Stability of a compound

Nernst further remarked that the stability of a compound is measured by the quantity which can exist under given conditions, and the previous equations enable one to determine this, at least approximately, with the help of the heats of formation. A compound under given conditions is in general either very stable or very unstable—equilibria in which all the components exist in appreciable concentrations are the exception rather than the rule. A considerable heat of formation usually corresponds with marked stability (cf. HC1, HBr, HI). 

Several kinetic parameters can be measured on different experimental systems to account for the interaction of a compound with CYPs. For example when studying the metabolic stability of a compound, it could be measured in a recombinant CYP system, in human liver microsomes, in hepatocytes and so on. Each system increases in biological complexity. Although in the recombinant CYP system only the cytochrome under consideration is studied, in the case of the human liver microsomes, there is a pool of enzyme present that includes several CYPs, and finally in the hepatocyte cell system, metabolizing enzymes play an important role in the metabolic compound stability. In addition, transport systems are also present that could involve recirculation or other transport phenomena. The more complex the experimental system, the more difficult it is to extract information on the protein/ligand interaction, albeit it is closer to the in vivo real situation and therefore to the mechanism that is actually working in the body. 

In order to assess the stability of a compound, one needs an appropriate method. The development of stability-indicating analytical method, particularly an impurity method, is a chicken and egg type of problem. That is, how does one develop an impurity method to detect degradation products... 

More the enthalpy of formation less will be the stability of a compound. 

Resonance stabilization energy (Sections 1.8 and 3.7) The extra stabilization of a compound because of resonance. 

From (20.12) it follows that the equilibrium mentioned is shifted to the right if K increases and to the left if Kf decreases. It also follows, from Eq. (20.13), that the equilibrium lies on the right (reaction products) for negative values of AG° and to the left (reactants) for positive values of AG°. Hence, the actual value of AG° is a quantitative measure of the stability of a compound, with respect to its elements. 

Infer a relationship between the stability of a compound and bond energy. Then suggest a reason why there are many more carbon-based compounds than silicon-based compounds. 

Stability of biopharmaceutical compounds should also be determined under conditions that mimic their normal usage. For instance, the stability of reconstituted lyophilized products should be assessed with respect to time and temperature and, if applicable, light and mechanical stimuli. Likewise, the stability of a compound included in implantable devices and controlled-release microsphere formulations should be determined over the course of its required use, under conditions which mimic the heat, moisture, light, and enzymatic physiological conditions to which it... 

As discussed already, radiopharmaceuticals are exposed to stability problems, particularly when radiolabeled compounds are involved. Decomposition of labeled compounds by radiolysis depends on the specific activity of the radioactive material, the energy of the emitted radiation, and the half-life of the radionuclide. Particles, such as a and p radiation, are more damaging than y rays, due to their short range and local absorption in matter. The stability of a compound is time dependent on exposure to light, change in temperature, and radiolysis. The longer a compound is exposed to these conditions, the more it will tend to break down. 

Because the allyl radical is electronically symmetrical, it can be drawn in either of trvo resonance forms with the unpaired electron on the left and the double bond on the right or with the unpaired electron on the right and the double bond on the left. Neither structure is correct by itself the true structure of the allyl radical is a resonance hybrid of the two. (You might want to review Sections 2.4-2.6 to brush up on resonance.l. As noted in Section 2.5, the greater the number of resonance forms, the greater the stability of a compound because bonding electrons are attracted to more nuclei.. An allyl radical, with two resonance forms, is therefore more stable than a typical alkyl radical, which has only a single structure. 

Use chemistry knowledge to assess the stability of a compound prior to isolation, and determine if special collection conditions may be necessary. 

For drugs with low solubility, special efforts must be made to bring the concentration into the therapeutically active range. In this section, some of the common methods to increase solubility will be discussed salt versus free form, inclusion compounds, prodrugs, solid form selection, and dissolution rate. It should be noted that efforts to increase solubility also have an influence (often negative) on the stability of a compound. For this reason, the most soluble form is often not the first choice when formulating the drug. 

Chemical Stability Chemical degradation of the drug includes reactions such as hydrolysis, dehydration, oxidation, photochemical degradation, or reaction with excipients. The constant presence of water and oxygen in our environment means that exposure to moisture or oxygen can affect the chemical stability of a compound. Chemical stability is very important, not only because a sufficient amount of the dmg is needed at the time of administration for therapeutic purposes, but also because chemical degradation products may adversely affect the properties of the formulated product and may even be toxic. 

Evaluation of the stability of a compound is more accurate and meaningful if it follows the quantitative change in the degradation products rather than the decrease in the intact compound. For most drugs, the change in concentration (of the intact drug molecule as a result of degradation) is small when a determination is made in a relatively short time period, and the precision of the analytical determination is broad. Thus, the accuracy is not reliable. 

In conclusion, when referring to the stability of a compound one must be precise. Many inorganic compounds can be prepared which are thermodynamically unstable but kinetically stable with respect to decomposition along various routes. In addition, inorganic compounds which react with oxygen or water can often be handled in inert atmospheres, where they can be regarded as perfectly stable. 

There is a profusion of terms used in the literature to refer to the enhanced stability of a compound over that of a hypothetical molecule of... 

Notice that AG° relates to the equilibrium constant of the reaction, whereas AG relates to the rate of the reaction. The thermodynamic stability of a compound is indicated by AG°. If AG° is negative, for example, the product is thermodynamically stable compared with the reactant, and if AG° is positive, the product is thermodynamically unstable compared with the reactant. The kinetic stability of a compound is indicated by AG. If AG for a reaction is large, the compound is kinetically stable because it does not undergo that reaction rapidly. If AG is small, the compound is kinetically unstable—it undergoes the reaction rapidly. Generally, when chemists use the term stability, they are referring to thermodynamic stability. 

The addition of H2 to a reaction is called hydrogenation. The heat of hydrogenation is the heat released in a hydrogenation reaction. The greater the stability of a compound, the lower is its energy and the smaller is its heat of hydrogenation. The more alkyl substituents bonded to the sp carbons of an alkene, the greater is its stability. Hence, carbocations, alkyl radicals, and alkenes are all stabilized by alkyl substituents. Trans alkenes are more stable than cis alkenes because of steric strain. 

When a proton is removed from a carbon adjacent to a carbonyl carbon, two factors combine to increase the stability of the base that is formed. First, the electrons left behind when the proton is removed are delocalized, and electron delocalization increases the stability of a compound (Section 7.6). More important, the electrons are delocalized onto an oxygen, an atom that is better able to accommodate the electrons because it is more electronegative than carbon. 

However, the stability of a compound is related not to enthalpies but to Gibbs energies. This will be dealt with in the next chapter. 

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