Stability Basic

Why stability studies ?

 Stability is an essential quality attribute for drug products.
 If there is any functionally relevant quality attribute of a drug product that
changes with time, this evaluation checked by pharmaceutical scientists and
regulators who quantify drug product stability and shelf life.
 The rate at which drug products degrade varies dramatically. e.g.
radiopharmaceutical products
 Since the evaluation of the stability of drug product is highly specialized and
esoteric nature.
 Drug stability concerns about drug product safety , efficacy, and quality, found it
to appropriate.
 Stability studies is done through the regulatory agencies such as the FDA and the
HPB (health protection branch )

Functional changes in dosage forms with time
• It may be related to changes in chemical or physical properties of drug and
excipients, coating materials etc. or it may be related to complex interaction
between components of dosage form.
• Chemical stability can be assessed similar to above for drugs and excipients.
• For assessments of physical changes to dosage form changes specific to each
dosage form should be evaluated.

Changes in Mechanical strength
• Storage in humid condition leads to moisture adsorption and so decreased
mechanical strength of tablet in blister packages.
• The change in mechanical strength can be described as a function of moisture
sensitivity, moisture permeability, and humidity condition which is used for
prediction of storage period.

Changes in drug dissolution from tablets and capsule
• Dissolution of a drug substance is very important characteristic for bioavailability
and it changes on storage
• Changes in melting time of suppositories
• Changes in release rate from polymeric matrix dosage for , including
microspheres
• Drug leakage from liposomes
• Aggregation in emulsion
• Discoloration
• Moisture adsorption

Effect of changes on drug stability of drug products
• Packaging play an important role in quality maintenance and the resistance of
packaging material to moisture and light can significantly affect the stability of
products

• Protection from light can be achieved using primary and secondary packaging
made up of light resistant material.
• Incorporating oxygen adsorbents such iron powder can reduce the effect of
oxygen.3

Relevant guidelines
 ICH Q1A(R2): Stability Testing of New Drug
Substances and Products
 ICH Q1B: Photostability Testing of New Drug
Substances and Products
 ICH Q1C: Stability Testing of New Dosage Forms
 ICH Q5C: Stability Testing of Biotechnological/
 Biological Products
 ICH Q1D: Bracketing and Matrixing Designs
 ICH Q1E: Stability Data Evaluation
 ICH Q1F: Stability Data Package for Zones III and IV

Potential adverse effects of instability in pharmaceutical products
There is a various mechanisms by which
drug products may degrade.
 Loss of active
 Increase in concentration of active
 Alteration in bioavailability
 Loss of content uniformity
 Decline of microbiological status
 Loss of content uniformity
 Decline of microbiological status
 Loss of pharmaceutical elegance and patient acceptability
 Formation of toxic degradation products
 Loss of package integrity
 Reduction of label quality
 Modification of any factor of functional relevance. 1

1. Loss of active
 loss of drug is main significance in the
stability studies of many pharmaceutical products.
 However, it is certainly true that for many products loss of potency is of major
importance.
 we regard any product that contains less than 90% of label claim of drug as
being of unacceptable quality.
 The potency of product stored at the appropriate temperature (250 C for products
to be labelled “store at controlled room temperature”)
2. Increase in concentration of active
 For some products, loss of vehicle can result in an increase in the concentration of
active drug .
 For e.g. lidocaine gels exhibit this behavior

 Perfusion bags sometimes allow solvent to escape and evaporate so that the
product within the bag shows an increase in concentration.

