Polarographic Studies of Some Antihistamine Compounds and Some Official Iron Preparations

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P U R D U E UNIVERSITY

TH IS IS TO CERTIFY THAT THE T H E SIS PREPA R ED U N D E R MY SU PE R V ISIO N

1Ï-------- Levi- EdMin-Bingenhe.imer-) _Jz%-------------- --------

ENTITLED

PQLARQGRAPHIC STUDIES OF SOME ANTIHISTAMINE

_________ CCMPQDNDS ANILSCME OFFICIAL IRON_PBEEARATIQNS_____

COMPLIES WITH THE UNIVERSITY REG ULA TIO NS O N GRADUATION T H E SE S

AND IS APPRO VED BY ME A S FULFILLIN G TH IS PART O F THE REQUIREM ENTS

F O R THE D EG R EE O F

----------Doctor of Philosophy----------------------------

P R O F E S S O R IN C H A R G E O F T H E S IS

H

ead o f

S

choox. o r

D

epa rtm en t

Jan u ary 21------------- 50-

TO THE LIBRARIAN:---ISTH IS T H E SIS IS NO T TO B E REGARDED A S CONFIDENTIAL.

PRO FRSSO R m

G R A D . S C H O O L F O R M 9 —3 - 4 9 —I M

CHARGE

PQLAEOOaAPHIC STUDIES OF SCME ANTIHISTAMINE COMPOUNDS AND SOME OFFICIAL IRON PREPARATIONS

A T hesis Subm itted to th e F a c u lty of Purdue U n iv e rs ity by L evi Edwin Bingenheim er, J r . In P a r t i a l F u lfillm e n t o f th e R e q u ir ^ e n ts f o r th e Degree of D octor o f Philosophy

J a n u a ry , 1950

ProQuest Number: 27712187

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 27712187 Published by ProQuest LLO (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 LLO. ProQuest LLO. 789 East Eisenhower Parkway P.Q. Box 1346 Ann Arbor, Ml 4 8 1 0 6 - 1346

ÂCKN0WLED&ME3S1TS The a u th o r w ishes t o acknowledge h is in d e b ted n ess t o P ro fe s s o rs J* £« C h r is tia n , Glenn L« J e n k in s , and G. £# Cwalina f o r t h e i r guidance and a s s is ta n c e i n t h i s w ork, and t o th e American F oundation f o r P h arm aceu tical E d u ca tio n , whose g r a n t o f fe llo w s h ip made t h i s work p o ssib le# The au th o r a ls o w ishes to ex p ress h is g r a titu d e to th e numerous m an u factu rers o f p h arm aceu tical ch em icals who g en ero u sly a s s is te d by supplying working sam ples o f t h e i r products#

TABLE OF CONTENTS

Page GENERAL INTBODUCTICM

............................................................................

1

The P o laro g rap h ic Method

1

A p p lic a tio n s o f th e P o laro g rap h ic Method . • • • • • • • • • « • • • « •

5

PART I .

POLAROGRAPHIC STUDIES OF SCME ANTIHISTAMINE

COMPOUNDS.........................

10

In tro d u c tio n

10

Survey of th e L i te r a t u r e

11

E xperim ental P a rt

..........

S upporting E le c tr o ly te s

.

12

..........

17

C h aracter o f R eduction Waves . . . . . . . . . . . . . . . . . . . . Summary and C onclusions PART I I .

18 21

POLAROGRAPHIC SÎUDIES OF SCME OFFICIAL IRON

PREPARATIONS............................................................................................

23

I n tro d u c tio n

23

...................

Survey o f th e L ite r a tu r e E xperim ental P a r t

..........

23

............

Development o f th e Method

24

................

27

P o laro g rap h ic A c tiv ity o f F e r r ic and F erro u s Iro n . . . .

27

Comparison o f Complexing Agents (S up p o rtin g E le c tr o ly te s ) E ffe c t o f pH

28 ......................................................................

A ir O x id atio n of F erro u s Io n

..........

. . ......

31 32

table of

CONTENTS (C o n t* d .)

Page I n te r f e r i n g

Complexes

A p p lic a tio n o f th e Method

32 33

SUMMARY..............................................................................................................

46

CCMCLUSIQNS

49

................................................................................

BIBLIOGRAPHY........... .............

51

LISTS OF TABLES AND FIGURES L is t o f T ables Table

Page

1

S tru c tu re o f A n tih istam in e Compounds S tu d ie d ..# ..

15

2

P o laro g rap h ic R éduction o f F e r r ic C hloride i n C i t r a t e , T a r t r a te , and O xalate Media . # . . . . . #

29

P o laro g rap h ic R eduction o f F erro u s S u lf a te in C i t r a t e , T a r tr a te , and O xalate Media ................

30

Methods and R e s u lts o f P o laro g rap h ic Assay o f O f f ic ia l I r o n P re p a ra tio n s

37

3 4

L i s t o f F ig u res F ig u re 1 2

P o laro g rap h With Tem perature C o n tro l and Dropping E le c tro d e Assembly

25

C lose-up o f Dropping E le c tro d e Assembly

26

POLAROGRAPHIC STUDIES OF SOME ANTIHISTAMINE COMPOUNDS AND SOME OFFICIAL IRON PREPARATIONS

GENERAL INTRODUCTION The P o laro g rap h ic M ethod^' The Heyrovsky p o laro g rap h may be d e fin e d as an in stru m e n t inhich an aly zes s u ita b le su b stan ces b o th q u a l i t a t i v e l y and q u a n t ita t iv e l y by m easuring th e v o lta g e r e q u ire d f o r th e e l e c t r o l y t i c re d u c tio n o r o x i­ d a tio n o f th e s u b sta n c e s, and th e c u rre n ts observed when such v o lta g e i s a p p lie d .

The measurements a re o b tain ed by th e u se o f an e l e c tr o ­

l y t i c c e l l c o n s is tin g o f one s m a ll, e a s ily p o la riz a b le e le c tro d e and one la r g e , n o n -p o la riz a b le e le c tr o d e . The sm all e le c tr o d e i n common use i s th e dropping mercinry e le c tr o d e .

S o lid m ic ro -e le c tro d e s can b e used in p la ce o f th e dropping

m ercury e le c tr o d e , b u t in o rd e r to o b ta in re p ro d u c ib le r e s u l t s th e su rfa c e must be c o n tin u a lly renewed.

This i s done by s c ra p in g o r o th e r

m echanical means b u t i s n o t h ig h ly s a t i s f a c t o r y .

The dropping m ercury

e le c tro d e has th e fo llo w in g advantages: (1)

The s u rfa c e o f th e m ercury drop i s p e r f e c t ly smooth, c o n tin u a lly renew ed, and p e r f e c tly re p ro d u c ib le .

