1. Stability of Drug Preparations Chapter 12

2. I. Introduction A.Importance Stability is the guarantee of safety and effectiveness of any preparations B.Types of stability studies (1)chemical one: chemical degradation (2)physical one: physical appearance (3)biological one: microorganism pollution (4)stability of bioavailability: in vivo

3. II. Chemical kinetics and drug stability A. Orders of reactions -dC/dt=kC n where -dC/dt is the rates of change for the reactants; k is the reaction rate constant; C is the concentration; n is the order of the reaction (n=0: zero-order; n=1: first-order; n=2: second-order…)

4. Rate Expressions for Zero-, First- and Second-Order Reactions second-order zero-order first-order a=b=c 0 a≠b Differential rate -dc/dt=k -dc/dt=kc -dc/dt=kc 2 -dc/dt=kc a c b expression Integrated rate k=(c 0 -c)/t k=(1/t)ln(c 0 /c) 1/c-1/c 0 =kt expression t 1/2 c 0 /(2k) 0.693/k 1/(c 0 k) t 0.9 c 0 /(10k) 0.105/k 0.11/(c 0 k)

5. B. The Arrhenius equation (1)showing the effect of temperature on the drug degradation rate (2)integrated: k=Ae -Ea/RT logarithmic: lgk=-E a /(2.303RT)+lgA rewritten as: ln(k 1 /k 2 )=(E a /R)(1/T 2 -1/T 1 ) where Ea is activation energy (a constant and independent of temperature); 1 and 2 denote the two different temperature conditions; k is the constant of reaction rate; R is gas constant

6. (3)It is possible to conduct kinetic experiments at elevated temperature and obtain estimates of rate constants at lower temperatures by extrapolation of the Arrhenius plot (Accelerated stability testing)

7. III. Routes by which pharmaceuticals degrade A.Chemical degradation routes (1)hydrolysis (2)oxidation (3)dehydration (4)isomerization (5)incompatibilities (6)others: hydration, decarboxylation, pyrolysis

8. (1)hydrolysis: esters (lactone) and amide (lactam) methods for delayed hydrolysis: adjusting pH controlling water content controlling T reduce the solubility of drugs solid forms

9. (2)oxidation: phenols, enols, unsaturated alcohol, arylamine mechanism: reaction of free radical chains induction: RH R +H (light, heat) transmission: R +O2 RO2 RO2 +RH ROOH +R ROOH RO + OH (metal ion) termination: RO2 +x inactive product RO2 + RO2 inactive product

10. methods for delayed oxidation: reduce oxygen content adjusting pH reduce metal ion lower T avoid light

11. B. Physical degradation routes (1)vaporization (2)aging (3)adsorption (4)physical instability in heterogeneous systems (suspensions, emulsions, creams and ointments)

12. IV. Formulation and Environmental factors that affect reaction rate A.pH—hydrolysis (1)lgk versus pH profiles of different drugs (specific acid-base catalysis)

13. 23456 1.0 0.5 0.0 HSS－S－ F pH

14. 567891011 4 6 8 10 12 14 pH k,1 0 - 4 s -1

15. 0246810 -6 -5 -4 pH 25 ℃ 12 -3

16. 0246810 pH 79.5 ℃ I ＝ 0.5 12 -4.5 -4.3 -4.1 -3.9 -3.7 lgk,s -1

17. 67891011 pH 80 ℃ 12 -5.5 -5.0 -4.5 -4.0 -3.5 lgk,s -1

18. 0 246810 -6 -5 -4 pH 60 ℃ 12 -3 14 lgk,s -1

19. 0246810 -6.5 -5.5 -4.5 pH 35 ℃ I ＝ 0.5 12 -3.5 lgk,s -1

20. 012345 -7 -6 -5 pH 70 ℃ 6 78 lgk, s -1

21. 0.5 0.70.91.11.31.5 -4.8 -4.6 -4.4 pH 91.3 ℃ 1.7 -4.2 1.9 lgk, s -1

22. 0 246810 -5 -4 -3 pH 25 ℃ 12 -2 14 lgk, s -1

23. (2) method: the optimum pH for stability—pH m calculating: pH m = 1/2pK w -1/2lgk OH- /K H+ through testing: a series of solutions with different pH values—accelerated testing— lgk~pH profiles—pH m (3)general acid-base catalysis PBS, ABS method: change the type or reduce the concentration

