Evaluation of Dissolution in the Lower Intestine and Its Impact on the Absorption Process of High Dose Low Solubility Drugs

Mol Pharm. 2017 Dec 4;14(12):4181-4191. doi: 10.1021/acs.molpharmaceut.6b01129. Epub 2017 Apr 13.


The purpose of this article was two-fold: first, to optimize a recently proposed two-stage single-compartment in vitro test for the evaluation of dissolution in the lower intestine with the mini-paddle apparatus in the fasted and fed state using two model high dose, low solubility drugs [sulfasalazine (Azulfidine) and micronized aprepitant] and one mesalamine colon targeting product (Asacol, 400 mg/tablet); second, to evaluate the impact of passive absorption from the lower intestine on the overall absorption process using three model high dose, low solubility drugs [micronized aprepitant, SB705498, and albendazole (Zentel)]. The intensity of agitation and the physicochemical characteristics of fluids simulating the environment in the distal ileum and the proximal colon were optimized and the importance of solid particles was evaluated. Dissolution data collected under conditions simulating the upper and lower intestine were coupled with physiologically based oral absorption modeling to simulate the average plasma levels or the average absorption process. Reliability of the modeling approach was evaluated based on previously collected data in adults. The impact of solid particles on dissolution in the lower intestine was found to be clinically insignificant for Asacol tablets, as well as for sulfasalazine (Azulfidine) and micronized aprepitant. Average plasma levels (micronized aprepitant and SB705498) and cumulative amount absorbed (albendazole) could be adequately simulated by referring only to events in the upper gastrointestinal lumen, indicating that the impact of absorption from the lower intestine on actual plasma levels was minimal. Dissolution of Asacol tablets and immediate release formulations in the lower intestine can be adequately evaluated by employing Level II biorelevant media. However, simulation of actual drug particle dissolution in the lower intestine is not typically necessary for adequate prediction of oral absorption from immediate release formulations containing discrete, dispersed particles of lipophilic drugs.

Keywords: PBPK modeling; SB705498; absorption; albendazole; aprepitant; colon; dissolution; ileum; mesalamine; sulfasalazine.

Publication types

  • Validation Study

MeSH terms

  • Administration, Oral
  • Adult
  • Body Fluids / chemistry
  • Chemistry, Pharmaceutical
  • Drug Liberation*
  • Fasting
  • Humans
  • Ileum / physiology
  • Intestinal Absorption*
  • Intestinal Mucosa / physiology*
  • Models, Biological*
  • Reproducibility of Results
  • Solubility
  • Tablets


  • Tablets