Toward Novel Solid-State Forms of the Anti-HIV Drug Efavirenz: From

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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 Ariane Carla Campos de Melo, Isadora Ferreira de Amorim, Marilia de Lima Cirqueira, and Felipe T. Martins Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/cg3018002 • Publication Date (Web): 14 Feb 2013 Downloaded from http://pubs.acs.org on February 26, 2013

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Crystal Growth & Design

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 Ariane Carla Campos de Melo, Isadora Ferreira de Amorim, Marilia de Lima Cirqueira, and Felipe Terra Martins* Instituto de Química, Universidade Federal de Goiás, Campus Samambaia, CP 131, 74001-970, Goiânia, GO, Brazil * To whom correspondence should be addressed. E-mail: [email protected] Phone: +55 62 3521 1097. Fax: +55 62 3521 1167

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Here two cocrystals of efavirenz, a non-nucleoside reverse transcriptase inhibitor largely used as part of anti-HIV therapies whose screening methods have few success as source of new solid state forms, were engineered with 4,4’-bipyridine-like coformers and a new polymorph was discovered.


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Abstract: 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 source of new solid forms. To the best of our knowledge, only two efavirenz cocrystals have been reported thus far. Based on 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 an either 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 non-classical 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 C-centered monoclinic lattice is reported for the first time here. It resembles a known orthorhombic form also with Z’ = 1 in terms of conformation and assembly of helical hydrogen bonded catemers, but their organization is unlike.


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1. Introduction Efavirenz is a highly potent nonnucleoside inhibitor of the human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) able to suppress viral replication and to avoid HIV-1-related cell damages even at nanomolar serum concentrations.1,2 It is a benzoxazinone derivative that had been initially approved by U. S. Food Drug Administration in 1998, being since then a first-line drug used into highly active antiretroviral therapy schemes.3 Recently, its clinical importance has been further highlighted due to the development of once-daily single-tablet dosages based on co-formulations of efavirenz together with integrase and protease inhibitors, which means an extremely desired simplification in the anti-HIV treatment.4 This second-generation non-nucleoside reverse transcriptase inhibitor (NNRTI), chemically designed as (4S)-6-chloro-4-(2-cyclopropylethynyl)-4-(trifluoromethyl)2,4-dihydro-1H-3,1-benzoxazin-2-one), is marketed into solid dosage forms by the pharmaceutical company Bristol-Myers Squibb under the brand names SUSTIVA® and STOCRIN®. However, even though this active pharmaceutical ingredient (API) has been incorporated into medicine formulations in the solid state for more than one decade, few reports concerning its crystal structures and properties can be found in the literature.5-7 Patent applications describe some polymorphic forms for efavirenz, but their characterizations are somewhat vague. In fact, three polymorphs,5-7 in which one of them also undergoes a solid state phase transition to a lower symmetry phase,7 a cyclohexane solvate, and cocrystals with 1,4-cyclohexanedione and 4,4’-bipyridine7 are well known from a structural point of view at least. Their molecular conformations and supramolecular features were elucidated using the single-crystal X-ray diffraction technique. Even so, cocrystal screenings could be better explored as a tool to solve the very-low aqueous solubility of this drug in its polymorphic forms (at 25°C ranging from 0.056±0.002 mM for the most thermodynamically stable polymorph, namely, form I, to 0.403±0.001 mM for the low melting form VI)8 and, therefore, the associated very low oral bioavailability (between 40% and 45%)9 that hinders its administration and oral absorption.10 As can be


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noted, the most stable form (pharmaceutically desirable) is the less soluble one (undesirable),8 hindering its incorporation into medicine formulations. To highlight the problems in its solubility, efavirenz has been classified as a drug belonging to the Biopharmaceutics Classification System Class II of high permeability but low water solubility and a dissolution rate-dependent absorption.11 The intrinsic dissolution rate of efavirenz is 0.037 mg min-1 cm-2,12 a very low value less than the cutoff (0.1 mg min-1 cm-2) for a drug to be not considered as a dissolution rate-limited absorption drug.13 As part of our continuous studies dealing with crystal engineering in molecular crystals of APIs, we were interested in efavirenz because its relevance in anti-HIV therapies and rareness of reports in this matter. Desiraju and coworkers has experienced few success using screening assays for this drug,7 which denotes the difficulty to search novel efavirenz solid forms. Even the obtained cocrystals and solvate needed considerable efforts to be isolated. Upon one of the two known cocrystals of efavirenz this study concerns, namely, that with 4,4’-bipyridine.7 Here, trans-1,2-bis(4-pyridyl)ethene (1) and 1,2-bis(4-pyridyl)ethane (2) (see below) were chosen into a crystal engineering strategy for selection of cocrystallizing agents and anticipation of structurally defined multicomponent molecular crystals. Both 4,4’-bipyridine-like coformers used in this study are pharmaceutically relevant and have been employed into crystal engineering strategies of many APIs.14 If obtained, new cocrystals of this drug not only would validate the applicability of the invoked synthon approaches but they could also own physicochemical properties attractive from a pharmaceutical point of view to solve its oral absorption problems. Such knowledge may be also useful to guide the design of other crystal forms of the drug with desired pharmaceutical performances. In addition, a new polymorph of the drug has been fortunately discovered in the course of our cocrystal screening assays and its preparation, structural data and a detailed comparison with another related antecedent form6 is presented in this study. This polymorph, named as form V according to Desiraju and coworkers7 nomenclature, resembles the orthorhombic form (P212121 space group) with Z’ = 1 described by Ravikumar and Sridhar6 because of


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the assembly of helical hydrogen bonded catemers, but their unlike packing results in the crystallization of efavirenz in a C-centered monoclinic lattice (C2 space group) also with Z’ = 1 reported for the first time here.

