Multiple conformations and supramolecular synthons in almost fifty crystal structures of the anti-HIV/HBV drug lamivudine

Lamivudine (β-L-2′,3′-dideoxy-3′-thiacytidine, 3 TC), is one of the most investigated drugs in the fields of solid state chemistry and crystal engineering. Already in the year 1996, there was the first report of two crystal forms of lamivudine. Since then, more than 45 solid forms have been discovered, totaling 47 different arrangements of the same drug in the solid state (4 true polymorphs, 2 hydrates, 22 salts, 7 cocrystals, 5 cocrystals of salts, 6 so-called duplexes and 1 solid solution). Lamivudine has received much attention and there are numerous publications on its solid state forms, which have indeed brought important advances in our knowledge about solid state structure and improvement of pharmaceutical performance, but have also introduced challenges with respect to analysis and reproducibility. The purpose of this review is to describe all lamivudine solid forms currently known, focusing on their structural features. The description and occurrence of all 5’-CH 2 OH conformations, oxathiolane puckers and supramolecular synthons in all available lamivudine crystal forms is presented here. These structural information and characterization data will be useful for pharmaceutical design and analysis, as well as demonstrating the applicability of crystal engineering strategies to drugs with the same motifs as lamivudine.