I. INTRODUCTION
Mosapride is a substituted benzamide that is used for its properties of stimulating gastrointestinal motility, helping in the digestion process to clean any residue that may have remained in the esophagus, stomach, and small intestine, without reaching the large intestine (Sweetman, Reference Sweetman2009). This drug is administered orally as the citrate dihydrate salt (Figure 1), but doses are expressed as anhydrous citrate.
Figure 1. Molecular diagram of mosapride dihydrogen citrate dihydrate (Mdcd).
In the Cambridge Structural Database (CSD) version 2024.1.0 (Groom et al., Reference Groom, Bruno, Lightfoot and Ward2016), there are several reports related to mosapride, one of them is the free base (Refcode: ZEHSEK; Morie et al., Reference Morie, Kato, Harada, Yoshida, Fujiwara and Matsumoto1995) and others correspond to anhydrous mosapride citrate and mosapride dihydrogen citrate dihydrate (Mdcd) (Refcodes: LUWQEC and LUWPOL, respectively; Ito et al., Reference Ito, Suzuki and Noguchi2020).
The structure determinations of the citrate salts were carried out at 93 K. A few additional reports of mosapride solvates-hydrates were found (Refcodes: GAWVAF, GAWVEJ, GAWVIN, and GAWVOT; Zhang et al., Reference Zhang, Yang, Yang, Gong, Du and Lu2022). No reports were found in the PDF-5+ 2024 database (Gates-Rector and Blanton, Reference Gates-Rector and Blanton2019) of the International Centre for Diffraction Data (ICDD).
Several studies have been published on Mdcd that include, among other characterization techniques, X-ray powder diffraction carried out at room temperature. They report the improvement of the therapeutic effect of tablets using super disintegrates (Ellakwa et al., Reference Ellakwa, Fahmy and Ellakwa2017), the preparation and characterization of inclusion complexes with the aim of improving the solubility and dissolution rate of Mdcd (Ali and Sayed, Reference Ali and Sayed2013), and the optimization of solid dispersions (Kim et al., Reference Kim, Lee, Lim and Kim2011). In these publications, relatively low-quality unindexed X-ray powder diffraction patterns of Mdcd were reported.
Since no data on Mdcd (C21H26ClFN3O3⋅C6H7O7⋅2H2O, 4-amino-5-chloro-2-ethoxy-N-{[(2RS)-4-(4-fluorobenzyl)morpholin-2-yl]methyl}benzamide monocitrate dihydrate, CAS number 636582-62-2) are reported in the ICDD PDF-5+ database (Gates-Rector and Blanton, Reference Gates-Rector and Blanton2019), the powder diffraction pattern of this pharmaceutical compound has been recorded and analyzed for inclusion in the Powder Diffraction File (PDF) of the ICDD as part of the Grant-in-Aid (GiA) program. This study is part of the research carried out in our laboratories on the identification of pharmaceutical compounds of interest with none or limited structural information reported (Dávila-Miliani et al., Reference Dávila-Miliani, Dugarte-Dugarte, Toro, Contreras, Camargo, Henao, Delgado and de Delgado2020; Dugarte-Dugarte et al., Reference Dugarte-Dugarte, Toro, van de Streek, Henao, de Delgado and Delgado2022, Reference Dugarte-Dugarte, Toro, van de Streek, Henao, Fitch, Dejoie, Delgado and de Delgado2023; Toro et al., Reference Toro, Dugarte-Dugarte, van de Streek, Henao, Delgado and de Delgado2022).
II. EXPERIMENTAL METHODS
A selected specimen of the sample, as provided by Genfar Laboratories, was ground and mounted in a flat sample holder. X-ray powder diffraction data were registered at room temperature on a BRUKER D8 ADVANCE diffractometer with Bragg-Brentano geometry. The pattern was recorded from 4.00° to 70.00° in steps of 0.02035° (2θ) at 1.2 s/step, using Cu Kα radiation, operating at 40 kV and 30 mA and a LynxEye detector.
III. COMPUTATIONAL STUDIES
CrystalExplorer21 software (Spackman et al., Reference Spackman, Turner, McKinnon, Wolff, Grimwood, Jayatilaka and Spackman2021) was used to produce “fingerprint plots” of the intermolecular interactions present in the structure. The d norm parameter mapped onto the Hirshfeld surface (Spackman and Jayatilaka, Reference Spackman and Jayatilaka2009) was calculated to visualize the atoms involved in intermolecular contacts and the strength of such contacts.