2. Material and Methods 2.1 Preparation of the efavirenz cocrystals with 1 and 2 Firstly, a quantity of efavirenz form I (following the nomenclature of Desiraju and coworkers7) (8.0 mg, 0.025 mmol), whose authenticity and purity were previously checked by powder X-ray diffraction technique (see Fig. S1 in the Supporting Information), was dissolved in 5 mL of either acetonitrile for preparation of the cocrystal with 1 or isopropyl alcohol for preparation of the cocrystal with 2, under stirring for 5 min at room temperature (298 K). In sequence, this solution was joined together with one another of the coformer (2.1 mg of 1 or 2.2 mg of 2, 0.012 mmol of both) in 5 mL of ethanol. A 2:1 drug:coformer stoichiometry was set in both cases. This solution was allowed to evaporate slowly upon standing for 7 days at 298 K. Extremely thin crystalline plates were formed on the bottom of the corresponding glass crystallizers. After selection of single crystals for structure determination experiments, the content of the glass crystallizers was powdered and analyzed by powder X-ray diffraction technique (see Fig. S1 in the Supporting Information). Experimental X-ray powder diffractograms of the cocrystals were overlaid to the calculated ones from their corresponding crystals structures, allowing us to conclude that cocrystals were prepared in the bulk from the crystallization systems abovementioned as the solid phases elucidated here.

2.2 Preparation of the efavirenz form V During the cocrystal screenings, efavirenz form V was isolated from a crystallization batch in which form I of the drug (8.0 mg, 0.025 mmol) was dissolved in 5 mL of n-butyl alcohol upon heating (323


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K) and stirring (5 min). This newly prepared solution was allowed to cool to room temperature when then another solution of the coformer 1 (2.1 mg, 0.012 mmol) in 5 mL of isopropyl alcohol was joined together. This resulting solution was kept standing for 10 days at 298 K. Block-shaped crystals of efavirenz form V were formed on the bottom of the glass crystallizers after the crystallization period. The simulated powder X-ray diffraction pattern from its crystal structure does not match to any diffractogram of the efavirenz solid phases reported in both open and patent literature,8,15 indicating that a new polymorph of the drug has been obtained.

2.3 Structure determination Well-shaped single crystals of efavirenz cocrystals with 1 and 2 and form V measuring 0.15 x 0.09 x 0.05 mm3, 0.09 x 0.08 x 0.04 mm3, and 0.21 x 0.12 x 0.09 mm3 were selected for the X-ray diffraction data collect. A cold N2 gas blower cryogenic device (Oxford Cryosystem) was used to keep temperature at 120 K when measuring X-ray diffraction data of both cocrystals, while the selected crystal of form V was exposed to X-ray beam for unit cell determination and intensities collect at 300 K. MoKα radiation from an IµS microsource with multilayer optics was employed (Bruker-AXS Kappa Duo diffractometer with an APEX II CCD detector). The diffraction frames were recorded by ϕ and ω scans using APEX2,16 and raw dataset treatment was performed using the program SAINT and SADABS.16 The structures were solved by direct methods with SHELXS-97,17 wherein C, O, N, F and Cl were readily assigned from the Fourier map. The initial models were refined by the full-matrix least squares method on F2 with SHELXL-97,17 adopting anisotropic thermal parameters for non-hydrogen atoms. Hydrogens were positioned stereochemically and refined with fixed individual isotropic displacement parameters [Uiso(H) = 1.2Ueq] using a riding model with fixed C—H bond lengths of either 0.95 Å (120 K)/0.93 Å (300 K) (aromatic), 0.99 Å (120 K)/0.97 Å (300 K) (methylene) or 1.00


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Å (120 K)/0.98 Å (300 K) (methine). NH hydrogen atoms were identified in the Fourier map but their fractional coordinates were fixed during refinements and follow those of the parent nitrogen atoms, with bond distance of 0.88 Å (120 K)/0.86 Å (300 K), because unsuitable bonding geometry was outputted after trial refinements setting free coordinates for these hydrogens. One drug molecule in asymmetry unit of the efavirenz cocrystal with 2 and the only molecule in asymmetry unit of efavirenz form V showed disordered sites for some of their atoms. They were refined by splitting the carbon and hydrogen atoms of the cyclopropylethynyl moiety over two positions. In the cocrystal, the atomic fractions with suffix B, following the overall molecule label for the atoms in full occupancy sites, have been fixed to 65% of site occupancy, whereas the atomic fractions with suffix D filled the remaining 35% occupancy. In the polymorph, both conformations had equal populations and 50% occupancy was fixed to the atom sites. The labels of cyclopropylethynyl moieties in each conformation were set apart by an upper line suffix. The programs MERCURY18 and ORTEP-319 were used within the WinGX19 software package to prepare artwork representations. CCDC reference numbers 909385, 909386 and 923049 contain the crystal data for the cocrystals with 1 and 2 and form V, respectively.

