Structural Determination of a Novel Polymorph of Sulfathiazole–Oxalic

Jul 25, 2014 - Synopsis. Two polymorphs of sulfathiazole and oxalic acid complexes prepared by different dry cogrinding methods, rod-milling and ball-...
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Structural Determination of a Novel Polymorph of Sulfathiazole− Oxalic Acid Complex in Powder Form by Solid-State NMR Spectroscopy on the Basis of Crystallographic Structure of Another Polymorph Ryuta Koike,† Kenjirou Higashi,† Nan Liu,† Waree Limwikrant,†,‡ Keiji Yamamoto,† and Kunikazu Moribe*,† †

Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan Department of Manufacturing Pharmacy, Faculty of Pharmacy, Mahidol University, 447 Sri Ayudhya Road, Ratchatewi, Bangkok 10400, Thailand

‡

S Supporting Information *

ABSTRACT: Two polymorphic forms of a sulfathiazole (STZ):oxalic acid (OXA) 1:1 complex were successfully prepared by different cogrinding methods and characterized by multiple analytical techniques. Rod-milled and ball-milled ground mixtures had different powder X-ray diffraction patterns, showing polymorph formation of the STZ-OXA complex (complex A and complex B). The heat of fusion from differential scanning calorimetry curves and terahertz timedomain spectra helped differentiating the polymorphs. According to infrared spectra, 13C NMR chemical shifts, and the relative intensities of 15N NMR peaks, both polymorphs were salts where the proton of a −COOH group in OXA was transferred to a −NH2 group in STZ. High-resolution 1H NMR and 1H−13C heteronuclear correlation NMR spectra indicated that complex B in powder form had a cocrystal type structure compared to complex A having a clathrate-type structure. Complex B structure suggested by solid-state NMR coincided well with the experimentally determined one, which was formed from three layers of thiazole rings, benzene rings, and OXAs, by using single-crystal X-ray diffraction (SC-XRD) measurement. Advanced solid-state NMR spectroscopy measurements was useful to elucidate the structure of a polymorph, for which SC-XRD data are not available, by referring to the SC-XRD data of another polymorph.

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INTRODUCTION High-throughput screening efficiently provides many novel candidates for active pharmaceutical ingredients (APIs) in a short time period.1−3 However, most of these API candidates have undesirable physicochemical properties such as poor water-solubility or low stability for producing a solid oral formulation.4 To improve the physicochemical properties, a preparation of a multicomponent complex with additives has been performed in the preformulation stage. Salts, cocrystals, solvates, and cyclodextrin inclusion complexes have so far been generally accepted as crystalline multicomponent complexes.5−11 A lot of methods such as solvent evaporation and dry/wet cogrinding methods have been utilized to prepare multicomponent complexes.12,13 In the preparation processes, polymorphs of the complexes have often been found using different solution/solvent media or different preparation methods.14−21 For example, pterostilbene-caffeine cocrystal polymorphs are obtained by dry cogrinding and vapor diffusion methods.22 Undesirable polymorphic forms of complexes may be formed during all stages of the development and formulation manufacture. Development of analytical methods for pharma© XXXX American Chemical Society

ceutical multicomponent complexes is essential for the efficient design of formulations and quality control. Single-crystal X-ray diffraction (SC-XRD) measurement is generally used to determine a drug structure because it provides the full three-dimensional conformation at the atomic level.23 However, it is typically difficult to prepare a pure single crystal of a multicomponent complex compared to a single component drug. Furthermore, only a powder sample is obtained when the cogrinding method is applied. In such cases, alternative analytical methods must be applied for powder samples, such as powder X-ray diffraction (PXRD), thermal analysis, and infrared (IR) spectroscopy. Asma et al. characterized carbamazepine-nicotinamide cocrystal polymorphs using rapid heating differential scanning calorimetry (DSC) and PXRD measurements.24 Recently, nuclear quadrupole resonance, Xray photoelectron spectroscopy, and other techniques have emerged that can evaluate the molecular states of multiReceived: April 26, 2014 Revised: July 7, 2014

