Solvent Inclusion by the Anti-HIV Drug Nevirapine - American

CRYSTAL GROWTH & DESIGN 2008 VOL. 8, NO. 1 17–23

Articles Part of the Special Issue “Facets of Polymorphism in Crystals.”

Solvent Inclusion by the Anti-HIV Drug Nevirapine: X-Ray Structures and Thermal Decomposition of Representative Solvates Mino R. Caira,*,† Nicole Stieger,‡ Wilna Liebenberg,‡ Melgardt M. De Villiers,§ and Halima Samsodien† Department of Chemistry, UniVersity of Cape Town, Rondebosch 7701, South Africa, Unit of Drug Research and DeVelopment, Faculty of Health Sciences, North-West UniVersity, Potchefstrom, South Africa, and School of Pharmacy, UniVersity of Wisconsin–Madison, Madison, Wisconsin ReceiVed June 8, 2007; ReVised Manuscript ReceiVed August 1, 2007

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. Introduction Nevirapine, a member of the dipyridodiazepinone class of anti-HIV drugs with the systematic name 11-cyclopropyl-5,11dihydro-4-methyl-6H-dipyrido[3,2-b:2′,3′-e][1,4]diazepin-6one (Figure 1), is a well-known synthetic non-nucleoside reverse transcriptase inhibitor (NNRTI) that is used in combination with other antiretrovirals to treat HIV-1 infection and AIDS.1 The drug is administered orally in the form of tablets containing nevirapine and as an oral suspension containing nevirapine hemihydrate. Our interest in this drug stems from both its recent, highly controversial history in the context of AIDS treatment in Africa2 as well as its unique chemical structure, which differs significantly from other commercially available NNRTIs. Specifically, from a crystal engineering viewpoint, the presence of the amide function CO–NH in the nevirapine * Corresponding author. Fax: 27 21 689 7499. Phone: 27 21 650 3071. E-mail: [email protected]. † University of Cape Town. ‡ North-West University. § University of Wisconsin–Madison.

molecule indicates the possibility of alternative modes of selfassociation, namely via a dimer or a catemer synthon,3 which would lead to crystal polymorphism, whereas interaction with solvent molecules having complementary donor and acceptor functions could result in the formation of solvates, significantly extending the solid-state chemistry of the drug. Solvents that do not have hydrogen bonding capacity could, in principle, also form solvates via enclathration by the host drug. Comprehensive studies aimed at exploring these possibilities for nevirapine are underway in our laboratories, driven by the continuing need to identify new solid forms of therapeutic agents and establish their structural and thermodynamic relationships. According to a recent patent,4 three polymorphs of nevirapine can be identified. More recently, in a study of nevirapine based on vibrational spectroscopy and quantum mechanical calculations,5 it was noted that the monographs of nevirapine included in the International and United States (XXIX) Pharmacopoeia refer to two crystalline forms of the drug, one of these being a hemihydrate.

10.1021/cg070522r CCC: $40.75  2008 American Chemical Society Published on Web 12/11/2007

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Caira et al.

Figure 1. Chemical structure of Nevirapine.

In this first report, we focus on the preparation and physicochemical characterization of five crystalline solvates of nevirapine, viz. nevirapine · (ethyl acetate)0.5 (1), nevirapine · (dichloromethane)0.5 (2), nevirapine · (toluene)0.5 (3),nevirapine · (water)0.5 (4), and nevirapine · (1,4-dioxane)1.5 (5). Crystals of 1–5 were analyzed by X-ray diffraction to establish the details of solvent inclusion in the crystals and by thermogravimetry (TGA) and differential scanning calorimetry (DSC) to determine their thermal stabilities, as well as to identify the polymorph(s) resulting from their desolvation. The modes of association of host nevirapine molecules

Figure 2. Morphologies of crystals 1–6. Crystal sizes range from 0.3 to 2.0 mm.

in crystals of the solvates are compared with that found in the crystal structure of an unsolvated form,6 which was

Table 1. Crystallographic Data and Experimental Details for Compounds 1–6 1 ratio

2:1 nevirapine: ethyl acetate

empirical formulaa fw T (K) wavelength (Å) cryst syst space group a (Å) b (Å) c (Å) R (deg) β (deg) γ (deg) V (Å3) Z dcalcd (Mg/m3) abs coeff (mm-1) cryst size (mm3) theta range for data collection index ranges no. of reflns collected no. of independent reflns completeness (%) abs corr max and min transmission refinement method data/restraints/params GOF on F2 final R indices [I > 2σ(I)] R indices (all data) largest diff peak and hole (e Å-3) a