3. Results and Discussion In the context of assembling molecular frameworks of a cocrystallizing agent, 1 and 2 keep strict similarity to 4,4’-bipyridine. They can be understood as a 4,4’-bipyridine where pyridine rings were spaced by an either ethylene in 1 or an ethane moiety in 2. Furthermore, such intercalations set the nitrogens into the pyridine rings in line through the bridge moieties, as in 4,4’-bipyridine. This arrangement of their hydrogen bonding functionalities similar to that of 4,4’-bipyridine is due to Estereochemistry in 1, setting the pyridine moieties in the opposite sides relative to the C=C double bond, and to the staggered conformation of the ethane moiety in 2, where the bulkier pyridine rings lie in anti-related positions because of major steric hindrance effects between them. In addition, the same


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conformational freedom observed in the bridge bond of 4,4’-bipyridine takes place in 1 and 2 because σ-bonds connect the pyridine rings to the ethylene/ethane carbons in our cocrystallizing agents. In this way, the cocrystals of efavirenz with 1 and 2, if it were obtained, were expected to be structurally related to the antecedent crystal phase with 4,4’-bipyridine. The effect of methylene and ethylene spacers groups of coformers in the cocrystal structures has been well investigated together with their impact on physicochemical properties as melting temperature.14,20-22 However, the isostructurality as observed in this study is not found sometimes. For instance, cocrystals of 3-cyanophenol with 1 and 2 show distinct packing and even different stoichiometry contents.20 But in these cocrystals no formation of the cyclic synthon involving both lactam hydrogen bonding functionalities of efavirenz and the vicinal nitrogen and CH moieties of the 4,4’-bipyridine-like coformers occurs. Indeed, this synthon is not relatively frequent in the CSD23 but it appears to be decisive for the assembly of the cocrystals reported here (see below). Successfully, both cocrystals with efavirenz were obtained as well as their isostructurality with respect to the antecedent one with 4,4’-bipyridine as expected was observed. Both efavirenz cocrystals with 1 and 2 crystallize in the triclinic space group P1 with two molecules of the API and one molecule of the cocrystallizing agent in the asymmetric unit (Fig. 1). Crystal data and refinement statistics are presented in Table 1. The same space group and 2:1 drug:coformer stoichiometry is also observed in the efavirenz-4,4’-bipyridyl cocrystal. Indeed, not only the unit cell symmetry and content of the efavirenz cocrystals with 1, 2 and 4,4’-bipyridine were identical, but their unit cell metrics were also similar. The cell volumes of the API cocrystals with 1 and 2 were slightly higher than that of the antecedent phase with 4,4’-bipyridine, even taking into account the cell contraction expected for our structures whose X-ray diffraction data were measured at 120 K while the Desiraju structure was determined at room temperature (298 K). Another straight difference between our structures and that of


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Desiraju and coworkers7 resides in the disorder of the cyclopropyl group that seems to be related to temperatures of single-crystal X-ray diffraction data collect. While in the cocrystal with 4,4’-bipyridine (298 K structure) the cyclopropylethynyl moiety of efavirenz is much disordered over two conformations at least,7 the degree of disorder is notably decreased for this moiety in both structures measured at 120 K (those having coformers 1 and 2). Nevertheless, the disorder involving the entire cyclopropylethynyl group of efavirenz B in the cocrystal with 2 could be modeled reliably with major and minor populations of 65% and 35% for the site occupancies of the carbons C10 to C14 and hydrogens bonded to C12 (methine), C13 and C14 (methylene). It is striking to state that trial unstable refinements with high correlation between ADPs and SOFs were used with the split-atom approach for the cyclopropylethynyl atoms of the other efavirenz conformers in the cocrystals with 1 and 2 and also for pyridyl carbons of 1, but the extra disordered sites are very close together, perhaps in more than two sites for each atom. In fact, cyclopropyl is the efavirenz moiety of higher conformational freedom. The orientation of this group differs for the conformers observed in the efavirenz cocrystals with 1, 2 and 4,4’bipyridine,7 which can be noticed by the values of the C10—C11—C12—Y torsion angles given comparatively in Table 2 for the three crystal forms. Theoretical approaches indeed evidence a low energy barrier for the rotation on the C11—C12 bond axis when the cyclopropylethynyl residue is either in the equatorial (2.42 kJ/mol) or in the axial position (2.83 kJ/mol) of the heterocyclic ring.7 Such a rotation on this bond axis sets different orientations of the cyclopropyl ring, being decisive even in determining the number of crystallographically independent conformers in the asymmetric unit (Z’). Even though the differences in the values of the C10—C11—C12—Y torsion angles, both conformers of the efavirenz cocrystal with 1 and one of the two ones of efavirenz cocrystal with 2, namely, that labeled with the suffix A, plus the minor conformer of that labeled as B can be described by a similar eclipsed-like conformation when projected along the C2—C10—C11—C12 linear path where the


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cyclopropyl moiety lies on the same side of the lactone part of the heterocyclic ring (Fig. 2). On the other hand, the other conformer of efavirenz cocrystal with 2, that labeled as B whose population is 65%, exhibits a staggered-like conformation with the C14 and C12 atoms of cyclopropyl in the axial position anti-related to —CF3 and in the equatorial orientation on the same side of the lactone moiety of the heterocycle, respectively (Fig. 2). Furthermore, in all conformers found in the efavirenz cocrystals with 1, 2 and 4,4’-bipyridine the cyclopropylethynyl group is in the equatorial position of the heterocycle, which is in agreement with the fact that this conformer was found to be the most stable one in the previous study.7 With respect to the six-membered heterocyclic ring, a similar conformation is observed for all conformers of the efavirenz cocrystals with 1, 2 and 4,4’-bipyridine. This moiety assumes a slightly distorted and flattened half-chair conformation with the C2 atom far away from the least-squares plane passing through the other coplanar atoms, lying to an opposite side of cyclopropylethynyl relative to this plane (see table 2 for C2 deviations from the least-squares planes calculated through the five O1— C1—N1—C7—C8 coplanar atoms of the heterocycle and their r.m.s.d.). The highest dihedral angles within the six-membered heterocycle of the drug molecules are on bonds of the C2 carbon, namely, the torsions C1—O1—C2—C8 and O1—C2—C8—C7 (Table 2). The cocrystallizing agents 1 and 4,4’-bipyridine are not completely planar in their efavirenz cocrystals. While 4,4’-bipyridine is present with a twist of ca. 9° between the pyridine rings, these moieties form angles of 13.1(7)° (PyA, the pyridine ring hydrogen bonded to efavirenz conformer A) and 15.7(7)° (PyB, the pyridine ring hydrogen bonded to efavirenz conformer B) with the least-squares plane calculated through the C=C carbons bridging them in 1. However, the pyridine rings of 1 are twisted only by 3.2(3)° in the cocrystal in query. This is a consequence of similar degree rotations on the σ-bonds of the coformer to opposite directions, bending noticeably the pyridine moieties with


