The document discusses drug stability and the factors that influence it. It defines stability as the extent to which a product retains its properties within specified limits throughout its shelf life. Drug stability depends on maintaining the physical, chemical, therapeutic and microbial properties of the dosage form over time. The purpose of stability studies is to determine shelf life and provide evidence of how quality varies with environmental factors like temperature and humidity. The types of stability that must be considered include chemical, physical, microbiological, therapeutic and toxicological stability. The document then discusses various types of degradation like physical, chemical and microbial and how they can be prevented. It also outlines ICH guidelines for stability testing.

1. DRUG
STABILITY
Presented by:-KUNAL

2. STABILITY:
– USP defines stability of pharmaceutical product as, “extent to
which a product retains with in specified limits and throughout its
period of storage and use (i.e. shelf life).
– The capacity or the capability of a particular formulation in a
specific container to remain with in particular chemical ,
microbiological , therapeutically , and toxicological specifications.

3. DRUG STABILITY
– Drug stability is defined as the ability of the pharmaceutical
dosage form to maintain the physical, chemical, therapeutic and
microbial properties during the time of storage and usage by the
patient.
– The purpose of stability studies is to provide evidence on how the
quality of the active substance or pharmaceutical product varies
with time under the influence of a variety of environmental factor
such as temperature, humidity and light.

4. Objective of the drug stability
– To determine maximum expiration date/ shelf life.
– To provide better safety to the patients.
– To prevent the drug product from different kind of instability.
– To provide better storage condition.
– To determine the packaging components.
– To gather information during preformulation stage to produce a
stable product.

5. TYPES OF STABILITY THAT MUST
BE CONSIDERED FOR ANY DRUG:-
– CHEMICAL:-
Each active ingredient retains its chemical integrity and labeled
potency within the specified limit.
– PHYSICAL:-
The physical stability properties includes appearance,
palatability ,uniformity ,dissolution and suspendability are
retained.
– MICROBIOLOGICAL:-
Sterility or resistance to microbial growth is retained according
to specified requirement.

6. – THERAPEUTIC:-
Therapeutic activity remains unchanged .
– TOXICOLOGIC:-
No significant increase in toxicity occurs.

7. TYPES OF DRUG
INSTABILITY:
– PHYSICAL DEGRADATION
– CHEMICAL DEGRADATION
– MICROBIAL DEGRADATION
– THERAPEUTIC DEGRADATION
– TOXICOLOGICAL DEGRADATION

8. PHYSICAL DEGRADATION
– LOSS OF VOLATILE COMPOUNDS
– LOSS OF WATER
– ABSORPTION OF WATER
– CRYSTAL GROWTH
– POLYMORPHISMS
– COLOUR CHANGES
– COLOUR CHANGES

9. LOSS OF VOLATILE
COMPOUNDS
– Some of volatile components alcohol, ether, Iodine, volatile oils, Camphor
menthol etc escape from the formulations exposé them degraded.
– EXAMPLE:
Some types of tablets (Nitroglycerine tablets) Aromatic water.
– PREVENTION:
Such product should be placed in well closed container.
Temperature should be proper.

10. LOSS OF WATER
– Water loss from liquid preparation (o/w emulsion) leads to changes in stability.
It causes crystallization of drug product .
which may lead to increase in potency , and decrease in weight.
– EXAMPLE :
Water evaporates from na2so4 .BORAX.
Creams: especially oil/water, they become dry by loss of water.
– PREVENTION:
Products should be placed in well-closed container.

11. ABSORPTION OF WATER
– Hygroscopic drugs absorb the water from external atmosphere causing the
physical degradation. Effervescent powders and tablets will deteriorate if stored
in a moist atmosphere.
– EXAMPLE:
– Powders: Liquification and degradation may occur as a result of absorption of
water
Suppositories which base made from hydrophilic substances as Glycerin,
Gelatin, and polyethylene glycol. The consistency of these forms becomes jelly-
like appearance.
– PREVENTION:
Products should be placed in well-closed container and in dry place.

12. CRYSTAL GROWTH
– Drugs when loose water, become saturated and crystal growth occurs.
Crystallization is enhanced in porous tablets . In solutions after super saturation
crystal growth occurs.
– EXAMPLE:
Injection of calcium gluconate.
In suspensions crystals settle down and caking occurs and suspension becomes
unstable.
Ophthalmic preparations.
– PREVENTION:
SOLUTIONS-Stabilizers are added
SUSPENSION:-
Incorporation of surface active agent.
By increasing viscosity of suspending material.

