AHFS Class:

8:12.16.08 Aminopenicillins

Generic Name

• Ampicillin Sodium

Ampicillin sodium is available in vials containing the equivalent of ampicillin 125 mg, 250 mg, 500 mg, 1 g, or 2 g as a powder.³²⁹¹

For intramuscular injection, the vials should be reconstituted with sterile water for injection or bacteriostatic water for injection in the following amounts:³²⁹¹

For administration by direct intravenous injection, the 125-, 250-, and 500-mg vials should be reconstituted with 5 mL of sterile water for injection or bacteriostatic water for injection; the 1- or 2-g vials should be reconstituted with 7.4 or 14.8 mL, respectively, of sterile water for injection or bacteriostatic water for injection.³²⁹¹ For administration by intravenous infusion, the reconstituted solution as prepared for direct intravenous injection should be further diluted in a compatible infusion solution prior to administration.³²⁹¹

Ampicillin sodium also is available in ADD-Vantage vials containing the equivalent of ampicillin 1 or 2 g as a powder.³²⁹² ADD-Vantage vials should be prepared with 50 or 100 mL of sodium chloride 0.9% or dextrose 5% in ADD-Vantage diluent bags.³²⁹²

Ampicillin sodium also is available in a pharmacy bulk package.³²⁹³ The 10-g pharmacy bulk package should be reconstituted with 94 mL of sterile water for injection; the resulting solution contains ampicillin 100 mg/mL.³²⁹³ The reconstituted pharmacy bulk package solution must be diluted further in a compatible infusion solution to achieve a solution with a final ampicillin concentration of 5 or 10 mg/mL.³²⁹³

pH

The reconstituted solution of ampicillin has a pH ranging from 8 to 10.³²⁹³; ³²⁹⁴ The pH values of various ampicillin solutions are shown below:²¹³

Osmolality

Reconstituted with sterile water for injection, ampicillin (Wyeth) 100 mg/mL has an osmolality of 602 mOsm/kg.⁵⁰ At a concentration of 125 mg/mL, Wyeth’s product was 702 mOsm/kg and Bristol’s product was 675 mOsm/kg.¹⁰⁷¹

In another study, the osmolality of ampicillin sodium (Bristol) diluted in sodium chloride 0.9% was determined to be 493 mOsm/kg for ampicillin 50 mg/mL and 664 mOsm/kg for ampicillin 100 mg/mL.¹³⁷⁵

The osmolality of ampicillin sodium 1 and 2 g was calculated for the following dilutions:¹⁰⁵⁴

The following maximum ampicillin concentrations were recommended to achieve osmolalities suitable for peripheral infusion in fluid-restricted patients:¹¹⁸⁰

Sodium Content

Ampicillin sodium contains approximately 2.9 mEq of sodium per gram of drug.³²⁹¹; ³²⁹²; ³²⁹³

Ampicillin sodium is administered by intramuscular or direct intravenous injection³²⁹¹ or by intravenous infusion.³²⁹¹; ³²⁹²; ³²⁹³

For direct intravenous injection, the reconstituted solutions of ampicillin prepared with 125-, 250-, and 500-mg vials should be administered slowly over 3 to 5 minutes; the reconstituted solutions of ampicillin prepared with 1- and 2-g vials should be administered slowly over at least 10 to 15 minutes.³²⁹¹ Solutions should not be administered more rapidly.³²⁹¹

Intact vials of ampicillin sodium should be stored at controlled room temperature.³²⁹¹; ³²⁹²; ³²⁹³

Reconstituted ampicillin solutions should be protected from freezing.³²⁹¹

Manufacturers recommended the use of only freshly prepared solutions.³²⁹¹; ³²⁹²; ³²⁹³ Reconstituted solutions of ampicillin for intramuscular or direct intravenous injection should be administered within 1 hour after preparation.³²⁹¹ Reconstituted solutions of ampicillin prepared from the pharmacy bulk package should be further diluted for intravenous infusion within 1 hour after preparation.³²⁹³

The stability of ampicillin in solution under various conditions has been the subject of much work and numerous articles. Several characteristics of the stability of ampicillin have emerged from these studies:

1. The stability is concentration dependent and decreases as the concentration increases.
2. Sodium chloride 0.9% appears to be a suitable diluent for the intravenous infusion of ampicillin.
3. The stability is greatly decreased in dextrose solutions.
4. Storage temperature and the pH of solution affect the stability.

