Thermodynamic investigation of the interaction between cyclodextrins and preservatives - Application and verification in a mathematical model to determine the needed preservative surplus in aqueous cyclodextrin formulations

René Holm; Niels Erik Olesen; Signe Dalgaard Alexandersen; Birgitte N Dahlgaard; Peter Westh; Huiling Mu

doi:10.1016/j.ejps.2015.09.011

Thermodynamic investigation of the interaction between cyclodextrins and preservatives - Application and verification in a mathematical model to determine the needed preservative surplus in aqueous cyclodextrin formulations

René Holm, Niels Erik Olesen, Signe Dalgaard Alexandersen, Birgitte N Dahlgaard, Peter Westh, Huiling Mu

7 Citations (Scopus)

Abstract

Preservatives are inactivated when added to conserve aqueous cyclodextrin (CD) formulations due to complex formation between CDs and the preservative. To maintain the desired conservation effect the preservative needs to be added in apparent surplus to account for this inactivation. The purpose of the present work was to establish a mathematical model, which defines this surplus based upon knowledge of stability constants and the minimal concentration of preservation to inhibit bacterial growth. The stability constants of benzoic acid, methyl- and propyl-paraben with different frequently used βCDs were determined by isothermal titration calorimetry. Based upon this knowledge mathematical models were constructed to account for the equilibrium systems and to calculate the required concentration of the preservations, which was evaluated experimentally based upon the USP/Ph. Eur./JP monograph. The mathematical calculations were able to predict the needed concentration of preservation in the presence of CDs; it clearly demonstrated the usefulness of including all underlying chemical equilibria in a mathematical model, such that the formulation design can be based on quantitative arguments.

Original language	English
Journal	European Journal of Pharmaceutical Sciences
Volume	87
Pages (from-to)	22-9
Number of pages	8
ISSN	0928-0987
DOIs	https://doi.org/10.1016/j.ejps.2015.09.011
Publication status	Published - 25 May 2016

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Holm, R., Olesen, N. E., Alexandersen, S. D., Dahlgaard, B. N., Westh, P., & Mu, H. (2016). Thermodynamic investigation of the interaction between cyclodextrins and preservatives - Application and verification in a mathematical model to determine the needed preservative surplus in aqueous cyclodextrin formulations. European Journal of Pharmaceutical Sciences, 87, 22-9. https://doi.org/10.1016/j.ejps.2015.09.011

Thermodynamic investigation of the interaction between cyclodextrins and preservatives - Application and verification in a mathematical model to determine the needed preservative surplus in aqueous cyclodextrin formulations. / Holm, René; Olesen, Niels Erik; Alexandersen, Signe Dalgaard et al.
In: European Journal of Pharmaceutical Sciences, Vol. 87, 25.05.2016, p. 22-9.

Research output: Contribution to journal › Journal article › Research › peer-review

Holm, R, Olesen, NE, Alexandersen, SD, Dahlgaard, BN, Westh, P & Mu, H 2016, 'Thermodynamic investigation of the interaction between cyclodextrins and preservatives - Application and verification in a mathematical model to determine the needed preservative surplus in aqueous cyclodextrin formulations', European Journal of Pharmaceutical Sciences, vol. 87, pp. 22-9. https://doi.org/10.1016/j.ejps.2015.09.011

Holm R, Olesen NE, Alexandersen SD, Dahlgaard BN, Westh P, Mu H. Thermodynamic investigation of the interaction between cyclodextrins and preservatives - Application and verification in a mathematical model to determine the needed preservative surplus in aqueous cyclodextrin formulations. European Journal of Pharmaceutical Sciences. 2016 May 25;87:22-9. doi: 10.1016/j.ejps.2015.09.011

Holm, René ; Olesen, Niels Erik ; Alexandersen, Signe Dalgaard et al. / Thermodynamic investigation of the interaction between cyclodextrins and preservatives - Application and verification in a mathematical model to determine the needed preservative surplus in aqueous cyclodextrin formulations. In: European Journal of Pharmaceutical Sciences. 2016 ; Vol. 87. pp. 22-9.

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title = "Thermodynamic investigation of the interaction between cyclodextrins and preservatives - Application and verification in a mathematical model to determine the needed preservative surplus in aqueous cyclodextrin formulations",

abstract = "Preservatives are inactivated when added to conserve aqueous cyclodextrin (CD) formulations due to complex formation between CDs and the preservative. To maintain the desired conservation effect the preservative needs to be added in apparent surplus to account for this inactivation. The purpose of the present work was to establish a mathematical model, which defines this surplus based upon knowledge of stability constants and the minimal concentration of preservation to inhibit bacterial growth. The stability constants of benzoic acid, methyl- and propyl-paraben with different frequently used βCDs were determined by isothermal titration calorimetry. Based upon this knowledge mathematical models were constructed to account for the equilibrium systems and to calculate the required concentration of the preservations, which was evaluated experimentally based upon the USP/Ph. Eur./JP monograph. The mathematical calculations were able to predict the needed concentration of preservation in the presence of CDs; it clearly demonstrated the usefulness of including all underlying chemical equilibria in a mathematical model, such that the formulation design can be based on quantitative arguments.",

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AU - Alexandersen, Signe Dalgaard

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AU - Westh, Peter

AU - Mu, Huiling

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AB - Preservatives are inactivated when added to conserve aqueous cyclodextrin (CD) formulations due to complex formation between CDs and the preservative. To maintain the desired conservation effect the preservative needs to be added in apparent surplus to account for this inactivation. The purpose of the present work was to establish a mathematical model, which defines this surplus based upon knowledge of stability constants and the minimal concentration of preservation to inhibit bacterial growth. The stability constants of benzoic acid, methyl- and propyl-paraben with different frequently used βCDs were determined by isothermal titration calorimetry. Based upon this knowledge mathematical models were constructed to account for the equilibrium systems and to calculate the required concentration of the preservations, which was evaluated experimentally based upon the USP/Ph. Eur./JP monograph. The mathematical calculations were able to predict the needed concentration of preservation in the presence of CDs; it clearly demonstrated the usefulness of including all underlying chemical equilibria in a mathematical model, such that the formulation design can be based on quantitative arguments.

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