Al Badr1985

ATROPINE
Abdullah A. Al-Badr and Farid J. Muhtadi

King Saud University
Riyadh, Saudi Arabia
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1. Description
1.1 Nomenclature
1.2 Formulae
1.3 Molecular Weight
1.4 Elemental Composition
1.5 Appearance, Color, Odor, and Taste
I .6 Dissociation Constant
1.7 pH range
2. Physical Properties
2. I Melting Point
2.2 SublimationRange
2.3 Solubility
2.4 X-Ray Crystallography
2.5 Spectral Properties
3. Isolation
4. Synthesis
4.1 Partial Synthesis
4.2 Total Synthesis
5 . Biosynthesis
5.1 Biosynthesis of Tropine
5.2 Biosynthesis of Tropic Acid
6. Metabolism
7. Pharmacokinetics
8. Therapeutic Uses of Atropine
9. Methods of Analysis
9.1 Identification Tests
9.2 Microcrystal Tests
9.3 Titrimetric Methods
9.4 Polarographic Methods
9.5 SpectrophotometricMethods
9.6 Chromatographic Methods
9.7 Radio-immunoassay
References
ANALYTICAL PROFILES OF DRUG SUBSTANCES

VOLUME 14
325
Copyright 0 1985
by the American Pharmaceutical Association
ISBN 0-12-260814-3
326
ABDULLAH A . AL-BADR AND FARID J . MUHTADI
1. Description
1.1 Nomenclature
1.1.1 Chemical Names
a) endo ( f)- a -( Hydroxymethyl) benzene-acetic

acid 8-methyl-8-azabicyclo [ 3.2.11 oct3-y1 ester.
b) Benzene-acetic acid a-( hydroxymethy1)-,
8-methyl-8-azabicyclo [ 3.2.11 oct-3-yl
ester, *-(
+)-
c)
la H,-:a
H-tropan-3a -ol( 2)-tropate.
1.1.2 Generic Names
Atropine, dl-hyoscyamine, (2)-hyoscyamine,

tropic acid ester with tropine, tropine ( 2 )
tropate, dl-tropyl tropate , ( 2 ) tropyl tropate
1.2
Formulae
1.2.1
Ebpirical
C
NO
17 23 3
1.2.2 Structural
7
6
The structure was confirmed by the total synthesis of atropine which was achieved by
several authors ( 1-4)
327
ATROPINE
1.2.3
CAS Registry No.
51-55-8
1.2.4
Wiswesser Line Notation
~ 5 A6 ANTJ A
-GOVYR & 1Q- DL
1.2.5
(5)
Stereochemistry
Examination of t h e NMR s p e c t r a of some tropane
deuterohalides has shown t h a t t h e N-substitue n t i n tropanes i s predominantly e q u a t o r i a l ( 6 1.
X-ray a n a l y s i s of t r o p i n e hydrobromide has
shown t h e presence of c h a i r conformation ( 7 ) .
Study of t h e dipole-moment and Kerr-constant
measurements of a number of tropane d e r i v a t i ves has shown t h a t t h e p i p e r i d i n e r i n g i s i n
t h e c h a i r form with t h e N-methyl e q u a t o r i a l
(8). Another study of t h e dipole-moments and
NMR s p e c t r a of some tropane d e r i v a t i v e s have
confirmed t h a t t h e p i p e r i d i n e r i n g i s i n t h e
c h a i r conformation with t h e N-methyl group
predominantly e q u a t o r i a l ( 9 ) . I n t r o p i n e ,
however, t h e predominant conformation i s t h e
p i p e r i d i n e r i n g i n a deformed c h a i r form t o gether with a minor amount i n t h e boat form
(10).
HO
Tropine
I n a t r o p i n e , t h e a-3-substituent i s of great e r bulk than t h e hydroxyl, and t h e boat form

may w i l l be favored because of t h e increased
i n t e r a c t i o n s involving t h e dimethylene bridge
i n t h e c h a i r confirmation (11).
ABDULLAH A. AL-BADR A N D FARlD J. MUHTADI
H
N-CH3
11
0-C-CH
NCH~OH
\
C6H5
A d e t a i l e d review i s a v a i l a b l e f o r t h e boat or c h a i r
conformation i n t r o p i n e s ( 1 2 ) .
Other PMR study suggested a preference f o r t h e boat

conformation i n s e v e r a l tropane d e r i v a t i v e s . This
study showed s t r o n g c r o s s - r i n g i n t r a m o l e c u l a r i n t e r C-=O
and N---H-O
were i n d i a c t i o n s of t h e t y p e N--c a t e d by t h e broadening of t h e proton s i g n a l due t o
t h e coupling between 1(5)-H and 2(4)-H protons i n t h e
boat conformer compared with t h e c h a i r . This broadening a r i s e s as a consequence of e c l i p s i n g of t h e s e
protons i n t h e boat conformer (13). Carbon-13 magnet i c resonance study has a l s o suggested a non-chair
conformations i n tropane d e r i v a t i v e s ( 1 4 ) .
1.3
Molecular Weipht
289.38
1.4
Elemental Composition
c,
1.5
70.56%; H , 8.01%; N ,
4.84%; 0 , 16.59%
Appearance, Color, Odor and Taste

C o l o r l e s s needle-like c r y s t a l s or white c r y s t a l l i n e
powder, o d o r l e s s and has a sharp b i t t e r t a s t e .
1.6
D i s s o c i a t i o n Constant
PKa 5.93
1.7 BH
range
pH of 0.0015 molar s o l u t i o n i s 10.0 (15),approximate

pH of s a t u r a t e d aqueous s o l u t i o n i s 9.5 ( 1 6 ) .
329
ATROPINE
2.
Physical P r o p e r t i e s
2.1 Melting P o i n t
114
114
2.2
- 116'
- 118'
(15)
(16)
Sublimation range
Atropine sublimes i n high vacuum a t 93-110'.
2.3
Solubility
One gram d i s s o l v e s i n 460 m l water, i n 90 m l water
a t 80, i n 2 ml a l c o h o l , 1.2 ml alcohol a t 60, i n
27 ml g l y c e r o l , 25 m l e t h e r . Soluble i n benzene
and d i l u t e a c i d s .
2.4 X-ray c r y s t a l l o g r a p h y
The X-ray c r y s t a l l o g r a p h y of t r o p i n e hydrobromide ( 7 ),
t r o p i n e ethobromide ( 1 7 ) pseudotropine (18) hyoscine
hydrobromide ( 1 9 ) and t r o p i c a c i d i n hyoscine N-oxide
(20 ) have been r e p o r t e d .
330
ABDULLAH A. AL-BADR AND FARID J . MUHTADI
2.5
Spectral Properties
U l t r a v i o l e t Spectrum
2.5.1
The W spectrum of a t r o p i n e i n e t h a n o l ( F i g . 1 )
was scanned from 200 t o 400 nm using DMS 90
'Varian Spectrophotometer. It e x h i b i t e d t h e
following W d a t a (Table 1).
Table 1. UV c h a r a c t e r i s t i c s o f a t r o p i n e
A m a . a t nm
20 5
246
251.5
257
263.5
271
A ( 1 % , 1 cm)
147.6
175.1
209.8
143.3
24.6
5.1
6.05
7-25
4.95
0.85
Other r e p o r t e d W s p e c t r a l d a t a f o r a t r o p i n e
i n 0 . 1 N sulfuric acid ( 21 ) :
h max a t . 252 mu ( E 1%, 1 cm 5 ) , 258 mu
( E I%, 1 cm 6 ) and 264 mu ( E 1%,
1 cm 5 ) .
2.5.2
I n f r a r e d Spectrum
The I R spectrum of a t r o p i n e as KBr-disc was
recorded on a Perkin Elmer 580 B I n f r a r e d
Spectrophotometer t o which I n f r a r e d Data stati 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 w i t h 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 Atropine
-1
Frequency cm
3070
2930
2810
1725
1595, 1580
Assignment
OH (hydrogen bonded)
CH ( s t r e t c h )
N-CH
B
0-C - ( e s t e r )
C=C aromatic
FIG, 1, THE UV SPECTRUM OF ATROPINE I N ETHANOL
44.
i
&O#
WAVE##H#FR
#o
asM
2060
fm
YO0
1400
FIG. 2 , THE I R SPECTRUM OF ATROPINE AS KBR-DISC
1000
800
680
&
333
ATROPINE
-1
Frequency cm
Assignment
1155, 1030
770,725,690
C-0-C
(ether)
5 H (mono s u b s t i t u t e d aromatics)
The I R e x h i b i t e d t h e following o t h e r c h a r a c t e r i s t i c
bands :-
1 4 5 0 , 1 4 2 0 , 1 3 7 0 , 1 3 5 5 , 1 3 3 5 , 1 2 7 0 , 1 2 ~ 5 , ~ 2 3 0 , ~ 2 2 0 , ~ 2,0 5
1190,1165,1132,1108,1065,975,920,845,805,515
cm-1.
Other I R d a t a f o r a t r o p i n e (5,21) have been a l s o
reported.
2.5.3
Nuclear Magnetic Resonance Spectra

2.5.3.1
Proton Spectra
The PMR s p e c t r a of both a t r o p i n e i n
C D C 1 3 and i n TFA ( T r i f l u o r o a c e t i c
a c i d ) were recorded on a Varian T~ O A ,60 MHz NMR Spectrometer using
TMS (Tetramethylsilane) as an i n t e r n a l reference. These are shown i n
Fig. 3 ( a ) and 3{b) r e s p e c t i v e l y . The
following s t r u c t u r a l assignments have
been made (Table 3 ) .
0- C9
Other PMR d a t a f o r a t r o p i n e are a l s o r e p o r t e d (5,9,

13,22).
334
ABDULLAH A . AL-BADR AND FARID J. MUHTADI
I
LO
TO
I
I
..
I
40
. I
.,
. . uI .
a# Rn(,)
. .I .
F I G . 3 I A ) . TPE PYR SPECTnWi OF ATROPI3E Ill C D C L ~
B.#
....i
1..
, I , .
1.0
335
ATROPINE
Table 3.
PMR c h a r a c t e r i s t i c s of a t r o p i n e
Chemical S h i f t (ppm)
Group
5 aromatic protons
1 3 , l b ,15,16,17
H-3
CH2
CH2
CDC13
TFA
7.23(s)
7.36( s 1
- OH
- OH,
1 0 CH
-
135 H
8-N-Me
2,4,6,7 H
s = s i n g l e t , d=doublet , t = t r i p l e t
m=mult iplet
2.5.3.2
, bs=broad
singlet ,
13C-NMR
The I3C-NMR n o i s e decoupled and o f f

resonance s p e c t r a a r e presented i n
Fig. 4 and Fig. 5 r e s p e c t i v e l y . Both
were recorded over 4000 Hz range i n
d e u t e r a t e d chloroform on a Varian
FT 80 A-80 MHz spectrometer, u s i n g
1 0 mm sample tube and t e t r a m e t h y l s i l ane as a r e f e r e n c e standard a t 2
1
'
.
The carbon chemical s h i f t s a r e assigned on t h e bases 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 o f f resonance s p l i t t i n g p a t t e r n (Table 4 ) .
8
11
15
10
17
16
336
1
1
1
FIG. 4 .
THE I3C-NER NOISE DECOUPLED SPECTRUE OF ATROPINE
337
ATROPINE
4.
Table
Carbon no.
C
Chemical S h i f t
[PPd
Carbon no.
171.92( s )
17
13
127.48 ( d )
15
3
67.63 ( d )
cll
63.54(t)
s = s i n g l e t , d=doublet
c4
c23
59.54(d)
40.08(q)
128.11 ( d )
Chemical S h i f t
[ P P ~
54.94 ( d )
10
128.66( d )
14 16
c5
c1
136.17 ( s 1
5 2
Carbon Chemical S h i f t s of Atropine
36.04(t
25.31(t)
24.93(t
t=triplet
q=quartet
Other l3C-NMR d a t a f o r a t r o p i n e ( 14,23 ) a t r o p i n e

