Aqueous Solubility Research Articles

Hierarchical Graph Attention Network with Positive and Negative Attentions for Improved Interpretability: ISA-PN.

With the advancement of deep learning (DL) methods in chemistry and materials science, the interpretability of DL models has become a critical issue in elucidating quantitative (molecular) structure-property relationships. Although attention mechanisms have been generally employed to explain the importance of molecular substructures that contribute to molecular properties, their interpretability remains limited. In this work, we introduce a versatile segmentation method and develop an interpretable subgraph attention (ISA) network with positive and negative streams (ISA-PN) to enhance the understanding of molecular structure-property relationships. The predictive performance of the ISA models was validated using data sets for aqueous solubility, lipophilicity, and melting temperature, with a particular focus on evaluating interpretability for the aqueous solubility data set. The ISA-PN model enables the quantification of the contributions of molecular substructures through positive and negative attention scores. Comparative analyses of the ISA, ISA-PN, and GC-Net (group contribution network) models demonstrate that the ISA-PN model significantly improves interpretability while maintaining similar accuracy levels. This study highlights the efficacy of the ISA-PN model in providing meaningful insights into the contributions of molecular substructures to molecular properties, thereby enhancing the interpretability of DL models in chemical applications.

Cyclodextrins as nanocarriers of hydrophobic silicon phthalocyanine dichloride for the enhancement of photodynamic therapy effect.

In this study, silicon phthalocyanine dichloride (SiCl2Pc) was successfully encapsulated in β-cyclodextrin (β-CD) and hydroxy-propyl-β-cyclodextrin (HP-β-CD) using the kneading method. Dynamic Light Scattering (DLS) demonstrated complexes of various hydrodynamic diameters with moderate stability in aqueous solutions. Their structural characterization by Infrared Spectroscopy (FT- IR) indicated that a part of phthalocyanine is located inside the cyclodextrin cavity. Both photophysical and photochemical studies showed that phthalocyanine's encapsulation in cyclodextrins increased its aqueous solubility. The photodynamic studies against A431 cancer cell line indicated that the complexes are more effective than pure SiCl2Pc. Pure SiCl2Pc's photodynamic effect is characterized as dose-dependent, whereas both complexes presented a biphasic dose-response photodynamic effect. For the highest energy dose of 3.24J/cm2, pure SiCl2Pc induced mild cell toxicity. SiCl2Pc-β-CD complex was the most promising photosensitizer, exhibiting the highest photodynamic effect when irradiated at 2.16J/cm2.

Synthesis and Antioxidant Effects of Edaravone-Loaded MPEG-2000-DSPE Micelles in Rotenone-Induced PC12 Cell Model of Parkinson’s Disease

Parkinson’s disease (PD) is the second most common neurodegenerative disorder globally that lacks any disease-modifying drug for prevention or treatment. Oxidative stress has been identified as one of the key pathogenic drivers of Parkinson’s disease (PD). Edaravone, an approved free-radical scavenger, has proven to have potential against PD by targeting multiple key pathologies, including oxidative stress, focal mitochondria, and neuroinflammation. However, its bioavailability is potentially restricted due to its poor solubility and short half-life. This study aims to develop a simple and effective drug delivery system for edaravone to enhance its solubility, stability, and bioavailability to improve its neuroprotective efficacy. An MPEG-2000-DSPE-edaravone (MDE) micelle was prepared via solvent evaporation using MPEG-2000-DSPE as a carrier to encapsulate edaravone. The morphology, particle size, zeta potential, chemical structure, and edaravone loading of MDE were evaluated. We then investigated whether such targeted edaravone delivery could provide enhanced neuroprotection. A cell model of PD was established in PC12 cells through exposure to rotenone. The effects of MDE on PC12 cells treated with or without rotenone were evaluated using a cell counting kit-8, calcein acetoxymethyl ester (AM)–propidine iodide (PI) staining, and flow cytometry. Cell migration was evaluated using a wound healing assay. Additionally, the intracellular antioxidant study was performed using an ROS-level-detecting DCFH-DA probe, and the mitochondrial membrane potentials were evaluated using a JC-1 assay. MDE with a drug-loading content of 17.6% and an encapsulation efficiency of 92.8% was successfully prepared. The resultant MDE had a mean particle size of 112.97 ± 5.54 nm with a zeta potential of −42 mV. Cytotoxicity assays confirmed that the MDE (≤200 ug/mL) exhibited promising cytocompatibility with no significant effect on cell viability, cell cycle regulation, or apoptosis levels. Likewise, compared with the free edaravone, no effect on cell migration was noted for MDE. MDE might be able to target edaravone delivery into PC12 cells, increasing the mitochondrial membrane potential and providing a significant local antioxidant effect. The results demonstrated that MPEG-2000-DSPE could be a promising material for enhancing edaravone’s aqueous solubility, stability, and antioxidant effects. MDE could be a potential drug formulation for treating PD and other diseases in which oxidative stress plays a key role in pathogenesis.

