Kinetics and drug stability

Kinetics and Drug Stability
Be-dilu A.
1
Contents
 Introduction
 Rates and orders of reactions
 Physical degradation
 Chemical degradation
 Factors affecting stability of drugs
 Influence of temperature on reaction rates
 Stability study
 Prediction of shelf life

2
Chapter objectives
o After completion of this chapter, you will be able to:
Define the term kinetics as it applies to pharmaceutical sciences;
Discuss the importance of studying kinetics;
Define the Rate and order of reactions, how their equations are derived,
apply the equations for solving drug decomposition problems;
Discuss the methods for determining the order of reaction;
Describe the various drug degradation pathways;

Discuss the Factors affecting rate of chemical reaction;
Understand the factors affecting stability of drugs;
Describe the types of drug stability determination methods; and
3 Understand drug product shelf life prediction.

Introduction
o Kinetics is study of the rate at which processes or changes occur.
▪ The changes may be
➢ chemical such as decomposition of a drug, radiochemical decay
➢ physical such as transfer across a boundary, such as the intestinal lining
or skin
o The rate of chemical change is influenced by:
• concentration of reactants, products, and other chemical species that
may be present and

• factors such as solvent, pressure, TO.
4
Introduction…
Importance of studying kinetics
✓ To determine stability of drugs (t1/2)
• The time necessary for a drug to decay by 50%
 e.g., From 100% to 50%, 50% to 25%, 20% to 10%
✓ To determine shelf life (t0.9)

• The time necessary for the drug to decay to 90% of its
original concentration.
✓ Selection of proper storage conditions

 Temperature
 Advising patient on storage conditions
5
Introduction…
✓ Selection of proper container for dispensing

 Glass vs. plastic
 Clear vs. amber vs. opaque
✓ Anticipation of interactions when mixing drugs

and dosage forms (incompatibilities)
 Active drugs
 Excipients
✓ ADME Processes in pharmacokinetics
6
Introduction…
Stability of drug products
o Drug stability can be defined as:
o the ability of the pharmaceutical dosage form to maintain the
physical, chemical, therapeutic and microbial properties during

the time of storage and usage by the patient.
o or the capacity of a drug product to remain within specifications
established to ensure its identity, strength, quality, and purity.
7
Introduction….
 Stability study
 is defined as the study of the extent to which the properties of a drug

substance or drug product remain within specified limits at certain
temperature and humidity.
 The properties may be physical, chemical, microbiological, or
performance properties such as disintegration and dissolution.
 The stability of the active ingredient of a drug is a major criterion in
the rational design and evaluation of drug dosage forms.
 It is measured by the rate of changes that take place in dosage forms
8
Introduction…
Importance of stability
o Extensive chemical degradation result in a substantial loss of
quantity of therapeutic agent in the dosage form
o Degradation products may result in adverse events or be unsafe
o Instability may cause
• Undesired change in performance, i.e.
dissolution/bioavailability
• Substantial changes in physical appearance of the dosage
9
form causing product failures
Introduction …
Applications of kinetics
 Hence, the most common applications of kinetics
in pharmaceutics is the study of:

» the rates of drug degradation in pharmaceutical
products,
» the determination of the proper shelf lives and
» the storage conditions of the products.

10
Rate and order of reactions
Rate of reaction
o Rate: is the speed of a reaction with which a reactant(s) undergo a
change.
o Can be measured by measuring the change in the conc. of a
reactant or product in a particular period of time.
➢ Given by; rate = ±dC/dt
11
Rate and order of rxn…
o According to law of mass action, the rate of a reaction is
proportional to the product of the molar concentration of

