STABILITY OF DOSAGE FORMS

 Dosage forms are designed to

perform certain functions.
For example: a specific dosage form
such as a traditional tablet might be
designed for rapid release of the
active drug upon exposure to an
aqueous medium.
 Iflarge changes in the dissolution
characteristics of the drug on long-
term storage of the dosage form are
observed,
 This would indicate that changes are
occurring in the dosage form that
may compromise the performance of
the dosage form in patients.
 Altered functioning of the dosage
form with time may be related to
changes in the chemical or physical
properties of the drug, excipients,
coating materials etc.,
 Or it may be related to complex
interactions between various
components of the dosage form.
CHANGES IN MECHANICAL STRENGTH
 Storage of solid dosage forms under
humid conditions may bring about
adsorption of moisture and lead to
changes in the mechanical strength of
tablets.
 Adsorption of moisture by tablets in
blister packages increased with increasing
humidity, and resulted in decreased
mechanical strength.
 The change in mechanical strength
was described as a function of:
I. The moisture sensitivity of the
tablet,
II. The moisture permeability of the
package, and
III. The humidity conditions.
CHANGES IN DRUG DISSOLUTION FROM
TABLETS AND CAPSULES
 Forexample :
The dissolution rate of carbamazepine
tablets decreased markedly when they
were stored at room temperature and
100% RH for a period as short as 6 days.

 Suchdramatic changes in dissolution rate

may alter the bioavailability of the drug.
EFFECT OF FORMULATION ON CHANGES
IN DISSOLUTION

 The stability of the dissolution characteristics of

dosage forms during storage can be affected by
formulation components and processing.

 A phenobarbital tablet containing gelatin as a

binder exhibited a marked decrease in
dissolution rate during storage at 98% RH.

 The dissolution rate of hydrochlorothiazide

tablets containing acacia increased during
storage at high temperatures.
A decrease in dissolution rate during
storage was also observed with a
hydrochlorothiazide bead formulation
containing sodium starch glycolate,

 whereas the dissolution rate of

nitrofurantoin capsules decreased during
storage at high humidity as the content of
carbomer increased, leading to a decrease
in bioavailability.
 As excipients affect the dissolution
characteristics of dosage forms over
time, the water content of dosage
forms can also affect stability
(dissolution).

 Ex:calcium 4-aminositlicylate
tablets at high humidity : long
disintegration time and low
dissolution rate.
CHANGES IN DRUG RELEASE FROM
COATED DOSAGE FORMS
 Thestability of the drug release
characteristics of film-coated tablets
and pellets is affected by the
stability of the films.

 Thisshould be the case especially

when the film contributes
significantly to the rate-limiting step
in the release.
 Drug release from enteric-coated and
sugar-coated tablets was more
susceptible to the effect of humidity
than that from film-coated tablets.

 Ex:storage of sugar-coated tablets

changed the disintegration time,
leading to increased or decreased
dissolution rate.
Enteric-coated aspirin tablets
exhibited a decrease in
dissolution rate during storage
at 33°C and 60% RH.

A similar decrease in dissolution

rate is reported for sugar-coated
chlorpromazine tablets.
 Although drug release from film-coated
tablets is generally more stable than that
from enteric-coated and sugar-coated
tablets, the release rates may change
depending on storage conditions.

 For example, film-coated chlorpromazine

tablets exhibited a change in drug release
at temperature conditions cycling between
30°C and room temperature.
 Storageof tableted
microencapsulated aspirin granules
prepared with polyacrylate-
polymethacrylate-based polymers
resulted in decreased drug release
with storage time.
CHANGES IN CAPSULE SHELLS WITH
TIME AND STORAGE CONDITIONS
 Capsules prepared from gelatin are
physically unstable at water contents
outside (>) the range of 12.18%.
 Storage of two chloramphenicol capsules
at high humidity prolonged the
disintegration time and decreased the
drug release rate.
 Decrease in the drug release from
ampicillin capsules during storage at high
humidity was suggested to be due to the
agglomeration of drug particles caused by
moisture.
 Drug release from capsules may change
owing to the reaction of the capsule shells
with the contents.
 A decrease in the drug release rate from
capsules containing polysorbate 80 was
explained by assuming that cross-linking
of gelatin was promoted by formaldehyde
formed from the oxidation of polysorbate
80.
 Interaction of dyes and gelatin in capsule
shells, especially under light, could
change the rate of drug release from
capsules.
CHANGES IN MELTING TIME OF
SUPPOSITORIES
 Suppositories are designed to melt
after rectal administration, and this
process is crucial to the release of
active ingredients.