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component complexes.25,26 The use of terahertz time-domain spectroscopy (THz-TDs) using a THz pulse with a weaker vibration than that of a mid-infrared wave has spread as laser technology has developed. THz-TDs detects weak molecular interactions and lattice vibrations.27,28 A weak interaction between ofloxacin and oxalic acid (OXA), which is difficult to characterize with IR spectroscopy, was detected in a complex by THz-TDs.29 Solid-state NMR, which observes the chemical environment of the atomic nucleus, is a powerful analytical technique for investigating multicomponent complexes. There are a number of reports in which complex formation and the molecular state are evaluated by one-dimensional (1D) solidstate NMR spectroscopy. Recently, two-dimensional (2D) solid-state NMR techniques have been used to directly investigate intermolecular interactions between drugs and the counter former.30,31 Interaction sites in the complexes are identified by the pulse sequences of 2D 1H−13C heteronuclear correlation (HETCOR) and 14N−1H heteronuclear multiplequantum coherence (HMQC).32−34 Garro et al. characterized two polymorphic forms of a ciprofloxacin-saccharinate complex by multinuclear solid-state NMR investigation, which included 1D 1H and 15N spectroscopies as well as 2D 1H−13C HETCOR and 1H−1H double quantum correlation spectroscopies.35 Sulfathiazole (STZ) is an antimicrobial agent used as a shortacting sulfa drug. The extreme polymorphism of STZ has been the subject of investigations in pharmaceutical sciences for over 70 years.36 A large number of polymorphs, hydrates, solvates, salts, and cocrystals have been reported thus far.37 Over 100 solvates of STZ were reported by Bingham et al.38 Five STZ polymorphs were evaluated by 13C solid-state NMR, DSC, THz, and single-crystal neutron diffraction measurements.36,39,40 Despite numerous reports, full characterization of the STZ polymorphs is still not easy because of their structural flexibility.37,41 OXA, a dicarboxylic acid, is often used in preformulation studies as a screening candidate for counter formers of multicomponent complexes.29,42,43 Recently, Hu et al. prepared a STZ/OXA 1:1 complex via a cogrinding method, and the structure was determined by SC-XRD measurement.44 Furthermore, it was reported that another complex is produced by the cogrinding of STZ with OXA dihydrate, but its composition and structure have not been established.44 In this study, we prepared two polymorphs of a STZ-OXA complex by different cogrinding methods. The characterization was carried out with several analytical methods including PXRD, DSC, IR, THz-TDs, solid-state NMR, and SC-XRD measurements to determine the structure of the STZ-OXA polymorphs in detail.

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Figure 1. Chemical structures of (a) sulfathiazole (STZ) and (b) oxalic acid (OXA). The alphabets, numbers, and Greek alphabets represent the nucleus corresponding to H, C, and N, respectively. Analytical Techniques. Powder X-ray Diffraction (PXRD). Powder X-ray diffraction patterns were obtained using a Rigaku Miniflex II diffractometer with CuKα radiation (Japan) at an ambient temperature using a scanning speed of 4 deg/min between a 2θ range of 3−40°. Water Content Determination. Water content was determined by a Karl Fischer method using a MKC-500 (Kyoto Electronics Manufacturing, Japan) moisture titrator. Differential Scanning Calorimetry. DSC measurements were performed on a Seiko Instruments EXSTAR6000 DSC 6200 (Japan). Operating conditions were as follows: sample weight, 5 mg; heating rate, 10 °C/min; pan, open-aluminum pan; and nitrogen gas flow rate, 100 mL/min. Terahertz Time-Domain Spectroscopy (THz-TDs). Terahertz timedomain spectra were acquired using a Tochigi Nikon Rayfact SpecTera (Japan) with a transmission method. The 10 mg of sample and 90 mg of polyethylene were thoroughly mixed and then manually pressed in a mold to form a measuring tablet with a diameter of 13 mm and thickness of ∼1 mm. Polyethylene is a good diluent for measuring the spectra of APIs because it is featureless and relatively transparent in the range below 100 cm−1. The measurement covered the range of 0.1−3 THz with a resolution of 0.024 THz (0.792 cm−1). Infrared (IR) Spectroscopy. Infrared measurements were performed by transmission method using a KBr disk. IR spectra were recorded using a Bruker FT-IR ALPHA spectrophotometer (Germany) in the range of 400−4000 cm−1. All spectra were the result of averaging 32 scans, and the resolution was 4.0 cm−1. Solid-State NMR Spectroscopy. All solid-state NMR spectra were recorded using a JEOL Resonance ECA600 NMR spectrometer (Japan), which has a magnetic field of 14.09 T and operates at 600 MHz for 1H, 150 MHz for 13C, and 60 MHz for 15N. Powder samples (∼100 mg) were filled into 4 mm silicon nitride (Si3N4) rotors. 13C and 15N spectra were acquired using variable amplitude crosspolarization (CP) together with magic angle spinning (MAS) at 15 kHz and a high power two-pulse phase-modulation 1H decoupling. 1H spectra were acquired at 9.5 kHz using a windowed phase modulated Lee−Goldburg 3 (wPMLG3), which is a kind of combined rotation and multiple-pulse spectroscopy (CRAMPS) method. 1H−13C heteronuclear correlation (HETCOR) spectra were acquired using a Lee−Goldburg CP (LGCP) at 9.5 and 13.5 kHz. The total scans for each sample depended on the required signal-to-noise ratio. Pertinent acquisition parameters included a CP contact time of 5 ms, a 1H 90° pulse of 2.7 μs, and relaxation delays of 300 s for STZ, 1200 s for OXA, 10 s for complex A, and 5 s for complex B. 13C chemical shifts were externally referenced to tetramethylsilane by setting the methine peak of hexamethylbenzene to 17.3 ppm. 15N chemical shifts were externally referenced to nitromethane at 0.00 ppm using 15N-labeled glycine and setting its resonance to −346.4 ppm. 1H chemical shifts were externally referenced to tetramethylsilane at 0.00 ppm using a silicone rubber setting with a resonance at 0.12 ppm.