2

3

4

5

6

2:1 nevirapine: toluene

2:1 nevirapine: water

2:3 nevirapine: 1,4-dioxane

nevirapine

H · (C4H8O2)0.5 310.35 113 ( 2 0.71073 triclinic P1j 7.7744(3) 8.4447(3) 12.4449(5) 84.610(3) 89.455(3) 68.243(2) 755.20(5) 2 1.365 0.093 0.08 × 0.08 × 0.07 1.00–25.68

2:1 nevirapine: dichloromethane H · (CH2Cl2)0.5 308.77 113 ( 2 0.71073 triclinic P1j 7.8021(2) 8.4374(2) 12.3320(4) 85.555(1) 88.437(1) 67.323(1) 746.79(4) 2 1.373 0.262 0.18 × 0.18 × 0.22 3.36–25.70

H · (C7H8)0.5 312.37 113 ( 2 0.71073 triclinic P1j 6.9121(1) 9.4512(1) 12.2050(2) 80.240(1) 91.056(1) 82.356(1) 778.12(2) 2 1.333 0.086 0.06 × 0.20 × 0.22 4.42–25.69

H · (H2O)0.5 275.31 113 ( 2 0.71073 monoclinic P21/n 8.7843(1) 31.8993(5) 9.9401(2) 90.0 104.10(1) 90.0 2701.43(8) 8 1.354 0.092 0.06 × 0.10 × 0.16 3.99–25.67

H · (C4H8O2)1.5 398.46 113 ( 2 0.71073 monoclinic P21/n 13.2678(1) 12.4358(1) 24.0672(3) 90.0 93.544(1) 90.0 3963.39(7) 8 1.336 0.094 0.15 × 0.18 × 0.25 3.03–26.03

H 266.30 113 ( 2 0.71073 monoclinic P21/c 6.9177(2) 18.7759(5) 9.6075(3) 90.0 97.026(1) 90.0 1238.51(6) 4 1.428 0.094 0.15 × 0.20 × 0.22 3.16–25.69

-9 e h e 9 -10 e k e 10 -13 e l e 15 5386 2848 [R(int) ) 0.0245] 93.3 None 0.9935 and 0.9926 full-matrix least-squares on F2 2848/14/255 1.086 R1 ) 0.0527

-9 e h e 9 -10 e k e 10 -15 e l e 15 16395 2813 [R(int) ) 0.0555] 98.9 none 0.9544 and 0.9447 full-matrix least-squares on F2 2813/0/210 1.083 R1 ) 0.0748





wR2 ) 0.1425 R1 ) 0.0775 wR2 ) 0.1569 0.835 and -0.319

wR2 ) 0.2004 R1 ) 0.0986 wR2 ) 0.2185 1.022 and -0.758

wR2 ) 0.0969 R1 ) 0.0440 wR2 ) 0.1035 0.196 and -0.201

wR2 ) 0.1000 R1 ) 0.0829 wR2 ) 0.1117 0.340 and -0.228

wR2 ) 0.0874 R1 ) 0.0704 wR2 ) 0.0973 0.222 and -0.298

wR2 ) 0.0825 R1 ) 0.0408 wR2 ) 0.0826 0.226 and -0.207

H ) host drug molecule, C15H14N4O.

Solvent Inclusion by Anti-HIV Drug Nevirapine

Crystal Growth & Design, Vol. 8, No. 1, 2008 19

Figure 3. Perspective view and atomic numbering of the nevirapine molecule as it occurs in the unsolvated form 6. Thermal ellipsoids are drawn at the 50% probability level.

