Search Results (455)

Background/Objectives: Holy basil (Ocimum tenuiflorum L.) essential oil exhibits antioxidant, antimicrobial, and anesthetic activities, mainly due to eugenol, methyl eugenol, and β-caryophyllene. However, its clinical application is limited by poor water solubility, instability, and low bioavailability. This study developed and compared two delivery systems, self-nanoemulsifying drug delivery systems (SNEDDS) and microemulsions (ME), to enhance their stability and fish anesthetic efficacy. Methods: The optimized SNEDDS (25% basil oil, 8.33% coconut oil, 54.76% Tween 80, 11.91% PEG 400) and ME (12% basil oil, 32% Tween 80, 4% sorbitol, 12% ethanol, 40% water) were characterized for droplet size, PDI, zeta potential, pH, and viscosity. Stability was evaluated by monitoring droplet size and PDI over time and by determining the retention of eugenol, methyl eugenol, and β-caryophyllene after storage at 45 °C. Fish anesthetic efficacy was tested in koi carp (Cyprinus carpio var. koi). Results: SNEDDS maintained a small droplet size (~22.78 ± 1.99 nm) and low PDI (0.188 ± 0.088 at day 60), while ME showed significant size enlargement (up to 177.10 ± 47.50 nm) and high PDI (>0.5). After 90 days at 45 °C, SNEDDS retained 94.45% eugenol, 94.08% methyl eugenol, and 88.55% β-caryophyllene, while ME preserved 104.76%, 103.53%, and 94.47%, respectively. In vivo testing showed that SNEDDS achieved faster anesthesia (114.70 ± 24.80 s at 120 ppm) and shorter recovery (379.60 ± 15.61 s) than ME (134.90 ± 4.70 s; 473.80 ± 16.94 s). Ethanol failed to induce anesthesia at 40 ppm and performed poorly compared to SNEDDS and ME at other concentrations (p < 0.0001). Conclusions: SNEDDS demonstrated superior physical stability and fish anesthetic performance compared to ME. These findings support SNEDDS as a promising formulation for delivering holy basil essential oil in biomedical and aquaculture applications. Full article

Background/Objectives: The major limitations of self-nanoemulsifying systems include complex processing and expensive instrumentation required for solidification approaches. In this study, smart poloxamer-based solidification strategies were used to develop and optimize febuxostat-loaded formulations. Methods: A self-nanoemulsifying drug delivery system (SNEDDS) component was selected based on solubility and emulsification tests. The influence of poloxamer molecular weight (low or high) and its concentration (2–10% w/w) on formulation performance was assessed through the design of experiments. Finally, in-vitro melting assessment and a comparative dissolution test were performed on the optimized SNEDDS formulation. Results: Imwitor 988 and Tween 20 were selected to prepare the formulations. Increasing the molecular weight and concentration of the poloxamer significantly increased the temperature and time required for the melting of the SNEDDS formulation. The optimized SNEDDS formulation comprised 3.98% w/w poloxamer 188, which melts at 36 °C within 111 s. In-vitro melting showed that the formulation completely converted to a liquid state upon exposure to body temperature. Finally, the optimized SNEDDS formulation exhibited superior dissolution efficiency (96.66 ± 0.28%) compared to raw febuxostat (72.09 ± 4.33%) and marketed tablets (82.23 ± 3.10%). Conclusions: The poloxamer-based approach successfully addressed the limitations associated with conventional solidification while maintaining superior dissolution performance. Therefore, it emerges as a promising alternative approach for enhancing the bioavailability of poorly water-soluble drugs. Full article

The number of newly developed substances with poor water solubility continually increases. Therefore, specialized formulation strategies are required to overcome the low bioavailability often associated with this property. This review provides an overview of novel physical modification strategies discussed in the literature over the past decades and focuses on oral dosage forms. A distinction is made between ‘brick-dust’ molecules, which are characterized by high melting points due to the solid-state properties of the substances, and ‘grease-ball’ molecules with high lipophilicity. In general, the discussed strategies are divided into the following three main categories: drug nanoparticles, solid dispersions, and lipid-based formulations. Full article

