Mechanism of Hydration and Dehydration of Ciclopirox Ethanolamine

Jul 31, 2009 - The antifungal agent ciclopirox ethanolamine (1:1), crystallizes as an anhydrate and a monohydrate. The single crystal X-ray diffractio...
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DOI: 10.1021/cg8013877

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

2009, Vol. 9 3918–3927

Mechanism of Hydration and Dehydration of Ciclopirox Ethanolamine (1:1) Ludovic Renou,†,§ Servane Coste,† Yohann Cartigny,*,† Marie-Noelle Petit,† Catherine Vincent,‡ Jean-Marie Schneider,‡ and Gerard Coquerel† †

UC2M2, EA3233, Universit e de Rouen, 76821 Mont Saint Aignan, France, and ‡ PCAS, Site de Seloc France, 78520 Limay, France. §Present address: Pharmorphix Solid State Services, member of the Sigma-Aldrich group, 250 Cambridge Science Park, Milton Road, Cambridge, CB4 0WE, U.K. Received December 19, 2008; Revised Manuscript Received July 2, 2009

ABSTRACT: The antifungal agent ciclopirox ethanolamine (1:1), a stoichiometric compound between ethanolamine and 6-cyclohexyl-1-hydroxy-4-methylpyridin-2-(1H)-one, crystallizes as an anhydrate and a monohydrate. The structures of both phases have been characterized by single crystal X-ray diffraction and suggest that, at ambient temperature, ciclopirox ethanolamine (1:1) anhydrate and monohydrate should be classified as salts from the position of the protons in the Fourier difference map. The thermal dehydration process has been elucidated by thermal analyses (TGA/DSC), temperature resolved X-ray powder diffraction and Hot-Stage Microscopy. Moisture sorption and desorption investigations at room temperature under static and dynamic conditions (DVS) reveal that, if the dehydration is not implemented under a sufficient ethanolamine vapor pressure, the dehydration-hydration mechanism is not reversible. This behavior suggests that, at elevated temperature, ciclopirox ethanolamine (1:1) monohydrate could be contemplated as a heterosolvate of water and ethanolamine molecules.

1. Introduction The formation of solvates and in particular hydrates is a widespread phenomenon especially for pharmaceutical materials. It has been shown that about 33% of organic compounds crystallize as hydrates and about 10% as solvates.1 The characterization of pharmaceutical hydrates is essential because the presence of water molecules in the crystalline structure may lead to very different physical properties as for example the solubility, dissolution rate, chemical stability, and bioavailibility.2,3 In addition, many solid-state properties may be altered by the presence of water, including mechanical behavior, such as grinding or tableting.4 Therefore, it is essential to perform a full characterization of the solid materials,5 which includes the studies devoted to the hydrationdehydration mechanisms. These reactions can proceed via numerous possible pathways.6,7 Indeed, upon dehydration, hydrates may for instance retain more or less their original crystal structures,8-11 they can lose their crystallinity to give amorphous solids, which may undergo a nucleation and growth process to give new material without any structural similarities to the original material (new polymorphic forms12,13) or they can transform to a lower hydrate.14-17 This paper reports the anhydrate and monohydrate crystalline structure of the ethanolamine salt of 6-cyclohexyl-1hydroxy-4-methylpyridin-2-(1H)-one, hereafter called ciclopirox ethanolamine (1:1) (the numbers in parentheses indicate

*Corresponding author. Phone: 33 (0)2 35 52 29 54. E-mail: yohann. [email protected]. pubs.acs.org/crystal

