Supramolecular Interaction of Atenolol and Propranolol with ß-Cyclodextrin Spectroscopic Characterization and Analytical Application.

Atenolol (ATE) and propranolol (PRO) inclusion complexes with ß-cyclodextrin have been investigated in aqueous solution. The aqueous solution was examined and characterized using UV-vis, fluorescence spectroscopy, and 1H NMR. The physical mixture was characterized using FTIR. The existence of inclusion complexes is confirmed by observing changes in spectroscopic properties. The ATE complex with ß-CD exhibited an interaction as host and (ß-CD) as a guest in a 1:1 ratio, with an inclusion constant K of 2.09 × 10-3 µM-1, as determined by the typical double-reciprocal graphs. Similarly, the PRO complex with ß-CD exhibited an interaction as host and (ß-CD) guest in 1:1 and 1:2 stoichiometry at the same time; the inclusion constants were K1 = 5.80 × 10-5 µM-1 and K2 = 4.67 × 10-8 µM-1, as determined by typical double-reciprocal graphs. The variables influencing the formation of the inclusion complexes were investigated and optimized. Based on the enhancement in fluorescence intensity due to the formation of inclusion complexes, spectrofluorometric methods were developed and validated for determination of each drug's pharmaceutical formulation. The quantification of the fluorescence intensity for ATE and PRO was conducted at λex/λem 226/302 nm and λex/λem 231/338 nm, respectively. Under the optimal reaction circumstances, linear relationships with good correlation coefficients of 0.9918 and 0.99 were found in the concentration ranges of 0.3-1.7 µM, and 0.1-1.1 µM for ATE and PRO, respectively. The limits of detection (LODs) were found to be 0.13 and 0.01 µM for ATE and PRO, respectively. The suggested approach was effectively applied to the analysis of both drugs' pharmaceutical formulations.

Sustainable Synthesis of the Active Pharmaceutical Ingredient Atenolol in Deep Eutectic Solvents.

Atenolol, one of the top five best-selling drugs in the world today used to treat angina and hypertension, and to reduce the risk of death after a heart attack, faces challenges in current synthetic methods to address inefficiencies and environmental concerns. The traditional synthesis of this drug involves a process that generates a large amount of waste and other by-products that need disposal. This study presents a one-pot DES-based sustainable protocol for synthesizing atenolol. The use of the DES allowed the entire process to be conducted with no need for additional bases or catalysts, in short reaction times, under mild conditions, and avoiding chromatographic purification. The overall yield of atenolol was 95%. The scalability of the process to gram-scale production was successfully demonstrated, emphasizing its potential in industrial applications. Finally, the 'greenness' evaluation, performed using the First Pass CHEM21 Metrics Toolkit, highlighted the superiority in terms of the atom economy, the reaction mass efficiency, and the overall process mass intensity of the DES-based synthesis compared with the already existing methods.

Performance and mechanistic studies of rapid atenolol degradation through peroxymonosulfate activation by V, Co, and bamboo carbon catalyst.

Developing the Co-based catalysts with high reactivity for the sulfate radical (SO4-·)-based advanced oxidation processes (SR-AOPs) has been attracting numerous attentions. To improve the peroxymonosulfate (PMS) activation process, a novel Co-based catalyst simultaneously modified by bamboo carbon (BC) and vanadium (V@CoO-BC) was fabricated through a simple solvothermal method. The atenolol (ATL) degradation experiments in V@CoO-BC/PMS system showed that the obtained V@CoO-BC exhibited much higher performance on PMS activation than pure CoO, and the V@CoO-BC/PMS system could fully degrade ATL within 5 min via the destruction of both radicals (SO4-· and O2-··) and non-radicals (1O2). The quenching experiments and electrochemical tests revealed that the enhancing mechanism of bamboo carbon and V modification involved four aspects: (i) promoting the PMS and Co ion adsorption on the surface of V@CoO-BC; (ii) enhancing the electron transfer efficiency between V@CoO-BC and PMS; (iii) activating PMS with V3+ species; (iv) accelerating the circulation of Co2+ and Co3+, leading to the enhanced yield of reactive oxygen species (ROS). Furthermore, the V@CoO-BC/PMS system also exhibited satisfactory stability under broad pH (3-9) and good efficiency in the presence of co-existing components (HCO3-, NO3-, Cl-, and HA) in water. This study provides new insights to designing high-performance, environment-friendly bimetal catalysts and some basis for the remediation of antibiotic contaminants with SR-AOPs.

