Article
Chemistry, Analytical
Matthias Vogel, Jochen Norwig
Summary: In 2018, the high levels of the carcinogen N-nitrosodimethylamine (NDMA) in the pharmaceutical ingredient valsartan led to regulatory actions and recalls by the pharmaceutical industry to ensure patient safety. The contamination was caused by unintended reactions during drug synthesis. Routine analysis of drug contents is necessary to prevent such incidents, and the use of validated analytical methods is important. The study presents a highly sensitive approach using liquid chromatography - tandem mass spectrometry (LC-MS/MS) for the detection of N-nitrosamines, which proved to be applicable for contaminated substances.
JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS
(2022)
Article
Chemistry, Multidisciplinary
Jimin Park, Megan A. Kelly, Jason X. Kang, Siddarth S. Seemakurti, Jasmine L. Ramirez, Marta C. Hatzell, Carsten Sievers, Andreas S. Bommarius
Summary: Current status and trends in API production: The production of active pharmaceutical ingredients (APIs) has shifted from developed countries to emerging economies, notably India and China. The recent COVID pandemic and logistical challenges have raised concerns about the existing supply chain model, calling for a rebalancing of global API supply chains and possibly reshoring some production to Europe and North America.
Article
Biochemistry & Molecular Biology
Anna B. Witkowska, Joanna Giebultowicz, Magdalena Dabrowska, Elzbieta U. Stolarczyk
Summary: A novel GC-MS method was developed for the simultaneous determination of nine carcinogenic nitrosamines in medical products. The method was validated according to ICH guidelines and demonstrated good linearity and low detection limits. This specific, accurate, and precise method was successfully applied for the quality control of active pharmaceutical ingredients.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Chemistry, Multidisciplinary
Wisut Wichitnithad, Orawan Sudtanon, Pawadee Srisunak, Kamonrak Cheewatanakornkool, Siriwan Nantaphol, Pornchai Rojsitthisak
Summary: Nitrosamine impurities in angiotensin II receptor antagonists containing a tetrazole group are a significant concern for API manufacturers and global regulators. A sensitive and high-throughput method based on HS-GC-MS was developed and validated for the simultaneous determination of four nitrosamines in losartan potassium API, meeting ICH guidelines with good accuracy and precision.
Article
Pharmacology & Pharmacy
Nejc Golob, Rok Grahek, Malcolm Ross, Robert Roskar
Summary: The recent focus of pharmaceutical regulatory authorities has been on reducing carcinogenic N-nitrosamines in drug products. A study discovered a new source of N-nitrosamines in finished drug products, which was found in the blister material of packaging. Further investigations revealed that nitrocellulose primer in a lidding foil acts as a nitrosating agent, forming N-nitrosamines in the packaging material. This contamination was found to transfer to the drug product during the blistering operation.
INTERNATIONAL JOURNAL OF PHARMACEUTICS
(2022)
Review
Chemistry, Medicinal
U. Holzgrabe
Summary: The presence of N-nitrosodialkylamines in pharmaceutical ingredients and drug products has raised concerns about the quality of drugs. It has been discovered that the quality control tests specified in international pharmacopoeias may not be sufficient. These N-nitrosodialkylamines are not limited by compendial tests, but by the ICH guideline M7 due to their mutagenic properties. Nitrosamine impurities related to the drug substances have been detected during the risk assessment process required by regulatory authorities. This review focuses on the formation, toxicity, and mitigation of these N-nitrosodialkylamine impurities.
JOURNAL OF PHARMACEUTICAL SCIENCES
(2023)
Article
Automation & Control Systems
Michel Thiel, Nicolas Sauwen, Tastiana Khamiakova, Tor Maes, Bernadette Govaerts
Summary: This paper introduces a practical framework based on different dimension-reduction and calibration methods for tracking chemical experiments organized in batches, aiming to visualize and interpret chemical reaction kinetics in real time or off-line, and predict chemical component concentrations over time. Results show that NMF and MCR provide better interpretability for chemical reactions compared to PCA, and unsupervised methods such as PCA, NMF or MCR can be used to predict concentrations of chemical compounds continuously with good precision and interpretability.
CHEMOMETRICS AND INTELLIGENT LABORATORY SYSTEMS
(2021)
Article
Chemistry, Medicinal
Justin Moser, Ian W. Ashworth, Laurence Harris, Michael C. Hillier, Kausik K. Nanda, Garry Scrivens
Summary: The potential presence of N-nitrosamines in medicinal products has raised concerns among health authorities and pharmaceutical companies, but there is limited information available on the formation of N-nitrosamines in pharmaceutical drug products. Experiments were conducted to investigate nitrosation of secondary and tertiary amines in solid drug products due to the presence of nitrite in excipients. The findings showed that N-nitrosamine formation can occur in solid drug product formulations, with the rate and extent depending on various factors such as amine solubility, nitrite level, water acidity, and processing mode.
