Polymorphism of Dehydro-Aripiprazole, the Active Metabolite of the

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Polymorphism of Dehydro-Aripiprazole, the Active Metabolite of the Antipsychotic Drug Aripiprazole (Abilify®) Tarek A. Zeidan, Jacob T. Trotta, Renato A. Chiarella, Mark A Oliveira, Magali B. Hickey, Örn Almarsson, and Julius F. Remenar Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/cg400104v • Publication Date (Web): 20 Mar 2013 Downloaded from http://pubs.acs.org on March 22, 2013

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Crystal Growth & Design

Polymorphism of Dehydro-Aripiprazole, the Active Metabolite of the Antipsychotic Drug Aripiprazole (Abilify®) Tarek A. Zeidan,* Jacob T. Trotta, Renato A. Chiarella, Mark A. Oliveira, Magali B. Hickey, Örn Almarsson, and Julius F. Remenar Alkermes, Inc., 852 Winter Street, Waltham, MA 02451-1420, USA

Crystal form exploration of dehydro-aripiprazole (dAPZ), the active metabolite of the antipsychotic drug aripiprazole (APZ), elucidated five polymorphs (I, II, III, IV and V), two methanol solvates and a monohydrate. The forms were characterized by thermal microscopy, differential scanning calorimetry (DSC), thermal gravimetric analysis (TGA), single and powder X-Ray diffraction (SCXRD and PXRD), and infrared spectroscopy. DSC analysis showed monotropic relationships among polymorphs I, II, III and IV and enantiotropic relationships for the two form pairs I↔V and II↔V. Solvent-mediated conversion experiments indicated that Form V is the thermodynamically stable form in the temperature range 5-60 °C and Form I is the stable form at ≥ 70 °C, where a transition temperature lies between 60 and 70 °C. Two polymorphs of the methanol solvate (SMeOH1 and SMeOH2) were crystallized from methanol solutions in 1:1 dAPZ:methanol molar ratio. SMeOH2 is the thermodynamically stable form of the

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two methanol solvates at ambient temperature.

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The monohydrate (SH2O) was obtained by

solvent-mediated conversion experiments of any of the methanol solvates in water. Singlecrystal structure analysis of polymorphs I, II, V and the two methanol solvates showed the formation of dimeric structures with N-H···O=C (amide-amide) hydrogen-bonded homodimer synthons. In the case of SH2O, two water molecules are present in-between the units of the dimer and each water molecule exhibits hydrogen-bonding with one of the piperazine nitrogen atoms of a third dAPZ molecule. Analysis of the crystal structures and PXRD patterns for both the APZ and dAPZ non-solvated polymorphs reveals that all the forms are distinct from one another. When solvates and hydrates were added to the comparison (a total of 18 crystalline forms of APZ and dAPZ), only SMeOH2 of dAPZ was found to have an identical packing arrangement to the APZ methanol solvate. This study illustrates that despite chemical structure similarity between dAPZ and APZ–the differences being one C=C double-bond vs a C-C single-bond and a molecular weight change of 2 Da out of 448–the observed crystal packing arrangement in the polymorphs of the active metabolite differ significantly from those observed for the parent drug.


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INTRODUCTION The study of polymorphism in pharmaceutical materials in the past couple of decades has demonstrated a general tendency of biologically active small molecules to crystallize in different forms, such as polymorphs1 or solvates.2,3,4 Based on the molecular design and action of drugs, the presence and relative positions of multiple polar and non-polar functionalities–coupled in many cases with conformational flexibility–creates opportunities for self-association and ultimate crystallization of the compound in multiple forms in the pure state.5,6 The consequences of crystal polymorphism of active pharmaceutical ingredients (API) are primarily shown to be significant in their impact on physico-chemical and material properties,7 such as stability,8 solubility,9 and mechanical properties.10,11,12 In the area of drug development, control of polymorphic form is important to pharmaceutical performance,13 process control,14 and regulatory acceptance.15 The price of unexpected (and therefore unpredictable) polymorphism occurring after the approval of a drug can be steep.16,17 While the science of polymorph prediction has advanced significantly in the past decade and developments in this area continue to look promising,18,19,20 experimental determination of the extent of polymorphism of a given compound remains an integral part of drug development activities. To date, published case studies of polymorphic drug compounds and chemically similar analogs illustrate the challenges of structure and property predictions. A small difference in molecular structure, such as in carbamazepine and 10,11-dihydrocarbamazepine can result in different packing.21 Other small differences, such as the replacement of a counterion in a salt form with a similar ion, can dramatically affect the observed crystal form diversity. For example, while sertraline HCl, the active ingredient in Zoloft®, is highly polymorphic,22 the HBr salt has not been shown to be overtly polymorphic to date.23 In a more recent study, data mining of


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crystal structures containing sodium and potassium salts of the same chemical entity shows that even small changes in a salt cation can result in large changes in crystal packing.24 In cases where the two forms are structurally very similar there can still be significant changes in physical properties.25 Importantly, while it may be expected that small changes in chemical composition may lead to differing crystal packing, the magnitude of the change and the resultant physical properties of a new form remains unpredictable. Given these subtleties, it is of continued interest to study the crystal form space and diversity of pharmaceutically relevant materials. Aripiprazole

