Impurities/degradants approach

The process of characterization of impurities described in this chapter uses a designed approach for the isolation of unknown impurities and degradants in pharmaceutical drug substances. This approach focuses on efficiency, so that the success of data collection is maximized. The isolation of pure material is crucial when trying to identify the structure of an unknown impurity/degradant. Once the unknown has been isolated, it can be submitted for structure elucidation using mass spectrometry and NMR spectroscopy. 

As the approach detailed above can result in the generation of numerous samples to be screened, it is frequently possible to combine some solutions into a set of selectivity solutions for some method development activities. However, there is also merit in analyzing the individual solutions separately to obtain information on degradation pathways and DS impurities that can facilitate the understanding of drug chemistry. 

Where the specific impnrity is unavailable or is too costly, the use of composite or degraded samples is possible. This approach involves the nse of a dirty sample of a drug substance or the creation of a mixture of impurities through the in situ forced degradation method. Both of these approaches are best nsed for qualitative uses. In each of these mixtures, the impurities are present in unknown quantities. The real benefit of this type of impnrity standard is the low cost and the ability to unequivocally identify the peak loci of the impurities. When these mixtures are used in conjunction with a compendial standard and a well-developed set of relative response factors the resnlts will meet most analytical needs. 

In reference 68, a different approach was used to verify the robustness of a CE separation of ibuprofen, codeine phosphate, degradation products, and impurities in a drug product (tablet). Small variations around the optimal conditions obtained during method optimization were introduced and the results were predicted from the response model. The variations in the factor levels during the robustness evaluation were smaller than those evaluated during method optimization. Since both migration times and resolutions were acceptably predicted, the method was considered robust with respect to the small changes. The examined factors... 

Contemporary approaches to chemical stmcture elucidation are now heavily reliant on mass spectrometry and NMR spectroscopy. Since the advent of 2D NMR methods, in many laboratories vibrational data are either not acquired or not considered, which represents a paradigm shift from approaches to chemical structure elucidation as recently as 20 years ago when vibrational spectroscopic data were an integral part of the structure elucidation data assembled to characterize an unknown structure. In contrast, we have found it useful to continue to acquire and utilize vibrational data for the characterization of impurities and degradation products [64,65]. 

Developing an isolation approach is an activity that is frequently overlooked or addressed as an afterthought. However, solubility and stability data may dictate the development of a chromatographic method that requires the elaboration of the isolation, that is, it is more complicated than a simple evaporation of the mobile phase. The development of the chromatographic process should be linked to and interactively codeveloped with the isolation. Ideally, the isolated impurity sample should not contain other compounds or artifacts, such as solvents, mobile-phase additives or particulate matter from the preparative chromatography, as they may interfere with the structure elucidation effort or adversely affect the stability of the impurity during the isolation process. Therefore, it is preferable to avoid or minimize the use of mobile-phase additives. However, should this prove to be impossible, the additive used should be easy to remove. The judicious choice of mobile phase in the HPLC process increases the ability to recover the compound of interest without or with minimum degradation. The most common... 

With the proliferation of mass spectrometers in dmg metabolism came a vast amount of data to be processed and understood. In particular, techniques and tools for identification of unknown compounds such as metabolites, degradation products, or impurities have seen continual improvement in recent years, especially with respect to data obtained under high-resolution (and presumed high-mass-accuracy) conditions. A few possible approaches are summarized here. 

Similar to previous structure identification methods described for metabolites, impurities, and degradants, the knowledge of the physiological or chemical process, in this case the adhesive synthesis process, helped in the rapid interpretation of the MS/MS spectra of the unknown components. No user input about the sample composition is needed for the data-dependent analysis scheme thus, these experiments are simple and rapid to perform. The result is a fairly routine approach to structural screening of unknown mixtures during the manufacturing stage. 

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