JOURNAL OF PHARMACEUTICAL SCIENCES
(2023)
Article
Engineering, Environmental
Mark Honti, Marton Zsugyel, Carolin Seller, Kathrin Fenner
Summary: This study developed the concept of persistence benchmarking for organic micropollutants in large rivers. By observing the dissipation rates of compounds, the researchers were able to distinguish between fast- and slow-degrading compounds and provide reasonable estimates on system half-lives.
ENVIRONMENTAL SCIENCE & TECHNOLOGY
(2023)
Review
Biochemistry & Molecular Biology
Baljit Kaur, Palwinder Singh
Summary: This study compiles information about the application of the epoxide functional group in medicinal compounds and biochemical probes, and explores the related advantages and challenges. It also analyzes the strategies that have been adopted for the successful development of epoxide-based compounds within drug discovery programs.
BIOORGANIC CHEMISTRY
(2022)
Review
Chemistry, Medicinal
Hongjie Guo, Shuyu Liu
Summary: This review summarizes the cocrystals of active pharmaceutical ingredients (APIs) derived from traditional Chinese medicines (TCMs) in terms of categories, Delta pKa rule, preparation, characterization, and physicochemical properties based on 113 literature reports. The formation of all cocrystals is found to be in accordance with Delta pKa rule. The most commonly used preparation methods are evaporation cocrystallization, grinding method, and suspension method, accounting for 44%, 27%, and 16% respectively. Almost all cocrystals are characterized by powder X-ray diffraction (PXRD). Thermal analysis techniques are used for 81% of cocrystals, and more than half of them are characterized by IR. Single crystal X-ray diffraction (SXRD) is used for 44% of cocrystals due to difficulties in obtaining single crystal samples. Most cocrystals of APIs in TCMs exhibit 1-10 folds enhancement in solubility, dissolution, dissolution rate, and bioavailability, with some showing even greater improvements. This review serves as a valuable reference for future pharmaceutical cocrystals of APIs in TCMs.
CHEMICAL & PHARMACEUTICAL BULLETIN
(2023)
Review
Multidisciplinary Sciences
Anand S. Burange, Sameh M. Osman, Rafael Luque
Summary: This review discusses the advantages and disadvantages of flow chemistry in today's scenario and recent developments in flow devices. It primarily focuses on the recent advancements in the flow synthesis of pharmaceutically important products in the last five years, as well as the critical steps and new developments in the flow synthesis of selected compounds.
Article
Thermodynamics
Vojtech Stejfa, Vaclav Pokorny, Alex Mathers, Kvetoslav Ruzicka, Michal Fulem
Summary: This study determined the condensed-phase heat capacities of selected pharmaceutical active pharmaceutical ingredients (APIs) using calorimetry, and found significant discrepancies and errors in previously published literature data. The research also investigated the heat capacities of supercooled liquid and the phase behavior of carbamazepine, revealing lower thermal stability than previously thought.
JOURNAL OF CHEMICAL THERMODYNAMICS
(2021)
Review
Chemistry, Multidisciplinary
Stefan Simic, Erna Zukic, Luca Schmermund, Kurt Faber, Christoph K. Winkler, Wolfgang Kroutil
Summary: Biocatalysis, using enzymes for organic synthesis, is a powerful tool for the synthesis of active pharmaceutical ingredients (APIs). Developments in molecular biology methods have led to the rapid development of process-stable enzymes through directed evolution. Enzymes are widely employed in the synthesis of small molecule APIs, enabling more efficient and sustainable routes.
Review
Chemistry, Multidisciplinary
Julia L. Shamshina, Robin D. Rogers
Summary: This Review summarizes the advances in active pharmaceutical ingredient ionic liquids (API-ILs) over the last 15 years, focusing on their synthesis, characterization, and pharmaceutical applications. The article highlights the challenges and prospects in translating API-ILs into pharmaceutical manufacturing.