hydrochloride ( 1 4 ) and a t r o p i n e methoiodide ( 1 4 ) have
a l s o been reported.
2.5.4
Mass Spectrum
The mass spectrum of a t r o p i n e i s presented
i n Fig. 6. This was obtained by e l e c t r o n i m pact i o n i z a t i o n on a Varian MAT 1020 by d i r e c t
i n l e t probe a t 270~. The e l e c t r o n energy was
70 eV. The spectrum scanned t o mass 300 amu.
The spectrum ( F i g . 6 ) shows a molecular ion
peak M+ a t m / e 289 with r e l a t i v e i n t e n s i t y
9.50%. The base peak i s 124 with r e l a t i v e
i n t e n s i t y 100%.
The most prominent fragments t h e i r r e l a t i v e
i n t e n s i t i e s and some proposed ion fragments
a r e given i n t a b l e 5.
...
CJ
T
.
339
ATROPINE
Table 5 .
Mass Fragments of Atropine
Relative i n t e n s i t y
Ions
9-50
M+
7.79
9.34
See below*
125- H
100.00
6.35
96
r-
10.67
c
95
94
8.60
96-H
22.66
954
83
18.87
82
25 * 97
67
14.78
44
5-15
42
21.83
41
8.36
:-CH2=N=CH2
r
42-H
Other r e p o r t e d mass s p e c t r a of a t r o p i n e ( 2 4 ) :
Base peak 1 2 4 , m/e: 4 2 , 55, 67, 82, 94, 1 0 4 ,
1 2 4 , 1 4 0 , 272, 289.
Tropine fragmentations a r e a l s o r e p o r t e d ( 25 ).
i
I
340
3.
ABDULLAH A . AL-BADR AND FARID I. MUHTADI
I s o l a t i o n of Atropine
Atropine occurs i n s e v e r a l solanaceous p l a n t s t h e s e
include s p e c i e s of Atropa, Datura, Hyoscyamus, Duboisia,
Mandragora and Scopolia ( 26).
It i s claimed t h a t a t r o p i n e does not occur as such i n t h e
p l a n t s , but 2-hyoscyamine p r e s e n t i n p l a n t s , (27) and
during e x t r a c t i o n p r o c e s s , 2-hyoscyamine undergoes racemization t o give a t r o p i n e . Hyoscyamus muticus from Egypt
i s t h e p r e f e r r e d source for t h e manufacture of a t r o p i n e
because of i t s high a l k a l o i d c o n t e n t , w i t h stramonium
next i n order ( 28 ) .
One of t h e b e s t methods f o r t h e i s o l a t i o n of a t r o p i n e
i s as follows ( 2 8 ) .
The powdered drug i s throughly moistened w i t h an aqueous s o l u t i o n of sodium carbonate and e x t r a c t e d w i t h e t h e r
or benzene. The a l k a l o i d a l bases a r e e x t r a c t e d from t h e
solvent with water a c i d i f i e d w i t h a c e t i c a c i d . The a c i d
s o l u t i o n i s t h e n shaken w i t h e t h e r as long as t h e l a t t e r
t a k e s up c o l o r i n g m a t t e r s . The a l k a l o i d s a r e p r e c e p i t a t e d
with sodium c a r b o n a t e , f i l t e r e d o f f , washed and d r i e d . The
d r i e d p r e c i p i t a t e i s d i s s o l v e d i n e t h e r or a c e t o n e , dehyd r a t e d w i t h anhydrous sodium s u l f a t e and f i l t e r e d . The
f i l t e r a t e i s c o n c e n t r a t e d , c o o l e d , when crude hyoscyamine
and a t r o p i n e c r y s t a l l i z e from t h e s o l u t i o n . The crude
c r y s t a l l i n e mass r e s u l t e d i s f i l t e r e d o f f and d i s s o l v e d i n
a l c o h o l , sodium hydroxide s o l u t i o n i s added and t h e mixt u r e i s allowed t o s t a n d u n t i l recemization of hyoscyamine
t o a t r o p i n e i s completed (as i n d i c a t e d by t h e absence of
optical activity).
The crude a t r o p i n e i s p u r i f i e d by c r y s t a l l i s a t i o n
from acetone.
4.
Synthesis of Atropine
4.1
P a r t i a l Synthesis
Landenburg i n 1879 (1) accomplished t h e f i r s t
s y n t h e s i s o f a t r o p i n e from t r o p i n e and t r o p i c a c i d ,
t h u s proving a t r o p i n e t o be t h e t r o p i n e e s t e r of
t r o p i c a c i d . Tropine and t r o p i c a c i d a r e heated i n
t h e presence of hydrogen c h l o r i d e t o g i v e a t r o p i n e .
b.2
T o t a l Synthesis
Since a t r o p i n e i s t h e t r o p i n e e s t e r of t r o p i c
341
ATROPINE
a c i d , schemes f o r t h e t o t a l s y n t h e s i s of t r o p i n e
and t h e t o t a l s y n t h e s i s of t r o p i c a c i d were reported.
4.2.1
Total Synthesis of Tropine

Four schemes f o r t h e t o t a l s y n t h e s i s o f
t r o p i n e a r e known. Scheme I1 w a s a l s o modif i e d t o give a much b e t t e r y i e l d .
Scheme I: W i l l s t a t t e r ' s t o t a l s y n t h e s i s of
tropine ( 2 ) .
Suberone (cycloheptanone) [ 1 1 i s reduced t o

suberol which i s t r e a t e d w i t h hydrogen iodide
t o give suberyl iodide [ 2 ] . This i s t r e a t e d
with potassium hydroxide i n ethanol t o give
cycloheptene [ 31. Cycloheptene i s brominated
t o give 1,2-dibromocycloheptane [ 41 which i s
t r e a t e d with dimethylamine t o y i e l d dimethylaminocyclohept-2-ene [ 51. The l a t t e r i s
converted t o cyclohepta-lY3-diene [61 by exh a u s t i v e methylation. [ 6 ] i s brominated a t
l Y 4 - p o s i t i o n s t o give 1,4-dibromocyclohept2-ene [ T I . Elimination of two moles of t h e
hydrogen bromide of [ T I i s e f f e c t e d by quino l i n e t o give cycloheptatriene [S].
Substance [8] i s t r e a t e d with hydrogen bromi d e t o give bromocyclohepta-3,5-diene [ g ]
which i s r e a c t e d with dimethylamine t o give
dimethyl aminocyclohepta-2 ,b-diene [lo1. The
l a t t e r i s t r e a t e d with sodium i n e t h a n o l f o l lowed by bromination t o give 1,2-dibromo-5dimethylamino-cycloheptane [ 111. This i s
warmed i n e t h e r when intramolecular alkylat i o n occurs t o give 2-bromotropane methobromide [12]. Hydrogen bromide i s eliminated
from [12] by t h e a c t i o n o f a l k a l i t o y i e l d
t r o p i d i n e methobromide [13]. This i s t r a n s formed t o t r o p i d i n e methochloride El41 by t h e
a c t i o n of potassium iodide followed by t h e
a c t ion of s i l v e r c h l o r i d e . Substance [ 1 4 1
i s pyrolized t o give t r o p i d i n e [IF].
Hydrogen bromide i s added t o an a c e t i c a c i d
s o l u t i o n o f t r o p i d i n e [15] t o y i e l d 3-bromotropane [I61 which i s hydrolysed with 10%
s d f u r i c a c i d a t 200-210' t o give pseudot r o p i n e [IT]. $-tropine [17J i s oxidized
with chromium t r i o x i d e t o give tropinone [18].
342
ABDULLAH A . AL-BADR AND FARlD J . MUHTADI
Scheme I: Willstatter's t o t a l synthesis of tropine
(ii)HI
exhaust.
+
methyln.
Qr
[41 Br
0 0
Br
q u i n o l ine
15ooc
HBr
____)
[SI
Br
[I11
343
ATROPINE
OH
N-CK3
Scheme 11: Robinson's total synthesis of

CHO
-t
CH-OH
CH3NH2
[21
CHO
[11
tropine
cond.
Ci-OH
[ 31
N-CH3
CH3
/"=O
CH3
[41
344
This ketone i s reduced with zinc and hydriodic acid t o tropine [lg].
Scheme 11:
Robinson's s y n t h e s i s ( 3 )
Succindialdehyde [ 11 i s condensed with methylamine [ 2 ] t o give t h e condensate b i s c a r b i n olamine [ 31. This i n t u r n condensed w i t h acet o n e [ h ] t o give tropinone [ 5 ] (This mixture
i s allowed t o s t a n d i n water a t o r d i n a r y temp e r a t u r e f o r h a l f an h o u r ) .
Tropinone [ 5 ] i s reduced with zinc and hydri o d i c a c i d t o t r o p i n e [61.
The y i e l d can be improved by s u b s t i t u t i o n
of t h e more r e a c t i v e acetone d i c a r b o x y l a t e or
i t s e s t e r f o r acetone.
Succindialdehyde [ 11 i s condensed w i t h methylamine [21 t o give biscarbinolamine [31. 131
i s condensed w i t h calcium acetonedicarboxyl a t e [ 4 ] t o a f f o r d t h e condensate [ 5 ] . This
i s warmed w i t h hydrochloric a c i d t o give t r o pinone [ 6 ] . Tropinone [ 6 ] i s reduced with
zinc and hydriodic a c i d t o t r o p i n e [ T I .
Scheme 111: W i l l s t a t t e r ' s second s y n t h e s i s ( 4 )
S u c c i n y l d i a c e t i c e s t e r [l] i s condensed with
methylamine [ 21 t o give diethyl-N-methylpyrr o l e d i a c e t a t e [ 3 ] . This i s reduced (H2+Pt)
t o a f f o r d diethyl-N-methylpyrrolidinediacetate [4].
The c& form of [ 4 ] i s c y c l i z e d i n
t h e presence of N a and p-cymene t o give e t h y l tropinone-2-carboxylate [ 51. Hydrolysis of
[ 5 ] w i t h 10% s u l f u r i c a c i d g i v e s e t h y l t r o p i none-2-carboxylic a c i d [6]. The l a t t e r i s
heated t o y i e l d t r o p i n o n e [ T I which i s reduced w i t h z i n c and hydriodic a c i d t o t r o p i n e [8].
Scheme
IV:
Tropinone can a l s o be s y n t h e s i z e d ( 2 9 ) using

methylamine hydrochloride,acetondicarboxylic
a c i d and g e n e r a t i n g succindialdehyde in situ
by t h e a c t i o n of a c i d on 2,5-dimethoxy t e t r a hydrofuran as follows :
CHO
c:
345
ATROPINE
Scheme 11: Robinson's s y n t h e s i s ( y i e l d improvement)

CH-OH
tNH2CH3
)-CH3
cond.
CH2COOCa
+ \
,C=O
[21
CH-OH
[11
[31
\4
CH2COOCa
[41
COOCa
COOCa
Scheme 111: Willstatter's second s y n t h e s i s
CH=
CH-
CH2-COOC
H
2 5
CH=
CNI
CH,-COOC
H
2 5
CH3-
CH=
C-
CH2-COOC
2 5
[11
H
I
CH2- C-
1 F1
H3C$
CH2-
CH2-COOC
2 5
y=O
CH
COOC H
2-
Na/p-c ymene
4 -
i"
-C-
CH2-?-
2 5
CH2-COOC H
h-CH3
25
I
I
CH2-COOC
CH
C-CH-COOH
31
- C1
I
CH2
______t
2 5
3%
ABDULLAH A . AL-BADR A N D FARID J . MUHTADl
CH
1 2
-CCF-CClr!
\- I 2
CH - - ~ H - - C H ~
2
CH2 - CH - CH2
"71
181
4.2.2 T o t a l S y n t h e s i s o f Tropic a c i d
S e v e r a l schemes f o r t h e t o t a l s y n t h e s i s of
t r o p i c a c i d are known (Scheme I t o V ) .
Scheme I : Landenburg's s y n t h e s i s ( 3 0 ) .
Acetophenone [l] i s c o n v e r t e d i n t o a , a - d i c h l o r o ethylbenzene [ 2 ] by t h e a c t i o n o f phosphorous
pentachloride.
121 i s r e a c t e d w i t h potassium
cyanide and e t h a n o l t o f u r n i s h ct-ethoxy-a-cyanoethylbenzene [ 3 ] . T h i s i s hydrolysed w i t h barium
hydroxide s o l u t i o n t o g i v e a t r o l a c t i c e t h y l e t h e r
[4]. The l a t t e r i s h e a t e d w i t h hydrogen c h l o r i d e
to y i e l d a t r o p i c a c i d [ 5 ] which i s c o n v e r t e d t o
t r o p i c a c i d [61.
Scheme I1 : McKenzie and Wood's s y n t h e s i s (31).
Acetophenone [l] i s c o n v e r t e d by t h e a c t i o n o f
potassium cyanide t o acetophenone cyanohydrine
[ 23. T h i s upon h y d r o l y s i s i s c o n v e r t e d i n t o
a t r o l a c t i c a c i d [ 3 ] . The l a t t e r i s h e a t e d under
p r e s s u r e t o y i e l d a t r o p i c a c i d [4]. Atropic a c i d
[4] i s t r e a t e d w i t h hydrogen c h l o r i d e i n e t h e r e a l
s o l u t i o n t o form 6 - c h l o r o h y d r a t r o p i c a c i d [ 5 ] .
T h i s upon b o i l i n g w i t h aqueous sodium c a r b o n a t e
i s changed t o t r o p i c a c i d [ 6 ] .
Scheme 111: Miller's s y n t h e s i s (32).
Ethylphenyl a c e t a t e [l] i s condensed w i t h e t h y l formate t o g i v e e t h y l a-formyl a c e t a t e [ 2 ] . T h i s
on r e d u c t i o n w i t h aluminium amalgam y i e l d s dlt r o p i c ester [3] which upon h y d r o l y s i s g i v e s
t r o p i c a c i d 141.
Scheme IV: Chambon's s y n t h e i s (33).
E t h y l a-bromophenylacetate [l] is t r e a t e d w i t h
Zn t o g i v e ethyl+-zincbromophenylaceate
[2]
which i s t r e a t e d w i t h formic a c i d t o g i v e d l t r o p i c e s t e r [ 3 ] which upon d y d r o l y s i s y i e l d s
t r o p i c a c i d [4].
Scheme I:
Landenburg's s y n t h e s i s
CH3
I
KCN
[41
[ 31
CH2
II
- COOH
_____)
CH20H
6~-COOH
I
Scheme 11: McKenzie and Wood's s y n t h e s i s
KCN
[ 31
CH2CI
I
CH20H
348
ABDULLAH A . AL-BADR A N D FARlD J . MUHTADI
Scheme I11:
Miiller I s synthesis
CHO
CH2OH
CH2OH
I
CH-COOEt
hydrolysis
Scheme IV: Chambon's synthesis
Br
Zn Br
CH-COO%
Zn
CH2OH
I
CH-COOEt
HCHO
______r
CH2OH
349
ATROPINE
Scheme V:
Blicke's synthesis (34).
Phenylacetic a c i d [l] i s b o i l e d w i t h isopropylmagnesium c h l o r i d e i n e t h e r e a l s o l u t i o n t o give

