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Journal logoCRYSTALLOGRAPHIC
COMMUNICATIONS
ISSN: 2056-9890
Volume 81| Part 3| March 2025|
https://doi.org/10.1107/S2056989025000714

Supra­molecular assembly of mebendazolium and di­hydrogen phosphate ions in a new anthelmintic salt

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Eduardo L. Gutiérrez,a* Marcos G. Russo,a Griselda E. Narda,a Elena V. Brusau,a Alejandro P. Ayalab and Javier Ellenac

aInstituto de Investigaciones en Tecnología Química (INTEQUI, CONICET-UNSL), Área de Química Orgánica, Facultad de Química, Bioquímica y Farmacia, Universidad Nacional de San Luis (UNSL), D5700APC, San Luis, Argentina, bDepartamento de Física, Universidade Federal do Ceará (UFC), 60.440-900, Fortaleza, CE, Brazil, and cInstituto de Física de São Carlos (IFSC), Universidade de São Paulo (USP), 13.566-590, São Carlos, SP, Brazil
*Correspondence e-mail: egutierrez@unsl.edu.ar

Edited by V. Jancik, Universidad Nacional Autónoma de México, México (Received 20 November 2024; accepted 27 January 2025; online 4 February 2025)

A new mebendazolium di­hydrogen phosphate phospho­ric acid solid material was obtained and characterized by single-crystal X-ray diffraction and complementary solid-state techniques {systematic name: 5-benzoyl-2-[(meth­oxy­carbon­yl)amino]-1H-1,3-benzo­diazol-3-ium di­hydrogen phosphate–phos­pho­ric acid (1/1), C16H14N3O3+·H2PO4−·H3PO4}. Structure solution confirmed proton transfer from phospho­ric acid towards the basic imidazole ring of mebendazole. The mebendazolium cation and the di­hydrogen phosphate anion assemble in the solid state in a cyclic hydrogen-bond-driven supra­molecular motif, as observed in all mebendazolium/oxyanions structures reported in the literature. This salt crystallizes in the monoclinic P21/c (No. 14) space group. A detailed study of the crystal structure performed by atom-to-atom and global Hirshfeld surface analysis indicates that several hydrogen bonds act as the main inter­molecular inter­actions stabillizing the material. The new material is stable up to 458 K.

CCDC reference: 2381432

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1. Chemical context

Mebendazole [MBZ, methyl N-(5-benzoyl­benzimidazol-2-yl) carbamate, in red in the scheme) is a synthetic broad-spectrum benzimidazole-derivative anthelmintic API (Active Pharmaceutical Ingredient) (Martins et al., 2009[Martins, F. T., Neves, P. P., Ellena, J., Camí, G. E., Brusau, E. V. & Narda, G. E. (2009). J. Pharm. Sci. 98, 2336-2344.]). MBZ is used extensively in human medicine being administrated orally as tablet formulation or suspension and is included in the World Health Organization (WHO) Model List of Essential Drugs (Agatonovic-Kustrin et al., 2008[Agatonovic-Kustrin, S., Glass, B. D., Mangan, M. & Smithson, J. (2008). Int. J. Pharm. 361, 245-250.]).

MBZ can exist as several tautomers, leading to the existence of three solid forms (i.e., desmotropes) with remarkable differences in their physicochemical properties and bioavailability (Ayala et al., 2008[Ayala, A. P., Siesler, H. W. & Cuffini, S. L. (2008). J. Raman Spectrosc. 39, 1150-1157.]). MBZ desmotropes can undergo tautomeric inter­conversion in the solid state under the effect of heat and moisture. In particular, investigations have indicated that the pharmaceutically preferred form C evolves into the inactive form A in commercial formulations (Calvo et al., 2016[Calvo, N. L., Kaufman, T. S. & Maggio, R. M. (2016). J. Pharm. Biomed. Anal. 122, 157-165.]). However, our results indicate that salification of the API prevents tautomeric transformation (Gutiérrez et al., 2020[Gutiérrez, E. L., Godoy, A. A., Narda, G. E. & Ellena, J. (2020). CrystEngComm, 22, 6559-6568.]).

Our objective is to design, on the basis of supra­molecular assembly, new MBZ multicomponent systems aiming to obtain materials incorporating the API and avoiding desmotrope inter­conversion and exhibiting a solubility and dissolution profile similar to those of the MBZ therapeutically preferred form C. In previous works, we reported the high statistical probability of formation of an R22(8) supra­molecular heterosynthon (Bernstein et al., 1995[Bernstein, J., Davis, R. E., Shimoni, L. & Chang, N.-L. (1995). Angew. Chem. Int. Ed. Engl. 34, 1555-1573.]; Motherwell et al., 2000[Motherwell, W. D. S., Shields, G. P. & Allen, F. H. (2000). Acta Cryst. B56, 466-473.]) between protonated mebendazole mol­ecules (i.e., the mebendazolium cation, shown in red in the scheme) and polyatomic oxyanions (Gutiérrez et al., 2018[Gutiérrez, E. L., Souza, M. S., Diniz, L. F. & Ellena, J. (2018). J. Mol. Struct. 1161, 113-121.], 2024[Gutiérrez, E. L., Godoy, A. A., Brusau, E. V., Vega, D., Narda, G. E., Suárez, S. & Di Salvo, F. (2024). RSC Adv. 14, 181-192.]).

