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Journal of
Oncology
Pharmacy
Original Article Practice
J Oncol Pharm Practice
0(0) 1–6

Stability study of carboplatin infusion ! The Author(s) 2014

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solutions in 0.9% sodium chloride DOI: 10.1177/1078155214546016
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in polyvinyl chloride bags

Alan L Myers1, Yang-Ping Zhang1, Jitesh D Kawedia1,

Van A Trinh2, Huyentran Tran2, Judith A Smith3,4 and
Mark A Kramer1

Abstract
Background and purpose: Carboplatin is a platinum-containing compound with efficacy against various malignancies.
The physico-chemical stability of carboplatin in dextrose 5% water (D5W) has been thoroughly studied; however, there
is a paucity of stability data in clinically relevant 0.9% sodium chloride infusion solutions. The manufacturer’s limited
stability data in sodium chloride solutions hampers the flexibility of carboplatin usage in oncology patients. Hence, the
purpose of this study is to determine the physical and chemical stability of carboplatin–sodium chloride intravenous
solutions under different storage conditions.
Methods: The physico-chemical stability of 0.5 mg/mL, 2.0 mg/mL, and 4.0 mg/mL carboplatin–sodium chloride solutions
prepared in polyvinyl chloride bags was determined following storage at room temperature under ambient fluorescent
light and under refrigeration in the dark. Concentrations of carboplatin were measured at predetermined time points up
to seven days using a stability-indicating high-performance liquid chromatography method.
Results: All tested solutions were found physically stable for at least seven days. The greatest chemical stability was
observed under refrigerated storage conditions. At 4 C, all tested solutions were found chemically stable for at least
seven days, with nominal losses of 6%. Following storage at room temperature exposed to normal fluorescent light, the
chemical stability of 0.5 mg/mL, 2.0 mg/mL, and 4.0 mg/mL solutions was three days, five days, and seven days,
respectively.
Conclusion: The extended physico-chemical stability of carboplatin prepared in sodium chloride reported herein
permits advance preparation of these admixtures, facilitating pharmacy utility and operations. Since no antibacterial
preservative is contained within these carboplatin solutions, we recommend storage, when prepared under specified
aseptic conditions, no greater than 24 h at room temperature or three days under refrigeration.

Keywords
Carboplatin, platinum compound, physical stability, chemical stability, polyvinyl chloride bags, normal saline

1
Department of Pharmacy Research, The University of Texas M.D.
Introduction Anderson Cancer Center, Houston, TX, USA
2
Department of Pharmacy Clinical Programs, The University of Texas
Carboplatin is a platinum-containing antineoplastic M.D. Anderson Cancer Center, Houston, TX, USA
agent that is a structural analogue of cisplatin.1 3
Departments of Gynecologic Oncology and Reproductive Medicine and
Carboplatin offers several advantages over cisplatin, Pharmacy Research, The University of Texas M.D. Anderson Cancer
including a more favorable toxicity profile.2,3 Center, Houston, TX, USA
4
Department of Obstetrics, Gynecology and Reproductive Sciences,
Used alone or in combination regimens, carboplatin The University of Texas Medical School at Houston, TX, USA
is effective against various malignancies, such as ovar-
Corresponding author:
ian, testicular, lung, brain, and skin cancers.4–8 An Alan L Myers, M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Unit
aquation reaction (water replacement) of carboplatin 90, Houston TX 77030, USA.
produces its active positively charged chemical moiety Email: almyers@mdanderson.org

