BEATA WELK et al.

196
Acta
Poloniac Pharmaceutica ~ Drug Research, Vol. 58 No. 3 pp~ 195-198, 2001
198
I

BEATA WELK
et aI.
Attempts
of4syrup with
3
2 at formulation
6
5theophylline

ISSN O()0l-6837
197
9
IO
Polish Pharmaceutical
Society

78

enhancing
solubility.
which
would
also0.670.67
stabilise
Table
2. Stability
of theophylline
in prepared
syrups
0.67
0.67
Theophylline
Table I . The composition of syrups

performed
analyses
gave
cur0.67
0.67 calibration
0.67
0.67The 0.67
0.67
ves described by linear equation y=ax+b.
0.01
Benzoic acid
0.03
0.03
0.02
For solution of acidic character the equation was:
EXPERIMENTAL
y=0.053x+().0396
at the correlation coefficient
0.015
Sodium benzoate
0.050.45
1.00
ATTEMPTS AT FORMULATION OF SYRUP
WITH THEOPHYLLINE
r=O.996
I .00
0.84
0.50
Citric acid
2.40 I .00
2.40
3.60
Materials and reagents
For solution of alkaline character the equation was:
BEATA
URSZULA
KURCZEWSKA and DARIA
ORSZULAK-MICHALAK
1.00
TartaricWELK,
acid anhydricum
I .of)
y=0.0623x+0.0200
at the correlation coeffiTheophyllinum
BPI,0088 (Margo),1.00 1.00
cient r=0.998
Theophylline
Reference Standard Lot
0.43
Hydrochloric(Sigma
acid Department
of Biopharmacy, Medical Unviersity of L6d,
Both equations were used to calculate the content
53H59521), propylene glycol (Sigma), glycerine
I Muszy6skiego Str., 90-151 Lodz 0.08
0.40
0.04
Sodium hydroxide
of theophylline in the
prepared liquid formulasolution 86% (POCh), methylpropylparaben (SigEthanol(Sigma),
96"
tions.
1.00
ma), methanol
propanol-2 p.a. (POCh),

the obtained solution.

Abstract: The aim of this study was attempt to formulate syrup with theophytline. This form of drug would

toluene enable
p.a.Mannitol
(Sigma), ammonia 25% cz.d.a.
1.50
easy adjustment of individual doses of drug for therapeutic purposes in children. Due to poor
solubility
Determinations
the presence
of theophylline
(POCh). tartaric
acid in(Sigma),
citricatacid
(Sigma),
of theophylline
water, attempts
increasing
of its solubility
by adding specialof
adjuvant
substances, which
20.80
Propylene
glycol
20.8026.00
5.20 by thin layer chromato20.80importance.
20.80
products
could increase
solubility and
stabilise thehydrochloric
obtained
solution, weredegradation
of particular
sodium
benzoate
solutions
(Sigma),
grapy
acid (Sigma),
sodium
mannitol
Glycerin
86% hydroxide (Sigma),8.60
Keywords: syrup, theophylline, adjuvant substances~ stahility~ solubility.
Storage of theophylline solutions may create
(Sigma), ethanol (Polmos), gustatory and fragrant
0.10
0. I O
0. I O
0. I O
Methyl0. 1 0
O. I O 0. I O
0. I O 0. 1 0
O. I O
conditions
in which theophylline may react with
substances (Dragocco), sacharose.

propylparaben (2:I)

the adjuvant substances or with environmental

WaterPreparation
+ Theophylline
gustatory of syrups
theophylline
is one with
of the
oldest and most
and fragrant
The
first
stage
concentrated
on New
findingundersa subcommonly used antiasthmatic drugs.
substances [ml]

up
to 100 It
ml
factors.
to molecular
the degradation
of theo]ar
groups, may
whichlead
cause
dispersion
of

phylline
and information
of theophyllidine
- prothe
substance
water. Thus,
they create soluble

