Research

22 pages, 4353 KiB

Open AccessArticle

Determination of Response Factors for Analytes Detected during Migration Studies, Strategy and Internal Standard Selection for Risk Minimization

by Nikolaos Kritikos, Anna Bletsou, Christina Konstantinou, Antonios-Dionysios Neofotistos, Constantinos Kousoulos and Yannis Dotsikas

Molecules 2023, 28(15), 5772; https://doi.org/10.3390/molecules28155772 - 31 Jul 2023

Cited by 1 | Viewed by 1366

Abstract

Migration studies are one of the few domains of pharmaceutical analysis employing wide-scope screening methodologies. The studies involve the detection of contaminants within pharmaceutical products that arise from the interaction between the formulation and materials. Requiring both qualitative and quantitative data, the studies [...] Read more.

Migration studies are one of the few domains of pharmaceutical analysis employing wide-scope screening methodologies. The studies involve the detection of contaminants within pharmaceutical products that arise from the interaction between the formulation and materials. Requiring both qualitative and quantitative data, the studies are conducted using Liquid Chromatography or Gas Chromatography coupled to a mass spectrometer (LC-MS and GC-MS). While mass spectrometry allows wide-scope analyte detection and identification at the very low Analytical Evaluation Threshold (AET) levels used in these studies, MS detectors are far from “universal response” detectors. Regulation brings the application of uncertainty factors into the picture to limit the risk of potential analytes detected escaping report and further evaluation; however, whether the application of a default value can cover any or all relevant applications is still debatable. The current study evaluated the response of species usually detected in migration studies, generating a suitable representative sample, analyzing said species, and creating a strategy and evaluation mechanism for acceptable classification of the detected species. Incorporating novel methodologies, i.e., Design of Experiments (DoE) for Design Space generation, the LC-MS-based methodology is also evaluated for its robustness in changes performed. Full article

(This article belongs to the Special Issue Mass Spectrometry in Pharmaceutical Analysis)

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17 pages, 3545 KiB

Open AccessArticle

Quantitative and Differential Analysis between Bupleurum chinense DC. and Bupleurum scorzonerifolium Willd. Using HPLC-MS and GC-MS Coupled with Multivariate Statistical Analysis

by Zhenhuan Wang, Lu Tian, Yusheng Xiao, Mengya Zhao, Yanyan Chang, Yujiang Zhou, Shuying Liu, Huanxi Zhao and Yang Xiu

Molecules 2023, 28(15), 5630; https://doi.org/10.3390/molecules28155630 - 25 Jul 2023

Cited by 4 | Viewed by 1260

Abstract

Bupleurum chinense DC. and Bupleurum scorzonerifolium Willd. have different clinical efficacies, with the former typically used to treat typhoid fever and the latter mainly used to clear liver heat. The differences in their clinical efficacy are closely related to their complex chemical composition, [...] Read more.

Bupleurum chinense DC. and Bupleurum scorzonerifolium Willd. have different clinical efficacies, with the former typically used to treat typhoid fever and the latter mainly used to clear liver heat. The differences in their clinical efficacy are closely related to their complex chemical composition, especially the active components. In this study, the saponins and volatile oils in two varieties of Radix Bupleuri grown in different regions were extracted and analyzed using high-performance liquid chromatography (HPLC) and gas chromatography coupled with mass spectrometry (MS), and the absolute contents of five saikosaponins were accurately quantified using an established HPLC-MS method in the multiple reaction monitoring mode. Multivariate statistical analysis was performed to reveal the difference in the active components between the two varieties. The saikosaponin content was significantly affected by variety and growing region, with all five saikosaponins being significantly higher in Bupleurum chinense DC. than in Bupleurum scorzonerifolium Willd. The results of principal component analysis and hierarchical cluster analysis show a clear distinction between the two varieties in terms of both saponins and volatile oils. Twenty-one saponins, including saikosaponin b2 and b1, and fifty-two volatile oils, including 2-tetradecyloxirane and chloromethyl cyanide, were screened and identified as differential compounds contributing to the significant difference between the two varieties. These compounds may also be responsible for the difference in clinical efficacy between Bupleurum chinense DC. and Bupleurum scorzonerifolium Willd. All the results suggest that the accumulation and diversity of active components in Radix Bupleuri are significantly affected by the variety. In contrast to previous reports, this study provides the absolute contents of five saikosaponins in Radix Bupleuri of different varieties and reduces the influence of the growing region on the analytical results by collecting samples from different regions. The results of this study may provide a reference for the identification and quality evaluation of different varieties of Radix Bupleuri. Full article

