International Journal of Pharmaceutics, 67 (1991) 195- 199

1991 El sevi er Sci ence Publ i s her s B.V. ( Bi omedi cal Di vi si on) 0378- 5173/ 91/ $03. 50
ADONI S 0378517391000610
195
I JP 02253
Stability of topical erythromycin formulations
G. M. R. Vandenbos s che 1, E. Vanhaecke 2 C. De Mu yn c k 1 and J. P. Re mo n 1
I Laboratory of Pharmaceutical Technology and e Laboratory of Pharmaceutical Microbiology and Hygiene, State University of Ghent,
Harelbekestraat 72, B-9000 Ghent (Belgium)
( Recei ved 20 J une 1990)
( Accept ed 18 J ul y 1990}
Key words: Drug stability; Erythromycin; Semi-solid; Formul at i on
Summary
The st abi l i t y of er yt hr omyci n, s us pe nde d i n a w/ o a nd a n o / w e mul s i on or di ssol ved in a n al cohol i c s ol ut i on a nd gel, was t est ed
over a 12 week peri od. The i nf l uence of p H a nd st or age t emper at ur e was eval uat ed. A shi f t i n p H f r om 6.3 t o 8.5 as well as an
i ncr ease in st or age t emper at ur e f r om 4 C t o 25 C s eemed t o decr ease t he st abi l i t y of er yt hr omyci n. The act i vi t y of e r yt hr omyc i n in
e mul s i ons wi t h an a que ous pha s e of p H 8.5 ha d onl y 40% of t he or i gi nal act i vi t y af t er 1 mo n t h s t or age at 25 o C. The al cohol i c
s ol ut i on a nd gel r et ai ned mor e t ha n 90% of t hei r i ni t i al act i vi t y af t er 1 mo n t h s t or age at 25 o C.
I nt r oduc t i on
Erythromycin is used as a topical (Hellgren and
Vincent 1980, 1983; Lesher et al., 1985; Broniarc-
zyk-Dyla and Arkuszewska 1989) and systemic
(Wansker, 1961; Akers et al., 1975)agent against
acne vulgaris and neonatal conjunctivitis (Bialer et
al., 1987). No stability problems were reported
when using fatty base ointments (Bialer et al.,
1987). Stability problems of erythromycin salts
were reported when used in intravenous admixture
programs (Bergstrom and Fites, 1975; Pluta and
Morgan 1986) and the pH seemed critical for the
stability of erythromycin or its salts. Studies in
vitro showed a decreasing activity when the pH
was lower than 8 (Heilman and Herrell, 1952), so
prescriptions often adjust the pH of the aqueous
Correspondence." J.P. Re mon, La bor a t or y of Phar maceut i cal
Technol ogy, St at e Uni ver s i t y of Ghe nt , Har el bekes t r aat 72,
B-9000 Ghent , Bel gi um.
phase of semi-solid preparations to 8.5.
In this study the stability of six formulations
was tested: an o / w emulsion, a w/ o emulsion
(both emulsions with and without a pH correc-
tion), an alcoholic solution and an alcohohc gel.
The influence of storage temperature on the stabil-
ity of erythromycin in the six formulations was
studied.
Ma t e r i a l s and Me t h o d s
The composition of the o / w base was as fol-
lows: cetyl alcohol, 15%; white beeswax, 1%; pro-
pylene glycol, 10%; sodium lauryl sulfate, 2%;
methyl p-hydroxybenzoate, 0.08%, propyl p-hy-
droxybenzoate, 0. 02%; deionized water, 72%.
