E L S E VI E R International Journal of Pharmaceutics 110 (1994) 55-63

i n t e r n a t i o n a l
j o u r n a l o f
p h a r m a c e u t i c s
Photochemical decomposition of sulfamethoxazole
We i Z h o u , Do u g l a s E. Mo o r e *
Department of Pharmacy, The University of Sydney, NSW 2006, Australia
Received 10 January 1994; modified version received 18 March 1994; accepted 28 March 1994
A b s t r a c t
Sulfamethoxazole (4-amino-N-(5-methyl-3-isoxazolyl)benzenesulfonamide) is extremely photolabile in acidic aque-
ous solution, giving rise to at least five primary photoproducts. The major product has been identified as
4-amino-N-(5-methyl-2-oxazolyl)benzenesulfonamide resulting from photoisomerization of the isoxazole ring. This
product was found to exist predominantly in its imido tautomeric form. Other products include sulfanilic acid,
aniline, 3-amino-5-methylisoxazole and a hydrated product. The pathways leading to the formation of the products
are postulated.
Key words: Sulfamethoxazole; NMR; Photodegradation; Photoisomerization; Photoproduct; Tautomerism
I . I n t r o d u c t i o n
Sul f amet hoxazol e (Fig. 1), an i nt er medi at e-
act i ng ant i bact er i al sul f onami de, is an essent i al
c ompone nt of co- t r i moxazol e, a fixed combi na-
t i on pr oduct cont ai ni ng sul f amet hoxazol e and
t r i met hopr i m in a 5 : 1 rat i o. The f or mul at i ons ar e
r egul ar l y appl i ed in t he t r eat ment of r espi r at or y
t r act i nfect i ons such as br onchi t i s ( Hughes and
Russel l , 1982) and Pneumocystis carinii pne umo-
ni a wi t h AI DS ( Amyes et al., 1986; Fischl et al.,
1988), severe ur i nar y t r act i nfect i ons ( Lude, 1987)
and ent er i c i nfect i ons ( Yunus et al., 1982). How-
ever, co- t r i moxazol e has been i mpl i cat ed in ad-
ver se phot ot oxi c and phot oal l er gi c skin r eact i ons
in pat i ent s exposed t o sunl i ght ( Aust r al i an Dr ug
* Corresponding author: Fax: + 61-2-552 3760; E-mail: de-
moore@pharmacy.pharm.su.oz.au.
Eval uat i on Commi t t ee, 1987) and sul f amet hoxa-
zol e is bel i eved t o be t he pr i me suspect in causi ng
such adver se effect s ( Mar t i ndal e, 1989) al t hough
t he phot osensi t i zat i on mechani s m r emai ns un-
known. The adver se phot osensi t i vi t y effect s may
ari se f r om sensi t i zat i on by ei t her of t he dr ugs or
f r om some of t he phot opr oduct s f or med follow-
ing i rradi at i on. The phot opr oduct s can be toxic,
or unst abl e and r eact f ur t her t o give toxic deri va-
tives ( Gr eenhi l l and McLel l and, 1990). To dat e
t her e has been one r epor t rel at i ng t he degr ada-
t i on of t r i met hopr i m in whi ch one phot opr oduct
5 6
Fig. 1. Structure of sulfamethoxazole (4-amino-N-(5-methyl-
3-isoxazolyl)benzenesulfonamide).
0378-5173/94/$07.00 1994 Elsevier Science B.V. All rights reserved
SSDI 0378-5 173(94)00 t 00-J
56 14~ Zhou. D.E. Moore / International Journal of Pharmaceulics 1 I0 (1994~ 55 03
was i dent i fi ed ( Ber gh et al., 1989). St udi es on
sul f amet hoxazol e have not been specifically re-
por t ed, but sul f ani l ami de and sul f acet ami de have
been i nvest i gat ed in t er ms of phot odecompos i t i on
( Rei sch and Ni emeyer , 1972; Pawl aczyk and Tur -
owska, 1976) and f r ee radi cal f or mat i on on pho-
tolysis (Chi gnel l et al., 198(/, 1981; Mot t en and
Chi gnel l , 1983). We have been st udyi ng t he pho-
t ochemi cal r eact i ons of sul f amet hoxazol e al one
and in combi nat i on wi t h t r i met hopr i m to gai n
i nf or mat i on cl ari fyi ng t he phot os ens i t i zat i on
mechani sm. He r e we r epor t t he i sol at i on and
i dent i fi cat i on of t he pr oduct s f r om t he phot ol ysi s
of sul f amet hoxazol e in aqueous sol ut i on.