The advancement of efficient drug delivery systems continues to pose a significant problem in pharmaceutical sciences, especially for compounds with limited water solubility. Lipid-based systems, including solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs), have emerged as viable options owing to their biocompatibility, capability to safeguard labile chemicals, and potential for prolonged release. Nonetheless, the encapsulation efficiency (EE) and release dynamics of these carriers can be enhanced by including cyclodextrins (CDs)—cyclic oligosaccharides recognized for their ability to form inclusion complexes with hydrophobic compounds. This article offers an extensive analysis of CD-modified SLNs and NLCs as multifunctional drug delivery systems. The article analyses the fundamental principles of these systems, highlighting the pre-complexation of the drug with cyclodextrins before lipid incorporation, co-encapsulation techniques, and surface adsorption after formulation. Attention is concentrated on the physicochemical interactions between cyclodextrins and lipid matrices, which influence essential factors such as particle size, encapsulation efficiency, and colloidal stability. The review includes characterization techniques, such as particle size analysis, zeta potential measurement, drug release studies, and Fourier-transform infrared spectroscopy (FT-IR)/Nuclear Magnetic Resonance (NMR) analyses. The study highlights the application of these systems across many routes of administration, including oral, topical, and mucosal, illustrating their adaptability and potential for targeted delivery. The review outlines current formulation challenges, including stability issues, drug leakage, and scalability concerns, and proposes solutions through advanced approaches, such as stimuli-responsive release mechanisms and computer modeling for system optimization. The study emphasizes the importance of regulatory aspects and outlines future directions in the development of CD-lipid hybrid nanocarriers, showcasing its potential to revolutionize the delivery of poorly soluble drugs. Full article

Background: The solubility and phase behavior of APIs are crucial for the development of medicines and ensuring their stability. However, conventional experimental approaches often do not allow for the precise determination of phase transitions and solubility limits, especially for poorly soluble compounds. Purpose: The aim of this study was to demonstrate the possibility of using the laser microinterferometry method, traditionally used to define the phase equilibria of polymer systems, to determine the thermodynamic solubility of the APIs. Methods: Using laser microinterferometry, the thermodynamic solubility and phase behavior of amorphous darunavir were determined in various pharmaceutical solvents, including vaseline and olive oils, water, glycerol, alcohols (methanol, ethanol, isopropanol), glycols (propylene glycol, polyethylene glycol 400, polypropylene glycol 425, polyethylene glycol 4000), and ethoxylated polyethylene glycol ether obtained from castor oil in the temperature range of 25–130 °C. Dissolution kinetics was estimated at 25 °C. Hansen solubility parameter calculations were also performed for comparison. Results: Darunavir is practically insoluble in olive and vaseline oils. In water and glycerol, an amorphous equilibrium with an upper critical solution temperature was observed, and phase diagrams were constructed for the first time. In alcohols, glycols, and ethoxylated polyethylene glycol ether obtained from castor oil, darunavir showed high solubility, accompanied by the formation of crystalline solvates. Kinetic evaluation showed that the dissolution rate of darunavir in methanol is four times faster than in ethanol and thirty times faster than in isopropanol. Comparison of the obtained data with previously published and calculated values of solubility parameters demonstrates a good correlation. Conclusions: Laser microinterferometry has been demonstrated as a potential tool for determining the thermodynamic solubility of APIs. This method allows for directly observing the dissolution process, determining the solubility limits, and detecting phase transitions. These studies are necessary for selecting appropriate excipients, preventing the formation of undesirable solvates and predicting formulation stability, which are all critical factors in early-stage drug development and pharmaceutical formulation design. Full article