[Scheme 1]

In the context of screening for new mebendazole multicomponent materials, we obtained a new mebendazolium di­hydrogen phosphate phospho­ric acid compound. This material can be considered as an ionic cocrystal (i.e., a cocrystal of a salt), since the phospho­ric acid mol­ecules are connected with the ionic components of the salt through non-covalent inter­actions (i.e., hydrogen-bonds) (Pavlović et al., 2024[Pavlović, G., Lekšić, E. & Meštrović, E. (2024). Acta Cryst. B80, 193-200.]; Smith et al., 2013[Smith, A. J., Kim, S.-H., Duggirala, N. K., Jin, J., Wojtas, L., Ehrhart, J., Giunta, B., Tan, J., Zaworotko, M. J. & Shytle, R. D. (2013). Mol. Pharm. 10, 4728-4738.]). Phospho­ric acid and its anions are approved coformers by the Food and Drug Administration (FDA) and U·S. Department of Health and Human Services (FDA, 2024[FDA (2024). Food and Drug Administration (FDA) and U.S. Department of Health and Human Services, Approved Drug Product with Therapeutic Equivalence Evaluations (‘Orange Book’), 44th ed. https://www.fda.gov/drugs/drug-approvals-and-databases/approved-drug-products-therapeutic-equivalence-evalu­ations-orange-book.]), which could make this new material suitable for pharmaceutical formulations.

2. Structural commentary

The solution of the structure confirmed the crystallization of a new mebendazole material, which is a mebendazolium (MBZH+) di­hydrogen phosphate phospho­ric acid compound, MBZH·PO2(OH)2·PO(OH)3, with 1:1:1 stoichiometry. ΔpKa between the MBZH+ cation and phospho­ric acid is 1.31 (see supporting information). This value falls in the ‘grey area’ for predictions on the location of the acidic proton. Around ΔpKa ∼1, predicting the location of the acid proton based on aqueous ΔpKa data alone is not possible: the model predicts a very similar likelihood of observing salts or cocrystals (Cruz-Cabeza, 2012[Cruz-Cabeza, A. J. (2012). CrystEngComm, 14, 6362-6365.]). This salt crystallizes in the monoclinic P21/c (No. 14) space group. An ORTEP-type view of the asymmetric unit of MBZH·PO2(OH)2·PO(OH)3 is shown in Fig. 1[link]. The atom labeling is according to the nomenclature used in previous related works.

[Figure 1]
Figure 1
View of the asymmetric unit in the crystal of MBZH·PO2(OH)2·PO(OH)3, showing the atom labeling and the 50% probability ellipsoids for non-hydrogen atoms. The hydrogen atoms are shown as sticks of arbitrary radii (color code. C: gray; H: white; O: red; N: blue; P: orange).

In the Supporting Information file we present a detailed analysis of the bond-length changes in the imidazole ring and the carbamate moiety, which confirms the protonation of the API. The MBZH+ cation is found in a conformation in which the carbamate moiety is coplanar with the benzimidazole ring. This conformation is favored by (i) the conjugation of these moieties and the partial double-bond character of the bonds O2—C2, C2—N1 and N1—C3 reinforced by the positive charge of the mol­ecule, and (ii) the intra­molecular resonance-assisted hydrogen bond between N2 and O2 [H⋯A: 2.10 (3) Å, 122 (3)°]. The benzimidazole and the benzene rings are not coplanar: the dihedral angle between the least-squares planes passing through the benzene (root-mean-square deviation, r.m.s.d., of fitted atoms: 0.004 Å) and the benzimidazole (r.m.s.d.: 0.003 Å) rings is 54.50 (17)°.

3. Supra­molecular features

Hirshfeld surface (HS) analysis and energy calculations (HF/3-21G model) were performed using the software Crystal Explorer 21.5 (Mackenzie et al., 2017[Mackenzie, C. F., Spackman, P. R., Jayatilaka, D. & Spackman, M. A. (2017). IUCrJ, 4, 575-587.]; Spackman et al., 2021[Spackman, P. R., Turner, M. J., McKinnon, J. J., Wolff, S. K., Grimwood, D. J., Jayatilaka, D. & Spackman, M. A. (2021). J. Appl. Cryst. 54, 1006-1011.]) with the CIF as the input file. The Hirshfeld surface for the title compound was mapped with the dnorm function over the range −0.025 to 0.750 a.u. (color code: from blue – distances longer than sum of van der Waals radii – through white to red – distances shorter than sum of van der Waals radii). Through HS analysis, it was confirmed that main inter­molecular inter­actions stabilizing the crystal structure are several hydrogen bonds. Fig. 2[link] shows the HS of the MBZH+ cation mapped with the dnorm function (Spackman et al., 2009[Spackman, M. A. & Jayatilaka, D. (2009). CrystEngComm, 11, 19-32.]), where the red spots are the regions in which the inter­atomic distances are shorter than the sum of the van der Waals radii and correspond to the hydrogen bonds.

[Figure 2]
Figure 2
Mebendazolium cation mapped with the dnorm function on the Hirshfeld surface (color code. C: gray; H: white; O: red; N: blue; P: orange).

