Salts of the anti-HIV drug lamivudine with phthalic and salicylic acids

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)(-) 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, crystallizing in the P2(1) monoclinic space group as a monohydrate whose (lamivudine)(+)(salicylic acid)(-) 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.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 - Universal 14/2011

Toward Novel Solid-State Forms of the Anti-HIV Drug Efavirenz: From Low Screening Success to Cocrystals Engineering Strategies and Discovery of a New Polymorph

Efavirenz is a first-line anti-HIV drug largely used as a non-nucleoside reverse transcriptase inhibitor as part of antiretroviral therapies. However, there are few reports on its solid-state structures and behaviors. Besides that, crystal engineering strategies have not been well-exploited for this drug and screening methods have been low promising as a source of new solid forms. To the best of our knowledge, only two efavirenz cocrystals have been reported thus far. On the basis of one of the two known cocrystals, namely, that with 4,4′-bipyridine, here we have used a rational approach for coformer selection and prediction of structurally defined multicomponent molecular crystals. Two 4,4′-bipyridine-like coformers, whose heterocycles are spaced by either an ethylene or an ethane moiety, were cocrystallized together with efavirenz into solid-state forms isostructural with respect to that of the drug cocrystal with the antecedent coformer. The formation of a three-molecule supramolecular entity based mainly on the NH hydrogen bonding donation from two efavirenz molecules to both pyridyl nitrogens of each coformer unit was kept in the three efavirenz cocrystals. Nevertheless, the introduction of the spacer groups in the coformers has altered the pattern of weak nonclassical hydrogen bonds of the type C–H···O and was also related to the formation of a π–π stacking interaction between pyridyl rings of the ethane-spaced coformer. In addition, a polymorphic form of the drug with only one molecule in the asymmetry unit of a <i>C</i>-centered monoclinic lattice is reported for the first time here. It resembles a known orthorhombic form also with <i>Z</i>′ = 1 in terms of conformation and assembly of helical hydrogen-bonded catemers, but their organization is unlike

Continuous Preparation of 1:1 Haloperidol–Maleic Acid Salt by a Novel Solvent-Free Method Using a Twin Screw Melt Extruder

Salts are generally prepared by acid–base reaction in relatively large volumes of organic solvents, followed by crystallization. In this study, the potential for preparing a pharmaceutical salt between haloperidol and maleic acid by a novel solvent-free method using a twin-screw melt extruder was investigated. The pH–solubility relationship between haloperidol and maleic acid in aqueous medium was first determined, which demonstrated that 1:1 salt formation between them was feasible (p<i>H</i>_max 4.8; salt solubility 4.7 mg/mL). Extrusion of a 1:1 mixture of haloperidol and maleic acid at the extruder barrel temperature of 60 °C resulted in the formation of a highly crystalline salt. The effects of operating temperature and screw configuration on salt formation were also investigated, and those two were identified as key processing parameters. Salts were also prepared by solution crystallization from ethyl acetate, liquid-assisted grinding, and heat-assisted grinding and compared with those obtained by melt extrusion by using DSC, PXRD, TGA, and optical microscopy. While similar salts were obtained by all methods, both melt extrusion and solution crystallization yielded highly crystalline materials with identical enthalpies of melting. During the pH-solubility study, a salt hydrate form was also identified, which, upon heating, converted to anhydrate similar to that obtained by other methods. There were previous reports of the formation of cocrystals, but not salts, by melt extrusion. ¹H NMR and single-crystal X-ray diffraction confirmed that a salt was indeed formed in the present study. The haloperidol–maleic acid salt obtained was nonhygroscopic in the moisture sorption study and converted to the hydrate form only upon mixing with water. Thus, we are reporting for the first time a relatively simple and solvent-free twin-screw melt extrusion method for the preparation of a pharmaceutical salt that provides material comparable to that obtained by solution crystallization and is amenable to continuous manufacturing and easy scale up