Article

Am J Hosp Pharm 35:669-672 (Jun) 1978

Compatibility and stability of diazepam injection foiiowing dilution

with intravenous fluids
Marilyn E. Morris

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The compatibility and stability of diazepam injection were studied following dilution to 10
different concentrations in aextrose5% in water, normal saline, Ringer's injection and lactated
Prepared solutions were examined for clarity and pH throughout a 24-hour period. Clear
solutions were filtered and then assayed 24 hours after preparation using UV spectrophotome­
try. Solutions which formed visible precipitates before 24 hours or which did not demonstrate
acceptable potency (>90%) were assayed after shorter time periods.
Dilutions lower than 1:20 (5 mg in 20 ml) resulted in immediate visible precipitates m all tour
diluents The 1*20 dilution was compatible with all four diluents and maintained acceptable
potency for four hours, whereas at 1:40 dilution (5 mg in 40 ml) diazepam was stable for at least
6-8 hours In the same diluents. At higher dilutions of 1:50,1:75 and 1:100 (5 mg in 50, 75 and
100 ml, riespectively) the injection was compatible with and stable in all four diluents for 24
hours. . r • u
Further studies are required before the use of diazepam injection as an infusion can be rec­
ommended. However, if in some circumstances it is necessary to administer diappam as an
infusion, it is recommended that it be diluted in dextrose 5% in water, normal saline. Ringer s
injection or lactated Ringer's injection to a dilution of at least 1:40 and used within 6 hours or
to a dilution of 1:50 and used within 24 hours.
Key words: Additives; Concentration; DeTctrose; Diazepam; Incompatibilities; Injections;
Ringer's injection; Sodium chloride; StalDility

There is.considerable controversy regarding the stabili­ cloudiness sometimes occurs when diazepam is diluted with
ty and compatibility of diazepam injection when diluted with water or saline solution, but it has been stated that no loss
intravenous fluids. Di^epam is practically insoluble in water of potency occurs.^ Jusko"* has stated that the maximum
and sparingly soluble in alcohol and propylene glycol.This dilution in normal saline that produces precipitation is about
limited aqueous solubility necessitates the formulation of 15-fold. Other reports have stated that there is no visible
diazepam in a solution containing 40% propylene glycol and precipitation at dilutions of 1:50 in 5% dextrose® or normal
10% alcohol buffered with 5% sodium benzoate and benzoic saline® or 1:25 in lactated Ringer's injection.® Although an
acid and preserved with 1.5% benzyl alcohol.^'^ The sodium infusion of 100 mg in 500 ml (1:25) in normal saline or dex­
benzoate .also serves to increase the solubility of diaze- trose injection has been recommended for use in one re­
view,*® it has also been recommended that 40 mg should be
pam.i
It has been recommended that diazepam injection not be diluted to at least 500 ml (1:62.5) in normal saline or dextrose
mixed or diluted with other solutions or drugs and not be injection.**
added to intravenous fluids.^ Diluting diazepam injection Diazepam is being used intravenously with increasing
with a small quantity of water,3 normal saline'* or dextrose frequency, partially because of its delayed bioavailability
injection® results in precipitation of diazepam, although with following intramuscular injection*®"*"* and partially because
further dilution the precipitate will redissolve.®"® Transitory of its growing list of indications for use. There have been a
number of studies in the literature in which diazepam in­
jection was administered after dilution with intravenous
fluids. Diazepam has been administered as an intravenous
infusion in the treatment of eclampsia,*®"*® convul­
Marilyn E. Morris, M.Sc., is Assistant Professor, College of Pharmacy, sions*®-®®"®® and tetanus,®-®'* as an adjunct to analgesia during
Dalhousie University, Halifax, Nova Scotia B3H 3J5, Canada.
The assistance of Lesley Reid and Dr. O.K. Yung is acknowledged. labor®® and to intravenous anesthesia,'* and as a sedative for
patients requiring prolonged artificial respiration.'* Because
Copyright © 1978, American Society of Hospital Pharmacists, Inc. All rights
of the confusion concerning the dilution of diazepam injec-
reserved.
Vol 35 June 1978 American Journal of Hospital Pharmacy 669
0002-9289/78/0601-0669$00.50
Diazepam Injection

tion, this study was designed to determine the compatibility 1:10 dilutions but only slight in the 1:15 dilutions. Dilutions
and stability of diazepam injection diluted to varying con­ of 1:15 resulted in white hazy solutions, the dextrose 5% in
centrations with commonly used intravenous fluids. water solution being the least hazy. Dilutions of 1:20 pro­
duced white crystalline precipitates after six to eight hours
in Ringer's injection and eight to 12 hours in lactated
Methodology Ringer's injection. No precipitation was noted in the solu­
Test dilutions of diazepam injection (5 mg/ml)® were tions of dextrose 5% in water or normal saline at this dilution.
prepared with 5% dextrose in water,'' normal saline," Ringer's All the higher dilutions remained clear throughout the 24-
injection'' and lactated Ringer's injection.® All dilutions were hour study period.
prepared in a laminar air flow hood' to minimize the possi­ The pH values of the admixtures are presented in Table
bility of particulate and bacterial contamination. Covered 1. They ranged from about 5.0 in dextrose 5% in watfer to
glass beakers which had been thoroughly cleaned and dried approximately 6.0 in lactated Ringer's injection and re­
were used as the containers for the test dilutions. The fol­ mained constant over the 24-hbur period.
The results of the USP assays, expressed as percentage

