Pharmaceutical Manufacturing Handbook: Production and

independent of initial drug concentration. Accelerated stability studies are conducted
to expedite the degradative reactions, where temperature is the commonly
used accelerant. The infl uence of temperature on drug stability kinetics is described
by the Arrhenius equation:
k Ae
STABILITY CHARACTERISTICS 967
−Ea/ RT = (21)
where k is a reaction rate constant, A is a frequency factor, E a is activation energy,
R is the gas constant, and T is absolute temperature. According to the Arrhenius
equation, every 10 ° C rise in temperature increases the reaction rate by two - to fi vefold
[31] . The usual temperatures selected for early stability studies include 5, 25, 37,
40, and 60 ° C to cover the temperatures encountered in processing, use, and storage
of the drug product. Using the Arrhenius equation, the rate constant from higher
temperatures can be extrapolated to determine the stability at room temperature
[31] . The slope of the plot of the reciprocal of temperature and the rate constant
gives the activation energy. The activation energy usually varies between 15 and
60 kcal/mol with a mean value of 19.8 kcal/mol [33] . A break in the line is usually
indicative of change in the activation energy due either to change in the reaction
order or the mechanism of degradation at higher temperature. In such cases, it
becomes imperative to conduct detailed studies to understand the drug degradation
mechanism. Some of the reactions seen at higher temperature may not be representative
of the reactions at room temperature. Hence, short - term high - temperature
studies should be supplemented with long - term real - time stability testing at room
temperature. Additionally, the drug is also exposed to moisture, oxygen, and UV light
(250 – 360 nm). The conditions used for stress studies may vary depending on the drug
type and the drug development stage [54] . The stability studies in this chapter are
discussed with respect to a solid dosage form which includes solid - state stability,
limited liquid state stability, and drug – excipient compatibility.
6.2.4.1 Solid - State Stability
In general, solid - state reactions are slow, complex, and at times diffi cult to quantify.
They may manifest as either physical and/or chemical instabilities. Physical instabilities
include solid – solid transformations, desolvation of hydrates, and change in color
[34] . On the other hand, chemical instabilities may involve a change in drug content
as a result of hydrolysis, oxidation, or light - induced degradations [32] . The infl uence
of temperature is studied by exposing the solid drug to increasing temperatures and
also exposing the drug to various relative humidities at room temperature for two
to eight weeks (Table 11 ). If substantial change is observed at higher temperatures,
the drug samples stored at 5 ° C are analyzed. If no degradation is seen at higher
temperature, then none can be expected at room temperature. The results from
higher temperature should be carefully interpreted. For instance, a hydrate may lose
moisture at higher temperatures and make a drug unstable which otherwise would
be stable at room temperature. Similarly, chlortetracycline hydrochloride converts
from the β form to the α form at above 65% relative humidity, in contrast to < 65%
relative humidity, where no transformations are observed [32] .
Oxidative degradation is studied by exposing the sample to an atmosphere of
40%. The oxygen is combined with heat to accelerate the reaction. The results