The MBZH+ cations and PO2(OH)2− anions form a heterosynthon described by the R22(8) graph-set motif (Bernstein et al., 1995[Bernstein, J., Davis, R. E., Shimoni, L. & Chang, N.-L. (1995). Angew. Chem. Int. Ed. Engl. 34, 1555-1573.]; Motherwell et al., 2000[Motherwell, W. D. S., Shields, G. P. & Allen, F. H. (2000). Acta Cryst. B56, 466-473.]) (scheme and Fig. 3[link], labeled as I), which is stabilized by moderate hydrogen bonds (Steiner, 2002[Steiner, T. (2002). Angew. Chem. Int. Ed. 41, 48-76.]). N3 and N1 act as proton donors, while O4 and O5 are acceptors, establishing two hydrogen-bond schemes: N3—H3⋯O4 [1.86 (2) Å] and N1—H1⋯O5 [1.96 (2) Å]. This supra­molecular motif is not planar according to the dihedral angle of 29.1 (4)° between the planes defined by the atoms N3, C3, and N1, and O4, P1, and O5, respectively. This inter­action is inherently stabilizing, with a calculated value of −477.2 kJ mol−1. The second most stabilizing inter­action according to our calculations is a predominantly electrostatic inter­action between the MBZH+ cation and a second PO2(OH)2− anion along the b-axis direction, which accounts for −393.5 kJ mol−1 (Fig. S1A). Three other distinct supra­molecular motifs are observed in the crystal packing, involving more complex hydrogen-bonding patterns. On the one hand, a phospho­ric acid mol­ecule in involved in a cyclic arrangement adjacent to the motif previously described. This motif is labeled as II in Fig. 3[link] and is described by the R32(10) graph-set motif. The inter­action between the phospho­ric acid mol­ecule and the MBZH+ cation is predominantly electrostatic and destabilizing (127.3 kJ mol−1). On the other hand, two MBZH+ cations are assembled by the two cyclic motifs labeled III [ R21(6)] and IV [ R22(8)] in Fig. 3[link], bringing together a pair of inversion-related cations. This arrangement is overall destabilizing (33.4 kJ mol−1). Finally, we also found C—H⋯π (114.1 kJ mol−1) and carbon­yl⋯π inter­actions relating adjacent MBZH+ cations (Fig. S1B), which are overall destabilizing. Hydrogen-bonding geometry parameters are shown in Table 1[link].

Table 1
Hydrogen-bond geometry (Å, °)

D—H⋯A D—H H⋯A D⋯A D—H⋯A
O5—H5⋯O10i 0.84 (2) 1.74 (2) 2.578 (3) 175 (4)
O9—H9A⋯O6ii 0.85 (2) 1.72 (2) 2.568 (3) 177 (5)
O8—H8⋯O4 0.87 (2) 1.68 (2) 2.544 (3) 171 (4)
O11—H11⋯O10iii 0.84 (2) 1.79 (2) 2.629 (3) 178 (4)
O7—H7A⋯O6iii 0.85 (2) 1.79 (2) 2.594 (3) 157 (4)
N2—H2⋯O2 0.90 (2) 2.10 (3) 2.680 (4) 122 (3)
N3—H3⋯O4iv 0.90 (2) 1.82 (2) 2.717 (3) 177 (3)
N1—H1⋯O5iv 0.88 (2) 1.96 (2) 2.831 (3) 174 (3)
Symmetry codes: (i) [x-1, -y+{\script{1\over 2}}, z-{\script{1\over 2}}]; (ii) [x, -y+{\script{1\over 2}}, z+{\script{1\over 2}}]; (iii) [x-1, y, z]; (iv) [x+1, y, z].
[Figure 3]
Figure 3
Hydrogen-bonding patterns found in the crystal packing of MBZH·PO2(OH)2·PO(OH)3 (color code. C: gray; H: white; O: red; N: blue; P: orange).

4. Database survey

A survey for the structure of the MBZH+ cation in the Cambridge Structural Database [CSD version: 5.46 (November 2024); Groom et al., 2016[Groom, C. R., Bruno, I. J., Lightfoot, M. P. & Ward, S. C. (2016). Acta Cryst. B72, 171-179.]], using ConQuest 5.45 software (Bruno et al., 2002[Bruno, I. J., Cole, J. C., Edgington, P. R., Kessler, M., Macrae, C. F., McCabe, P., Pearson, J. & Taylor, R. (2002). Acta Cryst. B58, 389-397.]), gave eleven matches, eight of them being anhydrous salts of oxyanions or carboxyl­ates. All eight structures, regardless of the space group of the compound and the geometry of the anions, feature the same R22(8) supra­molecular motif that was found in the title compound between the MBZH+ cation and the respective anion. Table S1 summarizes the relevant features of the hydrogen-bonding patterns related to the R22(8) supra­molecular motif found in the reported mebendazolium salts (Fig. S2) for further comparison with the compound reported here.

5. Synthesis and crystallization

A 15 mg (0.05 mmol) sample of MBZ desmotrope C was suspended in 30 mL of methanol at room temperature with constant magnetic stirring (1000 r.p.m.). An excess of phospho­ric acid (85% w/w, purchased from UCB) was added (3 mL) and the suspension was heated up to 333 K until complete dissolution of the solid. The resulting solution was filtered and covered with a Parafilm foil with small holes to regulate the speed of the evaporation of the solvent and was left to evaporate at room temperature. After approximately twenty days, the formation of small, colorless prismatic crystals was observed. These crystals were separated by filtration and washed several times with distilled water and then with n-hexane. The crystalline material was then stored at room temperature for further characterization (Fig. S3).

