Stability of Drug Preparations

Chapter 12

I. IntroductionA.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 stabilityA. 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

second-order

zero-order first-order a=b=c0 a≠b

Differential rate -dc/dt=k -dc/dt=kc -dc/dt=kc2 -dc/dt=kcacb

expression

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

expression

t1/2 c0/(2k) 0.693/k 1/(c0k)

t0.9 c0/(10k) 0.105/k 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 degradeA.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.pH—hydrolysis

(1)lgk versus pH profiles of different drugs

(specific acid-base catalysis)

2 3 4 5 6

1.0

0.5

0.0

HS S －F

pH

5 6 7 8 9 10 11

4

6

8

10

12

14

pH

k,1

0-

4 s-1

0 2 4 6 8 10

-6

-5

-4

pH

25℃

12

-3

0 2 4 6 8 10

pH

79.5℃I＝ 0.5

12

-4.5

-4.3

-4.1

-3.9

-3.7

lgk

,s-1

6 7 8 9 10 11

pH

80℃

12

-5.5

-5.0

-4.5

-4.0

-3.5

lgk

,s-1

0 2 4 6 8 10

-6

-5

-4

pH

60℃

12

-3

14

lgk

,s-1

0 2 4 6 8 10

-6.5

-5.5

-4.5

pH

35℃I＝ 0.5

12

-3.5

lgk

,s-1

0 1 2 3 4 5

-7

-6

-5

pH

70℃

6 7 8

lgk

,s-1

0.5 0.7 0.9 1.1 1.3 1.5

-4.8

-4.6

-4.4

pH

91.3℃

1.7

-4.2

1.9

lgk

,s-1

0 2 4 6 8 10

-5

-4

-3

pH

25℃

12

-2

14

lgk

,s-1

(2) method: the optimum pH for stability—pHm

calculating: pHm= 1/2pKw-1/2lgkOH-/KH+

through testing: a series of solutions with different pH values—accelerated testing—lgk~pH profiles—pHm

(3)general acid-base catalysis

PBS, ABS

method: change the type or reduce the concentration

B. solvent—hydrolysis

lgk=lgk∞-k’ZAZB/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 ∞ ， 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,respectively ， I 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. Light—oxidation, 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)

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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

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 [Van’t Hoff equation:

lnK=-ΔH/(RT)+α](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 , 75℃ ±5%, 90±5%) 10d

strong light (4500±500lx)

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)

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

D. Evaluation indices of stability testing for various dosage forms

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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