Fabrication and Characterization of Gelatin-Finger Citron Polysaccharide Nanoparticles for Enhanced Solubility and Bioavailability of Luteolin in Treating Acute Alcoholic Liver Disease.

Luteolin (Lut) is a natural flavonoid that has been widely used in the treatment of liver and glycolipid metabolic diseases. However, poor water solubility and bioavailability limit its efficacy and application. To overcome these challenges, a protein-polysaccharide composite nanoparticle (L-GF NPs) for Lut delivery was prepared by a self-assembly method based on amphiphilic gelatin and active finger citron polysaccharide (FCP). The L-GF NPs were approximately spherical in shape and were formed by hydrogen bonding, electrostatic interaction, and hydrophobic interaction. Lut was encapsulated in the nanoparticles in an amorphous state, and the encapsulating efficiency was 79.49%. The efficacy of L-GF NPs was evaluated by intragastric administration of an alcoholic liver disease (ALD) mouse model. L-GF NPs have been demonstrated to significantly ameliorate the symptoms of ALD mice, which are mainly achieved by reducing lipid accumulation and oxidative stress and inhibiting the NF-κB pathway. In conclusion, the aqueous solubility and bioavailability of Lut were markedly enhanced by FCP encapsulation. Meanwhile, the combined effect of Lut and FCP significantly ameliorated ALD and attenuated alcohol-induced lipid metabolic disorders and oxidative damage. This provides a new strategy to promote the prevention and treatment of ALD.

Nanocrystals in Dermal Drug Delivery: A Breakthrough for Enhanced Skin Penetration and Targeted Skin Disorder Treatments

One of the major challenges in dermal drug delivery is the adequate penetration of the active compound into the skin without causing any skin irritation and inflammation. Nanocrystals (NCs) are nanoscale particles, and their sizes are below 1000 nm. NCs are made up of drug particles only, which are used to improve the aqueous solubility and bioavailability of poorly water-soluble drugs. NCs are typically prepared either by bottom-up or top-down techniques. The advantages of using NC-based formulations in enhancing dermal drug delivery include increased drug loading capacity, easier and deeper penetration into the skin tissue, and increased passive diffusion. NC-based formulations with the capacity of enhanced dermal drug delivery can be effectively used to treat a wide range of skin disorders, including melanoma, inflammation, psoriasis, acne vulgaris, bacterial infections, fungal infections, eczema, skin aging, herpes simplex virus infections, skin manifestations of tick bites, frostbite-related infections, hyperpigmentation, and diabetic foot ulcer. In this review, major challenges in dermal drug delivery across the skin barrier, mechanism of action of dermal NCs, advantages of using NCs in enhancing dermal drug delivery, NC preparation methods, and applications of NCs in the treatment of various skin disorders have been discussed.

A Versatile "Synthesis Tag" (SynTag) for the Chemical Synthesis of Aggregating Peptides and Proteins.

