1. GUIDED BY: Dr. M. R. PATEL Principale & HOD in
pharmaceutics PRESENTEDE BY: SAHILHUSEN I . JETHARA M. PHARM I
(2013-14) ROLL NO. - 02 DEPARTMENT OF PHARMACEUTICS SHRI B. M. SHAH
COLLEGE OF PHARMACEUTICAL EDUCATION AND REASERCH, MODASA-2013
2. contents Introduction Types of Stability studies Arrhenius
equation Steps involved in prediction of shelf life Addition of
Overages Conclusion References
3. INTRODUCTION Stability of a pharmaceutical preparation is
the capability of a formulation in a specific container-closure
system to remain within its physical, chemical, microbiological,
therapeutic and toxicological specifications throughout its shelf
life. The time during which the product retains the same properties
and characteristics that it possessed at the time of manufacture.
Stability testing is used to: Provide evidence as to how the
quality of the drug product varies with time. Establish shelf life
for the drug product. Determine recommended storage conditions.
Determine container closure system suitability. Introduction
4. OBJECTIVES To predict shelf life of product by accelerating
rate of decomposition preferably by increasing the temperature. To
serve a rapid means of quality control. To serve as a rapid means
of selecting the best formulation from amongst a series of similar
formulations of the product. To predict the expiry date of
product
5. Why Stability studies are necessary ? Chemical degradation
of the product leads to lowering of the concentration of the drug
in the dosage form. Toxic products may be formed , due to chemical
degradation of the active ingredient. Advantages of Stability
studies Assurance to the patient Economic considerations Legal
requirement
6. According to ICH guidelines, The ambient study for drug
product must be continued for a sufficient period of time beyond 12
months to cover the shelf life of the product. Intermediate storage
condition data are required when a significant change occurs prior
to completion of study under the accelerated storage condition. The
accelerated storage condition must be >15 C above the ambient
storage conditions
7. Types of stability study Study Minimum time period covered
by data at submission Storage condition Long term 25 C 30 C 2 C /
60% 2 C / 65% 5% r.h or 5% r.h. 12 months Intermediate 30 C 2 C /
65% 5% r.h. 6 months Accelerated 40 C 2 C / 75% 5% r.h. 6 months
7
8. LONG TERM STABILITY STUDIES Study is performed at 250C/60%
or 300C/ 65%. Ideally 12 months data is to be generated but 6
months data is also acceptable in circumstances for submission of
registration dossier, continued till end of shelf life. For
parenterals stability has to carried out at 2-80 C for drugs to be
stored in freezer testing should be done at 200 C
9. ACCELERATED STABILITY STUDIES Storage condition of 400C and
relative humidity of 75% has been recommended for all the four
zones for drug substances and drug products. Studies carried out
for 6 months. Accelerated storage conditions must be at least 150C
above the expected actual storage temperature and appropriate
relative humidity
10. Testing Frequency: For Long term testing: during first year
sampling should be done every three months, during second year,
sampling should be done every six months and after two years,
sampling should be done once a year. Accelerated testing : should
be done atleast six months and it suggests sampling points of 0, 3,
6 months.
11. Accelerated Stability study to predict the shelf life of
the product, by accelerating the rate of decomposition, preferably
by increasing the temperature of reaction conditions. With the
advancement in branch of kinetics, shelf life of a dosage form can
be predicted within months based on accelerated stability reports
Preparations are subjected to high stresses during stability
testing. Common high stresses include : Temperature Humidity
Light
12. Arrhenius equation It explains the effect of temperature on
rate of a reaction. According to Arrhenius, for every 10 rise in
temperature, the speed of reaction increases about 2-3 times. k = A
e -Ea / RT Arrhenius factor Energy of activation Ideal gas constant
Log k = log A Ea / 2.303 RT Arrhenius factor is the frequency of
molecular collisions occuring between the molecules.
13. Estimation of k value The reaction is conducted at several
temperatures. Concentration of reactants is determined. Appropriate
graphs are drawn for the kinetic data. Data is processed for all
the orders. The order of the reaction is identified. From the
slopes of the lines, k values are calculated for all
temperatures.
14. Estimation of energy of activation A graph can be drawn by
taking log k on y-axis and reciprocal temperature (1/T) on x-axis.
A straight line is obtained, the slope of the line is negative and
the magnitude is Ea / 2.303 R. The intercept corresponds to log A
All the constants in the Arrhenius equation can be obtained from
the graph. Activation energy is the minimum energy that a molecule
should possess so that the molecular collisions produce the
product.
15. Steps involved in Accelerated Stability Testing Steps
involved in prediction of shelf life he Preparation is stored at
different elevated temperatures, to accelerate the degradation
Samples are withdrawn at different time intervals The Order of the
reaction is determined by plotting the appropriate function of
concentration against time and linear relationship is determined
Straight line in a graph permits the estimation of k value from the
slope Similarly graphs are drawn for different elevated
temperatures. K value for each temperature are calculated. By using
Arrhenius relationship, Log k values are plotted against reciprocal
of absolute temperature, energy of activation can be
calculated.
