1. MALLA REDDY COLLEGE OF PHARMACY
MAISAMMAGUDA,DHULPALLY SEC-BAD-14
PRODUCT STABILITY
PRESENTED BY:
Shweta patil
256213885024
M.PHARMACY(ANALYSIS)
GUIDED BY:
YASMEEN MADAM
M.PHARMA

2. CONTENTS
 INTRODUCTION
 ARRHENIUS EQUATION
 ACTIVATION ENERGY
 SHELF LIFE
 ACCELERATED STABILITY TESTING
 LIMITATIONS OF ACCELERATED STABILITY
 ADVANTAGES

4. INTRODUCTION
 Stability:
 Stability of pharmaceutical product may be
defined as the capability of a particular
formulation to remain in a specification.
 The container/closure system in which the
product will remain within its physical,
chemical, microbiological, therapeutic and
toxicological specification

5.  But the stability studies for any formulation is time
consuming and economical.
 Accelerated stability studies is the study of stability by the
accelerating the parameters like
• Temperature
• Humidity
• Light
 NEED FOR STABILITY TESTING:
 Provide evidence as to how the quality of the drug product
varies with time.
 Establish shelf life for the drug product.

6.  Essential quality attribute.
 Determine closure system suitability.
 Safety point of view of patient.
 Prevention of economical repercussion.
OBJECTIVES:
Main objective of the accelerated stability studies
 To predict the best formulation.
 To know the shelf life of the formulation.
 To provide quality formulations.

7. Arrhenius equation :
It explains the effect of temperature on rate of a reaction.
According to Arrhenius, for every 10º rise in temperature, the
speed of reaction increases about 2-3 times.
k = A e -Ea / RT
Where k=specific rate constant
A=frequency factor
Ea= activation energy
R=ideal gas constant
T=absolute temperature

8.  Arrhenius factor is the frequency of molecular collisions occuring
between the molecules.
 Take log on both sides,
ln k = ln A –Ea/RT ln e (2)
 Converting equation (2)to log 10
log k = log A – Ea/2.303RT
 By using Arrhenius equation at time zero and at any time it can be
ln = ln ko – Ea/R(1/T - 1/T0)

9. Estimation of k:
1.Reaction is conducted at several temperatures.
2.Concentrations is determined at different time period.
3.Order of reaction is identified.
4.From slope of line k is calculated.
slope=-k
2.303
Log(a)
Time(s)

10. ACTIVATION ENERGY:
 Activation energy is the minimum energy that a
molecule should possess so that the molecular
collisions produce the product.
 The activation energy of a reaction is usually
denoted by Ea, and given in units of kilojoules per
mole.

11.  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.
y-axis=lnk slope=-EA/R
x-axis=1/T

12. SHELF LIFE:
 t90 or t0. 9 : Time required to reduce the
concentration of the reactant to 90% of its
initial concentration.
 Stability of formulation can be determined
by shelf life.
 t90=0.105/k
where k=specific rate constant

13. SHELF LIFE :
Maximum and minimum time at which potency must
be atleast 90% of label claim at the temperature indicated in
order to predict a shelf life of two years at room temperature.
Temperature Maximum time
For study
Minimum time for
study
37*c 12 months 6.4months
45*c 8.3 months 2.9 months
60*c 4.1months 3 weeks
85*c 0.6 weeks 25 days

14. Calculation of shelf life:
Example: Shelf life of Aspirin suspension
 A prescription for liquid aspirin is called for it contains
325mg/5ml or 6.5g/100ml.
 Solution of aspirin at 25*c is 0.33g/100ml.therefore suspension will
definitely be suspension.
 Other ingredients in prescription cause the product to have PH of
6.
 1st order rate constant for aspirin degradation is 4.5 x10-6 sec-1.
 Calculate zero order rate constant.
 Determine shelf life assuming that product is satisfactory until at
the time at which it has decomposed to 90% of its original
concentration at 25*c

15. K0= k x (Aspirin in solution)
=(4.5 x 10-6 sec-1) x (0.33g/100ml)
Ko = 1.5 x 10-6 g/100ml sec-1
t90 = 0.10(A)0/k0
=0.10 x 6.5g/100ml
1.5 x 10-6g/100ml
=5days

