TY - JOUR
T1 - Accounting for the solubility-permeability interplay in oral formulation development for poor water solubility drugs
T2 - The effect of PEG-400 on carbamazepine absorption
AU - Beig, Avital
AU - Miller, Jonathan M.
AU - Dahan, Arik
N1 - Funding Information: This work was supported by a research grant from Abbott Laboratories.
PY - 2012/6/1
Y1 - 2012/6/1
N2 - The purpose of this paper was to study the solubility-permeability interplay in formulation development for oral administration of poor aqueous solubility drugs. The apparent solubility of the lipophilic drug carbamazepine was measured in systems containing various levels of the co-solvent PEG-400. The corresponding permeability was then measured in the PAMPA assay and in the rat jejunal perfusion model. Thermodynamic activity was maintained equivalent in all permeability studies (50% saturation). PEG-400 increased carbamazepine solubility in a concentration-dependent fashion. Decreased carbamazepine intestinal permeability with increased apparent solubility was observed in both PAMPA and rat perfusion models. Additionally, we have shown that the intestinal absorption of carbamazepine is membrane-controlled, with essentially no effective barrier function of the unstirred water layer. A mass transport analysis was employed to describe the solubility-permeability interplay. It was shown that the increased solubility in the aqueous GI milieu reduced the apparent membrane/aqueous partitioning, thereby reducing the driving force for membrane permeability. The model enabled excellent quantitative prediction of the effective permeability as a function of the solubility. In conclusion, a direct tradeoff between solubility increase and permeability decrease has been shown, which has to be accounted for when developing oral formulation for lipophilic drugs.
AB - The purpose of this paper was to study the solubility-permeability interplay in formulation development for oral administration of poor aqueous solubility drugs. The apparent solubility of the lipophilic drug carbamazepine was measured in systems containing various levels of the co-solvent PEG-400. The corresponding permeability was then measured in the PAMPA assay and in the rat jejunal perfusion model. Thermodynamic activity was maintained equivalent in all permeability studies (50% saturation). PEG-400 increased carbamazepine solubility in a concentration-dependent fashion. Decreased carbamazepine intestinal permeability with increased apparent solubility was observed in both PAMPA and rat perfusion models. Additionally, we have shown that the intestinal absorption of carbamazepine is membrane-controlled, with essentially no effective barrier function of the unstirred water layer. A mass transport analysis was employed to describe the solubility-permeability interplay. It was shown that the increased solubility in the aqueous GI milieu reduced the apparent membrane/aqueous partitioning, thereby reducing the driving force for membrane permeability. The model enabled excellent quantitative prediction of the effective permeability as a function of the solubility. In conclusion, a direct tradeoff between solubility increase and permeability decrease has been shown, which has to be accounted for when developing oral formulation for lipophilic drugs.
KW - Drug solubility
KW - Intestinal permeability
KW - Oral absorption
KW - Solubility-enabling formulations
KW - Solubility-permeability tradeoff
UR - http://www.scopus.com/inward/record.url?scp=84861593280&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.ejpb.2012.02.012
DO - https://doi.org/10.1016/j.ejpb.2012.02.012
M3 - Article
C2 - 22387337
SN - 0939-6411
VL - 81
SP - 386
EP - 391
JO - European Journal of Pharmaceutics and Biopharmaceutics
JF - European Journal of Pharmaceutics and Biopharmaceutics
IS - 2
ER -