• The most common cause of degradation of drugs in aqueous systems is hydrolysis and the most susceptible drugs are those containing ester, amide, lactone, lactam, imide or carbamate groups. Hydrolysis can be controlled by adjusting the pH to that of maximum stability or in some cases by the addition of nonaqueous solvents.

• Oxidative degradation is a problem with drugs possessing carbon-carbon double bonds such as the steroids, polyunsaturated fatty acids and polyene antibiotics. Such drugs can be stabilised by replacing the oxygen in the system with inert gases such as nitrogen; by avoiding contact with metals such as iron, cobalt and nickel, and by adding antioxidants or reducing agents to the solution. Some oxidative degradations are pH-dependent and can be stabilised by buffering the system.

• Loss of activity of solutions of some drugs such as the tetracyclines can occur because of epimerisation of the drug molecule, while others such as vitamin A lose activity because of geometrical isomerisation.

• Photochemical decomposition can be a problem with drugs such as the pheno-thiazine tranquillisers and can cause discoloration of the solution and loss of activity. Such systems have to be stored in amber glass containers, which remove the ultraviolet components of light.

• Reactions can be classified according to their order of reaction; the breakdown of drugs in the majority of preparations in which the drug is dissolved in aqueous solution follows first-order or pseudo firstorder kinetics. There are, however, many cases of drugs 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.

• The hydrolysis rate of drugs in liquid dosage forms is strongly influenced by the pH of the solution and can be catalysed not only by H + and OH- ions (specific acid-base catalysis) but also by the components of the buffer used (general acid-base catalysis). We have looked at the ways in which the effect of the buffer components can be removed so that the pH of maximum stability of the solution can be determined from the pH-rate profile and the rate constants for specific acid-base catalysis can be calculated.

• Temperature increase usually causes a pronounced increase of hydrolytic degradation. We have seen how to calculate the hydrolytic rate constant at room temperature from data at elevated temperatures using the Arrhenius equation.

• The addition of electrolyte can increase the hydrolysis rate if the reaction involves the interaction of the drug ion with an ion of similar charge. Similarly, a change of solvent to one of lower dielectric constant will stabilise only this type of system but not one involving the reaction between ions of opposite sign.

• In solid dosage forms containing drugs that are susceptible to hydrolysis, decomposition of the drug can occur if moisture is allowed to adsorb on the surface of the dosage form. Careful selection of packaging is important to reduce this possibility. Drug which dissolves in this surface layer will be affected by many of the factors which


1. P. R. Wells. Linear free energy relationships. Chem. Rev., 63, 171-219 (1963)

2. J. T. Cartensen, E. G. Serenson and J. J. Vance. Use of Hammett graphs in stability programs. J. Pharm. Sci., 53, 1547-8 (1964)

3. S. W. Hovorka and C. Schoneich. Oxidative degradation of pharmaceuticals: theory, mechanisms and inhibition. J. Pharm. Sci., 90, 253-69 (2001)

4. D. M. Johnson and W. F. Taylor. Degradation of fenprostalene in polyethylene glycol 400 solution. J. Pharm. Sci., 73, 1414-7 (1984)

5. L. Halbaut, C. Barbé, M. Aróztegui and C. de la Torre. Oxidative stability of semi-solid excipient mixtures with corn oil and its implication in the degradation of vitamin A. Int. J. Pharm, 147, 31-40 (1997)

6. G. B. Smith, L. DiMichele, L. F. Colwell, et al. Autooxidation of simvastatin. Tetrahedron, 49, 4447-62 (1993)

7. M. T. Lamy-Freund, V. F. N. Ferreira, A. Faljoni-Alário and S. Schreier. Effect of aggregation on the kinetics of autoxidation of the polyene antibiotic amphotericin B. J. Pharm. Sci., 82, 162-6 (1993)

influence the decomposition of drugs in aqueous solution. Excipients of the solid dosage form can affect the drug breakdown by increasing the moisture content of the dosage form.

• Temperature increase causes an increase in the rate of breakdown of drugs in solid dosage forms, which can often be described by the Arrhenius equation, although the effect of temperature change is usually far more complicated than for liquid formulations. This equation cannot be used for systems that show an approach to equilibrium. The van't Hoff equation is often useful to describe the effect of temperature on the decomposition of these systems.

• In liquid formulations the shelf-life of a formulation can be estimated by application of the Arrhenius equation. The protocol for stability testing of drug substances and drug products has been discussed.

