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 T
g
Presence of residual crystallinity (defect sites)
can be source for nucleation
In general, grinding/milling produces least stable
amorphous form
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 fisika
Stability of amorphous form
o Reactivity much more likely above T
g
o Above T
g
, reactions in the amorphous state may be
thought of as a continuation of reactions in the melt
o Hydroscopic nature can promote hydrolysis reactions
o May also be more sensitive to oxidation and
photochemical degradation
o small amounts of amorphous material is the source of
many stability problems observed
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 State
Stabilitas kimia
SIMPLEST DECOMPOSITION MODES
OF PURE SOLIDS
Solid is placed in a vacuum & exposed
by temperature
I Solid solid + solid
II Solid solid + liquid
III Solid liquid + liquid
IV Solid solid + gas
V Solid liquid + gas
VI Solid gas + gas
REACTION KINETICS
Faktor-faktor yang mempengaruhi
degradasi obat padat
1. Kelembaban
2. Eksipient
3. Kekerasan tablet
4. Material kemasan
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 free-energy 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 :
mempercepat hidrolisis tablet
Thiamin HCl
Talcum :
mempercepat perubahan warna
pada tablet yang mengandung
amina dan lactose
Mg Stearat :
meningkatkan degradasi tablet
aspirin
Asam stearat
dan kalsium
suksinat
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,l-
lactide) 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 water-
soluble 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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