EXPERIMENTAL SECTION

Materials. STZ and OXA were purchased from Alfa Aesar (U.S.A) and Wako Pure Chemical Industries (Japan), respectively. The chemical structures are shown in Figure 1 with the alphabets, numbers, and Greek alphabets for the 1H, 13C, and 15N NMR peak assignments, respectively. Polyethylene with ultrahigh molecular weight and surface-modified particles 53−75 μm in diameter was obtained from Sigma-Aldrich (U.S.A) for THz-TDs measurement. Methods. Preparation of Two Ground Mixtures. The physical mixture (PM) of STZ and OXA was prepared at a 1:1 molar ratio by mixing in a vortex mixer for 3 min. The PM was ground by a CMTT1-200 vibrational rod mill (Japan) for 60 min to prepare a rod-milled ground mixture, GM-R. The PM was ground by a Retsch PM100 planetary ball mill (Germany) for 180 min at a frequency of 5 Hz to prepare the ball-milled ground mixture, GM-B. A 50 mL stainless steel container and 10 stainless steel balls 10 mm in diameter were used as the ball-milling apparatus. B

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Single-Crystal X-ray Diffraction. A 25.5 mg (0.1 mmol) sample of STZ and 45.0 mg (0.5 mmol) sample of OXA were dissolved in 25 mL of acetonitrile and left to evaporate slowly at 40 °C. The resulting solid was filtered and washed with acetonitrile. The crystal formed was cut until it was a suitable size for SC-XRD measurement. The measurements were performed on a Rigaku R-AXIS RAPID diffractometer (Japan) using MoKα radiation (λ = 0.71075 Å) at 60 kV and 90 mA. The data were collected at a temperature of 23 °C to a maximum 2θ value of 55.5°. A total of 44 oscillation images were collected. All of the crystal structures were solved by direct methods with SHELXS-97 and refined with full-matrix least-squares SHELXL97.45 All non-hydrogen atoms were refined anisotropically and hydrogen atoms were included at their calculated positions.