Photocatalytic degradation of drugs in water mediated by acetylated riboflavin and visible light: A mechanistic study.

There is a current concern, among the scientific community, on the pollutants classified as "persistent organic pollutants (POPs)". Pharmaceuticals and personal care products (PPCPs) belong to this family of contaminants; therefore, it is necessary to find more efficient techniques able to achieve their removal from the environment. This study focuses on two different pharmaceuticals: carbamazepine and atenolol, chosen for their widespread use and their different chemical and medical properties. In this work, an organic dye, acetylated riboflavin, has been used in combination with visible light to achieve the photodegradation of these two POPs in <2 h. Moreover, photophysical experiments demonstrated the involvement of the singlet and triplet excited states of acetylated riboflavin and the generated singlet oxygen in the removal of these drugs. Besides, a detailed UFLC-MS-MS analysis of the photoproducts confirmed the oxidation of the drugs. Finally, a plausible mechanism has been postulated.

Enzyme Models-From Catalysis to Prodrugs.

Enzymes are highly specific biological catalysts that accelerate the rate of chemical reactions within the cell. Our knowledge of how enzymes work remains incomplete. Computational methodologies such as molecular mechanics (MM) and quantum mechanical (QM) methods play an important role in elucidating the detailed mechanisms of enzymatic reactions where experimental research measurements are not possible. Theories invoked by a variety of scientists indicate that enzymes work as structural scaffolds that serve to bring together and orient the reactants so that the reaction can proceed with minimum energy. Enzyme models can be utilized for mimicking enzyme catalysis and the development of novel prodrugs. Prodrugs are used to enhance the pharmacokinetics of drugs; classical prodrug approaches focus on alternating the physicochemical properties, while chemical modern approaches are based on the knowledge gained from the chemistry of enzyme models and correlations between experimental and calculated rate values of intramolecular processes (enzyme models). A large number of prodrugs have been designed and developed to improve the effectiveness and pharmacokinetics of commonly used drugs, such as anti-Parkinson (dopamine), antiviral (acyclovir), antimalarial (atovaquone), anticancer (azanucleosides), antifibrinolytic (tranexamic acid), antihyperlipidemia (statins), vasoconstrictors (phenylephrine), antihypertension (atenolol), antibacterial agents (amoxicillin, cephalexin, and cefuroxime axetil), paracetamol, and guaifenesin. This article describes the works done on enzyme models and the computational methods used to understand enzyme catalysis and to help in the development of efficient prodrugs.

Novel electro self-assembled DNA nanospheres as a drug delivery system for atenolol.

We describe new method for preparing DNA nanospheres for a self-assembled atenolol@DNA (core/shell) drug delivery system. In this paper, we propose the electrochemical transformation of an alkaline polyelectrolyte solution of DNA into DNA nanospheres. We successfully electrosynthesized DNA nanospheres that were stable for at least 2 months at 4 °C. UV-visible spectra of the prepared nanospheres revealed a peak ranging from 372 to 392 nm depending on the DNA concentration and from 361 to 398.3 nm depending on the electrospherization time. This result, confirmed with size distribution curves worked out from transmission electron microscopy (TEM) images, showed that increasing electrospherization time (6, 12 and 24 h) induces an increase in the average size of DNA nanospheres (48, 65.5 and 117 nm, respectively). In addition, the average size of DNA nanospheres becomes larger (37.8, 48 and 76.5 nm) with increasing DNA concentration (0.05, 0.1 and 0.2 wt%, respectively). Also, the affinity of DNA chains for the surrounding solvent molecules changed from favorable to bad with concomitant extreme reduction in the zeta potential from -31 mV to -17 mV. Principally, the attractive and hydrophobic interactions tend to compact the DNA chain into a globule, as confirmed by Fourier transform infrared spectroscopy (FTIR) and TEM. To advance possible applications, we successfully electro self-assembled an atenolol@DNA drug delivery system. Our findings showed that electrospherization as a cost-benefit technique could be effectively employed for sustained drug release. This delivery system achieved a high entrapment efficiency of 68.03 ± 2.7% and a moderate drug-loading efficiency of 3.73%. The FTIR spectra verified the absence of any chemical interaction between the drug and the DNA during the electrospherization process. X-ray diffraction analysis indicated noteworthy lessening in atenolol crystallinity. The present findings could aid the effectiveness of electrospherized DNA for use in various other pharmaceutical and biomedical applications.

