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Quinine Hydrochloride
QUININE HYDROCHLORIDE Farid J . Muhtadi, Mohammed A . Loutfy, and Mahmoud M.A. Hassan 1. Description 1. I Nomenclature 1.2 Formulae 1.3 Molecular Weight 1.4 Elemental Composition 1.5 Appearance, Color, Odor, and Taste 2. Physical Properties 2.1 Melting Range 2.2 Eutectic Temperature 2.3 Solubility 2.4 Loss on Drying 2.5 pH Range 2.6 Optical Rotation 2.7 Spectral Properties 3. Preparation of Quinine Hydrochloride 3.1 Synthesis of Quinine 3.2 Quinine Hydrochloride 4. Synthesis of Quinine 4.1 Partial Synthesis 4.2 Total Synthesis 5. Biosynthesis of Quinine 6. Metabolism 7. Pharmacokinetics 8. Indications and Dosages 8.1 For The Treatment of Malaria 8.2 For The Relief of Nocturnal Leg Cramps 9. Toxicity 10. Methods of Analysis 10.1 Identification 10.2 Gravimetric Methods 10.3 Titrimetric Methods 10.4 Chromatographic Methods 10.5 Spectroscopic Methods References
ANALYTlCAL PROFILES OF DRUG SUBSTANCES VOLUME 12
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548 548 548 554 554 554 554 554 554 554 554 555 555 555 567 567 567 569 569 569 583 586 587 587 587 588 588 589 589 59 1 591 595 606 612
Copyrighi by ihe American Pharmaceutical Assacration. ISBN 0-12-260812-7
FARID J. MUHTADI ETAL.
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1. Description 1.1. Nomenclature 1.1.1 Chemical Names
a) Cinchonan-9-01, 6'-methoxy, (8a, 9R) hydrochloride (1:l) salt, dihydrate.
1.1.2
b)
(8S, 9R)-6'-methoxy cinchonan-9-01, hydrochloride (1:1) salt, dihydrate.
c)
a-(6-methoxy-4-quinolyl)-5-vinyl-2-
d)
6-methoxy- a ( 5-vinyl-2-quinuclidinyl) -4-quinolinemethanol, hydrochloride (1:l) salt, dihydrate.
e)
( a s ) - ~.-(6-methoxy-quinolin-h y1)-
quinuclidinemethanol, hydrochloride (1:l) salt, dihydrate.
-
Generic Names Quinine Quinine Quinine Quinine
1.2.
a
-[ (2R, 4S, 5R)-( 5-vinylquinuclidin2 yl)] methanol, hydrochloride (1:l) salt, dihydrate.
hydrochloride j chloride; monohydrochloride; muriate.
Formulae 1.2.1 Empirical
549
QUININE HYDROCHLORIDE
1.2.2
Structural
The structure of quinine was finally postulated by Rabe (1)and was confirmed by the total synthesis of quinine which was achieved by several authors (2-7). 1.2.3
CAS Registry Number [ 130-89-2I
1.2.4
Wiswesser Line Notation T66 BNJ HOlE YQ-DT66 A B CNTJ AlUl & EH &
1.2.5
QH
(8)
Stereochemistry The stereochemistry of quinine and other related cinchona alkaloids is well summarised by Finar (9)and Turner and Woodward (10).
550
FARID J . MUHTADI ETAL.
If Q represents t h e quinoline h a l f , t h e s t r u c t u r e of q u i n i n e may be w r i t t e n as f o l l o w s :-
The above formula c o n t a i n s f i v e c h i r a l c e n t e r s : 1,3,4,8 and 9 . Since t h e b r i d g e must b e a c i s f u s i o n , c e n t e r s 1 and 4 behave as "one c h i r a l u n i t " , t h e r e f o r e , t h e number of o p t i c a l l y a c t i v e forms would be t h e same as o b t a i n e d from f o u r c h i r a l c e n t e r s . When t h e 1-8 bond i s broken, t h e c h i r a l i t y of t h e n i t r o g e n i s l o s t . Q u i n i n e , q u i n i d i n e , cinchonine and cinchonidine g i v e on d e g r a d a t i o n t h e o p t i c a l l y i d e n t i c a l 8oximino-3-vinylquinuclidine [ 1] , meroquinene [ 21 and c i n c h o l o i p o n i c a c i d [ 31. It t h e r e f o r e f o l l o w s t h a t t h e c o n f i g u r a t i o n s o f C and C4 are t h e same 3 f o r a l l t h r e e compounds.
Conclusive evidence f o r t h e c i s arrangement a t C3 and C 4 w a s provided by P r e l o g and Zalan (11). They reduced cinchonine t o dihydrocinchonine and converted t h e product i n t o c i n c h l o p i o n e t h y l e s t e r [ 4 1 i n which C3 and C 4 r e t a i n t h e o r i g i n a l conf i g u r a t i o n o f cinchonine. [ 4 ] w a s converted i n t o t h e dibromide [ 5 ] which by means o f a s e r i e s of r e a c t i o n s , a l l of which proceeded under mild c o n d i t i o n s and d i d not i n v o l v e t h e c h i r a l c e n t e r s , was converted i n t o 1,2-diethylcyclohexane [6]. This was shown t o be o p t i c a l l y i n a c t i v e ( i t could not be r e s o l v e d ) .
QUININE HYDROCHLORIDE
55 1
The o p t i c a l r e s u l t s provide c o n c l u s i v e evidence f o r a c i s arrangement of t h e two e t h y l groups i n t h e diethyl-cyclohexane [ 6 ] and s i n c e none of t h e s t e p s employed i n t h e conversion of c i n chonine t o [ 6 ] i n v o l v e s t h e c h i r a l c e n t e r s a t C3 and C4, t h e v i n y l group of t h e n a t u r a l cinchona b a s e s must be c i s t o t h e c7-c8 bond i n a l l alkaloids. The 9-deoxy d e r i v a t i v e s ( i : e , CH2 h a s r e p l a c e d CHOH) of cinchonine and c i n c h o n i d i n e have d i f f e r e n t s p e c i f i c r o t a t i o n s , a t + 179.3' and - 29.9', r e s p e c t i v e l y . Since t h e c o n f i g u r a t i o n s of C3 and C4 a r e t h e same i n b o t h b a s s e s and s i n c e C9 i s no l o n g e r o p t i c a l l y a c t i v e , t h e d i f f e r e n c e between t h e two must be a t c 8 , and t h i s i s therefore, a l s o t h e c a s e f o r cinchonine and cinchonidine. S i m i l a r l y s i n c e [ a ] o~f deoxyquinine i s - 97.7' and t h a t of deoxyq u i n i d i n e i s + 211.1', t h e n q u i n i n e and q u i n i d i n e d i f f e r a t c8. The assignment of c o n f i g u r a t i o n s a t c8 may be deduced from t h e f a c t t h a t q u i n i d i n e and c i n chonine a r e b o t h d e x t r o r o t a t o r y and b o t h can be converted i n t o t h e i r c y c l i c e t h e r s [ T I . On t h e o t h e r hand q u i n i n e and c i n c h o n i d i n e are b o t h l e v o r o t a t o r y and do not form c y c l i c e t h e r s .
FARID J. MUHTADI ETAL.
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The c y c l i c e t h e r s t r u c t u r e i s only p o s s i b l e if t h e group a t t a c h e d t o C 3 and C 8 are i n t h e endop o s i t i o n [ 81. Thus i n cinchonine and q u i n i d i n e , t h e hydrogen atoms a t C 3 and c8 a r e c i s with r e s p e c t t o each o t h e r . Also,because C 4 and C 8 a r e c i s - o r i e n t e d , it follows t h a t t h e hydrogen atoms a t C 3 , C 4 and C 8 a r e a l l c i s - o r i e n t e d i n cinchonine and quinidine whereas i n cinchonidine and quinine t h e hydrogens a t C 3 and C 4 are c i s , but t h e hydrogen a t C 3 and c8 are t r a n s . For each c o n f i g u r a t i o n a t c8, two isomers a r e p o s s i b l e which d i f f e r i n o r i e n t a t i o n a t Cg. Since a l l a l k a l o i d s a r e i d e n t i c a l i n c o n f i g u r a t i o n except a t c8 and Cg, four isomeric substances a r e p o s s i b l e i n each s e r i e s . For example, two of t h e s e substances are presented by quinine and q u i n i d i n e , t h e o t h e r two members a r e epiquinine and epiquinidine. The o t h e r two members a r e cinchonine, cinchonidine, epicinchonine and epicinchonidine. I n most r e s p e c t quinine and quinidine p a r a l l e l one another c l o s e l y i n t h e i r chemical behavior and d i f f e r q u a l i t a t i v e l y from t h e isomeric p a i r , epiquinine and epiquinidine. Since quinine and quinidine d i f f e r i n c o n f i g u r a t i o n a t c8, t h e s e f a c t suggest t h a t t h e two a l k a l o i d s d i f f e r a l s o i n configuration a t C It i s p o s s i b l e t o deduce t h e c o n f i g u r a t i o n a t 9 by comparing t h e b a s i c i t i e s of quinine and i t s Cg-epimer with t h e b a s i c i t i e s of (-)-ephedrine and (+)-$-ephedrine.
z.
:$CH2
H$UH:I3 Ph ( - )ephedrine
( pKt3
9.14
Hl*N CH2
k l . H 3
-
H
Ph Q Q ( +)-%ephedrine ( - )quinine (+) epiquinine 9.22
7.73
8.40
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QUININE HYDROCHLORIDE
The c o n f i g u r a t i o n of ephedrine (erythroc o n f i g u r a t i o n ) and $-ephedrine ( t h r e o c o n f i g u r a t i o n and t h e s t r u c t u r e of quinine and epiquinine have been drawn ( a s above) so t h a t comparison can be made for c8 and C 9 . Inspection of t h e pKa values shows t h a t JIephedrine i s a s t r o n g e r base t h a n ephedrine and t h a t epiquinine i s a s t r o n g e r base t h a n q u i n i n e , by a n a l o m , (+)-epiquinine i s t h e r e f o r e probably r e l a t e d t o (+)-$-ephedrine i n c o n f i g u r a t i o n and Thus, t h e con(-)-quinine t o (-)-ephedrine. f i g u r a t i o n s a t C 8 and C9 i n (-)-quinine and ( + ) epiquinine a r e probably t h o s e shown i n t h e above formulae. If t h e s e c o n f i g u r a t i o n s are accepted, then t h e r e l a t i v e c o n f i g u r a t i o n s a t C 3 , C 4 , c8 and Cg a r e now known. It i s now p o s s i b l e t o w r i t e t h e a b s o l u t e c o n f i g u r a t i o n s of t h e s e a l k a l o i d s . Lyle and Keefer ( l l a ) have confirmed t h a t t h e n a t u r a l cinchona a l k a l o i d s a r e a l l of t h e erythroc o n f i g u r a t i o n with r e s p e c t t o t h e i r C8 and C 9 systems.
HO --C
I
Q/H '
( - )quinine
H (+)quinidine
H--d Q '
,OH
epiquinine
epiquinidine
FARID J. MUHTADI E T A .
554
1.3.
Molecular Weight
396.88 ( d i h y d r a t e ) 360.88 (anhydrous )
1.4.
Elemental Composition C , 60.53%; H, 7.36%; N, 7.06%; 0 , 16.13%; C1, 8.92% ( d i h y d r a t e ) C, 0,
1.5.
66.57%; H, 6.98%; N, 7.76%; 8.87%; C 1 , 9.81% (anhydrous)
Appearance, C o l o r , Odor and Taste Fine c o l o r l e s s o r white s i l k y n e e d l e - l i k e c r y s t a l s , o f t e n grouped i n c l u s t e r s , o d o r l e s s , and has a v e r y b i t t e r t a s t e .
2.
Physical Properties 2.1.
Melting Range Quinine hydrochloride m e l t s a t : 145 - 153' ( 1 2 ) by hot s t a g e method ( 1 2 ) by h o t b a r method 162O 158 - 160° (13)
156
2.2.
2.3.
- woo
(8)
Eut ec t i c Tempera t u r e Phenacetin Benzanilide
100'
Phenacetin Benzanilide
106"
114'
118'
( 1 2 ) by h o t s t a g e method ( 1 2 ) by hot b a r method
Solubility One gram d i s s o l v e s i n 23 m l o f w a t e r a t 20°, i n 1 . 0 m l of a l c o h o l ( 9 6 % ), i n about 1 . 0 m l chloroform, i n about 7 . 0 m l g l y c e r o l and i n about 350 m l e t h e r .
2.4.
Loss on Drying When d r i e d t o c o n s t a n t weight a t 105O, l o s s e s 6.0 t o 10% of i t s weight ( u s i n g 2 . 0 g ) ( 1 4 ) .
555
QUININE HYDROCHLORIDE
2.5. pH Range 1% aqueous solution of quinine hydrochloride has a pH of 6.0 - 7.0.
2.6. Optical Rotation The following optical rotations were reported. [ a
,I
- 57.1 - 133.7 - 149.8 - 145.5 - 240 to
-
258
Solvent
Ref.
chloroform
(15)
water
(15)
1.3% in water 97% ethanol
(8) (15)
2% solution in 0.1 N hydrochloric acid
(13,14)
The specific rotation of quinine hydrochloride as 2% ethanolic solution has been determined by using a Parkin Elmer Polarmatic model 241 MC and found to be [ cy,]
2.7.
-144.25'
Spectral Properties
2.7.1
Ultraviolet Spectrum The UV spectrum of quinine hydrochloride in ethanol was scanned from 190 to 400 nm using DMS 90 Varian Spectrophotometer. It exhibited the following UV characteristics (Fig.1). Table 1 UV characteristics of quinine hydrochloride. X h x . at 205 232
277 321 332
E -
2381 2858 3334
Figure 1. The W Spectrum of Quinine Hydrochloride i n Ethanol
557
QUININE HYDROCHLORIDE
Other r e p o r t e d U.V. s p e c t r a l d a t a f o r quinine hydrochloride i n a l c o h o l ( 8 ) :-
Xmax. a t 278 nm (2512) and 331 nm (3236) and for quinine i n ethanol ( 1 6 ) :Xmax. a t 236 nm ( E 1%, 1 cm 1110), 278 nm ( E 1%, 1 cm 133) and 332 ( E 1%, 1 cm 1 6 3 ) . The UV absorption s p e c t r a of quinine and i t s hydrochloride s a l t i n o t h e r s o l v e n t s were also reported (16-18). 2.7.2
I n f r a r e d Spectrum The I R spectrum of quinine hydrochloride a s KBr-disc was recorded on a Perkin Elmer 580B I n f r a r e d Spectrophotometer t o which I n f r a r e d Data S t a t i o n i s a t t a c h e d (Fig. 2 ) . The s t r u c t u r a l assignments have been c o r r e l a t e d with t h e following frequencies (Table 2 ) . Table 2. I R c h a r a c t e r i s t i c s of quinine hydrochloride. Frequency cm
-1
Assignment
3300
OH bonded
2580 2960
NH ( q u i n u c l i d i n e ) CH s t r e t c h
1615 1600,1512,1480 1248,1230,1100,1030 860,838,808,725
+
CN
[ C=C ( a l k e n e ) C=C (aromatic ) e t h e r linkage T r i subst it u t ed benzene
Other c h a r a c t e r i s t i c absorption bands a r e : 1438,1365,1345,1320,1140,1130,1010,990 , 935, cm-1. Other I R d a t a f o r quinine hydrochloride ( 8 ) and f o r quinine (16) have been a l s o reported. Hayden and Sammul (19) described t h e I R s p e c t r a of dimorphous and amorphous forms of quinine.
FIG. 2
THE
IR
SPECTRUM OF Q U I N I K E HYDROCHLORIDE A S KBR DISC.
559
QUININE HYDROCHLORIDE
2.7.3
Nuclear Magnetic Rosonance S p e c t r a 2.7.3.1
Proton S p e c t r a The PMR s p e c t r a of q u i n i n e hydroc h l o r i d e i n d e u t e r a t e d chloroform and d e u t e r a t e d d i m e t h y l s u l f o x i d e were recorded on a Varian T - ~ O A , 60-MH, NMR Spectrometer u s i n g TMS ( T e t r a m e t h y l s i l a n e ) as an i n t e r n a l r e f e r e n c e . These a r e shown i n Fig. 3 and Fig. 4 r e s p e c t i v e l y . The f o l l o w i n g s t r u c t u r e assignments have been made (Table 3). Table 3 PMR c h a r a c t e r i s t i c s of quinine hydrochloride
Group
Chemical S h i f t (ppm) CDC13
DMSO
D6
s = s i n g l e t , d = doublet, q = quartet m = m u l t i p l e t b s = broad s i n g l e t bd = broad d o u b l e t , 2d = doublet of d o u b l e t s , b t = broad t r i p l e t . Other PMR s p e c t r a l d a t a of q u i n i n e and i t s hydroc h l o r i d e d i h y d r a t e s a l t i n C D C l have been r e p o r t e d 3 (8, 2 0 ) .
4
560
m
J V
n
-z
u
W
ff a
0 I J
V
0
e n >
Y
L'
W
--.3
c
U
0
E
0 3
e
u
l-
W
a VY
of
E M
2 LL
FIG. 4 Hf'%
SPECTRUM OF k J l N l N E
HYDROCHLORIDE I N Dr;sO-Dg
FARlD J . MUHTADI ETAL.
562
2.7.3.2
13
C-NMR
13
C-NMR n o i s e decoupled and o f f resonance s p e c t r a are p r e s e n t e d i n F i g . 5 and Fig. 6 r e s p e c t i v e l y . Both were recorded over 5000 Hz width i n C D C l 3 ( c o n c e n t r a t i o n 52.9 mg/l ml) on J e o l FX-100 NMR Spectrometer, u s i n g a 1 0 mm sample t u b e and TMS as a r e f e r e n c e s t a n dard a t 20'. The carbon chemical s h i f t s are a s s i g n e d on t h e b a s i s of t h e a d d i t i v i t y p r i n c i p a l s and t h e o f f resonance s p l i t t i n g p a t t e r n (Table 4 ) .
Table 4. Carbon no.
Carbon Chemical S h i f t s of q u i n i n e hydrochloride.
Chemical s h i f t [ PPm 1
Carbon no.
Chemical s h i f t [ PPm 1
c6
158.12(s)
c5 c10
99.79 ( d ) 65.99 ( d )
c3
146.81( d ) 144.34(s)
c11
60.14 ( d )
c9
143.42(s)
c16
56.99 ( t )
r w
El
-1
0
a I
U
0
a
CI
t I
2
W
-z -z
Q
0
LL
z 3 a I-
U W
n.
v)
n
W -I
0
3
n.
U
W
P L
v)
W
0
z
4
M
V
T
r
oc
4 In
2 LL
FIG. 6
13C-NMR
OFF RESONANCE SPECTRUM OF 3 U I N I N E
HYDROCHLORIDE.
QUININE HYDROCHLORIDE
‘18
137.37 ( d
‘8
131.03( d )
C4
C
7
c2 C
19
125.25(s) 122.17(d) 118.81(d)
117 15( t
565
c20 ‘1 5
‘17 ‘13 52 ‘14
54.70 ( 9 ) 44.11( t ) 37.12( d ) 26.91( a ) 24.29( t ) 18.13( t )
s = s i n g l e t , d = doublet, t = t r i p l e t , q = q u a r t e t . Other 13C-NMR s p e c t r a l d a t a of qninine have been r e p o r t e d (21, 22).
2.7.4
Mass Spectrum The mass spectrum of quinine hydrochloride obtained by e l e c t r o n impact i o n i z a t i o n which w a s recorded on a Finnigan Model 3000 D GC-MS-system. The spectrum scanned t o mass 500 with u n i t r e s o l u t i o n . Electron energy was 7Oev. The chemical i o n i z a t i o n mass s p e c t r a l d a t a were obtained on a Finnigan Model 1015D GC Mass Spectrometer. Methane w a s used as GC c a r r i e r gas and a l s o served as t h e C I r e a c t a n t gas i n t h e i o n source. The i o n source temperature w a s 180Oc and e l e c t r o n energy 100 ev., i o n r e p e l l e r , 3V. E l e c t r o n impact mass s p e c t r a l d a t a : Base Peak 136
Fig. 7 (23).
42, 55, 67, 81, 95, 117, 128, 136, 158, 172, 1.89, 202, 222, 251, 269, 295, 309, M+ 324 C I mass s p e c t r a l d a t a and prominent fragment i o n s are M.H+ 325 (1001, 136 (371, 307 (101,and 323 ( 7 ) .