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respect to the plane of the two sp2-hybridized spacer carbons but not much relative to each other. The pyridine planes adopt an anti-conformation in the efavirenz cocrystal with 2, forming an angle of 3.7(9)°. This value is much similar to that of the coformer 1 in the corresponding isostructural cocrystal, even though the centroid of each pyridine ring is more deviated from the plane of one another in the coformer 2 than in 1. The centroids calculated for PyA and PyB rings of 2 are offset by 1.5(3) Å and 1.2(4) Å from the least-squares planes crossing through PyB and PyA, respectively, while the corresponding measurements are 0.5(1) Å and 0.3(3) Å for the efavirenz cocrystal with 1. The supramolecular architecture of the efavirenz-4,4’-bipyridyl cocrystal was conserved in both crystal forms of the drug with 1 and 2. Even the introduction of the —CH=CH— and —(CH2)2— moieties spacing the pyridine rings of the coformers was not able to hinder the assembly of multicomponent molecular crystals as that of the efavirenz cocrystal with 4,4’-bipyridine. Such spacing into the cocrystallizing agents has increased the net distance between the nitrogen atoms of drug conformers A and B, both bonded to a same coformer unit, from ca. 12.7 Å in the efavirenz-4,4’bipyridyl cocrystal7 to 15.015(7) Å and 14.898(4) Å in the isostructures containing 1 and 2. Even so, the formation of a three-molecule supramolecular entity by mean of two different hydrogen bonding patterns occurs similarly in the three efavirenz cocrystals. In all three structures, efavirenz conformers A and B are classical hydrogen bonding donors to PyA and PyB in the N1A—H1A· · ·N1Py and N1B— H1B· · ·N2Py interactions, respectively, while the drug molecule B is also a non-classical hydrogen bonding acceptor from a CH group of PyB (Fig. 1). This last contact, namely, through the C10—H10Py· · ·O2B atoms, gives rise to a hydrogen bonded cycle together with the N1B—H1B· · ·N2Py interaction. This is due to the fact that the heterocycle plane of the efavirenz conformer B is almost coplanar to the PyB plane, allowing the formation of the two contacts aforementioned. Such a heterosynthon I (Fig. 3) as observed in these cocrystals is rarely found in the CSD23 (version 5.33 updated in August 2012, 624,927 entries). There are only 47 entries for the in plane cyclic hydrogen bonds responsible for the


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pairing between efavirenz B and the 4,4’-bipyridine-like coformers. This reflects the difficulty of assembling the structures of the cocrystals obtained here. On contrary, drug conformers A have their heterocycle planes almost perpendicularly oriented relative to the PyA plane. Consequently, the nonclassical hydrogen bonding donation from one CH moiety of PyA to the carbonyl O2A oxygen is not geometrically possible and only the N—H· · ·N contact occurs between efavirenz A and coformers. This heterosynthon II is more common in the CSD (786 entries) than synthon I (Fig. 3), which strengthens the fact that the limiting assembly step for the obtained cocrystals resides in the hydrogenbonded cycle formation. From a supramolecular point of view, this primary hydrogen bonding pattern with heterosynthons I and II gives rise to a 2:1 organization of columns made up of either drug or coformer molecules. Interestingly, in the three structures the two neighboring drug columns are arranged in a tail-to-tail fashion so that all cyclopropylethynyl branches and chlorobenzene portions of benzoxazinone of each column points toward the corresponding moieties of another one (Fig. 4). Consequently, the inner hydrophobic groups lay in the core of two pillared drug columns kept in contact by many van der Waals (vdW) interactions between the cyclopropylethynyl chains of neighboring molecules. Chlorine also participates of several vdW contacts with the alkyl tails. In turn, the hydrophilic motifs of each drug column are exposed and hydrogen-bonded to a coformer column which is between two efavirenz column pairs. Nevertheless, the further role of the spacer groups in the crystal assembly can be noticed when inspecting carefully the secondary non-classical hydrogen bonds of the type C—H· · ·O=C (Fig. 5). In the efavirenz cocrystal with 4,4’-bipyridine, neighboring CH groups at the 2,2’-positions of the pyridine rings are hydrogen bonding donors to the carbonyl oxygen of the drug conformer B in a bifurcated pattern, while only one contact, that involving the 2’-CH moiety (labeled as C12C—H12C in our coformers), occurs in the drug cocrystal with 1 and the corresponding groups of 2 do not interact with any drug conformer. The separations between CH hydrogens of coformers and carbonyl oxygens