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2 Journal of Oncology Pharmacy Practice 0(0)

that binds to DNA, forming intra- and inter-strand have been conducted in only glass containers, and none
adducts that disrupt DNA replication and cause cell have been studied under refrigerated conditions, to
death.9,10 the best of our knowledge. At our institution (The
Carboplatin is a light-sensitive, highly water soluble University of Texas M.D. Anderson Cancer Center;
compound that is supplied as either a lyophilized white UTMDACC), we prepare carboplatin admixtures in
powder11 or a 10 mg/mL premixed solution in sterile NS for special patient populations (e.g. diabetics,
water.12 Per a brand-name manufacturer’s recommen- obese) who are at a heightened risk of hypergly-
dations, the lyophilized powder can initially be recon- cemia.28–30 Moreover, many patients receive carbopla-
stituted to 10 mg/mL with sterile water for injection, tin after a 3-h infusion of paclitaxel, requiring the
5% dextrose in water (D5W), or 0.9% sodium chloride carboplatin–NS admixture to be prepared as on-call
(NS).11 The reconstituted solution or premixed prepar- status. Longer stability data are particularly important
ation is further diluted in D5W or NS to concentrations to facilitate carboplatin desensitization protocols that
as low as 0.5 mg/mL.11,12 Accordingly, the final diluted can take several hours to complete. In multiple agent
infusion solutions are stable up to 8 h at 25 C.11,12 regimens, too, it may be required to prepare admixtures
Currently, there is an abundance of stability data on of carboplatin with other cytotoxic agents using NS as
carboplatin solutions prepared in D5W.13–22 Many of the diluting solvent. Collectively, these operational
these studies have been reviewed elsewhere,23 and a challenges and the absence of unequivocal stability
comprehensive review of the data is beyond the scope data were the impetus to investigate extended carbopla-
of this manuscript. In brief, the stability of carboplatin- tin–NS stability in PVC bags.
D5W infusion solutions stored at room temperature The purpose of this study was to determine the phys-
(25 C) ranges from 1 day to 30 days in various admin- ical and chemical stability of multiple carboplatin infu-
istration packages.13,15–17,20,21 For example, 0.1 mg/mL sion solutions prepared in NS in PVC bags stored at
and 1.0 mg/mL solutions prepared in D5W in glass con- room temperature and under refrigeration.
tainers and stored at 25 C in a water bath were stable
up to one day,15 whereas a 3.2 mg/mL solution stored
in a glass bottle at 25 C was stable up to 28 days.20 In Methods
polyvinyl chloride (PVC) bags at 25 C, the stability of
Sample preparation
various solutions of 0.5 mg/mL was within the range
of 7–21 days.16 In the same study, carboplatin stability All solvents were of HPLC grade or higher purity and
under refrigeration was similar.16 purchased from Fisher Scientific (Fair Lawn, NJ).
Fewer stability studies, however, have been con- Water was prepared by a Milli-Q ultrapure water puri-
ducted on carboplatin solutions prepared in fication system (Millipore; Bedford, MA). Test
NS.15,17,24,25 The dearth of stability studies in NS solu- vials of 10 mg/mL carboplatin injection (10 mg/mL,
tions may be due to concerns of carboplatin instability Teva Parenteral Medicines Inc., Irvine, CA, Lot
in the presence of chloride ions, resulting in hydrolysis #31306252B) and 0.9% NS (USP, Baxter Healthcare
to cisplatin.26 Cheung et al.15 reported that a 0.3 mg/ Corporation, Deerfield, IL) were obtained from the
mL solution of carboplatin in NS in glass containers Division of Pharmacy, The University of Texas M.D.
stored at 25 C in a water bath exhibited a 4.7% intact Anderson Cancer Center (Houston, TX). Carboplatin
drug loss after 24 h. Although not quantified analytic- (Lot # 84H0770), authentic standard, was purchased
ally, they speculated that the observed loss was due to from Sigma-Aldrich Co. (St. Louis, MO).
carboplatin conversion to cisplatin, which they postu- A stock solution of carboplatin reference standard
lated may have clinical importance.15 On the contrary, (1.0 mg/mL) was prepared in water and stored at 4 C.
Perrone et al.24 measured the extent of cisplatin forma- Calibration solutions were diluted from the stock solu-
tion in carboplatin–NS admixtures in glass containers tion with water prior to analysis. Infusion solutions
using a stability-indicating high-performance liquid were prepared by adding appropriate amounts of the
chromatography (HPLC) method; they found only carboplatin injection solution (10 mg/mL) to NS (USP,
0.7% conversion to cisplatin over 24 h when stored at Baxter Healthcare Corporation, Deerfield, IL) in PVC
25 C in a water bath.24 Moreover, Krull et al.27 demon- bags (Baxter Healthcare Corporation, Deerfield, IL) to
strated that a 0.1 mg/mL carboplatin solution in NS a final volume of 100 mL. Carboplatin was filtered
stored at 37 C was stable up to seven days. through a 0.22 mm filter prior to entry into the bags
The manufacturer’s stability threshold of 8 h for NS to minimize the presence of particulates. The final car-
admixtures hampers routine pharmacy operations and boplatin concentrations in PVC bags were 0.5 mg/mL,
clinical practice, and in many clinical scenarios leads to 2.0 mg/mL, and 4.0 mg/mL. Test solutions were pre-
increased drug wastage and expenditures. In addition, pared in triplicate. To simulate routine inpatient phar-
the current literature stability studies on NS admixtures macy and clinical practice at UTMDACC, infusion

