Favipiravir, remdesivir, and lopinavir: metabolites, degradation products and their analytical methods.

Severe acute respiratory syndrome 2 (SARS-CoV-2) caused the emergence of the COVID-19 pandemic all over the world. Several studies have suggested that antiviral drugs such as favipiravir (FAV), remdesivir (RDV), and lopinavir (LPV) may potentially prevent the spread of the virus in the host cells and person-to-person transmission. Simultaneously with the widespread use of these drugs, their stability and action mechanism studies have also attracted the attention of many researchers. This review focuses on the action mechanism, metabolites and degradation products of these antiviral drugs (FAV, RDV and LPV) and demonstrates various methods for their quantification and discrimination in the different biological samples. Herein, the instrumental methods for analysis of the main form of drugs or their metabolite and degradation products are classified into two types: optical and chromatography methods which the last one in combination with various detectors provides a powerful method for routine and stability analyses. Some representative studies are reported in this review and the details of them are carefully explained. It is hoped that this review will be a good guideline study and provide a better understanding of these drugs from the aspects investigated in this study.

A versatile ratiometric fluorescence nanoprobe for the determination of clonazepam in patients' plasma samples.

Despite the necessity of the study of therapeutic drug monitoring of clonazepam (CLZ), there are only a few fast detection methods available for determining CLZ in biological media. This study aims to develop a cost-effective and ratiometric probe for the quantification of CLZ in plasma samples. Fluorescent polydopamine nanoparticles were produced through a self-polymerization process at a pH of 8.5. Rhodamine B molecules were employed as a fluorescent reference material, emitting stable fluorescence in the visible range. The fabricated probe exhibited a specific detection capability for CLZ. The fluorescence emission of the probe was enhanced in two concentration ranges: from 50 ng/mL to 1.0 µg/mL and from 1.0 to 15.0 µg/mL with a lower limit of quantification of 50 ng/mL, indicating the sensitivity of the probe for detecting CLZ plasma levels. The accuracy of the probe is favorable which could be recommended for CLZ monitoring in the biological media. Furthermore, this probe is highly specific towards CLZ in the presence of various interfering agents which is mainly caused by its ratiometric nature. The developed platform showed high reliability in quantifying CLZ concentrations in patients' plasma samples. Hence, the fabricated probe could be recommended as a reliable method for the routine detection of CLZ in clinical settings.

Solubility and thermodynamics of mesalazine in aqueous mixtures of poly ethylene glycol 200/600 at 293.2-313.2K.

In this study, the solubility of mesalazine was investigated in binary solvent mixtures of poly ethylene glycols 200/600 and water at temperatures ranging from 293.2K to 313.2K. The solubility of mesalazine was determined using a shake-flask method, and its concentrations were measured using a UV-Vis spectrophotometer. The obtained solubility data were analyzed using mathematical models including the van't Hoff, Jouyban-Acree, Jouyban-Acree-van't Hoff, mixture response surface, and modified Wilson models. The experimental data obtained for mesalazine dissolution encompassed various thermodynamic properties, including ΔG°, ΔH°, ΔS°, and TΔS°. These properties offer valuable insights into the energetic aspects of the dissolution process and were calculated based on the van't Hoff equation.

Solubility and thermodynamics properties of salicylic acid in binary mixtures 1-propanol and propylene glycol/ethylene glycol monomethyl ether at different temperatures.

The research aimed to investigate the solubility and thermodynamics of salicylic acid in two binary solvent mixtures of (1-propanol+propylene glycol) and (ethylene glycol monomethyl ether+1-propanol). The study was conducted in the temperature range of 293.2 to 313.2K. To analyze the experimental solubility data, several linear and nonlinear cosolvency models, such as the van't Hoff, Jouyban-Acree, Jouyban-Acree-van't Hoff, mixture response surface, and modified Wilson models were employed. The models' effectiveness was evaluated by comparing the mean relative deviations of the back-calculated solubility data to the experimental values. In addition, the apparent thermodynamic parameters, including Gibbs energy, enthalpy, and entropy, were calculated using the van't Hoff and Gibbs equations. Furthermore, the study measured the density values for salicylic acid-saturated mixtures and represented them mathematically through the Jouyban-Acree model.

