Transcript ******* 1

Drug stability
Prepared by :
Dima Alhashlamoun
Doaa Sider
Instructor :
Mr.Yaseen Qawasmi
 Druges
in liquid or solid dosage forms
susceptible to chemical decomposition which
leads to :
1) physical changes (discoloration)
2) Chemical changes (loss of potency)
To take the precautions to minimise the loss of potency
(activity) of drugs in certin enviromental conditions :
Study the kinetics of the decompostion process .
2) Determine the shelf-life : time taken for the concentration
of the drug to be reduced to 95% of it’s value when
prepared.
1)
Chemical decomposition process
 Hydrolysis
 Oxidation
 Isomerision
 Photochemical decomposition
 Polymerisation
I.
Hydrolysis
 The drug is susceptible to this type of degradation if it is a
derivative of carboxulic acid or contains functional groups
based on this moiety
Functional groups can hydrolysis
Functional
group
structure
Example
Imide
Glutethimide
Lactam
Penicillins
Cephalosporins
Lactone
Pilocarpine
Spironolactone
Ester
Aspirin,physostigmine,tetracaine,procai
ne
Amide
Ergometrine,benzylpenicllin sodium
 Hydrolysis in water and catalysed by :
Acid catalysis : by hydrogen ion(H+) or other acidic
species.
2) Basic catalysis: by hydroxyl ion(OH-) or other basic
species.
1)
Hydrolysis of esters
hydrolysis of amide
Controlling drug hydrolysis in solution
1) Optimisation of formulation
2) Modification of chemical structure of drug
Optimisation of formulation
 To stabilise a solution of a druge which is susceptible to acid-base
catalysed hydrolysis :
Detrmine the pH of maximum stability from kinetic experiments at
a range of pH values and to formulate the product at this pH.
2) Alteration of the dielectric constant by the addition of nonaqueous
solvents such as alcohol, glycerin or propylene glycol.
1)
3) Reducing the solubilty of the drug ,by using additives (such as
citrates, dextrose, sorbitol and gluconate for pencillin)
(Since only that portion of the drug which is in solution will be
hydrolysed, it is possible to suppress degradation by making the
drug less soluble)
4)Adding a compound that forms a complex with the drug. The
addition of caffeine to aqueous solutions of some druges
(procain) decreases the base-catalysed hydrolysis.
5) solubilisation of a drug by surfactants protects against hydrolysis
Modification of chemical structure of
drug
- The modification ( ex: substituention , elemnation)should
increase the drug stability without reducing the therapeutic
effiency.
- Hammett linear free energy relationship Used to measure the
effect of substituents on the rates of aromatic side-chain
reactions, such as the hydrolysis of esters.
Hammett linear free energy
relationship
Logk=logk0+σρ
Where:
k : the rate constants for the reaction of the substituted
k0 : the rate constants for the reaction of the unsubstituted
σ : the Hammett substituent constant ( determined by the
nature of the substituents and is independent of the reaction)
ρ : the reaction constant. (dependent on the reaction, the
conditions of reaction and the nature of the side-chains
undergoing reaction).
Hammett linear free energy
relationship
 a plot of log k against the Hammett constant is linear if this
relationship is obeyed, with a slope of ρ.
2. Oxidation
 oxidation is the next most common pathway for drug
breakdown After hydrolysis.
 the oxidative process has usually been eliminated by storage
under anaerobic conditions without an investigation of the
oxidative mechanism.
Oxidation process
 Initiation can be via free radicals formed from organic compounds by
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the action of light, heat or transition metals such as copper and iron
which are present in trace amounts in almost every buffer.
The propagation stage of the reaction involves the combination of
molecular oxygen with the free radical R to form a peroxy radical
ROO., which then removes H from a molecule of the organic
compound to form a hydroperoxide, ROOH, and in so doing creates
a new free radical
The reaction proceeds until the free radicals are destroyed by
inhibitors or by side-reactions which eventually break the chain.
The rancid odour which is a characteristic of oxidised fats and oils is
due to aldehydes, ketones and shortchain fatty acids which are the
breakdown products of the hydroperoxides.
Peroxides (ROOR,) and hydroperoxides (ROOH) are photolabile,
breaking down to hydroxyl (HO) and or alkoxyl (RO)radicals, which
are themselves highly oxidising species.
