Recent Applications of Quantum Dots in Pharmaceutical Analysis.

Nanotechnology has emerged as one of the most potential areas for pharmaceutical analysis. The need for nanomaterials in pharmaceutical analysis is comprehended in terms of economic challenges, health and safety concerns. Quantum dots (QDs)or colloidal semiconductor nanocrystals are new groups of fluorescent nanoparticles that bind nanotechnology to drug analysis. Because of their special physicochemical characteristics and small size, QDs are thought to be promising candidates for the electrical and luminescent probes development. They were originally developed as luminescent biological labels, but are now discovering new analytical chemistry applications, where their photo-luminescent properties are used in pharmaceutical, clinical analysis, food quality control and environmental monitoring. In this review, we discuss QDs regarding properties and advantages, advances in methods of synthesis and their recent applications in drug analysis in the recent last years.

Eco-friendly synchronous fluorescence spectrofluorimetric method for simultaneous determination of montelukast sodium and fexofenadine hydrochloride in their antiallergic rhinitis fixed-dose combination tablets.

An innovative, simple, accurate, sensitive, and eco-friendly synchronous fluorescence spectrofluorimetric method has been developed for the simultaneous analysis of montelukast sodium (MON) and fexofenadine hydrochloride (FEX). The method relies on measuring the relative synchronous fluorescence intensity of both drugs using Δλ of 60 nm in methanol at 405 nm for MON and 288 nm for FEX. The experimental parameters influencing the developed method were investigated and optimized. The method was linear over the ranges 0.1-2.0 and 2.0-20.0 µg/ml for MON and FEX, respectively. The limits of detection were 0.018 and 0.441 µg/ml, and the limits of quantitation were 0.055 and 1.336 µg/ml for MON and FEX, respectively. The developed method was applied successfully for the determination of the two drugs in their newly released fixed-dose combination prescribed for the treatment of allergic rhinitis. The mean per cent recoveries were found to be 100.680 ± 0.890 and 100.110 ± 0.940 for MON and FEX, respectively. Furthermore, the method was found to be eco-friendly green as was evaluated according to the Green Analytical Procedure Index tool guidelines and analytical eco-scale.

Formation of plasmonic silver nanoparticles by glucosamine reduction: Application to a colorimetric sensor for determination of glucosamine in its pharmaceutical preparations.

The purpose of this study is to develop a novel method for synthesizing silver nanoparticles using glucosamine as reducing agent and to utilize the developed method for colorimetric detection and quantitative determination of the non-chromophoric drug, glucosamine. Silver nanoparticles are prepared by reducing 0.02 mol/L silver nitrate by glucosamine in 0.075 mol/L ammonia and stabilizing the nanoparticles with 0.1% polyvinylpyrrolidone and the mixture is heated at 90 °C for 5 min. The prepared silver nanoparticles dispersed in water exhibit a bright yellow color due to a localized surface plasmon resonance band at 412 nm. The principle of glucosamine sensing is based on measuring the intensity of the surface plasmon resonance band at 412 nm which is directly proportional to the concentration of glucosamine with a linearity range (1 - 9 µg/mL), limit of detection 0.33 µg/mL and limit of quantitation 1.0 µg/mL. The proposed method was validated according to the ICH guidelines, and it was found to be accurate, precise, selective, and robust. The method was applied for determination of glucosamine in Joflex® capsules using the standard addition approach with mean % recovery ± standard deviation of 100.077 ± 1.786. The method is simple, rapid, and cost-effective and can be used for determination of glucosamine in bulk and in its pharmaceutical preparations.

Dual fluorescence-colorimetric sensor based on silver nanoparticles for determination of tobramycin in its pharmaceutical preparations.

