1

LECTURE - 6

Kinetics and Drug stability

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 OUTLINES
2

 Introduction
 Rates and orders of reactions

 Physical degradation

 Chemical degradation

 Factors affecting stability of drugs

 Stability study

 Prediction of shelf life

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 Introduction
3

 Chemical kinetics is the study of the

speed or rate at which a chemical
reaction occurs.

 Stability of a pharmaceutical product

may be defined as the capability of a
particular formulation, in a specific
container/closure system, to remain
within its physical, chemical,
therapeutic, microbiological and
toxicological specifications. 12/20/2024
 Introduction……………cont’d
Types of Conditions to be maintained throughout
4 stability the shelf life of the drug product
Chemical Each active ingredient retains its
chemical integrity and labeled
potency, within specified limits.
Physical The original physical properties, for
example, appearance, palatability,
uniformity, dissolution
suspendability are retained.
Microbiolo Sterility or resistance to microbial
gical growth is retained according to the
specified requirements. Antimicrobial
agents that exist retain effectiveness
within the specified limits.
Therapeut The therapeutic effect12/20/2024
remains
 Introduction……………cont’d
5

 Studying chemical kinetics is important

for determining shelf-life and storage
conditions.

 Shelf life is the time period during which

a drug product is expected to remain
within the approved specification for use,
provided that it is stored under the
conditions defined on the container label.

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 Rates and order of reactions
6
 The rate of reaction is the speed with
which a reactant or reactants undergoes
a chemical change.
 For the reaction of the type
aA + bB+… cC + dD+….
Where,
 the uppercase letters represent
chemical species
 The lowercase letters represent

stoichiometric coefficient12/20/2024
 Rates and order of
reactions……….cont’d
7

 For the reaction of the type

aA + bB+… → cC + dD+…

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 Rates and order of
reactions……….cont’d
8

Where,
[ ] denotes concentration,
(-) sign indicates that the concentration of
the reactants is decreasing
(+) sign indicates that the concentration of
the products is increasing
K is rate constant
 m & n are known as the order of reaction

with respect to A and B, respectively.

 The overall order of the reaction is m+n.
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Note: m ≠ a and n ≠ b
 Example,
9  2 NO(g) + 2 H2(g) → N2(g) + 2 H2O(g)
rate = k[NO]2[H2]
1. What is the order with respect to NO?
2. What is the order with respect to H2?
3. What is the overall order?
4. If [NO] is doubled, what is the effect on
the reaction rate?
5. If [H2] is halved, what is the effect on the
reaction rate?
6. What is the unit of k?
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 Classifying reactions
10

 Reactions are classified according to the

number of reacting species whose
concentration determine the rate at
which the reaction occurs, i.e., the order
of reaction.
 Zero order reaction: the reaction rate
is independent of the concentration of
any of the reactants.
 First order reaction: the reaction rate
is determined by one concentration
term. 12/20/2024
 Classifying reactions
11

 Second order reaction: the

reaction rate is determined by the
concentrations of two reacting species or
a function of concentration squared of
one species.

 Overall, zero, first, and second order

reactions kinetics are the most
frequently encountered kinetics in
pharmacy.
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 Classifying reactions
12

Zero order reaction

 In this type of reaction, the reaction

proceeds at constant rate and is

independent of the concentration of any
of the reactants.

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 Zero order reactions
13

 The rate expression for the change in

concentration by zero order can be
calculated as follows

where,
C0 is initial
concentration, time “t”
Ct is concentration
remaining after
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 First order reaction
14

 The rate of first order reaction is determined by

one concentration term and can be calculated as
follows:
Where, C0 is the initial concentration
of the
reactant,
Ct is the concentration of
reactant
remaining after time “t”
K is first order rate constant

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 Second order reaction
15

 There are two forms of second order

reaction
Type I: 2A  Product
e.g., decomposition of hydrogen
peroxide

Type II: A + B  Product

e.g., saponification of ethyl
acetate
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 Second order reaction………..cont’d
16