Editorial Material
Chemistry, Medicinal
Sarah Shuck, Amit S. Kalgutkar, Charles G. Knutson, Yinsheng Wang, Shana J. Sturla
CHEMICAL RESEARCH IN TOXICOLOGY
(2022)
Article
Medicine, Legal
Martyn L. Chilton, Anne Marie Api, Robert S. Foster, G. Frank Gerberick, Maura Lavelle, Donna S. Macmillan, Mihwa Na, Devin O'Brien, Catherine O'Leary-Steele, Mukesh Patel, David J. Ponting, David W. Roberts, Robert J. Safford, Rachael E. Tennant
Summary: This study updates the thresholds of dermal sensitisation by expanding the dataset and using in silico expert system. The new thresholds show similarity to the previously published ones, demonstrating their robustness and increasing confidence in their use.
REGULATORY TOXICOLOGY AND PHARMACOLOGY
(2022)
Article
Public, Environmental & Occupational Health
Niamh M. O'Boyle, Ida B. Niklasson, David J. Ponting, Miguel A. Ortega, Tina Seifert, Andreas Natsch, Kristina Luthman, Ann-Therese Karlberg
Summary: This study describes a novel epoxy resin monomer derived from plant lignan, which has reduced allergenic effect while maintaining excellent properties. Experimental results show that this monomer does not exhibit skin sensitizing properties at certain concentrations and possesses promising cross-linking properties. It could be used for the development of safer epoxy resin materials.
TOXICOLOGY AND INDUSTRIAL HEALTH
(2022)
Article
Chemistry, Medicinal
Robert Thomas, Rachael E. Tennant, Antonio Anax F. Oliveira, David J. Ponting
Summary: The discovery of carcinogenic nitrosamine impurities above safe limits in pharmaceuticals has created a need for methods to analyze the structure-activity relationship (SAR) using limited datasets. This study proposes a Bayesian multiple linear regression method that can estimate the effects of each structural feature independently, taking into account the combinations of features and reducing the impact of multiple testing.
CHEMICAL RESEARCH IN TOXICOLOGY
(2022)
Article
Chemistry, Medicinal
Joerg Schlingemann, Michael J. Burns, David J. Ponting, Carolina Martins Avila, Naiffer E. Romero, Mrunal A. Jaywant, Graham F. Smith, Ian W. Ashworth, Stephanie Simon, Christoph Saal, Andrzej Wilk
Summary: This article presents the findings of an analysis of over 12,000 small molecule drugs and drug impurities, revealing the prevalence of nitrosamines in pharmaceuticals. The study identifies potential nitrosamine precursors and highlights the risk to essential drug classes. It emphasizes the need for the application of established principles and open communication between the industry and regulatory authorities to ensure a balance between risk and benefit for patients.
JOURNAL OF PHARMACEUTICAL SCIENCES
(2023)
Article
Chemistry, Medicinal
Raman Sharma, Matthew S. Dowling, Kentaro Futatsugi, Amit S. Kalgutkar
Summary: We conducted SAR studies on amide-based inhibitors of DGAT2 and analyzed the metabolic liabilities of the liver-targeted DGAT2 inhibitor PF-06427878. Although PF-06427878 showed successful evasion of oxidative O-dearylation, its metabolic clearance was still high due to piperidine ring oxidation. Modification of the piperidine ring led to the discovery of azetidine 2 with lower clearance, but it underwent cytochrome P450-mediated oxidation and ring scission. Replacement of the azetidine substituent with a pyridine ring resulted in the more potent DGAT2 inhibitor 8, which mitigated the formation of electrophilic aldehyde metabolites. Further structural refinements in 8 led to the discovery of PF-06865571 (ervogastat), currently in phase 2 clinical trials for nonalcoholic steatohepatitis treatment.
CHEMICAL RESEARCH IN TOXICOLOGY
(2023)
Review
Chemistry, Medicinal
Deepak Dalvie, Amit S. S. Kalgutkar
Summary: A fundamental knowledge of applied organic chemistry is crucial for drug metabolism scientists involved in biotransformation studies or drug discovery. Understanding organic chemistry concepts helps elucidate complex metabolite structures and rationalize biotransformation mechanisms. Examples of using organic chemistry in studying toxicology relationships and metabolic activation pathways are highlighted in this manuscript.
MEDICINAL CHEMISTRY RESEARCH
(2023)
Article
Chemistry, Applied
David J. Ponting, Robert S. Foster
Summary: The definitions of the chemical classes in the Cohort of Concern (CoC) are based on structural alerts, particularly for N-nitroso compounds. Recent recalls have focused on potent carcinogenic dialkyl N-nitrosamine impurities. However, the class of "N-nitroso compounds" may be broader. This Perspective examines N-nitroso compounds at the edges of the cohort, questioning their classification based on changes in mechanism, metabolic activation potential, stability, or toxicity data.
