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Pharmaceuticals
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Analytical Techniques in the Pharmaceutical Sciences
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Analytical Techniques in the Pharmaceutical Sciences

A special issue of Pharmaceuticals (ISSN 1424-8247).

Deadline for manuscript submissions: closed (30 September 2021) | Viewed by 58948

Special Issue Editors

Dr. Luisa Barreiros

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Guest Editor
LAQV, REQUIMTE, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, Porto, Portugal
Interests: separation techniques; mass spectrometry; sample preparation; complex matrices; analytical and bioanalytical methods
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Marcela Segundo

E-Mail Website
Guest Editor
LAQV/REQUIMTE, Department of Chemistry, Faculty of Pharmacy, University of Porto, R Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal
Interests: high-throughput analysis; trace analysis of organics; automation; water analysis; pharmaceuticals
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The development of analytical techniques is extremely relevant to the pharmaceutical area, being required for a myriad of applications that comprise the identification and quantification of drug substances in pharmaceutical ingredients, pharmaceutical formulations and biological matrices. During the process of drug development, the assessment of the pharmacokinetics and pharmacodynamics of each target drug is crucial to define optimum dose and administration schedules. Moreover, therapeutic drug monitoring involving the measurement of drug concentrations in plasma, serum or blood is increasingly being applied to monitor patient treatment compliance. In recent years, the quantification of active compounds in drug delivery systems, in particular the determination of nanoparticles carrying drugs in biological samples, has emerged as hot topic. Furthermore, the rising number of biopharmaceuticals and biosimilars demands for the establishment of new methodologies for their characterization and quality control.

Many analytical methods have been developed over the years to detect and measure pharmaceutical compounds in different matrices and at different stages of the drug development process. Taking into account the complexity of real matrices and that target pharmaceutical compounds may be present at trace levels, the development of accurate and reliable techniques for their determination is still a challenge. Sample treatment procedures are generally necessary for analytes extraction, preconcentration and clean-up followed by instrumentally or biologically based techniques for analytical determination.

This Special Issue is dedicated to the most recent advances on the analytical determination of pharmaceutical compounds. We invite authors to submit review or original research articles on this topic, including the development of novel analytical and bioanalytical strategies based on state-of-the-art techniques, such as chromatography with mass spectrometry detection, and also innovative alternative methods toward a fast, simple, sustainable and cost-efficient analysis of pharmaceuticals.

Dr. Luisa Barreiros
Prof. Marcela A. Segundo
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceuticals is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • drug substances
  • pharmaceuticals
  • biopharmaceuticals
  • biosimilars
  • nanoparticles
  • biological matrices
  • sample preparation
  • separation techniques
  • mass spectrometry
  • screening methods
  • sensors

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Published Papers (21 papers)

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19 pages, 2108 KiB  
Article
Determination of Oxaliplatin by a UHPLC-MS/MS Method: Application to Pharmacokinetics and Tongue Tissue Distribution Studies in Rats
by Xiuqing Gao, Robert Y. L. Tsai, Jing Ma, Yang Wang, Xiaohua Liu, Dong Liang and Huan Xie
Pharmaceuticals 2022, 15(1), 52; https://doi.org/10.3390/ph15010052 - 31 Dec 2021
Cited by 2 | Viewed by 2103
Abstract
Oxaliplatin (OXP), a third-generation platinum-based chemotherapy drug, was often indirectly analyzed via total platinum by an ICP-MS because it was difficult to directly quantify using an LC-MS/MS method, due to its instability, bad column separability and severe MS signal inhibition. Here, we developed [...] Read more.
Oxaliplatin (OXP), a third-generation platinum-based chemotherapy drug, was often indirectly analyzed via total platinum by an ICP-MS because it was difficult to directly quantify using an LC-MS/MS method, due to its instability, bad column separability and severe MS signal inhibition. Here, we developed and validated a specific, sensitive and reproducible LC-MS/MS method for the quantification of OXP itself in rat plasma and tongue tissue on a SCIEX 4000 QTRAP® MS/MS system equipped with a Phenomenex Lux 5u Cellulose-1 column (250 × 4.6 mm, 5 μm). This method was validated at the lower limit of detection (LOD) and the lower limit of quantitation (LLOQ) of 5 ng/mL and 10 ng/mL, with linearity of 10–5000 ng/mL (r2 > 0.99) and 10–2500 ng/mL (r2 > 0.99), in rat plasma and tongue homogenates, respectively. The intra- and inter-day precision (CV%) and accuracy (RE%) were within 15% for LLOQ, low-, medium- and high-quality control samples. The mean extraction recoveries were around 50% and 80% for plasma and tongue homogenates, respectively. This assay was successfully applied to pharmacokinetics study following intravenous administration of OXP, as well as tongue tissue distribution after 1 h and 4 h of a novel oral mucosal patch application. Full article
(This article belongs to the Special Issue Analytical Techniques in the Pharmaceutical Sciences)
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20 pages, 3152 KiB  
Article
New Method for the Monitoring of Antidepressants in Oral Fluid Using Dried Spot Sampling
by Sofia Soares, Tiago Rosado, Mário Barroso and Eugenia Gallardo
Pharmaceuticals 2021, 14(12), 1284; https://doi.org/10.3390/ph14121284 - 08 Dec 2021
Cited by 10 | Viewed by 2787
Abstract
The increase in the consumption of antidepressants is a public health problem worldwide, as these are a class of compounds widely used in the treatment of several illnesses, such as depression and anxiety. This work aimed to develop and optimize a method for [...] Read more.
