TY - JOUR
T1 - Hydrotropic solubilization of lipophilic drugs for oral delivery
T2 - The effects of urea and nicotinamide on carbamazepine solubility-permeability interplay
AU - Beig, Avital
AU - Lindley, David
AU - Miller, Jonathan M.
AU - Agbaria, Riad
AU - Dahan, Arik
N1 - Publisher Copyright:
© 2016 Beig, Lindley, Miller, Agbaria and Dahan.
PY - 2016/10/25
Y1 - 2016/10/25
N2 - Hydrotropy refers to increasing the water solubility of otherwise poorly soluble compound by the presence of small organic molecules. While it can certainly increase the apparent solubility of a lipophilic drug, the effect of hydrotropy on the drugs' permeation through the intestinal membrane has not been studied. The purpose of this work was to investigate the solubility-permeability interplay when using hydrotropic drug solubilization. The concentration-dependent effects of the commonly used hydrotropes urea and nicotinamide, on the solubility and the permeability of the lipophilic antiepileptic drug carbamazepine were studied. Then, the solubility-permeability interplay was mathematically modeled, and was compared to the experimental data. Both hydrotropes allowed significant concentration-dependent carbamazepine solubility increase (up to ~30-fold). A concomitant permeability decrease was evident both in vitro and in vivo (~17-fold for nicotinamide and ~9-fold for urea), revealing a solubility-permeability tradeoffwhen using hydrotropic drug solubilization. A relatively simplified simulation approach based on proportional opposite correlation between the solubility increase and the permeability decrease at a given hydrotrope concentration allowed excellent prediction of the overall solubility-permeability tradeoff. In conclusion, when using hydrotropic drug solubilization it is prudent to not focus solely on solubility, but to account for the permeability as well; achieving optimal solubility-permeability balance may promote the overall goal of the formulation to maximize oral drug exposure.
AB - Hydrotropy refers to increasing the water solubility of otherwise poorly soluble compound by the presence of small organic molecules. While it can certainly increase the apparent solubility of a lipophilic drug, the effect of hydrotropy on the drugs' permeation through the intestinal membrane has not been studied. The purpose of this work was to investigate the solubility-permeability interplay when using hydrotropic drug solubilization. The concentration-dependent effects of the commonly used hydrotropes urea and nicotinamide, on the solubility and the permeability of the lipophilic antiepileptic drug carbamazepine were studied. Then, the solubility-permeability interplay was mathematically modeled, and was compared to the experimental data. Both hydrotropes allowed significant concentration-dependent carbamazepine solubility increase (up to ~30-fold). A concomitant permeability decrease was evident both in vitro and in vivo (~17-fold for nicotinamide and ~9-fold for urea), revealing a solubility-permeability tradeoffwhen using hydrotropic drug solubilization. A relatively simplified simulation approach based on proportional opposite correlation between the solubility increase and the permeability decrease at a given hydrotrope concentration allowed excellent prediction of the overall solubility-permeability tradeoff. In conclusion, when using hydrotropic drug solubilization it is prudent to not focus solely on solubility, but to account for the permeability as well; achieving optimal solubility-permeability balance may promote the overall goal of the formulation to maximize oral drug exposure.
KW - Drug absorption
KW - Hydrotropic solubilization
KW - Intestinal permeability
KW - Oral drug delivery
KW - Solubility
UR - http://www.scopus.com/inward/record.url?scp=84995450786&partnerID=8YFLogxK
U2 - 10.3389/fphar.2016.00379
DO - 10.3389/fphar.2016.00379
M3 - Article
AN - SCOPUS:84995450786
SN - 1663-9812
VL - 7
JO - Frontiers in Pharmacology
JF - Frontiers in Pharmacology
IS - OCT
M1 - 379
ER -