New Polymorph of Dehydroepiandrosterone Obtained via

Article pubs.acs.org/crystal

New Polymorph of Dehydroepiandrosterone Obtained via Cryomodification Vladimir V. Chernyshev,*,†,‡ Yurii N. Morozov,†,§ Ivan S. Bushmarinov,∥ Alexandr A. Makoed,† and Gleb B. Sergeev† †

Department of Chemistry, M.V. Lomonosov Moscow State University, 1-3 Leninskie Gory, Moscow 119991, Russian Federation A. N. Frumkin Institute of Physical Chemistry and Electrochemistry RAS, 31 Leninsky Prospect, Moscow 119071, Russian Federation § Department of Fundamental Science, Bauman Moscow Technical State University, 5 Second Baumanskaya Str., Moscow 105005, Russian Federation ∥ X-ray Structural Laboratory, A. N. Nesmeyanov Institute of Organoelement Compounds RAS, 28 Vavilov Str., Moscow 119991, Russian Federation ‡

S Supporting Information *

ABSTRACT: A new anhydrous polymorph of dehydroepiandrosterone (DHEA) is detected in cryomodified powder samples and designated as form VII. The crystal structure of form VII is determined from multiphase X-ray powder diffraction (XRPD) data. Additionally, the unknown crystal structures of anhydrous form III and the new monohydrated DHEA form designated as form S5 are also determined from multiphase XRPD data. To validate the crystal structures III, VII, and S5, energy minimization with dispersion-corrected density functional theory is performed in VASP. An extended list of the DHEA forms with the known crystal structures, which now covers anhydrous forms I, II, III, VI, and VII and solvated forms S1, S2, S4 and S5, allows quantification of DHEA solid-state transformations to be carried out.

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INTRODUCTION As one of the main issues of natural science, nanotechnology actively penetrates into biology and medicine, becoming an important part of pharmaceutical industry. Many modern drugs administrated in solid state form have poor solubility in water,1 which draws attention to their solubility, solubility rate, and bioavailability. The problem of poor solubility can often be solved by decreasing the size of drug particles and/or transforming the original compound into a new polymorphic modification with better physicochemical properties and better bioavailability.2,3 The most widely used technology of synthesizing drug nanoparticles consists of wet or dry grinding of the substance in mills of various types.4,5 Mechanical grinding has found practical application in preparation of therapeutic suspensions. The main drawbacks of mechanical grinding are associated with the wide size distribution of nanoparticles and possible widening of the particle size range due to the heat liberated upon grinding.6 Nowadays, various synthetic methods are used for preparation of drug nanoformsthe supercritical fluid technology,7 solvent substitution,8 laser ablation,9 synthesis in water−oil emulsions,10 flashevaporation technique,11 cryogenic technique based on clathrate formation and subsequent sublimation12,13 and others, which are discussed in ref 14. © 2016 American Chemical Society

In our group, a special cryochemical technology was developed15 for preparing nanoparticles from drug substances, which involves transferring the original substance into the gas state by its evaporation or sublimation in a flow of the gascarrier and directing the flow of molecules to a cooled surface. The interaction of the molecular flow with the cooled surface leads to condensation of the substance from the gas phase to form solid nanoparticles. The cryochemical technology has been successfully applied to the tranquilizer 7-bromo-1,3dihydro-5-(2-chlorophenyl)-2H-1,4-benzodiazepin-2-one (phenazepam16) and allowed us to produce its new polymorph,17 which exhibits higher anxiolytic activity and weaker muscle relaxation and sedative activity.18 Recently we started to apply the cryochemical technology to dehydroepiandrosterone (DHEA; 3β-hydroxyandrost-5-en-17one). DHEA was isolated in 1934 and for several decades was considered as an inert compound involved mainly in bioconversion of cholesterol to androgens and estrogens. However, the antiaging action of DHEA was claimed in 1990s together with therapeutic benefits in many medical Received: November 24, 2015 Revised: December 30, 2015 Published: January 8, 2016 1088

