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Recent Trends in Pharmaceutical Analytical Chemistry
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Recent Trends in Pharmaceutical Analytical Chemistry

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Analytical Chemistry".

Deadline for manuscript submissions: closed (31 May 2020) | Viewed by 41916

Printed Edition Available!
A printed edition of this Special Issue is available here.

Special Issue Editors

Dr. Constantinos K. Zacharis

E-Mail Website
Guest Editor
Laboratory of Pharmaceutical Analysis, Department of Pharmaceutical Technology, School of Pharmacy, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
Interests: pharmaceutical analytical chemistry; method development and validation; sample preparation (derivatization, microextraction, etc.); liquid and gas chromatography; capillary electrophoresis; mass spectrometry
Special Issues, Collections and Topics in MDPI journals
Dr. Aikaterini Markopoulou

E-Mail Website
Guest Editor
Laboratory of Pharmaceutical Analysis, Department of Pharmaceutical Technology, School of Pharmacy, Aristotle University of Thessaloniki, Thessaloniki, Greece
Interests: liquid and gas chromatography; mass spectrometry; FT-Raman; near-IR; chemometrics and implementation techniques; study and modeling of the retention mechanism of drugs on HPLC columns; drug-likeness by modeling and HPLC; bioanalysis; modern pharmaceutical formulations
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Modern analytical chemistry plays a vital role in pharmaceutical sciences. It provides identification and quantification data supporting drug discovery, purity of drug substances during its synthesis, pharmacokinetic studies, drug stability, elucidation of the drug metabolic pathways, drug-protein interactions, etc. New methodologies, state-of-the art instrumentation and materials, automated systems - offering precise and accurate analytical data – have become an important prerequisite in this field. Furthermore, chemometrics is a useful tool for the optimization of method parameters and also to identify and minimize the sources of variability that may lead to poor method robustness.

The present Special Issue will include review and full-length research articles covering the latest research trends and applications of Pharmaceutical Analytical Chemistry. Analytical scientists working on method development and validation, impurity profiling, pharmacokinetics, drug-protein/DNA interaction studies, bioanalysis, enantioseparation, etc are cordially invited to contribute a research or review article in this Special Issue. The degree of novelty and the significant of the research will be scrutinized prior to peer-reviewing process.

In the cases of review articles an additional brief (1-2 pages) description of the topic including a draft index is required. This preliminary step is essential to avoid overlapping of topics.

Dr. Constantinos K. Zacharis
Dr. Aikaterini Markopoulou
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. Molecules is an international peer-reviewed open access semimonthly 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 2700 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

  • impurity profiling
  • enantioseparation
  • bioanalytical chemistry
  • analytical quality by design (AQbD) - Chemometrics
  • separation techniques (LC, GC, CE, SFC, LC x LC, etc)
  • pharmacokinetics, Bioequivalence studies
  • drug-protein/DNA binding studies
  • automation
  • quality control & stability
  • sample preparation

Published Papers (13 papers)

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Editorial

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4 pages, 183 KiB  
Editorial
Recent Trends in Pharmaceutical Analytical Chemistry
by Constantinos K. Zacharis and Catherine K. Markopoulou
Molecules 2020, 25(16), 3560; https://doi.org/10.3390/molecules25163560 - 05 Aug 2020
Cited by 2 | Viewed by 3050
Abstract
Modern analytical chemistry plays a vital role in pharmaceutical sciences [...] Full article
(This article belongs to the Special Issue Recent Trends in Pharmaceutical Analytical Chemistry)

