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Understanding the Oral Absorption of Irbesartan Using Biorelevant Dissolution Testing and PBPK Modeling


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 :

Maximal concentration


Complete release


Differential scanning calorimetry




Gastrointestinal tract


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


Prediction error


Powder X-ray diffraction


Solubility (ionized + unionized form)

SO :

Intrinsic solubility


Scanning electron microscopy


Simulated gastric fluid


Simulated intestinal fluid

Tg :

Glass transition temperature

Tm :

Melting point

Tmax :

Time of maximal concentration


United States Pharmacopeia

Vd :

Volume of distribution


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Correspondence to Arvind Kumar Bansal.

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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).

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  • weak base
  • biorelevant
  • PBPK modeling
  • GastroPlus™