New Solvates of an Old Drug Compound (Phenobarbital): Structure

Article pubs.acs.org/JPCB

New Solvates of an Old Drug Compound (Phenobarbital): Structure and Stability Neslihan Zencirci,† Ulrich J. Griesser,*,† Thomas Gelbrich,† Volker Kahlenberg,‡ Ram K. R. Jetti,† David C. Apperley,§ and Robin K. Harris§ †

Institute of Pharmacy, University of Innsbruck, Innrain 52, 6020 Innsbruck, Austria Institute of Mineralogy and Petrography, University of Innsbruck, Innrain 52, 6020 Innsbruck, Austria § Department of Chemistry, University of Durham, South Road, Durham DH1 3LE, United Kingdom ‡

S Supporting Information *

ABSTRACT: The solvent formation of phenobarbital, an important drug compound with an unusually complex polymorphic behavior, was studied in detail. Monosolvates with acetonitrile, nitromethane, dichloromethane, and 1,4-dioxane were produced and characterized by single-crystal and powder X-ray diffraction, thermoanalytical methods, FT-IR, Raman, and solid-state NMR spectroscopy. Thermal desolvation of these compounds yields mainly mixtures of polymorphs III, II, and I. At a low relative humidity (25 °C) the solvates transform to polymorph III, and at higher relative humidity the monohydrate and the metastable polymorphs IV and VI can be present as additional desolvation products. These results highlight the potential complexity of desolvation reactions and illustrate that a tight control of ambient conditions is a prerequisite for the production of phase-pure raw materials of drug compounds. Transformation in aqueous media results in the monohydrate. Below room temperature, the 1,4-dioxane monosolvate undergoes a reversible single-crystal-to-single-crystal phase transition due to the ordering/ disordering of 50% of its solvent molecules. Dipolar-dephasing NMR experiments show that the solvent molecules are relatively mobile. Deuterium NMR spectra reinforce that conclusion for the dioxane solvent molecules. The crystal structure of an elusive 1,4-dioxane hemisolvate was also determined. This study clearly indicates the existence of “transient solvates” of phenobarbital. The formation of unstable phases of this kind must be considered in order to better understand how different solvents affect the crystallization of specific polymorphs.

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characteristics of its solid forms was given in previous reports.4 Each of the polymorphs VII−XI can form and exist only in a melt film preparation and in the presence of another 5,5substituted derivative of barbituric acid as a structure template (isomorphic seeding4a). Of the other six polymorphs, only I, II, and III were previously obtained by crystallization from solvents whereas the forms IV, V, and VI crystallize from the supercooled melt.4b Moreover, the existence of a monohydrate5 (H1) and a hemihydrate6 of Pbtl have been reported. Barbituric acid and many of its 5,5-substituted derivatives (Scheme 1) form multiple polymorphs,7 but only a little is known about their propensity for solvate formation. Indeed, our survey of 70 compounds (excluding salts) belonging to this class revealed only three documented cases of solvate formation, namely by barbituric acid8 (R1, R2 = H; 1,4-dioxane sesquisolvate), butobarbital9 (R1 = Et, R2 = Bu), and butallylonal10 (R1 = 1-methylpropyl, R2 = 2-bromoallyl; 1,4dioxane hemisolvate). Additionally, the existence of a 1,4dioxane solvate of Pbtl has been suggested, which was obtained

INTRODUCTION Phenobarbital (Pbtl, 5-ethyl-5-phenyl-2,4,6(1H,3H,5H)-pyrimidinetrione, Scheme 1) is a sedative and anticonvulsant drug Scheme 1. Structure Formula of Pbtl (Left) and General Formula for 5,5-Substituted Derivatives of Barbituric Acid (Right)

that today is primarily applied as an anesthetic and in the treatment of epilepsy and neonatal seizures. Pbtl has been in commercial use for more than 100 years and is listed in the WHO Essential Medicines Library.1 At least eleven polymorphs (denoted I−XI) have been identified,2 more than for almost any other small organic molecule.3 A detailed account of the very complex polymorphic behavior of Pbtl and of the © 2014 American Chemical Society

Received: September 14, 2013 Revised: January 28, 2014 Published: February 26, 2014 3267

dx.doi.org/10.1021/jp409201v | J. Phys. Chem. B 2014, 118, 3267−3280

The Journal of Physical Chemistry B

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Table 1. Crystallographic data moiety formula formula Mr (g mol−1) T (K) crystal system space group a (Å) b (Å) c (Å) α (deg) β (deg) γ (deg) V (Å3) Z/Z′ ρcalcd (g cm−3) crystal size (mm) no. of reflns collected no. of ind reflns, Rint R1 [F2 > 2σ(F2)] wR2 (all data) CCDC no.

SACN

SNiMe

SDCM

SDox

SDox_LT

SDoxH

Pbtl · C2H3N C14H15N3O3 273.29 173 triclinic P1̅ 10.1600(7) 10.3036(11) 14.0553(12) 99.674(8) 96.774(6) 97.811(7) 1422.0(2) 4/2 1.277 0.44 × 0.28 × 0.12 9567

Pbtl · CH3NO2 C13H15N3O5 293.30 173 triclinic P1̅ 10.2543(14) 10.4086(15) 13.7090(19 98.774(11) 96.171(11) 98.962(3) 1415.5(3) 4/2 1.376 0.44 × 0.28 × 0.16 8903

Pbtl · CH2Cl2 C13H14Cl2N2O3 317.16 173 monoclinic P21/n 8.6980(5) 11.9681(6) 14.2590(7) 90 97.470(5) 90 1471.74(13) 4/1 1.431 0.20 × 0.20 × 0.10 8638

Pbtl · C4H8O2 C16H20N2O5 320.34 293 monoclinic P21/n 10.6052(3) 10.5502(2) 14.6810(4) 90 92.028(2) 90 1641.58(7) 4/1 1.296 0.20 × 0.10 × 0.10 10031

Pbtl · C4H8O2 C16H20N2O5 320.34 173 monoclinic P21/c 17.639(2) 10.4165(8) 18.374(2) 90 108.281(9) 90 3205.6(6) 8/2 1.328 0.28 × 0.22 × 0.21 20015

Pbtl · 0.5 (C4H8O2) C14H16N2O4 276.29 253 monoclinic P21/n 6.86417(15) 11.9645(2) 16.6842(4) 90 98.071(2) 90 1356.64(5) 4/1 1.353 0.10 × 0.10 × 0.10 8534

