pubs.acs.org/crystal Published on Web 11/10/2009 r 2009 American Chemical Society DOI: 10.1021/cg900790f 2009, Vol. 9 5283–5292 Crystal Engineering of an Anti-HIV Drug Based on the Recognition of Assembling Molecular Frameworks Felipe T. Martins, † Nikolas Paparidis, † Ant^ onio C. Doriguetto, ‡ and Javier Ellena* ,† † Instituto de Fı´sica de S~ ao Carlos, Universidade de S~ ao Paulo, CP 369, 13560-970, S~ ao Carlos, SP, Brazil and ‡ Departamento de Ci ^ encias Exatas, Universidade Federal de Alfenas, Rua Gabriel Monteiro da Silva 700, 37130-000, Alfenas, MG, Brazil Received July 10, 2009; Revised Manuscript Received October 28, 2009 ABSTRACT: 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 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 CdC 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. Introduction The solid state properties of an active pharmaceutical ingredient (API) should be understood because they are directly related to drug performance. Among all physical and chemical properties dependent on the crystalline or amorphous phase of a drug into a pharmaceutical solid dosage form, stability and solubility are those most investi- gated because they profoundly impact in bioavailability of a drug. 1 The establishment of relationships between solid-state properties and crystal structures is not easy. Most molecular structures do not exhibit similarities enough to correlate them with physical and chemical behaviors. Even though few significant advances in this sense have been made, improve- ments of API solid state property are achieved by crystal engineering. 2 Salts are particularly interesting to obtain solid- phase variants of an API with better functional characteris- tics. 3,4 Beyond low costs of production, some advantages in synthesizing API salts include practical preparation proce- dures, higher yield, reproducibility, and purity. 5,6 Recently, multicomponent molecular crystals have been widely screened for several classes of APIs, 6,7 including the anti-HIV drugs. 8,9 The anti-HIV APIs are classified into three main categories according to molecular mechanism of action and chemical backbone: the nucleoside reverse transcriptase inhibitors (NRTIs), the non-nucleoside reverse transcriptase inhibitors (NNRTIs) and the protease inhibitors (PI). 10 Today, single-drug therapy has been changed to a multiple- drug one wherein at least one NRTI is ever present. Lami- vudine (β-L-2 0 ,3 0 -dideoxy-3 0 -thiacytidine, 3TC) is one of the most clinically used NTRI in anti-HIV therapy, 11 being marketed under the brand name EPIVIR. 12 Lamivudine is also used as a NRTI against hepatitis B virus. 13 Structurally, lamivudine is a 2 0 -deoxygenated cytidine ana- log in which there is an isosteric replacement of the ribose 3 0 -methylene group by a sulfur atom. Concerning the config- uration of their two chiral centers, lamivudine is the biologi- cally active (-)-cis enantiomer, crystallizing always in non- centrosymmetric space groups. At least eight crystalline phases are reported for lamivudine: (1) form I, a 0.2-hydrate crystallizing as needles in the P2 1 2 1 2 1 orthorhombic space group with four water and twenty lamivudine molecules per unit cell, 14 (2) form II, an anhydrous polymorph crystallizing in the tetragonal space group P4 3 2 1 2 with eight molecules per unit cell, 14 which is the pharmaceutically preferred crystalline modification because of adequate manufacturing features of their bipyramidal single crystals, 15 (3) form III, a hemihydrate crystallizing in the monoclinic space group P2 1 with one water and two lamivudine molecules per unit cell, 16 (4) a sac- charinate salt crystallizing in the P2 1 2 1 2 1 space group with four (lamivudine) þ (saccharin) - ionic pairs per unit cell, 8 (5) a 3,5-dinitrosalicylate salt with two water and two neutral lamivudine molecules, two (lamivudine) þ cations and two (3,5-dinitrosalicylic acid) - anions per monoclinic unit cell (P2 1 space group), 9 (6) a cocrystal with 4-quinolinone formed by two lamivudine and two 4-quinolinone units per unit cell (monoclinic, P2 1 ), 9 and (7) a hydrated cocrystal with zidovu- dine stoichiometrically comprising one lamivudine, one zido- vudine and one water, in which there are two units of each species per monoclinic unit cell (P2 1 space group). 9 As part of our crystal engineering researches, design and synthesis of lamivudine crystal modifications have been performed. Most recently, we have prepared (8) lamivudine duplex, which is a double-stranded helix self-assembled due to helical *To whom correspondence should be addressed. E-mail: javiere@ifsc. usp.br. Phone: þ55 16 3373 8096. Fax: þ55 16 3373 9881.