Application of an Artificial Stomach-Duodenum Reduced Gastric pH Dog Model for Formulation Principle Assessment and Mechanistic Performance Understanding.

The objective of this study was to develop an artificial stomach-duodenum (ASD) dissolution model as an in vitro evaluation tool that would simulate the gastrointestinal physiology of gastric pH-reduced dogs as a method to assess formulations for a poorly soluble free acid compound with ng/mL solubility. After establishing the ASD model with well-controlled duodenum pH, 5 formulations each applying different solubilization principles were developed and their performance in the ASD model and in vivo in dogs was evaluated. Excellent correlations were obtained between dog area under the curve (AUC) and ASD AUC of 5 formulations evaluated with simulated intestinal fluid (r2  = 0.987) and fasted-state simulated intestinal fluid (r2  = 0.989) as the duodenum dissolution medium, indicating that the approach of infusing NaOH into duodenum compartment to maintain duodenum pH of an ASD worked properly in simulating gastric pH-reduced dog. Raman spectroscopy was used to study drug dissolution kinetics associated with different solubilization principles and the results suggested that the solubilization principles performed as designed. Spectroscopic results also identified that the compound formed a gel during dissolution and hypromellose maintained the drug-gelled state to avoid further solid form conversion. The implication of the compound physical gelation to drug dissolution kinetics and in vivo exposure are discussed.