Published on Web 07/31/2009

the stoichiometry in ciclopirox and ethanolamine respectively). Until now, only the structure of the ciclopirox ethanolamine (2:1) was described in the literature.18 Ciclopirox ethanolamine (1:1) (scheme 1) is a broad spectrum antifungal agent, widely used in the treatment of a variety of fungal and yeast infections of the skin. In addition to the crystalline structure, structural changes upon hydration and then dehydration of ciclopirox ethanolamine (1:1) were examined using X-ray powder diffraction, TGA/DSC, sorption-desorption analyses, and hot-stage microscopy. The results were correlated with single-crystal structural data. 2. Experimental Section 2.1. Crystal Growth. Ciclopirox ethanolamine (1:1) single crystals were obtained by a two-step procedure, stirring a mixture of 4 g of ciclopirox ethanolamine (1:1) (supplied by PCAS (Limay, France)), 3.6 mL of ethanolamine (in excess) (VWR, anhydrous, melting point 10.5 °C) and 40 mL of 4-methyl-2-pentanone (hereafter called MIBK) (purity 99%, Acros Organics) at 20 °C under nitrogen flux. After filtration on filter paper, the saturated solution was stored in a sealed tube under nitrogen atmosphere at 4 °C. Needlelike crystals were grown in this solution. Ciclopirox ethanolamine (1:1) monohydrate crystals were prepared by stirring: 1 g of ciclopirox ethanolamine (1:1), 1 mL of ethanolamine, 10 mL of MIBK, and 0.13 mL of H2O (2 equivalents). The suspension was stirred in a thermostatted vial at 25 °C (( 0.2 °C) for 2 h. The saturated solution was then carefully pipetted and cooled down to 20 °C (( 0.2 °C) in 6 h. Needlelike crystals were allowed to grow in this solution by means of slow evaporation of the solvent. 2.2. GlpKa Measurement. Data were collected on a Sirius GlpKa instrument with a D-PAS spectrometer controlled from a computer r 2009 American Chemical Society

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3.1. Measured pKa. At 25 °C, three pKa measurements were obtained for ciclopirox at: 7.014 ( 0.001, 7.008 ( 0.001 and 7.004 ( 0.001. These results give a mean result at 7.01 ( 0.01. 3.2. Crystal Structure Determinations. (a) Data Collection and Refinement Data. For ciclopirox ethanolamine (1:1), the Bragg reflections were indexed according to a triclinic cell with a = 10.496(3) A˚, b = 10.669(3) A˚, c = 15.813(5) A˚, R = 72.684(4)°, β = 87.972(5)°, γ = 61.541(4)° and V = 1474.2(7) A˚3. After the empirical absorption correction, the reflections were merged according to the P1 space group, leading to Rint = 0.0313. Non-hydrogen atoms were located with initially isotropic and then anisotropic displacement parameters. Hydrogen atoms were located by Fourier difference syntheses except those of the methyl group, which were placed in position. No proton was located on the hydroxyl group of the ciclopirox molecule based on the difference map analysis. The acidic proton was located on the ethanolamine entity. The final cycle of full-matrix least-squares refinement on F 2 was based on 5959 observed reflections and 513 variable parameters and converged with unweighted and weighted agreement factors of R1 = Σ ( Fo| - |Fc )/Σ|Fo| = 0.1024 (0.050) (Fo >4.0 σ(Fo)) and wR2 =[ Σ [w(Fo2 - Fc2) 2]/Σ [w(Fo2)2 ]]1/2 = 0.155. For ciclopirox ethanolamine (1:1) monohydrate, the Bragg reflections were indexed according to a triclinic cell with a=9.837(1) A˚, b=10.504(1) A˚, c=15.304(1) A˚, R = 87.949(1)°, β = 80.336(1)°, γ = 89.540(1)°, and V = 1558.2(2) A˚3. After the empirical absorption correction, the reflections were merged according to the P-1 space group, leading to Rint = 0.0194. Non-hydrogen atoms were located with initially isotropic and then anisotropic displacement parameters. Hydrogen atoms were located by Fourier difference synthesis with the exception of the hydrogens of the disordered groups of the ethanolamine which were placed in position. No proton was located on the hydroxyl group on the ciclopirox molecule based on the difference map analysis. The acidic proton was located on the ethanolamine entity. The final cycle of full-matrix least-squares refinement on F 2 was based on 4418 observed reflections and 575 variable parameters and converged with unweighted and weighted agreement factors of R1=Σ( Fo| - |Fc )/Σ|Fo|=0.069 (0.048) (Fo > 4.0 σ(Fo)) and wR2=[Σ[w(Fo2-Fc2) 2]/Σ[w(Fo2)2 ]]1/2 = 0.127. Crystallographic data, refinement details, and related results are summarized in Table 1 (crystallographic data and fractional coordinates have been deposited at the Cambridge Crystallographic Data Center (CSD) and registrated under the deposition numbers CCDC 611793 and 611794). (b) Structure Descriptions. Ciclopirox ethanolamine (1:1): the asymmetric unit contains two molecules of ethanolamine and two molecules of ciclopirox (Z0 = 2, table 1). A thermal ellipsoid plot of the asymmetric unit is represented in Figure 1. The positive charge located on the ammonium group of the ethanolamine molecules (pKa =9.5)23 is neutralized by the negative charge of the hydroxyl group of the ciclopirox molecules (weak acid with a pKa at 7.0). The cyclohexane rings of ciclopirox take the chair conformation, the pyridinone ring being in equatorial position. As expected, these pyridinone rings are almost planar, the rootmean-square deviation (rmsd) for fitting the atoms in the plane of the pyridinone group has been calculated. For the group of molecule I, the rmsd is 0.02 A˚ with atom O2 showing the greatest deviation from planarity: 0.04 A˚. For )

