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Understanding the Structure-Release Relationships of Sepineo
Ayca Altay Benetti
National University of Singapore
The physical and mechanical characteristics of gel samples are of utmost importance in the development and manufacture of a wide variety of products. This work aims to provide a thorough examination of the impact of pH changes and ionization status of an API (diclofenac sodium) loaded in SepineoTM gels on the rheological behaviour, surface tension, in vitro release properties and ex vivo skin permeation profiles of the dosage form. Moreover, a comprehensive study on molecular dynamic simulations has been conducted to understand the relationship between drug molecules and SepineoTM at different pH ranges, considering the pKa value of diclofenac sodium.
To evaluate the impact of pH changes and diclofenac ionization, four different SepineoTM (3%) gels loaded with diclofenac sodium (0%, 0.1% or 1%) were prepared at different pH conditions; 2.55, 5.55, 7.4 and 11.56, respectively. As pH shifted from acidic to basic conditions, a change in the stiffness of Sepineo was observed with and without diclofenac loading. However, the elasticity behaviour wasn't affected by the changes of pH. On the other hand, the static contact angle measurement proved that the blank and 0.1% formulations had a pH-dependent behaviour (p<0.02, ANOVA test). In vitro release studies using Dispersion Releaser technology were performed at 25 RPM to understand the release mechanism from the SepineoTM gels loaded with 0.1% of diclofenac, whereby release profiles confirmed that ionized diclofenac had a quick release compared to the one with unionized formulation. The ex vivo permeation analysis of 0.1% gel formulations across pig ear skin was performed, with the expectation that fully ionized diclofenac would have permeated more. Surprisingly, the formulations at pH 11.56 showed lower release of drug and permeation through the skin. Overall, we found that the pH of the formulation, rather than the rheological properties, could significantly affect drug release and permeation profiles. Through these in-depth characterizations, it will be possible to optimize drug release and permeation of other APIs from gel formulations to achieve maximum efficacy.
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