By Melissa Merrell Rhoads, PharmD, PCCA Director of Formulation Development, and Suki Pramar, PhD, PCCA Compounding Consultant

Pharmacies add antimicrobial preservatives to water-containing (aqueous) compounded medications to protect them from microbial growth. This in turn protects patients from potential exposure to microbial contamination. It should go without saying that this is an incredibly important part of pharmacy compounding, so we have written this article to help pharmacies develop criteria for preservative selection for their aqueous compounded preparations. However, this article is not exhaustive, and pharmacies must look at all aspects of the preparation, including pH, other included ingredients and the dispensing device along with the properties of the desired preservative to determine the appropriate selection during formulation development. Ultimately, the only definitive proof that a preservative is appropriate for a given preparation is through USP <51> antimicrobial effectiveness testing.

Potential Contaminants in Common Aqueous Dosage Forms

USP Chapter <1112>, Application of Water Activity Determination to Nonsterile Pharmaceutical Products, lists some common aqueous dosage forms along with the greatest potential contaminant for consideration. We have listed a few below, but any water-containing compounded preparation with a water activity above 0.6 should be considered for appropriate preservation to protect the preparation from microbial growth.Preparations with a w ater activity below 0.6 are considered anhydrous.

General Considerations for Using Preservatives

USP Chapters <1151> and <51> provide general guidance on the use of preservatives. USP Chapter <1151>, Pharmaceutical Dosage Forms, suggests that preservatives should be added to most water-containing compounded preparations and states, “Acceptance criteria for preservative content in multidose products should be established. They are based on the levels of antimicrobial preservative necessary to maintain the product’s microbiological quality at all stages throughout its proposed usage and shelf life (see Antimicrobial Effectiveness Testing <51>).” ²

Regarding nonsterile compounds, USP Chapter <51>, Antimicrobial Effectiveness Testing, states, “Nonsterile dosage forms may have preservatives added to protect them from growth of microorganisms inadvertently introduced during or subsequent to the manufacturing process.” For sterile compounds, USP Chapter <51> says, “In the case of sterile articles packaged in multiple-dose containers, antimicrobial preservatives are added to inhibit the growth of microorganisms that may be introduced from repeatedly withdrawing individual doses. One or more antimicrobial preservative(s) are expected in all sterile multidose units.” ³

However, there are certain situations when a preservative may not be necessary, such as those listed below, but this should be evaluated on a case-by-case basis.

• When the preparation will be used immediately
• When no water is present or the water available for chemical or microbial activity is very low (that is, when the preparation is anhydrous)
• When the pH of the preparation is less than 3 or greater than 9
• When component ingredients included in the formulation have antimicrobial properties (such as ethyl alcohol in concentrations greater than 10%)

Here are important considerations for selecting a preservative to use in an aqueous compounded preparation:

• Dosage form and route of administration: oral, topical, nasal, ophthalmic, injection, etc.
• pH of the final preparation
• Solubility of the preservative within the formulation
• Compatibility with ingredients in the formulation

Commonly Used Preservatives in Compounded Medications

Preservatives are grouped into categories that include antibacterials or antifungals as well as some others. While they are grouped according to their primary activity, the majority of them may be active against both bacteria and fungi. Below are some of the most commonly used preservatives in compounded formulations. Please note that the antimicrobial activity of preservatives may be affected by other excipients in a formula, such as ionic surfactants, or certain types of plastic used in dispensing containers.

Antibacterial Agents

Antibacterial agents are active against Gram-positive and/or Gram-negative microorganisms.

• Benzyl alcohol
  • Bactericidal at 1-2%
  • Most effective at pH less than 5; minimal activity at pH 8 and above
  • Incompatible with methylcellulose
  • Polysorbates may reduce its activity
  • Water soluble
• Benzalkonium chloride
  • Most-used concentration is 0.01%
  • Most effective at pH range of 4–10
  • Should not be used orally because it is a gastrointestinal irritant
  • For ophthalmics, its bactericidal properties are improved by the addition of 0.1% EDTA
• Imidurea (imidazolidinyl urea)
  • Commonly used in topical formulations at a concentration of 0.03–0.5%
  • Most effective pH range of 3–9
• Chlorobutanol
  • Commonly used in ophthalmic and parenteral preparations at a concentration of 0.5%
  • Should be used in solutions buffered at pH 5–5.5
  • Carboxymethylcellulose and polysorbates may reduce antimicrobial activity
  • Methylcellulose does not interact with it
• Phenol
  • Primarily used in parenteral formulations and some topical preparations at a concentration of 0.15–1%
  • Optimal activity in acidic solutions

