Abstract
After oral administration, a drug’s solubility in intestinal fluid is an important parameter influencing bioavailability and if the value is known it can be applied to estimate multiple biopharmaceutical parameters including the solubility limited absorbable dose. Current in vitro measurements may utilise fasted human intestinal fluid (HIF) or simulated intestinal fluid (SIF) to provide an intestinal solubility value. This single point value is limited since its position in relation to the fasted intestinal solubility envelope is unknown. In this study we have applied a nine point fasted equilibrium solubility determination in SIF, based on a multi-dimensional analysis of fasted human intestinal fluid composition, to seven drugs that were previously utilised to investigate the developability classification system (ibuprofen, mefenamic acid, furosemide, dipyridamole, griseofulvin, paracetamol and acyclovir). The resulting fasted equilibrium solubility envelope encompasses literature solubility values in both HIF and SIF indicating that it measures the same solubility space as current approaches with solubility behaviour consistent with previous SIF design of experiment studies. In addition, it identifies that three drugs (griseofulvin, paracetamol and acyclovir) have a very narrow solubility range, a feature that single point solubility approaches would miss. The measured mid-point solubility value is statistically equivalent to the value determined with the original fasted simulated intestinal fluid recipe, further indicating similarity and that existing literature results could be utilised as a direct comparison. Since the multi-dimensional approach covered greater than ninety percent of the variability in fasted intestinal fluid composition, the measured maximum and minimum equilibrium solubility values should represent the extremes of fasted intestinal solubility and provide a range. The seven drugs all display different solubility ranges and behaviours, a result also consistent with previous studies. The dose/solubility ratio for each measurement point can be plotted using the developability classification system to highlight individual drug behaviours. The lowest solubility represents a worst-case scenario which may be useful in risk-based quality by design biopharmaceutical calculations than the mid-point value. The method also permits a dose/solubility ratio frequency distribution determination for the solubility envelope which permits further risk-based refinement, especially where the drug crosses a classification boundary. This novel approach therefore provides greater in vitro detail with respect to possible biopharmaceutical performance in vivo and an improved ability to apply risk-based analysis to biopharmaceutical performance. Further studies will be required to expand the number of drugs measured and link the in vitro measurements to in vivo results.
Highlights
The measured mid-point solubility value is statistically equivalent to the value determined with the original fasted simulated intestinal fluid recipe, further indicating similarity and that existing literature results could be utilised as a direct comparison
The drugs display solubility behaviour that is consistent with the drug’s physicochemical properties (Table 1) and the solubility drivers identified in the design of experiment (DoE) studies [14,17,19,22], see Section
For three drugs, the calculated lowest solubility limited absorbable dose (SLAD) is below the dose (Tables 4 and 5) and the lowest sol ubility based calculation could be applied as a quality by design parameter for particle size to reduce the risk of absorption issues [8]
Summary
The oral route is the most common method of drug administration. It permits self-administration, which provides patient acceptability, assists compliance and allows the pharmaceutical industry to meet this demand through the provision of adaptable and stable solid oral dosage forms. The apparent simplicity of this approach, hides a complexity arising from the combination of gastro-intestinal tract anatomy and physiology along with the physicochemical properties of the adminis tered drug and dosage form. European Journal of Pharmaceutics and Biopharmaceutics 170 (2022) 160–169 factors controlling drug absorption is the drug’s solubility in intestinal fluid since solid drug particles are not absorbed. This was formalised in the Biopharmaceutics Classification System [2], that linked solubility and permeability with in vitro and in vivo performance, with applica bility to regulatory situations covering oral products especially around solubility and dissolution. The recommendation proposed using solubility values in either fasted HIF or fasted SIF and a correlation between the two systems, based on literature results, is presented
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