Selecting the particle size distribution for drugs with low water solubility - mathematical model.
OBJECTIVE
To introduce guidelines in selecting the particle size distribution (n(0), cm(-1)) that will guarantee optimal oral absorption for drugs with low solubility.


METHODS
Unlike other multi-compartmental models the gastrointestinal tract is modeled as a continuous tube with spatially varying properties. The transport through the intestinal lumen is described using the dispersion model. The model accounts for the dissolution of poly-dispersed powders.


RESULTS
The model was used to examine the sensitivity of the absorption on permeability (P) and water solubility (C(s)) following administration in different log-normal powders. The absorption exhibits inverse sigmoidal dependence on the mean particle size (r(m), µm) regardless of the administrated dose or drug properties. Thus, there is an optimal r(m) that maximizes the benefit-cost ratio of the formulation; finer particles do not improve the absorption while coarser particles decrease it. Using the model we find that the optimal r(m) depends mainly on the drug C(s) and on the geometrical standard deviation (gSTD).


CONCLUSIONS
The results of this work provide the formulator with guidelines to select both r(m) and gSTD that guarantee optimal absorption.
The Selim and Rachel Benin School of Computer Science and Engineering, The Hebrew University of Jerusalem, Israel. yehudaa@iibr.gov.il
Yehuda
Y
Arav
Michel
M
Bercovier
Hanna
H
Parnas
D000284:Administration, Oral; D002626:Chemistry, Pharmaceutical / Q000379:methods; D041981:Gastrointestinal Tract / Q000378:metabolism*; D006118:Griseofulvin / Q000737:chemistry / Q000493:pharmacokinetics; D007408:Intestinal Absorption; D007700:Kinetics; D008956:Models, Chemical; D010316:Particle Size; D010539:Permeability; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D010599:Pharmacokinetics; D012995:Solubility; D014867:Water / Q000737:chemistry*
D004364:Pharmaceutical Preparations; D014867:Water; D006118:Griseofulvin