observed. The diffraction peaks in STZ/OXA 1:1 GM-B (Figure 2i) were different from those in the PM and GM-R, demonstrating complex formation with another form. The diffraction pattern of GM-R corresponded with the pattern of a STZ/OXA 1:1 salt.44 On the other hand, GM-B showed a similar pattern to that of the coground mixture of STZ with OXA dihydrate, whose composition and structure are not known.44 GM samples at a molar ratio of STZ/OXA 2:1 showed diffraction peaks of the new complexes in addition to peaks corresponding to the excess amount of STZ (Figures 2e, h). Meanwhile, the complex peaks and OXA dihydrate peaks (Supporting Information Figure S1a) were observed in STZ/ OXA 1:2 GM-R and GM-B (Figures 2g, j).46 OXA dihydrate was formed by grinding an OXA crystal under the same preparation conditions (Figure 2d), and it likely formed because of water adsorption from the atmosphere. The excess OXA that did not form a complex with STZ could transform into OXA dihydrate during the cogrinding process. The water contents of STZ/OXA 1:1 GM-R and GM-B were determined to be below 1.0% by the Karl Fischer method, indicating that both GMs were not hydrates. STZ/OXA 1:1 GM-R and GM-B are represented as complex A and complex B, respectively, in the following description. These PXRD experiments demonstrated that two polymorphic forms of STZ/OXA 1:1 complexes were prepared by different cogrinding methods. The force/heat in the grinding process with a vibrational rod mill is higher than with a ball mill, inducing the polymorph formation. We also reported the polymorph formation of carbamazepine-malonic acid cocrystals using a vibrational rod mill and ball mill, and we discussed the formation mechanism of cocrystal polymorphs.14 Hu et al., also reported that the cogrinding of STZ with OXA and OXA dihydrate produce different polymorphs of STX-OXA complex.44 It is noteworthy that polymorphs of the multicomponent complex are possibly formed according to subtle changes on experimental condition including grinding condition, water content, and molecular states of starting material, such as polymorph form. Differential Scanning Calorimetry. The DSC curves of the STZ-OXA system are shown in Figure 3. STZ crystals had endothermic peaks at 163 °C (Figure 3a) for the polymorph transformation from form IV to form I and at 201 °C for the melting of form I.37,47 OXA showed a melting endothermic peak at 149 °C (Figure 3b). In the curves of complex A (Figure 3c) and complex B (Figure 3d), the melting peaks of STZ and OXA crystals completely disappear, and new characteristic thermal peaks for the melting of the complexes were observed at 180 and 181 °C, respectively. The melting temperatures were almost the same for the polymorphs, but their heats of fusion (ΔH) were different (complex A, 173.0 ± 0.6 J/g; complex B, 213.3 ± 1.7 J/g; mean ± S.D, n=3). These results indicated that complex A and complex B were thermodynamically metastable and stable forms, respectively. A simultaneous PXRD-DSC measurement was carried out to confirm there was no polymorphic transition of these polymorphs during the increasing temperature (Supporting Information Figure S2). No change in the crystal structure was observed until the melting point for both diffraction patterns of complex A and complex B. Terahertz Time-Domain Spectroscopy. The molecular vibration of STZ-OXA polymorphs was evaluated by THz-TDs measurement in the range of 0.1−3.0 THz (Figure 4). The peaks of the STZ crystal were observed at 1.00, 1.15, and 1.88

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RESULTS AND DISCUSSION Powder X-ray Diffraction. Figure 2 shows the changes in the PXRD patterns of STZ-OXA complexes. The diffraction

Figure 2. Powder X-ray diffraction (PXRD) patterns of (a) STZ, (b) OXA, (c) STZ/OXA 1:1 physical mixture (PM), (d) OXA dihydrate, (e) STZ/OXA 2:1 rod-milled ground mixture (GM-R), (f) STZ/OXA 1:1 GM-R, (g) STZ/OXA 1:2 GM-R, (h) STZ/OXA 2:1 ball-milled ground mixture (GM-B), (i) STZ/OXA 1:1 GM-B, and (j) STZ/OXA 1:2 GM-B. ●, STZ; ▲, OXA; □, complex A; ◊, complex B; ▼, OXA dihydrate.

pattern of STZ (Figure 2a) was corresponded to that of reported STZ with form IV.37,41 The diffraction pattern of the PM (Figure 2c) shows both the characteristic peaks of STZ and OXA crystals (Figure 2b). In the diffraction pattern of STZ/ OXA 1:1 GM-R (Figure 2f), the peaks of STZ and OXA disappeared, and new peaks exhibiting complex formation were C

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Infrared Spectroscopy. The IR spectra were obtained to evaluate the molecular states of the two polymorphs of the STZ-OXA complex (Figure 5). STZ showed a peak

Figure 3. Differential scanning calorimetry (DSC) curves of (a) STZ, (b) OXA, (c) complex A, and (d) complex B. The numbers close to a peak represent the onset temperature. Heats of fusion (ΔH) of complex A and complex B were 173.0 ± 0 0.6 and 213.3 ± 1.7 J/g, (mean ± SD (n = 3)), respectively.

