Drug-related Substances Research Articles

Extension of impurity profiling on Eltrombopag olamine to in-silico Predictions: An Effort to Exploit correlated forced degradation products and known Drug-Related substances in drug discovery

The recent pandemic has highlighted the impact of diseases on global health and the economy. The rapid discovery of new hit molecules remains a tough challenge. Pharmaceutical impurity profiling can be linked to drug discovery through the identification of new hits from compounds identified during the analytical profiling. The present study demonstrates this linkage through the extension of the impurity (forced degradation) profiling of eltrombopag (ELT) olamine, a thrombopoietin (TPO) receptor agonist. The drug was exposed to standard degradation and the degradation products were primarily resolved and identified by UPLC-ESI-MS. This led to the identification of five forced degradation products (FDP). Thirty-three other known related substances (RS) of ELT, identified in the literature, were also considered. Molecular similarity checks were performed using Tanimoto similarity searches. A set of structurally and topologically similar molecules, including ELT and 15 RS, was established and subjected to in-silico toxicity-, absorption-, distribution-, metabolism-, and elimination (ADME) predictions. The RS, predicted with similar or lower toxicity than ELT and a comparable ADME profile, were subjected to molecular docking to trace changes in TPO receptor affinity. The results indicated that five RS had a high Jaccard’s similarity with ELT and higher or comparable docking scores. These compounds, along with few other impurities were predicted to have lower toxicity, better or comparable absorption, distribution, metabolism, and a better excretion profile than ELT. This justifies their entry as potential novel TPO receptor agonists in drug discovery.

Absorption, distribution, metabolism and excretion of linaprazan glurate in rats

Linaprazan (AZD0865, TX07) is one of potassium-competitive acid blockers. However, linaprazan is rapidly excreted from the body, shortening its acid inhibition property. Linaprazan glurate (X842) is a prodrug of linaprazan with a prolonged inhibitory effect on gastric acid secretion. Linaprazan glurate has entered clinical trials, but few studies have reported its metabolism in non-clinical and clinical settings. In this study, we studied the pharmacokinetics, tissue distribution, mass balance, and metabolism of linaprazan glurate in rats after a single oral dose of 2.4 mg/kg (100 µCi/kg) [14C]linaprazan glurate. The results demonstrated that linaprazan glurate was mainly excreted via feces in rats with 70.48% of the dose over 168 h. The plasma AUC0–∞ of linaprazan glurate in female rats was 2 times higher than that in male rats. Drug-related substances were mainly concentrated in the stomach, eyes, liver, small intestine, and large intestine after administration. In blood, drug-related substances were mostly distributed into plasma instead of hemocytes. In total, 13 metabolites were detected in rat plasma, urine, feces, and bile. M150 (2,6-dimethylbenzoic acid) was the predominant metabolite in plasma, accounting for 80.65% and 67.65% of AUC0–24h in male and female rats, respectively. Based on the structures, linaprazan glurate was mainly hydrolyzed into linaprazan, followed by a series of oxidation, dehydrogenation, and glucuronidation in rats. Besides, CES2 is the main metabolic enzyme involved in the hydrolysis of linaprazan glurate to linaprazan.

Pharmacokinetics, Mass Balance, Tissue Distribution and Metabolism of [14C]101BHG-D01, a Novel Muscarinic Receptor Antagonist, in Rats.

101BHG-D01, a novel long-acting and selective muscarinic receptor antagonist for the treatment of chronic obstructive pulmonary disease (COPD), is undergoing Phase Ib clinical trial in patients and has shown its potential efficacy. Its preparation method and medical use thereof have been patented in the United States (Patent No.US9751875B2). In this study, the pharmacokinetics, mass balance, tissue distribution and metabolism of radioactive 101BHG-D01 were investigated in rats after an intravenous dose of 1 mg/kg [14C]101BHG-D01 (100 μCi/kg). Radioactivity in rat plasma, urine, feces, and tissues was measured by liquid scintillation counting (LSC), and metabolite profiling and identification were conducted by UHPLC-β-RAM and UHPLC-Q-Exactive Plus MS. The total radioactivity of the study drug in rat plasma rapidly declined with an average terminal elimination half-life of 0.35 h. The radioactivity in most tissues reached the maximum concentration at 0.25 h post-- dosing. The radioactivity mainly concentrated in the kidney and pancreas. The drug-related substances tended to be distributed into the blood cells in the circulation. At 168 h post dosing, the mean recovery of the total radioactivity in urine and feces was 78.82%. Fecal excretion was the major excretion route, accounting for approximately 61% of the radioactive dose. The study drug was metabolized extensively, and a total of 17 metabolites were identified in rat plasma, urine, and feces. The major metabolic pathways involved oxidation, oxidation and dehydrogenation, and O-dephenylation. In conclusion, the study results are useful for better understanding the pharmacokinetic profiles of 101BHG-D01 and provide a robust foundation for subsequent clinical studies.