4994, 0.0344 0.0492 0.1319 951070

4612, 0.0272 0.0499 0.1160 951071

2587, 0.0334 0.0404 0.1159 951072

2965, 0.0214 0.0350 0.0885 951074

5666, 0.0484 0.0465 0.0895 951075

2655, 0.0235 0.0309 0.0781 951073

investigation of melt film samples. The microscale experiments are described in the Supporting Information. Thermal Analysis. Differential scanning calorimetry (DSC) experiments were performed with a DSC 7 instrument (PerkinElmer, Norwalk, Ct., USA) using the Pyris 2.0 software on 1−3 mg of sample (weighed with a UM3 ultramicrobalance, Mettler, Greifensee, Switzerland) placed in an 25 μL Al pan (purge gas: dry nitrogen; 20 mL min−1). This instrument was calibrated for temperature with pure benzophenone (mp 48.0 °C) and caffeine (mp 236.2 °C). The energy calibration was performed with 99.999% pure indium (mp 156.6 °C, heat of fusion 28.45 J g−1). Thermogravimetric measurements were recorded on 2−6 mg of sample placed in a 50 μL Pt pan (nitrogen purge; balance purge: 50 mL min−1, sample purge: 25 mL min−1) on a TGA 7 system (Perkin-Elmer, Norwalk, CT, USA). X-ray Diffraction. Experimental data of the single-crystal structure determinations are collected in Table 1. The intensity data for SNiMe and SDox were collected on a STOE-IPDS 2 diffractometer (Stoe & Cie GmbH, Darmstadt, Germany) using Mo Kα radiation (0.710 73 Å). The data collections for SACN, SDCM, SDoxH, and SDox_LT were performed on an Oxford Diffraction Xcalibur diffractometer equipped with a Ruby (Gemini R) detector (Oxford Diffraction Ltd., Abingdon, Oxfordshire, England) and Mo Kα radiation (0.71073 Å). Structure solution and refinement were carried with the SHELX program package.13 Hydrogen atoms were located in difference maps and those bonded to carbon atoms were refined using a riding model. The hydrogen positions in NH groups were refined with distance restraints, N−H = 0.88(2) Å. The methyl groups of both independent solvent molecules of SNiMe were found to be disordered over two positions, which are related by a rotation of 60° about C−N. The powder X-ray diffraction experiments are described in the Supporting Information. Solid-State NMR Studies. Experiments were performed at the University of Durham. Carbon-13 cross-polarization magicangle spinning (CPMAS) and direct polarization (DPMAS)

by freeze-drying a 1% solution of Pbtl in dioxane.6 This is a little surprising, considering that solvate formation is much more frequent (>15%) in the group of neutral drug compounds as a whole11 and also considering that the known propensity of barbiturates for the formation of multiple component structures has facilitated the synthesis of many molecular complexes (cocrystals) with desired structural properties.12 Here we report the formation of monosolvates of Pbtl with acetonitrile (SACN), nitromethane (SNiMe), dichloromethane (SDCM), and 1,4-dioxane (SDox) as well as their crystal structures, stability, thermomicroscopic, spectroscopic, and solid-state NMR properties. The character of the phase transition from SDox to the low-temperature (LT) form SDox_LT is interpreted on the basis of single-crystal X-ray and solid-state NMR data. The crystal structure of an elusive 1,4-dioxane hemisolvate (SDoxH) is also reported.

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EXPERIMENTAL SECTION Materials. Phenobarbital was purchased from Mallinckrodt Chemical Works (U.S.P. XIII Powder, USA). The product consisted of forms II and I. The solvents used in this study were of analytical grade. Crystals of SNiMe, SACN, SDCM, and SDox and were produced by slow evaporation from a saturated solution of Pbtl in the respective solvent. In one experiment, evaporation from a saturated solution resulted in single crystals of a dioxane hemisolvate SDoxH, which was confirmed by single-crystal structure determination, but decomposition of the produced crystal batch prevented their detailed characterization by other methods. The SDoxH phase was not reproducible in subsequent experiments that were carried out under different ambient conditions and where the monosolvate SDox was obtained instead of this “disappearing solvate”. Instruments and Procedures. Hot-stage Microscopy (HSM). An Olympus BH2 polarization microscope equipped with a Kofler hot stage and a Kofler hot bench (both Reichert, Vienna, Austria) were employed for the preparation and 3268



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spectra were obtained at 100.56 MHz and ambient probe temperature using a Varian VNMRS spectrometer based on a 9.4 T Oxford Instruments superconducting magnet. The probe accepts 4.0 mm (outside diameter) zirconia “pencil” rotors, which were fitted with Teflon end-caps. Proton decoupling with the TPPM protocol at a power equivalent to a frequency of 86 kHz was employed during acquisition. The MAS rates were between 6.8 and 8.0 kHz. Contact times for the CP experiments were 1 ms and a linear ramp on 1H was employed. The numbers of transients were between 56 and 250. Recycle delays were between 10 and 30 s. Dipolar-dephased spectra were obtained under the same conditions but with a decoupling window lasting 40 μs. For the DPMAS spectra the recycle delays were 1.0 s, and 1000 transients were accumulated. The spectra were referenced via the high-frequency signal for a replacement sample of adamantane (δC = 38.5 ppm) and are reported relative to the resonance of neat TMS. Deuterium spectra were recorded using the same spectrometer, operating at 61.38 MHz with a 6 mm o.d. MAS rotor. Direct excitation was employed without proton decoupling. Operating conditions: 45° pulse angle (calibrated on a sample of D2O); spin rate 6 kHz; recycle delay 120 s; 32 repetitions). Zero frequency is approximately that of a TMS signal. Low-temperature operation was carried out using cooled nitrogen gas. The temperatures were not calibrated and are therefore approximate. Vibrational Spectroscopy. Crystal samples were prepared on ZnSe discs and their Fourier transform infrared (FTIR) spectra were recorded using a Bruker IFS 25 spectrometer and Bruker IR microscope I (Bruker Analytische Messtechnik GmbH, Karlsruhe, Germany) with 15× Cassegrain objectives (spectral range 4000−600 cm−1, resolution 4 cm−1, 64 interferograms per spectrum). The Raman spectroscopy experiments are described in the Supporting Information.

