Solubility In Physiological Media Research Articles

Synthesis, Characterization, Bioavailability and Antimicrobial Studies of Cefuroxime-Based Organic Salts and Ionic Liquids

Low oral bioavailability is a common feature in most drugs, including antibiotics, due to low solubility in physiological media and inadequate cell permeability, which may limit their efficacy or restrict their administration in a clinical setting. Cefuroxime is usually administered in its prodrug form, cefuroxime axetil. However, its preparation requires further reaction steps and additional metabolic pathways to be converted into its active form. The combination of Active Pharmaceutical Ingredients (APIs) with biocompatible organic molecules as salts is a viable and documented method to improve the solubility and permeability of a drug. Herein, the preparations of five organic salts of cefuroxime as an anion with enhanced physicochemical characteristics have been reported. These were prepared via buffer-assisted neutralization methodology with pyridinium and imidazolium cations in quantitative yields and presented as solids at room temperature. Cell viability studies on 3T3 cells showed that only the cefuroxime salts combined with longer alkyl chain cations possess higher cytotoxicity than the original drug, and while most salts lost in vitro antibacterial activity against E. coli, P. aeruginosa and B. subtilis, one compound, [PyC10Py][CFX]2, retained the activity. Cefuroxime organic salts have a water solubility 8-to-200-times greater than the original drug at 37 °C. The most soluble compounds have a very low octanol-water partition, similar to cefuroxime, while more lipophilic salts partition predominantly to the organic phase.

Discovery and Development of Highly Potent and Orally Bioavailable Nonpeptidic αvβ6 Integrin Inhibitors.

A series of 3-aryl((S)-3-fluoropyrrolidin-1-yl)butanoic acids were developed as potent orally bioavailable αvβ6 integrin inhibitors. Starting from a zwitterionic peptidomimetic series optimized for inhaled administration, the balancing of potency and passive permeability to achieve suitable oral agents through modification and exploration of aryl substituents and pKa of the central cyclic amine is described. (S)-4-((S)-3-Fluoro-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)-3-(3-(2-methoxyethoxy)phenyl)butanoic acid was found to have highly desirable oral pharmacokinetic profiles in rat, dog, and minipig, with low to moderate clearance (26%, 7%, and 18% liver blood flow, respectively), moderate volumes of distribution (3.6, 1.4, and 0.9 L/kg, respectively), high to complete oral bioavailabilities, high αvβ6 integrin potency of pIC50 of 8.0, and high solubility in physiological media (>2 mg/mL). Equating to the estimated human dose range of 10-75 mg b.i.d. to achieve 90% αvβ6 target engagement at Cmin, it was selected for further investigation as a potential therapeutic agent for the treatment of idiopathic pulmonary fibrosis.

DNA Programmable Peroxidase Activity of Oxidized Polypyrrole Quantum Dots

AbstractSignificant progress has recently been made in the application of oxidized graphene (GO) quantum dots as enzyme mimics in various biomedical fields due to their bio‐compatibility and excellent solubility in physiological media. However, their catalytic performance and controllability are barely satisfactory. Here, this study constructs oxygen‐functionalized polypyrrole quantum dots (o‐ppy QDs) with excellent peroxidase activity in a mild condition. Compared with oxidized graphene QDs, o‐ppy QDs exhibit superior catalytic efficiency (120 times higher than HRP). More importantly, it is found that guanine (G) and adenine (A) bases possess higher binding affinities to o‐ppy QDs. G base is able to significantly increase the peroxidase activity while A base decreases the activity, providing a fascinating method to precisely regulate the catalytic activity of o‐ppy QDs in a programmable manner by the design of DNA sequences. The enhancement on the peroxidase by G base regulation is attributed to the existence of carbonyl group that promotes its catalytic activity, while A base tends to block the original carbonyl group on o‐ppy QDs. Based on this feature, a colorimetric and fluorescent dual‐mode biosensor for detecting DNA methylation is developed. This study holds significant theoretical and practical implications for the development of nanozymes and precise regulation of their catalytic activity.

