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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

Abstract

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.

KEY WORDS

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

Abbreviations

CBZ

Carbamazepine

BCS

Biopharmaceutics Classification System

CBZ-DH

Carbamazepine dihydrate

GIT

Gastrointestinal tract

SDDS

Supersaturating drug delivery systems

CoC

Cocrystal

ASD

Amorphous solid dispersion

G+

GastroPlusTM

PBPK

Physiologically based pharmacokinetic modeling

ACAT

Advanced compartmental absorption and transit

LR

Loo-Reigelman

SAC

Saccharin

HPMCAS

Hydroxypropyl methylcellulose acetate succinate

DSC

Differential scanning calorimetry

PXRD

Powder X-ray diffraction

CPCSEA

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

%PE

% prediction error

EHC

Enterohepatic circulation

SEM

Scanning electron microscopy

Notes

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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