Mimics of a R₂²(8) hydrogen-bond dimer motif: Synthesis and influence on the crystallisation of sulfathiazole and sulfapyridine

The bis[4-(hydroxyamino)phenylsulfonyl]piperazine 5, diketopiperazine 10 and benzene 14 were synthesised as mimics of an R₂²(8) motif, which occurs in one crystal polymorph of sulfathlazole and in several polymorphs of sulfapyridine. When present in crystallisations of sulfathlazole and sulfapyridine, these mimics were found to have little or no effect under crystallisation conditions that favour the formation of polymorphs not containing R₂²(8) motifs. However, the mimics were found to completely or partially inhibit: the formation of form. I sulfathiazole, which contains the Rju₂²(8) dimer, in crystallisations of sulfathiazole from 1-propanol. In crystallisations of sulfapyridine, the mimics were found to promote the formation of form. III, which does not contain the R₂²(8) motif. These compounds therefore appear to act as "tailor-made" additives, displaying polymorph-selective crystal, nucleation inhibition based on interaction with hydrogen-bond network motifs.