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Early Accelerated Stability Studies
Some drug substances are sensitive to the presence of water vapor or moisture. When
a drug substance interacts with moisture, the water is retained by either bulk or
surface adsorption. Moisture absorption can affect the stability of the drug substance
depending on how strongly the water is bounded, this depends on if the water is
in a free or bound state. Moisture can also cause a salt form to break down or disassociate
leaving to undesirable properties and stability concerns.
Selecting the most stable solid form prior to the GMP batch of active pharmaceutical
ingredient has the potential to facilitate subsequent drug development. In a recent
project, we designed a set of customized accelerated stability conditions so that,
within a very short period of time, our client had data which allowed them to select
between two different solid forms to identify the lead candidate with the highest
probability of success. This minimal up-front investment will potentially save numerous
days lost to issues that could have arisen in downstream process or manufacturing
phases by selecting the sub-optimal candidate that possesses stability issues.
Strategy: Two different solid forms were subjected to high temperature and
high humidity for a pre-determined period of time. Each form was tested by chemical
and physical means to determine any change from their initial results.
Methods: The two different forms were analyzed by use of X-ray Powder Diffraction
(XRPD), High Performance Liquid Chromatography (HPLC) for assay and related substances
data, Visual Appearance and Thermal Evaluation. TGA evaluation is quite useful in
determining hydrate formation. DSC, coupled with XRPD, may help in determining shifts
in melting temperatures due to drug substance and moisture interactions.
Result: In a shorter period of time than with a classical or typical stability
program, we were able to determine the lead candidate as one that was less hydroscopic
and more stable (e.g. less likely to form a polymorph, since material sensitive
to change in temperature can cause this). Accelerated stability studies may also
be used to determine the best storage conditions.
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