Complex I inhibitor of oxidative phosphorylation in advanced solid tumors and acute myeloid leukemia: phase I trials.

Although targeting oxidative phosphorylation (OXPHOS) is a rational anticancer strategy, clinical benefit with OXPHOS inhibitors has yet to be achieved. Here we advanced IACS-010759, a highly potent and selective small-molecule complex I inhibitor, into two dose-escalation phase I trials in patients with relapsed/refractory acute myeloid leukemia (NCT02882321, n = 17) and advanced solid tumors (NCT03291938, n = 23). The primary endpoints were safety, tolerability, maximum tolerated dose and recommended phase 2 dose (RP2D) of IACS-010759. The PK, PD, and preliminary antitumor activities of IACS-010759 in patients were also evaluated as secondary endpoints in both clinical trials. IACS-010759 had a narrow therapeutic index with emergent dose-limiting toxicities, including elevated blood lactate and neurotoxicity, which obstructed efforts to maintain target exposure. Consequently no RP2D was established, only modest target inhibition and limited antitumor activity were observed at tolerated doses, and both trials were discontinued. Reverse translational studies in mice demonstrated that IACS-010759 induced behavioral and physiological changes indicative of peripheral neuropathy, which were minimized with the coadministration of a histone deacetylase 6 inhibitor. Additional studies are needed to elucidate the association between OXPHOS inhibition and neurotoxicity, and caution is warranted in the continued development of complex I inhibitors as antitumor agents.

Drug compatibility with new polyolefin infusion solution containers.

PURPOSE: The compatibility of new polyolefin (VISIV) containers with seven drugs that have exhibited sorption to polyvinyl chloride (PVC) containers and sets and an additional four drugs that have exhibited leaching of plasticizer or other polymer matrix components from PVC containers and sets was studied. METHODS: For the sorption portion of the study, amiodarone hydrochloride, carmustine, regular human insulin, lorazepam, nitroglycerin, sufentanil citrate, and thiopental sodium and their respective reference standards were used. For the leaching portion of the study, docetaxel, paclitaxel, tacrolimus, teniposide, and diethylhexyl phthalate (DEHP) reference standard, were used. A 350-mL quantity of each test admixture was prepared, and 100-mL aliquots were transferred into three of the VISIV containers. The containers were stored at ambient temperature and exposed to fluorescent light. Samples for analysis were taken initially and after 24 hours for all drugs except carmustine, which was evaluated for only 6 hours because of its limited stability. High-performance liquid chromatography was used to evaluate each test solution. RESULTS: Of the seven drugs subject to sorption to PVC, only insulin showed a substantial loss in the VISIV containers. Carmustine exhibited a loss consistent with the drug's known chemical stability. None of the drugs that are known to leach plastic components, such as DEHP plasticizer, from PVC equipment exhibited any leached components in the VISIV containers. CONCLUSION: Of the drugs tested, only insulin exhibited sorption to the new VISIV polyolefin containers. No leaching of plastic components, such as plasticizer, from the containers was found with any of the surfactant-containing drugs.

Physical and chemical stability of palonosetron hydrochloride with dacarbazine and with methylprednisolone sodium succinate during simulated y-site administration.

The objective of this study was to evaluate the physical and chemical stability of mixtures of undiluted palonosetron hydrochloride 50 micrograms/mL with dacarbazine 4 mg/mL and with methylprednisolone sodium succinate 5 mg/mL in 5% dextrose injection during simulated Y-site administration. Triplicate test samples were prepared by admixing 7.5 mL of palonosetron hydrochloride with 7.5 mL of dacarbazine solution and, separately, methylprednisolone sodium succinate solution. Physical stability was assessed by using a multistep evaluation procedure that included both turbidimetric and particulate measurement as well as visual inspection. Chemical stability was assessed by using stability-indicating high-performance liquid chromatographic analytical techniques that determined drug concentrations. Evaluations were performed immediately after mixing and 1 and 4 hours after mixing. The palonosetron hydrochloride-dacarbazine samples were clear and colorless when viewed in normal fluorescent room light and when viewed with a Tyndall beam. Measured turbidities remained unchanged; particulate contents were low and exhibited little change. High-performance liquid chromatography analysis revealed that palonosetron hydrochloride and dacarbazine remained stable throughout the 4-hour test with no drug loss. Palonosetron hydrochloride is, therefore, physically compatible and chemically stable with dacarbazine during Y-site administration. Within 4 hours, the mixtures of palonosetron hydrochloride and methylprednisolone sodium succinate developed a microprecipitate that became a white precipitate visible to the unaided eye. The precipitate was analyzed and identified as methylprednisolone. Palonosetron hydrochloride is incompatible with methylprednisolone sodium succinate.