Figure 1. Pathways for phase transformations of Pbtl solvates occurring as a result of heating or exposure to moisture (H1 = monohydrate).

occur simultaneously. The desolvation behavior of a given crystal depends mainly on the kinetics of the diffusional loss of solvent and on the rates of nucleation and crystal growth of the solvent-free form. Measurements under different heating rates, variable atmospheric conditions (e.g., DSC experiments with sealed or perforated sample pan) and with samples of different crystal sizes enable the assessment of the kinetics of the individual steps and affords insight into the underlying reaction mechanisms. The desolvation of the solvate crystals (in a dry preparation or immersed in silicon oil) during heating to 180 °C involved homogeneous melting, inhomogeneous melting and pseudomorphosis.7b SACN and SNiMe each show an inhomogeneous melting process (Figure 2a) when heated in a preparation with silicon oil (HSM). A fraction of the solvate crystals melts, the nonsolvated form crystallizes at the same time, and the presence of gas bubbles indicates the release of the solvent. After further heating, the nonsolvated form melts. SDox crystals show inhomogeneous melting at low heating rates and homogeneous melting at high heating rates (Figure 2b), indicating that the nucleation rate is low under such conditions. The desolvation of SDCM crystals embedded in silicon oil occurs without an observable melting process but is indicated by the formation of gas bubbles and darkening of the crystals due to pseudomorphosis (Figure 2c). If highly viscous silicon oil is used, partial melting of SDCM crystals occurs at about 67 °C. In dry preparations all the solvates undergo a classical pseudomorphosis (Figure 2d−f). Thus, the clear solvate crystals transform into polycrystalline and opaque nonsolvated aggregates without alteration of the external crystal shape. The desolvation process starts at nucleation centers on the crystal surface. Additional details about the formation, optical characteristics and desolvation behavior as observed in microscale experiments can be found in the Supporting Information (first section). DSC experiments were performed with hermetically sealed 1 bar aluminum pans or pans with a pinholed lid to evaluate the

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RESULTS AND DISCUSSION Thermal Behavior and Stability. The transformation behavior of SACN, SNiMe, SDCM, and SDox under various conditions is summarized in Figure 1. The desolvation of all these forms under ambient conditions yields polymorph III, which was established from the melting behavior (hot-stage microscopy and DSC), PXRD, and spectroscopic characteristics of the obtained product in each case. As described in more detail in a previous report,4b the order of thermodynamic stability of the polymorphic forms of Pbtl between 20 °C and their melting point (at ambient pressure) was established as I > II > III > IV > V > VI. Due to the enantiotropic relationships of several of these forms, this order changes to III > I/II > VI > IV > V at absolute zero temperature and means that form III is the low-temperature stable polymorph, whereas form I is the thermodynamically stable polymorph in the higher temperature range (the exact transition point could not be established but lies below 0 °C). All other forms are metastable over the entire temperature range. Thus, it is obvious (Figure 1) that the desolvation processes predominantly result in kinetic forms (metastable polymorphs at the temperature of desolvation), which is also true for solvent crystallizations4b,6 of Pbtl. The order of the thermal stability of the solvates is SDCM < SACN < SNiMe ≈ SDox, which correlates well with the order of the boiling points (DCM, 40 °C; ACN, 82 °C; NiMe and Dox, 101 °C) and vapor pressures of the hosted solvents. Thermal desolvation is a complex process in which the melting, release of solvent vapor, and the crystallization of new phase(s) may 3269



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SNiMe exhibits a desolvation endotherm in the range 50−125 °C. The small shoulder at 126 °C coincides with the melting temperature of the solvate and indicates that the desolvation process was not fully completed before the melting temperature of the solvate was reached. It is followed by an exothermic part indicating recrystallization of nonsolvated Pbtl. The main thermal desolvation product of SACN and SNiMe is polymorph III, indicated by a melting event at 167 °C. Additionally, some form II is produced in the desolvation process. This fraction of form II quickly grows in the melt of form III, causing the exothermic process following the melting endotherm of form III. SACN and SNiMe behave in the same fashion under different heating rates (Figure 4), except for their different desolvation temperatures. At the highest heating rate mainly the melting peak (167 °C) of form III is recorded. Lower heating rates yield an exothermic part around 170 °C immediately after the melting process of polymorph III, which indicates that the higher melting forms (II and I) crystallize in the melt. The exothermic signal between the melting peaks of forms I and II (Figure 4, curve recorded at 2 K min−1) shows that I grows also during and after the melting process of modification II. Thus, seeds of polymorphs II and I probably form before the melting point of polymorph III is reached. However, these experiments suggest that the main fractions of polymorphs II and I develop only after the complete melting of polymorph III. In the case of SDCM and SDox only a small melting peak at 167 °C is observed under open conditions (Figure 3, open), suggesting that only traces of form III are formed during desolvation. The shape of the melting endotherm (peak with shoulder) indicates the presence of a mixture of forms II and I. At the applied heating rate of 10 K min−1 their endotherms overlap because of the small difference between the melting temperatures of forms II (174 °C) and I (176 °C). The DSC experiments at different heating rates (Figure 4) confirm that form I is the main product of the desolvation process of SDCM, which also yields a smaller amount of form II and only traces of polymorph III. The increase of the baseline in the DSC curve of SDox (Figure 3, open) is consistent with a slow desolvation process (∼70− 100 °C) prior to the inhomogeneous melting of the solvate at 100 °C. SDox has the lowest desolvation rate of the four solvates. The melting process of SDox is therefore detectable even at the smallest heating rates (Figure 4), whereas SACN and SNiMe undergo a complete desolvation before their respective melting temperature is reached. The weak melting endotherms at around 170 °C in the SDox curve, recorded with a rate of 15 K min−1, suggest that dioxane is tightly bound within the melt, so that the crystallization of any unsolvated from this “solution” is suppressed. The amount of dioxane released from SDox below its melting point increases with decreasing heating rate and the corresponding melting peak at 167 °C indicates (Figure 4) that the crystallization of form III is favored under such “mild” desolvation conditions. High heating rates yield only small amounts of form III but a larger share of forms I and II, suggesting that these polymorphs crystallize preferentially in the melt of SDox. All four TGA curves (Figure 3b) indicate a one-step loss of solvent above 55 °C and in a stoichiometric ratio of 1:1, which is consistent with the presence of monosolvates: SACN releases about 15.2% (w/w) of solvent (mainly between ∼60 and 95 °C), SNiMe 21.2% (∼50 to 120 °C), SDCM 26.7% (∼55 to 95 °C), and SDox 27.5% (∼60 to 100 °C) (theoretical values: SACN 15.0%, SNiMe 20.8%, SDCM 26.7%, SDox 27.5%).

