Partitioning of surfactant into drug-rich nanodroplets and its impact on drug thermodynamic activity and droplet size

The excipients present in an amorphous solid dispersion (ASD) are essential functional additives that ultimately influence the drug release performance and absorption. Herein, the effect of a polymer, hypromellose (HPMC), and three chemically diverse surfactants, sodium dodecyl sulfate (SDS), cetyltrimethylammonium bromide (CTAB), and polyoxyethylene sorbitan monooleate (Tween 80, Tween), on the size and stability of the colloidal ketoprofen (KTP)-rich phase generated by liquid-liquid phase separation was evaluated. In addition, the impact of the excipients on the thermodynamic activity of KTP at concentrations in excess of the amorphous solubility was evaluated. Dynamic light scattering measurements showed that using surfactant alone did not effectively suppress coarsening of the KTP-rich phase. In contrast, the combined use of surfactant and HPMC maintained the KTP-rich droplet size at around 200 nm, which was smaller than in HPMC solutions without surfactant. Solution nuclear magnetic resonance spectroscopy revealed that HPMC distributed into the KTP-rich phase, leading to a reduced thermodynamic activity of KTP, and a consequent decrease in the maximum achievable aqueous phase concentration. Moreover, substantial amounts of both CTAB and Tween distributed into the KTP-rich phase from the aqueous phase, while SDS remained predominantly in the aqueous phase. The combined use of HPMC with CTAB or Tween resulted in a further decrease in the thermodynamic activity of KTP relative to in the presence of HPMC alone, due to the mixing of both HPMC and surfactant with the KTP-rich phase. In contrast, the addition of SDS did not reduce the thermodynamic activity of KTP because of the limited distribution of SDS into the KTP-rich phase. A reduction in KTP thermodynamic activity translated to a decreased supersaturation and hence a reduction in the maximum achievable membrane flux. The present study illustrates the complex effects of surfactant and polymer on drug thermodynamic activity, factors which should be considered when optimizing ASD formulations to maximize oral drug absorption. Ideally, excipients that do not substantially impact drug thermodynamic activity should be selected, in particular for drugs where achieving high supersaturation is critical to drive their absorption. [Display omitted]