using Refinement Pro software (V.2.2.3, Sirius Analytical Instruments Ltd., UK). Ciclopirox was initially dissolved in pure DMSO to form a 10 mM stock solution and three measurements were made at 25 °C in “aqueous solution” (50 μL of stock solution was used per assay in 10 mL of water) by UV. A multiwavelength UV spectrum was measured while the sample was titrated. The titration media was ionic-strength adjusted (ISA) with 0.15 M KCl (aq). The measurement was carried out from pH 11.0 to 6.0 as a triple titration. 2.3. Crystal Structure Determinations. Suitable single crystals were selected, mounted on glass fibers and transferred to the full three-circle goniometer of a Bruker SMART APEX diffractometer (Mo KR, λ = 0.71073 A˚) with a CCD area detector. 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 determined by using SMART.19 Data integration and global cell refinement were performed with SAINT.20 Intensities were corrected for Lorentz, polarization, decay, and absorption effects with SADABS.20 The program package SHELXTL21 was used for space group determination, structure solution, and refinement. 2.4. X-ray Powder Diffraction (XRPD). XRPD data were obtained on a Siemens D5000matic apparatus (θ-θ set, fixed slits 1.6 mm) with Cu KR radiation (1.54056 A˚) (Ni Kβ filter) under 40 kV and 40 mA and collected on a scintillation detector. The range of measurement lies between 3° and 30° (step 0.04° 2θ; step time 4s). Temperature-resolved XRPD (TR XRPD) were obtained on a Siemens D5005 diffractometer equipped with a TTK 450 chamber. Heating rates of 2 °C min-1 were used to the desired temperature, which was maintained for the data collection (from 3 to 30°, 0.04° 2θ, step time 4s). All experiments were carried out under normal atmosphere. Experimental data were processed with EVA software.22 2.5. Thermal Analyses. Differential scanning calorimetry (DSC) coupled to thermogravimetric analysis (TGA) was performed on a TGA/DSC NETZSCH STA 449 C or 409PC instrument. Samples were put in a 30 μL aluminum crucible and heated at a rate 5 °C/min. He purging gas was used. The chemical nature of escaping gases during heating was identified by using a Netzsch QMS 403 C mass spectrometer coupled with the 449C TGA/DSC apparatus. 2.6. Water Vapor Sorption and Desorption. At ambient temperature, samples were placed in humidity chambers in which the relative humidity was controlled using K2SO4 saturated salt solutions (RH=97%). For desorption experiments, samples were stored over dried silica gel and P2O5. Water vapor sorption and desorption were also carried out with an accurate humidity and temperature controlled microbalance system (Dynamic Vapor Sorption (DVS-1 type), Surface Measurement System UK). Relative humidity (RH) was controlled by continuous gas flow containing pure nitrogen and water vapor in adequate proportions. Temperature and RH were measured with a precision of 0.1 °C and 0.5% respectively. Mass variations were recorded continuously with a precision of 0.1 μg. Isotherms were constructed with 10 consecutive steps of relative humidity between 90 and 0% RH at 20 °C. The mass measured at a given step was considered constant when relative mass variations dm/dt remained below 0.001% for 10 min. The maximum stabilization time was adjusted to 2000 min. 2.7. Hot-Stage Microscopy. Crystals of (1:1) ciclopirox ethanolamine monohydrate were heated at 5 °C min-1 between 30 and 100 °C under optical microscope (Nikon SMZ-10A).