(7-[4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy]-3,4-dihydro-2(1H)-

quinolinone, Scheme 1a) is an atypical antipsychotic drug approved for the treatment of schizophrenia,26 bipolar disorder,27,28 and as an adjunct in clinical depression.29 Aripiprazole (APZ) is marketed under the brand name Abilify® by Otsuka and Bristol Myers Squibb. Studies have established that APZ acts as a partial agonist with high affinity for dopamine D2 and D3 receptors. In addition, APZ has high affinity to serotonin receptors, acting as a partial agonist at the 5-HT1A receptor and antagonist at 5-HT2A.30 APZ is extensively metabolized in the liver through a metabolic process involving the CYP 2D6 enzyme. The main active metabolite is dehydro-aripiprazole

(7-[4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy]-2(1H)-quinolinone,

Scheme 1b), formed by dehydrogenation of the lactam ring of aripiprazole. In the patient population known to lack the capacity to metabolize CYP 2D6 substrates, dosage adjustment of aripiprazole is required due to risk of elevated exposure of APZ in CYP 2D6-deficient subjects. Dehydro-aripiprazole (dAPZ) retains affinity for dopamine D2 and serotonin receptors, having a pharmacological profile comparable to that of the parent drug with slightly longer elimination half-life in human (75 hours for APZ and 94 hours for dAPZ).31


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Scheme 1. Molecular structures of (a) APZ (C23H27Cl2N3O2, MW = 448.39) and (b) dAPZ (C23H25Cl2N3O2, MW = 446.37) illustrating the differences in the saturation of the C26-C27 bonds in the lactam ring.

Polymorphism of APZ has been studied and described in the literature. The first crystal structure of APZ was reported by Tessler and Goldberg.32 Later, Griesser at al. described five polymorphic modifications,33 a monohydrate and three solvates of APZ (methanol, ethanol and dichloroethane in 1:1, 2:1 and 2:1 mole ratio, respectively).34 More recently, Ravikumar et al. published the crystal structure of the sixth polymorph of APZ.35 To date, there have been no reports of form diversity and physical characterization of dAPZ in the literature. APZ and dAPZ differ chemically in the saturation about the C26-C27 bond of the carbostyril moiety, with APZ containing a single bond (known as dihydro-carbostyril moiety) whereas dAPZ contains a double bond (Scheme 1). Given the similarity to APZ, dAPZ is an attractive model to investigate the impact of a seemingly minor chemical modification on crystal structure and form diversity. This is particularly appealing from the perspective of packing arrangements and directional interactions in single-component systems which differ chemically, while retaining the primary hydrogen bond-donating or accepting balance resulting from preservation of polar functional groups in each molecule. Herein we report on the characterization of eight crystal forms of dAPZ, including five conformational polymorphs (I, II, III, IV and V), a monohydrate (SH2O) and two methanol solvates (SMeOH1 and SMeOH2). Finally,


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structure comparisons with the published structures for APZ polymorphs and solvates are also discussed.

EXPERIMENTAL SECTION Synthesis: Dehydro-aripiprazole was synthesized by following previously published procedures.36 Aripiprazole (12 g, 0.03 mol) was dissolved in anhydrous tetrahydrofuran (360 mL). Trifluoroacetic acid (12 mL) was added to the stirring solution. 1,2-Dichloro-4,5-dicyano quinone (24.3 g, 0.11 mol) was added and the mixture was stirred for 40 minutes at room temperature under nitrogen atmosphere. The reaction was quenched with water (1.5 L) and rendered basic (pH 12) with 1N NaOH. The mixture was extracted with dichloromethane (3 x 1L) and the combined organic layers were dried over anhydrous MgSO4. The crude product was purified by column chromatography (10% methanol in dichloromethane). The product was further purified by re-crystallization from 2-propanol to give the desired product (9.98 g, 84%) as an off white solid. 1H-NMR (400MHz, CDCl3) δ 12.33 (1H, br s), 7.72 (1H, d, J = 9.6 Hz), 7.42 (1H, d, J = 8.7 Hz), 7.16-7.11 (2H, m), 6.98-6.93 (1H, m), 6.83-6.79 (2H, m), 6.53 (1H, d, J = 9.3 Hz), 4.10 (2H, t, J = 6.2 Hz), 3.09 (3H, br s), 2.67 (3H, br s), 2.52 (2H, t, J = 7.3 Hz), 1.891.56 (4H, m). LCMS [M+H]+ 447.02. Microscopy:

Crystal morphology was determined with an Olympus BX51 Reflected

Polarized Light Microscope. Hot-stage microscopy experiments were carried out with a Linkam LTS420 hot-stage equipped with a T95 LinkPad temperature controller (Linkam Scientific Instruments). Samples were placed on glass slides and a heating rate of 10 °C/min was applied. Thermal Analysis: Differential Scanning Calorimetry (DSC) curves were acquired using a TA Instruments Q1000. Typically, 1-2 mg of sample were weighed into an aluminum pan, sealed


