AHFS Class:

40:12 Replacement Preparations

Generic Name

• Sodium Phosphates

Sodium phosphates additive solution is available in 5-, 15-, and 50-mL vials.³³⁰¹; ⁴⁰²⁵ Each mL contains monobasic sodium phosphate monohydrate 276 mg and dibasic sodium phosphate anhydrous 142 mg.³³⁰¹; ⁴⁰²⁵ The phosphorus concentration is 3 mmol/mL (93 mg/mL), and the sodium content is 4 mEq/mL (92 mg/mL).³³⁰¹; ⁴⁰²⁵ Aluminum also is present.³³⁰¹; ⁴⁰²⁵ The additive solution is a concentrate and must be diluted for use.³³⁰¹; ⁴⁰²⁵

pH

5.5 (5 to 6).³³⁰¹; ⁴⁰²⁵

Osmolarity

The osmolar concentration of sodium phosphates additive solution is calculated to be 7 mOsm/mL.³³⁰¹; ⁴⁰²⁵

Sodium phosphates additive solution must be diluted and thoroughly mixed in a larger volume of fluid before use.³³⁰¹; ⁴⁰²⁵

Sodium phosphates additive solution should be stored at controlled room temperature.³³⁰¹; ⁴⁰²⁵ The solution should be inspected for discoloration or particulate matter prior to use and should be used only if it is clear.³³⁰¹ The injection contains no antimicrobial agent or bacteriostat.³³⁰¹; ⁴⁰²⁵ Any unused portions should be discarded.³³⁰¹; ⁴⁰²⁵

Solution Compatibility

Additive Compatibility

Y-Site Injection Compatibility (1:1 Mixture)

Additional Compatibility Information

Calcium and Phosphate

Phosphates may be incompatible with metal ions such as magnesium and calcium. A number of studies using potassium phosphate have been performed. For additional information, refer to the potassium phosphate monograph.

UNRECOGNIZED CALCIUM PHOSPHATE PRECIPITATION IN A 3-IN-1 PARENTERAL NUTRITION MIXTURE RESULTED IN PATIENT DEATH.

The potential for the formation of a calcium phosphate precipitate in parenteral nutrition solutions is well studied and documented,¹⁷⁷¹; ¹⁷⁷⁷ but the information is complex and difficult to apply to the clinical situation.¹⁷⁷⁰; ¹⁷⁷²; ¹⁷⁷⁷ The incorporation of lipid emulsion in 3-in-1 parenteral nutrition solutions obscures any precipitate that is present, which has led to substantial debate on the dangers associated with 3-in-1 parenteral nutrition mixtures and when or if the danger to the patient is warranted therapeutically.¹⁷⁷⁰; ¹⁷⁷¹; ¹⁷⁷²; ²⁰³¹; ²⁰³²; ²⁰³³; ²⁰³⁴; ²⁰³⁵; ²⁰³⁶ Because such precipitation may be life-threatening to patients,²⁰³⁷; ²²⁹¹ FDA issued a Safety Alert containing the following recommendations:¹⁷⁶⁹

1. “The amounts of phosphorus and of calcium added to the admixture are critical. The solubility of the added calcium should be calculated from the volume at the time the calcium is added. It should not be based upon the final volume.
   Some amino acid injections for TPN admixtures contain phosphate ions (as a phosphoric acid buffer). These phosphate ions and the volume at the time the phosphate is added should be considered when calculating the concentration of phosphate additives. Also, when adding calcium and phosphate to an admixture, the phosphate should be added first.
   The line should be flushed between the addition of any potentially incompatible components.
2. A lipid emulsion in a 3-in-1 admixture obscures the presence of a precipitate. Therefore, if a lipid emulsion is needed, either (1) use a 2-in-1 admixture with the lipid infused separately, or (2) if a 3-in-1 admixture is medically necessary, then add the calcium before the lipid emulsion and according to the recommendations in number 1 above.
   If the amount of calcium or phosphate which must be added is likely to cause a precipitate, some or all of the calcium should be administered separately. Such separate infusions must be properly diluted and slowly infused to avoid serious adverse events related to the calcium.
3. When using an automated compounding device, the above steps should be considered when programming the device. In addition, automated compounders should be maintained and operated according to the manufacturer’s recommendations.
   Any printout should be checked against the programmed admixture and weight of components.
4. During the mixing process, pharmacists who mix parenteral nutrition admixtures should periodically agitate the admixture and check for precipitates. Medical or home care personnel who start and monitor these infusions should carefully inspect for the presence of precipitates both before and during infusion. Patients and care givers should be trained to visually inspect for signs of precipitation. They also should be advised to stop the infusion and seek medical assistance if precipitates are noted.
5. A filter should be used when infusing either central or peripheral parenteral nutrition admixtures. At this time, data have not been submitted to document which size filter is most effective in trapping precipitates.
   Standards of practice vary, but the following is suggested: a 1.2-µm air-eliminating filter for lipid-containing admixtures and a 0.22-µm air-eliminating filter for non-lipid-containing admixtures.
6. Parenteral nutrition admixtures should be administered within the following time frames: if stored at room temperature, the infusion should be started within 24 hours after mixing; if stored at refrigerated temperatures, the infusion should be started within 24 hours of rewarming. Because warming parenteral nutrition admixtures may contribute to the formation of precipitates, once administration begins, care should be taken to avoid excessive warming of the admixture.
   Persons administering home care parenteral nutrition admixtures may need to deviate from these time frames. Pharmacists who initially prepare these admixtures should check a reserve sample for precipitates over the duration and under the conditions of storage.
7. If symptoms of acute respiratory distress, pulmonary emboli, or interstitial pneumonitis develop, the infusion should be stopped immediately and thoroughly checked for precipitates. Appropriate medical interventions should be instituted. Home care personnel and patients should immediately seek medical assistance.”¹⁷⁶⁹

