Preservatives (Criteria for Selecting Preservatives Used in Liquid Formulation).pptx

Preservatives are added to pharmaceutical products to prevent microbial growth and extend shelf life. An ideal preservative kills microbes rapidly at low concentrations, is non-toxic, stable, and does not interact negatively with the product ingredients.

1. PRESERVATIVES Criteria for Selecting Preservatives Used in Liquid Formulation

2. 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). 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. Figure 1.Preservative usage based on 3,721 products surveyed.1 1.July 2020. Pharmacircle .

3. 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

4. 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).

5. Table 1 . Preservative usage in aqueous, non-aqueous, and lyophilized formulations. ( Based on literature and marketed product data) Preservative Aqueous Non-aqueous Lyophilized Benzalkonium chloride √ √ Unknown Boric acid √ √ √ Benzoic acid √ √ x Benzyl alcohol √ √ x Benzyl benzoate x √ x Methylparaben √ x √ Propylparaben √ x √ Phenol √ x x Sorbic acid √ x x Chlorobutanol √ √ x Thimerosal √ x x

6. pH OF FORMULATION

7. 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 . 2 .Elder D, Crowley P. 2012. Antimicrobial preservatives part two: Choosing a preservative. American Pharmaceutical Review. [Internet]. American Pharmaceutical Review: Available from: https://www.americanpharmaceuticalreview.com/Featured-Articles/38885-Antimicrobial-Preservatives-Part-Two-Choosing-a-Preservative/

8. Table 2.Preservative usage and their concentrations used in oral, parenteral, ophthalmic, topical, and nasal formulations.2 Preservative Oral Parenteral Ophthalmic Topical Nasal Benzalkonium chloride 0.02 % 0.01 – 0.02 % 0.01 - 0.02 % 0.01 - 0.2 % 0.003 – 0.12 % Benzyl alcohol 1 – 5 % 0.9 – 6.69 % NA 1 – 2.7 % 0.05 % Benzoic acid 0.01 – 0.25 % 0.1 – 0.2 % NA 1 – 2.7 % 0.05 % Sodium benzoate 0.02-0.5% 0.5% NA 0.24 % 0.1-0.5% (Cosmetics) NA Benzyl benzoate 0.06 % 15 – 51.43 % NA NA NA Boric acid 15 mg/mL 0.32 % 0.06 – 1.9 % 0.12 – 2 % NA Methylparaben 0.1 – 20 % 0.10 – 5 % 0.01 – 0.05 % 0.1 – 15 % NA Propylparaben 0.01 – 4 % 0.02 – 0.20 % 0.01 – 0.02 % 0.03 – 5.25 % 140 mg Phenol NA 0.06 – 1.33 % NA NA NA Sorbic acid 0.01 – 0.1 % NA 0.1 – 0.2 % 0.1 – 2.7 % NA Potassium sorbate 1000 mg/15 mL NA 0.47 % 0.25 % 1.2 mg/mL Thimerosal NA 0.002 – 0.01 % 0.004 – 1 % 0.005 – 0.4 % NA Chlorobutanol NA 0.4 – 1 % 0.5 – 0.65 % 0.3 – 1.1 % 0.023 – 0.5 %

9. SYNERGISTIC ANTIMICROBIAL ACTIVITY Preservatives can be used in combination with one another or with preservative synergists such as chelating agent ethylene diamine tetra acetic 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

10. 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.

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