Research

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13 pages, 1129 KiB  
Article
A Hydrophilic Interaction Liquid Chromatography–Tandem Mass Spectrometry Quantitative Method for Determination of Baricitinib in Plasma, and Its Application in a Pharmacokinetic Study in Rats
by Essam Ezzeldin, Muzaffar Iqbal, Yousif A. Asiri, Azza A Ali, Prawez Alam and Toqa El-Nahhas
Molecules 2020, 25(7), 1600; https://doi.org/10.3390/molecules25071600 - 31 Mar 2020
Cited by 10 | Viewed by 3515
Abstract
Baricitinib, is a selective and reversible Janus kinase inhibitor, is commonly used to treat adult patients with moderately to severely active rheumatoid arthritis (RA). A fast, reproducible and sensitive method of liquid chromatography-tandem mass spectrometry (LC-MS/MS) for the quantification of baricitinib in rat [...] Read more.
Baricitinib, is a selective and reversible Janus kinase inhibitor, is commonly used to treat adult patients with moderately to severely active rheumatoid arthritis (RA). A fast, reproducible and sensitive method of liquid chromatography-tandem mass spectrometry (LC-MS/MS) for the quantification of baricitinib in rat plasma has been developed. Irbersartan was used as the internal standard (IS). Baracitinib and IS were extracted from plasma by liquid–liquid extraction using a mixture of n-hexane and dichloromethane (1:1) as extracting agent. Chromatographic separation was performed using Acquity UPLC HILIC BEH 1.7 µm 2.1 × 50 mm column with the mobile phase consisting of 0.1% formic acid in acetonitrile and 20 mM ammonium acetate (pH 3) (97:3). The electrospray ionization in the positive-mode was used for sample ionization in the multiple reaction monitoring mode. Baricitinib and the IS were quantified using precursor-to-production transitions of m/z 372.15 > 251.24 and 429.69 > 207.35 for baricitinib and IS, respectively. The method was validated according to the recent FDA and EMA guidelines for bioanalytical method validation. The lower limit of quantification was 0.2 ng/mL, whereas the intra-day and inter-day accuracies of quality control (QCs) samples were ranged between 85.31% to 89.97% and 87.50% to 88.33%, respectively. Linearity, recovery, precision, and stability parameters were found to be within the acceptable range. The method was applied successfully applied in pilot pharmacokinetic studies. Full article
(This article belongs to the Special Issue Recent Trends in Pharmaceutical Analytical Chemistry)
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10 pages, 1807 KiB  
Article
A Fast and Validated High Throughput Bar Adsorptive Microextraction (HT-BAµE) Method for the Determination of Ketamine and Norketamine in Urine Samples
by Samir M. Ahmad, Mariana N. Oliveira, Nuno R. Neng and J.M.F. Nogueira
Molecules 2020, 25(6), 1438; https://doi.org/10.3390/molecules25061438 - 22 Mar 2020
Cited by 7 | Viewed by 2738
Abstract
We developed, optimized and validated a fast analytical cycle using high throughput bar adsorptive microextraction and microliquid desorption (HT-BAμE-μLD) for the extraction and desorption of ketamine and norketamine in up to 100 urine samples simultaneously, resulting in an assay time of only 0.45 [...] Read more.
We developed, optimized and validated a fast analytical cycle using high throughput bar adsorptive microextraction and microliquid desorption (HT-BAμE-μLD) for the extraction and desorption of ketamine and norketamine in up to 100 urine samples simultaneously, resulting in an assay time of only 0.45 min/sample. The identification and quantification were carried out using large volume injection-gas chromatography-mass spectrometry operating in the selected ion monitoring mode (LVI-GC-MS(SIM)). Several parameters that could influencing HT-BAµE were assayed and optimized in order to maximize the recovery yields of ketamine and norketamine from aqueous media. These included sorbent selectivity, desorption solvent and time, as well as shaking rate, microextraction time, matrix pH, ionic strength and polarity. Under optimized experimental conditions, suitable sensitivity (1.0 μg L−1), accuracy (85.5–112.1%), precision (≤15%) and recovery yields (84.9–105.0%) were achieved. Compared to existing methods, the herein described analytical cycle is much faster, environmentally friendly and cost-effective for the quantification of ketamine and norketamine in urine samples. To our knowledge, this is the first work that employs a high throughput based microextraction approach for the simultaneous extraction and subsequent desorption of ketamine and norketamine in up to 100 urine samples simultaneously. Full article
