solid state stability and shelf life

1. seminar on solid state stability
and shelf life assignments
PRESENTED BY:
Ranjeet singh
1st year M- Pharm

2. Definition:
Stability of a drug substance or product is defined as the extent
to which a product or substance remains within specified limits of
identity, strength quality, and purity throughout its period of
storage and use.
 It includes both physical and chemical stability
 Physical changes caused by Polymorphic transitions, amorphous
form, crystallization, Hydrate formation.
 Chemical changes such as oxidation, photolysis, temperature,
light, humidity.

3. Solid drug substance undergo the physical
transformation, as given below.
 Polymorphic transition
 Amorphous form
 Hydrate formation
 Crystallization material

4. Polymorphic transition:
 In the manufacture, metastable form of drug substance is preferred. During the storage,
the meta-stable form may be transferred into stable form. The mechanism of
transformation is diffusion controlled interaction. The moisture may diffuse into the layer
of metastable polymorph, solubilize and crystallize to stable polymorph.
TECHNIQUES OF DETERMINING POLYMORPHS:
 Analytical techniques-
o X-Ray powder diffraction [XRPD]
o Differential Scanning Calorimeter [DSC]
 These analytical techniques have been use for quantitative and qualitative analysis of
polymorphs.

5. Hydrates formation :
 Hydrate is a special class of solvate form where the solvent molecule
in the crystal structure is water. In higher relative humidity [RH] drug
substance can form hydrate
TECHNIQUES OF DETERMINING HYDRATES :
 Humidity-controlled thermo-gravimetric analysis (TGA),
 Near-infrared (NIR) Spectroscopy

6. AMORPHOUS FORM:
 Solid can occur either in crystalline form or amorphous form. The
chemical stability in crystalline form differ from amorphous form. In
most of cases, amorphous form are stable than the crystalline forms
under the same condition.
 Moisture promote the conversion of amorphous form to crystalline
form.
 Amorphous substance are preferred for the production of dosage
form. These are high energy substances and readily converted to
crystalline state at elevated temperature

7.  Eg. Novobiocine an antibiotic available in amorphous and
crystalline form , amorphous form of this drug have greater
solubility and higher dissolution rate than the crystalline form.
ANALYTICAL TECHNIQUES FOR STABILITY STUDIES OF
AMORPHOUS:
 Molecular level spectroscopy, FT-IR,
 DRIFT FT-Raman Solid-state NMR Near infrared spectroscopy
(NIR)

8. CRYSTALINE MATERIAL:
Physical changes of crystalline drug substances may includes -
 Loosening of intermolecular interactions Non-covalent bonds, [hydrogen
bonding, van der Waals force]
 effect of environmental factors (e.g., heat, light, mechanical forces, solvent,
and moisture) defects on crystal surface
 Nucleation of new phase Homogeneous or heterogeneous
 Crystal growth and formation of new form

9. Types of stability
 Physical: The original physical properties, including appearance, palatability,
uniformity, dissolution and suspend ability are retained.
 Chemical: Each active ingredient retains its chemical integrity and labelled
potency within the specified limits.
 Microbiological: Sterility or resistance to microbial growth is retained according to
the specified requirements. Antimicrobial agents retain effectiveness within
specified limits.
 Therapeutic: The therapeutic effect remains unchanged.
 Toxicological: No significant increase in toxicity occurs

10. Factors Influencing Drug Stability
The degradation of pharmaceutical product can be treated as zero order
reaction, first order reaction.
(1) Zero Order Reaction
 The reaction rate is independent on concentration of the reacting
substance.
(2) First Order Reaction
 The rate of reaction is directly proportional to the concentration of the
reacting substance.

11. (3) Influence of pH on Degradation
 The magnitude of rate of hydrolytic reaction catalysed by hydrogen and
hydroxyl ions can vary with pH .
 Hydrogen ion catalysis predominates at lower pH range.
 Hydroxyl ion catalysis at higher pH range.
 Most of the drugs are stable at pH 4 – 8.
 Weakly acidic and basic drugs are most soluble in ionized form and instability
is likely as they are charged.
(4) Influence of Temperature on Degradation
 In order for the rate constant or velocity of the degradation to be of use in the
formulation of pharmaceutical product, it is necessary to evaluate the
temperature dependency of the reaction.

12. ELEVATED TEMPERATURE STUDIES
 Tests are usually performed at 40°,50°,60°C 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 60°C
Stability prognosis is excellent.
 Arrhenius Treatment is used to determine the degradation rate
at lower temperature.

13. (5) Influence of Dehydration on Degradation
 In physical dehydration processes water removal does not create new bonds but often changes the
crystalline structure of the drug.
 Since anhydrous compounds have different dissolution rates compared to their hydrated, dehydration
reaction involving water of crystallization may potentially affect the absorption rate of the dosage
form.
(6) Influence of Hydrolysis on Degradation
 Drugs with functional group such as ester, amide, lactones may be susceptible to hydrolytic
degradation.
 It is probably the most commonly encountered mode of drug degradation because of the prevalence
of such group in medicinal agents.