 For the case,

2A  product
where,
C0 is initial
concentration,
Ct is concentration
remaining after time
“t”
k is second order
rate constant
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 Second order reaction………..cont’d
17

 For the case, A+B product,

concentration of A and B after time
“t”, can be calculated using

 If the initial concentration of A and B

is equal, we use
𝟏 𝟏
= + 𝐤𝐭
𝐂𝐭 𝐂𝐨 12/20/2024
 Example 1
18

A solution of drug contained 500 mg/mL

when prepared. It was analysed after 40
days and was found to contain 300
mg/mL. Assume the decomposition is zero
order,
 Calculate the zero order rate constant

 At what time will the drug decompose to

one-half of its original concentration

 t
90 (shelf-life)

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 Example 2
19

The initial concentration of drug

decomposing according to first order
kinetics is 94 units/mL. The specific
decomposition rate, k, of the drug is
2.09x10-5 hr-1 at room temperature, 25 oC.
Previous experiment has shown that when
the concentration of drug falls below 45
units/mL, it will not be sufficiently potent for
use and should be removed from the
market. What shelf-life should be assigned
to this product? Ans: 4.08 yrs.12/20/2024
 Example 3
20

The initial concentration of a drug in an

aqueous preparation was 5.0 x10-3 g/mL.
After 20 months, the concentration was
shown by analysis to be 4.2x10-3 g/mL. The
drug is known to be ineffective after it has
decomposed to 90% of its initial
concentration. Assume that the
decomposition follows first order kinetics,
calculate the half life of the drug. Ans:
12.04 min.
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 Example 4
21
A prescription for a liquid aspirin preparation
is called for. It is to contain 325 mg/mL or 6.5
g/100 mL. The solubility of aspirin at 25 oC is
0.33 g/100 mL; therefore, the preparation will
definitely be suspension. The other
ingredients in the preparation cause the
product to have a pH of 6.0. The first order
rate constant for aspirin degradation in this
solution is 4.5x10-6 sec-1 . Calculate,
 The zero order rate constant

 Determine the shelf life, t , for the liquid

90
preparation, assuming that the product is
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satisfactory until the time at which it had
 Physical degradation
22


Manifestations of Physical
degradation/instability

Solutions:
 Loss of clarity
 Lose of original color

 Lose of original odor

 Lose of original test

 Change in viscosity

 Gas evolution

 Microbial growth
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 Precipitation, etc
 Physical degradation….Cont’d
23

 Suspensions:
 Caking
 Crystal growth

 Lose of original color

 Lose of original odor

 Lose of original test

 Change in viscosity

 Microbial growth

 Change in drug dissolution

 etc,

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 Physical degradation………...cont’d
24

 Lose of
 Emulsions:
 Creaming original color
 Lose of
 Sedimentation
original odor
 Flocculation
 Lose of
 Coalescence
original test
 Breaking
 Change in
 Phase
viscosity
inversion  Gas evolution
 Microbial

growth
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 Physical degradation….Cont’d
25

 Ointments:  Lose of original

 Change in color
 Lose of original
consistency ( an
ointment can be odor
changed into soft or  Change in
stiff which is difficult viscosity
to extrude or apply)  Lose of
 Bleeding ( a
homogeneity
phenomenon where  Change in particle
liquid components
such as mineral oil size distribution
 Microbial growth
separate at the top
of an ointment).  etc,

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 Chemical degradation of drugs
26

 It is a chemical change/reaction in which a visible

change is not necessarily observed.
 The most frequently encountered chemical
reactions, which may occur within
pharmaceutical products are:
 Oxidation
 Reduction
 Hydrolysis
 Decarboxylation
 Polymerization
 Isomerization
 Photolysis
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 Chemical degradation of
drugs….Cont’d
27

 Oxidation
 In oxidation there is addition of
oxygen or the removal of
hydrogen or lose of electrons.
 Oxidation frequently involves free
radicals and subsequent chain
reactions.
 Only a very small amount of
oxygen is required to initiate a
chain reaction. 12/20/2024
 Oxidation…
28

 In practice, it is easy to remove

most of the oxygen from a
container, but very difficult to
remove it at all.