redetermined in our laboratory at low temperature and designated Form I (6). In an earlier analogous study of the anthelmintic drug Niclosamide,7 we reported that its solvates exhibit typical properties of clathrates, with solvent molecules occupying isolated sites, channels, or layers. Experimental Section Crystal Preparation and Preliminary Characterization. Nevirapine was supplied by Cipla Ltd. (batch 1001003, Mumbai, India). Generally, saturated solutions of the raw material were prepared by adding the requisite amount of drug to the respective neat solvents with heating to a few degrees below the boiling point of the solvent and continuous stirring. For preparation of solvate 4, the recrystallization medium was a methanol:water solution (1:1 v/v). The hot, saturated solutions were filtered (45 µm) and allowed to crystallize at ∼20 °C. All crystal samples were kept under mother liquor prior to analysis. A Mettler Toledo TG/SDTA 851e was used for TGA measurements, and DSC data were recorded on a Perkin Elmer PC-7 Series System and a Mettler Toledo DSC 823e instrument. Samples in the range 3–6 mg were placed in alumina crucibles for TGA and in vented Al pans for DSC. A heating rate of 10 K min-1 was generally employed with a nitrogen purge flow rate of 30 mL min-1. All instruments were calibrated with high-purity indium and zinc standards. Single-Crystal X-ray Diffraction. Intensity data were collected on a Nonius Kappa CCD diffractometer using graphite-monochromated MoKR radiation. Single crystals of 1–6 were mounted on cryogenic loops using Paratone N oil (Exxon) and exposed to a continuous stream of nitrogen vapor from a Cryostream cooler (Oxford Cryosystems, U.K.). Suitable combinations of φ- and Ω-scans based on strategies indicated by the program COLLECT8 were employed. Unit-cell refinement and data reduction were performed with DENZO-SMN.9 Structures were solved using SHELX-8610 and refined by full-matrix least-squares on F2 using SHELXL-9711 via the program interface X-Seed.12 Details of the treatment of solvent disorder accompany descriptions of individual structures below. Non-hydrogen atoms were generally refined anisotropically and H atoms isotropically in a riding model with Uiso values 1.2–1.5 times those of their parent atoms. Table 1 lists data collection and refinement details. Powder X-ray Diffraction. PXRD data were collected on a Huber Imaging Plate Guinier Camera 670 employing Ni-filtered CuKR1 radiation (λ ) 1.5405981 Å) produced at 40 kV and 20 mA by a Philips PW1120/00 generator fitted with a Huber long fine-focus tube PW2273/ 20 and a Huber Guinier Monochromator Series 611/15. Sample materials were gently ground (under mother liquor in the case of solvates) and the resulting fine powders were packed into Lindemann

Figure 4. Top: Perspective view of the centrosymmetric H-bonded nevirapine dimer occurring in solvates 1–3 and in unsolvated nevirapine 6. Bottom: The noncentrosymmetric dimer in solvate 5. Thermal ellipsoids are drawn at the 50% probability level. capillaries for multiple-scan data-collections with exposure times of 10–60 min over the 2θ range 4–100° with a step size of 0.005° in 2θ.

Results and Discussion Crystal Morphologies. Micrographs of crystals 1–6 are shown in Figure 2. Solvates 1 and 2 occur as triclinic blocks, 3 as tabular crystals, 4 as striated tabular crystals, 5 as massive prismatic aggregates, and 6 as columnar crystals. General Structural Features and Host Assembly in 1–6. Figure 3 shows the structure of the nevirapine molecule as it occurs in the unsolvated form 6. Principal molecular features are the “butterfly” conformation, with the pyridine rings intersecting at an acute angle (φ) of 58.14(4)°, and the adoption of a boat conformation by the seven-membered ring. These features correspond with those reported for the room-temperature

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Table 2. Hydrogen Bond Data for Compounds 1–6a compd

D–H · · · A

1 2 3 4

N2–H2 · · · O8i N2–H2 · · · · · · O8i N2–H2 · · · O8i N2A–H2A · · · O8B N2B–H2B · · · O21ii O21–H21A · · · N13A O21–H21B · · · O8Aiii N2A–H2A · · · O8B N2B–H2B · · · O8A N2–H2 · · · O1i

5 6

d(D–H) d(H · · · A) d(D · · · A) ∠(DHA) (Å) (Å) (Å) (deg) 0.88 0.88 0.88 0.88 0.88 0.95(4) 0.92(3) 0.88 0.88 0.88

2.02 2.02 2.01 2.02 1.99 1.87(4) 1.94(3) 2.03 1.96 2.05

2.900(2) 2.897(3) 2.884(1) 2.888(2) 2.760(2) 2.801(2) 2.845(2) 2.898(1) 2.838(1) 2.914(1)

174 172 170 168 145 166(3) 171(3) 169 172 167

a Symmetry transformations used to generate equivalent atoms: i 1 – x, 1 – y, 1 – z; ii 1/2 + x, 1/2 – y, -1/2 + z; iii: 1/2 + x, 1/2 – y, 1/2 + z; iv -1/2 + x, 1/2 – y, 1/2 + z.