FTIR spectroscopy and powder X-ray diffraction (PXRD) were used to check the identity and purity of the bulk material. Both techniques confirmed the obtention of a new material. MBZ, di­hydrogen phosphate and phospho­ric acid characteristic vibrational modes were observed in the FTIR spectrum (Fig. S4) of the solid. In particular, the carbamate C=O stretching mode of MBZ, which is very sensitive to the crystalline environment (Ayala et al., 2008[Ayala, A. P., Siesler, H. W. & Cuffini, S. L. (2008). J. Raman Spectrosc. 39, 1150-1157.]), was observed at 1753 cm−1. This band is extensively used to identify and quantify the MBZ desmotropes even in pharmaceutical products (Calvo et al., 2016[Calvo, N. L., Kaufman, T. S. & Maggio, R. M. (2016). J. Pharm. Biomed. Anal. 122, 157-165.]) and is observed at 1730 cm−1, 1697 cm−1 and 1715 cm−1 in MBZ A (Ferreira et al., 2010[Ferreira, F. F., Antonio, S. G., Rosa, P. C. P. & Paiva-Santos, C. O. (2010). J. Pharm. Sci. 99, 1734-1744.]), B (Bravetti et al., 2022[Bravetti, F., Bordignon, S., Alig, E., Eisenbeil, D., Fink, L., Nervi, C., Gobetto, R., Schmidt, M. U. & Chierotti, M. R. (2022). Chem. Eur. J. 28, e202103589.]) and C (Martins et al., 2009[Martins, F. T., Neves, P. P., Ellena, J., Camí, G. E., Brusau, E. V. & Narda, G. E. (2009). J. Pharm. Sci. 98, 2336-2344.]) spectra, respectively. The inorganic acid and the anion contribute to the broadening of the band in the range 3000–2500 cm−1, these species also being responsible for the band centered at 2350 cm−1. While several vibrational modes of the inorganic moieties are overlapped with those derived from mebendazolium, the ν(P—OH) vibration modes clearly appear as several bands in the 1200–900 cm−1 zone. The νas (O—P—O) vibration mode can be assigned to the bands at 553 and 496 cm−1. The assignment of selected vibrational modes on the FTIR spectrum is shown in Table S2.

The PXRD pattern (Fig. S5) of the bulk material was compared with the calculated patterns of MBZ A, B, and C, and with that calculated for the refined structure. Calculated patterns were obtained using Mercury (Macrae et al., 2020[Macrae, C. F., Sovago, I., Cottrell, S. J., Galek, P. T. A., McCabe, P., Pidcock, E., Platings, M., Shields, G. P., Stevens, J. S., Towler, M. & Wood, P. A. (2020). J. Appl. Cryst. 53, 226-235.]) with the CIFs as input. This comparison confirmed both the identity and the purity of the the new material as its pattern does not match with those of MBZ desmotropes and no characteristic peaks other than those of the new solid are present in the experimental pattern. In Table S3, we present a list of the main reflexions in the experimental PXRD pattern.

The material is stable up to 458 K, when the endothermic elimination of phospho­ric acid takes place (experimental mass loss, exp .: 15.90%, theoretical mass loss, theor.: 19.95%). The degradation of MBZH+ mol­ecule starts at 634 K and involves the elimination of the (meth­yl)formyl moiety (overall exp .: 36.91%, theor.: 31.69%). The differences of approx. 4% between the experimental and theoretical values are attributed to solvent and/or phospho­ric acid residues in the sample. Thermogravimetric Analysis and Differential Scanning Calorimetry curves are shown in Fig. S6.

6. Refinement

Crystal data, data collection and structure refinement details are summarized in Table 2[link]. All hydrogen atoms were refined using a DFIX restraint to ensure chemically reasonable bond lengths and angles, with their Uiso(H) values constrained to 1.5 times the Ueq of their pivot atoms for terminal sp3 carbon atoms and 1.2 times for all other carbon atoms. The structure was solved as a pseudomerohedral two-component twin [0.8510 (9)/0.1490 (9)] arising from a twofold axis using the twin law (−1 0 0, 0 − 1 0, 1 0 1).

Table 2
Experimental details

Crystal data
Chemical formula C16H14N3O3+·H2O4P−·H3O4P
Mr 491.28
Crystal system, space group Monoclinic, P21/c
Temperature (K) 302
a, b, c (Å) 4.7217 (3), 26.167 (2), 16.7888 (12)
β (°) 98.082 (5)
V (Å3) 2053.7 (3)
Z 4
Radiation type Cu Kα
μ (mm−1) 2.55
Crystal size (mm) 0.18 × 0.07 × 0.03
 
Data collection
Diffractometer Bruker D8 VENTURE dual wavelength Mo/Cu
Absorption correction Multi-scan (SADABS; Krause et al., 2015[Krause, L., Herbst-Irmer, R., Sheldrick, G. M. & Stalke, D. (2015). J. Appl. Cryst. 48, 3-10.])
Tmin, Tmax 0.647, 0.754
No. of measured, independent and observed [I > 2σ(I)] reflections 30433, 4094, 3363
Rint 0.076
(sin θ/λ)max (Å−1) 0.618
 
