Quanyun A Xu

Stability of Three Cephalosporin Antibiotics in AutoDose Infusion System Bags

OBJECTIVE To evaluate the physical and chemical stability of three commonly used cephalosporin antibiotic solutions packaged in AutoDose Infusion System bags stored and evaluated at appropriate intervals for up to 7 days at 23 degrees C and up to 30 days at 4 degrees C. SETTING Laboratory. INTERVENTIONS The test samples were prepared by adding the required amount of the cephalosporin antibiotic to the AutoDose Infusion System bags and diluting to the target concentration with 0.9% sodium chloride injection. MAIN OUTCOME MEASURES Physical stability and chemical stability based on drug concentrations initially and at appropriate intervals over periods of up to 7 days at 23 degrees C and up to 30 days at 4 degrees C. RESULTS All of the cephalosporin admixtures were clear when viewed in normal fluorescent room light and with a Tyndall beam. Measured turbidity and particulate content were low and exhibited little change. The cefazolin sodium-containing samples were colorless throughout the study. The admixtures with ceftazidime and ceftriaxone sodium had a slight yellow tinge initially, and the room temperature samples turned a frank yellow color after 5 days. The refrigerated samples did not change color. High-performance liquid chromatography analysis showed that cefazolin sodium and ceftriaxone sodium remained stable for 30 days and ceftazidime remained stable for 7 days at 4 degrees C. At room temperature, losses were much more rapid. Cefazolin sodium and ceftriaxone sodium retained at least 90% of their initial concentrations through 7 days and 5 days, respectively, when stored at 23 degrees C. Ceftazidime remained stable for only 1 day at 23 degrees C. CONCLUSION Cefazolin sodium, ceftazidime, and ceftriaxone sodium exhibited physical and chemical stabilities consistent with those found in previous studies of these drugs. The AutoDose Infusion System bags did not adversely affect the physical and chemical stabilities of these three cephalosporin antibiotics.

Compatibility and Stability of Paclitaxel Combined with Cisplatin and with Carboplatin in Infusion Solutions

OBJECTIVE: To evaluate the physical compatibility and chemical stability of paclitaxel at concentrations of 0.3 and 1.2 mg/mL with cisplatin 0.2 mg/mL in NaCl 0.9% injection and with carboplatin 2 mg/mL in NaCl 0.9% injection and dextrose 5% injection over 7 days at 4, 23, and 32°C. DESIGN: The test samples were prepared in polyolefin bags of the infusion solutions at the required drug concentrations. Evaluations were performed initially and after 4 hours, and 1, 3, 5, and 7 days of storage at temperatures of 4, 23, and 32°C for physical and chemical stability. Physical stability was assessed by using visual observation in normal light and using a high-intensity monodirectional light beam. In addition, turbidity and particle content were measured electronically. Chemical stability of the three drugs was evaluated by using three stability-indicating HPLC analytical techniques. RESULTS: All samples were physically stable through 1 day. However, microcrystalline precipitation of paclitaxel occurred in 3 days in some samples and within 5 days in all samples. Paclitaxel concentrations remained above 90% in all samples throughout the study. Cisplatin admixtures exhibited paclitaxel concentration-dependent decomposition with cisplatin losses of approximately 5–8% in 4 hours and approximately 20% in 1 day at 23 and 32°C in the paclitaxel 1.2 mg/mL admixtures. With paclitaxel 0.3 mg/mL in the admixtures, cisplatin losses were about 10% in 7 days at these temperatures. Carboplatin in admixtures with both concentrations of paclitaxel was stable for 7 days at 4°C, but sustained losses of about 10% and 12% in 3 days at 23 and 32°C, respectively. CONCLUSIONS: Admixtures of paclitaxel 0.3 and 1.2 mg/mL with cisplatin and carboplatin are limited in their utility time by both paclitaxel microcrystalline precipitation and decomposition of cisplatin and carboplatin. The admixture of paclitaxel 1.2 mg/mL with cisplatin 0.2 mg/mL in NaCl 0.9% injection exhibits unacceptable cisplatin loss in 24 hours. All other combinations were physically and chemically stable for at least 24 hours at 4, 23, and 32°C.

