Mechanisms of Reversible Phase Transitions in Molecular Crystals

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Mechanisms of Reversible Phase Transitions in Molecular Crystals: Case of Ciclopirox Clément Brandel, Yohann Cartigny, Nicolas Couvrat, M. Ermelinda S. Eusébio, João Canotilho, Samuel Petit, and Gérard Coquerel Chem. Mater., Just Accepted Manuscript • DOI: 10.1021/acs.chemmater.5b02389 • Publication Date (Web): 31 Aug 2015 Downloaded from http://pubs.acs.org on September 8, 2015

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Chemistry of Materials

Mechanisms of Reversible Phase Transitions in Molecular Crystals: Case of Ciclopirox Clément Brandel,# Yohann Cartigny,# Nicolas Couvrat,# M. Ermelinda S. Eusébio,ǂ João Canotilho,ǂ Samuel Petit,#* Gérard Coquerel# # Normandie Université, UR, Laboratoire SMS, EA 3233, Crystal Genesis Unit, F-76821 Mont Saint-Aignan Cedex, France ǂ CQC, Department of Chemistry, University of Coimbra, Rua Larga, 3004-535 Coimbra, Portugal ABSTRACT: The detailed characterization of several subambient solid state transitions occurring in the pharmaceutical ingredient Ciclopirox between -20 °C and -85 °C was performed by using a combination of DSC, cold-stage optical microscopy, vibrational spectroscopies, solid state NMR at controlled temperature, structural analyses by single crystal X-ray diffraction and temperature-resolved X-ray powder diffraction. The global analysis of the available data reveals that the mechanisms of these reversible transitions involve a subtle compromise between phenomena related to molecular disorder, cooperative release of strains induced by cooling, and structural reorganization associated to topotactic changes in crystal lattice and symmetry. However no major change in the main features of crystal packings is observed during the successive single crystal-to-single crystal transitions, which highlights the difficulty to classify such transitions in the frame of conventional theoretical frameworks. The successive thermal events and related structural changes or relaxations can be seen as the consequences of a deconvolution phenomenon for the global phase transition between the dynamically disordered room temperature form (C2/c, Z=8, Z’=1) and the ordered low-temperature form (P21/c, Z=48, Z’=12). In this respect, the intermediate form(s) can be seen as transient states of kinetic origin with a questionable genuine crystallographic relevance.

INTRODUCTION

framework for the elucidation of ssPT mechanisms. Originally deduced from the study of inorganic and metallic substances, this approach consists in identifying the ‘order’ of a transition from the behavior of Gibbs free energy derivatives at the transition. It is a matter of conventional wisdom to consider that first order ssPTs are discontinuous and occur by means of full destruction of the initial crystal phase (I) induced by the nucleation and growth of the final crystal phase (F) whereas second order ssPTs are continuous and proceed by a “mere distortion” of phase I, affording phase F. The degree of structural similarity between I and F has often been considered as a sufficient criterion to infer on the ‘order’ of the transition.

Solid-solid phase transitions (ssPTs) consist of significant and sudden structural changes affecting any physical and thermodynamic property of a material without alteration of its chemical composition.1 They can therefore be restricted to subtle order-disorder transitions or moderate reorganizations involving modulated structures,2-4 but can also induce a complete reorganization of the atomic, molecular or ionic arrangement, provided that different phases are involved.5 Among organic and molecular crystals, the most widely studied ssPTs are polymorphic transitions6-8 and are usually classified according to their reversibility: in opposition to enantiotropic transitions, monotropic systems depict the irreversible conversion from a metastable form to a more stable one. Such transitions are most often poorly predictable and can have dramatic consequences, for instance in the pharmaceutical context.9 Despite a few attempts to rationalize monotropic transitions,10-13 no mechanism of general relevance has been elaborated so far, and the control on irreversible ssPTs is limited by their insufficient understanding.

The relevance of the Ehrenfest classification to molecular crystals was deeply questioned during the 70’s by Mnyukh and coworkers.17-19 On the basis of skillful use of optical microscopy, these authors have demonstrated that some ssPTs that were acknowledged to undergo continuous transitions actually proceeded by nucleation and growth in the solid phase, i.e. a discontinuous process. It was argued by Mnyukh that any ssPT in molecular crystals proceeds by means of nucleation and growth, notwithstanding the degree of structural similarity between the different polymorphs. Two mechanisms have been proposed: on the one hand the nucleation of phase F occurs at specific voids in the microstructure of phase I

By contrast, a theoretical background for reversible (enantiotropic) ssPTs triggered by temperature changes was proposed almost 80 years ago by Ehrenfest and Landau,14-16 and is still considered as a valuable conceptual

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and crystal growth proceeds by a ‘molecule-by-molecule’ transfer from phase I to phase F, without particular orientational relationship (OR) between the two forms. On the other hand, it is possible that nucleation occurs at oriented cracks which gives rise to a specific OR during growth of phase F, the mechanism is thus ‘epitaxial’.20

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tals were allowed to grow from this solution by slow evaporation of the solvent at room temperature. The obtained crystals consisted of thick hexagonal rods. Differential Scanning Calorimetry (DSC) DSC experiments were performed using a TG/DSC NETZSCH Jupiter STA 449 C instrument. Enthalpy and temperature calibrations were performed with biphenyl and indium. Liquid nitrogen was used as a refrigerant to reach sub-ambient temperatures. Each DSC run was performed with 5 mg of a powdered sample ( 0.05 mg) in sealed aluminium pans with pierced lids. Measurements were carried out with heating/cooling rates in the range 5-15 K/min under a dry helium atmosphere (constant flow of 40 mL/min) and repeated at least twice to check the reproducibility of the measurements. The Netzsch-TA Proteus Software v4.8.4 was used for data processing.

