Two Concomitant Polymorphs of 1,2-Naphthoquinone-2-semicarbazone

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Published as part of a special issue of selected papers presented at the 8th International Workshop on the Crystal Growth of Organic Materials (CGOM8), Maastricht, Netherlands, September 15-17, 2008.

CRYSTAL GROWTH & DESIGN 2009 VOL. 9, NO. 8 3438–3443

Two Concomitant Polymorphs of 1,2-Naphthoquinone-2-semicarbazone Vale´rie Dureisseix,† Morgane Sanselme,*,† Yves Robin,‡ and Ge´rard Coquerel† Unite´ de Croissance Crystalline et de Mode´lisation Mole´culaire, SMS EA3233-IMR, UniVersite´ de Rouen, 76821 Mont Saint Aignan Cedex, France, and Isochem-SNPE Group, 12 Quai Henri IV, 75194 Paris Cedex 04, France ReceiVed December 15, 2008; ReVised Manuscript ReceiVed April 22, 2009

ABSTRACT: 1,2-Naphthoquinone-2-semicarbazone (i.e., naftazone) has been characterized by structural analysis (singlecrystal X-ray diffraction, powder X-ray diffraction) and by thermal analysis (differential scanning calorimetry, DSC). Although this molecule has no chiral center, the two forms crystallize in chiral space groups: the stable form I (P212121, Z ) 4, a ) 5.1187(7) Å, b ) 5.6092(7) Å, c ) 34.847(5) Å; V ) 1000.5(2) Å3) and the metastable form II (P21, Z ) 2, a ) 6.3349(1) Å, b ) 3.9263(1) Å, c ) 19.790(5) Å, β ) 92.424(4)°; V ) 491.8(2) Å3). At high concentration (c ) 30 g · L-1), the pure stable form I crystallizes regardless of the antisolvent (water) addition rate. At low concentration (c ) 15 g · L-1), the pure metastable form II crystallizes at low water addition rate (ψ ) 100 mL · h-1); however, the structurally pure form I is also obtained with a high water addition rate (ψ ) 72 × 103 mL · h-1). Concomitant polymorphs crystallize at intermediate antisolvent addition rate and concentration. Therefore in the majority of the operative conditions, these results appear to be in contradiction with Ostwald’s rule of stages. Introduction It is well-known that during a crystallization process of organic molecules several solids can appear (polymorphs, solvates, hydrates, cocrystals, host-guest complexes). Sometimes, these phases appear simultaneously; if they correspond to the same compound, the phenomenon has been termed concomitant polymorphism.1-4 As polymorphism can affect the bioavailability, the stability, the processability, and the solubility of the final active pharmaceutical ingredient,5-7 it is therefore necessary to control the structural purity8 of the final product, together with the shape, the size, and the chemical purity of the crystallized materials. Naftazone is the active pharmaceutical ingredient of Etioven, a veinotonic and vasculoprotector drug. The stable form I is the preferred form for pharmaceutical application. However, most of the time, the industrial process leads to a mixture of the two phases, form I and form II, which are therefore concomitant polymorphs. Thus, the understanding of this phenomenon would help in optimizing the crystallization process, close to room temperature, leading to form I only. This process should also reach satisfactory performances in terms of productivity, reproducibility, filterability, and well-defined specifications in terms of structural purity and particle size distribution. Previous studies have shown the influence of initial concentrations and solvent composition on crystallization and transformation processes.9 In the work reported here, the crystal structures and structural common features of two concomitant polymorphs of naftazone were first investigated (Figure 1), then the relative stability of these two forms (labeled I and II) at different * To whom correspondence should be addressed. Phone: +33 (2) 32 95 52 19. E-mail: [email protected]. † Universite´ de Rouen. ‡ Isochem-SNPE Group.

Figure 1. Developed formula of naftazone, 1,2-naphtoquinone-2semicarbazone (C11H9N3O2).

Figure 2. Molecular representation and numbering of the asymmetric unit of form II (a) and form I (b).

temperature was determined, and finally their accessibilities under the influence of different operating parameters (initial concentration, antisolvent addition rate)10 were investigated. Experimental Section Crystallization. Naftazone (300 mg) was dissolved at room temperature in DMF (10-20 mL; supplied by ACROS, used as such without further purification). The initial concentrations of naftazone ranged from 15 to 30 g · L-1. Crystallizations were carried out by adding distilled water (as an antisolvent) to the DMF solution. The rate of water addition varied from ψ ) 11 mL · h-1 to ψ ) 72 × 103 mL · h-1. As soon as the crystallization occurred, the slurry was filtered (without waiting for completion of the crystallization), and still wet, the filtration cake was sampled for a swift X-ray diffraction analysis.