The increase in the consumption of antidepressants is a public health problem worldwide, as these are a class of compounds widely used in the treatment of several illnesses, such as depression and anxiety. This work aimed to develop and optimize a method for the quantification of a number of antidepressants and their metabolites (fluoxetine, venlafaxine, O-desmethylvenlafaxine, citalopram, sertraline, and paroxetine) in 100 µL of oral fluid using the dried saliva spots (DSS) sampling approach and gas chromatography coupled with tandem mass spectrometry (GC–MS/MS). The method was validated, presenting linearity within the studied range, with detection and quantification limits ranging between 10 and 100 ng/mL, and coefficients of determination (R2) of at least 0.99 for all analytes. Recoveries were between approximately 13 and 46%. The analysis of precision and accuracy presented acceptable coefficients of variation and relative errors, considering the criteria usually accepted in the validation of bioanalytical procedures. The method herein described is the first to be reported using DSS for the extraction of antidepressants, proving to be a sensitive, simple, and fast alternative to conventional techniques, and capable of being routinely applied in clinical and forensic toxicology scenarios. Full article
(This article belongs to the Special Issue Analytical Techniques in the Pharmaceutical Sciences)
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20 pages, 16119 KiB  
Article
Quantification of 15 Antibiotics Widely Used in the Critical Care Unit with a LC-MS/MS System: An Easy Method to Perform a Daily Therapeutic Drug Monitoring
by Catherine Feliu, Celine Konecki, Tristan Candau, Damien Vautier, Cyril Haudecoeur, Claire Gozalo, Yoann Cazaubon and Zoubir Djerada
Pharmaceuticals 2021, 14(12), 1214; https://doi.org/10.3390/ph14121214 - 24 Nov 2021
Cited by 14 | Viewed by 2672
Abstract
Potential under- or overdose of antibiotics may occur in intensive care units due to high variability in plasma concentrations. The risk is either treatment failure or toxicity. Thus, therapeutic drug monitoring of antibiotics may guide dosing adjustment, maximising antibacterial efficacy and minimising toxicity. [...] Read more.
Potential under- or overdose of antibiotics may occur in intensive care units due to high variability in plasma concentrations. The risk is either treatment failure or toxicity. Thus, therapeutic drug monitoring of antibiotics may guide dosing adjustment, maximising antibacterial efficacy and minimising toxicity. The aim of this study was to develop and validate a method for the analysis of 15 antibiotics including beta-lactams, linezolid, fluoroquinolones, daptomycin, and clindamycin to have a complete panel in the management of infections. We proposed to develop a fast, sensitive, and quantitative method for the analysis of 15 antibiotics using ultra-performance liquid chromatography coupled with triple quadrupole mass spectrometer (UPLC-MS/MS) technology. this method required only 100 µL of plasma and consisted of a rapid liquid–liquid deproteinisation using methanol. Calibration curves ranged from 0.078 to 500 mg/L depending on the molecules, and were defined according to a therapeutic range. Inter- and intra-assay precisions values were less than 15%. This work described the development and the full validation of a precise, sensitive and accurate assay using UPLC-MS/MS technology. After validation, this new assay was successfully applied to routine therapeutic drug monitoring. Full article
(This article belongs to the Special Issue Analytical Techniques in the Pharmaceutical Sciences)
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17 pages, 3492 KiB  
Article
Acetonitrile Adducts of Tranexamic Acid as Sensitive Ions for Quantification at Residue Levels in Human Plasma by UHPLC-MS/MS
by Eduarda M. P. Silva, Luisa Barreiros, Sara R. Fernandes, Paula Sá, João P. Prates Ramalho and Marcela A. Segundo
Pharmaceuticals 2021, 14(12), 1205; https://doi.org/10.3390/ph14121205 - 23 Nov 2021
Cited by 1 | Viewed by 2480
Abstract
The quantitative analysis of pharmaceuticals in biomatrices by liquid chromatography coupled with electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS) is often hampered by adduct formation. The use of the molecular ion resulting from solvent adducts for quantification is uncommon, even if formed in high [...] Read more.
The quantitative analysis of pharmaceuticals in biomatrices by liquid chromatography coupled with electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS) is often hampered by adduct formation. The use of the molecular ion resulting from solvent adducts for quantification is uncommon, even if formed in high abundance. In this work, we propose the use of a protonated acetonitrile adduct for the quantitative analysis of tranexamic acid (TXA) by LC-MS/MS. The high abundance of the protonated acetonitrile adduct [M + ACN + H]+ was found to be independent of source-dependent parameters and mobile phase composition. The results obtained for TXA analysis in clinical samples were comparable for both [M + ACN + H]+ and [M + H]+, and no statistically significant differences were observed. The relative stability and structure of the [M + ACN + H]+ ions were also studied by analyzing probable structures from an energetic point of view and by quantum chemical calculations. These findings, and the studied fragmentation pathways, allowed the definition of an acetimidium structure as the best ion to describe the observed acetonitrile protonated adduct of TXA. Full article
(This article belongs to the Special Issue Analytical Techniques in the Pharmaceutical Sciences)
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17 pages, 5176 KiB  
Article
NanoUPLC-QTOF-MS/MS Determination of Major Rosuvastatin Degradation Products Generated by Gamma Radiation in Aqueous Solution
by Lucija Dončević, Ema Svetličić, Amela Hozić, Branka Mihaljević, Dorota Jarmużek, Ivana Tartaro Bujak, Donata Pluskota-Karwatka, Luka Ozdanovac, Iva Džeba and Mario Cindrić
Pharmaceuticals 2021, 14(11), 1160; https://doi.org/10.3390/ph14111160 - 13 Nov 2021
Cited by 2 | Viewed by 2256
Abstract
Rosuvastatin, a member of the statin family of drugs, is used to regulate high cholesterol levels in the human body. Moreover, rosuvastatin and other statins demonstrate a protective role against free radical-induced oxidative stress. Our research aimed to investigate the end-products of free [...] Read more.