Drugs susceptible to oxidation
1)
2)
Steroid and sterols: are subject to oxidative degradation
through the possession of carbon–carbon double bonds
(alkene moieties) to which peroxyl radicals can readily
add.
polyunsaturated fatty acids.
 From druges :
1) cholesterol-lowering agent simvastatin : contain
conjugated double bonds, addition of peroxyl radicals may
lead to the formation of polymeric peroxides, cleavage of
which produces epoxides which may further degrade into
aldehydes or ketones.
simvastatin
2) Polyene antibiotics, such as amphotericinB which contains
seven conjugated double bonds (heptaene moiety), are
subject to attack by peroxyl radicals, leading to aggregation
and loss of activity.
3) The oxidation of phenothiazines to the sulfoxide involves two
single-electron transfer reactions involving a radical cation
intermediate The sulfoxide is subsequently formed by
reaction of the cation with water.
4) ether group in drugs such as econazole nitrate and miconazole nitrate
is susceptible to oxidation.
The process involves removal of hydrogen from the C–H bonds in the αposition to the oxygen to produce radicals, which further degrade to
α-hydroperoxides and eventually to aldehydes, ketones, alcohols and
carboxylic acids.
Stabilisation against oxidation
1) The oxygen in pharmaceutical containers should be replaced
with nitrogen or carbon dioxide.
2) contact of the drug with heavy-metal ions such as iron,
cobalt or nickel, which catalyse oxidation, should be
avoided.
3) storage should be at reduced temperatures.
4) Using antioxidants.
antioxidants
- The propagation of the chain reaction may be prevented or
delayed by adding low concentrations of antioxidants that act
as inhibitors. interrupt the propagation by interaction with
the free radical.
- The antioxidant free radical so formed is not sufficiently
reactive to maintain the chain reaction and is eventually
annihilated.
- Reducing agents such as sodium metabisulfite may also be
added to formulations to prevent oxidation. These
compounds are more readily oxidised than the drug and so
protect them.
- Oxidation is catalysed by unprotonated amines such as
aminophylline, and hence amixture of susceptible drugs with
such compounds should be avoided.
Structures of some common
antioxidants
Isomerisation
 Isomerisation : is the process of conversion of the drug into
its optical or geometric isomers .
 various isomers of a drug are frequently of different activity,
such a conversion may be regarded as a form of degradation,
often resulting in a serious loss of therapeutic activity.
Racemisation of adrenaline at low pH
Isomerisation of vitamin A
(Cis–trans isomerisation )
Photochemical decomposition
Photodecomposition occur :
 during storage
 during use of the product. As sunlight is able to
penetrate the skin to a sufficient depth to cause
photodegradation of drugs circulating in the
surface capillaries or in the eyes of patients
receiving the drug.
 Primary photochemical reaction occurs when
1. the wavelength of the incident light is within the wavelength
range of absorption of the drug (usually within the ultraviolet
range, unless the drug is coloured), so that the drug molecule
itself absorbs radiation and degrades.
2. with drugs that do not directly absorb the incident radiation, as a
consequence of absorption of radiation by excipients in the
formulation (photosensitisers) which transfer the absorbed energy to
the drug, causing it to degrade.
The effect of ultraviolet light on
chlorpromazine (CLP).
V Polymer produced by the ultraviolet
irradiation of chlorpromazine under
anaerobic conditions
Stabilisation against photochemical
decomposition
 the use of coloured glass containers
 storage in the dark.
“Amber glass excludes light of wavelength `470 nm and so affords
considerable protection of compounds sensitive to ultraviolet
light.”
 Coating tablets with a polymer film containing ultraviolet
absorbers has been suggested as an additional method for
protection from light. In this respect, a film coating of vinyl
acetate containing oxybenzone as an ultraviolet absorber has been
shown to be effective in minimising the discoloration and
photolytic degradation of sulfasomidine tablets.
Polymerisation
Polymerisation is the process by which two or more identical drug
molecules combine together to form a complex molecule.
Dimerisation and hydrolysis of
ampicillin.
Kinetics of chemical decomposition in
solution
- Before we can predict the shelf-life of a dosage form it is
essential to determine the kinetics of the breakdown of the
drug under carefully controlled conditions.
Classifying reactions: the order of
reaction
 Reactions are classified according to the order of reaction:
number of reacting species whose concentration determines the
rate at which the reaction occurs.
 We will concentrate mainly on:
1) zero-order reactions, in which the breakdown rate is
independent of the concentration of any of the reactants.
2)
first-order reactions, in which the reaction rate is determined by
one concentration term.