16. Accelerated stability testing:
It involves studies designed to increase the rate of chemical
degradation or physical change of active substances or drug product
By using exaggerated storage condition as part of formal,definitive
Storage programme.
Accelerated stability testing involves four types:
They are:
 Test at elevated temperature.
 Test at high level intensity
 Test at high partial pressure.
 Test at high relative humidity

17.  Test at elevated temperature:
 Drug liquid preparation stored at 50, 60, 70,85,
 100 and 121˚c.
 Also study performed at R.T. and or refrigerator
temp.
 Sampling:
First year- 3 month interval
Second year- 6 month interval
 Four climatic zones:
Temperate zone 21˚c/45%RH
Mediterranean zone 25˚c/60%RH
Tropical zone 30˚c/70%RH
Desert zone 30˚c/35%RH

18. Test at high intensity of light:
 Drug substances fade or darken on exposing to light, can be
controlled by using amber glass or opaque container.
 By exposing drug substance to 400 & 900 (Foot candle)of
illumination for 4 & 2 weeks to light and another sample
examined protected from light .
 Results found on appearance and chemical loss may be recorded.
 Comparing color or using diffused reflectance spectroscopy for
examination.
 e.g. cycloprofen becomes very yellow after five days under 900
foot candles of light.

19. Test at high partial pressure of oxygen :
 Sensitivity of the drugs to atmospheric oxygen must be
evaluated from which it should be packed in inert atmospheric
condition with antioxidants is decided .
 Here, high oxygen tension plays important role to investigate
stability Usually ,40% of oxygen atmosphere allows for rapid
evaluation.
 Results were correlated with inert & without inert condition

20. Test at high relative humidity:
 Presence of moisture may cause hydrolysis and oxidation.
 These reactions may accelerated by exposing the drug to
different relative humidities.
 Control humidity by Lab desiccators
 Closed dessicator are placed in an oven to provide constant
temperature.

21. ACCELERATED STABILITY STUDIES
 Storage condition of 40*C 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

22. CLIMATIC ZONES/STORAGE CONDITIONS

23. CLIMATIC ZONES/STORAGE CONDITIONS

24. CLIMATIC ZONES/STORAGE CONDITIONS
Drug substances - intended for storage in a Refrigerator

25. CLIMATIC ZONES/STORAGE CONDITIONS
Drug products - General case

26. Limitations of accelerated stability testing:
 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.
 It is not useful when degradation is due to:
Microbial contamination
Photochemical reactions
Diffusion
Excessive agitation
 When the product looses its physical integrity at higher
temperatures.
 When the order changes at elevated..

27. Advantages:
 Storage conditions can be known.
 Stability of product can be estimated.
 Shelf life and expiry date can be known.
 Key assurance of quality of pharmaceuticals.
 Pharmaceutical products meet their specification
for identifying purity, quality and strength throughout their
defined storage period at specific storage condition.

28. SHELF LIFE ASSIGNMENT
 The validity of an assigned shelf life depends upon:
• Results of stability studies.
• Whether the batches used in the stability studies
accurately model to be marketed.
• Whether the analytical methodology was adequately
validated.
CONDITIONS:
 Assigning a shelf life is easier if results are available.
 For full duration of proposed shelf life.
 At maximum recommended storage condition.

29.  For all formulations and manufacturing methods.
 In exactly the packaging to be registered.
 At all the sites of manufacture of finished product and API.
 If these conditions are not met that’s when shelf life assignment
becomes difficult.
 There will be delays in approving the product.

30. SHELF LIFE DETERMINATION BASED ON ARRHENIUS PLOT
 We keep several samples of the drug product at atleast three
temperatures, such as 40,50 and 60*c.
 We determine the drug content at all three storage points by
taking a number of samples and take the mean drug content.we
do this for a few weeks.
 At each temperature we plot a graph between time and log
percent Drug remaining.If the decomposition is first order this
gives a Straight line.If it is zeroorder,percent drug remaining
versus time Will give a straight line.

