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Interactions between polysorbate and antimicrobial preservatives in aqueous parenteral products

Wahlgren, Marie LU orcid ; Börjesdotter, Anna-Maria LU ; Hjalte, Johanna LU ; Martín, Javier Lagares ; Zhang, LingPing ; Sjögren, Helen LU and Ulvenlund, Stefan LU (2025) In Journal of Drug Delivery Science and Technology 107.
Abstract

Biological drugs intended for multidose use normally contain both preservatives and non-ionic surfactants. However, most common preservatives and surfactants in parenteral formulations are considered to be physically incompatible with each other. In this study, the phase separation of polysorbate 20 and polysorbate 80 in the presence of phenolic preservatives is systematically mapped. The observed precipitation is found to be the result of a dramatic surfactant cloud point depression caused by the preservative. A limited study was also performed for poloxamer 188 and dodecylmaltoside. This verified that also poloxamer clouds in the presence of phenol. The concentration where poloxamers induce clouding of phenol is higher than for... (More)

Biological drugs intended for multidose use normally contain both preservatives and non-ionic surfactants. However, most common preservatives and surfactants in parenteral formulations are considered to be physically incompatible with each other. In this study, the phase separation of polysorbate 20 and polysorbate 80 in the presence of phenolic preservatives is systematically mapped. The observed precipitation is found to be the result of a dramatic surfactant cloud point depression caused by the preservative. A limited study was also performed for poloxamer 188 and dodecylmaltoside. This verified that also poloxamer clouds in the presence of phenol. The concentration where poloxamers induce clouding of phenol is higher than for polysorbates. No clouding was observed for dodecylmaltoside. The effect of other common excipients on polysorbate cloud point depression was also investigated, and it was demonstrated that the presence of sugar, salt, and buffer further increases the surfactant-preservative incompatibility area caused by clouding. Nonetheless, for all studied preservatives (phenol, metacresol, and benzyl alcohol) there is a region where it is possible to formulate stable, non-clouding solutions at relevant preservative concentrations.

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author
; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Clouding, Incompatibility, Parenteral formulations, Poloxamer, Polysorbates, Preservatives
in
Journal of Drug Delivery Science and Technology
volume
107
article number
106765
pages
7 pages
publisher
Editions de Sante
external identifiers
  • scopus:85219087278
ISSN
1773-2247
DOI
10.1016/j.jddst.2025.106765
language
English
LU publication?
yes
additional info
Publisher Copyright: © 2025
id
1cdbcaa0-b31a-4c5c-a7b8-e6bf4d5e2980
date added to LUP
2025-03-16 14:32:59
date last changed
2025-04-04 14:36:19
@article{1cdbcaa0-b31a-4c5c-a7b8-e6bf4d5e2980,
  abstract     = {{<p>Biological drugs intended for multidose use normally contain both preservatives and non-ionic surfactants. However, most common preservatives and surfactants in parenteral formulations are considered to be physically incompatible with each other. In this study, the phase separation of polysorbate 20 and polysorbate 80 in the presence of phenolic preservatives is systematically mapped. The observed precipitation is found to be the result of a dramatic surfactant cloud point depression caused by the preservative. A limited study was also performed for poloxamer 188 and dodecylmaltoside. This verified that also poloxamer clouds in the presence of phenol. The concentration where poloxamers induce clouding of phenol is higher than for polysorbates. No clouding was observed for dodecylmaltoside. The effect of other common excipients on polysorbate cloud point depression was also investigated, and it was demonstrated that the presence of sugar, salt, and buffer further increases the surfactant-preservative incompatibility area caused by clouding. Nonetheless, for all studied preservatives (phenol, metacresol, and benzyl alcohol) there is a region where it is possible to formulate stable, non-clouding solutions at relevant preservative concentrations.</p>}},
  author       = {{Wahlgren, Marie and Börjesdotter, Anna-Maria and Hjalte, Johanna and Martín, Javier Lagares and Zhang, LingPing and Sjögren, Helen and Ulvenlund, Stefan}},
  issn         = {{1773-2247}},
  keywords     = {{Clouding; Incompatibility; Parenteral formulations; Poloxamer; Polysorbates; Preservatives}},
  language     = {{eng}},
  publisher    = {{Editions de Sante}},
  series       = {{Journal of Drug Delivery Science and Technology}},
  title        = {{Interactions between polysorbate and antimicrobial preservatives in aqueous parenteral products}},
  url          = {{http://dx.doi.org/10.1016/j.jddst.2025.106765}},
  doi          = {{10.1016/j.jddst.2025.106765}},
  volume       = {{107}},
  year         = {{2025}},
}