The purpose of this study is to develop a dual fluorescence-colorimetric sensor for determination of the non-chromophoric drug, tobramycin using fluorescein-modified silver nanoparticles. Fluorescein is adsorbed on the surface of silver nanoparticles resulting in quenching of the fluorescence intensity of fluorescein at 513 nm. Upon addition of tobramycin to fluorescein-bound silver nanoparticles, tobramycin can displace fluorescein from the surface of nanoparticles resulting in nanoparticles aggregation and liberation of free fluorescein restoring its fluorescence. The interaction of tobramycin with fluorescein-bound silver nanoparticles is manifested by a decrease in the surface plasmon resonance band of silver nanoparticles at 395 nm, an increase in the fluorescence intensity of fluorescein at 513 nm and color change of the colloidal solution from yellow to light pink. These spectral effects are directly proportional to the concentration of tobramycin with a linearity range of 0.10 - 0.45 µg mL-1 and 0.05 - 0.45 µg mL-1 for the spectrophotometric and spectrofluorimetric methods, respectively. The proposed methods were applied for determination of tobramycin in Tobrin® ophthalmic solution with mean %recovery ± standard deviation of 99.036 ± 1.737 for the spectrophotometric method and 101.192 ± 1.315 for the spectrofluorimetric method. The optical sensor is simple, rapid, and cost-effective and can be used for determination of tobramycin in bulk and in its pharmaceutical preparations.

Probing the potential toxicity of trimetazidine by characterizing its interaction with human serum albumin.

The small molecular drugs pharmacodynamics and pharmacokinetics could be affected by human serum albumin (HSA) transport, so we studied the interaction between HSA and the widely used anti-ischemic agent, trimetazidine (TMZ), using different approaches. As shown by synchronous fluorescence spectroscopy, the interaction affects the microenvironment confirmation around tyrosine residues. The site-competitive experiments showed that TMZ had an affinity toward subdomain III A (site II) of HSA. The enthalpy and entropy changes (ΔH and ΔS), which were 37.75 and 0.197 K J mol-1, respectively, showed that the predominant intermolecular interactions are hydrophobic forces. According to FTIR research, the interaction between HSA and TMZ caused polypeptide carbonyl-hydrogen bonds to rearrange. The HSA esterase enzyme activity was decreased with TMZ. Docking analysis confirmed the site-competitive experiments and thermodynamic results. This study demonstrated that TMZ interacted with HSA, and the structure and function of HSA were influenced by TMZ. This study could aid in understanding the pharmacokinetics of TMZ and provide basic data for safe use.

Green and cost-effective voltammetric assay for spiramycin based on activated glassy carbon electrode and its applications to urine and milk samples.

A simple, cost-effective, and efficient differential pulse voltammetric (DPV) assay for monitoring spiramycin adipate (SPA) in its dosage forms, urine, and milk samples at an activated glassy carbon electrode (GCE) was developed. GCE was electrochemically activated by anodization at a high positive voltage (2.5 V). The activated glassy carbon electrode (AGCE) was surface characterized, optimized, and utilized for the electrochemical assay of SPA. The electrochemical behavior of the AGCEs was investigated using cyclic voltammetry (CV) which shows a remarkable increase in the anodic peak of SPA in comparison with GCE. This behavior reflects a remarkable increase in the electrocatalytic oxidation of SPA at AGCE. The impacts of various parameters such as scan rate, accumulation time, and pH were investigated. The analytical performance of the activated glassy carbon electrodes was studied utilizing DPV. Under optimum conditions, the oxidation peak current exhibited two linear ranges of 80 nm to 0.8 µM and 0.85-300 µM with a lower limit of detection (LOD) of 20 nM. The developed assay exhibited high sensitivity, excellent repeatability, and good selectivity. Additionally, the developed SPA-sensitive modified GCE was successfully applied for SPA assay in its pharmaceutical dosage form and diluted biological fluids as well, with satisfactory recovery results which correlated well with the results obtained using spectrophotometry.

Determination of rivaroxaban by utilizing its quenching effect on acetoxymercuric fluorescein reagent in pharmaceutical preparations and in spiked biological matrices.