31.  Next we take the log k or log of reaction constant on y-axis.
 And 1/T x10-3 on x-axis and draw a best fit line.This line is the
Arrhenius plot.We extrapolate this line to get k at 25*c and from
this we calculate the shelf life.
 If the reaction is following zero-order
 Expiration date at 25*c(tx)
 Initial potency-minimum potency/reaction rate at 25*c
tx  yo -
X Y O / K

32. oy = initial constant
 If the reaction is following first order:
Expiration date at 25*c(tx)=Log initial potency-log minimum potency
Reaction rate at 25*c
Where:
x y
= final potency
o k = zero order kinetics

33. SHELF LIFE DETERMINATION BASED ON REAL TIME
TESTING:
 Keep three batches for stability study at least for one year at
one fixed temperature.
 Test them at 0,1,3,6,9 and 12 months for drug content.At each
Testing time test a number of samples,so that you have a
mean and a standard deviation value of the result.
 Now plot the graph of % drug content on y-axis and time on x-axis
along with confidence intervals minimum potency,there
you fix the shelf life.

34. As an example : vitamin tablets stability confidence intervals at
40*c(confidence intervals means a range of values so defined that
There is a specified probability that the value of the parameters lies
Within it.)
Time
(months)
Results
(mg/tablet)
Lower
limit
Upper
limit
0 100.0 95.2 104.9
1 91.2 88.7 93.8
3 83.1 79.3 87.3
6 75.8 69.8 82.5
9 69.1 61.2 78.2
12 63.0 53.6 74.0

35. 1 ( y  -
i y )
2  n
2
y1 = predicted value at t1
n = sample size
Yi = standard error of line
Confidence intervals
D
r
u
G
%
 This method also helps the formulation scientists in fixing
 the amount of averages to be added to vitamin products.

36. Estimation of the shelf life(expiration period) of drug
products
 Shelf life is best defined as the time span over which the quality
of a product remains with specifications .
 Estimation of product shelf life is done by two methods-estimation
from data obtained under the same conditions as
those that the final product is expected to withstand and
estimation from tests conducted under accelerated conditions.
 The two methods for estimating shelf life of pharmaceuticals
when chemical degradation is the major contributor to
degradation process and degradation can be adequately
described by a rate expression.

37. Extrapolation from real-time data:
 The woolfe equation has been used to
Estimate the shelf life of a product from data obtained at the
sameTemperature/conditions as those expected for the final
product.
 The time at which the drug content diverges from its
Specifications is estimated by extrapolating the time course of
Degradation at a specific temperature/condition. when the time
Course of drug content(c) is represented by

38. t t c c 
b
 Where t = Average of t
 c = Average of c
 b = constant
 The woolfe equation allows one to estimate the confidence limit
Of t as a function of C

39. SHELF LIFE ESTIMATION FROM TEMPERATUREACCELERATED
STUDIES:
 In temperature-accelerated studies,shelf life at a storage
temperature T1 is estimated from the shelf life at an elevated
temperature T2 ,according to
ln) 1 (T 90 t
t90(T 2)
aE 
R
1
T1
- 1
T2
 Shelf life is reffered to as t90t1 when the lower specification
limit of the content is 90%.
 1/T is the temperature range when activation is constant .

40. Solid state stability
Stability of drug also can be defined as the time from the
date of manufacture and packaging of the formulation until
its chemical or predetermined level of labelled potency and
its physical characteristics have not changed appreciably.

41. Why Stability…?
 Provide a evidence on how the quality of a drug substance or drug
product varies with time under the influence of a variety of
environmental factors such as….. temperature, Humidity and
light.
 Establish a re-test period for the drug substance or a shelf life for
the drug product and recommended storage conditions.
 Because physical, chemical or microbiological changes might
impact the efficiency and security of the final product.

