A solid-state NMR study of amorphous ezetimibe dispersions in mesoporous silica.

PURPOSE: The purpose of this work is to examine the ability of methods based on multinuclear and multidimensional solid-state NMR (SSNMR) to perform detailed characterization of amorphous dispersions of ezetimibe adsorbed on mesoporous silica. METHODS: Ezetimibe was loaded into two types of mesoporous silica with average pore sizes of 2.5 and 21 nm. The mesoporous materials were characterized by powder X-ray diffraction (PXRD), vibrational spectroscopy, differential scanning calorimetry, and (1)H, (13)C, (19)F, and (29)Si SSNMR analysis including relaxation time measurements. Interactions between the drug and silica were investigated using 1D and 2D SSNMR methods based on dipolar correlation using cross-polarization (CP) and spin diffusion. RESULTS: PXRD was used to show the absence of crystalline ezetimibe in the mesoporous materials, and (19)F SSNMR was used to assess drug physical state and study mobility. (19)F-(29)Si CP methods were used to directly detect adsorbed ezetimibe. (1)H-(13)C, (1)H-(19)F, and (1)H-(29)Si, and heteronuclear correlation and (1)H homonuclear correlation experiments were used to investigate interactions between the drug and silica through (1)H environments. CONCLUSIONS: SSNMR methods were able to detect interactions between the drug and the silica substrate. Differences between the drug loaded onto silica with two different pore sizes were observed, including differences in hydrogen bonding environment and molecular mobility. These methods should be useful for characterization of similar systems.

The use of N-methylpyrrolidone as a cosolvent and oxidant in pharmaceutical stress testing.

The use of N-methylpyrrolidone (NMP) as an oxidant and cosolvent in pharmaceutical stress testing (forced degradation) is examined. Various active pharmaceutical ingredients were heated in NMP-water solutions under nitrogen, air, and oxygen and then analyzed by high-performance liquid chromatography, usually with ultraviolet diode array detection and mass spectrometry detection. In some cases, degradation products were isolated and characterized by nuclear magnetic resonance. The NMP-water-air-heat system provided oxidative and hydrolytic degradation products. The observed oxidation products were consistent with products expected from free radical autoxidation, reactions with hydroperoxides, and possibly singlet oxygen. Oxidative and hydrolytic pathways could be distinguished by comparison of the reactions carried out under air/oxygen and nitrogen. In many cases, the oxidation products observed during stress testing were also observed during formal stability studies of drug products. The NMP-water-air-heat stress condition facilitates various oxidative degradation pathways, which are often relevant to drug product on stability. This approach facilitates stability-indicating method development and helps elucidate degradation pathways.

An evaluation of chemical photoreactivity and the relationship to phototoxicity.

The existing regulatory guidance for photosafety testing of new drug products states that studies are warranted for those chemicals that both absorb light in the range of 290-700 nm, and that are either applied locally/topically, or "reach" (EMEA)/"significantly partition" (FDA) to the skin or eyes. The initial in vitro study recommended for the assessment of phototoxic potential is the 3T3 Neutral Red Uptake (NRU) Assay. The current study was undertaken to establish superior triggers for the initiation of biological photosafety testing. In this study, photophysical and photochemical parameters for 40 drug or drug-like molecules were studied. Principal Component Analysis (PCA), Partial Least Squares-Discriminant Analysis (PLS-DA), and a fivefold cross-validation PLS algorithm were used to evaluate the relationship between subsets of photophysical and photochemical parameters with the 3T3 NRU PIF/MPE (Photo Irritation Factor/Mean Photo Effect) results. The parameters most indicative of a 3T3 NRU positive PIF or MPE score were the extent of degradation in solution, the quantum yield of formation of singlet oxygen and the relative formation of superoxide anion. The results demonstrate that while absorption of light is critical to the induction of a light-induced process, it is the resultant events that may be used to predict the 3T3 NRU assay result. It is therefore proposed that the trigger for photosafety testing be revised to include a molecular basis for photoreactivity. From this limited investigation, estimated thresholds leading to 3T3 NRU positive results due to photodegradation, formation of singlet oxygen quantum yield or a relative superoxide anion formation value are proposed.