Figure 2. Bright field microphotographs (HSM) of typical single crystals of the solvates before (images in the leftmost column) and during heating (subsequent images in each row). Image series (a)−(c) show optical changes on heating the samples in silicon oil, and series (d)−(f) were obtained from dry preparations of the solvates. Bubbles (a), (c) indicate released solvent in oil preparations. The nucleation and growth of unsolvated Pbtl is apparent by the occurrence of dark regions/loss of transparency (c)−(f) within the single crystals (pseuomorphosis). (a) SNiMe: inhomogeneous melting with release of gas bubbles (80−125 °C) and crystallization of the nonsolvated form (125−155 °C). (b) SDox: homogeneous melting at approximately 100 °C. (c) S DCM: desolvation with bubble formation and pseudomorphosis (50−90 °C). The series (d)−(f) show desolvation and subsequent pseudomorphosis of (d) SDox in the temperature range 60−100 °C, (e) SNiMe between 50 and 100 °C, and (f) SDCM between 50 and 80 °C.

influence of different ambient conditions on the crystal on heating (Figure 3a). The effect of different heating rates on the desolvation reaction and the proportion of the different polymorphs (III, II, or I) in the obtained desolvation product are illustrated in Figure 4. In a sealed pan (Figure 3, sealed), the fraction of solvent that can be released is limited to the amount that saturates the vapor in the head space. Three of the solvates (SACN, SNiMe, SDox) melt homogeneously under these conditions so that a solution of Pbtl and the solvent is obtained. The order of the obtained melting points, SACN (92 °C), SDox (100 °C), SNiMe (126 °C), was consistent with the observations in hot-stage microscopy studies. Due to the pressure increase in the sample pan, irregular events, which are difficult to reproduce, occur in the DSC curves above the melting temperature of the solvates. SDCM shows an inhomogeneous melting process, which starts at about 60 °C and results in a mixture of polymorphs I and II and additional traces of form III. In a pinholed pan (Figure 3, open) SACN produces a broad desolvation peak between 40 and 95 °C, which is followed by several endo/exo events. Presumably, these peaks are caused by melting processes of larger crystals that were not completely desolvated below their melting temperature. The DSC curve for 3270



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Figure 3. (a) DSC curves of in closed (“sealed”) and pinholed (“open”) pans (heating rate 10 K min−1). (b) TGA curves recorded at a heating rate of 10 K min−1.

Structure Discussion. Nitromethane and Acetonitrile Monosolvates. SACN and SNiMe are isostructural and crystallize in the space group P1̅ with two formula units in the asymmetric unit. The corresponding XPac dissimilarity index14 x of 5.5 (calculated for a cluster comparison with 18 Pbtl molecules, using all 17 non-H positions per molecule) indicates that these two crystals contain the same principal substructures of Pbtl molecules, albeit with slightly different geometries to accommodate the specific spatial requirements of acetonitrile and nitromethane molecules. The independent Pbtl molecules A and B are NH···OC hydrogen bonded to one another via R22(8) rings15 so that a 1D looped chain of the C-1 type16 is formed (Figure 5a), which propagates parallel to the a-axis. Geometrical parameters associated with these interactions are summarized in Table 2. Both NH donor groups as well the O2 carbonyl group and one of the two equivalent O4/6 carbonyl groups (Scheme 1) per molecule are engaged in hydrogen bonding. The C-1 chain is the most common of the standard NH···OC bonded structures in 5,5-substituted alkyl/ alkenyl derivatives of barbituric acid.16 It is also present in the metastable polymorphs IX and X of Pbtl4a and in the cocrystal of Pbtl and pentobarbital (Scheme 1: R1 = ethyl, R2 = 1-methylbutyl).17 Neighboring C-1 chains are arranged in such a way that their nearly coplanar R22(8) rings are oriented along the (012̅ ) plane (Figure 6a). The interlayer space is occupied by solvent molecules and the interdigitating ethyl and phenyl units from adjacent Pbtl chains. The two independent solvent molecules occupy two types of channel parallel to [010] (denoted 1 and 2

in Figure 6). However, the continuous cross section of each channel type is not sufficiently wide to permit a movement of solvent molecules through these channels (see Figure S5 of the Supporting Information). Dichloromethane Monosolvate. The asymmetric unit of SDCM (space group P21/n) contains one formula unit. Each Pbtl molecule is linked to each of two neighboring Pbtl molecules via a two-point NH···OC connection so that two R22(8) rings are formed. In contrast to the structures of SACN and SNiMe, both of the equivalent O4 and O6 carbonyl groups accept one H-bond, whereas the O2 carbonyl group is not N H···OC bonded. The looped chain structure resulting from these interactions (Figure 5b) has the topology type16 C-2. This chain type is also present in the Pbtl forms I, II, and III.4b The H-bonded chain propagates along [010] (11.85 Å) in the SDCM structure and has a 21 symmetry. Its geometry resembles that of the C-2 chain in form III (corresponding translation along [010]: 11.97 Å). However, SDCM and polymorph III differ fundamentally in the twist angle between the phenyl and pyrimidine rings of their respective Pbtl molecules (see below). The solvent molecules of SDCM, which are not H-bonded to Pbtl, occupy channels parallel to [100] structure (Figure 7). A transport of dichloromethane molecules within these channels is unlikely due to the small continuous cross section of the latter (Figure S5 of the Supporting Information). Dioxane Monosolvate. The structure of the room-temperature (RT) form SDox (space group P21/n) is shown in Figure 8a. Its asymmetric unit consists of one Pbtl molecule (denoted A) and the halves of two centrosymmetric dioxane molecules I 3271



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Figure 5. NH···OC bonded structures: (a) C-1 looped chain (SACN, SNiMe); (b) C-2 looped chain (SDCM). NH···OC and N H···ODox bonded structures: (c) 1:1 zigzag chain of SDox and SDox_LT (molecule labels for SDox_LT); (d) 2:1 ladder of SDoxH. O and H atoms directly linked by H bonds are drawn as balls. H atoms not involved in hydrogen bonding have been omitted for clarity.

Figure 4. DSC thermograms for Pbtl solvates in pinholed pans (heating rates; 2, 4, 10, and 15 K min−1).

(Wyckoff position 2c: 1/2,0,1/2) and II (2b: 1/2,1/2,0). Molecule II is disordered over two positions with equal occupancy, which represent inverse dioxane geometries. This structure differs from the other solvates in that the Pbtl molecules are not directly N−H···OC bonded to one another. Instead, each Pbtl unit is N−H···ODox linked to two dioxane molecules so that a 1D infinite chain is formed and which propagates parallel to [011̅] (Figure 5c). On cooling below room temperature, SDox undergoes a reversible single-crystal-to-single-crystal phase transition to the low-temperature phase SDox_LT. The space group of SDox_LT is P21/c, and its asymmetric unit is composed of two Pbtl molecules (denoted A and B), one complete dioxane molecule (I), and the halves of another two centrosymmetric dioxane molecules (II and III). The phase transition SDox → SDox_LT is due to a structural change at the disordered dioxane site only and proceeds from a disordered state of higher symmetry to an ordered structure of lower symmetry. SDox may be interpreted as a stack of two alternate kinds of layer which lie parallel to the (101) plane (Figure 8a). The first layer consists of Pbtl and disordered dioxane molecules (A+II) and the second layer exclusively of dioxane molecules of type I. This fundamental layer arrangement is maintained after the transition into SDox_LT, but now there is just one dioxane geometry in each (Pbtl + dioxane) layer (Figure 8b). The two previously disordered inverse dioxane geometries now appear in two separate ordered layers, (A+II) and (B+III). From this it follows that the inversion symmetry situated at 1/2, 1/2, 0 (Wyckoff position 2b) in SDox is broken in the SDox_LT structure for the dioxane molecules II and III. However, the Pbtl molecules A and B are still related to one another by pseudoinversion symmetry and the same is also true for the

