This review systematically examines the pivotal applications of the Density Functional Theory (DFT) in drug formulation design, emphasizing its capability to elucidate molecular interaction mechanisms through quantum mechanical calculations. By solving the Kohn–Sham equations with precision up to 0.1 kcal/mol, DFT enables accurate electronic structure reconstruction, providing theoretical guidance for optimizing drug–excipient composite systems. In solid dosage forms, DFT clarifies the electronic driving forces governing active pharmaceutical ingredient (API)–excipient co-crystallization, predicting reactive sites and guiding stability-oriented co-crystal design. For nanodelivery systems, DFT optimizes carrier surface charge distribution through van der Waals interactions and π-π stacking energy calculations, thereby enhancing targeting efficiency. Furthermore, DFT combined with solvation models (e.g., COSMO) quantitatively evaluates polar environmental effects on drug release kinetics, delivering critical thermodynamic parameters (e.g., ΔG) for controlled-release formulation development. Notably, DFT-driven co-crystal thermodynamic analysis and pH-responsive release mechanism modeling substantially reduce experimental validation cycles. While DFT faces challenges in dynamic simulations of complex solvent environments, its integration with molecular mechanics and multiscale frameworks has achieved computational breakthroughs. This work offers interdisciplinary methodology support for accelerating data-driven formulation design.

The encapsulation of sodium sulfobutylether-β-cyclodextrin (SBE-β-CD) is influenced not only by the degree of substitution (DS) but also by the presence of strong-bonded water (SBW). Guests compete with SBW for positions within the cavity of SBE-β-CD. However, the correlation between DS and SBW was not clear. This study revealed a positive correlation between DS and SBW utilizing Karl Fischer titration. The mechanism may be attributed to molecular polarizability. To explore the impact of SBW inside SBE-β-CD with different DS on encapsulation, density functional theory was employed. Throughout the release process, an increase in enthalpy is unfavorable, while an increase in entropy favors spontaneous reaction occurrence. For SBE-β-CD (DS = 2, 3), enthalpy increase is the primary factor, leading to the retention of SBW within the cavities and consequently hindering guest entry. In contrast, for SBE-β-CD (DS = 4, 7), the situation differs. For SBE₁₀-β-CD, the influence of SBW is minimal. This study aims to elucidate the relationship between DS and SBW, as well as the effect of SBW inside SBE-β-CD with different DS on encapsulation. It is crucial for a comprehensive understanding of the factors affecting the encapsulation of SBE-β-CD, thereby promoting quality control and functional development of SBE-β-CD.

Background/Objectives: Polysorbate 80 (PS80), a complex surfactant mixture, is widely recognized for its ability to enhance drug permeation across the blood–brain barrier (BBB). While this effect is generally attributed to the combined actions of its components, the specific contribution and potential selectivity of individual minor components remain poorly understood. This study therefore aimed to isolate and compare the primary minor components of PS80 to determine whether they uniformly enhance BBB permeation or exhibit drug-specific functions. Methods: In this research, four primary minor components of PS80—polyoxyethylene sorbitan monooleate (PSM), polyoxyethylene isosorbide monooleate (PIM), polyoxyethylene sorbitan dioleate (PSD), and a polyethylene glycol/polyoxyethylene sorbitan/polyoxyethylene isosorbide mixture (PEG/PS/PI mixture)—were isolated using preparative liquid-phase chromatography. Drug-loaded formulations were then prepared using the solvent evaporation method incorporating five model drugs: 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindotricarbocyanine iodide (DiR, MW = 1013.39 Da), donepezil (MW = 379.49 Da), nimodipine (MW = 418.44 Da), chlorogenic acid (MW = 354.31 Da), and paclitaxel (MW = 853.92 Da). The permeability of these formulations across the BBB was evaluated in BALB/c mice after intravenous administration. Brain distribution of the lipophilic dye DiR was assessed using fluorescence imaging, whereas brain homogenate concentrations of therapeutic drugs were quantified by UPLC-MS/MS. Results: Results revealed that the enhancement of brain delivery was dependent on both the specific minor component and the drug. The PEG/PS/PI mixture specially enhanced the brain homogenate concentration of donepezil to 11.8 ± 1.2 ng/mL, representing a 6.9-fold enhancement, while PIM micelles increased the delivery of DiR, donepezil, and nimodipine. In contrast, PSM and PSD micelles improved transport of only DiR and donepezil. The broad performance of PIM suggests a more flexible formulation—a hypothesis that warrants further validation. Conversely, none of the different minor components enhanced the delivery of chlorogenic acid or paclitaxel, underscoring the critical role of specific drug–component interactions. Conclusions: This component-resolved insight challenges the conventional perception of PS80 and provides a rational framework for engineering precision brain-targeted delivery systems by selecting functional minor components.