3)
Second order reactions, in which the rate is determined by the
concentrations of two reacting species.
1) zero-order reactions
- Dx/dy=K0
- This type of reaction,can often occur
in suspensions of poorly soluble
drugs.In these systems the suspended
drug slowly dissolves as the drug
decomposes and so a constant drug
concentration in solution is maintained.
- Ex : hydrolysis of acetyl
-
salicylic acid
2) first-order reactions
- Dx/dy=K1[A]=K1(a-x)
- Ex : hydrolysis of homatropine
- pseudo first-order reaction: occurs when one of the reactants is in such a
large excess that any change in its concentration is negligible compared
with changes in the concentration the other reactants.
- Such reactions are often met in stability studies of drugs that hydrolyse
in solution,the water being in such excess that changes in its
concentration are negligible and hence the rate of reaction is dependent
solely on the drug concentration.
Second order reactions
Dx/dy=K1[A][B]
Dx/dy=K1[A] [B]=K1(a-x)(b-x)
Complex reactions
- There are many examples of drugs in which decomposition
occurs simultaneously by two or more pathways, or involves
a sequence of decomposition steps or a reversible reaction.
- Complex reaction:
Reversible reactions
b. Parallel reactions
c. Consecutive reactions
a.
Reversible reactions
 the kinetics of a reversible reaction involves two rate
constants :
- Kf: describe the rate of the forward reaction
- kr: describe the rate of the reverse reaction
 For the simplest example in which both of these reactions are
first-order ex: epimerisation of tetracycline
Parallel reactions
 The decomposition of many drugs involves two or more pathways,
the preferred route of reaction being dependent on reaction
condition.
 Ex: Nitrazepam decomposes in two pseudo first-order parallel
reactions giving different breakdown products in solution and in the
solid state.
Decomposition of nitrazepam tablets in the presence of moisture will
occur by both routes, the ratio of the two products being dependent
on the amount of water present.
 In other cases decomposition may occur simultaneously by two
different processes, as in the simultaneous hydrolysis and
epimerisation of pilocarpine .
Consecutive reactions
 where each step is a nonreversible first-order reaction. The
hydrolysis of chlordiazepoxide follows a first-order
decomposition
Solid dosage forms: kinetics of
chemical decomposition
1) Solids that decompose to give a solid and a
gas.
2) Solids that decompose to give a liquid and
a gas.
Solids that decompose to give a solid and
a gas
 Ex : p-aminosalicylic acid, which decomposes to a solid (p-
aminophenol) and a gas (carbon dioxide)
 The decomposition curves which result from such a reaction show
either:
(a) an initial rapid decomposition followed by a more gradual
decomposition rate.
- The shape produced called topochemical (contracting geometry).
- The model used in the treatment is that of a cylinder or sphere.
- it is assumed that the radius of the intact chemical substance decreases
linearly with time.
- For the contracting cylinder model, the mole fraction x decomposed
at time t is given by
(1 –x)1/2 = 1 – (K/r0)t
Example of this type decompostion of aspirin at elevated tempreture.
- For the contracting sphere model
(1-x)1/3 = 1- (k/r0)t
- A similarity between these and the first-order rate equations, this
similarity might account for the fact that many decompositions in
solid dosage forms appear to follow first-order kinetics.
Solids that decompose to give a liquid
and a gas
- An example of a solid in this category is p- aminobenzoic acid,
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which decomposes into aniline and carbon dioxide.
Decomposition causes a layer of liquid to form around the solid
which dissolves the solid.
The decomposition curves show an initial lag period which
corresponds to the establishment of the liquid layer.
Beyond this region, the plot represents the first-order
decomposition of the solid in solution in its liquid decomposition
products.
There are thus two rate constants, that for the initial
decomposition of the solid itself, and that for the decomposition
of the solid in solution.
Factors influencing drug stability
 For Liquid dosage forms:
1)
2)
3)
4)
5)
6)
7)
PH
Temperture
Ionic strength
Solvent effect
Oxygen
Light
Surfactant
PH
Studying the influence of pH on degradation rate:
- a pH rate profile : the hydrolysis rate of the drug in a series
of solutions buffered to the required pH is measured and the
hydrolytic rate constant is then plotted as a function of pH.
- this will almost certainly be influenced by the buffers used to
It is probable that a different pH rate profile would be
obtained using a different buffer.
• Acidic and alkaline pH influence the rate of decomposition of most
drugs.
