Kinetics of Drug

1. GURU JAMBESHWAR UNIVERSITY OF SCIENCE AND TECHNOLOGY
HISAR
TOPIC- KINETICS OF STABILITY AND STABILITY
TESTING
SUBMITTED TO – DR. REKHA RAO
SUBMITTED BY – SHEETAL SARDHNA

2. DRUG KINETICS
 Drug kinetics- Defined as how drug changes with time i.e.
study of rate of change.
 Many drugs are not chemically stable and the principle of
chemical kinetics are used to predict the time span for
which a drug will maintain its therapeutic effectiveness or
efficacy at a specified temperature.

3. IMPORTANCE OF STUDYING KINETICS
It determines
 Stability of drug / half life of drug- defined as time necessary for a
drug to decay to its half life or 50% conc.
 Shelf life- defined as the time required for a drug to decay 90% of its
original conc.

4. RATE AND ORDER OF REACTION
 The velocity with which a reaction or process occurs is called its rate.
 The Conc. of drug which influences the rate of reaction or process is called
its order of reaction.
 Consider the following chemical reaction
DRUGA---------------DRUG B
 The rate of forward reaction is expressed by-
-dA/dt
 As the reaction proceeds, the conc. Of drug B increases & rate of reaction
can be expressed by
dB/dt

5. The two commonly encountered rate processes are:
1. ZERO ORDER REACTION
2. FIRST ORDER REACTION

6. ZERO ORDER REACTION
 Also called as constant rate process.
 When the reaction rate is independent of concentration of reacting
substance, It depends on the zero power of the reactant and therefore it is
considered as Zero order reaction.
(Rate – k°C)
 In this type of reaction the limiting factor is something other than reaction,
the limiting factor is something other than concentration.

7. dC/dt = k0dt
Where,
C= concentration of drug at time t
Ko= Zero order rate constant

8. FIRST ORDER REACTION
These are the reactions whose rate is directly proportional to conc. Of the drugs
undergoing reaction i.e greater the conc., faster is the reaction.
When the concentration of drug is dependent upon the first power of the
reactant therefore considered as First order reaction
It follows linear kinetics.
dC/dt=-KC
Where, K= first order rate constant (per hour)
Rearranging the above equation
dC/C=-Kdt

9.  In terms of log
log C = log Co – kt /2.303
Graph of first order Kinetic showing linear relationship between rate of reaction
and concentration of drug

10. Factors affecting rate of reaction
 Temperature
 Light Solvent
 Phase & Surface Area
 Catalysis
 Concentration

11. Kinetic of drug decomposition
 The drug decomposition follows the degradation pathway-
 1. Hydrolysis
 2. Oxidation
 3. Photolysis.
 4. Racemization

12. HYDROLYSIS
 Many pharmaceuticals Such as ester, amides undergoes hydrolysis in solution.
e.g. anesthetics, antibiotics, vitamins, & barbiturates.
 The hydrolysis of an ester in acid & alcohol due to rupture of a covalent
linkage b/w Carbon and Oxygen atom. E.g. Aspirin.
 The hydrolysis of amide gives acid & amine. e.g. barbiturates,
chloramphenicol

13. Oxidation
 The oxidative decomposition can lead to instability of preparations such as
Steroids, Antibiotics, Epinephrine and vitamins.
 Reaction mediated either by free radicals or by molecular oxygen.
Autoxidation involves a free radical chain process.
AB ----------- A• + B
 These radicals are highly unstable substances, and readily take electrons from
other substances causing oxidation.
 Functional groups are susceptible to oxidation are Aldehydes, carboxylic
acids, Amines, ethers, Conjugated dienes etc.

14. Photolysis
 Photolytic degradation is due to exposure to UV or visible light in the
wavelength range approx. 300-800 nm.
 Photo degradation rates are directly dependent on the amount of incident
radiation & on the amount of radiation that is absorbed by the compound.
 Alcoholic solutions of hydrocortisone, prednisolone, & methylprednisolone
degrade by photolytic reactions following first-order kinetics.

15. Racemization
 An optically active substance loses its optical activity without changing its
chemical composition.
 Dextro form generally therapeutically less active than levo form.
 E.g. levo form of adrenaline is 20 times active than dextro.

16. STABILITY TESTING
 Stability: defined as capability of a particular formulation in a specific
container/closure system to remain within its physical, chemical,
microbiological, toxicological, protective and informational specifications.
 It is the extent to which a product retains, within the specified limits.
Throughout its period of its storage use, the same properties and
characteristics possessed at the time of its packaging.

17. SCOPE OF STABILITY TESTING
 Provide evidence as to how the quality of drug product varies with time.
 Establish shelf life of drug product.
 Determines recommended storage conditions
 Determine container closure system suitability.

18. IMPORTANCE OF STABILITY TESTING
 Assurance to patient that drug is safe.
 legal requirement to provide data.
 to protect the reputation of the manufacturer.
 to provide a database.
 To determine shelf life and storage conditions.
 To verify that no changes have been introduced in the formulation or
manufacturing process that can adversely affect the stability of the product.

19. TYPE OF STABILITY
 Chemical-Each active ingredient retains its chemical integrity and labeled
potency within specified limits.
 Physical - Includes appearance, palatability, uniformity, dissolution and
suspend ability are retained.
 Microbiological- Sterility or resistance to microbial growth is retained
according to specific requirement.
 Therapeutic - Activity remains unchanged.
 Toxicological- No significant increase in toxicity.

20. STABILITY TESTING METHODS
 1. REAL TIME STABILITY TESTING
 2. ACCELERATED STABILITY TESTING
 3. RETAINED SAMPLE STABILITY TESTING
 4. CYCLIC TEMPERATURE STRESS TESTING

21. REAL TIME STABILITY TESTING
 performed for longer duration of the test period in order to allow significant
product degradation under recommended storage conditions.
 depends upon the stability of the product which should be long enough to
indicate clearly that no measurable degradation occurs.
1. Data is collected at appropriate frequency
2. To distinguished instability from day to day
3. Stability of reference material include the stability of reagent as well as
consistency of performance

22. ACCELERATED STABILITY TESTING
 • A product is stressed at several high temp & the amount of heat input
required to cause product failure is determined.
 This is done to subject the product to a condition that accelerates
degradation.
 This information is then projected to predict shelf life or used to compare
the relative stability of alternative formulations.
Steps includes;
1. Samples subjected to stress
2. Refrigerated
3. Assayed simultaneously

23. RETAINED SAMPLE STABILITY TESTING
 usual practice for every marketed product for which stability data are
required.
 Only one batch a year are selected.
 If the number of batches marketed exceeds 50, stability samples from two
batches are recommended to be taken.
 Stability testing by evaluation of market samples is a modified method which
involves taking samples already in the market place and evaluating stability
attributes.

24. CYCLIC TEMPERATURE STRESS TESTING
 Is not a routine testing method for marketed products.
 In this method, cyclic temp, stress tests are designed on knowledge of the
product so as to mimic likely conditions in market place storage.
 The period of cycle mostly considered is 24 hours.
 The min and max. temp. for the cyclic stress testing is recommended to be
selected on a product by product basis and considering factors like
recommended storage temp. for the product and specific chemical and
physical degradation properties of storage the products.
 the test should normally have 20 cycles.

25. THANK YOU