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of the drug are shown in Fig. 5. Moreover, the CH moiety at the other ortho position of PyB (at 6’) interacts with the carbonyl oxygen of the efavirenz molecule A in the antecedent crystal form. This contact occurs analogously in the efavirenz cocrystals with 1 and 2, but with the hydrogen bonding donor groups as being either the ethylene C7C—H7C atoms of 1 or the methylene C7C—H7C2 ones of 2. In both cases, C7 carbons directly bond to PyB and the H7C and H7C2 atoms of 1 and 2 point towards the carbonyl O2A oxygens like the aromatic hydrogen at the 6’-position of 4,4’-bipyridine,7 with similar hydrogen bonding geometries (Fig. 5). This exposes the versatility of the carbonyl group of the conformer A to accept a CH hydrogen bonding donation in the isostructural lattices. Furthermore, this carbonyl oxygen also interacts with the CH group of PyA at the 3-position (C5C— H5C) in the efavirenz cocrystals with 1 and 2 (Fig. 5). This interaction occurs only in these structures. Furthermore, a π-π stacking can be noticed between the PyA and PyB rings of translation symmetry related units of 2 by the considerably short distance between the centroids calculated for these moieties (3.9(3) Å) (Fig. 6). No π-π stacking interactions take place in the other two related structures, even though a tendency for that is already found in the efavirenz cocrystal with 1. The distance between the PyA and PyB centroids as calculated for 2 is 4.2(3) Å, a value which is shorter than the shortest separation between pillared pyridyl moieties in the efavirenz-4,4’-bipyridyl cocrystal (ca. 5.3 Å).7 It is important to note that in the former cocrystal the centroids of equal pyridyl rings have the shortest distance, while in the cocrystals with 1 and 2 there is a slippage of the coformers along the [0 1 2] direction setting different pyridyl rings near to each other. More specifically, the overall three-molecule supramolecular entity is displaced along such direction. Such displacement can be viewed as an attempt to favor geometrically the π-π interaction in the cocrystal with 1, but unsuccessfully as occurs between coformer units of 2 in its cocrystal with efavirenz. Concerning the new efavirenz polymorph obtained as part of our screenings to synthesize the drug


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cocrystal with 1, namely, form V, its structure was solved in the C2 monoclinic space group with only one molecule in the asymmetry unit (Fig. 7). The only previously known structure of efavirenz with Z’ = 1 crystallizes in the P212121 orthorhombic space group.6 Even though this space group and crystal system differences, both forms are similar due to the formation of their supramolecular entities (see below) besides the same Z’ content. In form V, a disorder pattern similar to that of efavirenz molecule B in the cocrystal with 2 is observed. The cyclopropylethynyl group of this polymorph is disordered over two positions, with both conformations in the equatorial position of the heterocycle. The cyclopropyl ring adopts staggered-like and eclipsed-like conformations as those above described (Fig. 7 and Table 2 for torsion angles describing these conformations). However, these two conformations were present with major and minor populations of 65% and 35% in the drug molecule B of the cocrystal with 2, while these conformations are equally distributed over the crystal lattice of form V. Another similarity of form V with the drug conformers in the cocrystals with 4,4’-bipyridine-based coformers resides in the slightly distorted and flattened half-chair conformation of the six-membered heterocyclic ring. The C2 atom is the most deviated one from the least-squares plane passing through O1—C1—N1—C7—C8 (Table 2), staying on an opposite side of cyclopropylethynyl relative to this plane. As in the cocrystals reported in this study, the torsions on bonds of the C2 atom are present with the largest values among all dihedral angles within the six-membered heterocycle of form V (Table 2). The related form reported by Ravikumar and Sridhar is strictly similar to form V in terms of heterocycle conformation and also resembles its cyclopropylethynyl conformation, but the last comparison is not much reliable because of refinement constraints carried out with the antecedent polymorph. The Ravikumar and Sridhar’s form is present with the cyclopropylethynyl in the in the equatorial position of the heterocycle and an eclipsed-like cyclopropyl conformation. To the best of our knowledge, form V and that reported by Ravikumar and Sridhar are the only ones with just one drug molecule in the asymmetry unit. Besides the conformational similarity, both


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polymorphs are made up of helical catemers assembled through N1—H1· · ·O2 hydrogen bonds (homosynthon III in Fig. 3 and Fig. 8). Likewise, both forms have high densities calculated from their crystal structures (1.501 g cm-3 for form V and 1.486 g cm-3 for the antecedent polymorph), but this does not relate to the formation of the helical chains because even the polymorph reported by Tiekink and co-workers,5 which is present with N1—H1· · ·O2 hydrogen bonded cyclic dimmers instead of catemers and exhibits a calculated density of 1.519 g cm-3, is more dense than them. Moreover, one can note that form V is denser than Ravikumar and Sridhar’s polymorph. This is related to the packing of their helical supramolecular entities. In the antecedent form, helical catemers are side-to-side packed parallel to the [010] direction. Such [010]-packed catemers grow on same direction parallel to the a axis. However, 21-screw axis symmetry related helices running on opposite directions parallel to the a axis are packed along the [001] direction (Fig. 8), in an anti-parallel fashion. Furthermore, there is a slippage along the [010] direction when packing anti-parallel helices, giving rise to a hexagonal arrangement of the catemers (on bottom of Fig. 8). On the other hand, all helices of form V grow on the same direction along the b axis, in a parallel mode. In this polymorph, translation symmetry related helices are coherently packed along the [100] and [001] directions. This results in an organization of cyclopropylethynyl branches and chlorobenzene portions of benzoxazinone as that of the three 4,4’bipyridine-based cocrystals (Fig. 9). Furthermore, the supramolecular architecture of form V can be understood as those of the cocrystals studied here in which coformer columns are absent and drug columns were joined together to connect the primary hydrogen bonding sites, forming the helical N— H· · ·O motif made up of drug molecules rather than the N—H· · ·N pattern between efavirenz and coformers (see Figs. 4 and 9 for comparisons). A geometric parameter that reflects such observation is in the fact that drug molecules A and B spaced by the coformer 1 have their heterocycle planes almost perpendicularly oriented as well as the hydrogen bonded units assembling the helical catemer in form V. There are angles of 89.1(3)° and 89.5(5)° between these planes in the cocrystal with 1 and in form


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V, respectively. Therefore, the structure of form V appears to be guided by the presence of coformer 1 in the crystallization medium and its interaction pattern with the drug.

