ACCELERATED STABILITY

TEST OF FERROUS SULFATE

TABLETS IN WATER
 Stability study 1
 Stability of pharmaceutical product
- defined as the capability of particular formulation, in a specific container/ closure system, to remain within its
physical, chemical, microbiological, therapeutic, and toxicological specifications.
- As defined by the USP, is the extent to which a pharmaceutical product retains, within specified limits, and
throughout its period of storage and use (i.e., shelf-life), the same properties, and characteristics that it possessed
at the time of manufacture.
- Can also be defined as the time from the date of manufacture and packaging of the formulation until its
chemical or biological activity is not less than a predetermined level of labeled potency and its physical
characteristics have not changed appreciably or deleteriously (90% of labeled potency is generally recognized
as the minimum acceptable potency)
 Five types of stabilities considered:
STABILITY TYPE CONDITIONS MAINTAINED THROUGHOUT THE SHELF-LIFE OF THE DRUG
PRODUCT

Chemical Each active ingredient retains its chemical integrity and labeled potency, within specified limits

Physical The original physical properties, 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 within specified limits

Therapeutic The therapeutic effect remains unchanged

Toxicological No significant increase in toxicity occurs

 PHARMACEUTICAL INVESTIGATION
DEVELOPMENT STAGES COMMENTS

Preformulation  Pharmaceutical scientists determine the drug substance and its related salts stability/ compatibility
with various solvents, buffered solutions, and excipients considered for formulation development

First Formulation  Preparation of a “first in human” formulation which is often a non-elegant formulation optimized for
short-term dose-ranging clinical studies

Second formulation  Occurs to support Phase II and early Phase III clinical studies
 Product developed at this stage is usually the prototype for the commercial product
 The pharmaceutical product will be formulated based in part on the stability information obtained in
from the previous formulations and must meet stability requirements for longer-term clinical studies

Final formulation  For the commercial pharmaceutical product

 Building on the clinical requirements of the drug
 Must also incorporate the final market image of the product, which includes the container closure
system
 The stability of the product must be demonstrated to the appropriate regulatory agencies in order to
assign an expiration date for the product
 Regulatory Requirements

 cGMPs
- The GMP’s state that there shall be a written testing program designed to assess the stability characteristics of drug
products.
- The results shall be used to determine appropriate storage conditions and expiration testing.
- These regulations are updated periodically in light of current knowledge and technology.
 USP
- The compendia include discussion of stability considerations in dispensing practices and the responsibilities of both the
pharmaceutical manufacturer and dispensing pharmacist
- It is now required that product labeling of official articles provide recommended storage conditions and expiration date
assigned to the specific formulation and package
 FDA
- FDA guidelines provide recommendations for:
o The design of stability studies to establish appropriate expiration dating periods and product storage requirements
o The submission of stability information for investigational new drugs, biologicals, new drug applications, and
biological product license applications
 STABILITY PROTOCOL

MINIMUM
PROTOCOL CONDITIONS
PERIOD

Long-term testing Temp: 25C  2C 12 months

Nb.Alternate testing is required if RH: 60%  5%

significant change occurs during

6-month storage under conditions
of accelerated testing Accelerated testing Temp: 40C  2C 6 months
RH: 65%  5%

Alternate testing Temp: 30C  2C 12 months

RH: 65%  5%
FACTORS AFFECTING
STABILITY
 TEMPERATURE

 high temperature accelerates oxidation, reduction and hydrolysis

reaction which lead to drug degradation
 pH

- Acidic and alkaline pH influence the rate of decomposition of most drugs.

- Many drugs are stable between pH 4 and 8.
- Weakly acidic and basic drugs show good solubility when they are ionized, and they
also decompose faster when they are ionized
- So, if the pH of a drug solution has to be adjusted to improve solubility and the
resultant pH leads to instability then a way out of this tricky problem is to introduce a
water-miscible solvent into the product
- buffers such as acetate, citrate, lactate, phosphate and ascorbate buffers are utilized
to prevent drastic change in pH.
 MOISTURE

Water catalyzes chemical

reactions as oxidation, Water promotes microbial
hydrolysis and reduction growth
reaction
LIGHT

 Itaffects drug stability through its energy or thermal effect which

lead to oxidation
OXYGEN

- exposure of drug formulations to oxygen

affects their stability
 PHARMACEUTICAL DOSAGE FORMS
- Solid dosage forms are more stable than liquid dosage forms for presence of water.