(2)

The s u rfa c e a r e a of th e e le c tr o d e can b e c a lc u la te d frcm th e w eight o f th e d ro p s .

(3 )

M ercury amalgamates w ith most m e ta ls , removing them as th e y a r e d e p o s ite d .

(4)

Mercury g iv e s th e h ig h e s t ran g e of p o te n tia l above th e e v o lu tio n o f ty d ro g en .

2 The la rg e e le c tro d e i s u s u a lly a m ercury p o o l e le c tr o d e o r a s a tu r a te d calo m el e le c tr o d e .

For a c c u ra te measurements th e m ercury

p o o l e le c tro d e must be sta n d a rd iz e d a g a in s t a re fe re n c e e le c tro d e such as th e s a tu r a te d calom el e le c tr o d e , so t h a t i t i s p r e fe ra b le t o d isp en se w ith th e m ercury pool and u se th e calom el e le c tr o d e whenever a c c u ra te r e s u l t s a r e d e s ir e d . I n a d d itio n t o th e e l e c t r o l y t i c c e l l , th e p o laro g rap h c o n s is ts o f a source of th e e le c tro m o tiv e f o r c e , u s u a lly a b a t te r y ; a p o la riz in g u n i t , com prising a v o ltm e te r, a s lid e - w ire b r id g e , and s u ita b le r e ­ s is ta n c e ; and a galvanom eter o r some o th e r means o f m easuring c u r r e n t, The re c o rd in g p o laro g rap h a ls o has a photographic o r p en -ty p e r e c o r d e r . P olarography d i f f e r s fr >3H3

/

(1) A n th allan

J-co

H (2) A n tis tin e

^1

II

HoC

N

^

L

(3) B enadryl

-— .

5"3

CH3

( 4 ) Decapryn

U

—C H 2 , ^

(5) H is ta d y l

X H

o

^ N3Ho

16 Table 1 (G ont - C H ^ (7 ) Neohetramine

}N-CHpCHpN

^ ^ -C H 2 N = = X \

^CHo

(ô ) Pyribenzam ine

(9 ) Trimeton

A ll o f th e s e compounds c o n ta in one o r bo th o f th e a c tiv e groups m entioned i n th e l i t e r a t u r e su rv ey .

They a re o f f e r e d , w ith th e

e x ce p tio n o f A n th a lla n , a s th e w a te r-s o lu b le s a lts #

17 S u p p o rtin g E l e c tr o ly te s I n view o f th e h ig h ly n e g a tiv e re d u c tio n p o te n tia l s o f th e t e r t i a r y and q u a te rn a ry ammonium d e r iv a tiv e s i t seemed a d v isa b le t o u se tétraméthylammonium bromide o r tetraethylam m onium bromide a s su p p o rtin g e l e c t r o l y t e i n p la c e o f th e more common potassium c h lo r id e , which i s o f no v a lu e a t p o te n tia l s i n th e v i c i n i t y o f o r g r e a te r th a n i t s own h alf-w ave p o t e n t i a l of -1*86 v o l t s .

The tétraméthylammonium

bromide was p rep ared b y th e r e a c tio n o f m ethanol and sodium bromide in c o n c e n tra te d s u lf u r ic a c id to g iv e m ethyl brom ide, which was bubbled in to anhydrous trim eth y lam in e.

The q u a te rn a ry s a l t se p a ra te d from th e

s o lu tio n a s uniform w h ite c r y s ta l s and was su b seq u en tly p u r if ie d by r e c r y s t a l l i z a t i o n from w ater and ethanol#

Eastman*s re a g e n t grade o f

th e t e t r a e t h y l s a l t was u se d , a f t e r b ein g r e c r y s ta lli z e d . The f i r s t esqaeriments w ith q u a te rn a ry ammonium s a l t s showed t h a t th e p resen ce i n s o lu tio n o f th e s e s a l t s a t p o te n tia l s above -2*0 v o lt s r e s u l t s i n *'s tre a m in g ,” o r v ery ra p id dropping o f v ery sman drops from th e m ercury cath o d e.

This e f f e c t was le sse n e d by d ecre asin g

th e column h eig h t o f m ercury to give a r e l a t i v e l y slow dropping r a t e in itia lly .

A lthough b o th th e q u a te rn a ry s a l t s used were reduced a t

hig h v o lta g e s , t h e i r polarogram s showed maxima o r p eak s, n o t to be confused w ith oxygen maxima, which w u ld i n t e r f e r e w ith d ete rm in a tio n o f compounds red u cin g above - 2 .0 v o l t s . M etals such a s cadmium and p o tassiu m , vAiich a re reduced a t p o te n tia ls low enough t o av o id th e d e s c rib e d maxima, gave s a ti s f a c to r y re d u c tio n cu rv es i n th e presence o f th e q u a te rn a ry s a l t s .

Ammonium

c h lo rid e d id n o t g iv e s a t i s f a c t o r y cu rv es due to in te r f e r e n c e o f th e maxima.

lô Aimoniim c h lo r id e , in th e absence o f a su p p o rtin g e l e c t r o l y t e , gave a good r e d u c tio n curve v d th wave h eig h t p r o p o r tio n a l to concen­ tra tio n .

The e l e c t r o l y s i s o f v ary in g c o n c e n tra tio n s of t e t r a e t h y l -

ammonium bromide and t e t rame t hylammoniim bromide shoved no such r e l a t i o n ­ s h ip ; re d u c tio n p o te n tia l s were low i n com parison v d th th o s e re p o rte d by Van E y sselb erg h e and McGee?^, and waves were so i r r e g u l a r as t o make a c c u ra te measurement im p o ssib le . The above r e s u l t s were a t t r i b u t e d t o th e presen ce o f im puri­ t i e s i n th e q u a te rn a ry s a l t s .

The m a te r ia ls were each r e c r y s ta lli z e d

th re e tim e s from w ater and e th a n o l.

The r e d u c tio n p o te n tia l (uncor­

re c te d ) o f tetraethylam m onium bromide a f t e r r e c r y s t a l l i z a t i o n was - 2 .7 v o lt s ; th e re d u c tio n p o te n tia l o f tétraméthylammonium bromide was about -2 .6 5 v o l t s .

This a g re e s w ith th e f in d in g s o f Gropp^^, t h a t th e

t e t r a e t h y l s a l t i s th e most d i f f i c u l t l y re d u c ib le o f th e q u a te rn a ry s a lts .

C h arac ter o f R eduction Waves The f i r s t p re lim in a ry t e s t s w ith B enadryl and T herylene, made b e fo re th e o th e r m a te r ia ls were a v a ila b le in th e la b o ra to r y , showed th a t th e s e caapounds i n aqueous s o lu tio n and i n th e absence o f any su p p o rtin g e l e c t r o l y t e , gave re d u c tio n waves in th e neighborhood of - 2 .0 v o l t s .

