermic and Soluble Tablets

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P U R D U E U N IV ER SITY

THIS IS TO CERTIFY THAT THE THESIS PREPARED UNDER MY SUPERVISION

BY

Glen Jo sep h Sperandio

ENTITLED

THE MANUFACTURE OF CCMPRESSSD HYPO­ DERMIC AND SOLUBLE TABLETS__________

COMPLIES WITH THE UNIVERSITY REGULATIONS ON GRADUATION THESES

AND IS APPROVED BY ME AS FULFILLING THIS PART OF THE REQUIREMENTS

FOR THE DEGREE OF

Hoc t or of. P hilosophy

P r o f e sso r in C h a r g e o f T h e s is

H ea p o f S chool or D epartm ent

19

TO THE LIBRARIAN:---IS: THIS THESIS IS NOT TO BE REGARDED AS CONFIDENTIAL.

TO BE USED IN LIBRARY ONLY

THE MANUFACTURE OF COMPRESSED HYPODERMIC AND SOLUBLE TABLETS

A T hesis Subm itted to th e F a c u lty of

Purdue U n iv e rs ity by Glen Joseph Sperandio I n P a r t i a l F u lf illm e n t o f th e R equirem ents f o r th e Degree of Doctor o f P hilosophy

F e b ru ary , 1950

ProQuest Number: 27712250

All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is d e p e n d e n t upon the quality of the copy subm itted. In the unlikely e v e n t that the a u thor did not send a c o m p le te m anuscript and there are missing pages, these will be noted. Also, if m aterial had to be rem oved, a n o te will ind ica te the deletion.

uest ProQuest 27712250 Published by ProQuest LLC (2019). C opyright of the Dissertation is held by the Author. All rights reserved. This work is protected against unauthorized copying under Title 17, United States C o d e M icroform Edition © ProQuest LLC. ProQuest LLC. 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106 - 1346

ACKNOWLEDGEMENT I w ish t o e x p re ss my s in c e re a p p re c ia tio n t o Dr. H. George DeKay, under whose d i r e c ti o n t h i s work has been done.

I am a ls o g r a t e f u l t o Dean Glenn L.

Je n k in s and o th e rs who have a s s i s t e d me i n com pleting th is p ro je c t.

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

I

HISTORY............................

3

THE PHARMACY OF HYPODERMIC TABLETS.........................

8

EXPERIMENTAL...........................................................

10

SUMMARY AND CONCLUSIONS.............................................................................. BIBLIOGRAPHY..........................................................................................................

58

LIST OF TABLES

1

P r o p e r tie s o f L acto se G ra n u la tio n s Made W ith . . . ......................................... .... V arious Gums ......

2

C o m p re s sib ility o f L actose G ra n u la tio n s Shown i n Table 1 ...................................................

-

13

3

C o m p re s sib ility o f L acto se G ra n u la tio n s Made With Gums .................... . ....................

15

4

C o m p re s sib ility o f L actose G ra n u la tio n s Made . . . W ith Sugars ........... ..

19

. .

C o m p re s sib ility o f L acto se G ra n u la tio n s Made With C e llu lo se D e riv a tiv e s and Sodium A lg in ate

22

C o m p re s sib ility o f L actose G ra n u la tio n s Made With L iq u id G lucose ......... ........................... ..

24

7

C o m p re s sib ility o f D if fe re n t Mesh S iz e L actose G ra n u la tio n s ........... ...................................... ..

26

8

L actose G ra n u la tio n s W ith Talc As a L u b ric a n t . . . . . . .

28

9

L actose G ra n u la tio n s With Magnesium S te a r a te As a L u b ric an t ......... .................................................... .. .

29

L actose G ra n u la tio n s Made and D ried by D if f e r e n t Methods ......... ..

31

C o m p re s sib ility o f th e S tan d ard G ra n u la tio n With S o lu b le S a l t s As th e L u b ric a n ts ............. ..

34

C o m p re s sib ility o f th e S tan d ard G ra n u la tio n L u b ric a te d With L iq u id s

36

C o m p re s sib ility o f th e S tandard G ra n u la tio n L u b ric a te d W ith S u rfa c e -A c tiv e Agents . . . . . . . . . . . . . . . . . . . . . . . .

38

S o l u b i l i t y o f L iq u id W etting Agents i n O il and Water

39

C o m p re s sib ility o f G ra n u la tio n s Made W ith Aqueous Washings o f Fixed O ils . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

42

5

6

10

11

12 13 14 15

LIST OF TABLES (Continued) Table 16 17 IS 19 20 21

Page C o m p re s sib ility o f L actose G ra n u la tio n L u b ric a te d With C e llu lo s e Compounds

43

C o m p re s sib ility o f G ra n u la tio n s Hade W ith Carbo.......... waxes In S o l u t i o n

44

C o m p re s sib ility o f G ra n u la tio n s L u b ric a te d W ith Powdered Carbowax4000 .....................

46

D is in te g r a tio n and S o l u b i l i t y o f T a b le ts W ith D if f e r e n t Mesh S iz e L u b ric a n ts

48

Compressed

T a b le ts C ontaining M ixtures o f Sodium B enzoate and Sodium A c eta te As L u b ric a n ts .................

51

Hypodermic T a b le ts Compressed On th e R o tary T ab let Machine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

54

1 INTRODUCTION Modern m ed ica tio n s a re a d m in iste re d t o p a ti e n t s i n many d i f f e r e n t f o r a s , one o f which i s th e hypodermic i n j e c t i o n .

T his method o f

in tro d u c in g th e d ru g d i r e c t l y i n t o a body t i s s u e r e q u ir e s more p re ­ c a u tio n s i n b o th th e m anufacture and a d m in is tr a tio n o f th e p ro d u ct th a n a re n o r a a lly observed f o r o r a l o r t o p i c a l a d m in is tra tio n o f th e same d ru g .

M edication t o be g iv en by i n j e c t i o n i s e i t h e r i n s o lu tio n

o r su sp e n sio n , and th e e n t i r e p re p a ra tio n should be s t e r i l e , f r e e o f p y ro g en s, and o f e x a c t dosage.

C onsequently, i n j e c t a b l e p r e p a ra tio n s

a re lim ite d c h ie f ly to two c la s s e s :

ampuls and hypodermic t a b l e t s .

Hypodermic t a b l e t s , in tro d u c e d a s a c o n v en ien t method f o r having e x ac t d oses o f m ed ica tio n i n a r a p id ly s o lu b le form , were r e a d i ly a ccep ted by p h y sic ia n s (5 2 ).

Those d o c to rs who c a r r i e d t h e i r medi­

c in e s w ith them and gave home tre a tm e n t were p a r t i c u l a r l y im pressed w ith th e a d v an tag e s:

th e t a b l e t s were c o n v en ien t to c a r r y , o f a c c u r­

a te d o sag e, s t a b l e , and co u ld be d is s o lv e d i n a te a sp o o n fu l o f s t e r i l ­ iz e d w ater to make a s o lu tio n f o r i n j e c t i o n . Commercial m an u factu rers o f hypodermic t a b l e t s , w hile im proving on most o th e r methods o f m an u fa ctu re, s t i l l r e l y e s s e n t i a l l y on th e o r i g i n a l manner and equipm ent f o r making t h i s form o f m e d ic a tio n . The m ethod, by modern s ta n d a r d s , i s o u td a te d and i n e f f i c i e n t i n t h a t th e t a b l e t s a re molded by hand in s te a d o f com pressed by t a b l e t m achines, th u s r e q u ir in g much more tim e f o r p ro c e s s in g .

P robably th e

c h ie f re a so n f o r t h i s i s th e i n a b i l i t y o f th e m a n u fa ctu rers t o f in d a com bination o f s a t i s f a c t o r y in g r e d ie n ts which would le n d th em selv es t o com pression and a t th e same tim e conform t o t h e r i g i d s p e c i f i c a ti o n s

e s ta b lis h e d by th e t r a d e .

A hypodermic t a b l e t should conform to th e

fo llo w in g s p e c i f i c a ti o n s : I t m ust b e sm a ll and c o n ta in an a c c u ra te dosage o f th e d ru g . I t must be co m p letely so lu b le i n w a ter to form a c l e a r

s o l u t io n .

I t must have a r a p id r a t e o f d i s i n te g r a t i o n . I t must be s u f f i c i e n t l y firm to w ith sta n d h an d lin g and packaging . I t m ust c o n ta in d ilu e n ts which a re a c tiv e n e ith e r c h em ic ally n o r t h e r a p e u t i c a ll y . I t s m anufacture on a commercial b a s i s must be p r a c t i c a l and eco­ n o m ical. In th e p a s t few y e a rs hypodermic t a b l e t s have d e creased i n popu­ l a r i t y f o r two re a so n s :

Improved ampuls and m u ltip le -d o s e v i a l s o f

s o lu tio n s re a d y f o r i n j e c t i o n have been found t o b e f u l l y a s co n v en ien t and th e hypodermic t a b l e t s made by m olding o f te n te n d to crum ble o r c h ip a f t e r th e y have been packaged, making a c c u ra te dosage q u e s tio n a b le One la r g e m an u factu rer r e c e n tly d isc o n tin u e d making hypodermic t a b l e t s because o f th e d i f f i c u l t i e s in v o lv e d .

I f hypodermic t a b l e t s a r e t o

co n tin u e a s a w idely used ty p e o f m e d ic a tio n , an improved method o f m anufacture must be found, and p re p a ra tio n by m echanical com pression seems th e l o g ic a l s o lu tio n .

P rev io u s experim ents in d ic a te d t h a t th e s e

t a b l e t s m ight be made by com pression (8 1 ).

However, i n t h a t work a

d ilu e n t which made th e t a b l e t s to o expensive f o r m anufacture on a p r o f i ta b le b a s is was u se d .

The purpose o f t h i s work was to i n v e s t i ­

g a te th e p o s s i b i l i t i e s o f u sin g th e same d ilu e n t f o r com pressed t a b l e t s t h a t i s used f o r molded t a b l e t s and t o determ ine i f hypodermic t a b l e t s can be made com m ercially on a t a b l e t m achine.

3 HISTORY A lthough in tra v e n o u s m ed ic a tio n had been p r a c tic e d i n t e r m i t t e n t l y s in c e t h e se v e n te e n th c e n tu ry , i t was n o t u n t i l th e n in e te e n th c e n tu ry t h a t hypodermic m ed icatio n was i n i t i a t e d .

I t was f i r s t in tro d u c e d i n

th e U nited S ta te s i n May, 1856, by Dr. Fordyce B arker o f New Y ork, who had o b ta in e d a hypodem ic sy rin g e i n S co tlan d and b ro u g h t i t b ack w ith him on h is r e t u r n t o th e S ta te s (78)# The o r i g i n a l hypodermic m ed icatio n was i n s o lu tio n fo rm , b u t th e fo re ru n n e rs o f hypodermic t a b l e t s m ight be s a id t o have been i n i t i a t e d i n 1861 by L aFargue, who fo rm u lated p e l l e t s o f s o l i d m e d ica tio n f o r subcutaneous im p la n ta tio n on th e th e o ry t h a t t i s s u e f l u i d s would d i s ­ so lv e them and absorb th e d ru g .

LaFargue1s p e l l e t s were composed o f

s u g a r, a c a c ia , d i s t i l l e d w a te r, and th e m edication#

A lthough t h i s

method o f im p la n ta tio n was soon outmoded by th e use o f hypodermic f l u i d s , i t d id f o m th e b a s is f o r f u t u r e w o rk ers, sin c e D eansley and P a rk e s , i n 1937» d e sc rib e d a te c h n iq u e o f im p la n ta tio n o f com pressed t a b l e t s o f androgenic su b s ta n c e s (8 0 ).

I t has been s a id t h a t "perhaps

one o f th e g r e a t e s t b e n e f i ts r e s u l t i n g from hypodermic m ed ica tio n was t h a t i t encouraged p h y sic ia n s t o th in k i n term s o f p r e c is e dosages of s in g le a c tiv e p r in c ip le s " (2 2 ).

This p r e c is e dosage was one o f th e

c h ie f f a c t o r s le a d in g to th e in v e n tio n o f hypodermic t a b l e t s # P r io r t o 1877 th e Homeopathic p ro fe s s io n had been u sin g p e l l e t s s im ila r to LaFargue*s; i n t h a t y ear D r. G. H. P if f a r d p re s e n te d a paper b e fo re The New York Academy o f M edicine on "The Use o f C e rta in T r itu r a tio n s " i n which he claim ed to have compressed t r i t u r a t i o n s i n co n v en ient doses (5 3 ).

T his paper makes him th e f i r s t man t o p u b li-

4# c iz e th e m anufacture o f molded t a b l e t s .

A ccording to K e b le r, how ever.

D r. R obert M. P u l l e r i s th e o r i g in a to r o f t a b l e t t r i t u r a t e s and was " th e moving s p i r i t i n p la c in g th e in d u s tr y on a s u b s t a n t i a l b a s is " (53)e On March 9> 1878, a com plete a r t i c l e by Dr. F u l l e r ap p ea re d i n th e M edical Record i n which he d e s c rib e d i n d e t a i l h is in v e n tio n o f th e t a b l e t s and gave s p e c i f i c i n s t r u c t i o n s f o r t h e i r m an u fa ctu re.

In h i s

paper he l i s t e d th r e e ty p e s o f t a b l e t s which c o u ld b e made by m olding. S o lu b le t a b l e t s were d e s c rib e d as b eing made o f a m ix tu re o f a s o lu b le drug w ith l a c t o s e , made i n t o a p a s te w ith a lc o h o l o r w a te r , and m olded. T a b le t t r i t u r a t e s were d e fin e d as t r i t u r a t i o n s o f l a c to s e w ith m in e r a l, m e t a l l i c , o r v e g e ta b le su b sta n c e s made i n t o a p a s te w ith a lc o h o l o r w ater and molded.

T a b le t s a t u r a t e s were made by m olding a b lan k t a b l e t

o f la c to s e and s a tu r a tin g th e f in is h e d t a b l e t w ith a f l u i d e x t r a c t o r t i n c t u r e and a llo w in g i t to d ry . (6 ) A s p i r i t e d c o n tro v e rsy a ro s e betw een D r. F u l l e r and D r. P i f f a r d , each claim in g to be th e o r i g in a to r o f molded t a b l e t s .

K ebler a ffirm s

t h a t D r. F u l l e r i s th e t r u e o r ig in a to r and has j u s t c la im t o th e t i t l e of F a th e r o f t a b l e t t r i t u r a t e s .

I n 1882 Dr* F u l l e r p re s e n te d a n o th e r

p aper b e fo re th e New York M a te ria Medica S o c ie ty e n t i t l e d "A Convenient Method o f Dosage and A d m in is tra tio n .

The P ro cess o f Making T a b le ts

o f Simple and Compound Pow ders, In c lu d in g T r i t u r a t i o n s , Hypoderm ics, e t c ."

T his was an a m p lific a tio n o f th e work d e s c rib e d fo u r y e a rs

e a r l i e r , and i n t h i s a r t i c l e D r. F u lle r c la im s t o have experim ented from 1861 t o 1864, th r e e y e a rs b e fo re D r. P i f f a r d 's r e p o r t .

I n c o rre s ­

pondence w ith K ebler he e x p la in s t h a t he and D r. P i f f a r d had worked to g e th e r a f t e r he in v e n te d th e p ro c e ss and t h a t th e o r i g i n a l id e a was

5 h i s (53)«

I t i s s i g n i f ic a n t t h a t only t h i r t y days a f t e r D r. F u lle r * s

f i r s t r e p o r t , t a b l e t t r i t u r a t e s were o f f e r e d f o r s a l e by C asw ell, Hazard & Co. o f New Y ork, who a d v e r tis e d them a s b e in g made by F u lle r * s m ethod.

D r. H o ra tio N. F r a s e r , head o f t h a t f i m , s p r e s c r i p t io n

d ep artm en t, had been approached e a r l i e r by D r. F u l l e r , who e x p la in e d h is id e a s and method o f making th e t a b l e t s .

