Low-Temperature Phase Transition in Crystalline Aripiprazole Leads

Sep 9, 2014 - Department of Chemistry, Syracuse University, 1-014 Center for Science and Technology, Syracuse, New York 13244-4100, United States. ‡...
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Low-Temperature Phase Transition in Crystalline Aripiprazole Leads to an Eighth Polymorph Sean P. Delaney,† Tiffany M. Smith,† Duohai Pan,‡ Shawn X. Yin,‡ and Timothy M. Korter*,† †

Department of Chemistry, Syracuse University, 1-014 Center for Science and Technology, Syracuse, New York 13244-4100, United States ‡ Drug Product Science & Technology, Bristol-Myers Squibb, 1 Squibb Drive, New Brunswick, New Jersey 08903, United States S Supporting Information *

ABSTRACT: A new crystalline polymorph (Form VIII) of the antidepressant drug aripiprazole has been discovered, resulting from a previously unknown enantiotropic phase transition from Form II at 225 K. This finding makes aripiprazole one of the most polymorphic flexible organic solids currently known, equaling flufenamic acid in number of solved forms (eight polymorphs). Enantiotropic solid−solid phase transitions are relatively uncommon for pharmaceuticals; however, for the aripiprazole system, such phase transitions play a central role in several of its polymorphic transformations. A combination of solid-state density functional theory and single-crystal X-ray diffraction has been used to investigate the energies involved in the formation of Form VIII. This work reveals that Form VIII is stable despite containing molecules with unfavorable conformations. The stability of this polymorph originates from improved intermolecular binding energy due to enhanced London dispersion forces at low temperatures. proposed polymorphs and eight solved structures.7 Here, we investigate the polymorphism of aripiprazole, a commonly prescribed antipsychotic drug that is also used as an antidepressant (active ingredient in Abilify), which was previously known to exist in seven anhydrous polymorphs.8−11 In this study, an eighth explicitly solved structure of aripiprazole was recorded, tying this system with FFA for the most polymorphic organic solid. While aripiprazole is equal to FFA in terms of completely solved structures of phase-pure polymorphic forms, it has a total of 12 proposed anhydrous polymorphs (four that have been investigated only through powder X-ray diffraction) and an additional eight solvatomorphs.12 This makes aripiprazole one of the most flexible systems currently known, if not the most polymorphic rich organic crystal yet discovered. Identifying and characterizing pharmaceutical polymorphs is essential for application of these compounds, but understanding the underlying formation details is of fundamental importance in predicting the existence of additional undiscovered forms. All of these mechanisms involve specific phase transformations, which have been regarded in numerous ways throughout the history of polymorphism study. Three of the essential types of polymorphic transformations were originally discussed by Buerger in 1951.13 These transformations involve changes in packing arrangements (traditional polymorphism), conforma-

1. INTRODUCTION The ability of molecules to crystallize into multiple solid-state forms, polymorphism,1,2 is rooted in variations in the external binding and internal conformational forces that tip the energetic balance toward specific crystalline arrangements. While polymorphism is a common and widespread phenomenon, the occurrence of it in pharmaceutical compounds is of particular concern, since different polymorphs may have different physical properties (solubility, melting point, etc.), thus impacting manufacturing, storage, and bioavailability. Perhaps the most famous case of the importance of polymorphism in the pharmaceutical industry is the protease inhibitor ritonavir, which had to be temporarily withdrawn from the market due to the spontaneous formation of a previously unknown, and less soluble, polymorph.3 Given these issues, the search for and identification of drug polymorphs is crucial for realizing effective drug formulations and has become a key component for maintaining compliance with federal regulations.4 However, polymorph screening is not a trivial process, and it has been suggested that all systems exhibit polymorphism, with the number of forms found limited solely by the time spent searching.5 A few organic molecules show remarkable polymorphic flexibility. Since 2005, the most polymorphic system known was 5-methyl-2-[(2-nitrophenyl)amino]-3-thiophenecarbonitrile (ROY), with nine potential polymorphs and seven explicitly solved (by single-crystal X-ray diffraction) polymorphs.6 Recently, this record for explicitly solved polymorphs has been broken by flufenamic acid (FFA), which has nine © 2014 American Chemical Society

Received: April 23, 2014 Revised: August 8, 2014 Published: September 9, 2014 5004

