Michael
Svärd
*ab,
Gamidi Rama
Krishna
a and
Åke C.
Rasmuson
ab
aSynthesis and Solid State Pharmaceutical Centre, Department of Chemical and Environmental Science, Bernal Institute, University of Limerick, Castletroy, Ireland
bDepartment of Chemical Engineering, KTH Royal Institute of Technology, Stockholm, Sweden. E-mail: micsva@kth.se
First published on 1st December 2017
A new compound, 1-(2,2,3-trimethyl-1,3-oxazolidin-5-yl)-butane-1,2,3,4-tetrol, has been discovered, described, and its crystal polymorphism investigated. The crystal structures of two polymorphs have been solved with single-crystal X-ray diffraction. The molecule is chiral with four stereo centers, and both polymorphs crystallise in the non-centrosymmetric orthorhombic, chiral P212121 space group, with one molecule in the asymmetric unit. In both structures the molecules are arranged three dimensionally in an interlocked manner, stabilized by strong O–H⋯O and weaker C–H⋯O and π⋯π interactions. The polymorphs have been characterized by X-ray powder diffraction (XRPD) and infrared spectroscopy (IR). The thermodynamic stability relationship between the polymorphs from 280 K up to the melting points has been quantitatively determined by differential scanning calorimetry (DSC), through measurement of melting points, heats of fusion, and heat capacities of the solid phases and the supercooled melt. It is established that the relationship is most likely monotropic, with one polymorph (FI) stable throughout the entire evaluated temperature range. The stability relationship at room temperature has been confirmed by a slurry conversion experiment.
N-Methyl-D-glucamine (meglumine, C7H17NO5, CAS number 6284-40-8) is an amino sugar derived from sorbitol. Meglumine is a common pharmaceutical excipient compound, used to improve the shelf-life of the active pharmaceutical ingredients, as a salt former, and in the preparation of radiopaque contrast media. As a pentavalent antimony compound it also finds use as a therapeutic agent in the treatment of Leishmaniasis.10 Its molecular structure is shown in Fig. 1a. In the course of a previously reported study of this compound, a new derivative compound was serendipitously discovered while working in acetone solution. The derivative compound was isolated and identified as 1-(2,2,3-trimethyl-1,3-oxazolidin-5-yl)-butane-1,2,3,4-tetrol, C10H21NO5, Mw = 235.28 g mol−1. The molecular structure, shown in Fig. 1b, consists of a five-membered oxazole ring connected to an aliphatic side chain, containing one primary –OH and three secondary –OH functional groups.
The reaction of meglumine with acetone resulting in the title compound, shown in Scheme 1, is a condensation reaction between one meglumine and one acetone molecule, with the loss of one molecule of water. In effect, it is a reductive alkylation, resulting in the conversion of a secondary amine into an oxazolidine ring compound. To the best of our knowledge, this compound has never before been reported or described in the literature. Consequently, it lacks standard chemical identifiers, such as a CAS number. The new compound has been characterized by 1H-NMR and mass spectrometry. The two crystalline phases encountered have been characterized by differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD) and infrared spectroscopy (IR), and their crystal structures have been determined by single crystal X-ray diffraction (XRD). A quantitative thermodynamic analysis of the polymorphic stability relationship has been accomplished based on calorimetric data of the two solid phases.
A screening study was undertaken to probe the propensity for meglumine to react in a similar way with other ketone solvents. Slurries containing excess solid meglumine powder in 100 mL solutions of methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK), 2-butanone and 3-pentanone were prepared in round bottom flasks and heated under reflux for 3–6 h. The crystals were then filtered and analysed with IR. In the two solvents with the highest boiling points (MIBK and 3-pentanone) the IR spectra obtained after 3 h showed differences from the meglumine spectrum, indicating a reaction had occurred, while in MEK and 2-butanone the spectrum was unchanged after 6 h. The experiment shows that this particular type of reaction between meglumine and ketones is not restricted to acetone, which could have important implications for the pharmaceutical industry.
In all DSC runs, powder samples of approx. 5 mg were distributed evenly in Tzero aluminium pans. The furnace was purged with nitrogen gas (50 mL min−1) and the instrument was calibrated against the melting properties of indium. The heat capacity signal was calibrated using a sapphire sample, with a linear correction function of the temperature. Mass differences between sample and reference pans were always ≤0.20 mg.
The mass spectrum obtained for the title compound is provided as ESI.† The three peaks obtained, with a relative abundance ratio of approx. 100:12:2, have mass-to-charge ratios of 236.2, 237.2 and 238.2, respectively. This may be compared with the molar mass of the title compound of 235.28 g mol−1.