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with a pin-hole lid and heated at 10 ºC/min from 25 °C to 200 ºC. Similar sample preparation was performed for higher heating rates. Thermal Gravimetric Analysis (TGA) was performed on a TA Instruments TGA Q500. Samples of 10-30 mg were heated at 10 ºC/min from 25 to 250 ºC. The data were processed using Universal Analysis 2000 Version 4.3A. Powder X-ray Diffraction (PXRD): PXRD was performed on a Rigaku DMAX Rapid diffractometer (Rigaku/MSC, Woodlands, TX) with attached capillary goniometer with φ rotation and ω oscillation and a collimated Cu Kα radiation operating at 46 kV/40mA. Data were processed using Eva 2 (version 11.0.0.3). Single Crystal X-Ray Diffraction (SCXRD): A suitable crystal identified by microscopy was coated with Paratone N oil, suspended in a small fiber loop and placed in a cooled nitrogen gas stream at 175 or 253 K on a Bruker D8 SMART 1000 or APEX II CCD fine focus sealed tube diffractometer with graphite monochromated CuKα (1.54178 Å) radiation. Data were measured using a series of combinations of phi and omega scans with 10 second frame exposures and 0.3° frame widths. Data collection, indexing and initial cell refinements were all carried out using SMART software. Frame integration and final cell refinements were done using SAINT software. Crystal structures were solved using direct methods and difference Fourier techniques (SHELXTL, V5.10). Hydrogen atoms were calculated from molecular geometry, allowed to ride during refinement, and included in the final cycles of least squares with isotropic Uij‘s. Nonhydrogen atoms were refined anisotropically. Scattering factors and anomalous dispersion corrections were taken from the International Tables for X-ray Crystallography. Structure solution, refinement, graphics and generation of publication materials were performed by using SHELXTL, V5.10 software.


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Fourier-Transform Infrared Spectrometry (FT-IR): Infrared spectra were collected on neat solids on a Nexis 470-FTIR spectrometer equipped with a Smart OrbitTM attenuated total reflectance (ATR) sample accessory with a diamond window. Spectra were collected from 400 to 4000 cm-1 at a 4 cm-1 spectral resolution with 128 scans. Data were processed using Thermo Electron Corporation OMNIC software (version 7.3). Cambridge Structural Database Analysis: The structures used for comparison in this work were obtained by searching the Cambridge Structural Database (CSD)37 using the program ConQuest version 1.14.38 In addition to requiring the specific functional groups to be present, the following queries were used in order to obtain the subset: (i) structures must contain 3D coordinates, and (ii) organics only. Crystal structures were visualised using the program Mercury CSD version 3.1 and the same software was used, in combination with POV-Ray,39 for the generation of structural figures throughout.

RESULTS AND DICUSSION An initial polymorph screen of dAPZ was performed in more than 20 solvents at ambient temperature.40 Through the screening effort, dAPZ was found to crystallize in eight colorless crystalline modifications: five polymorphs (Form I, II, III, IV and V), a monohydrate (SH2O) and two methanol solvates (SMeOH1 and SMeOH2). The non-solvated polymorphs and the methanol solvates were numbered according to their chronological order of discovery. Thermal characterization The melting point ranges and enthalpies of fusion of all five dAPZ polymorphs were determined from DSC curves. An overlay of DSC traces is depicted in Figure 1.


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Figure 1. (a) Overlay of DSC curves of dAPZ polymorphs (10 °C/min heating rate). The inset shows an expanded view of the thermal transformation of Form IV to II. (b) Overlay of DSC curves of Form IV at different heating rates. Form I crystallized as prismatic crystals upon cooling of a hot solution in 2-propanol to ambient temperature. Form I melts at 162-164 ºC. It is the stable form at high temperature (≥ 70 °C) and can also be produced from the other forms through solvent-mediated slurry conversion in 2-propanol at temperatures above 70 ºC. Form II crystallized from toluene as thin plates with a melting point of 158-159 ºC, and can be obtained additionally from thermal desolvation of dAPZ monohydrate (SH2O). Form III crystallized from the super-cooled melt of dAPZ, as can be observed by DSC40 and by thermal microscopy. After cooling the melt to 25 ºC and then heating back to ca. 110 °C, nucleation of Form III occurred spontaneously. Crystals grew radially from nucleation sites and subsequently melted at 144-146 ºC (Figure 2).