3. Alteration in bioavailability
 Bioavailability of drug products is a subject of great importance to those
concerned with drug product quality .
 If the rate or extent of absorption that characterizes a product changes on storage,
then this of course, a stability problem.
 In particular, if any changes of dissolution test data with time it would effect
bioavailability
4. Loss of content uniformity
 Suspensions are the drug delivery systems most likely to show a loss of content
uniformity as function of time.
 For such systems, determination of ease of redispersion or sedimentation volume
may therefore be included in a stability protocol
5. Decline of microbiological status
 Basically, there are some possible ways in which the microbiological status of a
pharmaceutical product can change significantly with time.
 The microorganism present in the product at the time of manufacture may
reproduce and thus increase the number of viable organisms.
 Thus a product that, when assayed for total bioburden at the time of manufacture,
is within limits, then tested after 6 months storage, exceed the maximum
permitted bioburden is maximum.
6. Loss of pharmaceutical elegance and patient acceptability
 It includes any aspect of the product that might suggest that the product is
somehow substandard or variable.
 For example some drugs that contain amino functional groups, when made into
direct compression tablets that contain spray-dried lactose, which results the some
slight brown speckling on the surface of the tablet .
 This is due to the interaction of the drug with a minor component in the lactose
 Analysis of the tablets might reveal no loss potency or change in dissolution, but
no reputable manufacture will market tablets because of its look.
 It is important point about drug products is that attributes such as appearance,
taste, and smell should be reproducible and not so any significant batch to batch
variation .
7. Formation of toxic degradation products
 If a drug degrades to a molecular species that is toxic, there must be special
attention given to the quantity of such a species found in the product during its
shelf life.
 The classic example is epianhydrotetracycline from tetracycline.
8. Loss of package integrity
 Change in the package integrity during storage or distribution can be a stability
problem that may require careful monitoring.
 For example, if a plastic screw cap loses back-off –torque, the possibility of
chemical or microbiological hazard may be significantly increased.

9. Reduction of label quality
 The label of a drug product must be regarded as an essential element of the
product.
 It provides information on identity, use, and safety. Thus if any aspect of the label
deteriorates with time, this can be a serious stability problem.
 For example, if the plasticizer in a plastic bottle migrates into the label and causes
the ink to run and thus effects legibility, this is major problem.
10. Modification of any factor of functional relevance
 If there is any change of any functionality relevant attribute of a drug product that
adversely affects safety, efficacy, or patient acceptability.
 For example, when some transdermal patches were first introduce into the US, a
problem of adhesion ageing is observed .
 Freshly prepared patches show excellent skin adhesion, while it stored in room
temperature for weeks or months show loss of adhesion.
 Thus in use the patches had a tendency to fall off the patient’s skin 1.

Reasons for stability testing
 Our concerns for patients welfare
 To protect the reputation of the producer
 Requirements of regulatory agencies
 To provide a database that may be of value in the formation of other products
Modes of degradation
Chemical
 Chemical degradation is like solvolysis and oxidation.
 Our knowledge of kinetics can be of material assistance in dealing with chemical
degradation.
Physical
 Physical degradation can be caused by a
range of factors such as freezing, thawing, or shearing
 The physical methods that could be used in evaluation of tablet friability,
suspension redispersibilty, or injection syringeability
Biological
 In north America, Japan, and western Europe it is microbiological stability
problems.
 However, in some parts of the rats, ants,
and the non microbiological factors can be responsible for stability problems

Stability indicating method

General tests
 Appearance
 Assays/potency
 Sterility /container integrity
 Moisture
 Degradation products

Product specific tests
 Aggregation (proteins)
 Biological activity (proteins)

Dosage form specific tests
 Dissolution/release rate (tablets/patches)
 Leachable/extractable (injections)
 Particle size and turbidity( injection)
 Preservatives

The essential elements of stability program
 Commitment of the organization to quality
 Firm grasp of underlying scientific theory
 Up-to-date knowledge of all relevant polices of regulatory agencies and
applicable pharmacopoeial standards
 Effective communication between R&D, production, QC/QA, complaints, and
regulatory affairs
 Understanding of the limitations of the analytical methods used in the stability
program
 Careful monitoring of the stability budget
 Managerial skills to coordinate and optimize the program.1