reactants each raised to power equal to the number of molecules
undergoing reaction.
a A + bB Product
Rate α [A]a .[B]b
Rate =K [A]a .[B]b ……………………………….(1)
Order of reaction = sum of exponents
Order of A = a and B = b
Then overall order = a + b
➢ K is the rate constant or specific rate constant
12
Rate and order of reactions…
Order of reaction
o The order of a reaction refers to the way in which the concentration of
the reactant (s) influence the rate of a chemical rxn.
o Zero order rxn: the rate of rxn is independent of the concentration of the
reactants and constant with respect to time.
o First-order rxn: the rate of rxn is directly proportional to the
concentration reactant remaining with respect to time.
o Most commonly, zero-order and first-order reactions are encountered
in pharmacy.
13
Rate and order of reaction…
 Generally, Rate = -dC/dt = KCn
 Where, K is the rate constant
n is order of reaction
 -dC/dt = KC0 zero order reaction

 -dC/dt = KC1 = KC first order reaction
 -dC/dt = KC2 second order reaction
14
Rates and orders of reactions
Zero order reaction

o It is a reaction where reaction rate is not dependent on the
concentration of the reacting species.
o Rate is constant
A k Product (P)
Rate = - dC/dt = K [A]0
- dC/dt = k
dC = - k*dt
➢ where dC is the change in concentration with change in time t, ‘-’ sign
indicates that the concentration is decreasing.
15
Rates and orders of reactions…
o The rate equation may be integrated b/n the initial
concentration (Co) and concentration Ct after time t.
C = Co - kt (2)
16
Rates and orders of reactions
➢ When this linear equation is plotted with conc on the vertical
axis and time on the horizontal axis, the slope of the line gives-
K.
➢ Unit of K for zero order rxn is (moles Litre-1 second-1)

17
Half life of zero order reaction
o The half life is the time required for 50% of the material to
disappear; it is the time at which C is decreased to 1/2Co
Let C = Co /2 and t= t1/2
substituting this in to eq. 2, yields
C = Co – k t
t1/2 = Co / 2K = 0.5 Co/K (3)
18
Shelf life of a zero order reaction
➢ The shelf life is the time required for 10% of the material to
disappear; it is the time at which C has decreased to 90% of its
original concentration.
Let C = 0.9Co and t= t0.9
substitute in eq. 2;
C = Co –k t
𝑡1/2
t90% = t0.9 = 0.1 Co / k = (4)
5
 Note that t0.5 and t90 in zero-order reactions are concentration
19 dependent.
Q. 1. Drug X degrades by a zero-order process with a rate

constant of 0.05 mg/ ml/year at room temperature. If a 1
mg/ml solution is prepared and stored at room
temperature:
1. What concentration will remain after 18 months? Ans:
0.925 mg/ml
2. What is the half-life and shelf-life of the drug? Ans: 10
and 2 years.
20
First-order reaction
o Reactions in which the rate is determined by one concentration term, then the
reaction rate of change is proportional to drug concentration.
o The most common pharmaceutical reactions;

e.g.; drug absorption, drug degradation on storage
A K products
o The rate equation is given as
− 𝑑𝐶
= 𝑘𝐶 (5)
𝑑𝑡
Where C is the concentration of the reactant A remaining undecomposed at time
t and K is the first-order rate constant
21
o Integrating this equation b/n the limits of concentaration
Co at time t=0 and concentration C at t=t , we get
𝐶 𝑡
𝑑𝐶
න = −𝑘 න 𝑑𝑡
𝐶𝑜 𝐶 𝑜
ln C- ln Co = -k(t-0)
ln C = ln Co -kt
o Converting to a logarithmic form, we get
𝒌𝒕
log C = log Co- ( 6)
𝟐.𝟑𝟎𝟑
𝟐.𝟑𝟎𝟑 Co 𝟐.𝟑𝟎𝟑 Co
t= log k= log (7)
22
𝒌 C 𝒕 C
o If log C is plotted against time t, a straight line is obtained with
slope equal to –k/2.303.
o The rate constant k can be obtained from the slope of the line
and it has unit of Sec-1
23
o In exponential form, the equation becomes
or (9)
o The conc decrease exponentially with time.
24
Half life of first order reaction
C=1/2Co
substituting in the equation;
2.303 C
t = 𝑘 log Co
t1/2 =0.693
k
(10)
Shelf life of first order reaction