(This article belongs to the Special Issue Mass Spectrometry in Pharmaceutical Analysis)

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15 pages, 2128 KiB

Open AccessArticle

Interlaboratory Evaluation of a User-Friendly Benchtop Mass Spectrometer for Multiple-Attribute Monitoring Studies of a Monoclonal Antibody

by Claire I. Butré, Valentina D’Atri, Hélène Diemer, Olivier Colas, Elsa Wagner, Alain Beck, Sarah Cianferani, Davy Guillarme and Arnaud Delobel

Molecules 2023, 28(6), 2855; https://doi.org/10.3390/molecules28062855 - 22 Mar 2023

Cited by 8 | Viewed by 2752

Abstract

In the quest to market increasingly safer and more potent biotherapeutic proteins, the concept of the multi-attribute method (MAM) has emerged from biopharmaceutical companies to boost the quality-by-design process development. MAM strategies rely on state-of-the-art analytical workflows based on liquid chromatography coupled to [...] Read more.

In the quest to market increasingly safer and more potent biotherapeutic proteins, the concept of the multi-attribute method (MAM) has emerged from biopharmaceutical companies to boost the quality-by-design process development. MAM strategies rely on state-of-the-art analytical workflows based on liquid chromatography coupled to mass spectrometry (LC–MS) to identify and quantify a selected series of critical quality attributes (CQA) in a single assay. Here, we aimed at evaluating the repeatability and robustness of a benchtop LC–MS platform along with bioinformatics data treatment pipelines for peptide mapping-based MAM studies using standardized LC–MS methods, with the objective to benchmark MAM methods across laboratories, taking nivolumab as a case study. Our results evidence strong interlaboratory consistency across LC–MS platforms for all CQAs (i.e., deamidation, oxidation, lysine clipping and glycosylation). In addition, our work uniquely highlights the crucial role of bioinformatics postprocessing in MAM studies, especially for low-abundant species quantification. Altogether, we believe that MAM has fostered the development of routine, robust, easy-to-use LC–MS platforms for high-throughput determination of major CQAs in a regulated environment. Full article

(This article belongs to the Special Issue Mass Spectrometry in Pharmaceutical Analysis)

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13 pages, 4442 KiB

Open AccessArticle

QuEChERS-Based Approach to the Extraction of Five Calcium Channel Blockers from Plasma Determined by UPLC-MS/MS

by Tingting Zhao, Wen Jiang, Xiaolan Zhen, Chengcheng Jin, Yifan Zhang and Hui Li

Molecules 2023, 28(2), 671; https://doi.org/10.3390/molecules28020671 - 09 Jan 2023

Cited by 2 | Viewed by 1050

Abstract

Here, a QuEChERS (quick, easy, cheap, effective, rugged, and safe) pretreatment method was combined with UPLC-MS/MS to facilitate the rapid and reliable simultaneous detection of five calcium channel blockers (CCBs) in human plasma. For this approach, samples were treated with 1 mL of [...] Read more.

Here, a QuEChERS (quick, easy, cheap, effective, rugged, and safe) pretreatment method was combined with UPLC-MS/MS to facilitate the rapid and reliable simultaneous detection of five calcium channel blockers (CCBs) in human plasma. For this approach, samples were treated with 1 mL of acetonitrile, 350 mg of magnesium sulfate, and 70 mg of PSA adsorbent prior to centrifugation. Supernatants then underwent gradient elution for 8 min with an Agilent C18 column using an acetonitrile-water solution supplemented with 5 mmol⋅L⁻¹ of ammonium acetate. This technique exhibited a good linear response in the 1–800 ng⋅mL⁻¹ range for the analyzed drugs, with an R²≥ 0.9921, an accuracy of 87.54–113.05%, a matrix effect (ME) of 91.21–116.39%, a precision of 0.19–11.64%, and stability of no more than 10.05%. This time-saving QuEChERS reagent-based pretreatment technique thus allowed for the simultaneous and accurate detection of five CCBs in human plasma samples, providing a promising new basis for therapeutic drug monitoring in patients with hypertension. Full article