The incorporation of solid particles as a filler to a hydrogel is a strategy to modulate its properties for specific applications, or even to introduce new functionalities to the hydrogel itself. The efficacy of such a modification depends on the filler content and its interaction with the hydrogel matrix. In drug delivery applications, solid particles can be added to hydrogels to improve drug loading capacity, enable the inclusion of poorly soluble drugs, and modulate release kinetics. This work focuses on the case of alginate (ALG)-based hydrogels, obtained following an internal gelation procedure using CaCO₃ as the Ca²⁺ source and containing a high solid volume fraction (up to 50%) of metronidazole (MTZ), a drug with low water solubility, as a potential extrusion-based drug delivery system. The impact of the hydrogel precursor composition (ALG and MTZ content) on the rheological behavior of the filled hydrogel and precursor suspension were investigated, as well as the hydrogel stability and MTZ dissolution. In the absence of solid MTZ, the precursor solutions showed a slightly shear thinning behavior, more accentuated with the increase in ALG concentration. The addition of drugs exceeding the saturation concentration in the precursor suspension resulted in a substantial increase (about one order of magnitude) in the low-shear viscosity and, for the highest MTZ loadings, a yield stress. Despite the significant changes, precursor formulations retained their extrudability, as confirmed by both numerical estimates and experimental validation. MTZ particles did not affect the crosslinking of the precursors to form the hydrogel, but they did control its viscoelastic behavior. In unfilled hydrogels, the ALG concentration controls stability (from 70 h for the lowest concentration to 650 h for the highest) upon immersion in acetate buffer at pH 4.5, determining the MTZ release/hydrogel dissolution behavior. The correlations between composition and material properties offer a basis for building predictive models for fine-tuning their composition of highly filled hydrogel systems. Full article

Background/Objectives: Increasing the solid-state landscape of an active pharmaceutical ingredient (API) by generating new crystalline forms (e.g., polymorphs, cyclodextrin (CD) inclusion complexes, co-crystals, and salts) can yield products with significantly enhanced biopharmaceutical properties (especially increased water solubility), thereby improving API delivery and extending its lifetime. The aim of this study was the isolation of new solid forms of the poorly water-soluble non-steroidal anti-inflammatory drug fenbufen (FBF), for which relatively few solid phases have been reported to date. Further motivation for the study is the recent finding that it has potential for repurposing to treat acute pancreatitis. Methods: Interventions for generating new solid forms of FBF included (a) polymorph screening with a variety of solvent media, (b) attempts to form solid inclusion complexes with the native cyclodextrins α-, β-, and γ-CD using various preparative methods, and (c) co-crystallization with a series of coformers to produce co-crystals and/or molecular salts. Results: No new polymorphic forms of FBF were identified, but screening with CDs resulted in isolation and characterization of a new solid inclusion complex with γ-CD. However, co-crystallization of FBF with the water-soluble coformer isonicotinamide yielded two new products, namely a 1:1 co-crystal and an unusual multi-component ionic co-crystal, whose aqueous solubility indicated significant enhancement of FBF solubility. Conclusions: Due to its extremely low water solubility, FBF presented challenges during the study aimed at modifying its crystalline form. However, two new supramolecular forms, a co-crystal and an ionic co-crystal, were isolated, the latter phase having potential for further formulation owing to its significantly enhanced solubility. Full article

