(T1030-09-56) Split Decisions: Tracking Preservative Partitioning in Cream Formulations

Purpose: When formulating topical creams—or any preserved oil-and-water emulsion—there are varying philosophies on how best to incorporate preservatives. One traditional approach suggests that even oil-soluble preservatives should be added to the water phase of an oil-in-water (O/W) emulsion to ensure better contact with the aqueous phase and to avoid partitioning at the oil-water interface.¹ In contrast, another view recommends adding preservatives to their respective phases: water-based preservatives to the water phase and oil-based preservatives to the oil phase, prior to emulsification.² Additionally, the use of co-solvents to aid preservative incorporation is also common.³  The purpose of this study was to evaluate these techniques to determine whether the method of preservative incorporation affects its final distribution in a two-phase emulsion system.

Methods: A simple emulsion system was developed for evaluation (Table 1). The formulation consisted of an aqueous phase (~80%) and an oil phase (~20%, using isopropyl palmitate), with steareth-2 as the surfactant at either 2% or 6%. When testing the use of a co-solvent phase, 10% diethylene glycol monoethyl ether (DGME) was included in the aqueous phase. Six preservatives were evaluated: four antimicrobials (propylparaben, methylparaben, benzyl alcohol, phenoxyethanol) and two antioxidants (butylated hydroxyanisole [BHA] and butylated hydroxytoluene [BHT]). These were incorporated into different phases during the manufacturing process. A total of 10 emulsions were prepared: Five emulsions with 6% surfactant, designed to form stable creams that were later separated into individual phases via centrifugation. Five identical emulsions using only 2% surfactant, which allowed the emulsion to break spontaneously, enabling assessment of how quickly preservative partitioning occurs. For all formulations, the aqueous and oil phases (with the oil phase containing steareth-2) were heated separately to ~70°C before combining. Preservatives were added to specific phases as outlined below, followed by homogenization into a cream, and then cooled. The five emulsion types prepared were: No DGME; preservatives added to the aqueous phase; No DGME; preservatives added to the oil phase; DGME present (in aqueous phase); preservatives added to the aqueous phase; DGME present (in aqueous phase); preservatives added to the oil phase; DGME present; preservatives pre-dissolved in DGME and then added to the pre-formed emulsion. After manufacturing the 2% surfactant, emulsions were allowed to spontaneously separate (Figure 2A), while the 6% surfactant emulsions were held for one week (Figure 2B), then separated via centrifugation (Figure 2C) for sampling (Figure 2D).This allows us to see if the partitioning occurs during processing, or over time after the cream is formed. Samples were taken from the separated oil and aqueous phases from each formulation for determination of their respective preservative level. Each sampled phase was analyzed by HPLC for quantitative determination of the preservatives.

Results: The results, analyzed by HPLC, are presented both as content (% w/w) in Table 3A and as percent recovery of label claim in Figure 3B. It may appear that the preservative content and % recovery exceed the amount added to the drug product; this is due to partitioning effects, where preservatives concentrate within smaller phases, making their content appear higher. Overall, the data indicate that in most cases, the partitioning of each preservative between the oil and aqueous phases was minimal, regardless of when or where the preservatives were introduced. Emulsions that spontaneously separated typically showed higher recovery in the oil phase. However, this was likely due to lower surfactant levels, which trapped less preservative at the phase boundaries. All spontaneously separated formulations performed similarly, with only minor differences between samples that did and did not contain DGME. The phase of preservative addition had little impact. Likewise, delayed separation products containing DGME also showed consistent results, regardless of the preservative addition phase. In contrast, the stable emulsions without DGME showed the greatest variation. Among these, the formulation with preservatives added to the oil phase exhibited higher preservative content in the oil phase upon analysis.

Conclusion: In conclusion, the timing and location of preservative addition during manufacturing have a minimal impact on their final distribution once manufacturing is complete. Forcing an ingredient into a phase where it may not easily incorporate is unnecessary. For example, antimicrobial agents like parabens do not need to be dissolved in the water phase of a formulation and can rather be added to the oil or solvent phased without affecting their final partitioning into the water. It is recommended that preservatives be added in a manner that best supports long-term, large-scale operations for reproducibility and ease of operations.

References: 1 Eric S. Abrutyn, TPC2 Advisors Ltd. Optimizing Formula Preservation. Cosmetics & Toiletries. Feb 26th, 2010
2 Lotion Making. From Nature with Love. https://www.fromnaturewithlove.com/library/lotionmaking.asp#:~:text=Creams%20Vs.&text=Creams%20are%20usually%20about%202,than%20you%20expected%20upon%20cooling.
3 B De Spiegeleer, E Wattyn, G Slegers, P Van der Meeren, K Vlaminck, L Van Vooren. The importance of the cosolvent propylene glycol on the antimicrobial preservative efficacy of a pharmaceutical formulation by DOE-ruggedness testing. Pharm Dev Technol. 2006;11(3):275-84. doi: 10.1080/10837450600767342.

Formulation and prep images