Part of the Special Issue: Facets of Polymorphism in Crystals
Characterization of Polymorphs and Solvates of Terbutaline Sulfate
CRYSTAL GROWTH & DESIGN 2008 VOL. 8, NO. 1 80–90
Robin K. Harris,*,† Paul Hodgkinson,† Tomas Larsson,‡ Amsaveni Muruganantham,† Ingvar Ymén,§ Dmitry S. Yufit,† and Vadim Zorin† Department of Chemistry, UniVersity of Durham, South Road, Durham DH1 3LE, U.K., AstraZeneca Research & DeVelopment, Analytical DeVelopment 5, Lund S-22187, Sweden, and AstraZeneca Process R & D, Analytical Chemistry, Södertälje, S-15185, Sweden ReceiVed September 3, 2007; ReVised Manuscript ReceiVed NoVember 12, 2007
ABSTRACT: Five different crystalline modifications (two anhydrates, a monohydrate, a higher hydrate, and an acetic acid solvate) of an asthma-therapy drug, terbutaline sulfate, have been identified and characterized by several solid-state techniques. X-ray powder diffraction (XRPD) and thermal analysis, that is, thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC), were used as preliminary techniques to identify the different forms. Detailed solid-state characterization was carried out by 13C and 15 N solid state NMR (SSNMR), using the cross-polarization (CP) and magic-angle spinning (MAS) techniques. High-speed 1H MAS spectra show signals at high frequency arising from hydrogen bonds. A 13C,1H heteronuclear correlation spectrum, together with computations using the NMR-CASTEP program, yield further information on the hydrogen-bonding resonances. The structures of the monohydrate and of the higher hydrate were determined by single-crystal X-ray diffraction (XRD). The latter was found to be a 2.5 hydrate and to have some disordered atoms, including the hydroxyl group which conveys chirality on the molecule. The crystal structures of the anhydrate B, the acetic acid solvate, the monohydrate, and the higher hydrate are compared, stressing the extent of hydrogen bonding. The first three contain a common dimeric unit of terbutaline cations, linked by hydrogen bonds.
1. Introduction Questions of polymorphism and of solvate formation1 are of considerable importance in pharmaceutical industry, since the existence of various crystal modifications poses problems for controlled production,2 stability,3 formulation,4 storage, patent establishment, and patent protection.1–3 Consequently, much research effort is now placed on methods of reliably identifying and characterizing polymorphs and solvates.5 Traditionally, X-ray powder diffraction (XRPD) and infrared (IR)/Raman spectroscopy have been used to identify such modifications, while differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) have monitored transformations and stability. Single-crystal diffraction methods (using neutrons or, more generally, X-rays) are usually regarded as the gold standard for full characterization at the molecular level. However, diffraction techniques suffer from a number of limitations, and in recent years the use of high-resolution solid-state NMR has come to the fore.6,7 Single crystals are not required, and so microcrystalline powders are normally used. The technique gives ready identification in most cases and provides immediate molecular structure information. It also yields some direct crystallographic data (such as the number of molecules in the asymmetric unit) and can deal with problems of disorder, amorphicity, and heterogeneity. The presence of organic solvate molecules is immediately observable, and molecular-level mobility can also be monitored. In the present work, solid-state NMR has been used, together with XRPD, DSC, and TGA to study several crystal modifica* Author to whom correspondence should be addressed. Phone +44-(0)191334-2021; fax: +44-(0)191-384-4737; e-mail
[email protected]. † University of Durham. ‡ AstraZeneca Research & Development. § AstraZeneca Process R & D.
tions of terbutaline sulfate (TBS, I), which in formal chemical terms is bis-[1-(3,3-dihydroxyphenyl)-2-t-butylaminoethanol] sulfate. This compound is used in asthma therapy. It is known to exist in at least two anhydrous modifications (A and B), a monohydrate and an acetic acid solvate. A higher hydrate, supposedly a trihydrate (which has also been denoted as terbutaline hemisulfate sesquihydrate), has also been reported8 and structurally characterized. All five modifications have been investigated in the study reported herein. However, our work raises some queries about the precise water content in the “trihydrate”, so we will generally refer to it as the higher hydrate.