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tional changes in which the lattice structure remains the same (conformational polymorphism), and a mixture of both where some intermolecular bonds are broken and reformed to accommodate conformational changes elsewhere in the molecule (rotational transformations, characteristic of disordered crystals).5,13 These transformation mechanisms are still widely seen as the three main distinguishable types of solidstate phase transformations.14 Within the overarching concepts of phase transformations is the observance of enantiotropic vs monotropic phase transitions. When only one form is stable below the melting point of any phase, then the system is considered to be monotropic.2,14−18 Enantiotropic relationships between polymorphs occur if there is a coexistence point in the phase diagram where the free energies of both phases are equivalent, and therefore reversible, below the melting point of either phase.2,14−18 In an enantiotropic system, each polymorph has a specific temperature range where it is the most stable form. In addition to temperature, changes in pressure (such as via grinding during drug manufacturing1,19,20) can also affect the transition points, since increasing the pressure can lower the temperature barrier.20 Enantiotropic transitions pose the largest challenge to pharmaceutical manufacturers because multiple stable polymorphs could exist below the drug melting point, thus creating cases similar to ritonavir where unknown polymorphs may be present. Both monotropic and enantiotropic transitions can occur through four distinct methods: solid−solid (without passing through transient liquid or vapor phases), melt (heated past the melting point and then cooled), solution (dissolved in a solvent), or solution-mediated (solvent molecules facilitate the transition between metastable and stable forms).17 While all of these transition methods are important for the pharmaceutical industry, solid−solid phase transitions are less common in pharmaceutical compounds due to the high activation energies encountered in moving such large molecules.15,16 One welldocumented example of a solid−solid enantiotropic phase transition is observed in the crystalline polymorphs of carbamazepine, where there is a phase transition between Form I and Form III upon heating.21,22 Another example of an enantiotropic transition is illustrated by the β form of chlorpropamide, which undergoes two different solid−solid phase transformations when cooled from room temperature to 100 K.23 While solid−solid transitions are unusual in large pharmaceutical molecules, there are other pharmaceutical systems (including paracetamol, sulfathiozole, and theophylline) that undergo similar temperature-based phase transformations.24 Aripiprazole is known to exhibit enantiotropic solid−solid phase transitions, and the transition between Form V (P1̅, Z = 2, Z′ = 1) and Form I (P1̅, Z = 2, Z′ = 1) has been wellstudied.8 Aripiprazole Form II (Figure 1, Pna21, Z = 4, Z′ = 1) is also enantiotropically related to Form V8 and has been discovered in the current work to exhibit a previously unknown phase transition to a new polymorph that is stable at low (sub225 K) temperature. The new phase transformation primarily involves a conformational change in the aripiprazole molecules when Form II is cooled to low temperatures, resulting in the formation of Form VIII. The seven previously known polymorphs of aripiprazole exhibit remarkable conformational flexibility and have been examined thoroughly in a previous study.11 While Form II and Form VIII are not the active pharmaceutical ingredient (API) forms, investigating the basis

Figure 1. Molecular structure and unit cell molecular packing of aripiprazole Form II and Form VIII. Note similarities in packing and differences in the butoxyl chain conformation.

for the phase transformation between them can yield important insight into the origins of the extensive polymorphism of aripiprazole in general and further understanding of polymorphism in other complex solids. A combination of single-crystal X-ray diffraction and solidstate density functional theory (DFT) has been employed in the analysis of the new phase transition discovered between aripiprazole Form II and Form VIII. Single-crystal X-ray diffraction is the standard method for unambiguous polymorph characterization, and solid-state DFT has been shown to yield accurate reproductions of the molecular geometries, unit cell parameters, and relative energies of many different crystalline organic solids, including aripiprazole.11,25−27 Achieving the complete computational reproduction of the crystal structure signals that the utilized model is successfully describing the internal and external potential energy surfaces of the substance and therefore can be expected to yield valid energetic data, in terms of both electronic (relative energy, conformational strain, and cohesive binding) and thermodynamic (Gibbs free energy) factors. Thus, the solid-state simulations enable a better understanding of the relative energies of the two forms, including the specific contributions of conformational and cohesive energies, and the transition temperature between the two forms and can help to elucidate aspects of the mechanisms behind the considerable polymorphic nature of aripiprazole.