What is kinetics?
 kinetics is a rate of reaction which takes place in a particular compound.
 It may be change in parent compound either physical or chemical.
 Physical change include biotransformation.
 Chemical change include degradation
Application of kinetics in stability
 To understand the mechanism of what kind of change.
 To estimate the degradation time.
 Some time half life or shelf life may be determine by the kinetic.
 For prediction of process mean by keeping the compound, what kind of change
and how much time will be taken for that change will be estimated.3
Routes by which pharmaceuticals degrade
a. Chemical degradative routes
1. Solvolysis
2. Oxidation
3. Photolysis
4. Dehydration
5. Racemization
6. Incompatibilities

b. Physical degradative routes
1. Vaporization
2. Aging
3. Adsorption

4. Physical instability in Heterogeneous Systems

Rate of reaction
 Reaction can be of two type
1. Homogeneous
this is uniform process and taking place in single phase.
2. Heterogeneous
taking place in more than two phase.
• Eg. decomposition of drug in suspension and enzyme catalyzed reaction.
• Rate of reaction depended upon concentration of the reactant.
• Chemical kinetics deals with the experimental determination of reaction rates
from which rate laws and rate constants are derived.
• Relatively simple rate laws exist for zero order reactions (for which reaction rates
are independent of concentration), first order reactions, and second order
reactions, and can be derived for others.
• The activation energy for a reaction is experimentally determined through the
Arrhenius equation and the Eyring equation.

 The main factors that influence the reaction rate include:
1. the physical state of the reactants,
2. the concentrations of the reactants,
3. the temperature at which the reaction occurs, and
4. whether or not any catalysts are present in the reaction.

Factors affecting rate of reaction
1. Nature of the Reactants
 Depending upon what substances are reacting, the time varies.
 Acid reactions, the formation of salts, and ion exchange are fast reactions.
 When covalent bond formation takes place between the molecules and when large
molecules are formed, the reactions tend to be very slow.
2. Physical State
 The physical state (solid, liquid, or gas) of a reactant is also an important factor of
the rate of change.
 Reaction can only occur at their area of contact, in the case of a liquid and a gas,
at the surface of the liquid.
 Vigorous shaking and stirring may be needed to bring the reaction to completion.
This means that the more finely divided a solid or liquid reactant, the greater its
surface area per unit volume, and the more contact it makes with the other
reactant, thus the faster the reaction.
3. Concentration
 As the concentration of the reactants increases, the frequency of the molecules
colliding increases, striking each other more frequently by being in closer contact
at any given point in time.
 By increasing the amount of one or more of the reactants you cause these
collisions to happen more often, increasing the reaction rate.

4. Temperature
 Temperature usually has a major effect on the rate of a chemical reaction.
 Collision frequency is greater at higher temperatures, contributes very small
proportion to the increase in rate of reaction.
 The important factor is reactant molecule should have reactive energy higher then
activation energy ( E>Ea ) to react.
5. Catalysts
 A catalyst is a substance that accelerates the rate of a chemical reaction but
remains chemically unchanged afterwards.
 The catalyst increases rate reaction by providing a different reaction mechanism
to occur with a lower activation energy.
 Proteins that act as catalysts in biochemical reactions are called enzymes.5

 The manner in which the concentration of drug (or reactants) influences the rate
of reaction or process is called as the order of reaction.
 If C is the conc. of drug A, the rate of decrease in C of drug A as it is changed to
B can be expressed as a function of time t.
dC/dt = -K Cn
dC/dt = -K Cn _______(1)

K= rate constant
n= order of reaction

If n = 0 than zero order reaction,
If n =1 than first order reaction

dC/dt = term
 Change in conc. (dC) with respect to time (dt) called as rate of reaction

Zero order kinetics
(constant rate processes)
 if n = 0 than,
dC/dt = -K0 C0 = -K0 ____(2)
K0 = zero order rate constant