I n showing h is in v e n tio n

t o D r. F r a s e r , D r. F u l l e r made th e re q u e s t t h a t n e it h e r th e t a b l e t s n or th e equipment be p a te n te d , a s he w ished t o make th e p ro c e ss r e a d i l y a v a ila b le to a l l p r a c tic in g p h a rm a c ists.

O ther companies s t a r t e d mak­

in g t a b l e t t r i t u r a t e s a s soon a s i t was a p p a re n t t h a t th e y were b ein g a ccep ted by th e m ed ica l p ro fe s s io n ; i n May, 1888, a second m an u fa ctu rin g concern announced th e p ro d u c tio n o f " d o sim e tric t a b l e t t r i t u r a t e s ” and o th e r companies r a p id ly fo llo w ed s u i t . The o r i g i n a l i n t e n t o f D r. F u l l e r —t h a t o f having p r a c tic in g p h arm acists make t h e i r own t a b l e t s —was soon overshadowed by e x te n s iv e m anufacture o f t a b l e t t r i t u r a t e s by i n d u s t r i a l com panies, and w ith in th r e e y e a rs a f t e r t h e i r in tr o d u c tio n , t a b l e t t r i t u r a t e s were s ta n d a rd p ro d u c ts o f many f i r a s (2)» From 1886 t o th e e a r ly 1900*s a war o f words waged betw een th e p h arm acists and th e members o f th e m ed ical p ro f e s s io n o v er th e v a lu e o f t a b l e t s i n g e n e r a l and t a b l e t t r i t u r a t e s i n p a r t i c u l a r .

The

l i t e r a t u r e c o n ta in s many communications denouncing and d efending t a b l e t t r i t u r a t e s ( 9 ) , (1 0 ), ( l l ) , (2 0 ), (2 3 ) , (2 4 ) , (3 2 ).

The

o p p o s itio n claim ed th e y were o f u n c e rta in d o sag e, s u b je c t to d e t e r i ­ o r a t i o n , and to o a p t to cause c o n fu sio n s in c e th e y a l l looked a l i k e . (7) The a d v o cates claim ed t h a t th e y were e a s i l y made, c o n v e n ie n t, econom ical.

6 and more a c c u ra te i n dosage (9)*

The p u b l i c i t y , a d v erse as w e ll a s

f a v o r a b le , seemed to make th e t a b l e t t r i t u r a t e s more p o p u lar th a n e v er.

I n 1897> a Mr. R. D. S te u ffa c h e r w ro te:

“T ab let t r i t u r a t e s

were f i r s t in tro d u c e d and e x p lo ite d by such a campaign o f m isre p re ­ s e n ta tio n as i s w ith o u t p a r a l l e l i n th e h i s t o r y o f Pharmacy" (35)» P ro fe s s o r H a llb u rg , ov er a p e rio d o f f i v e y e a r s , b i t t e r l y a tta c k e d th e t a b l e t t r i t u r a t e s , say in g t h a t "None o f th e v a rio u s n o v e ltie s i n p h a rm acal sc ie n c e has le a p e d i n t o fa v o r a s q u ic k ly a s t a b l e t t r i t u r a t e s . th e su c ce ss th e y have met i s trem endous. ..a n d i f t h e i r use c o n tin u e s i t w i l l s e r io u s ly th r e a te n d isp e n sin g pharmacy" (2 3 ).

He f u r t h e r

s ta te d t h a t th e y were a v i o la t io n o f p h a rm a c e u tic a l, c h e m ic a l, and fundam ental p r i n c i p l e s , and claim ed t h a t th e y would le a d t o s e l f medi­ c a tio n ( 2 8 ) , (3 1 ). G ra d u ally th e m e r its of th e t a b l e t s began to outw eigh th e d i s ­ a d v a n ta g e s, and i n 1891 t h e i r s p e c if ic advantage f o r use a s hypodermic m ed ic a tio n was s t a te d by P a tc h , who w ro te:

"For hypodermic use***

t h i s form i s u ndoubtedly an advance o v er th e compressed p i l l o r com­ p re sse d t a b l e t t r i t u r a t e " (1 2 ).

C o n sid erab le co n fu sio n e x is te d i n

th e minds o f many people o v er th e d if f e r e n c e betw een t r u e t a b l e t t r i t u r a t e s and com pressed t a b l e t s , and fre q u e n tly a u th o rs w rote o f com pressed t a b l e t t r i t u r a t e s , alth o u g h a s e a rc h o f th e l i t e r a t u r e f a i l s t o r e v e a l any re p o rte d method f o r th e m anufacture by com pression. Compressed t a b l e t t r i t u r a t e s were made, b u t th e y d if f e r e d from th e t r u e a r t i c l e i n t h a t th e y c o n ta in e d in s o lu b le m a te r ia ls and were n o t used f o r i n j e c t i o n .

7 D isc u ssin g th e f u tu r e o f t a b l e t t r i t u r a t e s i n 1896, Dr» G. F» Payne s t a te d :

11The p h y sic ia n s have honored th e t a b l e t t r i t u r a t e s , and th e

p u b lic w i l l soon bow down and w orship them a ls o " (3 2 ).

T his prophecy

was f u l f i l l e d i n th e same y e a r when th e c i t y o f R a le ig h , i n N orth C a ro lin a , p a id th e l o c a l p h y sic ia n s f o r m ed icin es a d m in iste re d t o th e p o o r.

The d o c to rs p re s c rib e d t a b l e t t r i t u r a t e s to th e e x c lu sio n o f

o th e r ty p e s o f m ed ica tio n (3 3 ).

In 1901 P ro fe s s o r H allb u rg p r a is e d

t a b l e t t r i t u r a t e s a s la v i s h l y a s he had p re v io u s ly condemned them , s t a t i n g t h a t "hypodermic t a b l e t s .♦ • r e p r e s e n t th e o n ly le g itim a te u se o f compressed t a b l e t s , nam ely, a convenient f o r a o f dosage f o r th e extemporaneous p re p a ra tio n o f s o lu tio n s " .

I t i s to be n o ted t h a t here

a g ain th e method o f m anufacture was s t i l l c o n fu sed .

From t h i s tim e o n ,

a d i f f e r e n t i a t i o n began to be made between molded t a b l e t s and compressed t a b l e t s , th e term "hypodem ic" r e f e r r in g t o molded t a b l e t s e x c lu s iv e ly . I n 1908 a su g g e stio n was made t h a t a tte m p ts be s t a r t e d t o s ta n d a rd iz e and p ro v id e a g e n e r a lly a c c e p ta b le f o r a o f d ilu e n t f o r hypodermic t a b l e t s (47) b u t n o th in g f u r t h e r was r e p o rte d u n t i l 1925 when th e Bureau o f C hem istry s e t sta n d a rd s f o r th e degree o f a cc u ra c y o f hypodermic t a b l e t s , s t a t i n g t h a t " th e s e p re p a r a tio n s a re o f prim e im portance m e d ic in a lly " ( 6 3 ) . In 1931 a su rv e y of p ro fe s s io n a l pharm acies i n th e U nited S ta te s re v e a le d t h a t seven p r e s c r ip tio n s i n one hundred c a l le d f o r t a b l e t t r i t u r a t e s , and 28% o f th e p h arm acists made t h e i r own w h ile 58% r e l i e d on b ein g su p p lie d by com m ercial houses ( 6 5 ) .

I f such a su rv e y were

to be conducted to d a y , i t would undoubtedly r e v e a l t h a t a much sm a lle r p e rc en ta g e o f t a b l e t t r i t u r a t e s a re now made by p r a c tic in g p h a rm a c ists.

s th e m anufacture b e in g v i r t u a l l y m onopolized by com m ercial houses* Through p r iv a te com m unications, f i v e o f th e m ajor m an u fa c tu re rs o f hypodermic t a b l e t s were q u e stio n e d on methods

o f m anufacture* A ll f i v e

re p o r te d t h a t th e y were s t i l l m olding them by hand# W ith th e adv en t o f th e a n t i b i o t i c s a new ty p e o f t a b l e t has been in tro d u ced #

This t a b l e t i s e s s e n t i a l l y a hypodermic t a b l e t and i n

m ost in s ta n c e s i s made by molding#

I t c o n s is ts o f m ed ic a tio n in c o r ­

p o ra te d i n to a la c to s e b a se t o make a r a p id ly

s o lu b le t a b le t* The ta b ­

l e t i s p lac ed under th e tongue and allow ed to d i s s o l v e , o r i t may be d is s o lv e d i n m ilk , i n f a n t fe e d in g fo rm u la s, o r o th e r l i q u i d s .

D e sp ite

th e slow method o f m an u fa ctu re, t a b l e t t r i t u r a t e s o r s o lu b le t a b l e t s a re a p r e f e r r e d form o f m ed ica tio n i n many in s t a n c e s , and improved m ethods o f m anufacture would be o f g r e a t v a lu e to th e in d u stry *

THE PHARMACY OF HYPODERMIC TABLETS Hypodermic t a b l e t s d i f f e r from com pressed t a b l e t s n o t o n ly i n th e method by which th e y a re made, b u t a ls o i n th e n a tu re o f th e in g re ­ d ie n ts#

The form er c o n s is t sim ply o f two s u b s ta n c e s:

th e medicament

and a f i l l e r o f l a c t o s e , b o th o f which a r e r e a d i ly s o lu b le i n w ater t o form a c l e a r s o l u t io n .

The l a t t e r , w ith few e x c e p tio n s , a re

composed o f a number o f in g r e d ie n ts :

th e m e d ic a tio n , which may o r

may n o t be s o lu b le ; an ad h esiv e o f gum, s u g a r, o r s t a r c h ; a d i s i n t e ­ g r a t o r , which i s u s u a lly s ta r c h ; and a l u b r i c a n t , which i s alm ost always in so lu b le *

O bviously most com pressed t a b l e t s cannot be com­

p l e t e l y d is s o lv e d i n w ater and would n o t s a t i s f y th e f i r s t req u irem en t f o r a hypodermic t a b l e t *

9 W hile t a b l e t molds may d i f f e r i n s i z e and sh a p e , t h e i r b a s ic p r i n c i p le rem ains th e same* o f h a rd rubber*

A mold c o n s is ts o f two f l a t p l a t e s , u s u a lly

One p la te c o n ta in s from f i f t y to two hundred f i f t y

small h o le s o f uniform d iam ete r i n to which th e damp p a s te o f l a c to s e i s pressed*

The second p l a t e c o n ta in s c o rresp o n d in g p e r f o r a tio n s

h o ld in g pegs somewhat lo n g e r th a n th e th ic k n e s s o f th e f i r s t p la te * When th e f i l l e d p l a t e i s superim posed on th e p eg -co n ta in in g p l a t e , th e pegs l i f t th e f i n is h e d t a b l e t s o u t o f t h e i r m a tric e s and th e p ro c e ss o f rem oval i s accom plished*

Each peg su p p o rts a co rre sp o n d in g t a b l e t i n

a p o s itio n which fa v o rs ra p id d ry in g , and th e t a b l e t s a r e allow ed t o rem ain th u s u n t i l th e y a r e hard enough to endure h a n d lin g (6)* The p re s e n t t a b l e t s a re molded in s te a d o f com pressed b ecause la c to s e cannot no rm ally be compressed i n a t a b l e t m achine w ith o u t add­ in g to i t a lu b r ic a n t to p re v e n t s tic k in g to and b in d in g i n th e d ie s ; and s in c e th e known lu b r ic a n ts a re i n s o lu b le , th e y a re n o t a c c e p ta b le f o r u se i n hypodermic t a b l e t s * S u b stances s u i t a b l e f o r b a s e s o f hypodermic t a b l e t s a r e l i m i t e d , and few changes o r improvements o v er th e o r i g i n a l b a s e s have been made.

Aside from l a c t o s e , m ost su b sta n c e s e a r l i e r r e p o rte d a c c e p ta b le

a re now r e j e c t e d by th e m a n u fa c tu re rs .

I n 1891 Anderson l i s t e d , i n

a d d itio n to l a c t o s e , powdered su g a r and p r e c i p i t a t e d c h a lk a s d i lu ­ e n ts ( l l ) *

The fo llo w in g y e a r Healra su g g ested sodium c h lo r i d e , sodium

s u l f a t e , and sodium a c e ta te a s b a ses f o r hypodermic t a b l e t s (1 4 ).

In

a d is c u s s io n on com pressed t a b l e t s , McFerran s t a t e s t h a t a s a g e n e ra l r u l e th e co h esiv e p ro p e rty o f a m a te r ia l should be g r e a t e r th a n th e ad h esiv e p ro p e rty and t h a t in making t a b l e t t r i t u r a t e s l a c to s e a lo n e

10 i s u n s a tis f a c to r y because i t has no c o h e siv e n e ss and makes th e t a b l e t s to o b r i t t l e (1 6 ).

In a subsequent paper he su g g e sts u sin g w hite l i q u i d

p e tro la tu m a s a l u b r ic a n t and c la im s t h a t by p u ttin g th e f in is h e d ta b ­ l e t s i n to an ab so rb en t powder and a p p ly in g h e a t , most o f th e o i l w i l l d isa p p e a r ( I d ) .

A cacia has b een recommended as a b in d in g a g e n t f o r

hypodem ic t a b l e t s b u t i s n o t s a t i s f a c t o r y because i t te n d s to make th e t a b l e t s l e s s s o lu b le ( 2 ? ).

For t a b l e t s c o n ta in in g a c t iv e a l k a l o i d s ,

g ra n u la tio n s o f sugar o f m ilk w ith 10% cane su g a r a re s a id t o be b e s t (3 d ). Recommended lu b r ic a n t s a re ;

powdered t a l c , b o r ic a c i d , and a 2%

s o lu tio n o f w hite p e tro la tu m i n e th e r (3 6 ).

In 1909, B e rin g e r re p o r te d

u sin g sodium c h lo r id e and 10% b o r ic a c id a s l u b r ic a n t s f o r hypodermic t a b l e t s and advanced th e th e o ry t h a t th e r a p i d i t y o f d i s i n t e g r a t i o n v a r ie s d i r e c t l y w ith th e d if f e r e n c e o f s o l u b i l i t y o f th e in g r e d ie n ts (49) I n 1 9 U , Id n h a rt re p o rte d u sin g s t a r c h , sodium c h lo r id e , and e x t r a c t o f l i c o r i c e a s b a se s f o r t a b l e t t r i t u r a t e s (5 1 ).

M u ller su g g e ste d w hite

d e x tr in a s b o th a d ilu e n t and a d i s i n te g r a t o r (5 7 ).

In 1933, S h ro ff

re p o rte d t h a t p e c tin was a good b in d e r and a ls o a id e d i n d i s i n te g r a ­ t i o n (6 6 ), At th e p re s e n t tim e no s a t i s f a c t o r y form ula f o r compressed hypo­ dermic t a b l e t s h as been re p o rte d i n th e l i t e r a t u r e .

EXPERIMENTAL L acto se i s th e m ost g e n e r a lly a cc ep ted m a te r ia l f o r u se as a b a se f o r hypodermic t a b l e t s and i s th e i d e a l f i l l e r .

I t i s co m p letely and

q u ic k ly s o lu b le i n w a te r, n o n -to x ic , and in e x p e n siv e .

S ince no o th e r

11 m a te r ia l o f a s im ila r c o s t i s s u i t a b l e f o r use i n hypodermic t a b l e t s , th e ensuing work was c o n fin e d to t h i s one b a s e , and e f f o r t s were made to f e m u l a t e a s a t i s f a c t o r y g r a n u la tio n which would compress on a ta b ­ l e t m achine.

In fo rm u la tin g t h e g r a n u la tio n an a tte m p t was made t o

m a in ta in a s sim ple a form ula a s p o s s ib le . The f i r s t phase o f t h i s work was to f i n d a s u i t a b l e method f o r making a la c to s e g r a n u la tio n .

Samples o f l a c to s e were mixed w ith b o th

w ater and a lc o h o l and made in to a p a s te which was pushed th ro u g h a 20 mesh sc re e n and d r ie d .

The r e s u l t i n g g ra n u le s were examined f o r

h a rd n e ss , s o l u b i l i t y , and com pression.