Compatibility of palonosetron with cyclophosphamide and with ifosfamide during simulated Y-site administration.

PURPOSE: The physical and chemical compatibility of palonosetron with cyclophosphamide and with ifosfamide during simulated Y-site administration was studied. METHODS: Test samples were prepared in triplicate by mixing 7.5 mL of palonosetron hydrochloride 50 microg (of palonosetron) per milliliter with 7.5 mL of cyclophosphamide 10 mg/mL and with ifosfamide 20 mg/mL. Physical stability was assessed by turbidimetry, particle sizing, and visual inspection. Chemical stability was assessed by stability-indicating high-performance liquid chromatography. Evaluations were performed immediately and one and four hours after mixing. RESULTS: The samples were clear and colorless when viewed in normal fluorescent room light and when viewed with a high-intensity monodirectional light. Turbidity remained unchanged, and particulate content was low and exhibited little change. Palonosetron, cyclophosphamide, and ifosfamide remained chemically stable throughout the four-hour test period. CONCLUSION: Palonosetron hydrochloride was physically compatible with cyclophosphamide or ifosfamide during simulated Y-site administration.

Physical and chemical stability of palonosetron hydrochloride with Lorazepam and midazolam hydrochloride during simulated y-site administration.

The objective of this study was to evaluate the physical and chemical stability of undiluted palonosetron hydrochloride 50 micrograms/mL in combination with lorazepam 0.5 mg/mL or midazolam hydrochloride 2 mg/mL in 5% dextrose injection during simulated Y-site administration. Triplicate test samples were prepared by admixing 5 mL of palonosetron hydrochloride with 5 mL of the lorazepam or midazolam hydrochloride admixture. Physical stability was assessed by using a multistep evaluation procedure that included both turbidimetric and particulate measurements as well as visual inspection. Chemical stabililty was assessed by using stability-indicating high-performance liquid chromatographic analytical techniques that determined drug concentrations. Evaluations were performed initially upon mixing and again 1 and 4 hours after mixing. The samples were clear and colorless when viewed in normal fluorescent room light and when viewed with a Tyndall beam. Measured turbidity remained unchanged; particulate content was low and changed little. High-performance liquid chromatographic analysis revealed that palonosetron hydrochloride, lorazepam, and midazolam hydrochloride remained stable throughout the 4-hour test with no drug loss. Palonosetron hydrochloride is physically compatible and chemically stable with lorazepam or midazolam hydrochloride during Y-site administration.

Physical and chemical stability of palonosetron hydrochloride with topotecan hydrochloride and irinotecan hydrochloride during simulated y-site administration.

The objective of this study was to evaluate the physical and chemical stabilty of undiluted palonosetron hydrochloride 50 micrograms/mL in combination with topotecan hydrochloride 0.1 mg/mL or irinotecan hydrochloride 1 mg/mL in 5% dextrose injection during simulated Y-site administration. Triplicate test samples were prepared by admixing 5 mL of palonosetron hydrochloride with 5 mL of the topotecan hydrochloride or irinotecan hydrochloride admixture. Physical stabilty was assessed by using a multistep evaluation preocdure that included both turbidimetric and particulate measurement as well as visual inspection. Chemical stability was assessed by using stability-indicating high-performance liquid chromatographic analytical techniques to determine drug concentrations. Evaluations were performed initially upon mixing and again 1 and 4 hour after mixing. The palonosetron hydrochloride-topotecan hydrochloride samples were clear and pale yellow when viewed in normal fluorescent room light. When viewed with a Tyndall beam, the samples had a slight haziness. The palonosetron hydrochloride-irinotecan hydrochloride samples were clear and colorless when viewed in in normal fluorescent room light and with a Tyndall beam. Measured turbidities remained unchanged; particulate contents were low and changed little. High-performance liquid chromatographic analysis found that palonosetron hydrochloride, topotecan hydrochloride, and irinotecan hydrochloride remained stable throughout the 4-hour test. Little drug loss was observed. Palonosetron hydrochloride is physically compatible and chemically stable with topotecan hydrochloride and with irinotecan hydrochloride during Y-site administration.