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Figure 2. Microscope images of dAPZ Form III: (a) growing from the melt at ca. 110 °C, (b) crystallizing at 130 °C, and (c) melting at 146 °C. Thin plates of Form IV are obtained by solvent-mediated conversion from Form III in toluene at 5 oC. Form IV exhibits a thermal transformation at 146 ºC to Form II while heating at 10 ºC/min (inset in Figure 1a). At increased heating rates (100 and 200 ºC/min) the melt of Form IV at 145-149 oC seems to occur concomitantly with the crystallization of Form II (Figure 1b). Form V is the thermodynamically stable form between 5 and 60 ºC, and its crystals have a prismatic habit with a melting point of 156-157 ºC. Form V can be produced by a slurry of any dAPZ form in dichloromethane, 2-propanol or toluene at temperatures ≤ 60 ºC. In addition to the free form polymorphs, dAPZ exists in two polymorphic methanol solvates in a 1:1 dAPZ:methanol molar ratio (SMeOH1 and SMeOH2). Methanol solvates crystallize from cooling a hot methanol solution. The SMeOH1 solvate was discovered first and nearly a year later, serendipitously, the SMeOH2 solvate crystallized from identical conditions. Once SMeOH2 was isolated, it was not possible to reproduce a pure SMeOH1 phase. In some crystallization experiments, both forms crystallized concomitantly. Similar behavior of polymorphic crystal forms have been reported in the literature. 41,42,43 SMeOH1 crystallizes as thin plates and SMeOH2 as prismatic crystals. The thermal desolvation of SMeOH1 exhibits a broad endotherm in the DSC curve with an onset temperature at 75 °C.40 Following thermal desolvation, dAPZ Form I is


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formed. Conversely, the thermal desolvation of SMeOH2 is characterized by a sharp endotherm with a peak maximum at 110 ºC. Thermal desolvation of SMeOH2 primarily gives Form II with some formation of Form I. A monohydrate of dAPZ (SH2O) can be prepared from slurrying SMeOH1 in water at 60 ºC. Single crystals grew after cooling to ambient temperature a hot solution of 10% methanol in water as blocky crystals. Thermal dehydration of SH2O occurs as a broad endotherm and yields Form II.

Thermodynamic and kinetic stability of dAPZ polymorphs. To better visualize the relative thermodynamic relationships of dAPZ polymorphs, a semi-quantitative energy/temperature diagram was constructed based on the Burger-Ramberger rules for heat of fusion (HOF), density,44 and solvent mediated slurry conversion experiments (Figure 3).


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Figure 3. Semi-quantitative energy vs. temperature diagram constructed using BurgerRamberger’s heat of fusion rule, density rule and slurry conversion experiments. Tfus: melting point; G: Gibbs free energy; ∆fusH: enthalpy of fusion; Ttrs: transition point; ∆trsH: enthalpy of transition; liq: liquid phase (melt). The bold arrows/lines indicate experimentally determined values, and the horizontal double arrows indicate the temperature ranges where either Form I or V is the thermodynamically stable form. Based on the HOF rule, in a monotropic system the polymorph with the higher melting point will also have a higher HOF. In an enantiotropic pair, the polymorph with the higher melting point has the lower HOF. Among the dAPZ polymorphs, Form I has the highest melting point


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(165 ºC). Form I has also the largest heat of fusion (43.7 kJ/mol) of all other polymorphs with the exception of Form V (HOF = 47.5 kJ/mol).40

Consequently, Form I has monotropic

relationships with Forms II, III and IV, and an enantiotropic relationship with Form V. Form II has a higher melting point (158 ºC) than Form III (145 ºC) and Form V (156 ºC) while the HOF of Form II (41.1 kJ/mol) is larger than that of Form III (31.5 kJ/mol) but smaller than the HOF of Form V (47.5 kJ/mol).40 Therefore, a monotropic relationship exists between Forms II and III and an enantiotropic relationship between Forms II and V. Unfortunately, the HOF could not be determined accurately for Form IV due to the concomitant crystallization of Form II during the melting of Form IV (Figure 1). To confirm the thermodynamic relationships described above and to determine the thermodynamic relationships between Form IV and the other polymorphs, solvent mediated conversion experiments were performed at different temperatures. Mixtures of Forms I, II, III, IV and V slurried in dichloromethane at 5, 25 and 40 °C resulted in conversion to Form V. Similarly, mixtures of polymorphs in 2-propanol at 25, 40 and 60 °C showed total conversion to Form V. However, when the mixture was heated at 70 °C in 2-propanol, the forms converted to Form I. Based on these results, Form V is the thermodynamically stable form in the temperature range 5 to 60 °C, and Form I is the stable form at temperatures above 70 °C. Thus the enantiotropic pair I↔V has a transition temperature between 60 °C and 70 °C. When mixtures of only Forms III and IV were suspended and stirred in toluene between 5 and 70 °C, Form III converted to Form IV before converting eventually to Form V. These observations indicate that Forms III and IV have a monotropic relationship at temperature range 5-70 °C and that Form IV is thermodynamically more stable than Form III.


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Based on the density rule,44 efficient packing in a crystal structure relates to the free energy of the structure and accordingly, the most stable crystal structure should have the highest density. As shown in Table 1, the density values calculated from single-crystal structure solution for Forms I, II, and V indicate that stability follows the order of Form V > I > II, hence the relative form stability predicted by crystal packing density is in agreement with the experimental data. The density of Forms III and IV could not be calculated due to the lack of structural data. X-ray diffraction. Overlays of powder X-ray diffraction (PXRD) patterns of dAPZ polymorphs and solvates are depicted in Figure 4. Each form has a unique and distinguishable PXRD pattern. Structures of polymorphs I, II and V and solvates SH2O and SMeOH1 and SMeOH2 were determined by single-crystal X-Ray diffraction and their corresponding crystallographic data are shown in Table 1.