Rosuvastatin, a member of the statin family of drugs, is used to regulate high cholesterol levels in the human body. Moreover, rosuvastatin and other statins demonstrate a protective role against free radical-induced oxidative stress. Our research aimed to investigate the end-products of free radical-induced degradation of rosuvastatin. To induce the radical degradation, an aqueous solution of rosuvastatin was irradiated using different doses of gamma radiation (50–1000 Gy) under oxidative conditions. Rosuvastatin and related degradation products were separated on nanoC18 column under gradient elution, and identification was carried out on hyphenated nanoUPLC and nanoESI-QTOF mass spectrometer system. Elemental composition analysis using highly accurate mass measurements together with isotope fitting algorithm identified nine major degradation products. This is the first study of gamma radiation-induced degradation of rosuvastatin, where chemical structures, MS/MS fragmentation pathways and formation mechanisms of the resulting degradation products are detailly described. The presented results contribute to the understanding of the degradation pathway of rosuvastatin and possibly other statins under gamma radiation conditions. Full article
(This article belongs to the Special Issue Analytical Techniques in the Pharmaceutical Sciences)
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17 pages, 3275 KiB  
Article
An Improved LC–MS/MS Method for the Analysis of Thirteen Cytostatics on Workplace Surfaces
by Maria Francisca Portilha-Cunha, Sara Ramos, Adrián M. T. Silva, Pedro Norton, Arminda Alves and Mónica S. F. Santos
Pharmaceuticals 2021, 14(8), 754; https://doi.org/10.3390/ph14080754 - 31 Jul 2021
Cited by 4 | Viewed by 2393
Abstract
Cytostatics are drugs used in cancer treatment, which pose serious risks to healthcare workers. Dermal absorption via surface contamination is the key exposure route; thus, rapid, reliable, and validated analytical methods for multicomponent detection are crucial to identify the exposure risk. A surface-wipe-sampling [...] Read more.
Cytostatics are drugs used in cancer treatment, which pose serious risks to healthcare workers. Dermal absorption via surface contamination is the key exposure route; thus, rapid, reliable, and validated analytical methods for multicomponent detection are crucial to identify the exposure risk. A surface-wipe-sampling technique compatible with hospitals’ safety requirements (gauze, 1 mL isopropanol) and a fast and simple extraction method (1 mL acetonitrile, 20 min ultrasonic bath, evaporation, reconstitution in 200 µL acetonitrile), coupled with liquid chromatography–tandem mass spectrometry analysis, were developed. It allowed identification and quantification of 13 cytostatics on surfaces: cyclophosphamide, doxorubicin, etoposide, ifosfamide, paclitaxel, bicalutamide, capecitabine, cyproterone, flutamide, imatinib, megestrol, mycophenolate mofetil, prednisone. Good linearity, sensitivity, and precision were achieved (R2 > 0.997, IDLs < 4.0 pg/cm2, average CV 16%, respectively). Accuracy for four model surfaces (melamine-coated wood, phenolic compact, steel 304, steel 316) was acceptable (80 ± 12%), except for capecitabine and doxorubicin. Global uncertainty is below 35% for concentrations above 100 pg/cm2 (except for capecitabine and doxorubicin)—a guidance value for relevant contamination. Method application in a Portuguese university hospital (28 samples) identified the presence of seven cytostatics, at concentrations below 100 pg/cm2, except for three samples. The widespread presence of cyclophosphamide evinces the necessity to review implemented procedures. Full article
(This article belongs to the Special Issue Analytical Techniques in the Pharmaceutical Sciences)
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19 pages, 2610 KiB  
Article
Efficient Matrix Cleanup of Soft-Gel-Type Dietary Supplements for Rapid Screening of 92 Illegal Adulterants Using EMR-Lipid dSPE and UHPLC-Q/TOF-MS
by Beom Hee Kim, Wonwoong Lee, You Lee Kim, Ji Hyun Lee and Jongki Hong
Pharmaceuticals 2021, 14(6), 570; https://doi.org/10.3390/ph14060570 - 15 Jun 2021
Cited by 4 | Viewed by 2553
Abstract
An efficient matrix cleanup method was developed for the rapid screening of 92 illegal adulterants (25 erectile dysfunction drugs, 15 steroids, seven anabolic steroids, 12 antihistamines, 12 nonsteroidal anti-inflammatory drugs (NSAIDs), four diuretics, and 17 weight-loss drugs) in soft-gel-type supplements by ultra-high performance [...] Read more.
An efficient matrix cleanup method was developed for the rapid screening of 92 illegal adulterants (25 erectile dysfunction drugs, 15 steroids, seven anabolic steroids, 12 antihistamines, 12 nonsteroidal anti-inflammatory drugs (NSAIDs), four diuretics, and 17 weight-loss drugs) in soft-gel-type supplements by ultra-high performance liquid chromatography-quadrupole/time of flight-mass spectrometry (UHPLC-Q/TOF-MS). As representative green chemistry methods, three sample preparation methods (dispersive liquid-liquid microextraction (DLLME), “quick, easy, cheap, effective, rugged, and safe” dispersive solid-phase extraction (QuEChERS-dSPE), and enhanced matrix removal-lipid (EMR-Lipid) dSPE) were evaluated for matrix removal efficiency, recovery rate, and matrix effect. In this study, EMR-Lipid dSPE was shown to effectively remove complicated matrix contents in soft-gels, compared to DLLME and QuEChERS-dSPE. For the rapid screening of a wide range of adulterants, extracted common ion chromatogram (ECIC) and neutral loss scan (NLS) based on specific common MS/MS fragments were applied to randomly collected soft-gel-type dietary supplement samples using UHPLC-Q/TOF-MS. Both ECICs and NLSs enabled rapid and simple screening of multi-class adulterants and could be an alternative to the multiple reaction monitoring (MRM) method. The developed method was validated in terms of limit of detection (LOD), precision, accuracy, recovery, and matrix effects. The range of LODs was 0.1–16 ng/g. The overall precision values were within 0.09–14.65%. The accuracy ranged from 81.6% to 116.6%. The recoveries and matrix effects of 92 illegal adulterants ranged within 16.9–119.4% and 69.8–114.8%, respectively. The established method was successfully applied to screen and identify 92 illegal adulterants in soft-gels. This method can be a promising tool for the high-throughput screening of various adulterants in dietary supplements and could be used as a more environmentally friendly routine analytical method for screening dietary supplements illegally adulterated with multi-class drug substances. Full article
(This article belongs to the Special Issue Analytical Techniques in the Pharmaceutical Sciences)
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10 pages, 871 KiB  
Article
New Quality-Range-Setting Method Based on Between- and Within-Batch Variability for Biosimilarity Assessment
by Alexis Oliva and Matías Llabrés
Pharmaceuticals 2021, 14(6), 527; https://doi.org/10.3390/ph14060527 - 01 Jun 2021
Cited by 1 | Viewed by 2464
Abstract
Analytical biosimilarity assessment relies on two implicit conditions. First, the analytical method must meet a set of requirements known as fit for intended use related to trueness and precision. Second, the manufacture of the reference drug product must be under statistical quality control; [...] Read more.
