Low-temperature study of a new nevirapine pseudopolymorph

The title compound (systematic name: 11-cyclopropyl-4-methyl-5,11-dihydro-6H-dipyrido[3,2-b:2′,3′-e][1,4]diazepin-6-one butanol 0.3-solvate), C15H14N4O·0.3C4H9OH, was crystallized in a new triclinic pseudopolymorphic form, a butanol solvate, and the crystal structure determined at 150 K. The molecular conformation of this new form differs from that reported previously, although the main intermolecular hydrogen-bond pattern remains the same. N—H⋯O hydrogen bonds [N⋯O = 2.957 (3) Å] form centrosymmetric dimers and the crystal packing of this new pseudopolymorph generates infinite channels along the b axis.


Related literature
For the crystal structure of an earlier polymorph, see: Mui et al. (1992). For spectroscopic studies of three further polymorphs, see: Reguri & Chakka (2005); World Health Organization (2005  As most of the NNRTIs, nevirapine displays a "butterfly like" conformation, which is also preserved in complexes with the HIV-1 reverse transcriptase [Ren et al., 1995]. Comparing the NVP conformations, it could be seen that the dihedral angle between the least square planes through the pyridine rings is 123.89 (9)°, somewhat larger than the one found by Mui et al., 121°, but still smaller than the one determined from the enzyme-inhibitor complex structure and ab initio calculations (129.22°) [Ayala et al., 2007].
An electron delocalization effect is presented by the amide moiety of the 7-membered ring, allowing this group to adopt a planar conformation with a C6-C5-N2-C4 torsion angle of −2.7 (4)° (slightly smaller than the one found for I, −4°) and to which the cyclopropyl substituent, evolving away from the molecular framework, subtends a dihedral angle of 68.5 (1)°.
The molecular superposition of I and V, calculated by minimizing the root square distance between the atoms of the 7-membered rings, shows that the main conformational differences are mainly concentrated in the cyclopropyl group, which presents C14-C13-N4-C10 and C15-C13-N4-C11 torsion angles of 81.9 (3)°, −69.9 (3)° in V, and 74.6°, −78.1° in I, respectively. In addiction, the superposition shows a small difference in conformation of the methyl substituted pyridine ring. The asymmetric unit in V is completed by the presence of a disordered butanol molecule with an occupation factor of 0.3.
The analysis of the intermolecular interaction shows that, like in I, NEV molecules are linked essentially by two N-H···O hydrogen bonds, forming centrosymmetric dimers.
It is interesting to note that the main difference between both polymorphs is related to the crystal packing: while in I the intermolecular interaction generates a close packing with flat layers of nevirapine molecules separated by less than 4.4 Å, in V the three-dimensional arrangement generates infinite channels along de b axis with a diameter of more than 10.5 Å ( Figure 2). These infinite channels are filled with highly disordered molecules of butanol, and this new Nevirapine form is stable even when a solvent occupation factor as low as 30%.
These findings indicate that a wide spectrum of new nevirapine pseudopolymorphs could be generated by just changing the solvent used in the crystallization process, as long as the volume of the solvent matches the available channel volume.
supplementary materials sup-2 Experimental NVP raw materials from different commercial sources were analyzed. USP standards of anhydrous and hemihydrate NEV were used as references.

Refinement
All the hydrogen atoms were observed in the difference Fourier map, but positioned stereochemically (