Principles and kinetics

of
drug stability (PHR
416)

Nahla S Barakat, PhD

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PHR 416

Professor of Pharmaceutics

09/13/15

Course Description:
The course deals with different routes of drug

degradation principles and kinetics of

chemical degradation and stress stability
testing.
Means of prolonging shelf life of
pharmaceutical products are also included.

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Recommended text books:

Martins Physical pharmacy & Pharmaceutical
Sciences, Fifth Edition, Patrik J. Sinko (ED),
Lippincott Williams & Wilkins 2006,( Chapter 15).
Modern Pharmaceutics, Fourth Edition, G. S.
Banker, C. T, Rhods. Marcl Dekker In., 2002
Physicochemical principles of Pharmacy, Fourth
Edition, A.T Florence, D. Attwood, Pharmaceutical
Press,2006, (Chapter 4)
Recommended References:
US Pharmacopea
<1191> Stability consideration in dispensing
practice
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This course is a3 credit hoursubject &

correspond to300 marks

The marks are divided as follows:
1- Final exam ..120 Marks
2- Oral exam 30 Marks
2- Mid term . 60 Marks
3- Practical... 90 Marks

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Introduction
Basic requirements of pharmaceutical
products
Efficacy: Optimum therapeutic level for

specified period of time.

Safety: Minimum or no side effects.
Stability: The products should retain their
properties during storage.
This should guarantee the efficacy and safety

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The USP defines the stability of

pharmaceutical product as extent to
which a product retains within specified
limits and throughout its period of storage
and use (i.e its shelf life) the same
properties and characteristics that it
possessed at the time of its manufacturer

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 Stability of drug also can be defined as the time

from the date of manufacture and packaging of

the formulation until its chemical or
predetermined level of labelled potency and its
physical characteristics have not changed
appreciably.
For a drug substance, we need to study 3
categories of stabilitiesA. Solid state stability of drug only
B. Compatibility studies ( drug+ excipients )
C. Solution phase stability

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These
stability
data
involves
selected
parameters that taken together from the
stability profile.
Pharmaceutical products are expected to meet
their specification for identifying purity,
quality and strength throughout their defined
storage period at specific storage condition.
The stability of pharmaceutical product is
investigated throughout the various stages of
the development process.

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Importance of stability studies

Development of optimum formulation

(preformulation studies)
Finding the optimum storage conditions
(temperature, light, humidity).
Selecting the proper container for dispensing
(glass or plastic, clear or opaque, cap liners).
Predicting the shelf life of the drug.
Anticipating drug excipient interactions.
Stabilization of the drugs against degradation

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In some cases a pharmacist may need to

prepare stable compounded preparations

from existing dosage form.
It is the responsibility of the pharmacist

via the information of the manufacture to

instruct the patient in the proper storage
and handling of the drug product.

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Factors affecting drug stability:

1. Temperature: high temperature accelerate oxidation, reduction
and hydrolysis reaction which lead to drug degradation
2. pH:
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.
Sometimes pH can have a very serious effect on
decomposition. As little as 1 pH unit change in pH can cause a
change of ten fold in rate constant. So when we are formulating
a drug into a solution we should carefully prepare a pH
decomposition profile

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3. Moisture:
a. Water catalyses chemical reactions as
oxidation, hydrolysis and reduction reaction
b. Water promotes microbial growth
4. Light: affects drug stability through its energy
or thermal effect which lead to oxidation
5. Pharmaceutical dosage forms: solid dosage
forms are more stable than liquid dosage forms
for presence of water.
6. Concentration: rate of drug degradation is
constant for the solutions of the same drug with
different concentration. So, ratio of degraded
part to total amount of drug in diluted solution
is bigger than of concentrated solution.
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7. Drug incompatibility: reactions between

components of pharmaceutical dosage
forms it self or between these components
and cover of the container .
8. Oxygen: exposure of drug formulations to
oxygen affects their stability

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Expiry date: means that drug can not be used after

this date because the concentration of drug is
decreased and become lower than therapeutic
concentration. In addition, some products of drug
degradation are toxic and harmful to patients.
NOTE: The expiration date period should begin at the time
of manufacture of the lot.
PRODUCT TYPE
MAX. TIME PERIOD
Dosage forms:
5 years
Implants, injectables, tablets, capsules, soluble powders,
etc.
Note! After the opening of the drug container, the expiry
date will be shorter as a result of the decreased
concentration of drug during usage and the effects of
external factors. :

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Examples:
1. Eye drops: can be used for one month after
opening the droppers
2. Syrups and suspension of antibiotics: can be
used for one week by storage in room
temperature and for two weeks by storage in
4C.
3. Tablets and capsules remain stable in the
package but after removal the expiry date will
change
4. Ampoules: must be used immediately but the
vials (multidose) are stable for 24 h for the
presence of preservatives.
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Five stabilities of drug must be

considered::
1. Physical
2. Chemical
3. Microbiological
4. Toxicological
5. Therapeutic

