Kinetics of drug stability

The routes of decomposition of drugs, and the steps taken to prevent them, were considered in Chapter 8. In this chapter the rates of decomposition will be studied and useful information, such as shelf-life, will be predicted. Calculations of this type are important as there is little merit in producing the latest wonder drug designed to cure all ills only to watch it fall apart on the dispensary shelf as a result of decomposition. 

The underlying principle on which all of the science of kinetics is built is the law of mass action introduced in Chapter 1. This states that the rate of a chemical reaction (i.e. the speed of the reaction or, simply, how fast it is) is proportional to the active masses of the reacting substances. Active mass is a complicated term to measure, but, fortunately, if the solutions in question are dilute, the active mass may be replaced by concentration, which is much easier to handle. If the concentration of a solute is greater than about 0.1 mol LT1, significant interactions arise between the solute molecules or ions. In cases like this, effective and measured concentrations are not the same and use must be made of activity instead of concentration. 

The rate of a chemical reaction is, in a dilute solution, proportional to the concentrations of the various reactants each raised to the power of the number of moles of the reactant in the balanced chemical equation. This sounds too easy, and in fact it is. In practice, the rate of a chemical reaction depends only on a small number of concentration terms, and the sum of the powers to which these concentrations are raised is termed the order of the reaction. This is because chemical reactions occur in a number of steps, or stages (called a mechanism) and the rate of the overall reaction is often governed by the rate of the slowest step (called, not surprisingly, the ratedetermining step). Even if every other stage of a chemical reaction occurs essentially instantaneously, the rate of the reaction as a whole cannot exceed that of the slowest stage. 

For example, if the rate of a chemical reaction depended only on the concentration of compound A, this could be written as 

If the rate of the reaction depended on the concentrations of A and B, or on the concentration of A squared, this could be written as 

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As discussed in Chapter 1 (Sections III and TV), the kinetics of drug degradation has been the topic of numerous books and articles. The Arrhenius relationship is probably the most commonly used expression for evaluating the relationship between rates of reaction and temperature for a given order of reaction (For a more thorough treatment of the Arrhenius equation and prediction of chemical stability, see Ref. 13). If the decomposition of a drug obeys the Arrhenius relationship [i.e., k = A exp(—Ea/RT), where k is the degree of rate constant, A is the pre-exponential factor ... 

Like varying the solvent, varying the salt form also affects other crystal properties including morphology, polymorphs, crystallization kinetics, formulation, drug stability, etc. Therefore, selection of the salt form always involves other considerations in addition to solubility. 

Pawelczyk, E. and Marciniek, B. (1977) Kinetics of drug decomposition. XLVII. Effect of substituents on photochemical stability of perazine derivatives, Pol. J. Pharmacol. Pharm., 29, 143-149. 

Benoit JP, Benita S, Puisieux F, Thies C. Stability and release kinetics of drugs incorporated within microspheres. In Davis SS, Ilium L, McVie JG, Tomlinson E, eds. Microspheres and Drug Therapy Pharmaceutical, Immunological and Medical Aspects. Amsterdam, the Netherlands Elsevier 1984. 

The high proportion of counterionic condensation in PE-dmg aqueous dispersions determines many of the particular properties of these systems such as the effects of addition of electrolytes and non-electrolytes, the kinetic of drug release under different conditions, the raise of compatibihty of low solubility drugs, the improvement of chemical stability and the rheological behavior. 

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],... 

In preformulation one task is to establish the stability of the drug substance in both solid and dissolved state. In the latter case it is important, with small samples of drug substance, to assess (a) the effect of buffer type, (b) the effect of buffer concentration, (c) the effect of pH in a practical range, (d) the effect of temperature, and (e) the kinetic salt effect. 

The past two decades have produced a revival of interest in the synthesis of polyanhydrides for biomedical applications. These materials offer a unique combination of properties that includes hydrolytically labile backbone, hydrophobic bulk, and very flexible chemistry that can be combined with other functional groups to develop polymers with novel physical and chemical properties. This combination of properties leads to erosion kinetics that is primarily surface eroding and offers the potential to stabilize macromolecular drugs and extend release profiles from days to years. The microstructural characteristics and inhomogeneities of multi-component systems offer an additional dimension of drug release kinetics that can be exploited to tailor drug release profiles. 

H. Nogami, M. Horioka, Studies on Decomposition and Stabilization of Drugs in Solution. VI. Chemical Kinetic Studies in Aqueous Solution of Diphenhydramine , J. Pharm. Soc. Jap. (Yakugaku Zasshi) 1961, 81, 79 - 83. 

Varea et al. described a study of the stability of procaine hydrochloride in cardioplegie solutions, prepared from Ringer s solution and electrolytes (both un-buffered, or buffered with sodium bicarbonate) [156], The content of the drug was measured by ultraviolet speetrophotometry, and the was found to follow pseudo-first order kinetics. The stability of the drug entity in buffered solutions was estimated to be approximately 5-7 days. 

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