24. B. solvent—hydrolysis lgk=lgk ∞ -k’Z A Z B / ε where k is the reaction rate constant, k’is a constant, ε is the dielectric constant ， k ∞ is the reaction rate constant when ε ∞ ， Z A and Z B is the electric charge of the two ions of A and B, respectively

25. C. ion strength lgk=lgk 0 +1.02Z A Z B I 1/2 where k is the reaction rate constant, k 0 is the reaction rate constant when I=0, Z A 、 Z B is the electric charge of two ions,respectively ， I is the ion strength

26. D. Surfactants enhance or decrease the stability, determined by the results of testing E. Other excipients determined by the results of compatibility testing in order to choose correctly

27. F. Temperature In general, the higher T is, the faster the reaction rate is Arrhenius equation G. Light—oxidation, photodegradation Avoid light during preparation and storage package is very important

28. H. Air (oxygen)—oxidation inert gas (N 2, CO 2 ) vacuum-packed reducing agents adding antioxidants blockers of oxidation synergists (note: pH value range in which antioxidants are suitable to application) p272

29. I. Metal ions—initiate oxidation reactions employ raw materials and excipients with higher purities do not use metal instruments use chelating agents (EDTA, citric acid, and tartaric acid) J. Humidity (water)—major determinant of drug product in solid dosage forms lower RH% during preparation put drying agents in the package

30. K. Package materials glass, plastics, aluminum foil etc “package evaluation”

31. V. Stability and degradation kinetics of solid drug preparations A. Properties of stability of solid drug preparations (1)degradation slowly (2)be not uniform (3)difference between exterior and interior (4)multi-phase systems (5)obtain a balance [Van’t Hoff equation: lnK=-ΔH/(RT)+α] (6)effect of crystal form

32. B. Chemical degradation kinetics (1)nucleation theory (2)liquid-layer theory (3)topochemical reactions

33. VI. Stability testing in the pharmaceutical industry A. Impact factor testing (Stress testing) high T (60 ℃, 40 ℃ ) high H (25 ℃, 75±5%, 90±5%) 10d strong light (4500±500lx)

34. B. Accelerated testing done more frequently and for a shorter duration (1)in general, three batches, with package, 40±2 ℃, RH75±5%, 6m(3m for clinical testing and 6m for production) (2)specific preparations with various testing conditions (3)obtain “tentative” expiry date (shelf time)

35. C. Long-term testing (1)in general, three batches, with package, 25±2 ℃, RH60±10%, 6m for clinical testing, 12m for production and go on (2) specific preparations with various testing conditions (3)obtain “definitive” expiry date

36. D. Evaluation indices of stability testing for various dosage forms P279

37. F. Classical isothermal method--done in research (1)pre-testing to determine Ts and sampling time; determine analysis methods (2)put samples at predetermined Ts, take a sample at predetermined times (t), and determine the drug concentrations (3)obtain profiles of C ~t, and determine the reaction order (lgC~t: linearity, first-order) (4)according to the equation: k=(1/t)ln(C 0 /C), obtain k at different Ts (5)according to Arrhenius equation: lgk=-E a /(2.303RT)+lgA, obtain profiles of lgk~T (6)calculate t 0.9, k 25 ℃, E a, lgA

38. G. Stability testing in new medicine development (1)raw materials (2)stability in formulation and preparation process study (3)stability of package materials (4)accelerated and long-term testing of preparations (5)stability after marketing (6)stability testing for any change in formulation, preparation process or package