Immobilization of cellulase on monolith supported with Zr(IV)-based metal-organic framework as chiral stationary phase for enantioseparation of five basic drugs in capillary electrochromatography.

Metal-organic framework (UiO-66-NH2)-incorporated organic polymer monolith was prepared by thermal polymerization. By virtue of the superior physical and chemical properties, the UiO-66-NH2-modified organic monolith was then functionalized by chiral selector cellulase via the condensation reaction between the primary amino groups and aldehyde groups. The synthesized materials were characterized by Fourier transform infrared spectroscopy, high-resolution transmission electron microscopy, scanning electron microscopy, X-ray photoelectron spectrometry, thermogravimetric analysis, and nitrogen sorption isotherm. The cellulase@poly(glycidyl methacrylate-UiO-66-NH2-ethylene glycol dimethacrylate) (cellulase@poly(GMA-UiO-66-NH2-EDMA)) monolith was applied to enantiomerically separate the basic racemic forms of metoprolol, atenolol, esmolol, bisoprolol, and propranolol. In contrast to the cellulase@poly(GMA-co-EDMA) monolith without UiO-66-NH2, the cellulase@poly(GMA-UiO-66-NH2-EDMA) monolith reveals significantly improved enantiodiscrimination performance for metoprolol (Rs: 0 → 1.67), atenolol (Rs: 0 → 1.50), esmolol (Rs: 0 → 1.52), bisoprolol (Rs: 0 → 0.36), and propranolol (Rs: 0 → 0.44). The immobilization pH of cellulase, buffer pH, UiO-66-NH2 concentration, and the proportion of organic modifier were evaluated in detail with enantiomerically separating chiral molecules. The intra-day, inter-day, column-to-column, and inter-batch precision have been discussed, the result was preferable, and the relative standard deviation (RSD) of separation parameters was <4.3%. Schematic representation of the preparation of a UiO-66-NH2-modified organic polymer monolith for enantioseparating five racemic ß-blockers. UiO-66-NH2 was synthesized and converted into a monolith as the stationary phase. Then, the modified monolith containing cellulase as the chiral selector was applied in a capillary electrochromatography system for enantioseparating chiral drugs.

Highly exfoliated functionalized MoS2 with sodium alginate-polydopamine conjugates for electrochemical sensing of cardio-selective ß-blocker by voltammetric methods.

Molybdenum disulfide (MoS2) surface functionalization was performed with a catechol-containing polymer sodium alginate (SA) and dopamine (DA) through simultaneous MoS2 exfoliation and self-polymerization of DA. The MoS2/SA-PDA nanocomposite was characterized using spectroscopic, microscopic, and electroanalytical techniques to evaluate its electrocatalytic performance. The electrocatalytic behavior of the MoS2/SA-PDA nanocomposite modified electrode for the detection of acebutolol (ACE), a cardio-selective ß-blocker drug was explored  through cyclic voltammetric and differential pulse voltammetric techniques. The influence of scan rate, concentration, and pH value on the oxidation peak current of ACE was investigated  to optimize the deducting condition. The electrochemical activity of the MoS2/SA-PDA nanocomposite electrode was attributed to the existence of reactive functional groups being contributed from SA, PDA, and MoS2 exhibiting a synergic effect. The MoS2/SA-PDA nanocomposite modified electrode exhibits admirable electrocatalytic activity with a wide linear response range (0.009 to 520 µM), low detection limit (5 nM), and high sensitivity (0.354 µA µM-1 cm-2) also in the presence of similar (potentially interfering) compounds. The fabricated MoS2/SA-PDA nanocomposite modified electrode can be useful for the detection of ACE in pharmaceutical analysis.

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.

Comparative evaluation of metoprolol degradation by UV/chlorine and UV/H2O2 processes.