Although experimental results and interpretations published by Mnyukh were confirmed,21 the classification between first order and second order transitions remains the predominant theoretical background of reversible ssPTs.22 A literature overview covering the two last decades (see e.g.23-55) indicates however that such simple classification suffers insufficiencies, since the existence of complex behaviors cannot be readily addressed without extension or modification of the existing framework. Concepts such as cooperativity, packing frustration, concerted movements, microstructure and mosaicity, modulated structures, zip-like mechanisms, anomalous thermal expansion, lattice strains, internal molecular motions, mesoscopic effects, etc. illustrate recent attempts to go forward in our understanding of molecular mechanisms of ssPTs, demonstrating that a unified approach on this topic is desirable but still missing.

Temperature-Resolved X-ray Powder Diffraction (TR-XRPD) and Refinement of Unit Cell Parameters The TR-XRPD measurements were performed using a Panalytical X’Pert Pro diffractometer equipped with a Cu Kα radiation, a Ge(111) incident-beam monochromator (λ = 1.54178 Å) and an X’Celerator detector. Temperaturecontrolled diffraction patterns were collected by using an Oxford cryostat (Oxford cryosystems PheniX). Powdered CPX was sampled as thin pellets. A measurement was performed every 2 °C increments upon cooling down to 213 °C. Data collection was carried out in the scattering angle range 7.5°–37.5° (2θ) with a 0.0084° step over 90 min. These diffractograms were used to refine the lattice and peak parameters (Pearson VII, asymmetry, FWHM) by means of the Pawley method58 using the Material Studio® software.59.

In the present paper, we report the detailed experimental study of ssPTs detected when cooling the antifungal pharmaceutical ingredient Ciclopirox (CPX hereafter), commonly used in the formulation of cosmetic creams. The molecule (Chart 1) is made of a planar heterocyclic part linked to a cyclohexyl moiety by means of a single CC bond. The crystallization behavior of CPX has been recently investigated because CPX is prompt to form fluid inclusions during crystal growth conducted from solvents.56,57 After the complete structural and physicochemical characterization of ssPTs occurring in CPX crystals at low temperature, the final aim is to propose reliable hypotheses and interpretations about the underlying mechanisms at molecular and crystal lattice scales.

Single Crystal X-ray Diffraction (SC-XRD) The selected CPX single crystal was stuck on a glass fiber and mounted on the full three-circle goniometer of a Bruker SMART APEX diffractometer with a CCD area detector (Mo Kα1=0.71073 Å). Three sets of exposures (1800 frames) were recorded, corresponding to three ω scans, for three different values of φ. The cell parameters and the orientation matrix of the crystal were preliminary determined by using SMART Software. Data integration and global cell refinement were performed with SAINT Software.60 Intensities were corrected for Lorentz, polarization, decay and absorption effects and reduced to Fo2. The program package SHELX61 was used for space group determination, structure solution and refinement. After X-ray diffraction measurements at room temperature, the same crystal was cooled down to -173 °C by a regulated airflow exposed to liquid nitrogen and a new data set was measured for crystal structure determination.

Chart 1. Molecular structure of Ciclopirox (CPX, 6cyclohexyl-1-hydroxy-4-methylpyridin-2-one). EXPERIMENTAL SECTION Preparation of Powdered CPX Samples and CPX Single Crystals

Raman and Infrared Spectroscopies Raman analyses were carried out on a single crystal of CPX by using a confocal Raman microscope described elsewhere.62 The excitation of Raman scattering is operated with a helium-neon laser at a wavelength of 632.8 nm and the spectral resolution is 2 cm-1. Temperature was

Powdered CPX was provided by the PCAS company (Limay, France) and recrystallized under magnetic stirring from ethyl acetate (Fisher scientific, USA) prior to further treatments (HPLC purity ≥ 99.8%). For the preparation of single crystals, 3.6 g of ethyl acetate were saturated with 0.49 g of powdered CPX at 20 °C. Single crys-


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controlled by adapting a Linkam THMS 600 setup regulated by a flow of liquid nitrogen.

Further cooling/heating cycles resulted in the same thermogram, thus indicating complete reversibility of the associated physicochemical phenomena. Besides, the DSC profile was found insensitive to cooling/heating rate in the range 2-10 K/min.

Temperature-resolved FTIR spectroscopy was performed using a Nicolet 380 FTIR (Thermoscientific) apparatus fitted with a measurement cell designed for transmission measurements at low temperature and high vacuum (6.0 10-4 mbar) under the action of a turbomolecular pump. The temperature of the cell was controlled by successive additions of liquid nitrogen in the chamber. CPX was sampled as follows: 7.5 mg of freshly recrystallized CPX were triturated with 100 mg of potassium bromide and prepared as a thin pellet by collapsing the mixture under 10 tons with a mechanical press. Before analysis, the pellet was aged 1 h at 50 °C to ensure recrystallization of CPX. Measurements were performed every 10 degrees from room temperature to -100 °C, both upon heating and cooling, and involved scans in the 400-4000 cm-1 region at a resolution of 1 cm-1. Solid State NMR Spectroscopy Solid-state NMR (13C CP/MAS) analyses were conducted on powdered CPX and performed in collaboration with BRUKER Company (Wissembourg, France) on an Avance III 400 WB spectrometer equipped with a 4 mm DVT H/X probe.

Figure 1. DSC analysis conducted on 5 mg of powdered CPX. Heating and cooling rates are 5 K/min.

