Small scale in vitro method to determine a bioequivalent equilibrium solubility range for fasted human intestinal fluid

Abstract

Graphical abstract

Fasted intestinal solubility limits and distributions applied to the biopharmaceutics and developability classification systems

“…1 . The multiplier’s magnitude is smaller than in the original fasted DoE study [14] where for some drugs a three log variation was detected and this reflects the smaller variation noted in the bioequivalent media system [21] study. This was attributed to the elimination of statistically driven and non-biorelevant combinations of high and low media component concentrations.…”

“…1 and Table 4 ) in the bioequivalent media recipes, indicating that their solubility is not greatly influenced by media composition variation. This narrow solubility range behaviour was present for griseofulvin, as well as for tadalafil and phenytoin, in the initial statistically guided study [14] and has been replicated in a recent study that re-examined the behaviour of the original twelve drugs in the bioequivalent media system [21] . This result adds a further two drugs to this behaviour list (paracetamol and acyclovir), indicating that the multi-point solubility analysis is revealing an intestinal solubility property or behaviour that a single point measurement would miss.…”

“…1 (with the exception of griseofulvin) have not previously been analysed in DoE guided fasted media solubility experiments [14] , [17] , [19] , [22] and therefore no comparison with these data sets is possible. Griseofulvin has been previously analysed in the aforementioned DoE guided solubility experiments and comparisons to these data sets are analysed in a previous publication [21] . Where available, literature solubility measurement values for either fasted HIF or SIF are included in Fig.…”

“…In order to unify the various approaches, a recent study performed a multi-dimensional analysis of an extensive fasted HIF chemical compositional data set [11] to calculate eight points or HIF compositions [20] that provided a greater than ninety percent coverage of the compositional space in five dimensions. Along with a central distribution point, the nine compositions have been applied as a set of fasted SIF media recipes to explore equilibrium intestinal solubility [21] . The resulting solubility distributions are statistically equivalent to the previous DoE guided studies of the fasted state [14] , [17] , [22] , and encompass published solubility values in either fasted HIF samples or SIF recipes.…”

“…In this study, we have applied the fasted intestinal fluid media compositions identified using the multi-dimensional analysis [20] to the drugs (excluding digoxin) assessed in the original Developability Classification System [7] for the fasted state. The equilibrium solubility of ibuprofen, mefenamic acid, furosemide, dipyridamole, griseofulvin, paracetamol, and acyclovir, has been determined in the nine media recipes [20] , [21] , along with a value in simulated fasted simulated intestinal fluid (FaSSIFv1) version 1 [14] . The nine media recipes provide a range of solubility values that, due to the derivation from sampled HIF, covers the fasted HIF range and can therefore be considered bioequivalent.…”