Download L05.00 ADVANCED PHYSICAL Stability

Chemical Stability of Drugs
13 Nov 2016
Revise:
Types of drug/formulation instability,
Importance of drug stability studies,
Factors affecting drug stability,
Definition of degradation reaction rate,
Definition of degradation reaction order,
How to determine the reaction order,
Relation between reaction rate and reaction order,
How to determine the reaction rate constant,
Rates and Orders of Reactions
For
A ------ B , A + B--------C reactions
rate  [A] a
rate  [A] a[B] b
a, a+b = the orders of the reaction
Zero
Rate = K
first
Rate=K[A]
OR
second,.. ??
Rate =K[A][B]
Zero – Order Reactions
For A ------- B
dc
 k0 [ A]0  k0
dt
•
•
•
•
Slope = ?
Intercept = ?
T0.5=?
T0.9= ?
First Order Reactions
Decompostion of Hydrogen Peroxide at 25C in Aqeous Solution
dc

 Kc
dt
C  C010
 kt
2.303
60
Ct (mole/L)
C  C0 e
 kt
70
50
40
30
20
10
0
0
10
20
30
40
t (minutes)
50
60
70
Apparent Zero Order Reactions
Degradation in Suspensions
dc

 Kc
dt
C is rendered constant in suspension, so Kc = K0, thus
dc
  K0
dt
Factors Affecting Drug Chemical Stability
Temperature
The effect of temperature on
reaction rate is given by the
Arrhenius Equation:
k=Ae-Ea/RT
By taking the log of both sides,
the equation transforms
into:
log k= logA – Ea /2.303RT
The pH
Specific Acid – Base Catalysis
• Read the figure
• Importance of the pH
profile in the formulation
process
General Acid – Base Catalysis
• The catalytic effect
resulting from the buffer
components is called a
general acid – base
catalysis.
• Importance of the pH
profile in the
formulation process
Modes of Pharmaceutical Degradation
&
Protection Methods
• Hydrolysis
– Hydrolysis of esters and amides is the most common example, these
reactions are dependent on H+ and OH- ions as catalysts so in order to
stabilize the formulation, the pH must be adjusted to match the
minima in the stability-pH profile if possible.
• Oxidation
– Can be prevented by a variety of approaches including the
manufacturing and packaging under inert conditions, addition of
antioxidants (ascorbic acid, Na sulphite, metabisulfite and bisulfate),
the use of chelating agents, reduction in storage temperature and
formulation at optimum pH for stability.
•
Photolysis
Accelerated Stability Testing
• Stability testing and shelf life determination is usually
performed using accelerated stability protocols.
• Accelerated stability protocols have been developed to reduce
the time required to determine the products shelf life at the
storage conditions.
WHO Technical Report Series, No. 953, 2009
Stability testing of active pharmaceutical
ingredients and finished pharmaceutical
products.
Objectives of the guidelines
To exemplify the core stability data package required for
registration of active pharmaceutical ingredients (APIs) and
finished pharmaceutical products (FPPs).
……..
General principles
The purpose of stability testing is to provide evidence of how the
quality of an API or FPP varies with time under the influence
of a variety of environmental factors such as temperature,
humidity and light.
The stability programme also includes the study of productrelated factors that influence its quality, for example,
interaction of API with excipients, container closure systems
and packaging materials. In fixed-dose combination FPPs
(FDCs) the interaction between two or more APIs also has to
be considered.
Guidelines for :
Active pharmaceutical ingredient:
will not be presented here
Finished pharmaceutical product:
will be presented here in part
Definitions (WHO Technical Report Series, No. 863, 1996)
The definitions given below apply to the terms used in these
guidelines.
accelerated stability testing
Studies designed to increase the rate of chemical degradation and
physical change of a drug by using exaggerated storage
conditions as part of the formal stability testing programme. The
data thus obtained, in addition to those derived from real-time
stability studies, may be used to assess longer-term chemical
effects under nonaccelerated conditions and to evaluate the
impact of short-term excursions (deviations) outside the label
storage conditions, as might occur during shipping.
The results of accelerated testing studies are not always predictive
of physical changes.
batch
A defined quantity of product processed in a single process or series of
processes and therefore expected to be homogeneous. In continuous
manufacture, the batch must correspond to a defined fraction of
production, characterized by its intended homogeneity.
climatic zones
The four zones into which the world is divided based on the prevailing annual
.
climatic conditions
mean kinetic temperature
The single test temperature for a drug product corresponding to the effects
on chemical reaction kinetics of a given temperature-time distribution.