The influence of advanced materials on the analytical performance of semiconductor-based gas sensors.

Chemiresistive gas sensors are metal oxide-based sensors that have received significant attention in different fields. Ambient gas sensors are especially important in the fabrication of wearable probes for the real-time detection of biomarkers in human body samples. Usually, room temperature sensors are affordable due to their low power consumption, resulting in simple instrumentation and maintenance. To fabricate versatile gas sensors, i.e. sensitive, selective, ambient temperature operating gas sensors, and improve the sensing performance of the traditionally used sensor, new materials play an important role. In other words, new advanced materials are essential for designing and fabricating new gas sensors. Hence, in this review, the application and impact of new advanced materials in the fabrication of reliable gas sensors are discussed in detail. Special emphasis is given to the effect of new materials in the fabrication of room-temperature operating systems. Finally, future research outlook and possible challenges that may be encountered by reliable gas sensors are also explained.

Applications of Exhaled Breath Condensate Analysis for Drug Monitoring and Bioequivalence Study of Inhaled Drugs.

The exhaled breath condensate (EBC) presents a simple and non-invasive alternative approach for bioequivalence assessments and therapeutic drug monitoring of inhaled drugs. EBC better represents the drug at the site of action and eliminates the possibility of the contribution of a swallowed portion of the dose when systemic bioavailability is used for assessment. This review summarizes the recently reported analytical methods for the quantification of drugs in EBC. It also discusses the difficulties in the bioequivalence evaluation criteria of generic orally inhaled drug products suggested by various regulatory agencies that may be eliminated using the EBC analysis approach.

Corrigendum: Applications of exhaled breath condensate analysis for drug monitoring and bioequivalence study of inhaled drugs.

[This corrects the article DOI: 10.18433/jpps33121.].

A new method for investigating bioequivalence of inhaled formulations: A pilot study on salbutamol.

Purpose: An efficient, cost-effective and non-invasive test is required to overcome the challenges faced in the process of bioequivalence (BE) studies of various orally inhaled drug formulations. Two different types of pressurized meter dose inhalers (MDI-1 and MDI-2) were used in this study to test the practical applicability of a previously proposed hypothesis on the BE of inhaled salbutamol formulations. Methods: Salbutamol concentration profiles of the exhaled breath condensate (EBC) samples collected from volunteers receiving two inhaled formulations were compared employing BE criteria. In addition, the aerodynamic particle size distribution of the inhalers was determined by employing next generation impactor. Salbutamol concentrations in the samples were determined using liquid and gas chromatographic methods. Results: The MDI-1 inhaler induced slightly higher EBC concentrations of salbutamol when compared with MDI-2. The geometric MDI-2/MDI-1 mean ratios (confidence intervals) were 0.937 (0.721-1.22) for maximum concentration and 0.841 (0.592-1.20) for area under the EBC-time profile, indicating a lack of BE between the two formulations. In agreement with the in vivo data, the in vitro data indicated that the fine particle dose (FPD) of MDI-1 was slightly higher than that for the MDI-2 formulation. However, the FPD differences between the two formulations were not statistically significant. Conclusion: EBC data of the present work may be considered as a reliable source for assessment of the BE studies of orally inhaled drug formulations. However, more detailed investigations employing larger sample sizes and more formulations are required to provide more evidence for the proposed method of BE assay.

Dispersive solid-phase extraction of risperidone from plasma samples using graphene oxide aerogels and determination with liquid chromatography.

A graphene oxide-based aerogel was synthesized and applied to the extraction and the determinations with the high-performance liquid chromatography-ultraviolet detector. After the characterization of the produced graphene-aerogel, it was utilized as a dispersive solid-phase extraction sorbent for risperidone extraction from plasma samples. Aerogels are materials with a large surface area-to-mass ratio and plenty of core with functional groups which can easily attach to the analytes to extract them to the second phase. The suggested method determined risperidone in plasma samples in the wide dynamic range from 20 ng/ml to 3 µg/ml. The limits of detection and quantification of the developed method were calculated as 2.4 and 8.2 ng/ml, respectively. As a novel feature, the developed method has no need to precipitate plasma proteins, improving the analytical performance of the analysis. Also, for the first time, the produced materials were utilized for the extraction of risperidone from the plasma samples. The obtained results revealed that the developed approach could be employed as an accurate method for the quantification of risperidone in real plasma samples.

