Supersaturation of zafirlukast in fasted and fed state intestinal media with and without precipitation inhibitors

Madsen, Cecilie Maria; Boyd, Ben J.; Rades, Thomas

doi:10.1016/j.ejps.2016.05.026

Cited by 21 publications

(13 citation statements)

References 33 publications

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“…The μDISS profiler™ has also been applied to investigate the effect of prandial state and PIs on the precipitation of supersaturated zafirlukast . Further methods have also been employed in small‐scale precipitation testing …”

Section: Precipitation Inhibition: Theory and Practicementioning

confidence: 99%

Approaches to increase mechanistic understanding and aid in the selection of precipitation inhibitors for supersaturating formulations – a PEARRL review

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Ditzinger

Koehl

et al. 2018

Journal of Pharmacy and Pharmacology

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Section: Precipitation Inhibition: Theory and Practicementioning

confidence: 99%

Approaches to increase mechanistic understanding and aid in the selection of precipitation inhibitors for supersaturating formulations – a PEARRL review

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Ditzinger

Koehl

et al. 2018

Journal of Pharmacy and Pharmacology

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“…Buffer and salt were held at constant values as shown in Tables 1 and 2 following previous experiments [25,38] that showed both these constituents to have no significant solubility impact. The equilibrium solubility of 12 BCS class II drugs was studied: 3 acids (indomethacin, ibuprofen and valsartan), 5 bases (itraconazole, tadalafil, carvedilol, aprepitant and bromocriptine), 3 neutral drugs (fenofibrate, felodipine and probucol), and finally zafirlukast, which behaves in this system as an acid due to its pK a value of 4 [18,35].…”

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, it should be noted that situations where such simulations may be crucial, for example in the case of bioenabling products or conventional products where the API's physicochemical properties will drive variation in dissolution with changes in luminal conditions, have been studied to a very limited extent. Madsen et al . investigated in vitro the reported negative food effect observed with the amorphous formulation of zafirlukast, BCS class II (Accolate ® film‐coated tablets), as well as the effect of the precipitation inhibitors HPMC and PVP on supersaturation and precipitation.…”

Section: Simulating the Intraluminal Performance Of Drug Products In mentioning

confidence: 99%

The impact of food intake on the luminal environment and performance of oral drug products with a view toin vitroandin silicosimulations: a PEARRL review

Pentafragka

Symillides

McAllister

et al. 2018

Journal of Pharmacy and Pharmacology

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Supersaturation of zafirlukast in fasted and fed state intestinal media with and without precipitation inhibitors

Cited by 21 publications

References 33 publications

Approaches to increase mechanistic understanding and aid in the selection of precipitation inhibitors for supersaturating formulations – a PEARRL review

Approaches to increase mechanistic understanding and aid in the selection of precipitation inhibitors for supersaturating formulations – a PEARRL review

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

The impact of food intake on the luminal environment and performance of oral drug products with a view toin vitroandin silicosimulations: a PEARRL review

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