2. Materi al s and met hods
2.1. Chemicals
Sul f amet hoxazol e was obt ai ned f r om Si gma
Chemi cal Co. (St. Loui s, U. S. A. ) and used with-
out f ur t her pur i f i cat i on af t er bei ng pr oven pur e
by HPLC. Dimethyl-d~, sul foxi de (DMSO-d~, ) and
t he ot her deut er at ed sol vent s wer e pur chas ed
f r om Cambr i dge I sot ope Labor at or i es ( Wobur n,
MA, U. S. A. ). All ot her r eagent s wer e of anal yt i -
cal r eagent or hi gher grade. Or gani c sol vent s
used wer e pur i f i ed by f r act i onal distillation. The
wat er was doubl e distilled in an all-glass still.
2.2. Photodegradation of sulfarnethoxazole
1 l of aqueous sol ut i on of sul f amet hoxazol e
(1.0 10 -4 M, p H 3.4, acet at e buf f er ) was i rradi -
at ed at A > 290 nm for 4 - 6 h under magnet i c
st i rri ng in a Hanovi a phot ochemi cal r eact or wi t h
a 125 W me di um pr es s ur e mer cur y l amp shi el ded
by a Pyrex sl eeve as previ ousl y descr i bed ( Moor e,
1987). Ni t r ogen was bubbl ed t hr ough t he sol ut i on
for 15 rain pr i or to swi t chi ng on t he UV l amp and
cont i nued t hr oughout t he i r r adi at i on per i od. The
composi t i on of t he sol ut i on was moni t or ed by
wi t hdr awi ng sampl es for HPLC anal ysi s t o det er -
mi ne t he t i me of i r r adi at i on giving opt i mal yield
of t he pr i mar y pr oduct s. The pr epar at i ve i rradi a-
t i on was car r i ed out at p H 3.4 because of a hi gher
r at e of degr adat i on obt ai ned, c ompa r e d to i rradi -
at i on al pH 7.0 which led to i dent i cal pr oduct s
but at a much sl ower rat e.
2.3. HPLC assay
Hi gh- per f or mance liquid chr omat ogr aphy was
car r i ed out on an i socrat i c syst em consi st i ng of an
Al t ex 110A pump equi pped with a Spect ra-Physi cs
model 100 UV/ Vi s det ect or or a Hewl et t - Packar d
HP 1040A di ode ar r ay s pect r ophot omct r i c det ec-
t or and a Rheodyne 7125 syringe l oadi ng sampl e
i nj ect i on val ue. The col umn used was a Brownl ee
RP-18 (Spheri -5, 5 /xm, 100 mm x 4.6 mm). The
mobi l e phase consi st ed of 0.05 M phos phat e
buf f er ( pH 6.0) and acet oni t ri l e in t he pr opor t i on
95: 5. The UV spect r a of t he phot opr oduct s
f or med, and t he spect ral homogenei t y of the
chr omat ogr aphi c peaks, wer e assessed using t he
di ode array det ect or wi t h 2 nm bandwi dt h.
2.4. PreparatiL ~e chromatography
The i r r adi at ed aqueous sol ut i on was r educed
in vol ume to 5 ml under r educed pr essur e at
r oom t emper at ur e. The small amount of brown
a mor phous pr eci pi t at e was r emoved by cent ri fu-
gat i on and t he s uper nat ant was l oaded ont o a
short r ever se- phase pr epar at i ve col umn for initial
f r act i onat i on. The packi ng mat er i al for t he flash
c hr oma t ogr a phy was Mer ck 10 / , m Li chr osor b
RP-8. The cr ude f r act i ons wer e t hen pur i f i ed by
pr epar at i ve HPLC usi ng a Spect ra-Physi cs lso
Chr om LC pump and an Al l t ech Econosi l ( ' 8
col umn (10 /xm, 250 mm 10 ram). The sampl e
was el ut ed using a mi xt ur e of et hanol and wat er
( 20: 80) as mobi l e phase flowing at 2 ml / mi n .