Background: Self-emulsifying drug delivery system (SEDDS) is widely used to improve the oral bioavailability of hydrophobic drugs. Emulsion droplet size was revealed to be a critical parameter that influences the thermodynamic stability, drug solubility, and drug absorption of the SEDDS. A high proportion of surfactant and/or co-surfactant was usually employed to reduce the particle size, which may lead the low drug loading and undesirable gastrointestinal toxicity. Methods: This manuscript proposed a novel strategy to reduce the particle size of emulsions using the hybrid of medium and long-chain triglyceride (MCT and LCT) SEDDS without promoting the concentration of surfactants and co-surfactants. The composition of SEDDS was selected based on the drug solubility. Particle size distribution and zeta potential of emulsion particles were determined using the dynamic light scattering technique. The bioavailability of formulations was evaluated in a mouse model. Results: The particle size of the emulsion was reduced from 113.50 ± 0.34 nm (MCT SEDDS) and 371.60 ± 6.90 nm (LCT SEDDS) to 21.23 ± 0.30 nm (MCT&LCT SEDDS). Progesterone, a poorly water-soluble drug, was selected as the model drug in the investigation of SEDDS. The hybrid of MCT&LCT progesterone SEDDS exhibited reduced particle size, enlarged self-emulsifying ranges, and increased drug content in the aqueous phase after lipolysis compared with the conventional mono-MCT or LCT SEDDS. In addition, the bioavailability of progesterone in the MCT&LCT SEDDS formulation was 3.82-fold higher than that of Utrogestan^® (a clinical oral administrated product) in a mouse model. Full article

This study presents a methodology for developing a cyclodextrin-based delivery system for ceftobiprole, a poorly water-soluble and amphoteric drug, chemically stable in acidic conditions. Ceftobiprole is a broad-spectrum cephalosporin antibiotic administered clinically as its water-soluble prodrug, ceftobiprole medocaril, due to limited aqueous solubility of the parent compound. Solubility enhancement was achieved through complexation with anionic sulfobutylether-β-cyclodextrin (SBE-β-CD). At a pH below 3, ceftobiprole is protonated and cationic, which facilitates electrostatic interactions with the anionic cyclodextrin. An optimised high-performance liquid chromatography (HPLC) method was used to assess solubility, the impurity profile, and long-term chemical stability. X-ray powder diffraction (XRPD) confirmed the amorphous nature of the system and the absence of recrystallization. Nuclear magnetic resonance (NMR) and attenuated total reflection Fourier transform infrared (ATR-FTIR) spectroscopy supported the formation of a host–guest complex. The freeze-dried system prepared from 0.1 M formic acid solution contained negligible residual acid due to nearly complete sublimation. The most promising formulation was a ternary system of ceftobiprole, maleic acid, and SBE-β-CD (1:25:4 molar ratio), showing ~300-fold solubility improvement, low levels of degradation products, and stability after eight months at −20 °C. After pH adjustment to a parenterally acceptable level, the formulation demonstrated solubility and a pH comparable to the marketed drug product. Full article

Background/Objectives: Lipid-based formulations (LBFs) are enabling formulations for poorly water-soluble, mostly lipophilic drugs. In LBFs, the drug is pre-dissolved in the formulation which can consist of lipids, surfactants, and/or cosolvents. In cases where the administration of high amounts of a drug is required, exceeding the drug solubility in the lipidic vehicle at the administration temperature, supersaturated LBFs are an option. The standard method described in the literature for inducing supersaturation in LBFs is to dissolve the drug substance in the lipidic vehicle at an elevated temperature, e.g., at 60 °C, and then subsequently let the formulation cool to ambient temperature before administration (heat-based approach). In this work, an alternative approach to induce supersaturation in LBFs was investigated in order to evaluate if higher drug loads, i.e., the concentration of drug dissolved in the vehicle, could be reached compared to the loading obtainable via heating. Methods: A volatile solvent that is miscible with the lipid matrix and in which the compound has a high solubility is added to the lipid matrix, after which the solvent is evaporated. Both approaches were compared in this work investigating two different LBFs loaded with the BCS-class II drugs celecoxib and fenofibrate. Results: When inducing supersaturation by heat, drug loads of 238% for celecoxib and 278% for fenofibrate could be achieved relative to the solubility at ambient temperature. Using the solvent-based approach, drug loads of up to 475% for celecoxib and 557% for fenofibrate could be prepared in the LBFs using dichloromethane (DCM) as the volatile solvent. However, those highly supersaturated preparations showed suboptimal physical stability and quickly led to precipitation when the LBFs were stored at ambient temperature. In addition, selected formulations were analyzed with GC-headspace to determine the residual DCM after solvent evaporation using a vacuum evaporator. This analysis revealed that the DCM content exceeded regulatory requirements, with up to 21,883 ppm DCM in the formulations. Conclusions: Overall, the relatively high residual DCM concentration and the suboptimal physical stability do not make the approach easily usable for generating supersaturated lipid-based formulations. Full article