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3. Results and Discussion

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Scheme 1. Stoichiometric Compound between Ciclopirox and Ethanolamine

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Table 1. Crystallographic Data and Refinement Details empirical formula fw T (K) cryst syst space group a (A˚) b (A˚) c (A˚) R (deg) β (deg) γ (deg) Volume (A˚3) Z, Z0 calcd density (g cm-3) absorp coeff (mm-1) no. of measured /independent/observed reflens (I > 2σ(I)) no. of params R1 (obs)/R1 (all) wR2 (obs)/wR2 (all) Δσ(max)/Δσ(mean) Δjmax/Δjmin (e- A˚-3)

ciclopirox ethanolamine (1:1)

ciclopirox ethanolamine (1:1) monohydrate

C12H16NO2,C2H8NO 268.35 296(2) triclinic P1 10.496(3) 10.669(3) 15.813(5) 72.684(4) 87.972(5) 61.541(4) 1474.2(7) 4, 2 1.209 0.085 11378/5959/ 3406 513 0.050/ 0.102 0.126/ 0.155 0.000/0.000 0.22/-0.24

C12H16NO2, C2H8NO, H2O 286.37 296(2) triclinic P1 9.839(1) 10.504(1) 15.304(1) 87.949(1) 80.336(1) 89.540(1) 1558.2(2) 4, 2 1.221 0.089 12468/6264/4418 575 0.048/0.069 0.116/0.127 0.000/0.000 0.19/-0.17

Figure 2. Superimposition of the two independent ciclopirox molecules from the asymmetric unit of ciclopirox ethanolamine (1:1) (molecule I is represented in black and molecule II is represented in light gray).

Figure 1. Thermal ellipsoid plot of ciclopirox ethanolamine (1:1) with the adopted numbering scheme for non-hydrogen atoms. All non-hydrogen atoms are represented by their displacement ellipsoids drawn at the 50% probability level. Hydrogen bonds are represented by dotted lines and the corresponding hydrogens are labeled.

˚ with atom C18 the group of molecule II, the rmsd is 0.05 A ˚ . The dihedral angle showing the greatest deviation: 0.10 A between the two calculated planes is 17.7°. The independent molecules show very similar conformations (Figure 2) as do about 90% of such structures.24 The torsion angles of C4-N1-C3-C2, C4-C5-C1-C2, N1-C3-C2-C1 are -3.0°, -0.9°, 2.3° respectively for molecule I and C16-N2-C15-C14, C16-C17-C13-C14, N2-C15-C14C13 are -1.5°, -2.6°, -1.5°, respectively, for molecule II. The relative orientations of the cyclohexane rings with respect to the pyridinone rings are similar. The torsion angle of the N1-C4-C7-C12 chain in molecule I and the N2-C16C19-C20 chain in molecule II are -158.4° and -155.6 respectively. The torsion angles in the molecules of ethanolamine are also similar with N3-C25-C26-O5 and N4C27-C28-O6 equal to 58.5 and 53.2°, respectively. The crystal cohesion is ensured by ionic bonds and by a complex hydrogen bond network located around (x, 0.5, 0.5) (Figure 3) (table 2).

Figure 3. Projection of the ciclopirox ethanolamine (1:1) along the b axis showing the complex hydrogen bond network located around the (x, 0.5, 0.5) axis. Ciclopirox molecules are represented in capped sticks and ethanolamine molecules are represented in ball and stick. The hydrogen bonds (black pointed lines) are represented with the numbering scheme used in Table 2.

In ciclopirox ethanolamine (1:1) monohydrate: the asymmetric unit is composed of two independent salts and two independent water molecules (Z0 = 2, Table 1). A thermal ellipsoid plot of the asymmetric unit is represented in figure 4. The cyclohexane rings of ciclopirox take the chair conformation, the pyridinone ring being in equatorial position. The pyridinone rings are almost planar (Figure 5), the root-mean-square deviation (rmsd) for fitting the atoms in the plane of the pyridinone group has been calculated. For

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Table 2. Hydrogen-Bond Parameters for Ciclopirox Ethanolamine (1:1) Anhydrate and Monohydrate ciclopirox ethanolamine (1:1) no. 1 2 3 4 5 6 7 8 9 10