A simple, precise and inexpensive spectrofluorimetric method has been developed for assay of rivaroxaban raw material and its tablets. The method depends on the quenching effect of rivaroxaban on the fluorescence intensity of acetoxymercuric fluorescein (AMF). Parameters that may affect the reaction such as pH, AMF solution concentration, reaction time and diluting solvents were studied and optimized. The proposed method was applied for determination of rivaroxaban in tablets with percentage recovery of 100.4 ± 0.28, and in organic extract of spiked plasma samples with percentage recovery of 98.40 ± 1.08. The developed method was validated according to ICH guidelines in terms of accuracy, precision, linearity, range, limit of detection (LOD) and limit of quantification (LOQ).

Hydrophilic gold nanospheres: influence of alendronate, memantine, and tobramycin on morphostructural features.

Turkevich gold nanospheres are the original nanospheres that have been modified over time. Its combination with targeting medications such as alendronate, memantine, and tobramycin will provide additional benefits in targeting specific areas in the bone, brain, and microorganisms, respectively. Hence, The reactivity and stability of nanospheres with various drug concentrations (milli-,micro-, and nano-levels) have been studied. With alendronate, the absorbance spectra of nanospheres at [Formula: see text] 520 nm were always stable and no redshifts occurred. In contrast, the spectra with memantine and tobramycin were stable at the nano-level and redshifts occurred at the milli- and micro-levels. HRTEM and DLS revealed that the core diameter was relatively stable in all cases, whereas the hydrodynamic diameter and zeta potential varied with varying drug concentrations. Increasing concentration increased hydrodynamic diameter slightly with memantine (from 64.99 to 98.41 nm), dramatically with tobramycin (from 135.3 to 332.16 nm), and almost negligibly with alendronate (from 52.08 to 58.94 nm ). Zeta Potential, conversely, is reduced as concentration increases. Memantine had the greatest reduction in negativity, followed by tobramycin, but alendronate had a slight increase in negativity. Benefits from this research would be in targeted drug delivery, where stability and reactivity of gold nanospheres are critical.

A Critical Review of Analytical Applications of Chitosan as a Sustainable Chemical with Functions Galore.

Biomass and biowastes stand as sustainable and cost-effective environmentally benign alternative feedstock. Chitosan is a biocompatible, bioactive, and biodegradable biopolymer derived from chitin to achieve eight aspects out of the 12 green chemistry principles. Chitosan got significant attention in several fields including chemical analysis, in addition to chemical functionally, which enabled its use as adsorbent and its structural crosslinking using various crosslinkers. The physicochemical, technological, and optical properties of chitosan have been extensively exploited in analysis. Mainly, deacetylation degree and molecular weight are controlling its properties and hence controlling its functions. This review presents a structure, properties, and functions relationships of chitosan. It also aims to provide an overview of the different functions that chitosan can serve in each analytical technique such as supporting matrix, catalyst…etc. The contribution of chitosan in improving the ecological performance is discussed in each technique.

Glycerol as a new mobile phase modifier for green liquid chromatographic determination of ascorbic acid and glutathione in pharmaceutical tablets.

Fixed dose combinations of glutathione and ascorbic acid are marketed due to the synergetic effect of glutathione, which regenerates ascorbic acid, potentiates its action and prolongs its antioxidant potential. In this work, glycerol was introduced for the first time as a green mobile phase modifier for liquid chromatographic determination of glutathione and ascorbic acid in pharmaceutical tablets. The viscosity barrier was overcome by using water as a co-fluidifying solvents and by controlling the column temperature. Compared with methanol and acetonitrile, glycerol could result in better peak shapes and superior system suitability. To explore the retention process, free energy and enthalpy-entropy compensation were calculated for both glutathione and ascorbic acid. The chromatographic conditions were optimized using factorial design with the aid of Minitab 17® Software. The method was successfully validated according to the guidelines of the International Conference on Harmonization Q2 (R1) and was found linear in the range of 1 µg/mL to 300300 µg/mL for both drugs. The method was evaluated in terms of its greenness and then compared to the reported method. Glycerol has several advantages over commonly employed mobile phase modifiers, such as the high safety, the low UV cut-off point, low flammability, low volatility, the green features, and the biodegradability. This work paves the way for more applications of glycerol in green liquid chromatography.

