New Solid State Forms of the Anti-HIV Drug Efavirenz. Conformational

DOI: 10.1021/cg100342k

New Solid State Forms of the Anti-HIV Drug Efavirenz. Conformational Flexibility and High Z 0 Issues

2010, Vol. 10 3191–3202

Sudarshan Mahapatra, Tejender S. Thakur, Sumy Joseph, Sunil Varughese, and Gautam R. Desiraju* Solid State and Structural Chemistry Unit, Indian Institute of Science, Bangalore 560 012, India Received March 16, 2010; Revised Manuscript Received May 5, 2010

ABSTRACT: Structural information on the solid forms of efavirenz, a non-nucleoside reverse transcriptase inhibitor, is limited, although various polymorphic forms of this drug have been patented. We report here structural studies of four new crystal forms;a pure form, a cyclohexane solvate, and cocrystals with 1,4-cyclohexanedione and 4,40 -bipyridine. Temperature dependent single-crystal to single-crystal phase transitions are observed for the pure form and for the cyclohexane solvate with an increase in the number of symmetry independent molecules, Z 0 , upon a lowering of temperature. Other issues related to these solid forms, such as thermal stability, conformational flexibility, and high Z 0 occurrences, are addressed by using a combined experimental and computational approach.

*Telephone: þ91 80 22933311. E-mail: [email protected]. Fax: þ91 80 23602306.

drug that belongs to the category of non-nucleoside reverse transcriptase inhibitors (NNRTI).6 The high efficacy and low dosage requirement of efavirenz has made it an attractive candidate for a highly active antiretroviral therapy for the treatment of HIV infection in recent years.7 There are not many structural reports available on the various polymorphic forms of 1, although such forms have been patented.8 There is also some ambiguity about the actual number of solid forms (polymorphs and solvates) of the API, their methods of preparation, and their properties. Indeed, none of the existing patents contain indexed powder patterns of 1; in the worst cases, they do not even contain 2θ versus relative intensity information. Two polymorphs have been recently reported in the open literature: the first by Tiekink et al. and the second one by Ravikumar et al.9 However, these forms do not correspond to the stable form patented by DuPont (form 1). Interestingly, there is no structural information available on this stable form.8g The patent literature shows that all the polymorphs revert to form 1 under some condition or the other (Supporting Information). Here, we report the first structural analysis on form I (which is equivalent to form 1 mentioned in patent WO 99/644058g) and its temperature induced phase transition. Besides form I, we have identified and structurally characterized a cyclohexane solvate of efavirenz and cocrystals of the API with 1,4-cyclohexanedione and 4,40 -bipyridyl. These cocrystals and solvate were difficult to isolate, and screening methods have low hit rates for this particular API. During the course of this work, we noted that these structures give insights into some interesting topics in crystal engineering. Structures with Z0 > 1 are often kinetic forms as opposed to the most stable thermodynamic form. Therefore, a systematic analysis of molecular crystals with Z0 > 1 is interesting because such an analysis may provide clues as to the nature of the crystallization pathway.10 While crystals with Z0 > 1 have been described as “crystals on the way”, as “snapshot pictures at different stages of crystallization”, or as “fossil relics of the fastest growing crystal nucleus”, our knowledge of this phenomenon is, at best, restricted to the conclusion that Z0 > 1 is just one of the many options that organic molecules can exercise during the highly complex and seemingly mysterious process of

r 2010 American Chemical Society

Published on Web 05/25/2010

Introduction The majority of active pharmaceutical ingredients (APIs) are administered as solids because it is convenient to store a drug in its solid form.1 APIs exist in various solid forms such as polymorphs, solvates, salts, cocrystals, and amorphous solids, and these forms exhibit varying physicochemical properties.2 The effects of structure on the stability, bioavailability, and manufacturability of drug products have attracted the attention of both academic and industrial researchers.3 Accordingly, the discovery of new polymorphs and solvates is an important element in strategies toward successful development of marketable drugs. The study of polymorphism and cocrystallization also has the potential of increasing our fundamental understanding of phenomena such as crystallization and molecular recognition.4 Identification and isolation of the thermodynamically most stable form of an API is of strategic importance in these efforts. Any phase change during the storage and transportation of a drug may lead to serious issues related to the bioavailability, safety, and efficacy of the drug. The postmarketing phase transition exhibited by ritonavir (caused by conformational polymorphism), that leads to the formation of a therapeutically inefficient stable form, is an example of how an undesirable solid state transformation can cause havoc.5 Such occurrences are economically debilitating and need to be avoided at all costs.

Efavirenz, (4S)-6-chloro-4-(2-cyclopropylethynyl)-4-(trifluoromethyl)-2,4-dihydro-1H-3,1-benzoxazin-2-one (1), is a

pubs.acs.org/crystal

3192

Crystal Growth & Design, Vol. 10, No. 7, 2010

Mahapatra et al.

Scheme 1. The Temperature Cycle Employed for the Phase Transition Studies of I and II

