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Identification of lead compounds with higher molecular weight and lower aqueous solubility has become increasingly prevalent with the advent of high throughput screening. Poor aqueous solubility of these lipophilic compounds can drastically affect the dissolution rate and subsequently the drug absorbed in the systemic circulation, imposing a significant burden of time and money during drug development process. Various pre-formulation and formulation strategies have been applied in the past that can improve the aqueous solubility of lipophilic compounds by manipulating either the crystal lattice properties or the activity coefficient of a solute in solution or both, if possible. However, despite various strategies available in the armor of formulation scientist, solubility issue still remains an overriding problem in the drug development process. It is perhaps due to the insufficient conceptual understanding of solubility and dissolution phenomenon that hinders the judgment in selecting suitable strategy for improving aqueous solubility and/or dissolution rate. This article, therefore, focuses on (i) revisiting the theoretical and mathematical concepts associated with solubility and dissolution, (ii) their application in making rationale decision for selecting suitable pre-formulation and formulation strategies and (iii) the relevant research performed in this field in past decade.

The objective of this study was to fabricate and understand ethosomal formulations of diclofenac (DF) for enhanced anti-inflammatory activity using quality by design approach. DF-loaded ethosomal formulations were prepared using 4 × 5 full-factorial design with phosphatidylcholine:cholesterol (PC:CH) ratios ranging between 50:50 and 90:10, and ethanol concentration ranging between 0% and 30% as formulation variables. These formulations were characterized in terms of physicochemical properties and skin permeation kinetics. The interaction of formulation variables had a significant effect on both physicochemical properties and permeation kinetics. The results of multivariate regression analysis illustrated that vesicle size and elasticity of ethosomes were the dominating physicochemical properties affecting skin permeation, and could be suitably controlled by manipulation of formulation variables to optimize the formulation and enhance the skin permeation of DF-loaded ethosomes. The optimized formulation had ethanol concentration of 22.9% and PC:CH ratio of 88.4:11.6, with vesicle size of 144 ± 5 nm, zeta potential of -23.0 ± 3.76 mV, elasticity of 2.48 ± 0.75 and entrapment efficiency of 71 ± 4%. Permeation flux for the optimized formulation was 12.9 ± 1.0 µg/h cm(2), which was significantly higher than the drug-loaded conventional liposome, ethanolic or aqueous solution. The in vivo study indicated that optimized ethosomal hydrogel exhibited enhanced anti-inflammatory activity compared with liposomal and plain drug hydrogel formulations.

The results indicate that suitable rheological properties of C974 could facilitate in achieving desired skin permeation of diclofenac while acting as an efficient carrier system for ethosomal vesicles.

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