Cold Stage Microscopy

As a complementary approach for deeper characterization of these thermal events, CPX single crystals were analyzed by FTIR and Raman spectroscopies at controlled temperature as well as cold stage microscopy. As shown in Supporting Information, progressive changes of several band intensities were detected by vibrational spectroscopies upon cooling (mainly visible between -10 °C and 50 °C), but no major or sudden changes could be evidenced. For FTIR analyses, the most significant changes are highlighted by arrows at 2940 cm-1 (C-H stretching), 830 cm-1 and 660 cm-1. CPX single crystals selected for observations by cold stage optical microscopy consisted of small and elongated rods (ca. 1 µm long) with numerous internal macroscopic cracks (Figure 2). No specific event could be visualized upon cooling at 5 K/min from 25 °C to -60 °C (Figure 2-A, B, and C): the molecular phenomena giving rise to the two thermal events in DSC with smallest enthalpies (Figure 1) do not manifest at the macroscopic scale. However, thanks to the CCD camera, a weak but significant decrease (-0.3%) of the light transmitivity of the single crystals could be reproducibly measured from 20 °C to -45 °C, indicating a weak but detectable change of the optical properties of the material (see Supporting Information).

Selected CPX single crystals were loaded into a quartz cell with a cylindrical geometry (d=13 mm, h=1.3 mm) and sampled in a DSC600 temperature stage setup (Linkam) allowing accurate control of the sample temperature (± 1 °C). Liquid nitrogen was used as the refrigerant for cooling ramp down to -120 °C and the nitrogen flux into the cell was regulated via an automatic pump. The setup is coupled with a Leica DRMB microscope (magnification: ×200) connected to a computer for image capture by using a Sony CCD-IRIS/RCB video camera. RESULTS AND DISCUSSION 1. DSC, Cold-Stage Optical Microscopy and ssNMR Spectroscopy Figure 1 shows the DSC analysis performed at low temperature using 5 mg of powdered CPX. The starting material will be identified later on as CPX1 and its crystal structure will be discussed. The sample was first cooled down to -100 °C and then heated back to room temperature at 5 K/min. Three successive thermal events were detected. (i) The lower temperature event, occurring at -87.4 °C upon cooling and at -77.1 °C upon heating, exhibits a marked thermal hysteresis (10.3 °C) and an enthalpy of ca. 430 J.mol-1 (entropy of 2.3 J.K-1.mol-1). (ii) The event occurring at -39.8 °C does not show any detectable thermal hysteresis and has an enthalpy of ca. 80 J.mol-1 (entropy of 0.4 J.K-1.mol-1). (iii) The thermal event detected at ca. -20 °C is of very low intensity and neither hysteresis nor enthalpy could be reliably measured. A careful analysis of the deviation from the baseline between -40 °C and -20 °C indicates that this third thermal event is actually spread over a temperature range of at least 10 °C, roughly between 30 °C and -20 °C.



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Figure 2. Selected cold stage microscopy pictures captured during a cooling at 5 K/min from 25 °C to -120 °C of a CPX single crystal (out of window crystal boundaries are indicated by white dashed lines). The red dashed lines emphasize the evanescent propagation of an interface in the bulk of the crystal.

When reaching T=-95.0 °C upon further cooling, a peculiar phenomenon was observed which can be described as the fleeting propagation of a roughly planar wave or an interface throughout the bulk of the crystal from the left to the right of the main crystal axis. Because of the velocity of this phenomenon, its visualization is difficult from Figure 2-D, E and F, but is emphasized by red dashed areas. Although this interface leaves the microstructure of the crystal visually unchanged and does not affect the optical properties of the sample, the interface propagation is accompanied by a mechanical strain indicating a stress and giving rise to a sudden movement of the rod crystals. (video S1 in Supporting Information).

the cyclohexyl moiety (in red) and from the pyridinone (in green) obtained at different temperatures are also provided. At 25 °C, the peaks due to pyridinone are sharp whereas those of the cyclohexyl are broad, which may indicate some degree of disorder of the cyclohexyl substituent at room temperature while the pyridinone moiety is only weakly agitated. At -40 °C, no supplementary peak is detected: the peaks from the pyridinone are slightly shifted but remain sharp whereas the signals from the cyclohexyl region present a better resolution than at ambient temperature. At -83 °C, some peaks clearly present shouldering (marked by black arrows in Figure 3) and additional peaks appear while signals from the cyclohexyl moiety are sharper than at higher temperatures. This is in agreement with the existence of a different arrangements in the crystal structure at this temperature with reference to 25 °C and -40 °C.

This thermosalient phenomenon49 is of much lower intensity than in the case of oxitropium bromide50 but clearly indicates that the material undergoes a solid/solid transition.31,32 This phase transformation is associated with the lower thermal event detected at -87.4 °C using DSC with powdered CPX. In agreement with thermal analysis, upon reheating the CPX crystal from -100 °C to room temperature, an interface propagation evolving in the reverse direction (i.e. from right to left of the long crystal axis) was also observed at -80 °C, corresponding to the reverse transition. In addition, the occurrence of this phase transformation is perfectly reproducible upon several temperature cycling between -100°C and -60 °C.

From the combination of DSC, FTIR and Raman spectroscopies, cold-stage microscopy and ssNMR, it is established that CPX crystals undergo several successive solidstate rearrangements and/or polymorphic transitions. The polymorphic form at room temperature is labeled CPX1 hereafter and the polymorph existing below -90 °C is labeled CPX3. In the temperature range between -20 °C and -87 °C the existence of other polymorphs is not straightforward on the basis of cold stage microscopy and ssNMR, but spectroscopy suggests that some disorder of the cyclohexyl group might play an important role in the phenomena detected by DSC. A structural analysis was performed using both powder and single crystal X-ray diffraction to further characterize this system.

