The document discusses the importance of stability in pharmaceutical compounding and outlines factors that can affect stability. It defines stability as a product retaining its properties and characteristics within specified limits throughout its shelf life. There are five main types of stability: chemical, physical, microbiological, therapeutic, and toxicological. Factors like temperature, light, humidity, ingredients, dosage form, pH, and solvent composition can influence stability. Pharmacists must store products under proper conditions and expiration dates to ensure stability and prevent issues.

2. Introduction.
Definition of stability.
The five types of stability.
Factors affecting product stability.
Stability studies in manufacturing.
Observing products for evidence of
instability.
Responsibility of the pharmacist.
Reference.

3.  Pharmacist should establish and maintain compounding that
include the insurance of drug stability to help prevent
therapeutic failure and adverse responses.
Pharmacist should avoid ingredients and conditions that
could result in excessive physical deterioration or chemical
decomposition.
 The stability and clinical effect of manufactured dosage forms can be
greatly compromised be seemingly negligible alterations or
inappropriate prescription compounding.

4. Stability is defined as the extent
to which a product retains, within
specified limits, and throughout its
period of storage and use
(i.e., its shelf-life), the same
properties and characteristics that
it possessed at the time of its
manufacture.

5. Type of Stability Conditions maintained Throughout
the shelf-life of the drug product
Chemical Each active ingredient retains its chemical
integrity and labeled potency, within the
specified limits.
Physical The original physical properties, including
appearance, palatability, uniformity,
dissolution, and suspendability are
retained.
Microbiological Sterility or resistance to microbial growth
is retained according to the specified
requirements.
Antimicrobial agents that are present
retain effectiveness within specified limits.
Therapeutic The therapeutic effect remains unchanged.
Toxicological No significant increase in toxicity occurs.

6. Each ingredient whether therapeutically active or pharmaceutically
necessary can effect the drug product and dosage form stability.
1-Primary environmental factors reducing the
stability:
 Exposure to adverse temperature, light, humidity, carbon dioxide,
Oxygen.
2-Dosage form factors:
 Particle size( especially emulsion, suspensions), PH, solvent system
composition (I.e., percentage of free water and overall polarity),
compatibility of anions and cations , solution ionic strength , primary
container ,specific chemical additives, molecular binding and diffusion of
drugs and excipients.

7. Reactions in the dosage
forms causes loss of
active drug content and
they usually don’t provide
obvious visual evidence of
their occurrence.
Hydrolysis Epimerization
Decarboxylation
Oxidation
Photochemical
decompositionIonic strengthPh Effect
Interionic
compatibility
Solid state
stability
Temperature

8. • Esters and beta lactams are the chemical bonds that mostly hydrolyze in the
presence of water. For instance, acetyl ester in aspirin hydrolyze to acetic acid
and salicylic acid in the presence of moisture but in dry environment the
hydrolysis of aspirin is negligible. The hydrolysis rate of aspirin increases in
direct proportion to the water vapor pressure in an environment
• Amide also hydrolyzes but at slower rate than the esters. for example,
procaine( an ester) will hydrolyze upon autoclaving. But procainamide
will not.
• The amides or peptides bond in peptides and protein varies in the ability to
hydrolysis
• The lactam or azomethine (or imine) bonds in benzodiazepines are also
labile to hydrolysis.
• The major accelerators or catalyzers to hydrolysis are adverse pH, specific
chemicals. Such as, dextrose and copper in case of ampicillins hydrolysis

9. • Members of tetracycline are most likely to incur epimerization. This
reaction occur rapidly when exposed to a pH of intermediate range
(higher than 3) and it result in the steric rearrangement of
dimethylamino group . the epimer of tetracycline , epitetracycline has
little or no antibacterial activity.
• Some dissolved carboxylic acid such as, p-aminosalicylic acid loose
carbon dioxide from carboxyl group when heated. The resulting product
has reduced pharmacological potency.
• Beta-keto decarboxylation can occur in some solid antibiotics that has a
carbonyl group on the beta-carbon of carboxylic acid or carboxylate
anion. Such decarboxylation will occur in the following antibiotics:
carbencillin sodium, carbencillin free acid, ticarcillin sodium , ticarcillin
free acid.

10. • Acid catalyzed dehydration of tetracycline forms epianhyrotetracycline, a
product that has no antibacterial activity and causes toxicity.
• The molecular structures that most likely oxidize are the one with hydroxyl group
attached to aromatic ring( e.g.; phenol derivatives catecholamine and morphine) ,
conjugated dienes (vitamin A and unsaturated free fatty acid), heterocyclic aromatic
rings, nitroso and nitrites derivatives, aldehyde (flavorings).
• Products of oxidation usually lack therapeutic activity.
• Visual identification of oxidation. For instance, the change of colorless epinephrine to
amber colored products, may not be visible to some dilutions or some eyes.
Oxidation is catalyzed by pH values that are higher than optimum, polyvalent heavy
metal ions (copper,iron), and exposure to oxygen and UV illumination . the latter two
causes of oxidations justify the use of antioxidants chemicals, nitrogen atmospheres
during ampule and vial filling , opaque external packaging and transparent amber glass
or plastic containers.