• Many drugs are stable between pH 4 and 8.
• Weekly acidic and basic drugs show good solubility when they are
ionized and they also decompose faster when they are ionized.
Reactions catalyzed by pH are monitored by measuring degradation
rates against pH, keeping temperature, ionic strength and solvent
concentration constant. Some buffers such as acetate, citrate,
lactate, phosphate and ascorbate buffers are utilized to prevent
drastic change in pH.
- So if the pH of a drug solution has to be adjusted to improve
solubility and the resultant pH leads to instability then a way out of
this tricky problem is to introduce a water miscible solvent into the
product. It will increase stability by:
- reducing the extreme pH required to achieve solubility
- enhancing solubility
- reducing the water activity by reducing the polarity of the solvent.
For example, 20% propylene glycol is placed in chlordiazepoxide
injection for this purpose
Temperture
- Increase in temperature usually causes a very pronounced increase in
the hydrolysis rate of drugs in solution.
- Such studies are usually carried out at high temperatures, say 60 or
80°C, because the hydrolysis rate is greater at these temperatures and
can therefore be measured more easily.
- The equation which describes the effect of temperature on
decomposition, and which shows us how to calculate the rate of break
down at room temperature from measurements at much higher
temperatures, is the Arrhenius equation.
- When it is clear from stability determinations that a drug is
particularly unstable at room temperature, then of course it will need
to be labelled with instructions to store in a cool place.
This is the case, for example, with injections of penicillin, insulin,
oxytocin and vasopressin.
Ionic strength
 electrolytes add to drug solutions to control their tonicity, but
we must pay attention to any effect they may have on stability.
 The equation which describes the influence of electrolyte on the
rate constant is the Brønsted–Bjerrum equation:
Logk= logk0+2AZAZBЛ1/2
 In this equation:
- zA and zB are the charge numbers of the two interacting ions
- A is a constant for a given solvent and temperature.
- μ is the ionic strength of the solution.
Solvent effects
K is a constant for a given system at a given temperature.
We can see that a plot of log k as a function of the reciprocal of
the dielectric constant, ε, of the solvent should be linear with a
gradient of magnitude KzAzB
and an intercept equal to the logarithm of the rate constant
in a theoretical solvent of infinite dielectric constant.
 If the charges on the drug ion and the interacting species are the
same, then we can see that the gradient of the line will be
negative. In this case, if we replace the water with a solvent of
lower dielectric constant then we will achieve the desired effect
of reducing the reaction rate.
 If the drug ion and the interacting ion are of opposite signs,
however, then the slope will be positive and the choice of a
nonpolar solvent will only result in an increase of
decomposition.
Oxygen
 Since molecular oxygen is involved in many oxidation schemes, we
could use oxygen as a challenge to find out whether a particular
drug is likely to be affected by oxidative breakdown.
 We would do this by storing solutions of the drug in ampoules
purged with oxygen and then comparing their rate of breakdown
with similar solutions stored under nitrogen.
 Formulations that are shown to be susceptible to oxidation can be
stabilized by replacing the oxygen in the storage containers with
nitrogen or carbon dioxide, by avoiding contact with heavy metal
ions, and by adding antioxidants
Light
 Photolabile drugs are usually stored in containers which
exclude ultraviolet light, since exposure to light in this
wavelength range is the most usual cause of photodegradation
 Amber glass is particularly effective in this respect because it
excludes light of wavelength of less than about 470 nm.
 As an added precaution, it is always advisable to store
photolabile drugs in the dark.
Surfactants
kobs = kmfm + kwfw
kobs, km and kw are the observed, micellar and aqueous rate constants,
respectively, and fm and fw are the fractions of drug associated
with the micelles and aqueous phase, respectively.
 The value of km is dependent on the location of the drug within
the micelle.
 A solubilisate may be incorporated into the micelle in a
variety of locations.
 Nonpolar compounds are thought to be solubilised within
the lipophilic core and, as such, are likely to be more
effectively removed from the attacking species than those
compounds that are located close to the micellar surface.
 Where the drug is located near to the micellar surface, and
therefore still susceptible to attack, the ionic nature of the
surfactant is an important influence on decomposition rate.
 For base-catalysed hydrolysis, solubilisation into anionic micelles
affords an effective stabilisation due to repulsion of OH- by the
micelles.
 Conversely, solubilisation into cationic micelles might be expected
to cause an enhanced base-catalysed hydrolysis.