The i r r adi at ed sampl es and col l ect ed f r act i ons
wer e st or ed at 4C and pr ot ect ed f r om light.
2.5. SpectrophotometG
UV absor pt i on spect r a wer e obt ai ned on a
Per ki n- El mer La mbda 5 UV/ Vi s s pect r opho-
t omet er or t he Hewl et t Packar d HP 1040A di ode
ar r ay HPLC det ect or . I R spect r a wer e r ecor ded
using a KBr disc with a Bi o- Rad FTS 20/ 8( I
s pect r omet er .
W. Zhou, D.E. Moore/International Journal of Pharmaceutics 110 (1994) 55-63 57
2.6. Mass spectrometry
Chemical ionization mass spectra (CIMS) us-
ing CH 4 as reagent gas were obtained by desorp-
tion probe on a Finnigan Mat TSQ46 GC/ MS/
MS with an Incos data system. High resolution
electron impact mass spectrometry (EIMS) was
performed at 70 eV on an AEI MS-902 (with
Kratos MS 50 upgrade) mass spectrometer.
2.7. Nuclear magnetic resonance ( NMR) spec-
troscopy
I H- and ~3C-NMR spectra were obtained in
DMSO-d 6 using a Varian Gemini 300 MHz NMR
spectrometer. Chemical shifts are quoted on the
8 scale relative to DMSO (8 2.62 ppm) unless
stated otherwise. Proton chemical shift assign-
ments were achieved through selective spin-spin
decoupling experiments and two-dimensional ~H-
]H homonucl ear correl at i on spectroscopy
(COSY). 13C resonances were assigned by two-di-
mensional IH-a3C heteronuclear correlation
spectroscopy (HETCOR) and distortionless en-
hancement by polarization transfer (DEPT).
3. Re s u l t s a n d d i s c u s s i o n
3.1. Structure elucidation
?
CD
x
aO
r'
r'
X
r./]
l Oq
8
6
4
2
~o
o p H 3. 4
O
pH 7. 4
i J i L I I
0 1 2 3 4 5 6
I r r a d i a t i o n t i me ( h r )
Fig. 2. The phot odegr adat i on t i me cour se of sul f amet hoxazol e
in aqueous sol ut i on (1 10 - 4 M).
before sulfamethoxazole and are therefore more
polar than the parent. Less polar products were
formed in trace amount when a more concen-
trated solution was irradiated for a lengthy pe-
riod. These are believed to be secondary prod-
ucts. Irradiation of an air-saturated solution pro-
duced the same product profile. However, a ni-
trogen atmosphere was maintained to enhance
the stability of the photoproducts.
A homogeneous peak eluting at 10.9 rain in
the HPLC, designated I, represents the major
photoproduct from photolysis of sulfamethoxa-
zole in aqueous media. The quantum yield of
formation of product I is estimated to be about
Although sulfamethoxazole is relatively ther-
mostable (Rudy and Senkowski, 1973), it decom-
poses rapidly in aqueous solutions under the in-
fluence of UV light. The photodegradation time
course for irradiation of 1 10 -4 M sulfamethox-
azole at pH 3.4 and pH 7.4 is shown in Fig. 2.
The degradation is strongly dependent on the
state of ionization (pK a 5.6; Rudy and Senkowski,
1973) with the sulfamethoxazole anion being the
more stable form. The quantum yields for sul-
famethoxazole photodegradation were deter-
mined by use of monochromatic light and ferrox-
alate chemical actinometry (Moore, 1987), the
values of 0.47 (pH 3.4) and 0.084 (pH 9.0) being
obtained. Separated by reverse-phase chromatog-
raphy (Fig. 3), the primary photoproducts elute
IV
0
N
O
Q)
F
L -
III
0 5 10 15 20
R e t e n t i o n t i me [ mi n i
Fig. 3. Rever s e- phas e HPLC profi l e of sul famet hoazol e
aqueous sol ut i on at p H 3.4 i r r adi at ed for 4 h.