(This article belongs to the Special Issue Mass Spectrometry in Pharmaceutical Analysis)

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18 pages, 2945 KiB

Open AccessArticle

The Synergistic Mechanism of Total Saponins and Flavonoids in Notoginseng–Safflower against Myocardial Infarction Using a Comprehensive Metabolomics Strategy

by Meng Fang, Yuqing Meng, Zhiyong Du, Mengqiu Guo, Yong Jiang, Pengfei Tu, Kun Hua, Yingyuan Lu and Xiaoyu Guo

Molecules 2022, 27(24), 8860; https://doi.org/10.3390/molecules27248860 - 13 Dec 2022

Cited by 4 | Viewed by 1364

Abstract

Notoginseng and safflower are commonly used traditional Chinese medicines for benefiting qi and activating blood circulation. A previous study by our group showed that the compatibility of the effective components of total saponins of notoginseng (NS) and total flavonoids of safflower (SF), named [...] Read more.

Notoginseng and safflower are commonly used traditional Chinese medicines for benefiting qi and activating blood circulation. A previous study by our group showed that the compatibility of the effective components of total saponins of notoginseng (NS) and total flavonoids of safflower (SF), named NS–SF, had a preventive effect on isoproterenol (ISO)-induced myocardial infarction (MI) in rats. However, the therapeutic effect on MI and the synergistic mechanism of NS–SF are still unclear. Therefore, integrated metabolomics, combined with immunohistochemistry and other pharmacological methods, was used to systematically research the therapeutic effect of NS–SF on MI rats and the synergistic mechanism of NS and SF. Compared to NS and SF, the results demonstrated that NS–SF exhibited a significantly better role in ameliorating myocardial damage, apoptosis, easing oxidative stress and anti-inflammation. NS–SF showed a more significant regulatory effect on metabolites involved in sphingolipid metabolism, glycine, serine, and threonine metabolism, primary bile acid biosynthesis, aminoacyl-tRNA biosynthesis, and tricarboxylic acid cycle, such as sphingosine, lysophosphatidylcholine (18:0), lysophosphatidylethanolamine (22:5/0:0), chenodeoxycholic acid, L-valine, glycine, and succinate, than NS or SF alone, indicating that NS and SF produced a synergistic effect on the treatment of MI. This study will provide a theoretical basis for the clinical development of NS–SF. Full article

(This article belongs to the Special Issue Mass Spectrometry in Pharmaceutical Analysis)

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12 pages, 1385 KiB

Open AccessArticle

Quantitative Analysis of Isoniazid and Its Four Primary Metabolites in Plasma of Tuberculosis Patients Using LC-MS/MS

by Nguyen Ky Anh, Pham My Tung, Min Jung Kim, Nguyen Phuoc Long, Yong-Soon Cho, Dong-Hyun Kim and Jae-Gook Shin

Molecules 2022, 27(23), 8607; https://doi.org/10.3390/molecules27238607 - 06 Dec 2022

Cited by 1 | Viewed by 2058

Abstract

Isoniazid and its metabolites are potentially associated with hepatotoxicity and treatment outcomes in patients who receive antituberculosis (TB) therapy. To further understand the pharmacokinetic profiles of these molecules, a method based on LC-MS/MS was developed to determine the concentration of these compounds in [...] Read more.

Isoniazid and its metabolites are potentially associated with hepatotoxicity and treatment outcomes in patients who receive antituberculosis (TB) therapy. To further understand the pharmacokinetic profiles of these molecules, a method based on LC-MS/MS was developed to determine the concentration of these compounds in human plasma. Isoniazid, acetylisoniazid, and isonicotinic acid were directly analyzed, whereas hydrazine and acetylhydrazine were determined after derivatization using p-tolualdehyde. Chromatographic separation was conducted on reversed-phase C18 columns with gradient elution, and detection was carried out in multiple reaction monitoring mode. The calibration curves were linear with correlation coefficients (r) greater than 0.9947 for all analytes. The intra- and inter-day precision was less than 13.43%, and the accuracy ranged between 91.63 and 114.00%. The recovery and matrix effect of the analytes were also consistent (coefficient of variation was less than 9.36%). The developed method successfully quantified isoniazid and its metabolites in TB patients. The method has broad applications in clinical research, including isoniazid one-point-based therapeutic drug monitoring, genotype–phenotype association studies of isoniazid metabolic profile and isoniazid-induced hepatotoxicity, and the initial dose prediction of isoniazid using population pharmacokinetic modeling. Full article

