Azobisisobutyronitrile loaded on mesoporous silica particles: A new stressor for solid-state oxidative forced degradation studies.

A new approach for testing drug sensitivity to autooxidative degradation in the solid state is demonstrated in this work. A novel solid-state form of stressing agent for autooxidation has been proposed, based on azobisisobutyronitrile loaded into mesoporous silica carrier particles. The new solid-state form of the stressing agent was applied in degradation studies of two active pharmaceutical ingredients: bisoprolol and abiraterone acetate. The effectiveness and predictivity of the method were evaluated by comparing impurity profiles with those obtained by traditional stability testing of commercial tablets containing the investigated APIs. The results obtained by the new solid-state stressor were also compared with those obtained by an existing method for testing peroxide oxidative degradation in the solid state using a complex of polyvinylpyrrolidone with hydrogen peroxide. It was found that the new silica particle-based stressor was able to effectively predict which impurities could be formed by autooxidation in tablets and that this new approach is complementary to methods for testing peroxide oxidative degradation known from the literature.

Pharmaceutical Product Characterization and Manufacturability of Surfactant-Enriched Oil Marbles with Abiraterone Acetate.

The present study investigates the physicochemical properties and stability of a novel lipid-based formulation-surfactant-enriched oil marbles containing abiraterone acetate. While the biopharmaceutical performance of this formulation has been reported recently, this study aims to fill the gap between a promising in vivo performance and industrial applicability. A series of techniques were employed to assess the solid-state characteristics of oil marble cores along with their physicochemical properties upon stability testing. The chemical stability of abiraterone acetate in the formulation was also investigated. The core of the formulation was found to be stable both physically and chemically over 12 months of storage. The in vitro performance of stressed samples was evaluated using a dissolution experiment. The formulation has successfully self-emulsified upon incubation in bio-relevant media, resulting in a fast and complete API release. An important issue connected with the excipient used as a covering material of oil marbles has been identified. The seemingly insignificant water sorption caused agglomeration of the oil marbles and consequently compromised the dissolution rate in some of the stressed samples. Replacing HPMC with lactose as a covering material resulted in more favorable properties upon storage. Overall, it has been shown that oil marbles are an industrially applicable concept of the solidified lipid-based formulation.

Alternative method for canagliflozin oxidation analysis using an electrochemical flow cell - Comparative study.

This paper highlights the potential of electrochemical flow cells for oxidative-stress testing of active pharmaceutical ingredients using canagliflozin as a model substance. Based on design of experiments, we developed our method through a reduced combinatorial design, optimizing the following independent variables: cell size, electrolyte flow rate, electrolyte concentration, and electrolyte pH. Using ammonium phosphate buffer with methanol in a 50/50 vol ratio as a working electrolyte, we electrochemically oxidized samples and analyzed them by high-performance liquid chromatography, considering the following dependent variables: peak area of each impurity, peak area of canagliflozin, and the percentage of the corresponding peak areas. Our results showed that the most significant independent variables were electrolyte pH and flow rate. By data optimization, we determined the most suitable conditions for electrochemical oxidation of canagliflozin, namely 50 µm cell size, 300 mM electrolyte concentration, 0.1 mL/h electrolyte flow rate, and electrolyte pH = 4. The repeatability of the method, expressed as the relative standard deviation of the canagliflozin peak area, measured in ten separately oxidized samples, was 1.64%. For comparison purposes, we performed a degradation experiment using hydrogen peroxide, identifying five identical impurities in both cases, as confirmed by mass spectrometry. The degradation products formed when using the chemical method after 1, 3, and 7 days totaled 0.09%, 0.75%, and 3.75%, respectively, and the degradation products formed when using the electrochemical method after 3 h totaled 3.11%. Oxidation with hydrogen peroxide required 7 days, whereas electrochemical oxidation was completed in 3 h. Overall, the electrochemical method significantly saves time and reduces the consumption of active ingredients and solvents thanks to the miniaturized size of the electrochemical cell, thereby minimizing the costs of forced degradation studies.

Comparison of static and dynamic mode in the electrochemical oxidation of fesoterodine with the use of experimental design approach.

Electrochemical conversion of fesoterodine to one of its oxidation products was evaluated with the application of the wall-jet flow cell. A traditional, "static" mode of electrolysis was compared with the "dynamic" mode of cell performance. For statistical assessment of the data, experiments were planned and performed with the application of design of experiments approach, namely Taguchi L18 design. After screening phase, the experimental settings were broadened or adjusted according to the results and optimization was performed. All of the samples were electrolysed with the use of chronoamperometric method in a three electrode system. The electrolysed samples were analysed using UHPLC-PDA-QDA method. The chromatographic run was performed in gradient elution with the application of C8 column. The response was expressed as % area of the main peak found with the PDA detection method whereas QDA detector was used in positive SIM mode for structural confirmation. All data obtained for both screening and optimization were treated together and linear models were adjusted. The use of large-surface glassy carbon electrode along with pH~7 were found to be the most significant factors influencing electrochemical oxidation of fesoterodine in both modes. The major differences were identified in terms of voltage applied to the electrodes which yielded the highest amounts of oxidation product. Evolution of electrochemical methods may serve as complementary technique in stress degradation studies in pharmaceutical industry.

Gas chromatographic-mass spectrometric identification of 16alpha-hydroxy-dehydroepiandrosterone in human seminal plasma.

16alpha-hydroxydehydroepiandrosterone was for the first time detected in human seminal plasma by using a combination of extraction, solvent partition, HPLC separation and final quantification by GC-MS as pentafluorobenzyloxime trimethylsilyl ether derivative in SIM mode. Three effective mass fragments m/z 266, 356 and 446 were followed. The concentration of 16alpha-hydroxydehydroepiandrosterone amounted in average 1.06 nmol/l, being lower but close to- the product of concurrent DHEA metabolism, 7-hydroxydehydroepiandrosterone isomers, found recently in seminal plasma.