duct of bonds.
theophylline
degradationare- well
stance of
which
would
solubility
of theo- complex
tanding
asthma
as increase
a disease,thecaused
by chronic
Such properties
seen known
in somein
Composition
Theophylline
content
lg/100
ml}
in
syrups
in
literature
{10].
Even
though
theophyllidine
ispolyclaiphylline
in process,
water solution
to a greatest
degree. polar
inflammatory
bas changed
the therapeutic
organic solvents such as, mono- andtime
REFERENCES
med to form
at very
high temperature
in numehighly
CONCLUSIONS
Thus. wemaking
have studied
the solutionsdrugs
of compounds
approach,
anti-inflammatory
the first
hydroxide
alcohols,
glycols,
sugars
with
[days] [months}
alkaline
environment.
is no sorbitol,
evidence glucosaying
such substances.
as citric, benzoic and tartaric acids, sodium rous
choice
hydroxide
groups there
(mannitol,
6
6
30
2
3
that
it
cannot
form
in
other
conditions,
in
15
12
Cha'zan R.:
Farm. Pol. and
6, 271esters,
(1995).ethers par1. Wehydrochloric
have created
eight
compositions
of
benzoate,
acid,
sodium
hydroxide,
Current
studies
disclosed
anti-inflammatory,
se,1. fructose,
saccharose)
of
ticular
in
liquid
theophylfine
solutions
ofbevarious
Chazan
R.:
Terapia
i
leki
7,
205
(1991).
2.
syrups
withmannitol.
theophylline
concentration
of 100 0.677
ethanol
0.673
0.676
0.676
0.677
0.665
0.6590.620
but
also and
immunomodulatory
effect
0.677
of theophyllline
polyhydroxide
alcohols.
Solubility
can
imcomposition.
ebrowska
W.: Farm. Pol. 23, so3. Barteczko
mg/15
adjuvant
which inguaranloml,
the using
second
stage,
theinactive
substance
was 0.669
and
caused
renewed
interestsubstances
this drug,
parproved
also byJ.,organic
acid
0.669
0.660
0.618
0.672
0.637salts (benzoate
0.671
2
0.671 0.673
Therefore,
a
standard
theophylline
solution
5
(1993).
tee
obtaining
of
pharmaceutical
form
with
optimal
dissolved
in effect
the mixtures
mentioned
ticular
as this
can be of
seentheat above
very low
doses
dium, salicylate sodium), mono,
di- and trihyd4. Rybacki
0.668
0.666
0.668
0.668
0.6680.668
0.667
0.634
0.607
was
made
by
dissolving
50
mg
of
the
standard
3
rifuged
and
placed
on
chromatographic
plates
besiE.,
Kr6wczy6ski
L.:
Substancje
compositions
we
have
chosen
those,
where
the
physico-chemical
parameters.
substances
with
propylene
glycol
and
glycerine.
of theophylline (l, 2). According to the report of
roxybenzoates, carboxylic acids (tartaric poacid,
active
substance
in
5
ml
of
mixture
of
methyl
mocnicze
w
technologii
postaci
leku,
PZWL,
de
theophylline
standard.
When
observed
in
UV
smallest
amount
of
adjuvant
substance
increased
Then,
the
composition
of
syrups
containing
2. The4 (National
adjuvant
used, and
significantly
NHLBI/WHO
Heart, Lung
Blood
acid, citric
and compounds
with
0.669 benzoic
0.662acid) 0.647
0.669
0.615
0.670substances
0.667 0.668
0.670
alcohol
and
water
4:1.
Warszawa
1980.
radiation,
the
stains
standard
and importance
studiedml
subthe
solubility
of
theophylline
in water. such as, ethyltheophylline
in theofindose
of 100
mg/15
was
Institute),
published
1995,
the
of
increased
the
solubility
of
theophylline.
nitrogen
atom
in
their
molecules
0.664
0.669 0.668
0.664
0.669
0.643
0.628
5
5.0.667
Chromatography
on
glass
plates
Kluczykowska
B., was
Krasowska
H.,
Stozek
T.:
stances
similar
about
the0.669
shape and
Determined
amounts
of done
the active
substance
established.
The
of theophylline
theophyHine
was
chosen enediamine,
theophylline
in
thedose
controlled
treatment
ofposition
asthma
polyvinylpirolidone).
Solubility
in
3.wereThe
method
of
determination
covered
by
silica
gel
60F
254
from
Merck,
which