crystallization.11 The literature provides examples of various parameters;packing difficulties, pseudosymmetry, synthon frustration, and equi-energetic conformations;that contribute to the generation of high Z0 structures.12 Experimental Section Materials. Efavirenz was obtained from Hetero Drugs Ltd., Hyderabad, India, and was used without further purification. Crystallization. Efavirenz Form I. Class 2 and class 3 solvents and their mixtures with varying polarity were tried for the crystallization of 1. Efavirenz is highly soluble in most organic solvents, and this causes a major problem. All attempts to grow crystals from a wide variety of solvents such as acetone, acetonitrile, carbon tetrachloride, chloroform, diethyl ether, ethanol, methanol, DMSO, DMF, THF, and toluene failed, and so mixtures of solvents were tried by layering a solution of efavirenz over an antisolvent or precipitant. The layering method was tried with various solvents that are miscible with water (precipitant). In the end, fine needleshaped crystals were obtained at the interface of an acetonitrilewater solvent system. Crystals were also obtained from a THF-water mixture, and the unit cell dimensions were consistent with those obtained from a MeCN-water mixture. These crystals correspond to form I of efavirenz. Efavirenz-Cyclohexane 4:1 Solvate, Form II. Efavirenz (100 mg) was dissolved in 5 mL of cyclohexane by heating to 60 C with constant stirring. The solution was filtered and was kept for crystallization without any disturbance. Rectangular blocks of the efavirenzcyclohexane solvate (form II) were obtained after 2 days. Efavirenz-1,4-cyclohexanedione 4:3 Molecular Complex, Form III. Solvent drop grinding of a 1:1 molar mixture of efavirenz (0.078 g) and 1,4-cyclohexanedione (0.028 g) with the addition of four drops of n-heptane yielded a colorless solid with an entirely different powder diffraction pattern, indicating the formation of a possible cocrystal. The mixture was dissolved in n-heptane (20 mL) at 80 C with constant stirring and then filtered and kept for crystallization. Crystallization yielded only a colorless powder, and this may be due to the immediate supersaturation attained by the solution due to the reduced solubility of the cocrystal in n-heptane. To increase the solubility, we added varying amounts of THF to the hot saturated solution. We observed that 20% THF in n-heptane is the optimum mixture for crystallization, as an increased amount of THF reduces the yield of the product. Long needles of the cocrystal were obtained over a period of 7 days. Efavirenz-4,40 -bipyridyl 2:1 Molecular Complex, Form IV. The colorless mixture of equimolar amounts of efavirenz (0.078 g) and 4,40 -bipyridyl (0.039 g) obtained by solvent drop grinding (using THF as the solvent) was dissolved in 10 mL of THF at room temperature. Single crystals of the 2:1 molecular complex were obtained after 3 days. Differential Scanning Calorimetry (DSC). DSC data were recorded on a Mettler Toledo DSC 823e instrument. Heating of the sample was done at a rate of 10 K/min up to 160 C with the purging of dry nitrogen gas (20 mL/min).

Powder X-ray Diffraction (PXRD). All X-ray powder diffraction data were collected on a Philips X’pert Pro X-ray powder diffractometer equipped with an X’cellerator detector using the 2θ scan range, step size, and exposure time, 3-60, 0.02, and 1200 s/step, respectively. Single-Crystal X-ray Diffraction. Single-crystal data for the efavirenz crystal forms were collected on an Oxford single-crystal X-ray diffractometer (Microsource: Mova; Detector: Eos) with a liquid nitrogen cooling and heating facility. A number of data sets were collected at various temperatures (100-298 K) to study the single-crystal to single-crystal phase transition behavior, and the structures were solved with direct methods.13-15 The details of the cycles of heating and cooling on a single crystal of form I and the cyclohexane solvate (II) are given in Scheme 1, where the green boxes signify the collection of a single-crystal data set in the specified condition, and the red boxes signify the instances where a unique solution was not obtained. Data were collected for cocrystal III on a Rigaku Mercury375R/M CCD (XtaLAB mini) diffractometer using graphite monochromated Mo KR radiation, equipped with a Rigaku low temperature gas spray cooler. In these cases, data were processed with the Rigaku CrystalClear software.16 Structure solution and refinements were performed using SHELX9715 using the WinGX suite.17 The ORTEP diagrams and the additional powder diffraction patterns are provided in the Supporting Information. Computational Details. All geometry optimizations were performed with the Gaussian 0318 package, employing density functional theory (DFT) with the hybrid B3LYP functional19 at the 6-31þþG(d,p) basis set. Optimization was performed using the direct inversion of iterative subspace (GDIIS) method20 with tight convergence criteria (threshold values: maximum force = 0.000015 a.u.; rms force = 0.000010 a.u.; maximum displacement = 0.000060 a.u.; rms displacement = 0.000040 a.u.). A potential energy surface (PES) scan for the cyclopropyl group rotation was performed using the preoptimized efavirenz structure as an input, and the scan was performed at the B3LYP/6-31þþG(d,p) level of theory for the torsion angle range -180 to 180 with a step size of 5.

Results and Discussion We discuss the solid forms of efavirenz under the categories of polymorphs, solvate, and cocrystals, and also in terms of their phase transitions. Crystalline Forms of Efavirenz. The high solubility of efavirenz (1) in practically all common organic solvents makes it difficult to crystallize, and most of the time, a white polycrystalline residue was obtained. As the structural information on many of the patented forms is still not known, we initiated an exhaustive and systematic study to obtain novel solid state forms of 1 and studied their phase transitions. We obtained a new nonsolvated crystalline form (I), a cyclohexane solvate (II), and cocrystals with 1,4-cyclohexanedione (III) and 4,40 -bipyridyl (IV) (Scheme 2).

IV III

2(C14H9ClF3NO2):1.5(C6H8 O2) 768815 monoclinic C2 23.179(5) 7.187(1) 21.672(4) 90 91.91(3) 90 3608(1) 4 1.472 150(2) 0.263 50.00 15783 6352 0.1191 5279 487 1.095 0.0665 0.1708 4(C14H9ClF3NO2):1(C6H12) 767758 monoclinic C2 51.107(1) 8.720(1) 13.454(1) 90 93.260(2) 90 5986.1(8) 4 1.481 150(2) 0.294 58.46 24508 12774 0.0223 10346 820 0.991 0.0406 0.0946

IIa II

2(C14H9ClF3NO2):0.5(C6H12) 767757 monoclinic C2 13.665(3) 8.836(2) 26.370(6) 90 100.690(4) 90 3129 (1) 4 1.425 298(2) 0.282 50.06 11376 5474 0.0292 3230 432 0.872 0.0416 0.0922 C14H9ClF3NO2 767884 monoclinic P21 9.607(1) 27.159(2) 16.911(2) 90 104.620(8) 90 4269.5(6) 12 1.469 180(2) 0.304 58.60 26421 17077 0.1011 5236 1135 0.763 0.0738 0.1336

Ia I

Table 1. Crystallographic and Structure Refinement Details for the Various Solid State Forms of 1 Reported in This Study