In silico design and pharmacological evaluation of conjugates of atenolol with modified saccharide for cardiovascular targeting.

Amongst a wide range of biological macromolecules, saccharides exhibit the potential to be specifically recognized by cell-surface receptors and hence can be utilized as ligands in targeted drug delivery. The current study aims to use saccharides viz. Galactose, Pectin and Chitosan to improve targeting of Atenolol by oxalyl chloride mediated grafting. Conjugates were engineered by grafting Atenolol, a cardiovascular agent with the modified saccharide units. The conjugates were characterized by FTIR, DSC and 1H NMR study. Drug release analysis and cellular uptake study was carried out using H9c2 cell lines which represent that concentration of drug in cells treated with all atenolol-saccharide conjugates is enhanced by almost two-folds in comparison with cells treated with atenolol solution. Thus cell line study confers the evidence of selective cardiac delivery. No significant cytotoxicity was observed in case of all synthesized conjugates in the Brine shrimp lethality bioassay. Possible binding of the developed conjugates with the GLUT-4 receptors was assessed by in silico analysis using homology model developed by Swiss Model server. Hence it was concluded that the application of these conjugates with saccharides in selective cardiovascular drug delivery can be a promising approach to increase bioavailability, minimize drug loss by degradation and prevent harmful side effects by increasing specific cell targeting.

The adsorption performance and micro-mechanism of MoS2/montmorillonite composite to atenolol and acebutolol: Adsorption experiments and a novel visual study of interaction.

MoS2/montmorillonite (MoS2/Mt) composite was successfully synthesized through a simple hydrothermal method, and its adsorption performance for two emerging contaminants-atenolol (ATE) and acebutolol (ACE) was researched. The batch experiments revealed that the adsorption process can be described by the Pseudo-second order model and Langmuir model, and the adsorption capacity of MoS2/Mt, MoS2 and Mt for ATE were 132.08 mg/g, 60.68 mg/g and 74.23 mg/g, for ACE were 113.82 mg/g, 33.01 mg/g and 36.05 mg/g, respectively. Besides, Fourier-transform infrared spectroscopy (FTIR), BET specific surface area measurement and X-ray photoelectron spectroscopy (XPS) were also employed to analyze the adsorption mechanism. Moreover, quantitative molecular surface analysis and weak intermolecular interaction analysis with independent gradient model were combined to probe the microscopic interaction between the adsorbent and adsorbate. The results indicated the interactions included hydrogen bonding and vdW interaction. Mt and MoS2 interacted more strongly with ATE than ACE, which revealed the reason MoS2/Mt, Mt and MoS2 possessed higher adsorption capacity for ATE.

A study on the protease activity and structure of pepsin in the presence of atenolol and diltiazem.