Figure 5. Stereoview of the hydrogen-bonding scheme in the hemihydrate 4 (symmetry operations are listed under Table 2).

structure of the same crystal form,6 where the “butterfly angle was quoted as 121° (i.e., φ ) 59°). Examination of the seven crystallographically independent nevirapine host molecules present in the solvates studied here reveal that they maintain this conformation, with φ in the narrow range 53.14(6)–57.25(4)°. The amide group is generally planar, with the torsion angle range of 3.2(3)–6.4(3)° for C3–N2–C1–C7 for all species (excluding solvate 5) indicating little flexibility in the conformation of the seven-membered ring. In solvate 5, some distortion accompanies host assembly, as described below. The cyclopropyl ring, directed toward the convex face of the tricyclic system, is invariably orientated symmetrically as shown in Figure 3. The host nevirapine molecules assemble in three distinct modes in crystals 1–6. In the solvates 1–3 (with 2:1 host–guest stoichiometry) and in the unsolvated crystal 6 (Form I), the nevirapine molecules are present in the form of centrosymmetric, hydrogen-bonded (N–H · · · OdC) dimers. Figure 4 (top) shows the structure of the centrosymmetric dimer occurring in solvate 1 as representative and Table 2 lists hydrogen-bond data. In isostructural solvates 1 and 2, containing ethyl acetate and dichloromethane, respectively, these dimers pack in identical fashion, generating continuous channels parallel to the b-axis that accommodate the solvent molecules. However, in solvate 3, containing a larger guest molecule (toluene), the host dimers pack in a different mode, but with guest molecules again situated in channels. Aspects related to solvent inclusion are discussed in more detail below.

Figure 6. Inclusion of ethyl acetate molecules within channels parallel to [010] in crystals of solvate 1. The host arrangement in solvate 2 is identical to that shown here.

Figure 4 (bottom) shows the hydrogen-bonded dimer present in solvate 5 containing 1,4-dioxane, with H:G stoichiometry 2:3. This dimer is unique in the series, being composed of two crystallographically independent molecules (A, B) of the same handedness. The dimer as a whole has a distinctly concave shape, the cyclopropyl residues being in a syn-relationship. It is in this solvate specifically that the torsion angle C3–N2–C1–C7 has the largest values, namely, 16.3(2) and 14.8(2)° for nevirapine molecules A and B, respectively. These distortions are associated with small changes in the conformations of the seven-membered rings that accompany formation of this particular dimer, yielding two distinct N–H · · · OdC hydrogen bonds (Table 2). Finally, the hemihydrate 4 is the only solvate in which the host molecules do not form dimers of the type found in the other species. The asymmetric unit comprises two molecules of nevirapine (A, B) and one water molecule (Figure 5). Only one hydrogen bond (N–H · · · OdC) links two host molecules directly. Water molecules serve as bridges between such pairs of host molecules, with each water molecule engaging in three hydrogen bonds(as donor in OH · · · N(pyridine) and OH · · · OdC, and as acceptor in N–H · · · OH2, Table 2).

Table 3. Thermal Data for Compounds 1–5 solvate

guest

guest b.p. (°C)

DSC Ton (°C)

∆t (°C)

exp. TG mass loss (%)

calcd TG mass loss (%)

H:G ratio

1 2 3 4 5

ethyl acetate dichloromethane toluene water 1,4-dioxane

77 40 111 100 101

119 98 93 125 63

+42 +58 -18 +25 -38

13.4 13.1 14.4 3.6 32.8

14.2 13.8 14.7 3.3 33.2

2:1 2:1 2:1 2:1 2:3


Crystal Growth & Design, Vol. 8, No. 1, 2008 21

Figure 7. Inclusion of disordered toluene molecules within channels parallel to [100] in crystals of solvate 3.

Figure 9. Inclusion of 1,4-dioxane molecules in solvate 5 viewed along [100] (top) and [001] (bottom).

Figure 8. Inclusion of water molecules in nevirapine hemihydrate 4 viewed down [001].

In summary, even within this relatively small sample of solvated forms of nevirapine, the drug molecule displays significant variability in its modes of self-assembly when accommodating solvent molecules from various classes. Details of Guest Inclusion and Thermal Stabilities of 1–5. Crystallographic modeling of the guest molecules in the solvates was guided by the host–guest stoichiometries indicated from thermogravimetry (Table 3). As a measure of relative