Crystal Structure of Form I. Form I of efavirenz crystallizes in the space group P21212 (Table 1), with three molecules in the asymmetric unit. The structure solution of the form I crystal was not straightforward, as the (00l ) intensities were not intense enough to allow one to differentiate between P212121 and the uncommon space group P21212. Careful analysis of the hkl file led to the conclusion that the space group is P21212. Indeed, the structure solution was impossible in the space group P212121. The molecules exhibit a noticeable degree of conformational disorder in the cyclopropyl group, as indicated by large thermal ellipsoids. Only for one of the three molecules of 1 was the disorder clearly separable into the two cyclopropyl conformations and hence capable of being modeled. In the crystal, the molecules make double stranded helices (synthon A, Scheme 2) stabilized by N-H 3 3 3 O hydrogen bonds with three symmetry independent molecules per turn (Figure 1a). The geometries of these N-H 3 3 3 O hydrogen bonds are almost equivalent, and this gives an impression of a 31 screw symmetry, when the structure is viewed down the c-axis. The helices undergo self-assembly to yield a hexagonal close-packed structure in the three-dimensional arrangement (Figure 1b). Interaction geometries for the various intermolecular contacts are given in Table 2. As per the DuPont patent WO 99/64405, five different polymorphic forms (forms 1, 2, 3, 4, and 5) of efavirenz were claimed.8g This patent reported that form 1 is the most thermodynamically stable form, with a melting point of about 138-140 C, which is the highest of all the forms. The four other forms can be converted to form 1, by applying various reported conditions. Due to its increased stability, form 1 is commonly used for drug formulation. A powder X-ray diffraction study and the DSC analysis clearly demonstrate that the current crystal form I corresponds to the reported form 1, thus making this the first structural report of the thermodynamically stable form of efavirenz (Figure 1c and d). Tiekink and co-workers reported a crystalline form of efavirenz (Z0 = 2), obtained by layering a methanol solution over water.9a The molecules crystallize in the orthorhombic space group P212121, and the two symmetry independent molecules exhibit notable variation in the orientation of the

C14H9ClF3NO2 767883 orthorhombic P21212 16.781(1) 27.258(1) 9.698(2) 90 90 90 4436(1) 12 1.395 250(2) 0.292 53.26 68797 8531 0.2242 4496 606 0.893 0.0656 0.1484

Scheme 2. Solid Forms and Cocrystals of Efavirenz, Their Transformations, and Some Synthons Present in the Polymorphs of 1

3193

2(C14H9ClF3NO2):1(C10H8 N2) 767759 triclinic P1 5.2710(2) 8.8560(3) 20.1360(8) 93.230(3) 93.080(3) 107.230(3) 893.89(6) 1 1.444 298(2) 0.260 58.60 19713 8346 0.0262 5732 507 0.976 0.0473 0.1221


structural formula CCDC no. crystal system space group a (A˚) b (A˚) c (A˚) R (deg) β (deg) γ (deg) V (A˚3) Z Dcalc (g cm-3) T (K) μ (mm-1) 2θmax (deg) total reflns unique reflns R(int) reflns used no. of parameters GOF on F2 R1 wR2

Article

3194


Mahapatra et al.

Figure 1. Efavirenz, form I: (a) A view of the double helical chain viewed down the c-axis with the three symmetry independent molecules represented in red, green, and blue. The inset shows the formation of the double helical chains. (b) Hexagonal close packing of helices. (c) PXRD pattern for form 18g and form I. (d) DSC trace for form I.

cyclopropylethynyl residue with respect to the six-membered heterocyclic ring. The cyclopropylethynyl fragment in one of the molecules is disordered. Symmetry independent molecules make cyclic N-H 3 3 3 O amide interactions (synthon B, Figure 2a). We note that this form corresponds to none of the patented polymorphic forms of efavirenz. Our attempts to reproduce this form in our laboratory using Tiekink’s method failed, and only form I was obtained, as a colorless powder, from a methanol-water mixture. In the end, we obtained the Tiekink form by slow evaporation of an n-heptane solution. From a DSC analysis, we observed that this form converts to form I around 112 C (see Supporting Information). The second form of efavirenz (Z 0 = 1), reported by Ravikumar and co-workers, also crystallizes in the space group P212121.9b The packing involves the formation of helical hydrogen bonded catemers proceeding from the amide NH of each molecule to the amide carbonyl of a neighbor (synthon C, Figure 2b). This form corresponds to form β claimed by Ranbaxy in their patent WO 2006/040643 A2 (for the powder pattern analyses, refer to the Supporting Information).8e It may be noted that all three polymorphs of 1 crystallize in the orthorhombic crystal system. While the two reported

forms take space group P212121, the current structure (form I) adopts the space group P21212. Although the hydrogen bonds are formed by the secondary amide functionality in all three cases, the N-H 3 3 3 O hydrogen bond patterns in all of them are fundamentally different (Scheme 2), in spite of the fact that all these crystal forms are unsolvated. Crystal density is usually a major criterion in considering the efficiency of crystal packing and in turn the stability of the polymorphic form. So we compared the calculated density of the three crystal forms. The polymorphic form reported by Tiekink (1.519 g cm-3) as well as the one reported by Ravikumar (1.486 g cm-3) exhibit higher densities than form I (1.394 g cm-3). This large difference in densities is unusual for polymorphs. Also paradoxical is that the least dense crystal form is the most stable one. Further, the three forms exhibit varying Z0 values, with Z0 = 1 for the form reported by Ravikumar, Z0 = 2 for the Tiekink form, and Z0 = 3 for form I. This high value of Z0 is brought about by the conformational flexibility of the core and the rotational freedom enjoyed by the cyclopropylethynyl moiety of the efavirenz molecule. As expected, the high Z0 structure (form I) has a larger number of strong interactions (N-H 3 3 3 O) compared to the two other forms (Table 2). Also, the double helices adopt a quite efficient hexagonal

Article


close packing mode. All these factors might have contributed to the stability of form I. It has been suggested earlier by one of us that high Z0 crystals are generally kinetic forms with some connection to arrested crystallization.11a Accordingly, they are less stable and less dense than the lower Z0 forms of the substance. Also, high Z0 forms, being kinetic in nature, would tend to have Table 2. Hydrogen Bond Metrics for the Various Solid State Forms of 1 Reported in This Study temp (K) I

