Journal
CRYSTAL GROWTH & DESIGN
Volume 9, Issue 12, Pages 5283-5292Publisher
AMER CHEMICAL SOC
DOI: 10.1021/cg900790f
Keywords
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Funding
- 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)
- 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, APQ-6010-5.02/07, APQ-02685-09]
- CAPES (Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior) [PNPD2008]
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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 SO2 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.
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