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lowing dilutions were examined: 1;1,1:2,1:5,1:10,1:15,1:20,
1:40,1:50,1:75 and 1:100. These dilutions correspond to 5 of initial concentration of the injection, are presented in
mg of diazepam added to 1,2,5,10,15,20,40,50,75 and 100 Table 2. Diazepam exhibited acceptable potency in the
.ml of intravenous fluid. The total volumes of the dilutions dilutions of 1:50,1:75 and 1:100 in all four diluents 24 hours
were 8,9,12,22,32,'42,82,102,152 and 202 ml, respectively. after preparation. The 1:40 dilutions were of borderline
The pH of the dilutions was determined at 0,4,12 and 24 potency after 24 hours in dextrose 5% in water (89.6%),
hours after dilution of the diazepam.® Observations were Ringer's injection (87.9%) and lactated Ringer's injection
made for the presence of visible precipitate or haziness using (89.6%). The 1:20 dilutions were assayed fpur hours after
an Intravenous Visual Solution Clarity Inspection Station'' preparation and the assays demonstrated acceptable potency
at 0,0.25,0.5,1,2,4,6,8,12 and 24 hours after dilution. The in all four intravenous fluids.
clarity of each sample was compared with that of a sample
of the intravenous fluid set aside at the time of diazepam
dilution.
Twenty-four hours after dilution all clear solutions were Table 1. pH .of Diazepam Injection in Dextrose 5% in
filtered using a 0.45-jnm filter; they were then assayed ac­ Water (DW), Normai Saline (NS), Ringer's Injection (R)
cording to the USP XIX procedure for diazepam injection.^s and Lactated Ringer's injection (LR)® "
Potency was determined by comparing the ultraviolet ab- Solution
sorbance value of the sample solution with that of the as­ . Dilution DW NS R bR
sayed diazepam injection of the same lot number.' Accept­ 1;1 6.1 6.0 6.0 6.0
able potency was regarded as greater than or equal to 90% 1:2 5.9 6.0 5.7 11. 5.7
1;5 5.6 5.5 5.5 5.6
initial diazepam concentration. Time-zero UV determina­
1;10 5.6 5.4 5.5 5.5
tions were done for a number of samples and averaged to 1;15 5:4 5.4 5.4 5.6
obtain a value for the initial concentration. Dilutions which 1:20 5.2 5.4 5.3 5.6
1;40 5.2 5.4 5.3 5.7
were physically compatible but not of acceptable potency
1;50 5.1 5.4 5.4 5.8
after 24 hours, or dilutions which formed visible precipitates 1;75 5.2 5.5 5.4 5.8
several hours after preparation were repeated and then as­ " 1:100 5.1 5.5 5.4 5.9
sayed again after shorter time periods. ® Values are the means of at least two samples.
•" pH ranges; dextrose 5% In water, 4.1-4.4; normal saline, 6.0-6.3; Ringer's
Injection, 5.8-6.1; lactated Ringer's Injection, 6.4-6.5.
Results

The 1:1,1:2,1:5,1:10 and 1:15 dilutions of diazepam in­

jection in dextrose 5% in water, normal saline. Ringer's in­ Tabie 2. Percent of initiai Concentration of Diazepam
jection and lactated Ringer's injection resulted, in visible Injection in Dextrose 5% in Water (DW), Normai Saiine
white precipitates immediately following dilution. The (NS), Ringer's-injection (R) and Lactated Ringer's
, precipitation was moderate to heavy in the 1:1,1:2,1:5 and
Solution
Dilution ' Time (hr) DW NS R LR

1:20 4 93.6 98.8 92.5 95.3

" Marketed as Valium Injectable, 5 mg/ml, Lots 5300 and 5298, Hoffmann-La 1:40 - 8 • 94.0 — 101.2 101.7
Roche Limited, Vaudreuil, Quebec, Canada. 94.0 87.9 89.6
24 89.6
Baxter Laboratories, Malton, Ontario, Canada, Lot AP 113W1.
1:50 . 24 92.1 95.7 92.6 91.6 .
Baxter Laboratories, Lot AP 114AF.
1:75 24 99.4 93.3 97.1 93.9
Baxter Laboratories, Lot AP 95X2.
= Baxter Laboratories, Lot AP 111F2. 1:100 24 104.0 98.7 101.6 • 93.9
' Abbott Clean Air Center, Air Control, Inc., Norristown, PA 19006.
e Model 12 Research pH Meter, Corning Scientific, Corning, NY 14830. ® Values are the means of at least-two samples.
•' Contamination Control Laboratories, Livonia, MI 48150. " Pooled standard deviation of all data = 3.9; pooled standard error of the mean
' .Spectrophotometer PMO II, Carl Zeiss, West Germany. = 0.5.