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Myers et al. 3

solutions were stored at room temperature under was assessed by visual examination for color change
normal fluorescent light and under refrigeration in and precipitation, and by measuring turbidity, particu-
the dark. late size, and content. Visual examination of all samples
was performed under normal diffuse fluorescent room
light with the unassisted eye. Samples without obvious
Carboplatin assay
visual incompatibility were further examined using a
Carboplatin concentrations were determined by a sta- Tyndall Beam (Dolan-Jenner Industries, Woburn,
bility-indicating HPLC-UV method validated in our MA). Turbidity was assessed with a color-correcting
laboratory. The HPLC system consisted of a Waters turbidimeter (Hach Company, Loveland, CO). Any
2695 Alliance Separations Module (Waters infusion solutions lacking obvious, visible precipitation
Corporation, Milford, MA) equipped with a photo- and turbidity were evaluated using a liquid particle
diode array detector (PDA, Waters Corporation, counting system (Hach Ultra Analytics, Grants Pass,
Milford, MA). The chromatographic separation was OR). Physical instability was defined as visible particu-
achieved on a Vydac C8 (VydacÕ , Grace, Deerfield, late matter, haze, color change, or a change in
IL) analytical column (250  4.6 mm, 5 mm) protected measured turbidity of 0.5 nephelometric turbidity
with a Vydac C8 guard column (VydacÕ , Grace, units (NTU).
Deerfield, IL) by isocratic delivery of mobile phase at For chemical stability tests, 1 mL aliquots were
1.0 mL/min. The mobile phase consisted of water and removed from each bag initially and after 0.25, 1, 2,
methanol mixed in a ratio of 98:2. PDA detection was 3, 5, and 7 days and then transferred to a glass vial.
performed at 210 nm. Under these conditions, carbo- Aliquots of the 0.5 mg/mL, 2.0 mg/mL, and 4.0 mg/mL
platin eluted at approximately 4 min. Each sample ali- solutions were diluted 2.5-, 10-, and 20-fold, respect-
quot was diluted with water to a concentration of ively, prior to HPLC analysis. The initial carboplatin
200 mg/mL prior to HPLC analysis. The injection concentrations were defined as 100% and subsequent
volume was 15 mL. Duplicate HPLC determinations sample concentrations were expressed as percentage of
were performed on triplicate test samples for each con- initial concentrations remaining. Chemical stability of
centration, resulting in a total of six assays at each the drug was defined as not less than 90% of the initial
time point. Data were acquired and processed drug concentration remaining in the solutions.
with the Empower II Software (Waters Corporation,
Milford, MA).
The assay was stability indicating based on acceler- Results
ated degradation of carboplatin solutions. Degraded
samples of carboplatin were assayed by HPLC-PDA
Physical stability
to confirm separation of fresh intact drug from poten- All of the sample solutions were initially clear when
tial degradation products. In all samples, the degrad- viewed under normal laboratory fluorescent light and
ation product peaks were adequately resolved from under the Tyndall Beam. No precipitation occurred in
intact drug, and the PDA detector confirmed the any of the samples. The measured turbidities for all
purity of the carboplatin peak. For a concentration of solutions ranged from 0.15 to 0.2 NTU. No changes
carboplatin 200 mg/mL, the precision of the assay, in measured turbidity were observed at any concentra-
determined from 10 replicate injections, was tion over the duration of the study. The number of
201.1  0.4 mg/mL. Precision expressed as percentage particles sized 10 mm or larger was minimal, ranging
of the relative standard deviation was 0.2%. The from 2 to 30 particles in all samples and less than 10
intra-day and inter-day coefficients of variation were particles in most test solutions.
1.6% and 1.1%, respectively. The calibration curve
was linear in the range 50 mg/mL to 300 mg/mL
Chemical stability
(R2 ¼ 0.9983). Collectively, the assay specifications
were within acceptable limits to conduct the chemical Chemical stability data for carboplatin solutions of
stability testing mentioned herein.31–35 0.5 mg/mL, 2.0 mg/mL, and 4.0 mg/mL prepared in
NS are shown in Table 1. Carboplatin degradation at
room temperature was found to be inversely related to
Physical and chemical stability concentration, as greater stability was observed at the
For physical stability tests, 5 mL of each test sample highest concentration (4.0 mg/mL). Following pro-
was transferred to 15 mL borosilicate glass tubes with longed storage at room temperature, the 2.0 mg/mL
polypropylene screw caps. The tubes had been previ- and 4.0 mg/mL solutions were stable for five days and
ously washed with Milli-Q ultrapure water and air seven days, respectively. The measured carboplatin
dried. The physical stability of the infusion solutions losses of these solutions were 8.5% and 8.2%,

