What Process Challenges Does Polymorphism Cause?
Reduced Bioavailability and Patent Conflicts
Knowledge about stability of crystal forms and tightly controlled processing conditions are critical to obtain a desired polymorph. Often, a simple change in temperature, agitation, or solvent composition can cause the material to change from a metastable form (local energy minimum) to the stable form (global energy minimum). The change in crystal structure often means a change in the external shape, which can impact isolation properties.
If cube-like crystals change to thin platelets, filtration time can significantly be increased due to caking of the material on the filter. If the transformation forms a solvate, it often increases drying times until the additional solvent is evaporated. If formulators are used to a prismatic crystals and suddenly have to work with needles, formulation of the final product might not be possible. A more stable polymorphic form often shows lower solubility, which will reduce bioavailability and in vivo performance making a drug less effective.
Late discovery of a more stable polymorph canhave disastrous effects on the supply of a drug product and can even cause patent conflicts, if the more stable form is already patented.