Impact of polymer crosslinking on release mechanisms from long-acting levonorgestrel intrauterine systems

Polydimethylsiloxane (PDMS) crosslinking density is a critical material attribute of levonorgestrel intrauterine systems (LNG-IUSs) that affects drug release and may have a significant influence on product performance and safety. Accordingly, the objective of the present work was to investigate the impact of PDMS crosslinking on the release mechanisms of LNG-IUSs and thereby achieve better product understanding. To investigate the effect of PDMS crosslinking, LNG-IUSs with varying prepolymer ratios and different mixing conditions were prepared.

Highlights

• Crosslinking was sensitive to changes in prepolymer ratios and mixing conditions.

• A high polymer crosslinking density in LNG-IUSs leads to faster drug release.

•  PDMS crosslinking leads to the formation of a solid-state porous matrix.

• Non-crosslinked polymer exists in a gel state and coats the drug particles.

• Polymer crystallinity was reduced at high PDMS crosslinking densities.

Accelerated and real-time in vitro release of the LNG-IUSs were conducted for up to 80 days and 7 months, respectively. Contrary to conventional understanding, formulations with higher crosslinking density showed faster drug release rates. To further understand this anomalous release behavior, the microstructure and molecular properties (using scanning electron microscopy, mercury intrusion porosimetry, polymer swelling studies, solid-state silicon NMR, and wide-angle X-ray diffraction) were investigated. Interestingly, it was revealed that high PDMS crosslinking forms a solid-state porous branched network with amorphous polymer domains facilitating fast solvent uptake (in organic solvents) and easy access to the drug particles leading to rapid mass transport of the drug molecules.

Furthermore, formulations processed using planetary mixing showed higher crosslinking densities and faster drug release rates than those prepared using manual mixing. Model fitting of all LNG-IUSs were carried out using first order, two-phase (zero order plus Higuchi), and Korsmeyer-Peppas models. The first order model (which showed the best fitting for the full release profile) was used to establish correlations between the drug release rates and the PDMS crosslinking densities of LNG-IUSs. This is the first comprehensive report providing novel insights into crosslinking-induced microstructural changes and physicochemical properties that dictate drug release from LNG-IUSs. Continue reading

Suraj Fanse, Quanying Bao, Yuan Zou, Yan Wang, Diane J. Burgess,
Impact of polymer crosslinking on release mechanisms from long-acting levonorgestrel intrauterine systems,
International Journal of Pharmaceutics, Volume 612, 2022, 121383, ISSN 0378-5173,
https://doi.org/10.1016/j.ijpharm.2021.121383.