Poorly soluble weak bases form a significant proportion of the drugs available in the market thereby making it imperative to understand their absorption behavior. This work aims to mechanistically understand the oral absorption behavior for a weakly basic drug, Irbesartan (IRB), by investigating its pH dependent solubility, supersaturation, and precipitation behavior. Simulations performed using the equilibrium solubility could not accurately predict oral absorption. A multi-compartmental biorelevant dissolution testing model was used to evaluate dissolution in the stomach and duodenal compartment and mimic oral drug administration. This model exhibited sustained intestinal supersaturation (2–4-fold) even upon varying flow rates (4 mL/min, 7 mL/min, and mono-exponential transfer) from gastric to intestinal compartment. Simulation of oral absorption using GastroPlus™ and dissolution data collectively predicted plasma exposure with higher accuracy (% prediction error values within ± 15%), thereby indicating that multi-compartment dissolution testing enabled an improved prediction for oral pharmacokinetics of Irbesartan. Additionally, precipitates obtained in the intestinal compartment were characterized to determine the factors underlying intestinal supersaturation of Irbesartan. The solid form of these precipitates was amorphous with considerable particle size reduction. This indicated that following gastric transit, precipitate formation in the amorphous form coupled with an approximately 10 times particle size reduction could be potential factors leading to the generation and sustenance of intestinal drug supersaturation.
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Advanced compartmental absorption and transit model
Active pharmaceutical ingredient
Area under the curve
Biopharmaceutics classification system
- Cmax :
Differential scanning calorimetry
High pressure liquid chromatography
In vitro in vivo correlation
In vitro-in silico-in vivo
- Ksp :
Solubility product constant
Physiologically based pharmacokinetics
- pKa :
pH corresponding to 50% ionization
Powder X-ray diffraction
Solubility (ionized + unionized form)
- SO :
Scanning electron microscopy
Simulated gastric fluid
Simulated intestinal fluid
- Tg :
Glass transition temperature
- Tm :
- Tmax :
Time of maximal concentration
United States Pharmacopeia
- Vd :
Volume of distribution
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Kaur, N., Thakur, P.S., Shete, G. et al. Understanding the Oral Absorption of Irbesartan Using Biorelevant Dissolution Testing and PBPK Modeling. AAPS PharmSciTech 21, 102 (2020). https://doi.org/10.1208/s12249-020-01643-x
- weak base
- PBPK modeling