SOLID STATE STABILITY

Stabilitas padatan
Fisika
Transformasi Polimorfik
Kristalisasi, perubahan bentuk polimorf, interaksi
dengan eksipien, interaksi dengan lembab,
kontaminasi.

Kimia
o

Akibat perubahan pada intramolekular atau intermolekular

o Reaksi Hydrolysis, oxidation, photolysis

Stabilitas fisika
Stability of amorphous form
greatly depends on how is it prepared.
Crystallization above Tg
Presence of residual crystallinity (defect sites)
can be source for nucleation
In general, grinding/milling produces least stable
amorphous form

Stabilitas fisika
Stability of the crystalline state
Polymorphic transformation and solvation/desolvation
biggest problems
Stability of polymorphic form may depend upon
temperature
Presence of moisture can promote polymorphic and
pseudopolymorphic transformations
Polymorphic and pseudopolymorphic changes are often
observed upon scaling up a process

Stabilitas kimia
Stability of amorphous form
o

Reactivity much more likely above Tg

Above Tg, reactions in the amorphous state may be

thought of as a continuation of reactions in the melt
Hydroscopic nature can promote hydrolysis reactions
May also be more sensitive to oxidation and
photochemical degradation
small amounts of amorphous material is the source of
many stability problems observed

o
o
o

Stabilitas kimia
Stability of the crystalline state
Four steps to a solid-state reaction
1. Loosening of molecules at the reaction site necessary distortion of reaction cavity
2. Molecular change - breaking and forming of
chemical bonds
3. Solid-solution formation - reactant and product
both present in crystal
4. Separation of product - production of new
product crystals
.Molecular mobility can be enhanced by presence
of defect sites
.Common reactions in the solid state include
hydrolysis, oxidation, and photolysis

Stabilitas kimia

Stability of the crystalline state

Topochemical postulate :
reactions in crystals occur with a minimum of atomic
and molecular movement
Reaction Kinetic
Reaction kinetics in solid state much more
complicated than in solution
Nucleation-based mechanisms commonly used

Equations
Relating to
Decomposition
in the Solid

REACTION KINETICS
SIMPLEST DECOMPOSITION MODES OF
PURE SOLIDS
Solid is placed in a vacuum &
exposed by temperature
I
II
III
IV
V
VI

Solid solid + solid

Solid solid + liquid
Solid liquid + liquid
Solid solid + gas
Solid liquid + gas
Solid gas + gas

Faktor-faktor yang
mempengaruhi degradasi
obat padat
Kelembaban
2. Eksipient
3. Kekerasan tablet
4. Material kemasan
1.

Crystalline State and Polymorphism in Solid

Drugs

The

chemical stability of solid

drugs is affected by the
crystalline state of the drug.
Drugs in the crystalline state
have lower ground-state free
energy and exhibit higher G
and, therefore, slower reactivity.

Crystallization of Amorphous
Drugs
Attempts

are often made to formulate poorly

water-soluble drugs in their amorphous state,
because the solubility of amorphous materials
is generally higher than that of crystalline state
Because of the lower free energy of the
crystalline state, amorphous substances tend
to change to their more thermodynamically
stable crystalline state with time.
Therefore, crystallization of amorphous drug
substances may occur during long-term
storage and may lead to drastic changes in the
release characteristics of the drug

Formation and Growth of

Crystals
Molecules

in a crystal, and the crystals

themselves, should not be considered static
drug substances and excipients in solid dosage
forms, such as tablets and granules, may
recrystallize or sublime onto the surface of the
dosage form during storage.
So-called whisker crystallization
observed in tablets of ethenzamide and caffeine
anh
This crystallization was enhanced in porous
tablets and at higher temperatures.
Tablets containing lactose and mannitol
excipients have been shown to form whiskers

Polymorphism/Transitions in Crystalline
States
Polymorphs

are different crystalline forms of the

same drug.
Because these forms have different free energy
or chemical potentials, depending on
temperature conditions, transitions between
polymorphs occur.
Polymorphic transitions during storage may alter
critical properties of drugs because the solubility
and dissolution rate of drug substances
generally vary with changes in their crystalline
form.
From a storage perspective, temperature and
humidity affect polymorphic transitions.

