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.