13. POLYMORPHISMS
– Polymorphs show significant differences in important physiochemical properties
such as solubility, dissolution rate and melting point. In polymorphic changes
crystal forms are changed. This may cause change in solubility and possibly
crystalline growth in aqueous suspension.
– EXAMPLE:
Cortisone acetate suspension.
– PREVENTION:
suspension –suspending agent like methyl cellulose & ethyl cellulose

14. PHOTOLYSIS
– When molecules are exposed to electromagnetic radiation they absorb light
(photons) at characteristic wavelength which cause increase in energy which
can cause decomposition.
– EXAMPLE:
Sodium nitropruside in aqueous solution (which is administered by IV infusion
for management of acute hypertension).
Iodine
– PREVENTION:
Use of amber colored bottles.
Storing the product in dark, packaging in cartons also act as physical barrier to
light.

15. COLOUR CHANGES
– Colour changes indicate chemical or photochemical decomposition of the active
ingredients, dyes or other ingredients. Colour changes are of two types.
1) Loss of colour,
2) Development of colour.
– EXAMPLE:
Phenolphthalein color changes as the PH changes. It is colorless in acidic
solution and pink in basic.
ascorbic acid tablet turn yellowish brown.
– PREVENTION:
• Protect the product from light and air.
• Avoid the using reducing substances as additives.

16. CHEMICAL DEGRADATION
– HYDROLYSIS
– ISOMERIZATION
– RACEMIZATION
– EPIMERIZATION
– DECARBOXYLATION
– ELIMINATION
– OXIDATION

17. HYDROLYSIS
– ESTER
– AMIDE
– BARBITURATES, HYDANTOINS, AND IMIDES
– CARBON NITROGEN BOND CLEAVAGE

18. ISOMERIZATION
– Isomerization is the process by which one
molecule transformed into another molecule
which has exactly the same atoms, but the atoms
are rearranged.
– Examples:-
– Pilocarpine and Isopilocarpine

19. RACEMIZATION
–Racemization refers to partial
conversion of one enantiomer into
another. It involves the optically active
form of a drug into its enantiomorph.

20. EPIMERIZATION
– It occurs with the compound having more
than one asymetric carbon atom in the
molecule. At equilibrium, both epimers are
present, but not in equal proportion.
– EXAMPLE:
Under prolonged storage solution containing ergometrine is
decomposed by hydrolysis and isomerized to ergometrinine.

21. DECARBOXYLATION
–Elimination of CO2 from compound.
Drug substances having a carboxylic
acid group is sometimes susceptible to
decarboxylation.
– EXAMPLE:
4-Aminosalicylic acid procain.

22. ELIMINATION
– In elimination, reaction some groups of the
substance is eliminated.
– EXAMPLE:
Trimelamol eliminates its hydroxymethyl groups
and forms formaldehyde.

23. OXIDATION
– Removal of an electropositive atom, radical or electron, or the
addition of an electronegative atom or radical. Oxidation is
controlled by environment i.e., light, trace elements, oxygen and
oxidizing agent.
– AUTO-OXIDATION:-Oxidation in which the oxygen presents in the
air is involved. This process proceeds slowly under the influence of
atmospheric oxygen.
– PHOTO-OXIDATION:-Oxidation in which removal of the electron is
involved without presence of O2.

24. MICROBIAL DEGRADATION
– Contamination of a product may sometimes
cause a lot of damage and sometimes may not be
anything at
-Thus it is dependent on the type of microbe and
its level of toxicity it may produces.
-If parenterals or ophthalmic formulations are
contaminated, it may cause serious harm.

25. Source of microbial
contamination
– Water & air
– Raw material
– Container & closure
– Instruments and apparatus
– Personnel

26. Sources of microbial
contaminations
– Water :-Low demand gram-negative groups: Pseudomonas, Xanthamonas,
Flavobacterium, Achromobacter .
– Air :-Mould spores: Penicillium, Mucor, Aspergillus Bacterial spores: Bacillus
spp. Yeasts
– Raw Materials:-Micrococci
– Earths:-Anaerobic spore formers: Clostridium spp
– Pigments:-Salmonella
– Starches:-Coliforms
– Gums:-Actinomyces
– Animal products:-Salmonella, Coliforms
– Personnel:-Coliforms, Staphylococci, Sterptococci, Coryembacteria

27. PREVENTION
– Suitably designing the containers
– Usually using single dose containers
– Sticking to proper storage conditions
– Adding an antimicrobial substance as
preservative

28. THERAPEUTIC
DEGRADATION
–Therapeutic effect must be changed
due to hydrolysis, isomerisation or
epimerization .
–Example:
Adrenaline

29. TOXICOLOGICAL
DEGRADATION
– Some drugs may produce toxic product.
– Example:-
tetracycline,chloramphenicol.

30. POSSIBLE CHANGES (Visible
and invisible)
– Loss of active ingredient
– Alteration in bioavailability
– Loss of content uniformity
– Decline of microbiological status
– Loss of pharmaceutical elegance
– Formation of toxic degradation products
– Loss of package integrity
– Reduction of label quality
– Modification of any factor of functional relevance( dissolution, release, etc).