Analytical biosimilarity assessment relies on two implicit conditions. First, the analytical method must meet a set of requirements known as fit for intended use related to trueness and precision. Second, the manufacture of the reference drug product must be under statistical quality control; i.e., the between-batch variability is not larger than the expected within-batch variability. In addition, the quality range (QR) method is based on one sample per batch to avoid biased standard deviations in unbalanced studies. This, together with the small number of reference drug product batches, leads to highly variable QR bounds. In this paper, we propose to set the QR bounds from variance components estimated using a two-level nested linear model, accounting for between- and within-batch variances of the reference drug product. In this way, the standard deviation used to set QR is equal to the square root of the sum of between-batch variance plus the within-batch variance estimated by the maximum likelihood method. The process of this method, which we call QRML, is as follows. First, the condition of statistical quality control of the manufacture process is tested. Second, confidence intervals for QR bounds lead to an analysis of the reliability of the biosimilarity assessment. Third, after analyzing the molecular weight and dimer content of seven batches of a commercial bevacizumab drug product, we concluded that the QRML method was more reliable than QR. Full article
(This article belongs to the Special Issue Analytical Techniques in the Pharmaceutical Sciences)
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14 pages, 1146 KiB  
Article
Development and Validation of an RP-HPLC-PDA Method for Determination of Paracetamol, Caffeine and Tramadol Hydrochloride in Pharmaceutical Formulations
by Fernando J. Pereira, Aida Rodríguez-Cordero, Roberto López, Luis C. Robles and A. Javier Aller
Pharmaceuticals 2021, 14(5), 466; https://doi.org/10.3390/ph14050466 - 15 May 2021
Cited by 22 | Viewed by 5256
Abstract
Paracetamol (acetaminophen) (PAR), caffeine (CAF) and tramadol hydrochloride (TRA) are important drugs widely used for many clinical purposes. Determination of their contents is of the paramount interest. In this respect, a quick, simple and sensitive isocratic RP-HPLC method with photodiode array detection was [...] Read more.
Paracetamol (acetaminophen) (PAR), caffeine (CAF) and tramadol hydrochloride (TRA) are important drugs widely used for many clinical purposes. Determination of their contents is of the paramount interest. In this respect, a quick, simple and sensitive isocratic RP-HPLC method with photodiode array detection was developed for the determination of paracetamol, caffeine and tramadol in pharmaceutical formulations. An improved sensitive procedure was also evolved for tramadol using a fluorescence detector system. A C18 column and a mobile phase constituted by methanol/phosphate were used. LODs were found to be 0.2 μg/mL, 0.1 μg/mL and 0.3 μg/mL for paracetamol, caffeine and tramadol hydrochloride, respectively, using photodiode-array detection. Alternatively, LOD for tramadol decreased to 0.1 μg/mL with the fluorescence detector. Other notable analytical figures of merit include the linear concentration ranges, 0.8–270 μg/mL, 0.4–250 μg/mL and 1.0–300 (0.2–40) μg/mL, for the same ordered analytes (including the fluorescence detector). The proposed method was successfully applied for the quantitative determination of the three drugs in tablet dosage forms. Full article
(This article belongs to the Special Issue Analytical Techniques in the Pharmaceutical Sciences)
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15 pages, 3594 KiB  
Article
Development and Validation of an Up-to-Date Highly Sensitive UHPLC-MS/MS Method for the Simultaneous Quantification of Current Anti-HIV Nucleoside Analogues in Human Plasma
by Amedeo De Nicolò, Alessandra Manca, Alice Ianniello, Alice Palermiti, Andrea Calcagno, Micol Ferrara, Miriam Antonucci, Jessica Cusato, Valeria Avataneo, Elisa De Vivo, Stefano Bonora, Francesco Giuseppe De Rosa, Giovanni Di Perri and Antonio D’Avolio
Pharmaceuticals 2021, 14(5), 460; https://doi.org/10.3390/ph14050460 - 13 May 2021
Cited by 3 | Viewed by 2389
Abstract
Therapeutic options to treat HIV infection have widened in the past years, improving both effectiveness and tolerability, but nucleoside reverse transcriptase inhibitors (NRTIs) are still considered the standard backbone of the combination regimens. Therapeutic drug monitoring (TDM) can be useful for these drugs, [...] Read more.
