Article 1

316
International Journal of Pharmaceutical Compounding

Vol. 6 No. 4 July/August 2002
P E E R R E V I E W E D
Stability of Ketamine Hydrochloride Injection
After Reconstitution in Water for Injection and Storage
in 1-mL Tuberculin Polypropylene Syringes for Pediatric Use
Introduction
Ketamine hydrochloride (Figure 1) in-
jection is extensively used as a rapidly act-
ing anesthetic agent because it produces
minimal respiratory depression.
1
It is usu-
ally diluted with water from 100 mg/mL
(the commercially available strength) to
10 mg/mL for use in pediatric patients.
The diluted injection is usually filled into
1-mL tuberculin polypropylene syringes
t hat are st ored at room t emperat ure.
The stability of the diluted injection has
not been reported in the literature.
The purpose of this investigation was to
develop a stability-indicating assay method
for the quantitation of ketamine hydrochloride
injection and (for use in pediatric patients)
to study the stability of the diluted injec-
tion after storage in 1-mL tuberculin pol-
ypropylene syringes at 25C.
Materials and Methods
Chemicals and Reagents
All the chemicals and reagents, which
were USP-NF or ACS grade, were used
without further purification. Ketamine hy-
drochloride powder (Lot # 72416) was gen-
erously supplied by Professional Com-
pounding Centers of America (Houston,
Texas), and the injection (100 mg/mL)
(commercial Lot # 653153A) was obtained
from Abbott Laboratories (North Chica-
go, Illinois).
Equipment
A high-performance liquid chromato-
graphic system (ALC 202 Waters Associ-
ates, Milford, Massachusetts) equipped with
a universal injector (Rheodyne Model 7125,
Cotati, California), a multiple wavelength
detector (Schoeffels SF 770, Applied Biosys-
tems, Ramsey, New Jersey), and a recorder
(Omniscribe 5213-12, Houston Instru-
ments, Austin, Texas) was used. The col-
umn used (Beckman, Ultrasphere, 15 cm,
4.6 mm id, 5 m) was obtained from Phe-
nomenex Inc, Torrance, California.
Chromatographic Conditions
The mobile phase contained 23% (v/v)
acetonitrile in water containing 0.01 M
potassium dihydrogen phosphate buffer.
The pH of the mobile phase was adjusted
to approximately 3.9. The flow rate was
1.6 mL/min, the sensitivity was 0.1 AUFS
at 269 nm, the chart speed was 30.5 cm/hr,
and the temperature was ambient.
Preparation of
Injection for Stability Studies
Ketamine hydrochloride injection (100
mg/mL) was diluted with sterile water for
injection without preservative (Lot # 302661,
American Pharmaceutical Partners, Los
Angeles, California) to a concentration of
10 mg/mL. The injection was immediate-
ly filled into 1-mL tuberculin polypro-
pylene syringes (Becton, Dickinson and
Company, Franklin Lake, New Jersey) and
was stored at 25C ( 1C). On day zero,
the injection was assayed and the pH value
was recorded. The contents of the sy-
ringes were assayed again after 3, 7, 11, and
30 days. The pH values were also recorded.
Preparation of Standard Solutions
A 115.4-mg quantity of the ketamine hy-
drochloride powder was accurately weighed
(115.4 mg of the powder is equivalent to
100 mg of ketamine free base) and was dis-
solved in sufficient water to make 25 mL
of solution. That stock solution was used
to prepare solutions of lower concentra-
tions as needed. The most commonly used
standard solution of the drug (400 g/mL)
was prepared by diluting 2.5 mL of the
stock solution to 25 mL with water.
Preparation of Assay Solutions
A 2.0-mL quantity of the assay solution
was diluted to 50 mL with water.
Decomposition
of Ketamine Hydrochloride
Three solutions were prepared for analy-
sis according to the following procedures:
Procedure 1. A 25-mL quantity of the stan-
dard solution (400 g/mL) was transferred
to a 150-mL beaker and was heated to boil-
ing by means of a hot plate. More water
was added as needed. After 30 minutes, the
solution was allowed to cool, and volume
was brought to 25 mL with water.
Procedure 2. Procedure 1 was repeated, ex-
cept that 1 mL of 0.5 N NaOH solution
Vishnu D. Gupta, PhD
Pharmaceutics Division
University of Houston
Houston, Texas
Abstract
The stability of ketamine hydrochloride (10 mg/mL) in water for injection stored
in polypropylene syringes has been studied at 25C by means of a stability-indi-
cating high-performance liquid chromatographic assay method. The concentra-