C=0.9Co
2.303 Co
substituting in equation, t = log
C
𝑘
0.105
t90% = (11)
k
o the half life and shelf life of first order rxn is a constant
25 independent of the concentration.
Example: A solution of a drug contains 500 units/ml
when prepared. It was analyzed after 40 days and was
found to contain 300 units/ml. Assuming the
decomposition is first order, at what time will the drug
have decomposed to one-half of its initial concentration?
26
Q1. A solution of drug contained 680 units/ml when prepared. It was analysed after
a period of 60 days and was found to contain 400 units/ml. assuming the
decomposition is first order, at what time the drug have decomposed to one half
of its original concentration?
 Ans 78 days and 7 hrs
Q2. The initial concentration of a drug which decomposes according to 1st order
kinetics, is 94 units/ml. The specific decomposition rate K obtained from an
Arrhenius is 2.09 x 10-5 hr-1 at room T (25 0C). Previous experiments have
shown that below 45 units/ml, the drug is not fit for use &should be removed
from market. What expiry date should assigned to the product?
 Ans 3.525 x 10 4hr ≅ 4𝑦r.
Q3. Based on the Q 2 what the time taken for 5% of a drug to decompose?
Ans 2.45 x 10 3 sec
Q4. What is the remaining concentration C in mg ml–1 of a drug (initial concentration
Co = 7 mg ml–1) after a time equivalent to 3 half-lives assuming that the
decomposition follows first-order kinetics?
Q5. The initial concentration of active principle in an aqueous preparation was 5.0 x
10-3 gcm-3. After 20 months the concentration was shown by analysis to be 4.2 x10-3
gcm-3. The drug is known to be ineffective after it has decomposed to 70% of its
original concentration. Assuming that decomposition follows first order kinetics,
calculate the expiry date of the drug preparation. (Ans:3 yrs and 5 mths)
Q 6. The rate of decomposition of a 0.056 M glucose at 140 oC in acidic solution was

found to be as follows based on this data find K, half life and shelf life.
Time (in hrs) 0.0 0.5 2.0 4.0 6.0 8.0 12.0
Glucose remaining (x10-2 mol.liter-1) 5.65 5.52 5.31 5.02 4.80 4.52 4.09
28
 Q7. The concentration of drug X in aqueous solution
drops by 10% per month when stored at room
temperature. If the degradation occurs by first order,
what concentration will remain if a 5 mg/ml solution of
the drug is stored under the same conditions for 3
months? (Ans: C = 3.71 mg/ml)
29
Individual Assignment
 Second, third and pseudo order reactions
 Definition, cxcs, rate constants and calculations
30
Methods for determining the order of

reaction
● Substitution method
● Graphical method
● Half life method
31
Substitution method
o The data obtained from a kinetic experiment is substituted
in the relevant integrated equation (zero, first and second

–order reactions).
o The equation that yields a fairly constant value of K with
in the limits experimental variation indicates the order of

the reaction.
32
Graphical Method
o The data obtained from a kinetic experiment is plotted
in the relevant form to determine the order of a

particular reaction.
➢ If the data yield a linear graph when plotted as:
▪ t against C zero-order
▪ t against log C first-order
▪ t against 1/C second-order