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Table 1. Crystallographic data for dAPZ Forms I, II and V, and solvates SMeOH1, SMeOH2 and SH2O Form I

Form II

Form V

SMeOH1*

SMeOH2

SH2O

Formula

C23H25Cl2N3O2

C23H25Cl2N3O2

C23H25Cl2N3O2

C23H25Cl2N3O2•0.8(CH4O)

C23H25Cl2N3O2•CH4O

C23H25Cl2N3O2•H2O

FW (g/mol)

446.36

446.36

446.36

471.99

478.40

464.38

Temp. (K)

173(2)

173(2)

173(2)

173(2)

253(2)

173

Wavelength (Å)

1.54178

1.54178

1.54178

1.54178

1.54178

1.54178

Crystal system

Monoclinic

Monoclinic

Monoclinic

Triclinic

Triclinic

Monoclinic

Space group

P21/c

P21/c

P21/n

P-1

P-1

P21/c

morphology

Prismatic

Thin plate

Prismatic

Thin plate

Prismatic

Blocky

a (Å)

7.7801(3)

13.8150(3)

16.3186(3)

7.6794(2)

8.3321(7)

11.1026(14)

b (Å)

6.7905(2)

9.1160(2)

7.05320(10)

8.1951(2)

10.1219(8)

12.6790(14)

c (Å)

40.5837(16)

17.5978(3)

19.1212(3)

19.2697(4)

15.1680(13)

16.6841(19)

α (°)

90

90

90

85.791(2)

84.562(5)

90

β (°)

95.328(3)

102.7950(10)

105.8940(10)

88.984(2)

84.704(5)

97.475(8)

γ (°)

90

90

90

75.052(2)

68.879(4)

90

V (Å3)

2134.80(13)

2161.19(8)

2116.68(6)

1168.51(5)

1185.58(17)

2328.66

Z

4

4

4

2

2

4

dcalc (Mg/m3)

1.389

1.372

1.401

1.341

1.340

1.325

R1

0.0361

0.0331

0.0323

0.0397

0.0385

0.0416

[I > 2sigma(I)]

* Methanol molecules have occupancy of 0.8.


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Figure 4. PXRD of (a) non-solvated polymorphs and (b) solvates of dAPZ. Experimental (black) PXRD patterns were recorded at ambient conditions, and the corresponding powder patterns were calculated from the single-crystal data (grey). Forms I, II and V crystallize in equivalent space groups (P21/c and P21/n). Each structure contains one molecule of dAPZ in the asymmetric unit. Crystal structures of Forms I, II and V exhibit three different conformations of dAPZ molecules, as illustrated in Figure 5. The conformations differ mainly in torsion angles of the alkyl chain connecting the piperazine and the carbostyril moieties.40 Molecules of dAPZ in Form I exhibit two gauche conformations in the alkyl chain (N1, C13, C14, C15 = 57.99°, and C13, C14, C15, C16 = 66.36°) while only one of these gauche conformation (N1, C13, C14, C16 = 55.39 °) is present in Form V. In the case of Form II, the methylene groups in the alkyl chain adopt the anti conformation throughout the chain. The torsion angle formed by atoms C16, O17, C18, C19 depicts the conformation of the carbostyril moiety with respect to the alkyl chain with values of 176.1º, 7.8º and 178.0º for Forms I, II and V, respectively. Evidently, dAPZ polymorphism is characterized by conformational diversity. The nature of intermolecular interactions will be discussed separately in the following section.


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Figure 5. Overlay of the dAPZ molecules in Forms I, II, V and solvates SMeOH1, SMeOH2 and SH2O illustrating the difference in conformations for each form. The 2,3-dichlorophenyl moieties (right hand side) were overlapped, while the piperazine, alkyl chain and the carbostyril moieties (left hand side) sit in the spaces dictated by the geometry of the dAPZ molecule in each of the polymorphs. The solvates SMeOH1 and SMeOH2 crystallize in the space group P-1 with one molecule of dAPZ and one molecule of methanol in the asymmetric unit, while SH2O crystallizes in the space group P21/c with one molecule of dAPZ and one molecule of water in the asymmetric unit. From crystal structure analysis, the methanol molecule in SMeOH1 has occupancy of 0.8. TGA of different lots showed a range of weight loss (6.0-7.2 wt%),40 which is within the theoretical weight loss of 6.7 wt% for a 1:1 solvate. Thus it is thought that the crystal must have lost some of the solvent by the time the crystal structures was determined. The conformations of the alkyl chain based on torsion angles for dAPZ molecules of SH2O and SMeOH2 are comparable to those found in Form II (Figure 5).40 Such similarities may explain the preferential formation of Form II following the de-solvation of SH2O and SMeOH2, vide supra. Hydrogen Bonding and Crystal Packing. Forms I, II and V of dAPZ are arranged via an amide homodimer formed via hydrogen bonding between N-H and C=O atoms of the carbostyril


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group (Figure 6). Unlike Forms I and II, wherein the two carbostyril groups forming the dimer are in the same plane, the amide-amide dimer in Form V is not co-planar. The two planes defined by reciprocal N-H···O=C are shifted by 0.86 Å in Form V. The dAPZ molecules in Forms I and II exhibit hydrogen bonding between chlorine (C9-Cl) and hydrogen atoms (C10H). While the carbostyril moiety in Forms I and II are additionally interlinked by C-H···π and π···π interactions, the latter interactions are not observed in Form V.40 Furthermore, Form II exhibits close interactions between chlorine (C8-Cl) and the carbons C11 and C12 with a ClC11-C12 angle of 87°, which indicates a Cl···π interaction between the chlorine and the electron cloud of the phenyl ring.

