(M1530-07-45) Exploring Freeze-Dried Polymeric Complexes with Different Fatty Acid Salts for Enhanced Olaparib Solubility and Permeation

Purpose: The objective of this study was to explore freeze-dried polymeric complexes with different fatty acid salts to enhance the solubility and permeation of Olaparib, a poorly water-soluble anticancer drug. We investigated the effectiveness of various polymers and optimized the formulation by incorporating sodium fatty acid salts, as polymeric combinations and fatty acid salt types synergize the solubility and permeation interplay.

Methods: A prescreening solubility test was performed using various polymers, including polyvinyl compounds (PVA, PVP, Kollidon^® VA64) and cellulose derivatives (HPC, HPMC, HPMCP), with a 1% (w/v) concentration in distilled water. Based on prescreening results, binary formulations (Olaparib:PVA or HPMCP at 3:4, w/w), ternary formulation (Olaparib:PVA:HPMCP at 3:2:2, w/w), and quaternary formulation (Olaparib:PVA:HPMCP:Sodium octanoate at 3:2:2:1, w/w) of freeze-dried polymeric complexes were prepared. For the final quaternary formulation, various fatty acid salts were evaluated with sodium octanoate (C8, Sigma-Aldrich, USA) selected for optimal performance. All formulations were prepared by dissolving components in a cosolvent system of distilled water and ethanol (1:1, v/v), freezing at −80 °C, and freeze-drying at −130 °C and 0.019 torr. Equilibrium solubility tests were performed in distilled water and analyzed using RP-HPLC. In vitro permeation studies were conducted using a Franz cell (DHC-6TD) simulating the intestinal environment, with a PB-M membrane (Cellular membrane). The receptor compartment was set to ensure sink conditions, while the donor compartment contained the test formulations. The physicochemical properties of the freeze-dried polymeric complexes were evaluated using FE-SEM, FT-IR, DSC, and XRD.

Results: The prescreening solubility test identified polyvinyl alcohol (PVA) as the most effective solubilizer, exhibiting the highest solubility for Olaparib at 119.13 ± 0.37 μg/mL. Binary formulations (Olaparib:PVA or HPMCP at 3:4, w/w) significantly improved the equilibrium solubility in distilled water compared to pure Olaparib, showing a 10.96-fold increase with PVA (801.83 ± 18.85 μg/mL) and a 10.56-fold increase with HPMCP (772.85 ± 15.87 μg/mL). The ternary formulation (Olaparib:PVA:HPMCP= 3:2:2, w/w) demonstrated synergistic enhancement in solubility compared to the binary formulations and effectively inhibited recrystallization. To further enhance permeability, various sodium fatty acid salts were evaluated, with sodium octanoate (C8) selected because it exhibited the highest solubility among the tested fatty acid salts. The quaternary formulation containing sodium octanoate (Olaparib:PVA:HPMCP:Sodium octanoate = 3:2:2:1, w/w) exhibited significantly enhanced performance, with a 12.65-fold increase in solubility (925.37 ± 4.81 μg/mL) and a 1.92-fold improvement in cumulative drug permeation (Q₈_h) in the Franz cell intestinal model compared to pure Olaparib. FE-SEM analysis revealed uniform spherical particles with an average diameter of approximately 400 nm. FT-IR analysis indicated no significant chemical interactions between Olaparib and the excipients. DSC and XRD confirmed the amorphization of Olaparib, as evidenced by the disappearance of its characteristic thermal and crystalline peaks in freeze-dried complexes.

Conclusion: The quaternary freeze-dried polymeric complex with PVA, HPMCP, and sodium octanoate (C8) significantly enhanced the solubility and permeation interplay of Olaparib. Physicochemical analyses confirmed the amorphous state of Olaparib in the complexes, contributing to inhibition of recrystallization. These findings demonstrate that freeze-dried polymeric complexes with appropriate fatty acid salts offer a promising strategy for improving the delivery of poorly water-soluble drugs.

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Acknowledgements: This research was supported by Basic Science Research Program through the National Research Foundation of Korea(NRF) funded by the Ministry of Education (RS-2023-00245029).


Scheme. Freeze-dried polymeric complexes with fatty acid salts: A strategy to enhance solubility and permeation of Olaparib