250

Ia

180

II

298

IIa

150

III

293

150

298

IV

#

X-H 3 3 3 A N-H 3 3 3 O N-H 3 3 3 O N-H 3 3 3 O C-H 3 3 3 O C-H 3 3 3 O N-H 3 3 3 O N-H 3 3 3 O N-H 3 3 3 O N-H 3 3 3 O N-H 3 3 3 O N-H 3 3 3 O C-H 3 3 3 O C-H 3 3 3 O C-H 3 3 3 O N-H 3 3 3 O N-H 3 3 3 O N-H 3 3 3 O N-H 3 3 3 O N-H 3 3 3 O N-H 3 3 3 O C-H 3 3 3 π N-H 3 3 3 O N-H 3 3 3 O C-H 3 3 3 O C-H 3 3 3 O C-H 3 3 3 O Cl 3 3 3 Cl N-H 3 3 3 O N-H 3 3 3 O C-H 3 3 3 O C-H 3 3 3 O C-H 3 3 3 O Cl 3 3 3 Cl N-H 3 3 3 N N-H 3 3 3 N C-H 3 3 3 O C-H 3 3 3 O

H3 3 3A (A˚)#

X3 3 3A (A˚)

— X-H 3 3 3 A (deg)

1.98 2.05 2.00 2.50 2.48 2.01 2.03 1.99 1.99 2.05 2.04 2.43 2.42 2.48 1.88 1.85 1.87 1.87 1.86 1.87 2.95 1.86 1.92 2.42 2.42 2.43 1.90 1.93 2.35 2.38 2.39 1.89 1.94 2.44 2.38

2.940(4) 3.018(4) 2.956(5) 3.212(6) 3.331(5) 2.965(9) 3.018(10) 2.936(11) 2.967(10) 3.022(10) 2.999(10) 3.192(13) 3.276(12) 3.333(12) 2.841(4) 2.853(4) 2.820(2) 2.845(2) 2.831(3) 2.841(2) 3.742(3) 2.795(10) 2.885(12) 3.238(9) 3.284(13) 3.350(13) 3.290(2) 2.830(6) 2.877(6) 3.197(6) 3.236(6) 3.328(8) 3.343(2) 2.889(4) 2.876(4) 3.519(5) 3.219(4)

158 160 158 122 135 156 166 155 161 162 158 126 135 135 159 172 155 161 162 160 137 153 160 131 136 142 152 156 134 135 144 168 154 173 133

All H-atom positions are normalized to neutron diffraction values.

3195

better interactions than lower Z0 forms, where close-packing might prevail, perhaps with a concomitant increase in disorder. The theme here is that stability in a crystal is achieved either with better interactions (kinetic) or with better packing (thermodynamic). These suggestions have been commented upon by others.10,11b,c Nangia, for instance, has reviewed the behavior of 23 polymorph sets and has noted that, for roughly two thirds of the cases, the lower Z0 crystal does indeed correspond to the more stable phase.11c The behavior of efavirenz is in contrast to the above generalization. It falls in the one-third of the cases wherein the more stable form has the higher Z0 value. Among the three polymorphs, the most stable form not only has the highest Z0 value but it is also the least dense. About the disorder, it not possible to comment in detail;our form and Tiekink’s form are both disordered while Ravikumar’s form was refined with molecular constraints so that it is not possible to ascertain easily if it is disordered or not. Crystal Structure of Form II. In the cyclohexane solvate, II, the efavirenz molecules exhibit considerable variation in the orientation of the cyclopropylethynyl residue with respect to the six-membered heterocyclic ring. These disparities are closely related to the conformational variations observed in the crystal form reported by Tiekink. In the crystal, the two symmetry independent molecules correspond to the axial and equatorial isomers of 1 and are connected through the N-H 3 3 3 O amide dimer (synthon B). Adjacent dimers, stabilized by C-H 3 3 3 π interactions (Figure 3b), form a bilayer assembly stacked in three-dimensions to form columns. One-dimensional channels, along the z-axis, are formed between adjacent columns and are occupied by cyclohexane molecules (Figure 3c). These solvent channels are lined by a hydrophobic environment, brought about by the neighboring -CF3 and cyclopropyl residues. The guest cyclohexane molecules are disordered in the two chair conformations. Surprisingly, the cyclopropylethynyl moieties in form II are more ordered in contrast to form I. This could be due to the steric hindrance imposed by the guest molecules leaving little room for the rotation of the cyclopropyl group. The stability and desolvation of the cyclohexane solvate were studied with hot stage microscopy and DSC. The crystals are stable up to 85 C, at which stage the desolvation process commences (boiling point of cyclohexane is 81 C). At 90 C the crystal loses solvent and begins to disintegrate;

Figure 2. (a) Cyclic dimer formed between two symmetry independent molecules in the form of efavirenz reported by Tiekink et al. (b) Helical assembly in the form reported by Ravikumar et al. and hexagonal close-packing.

3196


Mahapatra et al.

Figure 3. Crystal structure of efavirenz form II: (a) N-H 3 3 3 O amide dimer; (b) C-H 3 3 3 π interaction between adjacent dimers; (c) crystal packing with the guest cyclohexane molecules represented in the space filling mode.

by 95 C the crystal converts to form I, which is further supported by powder X-ray diffraction (Figure 4a and b). The melting of the new form is initiated at 137 C and is complete by 140 C. The observations in the HSM are in accord with the DSC results (Figure 4c). In the DSC, two adjacent endothermic peaks are observed with an onset temperature of 87.7 C. This corresponds to the desolvation of cyclohexane followed by the appearance of form I. Melting of this solid occurs at 138 C, which is in good agreement with the previously observed melting point of form I (138 C, Figure 1d). It is interesting to note that, upon losing cyclohexane from the one-dimensional channels, the cyclic dimer in the cyclohexane solvate did not transform to the form reported by Tiekink (stabilized by dimers) but to the double helical form (I). This conversion indeed is an indication that the double helical form is more stable compared to the dimer or the single-helical polymorphic forms of the API. Perhaps it is this double helical motif that is responsible for the low density, high Z0 form being the most stable form, in contradiction with the suggestion made earlier by one of us11a and found to be true in two-thirds of the cases examined by Nangia.11c Thermal studies using single-crystal X-ray diffraction at variable temperature were carried out on single crystals of form I and the solvated form II. The observations and the phase transition behavior of these forms are discussed in the following section. Temperature Induced Single-Crystal to Single-Crystal PhaseTransition of Form I. At 180 K, form I (orthorhombic P21212, Z0 =3) exhibits a single-crystal to single-crystal phase transition to a lower symmetry form Ia (monoclinic P21, Z 0 = 6, Table 1). This increase in Z0 is followed by a noticeable increase in the calculated density (1.469 g cm-3). The comparison of the

