Track: Formulation and Delivery - Chemical - Formulation - Advanced Dissolution Testing
Category: Poster Abstract
Dissolution Kinetics of pH Sensitive Drugs in an Artificial Stomach and Duodenum Apparatus
Purpose: The purpose of this study was to investigate the impact of dynamic change of pH in gastrointestinal (GI) tract on the dissolution of pH sensitive drugs using an artificial stomach and duodenum (ASD) apparatus (Figure 1). Methods: Erlotinib (ERL, intrinsic solubility of 3.27 ± 0.05 μg/mL and pKa = 5.42), a weak base, was used as a model drug. To simulate the fasted state in human, the stomach chamber was initially filled with 50 mL of 0.01N HCl as resting liquid and approximately 200 mL DI water was then added to represent the liquid taken with the drug. The duodenum chamber contained 30 mL of FaSSIF (pH 6.5) medium. During the simulation, the fluid in the stomach chamber was emptied following a first-order kinetics with a half-life (t1/2) of 15 min and the fresh duodenal fluids (FaSSIF) was infused into the duodenum chamber at 2 mL/min. The fresh gastric liquid (0.01N HCl), however, was adjusted from 0.5 to 2.5 mL/min to simulate variations in secretion rate of gastric fluid. The relationship between precipitation induction time and supersaturation ratio was determined to facilitate the interpretation of the effect of pH variation in duodenum chamber as a result of varying gastric fluid secretion rate. Results: Increasing the gastric liquid secretion rate from 0.5 to 2.5 mL/min led to 5-fold increase in the dissolution of ERL in duodenum chamber with AUC varying from 3,000 to 14,000 (μg‧min)/mL (Figure 2), with visually much lower extent of precipitation. This profound effect on the dissolution of ERL in duodenum corresponding to a change of pH – time profile in the duodenum chamber with minimum pH values ranged from 3 to 5.5. In this pH range, the precipitation induction time of ERL was extremely sensitive to pH variation. This explained the profoundly different dissolution behaviors as gastric fluid secretion rate varied. Conclusion: For the ionizable drug, ERL, variations in gastric liquid secretion rate, e.g., due to differences in gender, age, disease, may suffer from large variations in clinical outcomes. Therefore, appropriate formulation strategies should be implemented to ensure a robust clinical performance against variations in gastric fluid secretion rate.