ORGANIC PROCESS RESEARCH & DEVELOPMENT
(2023)
Article
Chemistry, Medicinal
Michael J. Burns, David J. Ponting, Robert S. Foster, Benjamin P. Thornton, Naiffer E. Romero, Graham F. Smith, Ian W. Ashworth, Andrew Teasdale, Stephanie Simon, Joerg Schlingemann
Summary: The article discusses the mutagenic potential and risk of N-nitrosamines, as well as their formation mechanisms and distribution in small molecule drugs. The study finds that nitrosamines derived from secondary amine precursors have higher mutagenic potential, while those from tertiary amine precursors are more evenly distributed among different potency categories. The article also explores the impurity risk of secondary amine API and the quantification challenges of high potency nitrosamines.
JOURNAL OF PHARMACEUTICAL SCIENCES
(2023)
Article
Chemistry, Applied
Raphael Nudelman, Grace Kocks, Bruno Mouton, David J. Ponting, Joerg Schlingemann, Stephanie Simon, Graham F. Smith, Andrew Teasdale, Anne-Laure Werner
Summary: The N-nitrosamine (NA) saga in 2018 stemmed from small dialkyl N-nitrosamines in the synthesis of active pharmaceutical ingredients (APIs), but later investigations revealed a different type of NA impurities called nitrosamine drug-substance-related impurities (NDSRIs), which can form due to the presence of nitrosatable amine groups or nitrosating agents in APIs or API impurities. The unique properties of amine functional group in API synthesis make it irreplaceable. While efforts to control and analyze NA levels present significant challenges, the pharmaceutical industry is committed to implementing effective and realistic NA control strategies to ensure patient safety and secure access to important medicines.
ORGANIC PROCESS RESEARCH & DEVELOPMENT
(2023)
Article
Medicine, Legal
Rachael E. Tennant, David J. Ponting, Andrew Thresher
Summary: Mutagenicity data is essential for the safety assessment of new drug compounds, and the Ames test is commonly used as a primary screen to evaluate mutagenic risk. However, it may not be sensitive enough to detect the mutagenic potential of N-nitrosamines, highly potent carcinogens. This study analyzes variations to the OECD 471-compliant Ames test and their impact on its predictive performance for carcinogenicity.
REGULATORY TOXICOLOGY AND PHARMACOLOGY
(2023)
Article
Medicine, Legal
S. P. Felter, D. J. Ponting, A. M. Mudd, R. Thomas, A. A. F. Oliveira
Summary: The unexpected discovery of N-nitrosamine (NA) impurities in pharmaceutical products has posed significant challenges for the industry and regulatory bodies. New NAs associated with active pharmaceutical ingredients have been found, many of which have limited or no safety data. Establishing Acceptable Intake (AI) limits for NA impurities has been done using a tiered approach, utilizing chemical-specific data, read-across, or a class-specific TTC limit. Despite the limitations of available data, it is important to use the best scientific information to assess NA impurities and ensure consumer safety while minimizing potential drug shortages.
REGULATORY TOXICOLOGY AND PHARMACOLOGY
(2023)
Article
Toxicology
Robert Thomas, Antonio Anax F. Oliveira, David J. Ponting, Andrew Thresher
Summary: TD50 is a widely used measure of carcinogenic potency, but its applicability is questioned due to low-quality studies from earlier years.
TOXICOLOGY LETTERS
(2023)
Article
Pharmacology & Pharmacy
Siennah R. R. Greenfield, Heather Eng, Qingyi Yang, Chunyang Guo, Laura Byrnes, Alyssa Dantonio, Graham West, Li Di, Amit S. S. Kalgutkar
Summary: Plasma protein binding studies showed significant species differences in the SARS-CoV-2 main protease inhibitor nirmatrelvir, particularly in dogs and rabbits. Further investigations revealed that these differences were primarily due to variations in albumin and alpha-1-acid glycoprotein binding affinity. These findings have important implications for the pharmacokinetics and efficacy of nirmatrelvir in different animal species.
Article
Chemistry, Medicinal
Mario Oeren, Peter J. Walton, James Suri, David J. Ponting, Peter A. Hunt, Matthew D. Segall
Summary: This study presents methods for predicting isoform-specific metabolism and the general CYP metabolism for preclinical species. The models use semi-empirical quantum mechanical simulations to estimate the reactivity of each site of metabolism and combine it with the orientation and steric effects of the enzyme isoforms' binding pockets. The resulting ligand-based models achieve high accuracy in predicting the metabolism sites.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