(This article belongs to the Special Issue Mass Spectrometry in Pharmaceutical Analysis)

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24 pages, 2986 KiB

Open AccessArticle

An Untargeted Metabolomics Approach on Carfilzomib-Induced Nephrotoxicity

by Ioanna Barla, Panagiotis Efentakis, Sofia Lamprou, Maria Gavriatopoulou, Meletios-Athanasios Dimopoulos, Evangelos Terpos, Ioanna Andreadou, Nikolaos Thomaidis and Evangelos Gikas

Molecules 2022, 27(22), 7929; https://doi.org/10.3390/molecules27227929 - 16 Nov 2022

Cited by 2 | Viewed by 1914

Abstract

Background: Carfilzomib (Cfz) is an anti-cancer drug related to cardiorenal adverse events, with cardiovascular and renal complications limiting its clinical use. Despite the important progress concerning the discovery of the underlying causes of Cfz-induced nephrotoxicity, the molecular/biochemical background is still not well clarified. [...] Read more.

Background: Carfilzomib (Cfz) is an anti-cancer drug related to cardiorenal adverse events, with cardiovascular and renal complications limiting its clinical use. Despite the important progress concerning the discovery of the underlying causes of Cfz-induced nephrotoxicity, the molecular/biochemical background is still not well clarified. Furthermore, the number of metabolomics-based studies concerning Cfz-induced nephrotoxicity is limited. Methods: A metabolomics UPLC–HRMS–DIA methodology was applied to three bio-sample types i.e., plasma, kidney, and urine, obtained from two groups of mice, namely (i) Cfz (8 mg Cfz/ kg) and (ii) Control (0.9% NaCl) (n = 6 per group). Statistical analysis, involving univariate and multivariate tools, was applied for biomarker detection. Furthermore, a sub-study was developed, aiming to estimate metabolites’ correlation among bio-samples, and to enlighten potential mechanisms. Results: Cfz mostly affects the kidneys and urine metabolome. Fifty-four statistically important metabolites were discovered, and some of them have already been related to renal diseases. Furthermore, the correlations between bio-samples revealed patterns of metabolome alterations due to Cfz. Conclusions: Cfz causes metabolite retention in kidney and dysregulates (up and down) several metabolites associated with the occurrence of inflammation and oxidative stress. Full article

(This article belongs to the Special Issue Mass Spectrometry in Pharmaceutical Analysis)

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19 pages, 1332 KiB

Open AccessArticle

Quantification of Zonisamide in Dried Blood Spots and Dried Plasma Spots by UPLC–MS/MS: Application to Clinical Practice

by Milena Rmandić, Ana Stajić, Jasna Jančić, Janko Samardžić, Nebojša Jović and Anđelija Malenović

Molecules 2022, 27(15), 4899; https://doi.org/10.3390/molecules27154899 - 31 Jul 2022

Cited by 3 | Viewed by 1421

Abstract

In this research, a UHPLC–MS/MS method was developed and validated for the determination of zonisamide in dried plasma spots (DPS) and dried blood spots (DBS). Detection of zonisamide and internal standard, 1-(2,3-dichlorphenyl)piperazine, was carried out in ESI+ mode by monitoring two MRM transitions [...] Read more.

In this research, a UHPLC–MS/MS method was developed and validated for the determination of zonisamide in dried plasma spots (DPS) and dried blood spots (DBS). Detection of zonisamide and internal standard, 1-(2,3-dichlorphenyl)piperazine, was carried out in ESI+ mode by monitoring two MRM transitions per analyte. Total run time, less than 2.5 min, was achieved using Acquity UPLC BEH Amide (2.1 × 100 mm, 1.7 µm particle size) column with mobile phase comprising acetonitrile–water (85:15%, v/v) with 0.075% formic acid. The flow rate was 0.225 mL/min, the column temperature was 30 °C and the injection volume was 3 µL. Desolvation temperature, desolvation gas flow rate, ion source temperature and cone gas flow rate were set by the IntelliStart software tool in combination with tuning. All of the Guthrie cards were scanned, and DPS/DBS areas were determined by the image processing tool. The influence of hematocrit values (20–60%) on accuracy and precision was evaluated to determine the range within which method for DBSs is free from Hct or dependency is within acceptable limits. The validated method was applied to the determination of zonisamide levels in DPS and DBS samples obtained from patients confirming its suitability for clinical application. Finally, the distribution of zonisamide into the red blood cells was estimated by correlating its DPS and DBS levels. Full article

