Toward supramolecular architectures of the anti-HIV drug lamivudine: understanding the effect of the inclusion of water in a hydrochloride form

Two salts of the anti-HIV drug lamivudine, namely, lamivudine hydrochloride and lamivudine hydrochloride monohydrate, were prepared for the first time. Structural relationships and the role of water in crystal assembly and lamivudine conformation were established and allowed for a rational approach to understand how solid state properties could be changed by engineering new salts of the drug.Brazilian Research Council CNPq (Conselho Nacional de Desenvolvimento Cientifico e Tecnologico)Brazilian Research Council CNPq (Conselho Nacional de Desenvolvimento Cientifico e Tecnologico) [472623/2011-7]Consejo Superior de Investigaciones Cientificas (CSIC) of SpainConsejo Superior de Investigaciones Cientificas (CSIC) of Spai

Crystal Engineering of an Anti-HIV Drug Based on the Recognition of Assembling Molecular Frameworks

A rational strategy was employed for design of an orthorhombic structure of lamivudine with maleic acid. On the basis of the lamivudine saccharinate structure reported in the literature, maleic acid was chosen to synthesize a salt with the anti-HIV drug because of the structural similarities between the salt formers. Maleic acid has an acid-ionization constant of the anti first proton and an arrangement of their hydrogen bonding functionalities similar to those of saccharin. Likewise, there is a saccharin-like conformational rigidity in maleic acid because of the hydrogen-bonded ring formation and the Z-configuration around the C=C double bond. As was conceivably predicted, lamivudine maleate assembles into a structure whose intermolecular architecture is related to that of saccharinate salt of the drug. Therefore, a molecular framework responsible for crystal assembly into a lamivudine saccharinate-like structure could be recognized in the salt formers. Furthermore, structural correlations and structure-solubility relationships were established for lamivudine maleate and saccharinate. Although there is a same molecular framework in maleic acid and saccharin, these salt formers are Structurally different in some aspects. When compared to saccharin, neither out-of-plane SO(2) oxygens nor a benzene group occur in maleic acid. Both features could be related to higher solubility of lamivudine maleate. Here, we also anticipate that multicomponent molecular crystals of lamivudine with other salt formers possessing the molecular framework responsible for crystal assembly can be engineered successfully.Centro de Equivalencia Farmaceutica (Nucleo de Controle de Qualidade de Farmacos e Medicamentos, Universidade Federal de Alfenas, CEFAR-NCQ/UNIFAL-MG)Centro de Equivalencia Farmaceutica (Nucleo de Controle de Qualidade de Farmacos e Medicamentos, Universidade Federal de Alfenas, CEFAR-NCQ/UNIFAL-MG)Brazilian Research Council CNPq (Conselho Nacional de Desenvolvimento Cientifico c Tecnologico)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)FAPESP (Fundacao de Amparo a Pesquisa do Estado de Sao Paulo[2007/07185-5]FAPEMIG (Fundacao de Amparo A Pesquisa do Estado de Minas Gerais[APQ-2011-5.02/07]Fundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG)Fundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG)FAPEMIG (Fundacao de Amparo A Pesquisa do Estado de Minas Gerais[APQ-6010-5.02/07]FAPEMIG (Fundacao de Amparo A Pesquisa do Estado de Minas Gerais[APQ-02685-09]Fundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)CAPES (Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior)[PNPD2008