The title compound is chiral, with four stereo centers at carbon atoms along the carbon chain: C2 (R), C3 (R), C4 (S) and C5 (S). Both polymorphs FI and FII crystallise in the orthorhombic, non-centrosymmetric chiral space group P212121 with one molecule in the asymmetric unit (Z′ =1). Data for the crystal structures determined at 100 K are given in Table 1. ORTEP diagrams of the molecule in the FI and FII structures are shown in Fig. 2.
FI | FII | |
---|---|---|
Empirical formula | C10H21NO5 | |
Formula weight | 235.28 | |
Crystal system | Orthorhombic | Orthorhombic |
Space group | P212121 | P212121 |
Unit cell dimensions | a = 6.0781(3) Å | a = 7.0282(6) Å |
b = 10.8821(6) Å | b = 9.9007(8) Å | |
c = 17.8535(10) Å | c = 17.2379(15) Å | |
α = 90° | α = 90° | |
β = 90° | β = 90° | |
γ = 90° | γ = 90° | |
Cell volume | 1180.87(11) Å3 | 1199.48(18) Å3 |
Z | 4 | 4 |
Temperature | 100(2) K | 100(2) K |
Radiation | Mo Kα radiation | Mo Kα radiation |
Wavelength | λ = 0.71073 Å | λ = 0.71073 Å |
Absorption coefficient | μ = 0.105 mm−1 | μ = 0.103 mm−1 |
Crystal size | 0.45 × 0.24 × 0.20 mm3 | 0.33 × 0.22 × 0.19 mm3 |
Data collection | ||
Instrument | Bruker APEX D8 QUEST diffractometer | Bruker APEX D8 QUEST diffractometer |
Reflections measured | 20697 | 9958 |
Independent reflections | 2532 | 2631 |
Reflections with I > 2σ(I) | 2509 | 2471 |
R int | 0.0229 | 0.0312 |
Refinement | ||
R[F2 > 2σ(F2)] | 0.0228 | 0.0275 |
wR(F2) | 0.0595 | 0.0675 |
S | 1.072 | 1.030 |
Δρmax | 0.243 e Å−3 | 0.244 e Å−3 |
Δρmin | −0.141 e Å−3 | −0.149 e Å−3 |
Fig. 2 ORTEP representations of FI and FII, with displacement ellipsoids drawn at the 50% probability level. |
In the FI structure, the molecules are connected by 1D chains along the crystallographic a-axis via strong and directional R22 (10) synthons15 through O–H⋯O (O1–H1⋯O3: 2.7311(13) Å, 165(2)°; O4–H4A⋯O2: 2.7133(13) Å, 159(2)°) intermolecular interactions as shown in Fig. 3a. The 1D chains are stacked in a head-to-head fashion, with neighbouring chains arranged in opposite directions as shown in Fig. 3b. Thus, molecules are connected head-to-head along the b-axis by strong R33 (10) synthons through O–H⋯O (O2–H2A⋯O1: 2.7481(13) Å, 166.7(18)°; O3–H3A⋯O4: 2.7041(13) Å, 167(2)°) intermolecular interactions, forming corrugated 2D sheets along ab-plane as shown in Fig. 3c. In the third dimension, these 2D sheets are stabilized by weak C–H⋯O (C1–H1B⋯O5: 3.3627(16) Å, 166.9(15)°) and C–H⋯H intermolecular interactions. As a whole, the FI structure attains a 3D interlocked network packing.
In the FII structure, analogous to FI, the molecules are connected by R22 (10) synthons through O–H⋯O (O1–H1⋯O4: 2.7310(17) Å, 172(2)°; O2–H2⋯O1: 2.9168(17) Å, 108(2)°; O2–H2⋯O5: 2.8423(17) Å, 163(2)°; O4–H4⋯O2: 2.6666(17) Å, 175(2)°) interactions, leading to the formation of 1D chains along the crystallographic a-axis, as shown Fig. 4a. These 1D chains are connected through weak C–H⋯O (C2–H2A⋯O4: 2.9815(18) Å, 106.3(14)°; C6–H6B⋯O1: 3.247(2) Å, 140°) and van der Waals' interactions, to form 2D corrugated sheets as shown in Fig. 4b. The 2D sheets are stabilized in the third dimension by both C–H⋯O and O–H⋯N (O3–H3⋯N1: 2.8173(19) Å, 170(2)°) interactions. The overall structure can be described as a 3D interlocked crystal packing featuring O–H⋯O, O–H⋯N, C–H⋯O and π-stacking interactions.
One main difference between the FI and FII structures is that, whereas in the former the oxygen of the oxazole ring is involved in the formation of weak C–H⋯O intermolecular interactions, in the FII structure the oxazole oxygen acts as a hydrogen bonding acceptor, forming the O–H⋯O hydrogen bond with the secondary –OH functional group of the C2 carbon (>CH–OH). In addition, the structures differ with respect to molecular torsional angles of the aliphatic side chain (tabulated in ESI†), most notably for the torsion C1–C2–C3–C4 (FI: −176.8(1)°; FII: 157.2(1)°). The differences are sufficient for this to be considered a case of conformational polymorphism, as shown in the overlay diagram in Fig. 5.