(This article belongs to the Special Issue Mass Spectrometry in Pharmaceutical Analysis)

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17 pages, 3870 KiB

Open AccessFeature PaperArticle

Quantitative Analysis and Differential Evaluation of Radix Bupleuri Cultivated in Different Regions Based on HPLC-MS and GC-MS Combined with Multivariate Statistical Analysis

by Zhenhuan Wang, Huanxi Zhao, Lu Tian, Mengya Zhao, Yusheng Xiao, Shuying Liu and Yang Xiu

Molecules 2022, 27(15), 4830; https://doi.org/10.3390/molecules27154830 - 28 Jul 2022

Cited by 6 | Viewed by 1826

Abstract

The quality of Radix Bupleuri is greatly affected by its growing environment. In this study, Radix Bupleuri samples that were harvested from seven different regions across northwest China were examined by high-performance liquid chromatography (HPLC) and gas chromatography (GC) coupled with mass spectrometry [...] Read more.

The quality of Radix Bupleuri is greatly affected by its growing environment. In this study, Radix Bupleuri samples that were harvested from seven different regions across northwest China were examined by high-performance liquid chromatography (HPLC) and gas chromatography (GC) coupled with mass spectrometry (MS) to reveal significant differences in quality contributed by the cultivation region. An HPLC-MS method was firstly established and used in the multiple reaction monitoring mode for the quantitative analysis of five saikosaponins in Radix Bupleuri so as to evaluate the difference in the absolute content of saikosaponins attributable to the cultivation region. The effect on the components of Radix Bupleuri was further investigated based on the profiles of the representative saponins and volatile compounds, which were extracted from the Radix Bupleuri samples and analyzed by HPLC-MS and GC-MS. Multivariate statistical analysis was employed to differentiate the Radix Bupleuri samples cultivated in different regions and to discover the differential compositions. The developed quantitative method was validated to be accurate, stable, sensitive, and repeatable for the determination of five saikosaponins. Further statistical tests revealed that the collected Radix Bupleuri samples were distinctly different from each other in terms of both saponins and volatile compounds, based on the provinces where they were grown. In addition, twenty-eight saponins and fifty-eight volatile compounds were identified as the differentially accumulated compositions that contributed to the discrimination of the Radix Bupleuri samples. The Radix Bupleuri samples grown in Shouyang county showed the highest content of saikosaponins. All of the results indicated that the cultivation region significantly affected the accumulation and diversity of the main chemical components of Radix Bupleuri. The findings of this research provide insights into the effect of the cultivation region on the quality of Radix Bupleuri and the differentiation of Radix Bupleuri cultivated in different regions based on the use of HPLC-MS and GC-MS combined with multivariate statistical analysis. Full article

(This article belongs to the Special Issue Mass Spectrometry in Pharmaceutical Analysis)

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14 pages, 1550 KiB

Open AccessArticle

Gene Expression and Protein Abundance of Nuclear Receptors in Human Intestine and Liver: A New Application for Mass Spectrometry-Based Targeted Proteomics

by Christoph Wenzel, Lisa Gödtke, Anne Reichstein, Markus Keiser, Diana Busch, Marek Drozdzik and Stefan Oswald

Molecules 2022, 27(14), 4629; https://doi.org/10.3390/molecules27144629 - 20 Jul 2022

Cited by 5 | Viewed by 1746

Abstract

Background: Unwanted drug-drug interactions (DDIs), as caused by the upregulation of clinically relevant drug metabolizing enzymes and transporter proteins in intestine and liver, have the potential to threaten the therapeutic efficacy and safety of drugs. The molecular mechanism of this undesired but frequently [...] Read more.