N3-H3NA 3 3 3 O4 N3-H3NA 3 3 3 O3 N3-H3NB 3 3 3 O2 N3-H3NC 3 3 3 O1 O5-H5O 3 3 3 O3 N4-H4NA 3 3 3 O2 N4-H4NB 3 3 3 O5 N4-H4NC 3 3 3 O2 N4-H4NC 3 3 3 O1 O6-H6O 3 3 3 O4

distance (A˚) H 3 3 3 O 1.90 2.26 1.82 1.83 1.71 2.21 1.87 1.94 2.11 1.84

ciclopirox ethanolamine (1:1) monohydrate angle (deg) NHO

ID

154.26 127.15 163.47 163.91 174.58 158.98 164.77 149.27 131.30 162.15

a b c d e f g h i j k l m n

N3-H3NA 3 3 3 O7 N3-H3NB 3 3 3 O6 N3-H3NC 3 3 3 O2 N3-H3NC 3 3 3 O1 O5-H5O 3 3 3 O4 N4-H4NA 3 3 3 O4 N4-H4NA 3 3 3 O3 N4-H4NC 3 3 3 O8 N4-H4NB 3 3 3 O5 O6-H6O 3 3 3 O2 O7-H7OA 3 3 3 O4 O7-H7OB 3 3 3 O1 O8-H8OA 3 3 3 O2 O8-H8OB 3 3 3 O3

distance (A˚) H 3 3 3 O 1.91 1.88 2.18 2.05 1.84 2.17 2.01 1.89 1.89 1.77 1.86 1.89 1.89 1.96

angle (deg) NHO 171.00 171.22 140.12 142.54 163.65 137.58 144.81 172.07 177.8 169.81 177.54 176.02 172.24 170.07

Figure 5. Superimposition of the two independent ciclopirox molecules from the asymmetric unit of ciclopirox ethanolamine (1:1) monohydrate (molecule I is represented in black and molecule II is represented in light gray).

Figure 4. Thermal ellipsoid plot of the asymmetric unit of ciclopirox ethanolamine (1:1) monohydrate with the adopted numbering scheme for non-hydrogen atoms. All non-hydrogen atoms are represented by their displacement ellipsoids drawn at the 50% probability level. The minor contributions of ethanolamine molecules are represented by dotted bonds.

the group of molecule I, the rmsd is 0.02 A˚ with atom C6 showing the greatest deviation: 0.02 A˚. For the group of molecule II, the rmsd is 0.03 A˚ with atom C18 showing the greatest deviation from planarity: 0.06 A˚. The dihedral angle between the two calculated planes is 36.3°. The relative orientations of the cyclohexane rings with respect to the pyridinone rings are slightly different since the torsion angle of the N1-C4-C7-C12 chain in molecule I and the N2-C16-C19-C20 chain in molecule II are -108.5° and -132.2°, respectively. The ethanolamine molecules are both disordered with carbon atom positions split over two overlaid crystallographic sites: C25A-C26A and C25B-C26B with an occupancy ratio refined to 74%/26%, respectively, and C27A-C28A and C27B-C28B with an occupancy ratio refined to 65%/35%, respectively. Crystal packing is dominated by a complex hydrogenbonding interaction network between water, ethanolamine and ciclopirox molecules (Table 2). The hydrogen bond interactions are located within the (001) plane (Figure 6). In ciclopirox ethanolamine (2:1) anhydrate,18 the crystal packing is dominated by a hydrogen bonding interaction

Figure 6. Projection of ciclopirox ethanolamine (1:1) monohydrate along the a axis. Ciclopirox entities are represented in capped sticks, ethanolamine entities are represented are represented in ball-andstick and water molecules are represented in space fill. The hydrogen bonds (black pointed lines) are located within (001) planes and are represented with the numbering scheme used in Table 2.

network between ethanolamine and ciclopirox molecules (Figure 7). The hydrogen-bond interactions between ethanolamine molecules are mainly located within the (020) plane. The structures of ciclopirox ethanolamine anhydrate and monohydrate present some similarities. Indeed, the molecular arrangement shown in figure 8 can be described in both structures as a stacking of hydrogen-bonded (001) layers. These layers contain two slices, A and B, of ciclopirox molecules linked by van der Waals interactions. Both structures present then an alternation of H-bond-rich planes and apolar planes every half of length c. In both structures, ethanolamine molecules are located between two layers of ciclopirox molecules. The interlayer distance is ∼2.3 and ∼3.7 A˚ for the anhydrate and monohydrate phases, respectively.

