Stability study of carboplatin infusion solutions in 0.9% sodium chloride in polyvinyl chloride bags.

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Journal of

Oncology Pharmacy Practice

Original Article

Stability study of carboplatin infusion solutions in 0.9% sodium chloride in polyvinyl chloride bags

J Oncol Pharm Practice 0(0) 1–6 ! The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/1078155214546016 opp.sagepub.com

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

Introduction Carboplatin is a platinum-containing antineoplastic agent that is a structural analogue of cisplatin.1 Carboplatin offers several advantages over cisplatin, including a more favorable toxicity profile.2,3 Used alone or in combination regimens, carboplatin is effective against various malignancies, such as ovarian, testicular, lung, brain, and skin cancers.4–8 An aquation reaction (water replacement) of carboplatin produces its active positively charged chemical moiety

1 Department of Pharmacy Research, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA 2 Department of Pharmacy Clinical Programs, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA 3 Departments of Gynecologic Oncology and Reproductive Medicine and Pharmacy Research, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA 4 Department of Obstetrics, Gynecology and Reproductive Sciences, The University of Texas Medical School at Houston, TX, USA

Corresponding author: Alan L Myers, M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Unit 90, Houston TX 77030, USA. Email: [email protected]

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that binds to DNA, forming intra- and inter-strand adducts that disrupt DNA replication and cause cell death.9,10 Carboplatin is a light-sensitive, highly water soluble compound that is supplied as either a lyophilized white powder11 or a 10 mg/mL premixed solution in sterile water.12 Per a brand-name manufacturer’s recommendations, the lyophilized powder can initially be reconstituted to 10 mg/mL with sterile water for injection, 5% dextrose in water (D5W), or 0.9% sodium chloride (NS).11 The reconstituted solution or premixed preparation is further diluted in D5W or NS to concentrations as low as 0.5 mg/mL.11,12 Accordingly, the final diluted infusion solutions are stable up to 8 h at 25 C.11,12 Currently, there is an abundance of stability data on carboplatin solutions prepared in D5W.13–22 Many of these studies have been reviewed elsewhere,23 and a comprehensive review of the data is beyond the scope of this manuscript. In brief, the stability of carboplatinD5W infusion solutions stored at room temperature (25 C) ranges from 1 day to 30 days in various administration packages.13,15–17,20,21 For example, 0.1 mg/mL and 1.0 mg/mL solutions prepared in D5W in glass containers 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 polyvinyl chloride (PVC) bags at 25 C, the stability of various solutions of 0.5 mg/mL was within the range of 7–21 days.16 In the same study, carboplatin stability under refrigeration was similar.16 Fewer stability studies, however, have been conducted on carboplatin solutions prepared in NS.15,17,24,25 The dearth of stability studies in NS solutions may be due to concerns of carboplatin instability in the presence of chloride ions, resulting in hydrolysis to cisplatin.26 Cheung et al.15 reported that a 0.3 mg/ mL solution of carboplatin in NS in glass containers stored at 25 C in a water bath exhibited a 4.7% intact drug loss after 24 h. Although not quantified analytically, they speculated that the observed loss was due to carboplatin conversion to cisplatin, which they postulated may have clinical importance.15 On the contrary, Perrone et al.24 measured the extent of cisplatin formation in carboplatin–NS admixtures in glass containers using a stability-indicating high-performance liquid chromatography (HPLC) method; they found only 0.7% conversion to cisplatin over 24 h when stored at 25 C in a water bath.24 Moreover, Krull et al.27 demonstrated that a 0.1 mg/mL carboplatin solution in NS stored at 37 C was stable up to seven days. The manufacturer’s stability threshold of 8 h for NS admixtures hampers routine pharmacy operations and clinical practice, and in many clinical scenarios leads to increased drug wastage and expenditures. In addition, the current literature stability studies on NS admixtures

have been conducted in only glass containers, and none have been studied under refrigerated conditions, to the best of our knowledge. At our institution (The University of Texas M.D. Anderson Cancer Center; UTMDACC), we prepare carboplatin admixtures in NS for special patient populations (e.g. diabetics, obese) who are at a heightened risk of hyperglycemia.28–30 Moreover, many patients receive carboplatin after a 3-h infusion of paclitaxel, requiring the carboplatin–NS admixture to be prepared as on-call status. Longer stability data are particularly important to facilitate carboplatin desensitization protocols that can take several hours to complete. In multiple agent regimens, too, it may be required to prepare admixtures of carboplatin with other cytotoxic agents using NS as the diluting solvent. Collectively, these operational challenges and the absence of unequivocal stability data were the impetus to investigate extended carboplatin–NS stability in PVC bags. The purpose of this study was to determine the physical and chemical stability of multiple carboplatin infusion solutions prepared in NS in PVC bags stored at room temperature and under refrigeration.