33
Graphical Method…
Example
Q. Determine order??
➢ Data for hypothetical reaction
34
Graphical Method…
➢ Is this a Zero-Order reaction? C=Co-Kt; or At=Ao-Kt
35
Graphical Method…
➢ Is this a Second-Order reaction?
36
Graphical Method…
➢ Is this a First-Order reaction? log C= log Co-Kt/2.303
Linear fit of Log. Concentration(M) to time (s).
0.0
-0.2
-0.4
Log [A]
-0.6
-0.8
-1.0
-1.2
0 10 20 30 40 50 60
time (s)
37
Half life method
➢ This method is based on the relationship b/n the initial
conc. of the reactant, the half-life, and the reaction order.
➢ For zero-order reactions, t½ increases with increasing
concentration.
➢ For first-order reactions, t1/2 does not change with change
in concentration.
➢ For second order reaction, t1/2 is inversely proportional to
concentration.
➢ In general, t1/2
~ 1 / c n-1 ………………………..1
38
 Where C is concentration and n is order of the reaction.
 If the two reactions are run at different initial concentrations, a1 and a2,
the respective half-lives t1/2(1) and t1/2(2) are related as follows:
…………………….2
 Or in logarithmic form;
……………(3)
o The half-lives are determined graphically by plotting C versus t at two
different initial concentrations and reading the time at ½a1 and ½ a2.
o The values for the half-lives and the initial concentrations are then
substituted in to eq 3.
39
Q. 1. The kinetics of decomposition of a drug in aqueous
solution were studied using a series of solutions of different

initial drug concentrations, C0 . For each solution the time
taken for half the drug to decompose (that is, t0.5) was
determined with the following results:
C0 (mol dm-3) 4.625 1.698 0.724 0.288
t0.5(min) 87.17 240.1 563.0 1414.4
Determine the order of reaction.
40
Chemical and physical degradation
o Drug substances and expients have diverse
molecular structures
▪ susceptible to many degradation pathways.
1. chemical degradation pathways
▪ hydrolysis, dehydration, isomerization,

oxidation, decarboxylation and elimination and
photodegradation…
2. physical change
▪ Vaporization, Crystallization of Amorphous Drugs,
Transitions in Crystalline States, and Moisture
41
Adsorption…
Chemical and physical degradation…
Chemical degradation
Hydrolysis (solvolysis)
o interaction of drug molecules with water molecule
to yield breakdown product.
o Most important
▪ in system containing water such as emulsion,
suspensions, solutions
▪ for drug which are affected by trace of moisture in the
form of water vapour from the atmosphere.

42
● Esters hydrolysis
• Involves acyl-oxygen cleavage
• procaine, atropine, aspirin, tetracycline and physostigimine
● Amides hydrolysis
• Involves the cleavage of the amide linkage to give an amine.
• chloramphenicol, penicillin, cephalosporins, niacinamide,

and barbiturates.
43
❑ Ring hydrolysis
❑ Proceed by ring cleavage with subsequent attack by
hydrogen or hydroxyl ions.
✓penicillins, cephalosporins, nitrazepam and
chlordiazepoxide
44
Protection against hydrolysis

o Solid dosage form may be prevented by
→avoiding their contact with moisture at the time
of manufacture,
→packaging in suitable moisture resistant packs
→storage in controlled humidity and temperature
→incorporating a suitable desiccant in the pack
such as silica gel bags.

45
o Liquid dosage form can be prevented by:
o Selecting an optimum pH for maximum stability and the
formulation should be stabilized at this pH by inclusion of

proper buffering agent.
46
» by partial or complete replacement of water with

non-aqueous solvents such as alcohol, glycerin
and propylene glycol.
» By preparing insoluble derivatives of the drug

which can then be formulated in the form of
suspension.
» Formulating susceptible drugs such as penicillin

and its derivative in the form of dry powder for
reconstitution.
47
Oxidation
o In pharmaceutical dosage forms, oxidation is usually
mediated through reaction with atmospheric oxygen under

ambient conditions
o Autoxidation is the most common of oxidative degradation
that occur in many of the pharmaceutical preparation

• involves multiple pathways: initiation, propagation and
termination.
48
Initiation : RH R• +H (formation of free radical)
Propagation : R• + O2 ROO •
ROO• + RH ROOH + R•
Termination:
o Many oxidation reactions are catalyzed by:

➢Acids and bases
➢Heavy metals like copper, iron, cobalt
and nickel
➢Heat and light further influence the kinetics of
oxidative degradation process
49
Protection against oxidation
o Use of Antioxidants
▪ True antioxidants
➢Block chain reaction by reacting with free
radicals
Eg: Tocopherol, ascorbyl palmitate, propyl gallate
▪ Reducing agents
➢are more readily oxidized than the drug or

adjuvant,
50 Eg: sodium metabisulphite, sodium thiosulphate
Protection against oxidation…
51
Photodegradation
o sunlight or room light may cause substantial
degradation of drug molecules.
o The energy from light radiation must be absorbed
by the molecules to cause a photolytic reaction.