Figure 6. Hydrogen bonding of dAPZ Forms (a) I, (b) II and (c) V illustrating the N-H···O=C homodimer present in all three structures. In Form V, the homodimer is shifted from coplanarity by 0.86 Å. The packing motifs of Forms I, II and V are illustrated in Figure 7. Forms I and II adopt a bilayer motif, while in Form V dAPZ homodimers result in a packing motif comprised of dimeric pairs packed along the a axis (Figure 7c).


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Figure 7. Extended packing of dAPZ polymorphs view along the b-axis for dAPZ Forms: (a) I, (b) II and (c) V. The dAPZ molecules in the methanol solvates retain the homodimer synthon observed in Forms I, II and V. However, the methanol molecules in SMeOH1 are hydrogen bonded to the carbonyl group and occupy the same plane (homodimer plane) formed by the carbostyril moieties of two dAPZ molecules (Figure 8a). In contrast, methanol molecules in SMeOH2 are hydrogen bonded to one of the nitrogen atoms in the piperazine moiety (N1). The two dAPZ molecules of the homodimer are co-planar and the methanol molecules are located above and below the amide dimer plane (Figure 8b). The water molecules in SH2O are inserted between the dAPZ dimers (Figure 8c). Each water molecule is hydrogen bonded to one carbonyl oxygen atom (O28) and two nitrogen atoms (N24 of the carbostyril group and N1 of the piperazine ring) resulting in layers of tetramers (two molecules of dAPZ and two molecules of water) that are connected by hydrogen bonds to the piperazine groups of the neighboring layers.


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Figure 8. Hydrogen bonding of solvent molecules in dAPZ solvates (a) SMeOH1, (b) SMeOH2 and (c) SH2O. Packing diagrams for dAPZ SMeOH1, SMeOH2 and SH2O are shown in Figure 9a, b and c, respectively. All three structures exhibit bilayer packing motifs with alternating layers of dAPZ molecules and either methanol or water layers.

Figure 9. Molecular stacking with view along the a-axis for (a) SMeOH1 and (b) SMeOH2 and view along the c-axis for (c) SH2O. Solvent molecules are shown in space fill view. Hydrogen atoms were removed from SH2O for clarity.


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Fourier-Transform Infrared (FT-IR). Subtle differences among Forms I, II, III, IV and V are reflected in their FT-IR spectra, as shown in Figure 10a. The region for the N-H stretching (3100-3300 cm-1) for the polymorphs showed small shift in frequency. Furthermore, the C=O stretching region (1630-1700 cm-1) for Forms II, III, IV and V show band splitting, which is not observed in Form I. The distinctive and relatively sharp N-H stretching (3280 cm-1) in SMeOH1 and SH2O (Figure 10b) is attributed to the involvement of the carbonyl and the N-H in the hydrogen bonding with the solvent molecules, in agreement with the crystal structures. On the other hand, SMeOH2 is more similar to the polymorphs wherein the N-H···O=C homodimer motif is intact.

Figure 10. FT-IR spectra of dAPZ (a) polymorphs and (b) solvates. Relevant IR bands are denoted in dotted lines. Crystal Form Comparison of dAPZ and APZ. Aripiprazole (APZ), the parent molecule of dAPZ, exists in six known crystalline polymorphs (I, II, III, IV, X˚ and VI),33,35 three solvates (SEt, SMe and SDCE), and one monohydrate (H1).34 Molecules of APZ in Forms III, IV and VI are characterized by the homodimer motif (Figure 11a) while Forms I, II and X˚ are comprised of infinite catemeric chains (Figure 11b). Furthermore, APZ Forms III, IV and VI have two


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independent molecules in the asymmetric unit while Forms I, II and X˚ have one molecule in the asymmetric unit. Analysis of the solvated forms of APZ indicates that the three organic solvates have identical packing arrangement with formation of the homodimer synthon. Similar to dAPZ SH2O, the loss of the homodimer motif is also observed in the APZ monohydrate structure (H1). However, the monohydrate of APZ is comprised of water-APZ interactions in which hydrogen bonding between two APZ molecules is linked through two water molecules by N-H···OH···O···H-N hydrogen bonding network (Figure 11c). The water molecules in the hydrate structure act as both donor and acceptor and are consistent with the most prevalent water environments observed in organic structures.50