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Table 1. Chemical stability of carboplatin 0.5 mg/mL, 2.0 mg/mL, and 4.0 mg/mL solutions prepared in 0.9% sodium
chloride in PVC bags.

Percent initial concentration remaininga

Drug solution and storage
temperature 1 day 2 days 3 days 5 days 7 days

Carboplatin 0.5 mg/mLb

4 C 97.3  1.4 98.0  0.8 97.6  0.6 96.1  2.1 95.2  1.2
23 C 95.1  0.6 93.1  0.6 91.5  1.4 90.4  0.9 86.8  0.6
Carboplatin 2.0 mg/mLc
4 C 97.9  1.2 98.6  0.6 96.7  0.9 95.8  0.4 95.0  0.5
23 C 96.4  1.2 94.3  0.5 93.2  0.6 91.5  0.9 90.1  0.7
Carboplatin 4.0 mg/mLd
4 C 99.5  0.8 98.6  1.0 96.6  0.6 97.7  0.9 96.4  0.7
23 C 96.7  0.5 96.4  0.5 94.6  0.3 94.7  0.6 91.8  0.5
Infusion solutions stored at room temperature (23 C) were without light protection exposed to ambient fluorescent light, while
refrigerated samples (4 C) were protected from light.
a
The percent concentration remaining is expressed as mean  SD (N ¼ 6) of triplicate solutions (duplicate HPLC runs).
b
Infusion solutions were diluted by 2.5-fold with water prior to HPLC analysis.
c
Diluted 10-fold with water prior to HPLC analysis.
d
Diluted 20-fold with water prior to HPLC analysis.