Pepsin, as the main protease of the stomach, plays an important role in the digestion of food proteins into smaller peptides and performs about 20% of the digestive function. The role of pepsin in the development of gastrointestinal ulcers has also been studied for many years. Edible drugs that enter the body through the gastrointestinal tract will interact with this enzyme as one of the first targets. Continuous and long-term usage of some drugs will cause chronic contact of the drug with this protein, and as a result, the structure and function of pepsin may be affected. Therefore, the possible effect of atenolol and diltiazem on the structure and activity of pepsin was studied. The interaction of drugs with pepsin was evaluated using various experimental methods including UV-Visible spectroscopy, fluorescence spectroscopy, FTIR and enzymatic activity along with computational approaches. It was showed that after binding of atenolol and diltiazem to pepsin, the inherent fluorescence of the protein is quenched. Determination of the thermodynamic parameters of interactions between atenolol and diltiazem with pepsin indicates that the major forces in the formation of the protein-drug complexes are hydrophobic forces and also atenolol has a stronger protein bonding than diltiazem. Additional tests also show that the protease activity of pepsin, decreases and increases in the presence of atenolol and diltiazem, respectively. Investigation of the FTIR spectrum of the protein in the presence and absence of atenolol and diltiazem show that in the presence of atenolol the structure of protein has slightly changed. Molecular modeling studies, in agreement with the experimental results, confirm the binding of atenolol and diltiazem to the enzyme pepsin and show that the drugs are bind close to the active site of the enzyme. Finally, from experimental and computational results, it can be concluded that atenolol and diltiazem interact with the pepsin and change its structure and protease activity.

High-Silica Zeolites as Sorbent Media for Adsorption and Pre-Concentration of Pharmaceuticals in Aqueous Solutions.

The present work focused on the use of high-silica commercial zeolites as sorbent media for pharmaceuticals in an aqueous matrix. As drug probes, ketoprofen, hydrochlorothiazide, and atenolol were selected, because of their occurrence in surface waters and effluents from wastewater treatment plants. Pharmaceuticals adsorption was evaluated for two Faujasite topology zeolites with Silica/Alumina Ratio 30 and 200. The selected zeolites were demonstrated to be efficient sorbents towards all investigated pharmaceuticals, thanks to their high saturation capacities (from 12 to 32% w/w) and binding constants. These results were corroborated by thermal and structural analyses, which revealed that adsorption occurred inside zeolite's porosities, causing lattice modifications. Finally, zeolites have been tested as a pre-concentration media in the dispersive-solid phase extraction procedure. Recoveries higher than 95% were gained for ketoprofen and hydrochlorothiazide and approximately 85% for atenolol, at conditions that promoted the dissolution of the neutral solute into a phase mainly organic. The results were obtained by using a short contact time (5 min) and reduced volume of extraction (500 µL), without halogenated solvents. These appealing features make the proposed procedure a cost and time saving method for sample enrichment as well as for the regeneration of exhausted sorbent, rather than the more energetically expensive thermal treatment.

Fixed dose combinations for cardiovascular treatment via coaxial electrospraying: Coated amorphous solid dispersion particles.

As a result of an aging population, the need for fixed dose combinations in the treatment of cardiovascular diseases, that are easy to swallow and administer, has been growing remarkably. In this work, the feasibility of coaxial electrospraying (CES) was investigated to manufacture in one single step, a powder of individually coated particles containing atenolol (ATE), lovastatin (LOV) and acetylsalicylic acid (ASA). To improve the dissolution rate of the poorly water soluble LOV, an amorphous solid dispersion (ASD) of LOV with Soluplus® (SOL) was formulated and Eudragit S100®, an enteric copolymer that only dissolves above pH 7, was applied as coating to avoid LOV hydrolysis in acidic medium. Furthermore, ATE was added to the inner ASD compartment and the acidic ASA was embedded in the coating layer. With regard to the uncoated ASD particles, which were prepared with single nozzle electrospraying, the rate and extent of the LOV dissolution was increased, even to an extent of 100% for the 1/1/6 (ATE/LOV/SOL) ratio. Hence, this ratio was selected and coated particles with proper release of the three APIs could be successfully produced via CES. However, a peculiar behaviour of the coating performance was observed. Regarding LOV, the enteric layer of the particles performed as expected in acidic medium and supersaturation was obtained after the switch to a neutral pH, but in contrast, over 50% of ATE was released after 90 min in acidic medium. Nonetheless, hardly any ATE was released under acidic circumstances from ATE tablets that were, as a benchmark, manually dip-coated with Eudragit S100®. Two different model APIs, namely paracetamol (well soluble) and fenofibrate (poorly soluble) were tested as well, revealing similar discrepancy in the coating performance. The coating layer formed during CES is most likely less dense as compared to the layer produced with tablet coating and consequently, more permeable for highly soluble APIs, but not for the poorly soluble compounds.