two halves of dioxane molecule I. This is illustrated in Figure 8b where Pbtl molecules are yellow (y), green (g), red (r), and blue (b) according to their (pseudo)symmetry relationships: inversion (y/b, g/r), 21 (y/g, r/b), glide (y/r, g/b), or translation (y/y, g/g, b/b, r/r). All those crystallographic 21 and 1̅ elements, which in the structure of SDox lie in the (101) plane of type-I dioxane molecules, become pseudoelements in SDox_LT. The matrix 101 01̅0 101̅ describes the transformation of the P21/n unit cell of SDox into the larger P21/c cell of SDox_LT with the transformed cell (a = 17.804, b = 10.550, c = 18.413 Å, β = 108.32°; for the experimental SDox_LT parameters, see Table 1). XPac comparisons were carried between (a) the Pbtl substructures in SDox and SDox_LT and (b) the environments of the independent Pbtl molecules A and B in SDox_LT (using clusters of 16 Pbtl molecules and all 17 non-H positions per molecule; solvent molecules were not considered). The obtained dissimilarity indices14 x were (a) 3.7 and (b) 6.1, both indicating slight geometrical deviations between two supramolecular arrangements that are fundamentally the same (for the definition of x and reference examples, see refs 14 and 18). These results are consistent with an imperfect pseudosymmetry of the Pbtl substructure of the low-temperature phase SDox_LT. SDox_LT has the same hydrogen bonding structure as the room-temperature phase, and the mode of connectivity between its five independent molecular entities is illustrated in Figure 5d. The order−disorder single-crystal-to-single-crystal phase transition SDox_LT → SDox leads from a perfectly ordered chain to a situation where every other dioxane molecule bridging two Pbtl units is disordered. It can be expected that 3272



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Table 2. Geometrical Parameters (Å, deg) of Hydrogen Bondsa D−H···A

d(D−H)

N13−H13···O24i N11−H11···O22 N21−H21···O12 N23−H23···O14ii

0.874(13) 0.852(15) 0.836(15) 0.83(2)

N13−H13···O24i N11−H11···O22 N21−H21···O12 N23−H23···O14ii

0.860(17) 0.863(18) 0.868(18) 0.869(17)

N1−H1···O4iii N3−H3···O6iv

0.855(16) 0.854(16)

N1−H1···O1S N3−H3···O2S N3vH3···O2S′

0.861(9) 0.856(9) 0.856(9)

N11−H11···O11S N13−H13···O21S N21−H21···O12S N23−H23···O31S

0.882(16) 0.886(15) 0.888(16) 0.887(16)

N1−H1···O4v N3−H3···O1S

0.859(8) 0.868(15)

d(H···A) SACN 2.039(13) 1.984(16) 2.010(16) 2.04(2) SNiMe 2.022(17) 2.001(18) 1.959(18) 1.965(17) SDCM 1.973(16) 1.977(17) SDox 1.987(10) 2.023(13) 1.919(12) SDox_LT 1.932(17) 1.928(15) 1.929(17) 1.912(16) SDoxH 2.097(9) 1.891(15)

d(D···A)

∠(DHA)

2.903(2) 2.836(2) 2.842(2) 2.863(2)

170(2) 178.6(19) 174(2) 171(2)

2.879(2) 2.862(2) 2.823(2) 2.832(2)

175(2) 177(3) 174(3) 176(3)

2.827(2) 2.829(2)

176(2) 175(2)

2.8248(15) 2.873(8) 2.773(8)

164.2(15) 172.5(14) 177.0(14)

2.801(2) 2.812(2) 2.806(2) 2.797(2)

168(2) 175(2) 169(2) 175(2)

2.9326(12) 2.7568(12)

164.1(12) 176.2(14)

a Symmetry transformations used to generate equivalent atoms: (i) x − 1, y, z; (ii) x + 1, y, z; (iii) −x + 1/2, y − 1/2, −z + 3/2; (iv) −x + 1/2, y + 1/ 2, −z + 3/2; (v) x − 1, y, z.

CVVF calculations carried out by these authors showed a long “valley” centered at ϕ = 0°, which led to the conclusion that “the phenyl group is relatively free to rotate with little energetic cost”. The experimental ϕ and ω parameters for the solid forms of Pbtl confirm this assertion (Figure 10, bottom), as all observed ϕ values lie indeed in a very narrow range between −5° and +5°. The data points representing the solvate structures form a dense cluster centered at approximately ω = 5°, which indicates very similar molecular geometries with the phenyl ring oriented approximately perpendicular to the plane of the pyrimidine ring. The only exception from this is molecule type A of the isostructural solvates SACN and SNiMe, whose data points together with those of polymorphs I−III form a another cluster with a twist angle range from 34° to 70°. Structural Relationships. The C-2 chains of SDCM and polymorph III are geometrically similar but differ from one another with respect to the relative arrangement of their ethyl and phenyl groups. The C-1 chains of SACN and SNiMe contain dimer units of NH···OC linked A and B molecules (via C4/6 carbonyl groups) with a central R22(8) ring that are geometrically similar to the analogous centrosymmetric units in C-2 chains found in forms I and II. The structure comparisons carried out by us did not reveal any other significant structural similarities between the solvates and their desolvation products that could potentially point to a possible mechanism for the corresponding transition processes. Moreover, the variety of observed products (Figure 1) also suggests that the desolvation processes within the system involve a complete reorganization of the Pbtl substructure. The desolvation of SACN, SNiMe, and SDCM at room temperature yields primarily the kinetic form III, whereas the thermodynamically more stable modifications I and II are only formed at higher temperature. The latter two

the consumed/released energy for a phase transition involving such a minor structural modification is low. This was confirmed by DSC experiments, which revealed a small transition enthalpy of about 0.2 kJ mol−1 (Figure S2, Supporting Information). The small temperature shift between heating and cooling cycle indicates a weak kinetic control in this highly reversible phase transition. However, the DSC curves also show that the entire transition process proceeds over a relatively wide temperature range between about 5 and 27 °C, which suggests that the reorientation of the dioxane molecules is not a fully cooperative process. Dioxane Hemisolvate. The asymmetric unit of SDoxH contains one Pbtl molecule and one-half of a centrosymmetric dioxane molecule. Pbtl molecules are NH···OC bonded to one another via their O4 carbonyl groups. Two antiparallel strands of this kind are bridged by dioxane molecules via two (Pbtl)N−H···ODox bonds, yielding a ladder structure with centrosymmetric R66(26) rings15b that propagates parallel to [100] (Figure 5d). This H-bond topology is also present in the analogous hemisolvate of butallylonyl (Scheme 1: R1 = 2bromoallyl, R2 = 1-methylpropyl),10 and it is reminiscent of NH···OC bonded C-4 ladder structures16 found in form I of barbital19 (Scheme 1: R1, R2 = ethyl) and other barbiturate structures.4a,20 The central plane of the ladder structure is defined by the approximately coplanar pyrimidinetrione units of its individual constituent molecules. In the SDoxH crystal, the central planes of the H-bonded ladder structures form a fishbone pattern (Figure 9). Molecular Geometry. According to Day et al., the flexible geometry of a Pbtl molecule can be defined in terms of a rotation angle ϕ of the ethyl group and a twist angle ω between the phenyl and pyrimidine rings (Figure 10, top).21 DFT and 3273



