3.

Dosage Form Design:

Pharmaceutic and Formulation
Considerations
Contents
1. The need for dosage forms
2. General considerations in dosage
form design
3. Drug and drug product stability
4. Pharmaceutical ingredients
Drug substances are seldom administered alone
nonmedical
agents,
referred to as
pharmaceutic
ingredients
The pharmaceutic ingredients
solubilize,
suspend,
thicken
dilute
emulsify
stabilize
preserve
color
flavor

The general area of study concerned with the
formulation
manufacture
stability
effectiveness
of pharmaceutical dosage forms.
Physical
Chemical
Biological characteristics
Compatible
A drug product
stable
efficacious
attractive
easy to administer
safe
manufactured under appropriate measures
of quality control


1. The need for dosage forms
Besides providing the
mechanism for the safe and
convenient delivery of
accurate dosage, dosage
forms are needed for
additional reasons:
1) Protection from oxygen and
humidity (coated tablets,
sealed ampuls)
2) Protection from gastric
acid after oral
administration (enteric-
coated tablets)
3) To conceal the bitter,
salty, or offensive taste
or odor of a drug
substance (capsules,
coated tablets, flavored
syrups)

4)
insoluble
unstable
in the desired vehicle
Suspension
Liquid
preparation

5)
Clear liquid dosage forms
Syrups
solutions
6) To provide rate-controlled drug
action (various controlled-release
tablets, capsules and suspensions)
7) To provide topical drug action
from topical administration sites
(ointments, creams, transdermal
patches, ophthalmic, ear, and nasal
preparations)

8) To provide for the
insertion of a drug into
one of the bodys
orifices (e.g., rectal or
vaginal suppositories)
9) To provide for the
placement of drugs
directly into the
bloodstream or into
bodys tissues (e.g.,
injections)
10) To provide for topical
drug action through
inhalation therapy
(e.g., inhalants and
inhalation aerosols)
2. General considerations in dosage
form design
Desired features
Drug release profile
Bioavailability
Clinical effectiveness
Factors considered

the nature of illness
the manner in which it is treated
age
anticipated condition of the patient

Because they plays a role in dosage form design

Preformulation studies
Before the formulation of a drug substance into a
dosage form, it is essential that it will be
chemically and physically characterized.
1) Physical description
The majority of drug substances in use today
occur as solid materials. Most of them are pure
chemical compounds of either crystalline or
amorphous constitution.



A crystal or crystalline solid is a solid
material whose constituent atoms,
molecules, or ions are arranged in an orderly
repeating pattern extending in all three
spatial dimensions.
An amorphous solid is a solid in which there
is no long-range order of the positions of the
atoms.
The purity of the chemical substance is
essential for its identification as well as for
the evaluation of its chemical, physical, and
biologic properties.
Chemical properties
Structure,
form and reactivity
Physical properties
Physical description,
Particle size,
Crystalline structure,
Melting point,
Solubility
Biologic properties
Ability to get to a site
of action,
Elicit a biologic response
Drugs can be used therapeutically as solids,
liquids and gases. Liquids drugs are used to
a much lesser extent than solid drugs; gases,
even less frequently.
Many of the liquids are volatile substances
and as such must be physically sealed from
the atmosphere to prevent their loss.
Another problem associated with liquid
drugs is that those intended for oral
administration cannot generally be
formulated into tablet form.
Formulation and stability difficulties arise
less frequently with solid dosage forms than
with liquid pharmaceutical preparations.
2) Microscopic examination
Microscopic examination of the raw drug
substance is an important step in
preformulation work.

It gives an indication of particle size and
particle size range of the raw material as well
as the crystal structure.


3) Melting point depression
A characteristic of a pure substance is a
defined melting point or melting range. If
not pure, the substance will exhibit a
depressed melting point.

This phenomenon is commonly used to
determine the purity of a drug substances
before inclusion in the same dosage form.

The melting point, or freezing point, of a
pure crystalline solid is defined as that
temperature where the pure liquid and solid
exist in equilibrium.

The melting point/range of a drug can be
used as an indicator of purity of chemical
substances (a pure substance would
ordinarily be characterized by a very sharp
melting peak).

An altered peak or a peak at a different
temperature may be indicative of an
adulterated or impure drug.

