We hypothesised that Hansen Solubility Parameters (HSPs) can be used to predict drug-nail affinities. Our aims were to: (i) determine the HSPs (δD, δP, δH) of the nail plate, the hoof membrane (a model for the nail plate), and of the drugs terbinafine HCl, amorolfine HCl, ciclopirox olamine and efinaconazole, by measuring their swelling/solubility in organic liquids, (ii) predict nail-drug interactions by comparing drug and nail HSPs, and (iii) evaluate the accuracy of these predictions using literature reports of experimentally-determined affinities of these drugs for keratin, the main constituent of the nail plate and hoof. Many solvents caused no change in the mass of nail plates, a few solvents deswelled the nail, while others swelled the nail to varying extents. Fingernail and toenail HSPs were almost the same, while hoof HSPs were similar, except for a slightly lower δP. High nail-terbinafine HCl, nail-amorolfine HCl and nail-ciclopirox olamine affinities, and low nail-efinaconazole affinities were then predicted, and found to accurately match experimental reports of these drugs' affinities to keratin. We therefore propose that drug and nail Hansen Solubility Parameters may be used to predict drug-nail interactions, and that these results can assist in the design of drugs for the treatment of nail diseases, such as onychomycosis and psoriasis. To our knowledge, this is the first report of the application of HSPs in ungual research.

In vitro-in vivo correlations AdhesionIn vivo residence a b s t r a c t Pharmaceutical nail lacquers are used to topically treat nail fungal infections. The film's residence on the nail is an important factor, and in the laboratory, rapid in vitro adhesion and water resistance tests are often used to indicate their likely in vivo residence. However, the predictivity of such in vitro tests is unknown. The aim of this work was thus to determine whether, and to what extent, such in vitro tests can correctly predict the in vivo fate of nail lacquers. The in vivo residence of four commercially available nail lacquers (three pharmaceutical and one cosmetic) was determined in 16 volunteers. In vitro, the films' resistance to water, and their adhesion to a model nail plate was measured, and in vitro-in vivo correlations were explored. It was found that the in vitro films' resistance to water correctly predicted the in vivo residence of lacquers, while the adhesion tests did not.

The in vivo residence of nail lacquers (which are ideal topical drug carriers for the treatment of nail diseases) determines their frequency of application, and is thereby expected to influence patient adherence and success of treatment. Thus in vitro measurements to indicate lacquers' in vivo residence are routinely conducted during formulation development. However the literature on in vitro-in vivo correlations is severely limited. Thus, the aim of the work discussed in this paper was to investigate correlations between in vivo residence and in vitro film resistance to water, in vitro film adhesion and surface energy of lacquer films. In vivo measurements were conducted on fingernails in six volunteers. Seven commercially available nail lacquers were tested in commonly-used measurements. Correlations between in vivo residence and in vitro water resistance and adhesion were found to be extremely poor. The surface energies of the lacquer films (which were between 33 and 39 mJ/m 2 ) were also not predictive of in vivo residence. High density polyethylene (HDPE) sheet -whose surface energy was determined to be similar to that of the human nailplate -was found to be a suitable model for the nailplate (when investigating surface energy) and was used in a number of experiments.