Fig. 7
The Mass Spectrum of Quinine
QUININE HYDROCHLORIDE
3.
567
P r e p a r a t i o n of Quinine h y d r o c h l o r i d e 3.1.
I s o l a t i o n of Q u i n i n e Quinine i s t h e p r i n c i p a l a l k a l o i d o f cinchona b a r k of which s e v e r a l s p e c i e s are known. Cinchona o f f i c i n a l i s L. ( C . l e d g e r i a n a Moens) , Family Rubiaceae i s t h e most important. It c o n t a i n s about 8% q u i n i n e ( 2 4 ) . Q u i n i n e w a s i s o l a t e d from cinchona b a r k by P e l l e t i e r and Caventou i n 1820 ( 2 5 ) . S e v e r a l methods have been r e p o r t e d f o r t h e i s o l a t i o n of q u i n i n e from cinchona b a r k , t h e most important method i s as f o l l o w s ( 2 6 ) : Powdered cinchona (250g) i s w e l l mixed w i t h C a O ( 6 0 g ) , water (600 m l ) and 30% NaOH s o l u t i o n ( 3 0 m l ) and l e f t f o r 24 hours. The mixture i s t h e n e x h a u s t i v e l y e x t r a c t e d under r e f l u x w i t h benzene. The benzene e x t r a c t i s f i l t e r e d while h o t i n t o a s e p a r a t i n g f u n n e l c o n t a i n i n g c o n c e n t r a t e d H2S04 ( 7 g ) i n water (500 m l ) t o convert t h e a l k a l o i d s t o t h e i r b i s u l f a t e s a l t s . The mixture i s s e p a r a t e d and t h e a c i d aqueous l a y e r i s h e a t e d t o 90' and n e u t r a l i s e d w i t h 5% Na2C03 s o l u t i o n u s i n g l i t m u s as an i n d i c a t o r (The b i s u l f a t e s a l t s are now converted i n t o t h e s u l f a t e s a l t s ) . The c l e a r orange s o l u t i o n becomes t u r b i d due t o t h e s e p a r a t i o n of some r e s i n o u s m a t e r i a l . D i l u t e H2SO4 ( 2 d r o p s ) and animal c h a r c o a l ( 2 g ) a r e added and t h e r e s u l t i n g mixture i s h e a t e d a g a i n a t 90' f o r 1 5 minutes and f i l t e r e d . The f i l t e r a t e i s allowed t o c o o l down when q u i n i n e s u l f a t e s e p a r a t e s o u t and c o l l e c t e d by f i l t e r a t i o n . The q u i n i n e s u l f a t e s o c o l l e c t e d i s d i s s o l v e d i n b o i l i n g w a t e r and t r e a t e d w i t h Na2C03 s o l u t i o n t o p r e c i p i t a t e q u i n i n e which i s c o l l e c t e d and c r y s t a l l i z e d . The procedure o u t l i n e i s p r e s e n t e d i n F i g . 8.
3.2.
Quinine Hydrochloride Q u i n i n e h y d r o c h l o r i d e i s o b t a i n e d by n e u t r a l i z i n g t h e a l k a l o i d quinine with d i l u t e hydrochloric a c i d and r e c r y s t a l l i s i n g from b o i l i n g w a t e r t o g i v e f i n e c o l o r l e s s c r y s t a l s of q u i n i n e h y d r o c h l o r i d e .
FARID J. MUHTADl ETAL.
568
+
Powdered cinchona
CaO + NaOH with C6H6
1
reflUX
+
Water
filter
Hot f ilt erat e
Extract
with d i l . H2S04
I
I f
Alkaloids b i s u l f a t e s
Heating a 90 O
+
Na2C03
(PH 6 . 5 )
Alkaloids s u l f a t e s
+
Purify
+
charcoal b o i l and f i l t e r
Cool f i l t e r a t e
F i l t e r a t e of Quinidine cinchonine sulfates etc.
*
P r e c i p i t a t e of quinine s u l f a t e Na2S03
1
solution
Quinine
Fig. 8.
Procedure Outline f o r t h e I s o l a t i o n of Quinine.
QUININE HYDROCHLORIDE
569
4. Synthesis of Quinine 4.1.
Partial Synthesis Rabe and Kindler in 1918 (3) achieved the first partial synthesis of quinine from quinotoxine. Quinotoxine was converted by the action of sodium hypobromite into N-bromoquinotoxine which was cyclized by alkali with the l o s s of hydrogen bromide to give quininone. Reduction of the ketone with aluminium powder and ethanol in the presence of ethoxide gave a mixture of stereoisomeric alcohols from which quinine and quinidine were isolated. Gutzwiller and Uskokovic in 1973 (7) developed a slightly different scheme for the partial synthesis of quinine from quinotoxine. Quinitoxine was dissolved in dichloromethane and treated with sodium hypochlorite solution to give N-chloroquinotoxine. This was cyclized with phosphoric acid to give a mixture of quinone and quinidinone. The resulting mixture was dissolved in benzene and treated with a solution of diisobutylaluminium hydride in toluene to give a mixture of quinine and quinidine which was separated by crystallization.
4.2. Total Synthesis Several schemes (I to IV) for the total synthesis of quinine have been reported. The first total synthesis of quinine was completed in 1944 by Woodward and Doering (2). Rabe and Kindler (3) carried out a partial synthesis of quinine starting from quinotoxine. Woodward and Doering (2) completed the total synthesis by synthesizing (+)-quinotoxine. The first total synthesis of quinine is presented in Scheme I. m-Hydroxybenzaldehyde [l] is condensed with aminoacetal [2] to give 7-hydroxyisoquinoline [ 3 ] which is treated with formaldehyde in methanol containing piperidine to give 7-hydroxy-8-piperidinmethylisoquinoline [ 41. This by heating with methanolic sodium methoxide at 220° is converted
FARID J. MUHTADI ETAL.
570
into ~-hydroxy-8-methylisoquinoline[ 5 1. Compound [ 51 on catalytic reduction, followed by acetylation gives N-acetyl-7-hydroxy-8-methyl1,2,3,4-tetrahydroisoquinoline [6], which on further catalytic reduction by heating with a Raney nickel catalyst under pressure and then followed by oxidation with C r O 3 is converted into N-acetyl-~-keto-8-methyldecahydroisoquinoline[ T I . This compound is a mixture of cis-and trans-isomers, these are separated and the cis-isomer is treated with ethylnitrite in the presence of sodium ethoxide to give the homomeroquinene derivative [8]. This on reduction gives the corresponding aminocompound [g], which may now be written more conveniently as shown. Exhaustive methylation of [ 91 followed by hydrolysis gives t cis homomeroquinene [lo] which after esterification and benzoylation gives N-benzoylhomomeroquinene ethylester [ll]. On condensation of [ 111 with excess ethylquininate [lg] using sodium ethoxide produces the intermediate B-ketoester [20]. This on heating with hydrochloric acid is hydrolysed and decarboxylated to (+)-quinotoxine [21]. This is resolved via its dibenzoyltartrate. (+)-quinotoxine [ 221 which is converted into quininone [23] upon N-bromination and cyclization. Reduction of [23] with aluminium powder and ethanol gives a mixture of stereoisomeric quinine and quinidine [24]which are separated. Quinic acid required for the synthesis of quinine was prepared by Rabe et al. ( 27). panisidine [121 is condensed with acetoacetic ester [ 1 3 ] to give the condensate [14]. This is treated with sulfuric acid where ring closure occurs to give 2-hydroxy-4-methyl-6-methoxyquinoline [15]. The phenolic hydroxyl group of [15] is eliminated upon treatment with a mixture of phosphorous pentachloride and phosphorous oxychloride to give 2-chloro-4-methyl-6-methoxyquinoline [16] which upon hydrogenation gives 4-methyl6- methoxyquinoline [ 171. Knoevenagel condensation of the latter followed by oxidation gives quinic [l81 which upon esterification gives ethylquininate
[191
Scheme 11: Total synthesis of quinine and quinidine according to Uskokovic et al. (4).
QUININE HYDROCHLORIDE
Scheme I:
T o t a l S y n t h e s i s of Q u i n i n e (Woodward and Doering).
571
FARID J. MUHTADI ETAL.
572
-G H
i) H p R a n e y N i i i ) ~r03
- IJCOCH3
0
CH3
I
i ) C H ON0
2 5
i i ) C H ONa
[71
Q c g L T
H5c$2c H2N-CH
CH3
[91
‘
QN=C C
11
HO C H 3
O
2 5
C
H
[81
3
QUININE HYDROCHLORIDE
( f )-Quinine
1241 ( f ) Quinidine
573
Resoln.
( - )-Quinine
[241 (+)Quinidine
FARID J . MUHTADI ETAL.
574
P'
ii)KMnOq
H
F
O
COOC2H5 d
' 3 " " 3
C6H5CH0
ester.
L
[191
[181
575
QUININE HYDROCHLORIDE
N-benzoylhexahydroisoquinolone [ 11 is hydrogenated with rhodium on alumina catalyst to give predominantly cis-isoquinolone [2] which is treated with sodium azide in poly-phosphoric acid to give a mixture of the seven-membered lactams which is separated by fractional crystallisation to give [ 31. Lactam [3] is treated with dinitrogen tetroxide to give the N-nitrosolactam [4] which is rearranged upon heating to the diazolactone [5] and fragmented with extrusion of nitrogen to give a mixture of racemic N-benzoylmeroquinene [6] and the seven membered lactone [?a] (in 50 and 30% yield, respectively). The latter [5a] can be converted into [6] which upon esterification gives N-benzoylmeroquinene methyl ester [6a]. This ester is treated with 6-methoxylepidyllithium [7] in tetrahydrofuran to give the racemic N-benzoylketone [8]. This is treated with diisobutylaluminium hydride in toluene at - 78O [route a] to remove the benzoyl group with concommitant reduction of the ketone function to give the aminoalcohol [g] The aminoalcohol [9] is first acetylated with acetic acid containing 10% boron trifluoride etherate and treated with boiling benzene - acetic acid - sodium acetate where cyclization proceeds to give a mixture of desoxyquinine and desoxyquinidine [12]. This can also be achieved without acetylation. The aminoalcohol [9] is refluxed with benzene - acetic acid mixture (4:l) for 4-5 days when cyclization proceeds via dehydration [ 111 to give both desoxyquinine and desoxyquinidine [12]. Upon stirring a solution of [12] in dimethyls u l f o x i d e - t - b u t y l a l c o h o l ( 4 :1) containing potassium t-butoxide in an atmosphere of oxygen affords a mixture of quinine [13] and quinidine [14]. Separation can be effected by a combination of crystallization and chromatography.
.
An alternative synthetic route [b] via the amino epoxide [lo] is as follows:N-benzoylketone [8] is converted into a mixture of diastereomeric N-benzoyl epoxides [lo a] by bromination followed by sodium borohydride reduction. Reductive debenzoylation of [lo a] with diisobutylaluminium hydride in toluene at - 78' furnished a mixture of diastereomeric amino-
576
FARID J. MUHTADI ETAL
T o t a l Synthesis (Uskokovic etal. 1
Scheme 11:
EtOH HC1 [21
i;'
N-0
H '
[3
c
L41 0
N
I)R=H
[61
R=CH3 [ 6a 1
Ac6H5 I
c6H5
QUININE HYDROCHLORIDE
577
CHeLi
r
[6al
+
.
conden.
"71
4
0
A c6H5
H3C0
[81
H CO
3
191
578
FARID I. MUHTADI ETAL.
[91
[a1
L a c e t ylation
QUININE HYDROCHLORIDE
579
epoxides [lo]. Treatment of [lo] with tolueneethanol (19:l) at reflux for 12 hr. give quinine [13] and quinidine [14]. Separation is effected by preparative thin layer chromatography. Scheme 1II:Total synthesis according to Gates et al. ( 5 ) 6-methoxylepidine [ 11 is condensed with N-acetyl3-vinyl-4-piperidineacetic acid ester [ 21 to give the ketone [ 31. Reduction of [ 31 followed by dehydration of the resulting alcohol with acetic anhydride gives the intermediate [ 41. Saponification of the latter affords the secondary m i n e [5] Alkaline hydrolysis of [ 51 in aqueous alcohol under reflux, cyclization occurrs to give a mixture of desoxyquinine and its c8 epimer desoxyquinidine [ 61. Oxidation of the mixture [6] with oxygen in the presence of potassium t-butoxide and triphenylphosphine in dimethylformamide -t.-butyl alcohol introduces of the hydroxyl group at C9 giving the diasteromeric quinine and quinidine [ 73. The intermediate [4] can also be prepared by the Wittig reaction of quininaldehyde [8]with the quaternary phosphonium compound derived from the corresponding bromide obtained from meroquinene alcohol [g]. Scheme IV: Total synthesis according to Taylor and Martin (6) : 4-chloro-6-methoxyquinoline [l] is treated with 2 equiv. of methylenetriphenylphosphorane [ 21 to give [3]. This is condensed with N-acetyl-3(R)vinyl-4 (S)-piperidineacetaldehyde [ 41 to give the olefin [5]. Removal of the N-acetyl group in situ by hydrolysis followed by spontaneous intramolecular Michael addition to give a mixture of desoxyquinine and desoxyquinidine [6] which is converted by base-catalyzed hydroxylation to quinine [ 71 and quinidine [ 81. Other scheme for the total synthesis of quinine through the synthesis of homomeroquinene and quinotoxine is reported by Uskokovic et al. ( 7 ) .
FARID J . MUHTADI ETAL.
580
Scheme 111:
Total Synthesis (Gates e t a l . )
QUININE HYDROCHLORIDE
581
582
FARID J. MUHTADI ETAL.
Scheme I V : T o t a l S y n t h e s i s of Q u i n i n e (Taylor and M a r t i n )
c1
H 3 c 0+ y 3 CHO CH=PPh3
H3c000 I
+
[31
H3C0
H . .
conden.
COCH3
[41
-
\
583
QUININE HYDROCHLORIDE
5. Biosynthesis of Quinine Postulation of the biosynthetic pathway of cinchona alkaloids started in 1950 with the suggestion of Goutarel et al. ( 2 8 ) that quinine and other cinchona alkaloids are derived from indolic precursors, since cinchonamine (indole alkaloid) occurs as a minor alkaloid in cinchona. This was proved when Kowanko and Leete ( 2 9 ) have isolated labelled quinine upon feeding trypt0phan-2-~~C into cinchona plants. They have shown that the quinoline ring and Cg unit of quinine originated from tryptophan. Further studies have proved that quinine is biosynthesized by a combination of indolic and monoterpenoid units which leads to the corynanthe type indole alkaloids. Thus tryptophan ( 2 9 ) , geraniol (30-32) and loganin ( 3 3 ) were incorporated into quinine. Tracer experiments on Cinchona ledgeriana carried out by Battersby and Parry ( 3 4 ) have established the biosynthetic pathway of quinine as presented in scheme V. Scheme V:
Biosynthesis of Quinine
Loganin
Secologanin
+
p)-JyOH \
H
Tryptophan
Vincoside
-
FARID J. MUHTADI ETAI;.
584
LHO
Corynantheal
-
Cine honaminal
I
H
I
H
k
585
QUININE HYDROCHLORIDE
Quinidine
FARID J . MUHTADI ETAL.
586
6. Metabolism The cinchona alkaloids are extensively metabolized in the body, especially in the liver, so that less than 5% of an administered dose is excreted unaltered in the urine (35-37). The metabolism of quinine has been studied both in human and rat urines. The major urinary metabolites in man are hydroxyderivatives of quinine (37). The route of quinine metabolism in man proposed by Brodie et al. (37)involves two parallel pathways as presented in the f o l l o w i n g scheme. Scheme VI: Metabolism of quininein Man
\
H3CO
dihydroxy derivative (non-phenolic)
quinine carbostyri1
QUININE HYDROCHLORIDE
587
Barrow et al. (38) have separated eight metabolites of quinine in the urine of male Sprague-Dawley rats after Six of which have a single dose of quinine (50 mg/Lg). been identified as O-desmethylquinine, hydroxyquinine, quinine, quinine carbostyril and the two diastereoismers of quinine-10, ll-dihydrodiol. These were separated by reversed-phase HPLC on a semi-preparative column by gradient elution. Separation of these metabolites is presented in Fig. 12.
7.
Pharmacokinetics Quinine is readily absorbed after oral administration. Absorption occurs mainly from the upper small intestine, and is almost complete even in patients with marked diarrhea. Rectally administered doses are poorly absorbed and intramuscular or subcutaneous doses of quinine salts are slowly absorbed (13, 35). Peak plasma concentration of quinine occurs within 1 to 3 hours after a single oral dose (35). Therapeutic plasma concentrations appear to be in the range 3 to 7 ug/ml during therapy with oral doses of 500 to 650 mg thrice daily (13). Malarial infection inhibits hepatic metabolism and thus plasma concentrations resulting from a given dose will vary according to the severity of the infection (391. Plasma half-life 6-9 hours, which is increased up to 1 5 hours in malarial infection and decreased to about 3 to 4 hours in patients being treated with antiepileptic drugs (39). After termination of quinine therapy, the plasma level falls rapidly and only a negligible concentration is detectable after 24 hours. A large fraction (approximately 70%) of the plasma quinine is bound to proteins (35). Quinine is excreted mainly in the urine, but small amounts also appear in the feces, gastric juice, bile and saliva. Renal excretion of quinine is twice as rapid when the urine is acidic as when it is alkaline (35).
8. Indications and Dosages
8.1. For the Treatment of Malaria The usual oral dose of quinine or its salts is 325 mg four times daily for 7 days. The drug is given after meals, preferably in capsules, to
FARID J. MUHTADI E T A .
588
minimize gastric irritation (35). Intravenous injections of quinine are to be reserved for certain emergencies such as pernicious or cerebral malaria. The dihydrochloride is employed and I.v. injection should be given very slowly, preferably by the drip method (35). 8.2.
For the relief of Nocturnal Leg Cramps Recumbency leg muscle cramps (night cramps) are quickly and effectively relieved by quinine in most cases. The dose is 200 to 300 mg before retiring (35).
9.
Toxicity Poisoning by quinine is usually due to clinical overdosage or to hypersensitivity. The fatal oral dose of quinine for adults is approximately 8 g (35). When quinine is repeatedly given in full doses a typical cluster of symptoms occurs to which the term cinchonism has been applied. In its mildest form it consists in ringing in the ears, headache, nausea, and slightly disturbed vision. When medication is continued or after large single doses, symptoms also involve the gastrointestinal tract, the nervous and cardiovascular systems and the skin (35).
QUININE HYDROCHLORIDE
589
10. Methods of Analysis 10.1.
Identification
10.1.1 Color Tests The following c o l o r t e s t s have been described f o r t h e i d e n t i f i c a t i o n of quinine , H C 1 (12-14, 40 -44 ) : a. Dissolve 1 0 mg i n s u f f i c i e n t water t o produce 10 ml and t o 5 m l of t h e s o l u t i o n add 0.2 m l of bromine water and t h e n 1 m l of 2 M ammonia, an emeraldgreen c o l o r i s produced. b . Dissolve 5 mg i n 5 ml of water, add 1 ml of 2 M ammonia and 5 ml of e t h e r , shake and acidif'y with 2 M n i t r i c a c i d , t h e aqueous l a y e r y i e l d s r e a c t i o n s c h a r a c t e r i s t i c of chlorides. c . Quinine a l k a l o i d can be i d e n t i f i e d w i t h ammonium t e t r a k i s ( t h i o c y a n a t o ) z i n c a t e ( 4 2 ) . d. I n t o x i c o l o g i c a l work, it i s o f t e n d e s i r e d t o d e t e c t very s m a l l q u a n t i t y of quinine. A very s e n s i t i v e t e s t has been r e p o r t e d (45).
10.1.2 Micro-Crystal T e s t s The following micro-crystal t e s t s a r e a l s o u s e f u l i d e n t i f i c a t i o n t e s t s , photomicrographs of t h e c r y s t a l s have been described (16, 46-49) (Fig. 9 and 1 0 ) . i ) Platinic
iodide s o l u t i o n g i v e s curved s e r r a t e d needles ( s e n s i t i v i t y 1 i n 1 5 0 0 ) .
i i ) Sodium phosphate s o l u t i o n forms needles ( s e n s i t i v i t y 1 i n 1000). iii) Dissolve 1 mg i n 2 ml of water, a c i d i f y with d i l u t e s u l p h u r i c a c i d (1 drop) and add a few drops of an aqueous s o l u t i o n c o n t a i n i n g 5% of cadmium i o d i d e and 10% of potassium i o d i d e . Colorless c r y s t a l s a r e produced and t h e s o l u t i o n becomes t u r b i d .
