Stress testing acid/base

Drug substance stability is also addressed in analytical methods development validation studies that require a demonstration of selectivity as part of specificity testing. These results are included in CMC submissions in support of the analytical methods. In this testing, drug substance is commonly stressed with acid, base, oxidation, air, heat, light and other conditions to give rise to products that can be separated from the parent compound. 

Similar to accelerated studies, stress tests give a general picture of the chemical stability and degradation pathways under exaggerated conditions, such as under extreme pH conditions (acids and bases), heat, oxidative or reductive conditions, hydrolysis, and light irradiation (light irradiation tests at not less than 1.2 million lux hours are formalized as described in ICH QIB). These mostly non-formalized stress tests are only evaluated over a short term, e.g., 1 month. 

As these examples illustrate, historically there has been tremendous variation in the conditions employed in acid/base and oxidative stress testing studies. There has also been tremendous variation in defining the appropriate endpoint of the stress testing studies, i.e., what length of time (and temperature) or amount of degradation is sufficient to end the stress exposure. 

B. Solution Acid/Base Stress-Testing Results... 

At least two systems can be cited as catalysts of peroxide oxidation the first are the iron (III) porphyrins (44) and the second are the Gif reagents (45,46), based on iron salt catalysis in a pyridine/acetic acid solvent with peroxide reagents and other oxidants. The author s opinion is that more than systems for stress testing these are tools useful for the synthesis of impurities, especially epoxides. From another point of view, they are often considered as potential biomimetic systems, predicting drug metabolism. Metabolites are sometimes also degradation impurities, but this is not a general rule, because enzymes and free radicals have different reactivity an example is the metabolic synthesis of arene oxides that never can be obtained by radical oxidation. 

At what concentration of the parent drug should acid/base aqueous stress-testing studies be carried out ... 

Acid/base stress testing is performed to force the degradation of a drug substance to its primary degradation products by exposure to acidic and basic conditions over time. Functional groups likely to introduce acid/base hydrolysis are amides (lactams), esters (lactones), carbamates, imides, imines, alcohols (epimerization for chiral centers), and aryl amines. 

The most popular method involves 2-thiobarbituric acid (TBA) two molecules of 2-thiobarbituric acid are condensed with malonaldehyde. The emergent chromogen — the two tautomeric structures of the red TBA-malonaldehyde adduct — is determined at 532 nm, and also often at 450 nm, to determine aUcenals and aUcanals, respectively. The qualitative Kreis test was based on a similar principle it involved detection of the epihydrine aldehyde — a tautomeric malondialdehyde — in a color reaction with resorcine or phloroglucinol. The popularity of the TBA test stems from a correlation between the results and sensory evaluations. Paradoxically, this is related to the most important drawback of the TBA technique — its lack of specificity. In addition to the reaction with malonaldehyde, TBA forms compounds of identical color with other aldehydes and ketones, products of aldehyde interaction with nitrogen compounds, and also with saccharides, ascorbic acid, creatine, creatinine, trimethylamine oxide, trimethylamine, proteins, and amino acids. For this reason, the TBA test may even be treated as a proteolysis indicator (Kolakowska and Deutry, 1983). Recently, TBA-reactive substances (TEARS) were introduced, primarily to stress that the reaction involves hydroperoxides in addition to aldehydes. Due to the nonspecificity of the TEARS test, its results reflect the rancidity of food better than other conventional methods, especially off-flavor, which is caused by volatiles from lipids as well as being affected by products of lipids interaction with nitrogenous compounds. 

A tentative model has been proposed to relate the interfacial shear strength at the fibre-matrix interface, measured by a fragmentation test on single fibre composites, to the level of adhesion between both materials. This last quantity has been estimated from the surface properties of both the fibre and the matrix and was defined as the sum of dispersive and acid-base interactions. This new model clearly indicates that the micromechanical properties of a composites are mainly determined by the level of physical interactions established at the fibre-matrix interface and, in particular, by electron acceptor-donor interactions. Moreover, to a first approximation, our model is able to explain the stress transfer phenomenon through interfacial layers, such as crystalline interphases in semi-crystalline matrices and interphases of reduced mobility in elastomeric matrices. An estimation of the elastic moduli of these interphases can also be proposed. Furthermore, recent work [21] has shown that the level of interfacial adhesion plays a major role on the final performances (tensile, transverse and compressive strengths and strains) of unidirectional carbon fibre-PEEK composites. 

Smiechowski and Lvovich monitored the levels of acidity and basicity in industrial lubricant. The sensor was based on electrochemical impedance methodology. An iridium oxide potentiometric sensor was developed in both a conventional and MEMS configuration. Tests of the sensors in diesel lubricant showed good correlation between TAN, TEN, and the voltage output of each sensor [7]. Widera et al. used a potentiometric iridium oxide electrode as an indicating electrode with a silver/silver chloride reference electrode for the off-line monitoring of fuel acidity. The data showed that the iridium oxide sensor responds to compounds present in fuel that have acid-base character and it is possible to determine the acidity of different fuels and discriminate between unstressed and thermally stressed fuels. Experimental results indicated the ability to correlate the response of the iridium oxide sensor with the total acid numbers of different fuels [20]. 

Similar to the PLA and/or PCL HMA, the natural polymer based HMA can also be applied in packaging. Saara Inkinen et al. [81] discussed the stability of blends of a lactic acid-based hot melt adhesive (LHM), oxidized potato starch (dried or nondried) and polyethylene glycol (PEG). Table 6.4 shows the stress and strain at maximum load values of the samples, and Figs. 6.12, 6.13 and 6.14 are several test results. The test results suggest that the HMA can meet the requirements for packaging. Blumenthal et al. [95] successhilly prepared a... 

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