Another cream was prepared using the same for-
mula as mentioned previously but the pH was
adjusted from 6.3 to 8.5 by adding sodium hydrox-
196
ide. The compos i t i on of t he w/ o emul si on was as
fol l ows: whi t e beeswax, 8%; sper macet i , 10%;
cet i ol V, 60%; s or bi t an monool eat e, 2%; met hyl
p- hydr oxybenzoat e, 0.08%; pr opyl p- hydr oxybe n-
zoat e, 0.02%; dei oni zed wat er, 20%. As i n t he case
of t he first o / w emul si on, t he p H of t he aqueous
phas e was l eft unchanged. Anot her w/ o cr eam
was made wi t h dei oni zed wat er cont ai ni ng t he
s ame concent r at i on of s odi um hydr oxi de as in t he
o / w base. As wat er was t he i nt er nal phase, t he p H
of the emul si on obt ai ned coul d not be checked.
1.5% er yt hr omyci n ( Cer t a, Brussels, Bel gi um) was
suspended in all vehicles.
An al cohol i c sol ut i on, cont ai ni ng et hanol , pr o-
pyl ene glycol, dei oni zed wat er (40 : 20 : 40; v / v )
and 1.5% er yt hr omyci n, was pr epar ed. The er yt h-
r omyci n was di ssol ved in t he et hanol pr i or t o
mi xi ng. An al cohol i c gel was pr e pa r e d by addi ng
2% of a hydr oxyet hyl cel l ul os e der i vat i ve ( I dr or a m-
nos an , Ar i on, Brussels, Bel gi um) t o t he al cohol i c
mi xt ur e me nt i one d above.
The f our emul s i ons wer e st or ed in a l umi num
oi nt me nt t ubes ( Chi mexpor t , Ant wer p, Bel gi um)
at 4 and 25 o C. The al cohol i c sol ut i on and gel
wer e st or ed at 2 5 C in a r oom wi t h cont i nuous
art i fi ci al dayl i ght of mode r a t e i nt ensi t y and wer e
pa c ke d in a da r k br own glass bot t l e and an
a l umi num oi nt me nt t ube, respect i vel y.
A mi cr obi ol ogi cal met hod, modi f i ed f r om t he
me t hod descr i bed in t he Bri t i sh Pha r ma c opoe i a
(1988), usi ng an agar - wel l di f f usi on t echni que, was
used t o assay t he e r yt hr omyc i n concent r at i ons.
Met hanol i c s t a nda r d st ock sol ut i ons wer e pr e-
pa r e d f r om a powde r of known pot ency (950
%
120
100
80
zO
20
0
I I I I I I I
0 7 14 21 28 35 4 2
I I l I I I
4 9 56 63 7 0 77 84
Doys
Fig. 1. Stability of erythromycin in o/ w emulsions. Mean percentage of the initial activity (_+ SD on the measurements; n = 12) as a
function of time, of erythromycin in o/ w emulsions stored at 25 C (,x zx) and 4 C (n [:3) and with adjustment of the
pH to 8.5, stored at 25C (A A) and 4C (m m).
I U/ mg, WHO I nt er nat i onal St andar d) and st or ed
in liquid ni t rogen. Four wor ki ng st andar ds were
pr epar ed dai l y in a phos phat e buf f er p H 8.0 (0.7 g
KHzPO4, 12.2 g KzHP O 4- 2H20, wat er t o 1 1).
The suscept i bl e or gani sm used was Mi cr ococcus
l ut eus ( ATCC 9341, Amer i can Type Cul t ur e Col-
l ect i on, Rockville, MD, U.S.A.). 30 ml of ant i bi o-
tic medi um no. 11 ( Di f co no. 593, Di fco, Det r oi t ,
MI, U.S.A.), were pour ed i nt o st andar d pl ast i c
di sposabl e pet r i dishes (9 cm in di amet er). Wells,
6 mm in di amet er, were punched in t he seeded
agar. Four wells were filled wi t h 80 /~1 of t he
st andar d sol ut i on and t wo wells wi t h t he unknown
sol ut i on, obt ai ned by dissolving t he sampl e in
met hanol and di l ut i ng t he met hanol i c sol ut i on in
a phos phat e buf f er . Af t er gr owt h at 2 5 C f or 2
days, zone sizes were measur ed to an accur acy of
197
0.001 mm wi t h a Mi t ut oyo opt i cal compar at or
( Mi t ut oyo Lt d. , Tokyo, Japan). Six pet ri dishes
were used f or each unknown sampl e and t he re-
sults were cal cul at ed by t he met hod of least squares
wi t h t he use of t he i ndi vi dual cal i br at i ons curves.