With the increasing prevalence of dry eye syndrome and an aging population, multidose eye drops have become predominant in the market due to their convenience. However, the stability of the antimicrobial efficacy is crucial for patient safety, with the interaction between preservatives and packaging materials being particularly significant. This study systematically examined the effects of packaging material type, pH value, preservative type, and formulation components on the adsorption behavior using single-factor experiments, orthogonal design, X-ray photoelectron spectroscopy (XPS) analysis, and quantum mechanical calculations. The research showed that chlorobutanol exhibited the most significant adsorption (12.5% originates from single-factor analysis), and the degree of adsorption was closely related to the solution environment and the surface chemical properties of the materials. Orthogonal experiments indicated that the type of packaging material and the type of active pharmaceutical ingredient were the primary factors influencing preservative adsorption; the type of pH-adjusting agent had no significant effect on preservative adsorption; however, the solution pH acted synergistically with the preservative to influence its adsorption. XPS analysis revealed a synergistic effect between physical and chemical adsorption, while quantum mechanical calculations further demonstrated that the HOMO energy value (with more negative values indicating stronger adsorption) played a key role in determining the adsorption strength. This study provides a scientific basis for the formulation design and packaging material selection of eye drops, helping to enhance product safety and efficacy.

Background/Objectives: Intrathecal drug delivery is essential for treating CNS disorders, but the safety of commonly used excipients such as citric acid/sodium citrate (SC) remains unclear. This study aims to systematically evaluate the potential neuropharmacological effects of repeated intrathecal SC administration. Methods: Multimodal approaches were applied across murine and lagomorph models. Doses ranged from 1.833–14.664 μg/g in mice and 0.104–3.290 mg/rabbit. Behavioral, neurophysiological, and fiber photometry analyses were conducted to assess sensorimotor function, cortical activity, and calcium dynamics. Results: SC induced dose-dependent sensorimotor deficits, including hypolocomotion (45.7% reduced distance, p < 0.001) and impaired coordination (latency reduction 48.3–64.1%, p < 0.001). Mortality increased with dosage and repeated exposure. Neurophysiological data revealed biphasic cortical modulation: acute c-Fos suppression followed by delayed hyperactivity. Fiber photometry confirmed calcium chelation-mediated attenuation and subsequent potentiation of Ca²⁺ signals. Rabbits exhibited similar neurological symptoms, correlating with transient CSF calcium/magnesium depletion, though no structural neural damage was observed. Conclusions: These results provide the first comprehensive evidence that SC buffers can significantly disrupt neuronal calcium homeostasis and induce functional impairments upon intrathecal delivery. The findings emphasize the need for reassessing excipient safety in CNS-targeted formulations.

Objective: To design and implement a proficiency testing (PT) scheme for evaluating the competence of inspection agencies in measuring temperature and relative humidity (RH) in clean environments. The study assesses laboratories’ mastery of testing standards and their operational proficiency with thermohygrometers. Methods: The PT combined a written examination (evaluating theoretical knowledge of standards) and a field assessment (assessing instrument operation and field testing accuracy). Homogeneity of temperature and RH samples was verified using relative standard deviation (RSD). Participant performance was scored using weighted criteria: the written examination (40 points) and field test (z-score evaluation, 60 points). Results: Sample homogeneity met PT requirements. All 54 participating laboratories achieved satisfactory results (100% satisfaction rate). Field test z-scores indicated high consistency: 98.1% of temperature results (|z|≤ 2) and 94.4% of RH results (|z|≤ 2) fell within satisfactory ranges. Conclusion: Laboratories demonstrated robust testing capabilities, though improvements are recommended in standard interpretation and instrument calibration practices. This PT framework establishes a novel quality assessment method for pharmaceutical clean environments and serves as a reference for similar evaluations.