Pharmacokinetics, Mass Balance, Tissue Distribution, and Metabolism of [3H]Catalpol in Rats: the Main Bioactive Component of Rehmannia glutinosa for the Treatment of Ischemic Stroke.

Catalpol, one of the main bioactive components isolated from Rehmannia glutinosa, was developed by Suzhou Youseen for the treatment of ischemic stroke; however, preclinical information about its absorption, distribution, metabolism, and excretion (ADME) in animals is inadequate. This study aimed to illuminate the pharmacokinetics (PK), mass balance (MB), tissue distribution (TD), and metabolism of catalpol after a single intragastric administration of 30 mg/kg (300 μCi/kg) [3H]catalpol in rats. Radioactivity in plasma, urine, feces, bile, and tissues was measured by liquid scintillation counting (LSC), and metabolite profiling was characterized by UHPLC-β-ram and UHPLC-Q-Exactive plus MS. The radio pharmacokinetic results showed that catalpol was rapidly absorbed by Sprague‒Dawley (SD) rats, with a median Tmax of 0.75 h and an arithmetic mean half-life (t1/2) of the total radioactivity of approximately 1.52 h in plasma. The mean recovery of the total radioactive dose was 94.82%±1.96% over 168 h postdose (57.52%±12.50% in the urine and 37.30%±12.88% in the feces). The parent drug catalpol was the predominant drugrelated substance in rat plasma and urine, while M1 and M2, two unidentified metabolites, were detected in feces. When [3H]catalpol was incubated with β-glucosidase and rat intestinal flora, we found that the same metabolites M1 and M2 were produced in both incubation systems. Catalpol was excreted mainly through the urine. The drug-related substances were primarily concentrated in the stomach, large intestine, bladder, and kidney. Only the parent drug was detected in the plasma and urine, and M1 and M2 were detected in the feces. We speculate that the metabolism of catalpol in rats was mainly mediated by the intestinal flora, resulting in an aglycone-containing hemiacetal hydroxyl structure.

A mass balance study of [14C]SHR6390 (dalpiciclib), a selective and potent CDK4/6 inhibitor in humans.

SHR6390 (dalpiciclib) is a selective and effective cyclin-dependent kinase (CDK) 4/6 inhibitor and an effective cancer therapeutic agent. On 31 December 2021, the new drug application was approved by National Medical Product Administration (NMPA). The metabolism, mass balance, and pharmacokinetics of SHR6390 in 6 healthy Chinese male subjects after a single oral dose of 150mg [14C]SHR6390 (150µCi) in this research. The Tmax of SHR6390 was 3.00h. In plasma, the t 1/2 of SHR6390 and its relative components was approximately 17.50h. The radioactivity B/P (blood-to-plasma) AUC0-t ratio was 1.81, indicating the preferential distribution of drug-related substances in blood cells. At 312h after administration, the average cumulative excretion of radioactivity was 94.63% of the dose, including 22.69% in urine and 71.93% in stool. Thirteen metabolites were identified. In plasma, because of the low level of radioactivity, only SHR6390 was detected in pooled AUC0-24h plasma. Stool SHR6390 was the main component in urine and stool. Five metabolites were identified in urine, and 12 metabolites were identified in stool. Overall, faecal clearance is the main method of excretion.