8. H. H. Tonnesen. Formulation and stability testing of photolabile drugs. Int. J. Pharm., 225, 1-14 (2001)

9. J. V. Greenhill and M. A. McLelland. Photo-decomposition of drugs. Prog. Med. Chem, 27, 51-121 (1990)

10. C. L. Huang and F. L. Sands. Effect of ultraviolet irradiation on chlorpromazine. II. Anaerobic condition. J. Pharm. Sci., 56, 259-64 (1967)

11. Y. Matsuda, H. Inouye and R. Nakanishi. Stabilization of sulfisomidine tablets by use of film coating containing UV absorber: Protection of coloration and photolytic degradation from exaggerated light. J. Pharm. Sci., 67, 196-201 (1978)

12. H. Bundgaard. Polymerization of penicillins: kinetics and mechanism of di- and polymerization of ampicillin in aqueous solution. Acta Pharm. Suec., 13, 9-26 (1976)

13. J. T. Carstensen. Stability of solids and solid dosage forms. J. Pharm. Sci., 63, 1-14 (1974)

14. J. T. Carstensen. Drug Stability. Principles and Practices 2nd edn, Marcel Dekker, New York, 1995

15. R. Andersin and S. Tammilehto. Photochemical decomposition of midazolam. IV. Study of pH-dependent stability by high-performance liquid chromatography. Int. J. Pharm., 123, 229-35 (1995)

16. K. Torniainen, S. Tammilehto and V. Ulvi. The effect of pH, buffer type and drug concentration on the photodegradation of ciprofloxacin. Int. J. Pharm., 132, 53-61 (1996)

17. J. T. H. Ong and H. B. Kostenbauder. Effect of self-association on rate of penicillin G degradation in concentrated aqueous solutions. J. Pharm. Sci., 64, 1378-80 (1975)

18. A. E. Allen and V. Das Gupta. Stability of hydrocortisone in polyethylene glycol ointment base. J. Pharm. Sci., 63, 107-9 (1974)

19. V. Das Gupta. Effect of vehicles and other active ingredients on stability of hydrocortisone. J. Pharm. Sci., 67, 299-302 (1978)

20. M. J. Busse. Dangers of dilution of topical steroids. Pharm. J., 220, 25 (1978)

21. E. Ullmann, K. Thoma and G. Zelfel. The stability of sodium penicillin G in the presence of ionic surfactants, organic gel formers, and preservatives. Pharm. Acta. Helv., 38, 577-86 (1963)

22. B. Testa and J. C. Etter. Hydrolysis of pilocarpine in Carbopol hydrogels. Can. J. Pharm. Sci., 10, 16-20 (1975)

23. R. I. Poust and J. C. Colaizzi. Copper-catalyzed oxidation of ascorbic acid in gels and aqueous solutions of polysorbate 80. J. Pharm. Sci., 57, 2119-25 (1968)

24. J. Tingstad and J. Dudzinski. Preformulation studies. II. Stability of drug substances in solid pharmaceutical systems. J. Pharm. Sci., 62, 1856-60 (1973)

25. H. W. Jun, C. W. Whitworth and L. A. Luzzi. Decomposition of aspirin in polyethylene glycols. J. Pharm. Sci., 61, 1160-2 (1972)

26. C. W. Whitworth, L. A. Luzzi, B. B. Thompson and H. W. Jun. Stability of aspirin in liquid and semisolid bases. II. Effect of fatty additives on stability in a polyethylene glycol base. J. Pharm. Sci., 62, 1372-4 (1973)

27. R. Ekman, L. Liponkoski and P. Kahela. Formation of indomethacin esters in polyethylene glycol suppositories. Acta Pharm. Suec., 19, 241-6 (1982)

28. A. K. Amirjahed. Simplified method to study stability of pharmaceutical preparations. J. Pharm. Sci., 66, 785 (1977)

29. A. R. Rogers. An accelerated storage test with programmed temperature rise. J. Pharm. Pharmacol, 15, 101T (1963)

30. H. V. Maudling and M. A. Zoglio. Flexible non-isothermal stability studies. J. Pharm. Sci., 59, 333-7 (1970)

31. B. W. Madsen, R. A. Anderson, D. Herbison-Evans and W. Sneddon. Integral approach to noniso-thermal estimation of activation energies. J. Pharm. Sci., 63, 777-81 (1974)

32. A. I. Kay and T. H. Simon. Use of an analog computer to simulate and interpret data obtained from linear nonisothermal stability studies. J. Pharm. Sci., 60, 205-8 (1971)

33. M. A. Zoglio, H. V. Maudling, W. H. Streng and W. C. Vincek. Nonisothermal kinetic studies III: rapid nonisothermal-isothermal method for stability prediction. J. Pharm. Sci., 64, 1381 (1975)

34. ICH Harmonised Tripartite Guideline. Q1B: Photostability Testing of New Drug Substances and Products. Federal Register, 62, 27115 (1997)

35. L. Lachman. Physical and chemical stability testing of tablet dosage forms. J. Pharm. Sci., 54, 1519-26 (1965)

36. Stability testing of new drug substances and products (ICH), MCA EuroDirect Publication No. 3335/92.

0 0

Post a comment