10.1021/cg801361m CCC: $40.75  2009 American Chemical Society Published on Web 07/07/2009

Polymorphs of 1,2-Naphthoquinone-2-semicarbazone

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Table 1. Crystal Data and Structure Refinement for Polymorphs I and II form I empirical formula fw temp (K) wavelength (Å) CCDC deposit numbers crystal system space group unit cell dimension a (Å) b (Å) c (Å) β (deg) volume (Å3) Z, Z′ calcd density (g/cm3) abs coeff (mm-1) F(000) crystal size (mm3) θ range (deg) limiting indices completeness to 2θ reflns collected/unique data/restraints/params GOF on F2 final R indices [I > 2σ(I)]a R indices (all data)a largest diff. peak and hole (e · Å-3) a

form II C11H9N3O2 215.21 293(2) 0.71073

CCDC 709856 orthorhombic P212121

CCDC 710069 monoclinic P21

5.1187(7) 5.6092(7) 34.847(5)

6.3349(15) 3.9263(10) 19.790(5) 92.424(4) 491.8(2) 2, 1 1.453 0.104 224 0.6 × 0.4 × 0.1 3.09-26.30 -7 e h e 7, -4 e k e 4, -24 e l e 24 99.6% 3916/1148 [R(int) ) 0.0203] 1148/1/153 1.065 R1 ) 0.0344, wR2 ) 0.0959 R1 ) 0.0394, wR2 ) 0.0987 0.181 and -0.121

1000.5(2) 4, 1 1.429 0.102 448 0.3 × 0.2 × 0.05 2.34-26.41 -6 e h e 6, -6 e k e 7, -43 e l e 42 99.5% 7936/1258 [R(int) ) 0.0341] 1258/0/145 1.077 R1 ) 0.0424, wR2 ) 0.0999 R1 ) 0.0577, wR2 ) 0.1056 0.134 and -0.129

R1 ) ∑(||Fo| - |Fc||)/∑|Fo|; wR2 ) [∑[w(Fo2 - Fc2)2]/∑[w(Fo2)2]]1/2.

Single crystals of form I were obtained by using the following procedure: a solution of naftazone in DMF with an initial concentration of 30 g · L-1 was prepared; after precipitation of naftazone by adding water (ψ ) 88 mL · h-1), the suspension was filtered, and the filtrate was kept at room temperature for a slow evaporation. Single crystals were isolated from the filtrate and analyzed by means of single-crystal X-ray diffraction. In order to have single crystals of the metastable form II, 0.5 equiv of urea was added into a suspension of naftazone in DMF. After 24 h of stirring, the suspension was filtered, and the remaining solution was slowly evaporated at room temperature. Urea (as a structurally relative additive) was used to inhibit the nucleation or at least restrict the growth of the stable polymorphic form. For both forms, the single crystals present similar morphologies as flattened orange tablets. Thermal Analysis. A differential scanning calorimetry (DSC) experiment was performed using a SETARAM 141 system. A naftazone sample (10 mg) was sealed in a 30 µL aluminum pan with a pierced cover, and helium was used as the purge gas. The sample was equilibrated at 30 °C in helium for about 10 min and heated from 30 to 220 °C at a 5 °C · min-1 heating rate. Powder X-ray Diffraction. XRPD analyses were carried out on a SIEMENS D5005 diffractometer (θ-θ set) with Cu KR radiation (λKR1 ) 1.5405 Å and λKR2 ) 1.5444 Å; Ni Kβ filter) under 40 kV and 30 mA and collected on a scintillation detector. The diffraction patterns were collected by steps of 0.04° (2θ) over the angular range 3°-30°, with a counting time of 4 s per step. Single-Crystal X-ray Diffraction. SCXRD data collections of form I and form II were performed on a Bruker SMART APEX CCD area detector equipped diffractometer with graphite-monochromatized Mo KR (λ ) 0.71073 Å) radiation at room temperature. A total of 7936 (2042 unique, Rint ) 0.0322) reflections for form I (-6 e h e 6, -6 e k e 7, -43 e l e 42) and a total of 3916 (1976 unique, Rint ) 0.0178) reflections for form II (-7 e h e 7, -4 e k e 4, -24 e l e 24) were collected. The cell parameters and the orientation matrix of the crystals were determined by using SMART software.11 Data integration and global cell refinement were performed with SAINT software. Intensities were corrected for Lorentz, polarization, decay, and absorption effects (SAINT and SADABS softwares12) and reduced to Fo2. The program package WinGX13 was used for space group determination, structure solution (SHELXS14) and refinement (SHELXL15). Space groups were

