Stability of quinine dihydrochloride in commonly used
intravenous solutions
S. Lerkiatbundit
Department of Pharmacy Administration, Faculty of Pharmaceuficul Sciences, Prince of Songkla University, Hadyai, Songkla,
Thailand, 90110
SUMMARY
The stability of quinine dihydrochloride (Q) at a
concentration of 1-2mg/ml, in three common intra-
venous (i.v.) soIutions, was studied. Admixtures of
Q were prepared in the following vehicles, in glass
containers: 5% dextrose in water, 5% dextrose in
normal saline solution and normal saline solution.
The solutions were kept under fluorescent light
at room temperature. Concentrations of Q were
monitored for 24 h using a stability-indicating
high-pressure liquid chromatographic (HPLC)
method. More than 90% of the initial concentration
of Q remained in all solutions under the study
conditions, and all samples remained clear and
colourless over the entire 24-hperiod. Admixtures
containing Q at a concentration of 1.2 mg/ml in the
three solutions were stable (<10% decomposition)
for at least 24 h and did not require protection from
light. However, the use of the admixtures as soon
as possible after preparation is still recommended
because some decrease in concentration was
observed on storage.
INTRODUCTION
Intravenous quinine dihydrochloride (Q) is currently
the treatment of choice for severe malaria caused
by chloroquine-susceptible or chloroquine-resistant
Plasmodium fulcipunrrn (1-3). Treatment of severe
malaria, especially cerebral malaria, must be initiated as
soon as possible (1-4). Rapid i.v. administration of Q
has resulted in severe hypotension, arrhythmias, and
acute circulatory failure. Whenever Q is given i.v., the
drug should be administered by slow i.v. infusion and
blood pressure and pulse should be monitored fre-
quently (I). Most clinicians currently recommend that
Correspondence:Sanguan Lerkiatbundit, Department of Pharmacy
Administration, Faculty of Phmaceutid Sciences, Prince of
Songkla University, Hadyai, Songkla, Thailand, 90110.
adults receive a 600-mg dose of Q administeredby slow
i.v. infusion over 2 4 h. The dose is repeated every 8 h
until oral therapy can be initiated (1-3). In Thailand,
some clinicians reported that patients with cerebral
malaria, caused by Plnsrnodium falcipantm, may require
a loading dose to attain therapeutic plasma
concentrations rapidly (45).
It is recommended that for administration by slow
i.v. infusion, Q is dissolved in normal saline solution
(NS) (2,6),5%dextrose in water (D5W)or 5%dextrose
in normal saline solution (D/NSS) (6). However, no
stability data for Q in any of these solutions have been
reported (7).The purpose of this study was to determine
the stability of Q at a concentration of 1-2mg/ml in
D5W, D/NSS and NSS.
MATERIALS A N D METHODS
Chemical and reagents
Quinine dihydrochloride injection (Lot no. J309487)
was obtained from the Government Pharmaceutical
Organization of Thailand. Quinine sulphate (Lot
no. 276921-388) was purchased hom FIuka Chemie,
Switzerland.Diazepam (Lot no. 83C0516)was obtained
from Sigma (St Louis, MO, U.S.A.). D5W (Lot
no.120691) and DINS5 (Lot no. 110691) were
purchased from the Pharmacy Department of
Songklanagarind Hospital, Thailand. NSS (Lot
no. 0220291) was obtained from Thai Nakorn Patana,
Thailand. The package size of i.v. fluids was 500ml.
Methanol (Lot no. 20720) and acetonitrile (Lot
no. 00500) were purchased from Riedelde Haen
(Germany).Sodium pentansulphonate (Lot no. FCYOI)
was obtained from Tokyo Kasei Kogyo Uapan).
Apparatus
An HPLC pump (Model306, Gilson, WI) connected to a
multiple-wavelength ultraviolet light detector (Gilson,
343
344 S. Lerkiatbundit

model 115Uv) was used. A C, column (synchopak

10p,25 an x 4.6 rnm, Gilson) served as the station-
ary phase. The mobile phase consisted of acetonihile:
methanol:O-W1 M sodium pentanesulphonate (40:40:
20). The flow rate was 1 rnllmin. The wavelength was
set at 254 run with 0.05 absorbance unit full-scale. The
temperature was ambient.

