Pharmaceutics 12
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Transcript of 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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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