Figure 3. The π-π interactions (dashed yellow lines) in (a) form I and (b) form II. In form I, the naphthalene rings involved in the interchain π-π interactions are 113° apart. The distance between two aromatic rings from two consecutive chains is at ca. 3.6 Å. In form II, the naphthalene rings are 57° apart in the intrachain π-π interactions. The distance between two consecutive aromatic rings from the same chain is at ca. 3.5 Å. determined from systematic extinctions and relative Fo2 of equivalent reflections. The structure was solved by direct methods. Anisotropic displacement parameters were refined for non-hydrogen atoms. Hydrogen atoms linked to carbon atoms were located via geometrical constraints; the hydrogen atoms of the terminal amine function were located from the Fourier difference at the very end of the refinement. Crystal data and structure refinements for both polymorphs are summarized in Table 1.

Results and Discussion Form I and Form II Crystal Structures. Both polymorphs (forms I and II) crystallize in Sohnke (i.e., chiral) space groups: P212121 (Z′ ) 1) and P21 (Z′ ) 1), respectively. A previous study on achiral organic compounds that crystallize in chiral

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Figure 4. Projection along the a axis of (a) form I and (b) form II, with the symmetry elements represented (in violet). The intramolecular H bonds (pink dashed lines), intermolecular H bonds (green dashed lines), π-π interactions (orange dashed lines), and VdW interactions (yellow dashed lines) are reported on the different panels. The molecules are coiled around the 21 screw axis whatever the nature of the interactions involved between them.

space groups16 proposed different scenarios to explain this phenomenon. Pidcock showed that a flexible molecule with neither a chiral center nor a symmetry plan is 7.9 times more likely to be found in P21/c than in P212121, but this statistic decreases to 4.3 when a rigid molecule with a mirror plane is involved. In naftazone (Figure 1), the existence of two intramolecular hydrogen bonds, between the ketone (on the naphthalene ring) and the hydrogen of the NH group on the one side and between the nitrogen from the NH group and the hydrogen from the NH2 terminal function on the other side, restricts the molecule flexibility so that it becomes rigid. Moreover, the resulting planar conformation contains a mirror plane. Therefore and in accordance with Pidcock,16 this compound exhibits the characteristics of molecules deprived of a stereogenic center that have a non-negligible probability to crystallize in a chiral space group. The molecular conformations of both forms are very similar (Figure 2), due to the two intramolecular hydrogen bonds: O1-H(N2) and N1-H(N3) (respectively, 1.9(1) and 2.2(1) Å for form I; 2.0(1) and 2.3(1) Å for form II). The small difference observed in the torsion angle N1-N2-C11-N3 is not significant (1.1(4)° and -3.6(3)° for form I and form II, respectively). In both structures, molecules exhibit intermolecular hydrogen bonds between O2 and H(N3) (with a distance of 2.1(1) Å for form I and 2.0(1) for form II) coiled around the 21 screw axes. This second type of hydrogen bond generates helical chains propagating along the b axis (Figures 3 and 4). However, the angle formed by two consecutive naphthalene cycles along the chains in form I (113°) is almost twice that in form II (57°). While in form I the chain packing generates some interchain π-π interactions (distance of 3.6(1) Å) (Figure 3a),

