The comparative analysis of gastrointestinal toxicity of azithromycin and 3'-decladinosyl azithromycin on zebrafish larvae.

The most commonly reported side effect of azithromycin is gastrointestinal (GI) disorders, and the main acid degradation product is 3'-Decladinosyl azithromycin (impurity J). We aimed to compare the GI toxicity of azithromycin and impurity J on zebrafish larvae and investigate the mechanism causing the differential GI toxicity. Results of our study showed that the GI toxicity induced by impurity J was higher than that of azithromycin in zebrafish larvae, and the effects of impurity J on transcription in the digestive system of zebrafish larvae were significantly stronger than those of azithromycin.

A Rapid Assessment Model for Liver Toxicity of Macrolides and an Integrative Evaluation for Azithromycin Impurities.

Impurities in pharmaceuticals of potentially hazardous materials may cause drug safety problems. Macrolide antibiotic preparations include active pharmaceutical ingredients (APIs) and different types of impurities with similar structures, and the amount of these impurities is usually very low and difficult to be separated for toxicity evaluation. Our previous study indicated that hepatotoxicity induced by macrolides was correlated with c-fos overexpression.

Study on Isomeric Impurities in Cefotiam Hydrochloride.

In this study, two isomeric impurities were identified in cefotiam hydrochloride injection preparation and were characterized. Column-switching HPLC-MS and NMR techniques were used to identify the impurity 1 as the Δ3(4) isomers of cefotiam. Using software-based calculations, it was predicted that neither of the isomeric impurities was embryotoxic.

Liver toxicity of macrolide antibiotics in zebrafish.

Macrolide antibiotics (macrolides) are among the most commonly prescribed antibiotics worldwide and are used for a wide range of infections, but macrolides also expose people to the risk of adverse events include hepatotoxicity. Here, we report the liver toxicity of macrolides with different structures in zebrafish. The absorption, distribution, metabolism, excretion and toxicology (ADMET) parameters of macrolide compounds were predicted and contrasted by utilizing in silico analysis.

Microarray Expression Profiling and Raman Spectroscopy Reveal Anti-Fatty Liver Action of Berberine in a Diet-Induced Larval Zebrafish Model.

The prevalence of non-alcohol fatty liver disease (NAFLD) is increasing in children and adolescents who are mostly resulted from overfeeding. Previous studies demonstrate that berberine (BBR), a compound derived from plant, has beneficial effects on NAFLD in adults but poorly understood in the pediatric population. This study employed a larval zebrafish model to mimic the therapeutic effects of BBR in the pediatric population and the mechanisms underlying its hepatoprotection.

ADME and Toxicity Prediction of Ceftazidime and Its Impurities.

To improve the quality control of drugs, we predicted the absorption, distribution, metabolism, excretion, and toxicity (ADMET) of ceftazidime (CAZ) and its impurities via methods. We used three types of quantitative structure-activity relationship and docking software for precise prediction: Discovery Studio 4.0, OECD QSAR Toolbox 4.

Characterization of Solid-State Drug Polymorphs and Real-Time Evaluation of Crystallization Process Consistency by Near-Infrared Spectroscopy.

Herein, we aimed to develop a strategy for evaluating the consistency of pharmaceutically important crystallization processes in real time, focusing on two typical cases of polymorphism. Theoretical analysis using a combination of C solid-state nuclear magnetic resonance spectroscopy with other polymorphism analysis techniques identified a number of marker signals, the changes of which revealed the presence of two or more structural orientations (lattices and/or molecular conformations) in both cefazolin sodium pentahydrate (α-CEZ-Na) and cephathiamidine (CETD). The proportions of these forms were shown to be batch-dependent and were defined as critical quality attributes (CQAs) to evaluate process consistency.

Research on the relationship between cephalosporin structure, solution clarity, and rubber closure compatibility using volatile components profile of butyl rubber closures.

Objective: Establish an effective experimental strategy to determine the compatibility of rubber closures for drugs.

Significance: Various types of rubber closures with different compositions are available for drug packaging. Many additives of rubber closures can be released from rubber closures and may affect the quality of drugs and pose a risk to human health.