Stereoselective cell uptake of adrenergic agonists and antagonists by organic cation transporters.

Stereoselectivity is well described for receptor binding and enzyme catalysis, but so far has only been scarcely investigated in carrier-mediated membrane transport. We thus studied transport kinetics of racemic (anti)adrenergic drugs by the organic cation transporters OCT1 (wild-type and allelic variants), OCT2, OCT3, MATE1, and MATE2-K with a focus on stereospecificity. OCT1 showed stereoselective uptake with up to 2-fold higher vmax over their corresponding counterpart enantiomers for (R,R)-fenoterol, (R,R)-formoterol, (S)-salbutamol, (S)-acebutolol, and (S)-atenolol. Orciprenaline and etilefrine were also transported stereoselectively. The Km was 2.1-fold and 1.5-fold lower for the (S,S)-enantiomers of fenoterol and formoterol, while no significant difference in Km was seen for the other aforementioned drugs. Common OCT1 variants showed similar enantiopreference to wild-type OCT1, with a few notable exceptions (e.g. a switch in enantiospecificity for fenoterol in OCT1*2 compared to the wild-type). Other cation transporters showed strong differences to OCT1 in stereoselectivity and transport activity: The closely related OCT2 displayed a 20-fold higher vmax for (S,S)-fenoterol compared to (R,R)-fenoterol and OCT2 and OCT3 showed 3.5-fold and 4.6-fold higher vmax for the pharmacologically active (R)-salbutamol over (S)-salbutamol. MATE1 and MATE2-K generally mediated transport with a higher capacity but lower affinity compared to OCT1, with moderate stereoselectivity. Our kinetic studies showed that significant stereoselectivity exists in solute carrier-mediated membrane transport of racemic beta-adrenergic drugs with surprising, and in some instances even opposing, preferences between closely related organic cation transporters. This may be relevant for drug therapy, given the strong involvement of these transporters in hepatic and renal drug elimination.

Enhancement of iron-mediated activation of persulfate using catechin: From generation of reactive species to atenolol degradation in water.

Persulfate (PS) activation reaction, which forms sulfate radical (SO4-), can be used to degrade organic pollutants in water. However, a drawback of this reaction is that the regeneration of ferrous ions requires a high concentration of hydrogen peroxide (Fenton-like reaction) or use of UV radiation. Catechin (CAT), a non-toxic antioxidant of natural origin from tea, is used in this work to improve the sulfate radical-mediated degradation of atenolol (ATL, a model pollutant) in water using relatively low concentrations of reactive chemical species (less than 100 µM). To the best of the author's knowledge, the direct effect of CAT on the oxidation state of iron, which is promoted by the reduction of ferric into ferrous ions with the enhancement of SO4- formation in the presence of PS, is demonstrated for the first time. The enhancement versus inhibition effect of CAT and the chemical mechanism of the iron-based activation process are explained. Results show that UVA radiation, which is representative of solar light, accelerates the initial degradation of ATL by more than 30% through ferric iron photolysis. Finally, a reaction mechanism leading to the formation of hydroxyl radicals (HO) and SO4- is proposed considering the implication of different activation/reaction chemical steps.

New insight into transdermal drug delivery with supersaturated formulation based on co-amorphous system.