Compatibility and Stability of Linezolid Injection Admixed with Three Quinolone Antibiotics

OBJECTIVE: To evaluate the physical compatibility and chemical stability of linezolid 200 mg/100 mL admixed with ciprofloxacin 400 mg, ofloxacin 400 mg, and levofloxacin 500 mg for seven days at 4 and 23 °C. METHODS: The test samples were prepared by adding the required amount of the quinolone antibiotic to bags of linezolid injection. Evaluations for physical and chemical stability were performed initially and after one, three, five, and seven days of storage at temperatures of 4 and 23 °C. Physical stability was assessed using visual observation in normal light and using a high-intensity monodirectional light beam. In addition, turbidity and particle content were measured electronically. Chemical stability of the drugs was evaluated by using stability-indicating HPLC analytical techniques. RESULTS: The linezolid admixtures with levofloxacin and ofloxacin were clear and pale yellow when viewed in normal fluorescent room light, and slightly hazy with a green cast when viewed using a Tyndall beam. Measured turbidity and particulate content were low and exhibited little change. HPLC analysis found no loss of the drugs in any sample stored at either temperature throughout the study. The linezolid admixtures with ciprofloxacin stored at room temperature (23 °C) were clear and nearly colorless in normal room light and when viewed using a Tyndall beam. They exhibited little or no change in measured turbidity or particulate content during the study period. HPLC analysis found no loss of either drug in seven days. However, the refrigerated samples were only compatible for 24 hours and developed a gross white precipitate thereafter. CONCLUSIONS: Admixtures of linezolid 200 mg/100 mL with levofloxacin 500 mg and with ofloxacin 400 mg were physically compatible and chemically stable for at least seven days stored at 4 and 23 °C. Admixtures of linezolid with ciprofloxacin 400 mg were compatible and stable for seven days at 23 °C, but ciprofloxacin precipitation occurred after 24 hours stored under refrigeration. Linezolid/ciprofloxacin admixtures should not be stored under refrigeration.

Stability of Cefepime Hydrochloride in AutoDose Infusion System Bags

OBJECTIVE: To evaluate the physical and chemical stability of cefepime (as the hydrochloride) 1 g/100 mL and 4 g/100 mL admixed in NaCl 0.9% injection and packaged in AutoDose Infusion System bags. DESIGN: Triplicate test samples of cefepime hydrochloride in NaCl 0.9% injection were packaged in ethylene vinyl acetate plastic containers, AutoDose bags, designed for use in the AutoDose Infusion System. Samples were stored protected from light and evaluated at appropriate intervals for up to 7 days at room temperature of approximately 23 °C and 30 days under refrigeration at 4 °C. Physical stability was assessed using turbidimetric and particulate measurement, as well as visual inspection. Chemical stability was assessed by HPLC. RESULTS: All of the admixtures were initially clear and light yellow when viewed in normal fluorescent room light and with a Tyndall beam. Measured turbidity and particulate content were low initially but increased over time, eventually becoming a yellow or orange precipitate. The higher concentration precipitated earlier; refrigeration slowed precipitation for both test concentrations. HPLC analysis found that the 1-g/100 mL concentration maintained adequate stability for 2 days at 23 °C and up to 30 days at 4 °C. The 4-g/100 mL concentration maintained adequate stability for 1 day at room temperature and 7 days under refrigeration; however, unacceptable drug loss and precipitation developed after those time points. CONCLUSIONS: Cefepime hydrochloride exhibited physical and chemical stability consistent with previous stability studies. The AutoDose Infusion System bags were not found to affect adversely the physical and chemical stability of this drug.

Stability of Ciprofloxacin and Vancomycin Hydrochloride in AutoDose Infusion System Bags

The objective of this study was to evaluate the physical and chemical stability of ciprofloxacin 400 mg/100 mL and vancomycin as the hydrochloride 1 g/100 mL each admixed in 0.9% sodium chloride injection packaged in AutoDose Infusion System bags. Triplicate test samples were prepared by admixing the necessary amount of each antibiotic with a portion of 0.9% sodium chloride injection and bringing the admixture of each drug to a final volume of 100 mL with additional 0.9% sodium chloride injection. The test solutions were packaged in ethylene vinyl acetate (EVA) plastic containers (AutoDose dags) designed for use in the AutoDose Infusion System. Samples were protected from light and evaluated at appropriate intervals for up to 7 days at 23°C and up to 30 days at 4°C. Physical stability was assessed using a multistep evaluation procedure that included turbidimetric and particulate measurement as well as visual inspection. Chemical stability was assessed using stability-indicating HPLC analytical techniques based on the determination of drug concentrations initially and at appropriate intervals over the study periods. The admixtures were clear and colorless when viewed in normal fluorescent room light and with a Tyndall beam. Measured turbidity and particulate content were low and exhibited little change. HPLC analysis found that both ciprofloxacin and vancomycin hydrochloride remained stable for 30 days at 4°C and 7 days at 23°C. Both ciprofloxacin and vancomycin hydrochloride exhibited physical and chemical stability consistent with previous studies on these drugs. The AutoDose Infusion System bags were not found to affect adversely the physical and chemical stability of these antibiotics.

