Category: Formulation and Quality
Purpose: To characterize the partition rate (Pi) of 2-Naphthol (NAP) and Ritonavir (RTV) across the water-octanol interface and to investigate the influence of common pharmaceutical excipients on the Pi of NAP and RTV.
The experimental setting for determining the concentration-time profiles of NAP and RTV includes a USP 2 vessel with dual paddle, which contained 200 ml of aqueous buffer solution and 200 mL of octanol. Concentrated NAP and RTV solutions were injected directly into the aqueous buffer solutions, with the presence or absence of pre-dissolved excipients, through a syringe at the start of the experiment. NAP or RTV concentrations in both aqueous and octanol phases were determined by UV probes. Excipients were examined including polymeric substance (e.g., PVP-VA, HPMC, HPMCAS, PVP, PEG 8000), small molecules (e.g., glucose, lactose, maltoheptaose), and surfactant (e.g., Tween 80 and SDS) at concentration range of 0.01-10 µg/mL. The Pi values of RTV or NAP were determined by fitting the corresponding concentration-time profiles observed into a mechanistic model.1
Results: Noticeable (~10%) to signiﬁcant ( >40%) reduction in Pi values of both NAP and RTV across the water-octanol interface was observed with extremely low concentration (i.e., 0.1-0.01 µg/mL) of the selected excipients (Tween 80, SDS, HPMC AS, HPMC K4M, PVP-VA) in the aqueous media. The Pi values of RTV and NAP across the W/O interface was found to be sensitive to the molecule surface area, molecular weight and/or the degree of the polymerization of these pharmaceutical excipients shown in Figure 1, and (2) the ionization state of the model compound as shown in Figure 2.
Conclusion: Investigation of RTV and NAP partition kinetics across the W/O interface with the presence of a variety of common pharmaceutical excipients (e.g., polymers and surfactants) at extremely low concentration (i.e., 0.01- 0.1 µg/mL) reveals the presence of a surface excess of the excipients adsorbed at the W/O interface. The ﬁndings are in good agreement with our previous report of IBU partition kinetics2 under the same or similar conditions. The retarding effect on RTV and NAP partition from excipients present in the aqueous media is attributed to a steric obstruction mechanism for drug diffusion through the adsorbed surface layer. This work reveals a reliable and quantitative assessment of the drug transfer kinetics across the W/O interface and the influence of pharmaceutical excipients upon such transfer, which is very import for developing in vitro biphasic test to establish IVIVC.