Ascorbic acid is available as a preservative-free concentrate for injection in 50-mL pharmacy bulk packages containing sodium ascorbate equivalent to 500 mg/mL of ascorbic acid.2311; 3634 Each mL also contains edetate disodium 0.25 mg in water for injection with sodium hydroxide and sodium bicarbonate for pH adjustment.2311
Pressure may build up during storage of vials of ascorbic acid; caution should be exercised when withdrawing the concentrate for injection from the vial.2311
Ascorbic acid concentrate for injection must be diluted in a compatible infusion solution (e.g., dextrose 5%, sterile water for injection) to a concentration in the range of 1 to 25 mg/mL prior to administration.2311 The manufacturer states that the osmolarity of the intended dilution for infusion should be calculated prior to preparing the dilution for infusion and notes that appropriate solutes should be added to the diluted solution for infusion, as needed, to make the final infusion solution isotonic.2311
Equivalency
Sodium ascorbate 562.5 mg is equivalent to 500 mg of ascorbic acid.2311
Tonicity
Ascorbic acid 25 mg/mL prepared from ascorbic acid concentrate for injection in sterile water for injection is isotonic.2311
pH
Ascorbic acid 500-mg/mL concentrate for injection has a pH ranging from 5.6 to 6.6.2311
Osmolarity
The osmolarity of the ascorbic acid 500-mg/mL concentrate for injection is approximately 5900 mOsm/L.2311 The osmolarity of ascorbic acid 25 mg/mL prepared from ascorbic acid concentrate for injection in sterile water for injection is approximately 290 mOsm/L.2311
Trade Name(s)
Ascor
Ascorbic acid concentrate for injection may be administered intravenously following dilution in a compatible infusion solution that results in an isotonic solution for infusion.2311 The drug also has been administered by intramuscular and subcutaneous injection;2279 however, current labeling no longer includes this information.2311
Ascorbic acid concentrate for injection is a colorless to pale yellow solution.2311 Intact vials should be stored in a refrigerator at 2 to 8°C protected from light.2311
Using a suitable transfer device or dispensing set that allows for measured dispensing of the contents, the closure of a pharmacy bulk package should be penetrated only once.2311 The contents of the pharmacy bulk package should be used to prepare single doses of ascorbic acid intended for multiple patients within 4 hours after the bulk package closure has been penetrated.2311 The manufacturer states that doses prepared from the pharmacy bulk package must be used immediately.2311 Vials contain no bacteriostatic or antimicrobial agents; unused portions should be discarded.2311
Although refrigeration of ascorbic acid concentrate for injection is recommended,2311 one manufacturer (Lilly) had previously stated that its ascorbic acid product had a maximum room temperature stability of 96 hours853 and another manufacturer (Vitarine) had previously reported that its ascorbic acid product was stable for 4 years at room temperatures not exceeding 25°C.60
Ascorbic acid in solution is rapidly oxidized and should not be mixed with any elemental compounds that can be reduced (e.g., copper).2279; 2292; 2311
The stability of ascorbic acid from a multiple vitamin product in dextrose 5% and sodium chloride 0.9%, in both polyvinyl chloride (PVC) and ClearFlex containers, was evaluated. Analysis showed that ascorbic acid was stable at 23°C when protected from light, exhibiting less than a 10% loss in 24 hours. When exposed to light, however, ascorbic acid had losses of approximately 50 to 65% in 24 hours.1509
Ascorbic acid (Abbott) developed a grayish-brown color when left exposed to a stainless steel 5-µm filter needle (Monoject) for as little as 1 hour.1645
In one study, ascorbic acid (McGuff) was prepared at concentrations of 30 mg/mL in sodium chloride 0.9% and 50 mg/mL in dextrose 5%.3525 Spectrophotometric evaluation showed that the concentration of ascorbic acid remained greater than 90% for up to 96 hours in solutions stored at 4°C in the dark and in those stored at ambient temperature and light.3525
pH Effects
Literature reports of incompatibilities between various acid-labile drugs such as penicillin G potassium47; 165 and erythromycin lactobionate20 with pure ascorbic acid do not pertain to ascorbic acid injection, USP. The official product has a pH of 5.5 to 7.3864 Pure ascorbic acid is quite acidic.166 A solution of ascorbic acid 500 mg in 2 mL of diluent had a pH of 2.166 The incompatibilities between pure ascorbic acid and penicillin G potassium have been attributed to the pH rather than being a characteristic of the ascorbate ion.166
Light Effects
Ascorbic acid is light sensitive and gradually darkens on exposure to light.2279; 2311 Exposure to light should be minimized; vials should be protected from light during storage.2311
Sorption
Pure ascorbic acid (Merck) did not display significant sorption to a PVC plastic test strip in 24 hours.12
Drugs in Syringe Compatibility
Y-Site Injection Compatibility (1:1 Mixture)