 Nitrogen and carbon dioxide are

frequently used to displace the
headspace air in pharmaceutical
containers to help minimize
deterioration by oxidation.
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 Oxidation…

29

 The molecular structure most likely to

oxidize are those with
 hydroxyl group directly bonded to
an aromatic ring ( e.g., phenol
derivatives such as
catecholamines and morphine)
 Conjugated dienes (e.g., Vitamin
A and unsaturated free fatty acids
)
Hetrocyclic aromatic rings
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 Oxidation…
30

 Oxidation is catalysed by pH values

that are higher than optimum,
polyvalent heavy metal ions(e.g.,
copper and iron), exposure to
oxygen, UV illumination and
increase in temperature.

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 Oxidation…
31

 An increase in temperature leads to an

acceleration in the rate of oxidation.

 If the storage temperature of a

preparation can be reduced to 0 to 5 oC,
usually it can be assumed the rate of
oxidation will be at least halved.

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 Oxidation…
32

 Trace amount of heavy metals such as

cuppric, chromic, ferrous, or ferric
ions may catalyze oxidation reactions.
 For example, as little as 0.2 mg of
copper ion per liter considerably
reduces the stability of penicillin.
 Heavy metals can be sequestered from
water by addition of chelating agents.

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 Oxidation…
33

 Oxidation may be inhibited by the use of

antioxidants, called negative catalysts.

 These substances, which are easily

oxidizable, act by possessing lower
oxidation potential than the active
ingredients.

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 Reduction reaction

34

 Reduction reactions are much less

common than oxidation processes in
pharmaceutical practices.

 Examples, include the reduction of gold,

silver, or mercury salts by light to
form the corresponding free metal.

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 Hydrolysis
35

 Hydrolysis means “splitting by water’’.

 If the drug is derivative of carboxylic
acid or contain functional groups based
on this moiety, for example, esters,
amides, imides, lactone and lactam
functional groups are among those prone
to hydrolysis.

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 Hydrolysis…..
36

 Hydrolysis reactions are often pH

dependent and are catalyzed by either
hydronium ion or hydroxide ions.
 The rate of hydrolysis reaction also
depends on temperature.
 A much-quoted estimation is that for
each 10 oC rise in storage temperature,
the rate of reaction doubles or triples,
even though this is not always true.

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 Decarboxylation

37

 Some dissolved carboxylic acids, such as

p-aminosalicylic acid, lose carbon dioxide
from the carboxyl group when heated.

 The resulting product has reduced

pharmacological potency.

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 Decarboxylation……
38

 β-keto decarboxylation can occur in

some solid antibiotics that have a
carbonyl group on the β-carbon of a
carboxylic acid or carboxylate anion.

 Such decarboxylation will occur in the

following antibiotics: carbenicillin
sodium, carbenicillin free acid, ticarcillin
sodium, and ticarcillin free acid.

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 Decarboxylation……
39

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 Isomerization
40

 Isomerization is the process of

conversion of a drug into its optical or
geometric isomers.

 Since the various isomers of a drug have

different activities, such conversion may
be regarded as a form of degradation,
often resulting in a serious loss of
therapeutic activity.

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 Isomerization……..
41

 Cis-trans isomerization may be a cause

of loss of potency of a drug if the two
geometric isomers have different
therapeutic activities.

 For example, vitamin A (all-trans-retinol)

is enzymatically oxidized to the aldehyde
and then isomerized to yield 11-cis-
retinal, which has a decreased activity
compared with the all-trans molecule.
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 Isomerization……
42

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 Polymerization

43

 Polymerization is the process by which

two or more identical drug
molecules combine together to form a
complex molecule.

 It has been demonstrated that

polymerization process occurs during the
storage of concentrated aqueous
solutions of aminopenicillins, such as
ampicillin sodium.
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44
Polymerization…….Cont’d
 The reactive β-lactam bond of ampicillin
molecule is opened by reactions with
amine side chain of a second ampicillin
molecule and a dimer is formed. The
process can continue to form higher
polymers.