The degradation of metoprolol (MTP), a ß-blocker commonly used for cardiovascular diseases, by UV/chlorine and UV/H2O2 processes was comparatively evaluated. MTP direct photolysis at 254 nm could be neglected, but remarkable MTP degradation was observed in both the UV/chlorine and UV/H2O2 systems. Compared with UV/H2O2, UV/chlorine has a more pronounced MTP degradation efficiency. In addition to primary radicals (OH and Cl), secondary radicals (ClO and Cl2-) played a pivotal role in degrading MTP by UV/chlorine process. The relative contributions of hydroxyl radicals (OH) and reactive chlorine species (RCS) in the UV/chlorine system varied at different solution pH values (i.e., the contribution of RCS increased from 57.7% to 75.1% as the pH increased from 6 to 8). The degradation rate rose as the oxidant dosage increased in the UV/chlorine and UV/H2O2 processes. The presence of Cl- slightly affected MTP degradation in both processes, while the existence of HCO3- and HA inhibited MTP degradation to different extents in both processes. In terms of the overall cost of electrical energy, UV/chlorine is more cost efficient than UV/H2O2. The degradation products during the two processes were identified and compared, and the degradation pathways were proposed accordingly. Compared with the direct chlorination of MTP, pre-oxidation with UV/chlorine and UV/H2O2 significantly enhanced the formation of commonly known DBPs. Therefore, when using UV/chlorine and UV/H2O2 in real waters to remove organic pollutants, the possible risk of enhanced DBP formation resulting from the degradation of certain pollutants during post-chlorination should be carefully considered.

Development of covalent antagonists for ß1- and ß2-adrenergic receptors.

The selective covalent tethering of ligands to a specific GPCR binding site has attracted considerable interest in structural biology, molecular pharmacology and drug design. We recently reported on a covalently binding noradrenaline analog (FAUC37) facilitating crystallization of the ß2-adrenergic receptor (ß2ARH2.64C) in an active state. We herein present the stereospecific synthesis of covalently binding disulfide ligands based on the pharmacophores of adrenergic ß1- and ß2 receptor antagonists. Radioligand depletion experiments revealed that the disulfide-functionalized ligands were able to rapidly form a covalent bond with a specific cysteine residue of the receptor mutants ß1ARI2.64C and ß2ARH2.64C. The propranolol derivative (S)-1a induced nearly complete irreversible blockage of the ß2ARH2.64C within 30 min incubation. The CGP20712A-based ligand (S)-4 showed efficient covalent blocking of the ß2ARH2.64C at very low concentrations. The analog (S)-5a revealed extraordinary covalent cross-linking at the ß1ARI2.64C and ß2ARH2.64C mutant while retaining a 41-fold selectivity for the ß1AR wild type over ß2AR. These compounds may serve as valuable molecular tools for studying ß1/ß2 subtype selectivity or investigations on GPCR trafficking and dimerization.

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.

The solid-state structure of the ß-blocker metoprolol: a combined experimental and in silico investigation.

Metoprolol {systematic name: (RS)-1-isopropylamino-3-[4-(2-methoxyethyl)phenoxy]propan-2-ol}, C15H25NO3, is a cardioselective ß1-adrenergic blocking agent that shares part of its molecular skeleton with a large number of other ß-blockers. Results from its solid-state characterization by single-crystal and variable-temperature powder X-ray diffraction and differential scanning calorimetry are presented. Its molecular and crystal arrangements have been further investigated by molecular modelling, by a Cambridge Structural Database (CSD) survey and by Hirshfeld surface analysis. In the crystal, the side arm bearing the isopropyl group, which is common to other ß-blockers, adopts an all-trans conformation, which is the most stable arrangement from modelling data. The crystal packing of metoprolol is dominated by an O-H...N/N...H-O pair of hydrogen bonds (as also confirmed by a Hirshfeld surface analysis), which gives rise to chains containing alternating R and S metoprolol molecules extending along the b axis, supplemented by a weaker O...H-N/N-H...O pair of interactions. In addition, within the same stack of molecules, a C-H...O contact, partially oriented along the b and c axes, links homochiral molecules. Amongst the solid-state structures of molecules structurally related to metoprolol deposited in the CSD, the ß-blocker drug betaxolol shows the closest analogy in terms of three-dimensional arrangement and interactions. Notwithstanding their close similarity, the crystal lattices of the two drugs respond differently on increasing temperature: metoprolol expands anisotropically, while for betaxolol, an isotropic thermal expansion is observed.

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.

Photodegradation of metoprolol using a porphyrin as photosensitizer under homogeneous and heterogeneous conditions.

