Criteria for Selecting Preservatives Used in Liquid Formulation
Figure 1.Preservative usage based on 3,721 products surveyed.1
Using preservatives in pharmaceutical drug products helps increase the shelf life of products and prevent microbial decomposition growth. This is especially important for multi-use liquid formulations, which may include injectable liquid, ophthalmic liquid, topical semi-solid/liquid, oral liquid, and nasal solutions.
Based on an examination of 3,721 marketed formulations, 71% of preservatives used are parabens, benzalkonium chloride, benzyl alcohol, and sodium benzoate (Figure 1).1 However, a wide variety of preservatives can be used and making the selection of the best suitable preservative for your liquid formulation requires careful consideration.
Considerations When Selecting Preservatives
The ideal preservative should be:
- Active against a wide range of microbes
- Active in a broad pH range
- Compatible with your API and other excipients in your formulation
- Highly pure
- Chemically inert
- Non-toxic
Below, we examine the different aspects to consider when selecting preservatives for your liquid formulation.
Type of Molecule
Different preservatives are used for large molecule formulations (ex: vaccines, insulin) and for small molecule formulations.
Preservatives that can be used for large molecule formulations include:
- Benzyl alcohol
- Phenol
- Chlorobutanol
- Thimerosal
Preservatives that can be used for small molecule formulations include:
- Benzalkonium chloride
- Boric acid
- Benzoic acid
- Benzyl alcohol
- Benzyl benzoate
- Phenol
- Methylparaben
- Propylparaben
- Sorbic acid
- Chlorobutanol
Type of Formulation
Aqueous, non-aqueous, and lyophilized formulations all have different requirements for preservatives. The solubility and chemical properties of the preservative determine whether a preservative can be used for aqueous, non-aqueous, or lyophilized formulations (Table 1).
pH of Formulation
The preservative used should be selected based on whether it has maximal microbial activity at the pH of the formulation (Figure 2). A mixture of preservatives can be used to target a complete microbial population to inhibit microbial growth of the product across a wide pH range (e.g., benzyl benzoate with benzyl alcohol, boric acid with either benzalkonium chloride or sorbic acid). Because they are active in a broad pH range (pH 4-9), benzalkonium chloride and parabens are commonly used preservatives.
Figure 2.Approximate pH range where various preservatives can be used.
Route of Administration
Whether a drug is oral, parenteral, ophthalmic, topical, or nasally administered also determines what preservative can be used and at what concentration (Table 2). Phenol is used commonly for injections but is not used orally or for the ophthalmic route. On the other hand, benzalkonium chloride is one of the default preservatives used for ophthalmics.
Synergistic Antimicrobial Activity
Preservatives can be used in combination with one another or with preservative synergists such as chelating agent ethylenediaminetetraacetic acid (EDTA) or its salts to target a range of microbes including bacteria, yeast, and molds. Some common preservative synergies include:
- Benzalkonium chloride + EDTA
- Benzalkonium chloride + boric acid
- Sorbic acid + EDTA
- Chlorobutanol + boric acid
- Methylparaben + propylparaben
Targeted Patient Population
The same preservative might not be suitable in all target patient populations (e.g., pediatric or geriatric). For example, benzyl alcohol and benzoic acid should not be used in neonates and should be used with caution in children older than four weeks as they cannot be metabolized by the liver and can then cross the blood-brain barrier.
Preservative Profiles for Liquid Drug Formulation
With so many preservative options available, it can be difficult to identify the best preservative(s) for your liquid formulation. Taking the above-mentioned considerations can help you hone in on the best options. To learn more about a preservative in detail, see individual preservative profiles.
References
如要继续阅读，请登录或创建帐户。
暂无帐户？