Figure 5. Infrared spectra of (a) STZ, (b) OXA, (c) complex A, and (d) complex B.

corresponding to −NH− stretching at 3320 cm−1 (Figure 5a).37 This peak shifted to a higher wavenumber, 3167 and 3241 cm−1, in the spectra of complexes A and B, respectively. The spectrum of the OXA crystal (Figure 5b) showed a −CO− stretching peak at 1687 cm−1.29 This −CO− peak of OXA was divided into two peaks at 1659 and 1745 cm−1 in the spectrum of complex A, and at 1657 and 1719 cm−1 in the spectrum of complex B. Two −CO− carbons of OXA in different states existed in the complexes. The STZ crystal has two intermolecular hydrogen bonds between (1) −SO2− and −NH2 groups and (2) −NH2 and −NH− groups.49 The OXA molecule also forms an intermolecular hydrogen bond with another OXA molecule between the −COOH groups in the crystal structure.50 The significant IR peak shifts could be caused by breaking the intermolecular hydrogen bonds in the STZ and OXA crystals. New intermolecular interactions could form between a −NH2 group of STZ and a −COOH group of OXA because of the complex formation. The two −COOH peaks of OXA in both complex A and complex B suggest that one −COOH group interacted with the −NH2 group of STZ, while the other −COOH group maintained its intermolecular hydrogen bond between −COOH groups with another OXA molecule. Changes in the IR peak from complex formation were similar between complex A and complex B, but the degrees of the peak shifts were different. The strength of the intermolecular interaction between a -NH2 group of STZ and a −COOH group of OXA could vary between the polymorphs. 2-Dimentional 1H−13C NMR Spectroscopy for Peak Assignment. Multinuclear solid-state NMR measurements for 1 H, 13C, and 15N nuclei were performed to investigate the molecular states of STZ-OXA polymorphs in detail. 1H−13C HETCOR NMR measurements were performed to identify the 1 H and 13C peaks in the spectra of complex A and complex B. The reported 13C CP/MAS NMR spectrum of the STZ crystal and liquid state 1H spectrum of STZ in dimethyl sulfoxide-d6 were used to support the peak assignment.39,51 1H−13C HETCOR spectra of complex A and complex B with different contact times of 0.1 and 5 ms are shown in Figure 6. The 1 H−13C HETCOR spectrum with a short contact time allows for the detection of spin diffusion between atoms bound with covalent bonding.34 According to the 1H−13C HETCOR

Figure 4. Terahertz time-domain (THz-TD) spectra of (a) STZ, (b) OXA, (c) complex A, and (d) complex B.

THz, and the spectrum of OXA did not show any characteristic peaks.40,48 Here, it should be mentioned that the THz-TDs spectrum of STZ crystal (form IV) in this study is corresponded to that of form V in the reported article by Zeitler et al.40 This inconsistent is just derived from the different naming manner of the STZ polymorphs. In the spectrum of complex A, the peaks derived from STZ at 1.00 and 1.15 THz disappeared, and a new peak was observed at 1.29 THz. The vibrational modes of STZ and OXA changed because of the formation of complex A. Complex B also exhibited a new peak at 1.59 THz. The difference between the THz spectra of complex A and complex B reflected the difference in the vibrational modes between these polymorphs. There are very few reports that observed changes in the THz spectra with complex formation.27−29 To the best of our knowledge, this is the first time that a difference in the vibration modes between the polymorphs of pharmaceutical multicomponent complexes was detected. THz-TDs can be a useful technique to differentiate polymorphs even in a complicated multicomponent system. D

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Figure 6. 1H−13C heteronuclear correlation (HETCOR) spectra of (a) complex A (contact time = 0.1 ms, rotational speed = 13.5 kHz), (b) complex A (contact time = 5 ms, rotational speed = 13.5 kHz), (c) complex B (contact time = 0.1 ms, rotational speed = 9.5 kHz), and (d) complex B (contact time = 5 ms, rotational speed = 9.5 kHz). Solid and dashed lines represent strong and weak correlations between 1H and 13C, respectively.