 It is a reaction whose rate is independent of the concentration of drug undergoing
reaction, so the rate can’t be increased further by increasing the concentration of
reactants.
 Rearrangement of equation (2) yields:
dC = -K0 dt
 Integration of above equation:
C – C0 = -K0 t
C = C0 - K0t ______(3)
C = conc. of drug at time t
C0 =conc. of drug at time t = 0
 Eq. 3 states that the conc. of reactant decreases linearly with time.
 A plot of C vs. t yields straight line having slope –K0 and y-intercept C0

C0

Steady drug loss

Slope = -K0

C
dC/dt

time time

Zero order half life
 It is the time period req. for the conc. of drug to decrease by one-half.
 When t = t1/2 and C = C0 /2, then eq. 3 becomes
C0/2 = C0 – K0 t1/2
 Solving above eq.

t1/2 = C0/2K0 = 0.5C0/K0 ______(4)

 Eq. shows that t1/2 of a zero order process is not constant but proportional to the
initial conc. of drug C0 and inversely proportional to the zero order rate constant
K0. 4

First order kinetics (Linear kinetics)
 If n = 1 then eq. 1 becomes
dC/dt = -K C _____(5)
K = first order rate constant in time-1

 Rate of reaction is directly proportional to the conc. of drug undergoing reaction,
so greater the conc. , faster the reaction.

Slope = -K
dC/dt

C

 Rearrangement of eq. 5 yields
dC/C = -K dt
 Integration of above eq. gives.
ln C = ln C0 – Kt _____(6)
 This eq. can also be written as exponential form as:
C = C0 e-Kt
e = natural log base
 First order process is also known as monoexponential rate process and
characterized by logarithmic or exponential kinetics.
 Since ln = 2.303 log, eq. 6 can be written as

log C = log C0 – (Kt/2.303) _______(7)

 A semilogarithmic plot of eq. 7 gives a straight line with slope = -K/2.303 and y-
intercept = log C0

Log C0

log C Slope = -K/2.303

t1/2

time

Semilog graph of first order kinetics

First order half life

 put the value of C = C0/2 at t = t1/2 in eq.7 and solving it
t1/2 = 0.693/K _____(8)
 It indicate that half life of first order reaction is a constant and independent of
initial drug conc.
 Hydrolytic reaction of many drugs follows second order kinetics but after excess
amt. of water is added then conc. remain constant throughout the process. It called
apparent first order kinetics.
SECOND ORDER KINETICS
 If a drug substance A react with a second substance B then:
 A+B=C
 Then the rate eq. is
 -d[A]/dt = k [A][B]
MIXED ORDER KINETICS (NONLINEAR KINETICS)
 In some cases, the kinetics of a pharmacokinetic process change from predominantly
first order to predominantly zero order with increasing dose or chronic medication.
 A mixture of both first order and zero order kinetics is called as mixed order kinetics.
Also known as nonlinear kinetics or dose dependent kinetics.
 Nonlinearity observed in certain drugs like; vitamin C, naproxen, riboflavin. The
kinetics of such capacity limited processes can be described by the Michaelis-
Menten kinetics.
 Michaelis Menten Equation

 Mixed order kinetics is best described by this equation:

 -dC/dt = Vmax C/(Km + C) _____(9)

 -dC/dt = rate of decline of drug concentration with time,
 Vmax = theoretical maximum rate of the process,
 Km = Michaelis constant. 4

Factors affecting stability of drug and dosage form
• These factors can be broadly classified into 3 types depending on their effect on
different type of stability which are as follows:
• 1) Chemical factors
• 2) Physical factors
• 3) Biological factors

1) Chemical factors
Various ways of chemical degradation includes
• hydrolysis
• dehydration
• isomerization & racemization
• decarboxylation & elimination
• oxidation
• photo degradation
• drug – excipients & drug – drug interactions such as a) Reaction of bisulfite, an
oxidant
b) Reaction of amines with reducing sugars3

A) THE ROLE OF MOLECULAR STRUCTURE

• It has been noted earlier that molecular structure of drug substance determines its
degradation mechanisms and that substituents around the reaction centre can
strongly influence its reactivity.
• Example: drug sub. having an electron withdrawing group close to an ester bond
will probably exhibit a higher propensity nucleophilic attack by hydroxide ion
than will a similar ester without that functional group
• Steric factors can be significant for many chemical reactions.

