Hydrotropic Solubilization of Lipophilic Drugs for Oral Delivery: The Effects of Urea and Nicotinamide on Carbamazepine Solubility–Permeability Interplay

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.

Antiviral effect of phytochemicals from medicinal plants: Applications and drug delivery strategies

“…It should be noted that some solubility-enabling formulations may simultaneously decrease the drug's permeability, and overall absorption may be unimproved. This solubilitypermeability interplay was shown for formulations based on cyclodextrins [162][163][164], surfactants [165], cosolvents [166], and hydrotropes [167,168]. In amorphous solid dispersions (ASD), on the other hand, the solubility increases (via supersaturation) with unchanged permeability, and thus, ASD may be preferred over other carrier systems, given supersaturation can be achieved and maintained for sufficient time [169].…”

Peptidomimetics Therapeutics for Retinal Disease

“…[83] Kim et al evaluated the solubility enhancement of 13 water-insoluble drugs in which solubility could be enhanced 1000-to 10,000-fold by using N,N-diethylnicotinamide (DENA) and N,N-dimethylbenzamide (DMBA). [84,85] , Hydrotropic agents efficiently and easily solubilize drugs via a simple solid dispersion method; however, the drug-to-excipient ratio is extremely low. For example, 534 mg/mL of DENA is needed to solubilize nifedipine and progesterone (for glaucoma and dry-eye treatment, respectively) up to 5 mg/mL and 7 mg/mL, respectively.…”

“…Due to the lipophilic nature of the cell membrane, this solubilizing process can decrease the drug permeability. [85] The overall solubility-permeability tradeoff should be considered when determining the optimal amounts of excipients. Cyclodextrin is a supramolecular compound composed of a hydrophilic backbone along with hydrophobic cavities ideal for hydrophobic drug solubilization.…”

Solubility Enhancement of Oxcarbazepine by Melt Sonocrystallization Technique to Increase the Bioavailability

“…Techniques for Solubility Enhancement include -Particle size reduction, Micronization, nanosuspension, Hydrotropy. 3 Hot Melt Extrusion technique Steam aided granulation Floating granulation Sono crystallization Melt Sonocrystallization is a new particle design technology developed to modify the undesired properties of compounds such as poor flowability and solubility. 4 This technique is an efficient tool to influence the external appearance structure of crystalline products, smaller crystal size compared with conventional crystallization and cost-effectiveness of apparatus.…”