spectra using a contact time of 0.1 ms, the peaks of C2, 3, 5, 6, 8, 9 and Hc−i in complexes A and B were identified. The more distant correlations between 1H and 13C were observed in the 1 H−13C HETCOR spectra with a longer contact time.34 The spectra analysis gave a full identification of all the 1H and 13C peaks in complex A and complex B. The intermolecular interactions in the polymorphs suggested by the 1H−13C HETCOR spectra at longer contact times are discussed later. 1 H NMR Spectroscopy. High-resolution 1H NMR spectra acquired using the CRAMPS method and 1H chemical shifts are represented in Figure 7 and Supporting Information Table S1, respectively. The chemical shifts and shapes of the STZ peaks in the polymorph spectra changed compared to those of the STZ and OXA crystals. Furthermore, the molecular states of the polymorphs were considered to be significantly different from each other because the spectra of complexes A and B were different. The difference in the molecular states between the polymorphs could be caused by different intermolecular interactions and conformations, in agreement with the IR results (Figure 5). 13 C NMR Spectroscopy. The 13C CP/MAS NMR spectra and 13C chemical shifts are shown in Figure 8 and Supporting Information Table S2, respectively. The spectrum of STZ crystal (form IV) in this study coincided with that of form V in the article reported by Apperley et al.,39 which is just caused by the different naming manner of the STZ polymorphs.37 The C9 peak in the spectrum of STZ crystal had a small shoulder peak which was derived from a small amount of impurity of other polymorphs (less than 5%).39 The chemical shifts of all the

Figure 7. 1H combined rotation and multiple pulse spectroscopy (CRAMPS) NMR spectra using windowed phase modulated Lee− Goldburg 3 (wPMLG3) method at 9.5 kHz of (a) STZ, (b) OXA, (c) complex A, and (d) complex B.

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Figure 8. 13C cross-polarization/magic angle spinning (CP/MAS) NMR spectra of (a) STZ, (b) OXA, (c) complex A, and (d) complex B.

Figure 9. 15N CP/MAS NMR spectra of (a) STZ, (b) complex A, and (c) complex B.

carbons in the spectra of STZ and OXA crystals varied from those in complex A and complex B. The peak of C1 close to an −NH2 group in STZ shifted significantly upfield from 151.4 ppm in an STZ crystal to 136.7 and 138.6 ppm in complex A and complex B, respectively. The C4 peak near a −SO2− group of STZ also showed a significant downfield shift from 135.2 to 142.6 ppm in complex A and 142.8 ppm in complex B. The 13C chemical shift of a −COOH group in an OXA crystal at 161.0 ppm shifted downfield to 163.3 ppm in complex A, and two chemical shifts of the −COOH group of OXA were observed in complex B at 162.6 and 168.8 ppm. Apperley et al. discussed the NMR charge effect on the amino nitrogen of STZ using the 13 C CP/MAS NMR spectrum of STZ monosulfate hemihydrate.39 The reported chemical shifts of the C1 and C4 peaks in STZ monosulfate hemihydrate were 135.7 and 144.8 ppm, respectively, which were very similar to those in complex A and complex B. This suggested that complex B and complex A were STZ/OXA salts in which a proton transfer occurred from a −COOH group in OXA to an −NH2 group close to C1 in STZ. 15 N NMR Spectroscopy. Figure 9 and Supporting Information Table S3 show the 15N CP/MAS NMR spectra and chemical shifts of the 15N nuclei, respectively. Complex formation of STZ with OXA induced larger changes in the chemical shift of the −NH2 group (>10 ppm) than in the −NH− and −N groups. In addition, the relative 15N peak intensity of the −NH2 group in complex A and complex B was about two or three times higher than those of the −NH- and −N groups. Proton transfer from a −COOH group of OXA to a −NH2 group of STZ both in complex A and complex B could enhance the CP efficacy from the 1H to 15N nucleus, resulting in the higher intensity of a −NH2 group in STZ. There is a lot of literature to discriminate whether a complex of API and the counter former is a salt or cocrystal.8,26,52−56 Proton transfer from the acid to base does not occur in cocrystal formation, unlike salt formation, which is accompanied by a proton transfer.8 The acid ionization constant, pKa, is commonly used to predict an interaction mode in a solid

