Chemical Stability

Chemical stability is an important physicochemical property impacting bioavail-ability because in order for any compound to be bioavailable, it needs to be stable before it is absorbed in the gastric and intestinal fluid. The compound also needs to be stable for the shelf-life of the products and so the performance of the products including bioavailability will not be compromised.

For ionizable drugs, stability as a function of pH, pH-stability profile, is an important property for understanding the impact of stability on absorption and for developing stable formulations. For poorly soluble compounds, studying the stability as a function of pH is complicated by the solubility limitation in certain pH regions. Solubilizing agents may have to be used so that enough compounds can be in solution for stability studies. Acidic instability of many poorly soluble compounds may not present too big of an issue since many of them are not soluble in acidic media such as gastric fluids. However, it is still important to know if the compound can undergo acidic degradation or not since certain solubilization techniques may have to be used for improving bioavailability of these compounds, for example, for higher doses required for toxicological studies. Many of these solubilization techniques such as lipid-based systems can improve the compound's solubility in gastric fluid.

The main chemical reactions that lead to degradation of the administered drug in the GI include hydrolysis, oxidations, and reductions. They are often catalyzed by the pH conditions and/or enzymes in the small intestine, or the bacterial flora of the lower intestinal tract.

Some common classes of drugs that are subject to hydrolysis include ester, thiol ester, amide, sulfonamide, imide, lactam, lactone, and halogenated aliphatic (Stewart and Tucker, 1985). For compounds that desire modified or controlled release profiles, colonic stability is an important factor to consider. Some examples of drugs that are biotransformed by the large intestinal flora include atropine, digoxin, indomethacin, phenacetin, and sulfinpyrazone (Macheras et al., 1995).

Studies to investigate the effect of stability on absorption should be rather straightforward. After all, the compound only needs to be stable for at most 24 h in the gastric and intestinal fluid at 37 °C. Methods using high throughput with up to 96-well format equipped with robots have been reported (Kerns, 2001).

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