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Stability of Drug Preparations

Chapter 12


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I. IntroductionA.Importance

Stabilityis the guarantee of safetyand

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


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II. Chemical kinetics and drug

stabilityA. 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)


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

second-order

zero-order first-order a=b=c0 ab

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=ktexpression

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

t0.9 c0/(10k) 0.105/k 0.11/(c0k)


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B. The Arrhenius equation

(1)showing the effect of temperature on the drugdegradation 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


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(3)It is possible to conduct kinetic

experiments at elevated temperature

and obtain estimates of rate constants at

lower temperatures by extrapolation ofthe Arrhenius plot (Accelerated stability

testing)


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III. Routes by which

pharmaceuticals degradeA.Chemical degradation routes

(1)hydrolysis

(2)oxidation

(3)dehydration

(4)isomerization

(5)incompatibilities

(6)others: hydration, decarboxylation, pyrolysis


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(1)hydrolysis: esters (lactone) and amide (lactam)

methods for delayed hydrolysis:

adjusting pHcontrolling water content

controlling T

reduce the solubility of drugssolid forms


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(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 productRO2 + RO2 inactive product


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methods for delayed oxidation:

reduce oxygen content

adjusting pH

reduce metal ion

lower Tavoid light


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B. Physical degradation routes

(1)vaporization

(2)aging

(3)adsorption

(4)physical instability in heterogeneous

systems (suspensions, emulsions, creams

and ointments)


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IV. Formulation and Environmental

factors that affect reaction rate

A.pHhydrolysis

(1)lgk versus pH profiles of different drugs

(specific acid-base catalysis)


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2 3 4 5 6

1.0

0.5

0.0

HS SF

pH


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5 6 7 8 9 10 11

4

6

8

10

12

14

pH

k,1

0-

4s-1


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0 2 4 6 8 10

-6

-5

-4

pH

25

12

-3


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0 2 4 6 8 10

pH

79.5

I0.5

12

-4.5

-4.3

-4.1

-3.9

-3.7

lgk,s-1


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6 7 8 9 10 11

pH

80

12

-5.5

-5.0

-4.5

-4.0

-3.5

lgk,s-1


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02 4 6 8 10

-6

-5

-4

pH

60

12

-3

14

lgk,s-1


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0 2 4 6 8 10

-6.5

-5.5

-4.5

pH

35

I0.5

12

-3.5

lgk,s-1


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0 1 2 3 4 5

-7

-6

-5

pH

70

67 8

lgk,

s-1


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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


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02 4 6 8 10

-5

-4

-3

pH

25

12

-2

14

lgk,

s-1


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(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


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B. solventhydrolysis

lgk=lgk-kZAZB/

where k is the reaction rate constant, kis a

constant, is the dielectric constantkis the reaction rate constant when ZA andZB is the electric charge of the

two ions of A and B, respectively


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C. ion strength

lgk=lgk0+1.02ZAZBI1/2

where k is the reaction rate constant, k0 is

the reaction rate constant when I=0, ZAZB is the electric charge of twoions,respectivelyI is the ion strength


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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


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F. Temperature

In general, the higher T is, the faster thereaction rate is

Arrhenius equation

G. Lightoxidation, photodegradation

Avoid light during preparation and

storage package is very important


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H. Air (oxygen)oxidation

inert gas (N2, CO2)

vacuum-packed

reducing agentsadding antioxidants blockers of oxidation

synergists

(note: pH value range in whichantioxidants are suitable to application)

p272


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I. Metal ionsinitiate oxidation reactions

employ raw materials and excipients with higherpurities

do not use metal instruments

use chelating agents (EDTA, citric acid, and

tartaric acid)

J. Humidity (water)major determinant of drugproduct in solid dosage forms

lower RH% during preparation

put drying agents in the package


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K. Package materials

glass, plastics, aluminum foil etc

package evaluation


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V. Stability and degradation

kinetics of solid drug preparationsA. 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


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B. Chemical degradation kinetics

(1)nucleation theory

(2)liquid-layer theory

(3)topochemical reactions


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VI.Stability testing in the

pharmaceutical industryA. Impact factor testing (Stress testing)

high T (60, 40 )high H (25 , 755%, 905%) 10dstrong light (4500500lx)


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B. Accelerated testing

done more frequently and for a shorterduration

(1)in general, three batches, with package,402 , RH755%, 6m(3m for clinicaltesting and 6m for production)

(2)specific preparations with various testingconditions

(3)obtain tentative expiry date (shelf time)


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C. Long-term testing

(1)in general, three batches, with package,252 , RH6010%, 6m for clinicaltesting, 12m for production and go on

(2) specific preparations with varioustesting conditions

(3)obtain definitive expiry date


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D. Evaluation indices of stability testing for

various dosage formsP279


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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 sampleat 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


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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