▪ If this energy is sufficient to achieve activation,
degradation of the molecule is possible.
52
o Photolysis reactions often are associated

with oxidation.
▪ oxidation reactions can be initiated by light.
▪ But photolysis reactions are not restricted to oxidation
o Eg: phenothiazines, hydrocortisone, prednisolone,

riboflavin, nifedipine, colchicine and
chlorpromazine.
53
Protection against Photolysis

o use of coloured glass containers (amber glass
excludes light of wavelength < 470 nm)
o storage in the dark place
o Packaging in cartons (physical barrier to light)
o opaque shells for capsules
o Coating tablets with a polymer film containing

ultraviolet absorbers
54
Dehydration
o The elimination of a water molecule from structure of
the cpd.
Eg: prostaglandin E2 and tetracycline undergo dehydration

to form 5 (hydroxymethyl) furfural.
55
Isomerization
 The process of conversion of a drug in to its optical or
geometric isomers.
o may be regarded as a form of degradation resulting in
serious loss of therapeutic activity.

 Racemization and epimerization, which are reversible
conversions between optical isomers, are common.
 the optically active form of the drug is converted into its
enantiomer, which in most cases has less therapeutic
effect than the original drug.
56
o Examples of isomerization of drug substance
Trans-cis isomerization of amphotericin B and vitamine A
Pilocarpine undergoes epimerization by base catalysis,

tetracyclines and ergotamine exhibit epimerization by acid
catalysis.
Epinephrine undergoes racemization under strongly acidic

conditions
adrenaline at low pH undergoes racemisation – the conversion

of the therapeutically active form (levorotary form) into its less
57
active isomer.
Elimination
o Drug substances having a carboxylic acid group are
sometimes susceptible to decarboxylation.

o E.g. 4-Aminosalicylic acid under strongly acidic conditions.
o Other elimination reactions have been reported for
various drug substances

▪ E.g. levothyroxine eliminates iodine
58
Polymerisation
o is the process by which two or more identical drug

molecules combine together to form a complex molecule.
o a polymerisation process occurs during the storage of
concentrated aqueous solutions of aminopenicillins, such
as ampicillin sodium.
▪ The reactive β- lactam bond of the ampicillin molecule is
opened by reaction with the side-chain of a second
ampicillin molecule and a dimer is formed. The process
can continue to form higher polymers.
59 ▪ elicit pencilloyl specific allergic reactions
Routes by which pharmaceuticals degrade…
 Dimerisation and hydrolysis of ampicillin.
60
Physical Degradative Routes
Vaporization
o Some drugs and excipients possess sufficiently high vapor
pressures at room temperature that their volatilization

constitutes a major route of loss.
o Flavors, solvents and cosolvents (alcohols) may be lost
from the formulation.

➢ Volatility of solvents could leads to:
• potentially hazardous concentration of dugs.
• Crystallization of drug and excipients.