Microstructured drug-delivery systems as solid dispersions using peg 6000 and polysorbate 80 containing hydrochlorothiazide: development, synthesis, and physicochemical and morphological characterization

Bioavailability indicates the speed of dissolution and absorption of the drug by its active site, characterization of the potential pharmacological effect, dosage of a medication, and the effectiveness of treatment. Microstructured systems make it possible to increase the efficiency of drug release and absorption processes that have low solubility in physiological media and are extremely important in the area of ​​drug development and new pharmaceutical forms. The drug containing hydrochlorothiazide, distributed by RENAME and widely used for the treatment of arterial hypertension is classified as poorly permeable and poorly soluble, thus having low absorption and bioavailability, which requires administration of high doses to generate side effects. and lack of treatment adherence. The application of a microstructured drug-delivery system in the form of a solid dispersion containing hydrochlorothiazide, a lipophilic drug, dispersed in a solid matrix found by the hydrophilic carriers PEG 6000 (polyethylene glycol) and polysorbate80, given the increased solubility, dissolution profile and consequently the bioavailability of the drug. The system was extended physically-chemically and morphologically utilizing testicles such as scanning electron microscopy (SEM), in addition to thermogravimetry (TGA), differential scanning calorimetry (DSC), and infrared absorption spectroscopy, with satisfactory results in that region. formation of an efficient and innovative drug delivery system.

Porphyrinoids for Photodynamic Therapy (PDT) and Antimicrobial PDT

Photodynamic therapy combines light, molecular oxygen and a PS for the production of reactive oxygen species (ROS), such as singlet oxygen (1O2) and free radicals, leading to oxidative stress and eventual cell death. Phthalocyanines (Pcs) fulfil many of the requirements to be applied as photosensitizers for singlet oxygen generation. However, a major drawback of these compounds is their low solubility in physiological media. Functionalization of the macrocycle at the peripheral and/or axial positions with appropriate hydrophilic functions provides compounds with an enhanced solubility in water. In this respect, several strategies have been adopted to increase the hydrophilicity of Pcs and make them more bio-compatible, like their functionalization with charged groups, aminoacids or carbohydrates, or conjugation to appropriate nanocarriers. The introduction of such entities at Pc axial positions reduces the aggregation of the macrocycles in solution, thus improving their 1O2generation efficiency. For recent work of our group, see references 1 and 2, and articles cited therein. 1V. Almeida-Marrero, E. van de Winckel, E. Anaya-Plaza, T. Torres, A de la Escosura, “Porphyrinoid biohybrid materials as an emerging toolbox for biomedical light management“, Chem. Soc. Rev., 2018; 47: 7369-7400. 2 P.-C. Lo, M. S. Rodríguez-Morgade, R. K. Pandey, D. K. P. Ng, T. Torres, F. Dumoulin, "The unique features and promises of phthalocyanines as advanced photosensitisers for photodynamic therapy of cancer", Chem. Soc. Rev. 2020; 49: 1041-1056

Sila-Ibuprofen.

The synthesis, characterization, biological activity, and toxicology of sila-ibuprofen, a silicon derivative of the most common nonsteroidal anti-inflammatory drug, is reported. The key improvements compared with ibuprofen are a four times higher solubility in physiological media and a lower melting enthalpy, which are attributed to the carbon-silicon switch. The improved solubility is of interest for postsurgical intravenous administration. A potential for pain relief is rationalized via inhibition experiments of cyclooxygenases I and II (COX-I and COX-II) as well as via a set of newly developed methods that combine molecular dynamics, quantum chemistry, and quantum crystallography. The binding affinity of sila-ibuprofen to COX-I and COX-II is quantified in terms of London dispersion and electrostatic interactions in the active receptor site. This study not only shows the potential of sila-ibuprofen for medicinal application but also improves our understanding of the mechanism of action of the inhibition process.