Compatibility and Stability of Linezolid Injection Admixed with Three Cephalosporin Antibiotics

OBJECTIVE To evaluate the physical compatibility and chemical stability of linezolid (Zyvox-Pharmacia) 200 mg/100 mL admixed with cefazolin sodium 1 gram, ceftazidime 2 grams, and ceftriaxone sodium 1 gram for 7 days at 4 degrees C and 23 degrees C. DESIGN Controlled experimental trial. SETTING Laboratory. INTERVENTIONS The test samples were prepared by adding the required amount of the cephalosporin antibiotic to bags of linezolid injection 200 mg/100 mL. MAIN OUTCOME MEASURES Physical stability and chemical stability based on drug concentrations initially and after 1, 3, 5, and 7 days of storage at 4 degrees C and 23 degrees C protected from light. RESULTS All of the linezolid admixtures with cephalosporins were clear when viewed in normal fluorescent room light and with a Tyndall beam. Measured turbidity and particulate content were low and exhibited little change. The cefazolin sodium-containing samples were colorless throughout the study. The admixtures with ceftazidime and ceftriaxone sodium had a slight yellow tinge initially, and the room temperature samples became a frank yellow color after 5 days. The refrigerated samples did not change color. High-performance liquid chromatography analysis found little or no loss of linezolid in any sample stored at either temperature throughout the study. Cefazolin sodium and ceftazidime in the linezolid admixtures at 4 degrees C remained stable for 7 days, but at 23 degrees C cefazolin sodium was stable for 3 days and ceftazidime for only 24 hours before cephalosporin decomposition exceeded 10%. Ceftriaxone sodium was less stable in the admixtures; 10% loss occurred in 3 days at 4 degrees C and more than 20% loss occurred in 24 hours at 23 degrees C. CONCLUSION Admixtures of linezolid 200 mg/100 mL with cefazolin sodium 1 gram and ceftazidime 2 grams were physically compatible and chemically stable for at least 7 days stored at 4 degrees C protected from light and for 3 days and 1 day, respectively, at 23 degrees C protected from light. Admixtures of linezolid with ceftriaxone sodium 1 gram exhibited a rapid rate of cephalosporin loss at 23 degrees C, which precludes admixture of the two drugs.

Rapid loss of fentanyl citrate admixed with fluorouracil in polyvinyl chloride containers.

Objective To study the physical compatibility and chemical stability of fluorouracil 1 and 16 mg/mL with fentanyl citrate 12.5 μg/mL in dextrose 5% and in sodium chloride 0.9% injection. Design Test solutions of the drugs in dextrose 5% injection and in sodium chloride 0.9% injection were prepared in triplicate and stored at −20, 4, 23, and 32 °C. Samples were removed immediately and at various times over 7 days and stored at −70 °C until analyzed. Physical compatibility was assessed visually and by measuring turbidity with a color-correcting turbidimeter; particle content was measured with a light-obscuration particle sizer and counter. Chemical stability was determined by measuring the concentration of each drug in the test solutions in duplicate with stability-indicating HPLC. Results Fentanyl citrate was rapidly lost when admixed with fluorouracil in polyvinyl chloride (PVC) containers, losing about 25% in the first 15 minutes and about 50% in the first hour. The loss of fentanyl citrate was so rapid that accurate time zero determinations were not possible. The extent of fentanyl loss increased with time and occurred more rapidly at the higher temperatures (i.e., 23,32 °C). Losses of 70% or more occurred in all samples within 24 hours. Fentanyl underwent rapid sorption to the containers at the high pH (9.0–9.5) of the fluorouracil admixtures. Adjusting the pH of a fentanyl citrate solution (containing no fluorouracil) in PVC containers to pH 9 with sodium hydroxide also resulted in rapid sorption loss. Fentanyl citrate sorption did not occur when admixtures were prepared in polyethylene containers. Fluorouracil remained stable for at least 7 days at all temperatures. There were no visual or subvisual changes in turbidity or particle content in any of the test solutions at any time. Conclusions When admixed with fluorouracil 1 and 16 mg/mL in dextrose 5% injection and sodium chloride 0.9% injection, fentanyl citrate 12.5 μg/mL underwent rapid and extensive loss due to sorption to the PVC containers, making the combination unacceptable within minutes of mixing. The sorption results from the alkaline pH of the admixture and, presumably, could occur from the admixture of fentanyl citrate with any sufficiently alkaline drug.

