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Methixene Hydrochloride
METHIXENE HYDROCHLORIDE
Ezzat M. Abdel-Moety, Nashaat A . Khattab. and Mohammad Saleem Mian
Pharmaceutical Chemistry Department College of Pharmacy King Saud University P.O. Box 2457 Riyadh 1 145 I , Saudi Arabia
ANALYTICAL PROFILES OF DRUG SUBSTANCES AND EXCIPIENTS-VOLUME 22
317
Copyright 0 1993 by Academic Press, Inc. All rights of reproduction in any form reserved.
EZZAT M. ABDEL-MOETY ET AL.
318
CONTENTS 1. 2.
3.
4.
5.
6.
INTRODUCTORY DESCRIPTION 2.1 Nomenclature 2.11 Systemic Name 2.12 Other Chemical Names 2.13 P r o p r i e t a r y Names 2.14 CAS R e g i s t r y Number 2.2 Formulae and Molecular Weight 2.3 Appearance, Color and Taste. 2.4 The Cr ystal S t r u c t u r e and t h e Three-Dimensional Projection PHYSICAL CHARACTERISTICS 3.1 Elemental Composition M e l t i n g Range and B o i l i n g P o i n t 3.2 3.3 Thermal Behavior 3.4 Salubility 3.5 Crystallographic Characteristics 3.51 C r y s t a l 1i z a t i o n 3.52 X-ray D i f f r a c t i o n Pa t t e r n 3.6 Spectroscopic Data 3.61 U l t r a v i o l e t (UV) Absorption 3.62 I n f r a r e d ( I R ) Spectroscopy 3.63 Mass Spectrometry (MS) 3.64 Nuclear Magnetic Resonance (NMR) 3.641 1 H-NMR Spectrum 3.642 1JC-NMR Spectrum SYNTHESIS METHODS OF ANLAYSIS 5.1 Qualitative (Identification) 5.11 Color Tests 5.12 M i c r o c r y s t a l Test 5.2 Q u a n t i t a t i v e (Determination) 5.2 1 Col o r 1met r ic Determi n a t i o n 5.22 Fluorometric Determination 5.23 T it r imet r ic Dete r m i n a t ion 5.24 Chromatographic Techniques 5.241 Thin Layer Chromatography (TLC) 5.242 Gas L i q u i d Chromatography (GLC) 5.243 High-Performance L i q u i d Chromatography (HPLC) PHARMACOKINETICS 6.1 Absorption and E xcr etion 6.2 Biotr ansfor m ation
METHIXENE HYDROCHLORIDE
THERAPEUTIC CATEGORATION 7.1 Pharmacology 7 . 1 1 G a s t r o i n t e s t i n a l Tract ( G I T ) 7 . 1 2 Antiparkinsonism ACKNOWLEDGMENT REFERENCES 7.
319
EZZAT M. ABDEL-MOETY ET AL.
320
1.
INTRODUCTORY Methlxene h y d r o c h l o r i d e i s a t e r t i a r y amine antimuscarinic drug w i t h a r e l a t i v e l y h i g h s e l e c t i v i t y f o r t h e g a s t r o i n t e s t i n a l t r a c t . I t i s used i n t h e management o f c o n d l t i o n s i n w h i c h t h e r e i s h y p e r m o t i l i t y , as i n pylorospasm, b i l i a r y dyskinesia, s p a s t i c colon, duodenitis, and g a s t r i t i s and i n other disorders i n which i t i s d e s i r a b l e t o d i m i n i s h even normal m o t i l i t y , as i n duodenal u l c e r . I t does n o t d i m i n i s h g a s t r i c secretion. Although it i s recommended f o r use i n g a s t r i c u l c e r , a decrease i n m o t i l i t y can r e s u l t i n r e t e n t i o n o f a c i d and hence sometimes exacerbate t h e e r o s i v e process. I n c i d e n c e o f s i d e e f f e c t s i s low w i t h usual doses (1). The d r u g p o t e n t i a l l y has a l l t h e s i d e e f f e c t s o f antimusc a r i n i c s and t h e precautions and c o n t r a i n d i c a t i o n s a r e the same. I t i s a l s o mainly used f o r t h e symptomatic treatment o f a r t e r i o s c l e r o t i c , i d i o p a t h i c and p o s t e n c e p h a l i t i c parkinsonism. I t i s c l a i m e d t o be more e f f e c t i v e i n c o n t r o l l i n g t h e tremors ( 2 ) .
2.
DESCRIPTION 2.1
Nomenclature 2.11
Systemic Name (3)
M e t h i x e n e : l-Methyl-3-(9H-thioxanthen-9-y1met hy 11p i per id ine M e t h i xene hydroch1o r ide : 1-Methy 1- 3- ( 9H- t h i oxant hen-g- y 1-met hy 1) p i per id i ne monohydroch 1o r i de.
.
2.12
Other Chemical Names
Met h ixene is g- (N-me t hy 1-3- p i per idy 1methy 11t h ioxanthene ( 3 ) ; 9-(l-Methyl-3-piperidylmethyl)thloxanthene ( 4 ) ; (Methyl-l-piperidinyl-3-methyl)-9thioxanthene. 2.13
ProDrletary (Manufacturer) Name
T r e m o n i l ( S a n d o z , UK). methi xene hydrochloride 5 mg.
Tablets,
scored,
O t h e r P r o p r i e t a r y ( M a n u f a c t u r e r s ) names; Methyloxan (Jpn), T r e m a r l l (Sandoz, B e l g . , Denm.,
METHIXENE HYDROCHLORIDE
I t a l . , Neth., S. A f r . , Spain; Wander, Tremoquil (Astra, Swed.); T r e s t (USA) ( 2 ) .
32 1
Switz.);
Methixene Hydrochloride USAN S J 1977; A t o s i 1 (Teisan, Osaka, Jpn); C h o l i n f a l l (Tokyo Tanabe, Tokyo, Jpn); M e t h i x a r t (Fuso, Osaka, J p n ) ; Methyloxane (Nippon S h o j i , Osaka, Jpn); Raunans (Kowa Y., Tokyo, J p n ) ; Thioperkin (Hokuriku, Fukui , Jpn); Tremaril (Wander, B e l g . ; Sandoz, Denm., I t a l . 8, N e t h . ) ; T r e m a r i t (Wander, Ger.); Trernonil (Wander, Austral., Sandoz, UK); Tremoquil ( A s t r a ) , Swed.); T r e s t (Dorsey, USA)
(5). 2.14
Chemical Abstract Service (CAS) R e g i s t r y Number (3,4)
4969-02-2 (Methixene); 1553-34-0 (hydrochloride, anhydrous); 7081-40-5 (hydrochloride, monohydrate). Formulae and Molecular Weight
2.2
C
N-CH,
I
CH,
I
(Methixene) [ ( C ~ O H Z ~ N SM.W. ; ; 309.471
(Methixene.HC1) [ C ~ O H ~ S N S . H C M.W.; ~;
345.91
Methixene i s commercially a v a i l a b l e as t h e base and as t h e h y d r o c h l o r i d e s a l t ; each 100 p a r t s o f methixene base i s a p p r o x i m a t e l y e q u i v a l e n t t o 113 p a r t s o f methixene h y d r o c h l o r i d e anhydrous and 131 p a r t s o f t h e monohydrate s a l t .
EZZAT M. ABDEL-MOETY ET AL.
322
2.3
w a r a n c e . Color and Taste
Methixene i s s l i g h t l y y e l l o w v i s c o u s l i q u i d , w h i l e t h e HC1-salt i s f l a k e s o r c r y s t a l l i n e powder. Both t h e base and t h e s a l t have b i t t e r t a s t e . The powder o f t h e s a l t i s s t a b l e i n a i r , b u t darkens slowly as a r e s u l t o f l i g h t a c t i o n (1,3). 2.4
The C r y s t a l S t r u c t u r e and t h e Three-Dimensional Projecti o n (6 )
The c r y s t a l s t r u c t u r e o f methixene hydrochloride monohydrate, 9-(N-methyl-3-piperidylmethyl)thioxanthene hydrochloride monohydrate, C2oH23NS.HCl .H20, has been determined by t h e heavy-atom method and r e f i n e d three-dimensionally by t h e a n i s o t r o p i c least-squares method t o g i v e a f i n a l R-value a = 15.320 f 0.003, b = 9.118 f 0.002, c = 13.862 f 0.004 A, and i3 = 94.75 f 0.02’. A l l t h e hydrogen atoms were l o c a t e d on d i f f e r e n c e - F o u r i e r syntheses, b u t t h e i r parameters were n o t r e f i n e d . The c r y s t a l c o n t a i n s b o t h enantiomsrphs i n an equal amount. The benzenoid r i n g s are normal, and t h e best planes o f t h e benzene r i n g s make a d i h e d r a l angle o f 137.9”. The meso atoms, C ( 9 ) and S, a.re s i g n i f i c a n t l y displaced from t h e benzene ring. The p i p e r i d y l r i n g i s i n a c h a i r conformation. The p i p e r i d y l m e t h y l group i s ‘boat a x i a l ’ w i t h respect t o t h e c e n t r a l t h i o x a n t h e n e r i n g , and b o t h t h e thioxanthen-9-ylmethyl and N-methyl groups are i n an ‘ e q u a t o r i a l ’ p o s i t i o n w i t h respect t o t h e p i p e r i d y l r i n g . A l l i n t e r a t o m i c distances and angles are normal. The sulfur-carbon bond distance i s 1.765 f 0.003 A. The average carbon-carbon bond d i s t a n c e i s 1.524 2 0.006 A f o r carbon-carbon s i n g l e bonds, 1.384 f 0.006 A f o r carbon-carbon double bonds I n t h e benzenoid r i n g , and 1.505 k 0.005 A f o r carbon-carbon bonds i n v o l v i n g C(9) and t h e benzenoid r i n g . The mean value o f t h e nitrogen-carbon bond distance i s 1.488 2 0.006 A. Each c h l o r i d e i o n i s associated w i t h t h r e e hydrogen bonds; one l i n k s t o a quaternary ammonium i o n and t h e other two l i n k t o two d i f f e r e n t water molecules. The packing o f t h e molecules i n t h e c r y s t a l i s determined by t h e h y d r o g e n b o n d i n g and v a n d e r W a a l s i n t e r a c t i o n s . Table 1 demonstrates t h e f r a c t i o n a l atomic coordinates and t a b l e 2 shows t h e bond lengths and bond angles. Conformation angles w i t h i n t h e
METHlXENE HYDROCHLORIDE
323
p i p e r i d y l r i n g are presented i n t a b l e 3 . Hydrogen-bond distances and angles are reported i n t a b l e 4 . Table 1: F r a c t i o n a l Atomic Coordinates (6). Atom
Y
X
(X
Atom
2
Y
X
lo))*
(X
2
103)
Cl
5563 ( 1 )
7272 ( 1 )
280 ( 1 )
485
-37
170
9
3807 ( 1 )
1811 ( 1 )
4625 ( 1 )
461
-281
23 1
N
6622 ( 2 )
4671 ( 3 )
1186 ( 1 )
424
-316
399
C(1)
4642 ( 3 )
-811
(5)
2438 ( 3 )
38 1
-123
484
C(2)
4557 ( 3 )
-2013
(5)
2776 ( 4 )
249
396
452 333
C(3)
4268 ( 3 )
-2251
(6)
3668 ( 5 )
185
557
C(4)
4054 ( 3 )
-1077
(6)
4244 ( 4 )
249
557
183
C(5)
2757 ( 3 )
4023 ( 5 )
3917 ( 3 )
366
41 1
151
C(6)
2413 ( 3 )
4983 ( 5 )
3222 ( 4 )
463
212
197
C(7)
2735 ( 3 )
4978 ( 5 )
2321 ( 3 )
587
204
313 377
C(8)
3410 ( 2 )
4052 ( 4 )
2128 ( 3 )
527
313
C(9)
4550 ( 2 )
2140 ( 4 )
2647 ( 2 )
529
477
237
C(11)
4431 ( 2 )
600 ( 4 )
2998 ( 3 )
692
423
349 377
C(12)
4128 ( 2 )
337 ( 5 )
3903 ( 3 )
620
528
C(13)
3427 ( 2 )
3067 ( 4 )
3720 ( 3 )
646
686
244
C(14)
3779 ( 2 )
3103 ( 4 )
2822 (31
739
858
303
C(15)
5410 ( 2 )
2793 ( 4 )
3129 ( 3 )
757
615
136
C(16)
5782 ( 2 )
4079 ( 4 )
2592 ( 3 )
777
472
198
C(17)
6468 ( 3 )
4919 ( 5 )
3234 ( 3 )
662
278
190
C(l8)
6908 ( 3 )
6091 ( 5 )
2659 ( 4 )
570
306
121
C(l9)
7302 ( 3 )
5457 ( 5 )
1794 ( 4 )
652
355
-3
C(20)
6189 ( 2 )
3497 ( 4 )
1704 ( 3 )
739
335
43
C(21)
6992 ( 3 )
4062 ( 6 )
291 ( 4 )
731
480
0
O(W)
3860 ( 3 )
9389 ( 4 )
454
872
6
409
1045
-9
H(N)
618
544
-172 93
(3)
The c o n f i g u r a t i o n o f a m e t h i x e n e h y d r o c h l o r i d e monohydrate m o l e c u l e and t h e i d e n t i f i c a t i o n o f t h e atoms are shown i n f i g . 1. The t o r s i o n angles and t h e molecular packing diagram are presented i n f i g . 2 and 3 r e s p e c t i v e l y . The o r i e n t a t i o n o f t h e p i p e r i d i n y l
EZZAT M. ABDEL-MOETY ET AL.