Peripheral tetra-cationic Pt(II) porphyrins photo-inactivating rapidly growing mycobacteria: First application in mycobacteriology

In this manuscript, we report, for the first time, the photoinactivation evaluation of tetra-cationic porphyrins with peripheral Pt (II)-bpy complexes in the photodynamic inactivation (PDI) of rapidly growing mycobacterial strains (RGM). Two different isomeric Pt (II)-porphyrins were synthetized and applied. PDI experiments in the strains of Mycobacteroides abscessus subsp. Abscessus (ATCC 19977), Mycolicibacterium fortuitum (ATCC 6841), Mycobacteroides abscessus subsp. Massiliense (ATCC 48898), and Mycolicibacterium smegmatis (ATCC 700084) conducted with adequate concentration (without aggregation) of photosensitizers (PS) under white-light illumination for 90 min showed that the most effective PS significantly reduced the concentration of viable mycobacteria. The present results show that positively charged porphyrins at the meta position (3-PtTPyP) are more efficient PS against M. abscessus, M. fortuitum, M. massiliense, and M. smegmatis. The effectiveness of the molecule as PS for PDI studies is also clear with mycobacteria, which is strongly related with the porphyrin peripheral charge and coordination platinum (II) compounds and consequently their solubility in physiological media. Tetra-cationic PS may be promising anti-mycobacterial PDI agents with potential applications in medical clinical cases and bioremediation.

Phthalocyanines for Photodynamic Therapy

Photodynamic therapy combines light, molecular oxygen and a PS for the production of reactive oxygen species (ROS), such as singlet oxygen (1O2) and free radicals, leading to oxidative stress and eventual cell death. Phthalocyanines (Pcs) fulfil many of the requirements to be applied as photosensitizers for singlet oxygen generation.1,2 However, a major drawback of these compounds is their low solubility in physiological media. Functionalization of the macrocycle at the peripheral and/or axial positions with appropriate hydrophilic functions provides compounds with an enhanced solubility in water. In this respect, several strategies have been adopted to increase the hydrophilicity of Pcs and make them more bio-compatible, like their functionalization with charged groups,3 aminoacids4 or carbohydrates.5 The introduction of such entities at Pc axial positions reduces the aggregation of the macrocycles in solution, thus improving their 1O2 generation efficiency. For recent work of our group, see reference 1 and articles cited therein. 1Almeida-Marrero V, van de Winckel E, Anaya-Plaza E, Torres T and de la Escosura A. Chem. Soc. Rev., 2018; 47: 7369-7400. 2Dąbrowski JM, Pucelik B, Regiel-Futyra A, Brindell M, Kyzioł A, Stochel G, Macyk W and Arnaut LG. Coord. Chem. Rev., 2016; 325: 67-101. 3Setaro F, Ruiz-González R, Nonell S, Hahn U and Torres T. J. Inorg. Biochem., 2014; 136: 170-176. 4Chen Z, Zhou S, Chen J, Deng Y, Luo Z, Chen H, Hamblin MR, and Huang M. ChemMedChem, 2010; 5: 890-898. 5Alvarez-Mico X, Calvete MJF, Hanack M, Ziegler T. Tetrahedron Lett., 2006; 47: 3283-3286.

Encapsulation of florfenicol by in situ crystallization into novel alginate-Eudragit RS® blended matrix for pH modulated release

Florfenicol (FF) is a broad-spectrum antibiotic with the drawback of poor solubility in physiological media. Despite vehiculization of FF become an alternative, current devices usually showed low encapsulation efficiencies (EE) and uncontrolled fast release. In the present work, a novel drug delivery system based on alginate and Eudragit RS® (EuRS) for FF oral administration was developed. The strategy involved in situ crystallization of FF inside the matrix which allowed EE from 60 to 80%. Ionic gelation technique was used for pH-responsive beads preparation considering that alginate offers structural support for the hydrogel while hydrophobic EuRS delays the swelling of the system. Different formulations were analyzed by FTIR, DSC, XRD and SEM studies to demonstrate the presence of a blended polymeric matrix, the appearance of FF crystals and the role of EuRS in the FF release. A pH-dependent FF release was found when the drug and EuRS concentrations were modified. Approximately 40% and 20% of FF was released from alginate and alginate-EuRS beads at pH 7.4 in 1 h respectively, suggesting a modified release behavior. All formulations showed antimicrobial activity against Staphylococcus aureus and Escherichia coli. The blended formulation results a promising oral matrix adapted for the controlled release of FF along the intestine.