2. METHODS 2.1. X-ray Diffraction. Aripiprazole Form II crystals were prepared at elevated temperatures following the procedure discussed by Braun et. al,8 utilizing pre-existing Form II seed crystals obtained from Otsuka Pharmaceutical (Tokyo, Japan). The room-temperature (293 K) X-ray diffraction data was obtained from the literature.8 Lowtemperature crystallographic data was collected on a Bruker KAPPA APEX DUO diffractometer using Mo Kα radiation (λ = 0.71073 Å) containing an APEX II CCD system.28 The data collections were taken at multiple temperatures, including (in K): 270, 240, 230, 227, 226, 225, 224, 220, 210, 200, 190, 180, and 90, with an error of ±2 K for each measured temperature. The data were corrected for Lorentz and polarization29 effects, and adsorption corrections were made using SADABS.30 Structures were solved by direct methods. Refinements for each structure were carried out using the SHELXTL31 crystallographic 5005

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software. Following assigning all non-hydrogen atoms, the models were refined against F2 first using isotropic and then using anisotropic thermal displacement parameters. The hydrogen atoms were introduced in calculated positions and then refined isotropically. Neutral atom scattering coefficients along with anomalous dispersion corrections were taken from the International Tables, Vol. C.32 2.2. Computational. The simulations in this work were performed using the CRYSTAL09 software package33 utilizing the PBE34 density functional in combination with both the atom-centered Gaussian-type 6-31G(d,p)35 and 6-311G(2d,2p)36 basis sets. While the combination of PBE and 6-31G(d,p) has proven to be effective, previous results have indicated that a larger basis set can result in better structural reproductions.37 Thus, the PBE/6-311G(2d,2p) combination was utilized in this work for the calculation of structures used in the determination of the relative polymorph energies. Unfortunately, while useful for structure simulations, the size of the aripiprazole system (57 atoms per molecule, Z = 4) necessitated the use of the smaller 631G(d,p) basis set for frequency analyses due to hardware and time constraints. The total energy convergence criteria were ΔE < 10−8 hartree for geometry optimizations and ΔE < 10−11 hartree for frequency calculations. All structural optimizations were performed without limits on atomic positions or unit cell dimensions, other than those imposed by space group symmetry, and were begun using starting structures obtained from experimental X-ray diffraction measurements. The unit cell descriptions of the initial positions used for both the room-temperature and low-temperature conformations can be found in Table 1. The radial and angular distributions for DFT integration

dispersion force corrections are important augmentations to include in solid-state DFT investigations since these forces are generally underestimated in commonly used density functionals but play an integral role in solid-state characteristics. The solid-state DFT approach used in this study has been supplemented with corrections for London-type dispersion forces using a semiempirical method proposed by Grimme40 and then later modified for the CRYSTAL program by Civalleri et al.41 A global scaling factor (s6) of 0.65 was used and was determined through comparison of the calculated unit cell parameters (a, b, c, and volume) and the experimental 90 K X-ray data measured for Form VIII (Table 2).

Table 2. Comparison of the 90 and 226 K Experimental Unit Cell Dimensions and the Simulated Unit Cell Dimensions of Both Aripiprazole Form II and Form VIIIa Form II (226 K)

experimental a (Å) b (Å) c (Å) α (deg) β (deg) γ (deg) V (Å3) average % error

Table 1. X-ray Diffraction Determined Parameters of Aripiprazole Form II and Form VII Used as Starting Structures in the Computational Analyses Form IIa empirical formula f.w. crystal system space group a (Å) b (Å) c (Å) α (deg) β (deg) γ (deg) V (Å3) Z μ (mm−1) T (K) λ (Å) R1 wR2 a

Form VIIIa

a (Å) b (Å) c (Å) α (deg) β (deg) γ (deg) V (Å3) average % error

C23H27Cl2N3O2 448.38 orthorhombic Pna21 23.610(4) 21.627(4) 12.457(2) 12.9438(19) 7.7044(13) 7.6207(13) 90 90 90 90 90 90 2266.0(7) 2133.3(6) 4 4 1.314 1.396 226 K 90 K 0.71073 0.0417 0.0354 0.0727 0.0486

a

PBE/6-31G(d,p)

PBE/6-311G(2d,2p)

theoretical

theoretical

23.610 12.457 7.7044 90 90 90 2266.00

23.64 12.22 7.71 90.00 90.00 90.00 2227.38 0.95 Form VIII (90 K)

23.74 12.30 7.73 90.00 90.00 90.00 2256.31 0.63

PBE/6-31G(d,p)

PBE/6-311G(2d,2p)

experimental

theoretical

theoretical

21.627 12.9438 7.6207 90 90 90 2133.30

21.59 12.84 7.67 90.00 90.00 90.00 2125.66 0.50

21.63 12.91 7.68 90.00 90.00 90.00 2145.00 0.39

The simulations were performed using s6 = 0.65 for dispersion forces.