Storage and Usage Times

Savello and Shangraw offered the recommendations in Table 1 regarding storage conditions for ampicillin solutions.²¹⁰

Table 1. Suggested Storage Conditions for Ampicillin Solutions²¹⁰

Concentration Effects

The effect of concentration on ampicillin stability has been attributed to a self-catalyzing effect.²¹⁰ As the concentration increases, so does the rate of decomposition.¹⁷⁰; ²¹⁰ Savello and Shangraw reported that even though the initial pH values of various concentrations were 9.2 to 9.3, the higher concentrations of the drug maintained their pH longer because of their greater buffer capacity.²¹⁰ (See Table 2.)

Table 2. Percent Degradation of Ampicillin Solutions after Reconstitution with Water for Injection at 5°C after 8 Hours²¹⁰

This concentration dependence of the stability of ampicillin has been related to the polymerization of penicillins in concentrated solutions.⁶⁰¹; ⁶⁰² Dimerization is the predominant form of degradation with high ampicillin concentrations. The extent of this effect declines as the concentration drops but still remains significant in a 20-mg/mL solution. At lower concentrations, hydrolysis becomes the determining factor.⁶⁰³

At a concentration of 500 mg/mL, ampicillin formed dimers, trimers, tetramers, and pentamers during 24 hours of storage at 24°C in the dark. The polymer formed through a chain process by linkage of the amino group on the side chain to another molecule with a cleaved ß-lactam ring.¹⁴⁰⁰

In a 200-mg/mL solution of ampicillin adjusted to pH 8.5 and stored at 22°C, 90% of all decomposition products formed within 72 hours were dimers and polymers. In a 50-mg/mL solution, 70% of the decomposition products were dimers and polymers. However, a 10-mg/mL solution formed a-aminobenzylpenicilloic acid as the predominant decomposition product and a dimer concentration of 1 to 2%. The rate of dimerization was almost independent of pH in the range of 7 to 10, but increased strongly with increases in the initial ampicillin concentration.⁸⁵⁸

However, one study showed that if the pH of the solution was held constant at 8 or 9.15, there was little dependence of the rate of decomposition on concentration in the range of 20 to 100 mg/mL.²¹³

Infusion Diluents

Infusion diluents also affect the stability of ampicillin. Sodium chloride 0.9% appears to be a suitable diluent for the intravenous infusion of ampicillin sodium.

Dextrose is thought to exhibit an immense catalytic effect on the hydrolysis of ampicillin sodium,²¹⁰ decreasing the stability about one-half when compared to sterile water or sodium chloride 0.9%.²¹³ This has been well documented and has been regarded as an incompatibility.²¹⁰; ²¹³ (See Table 3.) This accelerated decomposition associated with dextrose extends to fructose as well, although it is not as extensive. It occurs in the alkaline pH range. Below pH 6 or 7, the decomposition rate with both dextrose and fructose appears to coincide with simple aqueous solutions.⁶⁰⁴

Table 3. Percent Degradation of Ampicillin 10 mg/mL in Dextrose 5% in Water According to Temperature and Time²¹⁰

Savello and Shangraw further showed that increasing the concentration of dextrose decreased the stability of ampicillin. (See Table 4.)

Table 4. Percent Degradation of Ampicillin 10 mg/mL at 5°C According to Dextrose Concentration and Time²¹⁰

pH Effects

The pH of the solution also plays a role in its stability. Hydrolysis has been shown to be catalyzed by hydroxide ions. An increase of 1 pH unit in an ampicillin solution has been shown to increase the rate of decomposition 10-fold.²¹³

The optimum pH for ampicillin stability has been variously reported as 5.8,¹⁰⁷² 5.85 at 35°C,²¹⁵ approximately 5.2 at 25°C,⁶⁰⁴ and 7.5 at room temperature.²⁰⁹ The pH of ampicillin solutions, however, is in the alkaline range, with higher pH values having been reported at higher concentrations.²¹³ (See pH under Products.)