IV. RESULTS AND DISCUSSION
The powder pattern recorded has been submitted to the ICDD to be incorporated in the Powder Diffraction File. The indexing of the pattern with DICVOL14 (Louër and Boultif, Reference Louër and Boultif2014) as implemented in the PreDICT graphical user interface (Blanton et al., Reference Blanton, Papoular and Louër2019) using the first 20 peaks produced a monoclinic unit cell. The analysis of all the 80 diffraction maxima registered led to the following unit-cell parameters: a = 18.695(4) Å, b = 9.610(2) Å, c = 18.196(5) Å, β = 114.17(2)°, and V = 2982.6 Å3. The de Wolff (de Wolff, Reference de Wolff1968) and Smith-Snyder (Smith and Snyder, Reference Smith and Snyder1979) figures of merit obtained were M 20 = 15.9 and F 30 = 45.5 (0.0085, 52), respectively. It must be noted that the cell parameters are similar to the values reported by Ito et al. (Reference Ito, Suzuki and Noguchi2020), indicating that the material under study corresponds to Mdcd.
For the data submitted to the PDF, integrated intensities were obtained by Le Bail refinement (Le Bail et al., Reference Le Bail, Duroy and Fourquet1988) using the FULLPROF software (Rodriguez-Carvajal, Reference Rodriguez-Carvajal1990). Weak reflections with I < 0.5% Imax were omitted. The fit led to the following unit-cell parameters: a = 18.707(4) Å, b = 9.6187(1) Å, c = 18.2176(4) Å, β = 114.164(1)°, and V = 2990.74(8) Å3.
The superposition of the pattern recorded in the present work with the patterns previously reported (Kim et al., Reference Kim, Lee, Lim and Kim2011; Ali and Sayed, Reference Ali and Sayed2013; Ellakwa et al., Reference Ellakwa, Fahmy and Ellakwa2017) digitized using the online JADE® Pattern Digitizer (ICDD, 2022) are shown in Figure 2. The patterns are similar indicating that all of them correspond to the same Mdcd phase.
Figure 2. Comparison of the powder pattern recorded for (a) Mdcd in the present study with the reported powder patterns from (b) Ali and Sayed (Reference Ali and Sayed2013); (c) Kim et al. (Reference Kim, Lee, Lim and Kim2011); and (d) Ellakwa et al. (Reference Ellakwa, Fahmy and Ellakwa2017).
Using as a starting structural model the structure reported by Ito et al. (Reference Ito, Suzuki and Noguchi2020), a Rietveld refinement was performed in order to assess the quality of the powder diffraction data recorded. The Pawley fit (Pawley, Reference Pawley1981) of the recorded pattern was carried out by modeling the background, sample displacement errors, absorption, surface roughness, cell parameters, and peak shape parameters (including anisotropic broadening) using TOPAS-Academic (Coelho, Reference Coelho2018). A 15-term Chebyshev polynomial was used to model the background. The intermediate Gaussian–Lorentzian function was employed with a correction for axial divergence as proposed by the program. The surface roughness was modeled using the Pitschke approximation (Pitschke et al., Reference Pitschke, Hermann and Mattern1993). The Pawley refinement produced a good fitting of all the diffraction maxima recorded with residuals R p = 0.0182, R wp = 0.0232, and GoF = 1.892, confirming the correctness of the unit cell and the single-phase nature of the material. The analysis of the reflection conditions with DASH 4.0.0 (Markvardsen et al., Reference Markvardsen, David, Johnson and Shankland2001) suggested P21/c, the same space group determined by Ito et al. (Reference Ito, Suzuki and Noguchi2020).