61
o Eg. Nitroglycerin
o Reduction of vapor pressure can be achieved through
dispersion of the volatile drug in macromolecules that

can provide physicochemical interactions.
o The addition of macromolecules such as polyethylene glycol,
polyvinylpyrrolidone, and microcrystalline cellulose allows for

preparation of ``stabilized'' nitroglycerin sublingual tablets.
o A β-cyclodextrin-nitroglycerin tablet is currently being
marketed .
62
Adsorption (Sorption)
o Drug-plastic interaction is a major potential problem when
IV solutions are stored in bags or infused via administration

sets that are made from polyvinyl chloride (PVC)
▪ up to 50% drug loss can occur after nitroglycerin is stored in PVC
infusion bags for 7 days at room temperature.
▪ more than 40% of a dose of quinidine gluconate was lost when the
drug was administered with a conventional PVC IV administration

set
o A diverse array of drugs, including diazepam, insulin,
isosorbide dinitrate has shown substantial adsorption to
63
PVC.
Crystallization of Amorphous Drugs
o Poorly water-soluble drugs formulated in their amorphous
state to improve the solubility.

▪ because of the lower free energy of the crystalline state,
amorphous substances tend to change to their more

thermodynamically stable crystalline state with time.
o 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
and, hence, the absorption.
64
Transitions in Crystalline States
o Polymorphs are different crystalline forms of the same
drug.
o have different free energy
▪ transitions between polymorphs
o may alter critical properties of drugs because the solubility
and dissolution rate of drug substances generally vary with

changes in their crystalline form.
o Temperature and humidity affect polymorphic transitions
➢ Examples:- Nitrofurantoin, Theophylline

65
physical changes in emulsion
o such as cracking, creaming …
physical changes in suspension
o which depends on the magnitude of opposing forces of
attraction and repulsion.

▪ caking
Changes in semisolids
o Gels, ointments and pastes may soften, harden or become
66
granular or gritty during storage.
67
Factors affecting rate of reaction
o Temperature
o Surface area of solid reactants
o Solvent
o Light
o Ionic strength
o Catalyst
68
Factors affecting rate of reaction
Temperature
o Reactions take place when particles collide with a certain
amount of energy.
• The minimum amount of energy needed for the particles to
react is called the activation energy.
o The rate of a reaction depends on:
• The frequency of collision between particles
• The energy with which particles collide
69
Effect of temperature on rate of reaction
Temperature…
• Higher temperatures increase the rate of a chemical reaction.
Why?
• according to classic collision theory reaction rates are
proportional to the number of collisions per unit time.
• Because the number of collisions increases as the temperature
increases, the reaction rate is expected to increase with
increasing temperature.
• The speed of many reactions increases about 2 to 3 x with each 10
degree rise in T.
• If a formulation has to be heat sterilized then its stability have to be
70 measured at elevated temperatures.

Factors affecting rate of reaction…
Solvent
o The effect of solvents on the rate of decomposition of drugs is related to
the relative solubility of reactants and the products in the given solvents
For a bimolecular rxn:
• Rate of reaction is dependent on the polarity of solvent
and that product formed from the reaction.

o Polar solvents tend to accelerate rxns in which the products formed
are more polar than the reactants

o If the products formed are less polar than the reactants then the rxn
71 proceeds better in the solvents of relatively low polarity.

Light
o Mostly visible light and UV light causes photo degradation rxn.
o Photochemical rxn do not depend on temp. for activation of
molecules and hence the rate of activation for such rxn is

independent of temp.
o a molecule may absorb quantum of radiant energy, this
molecule collide with other molecules raising the kinetic energy,

which may result in increase in temp of the system.
o Are complex rxns and proceed by a serious of steps.
72
Ionic strength
• The effect of ionic strength of a solution on the rate of degradation
may be expressed in the form of the following equation:
where
o zA and zB are the charge numbers of the two interacting ions
o K is the degradation rate constant for the reaction
o Ko is the rxn rate constant at infinite dilution
o µ is the ionic strength of the solution
• According to eq., increase in the ionic strength of the solution

