Background/Objectives: Pharmaceutical cocrystallization offers a promising strategy to enhance drug properties while preserving molecular integrity. Ezetimibe, a BCS Class II hypolipidemic agent, faces therapeutic limitations due to poor aqueous solubility. This study aimed to systematically evaluate cocrystallization of ezetimibe with organic acid (benzoic, tartaric, or succinic acid) at varying stoichiometric ratios (1:0.5–1:2) to optimize physicochemical properties and oral bioavailability. Methods: Cocrystals were prepared via solvent evaporation (SEV) and solvent/anti-solvent (SAS) methods. Structural characterization included Fourier-transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), and powder/single-crystal X-ray diffraction (PXRD/SCXRD). Physicochemical performance was assessed through saturation solubility, in vitro dissolution, and in vivo pharmacokinetics in male Sprague Dawley rats (n = 4/group). Results: Benzoic acid cocrystals (1:2 ratio, SEV) showed O−H⋯N hydrogen bonding (FTIR band shifts: 2928 → 3264 cm⁻¹) and novel crystalline phases (12.4°, 16.7°, and 24.9°). SCXRD confirmed monoclinic P2₁/n symmetry (a = 5.42 Å, b = 5.05 Å) for benzoic acid cocrystals. Ezetimibe/benzoic acid cocrystals (1:2) achieved 64-fold solubility enhancement and 2× faster dissolution vs. pure ezetimibe. Pharmacokinetics revealed 3× higher Cmax (18.38 ng/mL) and 4× greater AUC (40.36 h·ng/mL) for optimized cocrystals. Tartaric and succinic acid cocrystals showed moderate improvements, with melting points intermediate between parent compounds. Conclusions: Both stoichiometry and preparation method strongly determined cocrystal performance. Benzoic acid at a 1:2 ratio via SEV demonstrated superior solubility, dissolution, and bioavailability, addressing ezetimibe’s formulation challenges. These findings underscore the potential of rational cocrystal design to overcome solubility barriers in oral dosage development, particularly for hydrophobic therapeutics.

The success of mRNA-lipid nanoparticles (LNPs) vaccines during the COVID-19 pandemic has significantly increased global demand for stable, thermo-resistant biologicals. Lyophilization remains a cornerstone technology for enhancing the stability of these formulations; however, the freezing and drying processes impose major stresses that can compromise the integrity of fragile LNPs. This review systematically explores the molecular mechanisms by which lyoprotectants, including sugars, polyols, amino acids, and polymers, mitigate challenges such as ice-induced denaturation, dehydration-driven aggregation, and interfacial destabilization. This review emphasizes the importance of optimized sucrose-trehalose combinations and effective ice-nucleation control in preserving encapsulation efficiency and maintaining particle integrity. Furthermore, the review discusses advanced process optimization tools, including digital twin modeling and in-line Raman spectroscopy, which enhance lyophilization efficiency by reducing primary drying times by up to 40% while ensuring critical quality attributes are preserved. Additionally, emerging applications utilizing novel excipient combinations are highlighted, showcasing their potential to enable refrigerated storage of viral vectors. With 85% of commercial conjugates relying on lyophilization, recent advancements in continuous freeze-drying technology, such as spin-freeze approaches, have achieved cycle times that are three-fold faster. These developments provide a comprehensive roadmap for overcoming cold chain limitations while addressing the stabilization needs of next-generation biologicals, CRISPR-based systems, and personalized medicines.

Background: Arginine and related amino acids are widely used to suppress protein aggregation, thereby affecting stability, manufacturability, and therapeutic performance. However, their effectiveness remains limited, necessitating the exploration of alternative strategies. Previous studies have shown that N-acetyl-L-arginine (NA-Arg) can improve protein stability; however, the potential of other N-acetylated amino acids has not been fully explored. Methods: This study aimed to investigate the effects of multiple N-acetylated amino acids as alternative excipients on aggregation, colloidal stability, and viscosity in intravenous immunoglobulin (IVIG) formulations. Dynamic light scattering (DLS) was used to evaluate diffusion behavior and aggregation tendencies, while complementary analyses were performed using size-exclusion chromatography (SEC) and flow-imaging microscopy (FI). Results: Overall, N-acetylation of amino acids improved colloidal stability, shifting the kD values from −5.87 to 6.83 mL/g for arginine and from −8.17 to 16.22 mL/g for histidine, and increased the aggregation onset temperature (Tagg) to above 60 °C. Among the tested compounds, N-acetyl-L-histidine (NA-His) showed the most favorable results, increasing the monomer proportion by approximately 4%, reducing high-molecular-weight species to below 2%, and producing a greater than 10-fold decrease in subvisible particles relative to histidine hydrochloride after 5 days of agitation. At 50 mM, both NA-His and NA-Arg reduced the viscosity of highly concentrated 200 mg/mL IVIG formulations, with NA-His exhibiting the lowest viscosity (7.24 ± 0.12 mPa·s). Protein–protein interaction and surface charge analyses indicated improved colloidal stability relative to parent amino acids, attributable to the presence of the acetyl group. Conclusions: These findings support the potential of N-acetylation as a strategy to modulate interaction-driven instability and suggest NA-His as a promising candidate excipient for stabilizing highly concentrated therapeutic proteins at acidic pH.

Background/Objectives: This study aimed to enhance the oral delivery and therapeutic synergy of atorvastatin (AT) and docetaxel (DT) through a metronomic schedule using a transporter-targeted nanoemulsion (NE), with the goal of improving antitumor efficacy and immune modulation. Methods: AT and DT were co-encapsulated in a NE system (AT/DT-NE#E) incorporating deoxycholic acid–DOTAP (D-TAP), biotin-conjugated phospholipid (Biotin-PE), and d-α-tocopherol polyethylene glycol succinate (TPGS) to exploit bile acid and multivitamin transport pathways and inhibit P-glycoprotein efflux. The optimized NE was characterized physicochemically and evaluated for permeability in artificial membranes and Caco-2/HT29-MTX-E12 monolayers. Pharmacokinetics, tumor suppression, and immune cell infiltration were assessed in vivo using rat and CT26.CL25 mouse models. Results: AT/DT-NE#E showed enhanced permeability of AT and DT by 45.7- and 43.1-fold, respectively, across intestinal cell models and improved oral bioavailability by 118% and 376% compared to free drugs. In vivo, oral metronomic AT/DT-NE#E reduced tumor volume by 65.2%, outperforming intravenous AT/DT. Combination with anti-PD1 therapy achieved a 942% increase in tumor suppression over the control, accompanied by marked increases in tumor-infiltrating CD45⁺, CD4⁺CD3⁺, and CD8⁺CD3⁺ T cells. Conclusions: Oral metronomic administration of AT/DT via a dual-transporter-targeted NE significantly improves drug absorption, tumor inhibition, and immune response. This strategy presents a safe and effective approach for colon cancer therapy, particularly when combined with immunotherapy.