Pharmaceuticals degradation pathways

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. 

Stress testing is used to help identify degradation pathways under the influence of accelerated heat, light, and RH conditions in the presence or absence of air or oxygen. Such stability testing protocols represent an important aspect of a pharmaceutical ingredient process validation program. 

The degradation pathways of some organic molecules of pharmaceutical interest help illustrate the oxidative behavior of selected organic functional groups. This is not an exhaustive review, but only shows some significant examples. 

While this is a very positive boundary condition for the development of low-dose formulations, the major drawback of the low-dose formulation range is, as mentioned earlier, the potential exacerbation of chemical instability of active pharmaceutical ingredients. Thus, stabilization techniques are of high interest to the formulator dealing with this formulation space. Specifically, stabilizers from various classes of antioxidants have been applied.23,24 It is obvious that the specific knowledge of potential and actual degradation pathways of the drug will be crucial for the development of stable formulations. 

There are four major degradation pathways that an analytical chemists must focus on for pharmaceutical analysis thermolytic (heat), hydrolytic (water), oxidative (oxygen, light, peroxide), and photolytic (UV and Vis light). 

The key to the strategy outlined above is to have well-designed stress testing studies that form all potential degradation products. Thorough stress testing studies need to evaluate the four main degradation pathways of pharmaceuticals (1) hydrolytic, (2) thermolytic, (3) photolytic, and (4) oxidative. 

As mentioned previously, oxidative degradation pathways can be complex, and it is useful to consider the chemistry of oxidative degradation. The oxidative degradation of pharmaceuticals has been discussed in the literature,23-27 and we assert that there are three major pathways, (1) autoxidation or radical-mediated oxidation, (2) peroxide-mediated, and (3) photochemically induced (see Table 5). Traditionally, dilute aqueous peroxide solutions have been used for oxidative stress testing of pharmaceuticals. Landmark papers by Boccardi23 24 in 1992 and 1994 identified autoxidation as the major oxidative degradation pathway for pharmaceuticals. Boccardi showed that the use of radical initiators such as... 

Photodegradation of pharmaceuticals has been known for decades. A complication encountered when studying photodegradation reactions is that there are many degradation pathways that each have the potential to yield different products. When oxidizers are present, photodegradation can accompany oxidation. 

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