31. ICH
– ICH stands for International Conference on Harmonization of Technical
Requirements for Registration of Pharmaceuticals for Human use.
– Objectives of ICH:- 1.
1.Harmonization of registration applications within the three regions of the EU,
Japan and the United States.
2.ICH is a joint initiative involving both regulators and industry as equal partners
in the scientific and technical discussions of the testing procedures which are
required to ensure and assess the safety, quality and efficacy of medicines.
3.Tripartite guideline on stability testing of new drug substances and products
(Q1A) in 1993, has become standard for stability evaluation in Japan, US,
Europe.

32. ICH Guidelines
– Quality Guidelines “Q” (chemical and pharmaceutical QA) –
details see next slide
– Safety Guidelines “S” (in vitro and in vivo pre-clinical studies)
– covering Carcinogenicity Testing, Genotoxicity Testing, Toxicokinetics and
Pharmacokinetics ….. etc.
– Efficacy Guidelines “E” (clinical studies in human subject)
– Covering clinical safety, Dose Response Studies, Good Clinical Practices, Clinical
evaluation …. etc
– Multidisciplinary Guidelines “M”
– Covering Medical Terminology, Electronic Standards for Transmission of Regulatory
Information …… etc. –
Important for Stability !
» Guideline M4: The Common Technical Document (CTD)

33. GUIDELINES
– 500 C/ ambient humidity( to cover extremely hot and dry
conditions, 300 C/ 80% RH) to cover extremely high humidity
conditions ; one batch for 3 months.
– WHO DRAFT GUIDELINE 2007
For API, exposing a solid sample to elevated temperatures such as
60- 1200 C or 5- 100 C below the melting point can generate a
different degradation profile.
This approach usually generates degradation products that can be
used as a worst case to assess the performance of analytical
method

34. TYPE, SIZE, NUMBER OF
BATCHES
– ICH/ WHO GUIDELINES
– • At least 3 primary batches of drug product, should be
of the same formulation, packaged in same container as
proposed for marketing
– • 2 out of 3 batches should be pilot scale batches.
– • Stability to be performed on each strength, container
size.

35. STAGES OF DRUG AND PRODUCT
DEVELOPMENT AND STABILITY
TESTING
– Pre-clinical studies
– Clinical studies
– Pre- formulation
– Formulation development
– Scale up
– Commercial manufacturing
– Distribution and shipping
– Post approval changes
– Market surveillance

36. 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 280 C for
drugs to be stored in freezer testing should be done at -
200 C

37. 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

38. Climatic Zones / Storage
conditions:-
Countries Temp.
°C
MKT
°C
Humidity
% RH
Temp
°C
Humidity
% RH
Climatic Zone I "Temperate"
Japan, United Kingdom, Northern
Europe,Canada,Russia,United
States
20 20 42 21 45
Climatic Zone II "Mediterranean,
Subtropical" Japan, United States,
Southern Europe
26.4 22 52 25 60
Climatic Zone III "Hot, dry" Iran,
Iraq, Sudan
26.4 27.9 35 30 35
Climatic Zone IV "Hot, humid"
Brazil, Ghana, Indonesia,
Nicaragua, Philippines
26.7 27.4 76 30 70

39. Shelf life
– It is defined as the time required for the concentration of the
reactant to reduce to 90% of its initial concentration .
Represented as
t90 the units of time /conc.
t90 = (a-0.9a)/ ko = 0.1 a/ ko
Where,
a = initial concentration.
ko = specific rate constant for zero order reaction.

40. The instability possibilities in
different formulations :-
– Oral solutions
– Instability problems
1. Loss of flavour
2. Change in taste
3. Presence of off flavours due to interaction with plastic bottle
4. Loss of dye
5. Precipitation
6. Discoloration
– Effects
Change in smell or feel or taste.
– Steps to prevent instability
Use of proper excipients and suitable packing materials.

41. Parenteral solutions
– physical instability occurs due to:
– 1. Interaction of the contents with the container.
– 2. Changes in Chemical composition.
– Instability problems
1.Discoloration due to photo chemical reaction or oxidation. Ex: thiamine
hydrochloride
– 2. Presence of precipitate due to interaction with container or stopper.

42. – 3. Presence of “whiskers”. If some small pinholes are present in the
ampule due to improper sealing the solution wicks out, the liquid
evaporates and the solid settles on the outside. It further helps in
wicking out more solution and long lines of crystals form on the
outside of the vial which are called whiskers. This may happen due
too small hole (<0.5 µm) going undetected or the crack developing
during storage.
– 4. Clouds: A cloud will appear in the product due to:
– a. Chemical changes (an ester eg.: polysorbate may hydrolyse
producing an acid which is poorly soluble)
– b. Solubility product may be exceeded.
– c. The original preparation of a supersaturated solution or the use of
a metastable form (ex: calcium gluceptate).