 Many drugs associate to form micelles in aqueous solution and
several studies have been reported of the effect of this selfassociation on stability.
Semisolid dosage forms
 The chemical stability of active ingredients incorporated into
ointments or creams is frequently dependent on the nature of the
ointment or cream base used in the formulation.
 Such dilution is, unfortunately, common practice in cases where
the practitioner wishes to reduce the potency of highly active
topical preparations, particularly steroids. The pharmaceutical and
biopharmaceutical dangers of this procedure have been stressed.
 Of particular interest here are the problems of drug stability
which can occur through the use of unsuitable diluents.
 the dilution of betamethasone valerate cream with a cream
base having a neutral to alkaline pH. Under such conditions,
conversion of the 17-ester to the less-active betamethasone
21-ester can occur.
 Similarly, diluents containing oxidising agents could cause
chemical degradation of fluocinolone acetate to less-active
compounds.
Solid dosage forms
Moisture
 Water-soluble drugs present in a solid dosage form will
dissolve in any moisture which has adsorbed on the solid
surface. The drug will now be in an aqueous environment and
its decomposition could be influenced by many of the factors
which affect the liquid dosage forms.
 moisture is considered to be one of the most important
factors that must be controlled in order to minimise
decomposition.
The effect of water vapour pressure on
the decomposition of aminosalicylic
acid.
Excipients
 Excipients such as starch and povidone have particularly high
water contents (povidone contains about 28% equilibrium
moisture at 75% relative humidity).
 However, whether this high moisture level has an effect on
stability depends on how strongly it is bound and whether the
moisture can come into contact with the drug.
 Magnesium trisilicate causes increased hydrolysis of aspirin in
tablet form because, it is thought,of its high water content.
 Chemical interaction between components
in solid dosage forms may lead to increased
decomposition.
Reactions showing the postulated transacetylation
between aspirin and paracetamol and the direct
hydrolysis of paracetamol.
Development of free salicylic acid in aspirin–
paracetamol–codeine and aspirin–phenacetin–
codeine tablets at 37°C.
Temperature
The drug or one of the excipients may, for example,
1. melt or change its polymorphic form as temperature
is increased,
2. it may contain loosely bound water which is lost at
higher temperatures.
3. the relative humidity will change with temperature
and so we must take care to keep this at a constant
value.
Light and oxygen
 the stability problems which arise with drugs which are
susceptible to photodecomposition or oxidation.
 water contains dissolved oxygen and so the presence of
moisture on the surface of solid preparations may increase
the oxidation of susceptible drugs; such drugs must,
therefore, be stored under dry conditions.
Stability testing and prediction of
shelf-life
1. Effect of temperature on stability
 the basic method of accelerating the chemical decomposition by
raising the temperature of the preparations.
1. The order of reaction can be determined by plotting stability
data at several elevated temperatures according to the
equations relating decomposition to time for each of the
orders of reaction, until linear plots are obtained.
2. calculate values of rate constant at each temperature from
the gradient of these plots
3. plot the logarithm of k against reciprocal temperature
according to the Arrhenius equation:
 The required value of k can be interpolated from this plot at
room temperature, and the activation energy Ea can be
calculated from the gradient, which is –Ea/ 2.303R.Values of Ea
are usually within the range 50–96 kJ mol-1.
Example :
Expiry date calculation
 Once the rate constant is known at the required storage
temperature, it is a simple matter to calculate a shelf-life for
the product based on an acceptable degree of decomposition.
 The equations which we can use for 10% loss of activity are
obtained by substituting x=0.1a in the zero- and first-order
equations giving
where [D]0 is the initial concentration of drug.
t0.9 is usually used as an estimate of shelf-life, other percentage decompositions
may be required,
for example when the decomposition products produce discoloration or
have undesirable side-effects. The equired equations for these may be derived
by substituting in the relevant rate equations.
Example :
Suspensions
 stability testing of suspensions is the changes in the solubility
of the suspended drug with increase in temperature.
 With suspensions, the concentration of the drug in solution
usually remains constant because, as the decomposition
reaction proceeds, more of the drug dissolves to keep the
solution saturated. this situation usually leads to zero-order
release kinetics.
Solid state
 The main problems arising in stability testing of solid dosage
forms are:
(a) that the analytical results tend to have more scatter because
tablets and capsules are distinct dosage units rather than the
true aliquots encountered with stability studies on drugs in
solution.