While the solid-state simulations produce accurate stability rankings,11 finite basis sets impart an error to the final energies, necessitating a correction. In order to generate the best representation of the energy rankings, the basis set superposition error (BSSE) was removed from the stability values by the counterpoise method.42 In the calculation of BSSE, a single molecule was extracted from the already optimized solid-state unit cell and studied using the same theoretical method (PBE/6-311G(2d,2p)) as that for the periodic calculations. When dealing with periodic boundary condition simulations, a spatial cutoff must be defined for inclusion of neighboring basis functions in the counterpoise calculation. It was found, through monitoring of the energy differences, that 300 atoms within 5.0 Å of the molecule being evaluated were sufficient limits: these cutoffs return ≥95% of the BSSE energy.

This work.

were defined by a pruned (75, 974) grid. Truncation tolerances for Coulomb and HF exchange integrals were defined as 10−7, 10−7, 10−7, 10−7, 10−14 hartree (TOLINTEG command33,38). A shrinking factor of 5 (27 k points in the irreducible Brillouin zone) was determined after sampling and monitoring of the total energy convergence as a function of k-point count in reciprocal space according to the Pack−Monkhorst method.39 Normal-mode frequencies were then calculated for the optimized structures. The frequency of each normal mode was calculated within the harmonic approximation by numerical differentiation of the analytical gradient of the potential energy with respect to atomic position.38 The explicit consideration of weak noncovalent interactions in molecular solids can be a significant factor in achieving accurate simulations of crystalline structure and dynamics. London-type

3. RESULTS AND DISCUSSION 3.1. X-ray Diffraction. The unit cell parameters at 14 different temperatures of aripiprazole Form II/Form VIII can be found in the Supporting Information, Table S1. For visual comparison, the a, b, c, and volume values were graphed versus temperature (Figure 2), and the phase transformation became readily apparent at ∼225 K, since the a axis decreased by 8.17% and the b axis increased by 5.68% at that point. The c axis is the only axis without a large temperature response (0.73% 5006

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achieving accurate crystalline packing interactions is critical. Considering the PBE/6-311G(2d,2p) results first, the Form II simulation was found to be in very good agreement with the experimental unit cell parameters (0.63% error), and when comparing the 90 K X-ray structure of Form VIII to its simulation, even better structural reproduction (0.39% error) was found. These differences compare well with those found for other polymorphs of aripiprazole, with the structural simulations of Form VIII being the best reproduction of a cold crystal structure among all investigated polymorphs of aripiprazole.11 While the larger 6-311G(2d,2p) basis set has been shown to be an overall better performer (including reduced basis set superposition error),37 the structural reproductions by the smaller 6-31G(d,p) basis set were also in excellent agreement with the experimental data, resulting in only small increases in the average errors of the simulations. Additionally, the importance of the London-type dispersion forces in the solid simulations was tested for both Form II and Form VIII by performing full optimizations without inclusion of any corrections to the model. These tests resulted in an average unit cell volume expansion of ∼15%, confirming their need in these calculations to achieve physically reasonable crystal structures. Vibrational frequency analyses were performed on each of the polymorphs, verifying that the calculated structures corresponded to minima on the potential energy surface. The structural results and vibrational checks support that there are two distinct solid-state polymorphs, aripiprazole Form II and Form VIII, which are observed to be connected through a reversible solid-state enantiotropic phase transformation at ∼225 K. It is clear that the most significant difference in the two forms is the conformational changes within the aripiprazole molecules, but the origin of the transformation requires greater study. The details of the polymorphic change are subtle, and an extensive investigation of the solid-state energies, including conformational strain and cohesive binding, was performed. 3.3. Investigation of the Phase Transformation Energies. Exploring the origins of the total solid-state energies can yield new knowledge relevant to the formation of each crystalline arrangement. Both Form VIII and Form II crystallize in the same crystallographic unit cell (P21), with the same Z value, facilitating the investigation of the solid-state changes by studying the variations in the molecular conformation and cohesive binding within the cells. Through this partitioning of the energetic contributions, it can be determined which factor contributes more to the differences in energy between the forms. It is worth noting that comparison of the relative energies of the polymorphs represents only the initial and final states of the system. The neglect of the potential barriers between forms results in this being a simple approximation to a likely complex conversion mechanism. The total electronic relative energies reveal Form VIII to be the more stable form (0.00 kJ mol−1), with Form II being less stable by +1.33 kJ mol−1. The energy difference indicates that the two forms are separated by less than ambient roomtemperature energy (∼2.4 kJ mol−1 at 293 K). Therefore, it is not surprising to find that Form VIII exists at colder temperatures, since Form II requires greater entropic contributions provided at higher temperatures to stabilize its structure. Given that the most obvious difference between the two polymorphs is the conformational change in the butoxyl chain, at first approximation, one would expect the polymorph energies to be dominated by this coordinate. However, both the