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Reaction kinetics:
kinetic originates fromGreek kinetikos

that, in turn, originates from Greek

kinetos which means moving.
Kinetics: It is the study of how a system changes
as function of time.
Reaction kinetics: It is the study of rate of
chemical change and the way in which this rate
is influenced by conditions of
concentration of reactants and products,
solvent, ionic strength and temperature
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Rate and order of

reactions

Importance of the rate process:

For drug manufacturer as he must

demonstrate that his product is stable and

can be stored for reasonable length of time
without changing to inactive or toxic form.
The pharmacist must be aware of potential
instability of the drug that he handles.
The physician and the patient must be
assured that the prescribed drug will reach
the site of action in sufficient concentration.
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Rate and order of reactions

Fields of rate process:
Stability and incompatibility: Here the rate
process can lead to inactivation of the drug
through decomposition or conversion into
inactive or toxic form.
Dissolution: Here the main concern is the
rapidity with which a solid dosage form is
changed to molecular solution.

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 Pharmacokinetics: Concerns with the

rate of drug absorption, elimination and

metabolism.
Drug action at molecular level: Here it
is assumed that generation of a
response by a drug is a rate process.

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In general, reaction kinetics is the study of rate

of chemical change and the way in which this

rate is influenced by conditions of concentration
of reactants, products and other chemical
species which may be present, and the factors
such as solvent, pressure and temperature.
Reaction kinetics permits formulation of models
for the intermediate steps through which
reactants are converted into other chemical
compounds and is a powerful tool in elucidating
the mechanism by which chemical reactions
proceed.
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It provides a rational approach to stabilization

of drug products and prediction of shelf- life

and optimum storage conditions. e.g.
thiamine HCl is most stable at pH 2-3 and is
unstable at pH above 6. If this is combined
with a buffered vehicle of say pH 8 or 9 the
vitamin is rapidly inactivated.
Knowing the rate at which a drug deteriorates
at various hydrogen ion concentrations allows
one to choose a vehicle that will retard or
prevent the degradation.

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Reaction Rate
The rate of reaction is the velocity with
which a reactant or reactants undergo
chemical change.
The rate, velocity or speed of a reaction is
given by the expression dc / dt.
where dc is increase or decrease of
concentration over a time interval dt

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Rate and order of reaction

Rate:
The rate, velocity or speed of reaction is
given by:
dc/dt
This expression gives the increase (+) or
decrease (-) in concentration (C ) within a
given time intervals (dt )

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Reaction kinetics: Rate

Formation of ethyl acetate from ethyl alcohol and acetic

acid.
CH3COOH + C2H5OH = CH3COOC2H5 + H2O
In this reaction the rate of forward reaction (Rf) may be
calculated by measuring the concentration of acetic acid
or ethanol as the
reaction progresses.

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Reaction kinetics: Rate

CH3COOH + C2H5OH = CH3COOC2H5 + H2O
The rate of reverse reaction (Rr) may
calculated by measuring the concentration of
ethyl acetate or water as the reaction takes
place

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Reaction kinetics: Rate

According to the law of mass action:
The rate of a chemical reaction is proportional
to the product of molar concentrations of the
reactants each raised to a power equal to the
number of molecules of the substance
undergoing reaction.
aA + bB + .. = Products
Rate = k [A]a [B]b
Where k is rate constant.
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Order of reaction
aA + bB Product
Reaction rate = K [A]a [B]b
* If a=2 and b=1, the reaction rate = K
[A]2[B]1
* The reaction is second order with respect to
A and first order with respect to B.
* The overall order is the sum of the
exponents of
concentration terms that afford a linear plot,
i.e. third order
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Reaction of ethyl acetate with sod. hydroxide

in aqueous solution
CH3COOC2H5 + NaOHsoln CH3COONa +
C2H5O
The rate expression is:

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CH3COOC2H5 + NaOHsoln CH3COONa +

C2H5OH
The reaction is first order (a = 1) with
respect to ethyl acetate and first order (b=
1) with respect to sodium hydroxide
solution.
The overall reaction is second order
(a + b = 2)

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CH3COOC2H5 + xss NaOHsoln CH3COONa +

C2H5OH
Suppose that NaOH solution is used as solvent (i.e.
its conc. is very high) and ethyl acetate were in
low concentration.
As the reaction proceeds, ethyl acetate would
change appreciably from its original concentration,
Whereas the concentrations of NaOH solution would
remain
essentially unchanged because of its presence in
great
excess

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CH3COOC2H5 + xss NaOHsoln CH3COONa +

C2H5OH
In this case the reaction rate can be written as

where k' = K [NaOH]

The reaction is then said to be pseudo-firstorder
reaction because it depends only on the first
power (a = 1) of the concentration of ethyl
acetate
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In general, when one of the reactants is

present in such great excess that its
concentration may be considered constant
or
nearly so, the reaction is said to be of
pseudo-order.
Apparent or pseudo-order
"Apparent" or "pseudo"-order describes a
situation where one of the reactants is
present in large excess.

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