Background/Objectives: The Self-Nanoemulsifying Drug Delivery System (SNEDDS) has been widely applied in oral drug delivery, particularly for poorly water-soluble compounds. The successful development of SNEDDS largely depends on the precise composition of its components. This narrative review provides an in-depth analysis of Quality by Design (QbD), Design of Experiment (DoE), and in silico approach applications in SNEDDS development. Methods: The review is based on publications from 2020 to 2025, sourced from reputable scientific databases (Pubmed, Science direct, Taylor and francis, and Scopus). Results: Quality by Design (QbD) is a systematic and scientific approach that enhances product quality while ensuring the robustness and reproducibility of SNEDDS, as outlined in the Quality Target Product Profile (QTPP). DoE was integrated into the QbD framework to systematically evaluate the effects of predefined factors, particularly Critical Material Attributes (CMAs) and Critical Process Parameters (CPP_S), on the desired responses (Critical Quality Attributes/CQA), ultimately leading to the identification of the optimal SNEDDS formulation. Various DoEs, including the mixture design, response surface methodology, and factorial design, have been widely applied to SNEDDS formulations. The experimental design facilitates the analysis of the relationship between CQA and CMA/CPP, enabling the identification of optimized formulations with enhanced biopharmaceutical, pharmacokinetic, and pharmacodynamic profiles. As an essential addition to this review, in silico approach emerges as a valuable tool in the development of SNEDDS, offering deep insights into self-assembly dynamics, molecular interactions, and emulsification behaviour. By integrating molecular simulations with machine learning, this approach enables rational and efficient optimization. Conclusions: The integration of QbD, DoE, and in silico approaches holds significant potential in the development of SNEDDS. These strategies enable a more efficient, rational, and predictive formulation process. Full article

Amorphous solid dispersion (ASD) technology is popularly used for enhancing the solubility of poorly water-soluble drugs. Drug molecules in ASDs can be dispersed in the form of either amorphous (AASD) or molecular (MASD) forms. The boundary between AASDs and MASDs (A–M boundary) is defined as the drug concentration at which the existence of MASDs obviously influences the physicochemical properties of ASDs. In this work, fluorescence spectroscopy based on the aggregation-caused quenching (ACQ) phenomenon was used to determine the A–M boundary of curcumin (CUR) ASDs prepared via neat ball milling. The relationship between the fluorescence intensity and the loading of CUR in the sample is consistent with the Stern–Volmer equation. For the CUR ASDs with PVP, the samples with CUR loading below 10% show significantly increased fluorescence and have a higher solubility (~178 μg·mL⁻¹), suggesting the A–M boundary is around 10%. Similar A–M boundaries around 10% were also observed for CUR ASDs with PVPVA, Soluplus, HPMC, and HPMCAS. It is of great significance to define the A–M boundary of ASDs for guiding pharmaceutical ASD formulas by balancing drug loading, stability, and solubility. Full article

Vitamin B12 (B12), a crucial water-soluble vitamin, plays an essential role in various cellular functions, including DNA synthesis and cellular metabolism. This review explores recent advancements in B12 delivery systems and their potential applications in drug delivery. The unique absorption pathways of B12, which involve specific binding proteins and receptors, are highlighted, emphasizing the vitamin’s protective mechanisms that enhance its bioavailability. The review discusses the intricate multi-protein network involved in B12 metabolism and the implications of B12 deficiency, which can lead to significant health issues, including neurological and hematological disorders. Additionally, the potential of B12 as a drug carrier to improve the pharmacokinetic properties of poorly bioavailable medications is examined. The findings suggest that optimizing B12 delivery could enhance therapeutic outcomes in nanomedicine and other clinical applications. Full article