324
-
Fig. (1). The configuration of methixene HC1 molecule.
Fig. (2). The structure of one asymmetric unit of methixene hydrochloride.
METHIXENE HYDROCHLORIDE
325
methyl group r e l a t i v e t o t h i o x a n t h e n e r i n g i s a l s o shown in f i g . 4. Table 2: Bond lengths and bond angles ( w i t h estimated standard d e v i a t i o n s i n Darentheses) (6)
C(12) C(13) -N C(19) -N C(20) -N C(21) C(l)-C(2) C(l)-C(ll) C ( 2 1-C ( 3 C( 3 1-c (4) C(4)-C(12) C( 5 )-C( 6 1 C(5)-C(13) C ( 6 1--C ( 7 ) C(7 )-C(8) C ( 8 )-C ( 1 4) C(9)-C(ll) C(9)-C( 14) C(9 1-C( 1 5) C(ll)-C(12) C( 13)-C( 14) C( 15)-C ( 16) C(16)-C(17) C(16)-C(20) C( 17 )-C( 18) C( 18)-C( 19) c ( 1 2)-s-c ( 1 31 C( 19)-N-C(20) C(19)-N-C(21) C(20)-N-C(21) C(2)-C(l)-C(ll) S-
-S
1.769 1.761 1.485 1.492 1.487 1.371 1.403 1.364 1.391 1.381 1.374 1.391 1.380 1.378 1.380 1.502 1.508 1.546 1.393 1.397 1.524 1.526 1.521 1.523 1.502 100.5 111.9 111.2 110.8 120.8
(3) A C(l)--C(2)-C(3) (3) C(2)-C(3)-C(4) C(3)-C(4)-C(12) (6) (5) C ( 6 )-C ( 5 >-C ( 1 3 ) (6) C(5)-C(6)-C(7) C(6)-C(7)-C(8) (7) C(7)-C(8)-C(14) (6) (8) C(ll)-C(9)-C(14) C( 1 1 )-C(9)-C ( 15) (7) C(14)-C(9)-C(15) (6) (6) C(l)-C(ll)-C(9) (6) c ( 1 )-c ( 1 1 1-c ( 12) C(9)-C(ll)-C(12) (6) -S C( 12)-C(4) (6) -S C(12)-C(11) (5) C(4)--C(l2)-C(ll) (5) -S C(13)-C(5) (5) SC(13)-C(14) (5) c ( 5)-c ( 1 3 1-c ( 14) (5) (5) C ( 8)-C ( 1 4)-C ( 9) (5) C(8)-C(14)-C(13) (5) C(9)-C(l4)-C(13) (5) C(9)-C(15)-C(16) C(15)-C(16)-C(17) (7) (7) C(15)-C(16)-C(20) (2) C(17)-C(16)-C(20) C(16)-C(17)-C(18) (3) C(17)-C(18)-C(19) (3) (4) -N C( 19)-C( 18) N----C(20)-C(16) (4)
120.4 120.5 119.5 120.5 119.2 120.5 121.3 112.0 110.0 110.9 121.1 118.2 120.7 118.8 120.5 120.8 118.3 121.4 120.4 122.3 118.0 119.7 115.1 111.6 108.8 109.3 111.1 111.9 110.2 112.5
(5)A
(5)
(4) (4) (4) (4) (4) (3)
(3)
(3) (3) (3) (3) (3) (3) (4) (3) (3) (4) (3) (3) (3) (3) (3) (3) (3)
(4) (4) (4) (3)
326
EZZAT M. ABDEL-MOETY ET AL.
F i g . ( 3 ) . The t o r s i o n a n g l e s about t h e (a) C ( 1 9 ) - N , C ( l S ) and (c) C ( 1 5 ) - C ( 1 6 ) bonds.
-
F i g . ( 4 ) . The mol e c ula r packing diagram o f methixene hvdrochloride.
(b) C ( 9 ) -
METHIXENE HYDROCHLORIDE
321
Table 3: Conformation angles* w i t h i n t h e D i D e r i d v l
rins
C(16) C(17) C(18) C(19) N C(20)
- C(17)
- C(18) - C(19) -N - C(20) - C(16)
-t
52.9
- 55.5 -t
56.6
-t
56.1
- 56.8 - 53.9
*The conformation angle o f a d i r e c t e d bond C(17) C(18) i s d e f i n e d as t h e angle t h a t t h e p r o j e c t i o n o f t h e bond C(16) - C ( 1 7 ) makes w i t h r e s p e c t t o t h e p r o j e c t i o n o f t h e bond C(17) - C(18). The angle i s p o s i t i v e i f i t i s measured clockwise. Table 4: Hydrogen-bond d i s t a n c e s and angles.
N N 0
c1 c1 c1
c1
c1 c1 c1 N N N 0
0 Ma)* O(a) C(19) C(20) C(21) C1 (a)
0.051 A 3.051 3.280 3.051 3.051 3.051 3.280
3.280 A 3.203 3.203
3.203
157.5" 128.0 68.7 100.9 120.6 100.6 116.6
EZZAT M. ABDEL-MOETY ET AL.
328
3.
PHYSICAL CHARACTERISTICS Elemental Commsition
3.1
Element
Methixene
Methixene.HC1
[Calculated]
(%I
H
77.62 7.49
S
4.53 10.36
C
-
c1 N
3.2
69.38 6.94 10.26 4.05 9.37
M e l t i n g Range and B o i l i n g P o i n t M e l t i n g range, " C
Methi xene Methixene.HC1
215-217 ( 1 )
B o i l i n g p o i n t , 'C 171-175 ( 0 . 0 7 (1)
W II
Hg)
-
215-216 ( 2 ) 213-217 ( 3 ) 211-213 ( 4 )
3.3
Thermal Behavior ( 7 )
The d i f f e r e n t 5 a1 scanning c a l o r i m e t r y (DSC) thermal curve f o r methixene hydrochloride i s shown i n f i g . 5. The scanning has been r u n a t a r a t e o f 10°C m i n - l from 180 t o 2 5 0 ° C . The h y d r o c h l o r i d e s a l t o f methixene m e l t s a t 2 1 7 . 1 " C w i t h AH-value o f 3 4 . 7 Kj.mo1-1 f o r 9 9 . 4 4 mol% p u r i t y . A Dupont TA-9900 Thermal Analyzer attached t o a Dupont Data U n i t were used f o r t h e DSC-running.
Comment: 0.50:
r2!:.c
'.
I
'.
0.00-
-216.5
Y
.'
-0.50'
-216.0
ub "A
-1.00-
n.
-pi.so -
J
- 215.5
A
'1 I
-
L
I1
u
\
'J:
r
A
m
L-2.50U
a
-
I u-3.00-
-3.50-4.00-
,
a
I
-2.00-
?a
X r. O
rn
u
Purity : Melting P t : Depression : Delta H : Correction : H o l . HElghl: C e l l Const : Onset Slope:
99.45 Hole X 216.9 .C 0.33 'C
33.4 k J / m O l E 6.73 X 345.9 p/Hole 1.191
-215.0 L 7
*
-214.5
A.
Fi,D 7&
El
- A A
-214.0
A 0
u
A
a
- 213.5
-i.ii m W ' c
-213.0
b
t
;.
1EO
0
,
190
:
1
5
200
,:
10
210
.
, ' . I '5 ,
220
,v
n
. I
1.0 ta 1 Area,'Per t I a 1 A r e a
-4.50-
-u -
\
230
:
20
240
250
-212.5
b-
EZZAT M. ABDEL-MOETY ET AL.
330
45
20
Fig. (6). X--ray diffraction lines of methixene hvdrochloride.
0
METHIXENF.HYDROCHLORlDE
3.4
33 1
Solubility
While t h e methixene base i s water i n s o l u b l e , i t s hydrochloride s a l t i s s o l u b l e i n water, alcohol and chloroform b u t i n s o l u b l e i n e t h e r (1-4). 3.5
Crystallographic Characteristics 3.51
Crystallization
Methixene h y d r o c h l o r i d e c r y s t a l l i z e s as w h i t e f l a k e s f r o m e t h e r , mp. 215-217°C ( 1 ) o r f r o m alcohol-ether (1:2, v/v), mp. 211-213°C. 3.52
X-Ray D i f f r a c t i o n P a t t e r n ( 7 )
The X-ray d i f f r a c t o m e t r y o f methixene.HC1 has been undertaken on a P h i l i p s PW-1710 d i f f r a c t o m e t e r w i t h s i n g l e c r y s t a l monochromator and copper Ka r a d i a t i o n . The p a t t e r n s were recorded on a P h i l i p s PM-8210 p r i n t i n g recorder. The t a b l e o f 26, d-spacing (A), and count were a u t o m a t i c a l l y o b t a i n e d on a P h i l i p s d i g i t a l p r i n t e r , t a b l e 2 showing t h e c o l l e c t e d data i n summarized form. Fig. 6 shows t h e c h a r a c t e r i s t i c p r i n c i p a l l i n e s o f t h e X-ray powder d i f f r a c t i o n c a r r i e d out on a pure sample o f methixene.HC1 s a l t .
3.6
Spectroscopic Data 3.61
U l t r a v i o l e t (UV) AbsorPtion ( 8 )
The U.V. measurement has been c a r r i e d o u t f o r methixene h y d r o c h l o r i d e s o l u t i o n s i n 95% e t h a n o l , water and 0.1 N HCl against t h e corresponding blank u t i l i z i n g matched 1-cm quartz c e l l s . The A ( l % . , 1 cm)v a l u e s and t h e molar a b s o r p t i v i t i e s o f methixene hydrochloride s o l u t i o n s are c o l l e c t i v e l y summarized i n t a b l e 6. Figure 7 demonstrates t h e UV-spectra o f t h e d r u g substance in d i f f e r e n t solvents. The s p e c t r a scanning has been undertaken on a Varian DMS 90 1-cm quartz c e l l s .
332
EZZAT M. ABDEL-MOETY ET AL.
I
20 0
N/10 HC1
i0
F i g . ( 7 ) . UV s p e c t r a o f methixene HC1 i n d i f f e r e n t solvents.
333
METHIXENE HYDROCHLORIDE
Table 5: The X-ray d i f f r a c t i o n a l p r i n c i p a l l i n e s methixene hydrochloride. d(R)
26
3.197 6.332 11.568 12.733 13.607 15.081 16.519 17.414 17.931 19.196 19.907 20.460 21.372 22.675 23.281 23.798 24.510 25.279 25.718 26.524 27.439 28.448 29.883 30.668 31.639
2@
d(A)
[I/Io x 1001
87.8 50.2 54.6 97.1 16.5 25.8 52.9 31.3 61.6 72.2 39.9 28.8 61.6 48.5 34.5 24.5 100.0 18.3 35.3 53.3 53.4 9.3 8.1 28.6 7.5
32.496 33.535 33.867 34.598 34.979 35.203 36.190 36.651 37.759 38.505 38.907 39.415 40.280 41.151 41,755 42.855 44,250 45,445 46.462 47.401 48.446 48.935 51.136 51.663 52.48
2.7553 2.6722 2.6468 2.6925 2.5652 2.5493 2.4821 2.4518 2.3824 2.3380 2.3147 2.2861 2.2389 2.1936 2.1632 2.1102 2.0469 1.9958 1.9544 1.9179 1.8789 1.8613 1.7862 1.7692 1.7508
13.5 9.6 7.4 10.3 11.3 15.1 8.3 10.6 9.4 7.0 6.4 5.3 10.8 8.9 15.6 8.7 8.0 5.8 7.1 6.5 6.8 6.0 5.1 5.4 7.6
27.6380 13.9593 7.6496 6.9519 6,5072 5.8746 5.3664 5.0924 4.9468 4.6234 4.4600 4.3407 4.1574 3.9213 3.8207 3.7388 3.6319 3.5230 3.4639 3.3605 3.2504 3.1374 2.9899 2.9029 2.8279
Table 6:
Solvent
The UV-spectral c h a r a c t e r i s t i c s o f methlxene hydrochloride. Xrnax
95% ethanol Water 0.1 N HC1 +
[I/Io x 1001
(nm)
268 266 267
A(l%,
1 cm) 316 324 325+
reported a t 268 nm as 324 (3).
E
(l.mo1-1.cm-1)
10930 11194 11241
334
EZZAT M. ABDEL-MOETY ET AL.
Other reported UV-data i n o t h e r solvents (9) are a l s o as follows:
Sol vent. Acetonitrile Chl o r o f arm
3.62
Xmex 390 385
A(t%,
1 em)
€(~.mol-l.cm-l)
215.6 89.7
7458 3105
I n f r a r e d ( I R ) SDectroscoDy (8)
The IR-spectrum o f methixene h y d r o c h l o r i d e as K B r - d i s c was made on a P e r k i n Elmer i n f r a r e d spectrometer. F i g u r e 8, shows t h e o b t a i n e d IR-spectrum, w h i l e t a b l e 7 i l l u s t r a t e s t h e s t r u c t u r a l assignments w i t h t h e recorded frequencies. Table 7:
The I R - c h a r a c t e r i s t i c s o f methixene hydrochloride.
Frequency*, cm-
Group assignment
2950-2880 ( s ) 2480 (m) 1600-1680 ( W) 1460 (s) 1350-1 220 760 ( s )
CH3 ,CH2 ,CH s t r e t c h i n g HN+ , s t r e t c h i n g HN+ CHz ,-CH3 , CH-def ormat ion S-C s t r e t c h i n g . CHz, rocking.
