| OBSERVATION'S |
Polymorphs tend to convert from less stable to more stable forms. The rate of conversion depends on the required activation energy and the differences in free energies. But no method yet exists to predict the polymorphs of a solid compound with significant certainty. The search for polymorphs is largely an empirical exercise.It is best to work with the most stable polymorph--also called the ground-state form--because it will not convert any further. But the ground state usually is the least soluble. To improve bioavailability, drug companies sometimes trade off polymorph stability with solubility, "recognizing that they will have to deal with the possibility of an undesired conversion to a more thermodynamically stable form. Even with intermediates for API synthesis, polymorphism is an issue. Although intermediates eventually end up being dissolved--and once they are dissolved, polymorphism is no longer an issue--they are supplied as solids. At this stage, the issue is not so much stability but processibility. Metastable forms sometimes reject impurities and filter better than the most stable polymorph.
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