Kinetics of drug decomposition

W. J. Irwin, Kinetics of Drug Decomposition, Basic Computer Solutions, Elsevier Science, Amsterdam, 1990. 

Hansen, L.D., Lewis, E.A., Eastough, D.J., Bergstrom, R.G., DeGraft-Johnson, D. (1989). Kinetics of drug decomposition by heat conduction calorimetry. Pharm. Res. 6,20-27. 

Pawelczyk E, Knitter B. Kinetics of drug decomposition. Part 51 kinetics of indometha-cin photodegradation. Pharmazie 1977 32(ll) 608-609. 

Pawelczyk E, Plotkowiak Z, Ponitka E. Kinetics of drug decomposition. Part XIII. Photodegradation of sodium nalidixate in alkaline solutions. Dissert Pharm Pharmacol 1970 22(6) 449 53. 

Hamlin WE, Chulski T, Johnson RH, Wagner JG. A note on the photolytic degradation of antiinflammatory steroids. J Am Pharm Assoc (Sci Ed) 1960 49(4) 253-255. Pawelczyk E, Knitter B, Knitter K. Kinetics of drug decomposition. Part 50 graphic method for calculation of zero-order rate constants of indomethacin photodegradation. Pharmazie 1977 32(8-9) 483 85. 

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. 

Pawelczyk E, Hermann T, Sukowski R (1969) Kinetics of drug decomposition part V. Kinetics of acid catalyzed solvolysis of isoniazid. Dis Pharm Pharmacol 21 481-489... 

Hansen LD, Lewis EA, Eatough DJ, Bergstrom RG, DeGraft-Johnson D. Kinetics of Drug Decomposition by Heat Conduction Calorimetry. Pharm Res 1989 6 20-27. 

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 ... 

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],... 

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. 

Voltammetric techniques are quite useful for the direct measurement of the stability of some pharmaceuticals in aqueous solution. Depending on the compounds involved, voltammetry can be used to monitor either the decomposition of a drug or the formation of a decomposition product. This type of study is typically performed by applying a potential to the working electrode that is on the voltammetric plateau for the starting material or end product to be monitored. The resulting current versus time data provide the desired kinetic information. 

Johansen, M. and Bundgaard, H., Pro-dmgs as drug delivery systems. XIII. Kinetics of decomposition of N-Mannich bases of salicy-lamidc and assessment of their suitability as possible pro-drugs for amines, Int. J. Pharm., 7,119,1980 Chem. Abstr.. 94, 162641, 1981. 

The extent of photolytic decomposition depends on the pH, nature of the solvent(s) used, and the initid drug concentration (27). Degradation is faster in diluted solutions and at higher pHs. The photolysis is characterized in terms of first-order kinetics. 

Reactions can be classified according to their order of reaction the breakdown of drugs in the majority of preparations in which the dmg is dissolved in aqueous solution follows first-order or pseudo first-order kinetics. There are, however, many cases of dmgs in which decomposition occurs simultaneously by two or more pathways (parallel reactions), or involves a sequence of decomposition steps (consecutive reactions) or a reversible reaction. 

T. Suzuki, Studies on decomposition and stabilization of drugs in solution. X. Chemical kinetic studies on aqueous solution of succinylcholine chloride. 2. Overall velocity constants for succinylcholine chloride hydrolysis as a function of pH, Chem. Pharm. Bull. 10, 912-921(1962). 

E. Pawelczyk, B. Knitter, and W. Alejska, Drug decomposition kinetics. LVI. Mechanism and kinetics of hydrolysis of indomethacin in the acid medium, Acta Pol. Pharm. 36, 181-188(1979). 

Theorem 16.8. Disposition Decomposition of Nonlinear Disposition with Linear Distribution Kinetics The drug concentration response, c(t), resulting from a bolus input of a drug with a linear distribution kinetics can be decomposed as follows ... 

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] ... 

The in vitro degradation profiles of several TDI poly(phosphoester-ure thanes) are shown in Figure 2. It is not possible from this study to correlate the decomposition kinetics with the chemical structure, except for the fact that biodegradability is demonstrated. The in vitro release of 5-FU from PPU-7 is shown in Figure 3. After an initial burst, a reasonably steady and sustained release followed. The UV spectrum of the released 5-FU was identical to that of pure 5-FU, suggesting the chemical integrity of the drug. 

At times the solubility of a drug in water is insufficient at room temperature to allow a meaningful kinetic study, in which case it can, at times, be carried out at elevated temperature [58]. If done at several different temperatures, it may be possible to estimate the stability at room temperature by extrapolation. Frequently, a broad screen of stability is performed on the initial small sample used for initial performulation this is frequently referred to as forced decomposition studies [59], in which the drug is exposed to acid degradation, base degradation, aqueous degradation, drug powder... 

The decomposition of an active drug in an aqueous solution is investigated over a period of time at a constant temperature. The resulting data of the concentration vs. time are shown in Table 5.4. What is the approximate order of the degradation kinetics and its rate constant ... 

Bundgaard, H. and Johansen, M., Prodrugs as drug delivery systems. X. N-Mannich bases as novel pro-drug candidates for amides, imides, urea derivatives, amines and other NH-acidic compounds. Kinetics and mechanisms of decomposition and structure-reactivity relatioaships. Arch. Pharm. Cheni. Sci. Ed.. 8, 29, 1980. 

Degradation is a chemical transformation of the drug substance and can be expressed as a chemical reaction with the specific kinetics. These reactions can have different orders, which are characterized by the different rate of parent compound decomposition. The most common are zero, first and second order reactions. It is not a subject of this chapter to discuss reaction kinetics in details however, specific preformulation-related discussions can be found in reference 6, and a general approach with examples is very well described by Martin [44]. 

TG can be used with different atmospheres and under vacuum. TG has a huge number of pharmaceutical applications. Automated TG is extremely efficient to replace the loss on drying assay in drug substances, being able to separate loss of solvent from decomposition by using very small amounts of substance. Solvent entrapped or bounded as solvate is easily determined. A comprehensive article on TG has been recently written by Dunn and Sharp. Ozawa proposes the use of modulated TG for kinetic analysis. ... 

The initial concentration of active principle in an aqueous preparation was 5.0 x 10 g cm . After 20 months the concentration was shown by analysis to be 4.2 x 10 g cm . The drug is known to be ineffective after it has decomposed to 70% of its original concentration. Assuming that decomposition follows first-order kinetics, calculate the expiry date of the drug preparation. 

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