Drug solubility is a key parameter controlling oral absorption, but intestinal solubility is difficult to assess in vitro. Human intestinal fluid (HIF) aspirates can be applied but they are variable, difficult to obtain and expensive. Simulated intestinal fluids (SIF) are a useful surrogate but multiple recipes are available, and the optimum is unknown. This situation creates difficulties during drug discovery and development research. A recent study characterized fasted HIF (FaHIF) aspirates using a multidimensional approach and determined 9 fasted simulated intestinal fluid (Fa9SIF) media recipes that represented over ninety percent of HIF compositional variability. These Fa9SIF recipes have been applied to determine the equilibrium solubility of twenty-one drugs. The solubility measurements enclose literature solubility values in both FaHIF and SIF, and are statistically equivalent to the previous design of experiment (DoE) studies.
However, they have a narrower solubility range, suggesting an improved equivalence to in vivo solubility. This also highlights that intestinal solubility is a range and not a single value. The Fa9SIF media was examined and provided in the majority of cases a structured solubility behaviour, that is consistent with physicochemical properties and previous solubility studies. The study also indicates that the use of two appropriate bioequivalent fasted intestinal media from the nine will identify in vitro the maximum and minimum fasted solubility boundaries for drugs and due to the media derivation, this is probably applicable in vivo. Statistical comparisons were further carried out, of the Fa9SIF media system against FaHIF, and do not detect a difference, and individual drug analysis produces an 85% correlation. An innovative in vitro vs FaHIF correlation window was determined, which enclosed 94% of solubility values from an additional data set, further validating equivalence. The Fa9SIF media system represents a new methodology for in vitro in vivo solubility correlation, this radically transforms predictive ability which will benefit drug discovery, development and formulation studies. The equilibrium solubility of the twenty-one drugs were also used for further biopharmaceutical applications including the developability classification system, supersaturation techniques, and physiology based pharmacokinetic (PBPK) modelling.
| Date of Award | 9 May 2024 |
|---|
| Original language | English |
|---|
| Awarding Institution | - University Of Strathclyde
|
|---|
| Sponsors | University of Strathclyde |
|---|
| Supervisor | Ibrahim Khadra (Supervisor) & Gavin Halbert (Supervisor) |
|---|