Porphyrins are known as effective photosensitizers and can be an interesting key in phototreatment of water contaminated with micropollutants such as pharmaceuticals. They already showed to be efficient photocatalysts for the degradation of dyes, chlorophenols and other pollutants. This work demonstrates the applicability of 5,10,15,20-tetrakis(pentafluorophenyl)porphyrin (H2TF5PP) as photosensitizer for treatment of water contaminated with metoprolol, a highly prescribed ß-blocker, which is not completely removed in sewage treatment plants. Studies were firstly developed under homogeneous conditions with simulated solar radiation and porphyrin was found to be efficient in the photodegradation of metoprolol, following a pseudo-first order kinetics with ca. 90% metoprolol degradation after 12 h. Experiments in presence of scavengers confirmed the mechanism of degradation via singlet oxygen. Appearance of several new peaks in HPLC chromatograms indicates the formation of products, identified by HPLC-MSn. Furthermore, the porphyrin was immobilized on a silica support and used as heterogeneous photocatalyst in degradation of metoprolol. Experiments using this heterogeneous photocatalyst under real solar irradiation were also performed, and similar results were obtained. Kinetic comparison of metoprolol photodegradation in buffer solution and in real wastewater treatment plant effluent showed that the efficiency of the immobilized porphyrin was not decreased by the complex matrix of the effluent.

Sustained ophthalmic delivery of highly soluble drug using pH-triggered inner layer-embedded contact lens.

In the present work the feasibility of using inner layer-embedded contact lenses (CLs) to achieve sustained release of highly water soluble drug, betaxolol hydrochloride (BH) on the ocular surface was investigated. Blend film of cellulose acetate and Eudragit S100 was selected as the inner layer, while silicone hydrogel was used as outer layer to construct inner layer-embedded contact lenses. Influence of polymer ratio in the blend film on in vitro drug release behavior in phosphate buffered solution or simulated tear fluid was studied and drug-polymer interaction, erosion and swelling of the blend film were characterized to better understand drug-release mechanism. Storage stability of the inner layer-embedded contact lenses in phosphate buffer solution was also conducted, with ignorable drug loss and negligible change in drug release pattern within 30 days. In vivo pharmacokinetic study in rabbits showed sustained drug release for over 240 h in tear fluid, indicating prolonged drug precorneal residence time. In conclusion, cellulose acetate/Eudragit S100 inner layer-embedded contact lenses are quite promising as controlled-release carrier of highly water soluble drug for ophthalmic delivery.

The Influence of Fatty Acids on Metoprolol - Human Serum Albumin Interaction in Low Affinity Binding Sites: A Multifactorial NMR Approach.

BACKGROUND: Metoprolol (MTP) is a cardio-selective ß1-blocker used in hypertension, angina pectoris and chronic heart failure therapies. Serum albumin is the most frequently occurring protein in blood plasma. The binding of ligands to human serum albumin (HSA) has an important effect on pharmacokinetics and final clinical effects. OBJECTIVE: The objectives of this study included a detailed analysis of metoprolol - serum albumin interactions in low affinity binding sites, on the surface or within the hydrophobic subdomain of a macromolecule, as well as an analysis of the competition between MTP and fatty acids in binding with protein. METHODS: The analysis of the drug-albumin interaction was based on the observed chemical shifts in combination with correlation Times (T1 -1 = τ) [1/s], 2D NOESY 1H NMR spectra and association constants Ka [M-1]. For the determination of chemical shifts σ [ppm], relaxation times T1 [s] and for the NOESY experiment, the final concentrations of MTP and albumins (in the presence (HSA) and absence of fatty acids (dHSA)) were 5 x 10-3 M and 2 x 10-5 M - 4.55 x 10-4 M, respectively. In order to calculate the association constants, the final concentrations of MTP and both HSA and dHSA were 2.75 x 10-3 M - 6.25 x 10-2 M and 2.5 x 10-4 M, respectively. For the analysis, the MTP proton resonances of aliphatic H17, aromatic (H2/H6 and H3/H5) and the methoxy group H14 were chosen. RESULTS: Changes in the values of the 1H NMR chemical shift [ppm] are evidence of interaction between MTP, fatted (HSA) and defatted (dHSA) human serum albumin. With an increase of albumin concentration, changes in the chemical shift values were observed for the aromatic protons H2/H6 (Δσ = 0.013 ppm and 0.018 ppm) and H3/H5 (Δσ = 0.015 ppm and 0.019 ppm), the aliphatic proton H17 (Δσ = 0.018 ppm and 0.022 ppm) and the aliphatic protons of the methoxy group H14 (Δσ = 0.019 ppm and 0.022 ppm) for dHSA and HSA, respectively. Greater changes in chemical shifts in the presence of fatty acids (FA) were observed. Changes in the correlation times of MTP aromatic H2/H6 (Δτc = 0.224 1/s and 0.189 1/s) and H3/H5 (Δτc = 0.269 1/s and 0.210 1/s), aliphatic from the methoxy group H14 (Δτc = 0.472 1/s and 0.271 1/s) and aliphatic H17 protons (Δτc = 0.178 1/s and 0.137 1/s) for dHSA and HSA systems, respectively. It confirms the interaction between the drug and albumin are evidence for the dynamics of the process. In the presence of FA the relaxation time of all analyzed MTP proton resonance signals significantly increases (due to the decrease of correlation time). This phenomenon is due to the increase of electron density in the MTP protons' surroundings. Association constants for the MTP-dHSA complex in the low affinity site range between 0.29 x 102 M-1 and 0.47 x 102 M-1. The presence of FA results in a two to three-fold increase of the Ka values of protons from aromatic (H2/H6 and H3/H5), aliphatic H17 and methoxy (H14) groups. In 2D NOESY spectra proton magnetization transfer was observed between cysteine (Cys-34) and aromatic H3/H5 and H2/H6 protons. Cross-peaks were also observed between cysteine and aliphatic protons from the methoxy group. CONCLUSION: The selective changes in σ [ppm] and τc [1/s] values indicated the unequal participation of chemical groups of MTP in the interaction with HSA and dHSA. The data obtained suggest that the presence of fatty acids increases the accessibility of low affinity sites of serum albumin to MTP, which results in the higher affinity of albumin towards the drug. The results showed that the main binding site of MTP and fatty acid is probably a low affinity site in subdomain IB, where Cys-34 can be located.