Refinement
R[F2 > 2σ(F2)], wR(F2), S 0.044, 0.105, 1.06
No. of reflections 4094
No. of parameters 348
No. of restraints 19
H-atom treatment Only H-atom coordinates refined
Δρmax, Δρmin (e Å−3) 0.29, −0.32
Computer programs: APEX4 (Bruker, 2021[Bruker (2021). APEX4. Bruker AXS Inc., Madison, Wisconsin, USA.]), SAINT (Bruker, 2018[Bruker (2018). SAINT. Bruker AXS Inc., Madison, Wisconsin, USA.]), SHELXT (Sheldrick, 2015a[Sheldrick, G. M. (2015a). Acta Cryst. A71, 3-8.]), SHELXL (Sheldrick, 2015b[Sheldrick, G. M. (2015b). Acta Cryst. C71, 3-8.]) and OLEX2 (Dolomanov et al., 2009[Dolomanov, O. V., Bourhis, L. J., Gildea, R. J., Howard, J. A. K. & Puschmann, H. (2009). J. Appl. Cryst. 42, 339-341.]).

Supporting information

CCDC reference: 2381432

Crystal structure: contains datablock I. DOI: https://doi.org/10.1107/S2056989025000714/jq2039sup1.cif

Structure factors: contains datablock I. DOI: https://doi.org/10.1107/S2056989025000714/jq2039Isup2.hkl

Supporting information file. DOI: https://doi.org/10.1107/S2056989025000714/jq2039sup4.pdf

Supporting information file. DOI: https://doi.org/10.1107/S2056989025000714/jq2039Isup4.cml

checkCIF report


Computing details top

5-Benzoyl-2-[(methoxycarbonyl)amino]-1H-1,3-benzodiazol-3-ium dihydrogen phosphate–phosphoric acid (1/1) top
Crystal data top
C16H14N3O3+·H2O4P−·H3O4PF(000) = 1016
Mr = 491.28Dx = 1.589 Mg m−3
Monoclinic, P21/cCu Kα radiation, λ = 1.54178 Å
a = 4.7217 (3) ÅCell parameters from 9651 reflections
b = 26.167 (2) Åθ = 3.2–72.3°
c = 16.7888 (12) ŵ = 2.55 mm−1
β = 98.082 (5)°T = 302 K
V = 2053.7 (3) Å3Prism, clear light colourless
Z = 40.18 × 0.07 × 0.03 mm
Data collection top
Bruker D8 VENTURE dual wavelength Mo/Cu
diffractometer		4094 independent reflections
Radiation source: microfocus sealed X-ray tube, Incoatec Iµs HB3363 reflections with I > 2σ(I)
Multilayer mirrors monochromatorRint = 0.076
Detector resolution: 7.39 pixels mm-1θmax = 72.4°, θmin = 2.7°
ω and φ scansh = −5→5
Absorption correction: multi-scan
(SADABS; Krause et al., 2015)		k = −32→31
Tmin = 0.647, Tmax = 0.754l = −20→20
30433 measured reflections
Refinement top
Refinement on F2Hydrogen site location: difference Fourier map
Least-squares matrix: fullOnly H-atom coordinates refined
R[F2 > 2σ(F2)] = 0.044 w = 1/[σ2(Fo2) + (0.0387P)2 + 1.4065P]
where P = (Fo2 + 2Fc2)/3
wR(F2) = 0.105(Δ/σ)max < 0.001
S = 1.06Δρmax = 0.29 e Å−3
4094 reflectionsΔρmin = −0.32 e Å−3
348 parametersExtinction correction: SHELXL-2019/1 (Sheldrick 2015b), Fc*=kFc[1+0.001xFc2λ3/sin(2θ)]-1/4
19 restraintsExtinction coefficient: 0.00153 (15)
Primary atom site location: dual
Special details top

Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes.