The influence of water of crystallization in NIR-based MDMA·HCl detection

The large numbers of 3,4-methylenedioxy-N-methylamphetamine (MDMA) formulations encountered by the police and border security necessitates the need for safe, rapid and reliable tests to be performed on-site. Near-infrared (NIR) spectroscopy is a promising technique for on-scene illicit-drug detection because of its rapid analysis, non-invasive nature, broad scope to detect various substances, and small-sized sensors suitable for portable operation. The NIR spectrum of MDMA shows an intriguing, intense peak at ∼2000 nm that was found characteristic for MDMA within a large set of drugs and drug-related substances. Herein, we show that this peak can be attributed to water molecules of crystallization in the MDMA lattice. Drying experiments showed that both an anhydrous and hydrated form of MDMA·HCl exists with significantly different NIR spectra. At ambient conditions, the anhydrous form converted back to the hydrated form within 2 months. Our data analysis model was able to identify MDMA·HCl in mixtures of both forms. Assessment of seized casework materials showed that the majority of MDMA·HCl in The Netherlands is of the hydrated type. This is explained by the use of water-containing concentrated hydrochloric acid in the final conversion step of MDMA-base to the hydrochloride salt in clandestine laboratories. These findings provide insight in the challenges associated with NIR-based identification of drugs that may appear in various crystalline forms. Awareness on the existence of these forms and the consequences of library and data-model design to cope with this phenomenon will increase the robustness of on-site NIR-based drug detection.

Absorption, distribution, metabolism, and excretion of [14C]Mefuparib (CVL218), a novel PARP1/2 inhibitor, in rats.

Mefuparib (CVL218) is a novel second-generation poly-ADP-ribose polymerase (PARP) inhibitor for cancer treatment. CVL218 can easily enter the brain. However, the transport mechanism by which CVL218 crosses the blood-brain barrier (BBB) is unknown. (1) [14C] CVL218 metabolism in rats was traced by a liquid scintillation counter and oxidative combustion. (2) Metabolic profiles and metabolites were identified by UHPLC-β-RAM/UHPLC-Fraction Collector and UHPLC-Q Exactive Plus MS. (3) The partition coefficient Kp,uu,brain value was simulated by two strategies. One strategy was using ACD and GastroPlus Software based on the results of intravenous administration pharmacokinetics and plasma protein-binding studies. The reliability was confirmed by comparison with another strategy (brain/plasma distribution study). (1) Rapid drug elimination was observed 24h after intragastric administration. The total cumulative excretion in urine and feces within 168h accounted for 97.15% of the dose. The cumulative radioactive dose recovery in bile was 41.87% within 72h. The drug-related substances were extensively distributed to the tissues within 48h. (2) M8 was the major metabolite in plasma, urine, feces and bile. (3) CVL218 exhibited high brain protein-binding rate (88.16%). The Kp,uu,brain value (8.42) simulated by the simple software strategy was similar to that of the brain/plasma distribution study (7.01). CVL218 is a fast-metabolizing drug and is mainly excreted in feces. The B/P ratio prediction and observation data for CVL218 were consistent. Furthermore, the Kp,uu,brain value indicated that penetration through the BBB might be mediated by uptake transporters.

Possibilities of predictive toxicology in assessing the potential hepatotoxicity of medicinal substances

Currently, one of the "gold" standards for determining the potential toxicity of drugs is highly informative preventive screening (HCS). This method has become a powerful tool for the evaluation of molecular, cellular and tissue toxicity, especially in the field of predictive toxicology, aimed at predicting unwanted drug-related substances. It is critical for the pharmaceutical industry to identify and subsequently mitigate potential safety risks early in the R&D process and thus reduce toxicity and the safety-related shrinkage of drug development programs. In this article, we review some of the most common used HCS assays for predictive toxicology in the pharmaceutical industry. PubMed, Elsevier Science (Scopus), and Clarivate Analytics (Web of Science) research databases were searched for original research to identify the hallmarks of the HCS methodology. Hepatotoxicity is one of the most common causes of safety and toxicity related downsizing of potential drugs in the pharmaceutical industry, as well as drug withdrawals. Hepatotoxic substances are associated with xenobiotics, drugs, substances of natural origin and chemical agents that constitute an important cause of hepatic action. A single classification based on the mechanisms of toxicity makes it possible to distinguish between intrinsic hepatotoxicity (preliminary and dose-dependent) and idiosyncratic hepatotoxicity (invisible, non-mediated immune and metabolic reactions). HCS analyzes are not intended to replace animal testing because they cannot capture the full complexity of an organism. However, they can reduce the amount of animal testing by early detection of hazards and complement animal testing. Through early identification of safety risks and optimization of chemistry series across relevant safety endpoints, HCS assays for predictive toxicology hold the promise of enhancing the successful selection of new drug candidates with satisfactory toxicological properties.

