Pharmaceutics 12

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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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