Solid stability physical characteristic

1. PHYSICAL CHARACTERISTICS OF SOLIDS
Ph/Haroon Abdulsalam
Under supervised
/
Dr/Abdulwali Alshargabi

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.

5. SOLUBILITIES OF POLYMORPHS
 It can be follows the henry's law, that solubilities are (approximately) linearly related to vapor pressures (actually activities as solubility are linearly
related to fugacities).
 There are cases where the solubilities are close to one another over the entire temperature range, and in such cases it may be difficult to separate the
two polymorphs in the final purification (recrystallization, reprecipitation)

6. RATES OF CONVERSION IN MOIST STORAGE
 Good stability of a metastable compound can be achieved by
 (a)low temperature,
 (b) coarse crystals, and
 (c) dry storage.
 The moisture is the most significant contributor to conversion.
 Moisture will condense onto the surface of the metastable form which will then saturate and covert to stable form or to a
solution which is supersaturated.
 The conversion rate is therefore a function of the nucleation in Solution and it is well known that the nucleation rate
 That the nucleation rate is inversely proportional to the viscosity of the solution and also to the supersaturation ratio

7. EQUILIBRIUM MOISTURE CONTENT OF SOLIDS AND HYGROSCOPICITY
 Hygroscopicity is the potential for moisture uptake that a solid will exert in combination with the rate with which this
will happen.
 The condition of the atmosphere is an important factor as well, so a short, concise definition of hygroscopicity is not
possible.
 These conditions exist if the water vapor pressure in the surrounding atmospheres lower than the water vapor pressure
over a saturated solution of the solid, Then there will be a thermodynamic tendency for water to condense upon the
solid.
 The rate and extent of which moisture can condense on solids is usually collected under the term “hygroscopicity”

8. CRITICAL MOISTURE CONTENT
 There are humidities which a solid will not adsorb (considerable amounts of) moisture, i.e., not form a “bulk-
sorbed” layer. These are dictated by the solubility of the compound
 The rate with which it picks up moisture is determined by weighing the sample at given intervals.
 The actual uptake rates (determined from the linear portions).

9. 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

10. 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, sometime amorphous form are
stable than the crystalline forms under the same condition. But in general the crystalline is more stable.
 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

11. 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

12. 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

13. 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.

14. FACTORS INFLUENCING DRUG STABILITY
 1-Influence of pH on Degradation
 The magnitude of rate of hydrolytic reaction catalyzed 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.
 2-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.

15. FACTORS INFLUENCING DRUG STABILITY
 ELEVATED TEMPERATURE STUDIES
 Tests are usually performed at 40°,50°,60°Cin conjunction 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.

16. FACTORS INFLUENCING DRUG STABILITY
 3-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.
 4-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.

17. FACTORS INFLUENCING DRUG STABILITY
 5-Influence of Photolysis on Degradation
o 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.
o In this process, light may be initiator while the reaction may be oxidation, polymerization or ring rearrangement.
o Photolysis followed by a thermal reaction since light energy converted into heat energy.

18. 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.

19. NEED FOR SHELFLIFE 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

20. TYPES OF SHELFLIFE 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.

21. CONDITIONS TO DETERMINE THE SHELF LIFE OF DRUG
Test conditions ICH guidelines
1.Accelerated 40 °C±2°C, 75% RH ±5% for 6 months.
2.Real time 25 °C±2°C, 60% RH ±5% for 12 months,

22. ROLE OF STABILITYTESTING
 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.

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. Thank You