FARID J. MUHTADI ETAL.
590
F i G , 9,
MICROCHEMICAL CRYSTALS WITH DISODIUM HYDROGEN
OF Q U I N I N E PHOSPHATE,
F I G . 13. K I C R C C H E M I C A LCRYSTALS EETHYL I O D I D E .
HYDRCCHLORIDE
OF ~ U I P J I NWEI T P
QUININE HYDROCHLORIDE
591
i v ) A drop of t h e drug i s p u t on a microscope s l i d e next a drop of an almost s a t u r a t e d s o l u t i o n of p i c r i c a c i d o r of 3 $? g o l d c h l o r i d e , covered and observed f o r 1 5 minutes or more. If t h e p i r r a t - e ( o r a u r a t e ) does n o t c r y s t a l l i s e spontaneously, a s m a l l amount o f a suspension of f i n e s e e d c r y s t a l s i s added t o one edge of t h e drop and i t s e f f e c t observed. I d e n t i f i c a t i o n of q u i n i n e i n human u r i n e h a s been d e s c r i b e d (48) by t h e f o l l o w i n g method :
v)
A f t e r a c i d h y d r o l y s i s t o f r e e t h e b a s e from i t s g l u c u r o n i d e , q u i n i n e i s e x t r a c t e d from a l k a l i n e s o l u t i o n by chloroform. The s o l v e n t i s evaporated and t h e r e s i d u e , d i s s o l v e d i n methanol, i s s u b j e c t e d t o TLC. The p l a t e i s sprayed w i t h i o d o p l a t i n a t e , and t h e methanolic e x t r a c t o f t h e s p o t i s t h e n subjected t o s p e c i f i e d microscopical tests. The product i s i d e n t i f i e d by t h e c r y s t a l formed.
10.2.
Gravimetric Method B e r l i n and Robinson (50) have d e s c r i b e d a thermog r a v i m e t r i c d e t e r m i n a t i o n of q u i n i n e w i t h d i l i t u r i c a c i d . S o l u t i o n of q u i n i n e i n 50% e t h a n o l w a s t r e a t e d w i t h 0.02 M d i l i t u r i c a c i d i n 40% methanol s o t h a t t h e molar r a t i o of d i l i t u r i c a c i d t o q u i n i n e was approximately 7 : l . The p r e c i p i t a t e w a s washed w i t h c o l d 50% Ethanol s a t u r a t e d w i t h d i l i t u r i c a c i d followed by c o l d 95% e t h a n o l and t h e n d r i e d A i n t h e thermobalance between 140° and 195'. c o n s t a n t weight w a s o b t a i n e d i n 1 5 t o 20 m i n u t e s , corresponding t o anhydrous q u i n i n e d i l i t u r a t e . Amounts of q u i n i n e between 2 and 40 mg have been determined w i t h a maximum d e v i a t i o n of 3%.
lo.3.
T i t r i m e t r i c Methods 10.3.1
Aqueous Schneider ( 5 1 ) has p u b l i s h e d t h e a p p l i c a b i l i t y o f t h e s t r o n g l y b a s i c anion-exchangers t o t h e d e t e r m i n a t i o n of q u i n i n e , H C 1 and
FARID J. MUHTADI ETAL.
592
quinine ,H2SO4. In this method , the salt (about 0.1 gm) is dissolved in 90% ethanol (10 ml) , pass the solution through an anionexchange resin. Pass 90% ethanol (10 ml) through the column, then rapidly pass a further 20 ml. Dilute the combined percolates with freshly boiled, cooled water (50 to 70 m l ) and titrate the liberated mine with 0.1 N HC1 in the presence of Tashiro’s indicator, until the green-blue colour changed to violet (52). 10.3.2 Non-Aqueous Non-aqueous titration methods have been described for the analysis of quinine alkaloid or salt ( 53-59). The drug is titrated by perchloric acid in acetic acid and the end point is determined potentiometrically. The method is applied for the determination of small amounts of the alkaloid in the presence of an adsorption electrode ( 60). Quantitation of quinine in media of nitromethane and of chloroform-dioxane has been also reported (61) 10.3.3
Complexometric Application of volume-colorimetry to the micro-determination of alkaloids, including quinine, has been described (62). The assay method depends on the precipitation of the alkaloid with phosphotungstic acid reagent, the precipitate is treated with a reducing agent, the blue color of tungstic anhydride is titrated volumetrically with an oxidising agent. MaJlat and Bayer (63) have also reported the determination of quinine salts by titration with tungstosilicic acid. Complexometric determinations of alkaloids, including quinine, have been also described, by the use of EDTA (disodium salt) (64) or copper picrate (65). Budesinsky and Vanickova (66) have published a complexometric titration of quinine. The
QUININE HYDROCHLORIDE
593
drug i s p r e c i p i t a t e d a t pH 1 . 2 t o 1.5 w i t h bismuth potassium i o d i d e , and t h e excess of t h e reagent i s determined as b i s muth complexometrically. have described t h e Yeh and Tsang (67) q u a n t i t a t i o n of q u i n i n e , H SO4 by c a t i o n 2 exchange followed by complexometric t i t r a t i o n . The e r r o r i s 0.5-2%.
10.3.4
Conductimetric High-frequency t i t r a t i o n of q u i n i n e , HC1,quinine,H2S04, a n d o t h e r s a l t s of organic compounds , has been r e p o r t e d (68). Graphs i l l u s t r a t i n g t h e high-frequency conductimetric t i t r a t i o n of t h e s e s a l t s have been described. For quinine, H C 1 , t h e t i t r a n t i s 0.01 N s i l v e r n i t r a t e ; for quinine,H$O4, t h e t i t r a n t i s 0 . 0 1 M barium c h l o r i d e , 0.01 M barium a c e t a t e , or 0.008 N potassium hydroxide. I n t h e t i t r a t i o n of q u i n i n e , H2S@4with potassium hydroxide, e x t r a p o l a t i o n i s necessary t o determine t h e p o i n t of i n f l e c t i o n of t h e graph.
10.3.5
Amperometric Lemahieu e t a l . ( 6 9 ) have r e p o r t e d an aniperometric determination of q u i n i n e , H C 1 i n dimethyl sulphoxide. The method i s based on t i t r a t i o n w i t h s i l v e r n i t r a t e i n dimethyl sulphoxide t o give an end-point corresponding t o t h e formation of AgC1; and a less sharp end-point f o r t h e p r e c i p i t a t i o n of s i l v e r c h l o r i d e . U s e of t h e f i r s t end-point and two platinum i n d i c a t o r e l e c t r o d e s with a p o t e n t i a l d i f f e r e n c e of 100 mV allows t i t r a t i o n down t o a 0.2 m M c o n c e n t r a t i o n of q u i n i n e , HCI.. Use of one i n d i c a t o r e l e c t r o d e and a s i l v e r - Ag+ r e f e r e n c e e l e c t r o d e prodcces a l e s s sharp end-poir,t, not obtaina b l e below a m M concentration. Gengrinovich e t i z l . ( 7 0 ) have described t h e use of i o d i n e ch1ori.de and a r o t a t i n g platinum e l e c t r o d e for t h e amperometric t i t r a t i o n c f quint.ne, HC1. The t i t r a t i o n
FARID J. MUHTADI ETAL.
594
i s based on t h e a d d i t i o n o f I C 1 t o t h e v i n y l group of q u i n i n e . The r e a c t i o n i s complete i n 20-25 minutes. Charles and Knevel (71) have p u b l i s h e d coulometric a s s a y of q u i n i n e s u l p h a t e u s i n g an arseno-amperometric end-point d e t e c t i o n t e c h n i q u e . T h i s i s based on t h e f a c t t h a t t h e r e a c t i o n of bromine w i t h q u i n i n e s u l p h a t e i s t o o slow t o allow d i r e c t coulometric t i t r a t i o n of t h e drug. The c o e f f i c i e n t of v a r i a t i o n i s 0.5%.
10.3.6 Polarographic Souckova and Zyka(72,73) have r e p o r t e d a polarographic d e t e r m i n a t i o n of q u i n i n e , H C l by t i t r a t i o n with t u n g s t o s i l i c i c a c i d , tungstophosphoric, and molybdophosphoric acids (73). The a p p a r a t u s h a s a dropping mercury cathode and S.C.E. anode, t h e v o l t a g e b e i n g 0.65V. The pH o f t h e s o l u t i o n i s a d j u s t e d w i t h HC1. The m a x i m u m e r r o r i s f 1% w i t h t u n g s t o s i l i c i c a c i d and 22% w i t h t h e two o t h e r a c i d s . Molnar and Molnarwa (74) have d e s c r i b e d o s c i l l o p o l a r o g r a p h i c d e t e r m i n a t i o n of q u i n i n e a l k a l o i d . The o s c i l l o p o l a r o g r a p h i c behaviour of q u i n i n e d e r i v a t i v e s has been s t u d i e d and t h e i r oscillograms i n N LiC1, N LiCH, N NaOH, and N H$O4 were o b t a i n e d w i t h t h e u s e of dropping and streaming mercury e l e c t r o d e s . Concentration of 10-4 M s o l u t i o n of q u i n i n e a l k a l o i d s can b e d e t e c t e d with t h e use of o s c i l l o p o l a r o g r a p h i c methods. Q u a n t i t a t i v e o s c i l l o g r a p h i c polarography of c e r t a i n a l k a l o i d s , including quinine alkal o i d , have been a l s o r e p o r t e d Cinchona a l k a l o i d s g i v e c h a r a c t e r i s t i c o s c i l l o g r a m s which can b e used f o r t h e i r d e t e r m i n a t i o n with an accuracy of f 4%. Girard and R o u s s e l e t ( 7 6 ) have p u b l i s h e d a polarographic and c o l o r i m e t r i c d e t e r m i n a t i o n o f q u i n i c i n e i n t h e presence G f l a r g e amount of q u i n i n e .
595
QUININE HYDROCHLORIDE
1 0 . 4 . Chromatographic Methods
Chromatographic methods have been d e s c r i b e d f o r t h e s e p a r a t i o n , i d e n t i f i c a t i o n and q u a n t i t a t i o n of q u i n i n e i n pharmaceutical dosage forms and i n mixtures (77-93).
10.4.1
Paper Chromatography The f o l l o w i n g s c r e e n i n g procedure h a s been reported ( 9 4 ) f o r detecting quinine i n chemical-toxicological analysis of b io lo g ic a l m a t e r i a l (blood): To t h e blood ( 5 m l ) add water ( 3 1 . 5 m l ) and 10% Na2W04 s o l u t i o n (10 m l ) , mix, and add s l o w l y , w i t h s t i r r i n g , 10% H2S04 (3-5 m l ) . Heat t h e mixture i n a b o i l i n g - w a t e r b a t h for 10 minutes, f i l t e r , shake t h e cooled f i l t r a t e w i t h e t h e r (30 ml) , and d i s c a r d t h e e t h e r . Adjust t h e aqueous phase t o pH 9 w i t h c o n c e n t r a t e d aqueous ammonia, shake t h e s o l u t i o n with e t h e r ( 3 0 m l ) , d r y t h e e t h e r w i t h anhydrous sodium s u l p h a t e , e v a p o r a t e a t 37' i n a stream o f n i t r o g e n . D i s s o l v e t h e r e s i d u e i n one o r two drops of chloroform, apply t h e s o l u t i o n t o Whatman CT30 anionexchange paper, and c a r r y o u t ascending chromatography w i t h 0 . 1 M EDTA f o r 1 4 minutes. Examine t h e w e t paper i n UV l i g h t a t 254 nm.
R a m a and Singh (83) have p u b l i s h e d a r a p i d s e p a r a t i o n of q u i n i n e , and o t h e r a l k a l o i d s , by ascending paper chromatography on s t r i p s impregnated w i t h 0 . 1 M zirconium o x y c h l o r i d e by u s i n g aqueous s o l v e n t s c o n t a i n i n g 0.001 N H C 1 o r 0.001 N NaOH. The i n d i v i d u a l a l k a l o i d , 4 a l k a l o i d s , were as w e l l as mixtures o f s e p a r a t e d w i t h i n 15-20 minutes. Q u i n i n e and s e v e r a l o t h e r a l k a l o i d s have been s e p a r a t e d by u s i n g Whatman No. 1 paper which h a s been soaked i n S o r e n s e n ' s phosphate b u f f e r s o l u t i o n ( M / l 5 , pH 5 ) and d r i e d , w i t h b u t a n o l as t h e mobile phase. The s p o t s a r e l o c a t e d by s p r a y i n g w i t h i o d o p l a t i n a t e r e a g e n t ( 91 )
.
5%
FARID J. MUHTADI ETAL.
S t r e e t and Niyogi (95) have r e p o r t e d a new technique of chromatography and ionophoresis on ion-exchange paper. This has been a p p l i e d t o s e p a r a t i o n of a mixture of compounds including quinine. The mixture i s subjected t o ascending chromatography i n 0 . 1 M - EDTA on diethylaminoethylcellulose paper f o r 20 minutes and s u b j e c t t o ionophoresis a t a constant c u r r e n t of 1 0 m A f o r 30 minutes. Steger and Storz (96) have described microa n a l y t i c a l determination of a l k a l o i d s , including quinine, with paper chromatogram soaked with molybdosilicic a c i d . A f t e r drying with w a r m a i r , e x t r a c t with a reducing q u i n o l , sodium carbonate, and sodium s u l p h i t e . The e x t i n c t i o n of t h e b l u e s o l u t i o n i s measured c o l o r i m e t r i c a l l y a t 660 nm.
A l w a s e t a l . (88) have r e p o r t e d t h e s e p a r a t i o n and q u a n t i t a t i v e a n a l y s i s of quinine, and o t h e r a l k a l o i d s , by a p p l i c a t i o n of paper ionophoresis. Jakube e t a l . have described t h e use of paper chromatography i n t h e assay o f m i x t u r e s of pharmaceuticals, including quinine s a l t s . I n t h i s method, mixtures of water, low-boiling a l c o h o l (methanol, ethanol , o r isopropanol) , and ammonia have been found t o be t h e b e s t s o l v e n t s , and a mixture of FeC13 w i t h K 3 Fe (CN)6, t h e b e s t d e t e c t i n g agent. Quinine (0.005 t o 0.015 mg) , and some o t h e r a l k a l o i d s , have been d e t e c t e d i n s e v e r a l foods by using a paper-chromatographic method (98). I n t h i s method, e t h a n o l i c e x t r a c t i s s u b j e c t e d t o descending technique on Whatman N o d paperand development i s achieved by chloroform. A f t e r drying, t h e chromatogram i s sprayed with potassium iodoplatinate.
QUININE HYDROCHLORIDE
597
10.4.2 Thin-Layer Chromatography The TLC analysis of cinchona alkaloids has been thoroughly reviewed by Verpoorte , et a1 ( 7 9 ) . From the TLC systems described in the review, 18 solvent systems were found to be the most suitable for the separation of the 24 Cinchona alkaloids. Table 5 shows the 18 solvent systems used f o r quinine. Table 6 quinine.
describes TLC detection techniques for
The sensitivity of a number of separation methods has been described. Some general conclusions concerning the optimal conditions for specific separations are also described Oswald and Fluck (86) have reported separate determination of cincho.naalkaloids by TLC. Quinine, quinidine, and cinchonine are separated on silica gel G. , with benzene-ethyl ether diethylamine (20:12:5) as solvent; cinchonidine migrates with quinidine. The alkaloids are identified with Dragendorff reagent. The spot area, measured by planimeter, is directly proportional to the amount of alkaloid in the range of 3 to 4 p g. The limit of error is ?: 8%. Bralinova ( 7 7 ) has described 6 eluent systems in the separation of quinine and quinidine on silica gel, using chloroform-acetone-diethylamine (20:20:1) as solvent. Schwarz and Sarsunova (87) have published thin layer chromatographic data for 27 alkaloids, including quinine , on aluminium oxide. The most useful solvents are: benzene-ethanol; chloroformethanol; and ethyl ether-ethanol. Sarsunova and Hrivnak (114) have reported the separation and evaluation of cinchona alkaloids by TLC, on silica gel -254 with chloroform-acetonediethylamine (5:4:1) as solvent.
Table 5
TLC Techniques Used for Quinine
Solvent System
-
fn 00
RF ( RFxlOO )
1.
Chloroform-diethylamine ( 9 :1)
2.
Chloroform-methanol - 25% ammonia (85 :14:1)
3.
Chloroform-acetone-diethylamine (5:4:1)
4.
Chloroform-acetone ethanol) (5:4:1)
5.
Ref.
17 44 17
59 60 61
21
39
Chloroform-acetone-methanol -25% ammonia (60 :20 :20 :1)
37
61
6.
Chloroform-ethylacetate-isopropanol-diethylamine ( 2 0 :70:4 :6 )
11
7. 8.
Chloroform-dichloromethane-diethylamine (20:15:5)
22
Dichloromethaqe-diethyl ether -diethylamine (20:15:5)
23
9.
Kerosene-acetone-diethylamine (23:9 :9)
32
39 39 39 62
-
( 3 m l 25% ammonia + 17 m l absolute
10. Acetone - 25% ammonia (58:2)
-
25% ammonia (45:35:5) 12. Toluene-ethyl acetate - diethylamine (7:2:1) 13. Toluene-ethyl acetate-diethylamine (10:10:3) 1 4 . Toluene-diethyl ether-diethylamine (20:12:5) 15. Toluene-diethyl ether-dichloromethane-diethylam-ine (20 :20 :20 :8) 11. Ethyl acetate-isopropanol
16. Carbon tetrachloride-n-butanol-methanol-10% ammonia
18 18
39 39 63 39 64
20
65
-
39
32
49 12
(12 :9:9:1)
Solvent System 17.
Cyclohexanol diethylamine
- cyclohexane-n-hexane
18. Methanol-25% ammonia (100:1 )
(1:l:l)
+ 5%
41
66
45
61
Conditions : Silica gel plates Si 60 F 254 pre-coated aluminum sheets, 20x20 cm (Merck); temperature, 2422'; relative humidity, 2525%; normal chromatography chamber, saturated for 30 minutes before use
Table 6
TLC Detection of Quinine
Reagent
1.
Quenching, 254 nm
2.
Fluorescence 360 nm (formic a c i d o r s u l p h u r i c a c i d spray)
3.
Dragendorff's modification: Munier - Macheboeuf Munier Munier-sodium n i t r i t e
4.
Background Color
Color
Ref.
39 Light b l u e
39
Orange-red Orange-red Brown
39 67 67
Vaguj f a l v i Bregoff-Delwiche
Yellow Light-yellow Light -yellowwhite Light -yellow Light -yellow
Orange Orange
39 39
Iodine vapour
Yellow-white
Brown Brown Brown
39 68,69 60
5. 6.
Iodine i n K I
White
Iodine i n methanol
Light -yellow
7.
Iodine i n K I and s i l v e r a c e t a t e
8.
F e r r i c c h l o r i d e , iodine i n K I
Light greenyellow
Brown
70 71
9.
Iodoplat i n a t e
Dark v i o l e t
Violet
39
10.
Iodoplatinate, a c i d i f i e d
Dark v i o l e t
Violet
72
Light greenblue
Dark green blue
45
11. F e r r i c hexacyanoferrate
-
-
Background Color
Reagent
Color ~
12.
F e r r i c chloride-perchloric
13.
14.
Methyl orange Tetraphenylborate
15.
Phenothiazine, i o d i n e vapor
16.
Phenothiazine vapor )
acid
quercetin
Ref.
~~~
Yellow-white
Violet
39
Light orange
Orange
73
i n UV:blue
74
Violet
Brown
60
Violet
Light brown
60
-
bromine vapor (ammonia
FAFUD J. MUHTADI ETAL.