Physical and chemical stability of palonosetron HCl in 4 infusion solutions.

BACKGROUND: Palonosetron HCl is a selective 5-HT(3) receptor antagonist used for the prevention of chemotherapy-induced nausea and vomiting. Palonosetron HCl may be diluted in an infusion solution for administraton. Consequently, stability information is needed for palonosetron HCl admixed in common infusion solutions. OBJECTIVE: To evaluate the physical and chemical stability of palonosetron HCl in concentrations of 5 and 30 microg/mL in dextrose 5% injection, NaCl 0.9% injection, dextrose 5% in NaCl 0.45% injection, and dextrose 5% in lactated Ringer's injection. METHODS: Triplicate test samples of palonosetron HCl at each concentration in each diluent were tested. Samples were stored and evaluated at appropriate intervals for up to 48 hours at room temperature ( approximately 23 degrees C) and 14 days under refrigeration (4 degrees 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 colorless when viewed in normal fluorescent room light and with a Tyndall beam. Measured turbidity and particulate content were low initially and remained low throughout the study. The drug concentration was unchanged in any of the samples at either temperature throughout the study. CONCLUSIONS: Palonosetron HCl is physically and chemically stable in all 4 common infusion solutions for at least 48 hours at room temperature and 14 days under refrigeration.

Physical and Chemical Stability of Treprostinil Sodium Injection Packaged in Plastic Syringe pump Reservoirs.

The objective of this study was to evaluate the physical and chemical stability of treprostinil (as sodium) injections in concentrations of 1, 2.5, 5 and 10 mg/mL packaged in MiniMed plastic syringe pump reservoirs. Test samples of treprostinil (as sodium) injections having concentrations of 1, 2.5, 5, and 10 mg/mL were packaged as 3 mL of drug solution in 3-mL MiniMed plastic syringe pump reservoirs, sealed with plastic tip caps and stored at -20 deg C, 4 deg C, 23 deg C and 37 deg C for 60 days. Evaluations for physical and chemical stability were performed initially and throughout the storage periods. Physical stability was assessed using visual observation in normal room light and using a high-intensity monodirectional light beam. In addition, turbidity and particle content were measured electronically. Chemical stability of the drug was evaluated by using a stability-indicating high-performance liquid chromatographic analytical technique. All samples of treprostinil (as sodium) injection remained free of visible precipitation throughout the study. Little or no change in haze level and in particulates of greater than or equal to 10 micrometers was found. Changes in treprostinil concentration were found to be small; treprostinil sodium concentrations were found to be 95% or greater over 60 days at all temperatures studied. Treprostinil (as sodium) injections at concentrations ranging from 1 to 10 mg/mL can be packaged in MiniMed plastic syringe reservoirs, stored and shipped with little or no loss of drug stability.

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 degrees C and 30 days under refrigeration at 4 degrees 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 degrees C and up to 30 days at 4 degrees 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 Clindamycin Phosphate in AutoDose Infusion System Bags.

The physical and chemical stability of clindamycin phosphate 600mg/100mL and 1.2g/100mL admixed in 0.9% sodium chloride injection packaged in AutoDose Infusion System Bags was evaluated. Triplicate test samples were prepared by bringing the required amount of clindamycin phosphate injection to volume with 0.9% sodium chloride injection. A total of 100 mL of each of the test solutions was packaged in each of three ethylene vinyl acetate AutoDose bags designed for use in the AutoDose Infusion System. Samples were stored protected from light and were evaluated at appropriate intervals for up to 30 days at 4 deg C and up to 7 days at 23 deg C. Physical stability was assessed using a multistep evaluation procedure that included both turbidimetric and particulate measurement, as well as visual inspection. Chemical stability was assessed initially and at appropriate intervals during the study periods with stability-indicating high-performance liquid chromatographic anyalytical techinique based on the determination of drug concentrations. Throughout the study, 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 initially and exhibited little change throughout the study. The clindamycin phosphate samples exhibited no increase in measured particulates during the study period. High-performance liquid chromatographic analysis found little or no decomposition in the samples, and the analysis indicated that clindamycin phosphate in the test admixtures remained stable for 30 days at 4 deg C and for 7 days at 23 deg C. The clindamycin phosphate admixtures exhibited physical and chemical stability consistent with previous studies. The AutoDose Infusion System bags were not found to have an adverse effect on the physical and chemical stability of this drug.