To obtain more insights into the nature of the weak physico-chemical phenomena occurring between -20°C and -45 °C and to further confirm the existence of a solidsolid transition at ca. -87 °C, a temperature resolved ssNMR spectroscopy45 experiment was performed on a powdered CPX sample: the sample was first cooled down to -100 °C and heated back to room temperature. Figure 3 shows the 13C CP/MAS NMR spectrum of powdered CPX at room temperature. Enlargements of the signals from

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Chemistry of Materials Table 1. Crystallographic data and refinement parameters obtained at 25 °C for CPX1 and -173 °C for CPX3. Polymorphic form

CPX1 (25 °C)

Chemical formula (MW)

C12H17NO2 (207.28 g.mol )

Crystal system

Monoclinic

Space group

C2/c

a (Å)

16.2237(19)

25.3005(19)

b (Å)

13.7216 (16)

27.6357(20)

c (Å)

10.3539 (12)

19.1387(14)

92.607(2)

96.122(1)

2302.55

13305.41

β (°) 3

Volume (Å ) Z, Z’

CPX3 (-173 °C) -1

P21/c

8, 1

48, 12

calcd density (g.cm )

1.196

1.242

measured/unique data

9068/ 2366

107148/27114

obsvd data (Fo>4σ(Fo))

1352

16612

no. of restraints/ parameters

18/174

0/1645

GoF on F

1.028

0.882

R1/ wR2 (Fo>4σ(Fo))

0.0545/ 0.1769

0.0431/0.093

R1 (all data)

0.0843

0.0714

largest difference peak -3 and hole (e . Å )

0.137/-0.124

0.300/-0.345

-3

2

2. Structural Analyses of CPX phases A platelet shaped single crystal (ca. 500 μm, Figure 4) of CPX1 suitable for a SC-XRD experiment was prepared by slow evaporation at room temperature of a saturated ethyl acetate solution and was used for structural analyses. 2.1. Crystal Structure of CPX1 Data collection was first performed at room temperature to solve the structure of CPX1, leading to the crystallographic data (SG C2/c) and structural refinement parameters given in the left part of Table 1. Figure 5-a presents the asymmetric unit of CPX1: the cyclohexyl moiety is disordered and the C8, C9, C11 and C12 carbon atoms were modeled in two different positions with occupancy ratios of 63 % (purple atoms in Figure 5-a) and 37 % (orange atoms in Figure 5-a). This gives rise to two conformers in the asymmetric unit (i.e., Major and Minor), with two different values of the C2-C1-C7-C12 torsion angles (labeled τ, -32.1 and -67.3°, Table 2).

Figure 3. Temperature resolved 13C CP/MAS NMR spectra of CPX conducted on powdered CPX.

500 µm

Figure 6-a shows the reconstructed (h0l)* plan of the reciprocal lattice of CPX1 at room temperature. One can observe that the diffraction spots are large, indicating diffuse scattering due to partial disorder in the structure. Because of the inherent limitations of SC-XRD, the structural model established for CPX1 highlighting the existence of two conformers in the asymmetric unit (Figure 5a) cannot be conclusive alone about the nature of this disorder, but two hypotheses can be drawn:

Figure 4. Single crystal used for structural analyses, glued on a glass fiber.



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Table 2. Geometric parameters for the main hydrogen bonds and torsion angles τ in CPX1 and CPX3.

(i) The disorder is associated with the degree of freedom of the cyclohexyl moiety and its motion around the torsion angle τ. The rather large size and anisotropic shape of the thermal ellipsoids for the cyclohexyl carbon atoms (in particular for the Minor conformer, Figure 5-a) would therefore result from the time and space averaging of relatively large molecular motions around two mean positions τ = -32.1 and -67.3° (i.e., major and minor conformers). This molecular motion can be referred to as some kind of dynamic disorder.63

Polymorph

O2-H…O1

CPX1 (25 °C)

CPX3 (-173 °C)

Hydrogen Bonds

Hydrogen Bonds

D…A

D-H…A

Av D…A

Av D-H…A

2.604(1)

143.7

2.63 +/- 0.2

149.6 +/- 2.0

Torsion Angle (25 °C) Torsion Angle (-173 °C) τ

Figure 5. (a) ORTEP (50% probability ellipsoids) representation of the asymmetric unit of CPX1 at 25 °C. Disordered carbon atoms of the cyclohexyl are in purple (major part) and orange (minor part). (b) superimposition of the 12 CPX molecules of the asymmetric unit of CPX3. (c) Av A, major conformation in the asymmetric unit of CPX3 at -173 °C. (d) Av B, minor conformation in the asymmetric unit of CPX3 at -173 °C. Hydrogen atoms are removed for clarity.

Major

Minor

Av A

Av. B

-32.1(5)

-67.3(1)

-26.0 +/- 6.0

-97.0 +/- 4.0

*

Figure 6. (h0l) CPX1 reciprocal lattice plane of the CPX single crystal during SC-XRD at 25 °C (a), -73 °C (b) and 173 °C (c). Reciprocal unit cell vectors are given in the CPX1 reference unit cell.


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Figure 7. Projections of the CPX1 crystal packing along [001] (a) and along [010] (c) - only the major orientation of cyclohexyl is represented. View of the CPX3 crystal packing along [101] (b) and [010] (d). Non H-bonding atoms have been removed for clarity. Carbon atoms of CPX molecules from a same dimer are shown with the same (magenta or green) color to help visualizing the dimer organization in the structures.

be concluded that the first hypothesis is valid: the disorder in CPX crystals results from the degree of freedom relative to the torsion angle τ, giving rise to molecular motions, probably constrained either by packing forces or by steric hindrances in the solid state.