When 0.1!^ ammonium c h lo rid e was u sed a s th e su p p o rtin g

e l e c t r o l y t e , B enadryl gave a m easurable re d u c tio n wave up t o concen­ t r a t i o n s o f 6 mg^, above which th e wave merged w ith th e re d u c tio n wave o f th e su p p o rtin g e l e c t r o l y t e .

The h eig h t o f th e B enadryl wave

i n tétraméthylammonium bromide su p p o rtin g e l e c t r o l y t e was found n o t to

19 be re p ro d u c ib le w ith in a c c e p ta b le l i m i t s .

Comparison o f s e v e r a l con­

c e n tr a tio n s o f B enadryl i n d i s t i l l e d w a te r, 0*05^ ammonium c h lo r id e , 0 .1 ^ ammonium c h lo r id e , and 0 .1 m olar tetreaaethylammonium bromide showed t h a t o n ly i n d i s t i l l e d w a te r was wave h e ig h t even ap p ro x im ately p ro p o r tio n a l to c o n c e n tra tio n , w ith th e p o o re st r e s u l t s b ein g o b tain ed w ith th e q u a te rn a ry su p p o rtin g e l e c t r o l y t e . S e v e ra l c o n c e n tra tio n s o f B enadryl i n 0 .1 ^ ammonium c h lo rid e were e le c tr o ly z e d a t pH v a lu e s v ary in g from 3 to 7 .

The l a r g e s t curves

were o b ta in ed a t th e most a c id v a lu e , wave h e ig h t d e c re a sin g m arkedly a s pH approached 7 .

This would in d ic a te t h a t th e wave a t app ro x im ately

- 2 .0 v o lt s i s a c a t a l y t i c hydrogen wave r a t h e r th a n a t r u e re d u c tio n wave. S o lu tio n s o f th e n in e compounds s tu d ie d were e le c tro ly z e d i n a su p p o rtin g e l e c t r o l y t e s o lu tio n o f 0 .1 m olar ammonium c h lo rid e .

It

was n e c e ssa ry t o use a sm all amount o f h y d ro ch lo ric a c id to d is s o lv e th e A n th allan b a se ; th e o th e r ccmpounds were s u f f i c i e n t l y s o lu b le in w ater. A n th allan gave a good re d u c tio n wave; A n tis t i n e , Decapryn, Trim eton, and B enadryl gave sm all peaks; th e o th e r compounds gave no r e a c tio n .

A ll th e s o lu tio n s t e s t e d , w ith t h e ex ce p tio n o f t h a t o f

A n th a lla n , were i n th e ran g e o f pH 5»2-5.9* s o lu tio n was app ro x im ately 3#

The pH o f th e A n th allan

When th e o th e r s o lu tio n s were a d ju ste d

to pH 3 by a d d itio n of tw e n tie th - n o m a l h y d ro ch lo ric a c id , th e y a l l gave re d u c tio n w aves, alth o u g h n o t a s la r g e as i n th e case o f th e A n th allan s o lu tio n . E le c tr o ly s is o f corresponding s o lu tio n s c o n ta in in g 0 .1 m olar potassium c h lo rid e a s su p p o rtin g e l e c tr o l y te in s te a d o f potassium

20 c h lo rid e gave s im ila r bub u n s a tis f a c to r y r e s u l t s , some o f th e compounds a p p a re n tly b ein g red u ced a t p o te n tia l s more n e g a tiv e th a n th e re d u c tio n p o te n tia l o f potassium c h lo r id e .

Comparison o f hydrogen io n concen­

t r a t i o n w ith wave h e ig h ts i n th e above s o lu tio n s in d ic a te d t h a t th e re d u c tio n waves observed were th o s e o f th e hydrogen io n r a t h e r th a n of th e a n tih is ta m in e m a te r ia ls . A ll o f th e compounds s tu d ie d gave re d u c tio n waves i n 0 .1 m olar tetram etlylam m onium bromide su p p o rtin g e l e c t r o l y t e s o lu tio n s , a t poten­ t i a l s hig h enough to r u le out th e hydrogen io n .

The waves reco rd ed

were s o m e ^ a t i r r e g u l a r , and were n o t e a s il y m easured,

Neo-Antergan

and Trimeton most n e a r ly approached th e id e a l c o n d itio n of a re d u c tio n wave o f h e ig h t p r o p o r tio n a l to c o n c e n tra tio n .

The wave h e ig h ts were

no t re p ro d u c ib le . S im ila r ly , a l l o f th e compounds s tu d ie d gave re d u c tio n waves i n tetraethylam m onium bromide su p p o rtin g e l e c tr o l y te s o lu tio n s , b u t th e wave h e ig h ts were n o t p r o p o rtio n a l t o c o n c e n tra tio n , n o r were th e y re p ro d u c ib le .

I n most c a s e s th e c h a ra c te r o f th e wave changed m arkedly

w ith sm a ll changes i n c o n c e n tra tio n .

Orüy Decapryn gave any semblance

o f p r o p o r tio n a lity o f wave h e ig h t and c o n c e n tra tio n , and th e s e r e s u l t s were n ot s a t i s f a c t o r i l y re p ro d u c ib le . A fte r re p e a te d a ttem p ts t o o b ta in s a t i s f a c t o r y r e s u l t s , a l l o f which were u n s u c c e s s fu l, th e experim ents were brought to a c lo s e .

21 Summary and C onclusions The group o f a n tih is ta m in e compounds s tu d ie d in c lu d ed :

A n th a lla n ,

A n tis tin e , B en ad ry l, Decapryn, H is ta d y l (c h o n ic a lly id e n t i c a l w ith T henylene), N eo-A ntergan, N eohetram ine, Pyribenzam ine, and Trim eton. A ll o f th e s e compounds c o n ta in one o r more t e r t i a r y amine g ro u p s, and i n most o f them th e r e i s a n itro g e n h e te ro c y c le g ro u p . The fo llo w in g s a l t s were used a s su p p o rtin g e l e c tr o l y te s in th e co u rse o f th e in v e s tig a tio n :

ammonium c h lo r id e , 0.05^> 0 .1 ^ , and

0 .1 m olar; potassium c h lo r id e , 0 .1 m olar; tétraméthylammonium brom ide, 0 .1 m olar; and tetraethylam m onium brom ide, 0 .1 m olar. Ammonium c h lo rid e i s i t s e l f p o la ro g ra p h ic a lly r e d u c ib le , g iv in g a good c u rv e .

