Degradation formation

A major consequence of using regulatory limits based on degradant formation, rather than absolute change of the API level in the drug product, is that it necessitates the application and routine use of very sensitive analytical techniques [ 10]. In addition, the need to resolve both structurally similar, as well as structurally diverse degradants of the API, mandates the use of analytical separation techniques, for example, HPLC, CE, often coupled with highly sensitive detection modes, for example, ultraviolet (UV) spectroscopy, fluorescence (F) spectroscopy, electrochemical detection (EC), mass spectroscopy (MS), tandem mass spectroscopy (MS-MS) and so forth. 

HOFMANN DEGRADATION. Formation of an olefin and a tertiary amine hy pyrolysis of a quaternary ammonium hydroxide useful for the preparation of some cyclic olefins and for opening nitrogen-containing ring compounds. 

WEERMAN DEGRADATION. Formation of an aldose with one less carbon atom from and aklonic acid by a Hoffmann-type rearrangement of the corresponding amid. This is a general reaction of a-hydroxycarboxylic acids. 

Several experiments were conducted to study the influence of feed flux through the electromembrane reactor. The fluxes were varied in the region of 50-200 L m h and the variation in the flow rate of the feed solution through the electromembrane reactor had a significant effect on the phenol degradation, formation of intermediates, and COD removal. The best results were achieved at fluxes of 150 20 L m h for phenol degradation (complete degradation) and formation of aromatic intermediates (p-benzoquinone <20.0 mg L ). COD reduction of 60% was achieved under these conditions. 

Fig. 3.30 Thiamine degradation formation of aroma compounds (adapted from [71])...

According to Carlin et al. (1986), the exact mechanism of oxazole formation is not known, despite the previous schemes proposed by Vitzthum and Werkhoff (1974a,b) and by Ohloff and Flament (1978). Formation pathways were proposed by Baltes and Bochmann (1987d) and Mottram (1991). For Vitzthum and Werkhoff (1974b), one pathway could be the decarboxylation of serine or threonine into ethanolamine or methylethanolamine condensation with an aldehydic compound into an oxazolidine, then oxidation into an oxazole unsubstituted or methylated on position 5 and bearing an alkyl or an acyl radical on position 2. Another pathway could be the condensation of amino acids with a-dicarbonyl compounds, followed by a Strecker degradation, formation of an a-amino ketone which, after acylation... 

RCOCF3 — RCN. The degradative formation of nitriles (4 examples, 76-92%) involves successive treatment of trifluoromethyl ketones with MeAl(Cl)NH2 and f-BuOK. Conjugated nitriles can be prepared in this manner. 

As can be seen in the graph, the curvatures associated with first or second order processes do not have a significant impact on the functional form of the degradant formation with time curve compared to a zero-order function, up to at least 10% conversion. It is therefore reasonable to assume that all degradation processes follow a zero-order curve shape with respect to the shelf-life. This allows the rate constant for a degradation process to be determined using the initial slope of the degradant versus time plot. 

To carry out such an isoconversion study, one needs to know the amount of degradant formation as a function of temperature. Such studies will fall into two situations when one has no knowledge of the acmal stability of the sample, and when one has preliminary information. When no information is available, one can use average behavior. This approach is discussed further in conjunction with the combination of relative humidity effects (Section 6.4.3). If preliminary data are available (e.g., for repeats of formulations), the times ean be adjusted at any accelerated conditions to meet the isoconversion paradigm. For example, if a degradant has a specification limit of 0.50, and 0.25% was found at one week at 60°C (with... 

The more common effect of water activity (ERH) for shelf-life considerations is its effect on the API chemieal stability. This effect is mostly due to the impact of moisture on the mobility of species in the solid state. At a given temperature, the effect of the ERH on the rate constant for either degradant formation or API loss (k) is shown in Equation (6.11) (where B and C are constants) ... 

Figure 8.20 Probable pathways for nonradical thermal degradation formation oflactide and cyclic oligomers by intramolecular transesterification reactions (a, b), intermolecular transesterification reaction (c), hydrolytic degradation reaction (d), and cis-elimination reaction (e) [2721. (Reproduced with permission from ref [272]. Copyright Elsevier, 2003.)...

SCHEME 5.5 Synthesis of para-phenylene ladder polymers after Scherf and Mullen (MCP 1991) [64] (R, and R2 are typically n-alkyls with Cg-Cio, R3 is preferably a methyl group resulting in MeLPPP, R3 = H leads to LPPP ladder polymers which are sensitive to oxidative degradation-formation of keto defects [ 16,17,70,71 ]). 

Various compounding operations such as grafting, functionalisation, controlled degradation, formation of copolymerisation and polymerisation have been carried out in the twin-screw extruder [20]. 

The use of ultrasound for the destruction of dilute aqueous solutions of low molecular weight organic compounds (alcohols, ketones and aldehydes) at ambient temperature has been reported. An aqueous flow cell system was assembled to measure the oxidatively degraded formate and acetate products by on-line ion chromatography [48]. 

The activity of either isoenzyme, naturally, depends, to a great degree, upon which variant of a given multienzyme system will be realized. Since in some cases some of the enzyme molecules cannot associate, this could occur, for instance, as a result of a lack of conformational accordance. Thus, the complex effect of differences in translation rate and also post-translational events (assembly with membranes or inhibitors, degradation, formation of multienzyme complexes, etc.) is an important factor in the realization of differential expression of biochemical traits in the phenotype. 

Fig. 7. X-ray diffraction spectra of PLA50 after 0 and 27 weeks in vitro degradation formation of stereocomplex (Source from Ref 116)4...

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