(ii) A non-random distribution of static CPX conformers exists in CPX1 consisting mostly of a major conformation (τ = -32.1°) but also of several other geometries with larger angular frequency that SC-XRD averages into the minor contribution (τ = -67.3°) observed in the asymmetric unit, thus giving rise to large anisotropic displacement parameters.

The main molecular interaction in the crystal packing of CPX1 consists of a H-bond between the oximic N1-O2H hydrogen and the carbonyl oxygen O1 of a neighboring molecule (Table 2), thus forming dimeric synthons. The centroid-to-centroid distance between the pyridinone rings in a dimer is 7.276 Å. These dimers are packed in (200) molecular slices (Figure 7-a, only the major orientation of cyclohexyl is represented) thus giving rise to a layered structure consisting of an alternation of H-bond rich domains (in green in Figure 7-c) and van der Waals rich domains (in blue in Figure 7-b). One can see from Figure 7-a that the cyclohexyl moieties are stacked along the [110] and [1-10] crystallographic directions. The centroid-to-centroid distance between two neighboring cyclohexyl substituents along this direction is 5.36 Å and

To confirm one of these two hypotheses, several SCXRD experiments were performed on different CPX1 single crystals, prepared from different solvents. After structural refinements, the same disorder was observed in the asymmetric unit and the occupancy ratio relative to the two constituents was found to be reproducible, thus suggesting that this disorder is not static since it does not depend on sample history. Moreover, the progressive sharpening of the peaks stemming from the cyclohexyl moiety observed by ssNMR spectroscopy (Figure 3) indicates a progressive decrease in the number of configurations in the solid-state upon cooling. Such phenomenon cannot account for a static disorder and it can therefore

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Figure 8 shows that the van der Waals surfaces of the atoms from two vicinal cyclohexyls are interpenetrating, indicating that, although this moiety is probably dynamically disordered, no free rotation around the C1-C7 bond is possible when considering a single molecule in the crystal packing. It can however be presumed, assuming a dynamic disorder of cyclohexyl moieties, that concerted movements of adjacent substituents might reduce sterical hindrances and allow conformational rotations.

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aCPX3 = aCPX1 + 2cCPX1 (a) bCPX3 = 2bCPX1 cCPX3 = -aCPX1 + cCPX1 aCPX2 = bCPX1 – cCPX1

(b) bCPX2 = aCPX1 – cCPX1 cCPX2 = -aCPX1 –bCPX1 -3cCPX1 Chart 2. Relationships between unit cells of (a) CPX3 and CPX1 and (b) CPX2 and CPX1.

2.2. Crystal Structure of CPX3 After data acquisition at room temperature, the single crystal was cooled down to -173 °C (100 K) by flushing with a cold nitrogen flux in order to solve the crystal structure of CPX3. Crystallographic data and refinement parameters are provided in Table 1. Figure 6-c presents the reconstructed (h0l)*CPX1 plane of the reciprocal lattice at -173 °C from which one can see that (i) the single crystallinity of the particle has been preserved (in agreement with microscopy observations of a SC/SC ssPT,52 Figure 2), (ii) diffuse scattering has decreased upon cooling and (iii) a large number of superstructure diffraction spots have appeared. In consistency with this observation, a larger unit cell (with lower symmetry P21/c) was found for CPX3 (Table 1) and the structure determination revealed the existence of no less than 12 symmetry independent molecules (superimposed in Figure 5-b) in the asymmetric unit. A systematic search among organic and organometallic structures deposited in the Cambridge Structural Database (vers. 5.35, release November 2013) revealed that only 36 occurrences – out of 658 000 entries – could be found with at least 12 molecular formulas in the asymmetric unit. As expected, most of these high-Z’ structures exhibit a low symmetry, more than 50% of them crystallizing in the triclinic system. The Z’=12 value was found for 15 structures, and Z’=16 is also often encountered, with 11 occurrences. Although a high Z’ value is often concomitant with pseudosymmetry or hypersymmetry,64,65 it was shown by Desiraju and coworkers in the case of sodium saccharin dihydrate that the existence of 16 formulas in the asymmetric unit was associated with the presence of a disordered sub-region in the unit cell.66 This disordered part of the crystal packing was interpreted as a snapshot of a late transition state produced during the nucleation step and could therefore provide insights about preorganized states involved in nucleation.67 In the present case, the decrease in lattice symmetry and the large Z’ value might rather result from an ordering process occurring upon cooling, in which the best compromise has to be found between intermolecular interactions, conformational aspects and crystallographic constraints.

Figure 8. Centroid-to-centroid distance between two vicinal cyclohexyl substituents at 25 °C (CPX1) with van der Waals spheres (only the major cyclohexyl orientation has been considered).

It can also be seen that these 12 molecules can be gathered into two conformational groups owing to their τ torsion angles: for 7 CPX molecules (conformer labeled “Av A”, shown in Figure 5-c) the average τ value is -26.0 ° (± 6°), whereas the 5 other molecules (conformer labeled “Av B”, shown in Figure 5-d) exhibit a mean τ angle of -97 ° (± 4°).It is of interest to note that these two conformational groups are close to the major and minor conformations found in CPX1 (Table 2). In addition, the ratio Av. A/Av. B is 0.58/0.42, which is once again close to the 0.63/0.37 ratio found for the two disordered orientations in CPX1. Furthermore, the crystal packing of CPX3 resembles that of CPX1, consisting of the same type of layered structure (Figure 7-b and d). The centroid-to-centroid distance between the pyridinone rings within a dimer is 7.094 Å, indicating a decrease of 2.5 % with reference to the room temperature structure. Owing to the close similarity between CPX1 and CPX3 crystal structures, it was possible to establish the geometrical relationships between the unit cell dimensions of CPX3 and CPX1 (Chart 2-a), which suggests a topotactic character of the associated transitions. Such relationships can also be expressed by means of a Bärnighausen tree in the frame of the group-subgroup theory. In agreement with the International Tables for Crystallography, the associated shift of the origin for CPX1 (C2/c) to CPX3 (P21/c) is (-1/4 -1/4 0). 2.3. X-ray Diffraction Analysis at -73 °C

The shape of thermal ellipsoids for the cyclohexyl atoms was found almost isotropic and indicate that molecular motions of this moiety are of much lower amplitude than in CPX1, accounting for the less pronounced diffuse scattering in the reciprocal lattice (Figure 6-c).