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Figure 7. (a) Projection of ciclopirox ethanolamine (2:1) anhydrate along the c axis. Ciclopirox molecules are represented in capped sticks and ethanolamine molecules are represented are represented in ball and stick. Part of the hydrogen bonds (black pointed lines) and ethanolamine are located within (020) planes. (b) Hydrogenbonding interaction network between ethanolamine and ciclopirox molecules (black dotted lines) in the crystal structure of ciclopirox ethanolamine (2:1) anhydrate. For clarity, the ethanolamine molecule is represented in the ball-and-stick model, with the hydrogens in light blue and the carbon in green.

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However, in the monohydrate phase, each plane A or B contains ciclopirox molecules having the same orientation whereas in the anhydrate phase ciclopirox molecules adopt two opposite orientations in the same plane (Figure 8). Water loss would bring about a rotation of one ciclopirox out of two within every slice. This mechanism seems unlikely on account of steric hindrance of neighboring ciclopiroxate and ethanolaminium ions. Because of these important stacking differences, it seems difficult to envisage a cooperative mechanism during the dehydration process. 3.3. Moisture Sorption/Desorption Studies. Static moisture sorption-desorption studies were performed on ciclopirox ethanolamine (1:1). After a first hydration step under 97% RH, the hydrated salt was alternatively stored over dried silica gel/P2O5 and over 97% RH. XRPD analyses confirmed the ability of the dehydration/hydration process since either the monohydrate or the anhydrate were obtained (up to three cycles). However, it is worth to notice that this process is accompanied by the formation of the stable ciclopirox ethanolamine (2:1) compound (data not shown). Dynamic moisture sorption-desorption isotherms (T = 20 °C) were performed on ciclopirox ethanolamine (1:1) using the DVS apparatus (Figure 9). After a first storage at 90%RH, allowing the formation of the monohydrate, an initial desorption step induces, under dry conditions, a mass loss which is superior to the mass uptake due to the hydration (theoretical value 6.2%). The subsequent sorption/desorption cycles (cycles 1 and 2 in Figure 9) highlighted a similar behavior. Moreover, the mass uptake related to the hydration of ciclopirox ethanolamine (1:1) under RH > 60-80% was decreasing during the successive sorption-desorption cycles (Figure 9). The non reproducibility of the mass uptake/loss during successive cycles indicates that there was a degradation of the solid phase associated with a loss of matter during the drying step. This was confirmed by XRPD analyses carried out on product stored under drying condition after three sorption/desorption cycles (Figure 10): the powder was constituted by a mixture of ciclopirox ethanolamine (2:1) and ciclopirox ethanolamine (1:1). This irreversible transformation due to the departure of a part of ethanolamine molecules (evaporated by the drying nitrogen flux) certainly began during the first drying step. The apparent slow kinetic of the degradation of ciclopirox ethanolamine (1:1) under drying conditions (the maximum drying step time (2000 min) elapsed for every cycle) explains the presence of (1:1) and (2:1) ciclopirox ethanolamine on XRPD pattern (Figure 10). Thus, as the (2:1) ciclopirox ethanolamine is not sensitive to the high humidity

Figure 8. Projection along the b axis of the anhydrate structure (left) and along the a axis of the monohydrate (right). Ethanolamine molecules are represented as the ball-and-stick model and water molecules are represented in the space fill.

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(Figure 11) (even with a seeding of the ciclopirox ethanolamine (2:1) monohydrate), the only part of the mixture that uptakes moisture during the following sorption is the untransformed ciclopirox ethanolamine (1:1). The loss of a part of one-half of ethanolamine molecule during the drying step of the monohydrate implicates a destructive dehydration and a complete reorganization of the molecular structure. Moreover, the large hysteresis observed between the mass uptakes and losses during cycles indicate that the activation energies of hydration and dehydration are rather high and so that structural changes between anhydrate and monohydrate are considerable, consistent with a destructive reconstructive mechanism. (a) Experimental Conditions to Ensure a Reversibility of the Dehydration/Hydration Process. To study more thoroughly the dehydration/hydration mechanism of the ciclopirox ethanolamine (1:1) while preventing the desolvation effect, static moisture studies were carried out under a saturated atmosphere of ethanolamine. The ciclopirox etha-

Figure 9. Mass change at equilibrium (or after the maximum possible step time of 2000 min) versus relative humidity(%) recorded at 20 °C for ciclopirox ethanolamine (1:1).