An innovative spectrofluorimetric approach for determination of azelaic acid in bulk and pharmaceutical formulation through derivatization with 9-chloromethylanthracene.

A novel simple, selective and accurate spectrofluorimetric method has been developed for quantitation of azelaic acid (AZA) in bulk and cream dosage form. The proposed method depended on the reaction between dicarboxylic moiety of AZA and 9-chloromethylanthracence to produce fluorescent derivative that exhibited maximum fluorescence intensity at 413 nm after being excited at 365 nm. The numerous experimental parameters which affect the reaction product and stability have been carefully studied and optimized. The linearity of the calibration curve constructed has been 0.5-15 µg/ml (y = 26.864x + 31.793, r2 = 0.9999) with 0.143 and 0.434 µg/ml as LOD and LOQ values respectively. The method was used for quantitation of AZA in cream dosage form and the results showed that there was no interference from the cream excipients, the mean % recovery was 100.547% ± 0.775.

Multi-spectroscopic, thermodynamic and molecular docking studies to investigate the interaction of eplerenone with human serum albumin.

The binding of small molecular drugs with human serum albumin (HSA) has a crucial influence on their pharmacokinetics. The binding interaction between the antihypertensive eplerenone (EPL) and HSA was investigated using multi-spectroscopic techniques for the first time. These techniques include ultraviolet-visible (UV-vis) spectroscopy, Fourier-transform infrared (FTIR), native fluorescence spectroscopy, synchronous fluorescence spectroscopy and molecular docking approach. The fluorescence spectroscopic study showed that EPL quenched HSA inherent fluorescence. The mechanism for quenching of HSA by EPL has been determined to be static in nature and confirmed by UV absorption and fluorescence spectroscopy. The modified Stern-Volmer equation was used to estimate the binding constant (Kb ) as well as the number of bindings (n). The results indicated that the binding occurs at a single site (Kb = 2.238 × 103 L mol-1 at 298 K). The enthalpy and entropy changes (∆H and ∆S) were 58.061 and 0.258 K J mol-1 , respectively, illustrating that the principal intermolecular interactions stabilizing the EPL-HSA system are hydrophobic forces. Synchronous fluorescence spectroscopy revealed that EPL binding to HSA occurred around the tyrosine (Tyr) residue and this agreed with the molecular docking study. The Förster resonance energy transfer (FRET) analysis confirmed the static quenching mechanism. The esterase enzyme activity of HSA was also evaluated showing its decrease in the presence of EPL. Furthermore, docking analysis and site-specific markers experiment revealed that EPL binds with HSA at subdomain IB (site III).

Enantioselective chitosan-based racemic ketoprofen imprinted polymer: Chiral recognition and resolution study.

This work presented a novel racemic imprinting process employing the chiral properties of chitosan monomer. The preparation of racemic ketoprofen (RS-KTP) imprinted polymer (RS-MIP) was conducted using glutaraldehyde as a crosslinker. The nature of elution solvent affected the % desorption ratio suggesting a heterogenous nature of the formed binding sites. Good imprinting was indicated by an imprinting factor of 3.50 for S-KTP. The enantioselectivity of the RS-MIP was indicated by enantioselectivity coefficient of 2.31 and % enantiomeric excess (%ee) of 28.55%. A SPE cartridge packed with RS-MIP enabled resolution of RS-KTP using gradient elution solvent system. Scatchard plot revealed two binding sites types of different affinity towards S-KTP and density observed for the RS-MIP. The binding capacity of RS-MIP showed observed dependence on the % ee of S-KTP indicating its enantioselectivity. The success of using racemic template for the preparation of enantioselective MIP brings a new possibility to achieve enantioseparation of racemic mixtures having very expensive or unavailable pure enantiomers.