A calibration friendly approach to identify drugs of abuse mixtures with a portable near-infrared analyzer.

Both the increasing number and diversity of illicit‐drug seizures complicate forensic drug identification. Traditionally, colorimetric tests are performed on‐site, followed by transport to a laboratory for confirmatory analysis. Higher caseloads increase laboratory workload and associated transport and chain‐of‐evidence assurance performed by police officers. Colorimetric tests are specific only for a small set of drugs. The rise of new psychoactive substances therefore introduces risks for erroneous results. Near‐infrared (NIR)‐based analyzers may overcome these encumbrances by their compound‐specific spectral selectivity and broad applicability. This work introduces a portable NIR analyzer that combines a broad wavelength range (1300–2600 nm) with a chemometric model developed specifically for forensic samples. The application requires only a limited set of reference spectra for time‐efficient model training. This calibration‐light approach thus eliminates the need of extensive training sets including mixtures. Performance was demonstrated with 520 casework samples resulting in a 99.6% true negative and 97.6% true positive rate for cocaine. Similar results were obtained for MDMA, methamphetamine, ketamine, and heroin. Additionally, 236 samples were analyzed by scanning directly through their plastic packaging. Also here, a >97% true positive rate was obtained. This allows for non‐invasive, operator‐safe chemical identification of potentially potent drugs of abuse. Our results demonstrate the applicability for multiple drug‐related substances. Ideally, the combination of this NIR approach with other portable techniques, such as Raman and IR spectroscopy and electrochemical tests, may eventually eliminate the need for subsequent laboratory analysis; therefore, saving tremendous resources in the overall forensic process of confirmatory illicit drug identification.

Identification, synthesis and characterization of avanafil process impurities and determination by UPLC.

Avanafil is a phosphodiesterase type 5 inhibitor which is used to treat erectile dysfunction in men. The process-related impurities of avanafil were investigated, and four kinds of impurities in several laboratory batches with a content of 0.29–1.63% were detected by the newly developed gradient ultra-high performance liquid chromatography (UPLC). Based on the synthesis route and UPLC-MS research, the impurities are inferred as Imp-A, Imp-B, Imp-C and Imp-D. The structures of the impurities were inferred from LC-MS studies and confirmed by synthesis, followed by spectroscopic characterization such as NMR and mass spectrometry. Especially, the synthesis of Imp-D is firstly reported. The drug-related substances can be separated well by efficient and selective ultra-high performance liquid chromatography on a Waters ACQUITY HSS C18 (50 × 2.1 mm, particle size 1.8 μm) column at 35 °C, with the mobile phase consisting of ammonium formate (20 mM) and acetonitrile, and the detection at 239 nm with a DAD detector. The method was validated in terms of specificity, linearity, precision, accuracy and sensitivity, and satisfactory results were obtained. The results indicated this developed UPLC method for avanafil and the proposed synthesis mechanism can be used for quality control purposes as required by regulatory agencies to ensure the safety and efficacy of the product.

Absorption, distribution, metabolism, and excretion of [14C]NBP (3-n-butylphthalide) in rats

3-n-Butylphthalide (NBP) has a considerable neuroprotective effect and is currently used for the treatment of ischemic stroke. NBP was launched on the market in 2004. However, information on its metabolism in humans and preclinical animal models is insufficient. Although the metabolism of unradiolabeled NBP in humans has been reported, the quantitative metabolite profile, blood-to-plasma radioactivity concentration ratio (B/P), and tissue distribution of this drug remain unclear. We evaluated the pharmacokinetics, tissue distribution, mass balance, and metabolism of NBP in rats after a single oral dose of 60 mg/kg (100 μCi/kg) [14C]NBP to understand the biotransformation of NBP comprehensively and to provide preclinical drug metabolism data prior to human mass balance studies with [14C]NBP in the near future. NBP absorption was rapid (Tmax = 0.75 h) and declined with a terminal half-life of 9.73 h. In rats, the B/P was 0.63 during the 48 h postdose period, indicating that drug-related substances did not tend to be distributed into blood cells. Tissue distribution was determined by using the oxidative combustion method. NBP-related components were widely distributed throughout the body, and high concentrations were detected in the stomach, small intestine, fat, bladder, kidney, liver and ovary. At 168 h after oral administration, the mean cumulative recovered radioactivity was 99.85% of the original dose, and was 85.12% in urine and 14.73% in feces. Metabolite profiles were detected via radiochromatography. A total of 49 metabolites were identified in rat plasma, urine, and feces. The main metabolic pathways were oxidation, glucuronidation, and sulfation. Overall, NBP was absorbed rapidly, distributed throughout the body, and excreted in the form of metabolites. Urine was the main excretion route, and the absorption, distribution, metabolism and excretion of NBP showed no significant gender difference between male and female rats.