*s, m & w means strong, medium and weak, respectively. 3.63
Mass S D e c t r m e t r v (US) ( 8 )
The mass spectra o f methixene i s i l l u s t r a t e d i n f i g u r e 9, where a base peak appears a t m/e 197 due t o Ci3HioS i.e., t h i o x a n t h e n e . The mass spectrum o f methixene i s s a i d t o provide a s e n s i t i v e and s p e c i f i c mean f o r i d e n t i f i c a t i o n and q u a n t i f i c a t i o n i n i n pharmaceutical f o r m u l a t i o n . The mass f r a g m e n t a t i o n p a t t e r n f o r methixene i s shown i n t a b l e 8.
T R A N S M I T T A N C E
I
i?
0
0
u3
0 0 0 4
0
L n
0 4
0 0
0
hl
0 0 0 M
0
0
e
0
V
vr
.d
k
a
M
vr
Ld cd Q,
a
0
k
.r(
A
k
5 0 a > .c
a,
x
a,
E
.d
E
5 a, 0
w
cd k
V
c, a,
z
a a, k cd
k
H
F:
ru
c. W v
M L
.d
F
197 /
100
0
'
309
\
165
-
0
40
210 /
rn e
Fig.
(9).
Mass spectrum o f methixene.
235
0
337
METHIXENE HYDROCHLORIDE
Table 8:
Empirical structure
Mass fragmentation o f methixene.
Mass/charge r a t i o (m/e)
[Io/I
C5H10
44 58 58 70
68 72 72 8
CsHi oN
84
10
CsHi 3 N
99
66
C3 Ha C4H10
C3 H i NH
C7H15N
C2oH23NS
112
20
210
14
197
100
309
38
(%)I
Fragment i o n CH3 CH2 CH3 CH3 (CH2 CH3 (CH2
) 2 CH3 2 NH
CH3 (CH2 1 4 - 1
C
N-CH,
M+
EZZAT M. ABDEL-MOETY ET AL.
338
3.64
Nuclear Magnetic Resonance (NMR)
Both t h e p r o t o n n u c l e a r magnetic resonance (1H-NMR) and c a r b o n n u c l e a r m a g n e t i c resonance (13C-NMR) spectra o f methixene hydrochloride have been run on the same s o l u t i o n i n CDC13. 3.641 lH-NHR SDectrurn (8)
The 200 MHz proton magnetic resonance spectrum o f methixene hydrochloride i s given i n the f i g u r e 10 w h i l e Table 9 summarizes t h e chemical s h i f t and s p e c t r a l assignments o f t h e p r o t o n s o f methixene h y d r o c h l o r i d e . The r u n n i n g o f t h e s p e c t r a was undertaken i n CDCl3 using TMS as an i n t e r n a l standard on a V a r i a n XL-200 s p e c t r o m e t e r a t a m b i e n t temperature. Table 9: Chemical s h i f t s and spectral assignments o f 'H-NMR o f methixene hvd rochl o r ide
1 oCH,
5
~~~~
~~
~
4
~
Drug
Proton p o s i t i o n (Nr)
Methixene.HC1
aromatic; 1-8 ( 8 ) CHBN; 13 ( 3 ) CHz; 12,14-16 ( ) C H 2 ; 10 (2) CH; 9 ( 1 ) +NH (1)
(ppm, TMS)
Multiplicity
7.2-7.6 2.8-2.6 2.2-1.9 3.5-3 4.2-4.1 > 12
m S
m m S
M
I+
E
V n V a,
.r(
a 0
k
.d I+
k
0
5 x
a
c x
a, E a, .d
5 a, E
0
'U
cd k
a,
0
c,
2 p:
k
d
0
M L
.d
EZZAT M. ABDEL-MOETY ET AL.
340
3.642 'SC-NMR
Swctrun ( 8 )
The lJC-nuclear magnetic resonance spectrum o f methixene h y d r o c h l o r i d e was o b t a i n e d i n C D C l s a t ambient temperature using TMS as t h e i n t e r n a l standard on a Varian XL-200 spectrometer. The chemical s h i f t s , and s p e c t r a l assignments are given i n t a b l e 10, w h i l e Figure shows t h e obtained 13C-NMR spectrum. The DEPT and APT spectra o f methixene hydrochloride are given i n f i g u r e s (11-14). Figure 15 shows t h e HOMCOR (pulse seqence 1 H-1 H-NMR) spectrum o f t h e drug substance.
7
4
Table 10: Chemical s h i f t s and s p e c t r a l assignments o f 13C-NMR o f methixene hydrochloride. ~~
Carbon pos it i on
,
c2 3 , B , 9
c5,13 c6,11 c1,4,10,7 c12 c14
c19 c15 c20
c16
c17 C18
Chemical s h i f t (6, ppm) 128.84 132.1 137.24 128.9 46.2 22.54 32.04 59.3 43.96 54.5 28.6 35.8
Fig. (11) 13C-N&lR
s p e c t r a o f methixene HC1 in CDC13.
W
ti
F i g . ( 1 2 ) . 13C-NMR spectra of methixene HC1 in CDC1, (APT Program).
7 U Sec.
' 4 ' 4
e
Fig. (13).
15
C-NMR spectra of methixene HC1 in CDC13 (continuation of fig. 14).
CH3
CH2
Fig. (14). 13C-NMR s p e c t r a of methixene HC1 i n CDCl
3
(DEPT Program).
METHIXENE HYDROCHLORIDE
345
0
1 2 3 4
5
6 7
a 9 10 11
1
12
I
1
1 2 1 1 1 0 9
8
I
I
,
1
7
1
6
1
5
1
4
1
3
1
2
1
1
1
0
PPM
F i g . (15). HOMCOR ( p u l s e sequence 'H-lH-NMR) methixene h y d r o c h l o r i d e .
spectrum of
EZZAT M. ABDEL-MOETY ET AL.
346
4.
SYNTHESIS
Methixene and i t s s a l t s have been t o t a l l y s y n t h e s i z e d from prepared 9 - t h i o x a n t h y l sodium and N-methyl-3-chloromethylpiperidine by j u s t condensation. a n t h e s i s o f 9-thioxanthyl sodium: (Scheme I) To 4.9 p a r t s o f f i n e l y p u l v e r i z e d sodium i n 50 p a r t s o f abs. benzene add dropwise w i t h s t i r r i n g 12 p a r t s o f chlorobenzene i n 50 p a r t s o f absolute benzene. As soon as t h e exothermic r e a c t i o n begins, m a i n t a i n t h e temperature by c o o l i n g between 30°C and 3 5 " C , and continue s t i r r i n g f o r 2 t o 3 hours. To t h e r e s u l t i n g phenyl sodium add dropwise 19.8 p a r t s o f thioxanthene i n 120 p a r t s o f a b s o l u t e benzene. The s l i g h t l y exothermic r e a c t i o n ceases a f t e r about 1 t o If hours (10). PreDaratlon o f N - m e t h ~ l - 3 - c h l o r o m e t h ~ l ~ i p e r i (Scheme 11) 3 - P y r i d i n e methanol y i e l d s on r e a c t i o n w i t h methyl i o d i d e t h e quaternary s a l t ; which on h y d r o g e n a t i o n g i v e s t h e corresponding N-methy l -3 -p i p e ri d i n e methanol. T h i o n y l c h l o r i d e c o n v e r t s t h e a l c o h o l t o t h e e q u i v a l e n t N-methyl-3chloromethylpiperidine (4).
dine:
Coupling o f 9-thioxanthyl sodium w i t h N-methyl3 - c h l o r o r n e t h y l ~ i ~ e r i d n e : To t h e f r e s h l y p r e p a r e d 9-thioxanthyl sodium add dropwise, w i t h s t i r r i n g and c o o l i n g , 131.1 p a r t s o f N-methyl-3-chloromethylpiperid i n e i n 30 t o 40 p a r t s o f a b s o l u t e benzene, t h e n continue s t i r r i n g a t about 25°C f o r If hours, and heat subsequently t o 40°C. Decompose t h e r e s u l t l n g m i x t u r e by adding c a r e f u l l y a small amount o f water, and then e x t r a c t t h e newly formed base from t h e benzene s o l u t i o n by means o f d i l u t e h y d r o c h l o r i c a c l d . The aqueous h y d r o c h l o r l c s o l u t i o n i s made a l k a l i n e by adding d i l u t e sodium hydroxide, and t h e methixene base i s i s o l a t e d by e x t r a c t i o n w i t h ether. This r e s u l t s i n 22 p a r t s o f a s l i g h t l y yellow, viscous base o f BP 171 t o 175'C (10.07 mm.Hg). The base i s a c i d i f i e d w i t h a l c o h o l i c h y d r o c h l o r i c acid. Alcohol-ether (1:2) i s then added and hydrochloride s a l t i s r e c r y s t a l l i z e d as white f l a k e s m e l t i n g a t 211 t o 213°C (11).
a,
c E
N
a,
z
a,
e
ocd
c I
M N
U
v
0
ln I
M 0
M
U
+
3
z a, E a,
x
.I+
c E
a,
+J
348
EZZAT M. ABDEL-MOETY ET AL
Synthesis (Scheme 11)
CH3 I U C H 2 O H
+
QCH2OH
I CH3
3 - Pyridine methano 1
1
I+ @ : ! 9-Thioxanthyl sod.
Hydrogenat ion
N-methyl-3-piperidine met h an o 1
G
N-CH,.
HCI
PCH3 - Qjn alc. HC1
Methixene HC1. Met hixene
METHIXENE HYDROCHLORIDE
5.
349
METHODS OF ANALYSIS
Qualitative (Identification)
5.1
5.11
Color Tests ( 4 )
Some s p e c i f i c reagents g i v e c e r t a i n c o l o r a t i o n w i t h methixene and i t s HC1-salt. The f o l l o w i n g common c o l o r reagents are recommended f o r i d e n t i f i c a t i o n o f t h e drug. Reagent HCHO-H2 so4 L iebermann ’ s Mandelin’s H2 SO4
5.12
Color orange red orange orange orange ( f l u o r e s c e s under UV) M i c r o c r y s t a l Test
The aqueous s o l u t i o n o f methixene hydrochloride has been subjected t o some o f t h e most common reagents f o r m i c r o c r y s t a l l i z a t i o n examination. Only t h e aqueous s o l u t i o n o f ZnCl2 (5% w/v) y i e l d s c l e a r r o s s e t t e s a f t e r about 15 min. The f o l l o w i n g f i g . 16 shows t h e c r y s t a l shapes on r e a c t i n g t h e d r u g w i t h t h e p r e c i p i t a t i n g reagent.
Fig. 16: Microscouic examination o f d i f f e r e n t c r y s t a l forms obtained from r e a c t i n g methixene.HC1 w i t h ZnC12 solution.+ + t r a c i n g has been undertaken by using a L e i t z Camera Lucida (x attached t o a L e i t z p r o j e c t o r ; t h e stage scale micrometer was u t i l i z e d under t h e same m a g n i f i c a t i o n (8).
EZZAT M. ABDEL-MOETY ET AL
350
5 2
Q u a n t i t a t i v e (Determi n a t i o n ) 5.21
C o l o r i m e t r i c Determination
Wa'lash e t 87. ( 9 ) have presented a c o l o r i m e t r i c method f o r t h e q u a n t i t a t i v e determination o f methixene alongwith other thioxanthene d e r i v a t i v e s . A weighed amount o f powdered t a b l e t s (about 25 mg) was e x t r a c t e d 3 x 15 m l chloroform i n t o a 50-ml volumetric flask. An a l i q u o t o f the chloroform e x t r a c t equivalent t o 100-400 c(g o f t h e d r u g was p i p e t t e d i n t o a 10 m l f l a s k , evaporated t o dryness and t h e residue dissolved i n 2 m l a c e t o n i t r i l e followed by 1 m l tetracyanoethylene (0.2%) reagent and t h e mixture was d i l u t e d with 5 m l a c e t o n i t r i l e , heated a t 80'C i n water bath f o r 5 m i n u t e s , c o o l e d and c o m p l e t e d t o volume w i t h a c e t o n i t r i l e and absorbance was measured a t 390 nm. against a blank. 5.22
Fluorometric Determination
Hassan e t a7. (12) have presented a f l u o r o m e t r i c method f o r t h e determination o f methixene i n pure and dosage forms. The method i n v o l v e s t h e use of t h e hexamine-cobalt (111) t r i c a r b o n a t o c o b a l t a t e (111) (HCTC) as an oxidant i n aqueous s u l p h u r i c medium t o induce fluorscence. Sample PreDaration Stock s o l u t i o n (1.0 mg/ml) o f t h e methixene i n d l s t i l l e d water was f u r t h e r d i l u t e d w i t h aq. s u l p h u r i c a c i d (20% v/v) t o contain 1 pg o f t h e analyte per m l . Procedure f o r Authentic SamDle T r a n s f e r a 7 i q u o t s o f methixene h y d r o c h l o r i d e s o l u t i o n t o cover t h e concentration range (0.04-0.64 pg/ml), t o 25 m l volumetric f l a s k s , d i l u t e w i t h 5 m l o f aqueous s u l p h u r i c a c i d (20% v / v ) , add 0.1 m l o f HCTC s o l u t i o n ( 5 x M), then d i l u t e t o mark w i t h aqueous s u l p h u r i c a c i d . Leave f o r t h r e e minutes t o complete the reaction. The fluorescence was a t X m a x (368 nm) ( e x c i t a t i o n ) and X m a x (545 nm) (emission), where t h e concentration was read from t h e c a l i b r a t i o n graph.