Ampicillin (Bristol) 10 g/L was tested for stability at pH 3.4 to 9.2 in various buffer additives. A 7.6% potency loss was reported in 12 hours at room temperature at pH 7.5. Significantly higher degradation rates occurred as the pH varied from 7.5, with about 70% degradation occurring in 12 hours at room temperature at pH 3.4 and 9.2.²⁰⁹

In another evaluation, rate constants for ampicillin degradation at various pH values were calculated for an aqueous solution at 25°C. The pH providing maximum stability was 5.2. When tested in dextrose 10%, a minimum rate of decomposition was observed at approximately pH 5 to 5.5. The amount of ampicillin degradation was 10% or less in 24 hours at 25°C within a pH range of about 2.75 to 6.75. At pH 8, the time to 10% decomposition was only about 2 hours.⁶⁰⁴

The stability of ampicillin (Beecham) 250 mg/50 mL and 1 g/100 mL in sodium chloride 0.9% in polyvinyl chloride (PVC) bags was compared with the stability of the same solutions buffered with potassium acid phosphate 13.6% injection. The 50- and 100-mL containers were buffered with 1 and 2 mL, respectively, lowering the pH by nearly 2 pH units. Larger quantities of buffer caused precipitation. When stored at 5°C, the 250-mg/50 mL solution had a shelf life (t₉₀) of 12 days while the 1-g/100-mL solution had a shelf life of 6 days. This finding compares favorably to the shelf life of 1 to 2 days for the unbuffered solutions.¹⁸²⁰

The stability of ampicillin 12 g/L prepared from ampicillin (AAP) 2 g/16 mL and ampicillin (Auromedics) 10 g/100 mL in sodium chloride 0.9% in 1-L bags was compared with the stability of the same solution buffered with sodium phosphate injection (American Regent) 10 mmol.³⁴¹⁸ Addition of the buffer lowered the average initial pH from 9.25 to 8.15.³⁴¹⁸ At a room temperature of 25°C, the buffered solution was stable for at least 48 hours (calculated time to 10% loss of 57.6 hours) as compared with at least 24 hours (calculated time to 10% loss ranging from 32 to 41.7 hours) for the unbuffered solution.³⁴¹⁸ The buffered solution also was stable for up to 48 hours at 2 to 8°C followed by up to 24 hours at a room temperature of 25°C.³⁴¹⁸

Temperature Effects

The storage temperature of ampicillin solutions also may affect stability. It has been stated that freezing ampicillin solutions at -20°C increases the rate of decomposition over that at 5°C. For this reason, it has been recommended that ampicillin solutions not be stored in the frozen state.¹²³; ²¹³

Apparent increased ampicillin decomposition was found at -20°C over that at 5°C in 2 of the 10-mg/mL solutions tested (Tables 3 and 5). In a study of ampicillin 20 mg/mL, about 4 to 6% greater loss was found at -20°C than at 5°C in 24 hours in both dextrose 5% and sodium chloride 0.9%.²⁰⁸

Table 5. Percent Degradation of Ampicillin 10 mg/mL in Water According to Temperature and Time²¹⁰

An explanation of this phenomenon was proposed by Pincock and Kiovsky. Below the freezing point but above the eutectic temperature, there exists a liquid and solid phase in equilibrium. If it is assumed that -20°C is above the eutectic temperature, then liquid regions of a saturated solution of ampicillin exist, which result in increased decomposition.²¹⁴ Solutions of ampicillin stored at -78°C showed no decomposition within 24 hours.²¹⁰

In a study of long-term storage, ampicillin (Ayerst) 1 g/50 mL in dextrose 5% and also sodium chloride 0.9% was tested in PVC containers frozen at -20°C for 30 days. In sodium chloride 0.9%, they reported approximately 10% decomposition in 1 day and approximately 70% decomposition in 30 days. In dextrose 5%, even greater decomposition occurred. They reported about 50% decomposition in 1 day and virtually total decomposition in 30 days.²⁹⁹