Wybrane
zagadnienia
z
technologii
postaci
(RF
O.24).
0.666
directly
after
the
preparation
of
various
formula0.675
6
0.6730.675
0.639
0.672
0.674
0.617
0.675
to
enhance
individualisation
of
treatment
for
parincreased,
This precise
drug isdetermination
recommended
world
water of non electrolytes can be also changed by
used, enabled
of by
its content
werepresence
activated
hour.~ . substances
atof
120oC
before
the
leku
i 99.1%
biofarmacji,
Krak6w
1986.
tions
were
to 1101.1%
the theoretical
ticular
i.e.
enable
administration
of hig.,
experts
inpartients
all stages
chronic
of forionogenic
such as,
0.664
0.668
0.654
0.642 the 0.634
in
the created
of
the
drug.asthma.
7form of
" '-" ~ :' ..'
6. Lazowski
studied
and standard
solutions
were
added.
As
J.: Farm.
10,
561
(1981).
Determining
the stability
ofthe
liquid
theophyllline
Specific
gravity
ofPol.
the
created
syrups
wasthe
her Theophylline
doses, multiplicity
of
standard
volume
of value.
have
been
used
together
with
tartaric,
citric
and
benzoic
acids
and
their
salts,
4. The study0.669
on0.662
the stability 0.650
of obtained
0.642
7.0.630
mobile
phase,
ag/I,
mixture
toluene,
J.,
Halkiewicz
A.:
Farm.
Pol. 8, 481 and
formulations
I Barfeczko
.15amino
to 1.23acids
and
pHoffrom
2.1
to 2-propanol
8.6.
the solution 8(15 this
ml) and
possible
ethylenediamiffe;
formsmaller
of thedoses
drug
is during
nowto from
and
also
(4-8).
syrups
revealed
that
acidic
syrups
are
stabile
25%
solution
of
ammonia
30:60:10
was
used. The
(1991).
In order
choose optimal
the0.6770.676 Stability
ofnumerous
theophylline
in earlier
0.667
0.665
measure
and9to
administer
precisely.
0.665
0.677formulation,
0.675 occur0.677
controversial.
Numerous
adverse
reactions
Currently,0.672
preparations
of prepared
theophyltwelve months
fromstudied
preparation
whenbehaviour
stored at
8.
developing
process
was
done
in
a
glass
chamber
Brandys
J.,
Aniol
M.:
Farm.
Pol.
12,
669
determination
of
the
solutions
(content
presented
I ) was analysed
Therefore,
0.67
g of theophylline
was weigh- syrups
ring
after
the administration
of
theophylline
line0.675
are
present
at thein Table
pharmaceutical
0.668 market,
0.669
0.674
0.673 0.670
0.677
0.6720.673
room10
temperature.
In alkaline
syrups
after prepaseveral
saturated
with
solvent
vapours,
placed
in
a
dark
(1982).
during
storage
in
standard
conditions
is
important.
after
1
,
2,
3,
6,
15
and
30
days,
and
after
3,
6
and
12
ed andwith
dissolved
in respective
amounts
of ad- where lot of them are preparations of modified
rations
ethylenediamfne,
reported
in literature,
days opalescence
occurs.
9.
compartment
with
the
walls
protected
from
light
British
Pharmacopoeia
1988.
Thus,
stability
of
theophylline
syrups,
stored
at
months
from
their
preparation.
The
obtained
results
juvant
substances
used for the
are
ascribed
to thesolutions
latter compound
(3). preparaThus,
release rate or prolonged activity, They containby
l0~ Auterhoff
5.
The
thin
layer
chromatography
method
used,
special
paper.
The
was
continued
for
H.,
Hebler
M.F.: Arzncimittelforsroom
temperature
for
12
months,
was
studied.
The
are
presented
Table
2. developing
tion ofproducers
particularoftypes
of syrups.
Then, preseramounts
of inthe
active
substance
which
are sufleading
theophylline
preparations
hadid
not
show
any
symptoms
of
biodegradation
in
the
lOfl
minutes.
chung
9,
621
(1959).
study
included:
determination
of
the
content
of
the
The
same
time
intervals
were
used
to
control
vatives,
gustatory
and
fragrant
substances
were
ficient for adult patients. Large amounts of theove recently introduced forms containing only theostudied