Therapeutic options to treat HIV infection have widened in the past years, improving both effectiveness and tolerability, but nucleoside reverse transcriptase inhibitors (NRTIs) are still considered the standard backbone of the combination regimens. Therapeutic drug monitoring (TDM) can be useful for these drugs, due to concentration–effect relationship, with risk of ineffectiveness, toxicity or adherence concerns: in this scenario, robust and multiplexed methods are needed for an effective TDM activity. In this work, the first validated ultra-high spectrometry liquid chromatography coupled with tandem mass spectrometry (UHPLC-MS/MS) method is described for the high-sensitive simultaneous quantification of all the currently used NRTIs in human plasma, including tenofovir alafenamide (TAF), following FDA and EMA guidelines. The automated sample preparation consisted in the addition of an internal standard (IS) working solution, containing stable-isotope-linked drugs, protein precipitation and drying. Dry extracts were reconstituted with water, then, these underwent reversed phase chromatographic separation: compounds were detected through electrospray ionization and multiple reaction monitoring. Accuracy, precision, recovery and IS-normalized matrix effect fulfilled guidelines’ requirements. The application of this method on samples from people living with HIV (PLWH) showed satisfactory performance, being capable of quantifying the very low concentrations of tenofovir (TFV) in patients treated with TAF. Full article
(This article belongs to the Special Issue Analytical Techniques in the Pharmaceutical Sciences)
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11 pages, 3565 KiB  
Article
Quantification and Classification of Diclofenac Sodium Content in Dispersed Commercially Available Tablets by Attenuated Total Reflection Infrared Spectroscopy and Multivariate Data Analysis
by Eirini Siozou, Vasilios Sakkas and Nikolaos Kourkoumelis
Pharmaceuticals 2021, 14(5), 440; https://doi.org/10.3390/ph14050440 - 07 May 2021
Cited by 8 | Viewed by 3749
Abstract
A new methodology, based on Fourier transform infrared spectroscopy equipped with an attenuated total reflectance accessory (ATR FT-IR), was developed for the determination of diclofenac sodium (DS) in dispersed commercially available tablets using chemometric tools such as partial least squares (PLS) coupled with [...] Read more.
A new methodology, based on Fourier transform infrared spectroscopy equipped with an attenuated total reflectance accessory (ATR FT-IR), was developed for the determination of diclofenac sodium (DS) in dispersed commercially available tablets using chemometric tools such as partial least squares (PLS) coupled with discriminant analysis (PLS-DA). The results of PLS-DA depicted a perfect classification of the tablets into three different groups based on their DS concentrations, while the developed model with PLS had a sufficiently low root mean square error (RMSE) for the prediction of the samples’ concentration (~5%) and therefore can be practically used for any tablet with an unknown concentration of DS. Comparison with ultraviolet/visible (UV/Vis) spectrophotometry as the reference method revealed no significant difference between the two methods. The proposed methodology exhibited satisfactory results in terms of both accuracy and precision while being rapid, simple and of low cost. Full article
(This article belongs to the Special Issue Analytical Techniques in the Pharmaceutical Sciences)
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16 pages, 2794 KiB  
Article
A Comprehensive Approach to Compatibility Testing Using Chromatographic, Thermal and Spectroscopic Techniques: Evaluation of Potential for a Monolayer Fixed-Dose Combination of 6-Mercaptopurine and Folic Acid
by Edvin Brusač, Mario-Livio Jeličić, Matija Cvetnić, Daniela Amidžić Klarić, Biljana Nigović and Ana Mornar
Pharmaceuticals 2021, 14(3), 274; https://doi.org/10.3390/ph14030274 - 17 Mar 2021
Cited by 4 | Viewed by 2358
Abstract
In this work, a systematical compatibility investigation of 6-mercaptopurine and folic acid, two commonly used medications in the treatment of inflammatory bowel disease, for the needs of a fixed-dose combination development strategy is shown. Various techniques and approaches, such as differential scanning calorimetry, [...] Read more.
In this work, a systematical compatibility investigation of 6-mercaptopurine and folic acid, two commonly used medications in the treatment of inflammatory bowel disease, for the needs of a fixed-dose combination development strategy is shown. Various techniques and approaches, such as differential scanning calorimetry, isothermal stress testing, attenuated total reflectance–Fourier-transform infrared spectroscopy, dissolution medium stability and forced degradation studies, were used to elucidate the possible interactions from different aspects. The results predominantly point to the absence of physicochemical interactions between the examined substances in a variety of possible conditions. However, the forced degradation of the blend of substances and excipients in basic conditions showed a drastic degradation of 6-mercaptopurine, signifying that attention needs to be directed to the careful selection of the excipients for the formulation. To sum up, our findings indicate that a fixed-dose combination of 6-mercaptopurine and folic acid could be produced using one formulation blend, immensely simplifying its manufacture. Full article
(This article belongs to the Special Issue Analytical Techniques in the Pharmaceutical Sciences)
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10 pages, 1632 KiB  
Article
Development and Validation of an LC-MS/MS Method for Quantification of the Novel Antibacterial Candidate DA-7010 in Plasma and Application to a Preclinical Pharmacokinetic Study
by Mi Hye Kwon, Dae Young Lee and Hee Eun Kang
Pharmaceuticals 2021, 14(2), 163; https://doi.org/10.3390/ph14020163 - 18 Feb 2021
Cited by 2 | Viewed by 2343
Abstract
DA-7010 is a new candidate for an antibacterial agent that targets Gram-negative pathogens by acting as a leucyl-tRNA synthetase inhibitor. In this study, a simple and rapid liquid chromatography tandem mass spectrometry (LC-MS/MS) method was developed to determine DA-7010 levels in the plasma [...] Read more.