Validation of HPLC assay

The stability-indicating capacity of the chromato-
graphic method was tested by accelerating the
degradation of quinine. The aqueous solution of Q
(1.2mg/ml) was heated by direct flame for 15 min.
Heated and unheated samples were diluted and sub-
jected to the chromatographic system. The chromato-
grams were inspected for the appearance of additional
peaks.
Following this first phase of evaluation, the reproduci-
bility and linearity of standard curves was tested.
Within-run precision was determined by analysing
three sets of standard solution on the same day.
Between-run precision was determined by analysing
three sets of standard solutions prepared on three differ-
ent days. The coefficient of variation of the peak height
ratio of Q and internal standard at each concentration
were calculated to indicate precision.
Standard solution
We found that the absorbance of Q decreased with the
presence of sodium chloride in solution Therefore we
constructed two standard curves (with and without
sodium chloride). A standard curve, without sodium
chloride,was prepared each day by weighing 120 mg of
quinine sulphate. The powder was dissolved in water
and the volume was adjusted to looml with water.
Six aliquots were taken, mixed with Iml of internal
standard and diluted to 10 ml with methanol. These final
solutions represented concentrations of approximately
48,72,96,120,192 and 240 pg/ml. Twenty microlitres
of these solutions were injected into the chromato-
graph. Standard solutions containing sodium chloride
were prepared with the same procedure but 1 ml of NSS
was added before the solution was adjusted to IOml
with methanol.
DG
Fig. 1. Chromatograms of quinine and its degradation
product. (a) Quinine in aqueous solution after heating, (b)
1.2 mg/ml quinine standard in aqueous solution. Q, DZ and
DG represent quinine, diazepam (internal standard) and a
degradation product, respectively.
1.2mg/ml. All solutions were prepared in glass bottles
to avoid sorption of the drug by the plastic container.
Three separate experimental runs were carried out for
each i.v. fluid. All i.v. solutions were kept at room
temperature (27'0 under usual laboratory fluorescent
lighting to mimic storage conditions in the patient's
room. Samples (I ml) were drawnat time 0 and at 2,4,6,
10 and 24 h. Samples were mixed with 1 ml of internal
standard and the volume was adjusted to l o m l with
methanol. Each sample was assayed immediately after
collection. At each sampling time, a physical inspec-
tion of colour clarity and particles was carried out.
Particulate matter was sought visually against a white
and black background.
Q concentrations were considered within acceptable
limits if the concentration at any analysis was never less
than 90% of the initial concentration.
RESULTS A N D DISCUSSION

Validation of the HPLC method

Stability study
Six hundred milligrams of Q were added to DSW, The decomposition products were well resolved from
D/NSS and NSS (500 ml) to achieve a concentration of the peak of Q and internal standard as shown in Fig. 1.

Table 1. Percentage of initial quinine concentration remaining at various times
~ ~~~
Theoretical Actual initial Percentage concentration at indicated time (h)
Infusion concentration concentration
fluid (pg/ml) (Wml) 2 4
D5W 1200 1253.6 f42.3 103.10f2.86
D/NSS 1200 1157.6f36.9 96.60 f2.22
NSS 1200 1039.9f 15.2 96.82 f0.82
The retention times of diazepam, quinine and degra-
dation product were 1.91, 4.58 and 6*4min, respect-
ively. The presence of dextrose and sodium chloride in
the sample did not change the retention times of Q and
the internal standard. However the peak response of Q
in i.v. fluids containing sodium chlonde ( D I N S and
NSS)was lower than that of Q in D5W and methanol.
This may be due to a 'salt effect' (8). An increase in
ionic strength can change the quininesolvent inter-
action and cause slight differences in the absorption of
Q (8).Therefore, we constructed two standard curves; a
standard curve with sodium chloride to determine Q
concentrations in DMSS and NSS, and a standard curve
without sodium chloride to determine the concen-
trations of Q in D5W. Dextrose in the i.v. fluid had no
effect on the absorbance of Q.
The within-run and between-run precision at all con-
centrations was less than 2.5%. Within-run precision at
1.20mg/ml was 1.49% in solutions free from sodium
chloride and 1.21% in solutions containing sodium
chloride. Between-run precision at 1.2 m g / d was
0.57% in solution with sodium chloride and 0.53% in
solution without sodium chloride. All standard curves
were linear (r>0-997) over the calibration range (48-
240 pg/ml).
Quinine stability
A study period of 24 h was chosen because most hospi-
tals are unlikely to store quinine admixtures for any
longer period of time. Over the 24-h study period,
there was no more than a 10%change in quinine con-
centration in any sample solution (Table I). The
Stability of quinine in i.v. solutions 345
~
6 10 24
100.12 f 2.879864 f0.46 9773 f 1.87 98.96 & 1.01
99.05 f1.57 97.15 f4.35 98.79 f2.60 94.99 f3.32
94.98 f 1.02 96.68 f1.48 9542 f0.72 90.40 f0 2 9
percentage of the initial concentration remaining at 24 h
ranged from 90.4 to 98-946. All the solutions remained
clear and colourless and none had any visible particles.
In conclusion, under the conditions used in the study
quinine was stable for at least 24 h in all of the infusion
fluids studied and did not require protection from light
during 24 h. However some decrease in concentration
was observed on storage. Therefore quinine admixtures
should still be used as soon after preparation as possible.
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