Abstract
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 tradeoff when 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.
Highlights
In recent years, modern drug discovery efforts have been producing more and more lipophilic drug candidates, and according to some estimates more than 50% of new drug entities exhibit poor water solubility (Lipinski et al, 2001; Dahan et al, 2013b; Pham-The et al, 2013; Wolk et al, 2014)
Three main findings can be readily seen in Figure 1: (1) hydrotropic solubilization of carbamazepine, using either urea or nicotinamide, is a powerful solubilization method that can dramatically increase the drugs’ apparent solubility; (2) while carbamazepine’s solubility in the absence of any excipient is temperature-dependent, the two hydrotropes react very differently to temperature variation: it can be seen that the ability of urea to increase carbamazepine solubility is temperature-dependent, while nicotinamide is not; and (3) closer analysis of the effect of urea reveals that while at room temperature the increased solubility appears to be linear as urea level increases, at 37◦C carbamazepine shows biphasic solubility trend, with higher slope at hydrotrope levels above 10% w/v
A tradeoff between solubility increase and permeability decrease exists when using hydrotropic drug solubilization, which means that every solubility gain is accompanied by a concomitant permeability loss
Summary
Modern drug discovery efforts have been producing more and more lipophilic drug candidates, and according to some estimates more than 50% of new drug entities exhibit poor water solubility (Lipinski et al, 2001; Dahan et al, 2013b; Pham-The et al, 2013; Wolk et al, 2014). No such tradeoff was observed with amorphous solid dispersions (ASD) irrespective of the supersaturation level attained (Miller et al, 2012a; Dahan et al, 2013a, 2016). This fundamental difference between different solubilization methods and ASD formulations represent a significant advantage of the latter, as ASD may increase the drug flux across the intestinal barrier (which is the product of solubility times permeability) more than the above mentioned solubilization techniques
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