Stability of Drug Preparations

Chapter 12

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

II. Chemical kinetics and drug stability

A. Orders of reactions -dC/dt=kCn 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)

Rate Expressions for Zero-, First- and Second-Order Reactions

zero-order -dc/dt=k first-order -dc/dt=kc second-order a=b=c0 ab -dc/dt=kc2 -dc/dt=kcacb

Differential rate expression Integrated rate expression t1/2 t0.9

k=(c0-c)/t

k=(1/t)ln(c0/c) 1/c-1/c0=kt

c0/(2k) c0/(10k)

0.693/k 0.105/k

1/(c0k) 0.11/(c0k)

B. The Arrhenius equation (1)showing the effect of temperature on the drug degradation rate (2)integrated: k=Ae-Ea/RT logarithmic: lgk=-Ea/(2.303RT)+lgA rewritten as: ln(k1/k2)=(Ea/R)(1/T2-1/T1) 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

(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)

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

(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

(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

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

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

IV. Formulation and Environmental factors that affect reaction rate

A.pHhydrolysis (1)lgk versus pH profiles of different drugs (specific acid-base catalysis)

1.0

HS

0.5

0.0 2 3

pH

14

12

k,1 04s-1

10

4 5 6 7 8 9 10 11

pH

-3

25 -4

-5

-6

10

12

pH

-3.7 79.5 I0.5

-3.9

lgk,s-1
-4.1

-4.3

-4.5

10

12

pH

-3.5 80

-4.0

lgk,s-1
-4.5

-5.0

-5.5

10

11

12

pH

-3

60 -4

lgk,s-1
-5

-6

10

12

14

pH

-3.5 35 I0.5

-4.5

lgk,s-1

-5.5

-6.5

10

12

pH

-5 70

-6

lgk, s-1

-7

pH

-4.2

91.3

-4.4

lgk, s-1
-4.6

-4.8

0.5

0.7

0.9

1.1

1.3

1.5

1.7

1.9

pH

-2

25 -3

lgk, s-1

-4

-5

10

12

14

pH

(2) method: the optimum pH for stabilitypHm calculating: pHm= 1/2pKw-1/2lgkOH-/KH+ through testing: a series of solutions with different pH valuesaccelerated testing lgk~pH profilespHm (3)general acid-base catalysis PBS, ABS method: change the type or reduce the concentration

B. solventhydrolysis lgk=lgk-kZAZB/ where k is the reaction rate constant, kis a constant, is the dielectric constantk is the reaction rate constant when ZA and ZB is the electric charge of the two ions of A and B, respectively

C. ion strength lgk=lgk0+1.02ZAZBI1/2 where k is the reaction rate constant, k0 is the reaction rate constant when I=0, ZA ZB is the electric charge of two ions,respectivelyI is the ion strength

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

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

H. Air (oxygen)oxidation inert gas (N2, CO2) vacuum-packed reducing agents adding antioxidants blockers of oxidation synergists (note: pH value range in which antioxidants are suitable to application) p272

I. Metal ionsinitiate 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

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

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 [Vant Hoff equation: lnK=-H/(RT)+] (6)effect of crystal form

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

VI. Stability testing in the pharmaceutical industry

A. Impact factor testing (Stress testing) high T (60, 40 ) high H (25 , 755%, 905%) 10d strong light (4500500lx)

B. Accelerated testing done more frequently and for a shorter duration (1)in general, three batches, with package, 402 , RH755%, 6m(3m for clinical testing and 6m for production) (2)specific preparations with various testing conditions (3)obtain tentative expiry date (shelf time)

C. Long-term testing (1)in general, three batches, with package, 252 , RH6010%, 6m for clinical testing, 12m for production and go on (2) specific preparations with various testing conditions (3)obtain definitive expiry date

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

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(C0/C), obtain k at different Ts (5)according to Arrhenius equation: lgk=-Ea/(2.303RT)+lgA, obtain profiles of lgk~T (6)calculate t0.9, k25 , Ea , lgA

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