Issue 28, 2015

Isostructurality and the conformational role of the 2′,3′-moieties in the diversity of lamivudine crystal forms probed in halide salts

Abstract

Crystal engineering of the anti-HIV drug lamivudine has currently provided improvement in its pharmaceutical performance besides getting insights into several branches of nucleoside structural chemistry. Here, we demonstrated the synthon robustness and the role of the five-membered ring conformation in the diversity of lamivudine crystal forms even with supramolecular isomerism. Oxathiolane conformation defines the ability of lamivudine to assemble into different multicomponent molecular crystal forms. This was observed in a polymorph of lamivudine hydrochloride, which is related to the previously reported lamivudine hydrochloride monohydrate. The absence of water molecules has little effect on their supramolecular organization. If water is not present, just one conformational change from C3′-endo puckering in the monohydrate form to the C2′-endo one in the anhydrate form reported here is enough to cause a hydrogen bonding reorganization involving the 5′-OH group. DFT calculations reveal a low energy gap for this change in the oxathiolane conformation. Therefore, lamivudine can variably forward its 5′-OH group through changing oxathiolane conformations of similar energies. In addition, the isostructurality and robustness of the supramolecular synthons were illustrated in two halide salts of lamivudine with hydrobromic and hydrofluoric acids. While the previously reported lamivudine hydrochloride is strictly isostructural to the hydrobromide salt, the lamivudine hydrofluoride crystallized as a hydrofluoric acid cocrystal. HF cocrystallization appears to be primarily related to further stabilization between sheets rather than a major size effect.

Graphical abstract: Isostructurality and the conformational role of the 2′,3′-moieties in the diversity of lamivudine crystal forms probed in halide salts

  • This article is part of the themed collection: Polymorphism

Supplementary files

Article information

Article type
Paper
Submitted
01 Dec 2014
Accepted
18 Dec 2014
First published
18 Dec 2014

CrystEngComm, 2015,17, 5187-5194

Isostructurality and the conformational role of the 2′,3′-moieties in the diversity of lamivudine crystal forms probed in halide salts

J. C. Tenorio Clavijo, F. F. Guimarães, J. Ellena and F. T. Martins, CrystEngComm, 2015, 17, 5187 DOI: 10.1039/C4CE02373K

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