• decrease the rate of rxn b/n oppositely charged ions and
• Increase the rate of rxn b/n similarly charged ions
• Reaction between ions and neutral molecules are generally not
73 affected to significant extent by change in ionic concentration
 The gradient will be positive (i.e. the reaction rate will be
increased by electrolyte addition) when reaction is between

ions of similar charge, for example, the acid-catalysed
hydrolysis of a cationic drug ion.
 The gradient will be negative (i.e. the reaction rate will be
decreased by electrolyte addition) when the reaction is

between ions of opposite charge, for example, the base-
catalysed hydrolysis of positively charged drug species.
74
Catalyst
o Catalyst is defined as a substance that influences
the speed of a reaction with out itself being altered

chemically.
o It cannot change the position of the equilibrium of a reversible
reaction.
o They work by lowering the reaction’s activation
energy (Ea) so that the reaction will occur with little

75
energy.
Factors affecting the stability of drugs
1. Environmental factors
• Temperature
• Light
• Oxygen
• Moisture
76
• Drugs or excipients in the dosage form
o Particle size of drug
o pH of the vehicle
• Trace metal Contamination
• Leaching from containers
• Microbial contamination
• (Pyrogens-lipopolysaccharides, the metabolic products of bacterial
growth (G-ve) - if IV injected to patient-may cause chills and fever.

• Use of preservatives
77
2. Formulation factors
• Processing method
• Mixing/ Milling
78
Stability study
o The purpose of stability testing is to provide evidence on how the
quality of a drug substance (active ingredient) or drug product

(formulation) varies with time under the influence of a variety of
environmental factors (i.e, temperature, humidity, and light).
o Permits the establishment of recommended storage conditions,
retest periods, and shelf lives.
o Stability studies should include testing of those attributes of the
drug substance or drug product that are susceptible to change

during storage and are likely to influence quality, safety, and
efficacy.
79
Stability study…
Aims of stability tests
 Provides evidence on how the drug substance or product
quality varies with time under environmental conditions

during distribution.
 Helps to recommend storage conditions including
establishment of shelf life, expiry date or retest period
 Assurance of quality of pharmaceuticals.
80
Stability study…
o The testing should cover, as appropriate, the physical,
chemical, and microbiological attributes, preservative

content and functionality test.
o involve application of a suitable stress or challenge such
as
o temperature, light, RH, and microorganism over a period of
time and assess its effects.
81
Stability study…
Climatic zone
o According to ICH (international conference on
harmonization) and WHO guideline on stability studies,
the world has been divided in to four zones taking in to
account the prevalent annual climatic conditions of
temperature and humidity
• Zone I- temperate
• Zone II – subtropical with possible high humidity
• Zone III- hot, dry
• Zone IV –hot, humid

82
Stability study…
Stability testing protocols
o Stability testing requires the careful design of
protocols which must define clearly the following:

• The temperature and humidity for storage
• Storage time before sampling
• The number of batches to be sampled
• The number of replicates within each batch
• A suitable light challenge
• Details of assay
83 • container
Stability studies…
Type of stability study
o Major types of stability testes: are
a. Long term stability test
b. Field stability test
c. Accelerated stability test
84
Stability study…
Long term stability (Real time studies)
o ICH guideline :
• stability studies under the recommended storage

conditions for the retest period or shelf life proposed
or approved for labeling.
o WHO guideline defines long term testing as
• the stability testing during and beyond expected

shelf life under storage conditions in the intended
market.
85
Stability study… Long term stability
o Conducted in the laboratory under controlled stresses
similar to those likely to be encountered during storage
o Minimum of 12 months data, max for 5 yrs.
o For product to be stored at room temp: 25 ± 2oC and RH of
60 ± 5% (Zone I and II) and 30 ± 2 oC and RH 65 ± 5 %

(Zone III and IV)
o For drug substances and drug products recommended to be stored in a
refrigerator: 5 ± 3 o C
o For drug substances and drug product to be stored in a freezer: -20 ± 5
86 oC
Stability study…
Accelerated stability study
o Use of exaggerated conditions of temperature,
humidity, light & others.
o Accelerated stability tests are done:
• To detect the deterioration of the product rapidly, in

order to select the best formulation;
• To predict shelf life;
• To provide rapid means of quality control.
87
Stability study…
Accelerated storage condition
o For drug substance and drug products stored at
room temp: 40 ± 2 o C with 75 ± 5 % RH (for all

zone)
o For drug substance and drug products intended to
be stored in a refrigerator : 25 ± 2 o C and RH of

