Hydrolysis, drug stability

Jn drug stability studies, the rates of hydrolysis of indomethacin (Sigma-Chem.) were considerably slower in Pluronic F 127 (BASF) gels than in buffer alone. The degradation of indomethacin followed 1st order kinetics, with linear plots of the 1st order rate constant vs. pH in both Pluronic and aqueous solutions, allowing prediction of the time required for degradation of indomethacin."... 

Assessment of drug stability towards hydrolysis and radical-induced decomposition is an important preformulation exercise. Given the relative complexity of many modern pharmaceuticals, unexpected results from such studies are not uncommon, as illustrated by the following example. The antibiotic frenolicin-B, 1, was heated with AIBN in methanol in the presence of air for two days. This gave a number of "uncharacterizable materials" together with one major product which was shown to be the racemic pyranonaphthoquinone 2. 

Stewart PJ, Tucker IG. Prediction of drug stability. Part 2. Hydrolysis. Aust J Hosp Pharm 1985 15(1) 11-16. 

Enhanced drug stability (protection against oxidation, photodegradation, and hydrolysis in lipophilic systems). 

Drug stability studies may require the use of zero-, first-, or second-order reaction models. Reaction rates may be measured as a function of pH and buffer concentrations to determine the influence of various catalysis possibilities. For example, the hydrolysis of a compound may be pseudo first-order, as shown in Eq. (7) ... 

The control of drug stability by modifying chemical structure using appropriate substituents has been suggested for dmgs for which such a modification does not reduce therapeutic efficacy. The Hammett linear free energy relationship for the effect of substituents on the rates of aromatic side-chain reactions, such as the hydrolysis of esters, is given by... 

Reprinted with permission from Prediction of drug stability-Part 2 Hydrolysis, Hosp. Pharm., 1985, Vol. 15, pages 11-16. by P. J. Stewart and 1. G. Tucker, in Aust J. 

Stewart, P. J., and I. G. Tucker. 1985. Prediction of drug stability—Part 2 Hydrolysis. Aust. J. Ilosp. Pharm. 15 11-16. 

The common reaction mechanisms of chemical degradation of pharmaceutical compounds include hydrolysis, oxidation, isomerization/epimerization, decarboxylation, rearrangement, dimerization/polymerization, photolysis, and reactions with excipients and salt forms. Examples are shown in Table 7.6 Interested readers should consult reference books on drug stability for more information on degradation pathways [13, 22]. 

In these systems, CyDs can improve the drug stability (against light or hydrolysis), and enhance the encapsulation rate of poorly water-soluble drugs. 

Limitations on volnme of device only for highly active compounds stricter reqnirements to drug stability (absence of hydrolysis)... 

The most frequently encountered hydrolysis reaction in drug instability is that of the ester, but curtain esters can be stable for many years when properly formulated. Substituents can have a dramatic effect on reaction rates. For example, the tert-butyl ester of acetic acid is about 120 times more stable than the methyl ester, which, in turn, is approximately 60 times more stable than the vinyl analog [16]. Structure-reactivity relationships are dealt with in the discipline of physical organic chemistry. Substituent groups may exert electronic (inductive and resonance), steric, and/or hydrogen-bonding effects that can drastically affect the stability of compounds. A detailed treatment of substituent effects can be found in a review by Hansch et al. [17] and in the classical reference text by Hammett [18]. 

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