The evolving emphasis on clinical humanistic care has positioned pain management as a critical component of modern healthcare, with pain now recognized as the “fifth vital sign” in clinical practice (Swarm et al., 2019, Paice et al., 2023). This paradigm shift is particularly relevant in oncology and postoperative care, where inadequately managed pain adversely impacts patient quality of life and impedes postoperative recovery (Coveler et al., 2021, Treede et al., 2019, Zheng et al., 2021). Conventional opioid analgesics, while widely employed for such conditions, are associated with dose-limiting adverse effects including respiratory depression, tolerance, and dependence (Azzam et al., 2019, Bicket et al., 2017, Armenian et al., 2018, Kiyatkin, 2019). Dezocine (Dez), a mixed κ-opioid receptor agonist/μ-opioid receptor partial agonist with dual norepinephrine-serotonin reuptake inhibition properties, has emerged as a promising alternative (Ye et al., 2022, Wu et al., 2019, Wang et al., 2018). Its broad-spectrum analgesic efficacy, reduced adverse effect profile, and absence of typical opioid-induced respiratory depression distinguish it from traditional opioids (Liu et al., 2014, Liu et al., 2018, Yu et al., 2015). Nevertheless, the clinical utility of conventional Dez injections is constrained by pharmacokinetic limitations, including frequent dosing requirements, suboptimal patient compliance, and pronounced plasma concentration fluctuations (peak-valley phenomena) (Zhou et al., 2017, Wang et al., 2017).

Polymeric microspheres, as advanced extended-release drug delivery systems, offer a strategic solution to these challenges by enabling sustained drug release, minimizing dosing frequency, stabilizing therapeutic plasma levels, and mitigating toxicity (Su et al., 2021, Vlachopoulos et al., 2022, Wan et al., 2023, Lagreca et al., 2020). However, the development of Dez-loaded microspheres (Dez-Ms) remains technically demanding. Existing methodologies report suboptimal performance: Wang et al. achieved encapsulation efficiencies (EE) below 70 % (Wang et al., 2019), while Ma et al. obtained higher EE at the expense of excessive polymer carrier use, resulting in clinically impractical drug loading (DL) capacities (Ma et al., 2018). Our preliminary investigations further identified a critical formulation challenge termed the “quick sand” phenomenon, characterized by precipitated drug crystals failing to coalesce into spherical matrices. Mechanistic analysis revealed that conventional emulsion-based methods produce polydisperse oil-in-water (O/W) emulsions. Under identical solvent evaporation conditions, smaller emulsion droplets undergo rapid solvent depletion, promoting premature drug diffusion into the aqueous phase and subsequent particle aggregation. This size-dependent heterogeneity fundamentally limits microsphere uniformity and drug retention.

Microreactor technology presents a paradigm-shifting approach to address these limitations. By utilizing precision-engineered microfluidic channels (10–100 μm scale) for laminar flow manipulation (Ran et al., 2023, Tian et al., 2023, Morimoto et al., 2015), this platform enables monodisperse emulsion generation with superior batch-to-batch consistency compared to conventional stirred-tank systems (Zhao et al., 2021, Ahmed et al., 2022, Du et al., 2024). The integration of microreactors in microsphere fabrication allows precise control over solvent evaporation kinetics across uniformly sized emulsion droplets, thereby minimizing the “quick sand” phenomenon while enhancing DL and EE.

This study aimed to (1) develop a microreactor-based platform to overcome the “quick sand” limitation in Dez-Ms production; (2) systematically optimize formulation parameters (polymer-drug ratio, emulsifier concentration, solvent evaporation rate) through single-factor screening and orthogonal array design (L9(33)); (3) characterize critical quality attributes including particle size distribution, DL/EE, and morphology; (4) evaluate solid-state interactions; (5) establish pharmacokinetic profiles in Sprague-Dawley rats and develop an in vitro and in vivo correlation (IVIVC) model; and (6) validate sustained analgesic efficacy in murine models.