(b) that these dosage forms are heterogeneous systems often
involving a gas phase (air and water vapour), a liquid phase
(adsorbed moisture) and the solid phase itself. The
compositions of all of these phases can vary during an
experiment.
 The first of these problems can be overcome by ensuring
uniformity of the dosage form before commencing the
stability studies.
 The problems arising from the heterogeneity are more
difficult to overcome.
 The main complicating factor is associated with the presence
of moisture. moisture can have a significant effect on the
kinetics of decomposition and this may produce many
experimental problems during stability testing.
 For example, what happen with gelatin capsules.
To reduce some of these problems , particularly those
associated with moisture, during stability testing, the
following have been suggested:
(a) the use of tightly sealed containers, except where the effect
of packaging is to be investigated
(b) that the amount of water present in the dosage form should
be determined, preferably at each storage temperature
(c) that a separate, sealed ampoule should be taken for each
assay point and water determination, thus avoiding
disturbance of water equilibrium on opening the container.
2. Other environmental factors affecting
stability
- Light
Photostability testing of drug substances
1. the sample is irradiated at all absorbing wavelengths using a
broad-spectrum light source.
2. Those drugs or formulations which are shown to be
photosensitive are then subjected to more formal photostability
testing in which they are challenged with light of wavelength
comparable to that to which the formulations are exposed in
practical situations.
3. During their shelf-life it is most likely that the products will be
exposed to fluorescent light, direct daylight and daylight filtered
through window glass, and the stability testing procedures are
designed to cover these possibilities
- Oxygen
 Exaggeration of the effect of oxygen on stability may be
achieved by an increase in the partial pressure of oxygen in
the system.
- Moisture content
The stability of solid dosage forms is
usually very susceptible to the
moisture content of the
atmosphere in the container in
which they are stored
Protocol for stability testing
The stability test protocol should be found on :
 Drug substance is a pure material which exerts a
pharmacological action
 Drug product is a finished end product which may contain
one or more drug substances in combination with excipients
meant for use by humans and animals
Drug substances
 Stability information from accelerated and long-term testing
is required to be provided on at least three batches
manufactured to a minimum of pilot plant “ one tenth that of
the batch ”.
 The containers to be used in the long-term evaluation should
be the same as, or simulate, the actual packaging used for
storage and distribution.
 The testing should be designed to cover those features
susceptible to change during storage and likely to influence
quality, safety and/or efficacy, including, as necessary, the
physical, chemical and microbiological characteristics.
 The length of the studies and the storage conditions should
be sufficient to cover storage, shipment and subsequent use.
 The specifications for the long-term testing are a temperature of 25
± 2°C and 60±5% relative humidity (RH) for a period of 12
months.
 For accelerated testing the temperature is specified as 40 ± 2°C
and RH as 75 ± 5% for a period of 6 months. if a ‘significant
change’ occurs during this period, additional testing at an
intermediate temperature (such as 30±2°C,60% ± 5% RH)
should be conducted for drug substances.
 ‘Significant change’ at 40°C75% RH or 30°C60% RH is defined
as failure to meet the specification.
 Temperature sensitive drugs that should be stored at a lower
temperature, is tested under these conditions
 The long-term testing is required to be continued for a
sufficient period beyond 12 months to cover all appropriate
re-test periods.
 under the long term conditions this will normally be every 3
months over the first year, every 6 months over the second
year and then annually.
Drug product
 The conditions and time periods for long-term and accelerated
storage testing are the same as those outlined above for drug
substances but with special considerations arising from the nature
of the drug product.
 For example , If it is necessary to store the product at a lower
temperature because of its heat sensitivity then consideration
should be given to any physical or chemical change in the product
which might occur at this temperature; for example,
- suspensions or emulsions may sediment or cream,
- while oils and semi-solid preparations may show an increased
viscosity.
In the case of drug products, ‘significant change’ at the
accelerated condition is definedas
● A 5% potency loss from the initial assay value of a batch
● Any specified degradant exceeding its specification limit
● The product exceeding its pH limits
● Dissolution exceeding the specification limits for 12 capsules
or tablets
● Failure to meet specifications for appearance and physical
properties, e.g. colour, phase separation, resuspendability,
delivery per actuation, caking and hardness
 If significant change occurs at 40°C75% RH then it is
necessary to submit a minimum of 6 months’ data from an
ongoing one-year study at 30°C60% RH using the same
criteria for ‘significant change’.