Refinement. Refined as a 2-component twin. Single crystal X-ray diffraction data (φ scans and ω scans with κ and θ offsets) were collected on a Bruker D8 Venture κ-geometry diffractometer equipped with a Photon II CPAD detector and a IµS 3.0 Incoatec Cu Kα (λ = 1.54178 Å) microfocus source. A suitable crystal for the compound was chosen and mounted on a Kapton fiber with a MiTeGen MicroMount using immersion oil. The APEX 4 software was used for the unit cell determination and data collection (Bruker AXS Inc, 2021). The data reduction and global cell refinement were made using the Bruker SAINT+ software package (Bruker AXS Inc, 2019), and a multi-scan absorption correction was performed with SADABS (Krause et al., 2015). Using the Olex2 (Dolomanov et al., 2009) interface program to the SHELX suite, the structure was solved by the intrinsic phasing method implemented in ShelXT (Sheldrick, 2015b), allowing the location of most of the non-hydrogen atoms. The remaining non-hydrogen atoms were located from difference Fourier maps calculated from successive full-matrix least-squares refinement cycles on F2 with ShelXL (Sheldrick, 2015a) and refined using anisotropic displacement parameters.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2) top
xyzUiso*/Ueq
P20.43419 (16)0.27652 (3)0.23599 (4)0.03209 (18)
P10.81274 (16)0.23835 (3)0.50120 (4)0.03376 (19)
O50.2739 (5)0.31777 (8)0.17736 (11)0.0365 (5)
H50.205 (8)0.3072 (13)0.1312 (14)0.055*
O60.6963 (4)0.25750 (9)0.20482 (12)0.0418 (5)
O40.4896 (5)0.30257 (9)0.31664 (12)0.0437 (5)
O101.0793 (4)0.21012 (9)0.53275 (12)0.0411 (5)
O90.7150 (5)0.27629 (8)0.56206 (13)0.0433 (5)
H9A0.714 (10)0.2646 (14)0.6095 (14)0.065*
O80.8674 (5)0.26953 (10)0.42774 (13)0.0486 (6)
H80.726 (7)0.2791 (15)0.392 (2)0.073*
O110.5673 (5)0.20050 (9)0.47561 (15)0.0479 (6)
H110.412 (6)0.2044 (16)0.494 (2)0.072*
O70.2289 (5)0.23040 (9)0.23605 (16)0.0494 (6)
H7A0.054 (5)0.2366 (16)0.239 (3)0.074*
O20.4932 (6)0.43652 (10)0.20414 (14)0.0556 (6)
O10.7119 (6)0.39991 (10)0.10761 (14)0.0548 (6)
O30.6908 (6)0.49929 (9)0.63826 (14)0.0555 (7)
N20.7646 (6)0.42602 (10)0.35453 (15)0.0386 (6)
H20.617 (6)0.4437 (12)0.3285 (19)0.046*
N31.1169 (6)0.37031 (10)0.36730 (16)0.0408 (6)
H31.242 (7)0.3475 (11)0.353 (2)0.049*
N10.8972 (6)0.38874 (10)0.23461 (16)0.0413 (6)
H11.022 (7)0.3686 (12)0.216 (2)0.050*
C20.6798 (8)0.41106 (12)0.18303 (19)0.0422 (7)
C30.9242 (7)0.39500 (12)0.31555 (19)0.0384 (7)
C51.0829 (7)0.38557 (12)0.44514 (18)0.0375 (7)
C40.8619 (7)0.42140 (11)0.43686 (18)0.0373 (7)
C90.7723 (7)0.44463 (12)0.5018 (2)0.0417 (7)
H90.616 (6)0.4676 (11)0.501 (2)0.050*
C71.1270 (8)0.39411 (13)0.5865 (2)0.0431 (7)
H71.233 (7)0.3861 (13)0.6386 (14)0.052*
C61.2188 (7)0.37141 (13)0.5200 (2)0.0435 (7)
H61.365 (6)0.3460 (11)0.528 (2)0.052*
C80.9056 (7)0.43107 (12)0.57789 (19)0.0400 (7)
C110.8572 (7)0.43390 (12)0.72951 (19)0.0420 (7)
C100.8103 (7)0.45728 (12)0.64807 (19)0.0418 (7)
C160.8251 (10)0.38162 (13)0.7409 (2)0.0563 (10)
H160.761 (9)0.3601 (13)0.6951 (17)0.068*
C130.9560 (12)0.44489 (16)0.8727 (2)0.0694 (12)
H130.994 (10)0.4680 (14)0.9179 (19)0.083*
C150.8548 (12)0.36190 (15)0.8181 (2)0.0670 (12)
H150.821 (10)0.3261 (8)0.827 (3)0.080*
C120.9165 (9)0.46542 (14)0.7965 (2)0.0556 (10)
H120.930 (9)0.5011 (8)0.787 (2)0.067*
C140.9251 (11)0.39306 (16)0.8836 (2)0.0652 (12)
H140.944 (10)0.3788 (15)0.9370 (15)0.078*
