(T1330-12-80) Surfactant Selection in the Development of Oral Ternary Amorphous Solid Dispersions from the Perspective of Solubility and Supersaturation

Purpose: Amorphous solid dispersions (ASDs) have been increasingly utilised to improve oral absorption and bioavailability of poorly water-soluble drugs. However, drug supersaturation caused by dissolution of amorphous drug is transient and often rapid crystallisation occurs. The incorporation of pharmaceutical excipients to retard recrystallisation and stabilise the supersaturated state of drug during dissolution is a way of enhancing drug product performance. Since additives may result in synergistic precipitation inhibition or accelerated crystallisation when combined with particular binary ASDs, a prudent preliminary screening in terms of their effects on drug dissolution and solubility is of importance in the development of a successful ternary ASD system. Lumefantrine is currently one of the first-line antimalarial therapeutics, with extremely low aqueous solubility and therefore suboptimal clinical performance. The release performance of lumefantrine from a simple binary ASD system using Soluplus® as the carrier was found to be unsatisfactory, with less than 10% release, despite the fact that Soluplus® is a hydrophilic polymer, and the amorphous API exhibits a good solid-state stability in the ASD. This work aimed to assess the effect of various surfactants on enhancing the solubility and maintaining the supersaturation of lumefantrine with or without a matrix excipient, e.g., Soluplus® in this case. The surfactant candidates included Vitamin E TPGS, Kolliphor ELP (glycerol polyethylene glycol ricinoleate), Polysorbate 80 (PS80), Poloxamer 407 (P407) and Sodium Lauryl Sulfate (SLS).

Methods: Phase solubility study: excess amount of lumefantrine powder was placed in 10 mL of medium in the presence/absence of pre-dissolved 1mg/mL Soluplus®, containing one of surfactant candidates at the concentration of 0, 0.1 or 0.3 mg/mL. The studies were performed in both 0.1N HCl and phosphate buffer solution (PBS, pH 6.5). Samples were sealed and shaken at 37°C at a speed of 40 rpm for 72 hours in an incubator (ISF-7100 Incubated Shaker, Jeio Tech, UK). The dissolved drug concentration was measured using HPLC-UV (Agilent Technologies 1260 Infinity, USA). Anti-precipitation tests: Soluplus® and surfactants were pre-dissolved in the 0.1N HCl and PBS media and 100 μL of concentrated API solution in DMF (24 mg/mL) was added to 20 mL of medium with stirring at 200 rpm in a 37°C water bath. Aliquots (300 μL) were withdrawn at 10 min, 30 min, 1 hour, 2 hrs, and 4hrs, and centrifuged at 13700 rpm for 10 min. The supernatants were collected for HPLC-UV measurements. All reported data originated from at least three independent experiments. Significance tests were conducted with GraphPad Prism 9.5.1 (GraphPad Software, USA) using a one-way analysis of variance (ANOVA) followed by the Tukey's multiple comparisons test.

Results: The results of phase solubility study and supersaturation maintenance studies are presented in Table 1 and Table 2 respectively, with the significant differences in the effects of various surfactants, visually represented through colour coding. Red indicates a positive impact, with darker shades indicating stronger effects statistically, while blue indicates a negative impact. Overall, the addition surfactant had a varied impact on drug solubility and supersaturation. ELP and TPGS had the most significant impact in basic and acidic media, respectively. However, SLS appeared to accelerate drug precipitation. This may be attributed to the anionic nature of SLS. In a supersaturated solution of lumefantrine, the weakly basic API would be expected to crash out of solution forming insoluble salts with SLS[1]. Interestingly, in the presence of Soluplus, the supersaturated drug precipitates even faster. A possible explanation for this result may be that the presence of Soluplus® creates a competitive interaction where SLS and API competitively interacts with the polymer, thus reducing the drug-polymer micelle formation, leading to a Soluplus®- lumefantrine system that has less interactions[2] Regardless of the observed inhibition effect on the apparent supersaturation, competitive interactions may be a significant, but overlooked challenge in ternary systems, even where additives positively influence drug solubility and supersaturation. In our study, we show that the inclusion of Soluplus®, led to a smaller enhancement in drug supersaturation, when the surfactant concentration was increased relative to the drug-polymer matrix (Figure 1), with the exception of P407. It may be postulated that hydrophobic interactions between surfactant and polymer occupies hydrophobic sites on polymer, therefore limiting the interaction of the polymer and drug, which is important in stabilising the amorphous drug form. This study has shown that despite the mechanism by which a polymer stabilises supersaturated drug concentrations, the addition of a surfactant may act as a competitive species and destabilise the ternary system [3], [4].

Conclusion: To further enhance drug dissolution performance, several surfactants with different structures were evaluated in terms of their ability to improve apparent solubility and maintain supersaturation. ELP and TPGS demonstrated the best performance amongst the screened candidates. Whilst higher ratio of surfactants would not necessarily lead to a greater enhancement, as the competitive effect between surfactant and API for polymer binding may lead to decreased API stability in the aqueous media.

References: [1] Y. Guo, C. Wang, J. Dun, L. Du, M. Hawley, and C. C. Sun, “Mechanism for the Reduced Dissolution of Ritonavir Tablets by Sodium Lauryl Sulfate,” Journal of Pharmaceutical Sciences, vol. 108, no. 1, pp. 516–524, Jan. 2019.
[2] Y. Pui et al., “Maintaining Supersaturation of Nimodipine by PVP with or without the Presence of Sodium Lauryl Sulfate and Sodium Taurocholate,” Mol. Pharmaceutics, vol. 15, no. 7, pp. 2754–2763, Jul. 2018.
[3] Y. Chen et al., “Sodium Lauryl Sulfate Competitively Interacts with HPMC-AS and Consequently Reduces Oral Bioavailability of Posaconazole/HPMC-AS Amorphous Solid Dispersion,” Mol. Pharmaceutics, vol. 13, no. 8, pp. 2787–2795, Aug. 2016.
[4] T. M. Deshpande, H. Shi, J. Pietryka, S. W. Hoag, and A. Medek, “Investigation of Polymer/Surfactant Interactions and Their Impact on Itraconazole Solubility and Precipitation Kinetics for Developing Spray-Dried Amorphous Solid Dispersions,” Mol. Pharmaceutics, vol. 15, no. 3, pp. 962–974, Mar. 2018.

Acknowledgements: The researcher [Dijia Liu] is funded by a full scholarship from China Scholarship Council (CSC).


Figure 1. Comparison of anti-precipitation ability of varying surfactant concentrations in the presence and absence of Soluplus®.