The crystal structures of anhydrate B and the acetic acid solvate were known previously9–11 and are contained in the Cambridge Crystal Structure Database (CSD) under codes, ZIVKAQ and ZIVKAQ01, for the former, and ZIYXAG, for the latter. The crystal structure of the higher hydrate8 also appears in the CSD, under code BECVI0. This modification has two TBS ions in the asymmetric unit, but one of these was said to involve disorder of the chiral center at C7. However, j symmetry demonstrates that both chiralities the space-group (P1) are present in the unit cell. The published structure was obtained from diffraction experiments at ambient temperature. We have redetermined the structure at 120 K, with the aim of clarifying the disordered nature of the system. The crystal structure of
10.1021/cg700840j CCC: $40.75 2008 American Chemical Society Published on Web 01/02/2008
Polymorphs and Solvates of Terbutaline Sulfate
Crystal Growth & Design, Vol. 8, No. 1, 2008 81
Table 1. Structural Information on the Various Crystal Modifications of TBSa
space group a/Å b/Å c/Å R/° β/° γ/° V / Å3 Mw/g mol-1 Z Z′ Dcalc/g mL-1 T/K packing coefficient/% void volume/% of cell volume R-factor/% a
anhydrate B j P1 9.968/9.970 11.207/11.204 13.394/13.397 100/86/100.86 104.42/104.40 101.63/101.54 1374/1375 548.65 2 1 1.326/1.325 room temperature 67.8/67.7 1.2/1.0 6.2/7.3
monohydrate P1j 10.1636 11.7839 13.1905 64.02 89.97 87.46 1418.4 566.66 2 1 1.327 120 68.3 0 3.70
acetic acid solvate Pbca 16.560 21.740 19.440 90 90 90 6998.7 668.75 8 1 1.269 295 64.7 3.0 7.40
higher hydrate P1j 10.9566 11.7848 13.6136 105.36 108.84 106.11 1471.97 592.67 2 1 1.337 120 disordered 2.9 4.98
The data for anhydrate B are extracted from ZIVKAQ (left values) and ZIVKAQ01 (right values).
the monohydrate was not known previously but is reported in this paper. It will be discussed, together with those of anhydrate B, the acetic acid solvate, and the higher hydrate, in a later section. Table 1 contains information about all the known crystal structures for the relevant forms of TBS. To complement the experimental NMR work, the NMRCASTEP computer program,12–14 which explicitly takes account of the translational repetition inherent in crystalline systems, has been used to calculate the 13C and 1H chemical shifts of form B. This approach to understanding the chemical shifts of crystalline solids has already been employed with success on a number of occasions,15–20 including several cases involving polymorphism or solvate formation.
2. Experimental Details 2.1. Samples. TBS was obtained as pure anhydrate B or as pure acetic acid solvate from AstraZeneca Bulk Production in Södertälje, Sweden. All other crystal modifications were produced from these two batches. All samples were off-white microcrystalline powders, highly soluble in water. Samples of anhydrates A and B and the acetic acid solvate were kept in a desiccator, containing dry silica gel, between measurements, while the monohydrate and the higher hydrate were kept in tightly closed vials, at ambient temperature. 2.2. Crystallizations and Phase Diagram. Microcrystalline anhydrate A was prepared by drying the acetic acid solvate at 150 °C under high vacuum, for 10 h. Large, tabular single crystals of the monohydrate were prepared as follows: A saturated solution of anhydrate B, in a 50:50 w/w water/ ethanol mixture, was prepared and filtered through a 0.45 µm PALL Acrodisc Super Membrane filter, to remove any seed crystals of form B. The solution was transferred to a wide and flat crystallization vessel and evaporated at 60 °C, until it became highly viscous. Seeds of amorphous TBS were then added, and the vessel was covered with a glass and left to crystallize at 60 °C. Large, tabular single crystals of the higher hydrate were prepared by evaporative crystallization at room temperature. A saturated solution of anhydrate B, in a 70:30 w/w water:ethanol mixture, was prepared and filtered through a 0.45 µm PALL Acrodisc Super Membrane filter to remove any seed crystals of form B. The solution was transferred to a wide and flat crystallization vessel, which was left to evaporate until crystals appeared. Phase diagram21,22 data for the ternary system TBS, water, and ethanol at 4, 22, and 50 °C were obtained by a gravimetric method. A series of 12 mixtures of water and ethanol was prepared by weighing the solvents into small test tubes. The tubes were sealed with Chromacol silicon crimp caps and heated to experiment temperature in a TTP SolMate thermal block. Each vessel was then decapped, and a magnetic flea and an excess of TBS anhydrate B were added, so as to form a slurry. The vessel was recapped and stirred for an hour at the experiment temperature and then decapped once more for the addition of a