The addition of a second component to a pure
compound (A), resulting in a mixture, will result in
a melting point that is lower than that of the pure
compound.
The degree to which the melting point is lowered
is proportional to the mole fraction (N
A
) of the
second component that is added. This can be
expressed as:
AT=2.303RTT
0
logN
A
/AH
f
AH
f
is the molar heat of fusion
T is the absolute equilibrium temperature
T
0
is the melting point of pure A, and
R is the gas constant

Two things are noteworthy in contributing
to the extent of melting-point lowering.
Evident from this relationship is the
inverse proportion between the melting
point and the heat of fusion.
- When a second ingredient is added to a
compound with a low molar heat of fusion,
a large lowering of the melting point is
observed;
- Substances with a high molar heat of fusion
will show little change in melting point with
the addition of a second compound.

The extent of lowering of the melting point
is also related to the melting point itself.
- Compounds with low melting points are
affected to a greater extent than compounds
with high melting points upon the addition
of a second component
- Low-melting-point compounds will result in
a greater lowering of the melting point than
those with high melting points.

4) The phase rule
Phase diagrams are often constructed to
provide a visual picture of the existence and
extent of the presence of solid and liquid
phases in binary, ternary and other mixtures.

(

A phase diagram, or temperature-
composition diagram, represents the
melting point as a function of composition
of two or three component systems.

I
II
IV
III
T
Each phase is a
homogenous part of the
system, physically
separated by distinct
boundaries.
A description of the
conditions under which
these phases can exist is
called the Phase Rule,
which can be presented
as: F=C-P+X
F=C-P+X
where F is the number of degrees of freedom
.The degrees of freedom represent the
environment conditions which can be
independantly varied without changing the
number of phases in the system.
C is the number of components ,
P is the number of phases ,
X is a variable dependent upon selected
considerations of the phase diagram (1, 2 or 3)

5) Particle size
Certain physical and chemical properties of
drug substances are affected by the particle
size distribution, including drug dissolution
rate, bioavailability, content uniformity,
taste, texture, color and stability.
In addition, properties such as flow
characteristics and sedimentation rates,
among others, are also important factors
related to particle size.


Of specical interest is the effect of particle
size on the drugs absorption
griseofulvin
nitrofurantoin
spironolactone
procaine penicillin
6) Polymorphism
An important factor on formulation is the
crystal or amorphous form of the drug
substance.
Polymorphic forms usually exhibit different
physical-chemical properties including melting
point and solubility.
The changes in crystal characteristics can
influence bioavailability, chemical and physical
stability, and have important implications in
dosage form process functions.

Crystal structure
Polymorphism
Solvate form
Bioavailability
Chemical and physical stability
Dosage form process functions
Tableting
process (flow,
compaction
behaviour)
Hot stage microscopy
Thermal analysis
Infrared spectroscopy
X-ray diffraction
7) Solubility
A drug must possess some aqueous
solubility for therapeutic efficacy.
For a drug to enter the systemic circulation
to exert a therapeutic effect, it must first be
in solution.
Relatively insoluble compounds often
exhibit incomplete or erratic absorption.
If the solubility of the drug substance is less
than desirable, consideration must be given
to improve its solubility.
8) Solubility and particle size
Although solubility is normally considered a
physicochemical constant, small increases in
solubility can be accomplished by particle
size reduction.

The particle size and surface area of a drug exposed
to a medium can affect actual solubility, within
reason. For example, in the following relationship:
logS/S
0
=2V/(2.303RTr)

Where S is the solubility of the small particles,
S
0
is the solubility of the large particles,
is the surface tension
V is the molar volume
R is the gas constant
T is the absolute temperature
r is the radius of the small particles

9) Solubility and pH
pH is one of the most important factors
involved in the formulation process.
Two areas of critical importance are the
effects of pH on solubility and stability.
The effect of pH on solubility is critical in
the formulation of liquid dosage forms, from
oral and topical solutions to intravenous
solutions and admixtures.

The solubility of a weak acid or base is often
pH dependent.
The total quantity of a monoprotic weak
acid (HA) in solution at a specific pH is the
sum of the concentrations of both the free
acid and salt (A
-
) forms. The expression is:

HA H
+
+A
-
where K
a
is the dissociation constant.

K
a
There may be a certain pH level reached
where the total solubility (S
T
) of the drug
solution is saturated with respect to both the
salt and acid forms of the drug, i.e., the
pH
max


(pH
pH
max
)
.
The solution can be saturated with respect
to the salt at pH values higher than this, but
not with respect to the acid.
At pH values less than this, the solution can
be saturated with respect to the acid, but not
to the salt.