Additional Compatibility Information
Parenteral Nutrition Solutions
A 35% ascorbic acid loss was reported from a parenteral nutrition solution, composed of amino acids, dextrose, electrolytes, trace elements, and multivitamins, in 39 hours at 25°C with exposure to light. The loss was reduced to a negligible amount in 4 days by refrigeration and light protection.1063
The extent and rapidity of ascorbic acid decomposition in parenteral nutrition solutions composed of amino acids, dextrose, electrolytes, multivitamins, and trace elements in 3-L PVC bags stored at 3 to 7°C were reported. About 30 to 40% was lost in 24 hours. The degradation then slowed as the oxygen supply was reduced to the diffusion through the bag. About a 55 to 65% loss occurred after 7 days of storage. The oxidation was catalyzed by metal ions, especially copper. In the absence of copper from the trace elements additive, less than 10% degradation of ascorbic acid occurred in 24 hours. The author estimated that 150 to 200 mg is degraded in 2 to 4 hours at ambient temperature in the presence of copper, but that only 20 to 30 mg is broken down in 24 hours without copper. To minimize ascorbic acid loss, copper must be excluded. Alternatively, inclusion of excess ascorbic acid was suggested.1056
Extensive decomposition of ascorbic acid and folic acid was reported in a parenteral nutrition solution composed of amino acids 3.3%, dextrose 12.5%, electrolytes, trace elements, and M.V.I.-12 (USV) in PVC bags. Half-lives were 1.1, 2.9, and 8.9 hours for ascorbic acid and 2.7, 5.4, and 24 hours for folic acid stored at 24°C in daylight, 24°C protected from light, and 4°C protected from light, respectively. The decomposition was much greater than for solutions not containing catalyzing metal ions. Also, it was greater than for the vitamins singly because of interactions with the other vitamins present.1059
Ascorbic acid decomposition in TPN admixtures has been reported to result in the formation of precipitated calcium oxalate. Oxalic acid forms as one of the decomposition products of ascorbic acid. The oxalic acid reacts with calcium in the TPN admixture to form the precipitate.1060
The stability of numerous vitamins in parenteral nutrition solutions composed of amino acids (Kabi-Vitrum), dextrose 30%, and lipid emulsion 20% (Kabi-Vitrum) in a 2:1:1 ratio with electrolytes, trace elements, and both fat- and water-soluble vitamins was reported. The admixtures were stored in darkness at 2 to 8°C for 96 hours. Sodium ascorbate and its biologically active degradation product, dehydroascorbic acid, totaled 59 and 42% of the nominal starting concentration at 24 and 96 hours, respectively. However, the actual initial concentration was only 66% of the nominal concentration.1225
When the admixture was subjected to simulated infusion over 24 hours at 20°C, either exposed to room light or light protected, or stored for 6 days in the dark under refrigeration and then subjected to the same simulated infusion, once again the retinyl palmitate, alpha-tocopherol, and sodium riboflavin-5'-phosphate did not undergo significant loss. However, sodium ascorbate and its degradation product, dehydroascorbic acid, had initial combined concentrations of 51 to 65% of the nominal initial concentration, with further declines during infusion. Light protection did not significantly alter the loss of total ascorbic acid.1225
The stability of ascorbic acid in parenteral nutrition solutions, with and without lipid emulsion, was studied. Both with and without lipid emulsion, the total vitamin C content (ascorbic acid plus dehydroascorbic acid) remained above 90% for 12 hours when the solutions were exposed to fluorescent light and for 24 hours when they were protected from light. When stored in a cool dark place, the solutions were stable for 7 days.1227
The stability of several vitamins from M.V.I.-12 (Armour) was reported when admixed in parenteral nutrition solutions composed of different amino acid products, with or without Intralipid 10%, when stored in glass bottles and PVC bags at 25 and 5°C for 48 hours. Ascorbic acid was lost from all samples stored at 25°C, with the greatest losses occurring in solutions stored in plastic bags. No losses occurred in any sample stored at 5°C.1431
In another study, the stability of several vitamins (as M.V.I.-12) following admixture with 4 different amino acid products (Novamine, Neopham, FreAmine III, Travasol) with or without Intralipid was reported when stored in glass bottles or PVC bags at 25°C for 48 hours. Under high-intensity phototherapy light, ascorbic acid losses were significant with all amino acid products tested. When bisulfite was added to the Neopham admixture, ascorbic acid was unaffected. Ascorbic acid losses were increased with a more alkaline pH and that bisulfite addition offered some protection presumably by bisulfite being preferentially oxidized. The authors concluded that intravenous multivitamins should be added to parenteral nutrition admixtures immediately prior to administration to reduce losses since commercially available amino acid products may contain bisulfites and have varying pH values.487
