Polymorphism – Polymorph myths and misperceptions

Polymorphs are well-behaved

The commonest misperception, easily acquired merely by reading the literature, is that polymorphism is a simple, well-understood phenomenon and that polymorphs are well behaved. How often does one read that polymorph X found in a certain way transforms enantiontropically at a certain temperature to polymorph Y, independently formed in some other manner: no complications, no uncertainties! In over 50 years of contact with polymorphs, I have yet to come across a simple, well behaved, rational, reproducible and totally explicable system. This view has been much reinforced by access during expert witness work to hundreds upon hundreds of pages of experimental work conducted by experienced scientists in major pharmaceutical companies: the same intractable problems of puzzling solid-state behaviour are encountered as in ones’ own work.

Solvent of crystallisation is the sole determinant of polymorphic outcome

The most prominent of the misapprehensions is the repeated propaganda that polymorph outcome is uniquely determined by the solvent of crystallisation, a myth constantly reinforced by unelaborated statements such as ‘Polymorph A crystallised from ethanol and polymorph B from acetone’. Without some indication of how many replicates and under what range of conditions, it is a statement devoid of value, because crystallisation, especially uncontrolled or unrecorded crystallisation, is a notoriously erratic phenomenon. As in all the topics to be discussed, there is a kernel of truth in the statement; in this case that solvent is capable of changing the polymorph produced.