Implementing Quality by Design in Pharmaceutical Salt Selection

Active pharmaceutical ingredients (API)  typically fall into the category

of weak electrolytes.  That is they can be classified as molecules with

weakly acidic or basic functional groups.  In their neutral state, API’s

are often poorly water-soluble, which can limit the bioavailability of the

compound.  Salt formation is often a useful handle to not only increasing

the solubility, but also to alter the physical properties (melting point,

polymorphic landscape, etc).  In general, strong acids are needed to form

salts of basic API due to the relatively low pKa of amine functional

groups.  If a salt undergoes reformation of the neutral components, a

disproportionation reaction is said to take place.  This reaction is

important in the solid-state as it determines the shelf life of the product

but also in solution as the API experiences different pH regions of the

stomach and intestine enroute to absorption.  Here we will present current

progress on a first principles theoretical model to quantify the risk of

disproportionation, including the effects of excipients.  Experimental

results validating the model will also be presented.  The model allows one

to estimate the balance between solubility enhancement and risk of

disproportionation, enabling different salts to be evaluated using quality

by design principles.