Rediscovering Chirality - Role of S-Metoprolol in Cardiovascular Disease Management.

BACKGROUND: The process of drug discovery and development today encompass a myriad of paths for bringing a new therapeutic molecule that has minimal adverse effects and of optimal use to the patient. Chirality was proposed in the direction of providing a purer and safer form of drug [Ex- cetrizine and levocetrizine]. Decades have passed since the introduction of this concept and numerous chiral molecules are in existence in therapeutics, yet somehow this concept has been ignored. This review aims to rediscover the ignored facts about chirality, its benefits and clear some common myths considering the example of S-Metoprolol in the management of Hypertension and other cardiovascular diseases. METHODS: Relevant articles from Pubmed, Embase, Medline and Google Scholar were searched using the terms "Chiral", "Chirality", "Enantiomers", "Isomers", "Isomerism", "Stereo-chemistry", and "S-Metoprolol". Out of 103 articles found 17 articles mentioning in general about the concept of chirality and articles on study of S-metoprolol in various cardiovascular diseases were then reviewed. RESULTS: Many articles mention about the importance of chirality yet the concept has not been highlighted much. Clear benefits with chiral molecules have been documented for various drug molecules few amongst them being anaesthetics, antihypertensives, antidepressants. Benefits of S-metoprolol over racemate are also clear in terms of responder rates, dose of administration and adverse effects profile in various cardiovascular diseases. CONCLUSIONS: Chirality is a good way forward in providing a new drug molecule which is safe with lesser pharmacokinetic and pharmacodynamics variability, lesser side effects and more potent action. S-metoprolol is chirally pure form of racemate metoprolol and has lesser side effects, is safer in patients of COPD and Diabetes who also have hypertension and comparable responder rates at half the doses when compared to racemate.

Sublingual fast dissolving niosomal films for enhanced bioavailability and prolonged effect of metoprolol tartrate.

