Abstract
This study focused on optimizing the mechanism of zero-order active pre-programmed release of melatonin from a salted-out PLGA scaffold. A Box—Behnken design, modeled the formulations, required for optimizing the melatonin entrapment efficiency (EE), mean dissolution time at 30 days (MDT30) and the release rate constant (k). Response Surface Methodology depicted the influence of NaCl, CaCl2, and AlCl3 on the release kinetics. Qualitative structural kinetic modeling and quantitative mathematical modeling of release data supported the kinetic events, interaction parameters, and melatonin transport phenomena that resolved the constraints governing the rate and extent of melatonin release. A salted-out PLGA chain was evaluated by rheological studies and braided rope-coiling and nonbraided nonrope coiling with dynamic simulations capturing the coherent structural transitions in the turbulent release medium with the influence of salts on the swelling or erosion, energy dissipation, and subsequent melatonin release. The release was mainly governed by erosion and not affected by time-dependent diffusion resistance (Hopfenberg model; n = 0.95; R2
= 0.96; ke
= 0.11—4.69×10-3mm/min; D = 0.110—0.893 × 10 -8 cm2/s; Debrelease = 0.016—1.312). Swelling parameters confirmed that polymer swelling did not significantly influence melatonin release (δ = 0.232.00 mm, v = 0.027—0.181 cm/s, S w
= 0.010—0.542). EE values ranged between 46% and 90% and were dependant on the salt type and concentration. AlCl3 and NaCl blends increased the k values (0.0050) indicating their significance in melatonin release. The optimal scaffold (EE = 95%; MDT30 = 1; k = 0.0050) was predicted to comprise 1.1451 and 0.8264 w/v of NaCl and AlCl3, respectively, with the exclusion of CaCl2 in order to achieve zero-order kinetics over 30 days. The kinetic modeling approach enabled a qualitative and quantitative description of melatonin release patterns from the salted-out PLGA scaffolds thus facilitating the manipulation and prediction of drug release from PLGA modification by salting-out.