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.

Physical and Chemical Stability of Morphine Sulfate 5mg/mL and 50mg/mL Packaged in Plastic Syringes.

The objective of this study was to evaluate the physical and chemical stability of morphine sulfate in concentrations of 5 mg/mL in 0.9% sodium chloride injection and 50 mg/mL in both 0.9% sodium chloride injection and in sterile water for injection packaged in plastic syringes. Test samples of morphine sulfate 5-mg/mL and 50-mg/mL solutions were packaged as 20 mL of drug solution in 30-mL plastic syringes, sealed with plastic tip caps, and stored at 4 deg C and 23 deg C for 60 days. Test samples were also stored at -20 deg C and 37 deg C (temperature extremes that might be encountered during shipping) for 2 days. Evaluations of physical and chemical stability were performed initially and throughout the storage periods. Physical stability was assessed by means of visual observation in normal room light as well as with a high-intensity monodirectional light beam. In addition, turbidity and particle content were measured electronically. Chemical stabililty of the drug was evaluated by using a stability-indicating high-performance liquid chromatographic (HPLC) analytical technique. All samples of morphine sulfate 5-mg/mL solutions stored at 4 deg C, 23 deg C, and 37 deg C and the 50-mg/mL solutions stored at 23 deg C and 37 deg C remained free of precipitation throughout the study. In those solutions, little or no change in measured particulate burden or haze level was found, However, the solutions of morphine sulfate 50 mg/mL in 0.9% sodium chloride injection and in sterile water for injection exhibited an obvious precipitate within 2 to 4 days of storage at 4 deg C. Warming the solution to redissolve the visible precipitate left a substantial microparticulate content of up to 29,000 microparticulates/mL. When both morphine sulfate concentrations were frozen, precipitation was also noted. Upon thawing, the solutions yielded substantial measured microparticulate quantities of more than 20,000 microparticulates/mL in the 5-mg/mL concentration and more than 52,000 microparticulates/mL in the 50 mg/mL concentration. In addition, morphine sulfate 50mg/mL in both diluents exhibited a slight yellow discoloration after 30 days of storage at 23 deg C. Little or no loss of morphine sulfate occurred in any of the samples at any storage temperature throughout the study. Analysis of the samples after redissolving the visible precipitate in the low-temperature samples demonstrated that the morphine sulfate remained intact. Morphine concentrations were found to be 95% or greater over 60 days when stored at both 4 deg C and 23 deg C. In addition, morphine concentrations were greater than 97% when stored at -20 deg C, and they were 98% or greater when stored at 37 deg C after 2 days. However. exposure to low temperatures may result in precipitation, including microparticulate content that does not fully redissolve upon warming.

Physical and chemical stability of low and high concentrations of morphine sulfate with clonidine hydrochloride packaged in plastic syringes.

The objective of this study was to evaluate the physical and chemical stability of morphine sulfate 5 mg/mL with clonidine hydrochloride 0.25 mg/mL in 0.9% sodium chloride injection and morphine sulfate 50 mg/mL with clonidine hydrochloride 4 mg/mL in sterile water for injection when packaged in plastic syringes. Test samples of morphine sulfate 5-mg/mL with clonidine hydrochloride 0.25-mg/mL and morphine sulfate 50-mg/mL with clonidine hydrochloride 4-mg/mL solutions were packaged as 20 mL of drug solution in 30-mL plastic syringes, sealed with plastic tip caps, and stored at 4 deg C and 23 deg C for 60 days. Test samples were also stored at -20 deg C and 37 deg C (temperature extremes that might be encountered during shiping) for 2 days. Evaluations for physical and chemical stability were performed initially and throughout the storage periods. Physical stability was assessed by means of visual observation in normal room light and with a high-intensity monodirectional light beam. In addition turbidity and particle content were measured electronically. Chemical stability of the drug was evaluated by means of a stability-indicating high-performance liquid chromatographic (HPLC) analytical technique. All samples of morphine sulfate 5-mg/mL with clonidine hydrochloride 0.25mg/mL solutions stored at 4 deg C, 23 deg C, and 37 deg C and the morphine sulfate 50-mg/mL with clonidine HCl 4-mg/mL solrtions stored at 23 deg C and 37 deg C remained free of precipitation throughout the study. Little or no change in measured particulate burden and haze level were found in those solutions. However, morphine sulfate 50 mg/ml with clonidine HCl 4 mg/mL stored at 4 deg C exhibited an obvious precipitate within 2 to 4 days. Warming the solution to redissolve the precipitate left a substantial microparticulate content that was measured to be more than 33,000 microparticulates/mL. Upon freezing, both high- and low- concentration samples precipitated and yielded substantial measured microparticulate quantities up to 35,000 microparticulates/mL in the low-concentration combination and 50,000 microparticulates/mL in the high-concentration combination. In addition, as with morphine sulfate 50 mg/mL alone, the high-concentration combination exhibited a slight yellow discoloration after 30 days of storage at 23 deg C. Little or no loss of morphine sulfate and clonidine hydrochloride occurred in any of the samples at any storage temperature throughout the study. Morphine concentrations were found to be about 98% or greater, and clonidine hydrochloride concentrations were about 97% or greater throughout the study period under each storage condition. Morphine sulfate solutions at concentrations ranging from 5 to 50 mg/mL combined with clonidine hydrochloride ranging from 0.25 to 4 mg/mL can be packaged in plastic syringes, stored and shipped with little or no loss of drug. However, freezing should be avoided.