The aim of the present work was to prepare and evaluate sublingual fast dissolving films containing metoprolol tartrate-loaded niosomes. Niosomes were utilized to allow for prolonged release of the drug, whereas the films were used to increase the drug's bioavailability via the sublingual route. Niosomes were prepared using span 60 and cholesterol at different drug to surfactant ratios. The niosomes were characterized for size, zeta-potential, and entrapment efficiency. The selected niosomal formulation was incorporated into polymeric films using hydroxypropyl methyl cellulose E15 and methyl cellulose as film-forming polymers and Avicel as superdisintegrant. The physical characteristics (appearance, texture, pH, uniformity of weight and thickness, disintegration time, and palatability) of the prepared films were studied, in addition to evaluating the in vitro drug release, stability, and in vivo pharmacokinetics in rabbits. The release of the drug from the medicated film was fast (99.9% of the drug was released within 30 minutes), while the drug loaded into the niosomes, either incorporated into the film or not, showed only 22.85% drug release within the same time. The selected sublingual film showed significantly higher rate of drug absorption and higher drug plasma levels compared with that of commercial oral tablet. The plasma levels remained detectable for 24 hours following sublingual administration, compared with only 12 hours after administration of the oral tablet. In addition, the absolute bioavailability of the drug (ie, relative to intravenous administration) following sublingual administration was found to be significantly higher (91.06%±13.28%), as compared with that after oral tablet administration (39.37%±11.4%). These results indicate that the fast dissolving niosomal film could be a promising delivery system to enhance the bioavailability and prolong the therapeutic effect of metoprolol tartrate.

Piecewise function parameters as responses of the design of experiment in the development of a pulsatile release chronopharmaceutical system.

The aim of this work was to develop a pulsatile release system with metoprolol for chronotherapeutical use by coating swellable mini-tablets with Eudragit RS. To study the influence of the formulation factors (amount of coating polymer, plasticizer percentage in film coating and swelling agent percentage in mini-tablets), a Box-Behnken design of experiment (DoE) was used. To evaluate the influence of the studied factors on the sigmoid shape of the dissolution profile, piecewise function parameters were used as the responses of DoE. The results show that higher concentrations of coating polymer and higher concentrations of plasticizer polymer led to a thicker and more elastic polymeric film, which led to a delay in drug release. Using the parameters of the piecewise function as DoE responses, an optimum formulation with a sigmoid shape dissolution profile and a 2.5-h lag time followed by rapid drug release were obtained.

Formulation development and comparative in vitro study of metoprolol tartrate (IR) tablets.

The objective of the present work was to develop Immediate Release (IR) tablets of Metoprolol Tartrate (MT) and to compare trial formulations to a reference product. Six formulations (F1-F6) were designed using central composite method and compared to a reference brand (A). Two marketed products (brands B and C) were also evaluated. F1-F6 were prepared with Avicel PH101 (filler), Crospovidone (disintegrant) and Magnesium Stearate (lubricant) by direct compression. Pharmacopoeial and non-pharmacopoeial methods were used to assess their quality. Furthermore, drug profiles were characterized using model dependent and independent (f(2)) approaches. Brands B and C and F5 and F6 did not qualify the tests for content uniformity. Moreover, brand B did not meet weight variation criteria and brand C did not satisfy requirements for single point dissolution test. Of the trial formulations, F2 failed the test for uniformity in thickness while F4 did not disintegrate within time limit. Only F1 and F3 met all quality parameters and were subjected to accelerated stability testing without significant alterations in their physicochemical characteristics. Based on AIC and r(2)(adjusted) values obtained by applying various kinetic models, drug release was determined to most closely follow Hixson-Crowell cube root law. F1 was determined to be the optimized formulation.

Formulation development and optimization: Encapsulated system of Atenolol and Glyburide.

PURPOSE: Objective of this study is to develop; tablet-in-a capsule system, to deliver Atenolol 25mg and Glyburide 5mg in the hard gelatin capsule. In order to improve patient compliance and reduce problems associated with complex therapeutic regimen Atenolol (cardio-selective beta-blocker) and Glyburide (anti-diabetic; sulfonylurea) are commonly, prescribed to the diabetic hypertensive patient. Metgod: In present work six different formulations of Atenolol (AF1-AF6) and Glyburide (GF1-GF6) were prepared by direct compression method using Avicel, Lactose DC, Crospovidone and Magnesium Stearate in different proportions and encapsulated in hard gelatin shells. Post compression parameters i.e. weight variation, diameter variation, thickness variation, hardness variation, % friability, disintegration, % drug release were determined at different pH 1.2, 4.5 and 6.8, and subjected to dissolution profile comparison through similarity factor (ƒ2). RESULTS: Stability studies were performed and shelf lives were calculated by R-Gui Stab R console 2.15.2 and determined to be 15 and 27 months for Atenolol and Glyburide respectively. The percentage drug contents of Atenolol and Glyburide were estimated spectrophotometerically at 286 nm and 314.7 nm respectively. Formulations CF1-CF6 (encapsulated) were subjected to weight variation, disintegration and dissolution tests and subjected to model dependant analysis for dissolution studies. The simultaneous quantitation of Atenolol and Glyburide for content assay was done by HPLC method of analysis. CONCLUSION: formulation CF6 is showing highest coefficient of correlation values for all models applied. So we can conclude that the proposed system can improve patient compliance by increasing the ease of administration of two drugs together.