602
Suchocki e t a l . (115) have r e p o r t e d determination of quinine, H C 1 and o t h e r compounds, by TLC, on a s i l i c a g e l with one of s e v e r a l solvent systems. The s p o t s a r e l o c a t e d with conventional reagents and are evaluated d e n s i t o m e t r i c a l l y . Hashmi e t a l . (85) have described semi-quantitative determination of quinine by c i r c u l a r TLC. Thirteen a l k a l o i d s , i n c l u d i n g quinine , have been separated i n t o groups by an e x t r a c t i o n scheme with t h e use of water, chloroform and ethanol solvent systems. Aliquots of t h e various e x t r a c t s ( c o n t a i n i n g 0 . 1 t o 7.0 pg of t h e a l k a l o i d ) a r e a p p l i e d t o a l a y e r of s i l i c a g e l f o r chromatographic a n a l y s i s .
The following method has been described f o r d e t e c t i n g quinine i n t o x i c o l o g i c a l a n a l y s i s of b i o l o g i c a l materials. The sample of u r i n e ( 1 0 m l ) , b u f f e r e d a t pH 9.5 i s e x t r a c t e d with chloroform-isopropyl alcohol (24:l). A c o n t r o l sample of u r i n e c o n t a i n i n g quinine ( 1 0 Ug/10 m l ) i s a l s o e x t r a c t e d . The solvent l a y e r i s f i l t e r e d , b o i l e d t o remove ammonia, and a c i d i f i e d with 0.1 N HC1. The solvent i s evaporated and t h e r e s i d u e i s d i l u t e d with methanol. The s o l u t i o n i s then a p p l i e d , i n p o r t i o n s , t o s i l i c a g e l G and t h e chromatograms a r e developed w i t h ethanol-methanolconcentrated ammonia (17:2:1) as t h e solvent. The a i r - d r i e d p l a t e i s heated a t 75' f o r 10 minutes, t h e n sprayed w i t h i o d o p l a t i n a t e and Dragendorff reagents
.
D i f f e r e n t i a t i o n of quinine from i t s oxidation products has been i n v e s t i g a t e d ( 9 2 ) . A s e n s i t i v e d e t e c t i o n reagent f o r quinine on t h i n - l a y e r chromatogram has been a l s o described ( 9 3 ) . Small amounts of quinine can be separated from impure samples and b i o l o g i c a l materials by chromatographic procedures.
Fig. 11 GLC of Quinine Hydrochloride
QUININE HYDROCHLORIDE
10.4.3
603
Gas-Liquid Chromatography A GLC method f o r t h e determination of quinine, H C 1 has been c a r r i e d out i n our l a b o r a t o r y , using a Varian GC-3700 gas chromatograph equipped with Varian CDS 111 integrator. Column conditions: 3%OV-17 on chromosorb W-Hp (80-100mesh s i z e ) ; g l a s s column ( 2 m x 2 mm). The column run isothermally a t 280' f o r 1 0 minutes and then t h e temperature was programmed a t 10°/minute. Carrier gas : helium, flow r a t e w a s a d j u s t e d t o 25 m l / minute. Detector : FID, hydrogen and a i r flow r a t e s were a d j u s t e d t o 30/minute and 300 ml/minute, r e s p e c t i v e l y . Ethanol was used as t h e solvent and t h e c h a r t speed w a s a d j u s t e d t o give 1 cm/minute. The r e t e n t i o n t i m e = 13.4 minutes. The GLC of quinine, H C 1 i s presented i n Figure 11. Sarsunova and Hrivnak ( 1 1 4 ) have described q u a n t i t a t i v e determination of quinine , and o t h e r cinchona a l k a l o i d s , by e x t r a c t i o n of t h e s p o t s from t h e TLC p l a t e s followed by GLC. The a l c o h o l i c s o l u t i o n , containing codeine as an i n t e r n a l standard, i s analysed by GLC on a column of 2% of OV-17 on AW Gas-Chrom p. The method i s s p e c i f i c enough f o r r o u t i n e drug a n a l y s i s . A gas-liquid chromatographic procedure has been a l s o r e p o r t e d (120) f o r t h e determinat i o n of s e v e r a l b a s i c drugs, i n c l u d i n g quinine, i n s m a l l blood samples. Bonini, e t . a1 (121) have described gasphase chromatographic determination of four a n t i m a l a r i a l s , including quinine, s i n g l y and i n a mixture i n blood and u r i n e . I n t h i s method, a column packed w i t h . 2% OV-17 on Chromosorb W AW DMCS 100-120 mesh with N gas as t h e c a r r i e r gas and t h e column temperature programmed t o i n c r e a s e from 250 t o 350' a t 8O/minute. The l i m i t of d e t e c t i o n was 0.52 ng f o r quinine. The r e c o v e r i e s i n blood and u r i n e were 84.3 and 92.8% f o r 1 i.lg q u i n i n e / l m l .
604
FARID J . MUHTADI ETAL.
10.4.4
Hioh Performance Liquid Chromatography Quinine has been determined among other cinchona alkaloids by HPLC. A number of HPLC assay procedures for quinine and its impurities have been described (82). Pound and Sears (122) have used a silica gel column with a tetrahydrofuran-ammonium hydroxide mobile phase to analyse quinine in commercial formulations. Low and Kennedy (82,123) have described ion-pair reversed-phase chromatography in surveying the quinine products available in Australia. Table 7 sununarises the solvent systems used in the cited references. Barrow et al. (38) have reported HPLC separation and isolation of quinine metabolites in rat urine. The extract was evaporated under N, and a solution of the residue in methanol was analysed on a column of IJ Bondapak Cl8 and detection at 254 nm. Eight metabolites of quinine were separated and only 6 were identified. These were separated on either an analytical or a semi-preparative reversed-phase column by gradient elution (Fig. 12). HYDROXYQUININE+
I
I 1
0
I
QUININE-10,llDIHYDRODIOLS
10
,
20
30
40
0-DESMETHYLQUININE
J
50
lPiNINE -CARBOSTYRIL
60
1
70
min.
Fig. 12 HPLC Separation of Quinine Metabolites
Table System No.
7.
HPLC Systems of quinine
Column
Mobile phase
Merckosorb Si 60
Chloroform-methanol (8:2)
6.4
(7:3)
5.9
Diethyl ether-methanol (8:2)
3.9
(7:3)
2.7
(6:4)
2.2
A reversedphase, u Bondapak
Methanol-water-acetic acid (25:75:1)
‘18 4 Silica gel
Diethylether-waterdiethylamine
Li Chrosorb Si 60
Chloroform-isopropyl alcohol-diethylamine-wat r (940:57 :1:2.62)
Li Chrosorb Rp-8
Water-acetonitrile (1:3); adjusted to pH 3 with perchloric acid
Retention Time (minute)
-
-
-
Detect ion
Ref.
W , 254 and 280 nm.
80
W, 254 nm.
a2
-
124
W, 312 nm.
125
250 nm or
126
435 nm.
FARID J. MUHTADI ETAL.
606
A study of t h e r e t e n t i o n behavior of quinine, and some o t h e r b a s i c drug substances, by ion-pair HPLC has been described By appropriate adjustment of expe(127). rimental parameters, complex separations can be achieved.
Jeuring e t a l . (126) have reported a r a p i d determination of quinine and i t s hydrochloride i n s o f t drinks and t o n i c water by reversed-phase ion-pair chromatography. I n t h i s assay method, quinine i s determined i n t h e concentration range of 20-100 mg and recoveries ranged from 97 t o 103%. 10.5.
Spectroscopic Methods 10.5.1
Colorimetric Hasselmann (128) has reported a microdetermination of quinine i n serum by means of t h e colored compound formed with Rose bengal. The method i s s u i t a b l e f o r determining concentration up t o 1 mg per 100 ml. The reported method i s as follows: To serum (10 m l ) add 20% t r i c h l o r o a c e t i c a c i d ( 5 ml), shake and centrifuge. Adjust an a l i q u o t (10 ml) of f i l t r a t e t o pH 11.7 with N NaOH, add 2% Rose bengal s o l u t i o n (1 n i ~ )and chloroform (3.5 d).AUOW t o stand for several hours, shaking 5 o r 6 times during t h i s period. Measure t h e c o l o r i n t h e chloroform l a y e r a t 550 nm. A blank i s necessary. Drey (129) has described spectrophotometric assay of quinine, 2 H C 1 i n t a b l e t s .
-
Malat (130) has reported an e x t r a c t i o n spectrophotometric determination of organic bases, including quinine, with some metallochromic i n d i c a t o r s . The procedure involves t h e addition of t h e i n d i c a t o r t o a s o l u t i o n of quinine,H$O4, a d j u s t i n g t h e pH a t 1 . 4 t o 6.8 and e x t r a c t i o n with chloroform. The absorption spectrum i s then recorded from 400 t o 700 nm. Eriochrome red B i s t h e most s u i t a b l e f o r determination of quini n e ; t h e absorbance being measured a t 475nm.
QUININE HYDROCHLORIDE
607
Schmitz and Menges (131) have a l s o reported a colorimetric determination of quinine i n t i n c t u r e s with Tropaeolin 00. I n t h i s method, about 0.5 gm of t i n c t u r e of cinchona, i s d i l u t e d t o 250 m l with water, and a 5-ml portion i s mixed with 1 0 ml of an a c e t a t e b u f f e r s o l u t i o n of pH 4.6 and 3 m l of a saturated aqueous Tropaeolin 00 s o l u t i o n . The well-shaken mixture i s then e x t r a c t e d with chloroform and t h e combined e x t r a c t s are a c i d i f i e d with 3 ml of an a c i d reagent (1 ml of concentrated ~ 2 ~ and 0 4 99 ml of methanol), and made up t o 50 m l with chloroform. The e x t i n c t i o n i s then determined and quinine content i s estimated by comparison with standard curves. Blank determinat i o n i s necessary. Graham and Thomas (132) have described a q u a n t i t a t i v e determination of a l k a l o i d s , including quinine, using dichromate sulphuric a c i d . The s o l u t i o n containing t h e a l k a l o i d ( 0 . 1 - 4 P moles) i s mixed with 5% aqueous potassium dichromate s o l u t i o n (1 m l ) , heat a t 30° f o r 5 minutes , add concentrated ~ 2 S 0 4( 8 m l ) , mix, cool i n i c e f o r 20 minutes and measure t h e e x t i n c t i o n a t 650 nm. Subtract a reagent blank. The c h a r a c t e r i s t i c green c o l o r i s given by 25 a l k a l o i d s . Methanol, ethanol, u r e a , and many s a l t s i n t e r f e r e , but ethanol may be used a s a solvent i f an equal amount i s included i n the blank s o l u t i o n . 10.5.2
Ultraviolet Volkova and Getman (133) have described an extraction-photometric determination of quinine as t h e t e r n a r y complex with t i t a nium and s a l i c y l a t e . In t h i s method, t h e t e s t s o l u t i o n (10ml), containing 1ODg of quinine, i s mixed with 1 m l of 0.01 M Tic14 i n 0.8 N H C 1 , 1ml of 0.05 M sod. s a l i c y l a t e and 1 0 ml of CHC13. The pH of t h e s o l u t i o n i s adjusted t o 3 with 0.1 N NaOH and t h e yellow t e r n a r y complex i s completely e x t r a c t e d i n t o t h e C H C l 3 by vigorous shaking f o r 2 minutes. The e x t r a c t is f i l t e r e d , and t h e e x t i n c t i o n
-
FARID J . MUHTADI ETAL.
608
of t h e f i l t r a t e i s measured a t 380 o r 400nm. Chloride , s u l p h a t e , n i t r a t e , and a c e t a t e do n o t i n t e r f e r e . A t low c o n c e n t r a t i o n o f q u i n i n e , metal i o n s do n o t i n t e r f e r e ; i r o n can b e masked w i t h a s c o r b i c a c i d o r sodium t h i o s u l p h a te
.
Prudhomme (134) has r e p o r t e d a c o l o r i m e t r i c a s s a y of q u i n i n e i n b i o l o g i c a l f l u i d s and i n organs. I n t h i s method, q u i n i n e i s determined by adding 2% e o s i n t o t h e l i q u i d , b u f f e r e d t o pH 7 , and e x t r a c t i n g t h e r e d product w i t h chloroform and comparing the solution colorimetrically with standard s e r i e s . Liquids c o n t a i n i n g l e s s t h a n 0.01 mg of q u i n i n e are e x t r a c t e d f o r 24 hours. Urine i s f i r s t t r e a t e d w i t h l e a d a c e t a t e and H2SO4, and blood w i t h potassium o x a l a t e followed by s a t u r a t e d sodium s u l p h a t e and N H2SO4 a t 45-50'. Compounds of e o s i n w i t h q u i n i n e can b e d i f f e r e n t i a t e d by UV absorpt i o n s p e c t r a . The r a t e o f e l i m i n a t i o n o f q u i n i n e i n u r i n e , and i t s d i s t r i b u t i o n among organs have been s t u d i e d . P r o e t a l . (135) have r e p o r t e d s p e c t r o photometric d e t e r m i n a t i o n of q u i n i n e and h e r o i n (diamorphine ) I n t h i s method , equimolar c o n c e n t r a t i o n of t h e two a l k a l o i d s have almost t h e same a b s o r p t i o n a t 297.5 nm; w h i l s t a t 330 nm t h e a b s o r p t i o n i s due e n t i r e l y t o quinine. A 100 mg of t h e mixed a l k a l o i d s w i t h 10 m l of anhydrous methanol i s f i l t e r e d through a s b e s t o s , t h e f i l t r a t e and methanol washings b e i n g d i l u t e d w i t h 0 . 1 N NaOH, and of t h i s s o l u t i o n 10 m l are a g a i n d i l u t e d w i t h NaOH - methanol s o l u t i o n . The e x t i n c t i o n i s measured a t 297.5 and 330 nm. The s t a n d a r d d e v i a t i o n f o r b o t h c o n s t i t u e n t s i s 4 1 . 5 p.p.m. on m i x t u r e s c o n t a i n i n g 30 t o 90 p.p.m., and 6 t o 30 p.p.m of q u i n i n e and diamorphine, r e s p e c t i v e l y .
.
Hadorn and Z u r c h e r ( 1 3 6 ) have p u b l i s h e d t h e a n a l y s i s and composition of beverages c o n t a i n i n g q u i n i n e and i t s decomposition p r o d u c t s . I n t h i s method, 6 samples were
QUININE HYDROCHLORIDE
609
found t o contain ( p e r l i t r e ) 25-57 mg of quinine t o g e t h e r with o t h e r c o n s t i t u e n t s . The quinine e x t r a c t e d from t h e beverages with e t h y l e t h e r w a s pure, but t h e quinine e x t r a c t e d with chloroform or carbon t e t r a c h l o r i d e contained decomposition products t h a t could be d e t e c t e d by TLC; t h e s e d i d not i n t e r f e r e with t h e spectrophotometric determination of quinine i n d i l u t e H2SO4 medium a t 346 nm. The s p e c t r a of quinine i n e t h a n o l , chloroform, and carbon t e t r a c h l o r i d e d i f f e r e d only s l i g h t l y from one a n o t h e r , but widely from t h e spectrum of quinine i n d i l u t e H2SO4. Kamath e t a l . (137) have s t u d i e d t h e W absorption of cinchona a l k a l o i d s , i n c l u d i n g q u i n i n e , i n 11 a l i p h a t i c a l c o h o l s . Quinine can be determined i n t h e presence of o t h e r 14% i n a l i p h a t i c alkaloids t o within a l c o h o l medium. Schmitt (138) has described t h e q u a n t i t a t i v e and q u a l i t a t i v e determination of W-absorbi n g compounds i n substances t o o dark or t o o t u r b i d f o r d i r e c t a n a l y s i s . The f i r s t or second d e r i v a t i v e s of t h e W s p e c t r a a r e used. They show much more d e t a i l than t h e d i r e c t s p e c t r a . The determination of quinine i n a t u r b i d beverage by t h i s technique has been r e p o r t e d A q u a n t i t a t i v e spectrophotometric determinat i o n of quinine and o t h e r cinchona a l k a l o i d s has been a l s o described
10.5.3 Atomic Absorption Spectrometry Recently , Minami e t a l . (140) have developed a q u a n t i t a t i v e a n a l y s i s of a l k a l o i d s , includi n g q u i n i n e , by t h e atomic absorption s p e c t rometry. I n t h i s method, 1 ml of a s o l u t i o n of Reinecke s a l t ( 6 mg/l m l ) and 5-10 m l of nitrobenzene a r e added t o 5-20 m l s o l u t i o n of t h e a l k a l o i d ( c o n t a i n i n g 1.5-100 11 g/ml) i n 0 . 1 M HC1. The mixture i s shaken and t h e nitrobenzene l a y e r i s removed, d r i e d , and C r i s determined t h e r e i n by conventional flame a.a.s. at 357.87 nm. By t h i s
FARID J. MUHTADI ETAL.
610
procedure, quinine, and several other alkaloids, can be indirectly determined with good precision. There is no interference from up to 37-fold molar amounts of 15 common inorganic ions.
10.5.4 Spectrofluorimetric Ragazzi and Veronese (141) have published a fluorimetric determination of quinine and some other alkaloids, after separation by TLC on magnesium oxide. Quinine is separated from natural materials or from mixed pharmaceutical preparations on a layer prepared from a suspension of hydrated magnesium oxide in 2.5% aqueous CaC12, using ethyl acetate - acetone (4:l) as the developing solvent. After locating the spots of quinine under W light, they are removed from the plate and dissolved in acid and the solution is used for the fluorimetric determination. Quinine emits fluorescence at 450 nm when excited at 350 nm. Brzezinska and Dzeidzianowicz (142) have reported a fluorimetric assay of quinine in the presence of aspirin and phenacetin. Quinine is extracted from the mixture by a known volume of 0.1 N H2SO4 and the intensity of fluorescence of quinine sulphate extract is then measured and referred to a calibration graph. Beer's law is obeyed for 1 to 50 p.p.m. of quinine in the extract. Schmollack and Wenzel (143) have described a fluorimetric determination of quinine in the nanogram range with use of a chamber paper-analysis (KAPA) apparatus. Fluorimetric measurements of quinine sulphate solution is carried out at 366 nm, showing a rectilinear calibration between 5 and 50 pg/ml. For 48 measurements at 30 l.lg/ml, the coefficient of variation is 7.69%. Other fluorescence analysis of quinine as well as various natural and synthetic drugs has been reported (144). Fluorescence spectra have been determined in ethanol, concentrated HC1, 10% NaOH, and
QUININE HYDROCHLORIDE
611
aqueous solutions at 0.01-0.001 mg/d The following identification test has been described (146). Dissolve 1 gm in 50 m l of water; the solution is not fluorescent. Dilute with lOOml of water and add M H2S04, an intense blue fluorescence is produced.
( 145).
McCloskey et al. (147) have developed a spectrofluorimetric determination of quinine in the blood and urine, following the consumption of tonic preparations.
10.5.5
Phosphorimetric Harbaugh et al. (148)have reported pulsedsource time-resolved phosphorimetric method for the quantitative determination of quinine and other drugs. The phosphorescence emission spectra, life times, and relative signals (peak emissions) have been determined with the use of the apparatus and procedures previously describe& by Fischer and Winefordner Time-resolved phosphorimetry provides a useful means for identifying quinine and other drugs even in some of their mixtures. For a multi-component mixture, the parameters cited indicate which of the drugs can be separated spectrally or temporarily or by P conobination of the two techniques.
Acknowledgement The authors wish to thank M r . Uday C. Sharma of the Pharmacognosy Dept., College of Pharmacy, King Saud University, Riyadh, for his secretarial assistance in the reproduction of the manuscripts.
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H . J . J e u r i n g , V.H. W i l l e m , V.D. P i e t e r , and T.B. 281 R e i n i e r , Z. Lebensm. - U n t e r s . Forsch. (1979); Anal. A b s t r . , 38, 570 (1980).
127,
R.G.
128.
M. Hasselmann, Compt. Rend., Abstr. , 5, 2316 (1958).
, 169,
Achari and J.T.
81 (1980).
J a c o b , J. Liq. Chromatogr.,
3,
244, 2860 (1957); Anal.
620
129.
FARID J . MUHTADI ETAL.
R.E.A.
Drey, J. Pharm. and Pharmacol.,
2, 739 (1957).
130. M. Malat, Anal. Chim. Acta, log, 191 (1979). 131.
B. Schmitz and W. Menges, Dtsch. Apothztg., 747 (1957); Anal. Abstr. , 2, 1332 (1958).
a,
132. H.D. Graham and L.B. Thomas, J. Pharm. Sci.,
(19611.
133.
2,901
A.I. Volkova and T.E. Get'man, UKr. Khim. Zh., 1320 (1965); Anal. Abstr., L4 2187 (1967).