4. Conclusions In conclusion, our prediction on the structural similarity of efavirenz cocrystals with 1 and 2 to that with 4,4’-bipyridine does get success experimentally. This does mean that such crystal engineering approach based on the conservation of key stereochemical features and classical hydrogen bonding functionalities in the coformers is applicable for this cocrystal series of efavirenz even whether spacer groups have intercalated the pyridine rings. Even though the pattern of weak non-classical hydrogen bonds have been somewhat different for the three isostructural cocrystals, further leading to a formation of a π-π stacking interaction between units of 2 in its cocrystal with efavirenz, the threemolecule supramolecular entity made up of two drug units and one coformer has been kept and assembled similarly into the lattices of the efavirenz cocrystals with 4,4’-bipyridine, 1 and 2. In this way, besides the contribution to the knowledge of new efavirenz solid state structures, this study prospects the need to assess if other spacers (or the approximation of pyridine-like nitrogen atoms and vicinal CH moieties) and pyridine substitutions do not hinder the assembly of a multicomponent molecular architecture as described here. Likewise, the discovery and structural characterization of a new polymorph adds knowledge to solid state chemistry of efavirenz, even though its physicochemical properties and the phenomena involved in its formation need to be investigated. Acknowledgment. We thank the Brazilian Research Council CNPq (Conselho Nacional de Desenvolvimento Científico e Tecnológico) for the financial support (Processo 472623/2011-7 Universal 14/2011). We thank Altivo Pitaluga Jr. (Fundação Oswaldo Cruz - FIOCRUZ, Manguinhos, Rio de Janeiro, Brazil) for the gift of efavirenz sample. Thanks are due to the Consejo Superior de


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Investigaciones Científicas (CSIC) of Spain for the award of a license for the use of the Cambridge Structural Database (CSD). Supporting Information Available. Crystallographic Information Files (CIF) and Figure S1. This material is available free of charge via the Internet at http://pubs.acs.org.

References (1) Young, S. D.; Britcher, S. F.; Tran, L. O.; Payne, L. S.; Lumma, W. C.; Lyle, T. A.; Huff, J. R.; Anderson, P. S.; Olsen, D. B.; Carroll, S. S.; Pettibone, D. J.; O’Brien, J. A.; Ball, R. G.; Balani, S. K.; Lin, J. H.; Chen, I. -W.; Schleif, W. A.; Sardana, V. V.; Long, W. J.; Byrnes, V. W.; Emini, E. A.; Antimicrob. Agents Chemother. 1995, 39, 2602-2605. (2) De Clercq, E.; Antivir. Res. 1998, 38, 153-179. (3) Dobkin, J. F.; Infect. Med. 1998, 15, 747. (4) Llibre, J. M.; Clotet, B.; AIDS Rev. 2012, 14, 168-178. (5) 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. (6) Ravikumar, K.; Sridhar, B.; Mol. Cryst. Liq. Cryst. 2009, 515, 190-198. (7) Mahapatra, S.; Thakur, T. S.; Joseph, S.; Varughese, S.; Desiraju, G. R.; Cryst. Growth Des. 2010, 10, 3191-3202. (8) Chadha, R.; Arora, P.; Saini, A.; Jain, D. S.; J. Pharm. Pharmaceut. Sci. 2012, 15, 234-251. (9) (a) Chiappetta, D. A.; Hocht, C.; Sosnik, A.; Curr. HIV Res. 2002, 8, 223–231. (b) Gazzard, B.; Bernard, A. J.; Boffito, M.; Churchill, D.; Edwards, S.; Fisher, N.; Geretti, A. M.; Johnson, M.; Leen, C.; Peters, B.; Pozniak, A.; Ross, J.; Walsh, J.; Wilkins, E.; Youle, M.; HIV Med. 2006, 7, 487–503. (10) Sosnik, A.; Chiappetta, D. A.; Carcaboso, A. M.; J. Control. Release 2009, 138, 2–15.