Calcium Phosphate Precipitation Fatalities

Fatal cases of paroxysmal respiratory failure in 2 previously healthy women receiving peripheral vein parenteral nutrition were reported. The patients experienced sudden cardiopulmonary arrest consistent with pulmonary emboli. The authors used in vitro simulations and an animal model to conclude that unrecognized calcium phosphate precipitation in a 3-in-1 total nutrition admixture caused the fatalities. The precipitation resulted during compounding by introducing calcium and phosphate near to one another in the compounding sequence and prior to complete fluid addition. This resulted in a temporarily high concentration of the drugs and precipitation of calcium phosphate. Observation of the precipitate was obscured by the incorporation of 20% lipid emulsion, intravenous, into the nutrition mixture. No filter was used during infusion of the fatal nutrition admixtures.²⁰³⁷

In a follow-up retrospective review, 5 patients were identified who had respiratory distress associated with the infusion of the 3-in-1 admixtures at around the same time. Four of these 5 patients died, although the cause of death could be definitively determined for only 2.²²⁹¹

Calcium and Phosphate Conditional Compatibility

Calcium salts are conditionally compatible with phosphates in parenteral nutrition solutions. The incompatibility is dependent on a solubility and concentration phenomenon and is not entirely predictable. Precipitation may occur during compounding or at some time after compounding is completed.

NOTE: Some amino acid solutions inherently contain calcium and phosphate, which must be considered in any projection of compatibility.

A study determined the maximum concentrations of calcium (as chloride and gluconate) and phosphate that can be maintained without precipitation in a parenteral nutrition solution consisting of FreAmine II 4.25% and dextrose 25% for 24 hours at 30°C. It was noted that the amino acids in parenteral nutrition solutions form soluble complexes with calcium and phosphate, reducing the available free calcium and phosphate that can form insoluble precipitates. The concentration of calcium available for precipitation is greater with the chloride salt compared to the gluconate salt, at least in part because of differences in dissociation characteristics. Consequently, a greater concentration of calcium gluconate than calcium chloride can be mixed with sodium phosphate.⁶⁰⁸

In addition to the concentrations of phosphate and calcium and the salt form of the calcium, the concentration of amino acids and the time and temperature of storage altered the formation of calcium phosphate in parenteral nutrition solutions. As the temperature was increased, the incidence of precipitate formation also increased. This finding was attributed, at least in part, to a greater degree of dissociation of the calcium and phosphate complexes and the decreased solubility of calcium phosphate. Therefore, a solution possibly may be stored at 4°C with no precipitation, but on warming to room temperature a precipitate will form over time.⁶⁰⁸

The solubility characteristics of calcium and phosphate in pediatric parenteral nutrition solutions composed of Aminosyn 0.5, 2, and 4% with dextrose 10 to 25% were reported. Also present were electrolytes and vitamins. Sodium phosphate was added sequentially in phosphorus concentrations from 10 to 30 mmol/L. Calcium gluconate was added last in amounts ranging from 1 to 10 g/L. The solutions were stored at 25°C for 30 hours and examined visually and microscopically for precipitation. The authors found that higher concentrations of Aminosyn increased the solubility of calcium and phosphate. Precipitation occurred at lower calcium and phosphate concentrations in the 0.5% solution compared to the 2 and 4% solutions. For example, at a phosphorus concentration of 30 mmol/L, precipitation occurred at calcium gluconate concentrations of about 1, 2, and 4 g/L in the 0.5, 2, and 4% Aminosyn mixtures, respectively. Similarly, at a calcium gluconate concentration of 8 g/L and above, precipitation occurred at phosphorus concentrations of about 13, 17, and 22 mmol/L in the 0.5, 2, and 4% solutions, respectively. The dextrose concentration did not appear to affect the calcium and phosphate solubility significantly.¹⁰⁴²

The maximum allowable concentrations of calcium and phosphate in a 3-in-1 parenteral nutrition mixture for children (TNA #192 in Appendix) were reported. Added calcium was varied from 1.5 to 150 mmol/L, and added phosphate was varied from 21 to 300 mmol/L. These mixtures were stable for 48 hours at 22 and 37°C as long as the pH was not greater than 5.7, the calcium concentration was below 16 mmol/L, the phosphate concentration was below 52 mmol/L, and the product of the calcium and phosphate concentrations was below 250 mmol²/L².¹⁷⁷³