In Fig. 6, the X-ray powder diffractograms of the two polymorphs, experimentally determined at room temperature, are shown together with diffractograms simulated from the crystal structures. The experimental and simulated patterns correspond well for both polymorphs, and there are significant differences between the patterns of the two solid forms. The small peaks in the experimental FII pattern at 9.1° and 12.5° are most likely caused by the presence of a small amount of meglumine in the powder. Fig. 7 shows the IR spectra of the two polymorphs. There are significant differences between the spectra, most notably that i) FI has a strong single peak at 1270 cm−1 whereas FII has three smaller peaks in the range 1250–1300 cm−1, and ii) the two peaks at 1085 cm−1 and 1055 cm−1 in FI are replaced by one strong double peak at 1065 cm−1 in FII. The IR spectra are sufficiently different between the polymorphs to enable this technique to be used for polymorph identification and quantification.
The FI and FII structures were analysed with Hirshfeld surface analysis16 and the intermolecular interactions percentages were quantified by fingerprint plots, using the software Crystal Explorer v. 3.1,17 with energies calculated using dispersion-corrected density functional theory. The resulting surfaces are shown in Fig. 8a and b, and the fingerprint plots in Fig. 8c and d. Surface colours indicate interaction distance; red represents close contacts and blue longer distances, and white regions correspond to typical dispersion interaction distances. Although overall the Hirshfeld surfaces of the two polymorphs are quite similar, signifying a strong similarity with respect to intermolecular interactions, they do exhibit some distinct differences. The percentages of different intermolecular interactions of the two polymorphs have been quantified and compared in Fig. 8e. In both forms, H⋯H interactions are more dominant than any other interactions, as is common for all organic components. FI contains 72.3% H⋯H interactions whereas FII contains 70.3%. The other dominant interactions, which are stronger and more directional than H⋯H interactions, are: O–H⋯Oinside (13.5% in FI, 14.3% in FII), O–H⋯Ooutside (11.9% in FI, 12.8% in FII), O–H⋯Ninside (1.1% in FI, 1.3% in FII) and O–H⋯Noutside (1.1% in FI, 1.3% in FII).
Fig. 8 Hirshfeld surfaces of a) FI and b) FII, fingerprint plots of c) FI and d) FII, and e) percentages of different intermolecular interactions in the two polymorphs. |
Cp = aT + b | (1) |
Having access to melting data as well as heat capacities of both the solids and the supercooled melt allows estimation of the Gibbs energy, enthalpy and entropy of fusion as functions of temperature of the polymorphs.18 If the heat capacity curves are linear functions of temperature, and assuming the linear behavior can be extrapolated over the entire temperature range of interest, the difference in heat capacity between the melt and the respective solid form can be approximated by the function:
ΔCp = Cp,L − Cp,S = q + r(Tm − T) | (2) |
ΔfusG(T) = ΔfusH(T) − TΔfusS(T) | (3) |
(4) |
(5) |
For FI, the coefficients of eqn (2) obtained using linear regression are: q = 135.3 J mol−1 K−1, r = 0.7109 J mol−1 K−2, and for FII: q = 138.8 J mol−1 K−1, r = 0.6997 J mol−1 K−2. The resulting functions of fusion of the two polymorphs are shown in Fig. 9c, from 280 K up to melting. The similarity in the values of both enthalpy of fusion as well as heat capacity of the two polymorphs results in rather similar development of the respective Gibbs energy curves with temperature, and there is no transition in stability over the evaluated temperature range. Fig. 9d shows how the estimated Gibbs energy of transformation from FII into FI depends on temperature, together with its enthalpic and entropic components. The Gibbs energy of transformation approaches zero with decreasing temperature, but is not projected to cross the x-axis anywhere close to the experimental temperature range. For this reason, and because there is a significant amount of uncertainty associated with extrapolating data outside experimental limits, the conclusion is that the relationship is likely monotropic.
The thermodynamic stability relationship at room temperature was verified by a slurry conversion experiment. A suspension of equal amounts of FI and FII in acetone was prepared in a capped bottle equipped with a magnetic stir bar, and kept at 25 °C under agitation. After 5 days, a sample of the solids was collected and analysed with IR spectroscopy. The IR spectrum showed that all FII had converted into FI, confirming the stability order obtained using DSC data.
Footnote |
† Electronic supplementary information (ESI) available: Crystallographic torsion angles and experimental heat capacity values of FI and FII, NMR spectra, LC-MS spectrum. CCDC 1556517, 1556518 and 1579804. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c7ce01135k |
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