[ 2 ] and then t r e a t e d t h e product [ 2 ] , a Grignard reagent with formaldehyde t o give t r o p i c
acid [ 3 ] .
Scheme V:
BLicke's s y n t h e s i s
Tropine f i n a l l y can be combined with t r o p i c a c i d t o

give a t r o p i n e . This can be done by h e a t i n g t h e two toget h e r i n t h e presence of hydrogen c h l o r i d e (Fischer-Speier
e s t e r if i c at i o n )
atropine
350
4.2.3
S y n t h e s i s o f Labeled Atropine
S y n t h e s i s of Labeled Tropic a c i d
4.2.3.1
Benzylmagnesium c h l o r i d e [l] i s t r e a t e d w i t h I4CO2 followed w i t h magnesium

c h l o r i d e t o g i v e t h e condensate [ 2 ] .
This upon t h e a d d i t i o n of formaldehyde g i v e s l a b e l e d t r o p i c a c i d [3].
Synthesis of labeled t r o p i c a c i d i s
p r e s e n t e d i n scheme VI ( 35 ).
S y n t h e s i s of Labeled Tropine
4.2.3.2
- S y n t h e s i s of t r o p i n e - 6 , 7
T h a s been
a c h i e v e d by c a t a l y t i c tritium a d d i t i o n
t o 2 , 5-dimethoxy-2, 5 d i h y d r o f u r a n
and f o l l o w i n g Robinson's r o u t e t o
tropinone-6, 7 T , by subsequent reduct i o n w i t h hydrogen over Raney n i c k e l
(36).
- S y n t h e s i s o f methyl-14C l a b e l e d t r o -
p i n e i s c a r r i e d o u t from Na 1 4 C N ( 3 7 )
v i a 1nethylamine-~4C and b a s e d on Robi n s o n ' s r o u t e ; inethyl-l4C t r o p i n o n e
i s o b t a i n e d i n 70% o v e r a l l y i e l d and
tropine-14C i n 68% y i e l d .
S y n t h e s i s of b i 4 C t r o p i n e can be
s t a r t e d w i t h arabinose-5-l4C [ 11
conversion i n t o f u r a n [ 2 ] and a p p l i c a t i o n o f t h e Clauson-Kaas r o u t e t o succin-dialdehyde and t h e n t o 1-or 5-14Ct r o p i n o n e 31 ( 3 8 ) .
U i n g arabinose-3, 4-14C g i v e s 6 , 7l'C-tropinone
( 39
Scheme V I I
4.2.3.3
Labeled a t r o p i n e can be t h e n o b t a i n e d
by e s t e r i f i c a t i o n of l a b e l e d t r o p i c
a c i d or labeled t r o p i n e t o give e i t h e r
l a b e l e d a t r o p i n e or double l a b e l e d 7 . k
a t r o p i n e ( a r i s e d from l a b e l e d t r o p i c
a c i d and l a b e l e d t r o p i n e )
351
ATROPINE
Scheme V I :
Synthesis of Labeled Tropic a c i d
[21
Scheme VII : Labeled t r o p i n e
'
CH20H
Double l a b e l e d a t r o p i n e
352
5.
Biosynthesis of Atropine
Most s t u d i e s on t h e b i o s y n t h e s i s of a t r o p i n e and of
i t s isomer hyoscyamine have been performed on v a r i o u s
s p e c i e s of Datura, b u t a l l t h e a v a i l a b l e evidence suggests
t h a t s i m i l a r pathways occur i n o t h e r tropane a l k a l o i d producing p l a n t s ( 26 ). Because t h e c h a r a c t e r i s t i c a l k a l o i d s of t h e group are e s t e r s of hydroxylamines and v a r i o u s
a c i d s ( t r o p i c , t i g l i c , e t c . ) t h e r e a r e , for each a l k a l o i d ,
two d i s t i n c t b i o s y n t h e t i c r o u t e s ( 26 ).
5.1
Biosynthesis of t r o p i n e
Ornithine and t h e r e l a t e d aminoacids (glutamic
a c i d , p r o l i n e ) have been proved t o be t h e p r e c u r s o r s
of t h e p y r r o l i d i n e r i n g of t r o p i n e ( 40-45 ).
It w a s found t h a t feeding [2-l4C] o r n i t h i n e t o Datura
stramoniwn r e s u l t e d i n r a d i o a c t i v e hyoscyamine l a b e l l e d only a t C - 1 bridgehead carbon of t r o p i n e (46).
COOK
N-CH3
And t h a t [ 5-14C] p r o l i n e r e s u l t e d i n r a d i o a c t i v e
hyoscyamine l a b e l l e d only t h e C-5 p o s i t i o n of t r o p ine ( 4 4 ) .
It w a s a l s o r e p o r t e d t h a t [2-l4C, 6 - 1 5 N I o r n i t h i n e
incorporated i n t o t r o p i n e moiety of hyoscyamine and
t h e 6-aminogroup of o r n i t h i n e i s an e f f i c i e n t precur s o r of t h e t r o p i n e n i t r o g e n (44,46).
The i n c o r p o r a t i o n of glutamic a c i d and p r o l i n e i s
considered t o occur v i a o r n i t h i n e ( 46 ) .
Ornithine [l] i s i n c o r p o r a t e d i n t o t r o p i n e v i a 6-Nm e t h y l o r n i t h i n e [ 2 ] (47-49) as [ methyl-l4C ] 6 -Nmethyl-[ 2-&]
o r n i t h i n e w a s i n c o r p o r a t e d i n t o hyoscyamine l a b e l l i n g C - 1 and t h e N-methyl group. 121
i s decarboxylated t o y i e l d N-methylputrescine [ 41
( 50,51).
P u t r e s c i n e [ 3 ] has a l s o been shown t o be a p r e c u r s o r
of t h e t r o p i n e a l k a l o i d s (43 ,52-5&). It w a s suggested
( 4 6 ) t h a t p u t r e s c i n e [ 31 i s converted by c e r t a i n enzymes i n Datura p l a n t s t o N-methyl p u t r e s c i n e [ 4 ] .
Oxidation o f t h e primary a l c o h o l of [ 4 ] a f f o r d s 4methylaminobutanal [ 5 ] . This i s c y c l i z e d t o give Nmethyl- A l-pyrrolinium s a l t [ 6
I.
353
ATROPINE
Leete's Scheme: Biosynthesis of Atropine
COOH
COOH
-7
E N C H 3
x-
LrnCH3
+--
'
7
NHCH3
FyOH
f
-atropine
1141
354
ABDULLAH A . AL-BADR A N D FARID J . MUHT.4DI
Carbons 2 , 3 and 4 of t r o p i n e are d e r i v e d from acet a t e ( 55,56 ) and it i s assumed t h a t t h e a c e t a t e i s

incorporated v i a a c e t o a c e t i c a c i d or some s u i t a b l e
a c t i v a t e d d e r i v a t i v e such as coenzyme A e s t e r ( 46 ).
[ 6 ] is t h e r e f o r e condensed w i t h a c e t o a c e t a t e t o give
hygrine- a -carboxylic a c i d [ 71. Decarboxylation of
[7] a f f o r d s hygrine [8] which i s an e s t a b l i s h e d prec u r s o r of t r o p i n e ( 56,57 ).
[8] i s dehydrogenated
t o give dehydrohygrine [g].
The l a t t e r i s c y c l i z e d
t o y i e l d tropinone [lo]. S t e r e o s p e c i f i c r e d u c t i o n
of [lo] a f f o r d s t r o p i n e [ll].
5.2
Biosynthesis of t r o p i c a c i d
Tropic a c i d 1121 i s formed by t h e i n t r a m o l e c u l a r
rearrangement of phenylalanine I131 (58)
Compounds
which a r e m e t a b o l i c a l l y r e l a t e d t o phenylalanine such
as phenylpyruvic a c i d are a l s o i n c o r p o r a t e d i n t o t r o p i c a c i d ( 59,60).
shikimic
acid
(J
*CH2
[I31 +h-mH2
I
* COOH
JrJ
+ I
HOH2C-*C-H
I
.COOH [12]
Tropine [ll] i s f i n a l l y e s t e r i f i e d w i t h t r o p i c a c i d
[ 1 2 ] t o give a t r o p i n e [14].
ATROPINE
6.
355
Metabolism of Atropine
Atropine i s r a p i d l y absorbed from t h e g a s t r o i n t e s t i n a l
t r a c t and r e a d i l y absorbed from t h e mucous membranes and
t h e s k i n (21,151 ).Absorption from t h e i n t e s t i n a l t r a c t i s
complete i n 2 hours. About one-half of t h e a t r o p i n e c i r c u l a t e s i n t h e f r e e form i n t h e blood and t h e o t h e r h a l f
i s bound by t h e plasma p r o t e i n s ( 21). Atropine a l s o e n t e r s
t h e c i r c u l a t i o n when a p p l i e d l o c a l l y t o mucosal s u r f a c e s
of t h e body ( 6 1 ) . The t r a n s c o n j u n c t i v a l absorption of
a t r o p i n e i s considerable. About 95% of r a d i o a c t i v e a t r o p i n e i s absorbed and e x c r e t e d following subconjunctival
i n j e c t i o n i n t h e r a b b i t ( 62). The metabolism of a t r o p i n e
v a r i e s considerably from one s p e c i e s t o another. Hydrol y s i s t o t r o p i n e and t r o p i c a c i d i s not thought t o be a
major metabolic r o u t e s i n c e only t r a c e s of t r o p i c a c i d
a r e recovered i n t h e u r i n e ( 21).
Atropine disappears r a p i d l y from t h e blood and i s d i s t r i buted throughout t h e e n t i r e body ( 2 1 ) . The l i v e r , kidney,
lung and pancrea.s a r e t h e most important organs t h a t t a k e
up t h e l a b e l e d a t r o p i n e ( 6 2 ) . Most i s excreted i n t h e
u r i n e w i t h i n t h e f i r s t 1 2 hours, i n p a r t unchanged ( 2 1 ) .
Following intra-mascular a d m i n i s t r a t i o n of a s i n g l e 2 mg
doses of I4C-labelled a t r o p i n e i n man, Gosselin e t a l . ( 6 3 )
found t h a t 85 t o 88% of t h e r a d i o a c t i v i t y w a s e x c r e t e d i n
t h e u r i n e w i t h i n 24 hours, only a t r a c e could be e x t r a c t e d
from t h e f a e c e s ; about 50% of t h e dose appeared i n t h e
u r i n e unchanged, over 30% w a s e x c r e t e d as unknown metabol i t e s and l e s s than 2% appeared as f r e e t r o p i c a c i d .
A f t e r intravenous i n j e c t i o n of a t r o p i n e i n t h e mouse, approximately 25% of t h e dose i s e x c r e t e d i n t h e u r i n e as
a t r o p i n e , more t h a n 50% as conjugates with glucuronic a c i d
and t h e remaining 20-25% as i n t e r m e d i a t e o x i d a t i o n products
(probably p-hydroxyatropine and 3 , 4 4 i h y d r o x y a t r o p i n e ) and
tropine-modified a t r o p i n e s ( 6 2 ) . The metabolism of a t r o pine i s presented i n scheme I [ after ( 6 2 ) 1.
ABDULLAH A . AL-BADR A N D FARID J . MUHTADI
SCHEME
1; THE METABOLISM OF ATROPINE

C02
Noratropine (2%)
Rabbit, Guinea p i g
( aldehyde )
Noratropine
Apoatropine
Tropine
Tropic a c i d
i n v o
R a t liver
4
-
in vitro
Man
ATROP 1 NE >
-
Mouse
Tropine ,
Modified+Tropic
atropines
acid
(10%)
( 1%)
Mouse
p-hydroxyatropine (2%)4 m,p-Dihydroxyatropine
p-Glucuronosidoatropine
(5%)
my-Hydroxy-p-glucuronosidoatropine
(27%)
m,p-DiglucuronosidoatropineC-p-hydroxy-m(20%)
glue urano s idoatropine
ATROPINE
7.
357
Pharmacokinetics
The pharmacokinetics of a t r o p i n e were r e p o r t e d by
s e v e r a l authors.
Peak serum l e v e l s occur approximately 30 minutes followi n g intramuscular ( I . M . ) a d m i n i s t r a t i o n of 1 mg dose of
a t r o p i n e (64).
Serum l e v e l s following intravenous (I.V. ) a d m i n i s t r a t i o n
of a t r o p i n e drop w i t h i n t h e f i r s t 1 0 minutes and t h e n decrease more gradually. Levels one hour following e i t h e r I.V.
or I.M. a d m i n i s t r a t i o n s a r e very similar (64).
Following I.M. a d m i n i s t r a t i o n of 2 mg a t r o p i n e , t h e onset
and d u r a t i o n of e f f e c t on h e a r t r a t e a r e r e p o r t e d (65) t o
be m a x i m u m a t 15-50 minutes and up t o 5 hours, r e s p e c t i vity.
Following endotracheal a d m i n i s t r a t i o n of 1 mg a t r o p i n e
s u l f a t e , serum l e v e l s of a t r o p i n e were l e s s t h a n 5pg/ml
a t 30 seconds and U p g / d a t 10 minutes (66 ).
Atropine's h a l f - l i f e i s r e p o r t e d t o occur a t two r a t e s ,
w i t h an i n i t i a l fast r a t e of about 2 hours and a slow r a t e
ranges 12.5-38 hours (65).
The average h a l f - l i f e of a t r o p i n e i s 4.125 hours following
a s i n g l e 1 mg intravenous dose of a t r o p i n e i n humans (67).
The mean t o t a l plasma clearance of s i x normal human volun t e e r s following a s i n g l e 1 mg intravenous dose of a t r o p i n e i s r e p o r t e d t o be 533.35 ml/minute (67).
Maximum c y c l o p l e g i a u s u a l l y occurs w i t h i n s e v e r a l hours of
a d m i n i s t r a t i o n of t o p i c a l a t r o p i n e , though e f f e c t i v e cyclop l e g i a may occur i n 30 t o 40 minutes (68).
The mydriatic e f f e c t may p e r s i s t f o r up t o 10 days while
t h e cycloplegic a c t i o n may l a s t f o r 5 days (68).
358
8.
Therapeutic Uses of Atropine

1.
(69)
Pre-anaesthetic medication :
- t o decrease s e c r e t i o n s of s a l i v a r y , naso-pharyngeal
and b r o n c h i a l glands.
- t o prevent r e f l e x brancho-spasm.
- to
reduce r e f l e x bradycardia of i n h a l a t i o n a l anasthetics.
2.
Antispamodic i n :
Bronchial asthma.
Renal, b i l i a r y and i n t e s t i n a l c o l i c .
Peptic ulcer.
With p u r g a t i v e s .
3.
Vaso-Vagal syncope due t o r e f l e x lowering o f blood

p r e s s u r e and severe Bradycardia.
4.
Nocturnal e n u r e s i s and urgency of m i c t u r i t i o n t o

decrease u r i n a r y bladder r e f l e x i r r i t a b i l i t y .
5. I n Parkinsonian d i s e a s e t o reduce r e g i d i t y ( c e n t r a l
action).
6.
Antidote for parasympathomimetic poisoning e.g.

organo-phosphorous i n s e c t i c i d e poisoning.
7.
Mydxiatic and cycloplegic i n :