Figure 2. Experimental a (solid), b (dot), c (dash) crystallographic unit cell axis values for all X-ray diffraction data taken between 200 and 250 K (bottom graph). Experimental unit cell volumes values from 200 and 250 K are shown in the top graph.

decrease). The change in axes resulted in an overall unit cell volume decrease of 3.67% between 226 and 225 K. These large dimensional changes, particularly the volume decrease, indicate that there is a significant modification that occurs in the packing arrangement of the molecules upon cooling that enables greater density to be achieved. Cooling Form II to 225 K results in a polymorphic transformation to a new form, Form VIII. While there is a large change in the unit cell parameters, Form VIII is still similar to its room-temperature parent, with the key differences being in the aripiprazole molecular structure. Inspecting the molecular conformations of the two forms (Figure 1) reveals that there is a considerable conformational change between them originating from torsions in the butoxyl chain joining the ring systems. Presumably, it is this molecular structure change that leads to the phase transition, but it is also possible that temperature-dependent variations in the crystal packing lead to this observed modification in conformation. To better understand this solid-state transformation, rigorous solidstate simulations were completed on both Form II and Form VIII. 3.2. Comparison of the Theoretical and Experimental Structures. The quality of the structural calculations was evaluated on the basis of the ability of the full optimizations to simulate both the internal conformations and the unit cell parameters of Form II at 226 K and Form VIII at 90 K, both temperatures being the lowest available for each polymorph. Root-mean-squared deviations (RMSDs) were determined for the bond lengths, bond angles, and dihedral angles of the molecular structures between the experimental structures and the theoretically optimized structures. Considering the covalent bond lengths, the PBE/6-311G(2d,2p) simulations of Form II and Form VIII resulted in excellent structural reproductions, with bond length RMSDs of 0.0158 and 0.0121 Å, respectively. The switch to the smaller 6-31G(d,p) basis set increased the RMSD values slightly to 0.0191 Å for Form II and 0.0159 Å for Form VIII. The remaining RMSD values, including both basis sets, can be found in Table S2. While the internal RMSDs are important, the comparison of the predicted unit cell parameters to experiment (Table 2) is particularly useful in the study of solid-state polymorphs, where 5007

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presented in Figure 3 and show that Form VIII is more stable at low temperatures, while Form II is more stable at higher