syrups
and
products
of
theophylline.
Thein activated
chromatographic
plate
with
active
substance,
pH,
visual of
evaluation
of the soluchanges
and make
visual are
evaluation,
which
added.
The
created syrups
is pre- pH
phylline
these
preparations
not appropriate
phylline
as
the composition
active
substance,
6.
The
formulations
5,
9,
10
(described
in
a
marked
start
and
15
cm
of
chromatography
route
tions
and
determination
of
the
presence
of
deReceived.'
7.09.2000
may
show
physical
and
chemical
changes
of
the
sented
in
Table
I
.
for the treatment of children, in particular because
Theophylline is poorly soluble in water (8.3
Table Adding
I),products.
withsubstances
the least which
contents
of thesolubility,
adjuvant solutions.
gradation
covered
with 20 ml
of the
solution
and
ofwas
these
preparations
cannot
be studied
precisely
divided,
mg/I).
increase
substances
were
chosen
for
pharmacokinetic
tests
No
visual
changes
were
noted
in
acidic
syrups
Determination
of
theophylline
content
by
spectwhich
if the
are placed
to beininmake possible to include greater amount of theraIO mlisofnecessary,
the standard.
The doses
plate was
the
which
constitute the
stage oforour
RESULTS
during
the study.
formulations
of alkaline
rophotometry
dividualised,
and Inthus
if the
therapy
is the
to pH
be
peutic
substance
in next
the water
oilstudy.
solution, and
chromatographic
chamber
saturated
with
vaand 3OthWhen
days significant
opalescence
Theobtain
content
of theophylline
in suitable
created for
for- between
effective.
thus, to
a pharmaceutical
form
pours l6th
of solvent.
the chromatograms
were
was
noted,
which
may
indicate
that
strong
alkaline
In theconditions,
first
our study,
we
to
mulations
of stage
syrupsofAdding
was
done
by attempted
spectrophotoTherefore,
attempt
was
made
to
create
clinical
non-water
solvents
developed
to 15an
cm,
the plate
was
removed
from
environment
is dried
not
for the
theophylline
dissolve
theophylline
single
of
admeter mix
Spectrom
195inDsuch
by the
method
a the
form
of the
drug appropriate
therapeutically
attractive
due
which
with water
as, solutions
ethanol, described
glycerol
chamber,
at
l20oC and
chromatogThus,
wereat
excluded
juvant
substances
which
increase
its
in the
British
Pharmacopoeia
(BP improve
88)solubili{9].theTo formulations.
torams
highwere
degree
of these
fragmentation
and
bioavailabiand
other
glycols,
cancould
additionally
evaluated
in solutions
UV radiation
the wavestudy
7 and 8). Inasacid
ty.
Results of
were,
however,
not active
satisfactory.
determine
thesuch
content
of the
substance
lity
-further
the
syrup,
containing theophylline
the
absorption
therapeutic
substances
as,The
forin from
length
of 254
nm. (composition
syrups
changes
in
theophylline
content
not
second
stage
concerned
the dissolving
of the
active
the prepared
formulations,
calibration
curves
we- active The
substance
small were
children,
Due did
to samppoor
example,
theophylline
(4).
studiedfor
solutions
prepared
by
IO%.
No
ofintheophylline
degradasubstance
in separately
mixtures
offoradjuvant
with of exceed
re drawn
theophylline
solubility
theophylline
water, ititswith
solubility
Hydrotrophic
substances,
so substances
calledsolutions
intermeling of
15ofml
ofproducts
syrup and
mixing
5 ml of
tion
were
seen.
propylene
glycol
and
glycerine.
From
the
created
acidic
and
alkaline
character.
diate solvents, contain powerful hydrophilic poneeded
to beThen,
increased
by addingwere
substances
methanol.
the samples
shaken, centI

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195

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