In vitro release testing of levonorgestrel intrauterine systems: Correlation of accelerated release rates in organic/aqueous release media to Hansen Solubility Parameters.

Levonorgestrel intrauterine systems (LNG-IUSs) are poly(dimethyl siloxane) (PDMS)-based long-acting drug delivery systems. No generic versions of LNG-IUSs are available; this is due, in part, to challenging aspects of developing and testing these products. One issue is the long timescale of real-time in vitro release tests (IVRTs) and the difficulty of developing accelerated IVRTs. This study developed a correlation between accelerated release rates in organic/aqueous release media and the Hansen Solubility Parameters (HSPs) of LNG, PDMS, and the release media. This study had three parts. First, the LNG-IUS Skyla was analyzed by real-time IVRT and various physicochemical characterization techniques. The purpose of this was to characterize Skyla's release mechanism and develop a model system termed Drug Reservoir-Membrane (DR-M). Second, the HSPs of LNG and PDMS were determined by assessing LNG's solubility and PDMS's swelling in 22 different solvents. This allowed comparison of the HSPs of LNG and PDMS with the HSPs of organic/aqueous accelerated-release media. Third, DR-M samples were tested in accelerated IVRTs and the accelerated release rates were correlated to a novel HSP-based quantity termed HSP Area, which is the triangular area in HSP space between LNG, PDMS, and the tested organic/aqueous release medium. This correlation captured accelerated release rates that were up to nine times faster than the real-time release rate. Additionally, this correlation captured release rates in media with different organic solvents (e.g., ethanol and isopropyl alcohol), and in media with different loadings of organic solvent (e.g., 10%, 20% and 30% organic solvent). We posit that the HSP Area correlation captures two mechanistic effects of the organic/aqueous accelerated-release media: first, this correlation accounts for organic solvent sorption into PDMS and increased drug permeation through PDMS; second; this correlation accounts for increased LNG solubility in the release medium and corresponding increased partitioning of LNG from PDMS into the release medium.