58 W. Z h o u . D . E . M o o r e / I n t e r n a t i o n a l J o u r n a l o f P h a r m a c e u t i c s 1 1 0 : 1 9 9 4 ) 5 5 6 3
0.15 in acidic solution, while t he quant um yield of
t he phot odegr adat i on of sul f amet hoxazol e under
this condi t i on was det er mi ned to be 0.47, i.e.,
pr oduct I r epr esent s about 30% of t he t ot al pr od-
ucts f or med.
The CIMS spect r um of pr oduct 1 showed a
quasi mol ecul ar ion at m/ z 254 with adduct
ions at m/ z 282 ( [ M+ C2 Hs ] * ) and 294
( [ M + C 3 H5 ] + ) , respectively. The empi ri cal for-
mul a CI oHI I N303S, which is t he same as t hat of
sul famet hoxazol e, was est abl i shed by high resol u-
tion mass spect r omet r y. The obser ved value,
253.0510, is in good agr eement with t he calcu-
l at ed val ue of 253.0521. Thes e findings lead to
t he concl usi on t hat t he maj or pr oduct is an iso-
mer of sul f amet hoxazol e f or med t hr ough a pho-
t or ear r agement pathway. The El MS spect r um of
pr oduct I di spl ayed t he typical f r agment s f r om
t he sul f onami de moi et y, such as 92 ( H2NC6H4) ,
140 ( H2NC6H4SO) , 156 ( H2NC6H4SO 2) and 189
(M-SO2).
tH- and 13C-NMR dat a of pr oduct I and sul-
f amet hoxazol e are pr es ent ed in Tabl e 1. The
r esonances of I wer e assigned accordi ng to sev-
eral cri t eri a, begi nni ng with a compar i son with
t hose of sul famet hoxazol e. In t he : H- NMR spec-
t rum, signals at 3 2.08 ppm (3H), a 5.79 ppm
(2H), ,~ 6.53 ppm (2H) and 6 7.45 ppm (2H) were
similar to t hose of sul famet hoxazol e, suggesting
t hat t he H2N- C6H4- SO 2- gr oup and t he met hyl
gr oup wer e intact. The most downfi el d signal,
appear i ng at 6 11.3 ppm as a very br oad peak
i
7 . 0
i'
J
J
i
/
3 . o j '
I
o
6 0 5 s 4 0 ~.o 2. 0
' ] [ ; l '
F i g . 4. T w o - d i m e n s i o n a l C O S Y s p e c t r u m o f p h o t o p r o d u c l 1.
6. 0
"2- 5 . 0
4 . 0
which di sappear ed af t er addi t i on of a dr op of
D2 0 , c a n be assigned to t he exchangeabl e pr ot on
of t he -NH- gr oup ( Tur czan and Medwick, 1972).
The peak br oadeni ng mi ght be at t ri but abl e to
quadr upol e rel axat i on associ at ed with t he ni t ro-
gen ( Rahman, 1986; Kemp, 1987).
A homonucl ear cor r el at i on (COSY) spect r um
is shown in Fig. 4. Apar t from t hose caused by
t he ar omat i c prot ons, t he cross-peaks suggest ed a
coupl i ng bet ween H 4, and t he methyl prot ons.
The coupl i ng was also observed by one- di men-
Ta bl e 1
I H- a nd 13C- NMR da t a of pr oduc t 1 and s ul f a me t hoxa z ol e in DMS O- d ,
Nu mb e r of 6 I H ( p p m) ( mul t i pl i ci t y) , l u , u ( Hz )
t i or C Pr oduc t I SMX
Pr oduc t I SMX
~, 13C ( p p m)
Pr oduct 1 SMX
I
2, 6 7.45 (d) 7.46 (d) J2, 3. J, , > - 8.7 . l : ~ , J~,.5 = 8.8
3, 5 6.53 (d) 6.57 (d} J3, > J5.6 = 8.7 ,13.2, J s . , = 8.8
4
2' or 3'
4' 6.76 (d) 6.1)9 (d) J r , l " = 1.2 J4'A" - 0.82
5'
I" 2.08 ( d) 2.28 (d) J : , : , 1.2 .It,.4, = I).82
Ni t ~ 5.79 (s, b) 6.06 (s, b)
NH, 11.3 (s, b) 10.9 (s, b)
130.9 124.0
129.2 128.7
1 1 4 . 2 1 1 2 . 5
153.7 153.1
143.4 169.7
l 12.3 95.26
158.8 157.8
10.96 12.18
s. si ngl et ; d, doubl et ; q, qua r t e t ; b, br oa d.