Iritis
Kerat it i s
Corneal u l c e r a t i o n s o r i n j u r i e s
359
ATROPINE
9.
Methods of Analysis
9.1
I d e n t i f i c a t i o n Tests
The following i d e n t i f i c a t i o n t e s t s a r e mentioned i n
t h e B r i t i s h Pharmacopoeia of 1963 ( 7 0 )
-1 mg of a t r o p i n e i s added t o 4 drops of fuming n i t r i c
a c i d and t h e mixture i s evaporated t o dryness on a
water b a t h ; a yellow r e s i d u e i s obtained. 2 ml of
acetone and 4 drops of a 3% w/v s o l u t i o n of potassium hydroxide i n methyl a l c o h o l a r e added t o t h e
cooled r e s i d u e ; a deep v i o l e t c o l o r i s produced.
- 5 0 mg of a t r o p i n e i s d i s s o l v e d i n 5 m l of water a c i d i f i e d w i t h hydrochloric a c i d , gold c h l o r i d e s o l u t i o n

i s added; a lemon-yellow o i l y p r e c i p i t a t e i s formed
which r a p i d l y c r y s t a l l i z e s . This p r e c i p i t a t e a f t e r
r e c r y s t a l l i z a t i o n from b o i l i n g water a c i d i f i e d w i t h
hydrochloric a c i d , has a minutely c r y s t a l l i n e charac t e r , i s d u l l and p u l v e r u l e n t when dry, and has a
melting p o i n t about 136O.
Other i d e n t i f i c a t i o n t e s t s a r e as follows:Gerrard r e a c t i o n ( 7 1 ) .
To about 6 mg of a t r o p i n e , 1 m l of 2% s o l u t i o n o f
mercuric c h l o r i d e i n 50% aqueous methanol i s added;
a deep r e d c o l o r i s produced.
- The
-To a t r a c e of a t r o p i n e i n an evaporating d i s h , drops

of t h e p-dimethylaminobenzaldehyde reagent ( 2 g of
p-dimethylaminobenzaldehyde i s d i s s o l v e d i n 6 gm sulf i c a c i d ) are added as w e l l as 0.4 m l of water. The
r e s u l t i n g mixture i s heated on a b o i l i n g water bath;
an i n t e n s e r e d c o l o r i s produced which changing t o
Permanent cherry r e d on cooling.
- P h y s i o l o g i c a l t e s t : Induction of mydriasis
(can be performed on young c a t s , dogs and r a b b i t s ) .
An aqueous, alcohol free s o l u t i o n of a t r o p i n e or i t s
s u l f a t e i s dropped i n t o t h e c o n j u n c t i v a l sac of t h e
eye and h e l d so t h a t non i s l o s t by overflow of t e a r s .
It has been r e p o r t e d (71) t h a t 1 p a r t i n 40,000 or
t h a t 0.000 ,000,427 g of a t r o p i n e s u l f a t e w i l l cause
a d i s t i n c t d i l a t i o n of t h e p u p i l of t h e eye i n 1 hour.
360
ABDULLAH A. AL-BADR A N D FARID J . MUHTADI
Microcrystal tests
9.2
100 mg of a t r o p i n e d i s s o l v e d i n 5 m l water a c i d i f i e d
w i t h d i l u t e s u l f u r i c a c i d . The f o l l o w i n g microcrys t a l s were performed.
P i c r i c a c i d w i t h a t r o p i n e g i v e s bunches of p l a t e s
( 2 1 ) . The c r y s t a l s are shown i n F i g . 7.
- Wagner's r e a g e n t w i t h a t r o p i n e g i v e s i r r i g u l a r hexagons i n c l u s t e r s (21). The shape of c r y s t a l s i s

shown i n F i g . 8.
- Dragendorff's reagent with a tr o p in e gives i r r i g u l a r
9.3
9.3.1
r e c t a n g l e s as shown i n F i g . 9.
Mercuric c h l o r i d e w i t h a t r o p i n e g i v e s l o n g prisms
as shown i n F i g . 1 0 .
Kitrimetric Methods
Aqueous T i t r a t i o n s
Bobtelsky and B a r z i l y ( 7 2 ) have r e p o r t e d a misoh e t e r o m e t r i c t i t r a t i o n of l a r g e , o r g a n i c , n i t r o g e n c o n t a i n i n g compounds i n c l u d i n g a t r o p i n e . Micro
amount o f a t r o p i n e i s t i t r a t e d h e t e r o m e t r i c a l l y w i t h
t u n g s t o s i l i c i c a c i d , t u n g s t o p h o s p h o r i c a c i d or
molybdophosphoric a t pH 1 or 7 .
Other t i t r i m e t r i c methods for t h e a s s a y o f a t r o p i n e
have been p u b l i s h e d :
Determination o f a t r o p i n e , t r o p i n e and t r o p i c
a c i d i n decomposed a t r o p i n e p r o d u c t s ( 7 3 ) .
The a p p l i c a t i o n of sodium dodecyl s u l f a t e t i t r i metric s o l u t i o n i n t h e a n a ly s is of atropine
i n j e c t i o n s (74)
The i n f l u e n c e of s a l t s , p o l y h y d r i c compounds and

a b s o r b e n t s on t h e d e t e r m i n a t i o n of o r g a n i c b a s e s
by a n i o n i c s u r f a c t a n t i n two-phase systems.
The method was a p p l i e d t o a t r o p i n e among o t h e r
organic bases ( 7 5 ) .
Atropine i n a e r o s o l h a s been determined t i t r i m e t r i c a l l y by slowly e J e c t i n g t h e sample ( 2 g )
t h r o u g h a s t a n d a r d s o l u t i o n of a c i d and t i t r a t ing t h e excess a c i d ( 7 6 ) .
ATROPINE
361
~~
FIG. 7, MICROCRYSTALS OF
PICRIC ACID,
ATROPINE WITH
5
b
FIG, 8, MICROCRYSTALS
OF ATROPINE
WAGNER'S REAGENT,
362
F I G , 9, MICROCRYSTALS OF ATROPINE
DRAGENDORFF'S REAGENT,
--
-/-
FIG, 10. MICROCRYSTALS
OF ATROPINE
WITH MERCURIC CHLORIDE.
363
ATROPINE
e)
The i n f l u e n c e o f a t r o p i n e among o t h e r o r g a n i c
b a s e s on t h e p a r t i t i o n o f i n d i c a t o r a c i d s i n a
w a t er-chloroform system (77 )
f)
Atropine w a s d e t e c t e d and q u a n t i t a t i v e l y d e t e r mined i n decomposing t i s s u e s (78 ) .
A d i r e c t t i t r a t i o n method u s i n g l e a d n i t r a t e w a s
d e s c r i b e d f o r drug p r o d u c t s i n c l u d i n g a t r o p i n e
s u l f a t e (79 )
9.3.2
Non-Aqueous Titrat i o n
The USP XX 1980 ( 8 0 ) d e s c r i b e d a non-aqueous t i t r a t i o n f o r t h e a s s a y of a t r o p i n e as follows:
D i s s o l v e about 400 mg o f a t r o p i n e , a c c u r a t e l y weighed,
i n 50 m l of g l a c i a l a c e t i c a c i d , add 1 drop of
c r y s t a l v i o l e t TS, and t i t r a t e w i t h 0 . 1 N p e r c h l o r i c
a c i d VS t o a g r e e n end-point.
Perform a blank
d e t e r m i n a t i o n and make any n e c e s s a r y c o r r e c t i o n .
Each m l of 0 . 1 N p e r c h l o r i c a c i d i s e q u i v a l e n t t o
28.94 mg of a t r o p i n e ( C H NO ).
1 7 23 3
The B r i t i s h Pharmacopoeia 1980 (81) d e s c r i b e s a nonaqueous t i t r a t i o n f o r t h e a s s a y o f a t r o p i n e as
follows :
Dissolve 0 . 3 g i n 20 m l of anhydrous g l a c i a l a c e t i c
a c i d , and t i t r a t e w i t h 0 . 1 M p e r c h l o r i c a c i d VS and
determine t h e end-point p o t e n t iomet r i c a l l y
Dzyuba and S h r a i b e r ( 82 ) have q u a n t i t a t i v e l y d e t e r mined a t r o p i n e by t i t r a t i o n i n non-aqueous s o l v e n t s .

The t o t a l a l k a l o i d s of t h e a t r o p i n e group ( a t r o p i n e
p l u s hyoscyamine p l u s h y o s c i n e ) are determined by
tit rat i o n a g a i n s t HC104 i n anhydrous a c e t i c a c i d .
The method i s a p p l i e d t o leaves, e x t r a c t and t i n c t u r e
of belladonna, and t o t a b l e t s , s u p p o s i t o r i e s and eyedrops c o n t a i n i n g a t r o p i n e or belladonna. The endp o i n t i s determined p o t e n t i o m e t r i c a l l y ( quinhydrone
e l e c t r o d e w i t h S.C.E. as comparison e l e c t r o d e ) o r
w i t h c r y s t a l v i o l e t as i n d i c a t o r .
Symoni and Tokar ( 8 3 ) have r e p o r t e d new r e a g e n t for
t i t r a t i o n s o f a t r o p i n e and o t h e r a l k a l o i d s i n nonaqueous media by means o f t h e h y d r o c h l o r i c a c i d
363
colrplex of aluminium i s o p r o p o x y l a t e . The s t a n d a r d

s o l u t i o n c o n t a i n i n g t h e H C l complex o f aluminium
c h l o r o i s o p r o p o x y l a t e i s p r e p a r e d by d i s s o l v i n g
aluminium c h l o r o i s o p r o p o x y l a t e i n chloroform and
p a s s i n g t h e c a l c u l a t e d amount of H C 1 g a s i n t o i t , o r
by adding t h e s t o i c h e i o m e t r i c amount o f chloroform
s o l u t i o n of aluminium c h l o r o i s o p r o p o x y l a t e t o a
s t a n d a r d i z e d s o l u t i o n o f H C 1 (3% t o 4 % ) i n dry
chloroform. The s o l u t i o n must be k e p t v e r y d r y .
The above a u t h o r s ( 8 4 ) have a l s o r e p o r t e d a new reagent f o r t i t r a t i o n s i n non-aqueous media. The d e t e r mination o f a t r o p i n e and o t h e r a l k a l o i d s by means of
t h e h y d r o c h l o r i c a c i d complex of c h l o r o aluminium
i s o p r o x i d e . R e s u l t s w e r e d i s c u s s e d which have been
shown t h a t t h e H C 1 complex of c h l o r o aluminium i s o propoxide behaved as a monobasic a c i d when undergoing
s a l t formation w i t h v a r i o u s a l k a l o i d s . The a u t h o r
have given a method f o r t h e d e t e r m i n a t i o n o f a t r o p i n e
( a n d o t h e r a l k a l o i d s ) w i t h 0 . 1 N c h l o r o aluminium
i s o p r o p o x i d e i n chloroform. The d e v i a t i o n was C 1%
i n t h e range 38 t o 245 mg o f a l k a l o i d .
+
-
Simon et
( 8 5 ) have d e s c r i b e d a method f o r t h e
d e t e r m i n a t i o n of t r a c e amounts of a t r o p i n e by t i t r a t l o n i n anhydrous s o l v e n t s . For s o l i d a t r o p i n e
s u l f a t e , d i s s o l v e t h e sample i n anhydrous a c e t i c acid,
add 0.1% p-dimethyl aminoazobenzene s o l u t i o n i n
benzene, and t i t r a t e w i t h 0.005 N - H C l O 4 u n t i l t h e
c o l o r changes from y e l l o w t o pink. For aqueous solut i o n o f a t r o p i n e s u l p h a t e , make a l k a l i n e w i t h aqueous
sodium b i c a r b o n a t e , e x t r a c t w i t h chloroform and
t i t r a t e t h e e x t r a c t a s d e s c r i b e d above.
9.3.3
Gravimet r i c T i t rat i o n
Poethke and T r a b e r t ( 8 6 ) have u t i l i z e d potassium
iodobismuthate f o r t h e d e t e r m i n a t i o n of small q u a n t i t i e s o f a t r o p i n e and o t h e r a l k a l o i d s . The method i s
based on t h e p r i n c i p l e s developed f o r t h e determinat i o n o f 8-hydroxyquinoline (87) i s d e s c r i b e d . The
drug i s determined by p r e c i p i t a t i n g i t s iodobismuthate
and, e i t h e r d e t e r m i n i n g it g r a v i m e t r i c a l l y .
The above a u t h o r s ( 8 8 ) have a l s o determined a t r o p i n e
i n ampules, eye o i n t m e n t , p i l l s and e x t r a c t s o f
b e l l a d o n n a , and i n t a b l e t s and stomach powders cont a i n i n g b e l l a d o n n a . Good results were o b t a i n e d when
ATROPINE
365
a s s a y i n g comparatively s m a l l amounts o f t h e drug.
Van P i n x t e r e n et a1 (89) have r e p o r t e d t h e determinat i o n o f a t r o p i n e by means o f t e t r a p h e n y l b o r o n
( K a l i g n o s t ) . By u s i n g Flaschkas sodium t e t r a p h e n y l boron method ( 9 0 , 9 1 ) f o r t h e d e t e r m i n a t i o n o f a t r o p i n e
i n a l k a l o i d a l s a l t s and g a l e n i c a l s , r e c o v e r i e s v a r i n g
f r o m 8 l . g t o 99.6% were o b t a i n e d according t o t h e
volume o f s o l u t i o n analysed. Reasonable r e s u l t s were
o b t a i n e d by reducing t h e volume o f s o l u t i o n t o 25 m l
and w i t h 1 0 t o 25 mg o f a t r o p i n e . By applying t h e
g r a v i m e t r i c method t o 50 t o 100 ml samples o f
Maceratum R a d i c i s Belladonnae, a c c u r a t e results were
o b t a i n e d over t h e range o f about 0.020 t o 0.035% of
atropine.
9.3.4
Potentiometric Titrat ion