Metabolic disposition of the EGFR covalent inhibitor furmonertinib in humans.

Furmonertinib was designed for the treatment of non-small cell lung cancer (NSCLC) patients with EGFR T790M mutation. In this study, we investigated the metabolic disposition and mass balance in humans and tissue distribution in rats. After a single oral administration of 97.9 μCi/81.5 mg [14C]-furmonertinib mesylate to six healthy male volunteers, the absorption process of furmonertinib was fast with a tmax of total plasma radioactivity at 0.75 h. Afterward, furmonertinib was extensively metabolized, with the parent drug and active metabolite AST5902 accounting for 1.68% and 0.97% of total radioactivity in plasma. The terminal t1/2 of total radioactivity in plasma was as long as 333 h, suggesting that the covalent binding of drug-related substances to plasma proteins was irreversible to a great extent. The most abundant metabolites identified in feces were desmethyl metabolite (AST5902), cysteine conjugate (M19), and parent drug (M0), which accounted for 6.28%, 5.52%, and 1.38% of the dose, respectively. After intragastric administration of 124 μCi/9.93 mg/kg [14C]-furmonertinib to rats, drug-related substances were widely and rapidly distributed in tissues within 4 h. The concentration of total radioactivity in the lung was 100-fold higher than that in rat plasma, which could be beneficial to the treatment of lung cancer. Mass balance in humans was achieved with 77.8% of the administered dose recovered in excretions within 35 days after administration, including 6.63% and 71.2% in urine and feces, respectively. In conclusion, [14C]-furmonertinib is completely absorbed and rapidly distributed into lung tissue, extensively metabolized in humans, presented mostly as covalent conjugates in plasma, and slowly eliminated mostly via fecal route.

Simultaneous Determination of Cholecalciferol and 25- Hydroxycholecalceferol in Lipid-based Self-nanoemulsifying formulations and Marketed Product Vi-de 3® by UHPLC-UV

Background: The purpose of the current study was to develop a selective, precise, fast economical and advanced reverse phase ultra-high-performance liquid chromatography (UHPLC UV) method and validate it for the simultaneous estimation of cholecalciferol and its analogue 25- hydroxycholecalciferol in lipid-based self-nano emulsifying formulation (SNEDDS). Methods: The chromatographic separation was simply performed on a Dionex® UHPLC systems (Ultimate 3000, Thermo scientific) by using HSS C18 (2.1x50 mm, 1.8 µm) analytical column. The elution was carried out isocratically with the mobile phase consisting of acetonitrile and methanol in the ratio of 50:50 %v/v with a flow rate of 0.4 ml/min, followed by the UV detection at 265 nm. The injection volume was 1µl and the column temperature was maintained at 45°C. FDA regulatory guidelines were used to develop and validate the method. Results: The current developed UHPLC-UV method was found to be rapid (run time 2 min), and selective with the high resolution of cholecalciferol and 25-hydroxycholecalciferol (RT=0.530 min & 1.360 min) from different lipid matrices. The method was highly sensitive (Limit of Detection and Lower Limit of Quantification were 0.13 ppm & 0.51ppm, and 0.15 ppm & 0.54 ppm, respectively). The linearity, accuracy and precision were determined as suitable over the concentration range of 0.5-50.0 ppm for both the analytes. Conclusion: The proposed UHPLC-UV method can be used for the determination of cholecalciferol and 25-hydroxycholecalciferol in SNEDDS and marketed Vi-De 3® as pure forms (intact) with no interference of excipients or drug-related substances.