As mentioned before, the initial structural model, retrieved from CSD entry LUWPOL (Ito et al., Reference Ito, Suzuki and Noguchi2020), was used for the Rietveld refinement which was carried out with TOPAS-Academic (Coelho, Reference Coelho2018). The refinement included an overall scale parameter, the background, the sample displacement correction, surface roughness corrections, the peak shapes (including anisotropic broadening), unit-cell parameters, absorption correction, atomic coordinates, eight Biso parameters, and a March-Dollase parameter. The bond distances and angles were restrained based on the values suggested by Mogul Geometry Check (Bruno et al., Reference Bruno, Cole, Kessler, Luo, Sam Motherwell, Purkis, Smith, Taylor, Cooper, Harris and Guy Orpen2004). The weight factors for the distances were 10 000 and 1 for the angles. Four planar restraints, with a standard deviation of 0.01 Å, were applied to the molecule: the C7A-C12A and C16A-C21A aromatic rings, and the O2A-C6A-N2A-HN2 and C10A-N3A-H3N1-H3N2 fragments. The isotropic atomic displacement parameters for the hydrogen atoms were 1.2 times the parameter of the C, N, or O atom to which they are attached.
The refinement performed with TOPAS-Academic (Coelho, Reference Coelho2018) was very stable and proceeded smoothly. Figure 3 shows the final Rietveld refinement plot. In total, 311 parameters were refined with 2753 data points (874 reflections), 217 restraints, and 8 constraints. The final whole pattern fitting converged with good figures of merit: R e = 0.0142, R p = 0.0281, R wp = 0.0352, and GoF = 2.473. The March-Dollase preferred orientation parameter (Dollase, Reference Dollase1986) in the (1 0 0) plane was 0.779(1). The excellent fit obtained confirmed that the data recorded are consistent with the structural model obtained from the single crystal diffraction study reported by Ito et al. (Reference Ito, Suzuki and Noguchi2020) for the Mdcd phase. The molecular structure with the corresponding atom labels is presented in Figure 4, drawn with DIAMOND (Putz and Brandenburg, Reference Putz and Brandenburg2023). A CIF file containing this information is in the Supplementary material.
Figure 3. Rietveld refinement plot for Mdcd.
Figure 4. Molecular structure of Mdcd.
All the bond distances and bond angles fall within the normal ranges as indicated by the Mogul Geometry Check (Bruno et al., Reference Bruno, Cole, Kessler, Luo, Sam Motherwell, Purkis, Smith, Taylor, Cooper, Harris and Guy Orpen2004). The RMSD calculated with Mercury (Macrae et al., Reference Macrae, Sovago, Cottrell, Galek, McCabe, Pidcock, Platings, Shields, Stevens, Towler and Wood2020) for 15 molecules, comparing the refined structure with the structure reported in entry LUWPOL, was 0.144 Å.
The structure of Mdcd is governed by extensive hydrogen bonding and displaced face-to-face π⋯π interactions between the C-rings of two Msp+ molecules. These interactions contribute to the formation of dimers. Hirshfeld surface analysis displays the characteristic red areas corresponding to the hydrogen bonding interactions. The shape index and curvedness representations show the areas of π⋯π interactions. For the mosapride moiety, H⋯H and O⋯H/H⋯O contacts contribute 40 and 20%, respectively, while for the dihydrogen citrate the O⋯H/H⋯O contacts contribute 63.2% and the H⋯H contacts represent 25.9%.
Details of the structure, the crystal packing, and the crystallochemical analysis carried out are contained in the Supplementary material. This includes tables of bond distances and angles, the most important intermolecular interactions highlighting the hydrogen bonding scheme present, and the Hirshfeld surface and Fingerprint plots calculated for the Msp+, H2Cit−, and the water molecules, with the CrystalExplorer21 software (Spackman et al., Reference Spackman, Turner, McKinnon, Wolff, Grimwood, Jayatilaka and Spackman2021).
V. DEPOSITED DATA
Crystallographic Information Framework (CIF) files containing the results of the Rietveld refinement and a CIF with the data submitted for the GiA program were deposited with the ICDD. The data can be requested at [email protected]. The crystal structure data were also deposited with the Cambridge Crystallographic Data Centre (CCDC 2338435).
SUPPLEMENTARY MATERIAL
The supplementary material for this article can be found at https://doi.org/10.1017/S088571562400040X.
ACKNOWLEDGMENTS
The authors thank the support of Vicerrectoría de Investigación y Extensión of Universidad Industrial de Santander (UIS), Colombia. Access to the Cambridge Structural Database (CSD) for Universidad de Los Andes (Venezuela) was possible through the Frank H. Allen International Research & Education Programme (FAIRE) from the Cambridge Crystallographic Data Centre (CCDC).
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