In each c ase th e g ra n u le s were

s o f t and crum bled under v e ry l i t t l e p r e s s u r e .

Ihey d is s o lv e d r a p id ly

to make a c l e a r s o l u t io n , b u t when a tte m p ts were made to com press them on a sin g le -p u n c h t a b l e t m achine i t was found t h a t th e y would n o t com­ p re s s a t a l l .

B in d in g , c a p p in g , and s tic k in g o ccu rred a t once and th e

m achine vould n o t ru n .

O bviously, la c to s e must have an adh esiv e sub­

sta n c e added to i t to produce a g ra n u la tio n which w i l l com press s a t ­ is fa c to rily * I t was decided to make g ra n u la tio n s o f la c to s e u sin g th e more common gums and m ucilaginous su b sta n c es a s g r a n u la tin g a g en ts and to determ ine th e c o m p re s s ib ility o f th e r e s u l t i n g g r a n u la tio n s .

Accord­

in g ly , 400-gram p o rtio n s o f la c to s e were g ra n u la te d w ith th e fo llo w in g s o lu tio n s ; (a ) A 2%

s o lu tio n o f a c a c ia

(e ) A 1% s o lu tio n o f ag ar

(b ) A 2%

s o lu tio n o f tra g a c a n th

( f ) A 2% s o lu tio n o f chondrus

(c ) A 2%

s o lu tio n o f p e c tin

(g ) A 2% s o lu tio n o f gum k ara y a

(d ) A 2%

s o lu tio n o f g e l a t i n

(h ) A 2% m ucilage o f quince seed

12 A ll g ra n u la tio n s were made in th e same manner by m ixing th e s o lu tio n o f th e gum w ith th e powdered la c to s e by hand and pushing th e r e s u l t i n g mass th ro ugh a 20-mesh sc re e n .

The g r a n u la tio n was th e n d r ie d i n a i r

and a g a in pushed th ro u g h a 20-mesh s c re e n to in s u r e u n ifo rm ity *

The

d r ie d g ra n u la tio n s were examined f o r t h e i r p h y s ic a l p ro p e rtie s *

Uni­

fo rm ity o f s iz e was determ ined by exam ination under a m agnifying g la s s # The p e rc e n ta g e o f f in e powders was d eterm ined by s i f t i n g 20-gram sam ples th ro u g h a 40-mesh sc re e n and w eighing th e r e s id u e .

The h ard n e ss o f th e

g ra n u le s was t e s te d by c ru sh in g them a g a in s t a h ard s u r fa c e w ith a s p a t­ u l a , and i s o n ly r e l a t i v e .

The s o l u b i l i t y was t e s t e d by shaking one

gram o f th e g ra n u la tio n i n a t e s t tu b e c o n ta in in g 15 cc* o f w a te r, and th e c l a r i t y of th e s o lu tio n was m easured on a Dubosq c o lo r im e te r , u sin g d i s t i l l e d w a te r a s th e s ta n d a rd .

The p r o p e r tie s o f th e d i f f e r e n t g ran ­

u la tio n s a re shown i n Table 1. The c o m p re s s ib ility o f each g ra n u la tio n was t e s t e d on a S toke*s sin g le -p u n c h t a b l e t machine w ith f l a t s u rfa c e punches o f 3/2.6" diam­ e te r.

Compression was a ttem p ted a t th e r a t e o f 90 t a b l e t s a m inute.

The r e s u l t s o f a tte m p ts a t com pression a re shown i n Table 2#

13 Table 1 P r o p e r tie s o f L acto se G ra n u la tio n s Made W ith V arious Gums G ra n u la tio n

U niform ity of s iz e

% F in e s

H ardness

Time o f S o lu tio n

C la rity

Ease o f Flow

(a)

good

1756

+++

30 s e c .

c le a r

good

(b)

good

3056

+++

30 s e c .

c le a r

good

(c )

fa ir

4856

++

35 se c .

c le a r

fa ir

(d )

good

215%

+++

25 s e c .

fa ir

good

(e )

fa ir

3756

+

25 s e c .

c le a r

good

(f)

fa ir

2956

+

25 s e c .

hazy

good

(g )

fa ir

37%

+

40 se c .

hazy

good

00

fa ir

28%

35 s e c .

hazy

good

T able 2 C o m p re s sib ility o f L actose G ra n u la tio n s Shown i n Table 1 G ra n u la tio n (a) (b) (c) (d ) (e ) (f) (g) (h)

R e s u lts o f A ttem pts a t Compression Ran 30 seconds b e fo re s t i c k i n g . T a b le ts th e n s tu c k to punches, capped, caused b in d in g . G ra n u la tio n stu c k to punches im m ed iately . Machine would n o t ru n . G ra n u la tio n s tu c k to punches and caused se v ere b in d in g . Machine would n o t ru n . Ran 15 se co n d s, th e n g ra n u la tio n stu c k to punches and jammed m achine. G ra n u la tio n stu c k to punches im m ediately and machine would n o t r u n . G ra n u la tio n s tu c k t o punches and caused c ap p in g . Machine would n o t ru n . Severe s tic k in g a p p a re n t im m ediately. Machine would n o t ru n . Capping, s t i c k i n g , and b in d in g evidenced im m ediately. T a b le ts u n s a t is f a c to r y .

14 I t i s a p p a re n t t h a t none of th e above g ra n u la tio n s can b e com­ p re sse d by th em se lv e s.

The o n ly two g ra n u la tio n s which showed any

in d ic a tio n o f c o m p r e s s ib ility were th o se made w ith a c a c ia and w ith g e l­ a t i n a s th e g ra n u la tin g a g e n ts .

From Table 1 , i t can be seen t h a t th e s e

two g r a n u la tio n s were o f th e maximum h a rd n e ss and c o n ta in e d th e lo w e st p e rcen tag e of f i n e powder o f any o f th e g r a n u la tio n s made*

T his would

i n d ic a te t h a t th e c o m p r e s s ib ility o f a g r a n u la tio n may be in flu e n c e d by a number o f f a c t o r s , two o f which a re th e h ard n e ss and th e p e rc e n ta g e of fin e s . Both of th e s e p r o p e r tie s m ight c o n ce iv a b ly be im p arted to a granu ­ l a t i o n by th e r e l a t i v e amount o f a d h esiv e a g en t in c o rp o ra te d i n i t . I t was d ecid ed t o make g r a n u la tio n s o f la c to s e u sin g v a ry in g p e rc e n ta g e s o f a d h esiv e su b sta n c es so t h a t th e b e s t adh esiv e and th e optimum p e r­ cen tag e o f a d h esiv e f o r la c to s e g ra n u la tio n s m ight be found*

T h ir ty -

n in e d i f f e r e n t g ra n u la tio n s were made, u sin g d i f f e r e n t s tr e n g th s o lu ­ t io n s o f d i f f e r e n t gums and m ucilaginous su b s ta n c e s. th e same p ro ced u re was u sed :

I n ev ery in s ta n c e

th e powdered la c to s e was mixed by hand

w ith a s o lu tio n o f th e a d h e siv e , th e n pushed through a 20-mesh sc re e n and d r ie d o v e rn ig h t i n a i r .

The d r ie d g ra n u la tio n was a g a in s i f t e d

th rough a 20-mesh s c re e n to in s u re u n ifo rm ity , and com pression was attem p ted on a S to k e 1s sin g le -p u n c h t a b l e t m achine, u sin g a 3 / l 6 M d ie and ru n n in g a t th e r a t e o f 90 t a b l e t s a m in u te.

A fte r each a tte m p t a t

com pression, th e t a b l e t m achine was c le a n e d b e fo re a new g r a n u la tio n was ru n .

I t sh o u ld b e em phasized t h a t th e fundam ental id e a was n o t to f in d

a g r a n u la tio n which would ru n f r e e l y by i t s e l f , b u t r a t h e r to make com­ p a r a tiv e t e s t s on th e r e l a t i v e e ase o f com pression o f th e v a rio u s gran­ u l a t i o n s and d eterm in e which one would compress w ith a minimum of d i f f i c u l t y .

15 Hie r e s u l t s o f com pression a re shown i n th e fo llo w in g t a b l e : Table 3 C o m p re s sib ility o f L acto se G ra n u la tio n s Made W ith Gums G ra n u la tin g Agent

Amount Used . F or 300 unu

% Adhesive in G ra n u la tio n

C o m p re s s ib ility o f G ra n u la tio n

h% S o l. A cacia

60 c c .

0.80$

w o n 't compress - caps

6% S o l. A cacia

60 c c .

1.20$

b in d s & caps s e v e re ly

8% S o l. A cacia

50 c c .

1.33$

b in d s & caps

1096 Sol,, A cacia

45 cc*

1.5 0 $

b in d s , c a p s , s t i c k s

15$ Sol,» A cacia

40 cc •

2.00$

b in d s . c a p s , s t i c k s

20$ Sol,►A cacia

50 cc .

3.3 3 $

b in d s , c a p s , s t i c k s

25$ Sol,, A cacia

50 c c .

4.17$

b in d s , c a p s , s t i c k s

30$ Sol,►A cacia

50 c c .

5.00$

s t i c k s - w o n 't compress

35$ Sol,» A cacia

55 c c .

6.41$

s t i c k s — w o n 't compress

1$ Muc. T ragacanth

60 c c .

0.20$

b in d s & caps

2$ Muc. T ragacanth

60 c c .

0.40$

s t i c k s and b in d s

3$ Muc. T ragacanth

60 c c .

0.60$

s t i c k s and b in d s

4$ Muc. T ragacanth

50 c c .

0.66$

s t i c k s and b in d s

5$ Muc. T ragacanth

50 c c .

0.85$

s t i c k s and b in d s

1$ S o l. P e c tin

60 c c .

0.2 0 $

w o n 't com press — caps

2$ S o l. P e c tin

60 c c .

0.40$

b in d s and caps

3$ S o l. P e c tin

60 c c .

0 . 60 $

b in d s and caps

4$ S o l. P e c tin

60 c c .

0.80$

b in d s and cap s

5$ S o l. P e c tin

60 cc .

1.00$

b in d s and caps

1$ Muc. Chondrus

60 cc .

0.2 0 $

w o n 't com press - caps

2$ Muc. Chondrus

60 c c .

0.40$

w o n 't compress - caps

3$ Muc. Chondrus

60 c c .

0 . 60 $

w o n 't compress - caps

16 Table 3* - Continued C o m p re s s ib ility o f G ra n u la tio n

Amount Used For 300 gm.

$ Adhesive in G ra n u la tio n

1% Muc* Karaya

75 c c .

0,25%

caps & b in d s ; w o n 't ru n

2# Muc. Karaya

75 c c .

0,50%

caps & b in d s ; w o n 't ru n

3% Muc. Karaya

75 c c .

0.75%

caps & b in d s

4# Muc* Karaya

90 c c .

1 . 20 %

caps & b in d s

1% Muc. Quince Seed 75 c c .

0.25%

c ap s; w o n 't ru n

2% Muc. Quince Seed 75 c c .

0.50%

caps & s t i c k s

3% Muc. Quince Seed 75 c c .

0.75%

caps & s t i c k s

4$ Muc. Quince Seed 75 c c .

1 . 00 %

caps & s t i c k s

IS S o l. G e la tin

30 c c .

0 . 10 %

caps & s t i c k s

2% S o l. G e la tin

30 c c .

0 . 20 %

s t i c k s and b in d s

3% S o l. G e la tin

30 c c .

0 . 30 %

s t i c k s and b in d s

4% S o l. G e la tin

75 c c .

1 . 00 %

s t i c k s and b in d s

5% S o l. G e la tin

75 c c .

1.25%

s t i c k s and b in d s

0.25% S o l. Agar

75 c c .

0 . 06 %

cap s; w o n 't ru n

0.50% S o l. Agar

75 c c .

0 . 12 %

c ap s; w o n 't run

0,75% S o l. Agar

60 c c .

0.15%

caps and b in d s

1% S o l. Agar

75 c c .

0.25%

caps and b in d s

G ra n u la tin g Agent

I n com pressing th e g r a n u la tio n s made w ith a c a c ia , a d e f i n i t e p a tt e r n o f b e h a v io r o f th e g ra n u la tio n s was n o ticed *

The g r a n u la tio n

c o n ta in in g 0 *8$ ad h esiv e com pressed v e ry p o o rly and would n o t ru n on th e machine*

Ease o f com pression o f th e g ra n u la tio n s in c re a s e d a s th e

c o n te n t o f ad h esiv e m a te r ia l in c re a s e d u n t i l a 2% p ro p o rtio n o f th e

17 a d h esiv e i n th e g r a n u la tio n was re a c h e d .

W ith t h a t g r a n u la tio n , capp in g

and b in d in g were l e s s se v e re th a n i n any o th e r m ix tu re .

Then, a s th e

p e rc e n ta g e o f a d h e siv e i n th e g ra n u la tio n went s t i l l h ig h e r , capping d e creased b u t b in d in g and s tic k in g became more s e v e re . was th e same f o r a l l g r a n u la tio n s .

T his b e h a v io r

I t seems t h a t an optimum p e rc e n ta g e

o f 2# o f a m u cilag in o u s su b stan ce makes a l a c to s e g r a n u la tio n w hich i s most a c c e p ta b le t o com pression.

P e rc e n tag e s low er th a n 2% cau se

tr o u b le c h i e f l y by b in d in g and capping; p e rc e n ta g e s h ig h e r th a n 2% evidence s t i c k i n g .

I t i s to be n o ted t h a t th e approxim ate volume o f

l i q u i d needed t o make a p a s te o f th e p ro p er c o n s is te n c y f o r g ra n u la ­ t in g rem ains f a i r l y c o n s ta n t r e g a r d le s s o f th e amount o f a d h esiv e u n t i l v e ry t h ic k m ucilages a re u se d , when th e volume o f l i q u i d de­ c re a s e s . G ra n u la tio n s of la c to s e made w ith tra g a c a n th were a l l u n s a t is ­ fa c to ry .

With sm all p e rc e n ta g e s o f th e gum, e x c e ssiv e b in d in g and

capping o c c u rre d ; w ith h ig h e r p e rc e n ta g e s sev ere b in d in g and s t i c k i n g p rev en ted s a t i s f a c t o r y com pression.

L acto se g ra n u la tio n s made w ith

p e c tin were e q u a lly u n s a tis f a c to r y .

Severe b in d in g and capping

o c cu rred i n every in s ta n c e and com pression was n o t accom plished. Chondrus can be e lim in a te d as a p o s s ib le a d h e siv e .

G ra n u la tio n s

c o n ta in in g chondrus were d is c o lo re d and had a d i s t i n c t o d o r, which would be cause f o r r e j e c t i o n even i f th e g r a n u la tio n were c o m p re ssib le . L acto se g ra n u la tio n s made w ith b o th k aray a gum and quince seed m ucilage co u ld n o t be com pressed.

I n a l l c a s e s , se v e re b in d in g and

capping o c c u rre d r e g a r d le s s o f th e amount o f a d h esiv e c o n ta in e d i n th e g r a n u la tio n . G ra n u la tio n s o f la c to s e made w ith g e l a t i n fo llo w ed th e same

18 tr e n d a s th o s e made w ith a c a c ia ex ce p t t h a t th e y re q u ir e d l e s s o f th e s o lu tio n t o make a p a ste*

G ra n u la tio n s c o n ta in in g 0*1^ and 0*2% g e l­

a t i n com pressed, a lth o u g h s tic k in g and b in d in g were e v id en ced ; a s th e g e l a t i n c o n te n t o f th e g ra n u la tio n s in c r e a s e d , com pression became r e l ­ a t i v e l y more d i f f i c u l t .