thermal stability, Table 3 also lists the quantity ∆t ) ton - tb, the difference between the DSC desolvation onset temperature and the boiling point of the pure solvent.13 The asymmetric unit in the ethyl acetate solvate 1 comprises one nevirapine molecule and an ethyl acetate molecule with site-occupancy 0.5. The latter molecule is extended parallel to the crystal b-axis with its termini located near centers of inversion, thus giving an apparent continuum of solvent molecules in a channel. Figure 6, a view parallel to the channel direction, shows that the channel walls are constructed from centrosymmetric nevirapine dimers. In the solvate 2 (isostructural with 1 with respect to the host assembly), the asymmetric unit comprises one nevirapine molecule and a half-molecule of CH2Cl2. Whereas the ethyl acetate molecules in 1 could be clearly resolved, the CH2Cl2 molecules in 2 were found to be severely disordered around a center of inversion. The model for the solvent in the asymmetric unit, (CH2Cl2)0.5, included two disordered C atoms, each with site-occupancy factor (s.o.f.) 0.25, three Cl atoms with s.o.f. 0.25 each, and two Cl atoms with s.o.f. 0.125 each. This extensive disorder, common for the dichloromethane molecule, prevented addition of H atoms to the model. As the host arrangement in solvate 2 is identical to that in the ethyl acetate solvate 1, the dichloromethane molecules likewise form a quasi-

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Inclusion of 1,4-dioxane molecules in solvate 5 is shown in Figure 9. The solvent molecules are assembled in layers (Figure 9, top) such that within a layer, each nevirapine dimer is encircled by an elliptical belt comprising six contiguous 1,4-dioxane molecules (Figure 9, bottom). The three crystallographically independent 1,4-dioxane molecules engage in several C–H · · · O hydrogen bonds with C · · · O in the range 3.383(2)–3.537(2) Å. These interactions are quite heterogeneous, comprising four host–guest and one guest–guest interaction, the oxygen atoms of the solvent molecules generally acting as acceptors, and in one case, a solvent methylene group acting as a donor. Consequently, in contrast to the other solvates, whose thermal profiles generally display one-step desolvation, solvate 5 displays a more complex thermal profile, namely, a distinctly biphasic behavior in its TGA trace (Figure 10, top). The endotherm for solvent loss in the DSC trace (Figure 10, bottom) likewise shows subsidiary peaks indicating a complex mass loss event. The TGA trace indicates that about one-half of the 1,4-dioxane content is lost in the temperature range 70–104 °C, and the other half in the range 104–115 °C. Desolvation of all of the solvates reported here yielded the polymorph 6. This was demonstrated by recording the PXRD traces of the desolvated materials and finding that they correspond with the computed PXRD pattern for 6 (not shown). The temperature range for fusion of the desolvated products was 246–248 °C. A melting range of 247–249 °C for nevirapine has been reported in the literature.15 Conclusions Figure 10. TGA trace (top) and DSC trace (bottom) for the 1,4-dioxane solvate 5.

continuous array within the channels running parallel to [010]. Both 1 and 2 desolvate at significantly higher temperatures than those of their respective boiling points (Table 3, ∆t . 0). This common feature is consistent with their isostructurality. In 1, the guest carbonyl O atom engages in a (host cyclopropyl) C–H · · · O H-bond. (For 2, guest disorder prevented modeling of its H atoms). Space-filling diagrams indicate that the polar guest molecules in 1 and 2 fill the channels very efficiently and calculation reveals that the crystals contain negligible solventaccessible void space.14 The asymmetric unit in the toluene solvate 3 contains onehalf-of a guest molecule. This was found to be disordered around a center of inversion over two distinct positions, each with s.o.f. 0.25. Despite some similarity between the unit-cell parameters of the toluene solvate 3 and those of solvates 1 and 2 (Table 1), a significantly different host-packing arrangement occurs in 3 (Figure 7), presumably because of a significant increase in the size of the guest molecule. Toluene molecules are in van der Waals contact within the channels running parallel to [100] but the crystals of 3 desolvate fairly readily (Table 3, ∆t < 0), an effect that is consistent with the lack of host–guest H-bonding and guest channel occupation. Quantitative comparison with the desolvation data for 1 and 2 is not, however, warranted because of the different supramolecular host assembly in 3. The hydrogen-bonding role of water molecules in nevirapine hemihydrate 4 was illustrated earlier (Figure 5). The location of water molecules in isolated sites is evident in Figure 8, which shows an extended diagram of the projection down [001]. These structural features are consistent with the relatively large value of ∆t for 4 (Table 3).

