Thermodynamic and Computational (DFT) Study of Non-Covalent Interaction Mechanisms of Charge Transfer Complex of Linagliptin with 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and Chloranilic acid (CHA).

This study describes the non-covalent interactions of the charge transfer complex (CT), which was responsible for the synthesis of Linagliptin (LNG) with 2,3-Dichloro-5,6-Dicyano-1,4-benzoquinone (DDQ), or with Chloranilic acid (CHA) complexes in acetonitrile (MeCN) at temperatures of (25 ± 2 °C). Then, a UV-Vis spectrophotometer was utilized to identify Linagliptin (LNG) from these complexes. For the quantitative measurement of Linagliptin in bulk form, UV-Vis techniques have been developed and validated in accordance with ICH criteria for several aspects, including selectivity, linearity, accuracy, precision, LOD, LOQ, and robustness. The optimization of the complex synthesis was based on solvent polarization; the ratio of molecules in complexes; the association constant; and Gibbs energy (ΔG°). The experimental work is supported by the computational investigation of the complexes utilizing density functional theory as well as (QTAIM); (NCI) index; and (RDG). According to the optimized conditions, Beer's law was observed between 2.5-100 and 5-100 µM with correlation coefficients of 1.9997 and 1.9998 for LGN-DDQ and LGN-CHA complexes, respectively. For LGN-DDQ and LGN-CHA complexes, the LOD and LOQ were (1.0844 and 1.4406 µM) and (3.2861 and 4.3655 µM), respectively. The approach was successfully used to measure LGN in its bulk form with high precision and accuracy.

Binding and drug displacement study of colchicine and bovine serum albumin in presence of azithromycin using multispectroscopic techniques and molecular dynamic simulation.

The binding and displacement interaction of colchicine and azithromycin to the model transport protein bovine serum albumin (BSA) was evaluated in this study. Azithromycin, a macrolide antibiotic, has antiviral properties and hence, has been used concomitantly with hydroxychloroquine against SARS-CoV-2. Colchicine, a natural plant product is used to treat and prevent acute gout flares. Some macrolide antibiotics are reported to have fatal drug-drug interactions with colchicine. The displacement interaction between colchicine and azithromycin on binding to BSA was evaluated using spectroscopic techniques, molecular docking and molecular dynamic simulation studies. The binding constant recorded for the binary system BSA-colchicine was 7.44 × 104 whereas, the binding constant for the ternary system BSA-colchicine in presence of azithromycin was 7.38 × 104 and were similar. Azithromycin didn't bind to BSA neither did it interfere in binding of colchicine. The results from molecular docking studies also led to a similar conclusion that azithromycin didn't interfere in the binding of colchicine to BSA. These findings are important since there is possibility of serious adverse event with co-administration of colchicine and azithromycin in patients with underlying gouty arthritis and these patients need to be continuously monitored for colchicine toxicity.

Molecular docking and experimental investigation of new indole derivative cyclooxygenase inhibitor to probe its binding mechanism with bovine serum albumin.

The indole derivative 2-(5-methoxy-2-methyl-1H-indol-3-yl)-N'-[(E)-(3-nitrophenyl) methylidene]acetohydrazide (IND) was synthesized for its therapeutic potential to inhibit cyclooxygenase (COX)-II. Binding if IND to bovine serum albumin (BSA) was investigated was because most drugs bind to serum albumin in-vivo. Fluorescence, UV-vis spectrophotometry and molecular modeling methodologies were employed for studying the interaction mechanism. The intrinsic fluorescence of BSA was quenched by BSA and the quenching mechanism involved was static quenching. The binding constants between IND and BSA at the three studied temperatures (298, 301 and 306 K) were 1.09 × 105, 4.36 × 104 and 1.23 × 104 L mol-1 respectively. The most likely site for binding IND to BSA was Site I (subdomain IIA). The analysis of thermodynamic parameter revealed the involvement of hydrogen bonding and van der Waals forces in the IND-BSA interaction. Synchronous fluorescence spectroscopic (SFS) and UV-vis spectrophotometric studies suggested conformational change in BSA molecule post interaction to IND. Molecular docking and the experimental results corroborated one another. The study can prove as an insight for future IND drug development.