Antifungal Agents

• Sodium benzoate
  • Effective concentration 0.1–0.3%
  • Most effective in acidic solutions of pH 2–5; ineffective at a pH above 5
  • Effectiveness may be reduced by polysorbates
  • Water soluble
  • This is the preservative used in PCCA’s SuspendIt® (PCCA #30-4825), so it is important to check the pH of your compounded preparation to ensure adequate preservation
• Potassium sorbate
  • Effective concentration 0.1–0.2%
  • Ineffective at a pH above 6
  • Water soluble
• Methylparaben and propylparaben
  • Methylparaben effective concentration 0.05–0.25%/>
  • Propylparaben effective concentration 0.02–0.04%
  • Most effective when used in combination; the majority of PCCA’s formulas use a combination (PCCA members, see PCCA Formula #1686 Preserved Water (Parabens) (USP <51> Study))
  • Most effective over a broad pH range of 4–8
  • Parabens are FDA approved for use in oral, topical, rectal, vaginal, urethral, ophthalmic, nasal, inhalation, irrigation and parenteral products, but irritation has been reported with the use of parabens in ophthalmic preparations
  • Parabens are not compatible with Methocel (Hydroxypropyl Methylcellulose), Methylcellulose, Hydroxypropyl cellulose (HPC) and Hydroxyethyl cellulose (HEC), leading to compromised preservative effectiveness.

Other Potential Antimicrobial Agents

Other agents that are used as solvents or vehicles at certain concentrations may be self-preserving.

• Ethyl alcohol
  • While a common guideline is 10% or more ethyl alcohol can be a preservative, the concentration required for preservation is based on the amount of “free water” within the preparation
• Glycerin
  • Can be a preservative at concentrations of 50% and higher
• Propylene glycol
  • May be effective at a concentration of 10% and above; however, it may require up to 30% concentration to inhibit the growth of certain molds

We have listed commonly used preservatives per dosage form/route of administration below. This is only a general guide for educational purposes, and again, you must look at all aspects of the preparation, including pH, other included ingredients and the dispensing device along with the properties of the desired preservative to determine the appropriate selection for formulation development. Ultimately, the only definitive proof that a preservative is appropriate for a given preparation is through USP <51> antimicrobial effectiveness testing.

* Premade, proprietary PCCA bases contain preservatives, which should be evaluated based on your final preparation to ensure preservation. But as with all formulations, the only definitive proof of preservation is through USP <51> antimicrobial effectiveness testing.

PCCA members can also access our preservative chart (PCCA Document #97579) for a list of criteria on potential preservatives for formulations.

References

1. United States Pharmacopeial Convention. (2020). General chapter <1112> application of water activity determination to nonsterile pharmaceutical products. In United States pharmacopeia and national formulary (USP 43rd ed. & NF 38th ed.). https://www.uspnf.com/
2. United States Pharmacopeial Convention. (2020). General chapter <1151> pharmaceutical dosage forms. In United States pharmacopeia and national formulary (USP 43rd ed. & NF 38th ed.). https://www.uspnf.com/
3. United States Pharmacopeial Convention. (2020). General chapter <51> antimicrobial effectiveness testing. In United States pharmacopeia and national formulary (USP 43rd ed. & NF 38th ed.). https://www.uspnf.com/

Additional Works Consulted

Lester, D. E. (2018). A practical guide to contemporary pharmacy practice and compounding (4th ed.). Wolters Kluwer.

Sheskey, P. J., Hancock, B. C., Moss, G. P., & Goldfarb, D. J. (Eds.). (2020). Handbook of pharmaceutical excipients (9th ed.). Pharmaceutical Press.

Melissa Merrell Rhoads, PharmD, PCCA Director of Formulation Development, received her pharmacy degree from Mercer University in Atlanta, Georgia, in 1995. She currently is involved with and oversees the development and implementation of new formulas at PCCA. She had more than six years of compounding experience with pharmacies in Georgia and Florida prior to joining the PCCA staff in 2004. Her areas of interest include women’s health, veterinary and pain management compounding.

Suki Pramar, PhD, is a compounding consultant at PCCA. She earned her PhD in pharmaceutics from the University of Houston in 1991, and she joined PCCA’s staff in 1999. Suki was appointed to the American Pharmacists Association’s Compounding Pharmacy Task Force in 2016.