competing crystal modification (anhydrate A, the monohydrate, and/ or the higher hydrate were added to different vessels). After final capping the samples were stirred for 5 days, after which they were allowed to settle for one day. The clear saturated solutions were sampled using a needle, a syringe, and a 0.45 µm PALL Acrodisc Super Membrane filter, all of which were preheated or precooled to the temperature of the experiment. The solid residues in each vessel were sampled and analyzed for identification with XRPD. The saturated solutions were transferred to preweighed 5 mL Erlenmeyer flasks, fitted with ground glass stoppers. These were allowed to come to thermal equilibrium before being weighed. The solvent was then evaporated off in a fume hood, and the samples were dried in a vacuum oven at 80 °C, and then at 105 °C, until the weight was constant. The solubility data for each sample were calculated as weight percentages of TBS, water, and ethanol. After final weighing, the dried residues in each Erlenmeyer flask were analyzed with XRPD. 2.3. Analytical Techniques. 2.3.1. TGA. A Perkin-Elmer TGA7 instrument was used to record weight loss of all samples in the temperature range 30–200 °C. The measurements were made at a scan rate of 10 °C/min in a nitrogen atmosphere with sample amounts of 5–8 mg. 2.3.2. DSC. A Perkin-Elmer DSC7 instrument was used to record DSC data. All measurements were made in standard Perkin-Elmer Alcapsules with holes in the sides. The starting temperature was 30 °C for all samples, but the end temperature varied, due to degradation occurring immediately at the onset of melting, thus having a severe polluting effect on the sample furnace. The measurements were made at a scan rate of 10 °C/min, in a nitrogen atmosphere, with sample amounts of 1.5–6 mg. 2.3.3. XRPD. A PANalytical X′Pert PRO diffractometer, equipped with an X′Celerator detector and Ni-filtered Cu KR radiation, was used for the X-ray powder diffraction work. A thin layer of 5–10 mg of sample was spread out on a silicon zero-background sample-holder. The sample was mounted on a 2°/min spinning sample holder, and a diffractogram was collected in reflection mode. An angular range of 2 to 40° in 2θ was covered in 2274 steps, during a scan time of just over one hour. An automatic divergence slit, 0.02 rad Soller slits and a 10 mm beam mask were used in the incident beam path, and an automatic antiscatter slit and 0.02 rad Soller slits were used in the diffracted beam path. The active length of the X′Celerator detector was 0.518°. 2.3.4. Single-Crystal XRD. The single-crystal X-ray data were collected on a Bruker SMART CCD 6000 diffractometer (ω-scan, 0.3°/ frame) at 120 K using graphite monochromated Mo KR radiation (λ ) 0.71073 Å). Both structures were solved by direct methods and refined by full-matrix least-squares on F2 for all data using SHELXTL software. All nonhydrogen atoms (except the disordered ones in the structure of the higher hydrate) were refined with anisotropic displacement parameters, whereas hydrogen atoms were located on the difference map and refined isotropically. The positions of hydrogen atoms of water molecules in the structure of the higher hydrate were refined with fixed isotropic temperature factors. Crystallographic data for the structures are available as Supporting Information. They have also been deposited
82
Crystal Growth & Design, Vol. 8, No. 1, 2008