(This article belongs to the Special Issue Recent Trends in Pharmaceutical Analytical Chemistry)
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16 pages, 3827 KiB  
Article
Partial Least Square Model (PLS) as a Tool to Predict the Diffusion of Steroids Across Artificial Membranes
by Eleni Tsanaktsidou, Christina Karavasili, Constantinos K. Zacharis, Dimitrios G. Fatouros and Catherine K. Markopoulou
Molecules 2020, 25(6), 1387; https://doi.org/10.3390/molecules25061387 - 18 Mar 2020
Cited by 10 | Viewed by 2772
Abstract
One of the most challenging goals in modern pharmaceutical research is to develop models that can predict drugs’ behavior, particularly permeability in human tissues. Since the permeability is closely related to the molecular properties, numerous characteristics are necessary in order to develop a [...] Read more.
One of the most challenging goals in modern pharmaceutical research is to develop models that can predict drugs’ behavior, particularly permeability in human tissues. Since the permeability is closely related to the molecular properties, numerous characteristics are necessary in order to develop a reliable predictive tool. The present study attempts to decode the permeability by correlating the apparent permeability coefficient (Papp) of 33 steroids with their properties (physicochemical and structural). The Papp of the molecules was determined by in vitro experiments and the results were plotted as Y variable on a Partial Least Squares (PLS) model, while 37 pharmacokinetic and structural properties were used as X descriptors. The developed model was subjected to internal validation and it tends to be robust with good predictive potential (R2Y = 0.902, RMSEE = 0.00265379, Q2Y = 0.722, RMSEP = 0.0077). Based on the results specific properties (logS, logP, logD, PSA and VDss) were proved to be more important than others in terms of drugs Papp. The models can be utilized to predict the permeability of a new candidate drug avoiding needless animal experiments, as well as time and material consuming experiments. Full article
(This article belongs to the Special Issue Recent Trends in Pharmaceutical Analytical Chemistry)
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9 pages, 2016 KiB  
Communication
Chemometric Analysis of Low-field 1H NMR Spectra for Unveiling Adulteration of Slimming Dietary Supplements by Pharmaceutical Compounds
by Nao Wu, Stéphane Balayssac, Saïda Danoun, Myriam Malet-Martino and Véronique Gilard
Molecules 2020, 25(5), 1193; https://doi.org/10.3390/molecules25051193 - 06 Mar 2020
Cited by 18 | Viewed by 3424
Abstract
The recent introduction of compact or low-field (LF) NMR spectrometers that use permanent magnets, giving rise to proton (1H) NMR frequencies between 40 and 80 MHz, have opened up new areas of application. The two main limitations of the technique are [...] Read more.
The recent introduction of compact or low-field (LF) NMR spectrometers that use permanent magnets, giving rise to proton (1H) NMR frequencies between 40 and 80 MHz, have opened up new areas of application. The two main limitations of the technique are its insensitivity and poor spectral resolution. However, this study demonstrates that the chemometric treatment of LF 1H NMR spectral data is suitable for unveiling medicines as adulterants of slimming dietary supplements (DS). To this aim, 66 DS were analyzed with LF 1H NMR after quick and easy sample preparation. A first PLS-DA model built with the LF 1H NMR spectra from forty DS belonging to two classes of weight-loss DS (non-adulterated, and sibutramine or phenolphthalein-adulterated) led to the classification of 13 newly purchased test samples as natural, adulterated or borderline. This classification was further refined when the model was made from the same 40 DS now considered as representing three classes of DS (non-adulterated, sibutramine-adulterated, and phenolphthalein-adulterated). The adulterant (sibutramine or phenolphthalein) was correctly predicted as confirmed by the examination of the 1H NMR spectra. A limitation of the chemometric approach is discussed with the example of two atypical weight-loss DS containing fluoxetine or raspberry ketone. Full article