B) TEMPERATURE
• It is one of the primary factors affecting drug stability.
• The rate constant/temperature relationship has traditionally been described by
the Arhenius equation,
k = A exp (-Ea/RT)

• where Ea = activation energy
A = frequency factor

• Arhenius equation has traditionally been used to describe the temperature
dependency for various chemical reaction by regarding A and Ea as independent
of temperature.

• Temperature is obviously an important parameter because most reactions proceed
faster at elevated temperatures than at lower temperatures.

• The terms Ea and ∆H are a measure of how sensitive the degradation rate of a
drug is to temperature changes.

• Quantitation of the temperature Dependency of degradation rate constants can be
done by 3 ways:
1) Prediction of Degradation rate by Linear Regression Analysis of the Arhenius
Equation
2) Prediction of degradation rate by Nonlinear Regression Analysis of the Arhenius
Equation.
3) Nonisothermal Prediction of Degradation Rate

C) pH AND pH RATE PROFILES
• Second most important parameter
• The effect of pH on degradation rate can be explained by the catalytic effects that
hydronium or hydroxide ions can have on various chemical reactions.
• If critical path in a reaction involves a proton transfer or abstraction step, other
acids and bases present in solution can affect the rate of reaction.
• For ionizable drugs, the fraction of drug present in any particular form will
depend on the pH of the solution,
• So, if the reactivity of the drug depends on its form, its reactivity will be pH-
dependent.
• A reaction in which hydronium ion, hydroxide ion, and water catalysis are
observed can be described by

Kobs = kH+ aH+ + KH2O + KoH- aOH-

Where Kobs = sum of specific rate constants
aH+ = activities of hydronium ion
aOH- =activities of hydroxide ion
This equation is for the case when drug is neutral in the pH range of study.i.e.where the
ionization of drug does not have to take into account

D) BUFFER

• These buffer species, like H+ and OH-, participates in formation of break down of
activated complexes of various reaction and determine their reaction rate.
• These catalytic species are referred to as general acid-base catalysts

• Studies with phosphate buffer indicates that it enhance the degradation of various
drug substances such as carbenicillin etc.
• In addition to acting as proto donor or accepter, buffer species can also act as
Lewis acid and base through nucleophilic or electrophilic mechanisms.

E) IONIC STRENGTH-PRIMARY SALT EFFECT

• For drug degradation involving reactions with or between ionic species, the rate is
affected by the presence of other ionic species such as salts of NaCl.
• Ionic strength affects the observed degradation rate constants, k, by its effect on
the reactivity coefficients, f.
• Ionic strength µ is described by

µ = ½ ε Ci Zi2

Where Ci = conc. Of ionic species I
Zi =its electric change

• As ionic strength increases, the rate of reaction between ions of opposite charge
decreases and the rate of reaction between ions of similar charges increases.
• So, studying the effect of ionic strength can help our understanding of the possible
charges of the species involved in the degradation.

F) OXYGEN

• Drugs can be affected by the availability of oxygen.
• Some photo degradation reactions involve photo oxidative mechanisms that are
dependent on conc. of oxygen.
• Oxygen participates as reactant and also alters the degradation rate
• Oxygen exists in various states such ground state triplate oxygen, etc.
• Singlate oxygen is highly oxidizing and capable of attacking olfenic bonds.
• Super oxide species is a mild reductant while hydrogen peroxide is fairly specific
oxidant.
G) LIGHT

• The number and wavelength of incident photons affect the photo degradation rate
of drugs.
• It is not easy to study the effect of light quantitatively as the wavelength
dependence of degradation varies among drug substances and because light
sources have different spectral distributions.
• Photo degradation for drug strongly dependence on the spectral properties of the
drug substances and the spectral distribution of the light source.