Solid-phase peptide synthesis (SPPS) and native chemical ligation (NCL) are powerful methods for obtaining peptides and proteins that are otherwise inaccessible. Nonetheless, numerous sequences are difficult to prepare via SPPS, and cleaved peptides often have low aqueous solubility. To address these challenges, we developed a "Synthesis Tag" consisting of six arginines connected to the target sequence via a cleavable MeDbz linker. "SynTag" effectively improves batch- and flow-SPPS of "difficult sequences", enhances the solubility of the cleaved peptides, and provides direct access to native sequences by hydrolysis, or peptide thioesters for NCL. We demonstrate its utility in the first chemical synthesis of the MYC transactivation domain with a single NCL. We envisage SynTag to become a broadly applicable tool that enables the synthesis and study of previously unattainable peptides and proteins.

Enhancing cancer therapy: advanced nanovehicle delivery systems for oridonin

Oridonin (ORI), an ent-kaurane diterpenoid derived from Rabdosia rubescens (Hemsl.) H.Hara, serves as the primary bioactive component of this plant. It demonstrates a broad spectrum of therapeutic activities, including moderate to potent anticancer properties, alongside anti-inflammatory, antibacterial, antifibrotic, immunomodulatory, and neuromodulatory effects, thus influencing diverse biological processes. However, its clinical potential is significantly constrained by poor aqueous solubility and limited bioavailability. In alignment with the approach of developing drug candidates from natural compounds, various strategies, such as structural modification and nanocarrier systems, have been employed to address these challenges. This review provides an overview of ORI-based nano-delivery systems, emphasizing their potential to improve the clinical applicability of oridonin in oncology. Although some progress has been made in advancing ORI nano-delivery research, it remains insufficient for clinical implementation, necessitating further investigation.

Formulating abiraterone acetate-HPMCAS-based amorphous solid dispersions: insights into in vitro and biorelevant dissolution assessments and pharmacokinetic evaluations.

Abiraterone acetate (ABTA) is used as a primary treatment for metastatic castration-resistant prostate cancer. Its low aqueous solubility results in inadequate dissolution and poor oral bioavailability (<10%), necessitating the consumption of large doses of ABTA (1000 mg per day) for desired efficacy. The aim of this study is to enhance the solubility, dissolution, and bioavailability of ABTA through amorphous solid dispersions (SDs). ABTA-SD was prepared via a solvent granulation method with different grades of hydroxypropyl methylcellulose acetate succinate (HPMCAS 716 and 912). The theoretical solubility parameter between ABTA and HPMCAS was below 7 MPa1/2, indicating miscibility between the drug and the polymer according to the Hansen solubility parameter. HPMCAS showed a remarkable recrystallization inhibition of up to 180 min compared to the free drug (10 min), maintaining the soluble drug in supersaturation state and exhibiting the "spring and parachute" phenomenon. ABTA-SD exhibited a higher solubility (1.16-fold to 52-fold) in different media than free ABTA. The results of DSC, PXRD, ATR-FTIR, and FE-SEM indicated that the crystallinity of ABTA was completely transformed to an amorphous form and maintained in the SD formulation. In vitro and bio-relevant dissolution behavior of ABTA was studied in various dissolution media, indicating the higher dissolution of ABTA-SD than that of free ABTA. The pharmacokinetic study conducted in Wistar rats revealed that C max and AUC0-t of the optimized ABTA-SD formulation were significantly enhanced by 1.92-fold and 2.87-fold, respectively, compared to those of free ABTA.

