Control of the Mode of Polymorphic Transition Inducing Preferential Enrichment by Modifying the Molecular Structure or Adding Seed Crystals: Significant Influence of CH/F Hydrogen Bonds

The occurrence, induction, or inhibition of preferential enrichment is described for four new analogous racemic ammonium sulfonates. Racemic [2-[4-(2-hydroxy-3-phenoxypropoxy)phenylcarbamoyl]ethyl]trimethylammonium p-nitrobenzenesulfonate [(±)-1a] showed preferential enrichment in EtOH, but the efficiency was modest. The deposited crystals were an α1-form or a mixture of the α1-form and a new μ-form, depending on the solvent used. The terminal p-fluorophenoxy analogue (±)-1b showed more efficient preferential enrichment in EtOH, followed by the exclusive deposition of the α1-form crystals. On the other hand, (±)-[2-[4-(2-hydroxy-3-phenoxypropoxy)phenylcarbamoyl]ethyl]trimethylammonium p-toluenesulfonate [(±)-2a] failed to show preferential enrichment in any solvent to give the μ-form deposited crystals exclusively, whereas the terminal p-fluorophenoxy analogue (±)-2b showed very efficient preferential enrichment in EtOH, accompanied by the exclusive deposition of the α1-form crystals. Addition of the α1-form seed crystals of (±)-2b to the supersaturated EtOH solution of (±)-2a successfully induced the epitaxial transition to lead to the occurrence of preferential enrichment of (±)-2a, accompanied by the exclusive deposition of the α1-form crystals. From these results, it has been concluded that (i) polymorphic transition of the initially formed γ-form into the α1-form is essential for the occurrence of preferential enrichment of (±)-1 and (±)-2 and (ii) the direct transformation of the γ-form polymorph into the μ-form fails to show preferential enrichment.