When a n e u t r a l 0 .1 m olar s o lu tio n o f ammonium c h lo rid e

was used a s a su p p o rtin g e l e c t r o l y t e , none o f th e a n tih is ta m in e s gave re d u c tio n w aves, b u t vfaen th e s o lu tio n s were a d ju ste d to pH 3 by a d d itio n of h y d ro c h lo ric a c id a curve was o b ta in ed i n ev ery c a s e .

This

c u rv e , however, proved to be due to th e re d u c tio n o f th e ex cess hydro­ gen io n i n s o lu tio n and n o t t o r e d u c tio n o f th e n itro g e n compounds. S im ila r r e s u l t s were o b ta in ed when 0 .1 m olar potassium c h lo r­ id e was used as a su p p o rtin g e l e c t r o l y t e , in d ic a tin g t h a t th e re d u c tio n o f th e a n tih is ta m in e s ta k e s p la c e , i f a t a l l , i n th e p o t e n t i a l range above th e re d u c tio n p o te n tia l s o f potassium and ammonium io n s . P r e l im i n a r y s tu d ie s w ith th e q u a te rn a ry ammonium s a l t s

in d ic a te d th e p resen ce o f im p u ritie s which were reduced a t approx­ im a te ly - 2 .0 v o l t s .

Tétraméthylammonium bromide and t e t r a e t h y l ­

ammonium brcanide were r e c r y s t a l l i z e d th r e e tim es from w ater and e th a n o l. The t e t r a e t h y l s a l t th u s p u r if ie d gave a lim itin g p o te n tia l o f about

22 2*7 v o lt s ; th e te tra m e th y l s a l t gave a s l i g h t l y more p o s itiv e v a lu e . The r e a c tio n o f a l l th e a n tih is ta m in e compounds s tu d ie d i n q u a te rn a ry ammonium su p p o rtin g e l e c tr o l y te s were s im i la r .

R eduction

cu rv es were o b ta in e d which s t a r t e d i n a v ery r e g u la r m anner, b u t b e fo re th e peak was reached i n each case th e curve became rough, and wave h e ig h ts v a rie d g r e a t ly .

The s iz e o f th e cu rv es b o re o n ly a

s l i g h t r e la tio n s h ip to c o n c e n tra tio n , and th e shape v a r ie d m arkedly w ith sm all changes i n c o n c e n tra tio n .

Curves were n o t found t o be

re p ro d u c ib le . In view o f th e s e f in d in g s , i t was concluded th a t p o laro g rap h ic re d u c tio n i s n o t a s a t i s f a c t o r y b a s is f o r q u a n tita tiv e d ete rm in a tio n o f th e a n tih is ta m in e d ru g s.

23 PART I I POLAROGRAPHIC STUDIES OF SOME OFFICIAL IRON PREPARATIONS In tro d u c tio n I ro n and i t s compounds have been used i n m edicines f o r many y e a r s , as h em atin ics and s t y p t i c s .

There a r e o f f i c i a l i n th e U* 8 .

Pharmacopoeia and th e N a tio n a l Form ulary some t h i r t y - e i g h t p re p a ra tio n s of iro n .

The f e r r i c s a l t s appear to have th e most v alu e as s t y p t i c s ,

b ein g r e l a t i v e l y i r r i t a t i n g when ta k e n i n t e r n a l l y , i n com parison w ith th e f e r r o u s s a l t s , which a r e ta k e n i n t e r n a l l y f o r t h e i r hem atinic p r o p e r tie s .

Complex f e r r i c s a l t s , such a s F e r r ic C acodylate and F e r r ic

Ammonium C i t r a t e , however, are g iv e n i n t e r n a ll y as to n ic s and a n t i anemic s ,

There a re a ls o s e v e r a l compounds o f ir o n o f f i c i a l which serv e

only as c o lo rin g a g e n ts i n o th e r o f f i c i a l p re p a ra tio n s . The o f f i c i a l p re p a ra tio n s o f f e r r i c ir o n a r e a H assayed v o lu m e tric a U y .

The p r in c ip le o f th e assay i s th e o x id a tio n o f potassium

io d id e by th e f e r r i c io n to l i b e r a t e f r e e io d in e , which i s t i t r a t e d w ith s ta n d a rd sodium t h i o s u l f a t e s o lu tio n .

Almost a l l o f th e fe rro u s

compounds a re assay ed by t i t r a t i o n w ith s ta n d a rd e e r ie s u l f a t e , u sin g o rth o p h e n a n th ro lin e as th e in d i c a to r .

There i s one in s ta n c e o f

d ir e c t t i t r a t i o n w ith potassium perm anganate, and i n one c a s e , th a t o f F erro u s Io d id e Syrup, th e amount o f th e ir o n s a l t i s determ ined by a rg e n to m e tric t i t r a t i o n o f th e an io n .

Survey o f th e L ite r a tu r e Leonhardt^ and Bowman^ re p o rt th e u se o f th e p o larograph to d e te c t th e p resen ce o f sm all amounts o f im p u r itie s , in c lu d in g th e

24 heavy m e ta ls , such a s i r o n , i n p h arm aceu tical p ro d u c ts .

Kamegai*^^

m entions th e use of th e p o laro g rap h f o r d e te rm in a tio n o f ir o n in b io lo g ic a l m a te r ia ls .

The b u lk o f th e l i t e r a t u r e , however, d e a ls w ith

th e a ssa y o f ir o n and s t e e l a l lo y s , examples o f which a re p ap ers by S tru b l7 4 and P r a jz le r ^ ^ .

V arious complexes o f ir o n have been suggested

f o r p o la ro g ra p h ic s tu d y ,

S an ig ar^^ has in v e s tig a te d th e fe rro c y a n id e ,

S ta c k e lb e rg and Freyhold^? th e o x a la te and f lu o r id e com plexes, and Komarek^® th e fe r r ic H n a n n ito l complex.

L ingane^^' ^

has g iven an

in t e r p r e t a t i o n o f th e p o la ro g ra p h ic a c t i v i t y o f complex m e tal io n s , and has review ed t h e a c tio n of o x a la te , c i t r a t e , and t a r t r a t e complexes o f ir o n .

There i s no re c o rd o f th e a p p lic a tio n o f th e p o la ro g ra p h ic

method t o th e d e te rm in a tio n o f th e m e d icin a l p re p a ra tio n s o f i r o n .

E xperim ental P a rt This in v e s tig a tio n was un d ertak en f o r th e purpose of stu d y in g th e p o la ro g ra p h ic r e a c tio n s of th e o f f i c i a l ir o n p re p a r a tio n s , w ith th e id e a o f dev elo p in g a workable p o la ro g ra p h ic a ssa y f o r t h i s group o f m e d icin a l s u b sta n c e s . The in stru m en t u sed was th e S arg en t Model XX v i s i b l e reco rd in g p o la ro g ra p h . (F ig u re 1 ) .