Polymorphism
Many

drug substances exhibit polymorphism

Each crystalline state has a different ground-state
free-energy level and a different chemical
reactivity
Ex : Solid-state hydrolysis of carbamazepine from
needle-shaped crystals with a higher Crystalline
order is faster than that of beam-shaped and
prismatic forms
Reactivity of carbamazepine to light also depends
on the crystalline form of the drug
Differences in reactivity among different
crystalline forms have also been reported for
photodegradation of furosemide.

The

stability of drugs in their

amorphous form is generally lower
than that of drugs in their crystalline
form, because of the higher freeenergy level of the amorphous state.
Decreased chemical stability of solid
drugs brought by mechanical
stresses such as grinding is due to a
change in crystalline state
A relationship between the stability
and grinding time was attributed to
the increased solubility

Effect of grinding time on the degradation of aspirin in

suspension at 40C.

The

chemical stability of solid

drugs is also affected by the
crystalline state of the drug
through differences in surface area.
For reactions that proceed on the
solid surface of the drug, an
increase in the surface area can
increase the amount of drug
participating in the reaction.

Effect of Moisture and

Humidity on Solid Drugs
The

effect of moisture and

humidity on the degradation
kinetics of ascorbic acid, thiamine
salts,aspirin, vitamin A and
ranitidine hydrochloride has been
reported.
Moisture plays two primary roles in
catalyzing chemical degradation

mechanism
water

participates in the drug degradation

process itself as a reactant, leading to
hydrolysis. degradation rate is directly affected
by the concentrations of water, hydronium ion,
or hydroxide ion
water adsorbs onto the drug surface and forms a
moisture-sorbed layer in which the drug is
dissolved and degraded.
Water adsorption may also change the physical
state of drugs, thereby affecting their reactivity.
Thus, water affects drug degradation indirectly
by providing a favorable environment for
degradation

The

mechanisms for these effects

of water are determined by the
physical state of water
molecules.
For example, for drugs that form
hydrates, water of crystallization
is trapped in the crystals and,
generally, cannot participate in
chemical reactions.

Water

of crystallization can participate in

drug degradation when it is released from
the crystalline state by actions such as
grinding.
This has been reported for the hydrolysis
of sodium prasterone sulfate and
ampicillin trihydrate.
The degradation rate of ampicillin
trihydrate increased with increasing
grinding time

Effect

of grinding on the degradation of ampicillin trihydrate during

storage at 40C. Grinding time, 0, , 15 min; , 30 min; ,60 min;120 min;
, 180 min.

Moisture Adsorption
Moisture

adsorption during storage can

also affect the physical stability of
pharmaceuticals, leading to changes in
such properties as appearance and
dissolution rate.
Adsorption of moisture is governed by
the physical properties of the drug
substance and excipients.
For example, the adsorption of moisture
by aspirin crystals was enhanced by
adding hydrophilic excipients

Effect of excipients
Examples:

the accelerating effect of talc on the

hydrolysis of thiamine hydrochloride
powders
the accelerating effect of magnesium
stearate on discoloration of tablets
containing amines and lactose
the effect of talc impurities,stearic
acid,and calcium succinate on the
degradation of aspirin tablets.