with the Cambridge Crystallographic Data Centre and given codes 664460 (monohydrate) and 664461 (higher hydrate). 2.3.4.1. Crystal Data for the Higher Hydrate. 2[C12H20NO3]+ · j a ) 10.9566(4), SO42- · 2.5H2O, M ) 592.67, triclinic, space group P1, b ) 11.7848(4), c ) 13.6136(4) Å, R ) 105.36(1), β ) 108.84(1), γ ) 106.11(1)°, U ) 1471.97(9) Å3, F(000) ) 636, Z ) 2, Dc ) 1.337 mg m-3, µ ) 0.174 mm-1. 18 534 reflections were collected, yielding 9237 unique pieces of data (Rmerg ) 0.0164). Final wR2(F2) ) 0.1342 for all data (558 refined parameters); conventional R(F) ) 0.0498 for 8159 reflections with I g 2σ, GOF ) 1.081. 2.3.4.2. Crystal Data for the Monohydrate. 2[C12H20NO3]+ · j a ) 10.1636(2), SO42- · H2O, M ) 566.66, triclinic, space group P1, b ) 11.7839(4), c ) 13.1905(4) Å, R ) 64.02(1), β ) 89.97(1), γ ) 87.46(1)°, U ) 1418.4(1) Å3, F(000) ) 608, Z ) 2, Dc ) 1.327 mg m-3, µ ) 0.174 mm-1. 19014 reflections were collected, yielding 7858 unique pieces of data (Rmerg ) 0.0466). Final wR2(F2) ) 0.1030 for all data (511 refined parameters); conventional R(F) ) 0.0370 for 5772 reflections with I g 2σ, GOF ) 0.955. 2.3.5. Nuclear Magnetic Resonance. The 13C and 1H solutionstate spectra of TBS (in D2O), together with an HSQC spectrum, were acquired on a 400 MHz Varian Mercury spectrometer, to assist assignment of the solid-state spectra. All the 13C CP MAS experiments, except for those on the higher hydrate, were performed on a Chemagnetics CMX 200 spectrometer (unless otherwise mentioned), operating at 50.33 MHz, and using a 7.5 mm probe with the following acquisition and processing parameters: spin rate 5 kHz, number of acquisitions 2048, recycle delay 10 s, and contact time 1 ms. The spectra were processed with 8k data points and then apodized with a line broadening factor of 10 Hz. The dipolar dephasing (nonquaternary suppression) experiment,23 used for assignment purposes, employed a nondecoupling window of 50 µs. The higher hydrate 13C CP MAS experiments were performed on a Varian Inova 300 spectrometer, operating at 75.398 MHz, and using a 5.0 mm probe with the following acquisition and processing parameters: spin rate 8.21 kHz, number of acquisitions 2200, recycle delay 2 s, and contact time 1 ms. The spectra were processed with 16k data points and then apodized with a line-broadening factor of 10 Hz. The 30.40 MHz 15N CPMAS spectra were recorded with a Varian UnityPlus 300 MHz spectrometer, using 7.5 mm rotors spinning at 5 kHz. The contact time and the recycle delay were the same as for the 13 C spectra. A 40.52 MHz 15N CPMAS spectrum of modification B was recorded using a Varian VNMRS 400 spectrometer. Fast-MAS 1H spectra were obtained at 499.7 MHz on a Varian Infinity 500 spectrometer using a 2.5 mm rotor spinning at 28 kHz. The FIDs were accumulated with 4 acquisitions. While the samples were spinning at high speed, proton relaxation measurements at ambient probe temperature were carried out to derive information to guide choice of parameters for the cross polarization and for the proton experiments. All the T1 data fall within a narrow range (0.74 to 0.91 s), presumably partly because of spin diffusion. The existence of acetic acid protons does not seem to have a major effect for the acetic acid solvate. However, results for T1F are significantly more variable, ranging generally from 0.1 to 4.7 ms. Moreover, the T1F values for the acetic acid solvate are distinctly longer (9-11 ms), indicating a strong contribution from the acetic acid protons (and suggesting solvent molecule mobility on the time scale of the radiofrequency power). The 13C, 1H heteronuclear correlation experiment was carried out using the pulse sequence introduced by Vega24 and modified by Fyfe, Zhang, and Aroca25 (and also by Schmidt-Rohr, Clauss and Spiess26). This was further improved for the present work to cope with fast MAS (25 kHz) by ramping the 1H RF amplitude over a 15% range of intensity. Decoupling power equivalent to 100 kHz was applied during acquisition. The indirect dimension contained 32 increments. Shielding computations were carried out with the NMR-CASTEP program.12–14 The PBA functional was used and the planewave cutoff energy was set at 600 eV. A 3 × 2 × 2 grid (6 k-points) was used to sample the Brillouin zone. The isotropic shielding constants were converted to chemical shifts by using the shielding value of 171.49 ppm for TMS, obtained by equating the average computed shielding to the average observed chemical shift.
Harris et al.
Figure 1. Ternary phase diagram for TBS-water-ethanol, with solubility curves at 4 (lower line), 22 (middle line), and 50 °C (upper line). In area I the solution is not saturated, whereas in area II the solution is saturated and in equilibrium with crystals of TBS anhydrate B.