Magnetic cationic liposomal nanocarriers for the efficient drug delivery of a curcumin-based vanadium complex with anticancer potential

In this work novel magnetic cationic liposomal nanoformulations were synthesized for the encapsulation of a crystallographically defined ternary V(IV)-curcumin-bipyridine (VCur) complex with proven bioactivity, as potential anticancer agents. The liposomal vesicles were produced via the thin film hydration method employing N-[1-(2,3-dioleoyloxy)propyl]-N,N,N-trimethylammonium (DOTAP) and egg phosphatidylcholine lipids and were magnetized through the addition of citric acid surface-modified monodispersed magnetite colloidal magnetic nanoparticles. The obtained nanoformulations were evaluated for their structural and textural properties and shown to have exceptional stability and enhanced solubility in physiological media, demonstrated by the entrapment efficiency and loading capacity results and the in vitro release studies of their cargo. Furthermore, the generated liposomal formulations preserved the superparamagnetic behavior of the employed magnetic core maintaining the physicochemical and morphological requirements for targeted drug delivery applications. The novel nanomaterials were further biologically evaluated for their DNA interaction potential and were found to act as intercalators. The findings suggest that the positively charged magnetic liposomal nanoformulations can generate increased concentration of their cargo at the DNA site, offering a further dimension in the importance of cationic liposomes as nanocarriers of hydrophobic anticancer metal ion complexes for the development of new multifunctional pharmaceutical nanomaterials with enhanced bioavailability and targeted antitumor activity.

Preliminary evaluation of the positively and negatively charge effects of tetra-substituted porphyrins on photoinactivation of rapidly growing mycobacteria

This manuscript reports, at the first time, the photoinactivation evaluation of tetra-cationic and anionic porphyrins as photosensitizers (PS) for the photodynamic inactivation (PDI) of rapidly growing mycobacteria strains. Two different charged porphyrin groups were obtained commercially. PDI experiments in the strains Mycobacterium massiliense e Mycobacterium fortuitum conducted with adequate concentration (without aggregation) of photosensitizer under white light at a fluence rate of 50 mW/cm2 over 90 min showed that the most effective PS caused a 100 times reduction in the concentration of viable mycobacteria. The present results show that porphyrin with positively charge are more efficient PS than anionic porphyrin (negatively charged) against M. massiliense e M. fortuitum. It is also clear that the effectiveness of the molecule as PS for PDI studies with mycobacteria is strongly related with the porphyrin peripheral charge, and consequently their solubility in physiological media. Cationic PSs might be promising anti-mycobacteria PDI agents with potential applications in medical clinical cases and bioremediation.

Formation of dendrimer-guest complexes as a strategy to increase the solubility of a phenazine N, N′-dioxide derivative with antitumor activity

Poly(amidoamine) and Poly(propylenimine) dendrimers with different generations and peripheral groups were studied as solubility enhancers and nanocarriers for 7-bromo-2-hydroxy-phenazine N5,N10-dioxide. This compound possesses potential antitumoral and anti-trypanosomal activity, but its low solubility in physiological media precludes its possible application as therapeutic drug. The amino terminated dendrimers association with the active compounds as observed trough NMR studies showed that electrostatic interactions are essential in the solubilization enhancement process. The obtaining of a stable and no cytotoxic formulation makes the drug-carried association a suitable strategy for the generation of a drug delivery system for phenazine derivatives.

Aqueous Drug Solubility: What Do We Measure, Calculate and QSPR Predict?

Detailed critical analysis of publications devoted to QSPR of aqueous solubility is presented in the review with discussion of four types of aqueous solubility (three different thermodynamic solubilities with unknown solute structure, intrinsic solubility, solubility in physiological media at pH=7.4 and kinetic solubility), variety of molecular descriptors (from topological to quantum chemical), traditional statistical and machine learning methods as well as original QSPR models.

Micellar Iron Oxide Nanoparticles Coated with Anti-Tumor Glycosides.