42. Stability tests are performed 0n:
 Drug Substances (DS) : The unformulated drug substance that
may subsequently be formulated with excipients to produce the
dosage form.
 Drug Products (DP) :The dosage form in the final immediate
packaging intended for marketing……. controlled and
documented determination of acceptable changes of the drug
substance or drug product

43. What are the changes….?
 Physical changes
• Appearance
• Melting point
• Clarity and color of solution
• moisture
• Crystal modification (Polymorphism)
• Particle size
 Chemical changes
• Increase in Degradation
• Decrease of Assay
 Microbial changes

44. Forced degradation studies:
 Acidic & Basic conditions.
 Dry heat exposure
 UV radiation exposure
 Influence of pH
 Influence of temperature
 Influence of ionic strength

45. Stability
 Ideally any commercial pharmaceutical product should have a shelf
life of 5 years and should not fall below 90-95% potency under
recommended storage.
 In designing a solid dosage form it is necessary to know the
inherent stability of the drug substance, excipients to be used,
formulation procedure.
 For a drug substance, we need to study 3 categories of stabilities-
1. Solid state stability of drug only
2. Compatibility studies ( drug+ excipients )
3. Solution phase stability

46. Solid state stability
 It includes both physical and chemical stability.
 Physical changes by polymorphic transitions and hygroscopicity.
 Polymorphic transitions- It is the ability of the compound to
Crystallize in one or more crystalline forms with different
Internal lattices.
 Hygroscopicity-It is the ability of the substance too attract and
Hold water molecules from the surrounding environment.
Ex:Cellulose fibres,Sugar,Caramel,Glycerol,ethanol
Sulfuric acid.

47. Chemical changes such as solvolysis,oxidation,photolysis
Pyrolysis.
 Solvolysis: It is a special type of nucleophilic solution or
Elimination where nucleophile is a solvent molecule.
 Oxidation: It is any chemical reaction that involves the moving
Of electrons.
(or)
Oxidation is gain of oxygen.
2 fe 3 o 3 + CO2 o + 3CO2

48.  Photolysis: The decomposition or separation of molecules by
action of light.
 Example: Decomposition of ozone to oxygen in the atmosphere
 Example: Synthesis of chloromethane from methane and chlorine
initiated by light.
 Pyrolysis: It is a thermochemical decomposition of organic
material at elevated temperature in the absence of oxygen. It
involves simultaneous change of chemical composition and
physical phase is irreversible.

49. PHYSICAL CHANGES /INSTABILITY
 pKa
 Melting point
 Crystal form
 Equilibrium moisture content.
 Solubility
 Example- amorphous materials are less stable than their
crystalline counterparts.
 A relatively dense material may better withstand ambient stresses
aminobenzylpenicillin trihydrate is more denser and stable than its
amorphous form.

50. CHEMICAL CHANGES/INSTABILITY
 Solid state reactions are generally slow and it is customary to use
stress conditions in investigation of stability.
 Data obtained under stress is then extrapolated to make
prediction of stability.
 High temperature can drive moisture out of a sample and render
the material apparently stable otherwise prone to hydrolysis.
Example- Above 65% relative humidity the beta form of
chlortetracycline hydrochloride transforms into alpha form.

51. ELEVATED TEMPERATURE STUDIES
 Tests are usually performed at 40 ,50 ,600C in conjuction with
ambient humidity.
 Higher temperatures are also used, samples kept at highest
temperature examined for chemical and physical changes at
weekly intervals- if no change is seen after 30 days at 600C
Stability prognosis is excellent.
 Arrhenius Treatment is used to determine the degradation rate at
lower temperature.

52. K = Se-Ha /RT
where,
ARRHENIUS EQUATION
(Effect of temperature)
k = specific rate of degradation.
R = gas constant ( 1.987 calories degree-1mole).
T = absolute temperature.
S = frequency factor.

53. STABILITY UNDER HIGH HUMIDITY CONDITIONS
o In presence of moisture, many drug substances hydrolyze react
with other excipients or oxidize.
o These tests are performed by exposing the drugs to different
relative humidity conditions
o Preformulation data of this type is helpful in determining if the
material should be protected and stored in a controlled low-humidity
environment or if aqueous based granulation should be
avoided.

54. PHOTOLYTIC STABILITY
Many drugs fade or darken on exposure to light and this leads
to an aesthetic problem which can be controlled by using:
1 Amber Glass Container
2 Opaque Container
3 Incorporating a Dye.

55. STABILITY TO OXIDATION
 Stability to oxygen must be evaluated to establish that the final
product should be packaged under inert atmosphere or it requires
an antioxidant.
 A 40% oxygen atmosphere allows for rapid evaluation
 The samples are kept in dessicators.
 Process is repeated 3-4 times to assure 100% of desired
atmosphere.

56. 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.

58. THANK
YOU