DA-7010 is a new candidate for an antibacterial agent that targets Gram-negative pathogens by acting as a leucyl-tRNA synthetase inhibitor. In this study, a simple and rapid liquid chromatography tandem mass spectrometry (LC-MS/MS) method was developed to determine DA-7010 levels in the plasma from mice, rats, and dogs. Plasma samples were mixed with methanol for protein precipitation. Chromatographic separation was carried out using a reversed-phase C18 column (Agilent Poroshell 120, 50 × 3.0 mm, 2.7 μm). An isocratic elution of the mobile phase consisting of 5 mM formic acid in water and acetonitrile at a ratio of 84:16 (v/v) was applied at a flow rate of 0.3 mL/min. The total chromatographic run time was 3.5 min. Multiple reaction monitoring (MRM) mode was used for mass spectrometric detection using an Agilent 6460 triple quadrupole coupled with an electrospray ionization (ESI) source operated in positive-ion mode. The MRM transitions analyzed were m/z 220.1→162.1 for DA-7010 and m/z 206.1→170.1 for the internal standard (structural analogue of DA-7010). Calibration curves were constructed in the range of 10–10,000 ng/mL. The intra- and interday precision and accuracy were within 11.3%, excluding those for the lower limit of quantification (LLOQ) samples, which were within 17.1%. The developed LC-MS/MS method was successfully validated and applied in preclinical pharmacokinetic studies of DA-7010 in mice, rats, and dogs following single oral administrations. The oral absorption of DA-7010 was rapid, and the systemic exposure was approximately four times higher in the dogs than in the mice or rats. Full article
(This article belongs to the Special Issue Analytical Techniques in the Pharmaceutical Sciences)
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14 pages, 1609 KiB  
Article
Immobilization of Chondroitin Sulfate A onto Monolithic Epoxy Silica Column as a New Chiral Stationary Phase for High-Performance Liquid Chromatographic Enantioseparation
by Ratih Ratih, Hermann Wätzig, Azminah Azminah, Mufarreh Asmari, Benjamin Peters and Sami El Deeb
Pharmaceuticals 2021, 14(2), 98; https://doi.org/10.3390/ph14020098 - 27 Jan 2021
Cited by 8 | Viewed by 2511
Abstract
Chondroitin sulfate A was covalently immobilized onto a monolithic silica epoxy column involving a Schiff base formation in the presence of ethylenediamine as a spacer and evaluated in terms of its selectivity in enantioseparation. The obtained column was utilized as a chiral stationary [...] Read more.
Chondroitin sulfate A was covalently immobilized onto a monolithic silica epoxy column involving a Schiff base formation in the presence of ethylenediamine as a spacer and evaluated in terms of its selectivity in enantioseparation. The obtained column was utilized as a chiral stationary phase in enantioseparation of amlodipine and verapamil using a mobile phase consisting of 50 mM phosphate buffer pH 3.5 and UV detection. Sample dilution by organic solvents (preferably 25% v/v acetonitrile-aqueous solution) was applied to achieve baseline enantioresolution (Rs > 3.0) of the individual drug models within 7 min, an excellent linearity (R2 = 0.999) and an interday repeatability of 1.1% to 1.8% RSD. The performance of the immobilized column for quantification of racemate in commercial tablets showed a recovery of 86–98% from tablet matrices. Computational modeling by molecular docking was employed to investigate the feasible complexes between enantiomers and the chiral selector. Full article
(This article belongs to the Special Issue Analytical Techniques in the Pharmaceutical Sciences)
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16 pages, 1362 KiB  
Article
Validation of a UHPLC-MS/MS Method to Quantify Twelve Antiretroviral Drugs within Peripheral Blood Mononuclear Cells from People Living with HIV
by Amedeo De Nicolò, Alice Ianniello, Micol Ferrara, Valeria Avataneo, Jessica Cusato, Miriam Antonucci, Elisa De Vivo, Catriona Waitt, Andrea Calcagno, Alice Trentalange, Giampiero Muccioli, Stefano Bonora, Giovanni Di Perri and Antonio D'Avolio
Pharmaceuticals 2021, 14(1), 12; https://doi.org/10.3390/ph14010012 - 25 Dec 2020
Cited by 7 | Viewed by 2788
Abstract
Recently, anti-HIV treatment has achieved high efficacy and tolerability. Nevertheless, few data are available about the intracellular penetration of antiretrovirals, partly due to the technical challenges related to intracellular quantification. This work aimed to validate an ultra-high performance liquid chromatography (UHPLC) tandem mass [...] Read more.
Recently, anti-HIV treatment has achieved high efficacy and tolerability. Nevertheless, few data are available about the intracellular penetration of antiretrovirals, partly due to the technical challenges related to intracellular quantification. This work aimed to validate an ultra-high performance liquid chromatography (UHPLC) tandem mass spectrometry (MS/MS) method for the simultaneous quantification of maraviroc, nevirapine, rilpivirine, dolutegravir, raltegravir, cobicistat, darunavir, ritonavir, atazanavir, efavirenz, elvitegravir, and etravirine within peripheral blood mononuclear cells (PBMCs) and apply it to samples from patients. PBMCs were isolated by density gradient on cell preparation tubes (CPT). Samples were prepared by addition of internal standards (IS), sonication, centrifugation, and drying. Reconstituted extracts underwent chromatographic separation by reversed phase UHPLC and detection was performed by electrospray ionization and multiple reaction monitoring. Method validation followed FDA and EMA guidelines, showing acceptable accuracy, precision, recovery and IS-normalized matrix effect. The application to 56 samples from patients undergoing antiretroviral treatment provided description of intracellular penetration, showing method eligibility for future studies. Full article
(This article belongs to the Special Issue Analytical Techniques in the Pharmaceutical Sciences)
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8 pages, 865 KiB  
Article
Improved Detection Criteria for Detecting Drug-Drug Interaction Signals Using the Proportional Reporting Ratio
by Yoshihiro Noguchi, Keisuke Aoyama, Satoaki Kubo, Tomoya Tachi and Hitomi Teramachi
Pharmaceuticals 2021, 14(1), 4; https://doi.org/10.3390/ph14010004 - 23 Dec 2020
Cited by 9 | Viewed by 2390
Abstract
There is a current demand for “safety signal” screening, not only for single drugs but also for drug-drug interactions. The detection of drug-drug interaction signals using the proportional reporting ratio (PRR) has been reported, such as through using the combination risk [...] Read more.