A ll o f th e l a c to s e g ra n u la tio n s made w ith a g a r

were t o t a l l y u n s a t is f a c to r y as i n no c ase was com pression p o s s ib le . From th e r e s u l t s o b ta in e d th u s f a r , th e fo llo w in g c o n c lu sio n s were rea ch e d : (1 ) None o f th e gums o r m ucilaginous su b sta n c es t e s t e d w i l l y ie ld a g ra n u la tio n w ith la c to s e t h a t i s co m p ressib le w ith o u t th e a d d itio n o f a l u b r i c a n t . (2) G ra n u la tio n s o f la c to s e c o n ta in in g gums have more o f a tendency to cap and bind in th e d ie th a n to s t i c k t o th e s u rfa c e s o f th e punches. (3 ) Of a l l th e gums and m u cilaginous su b sta n c e s t r i e d , a c a c ia and g e l a t i n seem t o be th e on ly ad h esiv es showing prem ise o f making a p o s s ib le la c to s e g ra n u la tio n f o r hypodermic t a b l e t s , b u t n e it h e r o f th e s e i s e n t i r e l y s a tis f a c to r y * S ince su cro se has lo n g been used a s an a d h esiv e and b in d in g a g en t f o r p i l l s , i t was d e cid ed t o t e s t th e e f f ic ie n c y o f su cro se and o th e r su g ars a s g ra n u la tin g a g e n ts f o r l a c t o s e .

The procedure was th e same

a s t h a t used f o r making g ra n u la tio n s o f la c to s e w ith gums. omy* s sa k e , 100-gram sam ples o f la c to s e were u se d .

F or econ­

Compression o f th e

g r a n u la tio n s was a g ain a tte m p te d on a Stoke *s sin g le -p u n c h t a b l e t machine u sin g a 3/16" d ie and running a t t h e r a t e o f 90 t a b l e t s a min­ u te .

The r e s u l t s o f com pression a r e shown i n Table 4#

19 Table 4 C o m p re s s ib ility o f L ac to se G ra n u la tio n s Made W ith Sugars C o m p re s sib ility o f G ra n u la tio n

Amount Used For 100 gnu _

% Adhesive i n G ra n u la tio n

Z% Sol* Sucrose

15 c e .

0.30%

c a p s; s t i c k s t o punches

5$ S o l. Sucrose

15 c c .

0.75%

c a p s; s t i c k s to punches

10% S o l, S ucrose

20 c c .

2.00%

s t i c k s , b in d s , caps

20% S o l, Sucrose

20 c c .

4.00%

s t i c k s & b in d s

25% Sol* Sucrose

20 c c .

5.00%

s t i c k s & b in d s b a d ly

30% S o l. Sucrose

20 c c .

6.00%

s t i c k s & b in d s b a d ly

40% S o l. Sucrose

20 c c .

0.00%

s t i c k s ; w o n 't compress

50% S o l. Sucrose

20 c c .

10.00%

s t i c k s ; w o n 't com press

2% S o l. M altose

20 c c .

0.40%

s t i c k s & caps

5% S o l. M altose

20 c c .

1.00%

s t i c k s & caps

10% S o l. M altose

15 c c .

1.50%

s t i c k s , c a p s , b in d s

2Q% S o l. M altose

15 c c .

3.00%

s t i c k s s e v e re ly

25% S o l. M altose

15 c c .

3.75%

s t i c k s s e v e re ly

30% S o l. M altose

15 c c .

4.50%

s t i c k s ; w o n 't ru n

2% S o l. F ru c to se

20 c c .

0.40%

s t i c k s s e v e re ly

5% S o l. F ru c to se

20 c c .

1.00%

s t i c k s s e v e re ly

10% S o l. F ru c to se

25 c c .

2.50%

s t i c k s se v e re ly

20% S o l. F ru c to se

25 c c .

5.00%

s t i c k s & b in d s

25% S o l. F ru c to se

25 c c .

6.25%

s t i c k s & b in d s

2% S o l. L iq . G lucose

20 c c .

0.40%

ru n s w eH ; b in d s

5% S o l. Liq* G lucose

20 c c .

1.00%

s l i g h t b in d in g

10% S o l. L iq . G lucose

20 c c .

2.00%

b in d s & s t i c k s

15% S o l. L iq . Glucose

20 c c .

3.00%

s t i c k s , b in d s , caps

G ra n u la tin g Agent

20 Table 4* - Continued G ra n u la tin g Agent

Amount Used For 100 sm.

% A dhesive i n G ra n u la tio n

C o m p re s sib ility o f G ra n u la tio n

20% Sol» L iq , Glucose

20 c c .

4.00%

s t i c k s , b in d s , caps

25% Sol» L iq . G lucose

20 c c .

5.00%

s t i c k s s e v e re ly

2% S o l. Sorbose

20 c c .

0.40%

c ap s; w o n 't compress

5% S o l. Sorbose

20 c c .

1.00%

s t i c k s & b in d s

10% S o l. Sorbose

20 c c .

2.00%

s t i c k s s e v e re ly

20% S o l, Sorbose

20 c c .

4.00%

s t i c k s ; w o n 't run

25% S o l. Sorbose

20 c c .

5.00%

s t i c k s ; w o n 't ru n

A ll o f th e g ra n u la tio n s made w ith s u c ro s e , r e g a r d le s s o f th e amount p r e s e n t, com pressed o n ly w ith g r e a t d i f f ic u lt y »

S tic k in g t o th e

s u rfa c e s o f b o th punches was n o tic e a b le im m ediately upon s t a r t i n g com­ p r e s s io n , follow ed by s tic k in g i n th e d ies»

As th e su c ro se c o n te n t

became h ig h e r , th e s tic k in g became more pronounced u n t i l a c o n c e n tra ­ t i o n o f 0«00% su c ro se i n th e g ra n u la tio n was re a c h e d , a f t e r which th e machine would n o t run*

G ra n u la tio n s made w ith m alto se and w ith f ru c ­

to s e were e q u a lly u n s a tis f a c to ry » L acto se g ra n u la tio n s made w ith s o lu tio n s o f l iq u i d g lu co se o ffe re d d e f i n i t e p o s s i b i l i t i e s f o r com pression w ith a minimum o f d i f f i c u l t y . The g r a n u la tio n made w ith a 2# s o lu tio n o f l i q u i d glu co se compressed e a s i l y i n to t a b l e t s w ith o n ly a s l i g h t amount o f b in d in g and no appar­ en t s tic k in g .

G ra n u la tio n s made w ith 5% and 10% s o lu tio n s a ls o

com pressed, b u t th e b in d in g became more in te n s e a s th e g lu co se c o n te n t in c re a s e d .

A d d itio n a l g ra n u la tio n s u sin g a 1% s o lu tio n o f l i q u i d

g lu co se w ere made and com pression was a tte m p te d , b u t th e s e g ra n u la tio n s

21 were to o s o f t and powdered e a s i l y , cau sin g more b in d in g th a n o ccu rred w ith th e g ra n u la tio n made w ith a 2% s o lu tio n »

U n q u estio n ab ly , th e

la c to s e g r a n u la tio n made w ith a 2% s o lu tio n o f l iq u i d g lu co se i s th e b e s t th u s f a r . G ra n u la tio n s made w ith sorbose were o f no v a lu e a t a l l .

I n ev ery

c ase se v e re b in d in g and s tic k in g p rev e n ted s a t i s f a c t o r y com pression. From Table 4 , i t can be seen t h a t g ra n u la tio n s o f la c to s e made w ith su g a rs a s th e ad h esiv e a g e n ts a l l e x h ib it th e same ten d en cy t o cause tr o u b le i n com pression c h i e f l y by s tic k in g to th e s u rfa c e s o f th e p u n ch es, w h ile th o s e made w ith gums a s th e a d h esiv e a g e n ts te n d to h in d e r com pression by b in d in g i n th e d i e s . M ethyl c e l lu l o s e and c e llu lo s e d e riv a tiv e s have found a p p lic a tio n s i n p h a rm a c e u tic a l p r e p a r a tio n s , and i t was th o u g h t t h a t p o s s ib ly one o f th e s e compounds m ight make a s a t i s f a c t o r y g ra n u la tin g agent f o r l a c to s e .

Samples o f m ethyl c e l l u l o s e , h y droxyethyl c e l l u l o s e , and

carboxym ethyl c e llu lo s e were o b ta in e d from com m ercial m an u fa ctu rers and an in v e s ti g a t i o n was made o f t h e i r a p p l i c a b i l i t y t o th e problem . Samples o f sodium a lg i n a t e were t e s t e d a t th e same tim e .

One hundred

gram sam ples o f l a c to s e were g ra n u la te d w ith v a ry in g s tr e n g th s o lu ­ t io n s o f th e s e compounds, th e procedure b ein g th e same as t h a t p re v io u s ly u sed :

th e powdered la c to s e was made i n to a p a s te w ith

s u f f i c i e n t o f th e ad h esiv e i n aqueous s o l u t io n , pushed by hand th ro u g h a 20-mesh s c re e n , d r i e d , and re s ie v e d th ro u g h a 20-mesh s c re e n .

Com pression was a g a in attem p ted on th e Stoke *s s in g le —punch

m achine a t th e r a t e o f 90 t a b l e t s a m in u te. i n Table 5.

The r e s u l t s a re shown

22 Table 5 C o m p re s s ib ility o f L acto se G ra n u la tio n s Made W ith C e llu lo se D e riv a tiv e s and Sodium A lg in a te G ra n u la tin g Agent ___

Amount Used For 100 sm.

% Adhesive in G ra n u la tio n

X% S o l. M ethyl Cel­ lu lo s e 9 15 CPS

20 c c .

0.20%

c ap s; s t i c k s s l i g h t l y

1% Sol* M ethyl C el­ l u l o s e , 100 CPS

20 c c .

0.20%

caps & b in d s

1% S o l. M ethyl Cel­ l u lo s e , 400 CPS

20 c c .

0.20%

caps & b in d s s l i g h t l y

1% S o l. M ethyl Cel­ l u lo s e , 1500 CPS

20 c c .

0.20%

ru n s w e ll; s l i g h t s t i c k ! :

1% S o l. M ethyl Cel­ l u l o s e , 4000 CPS

20 c c .

0.20%

c ap s & b in d s b a d ly

1$ S o l. Hydroxy­ e th y l C e llu lo se

20 c c .

0.20%

b in d s ; wonH com press

2% S o l. Hydroxy­ e th y l C e llu lo s e

20 c c .

0.20%

b in d s ; w o n 't com press

1$ S o l. Carboxy­ m ethyl C e llu lo se

20 c c .

0.20%

b in d s , c a p s , s t i c k s

2% S o l. Carboxy­ m ethyl C e llu lo se

20 c c .

0.20%

b in d s , c a p s , s t i c k s

0.25% S o l. Sodium A lg in ate

20 c c .

0.05%

s t i c k s & b in d s

0*50% S o l. Sodium A lg in ate

20 c c .

0.10%

s t i c k s & b in d s

1.00% S o l. Sodium A lg in ate

20 c c .

0.20%

s t i c k s , b in d s , caps

2.00% S o l. Sodium A lg in ate

20 c c .

0.40%

caps & b in d s b a d ly

C o m p re s s ib ility o f G ra n u la tio n

23 The la c to s e g r a n u la tio n s made w ith m eth y l c e l lu l o s e seemed t o v a ry i n c o m p r e s s ib ility a cc o rd in g to th e ty p e o f m ethyl c e l lu l o s e u se d . G ra n u la tio n s made w ith 1% s o lu tio n s o f th e 1 5 , 100, and 400 CPS a l l evidenced s l i g h t capping and b in d in g b u t were c o m p re ssib le .

The g ran ­

u l a t i o n made w ith 1500 CPS com pressed v e ry w e ll w ith o n ly s l i g h t s t i c k ­ in g t o th e punches, but i n a l l c a s e s t h e t a b l e t s were n o t s a t i s f a c t o r y from a s o l u b i l i t y s ta n d p o in t.

They were v e ry slow to d i s i n t e g r a t e ,

r e q u ir in g an a v erag e o f th r e e m in u tes to b re a k u p , and sm a ll p a r t i c l e s o f th e m ethyl c e llu lo s e rem ained d is p e rs e d i n th e l i q u i d w ith o u t d is ­ s o lv in g f o r some tim e a f t e r d i s i n t e g r a t i o n .

A ll o f th e g r a n u la tio n s

made w ith sodium a lg in a te were u n s a t is f a c to r y .

None com pressed w e ll

and a l l evidenced s tic k in g and b in d in g a s soon as com pression was a ttem p ted . None o f th e s e su b sta n c es i s s a t i s f a c t o r y f o r use i n hypodermic t a b l e t s because of t h e i r slow s o l u b i l i t y .

Although m ethyl c e llu lo s e

1500 CPS does o f f e r p o s s i b i l i t i e s a s a g ra n u la tin g a g e n t f o r com pressed t a b l e t s , i t cannot be used where ra p id s o l u b i l i t y i s needed. Of a H th e su b sta n c e s t r i e d , a s o l u t io n o f l iq u i d g lu co se makes th e m ost s a t i s f a c t o r y la c to s e g r a n u la tio n .

P rev io u s work had in d ic a te d

t h a t i t was th e m ost a c c e p ta b le g ra n u la tin g a g en t f o r hypodermic ta b ­ l e t s (8 1 ) and t h i s i s now confirm ed.

A d d itio n a l g ra n u la tio n s o f

la c to s e w ith v a ry in g amounts o f l i q u i d g lu co se were made and t e s t e d f o r c o m p r e s s ib ility i n an e f f o r t to f in d th e optimum amount o f ad h esiv e and th e b e s t c o n c e n tra tio n o f s o lu tio n f o r making a g r a n u la tio n . G ra n u la tio n and com pression were b o th accom plished i n th e same manner as th e p rev io u s e x p e rim e n ts.

R e s u lts a r e shown i n T able 6 .

24 Table 6 C o m p re s sib ility o f L acto se G ra n u la tio n s Hade W ith L iq u id Glucose Amount Used F or 100 gnu

G ra n u la tin g Aaent

% L iq . Glucose i n G ra n u la tio n

C o m p re s s ib ility o f G ra n u la tio n

2$ S o l. L iq . G lucose

20 c c .

0.40%

ru n s w e ll; b in d s

1 .5 $ S o l. L iq . G lucose

20 c c .

0.30%

b in d s & s t i c k s

1 .0 $ S o l. L iq . Glucose

20 c c .

0 . 20 %

b in d s , s t i c k s , caps

0.5 $ S o l. L iq . Glucose

20 c c .

0 . 10 %

c a p s; w o n 't ru n

From t h i s t a b l e i t can b e seen t h a t a 2% s o lu tio n o f l i q u i d g lu ­ cose i s th e g ra n u la tin g a g en t o f choice f o r l a c t o s e .

I t makes a

g ra n u la tio n c o n ta in in g th e minimum amount o f ad h esiv e t o form g ra n u le s which com press w ith th e l e a s t d i f f i c u l t y .

In a l l f u t u r e work, a 2%

s o lu tio n o f l i q u i d g lu co se i n th e r a t i o o f 20 c c . f o r 100 grams o f la c to s e w i l l be used to make th e s ta n d a rd g r a n u la tio n ; t h i s g r a n u la tio n w i l l be c o n sid e re d th e b e s t g ra n u la tio n f o r hypodermic t a b l e t s t o be made b y com pression on a t a b l e t m achine. Hypodermic t a b l e t s a re v e ry s m a ll, seldom w eighing over one g r a in .

I n com pressing them on a t a b l e t m achine, a s m a lle r s iz e g ran ­

u l a t i o n must o f n e c e s s ity be u sed th a n i s norm ally used f o r o th e r compressed t a b l e t s .

The n e x t phase o f t h i s in v e s tig a tio n was t o

determ ine th e s iz e o f g ra n u le m ost a c c e p ta b le f o r making hypodermic t a b l e t s and what e f f e c t th e g ran u le s iz e has on th e e ase o f com pression o f a g r a n u la tio n . G ra n u la tio n s o f l a c to s e were made i n th e u s u a l manner w ith a 2% s o lu tio n o f l i q u i d g lu co se and pushed by hand th ro u g h sc re e n s o f

25 d i f f e r e n t mesh s i z e s v ary in g from 16 — mesh t o 100-m esh.

The g r a n u la tio n s

were d r ie d and a g a in pushed th ro u g h th e same sc re e n to in s u r e u n ifo rm ity . Compression was attem p ted on t h e Stoke*s sin g le -p u n c h t a b l e t m achine, th e same a d ju stm e n ts f o r w eight and p re s s u re b eing k e p t f o r each g ran ­ u la tio n .