3. Results and Discussion 3.1. Ternary Phase Diagrams. In Figure 1, solubility data at 4, 22, and 50 °C have been plotted onto a ternary phase diagram TBS-water-ethanol. In all experiments, at all temperatures, only anhydrate B remained in the slurry after stirring for 5 days previously. This is thus the single thermodynamically stable crystal modification under these conditions. In the phase diagram, area I describes where the solution is not saturated, and the lines separating areas I and II are the solubility curves, at the respective temperatures. Area II defines the existence of anhydrate B, in equilibrium with a saturated solution, the composition of which is described by the respective solubility curves. Although it is the thermodynamically stable modification in all compositions, and at all investigated temperatures, anhydrate B did not always crystallize when the saturated solutions of water and ethanol were left to evaporate to dryness at room temperature (see Table 2). The data contained in Table 2 have been plotted into a “kinetic” phase diagram in Figure 2. It is obvious that, at low temperatures, high water contents favor the formation of the higher hydrate, whereas low water contents favor the formation of glass. By raising the initial temperature, anhydrate B is more likely to crystallize in the whole concentration range, except for the possible appearance of the monohydrate in the mid concentration range. The data in Figure 2 were utilized for growing large single crystals of the higher hydrate and the monohydrate. Practically all evaporative crystallizations at room temperature in the range of 10–30 weight % ethanol yielded the higher hydrate, whereas all nonseeded crystallizations at 50–60 °C in the 40–60 weight % ethanol range gave mixtures of anhydrate B and the monohydrate. To improve the yield of the monohydrate, seeds of amorphous, anhydrous TBS were added. This led to 100% yield of the monohydrate. 3.2. Crystal Structure of Anhydrate B. The two published structures9,11 ZIVKAQ and ZIVKAQ01 are essentially the same (Table 1). Since neither of the corresponding papers contains a description of the crystal structure, we include it here. In the discussion below we refer to the ZIVKAQ structure, since it has a significantly lower R-value. TBS is a chiral molecule, with an asymmetric center at the central sp3-hybridized carbon atom, C7. The crystal structure of anhydrate B is centrosymmetric (molecules with both handedness are therefore present) with an asymmetric unit
Polymorphs and Solvates of Terbutaline Sulfate
Crystal Growth & Design, Vol. 8, No. 1, 2008 83
Table 2. Identity of Solid Phases Obtained from Evaporation of Saturated Solutions from the TBS-Water-Ethanol Ternary Phase Diagram Experimentsa
a
composition ethanol/water/%w/w
T ) 4 °C
T ) 22 °C
T ) 50 °C
80:20 70:30 60:40 50:50 40:60 30:70 20:80 10:90 0:100
glass glass glass higher hydrate glass higher hydrate higher hydrate higher hydrate anhydrate B
glass glass anhydrate B anhydrate B anhydrate B higher hydrate higher hydrate higher hydrate anhydrate B
anhydrate B anhydrate B anhydrate B anhydrate B anhydrate B and monohydrate anhydrate B and higher hydrate anhydrate B and higher hydrate higher hydrate higher hydrate
For samples 100:0, 95:5, and 90:10 there was not enough for analysis.
Figure 2. Plot of temperature versus solvent composition, with approximate areas showing which crystal modification is likely to be obtained by evaporative crystallization from mixtures of water and ethanol. Since all crystal modifications except anhydrate B are metastable, the dotted lines should be regarded as indicating the kinetically favored modifications.
consisting of two terbutaline cations and one sulfate anion. The basic unit in the crystal structure is an inversion-related terbutaline ion dimer (Figure 3), with hydrogen bonds between the central amine and alcohol groups (N · · · O ) 2.876 Å). The dimer is further hydrogen bonded to two terbutaline ions (O · · · O ) 2.798 and 2.914 Å) and two sulfate ions (Figure 3). The sulfate group is hydrogen bonded to one of the terbutaline ions in the dimer, utilizing the central amine and alcohol groups (N · · · O ) 2.799 and O · · · O ) 2.658 Å), and to the other terbutaline ion, utilizing one of the aromatic ring alcohols (O · · · O ) 2.639 Å). Each of the two symmetry-related sulfate ions then further hydrogen bonds to three more terbutaline ions, so that the sulfate ions are each surrounded by five terbutaline ions, accepting a total of six hydrogen bonds (3 N-H · · · O plus 3 O-H · · · O). Each of the two terbutaline ions donates five and accepts two hydrogen bonds. In the crystal structure, a total of 11 different hydrogen bonds are formed, with 100% donor utilization and only two potential acceptor atoms not being utilized. The hydrogen bonding occurs mainly in a sheet parallel to the bc-plane at a ) ½ (see Figure 4). Half way between such sheets there is a hydrogen bond cross-linking to a threedimensional (3D), hydrogen-bonded structure, by the hydrogen bonds O1 · · · O8 and O6 · · · O10, and weak pi-stacking in pairs of all the aromatic rings, whose orientations are nearly parallel (the angle between planes is approximately 10°). 3.3. Crystal Structure of the Acetic Acid Solvate. The published structure10 ZIYXAG only contains data but no discussion. Therefore, a structural description is supplied here.