Excipients
excipients

may participate directly in

degradation as reactants, such as addition
reactions with drugs.
Excipients may also exhibit catalyzing
effects toward drug degradation (ex. the
nucleophilic catalysis effect of sugars (such
as glucose and sucrose) and amines on the
degradation of ester or amide drugs)
Other mechanisms include the effect of
moisture present in excipients,
the effect of pH changes caused by
excipients

Eksipient
Beberapa

eksipient dilaporkan
meningkatkan kecepatan degradasi
seperti :
Talcum :

mempercepat hidrolisis tablet

Thiamin HCl

Mg
Stearat :

mempercepat perubahan
warna pada tablet yang
mengandung amina dan
lactose

Asam
stearat dan
kalsium
suksinat

meningkatkan degradasi
tablet aspirin

Effect of the Amount of

Moisture Present in Excipients
Excipients

can affect drug stability by being a source of

moisture.
For example, owing the high moisture content of
polyvinylpyrrolidone and urea, aspirin hydrolysis was
enhanced in solid dispersions with these excipients
Decreased drug stability caused by excipients having
higher moisture-containing ability has been reported
for tablets of aspirin and ascorbic acids
Degradation of ascorbic acid in the presence of silica
gel increased with increasing water content
The higher degradation rate observed in the presence
of silica gel compared to that for ascorbic acid alone at
the same moisture content suggested an accelerating
effect of silica gel itself or of one of its impurities

Effect of the Physical State of

Water Molecules in Excipients
water

present in excipients exists in various

physical states, being either weakly or
strongly adsorbed to the excipient.
The physical state of water can affect drug
degradation.
Excipients having strong water-entrapping
abilities tend to inhibit drug degradation
excipients having higher adsorption energy
decrease water reactivity and thereby
decrease the relative hydrolysis rates
Like how antioxidant works

Other Properties of
Excipients
Excipients

can also affect drug stability by altering

microclimate pH.
The surface acidity of excipients has been reported to
be a factor contributing to drug degradation
Lomustine exhibited faster degradation in poly( d,llactide) microspheres than in its pure crystalline state
enhanced degradation has been attributed to
molecular dispersion of the drug in the microspheres,
the possibility that the terminal carboxylic acid
groups of poly( d,l-lactide) effect micro-pH changes
Enhanced degradation of solid oxazolam in the
presence of microcrystalline cellulose may be
attributed to carboxylic acid groups on the cellulose
surface

Miscellaneous Factors
Excipients

affect drug degradation via

various mechanisms other than pH changes.
The effect of stearate on the degradation of
aspirin has been explained by a change in
melting behavior rather than pH changes
Dye excipients may enhance oxidation and
photodegradation of drugs by producing
singlet oxygen that participates in chain
reactions.
Ex: enhancement of the oxidation of
phenylbutazone and ascorbic acid by dye
excipients.

Miscellaneous Factors

irradiation is employed for the

sterilization of some
pharmaceutical products, and its
effect on drug stability should
therefore be considered.

Vapor-Phase Transfers
Including Sublimation
Pharmaceuticals

containing components
that sublime easily may undergo changes in
drug content owing to the sublimation of
the drug substances or excipients.
In the case of nitroglycerin, which is a liquid
with a significant vapor pressure, sublingual
tablets exhibited significant variations in
drug content during storage owing to inter
tablet migration through the vapor phase
This transfer was inhibited by adding watersoluble nonvolatile fixing agents such as
polyethylene glycol.

Kinetics of Solid-Phase
Transitions
The

Hancock.Sharp equation is often

used to describe the kinetics of
polymorphic transitions:
In [In( 1 . ) = In B + m In t
B is a constant
is the fraction of drug in the product state
over the fraction in the starting state.
By

plotting the left-hand side of Eq.

against the logarithm of time, a linear
relationship with a slope of m is
obtained.

Effect of Packaging on
Stability of Drug Products
primary

role of packaging, other than its

esthetic one, is to protect the dosage forms
from moisture and oxygen present in the
atmosphere, light, and other types of exposure,
especially if these factors affect the overall
quality of the product on long-term storage.
Protection from light can be achieved using
primary packaging (packaging that is in direct
contact with the dosage forms) and secondary
packaging made of light-resistant materials.
Incorporating oxygen adsorbents such as iron
powder in packaging units can reduce the effect
of oxygen

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