DOI: 10.1021/acs.cgd.5b01666 Cryst. Growth Des. 2016, 16, 1088−1095

Crystal Growth & Design

Article

in crystal structure determination from two-phase powder patterns,29 we have decided to reach two goals, namely, solve the crystal structure of the new form VII and investigate the solid-state transformations of DHEA under ambient conditions. In the framework of this study, the unknown crystal structures of FIII and new monohydrated form S5 were determined from XRPD data too. All the results are presented below.

conditions. It was shown that DHEA and its derivatives are efficient neuromodulators in the central nervous system and in peripheral tissues, and all these discoveries help to understand why DHEA still remains in the focus of scientific investigations.19−22 Six crystalline forms of DHEA (FI−FVI) and four forms of its solvates (S1−S4) were described,23−25 and crystal structures for some of them were reported, namely, for FI,26 FII,27 FVI,25 S1,26 S2,28 and S4.26 Our attempts to synthesize nanoparticles of DHEA with the use of the cryochemical technology involved characterization of the obtained powder samples by X-ray powder diffraction (XRPD) immediately after the synthesis. Experimental powder patterns revealed two new polymorphic forms of DHEA in each newly synthesized sample, which can be characterized by two sets of diffraction peaks differing in widthall “narrow” peaks were attributed to form VII, and four “broad” peaks were attributed to form VIII. The combined differential scanning calorimetry-thermogravimetric analysis (DSC-TG) analysis has shown that all cryomodified DHEA samples contained no solvent in a few hours after the synthesis. Therefore, forms VII and VIII are anhydrous. All diffraction peaks attributed to FVII were indexed in the monoclinic unit cell with the volume of 830 Å3 and space group P21. Inspired by the successful crystal structure determination for FVI based on the XRPD data,25 we have decided to solve the crystal structure of FVII in the same way. However, our attempts to achieve this target met two serious obstacles. First, we failed to obtain single-phase samples either for FVII or for FVIII, and, second, both these forms turned out to be unstable, so every new XRPD measurement produced a new powder pattern.

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EXPERIMENTAL SECTION

Materials. Commercially available forms I and II of DHEA (Bayer HealthCare Pharmaceuticals) were used as the starting materials in all synthetic procedures. Synthesis. Cryochemical technology of organic substance modification (cryomodification) was described earlier30 (see also Supporting Information). In the cryomodications used in this study, the carrier gas was CO2, the relative molar flow rate of carrier gas (the ratio of the molar flow rate of carrier gas to the area of the nozzle sublimator - evaporator) is 0.067 mol/(m2 s), and the distance from the nozzle of the evaporator to the cold surface is 12 mm. Several samples were synthesized using various synthetic procedures. Sample 1 was obtained by cryomodification of FI at evaporator temperature of 140 °C. Sample 2 was obtained by cryomodification of FI at evaporator temperature of 120 °C. Sample 3 was obtained by cryomodification of FII at evaporator temperature of 100 °C. Sample 4 was obtained in attempts to make a single-phase sample of FIII from the methanol hemisolvate form S4, prepared with a known method.26 Form S4 was kept in vacuo for 24 h at T = 55 °C. Sample 4 contained some amounts of S4 and FII, so our attempts to obtain the “pure” sample of FIII were unsuccessful like the previous attempts of Stahly et al.25 Sample 5 was obtained unintentionally in the framework of our accompanying study of hydrated forms of DHEA. Particularly, it was obtained from the sample 1, which was placed into a sealed box and kept at room temperature and 100% relative humidity until mass stabilization (see Table S4). Samples 1 and 3 were characterized by combined DSC-TGA and Fourier transform infrared (FTIR) spectroscopy measurements (see Supporting Information). The combined DSC-TG analysis has shown no weight loss in 1 and 3 until melting, which ensured the absence of any solvents in these samples just after cryomodification.