unit cell dimensions (Table 1) clearly indicates a possible modulation behavior. In the modulated forms, the symmetry independent efavirenz molecules differ mainly in the orientation of the cyclopropyl groups (Figure 5). A low energy rotation barrier for the cyclopropyl group can be a possible cause of such an observation (further shown by the DFT calculations discussed later in the paper). At 250 K, the Z 0 = 3 form is characterized by a fast rotation, as is evident from the disordered nature of all the cyclopropyl groups (Figure 5a). However, on decreasing the temperature to 180 K, the rate of rotation of the cyclopropyl group slows down, and this causes a separation of the possible conformers. This results in the lowering of the crystal symmetry to P21 and an increase in the number of molecules in the asymmetric unit from Z0 = 3 to Z0 = 6, with a concomitant decrease in the degree of disorder (Figure 5b). An interesting point to note here is the onset of crystal mosiacity in form Ia on further lowering of temperature to 100 K. This can be due to the further isolation of the other closely lying cyclopropyl isomers due to thermal ordering thus leading to a fuzzy situation where the unambiguous indexing of the unit cell fails, resulting in a mosaic structure (Supporting Information). The six conformations of the molecule in form Ia can be divided into three sets, based on the cyclopropyl orientations;set A (red and pink), set B (green and light green), and set C (blue and light blue). In the high temperature form I, these six orientations reduce to a total of three conformations due to thermal averaging. The crystal packing in the low temperature phase Ia remains essentially the same as that of form I with the formation of N-H 3 3 3 O double helical chains, with the complementary strands consisting of two sets of symmetry independent molecules (three each), as shown in Figure 6. Temperature Induced Single-Crystal to Single-Crystal Phase Transitions of Form II. Similar to form I, a temperature

Article


3197

Figure 4. (a) HSM images of II (corresponding temperatures are given in parentheses). Notice the frontal migration of departing solvent at 85 C. (b) PXRD patterns of forms I and II and the heated sample of form II. (c) DSC plot for form II.

Figure 5. Overlay diagram for (a) the three conformers observed in I and (b) the six conformers observed in Ia (showing further splitting of conformers from three to six on transformation from I to Ia). The three sets of molecules are shown as three color variants. In all of the conformers, the cyclopropylethynyl group occupies the equatorial position in the heterocycle.

dependent phase change behavior is also observed for the cyclohexane solvate. A single-crystal to single-crystal phase transition of the 2:0.5 (Z0 = 2) form II to a 4:1 (Z0 = 4) form IIa is observed at 150 K (Table 1). This results in a clear fixing of the cyclopropyl conformers corresponding to the axial and equatorial isomers (Figure 7a and b and Supporting Information). The overlay of symmetry independent molecules in forms Ia and IIa is given in Figure 7c. While one set of conformers (blue and light blue; I and J, Table 3) closely relates to

Figure 6. Formation of the assembly by six symmetry independent molecules in Ia.

that observed in Ia (corresponds to the cyclopropyl conformers of the equatorial isomer), a new set of cyclopropyl conformers (yellow and light yellow) in which the cyclopropylethynyl group occupies an axial position (G and H, Table 3) is found in the solvate. The cyclohexane guest molecules remain disordered even with the lowering of temperature. The fast axial-equatorial flip transition between the two chair conformers in the cyclohexane21 solvent molecules shows a clear damping of the transition rate at the lower temperature, and the time averaged picture of the two chair conformers becomes

3198


Mahapatra et al.

Figure 7. Overlap diagram of conformers in (a) II and (b) IIa. (c) All of the conformers found in Ia and IIa. (d) Schematic representation of the two chair conformers observed in IIa. Table 3. Comparison of Torsion Angle Geometries of Various Conformers Observed in the Different Forms of Efavirenz Pure (Ia) and Efavirenz Solvate (IIa) conformer fully optimized structure 1 2 Ia A B C D E F IIa G H I J

cyclopropyl orientation

τ (deg)

E (Hartree)

ΔE (kJ/mol)

equatorial axial

-160.67 -141.62

-1503.8168 -1503.8150

0.00 1.17

equatorial equatorial equatorial equatorial equatorial equatorial

30.04 78.44 19.37 -161.96 -167.74 88.23

-1503.8163 -1503.8158 -1503.8164 -1503.8168 -1503.8168 -1503.8158

0.31 0.63 0.29 0.00 0.01 0.66

axial axial equatorial equatorial

89.38 97.19 -136.18 -132.18

-1503.8149 -1503.8149 -1503.8158 -1503.8158

0.67 0.67 0.01 0.02

observable in form IIa. Similar temperature dependent phase transitions are not observed for the efavirenz cocrystals (III and IV). Perhaps for an API such as efavirenz, the strategy of cocrystallization is an efficient way of curbing the prevalence of numerous solid forms. High Z0 Structures and Energy Considerations. The structural overlay of the symmetry independent molecules (Figure 7c) clearly shows that they differ mostly in the relative orientations of the cyclopropylethynyl groups, which in the end is responsible

for the origin of high Z0 in structures I and II. In order to understand the temperature induced orientational ordering of the cyclopropyl group, a relaxed potential energy surface (PES) scan for the cyclopropyl group rotation was performed at the B3LYP/6-31þþG(d,p) level of theory for both the axial and equatorial isomers. The equatorial conformer was found to be more stable than the axial conformer by 1.17 kJ/mol. The PES scan for the rotation of the cyclopropyl group for the axial and equatorial cyclopropyl conformers is shown in Figure 8.

