Abstract
Oral administration of a solid dosage form requires drug dissolution in the gastrointestinal tract before absorption. Solubility is a key factor controlling dissolution, and it is recognized that, within the intestinal tract, this is influenced by the luminal fluid pH, amphiphile content, and composition. Various simulated intestinal fluid recipes have been introduced to mimic this behavior and studied using a range of different experimental techniques. In this article, we have measured equilibrium solubility utilizing a novel four component mixture design (4CMD) with biorelevant amphiphiles (bile salt, phospholipid, oleate, and monoglyceride) within a matrix of three pH values (5, 6, and 7) and total amphiphile concentrations (11.7, 30.6, and 77.5 mM) to provide a topographical and statistical overview. Three poorly soluble drugs representing acidic (indomethacin), basic (carvedilol), and neutral (fenofibrate) categories have been studied. The macroscopic solubility behavior agrees with literature and exhibits an overall increasing solubility from low pH and total amphiphile concentration to high pH and total amphiphile concentration. Within the matrix, all three drugs display different topographies, which can be related to the statistical effect levels of the individual amphiphiles or amphiphile interactions on solubility. The study also identifies previously unreported three and four way factor interactions notably between bile salt, phospholipid, pH, and total amphiphile concentration. In addition, the results also reveal that solubility variability is linked to the number of amphiphiles and the respective ratios in the measurement fluid, with the minimum variation present in systems containing all four amphiphiles. The individual 4CMD experiments within the matrix can be linked to provide a possible intestinal solubility window for each drug that could be applied in PBPK modeling systems. Overall the approach provides a novel overview of intestinal solubility topography along with greater detail on the impact of the various factors studied; however, each matrix requires 351 individual solubility measurements. Further studies will be required to refine the experimental protocol in order the maximize information garnered while minimizing the number of measurements required.
Highlights
Oral administration of solid dosage forms is simple and convenient, and it is the predominant route of drug administration
That pH and amphiphile concentrations vary along the length of the intestinal tract coupled with intra- and interindividual variations.[14−16] In order to determine if the solubility complexity demonstrated using a single 4CMD condition[25] is retained when pH and amphiphile concentration varies, we have extended the 4CMD approach to cover additional pH (5 and 6) and total amphiphile concentration (30.6 and 77.5 mM) values to provide a 3 × 3 matrix that spans the likely range of biorelevant intestinal values or conditions
One internal point lies on a lower whisker at low pH and total amphiphile concentration, which is similar for fenofibrate, where two sit on the low whisker at low pH and total amphiphile concentration of 30.6 mM
Summary
Oral administration of solid dosage forms is simple and convenient, and it is the predominant route of drug administration. Despite the routine process of oral administration, the drug must be absorbed from the gastrointestinal tract into the circulation if systemic therapeutic effects are to occur. The rate and extent of drug absorption is influenced by a multitude of factors related to the drug’s physicochemical properties, the formulation, gastro-intestinal tract physiology, and the patient, with respect to food intake or clinical status.[1] A preeminent factor is the drug’s aqueous solubility, since solid drug is not absorbed, and dissolution, which is in part controlled by solubility,[2] has to occur after the administration of a solid dosage form. It has been recognized, that a simple aqueous assessment does not always reflect gastrointestinal solubility[5] due to the presence of multiple components (for example bile salts) or physiological conditions (for example pH) which influence solubility
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