A mean kinetic temperature is calculated for each of the four world climatic
zones according to certain formula.
It is normally higher than the arithmetic mean temperature.
expiry date
The date given on the individual container (usually on the label)
of a drug product up to and including which the product is
expected to remain within specifications, if stored correctly. It
is established for each batch by adding the shelf-life period to
the date of manufacture.
shelf-life
The period of time during which a drug product, if stored
correctly, is expected to comply with the specification1 as
determined by stability studies on a number of batches of the
product. The shelf-life is used to establish the expiry date of
each batch.
real-time (long-term) stability studies
Experiments on the physical, chemical, biological,
biopharmaceutical and microbiological characteristics of a
drug, during and beyond the expected shelf-life and storage
periods of samples under the storage conditions expected in
the intended market.
The results are used to establish the shelf-life, to confirm the
projected shelflife, and to recommend storage conditions.
Stability
The ability of a pharmaceutical product to retain its chemical,
physical, microbiological and biopharmaceutical properties
within specified limits throughout its shelf-life.
stability tests
A series of tests designed to obtain information on the stability
of a pharmaceutical product in order to define its shelf-life
and utilization period under specified packaging and storage
conditions.
Guidelines for Finished pharmaceutical product
General
The design of the stability studies for the FPP should be based on
knowledge of the behaviour and properties of the API,
information from stability studies on the API and on
experience gained from preformulation studies and
investigational FPPs.
Selection of batches
Data from stability studies should be provided on at least three
primary batches of the FPP. The primary batches should be of
the same formulation and packaged in the same container
closure system as proposed for marketing.
The manufacturing process used for primary batches should
simulate that to be applied to production batches and should
provide product of the same quality and meeting the same
specification as that intended for marketing.
In the case of conventional dosage forms with APIs that are
known to be stable, data from at least two primary batches
should be provided.
…………..
Stability studies should be performed on each individual
strength, dosage form and container type and size of the
FPP………
Container closure system
Stability testing should be conducted on the dosage form
packaged in the container closure system proposed for
marketing. …..
Storage conditions
In general an FPP should be evaluated under storage conditions
with specified tolerances that test its thermal stability and, if
applicable, its sensitivity to moisture or potential for solvent
loss.
The storage conditions and the lengths of studies chosen should
be sufficient to cover storage, shipment and subsequent use
with due regard to the climatic conditions in which the
product is intended to be marketed.
In general “significant change” for an FPP is defined as:
• A change from the initial content of API(s) of 5% or more
detected by assay, or failure to meet the acceptance criteria
for potency when using biological or immunological
procedures. (Note: Other values may be applied, if justified, to
certain products, such as multivitamins and herbal
preparations.)
• Any degradation product exceeding its acceptance criterion.
• Failure to meet the acceptance criteria for appearance,
physical attributes and functionality test (e.g. colour, phase
separation, resuspendability, caking, hardness, dose delivery
per actuation). ………………………..…….
Statements and labelling
A storage statement should be established for the label based on
the stability evaluation of the FPP.
Where applicable, specific instructions should be provided,
particularly for FPPs that cannot tolerate freezing.
Terms such as “ambient conditions” or “room temperature”
must be avoided.
There should be a direct link between the storage statement on
the label and the demonstrated stability of the FPP.
An expiry date should be displayed on the container label.
Long-term stability testing conditions
Four different long-term testing conditions were defined, which match with
the climatic conditions of the target markets categorized in just four
different climatic zones.
This concept is described in regulatory guidelines and pharmacopoeias and
has become an established standard in developing finished
pharmaceutical products (FPPs).
It was then recommended to split the current Climatic Zone IV (hot and
humid) into two zones: Climatic Zone IVA – for which 30 °C/65% RH will
remain the standard long-term testing condition – and Climatic Zone IVB
for which, if justified, 30 °C/75% RH will become the long-term testing
condition.
