stability of diluted dexamethasone sodium phosphate injection at

stability of diluted dexamethasone sodium phosphate injection at

STABILITY OF DILUTED DEXAMETHASONE SODIUM PHOSPHATE
INJECTION AT TWO TEMPERATURES
Ralph A. Lugo and Milap C. Nahata
Premature neonates with bronchopulmonary dysplasia
frequently are treated with intravenous dexamethasone for their
chronic lung disease. The injection volumes of the commercially
available products often are too small to measure accurately. The
objective of this study was to evaluate the stability over 28 days of
dexamethasone sodium phosphate injection 4 mg/mL diluted with
bacteriostatic NaCl 0.9% to I mg/mL.
OBJECTIVE:
DESIGN: Ten vials of dexamethasone I mg/mL were prepared from
dexamethasone sodium phosphate injection, USP 4 mg/mL and
bacteriostatic NaCl 0.9% injection. Five vials were stored at 4 ·C
and five at 22 "C, Dexamethasone was measured on days 0, 1,3,7,
14,21, and 28 by an accurate, reproducible, and stability-indicating
HPLC method. Samples were also inspected visually for
precipitation or discoloration on each study day.
RESULTS: The samples retained at least 97.7 percent of the original
concentration of dexamethasone sodium phosphate when stored at
either 4 or 22 ·C for 28 days. No discoloration or precipitation was
observed.
CONCLUSIONS: Dexamethasone sodium phosphate injection I mg/mL
in bacteriostatic NaCl 0.9% was stable for 28 days at 4 and 22·C.
Ann Pharmacother 1994;28:1018-9.
BRONCHOPULMONARY DYSPLASIA is a chronic lung disease
in premature neonates that occurs in up to 50 percent of
those weighing less than 1000 g at birth. I The treatment of
bronchopulmonary dysplasia includes the use of intravenous dexamethasone, which expedites weaning from
mechanical ventilation.t" The most common initial dosage
in this population is 0.25 mg/kg q12h, and dosages as low
as 0.05 mg/kg may be used during the dosage taper. As a
result, it is often difficult to accurately measure injection
volumes as small as 0.01 mL of the commercially available product. Dexamethasone sodium phosphate for injection diluted to a concentration of 1 mg/mL may improve
the accuracy of administration, even in the smallest of
neonates. Furthermore, bulk preparation and storage of this
extemporaneously prepared dilution may produce cost savings. No data have been available on the stability of diluted
dexamethasone sodium phosphate injection.
This study evaluated the stability of dexamethasone sodium phosphate for injection diluted from 4 to 1 mg/mL with
bacteriostatic NaCl 0.9% injection, and stored at 4 and
22 ·C for 28 days.
RALPH A. LUGO, Pharm.D; at the time of writing, was a Fellow in Pediatric Pharmacotherapy, Ohio State University and Children's Hospital, Columbus, OH; he now
is an Assistant Professor of Clinical Pharmacy, College of Pharmacy, University of
Utah, Salt Lake City, UT; and MILAP C. NAHATA, Pharm.D; is a Professor, Colleges ofPhannacy and Medicine, Ohio State University, and Wexner Institute for Pediatric Research, Children's Hospital, Columbus, OH. Reprints: Milap C. Nahata,
Pharm.D., College of Pharmacy, Ohio State University, 500 W. 12th Ave., Columbus. OH 43210, FAX 6l4n22-27l6.
1018 •
TheAnnalsofPhannacotherapy
•
Methods
PREPARATION OF SAMPLES
Using sterile technique in a laminar flow hood, I mL of dexamethasone sodium phosphate injection, USP, 4 mg/mL" was injected into 10
lO-mL sterile vials. Three milliliters of bacteriostatic NaCI 0.9%b was
added to each vial followed by vigorous agitation of the vial contents.
Five vials were stored at 4 ·C in the refrigeratorand 5 at 22 ·C under fluorescent light.
On days 0, 1,3,7,14,21, and 28, samples were inspectedvisuallyfor
any precipitationor discolorationand immediatelyprepared for analysis.
Aliquots of 50 J.lL were removed from each vial and diluted with 50 J.lL
of internal standard solution followed by 650 J.lL of mobile phase.
Aliquots of 10 J.lL of each diluted sample were analyzed in triplicate.
Dexamethasone was considered to be stable if its concentration at any
time point was greater than or equal to 90 percent of the initial concentration.
CHROMATOGRAPIllC ANALYSIS
The HPLC method used to measure dexamethasone sodium phosphate concentration was modified from a previously published report.'
The stabilityassay was stability-indicating as documentedby accelerated
degradation of dexamethasone. Aqueous samples of dexamethasone
were diluted with equal volumes of 2 M hydrochloric acid or 2 N sodium hydroxideand incubatedat 80 ·C. Samples were analyzedat baseline
and every two hours until degradationof dexamethasoneoccurred,as indicated by chromatographicdetection of degradationproducts. Degradation product peaks did not interfere with either dexamethasone or internal standardpeaks.