Physical and chemical stability of low and high concentrations of morphine sulfate with bupivacaine hydrochloride packaged in plastic syringes.

The objective of this study was to evaluate the physical and chemical stability of morphine sulfate 5 mg/mL with bupivacaine hydrochloride 2.5 mg/mL in 0.9% sodium chloride injection and morphine sulfate 50 mg/mL with bupivacaine hydrochloride 25 mg/mL in sterile water for injection packaged in plastic syringes. Test samples of morphine sulfate 5-mg/mL with bupicvacaine hydrochloride 2.5-mg/mL and morphine sulfate 50-mg/mL with bupivacaine hydrochloride 25-mg/mL solutions were packaged as 20 mL of drug solution in 30-mL plastic syringes, sealed with plastic tip caps, and stored at 4 deg C and 23 deg C for 60 days. Test samples were also stored at -20 deg C and 37 deg C (temperature extremes that might be encountered during shipping) for 2 days. Evaluations for physical and chemical stability were performed initially and throughout the storage periods. Physical stability was assessed by means of visual observation under normal room light and with a high-intensity monodirectional light beam. In addition, turbidity and particle content were measured electronically. Chemical stability of the drug was evaluated with a stability-indicating high-performance liquid chromatographic (HPLC) analytical technique. All test samples remained free of visible precipitation throughout the study. The inclusion of the bupivacaine hydrochloride prevented the precipitation of morphine sulfate that occurs at a lower storage temperature. For solutions stored at 4 deg C, 23 deg C, and 37 deg C, little or no change in measured particulate burden and haze level were found. However, samples stored frozen at -20 deg C exhibited a substantial microparticulate content upon thawing that was measured to be nearly 12,000 microparticulates/mL. Most samples were clear and colorless throughout the study. However, morphine sulfate 50 mg/mL exhibited a slight yellow discoloration after 7 days of storage at 23 deg C. Little or no loss of morphine sulfate and bupivacaine hydrochloride occurred in any of the samples at any storage temperature throughout the study. Morphine concentrations were found to be about 97% or greater, and bupivacaine hydrochloride concentrations were about 95% or greater throughout the study period under each storage condition. Morphine sulfate solutions at concentrations ranging from 5 mg/mL to 50 mg/mL combined with bupivacaine hydrochloride 2.5 mg/mL to 25 mg/mL can be packaged in plastic syringes stored, and shipped with little or no loss of drug. However, freezing should be avoided.

Physical and Chemical Stability of Hydromorphone Hydrochloride 1.5 and 80 mg/mL Packaged in Plastic Syringes.

