(M1030-12-78) Hydrolysis Kinetics of the Prodrug Dodecyl Nicotinate in Buffered Solutions, and Skin and Liver Homogenates

Purpose: The prodrug Dodecyl Nicotinate was produced to facilitate its transdermal delivery and to reduce the incidence of side effects of the original drug. The purpose of this study is to evaluate the influence of formulation factors that affect its hydrolysis rate. The prodrug hydrolysis in skin and liver homogenate was performed to foresee its behavior in vivo.

Methods: The kinetics of hydrolysis of dodecyl nicotinate was studied in an aqueous phosphate buffer solution in the pH range of 5-10 at 80 °C and at a constant ionic strength. The effect of temperature, ionic strength, buffer concentrations, and buffer type was also studied. The degradation was monitored using a validated HPLC method. The kinetics of the hydrolysis of dodecyl nicotinate was also studied in skin and liver homogenates.

Results: The hydrolysis of the prodrug was found to follow pseudo-first-order kinetics. The pseudo-first-order rate constants were calculated from the slope of a linear plot of Ln transformation (Ln) of the remaining parent prodrug concentration versus time. The hydrolysis was found pH-dependent, and the pH rate profile was constructed. Also, the hydrolysis rate of dodecyl nicotinate was found to be buffer species dependent. Carbonate buffer has the most catalytic effect over borate and phosphate buffers. The hydrolysis of the prodrug was found to be faster in liver and skin homogenates than those in aqueous buffer solutions. The pseudo-first-order rate constants were found to be 0.002, and 0.011min-1 for dodecyl nicotinate in liver and skin homogenates respectively.

Conclusion: Dodecyl Nicotinate can be prepared as a stable aqueous solution. The formulation factors and the conditions that influence the stability of the prodrug were identified. Hydrolysis of the prodrug in the skin and liver homogenates demonstrated the release of nicotinic acid from the prodrug in vivo in a sustained manner.

Acknowledgements: This work is funded by a research grant from the Deanship of Research at Jordan University of Science and Technology. This work is dedicated to the soul of Prof. Bassam Tashtoush who was the initiator of the study.

pH-hydrolysis rate profile of dodecyl nicotinate at 80°C.

Hydrolysis of dodecyl nicotinate in different buffer solutions at pH 9.

Lineweaver-Burk plot of dodecyl nicotinate hydrolysis in skin homogenate.