Nevertheless, having an impressive collection of powder patterns of cryomodified DHEA samples and some experience

Table 1. Crystallographic Data for FIII, FVII, and S5 (Multiphase Refinements)

empirical formula formula weight crystal system space group a, Å b, Å c, Å β, deg V, Å3 M20 F30 Z diffractometer radiation ρcalc, g/cm3 μ, mm−1 2θmin−2θmax, increment, deg number of parameters/restraints Rp/Rwp/Rexp goodness-of-fit

FIII

FVII

C19H28O2 288.41 monoclinic P21 14.5339(18) 10.3792(14) 11.8253(14) 111.559(18) 1659.1(4) 27 55 (0.009, 39) 4 Huber G670 Guinier CuKα1 1.155 0.563 3.00−70.00, 0.01 183/123 0.0256/0.0338/0.0212 1.595

C19H28O2 288.41 monoclinic P21 13.105(2) 5.9034(18) 10.829(2) 97.64(2) 830.3(3) 21 45 (0.011, 43) 2 Empyrean CuKα 1.154 0.562 5.00−45.00, 0.017 84/81 0.0313/0.0417/0.0302 1.382 1089

S5 C19H28O2·H2O 306.43 orthorhombic P212121 22.506(3) 11.197(2) 6.8094(18) 1716.0(6) 34 67 (0.007, 45) 4 Empyrean CuKα 1.186 0.615 3.00−40.00, 0.033 81/61 0.0399/0.0544/0.0246 2.211 DOI: 10.1021/acs.cgd.5b01666 Cryst. Growth Des. 2016, 16, 1088−1095


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X-ray Powder Diffraction. Powder patterns were measured using two powder diffractometers, namely, a Huber G670 Guinier camera (Cu Kα1 radiation, λ = 1.54059 Å, transmission mode) and Empyrean (Cu Kα radiation, Ni β-filter, Bragg−Brentano mode) (see Table 1 for data collection details). Indexing. All samples 1−5 contained two or more crystalline phases of DHEA; therefore, the correct identification of diffraction peaks from each new polymorphic form was extremely important, especially for samples 1 and 2, which did not contain any previously described form of DHEA. The powder patterns of 1 and 2 contained four diffraction peaksat angles 15.37, 16.09, 17.55, and 20.90° and with the ratio of intensities 4:8:2:1which were several times wider than other peaks. A comparison of powder patterns of 1 and 2 (Figure 1) has shown a systematic increase of intensities of four broad peaks in

Figure 2. A portion of the Rietveld plot for FVII (sample 1). Experimental (Empyrean) pattern is shown in black, specifically calculated background − in red, the difference between the experimental and calculated patterns − in blue. refinement of its powder pattern will be discussed in the following section. Crystal structures III and S5 were refined with the powder patterns measured for samples 4 (see Figure 3) and 5 (see Figure 4),

Figure 1. Powder patterns of the samples 1 (red) and 2 (blue).

2 versus 1, while the internal ratio of their intensities was constant in both patterns. Removing these four peaks from the list of 25 low-angle peak positions led to successful indexing of all narrow peaks, which were attributed to the new monoclinic form VII. Four broad peaks observed at angles 15.37, 16.09, 17.55, and 20.90° in all samples synthesized in the same way as 1 were attributed to the new unknown form VIII. Unit-cell dimensions for new crystalline phases were determined using three indexing programs: TREOR90,31 ITO,32 and AUTOX.33,34 Space groups for all phases were assigned taking into account the systematic extinctions. The unit-cell parameters and space groups were tested further with the use of the Pawley fit35 and confirmed by crystal structure solution. Structure Determination. The crystal structures of forms III, VII, and S5 were solved with the use of simulated annealing technique36 based on the set of 70 (for VII) or 150 low-angle Xobs values37 extracted from two-phase powder patterns after a Pawley fit with the program MRIA.38 The rigid model of DHEA molecule used in a direct space search was taken from the literature.27 Structure Refinement. The solutions were refined with the program MRIA via a multiphase bond-restrained Rietveld approach in the same way as was reported earlier.29 A special technique has been applied in the refinement of crystal structure FVII in the presence of broad peaks from the unknown phase FVIII in the powder pattern 1. Four broad peaks from FVIII were incorporated in the background calculations to minimize the errors introduced by these (FVIII) peaks into intensities of the neighboring peaks from the target FVII. The Rietveld plot for the refinement of FVII with specifically approximated background is shown in Figure 2. To prove the existence of the unknown form VIII and validate the crystal structure FVII, we tried to get a sample containing FVII without any broad peaks from FVIII. Varying the evaporator temperature during cryomodification we obtained sample 3, which contained three anhydrous forms, namely, II, III, and VII, without any additional peaks. Three-phase Rietveld

