Estimation of Hansen Solubility Parameters (HSP) for Mobile Phase Selection

Miconazole (MCZ) is chemically a potential azole (imidazole) to treat fungal infection (mucocutaneous candidiasis, oropharyngeal candidiasis, and vaginal candidiasis) with few reported activities against Gram-positive bacteria. The drug is associated with low molecular weight (416 g/mol), high lipophilicity (log P = 6.1), and poor aqueous solubility (0.0007 mg/mL). Pharmacologically, MCZ inhibits ergosterol synthesis of the fungal cell wall. The drug has 0 and 2 hydrogen bond donor count and hydrogen bond acceptor count, respectively.¹³ Several topical creams and related products are available in the market with limited therapeutic efficacy due to poor drug solubility and permeation across the skin barrier. Thus, selection of a suitable solvent, surfactant, lipid, and cosurfactant could be a promising approach to formulate an alternative transdermal product with anticipated permeation and therapeutic benefits after topical application. In the preliminary study, selection of excipients and the subsequent optimization process led to several benefits such as reduced time of product development, reduced product cost, high patient compliance, and high regulatory acceptance. For this, the predictive program (Hansen solubility parameter, HSP) and Design Expert (experimental design tool) played a vital role during product development. HSPiP software is conceptually based on the total energies of the drug and solvent. Compounds possessed total cohesive energy distributed as polarity energy, dispersion energy, and hydrogen bond formation ability energy.^14,15 Mathematically, this was expressed below as eq 1

where δ_d, δ_p, and δ_h are the solvent dispersion power, the solvent polarity (due to the dielectric nature), and the solvent hydrogen bond formation capability, respectively. Hansen estimated δ_p and δ_h values of a polymer in a targeted solvent by an empirical method (experimentally) to get the best “volume”. They were adopted as three coordinates of axes for developing a three-dimensional solubility sphere with radius “Ro”. The program classified “good” or “bad” solvent depending upon the position of the solvent in a three-dimensional solubility sphere. A solvent falling within the sphere or on the surface is considered “good” and vice versa.¹⁴ Various input parameters were used to run the program obtained from the literature, by default, and the experiment. Then, targeted HSP values of the combined ratio of two solvents were estimated at a given radius and 100% check value (composition not exceeding 100%). Theoretically, the difference of any HSP between the drug and solvent should be close to zero or zero for maximum solubilization in the studied solvent or binary mixture at fixed temperature (δ_d of solute – δ_d of solvent ∼ zero, δ_p of solute – δ_p of solvent ∼ zero, and δ_h of solute – δ_h of solvent ∼ zero).^14,15 We explored various transdermal and nontopical products with improved drug solubility and high permeability by implementing HSP (estimated from the program). In the program, various trials were run to select a suitable composition of solvents and their ratios for maximum drug solubility. During screening, HSP values of the drug and HSP values of human skin were taken into consideration for developing the mobile phase and the drug extraction from skin, respectively. The HSP of human skin was obtained from the literature as presented in the Results and Discussion section.^14,15