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45
Polymerization…….Cont’d
 Such polymeric have been shown to be
highly antigentic in animals and they are
considered to play a part in eliciting
pencilloyl-specific allergic reactions to
ampicillin in humans.

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 Factors affecting stability of drugs
46

Environmental factors
 Temperature
o The speed of many reactions
increases about two to three times
with each 10 oC rise in
temperature.

 For example, there is pronounced

increase in hydrolysis rate of many
drugs by increase in temperature.
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 Light
47
• Ultraviolet light is the most usual
cause of photodegradation.
• Photolabile drugs are usually stored
in containers which exclude
ultraviolet light.
• Amber glass is particularly effective
in this respect because it excludes
light of wave length of less than
about 470 nm.
• As added precaution, it is always
advisable to store phtolabile drugs in
dark place. 12/20/2024
 Factors affecting stability of
drugs…Cont’d
48

 Moisture
• Moisture, which is water existing in the air
when adsorbed on to many drug products
cause hydrolysis of drugs.
 Oxygen
• Oxygen is involved in many oxidative
schemes.
• Formulations that are shown to be
susceptible to oxidation can be stabilized
by replacing the oxygen in the storage
container with nitrogen or
carbondioxide, or by adding
antioxidants.
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 Factors affecting stability of
drugs…Cont’d
49

 Formulation factors
pH
 pH is perhaps the most important
parameter which affects hydrolysis rate
of drugs in liquid formulations.

 It also affects oxidative degradation of

some drugs in solution. For example,
oxidation of predinsolone

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 Factors affecting stability of
drugs…Cont’d
50

 Excipients
 Aspirin and hydrocortisone
decompose in several PEGs which are
often used as suppository bases.

 Some excipients absorb moisture.

 Starch and povidone absorb
water when stored at high relative
humidity. As the result they affect
stability of products which contains
them.
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 Factors affecting stability of
drugs….Cont’d
51

 Other factors which affect stability

of drugs:
 manufacturing process,
 nature of the container-closure
system

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 Methods of stabilization of
drugs
52
 Protecting from light, exclusion from
oxygen, and use of antioxidants
 Some drug decomposition reactions,
such as photolytic and oxidative
reactions, are relatively easy to avoid by
protecting the components from light
(photo-decomposition) or exclusion of
oxygen and by use of antioxidants.

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 Methods of stabilization of drugs…….cont’d

53

 Hydrolysis reactions, however, cannot

be stopped by such procedures.

 The following approaches may be useful

attempts to retard hydrolysis reactions:

 selection of optimum pH,

 use of buffer and
 selection of solvent
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 Stabilization of drug
products………..cont’d
54

 Selection of optimum pH, buffer

and solvent
 Consideration of the mechanism of the
reaction and the way in which the
reaction rate is influenced by pH, buffer
species and solvent permits the
selection of the optimum conditions for
drug stability.

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 Stabilization of drug
products….cont’d
55


Often, however, ideal conditions for
maximum stability may be
unacceptable from the viewpoint of
pharmaceutically acceptable
formulation or therapeutic efficacy.
Thus, it may be necessary to prepare a
formulation with conditions less than
optimum for drug stability.

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 Stabilization of drug
products…..Cont’d
56

 If a suitable compromise between

conditions for maximum stability and
conditions for a pharmaceutically
acceptable formulation cannot be
achieved, techniques such as described
below may be useful in retarding
hydrolysis reactions:
 using specific complexing
agents
 using surfactants
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 formulating suspension
 Stabilization of drug
products…….cont’d
57

 Using specific complexing agents

 The rate of hydrolysis of the ester
function of benzocaine can be retarded
significantly in the presence of caffeine.
 Caffeine forms a soluble complex with
benzocaine.
 In this system the complexed
benzocaine does not hydrolyze at all.

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 Stabilization of drug products…
cont’d
58

 Benzocaine
caffeine

 epinephrine

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 Stabilization of drug
products…..Cont’d
59

 Boric acid chelation of the catechol

function of epinephrine stabilizes
epinephrine against the attach by
bisulfite and sulfite.
 Surfactants
 It has been demonstrated that the
incorporation of benzocaine into
surfactant micelles could retard
significantly the rate of ester hydrolysis.

