Solvent Inclusion by the Anti-HIV Drug Nevirapine: X-Ray Structures and Thermal Decomposition of Representative Solvates

Abstract

The preparation, X-ray crystal structures, and thermal analyses of five solvates of the non-nucleoside reverse transcriptase inhibitor Nevirapine are reported. Thermogravimetric traces for the solvates indicated the following compositions (N ) nevirapine): N • (ethyl acetate) 0.5 (1), N • (dichloromethane) 0.5 (2), N • (toluene) 0.5 (3), N • (water) 0.5 (4), and N • (1,4-dioxane) 1.5 (5). Centrosymmetric, hydrogen-bonded nevirapine dimers occur in the crystals of 1-3 and in a previously characterized, unsolvated form of the drug 6. In crystals of 4, drug molecules are linked by a single N-H • • • OdC hydrogen bond only, whereas solvate 5 contains noncentrosymmetric nevirapine dimers. Solvent molecules in 1-3 occupy channels, whereas the water molecules in 4 occupy isolated sites and 1,4-dioxane molecules in 5 occupy layers. These inclusion modes are described with reference to the thermal behaviors of the solvates recorded in TGA and DSC.

Channel inclusion of primary alcohols in isostructural solvates of the antiretroviral nevirapine: an X-ray and thermal analysis study

“…Comparison of these traces with those for the previously described solvates nevirapineÁ(ethyl acetate) 0.5 and nevirapineÁ(dichloromethane) 0.5 [2] enabled us to deduce a common isostructurality of the host lattice. Based on our previously reported crystallographic data, it was thus possible to deduce that the members of the present series of solvates, containing a homologous series of primary alcohols, crystallize in the triclinic space group P(-1) with predicted unit cell dimensions a *7.8 Å , b *8.4 Å , c *12.4 Å , a *86, b *88°, c *68°.…”

“…Based on our previously reported crystallographic data, it was thus possible to deduce that the members of the present series of solvates, containing a homologous series of primary alcohols, crystallize in the triclinic space group P(-1) with predicted unit cell dimensions a *7.8 Å , b *8.4 Å , c *12.4 Å , a *86, b *88°, c *68°. In addition, by analogy with the known structures [2], it was possible to deduce that the common features in solvates 2-7 are: (a) a practically invariant host (nevirapine) framework, composed of centrosymmetric, N-HÁÁÁO hydrogen-bonded dimers, and (b) a channel running parallel to the crystal b-axis which accommodates the solvent molecules. These predictions, based on isostructurality analogy, were confirmed by single crystal X-ray diffraction studies (see below) and led us to describe these solvates more accurately as a series of isostructural channel-inclusion compounds.…”

“…Potential advantages include, e.g., improved stability, favourable morphology, and more rapid dissolution. In a previous paper [2], we reported the tendency of nevirapine to form crystalline solvates and described the crystal structures and features of the thermal decomposition of a series of nevirapine solvates containing a variety of solvents, namely ethyl acetate, dichloromethane, toluene, 1,4-dioxane and water. While only the hemi-hydrate in that series would be considered to have direct pharmaceutical significance, the structural investigation of these solvates revealed unexpected solid-state features, inter alia association of the nevirapine molecules into diverse hydrogen-bonded motifs (centrosymmetric and non-centrosymmetric) as well as accommodation of certain of the guest solvent molecules within channels formed by the host superstructure.…”

Solvated Crystalline Forms of Nevirapine: Thermoanalytical and Spectroscopic Studies

“…The alternate solid forms may have improved solubility and dissolution properties. Nevirapine has been reported in three polymorphic forms (26,27) and as some solvates or hydrates (24,28,29). However, not much information is available on the thermal properties.…”

Crystal Forms of Anti-HIV Drugs: Role of Recrystallization

“…The authors have reported the crystal structure of two solvate forms of nevirapine, hemihydrate (NEV3) and hemiethylacetate (NEV4) (Figure 4). Caira et al have also reported five different solvates of nevirapine (Caira et al, 2008 Figure 5). However, in the toluene solvate containing a larger guest molecule, the host dimers are packed in a different mode, but the guest molecules are again situated in channels.…”