Drugs, decomposition reactions

Figure 6-3. Distriburion of Arrhenius activation energies for 147 drug decomposition reactions.

A collection of pH-rate profiles for drug decomposition reactions has been published. ... 

A histogram showing the distribution of the activation energies for 147 drug decomposition reactions. The activation energies on the horizontal axis are divided into increments of lOkJmol". ... 

The magnitudes of the thermodynamic parameters, A77 and AS sometimes provide evidence supporting proposed mechanisms of drug decomposition. The enthalpy of activation is a measure of the energy barrier that must be overcome by the reacting molecules before a reaction can occur. As can be seen from Eq. (28), its numerical value is less than the Arrhenius... 

TG is a powerful adjunct to DSC studies, and are routinely obtained during evaluations of the thermal behavior of a drug substance or excipient component of a formulation. Since TG analysis is restricted to studies involving either a gain or a loss in sample mass (such as desolvation decomposition reactions), it can be used to clearly distinguish thermal events not involving loss of mass (such as phase transitions). 

Another reason to avoid highly acidic conditions for QC purposes is that many drugs show poorer stability in this range than at near neutral pH, due to acid catalysis of the decomposition reaction (e.g., acid-catalyzed hydrolysis). An exception might be compounds that undergo oxidation these compounds are usually stable at acid pH but start to decompose more quickly in the near neutral to basic region. 

One complication which arises when we are carrying out stability testing of suspensions is the changes in the solubility of the suspended drug with increase in temperature. With suspensions, the concentration of the drug in solution usually remains constant because, as the decomposition reaction proceeds, more of the dmg dissolves to keep the solution saturated. As we have seen, this situation usually leads to zero-order release kinetics. If the acmal decomposition of dissolved dmg is first-order, then we can express the decrease of concentration, c, with time, t, as... 

Drugs sometimes have quite complicated chemical structures and are, by definition, biologically active compounds. It should not, therefore, come as a surprise that these reactive molecules undergo chemical reactions that result in their decomposition and deterioration, and that these processes begin as soon as the drug is synthesised or the medicine is formulated. Decomposition reactions of this type lead to, at best, drugs and medicines that are less active than intended (i.e. of low efficacy)-, in the worst-case scenario, decomposition can lead to drugs that are actually toxic to the patient. This is clearly bad news to all except lawyers, so the processes of decomposition and deterioration must be understood in order to minimise the risk to patients. 

Barbiturates, hydantoins, and imides contain functional groups related to amides but tend to be more reactive. Barbituric acids such as barbital, phenobarbital, amobarbital, and metharbital undergo ring-opening hydrolysis, as shown in Scheme 15.80-81 Decomposition products formed from these drug substances are susceptible to further decomposition reactions such as decarboxylation. The hydrolysis rates of these substances depend on the substituents Ri, R2, and R3. For some allylbarbituric acids, the effects of these substituents on hydrolysis rates can be explained in terms of Hammett s o value.82... 

Addition of O2 to the Fe(II)—BLM complex produces an ESR-silent adduct which rapidly breaks down but is stabilized in the presence of DNA the Fe(II)BLM—O2 reaction thus results in considerable drug decomposition, unless DNA is present [64]. Spectral and kinetic studies distinguished three events in the Fe(II)—O2 reaction (a) formation of the short-lived, ESR silent species with ti/2 == 6 s at 2 C (b) the decay of this species to an activated complex, capable of cleaving DNA and (c) a slower decay of this second species to Fe(III)BLM, t 2 = 60 s at 2°C [70]. Upon addition of Fe(II) to a bleomycin—DNA mixture in air, a long-lived hn 45 min), ESR silent species is formed [71]. The formation of this species consumes one mole of oxygen and the complex eventually decomposes to Fe(III)BLM [71]. The initial Fe(II)02BLM species was shown initially to yield a 1 1 mixture of activated BLM and Fe(III)BLM, the reaction perhaps occurring by reduction of Fe(II)02—BLM by Fe(II)— BLM [72] ... 

In this type of reaction the active drug undergoes decomposition following reaction with the solvent present. Usually the solvent is water, but sometimes the reaction may involve pharmaceutical cosolvents such as ethyl alcohol or polyethylene glycol. These solvents can act as nucleophiles, attacking the electropositive centers in drug molecules. The most common solvolysis reactions encountered in pharmaceuticals are those involving labile carbonyl compounds such as esters, lactones, and lactams (Table 1). 

The stability of suspensions, emulsions, creams, and ointments is dealt with in other chapters. The unique characteristics of solid-state decomposition processes have been described in reviews by D. C. Monkhouse [79,80] and in the monograph on drug stability by J. T. Carstensen [81]. Baitalow et al. have applied an unconventional approach to the kinetic analysis of solid-state reactions [82], The recently published monograph on solid-state chemistry of drugs also treats this topic in great detail [83],... 

A rational way to develop approaches that will increase the stability of fast-degrading drugs in pharmaceutical dosage forms is thorough study of the factors that can affect such stability. In this section, the factors that can affect decomposition rates are discussed it will be seen that under certain conditions of pH, solvent, presence of additives, and so on, the stability of a drug may be drastically affected. Equations that may allow prediction of these effects on reaction rates are discussed. 

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