H) Crystalline state and polymorphism in solid drugs
• Drugs in the crystalline state have lower ground state free energy and exhibit
higher ∆G and so, slow reactivity.
• Many drug substances exhibit polymorphism-each crystalline state has a different
ground state free energy level and a different chemical reactivity.
• The stability of drugs in their amorphous form is generally lower than that of
drugs

• In their crystalline form due to higher free energy level of amorphous form.
• Decreased chemical stability of solid drugs brought about by mechanical stresses
such as grinding is said to be due to change in crystalline state -eg: grinding of
aspirin increased degradation rate in suspension form.3

I) MOISTURE AND HUMIDITY

• Drug degradation in heterogeneous system such as solid and semisolid states is
affected by moisture.
• Moisture plays important role in catalyzing chemical degradation:
1) Water participates in the drug degradation process itself as a reactant, leading to
hydrolysis; hydration etc. Here degradation rate is directly affected by the
concentration of water, hydronium ion, hydroxide ion.

2) Water absorbs 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 the drugs, thereby
affecting their reactivity.

J) EXCIPIENTS

• The role that excipients play in drug stability has been extensively reported-e.g.:
accelerating the effect of talc on hydrolysis of thiamine hydrochloride, the
accelerating effect of magnesium stearate on tablet containing amines and lactose
etc.
• Additional informations include reports on compatibility and incompatibility of
drugs.
• Excipients can affect drug stability via various mechanisms.
• The most obvious examples are those in which the excipients participate directly
in degradation as reactants.

• Other mechanisms:

1) Effect of moisture present in excipients
2) The effect pH changes caused by excipients:
3) Effect of surfactants

K) MISCELLANEOUS FACTORS

• Effect of γ irradiation:
− not a common variable
− employed for sterilization of pharmaceuticals e.g. decreased activity of
insulin after γ irradiations
• Components of pharmaceuticals exist in various physical states like amorphous,
hydrated and solvated form.
• The rate of conversion will depend on chemical potential corresponding to the
free energy difference between 2 states.

The various physical changes that can occur in drugs and excipients are as
follow:

1) Crystallization of amorphous drugs
• Attempts are made to formulate poorly soluble drugs into amorphous form as it
has higher solubility that of crystalline state.
• But amorphous form change to crystalline state duo low free energy of it.
• So crystallization of amorphous drug may occur on long storage leading to change
in release character of drugs and so in its effect.
• E.g. :amorphous nifedipine co precipitated with polyvinylpyrrolidone, undergoes
partial crystallization under high humidity conditions resulted altered dissolution
and solubility

2) Vapor phase transfers including sublimation
• Pharmaceuticals containing components that easily sublime may undergo changes
in drug content due to sublimation of it.
• E.g. nitroglycerine , which is liquid with significant vapor pressure,sublinguel
tablet exhibited significant changes in drug content during storage due to inter
tablet migration through the vapor phase

3) Moisture Adsorption
• generally observed with solid pharmaceuticals
• It leads changes in physical properties such as appearance and dissolution rate.
• Moisture adsorption is governed by the physical properties of drug and excipients.
• E.g. :adsorption moisture by aspirin crystals enhanced by addition of hydrophilic
excipients3

references

1. Drug stability: principles and practices, 3rd edition, by Jens T. Carstensen and C.
T. Rhodes

2. Modern pharmaceutics, 4th edition, by Gilbert S. Banker and Christopher T.
Rhodes
3. Stability of drugs and dosage forms by Sumie Yoshioka and Valentino J. Stella;
Springer Publication
4. The theory & practice of Industrial Pharmacy by Leon Lachman, 3rd edition
5. www.wikipedia.com

Stability Basic

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