S70 American Journal of Hospital Pharmacy Vol 35 June 1978

 Diazepam in|ecllon

Discussion Although there have been numerous reports of the use of

diazepam as an infusion®-®-*®"®® and reviews recommending
The results of this investigation indicate that diazepam the use of diazepam infusions,®-*®-** the manufacturer does
injection may be diluted with dextrose 5% in water, normal not recommend dilution of the product,® and the stability
saline, Ringer's injection and lactated Ringer's injection of the product following dilution with any intravenous fluid
without incompatibility or instability. However, the dilution has not previously been studied. Dundee and Haslett® stated
must be higher than 1:20 (5 mg in 20 ml). All lower dilutions that no loss of potency occurs when diazepam injection is
resulted in immediate visible precipitation. The composition diluted with water or saline solution, but this statement was
of the precipitates in this investigation.was not determined. not referenced and appears to have been based upon clinical
Jusko et al,'' however, demonstrated that the precipitate impression. The intravenous fluid used in the infusion may
formed by the addition of diazepam injection to normal sa­ affect the stability of diazepam since the drug undergoes
line is composed almost entirely of diazepam. In this inves­ hydrolysis at high or low pH levels.® Based on the results of •
tigation, the final concentration of the drug in solution could this investigation, there was no perceptible difference be­
have been affected by the instability of the drug in solution tween the stability of diazepam injection in dextrose 5% in

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and by the filtering out of microcrystals of diazepam. water, normal saline, Ringer's injection or lactated Ringer's
Precipitation of diazepam injection following intravenous injection. The small differences in pH of the admixtures did
injection of the drug may be a problem in clinical practice. not appear to affect the stability of the drug although it is
Langdon et al^'? stated that 22% of their 1,500 patients who possible that admixtures with a higher or lower pH may
received diazepam intravenously reported pain on injection, cause increased degradation of diazepam. Whether or not
while 3.5% developed clinical thrombophlebitis. Precipita­ diazepam injection is compatible with and stable in other
tion of the drug could account for this since precipitation has intravenous fluids has not been studied; therefore, dilution
been shown to occur when diazepam is added to human with fluids other than those investigated in this study can
plasma,"* and since Langdon et al found that thrombophle­ not be recommended.
bitis occurred less frequently when smaller veins were Before diazepam injection can be recommended for use
avoided and when injection of diazepam was followed by as an infusion in clinical practice, further studies are nec­
vigorous flushing with normal saline.^'^ Other investigators essary. In this investigation, the concentrations of the as­
used either normal saline^s or the patient's own blood^^ to sayed solutions may have been affected by filtering out mi­
dilute diazepam in an effort to decrease the incidence of crocrystals of diazepam. Microcrystal formation is a possible
thrombophlebitis. It is also possible that the thrombophle­ problem which has not been studied. Also, this investigation
bitis may be due to irritation of the endothelium of veins by examined the compatibility and stability of diazepam in­
propylene glycol.®® Diazepam injection contains 40% pro­ jection only when added to intravenous fluid in glass beakers.
pylene glycol because of the limited solubility of diazepam.*-® Adsorption to plastic bags or the tubing of administration
A reduction in the amount of propylene glycol® or a change sets is another possible problem which has not been stud­
in the solvent system of diazepam injection®* was found to ied.
decrease the incidence of pain at the injection site. Graham
et al®® found that the intravenous infusion of both benzyl
Conclusions
alcohol and propylene glycol resulted iii an inflammatory
response, suggesting that they play a role in the tissue injury Diazepam injection is soluble in dextrose 5% in water,
following the intravenous use of diazepam injection. normal saline, Ringer's injection and lactated Ringer's in­
Precipitation could occur if diazepam is injected via the. jection if it is diluted to at least 5 mg in 20 ml. Acceptable
tubing of an intravenous infusion rather than directly into potency was maintained for four hours at 5 mg in 20 ml, for
the vein, and this precipitation could also be responsible for six to eight hours at 5 mg in 40 ml and for 24 hours at higher
some of thfe observed phlebitis. It has been recommended dilutions.
that diazepam, when used intravenously, should be injected Further studies are required before diazepam injection
slowly directly into the vein, taking at least one minute for can be recommended for use as an infusion. However, if it
each 5 mg administered,® Korttila et al® found that when is necessary in practice to administer diazepam as an infu­
diazepam was injected into the tubing of a running infusion, sion, it is recommended that it be diluted in dextrose 5% in
the rate of infusion of dextrose 5% in water or normal saline water, normal saline. Ringer's injection or lactated Ringer's
had to be as fast as 20 ml/min in order to prevent visible injection to a dilution of 1:50 or higher and used within 24
precipitation. Jusko et al"* calculated that when diazepam hours. These conditions for use allow a margin of safety to
is injected into the tubing of an intravenous infusion, the take into account the more variable conditions that may exist
flow rate of normal saline would have to exceed 17 ml/min in practice.
to maintain diazepam in solution. This calculation was based
on the maximum apparent solubility of diazepam in normal
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672 American Journal of Hospital Pharmacy Vol 35 June 1978