2,
134. R.O. Prudhomme, J. Pharm. Chim. , 2, 8 (1940). 135. M.J. Pro, W.P. Butler, and A.P. Mathers, J. Ass. Off. Agri. Chem., 3, 849 (1955); Anal. Abstr., -3 , 1845 (1956). 136. H. Hadorn and K. Zurcher, Mitt. Lebensmitt. Hyg., Bern, 55, 194 (1964); Anal. Abstr. , l2, 4856 (1965)
.
137. B.R. Kamath, C.V. Bhat, and S.L. Bafna, Indian J. Chem. , 6 , 510 (1968); Anal. Abstr. , l8, 1204 (1970) 138. A. Schmitt , Chem. Abstr. , 92, 37108 (1980). 139. V.K. Vera and B. Zora, Acta Pharm. Jugosl., Id, 111 (1968); Anal. Abstr. , 2,4337 (1970).
140. Y. Minami, T. Mitsui, and Y. Fujimura, Bunseki Kagaku, 30, 811 (1981); Anal. Abstr., 43,70 (1982). 141. E. Ragazzi and G. Veronese, Mikrochim. ichnoanalyst. Acta, 5-6, 966 (1965); Anal. Abstr., l b ,2188 (1967).
-
142. D. Brzezinska and W. Dziedzianowicz, Farmacja Pol., 22 , 416 (1966);Anal. Abstr., 7092 (1967).
14,
143. W. Schmollack and U. Wenzel, Pharmazie, 29, 583 (1974).
144. K. Nikolic, D. Malesev, and K. Velasevic, Acta Pharm. Jugosl., l8, 209 (1968); Anal. Abstr.
a,4330 (1970).
145. R.N. Alekseichik, V.P. Korolyuk, E.A. Tukalo, and E.D. Safonova, Chem. Abstr., 92, 99616 (1980).
146. J.M. Meola and M. Vanko, Clin. Chem.,
20,
184 (1974).
621
QUININE HYDROCHLORIDE
147.
K.L. McCloskey, J . C . G a r r i o t t , and S.M. R o b e r t s , J. Anal. Toxicol., 2, 110 (1978).
148.
K.F. Harbaugh, C.M. 0' Donnell, and J . D . Analyt. Chem. , 4 6 , 1206 (1974).
149. L. F i s h e r and J . D . 5073 (1972).
Winefordner,
Winefordner, Anal. A b s t r . ,
23,
ANALYTlCAL PROFILES OF DRUG SUBSTANCES VOLUME 12
547
548 548 548 554 554 554 554 554 554 554 554 555 555 555 567 567 567 569 569 569 583 586 587 587 587 588 588 589 589 59 1 591 595 606 612
Copyrighi by ihe American Pharmaceutical Assacration. ISBN 0-12-260812-7
FARID J. MUHTADI ETAL.
548
1. Description 1.1. Nomenclature 1.1.1 Chemical Names
a) Cinchonan-9-01, 6'-methoxy, (8a, 9R) hydrochloride (1:l) salt, dihydrate.
1.1.2
b)
(8S, 9R)-6'-methoxy cinchonan-9-01, hydrochloride (1:1) salt, dihydrate.
c)
a-(6-methoxy-4-quinolyl)-5-vinyl-2-
d)
6-methoxy- a ( 5-vinyl-2-quinuclidinyl) -4-quinolinemethanol, hydrochloride (1:l) salt, dihydrate.
e)
( a s ) - ~.-(6-methoxy-quinolin-h y1)-
quinuclidinemethanol, hydrochloride (1:l) salt, dihydrate.
-
Generic Names Quinine Quinine Quinine Quinine
1.2.
a
-[ (2R, 4S, 5R)-( 5-vinylquinuclidin2 yl)] methanol, hydrochloride (1:l) salt, dihydrate.
hydrochloride j chloride; monohydrochloride; muriate.
Formulae 1.2.1 Empirical
549
QUININE HYDROCHLORIDE
1.2.2
Structural
The structure of quinine was finally postulated by Rabe (1)and was confirmed by the total synthesis of quinine which was achieved by several authors (2-7). 1.2.3
CAS Registry Number [ 130-89-2I
1.2.4
Wiswesser Line Notation T66 BNJ HOlE YQ-DT66 A B CNTJ AlUl & EH &
1.2.5
QH
(8)
Stereochemistry The stereochemistry of quinine and other related cinchona alkaloids is well summarised by Finar (9)and Turner and Woodward (10).
550
FARID J . MUHTADI ETAL.
If Q represents t h e quinoline h a l f , t h e s t r u c t u r e of q u i n i n e may be w r i t t e n as f o l l o w s :-
The above formula c o n t a i n s f i v e c h i r a l c e n t e r s : 1,3,4,8 and 9 . Since t h e b r i d g e must b e a c i s f u s i o n , c e n t e r s 1 and 4 behave as "one c h i r a l u n i t " , t h e r e f o r e , t h e number of o p t i c a l l y a c t i v e forms would be t h e same as o b t a i n e d from f o u r c h i r a l c e n t e r s . When t h e 1-8 bond i s broken, t h e c h i r a l i t y of t h e n i t r o g e n i s l o s t . Q u i n i n e , q u i n i d i n e , cinchonine and cinchonidine g i v e on d e g r a d a t i o n t h e o p t i c a l l y i d e n t i c a l 8oximino-3-vinylquinuclidine [ 1] , meroquinene [ 21 and c i n c h o l o i p o n i c a c i d [ 31. It t h e r e f o r e f o l l o w s t h a t t h e c o n f i g u r a t i o n s o f C and C4 are t h e same 3 f o r a l l t h r e e compounds.
Conclusive evidence f o r t h e c i s arrangement a t C3 and C 4 w a s provided by P r e l o g and Zalan (11). They reduced cinchonine t o dihydrocinchonine and converted t h e product i n t o c i n c h l o p i o n e t h y l e s t e r [ 4 1 i n which C3 and C 4 r e t a i n t h e o r i g i n a l conf i g u r a t i o n o f cinchonine. [ 4 ] w a s converted i n t o t h e dibromide [ 5 ] which by means o f a s e r i e s of r e a c t i o n s , a l l of which proceeded under mild c o n d i t i o n s and d i d not i n v o l v e t h e c h i r a l c e n t e r s , was converted i n t o 1,2-diethylcyclohexane [6]. This was shown t o be o p t i c a l l y i n a c t i v e ( i t could not be r e s o l v e d ) .
QUININE HYDROCHLORIDE
55 1
The o p t i c a l r e s u l t s provide c o n c l u s i v e evidence f o r a c i s arrangement of t h e two e t h y l groups i n t h e diethyl-cyclohexane [ 6 ] and s i n c e none of t h e s t e p s employed i n t h e conversion of c i n chonine t o [ 6 ] i n v o l v e s t h e c h i r a l c e n t e r s a t C3 and C4, t h e v i n y l group of t h e n a t u r a l cinchona b a s e s must be c i s t o t h e c7-c8 bond i n a l l alkaloids. The 9-deoxy d e r i v a t i v e s ( i : e , CH2 h a s r e p l a c e d CHOH) of cinchonine and c i n c h o n i d i n e have d i f f e r e n t s p e c i f i c r o t a t i o n s , a t + 179.3' and - 29.9', r e s p e c t i v e l y . Since t h e c o n f i g u r a t i o n s of C3 and C4 a r e t h e same i n b o t h b a s s e s and s i n c e C9 i s no l o n g e r o p t i c a l l y a c t i v e , t h e d i f f e r e n c e between t h e two must be a t c 8 , and t h i s i s therefore, a l s o t h e c a s e f o r cinchonine and cinchonidine. S i m i l a r l y s i n c e [ a ] o~f deoxyquinine i s - 97.7' and t h a t of deoxyq u i n i d i n e i s + 211.1', t h e n q u i n i n e and q u i n i d i n e d i f f e r a t c8. The assignment of c o n f i g u r a t i o n s a t c8 may be deduced from t h e f a c t t h a t q u i n i d i n e and c i n chonine a r e b o t h d e x t r o r o t a t o r y and b o t h can be converted i n t o t h e i r c y c l i c e t h e r s [ T I . On t h e o t h e r hand q u i n i n e and c i n c h o n i d i n e are b o t h l e v o r o t a t o r y and do not form c y c l i c e t h e r s .
FARID J. MUHTADI ETAL.
552
The c y c l i c e t h e r s t r u c t u r e i s only p o s s i b l e if t h e group a t t a c h e d t o C 3 and C 8 are i n t h e endop o s i t i o n [ 81. Thus i n cinchonine and q u i n i d i n e , t h e hydrogen atoms a t C 3 and c8 a r e c i s with r e s p e c t t o each o t h e r . Also,because C 4 and C 8 a r e c i s - o r i e n t e d , it follows t h a t t h e hydrogen atoms a t C 3 , C 4 and C 8 a r e a l l c i s - o r i e n t e d i n cinchonine and quinidine whereas i n cinchonidine and quinine t h e hydrogens a t C 3 and C 4 are c i s , but t h e hydrogen a t C 3 and c8 are t r a n s . For each c o n f i g u r a t i o n a t c8, two isomers a r e p o s s i b l e which d i f f e r i n o r i e n t a t i o n a t Cg. Since a l l a l k a l o i d s a r e i d e n t i c a l i n c o n f i g u r a t i o n except a t c8 and Cg, four isomeric substances a r e p o s s i b l e i n each s e r i e s . For example, two of t h e s e substances are presented by quinine and q u i n i d i n e , t h e o t h e r two members a r e epiquinine and epiquinidine. The o t h e r two members a r e cinchonine, cinchonidine, epicinchonine and epicinchonidine. I n most r e s p e c t quinine and quinidine p a r a l l e l one another c l o s e l y i n t h e i r chemical behavior and d i f f e r q u a l i t a t i v e l y from t h e isomeric p a i r , epiquinine and epiquinidine. Since quinine and quinidine d i f f e r i n c o n f i g u r a t i o n a t c8, t h e s e f a c t suggest t h a t t h e two a l k a l o i d s d i f f e r a l s o i n configuration a t C It i s p o s s i b l e t o deduce t h e c o n f i g u r a t i o n a t 9 by comparing t h e b a s i c i t i e s of quinine and i t s Cg-epimer with t h e b a s i c i t i e s of (-)-ephedrine and (+)-$-ephedrine.
z.
:$CH2
H$UH:I3 Ph ( - )ephedrine
( pKt3
9.14
Hl*N CH2
k l . H 3
-
H
Ph Q Q ( +)-%ephedrine ( - )quinine (+) epiquinine 9.22
7.73
8.40
553
QUININE HYDROCHLORIDE
The c o n f i g u r a t i o n of ephedrine (erythroc o n f i g u r a t i o n ) and $-ephedrine ( t h r e o c o n f i g u r a t i o n and t h e s t r u c t u r e of quinine and epiquinine have been drawn ( a s above) so t h a t comparison can be made for c8 and C 9 . Inspection of t h e pKa values shows t h a t JIephedrine i s a s t r o n g e r base t h a n ephedrine and t h a t epiquinine i s a s t r o n g e r base t h a n q u i n i n e , by a n a l o m , (+)-epiquinine i s t h e r e f o r e probably r e l a t e d t o (+)-$-ephedrine i n c o n f i g u r a t i o n and Thus, t h e con(-)-quinine t o (-)-ephedrine. f i g u r a t i o n s a t C 8 and C9 i n (-)-quinine and ( + ) epiquinine a r e probably t h o s e shown i n t h e above formulae. If t h e s e c o n f i g u r a t i o n s are accepted, then t h e r e l a t i v e c o n f i g u r a t i o n s a t C 3 , C 4 , c8 and Cg a r e now known. It i s now p o s s i b l e t o w r i t e t h e a b s o l u t e c o n f i g u r a t i o n s of t h e s e a l k a l o i d s . Lyle and Keefer ( l l a ) have confirmed t h a t t h e n a t u r a l cinchona a l k a l o i d s a r e a l l of t h e erythroc o n f i g u r a t i o n with r e s p e c t t o t h e i r C8 and C 9 systems.
HO --C
I
Q/H '
( - )quinine
H (+)quinidine
H--d Q '
,OH
epiquinine
epiquinidine
FARID J. MUHTADI E T A .
554
1.3.
Molecular Weight
396.88 ( d i h y d r a t e ) 360.88 (anhydrous )
1.4.
Elemental Composition C , 60.53%; H, 7.36%; N, 7.06%; 0 , 16.13%; C1, 8.92% ( d i h y d r a t e ) C, 0,
1.5.
66.57%; H, 6.98%; N, 7.76%; 8.87%; C 1 , 9.81% (anhydrous)
Appearance, C o l o r , Odor and Taste Fine c o l o r l e s s o r white s i l k y n e e d l e - l i k e c r y s t a l s , o f t e n grouped i n c l u s t e r s , o d o r l e s s , and has a v e r y b i t t e r t a s t e .
2.
Physical Properties 2.1.
Melting Range Quinine hydrochloride m e l t s a t : 145 - 153' ( 1 2 ) by hot s t a g e method ( 1 2 ) by h o t b a r method 162O 158 - 160° (13)
156
2.2.
2.3.
- woo
(8)
Eut ec t i c Tempera t u r e Phenacetin Benzanilide
100'
Phenacetin Benzanilide
106"
114'
118'
( 1 2 ) by h o t s t a g e method ( 1 2 ) by hot b a r method
Solubility One gram d i s s o l v e s i n 23 m l o f w a t e r a t 20°, i n 1 . 0 m l of a l c o h o l ( 9 6 % ), i n about 1 . 0 m l chloroform, i n about 7 . 0 m l g l y c e r o l and i n about 350 m l e t h e r .
2.4.
Loss on Drying When d r i e d t o c o n s t a n t weight a t 105O, l o s s e s 6.0 t o 10% of i t s weight ( u s i n g 2 . 0 g ) ( 1 4 ) .
555
QUININE HYDROCHLORIDE
2.5. pH Range 1% aqueous solution of quinine hydrochloride has a pH of 6.0 - 7.0.
2.6. Optical Rotation The following optical rotations were reported. [ a
,I
- 57.1 - 133.7 - 149.8 - 145.5 - 240 to
-
258
Solvent
Ref.
chloroform
(15)
water
(15)
1.3% in water 97% ethanol
(8) (15)
2% solution in 0.1 N hydrochloric acid
(13,14)
The specific rotation of quinine hydrochloride as 2% ethanolic solution has been determined by using a Parkin Elmer Polarmatic model 241 MC and found to be [ cy,]
2.7.
-144.25'
Spectral Properties
2.7.1
Ultraviolet Spectrum The UV spectrum of quinine hydrochloride in ethanol was scanned from 190 to 400 nm using DMS 90 Varian Spectrophotometer. It exhibited the following UV characteristics (Fig.1). Table 1 UV characteristics of quinine hydrochloride. X h x . at 205 232
277 321 332
E -
2381 2858 3334
Figure 1. The W Spectrum of Quinine Hydrochloride i n Ethanol
557
QUININE HYDROCHLORIDE
Other r e p o r t e d U.V. s p e c t r a l d a t a f o r quinine hydrochloride i n a l c o h o l ( 8 ) :-
Xmax. a t 278 nm (2512) and 331 nm (3236) and for quinine i n ethanol ( 1 6 ) :Xmax. a t 236 nm ( E 1%, 1 cm 1110), 278 nm ( E 1%, 1 cm 133) and 332 ( E 1%, 1 cm 1 6 3 ) . The UV absorption s p e c t r a of quinine and i t s hydrochloride s a l t i n o t h e r s o l v e n t s were also reported (16-18). 2.7.2
I n f r a r e d Spectrum The I R spectrum of quinine hydrochloride a s KBr-disc was recorded on a Perkin Elmer 580B I n f r a r e d Spectrophotometer t o which I n f r a r e d Data S t a t i o n i s a t t a c h e d (Fig. 2 ) . The s t r u c t u r a l assignments have been c o r r e l a t e d with t h e following frequencies (Table 2 ) . Table 2. I R c h a r a c t e r i s t i c s of quinine hydrochloride. Frequency cm
-1
Assignment
3300
OH bonded
2580 2960
NH ( q u i n u c l i d i n e ) CH s t r e t c h
1615 1600,1512,1480 1248,1230,1100,1030 860,838,808,725
+
CN
[ C=C ( a l k e n e ) C=C (aromatic ) e t h e r linkage T r i subst it u t ed benzene
Other c h a r a c t e r i s t i c absorption bands a r e : 1438,1365,1345,1320,1140,1130,1010,990 , 935, cm-1. Other I R d a t a f o r quinine hydrochloride ( 8 ) and f o r quinine (16) have been a l s o reported. Hayden and Sammul (19) described t h e I R s p e c t r a of dimorphous and amorphous forms of quinine.
FIG. 2
THE
IR
SPECTRUM OF Q U I N I K E HYDROCHLORIDE A S KBR DISC.
559
QUININE HYDROCHLORIDE
2.7.3
Nuclear Magnetic Rosonance S p e c t r a 2.7.3.1
Proton S p e c t r a The PMR s p e c t r a of q u i n i n e hydroc h l o r i d e i n d e u t e r a t e d chloroform and d e u t e r a t e d d i m e t h y l s u l f o x i d e were recorded on a Varian T - ~ O A , 60-MH, NMR Spectrometer u s i n g TMS ( T e t r a m e t h y l s i l a n e ) as an i n t e r n a l r e f e r e n c e . These a r e shown i n Fig. 3 and Fig. 4 r e s p e c t i v e l y . The f o l l o w i n g s t r u c t u r e assignments have been made (Table 3). Table 3 PMR c h a r a c t e r i s t i c s of quinine hydrochloride
Group
Chemical S h i f t (ppm) CDC13
DMSO
D6
s = s i n g l e t , d = doublet, q = quartet m = m u l t i p l e t b s = broad s i n g l e t bd = broad d o u b l e t , 2d = doublet of d o u b l e t s , b t = broad t r i p l e t . Other PMR s p e c t r a l d a t a of q u i n i n e and i t s hydroc h l o r i d e d i h y d r a t e s a l t i n C D C l have been r e p o r t e d 3 (8, 2 0 ) .
4
560
m
J V
n
-z
u
W
ff a
0 I J
V
0
e n >
Y
L'
W
--.3
c
U
0
E
0 3
e
u
l-
W
a VY
of
E M
2 LL
FIG. 4 Hf'%
SPECTRUM OF k J l N l N E
HYDROCHLORIDE I N Dr;sO-Dg
FARlD J . MUHTADI ETAL.
562
2.7.3.2
13
C-NMR
13
C-NMR n o i s e decoupled and o f f resonance s p e c t r a are p r e s e n t e d i n F i g . 5 and Fig. 6 r e s p e c t i v e l y . Both were recorded over 5000 Hz width i n C D C l 3 ( c o n c e n t r a t i o n 52.9 mg/l ml) on J e o l FX-100 NMR Spectrometer, u s i n g a 1 0 mm sample t u b e and TMS as a r e f e r e n c e s t a n dard a t 20'. The carbon chemical s h i f t s are a s s i g n e d on t h e b a s i s of t h e a d d i t i v i t y p r i n c i p a l s and t h e o f f resonance s p l i t t i n g p a t t e r n (Table 4 ) .
Table 4. Carbon no.
Carbon Chemical S h i f t s of q u i n i n e hydrochloride.
Chemical s h i f t [ PPm 1
Carbon no.
Chemical s h i f t [ PPm 1
c6
158.12(s)
c5 c10
99.79 ( d ) 65.99 ( d )
c3
146.81( d ) 144.34(s)
c11
60.14 ( d )
c9
143.42(s)
c16
56.99 ( t )
r w
El
-1
0
a I
U
0
a
CI
t I
2
W
-z -z
Q
0
LL
z 3 a I-
U W
n.
v)
n
W -I
0
3
n.
U
W
P L
v)
W
0
z
4
M
V
T
r
oc
4 In
2 LL
FIG. 6
13C-NMR
OFF RESONANCE SPECTRUM OF 3 U I N I N E
HYDROCHLORIDE.
QUININE HYDROCHLORIDE
‘18
137.37 ( d
‘8
131.03( d )
C4
C
7
c2 C
19
125.25(s) 122.17(d) 118.81(d)
117 15( t
565
c20 ‘1 5
‘17 ‘13 52 ‘14
54.70 ( 9 ) 44.11( t ) 37.12( d ) 26.91( a ) 24.29( t ) 18.13( t )
s = s i n g l e t , d = doublet, t = t r i p l e t , q = q u a r t e t . Other 13C-NMR s p e c t r a l d a t a of qninine have been r e p o r t e d (21, 22).
