N-Nitrosodimethylamine formation in metformin hydrochloride sustained-release tablets: Effects of metformin and hypromellose used in drug product formulation.

In recent years, nitrosamines have been discovered in some types of drug products that becomes a current regulatory hotspot, and have attracted a lot attention from both regulatory authorities and industry. This manuscript provided an industry perspective on the nitrosamines research. A liquid chromatography coupled with tandem mass spectrometry（LC-MS/MS）method was developed and applied for the quantification of N-nitrosodimethylamine (NDMA) in metformin hydrochloride sustained-release tablets (MET). The key factors resulting in the NDMA formation in MET were identified through forced degradation and drug-excipient studies, which included high temperature, dimethylamine, strong alkali and oxidation conditions, peroxide and alkaline components contained in the formulation as well as the nitrite and nitrate impurities that might be presented in certain excipients. Further, API particle size and water content of the drug product would also affect the growth rate of NDMA. Therefore, the following mitigation strategies to reduce the risk of nitrosamines in the finished drug product are proposed in this manuscript: 1) avoid the use of excipients containing nitrite, nitrate and peroxide impurities; 2) avoid high temperature and strong alkaline environment in the production and storage condition; 3) maintain an appropriate water content level in the formulation. Based on the above principles, it was recommended to add antioxidant or incorporate excipient such as Na2CO3 to modify the formulation pH to weak basic environment in the formulation of MET, which can could effectively prevent formation of NDMA in the stability process.

Primary and metastatic squamous cell carcinoma of the thyroid gland: Two case reports.

This study reports two cases of squamous cell carcinoma of the thyroid (SCCT) presenting as the thyroid goiter, involving one case of primary squamous cell carcinoma originating from the thyroid (PSCCT) and the other case of secondary SCCT of the thyroid. A retrospective analysis of the clinical and pathological findings was done in this study report. In case 1, the thyroid ultrasound showed multi-hypoechoic well-defined nodules, labeled as 3 using Thyroid Imaging Reporting and Data System, measuring 34.1 mm × 28.9 mm × 30.3 mm and 26.5 mm × 22.2 mm × 23.9 mm in the left in the right lobar thyroid, respectively. The patient underwent surgery and was histologically diagnosed with PSCCT. In case 2, the thyroid ultrasound showed a 25.2 mm × 22.2 mm × 18.8 mm hypoechoic nodule in the right lobar thyroid. The patient underwent a frozen biopsy, the results of which increased suspicion of squamous cell carcinoma. A frozen biopsy was followed by an endoscopic evaluation that detected an ulcerative mass measuring 3.0 cm within the mucosa of esophagus. Due to a scarcity of cases, SCCT is a great challenge for the pathologists and the managing team to come up with the best treatment strategy for the patients.

Special Application of ms/ms Method on Determination of Regiochemistry of Sugammadex Series Compounds: Synthesis, Isolation and Structural Characterization for Two Potential Oxidative Impurities in Sugammadex Sodium Finished Pharmaceutical Product.

Two oxidative degradation impurities of sugammadex sodium have been successfully synthesized under stress conditions and isolated by preparative high performance liquid chromatography, which would be extremely difficult to prepare stochiometrically by conventional methods due to their structural complexity. Characteristic fragmentation pattern observed by mass spectrometry for sugammadex series compounds helped distinguish the two regioisomeric di-sulfoxide impurities. Confirmed by nuclear magnetic resonance analysis, Impurity I was identified as ortho-disulfoxide sugammadex and Impurity II as meta-disulfoxide sugammadex. It is the first time detailed structures of these two impurities are reported. Additionally, HPLC analysis also indicated the observance of these two impurities in long-term stored sugammadex sodium finished pharmaceutical product but absence in three pilot batches of sugammadex sodium drug substance which met ICH requirements. The compounded analysis technique has proven to be successful and reliable, and we hope that it could be well applied to structure identification for other sugammadex impurities and will be beneficial for other researchers focusing on this field.

Azithromycin "ghost peak": A solution degradation product of azithromycin via leaching from borosilicate glass volumetric flasks and vials.

An interference peak was found while detecting related substances of azithromycin. It is impressive that the degradation peak occurred at about 70 min in the next injection of the test solution (4 mg/mL or higher). Once the degradation peak was observed, it would keep growing. By using a strategy that Q-TOF high resolution mass spectrometry with mechanism-based stress studies, followed by preparative subsequent structure characterization by 1D and 2D NMR, the unknown peak was identified as azithromycin hydrogen borate. It apparently results from azithromycin and residual boron leaching out of the inner surface of the glass volumetric flasks and vials used in the sample preparation. By simulating the above chemical process, boric acid and azithromycin were dissolved in the same extraction diluent and a big interference peak occurred. It was found that boron-free flasks and vials, such as PMP or PP flasks and PTFE or PP vials could be used for the detection of azithromycin related substances to avoid the production of azithromycin hydrogen borate.

Peak distortion in reversed-phase liquid chromatography separation of active carbonyl-containing compounds: Mechanism and solution for this overlooked phenomenon.

Peak distortion is frequently encountered for compounds containing active carbonyl groups during reversed-phase (RP) LC separation. However, as being commonly overlooked or misdiagnosed, this problem is rarely reported in the literature and lacks an effective solution. In the present study, six pharmaceutical-related compounds containing keto or aldehyde groups, that exhibited severe peak distortion in early method development, were selected as the model compounds for further investigation. Systematic pH-screening experiments and a series of LC quadrupole-time of flight (Q-TOF) MS and NMR experiments were conducted on each model compound. The underlying chemical behavior of this type of compound during RP-LC separation was explicitly revealed. The formation of gem-diol/hemiketal/hemiacetal species via nucleophilic addition with H2O/MeOH will occur in a low pH eluent, but will be completely suppressed when the pH is higher than an analyte-specific value. As further validated by twelve other pharmaceutical-related compounds belonging to this type, we confirmed that increasing the eluent pH using buffers without nucleophilicity is a simple and effective method to solve this peak distortion problem.