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Figure 7. Crystal structure of SDCM viewed parallel to [100]. Atoms of the solvent molecules are drawn as balls. H atoms not involved in hydrogen bonding have been omitted for clarity.

magnitude, though the phenyl regions differ somewhat more significantly. Indeed, the NMR spectra suffice, on their own, to establish the isomorphous nature of SACN and SNiMe, as was the case for four solvates of finasteride hydrate.22 This conclusion is fully in agreement with the structures determined by X-ray diffraction. The dichloromethane solvate and the dioxane monosolvate, on the other hand, have distinctively different spectra, strongly suggesting that, as found by XRD, the structures are not isomorphous with those of the other two solvates. Moreover, splittings in the SACN and SNiMe spectra clearly indicate that the crystallographic asymmetric units consist of two molecules of the host Pbtl, whereas for SDCM only one independent molecule is indicated by the spectrum, again in agreement with the diffraction results. In the case of SACN two molecules of the “solvent” are shown to be in the asymmetric unit, whereas only one is suggested by the SDCM spectrum. For SNiMe, the spectrum does not clearly show the number of molecules of nitromethane in the asymmetric unit. At room temperature, the spectrum of the dioxane monosolvate (Figure 11) indicated an asymmetric unit comprising one molecule of both the Pbtl host and the “solvent”. This observation was, however, irreconcilable with the X-ray diffraction data recorded at −100 °C. These showed a pseudosymmetric structure whose asymmetric unit contains two Pbtl and two (1 + 1/2 + 1/2) dioxane molecules, as discussed in the previous section and illustrated in Figure 8b. The apparent discrepancy between room-temperature NMR and low-temperature X-ray results prompted variable-temperature studies by the two techniques which led to the discovery of a reversible single-crystal-to-single-crystal phase transition between a RT form SDox and a LT form SDox_LT. Thus, as the temperature is lowered, the NMR resonance for C9 splits. However, this process starts to occur at ca. 15 °C, i.e., above the apparent transition temperature to the low-temperature form (possibly as a result of the very different sampling conditions between NMR and thermal methods). A spectrum recorded at ca. −80 °C (Figure 11, bottom) shows a clear splitting for C7 also, with a smaller splitting for C8. Thus the asymmetric unit now involves two molecules of Pbtl, though the status of the pyrimidinetrione ring is not clear. The dioxane signal also splits at ca. −80 °C, in this case into three peaks in intensity ratio

Figure 6. Crystal structure of SNiMe, viewed (b) parallel to [100] and (b) parallel to [010]. Atoms of the solvent molecules are drawn as balls. H atoms not involved in hydrogen bonding have been omitted for clarity.

polymorphs are structurally very similar to one another,4b and both contain a complex NH···OC bonded layer structure in addition to C-2 chains, whose formation may require a higher level of molecular mobility. Solid-State NMR. The 13C CPMAS spectra of SACN, SNiMe, SDCM, SDox, and SDox_LT are displayed in Figure 11, and the chemical shifts are given in Table 3. Their assignments to the individually chemically distinct nuclei are straightforward except for those of the phenyl group. However, dipolar-dephased spectra clearly distinguish between the C9 resonances and those of the other phenyl carbons. The signals for the “solvent” molecules immediately confirm their presence in the crystal structures. The spectra for SACN and SNiMe are remarkably similar (except for the “solvent” signals), as would be expected from their isostructural crystal structures. Most shift differences between them for analogous nuclei are less than 0.4 ppm in 3274



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Figure 9. Crystal structure of SDoxH, viewed along [100], i.e., parallel to the translation vector of the H-bonded ladders of Figure 5d. O and H atoms directly engaged in H-bonds are shown as balls; all other H atoms have been omitted for clarity.

Figure 8. (a) Crystal structure SDox viewed parallel to [010]. Only one disorder component of dioxane molecule II is shown in the packing diagram. Details of the disorder are illustrated in the right part. (b) Crystal structure of SDox_LT viewed parallel to [010]. Broken lines: outline of the unit cell of SDox. Crystallographic symmetry elements and pseudo-elements (SDox_LT) are denoted by full and open symbols, respectively. H atoms have been omitted for clarity.

Figure 10. Top: definition of the flexible torsion angles ϕ and ω used to characterize the molecular geometry of Pbtl. Bottom: experimental twist angle ω between the phenyl and pyrimidine rings plotted against the corresponding rotation angle ϕ of the ethyl group for the Pbtl molecules contained of the solvates (this work), polymorphs I, II, III (ref 4b), and the monohydrate H1 (ref 5).

approximately 2:5:1, the central peak being rather broad. Table 3 gives the chemical shifts for all the signals for both high- and low-temperature forms. The low-temperature NMR information is now in agreement with the X-ray results for SDox_LT, just as the room-temperature X-ray data for SDox agree with the previously recorded NMR spectrum. There is negligible change with temperature in the 13C chemical shifts for C5, C2, and C4/C6. The low-temperature NMR spectrum for SDox_LT is still

distinct from those of the other two solvates, so NMR confirms that the structure is not isomorphic with them. The signals for C2 and (to some extent) for C4/C6, and also some “solvent” signals, are broadened by second-order effects originating in coupling to quadrupolar 14N nuclei,23 though the 3275