respectively. The 0.5 mg/mL solution at room tempera- days, respectively. Following the stricter USP guide-
ture was chemically stable for at least three days, in lines for stability criterion (95% initial concentra-
which 8.5% drug loss was observed. The chemical sta- tion),36 the 0.5 mg/mL, 2.0 mg/mL, and 4.0 mg/mL
bility of all admixtures was greater when refrigerated. solutions were stable for at least three days, seven
After the seven-day storage period at 4 C, carboplatin days, and seven days, respectively, when stored under
losses were 6.0% for all test solutions. refrigeration. Also, the stability following storage at
room temperature was at least 24 h, 24 h, and two
days, respectively, when using the 95% criterion.
Discussion Thus, our data confirm that carboplatin is physico-che-
Carboplatin is an essential component of several che- mically stable beyond the manufacturer’s standard of
motherapeutic combinations for the treatment of many 8 h. This information permits greater versatility for car-
solid tumors.4–8 Intravenous admixtures of carboplatin boplatin preparation and administration in NS, such as
are typically prepared in D5W due to concerns of car- in clinical scenarios where patients are more susceptible
boplatin’s instability in NS solutions. However, there to hyperglycemia.
is convincing scientific evidence to indicate that carbo- Cheung et al.15 found that a 1.0 mg/mL carboplatin–
platin’s degradation to cisplatin is clinically insignifi- NS solution prepared in glass containers was stable up
cant.24,27 In designated patient populations (e.g. to 24 h at room temperature (4.7% loss). Our results in
diabetics, obese, renal insufficiency) and in certain clin- more cost-efficient PVC bags are comparable, with only
ical circumstances, preparing carboplatin infusion solu- 4.9% observed carboplatin losses for the three studied
tions in NS is warranted. The current stability data of concentrations. Gust and Schnurr17 studied several car-
carboplatin in NS are limited to only a few studies boplatin–NS admixtures (0.5–10 mg/mL), and reported
which primarily focused on stability in glass containers carboplatin losses of 9.9–10.1% after a seven-day stor-
at room temperature.15,17,24,25 Thus, additional stability age period in brown, glass flasks at room temperature.
data on carboplatin–NS admixtures in more cost-effi- Again, our results in PVC bags are comparable in that
cient PVC bags are required to improve pharmacy we observed carboplatin losses of 8.2–13.2% after
operations and carboplatin administration protocols. seven days with the best stability observed in refriger-
Herein we demonstrate that carboplatin infusion ated samples.
solutions of 0.5 mg/mL, 2.0 mg/mL, and 4.0 mg/mL Platinum compounds such as carboplatin are light-
prepared in NS in PVC bags are physically and chem- sensitive.14,22,37,38 For instance, Torres et al.22 found
ically stable for at least seven days under refrigeration. that in 0.8 mg/mL and 3.2 mg/mL solutions of carbo-
When stored at room temperature without protection platin-5% glucose exposed to light, 10% degradation
from light, these solutions were physico-chemically occurred within 1–10 h depending on light intensity.22
stable for at least three days, five days, and seven Similarly, Pujol et al.38 found that carboplatin

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Myers et al. 5

degradation increased notably under illumination than 7. Giovannetti E, Toffalorio F, De Pas T, et al.
in the dark. On the contrary, our present results dem- Pharmacogenetics of conventional chemotherapy in
onstrate only 5% and 13% degradation after one- non-small-cell lung cancer: a changing landscape?
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light. A possible explanation for this trend of a possible 8. Kushner BH, Modak S, Kramer K, et al. Ifosfamide,
carboplatin, and etoposide for neuroblastoma: a high-
slower rate of photodegradation, which is in contradic-
dose salvage regimen and review of the literature.
tion with previous studies, is scientifically intriguing but
Cancer 2013; 119: 665–671.
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these data further support a greater flexibility of use of chemotherapy. Cytotechnology 1998; 27: 187–201.
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11. Bristol Myers Squibb Company, Princeton, NJ. Paraplatin
Conclusion (carboplatin) for injection package insert, 2010.
In conclusion, carboplatin infusion solutions of 0.5 mg/ 12. Teva Pharmaceuticals USA, Sellersville, PA. Carboplatin
mL, 2.0 mg/mL, and 4.0 mg/mL prepared in NS in PVC injection package insert, 2012.
bags are all physico-chemically stable for at least seven 13. Benaji B, Dine T, Luyckx M, et al. Stability and compati-
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Funding
604.
This research received no specific grant from any funding 17. Gust R and Schnurr B. Investigations on the stability of
agency in the public, commercial, or not-for-profit sectors. carboplatin infusion solutions. Monatshefte fur Chemie
1999; 130: 637–644.
Conflict of interest 18. Hadfield JA, McGown AT, Dawson MJ, et al. The suit-
ability of carboplatin solutions for 14-day continuous
None declared.
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