HPLC-fluorescence method for the enantioselective analysis of propranolol in rat serum using immobilized polysaccharide-based chiral stationary phase.

A stereoselective high-performance liquid chromatographic (HPLC) method was developed and validated to determine S-(-)- and R-(+)-propranolol in rat serum. Enantiomeric resolution was achieved on cellulose tris(3,5-dimethylphenylcarbamate) immobilized onto spherical porous silica chiral stationary phase (CSP) known as Chiralpak IB. A simple analytical method was validated using a mobile phase consisted of n-hexane-ethanol-triethylamine (95:5:0.4%, v/v/v) at a flow rate of 0.6 mL min(-1) and fluorescence detection set at excitation/emission wavelengths 290/375 nm. The calibration curves were linear over the range of 10-400 ng mL(-1) (R = 0.999) for each enantiomer with a detection limit of 3 ng mL(-1). The proposed method was validated in compliance with ICH guidelines in terms of linearity, accuracy, precision, limits of detection and quantitation, and other aspects of analytical validation. Actual quantification could be made for propranolol isomers in serum obtained from rats that had been intraperitoneally (i.p.) administered a single dose of the drug. The proposed method established in this study is simple and sensitive enough to be adopted in the fields of clinical and forensic toxicology. Molecular modeling studies including energy minimization and docking studies were first performed to illustrate the mechanism by which the active enantiomer binds to the ß-adrenergic receptor and second to find a suitable interpretation of how both enantiomers are interacting with cellulose tris(3,5-dimethylphenylcarbamate) CSP during the process of resolution. The latter interaction was demonstrated by calculating the binding affinities and interaction distances between propranolol enantiomers and chiral selector.

Avanafil: A comprehensive drug profile.

Avanafil is an oral medication used to treat erectile dysfunction (ED). As a phosphodiesterase type 5 (PDE5) inhibitor, it functions by inhibiting the PDE5 enzyme, which ultimately results in increased levels of cyclic guanosine monophosphate (cGMP) and improved blood flow to the penis. Approved by the FDA in 2012, avanafil is recognised for its rapid onset of action, short half-life, and favourable side-effects profile. While it has been explored for other potential therapeutic applications, its current approved use is limited to ED and should be used as prescribed by a medical professional. This chapter provides a comprehensive review of avanafil, encompassing its nomenclature, physicochemical properties, methods of preparation, and identification. Various techniques for analysing avanafil, such as electrochemical analysis, spectrophotometric, spectrofluorimetric, and chromatographic techniques, are discussed. The pharmacology of avanafil, including its pharmacokinetics and pharmacodynamics, is also examined.

Lodenafil.

Lodenafil is a class of drugs called an inhibitor of PDE5 which also include a wide range of other erectile medicines, such as sildenafil, tadalafil and vardenafil. It is part of a new generation of PDE5 inhibitors that includes udenafil and avanafil. Lodenafil is a prodrug manufactured in the form of lodenafil carbonate, the carbonate dimer that divides in the body into two active drug lodenafil molecules. The oral bioavailability of this formulation is higher than that of the parent drug. This article discusses, by a critical comprehensive review of the literature on lodenafil in terms of its description, names, formulae, elemental composition, appearance, and therapeutic uses. The article also discusses the methods for preparation of lodenafil, its physical-chemical properties, analytical methods for its determination, pharmacological-toxicological properties, and dosing information.

Influence of antioxidant flavonoids quercetin and rutin on the in-vitro binding of neratinib to human serum albumin.

This study was designed to examine the interaction of neratinib (NRB) with human serum albumin (HSA) in presence of flavonoids quercetin and rutin. Both quercetin and rutin can compete with NRB to bind to HSA and displace NRB from its binding site. The interaction mechanism was studied with several spectroscopic techniques and molecular docking. Static fluorescence quenching mechanism was observed on interaction of HSA with NRB. van der Waals force and hydrogen bond were involved in the HSA-NRB interaction as per the results of thermodynamic parameters. Further, the conformational changes were observed in the HSA on its interaction with NRB. Interaction of NRB with HSA in presence of quercetin and rutin resulted in changes in the binding constants of HSA-NRB suggesting some impact on the binding of NRB in the presence of flavonoids.

