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Compatability Experiments
In formulating a drug product there are
many
ingredients, or excipients, that are needed in addition to the drug
substance itself. Of ten times there are incompatibilities between the
drug substance and these excipients that lead to degradation and
stability problems. Compatability experiments involve adding the drug
substance to the various excipients, at a variety of levels or
concentrations, and exposing these mixtures to different environmental
storage conditions (e.g., moisture, elevated temperature, etc.). After
mixing and exposure the amount of drug substance is determined
(typically by HPLC); any degradation indicates an incompatibility
between the drug substance and the particular excipient(s). While these
experiments can be conducted in the solution phase, the preferred
experiement involves dealing with solid drug substance and neat
excipients (either solid or liquid depending on the particular
excipient).
Solubility Experiments
A critical factor in developing a drug
product
is the chemical entity's solubility in aqueous solution. Aqeuous
solubility is often measured in a variety of solutions that range in
composition from low pH to high pH, or low ionic strength to high ionic
strength. These experiments consist of adding a compound to a range of
buffers, in a range of concentrations, and measuring the solubility of
the compound (by UV absorbance, nephelometry, or HPLC). The most
desired way to carry out these experiments is to deliver the compunds
as a solid, so that the inherent solubility can be determined. However,
due to the difficulty of delivering very small amounts of a variety of
solid samples, most experiments are carried out by first dissolving the
compound in a suitable solvent and then delivering as small a volume of
liquid sample as possible to the buffer solutions. By minimizing the
sample volume containing the compound, one can minimize the enhanced
solubility that the solvent gives the compound.
Dosing Studies
Most animal dosing studies typically
involve
dosing compounds in suspensions. This is because there is often not a
feasible or viable solution-based vehicle suitable for dosing. As a
result there can be a discrepancy between the bioavailability measured
in an animal dosing study and the inherent potential of a compound due
to the dosing vehicle that is used. Dosing with solution-based vehicles
(both aqueous and non-aqueous) allows for more accurate prediction of
bioavailability and therefore provides a better chance to maximize the
potential of a particular compound.
Dosing screens are typically conducted by creating a range of vehicles
from both aqueous and non-aqueous excipients. These mixtures can be
created through combinatorial means, or can be made up as simple ratios
of ingredients. A common strategy is to create a "library" of vehicles
and use this library as a screen for all compounds. Alternatively, a
unique set of vehicles can be created for a particular compound based
on the specific chemistry or functionality of the compound of interest.
Once the compound has been added to the range of vehicles, selection of
the most suitable formulation is based on determining or estimating the
compounds solubility in the vehicle. This can be accomplished either by
quantitative measurement (e.g., HPLC) or by visual inspection for
solubitlity (i.e. presence of un-dissolved compound or precipitation).
_________________________________________________________________ Sources:
Cherng,
JP.; Gonzalez-Zugasti, J.; Kane N.; Cima, M.J.; Lemmo, A.V.
"Integration of an Opto-Mechanical Mass Sensor With a Powder Dispensing
Device for Microgram Sensitivity", JALA, 2004, vol.9, no.4, 228-237.
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