METHIXENE HYDROCHLORIDE
3s I
Procedure f o r t h e Dosane Forms T r a n s f e r a weighed amount o f t h e powdered t a b l e t s equivalent t o 30 mg o f t h e drug, i n t o a small c o n i c a l f l a s k . E x t r a c t 3 x 30 m l d i s t . H20. Transfer t h e s o l u t i o n t o a 100 m l volumetric f l a s k and d i l u t e w i t h H20. Further d i l u t e t h i s s o l u t i o n w i t h aq. H2S04 (20% v/v) t o give an analyte concentration o f % l pg/ml and analyse as f o r t h e authentic sample. 5.23
T i t r i m e t r i c Determination
B e l a l e t a l . ( 1 3 ) have presented a t i t 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 o f m e t h i x e n e h y d r o c h l o r i d e . I n t h e procedure HCTC i s used as a t i t r a n t w i t h v i s u a l d e t e c t i o n o f t h e end p o i n t using f e r r o i n as an i n d i c a t o r ( t h e complete disappearance o f orange c o l o r ) . El-Brashy (14) has reported an i n d i r e c t method f o r t h e determination o f methixene i n pure and dosage forms. The procedure involves t h e preparation o f a 1.0 mg/ml s o l u t i o n o f methixene i n 3 M HC1. Add an a l i q u o t o f t h e s o l u t i o n t o a known volume o f 0 . 0 0 5 M 2-iodylbenroate s o l u t i o n i n a glass stoppered Erlenmeyer f l a s k . Shake t h e mixture o c c a s i o n a l l y and a f t e r 15 m i n u t e s add 10 m l o f 100 mg/ml potassium i o d i d e s o l u t i o n and t i t r a t e t h e l i b e r a t e d i o d i n e w i t h 0.02M sodium t h i o s u l p h a t e , using s t a r c h as i n d i c a t o r . Repeat t h e experiment without methixene. The amount o f t h e drug was c a l c u l a t e d from t h e f o l l o w i n g equation.
where VI and V 2 a r e t h e volumes o f t h i o s u l p h a t e s o l u t i o n ( m l ) used i n t i t r a t i o n o f t h e b l a n k and sample r e s p e c t i v e l y . R i s t h e molecular weight o f t h e drug and M i s t h e m o l a r i t y o f t h e t i t r a n t . For t h e assay o f t h e drug i n dosage forms, e x t r a c t a weighed amount o f t h e p u l v e r i z e d t a b l e t s equivalent t o 100 mg o f t h e drug 3 x 20 m l o f 3M HC1. F i l t e r t h e combined e x t r a c t s i n t o a 100 m l standard f l a s k and d i l u t e t o volume w i t h t h e used solvent. Transfer an a c c u r a t e l y measured volume o f t h i s s o l u t i o n ; equivalent t o 5-12 mg o f t h e drug, i n t o i o d i n e f l a s k and proceed as described above.
EZZAT M. ABDEL-MOETY ET AL.
352
5.24
Chromatographic Techniques 5.241
4 (15)
Thin layer chromatography o f methixene has been done w i t h the f o l l o w i n g conditions: Adsorbent: Precoated s i l i c a gel f 2 5 4 (E. Merck). Developer: Methanol t 25% aq. ammonia (110:1.5, v/v). Detection: Dragendorff’s reagent. Reference substance: Bupranolol (relative-Rr: 1.05). 5.242 Gas L i a u i d Chromatography (GLC) ( 1 5 )
Some GLC systems and conditions f o r t h e analysis o f methixene hydrochloride are presented i n t a b l e 11. 5.243 High Performance L i a u i d Chromatography
(HPLC)
I s o c r a t i c multi-column HPLC as a technique f o r t h e q u a t i t a t i v e a n a l y s i s o f t h e d r u g w i t h some phenothiazines have been reported (16). 6.
PHARMACOKINETICS 6.1
m o m t i o n and Excretion
Methixene s a l t i s water s o l u b l e and can be e a s i l y absorbed a f t e r o r a l administration. The drug i s excreted i n the urine, p a r t l y unchanged and mostly as f r e e o r conjugated metabol it e s [ 2 I . 6.2
Biotransformation
As most o f t h e thioxanthene s a l t s , methixene hydrochloride s u f f e r s from S-oxidation i n t o i t s two main i s o m e r l c s u l p h o x i d e s . Another p a r t o f t h e S - o x i d a t i o n products may be i n t h e form o f t h e N-demethylated methixene s a l t , i . e . normethixene sulphoxides. The f o l l o w i n g scheme i l l u s t r a t e s t h e metabolic transformation o f methixene. The bio-sulphoxidation o f methixene r e s u l t s i n the formation o f t h e monosulphoxide [ l , a ] ; which can be transformed t o the disulphoxide [ l , b l . Equivalent N-demethylation y i e l d s t h e corresponding normethixene,
G
G
N-CH,
N -CH,
Qj& 4
/
0
methixene
G
N-CH,
CH
/+ 0
0
Normethixene Extretion
d
-
Excretion (unchanged)
EZZAT M. ABDEL-MOETY ET AL.
354
which can be a l s o s u l p h o x i d i z e d t o t h e monoand/or t h e disulphoxide [2bl.
[2al
Table 11: Summary o f t h e GLC-conditions used f o r i d e n t i f i c a t i o n and determination o f methixene hydrochloride (15). Col umn
Temperatures
Reference substance
6 f t x 2 mm packed 3% OV-1 on Chromosorb W-HP 100-120 mesh.
150-25O'C with t h e rate of 1O'C min-1
2-Amino-5c h l orbenazophenone
1.67
6 ft x 2 mm packed 3% OV-17 on Chromosorb W-HP 100-120 mesh.
150-250 " C w i t h the rate o f 10°C min-1
Methaqualone
1.26
3 f t x 2 mm packed 3% OV-1 on Chromosorb W-HP 100-120 mesh.
200-280 " C with t h e rate o f 10°C min-1
Thioridazine
0.35
3 f t x 2 mm packed 3% OV-17 on Ch romosorb W-HP 100-120 mesh.
220-280 c with the rate o f 1O'C min-1
Thior i daz ine
0.42
* ** 7.
O
Re1a t i v e Rf
i n i t i a l time o f 1 min; detection w i t h PND a t 300°C. C a r r i e r gas i s N2 a t 50 rnl.min-1 other gases are a i r (120 ml.min-'1 and hydrogen ( 2 ml.min-1). THERAPEUTIC CATEGORATION
7.1
Pharmacology 7.11
G a s t r o i n t e s t i n a l T r a c t (GIT)
Methixene h y d r o c h l o r i d e i s an a n t i c h o l e n e r g i c agent t h a t may be e f f e c t i v e as an a d j u n c t i n t h e treatment o f g a s t r o i n t e s t i n a l hypermotil i t y and spasm associated w i t h f u n c t i o n a l bowel disorders. There i s
METHIXENE HYDROCHLORIDE
355
no evidence t h a t methixene hydrochloride s i g n i f i c a n t l y decrease g a s t r i c s e c r e t i o n ( 1 7 ) . Although methixene c o n t a i n s t h e same t h i o x a n t h e n e n u c l e u s a s chloroprothixene, a major t r a n q u i l i z e r . I t s pharmacological a c t i o n i s p r i m a r i l y a n t i c h o l e n e r g i c . I t has l i t t l e e f f e c t on CNS. Methixene d i l a t e s t h e p u p i l s and i n h i b i t s s a l i v a r y secreation t o a l e s s e r d e g r e e t h a n t h a t due t o a t r o p i n e . Results o f experiments i n several animal species i n d i c a t e t h a t methixene has an i n h i b i t o r y e f f e c t on g a s t r o i n t e s t i n a l motor a c t i v i t y , w i t h o n l y a minimal e f f e c t on g a s t r i c s e c r e t i o n o f h y d r o c h l o r i c acid. Methixene sometimes produces undesired e f f e c t s t y p i c a l l y o f t h e a n t i c h o l e n e r g i c drugs. Dryness o f t h e mouth, mydriasis c y d o p l e g i a , r a s h and u r i n a r y r e t e n t i o n have been noted, e s p e c i a l l y when l a r g e doses have been given. A l t h o u g h no t e r a t o g e n i c e f f e c t s have been demonstrated i n animal s t u d i e s , t h e p o s s i b i l i t y r i s k t o t h e f e t u s must be weighed a g a i n s t t h e expected t h e r a p e u t i c b e n e f i t s i f methixene i s considered f o r a d m i n i s t r a t i o n t o a pregnant woman. Also methixene i s c o n t r a i n d i c a t e d i n presence o f angl e-closure glucoma, py l o r i c o b s t r u c t i o n p r o s t a t i c hypertrophy, bladder-neck o b s t r u c t i o n o r eardiospasm (17).
The c h a r a c t e r i s t i c pharmacological a c t i v i t y o f t h e d r u g has been demonstrated i n mice, r a t s and g u i n e a p i g s . The r e l a t i v e p o t e n c y o f m e t h i x e n e hydrochloride compared w i t h a t r o p i n e w i t h t h e respect t o e f f e c t on g a s t r o i n t e s t i n a l m o t i l i t y v a r i e s from 1.0 t o 2.2 (when assayed i n t h e mouse f o r i n h i b i t i o n o f chareoal passage) t o 1.0 t o 1 6 . 7 f o r i n h i b i t i o n o f t h e p e r i s t a l t i c r e f l e x i n guenia p i g s . However, i n t h e i n h i b i t i o n o f s a l i v a t i o n a t r o p i n e i s 32 t i m e s as potent i n t h e mouse, 6 4 . 5 times as potent i n guenia p i g and 87 times as potent i n t h e r a t . I n rnydriatic a c t i v i t y i n mouse, a t r o p l n e is 20 t i m e s as p o t e n t as methixene h y d r o c h l o r i d e . Thus s t u d i e s i n e x p e r i m e n t a l animals i n d i c a t e t h a t t h e parasympatholytic a c t i v i t i e s o f methixene hydrochloride are r e l a t i v e l y greater w i t h respect t o i n h i b i t i o n o f g a s t r o i n t e s t i n a l m o t i l i t y than they are w i t h reference t o i n h i b i t i o n o f s a l i v a t i o n o r
EZZAT M. ABDEL-MOETY ET AL.
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p r o d u c t i o n o f a m y d r i a t i c e f f e c t . The dose t h a t r e 1i eve symptoms o f hypermot i1 it y in human b e i ngs might n o t produce t h e s i d e e f f e c t s commonly expected when t h e r a p e u t i c a l l y e f f e c t i v e dose o f p o t e n t sympatholytic agents are employed ( 1 8 ) . 7.12
Antiparkinsonism
I n t r a v e n o u s methixene h y d r o c h l o r i d e has been administered t o 48 p a t i e n t s s u f f e r i n g from a v a r i e t y o f neurological and p s y c h i a t r i c disorders. The r e s u l t s o f such a d m i n i s t r a t i o n i n d i c a t e t h a t methixene i s capable o f a c t i v a t i n g d i a g n o s t i c ECG abnormalities i n p a t i e n t s p r e s e n t i n g w i t h e p i l e p s y o f temporal l o b e o r i g i n . No a c t i v a t i o n o f t h e ECG was d e t e c t e d i n a p a t i e n t s w i t h organic b u t non-epl leptogenic disorders o f t h e c e n t r a l nervous system and i n 10 p a t i e n t s w i t h chronic p s y c h i a t r i c disorders. A l l o f whom has never been s u b j e c t t o e p i l e p t i c s e i z u r e s . The o n l y s i g n i f i c a n t s i d e - e f f e c t observed f o l l o w i n g t h e intravenous i n j e c t i o n o f methixene hydrochloride was appearance o f a m i l d c o r t i c o s p f n a l hemiparesis l a s t i n g f o r a p e r i o d o f 30-60 minutes i n one o f 2 p a t i e n t s l a t e r found t o have a cerebral tumour, m i l d dryness o f mouth and tongue was r e p o r t e d i n almost a l l t h e p a t i e n t s . A c a s e - r e p o r t o f a p a t i e n t w i t h temporal lobe epilepsy o f l a t e r ones was b r i e f l y reported. The o n l y abnormality discovered i n t h s p a t i e n t was i n t h e ECG a f t e r t h e a d m i n i s t r a t i o n o f drug; a t autopsy a s m a l l a s t r o c y t o m a was f o u n d n the epsilateral amygdala (19).
ACKNOWLEDGMENT The authors a r e h i g h l y t h a n k f u l t o M r . Tanvlr A. B u t t f o r t y p i n g t h e manuscript and M r . Osama Shabaan f o r drawing t h e s p e c t r a , b o t h from College o f Pharmacy, King-Saud U n i v e r s i t y , Riyadh, Saudi Arabia.
METHIXENE HYDROCHLORIDE
357
REFERENCES 1.
"Remington's Pharmaceutical Sciences", (16th, ed. ) , Mack P u b l i s h i n g Co. Easton, Pennsylvania 18042 (19801, p. 859.
2.
"Martindale, The E x t r a Pharmacopoea" (29th' ed. ) , The Pharmaceutical Press, London (19891, p. 539.
3.
"The Merck Index", ( l l t h , ed.), Merck and Co., Rahway, N.J., No. 392-d, p. 539 (1989).
4.
" C l a r k ' s I s o l a t i o n and I d e n t i f i c a t i o n o f Drugs" (2nd, e d . ) , The P h a r m a c e u t i c a l Press, London (19861, p. 151-752.
5.
"Index Nominum", Swiss Pharmaceutical Society. (19871, p. 695.
6.
S.C. Chu S h i r l e y ; Acta Cryst. (1972).
7.
R.R. Abu-Shabaan, Pharmaceutics Department, College o f Pharmacy, King-Saud U n i v e r s i t y , Personal Communication (1992).
8.
E . M . Abdel-Moety and N.A.
9.
M.I. Walash, M. R i z k and A . M . E l Brashy; Pharmazeutische Weekblad ( S c i e n t i f i c E d i t i o n l o : t3, 234-238 (1986).