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nolamine (1:1) was alternatively stored at ambient temperature over 100% RH and P2O5 (0% RH) in hygrostat in which the atmosphere was saturated in vapor of ethanolamine by open flask containing liquid ethanolamine (vapor pressure of bulk ethanolamine at 20 °C: 0.5 mBar = 50 Pa). XRPD patterns in Figure 12 show the reversible behavior of the dehydration-hydration process because either the monohydrate or the anhydrate were obtained during successive cycles without appearance of (2:1) ciclopirox ethanolamine. 3.4. Thermal Analyses. Figure 13a presents the TGA/DSC curves obtained for ciclopirox ethanolamine (1:1). The first endothermic peak is observed at Tonset = 116.9 °C and is associated to a mass loss of 11.31%. This phenomenon corresponds to the transformation of the ciclopirox ethanolamine (1:1) into ciclopirox ethanolamine (2:1) with the loss of half the amount of ethanolamine molecule (theoretical value 11.5%) (detected with coupled mass spectrometer, data not shown). TGA/DSC analyzes were also performed on the hydrated phase obtained at RH 97% to check the stoichiometry in water and to determine the dehydration temperature. As shown in Figure 13b, the dehydration event occurs at about 59 °C in a single step process and is associated as expected to a loss of one water molecule (experimental value 5.94%, theoretical value 6.2%). The subsequent events are similar to those observed when starting with ciclopirox ethanolamine (1:1). 3.5. Temperature-Resolved X-ray Powder Analyses. In order to detect any changes in the crystal structure of ciclopirox ethanolamine (1:1) on heating, TR XRPD patterns between 3 and 30° 2θ were recorded from ambient temperature to 100 °C. Starting from 60 °C, the release of half of the aminoethanol molecules induced the formation of ciclopirox ethanolamine (2:1) (Figure 14). Nevertheless, at 100 °C the complete conversion was not achieved yet as the kinetics of dehydration during this experiment was relatively slow.

Figure 10. XRPD patterns of (a) ciclopirox ethanolamine (1:1) stored under drying condition in the DVS apparatus after three sorptiondesorption cycles compared to (b) ciclopirox ethanolamine (1:1) calculated and (c) ciclopirox ethanolamine (2:1) calculated.

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The same experiment was performed with ciclopirox ethanolamine (1:1) monohydrate obtained at 97% RH. From the calculated patterns of each phase, characteristic peaks (at 2θ = 6.5° and 6.8° in ciclopirox ethanolamine (2:1), 2θ = 10.5 and 13.8° in ciclopirox ethanolamine (1:1) and 2θ = 12.4° in ciclopirox ethanolamine (1:1) monohydrate) were identified and monitored throughout the dehydration. The result of the thermal study is reported in Figure 15. At 45 °C, the peak at 2θ = 12.4° completely disappeared, whereas the peaks at 2θ = 10.5, 13.8, 6.5, and 6.8° appeared. At 80 °C, peaks at 2θ = 10.5 and 13.8° completely disappeared. These data demonstrate that the monohydrate phase has lost its water molecule and gave successively, but with overlapping, the anhydrate phase (1:1) and then the hemiethanolamine phase (2:1). This behavior correlates the TGA/ DSC analyses. No intermediate amorphous phase has been observed (in the limit of detection of the diffractometer).

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3.6. Hot-Stage Microscopy. The heating rate applied on crystals of (1:1) ciclopirox ethanolamine monohydrate (5 °C. min-1) was the same as that used during the TGA/DSC measurements. Series of pictures made at different temperatures are presented in Figure 16. From 60 to 80 °C the crystal lost its initial habitus to adopt a new one at 80 °C (the crystal was surrounded by a saturated solution). At 85 °C, a nucleation occurred and the crystallization of a new phase occurred. The high-temperature phase started dissolving at 95 °C, which corresponds to the beginning of the loss of ethanolamine molecule. The thermal evolution of the initial crystal of ciclopirox ethanolamine (1:1) monohydrate could be related to the sequential departure of water and ethanolamine proposed by TGA/DSC. Hot stage microscopy highlights the crystallization of the anhydrate form after the dehydration (60 °C < T < 80 °C), which is quickly followed by the transformation in (2:1) ciclopirox ethanolamine salt (T = 85 °C). 4. Discussion

Figure 11. Mass change at equilibrium (or after the maximum possible step time of 2000 min) versus the corresponding relative humidity (%) recorded at 20 °C for ciclopirox ethanolamine (2:1) monohydrate.