Figure 11. Hydrogen-bond motif present in APZ polymorphs: (a) homodimer represented in Form III (CSD Ref Code MELFIT03); (b) catemeric chain represented in Form I (CSD Ref Code MELFIT01) and (c) APZ monohydrate (H1) (CSD Ref Code MELFUF01) depicting hydrogen bonding associated with water molecules (Hydrogen atoms were removed for clarity). In the cutouts of (a) and (b), only the dihydro-carbosyril moiety is shown for clarity. As stated in the introduction, the only difference between APZ and dAPZ is the substitution of the single bond between C16 and C27 with a double bond of the carbostyril ring (Scheme 1). This difference leads to the transformation of the partially puckered dihydro-carbostyril moiety in APZ to a fully planar carbostyril moiety in dAPZ as a consequence to the aromatic character


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of the unsaturated lactam ring in the carbostyril moiety. Such structural difference, though seemingly minor, contributes significantly to the way the molecules pack in the crystal lattice. Inspection of the polymorphs of APZ reveals C-H···O interactions in Forms II and III, C-H···Cl interaction in Form VI, and C-H···π interactions in Forms I, III, IV, and X˚ with hydrogen atoms on C(26) or C(27) acting as donor groups.33 In contrast, no hydrogen bond donation from the C(26) or C(27) hydrogen atoms were observed in the dAPZ polymorphs. When the PXRD patterns of the six polymorphs for APZ and the five polymorphs of dAPZ are compared, each form is found to have a distinctive pattern indicating that the packing arrangement in each form is unique.40 Inspection of the available crystal structures of the 9 polymorphs (6 for APZ and 3 for dAPZ) confirms that the molecular conformation of each APZ and dAPZ molecule is indeed unique (Figure 12). It is noteworthy that the apparent range of conformational space is smaller for APZ compared with dAPZ in the polymorphic sets of the two compounds.

Figure 12. Overlay of APZ (Forms I, II, III, IV, VI, and X˚) and dAPZ (Forms I, II, and V) conformations. dAPZ Form I = blue, Form II = green, Form V = red. Both molecules in the APZ Forms II, IV, and VI asymmetric units are shown. The 2,3-dichlorophenyl moieties were overlapped, while the piperazine, alkyl chain and (dihydro)-carbostyril moieties sit in the spaces dictated by the geometry of the APZ or dAPZ molecule in each of the polymorphs.


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Packing arrangements of the two methanol solvates and monohydrate in dAPZ show that the solvent molecules in SMeOH1 and SH2O interact with dAPZ molecules differently from the way these solvent molecules interact in the APZ methanol solvate (SMe) and monohydrate (SH1), respectively. However, comparison of the stable form of dAPZ methanol (SMeOH2) and the methanol solvate of APZ (SMe) based on PXRD and single-crystal X-ray diffraction indicates that the packing arrangement of these two forms is identical, as shown in Figure 13.

Figure 13. Overlay of (a) APZ methanol solvate in grey (SMe; CSD Ref code MELFOZ) and SMeOH2 in black (methanol molecules and hydrogen atoms are omitted for clarity), and (b) PXRD patterns of the methanol solvates of APZ (SMe) and dAPZ (SMeOH2). A search within the CSD was conducted in order to determine whether the presence or absence of the amide homodimer is consistent with the published structures containing either dihydrocarbostyril or carbosyril moieties. As shown in Table 2, the prevalence of the homodimer synthon in CSD is similar in both the carbostyril (71%) and the dehydro-carbostyril (73%) moieties. This is also true for the prevalence of catemers, though the occurrence of the latter is much less common (8-9%).


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Table 2. CSD Search criteria and results obtained from inspection of supramolecular synthons Core chemical structure

dihydro-carbostyril

carbostyril

Total number found:

64

75

47 (73%)

53 (71%)

5 (8%)

7 (9%)

H

Structures forming homodimer:

N O

O N

H

Structures forming catemers:a

a

The remaining structures do not fall into either categories

Halogen interactions in APZ and dAPZ. The crystal structures obtained from the study of form diversity for APZ and dAPZ have been described and defined according to criteria surrounding hydrogen bonding and supramolecular building blocks. While the former likely represents the most significant interactions leading to the geometric arrangements observed in the crystal structures of APZ and dAPZ, a thorough inspection of all structures has been conducted to specifically understand halogen (chlorine) interactions within these structures. In the case of APZ, most structures indicate halogen interactions of the C-H···Cl type with H···Cl distances of ~ 3Å, consistent with the sum of the van der Waals radii for hydrogen (1.20 Å) and chlorine (1.75 Å). While these interactions appear to be abundant in crystal structures containing halogens, debate continues about their role in supramolecular chemistry and molecular recognition.45,46,47 In APZ Form I (CSD Ref codes MELFIT01), C-N···Cl interactions