Educational attainment and prescription drug misuse: The importance of push and pull factors for dropping out

PurposeYoung adults who do not complete high school are at increased risk for substance use and offending behavior. A limitation of this research is that dropouts are often treated as a homogeneous group, which ignores the various push (e.g., academic failure or disciplinary problems) and pull (e.g., family responsibility or economic need) factors for leaving school. MethodsThe current study relies on multiple years of data from the National Survey on Drug Use and Health (2009–2014) and examines several dependent variables, including prevalence of prescription drug misuse, frequent prescription drug misuse, and prescription drug-related substance use disorder symptoms. We assess the importance of push and pull factors for dropping out, and compare dropouts to respondents who completed school. ResultsMultivariable logistic regression analyses produce two important findings. First, push factors increase the risk of various types of prescription drug misuse compared to pull factors. Additionally, respondents who attend college are at a decreased risk for various types of prescription opioid and sedative/tranquilizer misuse and disorder. DiscussionThe current research identifies important differences in prescription drug misuse and disorders among dropouts based on the reason they left school. Additionally, college attendance appears to be a strong protective factor.

Metabolites characterization of a novel DPP-4 inhibitor, imigliptin in humans and rats using ultra-high performance liquid chromatography coupled with synapt high-resolution mass spectrometry

Imigliptin has been reported as a novel dipeptidyl-peptidase-IV (DPP-4) inhibitor to treat type 2 Diabetes Mellitus (T2DM), and is currently being tested in clinical trials. In the first human clinical study, imigliptin was well tolerated and proved to be a potent DPP-4 inhibitor. Considering its potential therapeutic benefits and promising future, it is of great importance to study the metabolite profiles in the early stage of drug development. In the present study, a robust and reliable analytical method based on the ultra-high performance liquid chromatography/quadrupole time-of-flight mass spectrometry (UHPLC/Q-TOF MS) method combined with MassLynx software was established to investigate the characterization of metabolites of imigliptin in human and rat plasma, urine and feces after oral administration. As a result, a total of 9 metabolites were identified in humans, including 6, 9 and 8 metabolites in human plasma, urine, and feces, respectively. A total of 11 metabolites were identified in rats, including 7, 10 and 8 metabolites in rat plasma, urine, and feces, respectively. In addition, 6 of the metabolites detected in humans and rats were phase I metabolites, including demethylation, carboxylation, hydroxylation and dehydrogenation metabolites, and 5 of the metabolites were phase II metabolites, including acetylation and glucuronidation. There was no human metabolite detected compared to those in rats. The major metabolites detected in human plasma (M1 and M2) were products resulting from acetylation, and hydroxylation followed by dehydrogenation. M1 was the major metabolite in rat plasma. M2 and the parent drug were the major drug-related substances in human urine. The parent drug was the major drug-related substances in rat urine. M2, M5 (hydroxylation product) and M6 (2 × hydroxylation and acetylation product) were the predominant metabolites in human feces. M2 and M5 were the major metabolites in rat feces. In addition, renal clearance was the major route of excretion for imigliptin.

Adverse childhood experiences and illicit drug use in adolescents: Findings from a national addictions treatment population in Singapore

ABSTRACTAim: Adolescence is a particularly vulnerable period for illicit drug use. The present study aimed to examine the prevalence of adverse childhood experiences (ACEs) among adolescents in a national addiction treatment sample, and investigate the role of ACEs in adolescent drug use. Methods: The study examined data from 260 adolescents, information on ACE exposure and drug use were obtained from retrospective chart review. Results: About 46.5% of the sample experienced at least one ACE and 25.0% experienced two or more ACEs. Results showed that exposure to household dysfunction was associated with drug-related substance use disorders (SUDs). Additionally, exposure to multiple ACEs was associated with SUDs, earlier drug initiation, and more severe drug use. Conclusions: Given that a significant proportion of adolescents presenting for addiction treatment had a history of ACEs, the associations between ACEs and deleterious patterns of illicit drug use highlight the potential adverse impact of ACEs on proximal outcomes in adolescents.

