Bacteriostatic Water

At a glance

Strengths

3 mL and 10 mL

Also known as

Bacteriostatic Water, Water,bacteriostatic

PubChem CID

962 (water); 244 (benzyl alcohol)

What bacteriostatic water is

Hospira's label describes bacteriostatic water (USP) as a sterile, nonpyrogenic preparation of water with 0.9% (9 mg/mL) or 1.1% (11 mg/mL) benzyl alcohol added as a bacteriostatic preservative ¹. It is supplied in a container from which repeated withdrawals may be made to dilute or dissolve other drugs ¹. Its label states that it is to be used only as a diluent or solvent ¹. The preservative is there for the period after the vial is first opened: FDA describes antimicrobial effectiveness testing as determining whether a product prevents microbial growth if the container is contaminated during use ⁵.

FDA-approved labels for some freeze-dried peptide and protein products name bacteriostatic water as the diluent supplied in the package ¹³¹⁴. Egrifta WR, a lyophilised form of tesamorelin, comes with a 30 mL bottle of bacteriostatic water (USP), and each vial of Novarel, a urine-derived chorionic gonadotropin, comes with a 10 mL vial containing 0.9% benzyl alcohol ¹³¹⁴. On this site it is listed as a laboratory diluent alongside freeze-dried research peptides such as BPC-157 and GHK-Cu.

Composition

The label lists two components, water and benzyl alcohol, and no other ingredient ¹. Hospira supplies the 0.9% (9 mg/mL) solution in 30 mL plastic vials and a 1.1% (11 mg/mL) solution in 20 mL glass vials ¹. The label gives a pH of 5.7, with a range of 4.5 to 7.0 ¹. The plastic vial is a polyolefin, a copolymer of ethylene and propylene, and the label states that it needs no vapour barrier to keep its labelled volume ¹.

• Water: PubChem CID 962, formula H2O, molecular weight 18.015 g/mol ³.
• Benzyl alcohol: PubChem CID 244, also called phenylmethanol (CAS 100-51-6), formula C7H8O, molecular weight 108.14 g/mol ⁴.

The ChEBI description in PubChem defines benzyl alcohol as an aromatic alcohol consisting of benzene bearing a single hydroxymethyl substituent, with roles that include solvent and antioxidant ⁴.

Why it contains benzyl alcohol

FDA's 2018 guidance on package types defines a container meant to be entered more than once as one holding a sterile medication, a term that covers diluents as well as active drugs, that has met antimicrobial effectiveness testing requirements (or is excluded from such testing by FDA regulation) ⁵. The guidance notes that some formulations pass that testing without an added preservative, while others rely on one ⁵. It adds that such containers are generally expected to hold 30 mL or less ⁵. A 1982 CDC report described benzyl alcohol as an aromatic alcohol usually used at 0.9% as a bacteriostatic preservative in vials of solutions or drugs for parenteral therapy ⁸. A 2007 review of licensed parenteral products found that phenol and benzyl alcohol were the two most common antimicrobial preservatives in peptide and protein products ⁷. The same review found benzyl alcohol, or methylparaben with propylparaben, generally used in small-molecule formulations ⁷.

Bacteriostatic water, sterile water and sodium chloride 0.9%

These are three different solutions, and their FDA labels describe them differently.

• Sterile water (USP) is the same grade of water with no preservative: its label states that it contains no bacteriostat, antimicrobial agent or added buffer and is supplied only in containers meant for one use, with any unused portion discarded ⁹.
• Sodium chloride 0.9% (USP) contains 900 mg of sodium chloride per 100 mL, with a calculated osmolarity of 308 mOsmol/L that its label calls isotonic ¹⁰. That label also states the solution contains no bacteriostat, antimicrobial agent or added buffer ¹⁰.
• Bacteriostatic sodium chloride 0.9% (USP) combines the two ideas: 9 mg of sodium chloride and 9 mg of benzyl alcohol per mL, in a container for repeated withdrawals, with a pH of 5.0 (4.5 to 7.0) ⁶.

Both water labels state that the water must be made approximately isotonic before use, and both warn that intravenous administration of the water without a solute may result in hemolysis ¹⁹. Bacteriostatic water therefore differs from saline in containing no sodium chloride, and from sterile water in containing a preservative ¹⁹¹⁰.

Regulatory status

Drugs@FDA lists Hospira's bacteriostatic water in plastic containers under NDA 018802, a prescription product first approved on October 27, 1982 ². Its label is marked Rx only ¹. The bacteriostatic water on this page is supplied as a laboratory research material; the FDA labels quoted here describe the approved USP product and are cited to define the material.

Label warnings

The label opens with the warning "not for use in neonates" ¹. It states that benzyl alcohol has been associated with toxicity in neonates, and that where water is needed to prepare or dilute medications for neonates, only preservative-free sterile water should be used ¹. Its contraindications add that preparations with benzyl alcohol should not be used for fluid replacement or in epidural or spinal anaesthesia procedures ¹. The label also notes that some drugs may be incompatible in a vehicle containing benzyl alcohol ¹.

Reports of neonatal toxicity date to 1982, when CDC reported 16 deaths of pre-term infants at two medical centres whose intravascular catheters had been flushed periodically each day with bacteriostatic saline containing 9 mg/mL benzyl alcohol ⁸. The infants developed metabolic acidosis that progressed to respiratory distress and gasping respirations ⁸. The report explained that benzyl alcohol is normally oxidised to benzoic acid, conjugated with glycine in the liver and excreted as hippuric acid, a pathway that may not be well developed in premature infants ⁸. FDA then recommended that flush solutions containing benzyl alcohol not be used for newborns ⁸. A 1986 review of 26 months of records at one neonatal intensive care unit found that, among infants under 1,000 g, mortality fell from 80.7% to 45.7% after solutions containing benzyl alcohol were stopped ¹¹.

Storage as stated on the label

The label states that the vials are stored at 20 to 25 °C (68 to 77 °F), USP controlled room temperature ¹. It also states that the solution is not to be used unless it is clear and the seal is intact ¹. For a container of this type that has been opened or entered, FDA's guidance gives a beyond-use date of 28 days unless the manufacturer's label specifies otherwise ⁵. For that reason such containers do not normally carry a discard statement, and Hospira's label gives no other period ¹⁵.

What is not known

Benzyl alcohol can affect the material dissolved in it. In a 2005 study of a freeze-dried recombinant protein, interleukin-1 receptor antagonist, dissolving the dried solid in 0.9% benzyl alcohol caused more aggregation than dissolving it in water ¹². The extent depended on how much native structure the protein kept through freeze-drying, and benzyl alcohol did not accelerate aggregation during later storage at room temperature ¹². That study concerned one protein, so it does not establish how any other peptide or protein behaves in benzyl alcohol ¹². FDA's 28-day period is an assumed default for entered containers, and the guidance asks for a discard statement supported by data when a product's period differs ⁵. Published certificates of analysis are listed with our lab results.