Article


3199

The PES scans suggest a low energy rotational barrier for the cyclopropyl group for both the equatorial and axial orientations (2.42 and 2.83 kJ/mol, respectively). This suggests in turn that various efavirenz conformers are possible, corresponding to the cyclopropyl group rotations and axial-equatorial orientations of the heterocyclic ring. At low temperature a further locking of these conformers into the local minima of the potential energy hypersurface of the crystal possibly leads to asymmetry in packing and therefore to the high Z0 forms. The relative energies of the various conformers of 1 found in Ia and IIa with respect to the fully optimized efavirenz structure are given in Table 3. In the calculation of these energies the torsion angles of the conformers are fixed at the X-ray determined values. Conformational energies for the other efavirenz structures reported in this paper are given in the Supporting Information. Identification and Isolation of Cocrystals of Efavirenz. From solvent drop grinding experiments conducted with Scheme 3. Anticipated Synthons for Cocrystal III Figure 8. Relaxed potential energy surface scan for the cyclopropyl group rotation for the equatorial and axial orientations of the heterocyclic ring of the efavirenz molecule. The two PES profiles are shown with the same relative energy scale in the figure (The two orientations differ by 1.17 kJ/mol in energy, see Table 3). Ia through III and IV correspond to the new solid forms of efavirenz reported in the paper. Data points RK and TK correspond to the cyclopropyl group orientations of efavirenz molecules in the structures reported by Ravikumar et al. and Tiekink et al.

Figure 9. Cocrystal of efavirenz and 1,4-cyclohexanedione: (a and b) two distinct recognition patterns; (c) crystal packing (inset A is a schematic representation, and inset B is an overlay of the two symmetry independent dione molecules in the crystal (red and purple) along with the conformation in the native dione crystal (green)).

3200


Mahapatra et al.

Figure 10. Cocrystal IV: (a) three-molecule supramolecular entity; (b) crystal packing.

various coformers and subsequent powder X-ray diffraction studies, we identified some new crystalline phases indicating the possible formation of cocrystals. Several experiments were conducted under various conditions and with many solvent and solvent mixtures. We were successful in obtaining crystals only in the case of 1,4-cyclohexanedione, where a 4:3 complex (III) with efavirenz was obtained, and with 4,40 -bipyridyl, for which a 2:1 molecular complex (IV) with efavirenz was isolated. Efavirenz-1,4-cyclohexanedione 4:3 Complex (III). Efavirenz forms a 4:3 molecular complex with 1,4-cyclohexanedione. Crystals suitable for X-ray analysis were obtained from a heptane-THF solution. In the crystal, there are two symmetry independent dione molecules, and both exhibit a skewed conformation. This is in good agreement with the native crystal structure of the dione (Table 1, Figure 8). Unlike the amide dimers and catemers found in forms I and II, the API molecule makes an entirely different pattern in complex III, characterized by C-H 3 3 3 O hydrogen bonds. Two distinct recognition patterns are seen. A molecule of cyclohexanedione makes bifurcated N-H 3 3 3 O/C-H 3 3 3 O hydrogen bonds with two symmetry related molecules of efavirenz, forming a three-molecular entity (Figure 9a). The second symmetry independent dione molecule makes linear chains with bifurcated C-H 3 3 3 O hydrogen bonds, and the efavirenz molecules are pendant to the chains through N-H 3 3 3 O and C-H 3 3 3 O hydrogen bonds (Figure 9b). The two patterns (represented in red and green) stack over one another to form a grill-ribbon structure (Figure 9c). Additionally, type-I Cl 3 3 3 Cl interactions are formed between adjacent efavirenz units. We have noted that, with a lowering of the temperature to 150 K, the C-H 3 3 3 O hydrogen bonds are shortened; that is, they are attractive in nature (Table 2) while the Cl 3 3 3 Cl interactions become longer (more repulsive). Variable temperature measurements offer an attractive route for the evaluation of weak interactions, such as C-H 3 3 3 O hydrogen bonds and Cl 3 3 3 Cl interactions. True hydrogen bonds become shorter and more linear with a lowering of temperature. Short repulsive contacts show the opposite effect. We have made similar observations in recent studies on cocrystals formed by barbital with urea and acetamide, respectively.22 It is pertinent to comment about the choice of 1,4-cyclohexanedione as a coformer with efavirenz. We noted that the drug forms a solvate (II) with cyclohexane in which the solvent molecule acts as a spacer between the efavirenz

columns. Accordingly, cocrystal formation was attempted with the similarly shaped 1,4-dioxane and cyclohexanone molecules. Both experiments were unsuccessful. At this stage it was postulated that the former molecule is chemically too different from cyclohexane while the latter, which can form a chemically reasonable heterosynthon with efavirenz (Scheme 3), suffers from the fact that it cannot lie on a center of symmetry, like cyclohexane does in form II (assuming that the crystal structure is ordered). Accordingly, cocrystallization was attempted with the symmetrical molecule, 1,4cyclohexanedione, which can lie on a center of inversion and can also form a chemically reasonable heterosynthon with the secondary amide functionality of the API. While a cocrystal was obtained with the API, the expected synthon was not formed! Perhaps cocrystal formation is still more a matter of high throughput screening rather than being predictable from a synthon based retrosynthetic analysis. In any event, of the two symmetry independent dione molecules in the crystal, one of them lies on a center of inversion. This observation at least is somewhat heartening. Efavirenz-4,40 -bipyridyl Cocrystal (IV). A 2:1 cocrystal, IV, was obtained by the cocrystallization of 1 with 4,40 bipyridyl from acetonitrile. Unlike I and II, preliminary screening in different heating and cooling cycles for IV did not show any phase transition, so a room temperature data set was collected for this compound and the structure was solved via direct methods12-14 (Table 1). In this crystal, the molecules make two distinct heterosynthons. While one of the efavirenz molecules interacts with the bipyridyl through cyclic N-H 3 3 3 N/C-H 3 3 3 O hydrogen bonds, the other end of the pyridine compound makes a single-point N-H 3 3 3 N hydrogen bond with another molecule of 1 (Table 2 and Figure 10a). This makes for a three molecule grouping, and adjacent units stack to form pillared assemblies separated by hydrophobic cyclopropyl residues. The bipyridyl molecule does not lie on an inversion center. As observed in forms I and II, the cyclopropylethynyl residue of 1 is also disordered in cocrystal IV. Conclusions Novel solid state forms, namely a polymorph, a solvate, and two cocrystals, of the anti-HIV drug efavirenz have been identified, isolated, and structurally characterized. Systematic temperature dependent studies on single crystals of the nonsolvated form (I) reveal an interesting single-crystal to