Carbon quantum dots as a sensitive fluorescent probe for quantitation of pregabalin; application to real samples and content uniformity test.

A novel optical nano-sensor for the detection of pregabalin (PG) in its pharmaceutical (Lyrica®) capsules and biological samples was reported. For the fabrication of highly fluorescent carbon quantum dots (CQDts), a simple green hydrothermal approach was described, and ascorbic acid (AA) was used as a carbon source. The obtained CQDts were confirmed by spectroscopic characterization such as transmission electron microscopy (TEM) and Fourier-transform infrared (FTIR) spectra. The synthesized CQDts were capped by alcohol to form yellow emitters, showing strong fluorescent emission at 524 nm, and excitation at 356 nm. The method is based on fluorescence quenching of CQDts in the presence of PG. The proposed analytical method was validated according to ICH guidelines. PG was successively assayed in the concentration range of 4.0 to 100 µg/ml). The detection and quantitation limits were 1.12 and 3.39 µg/ml, respectively. The proposed method could be used in both quality control and pharmacokinetic research for the studied drug.

One-pot synthesis of fluorescent nitrogen and sulfur-carbon quantum dots as a sensitive nanosensor for trimetazidine determination.

Water-soluble and highly stable N,S-doped CQDs (N,S-CQDs) were synthesized using a low-cost strategy with citric acid and thiosemicarbazide in one step for use as a fluorescent nanosensor. The achieved N,S-CQDs produced strong emission at 446 nm upon excitation at 370 nm and a high quantum yield of 58.5%. The quenching effect on the prepared N,S-CQDs was utilized for determination of trimetazidine (TMZ) spectrofluorimetrically over a wide linear range 0.04-0.5 µM (0.0106-0.133 µg ml-1 ) and a low limit of detection of 0.01 µM (0.002 µg ml-1 ). Furthermore, CDs were used as a simple and rapid fluorescent probe to determine TMZ in its pharmaceutical formulations as well as in human plasma. The method was tested in compliance with International Council for Harmonisation guidelines. The results obtained were compared statistically with those given for a reported method showing no significant variation regards accuracy and precision.

UV spectrophotometric methods for quantitative determination of masitinib; extraction of qualitative information.

Masitinib is an orally administered selective tyrosine kinase inhibitor. It has emerged as a promising drug for multiple diseases including cancer and inflammation in either human or veterinary medicine. Five new and simple UV spectrophotometric methods were developed for its determination in bulk and in pharmaceutical tablets. These methods are based on measuring the absorbance of masitinib in either zero order or first, second, third or fourth derivative spectra. Measurements are optimized so as to minimize excipients' interferences. The methods are suitable for micro-analysis of masitinib. The proposed methods were validated according to the ICH-Q2(R1) guidelines and was successfully applied for determination of masitinib in laboratory prepared tablet. The presented methods are simple, fast, cost-effective and suitable for routine pharmaceutical analysis. Moreover, two derivative spectrophotometric-based methods were developed for identification of masitinib, the derivative ratio method and log-A derivative method. The impact of the developed methods on the environment was assessed by both analytical Eco-Sale and the Green Analytical Procedure Index (GAPI). The present work proves how derivative spectrophotometry could greatly extract qualitative and quantitative information from UV spectra.

A Novel Eplerenone Ecofriendly Fluorescent Nanosensor Based on Nitrogen and Sulfur-Carbon Quantum Dots.