(Sec. B):
Inc.,
Zurich
28, 3625-3633
Khattab; Unpublished data.
10.
J. Schmutz; U.S. Patent 2,905,590, (assigned t o t h e Wander Company).
11.
" P h a r m a c e u t i c a l M a n u f a c t u r i n g E n c y c l o p e d i a " , (M. S i t t i n g , Ed.), Noyes Data Corporation, Park Ridge N.J. (19791, p. 409.
12.
S.M. Hassan, F. B e l a l , F. I b r a h i m and f . A . Talanta: 3 6 ( 5 ) , 557-560 (1989).
13.
F. B e l a l , M . I . Walash, F.A. A l y ; Microchem. J.: 295-299 (1988).
14.
A.M.
El-Brashy;
September 22,
1959,
Aly; 38(31,
Talanta: 37f111, 1087-1090 (1990).
358
EZZAT M. ABDEL-MOETY ET AL.
15.
T. Daldrup, F. Susanto and P. M i l c h a l k e ; Fresenius’ 2 . Anal. Chem;. 308: 413-424 (1981).
16.
B.B. Wheals; J. Chromatow.: 187, 65-85 (1980).
17.
R . C a v i e z e l , E. E i c h e n b e r g e r , F. Kunzle and J. Schmutz; Pharm. Acta H e l v . : 33, 447-452 (1958).
18.
W.M. Abruzzi; The Journal o f New Drugs: M a r c h - A w i l , 109-113 (1965).
19.
C.J. Vas, K . A . Exley and M.J. Parsonege; EDeleDsia: 252-259 ( 1967).
8,
Ezzat M. Abdel-Moety, Nashaat A . Khattab. and Mohammad Saleem Mian
Pharmaceutical Chemistry Department College of Pharmacy King Saud University P.O. Box 2457 Riyadh 1 145 I , Saudi Arabia
ANALYTICAL PROFILES OF DRUG SUBSTANCES AND EXCIPIENTS-VOLUME 22
317
Copyright 0 1993 by Academic Press, Inc. All rights of reproduction in any form reserved.
EZZAT M. ABDEL-MOETY ET AL.
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CONTENTS 1. 2.
3.
4.
5.
6.
INTRODUCTORY DESCRIPTION 2.1 Nomenclature 2.11 Systemic Name 2.12 Other Chemical Names 2.13 P r o p r i e t a r y Names 2.14 CAS R e g i s t r y Number 2.2 Formulae and Molecular Weight 2.3 Appearance, Color and Taste. 2.4 The Cr ystal S t r u c t u r e and t h e Three-Dimensional Projection PHYSICAL CHARACTERISTICS 3.1 Elemental Composition M e l t i n g Range and B o i l i n g P o i n t 3.2 3.3 Thermal Behavior 3.4 Salubility 3.5 Crystallographic Characteristics 3.51 C r y s t a l 1i z a t i o n 3.52 X-ray D i f f r a c t i o n Pa t t e r n 3.6 Spectroscopic Data 3.61 U l t r a v i o l e t (UV) Absorption 3.62 I n f r a r e d ( I R ) Spectroscopy 3.63 Mass Spectrometry (MS) 3.64 Nuclear Magnetic Resonance (NMR) 3.641 1 H-NMR Spectrum 3.642 1JC-NMR Spectrum SYNTHESIS METHODS OF ANLAYSIS 5.1 Qualitative (Identification) 5.11 Color Tests 5.12 M i c r o c r y s t a l Test 5.2 Q u a n t i t a t i v e (Determination) 5.2 1 Col o r 1met r ic Determi n a t i o n 5.22 Fluorometric Determination 5.23 T it r imet r ic Dete r m i n a t ion 5.24 Chromatographic Techniques 5.241 Thin Layer Chromatography (TLC) 5.242 Gas L i q u i d Chromatography (GLC) 5.243 High-Performance L i q u i d Chromatography (HPLC) PHARMACOKINETICS 6.1 Absorption and E xcr etion 6.2 Biotr ansfor m ation
METHIXENE HYDROCHLORIDE
THERAPEUTIC CATEGORATION 7.1 Pharmacology 7 . 1 1 G a s t r o i n t e s t i n a l Tract ( G I T ) 7 . 1 2 Antiparkinsonism ACKNOWLEDGMENT REFERENCES 7.
319
EZZAT M. ABDEL-MOETY ET AL.
320
1.
INTRODUCTORY Methlxene h y d r o c h l o r i d e i s a t e r t i a r y amine antimuscarinic drug w i t h a r e l a t i v e l y h i g h s e l e c t i v i t y f o r t h e g a s t r o i n t e s t i n a l t r a c t . I t i s used i n t h e management o f c o n d l t i o n s i n w h i c h t h e r e i s h y p e r m o t i l i t y , as i n pylorospasm, b i l i a r y dyskinesia, s p a s t i c colon, duodenitis, and g a s t r i t i s and i n other disorders i n which i t i s d e s i r a b l e t o d i m i n i s h even normal m o t i l i t y , as i n duodenal u l c e r . I t does n o t d i m i n i s h g a s t r i c secretion. Although it i s recommended f o r use i n g a s t r i c u l c e r , a decrease i n m o t i l i t y can r e s u l t i n r e t e n t i o n o f a c i d and hence sometimes exacerbate t h e e r o s i v e process. I n c i d e n c e o f s i d e e f f e c t s i s low w i t h usual doses (1). The d r u g p o t e n t i a l l y has a l l t h e s i d e e f f e c t s o f antimusc a r i n i c s and t h e precautions and c o n t r a i n d i c a t i o n s a r e the same. I t i s a l s o mainly used f o r t h e symptomatic treatment o f a r t e r i o s c l e r o t i c , i d i o p a t h i c and p o s t e n c e p h a l i t i c parkinsonism. I t i s c l a i m e d t o be more e f f e c t i v e i n c o n t r o l l i n g t h e tremors ( 2 ) .
2.
DESCRIPTION 2.1
Nomenclature 2.11
Systemic Name (3)
M e t h i x e n e : l-Methyl-3-(9H-thioxanthen-9-y1met hy 11p i per id ine M e t h i xene hydroch1o r ide : 1-Methy 1- 3- ( 9H- t h i oxant hen-g- y 1-met hy 1) p i per id i ne monohydroch 1o r i de.
.
2.12
Other Chemical Names
Met h ixene is g- (N-me t hy 1-3- p i per idy 1methy 11t h ioxanthene ( 3 ) ; 9-(l-Methyl-3-piperidylmethyl)thloxanthene ( 4 ) ; (Methyl-l-piperidinyl-3-methyl)-9thioxanthene. 2.13
ProDrletary (Manufacturer) Name
T r e m o n i l ( S a n d o z , UK). methi xene hydrochloride 5 mg.
Tablets,
scored,
O t h e r P r o p r i e t a r y ( M a n u f a c t u r e r s ) names; Methyloxan (Jpn), T r e m a r l l (Sandoz, B e l g . , Denm.,
METHIXENE HYDROCHLORIDE
I t a l . , Neth., S. A f r . , Spain; Wander, Tremoquil (Astra, Swed.); T r e s t (USA) ( 2 ) .
32 1
Switz.);
Methixene Hydrochloride USAN S J 1977; A t o s i 1 (Teisan, Osaka, Jpn); C h o l i n f a l l (Tokyo Tanabe, Tokyo, Jpn); M e t h i x a r t (Fuso, Osaka, J p n ) ; Methyloxane (Nippon S h o j i , Osaka, Jpn); Raunans (Kowa Y., Tokyo, J p n ) ; Thioperkin (Hokuriku, Fukui , Jpn); Tremaril (Wander, B e l g . ; Sandoz, Denm., I t a l . 8, N e t h . ) ; T r e m a r i t (Wander, Ger.); Trernonil (Wander, Austral., Sandoz, UK); Tremoquil ( A s t r a ) , Swed.); T r e s t (Dorsey, USA)
(5). 2.14
Chemical Abstract Service (CAS) R e g i s t r y Number (3,4)
4969-02-2 (Methixene); 1553-34-0 (hydrochloride, anhydrous); 7081-40-5 (hydrochloride, monohydrate). Formulae and Molecular Weight
2.2
C
N-CH,
I
CH,
I
(Methixene) [ ( C ~ O H Z ~ N SM.W. ; ; 309.471
(Methixene.HC1) [ C ~ O H ~ S N S . H C M.W.; ~;
345.91
Methixene i s commercially a v a i l a b l e as t h e base and as t h e h y d r o c h l o r i d e s a l t ; each 100 p a r t s o f methixene base i s a p p r o x i m a t e l y e q u i v a l e n t t o 113 p a r t s o f methixene h y d r o c h l o r i d e anhydrous and 131 p a r t s o f t h e monohydrate s a l t .
EZZAT M. ABDEL-MOETY ET AL.
322
2.3
w a r a n c e . Color and Taste
Methixene i s s l i g h t l y y e l l o w v i s c o u s l i q u i d , w h i l e t h e HC1-salt i s f l a k e s o r c r y s t a l l i n e powder. Both t h e base and t h e s a l t have b i t t e r t a s t e . The powder o f t h e s a l t i s s t a b l e i n a i r , b u t darkens slowly as a r e s u l t o f l i g h t a c t i o n (1,3). 2.4
The C r y s t a l S t r u c t u r e and t h e Three-Dimensional Projecti o n (6 )
The c r y s t a l s t r u c t u r e o f methixene hydrochloride monohydrate, 9-(N-methyl-3-piperidylmethyl)thioxanthene hydrochloride monohydrate, C2oH23NS.HCl .H20, has been determined by t h e heavy-atom method and r e f i n e d three-dimensionally by t h e a n i s o t r o p i c least-squares method t o g i v e a f i n a l R-value a = 15.320 f 0.003, b = 9.118 f 0.002, c = 13.862 f 0.004 A, and i3 = 94.75 f 0.02’. A l l t h e hydrogen atoms were l o c a t e d on d i f f e r e n c e - F o u r i e r syntheses, b u t t h e i r parameters were n o t r e f i n e d . The c r y s t a l c o n t a i n s b o t h enantiomsrphs i n an equal amount. The benzenoid r i n g s are normal, and t h e best planes o f t h e benzene r i n g s make a d i h e d r a l angle o f 137.9”. The meso atoms, C ( 9 ) and S, a.re s i g n i f i c a n t l y displaced from t h e benzene ring. The p i p e r i d y l r i n g i s i n a c h a i r conformation. The p i p e r i d y l m e t h y l group i s ‘boat a x i a l ’ w i t h respect t o t h e c e n t r a l t h i o x a n t h e n e r i n g , and b o t h t h e thioxanthen-9-ylmethyl and N-methyl groups are i n an ‘ e q u a t o r i a l ’ p o s i t i o n w i t h respect t o t h e p i p e r i d y l r i n g . A l l i n t e r a t o m i c distances and angles are normal. The sulfur-carbon bond distance i s 1.765 f 0.003 A. The average carbon-carbon bond d i s t a n c e i s 1.524 2 0.006 A f o r carbon-carbon s i n g l e bonds, 1.384 f 0.006 A f o r carbon-carbon double bonds I n t h e benzenoid r i n g , and 1.505 k 0.005 A f o r carbon-carbon bonds i n v o l v i n g C(9) and t h e benzenoid r i n g . The mean value o f t h e nitrogen-carbon bond distance i s 1.488 2 0.006 A. Each c h l o r i d e i o n i s associated w i t h t h r e e hydrogen bonds; one l i n k s t o a quaternary ammonium i o n and t h e other two l i n k t o two d i f f e r e n t water molecules. The packing o f t h e molecules i n t h e c r y s t a l i s determined by t h e h y d r o g e n b o n d i n g and v a n d e r W a a l s i n t e r a c t i o n s . Table 1 demonstrates t h e f r a c t i o n a l atomic coordinates and t a b l e 2 shows t h e bond lengths and bond angles. Conformation angles w i t h i n t h e
METHlXENE HYDROCHLORIDE
323
p i p e r i d y l r i n g are presented i n t a b l e 3 . Hydrogen-bond distances and angles are reported i n t a b l e 4 . Table 1: F r a c t i o n a l Atomic Coordinates (6). Atom
Y
X
(X
Atom
2
Y
X
lo))*
(X
2
103)
Cl
5563 ( 1 )
7272 ( 1 )
280 ( 1 )
485
-37
170
9
3807 ( 1 )
1811 ( 1 )
4625 ( 1 )
461
-281
23 1
N
6622 ( 2 )
4671 ( 3 )
1186 ( 1 )
424
-316
399
C(1)
4642 ( 3 )
-811
(5)
2438 ( 3 )
38 1
-123
484
C(2)
4557 ( 3 )
-2013
(5)
2776 ( 4 )
249
396
452 333
C(3)
4268 ( 3 )
-2251
(6)
3668 ( 5 )
185
557
C(4)
4054 ( 3 )
-1077
(6)
4244 ( 4 )
249
557
183
C(5)
2757 ( 3 )
4023 ( 5 )
3917 ( 3 )
366
41 1
151
C(6)
2413 ( 3 )
4983 ( 5 )
3222 ( 4 )
463
212
197
C(7)
2735 ( 3 )
4978 ( 5 )
2321 ( 3 )
587
204
313 377
C(8)
3410 ( 2 )
4052 ( 4 )
2128 ( 3 )
527
313
C(9)
4550 ( 2 )
2140 ( 4 )
2647 ( 2 )
529
477
237
C(11)
4431 ( 2 )
600 ( 4 )
2998 ( 3 )
692
423
349 377
C(12)
4128 ( 2 )
337 ( 5 )
3903 ( 3 )
620
528
C(13)
3427 ( 2 )
3067 ( 4 )
3720 ( 3 )
646
686
244
C(14)
3779 ( 2 )
3103 ( 4 )
2822 (31
739
858
303
C(15)
5410 ( 2 )
2793 ( 4 )
3129 ( 3 )
757
615
136
C(16)
5782 ( 2 )
4079 ( 4 )
2592 ( 3 )
777
472
198
C(17)
6468 ( 3 )
4919 ( 5 )
3234 ( 3 )
662
278
190
C(l8)
6908 ( 3 )
6091 ( 5 )
2659 ( 4 )
570
306
121
C(l9)
7302 ( 3 )
5457 ( 5 )
1794 ( 4 )
652
355
-3
C(20)
6189 ( 2 )
3497 ( 4 )
1704 ( 3 )
739
335
43
C(21)
6992 ( 3 )
4062 ( 6 )
291 ( 4 )
731
480
0
O(W)
3860 ( 3 )
9389 ( 4 )
454
872
6
409
1045
-9
H(N)
618
544
-172 93
(3)
The c o n f i g u r a t i o n o f a m e t h i x e n e h y d r o c h l o r i d e monohydrate m o l e c u l e and t h e i d e n t i f i c a t i o n o f t h e atoms are shown i n f i g . 1. The t o r s i o n angles and t h e molecular packing diagram are presented i n f i g . 2 and 3 r e s p e c t i v e l y . The o r i e n t a t i o n o f t h e p i p e r i d i n y l
EZZAT M. ABDEL-MOETY ET AL.