Additional calcium and phosphate solubility curves were reported for specialty parenteral nutrition solutions based on NephrAmine and also HepatAmine at concentrations of 0.8, 1.5, and 2% as the sources of amino acids. The solutions also contained dextrose 10%, with cysteine and pH adjustment to simulate addition of lipid emulsion used in some admixtures. Calcium and phosphate solubility followed the hyperbolic patterns previously reported.⁶⁰⁹ Temperature, time, and pH affected calcium and phosphate solubility, with pH having the greatest effect.²⁰³⁸

The maximum sodium phosphate concentrations were reported for given amounts of calcium gluconate that could be admixed in parenteral nutrition solutions containing TrophAmine in varying quantities (with cysteine hydrochloride 40 mg/g of amino acid) and dextrose 10%. The solutions also contained magnesium sulfate 4 mEq/L, potassium acetate 24 mEq/L, sodium chloride 32 mEq/L, pediatric multivitamins, and trace elements. The presence of cysteine hydrochloride reduces the solution pH and increases the amount of calcium and phosphate that can be incorporated before precipitation occurs. The results of this study cannot be safely extrapolated to TPN solutions with compositions other than the ones tested. The admixtures were compounded with the sodium phosphate added last after thorough mixing of all other components. The authors noted that this is not the preferred order of mixing (usually phosphate is added first and thoroughly mixed before adding calcium last); however, they believed this reversed order of mixing would provide a margin of error in cases in which the proper order is not followed. After compounding, the solutions were stored for 24 hours at 40°C. The maximum calcium and phosphate amounts that could be mixed in the various solutions were reported tabularly and are shown in Table 1.²⁰³⁹ However, these results are not entirely consistent with another study.²¹⁹⁶

Table 1. Maximum Amount of Phosphate (as Sodium) (mmol/L) Not Resulting in Precipitation.²⁰³⁹ See CAUTION below.^a

^aCAUTION: The results cannot be safely extrapolated to solutions with formulas other than the ones tested. See text.

Calcium phosphate precipitation phenomena was evaluated in a series of parenteral nutrition admixtures composed of dextrose 22%, amino acids (FreAmine III) 2.7%, and lipid emulsion (Abbott) 0, 1, and 3.2%. Incorporation of calcium gluconate 19 to 24 mEq/L and phosphate (as sodium) 22 to 28 mmol/L resulted in visible precipitation in the fat-free admixtures. New precipitate continued to form over 14 days, even after repeated filtrations of the solutions through 0.2-µm filters. The presence of the amino acids increased calcium and phosphate solubility, compared with simple aqueous solutions. However, the incorporation of the lipid emulsion did not result in a statistically significant increase in calcium and phosphate solubility. The authors noted that the kinetics of calcium phosphate precipitate formation do not appear to be entirely predictable; both transient and permanent precipitation can occur either during the compounding process or at some time afterward. Because calcium phosphate precipitation can be very dangerous clinically, the use of inline filters was recommended. The authors suggested that the filters should have a porosity appropriate to the parenteral nutrition admixture—1.2 µm for fat-containing and 0.2 or 0.45 µm for fat-free nutrition mixtures.²⁰⁶¹

A 2-mL fluid barrier of dextrose 5% in a microbore retrograde infusion set failed to prevent precipitation when used between calcium gluconate 200 mg/2 mL and sodium phosphate 0.3 mmol/0.1 mL.¹³⁸⁵

A 2-in-1 parenteral nutrition admixture with final concentrations of TrophAmine 0.5%, dextrose 5%, L-cysteine hydrochloride 40 mg/g of amino acids, calcium gluconate 60 mg/100 mL, and sodium phosphates 46.5 mg/mL was found to result in visible precipitation of calcium phosphate within 30 hours stored at 23 to 27°C. Despite the presence of the acidifying L-cysteine hydrochloride, precipitation occurred at clinically utilized amounts of calcium and phosphates.²⁶²²

The presence of magnesium in solutions may also influence the reaction between calcium and phosphate, including the nature and extent of precipitation.¹⁵⁸; ¹⁵⁹

The interaction of calcium and phosphate in parenteral nutrition solutions is a complex phenomenon. Various factors have been identified as playing a role in the solubility or precipitation of a given combination, including⁶⁰⁸; ⁶⁰⁹; ¹⁰⁴²; ¹⁰⁶³; ¹⁴²⁷; ²⁷⁷⁸:

1. Concentration of calcium
2. Salt form of calcium
3. Concentration of phosphate
4. Concentration of amino acids
5. Amino acids composition
6. Concentration of dextrose
7. Temperature of solution
8. pH of solution
9. Presence of other additives
10. Order of mixing

Enhanced precipitate formation would be expected from such factors as high concentrations of calcium and phosphate, increases in solution pH, decreased amino acid concentrations, increases in temperature, addition of calcium prior to phosphate, lengthy standing times or slow infusion rates, and use of calcium as the chloride salt.⁸⁵⁴

For a list of references cited in the text of this monograph, search the monograph titled References.

ASHP^® Injectable Drug Information^TM. Selected Revisions December 5, 2024. © Copyright, 2024. American Society of Health-System Pharmacists^®, 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.