11. • Exposure to primary UV illumination cause oxidation(photo-oxidation)
and scission (photo-lysis)of covalent bonds.
• Nifedipine , nitoprusside , riboflavin and phenothiazine are very labile to photo
oxidation . in susceptible compounds , photochemical energy creates free radical
intermediate, which can perpetuate chain reaction.
• The effect of total concentration of dissolved electrolytes on the rate of hydrolysis
reaction results from the influence of ionic strength on interionic attraction.
• In general the hydrolysis rate constant is inversely proportional to ionic
strength with oppositely charged ions for example drug cation and excipient
anions . and directly proportional to ionic strength with ions of like charge.
• A reaction that produce an ion of opposite charge to the original drug ion can
increase the drug hydrolysis rate as the reaction proceeds, because of the
increasing ionic strength. High ionic strength of inorganic salts can reduce the
solubility of some other drugs.

12. • The degradation of many drugs in solution accelerate or decelerate exponentially
as the pH increased or decreased over a specific range of pH values.
• Improper pH ranks with exposure to elevated temperature as a factor most likely to
cause clinical significant loss of drug, resulting from hydrolysis and oxidation
reaction.
• A pH buffer system, which is usually weak acid or base and its salt, is a common
excipient used in liquid preparations to maintain a pH at a range to minimizes the drug
degradation rate.
• The compatibility or solubility of oppositely charged ions depends mainly on the
number of chargers per ion and molecular size of ions.
• In general polyvalent ions of opposite charges are more likely to be incompatible.
Thus, an incompatibility is likely to occur upon the addition of large ion with a
charge of that opposite to the drug.

13. :
• Solid state reactions are relatively small; thus, stability of drugs in solid state is
rarely a dispensing concern.
• The degradation rate of dry solids is characterized by first order kinetic or a sigmoid
curve. Therefore, solid drugs with low melting point should not be combined with
other chemicals that would form eutectic mixture.
• When moisture is present, the solid drug decomposition may change to zero order
chemical kinetic.
• In general the rate of chemical reaction increase exponentially for each 10o increase
in temperature.
• The shelf life of the drug at controlled room temperature should be expected to
decrease to one-forth to one-twenty-fifth of its shelf life under refrigeration.

14. • The pharmacist must be aware
that inappropriately cold
temperature could be harm.
For example, refrigeration may
cause some liquid preparations to
become extremely viscous and
supersaturated on others.
1. increase droplet size of breaking of the emulsion.
2. It can denature the protein.
3. In rare cases, it can cause less soluble polymorphic states in
some drugs to form.

16. Determining effect of temperature, light, trace metals, pH,… etc.
Formulation is prepared. (one or more):
Regarding: preparation, packaging, storage… etc.
Samples are assayed.
Regarding: potency, physical change, microbial resistance… etc.
MAINLY BIOAVAIABILITY.
Selection of formulation; containers, storage conditions and expiry date.

18. If necessary, the manufacturer is consulted
In filling: Suitable containers, expiry date & beyond-use date is put on the label.
Single unit: Appropriate packaging.
Stock limited-time-use if there's no data available.
Lot number & Beyond-Use date.
Sterile products: if not used, dispose within 24 hours unless data is available
Immediate use products: Records; Number of manufacturer, lot numberand the
information of the personnel who did the packaging.
Use of container closure systems.

19. Observe good professional & scientific procedures
against incompatibility or instability. (Belladonna &
Digitalis)
Labelling should be routinely consulted. (Changed
Formulas)
Stability of extemporaneously prepared products is
unknown.
Powder in liquid antibiotics should never be mixed.
Parenteral use.

22. • Loss of Potency usually results from a chemical change, the most common
reactions are: Hydrolysis, oxidation-reduction, and photolysis.
• Chemical changes may occur also through interaction between ingredients
within a product, or rarely between product and container.
• An apparent gain in potency usually is caused by solvent evaporation or by
leaching of materials from the container-closure system.
Ingredient
Ingredient
Product
Container

23. • Potency is determined by means of an assay procedure that differentiates
between the intact molecule and its degradation products. Chemical stability
data should be available from the manufacturer.
• Excessive chemical degradation is sometimes accompanied by observable
physical changes. Such as change in:
• It should be assumed that a product that has undergone a physical change not
explained in the labeling may also have undergone chemical changes and such a
product should never be dispensed.
Color Odor Formation

24. Common physical signs of deterioration of dosage forms include:
Solid Dosage Form:
Are designed for storage under low-moisture conditions and should be stored in tight containers.
The appearance of fog or liquid droplets
Hard and Soft Gelatine Capsules:
a change in gross physical appearance or consistency, including hardening or softening of the
shell, is the primary evidence of instability. Evidence of release of gas, such as a distended paper
seal, is another sign of instability.
Uncoated Tablets:
Evidence of physical instability in uncoated tablets may be shown by excessive powder and/or pieces f tablet at the
bottom of the container, cracks or chips in tablet surfaces; swelling; mottling; discoloration; fusion between tablets;
or the appearance of crystals that obviously are not part of the tablet itself on the container walls or on the tablets.
Coated Tablets:
Evidence of physical instability in coated tablets is shown by cracks,
mottling, or tackiness in the coating and the clumping of tablets.

