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
Differential rate
expression
Integrated rate
expression
zero-order
-dc/dt=k
k=(c0-c)/t
first-order
-dc/dt=kc
second-order
a=b=c0
a≠b
-dc/dt=kc2 -dc/dt=kcacb
k=(1/t)ln(c0/c) 1/c-1/c0=kt
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 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.pH—hydrolysis
(1)lgk versus pH profiles of different drugs
(specific acid-base catalysis)
1.0
F
S－
HS
0.5
0.0
2
3
4
pH
5
6
14
12
k,1
04s-1
10
8
6
4
5
6
7
8
pH
9
10
11
-3
25℃
-4
-5
-6
0
2
4
6
pH
8
10
12
-3.7
79.5℃
I＝0.5
-3.9
lgk,s-1
-4.1
-4.3
-4.5
0
2
4
6
pH
8
10
12
-3.5
80℃
-4.0
lgk,s-1
-4.5
-5.0
-5.5
6
7
8
9
pH
10
11
12
-3
60℃
-4
lgk,s-1
-5
-6
0
2
4
6
pH
8
10
12
14
-3.5
35℃
I＝0.5
-4.5
lgk,s-1
-5.5
-6.5
0
2
4
6
pH
8
10
12
-5
70℃
-6
lgk,
s-1
-7
0
1
2
3
4
pH
5
6
7
8
-4.2
91.3℃
-4.4
lgk,
s-1
-4.6
-4.8
0.5
0.7
0.9
1.1
pH
1.3
1.5
1.7
1.9
-2
25℃
-3
lgk,
s-1
-4
-5
0
2
4
6
pH
8
10
12
14
(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