IV.. Zhou, D.E. Moore/International Journal of Pharmaceutics 110 (1994) 55-63 59
sional homonuclear decoupling experiments and
the coupling constant was determined to be 1.2
Hz, while Ja',r' in sulfamethoxazole was 0.82 Hz.
The 13C-NMR data of product I showed that
the 10 carbon atoms in the molecule exhibited
eight distinct resonances, all of which were simi-
lar to those of sulfamethoxazole except those
related to the isoxazole ring. Assignment of all
the carbon resonances was achieved with the aid
of DEPT and HETCOR experiments and also by
comparison with those of sulfamethoxazole and
other sulfonamides. The DEPT spectrum re-
vealed the existence of three CH resonances and
one methyl resonance. The resonances at 6 114.2
and 129.2 ppm represent the two pairs of proto-
nated aromatic carbons, verified by the HET-
COR experiment, which further proved that H a,
(6 6.76 ppm) is directly attached on C a, (6 112.3
ppm) as expected from 1H-NMR.
From the MS and NMR information, it was
concluded that the structure of product I is 4-
amino-N-(5-methyl-2-oxazolyl)benzenesulfonamide
which is depicted in Fig. 5. The UV spectrum of
product I exhibits two absorption bands with
maximum wavelengths at 240 and 264 nm, respec-
tively, which is significantly different in shape
from that of sulfamethoxazole (Fig. 6). An expla-
nation is that the compound exists predominantly
in its imido tautomeric form in aqueous solution
(Fig. 7), in contrast to sulfamethoxazole for which
the amido form dominates (Bult, 1983). The same
UV feature was observed for sulfamoxol, a sul-
fonamide containing the oxazole ring, which also
exists predominantly in imido form (Bult and
Klasen, 1978). Furthermore, it has been shown
that the SO 2 symmetric stretching band, one of
the strongest absorptions in the IR spectra of
sulfonamides, could be used as a criterion of the
tautomeric forms, i.e., sulfonamides in the amido
form absorb in the region 1170-1145 cm-l , while
sulfonamides in the imido form absorb in the
region 1145-1130 cm -1 (Uno, 1963). The posi-
tion of this band of product I was observed at
1132 cm -1 in the IR spectrum, confirming the
imido structure.
Product II eluted at 2.4 rain on the reverse-
phase HPLC. Its UV spectrum resembled that of
sulfamethoxazole with , h . m a x at 256 nm. From the
proton NMR data (Table 2), it was evident that
the sulfonamide moiety was present. In the CIMS
spectrum the quasimolecular ion at m / z 272
with appropriate adduct ions at m , / z 300 ([M +
C2H5] +) and 312 ([M + C3H5] +) suggested a for-
mula of C1 0 H1 3 N3 Oa S. The resonance in the
~H-NMR spectrum at about 6 6.5 ppm was deter-
mined to be an exchangeable proton assigned to
H 2 N ~ S O2--NH'-" ~
~,NN~ OH3
S
H2N N ~ O ~ C H 3
V
\ 0 / - C H 3
lJI
II
Fig. 5. Photochemical decomposition products from sulfamethoxazole.
I~ N~SO3H
W
60 l,K. Zhou, D.E. Moore / International Journal of Pharmaceutics 110 (1994) 55- 63
o
tO ~ " '
O \,>
< '<.
\ ,
\
' \ .
E20 240 260 280 300 3E0
W a v e l e n g t h ( n m)
Fig. 6. Nor mal i zed UV s pe c t r um of s ul f amet hoxazol e ( con-
t i nuous l i ne) and phot opr oduc t 1 ( br oken l i ne) in a que ous
sol ut i on at pH 6 obt a i ne d us i ng t he di ode ar r ay HPLC det ec-
tor.
an -NH- group. The methylene protons are mag-
netically nonequivalent, appearing as a split sig-
nal at `5 3.8 ppm. A test for the carbonyl func-
tional group using 2,4-dinitrophenylhydrazine
(Shriner et al., 1980) indicated the presence of a
carbonyl (C = O) group. On the basis of the spec-
tral data, product II was deduced to be a hy-
drated product (Fig. 5) of 2H-azirine, a metastable
product formed as discussed below.