Darunavir: A comprehensive profile.

Darunavir: (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl [(2S,3R)-4-{[(4-aminophenyl)sulfonyl] (isobutyl)amino}-3-hydroxy-1-phenyl-2-butanyl]carbamate is a synthetic non-peptide protease inhibitor. On June 2006, it was first approved by the Food and Drug administration (FDA) for treatment of resistant type-1 of the human immunodeficiency virus (HIV). In July 2016, the FDA expanded the approval for use of darunavir in pregnant women with HIV infection. Darunavir prevents the replication of HIV virus by inhibiting the catalytic activity of the HIV-1 protease enzyme, and selectively inhibits the cleavage of HIV encoded Gag-Pol polyproteins in virus-infected cells, which prevents the formation of mature infectious virus particles. Darunavir is unique among currently available protease inhibitors because it maintains antiretroviral activity against a variety of multidrug-resistant HIV strains. This article discusses, by a critical extensive review of the literature, the description of darunavir in terms of its names, formulae, elemental composition, appearance, and use in the treatment of HIV-infected patients. The article also discusses the methods for preparation of darunavir, its physical-chemical properties, analytical methods for its determination, pharmacological properties, and dosing information.

Evaluation of competitive binding interaction of neratinib and tamoxifen to serum albumin in multidrug therapy.

Co-administration of two drugs to obtain a therapeutic goal is a common practice clinically and for effective use of drug therapy. However, the co-administration can sometimes cause adverse effects due to pharmacokinetic drug interactions. Breast Cancer treatment regimen include tyrosine kinase inhibitor neratinib (NRB) and/or tamoxifen (TMX). In this study neratinib and tamoxifen interaction with bovine serum albumin (BSA) and human serum albumin (HSA) individually and in combination using fluorescence spectroscopy was studied. The aim of this study was to find out whether there is a possibility of either of the two drugs interfering in the plasma protein binding of the other drug. Subdomain IIA of both the BSA and HSA was found to bind tamoxifen and neratinib. The λex = 280 nm and 295 nm were used for the analysis of neratinib-SA, tamoxifen-SA, neratinib: SA in presence of constant concentration of tamoxifen and similarly tamoxifen-SA in presence of constant concentration of neratinib. The interaction study of the binary and the ternary systems suggest that neratinib doesn't affect the interaction between SA and tamoxifen. In contrast, the interaction between neratinib and SA was affected by tamoxifen. The binding constant and quenching constant values suggest that tamoxifen dislodges neratinib from its serum albumin complex whereas neratinib doesn't affect the interaction between SA and tamoxifen. Thus, it was concluded from the results the study that during simultaneous administration of neratinib and tamoxifen, their competition for the SA binding sites should be taken into account.

Azilsartan medoxomil.

Azilsartan is used for treatment of the high blood pressure (hypertension). Reducing high blood pressure enables avoid strokes, heart attacks and problems of kidneys. Azilsartan comes under the name angiotensin receptor blocker (ARBs) as a class of drugs. It acts by relaxing blood vessels to make it easier for blood to flow. Azilsartan Medoxomil's a comprehensive profile containing the description, formulae, Elemental Analysis, Uses and application. Furthermore, methods and schemes are outlined for the preparation of the drug substance. The physical properties of the medication include constant of ionization, solubility, X-ray powder diffraction pattern, differential scanning calorimetry, thermal conduct and spectroscopic studies are investigated. The methods employed in bulk medicines and/or in pharmaceutical formulations to analyze the drug substance include spectrophotometric, electrochemical and the chromatographic methods. Other studies on this drug substance include drug stability, Pharmaceutical Applications, Mechanism of Action, Pharmacodynamics, and a Dosing Information are reviewed. At the end of this profile, there are more than sixty references were listed.

Emtricitabine.