25. Common physical signs of deterioration of dosage forms include:
Dry Powders And Granules:
Not intended for constitution: may cake into hard masses or change colour, which may render
them unacceptable.
Powders And Granules Intended For Constitution As
Suspensions: require special attention, they are sensitive to moisture. Since they are
always dispensed in the original container, they generally are not subject to contamination by
moisture. However, an unusual caked appearance necessitates careful evaluation, and the
presence of a fog or liquid droplets inside the container generally renders the preparation unfit
for use. Presence of an objectionable odour also may be evidence of instability.
Effervescent Tablets, Granules, And Powders:
sensitive to moisture. Swelling of the mass or development of gas pressure is a specific
sign of instability, indicating that some of the effervescent action has occurred
prematurely.
Liquid Dosage Forms:
Of primary concern with respect to liquid dosage forms are homogeneity and freedom
from excessive microbial contamination and growth. Instability may be indicated by
cloudiness or precipitation in a solution, breaking of an emulsion, nonresuspendable
caking of a suspension, or organoleptic changes.

26. Common physical signs of deterioration of dosage forms include:
Solutions, Elixirs, And Syrups:
Precipitation and evidence of microbial or chemical gas formation are the two major signs of
instability.
Emulsions:
The breaking of an emulsion is a characteristic sign of instability; this is not to be
confused with creaming, an easily redispersible separation of the oil phase that is a
common occurrence with stable emulsions.
Suspensions:
A caked solid phase that cannot be resuspended by a reasonable amount of shaking is
a primary indication of instability in a suspension. The presence of relatively large
particles may mean that excessive crystal growth has occurred
Tinctures And Fluidextracts:
are usually dark because they are concentrated, and thus they
should be scrutinized carefully for evidence of precipitation.

27. Common physical signs of deterioration of dosage forms include:
Sterile Liquids:
The presence of microbial contamination in sterile liquids usually cannot be detected visually, but any haze, colour
change, cloudiness, surface film, particulate or flocculent matter, or gas formation is sufficient reason to suspect
possible contamination. Clarity of sterile solutions intended for ophthalmic or parenteral use is of utmost importance.
Semisolids:
the primary indication of instability is often either discoloration or a noticeable change in consistency or odor.
Creams:
Unlike ointments, creams usually are emulsions containing water and oil. Indications of instability
in creams are emulsion breakage, crystal growth, shrinking due to evaporation of water, and gross
microbial contamination
Ointments:
Common signs of instability in ointments are a change in consistency and excessive “bleeding”
(i.e., separation of excessive amounts of liquid) and formation of granules or grittiness.
Suppositories:
Excessive softening is the major indication of instability in suppositories, although some
suppositories may dry out and harden or shrivel. Suppositories should not be stored in refrigerator.

29. Pharmacists help to ensure that the products under their supervision
meet acceptable criteria of stability by :
Dispensing oldest stock first and observing expiration dates.
Storing products under the environmental conditions stated in the individual
monographs, labeling, or both.
Observing products for evidence of instability.
Properly treating and labeling products that are repackaged, diluted, or
mixed with other products.
Dispensing in the proper container with the proper closure.
Informing and educating patients concerning the proper storage and use of the
products.

30. • Proper rotation of stock is necessary to ensure the dispensing of
suitable products
• A product that is dispensed infrequently should be closely monitored
so that old stocks are given special attention, particularly with regard to
expiration dates.
• The manufacturer can guarantee the quality of a product up to the time
designated as its expiration date only if the product has been stored in
the original container under recommended storage conditions.

31. • These conditions are stated on the label it is
imperative to adhere to those conditions.
• They may include a specified temperature
range or a designated storage place or
condition.
(e.g., “refrigerator,” or “controlled room
temperature”) as defined in the General Notices.
• Supplemental instructions, such as a direction to protect the product from
light, also should be followed carefully.

32. • In the absence of specific instructions, the product should
be stored at controlled room temperature.
• Where a product is required to be protected from light and
is in a clear or translucent container enclosed in an
opaque outer covering, such outer covering is not to be
removed and discarded until the contents have been used.
• The product should be stored away from locations where
excessive or variable heat, cold, or light prevails, such as
those near heating pipes or fluorescent lighting.

33. Stability testing is an essential part of the
process of ensuring that the patient receives a
product that meets established standards of
safety, efficacy and quality.

34. USP – United States
Pharmacopeia, 2008.
{1191} Stability
consideration in
dispensing practice/
General information, page
2414.