Article


single-crystal transformation from an orthorhombic P21212 structure to a monoclinic P21 structure with a concomitant increase of Z0 from 3 to 6 on cooling to 180 K. This is accompanied by an arresting of the disorder of the cyclopropylethynyl residue. A similar transformation was observed in the cyclohexane solvate. A lowering of the temperature to 150 K leads to Z0 increasing from 2 to 4. A low energy rotation barrier for the cyclopropyl group could possibly be responsible for the aforementioned high Z0 structures, as revealed by DFT calculations. Presently we are in the process of identifying more solid forms of this important drug molecule. Formation of cocrystals of efavirenz seems to be a largely unpredictable matter. Only two cocrystals were obtained after at least 27 screening experiments. In the cocrystal formed with 1,4-cyclohexanedione, the major synthons cannot be easily anticipated. In the cocrystal with 4,40 -bipyridyl, the synthons are more easily predictable. Acknowledgment. S.M. thanks the CSIR for the award of a Research Associateship. T.S.T. thanks the Indian Institute of Science for the award of a Research Associateship. S.J. thanks the UGC for the award of a D. S. Kothari Bridge fellowship. S.V. thanks the DST for the award of a Young Scientist fellowship. G.R.D. thanks the DST for the award of a J. C. Bose fellowship. We thank the Rigaku Corporation for their support. Supporting Information Available: ORTEP diagrams, PXRD patterns, and other helpful data. This material is available free of charge via the Internet at http://pubs.acs.org.

(5)

(6) (7)

(8)

(9)

References (1) (a) Brittain, H. G. Physical Characterization of Pharmaceutical Solids; Marcel Dekker, Inc.: New York, 1995. (b) Byrn, S. R.; Xu, W.; Newman, A. W. Adv. Drug Delivery Rev. 2001, 48, 115–136. (c) Guo, Y.; Byrn, S. R.; Zografi, G. J. Pharm. Sci. 2000, 89, 241–249. (d) Lai, M. C.; Hageman, M. J.; Schowen, R. L.; Borchardt, R. L.; Topp, E. M. J. Pharm. Sci. 2000, 88, 1073–1080. (e) Airaksinen, S.; Karjalainen, M.; Kivikero, N.; Westermarck, S.; Schevchenko, A.; Rantanen, J.; Yliruusi, J. AAPS PharmSciTech 2005, 6, E311–E322. (f) Wildfong, P. L. D.; Morris, K. R.; Anderson, C. A.; Short, S. M. J. Pharm. Sci. 2007, 96, 1100–1113. (2) (a) Polymorphism in the Pharmaceutical Industry; Hilfiker, R., Ed.; Wiley-VCH: Weinheim, Germany, 2006. (b) Polymorphism in Pharmaceutical Solids; Brittain, H. G., Ed.; Marcel Dekker, Inc.: New York, 1999. (c) Byrn, S.; Pfeiffer, R.; Stephenson, G.; Grant, D. J. W.; Gleason, W. B. Chem. Mater. 1994, 6, 1148–1158. (d) Byrn, S.; Pfeiffer, R.; Ganey, M.; Hoiberg, C.; Poochikan, G. Pharm. Res. 1995, 12, 945–954. (e) Pfeffer-Hennig, S.; Piechon, P.; Bellus, M.; Goldbronn, C.; Tedesco, R. J. Therm. Anal. Calorim. 2004, 77, 663– 679. (f) Karpinski, P. H. Chem. Eng. Technol. 2006, 29, 233–237. (g) Mirmehrabi, M.; Rohani, S.; Murthy, K. S. K.; Radatus, B. Cryst. Growth Des. 2006, 6, 141–149. (h) Tawashi, R. Science 1968, 160, 76. (i) Vippagunta, S. R.; Brittain, H. G.; Grant, D. J. W. Adv. Drug Delivery Rev. 2001, 48, 3–26. (3) (a) Brits, M.; Liebenberg, W.; De Villiers, M. M. J. Pharm. Sci. 2010, 99, 1138–1151. (b) Bhatt, P. M.; Ravindra, N. V.; Banerjee, R.; Desiraju, G. R. Chem. Commun. 2005, 1073–1075. (c) Cheney, M. L.; Shan, N.; Healey, E. R.; Hanna, M.; Wojtas, L.; Zaworotko, M. J.; Sava, V.; Song, S.; Sanchez-Ramos, J. R. Cryst. Growth Des. 2010, 10, 394–405. (d) Grant, D. J. W.; Brittain, H. G. Solubility of Pharmaceutical Solids. In Physical Characterization of Pharmaceutical Solids; Brittain, H. G., Ed.; Marcel Dekker, Inc.: New York, 1995; pp 321-386. (e) Jones, W.; Motherwell, W. D. S.; Trask, A. V. MRS Bull. 2006, 31, 875–879. (f) Karki, S.; Friscic, T.; Fabian, L.; Laity, P. R.; Day, G. M.; Jones, W. Adv. Mater. 2009, 21, 3905–3909. (g) Schultheiss, N.; Newman, A. Cryst. Growth Des. 2009, 9, 2950– 2967. (h) Trask, A. V.; Motherwell, W. D. S.; Jones, W. Cryst. Growth Des. 2005, 5, 1013–1021. (4) (a) Bernstein, J. Conformational Polymorphism. In Organic Solid State Chemistry; Desiraju, G. R., Ed.; Elsevier: Amsterdam, 1987;

(10)

(11)

(12)

(13) (14) (15) (16) (17) (18)