2.7.4
Mass Spectrum The mass spectrum of quinine hydrochloride obtained by e l e c t r o n impact i o n i z a t i o n which w a s recorded on a Finnigan Model 3000 D GC-MS-system. The spectrum scanned t o mass 500 with u n i t r e s o l u t i o n . Electron energy was 7Oev. The chemical i o n i z a t i o n mass s p e c t r a l d a t a were obtained on a Finnigan Model 1015D GC Mass Spectrometer. Methane w a s used as GC c a r r i e r gas and a l s o served as t h e C I r e a c t a n t gas i n t h e i o n source. The i o n source temperature w a s 180Oc and e l e c t r o n energy 100 ev., i o n r e p e l l e r , 3V. E l e c t r o n impact mass s p e c t r a l d a t a : Base Peak 136
Fig. 7 (23).
42, 55, 67, 81, 95, 117, 128, 136, 158, 172, 1.89, 202, 222, 251, 269, 295, 309, M+ 324 C I mass s p e c t r a l d a t a and prominent fragment i o n s are M.H+ 325 (1001, 136 (371, 307 (101,and 323 ( 7 ) .
Fig. 7
The Mass Spectrum of Quinine
QUININE HYDROCHLORIDE
3.
567
P r e p a r a t i o n of Quinine h y d r o c h l o r i d e 3.1.
I s o l a t i o n of Q u i n i n e Quinine i s t h e p r i n c i p a l a l k a l o i d o f cinchona b a r k of which s e v e r a l s p e c i e s are known. Cinchona o f f i c i n a l i s L. ( C . l e d g e r i a n a Moens) , Family Rubiaceae i s t h e most important. It c o n t a i n s about 8% q u i n i n e ( 2 4 ) . Q u i n i n e w a s i s o l a t e d from cinchona b a r k by P e l l e t i e r and Caventou i n 1820 ( 2 5 ) . S e v e r a l methods have been r e p o r t e d f o r t h e i s o l a t i o n of q u i n i n e from cinchona b a r k , t h e most important method i s as f o l l o w s ( 2 6 ) : Powdered cinchona (250g) i s w e l l mixed w i t h C a O ( 6 0 g ) , water (600 m l ) and 30% NaOH s o l u t i o n ( 3 0 m l ) and l e f t f o r 24 hours. The mixture i s t h e n e x h a u s t i v e l y e x t r a c t e d under r e f l u x w i t h benzene. The benzene e x t r a c t i s f i l t e r e d while h o t i n t o a s e p a r a t i n g f u n n e l c o n t a i n i n g c o n c e n t r a t e d H2S04 ( 7 g ) i n water (500 m l ) t o convert t h e a l k a l o i d s t o t h e i r b i s u l f a t e s a l t s . The mixture i s s e p a r a t e d and t h e a c i d aqueous l a y e r i s h e a t e d t o 90' and n e u t r a l i s e d w i t h 5% Na2C03 s o l u t i o n u s i n g l i t m u s as an i n d i c a t o r (The b i s u l f a t e s a l t s are now converted i n t o t h e s u l f a t e s a l t s ) . The c l e a r orange s o l u t i o n becomes t u r b i d due t o t h e s e p a r a t i o n of some r e s i n o u s m a t e r i a l . D i l u t e H2SO4 ( 2 d r o p s ) and animal c h a r c o a l ( 2 g ) a r e added and t h e r e s u l t i n g mixture i s h e a t e d a g a i n a t 90' f o r 1 5 minutes and f i l t e r e d . The f i l t e r a t e i s allowed t o c o o l down when q u i n i n e s u l f a t e s e p a r a t e s o u t and c o l l e c t e d by f i l t e r a t i o n . The q u i n i n e s u l f a t e s o c o l l e c t e d i s d i s s o l v e d i n b o i l i n g w a t e r and t r e a t e d w i t h Na2C03 s o l u t i o n t o p r e c i p i t a t e q u i n i n e which i s c o l l e c t e d and c r y s t a l l i z e d . The procedure o u t l i n e i s p r e s e n t e d i n F i g . 8.
3.2.
Quinine Hydrochloride Q u i n i n e h y d r o c h l o r i d e i s o b t a i n e d by n e u t r a l i z i n g t h e a l k a l o i d quinine with d i l u t e hydrochloric a c i d and r e c r y s t a l l i s i n g from b o i l i n g w a t e r t o g i v e f i n e c o l o r l e s s c r y s t a l s of q u i n i n e h y d r o c h l o r i d e .
FARID J. MUHTADl ETAL.
568
+
Powdered cinchona
CaO + NaOH with C6H6
1
reflUX
+
Water
filter
Hot f ilt erat e
Extract
with d i l . H2S04
I
I f
Alkaloids b i s u l f a t e s
Heating a 90 O
+
Na2C03
(PH 6 . 5 )
Alkaloids s u l f a t e s
+
Purify
+
charcoal b o i l and f i l t e r
Cool f i l t e r a t e
F i l t e r a t e of Quinidine cinchonine sulfates etc.
*
P r e c i p i t a t e of quinine s u l f a t e Na2S03
1
solution
Quinine
Fig. 8.
Procedure Outline f o r t h e I s o l a t i o n of Quinine.
QUININE HYDROCHLORIDE
569
4. Synthesis of Quinine 4.1.
Partial Synthesis Rabe and Kindler in 1918 (3) achieved the first partial synthesis of quinine from quinotoxine. Quinotoxine was converted by the action of sodium hypobromite into N-bromoquinotoxine which was cyclized by alkali with the l o s s of hydrogen bromide to give quininone. Reduction of the ketone with aluminium powder and ethanol in the presence of ethoxide gave a mixture of stereoisomeric alcohols from which quinine and quinidine were isolated. Gutzwiller and Uskokovic in 1973 (7) developed a slightly different scheme for the partial synthesis of quinine from quinotoxine. Quinitoxine was dissolved in dichloromethane and treated with sodium hypochlorite solution to give N-chloroquinotoxine. This was cyclized with phosphoric acid to give a mixture of quinone and quinidinone. The resulting mixture was dissolved in benzene and treated with a solution of diisobutylaluminium hydride in toluene to give a mixture of quinine and quinidine which was separated by crystallization.
4.2. Total Synthesis Several schemes (I to IV) for the total synthesis of quinine have been reported. The first total synthesis of quinine was completed in 1944 by Woodward and Doering (2). Rabe and Kindler (3) carried out a partial synthesis of quinine starting from quinotoxine. Woodward and Doering (2) completed the total synthesis by synthesizing (+)-quinotoxine. The first total synthesis of quinine is presented in Scheme I. m-Hydroxybenzaldehyde [l] is condensed with aminoacetal [2] to give 7-hydroxyisoquinoline [ 3 ] which is treated with formaldehyde in methanol containing piperidine to give 7-hydroxy-8-piperidinmethylisoquinoline [ 41. This by heating with methanolic sodium methoxide at 220° is converted
FARID J. MUHTADI ETAL.
570
into ~-hydroxy-8-methylisoquinoline[ 5 1. Compound [ 51 on catalytic reduction, followed by acetylation gives N-acetyl-7-hydroxy-8-methyl1,2,3,4-tetrahydroisoquinoline [6], which on further catalytic reduction by heating with a Raney nickel catalyst under pressure and then followed by oxidation with C r O 3 is converted into N-acetyl-~-keto-8-methyldecahydroisoquinoline[ T I . This compound is a mixture of cis-and trans-isomers, these are separated and the cis-isomer is treated with ethylnitrite in the presence of sodium ethoxide to give the homomeroquinene derivative [8]. This on reduction gives the corresponding aminocompound [g], which may now be written more conveniently as shown. Exhaustive methylation of [ 91 followed by hydrolysis gives t cis homomeroquinene [lo] which after esterification and benzoylation gives N-benzoylhomomeroquinene ethylester [ll]. On condensation of [ 111 with excess ethylquininate [lg] using sodium ethoxide produces the intermediate B-ketoester [20]. This on heating with hydrochloric acid is hydrolysed and decarboxylated to (+)-quinotoxine [21]. This is resolved via its dibenzoyltartrate. (+)-quinotoxine [ 221 which is converted into quininone [23] upon N-bromination and cyclization. Reduction of [23] with aluminium powder and ethanol gives a mixture of stereoisomeric quinine and quinidine [24]which are separated. Quinic acid required for the synthesis of quinine was prepared by Rabe et al. ( 27). panisidine [121 is condensed with acetoacetic ester [ 1 3 ] to give the condensate [14]. This is treated with sulfuric acid where ring closure occurs to give 2-hydroxy-4-methyl-6-methoxyquinoline [15]. The phenolic hydroxyl group of [15] is eliminated upon treatment with a mixture of phosphorous pentachloride and phosphorous oxychloride to give 2-chloro-4-methyl-6-methoxyquinoline [16] which upon hydrogenation gives 4-methyl6- methoxyquinoline [ 171. Knoevenagel condensation of the latter followed by oxidation gives quinic [l81 which upon esterification gives ethylquininate
[191
Scheme 11: Total synthesis of quinine and quinidine according to Uskokovic et al. (4).
QUININE HYDROCHLORIDE
Scheme I:
T o t a l S y n t h e s i s of Q u i n i n e (Woodward and Doering).
571
FARID J. MUHTADI ETAL.
572
-G H
i) H p R a n e y N i i i ) ~r03
- IJCOCH3
0
CH3
I
i ) C H ON0
2 5
i i ) C H ONa
[71
Q c g L T
H5c$2c H2N-CH
CH3
[91
‘
QN=C C
11
HO C H 3
O
2 5
C
H
[81
3
QUININE HYDROCHLORIDE
( f )-Quinine
1241 ( f ) Quinidine
573
Resoln.
( - )-Quinine
[241 (+)Quinidine
FARID J . MUHTADI ETAL.
574
P'
ii)KMnOq
H
F
O
COOC2H5 d
' 3 " " 3
C6H5CH0
ester.
L
[191
[181
575
QUININE HYDROCHLORIDE
N-benzoylhexahydroisoquinolone [ 11 is hydrogenated with rhodium on alumina catalyst to give predominantly cis-isoquinolone [2] which is treated with sodium azide in poly-phosphoric acid to give a mixture of the seven-membered lactams which is separated by fractional crystallisation to give [ 31. Lactam [3] is treated with dinitrogen tetroxide to give the N-nitrosolactam [4] which is rearranged upon heating to the diazolactone [5] and fragmented with extrusion of nitrogen to give a mixture of racemic N-benzoylmeroquinene [6] and the seven membered lactone [?a] (in 50 and 30% yield, respectively). The latter [5a] can be converted into [6] which upon esterification gives N-benzoylmeroquinene methyl ester [6a]. This ester is treated with 6-methoxylepidyllithium [7] in tetrahydrofuran to give the racemic N-benzoylketone [8]. This is treated with diisobutylaluminium hydride in toluene at - 78O [route a] to remove the benzoyl group with concommitant reduction of the ketone function to give the aminoalcohol [g] The aminoalcohol [9] is first acetylated with acetic acid containing 10% boron trifluoride etherate and treated with boiling benzene - acetic acid - sodium acetate where cyclization proceeds to give a mixture of desoxyquinine and desoxyquinidine [12]. This can also be achieved without acetylation. The aminoalcohol [9] is refluxed with benzene - acetic acid mixture (4:l) for 4-5 days when cyclization proceeds via dehydration [ 111 to give both desoxyquinine and desoxyquinidine [12]. Upon stirring a solution of [12] in dimethyls u l f o x i d e - t - b u t y l a l c o h o l ( 4 :1) containing potassium t-butoxide in an atmosphere of oxygen affords a mixture of quinine [13] and quinidine [14]. Separation can be effected by a combination of crystallization and chromatography.
.
An alternative synthetic route [b] via the amino epoxide [lo] is as follows:N-benzoylketone [8] is converted into a mixture of diastereomeric N-benzoyl epoxides [lo a] by bromination followed by sodium borohydride reduction. Reductive debenzoylation of [lo a] with diisobutylaluminium hydride in toluene at - 78' furnished a mixture of diastereomeric amino-
576
FARID J. MUHTADI ETAL
T o t a l Synthesis (Uskokovic etal. 1
Scheme 11:
EtOH HC1 [21
i;'
N-0
H '
[3
c
L41 0
N
I)R=H
[61
R=CH3 [ 6a 1
Ac6H5 I
c6H5
QUININE HYDROCHLORIDE
577
CHeLi
r
[6al
+
.
conden.
"71
4
0
A c6H5
H3C0
[81
H CO
3
191
578
FARID I. MUHTADI ETAL.
[91
[a1
L a c e t ylation
QUININE HYDROCHLORIDE
579
epoxides [lo]. Treatment of [lo] with tolueneethanol (19:l) at reflux for 12 hr. give quinine [13] and quinidine [14]. Separation is effected by preparative thin layer chromatography. Scheme 1II:Total synthesis according to Gates et al. ( 5 ) 6-methoxylepidine [ 11 is condensed with N-acetyl3-vinyl-4-piperidineacetic acid ester [ 21 to give the ketone [ 31. Reduction of [ 31 followed by dehydration of the resulting alcohol with acetic anhydride gives the intermediate [ 41. Saponification of the latter affords the secondary m i n e [5] Alkaline hydrolysis of [ 51 in aqueous alcohol under reflux, cyclization occurrs to give a mixture of desoxyquinine and its c8 epimer desoxyquinidine [ 61. Oxidation of the mixture [6] with oxygen in the presence of potassium t-butoxide and triphenylphosphine in dimethylformamide -t.-butyl alcohol introduces of the hydroxyl group at C9 giving the diasteromeric quinine and quinidine [ 73. The intermediate [4] can also be prepared by the Wittig reaction of quininaldehyde [8]with the quaternary phosphonium compound derived from the corresponding bromide obtained from meroquinene alcohol [g]. Scheme IV: Total synthesis according to Taylor and Martin (6) : 4-chloro-6-methoxyquinoline [l] is treated with 2 equiv. of methylenetriphenylphosphorane [ 21 to give [3]. This is condensed with N-acetyl-3(R)vinyl-4 (S)-piperidineacetaldehyde [ 41 to give the olefin [5]. Removal of the N-acetyl group in situ by hydrolysis followed by spontaneous intramolecular Michael addition to give a mixture of desoxyquinine and desoxyquinidine [6] which is converted by base-catalyzed hydroxylation to quinine [ 71 and quinidine [ 81. Other scheme for the total synthesis of quinine through the synthesis of homomeroquinene and quinotoxine is reported by Uskokovic et al. ( 7 ) .
FARID J . MUHTADI ETAL.
580
Scheme 111:
Total Synthesis (Gates e t a l . )
QUININE HYDROCHLORIDE
581
582
FARID J. MUHTADI ETAL.
Scheme I V : T o t a l S y n t h e s i s of Q u i n i n e (Taylor and M a r t i n )
c1
H 3 c 0+ y 3 CHO CH=PPh3
H3c000 I
+
[31
H3C0
H . .
conden.
COCH3
[41
-
\
583
QUININE HYDROCHLORIDE
5. Biosynthesis of Quinine Postulation of the biosynthetic pathway of cinchona alkaloids started in 1950 with the suggestion of Goutarel et al. ( 2 8 ) that quinine and other cinchona alkaloids are derived from indolic precursors, since cinchonamine (indole alkaloid) occurs as a minor alkaloid in cinchona. This was proved when Kowanko and Leete ( 2 9 ) have isolated labelled quinine upon feeding trypt0phan-2-~~C into cinchona plants. They have shown that the quinoline ring and Cg unit of quinine originated from tryptophan. Further studies have proved that quinine is biosynthesized by a combination of indolic and monoterpenoid units which leads to the corynanthe type indole alkaloids. Thus tryptophan ( 2 9 ) , geraniol (30-32) and loganin ( 3 3 ) were incorporated into quinine. Tracer experiments on Cinchona ledgeriana carried out by Battersby and Parry ( 3 4 ) have established the biosynthetic pathway of quinine as presented in scheme V. Scheme V:
Biosynthesis of Quinine
Loganin
Secologanin
+
p)-JyOH \
H
Tryptophan
Vincoside
-
FARID J. MUHTADI ETAI;.
584
LHO
Corynantheal
-
Cine honaminal
I
H
I
H
k
585
QUININE HYDROCHLORIDE
Quinidine
FARID J . MUHTADI ETAL.
586
6. Metabolism The cinchona alkaloids are extensively metabolized in the body, especially in the liver, so that less than 5% of an administered dose is excreted unaltered in the urine (35-37). The metabolism of quinine has been studied both in human and rat urines. The major urinary metabolites in man are hydroxyderivatives of quinine (37). The route of quinine metabolism in man proposed by Brodie et al. (37)involves two parallel pathways as presented in the f o l l o w i n g scheme. Scheme VI: Metabolism of quininein Man
\
H3CO
dihydroxy derivative (non-phenolic)
quinine carbostyri1
QUININE HYDROCHLORIDE
587
Barrow et al. (38) have separated eight metabolites of quinine in the urine of male Sprague-Dawley rats after Six of which have a single dose of quinine (50 mg/Lg). been identified as O-desmethylquinine, hydroxyquinine, quinine, quinine carbostyril and the two diastereoismers of quinine-10, ll-dihydrodiol. These were separated by reversed-phase HPLC on a semi-preparative column by gradient elution. Separation of these metabolites is presented in Fig. 12.
7.
Pharmacokinetics Quinine is readily absorbed after oral administration. Absorption occurs mainly from the upper small intestine, and is almost complete even in patients with marked diarrhea. Rectally administered doses are poorly absorbed and intramuscular or subcutaneous doses of quinine salts are slowly absorbed (13, 35). Peak plasma concentration of quinine occurs within 1 to 3 hours after a single oral dose (35). Therapeutic plasma concentrations appear to be in the range 3 to 7 ug/ml during therapy with oral doses of 500 to 650 mg thrice daily (13). Malarial infection inhibits hepatic metabolism and thus plasma concentrations resulting from a given dose will vary according to the severity of the infection (391. Plasma half-life 6-9 hours, which is increased up to 1 5 hours in malarial infection and decreased to about 3 to 4 hours in patients being treated with antiepileptic drugs (39). After termination of quinine therapy, the plasma level falls rapidly and only a negligible concentration is detectable after 24 hours. A large fraction (approximately 70%) of the plasma quinine is bound to proteins (35). Quinine is excreted mainly in the urine, but small amounts also appear in the feces, gastric juice, bile and saliva. Renal excretion of quinine is twice as rapid when the urine is acidic as when it is alkaline (35).
8. Indications and Dosages
8.1. For the Treatment of Malaria The usual oral dose of quinine or its salts is 325 mg four times daily for 7 days. The drug is given after meals, preferably in capsules, to
FARID J. MUHTADI E T A .
588
minimize gastric irritation (35). Intravenous injections of quinine are to be reserved for certain emergencies such as pernicious or cerebral malaria. The dihydrochloride is employed and I.v. injection should be given very slowly, preferably by the drip method (35). 8.2.
For the relief of Nocturnal Leg Cramps Recumbency leg muscle cramps (night cramps) are quickly and effectively relieved by quinine in most cases. The dose is 200 to 300 mg before retiring (35).
9.
Toxicity Poisoning by quinine is usually due to clinical overdosage or to hypersensitivity. The fatal oral dose of quinine for adults is approximately 8 g (35). When quinine is repeatedly given in full doses a typical cluster of symptoms occurs to which the term cinchonism has been applied. In its mildest form it consists in ringing in the ears, headache, nausea, and slightly disturbed vision. When medication is continued or after large single doses, symptoms also involve the gastrointestinal tract, the nervous and cardiovascular systems and the skin (35).
QUININE HYDROCHLORIDE
589
10. Methods of Analysis 10.1.
Identification
10.1.1 Color Tests The following c o l o r t e s t s have been described f o r t h e i d e n t i f i c a t i o n of quinine , H C 1 (12-14, 40 -44 ) : a. Dissolve 1 0 mg i n s u f f i c i e n t water t o produce 10 ml and t o 5 m l of t h e s o l u t i o n add 0.2 m l of bromine water and t h e n 1 m l of 2 M ammonia, an emeraldgreen c o l o r i s produced. b . Dissolve 5 mg i n 5 ml of water, add 1 ml of 2 M ammonia and 5 ml of e t h e r , shake and acidif'y with 2 M n i t r i c a c i d , t h e aqueous l a y e r y i e l d s r e a c t i o n s c h a r a c t e r i s t i c of chlorides. c . Quinine a l k a l o i d can be i d e n t i f i e d w i t h ammonium t e t r a k i s ( t h i o c y a n a t o ) z i n c a t e ( 4 2 ) . d. I n t o x i c o l o g i c a l work, it i s o f t e n d e s i r e d t o d e t e c t very s m a l l q u a n t i t y of quinine. A very s e n s i t i v e t e s t has been r e p o r t e d (45).