I t was found t h a t th e l a r g e r mesh g r a n u la tio n s com pressed w ith

l e s s d i f f i c u l t y th a n th e s m a lle r , th e degree o f b in d in g and capping in c re a s in g a s th e g ra n u le s i z e d e c re a se d .

T h ir ty - e ig h t a d d it i o n a l g ran ­

u la tio n s w ith v a ry in g ty p e s and amounts o f g ra n u la tin g a g e n ts were made, and com pression was a ttem p ted on th e same m achine i n an e f f o r t t o e s t a b l is h a d e f i n i t e r e l a t i o n s h i p betw een th e g ra n u le s i z e and th e e ase o f com pression.

Again i t was found t h a t ease o f com pression

d ecreased a s t h e g ra n u le s iz e became s m a lle r.

The r e s u l t s a re shown

i n Table 7 . An exam ination o f th e r e s u l t s in d ic a te d i n th e fo llo w in g ta b le shows t h a t th e r e i s a d e f i n i t e r e l a t i o n s h i p between t h e c o m p re s s ib ility o f a g r a n u la tio n and th e g ra n u le s i z e .

As th e s iz e o f th e g ra n u le s

becomes s m a lle r , th e g r a n u la tio n becomes more d i f f i c u l t to compress w ith o u t a l u b r i c a n t . Table 7»

This i s evidenced i n ev ery c ase shown i n

A ll g r a n u la tio n s , even th o se which compressed p o o rly ,

evidenced more c o m p re s s ib ility i n a 20 -mesh s iz e th a n i n any s m a lle r s iz e .

Ihe 20 -mesh g r a n u la tio n was found to be more s a t i s f a c t o r y th a n

th e 16 -mesh b ecause th e t a b l e t s produced were more uniform i n s iz e and w eig h t. To a s c e r t a i n th e optimum s iz e g ra n u la tio n f o r hypodermic t a b l e t s from th e sta n d p o in t o f needing th e l e a s t amount o f a l u b r i c a n t , a d d itio n a l ex p erim en ts were ru n u sin g su b sta n c e s known to be good

26 Table 7 C o m p re s sib ility o f D if f e r e n t Mesh S iz e L acto se G ra n u la tio n s G ra n u la tio n

Mesh S iz e

L acto se & 1% S o l. G lucose

C o m p re s s ib ility

30

caps & b in d s

«

« II

It

n

40

caps & b in d s b a d ly

«

it Il

II

n

60

b in d s 5 w o n 't ru n

n

it It

11

»

80

b in d s ; w o n 't ru n

M

n II

It

n

100

b in d s ; w o n 't ru n

L acto se & 2% S o l. Glucose

16

caps & b in d s

«

n Il

II

h

20

b in d s s l i g h t l y

«

it It

It

»

30

caps & b in d s

«

h

II

11

«

40

caps & b in d s b a d ly

»

it Il

It

n

60

caps & b in d s b a d ly

h

ii It

It

ti

80

b in d s; w o n 't ru n

«

it 11

II

it

100

b in d s ; w o n 't ru n

L acto se & 5% S o l. Glucose

30

c a p s , s t i c k s , b in d s

n

ii »

it

«

40

s t i c k s & b in d s b a d ly

ii

ii it

it

it

60

b in d s ; w o n 't ru n

it

h

it

«

ii

80

b in d s ; w o n 't ru n

30

cap s & b in d s b a d ly

L acto se & 10% Sol,. Glucose n

it 11

II

it

40

s t i c k s & b in d s b a d ly

it

it II

11

«

60

w o n 't ru n

«

ii II

11

n

80

w o n 't ru n

30

s t i c k s & b in d s

40

s t i c k s & b in d s b a d ly

L acto se & 20% S ol . Glucose »

it it

it

ii

27 Table 7» - Continued

Mesh S ize

G ra n u la tio n

L acto se & 7Ù% Sol* Glucose ii

ii

«

n

»

L acto se & 4% Sol* A cacia

Compre s s i b i l i t y

60

wonft ru n

80

w o n 't ru n

40

caps & b in d s b a d ly

n

n

n

»

n

60

w o n 't ru n

n

n

n

n

n

80

w o n 't ru n

40

caps & b in d s b a d ly

L actose & 10$ Sol* A cacia n

ii

n

»

n

60

w o n 't ru n

n

n

n

n

n

80

w o n 't ru n

40

w o n 't ru n

60

w o n 't ru n

40

s t i c k s , b in d s , caps

L actose & 20$ Sol* A cacia n

n

n

n

n

L acto se & 2$ Sol* G e la tin «

n

n

n

n

60

w o n 't ru n

n

n

n

ii

n

80

w on't run

L acto se & 1$ Sol* M ethyl C e llu lo se 15 CPS

40

caps & b in d s

L acto se & 1$ Sol* M ethyl C e llu lo s e 15 CPS

60

b in d s b a d ly

L acto se & 1$ Sol* M ethyl C e llu lo se 15 CPS

80

w o n 't run

L acto se & 1$ Sol* M ethyl C e llu lo s e 1500 CPS

40

caps & b in d s

L actose & 1$ Sol* M ethyl C e llu lo se 1500 CPS

60

b in d s b a d ly

L actose & 1$ Sol* M ethyl C e llu lo se 1500 CPS

80

w on't ru n

28 t a b l e t lu b r ic a n t s and d e te m in in g th e minimum amount o f each needed f o r s a t i s f a c t o r y com pression o f each s iz e g r a n u la tio n .

Samples o f th e

sta n d a rd g r a n u la tio n were p re p a re d ran g in g i n g ra n u le s i z e from l 6 -mesh to 100 -mesh.

Ihe g r a n u la tio n s were th e n mixed w ith v a ry in g p e rc e n ta g e s

o f t a l c and o f magnesium s t e a r a t e and tum bled i n a c lo s e d c o n ta in e r u n t i l u n ifo rm ly m ixed.

In c re a s in g amounts o f th e lu b r ic a n t were added

t o each g ra n u la tio n u n t i l s a t i s f a c t o r y com pression was a c h ie v e d , th u s determ in ing th e minimum amount o f each lu b r ic a n t needed f o r s a t i s f a c t o r y com pression o f each s i z e g r a n u la tio n .

The r e s u l t s a re shown i n T ables

8 and 9 .

Table 8 L acto se G ra n u la tio n s W ith Talc As A L u b ric an t

Mesh S ize

1% Talc

2% Talc

3% T alc

k% T alc

16 mesh

b in d s

b in d s

ru n s OK

—

—

20 mesh

b in d s

b in d s

ru n s OK

—

—

30 mesh

b in d s

b in d s

b in d s

b in d s

ru n s OK

40 mesh

b in d s

b in d s

b in d s

b in d s

b in d s

60 mesh

b in d s

b in d s

b in d s

b in d s

b in d s

80 mesh

b in d s

b in d s

b in d s

b in d s

b in d s

100 mesh

b in d s

b in d s

b in d s

b in d s

b in d s

5% T alc

29 Table 9 L acto se G ra n u la tio n s W ith Magnesium S te a r a te As A L u b ric an t

Mesh S iz e

X% Mag* S te a r a te

2$ Mag* S te a r a te

3% Mag. S te a r a te

k% Mag* S te a r a te

—

5% Mag* S te a r a te —

16 mesh

b in d s

ru n s OK

20 mesh

b in d s

ru n s OK

30 mesh

b in d s

b in d s

b in d s

b in d s

ru n s OK

40 mesh

b in d s

b in d s

b in d s

b in d s

b in d s

60 mesh

b in d s

b in d s

b in d s

b in d s

b in d s

00 mesh

b in d s

b in d s

b in d s

b in d s

b in d s

100 mesh

b in d s

b in d s

b in d s

b in d s

b in d s

—

—

These r e s u l t s confirm t h e f a c t t h a t th e amount o f lu b r ic a n t needed f o r a g r a n u la tio n in c r e a s e s a s th e g ra n u le s iz e d e c re a s e s .

In th e

above c a s e s no more th a n 5% lu b r ic a n t was added to any g r a n u la tio n , 5% b e in g c o n sid e re d th e maximum amount o f lu b r ic a n t a llo w ab le f o r a good g r a n u la tio n .

With b o th l u b r i c a n t s , g r a n u la tio n s s m a lle r th a n

3 0 -mesh would n o t compress s a t i s f a c t o r i l y w ith 5 $ o f t h e l u b r ic a n t ,

w h ile t h e 16 -mesh and 20 -mesh g ra n u le s com pressed q u ite w e ll w ith 3>% t a l c and w ith 2% magnesium s t e a r a t e .

The 20-mesh g r a n u la tio n was p re ­

f e r r e d o v er t h e 16 -mesh g ra n u la tio n because i t had a b e t t e r flow and made p o s s ib le th e com pression o f more uniform t a b l e t s a s f a r a s s iz e and w eight were concerned.

On th e b a s i s o f th e s e f in d in g s , a 20-mesh

g r a n u la tio n o f la c to s e was a cc e p te d a s th e one re q u ir in g l e a s t l u b r i ­ c a tio n f o r com pression*

30 S in ce th e p e rc e n ta g e o f f i n e powders i n a g r a n u la tio n a f f e c t s i t s c o m p r e s s ib ility , a tte m p ts were made to d e te rm in e how b e s t t o make g r a n u la tio n s c o n ta in in g th e l e a s t amount o f f in e powder.

Three d i f f e r e n t

methods o f g ra n u la tin g and t h r e e d i f f e r e n t m ethods of d ry in g were com­ p a re d .

G ra n u la tio n s were made by pushing th e wet mass th ro u g h a sc re e n

by hand; by use o f t h e C olton g r a n u la to r , which au to m atic a l l y pushes th e wet mass a g a in s t and th ro u g h a c y li n d r ic a l sc re e n by th e use o f r o t a t ­ in g m e ta l b la d e s ; and by use o f th e F i t z p a t r i c k com m inutor, which pushes th e wet mass th ro u g h an arch ed sc re e n by means o f re v o lv in g k n iv e s . p o r tio n s :

The g ra n u la tio n s made by each method were d iv id e d i n t o th r e e one p o r tio n was d r ie d i n a i r a t room te m p e ra tu re , a n o th e r

was d r ie d in a h o t - a i r oven a t 140 deg rees F . , and th e t h i r d was d rie d under i n f r a - r e d lam ps.

Bach g ra n u la tio n was th e n s i f t e d th ro u g h a

20 -mesh sc re e n over a 60 -mesh sc re e n and any f i n e powders p a ssin g

th ro u g h th e 60 -mesh sc re e n were weighed.

Both th e s i f t e d and th e

u n s if te d g ra n u la tio n s were compressed on th e sin g le -p u n c h t a b l e t m achine.

The r e s u l t s a re shown i n Table 10*

31 Table 10 L acto se G ra n u la tio n s Made and D ried By D if fe re n t Methods Method o f G ra n u la tin g

Method o f D rying

Appearance o f G ra n u la tio n

Hand

a ir

good - uniform

8%

b in d s

b in d s

Hand

oven

good - powdery

12 %

b in d s

b in d s

Hand

in fra -re d

good - uniform

9%

b in d s

b in d s

C olton

a ir

powdery

15%

caps

caps

C olton

oven

powdery

20 %

caps and b in d s

C olton

in fra -re d

powdery

1A%

caps and b in d s

F itz p a tric k

a ir

excess powder

37%

b in d s s e v e re ly

F itz p a tric k

oven

excess powder

48%

b in d s s e v e re ly

F i tz p a tr ic k

in fra -re d

excess powder

35%

b in d s s e v e re ly

i F ine Powders

Compre s s ib i l i t y S i f t e d U n sifte d

From th e r e s u l t s shown above, i t can be seen t h a t th e method used i n making a g ra n u la tio n d e f i n i t e l y d e te rm in e s th e p h y s ic a l p r o p e r tie s o f t h a t g ra n u la tio n *

G ra n u la tio n s pushed th ro u g h a sc re e n by hand w i l l

c o n ta in a sm a lle r p e rc en ta g e o f f in e powders and an e q u a lly h ig h e r p ercen tag e o f uniform g ra n u le s th a n w i l l th o se made by m achinery and g ra n u la te d w ith more fo rce* g r a n u la tio n .

The method o f d ry in g a ls o a f f e c t s th e

Those g ra n u la tio n s d rie d i n a i r a t room te m p e ra tu re and

th e ones d r ie d under i n f r a - r e d lamps a re more uniform and c o n ta in l e s s f i n e powders th a n th o s e s u b je c te d t o d ry in g a t h ig h e r tem p era tu re s* I n a d d itio n , i t i s t o be n o tic e d t h a t th e c o m p r e s s ib ility o f t h e s i f t e d g ra n u la tio n s does n o t m a te r ia lly d i f f e r from t h a t o f th e u n s if te d ones* Thus, alth o u g h th e p erc en ta g e o f f in e s i n a g ra n u la tio n may a f f e c t i t s

32 c o m p r e s s ib ility t o some e x te n t, t h e d i f f i c u l t y cannot b e rem edied e n t i r e l y by s i f t i n g o u t th e f i n e s . Slugging o r precom pression i s u sed i n in d u s tr y as a means o f p re ­ p a rin g d i f f i c u l t g ra n u la tio n s f o r com pression.

In t h i s p ro ce ss th e

in g r e d ie n ts o f a g r a n u la tio n a re mixed d ry and com pressed on a t a b l e t machine i n to l a r g e s lu g s , w ith no a t t e n t i o n b ein g p a id to s i z e , w e ig h t, o r appearance o f th e f in is h e d t a b l e t s .

These t a b l e t s a re th e n broken

up and pushed th ro u g h a sc re e n o f th e d e s ir e d mesh s iz e to make a uniform g r a n u la tio n .

A ttem pts were made to com press two pounds o f la c to s e i n

t h i s m anner, u sin g 7/16*' punches.

The r e s u l t was a com plete f a i l u r e .

The powdered l a c to s e would n o t flo w ev en ly in to th e d i e , and th e machine stu c k and would n o t ru n .

A d d itio n a l a tte m p ts were made t o com press th e

powder on a r o t a r y t a b l e t m achine b u t a g ain com pression could n o t be accom plished.

T his method was abandoned a s b ein g o f no v a lu e i n p re ­

p a rin g a l a c to s e g r a n u la tio n . Trying a m o d ified form of slu g g in g , sam ples o f th e sta n d a rd l a c ­ to s e g r a n u la tio n were com pressed i n to t a b l e t s which were th e n broken up and pushed through a 20-mesh s c re e n .

A ttem pts to compress t h i s

g r a n u la tio n r e s u l te d i n f a i l u r e also* I t was concluded t h a t th e la c to s e g ra n u la tio n must have an added lu b r ic a n t to f a c i l i t a t e com pression. and m ust form a c l e a r s o lu tio n .

The lu b r ic a n t must be s o lu b le

No s a t i s f a c t o r y so lu b le lu b r ic a n t has

been re p o r te d i n th e l i t e r a t u r e , so i t was decid ed t o t r y v a rio u s sub­ sta n c e s i n v a ry in g p ro p o rtio n s in th e hope o f fin d in g some compound which m ight have a s p e c if ic lu b r ic a tin g a c tio n f o r th e l a c to s e granu­ la tio n *

33 A number o f s o lu b le s a l t s were chosen f o r th e i n i t i a l ex p erim en ts i n t h i s phase o f th e i n v e s ti g a t i o n .

I n every in s ta n c e th e same p ro ­

ced u re was used:

th e s a l t was f i n e l y powdered and s i f t e d th ro u g h a

40-mesh sc re e n .

One hundred-gram sam ples o f th e s ta n d a rd g ra n u la tio n

were th e n mixed w ith amounts v a ry in g from 1% t o 5% o f th e powdered s a l t and tum bled i n a c lo s e d c o n ta in e r u n t i l u n ifo rm ly mixed*

Com­

p re s s io n was a ttem p ted on a S to k e 1s sin g le -p u n c h t a b l e t machine u sin g 3/16" punches and running a t th e r a t e o f 90 t a b l e t s a m in u te.