This crystal structure is centrosymmetric, containing molecules of both handedness, and the asymmetric unit consists of two terbutaline cations, one sulfate anion, and two acetic acid molecules. As in anhydrate B, there are hydrogen-bonded terbutaline ion dimers, but, in contrast, they are not symmetry related, and consequently there are two different N · · · O bonds with distances 2.914 and 2.947 Å, respectively. In a similar way to anhydrate B, the terbutaline dimer connects to two sulfate ions. Each sulfate is linked to one terbutaline ion via double hydrogen bonds to the central groups (N · · · O ) 2.888 and 2.840 Å and O · · · O ) 2.695 and 2.726 Å) and to the other via a single hydrogen bond (O · · · O ) 2.670 and 2.686 Å). The unit thus formed is almost identical to the corresponding unit in anhydrate B, but it lacks an inversion center (Figure 3b). Additionally, each sulfate ion accepts two hydrogen bonds, from one acetic acid molecule (this is thus a bifurcated bond from the acetic acid OH-groups with O · · · O ) 2.892 and 2.972 Å), and three more hydrogen bonds, from two terbutaline ions. Altogether the sulfate ion is surrounded by four terbutaline ions and one acetic acid molecule, accepting a total of eight hydrogen bonds (2 N-H · · · O plus 6 O-H · · · O). Each of the two terbutaline ions donates five and accepts two hydrogen bonds. One of the two acetic acid molecules accepts one hydrogen bond (from a terbutaline ion) and donates two hydrogen bonds, whereas the other only donates one hydrogen bond (to a terbutaline ion), but accepts none. It should be noted that the hydrogen on this acetic acid molecule has been positioned on the wrong oxygen atom in the published structure, thereby indicating that it does not donate a hydrogen bond. However, a O4 · · · O8 distance of 2.921 Å to a neighboring terbutaline ion, which already has donated its hydrogen to a sulfate ion, shows the presence of a hydrogen bond. A total of 14 hydrogen bonds are formed, with 100% donor utilization and only one potential acceptor atom (in the second acetic acid molecule) not being utilized. As a result of the hydrogen bonding, hydrophilic sheets are formed parallel to the ab-plane at c ) 0.25 and 0.75. Between them, hydrophobic sheets are formed at c ) 0.5, by interactions mainly involving tert-butyl groups, methyl groups from one of the two acetic acid molecules, and the aromatic rings (Figure 5). It should be noted that the aromatic rings do not orient in a parallel fashion as in anhydrate B. 3.4. Crystal Structure of the Monohydrate. The crystal structure of the monohydrate has not been determined previj with a complete ously. We find it has space group P1, di-terbutaline monosulfate monohydrate formula unit in the asymmetric unit (see Table 1), as determined earlier by our NMR measurements. The basic structural unit is the same terbutaline ion dimer, with two sulfate ions, as in anhydrate B and in the acetic acid solvate. In a similar fashion to anhydrate B (see Figure 3), this unit is formed around an inversion center. The dimer N · · · O hydrogen bond distance is 2.929 Å, and the
84
Crystal Growth & Design, Vol. 8, No. 1, 2008
Harris et al.
Figure 3. Left: The hydrogen-bonded molecules that surround the terbutaline ion dimers in TBS anhydrate B. N-H · · · O hydrogen bonds are indicated as blue and O-H · · · O hydrogen bonds are indicated as red. Right: The hydrogen-bonded dimer of the acetic acid solvate, which is almost identical with those in anhydrate B and in the monohydrate.