The L in g an e-L aitin e n H-type e l e c tr o l y s i s

c e l l (S arg en t #3-29322) was used w ith s a tu r a te d calom el e le c tro d e and a g ar plug p rep ared as d e s c rib e d by Lingane and L aitinen® ^.

Temperature

c o n tro l was m ain tain ed w ith in a range o f 25® G. - 1® by th e use of a la rg e w ater b a th c o n ta in in g a co o lin g c o i l o f s o f t copper tu b in g connected t o a P re c is io n S c ie n tif i c Company c o n sta n t tem p eratu re w ater c i r c u l a t o r (F ig u res 1 and 2 ) .

The oxygen maximum was su p p ressed by

25

F ig . 1—P olarograph With Temperature C o n tro l and Dropping E le c tro d e Assembly

2Ô

1

F ig . 2—C lose-up o f Dropping E le c tro d e Assembly

27 th e a d d itio n o f a sm all amount o f g e l a tin ( f i n a l c o n c e n tra tio n .005^) t o each s o lu tio n , fo llo w ed by b u b b lin g w ith n itro g e n w hich had f i r s t been s a tu r a te d w ith w ater by p a ssin g thro u g h a w ater t r a p (F ig u re 2 ) , A c o n s ta n t column o f mercury—60 cm. from th e to p o f th e m eniscus to th e t i p of th e c a p i lla r y —was used w ith th e dropping e le c ­ tr o d e .

The damping c o n tr o l o f th e in stru m en t was k ep t i n th e t h i r d

p o s itio n , and c o n c e n tra tio n s o f s o lu tio n s were a d ju s te d so a s to perm it th e use o f s e n s i t i v i t i e s i n th e second range o f th e in s tru m e n t.

Develonment o f th e Method P o laro g rap h ic A c tiv ity o f F e r r ic and F erro u s I r o n .

As a p re­

lim in a ry t o th e stu(fy o f th e o f f i c i a l ir o n p re p a ra tio n s , th e work o f L in g a n e ^ i n review ing th e r e a c tio n s o f th e t a r t r a t e , c i t r a t e , and o x a la te complexes o f f e r r i c and fe r r o u s io n s was re p e a te d .

D if f ic u l ty

was ex p erien ced i n reco rd in g re d u c tio n cu rv es i n some o f th e more a lk a lin e s o lu tio n s , due t o ju * e c ip ita tio n o f f e r r i c h y d roxide.

In th e

range o f pH from 5 to 7 & r e v e r s ib le system was o b serv ed , c o n s is tin g of an anodic wave corresp o n d in g to th e o x id a tio n of f e r r o u s to f e r r i c io n and g ra d u a lly s h if ti n g w ith in c re a s in g p o te n tia l to th e re d u c tio n o f th e f e r r i c complex to f e r r o u s io n . Half-wave p o te n tia l v a rie d w ith pH and w ith a change i n th e com plexing a g e n t—c i t r a t e , t a r t r a t e , o r o x a la te .

R eduction o f f e r r i c

complex to f e r r o u s io n o ccu rred below one v o l t .

R eduction o f fe rro u s

io n to th e m e ta llic s t a t e was observed o n ly in f a i r l y s tro n g ly a lk a lin e s o lu tio n (about pH 10 o r g r e a t e r ) .

The half-w ave p o t e n t i a l v a rie d w ith

pH and complexing a g e n t, b u t was i n th e neighborhood o f - 1 .5 v o lts#

2S A lthough no a c c u ra te measuremenbs were made, wave h e ig h ts appear to b e p r o p o rtio n a l to c o n c e n tra tio n , and w ith o u t any n o tic e a b le v a r ia tio n due t o change i n pH o r complexing a g e n t. Comparison o f Complexing Agents (S upporting E L e c tro lv te s ) .

The

p o la ro g ra p h ic re a c tio n s o f , f e r r i c c h lo rid e and fe r r o u s s u lf a t e were s tu d ie d ,

A s e r ie s o f d i l u tio n s — 2 x 10"*^ m o lar, 4 x 10"*^ m o lar,

6 X 10*“5 m o lar, Ô x 10"^ m o lar, and 10"^ m olar—o f each s a l t i n each o f a group o f su p p o rtin g e l e c tr o l y te s which a ls o serv ed a s complexing a g e n ts—0 .5 m olar sodium c i t r a t e , 0 .5 m olar sodium t a r t r a t e , 0 .5 m olar ammonium t a r t r a t e , 0 .5 m olar ammonium t a r t r a t e w ith excess ammonia (2 c c . o f s tr o n g e r ammonia w ater was added f o r each 100 c c , o f s o lu tio n ) , and 0 .2 m olar sodium o x a la te —was e le c tr o ly z e d and th e polarogram s re c o rd e d .

For each s e r i e s o f d il u tio n s a graph o f wave h eig h t v s .

c o n c e n tra tio n was p lo t t e d , and th e average d e v ia tio n o f th e ex p erim en tal r e s u l t s from th e id e a l s i t u a t i o n —a s t r a i g h t l i n e graph—was determ ined. For f e r r i c c h lo rid e th e r e a c tio n s in v o lv ed a re p robably th e re d u c tio n o f th e f e r r i c complex fo m ed w ith th e o rg an ic a c id r a d ic a l to th e fe r r o u s io n , follo w ed i n some c a s e s by th e re d u c tio n e i t h e r of a fe r r o u s complex o r th e fe rro u s io n t o th e f r e e s t a t e . In th e case o f fe r r o u s s u l f a t e an anodic wave in d ic a te d th e o x id a tio n o f f e r r o u s io n t o f e r r i c io n b e fo re a p p lic a tio n o f p o te n tia l , accord in g t o th e r e a c tio n Fe++ + w ith m ercurous io n s from th e anode.

Fe+++ + Hg® This wave was i n some in s ta n c e s

follow ed by a c ath o d ic wave o r waves r e s u l t i n g from th e re d u c tio n of fe rro u s complex a n d /o r f r e e fe rro u s io n s to th e m e ta llic s t a t e .

29 The d isc o v e ry o f some in c o n s is te n c ie s caused th e e n t ir e e x p e ri­ ment to b e r e p e a te d , u s in g a h ig h e r in stru m e n t s e n s i t i v i t y wherever p o s s ib le , and w ith p re c a u tio n s a g a in s t a i r o x id a tio n o f th e fe rro u s s a lt.

The c h a r a c t e r i s t i c s o f th e cu rv es observed a re in d ic a te d in

T ables 2 and 3 , along w ith q u a n tita tiv e r e s u l t s o f th e experim ent. Table 2 P o laro g rap h ic R eduction o f F e r r ic C hloride in C i t r a t e , T a r t r a te , and O xalate Media Average D ev iatio n

Type o f Medium

Wave C h a r a c te r is tic s

0*5 M sodium c i t r a t e

Very re g u la r wave w ith lo n g , f l a t p la te a u , i d e a l f o r a c c u ra te m easurm ient.