If a

su b stan ce d id n o t show evidence o f l u b r ic a tin g p r o p e r tie s w ith a t l e a s t 5% o f i t i n th e g r a n u la tio n , i t was n o t c o n sid e re d f o r f u r t h e r i n v e s t i ­ g a tio n .

The r e s u l t s a re shown i n Table H *

From t h i s t a b l e , i t can be seen t h a t v e ry few o f t h e s a l t s t r i e d have any l u b r ic a tin g a c tio n on th e la c to s e g ra n u la tio n . o ffe re d evidence o f lu b r ic a t i o n :

Four compounds

sodium b e n z o a te , sodium o l e a t e ,

sodium l a u r y l s u l f a t e , and sodium s t e a r a t e .

The t a b l e t s made w ith

sodium b e n zo ate as a l u b r ic a n t were th e most s a t i s f a c t o r y , b u t had a slow d is i n te g r a t i o n tim e (2 m in u te s).

Sodium o le a te and sodium l a u r y l

s u l f a t e i n 2% p ro p o rtio n s and sodium s t e a r a t e i n 1% p ro p o rtio n s were s a t i s f a c t o r y lu b r ic a n ts b u t th e t a b l e t s r e s u l ti n g were u n s a tis f a c to r y b o th from th e s ta n d p o in t o f d i s in te g r a tio n and c l a r i t y o f th e r e s u l t i n g s o lu tio n s .

Those made w ith sodium o le a te and sodium s t e a r a t e gave

cloudy s o lu tio n s and th o s e c o n ta in in g sodium l a u r y l s u l f a t e y ie ld e d foamy s o l u t io n s , none o f which would be a c c e p ta b le i n hypodermic ta b le ts *

Compressibility

of the Standard Granulation

With Soluble

Salts As L ubricants

34

35

flj ,0 m

%

"8

I

I

•8

3

I I

cr\

rO

to ti

35 O

•ti

+1

•H 43

to

to X»

bd O

•H 43

to

ti

to ti

•H 43

n 'S ti

•H 43

« •g q

•H 43

|

to 't i ti •H 43

to

Sto

'ti ti

to

43

I to

!

3

rO

1

xa

(0

to

3

^3

1

I

to ti ti

to

to

«

3

3

3

»rl 43

to

to ti

ti

ti

i i!

!

m

xf ti •H

'ti

43

43

to

ai

3

•g q •H 43

3

3

x»

43

to

•H 43

43 to

s-

.0

rO

^3

x>

,0

to 3

J3

Xi

to

*s

3

43

3

I

i43

o

43

1 £

» 3

x>

3

x>

1

to

ti ti

•H 43

to ti ti *rl 43

-S ti •>

s,

ti

to ti ti

to ti ti

*H X

X

to ti ti

•H

X

cd o

1

Table 11» » Continued

5 to

to

xa jd

m

to

to

8

0

H to C5 x

1

O,

•H C/2

1

O ti

î

en

§

%

en

••g

"8

1

to

0>

O X 0 (ti •H co cd

1

?en ai

1

en

X cd X CL,

en

, 18%, and 20% Carbo­ wax 4000 i n 2% l i q u i d glu co se and com pression a ttem p ted i n th e u s u a l

46 m anner.

G ra n u la tio n s made w ith 12% and 15% s o lu tio n s compressed q u ite

w e ll b u t s t i l l evidenced s l i g h t s tic k in g ; th o s e made w ith 18% and 20% s o lu tio n s evidenced d e f i n i t e s tic k in g and were not c o m p re ssib le .

T his

would in d ic a te t h a t Carbowax 4000, when in c o rp o ra te d i n th e g r a n u la tio n i n a s o l u t io n , o f f e r s th e b e s t l u b r ic a t i n g a c tio n when p re s e n t i n th e amount o f 2% o f th e w eig h t o f th e g r a n u la tio n .

This l u b r ic a t i n g a c t i o n ,

however, i s n o t p e r f e c t a s th e f in is h e d t a b l e t s s t i l l show s ig n s o f s lig h t s tic k in g . I t was n e x t decided to t r y th e l u b r ic a tin g a c tio n o f Carbowax 4000 when added to th e g r a n u la tio n i n d ry powdered form .

Carbowax 1500 was

d isc a rd e d b ecause i t i s to o s o f t to be powdered by o rd in a ry means. Samples o f Carbowax 4000 were pushed by hand th ro u g h a 30-mesh sc re e n and v a ry in g p e rc e n ta g e s o f th e powder were added t o sam ples o f th e sta n d a rd g ra n u la tio n and mixed by tum bling in a c lo s e d c o n ta in e r . Compression was a ttem p ted on th e Stoke*s sin g le-p u n c h t a b l e t machine u sin g 3 / l 6 n punches and ru n n in g a t th e r a t e o f 90 t a b l e t s a m inute. The r e s u l t s a re shown below . Table 18 C o m p re s sib ility o f G ra n u la tio n s L u b ric a te d W ith Powdered Carbowax 4000 % Carbowax i n G ra n u la tio n

C o m p re s sib ility o f G ra n u la tio n

1 %

b in d s

2%

b in d s

3%

b in d s s l i g h t l y

4%

ru n s s a t i s f a c t o r i l y

5%

s tic k s s lig h tly

47 Prom t h i s t a b l e i t can be se en t h a t powdered Carbowax 4000 o f 30-mesh s iz e i n a 4% p ro p o rtio n o f f e r s s a t i s f a c t o r y l u b r ic a tio n i n th e la c to s e g r a n u la tio n .

P e rc e n ta g e s l e s s th a n 4% o r more th a n 4% do no t

o ffe r p e rfe c t lu b ric a tio n .

This f a c t was v e r i f i e d by com pressing

a d d it i o n a l amounts o f th e g r a n u la tio n lu b r ic a te d w ith 4% o f th e powdered Carbowax 4000*

A fte r 500 t a b l e t s had been com pressed, th e m achine was

stopped and th e punches and d ie were examined f o r sig n s o f s tic k in g a n d /o r binding*

None were d is c e rn ib le *

A sample o f th e g ra n u la tio n

was th e n lu b r ic a te d w ith 5% powdered Carbowax 4000 and com pressed, and a g ain s tic k in g was evidenced.

T his g ra n u la tio n was removed from th e

machine and to i t was added enough o f th e u n lu b ric a te d g ra n u la tio n to b rin g th e t o t a l p erc en ta g e o f lu b r ic a n t down to 4%* cle an e d and t h i s g ra n u la tio n was com pressed.

The m achine was

At t h e end o f com pression

th e punches and d ie were a g a in examined f o r sig n s o f b in d in g o r s t i c k ­ in g and a g a in none were found.

T h e re fo re , Carbowax 4000 powdered t o a

30-mesh s iz e o f f e r s d e f i n i t e l u b r ic a tio n to th e s ta n d a rd g r a n u la tio n , b u t o n ly i n th e s p e c if ic amount o f 4%* The t a b l e t s th u s made were examined and found to be o f e x c e lle n t ap p earan ce.

They would be h ig h ly s a t i s f a c t o r y f o r u se a s s o lu b le

t a b l e t s b u t n o t a s hypodermic t a b l e t s s in c e th e y had an average d i s i n te g r a t i o n tim e o f 2 m in u te s.

I t was n o tic e d t h a t upon d i s i n t e ­

g r a t i o n , sm a ll b i t s o f th e Carbowax 4000 rem ained i n su sp en sio n i n th e l i q u i d , r e q u ir in g s e v e r a l m inutes to go i n to s o lu tio n .

T h is, t o o ,

would be o b je c tio n a b le i n hypodermic t a b l e t s . T h eorizing t h a t th e f in e n e s s o f th e lu b r ic a n t m ight a f f e c t th e speed o f d i s i n t e g r a t i o n of th e t a b l e t s , a tte m p ts were made to determ ine

48 th e optimum mesh s iz e lu b r ic a n t f o r t h e s ta n d a rd g r a n u la tio n .

Accord­

in g ly , sam ples o f th e Carbowax 4000 were made i n v a ry in g d e g re es o f f in e n e s s by pushing them th ro u g h sc re e n s ra n g in g i n s iz e from 30-mesh t o 80-mesh.

Samples o f th e sta n d a rd g r a n u la tio n were th e n mixed w ith

p o rtio n s o f th e powdered lu b r ic a n t i n in c r e a s in g ly la r g e amounts u n t i l s a t i s f a c t o r y com pression was o b ta in e d .

The minimum amount o f each mesh

s iz e l u b r ic a n t needed f o r s a t i s f a c t o r y com pression was determ ined and t h e r e s u l t i n g t a b l e t s were t e s t e d f o r d i s i n te g r a t i o n and s o l u b i l i t y . The r e s u l t s a re shown i n Table 19* Table 19 D is in te g r a tio n and S o l u b i l it y o f T a b le ts Compressed With D iff e re n t Mesh S ize L u b ric an ts Mesh S iz e of L u b ric an t

S o l u b i l it y Time o f T a b le ts

Minimum Needed For L u b ric a tio n

D is in te g r a tio n Time of T a b le ts

30

k%

3 m inutes

4 m inutes

40

■

%$23 seconds

1 m inute

60

2#

17 seconds

45 seconds

80

2%

40 seconds

70 seconds

From th e s e r e s u l t s i t would appear t h a t a sm a lle r amount o f a powdered lu b r ic a n t i s needed when i t i s i n a f i n e r s t a t e o f sub­ d i v is io n , and t h a t th e d i s i n te g r a t i o n tim e o f th e t a b l e t i s decreased when th e p a r t i c l e s iz e o f th e lu b r ic a n t i s d e c re a se d .

A lso, i n th e

c ase o f Carbowax 4000, a 6Q~mesh s iz e powder o f f e r s more ra p id d i s i n ­ t e g r a t i o n to th e t a b l e t th a n o th e r mesh s iz e s o f th e same compound* P o s s ib ly t h i s compound may be used a s a so lu b le lu b r ic a n t f o r hypo­

dermic t a b l e t s sin c e i t has been re p o rte d to have a r e l a t i v e l y low degree o f t o x i c i t y (73)> (7 4 ). Up t i l l now, a l l com pression had been t e s t e d on th e sin g le -p u n c h t a b l e t m achine.

Having found a w orkable fo rm u la , i t was d e cid ed to

conduct f u tu r e experim ents on th e Stoke *s R otary t a b l e t m achine, u sin g s p e c ia l hypodermic t a b l e t s iz e punches and running a t th e r a t e o f 300 t a b l e t s a m in u te , s in c e t h i s would be th e norm al method o f commercial p ro d u c tio n . Compression o f th e sta n d a rd g r a n u la tio n lu b r ic a te d w ith 2% pow­ dered Carbowax 4000 was attem p ted on th e r o ta r y t a b l e t m achine.

A

t r i a l l o t o f 3000 t a b l e t s was compressed u sin g 3 /1 6 ” punches, th e w eight o f each t a b l e t b e in g one g r a in .

Compression was s a t i s f a c t o r y

and th e machine ru n w ith o u t d i f f i c u l t y .

Upon co m pletion o f th e ru n ,

th e punches and d ie s were examined f o r evidence o f s tic k in g o r b in d in g A s l i g h t s tic k in g t o th e s u rfa c e s o f th e upper punches was n o tic e d . I t was tho u g h t t h a t p o s s ib ly an ex cess o f lu b r ic a n t m ight be re s p o n s i­ b le f o r t h i s ; a c c o rd in g ly , a d d itio n a l samples o f th e g ra n u la tio n were lu b r ic a te d w ith 1% and w ith 3% o f th e lu b r ic a n t and com pression was a tte m p te d .

Both g ra n u la tio n s com pressed, b u t n e ith e r was a s s a t i s ­

f a c to r y as th e g ra n u la tio n c o n ta in in g 2% l u b r ic a n t , and i n b o th c ase s in c re a s e d s tic k in g o c c u rre d .

To e lim in a te th e p o s s i b i l i t y o f uneven

punch s u r f a c e s , th e punches were machined and p o lis h e d .

Compression

o f th e sta n d a rd g ra n u la tio n was ag ain a ttem p ted b u t s l i g h t s tic k in g was s t i l l n o tic e d .

A d d itio n a l b a tc h e s o f t a b l e t s were compressed

u sin g l e s s p re s s u re and i t was found t h a t th e d eg ree o f p re s su re used m a te r ia lly a f f e c t s b o th th e degree o f s tic k in g and th e r a t e o f d i s i n ­

50 t e g r a t i o n o f th e f i n is h e d t a b l e t .

By c a r e f u l l y a d ju s tin g th e p re s su re

to y i e l d a firm t a b l e t w ith a h a rd n ess o f 2 Kg. a s m easured by th e Monsanto h a rd n e ss t e s t e r , a t a b l e t was o b ta in e d which d id not s t i c k and which d i s i n te g r a t e d in 30 seconds.

Sm all p a r t i c l e s o f th e Carbowax

rem ained i n su sp e n sio n , r e q u ir in g an a d d itio n a l 15 seconds to d is s o lv e . From th e s e r e s u l t s i t can b e seen t h a t a hypodermic t a b l e t w ith an average d i s i n te g r a t i o n tim e o f 45 seconds can be made by com pression on a r o t a r y t a b l e t m achine. S ince p re v io u s ex perim ents had in d ic a te d t h a t sodium b en zo ate m ight a ls o be a s a t i s f a c t o r y l u b r ic a n t f o r th e la c to s e g r a n u la tio n , a d d itio n a l t e s t s u sin g i t a s a lu b r ic a n t were ru n .

A ccording to S c o v ille , sodium

a c e ta te in c re a s e s th e s o l u b i l i t y o f sodium ben zo ate ( ? 6 ) .

I t was

d ecid ed to t r y m ix tu res o f th e s e two su b sta n c e s as p o s s ib le r a p id ly so lu b le l u b r ic a n t s .

D iff e re n t sam ples o f th e s ta n d a rd g ra n u la tio n

were lu b r ic a te d w ith v a ry in g m ix tu res o f sodium b e n zo a te and sodium a c e ta te and com pressed on th e r o ta r y machine as b e f o r e . a re shown i n Table 20.

The r e s u l t s

51 Table 20 T a b le ts C ontaining M ixtures of Sodium Benzoate and Sodium A c eta te a s L u b ric a n ts

L u b ric a n t

C o m p re s s ib ility

S o l u b i l it y o f T ab let

3% Sodium Benzoate & 1$ Sodium A c eta te

s l i g h t s tic k in g & b in d in g

35 seconds

3% Sodium B enzoate & 2$ Sodium A cetate

sev ere s tic k in g & b in d in g

t a b l e t s u n s a t is ­ fa c to r y

3% Sodium B enzoate & 3% Sodium A cetate

s t i c k s , b in d s , c a p s; won1t compress

4# Sodium Benzoate & 1% Sodium A c e ta te

com presses v ery w e ll

30 seconds

4% Sodium B enzoate & 2% Sodium A c eta te

s l i g h t s tic k in g & b in d in g

35 seconds

4% Sodium Benzoate & 3% Sodium A c eta te

s t i c k s & cap s; w on't compress

- ..-1

u

From t h i s t a b l e i t can be seen t h a t th e o n ly m ix tu re of sodium b en zo ate and sodium a c e ta te t r i e d tfiic h w i l l p erm it s a t i s f a c t o r y com­ p re s s io n a ls o g iv e s a t a b l e t having th e low est d i s i n te g r a t i o n tim e . A m ix tu re o f 4% sodium b en zo ate and 1$ sodium a c e ta te o f f e r s s a t i s ­ f a c to r y l u b r i c a t i o n t o th e s ta n d a rd g r a n u la tio n . T r ia l b a tc h e s o f fo u r d i f f e r e n t hypodermic t a b l e t s were made u sin g th e fo llo w in g g e n e ra l fo n n u la : M edication,....the L a c t o s e ............... qs 2% S o lu tio n G lu c o s e ..20 Sodium B enzoate 4$ Sodium A cetate 1

d e s ire d dosage to 0 .9 g r a in p e r t a b l e t c c . p e r 100 grams of th e w eight o f th e d ry g ra n u la tio n of th e w eig h t o f th e d ry g ra n u la tio n

...... %

The g r a n u la tio n s were made and lu b r ic a te d i n th e s ta n d a rd manner and

52 com pressed on th e r o t a r y t a b l e t machine a t th e r a t e o f 300 p e r m in u te. The t a b l e t s made w ere:

S try c h n in e s u l f a t e 1 /6 0 g r a in and 1/3 0 g r a i n ,

a tr o p in e s u l f a t e 1 /5 0 g r a in , and scopolam ine hydrobromide 1/300 g r a in . I n each c a se com pression was s a t i s f a c t o r y and th e t a b l e t s were o f u n i­ form w eight and appearance.

