Fed intestinal solubility limits and distributions applied to the Developability classification system.

For solid oral dosage forms drug solubility in intestinal fluid is an important parameter influencing product performance and bioavailability. Solubility along with permeability are the two parameters applied in the Biopharmaceutics and Developability Classification Systems (DCS) to assess a drug's potential for oral administration. Intestinal solubility varies with the intestinal contents and the differences between the fasted and fed states are recognised to influence solubility and bioavailability. In this study a novel fed state simulated media system comprising of nine media has been utilised to measure the solubility of seven drugs (ibuprofen, mefenamic acid, furosemide, dipyridamole, griseofulvin, paracetamol and acyclovir) previously studied in the fasted state DCS. The results demonstrate that the fed nine media system provides a range of solubility values for each drug and solubility behaviour is consistent with published design of experiment studies conducted in either the fed or fasted state. Three drugs (griseofulvin, paracetamol and acyclovir) exhibit very narrow solubility distributions, a result that matches published behaviour in the fasted state, indicating that this property is not influenced by the concentration of simulated media components. The nine solubility values for each drug can be utilised to calculate a dose/solubility volume ratio to visualise the drug's position on the DCS grid. Due to the derivation of the nine media compositions the range and catergorisation could be considered as bioequivalent and can be combined with the data from the original fed intestinal fluid analysis to provide a population based solubility distribution. This provides further information on the drugs solubility behaviour and could be applied to quality by design formulation approaches. Comparison of the fed results in this study with similar published fasted results highlight that some differences detected match in vivo behaviour in food effect studies. This indicates that a combination of the fed and fasted systems may be a useful in vitro biopharmaceutical performance tool. However, it should be noted that the fed media recipes in this study are based on a liquid meal (Ensure Plus) and this may not be representative of alternative fed states achieved through ingestion of a solid meal. Nevertheless, this novel approach provides greater in vitro detail with respect to possible in vivo biopharmaceutical performance, an improved ability to apply risk-based approaches and the potential to investigate solubility based food effects. The system is therefore worthy of further investigation but studies will be required to expand the number of drugs measured and link the in vitro measurements to in vivo results.

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Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.