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 Stabilization of drug
products…..Cont’d
60

 Nonionic and anionic surfactants retard

the hydroxide-ion catalyzed hydrolysis,
but cationic surfactants somewhat
increase the rate of hydroxide-ion-
catalyzed hydrolysis of benzocaine.

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 Stabilization of drug
products…..Cont’d
61

 Formulating suspensions
 If the solubility of a labile drug is reduced
and the drug is prepared in a suspension
form, the rate at which the drug degrades
will be reduced.
 Refrigeration
 Storage below room temperature usually
will retard hydrolysis reaction.
 Storage in the frozen state generally is an
effective means of retarding degradative
reaction. 12/20/2024
62
Stability study
 The purpose of stability testing is to
provide evidence on how the quality of
an active substance or
pharmaceutical product varies with
time under the influence of a variety of
environmental factors such as
temperature, humidity and light.

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 Stability study……cont’d
63

 Finally, the results of stability studies are

used to determine appropriate
storage conditions and expiration
dating.
 The latter is to ensure that the
pharmaceutical product meets
applicable standards of identity,
strength, quality and purity at the
time of use.
 Stability study is done for new
formulations before being marketed.
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 Stability study protocols
64

Table 1: Stability study protocol for

drugs intended for storage at room
temperature( 20 oC- 25 oC).
Conditions Minimum time period for
study
Long-term testing
25oC±2oC/60% 12 months
±5% RH
Accelerated
testing
40oC±2oC/75% 6 months
±5% RH 12/20/2024
 Stability study protocols……
cont’d
65

Table 2: Stability study protocol for

drugs intended for storage in
refrigerator . Minimum time period for
Conditions
study
Long-term 12 months
testing
5oC±3oC
Accelerated
testing
25oC±2oC/60% 6 months
±5% RH
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or
 Parameters to be studied during
stability study
66

o Some parameters to be studied

during stability study of drug
substances
Appearance (visual)
Identity
Assay (HPLC)
Impurities (HPLC)
Moisture content (Karl Fisher test)
Dissolution (for solid dosage
forms, USP method)
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etc
 Stability study..…..cont’d
67

 Accelerated testing can help to identify the

likely degradation products, which can in
turn help establish the degradation
pathways and the intrinsic stability of the
molecule.

 In stability testing for products to be stored

under room temperature, alternate testing
is required if ‘significant change’ occurs
during 6-months under conditions of
accelerated testing.
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 Stability study..…..cont’d
68

What are the ‘significant changes’?

 Significant changes at accelerated
condition is defined as
 A 5% potency loss from the initial assay
value
 Any specific degradant exceeding its

specification limit
 The product exceeding its pH limits

 Failure to meet specifications for

appearance, color, phase separation,

resuspendability, caking, hardness,
12/20/2024 etc.
 Stability study …..cont’d
69

 The long-term testing is required to be

continued for a sufficient period beyond
12 months to cover all appropriate re-test
periods.
 The frequency of testing should be
sufficient to establish the stability
characteristics of the drug substances;
 Under long-term conditions this will
normally be every 3 months over the first
year, every 6 months over the second
year and then annually 12/20/2024
 Parameters to be studied during
stability study for dosage forms
70
Dosage form Parameters to be studied
Formation of precipitate, clarity of
Oral solutions, pH, viscosity, extractables,
solution level of microbial contamination
Caking, crystal growth, pH, viscosity,
extractables, level of microbial
contamination, redispersibility,
Suspension rheological properties and mean size
and size distribution of particles
Phase separation, pH, viscosity, level of
microbial contamination, and mean size
Emulsions and size
distribution of dispersed globules
Ointments, clarity, homogeneity, pH, consistency,
creams, viscosity, particle size distribution (for
paste, gel, insoluble drugs), level of12/20/2024
microbial
 Prediction of shelf life
71

 An expiration date, which is expressed

traditionally in terms of months and
years, denotes the last day of the
month.

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