The document discusses the stability of pharmaceutical formulations. It defines stability as a formulation remaining within its physical, chemical, microbiological, therapeutic and toxicological specifications. Stability is important to ensure drug products maintain quality and intended effects until expiration. Chemical and physical degradation pathways include hydrolysis, oxidation, photodegradation, and interactions with excipients or other drugs. Factors like temperature, pH, moisture, and light can affect the rate of degradation. The document focuses on hydrolysis and oxidation as two major degradation pathways and provides examples of each.

1. Presented by:
Rajina Shakya
B.Pharm
4th year , 7th semester

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:

22.  Oxidation of Alcohol, Carbonyl and
Carboxylic Acid
Aldehyde
alcohol
CH3CH2OH CH3CHO CH3COOH
dehydrogenase
dehydrogenase
Ethanol Acetaldehyde Aceticacid
 Oxidative aromatization /dehydrogenation:
COOCH3 COOH
NO2 NO2 CH2OH
CH3
NH N
CH3 CH3
COOCH3 COOCH3
Nitedipine Pyridine metabolite

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)

25. Degradation of some aromatic
compounds because of photolysis

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

30. Reference
 http://www.scribd.com/doc/25293385/Stability-of-
Drugs-and-Dosage-Forms
 http://www.google.com/url?sa=t&rct=j&q=&esrc=s&so
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2Fpubs.acs.org%2Fdoi%2Fabs%2F10.1021%2Fjo00436a
016&ei=wYQiUOiLKcPjrAfZoYCQBw&usg=AFQjCNGF
0H71UUQWgb22bS6iKLZjF64SZg&sig2=r-
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