Pernarowski and Blackburn ( 9 2 ) have c a r r i e d out a
p o t e n t i o m e t r i c t i t r a t i o n of a t r o p i n e . The t i t r a t i o n
i s c a r r i e d o u t i n chlorobenzene w i t h g l a s s and sleevet y p e calomel e l e c t r o d e s ; 0 . 0 5 N H C l O 4 i n g l a c i a l
a c e t i c a c i d i s t h e most s u i t a b l e t i t r a n t . Bromophendl
blue i s a suitable indicator f o r t i t r a t i o n s i n
chlorobenzene t o a v i s u a l end p o i n t . The r e s u l t s o f
s i x t i t r a t i o n s o f a t r o p i n e showed a n average recovery
of 99.7% and s t a n d a r d d e v i a t i o n of 0.55%.
9 . 4 P o l a r o g r a p h i c Methods
Souckova and Zyka (93,94) have r e p o r t e d two p o l a r o g r a p h i c t i t r a t i o n methods f o r t i t r a t i o n o f o r g a n i c b a s e s
i n c l u d i n g a t r o p i n e . The f i r s t method i s t h e t i t r a t i o n w i t h t u n g s t o s i l i c i c a c i d , and t h e second i s
t i t r a t i o n w i t h tungstophosphoric and molybdo phosp h o r i c a c i d s . The l a t t e r method i s r e p o r t e d t o b e
u n s a t i s f a c t o r y f o r a t r o p i n e . The f i r s t method a l l o w s
a c c u r a t e d e t e r m i n a t i o n of 1 0 t o 20 mg of a base.
Novotny ( 9 5 ) have published a p o l a r o g r a p h i c determinat i o n o f a t r o p i n e i n m i x t u r e s . The drug 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 w i t h chloroform, evaporated
and a t r o p i n e i s n i t r a t e d w i t h HNO3-H2SOq mixture
( > 1O:l) on water b a t h for 30 minutes. The m i x t u r e
i s made a l k a l i n e and, a f t e r removing oxygen by means
o f n i t r o g e n , polarography o f t h e s o l u t i o n i s c a r r i e d
o u t . The polarogram i s compared w i t h one prepared
from a s i m i l a r sample t o which a known amount of
a t r o p i n e i s added.
366
ABDULLAH A . AL-BADR A N D FARID J . MUHTADI
An O s i l l o p o l a r o g r a p h i c s t u d y o f a t r o p i n e and o t h e r
a l k a l o i d s i s r e p o r t e d by Habersberger and Zyka ( 9 6 ) .
O s i l l o p o l a r o g r a p h i c curve o f a t r o p i n e w a s s t u d i e d
w i t h a dropping mercury e l e c t r o d e . A carbon e l e c t r o d e
was used a r e f e r e n c e e l e c t r o d e .
Some a s p e c t s of t h e 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 o f
a t r o p i n e i s r e p o r t e d by Benraad and U f f e l i e ( 9 7 ) .
Experimental evidence i s produced which i n d i c a t e s t h e
r e a c t i o n o f a t r o p i n e a t t h e droping mercury e l e c t r o d e
i n 0 . 1 N L i C l i s a simple r e d u c t i o n p r o c e s s .
9.5
Spectrophotometric Methods
9.5 .1 Colorimetry
Atropine h a s been determined c o l o r i m e t r i c a l l y ,
among o t h e r a t r o p a a l k a l o i d s , by t h e u s e of
new r e a g e n t s . An a b s o r p t i o m e t r i c method i s
d e s c r i b e d ( 9 8 ) f o r t h e d e t e r m i n a t i o n of a t r o p i n e and r e l a t e d a l k a l o i d s . The well-known
Vitali-Morin r e a c t i o n w a s i n v e s t i g a t e d w i t h a
view t o improving t h e s t a b i l i t y o f t h e c o l o r e d
formed. It w a s found t h a t t h e b e s t r e s u l t s
were o b t a i n e d w i t h tetraethylammonium hydrox i d e as t h e b a s e and dimethylformamide as t h e
s o l v e n t . The s o l u t i o n (0.05-0.15 mg of
a l k a l o i d ) i s evaporated t o d r y n e s s , n i t r a t e d
w i t h 0 . 2 t o 0 . 3 m l o f fuming HNO3, a g a i n
e v a p o r a t e d , d i s s o l v e d i n dimethylformamide,
t r e a t e d w i t h 0.3 ml o f 25 p e r c e n t aa. t e t r a e thylammonim hydroxide and d i l u t e d t o 1 0 ml
w i t h dimethylformamide. The o p t i c a l d e n s i t y
i s determined a t 540 mu i n . 1-cm c e l l s a g a i n s t
dimethylformamide and t h e a l k a l o i d a l c o n t e n t
i s a s c e r t a i n e d from a c a l i b r a t i o n graph which
is linear.
Simonyi and Tokar ( 9 9 ) have r e p o r t e d a new
c o l o r i m e t r i c method f o r t h e d e t e r m i n a t i o n of
s m a l l amounts o f t r o p i c a c i d and i t s e s t e r s .
A t r o p i n e w a s n i t r a t e d f o r 1 5 minutes at 50'
w i t h a s o l u t i o n of 20% mO3 i n conc. H2S04.
On making t h e product a l k a l i n e w i t h hot 18 t o
20% N a O H , a c o l o r develops i n 30 m i n u t e s . This
i s e s t i m a t e d by u s i n g an S42, S47 o r S50
f i l t e r i n t h e P u l f r i c h photometer. The s e n s i t i v i t y i s 50 and 60 ug o f a t r o p i n e p e r ml. The
3%.
probable e r r o r i s
ATROPINE
367
Nir-Grosfeld and Weissenberg (100)have
r e p o r t e d two c o l o r i m e t r i c methods f o r t h e
d e t e r m i n a t i o n o f a t r o p i n e i n pharmaceutical
p r e p a r a t i o n s . Recovery experiments i n d i c a t e
an accuracy of ? 1%.The results a g r e e w i t h
t h e s e o b t a i n e d by t h e method o f USPXV.
I n method I , a chloroform e x t r a c t , prepared by
t h e USP method, i s evaporated t o dryness on a
water b a t h . N i t r i c a c i d (fuming) w a s added,
and h e a t e d t i l l fuming c e a s e d , d r i e d a t l O 5 O
f o r 1 5 min and allowed t o c o o l . The r e s i d u e
o b t a i n e d w a s d i s s o l v e d i n a c e t o n e and d i l u t e d
t o 25 m l . An a l i q u o t ( 5 m l ) w a s mixed w i t h
isoproprylamine and 0.1% methanolic KOH and
t h e e x t i n c t i o n a t 540 mu w a s measured a f t e r
one minute.
I n method 11. The compound i s n i t r a t e d as i n
method I and d i s s o l v e d i n 50% e t h a n o l ( 1 0 m l )
Heated on a water bath w i t h 1% HC1 and z i n c
d u s t f o r 1 0 minutes, cooled and f i l t e r e d . The
z i n c r e s i d u e w a s washed w i t h H2O and t h e
washings were added t o t h e f i l t r a t e . 1% o f
NaN02 i s added,
mixed and allowed t o s t a n d
for 1 0 minutes. To t h i s 92.5% s o l u t i o n of
ammonium sulphamate was added, shaken and
allowed t o s t a n d f o r 1 0 minutes. N-lnaphthylethylenediamine d i h y d r o c h l o r i d e solut i o n was added, d i l u t e d w i t h water t o 25 ml
and a f t e r 30 min, t h e e x t f n c t i o n a t 550 mu w a s
measured.
Pohm (101) r e p o r t e d a micro-determination o f

a t r o p i n e c o l o r i m e t r i c a l l y , by means of pdimethylaminobenzaldehyde. Atropine i s mixed
w i t h e t h e r and aq. N H 3 and s i t a s i d e f o r two
hours and f i l t e r e d . The f i l t e r e d e x t r a c t i s
extra.cted w i t h 0.05 N H C 1 . The HC1 e x t r a c t i s
made a l k a l i n e (NaOH) and e x t r a c t e d w i t h chloroform, evaporated t o d r y n e s s . Three drops o f
aq. bromine are added and evaporated o f f . The
r e s i d u e i s d i s s o l v e d i n methanol and a g a i n
evaporated w i t h 3 drops o f aq. bromine. A f t e r
drying f o r 2 hours o v e r P2O5, t h e r e s i d u e i s
t r e a t e d w i t h 7 drops of Wasicky reagent ( a
s o l u t i o n o f 1.
gm of p-dimethylaminobenzaldehyde i n 9
o f 88% H2SO4) and s i t a s i d e f o r
2 minutes. It i s t h e n h e a t e d f o r 3 minutes i n
368
a b o i l i n g w a t e r b a t h a n d cooled i n i c e f o r 1 5
seconds. A c e t i c anhydride i s added w i t h
s t i r r i n g and a f t e r 30 m i n u t e s , t h e e x t i n c t i o n
i s measured at 500 mu.
Atropine h a s been determined @02) c o l o r i m e t r i c a l l y by means of Reineck's s a l t . Ammonium
r e i n e c k a t e w a s used f o r t h e d e t e r m i n a t i o n of
a t r o p i n e i n 1% H2SO4. Ammonium r e i n e c k a t e
s o l u t i o n ( 0 . 5 % ) w a s added t o t h e t e s t s o l u t i o n ,
t h e m i x t u r e was p l a c e d i n a r e f r i g e r a t o r f o r
30 minutes and t h e p r e c i p i t a t e i s c o l l e c t e d on
a g l a s s f i l t e r , washed w i t h c o o l e d water and
d i s s o l v e d i n a c e t o n e . The e x t i n c t i o n i s t h e n
measured a g a i n s t a r e a g e n t b l a n k .
The e x t r a c t ion-spectrophotometric determination
method f o r t h e a s s a y o f a t r o p i n e w i t h t h e u s e
o f vanadium c a t e c h o l a t e h a s been r e p o r t e d by
S h e s t e r o v a e t a l . (103). The method i n v o l v e s
formation o f a w a t e r - i n s o l u b l e V'v-catechola t r o p i n e (1:2:1) complex ( I ) i n an aq. medium
a d j u s t e d t o pH 3 t o 4 w i t h hydrogen p h t h a l a t e
b u f f e r s o l u t i o n c o n t a i n i n g a 200-fold molar
e x c e s s ( r e l a t i v e t o I ) o f VO; and an 8000-f01d
molar e x c e s s o f c a t e c h o l and e x t r a c t i o n o f
t h i s complex i n t o chloroform.
The complex
e x h i b i t s max. a b s o r p t i o n a t 620 nm.
Semenicheva Qo4) r e p o r t e d a method f o r t h e
d e t e r m i n a t i o n o f a t r o p i n e s u l p h a t e i n eye
drops. Atropine sulphate i n n e u t r a l s o lu tio n
i s t r e a t e d w i t h sodium p i c r a t e and t h e atropine
p i c r a t e formed i s e x t r a c t e d w i t h chloroform;
a f t e r removal o f chloroform, t h e p i c r a t e i s
t r e a t e d w i t h sodium s u l p h i d e s o l u t i o n and t h e
c o l o r o f t h e sodium p i c r a m a t e formed i s compared w i t h s t a n d a r d p r e p a r e d by reducing p i c r i c
a c i d s o l u t i o n i n t h e same way.
9.5.2
Photometric A n a l y s i s
Akopyan (105) h a s r e p o r t e d a photometric method
for t h e d e t e r m i n a t i o n of a t r o p i n e and o t h e r
t r o p a n a l k a l o i d s i n pharmaceutical m i x t u r e s .
The d e t e r m i n a t i o n i s based on t h e r e a c t i o n o f
t h e a l k a l o i d ( a t r o p i n e ) w i t h p-aminobenzaldehyde on c o n c e n t r a t e d s u l p h u r i c a c i d . The
369
ATROPINE
i n t e n s i t y o f t h e c o l o r produced being measured

i n a photometric a b s o r p t i o m e t e r w i t h a g r e e n
filter
--
Fahmy e t a l . (106,107)have p u b l i s h e d a compar a t i v e s t u d y o f t h e d i f f e r e n t photometric

methods o f d e t e r m i n a t i o n o f a t r o p i n e : I.
The t u n g s t o s i l i c i c a c i d , tungstophosp h o r i c a c i d , copper s u l p h a t e , sodium

p i c r a t e and p-dimethylaminobenzaldehyde
methods are s u i t a b l e f o r t h e microdetermination o f a t r o p i n e i n t o x i c o l o g i c a l
samples. V i t a l i ' s method i s p r e f e r r e d .
11.
The u s e of bromothymol b l u e , bromocresol

p u r p l e , M e t a n i l yellow (C.I. a c i d yellow
36) and methyl orange, and v a r i o u s
o r g a n i c s o l v e n t s , i n t h e alkaloid-dye
method of d e t e r m i n a t i o n h a s been s t u d i e d .
The combination of M e t a n i l yellow and
chloroform i s most convenient.
The u s e o f ammonium r e i n e c k a t e i n t h e photom e t r i c d e t e r m i n a t i o n o f a t r o p i n e , h a s been

d e s c r i b e d (108). The procedure i s as follows:
To t h e s o l u t i o n c o n t a i n i n g from 2 t o 1 0 mg of
a t r o p i n e add 0.5 N H$O4
( 2 d r o p s ) and s a t u r a t e d ammonium r e i n e c k a t e s o l u t i o n , w i t h s t irri n g . C o l l e c t t h e p r e c i p i t a t e on a s i n t e r e d g l a s s f i l t e r (Gb), wash it w i t h c o l d water,
and d i s s o l v e it i n dioxan a c i d i f i e d w i t h 0.5 NH2SO4. Measure t h e e x t i n c t i o n o f t h e dioxan
s o l u t i o n a t 530 mu, and refer t h e r e s u l t s t o a
c a l i b r a t i o n curve. The method w a s used for
determining a t r o p i n e i n t a b l e t s .
Levine and Roe 609) have d e s c r i b e d a method
for t h e d e t e r m i n a t i o n o f a t r o p i n e and t r o p i c
acid.
Atropine and t r o p i c a c i d were s e p a r a t e d from
each o t h e r and from p r e s e r v a t i v e s such as
benzyl a l c o h o l or phenol by p a r t i t i o n chromatography and determined by a modified V i t a l i procedure. The chromatographic procedure employs
two columns connected i n s e r i e s , w i t h C e l i t e
545 as s u p p o r t i n g phase. I n column A t h e
370
ABDULLAH A . AL-BADR A N D FARID 3 . MUHTADI
sample ( 2 m l ) made a l k a l i n e w i t h N NaHC03