16. Packaging material:in selecting packaging material, the
following has to be considerd : Packaging material: in selecting
packaging material, the following has to be considerd Packaging
materials permeable to water vapor result in a falsification of the
results for semisolid and liquid dosage forms if varying degrees of
weight loss occur that leads to differences in the active
ingredient concentration or ion strength. The use of inert standard
packaging materials that are impermeable to water vapor is
important precondition for stress tests that are evaluated in terms
of reaction kinetics, and on the results on which stability
predictions are to be tested.
17. Most of the stress tests are carried out in standard
packaging material.The following standard packaging materials are
used: Most of the stress tests are carried out in standard
packaging material. The following standard packaging materials are
used: Solid dosage forms: 50-mL glass container with twist-off
closure polypropylene tube Semisolid dosage forms: Standard tube,
small volumetric flask, Aluminum tube, inert internal lacquering
Liquid dosage forms: 25mL volumetric flask with ground-glass
stopper However, furture investigations for the selection of the
final packaging are necessary.
18. Selection of packaging material for solid dosage forms. :
On the basis of the results of the stress tests for solid dosage
forms, the sensitivity to moisture can be determined and suitable
packaging materials can be selected. As a rule, no interactions are
to be expected. If the final packaging material has been selected
and samples packed in the final packaging material are available,
the investigation of photostability should be performed.
Photostability :The samples with and without container are
irradiated with a Xenon lamp for 24 hours.
19. Selection of packaging material for semisolid dosage forms
1. Selection of packaging material for semisolid dosage forms.
Packaging: Aluminum tube internally lacquered, plastic tubes. 2.
Problems: Corrosion , permeation, sorption. Tests packaging
material dosage form: To test for corrosion ,the filled metal tubes
are stored horizontally upright and inverted at 400C, for 3 months
and are then investigated. 3. To test for permeation and sorption
the filled plastic tubes are stored for 3 months at 500C, 400C,
300C/70%. If the final packaging material has been selected, the
investigations on the photostability are performed.
20. Selection of packaging material for liquid dosage forms :
Selection of packaging material for liquid dosage forms Packaging
ampoule, injection vial with rubber stopper, glass bottle or
plastic bottle with screw closure. Problems: leakage. To test for
permeation, and leakage, the finale formulation solution is filled
in the container, and for desorption placebo solution is used. The
samples are stored vertically and inverted under 500C, 400C,
300C/70% for up to 12 weeks. Tested intervals: 0, 1, 2, 3 months.
If the final packaging material has been selected the
investigations on the photostability are performed.
21. Accelerated Stability Testing in Emulsions An emulsion is
stored at elevated temperature. This decreases viscosity of the
continuous phase. If the emulsion withstands this stress it is
assumed to be stable at normal conditions of storage.
Centrifugation Method: Creaming and flocculation are slow
processes. Centrifugation accelerates rate of creaming and
flocculation in emulsions. The emulsion is subjected to different
centrifugal speeds and separation of phases is observed at
different time periods. Bad emulsion separates oil instantly. Good
emulsion does not exhibit detectable separation of oil phase until
certain time period.
22. Accelerated tests for Suspensions Cake formation is
accelerated by centrifugation. High speed centrifugation is hence
not preferred, low speed centrifugation is used to study the
physical stability. A Freeze-Thaw cycling technique is one of the
stress testing . This cycling treatment promotes particle growth
and has primary importance for changes in absolute particle size,
particle size distribution and crystal habit.
23. Accelerated Tests for moisture absorption In this method,
products are placed in an environment of high relative humidity and
controlled temperature. Their physical and chemical stabilities are
assessed. The results will indicate whether the product is
susceptible to moisture and also whether the container needs to
provide a high degree of protection
24. Limitations Stability predictions based on Arrhenius
equation are valid only when the break down depends on temperature.
The energy of activation obtained in the study should be between 10
to 30 kcal/mole. When degradation is due to Microbial contamination
Photochemical reactions When the product looses its physical
integrity at higher temperatures. When the order changes at
elevated temperatures. In case of disperse systems, when
temperature is elevated viscosity is decreased and this may
introduce errors in the prediction of stability.
25. ADDITION OF OVERAGES Excess amount of the drug can be added
to the preparation to maintain 100% of the labelled amount during
the shelf life of the product. Overages are calculated from the
accelerated stability studies and added to the preparation at the
time of manufacture. They should be within the limits compatible
with the therapeutic requirement. Addition of overages doubles the
shelf life of the product. Overages are added in multi vitamin
preparations Addition of Overages
26. Conclusion Knowledge of stability of a formulation is very
important for three primary reasons: A Pharmaceutical product must
appear fresh, elegant and professional for as long as it remains on
the shelf. Since some products are dispensed in multiple dose
containers, uniformity of dose of the active ingredient over time
must be ensured . The active ingredient must be available to the
patient through out the expected shelf life of the preparation. A
breakdown in the physical system can lead to non availability or of
the medication to the patient.
27. References : Martins Physical Pharmacy and Pharmaceutical
Sciences. Theory and practice of Industrial Pharmacy - Lechman
International Stability Testing Drug stability- Cartensen C.V.S
Subramaniyam www.google.com