(This article belongs to the Special Issue Recent Trends in Pharmaceutical Analytical Chemistry)
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8 pages, 1582 KiB  
Article
Determination of Polyhexamethylene Biguanide Hydrochloride Using a Lactone-Rhodamine B-Based Fluorescence Optode
by Akane Funaki, Yuta Horikoshi, Teruyuki Kobayashi and Takashi Masadome
Molecules 2020, 25(2), 262; https://doi.org/10.3390/molecules25020262 - 09 Jan 2020
Cited by 4 | Viewed by 2924
Abstract
A new determination method for polyhexamethylene biguanide hydrochloride (PHMB) using a lactone-rhodamine B (L-RB) based fluorescence optode has been developed. The optode membrane consists of 2-nitrophenyl octyl ether as a plasticizer, L-RB, and poly (vinyl chloride). The optode responds to tetrakis (4-fluorophenyl) borate, [...] Read more.
A new determination method for polyhexamethylene biguanide hydrochloride (PHMB) using a lactone-rhodamine B (L-RB) based fluorescence optode has been developed. The optode membrane consists of 2-nitrophenyl octyl ether as a plasticizer, L-RB, and poly (vinyl chloride). The optode responds to tetrakis (4-fluorophenyl) borate, sodium salt (NaTPBF) in the μM range. The fluorescence intensity of the L-RB film for PHMB solution containing 20 μM NaTPBF decreased linearly as the concentration of the PHMB solution increased in the concentration range from 0 to 8.0 μM, which shows that PHMB with a concentration range of 0 to 8.0 μM is determined by the L-RB film optode. The concentration of PHMB in the contact lens detergents by the proposed method was in accord with its nominal concentration. Full article
(This article belongs to the Special Issue Recent Trends in Pharmaceutical Analytical Chemistry)
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14 pages, 1358 KiB  
Article
Pharmacokinetics and Tissue Distribution of Anwuligan in Rats after Intravenous and Intragastric Administration by Liquid Chromatography-Mass Spectrometry
by Yang Song, Yuan Zhang, Xiao-Yi Duan, Dong-Wei Cui, Xin Qiu, Yu Bian, Ke-Fei Wang and Xue-Song Feng
Molecules 2020, 25(1), 39; https://doi.org/10.3390/molecules25010039 - 20 Dec 2019
Cited by 5 | Viewed by 2800
Abstract
Anwuligan, a natural 2,3-dibenzylbutane lignan from the nutmeg mace of Myristica fragans, has been proved to possess a broad range of pharmacological effects. A rapid, simple, and sensitive liquid chromatography tandem mass spectrometry (LC-MS/MS) method has been established and successfully applied to [...] Read more.
Anwuligan, a natural 2,3-dibenzylbutane lignan from the nutmeg mace of Myristica fragans, has been proved to possess a broad range of pharmacological effects. A rapid, simple, and sensitive liquid chromatography tandem mass spectrometry (LC-MS/MS) method has been established and successfully applied to the study of pharmacokinetics and tissue distribution of anwuligan after intravenous or intragastric administration. Sample preparation was carried out through a liquid-liquid extraction method with ethyl acetate as the extraction reagent. Arctigenin was used as the internal standard (IS). A gradient program was employed with a mobile phase consisting of 0.1% formic acid aqueous solution and acetonitrile. The mass spectrometer was operated in a positive ionization mode with multiple reaction monitoring. The transitions for quantification were m/z 329.0→205.0 for anwuligan and m/z 373.0→137.0 for IS, respectively. Calibration curves were linear over the ranges of 0.5–2000 ng/mL for both plasma samples and tissue samples (r > 0.996). The absolute bioavailability is 16.2%, which represented the existing of the obvious first-pass effect. An enterohepatic circulation was found after the intragastric administration. Anwuligan could be distributed rapidly and widely in different tissues and maintained a high concentration in the liver. The developed and validated LC-MS/MS method and the pharmacokinetic study of anwuligan would provide reference for the future investigation of the preclinical safety of anwuligan as a candidate drug. Full article
