Drug substances degradation

Category II methods are intended to determine impurities in bulk drug substance, degradation products in finished drug product, or for verification of cleaning processes. These methods are further subdivided into quantitative tests and limit tests. 

Trace metal impurities in excipients can lead to oxidative catalysis resulting in drug substance degradation.14 The metals most commonly... 

Discovery of NCE and high-throughput screening Solid-state analysis of drug substances Degradation and impurity analysis of drug substances Preformulation analysis... 

Drug Substance. Methods should separate the API and the synthetic process impurities and drug substance degradation products observed at significant levels (see Chapter 4) using the early-phase methods. 

The guideline on impurities in new medicinal products parallels the drug substance text, but the designated thresholds concern only degradation products. The thresholds should be applied to the product at the end of its shelf-life, as that is when the greatest level of degradation is expected to have occurred. 

CREAM.dat A batch of cream containing two drug substances was put on stability and tested for at f = 0, 3, 7, and 24 months. Active component 1 remains stable, while AC2 degrades so fast that a shelf-life of only 26 months can be demonstrated for SL = 90%. Use with SHELFLIFE. 

The comprehensive profiling of drug substances and pharmaceutical excipients as to their physical and analytical characteristics remains at the core of pharmaceutical development. As a result, the compilation and publication of comprehensive summaries of physical and chemical data, analytical methods, routes of compound preparation, degradation pathways, uses and applications, etc., has always been a vital function to both academia and industry. 

Modern spectroscopy plays an important role in pharmaceutical analysis. Historically, spectroscopic techniques such as infrared (IR), nuclear magnetic resonance (NMR), and mass spectrometry (MS) were used primarily for characterization of drug substances and structure elucidation of synthetic impurities and degradation products. Because of the limitation in specificity (spectral and chemical interference) and sensitivity, spectroscopy alone has assumed a much less important role than chromatographic techniques in quantitative analytical applications. However, spectroscopy offers the significant advantages of simple sample preparation and expeditious operation. 

Except for bulk drug substances, samples can rarely be analyzed directly following simple preparation steps. In many cases, an active ingredient is found in a formulated form or in a physiological fluid or tissue. Likewise, interferences associated with the matrix and the presence of possible degradation products, metabolites, and other closely related compounds mean the target analyte is often highly diluted. Also, an analyte may be difficult to detect. Effective sample preparation steps serve up to three broad purposes (1) eliminate and/or minimize possible interferences, (2) concentrate the sample, and (3) render the analyte of interest into a more easily detectable form. 

Fig. 4.23. Cyclic DSC studies of the drug substance in Fig. 22 proving that the compound does not degrade at temperatures near or below 150°C.

Fig. 13.28. Drug substance and degradant respond differently to derivatizing agents.

When a TLC method is validated, two of the tests that are done are (1) stability on plate and (2) stability in solution of the drug substance to determine how quickly a sample must be applied to the HPTLC plate and developed before degradation occurs, if it occurs at all. For example, five vials are prepared by placing 25 mg of drug substance in each vial, and labeling them as time 0,1,2, 3, and 4 h. The experiment begins... 

The five vials on the bench top are also then applied to a fresh HPTLC plate to examine any degradation of the drug substance in solution. In this case, the plates looked very similar, indicating similar degradation in solution within 1 hour also. 

Tablet excipient interactions are occasionally observed when evaluating a drug product for purity. Since there are many excipients in a typical pharmaceutical tablet, known bands need to be identified to make it easier to evaluate for degradation products. Unfortunately, occasionally an inert excipient may react with a derivatizing agent used in TLC making this entity appear as a band that now needs to be identified. In Fig. 13.33, a placebo tablet, an extracted tablet, a handmade tablet blend of all components, and the drug substance standard are all applied to the same HPTLC plate and developed. These results alert the analyst to any excipients that may interfere in the evaluation of the tablet for purity. In this case, the only bands observed in the tablet blend and extracted tablet are the same bands seen in the tablet blend.

If an excipient had been observed, it would need to be identified. In Fig. 13.34, the drug substance standard is applied on lane 1 next to the extracted tablet. The remaining lanes labeled 2-12 are individual excipients in this particular tablet. Only one excipient, number 6, appears and it does in fact have the same R value as the band observed in the tablet. This confirmatory test is commonly used to identify interfering excipients. Now this band can be labeled appropriately, rather than mistakenly labeled as a degradant or impurity. 

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