Effects of Different Weak Small Organic Acids on Clofazimine Solubility in Aqueous Media

Background/Objectives: Clofazimine (CFZ) is a Biopharmaceutics Classification System (BCS) II drug introduced in the US market in 1986 for the treatment of leprosy. However, CFZ was later withdrawn from the market due to its extremely low aqueous solubility and low absorption. In the literature, the intrinsic solubility of CFZ has been estimated to be &lt;0.01 μg/mL, and solubilities of its different salt forms in simulated gastric and intestinal fluids are &lt;10 µg/mL. These are extremely low solubilities for the dissolution of a drug administered orally at 100–200 mg doses. Methods: In the present investigation, seven weak organic acids (adipic, citric, glutaric, maleic, malic, succinic, and tartaric) were tested by determining the aqueous solubility of CFZ as the function of acid concentration to investigate whether any of the acids would lead to the supersolubilization of CFZ. Results: There were only minimal increases in solubilities when concentrations of acids in water were increased up to 2.4 M. The solubilities, however, increased to 0.32, 1.23, and 10.68 mg/mL, respectively, in 5 M solutions of tartaric, malic, and glutaric acids after equilibration for 24 h at 25 °C. Crystalline solids were formed after the equilibration of CFZ with all acids. Apparently, salts or cocrystals were formed with all acids, except for glutaric acid, as their melting endotherms in DSC scans were in the range of 207.6 to 248.5 °C, which were close to that of CFZ itself (224.8 °C). In contrast, the adduct formed with glutaric acid melted at the low temperature of 77 °C, and no other peak was observed at a higher temperature, indicating that the material converted to an amorphous state. Conclusions: The increase in CFZ solubility to &gt;10 mg/mL in the presence of 5 M glutaric acid could be called supersolubilization when compared to the intrinsic solubility of the basic drug. Such an increase in CFZ solubility and the conversion of the glutarate adduct to an amorphous state are being exploited to develop rapidly dissolving dosage forms.

Depicting polymorphism in eutectic mixtures

The current investigation reveals the presence of polymorphism within linezolid eutectic mixtures containing syringic acid, fumaric acid, and isonicotinamide. Linezolid was combined with the said coformers through co-grinding in 1:1 stoichiometric ratios to produce binary mixtures. Through techniques such as differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), and Fourier transform infrared (FTIR) spectroscopy, the eutectic nature of these mixtures was confirmed. Polymorphism was identified further through the emergence of an exothermic event positioned between the two melting endotherms in DSC thermograms. This endo-exo-endo transition signifies the thermally-induced polymorphic transformation occurring within the eutectic mixtures. The observed behavior was validated through real-time visual analysis using hot-stage microscopy analysis (HSM). Utilizing PXRD data, quantitative phase analysis (QPA) was employed to determine the weight fractions of individual components in various eutectic polymorphs, yielding reliable outcomes. The morphological characteristics and surface alterations of eutectic polymorphs were scrutinized via scanning electron microscopy (SEM). Moreover, eutectic polymorphs formed by the combination of linezolid and isonicotinamide demonstrated fivefold increase in aqueous solubility and a fourfold faster intrinsic dissolution rate (IDR) compared to marketed linezolid.

In silico Exploration of a Novel ICMT Inhibitor with More Solubility than Cysmethynil against Membrane Localization of KRAS Mutant in Colorectal Cancer.