10.1.2 Micro-Crystal T e s t s The following micro-crystal t e s t s a r e a l s o u s e f u l i d e n t i f i c a t i o n t e s t s , photomicrographs of t h e c r y s t a l s have been described (16, 46-49) (Fig. 9 and 1 0 ) . i ) Platinic
iodide s o l u t i o n g i v e s curved s e r r a t e d needles ( s e n s i t i v i t y 1 i n 1 5 0 0 ) .
i i ) Sodium phosphate s o l u t i o n forms needles ( s e n s i t i v i t y 1 i n 1000). iii) Dissolve 1 mg i n 2 ml of water, a c i d i f y with d i l u t e s u l p h u r i c a c i d (1 drop) and add a few drops of an aqueous s o l u t i o n c o n t a i n i n g 5% of cadmium i o d i d e and 10% of potassium i o d i d e . Colorless c r y s t a l s a r e produced and t h e s o l u t i o n becomes t u r b i d .
FARID J. MUHTADI ETAL.
590
F i G , 9,
MICROCHEMICAL CRYSTALS WITH DISODIUM HYDROGEN
OF Q U I N I N E PHOSPHATE,
F I G . 13. K I C R C C H E M I C A LCRYSTALS EETHYL I O D I D E .
HYDRCCHLORIDE
OF ~ U I P J I NWEI T P
QUININE HYDROCHLORIDE
591
i v ) A drop of t h e drug i s p u t on a microscope s l i d e next a drop of an almost s a t u r a t e d s o l u t i o n of p i c r i c a c i d o r of 3 $? g o l d c h l o r i d e , covered and observed f o r 1 5 minutes or more. If t h e p i r r a t - e ( o r a u r a t e ) does n o t c r y s t a l l i s e spontaneously, a s m a l l amount o f a suspension of f i n e s e e d c r y s t a l s i s added t o one edge of t h e drop and i t s e f f e c t observed. I d e n t i f i c a t i o n of q u i n i n e i n human u r i n e h a s been d e s c r i b e d (48) by t h e f o l l o w i n g method :
v)
A f t e r a c i d h y d r o l y s i s t o f r e e t h e b a s e from i t s g l u c u r o n i d e , q u i n i n e i s e x t r a c t e d from a l k a l i n e s o l u t i o n by chloroform. The s o l v e n t i s evaporated and t h e r e s i d u e , d i s s o l v e d i n methanol, i s s u b j e c t e d t o TLC. The p l a t e i s sprayed w i t h i o d o p l a t i n a t e , and t h e methanolic e x t r a c t o f t h e s p o t i s t h e n subjected t o s p e c i f i e d microscopical tests. The product i s i d e n t i f i e d by t h e c r y s t a l formed.
10.2.
Gravimetric Method B e r l i n and Robinson (50) have d e s c r i b e d a thermog r a v i m e t r i c d e t e r m i n a t i o n of q u i n i n e w i t h d i l i t u r i c a c i d . S o l u t i o n of q u i n i n e i n 50% e t h a n o l w a s t r e a t e d w i t h 0.02 M d i l i t u r i c a c i d i n 40% methanol s o t h a t t h e molar r a t i o of d i l i t u r i c a c i d t o q u i n i n e was approximately 7 : l . The p r e c i p i t a t e w a s washed w i t h c o l d 50% Ethanol s a t u r a t e d w i t h d i l i t u r i c a c i d followed by c o l d 95% e t h a n o l and t h e n d r i e d A i n t h e thermobalance between 140° and 195'. c o n s t a n t weight w a s o b t a i n e d i n 1 5 t o 20 m i n u t e s , corresponding t o anhydrous q u i n i n e d i l i t u r a t e . Amounts of q u i n i n e between 2 and 40 mg have been determined w i t h a maximum d e v i a t i o n of 3%.
lo.3.
T i t r i m e t r i c Methods 10.3.1
Aqueous Schneider ( 5 1 ) has p u b l i s h e d t h e a p p l i c a b i l i t y o f t h e s t r o n g l y b a s i c anion-exchangers t o t h e d e t e r m i n a t i o n of q u i n i n e , H C 1 and
FARID J. MUHTADI ETAL.
592
quinine ,H2SO4. In this method , the salt (about 0.1 gm) is dissolved in 90% ethanol (10 ml) , pass the solution through an anionexchange resin. Pass 90% ethanol (10 ml) through the column, then rapidly pass a further 20 ml. Dilute the combined percolates with freshly boiled, cooled water (50 to 70 m l ) and titrate the liberated mine with 0.1 N HC1 in the presence of Tashiro’s indicator, until the green-blue colour changed to violet (52). 10.3.2 Non-Aqueous Non-aqueous titration methods have been described for the analysis of quinine alkaloid or salt ( 53-59). The drug is titrated by perchloric acid in acetic acid and the end point is determined potentiometrically. The method is applied for the determination of small amounts of the alkaloid in the presence of an adsorption electrode ( 60). Quantitation of quinine in media of nitromethane and of chloroform-dioxane has been also reported (61) 10.3.3
Complexometric Application of volume-colorimetry to the micro-determination of alkaloids, including quinine, has been described (62). The assay method depends on the precipitation of the alkaloid with phosphotungstic acid reagent, the precipitate is treated with a reducing agent, the blue color of tungstic anhydride is titrated volumetrically with an oxidising agent. MaJlat and Bayer (63) have also reported the determination of quinine salts by titration with tungstosilicic acid. Complexometric determinations of alkaloids, including quinine, have been also described, by the use of EDTA (disodium salt) (64) or copper picrate (65). Budesinsky and Vanickova (66) have published a complexometric titration of quinine. The
QUININE HYDROCHLORIDE
593
drug i s p r e c i p i t a t e d a t pH 1 . 2 t o 1.5 w i t h bismuth potassium i o d i d e , and t h e excess of t h e reagent i s determined as b i s muth complexometrically. have described t h e Yeh and Tsang (67) q u a n t i t a t i o n of q u i n i n e , H SO4 by c a t i o n 2 exchange followed by complexometric t i t r a t i o n . The e r r o r i s 0.5-2%.
10.3.4
Conductimetric High-frequency t i t r a t i o n of q u i n i n e , HC1,quinine,H2S04, a n d o t h e r s a l t s of organic compounds , has been r e p o r t e d (68). Graphs i l l u s t r a t i n g t h e high-frequency conductimetric t i t r a t i o n of t h e s e s a l t s have been described. For quinine, H C 1 , t h e t i t r a n t i s 0.01 N s i l v e r n i t r a t e ; for quinine,H$O4, t h e t i t r a n t i s 0 . 0 1 M barium c h l o r i d e , 0.01 M barium a c e t a t e , or 0.008 N potassium hydroxide. I n t h e t i t r a t i o n of q u i n i n e , H2S@4with potassium hydroxide, e x t r a p o l a t i o n i s necessary t o determine t h e p o i n t of i n f l e c t i o n of t h e graph.
10.3.5
Amperometric Lemahieu e t a l . ( 6 9 ) have r e p o r t e d an aniperometric determination of q u i n i n e , H C 1 i n dimethyl sulphoxide. The method i s based on t i t r a t i o n w i t h s i l v e r n i t r a t e i n dimethyl sulphoxide t o give an end-point corresponding t o t h e formation of AgC1; and a less sharp end-point f o r t h e p r e c i p i t a t i o n of s i l v e r c h l o r i d e . U s e of t h e f i r s t end-point and two platinum i n d i c a t o r e l e c t r o d e s with a p o t e n t i a l d i f f e r e n c e of 100 mV allows t i t r a t i o n down t o a 0.2 m M c o n c e n t r a t i o n of q u i n i n e , HCI.. Use of one i n d i c a t o r e l e c t r o d e and a s i l v e r - Ag+ r e f e r e n c e e l e c t r o d e prodcces a l e s s sharp end-poir,t, not obtaina b l e below a m M concentration. Gengrinovich e t i z l . ( 7 0 ) have described t h e use of i o d i n e ch1ori.de and a r o t a t i n g platinum e l e c t r o d e for t h e amperometric t i t r a t i o n c f quint.ne, HC1. The t i t r a t i o n
FARID J. MUHTADI ETAL.
594
i s based on t h e a d d i t i o n o f I C 1 t o t h e v i n y l group of q u i n i n e . The r e a c t i o n i s complete i n 20-25 minutes. Charles and Knevel (71) have p u b l i s h e d coulometric a s s a y of q u i n i n e s u l p h a t e u s i n g an arseno-amperometric end-point d e t e c t i o n t e c h n i q u e . T h i s i s based on t h e f a c t t h a t t h e r e a c t i o n of bromine w i t h q u i n i n e s u l p h a t e i s t o o slow t o allow d i r e c t coulometric t i t r a t i o n of t h e drug. The c o e f f i c i e n t of v a r i a t i o n i s 0.5%.
10.3.6 Polarographic Souckova and Zyka(72,73) have r e p o r t e d a polarographic d e t e r m i n a t i o n of q u i n i n e , H C l by t i t r a t i o n with t u n g s t o s i l i c i c a c i d , tungstophosphoric, and molybdophosphoric acids (73). The a p p a r a t u s h a s a dropping mercury cathode and S.C.E. anode, t h e v o l t a g e b e i n g 0.65V. The pH o f t h e s o l u t i o n i s a d j u s t e d w i t h HC1. The m a x i m u m e r r o r i s f 1% w i t h t u n g s t o s i l i c i c a c i d and 22% w i t h t h e two o t h e r a c i d s . Molnar and Molnarwa (74) have d e s c r i b e d o s c i l l o p o l a r o g r a p h i c d e t e r m i n a t i o n of q u i n i n e a l k a l o i d . The o s c i l l o p o l a r o g r a p h i c behaviour of q u i n i n e d e r i v a t i v e s has been s t u d i e d and t h e i r oscillograms i n N LiC1, N LiCH, N NaOH, and N H$O4 were o b t a i n e d w i t h t h e u s e of dropping and streaming mercury e l e c t r o d e s . Concentration of 10-4 M s o l u t i o n of q u i n i n e a l k a l o i d s can b e d e t e c t e d with t h e use of o s c i l l o p o l a r o g r a p h i c methods. Q u a n t i t a t i v e o s c i l l o g r a p h i c polarography of c e r t a i n a l k a l o i d s , including quinine alkal o i d , have been a l s o r e p o r t e d Cinchona a l k a l o i d s g i v e c h a r a c t e r i s t i c o s c i l l o g r a m s which can b e used f o r t h e i r d e t e r m i n a t i o n with an accuracy of f 4%. Girard and R o u s s e l e t ( 7 6 ) have p u b l i s h e d a polarographic and c o l o r i m e t r i c d e t e r m i n a t i o n o f q u i n i c i n e i n t h e presence G f l a r g e amount of q u i n i n e .
595
QUININE HYDROCHLORIDE
1 0 . 4 . Chromatographic Methods
Chromatographic methods have been d e s c r i b e d f o r t h e s e p a r a t i o n , i d e n t i f i c a t i o n and q u a n t i t a t i o n of q u i n i n e i n pharmaceutical dosage forms and i n mixtures (77-93).
10.4.1
Paper Chromatography The f o l l o w i n g s c r e e n i n g procedure h a s been reported ( 9 4 ) f o r detecting quinine i n chemical-toxicological analysis of b io lo g ic a l m a t e r i a l (blood): To t h e blood ( 5 m l ) add water ( 3 1 . 5 m l ) and 10% Na2W04 s o l u t i o n (10 m l ) , mix, and add s l o w l y , w i t h s t i r r i n g , 10% H2S04 (3-5 m l ) . Heat t h e mixture i n a b o i l i n g - w a t e r b a t h for 10 minutes, f i l t e r , shake t h e cooled f i l t r a t e w i t h e t h e r (30 ml) , and d i s c a r d t h e e t h e r . Adjust t h e aqueous phase t o pH 9 w i t h c o n c e n t r a t e d aqueous ammonia, shake t h e s o l u t i o n with e t h e r ( 3 0 m l ) , d r y t h e e t h e r w i t h anhydrous sodium s u l p h a t e , e v a p o r a t e a t 37' i n a stream o f n i t r o g e n . D i s s o l v e t h e r e s i d u e i n one o r two drops of chloroform, apply t h e s o l u t i o n t o Whatman CT30 anionexchange paper, and c a r r y o u t ascending chromatography w i t h 0 . 1 M EDTA f o r 1 4 minutes. Examine t h e w e t paper i n UV l i g h t a t 254 nm.
R a m a and Singh (83) have p u b l i s h e d a r a p i d s e p a r a t i o n of q u i n i n e , and o t h e r a l k a l o i d s , by ascending paper chromatography on s t r i p s impregnated w i t h 0 . 1 M zirconium o x y c h l o r i d e by u s i n g aqueous s o l v e n t s c o n t a i n i n g 0.001 N H C 1 o r 0.001 N NaOH. The i n d i v i d u a l a l k a l o i d , 4 a l k a l o i d s , were as w e l l as mixtures o f s e p a r a t e d w i t h i n 15-20 minutes. Q u i n i n e and s e v e r a l o t h e r a l k a l o i d s have been s e p a r a t e d by u s i n g Whatman No. 1 paper which h a s been soaked i n S o r e n s e n ' s phosphate b u f f e r s o l u t i o n ( M / l 5 , pH 5 ) and d r i e d , w i t h b u t a n o l as t h e mobile phase. The s p o t s a r e l o c a t e d by s p r a y i n g w i t h i o d o p l a t i n a t e r e a g e n t ( 91 )
.
5%
FARID J. MUHTADI ETAL.
S t r e e t and Niyogi (95) have r e p o r t e d a new technique of chromatography and ionophoresis on ion-exchange paper. This has been a p p l i e d t o s e p a r a t i o n of a mixture of compounds including quinine. The mixture i s subjected t o ascending chromatography i n 0 . 1 M - EDTA on diethylaminoethylcellulose paper f o r 20 minutes and s u b j e c t t o ionophoresis a t a constant c u r r e n t of 1 0 m A f o r 30 minutes. Steger and Storz (96) have described microa n a l y t i c a l determination of a l k a l o i d s , including quinine, with paper chromatogram soaked with molybdosilicic a c i d . A f t e r drying with w a r m a i r , e x t r a c t with a reducing q u i n o l , sodium carbonate, and sodium s u l p h i t e . The e x t i n c t i o n of t h e b l u e s o l u t i o n i s measured c o l o r i m e t r i c a l l y a t 660 nm.
A l w a s e t a l . (88) have r e p o r t e d t h e s e p a r a t i o n and q u a n t i t a t i v e a n a l y s i s of quinine, and o t h e r a l k a l o i d s , by a p p l i c a t i o n of paper ionophoresis. Jakube e t a l . have described t h e use of paper chromatography i n t h e assay o f m i x t u r e s of pharmaceuticals, including quinine s a l t s . I n t h i s method, mixtures of water, low-boiling a l c o h o l (methanol, ethanol , o r isopropanol) , and ammonia have been found t o be t h e b e s t s o l v e n t s , and a mixture of FeC13 w i t h K 3 Fe (CN)6, t h e b e s t d e t e c t i n g agent. Quinine (0.005 t o 0.015 mg) , and some o t h e r a l k a l o i d s , have been d e t e c t e d i n s e v e r a l foods by using a paper-chromatographic method (98). I n t h i s method, e t h a n o l i c e x t r a c t i s s u b j e c t e d t o descending technique on Whatman N o d paperand development i s achieved by chloroform. A f t e r drying, t h e chromatogram i s sprayed with potassium iodoplatinate.
QUININE HYDROCHLORIDE
597
10.4.2 Thin-Layer Chromatography The TLC analysis of cinchona alkaloids has been thoroughly reviewed by Verpoorte , et a1 ( 7 9 ) . From the TLC systems described in the review, 18 solvent systems were found to be the most suitable for the separation of the 24 Cinchona alkaloids. Table 5 shows the 18 solvent systems used f o r quinine. Table 6 quinine.
describes TLC detection techniques for
The sensitivity of a number of separation methods has been described. Some general conclusions concerning the optimal conditions for specific separations are also described Oswald and Fluck (86) have reported separate determination of cincho.naalkaloids by TLC. Quinine, quinidine, and cinchonine are separated on silica gel G. , with benzene-ethyl ether diethylamine (20:12:5) as solvent; cinchonidine migrates with quinidine. The alkaloids are identified with Dragendorff reagent. The spot area, measured by planimeter, is directly proportional to the amount of alkaloid in the range of 3 to 4 p g. The limit of error is ?: 8%. Bralinova ( 7 7 ) has described 6 eluent systems in the separation of quinine and quinidine on silica gel, using chloroform-acetone-diethylamine (20:20:1) as solvent. Schwarz and Sarsunova (87) have published thin layer chromatographic data for 27 alkaloids, including quinine , on aluminium oxide. The most useful solvents are: benzene-ethanol; chloroformethanol; and ethyl ether-ethanol. Sarsunova and Hrivnak (114) have reported the separation and evaluation of cinchona alkaloids by TLC, on silica gel -254 with chloroform-acetonediethylamine (5:4:1) as solvent.
Table 5
TLC Techniques Used for Quinine
Solvent System
-
fn 00
RF ( RFxlOO )
1.
Chloroform-diethylamine ( 9 :1)
2.
Chloroform-methanol - 25% ammonia (85 :14:1)
3.
Chloroform-acetone-diethylamine (5:4:1)
4.
Chloroform-acetone ethanol) (5:4:1)
5.
Ref.
17 44 17
59 60 61
21
39
Chloroform-acetone-methanol -25% ammonia (60 :20 :20 :1)
37
61
6.
Chloroform-ethylacetate-isopropanol-diethylamine ( 2 0 :70:4 :6 )
11
7. 8.
Chloroform-dichloromethane-diethylamine (20:15:5)
22
Dichloromethaqe-diethyl ether -diethylamine (20:15:5)
23
9.
Kerosene-acetone-diethylamine (23:9 :9)
32
39 39 39 62
-
( 3 m l 25% ammonia + 17 m l absolute
10. Acetone - 25% ammonia (58:2)
-
25% ammonia (45:35:5) 12. Toluene-ethyl acetate - diethylamine (7:2:1) 13. Toluene-ethyl acetate-diethylamine (10:10:3) 1 4 . Toluene-diethyl ether-diethylamine (20:12:5) 15. Toluene-diethyl ether-dichloromethane-diethylam-ine (20 :20 :20 :8) 11. Ethyl acetate-isopropanol
16. Carbon tetrachloride-n-butanol-methanol-10% ammonia
18 18
39 39 63 39 64
20
65
-
39
32
49 12
(12 :9:9:1)
Solvent System 17.
Cyclohexanol diethylamine
- cyclohexane-n-hexane
18. Methanol-25% ammonia (100:1 )
(1:l:l)
+ 5%
41
66
45
61
Conditions : Silica gel plates Si 60 F 254 pre-coated aluminum sheets, 20x20 cm (Merck); temperature, 2422'; relative humidity, 2525%; normal chromatography chamber, saturated for 30 minutes before use
Table 6
TLC Detection of Quinine
Reagent
1.
Quenching, 254 nm
2.
Fluorescence 360 nm (formic a c i d o r s u l p h u r i c a c i d spray)
3.
Dragendorff's modification: Munier - Macheboeuf Munier Munier-sodium n i t r i t e
4.
Background Color
Color
Ref.
39 Light b l u e
39
Orange-red Orange-red Brown
39 67 67
Vaguj f a l v i Bregoff-Delwiche
Yellow Light-yellow Light -yellowwhite Light -yellow Light -yellow
Orange Orange
39 39
Iodine vapour
Yellow-white
Brown Brown Brown
39 68,69 60
5. 6.
Iodine i n K I
White
Iodine i n methanol
Light -yellow
7.
Iodine i n K I and s i l v e r a c e t a t e
8.
F e r r i c c h l o r i d e , iodine i n K I
Light greenyellow
Brown
70 71
9.
