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-ß-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 0.61, 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.