(1m l ) absorbed on C e l i t e (4 g + 1 g ) , c o n s t i t u t e s t h e s t a t i o n a r y phase and i n column 8 t h e
s t a t i o n a r y phase i s 0.2 N H2SO4 ( 2 ml) absorbed
on C e l i t e ( 3 g + 1 g ) . On washing t h e columns
w i t h chloroform ( 1 0 0 m l + 25 m l t h r o u g h column
B o n l y ) , t r o p i c a c i d remains on column A .
Atropine i s absorbed column B , and p r e s e r v a t i v e s p a s s b o t h columns. Tropic a c i d i s
e l u t e d from column A w i t h e i t h e r a f t e r a c i d i f i c a t i o n o f t h e column w i t h a c e t i c a c i d i n
e t h e r , and a t r o p i n e i s e l u t e d from column B
w i t h chloroform a f t e r n e u t r a l i z a t i o n o f t h e
column w i t h aqueous ammonia. A t r o p i n e and
t r o p i c a c i d are converted i n t o t h e i r s a l t s by
a d d i t i o n o f HC1 and aqueous ammonia respect i v e l y , and evaporated t o d r y n e s s . For the
modified c o l o r i m e t r i c p r o c e d u r e , t r e a t t h e d r y
r e s i d u e on a steam b a t h f o r 30 minutes w i t h
fuming n i t r i c a c i d (1m l ) i n a covered f l a s k .
Add w a t e r ( 1 0 m l ) , aqueous ammonia, ( 2 m l ) ,
sodium d i t h i o n i t e ( a b o u t 50 mg) and 5% NaN02
s o l u t i o n ( 5 m l ) and h e a t f o r a f u r t h e r f i v e
m i n u t e s , add 5% sulphamic a c i d s o l u t i o n ( 1 0 m l )
and remove n i t r o u s fumes i n a c u r r e n t o f air.
Add 25 mg o f s o l i d N-1-naphthylethylenediamine
d i h y d r o c h l o r i d e , make up t o volume, s e t a s i d e
f o r 0 . 5 t o 4 h o u r s , and compare t h e e x t i n c t i o n
a t 550 mu w i t h v a l u e s o b t a i n e d from s t a n d a r d s
t r e a t e d s i m i l a r l y . Beer's l a w i s obeyed up t o
a t le a s t 4 mg r e c o v e r i e s were from 1 0 0 t o 103%.
Febvre (11.0) r e p o r t e d t h a t Vitali-Morin r e a c t i o n f o r a t r o p i n e i s modified t o g i v e a reprod u c i b l e c o l o r t h a t can be used q u a n t i t a t i v e l y .
A knotjnvolume o f t h e sample i s evaporated t o
d r y n e s s under vacuum i n a c e n t r i f u g e t u b e ,
t h e n t r e a t e d w i t h a f e w drops o f a m i x t u r e o f
7 rd. of H2SO4 (66" B e ' ) and 2 m l o f fuming H N O ~
and s t i r r e d t o make t h e s o l u t i o n homogenous.
Acetone ( 2 m l ) i s added qnd 10% a b s o l u t e e t h a n o l i c KOH ( t h e p r e s e n c e of water o r methanol
v i t i a t e s r e a c t i o n ) drop by drop u n t i l t h e s o l u t i o n i s n e u t r a l i z e d , when t h e c o l o r a p p e a r s a t
once. A f t e r c e n t r i f u g a t i o n t o remove s o l i d
p r e c i p i t a t e d by t h e a c e t o n e and making up t o
1 0 ml w i t h a c e t o n e ; t h e e x t i n c t i o n i s measured
(Filter 63 o f t h e Jobin - Yvon Spectrophotometer).
371
ATROPINE
The e x t i n c t i o n i s s t a b l e f o r 1 0 minutes at
20'.
The Beer-Lambert's l a w i s followed
o n l y f o r c o n c e n t r a t i o n from 5 t o 20 vg p e r m l ,
but f o r h i g h e r c o n c e n t r a t i o n , a c a l i b r a t i o n
curve can be used. Above 100 ug p e r m l t h e
s e n s i t i v i t y f a l l s o f f . The mean e r r o r i s
about 1%. No c o l o r i s g i v e n by t h e h y d r o l y s i s
products of atropine
9.5.3
U l t r a v i o l e t Spectrophotometric Methods
Systematic t o x i c o l o g i c a l a n a l y s i s by s p e c t r o photometric methods have been p u b l i s h e d (111).
The sample o f t i s s u e i s homogenized w i t h 25 m l
o f 0 . 1 N HC1; t h e homogenate i s e x t r a c t e d on a
w a t e r b a t h w i t h 75 m l 95% e t h a n o l and 2 m l , 10%
Na2W04. The r e s i d u e i s being d i s s o l v e d i n 50
m l o f M c l l r a i n s ' s b u f f e r a t pH 7 and e x t r a c t e d
w i t h chloroform ( 5 0 m l ) . The s e p a r a t e d
chloroform l a y e r i s t h e n e x t r a c t e d 1 0 0 m l o f
0 . 1 N HC1. The c h a r a c t e r i s t i c U.V. a b s o r p t i o n
curves f o r 30 a l k a l o i d s i n d i l . HC1 a r e pres e n t e d ; a t r o p i n e can be determined q u a n t i t a t i v e l y by t h i s method.
Cross e t a l . Q12) have determined some a l k a l o i d s including atropine spectrophotometrically

and d e s c r i b e d i t s a p p l i c a t i o n t o pharmaceutical
p r e p a r a t i o n s . To determine a t r o p i n e , add 1%
sodium p i c r a t e s o l u t i o n ( 3 m l ) t o a s o l u t i o n o f
a t r o p i n e (1mg) i n phosphate b u f f e r s o l u t i o n
(pH 7 ) ( 2 0 m l ) , e x t r a c t w i t h chloroform, shake
t h e e x t r a c t w i t h phosphate b u f f e r s o l u t i o n ,
(pH 11.2 t o 1 1 . 5 ) ( 4 0 m l ) d i l u t e t h e aq. phase
w i t h t h e same b u f f e r s o l u t i o n t o 1 0 0 m l , and
measure t h e e x t i n c t i o n at 355 m u .
Waaler and Bjerkelund (ll3) have d e s c r i b e d t h e
f o l l o w i n g p r o c e d u r e , for t h e u l t r a v i o l e t
d e t e n n i n a t i o n o f a p o a t r o p i n e and b e l l a d o n i n e
i n atropine:
"Prepare a s o l u t i o n of t h e m i x t u r e i n 0 . 1 N H2S04 c o n t a i n i n g 15% o f e t h a n o l , and measure
t h e e x t i n c t i o n a t 261.5, 257.5 and e i t h e r
248.5 or 254.0 my".
Calculate t h e content of
each a l k a l o i d by s o l u t i o n o f t h e t h r e e appropr i a t e simultaneous e q u a t i o n s . The e x t i n c t i o n
c o e f f i c i e n t o f each compound at each wavelength
i s given.
372
A t r o p i n e w a s determined s p e c t r o p h o t o m e t r i c a l l y
i n eye drops by Zabrak and Farkas (114). The
a b s o r p t i o n s p e c t r a o f a t r o p i n e show a m a x i m a
a t 186 mu. D i l u t e 1 m l o f t h e sample t o 100
ml and 5 ml o f t h i s s o l u t i o n i s f u r t h e r
d i l u t e d t o 100 ml w i t h w a t e r and measure t h e
e x t i n c t i o n a t 186 m u a g a i n s t water. Beer's
l a w i s obeyed o v e r t h e r a n g e 0 t o 8 pg p e r ml.
The r e s u l t s o b t a i n e d by t h i s method are w i t h i n
1%
o f t h o s e o b t a i n e d by e x t r a c t i o n methods.
Uhlmann (115) r e p o r t e d a s p e c t r o p h o t o m e t r i c
a s s a y method f o r a t r o p i n e and some n a r c o t i c s
To
and a l k a l o i d s i n g a l e n i c a l compositions.
a s s a y t h e drug i n aq. s o l u t i o n o f i t s s a l t ,
t h e e x t i n c t i o n o f t h e d i l u t e d sample i s
determined at t h e wavelength f o r maximum
a b s o r p t i o n (257 t o 286 nm) and compared w i t h
t h a t o f p r o g r e s s i v e l y d i l u t e d samples o f s t o c k
s o l u t i o n . The method i s c h i e f l y designed f o r
use on aq. p r e p a r a t i o n s ( ampoules).
9.5.4
I n f r a - r e d S p e c t r o p h o t o m e t r i c Method
The a p p l i c a t i o n o f i n f r a - r e d s p e c t r o m e t r y t o
q u a n t i t a t i v e analysis of a tro p in e i n t h e s o l i d
phase h a s been r e p o r t e d by Browning e t a l .
(116). The p r e s s e d potassium bromide b e l l e t
t e c h n i q u e h a s been s u c c e s s f u l l y a p p l i e d as a n
a i d i n t h e quantitative determination of atrop i n e by I R spectrophotometry.
9.5.5
F l u o r o m e t r i c Analysis
Laugel (119have p u b l i s h e d a method f o r t h e
d e t e r m i n a t i o n o f a t r o p i n e and , o t h e r a l k a l o i d ,
based on t h e f l u o r e s c e n c e o f compounds o f t h e
t y p e a c i d dye-azo b a s e . The c o n c e n t r a t i o n of
a t r o p i n e i n pharmaceutical p r e p a r a t i o n i s
determined ( t o w i t h i n 4%) by measuring t h e
f l u o r e s c e n c e o f t h e complex formed q u a n t i t a t i v e l y , i n chloroform s o l u t i o n , by a t r o p i n e
w i t h a d i h y d r o x y l l u r a n a c i d dye, e . g . c o s i n .
The c o n c e n t r a t i o n which i s d i r e c t l y proport i o n a l t o t h e f l u o r e s c e n c e (measured at 550
m u ) , i s o b t a i n e d from a s t a n d a r d c a l i b r a t i o n
curve for a t r o p i n e . Beer's l a w b e i n g obeyed
f o r 1 0 t o 60 pg o f a t r o p i n e .
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ATROPINE
Shuntaro Ogawa e t a l . (118) have determined t h e

f l u o r i m e t r y of a t r o p i n e with e o s i n yellowish
( C . I . Acid Red 87). The method which i s simple
and r a p i d i s based on t h e formation of f l u o r e s cent complex between a t r o p i n e and eosine. To a
s o l u t i o n of a t r o p i n e i n chloroform ( 9 m l ) i s
added 0.1% eosine s o l u t i o n (1m l ) , t h e mixture
i s shaken thoroughly and t h e fluorescence
i n t e n s i t y at 556 mu ( e x c i t a t i o n a t 365 mu) i s
measured a f t e r 1 0 minutes. Beer's law i s
obeyed with 1 t o 5 pg of a t r o p i n e p e r m l ; t h e
c o e f f i c i e n t of v a r i a t i o n i s 2.6%.
9.5.6
Phosphorimetric Analysis
Winefordner and Tin (119) have determined a t r o p i n e i s u r i n e . A r a p i d method w a s described
f o r t h e e x t r a c t i o n of a t r o p i n e from body
f l u i d s ; t h e concentration of t h e drug i s
determined by phosphoresence measurement and
comparison w i t h standard s o l u t i o n .
9.6
Chromatographic Methods
9.6.1
Paper Chromatography
Clarke ( 2 1 ) described two systems:
Whatman No. 1, sheet 1 4 X 6 i n , b u f f e r e d
by dipping i n a 5% s o l u t i o n o f sodium
hydrogen c i t r a t e , b l o t t i n g and drying a t
25' f o r one hour. It can be s t o r e d i n d e f i n i t e l y . A sample of 3 1.111% s o l u t i o n i n
2 N a c e t i c a c i d o r i n ethanol i s used.
Solvent system: 4.8 gm of c i t r i c a c i d i n
a mixture of 130 m l of water and 870 m l of
n-butanol ( t h i s solvent may be used f o r
s e v e r a l weeks i f water i s added from t i m e
t o t i m e t o keep t h e s p e c i f i c g r a v i t y ak
0.843 t o 0.844). The chromatogram i s
developed, ascending i n a t a n k 8 X 11 X 15%
i n . 4 Sheets being run at a time. Locat i o n i s done under u l t r a v i o l e t l i g h t and
t h e l o c a t i o n reagent i s i o d o p l a t i n a t e
spray,Rf = 0.37.
2)
Whatman No. 1 o r No. 3, sheet 17 X 19 cm,

impregnated by dipping i n a 10% s o l u t i o n
3 74
o f t r i b u t y r i n i n a c e t o n e and d r y i n g i n
a i r . A sample o f 5 1.11o f 1 t o 5 % s o l u t i o n
i n e t h a n o l or chloroform, u s i n g a c e t a t e
b u f f e r (pH 4.58) as s o l v e n t . The beaker
containing t h e solvent i s equilibrated i n
a t h e r m o s t a t i c a l l y c o n t r o l l e d oven a t 9 5 O
f o r 1 5 minutes. The chromatogram i s
developed, a s c e n d i n g , where t h e paper i s
f o l d e d i n t o a c y l i n d e r and c l i p p e d . The
c y l i n d e r i s i n s e r t e d i n t h e beaker c o n t a i n i n g t h e s o l v e n t which i s n o t removed from
t h e oven. A p l a t e - g l a s s d i s k t h i c k l y
smeared w i t h s i l i c o n e g r e a s e may s e r v e as
a c o v e r . T i m e run 1 5 t o 20 minutes. The
location reagent i s iodoplatinate spray
and Rf = 0.94.
Other paper chromatography systems have been
p u b l i s h e d (120-136).
9.6.2
Thin-Layer Chromatography
Clarke (21) d e s c r i b e d t h e f o l l o w i n g system f o r
t h e separation of atropine:
Glass p l a t e s 20 X 20 em, c o a t e d w i t h a s l u r r y
c o n s i s t i n g o f 30 g of s i l i c a g e l G i n 60 m l o f
water t o g i v e a l a y e r 0 . 2 5 mm t h i c k and d r i e d
at llOo f o r 1 hour. A sample o f 1 . 0 1-11of 1%
s o l u t i o n i n 2 N a c e t i c a c i d , t a k e n by a micro
d r o p , i s used. The s o l v e n t system c o n s i s t s
of s t r o n g ammonia s o l u t i o n : methanol (1.5 :
1 0 0 ) . It should be changed a f t e r two r u n s .
Solvent i s allowed t o s t a n d i n t h e t a n k f o r 1
hour. The ascending chromatogram i s developed
i n a t a n k 2 1 X 2 1 X 10 em, t h e end o f t h e t a n k
being covered w i t h f i l t e r paper t o a s s i s t
e v a p o r a t i o n . Time o f run 30 m i n u t e s . The
l o c a t i o n r e a g e n t i s an a c i d i f i e d i o d o p l a t i n a t e
spray: and t h e Rf v a l u e i s 0.18.
Other TLC systems have been p u b l i s h e d (133435,