Two-photon fluorescence probe for quantification of cyclosporine.

A novel ratiometric fluorescent sensor was fabricated for the fast and facile determination of cyclosporine A (CsA). Due to the narrow therapeutic index of CsA, its desired therapeutic effects are evident within a limited range of blood concentration, indicating the fundamental role of therapeutic drug monitoring in CsA pharmacological response. In this study, a two-photon fluorescence probe based on the zeolitic imidazolate framework (ZIF-8) and norepinephrine-capped silver nanoparticles (AgNPs@NE) was employed for the quantification of the CsA in human plasma samples. In the presence of CsA, the fluorescent emission intensity of ZIF-8-AgNPs@NE was quenched. Under the optimum conditions, the proposed probe determines CsA in plasma samples in two linear ranges of 0.01 to 0.5 µg mL-1 and 0.5 to 10 µg mL-1. The developed probe demonstrates the advantages of a facile and fast platform with limit of detection as low as 0.007 µg mL-1. At last, this method was applied to find CsA concentration in four patients receiving oral CsA regimen which indicates it as a promising method for on-site detection applications.

Dual-emission ratiometric fluorescent probe based on N-doped CQDs@UiO-66/PVA nanocomposite hydrogel for quantification of pethidine in human plasma.

A synchronous fluorescence spectroscopy (SFS) sensor for pethidine detection is described based on UiO-66 metal-organic frameworks (MOFs) modified with N-doped carbon quantum dots (N-CQDs) embedded in hydrogel nanocomposites. Benefitting from the inovative  design of the doping method in the carbonaceous structure, N-CQDs were successfully deposited in the pores of the UiO-66 network. Then, N-CQDs were employed as a sensitive segment toward the target molecules. UiO-66 was used for sensitive and selective sensing of the bonding interactions between N-CQDs and pethidine so that the electron transfer process from UiO-66 to the pethidine-N-CQD complex results in quenching the SFS intensity of UiO-66. To embed the stable and suitable sensing interface for pethidine assessment, the designed nanomaterial was inserted into the hydrogel network. This nanocomposite hydrogel showed two well-resolved emission peaks at 300 nm and 350 nm under ∆λ = 70, which corresponded to N-CQDs and UiO-66, respectively. The SFS sensing platform was employed for ratiometric detection of pethidine with a low limit of detection of 0.002 µg mL-1 over a wide concentration range from 0.005 to 1.0 µg mL-1. The accurate monitoring of pethidine with a good recovery of 90.8-101.5% indicated their independency from matrix effects for pethidine detection in human plasma being a complicated biological matrix. Scheme 1. General procedure for synthesizing N-CQDs@UiO-66/PVA hydrogel-based nanoprobe and its application for pethidine determination.

Thienopyrimidine-based agents bearing diphenylurea: Design, synthesis, and evaluation of antiproliferative and antiangiogenic activity.

An important role has been considered for the vascular endothelial growth factor receptor 2 (VEGFR-2) in the angiogenesis process, so that its inhibition is an important scientific way for cancer treatment. In this work, new thienopyrimidine derivatives were synthesized and evaluated. Compared with sorafenib, the majority of the target compounds had antiproliferative activity against the PC3, HepG2, MCF7, SW480, and HUVEC cell lines, especially 9h with IC50 values of 4.5-15.1 µM, confirming the noticeable cytotoxic effects on the listed cell lines (PC3, HepG2, SW480, and HUVEC). Analyses by flow cytometry on SW480 and HUVEC cells revealed that 9n, 9k, 9h, and 9q led to apoptotic cell death. The result of the chick chorioallantoic membrane assay showed that 9h effectively reduced the number of corresponding blood vessels. Finally, the inhibitory effect on VEGFR-2 phosphorylation was considered as the outcome of Western blot analysis of compound 9h.