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give well-resolved signals is, perhaps, a little surprising, though this may be a result of differing orientations with respect to the phenyl rings or of variations in the intermolecular environments. The chemical shifts for SDCM (Table 3 and Figure 11) demonstrate conclusively that the C4/C6 carbons are involved in hydrogen bonding, whereas C2 carbons are not. The lack of any observable splitting for C4/C6 in SDox is probably associated with the twist between rings being close to zero for both independent units. The C2 resonances for SACN and SNiMe, occur over 3 ppm to high frequency of those for polymorphs I, II, and III.2b This immediately demonstrates that the C2 carbonyl group is involved in hydrogen bonding in the solvates. The C2 shifts for SDox and SDox_LT are ca. 2 ppm lower than for SACN and SNiMe, indicating the lack of hydrogen bonding in the dioxane solvates. The dipolar-dephased spectrum of SACN (Figure 12a) reveals some interesting features of molecular-level mobility in these solvates. The methyl signals of the host are retained, as is usual because of rapid internal rotation about the C−CH3 bond, but the CH2 signals are entirely missing, indicating relative rigidity about the ring−methylene bond. There is retention of small signals for the phenyl CH carbons (presumably except for C12) suggesting that the phenyl ring has some mobility. The tendency for the “solvent” molecules to escape from the lattice precluded higher-temperature NMR investigations. Further evidence of the internal rotation of the phenobarbital methyl group (leading to a relatively short relaxation time T1) was provided by direct polarization (DP) spectra (with recycle delays of 1 s), which showed (Figure 12b) strong signals from such carbons (only). Interestingly, the DP spectra of both SACN and SNiMe showed the high-frequency phenobarbital methyl signal to be distinctly weaker than that of its companion signal, suggesting that there is a difference in the mobility of the methyls in the two molecules of the asymmetric unit causing variations in their 13C spin−lattice relaxation times, presumably

Figure 11. Solid-state 13C CPMAS NMR spectra of (top to bottom) SACN, SNiMe, SDCM, SDox (room temperature), and SDox_LT (low temperature). The arrows indicate the “solvent” peaks. The spectrum of SDox_LT is presented after subtraction of peaks arising from minor amounts of a desolvate (form III); weak residual signals from the latter can still be seen.

magnitudes of such splittings are small at the magnetic field employed. Differences in hydrogen bonding are a major factor in causing the distinctive pattern of four resonances for C4/C6 in SACN and SNiMe. Two of the relevant carbonyl groups are involved in hydrogen bonding, whereas the other two remain free. Similar variations have been reported for polymorphs I and II of Pbtl itself,4b and these have been adequately predicted by shielding computations.4c The fact that all four such carbons

Table 3. Carbon-13 Chemical Shifts and Assignments for Solvates of Pbtl form

Z′

4,6a

2a

2

∼152.7

5

7

8

9

SDCM

1

∼176.6 ∼174.8 ∼172.7 ∼171.3 ∼176.8 ∼175.1 ∼172.6 ∼171.6 ∼177.5

SDoxf

1

∼172.7

∼150.4

59.9

27.4

9.3

139.7

SDox_LTh

2

∼172.6

∼150.7

59.5

27.7

9.5

140.1

26.7

9.1

138.9

SACN

SNiMe

2

61.8

31.4

9.9

138.2

60.1

29.9

8.8

137.4

61.6c

32.2

10.1

138.4

60.2

27.2

8.8

137.8

∼147.6

60.5

31.4

10.4

137.8

∼152.9

10−14 b

131.7 130.1b 129.0b 126.7b 131.4d 129.7d 128.1d 126.9d 129.3e 128.1e 126.9e 130.7g 129.6g 128.1g 131.2i 130.5i 129.5i 128.3i

solvent 0.0 and 0.4 117.2a 62.2a,c

55.9

66.7

67.0j 66.1j 65.4j

a

Carbons 2, 4, and 6 (and some solvent carbons) are bonded to nitrogen and therefore show the characteristic broadening/splitting arising from residual dipolar coupling to 14N, hence the uncertainty in their precise chemical shifts. bThe relative intensities are difficult to determine but are probably in the ratio 1:3:3:3 (high to low frequency). cPossibly the assignments of these two signals should be interchanged. dThe relative intensities are difficult to determine but are probably in the ratio 3:3:1:3 (high to low frequency). eRelative intensities 2:1:2. fAmbient probe temperature. gThe relative intensities are difficult to determine but are probably in the ratio 1:2:2 (high to low frequency). hAt ca. −80 °C. iRelative intensities (high to low frequency) 1:2:2:5. jRelative intensities (high to low frequency) 3:5:2. 3276



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spread of spinning sidebands does not appear to change. The H spectra indicate some mobility of the dioxane molecules but this is a gradual process; no sharp change occurs as the transition temperature between the two forms is passed through. This result is consistent with the DSC investigations of the SDox (Figure S2, Supporting Information), which also indicated that the transition process occurs within a large temperature interval. Infrared Spectroscopy. Characteristic bands in the FT-IR spectra (Figure 13) of SACN, SNiMe, SDCM and SDox are listed in 2

Figure 12. MAS spectra of SACN: (a) CP with dipolar dephasing; (b) DP.

from internal rotation about the C−CH3 axis in SNiMe, perhaps involving jumps between the two disordered positions present. Both acetonitrile signals are retained in the dipolar-dephased spectrum but appear only very weakly in the DPMAS spectrum, which indicates that, though the “solvent” molecules have a moderately high degree of mobility, their 13C spin−lattice relaxation times are substantially longer than 1.0 s. Such mobility information represents a significant way in which NMR crystallography is complementary to diffraction crystallography. It is noteworthy that SACN possesses clearly resolved signals for the “solvent” methyl carbons, showing that there is no exchange between the two independent acetonitrile molecules. SDox shows a single broad resonance for the “solvent” at room temperature, though a weak peak separates to high frequency at low temperature, suggesting a slowing of motion or a change in crystal structure. It is possible that dioxane ring inversion is occurring at room temperature, as it does, for instance, in the finasteride hydrate dioxane solvate,24 and this may conform to the disorder of the dioxane molecules with increasing temperature revealed by the room-temperature X-ray diffraction results. The “solvent” signals occur close to their liquid-state chemical shifts (acetonitrile 1.39 and 118.69 ppm; nitromethane 62.80 ppm; dichloromethane 54.00; dioxane 66.66 ppm at ambient temperature). To further examine the effects of molecular-level mobility for SDox, a sample was prepared using the deuterated “solvent”, C4D8O2. The 2H spectrum at −60 °C is shown at the bottom in Figure S8 of the Supporting Information. The spread of spinning sidebands is consistent with a relatively rigid dioxane molecule. An approximate analysis suggests a nuclear quadrupole coupling constant of ca. 160 kHz. The situation is clearly very different from that of bisfinasteride monohydrate monodioxane-d8, for which the quadrupole coupling constant ranges from ca. 12 kHz at +18 °C to ca. 26 kHz at −50 °C.24 The reason is that in the Pbtl case the dioxane is tied down by hydrogen-bonding to the host molecules, whereas there are no such interactions for dioxane in the finasteride case (thus leading to considerable overall mobility). However, that does not preclude ring inversion (which is the process relating the disordered molecules in the room-temperature form). As the temperature is raised, the lines for the Pbtl dioxane solvate broaden (Figure S9 of the Supporting Information) but the

Figure 13. FT-IR spectra of solvates of Pbtl.

