(T1130-11-73) Influence of Drug Load and Surfactant Concentration on the Release Performance of Ternary Amorphous Solid Dispersions

Purpose: A substantial challenge during development of new medicinal products is overcoming poor aqueous solubility of the active pharmaceutical ingredient (API). APIs with physical-chemical properties that do not favor dissolution can be classified as IIa, IIb or IV in the refined developability classification system (rDCS), and may suffer from inadequate and varying bioavailability [1]. Amorphous solid dispersions (ASDs) are a promising technology to improve the oral absorption of such APIs. This study sets out to elucidate the compensatory nature of drug loads (DLs) and ionic surfactant concentrations in ternary ASDs during API release, as well as the surfactant effect on the limit of congruency (LoC) of the mixture [2]. The ternary ASD formulations investigated were prepared with a model drug, Compound A, the amorphous polymeric carrier Soluplus® and the ionic surfactants sodium dodecyl sulfate (SDS), docusate sodium (DOSS) and sodium oleate (C18:1).

Methods: The supersaturation potential of Compound A was evaluated as a function of DL and ionic surfactant added by a previously published miniaturized assay for rapid polymer suitability (SPADS) assessments [3]. In brief, binary Soluplus® -compound A samples at DL ranging from 10-40% [w/w] were prepared by solvent casting into 96-well plates. To assess the dissolution performance of each film, stirring bars and 200 µL of FaSSIF-V1 were added to each well and mixed by head-over-head rotation at 37 °C. The amount of dissolved drug was determined after 60 and 180 minutes by UPLC and 1H-NMR. Prior to UPLC injection, the samples were filtered through a 96-well 0.4 µm modified PCTE membrane and diluted appropriately with N-methyl-pyrrolidone. Based on the results obtained for the binary films, the influence of SDS; DOSS or C18:1 at concentrations of 4-8 % [w/w] on the dissolution kinetics by causing a change in the LoC was investigated.

Results: The release of the drug was greatly dependent on the DL, as demonstrated in Figure 1. Poor dissolution performance was observed at higher DLs, while a DL of 10% [w/w] facilitated complete drug release, resulting in the highest concentration. These results suggest that a transition from drug-controlled to polymer-controlled release occurs with an LoC between 20 and 10 % [w/w] DL. In order to investigate the effect of surfactant incorporation, a DL of 20% [w/w] was chosen. Adding ionic surfactants increased the LoC with increasing concentration, as shown in Fig. 2. To keep the amount of ionic surfactant added to a minimum, formulations containing 6% [w/w] surfactant incorporated were selected for further investigations. Measuring the thermodynamic solubility of these samples revealed that the incorporation of SDS and DOSS facilitated an apparent degree of supersaturation of 7.24 and 8.38 respectively, compared to 1.26 for binary samples at a DL of 20% [w/w] after 1 hour. Incorporation of C18:1 had no effect on the dissolution performance of the prepared films. The discrepancy in drug concentrations detected by UPLC (999 µg/ml) compared to 1H-NMR (approx. 10 µg/ml) suggested the formation of phase-separated nanostructures. This was verified by extracting the samples with MeOD, which led to recovery of the nominal concentration determined by UPLC quantification.

Conclusion: This study demonstrated that the binary combination of compound A and Soluplus® has a LoC between 20 and 10 % [w/w] DL. Adding the ionic surfactants SDS and DOSS greatly enhanced the dissolution behavior at 20 % DL. By analyzing samples of dissolved Compound A, Soluplus®, SDS and DOSS with 1H-NMR, the presence of a phase separated state could be confirmed. This phenomenon warrants further investigations about the morphology of such nanostructures and elucidation of their impact on bioavailability.

References: 1. Rosenberger, J., Butler, J., & Dressman, J. (2018). J. Pharm. Sci., 107(8), 2020–2032.
2. A. S. Indulkar, X. Lou, G. G. Z. Zhang, L. S. Taylor, Mol. Pharm. 16 (3) (2019) 1327–1339.
3. Wyttenbach, N., et al. (2013). Eur. J. Pharm. Biopharm., 84(3), 583–598.

Acknowledgements: This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No. 955756

Fig. 1: Drug load dependent dissolution of Compound A after 1 and 3 hours.

Fig. 2: Dissolution of Compound A after 1 and 3 hours at a DL of 20% [w/w] as a function of the amount of ionic surfactant incorporated.