Stability and Compatibility of Fluorouracil with Morphine Sulfate and Hydromorphone Hydrochloride

OBJECTIVE: To study the physical compatibility and chemical stability of fluorouracil 1 and 16 mg/mL with morphine sulfate 1 mg/mL and with hydromorphone hydrochloride 0.5 mg/mL in dextrose 5% injection and in NaCl 0.9% injection. DESIGN: Test solutions of the drugs in dextrose 5% and in NaCl 0.9% were prepared in triplicate and stored at −20, 4, 23, and 32°C. Samples were removed immediately and at various time points over 35 days and stored at −70 °C until analyzed. Physical compatibility was assessed visually and by measuring turbidity with a color-correcting turbidimeter and particle content with a light-obscuration particle sizer and counter. Chemical stability was determined by measuring the concentration of each drug in the test solutions in duplicate with stability-indicating HPLC. RESULTS: The morphine test solutions all rapidly developed crystalline precipitation when admixed with fluorouracil. Further, substantial loss of morphine content, usually around 60-80%, occurred in all samples within 24 hours at all temperatures. There were no visual or subvisual changes in turbidity or particle content in any of the fluorouracil with hydromorphone test solutions at any of the time points. Further, there was no loss of fluorouracil over 7 days at 32 °C and 35 days at 23, 4, and −20 °C. Hydromorphone also was stable for 7 days at 32 °C and for 35 days at the other temperatures when combined with fluorouracil 1 mg/mL and at −20 and 4 °C with fluorouracil 16 mg/mL. However, with fluorouracil 16 mg/mL, hydromorphone was stable only for 3 days at 32 °C and for 7 days at 23 °C, exhibiting approximately 10% loss after those times. CONCLUSIONS: When admixed in dextrose 5% injection and NaCl 0.9% injection, fluorouracil 1 and 16 mg/mL and morphine 0.5 mg/mL were immediately physically incompatible in all samples resulting in substantial loss of morphine content as precipitated crystals. Fluorouracil 1 mg/mL plus hydromorphone 0.5 mg/mL were compatible and stable for at least 7 days at 32 °C and for at least 35 days at 23, 4, and −20 °C. Admixed with fluorouracil 16 mg/mL, hydromorphone was stable for 3 days at 32 °C, 7 days at 23 °C, and 35 days at 4 and −20 °C.

Stability of busulfan injection admixtures in 5 % dextrose injection and 0.9% sodium chloride injection:

Objective. The purpose of this study was to deter mine the stability of busulfan injection at 0.5 and 0.1 mg/mL admixed in 5% dextrose injection and 0.9% sodium chloride injection in PVC and polyolefm bags over 24 hours at 23°C. Methods. The busulfan injection was prepared by dissolving the bulk powder in a 1:2 mixture of N,N-dimethylacetamide and polyethylene glycol 400 to form a 6 mg/mL solution. The injection was filtered and admixed in the infusion solutions to yield busulfan concentrations of 0.5 and 0.1 mg/mL. Evaluations were performed initially and after 4, 8, and 24 hours of storage for physical and chemical stability. The admix tures were evaluated for physical stability using visual observation in normal light and using a high-intensity monodirectional light beam as well as measuring turbidity. The chemical stability was evaluated by using a stability-indicating HPLC analytical technique. Results. No physical instabilities were observed. However, busulfan is chemically unstable. At 0.5 mg/mL, potency of at least 95% was retained through 4 hours and at least 90% was retained through 8 hours. After 24 hours, losses of 20% to 30% occurred. At 0.1 mg/mL, drug loss was more rapid. Potency of at least 90% was retained through 4 hours. Losses after 24 hours were about 30% to 40%. Conclusions. Busulfan injection admixed in 5% dextrose injection or 0.9% sodium chloride injection is unstable. At a concentration of 0.5 mg/mL, ade quate drug delivery is provided within 8 hours of admixture. At the lower concentration of 0.1 mg/mL, adequate drug delivery is only provided for 4 hours.

Compatibility of Ondansetron Hydrochloride with Meperidine Hydrochloride for Combined Administration

Objective: To determine the physical compatibility and chemical stability of ondansetron hydrochloride 0.1 and 1 mg/mL with meperidine hydrochloride 4 mg/mL admixed in NaCl 0.9% injection USP. Design: Triplicate test solutions of the drugs in NaCl 0.9% injection USP were prepared and stored at 4,22, and 32 °C. Samples were removed initially and at various time points over 31 days and were stored at −70 °C until they were analyzed. Physical compatibility was assessed by measuring solution turbidity with a color-correcting turbidimeter and particle content with a light-obscuration particle sizer/counter, as well as by visual assessment. Chemical stability of the drugs was determined using a stability-indicating HPLC analytic method. Duplicate determinations were performed on each sample to measure the concentration of each drug. Results: All admixtures were found to exhibit no visual or subvisual changes of consequence in turbidity or particle content at all observation points. Further, little or no loss of any of the drugs occurred in any concentration throughout the study. Conclusions: The physical compatibility and chemical stability of ondansetron hydrochloride with meperidine hydrochloride under the conditions of this study have been established for 7 days at 32 °C and 31 days at 4 and 22 °C.