The synthesis procedure of nanoparticles based on thermal degradation produces organic solvent dispersible iron oxide nanoparticles (OA-IONP) with oleic acid coating and unique physicochemical properties of the core. Some glycosides with hydrophilic sugar moieties bound to oleyl hydrophobic chains have antimitotic activity on cancer cells but reduced in vivo applications because of the intrinsic low solubility in physiological media, and are prone to enzymatic hydrolysis. In this manuscript, we have synthetized and characterized OA-IONP-based micelles encapsulated within amphiphilic bioactive glycosides. The glycoside-coated IONP micelles were tested as Magnetic Resonance Imaging (MRI) contrast agents as well as antimitotics on rat glioma (C6) and human lung carcinoma (A549) cell lines. Micelle antimitotic activity was compared with the activity of the corresponding free glycosides. In general, all OA-IONP-based micellar formulations of these glycosides maintained their anti-tumor effects, and, in one case, showed an unusual therapeutic improvement. Finally, the micelles presented optimal relaxometric properties for their use as T2-weighed MRI contrast agents. Our results suggest that these bioactive hydrophilic nano-formulations are theranostic agents with synergistic properties obtained from two entities, which separately are not ready for in vivo applications, and strengthen the possibility of using biomolecules as both a coating for OA-IONP micellar stabilization and as drugs for therapy.

Fullerenes: Chemistry and Its Applications

Fullerenes being allotropes of carbon, have been considered as new class of molecules. Unlike diamond and graphite, this is made up of hollow carbon cage structure. The idea of spheroidal cage structures of C60 arose from construction of geodesic domes made by renowned architect Buckminster Fuller. Although fullerenes have low solubility in physiological media they finds promising biological applications. The photo, electrochemical and physical properties of C60 and other fullerene derivatives finds applications in medical fields. The ability of fullerenes to fit inside the hydrophobic cavity of HIV proteases makes them potential inhibitor for substrates to catalytic active site of enzyme. It possesses radical scavenging and antioxidant property. At the same time, when it exposed to light it can form singlet oxygen in high quantum yields which with direct electron transfer from excited state of fullerenes and DNA bases finally results in cleavage of DNA. The fullerenes are also used as a carrier for gene and drug delivery system. The associated low toxicity of fullerenes is sufficient to attract the researchers for investigation of these interesting molecules. Keywords: Applications, buckyball, C60, drug delivery, fullerene, toxicity.

Thermodynamic equilibrium solubility measurements in simulated fluids by 96-well plate method in early drug discovery.

An early prediction of solubility in physiological media (PBS, SGF and SIF) is useful to predict qualitatively bioavailability and absorption of lead candidates. Despite of the availability of multiple solubility estimation methods, none of the reported method involves simplified fixed protocol for diverse set of compounds. Therefore, a simple and medium-throughput solubility estimation protocol is highly desirable during lead optimization stage. The present work introduces a rapid method for assessment of thermodynamic equilibrium solubility of compounds in aqueous media using 96-well microplate. The developed protocol is straightforward to set up and takes advantage of the sensitivity of UV spectroscopy. The compound, in stock solution in methanol, is introduced in microgram quantities into microplate wells followed by drying at an ambient temperature. Microplates were shaken upon addition of test media and the supernatant was analyzed by UV method. A plot of absorbance versus concentration of a sample provides saturation point, which is thermodynamic equilibrium solubility of a sample. The established protocol was validated using a large panel of commercially available drugs and with conventional miniaturized shake flask method (r(2)>0.84). Additionally, the statistically significant QSPR models were established using experimental solubility values of 52 compounds.

Platinum on Nanodiamond: A Promising Prodrug Conjugated with Stealth Polyglycerol, Targeting Peptide and Acid‐Responsive Antitumor Drug