324
-
Fig. (1). The configuration of methixene HC1 molecule.
Fig. (2). The structure of one asymmetric unit of methixene hydrochloride.
METHIXENE HYDROCHLORIDE
325
methyl group r e l a t i v e t o t h i o x a n t h e n e r i n g i s a l s o shown in f i g . 4. Table 2: Bond lengths and bond angles ( w i t h estimated standard d e v i a t i o n s i n Darentheses) (6)
C(12) C(13) -N C(19) -N C(20) -N C(21) C(l)-C(2) C(l)-C(ll) C ( 2 1-C ( 3 C( 3 1-c (4) C(4)-C(12) C( 5 )-C( 6 1 C(5)-C(13) C ( 6 1--C ( 7 ) C(7 )-C(8) C ( 8 )-C ( 1 4) C(9)-C(ll) C(9)-C( 14) C(9 1-C( 1 5) C(ll)-C(12) C( 13)-C( 14) C( 15)-C ( 16) C(16)-C(17) C(16)-C(20) C( 17 )-C( 18) C( 18)-C( 19) c ( 1 2)-s-c ( 1 31 C( 19)-N-C(20) C(19)-N-C(21) C(20)-N-C(21) C(2)-C(l)-C(ll) S-
-S
1.769 1.761 1.485 1.492 1.487 1.371 1.403 1.364 1.391 1.381 1.374 1.391 1.380 1.378 1.380 1.502 1.508 1.546 1.393 1.397 1.524 1.526 1.521 1.523 1.502 100.5 111.9 111.2 110.8 120.8
(3) A C(l)--C(2)-C(3) (3) C(2)-C(3)-C(4) C(3)-C(4)-C(12) (6) (5) C ( 6 )-C ( 5 >-C ( 1 3 ) (6) C(5)-C(6)-C(7) C(6)-C(7)-C(8) (7) C(7)-C(8)-C(14) (6) (8) C(ll)-C(9)-C(14) C( 1 1 )-C(9)-C ( 15) (7) C(14)-C(9)-C(15) (6) (6) C(l)-C(ll)-C(9) (6) c ( 1 )-c ( 1 1 1-c ( 12) C(9)-C(ll)-C(12) (6) -S C( 12)-C(4) (6) -S C(12)-C(11) (5) C(4)--C(l2)-C(ll) (5) -S C(13)-C(5) (5) SC(13)-C(14) (5) c ( 5)-c ( 1 3 1-c ( 14) (5) (5) C ( 8)-C ( 1 4)-C ( 9) (5) C(8)-C(14)-C(13) (5) C(9)-C(l4)-C(13) (5) C(9)-C(15)-C(16) C(15)-C(16)-C(17) (7) (7) C(15)-C(16)-C(20) (2) C(17)-C(16)-C(20) C(16)-C(17)-C(18) (3) C(17)-C(18)-C(19) (3) (4) -N C( 19)-C( 18) N----C(20)-C(16) (4)
120.4 120.5 119.5 120.5 119.2 120.5 121.3 112.0 110.0 110.9 121.1 118.2 120.7 118.8 120.5 120.8 118.3 121.4 120.4 122.3 118.0 119.7 115.1 111.6 108.8 109.3 111.1 111.9 110.2 112.5
(5)A
(5)
(4) (4) (4) (4) (4) (3)
(3)
(3) (3) (3) (3) (3) (3) (4) (3) (3) (4) (3) (3) (3) (3) (3) (3) (3)
(4) (4) (4) (3)
326
EZZAT M. ABDEL-MOETY ET AL.
F i g . ( 3 ) . The t o r s i o n a n g l e s about t h e (a) C ( 1 9 ) - N , C ( l S ) and (c) C ( 1 5 ) - C ( 1 6 ) bonds.
-
F i g . ( 4 ) . The mol e c ula r packing diagram o f methixene hvdrochloride.
(b) C ( 9 ) -
METHIXENE HYDROCHLORIDE
321
Table 3: Conformation angles* w i t h i n t h e D i D e r i d v l
rins
C(16) C(17) C(18) C(19) N C(20)
- C(17)
- C(18) - C(19) -N - C(20) - C(16)
-t
52.9
- 55.5 -t
56.6
-t
56.1
- 56.8 - 53.9
*The conformation angle o f a d i r e c t e d bond C(17) C(18) i s d e f i n e d as t h e angle t h a t t h e p r o j e c t i o n o f t h e bond C(16) - C ( 1 7 ) makes w i t h r e s p e c t t o t h e p r o j e c t i o n o f t h e bond C(17) - C(18). The angle i s p o s i t i v e i f i t i s measured clockwise. Table 4: Hydrogen-bond d i s t a n c e s and angles.
N N 0
c1 c1 c1
c1
c1 c1 c1 N N N 0
0 Ma)* O(a) C(19) C(20) C(21) C1 (a)
0.051 A 3.051 3.280 3.051 3.051 3.051 3.280
3.280 A 3.203 3.203
3.203
157.5" 128.0 68.7 100.9 120.6 100.6 116.6
EZZAT M. ABDEL-MOETY ET AL.
328
3.
PHYSICAL CHARACTERISTICS Elemental Commsition
3.1
Element
Methixene
Methixene.HC1
[Calculated]
(%I
H
77.62 7.49
S
4.53 10.36
C
-
c1 N
3.2
69.38 6.94 10.26 4.05 9.37
M e l t i n g Range and B o i l i n g P o i n t M e l t i n g range, " C
Methi xene Methixene.HC1
215-217 ( 1 )
B o i l i n g p o i n t , 'C 171-175 ( 0 . 0 7 (1)
W II
Hg)
-
215-216 ( 2 ) 213-217 ( 3 ) 211-213 ( 4 )
3.3
Thermal Behavior ( 7 )
The d i f f e r e n t 5 a1 scanning c a l o r i m e t r y (DSC) thermal curve f o r methixene hydrochloride i s shown i n f i g . 5. The scanning has been r u n a t a r a t e o f 10°C m i n - l from 180 t o 2 5 0 ° C . The h y d r o c h l o r i d e s a l t o f methixene m e l t s a t 2 1 7 . 1 " C w i t h AH-value o f 3 4 . 7 Kj.mo1-1 f o r 9 9 . 4 4 mol% p u r i t y . A Dupont TA-9900 Thermal Analyzer attached t o a Dupont Data U n i t were used f o r t h e DSC-running.
Comment: 0.50:
r2!:.c
'.
I
'.
0.00-
-216.5
Y
.'
-0.50'
-216.0
ub "A
-1.00-
n.
-pi.so -
J
- 215.5
A
'1 I
-
L
I1
u
\
'J:
r
A
m
L-2.50U
a
-
I u-3.00-
-3.50-4.00-
,
a
I
-2.00-
?a
X r. O
rn
u
Purity : Melting P t : Depression : Delta H : Correction : H o l . HElghl: C e l l Const : Onset Slope:
99.45 Hole X 216.9 .C 0.33 'C
33.4 k J / m O l E 6.73 X 345.9 p/Hole 1.191
-215.0 L 7
*
-214.5
A.
Fi,D 7&
El
- A A
-214.0
A 0
u
A
a
- 213.5
-i.ii m W ' c
-213.0
b
t
;.
1EO
0
,
190
:
1
5
200
,:
10
210
.
, ' . I '5 ,
220
,v
n
. I
1.0 ta 1 Area,'Per t I a 1 A r e a
-4.50-
-u -
\
230
:
20
240
250
-212.5
b-
EZZAT M. ABDEL-MOETY ET AL.
330
45
20
Fig. (6). X--ray diffraction lines of methixene hvdrochloride.
0
METHIXENF.HYDROCHLORlDE
3.4
33 1
Solubility
While t h e methixene base i s water i n s o l u b l e , i t s hydrochloride s a l t i s s o l u b l e i n water, alcohol and chloroform b u t i n s o l u b l e i n e t h e r (1-4). 3.5
Crystallographic Characteristics 3.51
Crystallization
Methixene h y d r o c h l o r i d e c r y s t a l l i z e s as w h i t e f l a k e s f r o m e t h e r , mp. 215-217°C ( 1 ) o r f r o m alcohol-ether (1:2, v/v), mp. 211-213°C. 3.52
X-Ray D i f f r a c t i o n P a t t e r n ( 7 )
The X-ray d i f f r a c t o m e t r y o f methixene.HC1 has been undertaken on a P h i l i p s PW-1710 d i f f r a c t o m e t e r w i t h s i n g l e c r y s t a l monochromator and copper Ka r a d i a t i o n . The p a t t e r n s were recorded on a P h i l i p s PM-8210 p r i n t i n g recorder. The t a b l e o f 26, d-spacing (A), and count were a u t o m a t i c a l l y o b t a i n e d on a P h i l i p s d i g i t a l p r i n t e r , t a b l e 2 showing t h e c o l l e c t e d data i n summarized form. Fig. 6 shows t h e c h a r a c t e r i s t i c p r i n c i p a l l i n e s o f t h e X-ray powder d i f f r a c t i o n c a r r i e d out on a pure sample o f methixene.HC1 s a l t .
3.6
Spectroscopic Data 3.61
U l t r a v i o l e t (UV) AbsorPtion ( 8 )
The U.V. measurement has been c a r r i e d o u t f o r methixene h y d r o c h l o r i d e s o l u t i o n s i n 95% e t h a n o l , water and 0.1 N HCl against t h e corresponding blank u t i l i z i n g matched 1-cm quartz c e l l s . The A ( l % . , 1 cm)v a l u e s and t h e molar a b s o r p t i v i t i e s o f methixene hydrochloride s o l u t i o n s are c o l l e c t i v e l y summarized i n t a b l e 6. Figure 7 demonstrates t h e UV-spectra o f t h e d r u g substance in d i f f e r e n t solvents. The s p e c t r a scanning has been undertaken on a Varian DMS 90 1-cm quartz c e l l s .
332
EZZAT M. ABDEL-MOETY ET AL.
I
20 0
N/10 HC1
i0
F i g . ( 7 ) . UV s p e c t r a o f methixene HC1 i n d i f f e r e n t solvents.
333
METHIXENE HYDROCHLORIDE
Table 5: The X-ray d i f f r a c t i o n a l p r i n c i p a l l i n e s methixene hydrochloride. d(R)
26
3.197 6.332 11.568 12.733 13.607 15.081 16.519 17.414 17.931 19.196 19.907 20.460 21.372 22.675 23.281 23.798 24.510 25.279 25.718 26.524 27.439 28.448 29.883 30.668 31.639
2@
d(A)
[I/Io x 1001
87.8 50.2 54.6 97.1 16.5 25.8 52.9 31.3 61.6 72.2 39.9 28.8 61.6 48.5 34.5 24.5 100.0 18.3 35.3 53.3 53.4 9.3 8.1 28.6 7.5
32.496 33.535 33.867 34.598 34.979 35.203 36.190 36.651 37.759 38.505 38.907 39.415 40.280 41.151 41,755 42.855 44,250 45,445 46.462 47.401 48.446 48.935 51.136 51.663 52.48
2.7553 2.6722 2.6468 2.6925 2.5652 2.5493 2.4821 2.4518 2.3824 2.3380 2.3147 2.2861 2.2389 2.1936 2.1632 2.1102 2.0469 1.9958 1.9544 1.9179 1.8789 1.8613 1.7862 1.7692 1.7508
13.5 9.6 7.4 10.3 11.3 15.1 8.3 10.6 9.4 7.0 6.4 5.3 10.8 8.9 15.6 8.7 8.0 5.8 7.1 6.5 6.8 6.0 5.1 5.4 7.6
27.6380 13.9593 7.6496 6.9519 6,5072 5.8746 5.3664 5.0924 4.9468 4.6234 4.4600 4.3407 4.1574 3.9213 3.8207 3.7388 3.6319 3.5230 3.4639 3.3605 3.2504 3.1374 2.9899 2.9029 2.8279
Table 6:
Solvent
The UV-spectral c h a r a c t e r i s t i c s o f methlxene hydrochloride. Xrnax
95% ethanol Water 0.1 N HC1 +
[I/Io x 1001
(nm)
268 266 267
A(l%,
1 cm) 316 324 325+
reported a t 268 nm as 324 (3).