Table 4. Solid-State FT-IR Bands (cm−1) for Solvates of Pblt solvate

SACN

SNiMe

SDCM

SDox

ν(NH)

3207 3096

3205 3094

ν(CO)

1760 1710a

1754 1710a

3212 3161 3073 1767 ∼1736b 1719 1700 1679 873

3207 3158 3077 1754 1739b 1720b 1700

ν(NH) out of plane a

851

856

870

b

Broad. Shoulder.

Table 4 and highlighted in Figure 13. The main differences between these solvates are related to N−H···OC interactions and N−H out-of-plane vibrations. Though the spectra of the isostructural SACN and SNiMe solvates are very similar, they differ fundamentally in that the SNiMe spectrum shows a strong band at 1560 cm−1 which is associated with the NO2 group of its solvent molecule. A classification scheme linking IR characteristics of barbiturate structure with their specific NH···OC-bond structures has been devised recently.4a In this context, the IR characteristics of SACN and SNiMe are consistent with those of 3277



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arrangements). The validity of this statement is demonstrated by the isostructural solvates (with dichloroethane, ethanol, and methanol) of aripiprazole,26 which show an inverse relationship between solvate stability and boiling points/vapor pressure of the solvent. However, in the case of the Pbtl solvates the solvent molecules are rather weakly bound and their spatial arrangement within the host lattice allows a diffusional loss of the solvent molecules before the lattice collapses. This might explain the correspondence between solvate stability and volatility of the solvent. Acetonitrile and nitromethane are both weak donor solvents with very similar solubility parameters and molecular dimensions27 which is a prerequisite for the formation of isostructural solvates. The isostructurality of SACN and SNiMe is also reflected by a similar thermal behavior and comparable transformation pathways to unsolvated forms of Pbtl upon desolvation. These two solvates yield preferentially form III under thermal desolvation conditions whereas the formation of mixtures of forms I and II is favored in the thermal desolvation of SDCM. However, the isostructurality of SACN and SNiMe is not reflected in the melting points of these solvates under saturated solvent vapor conditions, 92 °C (SACN) and 126 °C (SNiMe). This highlights the complexity of such phase transitions in solvates, which cannot be explained by simply considering obvious solvent parameters, not even in the case of isostructural solvent adducts. Depending on the applied experimental conditions, the desolvation processes of the Pbtl solvates can yield either a specific pure phase or a mixture of different phases. A very tight control of ambient conditions is therefore necessary for the preparation of phase-pure raw material of a drug compound from a given solvate. There is not necessarily a close structural link between a solvate and its desolvated form, indicating that extensive destruction of the original solvate structure is followed by a complex reorganization process. Our observations support the notion11 that highly unstable solvates28 are more common among small organic molecules than is generally believed. The phase identity of solvent crystallization products is usually established in the dry state, where such “transient solvates” are difficult to detect. This may then lead to incorrect assumptions on how a particular solvent affects the formation (nucleation) of a specific polymorph. Therefore, much caution is needed when phase relationships are interpreted on the basis of studies in which the crystallization process from a solvent was not monitored with sufficient accuracy.

other structures containing the C-1 chain type (Figure 5a), such as forms IX and X of Pbtl.4a On the basis of the IR characteristics of SDCM, the correlation scheme indicated the presence of the C-2 chain type (Figure 5b), which was confirmed by the crystal structure determination. The IR spectra of SDCM and III (also containing C-2 chains) are remarkably similar (Figure S10 of the Supporting Information). In the spectrum of SDox, the bathochromic shift of the strongest N−H stretching vibration indicates that hydrogen bonding is stronger than in the other three solvents, which is consistent with the observed higher stability SDox. Moisture Stability. Storage experiments at low relative humidities (0−30% RH) showed that all the monosolvates transform to polymorph III. PXRD experiments indicated that at high humidity (98% RH, saturated K2SO4 solution) either the pure monohydrate H1 or a mixture of the forms H1, IV, VI, and III exists. However, SDCM transforms only to form III and H1. Moisture-induced desolvation of SNiMe proceeds via form IV as an intermediate phase. A hot-stage microscopy experiment confirmed this observation. FT-Raman spectra were continuously recorded after a small amount of water was added to the solvate to monitor moisture-induced structural changes and detect intermediate forms (Figure S10, Supporting Information). Rapid transformation to H1 occurs in each case, and no intermediate phases were detected.

■

CONCLUSIONS When barbiturates were first introduced, optical microscopy was the method of choice for the study of solid forms and many polymorphs of barbiturates were produced from the melt and by sublimation. Extensive solvent screening was not routinely performed at that time and analytical tools to deal with unstable solvates were not commonplace. For these historical reasons, solvate formation by barbiturates is still significantly underreported. This is illustrated by the case of Pbtl, one of the most important and most extensively investigated barbiturates. In the course of our study we have identified a new hemisolvate (1,4dioxane/SDoxH) of Pbtl, three new monosolvates (acetonitrile/ SACN, dichloromethane/SDCM, nitromethane/SNiMe) and we confirmed the existence of a fifth solvate (1,4-dioxane monosolvate/SDox). The latter solvate was found to be polymorphic and to undergo a single-crystal-to-single-crystal phase transition on cooling (SDox_LT), which is associated with a disorder → order conversion. Solid-state NMR was a key technique in detecting this transition and complements the Xray diffraction results, providing some information on molecular-level mobility. It confirms the isomorphous nature for SACN and SDCM (and establishes the size of the asymmetric units), while showing that the structures of the dioxane and dichloromethane solvents are different. All solvates show a relatively low stability and transform within hours after harvesting from the solvent of crystallization to unsolvated forms of Pbtl. The order of the thermal stability (SDCM < SACN < SNiMe ≈ SDox) follows the order of the boiling points and vapor pressures of the entrapped solvents. This may seem logical,25 but we have to consider that the solvent is not present in a liquid-like state. Instead, the solvent molecules are located at specific sites within the structure formed by the host molecule and typically isolated from each other. Thus, the stability of a solvate depends strongly on how the solvent molecules are accommodated in the host structure, i.e., the interaction energies between solvent and host molecules and spatial characteristics (open voids such as tunnels or cage-like

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ASSOCIATED CONTENT

S Supporting Information *

Microscale experiments, low-temperature DSC of the dioxane monosolvate, experimental and simulated PXRD patterns, crystal structure packing diagrams, additional solid-state NMR data, additional FT-IR spectra, Raman spectroscopy, moisture stability experiments, crystallographic information file. This material is available free of charge via the Internet at http:// pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Author

*U. J. Griesser: e-mail, [email protected]; tel, +43 (0) 512 507 58650. 3278



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Notes

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The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank Denise Rossi for assistance with experimental work. T.G. gratefully acknowledges funding by the Austrian Science Fund (FWF), project M1135-N17. The NMR work was supported by the U.K. EPSRC under grant EP/D057159.

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New Solvates of an Old Drug Compound (Phenobarbital): Structure

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