Synthesis, Characterization, and Atenolol Delivery Application of Functionalized Mesoporous Hydroxyapatite Nanoparticles Prepared by Microwave-Assisted Co-precipitation Method.

BACKGROUND: Atenolol has been used to treat angina and hypertension, either alone or with other antihypertensives. Despite its usefulness, it shows some side effects such as diarrhea and nausea in some patients. A method for slow release of atenolol in intestine is helpful to prevent such side effects. METHODS: A facile co-precipitation microwave-assisted method was used to fabricate mesoporous hydroxyapatite nanoparticles (mHAp). It was then functionalized to have SO3H groups. The synthesized material was used for storage/slow release study of atenolol. RESULTS: Atenolol loaded mHAp shows immediate release of atenolol in pH 8, whileafter functionalizing shows up to ca. 30% release at the beginning. In pH 1, 50% of drug was released after 10 h from AT@mHAp and after 18h the drug was almost completely released.The drug release profiles of functionalized HAp at pH value 1 and 8reveals the complete release of atenolol in intestine pH, while no complete release is observed in stomach environment. CONCLUSION: The aims of this work were synthesis and characterization of mesoporous HAp through the microwave-assisted co-precipitation method and elucidate the underlying drug release capability of mesoporous HAp nanoparticles. The SO3H group was incorporated into the mesoporous HAp and then used as drug delivery carriers using atenolol as a model drug to investigate their drug storage/release properties in simulated body fluid (SBF). Increasing pH value to 8 causes increase in the drug release.

Aqueous chlorination of acebutolol: kinetics, transformation by-products, and mechanism.

This study investigated the reaction kinetics and the transformation by-products of acebutolol during aqueous chlorination. Acebutolol is one of the commonly used ß-blockers for the treatment of cardiovascular diseases. It has been frequently detected in the aquatic environment. In the kinetics study, the second-order rate constant for the reaction between acebutolol and chlorine (k app) was determined at 25 ± 0.1 °C. The degradation of acebutolol by free available chlorine was highly pH dependence. When the pH increased from 6 to 8, it was found that the k app for the reaction between acebutolol and free available chlorine was increased from 1.68 to 11.2 M(-1) min(-1). By comparing with the reported k app values, the reactivity of acebutolol toward free available chlorine was found to be higher than atenolol and metoprolol but lower than nadolol and propranolol. Characterization of the transformation by-products formed during the chlorination of acebutolol was carried out using liquid chromatography-quadrupole time-of-flight high-resolution mass spectrometry. Seven major transformation by-products were identified. These transformation by-products were mainly formed through dealkylation, hydroxylation, chlorination, and oxidation reactions.

Formulation and in-vitro evaluation of floating bilayer tablet of lisinopril maleate and metoprolol tartrate.

The purpose of this study was to introduce the technology for the development of rate-controlled oral drug delivery system to overcome various physiological problems. Several approaches are being used for the purpose of increasing the gastric retentive time, including floating drug delivery system. Gastric floating lisinopril maleate and metoprolol tartrate bilayer tablets were formulated by direct compression method using the sodium starch glycolate, crosscarmellose sodium for IR layer. Eudragit L100, pectin, acacia as sustained release polymers in different ratios for SR metoprolol tartrate layer and sodium bicarbonate, citric acid as gas generating agents for the floating extended release layer. The floating bilayer tablets of lisinopril maleate and metoprolol tartrate were designed to overcome the various problems associated with conventional oral dosage form. Floating tablets were evaluated for floating lag time, drug contents and in-vitro dissolution profile and different kinetic release models were applied. It was clear that the different ratios of polymers affected the drug release and floating time. L2 and M4 showed good drug release profile and floating behavior. The linear regression and model fitting showed that all formulation followed Higuchi model of drug release model except M4 that followed zero order kinetic. From the study it is evident that a promising controlled release by floating bilyer tablets of lisinopril maleate and metoprolol tartrate can be developed successfully.