ICMT (isoprenylcysteine carboxyl methyltransferase) is an enzyme that plays a key role in the post-translational modification of the K-Ras protein. The carboxyl methylation of this protein by ICMT is important for its proper localization and function. Cysmethynil (2-[5-(3-methylphenyl)-l-octyl-lH-indolo-3-yl] acetamide) causes K-Ras mislocalization and interrupts pathways that control cancer cell growth and division through inhibition of ICMT, but its poor water solubility makes it difficult and impractical for clinical use. This indicates that relatively high amounts of cysmethynil would be required to achieve an effective dose, which could result in significant adverse effects in patients. The general objective of this work was to find virtually new compounds that present high solubility in water and are similar to the pharmacological activity of cysmethynil. Pharmacophore modeling, pharmacophore-based virtual screening, prediction of ADMET properties (absorption, distribution, metabolism, excretion, and toxicity), and water solubility were performed to recover a water-soluble molecule that shares the same chemical characteristics as cysmethynil using Discovery Studio v16.1.0 (DS16.1), SwissADME server, and pkCSM server. In this study, ten pharmacophore model hypotheses were generated by exploiting the characteristics of cysmethynil. The pharmacophore model validated by the set test method was used to screen the "Elite Library®" and "Synergy Library" databases of Asinex. Only 1533 compounds corresponding to all the characteristics of the pharmacophore were retained. Then, the aqueous solubility in water at 25°C of these 1533 compounds was predicted by the Cheng and Merz model. Among these 1533 compounds, two had the optimal water solubility. Finally, the ADMET properties and Log S water solubility by three models (ESOL, Ali, and SILICOS-IT) of the two compounds and cysmethynil were compared, resulting in compound 2 as a potential inhibitor of ICMT. According to the results obtained, the identified compound presented a high solubility in water and could be similar to the pharmacological activity of cysmethynil.

2-Aminobenzothiazole based adjuvant of polymyxin E against Gram-negative bacteria

Antibiotic resistance has emerged as a pressing global health issue. Polymyxin E, commonly regarded as a clinically important antibiotic, faces limitations due to its dose-dependent toxicity. A crucial strategy to combat this is the development of an antibiotic adjuvant to enhance efficacy while reducing dosage. Screening from our extensive in-house compound library, KJ1071 emerged as a promising adjuvant candidate for polymyxin E. Subsequent structure–activity relationship studies led to the discovery of compound A35, which demonstrated superior synergistic activity. However, its limited aqueous solubility posed challenges for biological experiments. To address this, we carried out a structural derivatization aimed at enhancing its solubility. The amino acid derivative A59 notably improved aqueous solubility to 3.237 mg/mL, a substantial 3237-fold increase compared to compound A35. Moreover, A59 amplified the efficacy of polymyxin E in eradicating a variety of Gram-negative bacteria, including certain clinical strains that are resistant to polymyxin E. The mechanism studies indicated that A59 might target the bacterial membrane. These findings suggest that the discovery of this innovative scaffold could provide critical insights for new adjuvant therapies.

Engineering sodium alginate microparticles with different crystallinities for niclosamide repositioning and solubilization to improve solubility and oral bioavailability in rats

Niclosamide is a commonly used anthelmintic; however, its poor aqueous solubility limits its oral bioavailability. Enhancing its solubility and oral bioavailability is crucial for its repositioning as an anticancer agent. Here, we aimed to develop new sodium alginate–poloxamer microparticles with different crystallinities to increase drug solubility and oral bioavailability. Sodium alginate and poloxamer were used as the polymer and surfactant, respectively, to prepare niclosamide-loaded microparticles via spray drying. The optimized amorphous and crystalline microparticles were prepared with niclosamide/sodium alginate/poloxamer weight ratios of 1:2.5:3 and 1:1.125:0.375, respectively. Their solubilities, dissolution rates, physicochemical properties, and oral bioavailabilities were compared with those of drug powder in rats. Physicochemical characterization of the developed particles revealed changed structure from crystalline to amorphous, with no irregular crystalline characteristics but decreased particle size. Compared to the pure drug powder, crystalline microparticles retained their crystalline nature with no significant changes in particle size. Both microparticles showed significantly higher aqueous solubilities, dissolution rates, and oral bioavailabilities than niclosamide powder in rats. Amorphous microparticles showed higher solubility (approximately 1775-fold) and oral bioavailability (approximately 5.6-fold) than niclosamide powder due to the crystalline-to-amorphous change and decreased particle size. The developed amorphous microparticles can be used to improve niclosamide solubility and oral bioavailability.

N,N-Disubstituted 4-Sulfamoylbenzoic Acid Derivatives as Inhibitors of Cytosolic Phospholipase A2α: Synthesis, Aqueous Solubility, and Activity in a Vesicle and a Whole Blood Assay.