Product III eluted at 9.2 min on the reverse-
phase HPLC. The compound possessed identical
chromatographic features and UV and mass spec-
tra to those of an authentic sample of aniline.
Product IV, one of the most polar phot oprod-
ucts, was formed in a relatively high yield. It
coeluted on the HPLC at very short retention
time (1.7 min) with some other component s as
shown in Fig. 3. After further purification by
preparative HPLC, the fraction afforded a single
peak on the analytical HPLC using a more polar
mobile phase (1% acetonitrile in 0.05 M acetate
Tabl e 2
i H- NMR dat a of pr oduct 11 in DMSO- d6
H 6 ( ppm) Ju, u ( Hz)
(mul t i pl i ci t y)
H 2, H~> 7.46 (d)
H 3, H, 6.53 (d)
H ,, 3.79 (d)
H 4, 2.00 (s)
Ni t 5.82 (s, b)
SO~NH 10.6 ( s , b )
NH 6.57 (s, b)
J , , Jf~.~ = 8.5
J~2, J ~ = 8.5
s, si ngl et ; d, doubl et ; b, br oad.
buffer, pH 3.0; flow rate, 0.25 ml / mi n). The UV
spectrum was uniform throughout the peak and
was identical to that of sulfanilic acid. The CIMS
and EIMS data were also identical to those of a
sulfanilic acid standard.
Product V, eluted at 3.8 rain on the reverse-
phase HPLC, was observed more strongly when
the detection wavelength was shifted to 230 nm.
The UV spectrum of V exhibited a maximum
absorption at 210 nm, suggesting a lack of aro-
matic characteristics. The C1MS spectrum dis-
played a quasimolecular ion at m/ z 99 ([M +
H] +) with adduct ions at m / z 127 ([M + C 2 H ~ ] + )
and m/ z 139 ( [ M+C3Hs ] +) . The EIMS spec-
trum of V gave a highest mass of 98. The empiri-
cal formula C4H6N20 was then established by
high resolution mass spectrometry. The NMR
data of product V are presented in Table 3. In
the I H- NMR spectrum, three proton resonanccs
were observed at 6 2.30 ppm (3H), `5 3.53 ppm
(2H) and ,5 5.56 ppm (IH), respectively. The
signal at 6 3.53 ppm was broad and exchange-
able, and was assigned as an amino group. The
resonance at ,~ 2.30 ppm represents a methyl
group which was found to couple with H 4 (' 11' 4
0.72 Hz). The 13C-NMR spectrum and DEPT
H2 N- - ~ J ) / ~ - S O2 - N- ~ , _ EL -
",~-J O ~ ~'CH3
H
O~ " C Ha
(amido) (imido)
Fig. 7. Ta u t o me r i s m of phot opr oduc t 1.
W.. Zhou, D.E. Moore/ I nt ernat i onal Journal o f Pharrnaceutics 110 (1994) 55- 63 61
Tabl e 3
IH- and I3C-NMR dat a of product V in CDC13
Number t5 1H (ppm) JH,H (Hz) ~ laC (ppm)
of H, C (multiplicity)
3 169.4
4 5.56 (s) 94.24
5 163.4
1' 2.30 (d) Jl',4 = 0.72 12.55
NH 2 3.53 (s, b)
s, singlet; d, doublet; b, broad.
experiment revealed the existence of two quater-
nary carbons, one CH carbon and a methyl car-
bon. The evidence allowed the assignment of
product V as 3-amino-5-methylisoxazole.
3.2. Photodecomposition pathways
Formation of the identified photoproducts in-
dicates that sulfamethoxazole photodegrades in
aqueous solution by several pathways, the most
important of which is a rearrangement of the
isoxazole ring resulting from rupture of the nitro-
gen-oxygen bond. A postulated pathway for the
photoisomerization is summarized in Fig. 8. The
initial step is the UV-induced cleavage of the
labile N-O bond of the five-membered ring. The
reactive diradical so formed then undergoes recy-
clization to produce an intermediate believed to
be the 2H-azirine (X) which has not been suc-
cessfully isolated. The intermediate quickly rear-
ranges to form the oxazole ring via the carbonyl-
stablized nitrile ylide as suggested previously for
the general isoxazole ring (Singh and Ullman,
1967; Sato and Saito, 1974). Product II can be
formed by hydration of intermediate X. Aniline
and sulfanilic acid have been identified as photo-
products from photolysis of other sulfonamides
(Pawlaczyk et al., 1974; Pawlaczyk and Turowska,
1976). These two products were believed to be
formed from free radicals following homolytic
y-fission and 6-fission of sulfonamides (Chignell
et al., 1981). Formation of 3-amino-5-methyliso-
xazole could be via free radical reaction initiated
either by 6-fission or by hydrolysis of sul-
famethoxazole under UV irradiation.