tions of the drug were directly related to peak heights, and the percent relative stan-
dard deviation based on five injections was 1.9. The drug decomposed only when
the solution was boiled after sodium hydroxide was added. It did not decompose
in the presence of an acid or after 30 minutes of boiling. The injection did not
lose potency after 30 days of storage at 25C, and the pH value of 4.2 did not change.
Ketamine hydrochloride appears to be a very stable drug.
Figure 1. Structure
of Ketamine Hydrochloride.
NHCH
3
CI
O
HCI
was added before the solution was heated,
and the solution was allowed to cool af-
ter 5 minutes of boiling. The resultant mix-
ture was made weakly acidic by the addi-
ti on of 0. 5 N H
2
SO
4
sol uti on and was
brought to volume (25 mL) with water.
Procedure 3. Procedure 2 was repeated,
except that 1 mL of 0.5 N H
2
SO
4
solution
was added before the solution was boiled.
Before it was brought to volume (25 mL)
with water, the solution was made weakly
acidic by the addition of 0. 5 N NaOH
solution.
These solutions were injected into the
chromatograph according to the proce-
dure described below.
Assay Procedure and Calculations
An 80-L quanti ty of assay sol uti on
was i nj ect ed i nt o t he chromat ograph
under the conditions described. For com-
parison, a similar volume of the standard
solution containing the same concentra-
tion of the drug (based on the label claim)
was i nj ected. Because peak hei ghts of
the drug were directly related to the con-
centrations (320 to 440 g/mL), the re-
sults were calculated by means of a simple
equation:
(Ph)
a
/(Ph)
s
x 100 = Percentage of the
label claim found
where (Ph)
a
is the peak height of drug of
the assay solution and (Ph)
s
is that of the
standard solution.
The results of these evaluations are pre-
sented in Table 1.
Results and Discussion
Assay Method
The assay method developed is precise
and accurate; the percent relative standard
deviation is 1.9 (based on five readings).
Apparently, the large injection volume (80
L) produced accurate and precise results
without the use of an internal standard.
The concentrations of the drug were di-
rectly related to the peak heights (range
tested, 320 to 440 g/mL). It is important
that the volume of injection (80 L) re-
mai n constant to ensure a l i near rel a-
tionship between the concentrations and
the peak heights. A chromatogram of in-
tact ketamine is shown in Figure 2A. The
standard solution, which was decomposed
by heat and sodium hydroxide, decreased
in potency by approximately 20% (Figure
2B). There was no new peak from the prod-
ucts of decomposition. The standard so-
lution, which was decomposed with either
sulfuric acid or by having been boiled for
30 minutes, did not decrease in potency.
The potency or pH value of the ketamine
injection (10 mg/mL), which was stored at
25C for 30 days in 1-mL tuberculin sy-
ringes, did not change (Table 1). Ketamine
hydrochloride is a very stable compound
because the potency of the standard so-
lution did not decrease during the study,
even after 30 minutes of boiling.
Reference
1. Ketamine hydrochloride injection [package
insert]. North Chicago, IL:Abbott Laboratories;
1998:1.
Addre s s c o r re s po nde nc e t o : Vi s hnu D.
Gupt a, PhD, Phar mac e ut i c s Di vi s i on,
Uni vers i ty of Hous ton, 1441 Mours und
S t , Ho u s t o n , T X 7 7 0 3 0 . E - ma i l :
vgupta@uh. edu
317
International Journal of Pharmaceutical Compounding
Vol. 6 No. 4 July/August 2002
P E E R R E V I E W E D
Table 1. Assay Results for Ketamine Hydrochloride Injection
(10 mg/mL) Stored at 25C in Becton-Dickinson 1-mL Tuberculin Syringes.
Percent of Label Claim Percent RSD
Time (days) (based on 100% on day zero)
a
n = 5
3 100.8 1.9
7 100.2 1.8
11 101.4 1.9
30 101.5 1.9
a
The injections remained clear throughout this study; the pH, which was 4.2, did not change
after 30 days of storage.
RSD = Relative standard deviation.
Peak 1 is from ketamine. Chromatogram A is from a standard sol ution, and B is from
a s ol ut i on dec ompos ed by t he addi t i on of s odi um hydroxi de ( s ee t he t ext ) . For t he
chromatographic conditions, see the text.
Figure 2. Sample Chromatograms from Ketamine,
Standard Solution, and Solution Decomposed with Sodium Hydroxide.
1
D
e
t
e
c
t
o
r

R
e
s
p
o
n
s
e
Time (minutes)
A B
0 4 0 4
1
I
n
j
e
c
t
I
n
j
e
c
t

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