Dual Level Statistical Investigation of Equilibrium Solubility in Simulated Fasted and Fed Intestinal Fluid

Abstract

The oral route is the preferred option for drug administration but contains the inherent issue of drug absorption from the gastro-intestinal tract (GIT) in order to elicit systemic activity. A prerequisite for absorption is drug dissolution, which is dependent upon drug solubility in the variable milieu of GIT fluid, with poorly soluble drugs presenting a formulation and biopharmaceutical challenge. Multiple factors within GIT fluid influence solubility ranging from pH to the concentration and ratio of amphiphilic substances, such as phospholipid, bile salt, monoglyceride, and cholesterol. To aid in vitro investigation simulated intestinal fluids (SIF) covering the fasted and fed state have been developed. SIF media is complex and statistical design of experiment (DoE) investigations have revealed the range of solubility values possible within each state due to physiological variability along with the media factors and factor interactions which influence solubility. However, these studies require large numbers of experiments (>60) and are not feasible or sensible within a drug development setting. In the current study a smaller dual level, reduced experimental number (20) DoE providing three arms covering the fasted and fed states along with a combined analysis has been investigated. The results indicate that this small scale investigation is feasible and provides solubility ranges that encompass published data in human and simulated fasted and fed fluids. The measured fasted and fed solubility ranges are in agreement with published large scale DoE results in around half of the cases, with the differences due to changes in media composition between studies. Indicating that drug specific behaviors are being determined and that careful media factor and concentration level selection is required in order to determine a physiologically relevant solubility range. The study also correctly identifies the major single factor or factors which influence solubility but it is evident that lower significance factors (for example bile salt) are not picked up due to the lower sample number employed. A similar issue is present with factor interactions with only a limited number available for study and generally not determined to have a significant solubility impact due to the lower statistical power of the study. The study indicates that a reduced experimental number DoE is feasible, will provide solubility range results with identification of major solubility factors however statistical limitations restrict the analysis. The approach therefore represents a useful initial screening tool that can guide further in depth analysis of a drug’s behavior in gastrointestinal fluids.

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

“…However in four cases, ibuprofen, valsartan, bromocriptine, itraconazole in the fasted state comparable large scale DoE results were not available, reducing the number of possible comparisons to twenty. Due to the small number of data points within the reduced DoE and previous reports that DoE solubility distributions are not universally normally distributed [1] a non-parametric Mann Whitney comparison was performed. Where a statistically significant difference was observed this has been noted on the relevant figure along with the determined level of significance.…”

“…especially in fasted media [7], see solubility factor section. For basic and neutral compounds the spread of solubility ratios is greater, probably related to the greater impact of media components, concentrations and ratios [1,7,14,37,38] on the solubility of these compound categories in simulated media, see solubility factor section.…”

“…Recent work within our group has focused on the investigation of gastrointestinal solubility of BCS Class II compounds through the use of simulated fluids in statistical Design of Experiment (DoE) style investigations. This allows media components such as bile salt, pH, oleate, lecithin and monoglyceride concentrations to be systematically examined to provide an overall view of the individual component's role and interactions within a compound's solubility envelope [1,14,25,38]. Myers [22] described a DoE system as being able to investigate the effects of numerous variable factors to be studied in one single experiment leading to enhanced understanding of the system in a time and consumable efficient manner.…”

“…Although these studies provided novel, interesting and valuable results a subsequent study was carried out to combine both the fasted and fed studies with a reduced experimental load [25] using a 1/8 fraction factorial DoE. This approach reduced the number of samples required for the DoE however, differentiation could no longer be observed between the fasted and fed states leading to the design of a dual level DoE [1]. 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.…”

Impact of bile salts and a medium chain fatty acid on the physical properties of self-emulsifying drug delivery systems

“…Medium-chain fatty acids (C8-12) such as decanoate are recognized for their detergent properties and used as additives to promote drug absorption [34]. According to the literature, a concentration of fatty acids in the range of 0.1-15 mM corresponds to the physiological concentration at the fasted state [35,36]. The concentration of fatty acids at fed state varies depending on the daily fat intake.…”