Second Level Studentstec.horus.edu.eg/wp-content/uploads/2018/03/stability-4.pdfVolatile components...
Transcript of Second Level Studentstec.horus.edu.eg/wp-content/uploads/2018/03/stability-4.pdfVolatile components...
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Second Level Students
Mariza Fouad Farag
Lecturer of Pharmaceutics
Faculty of Pharmacy
Mansoura University
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Stability and types of stability
Types of Drug Instability
Physical degradation
Chemical degradation
Hydrolysis, Isomerization and Racemization
Dehydration, Decarboxylation and Elimination
Oxidation, Photodegradation
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It is the ability of a drug substance or the
pharmaceutical dosage form to maintain
the physical, chemical, therapeutic and
microbial properties during the time of
storage and usage by the patient. It is
measured by the rate of changes that take
place in the pharmaceutical dosage forms.
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Importance of studying drug stability
1. Safety of the patient:
a-Chemical and physical degradation of drugsubstances may change their pharmacologicaleffects, resulting in altered therapeutic efficacy.
b- The drug may degrade to a toxic substance.Therefore, it is important to determine not onlyhow much drug is lost with time but also what areits degradation products.
In some cases, the degradants may be of knowntoxicity.
For example, the drug pralidoxime degrades underbasic pH conditions, giving the toxic productcyanide.
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Importance of studying drug stability
2. Pharmaceuticals should be stable and
maintain their quality until the time of
usage or until their expiration date.
3. The quality should be maintained under
the various conditions that
pharmaceuticals encounter, during
production, transportation, and
storage in hospital and community
pharmacies, as well as in the home.
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Toxicological
Chemical
Physical
Microbiological
Therapeutic
Types of Stability
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Chemical Each active ingredient retains its chemical
integrity, and labeled potency, within the specified
limits.
Physical The original physical properties, are retained
including appearance, palatability,
uniformity, dissolution, and suspendability.
Microbiological Sterility or resistance to microbial growth is
retained according to the specified requirements.
Antimicrobial agents that are present retain
effectiveness.
Therapeutic The therapeutic effect remains unchanged.
Toxicological No significant increase in toxicity occurs
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It is the inability of a particular formulation
in a specific container to remain within a
particular chemical, microbiological,
therapeutical, physical & toxicological
specification.
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Physical
degradation
Types of Drug Instability
Chemical
degradation
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Volatile components such as alcohol, ether,
iodine, volatile oils, camphor, and menthol,
escape from the formulations.
Example: In tablets containing volatile drugs, such
as nitroglycerin, the drug may migrate between
tablets in the container, resulting in a lack of
uniformity among the tablets.
Prevention: nitroglycerin tablets should be
preserved in tight containers, of glass, at
controlled room temperature.
Loss of volatile components
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Loss of water from liquid preparations (ex.:
o/w emulsions) leads to stability changes.
Water evaporates causing the
crystallization of the drug, which may lead
to :
increase in potency and
decrease in weight.
This tendency depends on temperature and
humidity of surrounding environment.
Prevention: through storage of products in
well closed containers.
Loss of water
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Hygroscopic drugs (or pharmaceutical preparations
that are hygroscopic in nature) absorb the water
from external atmosphere causing physical
degradation. This depends on temperature and
humidity of surrounding material.
Example: Glycerin suppositories may become
opaque.
Gelatin capsule may soften
Some deliquescent salts calcium chloride, potassium
citrate.
Prevention: through storage of products in well
closed containers.
Absorption of water
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Crystal growth occurs in solutions after super
saturation.
This may occur due to the fall in temperature
and a consequent decrease in solubility of the
solute.
Examples:
Injection of calcium gluconate.
In suspensions, crystals settle down, bind
together forming a hard cake that is difficult
to redisperse, and suspension becomes
unstable.
Crystal Growth
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Prevention of crystal growth:
◦ Storage in an environment with minimum
temperature fluctuations.
◦ Use of particles of narrow size range.
◦ Addition of surface active agents, which
are absorbed onto the crystal surface,
thus inhibiting the deposition of solute
molecules.
◦ Increasing the viscosity of the suspending
medium.
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In polymorphic changes, crystal forms are
changed upon storage.
This may cause alteration in solubility.
Prevention: formulated products should
contain a stable crystalline form of the
drug.
Polymorphic Changes
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Colour Changes
Colour changes are of two types
Loss of colour
due to:
·PH change
·Presence of reducing agent
Development of colour
due to:
Exposure to light
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Prevention:
◦ PH should not be changed.
◦ Exposure to light should be avoided.
◦ Prevention of fading by incorporating
UV light absorbing material.
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Chemical Degradation Pathways
Hydrolysis
Dehydration
Isomerization
Racemization
Elimination
Oxidation
Photodegradation
Complex interactions with excipients
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1- Hydrolysis
It is one of the most common
reactions seen with pharmaceuticals,
and is often the main degradation
pathway for drug substances having
ester and amide functional groups
within their structure.