Cytosolic phospholipase A2α (cPLA2α) is the key enzyme that initiates the arachidonic acid cascade through which pro-inflammatory lipid mediators can be formed. Therefore, cPLA2α is considered an interesting target for the development of anti-inflammatory drugs. Although several effective inhibitors of the enzyme have been developed, none of them has yet reached clinical application. Recently, we have prepared new 4-sulfamoylbenzoic acid derivatives based on a cPLA2α inhibitor found in a ligand-based virtual screening. The most effective of these compounds were now subjected to further variations in which the substitution pattern on the sulfamoyl nitrogen atom was changed.. The new compounds were tested in vitro in a vesicle assay for cPLA2α inhibition as well as for their water solubility, metabolic stability, and selectivity towards related enzymes. In addition, they were evaluated ex vivo in a whole blood assay in which metabolites of the arachidonic acid cascade formed after activation of cPLA2α were quantified using a combined online dilution/ online solid phase extraction HPLC-MS method. Inhibitors with submicromolar inhibitory in vitro potency were found with favourable water solubility and selectivity. However, their efficacy did not match that of the highly effective, known, structurally related cPLA2α inhibitor giripladib, which was also tested as a reference. One advantage of some of the new compounds compared to giripladib was their significantly improved water solubility. When analyzing the substances in the ex vivo whole blood assay, it was found that the obtained inhibition data correlated better with the in vivo results when the phorbol ester 12-Otetradecanoylphorbol- 13-acetate was used for activation of the enzyme in the blood cells instead of the calcium ionophore A23187. New compounds with good activity towards cPLA2α and reasonable physicochemical properties were identified. Overall, the results obtained could be helpful in the development of clinically applicable inhibitors of this enzyme.

Leveraging solid solubility and miscibility of etoricoxib in Soluplus® towards manufacturing of 3D printed etoricoxib tablets by additive manufacturing

This research focuses on exploring the solid solubility and miscibility of Etoricoxib, a poorly water-soluble anti-inflammatory drug, within Soluplus®, a polymer used as a matrix for 3D-printed tablets. By utilizing hot-melt extrusion (HME), the drug was dispersed within Soluplus® to enhance its solubility. The extrudates were then employed in 3D printing to create customized solid oral dosage form. This study’s novelty lies in combining HME and 3D printing, aiming to improve drug incorporation, stability, and effectiveness in the final formulation. Comprehensive characterization techniques, including hot stage microscopy (HSM), scanning electron microscopy (SEM), micro-computed tomography (Micro-CT), florescence microscopy, optical microscopy, X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), solubility studies, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and aqueous solubility study were utilized to elucidate the physicochemical properties, thermal stability, and structural integrity for the extruded filaments (the printing ink), and 3D printed tablets made thereof. Furthermore, the in vitro drug release profile of the 3D printed tablet was systematically evaluated, revealing a controlled drug release pattern from the finished dosage form. The systematic investigation reported herein, starting from theoretical miscibility to the printing ink development through HME, detailed characterization of the extruded filaments, and further solid oral formulation development by additive manufacturing can be utilized as a platform technology or a pathway for the development of personalized medicine with drugs having similar physicochemical properties.

Nanostructured lipid carriers as a strategy to enhance oral levosulpiride delivery: An in vitro and ex vivo assessment.

Oral absorption is limited for many small-molecule drugs due to their poor aqueous solubility as well as, for some, poor membrane permeation. One such is levosulpiride (LSP), used to treat psychotic and other conditions. The present study aims to explore the effect of nanostructured lipid carriers (NLCs) for the delivery of LSP. The permeation of LSP in vitro and ex vivo as well as effects on the epithelium and mucosa was monitored. In vitro and ex vivo permeation studies exhibited an 8-fold and 1.6-fold increase in the Papp of LSP respectively, as compared to unformulated LSP applied as a suspension. Transepithelial electrical resistance (TEER) measured in real-time by impedance spectroscopy decreased during exposure yet recovered upon removal of the NLCs. Together with the increased passage of the paracellular markers [14C]-mannitol and FD4 applied together with blank NLCs, but not the transcellular marker [3H]-metoprolol, this indicates permeation of LSP via the paracellular pathway. The reversible effect on integrity was associated with altered cell morphology confirmed by occludin and f-actin localization with insignificant effect on metabolic activity. These results suggest that the NLCs and/or components thereof can mediate improved absorption of drugs by increasing the permeability of the intestinal epithelial membrane, further facilitated by increased drug solubilization.