To explain the desolvation process, we can used the Rouen96 model,7 which is devoted to the dehydration mechanism of molecular crystals. The first criterion of this model is of topological nature. It is related to the possibility of evacuating water molecules through channels or interlayer spaces of sufficient size (>3.5 A˚). In the hydrate structure, water molecules are located between ciclopirox layers that are ∼3.7 A˚ apart. But, as mentioned earlier, these interlayer spaces are also occupied by ethanolamine molecules. The release of water molecules is therefore likely to induce a concomitant loss of ethanolamine and a local collapse of the crystal lattice. Moreover, this type of mechanism is corroborated by the lack of structural similarities between the hydrated and anhydrated phases. As pointed out in the crystal structure descriptions,

Figure 12. Comparison of the XRPD patterns (zoom between 2θ = 5.1 and 16°) of ciclopirox ethanolamine (1:1) versus time of exposure over 100% RH and 0% RH at 23 °C under saturated vapor pressure of ethanolamine: (a) anhydrate calculated, (b) monohydrate calculated, (c) anhydrate at t = 0, (d) after 7 days over 100% RH, (e) followed by 7 days under drying conditions (P2O5), (f) reconditioned over 100% RH during 7 days.

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Figure 13. (a) TGA/DSC curves recorded at 5 K min-1 for ciclopirox ethanolamine (1:1) and (b) ciclopirox ethanolamine (1:1) monohydrate.

Figure 14. Temperature-resolved XRPD patterns of ciclopirox ethanolamine (1:1) between 20 and 100 °C.

the removal of water molecules from the unit cell of the monohydrate induces a change in the orientation of the ciclopirox molecules. The moisture sorption/desorption studies (under normal conditions) confirm the destructive process of the dehydration because of the formation of (2:1) salt by concomitant departure of water and ethanolamine molecules. This irreversible transformation is probably due to the weakness of the ionic bond in ciclopirox ethanolamine (1:1) salt consistent with a Δ pKa =2.5.

The shift in ciclopirox/ethanolamine ratio upon dehydration can be prevented by working under saturated ethanolamine vapor pressure. Under these static conditions, the dehydration/hydration is thermodynamically reversible but not mechanistically. According to the Rouen-96 model, the dehydration mechanism can therefore be defined as class I-Destructive-Reconstructive. However, when working under normal condition, this study indicates that the most stable salt of the system is the (2:1) ciclopirox ethanolamine salt. Indeed, this salt is the end

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Figure 15. Temperature-resolved XRPD patterns of ciclopirox ethanolamine (1:1) monohydrate between 20 and 80 °C. The selected patterns are recorded at (a) 20, (b) 45, and (c) 80 °C. Characteristic peaks of ciclopirox ethanolamine (1:1) monohydrate, (1:1) anhydrate, and (2:1) anhydrate are highlighted with triangle, squares, and circles, respectively.

Figure 16. Hot stage microscopy made on a crystal of (1:1) ciclopirox ethanolamine monohydrate between 30 and 100 °C (heating rate: 5 K min-1.

point of the (1:1) ciclopirox ethanolamine salt (anhydrate and monohydrate) evolution when the temperature and/or humidity conditions vary (Figure 17). As an introduction to this part of the discussion, one can notice that whatever the definition used in the literature,25 cocrystals can be depicted as “structurally homogeneous crystalline materials that contain two or more neutral building blocks that are present in definite stoichiometric amounts”(after Aakeroy et al.26). This definition includes solvates (as ciclopirox ethanolamine) and heterosolvates (as ciclopirox

ethanolamine monohydrate). From a thermodynamic point of view, cocrystals and salts are described as “stoichiometric compounds” but a thorough analysis of the structure and especially on the location of the proton between an acidic and a basic moiety could permit us to correctly name the solid compound. This work highlights the difficulty of classifying ciclopirox ethanolamine (anhydrate and hydrate) as a salt or a cocrystal. Indeed, as it is well accepted, the ΔpKa criterion (pKa(base) pKa(acid)) indicates the ability of an acido-basic system to

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Figure 17. Stability chart of ciclopirox ethanolamine salts versus temperature and/or humidity (full line, normal conditions; dotted line, under ethanolamine vapor pressure).

generate a salt (ΔpKa >3) or cocrystal (ΔpKa