(This article belongs to the Special Issue Recent Trends in Pharmaceutical Analytical Chemistry)
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10 pages, 1699 KiB  
Article
Automated Stopped-Flow Fluorimetric Sensor for Biologically Active Adamantane Derivatives Based on Zone Fluidics
by Paraskevas D. Tzanavaras, Sofia Papadimitriou and Constantinos K. Zacharis
Molecules 2019, 24(21), 3975; https://doi.org/10.3390/molecules24213975 - 03 Nov 2019
Cited by 7 | Viewed by 2174
Abstract
A zone-fluidics (ZF) based automated fluorimetric sensor for the determination of pharmaceutically active adamantine derivatives, i.e., amantadine (AMA), memantine (MEM) and rimantadine (RIM) is reported. Discrete zones of the analytes and reagents (o-phthalaldehyde and N-acetylcysteine) mix and react under stopped-flow [...] Read more.
A zone-fluidics (ZF) based automated fluorimetric sensor for the determination of pharmaceutically active adamantine derivatives, i.e., amantadine (AMA), memantine (MEM) and rimantadine (RIM) is reported. Discrete zones of the analytes and reagents (o-phthalaldehyde and N-acetylcysteine) mix and react under stopped-flow conditions to yield fluorescent iso-indole derivatives (λex/ λem = 340/455 nm). The proposed ZF sensor was developed and validated to prove suitable for quality control tests (assay and content uniformity) of commercially available formulations purchased from the Greek market (EU licensed) and from non-EU web-pharmacies at a sampling rate of 16 h−1. Interestingly, a formulation obtained through the internet and produced in a third—non-EU—country (AMA capsules, 100 mg per cap), was found to be out of specifications (mean assay of 85.3%); a validated HPLC method was also applied for confirmatory purposes. Full article
(This article belongs to the Special Issue Recent Trends in Pharmaceutical Analytical Chemistry)
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12 pages, 1812 KiB  
Article
Development and Validation of a Sensitive UHPLC-MS/MS Method for the Measurement of Gardneramine in Rat Plasma and Tissues and Its Application to Pharmacokinetics and Tissue Distribution Study
by Nan Zhao, Hao-ran Tan, Qi-li Chen, Qi Sun, Lin Wang, Yang Song, Kamara Mohamed Olounfeh and Fan-hao Meng
Molecules 2019, 24(21), 3953; https://doi.org/10.3390/molecules24213953 - 31 Oct 2019
Cited by 4 | Viewed by 2476
Abstract
As a novel monoterpenoid indole alkaloid, gardneramine has been confirmed to possess excellent nervous depressive effects. However, there have been no reports about the measurement of gardneramine in vitro and in vivo. The motivation of this study was to establish and validate a [...] Read more.
As a novel monoterpenoid indole alkaloid, gardneramine has been confirmed to possess excellent nervous depressive effects. However, there have been no reports about the measurement of gardneramine in vitro and in vivo. The motivation of this study was to establish and validate a specific, sensitive, and robust analytical method based on UHPLC-MS/MS for quantification of gardneramine in rat plasma and various tissues after intravenous administration. The analyte was extracted from plasma and tissue samples by protein precipitation with methanol using theophylline as an internal standard (I.S.). The analytes were separated on an Agilent ZORBAX Eclipse Plus C18 column using a gradient elution of acetonitrile and 0.1% formic acid in water at a flow rate of 0.3 mL/min. Gardneramine and I.S. were detected and quantified using positive electrospray ionization in multiple reaction monitoring (MRM) mode with transitions of m/z 413.1→217.9 for gardneramine and m/z 181.2→124.1 for I.S. Perfect linearity range was 1–2000 ng/mL with a correlation coefficient (r2) of ≥0.990. The lower limit of quantification (LLOQ) of 1.0 ng/mL was adequate for application to different preclinical studies. The method was successfully applied for determination of gardneramine in bio-samples. Full article
(This article belongs to the Special Issue Recent Trends in Pharmaceutical Analytical Chemistry)
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12 pages, 1800 KiB  
Article
Interaction Effects between Doxorubicin and Hernandezine on the Pharmacokinetics by Liquid Chromatography Coupled with Mass Spectrometry
by Yang Song, Yuan Zhang, Wei-Peng Zhang, Bao-Zhen Zhang, Ke-Fei Wang and Xue-Song Feng