Re s ul t s and Di s c u s s i o n
As Fig. 1 i ndi cat es, t he act i vi t y of er yt hr omyci n
decr eased t o 70% of t he ori gi nal act i vi t y wi t hi n t he
first week when t he o / w emul si on was st or ed at
25 C. The o / w emul si on st ored at 4 C r et ai ned
mor e t han 90% of t he ori gi nal act i vi t y dur i ng the
first mont h. A fast er decr ease in act i vi t y was not ed
f or t he o / w emul si on wi t h a p H adjust ed t o 8.5
and st ored at 25 C in compar i s on t o t he ori gi nal
%
123
83
23
i I i l I I l I I I I I
0 7 14 21 28 35 42 49 56 63 70 77 84
Days
Fig. 2. St abi l i t y of e r yt hr omyc i n in w/ o emul s i ons . Me a n per cent age of t he i ni t i al act i vi t y ( + SD on t he me a s ur e me nt s ; n = 12) as a
f unc t i on of t i me, of e r yt hr omyc i n i n w/ o e mul s i ons s t or ed at 25 C (zx zx) a nd 4 C (rn D) a nd wi t h a dj us t me nt of t he
p H t o 8.5, s t or ed at 2 5 C (A A) a nd 4 C (11 II).
%
120
o / w emulsion. After 1 and 2 months the activity
of the emulsion with a pH adjusted to 8.5, stored
at 25C decreased to about 40 and 30% of the
original activity, respectively.
As Fig. 2 indicates, the activity of the w/ o
emulsions retained more than 90% of the original
activity during the 12 week test period except for
the emulsion adjusted to pH 8.5, stored at 25 C.
This emulsion lost about 35% of the original activ-
ity after 1 week and more than 65% after 2 months.
The activity of the alcoholic solution and the
gel decreased to 90% during the first 3 weeks (Fig.
3). More than 80% of the activity remained 2
months after preparation, when stored at 25 C.
This study showed the influence of the choice
of vehicule and pH on the stability of topical
preparations containing erythromycin. In conclu-
sion, although erythromycin is more active at an
alkaline pH (Heilman and Herrell, 1952), the pH
adjustment to 8.5 has a deleterious influence on
the stability of the active compound. The confu-
sion concerning the stability of erythromycin in
ointments might have its origin in the data pub-
lished by Sheinaus and Lee (1955) where the
authors stated that erythromycin in an o / w emul-
sion was most stable at a pH of 8.6. It should be
emphasized that this former study did not include
controls for the microbiological dosage of eryth-
romycin while the absence of a calibration curve
made the interpretation of the results doubtful.
All tested emulsions, stored at 4 C, the w/ o
emulsion without pH adjustment, the alcoholic
t [ I i ]
80
198
83
40
23
0
I I | I I I I I I i I |
0 7 14 21 2 8 3 5 4 2 4 9 5 6 6 3 7 0 7 7 8 4
Days
Fig. 3. Stability of eryt hromyci n in sol ut i on or gel. Mean percent age of the initial activity ( + SD on the measur ement s; n = 12) as a
funct i on of time, of an eryt hromyci n alcoholic sol ut i on ( ~ O) and gel (O 4 ) st ored at 25 o C.
solution and the gel, stored at 25 C, showed an
acceptable stability ( > 90% activity) during 1
mont h after preparation.
Acknowledgement
G.V. acknowledges his position of Research
Associate of the National Fund for Scientific Re-
search (NFWO).
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