in form II these π-π interactions are established inside chains (distance of 3.5(1) Å) (Figure 3b). In this latter form, there is a redundancy inside the chains between the hydrogen bonds and the π-π interactions; thus the cohesion between chains is only ensured by van der Waals (VdW) interactions (distance of 3.8(1) Å between carbon atoms), whereas in form I the interchain cohesion is ensured by both van der Waals (distance of 3.8(1) Å between carbon atoms) and π-π interactions. Projections along the b axis of both structures are displayed in Figure 5. In form I, the (002) slices are regenerated by the binary screw axis parallel to the c axis, whereas in form II, the slices (001) are regenerated only by translations. However, for both structures the slices are linked by van der Waals interactions. Moreover, both of the polymorphic forms exhibit urea and naphthalene moieties as protruding functions alternatively on 001 and 002 for form II and 004 and 002 for form I. Relative Thermodynamic Stability between Form I and Form II. Several cross-seeding experiments performed at different temperatures in methanol and in mixture H2O/DMF (70/30 v/v) led to systematic irreversible evolutions toward form I. The DSC curve in Figure 6 shows in the following order (i) the fusion of the metastable form II at 183.3 °C, (ii) the recrystallization of the stable form I, (iii) the fusion of the stable form I at 189.6 °C, and (iv) an irreversible chemical degradation. Therefore, form II presents a monotropic character at P ) 1 atm. The less stable form II presents a slightly greater density of d ) 1.453 than for form I (d ) 1.429). As shown by Burger,17 when the directed forces implied in the crystal packing are longrange interactions such as hydrogen bonds, the optimal arrangement could lead to rather long distances between molecular surfaces. So there would be no more correlation between density

Polymorphs of 1,2-Naphthoquinone-2-semicarbazone

Figure 5. Projection along the b axis of (a) form I and (b) form II with intramolecular H bonds (pink dashed lines), intermolecular H bonds (green dashed lines), π-π interactions (orange dashed lines), and VdW interactions (yellow dashed lines). The slice thickness is reported on each panel.

and potential energy, leading Burger17 to conclude that in these cases the density of the metastable phase may be higher than that of the stable one. Thus, the less efficient packing of form

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I should be compensated by the energy optimization of the longrange interactions. This phenomenon has been already reported in literature.18 Impact of the Initial Concentrations and Antisolvent Addition Rate on the Final Crystalline Forms. Figure 7 represents the superimposition between experimental XRPD patterns obtained with a slow addition of water (ψ ) 70 mL · h-1) for c ) 15 g · L-1 (panel c) and c ) 30 g · L-1 (panel d) and the calculated XRPD pattern of the pure form I (panel a) and pure form II (panel b). At low antisolvent addition rate, the structurally pure metastable form II detected by XRPD is obtained for a low concentration (from 15 to 20 g · L-1) whereas for a higher concentration (from 25 to 30 g · L-1), the pure stable form I is obtained (Figure 7). The water antisolvent addition rate, ψ [mL · h-1] versus naftazone initial concentration in DMF, ci (g · L-1), is presented in Figure 8. Three regions can be defined: (1) at low initial concentrations and for a low antisolvent addition rate (ψ ≈ 100 mL · h-1), the pure metastable form II crystallizes; (2) for intermediate initial concentrations and antisolvent addition rates, the two concomitant polymorphs form I and form II are obtained; a similar finding has recently been reported for orthoaminobenzoic acid;19 (3) the pure stable form I is obtained at high antisolvent addition rates whatever the initial concentrations explored in this work and low antisolvent addition rates for high initial concentrations. When the antisolvent addition rate exceeds 72 × 103 mL · h-1, a mass set (“prise en masse” phenomenon) is observed at a 30 mL scale, which raises the question of filterability at the industrial scale (dashed pink area in Figure 8). Ostwald’s rule of stages20 is defined by the irreversible evolution of a system from the least stable state, close to the initial state, to the stable thermodynamic equilibrium through different stages, each stage representing the smallest possible change in free energy. It implies that in crystallization from the melt or from solution, the first solid formed will be the least stable of the polymorphs. In the present case, the metastable form II should crystallize first when the system is out of equilibrium (kinetically controlled), that is, at high water addition rate, whereas the stable form I should be observed when the system is evolving close to thermodynamic equilibrium, that is, at low initial concentration and water addition rate. Experimentally, at low concentration [c ) 15 g · L-1] (see Figure 8) and low water addition rate, the opposite occurs; the first form to crystallize is the metastable one. When the system departs more from thermodynamically controlled conditions (by increase of the water

Figure 6. Detail of the differential scanning calorimetry profile of nafatzone (pure form II as starting material; heating rate ) 5 °C/min from 30 to 220 °C).