After data acquisition at -173 °C, the crystal was slowly heated to -73 °C to probe the crystal structure of CPX at this temperature. Figure 6-b (-73 °C) shows the corresponding reconstructed (h0l)*CPX1 plane from which one can see that (i) the superstructure peaks of CPX3 have disappeared and that (ii) marked streaks appear in the reciprocal lattice (highlighted by circles). This peculiar


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phenomenon is not due to delamination35 of the crystal nor to a loss of single crystallinity (single-crystal to polycrystal transition,48 or increase of mosaic spread51) since a homogeneous single crystal of CPX1 or CPX3 could be reobtained by subsequent re-heating or cooling. The streaks could thus be attributed to a constrained packing25,28-30 involving the coexistence of several sub-lattices or to a modulated structure.2,4 The streaks remain present in the reciprocal lattice up to -20 °C and jeopardize the use of the CPX1 unit cell. Actually, the indexing of the diffracted spots allowed the determination of a very large triclinic unit cell with the following lattice parameters: a = 17.074 Å, b = 19.417 Å, c = 36.651 Å, α = 84.919°, β = 79.447°, γ = 70.893° V = 11282 Å3, existing between -20 °C and -90 °C. Due to the too large number of parameters required to solve this putative structure, no solution could be envisaged for this presumed intermediate phase but the relationships between unit cells of CPX2 and CPX1 are given in Chart 2-b. The existence of a distinct polymorphic form in the temperature range of -20 °C/-85 °C was however assumed. This crystal form might actually account for two ‘sub-polymorphs’ according to the DSC observations: CPX1LT from -20 °C to -40 °C and CPX2 from -40 °C to 85 °C.

Along the progressive cooling down to -105 °C, one can see that the main diffraction peaks of CPX1 are preserved while the crystal structure successively changes to CPX2 and to CPX3. This is consistent with the preservation of the main diffraction spots of CPX1 observed in Figure 6 and confirms that the crystal structures of CPX1, CPX1LT, CPX2 and CPX3 present strong similarities in terms of packing. The transformation from CPX1 to CPX2 is detected by the appearance of small diffraction peaks (marked by stars in Figure 9) in the temperature range from -33 °C to -43 °C (CPX2) rather than at a defined temperature, but several weak supplementary peaks can already be seen at -27 °C and -33 °C (CPX1LT). This progressive evolution of XRPD patterns from -19 °C to -85 °C seems consistent with the continuous changes observed by temperature-resolved FTIR and Raman spectroscopies (Supporting Information). By contrast, the transformation from CPX2 to CPX3 is detected by slight but sudden peak shifts and by the appearance of numerous additional diffraction peaks at -95 °C, which is are consistent with the lower symmetry of the packing (in particular the change from mode C to P). The monitoring of XRPD patterns versus temperature was used to probe changes of packing dimensions as a function of temperature, expressed via the CPX1 unit cell. For that purpose, each diffractogram was used to refine unit cell parameters and peak parameters by means of the Pawley method.58

2.4. Temperature Resolved XRPD Study A finely ground sample of carefully recrystallized CPX was used to perform a temperature-resolved X-ray powder diffraction study (TR-XRPD). The continuous evolution of diffraction patterns is shown in Figure S4 (Supporting Information) and Figure 9 shows diffractograms obtained at different temperatures upon cooling at 5 K/min from room temperature to -105 °C. At 29 °C, the diffraction pattern fits almost perfectly with the ticks calculated using the structural model of CPX1.

Upon cooling from 25° to -35 °C, Figure 10 indicates that the c and β parameters of CPX1 unit cell decrease progressively, while the a and b parameters increase. Although the expansion of unit cell parameters upon cooling is unusual among organic crystals,29,30,44 such behavior can be understood by considering the [110] packing direction of cyclohexyl moieties in CPX1 (Figure 7-a). Indeed, the centroid-to-centroid distance between two cyclohexyl substituents can be expressed as the length ( + )/4 and the representation of the van der Waals spheres (Figure 8) highlights that decreasing this distance upon cooling would necessarily induce unfavorable interpenetrations of the spheres. An increase of a and b parameters therefore occurs in particular from -20 °C to -40 °C (Figure 10). However, the small but significant thermal event detected by DSC at -20 °C (Figure 1) can only be related to a moderate slope change of b and c unit-cell parameters, which might distinguish the two forms CPX1LT and CPX2. When the stability domain of CPX2 (i.e. from ca. -40 °C down to -85 °C) is reached, the CPX1LT to CPX2 solid-solid transition is characterized by various slope changes in the evolution of unit cell parameters, with the most pronounced effect for the a=f(T) function. Indeed, the a parameter exhibits a discontinuity and then decreases upon further cooling. By contrast, after a slope break, c and β = f(T) functions continue to decrease while b reaches a plateau. As a result of the non monotonous evolution of a and b parameters, Figure 11 shows that the centroid-tocentroid distance of vicinal cyclohexyl groups (i.e., (a+b)/4) increases in the temperature range of CPX1 and CPX1LT (25 °C down to -40 °C) and then decreases in the temperature domain of CPX2 (-40°C down to -85 °C).

