AAPS PharmSciTech

, 20:179 | Cite as

Assessment of Biopharmaceutical Performance of Supersaturating Formulations of Carbamazepine in Rats Using Physiologically Based Pharmacokinetic Modeling

  • Samarth D. Thakore
  • Poonam Singh Thakur
  • Ganesh Shete
  • Rahul Gangwal
  • Ajit S. Narang
  • Abhay T. Sangamwar
  • Arvind Kumar BansalEmail author
Research Article


There is an overgrowing emphasis on supersaturating drug delivery systems (SDDS) with increase in number of poorly water-soluble compounds. However, biopharmaceutical performance from these formulations is limited by phase transformation to stable crystalline form due to their high-energy physical form. In the present study, in vitro kinetic solubility in water and dissolution in biorelevant medium integrated with in silico physiologically based pharmacokinetic (PBPK) modeling was used to predict biopharmaceutical performance of SDDS of poorly water-soluble compound, carbamazepine (CBZ). GastroPlus™ with advanced compartmental absorption and transit model was used as a simulation tool for the study. Wherein, the model was developed using physicochemical properties of CBZ and disposition parameters obtained after intravenous administration of CBZ (20 mg/kg) into Sprague-Dawley (SD) rats. Biorelevant medium was selected by screening different dissolution media for their capability to predict oral plasma concentration-time profile of marketed formulation of CBZ. In vivo performance of SDDS was predicted with the developed model and compared to observed plasma concentration-time profile obtained after oral administration of SDDS into SD rats (20 mg/kg). The predictions, with strategy of using kinetic solubility and dissolution in the selected biorelevant medium, were consistent with observed biopharmaceutical performance of SDDS. Additionally, phase transformation of CBZ during gastrointestinal transit of formulations was evaluated and correlated with in vivo dissolution deconvoluted by Loo-Reigelman analysis.


carbamazepine supersaturation phase transformation Loo-Riegelman analysis physiologically based pharmacokinetic modeling 





Biopharmaceutics Classification System


Carbamazepine dihydrate


Gastrointestinal tract


Supersaturating drug delivery systems




Amorphous solid dispersion




Physiologically based pharmacokinetic modeling


Advanced compartmental absorption and transit






Hydroxypropyl methylcellulose acetate succinate


Differential scanning calorimetry


Powder X-ray diffraction


Committee for the Purpose of Control and Supervision of Experiments on Animals


% prediction error


Enterohepatic circulation


Scanning electron microscopy


Supplementary material

12249_2019_1386_MOESM1_ESM.doc (1.3 mb)
ESM 1 (DOC 1315 kb)


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Copyright information

© American Association of Pharmaceutical Scientists 2019

Authors and Affiliations

  • Samarth D. Thakore
    • 1
  • Poonam Singh Thakur
    • 1
  • Ganesh Shete
    • 1
  • Rahul Gangwal
    • 2
  • Ajit S. Narang
    • 3
  • Abhay T. Sangamwar
    • 1
  • Arvind Kumar Bansal
    • 1
    Email author
  1. 1.Department of PharmaceuticsNational Institute of Pharmaceutical Education and ResearchMohaliIndia
  2. 2.Department of PharmacoinformaticsNational Institute of Pharmaceutical Education and ResearchMohaliIndia
  3. 3.Small Molecule Pharmaceutical SciencesGenentech, Inc.CaliforniaUSA

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