2. STABILITY
It is the capability of a particular
formulation to remain within its physical,
chemical,microbiological, therapeutic and
toxicological condition.
3. Importance of stability in
pharmaceutics
Drug products complex chemical and physical stability kinetics .
Chemical and physical degradation of drug substances may
change their pharmacological effects, resulting in altered
efficacy therapeutic as well as toxicological consequences.
Because pharmaceuticals are used therapeutically based on their
efficacy and safety, they should be stable
Maintainance of quality until the time of usage or until
their expiration date.
The quality should be maintained under the various conditions
that pharmaceuticals encounter, during production, storage in
warehouses, transportation, and storage in hospital and
community pharmacies, as well as in the home.
4. Chemical stability of drug
substances
Pathways of chemical degradation
Hydrolysis
Dehydration
Isomerization and Racemization
Decarboxylation and Elimination
Oxidation
Photodegradation
Drug-Excipienand Drug-Drug Interactions
5. Factors affecting Chemical stability
Temperature
pH and pH rate profiles
Ionic strength (primary salt effects)
Dielectric constant of solvents
Oxygen
Light
Crystalline state and polymorphism in solid drugs
Effect of moisture and humidity on solid and semi solid drugs
Excipients
effects of the amount of moisture present in excipients
effects of the physical state of water molecules in excipients
effect of the mobility of water molecules in excipients on drug
degradation
other properties of excipients
Miscellaneous Factors
6. physical stability of drug
substances
physical degradation
crystallization of amorphous drugs
transitions in crystalline states
formation and growth of crystals
Vapor-phase Transfers including sublimation
Moisture Absorption
7. Hydrolysis
A chemical reaction in which the interaction of
a compound with water results in
the decomposition of that compound.In this
reaction,a water molecule (HOH) and a reactant
exchange functional groups resulting in two end
products, one containing the hydrogen cation (H) and
the other the hydroxyl anion (OH).
hydrolysis is one of the most common reactions seen
with pharmaceuticals mainly in parenteral products.
8. Hydrolytic reactions
1) Hydrolysis of Esters and Ethers
2) Hydrolysis of Amides.
3) Hydrolytic cleavage of non aromatic heterocycles.
4) Hydrolytic Dehalogination.
5) Miscellaneous hydrolytic reactions.
9. Hydrolysis of esters and ethers:
O O
R-C-OR' R-C-OH + R'-OH
Organic acid esters:
COOC2H5 COOH
Cl O CH3 Cl O CH3 C2H5OH
CH3 CH3
+
Clofibrate Free acid metan
10. Inorganic acid esters:
Phosphates:
OH C 2H5 OH C 2H5
O P O O P O HO OH + 2 H3PO4
OH C 2H5 OH C 2H5
Stilbestrol diphosphate stilbestrol
Sulfates:
CH3 O CH3 O
H3C O S CH3 H3C OH + HO S CH3
H O H O
Isopropyl methnesulfonate isopropanol methanesulfonic
11. Hydrolysis of amides:
C2H5 O C2H5
O
H2N N C C N H2N + H2N C C N
H2 H2 C2H5
H H2 H2 C2H5
OH
Procanamide PABA
Hydrolytic cleavage of non
aromatic heterocyclics:
O O
H H
C N S CH3 C N
H2 S CH3
H2
N CH3 HO N CH3
O
COOH O
COOH
Penicillin G Penicinoic acid metabolite
12. Hydrolytic dehalogenation:
H -HCL H
Cl Cl Cl Cl
CCl 3 CCl 2
DDT DDE
Miscellaneous hydrolytic reactions:
Include hydration of epoxides and arene oxides,
hydrolysis of Sulfonylureas, Carbamates,
Hydroxamates and alpha Glucuronide and sulfate
conjugates
13. OXIDATION
Oxidation is defined as the interaction
between oxygen molecules and all the different
substances they may contact, from metal to
living tissue.
Technically, however, with the discovery of
electrons, oxidation came to be more precisely
defined as the loss of at least one electron when
two or more substances interact.
14. Oxidative reactions:
1) Oxidation of aromatic carbon atoms
2) Oxidation of olefins (C=C bonds)
3) Oxidation of Benzylic, Allylic carbon atoms &
carbon atoms alpha to carbonyl & imines
4) Oxidation of aliphatic carbon atoms
5) Oxidation of alicyclic carbon atoms
15. 6) Oxidation of carbon-heteroatom systems:
A. Carbon-Nitrogen system
N- Dealkylation.