Identification, synthesis and structural characterization of process related and degradation impurities of acrivastine and validation of HPLC method

Four impurities (Imp-I–IV) were detected using gradient HPLC method in few laboratory batches of acrivastine in the level of 0.03–0.12% and three impurities (Imp-I–III) were found to be known and one (Imp-IV) was unknown. In forced degradation study, the drug is degraded into four degradation products under oxidation and photolytic conditions. Two impurities (Imp-III and -IV) were concurred with process related impurities whereas Imp-V and -VI were identified as new degradation impurities. Based on LC-ESI/MSn study, the chemical structures of new impurities were presumed as 1-[(2E)-3-(4-methylphenyl)-3-{6-[(1E)-3-oxobut-1-en-1-yl]pyridin-2-yl}prop-2-en-1-yl]pyrrolidin-1-ium-1-olate (Imp-IV), 1-{[3-(4-methylphenyl)-3-{6-[(1E)-3-oxobut-1-en-1-yl]pyridin-2-yl}oxiran-2-yl]methyl}pyrrolidin-1-ium-1-olate (Imp-V) and 2-[2-(4-methylphenyl)-3-[(1-oxidopyrrolidin-1-ium-1-yl)methyl]oxiran-2-yl]-6-[(1E)-3-oxobut-1-en-1-yl]pyridin-1-ium-1-olate (Imp-VI), and confirmed by their synthesis followed by spectroscopic analysis, IR, NMR (1H, 13C) and mass. An efficient and selective high-performance liquid chromatography method has been developed and resolved well the drug related substances on a Phenomenex Gemini C-18 (250×4.6mm, particle size 5μm) column. The mobile phase was composed of sodium dihydrogen phosphate (10mM) and methanol, temperature at 25°C, and a PDA detector set at 254nm used for detection. The method was validated with respect to specificity, linearity, precision, accuracy, and sensitivity and satisfactory results were achieved. Identification, synthesis, characterization of impurities and method validation were first reported in this paper.

Recent advances in capillary electrophoretic migration techniques for pharmaceutical analysis (2013-2015).

This review updates and follows-up a previous review by highlighting recent advancements regarding capillary electromigration methodologies and applications in pharmaceutical analysis. General approaches such as quality by design as well as sample injection methods and detection sensitivity are discussed. The separation and analysis of drug-related substances, chiral CE, and chiral CE-MS in addition to the determination of physicochemical constants are addressed. The advantages of applying affinity capillary electrophoresis in studying receptor-ligand interactions are highlighted. Finally, current aspects related to the analysis of biopharmaceuticals are reviewed. The present review covers the literature between January 2013 and December 2015.

Externalizing behavior and emotion dysregulation are indicators of transmissible risk for substance use disorder

BackgroundPsychological items discriminating children of fathers diagnosed with an illicit drug-related substance use disorder and normal controls are indicators of a unidimensional construct termed transmissible liability index (TLI) (Vanyukov et al., 2009). TLI is a highly heritable (Vanyukov et al., 2009; Hicks, Iacono, McGue, 2012) and valid (Vanyukov et al., 2009; Hicks et al., 2009; Kirisci et al., 2013a) measure of childhood liability to substance use disorders (SUDs). AimsThis longitudinal study determined whether TLI has incremental validity for predicting SUD beyond commonly measured psychological indicators of risk. MethodsTLI and measures of executive cognitive capacity, emotion dysregulation and externalizing disturbance were administered to boys at ages 10–12 and 16. SUD outcome determined at age 22 was assessed as (1) any SUD, (2) the number of drug-specific SUDs, and (3) SUD severity. ResultsTLI predicted SUD beyond the contribution of measures of emotion dysregulation, executive cognitive capacity and externalizing disturbance. The association of emotion dysregulation and externalizing behavior at ages 10–12 and 16 with SUD at age 22 was also reduced to non-significance after controlling for transmissible risk measured by TLI. ConclusionsTLI's incremental validity beyond these latter indicators of risk points to its utility for identifying vulnerable youths requiring intervention.

Recent advances in capillary electrophoretic migration techniques for pharmaceutical analysis

Since the introduction about 30 years ago, CE techniques have gained a significant impact in pharmaceutical analysis. The present review covers recent advances and applications of CE for the analysis of pharmaceuticals. Both small molecules and biomolecules such as proteins are considered. The applications range from the determination of drug-related substances to the analysis of counterions and the determination of physicochemical parameters. Furthermore, general considerations of CE methods in pharmaceutical analysis are described.