Emtricitabine (Emtriva, FTC) is an antiviral medicine which decreases the body's amount of HIV. Emtricitabine on of Anti-HIV drugs slow down or protect the immune system against damage and reduce the risk of diseases related to developing of AIDS. Emtricitabine use also for treatment of hepatitis B virus. Emtricitabine is a drug class known as nucleoside reversing transcriptase inhibitors (NRTIs). In view of Emtricitabine's clinical significance, a thorough review of the physical and pharmaceutical characteristics and details of the multiple analytical techniques used to test the drug in pharmaceutical and biological systems was conducted. The methods investigated include identification test, Spectroscopy, chromatography, electrochemicals, and Thermal. Beside the analytical profile, the degradation and stability of Emtricitabine, its pharmacology and pharmacokinetics, Pharmaceutical Applications, Mechanism of Action, dosage forms and dose, ADME profile, and interactions have been debated.

New nonextractive and highly sensitive high-performance liquid chromatographic method for determination of paroxetine in plasma after offline precolumn derivatization with 7-chloro-4-nitrobenzo-2-oxa-1,3-diazole.

New nonextractive and simple offline precolumn derivatization procedures have been proposed, for the first time, for the trace determination of paroxetine (PXT) in human plasma by HPLC with fluorescence detection. Trimetazidine (TMZ) was used as an internal standard. Plasma samples were treated with acetonitrile for protein precipitation and then derivatized with 7-chloro-4-nitrobenzo-2-oxa-1,3-diazole in borate buffer of pH 8 at 70 degrees C for 30 min. Separations of the derivatized PXT and TMZ were performed on a Nucleosil CN column using a mobile phase consisting of acetonitrile-10 mM sodium acetate buffer (pH 3.5)-methanol (47 + 47 + 6, v/v) at a flow rate of 1.0 mL/min. The derivatized samples were excited at 470 nm and monitored at an emission wavelength of 530 nm. Under the optimum chromatographic conditions, a linear relationship with good correlation coefficient (r = 0.9998, n = 7) was found between the peak area ratio and PXT concentrations in the range of 5-600 ng/mL. The LOD and LOQ were 1.37 and 4.14 ng/mL, respectively. The intraday and interassay precisions were satisfactory; the RSD did not exceed 4.2%. The accuracy of the method was proved by recovery of PXT from spiked human plasma at levels of 97.28-104.38 +/- 0.41-3.62%. The proposed method had high throughput, as the analysis involved a simple sample pretreatment procedure and short run time (< 10 min). The results demonstrated that the method would have a great value when it is applied in the therapeutic monitoring of PXT.

Olmesartan.

Olmesartan is an angiotensin receptor blockers with actions similar to those of losartan; it is used for the treatment of high blood pressure by relaxing blood vessels for this reason blood can flow more easily. It could be used alone or in combination with other antihypertensive drugs. This chapter gives a comprehensive profile of olmesartan, containing detailed nomenclature, formulae, elemental analysis, and appearance of the drug. In addition this chapter also describes several methods of synthesis and usage of the olmesartan. The profile covers the physicochemical properties including pKa value, solubility, X-ray powder diffraction, melting point, and procedures of analysis (compendial, spectroscopic, electrochemical, and chromatographic techniques of analysis). Comprehensive pharmacology is also presented (pharmacological actions, therapeutic uses and dosing, interactions, and adverse effects and precautions). Eighty references were given as a proof of the above-mentioned studies.

Propranolol.

Propranolol is a noncardioselective ß-blocker. It is reported to have membrane-stabilizing properties, but it does not own intrinsic sympathomimetic activity. Propranolol hydrochloride is used to control hypertension, pheochromocytoma, myocardial infarction, cardiac arrhythmias, angina pectoris, and hypertrophic cardiomyopathy. It is also used to control symptoms of sympathetic overactivity in the management of hyperthyroidism, anxiety disorders, and tremor. Other indications cover the prophylaxis of migraine and of upper gastrointestinal bleeding in patients with portal hypertension. This study provides a detailed, comprehensive profile of propranolol, including formulas, elemental analysis, and the appearance of the drug. In addition, the synthesis of the drug is described. The chapter covers the physicochemical properties, including X-ray powder diffraction, pK, solubility, melting point, and procedures of analysis (spectroscopic, electrochemical, and chromatographic). In-depth pharmacology is also presented (pharmacological actions, therapeutic dosing, uses, Interactions, and adverse effects and precautions). More than 60 references are given as a proof of the abovementioned studies.

Clenbuterol Hydrochloride.