Background: Unwanted drug-drug interactions (DDIs), as caused by the upregulation of clinically relevant drug metabolizing enzymes and transporter proteins in intestine and liver, have the potential to threaten the therapeutic efficacy and safety of drugs. The molecular mechanism of this undesired but frequently occurring scenario of polypharmacy is based on the activation of nuclear receptors such as the pregnane X receptor (PXR) or the constitutive androstane receptor (CAR) by perpetrator agents such as rifampin, phenytoin or St. John’s wort. However, the expression pattern of nuclear receptors in human intestine and liver remains uncertain, which makes it difficult to predict the extent of potential DDIs. Thus, it was the aim of this study to characterize the gene expression and protein abundance of clinically relevant nuclear receptors, i.e., the aryl hydrocarbon receptor (AhR), CAR, farnesoid X receptor (FXR), glucocorticoid receptor (GR), hepatocyte nuclear factor 4 alpha (HNF4α), PXR and small heterodimer partner (SHP), in the aforementioned organs. Methods: Gene expression analysis was performed by quantitative real-time PCR of jejunal, ileal, colonic and liver samples from eight human subjects. In parallel, a targeted proteomic method was developed and validated in order to determine the respective protein amounts of nuclear receptors in human intestinal and liver samples. The LC-MS/MS method was validated according to the current bioanalytical guidelines and met the criteria regarding linearity (0.1–50 nmol/L), within-day and between-day accuracy and precision, as well as the stability criteria. Results: The developed method was successfully validated and applied to determine the abundance of nuclear receptors in human intestinal and liver samples. Gene expression and protein abundance data demonstrated marked differences in human intestine and liver. On the protein level, only AhR and HNF4α could be detected in gut and liver, which corresponds to their highest gene expression. In transfected cell lines, PXR and CAR could be quantified. Conclusions: The substantially different expression pattern of nuclear receptors in human intestinal and liver tissue may explain the different extent of unwanted DDIs in the dependence on the administration route of drugs. Full article

(This article belongs to the Special Issue Mass Spectrometry in Pharmaceutical Analysis)

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12 pages, 2106 KiB

Open AccessArticle

Simultaneous Determination of Six Immunosuppressants in Human Whole Blood by HPLC-MS/MS Using a Modified QuEChERS Method

by Min Zheng, Jianshi Song, Hua Xue, Hui Li and Kaoqi Lian

Molecules 2022, 27(13), 4087; https://doi.org/10.3390/molecules27134087 - 25 Jun 2022

Cited by 1 | Viewed by 1756

Abstract

A high-performance liquid chromatography-tandem mass spectrometry method was established for the simultaneous determination of mycophenolic acid, mycophenolate mofetil, tacrolimus, rapamycin, everolimus and pimecrolimus in human whole blood by optimizing the QuEChERS (Quick, Easy, Cheap, Effective, Rugged, and Safe) preparation method. Whole blood was [...] Read more.

A high-performance liquid chromatography-tandem mass spectrometry method was established for the simultaneous determination of mycophenolic acid, mycophenolate mofetil, tacrolimus, rapamycin, everolimus and pimecrolimus in human whole blood by optimizing the QuEChERS (Quick, Easy, Cheap, Effective, Rugged, and Safe) preparation method. Whole blood was extracted into ethyl acetate, salted out with anhydrous magnesium sulfate, and purified with ethylenediamine-N-propyl silane adsorbent. The supernatant was evaporated under nitrogen until dry and finally reconstituted in methanol. Chromatographic separation was performed on an Agilent Poroshell 120 EC-C18 column in methanol (mobile phase A)-water (optimized for 0.1% acetic acid and 10 mM ammonium acetate, mobile phase B) at a 0.3 mL·min⁻¹ flow rate. Electrospray ionization and positive ion multiple reaction monitoring were used for detection. The time for of analysis was 13 min. The calibration curves range of tacrolimus, rapamycin, everolimus and pimecrolimus were in the range of 1–100 ng·mL⁻¹, mycophenolate mofetil in the range of 0.1–10 ng·mL⁻¹ and mycophenolic acid at 10–1000 ng·mL⁻¹. All correlation coefficients were >0.993. The coefficients of variation (CV, %) for inter-day and intra-day precision were less than 10%, while the spiked recoveries were in the range of 92.1% to 116%. Our method was rapid, sensitive, specific, and reproducible for the simultaneous determination of six immunosuppressants in human whole blood. Importantly, our approach can be used to monitor drug concentrations in the blood to facilitate disease treatment. Full article

(This article belongs to the Special Issue Mass Spectrometry in Pharmaceutical Analysis)

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