The objective of this study was to prepare a supersaturated formulation based on formation of a co-amorphous system of a drug and a coformer in order to enhance skin permeation. Atenolol (ATE) and urea (URE) were used as the model drug and the coformer, respectively. Thermal analysis of physical mixtures of ATE and URE showed decreases in the melting points and the formation of a co-amorphous system which was in a supercooled liquid state because of a low glass transition temperature. Supersaturated solutions of ATE and URE at different molar ratios in polyethylene glycol 400 (PEG400) were prepared. The precipitations were observed under storage at 25 °C for all formulations except for ATE-URE at 1:8 molar ratio which remained in the supersaturated state for 2 months. 1H NMR analysis confirmed the interactions between ATE and URE in PEG400. The ATE-URE supersaturated formulation showed higher permeability for mice skin than that of ATE saturated formulation, which was superior to the expected permeability from the degree of supersaturation. We concluded that co-amorphous based supersaturated formulation offers much promise for transdermal drug delivery.

Molecular conformation, vibrational spectroscopic and NBO analysis of atenolol and atenolol-hydrochlorothiazide cocrystals.

Geometry optimization of atenolol (ATN) in the gas phase was carried out using B3LYP-D3BJ/6-31++G(d,p), CAM-B3LYP/6-31++G(d,p) and M06-2X/6-31++G(d,p) levels of DFT. The computed structural parameters were compared with the data obtained by single crystal X-ray diffraction experiment. Chemical reactivity (electronegativity, electrophilicity, hardness, chemical softness and chemical potential) was predicted with the help of HOMO- LUMO energy values. Experimental FT-IR was recorded and the calculated values were also analyzed using the same level of DFT. A complete vibrational spectrum was made to analyze the potential energy distribution (PED). Stability of the molecule arising from hyperconjugative interaction was analyzed by the natural bond orbital (NBO) analysis. The molecular electrostatic potential map was used to detect the possible electrophilic and nucleophilic sites in ATN molecule. Cocrystallization of atenolol-hydrochlorothiazide (ATN-HCTZ) was performed and the structure was analyzed by powder X-ray diffraction. NBO analysis was carried out on the ATN-HCTZ cocrystal for the elucidation of inter and intra-molecular hydrogen bonding interactions in the structure. Atenolol interaction with human serum albumin (HSA) was investigated by a molecular docking study.

Comprehensive analysis of the atenolol - DNA complex by viscometric, molecular docking and spectroscopic techniques.

This paper discusses multi-spectroscopic and molecular docking analysis of the interaction between atenolol (ATN) and deoxyribose nucleic acid (DNA) using alizarin (ALZ) as a spectroscopic probe. ATN is a ß1 -receptor antagonist belonging to the ß-blocker class of molecules. Experimental findings that were based on different spectroscopic analysis, melting studies, viscometric analysis, 1 H nuclear magnetic resonance and circular dichroism studies revealed the presence of a grove-binding mode. The effect of ionic strength was also studied, and observations suggested that electrostatic interaction also played a minor role during interaction. Molecular docking analysis suggested that the dominant force for the grove-binding phenomenon was hydrogen bonding between the 24-H residue of ATN and O of the 10-G residue, and the 40-H residue of ATN and N of the 17-A base residue. Competitive binding study of the ALZ-DNA complex with ATN showed that, despite an increase in the amount of ATN in the ALZ-DNA complex, the overall absorbance remained unchanged. The decrease in fluorescence in the ALZ-DNA system may be due to new non-fluorescent ATN-DNA-ALZ complex formation.

Measurements and correlations in solution-state for charge transfer products caused from the 1:2 complexation of TCNE acceptor with several important drugs.

In our previous work, we highlighted the thermodynamic and spectroscopic characteristics of the 1:1 charge transfer (CT) complexation of TCNE acceptor with various medically important drugs. Continuing that work, we further examine drugs that react with the TCNE acceptor via a 1:2 interaction. The examined drugs are atenolol, quinidine, cimetidine, reserpine, and levofloxacin. We aimed through this study to: i) make the spectrophotometric and thermodynamic data of the examined drugs, both initially and when reacted via a 1:2 M ratio with the TCNE acceptor, available to use in the determination or detection of these drugs in pharmaceuticals and other environments; and ii) compare the mode of interactions and the spectrophotometric and thermodynamic properties between drugs that react via a 1:1 or 1:2 ratio with the TCNE acceptor. To achieve these aims, the five examined drugs were reacted with TCNE in acetonitrile (MeCN) solvent at room temperature. Several thermodynamic and spectroscopic data were experimentally estimated using the van't Hoff and the Benesi-Hildebrand equations and discussed.