14. (7) Influence of Photolysis on Degradation
 Photolysis is the process by which the light sensitive drug or excipient molecules are
chemically degraded by light, room light, or sunlight. The variation of degradation
depends on the wavelength of light.
 In this process, light may be initiator while the reaction may be oxidation,
polymerization or ring rearrangement.
 Photolysis followed by a thermal reaction since light energy converted into heat
energy.

15. Shelf life assignments
 DEFINITION: Shelf-life of a drug product is defined as the time
at which the average drug characteristic (e.g. Potency) remains
within an approved specification after manufacture.
or
 Shelf life is the time required for 10%of the material to
disappear; it is the time at which it has decreased up to 90% of
its initial conc.

16. NEED FOR SHELF LIFE DETERMINATION
 Expiry date is defined as the time in which a drug product in a specific
packaging configuration will remain stable when stored under
recommended conditions.
 Expiry date is expressed in terms of months & years and is clearly
indicated on the primary (immediate) pack as well as the secondary pack.
 Shelf life values are normally given to the product rather than a batch

17. TYPES OF SHELF LIFE STUDY
1. Real time stability study.
2. Accelerated stability study.
1. REAL TIME STABILITY STUDY
• In real-time stability testing, a product is stored at recommended storage
conditions and monitored until it fails the specification.
• Real time stability testing is normally performed for longer duration of the test
period in order to allow significant Product degradation under recommended
storage conditions.

18. A product stored at recommended storage condition and monitored
until it fail the specification.
↓
during the testing, data is collected at an appropriate frequency.
↓
the reliability of data interpretation can be increased by including a
single batch of reference material for which stability characteristics have
already been established
↓
its performed for longer duration the shelf life is determine by testing
of product at different time intervals.

19. 2. ACCELERATED STABILITY TESTING :
the preparation is stored at different elevated temp.
to accelerate the degradation
↓
sample are withdrawn at different time intervals
↓
the order of reaction is determine by plotting the graph
between conc. Against time and linear relationship is determined
↓
similarly graph are drawn for different elevated temp.
↓
K-value for each temp. calculated by using Arrhenius equation
log k values are plotted against reciprocal of absolute temp.
from this energy of activation can be calculated
↓
extrapolate the straight line to room temp. (k25) read the
log k value on y-axis.
↓
substitute the k value in equation to get shelf life of product.

20. Conditions to determine the shelf life of drug
Test
conditions ICH guidelines
Accelerated
40 °C±2°C, 75% RH ± 5% for 6
months.
Real time
25 °C±2°C, 60% RH ± 5% for 12
months,

21. ROLE OF STABILITY TESTING
 Provides evidence on how the drug substance or product
quality varies with time under environmental conditions during
distribution.
 Helps to recommend storage conditions including
establishment of shelf life, expiry date or retest period
 Key assurance of quality of pharmaceuticals.

22. Strategies for improving drug stability
degradation process method of protection
Hydrolysis adjusting the ph 3-4 using buffer
removing the contact of water
removing moisture ( use of dry desiccant )
lowering the water activity
eliminating substance having hygroscopicity
changing excipients that poses problem
using solid dosage form
Oxidation removing the contact of oxygen ( use of nitrogen and carbon
dioxide or helium gas.
adjusting the ph 3-4 using buffer
adding antioxidants ( ascorbic acid and sulphates )
adding chelating agents for reducing the influence of metal
ion ( EDTA )
photolysis protecting from light appropriate
packaging the product appropriate
temperature keeping the product in refrigerator at 4°c
storing the product in cool place ≤ 15°c

23. CONCLUSION:
 Stability testing is now the key procedural component in the pharmaceutical
development program for a new drug as well as new formulation.
 Stability tests are carried out so that recommended storage conditions and shelf
life can be included on the label to ensure that the medicine is safe and
effective throughout its shelf life.
 Therefore, the stability tests should be carried out following proper scientific
principles and after understanding of the current regulatory requirements and as
per the climatic zone.
 Stability studies should be based on the basis of pharmaceutical R&D and
regulatory requirements.

24. REFERENCES
 L. Lachman & H Lieberman; The Theory & Practice of industrial Pharmacy;
CBS Publishers & Distributors PVT LTD; 2009; P760-803
 J Carstensen, C Rhodes; Drug Stability Principles & Practice; Third Edison;
2008; P145-190
 Robert.T. Magari.(2003); Assessing shelf life using real-time and accelerated
stability test. Biopharm International;16(11)
 Thorat. P, Warad.S, Solunke. R, Ashok.S, Anagha. B, and
Asha.S.(2014);Stability study of dosage form: An inovative step. World J of
pharmacy and pharm Sci;3(2) pp1031-1050