 CONCENTRATION
- Rate of drug degradation is constant for the solutions of the same drug with different
concentration.
- So, ratio of degraded part to total amount of drug in diluted solution is bigger than of
concentrated solution

 DRUG INCOMPATIBILITY
- pharmaceutical dosage forms itself or between these components and cover of the container.
ACCELERATED STABILITY

This enables the researcher to predict the shelf life of a product within a short period of time.

Accelerating stress conditions are often used to intensify the degradation loss within time.

Assessment of product stability by using accelerated stress conditions can prove beneficial
provided careful consideration is given to the interpretation of results.

Shelf life is calculated by using the Arrhenius equation, if applicable, or by regression line
analysis by method of least squares
BIOAVIALABILIT
Y STUDY
BIOAVAILABILITY
 A termthat indicates
measurement of both the rate of
drug absorption and total
amount (extent) of drug that
reaches the general circulation
from an administered dosage
form
 EQUIVALENCE

 A more general, relative term that indicates a comparison of one drug product with another or
with a set of established standards
 DIFFERENT WAYS TO DETERMINE
EQUIVALENCE
o Chemical equivalence
 Indicates that two or more dosage forms contain the same labeled quantities (plus or minus specified range
limits) of the drug
o Clinical equivalence
 Occurs when the same drug from two or more dosage forms gives identical in vivo effects as measured by a
pharmacological response or by control of a symptom or disease
o Therapeutic equivalence
 Implies that two brands of a drug product are expected to yield the same clinical result
 The FDA classifies as therapeutically equivalent those products that meet the following general criteria:
 They are approved as safe and effective
 They are pharmaceutical equivalents in that they (1) contain the same amounts of active ingredient in
the same dosage form and route of administration and (2) meet compendial or other applicable
standards of strength, quality, purity, and identity
 They are bioequivalent in that (1) they do not present a known or potential bioequivalence problem, and
that they meet an acceptable in vitro standard, or (2) if they do present such a known or potential
problem, they are shown to meet an appropriate bioequivalence standard
 They are adequately labeled
 They are manufactured in compliance with CGMP regulations
BIOEQUIVALENCE

 Indicates that a drug in two or more similar

dosage forms reaches the general circulation
at the same relative rate and the save relative
extent (i.e., that the plasma level profiles of
the drug obtained using the two dosage forms
are the same)
PHARMACEUTICAL EQUIVALENCE

 Drug products in identical dosage forms that contains the same active
ingredients, use, the same route of administration, and are identical in strength
or concentration, quality, purity, content uniformity, but differ in excipients
BIOEQUIVALENCE
(POINTS TO
CONSIDER)
 SUBJECTS

- Bioequivalence studies are usually conducted in healthy adults under standardized

conditions
- The protocol should define the acceptable age and weight range for the subjects to be
included in the study as well as clinical parameters that will be used to characterize a
healthy adult (e.g., physical examination observations, clinical chemistry, and
hematological evaluations)
- The subjects should have been drug-free for at least two-weeks prior to testing to
eliminate possible drug-induced influences on liver enzyme systems.
- Normally, the subjects will fast overnight for at least 10 hours prior to dosing and
will not eat until a standard meal is provided 4 hours post-dosing
 PROCESS
 EXPERIMENTAL DESIGN
- The standard bioequivalence study is conducted in a crossover fashion in a small
number of volunteers
 MANNER OF ADMINISTRATION
- The dosage forms should be given to subjects in a randomized, manner, using a
suitable crossover design, so that possible daily variations are distributed equally
between the dosage forms tested.
 SAMPLE COLLECTION
- The protocol should define sample collection times and techniques to collect
biological fluid.
- The method of sample storage should also be defined.
 CRITERIA FOR BIOEQUIVALENCE

- Bioequivalence of different formulations of the same drug substance involves

equivalence with respect to the rate and extent of drug absorption.
- Two formulations whose rate and extent of absorption differ by  20% or less are
generally considered bioequivalent. The use of the  20% criteria is based on a
medical decision that for most drugs, a  20% difference in the concentration of the
active ingredient in blood will not be clinically significant.
STATISTICAL TREATMENT OF
DATA
 ANALYSIS OF VARIANCE

An ANOVA test is a way to find out if

survey or experiment results
are significant.
In other words, they help you to
figure out if you need to reject the
null hypothesis or accept the alternate
hypothesis.
Basically, you’re testing groups to see if
there’s a difference between them
TURKEY HSD TEST

o The Tukey Test (or Tukey procedure), also called Tukey’s Honest

Significant Difference test, is a post-hoc test based on the studentized
range distribution.
o used to test differences among sample means for significance.
o After you have run an ANOVA and found significant results, then you
can run Tukey’s HSD to find out which specific groups' means
(compared with each other) are different.

o The test compares all possible pairs of means