The HPLC method used a 25 cm x 4.6 mm reverse-phase C I8 5-~
column", Mobile phase consisted of 30:70 v/v HPLC-grade acetonitrile'
and 0.05 M potassium phosphate, monobasic buffer! The solvent delivery system' isocratically delivered mobile phase at a rate of I mLlmin.
Column effluent was monitored at 230 nm using a variable wavelength
ultravioletlight detector," and peak heights were calculatedby a chromatointegrator," Under these conditions, the retention times of dexamethasone sodium phosphate and internal standard (hydrocortisone)were 4.2
and 8.0 minutes,respectively.
PREPARATION OF CALmRATION STANDARDS
Dexamethasone phosphate disodium salt' was used to prepare five
calibration standards: 0.6, 0.8, I, 1.2,and 1.4 mg/mL. The internal standard, hydrocortisone hydrochloride,' was dissolved in 50:50 v:v methanol and 0.05 M hydrochloric acid to yield a final concentration of 1
mg/mL. A 50-J.lL aliquot of each calibration standard was diluted with
50 J.lL of internal standard solution followed by 650J.lL of mobile phase.
Aliquotsof 10 J.lL of each diluted standard were analyzed in triplicate.
"Lyphomed lot 121122, Deerfield, IL.
bAbboll Laboratories lot 73-201-0K, North Chicago, IL.
'Ulrrasphere, Beckman Instruments. Toronto, Ontario, Canada.
dBaxter CP80115-4, McGraw Park, IL.
·Sigma Chemical Co. P-0662, St. Louis, MO.
rVarian 2010. Sugar Land. TX.
8Varian 2050, Sugar Land, TX.
bAnspec 0-2000, Hitachi, Tokyo. Japan.
(Sigma Chemical, 0-1159, si. Louis, MO.
i Aldrich Chemical 28,609-5. Milwaukee, WI.
1994 September, Volume 28
Research/Practice
Standard curves were constructed by least-squares analysis of peak
height ratios of dexamethasone and internal standard at each dexamethasone concentration. The relationships were linear with a mean ± SD correlation coefficient of 0.9993 ± 0.0004. A minimum of seven replicates
on different days resulted in an interday coefficient of variation of less
than 1.3 percent. The accuracy of the assay ranged from 97.9 to 101.2
percent during the study.
Table 1. Stability of Diluted Dexamethasone
Injection at Two Temperatures
PERCENT OF INITIAL
CONCENTRATIONa
DAY
0
I
3
7
14
21
28
Resultsand Discussion
Table I summarizes the percent of initial dexamethasone remaining on each of the study days. During the 28day study, samples of dexamethasone sodium phosphate 1
mg/mL retained at least 97.7 percent of their original concentration when stored at either 4 or 22 "C. No discoloration or precipitation was observed in the samples at any
of the times evaluated.
We conclude that dexamethasone sodium phosphate injection diluted from 4 to 1 mg/mL with bacteriostatic NaCl
0.9% was stable at 4 and 22 ·C for 28 days. Dilution of the
commercially available preparation may minimize errors
in measuring the small dexamethasone dosages used in
neonates. Furthermore, bulk preparation and storage may
reduce personnel time and drug wastage, particularly in
hospitals with large neonatal intensive care units. ~
References
I. Ariagno RL. Use of steroids. In: Merritt A, Northway WH, BoyntonBR,
2.
3.
4.
5.
6.
7.
eds. Bronchopulmonary dysplasia. Boston: Blackwell Scientific Publications, 1988:375-402.
Cummings JJ, D'Eugenio DB, Gross SJ. A controlled trial of dexamethasone in preterm infants at high risk for bronchopulmonary dysplasia. N Engl J Med 1989;320: 1505-10.
Harkavy KL, Scanlon JW, Chowdhry PK, Grylack LJ. Dexamethasone therapyfor chroniclung disease in ventilator- and oxygen-dependent infants: a controlled trial. J Pediatr 1989;115:979-83.
Avery GB, Fletcher AB, Kaplan M, Brudno S. Controlled trialof dexamethasone in respirator-dependent infantswithbronchopulmonary dysplasia. Pediatrics 1985;75: 106-11.
Yeh TF, Torre JA, Rastogi A, Anyebuno MA, Pildes RS. Earlypostnatal dexamethasone therapyin premature infantswith severerespiratory
distress syndrome: a double-blind, controlled study.J Pediatr 1990; 117:
273-82.
Collaborative Dexamethasone Trial Group. Dexamethasone therapyin
neonatal chroniclung disease: an international placebo-controlled trial.
Pediatrics 1991;88:421-7.
Walker SE, DeAngelis C, Iazzetta J, Eppel JG. Compatibility of dexamethasone sodium phosphatewith hydromorphone hydrochloride or
diphenhydramine hydrochloride. Am J Hosp Pharm 1991;48:2161-6.
