Design and evaluation of oseltamivir phosphate dual-phase extended-release tablets for the treatment of influenza.

In this study, once-daily extended-release tablets with dual-phase release of oseltamivir phosphate were developed for the treatment of influenza. The goal was to improve patient adherence and offer more therapeutic choices. The tablets were manufactured using wet granulation, bilayer tablet compression, and enteric membrane-controlled coating processes. Various polymers, such as hydroxypropyl methylcellulose (HPMC K100MCR, K15MCR, K4MCR, K100LV), enteric polymers (HPMC AS-LF, Eudragit L100-55) and membrane-controlled polymers (OPADRY® CA), were used either individually or in combination with other common excipients. The formulations include enteric-coated extended-release tablet (F1), hydrophilic matrix extended-release tablet (F2), semipermeable membrane-controlled release tablet (F3) and a combination extended-release tablet containing both enteric and hydrophilic matrix (F4). The in vitro drug release profile of each formulation was fitted to the first-order model, and the Ritger-Peppas model suggested that Fickian diffusion was the primary mechanism for drug release. Comparative bioequivalence studies with Tamiflu® (oseltamivir phosphate) capsules revealed that formulations F1, F2, and F3 did not achieve bioequivalence. However, under fed conditions, formulation F4 achieved bioequivalence with a relative bioavailability of 95.30% (90% CI, 88.83%-102.15%). This suggests that the formulation F4 tablet could potentially be a new treatment option for patients with influenza.

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.

Characterization of two excipient interaction degradation products in oseltamivir phosphate powder for oral suspension by MS and NMR.

Oseltamivir phosphate is widely used to treat and prevent influenza, and is available in the form of capsules, powder for oral suspension, pediatric solutions, and granules. Because of the amino group, oseltamivir is easy to react with the excipients of the formulation to generate drug-excipient interaction impurities. In this research, two degradation products in a commercial oseltamivir phosphate powder for oral suspension due to interaction between API and citrate were investigated. They were characterized to be 3-((-6-acetamido-3-(ethoxycarbonyl)-5-(pentan-3-yloxy)cyclohex-3-en-1-yl)carbamoyl)-3-hydroxypentanedioic acid and 2-(2-((-6-acetamido-3-(ethoxycarbonyl)-5-(pentan-3-yloxy)cyclohex-3-en-1-yl)amino)-2-oxoethyl)-2-hydroxysuccinic acid by MS and NMR, respectively. Furthermore, the formation mechanisms of these impurities were verified, and the method of analysis of covariance was used to assess the rate of impurities' degradation. HIGHLIGHTS: Two excipient interaction degradation products in commercial oseltamivir phosphate powder for oral suspension were studied and elucidated in detail via LC-MS/MS and NMR. The incompatibility risk of pH conditioners such as citrate and citric acid with formulations that contain an amino group was disclosed in this article. Analysis of covariance was demonstrated to assess the impact of various formulations and preparation techniques on the rate of impurity degradation.

"Ghost peaks" of olmesartan medoxomil: Two solution degradation products of olmesartan medoxomil via oxidation mediated by metal ions.

Two unknown solution degradants were found during the dissolution testing in 0.1-M HCl for olmesartan medoxomil (OLM) tablets. The structure of the degradants was identified and characterized by liquid chromatography-ultraviolet (LC-UV), liquid chromatography with tandem mass spectrometry (LC-MS/MS), and nuclear magnetic resonance (NMR) and demonstrated to be cyclization of tetrazole and benzene in the olmesartan (OL) and OLM structures. A series of studies including stress studies, simulation studies, and mechanism-based studies were performed to reveal the potential mechanisms that lead to the formation of the unknown degradants. The study results demonstrated that the degradation was catalyzed with radicals that originated from the metal ions leached from the inner surface of high-performance liquid chromatography (HPLC) glass vials with dissolved oxygen under acidic condition. Prerinsing the glass vials with acidic solution dissolved with EDTA can effectively avoid the generation of such oxidative impurities. The present work provides new insights into the understanding of degradation pathways of OLM, which might support the development of OLM tablets.