0 .3 $

0*5 M sodium t a r t r a t e

F i r s t wave—R eg u lar, b u t w ithout th e lo n g , f l a t p la te a u noted i n th e c i t r a t e so lu tio n * Second wave—L arge, i r r e g u l a r in sh ap e, su g g estin g re d u c tio n o f b o th a fe rro u s complex and fe rro u s io n a t s im ila r poten­ t i a l s , b len d in g in to th e wave of th e su p p o rtin g e le c tr o ly te *

1 .1 ^

0*5 M ammonium t a r t r a t e

R egular wave, w ith a long p la te a u . F i r s t wave—R e g u la r, rounded on to p , w ith a s h o rt p lateau * Second wave—Very r e g u la r , w ith a good, b u t n o t lo n g , p la te a u .

0,(>%

Very re g u la r wave, w ith lo n g , f l a t p la te a u f o r easy measure­ m ent.

0 .9 $

0*5 M ammonium t a r t r a t e w ith ex cess ammonia

0*2 M sodium o x a la te

1 .^ o,n%

30 T ab le

3

P o laro g rap h ic R eduction of F erro u s S u lfa te i n C i t r a t e , T a r t r a te , and O xalate Media Average D ev iatio n

Type o f Medium

Wave C h a r a c te r is tic s

0 .5 M sodium c i t r a t e

Anodic wave—r e g u la r , good i n i t i a l p la te a u f o r easy measurement.

0 .6 $

0 .5 M sodium t a r t r a t e

Anodic wave—r e g u la r , b u t w ith s h o rt i n i t i a l p la te a u vAiich becomes s h o r te r a s c o n c e n tra tio n i s in c re a s e d . Cathod wave—r e g u la r , b u t rounded, w ith a v e ry s h o r t, in c lin e d p la te a u .

1.3%

0 .5 M ammonium t a r t r a t e

Anodic wave—r e g u la r , b u t w ith sh o rt i n i t i a l p la te a u .

1.2%

0 .5 M ammonium t a r t r a t e w ith ex cess ammonia

F i r s t wave—i r r e g u l a r , p a r tl y a n o d ic , p a r tl y c a th o d ic , p ro b ab ly combining two o r th r e e e n t i t i e s a t o v erlap p in g p o te n tia l ra n g e s; no u sab le p la te a u . Second (c a th o d ic ) w a v e r e g u la r , w ith a good, f l a t , b ut not lo n g , p la te a u , h e ig h t not in c re a s in g in p ro p o rtio n to c o n c e n tra tio n .

k .l$

0 .2 M sodium o x a la te

Anodic wave—r e g u la r , w ith good i n i t i a l p la te a u .

1.0%

over 20%

0.6%

On th e b a s is of th e above o b s e rv a tio n s , th e t a r t r a t e s appear to be l e s s s a t i s f a c t o r y th a n th e o th e r s a l t s .

The e s p e c ia lly poor r e s u l t s

i n th e c a se o f ammoniacal ammonium t a r t r a t e may b e a t t r i b u t e d to th e lo s s o f ammonia from s o lu tio n , o r , more l i k e l y , p r e c i p ita tio n o f b a sic s a l t s o r hydroxides a t th e h ig h pH v a lu e produced.

31 F e r r ic ammonium c i t r a t e and fe rro u s ammonium s u l f a t e were s tu d ie d in c i t r a t e and o x a la te s o lu tio n s .

F erro u s ammonium s u lf a t e

gave good waves i n b o th m edia, average d e v ia tio n b ein g 1.6% i n c i t r a t e s o lu tio n and 1 .2 ^ i n o x a la te s o lu tio n .

The waves from f e r r i c ammonium

c i t r a t e were r e g u la r , b u t showed a g r e a te r d e v ia tio n —3*6^ i n o x a la te s o lu tio n and 2 .5 ^ in c i t r a t e s o lu tio n .

The o u tsta n d in g c h a r a c t e r i s t i c

was a len g th en in g ( in th e v o lta g e a x is ) o f th e upper p a r t o f th e c u rv e , which was more pronounced i n th e case o f th e c i t r a t e medium. E f f e c t o f p H.

S o lu tio n s o f 0 .01 m olar f e r r i c c h lo rid e in h a lf ­

m olar sodium c i t r a t e were an aly zed a t 0 .5 u n it i n t e r v a ls o v er th e pH range 2.O -Ô .0.

Below pH 4*5 i t was im p o ssib le t o g e t a m easurable

curve because o f th e co in cid en ce of th e anodic wave o f hydroxyl io n ( s i K +0.0Ô V .).

R e s u lts were s a ti s f a c to r y up to pH 6 .5 .

At pH 7 .0

and h ig h e r th e wave se p a ra te d in to two sm a lle r waves. S im ila r s o lu tio n s were an aly zed over th e range o f pH 4*5-7*0, th e i n t e r v a ls b ein g 0 .1 pH u n i t .

Wave h eig h t was found to be p r a c t i ­

c a l l y unchanged from pH 4 .5 to 6,7* above o c c u rs .

Above pH 6 .7 th e s e p a ra tio n n o ted

S t a t i s t i c a l a n a ly s is o f th e r e s u l t s gave a mean v a lu e ,

a f t e r obvious f r e a k s were d is c a rd e d , of 189.3 - 1*2 mm., a mean d ev i­ a tio n o f c o n sid e ra b ly l e s s th a n IS , o r so sm all as to be i n s i g n i f i c a n t . A s im ila r study was made u sin g 0*2 m olar sodium o x a la te in ­ s te a d o f h a lf-m o la r sodium c i t r a t e a s complexing agent and su p p o rtin g e le c tro ly te .

D eterm in atio n s were made over th e range of pH 2 .0 - 7 .0 ,

a t 0 .5 u n it i n t e r v a l s .

Good cu rv es were o b ta in ed th ro u g h o u t.

In th e

neighborhood o f pH 7 a drop i n wave h e ig h t accompanies th e fo rm atio n o f a p r e c i p ita te o f f e r r i c hydroxide.

From pH 2 .0 t o 6 .0 o r 6 .5 th e re

i s a sm all d e c re a se i n wave h e ig h t, about 0 .5 ^ p e r u n it o f pH,

32 A ir o x id a tio n o f fe rro u s s o lu tio n s in t e r f e r e d w ith d eterm ina­ t i o n s o f pH e f f e c t s on anodic wave h e ig h ts of fe r r o u s io n .