Figure 9. Selected experimental XRPD patterns of CPX upon cooling at different temperatures (indicated on the diffractograms). Arrows indicate peaks that exhibit peculiar evolutions upon cooling. Stars indicate characteristic peaks of CPX2. Calculated systematic peaks of polymorphs CPX1 (upper) and CPX3 (lower) are given below XRPD patterns.



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From -85 °C to -95 °C, i.e. when entering in the temperature range of CPX3, it can be seen from Figure 10 that, once again except for a, each parameter is subjected to a jump, in consistency with the sudden peak shifts observed in the diffractograms (Figure 9). The centroid-to-centroid distance of vicinal cyclohexyl groups also exhibits a sharp jump at the transition into CPX3 (Figure 11). This sudden increase of distance between -80 °C and -90 °C is also consistent with the reconstructive character of the CPX2 – CPX3 transition

Figure 10. Evolution versus temperature of CPX1 unit cell dimensions upon cooling and variations of Rwp versus temperature. Error bars are smaller than experimental points.

Figure 11. d[110]/4 (i.e. centroid-to-centroid distance of vicinal cyclohexyl) as a function of temperature.

The thermal evolution of the unit cell volume is shown in Figure 10 and continuously decreases upon cooling down to -85 °C but is subjected to a small jump when the transformation from CPX2 to CPX3 occurs (volume change is characterized by a loss of ca. 0.87%).


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Figure 12. Schematic representation of the successive transitions in CPX as a function of temperature. The major and minor conformations of the cyclohexyl substituent are colored in magenta and green respectively.

As usually observed for such transitions,51-55 crystal packings exhibit significant similarities, which is demonstrated here from XRPD studies and crystal structure determinations (Figures 7 and 9). Consistently the associated enthalpies measured by DSC are weak (Figure 1) and only limited changes of particle shapes and transparency were observed by optical microscopy.

The increase of the Rwp statistical indicators upon cooling, also shown in Figure 10, results from the appearance of the new diffraction peaks related to CPX2 and CPX3 which are not indexed in the C2/c unit cell. 3. Mechanism of Subambient Transitions between CPX Phases

Besides, and whatever the physical state (powder or single crystal) of the studied samples, the reproducibility and reversibility of the 3 successive thermal events at ca. 20 °C, -40 °C and -80 °C were unambiguously established by repeated DSC and X-ray diffraction analyses. From a structural point of view, each of these transitions is related to distinct changes involving both molecular and crystallographic aspects, with an interesting complementarity between the successive events.

Considering the series of experimental observations depicted above, a description of the successive ssPTs of CPX can be proposed, and is schematically presented in Figure 12. It should be first highlighted that the successive transitions from CPX1 to CPX3 occur as single crystal-to-single crystal events, indicative of non-fully destructive and topotactic mechanisms so as to preserve the integrity of single particles.#

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ably characterized by concerted rotations of cH groups, similar to a cogwheel arrangement.

• At -20 °C and -40 °C, changes in the type of disorder for the cyclohexyl (cH) substituent occur, switching from a dynamic to a static nature upon cooling down to ca. -40 °C, as deduced from both X-ray diffraction and ssNMR investigations (Figure 3), combined with a partial loss of crystalline order highlighted by diffuse scattering (Figure 6). By contrast with DSC results, temperatureresolved XRPD (Figure 9) and Raman spectroscopy (Supporting Information) suggest a continuous evolution of structural features during these transitions rather than sudden events. This apparent disagreement might actually result from the continuous character of vibration mode softening associated with phase transitions (as observed by spectroscopic methods) whilst associated DSC data depict sharp thermal events.68

(iii) At ca. -40 °C, molecular movements of large substituents are no longer possible, and the thermal event detected by DSC is related to a freezing phenomenon toward the static disorder evidenced by solid state NMR. From a crystallographic point of view, the C2/c symmetry is no longer valid, so the disordered and constrained form obtained (CPX2) appears incompatible with conventional symmetries. However this loss of crystalline order allows the system to reduce its thermal motions, and CPX2 appears as a compromise between the necessary decrease of molecular motions (Figure 10) and the persistence of a conformational disorder (Figure 11). (iv) At -87 °C, the previous compromise does not hold anymore, so a deep reorganization occurs, consisting of the establishment of a crystalline order in which each molecular entity adopts a symmetry-defined location and orientation. Since both conformations persist in the packing, this ordering process imposes a large number of molecules in the asymmetric unit so as to recover a conventional crystal symmetry (P21/c).

• At -20 °C and -80 °C, changes in space group, number of molecules per unit cell (Z) and number of molecules per asymmetric unit (Z’) are evidenced, associated with the progressive freezing upon cooling of cH substituent (CPX1LT → CPX2) and of the molecular dimers for the CPX2 → CPX3 transition. The transition at ca. -40 °C is also specifically characterized (upon cooling) by a progressive decrease in transmittivity over a temperature range, an absence of hysteresis and, owing to X-ray diffraction data (Figures 6 and 9), to limited changes in the crystal lattice. Most crystallographic parameters undergo a slope disruption without sharp transition, but with an inversion of slope for the curve representing (cH-cH) distances between closest molecular dimers (Figure 11). By contrast, the transition at ca. 80 °C is associated with a marked hysteresis, the propagation of an interface detected by optical microscopy and significant structural changes evidenced by diffraction patterns (Figure 9) and reciprocal lattice (Figure 6). Consistently all crystallographic parameters (except a) undergo a clear disruption revealing a larger reorganization of the crystal lattice. This reordering process at the lattice scale occurs at the cost of a large increase in the number of molecules in the asymmetric unit.