3201

pp 471-518. (b) Castro, R. A. E.; Maria, T. M. R.; Evora, A. O. L.; Feiteira, J. C.; Silva, M. R.; Beja, A. M.; Canotilho, J.; Eusbio, M. E. S. Cryst. Growth Des. 2010, 10, 274–282. (c) Desiraju, G. R. Angew. Chem., Int. Ed. 2007, 46, 8342–8356. (d) Dunitz, J. D. Pure Appl. Chem. 1991, 63, 177–185. (e) Griesser, U. J.; Jetti, R. K. R.; Haddow, M. F.; Brehmer, T.; Apperley, D. C.; King, A.; Harris, R. K. Cryst. Growth Des. 2008, 8, 44–56. (f) Threlfall, T. L. Analyst 1995, 120, 2435–2460. (a) Bauer, J.; Spanton, S.; Henry, R.; Quick, J.; Dziki, W.; Porter, W.; Morris, J. Pharm. Res. 2001, 18, 859–866. (b) Chemburkar, S. R.; Bauer, J.; Deming, K.; Spiwek, H.; Patel, K.; Morris, J.; Henry, R.; Spanton, S.; Dziki, W.; Porter, W.; Quick, J.; Bauer, P.; Donaubauer, J.; Narayanan, B. A.; Soldani, M.; Riley, D.; McFarland, K. Org. Process Res. Dev. 2000, 4, 413–417. (a) Adkins, J. C.; Noble, S. Drugs 1998, 56, 1055–1064. (b) Gazzard, B. G. Int. J. Clin. Pract. 1999, 53, 60–64. (c) de Clercq, E. Rev. Med. Virol. 2009, 19, 287–299. (a) Markowitz, M.; Nguyen, B. Y.; Gotuzzo, E.; Mendo, F.; Ratanasuwan, W.; Kovacs, C.; Prada, G.; Morales-Ramirez, J. O.; Crumpacker, C. S.; Isaacs, R. D.; Campbell, H.; Strohmaier, K. M.; Wan, H.; Danovich, R. M.; Teppler, H. J. Acquired Immune Defic. Syndr. 2009, 52, 350–356. (b) Young, J.; Bucher, H. C.; Guenthard, H. F.; Rickenthard, H. F.; Rickenbach, M.; Fux, C. A.; Hirschel, B.; Cavassini, M.; Vernazza, P.; Bernasconi, E.; Battegay, M. Antiviral Ther. 2009, 14, 771–779. (a) Crocker, L. S.; Kukura, J. L., II; Thompson, A. S.; Stelmach, C.; Young, S. D. U.S. Patent 6,939,964 B2, 2005. (b) Crocker, L. S.; Kukura, J. L., II; Thompson, A. S.; Stelmach, C.; Young, S. D. US 6,639,071 B2, 2003. (c) Khanduri, C. H.; Panda, A. K.; Kumar, Y. WO 2006/030299 A1, 2006. (d) Reddy, P.; Rathnakar, R. K.; Raji, R. R.; Muralidhara, R. D.; Subhash, C. D. K. WO 2006/018853 A2, 2006. (e) Sharma, R.; Bhushan, K. H.; Aryan, R. C.; Singh, N.; Pandya, B.; Kumar, Y. WO 2006/040643 A2, 2006. (f) Tyagi, O. M.; Jetti, R. K. R.; Ramireddy, B. A. WO 2009/087679 A2, 2009. (g) Radesca, L. A.; Maurin, M. B.; Rabel, S. R.; Moore, J. R. WO 99/64405, 1999. (a) Cuffini, S.; Howie, R. A.; Tiekink, E. R. T.; Wardell, J. L.; Wardell, S. M. S. V. Acta Crystallogr., Sect. E 2009, 65, o3170– o3171. (b) Ravikumar, K.; Sridhar, B. Mol. Cryst. Liq. Cryst. 2009, 515, 190–198. (a) Nichol, G. S.; Clegg, W. Cryst. Growth Des. 2006, 6, 451–460. (b) Das, D.; Banerjee, R.; Mondal, R.; Howard, J. A. K.; Boese, R.; Desiraju, G. R. Chem. Commun. 2006, 555–557. (c) Babu, N. J.; Nangia, A. Cryst. Growth Des. 2006, 6, 1995–1999. (d) Anderson, K. M.; Goeta, A. E.; Hancock, K. S. B.; Steed, J. W. Chem. Commun. 2006, 2138–2140. (e) Nichol, G. S.; Clegg, W. CrystEngComm 2007, 9, 959–960. (f) Bishop, R.; Scudder, M. L. Cryst. Growth Des. 2009, 9, 2890–2894. (g) Dey, A.; Desiraju, G. R. CrystEngComm 2006, 8, 477– 481. (a) Desiraju, G. R. CrystEngComm 2007, 9, 91–92. (b) Anderson, K. M.; Steed, J. W. CrystEngComm 2007, 9, 328–330. (c) Nangia, A. Acc. Chem. Res. 2008, 41, 595–604. (d) Gavezzotti, A. CrystEngComm 2008, 10, 389–398. (a) Anderson, K. M.; Afarinkia, K.; Yu, H.; Goeta, A. E.; Steed, J. W. Cryst. Growth Des. 2006, 6, 2109–2113. (b) Chandran, S. K.; Nath, N. K.; Roy, S.; Nangia, A. Cryst. Growth Des. 2008, 8, 140–154. (c) Sangwal, K.; Smith, K. W. Cryst. Growth Des. 2010, 10, 640–647. Oxford diffraction Ltd., Xcalibur CCD system, CrysAlisPro Software System, Version 1.171.32, 2007. Altomare, A.; Cascarano, G.; Giacovazzo, C.; Guagliardi, A. SIR92. A program for crystal structure solution. J. Appl. Crystallogr. 1993, 26, 343–350. Sheldrick, G. M. SHELX97. Program for crystal structure refinement; University of G€ottingen: Germany, 1997. (a) CrystalClear 2.0; Rigaku Corporation: Tokyo, Japan. (b) Pflugrath, J. W. Acta Crystallogr., Sect. D 1999, 55, 1718–1725. Farrugia, L. J. Wingx suite for small-molecule single-crystal crystallography. J. Appl. Crystallogr. 1999, 32, 837–838. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Montgomery, J. A., Jr.; Vreven, T.; Kudin, K. N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.;

3202


Daniels, A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.; Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian 03, Revision C.02; Gaussian, Inc.: Wallingford, CT, 2004.

Mahapatra et al. (19) (a) Becke, A. D. J. Chem. Phys. 1993, 98, 5648–5652. (b) Lee, C.; Yang, W.; Parr, R. G. Phys. Rev. B 1988, 37, 785–789. (20) Farkas, O.; Schlegel, H. B. Phys. Chem. Chem. Phys. 2002, 4, 11–15. (21) (a) McGrath, K. J.; Weiss, R. G. J. Phys. Chem. 1993, 97, 2497– 2499. (b) Jensen, F. R.; Noyce, D. S.; Sederholm, C. H.; Berlin, A. J. J. Am. Chem. Soc. 1962, 84, 386–389. (22) Thakur, T. S.; Azim, Y.; Srinu, T.; Desiraju, G. R. Curr. Sci. 2010, 6, 793–802.

New Solid State Forms of the Anti-HIV Drug Efavirenz. Conformational

Recommend Documents