Phase-Inversion In Situ Implants for Dental Drug Delivery: A QbD-Guided In Vitro Technological Evaluation.

Phase-inversion in situ implants (PIISIs) represent a versatile polymer platform in which the rational choice of matrix former and solvent system directly governs the macroscopic properties of the resulting depot. This study applied a Quality by Design (QbD) approach to rationalize a bleached shellac-based PIISI, with particular focus on the physicochemical interactions between the polymer and the injection vehicle. Bleached shellac-a natural, low-cost, biodegradable oligomeric resin bearing -COOH, -OH, and ester functional groups-was selected as the matrix former and screened in seven neat solvents and five 1:1 binary combinations at 25% (m/m). Twelve formulations were evaluated against a predefined set of critical quality attributes, including injectability, phase-inversion kinetics, solvent diffusion volume, and implant structure (n = 5 per formulation; mean ± standard deviation (SD); one-way analysis of variance (ANOVA) with Tukey's post hoc test, p < 0.05). Three lead solvent systems-propylene glycol/N-methylpyrrolidone (PG+NMP), PG/dimethyl sulfoxide (PG+DMSO), and DMSO/benzyl alcohol (DMSO+BA)-were identified as those providing an optimal balance between hydrogen-bond donor/acceptor solvation and controlled solvent extraction. In the second stage, shellac concentration (20-35%) was optimized, with 30% shellac in PG+NMP yielding the fastest phase inversion (~50 s), a structurally uniform matrix, and the lowest swelling (22%). A working mechanistic framework consistent with all observed critical quality attribute (CQA) trends in which solvent hydrogen-bond donor/acceptor balance and water miscibility govern implant architecture is proposed, and it is intended as a hypothesis-generating basis for the rational design of PIISI formulations; direct validation by spectroscopic, thermal-analytical, and biological methods is identified as the next step. The developed formulations are presented as a preliminary physicochemical platform; biological validation (in vitro cytocompatibility and inflammatory response assessment) is required before the system can be considered a validated formulation for dental drug delivery.