Biochemical investigation and in silico analysis of the therapeutic efficacy of Ipriflavone through Tet-1 Surface-Modified-PLGA nanoparticles in Streptozotocin-Induced Alzheimer’s like Disease: Reduced oxidative damage and etiological Descriptors

Ipriflavone (IPRI), an isoflavone derivative, is clinically used to prevent postmenopausal bone loss in addition to its antioxidant and cognitive benefits. However, its poor aqueous solubility retained its bioavailability. New strategies have been developed to improve the bioavailability and solubility of neurological medications to enhance their potency and limit adverse effects. This study aimed to prepare targeted IPRI-poly-lactic-co-glycolic acid (PLGA) nanoparticles coupled with Tet-1 peptide to increase the therapeutic potency of IPRI in a rat model of Alzheimer’s disease (AD). Streptozotocin (STZ) exacerbates Alzheimer-related alterations by promoting central insulin resistance resulted from defective signaling pathways related to neuroinflammation and neurotoxicity. Bilateral intracerebroventricular (icv) injection of STZ was used to introduce the AD model. Icv-STZ injection significantly affected brain insulin, oxidative stress, inflammatory, and apoptotic indicators and caused behavioral abnormalities. STZ promoted the formation of amyloid β42 (Aβ42) by increasing BACE1 and reducing ADAM10 and ADAM17 expression levels. STZ also triggered the accumulation of neurofibrillary tangles and synaptic dysfunction, which are crucial for neurological impairments. Icv-STZ injection showed evident degenerative changes in the pyramidal cell layer and significantly reduced the count of viable cells in both CA1 and prefrontal cortex, indicating increased neuronal cell death. IPRI successfully ameliorated cognitive dysfunction by improving the phosphorylated forms of cAMP-response element-binding protein (pCREB) and extracellular signal-regulated kinase 1/2 (pERK1/2) related to synaptic plasticity. Targeted IPRI nanoparticles exceeded free IPRI potential in reducing oxidative stress, acetylcholinesterase/monoamine oxidase activities, Tau phosphorylation, and Aβ42 levels revealing less degenerative changes and increased viable neuron counts. IPRI-targeted nanoparticles improved the neuroprotective potential of free IPRI, making this strategy applicable to treat many neurodegenerative diseases. Finally, the in silico study predicted its ability to cross the BBB and to bind various protein targets in the brain.

ENHANCING FLUCONAZOLE SOLUBILITY AND BIOAVAILABILITY THROUGH SOLID DISPERSION TECHNIQUES: EVALUATION OF POLYETHYLENE GLYCOL 6000 AND SODIUM CARBOXYMETHYLCELLULOSE SYSTEMS USING FIBER OPTICS

Objective: The triazole antifungal fluconazole is widely used for treating mycotic infections, but its efficacy is limited by its poor aqueous solubility and low dissolution rate, leading to reduced oral bioavailability. This study aimed to enhance the solubility and dissolution rate of fluconazole using solid dispersion techniques with Polyethylene Glycol 6000 (PEG 6000) and Sodium Carboxymethylcellulose (SCMC) as carriers. Methods: Solid dispersions were prepared using the fusion method, and their physicochemical properties were evaluated against physical mixtures and pure drug samples. Results: The solid dispersion showed a significant increase in the dissolution rate, achieving 89.01% drug release in 180 min compared to 40.3% for the pure drug (p&lt;0.0032) and 84.1% for the physical mixture (p&lt;0.0453). The encapsulation efficiency of the solid dispersion was 39.24%, with a drug loading capacity of 19.62%. Fourier Transform Infrared (FTIR) spectroscopy confirmed the stability of the drug within the dispersion, while Scanning Electron Microscopy (SEM) revealed amorphous particles, indicating enhanced solubility. Conclusion: These results demonstrate that the solid dispersion of fluconazole with PEG 6000 and SCMC significantly improves its dissolution rate and flow properties, providing a promising strategy for enhancing the oral bioavailability of poorly water-soluble drugs.

