Influence of Hydrophobic and Hydrophilic Chain Length of CiEj Surfactants on the Solubilization of Active Pharmaceutical Ingredients.

Up to 90% of all newly developed active pharmaceutical ingredients (APIs) are poorly water soluble, most likely also showing a low oral bioavailability. In order to increase the aqueous solubility of these APIs, surfactants are promising excipients to increase both solubility and consequently bioavailability (e.g., in lipid- and surfactant-based drug delivery systems). In this work, we investigated the influence of hydrophobic and hydrophilic chain lengths of CiEj surfactants (C8E6, C10E6, and C10E8) toward the solubilization of fenofibrate, naproxen, and lidocaine. Furthermore, we investigated the partitioning of these APIs between the surfactant aggregates and the surrounding aqueous bulk phase. For all APIs considered, we determined the locus of API solubilization as well as the individual aggregation numbers (Nagg) of surfactants and API molecules in an API/surfactant aggregate. We further determined the hydrodynamic radius (Rh) of the API/surfactant aggregates in the absence and presence of the APIs. The size of the API/surfactant aggregates (Nagg, Rh) passes through a minimum upon lidocaine solubilization; it gradually increases upon naproxen solubilization and is almost constant upon fenofibrate solubilization. The results give valuable insights into the solubilization mechanisms of APIs in the CiEj surfactant aggregates. Our results reveal that fenofibrate is solely solubilized in the hydrophobic core of the CiEj surfactant aggregates, as only the hydrophobic chain length of the surfactant influences its solubilization. Naproxen is solubilized in the palisade layer of the surfactant aggregates, as both the hydrophobic and hydrophilic chain lengths are decisive for its solubilization. Lidocaine is mainly solubilized in the rather hydrophilic corona region of the surfactant aggregates, as the hydrophilic chain length of the surfactant governs its solubilization. The results further reveal that the hydrophilic/lipophilic balance is not an appropriate measure to estimate the solubilization capacity of surfactant aggregates.

In-Silico Screening of Lipid-Based Drug Delivery Systems.

PURPOSE: This work proposes an in-silico screening method for identifying promising formulation candidates in complex lipid-based drug delivery systems (LBDDS). METHOD: The approach is based on a minimum amount of experimental data for API solubilites in single excipients. Intermolecular interactions between APIs and excipients as well as between different excipients were accounted for by the Perturbed-Chain Statistical Associating Fluid Theory. The approach was applied to the in-silico screening of lipid-based formulations for ten model APIs (fenofibrate, ibuprofen, praziquantel, carbamazepine, cinnarizine, felodipine, naproxen, indomethacin, griseofulvin and glibenclamide) in mixtures of up to three out of nine excipients (tricaprylin, Capmul MCM, caprylic acid, Capryol™ 90, Lauroglycol™ FCC, Kolliphor TPGS, polyethylene glycol, carbitol and ethanol). RESULTS: For eight out of the ten investigated model APIs, the solubilities in the final formulations could be enhanced by up to 100 times compared to the solubility in pure tricaprylin. Fenofibrate, ibuprofen, praziquantel, carbamazepine are recommended as type I formulations, whereas cinnarizine and felodipine showed a distinctive solubility gain in type II formulations. Increased solubility was found for naproxen and indomethacin in type IIIb and type IV formulations. The solubility of griseofulvin and glibenclamide could be slightly enhanced in type IIIb formulations. The experimental validation agreed very well with the screening results. CONCLUSION: The API solubility individually depends on the choice of excipients. The proposed in-silico-screening approach allows formulators to quickly determine most-appropriate types of lipid-based formulations for a given API with low experimental effort. Graphical abstract.