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with distances of 3.187 Å are observed. Non-covalent interactions of the type C-N···X (where X is a halogen) have been exploited and described in crystal engineering.48 While these interactions can be directional in some systems it is difficult to say whether they play a similar role in the form diversity observed for APZ. When the structures of dAPZ are analyzed, similar halogen bonding trends to those in APZ are observed, but one important difference is noted. The thermodynamically stable form of dAPZ at ambient temperature, Form V, has a unique C=O···Cl contact with an O···Cl distance of 3.154 Å, a C=O···Cl angle of ~119° and a C-Cl···O angle of ~170° (Figure 14). This interaction, which has been previously described in the literature as charge-transfer or an electron-donor-acceptor bond, is now defined as a halogen bond between an atom containing one or more lone pair of electrons (i.e. O, N, S) and a halogen atom (i.e. Cl, Br, I, F).49 This type of halogen bonding appears to be mainly electrostatic in origin. Among the set of polymorphs and solvates of APZ and dAPZ, only dAPZ Form V shows such halogen bonding interaction which may be contributing to the more efficient packing and increased density observed. In addition, a search in the CSD for structures containing the amide moiety exhibiting a short contact with any halogen (≤ the sum of the van der Waals radii) indicates that of the 386 structures obtained, 198 (~51%) have halogen bonding with chlorine as the halogen atom. Among the 198 structures, only one structure (CSD Ref Code RUVSOQ) showed interaction between chlorine and the oxygen (Cl···O=C) of the dihydro-carbostyril group, while no structures were found for Cl···O=C interaction in carbostyril containing molecules. This observation makes dAPZ the first molecule containing carbostyril moiety to exhibit Cl···O=C interaction.


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Figure 14.

Halogen bonding (Cl···O=C) observed in the dAPZ Form V crystal structure.

Halogen bond distance and angles are shown. Hydrogen atoms that are not involved in hydrogen bonding were omitted for clarity. CONCLUSIONS Five polymorphs and three solvates were identified for dAPZ, the active metabolite of Aripiprazole (APZ). Thermal analysis and solvent mediated conversion experiments elucidated thermodynamic relationships between the dAPZ polymorphs. Form V is reported herein as the thermodynamic stable form at ambient temperature, and Form I is the stable form at elevated temperatures (≥ 70 ºC). Forms I, II, III and IV have monotropic relationship and enantiotropic relationships exist between the form pairs I↔V and II↔V. Two polymorphic methanol solvates (SMeOH1 and SMeOH2) and one hydrate (SH2O) crystallized in 1:1 molar ratio. The methanol solvates have different desolvation temperatures. Crystal structure analysis of Forms I, II, V, SMeOH1, and SMeOH2 shows that the dAPZ molecules adopt a homodimer motif between amides of the lactam ring of the carbostyril moiety. The methanol molecules in dAPZ interact differently with the homodimers, in that the solvent molecules in SMeOH1 are hydrogen bonded to the oxygen of the carbonyl group, while in SMeOH2 they are hydrogen bonded to the piperazine


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nitrogen atom. In the case of dAPZ monohydrate (SH2O), water molecules are present between the dimer resulting in a structure held by water-piperazine hydrogen bonding interactions. Despite molecular structure similarity with APZ, the crystal packing observed in the polymorphs of dAPZ differs significantly from those known for the parent drug. With the exception of SMeOH2, in which packing is identical to the published APZ methanol solvate (SMe), structural comparison of polymorphs and solvates of APZ and dAPZ showed that each form exhibits unique crystal packing arrangements. Our findings further illustrate the challenges for predicting form diversity. Indeed, the supramolecular synthons present in the APZ and dAPZ forms are consistent with hydrogen bonding patterns described for dihydro-carbostyril and carbostyril moieties.50,51,52 Interestingly, a unique feature of dAPZ Form V relative to other polymorphs and solvates of the compound is the presence of a C-Cl···O=C interactions which also are not observed in polymorphs or solvates of APZ. Such observations regarding halogen interactions in these two compounds merit further study.

AUTHOR INFORMATION Corresponding Author * To whom correspondence should be addressed. Phone: +1 781 609 6538. Fax: +1 781 609 5855. Email: [email protected]. ACKNOWLEDGMENT The authors are grateful to Renovo Research (749 Moreland Ave SE, Suite A201, Atlanta, GA 30316) for structure solution of all dAPZ forms. The authors are also grateful to Dr. Juan Alvarez and Dr. Demetri Moustakas for useful discussion surrounding halogen interactions.


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Supporting Information Available: Experimental, microscope images, physicochemical data, geometrical parameters, crystallographic data and crystal packing diagrams. The crystallographic data of the polymorphs and solvates have been deposited with the Cambridge Crystallographic Data Center, CCDC Nos. 928296 (I), 928297 (II), 928298 (V), 928295 (SMeOH1), 928299 (SMeOH2), and 928294 (SH2O1). This information is available free of charge via the Internet at https://pubs.acs.org.


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For Table of Contents Use Only

Polymorphism of Dehydro-Aripiprazole, the Active Metabolite of the Antipsychotic Drug Aripiprazole (Abilify®) Tarek A. Zeidan,* Jacob T. Trotta, Renato A. Chiarella, Mark A. Oliveira, Magali B. Hickey, Örn Almarsson, and Julius F. Remenar

Dehydro-aripiprazole (dAPZ), the active metabolite of Aripiprazole (APZ), crystallized in eight different forms, including five non-solvated polymorphs, two methanol solvates and a hydrate. Despite molecular structure similarity with APZ, the crystal packing observed in the polymorphs of dAPZ differ significantly from those known for the parent drug.


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164x131mm (150 x 150 DPI)


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Polymorphism of Dehydro-Aripiprazole, the Active Metabolite of the

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