137-140) for t h e s e p a r a t i o n o f a t r o p i n e .
9.6.3
Eigh P r e s s u r e Liquid Chromatography

S t u t z and S a s s (141) have d e s c r i b e d a highspeed, h i g h p r e s s u r e l i q u i d chromatography of
375
ATROPINE
a t r o p i n e and o t h e r t r o p a n e a l k a l o i d s . The
compound w a s s e p a r a t e d on a s t a i n l e s s - s t e e l
column (1meter X 4.6 mm) packed w i t h s i l - X
absorbent w i t h 28% aq. NH3-tetrahydrofuran
(1:lOO) as s o l v e n t and w i t h a column i n l e t
p r e s s u r e o f 500 l b p e r s q . i n . A d i f f e r e n t
r e f r a c t i v e index d e t e c t o r and a W d e t e c t o r
o p e r a t i n g at 254 nm were used t o monitor t h e
e l u a t e . When a p p l i e d q u a n t i t a t i v e l y , recover i e s o f a t r o p i n e s u l p h a t e added t o v a r i o u s
a l k a l o i d samples were between 88 and 94.5% a t
t h e = 25 pg l e v e l .
F e l l e t a l . (142) have r e p o r t e d an a n a l y s i s o f
a t r o p i n e s u l p h a t e and i t s d e g r a d a t i o n p r o d u c t s
by reversed-phase high-pressure l i q u i d chromatography. Atropine was determined on a
column o f H y p e r s i l ODS ( 5 pm) w i l l 50 mM.
Sodium a c e t a t e i n 1 0 mM -tetrabutylammonium
s u l p h a t e (pH 5 . 5 ) - a c e t o n i t r i l e ( 3 : l ) a s
mobile phase and d e t e c t i o n a t 254 nm. The
i n t e r n a l s t a n d a r d was p - t o l u i c a c i d . Atropine
w a s w e l l s e p a r a t e d from it d e g r a d a t i o n prod u c t s , t r o p i c a c i d a t r o p i c a c i d and apoatropine.
e.
V a n Buuren et
(143) have published a
reversed-phase l i q u i d chromatography of b a s i c
drugs i n c l u d i n g a t r o p i n e - w i t h a f l u o r o g e n i c
ion-pair extraction detector.
Lawrance e t al. (144) have s e p a r a t e d a t r o p i n e
from o t h e r b a s i c o r g a n i c compounds by c o n t i nuous post-column i o n - p a i r e x t r a c t i o n d e t e c t i o n
i n normal-phase chromatography. The column
( 6 cm X 3 mm) of LiChrosorb S i 60 ( 5 pm) w i t h
a mobile phase (1m l min-l) o f 10% methanol
s o l u t i o n i n chloroform c o n t a i n i n g 0 . 1 M butyric acid. Detection of t h e fluorescence
o f t h e o r g a n i c phase w a s measured at 452 nm.
9. 6.4
Ion-Exchange Chromatography
Morphine s u l p h a t e w a s s e p a r a t e d from a t r o p i n e
s u l p h a t e by t h e ion-exchange chromatographytechnique (145). Determination w a s done by measuring
t h e u l t r a v i o l e t a b s o r p t i o n a t 258 mp E 1%
1 cm = 40. The two drugs cannot be s e p a r a t e d
376
on a weakly b a s i c r e s i n , which c o n v e r t s b o t h
t o t h e f r e e a l k a l o i d s , b u t t h e a l k a l o i d s can
be s e p a r a t e d on a s t r o n g l y b a s i c r e s i n which
r e t a i n s o n l y t h e ( p h e n o l i c ) morphine. The
procedure o f t h e s e p a r a t i o n have been desc r i b e d as f o l l o w s :
D i l u t e t h e sample ( c o n t a i n i n g 400 mg of morp h i n e s u l p h a t e and 10 mg o f a t r o p i n e s u l p h a t e ,
t o 50 m l w i t h 75 p e r c e n t methanol. To d e t e r mine t h e c o n c e n t r a t i o n o f morphine s u l p h a t e ,
d i l u t e a 10 m l a l i q u o t t o 1000 m l w i t h w a t e r
and measure t h e e x t i n c t i o n a t 285 mp. To
determine t h e c o n c e n t r a t i o n o f a t r o p i n e s u l p h a t e , p a s s a 25 m l a l i q u o t t h r o u g h a two-bed
column c o n t a i n i n g h b e r l i t e IR-4B ( 1 0 m l ) above
Amberlite IRA-410 ( 1 0 m l ) , e l u t e w i t h 7 5 p e r c e n t methanol (4 X 1 0 ml) and t i t r a t e t h e
e l u t e w i t h 0.02 N H C 1 w i t h bromothymol b l u e as
indicator.
9.6.5
Gas Chromatography
Clarke ( 2 1 ) d e s c r i b e s t h e f o l l o w i n g t h r e e
systems f o r t h e s e p a r a t i o n o f a t r o p i n e : Column: 1% SE-30 on 100-120 mesh Anakrom
ABS. 6 f t X 4 mm i n t e r n a l d i a m e t e r boros i l i c a t e g l a s s column. Column t e m p e r a t u r e :
180. Carrier g a s : Argon. Gas flow: 6 5
m l p e r minute a t 180. D e t e c t o r : Argon
i o n i s a t i o n d e t e c t o r o r flame i o n i s a t i o n
d e t e c t o r . Retention t i m e :
3.22 rnin.
r e l a t i v e t o diphemhydramine.
Column: 3% Q?-1 on 100-120 mesh Anakran
ABS, Column t e m p e r a t u r e : 200'.
Carrier
g a s : Argon. Gas flow: 80 ml p e r minute.
Other c o n d i t i o n s are as i n system a.
R e t e n t i o n t i m e : 3.80 min. r e l a t i v e t o
diphenhydramine.
Column:
W AW.
5% SE-30 on 60-80 mesh Chromosorb

5 f t X 1/8 i n c h i n t e r n a l d i a m e t e r
s t a i n l e s s s t e e l column. Column temperature:

230'.
Carrier g a s : n i t r o g e n . Gas flow:
30.7 m l p e r minute. Detector: flame i o n i z a t i o n d e t e c t o r , hydrogen 22 m l p e r minutes.
R e t e n t i o n t i m e : 0 . 5 9 min r e l a t i v e t o codeine.
311
ATROPINE
Santoro e t al,. Q46) have r e p o r t e d a s e l e c t i v e

d e t e r m i n a t i o n o f belladonna a l k a l o i d s by g a s
l i q u i d chromatography. Atropine w a s d e t e r mined i n pharmaceutical p r e p a r a t i o n s i n t h e
presence o f c e r t a i n m i n e s . A f t e r e x t r a c t i o n ,
t h e r e s i d u e i s d i s s o l v e d i n dichloromethane
and i n j e c t e d g l c on a g l a s s column (4 f t X 4
mm) c o n t a i n i n g 3% OV-17 on Gas-Chrom Q ( 8 0 t o
100 mesh) o p e r a t e d at 210' w i t h H e l i u m as
c a r r i e r g a s (50 m l p e r min) and flame i o n i z a t i o n d e t e c t i o n and measure t h e peak h i g h t s .
Nishimoto e t a l . &47) have d e s c r i b e d a s i m p l i f i e d q u a n t i t a t i v e a n a l y s i s o f a t r o p i n e and
o t h e r a l k a l o i d s i n s c o p o l i a e x t r a c t . Analysis
i s c a r r i e d o u t by g l c on columns (1mm X 3 mm)
packed w i t h 0.75% o f D e x s i l 300 GC on Gas
Chrom Q, w i t h n i t r o g e n (40 m l min-1) as c a r r i e r
gas; w i t h t h e column at ( u s u a l l y ) 180", a t r o pine (as i t s t r i m e t h y l s i l y l derivative i s
s e p a r a t e d from hyoscine, a p o a t r o p i n e and homa t r o p i n e ( t h e i n t e r n a l s t a n d a r d . With t h e
column at 90' and t h e c a r r i e r g a s flow a t 30
m l min-l, a t r o p i n e i s e l u t e d i n about 7
minutes. Thermon 1000 w a s a l s o used as a
s t a t i o n a r y phase and diphenhydramine i s used
a s i n t e r n a l s t a n d a r d . The method i s a p p l i e d
t o g a s t r o i n t e s t i n a l drugs as w e l l as e x t r a c t s
o f s c o p o l i c r o o t s . The peak h i g h t r a t i o v s
a t r o p i n e c o n t e n t i s r e c t i l i n e a r f o r 25 t o 75
ng o f a t r o p i n e .
Other GC methods
Atropine t a b l e t s were e x t r a c t e d w i t h chloroform i n an a l k a l i n e media and analyzed u s i n g
a GC method w i t h diphenhydramine as t h e i n t e r n a l s t a n d a r d (148).
9.6.6
Colwnn Chromatography
Kamienski and Puchalka (149)have r e p o r t e d t h e
s e p a r a t i o n of a t r o p i n e and hyoscyamine by a
pot-entiometric chromatographic method. The
a l c o h o l i c e x t r a c t s from t h e l e a v e s Datura
stramonium and t h e r o o t s o f Atropa belladonna
were d i l u t e d u n t i l t h e i r a l k a l o i d c o n c e n t r a t i o n
approximately reached 0 . 0 0 1 M. The s e p a r a t i o n
o f a t r o p i n e and hyoscyamine i n t h e s e s o l u t i o n s
378
ARDULLAH A . AL-BADR AND FARlD J . MUHTADI
w a s s t u d i e d . Four m l o f each s o l u t i o n were

p l a c e d on alumina columns and e l u t e d w i t h
e i t h e r aqueous e t h a n o l ( 6 0 o r 80%) or a mixture
o f benzene; w a t e r and e t h a n o l (14.5%, 8.5% and
77% r e s p e c t i v e l y ) , t h e antimony m i c r o e l e c t r o d e
b e i n g used t o measure p o t e n t i a l change i n t h e
e l u t e d s o l u t i o n a g a i n s t t h e volume of t h e
e l u a t e . The most e f f i c i e n t s e p a r a t i o n was
achieved w i t h t h e benzene - e t h a n o l e l u t i n g
s o l u t i o n , and a 20 cm column o f Merck's
alumina.
9.6.7 Paper E l e c t r o p h o r e s e s
Atropine and hyoscine were s e p a r a t e d q u a n t i t a t i v e l y by paper e l e c t r o p h o r e s e s (150). They
were s e p a r a t e d w i t h 0 . 1 N aq. N H 3 a s t h e
e l e c t r o l y t e , and d e t e c t e d as brown s p o t s by
exposure t o i o d i n e vapour. After e l u t i o n o f
t h e spots, t h e solvent w a s evaporated, t h e
r e s i d u e w a s n i t r a t e d w i t h fuming H N O 3 , t h e n
d i s s o l v e d i n dimethylformamide and t e t r a e t h y l ammonium hydroxide w a s added a c c o r d i n g t o t h e
method o f Freenan ( 9 8 ) . The e x t i n c t i o n ( y )
o f each s o l u t i o n at 545 mp w a s measured and t h e
c o n c e n t r a t i o n o f each a l k a l o i d i s c a l c u l a t e d
from a given e q u a t i o n .
9.7. Radio-immunoassay
~y u s i n g 3~ a t r o p i n e as t r a c e r , an a n t i s e r u m w a s
r a i s e d by immunisation o f r a b b i t s w i t h an immunogen
prepared by c o u p l i n g t o human serum albumen. The
d e t e c t i o n of down t o 9 nM a t r o p i n e i n 0 . 1 m l o f serum
or plasma i s p o s s i b l e . The r e c o v e r y of a t r o p i n e
added a t v a r i o u s c o n c e n t r a t i o n t o pooled normal human
plasma w a s n e a r 100%. Atropine r e a c t s w i t h t h e a n t i b o d i e s ; o t h e r s t r u c t u r a l l y r e l a t e d drugs and a t r o p i n e h y d r o l y s i s p r o d u c t s ( t r o p i n e and t r o p i c a c i d ) do not
i n t e r f e r e . The u s e f u l n e s s o f t h i s method i n pharmac o k i n e t i c s s t u d i e s have been demonstrated i n a s s a y s o f
a t r o p i n e i n s e r i a l serum samples from two p a t i e n t s
who r e c i e v e d 1 . 3 mg o f a t r o p i n e i n c o n n e c t i o n w i t h
a n a e s t h e s i a (151).
A p r e c i s e , s e n s i t i v e and r a p i d radioimmunoassay f o r
t h e a n a l y s i s of a t r o p i n e from u n p u r i f i e d e t h a n o l i c
e x t r a c t s of a t r o p i n e b e l l a d o n n a i s d e s c r i b e d (152).
379
ATROPINE
F a s t h e t a l . (153) d e s c r i b e d t h e f i r s t radioimmunoa s s a y for a t r o p i n e u s i n g rabbit antiserum.
- Wurzburger
e t a l . (154) r e p o r t e d and s e n s i t i v e and

s p e c i f i c radioimmunoassay for a t r o p i n e and showed
c l e a r a n c e curve f o r drog plasma.
Radioimmunoassay (RIA) w a s a p p l i e d t o measure a t r o p i n e i n himan plasma u s i n g a n t i s e r u m , t h e plasma

c l e a r a n c e of a t r o p i n e i n f o u r a d u l t v o l u n t e e r s w a s
measured.
The measurement accomplished by a c o m p e t i t i v e R I A
u s i n g r a b b i t a n t i - a t r o p i n e antibody. T r i t i a t e d
a t r o p i n e i s used as t h e r a d i a l i g a n d (155).
Acknowledgement
The a u t h o r s would l i k e t o thank Mr. Uday C. Sharma and
Tanvir A. B u t t , b o t h of College of Pharmacy, King Saud
University for t h e i r valuable s e c r e t a r i a l assistance i n
t y p i n g of t h i s manuscript.
ABDULLAH A. AL-BADR AND FARlD J . MUHTADl
3 80
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I , Simonyi and G. Tokar , Magyar K e . Foly. , &(
84.
I . Simonyi and G. Tokar (Verein. Arznel - Und Nahrmitt e l f a b r i k , Budapest). Acta Chim. Acad. S c i . Hung.,
17 (1957).
S h r a i b e r , Aptechn.
Delo, 5 ( 6 ) ,
(1958)
4 ) , 151
2 5 ( 3 ) , 305 (1960).
85.
I . S . Simon, W.P. Dzyuba and Yu. V. Shostenko, Aptech.