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(11) (a) Kasim, N. A.; Whitehouse, M.; Ramachandran, C.; Bermejo, M.; Lennernas, H.; Hussain, A. S.; Junginger, H. E.; Stavchansky, S. A.; Midha, K. K.; Shah, V. P.; Amidon, G. L.; Mol. Pharm. 2004, 1, 85–96. (b) Takano, R.; Sugano, K.; Higashida, A.; Hayashi, Y.; Machida, M.; Aso, Y.; Yamashita, S.; Pharm. Res. 2006, 23, 1144–1156. (12) Sathigari, S.; Chadha, G.; Lee, Y. H.; Wright, N.; Parsons, D. L.; Rangari, V. K.; Fasina, O.; Babu, R. J.; AAPS PharmSciTech 2009, 10, 81–87. (13) Kaplan, S.; Drug Metab. Rev. 1972, 1, 15–34. (14) (a) Weyna, D. R.; Shattock, T.; Vishweshwar P.; Zaworotko, M. J.; Cryst. Growth Des. 2009, 9, 1106-1123. (b) Vangala, V. R.; Chow, P. S.; Tan, R. B. H.; Cryst. Growth Des. 2012, 12, 59255938. (15) (a) Radesca, L. A.; Maurin, M. B.; Rabel, S. R.; Moore, J. R. WO 99/64405, 1999. (b) Crocker, L. S.; Kukura, J. L., II; Thompson, A. S.; Stelmach, C.; Young, S. D. US 6,639,071 B2, 2003. (c) Crocker, L. S.; Kukura, J. L., II; Thompson, A. S.; Stelmach, C.; Young, S. D. U.S. Patent 6,939,964 B2, 2005. (d) Khanduri, C. H.; Panda, A. K.; Kumar, Y.WO 2006/030299 A1, 2006. (e) Reddy, P.; Rathnakar, R. K.; Raji, R. R.; Muralidhara, R. D.; Subhash, C. D. K. WO 2006/018853 A2, 2006. (f) Sharma, R.; Bhushan, K. H.; Aryan, R. C.; Singh, N.; Pandya, B.; Kumar, Y.WO 2006/040643 A2, 2006. (g) Tyagi, O. M.; Jetti, R. K. R.; Ramireddy, B. A. WO 2009/087679 A2, 2009. (h) Sathigari, S.; Radhakrishnan, V. K.; Davis, V. A.; Parsons, D. L.; Babu, R. J.; J. Pharm. Sci. 2012, 101, 3456–3464. (16) SADABS, APEX2 and SAINT. Bruker AXS Inc., Madison, Wisconsin, USA, 2009. (17) Sheldrick, G. M.; Acta Crystallogr. Sect. A 2008, 64, 112-122. (18) Macrae, C. F.; Bruno, I. J.; Chisholm, J. A.; Edgington, P. R.; Mccabe, P.; Pidcock, E.; Monge, L. R.; Taylor, R.; van de Streek, J.; Wood, P. A.; J. Appl. Crystallogr. 2008, 41, 466-470. (19) Farrugia, L. J.; J. Appl. Crystallogr. 2012, 45, 849-854.


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(20) Bis, J. A.; Vishweshwar, P.; Weyna, D.; Zaworotko, M. J.; Mol. Pharmaceutics 2007, 4, 401– 416. (21) Vangala, V. R.; Bhogala, B. R.; Dey, A.; Desiraju, G. R.; Broder, C. K.; Smith, P. S.; Mondal, R.; Howard, J. A. K.; Wilson, C. C.; J. Am. Che. Soc. 2003, 125, 14495–509. (22) Vishweshwar, P.; Nangia, A.; Lynch, V. M.; Cryst. Growth Des. 2003, 3(5), 783–790. (23) Allen, F. H.; Acta Crystallogr. Sect. B 2002, 58, 380–388.


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Figure 1. From top to bottom, asymmetric units of efavirenz cocrystals with 1, 2 (120 K structures), and 4,4’-bipyridine (298 K structure).7 Non-hydrogen atoms of efavirenz cocrystals with 1 and 2 are represented as 50% probability ellipsoids, while those of the drug cocrystal with 4,4’-bipyridine and all hydrogens are displayed as arbitrary radius spheres. The cyclopropylethynyl group of efavirenz molecule B in the cocrystal with 2 is distributed over two occupancy sites: a major of 65% occupancy drawn as the other atoms, and a minor of 35 % occupancy drawn with opacity. Figure 2. Superposition of the efavirenz molecules A (left) and B (right) in the cocrystals with 1 (blue), 2 (green for molecule A and molecule B at 65% occupancy sites, cyan for molecule B at 35% occupancy sites), and 4,4’-bipyridine7 (yellow). The hydrogen atoms were hidden for clarity. In panel (a), views almost onto the benzoxazinone mean plane are depicted, while projections along the C2— C10—C11—C12 linear path highlight the cyclopropyl conformation in panel (b). Figure 3. Heterosynthons I and II observed in the efavirenz cocrystals with coformers 1, 2 (both from this study) and 4,4’-bipyridine7, and homosynthon III responsible for the catemers assembly in both form V (this study) and Ravikumar and Sridhar’s6 form. Figure 4. Views of three efavirenz column pairs projected along the [100] (top, b axis in the vertical and c axis in the horizontal) and [010] (bottom, a axis in the vertical and c axis in the horizontal) directions of the drug cocrystals with 1, 2 and 4,4’-bipyridine. The intercolumn hydrophobic cores are highlighted in grey and the primary hydrogen bonding sites in cyan. Each two drug columns are kept away from two others by an intercalating coformer column (not shown in the picture, cyan region). Figure 5. The weak hydrogen bonding interactions (represented as dashed rods) of the type C—H· · ·O in the efavirenz cocrystals with 1, 2 and 4,4’-bipyridine (from left to right). Relevant distances between CH hydrogens of coformers and carbonyl oxygens of the drug are depicted in the illustration, even


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whether no weak hydrogen bonds take place (arrows). The three-molecule supramolecular entities are assembled along the [0 1 2] direction. Figure 6. Packing of the supramolecular entities parallel to the [0 1 0] direction in efavirenz cocrystals with 1, 2 and 4,4’-bipyridine (from top to bottom). Distances between the centroids calculated through the pyridyl atoms are displayed (arrows), even though a π-π interaction (represented as dashed rods as well as hydrogen bonds responsible for the three-molecule entity assembly) occurs only in the efavirenz cocrystal with 2. Figure 7. Asymmetric unit of efavirenz form V (300 K structure) whose non-hydrogen atoms are represented as 50% probability ellipsoids and hydrogens as arbitrary radius spheres (top). The cyclopropylethynyl group is distributed over two sites of equal occupancies (one is drawn with opacity). Projections along the C2—C10—C11—C12 linear path showing the two cyclopropyl conformations in the bottom. Figure 8. The helical hydrogen bonded catemers responsible for the assembly of form V and the polymorph described by Ravikumar and Sridhar6 and their distinct packing. Figure 9. Views of three efavirenz column pairs in form V projected along the directions [010] (top, a axis in the vertical and c axis in the horizontal) and [100] (bottom, b axis in the vertical and c axis in the horizontal). The hydrophobic cores are highlighted in grey and the hydrogen bonding sites in cyan.