E
(l.mo1-1.cm-1)
10930 11194 11241
334
EZZAT M. ABDEL-MOETY ET AL.
Other reported UV-data i n o t h e r solvents (9) are a l s o as follows:
Sol vent. Acetonitrile Chl o r o f arm
3.62
Xmex 390 385
A(t%,
1 em)
€(~.mol-l.cm-l)
215.6 89.7
7458 3105
I n f r a r e d ( I R ) SDectroscoDy (8)
The IR-spectrum o f methixene h y d r o c h l o r i d e as K B r - d i s c was made on a P e r k i n Elmer i n f r a r e d spectrometer. F i g u r e 8, shows t h e o b t a i n e d IR-spectrum, w h i l e t a b l e 7 i l l u s t r a t e s t h e s t r u c t u r a l assignments w i t h t h e recorded frequencies. Table 7:
The I R - c h a r a c t e r i s t i c s o f methixene hydrochloride.
Frequency*, cm-
Group assignment
2950-2880 ( s ) 2480 (m) 1600-1680 ( W) 1460 (s) 1350-1 220 760 ( s )
CH3 ,CH2 ,CH s t r e t c h i n g HN+ , s t r e t c h i n g HN+ CHz ,-CH3 , CH-def ormat ion S-C s t r e t c h i n g . CHz, rocking.
*s, m & w means strong, medium and weak, respectively. 3.63
Mass S D e c t r m e t r v (US) ( 8 )
The mass spectra o f methixene i s i l l u s t r a t e d i n f i g u r e 9, where a base peak appears a t m/e 197 due t o Ci3HioS i.e., t h i o x a n t h e n e . The mass spectrum o f methixene i s s a i d t o provide a s e n s i t i v e and s p e c i f i c mean f o r i d e n t i f i c a t i o n and q u a n t i f i c a t i o n i n i n pharmaceutical f o r m u l a t i o n . The mass f r a g m e n t a t i o n p a t t e r n f o r methixene i s shown i n t a b l e 8.
T R A N S M I T T A N C E
I
i?
0
0
u3
0 0 0 4
0
L n
0 4
0 0
0
hl
0 0 0 M
0
0
e
0
V
vr
.d
k
a
M
vr
Ld cd Q,
a
0
k
.r(
A
k
5 0 a > .c
a,
x
a,
E
.d
E
5 a, 0
w
cd k
V
c, a,
z
a a, k cd
k
H
F:
ru
c. W v
M L
.d
F
197 /
100
0
'
309
\
165
-
0
40
210 /
rn e
Fig.
(9).
Mass spectrum o f methixene.
235
0
337
METHIXENE HYDROCHLORIDE
Table 8:
Empirical structure
Mass fragmentation o f methixene.
Mass/charge r a t i o (m/e)
[Io/I
C5H10
44 58 58 70
68 72 72 8
CsHi oN
84
10
CsHi 3 N
99
66
C3 Ha C4H10
C3 H i NH
C7H15N
C2oH23NS
112
20
210
14
197
100
309
38
(%)I
Fragment i o n CH3 CH2 CH3 CH3 (CH2 CH3 (CH2
) 2 CH3 2 NH
CH3 (CH2 1 4 - 1
C
N-CH,
M+
EZZAT M. ABDEL-MOETY ET AL.
338
3.64
Nuclear Magnetic Resonance (NMR)
Both t h e p r o t o n n u c l e a r magnetic resonance (1H-NMR) and c a r b o n n u c l e a r m a g n e t i c resonance (13C-NMR) spectra o f methixene hydrochloride have been run on the same s o l u t i o n i n CDC13. 3.641 lH-NHR SDectrurn (8)
The 200 MHz proton magnetic resonance spectrum o f methixene hydrochloride i s given i n the f i g u r e 10 w h i l e Table 9 summarizes t h e chemical s h i f t and s p e c t r a l assignments o f t h e p r o t o n s o f methixene h y d r o c h l o r i d e . The r u n n i n g o f t h e s p e c t r a was undertaken i n CDCl3 using TMS as an i n t e r n a l standard on a V a r i a n XL-200 s p e c t r o m e t e r a t a m b i e n t temperature. Table 9: Chemical s h i f t s and spectral assignments o f 'H-NMR o f methixene hvd rochl o r ide
1 oCH,
5
~~~~
~~
~
4
~
Drug
Proton p o s i t i o n (Nr)
Methixene.HC1
aromatic; 1-8 ( 8 ) CHBN; 13 ( 3 ) CHz; 12,14-16 ( ) C H 2 ; 10 (2) CH; 9 ( 1 ) +NH (1)
(ppm, TMS)
Multiplicity
7.2-7.6 2.8-2.6 2.2-1.9 3.5-3 4.2-4.1 > 12
m S
m m S
M
I+
E
V n V a,
.r(
a 0
k
.d I+
k
0
5 x
a
c x
a, E a, .d
5 a, E
0
'U
cd k
a,
0
c,
2 p:
k
d
0
M L
.d
EZZAT M. ABDEL-MOETY ET AL.
340
3.642 'SC-NMR
Swctrun ( 8 )
The lJC-nuclear magnetic resonance spectrum o f methixene h y d r o c h l o r i d e was o b t a i n e d i n C D C l s a t ambient temperature using TMS as t h e i n t e r n a l standard on a Varian XL-200 spectrometer. The chemical s h i f t s , and s p e c t r a l assignments are given i n t a b l e 10, w h i l e Figure shows t h e obtained 13C-NMR spectrum. The DEPT and APT spectra o f methixene hydrochloride are given i n f i g u r e s (11-14). Figure 15 shows t h e HOMCOR (pulse seqence 1 H-1 H-NMR) spectrum o f t h e drug substance.
7
4
Table 10: Chemical s h i f t s and s p e c t r a l assignments o f 13C-NMR o f methixene hydrochloride. ~~
Carbon pos it i on
,
c2 3 , B , 9
c5,13 c6,11 c1,4,10,7 c12 c14
c19 c15 c20
c16
c17 C18
Chemical s h i f t (6, ppm) 128.84 132.1 137.24 128.9 46.2 22.54 32.04 59.3 43.96 54.5 28.6 35.8
Fig. (11) 13C-N&lR
s p e c t r a o f methixene HC1 in CDC13.
W
ti
F i g . ( 1 2 ) . 13C-NMR spectra of methixene HC1 in CDC1, (APT Program).
7 U Sec.
' 4 ' 4
e
Fig. (13).
15
C-NMR spectra of methixene HC1 in CDC13 (continuation of fig. 14).
CH3
CH2
Fig. (14). 13C-NMR s p e c t r a of methixene HC1 i n CDCl
3
(DEPT Program).
METHIXENE HYDROCHLORIDE
345
0
1 2 3 4
5
6 7
a 9 10 11
1
12
I
1
1 2 1 1 1 0 9
8
I
I
,
1
7
1
6
1
5
1
4
1
3
1
2
1
1
1
0
PPM
F i g . (15). HOMCOR ( p u l s e sequence 'H-lH-NMR) methixene h y d r o c h l o r i d e .
spectrum of
EZZAT M. ABDEL-MOETY ET AL.
346
4.
SYNTHESIS
Methixene and i t s s a l t s have been t o t a l l y s y n t h e s i z e d from prepared 9 - t h i o x a n t h y l sodium and N-methyl-3-chloromethylpiperidine by j u s t condensation. a n t h e s i s o f 9-thioxanthyl sodium: (Scheme I) To 4.9 p a r t s o f f i n e l y p u l v e r i z e d sodium i n 50 p a r t s o f abs. benzene add dropwise w i t h s t i r r i n g 12 p a r t s o f chlorobenzene i n 50 p a r t s o f absolute benzene. As soon as t h e exothermic r e a c t i o n begins, m a i n t a i n t h e temperature by c o o l i n g between 30°C and 3 5 " C , and continue s t i r r i n g f o r 2 t o 3 hours. To t h e r e s u l t i n g phenyl sodium add dropwise 19.8 p a r t s o f thioxanthene i n 120 p a r t s o f a b s o l u t e benzene. The s l i g h t l y exothermic r e a c t i o n ceases a f t e r about 1 t o If hours (10). PreDaratlon o f N - m e t h ~ l - 3 - c h l o r o m e t h ~ l ~ i p e r i (Scheme 11) 3 - P y r i d i n e methanol y i e l d s on r e a c t i o n w i t h methyl i o d i d e t h e quaternary s a l t ; which on h y d r o g e n a t i o n g i v e s t h e corresponding N-methy l -3 -p i p e ri d i n e methanol. T h i o n y l c h l o r i d e c o n v e r t s t h e a l c o h o l t o t h e e q u i v a l e n t N-methyl-3chloromethylpiperidine (4).
dine:
Coupling o f 9-thioxanthyl sodium w i t h N-methyl3 - c h l o r o r n e t h y l ~ i ~ e r i d n e : To t h e f r e s h l y p r e p a r e d 9-thioxanthyl sodium add dropwise, w i t h s t i r r i n g and c o o l i n g , 131.1 p a r t s o f N-methyl-3-chloromethylpiperid i n e i n 30 t o 40 p a r t s o f a b s o l u t e benzene, t h e n continue s t i r r i n g a t about 25°C f o r If hours, and heat subsequently t o 40°C. Decompose t h e r e s u l t l n g m i x t u r e by adding c a r e f u l l y a small amount o f water, and then e x t r a c t t h e newly formed base from t h e benzene s o l u t i o n by means o f d i l u t e h y d r o c h l o r i c a c l d . The aqueous h y d r o c h l o r l c s o l u t i o n i s made a l k a l i n e by adding d i l u t e sodium hydroxide, and t h e methixene base i s i s o l a t e d by e x t r a c t i o n w i t h ether. This r e s u l t s i n 22 p a r t s o f a s l i g h t l y yellow, viscous base o f BP 171 t o 175'C (10.07 mm.Hg). The base i s a c i d i f i e d w i t h a l c o h o l i c h y d r o c h l o r i c acid. Alcohol-ether (1:2) i s then added and hydrochloride s a l t i s r e c r y s t a l l i z e d as white f l a k e s m e l t i n g a t 211 t o 213°C (11).
a,
c E
N
a,
z
a,
e
ocd
c I
M N
U
v
0
ln I
M 0
M
U
+
3
z a, E a,
x
.I+
c E
a,
+J
348
EZZAT M. ABDEL-MOETY ET AL
Synthesis (Scheme 11)
CH3 I U C H 2 O H
+
QCH2OH
I CH3
3 - Pyridine methano 1
1
I+ @ : ! 9-Thioxanthyl sod.
Hydrogenat ion
N-methyl-3-piperidine met h an o 1
G
N-CH,.
HCI
PCH3 - Qjn alc. HC1
Methixene HC1. Met hixene
METHIXENE HYDROCHLORIDE
5.
349
METHODS OF ANALYSIS
Qualitative (Identification)
5.1
5.11
Color Tests ( 4 )
Some s p e c i f i c reagents g i v e c e r t a i n c o l o r a t i o n w i t h methixene and i t s HC1-salt. The f o l l o w i n g common c o l o r reagents are recommended f o r i d e n t i f i c a t i o n o f t h e drug. Reagent HCHO-H2 so4 L iebermann ’ s Mandelin’s H2 SO4
5.12
Color orange red orange orange orange ( f l u o r e s c e s under UV) M i c r o c r y s t a l Test
The aqueous s o l u t i o n o f methixene hydrochloride has been subjected t o some o f t h e most common reagents f o r m i c r o c r y s t a l l i z a t i o n examination. Only t h e aqueous s o l u t i o n o f ZnCl2 (5% w/v) y i e l d s c l e a r r o s s e t t e s a f t e r about 15 min. The f o l l o w i n g f i g . 16 shows t h e c r y s t a l shapes on r e a c t i n g t h e d r u g w i t h t h e p r e c i p i t a t i n g reagent.
Fig. 16: Microscouic examination o f d i f f e r e n t c r y s t a l forms obtained from r e a c t i n g methixene.HC1 w i t h ZnC12 solution.+ + t r a c i n g has been undertaken by using a L e i t z Camera Lucida (x attached t o a L e i t z p r o j e c t o r ; t h e stage scale micrometer was u t i l i z e d under t h e same m a g n i f i c a t i o n (8).
EZZAT M. ABDEL-MOETY ET AL
350
5 2
Q u a n t i t a t i v e (Determi n a t i o n ) 5.21
C o l o r i m e t r i c Determination
Wa'lash e t 87. ( 9 ) have presented a c o l o r i m e t r i c method f o r t h e q u a n t i t a t i v e determination o f methixene alongwith other thioxanthene d e r i v a t i v e s . A weighed amount o f powdered t a b l e t s (about 25 mg) was e x t r a c t e d 3 x 15 m l chloroform i n t o a 50-ml volumetric flask. An a l i q u o t o f the chloroform e x t r a c t equivalent t o 100-400 c(g o f t h e d r u g was p i p e t t e d i n t o a 10 m l f l a s k , evaporated t o dryness and t h e residue dissolved i n 2 m l a c e t o n i t r i l e followed by 1 m l tetracyanoethylene (0.2%) reagent and t h e mixture was d i l u t e d with 5 m l a c e t o n i t r i l e , heated a t 80'C i n water bath f o r 5 m i n u t e s , c o o l e d and c o m p l e t e d t o volume w i t h a c e t o n i t r i l e and absorbance was measured a t 390 nm. against a blank. 5.22
Fluorometric Determination
Hassan e t a7. (12) have presented a f l u o r o m e t r i c method f o r t h e determination o f methixene i n pure and dosage forms. The method i n v o l v e s t h e use of t h e hexamine-cobalt (111) t r i c a r b o n a t o c o b a l t a t e (111) (HCTC) as an oxidant i n aqueous s u l p h u r i c medium t o induce fluorscence. Sample PreDaration Stock s o l u t i o n (1.0 mg/ml) o f t h e methixene i n d l s t i l l e d water was f u r t h e r d i l u t e d w i t h aq. s u l p h u r i c a c i d (20% v/v) t o contain 1 pg o f t h e analyte per m l . Procedure f o r Authentic SamDle T r a n s f e r a 7 i q u o t s o f methixene h y d r o c h l o r i d e s o l u t i o n t o cover t h e concentration range (0.04-0.64 pg/ml), t o 25 m l volumetric f l a s k s , d i l u t e w i t h 5 m l o f aqueous s u l p h u r i c a c i d (20% v / v ) , add 0.1 m l o f HCTC s o l u t i o n ( 5 x M), then d i l u t e t o mark w i t h aqueous s u l p h u r i c a c i d . Leave f o r t h r e e minutes t o complete the reaction. The fluorescence was a t X m a x (368 nm) ( e x c i t a t i o n ) and X m a x (545 nm) (emission), where t h e concentration was read from t h e c a l i b r a t i o n graph.