Molecules 2019, 24(19), 3622; https://doi.org/10.3390/molecules24193622 - 08 Oct 2019
Cited by 4 | Viewed by 2784
Abstract
Doxorubicin (DOX) is an effective anti-tumor drug widely used in clinics. Hernandezine (HER), isolated from a Chinese medicinal herb, has a selective inhibitory effect on DOX multidrug resistance, making DOX more effective in treating cancer. The aim of this study was to investigate [...] Read more.
Doxorubicin (DOX) is an effective anti-tumor drug widely used in clinics. Hernandezine (HER), isolated from a Chinese medicinal herb, has a selective inhibitory effect on DOX multidrug resistance, making DOX more effective in treating cancer. The aim of this study was to investigate the effect of the interaction of HER and DOX on pharmacokinetics. Male Sparague–Dawley rats were randomly divided into three groups: a single DOX group, a single HER group, and a combination group. Plasma concentrations of DOX and HER were determined by the LC-MS/MS method at specified time points after administration, and the main pharmacokinetic parameters were estimated. The results showed that there were significant differences in the Cmax and AUC0–∞ of DOX in the single drug group and combined drug group, indicating that HER could improve the absorption of DOX. However, DOX in combination, in turn, reduced the free drug concentration of HER, possibly because DOX enhanced the HER drug–protein binding effect. The results could be used as clinical guidance for DOX and HER to avoid adverse reactions. Full article
(This article belongs to the Special Issue Recent Trends in Pharmaceutical Analytical Chemistry)
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18 pages, 820 KiB  
Article
Pharmacokinetic Profiling and Simultaneous Determination of Thiopurine Immunosuppressants and Folic Acid by Chromatographic Methods
by Edvin Brusač, Mario-Livio Jeličić, Daniela Amidžić Klarić, Biljana Nigović, Nikša Turk, Ilija Klarić and Ana Mornar
Molecules 2019, 24(19), 3469; https://doi.org/10.3390/molecules24193469 - 24 Sep 2019
Cited by 10 | Viewed by 3122
Abstract
With the increase in the number of medicines patients have to take, there has been a rapid rise of fixed-dose combinations (FDCs) in the last two decades. Prior to FDC development, pharmacokinetic properties of active pharmaceutical ingredients (APIs) have to be evaluated, as [...] Read more.
With the increase in the number of medicines patients have to take, there has been a rapid rise of fixed-dose combinations (FDCs) in the last two decades. Prior to FDC development, pharmacokinetic properties of active pharmaceutical ingredients (APIs) have to be evaluated, as well as methods for their determination developed. So as to increase patient compliance in inflammatory bowel disease, three novel FDCs of thiopurine immunosuppressants and folic acid are proposed; physico-chemical and pharmacokinetic properties such as hydrophobicity, lipophilicity and plasma protein binding of all APIs are evaluated. Moreover, experimental results of different properties are compared to those computed by various on-line prediction platforms so as to evaluate the viability of the in silico approach. A simultaneous method for their determination is developed, optimized, validated and applied to commercial tablet formulations. The method has shown to be fast, selective, accurate and precise, showing potential for reliable determination of API content in proposed FDCs during its development. Full article
(This article belongs to the Special Issue Recent Trends in Pharmaceutical Analytical Chemistry)
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15 pages, 1232 KiB  
Article
Pharmacokinetics and Tissue Distribution of Alnustone in Rats after Intravenous Administration by Liquid Chromatography-Mass Spectrometry
by Yang Song, Yu Zhou, Xiao-Ting Yan, Jing-Bo Bi, Xin Qiu, Yu Bian, Ke-Fei Wang, Yuan Zhang and Xue-Song Feng
Molecules 2019, 24(17), 3183; https://doi.org/10.3390/molecules24173183 - 02 Sep 2019
Cited by 6 | Viewed by 2703
Abstract
Alnustone, a nonphenolic diarylheptanoid, first isolated from Alnus pendula (Betulaceae), has recently received a great deal of attention due to its various beneficial pharmacological effects. However, its pharmacokinetic profile in vivo remains unclear. The purpose of this study is to establish a fast [...] Read more.
