Salts of the anti-HIV drug lamivudine with phthalic and salicylic acids { Cameron Capeletti da Silva, a Renan Rezende Coelho, a Marilia de Lima Cirqueira, a Ariane Carla Campos de Melo, a Iara Maria Landre Rosa, b Javier Ellena c and Felipe Terra Martins* a Received 19th March 2012, Accepted 18th April 2012 DOI: 10.1039/c2ce25386k Salts of the anti-HIV drug lamivudine, with phthalic acid and salicylic acid as counterions, were investigated in this study. Neither the packing of the (lamivudine) + (phthalic acid) 2 ion pairs nor the conformation of the lamivudine moiety itself were similar to those found in other multicomponent molecular salts of the drug, such as hydrogen maleate and saccharinate ones, even though all three salts crystallize in the same P2 1 2 1 2 1 orthorhombic space group with similar unit cell metrics. Lamivudine salicylate assumes a different crystal structure to those of the hydrogen maleate and saccharinate salts, crystal- lizing in the P2 1 monoclinic space group as a monohydrate whose (lamivudine) + (salicylic acid) 2 ion pair is assembled through two hydrogen bonds with cytosine as a dual donor to both oxygens of the carboxylate, such as in the pairing of lamivudine with a phthalic acid counterion. In lamivudine salicylate monohydrate, the drug conformation is related to the hydrogen maleate and saccharinate salts. However, such a conformational similarity is not related to the intermolecular interaction patterns. Lamivudine and water molecules alternate into helical chains in the salicylate salt monohydrate. Lamivudine (b-L-29,39-dideoxy-39-thiacytidine, 3TC) is a nucleo- side reverse transcriptase inhibitor (NRTI) widely used in anti-HIV (human immunodeficiency virus) and anti-HBV (hepatitis B virus) therapies. 1 Lamivudine is a cytidine analog featuring an isosteric replacement of the ribose 39-methylene group with a sulfur atom. This drug has two chiral carbons, namely, C19 and C49, whose absolute configurations are S and R, respectively. As a consequence of its chirality, all known crystal structures of lamivudine have been solved in non-centrosymmetric space groups. This can be seen in the eleven crystal structures which have already been reported for lamivudine thus far, wherein seven of them were solved in the P2 1 monoclinic space group (form III, (a hemihydrate), 2 a 3,5-dinitrosalicylate salt hydrate with 2 : 1 : 1 lamivudine : 3,5-dinitrosalicylic acid : H 2 O lstoichiometry, 3 la 4-quinolinone cocrystal, 3 a zidovudine cocrystal hydrate with 1:1:1 lamivudine : zidovudine : H 2 O stoichiometry, 3 a lamivudine duplex with 8:2:2:1:4 lamivudine : maleic acid : HCl : (CH 3 ) 2 CHOH : H 2 O stoichiometry, 4 a hydrochloride salt anhydrate 5 and a hydrochloride salt monohydrate 5 ), three in the P2 1 2 1 2 1 orthorhombic space group (form I (a 0.2-hydrate), 6 a saccharinate salt, 7 and a hydrogen maleate salt 8 ) and one in the P4 3 2 1 2 tetragonal space group (form II, an anhydrous poly- morph). 6 As can be observed, this drug has been extensively investigated due to its ability to crystallize together with different small molecules in multicomponent molecular solid state phases. Recently, crystal engineering studies have focused on many drugs. 9 Concerning lamivudine, we designed a hydrogen maleate salt 8 by invoking physicochemical principles and recognizing key assembling frameworks in the antecedent structure of lamivudine saccharinate. 7 The choice of maleic acid to crystallize together with lamivudine was based on chemical and structural similarities to saccharin, such as the acid-ionization constant (pK a ) and intramolecular features including hydrogen bonding functionalities and stereochem- istry. Lamivudine hydrogen maleate was successfully obtained and a lamivudine saccharinate-like P2 1 2 1 2 1 orthorhombic structure was assumed by the designed salt. On the basis of packing and conformational similarities between hydrogen maleate and saccharinate versions of the drug, it was possible to point out a molecular motif present in both the maleic acid and saccharin counterions responsible for the crystal assem- bly of these two isostructural lamivudine salts. 8 As part of the ongoing studies in crystal engineering of molecular crystals of lamivudine, other salt formers were investigated in this study. Here, phthalic acid and salicylic acid were selected as salt formers. Their salts with lamivudine were prepared{ and structurally elucidated by single-crystal X-ray diffraction.§ The experimental X-ray powder diffractograms of the salts were overlaid onto the calculated results from their corresponding crystals structures." The observed Bragg peak positions are in good agreement with the simulated positions, although there are differences in the reflection intensities which resulted from the preferred orientation effects on the X-ray powder diffraction measurements of both salts (Fig. 1). Since neither a pronounced broad hump from an amorphous solid nor extra Bragg peaks from other crystalline phases other than that of the sample were observed in the experimental diffractograms, it a Instituto de Quı ´mica, Universidade Federal de Goia ´s, Campus Samambaia, CP 131, 74001-970, Goia ˆnia, GO, Brazil. E-mail: felipe@quimica.ufg.br; Fax: 55 62 3521 1167; Tel: 55 62 3521 1097 b Laborato ´rio de Cristalografia, Instituto de Quı ´mica, Universidade Federal de Alfenas, Unifal-MG, Rua Gabriel Monteiro da Silva 700, 37130-000, Alfenas, MG, Brazil c Instituto de Fı ´sica de Sa ˜o Carlos, Universidade de Sa ˜o Paulo, CP 369, 13560-970, Sa ˜o Carlos, SP, Brazil { Electronic supplementary information (ESI) available: CCDC reference numbers 871607 and 871608. See DOI: 10.1039/c2ce25386k CrystEngComm Dynamic Article Links Cite this: CrystEngComm, 2012, 14, 4562–4566 www.rsc.org/crystengcomm COMMUNICATION 4562 | CrystEngComm, 2012, 14, 4562–4566 This journal is ß The Royal Society of Chemistry 2012 Downloaded by UNIVERSIDAD SAO PAULO on 20 August 2012 Published on 25 April 2012 on http://pubs.rsc.org | doi:10.1039/C2CE25386K View Online / Journal Homepage / Table of Contents for this issue