changes in conformational energy and the concomitant changes in intermolecular binding energy need to be considered. Single-molecule conformational energies were calculated using the same extracted single molecule used for BSSE determination and the same theoretical method that has been used throughout. Examining the conformational energies reveals that Form II has the more stable conformation (0.00 kJ mol−1), with Form VIII being less conformationally stable by +2.29 kJ mol−1. This difference is unexpected since the most stable polymorph (Form VIII) in terms of total solid-state energy does not possess the most stable molecular conformation. This finding indicates that molecular structure alone is not the determining factor in the polymorph formation. The conformational energies do give some insight into the total energy rankings of the polymorphs, but they do not explain everything, resulting in the necessity for investigating the remaining energetic component, cohesive binding. Intermolecular interactions are of central importance for the formation and the energetics of the different polymorphs of aripiprazole, and these interactions can be considered as a whole by evaluating the cohesive binding energy of the solids. The binding energy can be determined from the total BSSEcorrected solid-state energies and the energies of the individual isolated molecules extracted from the crystalline solids. The difference between the total solid energy and the summation of its molecular component energies is the cohesive energy of the crystal. It was found that Form VIII has the greater amount of binding energy (−185.19 kJ mol−1) and Form II has less cohesive binding at −181.57 kJ mol−1. While the overall binding energies are different between the two polymorphs, the hydrogen bonding and dipole−dipole interactions are similar. There is no appreciable change in the hydrogen-bond lengths between the two polymorphs (2.800 Å in Form II vs 2.804 Å in Form VIII) and no significant change in the dipole moment magnitudes (3.62 D in Form II vs 3.71 D in Form VIII, as estimated by single-molecule simulations using Gaussian0943) or orientations based on the packing of the molecules in these polymorphs. Given these observations, the London-type dispersion forces must play a large role in the stabilities of the polymorphs, which is made apparent by the large volume expansion in their absence during full structural optimizations tests. To this point, the simulations have suggested a possible transition temperature of ∼160 K between Form II and Form VIII based solely upon a simple interpretation of the 1.33 kJ mol−1 difference in calculated stabilities. However, these solidstate DFT simulations are done at effectively zero Kelvin and therefore, while they provide useful energetic details, further work is needed to explicitly involve the role of temperature. This can be achieved by evaluating the Gibbs free energies of the solids. 3.4. Thermodynamic Analyses. The solid-state simulations used in this work can help to clarify this proposed transition temperature by examining the temperature dependence of the thermodynamic properties of both forms, specifically their Gibbs free energies. The thermodynamic analyses were performed (ignoring any volume changes caused by temperature) by combining the electronic energy values with the relevant thermodynamic quantities (S*T, P*V, thermal contribution to the vibrational energy, and zero-point energy corrections). The relative thermodynamic energies were corrected for BSSE using the average value between the two forms. Plots of Gibbs free energy versus temperature are

Figure 3. Gibbs free energy curves of aripiprazole Form VIII (solid) and Form II (dash).

temperatures, indicating that a solid−solid phase transition occurs at ∼211 K. This theoretical value matches well with the experimental data, where a 225 ± 1 K transition point was found between the two polymorphs. The computational thermodynamic study verifies that Form II undergoes an enantiotropic solid−solid phase transformation upon cooling, changing to the newly discovered Form VIII polymorph. While this type of phase transition is rarely seen in large pharmaceutical molecules,15,16 it is not such an unusual phenomenon for this particular molecule, since a similar transformation has been reported for crystalline aripiprazole between two of its other polymorphs, Form I and Form V.8 The thermodynamics of the solid−solid transformation between Forms I and V were also investigated here in order to allow comparison with the new Form II/Form VIII data. Both Form I and Form V8 were structurally optimized, and vibrational frequencies were calculated from the simulated structures. A detailed description of the simulation of these polymorphs has been previously published.11 Gibbs free energy curves vs temperature were constructed for both polymorphs and are shown in Figure 4. The theoretical results indicate that there is a phase transition at ∼330 K, while experimental data suggests that this transition occurs at ∼350 K.8 The exact temperatures are not identical, but it is clear that there is a phase transition at elevated temperatures between Form V and Form I. This phase transition is similar to the transition observed between Form II and Form VIII and demonstrates how atypical of a molecule aripiprazole is. Since Form II is known to be enantiotropically related to Form I and Form V,8 an investigation into their relationship with Form VIII was also completed. The analyses of the thermodynamic properties among Form VIII, Form II, Form I, and Form V reveal that there are enantiotropic transitions between Form II, Form V, and Form VIII and also between Form I and Form V. The Gibbs free energy curve of Form I never crosses that of Form II or Form VIII; however, there is still a purely enantiotropic relationship between these forms, with a transition into Form V between the two polymorphs. This enantiotropic relationship is confirmed in a study that revealed that Form I can not only be 5008

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undergo a conformational polymorphic transformation upon cooling. Such enantiotropic transformations form the basis of the great polymorphic flexibility of aripiprazole. Form VIII is the more stable of the two below ∼225 K, and this is made possible by increased intermolecular binding energy countering internal conformational strain. The increased binding energy at low temperature is driven by anharmonic constriction of the unit cell and subsequent enhancement of the London force interactions. In summary, at low temperatures, binding energy supersedes conformational strain, making it possible to have a stable polymorph composed of molecules with unfavorable internal conformations.