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Hydrolysis
Although hydrolysis will occur mainly with
drugs in aqueous solution, suspensions
and solid dosage forms are also
susceptible to hydrolysis.
Ex: Aspirin hydrolysis.
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Moisture is rapidly absorbed on to the surface of aspirin
particles
causing solution of a portion of the drug
in water layer around the particles
As the aspirin in
solution hydrolyses,
more of the solid
material dissolves
and decomposition
continues
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Ester
Hydrolysis
Hydrolysis
Amide
Hydrolysis
Hydrolysis
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R1-COOR2 R1-COOH + R2OH
Ester hydrolysis is characterized by rupture of the
covalent bond between the carbonyl carbon (C=0) and
oxygen, resulting in producing acid and alcohol.
The reaction is catalyzed by acids or alkalies.
Ester Hydrolysis
H2O or H+ or OH¯
acid
alcohol
covalent bond between
the carbonyl carbon (C=0)
and oxygen
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Aspirin
Atropine
Benzocaine
Procaine
Ethylparaben
Scopolamine
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Aspirin (Acetylsalicylic acid) hydrolysis:
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Procaine
H+ or OH¯
P- aminobenzoic acid
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Amide hydrolysis is characterized by rupture of the
covalent bond between the carbonyl carbon (C=0)
and nitrogen atom.
Amide Hydrolysis
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Acetaminophen
Chloramphenicol
Lincomycin
Indomethacin
Sulfacetamide
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Paracetamol (Acetaminophen)
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1. Hydrolysis is frequently catalysed by
hydrogen ions (specific acid-catalysis) or,
hydroxyl ions (specific base-catalysis).
Several methods are available to stabilize asolution of a drug which is susceptible to acid–base hydrolysis.
The usual method is to determine the pH ofmaximum stability and to formulate theproduct at this pH.
2. Alteration of the dielectric constant by theaddition of non-aqueous solvents such asalcohol, glycerin or propylene glycol mayreduce hydrolysis.
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3. Adding a compound that forms a complex
with the drug can increase stability.
Ex:
The addition of caffeine to aqueous solutions
of benzocaine, procaine and tetracaine was
shown to decrease the base-catalysed hydrolysis
of these local anaesthetics in this way.
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Erythromycin is susceptible to acid
catalyzed dehydration.
Sugars such as glucose and lactose are
known to undergo dehydration.
2- Dehydration
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It is the process of conversion of a
drug into its optical or geometric
isomers, which are often of lower
therapeutic activity.
Examples :
◦ Vitamin A (cis–trans isomerisation).
◦ Epinephrine (adrenaline) undergoes
racemization under strongly acidic
conditions.
3- Isomerization and Racemization
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4- Decarboxylation and Elimination
Drug substances having a carboxylic acid
group are sometimes susceptible to
decarboxylation.
Example: 4-Aminosalicylic acid
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Examples: p-aminobenzoic acid
Hydrolysis of procaine yields p-aminobenzoic
acid, which in weakly acidic solution,
decarboxylates slowly into aniline.
Decarboxylation and Elimination
p-aminobenzoic acid Aniline
Aniline darkens on exposure to light,
and this explains the development of
colour in old procaine injections.
H+
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5- Oxidation
Oxidation is a well-known chemical
degradation pathway for pharmaceuticals.
Autoxidations occur spontaneously
under the initial influence of atmospheric
oxygen and proceed slowly at first and
then more rapidly.
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Oxidation
Oils and fats containing unsaturatedlinkages in the molecules are moresusceptible to autoxidation.
Examples:
◦ Methyldopa and epinephrine.
◦ Polyunsaturated molecules such as vitamin A.
◦ Hydrocortisone.
◦ Volatile oils e.g. clove and cinnamon changecolour, odour and consistency due toautoxidation.
◦ Fixed oils e.g. arachis oil develop an unpleasantodour and taste (become rancid).
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1. The oxygen in pharmaceutical containers should be
replaced with nitrogen or carbon dioxide.
2. Contact of the drug with heavy-metal ions such as
iron, cobalt or nickel, which catalyse oxidation,
should be avoided; and storage should be at
reduced temperatures.
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3. Use of antioxidants
Anti oxidants are added to pharmaceutical
formulations as oxygen scavengers – that is
they have a higher capacity to undergo oxidation
than the drug moiety.
Examples:
sodium metabisulfite
ascorbic acid
Thiourea
thioglycolic acid.
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4. Use of Chelating agents
Chelating agents form complexes with
heavy metal ions and prevent them from
catalyzing oxidative decomposition.
Some good examples of chelating agents are:
ethylenediamine tetracetic acid derivatives and
salts
dihydroxyethyl glycine
citric acid and tartaric acid.
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Examples of drugs that degrade when
exposed to light include riboflavin and folic
acid.
Pharmaceutical products can be adequately
protected from photo-induced decomposition
by the use of coloured glass containers
(amber glass) and storage in the dark.
Coating tablets with a polymer film containing
ultraviolet absorbers has been suggested as
an additional method for protection from light.
6- Photodegradation
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