Such r e s u l t s

a s co u ld be o b ta in ed in d ic a te d t h a t i n o x a la te medium th e fe r r o u s wave d e c re a se s s l i g h t l y i n s iz e fr Q bO 6 flJ k 2 > ko H »

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19 SUMMARY AND CONCLUSIONS A number o f a n tih ls ta B iin ic compounds o f p h arm aceu tical im portance were s tu d ie d p o la ro g ra p h ic a lly .

The in o rg an ic s a l t s commonly u sed as

su p p o rtin g e l e c tr o l y te s in p o laro g rap h ic work were n o t u sa b le i n t h i s case because o f t h e i r r e l a t i v e l y low re d u c tio n p o te n tia ls *

T e tra m e tiy l—

ammonium bromide and tetraethylam m onium bromide vdiich had been r e p e a t­ ed ly r e c r y s t a l l i z e d were s a ti s f a c to r y su p p o rtin g e le c tr o ly te s *

AH o f

th e compounds s tu d ie d gave p o laro g rap h ic re d u c tio n waves> vdaich were n o t, however, p r o p o rtio n a l t o c o n c e n tra tio n , were n o t a lto g e th e r re p ro d u c ib le , and ten d ed to change i n shape w ith sm all changes i n co n cen tratio n * I n view o f th e s e f in d in g s , i t was concluded t h a t p o la ro g ra p h ic re d u c tio n i s n o t a s a ti s f a c to r y b a s is f o r q u a n tita tiv e d e te rm in a tio n o f th e a n tih is ta m in e drugs* The p o laro g rap h ic method o f a ssa y was a p p lied to a group o f tw e n ty -th re e o f th e t h i r t y - e i g h t o f f i c i a l s a l t s and p re p a ra tio n s o f iro n # These in c lu d ed a l l th e o f f i c i a l s a l t s and a t l e a s t one r e p r e s e n ta tiv e o f each ty p e o f p re p a ra tio n i n which ir o n i s o f f i c i a l —powders, cap­ s u le s , p i l l s , t a b l e t s , m ix tu re s, sy ru p s, and aqueous, a lc o h o lic , and h y d ro alc o h o lic s o lu tio n s . I t may be concluded th a t th e p o laro g rap h ic method i s s a t i s f a c t o r y f o r th e assay of most o f th e sim ple o r m oderately complex o f f i c i a l ir o n s a l t s and p re p a ra tio n s —F e r r ic Ammonium C it r a te , Green F e r r ic Ammonium C i t r a t e , F e r r ic C acodylate Ampuls, F e r r ic C hloride S o lu tio n , F e r r ic C hlorid e T in c tu re , F e r r ic C itro c h lo rid e T in c tu re , F e r r ic G lycerophos­ p h a te , F e r r ic H ypophosphite, Bed and Yellow F e r r ic O xides, S o lu b le F e r r ic P h osphate, F e r r ic S u b su lfa te S o lu tio n , F e r r ic S u lfa te S o lu tio n ,

20 F errou s S u lf a t e , F erro u s S u lf a te T a b le ts , F errous Carbonate P i l l s , S acch arated F erro u s C arbonate, F erro u s G luconate, and Reduced Iro n Capsules*

I n th e c a s e s o f F e r r ic Ammonium C itr a te and F e rric G lycero­

phosphate th e p o la ro g ra p h ic method appears to be more a c c u ra te th a n th e o f f i c i a l a s s a y s , th e c o n d itio n s o f which do n ot fa v o r com plete r e a c tio n and so te n d tow ard erroneous r e s u l t s . In th e case o f p re p a ra tio n s co n tain in g la rg e amounts o f org an ic m a tte r—B eef, Iro n and Wine; Iro n and Ammonium A cetate S o lu tio n ; Pepto­ n iz e d Iro n and Manganese S o lu tio n ; F errous Io d id e Syrup—th e d i f f i c u l t y i n s e p a ra tin g th e ir o n from m a te r ia ls vAiich would i n t e r f e r e w ith p o la ro ­ g rap h ic d e te rm in a tio n , and th e r e l a t i v e l y low degree o f a c c u racy , p rev en t th e acceptance o f th e p o la ro g ra p h ic method as a co m p letely p r a c t i c a l s u b s t itu t e f o r th e o f f i c i a l assay s o f th e s e p a r ti c u la r p re p a ra tio n s* The advantages o f th e p o la ro g ra p h ic method i n th e a ssa y o f th e o f f i c i a l ir o n p re p a ra tio n s l i e m ain]^ i n i t s a d a p t a b il ity to a n a l y tic a l c o n tr o l in v o lv in g th e a n a ly s is o f la r g e numbers o f sam ples.

Once th e

c a l ib r a t io n o f wave h e ig h t a g a in s t a known c o n c e n tra tio n o f ir o n has been com pleted f o r a g iv en c a p illa r y and g iv e n in stru m en t s e t t i n g s , no f u r t h e r c a l ib r a t io n i s n e c e ssa ry .

The need f o r s ta n d a rd s o lu tio n s

\diich must be c a r e f u l ly sta n d a rd iz e d and th e n re s ta n d a rd iz e d from tim e t o tim e , as i s th e case w ith sodium t h i o s u l f a t e and potassium peiroang a n a te s o lu tio n s , i s e lim in a te d .

I n a d d itio n , th e polarogram a ffo rd s

a d i r e c t , pennanent re c o rd o f each d e te rm in a tio n . The main disad v an tag e o f th e p o laro g rap h ic method f o r th e assay o f o f f i c i a l ir o n p re p a ra tio n s l i e s i n th e n e c e s s ity o f o b ta in in g th e ir o n i n th e com pletely io n iz e d f e r r i c s t a t e .

Iro n r e a d ily form s com­

p le x e s w ith a wide v a r ie ty o f organic m a te r ia ls , and th e d e s tr u c tio n o f th e s e complexes re q u ire s s p e c ia l tim e— consuming tre a tm e n t o f th e sam ples.

21 BIBLIOGRAPHY !♦

Shakhov, A* S . , "The use o f th e p o laro g rap h ic method i n pharmaceu­ t i c a l ch e m istry ," Chem. Z e n tr. 1938. I , 3947*

2.

L eo n h ard t, H ., "New p h y s ic a l and physicochem ical pro ced u res f o r th e e v a lu a tio n o f m é d ic in a le ," E. M erck's J a h re s b e r. jO , 141 (1 9 3 6 ).

3»

Bowman, P* T ., e t a l , "The p o laro g rap h . A new a n a l y tic a l t o o l f o r p h arm a ceu tical re s e a rc h ," P ro c. Am. Pharm. M frs. A sso c ., D ec., 1942, Mid-Year M eeting, 30.

4.

K iriq ja tric k , H, F, W., "P olarographic stu d y o f a lk a lo id s . I , " Q u art. J . Pharm. Pharmacol. I g , 245 (1945).