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Table 1. Crystal data and refinement statistics of the efavirenz cocrystals with 1 and 2 and form V. cocrystal with 1 structural formula fw cryst syst space group Z T (K) unit cell dimensions

(C14H9Cl1F3N1O2)2(C12H10N2) 813.56 triclinic P1 1 120(2) a (Å) b (Å) c (Å) α (°) β (°) γ (°)

V (Å3) calculated density (Mg/m3) absorption coefficient (mm-1) Absorption correction

θ range for data collection (°) index ranges

data collected unique reflections symmetry factor (Rint) completeness to θ = 25° (%) F (000) parameters refined goodness-of-fit on F2 final R factors for I >2σ(I) R factors for all data largest diff. peak / hole (e/Å3) absolute structure Flack parameter Friedel pairs CCDC deposit number

cocrystal with 2 (C14H9Cl1F3N1O2)2(C12H12N2) 815.58 triclinic P1 1 120(2)

form V C14H9Cl1F3N1O2 315.67 monoclinic C2 4 300(2)

5.1586(6) 8.9072(9) 20.768(2) 86.317(7) 86.355(7) 73.313(7) 911.18(17) 1.483 0.258 Multi-scan Tmin / Tmax = 0.801 1.97 - 29.83 -5 to 6 -10 to 12 -28 to 26 8,100 5,768 0.0339 97.5 416 506 1.025 R1 = 0.0780 wR2 = 0.1984 R1 = 0.0905 wR2 = 0.2095 0.507/-0.529

5.3101(4) 8.6465(5) 20.7050(14) 84.956(4) 85.946(4) 74.581(4) 911.77(11) 1.485 0.258 Multi-scan Tmin / Tmax = 0.808 1.98 - 26.50 -6 to 6 -10 to 10 -25 to 24 7,616 5,292 0.0170 98.1 418 538 1.023 R1 = 0.0379 wR2 = 0.0924 R1 = 0.0426 wR2 = 0.0963 0.372/-0.379

16.656(7) 5.312(2) 17.227(7) 90 113.59(3) 90 1396.9(10) 1.501 0.310 Multi-scan Tmin / Tmax = 0.921 2.46 - 26.49 -20 to 19 -6 to 6 -21 to 21 5,563 2,493 0.0283 99.2 640 235 1.024 R1 = 0.0418 wR2 = 0.0870 R1 = 0.0854 wR2 = 0.1060 0.176/-0.213

0.08(12)

-0.04(6)

-0.01(12)

2072 909385

1621 909386

909 923049


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1 2 3 4 Table 2. Torsion angles (°) and planarity descriptors (r.m.s.d. and C2 deviation in Å) of the efavirenz conformation 5 6 for its cyclopropyl and heterocyclic moieties in the cocrystals with 1, 2, form V (all from this study) and 4,4’7 bipyridine.7 8 O1-C1-N1-C7-C8 C2 deviation from C10-C11-C12-C13 C10-C11-C12-C14 C1-O1-C2-C8 O1-C2-C8-C7 9 plane r.m.s.d. O1-C1-N1-C7-C8 10 Cocrystal with 1 11 Molecule A -114.8(17) -45.0(18) -37.4(7) 27.2(7) 0.0294 -0.426(6) 12 B -121.4(12) -56.0(12) -37.4(8) 26.9(8) 0.0308 0.418(7) 13 Cocrystal with 2 14 Molecule A -137.7(7) -68.6(7) -37.3(3) 27.7(4) 0.0136 -0.437(3) 15 B (65%) 11.4(13) 80.4(14) 16 -34.4(4) 24.4(4) 0.0152 0.392(4) B (35%) -160.5(14) -92.8(15) 17 Efavirenz form V 18 109.2(7)/-162.3(8)a -175.4(7)/-85.1(7)a -37.7(5) 27.0(5) 0.0189 0.432(4) 19 Cocrystal with 4,4’20 bipyridine7 21 Molecule A -140.8 -83.4 -37.5 28.3 0.0255 -0.411(3) 22 B -132.0 172.1 -36.7 26.9 0.0173 0.435(3) 23 a The two torsion angle values refer to cyclopropylethynyl moiety over two positions of equal populations in this efavirenz polymorph. 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 ACS Paragon Plus Environment

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Scheme


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Figure 1


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Figure 2


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Figure 3


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Figure 5


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Figure 7


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For Table of Contents Use Only

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 Ariane Carla Campos de Melo, Isadora Ferreira de Amorim, Marilia de Lima Cirqueira, and Felipe Terra Martins.

Synopsis: Here two cocrystals of efavirenz, a non-nucleoside reverse transcriptase inhibitor largely used as part of anti-HIV therapies whose screening methods have few success as source of new solid state forms, were engineered with 4,4’bipyridine-like coformers and a new polymorph was discovered.


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Toward Novel Solid-State Forms of the Anti-HIV Drug Efavirenz: From

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