Background/Objectives: Difenoconazole (DFC) is a broad-spectrum fungicide. However, its application is limited due to poor aqueous solubility. Drugs with low solubility can be better absorbed using nanostructured lipid carriers (NLCs). Hence, the application of DFC in an NLC delivery system is proposed. Methods: Difenoconazole-loaded nanostructured lipid carriers (DFC-NLCs) with different solid–liquid lipid ratios were prepared by solvent diffusion method. Key physicochemical parameters, including particle diameter, surface charge (zeta potential), drug encapsulation efficiency, and morphological characteristics, were systematically characterized. Using Rhizoctonia solani (R. solani) as the model strain, inhibitory efficiency of DFC-NLC dispersion was compared with that of commercial dosage forms, such as 25% DFC emulsifiable concentrate (DFC-EC) and 40% DFC suspension concentrate (DFC-SC). Additionally, uptakes of DFC-NLC dispersions in R. solani were further observed by fluorescence probe technology. The safety profiles of DFC-NLCs and commercial dosage forms were evaluated using zebrafish as the model organism. Acute toxicity studies were conducted to determine the maximum non-lethal concentration (MNLC) and 10% lethal concentration (LC₁₀). Developmental toxicity studies were performed to observe toxic phenotypes. Results: DFC-NLC dispersions were in the nanometer range (≈200 nm) with high zeta potential, spherical in shape with encapsulation efficiency 69.1 ± 1.8%~95.0 ± 2.6%, and drug loading 7.1 ± 0.3%~9.7 ± 0.6% determined by high-performance liquid chromatography coupled with tandem mass spectrometry (HPLC-MS/MS). Compared with commercial dosage forms, the antifungal effect of the DFC-NLC on R. solani was significantly improved in in vitro antibacterial experiments (p < 0.05). The 50% effective concentration (EC₅₀) values were 0.107 mg·L⁻¹ (DFC-NLC), 0.211 mg·L⁻¹ (DFC-EC), and 0.321 mg·L⁻¹ (DFC-SC), respectively. The uptakes of FITC-labeled DFC-NLC demonstrated that an NLC was appropriate to deliver DFC into pathogen to enhance the target effect. In safety assessment studies, DFC-NLCs exhibited a superior safety profile compared with commercial formulations (p < 0.05). Conclusions: This study investigates the feasibility of NLCs as delivery systems for poorly water-soluble fungicides, demonstrating their ability to enhance antifungal efficacy and reduce environmental risks. Full article

Cyclodextrins (CDs) enhance the solubility of poorly water-soluble drugs like ibuprofen (IBU), making them promising carriers for pulmonary drug delivery. This route lowers the required dose, minimizing side effects, which could be beneficial in treating cystic fibrosis. In this study, a nano-spray-drying technique was applied to prepare CD/IBU complexes using sulfobutylether-β-cyclodextrin (SBECD) or (2-Hydroxy-3-N,N,N-trimethylamino)propyl-beta-cyclodextrin chloride (QABCD) as carriers as well as mannitol (MAN) and leucine (LEU) as aerosolization excipients. Various investigation techniques were utilized to examine and characterize the samples, including a Master Sizer particle size analyzer, scanning electron microscopy (SEM), X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), and Fourier-transform infrared spectroscopy (FT-IR). We applied in vitro Andersen Cascade Impactor measurements and in silico simulation analysis to determine the sample’s aerodynamic properties. We also performed in vitro dissolution and diffusion tests. Applying formulations with optimal aerodynamic properties, we achieved an improved ~50% fine particle fraction values based on the Andersen Cascade Impactor measurements. The in vitro dissolution and diffusion studies revealed rapid IBU release from the formulations; however, the QABCD-based sample exhibited reduced membrane diffusion compared to SBECD due to the formation of electrostatic interactions. Full article