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Figure 7. Calculated XRPD pattern of (a) form I and (b) form II and experimental XRPD pattern obtained with (c) c ) 15 g · L-1 [pure form II] and (d) c ) 30 g · L-1 [pure form I].

Figure 8. Impact of the initial concentrations (g · L-1) and antisolvent addition rates ln(mL · h-1) on the final crystalline forms.

addition rate), it is the stable polymorphic form that appears, leading to a clear contradiction with Ostwald’s rule of stages. Even if most of the time Ostwald’s rule of stages has been satisfied19 up to now, it has neither been backed by theoretical calculations nor fully explained.21 This case deserves further attention to understand why in the majority of the experiments reported an “anti-Ostwald’s rule of stages” is obtained. Conclusions Two crystal forms of naftazone have been characterized. Form I is more stable than form II from room temperature

to fusion (under normal pressure). Despite similarities in morphology between the two phases and a probable small difference between their free enthalpies, the irreversible solid-solid transition from form II to form I (because of the monotropic character of form II at P ) 1 atm demonstrated in this study) is not expected to take place except via a destructive-reconstructive mechanism mediated by the molten state or a solution. The nature of the polymorph that crystallizes at room temperature depends on the initial concentration of the solution and the water-addition rate, that is, kinetics. Operating conditions

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were determined to crystallize either each of the two pure forms independently or the two polymorphs concomitantly. According to these operating conditions, most of the results obtained in this work are in contradiction with Ostwald’s rule of stages. Further work on kinetics or on crystal growth versus nucleation should be carried out for a better understanding of this phenomenon.

(6) (7) (8) (9) (10) (11)

Supporting Information Available: CIF files of form I (CCDC 709856) and form II (CCDC 710069). This material is available free of charge via the Internet at http://pubs.acs.org.

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References (1) Bernstein, J. Polymorphism in Molecular Crystals; Oxford University Press: Oxford, U.K., 2002. (2) Brittain, H. G. Polymorphism in Pharmaceutical Solids; Marcel Dekker, Inc.: New York, 1999. (3) Hilfiker, R. Polymorphism in the pharmaceutical Industry; WileyVCH: Weinheim, Germany, 2006. (4) Bernstein, J.; Davey, R. J.; Henck, J.-O. Angew. Chem., Int. Ed. 1999, 38, 3440–3461. (5) Rollinger, J. M.; Gstrein, E. M.; Burger, A. Eur. J. Pharmacol. Biopharm. 2002, 75, 53.

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Matsuda, Y.; Tatsumi, E. Int. J. Pharmacol. 1990, 60, 11. Kitamura, M. J. Cryst. Growth 2002, 2205, 237–239. Coquerel, G. Chem. Eng. Process. 2006, 45, 857–862. Kitamura, M.; Sugimoto, T. J. Cryst. Growth 2003, 257, 177–184. Wang, X.; Ching, B. Cryst. Growth Des. 2007, 7, 1590–1598. SMART, version 5.622; Bruker Advanced X Ray Solutions, Inc.: Madison, WI, 2001. SAINT+, version 6.02; Bruker Advanced X Ray Solutions, Inc.: Madison, WI, 2000. WinGX: Version 1.70.01: An integrated system of Windows Programs for the solution, refinement and analysis of single crystal X-ray diffraction data, by Louis J. Farrugia, Dept. of chemistry, University of Glasgow. Farrugia, L. J. J. Appl. Crystallogr. 1999, 32, 837–838. SHELXS-97: Sheldrick, G. M. Acta Crystallogr. 1990, A46, 467. Sheldrick G. M. SHELXL-97, a program for crystal structure refinement; University of Goettingen, Germany, 1997, release 97-2. Pidcock, E. Chem Commun. 2005, 3457–3459. Burger, A.; Ramberger, R. Mikrochim. Acta II 1979, 259–279. Coste, S; Schneider, J.-M.; Petit, M.-N.; Coquerel, G. Cryst. Growth Des. 2004, 4, 1237–1244. Jiang, S.; Ter Horst, J. H.; Jansen, P. J. Cryst. Growth Des. 2008, 8 (1), 37–43. Ostwald, W. Z. Phys. Chem. 1897, 119, 227. Threlfall, T. Org. Process Res. DeV. 2003, 7 (6), 1017–1027.

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