complex.55 A crystalline acid−base complex usually has a ΔpKa (pKa of base−pKa of acid) of greater than three or less than zero; the salt is likely formed at a large ΔpKa (i.e., greater than two or three) while cocrystal formation occurs at a ΔpKa less than zero.52,57 The few exceptions with ΔpKa between zero and three fall into either the cocrystal or salt categories.52 STZ has two pKa, at 2.0 as a base and at 7.1 as an acid, while the pKa of OXA is 1.3 as an acid.57,58 The STZ/OXA complex at ΔpKa = 0.7 comes in under the exceptions. Hence, it was difficult to tell whether the complex of STZ-OXA is a salt or a cocrystal only by the ΔpKa. The 13C and 15N CP/MAS NMR spectra clearly indicated that both complex A and complex B were in the salt form where a proton of the −COOH group of OXA transferred to the −NH2 group of STZ. Solid-state NMR techniques, even using 1D spectroscopy, work effectively for differentiating salts and cocrystals. 2-Dimensional 1H−13C NMR Spectroscopy for Structural Elucidation of Complex B. The structure of complex A and B were discussed using 1H−13C HETCOR NMR spectra with longer contact times at 5 ms (Figures 6b, d). 1H−13C HETCOR NMR spectra of both complex A and B demonstrated correlation peaks between Ha,b of STZ and C1′,2′ of OXA, indicating intermolecular interaction between the −COOH group of OXA and −NH2 group of STZ. Meanwhile, the polymorphs showed some different correlations in other regions of the spectra. 1H−13C correlations between Hi,h in the thiazole ring and C1−6 of the benzene ring were strong in the spectrum of complex A. By taking the STZ chemical structure into account, this correlation could be derived not from the intramolecular interaction but the intermolecular interaction between the thiazole ring of one STZ and benzene ring of another STZ. This result coincided well with the crystal structure of complex A (Supporting Information Figure S3a).44 In contrast, weak correlations were detected between Hi,h and C1−6 in the spectrum of complex B, indicating that the thiazole ring was distant from the benzene ring. The chemical shifts of the thiazole ring protons (Hh, (i) in the 1H NMR spectrum of complex B (Figure 7d) were quite F

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different from those of complex A (Figure 7c), which supported a different interaction mode between complex A and B around the thiazole ring. Bingham et al. reported that over one hundred STZ solvates were categorized mainly into two type of structures, clathrate and cocrystal types.38 The term cocrystal in the reported article was used as the generic name to describe the complex type of STZ and is different from the so-called “cocrystal” definition.8 In the clathrate type, the host molecule, namely STZ, forms channel, layer, and 3D framework structures, while the guest molecules or counter formers work as the cavity filling with or without additional bonding. On the other hand, the counter former works as an essential part of the 3D structure of the complex in a cocrystal type. The authors also found some salts both in cocrystal and clathrate type complexes where proton transfer occurred between STZ and the counter former. Recently, the tetragonal and monoclinc polymorphs of a STZ:pyridine 1:1 complex, which corresponds to clathrate and cocrystal types, respectively, were reported.59,60 Complex A was classified as a clarthrate-type rather than cocrystal-type based on the crystal structure, and the STZ molecule forms a basic 3D framework with a series of thiazole rings of one STZ directly connected to the benzene ring of another STZ (Supporting Information Figure S3b).44 The C1′,2′ NMR peaks of OXA in complex A were much broader than the STZ carbon peaks in complex A (Figure 8c). The line broadening of OXA carbon peaks could be attributed to a distribution of the chemical shifts, indicating that OXA molecules behaved as the guest in disordered positions in host spaces formed by STZ.61 According to the reported crystal structure and solid-state NMR results, complex A could have a clarthrate type structure. In contrast, the C1′,2′ peaks of OXA in complex B were as sharp as the proton peaks of STZ (Figure 8d) suggesting that OXA molecules were strongly incorporated into the ordered packing of complex B and played an important role in the formation of its 3D framework. From the 2D 1H−13C HETCOR NMR spectrum and line-width of the carbon peak of complex B, it was speculated that complex B could have a cocrystal-type structure where the benzene ring, thiazole ring, and OXA formed a separated layer, respectively. Single-Crystal X-ray Diffraction. SC-XRD measurements were performed to identify the crystal structures of complex B. The molecular structure of complex B from SC-XRD measurement is illustrated in Figure 10. The calculated PXRD pattern from SC-XRD data (Supporting Information Figure S1b) coincided with the experimental one (Figure 2i). The crystal structure of GM-B showed a monoclinic space group P21/c where one STZ and one OXA molecule were included in a unit cell (Table 1). STZ and OXA were connected by three intermolecular interactions via a NH2 ··COOH heterosynthon between STZ and OXA. The details of these three interactions are shown in Supporting Information Table S4. Steiner summarized the correlation of the O···H bond length against N···H or O···N distances.62 The bond lengths of O3′···Hb′ and O4′ ···Ha,b at 1.87−2.26 Å against those of Nα···Ha,b,b′ at 0.89 Å and O3′ 4′···Nα at 2.71−2.98 Å clearly indicated the interaction mode of a NH2 ··COOH heterosynthon as O···H−N rather than O− H···N.62 By comparing the reported atom distances with the experimental ones, it was evident that proton transfer occurred from a −COOH group in OXA to an −NH2 group in STZ via this complex formation. This clearly confirmed that complex B was a salt formed by STZ and OXA. In addition to these interactions between STZ and OXA, one STZ molecule formed

Figure 10. An oak ridge thermal ellipsoid program (ORTEP) view of complex B with the atomic numberings.

