title: Mechanism of 2-hydropropyl-beta-cyclodextrin in the stabilization of frozen formulations.
abstract: Freezing of commonly used parenteral products to increase pharmaceutical stability for cost-saving purposes is a common practice in patient care. However, frozen meropenem, a model drug, in saline has a shelf life of less than a month due to the low glass transition temperature (Tg'): below -40°C. When meropenem is formulated with the 2-hydroxypropyl-β-cyclodextrin (HPBC) the shelf life (⩾90% potency) is extrapolated to be greater than one year at -25°C based on data for storage at 6months. The mechanisms that may explain meropenem-HPBC formulation frozen stability include vitrification and/or formation of an inclusion complex. Although NMR data indicated complexation of meropenem by HPBC in a ratio of 0.6:1, inclusion was unlikely to be the mechanism as stability was not extended to the thawed solutions. Therefore, vitrification is concluded to be the stabilization mechanism. The Tg' for meropenem-HPBC (13.3%) formulation at pH 7.9 was -17.75°C which was similar to that of a meropenem solution formulated with a known vitrifying agent, Dextran 40. This higher Tg' for HPBC was unexpected based on trends predicted by the Fox-Flory equation. Trial formulations containing either Dextran 1, Dextran 40, hydroxyethyl starch, or sulfobutyl-beta-cyclodextrin heptasodium (Captisol®) were also unable to stabilize meropenem as the Tg' values were below the frozen storage temperature. Upon 6-month storage, potency losses were -3.0% and -7.7% for meropenem frozen premix formulated in 13.3% HPBC (pH 7.9) at -25 and -20°C storage, respectively; versus -31.2% and -60.8% for controls. Frozen premixes with high ionic strength (containing NaCl or Captisol®) and/or at pH 7.3 were also found to be unstable.
authors.affiliation: Drug Development, Medical Products, Baxter Healthcare Corporation, Round Lake, IL 60073, United States. Electronic address: joe_wong@baxter.com.
authors.forename: Joseph
authors.initials: J
authors.lastname: Wong
authors.affiliation: Drug Development, Medical Products, Baxter Healthcare Corporation, Round Lake, IL 60073, United States.
authors.forename: James E
authors.initials: JE
authors.lastname: Kipp
authors.affiliation: Drug Development, Medical Products, Baxter Healthcare Corporation, Round Lake, IL 60073, United States.
authors.forename: Reagan L
authors.initials: RL
authors.lastname: Miller
authors.affiliation: Analytical Resources, Medical Products, Baxter Healthcare Corporation, Round Lake, IL 60073, United States.
authors.forename: Lakshmy M
authors.initials: LM
authors.lastname: Nair
authors.affiliation: Structure Elucidation, Medical Products, Baxter Healthcare Corporation, Round Lake, IL 60073, United States.
authors.forename: G Joseph
authors.initials: GJ
authors.lastname: Ray
mesh_terms: D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000900:Anti-Bacterial Agents / Q000737:chemistry*; D003911:Dextrans / Q000737:chemistry; D004355:Drug Stability; D004356:Drug Storage; D005615:Freezing; D009682:Magnetic Resonance Spectroscopy; D000077731:Meropenem; D013845:Thienamycins / Q000737:chemistry*; D044366:Transition Temperature; D058989:Vitrification; D047392:beta-Cyclodextrins / Q000737:chemistry*
chemical_list: D000900:Anti-Bacterial Agents; D003911:Dextrans; D013845:Thienamycins; D047392:beta-Cyclodextrins; D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000077731:Meropenem; C579662:dextran 1
keywords: 2-Hydroxypropyl-β-cyclodextrin; Frozen stability; Glass transition temperature (Tg′); Meropenem; Vitrification