60 ± 5 %
88
Stability study…
Accelerated storage condition…
 Limitations of accelerated stability testing based on
elevated temperatures:
Suitable only if the reaction rate is a thermal phenomenon
 Not suitable if the degradation:
• depends on diffusion or is a photochemical reaction
• is caused by freezing, microbial growth or excessive shaking.
 Can not be used for products containing suspending or thickening
agents that coagulate on heating (Methyl Cellulose).
 Not suitable for ointments and suppositories
89
Stability study…
Field stability test
o Done at manufacturers laboratory after the
packaged drug product has transported to a typical

pharmacy level and stored at different levels.
o For at least 06 months, max 1yrs.
90
Stability study…
Testing frequency
o For long term storage condition should be
o every 3 months over the first year,
o every 6 month over the second year and
o annually thereafter through the proposed shelf life.
o At the accelerated storage condition, a minimum of three
points, including the initial and final time points (0, 3 and 6
months).
91
Thank you
92

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 Rates and orders of reactions

 Factors affecting stability of drugs

 Influence of temperature on reaction rates

 Prediction of shelf life

Describe the various drug degradation pathways;

3 Understand drug product shelf life prediction.

▪ The changes may be

➢ chemical such as decomposition of a drug, radiochemical decay

➢ physical such as transfer across a boundary, such as the intestinal lining

o The rate of chemical change is influenced by:

• concentration of reactants, products, and other chemical species that

may be present and

✓ To determine shelf life (t0.9)

✓ Selection of proper storage conditions

✓ Selection of proper container for dispensing

✓ Anticipation of interactions when mixing drugs

✓ ADME Processes in pharmacokinetics

o Drug stability can be defined as:

o the ability of the pharmaceutical dosage form to maintain the

physical, chemical, therapeutic and microbial properties during

established to ensure its identity, strength, quality, and purity.

 is defined as the study of the extent to which the properties of a drug

quantity of therapeutic agent in the dosage form

o Degradation products may result in adverse events or be unsafe

o Instability may cause

• Undesired change in performance, i.e.

• Substantial changes in physical appearance of the dosage

in pharmaceutics is the study of:

» the storage conditions of the products.

o Rate: is the speed of a reaction with which a reactant(s) undergo a

o Can be measured by measuring the change in the conc. of a

reactant or product in a particular period of time.

➢ Given by; rate = ±dC/dt

proportional to the product of the molar concentration of

the reactant (s) influence the rate of a chemical rxn.

reactants and constant with respect to time.

o First-order rxn: the rate of rxn is directly proportional to the

concentration reactant remaining with respect to time.

o Most commonly, zero-order and first-order reactions are encountered

 -dC/dt = KC0 zero order reaction

Zero order reaction

concentration (Co) and concentration Ct after time t.

➢ Unit of K for zero order rxn is (moles Litre-1 second-1)

disappear; it is the time at which C is decreased to 1/2Co

Let C = Co /2 and t= t1/2

substituting this in to eq. 2, yields

t1/2 = Co / 2K = 0.5 Co/K (3)

Q. 1. Drug X degrades by a zero-order process with a rate

1. What concentration will remain after 18 months? Ans:

2. What is the half-life and shelf-life of the drug? Ans: 10

o The most common pharmaceutical reactions;

o In exponential form, the equation becomes

o The conc decrease exponentially with time.

Shelf life of first order reaction

Q 6. The rate of decomposition of a 0.056 M glucose at 140 oC in acidic solution was

 Second, third and pseudo order reactions

 Definition, cxcs, rate constants and calculations

Methods for determining the order of

● Half life method

o The data obtained from a kinetic experiment is substituted

in the relevant integrated equation (zero, first and second

o The equation that yields a fairly constant value of K with

in the limits experimental variation indicates the order of