Figure 3. Rietveld plot for the laboratory (Huber) pattern of 4 showing the experimental (black dots), calculated (red) and difference (blue) curves. The vertical green bars denote the calculated positions of diffraction peaks for crystalline phases S4 (top raw), FIII (middle raw), and FII (bottom raw). respectively. Sample 4 contained three crystalline forms of DHEA III, S4, and II, and sample 5 contained only two crystalline formsS5 and S1. In refining new structures, one common Uiso parameter was refined for all non-H atoms in each independent molecule; H atoms were positioned geometrically (C−H 0.93−0.98 Å; O−H 0.85 Å) and left unrefined. Table 1 shows the crystal data, data collection, and refinement parameters for crystalline phases FVII, FIII, and S5. DFT-D Calculations. To validate the crystal structures of forms III, VII, and S5 obtained from multiphase samples measured by means of laboratory powder diffractometers, we applied energy-minimization with dispersion-corrected density functional theory (DFT-D). The PBE-D3/PW optimization including the unit-cell parameters was performed in VASP 5.4.139−42 by using the PBE functional43 corrected by Grimme D3 van der Waals correction44 with Becke-Johnson damping.45 A plane-wave basis set (cutoff energy of 600 eV) with 1090



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Figure 5. Rietveld plot for the laboratory (Empyrean) pattern of 3 showing the experimental (black dots), calculated (red), and difference (blue) curves. The vertical green bars denote the calculated positions of diffraction peaks for crystalline phases FIII (top raw), FII (middle raw), and FVII (bottom raw).

Figure 4. Rietveld plot for the laboratory (EMPYREAN) pattern of 5. The vertical green bars denote the calculated positions of diffraction peaks for crystalline phases S5 (top raw) and S1 (bottom raw).

“normal” projector augmented wave (PAW) pseudopotentials46,47 as supplied with VASP was employed. A Γ-centered Monkhorst−Pack kpoint mesh was generated for each structure, with the number Ni of subdivisions along each reciprocal lattice vector bi calculated as Ni = ⌊max{1,10|bi| + 0.5}⌋ (|bi| is defined in Å−1). Optimization was considered converged when the maximum force per atom reached 0.03 eV Å−1.

and prepared two extended tables for anhydrous (Table S1) and solvated (Table S2) forms of DHEA. DFT-D Optimization. The use of dispersion-corrected periodic DFT calculations for verification and completion of the molecular crystal structures determined from powder data has become increasingly popular in recent years. These calculations were applied in structure determination of the 1:1 cocrystal of indomethacin and nicotinamide,49 monomethyl alkanes (C26−C32),50 2-ammoniobenzenesulfonates,51 1:1 cocrystal of theophylline and 4-aminobenzoic acid,52 and Pigment Yellow 181 dimethyl sulfoxide N-methyl-2-pyrrolidone (1:1:1) solvate,53 among many others. Van de Streek and Neumann have systematically compared structures obtained from single-crystal54 and powder diffraction55 studies to the results of DFT-D optimizations. According to their data, the root-mean-square difference between Cartesian atomic coordinates of calculated and experimental structures (RMSD) is a useful metric for identification of suspicious structures. They have found that high-quality single-crystal (SC) structures usually demonstrate RMSD below 0.25 Å (0.084 average), and SC structures with RMSD > 0.3 Å are problematic with high probability. A similar study using historical data on Rietveld refined models (including every organic structure derived from powder data and published in IUCr journals) demonstrated a larger spread of RMSD, with typical RMSD values for correct powder structures below 0.35 Å (0.16 average), and RMSD > 0.4 Å observed for problematic entries. In our study, the following crystal structures were optimized by PBE-D3/PW periodic calculationsanhydrous forms I (single-crystal, CSD refcode ZOYMOP03 (CCDC 1019367)), II (single-crystal, QOYNOU), III (powder), VI (single-crystal, ZOYMOP04 (CCDC 1019369)), VII (powder), and monohydrates S2 (single-crystal, VEFPUR (CCDC 1281337)), and S5 (powder). Table 2 summarizes the calculated values of energies and RMSD for all structures, Table S3 (Supporting Information) contains the unit cell parameters after energy minimization. On the basis of the data of Table 2 and RMSD limits,54,55 one can state that crystal structures I, II, III, VI, S2, and S5 are correct, while form VII lies in a “gray area”. However, the relatively high root mean-square deviation of