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ASSOCIATED CONTENT

S Supporting Information *

The experimental unit cell parameters (a, b, c, and volume) of aripiprazole during the Form II to Form VIII temperaturedependent phase transformation, and RMSD values for bond lengths, bond angles, and dihedral angles of Form II and Form VIII of aripiprazole. This material is available free of charge via the Internet at http://pubs.acs.org. CCDC 975709, 982735, and 982965−982973 contain supplemental crystallographic data for this paper. These data can be obtained free of charge from the Cambridge Crystallographic Data Centre via http:// www.ccdc.cam.ac.uk/Community/Requestastructure/Pages/ DataRequest.aspx?.

Figure 4. Gibbs free energy curves of aripiprazole Form V (solid) and Form I (dash).

made directly from the aripiprazole melt (above ∼418 K) or by solution-mediated mechanisms12 but also through an enantiotropic transition between Form I and Form V. Exploration into the similarities of these two enantiotropic phase transitions actually revealed key differences in the solidstate energies related to the transitions. Analyses of Form I and Form V reveal Form V to be the more stable form (0.00 kJ mol−1), with Form I being less stable by +3.46 kJ mol−1. Inspecting the details of these stabilities showed that Form V exhibited greater cohesive binding energy (−180.12 vs −178.30 kJ mol−1), and simultaneously the more stable conformation (0.00 vs +1.64 kJ mol−1), as compared to Form I. Clearly, the relative conformational and binding energies of Form I vs Form V follow a different pattern than what is seen in Form II vs Form VIII. Form I has less favorable energy values across all three categories, an expected finding since its creation is dependent on the application of high temperature to promote the less stable molecular conformation, upon which it is based. For the Form II−Form VIII transition, the opposite is true, and the polymorph with the less stable aripiprazole conformation is achieved at lower temperatures by enhancement of the cohesive binding. This enhancement most likely occurs because anharmonicity in the potential energy surface of the crystalline lattice results in constriction of the lattice dimensions at reduced temperature.44 The increased density and greater London force contributions in the reduced unit cell size ultimately leads to improved cohesive binding in Form VIII. In short, the Form I−Form V phase transformation is triggered by molecular conformation changes, while the Form II−Form VIII phase transformation is an anharmonicity-driven enantiotropic phase transformation that is governed by London dispersion forces.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This research was funded by a grant from the National Science Foundation CAREER program (CHE-0847405). The authors also thank Prof. Jerry Goodisman (Syracuse University) for helpful discussions and Syracuse University for continued support.

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REFERENCES

(1) Bernstein, J. Polymorphism in Molecular Crystals; Oxford University Press: New York, 2002. (2) Threlfall, T. L. Analyst 1995, 120, 2435−2460. (3) Bauer, J.; Spanton, S.; Henry, R.; Quick, J.; Dziki, W.; Porter, W.; Morris, J. Pharm. Res. 2001, 18, 859−866. (4) ANDAs: Pharmaceutical Solid Polymorphism. Chemistry, Manufacturing, and Controls Information; Food and Drug Administration Center for Drug Evaluation and Research (CDER): Silver Spring, MD, 2007. (5) McCrone, W. C. Polymorphism. In Physics and Chemistry of the Organic Solid State, 2nd ed.; Fox, D., Labes, M. M., Weissberger, A., Eds.; Interscience Publishers: New York, 1963. (6) Chen, S.; Guzei, I. A.; Yu, L. J. Am. Chem. Soc. 2005, 127, 9881− 9885. (7) López-Mejías, V.; Kampf, J. W.; Matzger, A. J. J. Am. Chem. Soc. 2012, 134, 9872−9875. (8) Braun, D. E.; Gelbrich, T.; Kahlenberg, V.; Tessadri, R.; Wieser, J.; Griesser, U. J. J. Pharm. Sci. 2009, 98, 2010−2026. (9) Tessler, L.; Goldberg, I. J. Inclusion Phenom. Macrocyclic Chem. 2006, 55, 255−261. (10) Nanubolu, J. B.; Sridhar, B.; Babu, V. S. P.; Jagadeesh, B.; Ravikumar, K. CrystEngComm 2012, 14, 4677−4685.

4. CONCLUSIONS In this study, a new polymorph of aripiprazole (Form VIII) has been discovered, making aripiprazole one of the most polymorphic rich systems currently known, now with eight fully solved structures. The energetic details for the formation of this new polymorph were investigated using solid-state density functional theory, revealing the relative stabilities of its crystalline arrangement and that of its parent (Form II). Form II and Form VIII have an enantiotropic relationship and 5009

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dx.doi.org/10.1021/cg500569x | Cryst. Growth Des. 2014, 14, 5004−5010