Ampicillin (Wyeth) 1 g/50 mL of dextrose 5% was tested in PVC bags frozen at -20°C for 30 days and then thawed by exposure to ambient temperature or microwave radiation. The admixtures showed essentially total loss of ampicillin activity determined microbiologically.⁵⁵⁴ At -30°C, only 18% of the ampicillin remained in 30 days. A storage temperature of -70°C was required to retain at least 90% of the original activity for 30 days.⁵⁵⁵

The same concentration in sodium chloride 0.9% showed a 29% loss of ampicillin activity at -20°C but only about a 4% loss at -30 and -70°C after 30 days. Subsequent thawing of the -30 and -70°C samples by exposure to microwave radiation and storage at room temperature for 8 hours resulted in additional losses of activity, with the final concentration totaling about 90% of the initial amount. The authors concluded that ampicillin in sodium chloride 0.9% could be stored for 30 days at -30°C, which was presumably below the eutectic point for this admixture. However, -30°C was believed to be above the eutectic point for the dextrose 5% admixture because decomposition continued to occur.⁵⁵⁵

Even within acceptable limits for room temperature, significant differences in the rate of ampicillin decomposition can occur. In one solution at 20°C, a 10% ampicillin loss resulted in 44 hours. This same solution at 30°C exhibited a 10% loss in 12 hours. Over the range of 20 to 35°C, each 5°C rise approximately doubled the rate of decomposition.⁶⁰⁴

Sorption

Ampicillin was shown not to exhibit sorption to PVC bags and tubing, polyethylene tubing, Silastic tubing, polypropylene syringes, and trilayer solution bags composed of polyethylene, polyamide, and polypropylene.⁵³⁶; ⁶⁰⁶; ¹⁰³⁵; ¹⁹¹⁸

Filtration

Filtration of ampicillin sodium (Wyeth) is stated to result in no adsorption, yielding solutions that maintain their potency.⁸²⁹

Ampicillin (Bristol) 1.97 mg/mL in sodium chloride 0.9% was filtered through a 0.22-µm cellulose ester membrane filter (Ivex-HP, Millipore) over 5 hours. No significant drug loss due to binding to the filter was noted.¹⁰³⁴

Central Venous Catheter

Ampicillin (Apothecon) 5 mg/mL in sodium chloride 0.9% was found to be compatible with the ARROWg+ard Blue Plus (Arrow International) chlorhexidine-bearing triple-lumen central catheter. Essentially complete delivery of the drug was found with little or no drug loss occurring. Furthermore, chlorhexidine delivered from the catheter remained at trace amounts with no substantial increase due to the delivery of the drug through the catheter.²³³⁵

Solution Compatibility

Additive Compatibility

Drugs in Syringe Compatibility

Y-Site Injection Compatibility (1:1 Mixture)

Additional Compatibility Information

Peritoneal Dialysis Solutions

The stability of ampicillin (Bristol) 50 mg/L in peritoneal dialysis solutions (Dianeal 137 and PD-2) with heparin sodium 500 units/L was evaluated at 25°C. Approximately 93 ± 10% activity remained after 24 hours.¹²²⁸ However, ampicillin (Bristol) 2.5 g/L in peritoneal dialysis concentrate (Travenol) containing dextrose 30% with and without heparin sodium 2500 units/L underwent substantial reduction in activity within as little as 10 minutes.²⁷³

The stability of ampicillin (Aspen Pharmacare) 125 mg/L in pH-neutral Balance (Fresenius), icodextrin-based Extraneal (Baxter), and dextrose-based Dianeal PD-4 (Baxter) peritoneal dialysis solutions was evaluated.²⁹⁸⁴ At 4, 25, and 37°C, ampicillin was stable in Balance for 336, 12, and 12 hours, respectively; in Extraneal for 336, 48, and 24 hours, respectively; and in Dianeal PD-4 for 336, 72, and 24 hours, respectively.²⁹⁸⁴

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.