Alnustone, a nonphenolic diarylheptanoid, first isolated from Alnus pendula (Betulaceae), has recently received a great deal of attention due to its various beneficial pharmacological effects. However, its pharmacokinetic profile in vivo remains unclear. The purpose of this study is to establish a fast and sensitive quantification method of alnustone using liquid chromatography tandem mass spectrometry (LC-MS/MS) and evaluate the pharmacokinetic and tissue distribution profiles of alnustone in rats. The sample was precipitated with acetonitrile with 0.5% formic acid and separated on BEH C18 Column. The mobile phase was composed of 0.1% formic acid in water and methanol at a flow rate of 0.3 mL/min. Alnustone and the internal standard (caffeine) were quantitatively monitored with precursor-to-product ion transitions of m/z 262.9→105.2 and m/z 195.2→138.0, respectively. The calibration curve for alnustone was linear from 1 to 2000 ng/mL. The intra- and inter-day assay precision (RSD) ranged from 1.1–9.0 % to 3.3–8.6%, respectively and the intra- and inter-day assay accuracy (RE) was between −8.2–9.7% and −10.3–9.9%, respectively. The validated method was successfully applied to the pharmacokinetic studies of alnustone in rats. After single-dose intravenous administration of alnustone (5 mg/kg), the mean peak plasma concentration (Cmax) value was 7066.36 ± 820.62 ng/mL, and the mean area under the concentration-time curve (AUC0–t) value was 6009.79 ± 567.30 ng/mL∙h. Our results demonstrated that the residence time of alnustone in vivo was not long and it eliminated quickly from the rat plasma. Meanwhile, the drug is mainly distributed in tissues with large blood flow, and the lung and liver might be the target organs for alnustone efficacy. The study will provide information for further application of alnustone. Full article
(This article belongs to the Special Issue Recent Trends in Pharmaceutical Analytical Chemistry)
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10 pages, 1462 KiB  
Article
A Cell-Based Strategy for Bioactivity Determination of Long-Acting Fc-Fusion Recombinant Human Growth Hormone
by Wenrong Yao, Lei Yu, Wenhong Fan, Xinchang Shi, Lan Liu, Yonghong Li, Xi Qin, Chunming Rao and Junzhi Wang
Molecules 2019, 24(7), 1389; https://doi.org/10.3390/molecules24071389 - 09 Apr 2019
Cited by 4 | Viewed by 3631
Abstract
The long-acting growth hormone (LAGH) is a promising alternative biopharmaceutical to treat growth hormone (GH) deficiency in children, and it was developed using a variety of technologies by several pharmaceutical companies. Most LAGH preparations, such as Fc fusion protein, are currently undergoing preclinical [...] Read more.
The long-acting growth hormone (LAGH) is a promising alternative biopharmaceutical to treat growth hormone (GH) deficiency in children, and it was developed using a variety of technologies by several pharmaceutical companies. Most LAGH preparations, such as Fc fusion protein, are currently undergoing preclinical study and clinical trials. Accurate determination of bioactivity is critical for the efficacy of quality control systems of LAGH. The current in vivo rat weight gain assays used to determine the bioactivity of recombinant human GH (rhGH) in pharmacopoeias are time-consuming, expensive, and imprecise, and there are no recommended bioassays for LAGH bioactivity in pharmacopoeias. Therefore, we developed a cell-based bioassay for bioactivity determination of therapeutic long-acting Fc-fusion recombinant human growth hormone (rhGH-Fc) based on the luciferase reporter gene system, which is involved in the full-length human GH receptor (hGHR) and the SG (SIE and GAS) response element. The established bioassay was comprehensively validated according to the International Council for Harmonization (ICH) Q2 (R1) guidelines and the Chinese Pharmacopoeia, and is highly precise, time-saving, simple, and robust. The validated bioassay could be qualified for bioactivity determination during the research, development, and manufacture of rhGH-Fc, and other LAGH formulations. Full article
(This article belongs to the Special Issue Recent Trends in Pharmaceutical Analytical Chemistry)
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