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RESULTS AND DISCUSSION Multiphase Refinement. Multiphase composition of all of the samples required an accurate approach to the choice of the pattern used in the final refinement. For each new crystalline phase, we picked up a pattern that would satisfy two conditions: (i) the diffraction peaks from the new phase should be the strongest; i.e., this new phase is the main crystalline phase in the sample, and (ii) all the other diffraction peaks should belong to the known phases of DHEA with the determined crystal structures. In the final refinement, the atomic coordinates and displacement parameters for the known phases were fixed, so that only structural parameters of the new phase were refined. On the basis of the results of refinements, the phase content of sample 4 (Figure 3) was estimated as III:S4:II = 10:1:1, and phase content of sample 5 (Figure 4) was estimated as S5:S1 = 40:1; thus, both conditions (i) and (ii) were fulfilled for both patterns. However, in the case of form VII, our attempts to select such a pattern for the final refinement failed. Therefore, its crystal structure has been refined with the two-phase pattern containing the peaks from two new phases (Figure 2) and then proven by the Rietveld refinement with the three-phase pattern from sample 3 (Figure 5). In the latter refinement, the structural parameters of all three crystalline phases were fixed, and the phase content of the sample 3 was estimated as VII:III:II ≈ 1:1:1. For the multiphase samples of DHEA, the list of characteristic diffraction peaks helps in preliminary phase identification. The useful tables of such characteristic peaks for forms I−III and S1−S4 can be found in ref 48 (Table 9 entitled The X-ray powder diffraction data for polymorphs and pseudopolymorphs of DHEA) and also for form VI in ref 25. We have summarized these tables, added our data for the new forms VII, VIII, and S5, 1091



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Table 2. Energies (E), Number of Formula Units in the Unit Cell (Z) and Deviations from the Experimental Geometries (RMSD) for the PBE-D3/PW Optimized Structures of DHEA Forms E, eV

Z

ΔE, kcal/mol

RMSD, Å

−1167.09441 −1167.17016 −1167.19743 −583.53089 −583.51228

4 4 4 2 2

0.59 0.16 0 0.78 1.00

0.031 0.034 0.104 0.022 0.367

−2452.69751 −1226.35226

8 4

0.02 0

0.202 0.133

DHEA form anhydrous I II III VI VII monohydrates S2 S5

Figure 6. DHEA molecule in FVII showing the atomic numbering and 50% probability displacement spheres. C-bound H atoms were omitted for clarity.

0.367 Å for the crystal structure VII is most likely caused by the low quality of the corresponding powder data containing broad peaks from the unknown DHEA form. Interestingly, the maximum atomic displacement during the DFT calculations was observed in the literature structure S2,28 where one water molecule (O3) moved 1.3 Å from its initial position. This result suggests the presence of dynamic disorder in S2, which is also manifested by the suspicious H atom positions (no hydrogen bonds; O3−H8 distance of 0.56 Å) for this water molecule in the published structure.28

Figure 7. A portion of the crystal packing of FVII showing the hydrogen-bonded (thin blue lines) helical chain extended in [010].