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3s I
Procedure f o r t h e Dosane Forms T r a n s f e r a weighed amount o f t h e powdered t a b l e t s equivalent t o 30 mg o f t h e drug, i n t o a small c o n i c a l f l a s k . E x t r a c t 3 x 30 m l d i s t . H20. Transfer t h e s o l u t i o n t o a 100 m l volumetric f l a s k and d i l u t e w i t h H20. Further d i l u t e t h i s s o l u t i o n w i t h aq. H2S04 (20% v/v) t o give an analyte concentration o f % l pg/ml and analyse as f o r t h e authentic sample. 5.23
T i t r i m e t r i c Determination
B e l a l e t a l . ( 1 3 ) have presented a t i t 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 o f m e t h i x e n e h y d r o c h l o r i d e . I n t h e procedure HCTC i s used as a t i t r a n t w i t h v i s u a l d e t e c t i o n o f t h e end p o i n t using f e r r o i n as an i n d i c a t o r ( t h e complete disappearance o f orange c o l o r ) . El-Brashy (14) has reported an i n d i r e c t method f o r t h e determination o f methixene i n pure and dosage forms. The procedure involves t h e preparation o f a 1.0 mg/ml s o l u t i o n o f methixene i n 3 M HC1. Add an a l i q u o t o f t h e s o l u t i o n t o a known volume o f 0 . 0 0 5 M 2-iodylbenroate s o l u t i o n i n a glass stoppered Erlenmeyer f l a s k . Shake t h e mixture o c c a s i o n a l l y and a f t e r 15 m i n u t e s add 10 m l o f 100 mg/ml potassium i o d i d e s o l u t i o n and t i t r a t e t h e l i b e r a t e d i o d i n e w i t h 0.02M sodium t h i o s u l p h a t e , using s t a r c h as i n d i c a t o r . Repeat t h e experiment without methixene. The amount o f t h e drug was c a l c u l a t e d from t h e f o l l o w i n g equation.
where VI and V 2 a r e t h e volumes o f t h i o s u l p h a t e s o l u t i o n ( m l ) used i n t i t r a t i o n o f t h e b l a n k and sample r e s p e c t i v e l y . R i s t h e molecular weight o f t h e drug and M i s t h e m o l a r i t y o f t h e t i t r a n t . For t h e assay o f t h e drug i n dosage forms, e x t r a c t a weighed amount o f t h e p u l v e r i z e d t a b l e t s equivalent t o 100 mg o f t h e drug 3 x 20 m l o f 3M HC1. F i l t e r t h e combined e x t r a c t s i n t o a 100 m l standard f l a s k and d i l u t e t o volume w i t h t h e used solvent. Transfer an a c c u r a t e l y measured volume o f t h i s s o l u t i o n ; equivalent t o 5-12 mg o f t h e drug, i n t o i o d i n e f l a s k and proceed as described above.
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5.24
Chromatographic Techniques 5.241
4 (15)
Thin layer chromatography o f methixene has been done w i t h the f o l l o w i n g conditions: Adsorbent: Precoated s i l i c a gel f 2 5 4 (E. Merck). Developer: Methanol t 25% aq. ammonia (110:1.5, v/v). Detection: Dragendorff’s reagent. Reference substance: Bupranolol (relative-Rr: 1.05). 5.242 Gas L i a u i d Chromatography (GLC) ( 1 5 )
Some GLC systems and conditions f o r t h e analysis o f methixene hydrochloride are presented i n t a b l e 11. 5.243 High Performance L i a u i d Chromatography
(HPLC)
I s o c r a t i c multi-column HPLC as a technique f o r t h e q u a t i t a t i v e a n a l y s i s o f t h e d r u g w i t h some phenothiazines have been reported (16). 6.
PHARMACOKINETICS 6.1
m o m t i o n and Excretion
Methixene s a l t i s water s o l u b l e and can be e a s i l y absorbed a f t e r o r a l administration. The drug i s excreted i n the urine, p a r t l y unchanged and mostly as f r e e o r conjugated metabol it e s [ 2 I . 6.2
Biotransformation
As most o f t h e thioxanthene s a l t s , methixene hydrochloride s u f f e r s from S-oxidation i n t o i t s two main i s o m e r l c s u l p h o x i d e s . Another p a r t o f t h e S - o x i d a t i o n products may be i n t h e form o f t h e N-demethylated methixene s a l t , i . e . normethixene sulphoxides. The f o l l o w i n g scheme i l l u s t r a t e s t h e metabolic transformation o f methixene. The bio-sulphoxidation o f methixene r e s u l t s i n the formation o f t h e monosulphoxide [ l , a ] ; which can be transformed t o the disulphoxide [ l , b l . Equivalent N-demethylation y i e l d s t h e corresponding normethixene,
G
G
N-CH,
N -CH,
Qj& 4
/
0
methixene
G
N-CH,
CH
/+ 0
0
Normethixene Extretion
d
-
Excretion (unchanged)
EZZAT M. ABDEL-MOETY ET AL.
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which can be a l s o s u l p h o x i d i z e d t o t h e monoand/or t h e disulphoxide [2bl.
[2al
Table 11: Summary o f t h e GLC-conditions used f o r i d e n t i f i c a t i o n and determination o f methixene hydrochloride (15). Col umn
Temperatures
Reference substance
6 f t x 2 mm packed 3% OV-1 on Chromosorb W-HP 100-120 mesh.
150-25O'C with t h e rate of 1O'C min-1
2-Amino-5c h l orbenazophenone
1.67
6 ft x 2 mm packed 3% OV-17 on Chromosorb W-HP 100-120 mesh.
150-250 " C w i t h the rate o f 10°C min-1
Methaqualone
1.26
3 f t x 2 mm packed 3% OV-1 on Chromosorb W-HP 100-120 mesh.
200-280 " C with t h e rate o f 10°C min-1
Thioridazine
0.35
3 f t x 2 mm packed 3% OV-17 on Ch romosorb W-HP 100-120 mesh.
220-280 c with the rate o f 1O'C min-1
Thior i daz ine
0.42
* ** 7.
O
Re1a t i v e Rf
i n i t i a l time o f 1 min; detection w i t h PND a t 300°C. C a r r i e r gas i s N2 a t 50 rnl.min-1 other gases are a i r (120 ml.min-'1 and hydrogen ( 2 ml.min-1). THERAPEUTIC CATEGORATION
7.1
Pharmacology 7.11
G a s t r o i n t e s t i n a l T r a c t (GIT)
Methixene h y d r o c h l o r i d e i s an a n t i c h o l e n e r g i c agent t h a t may be e f f e c t i v e as an a d j u n c t i n t h e treatment o f g a s t r o i n t e s t i n a l hypermotil i t y and spasm associated w i t h f u n c t i o n a l bowel disorders. There i s
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no evidence t h a t methixene hydrochloride s i g n i f i c a n t l y decrease g a s t r i c s e c r e t i o n ( 1 7 ) . Although methixene c o n t a i n s t h e same t h i o x a n t h e n e n u c l e u s a s chloroprothixene, a major t r a n q u i l i z e r . I t s pharmacological a c t i o n i s p r i m a r i l y a n t i c h o l e n e r g i c . I t has l i t t l e e f f e c t on CNS. Methixene d i l a t e s t h e p u p i l s and i n h i b i t s s a l i v a r y secreation t o a l e s s e r d e g r e e t h a n t h a t due t o a t r o p i n e . Results o f experiments i n several animal species i n d i c a t e t h a t methixene has an i n h i b i t o r y e f f e c t on g a s t r o i n t e s t i n a l motor a c t i v i t y , w i t h o n l y a minimal e f f e c t on g a s t r i c s e c r e t i o n o f h y d r o c h l o r i c acid. Methixene sometimes produces undesired e f f e c t s t y p i c a l l y o f t h e a n t i c h o l e n e r g i c drugs. Dryness o f t h e mouth, mydriasis c y d o p l e g i a , r a s h and u r i n a r y r e t e n t i o n have been noted, e s p e c i a l l y when l a r g e doses have been given. A l t h o u g h no t e r a t o g e n i c e f f e c t s have been demonstrated i n animal s t u d i e s , t h e p o s s i b i l i t y r i s k t o t h e f e t u s must be weighed a g a i n s t t h e expected t h e r a p e u t i c b e n e f i t s i f methixene i s considered f o r a d m i n i s t r a t i o n t o a pregnant woman. Also methixene i s c o n t r a i n d i c a t e d i n presence o f angl e-closure glucoma, py l o r i c o b s t r u c t i o n p r o s t a t i c hypertrophy, bladder-neck o b s t r u c t i o n o r eardiospasm (17).
The c h a r a c t e r i s t i c pharmacological a c t i v i t y o f t h e d r u g has been demonstrated i n mice, r a t s and g u i n e a p i g s . The r e l a t i v e p o t e n c y o f m e t h i x e n e hydrochloride compared w i t h a t r o p i n e w i t h t h e respect t o e f f e c t on g a s t r o i n t e s t i n a l m o t i l i t y v a r i e s from 1.0 t o 2.2 (when assayed i n t h e mouse f o r i n h i b i t i o n o f chareoal passage) t o 1.0 t o 1 6 . 7 f o r i n h i b i t i o n o f t h e p e r i s t a l t i c r e f l e x i n guenia p i g s . However, i n t h e i n h i b i t i o n o f s a l i v a t i o n a t r o p i n e i s 32 t i m e s as potent i n t h e mouse, 6 4 . 5 times as potent i n guenia p i g and 87 times as potent i n t h e r a t . I n rnydriatic a c t i v i t y i n mouse, a t r o p l n e is 20 t i m e s as p o t e n t as methixene h y d r o c h l o r i d e . Thus s t u d i e s i n e x p e r i m e n t a l animals i n d i c a t e t h a t t h e parasympatholytic a c t i v i t i e s o f methixene hydrochloride are r e l a t i v e l y greater w i t h respect t o i n h i b i t i o n o f g a s t r o i n t e s t i n a l m o t i l i t y than they are w i t h reference t o i n h i b i t i o n o f s a l i v a t i o n o r
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p r o d u c t i o n o f a m y d r i a t i c e f f e c t . The dose t h a t r e 1i eve symptoms o f hypermot i1 it y in human b e i ngs might n o t produce t h e s i d e e f f e c t s commonly expected when t h e r a p e u t i c a l l y e f f e c t i v e dose o f p o t e n t sympatholytic agents are employed ( 1 8 ) . 7.12
Antiparkinsonism
I n t r a v e n o u s methixene h y d r o c h l o r i d e has been administered t o 48 p a t i e n t s s u f f e r i n g from a v a r i e t y o f neurological and p s y c h i a t r i c disorders. The r e s u l t s o f such a d m i n i s t r a t i o n i n d i c a t e t h a t methixene i s capable o f a c t i v a t i n g d i a g n o s t i c ECG abnormalities i n p a t i e n t s p r e s e n t i n g w i t h e p i l e p s y o f temporal l o b e o r i g i n . No a c t i v a t i o n o f t h e ECG was d e t e c t e d i n a p a t i e n t s w i t h organic b u t non-epl leptogenic disorders o f t h e c e n t r a l nervous system and i n 10 p a t i e n t s w i t h chronic p s y c h i a t r i c disorders. A l l o f whom has never been s u b j e c t t o e p i l e p t i c s e i z u r e s . The o n l y s i g n i f i c a n t s i d e - e f f e c t observed f o l l o w i n g t h e intravenous i n j e c t i o n o f methixene hydrochloride was appearance o f a m i l d c o r t i c o s p f n a l hemiparesis l a s t i n g f o r a p e r i o d o f 30-60 minutes i n one o f 2 p a t i e n t s l a t e r found t o have a cerebral tumour, m i l d dryness o f mouth and tongue was r e p o r t e d i n almost a l l t h e p a t i e n t s . A c a s e - r e p o r t o f a p a t i e n t w i t h temporal lobe epilepsy o f l a t e r ones was b r i e f l y reported. The o n l y abnormality discovered i n t h s p a t i e n t was i n t h e ECG a f t e r t h e a d m i n i s t r a t i o n o f drug; a t autopsy a s m a l l a s t r o c y t o m a was f o u n d n the epsilateral amygdala (19).
ACKNOWLEDGMENT The authors a r e h i g h l y t h a n k f u l t o M r . Tanvlr A. B u t t f o r t y p i n g t h e manuscript and M r . Osama Shabaan f o r drawing t h e s p e c t r a , b o t h from College o f Pharmacy, King-Saud U n i v e r s i t y , Riyadh, Saudi Arabia.
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