Isolation, identification and in silico toxicity predictions of two isomers from cefotiam hydrochloride.

Two structural isomers of cefotiam in cefotiam hydrochloride for injection were observed, and the structures of the isomers were determined by mass spectrometry and various 1D and 2D NMR techniques. The thermo-isomerization mechanism of cefotiam was also discussed. Thermo-isomerization occurred not only in cefotiam but also in cephalosporins containing a 1-alkyl-1H-tetrazole-5-thiol side chain at C-3.

Compilation of a Near-Infrared Library for Construction of Quantitative Models of Oral Dosage Forms for Amoxicillin and Potassium Clavulanate.

The accuracy of quantitative models for near-infrared (NIR) spectroscopy is dependent upon calibration samples with concentration variations. Conventional sample-collection methods have shortcomings (especially time-consumption), which creates a "bottleneck" in the application of NIR models for Process Analytical Technology (PAT) control. We undertook a study to solve the problem of sample collection for construction of NIR quantitative models.

Application of Solid-State NMR to Reveal Structural Differences in Cefazolin Sodium Pentahydrate From Different Manufacturing Processes.

Solid-state Nuclear magnetic resonance, thermogravimetric analysis, X-ray diffraction, and Fourier-transform infrared spectroscopy were combined with theoretical calculation to investigate different crystal packings of α-cefazolin sodium obtained from three different vendors and conformational polymorphism was identified to exist in α-cefazolin sodium. Marginal differences observed among cefazolin sodium pentahydrate 1, 2, and 3 were speculated as being caused by the proportion of conformation .

Embryo and Developmental Toxicity of Cefazolin Sodium Impurities in Zebrafish.

Cefazolin sodium is an essential drug that is widely used in clinical therapy for certain infective diseases caused by bacteria. As drug impurities are considered to be one of the most important causes of drug safety issues, we studied embryotoxicity, cardiotoxicity, and neurotoxicity of nine cefazolin sodium impurities in zebrafish embryo and larvae for the objective control of impurity profiling. LC-MS/MS was employed to analyze the compound absorbance , and the structure-toxicity relationship was approached.

[Drug Discrimination Method Based on Near Infrared Reflectance Spectrum and Balance Cascading Sparse Representation Based Classification].

The combination of near infrared spectrum and pattern recognition methods has a wide application prospect in rapid and nondestructive supervision and management of drugs. The traditional identification methods regard the smallest error rate as the goal while the imbalance of classes is ignored. This makes the positive class is overwhelming covered by the negative class and reduces its effect for the classifier, so that the classification results tend to recognize the negative class correctly, which severely affects the identification accuracy.

Rapid Analysis of the Quality of Amoxicillin and Clavulanate Potassium Tablets Using Diffuse Reflectance Near-Infrared Spectroscopy.

The cycle-closed dimer of amoxicillin influences its critical quality and is an important impurity in amoxicillin and clavulanate potassium tablets. The quality of the tablets could be rapidly evaluated using the impurity as an indicator. Here, we report a quantitative model to determine the cycle-closed dimer in samples from different manufacturers using diffuse reflectance near-infrared (NIR) spectroscopy by partial least squares regression for one y variable (PLS1) and hierarchical cluster analysis.

[Study on the Selection of Parameters for Evaluating Drug NIR Universal Quantitative Models].

In order to find out the optimum combination of the evaluation parameters for the selection of the best drug near infrared (NIR) universal quantitative model during model optimization, 13 common evaluation parameters of NIR quantitative models were collected and arranged from commercial chemometrics software or References based on the requirements of validation of quantitative analytical procedures of ICH (International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use). Then all these parameters of 92 drug NIR universal quantitative models were calculated and analyzed. By studying the correlation of these parameters, the optimum combination of evaluation parameters for drug NIR universal quantitative models was determined.

[The control of the critical quality attributes of amoxicillin and clavulanate potassium tablet].

The critical attribute was analyzed in clavulanate potassium tablet of amoxicillin according to the principle QbD. By investigation of the drug impurity profile, the cycle-closed dimer and penicilloic acid of amoxicillin were considered to be the critical impurities, and the sources and the degradation pathways of these two impurities were discussed. The research confirmed that crystal form was the critical attribute of drug substance.