W hile some t a b l e t s d is s o lv e d i n 30 sec­

on d s, th e o v e r - a l l av erag e tim e f o r d i s i n te g r a t i o n and com plete so lu ­ t i o n was one m in u te .

Samples o f th e t a b l e t s o f stry c h n in e s u l f a t e

were se n t t o two d i f f e r e n t m anufacturing houses w ith re q u e s ts f o r c r i t ic i s m s and su g g e s tio n s .

Both firm s re p o rte d th e t a b l e t s t o be

so lu b le and o f good a p p ea ra n c e , b u t su g g ested t h a t th e d i s i n te g r a t i o n tim e be made s h o r te r i f p o s s ib le .

The su g g e stio n was made t h a t by

u sin g a s m a lle r d ie and making th e t a b l e t s weigh only o n e -h a lf g r a in , t h i s m ight be accom plished. S ince sm a lle r d ie s and punches were no t a v a ila b le f o r th e r o ta r y t a b l e t m achine, a d d itio n a l g r a n u la tio n s were made and com pression attem p ted on th e sin g le-p u n c h t a b l e t machine u sin g punches.

l / S ” d ie and

I n no c a s e was s a t i s f a c t o r y com pression accom plished.

T his

was found t o be due t o an uneven f i l l i n g o f th e d ie w ith th e granu­ l a t i o n , th e d ie b e in g to o sm a ll to perm it an even f i H f o r each com­ p ressio n # Using th e form ula on page 51, a d d itio n a l g ra n u la tio n s were made acco rd in g to th e s ta n d a rd p ro ce d u re.

A fte r d ry in g , each o f th e s e

g r a n u la tio n s was d iv id e d in to eq u al p a r t s , one p a r t b e in g lu b r ic a te d w ith a m ix tu re o f 4% powdered sodium b e n zo a te p lu s 1% powdered sodium a c e ta te and th e o th e r w ith 2% powdered Carbowax 4000 i n a 6o~mesh s i z e . Each o f th e g r a n u la tio n s was compressed on th e r o t a r y t a b l e t m achine

53 w ith a minimum a c c e p ta b le amount o f p re s s u re and th e r e s u l t i n g t a b l e t s were examined f o r t h e i r p h y s ic a l p r o p e r tie s a s shown i n Table ZL* L u b ric a n t A d e s ig n a te s th e sodium benzoate-sodium a c e ta te m ix tu re ; lu b r ic a n t B d e s ig n a te s powdered Carbowax 4000. From th e t a b l e , i t can b e seen t h a t , w h ile b o th l u b r ic a n ts p e r­ m it s a t i s f a c t o r y com pression, t h e t a b l e t s c o n ta in in g th e sodium b e n z o a te -a c e ta te m ix tu re have a more r a p id s o l u b i l i t y tim e .

Of n in e

d i f f e r e n t fo rm u la tio n s a tte m p te d , e ig h t r e s u lte d i n a c c e p ta b le t a b ­ le ts .

The sodium s a c c h a rin g ra n u la tio n s would n o t compress s a t i s ­

f a c t o r i l y because o f s t i c k i n g . p r o p e r tie s o f th e s a l t .

This i s a t t r i b u t e d t o th e p h y s ic a l

The t a b l e in d ic a te s t h a t so lu b le t a b l e t s can

be com pressed by machine u sin g e i t h e r o f th e two re p o rte d l u b r ic a n t s . W hile th e d i s i n t e g r a t i o n and s o l u b i l i t y tim es a r e lo n g e r th a n i s d e s ire d f o r hypodermic t a b l e t s , th e y a re a c c e p ta b le f o r th e so lu b le t a b l e t s now b ein g made by m olding.

This fo rm u la tio n and procedure

a re recommended f o r comm ercial a p p lic a tio n .

I t i s p o s s ib le t h a t , by

u sin g 1 / 8 " d ie s and punches on a r o ta r y t a b l e t machine and c a r e f u l l y a d ju s tin g th e p re s s u r e , s a t is f a c to r y compressed hypodermic t a b l e t s can a ls o be made i n t h e same m anner. The form ulas and p rocedures f o r compressed s o lu b le t a b l e t s may be w r i t te n a s fo llo w s: T ab lets c o n ta in in g I n g re d ie n ts l e s s th an 1 /4 g ra in ____________o f m e d ic a tio n _____

T ab lets c o n ta in in g more th a n 1 /4 g r a in o f m ed ica tio n ______

M ed icatio n

re q u ire d amount

re q u ire d amount

L acto se

qs t o 0 .5 g r a in p er ta b le t

qs to 0 .9 g r a in per ta b le t

2% S o lu tio n of I d q . G lucose

20 c c . p e r 100 grams

20 c c . p e r 100 grams

54

tfypodermic

Table 21 Tablets Compressed On the Rotary

Tablet Machine

s i

to (—I

i

ux CA

* P © © CM C*X

I

O o bO

«8

4) rH

< 8 (1 898).

(3 8 )

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(? 6 )

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(81)

S p e ran d io , G. J . and DeKay, H. G. The M anufacture o f Hypodermic T ab lets J . Am. P h am . A ssoc. P r a c t. E d ., 10, 572 (1949)•

THE MANUFACTURE OF COMPRESSED HYPODERMIC AND SOLUBLE TABLETS An A b stra c t of A T hesis Subm itted to th e F a c u lty of Purdue U n iv e rs ity by Glen Joseph Sperandio In P a r t i a l F u lfillm e n t o f th e R equirem ents f o r th e Degree of D octor o f P hilosophy

F eb ru ary , 1950

1 ABSTRACT A lthough in tra v e n o u s m ed ica tio n had been p r a c tic e d i n te r m i t t e n t l y s in c e th e se v e n te e n th c e n tu r y , i t was no t u n t i l th e n in e te e n th c e n tu ry t h a t hypodem ic m e d ica tio n was i n i t i a t e d .

I t was in tro d u c e d i n th e

U nited S ta te s i n May, 1856, by Dr. Fordyce B arker o f New York, who had o b ta in e d a hypodermic sy rin g e i n S c o tla n d and b ro u g h t i t back w ith him on h i s r e t u r n (1 2 ). The fo re ru n n e rs o f hypodermic t a b l e t s m ight be s a id to have been d ev ised i n 1861 by L aF arge, who f e m u la te d p e l l e t s o f s o lid m ed icatio n f o r subcutaneous im p la n ta tio n *

These p e l l e t s were composed o f su g a r,

a c a c ia , d i s t i l l e d w a te r, and th e m edication*

M odified forms o f t h i s

te c h n iq u e a re i n use to d a y , p a r t i c u l a r l y i n th e a d m in is tra tio n o f androgenic su b sta n c es (1 3 ). P r io r t o 1877 th e Homeopathic p ro fe s s io n had been u sin g p e l l e t s s im ila r to L aFargue’ s , b u t in t h a t y e a r D r. G-. H. P i f f a r d p re se n te d a p aper b e fo re The New York Academy o f M edicine on "The Use o f C e rta in T r itu r â t io n s " i n which he claim ed to have com pressed t r i t u r a t i o n s in convenient doses ( 8 ) .

A ccording to K e b ler, however. Dr. R obert M.

F u lle r i s th e o r i g in a to r o f t a b l e t t r i t u r a t e s and was " th e moving s p i r i t i n p la c in g th e in d u s try on a s u b s ta n t ia l b a s is " ( 8 ) .

On March 9 , 1878,

a com plete a r t i c l e by Dr. F u lle r appeared in th e M edical Record i n which he d e sc rib e d i n d e t a i l h is in v e n tio n o f th e t a b l e t s and gave s p e c if ic i n s t r u c t i o n s f o r t h e i r m anufacture.

I n correspondence w ith

K eb ler, Dr. F u l l e r e x p la in s t h a t he and D r. P i f f a r d had worked t o ­ g e th e r a f t e r he in v e n te d th e p ro cess and t h a t th e o r i g i n a l id e a was h is ( F u l l e r 's ) .

I t i s s i g n i f i c a n t t h a t o n ly t h i r t y days a f t e r Dr.

2 F u lle r * s f i r s t r e p o r t , t a b l e t t r i t u r a t e s were o f fe r e d f o r s a l e by C asw ell, Hazard & Co* o f New York, who a d v e r tis e d them a s b e in g made by F u lle r * s m ethod.

O ther com panies s t a r t e d making t a b l e t t r i t u r a t e s

as soon a s i t was a p p a re n t t h a t th e y were b ein g a c c e p te d by th e med­ i c a l p r o f e s s io n , and w ith in th r e e y e a rs a f t e r t h e i r i n tr o d u c tio n , t a b l e t t r i t u r a t e s were s ta n d a rd p ro d u c ts o f many firm s (S ). From 18B6 t o th e e a r ly 1900*s a war o f words waged betw een th e p h arm acists and th e members o f th e m ed ic a l p r o fe s s io n o v er th e v a lu e o f t a b l e t s i n g e n e ra l and t a b l e t t r i t u r a t e s i n p a r t i c u l a r .

Those

opposed t o t h e i r u se claim ed th e y were o f u n c e r ta in d o sag e, s u b je c t to d e te r i o r a t i o n , and to o a p t to cause c o n fu sio n because th e y a U looked a lik e ( l) «

The ad v o cates o f t a b l e t t r i t u r a t e s claim ed th e y were e a s i l y

made, c o n v e n ie n t, econom ical, and more a c c u ra te i n dosage ( 2 ) .

Con­

s id e r a b le c o n fu sio n e x is te d i n th e minds o f many people over th e d i f f e r ­ ence betw een tr u e t a b l e t t r i t u r a t e s and compressed t a b l e t s , and f r e q u e n tly a u th o rs w rote o f compressed t a b l e t t r i t u r a t e s , alth o u g h a se a rc h o f th e l i t e r a t u r e f a i l s to r e v e a l any re p o rte d method f o r th e m anufacture by com pression.

Compressed t a b l e t t r i t u r a t e s were made,

b u t th e y d i f f e r e d from th e t r u e a r t i c l e i n t h a t th e y c o n ta in e d in s o l­ u b le e x c ip ie n ts and were n o t used f o r i n j e c t i o n . G ra d u ally t a b l e t t r i t u r a t e s became an a c c ep ted form o f m e d ic a tio n , p a r t i c u l a r l y f o r hypodermic th e ra p y ; and a d i f f e r e n t i a t i o n was made betw een molded t a b l e t s and com pressed t a b l e t s , th e term "hypodermic" r e f e r r in g to molded t a b l e t s e x c lu s iv e ly . With th e advent o f th e a n t i b i o t i c s a new ty p e of t a b l e t has made i t s ap p earan ce.

I t i s e s s e n t i a l l y a hypodermic t a b l e t and i s made i n

3 most in s ta n c e s by m olding.

I t c o n s is ts o f m ed ic a tio n in c o rp o ra te d

i n to a l a c to s e base t o make a r a p id ly s o lu b le t a b l e t which can be p laced under th e tongue to d is s o lv e , o r may be added to m ilk , in f a n t fo rm u la s, o r o th e r l i q u i d s .

D e sp ite th e slow method o f m an u factu re,

s o lu b le t a b l e t s a re a p r e f e r r e d form o f m ed ic a tio n i n many in s ta n c e s , and improved m ethods o f m anufacture would be o f g re a t v alu e to th e in d u s tr y . tiypodermic t a b l e t s d i f f e r from compressed t a b l e t s no t o n ly i n th e method o f m an u fa ctu re, b u t a ls o i n th e n a tu re o f th e in g r e d ie n ts . form er c o n s i s t sim ply o f two su b sta n c e s:

The

th e medicament and a la c to s e

f i l l e r , b o th o f which a re r e a d i ly s o lu b le i n w ater to f o r a a c le a r s o lu tio n . d ie n ts :

The l a t t e r , w ith few e x c e p tio n s , c o n ta in a number o f in g re ­ th e m e d ic a tio n , which may or may n o t be so lu b le ; an adhesive

o f gum, s u g a r, o r s ta r c h ; a d i s i n te g r a t o r which i s u s u a lly s ta r c h ; and a lu b r ic a n t which i s alm ost alw ays in s o lu b le . S u bstances s u ita b le a s b a se s f o r hypodermic t a b l e t s a re lim ite d , and few changes o r improvements over th e o r ig in a l b a se s have been made. In 1891 Anderson l i s t e d , i n a d d itio n to l a c t o s e , powdered su g a r and c h alk a s "d ilu en ts ( 4 ) .

The fo llo w in g y e a r Healm suggested sodium

c h lo r id e , sodium s u l f a t e , and sodium a c e ta te as p o s s ib le b a ses ( 5 ) , A cacia has been recommended as a b in d in g ag en t f o r hypodermic t a b l e t s b u t i s n o t s a t i s f a c t o r y because i t te n d s t o make th e t a b l e t s l e s s s o lu b le ( ? ) •

Recommended lu b r ic a n ts a re :

powdered t a l c , b o ric a c id ,

and a 2% s o lu tio n o f w h ite p e tro latu m i n e th e r ( 6 ) .

White d e x trin and

p e c tin have been su g g ested a s d ilu e n ts and d i s i n te g r a t i n g ag en ts a ls o ( 9 ) , (1 0 ).

At th e p re s e n t tim e no s a t i s f a c t o r y form ula f o r compressed

4 hypodermic t a b l e t s has been re p o r te d i n th e l i t e r a t u r e *

EXPERIMENTAL S in ce la c to s e i s th e most p r a c t i c a l and econom ical f i l l e r f o r molded t a b l e t s , th e ensuing work was co n fin ed t o an i n v e s tig a tio n o f t h i s m a te r ia l a s a base f o r hypodermic t a b l e t s , and e f f o r t s were made t o fo rm u la te a s a t i s f a c t o r y g ra n u la tio n which would compress on a t a b l e t m achine. The f i r s t phase o f t h i s work was to f i n d a s u ita b le method f o r making a la c to s e g ra n u la tio n .

Samples o f la c to s e were mixed w ith b o th

w ater and a lc o h o l and made in to a p a s te which was pushed through a 20-mesh s c re e n and d r ie d .

AH o f th e s e g ra n u la tio n s were very s o f t

and would n o t com press a t a l l .

O bviously, an adhesive substance must

be added t o la c to s e t o produce a firm e r g r a n u la tio n . G ra n u la tio n s o f la c to s e were made u sin g th e fo llo w in g m ucilaginous su b sta n c e s i n s o lu tio n as g ra n u la tin g a g e n ts:

a c a c ia , tra g a c a n th ,

p e c t in , g e l a t i n , a g a r , chondrus, gum k a ra y a , and quince seed.

A 1#

m ucilage o f a g a r was used; 2$ s o lu tio n s o f th e o th e rs were used. A ttem pts t o com press th e s e g ra n u la tio n s on a s in g le —punch t a b l e t machine u sin g f l a t s u rfa c e punches o f 3/16" diam eter f a i l e d .

In

ev ery case sev ere s tic k in g and b in d in g p rev en ted th e com pression o f s a tis fa c to ry t a b l e t s . T h irty —n in e a d d it i o n a l g ra n u la tio n s were made, usin g d i f f e r e n t s tr e n g th s o lu tio n s o f m ucilaginous su b sta n c e s. same p ro cedure was used:

In every in s ta n c e th e

th e powdered la c to s e was mixed by hand w ith

a s o lu tio n o f th e a d h e siv e , pushed through a 20-mesh s c re e n , and d rie d

5 o v e rn ig h t i n a i r .