43. – Effects
– Change in appearance and in bioavailability.
– Steps to prevent instability
– 1. Use of antioxidants (0.5%) Acetylcystane or 0.02 – 1% Ascorbic
acid) or Chelating agents (0.01 – 0.075 sodium edetate) to prevent
discoloration.
– 2. Change in stopper or material of the container will eliminate the
problem.
– 3. Checking of the manufacturing process Increasing solubility by the
use of cosolvents (eg: polyethylene glycol) or by other methods such
as micellar approach or complexation will reduce clouding.

44. Suspensions
– a. Particle diameter
b. Concentration of resuspending agent
c. Viscosity of surrounded media
d. Temperature
e. pH f. Presence of microbes
– Instability problems
1. Settling
2. Caking
3. Crystal growth

45. – Effects
Loss of drug content uniformity in different
doses from the bottle and loss of elegance.
– Steps to prevent instability
Design of product based on proper pre-
formulation studies

46. Emulsions
– a. Droplet diameter
b. Viscosity
c. Difference in Density
d. Temperature
e. pH f. Presence of microbes
– Instability problems
1. Creaming
2. Cracking
– Effects Loss of drug content uniformity in different doses from the bottle and
loss of elegance.
– Steps to prevent instability
Design of product based on proper pre-formulation studies.

47. Semisolids (Ointments and
suppositories)
– 1. Changes in:
a. Particle size b.
Polymorphic state, or hydration or solvation state c.
Consistency d. drug release rate
2. Caking or coalescence.
3. Bleeding
– Effects
Loss of drug content uniformity, loss of elegance and change in drug release rate.
– Steps to prevent instability
– Design of product based on proper pre-formulation studies.

48. Tablets
– a. Disintegration time
– b. Dissolution profile
– c. Hardness
– d. Appearance
– Effects
Change in drug release
– Steps to prevent instability
Design of product based on proper pre-formulation studies.

49. Capsules
– a. Appearance
– b. Dissolution
– c. Strength
– Effects
Change in drug release
– Steps to prevent instability
– Design of product based on proper pre-formulation studies

50. Recent development in ICH
Guidelines
– In February this year two new ICH Guidelines on the topic of
stability testing were published. They can now be commented.
Q1E Draft Consensus Guideline Evaluation of Stability Data
– Q1F Draft Consensus Guideline Stability Data Package for
Registration in Climatic Zones III and IV
– Both new Drafts refer to the revised ICH Guideline Q1A(R) –
"Stability Testing of New Drug Substances and Products.

51. Recent development in ICH
Guidelines
– The Guideline "Evaluation of Stability Data" describes when and how an
extrapolation of the data can be undertaken in order to establish the re-test
period for a drug substance or the shelf life for a drug product beyond the
observed range itself, based on the data resulting from the long-term stability
testing.
– The Guideline on stability testing for Climatic Zone III and IV takes up a proposal
made by WHO and now defines not only storage conditions for stability testing
relevant for the ICH tripartite regions (Europe, USA, Japan), but also completes
the recommendations for the standardization of the storage conditions for the
Climatic Zones III (dryhot) and IV (very hot/humid).

52. – For these Climatic Zones, the following
standard conditions are recommended:
– Long-term testing: 30°C / 65% RH
– Accelerated conditions: 40°C / 75% RH
– This means that the "accelerated
conditions" remain the same as in the
Q1A(R) Guideline and only the "long-term
storage conditions" have to be modified.

53. REFERENCE
– http://www.slideshare.net/GajananSanap/stability-studies-58779043on date15/10/2016
– C.V.S Subrahmanyam “Textbook of Physical Pharmaceutics” vallabh prakashan, second edition,
reprint 2007, page no: 13-50, 51-84.
– http://www.slideshare.net/bknanjwade/drug-stability-and-stabilizationtechniques. On date
19/10/2016
– http://uchpel.vscht.cz/files/uzel/0022888/Chemical%20and%20physical%20deg
radation%202015.pdf. On date 21/10/2016
– http://www.slideshare.net/alaaalfayez/stability-tests-for-pharmaceuticalproducts on date
19/10/2016
– http://cst-kh.edu.ps/staff/mabujamee/wp-content/uploads/2010/10/Unit-4Drug-Stability.pdf.
– Cartensen J, Marcel Dekker “ Drug Stability Principles and Practises ”Informa healthcare, third
edition,vol 107, 1990, page no:
– drugstabilityandstabilizationtechniques-150102055002-conversion-gate01.pdf
– drugstabilityconsiderationanddegradation-150228025437-conversion-gate02.pdf

54. THANK
YOU