Spanlastic Nano-Vesicles: A Novel Approach to Improve the Dissolution, Bioavailability, and Pharmacokinetic Behavior of Famotidine

Background/Objectives: Drugs exhibiting poor aqueous solubility present a challenge to efficient delivery to the site of action. Spanlastics (a nano, surfactant-based drug delivery system) have emerged as a powerful tool to improve solubility, bioavailability, and delivery to the site of action. This study aimed to better understand factors affecting the physicochemical properties of spanlastics, quantify their effects, and use them to enhance the bioavailability of famotidine (FMT), a model histamine H2 receptor antagonist (BCS class IV). Methods: FMT was incorporated into nano-spanlastics drug delivery system. The ethanol injection method, Box–Behnken design, and mathematical modeling were utilized to fabricate famotidine-loaded nano-spanlastics and optimize the formula. Spanlastics were characterized for their particle size, polydispersity index, zeta potential, entrapment efficiency, drug loading, compatibility of the excipients (using DSC), in vitro drug release, and in vivo pharmacokinetics. Results: Span 60 (the non-ionic surfactant) and tween 60 (the edge activator) gave rise to spanlastics with the best characteristics. The optimal spanlastic formulation exhibited small particle size (&lt;200 nm), appropriate polydispersity index (&lt;0.4), and zeta potential (&gt;−30 mV). The entrapment efficiency and drug loading of the optimum formula assured its suitability for hydrophobic drug entrapment as well as practicability for use. DSC assured the compatibility of all formulation components. The drug release manifested a biphasic release pattern, resulting in a fast onset and sustained effect. Spanlastics also showed enhanced Cmax, AUC0–24, and bioavailability. Conclusions: Spanlastics manifested improved FMT dissolution, drug release characteristics, membrane permeation, and pharmacokinetic behavior.

Preparation and Characterization of Apixaban Cocrystals with Coformers for Improving Physical Properties

Background: Cocrystals are stoichiometric, multicomponent crystalline materials composed of an active pharmaceutical ingredient (API) and a coformer arranged in a crystalline structure. Apixaban (APX) is an oral blood thinner that has a low aqueous solubility of 0.028mg/mL at 24 °C and a weak oral bioavailability of about 50% for doses below 10 mg, decreasing as doses above 25 mg are taken. Objectives: To develop and assess APX cocrystal to improve its solubility. Methods: Cocrystals of APX with diverse coformers were synthesized using the solvent evaporation technique in varying molar ratios. The structure of the synthesized cocrystals was validated by DSC, PXRD, and FTIR analyses. Saturation solubility of APX and cocrystals in water was also investigated. Results: APX cocrystals with diverse coformers exhibited distinct physicochemical features. The co-crystal of APX with oxalic acid at a 1:1 ratio exhibited a 2.54-fold enhancement in solubility relative to that of pure APX in water. Each coformer enhanced the solubility of the APX co-crystals. The FTIR spectra of the cocrystals indicated no interaction between the APX and the coformers. The DSC analysis revealed distinct endothermic peaks corresponding to its melting point, indicating the development of cocrystals. The PXRD diffractogram demonstrated fluctuation of 2 theta values of peaks and confirmed cocrystallization of APX. Conclusions: Cocrystallization may serve as a potential method to improve the solubility of APX.