The d r ie d g ra n u la tio n was a g a in pushed th ro u g h a

20-mesh s c re e n and com pression was attem p ted on th e sin g le -p u n c h t a b l e t m achine.

None o f th e g ra n u la tio n s compressed s a t i s f a c t o r i l y .

I t was d e cid ed to t e s t th e e f f i c ie n c y o f su g ars a s g ra n u la tin g a g e n ts f o r l a c to s e .

T h irty d i f f e r e n t g ra n u la tio n s were made, u sin g

d i f f e r e n t s tr e n g th s o lu tio n s o f th e fo llo w in g su g a rs: f r u c t o s e , s o rb o s e , and l iq u i d g lu c o s e .

su c ro se , m a lto se ,

The g ra n u la tio n s were «1.1 made

and com pressed i n th e same manner a s b e fo re .

In most c a se s sev ere b in d ­

in g and s tic k in g p rev e n ted s a t i s f a c t o r y com pression; however, th e gran­ u la tio n s made w ith a 2% s o lu tio n o f liq u i d g lu co se compressed e a s i l y i n to t a b l e t s w ith no a p p aren t s tic k in g and only a s l i g h t amount o f b in d in g . The p o s s i b i l i t y o f c e llu lo s e d e riv a tiv e s a s b in d e rs was next in v e s­ tig a te d .

T h irte e n g r a n u la tio n s were made w ith s o lu tio n s o f v a ry in g

s tr e n g th s o f m ethyl c e l l u l o s e , hydroxyethyl c e l lu l o s e , carboxym ethyl c e l l u l o s e , and sodium a lg i n a t e .

With th e e x c e p tio n o f m ethyl c e llu lo s e

1500 CPS, none of th e su b stan ces y ie ld e d a com p ressib le g r a n u la tio n . G ra n u la tio n s made w ith m ethyl c e llu lo s e 1500 CPS compressed w e ll, but d id n o t d is s o lv e c o m p letely because o f th e slow s o l u b i l i t y o f th e m ethyl c e l lu l o s e . A d d itio n a l g ra n u la tio n s were made and compressed w ith 0,5%* 1*0%, 1*5#, and 2.0% s o lu tio n s o f l iq u i d g lu c o se .

Again th e g ra n u la tio n

made w ith th e 2% s o lu tio n o ffe re d th e l e a s t d i f f i c u l t y to com pression. I t was d ecid ed to use a 2% s o lu tio n o f l i q u i d glu co se a s t h e granu­ l a t i n g a g en t o f ch o ice f o r l a c to s e . The n ex t phase o f t h i s in v e s tig a tio n was to determ ine th e s iz e

6 g ra n u le most a c c e p ta b le f o r making hypodermic t a b l e t s and what e f f e c t th e g ra n u le s iz e has on th e e a se o f com pression. G ra n u la tio n s o f la c to s e w ith a 2% s o lu tio n o f

liq u i d glu co se were

made and pushed by hand th ro u g h s c re e n s o f d i f f e r e n t mesh s iz e s ran g in g from l6-m esh t o 100-mesh.

Compression o f each g ra n u la tio n was attem pted

on th e sin g le -p u n c h t a b l e t m achine, th e same ad ju stm en ts f o r w eight and p re s s u re b e in g k ep t f o r each g ra n u la tio n .

T h ir ty - e ig h t a d d itio n a l

g ra n u la tio n s w ith v a ry in g ty p e s and amounts o f g ra n u la tin g a g e n ts were made and com pression a tte m p te d on th e same machine i n an e f f o r t to e s t a b l i s h a d e f i n i t e r e l a ti o n s h i p between th e g ra n u le s iz e and th e ease o f com pression.

I t was found t h a t th e e ase o f com pression d ecrea se s as

th e g ra n u le s iz e becomes s m a lle r, and a 20-mesh g ra n u la tio n was found to be th e optimum s iz e g ra n u la tio n f o r hypodermic t a b l e t s . S in ce th e p e rcen tag e o f f i n e powders i n a g ra n u la tio n a f f e c t s i t s c o m p r e s s ib ility , a tte m p ts were made to determ ine how b e s t to make g ra n u la tio n s c o n ta in in g th e l e a s t amount o f f in e powder.

Three d i f f e r ­

e n t methods o f g ra n u la tin g and th re e d i f f e r e n t methods o f d rying were compared.

G ra n u la tio n s were made by hand, by use o f th e C olton granu­

l a t o r , and by use of th e F i t z p a t r i c k coraminutor.

The g ra n u la tio n s

made b y each method were d iv id e d in to th r e e p o r tio n s :

one p o rtio n was

d rie d in a i r a t room te m p e ra tu re , a second was d rie d i n a h o t - a i r oven a t 140 d e g re es F . , and th e t h i r d was d rie d under in f r a - r e d lam ps. Each g ra n u la tio n was th e n s i f t e d through a 20-mesh sc ree n over a 60 -mesh s c re e n , and any f i n e powders p assin g th ro u g h th e 60 -mesh sc re e n

were w eighed.

I t was found t h a t g ra n u la tio n s pushed thro u g h a sc re e n

by hand c o n ta in l e s s f i n e powder th a n th o s e made by m echanical m eans.

7 and t h a t g ra n u la tio n s d r ie d in a i r o r un d er i n f r a - r e d lamps c o n ta in l e s s f i n e powder th a n th o s e su b je c te d t o d ry in g a t h ig h e r te m p e ra tu re s. I n an a tte m p t t o f in d a w a te r-s o lu b le lu b r ic a n t f o r th e la c to s e g r a n u la tio n , f o r t y - e i g h t d i f f e r e n t s o lu b le s a l t s were t e s te d f o r t h e i r l u b r ic a tin g p r o p e r t i e s .

In every in s ta n c e th e same procedure was used:

th e s a l t was f i n e l y powdered and s i f t e d th ro u g h a 60 -mesh s c re e n .

One

hundred-gram sam ples o f th e la c to s e g ra n u la tio n were th e n mixed w ith amounts v a ry in g from 1$ to 5% o f t h e powdered s a l t and tum bled in a c lo s e d c o n ta in e r u n t i l u n ifo rm ly m ixed.

Compression was attem p ted on

a S to k e 1s sin g le -p u n c h t a b l e t machine u sin g 3 / l 6 M punches and running a t th e r a t e o f 90 t a b l e t s a m in u te.

I f a su b stan ce d id n o t show e v i­

dence o f lu b r ic a t i n g p r o p e r tie s w ith a t l e a s t 5% o f i t i n th e granu­ l a t i o n , i t was n o t c o n sid ere d f o r f u r t h e r i n v e s ti g a t i o n . compounds o f f e re d evidence o f lu b r ic a tio n :

Only fo u r

sodium b e n z o a te , sodium

o l e a te , sodium s t e a r a t e , and sodium l a u r y l s u l f a t e .

The t a b l e t s made

w ith sodium b en zo ate a s a lu b r ic a n t were th e most s a t i s f a c t o r y , b u t had a slow d i s i n te g r a t i o n tim e (2 m in u te s).

Sodium o le a te and sodium

l a u r y l s u l f a t e i n 2% p ro p o rtio n s and sodium s t e a r a te in 1$ p ro p o rtio n s were s a t i s f a c t o r y lu b r ic a n t s b u t th e r e s u l ti n g t a b l e t s were n o t a c c e p t­ a b le e i t h e r from th e sta n d p o in t o f d i s i n te g r a t i o n o r c l a r i t y o f so lu ­ tio n ,

Sodium b e n zo a te i n th e amount o f b% was th e b e s t lu b r ic a n t found

f o r th e la c to s e g r a n u la tio n . I n l i t e r a t u r e of th e Carbon and C arbide Chemical C o rp o ratio n , th e Carbowax compounds a re advocated f o r u se a s w a te r-so lu b le waxes.

T heir

s u i t a b i l i t y a s l u b r ic a t i n g a g e n ts f o r th e la c to s e g ra n u la tio n was in v e s tig a te d .

V arying p e rc e n ta g e s o f Carbowax 1500 and Carbowax 4000

a were d is s o lv e d i n t h e g ra n u la tin g s o lu tio n o f l i q u i d g lu co se and la c to s e g r a n u la tio n s were made, d r ie d , and com pressed.

G ra n u la tio n s c o n ta in in g

Carbowax 1500 d id n o t compress w e ll a t a l l ; th o s e c o n ta in in g 2$ o f Carbowax 4000 com pressed q u ite w e ll but s l i g h t b in d in g was s t i l l e v i­ denced. I t was n e x t d ecid ed t o t r y th e lu b r ic a tin g a c tio n of Carbowax 4000 when added to th e g ra n u la tio n i n d ry powdered form .

Samples o f th e

compound were pushed by hand th ro u g h a 30-mesh s c re e n , and v ary in g p e rc en ta g es of th e powder were added t o sam ples o f th e sta n d a rd granu­ l a t i o n and mixed by tum bling in a c lo se d c o n ta in e r .

Compression was

attem p ted on th e S to k e f s sin g le -p u n c h t a b l e t m achine a s b e fo re .

I t was

found t h a t 4% o f th e powdered Carbowax 4000 o ffe re d s a t i s f a c t o r y l u b r i ­ c a tio n to th e g r a n u la tio n .

The t a b l e t s th u s made were examined and

found t o be o f e x c e lle n t ap p earan ce.

They would be h ig h ly s a t is f a c to r y

f o r u se a s so lu b le t a b l e t s , b u t n o t as hypodermic t a b l e t s s in c e th e y had an a v erag e d i s i n te g r a t i o n tim e o f two m in u té s.

Upon d i s i n t e g r a t i o n ,

sm all p a r t i c l e s o f th e Carbowax 4000 rem ained i n suspension i n th e l i q u i d , r e q u ir in g a d d itio n a l tim e to go i n to s o lu tio n .

T heorizing

t h a t th e f in e n e s s o f th e lu b r ic a n t m ight a f f e c t th e speed o f d i s i n t e ­ g r a tio n o f th e t a b l e t s , a tte m p ts were made to determ ine th e optimum mesh s iz e lu b r ic a n t f o r th e la c to s e g r a n u la tio n .

Samples o f th e Carbo—

wax 4000 were made i n v ary in g d eg rees o f fin e n e s s by pushing th e m a te r ia l th ro u g h sc re e n s ran g in g in s iz e from 30-mesh to 80-mesh. P o rtio n s o f th e g r a n u la tio n were th e n lu b r ic a te d w ith each o f th e powdered Carbowaxes i n in c r e a s in g ly la rg e amounts u n t i l s a t is f a c to r y com pression was a t t a i n e d .

The minimum amount o f each mesh s iz e l u b r i —

9 c a n t needed f o r s a t i s f a c t o r y com pression was determ ined and th e r e s u l ti n g t a b l e t s were t e s te d f o r d i s i n t e g r a t i o n and s o lu b ility *

The r e s u l t s a re

shown i n T able 1 . Table 1 D is in te g r a tio n and S o l u b i l it y o f T a b le ts Compressed With D iffe re n t Mesh S ize L u b ric a n ts Mesh S iz e o f L u b ric a n t

Minimum Needed For L u b ric a tio n

Di s in te g r a tio n Time of T a b le ts

30

k%

3 m inutes

40

3%

23 seconds

1 m inute

60

2%

17 seconds

45 seconds

80

2%

40 seconds

70 seconds

S o l u b i l it y Time o f T ab lets 4 m inutes

I t was concluded t h a t th e d i s i n te g r a t i o n tim e o f a t a b l e t i s d ecreased when th e p a r t i c l e s iz e o f th e lu b r ic a n t i s d e c re a se d , and t h a t i n th e c a se o f Carbowax 4000, a 60-jnesh powder o f f e r s more r a p id d i s i n te g r a t i o n to th e t a b l e t th a n o th e r mesh s iz e s o f th e same compound. An a c c e p ta b le lu b r ic a n t f o r th e la c to s e g ra n u la tio n i s 2% powdered Carbowax 4000 ( 60 -mesh)* A d d itio n a l g r a n u la tio n s were made and lu b r ic a te d w ith 2% powdered Carbowax 4000 (60-m esh) and com pression was n ex t attem p ted on th e S to k e 1s r o t a r y t a b l e t machine u sin g 3 /l6 " punches and running a t th e r a t e o f 300 t a b l e t s a m in u te . machine r a n w ith o u t d i f f i c u l t y .

Compression was s a t is f a c to r y and th e I t was found t h a t by c a r e f u lly reg ­

u l a t i n g th e p r e s s u r e , t a b l e t s w ith a d i s i n te g r a t i o n tim e of 45 seconds co u ld be com pressed.

This d i s i n t e g r a t i o n tim e i s s t i l l high f o r hypo­

10 derm ic t a b l e t s , so i t was d ecid ed t o t r y a d d itio n a l com pressions w ith sodium b en zo ate a s a l u b r i c a n t .

According to S c o v i ll e , sodium a c e ta te

in c r e a s e s th e s o l u b i l i t y o f sodium b en zo ate ( l l ) , and m ix tu re s o f th e s e two su b sta n c e s were t r i e d i n an e f f o r t t o f in d a r a p id ly so lu b le lu b ric a n t.

I t was found t h a t th e o n ly m ix tu re which w i l l p erm it s a t ­

i s f a c t o r y com pression w ith th e la c to s e g ra n u la tio n was one c o n ta in in g k% sodium b en zo ate and 1# sodium a c e ta te . G ra n u la tio n s c o n ta in in g m ed icatio n were made by th e sta n d a rd pro­ c ed u re.

A fte r d ry in g , each o f th e s e g ra n u la tio n s was d iv id e d i n to

e q u al p a r t s , one p a r t b e in g lu b r ic a te d w ith th e sodium benzoate-sodium a c e ta te m ix tu re i n a 6 0 -mesh powder and th e o th e r w ith 2% powdered Carbowax 4000 ( 60 -m esh).

Each o f t h e g ra n u la tio n s was compressed on

th e r o t a r y t a b l e t machine w ith a minimum a c c e p ta b le amount o f p re s s u re and t h e r e s u l t i n g t a b l e t s were examined f o r t h e i r p h y s ic a l p r o p e r tie s a s shown i n Table 2 ,

L u b rican t A d e sig n a te s th e sodium benzoat e-sodium

a c e ta te m ix tu re and lu b r ic a n t B d e sig n a te s th e powdered Carbowax 4000. I t can be seen t h a t , w hile b o th lu b r ic a n ts p erm it s a t is f a c to r y com pression, th e t a b l e t s c o n ta in in g th e sodium benzoate-sodium a c e ta te m ix tu re have a more r a p id s o l u b i l i t y tim e .

Of n in e d i f f e r e n t formu­

l a t i o n s a tte m p te d , e ig h t r e s u lte d in a c c e p ta b le t a b l e t s .

The sodium

s a c c h a rin t a b l e t s would not compress s a t i s f a c t o r i l y because of s t i c k ­ in g .

T his was a t t r i b u t e d to th e p h y s ic a l p r o p e r tie s o f th e s a l t .

The t a b l e in d ic a te s t h a t so lu b le t a b l e t s can be compressed by machine u sin g e i t h e r o f th e two re p o rte d l u b r i c a n t s .

While th e d i s in te g r a tio n

and s o l u b i l i t y tim e s a re lo n g e r th a n i s d e s ire d f o r hypodermic ta b ­ l e t s , th e y a re a c c e p ta b le f o r th e so lu b le t a b l e t s now b ein g made by

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he re s ig n e d h is p o s itio n and e n te re d Purdue Uni­

v e r s i ty a s a g rad u ate a s s i s t a n t i n Pharmacy.

The fo llo w in g y e a r , he

was made an i n s t r u c t o r i n Pharmacy and has continued in t h a t p o s itio n to d a te .

He re c e iv e d th e degree o f M aster o f S cience from. Purdue

U n iv e rs ity i n F e b ru a ry , 1947, and com pleted th e work f o r th e degree of D octor o f P hilosophy i n F e b ru ary , 1950. He i s a r e g is te r e d pharm acist in th e s t a t e o f M issouri and i s a member o f th e American P h arm aceu tical A s s o c ia tio n , Rho C hi, Sigma X i, and Phi Lambda U psilon*