(pHpH


To calculate the total quantity of drug that
can be maintained in solution at a selected
pH, two different equations can be used,
depending on whether the product is to be
in a pH region above or below the pH
max

when below the pH
max
S
T
=S
a
(1+K
a
/|H
+
|)
when above the pH
max
S
T
=S
a
(1+|H
+
|/K
a
)
Where S
a
is the saturation solubility of the
free acid, S
a
is the saturation solubility of
the salt form.
10) Dissolution
Dissolution rate can affect the onset, intensity, and
duration of response, and control the overall
bioavailability of the drug from the dosage form.
The dissolution rate of drugs may be increased by
decreasing the drugs particle size.
It may also be increased by increasing its solubility
in the diffusion layer. The most effective means of
obtaining higher dissolution rates is to use a highly
water soluble salt of the parent substance.
Ficks laws of diffusion and the Noyes-
Whitney equation
When individual molecules move within a
substance, diffusion is said to occur. This may
occur as the result of a concentration gradient
or by random molecular motion.
Ficks First Law involving steady-state
diffusion (where dc/dx does not change) is
derived from the following expression for the
quantity of material (M) flowing through a
cross-section of a barrier (S) in unit time (t)
expressed as the flux (J)
J=dM/(Sdt)
Under a concentration gradient (dc/dx), Ficks
First Law can be expressed as
J=D|(C
1
-C
2
)/h| or J=-D(dC/dx)
where J is the flux of a component across a plane
of unit area,
C
1
and C
2
are the concentrations in the donor and
receptor compartments,
h is the membrane thickness,
D is the diffusion coefficient (or diffusivity).
The sign is negative denoting that the flux is in the
direction of decreasing concentration.
To study the rate of change of the drug in
the system, one needs an expression that
relates the change in concentration with
time at a definite location in place of the
mass of drug diffusing across a unit area of
barrier in unit time, this expression is known
as Ficks Second Law.

Fick
This law can be summarized as it states that
the change in concentration in a particular
place with time is proportional to the change
in concentration gradient at that particular
place in the system.

(

The concentration of drug in the membrane can be
calculated using the partition coefficient (K) and
the concentration in the donor and receptor
compartments
K=C
1
/C
d
=C
2
/C
r
The expression can be written
dM/dt=|DSK(C
d
-C
r
)|/h
or, in sink conditions,
dM/dt=DSKC
d
/h=PSC
d

The permeability coefficient (cm/sec) can be
obtained by rearranging to
P=DK/h
In the dissolution of particles of drug, the
dissolved molecules diffuse away from the
individual particle body. An expression to
describe this was derived from Ficks
equations and is known as the Noyes and
Whitney expression. It can be written as
follows:
dC/dt =(DS/h)(C
s
-C)
where C is the concentration of drug
dissolved at time t,
D is the diffusion coefficient of the solute in
solution,
S is the surface area of the exposed solid
h is the thickness of the diffusion layer
C
s
is the saturation solubility of the drug

k=DS/h
dc/dt=k (C
s
-C)
11) Membrane permeability
To produce a biological response, the drug
molecule must first cross a biological
membrane.
The biological membrane acts as a lipid
barrier to most drugs and permits the
absorption of lipid soluble substances by
passive diffusion while lipid insoluble
substances can diffuse across the barrier
only with considerable difficulty.
Specifically, pKa, solubility, and dissolution rate
provide an indication of absorption expectations.
To enhance these data, a technique using the
everted intestinal sac
may be used in evaluating absorption
characteristics of drug substances.
Through this method, both passive and active
transport can be evaluated.
In the later stages of preformulation testing, in
vitro/in vivo correlation will be studied.

12) Partition coefficient
In formulation development, the octanol-water
partition coefficient is commonly used.
Following the illustrations provided above, it
is defined as
P=(Conc. of drug in octanol)/(Conc. of drug in water)
P is dependent on the drug concentration only
if the drug molecules have a tendency to
associate in solution.
For an ionizable drug, the following equation
is applicable:
P=(Conc. of drug in octanol)/|1-o|(Conc. of
drug in water)
where o equals the degree of ionization.
13) pKa/Dissociation constants
Extent of ionization has an important effect
on the formulation and pharmcokinetic
parameter of the drug.
The extent of dissociation/ionization is, in
many cases, highly dependent on the pH of
the medium containing the drug.
In the pharmacokinetic area, the extent of
ionization of a drug is an important factor of
its extent of absorption, distribution, and
elimination.