 If
storage results in hardening of the
suppositories such that the time to
melt is prolonged.
 long-term storage of some products, even
at 20°C, resulted in a prolongation of
melting times.
 The hardening effect increased with
increased storage temperature up to
25°C but decreased at higher
temperatures owing to partial melting of
the suppository base.
 Thus, in this case, accelerated testing at a
higher temperature would not have been
useful.
 Many suppository bases are made up of
various acylglycerols.
 Hardening of suppositories is considered
to result from various phase transitions,
crystallization, and transesterification
reactions in these lipids.
 The DSC thermograms of a
semisynthetic, hard base triglyceride
indicate that a polymorphic phase
transition occurred during storage.
CHANGES IN DRUG RELEASE RATE FROM
POLYMERIC MATRIX DOSAGE FORMS,
INCLUDING MICROSPHERES

 Polymeric matrix dosage forms

intended for controlled release may
undergo changes in drug release rate
upon storage.
 For example, poly( d,l-lactic acid)
microspheres exhibited shrinkage
and decreased release rates of
phenobarbitone after 6-month
storage at 37°C.
 Various physical properties of the
matrix such as the glass-transition
temperature (Tg) and the crystalline
states of polymers affect drug release
from polymeric matrix dosage forms.

 Changes in these properties during

storage can lead to changes in the
drug release rate.
 An increase in the Tg of poly( d, l-lactide-co-
glycolide) microspheres was observed during
storage at 40°C.

 The Tg of biodegradable microspheres may also

decrease as a result of polymer decomposition
during storage.

 The lowered Tg of poly( l-lactide) microspheres

due to the lowered molecular weight of the
polymer resulted in an increase in drug release
rate from the microspheres.
 Changes in the crystalline state of
polymer matrices during storage may
result in changes in drug release from
microspheres.

 Amorphous poly( l-lactide) microspheres

containing progesterone exhibited an
increased release rate following storage
due to polymer crystallization.
DRUG LEAKAGE FROM LIPOSOMES
 During storage, liposomes may exhibit physical
instability, leading to leakage of intraliposomal
entrapped drugs.

 In addition, chemical degradation of lipid

membrane components resulting from oxidation
and hydrolysis also changes drug release rates
from liposomes.

 For example, phospholipid hydrolysis increased

the permeability of a liposome membrane,
resulting in increased leakage.
 Drug leakage from liposomes following storage
depends on liposomal structure and membrane
components.

 Optimization of membrane components and

excipients to reduce drug leakage during storage
has been attempted.

 Liposomes made from egg yolk lecithin exhibited

drug leakage following storage; however, this
effect was reduced by storage at low temperature
in an oxygen-free atmosphere or by including
antioxidants such as α -tocopherol in the
formulation.
 Drug leakage was diminished in collagen-
containing solutions, suggesting that
collagen produced a decrease in liposome
permeability through an antioxidant
effect.
 Aggregationof liposomes upon storage
also depends on membrane components.

 Liposomes that included taurine as an

isotonic solute were most stable at an
optimal content of benzalkonium chloride.

 Repulsive energy forces between particles

described by the Deryaguin-Verwey-
Overbeek theory appeared to account for
the stabilization.
AGGREGATION IN EMULSIONS
 Aggregation
is a normal physical
phenomenon in emulsion formulations.

 Oxygen-transporting emulsions of
perfluorodecalin needed stabilizing
additives to prevent aggregation.

A series of total parenteral nutrition

admixtures exhibited changes in the
droplet size during storage, which was
detected by Coulter counter and laser
diffractometry measurements.
Theemulsion stability was
dependent on the emulsion zeta
potential and was predicted by
the Deryaguin-Landau-Verey-
Overbeek theory.
 Increasing the storage temperature
from 25 to 40°C markedly reduced
the stability of a clofibride emulsion
for oral administration, whereas
storage at 4°C caused rapid phase
separation owing to decreased
solubility.
 In this study, the physical stability of
emulsions under stressed conditions was
evaluated by subjecting them to
ultracentrifugation (25,500 x g over 1 h),
repeated freeze-thaw cycles (16 h of
freezing at -18°C and 8 h of thawing at
25°C), and excessive shaking (150
strokes/min at 25°C over 48 h).
MOISTURE ADSORPTION
 Moisture adsorption by solid dosage
forms can result not only in
increased chemical drug degradation
but also in changes in the functional
stability of dosage forms.

A hard gelatin capsule exhibited

moisture sorption depending on
humidity.
 The moisture permeation rate of a
sugar coating composed of sucrose,
talc, and other minor components
was reported to conform to Fick’s
equation.