Table 1. Crystallographic Data of STZ/OXA 1:1 Complex B STZ/0XA = 1:1 complex B empirical formula formula weight crystal color, habit crystal dimensions crystal system lattice type lattice parameters

space group Z value Dcalc F000 u(MoKa) R1 (l > 2.00s(I)) R (all reflections) wR2 (all reflections) goodness of fit indicator

C11H11N3O6S2 345.34 colorless, block 0.746 × 0.512 × 0.270 mm monoclinic primitive a = 10.6915(6) Å b = 10.5459(5) Å c = 13.2126(6) Å β = 112.410(8)° V = 1377.24(14) Å3 P21/c (No. 14) 4 1.665 g/cm3 712.00 4.212 cm−1 0.0333 0.0349 0.0901 1.255

a hydrogen bond with another STZ molecule via Nγ Hg···O2. Meanwhile, OXA molecules formed a dimeric structure via a homosynthon of −COOH groups. Figure 11 shows the packing diagram of a complex B crystal structure viewed along the baxis. Complex B has a layer structure composed of a series of thiazole rings, benzene rings, and OXA layers. The thiazole ring layer was formed by intermolecular hydrogen bonds between STZ molecules, and the OXA layers were stabilized by the homosynthon of −COOH groups in OXA. The suggested structure of complex B from the 2D solid-state NMR analysis and SC-XRD data of its polymorph complex A was a cocrystal type, which was corresponded well with the structure experimentally determined by SC-XRD measurement. Linck G

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Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors would like to express their sincere gratitude to the National Research Institute of Police Science, Japan, for use of their terahertz spectroscopy equipment. This study was supported in part by a Grant-in Aid from the Ministry of Education, Culture, Sports, Science and Technology (Monbukagakusho) of Japan.

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Figure 11. Packing diagram of the crystal structure of complex B viewed along the b-axis.

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et al. predicted one polymorph structure of a ciprofloxacinsaccharinate complex using multinuclear solid-state NMR measurement based on reported SC-XRD data of an another polymorphic form.35 Evaluation by advanced solid-state NMR spectroscopies based on the SC-XRD data of one polymorph is very useful, even in a complicated multicomponent complex, for extracting the structure of an another polymorph in powder form for which SC-XRD data is not available.

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CONCLUSION Polymorphs of a STZ/OXA complex at a molar ratio of 1:1, complex A and complex B, were successfully prepared by different cogrinding methods and characterized by multiple analytical techniques. Both polymorphs were salts where proton transfer occurred from a −COOH group of OXA to an −NH2 group of STZ. The structure of complex B in powder form was suggested by multiple solid-state NMR measurements and the crystal structure of its polymorph, complex A. The suggested complex B structure by solid-state NMR techniques coincided well with the experimentally determined one by SC-XRD measurement. THz-TDs, as well as the conventional analytical methods of PXRD, DSC, and IR spectroscopy, can be useful to discriminate polymorphs of a multicomponent complex in powder form. Furthermore, a detailed characterization and structural elucidation is possible with the combination of solidstate NMR and SC-XRD techniques. The knowledge in this study can contribute to a greater understanding of pharmaceutical complex polymorphism, which is becoming more prevalent during preformulation and manufacturing processes.

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ASSOCIATED CONTENT

S Supporting Information *

1

H, 13C, and 15N chemical shifts of STZ and OXA in the complexes (Table S1−3), possible intermolecular interactions in complex B (Table S4), powder X-ray diffraction patterns calculated from 3D crystalline structure of OXA dihydrate and complex B (Figure S1), simultaneous PXRD-DSC measurement of complex A and complex B (Figure S2), and the reported crystal structure of complex A (Figure S3). This material is available free of charge via the Internet at http:// pubs.acs.org.

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REFERENCES

AUTHOR INFORMATION

Corresponding Author

*Tel.: +81-43-226-2865. Fax: +81-43-226-2867. E-mail: [email protected]. Author Contributions

R.K. and K.H. contributed equally to this manuscript. H

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