Activation of peroxymonosulfate by BiOCl@Fe3O4 catalyst for the degradation of atenolol: Kinetics, parameters, products and mechanism.

BiOCl@Fe3O4 photocatalyst was synthesized to activate peroxymonosulfate (PMS) for atenolol (ATL) degradation under simulated sunlight irradiation in present study. XRD, SEM, adsorbability and pore size distribution of BiOCl@Fe3O4 were analyzed. Magnetic BiOCl performed high activity in PMS activation and could be easily solid-liquid separation by applying an external magnetic field. Many parameters were inspected, including scavengers, PMS concentration, catalyst dosage, pH, anions (Cl- and CO3-). h+, SO4-, HO, O2-, SO5- were involved in ATL degradation in BiOCl@Fe3O4/PMS/sunlight system. The second-order rate constant of the reaction between ATL and SO4- (kATL, SO4-) was estimated via laser flash photolysis experiments. Moreover, ATL mineralization was followed by TOC analyzer. Twelve possible intermediate products were identified through LC-QTOF-MS analysis, and six ATL degradation pathways were concluded. This type of magnetic photocatalyst is characterized by ease of separation, high activation and good reusability. It may have application potential in refractory organic pollutants degradation.

Ion-pair approach coupled with nanoparticle formation to increase bioavailability of a low permeability charged drug.

Atenolol is a drug widely used for the treatment of hypertension. However, the great drawback it presents is a low bioavailability after oral administration. To obtain formulations that allow to improve the bioavailability of this drug is a challenge for the pharmaceutical technology. The objective of this work was to increase the rate and extent of intestinal absorption of atenolol as model of a low permeability drug, developing a double technology strategy. To increase atenolol permeability an ion pair with brilliant blue was designed and the sustained release achieved through encapsulation in polymeric nanoparticles (NPs). The in vitro release studies showed a pH-dependent release from NPs, (particle size 437.30 ±â€¯8.92) with a suitable release profile of drug (atenolol) and counter ion (brilliant blue) under intestinal conditions. Moreover, with the in vivo assays, a significant increase (2-fold) of atenolol bioavailability after administering the ion-pair NPs by oral route was observed. In conclusion, the combination of ion-pair plus polymeric NPs have proved to be a simple and very useful approach to achieve a controlled release and to increase the bioavailability of a low permeability charged drugs.

Improved Enantioselectivity for Atenolol Employing Pivot Based Molecular Imprinting.

In the last few decades, molecular imprinting technology went through a spectacular evolution becoming a well-established tool for the synthesis of highly selective biomimetic molecular recognition platforms. Nevertheless, there is still room for advancement in the molecular imprinting of highly polar chiral compounds. The aim of the present work was to investigate the favorable kosmotropic effect of a ternary complex involving a polar chiral template (eutomer of atenolol) and a functional monomer, bridged by a central metal ion through well-defined, spatially directional coordinate bonds. The efficiency of the chiral molecular recognition was systematically assessed on polymers obtained both by non-covalent and metal-mediated molecular imprinting. The influence on the chromatographic retention and enantioselectivity of different experimental variables (functional monomers, cross-linkers, chaotropic agents, metal ions, porogenic systems, etc.) were studied on both slurry packed and monolithic HPLC columns. Deliberate changes in the imprinting and rebinding (chromatographic) processes, along with additional thermodynamic studies shed light on the particularities of the molecular recognition mechanism. The best performing polymer in terms of enantioselectivity (α = 1.60) was achieved using 4-vinyl pyridine as functional monomer and secondary ligand for the Co(II)-mediated imprinting of S-atenolol in the presence of EDMA as cross-linker in a porogenic mixture of [BMIM][BF4]:DMF:DMSO = 10:1:5, v/v/v.