There is a current demand for “safety signal” screening, not only for single drugs but also for drug-drug interactions. The detection of drug-drug interaction signals using the proportional reporting ratio (PRR) has been reported, such as through using the combination risk ratio (CRR). However, the CRR does not consider the overlap between the lower limit of the 95% confidence interval of the PRR of concomitant-use drugs and the upper limit of the 95% confidence interval of the PRR of single drugs. In this study, we proposed the concomitant signal score (CSS), with the improved detection criteria, to overcome the issues associated with the CRR. “Hypothetical” true data were generated through a combination of signals detected using three detection algorithms. The signal detection accuracy of the analytical model under investigation was verified using machine learning indicators. The CSS presented improved signal detection when the number of reports was ≥3, with respect to the following metrics: accuracy (CRR: 0.752 → CSS: 0.817), Youden’s index (CRR: 0.555 → CSS: 0.661), and F-measure (CRR: 0.780 → CSS: 0.820). The proposed model significantly improved the accuracy of signal detection for drug-drug interactions using the PRR. Full article
(This article belongs to the Special Issue Analytical Techniques in the Pharmaceutical Sciences)
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25 pages, 5336 KiB  
Article
Determination of Antidepressants in Human Plasma by Modified Cloud-Point Extraction Coupled with Mass Spectrometry
by Elżbieta Gniazdowska, Natalia Korytowska, Grzegorz Kłudka and Joanna Giebułtowicz
Pharmaceuticals 2020, 13(12), 458; https://doi.org/10.3390/ph13120458 - 12 Dec 2020
Cited by 10 | Viewed by 2712
Abstract
Cloud-point extraction (CPE) is rarely combined with liquid chromatography coupled to mass spectrometry (LC–MS) in drug determination due to the matrix effect (ME). However, we have recently shown that ME is not a limiting factor in CPE. Low extraction efficiency may be improved [...] Read more.
Cloud-point extraction (CPE) is rarely combined with liquid chromatography coupled to mass spectrometry (LC–MS) in drug determination due to the matrix effect (ME). However, we have recently shown that ME is not a limiting factor in CPE. Low extraction efficiency may be improved by salt addition, but none of the salts used in CPE are suitable for LC–MS. It is the first time that the influences of a volatile salt—ammonium acetate (AA)—on the CPE extraction efficiency and ME have been studied. Our modification of CPE included also the use of ethanol instead of acetonitrile to reduce the sample viscosity and make the method more environmentally friendly. We developed and validated CPE–LC–MS for the simultaneous determination of 21 antidepressants in plasma that can be useful for clinical and forensic toxicology. The selected parameters included Triton X-114 concentration (1.5 and 6%, w/v), concentration of AA (0, 10, 20 and 30%, w/v), and pH (3.5, 6.8 and 10.2). The addition of 10% of AA increased recovery twice. For 20 and 30% (w/v) of AA, three phases were formed that prolonged the extraction process. The developed CPE method (6% Triton X-114, 10% AA, pH 10.2) was successfully validated through LC–MS/MS simultaneous determination of 21 antidepressants in human plasma. The linearity was in the range of 10–750 ng/mL (r2 > 0.990). Full article
(This article belongs to the Special Issue Analytical Techniques in the Pharmaceutical Sciences)
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16 pages, 3178 KiB  
Article
Bioanalytical Assay Development and Validation for the Pharmacokinetic Study of GMC1, a Novel FKBP52 Co-chaperone Inhibitor for Castration Resistant Prostate Cancer
by Oscar Ekpenyong, Candace Cooper, Jing Ma, Naihsuan C. Guy, Ashley N. Payan, Fuqiang Ban, Artem Cherkasov, Marc B. Cox, Dong Liang and Huan Xie
Pharmaceuticals 2020, 13(11), 386; https://doi.org/10.3390/ph13110386 - 13 Nov 2020
Cited by 1 | Viewed by 2000
Abstract
Background: GMC1 (2-(1H-benzimidazol-2-ylsulfanyl)-N-[(Z)-(4-methoxyphenyl) methylideneamino] acetamide) effectively inhibits androgen receptor function by binding directly to FKBP52. This is a novel mechanism for the treatment of castration resistant prostate cancer (CRPC). Methods: an LC-MS/MS method was developed and validated to quantify GMC1 in [...] Read more.
Background: GMC1 (2-(1H-benzimidazol-2-ylsulfanyl)-N-[(Z)-(4-methoxyphenyl) methylideneamino] acetamide) effectively inhibits androgen receptor function by binding directly to FKBP52. This is a novel mechanism for the treatment of castration resistant prostate cancer (CRPC). Methods: an LC-MS/MS method was developed and validated to quantify GMC1 in plasma and urine from pharmacokinetics studies in rats. An ultra-high-performance liquid chromatography (UHPLC) system equipped with a Waters XTerra MS C18 column was used for chromatographic separation by gradient elution with 0.1% (v/v) formic acid in water and methanol. A Sciex 4000 QTRAP® mass spectrometer was used for analysis by multiple reaction monitoring (MRM) in positive mode; the specific ions [M+H]+m/z 340.995 → m/z 191.000 and [M+H]+ m/z 266.013 → m/z 234.000 were monitored for GMC1 and internal standard (albendazole), respectively. Results: GMC1 and albendazole had retention times of 1.68 and 1.66 min, respectively. The calibration curves for the determination of GMC1 in rat plasma and urine were linear from 1–1000 ng/mL. The LC-MS/MS method was validated with intra- and inter-day accuracy and precision within the 15% acceptance limit. The extraction recovery values of GMC1 from rat plasma and urine were greater than 95.0 ± 2.1% and 97.6 ± 4.6%, respectively, with no significant interfering matrix effect. GMC1 is stable under expected sample handling, storage, preparation and LC-MS/MS analysis conditions. Conclusions: Pharmacokinetic evaluation of GMC1 revealed that the molecule has a biexponential disposition in rats, is distributed rapidly and extensively, has a long elimination half-life, and appears to be eliminated primarily by first order kinetics. Full article
(This article belongs to the Special Issue Analytical Techniques in the Pharmaceutical Sciences)
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17 pages, 3703 KiB  
Article
Quality-by-Design Is a Tool for Quality Assurance in the Assessment of Enantioseparation of a Model Active Pharmaceutical Ingredient
by Dina Aboushady, Maria Kristina Parr and Rasha S. Hanafi
Pharmaceuticals 2020, 13(11), 364; https://doi.org/10.3390/ph13110364 - 04 Nov 2020
Cited by 9 | Viewed by 2593
Abstract
The design of experiments (DoE) is one of the quality-by-design tools valued in analytical method development, not only for cost reduction and time effectiveness, but also for enabling analytical method control and understanding via a systematic workflow, leading to analytical methods with built-in [...] Read more.
