Drug Stability

Learning Objectives

At the end of this lecture, students will be able to

• Describe the physical factors affecting the degradation of pharmaceutical products
• Describe the chemical factors causing the 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

              E_a= 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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