Abstract
Gastrointestinal fluid is a complex milieu and it is recognised that gut drug solubility is different to that observed in simple aqueous buffers. Simulated gastrointestinal media have been developed covering fasted and fed states to facilitate in vitro prediction of gut solubility and product dissolution. However, the combination of bile salts, phospholipids, fatty acids and proteins in an aqueous buffered system creates multiple phases and drug solubility is therefore a complex interaction between these components, which may create unique environments for each API. The impact on solubility can be assessed through a statistical design of experiment (DoE) approach, to determine the influence and relationships between factors. In this paper DoE has been applied to fed simulated gastrointestinal media consisting of eight components (pH, bile salt, lecithin, sodium oleate, monoglyceride, buffer, salt and pancreatin) using a two level D-optimal design with forty-four duplicate measurements and four centre points. The equilibrium solubility of a range of poorly soluble acidic (indomethacin, ibuprofen, phenytoin, valsartan, zafirlukast), basic (aprepitant, carvedilol, tadalafil, bromocriptine) and neutral (fenofibrate, felodipine, probucol, itraconazole) drugs was investigated. Results indicate that the DoE provides equilibrium solubility values that are comparable to literature results for other simulated fed gastrointestinal media systems or human intestinal fluid samples. For acidic drugs the influence of pH predominates but other significant factors related to oleate and bile salt or interactions between them are present. For basic drugs pH, oleate and bile salt have equal significance along with interactions between pH and oleate and lecithin and oleate. Neutral drugs show diverse effects of the media components particularly with regard to oleate, bile salt, pH and lecithin but the presence of monoglyceride, pancreatin and buffer have significant but smaller effects on solubility. There are fourteen significant interactions between factors mainly related to the surfactant components and pH, indicating that the solubility of neutral drugs in fed simulated media is complex. The results also indicate that the equilibrium solubility of each drug can exhibit individualistic behaviour associated with the drug's chemical structure, physicochemical properties and interaction with media components. The utility of DoE for fed simulated media has been demonstrated providing equilibrium solubility values comparable with similar in vitro systems whilst also providing greater information on the influence of media factors and their interactions. The determination of a drug's gastrointestinal solubility envelope provides useful limits that can potentially be applied to in silico modelling and in vivo experiments.
Highlights
The current trend in drug discovery towards molecules with a higher molecular weight and increased lipophilicity continues to result in a greater number of drug candidates with decreasing aqueous solubility (Sugano et al, 2007), (Lipinski, 2000)
In this paper we have extended the design of experiment (DoE) approach (Khadra et al, 2015) to simulated fed gastrointestinal media using the same components at higher concentrations and with the addition of monoglyceride as an additional fed media component, Table 1 (Jantratid et al, 2008a; Kleberg et al, 2010)
Literature equilibrium solubility values (Augustijns et al, 2014) in either HIF or fed simulated gastrointestinal media are superimposed on Fig. 1 and lie within the DoE values
Summary
The current trend in drug discovery towards molecules with a higher molecular weight and increased lipophilicity continues to result in a greater number of drug candidates with decreasing aqueous solubility (Sugano et al, 2007), (Lipinski, 2000). Aqueous solubility is a key parameter influencing biological activity (Stegemann et al, 2007), Abbreviations: BCS, Biopharmaceutics Classification System; DoE, Design of Experiment; FASSIF, Fasted Simulated Intestinal Fluid; FESSIF, Fed Simulated Intestinal Fluid; IVIVC, In vitro In vivo correlation. Z. Zhou et al / European Journal of Pharmaceutical Sciences 99 (2017) 95–104 absorption equilibrium aqueous solubility is demonstrably still a key parameter controlling rate and extent of absorption (Sugano and Terada, 2015). Zhou et al / European Journal of Pharmaceutical Sciences 99 (2017) 95–104 absorption equilibrium aqueous solubility is demonstrably still a key parameter controlling rate and extent of absorption (Sugano and Terada, 2015) This is recognised in the Biopharmaceutics Classification System where drugs are allocated to categories based on solubility with respect to dose either high or low and gastrointestinal permeability (Amidon et al, 1995). Low solubility drugs present problems during formulation and development (Butler and Dressman, 2010) and in order to avoid solubility related failures during drug discovery, an early and comprehensive assessment of a drug's solubility is essential (Bergstrom et al, 2014)
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