The objective of this study was to evaluate the physical and chemical stability of hydromorphone hydrochloride in concentrations of 1.5 and 80 mg/mL in 0.9% sodium chloride injection packaged in plastic syringes. Test samples of hydromorphone hydrochloride 1.5- and 80-mg/mL solutions were packaged as 20 mL of drug solution in 30-mL plastic syringes, sealed with plastic tip caps, and stored at 4 deg C and 23 deg C for 60 days and at -20 deg C and 37 deg C (temperature extremes that might be encounterd during shipping) for 2 days. Evaluations for physical and chemical stability were performed initially and throughout the storage periods. Physical stability was assessed by means of visual observation in normal room light with a high-intensity monodirectional light beam. In addition, turbidity and particle content were measured electronically. The chemical stability of the drug was evaluated by means of a stability-indicating high-performance liquid chromatographic (HPLC) analytical technique. All samples of hydromorphone hydrochloride remained free of visible precipitation throughout the study. Those solutions stored at 4 deg C, 23 deg C, or 37 deg C exhibited little or no change in measured particulate burden and haze level. Freezing the solution resulted in an increase in microparticulate content that did not redissolve when the solution was warmed at room temperature. Little or no loss of hydromorphone hydrochloride occurred in any of the samples at any storage temperature throughout the study. Hydromorphone hydrochloride concentrations were found to be 95% or greater over 60 days at both 4 deg C and 23 deg C; concentrations were greater than 97% at both -20 deg C and 37 deg C after 2 days. Hydromorphone hydrochloride solutions at concentrations ranging from 1.5 to 80 mg/mL in 0.9% sodium chloride injection can be packaged in plastic syringes, stored, and shipped with little or no loss of drug. Freezing should be avoided.

Stability of Gentamicin Sulfate and Tobramycin Sulfate in AutoDose Infusion System Bags.

The objective of this study was to evaluate the physical and chemical stability of gentamicin sulfate 85mg/100mL and tobramycin sulfate 95mg/100mL, each of which was admixed in 0.9% sodium chloride injection and packaged in AutoDose Infusion System bags. Triplicate test samples were prepared by admixing the necessary amounts of the aminoglycoside antibiotics with a portion of 0.9% sodium chloride injection and bringing the admixture of each drug to a final volume of 100mL with additional 0.9% sodium chloride injection. The test solutions were packaged in ethylene vinyl acetate (EVA) plastic containers (AutoDose bags) designed for use in the AutoDose Infusion System. Samples were stored protected from light and were evaluated at appropriate intervals for up to 7 days at 23 deg C and up to 30 days at 4 deg C. Physical stability was assessed by means of a multistep evaluation procedure that included both turbidimetric and particulate measurement, as well as visual inspection. Chemical stability was assessed initially and at appropriate intervals during the study periods with stability-indicating high-performance liquid chromatographic (HPLC) analytical techniques based on the determination of drug concentrations. The aminoglycoside 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 indicated that both gentamicin sulfate and tobramycin sulfate remained stable for 30 days at 4 deg C and for 7 days at 23 deg C. Both gentamicin sulfate and tobramycin sulfate exhibited physical and chemical stability that were consistent with previous studies of those drugs. The AutoDose Infusion System bags did not adversely affect the physical and chemical stability of those aminoglycoside anitbiotics.

Stability of 4-aminopyridine and 3,4-diaminopyridine oral capsules.

The objective of this study was to evaluate the chemical stability of 4-aminopyridine 5-mg capsules and 3,4-diaminopyridine 5-mg capsules under a variety of storage conditions. Each of the two drug preparations was extemporaneously prepared in hard gelatin capsules; lactose and micronized silica gel were used as excipients. Samples were stored under three conditions: refigeration at 4 deg C and protected from light for 6 months, protected from light at room temperature that ranged from 22 deg C to 24 deg C for 6 months, and at a temperature of 37 deg C and protected from light for 1 month. Once each month, visual inspection of the capsules and their powder contents was performed to identify observable changes (color, texture, etc) and the weight of the capsule content was measured individually. Chemical stability was assessed initially and at monthly intervals by means of a stability-indicating high-pressure liquid chromatography (HPLC) analytical technique based on the determination of drug content. No visible changes were observed in any of the samples under any of the storage conditions. The hard gelatin capsules remained clear and colorless, and the content of the capsules remained an off-white powder when viewed under normal fluorescent room light. Capsule content weight did not change during the study. Both 4-aminopyridine and 3,4-diaminopyridine exhibited excellent chemical stability under all study conditions. Little or no loss of drug content occurred in either product under refrigeration, at room temperature, and even at the elevated temperature of 37 deg C. The oral 5-mg capsules of 4-aminopyridine and 3,4 diaminopyridine did not undergo decomposition or other adverse changes within 6 months at refrigerated room temperature or within 1 month of storage at 37 deg C.