The stability of ascorbic acid and dehydroascorbic acid was evaluated in a 3-in-1 admixture containing Vamin 14, dextrose 30%, Intralipid 20%, potassium phosphate, Cernevit, and trace elements in ethylene vinyl acetate (EVA) bags over a temperature range of 2 to 22°C. They observed an 89% loss of ascorbic acid and 37% loss of dehydroascorbic acid over 7 days. Oxygen, trace elements, temperature, and an underfilled bag were the greatest determinants of ascorbic acid loss.2462
The long-term stability of ascorbic acid in 3-in-1 admixtures containing amino acids (Eloamin) 10%, dextrose 20%, lipid emulsion (Elolipid) 20%, calcium gluconate, M.V.C. 9 + 3, and trace elements mixed in EVA and multilayer (Ultrastab) bags at 5°C was evaluated. Ascorbic acid losses were greater than 75% in the first 24 hours and 100% after 48 to 72 hours in the EVA bags. In the multilayer bags, ascorbic acid showed a 20 and 40% loss over the first 24 hours with and without lipid emulsion, respectively. The initial rapid fall in ascorbic acid was presumably due to the initial oxygen content of the admixtures despite the use of the less oxygen-permeable multilayer bags. The ascorbic acid concentration remained stable for up to 28 days in the multilayer bags after the initial fall. Adding additional ascorbic acid to compensate for the losses was recommended to facilitate extended shelf-life.2463
Because of these interactions, recommendations to separate the administration of vitamins and trace elements have been made.1056; 1060; 1061 Other researchers have termed such recommendations premature based on differing reports895; 896 and the apparent absence of epidemic vitamin deficiency in parenteral nutrition patients.1062
The influence of several factors on the rate of ascorbic acid oxidation in parenteral nutrition solutions was evaluated. Ascorbic acid is regarded as the least stable component in TPN admixtures. The type of amino acid used in the TPN was important. Some, such as FreAmine III and Vamin 14, contain antioxidant compounds (e.g., sodium metabisulfite or cysteine). Ascorbic acid stability was better in such solutions compared with those amino acid solutions having no antioxidant present. Furthermore, the pH of the solution may play a small role, with greater degradation as the pH rises from about 5 to about 7. Adding air to a compounded TPN container can also accelerate ascorbic acid decomposition. The most important factor was the type of plastic container used for the TPN. EVA containers (Mixieva, Miramed) allow more oxygen permeation, which results in substantial losses of ascorbic acid in relatively short time periods. In multilayer TPN bags (Ultrastab, Miramed) designed to reduce gas permeability, the rate of ascorbic acid degradation was greatly reduced. TPNs without antioxidants packaged in EVA bags had an almost total loss of ascorbic acid activity in 1 or 2 days at 5°C. In contrast, in TPNs containing FreAmine III or Vamin 14 and packaged in the multilayer bags, most of the ascorbic acid content was retained for 28 days at 5°C. The TPNs made with antioxidant-containing amino acids and packaged in multilayer bags that reduce gas permeability can safely be given extended expiration dates and still retain most of the ascorbic acid activity.2163
The initial degradation product of ascorbic acid (dehydroascorbic acid) was evaluated in a 2-in-1 admixture containing Synthamin 14, glucose 20%, and trace elements over a temperature range of 5 to 35°C. The presence of trace elements, including copper, had no influence on the degradation of dehydroascorbic acid. At room temperature and 5°C, there was a greater than 50% loss of dehydroascorbic acid noted within 2 and 24 hours, respectively. The authors concluded this degradation was temperature dependent.2461
The degradation of vitamins A, B1, C, and E from Cernevit (Roche) multivitamins was evaluated in NuTRIflex Lipid Plus (B. Braun) admixtures prepared in ethylene vinyl acetate (EVA) bags and in multilayer bags. After storage for up to 72 hours at 4, 21, and 40°C, greater vitamin losses occurred in the EVA bags: vitamin A (retinyl palmitate) losses were 20%, thiamine hydrochloride losses were 25%, alpha-tocopherol losses were 20%, and ascorbic acid losses were approximately 80 to 100%. In the multilayer bags (presumably a better barrier to oxygen transfer), losses were less: vitamin A (retinyl palmitate) losses were 5%, thiamine hydrochloride losses were 10%, alpha-tocopherol losses were 0%, and ascorbic acid losses were approximately 25 to 70%.2618
The vitamins in Cernevit (Baxter) diluted in three 2-in-1 parenteral nutrition admixtures were tested for stability over 48 hours. While all of the vitamins retained their initial concentrations, ascorbic acid exhibited losses of about 5%, 13%, and 17% in TPNs with dextrose concentrations of 10, 15, and 25%, respectively.2796
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