[Determination of furbenicillin sodium and its related substances by HPLC].

Furbenicillin is a broad-spectrum semisynthetic penicillin with strong antibacterial activity against Gram-negative bacteria. Furbenicillin sodium is determined by volumetric method in current criteria. However, the criteria does not contain an assay of related substances of furbenicillin sodium.

[Construction of the quantitative structure retention relationship of cefdinir related substances].

The molecular descriptors of impurities with known structure in cefdinir were calculated, selected and associated with the chromatographic retention behavior to establish a model. This quantitative structure retention relationships (QSRR) model for the related substances of cefdinir was established under specific chromatographic condition and verified by other impurities. 12 molecular descriptors were used to establish the QSRR model, F_AFRBWF, Blbn_J, SsCH3, SssCH2, SsNH2, SssNH, SssS, SHdCH2, EEM_AFc, EEM_AFpl, EEM_XFpl and Pi_MaxQ.

Factors Influencing the HPLC Determination for Related Substances of Azithromycin.

The European Pharmacopoeia, the U.S. Pharmacopoeia, and the Pharmacopoeia of the People's Republic of China all prescribe a high-performance liquid chromatography-ultraviolet method within a C18 column system for the separation of Azithromycin (AZT) and its related substances.

Guidelines and strategy of the International Conference of Harmonization (ICH) and its member states to overcome existing impurity control problems for antibiotics in China.

In the present report, we review the technical guidelines and principles on impurity research and control for antibiotics established by various agencies, including the International Conference of Harmonization (ICH), the US Food and Drug Administration (FDA), the European Medicines Agency (EMA) and the China Food and Drug Administration (CFDA). Progresses with the US Pharmacopoeia (USP), the European Pharmacopoeia (EP) and the Chinese Pharmacopoeia (ChP) to control impurities in antibiotics are also presented. Next, our discussion is focused on analyzing the CFDA's requirements on impurity research and control for antibiotics, and the implementation of ICH, FDA and other technical guidelines for generic drugs impurity control in China.

Antibiotic toxicity and absorption in zebrafish using liquid chromatography-tandem mass spectrometry.

Evaluation of drug toxicity is necessary for drug safety, but in vivo drug absorption is varied; therefore, a rapid, sensitive and reliable method for measuring drugs is needed. Zebrafish are acceptable drug toxicity screening models; we used these animals with a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method in a multiple reaction monitoring mode to quantify drug uptake in zebrafish to better estimate drug toxicity. Analytes were recovered from zebrafish homogenate by collecting supernatant.

[Update of near-infrared models for testing ceftazidime, water and arginine in ceftazidime for injection].

Unlabelled: To find a more reasonable index to decide whether the universal quantitative NIR model needs to be updated and to develop a general method to update universal quantitative NIR models, the quantitative models for testing ceftazidime, water and arginine contents in ceftazidime for injection were taken as example. The study was performed by analyzing the similarity between new sample spectra and the training set spectra of the original models. At first, new samples of ceftazidime for injection were divided into five groups by cluster analysis.

[Development and application of reference materials containing mixed degradation products of amoxicillin and ampicillin].

Reference materials containing mixed degradation products of amoxicillin and ampicillin were developed after optimization of preparation processes. The target impurities were obtained by controlled stress testing, and each major component was identified with HPLC-MS and compared with single traceable reference standard each. The developed reference materials were applied to system suitability test for verifying HPLC system performed in accordance with set forth in China Pharmacopeia and identification of major impurities in samples based on retention and spectra information, which have advantages over the methods put forth in foreign pharmacopoeias.

Identification of a new isomer from a reversible isomerization of ceftriaxone in aqueous solution.

A reversible isomerization of ceftriaxone in aqueous solution was observed, and the structure of the isomer was determined by mass spectrometry and various 1D and 2D NMR techniques. The mechanism of isomerization was also discussed. Finally, molecular docking simulations were performed and the antimicrobial activities of the isomers were measured.