C10.4836 (12)0.4184 (2)0.0479 (3)0.0725 (13)
H1A0.296 (7)0.408 (2)0.061 (3)0.109*
H1B0.523 (12)0.4067 (19)−0.0048 (18)0.109*
H1C0.495 (12)0.4556 (8)0.054 (3)0.109*
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
P20.0239 (4)0.0416 (4)0.0303 (4)0.0020 (3)0.0024 (3)0.0008 (3)
P10.0265 (4)0.0441 (4)0.0302 (4)0.0004 (3)0.0022 (3)0.0038 (3)
O50.0369 (11)0.0417 (11)0.0290 (10)0.0030 (9)−0.0014 (9)−0.0010 (8)
O60.0257 (11)0.0621 (14)0.0380 (11)0.0064 (10)0.0057 (9)−0.0029 (10)
O40.0454 (13)0.0566 (13)0.0272 (10)0.0116 (11)−0.0019 (9)−0.0038 (9)
O100.0295 (11)0.0587 (13)0.0348 (11)0.0086 (10)0.0029 (9)0.0083 (9)
O90.0470 (13)0.0449 (12)0.0387 (11)0.0064 (10)0.0082 (10)−0.0002 (9)
O80.0385 (13)0.0701 (15)0.0361 (12)−0.0018 (12)0.0013 (9)0.0203 (11)
O110.0290 (12)0.0548 (14)0.0613 (15)−0.0072 (10)0.0111 (11)−0.0141 (11)
O70.0294 (12)0.0437 (12)0.0744 (16)−0.0031 (10)0.0047 (11)0.0111 (11)
O20.0539 (16)0.0607 (15)0.0509 (14)0.0188 (13)0.0026 (12)−0.0070 (12)
O10.0538 (15)0.0708 (16)0.0403 (13)0.0102 (13)0.0080 (11)0.0001 (11)
O30.0720 (18)0.0470 (13)0.0474 (13)0.0184 (13)0.0077 (13)−0.0015 (10)
N20.0352 (15)0.0418 (14)0.0391 (14)0.0089 (11)0.0061 (11)−0.0013 (11)
N30.0354 (15)0.0442 (15)0.0434 (15)0.0087 (12)0.0077 (12)−0.0018 (12)
N10.0404 (16)0.0458 (15)0.0388 (14)0.0064 (12)0.0096 (12)−0.0027 (11)
C20.0442 (19)0.0423 (17)0.0412 (17)0.0010 (15)0.0098 (15)−0.0005 (13)
C30.0347 (17)0.0396 (16)0.0419 (17)−0.0012 (13)0.0081 (13)−0.0035 (13)
C50.0353 (17)0.0396 (16)0.0387 (16)0.0023 (13)0.0092 (13)−0.0013 (12)
C40.0368 (17)0.0372 (15)0.0376 (16)0.0037 (13)0.0040 (13)0.0000 (12)
C90.0429 (19)0.0389 (16)0.0438 (17)0.0101 (14)0.0076 (14)−0.0011 (14)
C70.0413 (19)0.0462 (17)0.0408 (17)0.0070 (15)0.0021 (14)0.0022 (14)
C60.0366 (18)0.0449 (17)0.0487 (19)0.0088 (14)0.0050 (15)0.0017 (14)
C80.0416 (19)0.0366 (15)0.0423 (17)0.0032 (13)0.0071 (14)−0.0019 (13)
C110.047 (2)0.0396 (16)0.0391 (17)0.0048 (14)0.0068 (14)0.0006 (13)
C100.046 (2)0.0373 (16)0.0417 (17)0.0057 (14)0.0038 (14)−0.0026 (13)
C160.077 (3)0.0429 (19)0.049 (2)−0.0025 (18)0.011 (2)0.0005 (15)
C130.102 (4)0.058 (2)0.046 (2)−0.002 (2)0.002 (2)−0.0045 (18)
C150.100 (4)0.050 (2)0.055 (2)0.001 (2)0.023 (2)0.0097 (18)
C120.072 (3)0.0444 (19)0.048 (2)0.0001 (18)0.0008 (18)−0.0010 (16)
C140.090 (3)0.062 (2)0.045 (2)0.009 (2)0.012 (2)0.0082 (18)
C10.079 (3)0.089 (3)0.046 (2)0.021 (3)0.000 (2)0.004 (2)
Geometric parameters (Å, º) top
P2—O51.580 (2)C5—C41.395 (4)
P2—O61.495 (2)C5—C61.379 (4)
P2—O41.506 (2)C4—C91.366 (4)
P2—O71.548 (2)C9—H90.950 (19)
P1—O101.491 (2)C9—C81.389 (4)
P1—O91.541 (2)C7—H70.968 (18)
P1—O81.531 (2)C7—C61.386 (5)
P1—O111.539 (2)C7—C81.417 (4)
O5—H50.843 (18)C6—H60.956 (19)
O9—H9A0.854 (19)C8—C101.487 (4)
O8—H80.869 (19)C11—C101.486 (4)
O11—H110.842 (19)C11—C161.393 (5)
O7—H7A0.851 (19)C11—C121.391 (5)
O2—C21.197 (4)C16—H160.966 (19)
O1—C21.329 (4)C16—C151.384 (5)
O1—C11.448 (5)C13—H130.966 (19)
O3—C101.236 (4)C13—C121.376 (5)
N2—H20.899 (18)C13—C141.379 (6)
N2—C31.339 (4)C15—H150.965 (19)
N2—C41.399 (4)C15—C141.371 (6)
N3—H30.897 (19)C12—H120.952 (19)
N3—C31.333 (4)C14—H140.964 (19)
N3—C51.397 (4)C1—H1A0.98 (2)
N1—H10.879 (19)C1—H1B0.98 (2)
N1—C21.377 (4)C1—H1C0.98 (2)
N1—C31.357 (4)
O6—P2—O5110.91 (12)C4—C9—H9127 (2)
O6—P2—O4114.70 (13)C4—C9—C8118.0 (3)
O6—P2—O7106.86 (13)C8—C9—H9115 (2)
O4—P2—O5104.97 (12)C6—C7—H7117 (2)
O4—P2—O7112.45 (14)C6—C7—C8121.4 (3)