EFFECT OF STORAGE TEMPERATURE ON
THE STABILITY OF TOTAL
PARENTERAL NUTRITION ADMIXTURES
PREPARED FOR INFANTS
Acta Poloniae Pharmaceutica n Drug
Research, Vol. 72 No. 5 pp. 843n849,
2015
Introduction: Read from the article
Materials
Vitamines, Amino acids, salts, lipids,…
Methods involve determination of:
 Physical Stability: Zeta potential, particle size,
 Chemical stability: for ascorbic acid and L-alanyl-Lglutamine
 Microbiological stability
Zeta-potential measurements ( ‫)أهميتها؟؟‬
Carried out at 25C using Zetasizer apparatus. An electric field
is applied to the dispersion of particles, which would then
move with a velocity related to their zeta potential.
This velocity is measured and converted to “ electrophoretic
mobility” which is used in the calculation of Zeta potential,
in mV, using Smoluchowsky equation .
The zeta potential values indicates the instability of these
systems with the values smaller than ―30 mV. The results
showed decreasing tendency especially in samples stored
at low temperature.
Smoluchowsky Equation
Results: zeta potential
The most important condition of the nutrition is that the
foods should be digested and the nutrients in the
digestive system can convert into small molecules.
A suitable zeta potential (negative electrical charge) is
required, i.e., the nutrients have to get easily into the
cells and to leave from there.
As long as the negatively charged nutrients and positively
charged intracellular fluid are maintained in
equilibrium, the cell metabolism is proper and the way
you feel is good.
Figure 1 illustrates that the negative zeta potential
remained under each storage temperature in the
whole 14- day-storage period.
Figure 1. Zeta potential values measured at different
storage temperatures as a function of storage time.
Particle size measurements
Mean droplet size (MDS), size distribution and
polydispersity of the emulsion droplets were
measured at 25C using Zetasizer apparatus.
Dynamic Light Scattering (DLS) is used to measure
particle diameter.
Particle size range for size measurement is
from 0.6 nm to 6 μm.
Results : Particle size
… If a patient is unable to be nourished, the
parenteral infusion is lifesaver, but efforts should
be made to induce fewer side effects with it.
It is particularly important that the fat emulsion
must have smaller particle size.
Under each storage conditions the particle size of
the admixtures not even come close to 10
microns during 14 days long study.
The larger particles, which were present in average
in 4.6%, did not exceed an average size of 5
microns long red blood cells.
Determination of the ascorbic acid
concentration
Ascorbic acid was diluted in deionized water to
obtain solutions at appropriate concentrations
for implementation.
They were freshly prepared before use. The
samples were ultrafiltrated with 10 kDa filter
before the chemical analysis.
Results: Ascorbic acid stability
….. However, it was not possible to detect
ascorbic acid at 25C and 30C after 24 h.
Samples, which were stored at 2-8C, contained
ascorbic acid after 48 h, but after 3 days, the
ascorbic acid became immeasurable, hence
completely decomposed in each sample (Fig.
2).
Figure 2. Changes in the concentration of ascorbic acid
in the samples stored at 2-8C
Examination of the stability of L-alanyl-L-glutamine
The stability assay took 14 days at three temperatures (28C, 25C, 30C).
The L-alanyl-L-glutamine was diluted in deionized water
to obtain solutions at appropriate concentrations for
implementation.
In contrast to the ascorbic acid, L-alanyl- L-glutamine can
be stored for 14 days without decomposition at each of
the examined temperature.
Figure 3 confirms that the concentration changes of Lalanyl-L-glutamine remained within the acceptable
limits.
Figure 3. Changes in the concentration of L-alanyl-L-glutamine
at different temperatures as a function of storage time
Microbiological examinations
The parenteral formula was studied at three different
temperatures (2-8C, 25C, 30C) for 14 consecutive days.
Aerobic bacterial and mycological cultures were prepared
according to the pharmacopoeia monographs.
The samples were treated and evaluated according to the
rules of microbiological sample processes.
Result:
Each sample remained sterile within the whole storage
interval.
DISCUSSION AND CONCLUSION
There were no significant differences in the average
particle size and zeta potential values of
admixtures depending on the storage
temperatures.
After examination of the samples, the storage time
exceeded even 14 days at all three temperatures.
Moreover, the results show that the values were
the best at 30C.
…… According to the results of the physicochemical
examinations, 10-day storage period of this type
of TPN admixtures at room temperature can be
accepted.
Their storage does not require refrigeration (2-8C),
thus they can be administered without special
preheating ensuring better physiological
tolerance.
Because of the rapid decomposition of vitamin C,
the water-soluble Soluvit multivitamin has to be
added into the admixture in every day, while the
glutamine can be mixed with the amino acid
infusion because of its adequate stability.