Dissolution constant or pKa is usually
determined by potentiometric titration.
(pKa

Drug and drug product stability
One of the most important activities of
preformulation work is the evaluation of the
physical and chemical stability of the pure
drug substance.
1) Drug stability: mechanisms of degradation
- Chemical instability of medicinal agents may
take many forms.
- The most frequently encountered destructive
processes are hydrolysis and oxidation.
Hydrolysis is a solvolysis process in which
(drug) molecules interact with water
molecules to yield breakdown products of
different chemical constitution.

A great number of medicinal agents are
esters or contain such other groupings as
substituted amides, lactones
, and lactams , which are
susceptible to the hydrolytic process.

1.
H
+
OH
-

OH
-

-OH
-

pH
pH

2.


1
+ CHCl
2
COOH C C
OH
H
H
NH
2
CH
2
OH O
2
N C C
OH
H
H
NHCOCHCl
2
CH
2
OH O
2
N

pH7




pH
pH2~7 pH
pH 6
pH<2 or pH>8




120C


pH 5.4

1

|-H
+
OH
-

o
|-

B

3.
O
OH
O
NH
2
N
N
CH
2
OH
O
HO
O
O
N
HN
CH
2
OH
H
+
Another destructive process is oxidation.
The oxidative process is destructive to many
drug types, including aldehydes, alcohols,
phenols, sugars, alkaloids, and unsaturated
fats and oils.

Many of the oxidative changes in
pharmaceutical preparations have the
character of autoxidations.

Autoxidations occur spontaneously under
the initial influence of atmospheric oxygen
and proceed slowly at first and then more
rapidly as the process continues.

1.
2.
C

23
L-

H
+

-AD



3.
1.
(optical
isomerization)(geometric
isomerization)





(racemization)
(epimerization)

pH 4
50%pH

44

pHa-

(ergometrinine)
1

A
(all-trans)
A
2, 6

2



|-

400

2.(polymerization)

3.
2) Drug and drug product stability: kinetics
and shelf-life
There are five types of stability of concern:
Chemical
Each active ingredient retains its chemical
integrity and labeled potency, within the
specified limits.(shelf life)
Physical
The original physical properties, including
appearance, palatability, uniformity,
dissolution and suspendability are retained.
Microbiologic
Sterility or resistance to microbial growth is
retained according to the specified
requirements. Antimicrobial agents that are
present retain effectiveness within specified
limits.
Therapeutic
The therapeutic effect remains unchanged.
Toxicologic
No significant increase in toxicity occurs.

Stability and expiration dating are based on
reaction kinetics, i.e.,
the study of the rate of chemical change
the way this rate is influenced by conditions
of concentration of reactants, products, and
other chemical species that may be present,
and by factors such as solvent, pressure, and
temperature.
In considering chemical stability of a
pharmaceutical, one must know the reaction
order and reaction rate.
3) Rate reactions
The reaction rate expression is a description
of the drug concentration with respect to
time.
Most commonly, zero-order and first-order
reactions are encountered in pharmacy.

Zero order rate reactions
If the loss of drug is independent of the
concentration of the reactants and constant
with respect to time (i.e., 1mg/ml/hour), the
rate is called zero order. The mathematical
expression is: -dC/dt=k
0
where k
0
is the zero-order rate constant
[concentration(C)/time(t)]
The integrated, and more useful form of the
equation, is: C=-k
0
t+C
0
A drug suspension (125mg/ml) decays by
zero-order kinetics with a reaction rate
constant of 0.5 mg/ml/hour. What is the
concentration of intact drug remaining after
3 days (72 hours)?
C=-k
0
t+C
0

How long will it take for the suspension to
reach 90% of its original concentration?
First order rate reactions
If the loss of drug is directly proportional to the
concentration remaining with respect to time, it
is called a first-order reaction and has the units
of reciprocal time, i.e., time
-1
. the mathematical
expression is
-dC/dt=kC
where C is the concentration of intact drug remaining,
t is time,
(-dC/dt) is the rate at which the intact drug degrades,
k is the specific reaction rate constant.
The integrated and more useful form of the
equation is
logC=-kt/2.303+logC
0
where C
0
is the initial concentration of the
drug.
In nature log form, the equation is
lnC=-kt+lnC0
4) Q
10
method of shelf-life estimation
The Q
10
method of shelf-life estimation
allows the pharmacist quickly to calculate
estimates of shelf-life for a product that may
have been stored or is going to be stored
under a different set of conditions.
The Q
10
approach, based on Ea, is
independent of reaction order and is
described as:

Q
10
=e
{(Ea/R)[1/(T+10)-(1/T)]}
where E
a
is the energy of activation,
R is the gas constant, and
T is the absolute temperature.
In usable terms, Q
10
is the ratio of two
different reaction rate constants, is defined
as
Q
10
=K
(T+10)
/K
T
The equation to use for Q
10
shelf-life estimates is
t
90
(T
2
)=t
90
(T
1
)/Q
10
(AT/10)
where
t90(T2) is the estimated shelf-life
t90(T1) is the given shelf-life at a given
temperature,
AT is the difference in the temperature T
1
and T
2
As is evident from this relationship, an increase in
AT will decrease the shelf-life and a decrease in
AT will increase shelf-life.
Buffer Capacity

pH,buffers, and buffer capacity are especially
important in drug product formulation, since
they affect the drugs solubility, absorption,
and stability and the patients comfort.
pH=pKa+log(base/acid)
The ability of a buffer solution to resist changes in
pH upon the addition of an acid or a base is called
buffer capacity() and is defined thus:
=B/ pH
B is molar concentration of acid or base added
pH is change in pH due to addition of acid or base,
And can be determined experimentally or calculated using the
Henderson-Hasselbach equation
5) Enhancing stability of drug products
There are several approaches to the
stabilization of pharmaceutical preparations
containing drugs subject to deterioration by
hydrolysis.
- the reduction and the elimination of water
from the pharmaceutical system,
This may be accomplished by applying a
waterproof protective coating over tablets or
by enclosing and maintaining the drug in
tightly closed containers.

In liquid preparations, water can frequently
be replaced or reduced in the formulation
through the use of substitute liquids such as
glycerin, propylene glycol, and alcohol.
In certain injectable products, anhydrous
vegetable oils may be used as the drugs
solvent to reduce the chance of hydrolytic
decomposition.
For certain unstable antibiotic drugs, when an
aqueous preparation is desired, the drug may
be supplied to the pharmacist in a dry form for
reconstitution by adding a specified volume of
purified water just before dispensing.
For most hydrolyzable drugs the pH of
optimum stability is on the acid side,
somewhere between pH5 and 6.
Therefore, through judicious use of buffering
agents, the stability of otherwise unstable
compounds can be increased.

The oxidative process is diverted, and the
stability of the drug is preserved by agents
called antioxidants, which react with one or
more compounds in the drug to prevent
progress of the chain reaction.
Various antioxidants are employed in
pharmacy. Among those more frequently
used in aqueous preparations are sodium
sulfite (Na
2
SO
3
), sodium bisulfite (NaHSO
3
),
hypophosphorous acid (H
3
PO
2
), and
ascorbic acid.
Because the stability of oxidizable drugs
may be adversely affected by oxygen, certain
pharmaceuticals may require an oxygen-free
atmosphere during their preparation and
storage.
Oxygen-sensitive drugs may be prepared in
the dry state and they, as well as liquid
preparations, may be packaged in sealed
containers with the air replaced by an inert
gas such as nitrogen.
Stability Testing
3. Pharmaceutical ingredients
To prepare a drug substance into a final
dosage form, pharmaceutical ingredients are
required.
Solvents To dissolve the drug substance
Flavors and sweeteners To make the
product more palatable
Colorants To enhance product appeal
Preservatives To prevent microbial growth
Stabilizers To prevent drug decomposition
Diluents or fillers
To increase the bulk of the formulation
Binders
To cause the adhesion of the powdered drug
and pharmaceutic substances
Lubricants
To assist the smooth tableting process
Disintegrating agents
To promote tablet break-up after
administration
1) Handbook of pharmaceutical excipients
which presents monographs () on over
200 excipients used in pharmaceutical
dosage form preparation.
Nonproprietary , chemical,
and commercial names,
Empirical() and chemical formulas
and molecular weight,
Pharmaceutical specifications and chemical
and physical properties,
Incompatibilities and interactions with other
excipients and drug substances,
Regulatory status,
Applications in pharmaceutic formulation or
technology.
2) Appearance and palatability
Modern pharmaceutical preparations
present drug substances to the patient as
colorful, flavorful formulations attractive to
the sight, smell, and taste.
An appropriate drug will have its most
beneficial effect when it is accepted and
taken properly by the patient. The proper
combination of flavor, fragrance, and color
in a pharmaceutical product contributes to
its acceptance.
3) Coloring
Coloring agents are used in pharmaceutical
preparations for purposes of esthetics
.
Most pharmaceutical colorants in use today
are of synthetic origin, a few are obtained from
natural mineral and plant sources.
A color additive must be safe. In the case of
pharmaceutical preparations, color additives
must not interfere with the therapeutic efficacy
of the product in which they are used.
Dyes generally are added to pharmaceutical
preparations in the form of diluted solutions
(0.0005 and 0.001%) rather than as
concentrated dry powders. This permits
greater accuracy in measurement and more
consistent color production.
A formulation pharmacist must select the dyes
to be used in a particular formula on the basis
of the physical and chemical properties of the
dyes available.

