Polymorphism – Polymorph myths and misperceptions

The past quarter of a century has seen an enormous increase in the number of papers on the behaviour of the organic solid state, particularly those concerning pharmaceutical polymorphs and solvates. High profile patent cases (ranitidine hydrochloride, paroxetine hydrochloride) combined with product polymorph issues (ritonavir), all of which have carried astronomical monetary implications have undoubtedly contributed to this proliferation. This increasing awareness and accessibility of polymorph information has been unfortunately accompanied by illusions about polymorphs and their behaviour. Since this is not a witch-hunt, references to examples of gross misunderstandings will not be provided, but many examples will be seen by the observant.

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.

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