 Thepermeation rate appeared to be

rate-controlling for moisture
adsorption by sugar-coated tablets.
DISCOLORATION
 Although the discoloration of dosage
forms may result from chemical
degradation, the mechanisms are
usually unclear.
 Thus, discoloration is generally
considered to be a physical
degradation (degradation of
.appearance.).
 Empirical equations such as the
Weibull equation have been used to
predict discoloration of some dosage
forms.

 Discolorationof a parenteral
formulation of ascorbic acid was
described by the Weibull equation.
EFFECT OF PACKAGING ON STABILITY
OF DRUG PRODUCTS

 The role that packaging plays in the overall

perceived and actual stability of the dosage form
is well established.

 Packaging plays an important role in quality

maintenance, and the resistance of packaging
materials to moisture and light can significantly
affect the stability of drugs and their dosage
forms.

 It is crucial that stability testing of dosage forms

in their final packaging be performed.
 The 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.
Moisture Penetration
 Many studies have been conducted on
predicting the role of packaging in
moisture adsorption by dosage forms.

 Adsorption of moisture by tablets

contained in polypropylene films was
successfully modeled from storage
temperature and the difference in water
vapor pressure between the inside and
outside of the packaging,
 Themoisture adsorption of moisture by
cloxazolam tablets through packaging
composed of polyvinyl chloride and on
aluminum film under nonisothermal
conditions was predicted from the
moisture permeability coefficient of the
packaging as well as from temperature
and humidity conditions inside and
outside the packaging.
 Chemical and physical degradation of packaged
dosage forms caused by moisture adsorption has
been predicted from the moisture permeability of
the packaging.

 For example, strength changes of lactose-corn

starch tablets in strip packaging (SP).

 Discoloration of sugar-coated tablets of ascorbic

acid and hydrolysis of aspirin aluminum tablets
in glass bottles738 were predicted using the
moisture permeability coefficient of the
packaging.
 Desiccantsare often used to
eliminate moisture in packaging
when the moisture resistance of the
packaging itself is not sufficient to
prevent exposure.

 Theutility of desiccants has been

assessed based on a sorption-
desorption moisture transfer model.
ADSORPTION ONTO AND ABSORPTION INTO
CONTAINERS AND TRANSFER OF CONTAINER
COMPONENTS INTO PHARMACEUTICALS

 Pharmaceuticals may interact with packaging

and containers, resulting in the loss of drug
substances by adsorption onto and absorption
into container components and the incorporation
of container components into pharmaceuticals.

 Diazepam in intravenous fluid containers and

administration sets exhibited a loss during
storage due to adsorption onto glass and
adsorption onto and absorption into plastics.
 Nitroglycerin,
a liquid with a significant
vapor pressure, is also significantly
adsorbed onto and absorbed into
containers.

 Decreases in the drug content of

nitroglycerin tablets in strip packaging
and nitroglycerin solutions in glass and
plastic containers due to
adsorption/absorption were analyzed by a
diffusion model and a model consisting of
adsorption onto the surface followed by
partitioning into the plastic.
 Polyvinyl chloride (PVC), a polymer often used
for pharmaceutical containers, is known to
interact with various drug substances.

 Adsorption and absorption of nitroglycerin onto

and into PVC conformed to apparent first-order
kinetics, and the apparent rate constant
describing uptake showed nonlinear Arrhenius
behavior.

 Absorption of clomethiazole edisylate and

thiopental sodium into PVC infusion bags was
observed.
 The pH dependence of
adsorption/absorption of acidic drug
substances such as warfarin and
thiopental and basic drug substances such
as chlorpromazine and diltiazem indicates
that only the un-ionized form of the drug
substance is adsorbed onto or absorbed
into PVC infusion bags.

 Theabsorption was correlated to the

octanol-water partition coefficients of the
drugs, suggesting that prediction of
absorption from partition data is possible.
 Polymers such as nylon 6
(polycaprolactam) are known to adsorb
drug substances such as benzocaine.

 Glasssurfaces are also known to adsorb

drug substances.

 Chloroquine solutions in glass containers

decreased in concentration owing to
adsorption of the drug onto the glass.
 Rubberclosures are also known to absorb
materials, including drugs.

 Absorption of preservatives such as

chlorocresol into the rubber closures of
injectable formulations has been studied
extensively.
 Water permeability of rubber
closures used in injection vials is
considered an important parameter
in assessing the closures, but
quantitative prediction of water
permeability through rubber
closures is difficult because the
diffusion coefficient of water is
dependent on relative humidity.