Engineering long-acting injectable in situ forming implants for sustained delivery of citalopram in depression...

Long-acting injectable formulations have emerged as promising systems for managing chronic psychiatric conditions by reducing dosing frequency and improving patient adherence. Oral antidepressants such as citalopram hydrobromide require daily administration, posing a significant risk of non-compliance in patients with Major Depressive Disorder (MDD). This study aimed to develop and characterize a poly (lactic-co-glycolic acid) (PLGA)-based in situ forming implant (ISFI) for the sustained parenteral delivery of citalopram hydrobromide over 10 days. Systematic formulation screening across polymers, solvents, and lipid excipients identified the optimized formulation (F4) composition, which was evaluated for viscosity, syringeability, in vitro drug release, ex vivo depot formation, release kinetics, cytotoxicity, and in vivo pharmacokinetic prediction. The optimized formulation exhibited Newtonian flow behavior (viscosity 0.35 Pa.s) with a maximum expulsion force of 16.49 N through a 20G needle, confirming adequate injectability. The in vitro release profile demonstrated a moderate initial burst of ~ 13% within 24 h, followed by near-linear sustained release reaching ~ 87% by Day 10. The Korsmeyer-Peppas model provided the best fit (R² = 0.99, n = 0.865), confirming Super case II and non-Fickian diffusion-erosion transport. A strong in vitro-ex vivo correlation (R² = 0.9259) validated the release model. Cytotoxicity assessment confirmed biocompatibility with an IC₅₀ of 34.92 ± 2.28 µg/mL, representing a 300-fold safety margin above therapeutic plasma concentrations. Convolution-based pharmacokinetic prediction demonstrated sustained systemic exposure over 10 days from a single intramuscular injection. This study demonstrates the feasibility of a PLGA-based long-acting injectable platform for sustained citalopram delivery, supporting its potential utility in the management of Major Depressive Disorder.