Methods Sample preparation All solvents were of HPLC grade or higher purity and purchased from Fisher Scientific (Fair Lawn, NJ). Water was prepared by a Milli-Q ultrapure water purification system (Millipore; Bedford, MA). Test vials of 10 mg/mL carboplatin injection (10 mg/mL, Teva Parenteral Medicines Inc., Irvine, CA, Lot #31306252B) and 0.9% NS (USP, Baxter Healthcare Corporation, Deerfield, IL) were obtained from the Division of Pharmacy, The University of Texas M.D. Anderson Cancer Center (Houston, TX). Carboplatin (Lot # 84H0770), authentic standard, was purchased from Sigma-Aldrich Co. (St. Louis, MO). A stock solution of carboplatin reference standard (1.0 mg/mL) was prepared in water and stored at 4 C. Calibration solutions were diluted from the stock solution with water prior to analysis. Infusion solutions were prepared by adding appropriate amounts of the carboplatin injection solution (10 mg/mL) to NS (USP, Baxter Healthcare Corporation, Deerfield, IL) in PVC bags (Baxter Healthcare Corporation, Deerfield, IL) to a final volume of 100 mL. Carboplatin was filtered through a 0.22 mm filter prior to entry into the bags to minimize the presence of particulates. The final carboplatin concentrations in PVC bags were 0.5 mg/mL, 2.0 mg/mL, and 4.0 mg/mL. Test solutions were prepared in triplicate. To simulate routine inpatient pharmacy and clinical practice at UTMDACC, infusion



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solutions were stored at room temperature under normal fluorescent light and under refrigeration in the dark.

Carboplatin assay Carboplatin concentrations were determined by a stability-indicating HPLC-UV method validated in our laboratory. The HPLC system consisted of a Waters 2695 Alliance Separations Module (Waters Corporation, Milford, MA) equipped with a photodiode array detector (PDA, Waters Corporation, Milford, MA). The chromatographic separation was achieved on a Vydac C8 (VydacÕ , Grace, Deerfield, IL) analytical column (250 4.6 mm, 5 mm) protected with a Vydac C8 guard column (VydacÕ , Grace, Deerfield, IL) by isocratic delivery of mobile phase at 1.0 mL/min. The mobile phase consisted of water and methanol mixed in a ratio of 98:2. PDA detection was performed at 210 nm. Under these conditions, carboplatin eluted at approximately 4 min. Each sample aliquot was diluted with water to a concentration of 200 mg/mL prior to HPLC analysis. The injection volume was 15 mL. Duplicate HPLC determinations were performed on triplicate test samples for each concentration, resulting in a total of six assays at each time point. Data were acquired and processed with the Empower II Software (Waters Corporation, Milford, MA). The assay was stability indicating based on accelerated degradation of carboplatin solutions. Degraded samples of carboplatin were assayed by HPLC-PDA to confirm separation of fresh intact drug from potential degradation products. In all samples, the degradation product peaks were adequately resolved from intact drug, and the PDA detector confirmed the purity of the carboplatin peak. For a concentration of carboplatin 200 mg/mL, the precision of the assay, determined from 10 replicate injections, was 201.1 0.4 mg/mL. Precision expressed as percentage of the relative standard deviation was 0.2%. The intra-day and inter-day coefficients of variation were 1.6% and 1.1%, respectively. The calibration curve was linear in the range 50 mg/mL to 300 mg/mL (R2 ¼ 0.9983). Collectively, the assay specifications were within acceptable limits to conduct the chemical stability testing mentioned herein.31–35

Physical and chemical stability For physical stability tests, 5 mL of each test sample was transferred to 15 mL borosilicate glass tubes with polypropylene screw caps. The tubes had been previously washed with Milli-Q ultrapure water and air dried. The physical stability of the infusion solutions

was assessed by visual examination for color change and precipitation, and by measuring turbidity, particulate size, and content. Visual examination of all samples was performed under normal diffuse fluorescent room light with the unassisted eye. Samples without obvious visual incompatibility were further examined using a Tyndall Beam (Dolan-Jenner Industries, Woburn, MA). Turbidity was assessed with a color-correcting turbidimeter (Hach Company, Loveland, CO). Any infusion solutions lacking obvious, visible precipitation and turbidity were evaluated using a liquid particle counting system (Hach Ultra Analytics, Grants Pass, OR). Physical instability was defined as visible particulate matter, haze, color change, or a change in measured turbidity of 0.5 nephelometric turbidity units (NTU). For chemical stability tests, 1 mL aliquots were removed from each bag initially and after 0.25, 1, 2, 3, 5, and 7 days and then transferred to a glass vial. Aliquots of the 0.5 mg/mL, 2.0 mg/mL, and 4.0 mg/mL solutions were diluted 2.5-, 10-, and 20-fold, respectively, prior to HPLC analysis. The initial carboplatin concentrations were defined as 100% and subsequent sample concentrations were expressed as percentage of initial concentrations remaining. Chemical stability of the drug was defined as not less than 90% of the initial drug concentration remaining in the solutions.

Results Physical stability All of the sample solutions were initially clear when viewed under normal laboratory fluorescent light and under the Tyndall Beam. No precipitation occurred in any of the samples. The measured turbidities for all solutions ranged from 0.15 to 0.2 NTU. No changes in measured turbidity were observed at any concentration over the duration of the study. The number of particles sized 10 mm or larger was minimal, ranging from 2 to 30 particles in all samples and less than 10 particles in most test solutions.

