Improved Prediction of in Vivo Supersaturation and Precipitation of Poorly Soluble Weakly Basic Drugs Using a Biorelevant Bicarbonate Buffer in a Gastrointestinal Transfer Model

Mol Pharm. 2019 Sep 3;16(9):3938-3947. doi: 10.1021/acs.molpharmaceut.9b00534. Epub 2019 Aug 7.


The characterization of intestinal dissolution of poorly soluble drugs represents a key task during the development of both new drug candidates and drug products. The bicarbonate buffer is considered as the most biorelevant buffer for simulating intestinal conditions. However, because of its complex nature, being the volatility of CO2, it has only been rarely used in the past. The aim of this study was to investigate the effect of a biorelevant bicarbonate buffer on intestinal supersaturation and precipitation of poorly soluble drugs using a gastrointestinal (GI) transfer model. Therefore, the results of ketoconazole, pazopanib, and lapatinib transfer model experiments using FaSSIFbicarbonate were compared with the results obtained using standard FaSSIFphosphate. Additionally, the effect of hydroxypropyl methylcellulose acetate succinate (HPMCAS) as a precipitation inhibitor was investigated in both buffer systems and compared to rat pharmacokinetic (PK) studies with and without coadministration of HPMCAS as a precipitation inhibitor. While HPMCAS was found to be an effective precipitation inhibitor for all drugs in FaSSIFphosphate, the effect in FaSSIFbicarbonate was much less pronounced. The PK studies revealed that HPMCAS did not increase the exposure of any of the model compounds significantly, indicating that the transfer model employing bicarbonate-buffered FaSSIF has a better predictive power compared to the model using phosphate-buffered FaSSIF. Hence, the application of a bicarbonate buffer in a transfer model set-up represents a promising approach to increase the predictive power of this in vitrotool and to contribute to the development of drug substances and drug products in a more biorelevant way.

Keywords: IVIVR; bicarbonate buffer; enteric polymers; precipitation; rat PK; supersaturation; transfer model.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Animals
  • Bicarbonates / chemistry*
  • Bicarbonates / pharmacology*
  • Buffers
  • Chemical Precipitation / drug effects*
  • Drug Delivery Systems / methods*
  • Drug Liberation / physiology*
  • Female
  • Gastrointestinal Absorption / physiology*
  • Gastrointestinal Tract
  • Hydrogen-Ion Concentration
  • Indazoles
  • Ketoconazole / administration & dosage
  • Ketoconazole / blood
  • Ketoconazole / chemistry
  • Ketoconazole / pharmacokinetics
  • Lapatinib / administration & dosage
  • Lapatinib / blood
  • Lapatinib / chemistry
  • Lapatinib / pharmacokinetics
  • Methylcellulose / analogs & derivatives
  • Methylcellulose / pharmacology
  • Models, Biological*
  • Phosphates / chemistry
  • Pyrimidines / administration & dosage
  • Pyrimidines / blood
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacokinetics
  • Rats
  • Rats, Wistar
  • Solubility
  • Sulfonamides / administration & dosage
  • Sulfonamides / blood
  • Sulfonamides / chemistry
  • Sulfonamides / pharmacokinetics


  • Bicarbonates
  • Buffers
  • Indazoles
  • Phosphates
  • Pyrimidines
  • Sulfonamides
  • Lapatinib
  • hydroxypropylmethylcellulose acetate succinate
  • pazopanib
  • Methylcellulose
  • Ketoconazole