Degradation prediction, drug substances

In conclusion, on the basis of evaluation of the literature and kinetic considerations in conjunction with our stress-testing experience over the last 15 years, temperatures of up to 70°C (at high and low humidities) should provide a rapid, reasonably predictive assessment of the solid-state degradation pathways and relative stabilities of most drug substances at... 

As a characterization technique, UV absorption can be used as an important piece of confirmatory evidence for a proposed structure. Simple rules for the prediction of absorption maxima for structures can be found in introductory texts.19 More advanced techniques for the uses of HPLC-DAD have been previously presented.20 Often, HPLC-DAD data are used to show that an impurity or degradant is similar (electronically) to the drug substance by virtue of the same chromophore.21... 

Examination of the synthetic route used in production allows for the prediction of potential residual synthetic impurities present in the drug substance. The API structure allows for the postulation of degradation pathways via hydrolytic, oxidative, catalytic, and other mechanisms. Both of these evaluations serve to facilitate the interpretation of (subsequent) identification tests. An examination of the physicochemical properties also allows for the rational establishment of method screening experiments by precluding certain conditions. For example, the use of normal-phase HPLC will be eliminated if the API is a salt or shows limited solubility in nonpolar organic solvents. Similarly, if the API (or suspected related substances) has no significant chromophore above 250 nm, the use of tetrahydrofuran (THE) and other solvents as mobile-phase components is severely limited. For compounds with an ionizable group, variation of pH will have considerable influence on elution behavior and can be exploited to optimize the selectivity of a reversed-phase separation. 

Whereas the stress conditions will usually be more severe than the drug substance will experience under normal conditions, the distribution of degradation products that is obtained can be used to predict the exact degradation... 

Drug substances used as pharmaceuticals have diverse molecular structures and are, therefore, susceptible to many and variable degradation pathways. Possible degradation pathways include hydrolysis, dehydration, isomerization and racemization, elimination, oxidation, photodegradation, and complex interactions with excipients and other drugs. It would be very useful if we could predict the chemical instability of a drug based on its molecular structure. This would help both in the design of stability studies and, at the earliest... 

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