Drug Stability
Contents
• Physical degradation of pharmaceutical products
• Chemical decomposition of drugs and preventive measures
• Influence of light on drug decomposition
• Effect of temperature on drug decomposition
• Chemical stability testing
Learning
Objectives
At the end of this
lecture, student will be able to
• Describe the physical factors affecting degradation of
pharmaceutical products
• Describe the chemical factors causing degradation of drugs
and the preventive measures
• Describe the influence of light and temperature on drug
Degradation
• Describe the accelerated stability testing of drug
products
• Explain the different methods of conducting accelerated
stability testing
Drug Stability
• Drug decomposition or degradation occurs during storage
due to chemical alteration of the active ingredients
• Stability is defined as the time lapse during which the
drug product retains the same properties and characteristics that it possessed
at the time of manufacture
• Stability studies are necessary for the following reasons:
- Chemical degradation may lead to under medication
- Decomposition of active drug may lead to formation of
toxic product
- Instability may be due to change in physical
Drug stability- Physical Degradation of Pharmaceutical Product
• The different forms of physical degradation of
pharmaceutical products are:
- Loss of volatile constituents
- Loss of water
- Absorption of water
- Crystal growth
- Polymorphism
- Colour change
Drug Stability- Chemical Decomposition and Preventive Measures
Hydrolysis
• The principles that governs the hydrolysis reactions are:
- Drugs with ester and amide groups
- Drugs in the form of weak acids or weak bases
- Hydrolysis reaction are catalysed by H+ and (OH)-
• Drugs which decompose by hydrolytic pathways are: Aspirin,
Atropine, Chloramphenicol, Cephalosporins etc.
Protection against hydrolysis
- Buffers
- Complexation
- Suppression of solubility
- Removal of water
Oxidation
• The general principles that govern oxidation reaction are:
- Presence of atmospheric oxygen
- Light energy induced free radical chain reaction
- Presence of trace metals
- Organic peroxide induced chain initiation
- Drugs in the form of weak acids or weak bases
- Oxidation reaction catalyzed by H+ and OH-
• Drugs which decompose by oxidation reaction are:
Promethazine, Epinephrine, Vitamin A, Riboflavin, ascorbic acid etc.
Protection against oxidation
- Antioxidants
- Chelating agents
- Vehicles
- Micellar solubilisation
- Buffers
Influence of Light on Drug Stability
• Light energy activate molecules and enhance the rate of a
reaction
• Drugs which undergo light induced chemical degradation are
called photolabile (photosensitive) drugs
• Examples of photosensitive drugs are Riboflavin,
Tetracycline, Chlorpromazine etc.
• The photochemical decomposition of pharmaceuticals are due
to absorption of sunlight in the spectral region of visible blue and violet U.V
wavelengths (500- 300 nm)
Influence of Temperature on Drug Decomposition- Arrhenius Equation
• The speed of many reactions increases two to three times
with every 100 C rise in temperature
• Arrhenius equation explains the effect of temperature on
the rate of a reaction
Where, k= specific rate constant
A=
Arrhenius or frequency factor
Ea=
energy of activation
R= ideal
gas constant
T=
absolute temperature
• Taking logarithms on both side of equation (1)
Converting equation (2) to log base 10 gives
• Energy of activation is the minimum energy a molecule
should possess so that the molecular collision produce the product
• Arrhenius factor is defined as the frequency of collisions
which can occur between the molecules
Chemical Stability Testing-Accelerated Stability Studies
• The method of accelerated testing of pharmaceutical
products based on the principles of chemical kinetics
Method 1
• The k values for the decomposition of a drug in solution
at various elevated temperature are obtained by plotting some function of
concentration against time
• The logarithms of the specific rates of decomposition are
then plotted against the reciprocals of the absolute temperature
Method 2
• Fractional life period is plotted against reciprocal
temperatures and the time in days required for the drug to decompose at room
temperature is obtained
Method 3-
Nonisothermal kinetics
• Temperature and time are related through an appropriate
function:
1/T = 1/T0 + at……………..(4)
Where T0 is the initial temperature and a is a
reciprocal heating rate constant
• The Arrhenius equation for time zero and time t can be
written as
• Substituting equation (4) into (5) gives:
• Because temperature is a function of time, t, a measure of
stability kt, is directly obtained over a range of temperatures
Method 4- Stress
testing
• The testing typically includes the effects of temperature
in 100 C increments above that for accelerated testing
• Other conditions like humidity (75% relative humidity and
greater), where appropriate oxidation, photolysis are also considered
• This testing is undertaken to assess the effect of severe
conditions on the drug product
Method 5 – Q10
method
• Using this method, the effect of 100 C rise in temperature
on the stability of pharmaceuticals can be estimated
• Q10 can be defined by the equation:
• Q10 can be calculated from the equation:
Summary
• The different forms of physical degradation of
pharmaceutical products are: Loss of volatile constituents, Loss of water,
Absorption of water, Crystal growth, and polymorphism
• Chemical factors affecting the degradation of drugs are hydrolysis
and oxidation
• Light energy activate molecules and enhance the rate of a
reaction
• The speed of many reactions increases two to three times
with every 100 C rise in temperature
• Arrhenius equation explains the effect of temperature on
the rate of a reaction
• Accelerate dstability studies can be conducted by:
- Graphical methods
- Nonisothermal kinetics
- Stress testing method
- Q10 calculation method
- Freeze thaw method
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