Iodoplat i n a t e
Dark v i o l e t
Violet
39
10.
Iodoplatinate, a c i d i f i e d
Dark v i o l e t
Violet
72
Light greenblue
Dark green blue
45
11. F e r r i c hexacyanoferrate
-
-
Background Color
Reagent
Color ~
12.
F e r r i c chloride-perchloric
13.
14.
Methyl orange Tetraphenylborate
15.
Phenothiazine, i o d i n e vapor
16.
Phenothiazine vapor )
acid
quercetin
Ref.
~~~
Yellow-white
Violet
39
Light orange
Orange
73
i n UV:blue
74
Violet
Brown
60
Violet
Light brown
60
-
bromine vapor (ammonia
FAFUD J. MUHTADI ETAL.
602
Suchocki e t a l . (115) have r e p o r t e d determination of quinine, H C 1 and o t h e r compounds, by TLC, on a s i l i c a g e l with one of s e v e r a l solvent systems. The s p o t s a r e l o c a t e d with conventional reagents and are evaluated d e n s i t o m e t r i c a l l y . Hashmi e t a l . (85) have described semi-quantitative determination of quinine by c i r c u l a r TLC. Thirteen a l k a l o i d s , i n c l u d i n g quinine , have been separated i n t o groups by an e x t r a c t i o n scheme with t h e use of water, chloroform and ethanol solvent systems. Aliquots of t h e various e x t r a c t s ( c o n t a i n i n g 0 . 1 t o 7.0 pg of t h e a l k a l o i d ) a r e a p p l i e d t o a l a y e r of s i l i c a g e l f o r chromatographic a n a l y s i s .
The following method has been described f o r d e t e c t i n g quinine i n t o x i c o l o g i c a l a n a l y s i s of b i o l o g i c a l materials. The sample of u r i n e ( 1 0 m l ) , b u f f e r e d a t pH 9.5 i s e x t r a c t e d with chloroform-isopropyl alcohol (24:l). A c o n t r o l sample of u r i n e c o n t a i n i n g quinine ( 1 0 Ug/10 m l ) i s a l s o e x t r a c t e d . The solvent l a y e r i s f i l t e r e d , b o i l e d t o remove ammonia, and a c i d i f i e d with 0.1 N HC1. The solvent i s evaporated and t h e r e s i d u e i s d i l u t e d with methanol. The s o l u t i o n i s then a p p l i e d , i n p o r t i o n s , t o s i l i c a g e l G and t h e chromatograms a r e developed w i t h ethanol-methanolconcentrated ammonia (17:2:1) as t h e solvent. The a i r - d r i e d p l a t e i s heated a t 75' f o r 10 minutes, t h e n sprayed w i t h i o d o p l a t i n a t e and Dragendorff reagents
.
D i f f e r e n t i a t i o n of quinine from i t s oxidation products has been i n v e s t i g a t e d ( 9 2 ) . A s e n s i t i v e d e t e c t i o n reagent f o r quinine on t h i n - l a y e r chromatogram has been a l s o described ( 9 3 ) . Small amounts of quinine can be separated from impure samples and b i o l o g i c a l materials by chromatographic procedures.
Fig. 11 GLC of Quinine Hydrochloride
QUININE HYDROCHLORIDE
10.4.3
603
Gas-Liquid Chromatography A GLC method f o r t h e determination of quinine, H C 1 has been c a r r i e d out i n our l a b o r a t o r y , using a Varian GC-3700 gas chromatograph equipped with Varian CDS 111 integrator. Column conditions: 3%OV-17 on chromosorb W-Hp (80-100mesh s i z e ) ; g l a s s column ( 2 m x 2 mm). The column run isothermally a t 280' f o r 1 0 minutes and then t h e temperature was programmed a t 10°/minute. Carrier gas : helium, flow r a t e w a s a d j u s t e d t o 25 m l / minute. Detector : FID, hydrogen and a i r flow r a t e s were a d j u s t e d t o 30/minute and 300 ml/minute, r e s p e c t i v e l y . Ethanol was used as t h e solvent and t h e c h a r t speed w a s a d j u s t e d t o give 1 cm/minute. The r e t e n t i o n t i m e = 13.4 minutes. The GLC of quinine, H C 1 i s presented i n Figure 11. Sarsunova and Hrivnak ( 1 1 4 ) have described q u a n t i t a t i v e determination of quinine , and o t h e r cinchona a l k a l o i d s , by e x t r a c t i o n of t h e s p o t s from t h e TLC p l a t e s followed by GLC. The a l c o h o l i c s o l u t i o n , containing codeine as an i n t e r n a l standard, i s analysed by GLC on a column of 2% of OV-17 on AW Gas-Chrom p. The method i s s p e c i f i c enough f o r r o u t i n e drug a n a l y s i s . A gas-liquid chromatographic procedure has been a l s o r e p o r t e d (120) f o r t h e determinat i o n of s e v e r a l b a s i c drugs, i n c l u d i n g quinine, i n s m a l l blood samples. Bonini, e t . a1 (121) have described gasphase chromatographic determination of four a n t i m a l a r i a l s , including quinine, s i n g l y and i n a mixture i n blood and u r i n e . I n t h i s method, a column packed w i t h . 2% OV-17 on Chromosorb W AW DMCS 100-120 mesh with N gas as t h e c a r r i e r gas and t h e column temperature programmed t o i n c r e a s e from 250 t o 350' a t 8O/minute. The l i m i t of d e t e c t i o n was 0.52 ng f o r quinine. The r e c o v e r i e s i n blood and u r i n e were 84.3 and 92.8% f o r 1 i.lg q u i n i n e / l m l .
604
FARID J . MUHTADI ETAL.
10.4.4
Hioh Performance Liquid Chromatography Quinine has been determined among other cinchona alkaloids by HPLC. A number of HPLC assay procedures for quinine and its impurities have been described (82). Pound and Sears (122) have used a silica gel column with a tetrahydrofuran-ammonium hydroxide mobile phase to analyse quinine in commercial formulations. Low and Kennedy (82,123) have described ion-pair reversed-phase chromatography in surveying the quinine products available in Australia. Table 7 sununarises the solvent systems used in the cited references. Barrow et al. (38) have reported HPLC separation and isolation of quinine metabolites in rat urine. The extract was evaporated under N, and a solution of the residue in methanol was analysed on a column of IJ Bondapak Cl8 and detection at 254 nm. Eight metabolites of quinine were separated and only 6 were identified. These were separated on either an analytical or a semi-preparative reversed-phase column by gradient elution (Fig. 12). HYDROXYQUININE+
I
I 1
0
I
QUININE-10,llDIHYDRODIOLS
10
,
20
30
40
0-DESMETHYLQUININE
J
50
lPiNINE -CARBOSTYRIL
60
1
70
min.
Fig. 12 HPLC Separation of Quinine Metabolites
Table System No.
7.
HPLC Systems of quinine
Column
Mobile phase
Merckosorb Si 60
Chloroform-methanol (8:2)
6.4
(7:3)
5.9
Diethyl ether-methanol (8:2)
3.9
(7:3)
2.7
(6:4)
2.2
A reversedphase, u Bondapak
Methanol-water-acetic acid (25:75:1)
‘18 4 Silica gel
Diethylether-waterdiethylamine
Li Chrosorb Si 60
Chloroform-isopropyl alcohol-diethylamine-wat r (940:57 :1:2.62)
Li Chrosorb Rp-8
Water-acetonitrile (1:3); adjusted to pH 3 with perchloric acid
Retention Time (minute)
-
-
-
Detect ion
Ref.
W , 254 and 280 nm.
80
W, 254 nm.
a2
-
124
W, 312 nm.
125
250 nm or
126
435 nm.
FARID J. MUHTADI ETAL.
606
A study of t h e r e t e n t i o n behavior of quinine, and some o t h e r b a s i c drug substances, by ion-pair HPLC has been described By appropriate adjustment of expe(127). rimental parameters, complex separations can be achieved.
Jeuring e t a l . (126) have reported a r a p i d determination of quinine and i t s hydrochloride i n s o f t drinks and t o n i c water by reversed-phase ion-pair chromatography. I n t h i s assay method, quinine i s determined i n t h e concentration range of 20-100 mg and recoveries ranged from 97 t o 103%. 10.5.
Spectroscopic Methods 10.5.1
Colorimetric Hasselmann (128) has reported a microdetermination of quinine i n serum by means of t h e colored compound formed with Rose bengal. The method i s s u i t a b l e f o r determining concentration up t o 1 mg per 100 ml. The reported method i s as follows: To serum (10 m l ) add 20% t r i c h l o r o a c e t i c a c i d ( 5 ml), shake and centrifuge. Adjust an a l i q u o t (10 ml) of f i l t r a t e t o pH 11.7 with N NaOH, add 2% Rose bengal s o l u t i o n (1 n i ~ )and chloroform (3.5 d).AUOW t o stand for several hours, shaking 5 o r 6 times during t h i s period. Measure t h e c o l o r i n t h e chloroform l a y e r a t 550 nm. A blank i s necessary. Drey (129) has described spectrophotometric assay of quinine, 2 H C 1 i n t a b l e t s .
-
Malat (130) has reported an e x t r a c t i o n spectrophotometric determination of organic bases, including quinine, with some metallochromic i n d i c a t o r s . The procedure involves t h e addition of t h e i n d i c a t o r t o a s o l u t i o n of quinine,H$O4, a d j u s t i n g t h e pH a t 1 . 4 t o 6.8 and e x t r a c t i o n with chloroform. The absorption spectrum i s then recorded from 400 t o 700 nm. Eriochrome red B i s t h e most s u i t a b l e f o r determination of quini n e ; t h e absorbance being measured a t 475nm.
QUININE HYDROCHLORIDE
607
Schmitz and Menges (131) have a l s o reported a colorimetric determination of quinine i n t i n c t u r e s with Tropaeolin 00. I n t h i s method, about 0.5 gm of t i n c t u r e of cinchona, i s d i l u t e d t o 250 m l with water, and a 5-ml portion i s mixed with 1 0 ml of an a c e t a t e b u f f e r s o l u t i o n of pH 4.6 and 3 m l of a saturated aqueous Tropaeolin 00 s o l u t i o n . The well-shaken mixture i s then e x t r a c t e d with chloroform and t h e combined e x t r a c t s are a c i d i f i e d with 3 ml of an a c i d reagent (1 ml of concentrated ~ 2 ~ and 0 4 99 ml of methanol), and made up t o 50 m l with chloroform. The e x t i n c t i o n i s then determined and quinine content i s estimated by comparison with standard curves. Blank determinat i o n i s necessary. Graham and Thomas (132) have described a q u a n t i t a t i v e determination of a l k a l o i d s , including quinine, using dichromate sulphuric a c i d . The s o l u t i o n containing t h e a l k a l o i d ( 0 . 1 - 4 P moles) i s mixed with 5% aqueous potassium dichromate s o l u t i o n (1 m l ) , heat a t 30° f o r 5 minutes , add concentrated ~ 2 S 0 4( 8 m l ) , mix, cool i n i c e f o r 20 minutes and measure t h e e x t i n c t i o n a t 650 nm. Subtract a reagent blank. The c h a r a c t e r i s t i c green c o l o r i s given by 25 a l k a l o i d s . Methanol, ethanol, u r e a , and many s a l t s i n t e r f e r e , but ethanol may be used a s a solvent i f an equal amount i s included i n the blank s o l u t i o n . 10.5.2
Ultraviolet Volkova and Getman (133) have described an extraction-photometric determination of quinine as t h e t e r n a r y complex with t i t a nium and s a l i c y l a t e . In t h i s method, t h e t e s t s o l u t i o n (10ml), containing 1ODg of quinine, i s mixed with 1 m l of 0.01 M Tic14 i n 0.8 N H C 1 , 1ml of 0.05 M sod. s a l i c y l a t e and 1 0 ml of CHC13. The pH of t h e s o l u t i o n i s adjusted t o 3 with 0.1 N NaOH and t h e yellow t e r n a r y complex i s completely e x t r a c t e d i n t o t h e C H C l 3 by vigorous shaking f o r 2 minutes. The e x t r a c t is f i l t e r e d , and t h e e x t i n c t i o n
-
FARID J . MUHTADI ETAL.
608
of t h e f i l t r a t e i s measured a t 380 o r 400nm. Chloride , s u l p h a t e , n i t r a t e , and a c e t a t e do n o t i n t e r f e r e . A t low c o n c e n t r a t i o n o f q u i n i n e , metal i o n s do n o t i n t e r f e r e ; i r o n can b e masked w i t h a s c o r b i c a c i d o r sodium t h i o s u l p h a te
.
Prudhomme (134) has r e p o r t e d a c o l o r i m e t r i c a s s a y of q u i n i n e i n b i o l o g i c a l f l u i d s and i n organs. I n t h i s method, q u i n i n e i s determined by adding 2% e o s i n t o t h e l i q u i d , b u f f e r e d t o pH 7 , and e x t r a c t i n g t h e r e d product w i t h chloroform and comparing the solution colorimetrically with standard s e r i e s . Liquids c o n t a i n i n g l e s s t h a n 0.01 mg of q u i n i n e are e x t r a c t e d f o r 24 hours. Urine i s f i r s t t r e a t e d w i t h l e a d a c e t a t e and H2SO4, and blood w i t h potassium o x a l a t e followed by s a t u r a t e d sodium s u l p h a t e and N H2SO4 a t 45-50'. Compounds of e o s i n w i t h q u i n i n e can b e d i f f e r e n t i a t e d by UV absorpt i o n s p e c t r a . The r a t e o f e l i m i n a t i o n o f q u i n i n e i n u r i n e , and i t s d i s t r i b u t i o n among organs have been s t u d i e d . P r o e t a l . (135) have r e p o r t e d s p e c t r o photometric d e t e r m i n a t i o n of q u i n i n e and h e r o i n (diamorphine ) I n t h i s method , equimolar c o n c e n t r a t i o n of t h e two a l k a l o i d s have almost t h e same a b s o r p t i o n a t 297.5 nm; w h i l s t a t 330 nm t h e a b s o r p t i o n i s due e n t i r e l y t o quinine. A 100 mg of t h e mixed a l k a l o i d s w i t h 10 m l of anhydrous methanol i s f i l t e r e d through a s b e s t o s , t h e f i l t r a t e and methanol washings b e i n g d i l u t e d w i t h 0 . 1 N NaOH, and of t h i s s o l u t i o n 10 m l are a g a i n d i l u t e d w i t h NaOH - methanol s o l u t i o n . The e x t i n c t i o n i s measured a t 297.5 and 330 nm. The s t a n d a r d d e v i a t i o n f o r b o t h c o n s t i t u e n t s i s 4 1 . 5 p.p.m. on m i x t u r e s c o n t a i n i n g 30 t o 90 p.p.m., and 6 t o 30 p.p.m of q u i n i n e and diamorphine, r e s p e c t i v e l y .
.
Hadorn and Z u r c h e r ( 1 3 6 ) have p u b l i s h e d t h e a n a l y s i s and composition of beverages c o n t a i n i n g q u i n i n e and i t s decomposition p r o d u c t s . I n t h i s method, 6 samples were
QUININE HYDROCHLORIDE
609
found t o contain ( p e r l i t r e ) 25-57 mg of quinine t o g e t h e r with o t h e r c o n s t i t u e n t s . The quinine e x t r a c t e d from t h e beverages with e t h y l e t h e r w a s pure, but t h e quinine e x t r a c t e d with chloroform or carbon t e t r a c h l o r i d e contained decomposition products t h a t could be d e t e c t e d by TLC; t h e s e d i d not i n t e r f e r e with t h e spectrophotometric determination of quinine i n d i l u t e H2SO4 medium a t 346 nm. The s p e c t r a of quinine i n e t h a n o l , chloroform, and carbon t e t r a c h l o r i d e d i f f e r e d only s l i g h t l y from one a n o t h e r , but widely from t h e spectrum of quinine i n d i l u t e H2SO4. Kamath e t a l . (137) have s t u d i e d t h e W absorption of cinchona a l k a l o i d s , i n c l u d i n g q u i n i n e , i n 11 a l i p h a t i c a l c o h o l s . Quinine can be determined i n t h e presence of o t h e r 14% i n a l i p h a t i c alkaloids t o within a l c o h o l medium. Schmitt (138) has described t h e q u a n t i t a t i v e and q u a l i t a t i v e determination of W-absorbi n g compounds i n substances t o o dark or t o o t u r b i d f o r d i r e c t a n a l y s i s . The f i r s t or second d e r i v a t i v e s of t h e W s p e c t r a a r e used. They show much more d e t a i l than t h e d i r e c t s p e c t r a . The determination of quinine i n a t u r b i d beverage by t h i s technique has been r e p o r t e d A q u a n t i t a t i v e spectrophotometric determinat i o n of quinine and o t h e r cinchona a l k a l o i d s has been a l s o described
10.5.3 Atomic Absorption Spectrometry Recently , Minami e t a l . (140) have developed a q u a n t i t a t i v e a n a l y s i s of a l k a l o i d s , includi n g q u i n i n e , by t h e atomic absorption s p e c t rometry. I n t h i s method, 1 ml of a s o l u t i o n of Reinecke s a l t ( 6 mg/l m l ) and 5-10 m l of nitrobenzene a r e added t o 5-20 m l s o l u t i o n of t h e a l k a l o i d ( c o n t a i n i n g 1.5-100 11 g/ml) i n 0 . 1 M HC1. The mixture i s shaken and t h e nitrobenzene l a y e r i s removed, d r i e d , and C r i s determined t h e r e i n by conventional flame a.a.s. at 357.87 nm. By t h i s
FARID J. MUHTADI ETAL.
610
procedure, quinine, and several other alkaloids, can be indirectly determined with good precision. There is no interference from up to 37-fold molar amounts of 15 common inorganic ions.
10.5.4 Spectrofluorimetric Ragazzi and Veronese (141) have published a fluorimetric determination of quinine and some other alkaloids, after separation by TLC on magnesium oxide. Quinine is separated from natural materials or from mixed pharmaceutical preparations on a layer prepared from a suspension of hydrated magnesium oxide in 2.5% aqueous CaC12, using ethyl acetate - acetone (4:l) as the developing solvent. After locating the spots of quinine under W light, they are removed from the plate and dissolved in acid and the solution is used for the fluorimetric determination. Quinine emits fluorescence at 450 nm when excited at 350 nm. Brzezinska and Dzeidzianowicz (142) have reported a fluorimetric assay of quinine in the presence of aspirin and phenacetin. Quinine is extracted from the mixture by a known volume of 0.1 N H2SO4 and the intensity of fluorescence of quinine sulphate extract is then measured and referred to a calibration graph. Beer's law is obeyed for 1 to 50 p.p.m. of quinine in the extract. Schmollack and Wenzel (143) have described a fluorimetric determination of quinine in the nanogram range with use of a chamber paper-analysis (KAPA) apparatus. Fluorimetric measurements of quinine sulphate solution is carried out at 366 nm, showing a rectilinear calibration between 5 and 50 pg/ml. For 48 measurements at 30 l.lg/ml, the coefficient of variation is 7.69%. Other fluorescence analysis of quinine as well as various natural and synthetic drugs has been reported (144). Fluorescence spectra have been determined in ethanol, concentrated HC1, 10% NaOH, and
QUININE HYDROCHLORIDE
611
aqueous solutions at 0.01-0.001 mg/d The following identification test has been described (146). Dissolve 1 gm in 50 m l of water; the solution is not fluorescent. Dilute with lOOml of water and add M H2S04, an intense blue fluorescence is produced.
( 145).
McCloskey et al. (147) have developed a spectrofluorimetric determination of quinine in the blood and urine, following the consumption of tonic preparations.
10.5.5
Phosphorimetric Harbaugh et al. (148)have reported pulsedsource time-resolved phosphorimetric method for the quantitative determination of quinine and other drugs. The phosphorescence emission spectra, life times, and relative signals (peak emissions) have been determined with the use of the apparatus and procedures previously describe& by Fischer and Winefordner Time-resolved phosphorimetry provides a useful means for identifying quinine and other drugs even in some of their mixtures. For a multi-component mixture, the parameters cited indicate which of the drugs can be separated spectrally or temporarily or by P conobination of the two techniques.
Acknowledgement The authors wish to thank M r . Uday C. Sharma of the Pharmacognosy Dept., College of Pharmacy, King Saud University, Riyadh, for his secretarial assistance in the reproduction of the manuscripts.
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