5*

■

"P o laro g rap h ic stu d y o f a lk a lo id s . I I , " i b i d . . 338 (1945)*

6.

. "P o laro g rap h ic stu d y o f a lk a lo id s . I l l , " i b i d . . 1 9 . 8 (1 9 4 6 ).

7#

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"P o laro g rap hic stu d y o f a lk a lo id s . IV ," i b i d . . 12? (1946)#

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. "P o laro g rap hic stu d y o f a lk a lo id s . V," i b i d . . 526 (1946)*

9.

D e z e lic , M ., and Herak, J . , "P olarographic in v e s tig a tio n s o f g lu c o s id e s . I . S a lic in and i t s d e r iv a tiv e s ," Chem. Z e n tr. 19A3. I I . 1086#

10.

H ershberg, E. B ., W olfe, J . K ., and F ie s e r , L. F . , "P o laro g rap h ic d e te rm in a tio n o f c e r t a in n a tu r a l p ro d u c ts ," J . Am. Chem. Soc. 62. 3517 (1940).

11#

G illam , W. S . , "P o laro g rap h ic d eterm in a tio n o f v ita m in C i n f r u i t s and v e g e ta b le s ," In d . Eng. Chem., A nal. Ed. XL» 217 (1945)*

12,

Tompkins, P . C ., and Schm idt, 0 . L. A ., "P o laro g rap h ic c h a ra c te r­ i z a tio n o f n ic o tin ic a c id and r e la te d compounds. I . P y rid in e and n ic o tin i c a c id ," J . B io l. Chem. 143. 643 (1942).

13,

W oHeriberger, A ., "A c a t a l y t i c e f f e c t o f tliiam ine a t th e dropping m ercury e le c tr o d e ," S cience 101. 386 (1945)*

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B rd ic k a , R ., and Knobloch, S ., "P o laro g rap h ic stu d y o f r ib o f l a v in . I# D eterm in atio n o f o x id a tio n -re d u c tio n p o t e n t i a l s ," Z. Elektrochem . XL» 721 (1 941).

15*

Page, J . E . , and Robinson, F. A ., "P o laro g rap h ic s tu d ie s . I I . Mold m e ta b o lite s and r e l a t e d q u in o n es," J . Chem. Soc. 1943. 133,

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Levy, G. B ., Schwed, P ., and S a c k e tt, J . W., "P o laro g rap h ic a n a ly s is o f stre p to m y c in ," J . Am. Chem. Soc. 528 (1946),

17 .

M u lli, K ., and W erner, H ., "A physicochem ical method f o r th e assay o f in s u l i n p re p a ra tio n s ," Deut. med. Wochschr. 1941 (1 9 3 7 ).

22 18.

Thomassen, J . , "P o laro g rap h ic s tu d ie s o f th e growth hormone, in s u l i n and o th e r hormones o f p ro te in s t r u c t u r e ," A cta B revia N eerland P h y s io l., Pharm acol. M ic ro b io l. 2» ^3 (1 939).

19#

Duncan, J . B ., and C h r is tia n , J . E ,, "P o laro g rap h ic d eterm in a tio n o f f o l i c a c id and zin c s a l t s i n p h a rm a c e u tic a ls," J . Am. Pharm. A sso c., S c i. Ed. ]%, 50? (1 948).

20.

M ader, J . W., and F r e d ia n i, H. A ., "P o laro g rap h ic d ete rm in a tio n o f f o l i c a c id ," A nal. Chem. 1199 (1948).

21.

W essely, F . , and W r a til, J . , "The p o laro g rap h ic b eh av io r o f s tilb e n e d e r iv a tiv e s ," Microchemie v e r . Mikrochim. Acta 21» 248 (1 9 4 7 ).

22*

B ingenheim er, L. E ., J r . and C h r is tia n , J . E ., "P o laro g rap h ic s tu d ie s o f d i e t h y l s t i l b e s t r o l ," J . Am. Pharm. A sso c., S c i. Ed. 117 (1949)#

23.

P ech, J . , "P o laro g rap h ic s tu d ie s w ith th e dropping-m ercury cath o d e. XXXVIII. R eduction of some a lip h a tic am ines, q u in o lin e , and s a c c h a rin ," C o lle c tio n Czech. Chen. Commun. 6 , 126 (1 9 3 4 ).

24.

Gropp, A. H ., "P o laro g rap h ic re d u c tio n o f m ethyl and e th y l r a d ic a ls o f q u a te rn a ry ammonium s a l t s , " Unpublished Ph.D. t h e s i s . U n iv e rs ity o f Oregon, 1947.

25.

L ingane, J . J . , "P o laro g rap h ic in v e s tig a tio n of o x a la te , c i t r a t e , and t a r t r a t e complexes of f e r r i c and fe rro u s ir o n ," J . Am. Chem. Soc. 2448 (1946).

26.

L ingane, J . J . , and L a itin e n , H. A ., " C e ll and dropping e le c tro d e f o r p o la ro g ra p h ic a n a ly s is ," In d . Eng. Chem., A nal. Ed. H » 504 (1939).

27.

P e rra c h io , E. S . , and Meloche, V. W., " E ffe c ts o f s o lv e n ts on p o la ro g ra p h ic wave h e ig h ts ," J . Am. Chem. Soc. 1770 (1 9 3 8 ).

VITA L evi Edwin B ingenheim er, J r . , was b o m on August 13, 1921, a t B raggadocio, M isso u ri, and a tten d ed elem en tary and hig h sch o o ls th e r e .

He m a tric u la te d in th e U n iv e rsity o f Tennessee School o f

P ham acy, re c e iv in g th e degree o f B achelor o f S cience i n Pharmacy i n J u n e , 1941. A fte r g ra d u a tio n he was employed f o r e ig h t months a s manager o f a r e t a i l drug s to r e , and f o r s ix te e n months a s a c o n tro l chem ist by th e A tla s Powder Company, Weldon S p rin g , M isso u ri.

He served in

th e M edical Department o f th e Army f o r two and o n e -h a lf y e a r s , as p h a m a c is t and c l i n i c a l la b o ra to ry te c h n ic ia n i n Army h o s p ita ls in t h i s co u n try and Europe* He e n tered th e G raduate School o f Purdue U n iv e rs ity in Septem ber, 1946, and accep ted an American Foundation f o r Pharmaceu­ t i c a l E ducation fe llo w s h ip in p h arm aceu tical ch em istry i n J u ly , 1947, re c e iv in g th e degree o f M aster o f S cience i n Ju n e , 1948, and th e d eg ree o f D octor o f Philosophy in F eb ru ary , 1950. Mr. Bingenheimer i s r e g is te r e d a s a pharm acist i n M isso u ri and i s a member o f Kappa P s i, Rho C hi, P h i Lambda U p silo n , and Sigma Xi*