In this work, a novel ecofriendly optical nanosensor for detection of Eplerenone (EPL) in biological samples was reported. Highly luminescent water-soluble nitrogen and sulfur doped carbon quantum dots (N, S-CQDs) have been prepared successfully. The synthesis was based on the reaction of thiosemicarbazide (TS) as source of N and S and citric acid (CA) as source of carbon in one-step aqueous base reflux treatment. The produced N, S-CQDs have a small particle size in the range of 4.7 nm with a high quantum yield (58.5%) and high emission intensity at 446 nm under excitation wavelength of 370 nm. The unique properties of N, S-CQDs make them useful tool as a nano fluorescent probe for sensitive determination of EPL. EPL has been found to decrease the fluorescence of S, N-CDs significantly through static quenching according to the Stern - Volmer plot. The decreased intensity of S, N-CDs fluorescence was proportional to EPL in the 0.2-3.0 µM range. The limit of detection and quantitation were 0.05 and 0.15 µM, respectively. The assay of EPL by this approach was successfully done in drug formulations and in spiked human serum samples.

Chitosan-based molecular imprinted polymer for extraction and spectrophotometric determination of ketorolac in human plasma.

A selective chitosan-based ion exchange molecular imprinted polymer (MIP) was prepared for ketorolac (KET) using the sol-gel method and glutaraldehyde as a crosslinker. The nonimprinted polymer (NIP) was prepared and used as a control, during the whole experiment. The chemical and morphological characteristics of the prepared polymers were investigated using FTIR and SEM, respectively. The prepared MIP was applied to determine the optimum operational conditions for KET extraction from dilute aqueous solutions. The adsorption step was performed at pH 5 and a contact time of 20 min, using 0.1 N HCl as an elution solvent for 30 min. The specificity of the prepared polymer was indicated by an imprinting factor of 1.45. The prepared MIP was successfully applied for selective solid phase extraction and subsequent determination of KET in spiked human plasma samples over a range of 2-20 µg/mL, with a mean % recovery of 94.62% using derivative spectroscopy.

A fast and green reversed-phase HPLC method with fluorescence detection for simultaneous determination of amlodipine and celecoxib in their newly approved fixed-dose combination tablets.

A fast, green, sensitive, and accurate analytical method using high-performance liquid chromatography couple with fluorescence detection was established and validated for the simultaneous determination of amlodipine besylate and celecoxib in their recently approved fixed-dose combination tablets (1:20). Separation of the two drugs was achieved on C18 reversed-phase column (Thermo ODS Hypersil, 4.6 × 250 mm, particle size 5 µm) using acetonitrile:potassium phosphate buffer (50 mM; pH 5.5, 60:40 v/v) as a mobile phase at 40°C, which eluted at a rate of 1 mL/min. Detection was carried out with excitation and emission wavelengths of 360 and 446 nm for amlodipine and 265 and 359 nm for celecoxib, respectively. The method was linear over a concentration range of 0.05-2 and 0.05-10 µg/mL and limit of detection reached to 0.017 and 0.0167 µg/mL for amlodipine and celecoxib, respectively. The developed method was successfully applied to assess the cited drugs in their newly FDA approved fixed-dose combination tablet dosage form. Furthermore, the method was found to be sensitive and eco-friendly green alternative to the reported methods as it was evaluated according to the green analytical procedure index tool guidelines and analytical Eco-Scale.

Simple spectrofluorimetric methods for determination of veterinary antibiotic drug (apramycin sulfate) in pharmaceutical preparations and milk samples.

This work describes the development of highly sensitive as well as simple two spectrofluorimetric methods for the determination of apramycin sulfate. The first method depends on measuring the inherent native fluorescence of the aqueous neutral solution of the drug at 388 nm (λex 335 nm). While the second method mainly based on enhancing the native fluorescence intensity of the drug using sodium dodecyl sulfate (SDS) micellar media by about 4 fold enhancement. The fluorescence intensity - concentration relationship for the two methods was found rectilinear over the concentration range 1.0-100.0 and 0.1-20.0 µg/mL for the first and second method respectively. The limit of detection for method I and II were 0.05 and 0.02 µg/mL respectively. The proposed methods can be effectively connected for the assurance of the medication without impedances from common normal excipients. Furthermore, the two methods were high sensitive enough for the assurance of the drug in spiked milk samples with high percentage recoveries.