4 . C o n c l u s i o n s
The main photoproducts from sulfamethoxa-
zole are closely related to known sulfonamides,
R
CH 3
N - - c ~ H
l \
R - C o ~ C - C H 3
/
R o O H 3
(Product I)
R
N O ~ C H 3 " ~ ' ~ - ' ~
R ~ C OC H 3
N
( x )
,~201H+
R
N o ~ C H 3
H
R . . I
H o / C = N - - C H 2 - - C O C H 3 ~ - R _ C _ N ~ C H 2 _ _ C O C H 3
II
o
(Product 1I)
(R = H2NC6H4802NH)
Fig. 8. Postulated pathways of formation of phot oproduct s I and I1.
62 14~ Zhou, D.E, Moore / btternational Journal 01-' Pharrnaceutics 110 (1994) 55--03
but t hat do e s no t e xc l ude t he m from s us pi c i on o f
i nvol ve me nt in advers e phot os e ns i t i vi t y. Chl or-
di a z e po x i de is o n e i ns t ance whe r e a c l os e l y re-
l at ed me t a bo l i t e is r e s pons i bl e f or a pho t o t o x i c
ef f ect ( Co r ne l i s s e n et al., 19791. Al t ernat i vel y,
s o me me t as t abl e i nt e r me di at e s a n d / o r f ree radi -
cal s may be r e s pons i bl e for t he advers e p h o t o i n -
duc e d ef f ect . Irradi at i on o f s ul pha ni l a mi de c aus e d
c oval e nt bi ndi ng t o nuc l e i c aci ds and pr ot e i ns ,
ni cki ng o f c l os e d ci rcul ar D N A as wel l as
cros s l i nki ng o f cal f t hymus D N A and huma n
serum al bumi n ( Si nha et al., 19821. The s e ef f ect s
have be e n at t ri but ed t o t he f ree radi cal i nt erme-
di at es , a mo ng whi c h SO~ is be l i e ve d t o be hi ghl y
t oxi c ( Mo t t e n and Chi gne l l , 19831. Un d o u b t e d l y ,
t he pho t o a l l e r g i c r e s pons e o f s ul pha ni l a mi de re-
sul t s f rom t he c oval e nt modi f i c at i on of bi ol ogi cal
ma c r o mo l e c ul e s by me t as t abl e pho t o pr o duc t s t o
pr oduc e an ant i ge n ( Chi gne l l ct al., 198{)). Al -
t h o u g h t he r e is s o me r e s e mbl anc e be t we e n sul -
f a me t ho x a z o l e and s ul pha ni l a mi de in t hei r pho-
t o d e e o mp o s i t i o n pat hways , it ma y be p r e ma t u r e
t o c o n c l u d e t hat t hei r adverse pho t o s e ns i t i z a t i o n
me c ha ni s ms are similar. Fur t he r e xpe r i me nt al i n-
ve s t i gat i ons are be i ng unde r t a ke n in whi c h bi o-
l ogi cal l y rel evant ma c r o mo l e c ul e s are pr e s e nt
duri ng t he i rradi at i on of s ul f a me t ho x a z o l c .
Ac knowl e dgme nt s
Thi s proj ect was s uppo r t e d by a grant f rom
t he Aus t r al i an Re s e ar c h Counc i l Smal l Gr ant s
Sc he me . The Uni ve r s i t y of Sydne y is t hanke d f or
t he award o f an Overs eas Pos t gr aduat e Re s e ar c h
Sc hol ar s hi p t o W. Z. Thi s work was pr e s e nt e d at
t he 1993 me e t i ng o f t he Aus t ral as i an Phar mac e u-
tical Sc i e nc e As s o c i a t i o n.
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