Upon heating, the reverse scenario can be envisaged, consisting mainly of successive relaxations as soon as kT becomes sufficient. It is noteworthy that each of the three thermal events is related to distinct types of structural changes. Actually it can be envisaged, as shown in Chart 3, that the various events reported above might constitute ‘sub-steps’ or deconvoluted fractions of a single phase transition between CPX1 and CPX3, involving a combination of ordering/disordering contributions and crystallographic changes. The three (or even four) crystal forms of Ciclopirox might thus appear as isomorphic polymorphs, according to the definition recently proposed by Coles et al.69 The exact status of CPX1LT and CPX2 has actually to be carefully considered: owing to DSC and X-ray diffraction methods, CPX2 might appear as a modulated, distorted or constrained variation of CPX1, but recent investigations using SHG,70 dielectric investigations,71 or solid state NMR72 have illustrated that apparent similarities may hide profound differences in terms of molecular mobility, partial molecular disorders and dynamics in the solid state. In the present case, CPX2 could for instance enter in the class of pseudo glassy or plastic crystals resulting from a specific relaxation behavior associated with disordered but correlated molecular motions.73-75 Although further investigations are required to establish the exact nature of CPX1LT and CPX2, this solid phase should definitely be considered as a transient phase of kinetic origin in the polymorphic landscape of Ciclopirox. Chart 3 illustrates the possibility that a conventional reversible A ↔ B transition is deconvoluted into successive events spreading over a temperature range of ca. 60° C.

From this summary of the various molecular or structural changes and their physical consequences, a reliable description of the successive events occurring upon cooling can be proposed: (i) At room temperature, the high symmetry of the crystal lattice (C2/c) is associated with a dynamic molecular disorder of the cH substituent. Thermal motions are relatively large, allowing random and non-correlated changes between the major and minor conformations depicted in Figure 5a. (ii) When temperature is reduced to ca. -20 °C, thermal motions are restrained, preventing the persistence of free rotations for the cH moiety. Together with an alteration of the crystallographic lattice (partial decrystallization), the consequence is the progressive appearance of a necessary correlation or cooperativity between movements of neighboring molecules, and the dynamic character of the molecular disorder between -20 °C and -40 °C is presum-


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Chart 3. Deconvolution of a classical (A ↔ B) solid-solid phase transitions in several sub-steps inducing the existence of an intermediate state. In Ciclopirox, the CPX2 and CPX1LT forms spread over ca. 60° C.

crystals: FTIR and Raman spectra, light transmittivity and XRPD patterns. Video recording of optical microscopy observations of a single crystal showing the CPX2-CPX3 transition. This material is available free of charge via the Internet at http://pubs.acs.org.

4. Conclusion The study of the sub-ambient ssPTs in CPX single crystals illustrates, in consistency with other recent case studies, some insufficiencies of the conventional framework of phase transition theories (mainly derived from inorganic systems) as soon as molecular crystals are concerned. These theories cannot satisfactorily account for important aspects such as molecular flexibility, packing frustrations or strains, partial molecular disorder and concerted molecular displacements. True polymorphic transitions (in Mnyukh’s definition) occur upon temperature change when a distinct crystal form of lower energy has to nucleate and grow, but various types of structural changes may happen because of an accumulated stress or frustration, then requiring only a release of structural strain and an optimization of the crystal packing, possibly associated with macroscopic mechanical consequences (thermosalient effect). The thermal behavior of CPX crystals suggests that the CPX1 – CPX3 transition might be decomposed into several sub-steps spreading over a large temperature range. This highlights that phase transitions can actually involve various contributions occurring at different temperatures, providing a unique opportunity to get more detailed insights into each of these contributions.

AUTHOR INFORMATION Corresponding Author * E-mail: [email protected]. Phone: +33235522428. Fax: +33235522959

Author Contributions The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.

Note The authors declare no competing financial interest. # A similar discussion about molecular mechanisms of phase transitions was recently derived from a careful analysis of the polymorphic behavior of DL-norleucine. This complementary and interesting work by H. Meekes and coworkers (Radboud Univ., Nijmegen, NL) is to be published in Cryst. Growth Des., 2015.

ACKNOWLEDGMENT

By contrast with restrictive and sometimes simplistic classifications (first order vs second order, continuous vs nucleation and growth, etc.), such behavior might enlarge our views about molecular mechanisms of phase transitions. Complementary studies, in particular by performing accurate temperature-resolved solid state NMR analyses, are in progress in order to get insights into the structural features of CPX1LT and CPX2.

The French Ministery of Research is acknowledged for financial support to C.B. via the E.D. n°351 (SPMII). Thanks are also due to CRIHAN (Région Haute-Normandie, France) for providing access to software Material Studio (v. 6.0, Accelrys Inc.) and Sybyl.X (v. 1.3, Tripos). The “Laboratoire de Cristallographie, Résonnance Magnétique et Modélisation” (‘Service Commun de Diffraction X’ of ‘Université de Lorraine’) is acknowledged for providing access to Crystallographic facilities (temperature-resolved XRPD analyses). Dr. Servane Coste, Dr. Morgane Sanselme and Dr. Valérie Dupray are acknowledged for their crystallographic and spectroscopic assistance. Bruker BioSpin GmbH is thanked for solid state NMR analyses.

ASSOCIATED CONTENT Supporting Information. Cif files of the 2 crystal structures (data deposited to the CSD with refcodes CCDC 1406505 and 1406506. Subambient temperature-resolved analyses of CPX

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SYNOPSIS TOC


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Mechanisms of Reversible Phase Transitions in Molecular Crystals

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