Delo, Q ( 5 ) , 68 (1964).
86.
W. Poethke and H. T r a b e r t , Pharm. Z e n t r a l h ,
87.
Ibid,
88.
W. Poethke and H. Tabert
89.
J.A.C. Van P i n x t e r e n , M.E. Verloop and D. Westerink,

Pharm. Weekbl, %( 2 4 ) , 873 (1956).
90.
A.M.
91.
Ibid; 138, 2 4 1 (1953).
92.
M. Pernarowski and D.W. Blackburn, J . Amer. Pharm. A s s . ,

S c i . Ed., _L7(8), 585 (1958).
93.
M. Souckova and J. Zyka, Ceskosl. Farmac.,
94.
M. Souckova and J. Zyka, I b i d . , 4!5), 227 (1955).
95.
B. Novotny ( S t a t e I n s t . f o r Control of Drugs, Prague,

Czechoslovakia). Ceskosl. Farmac. , 9 ) 448 (1955).
96.
K. Habersberger and J . Zyka ( I n s t . Anal. Chem. , Charles

Univ. , Prague , Czechoslovakia). Ceskosl. Farmac , l(5 )
(1955).
Pharm. Z e n t r a l h . ,
(1955)
91,284
, Pharm.
94(6), 219
(1952).
Zentralh.,
Amin and A. Holasek, Z. Anal. Chem.
(1955).
94(11) 432
, 136 99
(1952).
4(4),181
k(
264 (1956).
97.
T . J . Benraad and O.F. U f f e l i e (Pharm. Lab., R i j k s u n i v . ,

Utrecht , N e t h e r l a n d s ) . Pharm. Weekbl. , $( 6 ) 201
(1961).
386
ABDULLAH A. AL-BADR AND FARlD J . MUHTADI
80,
520 (1955).
98
P.M.
99
I . Simony? and C. Tokar, Fagyar K e n . Foly, g(lO), 348
100.
Freeman, Analyst,
(1956).
I , Nir-Grosfeld and E. Weissenberg, Drug Standards,
25051,
180
(mi).
(L),120
(1958).
101.
P. Pohm, Mikrochim. Acta,
102.
S. Bartkowicz, Dessert. Pharm.
103.
I.P. Shesterova, Sh. T. Talipov, E.E. Karibyan and M.

Yakubova; Zh A n a l Khim., 2 1 4 1 (1980).
104.
A.A.
Semenicheva; Aptechnoe Delo,
105.
O.A.
Akopyan, Aptechnoe Delo, 7 ( 2 ) , 19 (1958).
-3 2 1 ,
I.R.
Fahmy, Z.F. Ahmad and S.A. Eid, J. Chem. U.A.R.,

229 (1961).
107.
I.R.
Fahmy, Z.F. Ahmad and S.A. Eid.
108.
J. Weyers and M. Skora, Dissert. Pharm., 14(2), 201

(1362).
106.
(1961)
109. J . Levine and J.E.

693 (1959).
110.
111.
M.?.
, E ( 2 ) , 113 (1960).
2, 18 (1953).
Ibid,
( 2 ) , 241
Roe, J. A s s . Off. Agric. Chem.,
42(4),
Febvre, Ann. Pharm. France, %(11),635 (1957).
E. Berman and H.N.
8(61,
518 (1953).
Wright, Arch. Ind. Hyc. Occ. Med.,
112. A.H. J. Cross, D. McClaren and S.G.E. Stevens, J. Pharm.

Pharmacol. , 11 (Suppl. ) , 103T (1959).
113.
T. Waaler and E. Bjerkelund, Pharm. Acta Helv., 2 ( 3 ) ,
114.
E. Zabrak and S. Farkas, Acta Pharm. Hung, &(5),

( 19641
115.
Uhlmann, Hans-Jocken,
( 1973)
150 (1964).
Pharm. Ztg, Ber., *(50),
207
2029
387
ATROPINE
116. R.S. Browning, S.E. Wiberley and F.C. Nachod, Anal.

Chem., a(1)
7,
(1955).
117. P. Laugel, Compt. Rend.,
255(4),
692 (1962).
118. S. Ogawa, M. Morita, K. Nishiura and K. Fujiwara, J.

Fharm. SOC. Japan, &(7) , 650 (1955).
119. L.D. Winefordner and M. Tin, Analytica Chim. Acta, %(1),
64 (1965).
120. H. Kaiser and H. Tori, Arch. Pharm., Berlin, 28J(4),

224; (51, 253 (1954).
121. A. Resplandy, Compt. Rend., *(26),
122. F. Vorel, Soudri LeKarstvi, ($1,
2527 (1954).
43;
(11,109 (1958).
123. W. Debska and K. Kostujak, Biol. Inst. Roslin

Leczniczych, z(2)
, 97 (1959).
124. A. Liukkonen, Farm. Aikakauslehtic,
125. N. Mesicek, Mikrochim. Acta,
69,
286 (1960).
(z), 283 (1961).
126. A. Waksmundzki and E. Soezewinski, Roczn. Chem., 2(5),

1363 (1961).
127. V. Koen, Farmatisiya, Sofia, g ( 3 ) , 36 (1962).
J
(
2
)
,
128. J. Jankulov, Compt. Rend. Acad. Bulg. Sci., l
(1964)
183
129. J. Zarnack and S. Pfeifer, Pharmazie, 19(2), 111 (1964).
130. H. Czlonkowska and I. Gradecka Pob, Farmacja Pol.,

20(19-20), 739 (1964).
131.
E. Soczewinski and B. Szabelska, Dissnes Pharm., Warsz,
17(1),
53 (1965).
, 618
132. W. Deckers and A. Muller, J. Chromat. , x(3)
(19651.
388
ABDULLAH A . AL-BADR AND FARlD J. MUHTADI
13. 2 . Buchi and A. Zimmermann, Pharm. Acta Helv., &(7),

395 (1965).
134.
,J. Buchi and A.
Zimmermann, Pharm. Acta Helv., & ( 6 ) ,
135.
2 . Buchi and A.
Zimmermann, Pharm. Acta Helv., 4 0 ( 5 ) ,
136.
361 (1965).
292
(1965).
Rao, ?I.V.
b9151,
Rama; and Singh, Narendra J., Curr. S c i . ,
193 (1980).
T e i j g e l e r , Pharm. Weekbl., =(14),
507 (1962).
137.
C.A.
138.
A. Negh, 2. Eudvari, G. S z a s z , A.
139.
Mohammed Ikram a;nd M. Khudn Bakhsh, Anal. Chem., &(1),
14'3.
K. Karatodorov; R. Kolarova, IZV. Durzh. I n s t .

1 0 , 29 (1977).
Kontrol. Lek. S r e d s t v a , -
1L1.
?,!.H. S t u t z , and S. S a s s , Anal. Chem., 4 5 ( 1 2 ) , 2131
142.
A.F. F e l l , S.J.K. J o h n s t o n e , and G. Smith, J. Pharm.

Pharmacol. , 2 ( S u p p l ) 20 (1979).
1113.
Van Buuren, J.F. Lawrance, U.A.T. Brinkman, I.L.

Ho9gberg and R.W. F r e i ; Anal. Chem. 52, 700 ( 1 9 8 0 ) .
144.
J.F. Lawrance, U.A.T. Brinkman and R.W.

Chrornat.
473 (1979).
1145.
S.N.
Gracza.
Ibid.
, 3 3 ( 2 ) , 67 (1963).
111 (1964).
( 19731
B r a n t n e r and K.
185,
Blaug, Drug S t a n d a r d s ,
23(4),
F r e i ; J.
143 (1955).
11;6. R.S. S a n t o r o ; P.P. Progner, E.A. Ambush, and D.E.

Guttman, J. Pharm. S c i . , e ( 8 ) , 1346 (1973).
1h7.
N. Yishimoto; R. Kato, ar.d S. Hayashi, Jakugaku Z a s s h i ,
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1118. B. N i k o l i n , M. Maksimovic and A. N i k o l i n ; Arh. Farm.,

31, 283 ( 5 - 6 ) (1981).
149.
B. Kamienski and K. Puchalka, B u l l Acad Polon S c i . ,

305-309 ( 1953).
389
ATROPINE
150.
K. Yamaguchi and M. I t o , J. Pharm. SOC. Japan, & ( 2 ) ,
151.
R. Virtanem, J , Kanto, and E. L i s a l o ; Acta Pharmacol.

Toxicol, k
J(3 ) , 208 ( 1 9 8 0 ) .
152.
179 (1961)
T. L e h t o l a , A. Huhtikangas and R. Virtanem, P l a n t a Med.

237 (Aug) ( 1 9 8 2 ) .
45,
153.
A. F a s t h , J. S o l l e n b e r g , B. Sorbo; "Production and

c h a r a c t e r i s a t i o n of a n t i b o d i e s t o Atropine", Acta Pharm.
Suec. 12, 311 (1975).
154.
R . J . Wurzhurger, R.L. Miller Boxenbaum "Radioimmunoa s s a y of a t r o p i n e i n plasma", J. Pharm. Exper. Therp.

203, 435 (1977)
155 *
P.W. Hayden, S.M. Larson and S. Lakshminarayanan, J.

Nuclear Med. %(4 ) 366 (1979).

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ATROPINE

Abdullah A. Al-Badr and Farid J. Muhtadi

ANALYTICAL PROFILES OF DRUG SUBSTANCES

ABDULLAH A . AL-BADR AND FARID J . MUHTADI

a) endo ( f)- a -( Hydroxymethyl) benzene-acetic

H-tropan-3a -ol( 2)-tropate.

1.1.2 Generic Names

Atropine, dl-hyoscyamine, (2)-hyoscyamine,

CAS Registry No.

Wiswesser Line Notation

I n a t r o p i n e , t h e a-3-substituent i s of great e r bulk than t h e hydroxyl, and t h e boat form

ABDULLAH A. AL-BADR A N D FARlD J. MUHTADI

Other PMR study suggested a preference f o r t h e boat

Appearance, Color, Odor and Taste

pH of 0.0015 molar s o l u t i o n i s 10.0 (15),approximate

ABDULLAH A. AL-BADR AND FARID J . MUHTADI

FIG, 1, THE UV SPECTRUM OF ATROPINE I N ETHANOL

FIG. 2 , THE I R SPECTRUM OF ATROPINE AS KBR-DISC

Nuclear Magnetic Resonance Spectra

Other PMR d a t a f o r a t r o p i n e are a l s o r e p o r t e d (5,9,

ABDULLAH A . AL-BADR AND FARID J. MUHTADI

F I G . 3 I A ) . TPE PYR SPECTnWi OF ATROPI3E Ill C D C L ~

The I3C-NMR n o i s e decoupled and o f f

ABDULLAH A. AL-BADR AND FARID J . MUHTADI

THE I3C-NER NOISE DECOUPLED SPECTRUE OF ATROPINE

Carbon Chemical S h i f t s of Atropine

Other l3C-NMR d a t a f o r a t r o p i n e ( 14,23 ) a t r o p i n e

Mass Fragments of Atropine

ABDULLAH A . AL-BADR AND FARID I. MUHTADI

Total Synthesis of Tropine

Suberone (cycloheptanone) [ 1 1 i s reduced t o

ABDULLAH A . AL-BADR AND FARlD J . MUHTADI

Scheme I: Willstatter's t o t a l synthesis of tropine

Scheme 11: Robinson's total synthesis of

ABDULLAH A. AL-BADR AND FARID J . MUHTADI

Tropinone can a l s o be s y n t h e s i z e d ( 2 9 ) using

Scheme 11: Robinson's s y n t h e s i s ( y i e l d improvement)

Scheme 111: Willstatter's second s y n t h e s i s

ABDULLAH A . AL-BADR A N D FARID J . MUHTADl

Scheme 11: McKenzie and Wood's s y n t h e s i s

ABDULLAH A . AL-BADR A N D FARlD J . MUHTADI

Scheme IV: Chambon's synthesis

Blicke's synthesis (34).

Phenylacetic a c i d [l] i s b o i l e d w i t h isopropylmagnesium c h l o r i d e i n e t h e r e a l s o l u t i o n t o give

Tropine f i n a l l y can be combined with t r o p i c a c i d t o

ABDULLAH A. AL-BADR AND FARID J . MUHTADI

Benzylmagnesium c h l o r i d e [l] i s t r e a t e d w i t h I4CO2 followed w i t h magnesium

Synthesis of Labeled Tropic a c i d

Scheme VII : Labeled t r o p i n e

ABDULLAH A . AL-BADR AND FARID J . MUHTADI

Leete's Scheme: Biosynthesis of Atropine

ABDULLAH A . AL-BADR A N D FARID J . MUHT.4DI

Carbons 2 , 3 and 4 of t r o p i n e are d e r i v e d from acet a t e ( 55,56 ) and it i s assumed t h a t t h e a c e t a t e i s

ABDULLAH A . AL-BADR A N D FARID J . MUHTADI

1; THE METABOLISM OF ATROPINE

p-hydroxyatropine (2%)4 m,p-Dihydroxyatropine

ABDULLAH A. AL-BADR AND FARID J . MUHTADI

Therapeutic Uses of Atropine

reduce r e f l e x bradycardia of i n h a l a t i o n a l anasthetics.

Vaso-Vagal syncope due t o r e f l e x lowering o f blood

Nocturnal e n u r e s i s and urgency of m i c t u r i t i o n t o

Antidote for parasympathomimetic poisoning e.g.

Mydxiatic and cycloplegic i n :

- 5 0 mg of a t r o p i n e i s d i s s o l v e d i n 5 m l of water a c i d i f i e d w i t h hydrochloric a c i d , gold c h l o r i d e s o l u t i o n