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.
authors.affiliation: Biologics and Pharmaceutical Science, H. Lundbeck A/S, Ottiliavej 9, DK-2500 Valby, Denmark; Department of Pharmacy, Faculty of Health and Medical Sciences, Copenhagen University, Universitetsparken 2, DK-2100 Copenhagen, Denmark. Electronic address: rhol@lundbeck.com.
authors.forename: René
authors.initials: R
authors.lastname: Holm
authors.affiliation: Biologics and Pharmaceutical Science, H. Lundbeck A/S, Ottiliavej 9, DK-2500 Valby, Denmark; NSM, Research Unit for Functional Biomaterials, Roskilde University, Universitetsvej 1, DK-4000 Roskilde, Denmark.
authors.forename: Niels Erik
authors.initials: NE
authors.lastname: Olesen
authors.affiliation: Biologics and Pharmaceutical Science, H. Lundbeck A/S, Ottiliavej 9, DK-2500 Valby, Denmark; Department of Pharmacy, Faculty of Health and Medical Sciences, Copenhagen University, Universitetsparken 2, DK-2100 Copenhagen, Denmark.
authors.forename: Signe Dalgaard
authors.initials: SD
authors.lastname: Alexandersen
authors.affiliation: Pharmaceutical Development, H. Lundbeck A/S, Ottiliavej 9, DK-2500 Valby, Denmark.
authors.forename: Birgitte N
authors.initials: BN
authors.lastname: Dahlgaard
authors.affiliation: NSM, Research Unit for Functional Biomaterials, Roskilde University, Universitetsvej 1, DK-4000 Roskilde, Denmark.
authors.forename: Peter
authors.initials: P
authors.lastname: Westh
authors.affiliation: Department of Pharmacy, Faculty of Health and Medical Sciences, Copenhagen University, Universitetsparken 2, DK-2100 Copenhagen, Denmark.
authors.forename: Huiling
authors.initials: H
authors.lastname: Mu
mesh_terms: D002626:Chemistry, Pharmaceutical; D003505:Cyclodextrins / Q000737:chemistry*; D008962:Models, Theoretical; D011310:Preservatives, Pharmaceutical / Q000737:chemistry*; D013816:Thermodynamics
chemical_list: D003505:Cyclodextrins; D011310:Preservatives, Pharmaceutical
keywords: Benzoic acid; Cyclodextrins; Equilibrium; Parabens; Preservation; Stability constant