Figure 4. The crystal structure of anhydrate B shown viewed along the bc-diagonal (the a-axis points vertically downward). Note the hydrogen-bonded, hydrophilic sheet parallel to the bc-plane (the middle horizontal section of the figure, incorporating all the sulfate ions). Also note the cross-linking of these sheets to a 3D structure and the pairwise pi-stacking of nearly parallel aromatic rings in the hydrophobic planes parallel to the bc-plane (above and below the hydrophilic plane).
hydrogen-bond distances between the sulfate ion and the terbutaline ions are N · · · O ) 2.765 Å, O · · · O ) 2.758 Å, and O · · · O ) 2.702 Å. As a result of further hydrogen bonding, two-dimensional, hydrophilic sheets are formed, which crosslink, by one hydrogen bond, O · · · O ) 2.777 Å (Figure 6), to form a 3D structure. The tert-butyl groups are van der Waalspacked perpendicular to the sheets. There is no obvious pi-stacking, and the aromatic rings take two orientations in the structure, with an angle of 64° between them (Figure 6). The water molecules are embedded in the hydrophilic sheet where they are hydrogen bonded to three terbutaline ions, thereby donating two hydrogen bonds, O(W) · · · O ) 2.838 and 2.783 and accepting one O · · · O(W) ) 2.659 Å. One of the two independent terbutaline ions donates five hydrogen bonds and accepts two, while the other donates five and accepts three. The sulfate ion accepts seven hydrogen bonds from five terbutaline ions. In the crystal structure the hydrogen-bond donor utilization is 100% and only one acceptor atom remains not utilized (in the second terbutaline ion).
Figure 5. The crystal structure of the acetic acid solvate viewed along the a-axis (b is horizontal and c is vertical). Note the hydrogen-bonded sheet parallel to the ab-plane and cutting the c-axis at c ) 1/4 and 3/4 and also the van der Waals packing of these sheets in a hydrophobic layer at c ) ½. One of the acetic acid molecules (green with red oxygen atoms) resides in the hydrogen-bonded sheet and the other orients its methyl group into the hydrophobic layer. The two orientations of the aromatic rings are easily seen.
3.5. Crystal Structure of the Higher Hydrate. For the higher hydrate, we have redetermined the structure at 120 K, with the aim of clarifying the disordered nature of the system. The structure we have determined (see Table 1) is close to that in the CSD8 as BECVI0, but there are some significant differences. We also find substantial disorder, which renders satisfactory refinement difficult; the structure was therefore modeled using a number of constraints. This disorder is of three types. First, two of the oxygen atoms of the sulfate group are disordered (over two positions, each with 50% occupancies). This is understandable in that the hydrogen-bonding network is essentially retained for both the sulfate positions. Second, one of the three water sites in our crystal is only 50% occupied, so the system is a 2.5 hydrate, an apparent difference from the earlier work. Finally, we also find that both the independent C7 hydroxyl groups are disordered, over two positions. The occupancies appear to be 80:20 in one case and 60:40 in the other, but some of the atomic positions are unsatisfactory. These disorders involve the chirality of the molecules, though a center of symmetry relates the four molecules in the unit cell in pairs
Polymorphs and Solvates of Terbutaline Sulfate
Figure 6. The crystal structure of TBS monohydrate. Note the hydrogen-bonded sheets (hydrogen bonds in the sheet are blue) and the cross-linked O-H · · · O hydrogen bond (red). Also, note the tertbutyl groups, van der Waals packed perpendicular to the sheets.
Crystal Growth & Design, Vol. 8, No. 1, 2008 85
Figure 8. The crystal structure of TBS higher hydrate viewed along the a-axis with the b-axis horizontal and the c-axis pointing up towards the right. Note that the hydrogen-bonded chain stretches diagonally from upper right to lower left (the direction of the c-axis). This chain is hydrogen bonded to a hydrophilic sheet, parallel to the ac-plane. All water molecules reside in this sheet and the tert-butyl groups orient perpendicular to it. Alternative positions with low occupancy factors are indicated as small red spheres.
Figure 7. An idealized view of the asymmetric unit for the higher hydrate of terbutaline sulfate. For reasons of clarity, no disorder is shown.
so that the two chiral forms are always equally present in the unit cell. An attempt at the refinement of the structure in the noncentrosymmetric space group P1 produced the same disorder. Figure 7 shows an idealized asymmetric unit free of disorder. It appears that there are no direct hydrogen bonds involving the C7 hydroxyl groups between different TBS ions, so that the chirality of the ions does not significantly influence interactions between unit cells. Therefore, the energy differences between the disordered situations are small, thus accounting for the disorder. In addition, it is possible that there is some mobility of the hydroxyl hydrogen atoms. The new crystal structure is placed in the CSD. There is no mention of any of the three water sites in the structure given as BECVI0 being less than fully occupied, although the atomic displacement parameters of one of the water oxygen atoms in this structure looks higher than those of the others. Our data imply that water is readily lost while the structure is retained. Whether the 2.5 hydrate is a well-defined composition is open to discussion. In contrast to the other three crystal structures, the higher hydrate does not contain any hydrogen-bonded terbutaline ion dimers. The only intermolecular hydrogen bonding between terbutaline ions in the higher hydrate links the two independent molecules in pairs, via the aromatic hydroxyl groups, in each molecule (O · · · O ) 2.700 Å). These terbutaline ions are further oriented head-to-tail to other terbutaline ions aligning them all along the a-axis. They also position around the inversion center at (0, ½, ½), where they form pi-stacked pairs. The terbutaline
Figure 9. Experimental XRPD diffractograms of, from the bottom up, TBS acetic acid solvate, anhydrate A and anhydrate B.