The first substantial data relating to the effect of different included solvents on nevirapine molecule association in the solid state are reported here. Centrosymmetric, hydrogenbonded (N–H · · · OdC) nevirapine dimers that occur in an unsolvated form of nevirapine6 also occur in its solvates with ethyl acetate, dichloromethane, and toluene. However, in the hemihydrate of nevirapine, hydrogen-bonding competition from included water molecules disrupts this arrangement, resulting in only a single N–H · · · OdC hydrogen bond linking a pair of drug molecules. The solvate containing 1,4-dioxane is unique in both structure and thermal behavior, containing noncentrosymmetric drug dimers and desolvating in two distinct steps. The ethyl acetate and dichloromethane solvates of nevirapine, with isostructural host frameworks, display similar thermal behavior. Despite the variety of solvent inclusion modes in crystals of representative solvates of nevirapine reported here, as well as the different dimeric nevirapine motifs identified, desolvation leads to a common polymorph of the drug. Other aspects of the solid-state chemistry of nevirapine, including its polymorphism, other forms of supramolecular association, and pharmaceutically relevant properties are under investigation in our laboratories. Acknowledgment. We are grateful to the University of Cape Town, North-West University (Potchefstroom campus), and the NRF for research support. Thanks are due to Dyanne Cruickshank for technical assistance. Note Added in Proof. While the proofs of this paper were in preparation, it came to the authors’ attention that the crystal structures and characterization of solvates 1 and 4 reported in this paper were published on the Web on September 11, 2007. See Pereira, B. G.; Fonte-Boa, F. D.; Resende, J. A. L. C.; Pinheiro, C. B.; Fernandes, N. G.; Yoshida, M. I.; Vianna-


Soares, C. D. Polymorphs and Intrinsic Dissolution of Nevirapine. Cryst. Growth Des. 2007, 7 (10), 2016--2023. Supporting Information Available: X-ray crystallographic information for the six crystal structures (PDF); they have also been deposited with the Cambridge Crystallographic Data Centre, CCDC Nos. 649751–649756. This material is available free of charge via the Internet at http://pubs.acs.org.

References (1) Pedersen, O. S.; Pedersen, E. B. AntiViral Chem. Chemother. 1999, 10, 285–314. (2) http://www.aidsnews.org/2004/12/nevirapine-ap.html (Accessed 05/ 29/2007) (3) McMahon, J. A.; Bis, J. A.; Vishweshwar, P.; Shattock, T. R.; McLaughlin, O. L.; Zaworotko, M. J. Z. Kristallogr. 2005, 220, 340– 350. (4) Reguri, B. R.; Chakka, R. U.S. Patent 2005059653, March 17, 2005. (5) Ayala, A. P.; Siesler, H. W.; Wardell, S. M. S. V.; Boechat, N.; Dabbene, V.; Cuffini, S. L. J. Mol. Struct. 2007, 828, 201–210.

Crystal Growth & Design, Vol. 8, No. 1, 2008 23 (6) Mui, P. W.; Jacober, S. P.; Hargrave, K. D.; Adams., J. Med. Chem. 1992, 35, 201–202. (7) Caira, M. R.; Van Tonder, E. C.; De Villiers, M. M.; Lotter, A. P. J. Inclusion Phenom. Mol. Recognit. Chem. 1998, 31, 1–16. (8) Hooft, R. Collect; Nonius B. V.: Delft, The Netherlands, 2002. (9) Otwinowski, Z.; Minor, W. Methods Enzymol. 1997, 276, 307–326. (10) Sheldrick, G. M. In Crystallographic Computing; Sheldrick, G. M., Kruger, C., Goddard, R., Eds.; Oxford University Press: Oxford, U.K., 1985; Vol. 3, p 175. (11) Sheldrick, G. M. SHELXL-97, Program for Crystal Structure Refinement; University of Göttingen: Göttingen, Germany. (12) Barbour, L. J. J. Supramol. Chem. 2003, 1, 189–191. (13) Caira, M. R. Nassimbeni, L. R. In ComprehensiVe Supramolecular Chemistry; Atwood, J. L., Davies, J. E. D., McNicol, D. D., Vögtle, F., Eds.; Pergamon: Oxford, U.K.; Vol. 6,Chapter 25, pp 825–850. (14) Spek, A. PLATON. A Multipurpose Crystallographic Tool; Utrecht University: Utrecht, The Netherlands, 2005; http://www.cryst.chem.uu.nl/ platon/, http://www.chem.gla.ac.uk/∼louis/software/platon. (15) Budavari, S., Ed. The Merck Index, 12th ed.; Merck & Co.: Whitehouse Station, N.J., 1996; p 1114.

CG070522R

Solvent Inclusion by the Anti-HIV Drug Nevirapine - American

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