Chemical stability Chemical stability data for carboplatin solutions of 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 concentration, as greater stability was observed at the highest concentration (4.0 mg/mL). Following prolonged storage at room temperature, the 2.0 mg/mL and 4.0 mg/mL solutions were stable for five days and seven days, respectively. The measured carboplatin losses of these solutions were 8.5% and 8.2%,



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Journal of Oncology Pharmacy Practice 0(0) 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 Carboplatin 0.5 mg/mLb 4 C 23 C Carboplatin 2.0 mg/mLc 4 C 23 C Carboplatin 4.0 mg/mLd 4 C 23 C

1 day

2 days

3 days

5 days

7 days

97.3 1.4 95.1 0.6

98.0 0.8 93.1 0.6

97.6 0.6 91.5 1.4

96.1 2.1 90.4 0.9

95.2 1.2 86.8 0.6

97.9 1.2 96.4 1.2

98.6 0.6 94.3 0.5

96.7 0.9 93.2 0.6

95.8 0.4 91.5 0.9

95.0 0.5 90.1 0.7

99.5 0.8 96.7 0.5

98.6 1.0 96.4 0.5

96.6 0.6 94.6 0.3

97.7 0.9 94.7 0.6

96.4 0.7 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 temperature was chemically stable for at least three days, in which 8.5% drug loss was observed. The chemical stability of all admixtures was greater when refrigerated. After the seven-day storage period at 4 C, carboplatin losses were 6.0% for all test solutions.

Discussion Carboplatin is an essential component of several chemotherapeutic combinations for the treatment of many solid tumors.4–8 Intravenous admixtures of carboplatin are typically prepared in D5W due to concerns of carboplatin’s instability in NS solutions. However, there is convincing scientific evidence to indicate that carboplatin’s degradation to cisplatin is clinically insignificant.24,27 In designated patient populations (e.g. diabetics, obese, renal insufficiency) and in certain clinical circumstances, preparing carboplatin infusion solutions in NS is warranted. The current stability data of carboplatin in NS are limited to only a few studies which primarily focused on stability in glass containers at room temperature.15,17,24,25 Thus, additional stability data on carboplatin–NS admixtures in more cost-efficient PVC bags are required to improve pharmacy operations and carboplatin administration protocols. Herein we demonstrate that carboplatin infusion solutions of 0.5 mg/mL, 2.0 mg/mL, and 4.0 mg/mL prepared in NS in PVC bags are physically and chemically stable for at least seven days under refrigeration. When stored at room temperature without protection from light, these solutions were physico-chemically stable for at least three days, five days, and seven

days, respectively. Following the stricter USP guidelines for stability criterion (95% initial concentration),36 the 0.5 mg/mL, 2.0 mg/mL, and 4.0 mg/mL solutions were stable for at least three days, seven days, and seven days, respectively, when stored under 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. Thus, our data confirm that carboplatin is physico-chemically stable beyond the manufacturer’s standard of 8 h. This information permits greater versatility for carboplatin preparation and administration in NS, such as in clinical scenarios where patients are more susceptible to hyperglycemia. Cheung et al.15 found that a 1.0 mg/mL carboplatin– NS solution prepared in glass containers was stable up to 24 h at room temperature (4.7% loss). Our results in more cost-efficient PVC bags are comparable, with only 4.9% observed carboplatin losses for the three studied concentrations. Gust and Schnurr17 studied several carboplatin–NS admixtures (0.5–10 mg/mL), and reported carboplatin losses of 9.9–10.1% after a seven-day storage period in brown, glass flasks at room temperature. Again, our results in PVC bags are comparable in that we observed carboplatin losses of 8.2–13.2% after seven days with the best stability observed in refrigerated samples. Platinum compounds such as carboplatin are lightsensitive.14,22,37,38 For instance, Torres et al.22 found that in 0.8 mg/mL and 3.2 mg/mL solutions of carboplatin-5% glucose exposed to light, 10% degradation occurred within 1–10 h depending on light intensity.22 Similarly, Pujol et al.38 found that carboplatin



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degradation increased notably under illumination than in the dark. On the contrary, our present results demonstrate only 5% and 13% degradation after oneday and seven-day storage under ambient fluorescent light. A possible explanation for this trend of a possible slower rate of photodegradation, which is in contradiction with previous studies, is scientifically intriguing but is beyond the scope of the current study. Nonetheless, these data further support a greater flexibility of use of carboplatin–NS intravenous solutions in routine clinical practice.

Conclusion In conclusion, carboplatin infusion solutions of 0.5 mg/ mL, 2.0 mg/mL, and 4.0 mg/mL prepared in NS in PVC bags are all physico-chemically stable for at least seven days under refrigeration stored in dark conditions. The same solutions stored at room temperature, exposed to ambient fluorescent light, are physico-chemically stable for at least three days, five days, and seven days, respectively. However, since no antibacterial preservative is contained within these carboplatin formulations, we recommend that these intravenous solutions, when prepared under proper aseptic techniques, be used within 24 h at room temperature or three days under refrigeration. Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflict of interest None declared.

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