Clenbuterol (Broncodil and trade) is a direct-acting sympathomimetic agent with mainly beta-adrenergic activity and a selective action on ß2 receptors (a ß2 agonist). It has properties similar to those of salbutamol. It is used as a bronchodilator in the management of reversible airways obstruction, as in asthma and in certain patients with chronic obstructive pulmonary disease. The uses, applications, and the synthetic pathways of this drug are outlined. Physical characteristics including: ionization constant, solubility, X-ray powder diffraction pattern, thermal methods of analysis, UV spectrum, IR spectrum, mass spectrum are all produced. This profile also includes the monograph of British Pharmacopoeia, together with several reported analytical methods including spectrophotometric, electrochemical, chromatographic, immunochemical methods, and capillary electrophoretic methods. The stability, the pharmacokinetic behavior, and the pharmacology of the drug are also provided.

Kinetic spectrophotometric determination of josamycin in formulations and spiked human plasma using 3-methylbenzothiazolin-2-one hydrazone/Fe+3 system.

A simple kinetic spectrophotometric method was developed for the determination of josamycin in its dosage forms and spiked human plasma. The method is based on reaction of the drug with 3-methylbenzothiazolin-2-one hydrazone/ferric chloride system for a fixed time of 20 min at 70 degrees C and measuring the produced color at 665 nm. The absorbance-concentration plot is rectilinear over the range of 5.0-30.0 microg/mL with detection limit of 1.0 microg/mL (1.2 x 10(-6) M). The determination of josamycin by the fixed concentration and the rate-constant methods is also feasible with the calibration equations obtained, but the fixed-time method proved to be more applicable. The procedure was successfully applied to commercial tablets. The results obtained were favorably compared with those given by reference methods. The method was further extended to the in vitro determination of josamycin in spiked human plasma. The recovery (n = 8) was 100.76 +/- 3.43%. The stoichiometry of the reaction between the drug and the reagent was studied by adopting the limiting logarithmic method, and a proposal of the reaction pathway was presented.

Kinetic spectrophotometric determination of the macrolide antibiotic josamycin in formulations.

A simple kinetic spectrophotometric method was developed for the determination of josamycin in its dosage forms. The method is based on oxidation of the drug with alkaline potassium permanganate at room temperature for a fixed time of 20 min and measuring the produced green color at 611 nm. The absorbance-concentration plot is rectilinear over the range of 2-10 microg/mL (2.4 x 10(6)-1.2 x 10(-5)M) with minimum detectability of 1.0 microg/mL (1.2 x 10(-6)M). The determination of josamycin by fixed concentration and the rate-constant methods is also feasible with the calibration equations obtained, but the fixed-time method proved to be more applicable. The procedure was applied successfully to commercial tablets, and statistical analysis showed that the results compared favorably with those obtained by reference methods. The effect of sensitizers and surfactants on the performance of the proposed method was also studied. A proposal of the reaction pathway was presented.

A Stability-Indicating HPLC-DAD Method for Determination of Stiripentol: Development, Validation, Kinetics, Structure Elucidation and Application to Commercial Dosage Form.

A rapid, simple, sensitive, and accurate isocratic reversed-phase stability-indicating high performance liquid chromatography method has been developed and validated for the determination of stiripentol and its degradation product in its bulk form and pharmaceutical dosage form. Chromatographic separation was achieved on a Symmetry C18 column and quantification was achieved using photodiode array detector (DAD). The method was validated in accordance with the ICH requirements showing specificity, linearity (r (2) = 0.9996, range of 1-25 µg/mL), precision (relative standard deviation lower than 2%), accuracy (mean recovery 100.08 ± 1.73), limits of detection and quantitation (LOD = 0.024 and LOQ = 0.081 µg/mL), and robustness. Stiripentol was subjected to various stress conditions and it has shown marked stability under alkaline hydrolytic stress conditions, thermal, oxidative, and photolytic conditions. Stiripentol degraded only under acidic conditions, forming a single degradation product which was well resolved from the pure drug with significantly different retention time values. This degradation product was characterized by (1)H-NMR and (13)C-NMR spectroscopy as well as ion trap mass spectrometry. The results demonstrated that the method would have a great value when applied in quality control and stability studies for stiripentol.