O7—P2—O5106.72 (12)C8—C7—H7121 (2)
O10—P1—O9113.59 (13)C5—C6—C7117.4 (3)
O10—P1—O8108.71 (13)C5—C6—H6123 (2)
O10—P1—O11110.19 (14)C7—C6—H6119 (2)
O8—P1—O9106.93 (14)C9—C8—C7120.0 (3)
O8—P1—O11108.89 (14)C9—C8—C10117.6 (3)
O11—P1—O9108.40 (13)C7—C8—C10122.4 (3)
P2—O5—H5116 (3)C16—C11—C10121.7 (3)
P1—O9—H9A115 (3)C12—C11—C10119.1 (3)
P1—O8—H8121 (3)C12—C11—C16119.0 (3)
P1—O11—H11118 (3)O3—C10—C8119.2 (3)
P2—O7—H7A118 (3)O3—C10—C11119.7 (3)
C2—O1—C1114.4 (3)C11—C10—C8121.1 (3)
C3—N2—H2122 (2)C11—C16—H16119 (2)
C3—N2—C4107.5 (3)C15—C16—C11119.7 (4)
C4—N2—H2130 (2)C15—C16—H16120 (2)
C3—N3—H3124 (2)C12—C13—H13118 (3)
C3—N3—C5108.3 (3)C12—C13—C14120.3 (4)
C5—N3—H3128 (2)C14—C13—H13121 (3)
C2—N1—H1121 (2)C16—C15—H15120 (3)
C3—N1—H1117 (2)C14—C15—C16120.7 (4)
C3—N1—C2122.4 (3)C14—C15—H15119 (3)
O2—C2—O1126.3 (3)C11—C12—H12117 (2)
O2—C2—N1124.4 (3)C13—C12—C11120.4 (3)
O1—C2—N1109.3 (3)C13—C12—H12123 (2)
N2—C3—N1125.6 (3)C13—C14—H14120 (3)
N3—C3—N2110.8 (3)C15—C14—C13119.8 (4)
N3—C3—N1123.6 (3)C15—C14—H14120 (3)
C4—C5—N3106.4 (3)O1—C1—H1A111 (3)
C6—C5—N3132.5 (3)O1—C1—H1B108 (3)
C6—C5—C4121.1 (3)O1—C1—H1C104 (3)
C5—C4—N2107.1 (3)H1A—C1—H1B114 (5)
C9—C4—N2130.9 (3)H1A—C1—H1C107 (5)
C9—C4—C5122.1 (3)H1B—C1—H1C113 (4)
N2—C4—C9—C8177.9 (3)C7—C8—C10—O3156.5 (3)
N3—C5—C4—N21.2 (3)C7—C8—C10—C11−23.3 (5)
N3—C5—C4—C9−179.7 (3)C6—C5—C4—N2−178.1 (3)
N3—C5—C6—C7−179.0 (3)C6—C5—C4—C91.0 (5)
C2—N1—C3—N2−5.9 (5)C6—C7—C8—C91.1 (5)
C2—N1—C3—N3173.8 (3)C6—C7—C8—C10−177.8 (3)
C3—N2—C4—C5−1.1 (3)C8—C7—C6—C5−1.1 (5)
C3—N2—C4—C9180.0 (3)C11—C16—C15—C14−2.2 (8)
C3—N3—C5—C4−0.9 (4)C10—C11—C16—C15−176.3 (4)
C3—N3—C5—C6178.3 (4)C10—C11—C12—C13178.9 (4)
C3—N1—C2—O2−2.0 (5)C16—C11—C10—O3141.1 (4)
C3—N1—C2—O1177.9 (3)C16—C11—C10—C8−39.1 (5)
C5—N3—C3—N20.3 (4)C16—C11—C12—C133.0 (7)
C5—N3—C3—N1−179.5 (3)C16—C15—C14—C132.5 (8)
C5—C4—C9—C8−0.9 (5)C12—C11—C10—O3−34.6 (5)
C4—N2—C3—N30.5 (4)C12—C11—C10—C8145.2 (4)
C4—N2—C3—N1−179.7 (3)C12—C11—C16—C15−0.6 (6)
C4—C5—C6—C70.1 (5)C12—C13—C14—C150.0 (8)
C4—C9—C8—C7−0.1 (5)C14—C13—C12—C11−2.8 (8)
C4—C9—C8—C10178.9 (3)C1—O1—C2—O2−4.3 (6)
C9—C8—C10—O3−22.4 (5)C1—O1—C2—N1175.9 (3)
C9—C8—C10—C11157.8 (3)
Hydrogen-bond geometry (Å, º) top
D—H···AD—HH···AD···AD—H···A
O5—H5···O10i0.84 (2)1.74 (2)2.578 (3)175 (4)
O9—H9A···O6ii0.85 (2)1.72 (2)2.568 (3)177 (5)
O8—H8···O40.87 (2)1.68 (2)2.544 (3)171 (4)
O11—H11···O10iii0.84 (2)1.79 (2)2.629 (3)178 (4)
O7—H7A···O6iii0.85 (2)1.79 (2)2.594 (3)157 (4)
N2—H2···O20.90 (2)2.10 (3)2.680 (4)122 (3)
N3—H3···O4iv0.90 (2)1.82 (2)2.717 (3)177 (3)
N1—H1···O5iv0.88 (2)1.96 (2)2.831 (3)174 (3)
Symmetry codes: (i) x−1, −y+1/2, z−1/2; (ii) x, −y+1/2, z+1/2; (iii) x−1, y, z; (iv) x+1, y, z.
 

Acknowledgements

The authors acknowledge Farm. Elbio Saidman from the Laboratorio de Control de Calidad de Medicamentos (UNSL) for kindly supplying the MBZ C samples.

Funding information

Funding for this research was provided by: Consejo Nacional de Investigaciones Científicas y Técnicas (scholarship to E. L. Gutiérrez; grant to G. E. Narda); Universidad Nacional de San Luis (grant to G. E. Narda); Financiadora de Estudos e Projetos (grant to A. P. Ayala); Conselho Nacional de Desenvolvimento Científico e Tecnológico (grant to J. Ellena).

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Volume 81| Part 3| March 2025|
https://doi.org/10.1107/S2056989025000714
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