Table 3. Hydrogen-Bonding Geometry (Å, o) in FIII, FVII, and S5a D−H···A

D−H

H···A

D···A

D−H···A

2.22 1.97

3.016(14) 2.775(14)

157 158

2.37

2.999(6)

131

2.19 2.06 2.34

3.02(2) 2.88(3) 3.18(2)

165 160 172

The asymmetric unit of the monoclinic form III contains two independent moleculesA and B (Figure 8) being in agreement with the conclusion made by Stahly et al.25 based on the results of solid-state NMR measurements that the crystal structure of FIII consists of two crystallographically independent molecules. The hydrogen-bonding scheme in FIII differs from those described earlier for the anhydrous forms. In molecule A, only one hydroxyl oxygen atom O1A participates in hydrogen bonding (Table 2), while in molecule B two oxygen atoms (O1B and O2B) are involved in formation of hydrogen-bonded helical chains consisting of alternating independent molecules and running along the screw axis 21 (Figure 9). The asymmetric unit of the orthorhombic hydrated form S5 contains one DHEA molecule and one lattice water molecule (Figure 10). The crystal packing of S5 (Figure 11) is consolidated by intermolecular O−H···O hydrogen bonds (Table 2) which link all moieties into a three-dimensional framework. Comparing the orthorhombic unit cell dimensions of S5 (Table 1) and S2 (a, b, c = 22.545(7), 22.67(2), 6.819(2) Å)28 one can see that they are close, taking into account the multiplier 2 at parameter b. Nonetheless, the powder diffraction allows easily distinguishing these two hydrated forms because the X-ray pattern of S2 contains two characteristic peaks at 2θ angles 12.37 and 17.93°48 (see also Table S2) which are absent in the X-ray pattern of S5 (containing no diffraction peaks in the vicinity of these angles). Solid-State Transformations. All samples used in this study changed their phase composition with time. These changes were confirmed by the repeated XRPD measurements. For example, all four powder patterns of sample 5 measured in 0, 0.5, 3, and 6 h after the synthesis (Figure 12) turned out to be different pointing to some fast phase transformations

FIII O1A−H1A···O2B O1B−H1B···O1AI

0.85 0.85

O1−H1···O1ii

0.85

FVII S5 O1−H1···O3Wiii O3W−H3W1···O1 O3W−H3W2···O2iv

0.85 0.85 0.85

a Symmetry codes: (i) 1 − x, y − 1/2, −z. (ii) −x, 1/2 + y, −z − 1. (iii) 3/2 − x, −y, 1/2 + z. (iv) 1 − x, 1/2 + y, −1/2 − z.

The energy differences (Table 2) between the anhydrous DHEA polymorphs are below 1 kcal/mol, allowing them to coexist at room temperature. The same result is observed for the hydrated forms S2 and S5. Finally, taking into account the aforementioned arguments, we believe that three crystal structuresIII, VII, and S5determined from X-ray powder diffraction data are correct. Crystal Structures. The asymmetric unit of the monoclinic form VII contains one independent molecule (Figure 6). The DHEA molecule has a rigid molecular skeleton, so no significant changes in geometric parameters were observed during the refinement. The main feature of this new form VII is its crystal packing. In the known crystal structures of anhydrous forms I, II, and VI, the DHEA molecules are hydrogen-bonded via O−H···O interactions in a head-to-tail manner to form chains, so that both oxygen atomsin hydroxyl (O1) and carbonyl (O2) groupsare involved in hydrogen-bonding. However, in FVII, only hydroxyl group participates in hydrogen bonds (Table 2) linking the molecules into helical chains running along the screw axis 21 (Figure 7). 1092



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Figure 8. Two independent molecules (A and B) in the asymmetric part of FIII showing the atomic numbering and 50% probability displacement spheres. In molecules A and B, the labels at C atoms correspond to those in Figure 6 with the added letters A and B, respectively. C-bound H atoms were omitted for clarity.

occurring in the sample under ambient conditions in an open air.