Another important consideration when
selecting a dye for use in a liquid
pharmaceutical is the pH and pH stability of
the preparation to be colored.
The dye also must be chemically stable in the
presence of the other formulative ingredients
and must not interfere with the stability of the
other agents.
Dyes must also be reasonably photostable.
4) Preservatives
Some types of pharmaceutical products like
ophthalmic and injectable preparations are
sterilized by physical methods.
Autoclaving for
20 minutes at 15 pounds pressure and 121
o
C,
dry heat at 180
o
C for 1 hour,
by bacterial filtration.
Other types of preparations such as syrups,
emulsions, suspensions and some semisolid
preparations, particularly creams that are not
sterilized during their preparation.
They are protected by the addition of an
antimicrobial preservative.
Most alcohol-containing pharmaceuticals such as
elixirs, spirits, and tinctures

are self-sterilizing and do not require

additional preservation.

General preservative considerations
Only the undissociated fraction or molecular
form of a preservative possesses preservative
capability, because the ionized portion is
incapable of penetrating the microorganism.
The preservative selected must be largely
undissociated at the pH of the formulation
being prepared.
Mode of action
Preservatives interfere with microbial growth,
multiplication, and metabolism through one or
more of the following mechanisms:

- Modification of cell membrane permeability
and leakage of cell constituents (partial lysis)
- Lysis and cytoplasmic leakage
- Irreversible coagulation of cytoplasmic
constituents (e.g., protein precipitation)

- Inhibition of cellular metabolism as through
interference with enzyme systems or
inhibition of cell wall synthesis
- Oxidation of cellular constituents
- hydrolysis


Preservative utilization
Certain intravenous preparations given in
large volumes as blood replenishers or as
nutrients are not permitted to contain
bacteriostatic additives, because the
amounts required to preserve such large
volumes would constitute a health hazard
when administered to the patient.
Examples of the preservatives and their
concentrations commonly employed in
pharmaceutical preparations are:
Benzoic acid (0.1 to 0.2%)
Sodium benzoate (0.1 to 0.2%)
Alcohol (15 to 20%)
Phenylmercuric nitrate and acetate (0.002 to
0.01%)
Phenol (0.1 to 0.5%)
Cresol (0.1 to 0.5%)
Chlorobutanol (0.5%)
Benzalkonium chloride (0.002 to 0.01%)

Combinations of methylparaben(and
propylparaben (0.1 to 0.2%) (, this is
especially good against fungas.
For each type of preparation to be preserved, the
research pharmacist must consider the influence of
the preservative on the comfort of the patient.

23

1~2

stress testing

s5mm
s10mm

60C

5%40C
60C
40C

1.
25C
905%

5%
75%5%
5%

NaCl751%15.5~60C
KNO
3
92.5%, 25C
2.

4500500Lx
120Lxh

200whr/m
2

3.
(Accelerated testing)

402C755%

2C
5%



3
6

302C605%
NaNO
2
25~40C
64%~61.5%


4~8C
252C
605%

302C605%

202%
CH
3
COOK. 1.5H
2
O25C
22.5%



(Long-term testing)
252


252C
6010%123
036912

121824
360



6
12


62C12
12

pH
















pH











PH

yy 95%
yz
yyy+zy-z
90%

lgC=-kt/2.303+lgC
0

1.
2.
3.lgCt
k
T

4.k1/T

5.T=298
t
0.9
=0.1054/k

K=Ae
-E/RT
lgK=-E/2.303RT +lgA
80025
600

1402
3

1k

C =C
0
e
K/RT

K=2.303tlogC
0
/C


K=2.30330log800/600=0.00961
0.0096=2.30340log800/C
C =545
2
t
1/2
0.693/0.0096 = 72.7


3
t
0.9
0.1054/0.0096 = 11