Oxidative deamination
N-Oxide formation
N-Hydroxylation
B. Carbon-Sulfur system
S- Dealkylation
Desulfuration
S-oxidation
C. Carbon-Oxygen systems(O- Dealkylation)
7) Oxidation of Alcohol, Carbonyle and Acid functios.
8) Miscellaneous oxidative reactions.
16. Oxidation of aromatic carbon atoms
(aromatic hydroxylation):
R
OH
Arenol (major)
R R R OH
H2O
O
epoxide hydrase
OH
Arene oxide
Arene (highly reactive electrophile) Dihyrdrodiol
GSH
5-epoxide transferase
R
R OH OH
SG OH
Tissue toxicity in instances
Glutathione conjugate Catechol(min. Pro.)
when glutathione is depleted.
(min.pro.)
E.g. Epoxides of Bromobenzene and Benzopyrene.
17. Oxidation of olefins (C=C bonds):
O HO OH
H2O
N
N epoxide hydrase N
CONH2 CONH2 CONH2
Carbamazepine Carbamazepine-10,11 Trans-10,11
epoxide dihydroxy
carbamazepine
Oxidation of Benzylic Carbon Atoms:
CH2OH CHO COOH
CH3
Alcohol
dehydrogenase
SO2NHCONHC4H9 SO2NHCONHC4H9
Corresponding Corresponding
aldehyde carboxylic acid.
Tolbutamide Prmary carbinol
18. Oxidation of Allylic carbon Atoms:Allylic carbon atom
OH
3'
2'
H3C H3C
O O O O
HN N HN N
CH3 CH3
O O
Oxidation of Carbon Atoms Alpha to
Hexobarbital 3'-Hydroxy Hexobarbital
Carbonyls and Imines: O
N N
OH
N N
IC IC
Diazepam 3-Hydroxy diazepam
19. Oxidation of Aliphatic Carbon Atoms
(Aliphatic Hydroxylation):
H CH3 OH CH3
H3C C C C COOH H3C C C C COOH
H2 H H2 H
CH3 CH3
Ibuprofen Tertiary alcohol metabolite
Oxidation of Alicyclic Carbon Atoms
(Alicyclic Hydroxylation):
H2N H2N
N N
O N N 4' O N N OH
H2N
H2N
Minoxidil 4'-Hydroxy Minoxidil
20. Oxidation of Carbon-Nitrogen System:
H OH
O C
NH
N C N C +
H H
Carbonyl
N-Dealkylated
Carbinolamine metabolite
Intermediate
N-Hydroxylation:- CH3
CH3
O C2H5
O C2H5
N C C N
N C C N
H2
H H2
OH C2H5
C2H5
CH3
CH3
N- Hydroxy Lidocaine
Lidocaine
21. Oxidation of Carbon-Sulfur Systems:
SCH3 SCH2OH SH
N N N
N N N
+ HCHO
N N N
N N N
H H H
6-Methyl Hydroxylated
intermediate 6-Mercaptopuri9ne
Mercaptopurine
Desulfuration:
23. Photolysis
chemical reaction in which a chemical compound is
broken down by photons.
is not limited to visible light. Any photon with
sufficient energy can affect the chemical bonds of a
chemical compound
24. Photochemical transformation reactions
Direct photolysis = transformation of a
compound due to its absorption of UV light
Indirect photolysis = transformation of a
compound due to its interaction with a reactant
generated by the influence of UV light
(photosensitizer or reactive oxygen species)
27. Stabilization of drug substances
against chemical degradation
stabilization by modification of molecular structures of
drug substances
stabilization by complex formation
stabilization by the formation of inclusion complexes
with cyclodextrins
stabilization by incorporation into liposomes, micelles,
or emulsions
addition of stabilizers such as antioxidants and
stabilization through the use of packaging
28. Stability of dosage forms
preformulation and formulation stability studies
mothods for detecting chemical and physical degration
Functional changes in dosage forms with time
changes in mechanical strength
changes in drug dissolution from tablets and capsules
effects of formulation on changes in dissolution
changes in drug release from coated dosage form
changes in capsule shells with time and storage conditions
prediction of changes in dissolution
changes in melting time of suppositories
changes in drug release rate from polymeric matrix dosage forms,including
microspheres
drug leakage from liposomes
aggregation in emulsions
moisture adsorption
discoloration
Effect of packaging on stability of drug products
29. Stability of dosage forms cont…
moisture penetration
Adsorption onto and absorption into containers and transfer
of container components into pharmaceuticals
estimation of the shelf life (expiration period) of drug
products
5.4.3 estimation of shelf life under temperature-
fluctuating conditions
