Chapter of M pharm First semester, Which covers order and rate of reaction,first order and zero order kinetics , ICH guidelines for stability testing,Storage conditions,etc.

1. STABILITY STUDY AND KINETIC
Guided by,
Dr.L.R.ZAWAR
H.O.D of Pharmaceutics:
DEORE SHUBHAM DEVIDAS.
PHARMACEUTICS
MPH 102
H.R PATEL INSTITUTE OF PHARMACEUTICAL
EDUCATION AND RESEARCH,SHIRPUR.
Presented by,

2.  Defination of kinetics
 Importance of studying kinetics
 Rate and order of reaction
 Factors affecting rate of reaction
 Kinetics of drug decomposition
 Stability testing
 Importance of stability study
 Types of stability
 Stability testing method
 Guidelines of stability testing
 Climatic zones for stability testing
 Test storage Conditions
Table of content

3. Defination of kinetics
 Defined as how drug changes with time i.e study of
rate of change.
 Many drugs are not chemically stable .
 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.

4. Importance of studying kinetics
It determines-
• Stability of drug / half life of drug-
Defined as time required for a drug to
decay to its half life or 50% conc.
(eg.100% -50%, 50%-25%).
• Shelf life- Defined as the time required
for a drug to decay to 90% of its
original conc..

5. 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.

6. ZERO ORDER REACTION
FIRST ORDER REACTION
The two commonly encountered techniques are,

7. Also called as constant rate process.
The rate of reaction is independent of conc. i.e rate of reaction cannot be
increased further by increasing the conc. of reactant.
dC/dt = - K, C= -Ko
where, K0 = zero order rate constant (in mg/min)
Rearranging eq" 1
dC = - K_{0} dt eq.1
𝒄𝒂
𝒄
ⅆℂ =
𝟎
𝒕
−𝒌𝟎 ⅆ𝒕
𝐶 − 𝐶0 = −𝑘0𝑡
Zero order reaction

8. These are the reactions whose rate is directly proportional to conc. of the
drugs undergoing reaction .
i.e greater the conc., faster the reaction.
It follows linear kinetics.
dC/dt =КС
Where, K= first order rate constant (per hour)
Rearranging the above equation
dC/CKdt.A
FIRST ORDER REACTION

9. Temperature
Concentration
Phase/
Surface
area
Factors affecting rate
of reaction
Solvent

10. Kinetics of drug decomposition
Hydrolysis Oxidation
Photolysis Racemization

11.  Many pharmaceuticals ester or amide
hydrolysis in solution. e.g.anesthetics, antibiotics,
vitamins, & barbiturates.
 The hydrolysis of an ester acid &
alcohol rupture of a covalent linkage
between C & O atom. e.g. Aspirin.
 The hydrolysis of amide acid, & amine.
e.g.barbiturates, chloramphenicol.
Hydrolysis

12. Oxidation
The oxidative decomposition instability of
preparations such as steroids, vitamins, antibiotics, & epinephrine.
Reaction mediated either by free radicals or by molecular oxygen
Autoxidation involves a free radical chain process.
These radicals are highly unstable & readily take electrons from
other substances, causing oxidation.
AB A+B

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

14.  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.
Racemization

15. Stability testing
1
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
2
It is the extent to which a product retains,
within the specified limits, throughout its
period of storage and use, the same properties
and characteristics possessed at the time of its
packaging.

16. Importance of stability study
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

17. Types of stability
Chemical
Each active ingredient retains its chemical
integrity and labeled potency within specified
limits.
Physical
Microbiological
Therapeutic
Includes appearance, palatability, uniformity,
dissolution and suspend ability are retained.
Sterility or resistance to microbial growth is
retained according to specific requirement.
Activity remains unchanged.
No significant increase in toxicity.
Toxicologic

18. Real time stability testing
Accelereted stability testing
Retained sample stability testing
Cyclic temperature stress testing
Stability testing method

19.  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.
Data collected
at frequency
Stability of
reference material
include the stability
of reagent as well as
consistency of
performance
To distinguish
instability from
day to to day
Real time stability testing

20.  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 native stability of alternative formulations.
2. ACCELERATED STABILITY
TESTING

21.  The concept of accelerated stability testing is based upon the
Arrhenius equation
K = In A + ΔΕ T
Where,K = degradation rate/s,
A= frequency factor/s,
AE = activation energy (kJ/mol),
R = universal gas constant (0.00831 kJ/mol),T=absolute
temperature (K)
Continued……

22.  Usual practice for every marketed product for which
stability data are reuired.
 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.
3. RETAINED SAMPLE STABILITY
TESTING

23.  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 the products.
 The test should normally have 20 cycles.
4. CYCLIC TEMPERATURE STRESS
TESTING

24. ICH
CODE
GUIDELINE TITLE
Q1A Stability testing of New Drug Substances and Products (Second
Revision)
Q1B Stability testing Photo stability testing of New Drug Substances and
Products
Q1C Stability testing of New Dosage Form
Q1D Bracketing and Matrixing Designs for stability testing of Drug
Substances and Products
Q1E Evaluation of stability data
Q1F Stability data package for Registration Applications in Climatic Zones
III and IV
Q5C Stability testing of Biotechnological/Biological Products

25. Zone 1 Zone II Zone III Zone IV
( TEMPERATURE ) ( SUBTROPICAL &
MEDITERRANEAN)
( HOT & DRY ) (HOT & HUMID)
• United
kingdom,
• Northern
Europe,
• Russia,
• United states.
Long term testing
conditions –
21ºC/45 % RH
• Japan
• Southern
Europe.
Long term
testing
conditions-
25ºC/60% RH
• Iraq,
• India
Long term
testing
conditions-
30ºC/35 % RH
• Iran,
• Egypt.
Long term
testing
conditions-
21ºC/45 % RH
Climatic zones for stability testing

26. Intended
storage
condition
Study Storage conditions Minimum time
period covered
Room
temperature
Long term 25ºC ±2ºC/60%
RH±5%RH
12 months
Intermediate 30ºC ±2ºC/65%
RH±5%RH
6 Months
Accelerated 40ºC ±2ºC/75%
RH±5%RH
6 Months
Refrigerated Long 5ºC ±2ºC 12 Months
Accelerated 25ºC ±2ºC/60%
RH±5%RH
6 Months
Long Long -20ºC ±5ºC 12 Months
Test storage Conditions

27. ● Lachman & Lieberman, The Theory and Practice of Industrial
Pharmacy.
● https://www.slideshare.net/SidharthMehta15/kinetics-of-stability-
stability-testing.
● N.Fathima, Kajal Ahir, Vandana Patel, Lata Manani, Chirag Patel
Stability testing and its importance in dosage form development,
Journal of applied Pharmaceutical Science 2011
● Slideshare.net/gaurav11288/stability-testing-15409502
● Bapi Gorain, Hira Choudhury, Manisha Pandey, Thiagarajan
Madheswaran, Prashant Kesharwani and Rakesh K. Tekade Drug-
Excipient Interaction and Incompatibilities 2018
Resources

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