4'C
22'C
b
100.00± 1.39
97.90 ± 1.03
99.30±0.89
97.83 ± 1.35
97.68 ± 1.16
99.01 ± 1.07
98.46 ± 0.71
100.00± 1.60'
99.30 ± 1.25
101.90± 0.53
99.21 ±0.94
99.03 ± 1.18
99.83 ±0.98
97.98 ± 1.16
"Mean ± SD of three determinations for each of five samples (n=15).
"Actual initial concentration was 1.014 mg/mL.
cActual initial concentration was 1.00I mglmL.
de evaluar la estabilidad del fosfato dis6dico de dexametasona 4 mglmL
para injeccion, dilufdo a I mg/ml, con c1oruro de sodio bacteriostatico aI
0.9%, Y a1macenadopor un perfodo de 28 mas.
Diez viales de I mg/ml, de dexametasona fueron preparados a
partir de fosfato dis6dico de dexametasona 4 mg/ml., USP, para
injeccion, y c1oruro de sodio bacteriostatico aI 0.9% para injeccion.
Cinco viales fueron a1macenados a 4 ·C y cinco a 22 ·C. La
concentracion de dexametasona en las soluciones fue determinada los
mas 0, 1,3,7,14,21, Y 28 del estudio, mediante un metodo
cromatografico liquido de alta resolucion, preciso y reproducible,
indicador de estabilidad. Durante el estudio, las muestras fueron
exarninadas diariamente en btisqueda de precipitacion 0 descoloracion
de las soluciones.
DISENO:
RESULTADOS: Las muestras retuvieron aI menos 97.7 por ciento de la
concentracion original de fostato sodico de dexametasona, cuando
fueron alrnacenadas a 4· 0 22 ·C por 28 dfas. Ademas, no hubo
descoloracion 0 precipitacion de las soluciones.
CONCLUSIONFS: EI fosfato dis6dico de dexametasona para injeccion,
dilufdo a 1 mg/ml, con c1oruro de sodio bacteriostatico aI 0.9%
permanecio estable por 28 mas a 4 • Y 22 ·C.
ENCARNACION C. SUAREZ
RESUME
La dexamethasone par voie intraveineuse est souvent
administree aux nouveau-nes prematures atteints de dysplasie
bronchopulmonaire. Malheureusement, les volumes requis sont souvent
trop petits pour assurer une mesure precise de la dose. L' objectif de cette
etude etait d'evaluer la stabilite, pendant une periode de 28 jours, d'une
solution de phosphate sodique de dexamethasone 4 mg/ml, diluee dans
une solution saline bacteriostatique a0.9% permettant d'obtenir une
concentration finale de 1 mg/ml.,
OBJECI1F:
Dix flacons de dexamethasone I mg/ml, ont ete
prepares apartir d'une solution de phosphate sodique de dexamethasone
4 mg/ml, (norme USP) et d'une solution saline bacteriostatique a 0.9%.
Cinq de ces flacons ont ete entreposes a4 ·C alors que les cinq autres
I'etaient a 22 ·C. La concentration de dexamethasone a ete rnesuree aux
jours 0, I, 3, 7, 14, 21, et 28 par chromatographie liquide haute
performance. Les echantillons ont ete aussi inspectes visuellement afin
d'y deceler toute trace de precipite ou de decoloration.
DEVIS EXPERIMENTAL:
EXTRACfO
Los neonatos prematuros con displasia broncopulmonar son
frecuentemente tratados con dexametasona intravenosa para el control
de su enfermedad pulmonar cronica. Los volumenes de injeccion de los
productos disponibles comercialrnente son frecuentemente muy
pequeiios para ser medidos con precision. EI fosfato dis6dico de
dexametasona para injeccion, dilufdo a una concentracion de I mg/ml.,
puede incrementar la precision con que se administran dosis pequeiias
del medicamento. Adernas, la preparacion de esta solucion en grandes
cantidades para su a1macenarniento extemporaneo puede reducir los
costos asociados aI uso de este medicamento. Se sabe que no existe
informacion acerca de la estabilidad del fosfato dis6dico de
dexametasona dilufdo para injeccion, EI objetivo de este estudio fue el
OBJETIVO:
RESULTATS: Les echantillons ont conserves au moins 97.7 pour cent de la
concentration originale de phosphate sodique de dexamethasone, et ce,
peu importe la temperature a laquelle ils etaients conserves. Aucune
decoloration et aucun precipite n' ont ete observes.
La solution de phosphate sodique de dexamethasone
preparee a partir d'une solution commerciale et d'une solution saline
bacteriostatiqueest stable pendant 28 jours a4 et 22 "C,
CONCLUSIONS:
TheAnnalsofPharmacotherapy •
SUZANNE LAPLANTE
1994 September, Volume 28 •
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