In the field of nanomedicine, nanoparticles with various functions are required for in vivo applications such as biomedical imaging and drug delivery. Therefore, chemical functionalization of nanoparticles has been extensively investigated. Herein, nanodiamond (ND) coated with polyglycerol (PG) and its derivatives is reported to impart good solubility in a physiological environment, a stealth nature to avoid nonspecific uptake, a targeting property to be taken up by a specific cell, and an acid‐responsive drug release property to kill cancer cells. ND is first grafted with PG and the resulting ND‐PG has a high solubility in physiological media. Since a large number of hydroxyl groups in PG provide scaffolds for further surface functionalization, the targeting RGD peptide and Pt‐based drug are immobilized to give ND‐PG‐RGD, ND‐PG‐Pt and ND‐PG‐RGD‐Pt. The ND with intrinsic fluorescence is also functionalized by PG and RGD to confirm cellular uptake and intracellular localization fluorescently. The results of the cell experiments indicate that PG coating shielded fND from the uptake by HeLa and U87MG cells. In contrast, fND‐PG‐RGD is taken up by U87MG, not HeLa cells, exhibiting high targeting efficacy. When ND‐PG‐RGD‐Pt is applied, U87MG is selectively killed against HeLa. The multi‐functional ND is a promising prodrug in targeting chemotherapy.

Photodynamic inactivation of Penicillium chrysogenum conidia by cationic porphyrins

This work reports the photophysical and biological evaluation of five cationic porphyrins as photosensitizers (PS) for the photodynamic inactivation (PDI) of Penicillium chrysogenum conidia. Two different cationic porphyrin groups were synthesized from 5,10,15,20-tetrakis(4-pyridyl)porphyrin and 5,10,15,20-tetrakis(pentafluorophenyl)porphyrin. The photostability and singlet oxygen generation studies showed that these molecules are photostable and efficient singlet oxygen generators. PDI experiments of P. chrysogenum conidia conducted with 50 μmol L(-1) of photosensitiser under white light at a fluence rate of 200 mW cm(-2) over 20 min showed that the most effective PS caused a 4.1 log reduction in the concentration of viable conidia. The present results show that porphyrins 1a and 1b are more efficient PSs than porphyrin 2a while porphyrins 1c and 2b show no inactivation of P. chrysogenum. It is also clear that the effectiveness of the molecule as PS for antifungal PDI is strongly related with the porphyrin substituent groups, and consequently their solubility in physiological media. The average amount of PS adsorbed per viable conidium was a determining factor in the photoinactivation efficiency and varied between the different studied PSs. Cationic PSs 1a and 1b might be promising anti-fungal PDI agents with potential applications in phytosanitation, biofilm control, bioremediation, and wastewater treatment.

Inhibition of DC-SIGN-Mediated HIV Infection by a Linear Trimannoside Mimic in a Tetravalent Presentation

HIV infection is pandemic in humans and is responsible for millions of deaths every year. The discovery of new cellular targets that can be used to prevent the infection process represents a new opportunity for developing more effective antiviral drugs. In this context, dendritic cell-specific ICAM-3 grabbing non-integrin (DC-SIGN), a lectin expressed at the surface of immature dendritic cells and involved in the initial stages of HIV infection, is a promising therapeutic target. Herein we show the ability of a new tetravalent dendron containing four copies of a linear trimannoside mimic to inhibit the trans HIV infection process of CD4+ T lymphocytes at low micromolar range. This compound presents a high solubility in physiological media, a neglectable cytotoxicity, and a long-lasting effect and is based on carbohydrate-mimic units. Notably, the HIV antiviral activity is independent of viral tropism (X4 or R5). The formulation of this compound as a gel could allow its use as topical microbicide.

Glycodendritic structures based on Boltorn hyperbranched polymers and their interactions with Lens culinaris lectin.

Multivalent scaffolds bearing carbohydrates have been prepared to mediate biological processes where carbohydrates are involved. These systems consist of dendritic structures based on Boltorn H20 and H30 hyperbranched polymers to which carbohydrates are linked through a convenient spacer. Mannose has been chosen as a sugar unit to test the viability of this strategy. These glycodendritic compounds have been prepared in a few steps with good yields, showing a high solubility in physiological media and low toxicity. The binding of these dendritic polymers to the mannose-binding lectin Lens culinaris (LCA) was studied using STD-NMR experiments and quantitative precipitation assays. The results demonstrate the existence of a clear interaction between the mannose derivative systems and the Lens lectin where the dendritic scaffold does not have an important role in mannose binding but supplies the necessary multivalence for lectin cluster formation. These glycodendritic structures are able to interact with a receptor, and therefore they can be considered as promising tools for biological studies.