Effect of composition of simulated intestinal media on the solubility of poorly soluble compounds investigated by design of experiments

Madsen, Cecilie Maria; Feng, Kung-I; Leithead, Andrew; Canfield, Nicole; Jørgensen, Søren Astrup; Müllertz, Anette

doi:10.1016/j.ejps.2017.10.003

Cited by 29 publications

(36 citation statements)

References 34 publications

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“…Increasing the pH one unit away from the pKa-value (from pH 6.5 to 7.5) will increase the concentration of the ionised form of furosemide by a factor 10, resulting in a higher solubility in water. Additionally, increasing the concentration of bile acids and phospholipids have shown to increase the solubility of many poorly water-soluble compounds [33,34]. Hence, the increase in total concentration of bile acids and phospholipids from 12.5 mM in the human intestinal medium to 27.8 mM in RIM could also contribute to the increased dissolution.…”

Section: Evaluation Of the Biorelevant Media And The Two-step In Vitrmentioning

confidence: 99%

Developing a predictive in vitro dissolution model based on gastrointestinal fluid characterisation in rats

Christfort

Strindberg

Plum

et al. 2019

European Journal of Pharmaceutics and Biopharmaceutics

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Section: Evaluation Of the Biorelevant Media And The Two-step In Vitrmentioning

confidence: 99%

Developing a predictive in vitro dissolution model based on gastrointestinal fluid characterisation in rats

Christfort

Strindberg

Plum

et al. 2019

European Journal of Pharmaceutics and Biopharmaceutics

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“…This was a customised 1/8 fraction factorial design incorporated into the DoE approach described in the Perrier publication, which reduced samples to 32 individual experiments and allowed for results to distinguish between fasted and fed environments. An alternative approach looked to assess the influence of SIF composition on the solubility of BCS class II compounds utilising a DoE with reduced media parameters [19], which also allows for a smaller number of experiments. However, a recent solubility investigation of SIF composition applying an alternate four component mixture design statistical technique [7] indicates that solubility variability is inversely related to the number of amphiphilic components present.…”

Section: Introductionmentioning

confidence: 99%

Small scale design of experiment investigation of equilibrium solubility in simulated fasted and fed intestinal fluid

McPherson

Perrier

Dunn

et al. 2020

European Journal of Pharmaceutics and Biopharmaceutics

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It is widely recognised that drug solubility within the gastrointestinal tract (GIT) differs from values determined in a simple aqueous buffer and to circumvent this problem measurement in biorelevant fluids is determined. Biorelevant fluids are complex mixtures of components (sodium taurocholate, lecithin, sodium phosphate, sodium chloride, pancreatin and sodium oleate) at various concentrations and pH levels to provide systems simulating fasted (FaSSIF) or fed (FeSSIF) intestinal media. Design of Experiment (DoE) studies have been applied to investigate FaSSIF and FeSSIF and indicate that a drug's equilibrium solubility varies over orders of magnitude, is influenced by the drug type and individual or combinations of media components, with some of these interactions being drug specific. Although providing great detail on the drug media interactions these studies are resource intensive requiring up to ninety individual experiments for FeSSIF. In this paper a low sample number or reduced DoE system has been investigated by restricting components with minimal solubility impact to a single value and only investigating variations in the concentrations of sodium taurocholate, lecithin, sodium oleate, pH and additionally in the case of fed media, monoglyceride. This reduces the experiments required to ten (FaSSIF) and nine (FeSSIF). Twelve poorly soluble drugs (Ibuprofen, Valsartan, Zafirlukast, Indomethacin, Fenofibrate, Felodipine, Probucol, Tadalafil, Carvedilol, Aprepitant, Bromocriptine and Itraconazole) were investigated and the results compared to published DoE studies and literature solubility values in human intestinal fluid (HIF), FaSSIF or FeSSIF. The solubility range determined by the reduced DoE is statistically equivalent to the larger scale published DoE results in over eighty five percent of the cases. The reduced DoE range also covers HIF, FaSSIF or FeSSIF literature solubility values. In addition the reduced DoE provides lowest measured solubility values that agree with the published DoE values in ninety percent of the cases. However, the reduced DoE only identified single and in some cases none of the major components influencing solubility in contrast to the larger published DoE studies which identified multiple individual components and component interactions. The identification of significant components within the reduced DoE was also dependent upon the drug and system under investigation. The study demonstrates that the lower experimental number reduces statistical power of the DoE to resolve the impact of media components on solubility. However, in a situation where only the solubility range is required the reduced DoE can provide the desired information, which will be of benefit during in vitro development studies. Further refinements are possible to extend the reduced DoE protocol to improve biorelevance and application into areas such as PBPK modelling.

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“…However, over the last two decades a large number of modified media have also been developed, with the aim of better predicting the intestinal solubility of new compounds in vivo ( Fuchs et al, 2015 , Galia et al, 1998 , Jantratid et al, 2008 ). Recently also media mimicking the interindividual variability of the composition of intestinal fluids in fasted and fed state have been explored for their influence on drug solubility ( Khadra et al, 2015 , Madsen et al, 2018 , Perrier et al, 2017 ). These more biorelevant solvents include additives such as bile salts, phospholipids, cholesterol and lipids to reflect fasted and fed intestinal states.…”

Section: Introductionmentioning

confidence: 99%

Computational prediction of drug solubility in water-based systems: Qualitative and quantitative approaches used in the current drug discovery and development setting

Bergström

Larsson

2018

International Journal of Pharmaceutics

190

106

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Effect of composition of simulated intestinal media on the solubility of poorly soluble compounds investigated by design of experiments

Cited by 29 publications

References 34 publications

Developing a predictive in vitro dissolution model based on gastrointestinal fluid characterisation in rats

Developing a predictive in vitro dissolution model based on gastrointestinal fluid characterisation in rats

Small scale design of experiment investigation of equilibrium solubility in simulated fasted and fed intestinal fluid

Computational prediction of drug solubility in water-based systems: Qualitative and quantitative approaches used in the current drug discovery and development setting

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