Integrated Smart Gas Tracking Device with Artificially Tailored Selectivity for Real-Time Monitoring Food Freshness.

The real-time monitoring of food freshness in refrigerators is of significant importance in detecting potential food spoiling and preventing serious health issues. One method that is commonly reported and has received substantial attention is the discrimination of food freshness via the tracking of volatile molecules. Nevertheless, the ambient environment of low temperature (normally below 4 °C) and high humidity (90% R.H.), as well as poor selectivity in sensing gas species remain the challenge. In this research, an integrated smart gas-tracking device is designed and fabricated. By applying pump voltage on the yttria-stabilized zirconia (YSZ) membrane, the oxygen concentration in the testing chamber can be manually tailored. Due to the working principle of the sensor following the mixed potential behavior, distinct differences in sensitivity and selectivity are observed for the sensor that operated at different oxygen concentrations. Typically, the sensor gives satisfactory selectivity to H2S, NH3, and C2H5OH at the oxygen concentrations of 10%, 30%, and 40%, respectively. In addition, an acceptable response/recovery rate (within 24 s) is also confirmed. Finally, a refrigerator prototype that includes the smart gas sensor is built, and satisfactory performance in discriminating food freshness status of fresh or semi-fresh is verified for the proposed refrigerator prototype. In conclusion, these aforementioned promising results suggest that the proposed integrated smart gas sensor could be a potential candidate for alarming food spoilage.

Comparative Drug Solubility Studies Using Shake-Flask Versus a Laser-Based Robotic Method.

Drug solubility is of central importance to the pharmaceutical sciences, but reported values often show discrepancies. Various factors have been discussed in the literature to account for such differences, but the influence of manual testing in comparison to a robotic system has not been studied adequately before. In this study, four expert researchers were asked to measure the solubility of four drugs with various solubility behaviors (i.e., paracetamol, mesalazine, lamotrigine, and ketoconazole) in the same laboratory with the same instruments, method, and material sources and repeated their measurements after a time interval. In addition, the same solubility data were determined using an automated laser-based setup. The results suggest that manual testing leads to a handling influence on measured solubility values, and the results were discussed in more detail as compared to the automated laser-based system. Within the framework of unavoidable uncertainties of solubility testing, it is a possibility to combine minimal experimental testing that is preferably automated with mathematical modeling. That is a practical suggestion to support future pharmaceutical development in a more efficient way.

A new set of solute descriptors to calculate solubility of drugs in mono-solvents.

A new set of solute parameters derived from a correlation model using Catalan parameters. The parameters represent the interaction of the solute with the mono-solvents at 298.15K. The computational procedure was adopted from Abraham's solvation model and the obtained results are promising. In this work, the calculated parameters were used to back-calculate the drugs solubility in various mono-solvents at different temperatures employing the van't Hoff's model as the skeleton on the derived model. The obtained mean percentage deviations (MPDs) were in the range of 3.1 to 88.5% with the overall MPD of 29.1%. (1) Derivation of a new set of solute parameters from a correlation model using Catalan parameters; (2) adoption of the calculation method of Abraham's solvation model with the skeleton of van't Hoff's equation; (3) using the achieved parameters for back-calculation of drugs solubility in various mono-solvents; (4) obtaining an overall acceptable mean percentage deviation of 29.1% from calculations.

Review of Pharmaceutical Applications of Diethylene Glycol Monoethyl Ether.

Diethylene glycol monoethyl ether (DEGME) is a hydroalcoholic solvent that gained tremendous attention in the cosmetics, food, nanoformulations, and pharmaceutical industries. Due to its physicochemical features, it has been widely used as a penetration enhancer, surfactant, and solubilizer. Among numerous tradenames defined for DEGME -- Carbitol® (by Dow Chemical Co., USA), and Transcutol® HP, CG, and P. (by Gattefossé Co., France) -- are known to be employed in pharmaceutical industries. Transcutol® CG is utilized only in cosmetics; however, Transcutol® P and Carbitol® are both used in various pharmaceutical topical dosage forms such as creams, gels, etc. Additionally, Transcutol® HP is used in all administration routes. In view of this, the application of DEGME is highlighted in the areas of industry and pharmaceutical sciences. Moreover, in this review the prominent characteristics, pharmacokinetics, and toxicity of DEGME are examined and it is suggested that DEGME is a promising solvent/solubilizer with comparable assignments to other conventional excipients.