The design of experiments (DoE) is one of the quality-by-design tools valued in analytical method development, not only for cost reduction and time effectiveness, but also for enabling analytical method control and understanding via a systematic workflow, leading to analytical methods with built-in quality. This work aimed at using DoE to enhance method understanding for a developed UHPLC enantioseparation of terbutaline (TER), a model chiral drug, and to define quality assurance parameters associated with using chiral mobile phase additives (CMPA). Within a response surface methodology workflow, the effect of different factors on both chiral resolution and retention was screened and optimized using Plackett-Burman and central composite designs, respectively, followed by multivariate mathematical modeling. This study was able to delimit method robustness and elucidate enantiorecognition mechanisms involved in interactions of TER with the chiral modifiers. Among many CMPAs, successful TER enantioresolution was achieved using hydroxypropyl β-cyclodextrin (HP-β-CD) added to the mobile phase as 5.4 mM HP-β-CD in 52.25 mM ammonium acetate. Yet, limited method robustness was observed upon switching between the different tested CMPA, concluding that quality can only be assured with specific minimal pre-run conditioning time with the CMPA, namely 16-column volume (60 min at 0.1 mL/min). For enantiorecognition understanding, computational molecular modeling revealed hydrogen bonding as the main binding interaction, in addition to dipole-dipole inside the CD cavity for the R enantiomer, while the S enantiomer was less interactive. Full article
(This article belongs to the Special Issue Analytical Techniques in the Pharmaceutical Sciences)
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15 pages, 516 KiB  
Review
Therapeutic Drug Monitoring of Antiseizure Medications Using Volumetric Absorptive Microsampling: Where Are We?
by Annachiara D’Urso, Marcello Locatelli, Angela Tartaglia, Linda Molteni, Cristian D’Ovidio, Fabio Savini, James Rudge and Ugo de Grazia
Pharmaceuticals 2021, 14(7), 627; https://doi.org/10.3390/ph14070627 - 29 Jun 2021
Cited by 10 | Viewed by 3165
Abstract
Therapeutic drug monitoring (TDM) of antiseizure medications (ASMs) represents a valuable tool to establish an appropriate patient therapy, to collect important information about drugs’ interactions and to evaluate patient’s metabolic capabilities. In recent years, a new volumetric absorptive microsampling technique using VAMS® [...] Read more.
Therapeutic drug monitoring (TDM) of antiseizure medications (ASMs) represents a valuable tool to establish an appropriate patient therapy, to collect important information about drugs’ interactions and to evaluate patient’s metabolic capabilities. In recent years, a new volumetric absorptive microsampling technique using VAMS® technology and Mitra® devices, consisting of a sampling technique for the collection of fixed-volume capillary blood, was developed. These new devices provide a new home-sampling technique for whole blood that has been spread out to simplify sample collection from finger-pricks. This review is aimed to compare published articles concerning the application of VAMS® in epilepsy and to identify the strengths and improvement points for the TDM of antiseizure medications. VAMS® allowed a minimally invasive blood sampling even in the absence of trained personnel. Good stability data have indicated that storage and delivery can be facilitated only for specific ASMs. Trueness and precision parameters have been evaluated, and the hematocrit (HCT) effect was minimized. Full article
(This article belongs to the Special Issue Analytical Techniques in the Pharmaceutical Sciences)
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32 pages, 8150 KiB  
Review
Cytostatics in Indoor Environment: An Update of Analytical Methods
by M. Francisca Portilha-Cunha, A. Alves and Mónica S. F. Santos
Pharmaceuticals 2021, 14(6), 574; https://doi.org/10.3390/ph14060574 - 15 Jun 2021
Cited by 6 | Viewed by 2077
Abstract
Periodic and adequate environmental monitoring programs are crucial to assess and reduce the occupational exposure of healthcare workers to cytostatics. The analytical methods employed should be rapid, reliable, sensitive, standardized, and include multiple compounds. A critical overview of recent overall procedures for surface [...] Read more.
Periodic and adequate environmental monitoring programs are crucial to assess and reduce the occupational exposure of healthcare workers to cytostatics. The analytical methods employed should be rapid, reliable, sensitive, standardized, and include multiple compounds. A critical overview of recent overall procedures for surface and air contamination with cytostatics in workplace settings is presented, with a focus on sampling, sample preparation, and instrumental considerations. Limitations are also addressed and some recommendations and advice are provided. Since dermal absorption is the main exposure route, surface contamination is the preferred indicator of biological uptake and its methods have significantly improved. In contrast, cytostatics’ inhalation is rare; thus, air contamination has been poorly studied, with little improvement. Still, some elements of the analytical methods have not been extensively explored, namely: the amount of wetting solution, the extraction procedure, surface chemistry and roughness, recovery studies from specific surfaces, and cytostatics stability (in surfaces and during shipping and storage). Furthermore, complete validation data (including precision, accuracy, and instrumental and method detection limits) and estimation of global uncertainty are still lacking in most studies, thus preventing method comparison and proposal of standardized procedures. Full article
(This article belongs to the Special Issue Analytical Techniques in the Pharmaceutical Sciences)
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