Plum J, Madsen CM, Teleki A, Bevernage J, da Costa Mathews C, Karlsson EM, Carlert S, Holm R, Müller T, Matthews W, Sayers A, Ojala K, Tsinsman K, Lingamaneni R, Bergström CA, Rades T, Müllertz A
Mol. Pharm. 14 (12) 4161-4169 [2017-12-04; online 2017-11-07]
The high number of poorly water-soluble compounds in drug development has increased the need for enabling formulations to improve oral bioavailability. One frequently applied approach is to induce supersaturation at the absorptive site, e.g., the small intestine, increasing the amount of dissolved compound available for absorption. However, due to the stochastic nature of nucleation, supersaturating drug delivery systems may lead to inter- and intrapersonal variability. The ability to define a feasible range with respect to the supersaturation level is a crucial factor for a successful formulation. Therefore, an in vitro method is needed, from where the ability of a compound to supersaturate can be defined in a reproducible way. Hence, this study investigates the reproducibility of an in vitro small scale standardized supersaturation and precipitation method (SSPM). First an intralaboratory reproducibility study of felodipine was conducted, after which seven partners contributed with data for three model compounds; aprepitant, felodipine, and fenofibrate, to determine the interlaboratory reproducibility of the SSPM. The first part of the SSPM determines the apparent degrees of supersaturation (aDS) to investigate for each compound. Each partner independently determined the maximum possible aDS and induced 100, 87.5, 75, and 50% of their determined maximum possible aDS in the SSPM. The concentration-time profile of the supersaturation and following precipitation was obtained in order to determine the induction time (t ind) for detectable precipitation. The data showed that the absolute values of tind and aDS were not directly comparable between partners, however, upon linearization of the data a reproducible rank ordering of the three model compounds was obtained based on the β-value, which was defined as the slope of the ln(tind) versus ln(aDS)-2 plot. Linear regression of this plot showed that aprepitant had the highest β-value, 15.1, while felodipine and fenofibrate had comparable β-values, 4.0 and 4.3, respectively. Of the five partners contributing with full data sets, 80% could obtain the same rank order for the three model compounds using the SSPM (aprepitant > felodipine ≈ fenofibrate). The α-value is dependent on the experimental setup and can be used as a parameter to evaluate the uniformity of the data set. This study indicated that the SSPM was able to obtain the same rank order of the β-value between partners and, thus, that the SSPM may be used to classify compounds depending on their supersaturation propensity.