Application of microcrystalline cellulose as an efficient and cheap sorbent for the extraction of metoprolol from plasma and wastewater before HPLC-MS/MS determination.

A dispersive solid-phase extraction method based on a new sorbent has been performed on plasma and wastewater samples to determine metoprolol by high-performance liquid chromatography-tandem mass spectrometry. In this study, the analyte was adsorbed from the samples onto microcrystalline cellulose as a green and efficient sorbent and then eluted for use in the determination step. In the mass spectrometer, the analyte was detected in the positive mode and selectivity of the analysis was increased by sequential mass analysis through multiple reaction monitoring. All of the effective parameters in the extraction of metoprolol from plasma and wastewater were optimized. Under optimal conditions the method was linear in the ranges of 1-1,000 and 0.1-1,000 ng/ml in plasma and wastewater samples, respectively. The detection limits of the method were 0.30 and 0.03 ng/ml in plasma and wastewater samples, respectively. The data showed that the method provides low detection limit, wide linear range, good precision and high extraction recovery. Finally several plasma and wastewater samples were successfully analyzed using the method. The use of a small amount of a green and inexpensive sorbent and a low volume of plasma without the need for further pretreatment steps are the main advantages of the method.

Solubility of favipiravir (as an anti-COVID-19) in supercritical carbon dioxide: An experimental analysis and thermodynamic modeling.

Favipiravir is one of the most commonly prescribed drugs in the treatment of COVID-19 in the early stages of the disease. In this work, the solubility of favipiravir was measured in supercritical CO2 at temperatures ranging from 308 to 338 K and pressures ranging from 12 to 30 MPa. The mole fraction solubility of favipiravir was in the range of 3.0 × 10-6 to 9.05 × 10-4. The solubility data were correlated with three types of methods including; (a) density-based models (Chrastil, Garlapati and Madras, Sparks et al., Sodeifian et al., K-J and Keshmiri et al.), (b) Equations of states SRK with quadratic mixing rules) and (c) expanded liquid theory (modified Wilson model). According to the results, modified Wilson and K-J models are generally capable of providing good correlation of solubility. Finally, the approximate values of total ( Δ H total ), vaporization ( Δ H vap ), and solvation ( Δ H sol ) enthalpies were computed.

Drug Solubility Correlation Using the Jouyban-Acree Model: Effects of Concentration Units and Error Criteria.

An important factor affecting the model accuracy is the unit expression type for solute and solvent concentrations. One can report the solute and solvent concentration in various units and compare them with various error scales. In order to investigate the unit and error scale expression effects on the accuracy of the Jouyban-Acree model, in the current study, seventy-nine solubility data sets were collected randomly from the published articles and solute and solvent concentrations in the investigated systems were expressed in various units. Mass fraction, mole fraction, and volume fraction were the employed concentration units for the solvent compositions, and mole fraction, molar, and gram/liter were the investigated concentration units for the solutes. The solubility data, with various solute/solvent concentration units, were correlated using the Jouyban-Acree model, and the accuracy of each model for correlating the data was investigated by calculating different error scales and discussed.

Applications of scaffold-based advanced materials in biomedical sensing.

There have been many efforts to synthesize advanced materials that are capable of real-time specific recognition of a molecular target, and allow the quantification of a variety of biomolecules. Scaffold materials have a porous structure, with a high surface area and their intrinsic nanocavities can accommodate cells and macromolecules. The three-dimensional structure (3D) of scaffolds serves not only as a fibrous structure for cell adhesion and growth in tissue engineering, but can also provide the controlled release of drugs and other molecules for biomedical applications. There has been a limited number of reports on the use of scaffold materials in biomedical sensing applications. This review highlights the potential of scaffold materials in the improvement of sensing platforms and summarizes the progress in the application of novel scaffold-based materials as sensor, and discusses their advantages and limitations. Furthermore, the influence of the scaffold materials on the monitoring of infectious diseases such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and bacterial infections, was reviewed.