Figure 9. A portion of the crystal packing of FIII showing the hydrogen-bonded (thin blue lines) helical chain extended in [010]. The positions of independent molecules and their equivalents in the chain are marked by letters A and B.

Figure 12. Powder patterns of sample 5 measured in 0 h (green), 0.5 h (red), 3 h (blue), and 6 h (black dots) after the synthesis.

Despite the large number of diffraction peaks, all of them in each pattern can be attributed to the crystalline forms with the known crystal structures, which allows one to quantify the phase content of sample 5 in each moment of measurements. Three crystalline forms were detected in 5 during the measurementsS5, S1, and FIII; subsequent multiphase Rietveld refinements have shown that the main phase S5 (98%) in sample 5 has transformed into two crystalline phasesS1 (69%) and FIII (31%) in 6 h (Table 4).

Figure 10. Content of the S5 asymmetric part showing the atomic numbering and 50% probability displacement spheres. The labels at C atoms in the DHEA molecule correspond to those in Figure 6. Cbound H atoms were omitted for clarity.

Table 4. Phase Content (%) of the Sample 5 after the Synthesis 0h 0.5 h 3h 6h

S5

S1

III

97.6 80 31

2.4 16 51 69

4 18 31

Sample 1 being in contact with atmosphere also demonstrates phase transformations, which, however, are more gradual than those in 5 and require weeks and months. The powder pattern measured one year later after the synthesis (Figure 13) has shown that the phase content of sample 1 has changed from two crystalline phasesVII and VIII, to five crystalline phasesIII, II, VII, S2, and S1 in a ratio 2:6:10:3:1. In the

Figure 11. Crystal packing of S5 viewed down the c-axis.

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of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12, Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This study was supported by RFBR Grant No. 15-03-05178 A. ISB is grateful to the Russian Scientific Foundation for financial support, Grant No. 14-13-00884. X-ray measurements were performed using equipment of CKP FMI (Institute of Physical Chemistry and Electrochemistry RAS, Moscow).

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Figure 13. Rietveld plot for the laboratory (Empyrean) powder pattern of sample 1 measured one year after the synthesis.

multiphase Rietveld refinement, the atomic coordinates and isotropic displacement parameters were fixed in all five phases. Considering the values of fwhm (full-width-at-half-maximum of the peak) parameter obtained for each phase, we discovered that its value for FVII (= 0.30°) is three times higher than fwhm values (0.1−0.12°) for the other four phases and is even slightly higher than its initial value of 0.28° extracted from the pattern measured just after the synthesis of 1 (Figure 2). These observations made it possible to state that after one year of storage under ambient conditions, new crystalline phases of DHEA were formed in sample 1, and the particle size in these new phases was several times higher as compared with FVII; i.e., whereas the particles of new phases crystallized and grew, the particles of FVII and FVIII degraded and decreased. Analyzing all the samples obtained via cryomodification of DHEA, we found that form I has never been observed in the samples during their storage under ambient conditions. Chang et al.24 reported that FI was found to be the only stable anhydrous form of DHEA. However, it is interesting to note that there are no published reports of the phase transitions FII → FI or FIII → FI observed without external action (for example, heating). The absence of polymorphic transformations (FII, FIII, FVII) → FI under ambient conditions may indicate that the FI-occupied global minimum on the crystal packing energy surface of anhydrous DHEA and the local minima occupied by FII, FIII, and FVII are separated by a significant energy barrier. On the other side, observed transformations FVII → FIII → FII show that the energy barriers between these forms are very low.

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REFERENCES

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.cgd.5b01666. HPLC, MS, FTIR, DSC-TG data, positions of characteristic XRPD peaks, X-ray and DFT-D optimized unit cell dimensions (PDF) DFT-D optimized structures of DHEA forms I, II, III, VI, VII, S2 and S5 (CIF) Accession Codes

CCDC 1437560−1437562 contains the supplementary crystallographic data for this paper. These data can be obtained free 1094



Article

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New Polymorph of Dehydroepiandrosterone Obtained via

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