ions are linked, by hydrogen bonding, to a chain, formed along the c-axis, by hydrogen-bonded sulfate ions and water molecules (N · · · O ) 2.727*, 2.789*, 2.822 and O · · · O ) 2.735, 2.788*, 2.707*, 2.793*, 2.679* Å, where starred values indicate bonding to partially occupied positions). The terbutaline ions cross-link such chains to a hydrophilic, hydrogen-bonded sheet, parallel to the ac-plane (Figure 8). It should be noted that all terbutaline ions have their aromatic groups oriented almost parallel to the sheet (that is, to the ac-plane). In the b-direction, the hydrophilic sheets are packed with the tert-butyl groups facing aromatic rings in weak C-H · · · pi contacts. The donor/acceptor situation is a bit unclear because of the disorder. Probably, each of the two terbutaline ions in the asymmetric unit donates five hydrogen bonds and accepts two, and the sulfate ions probably accept six hydrogen bonds. One of the water molecules, O1W with full occupancy, is linked to one sulfate ion and at least two terbutaline ions, by donating two (O · · · O ) 2.853 and 2.840 Å) and accepting one (O · · · O ) 2.866 Å) hydrogen bond. The second water molecule with full occupancy, OW2, donates both its hydrogens to partly occupied oxygens of sulfate ions (O · · · O ) 2.859 and 2.861 Å) and accepts one hydrogen bond from a terbutaline ion (O · · · O ) 2.719 Å). It also accepts one hydrogen bond from
86
Crystal Growth & Design, Vol. 8, No. 1, 2008
Harris et al.
Figure 10. Experimental XRPD diffractograms of TBS monohydrate (bottom) and TBS higher hydrate (top).
Figure 11. TGA weight losses for the monohydrate (middle line), the higher hydrate (bottom line) and the acetic acid solvate (black) of terbutaline sulfate.
Figure 12. DSC thermographs for terbutaline sulfate modifications: the monohydrate (line 1), the higher hydrate (line 2), and the acetic acid solvate (line 3). For reasons of clarity, data above 250 °C have been omitted.
the partly occupied water molecule (O · · · O ) 2.590 Å). The partly occupied water molecule, OW3, possibly also accepts a hydrogen bond from a terbutaline ion amine group (N · · · O ) 2.823 Å). It may be assumed that the partly occupied water molecule OW3 is the one that is lost at low temperature (see Figures 11 and 12). Most probably, OW2 is also lost at low temperature, while OW1, which forms bonds only to fully occupied atoms, is lost at higher temperature. All potential donors, except for one hydrogen on the partially occupied water molecule, seem to be utilized in hydrogen bonding. 3.6. Powder XRD Information. XRPD diffractograms for anhydrates A and B and for the acetic acid solvate are shown in Figure 9. Those for anhydrate B and the acetic acid solvate agree with simulated diffractograms from the crystal structures. It should be noted that the diffraction peaks for modification A are slightly broadened and that the background level is somewhat enhanced. This is consistent with the fact that anhydrate A is a residual after desolvation of the acetic acid
Figure 13. Carbon-13 CP and dipolar dephased spectra of TBS modification B, obtained at 50 MHz.
solvate, a process that gives rise to a small crystallite size and possibly also some glassy material and/or structural disorder. Figure 10 illustrates the experimental diffractograms for the two hydrates of TBS, which provide fingerprints for the modifications. We have also simulated the patterns (not shown) from the crystal structure determinations. The agreements between experimental and simulated patterns are good, though not perfect, and they suffice to show that the single crystals studied are representative of the bulk samples. 3.7. Thermal Measurements. TGA was used both to measure weight losses for the solvated modifications and to confirm the anhydrous nature of anhydrates A and B. These lost
