Crystallization Features of the Chiral Drug Timolol Precursor: The

Article pubs.acs.org/crystal

Crystallization Features of the Chiral Drug Timolol Precursor: The Rare Case of Conglomerate with Partial Solid Solutions Alexander A. Bredikhin,* Dmitry V. Zakharychev, Aidar T. Gubaidullin, Robert R. Fayzullin, Alexander V. Pashagin, and Zemfira A. Bredikhina A.E. Arbuzov Institute of Organic and Physical Chemistry, Kazan Scientific Center of Russian Academy of Sciences, Arbuzov Street, 8, Kazan 420088, Russian Federation S Supporting Information *

ABSTRACT: A synthetic precursor of the chiral drug timolol, 4-[4-(oxiran-2-ylmethoxy)-1,2,5-thiadiazol-3-yl]-morpholine (2) represents a rare case of conglomerate with partial solid solution. This fact was established by inspection of an original solubility test, by the originally developed IR spectra analysis, and by construction of a binary phase diagram which is totally based on thermochemical measurements. The special procedure was developed for quantitative analysis of complex differential scanning calorimetry traces for incongruently melting samples of intermediate enantiomeric composition. The X-ray analyses were performed on a single crystal of 2 grown from the enantiopure feed material and on a single crystal picked out from the racemic polycrystalline sample. The structure of the enantiopure crystal was solved and refined in the P212121 space group with the only symmetry independent molecule in the unit cell. The structure of the crystal picked out from the racemic 2 sample was solved and refined in the P1 space group with four symmetry independent molecules in the unit cell. The epoxy moieties of the independent molecules in this crystal were found to be disordered over two positions with almost equal relative occupancies of opposite enantiomers for all the molecules. The quantitative characteristics of the disorder, 0.78(0.02):0.22(0.02), are close to those found by an independent method of the Tammann diagram.

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INTRODUCTION

4-[4-(oxiran-2-ylmethoxy)-1,2,5-thiadiazol-3-yl]morpholine (Scheme 1) is frequently used among the timolol precursors.4c,d The “liquid-solid” phase transition (i.e., crystallization and the inverse phenomenon of melting or dissolution) governs many processes of concentration, isolation, and purification of chemical products, including enantiopure drugs.5 Timolol maleate and compound 2 are solid crystalline substances, and thus crystallization is usually used to purify these materials. The course and the results of chiral substances crystallization are governed by the peculiarities of their binary (melting) and/or ternary (solubility) phase diagrams.6 The partially reconstructed binary phase diagram for timolol maleate reveals that this compound forms continuous solid solutions between its enantiomers in all concentration limits.7 Crystallization of the timolol maleat samples of intermediate enantiomeric purities leads to the enantiomeric excess (ee) decrease for the crystalline crop (and the simultaneous ee increase for the mother liquor).7 Consequently, the high enantiomeric purity of the timolol maleat should be provided at the stage of the nonracemic precursor preparation.

The unselective β-adrenoblocking agent timolol, (S)-1-[(1,1dimethylethyl)-amino]-3-[[4-(morpholinyl)-1,2,5-thiadiazol-3yl]oxy]-2-propanol (1) (Scheme 1), as the hydrogen maleate salt 1·(HO2CCH)2, has gained a wide acceptance as a antihypertensive and antiglaucoma remedy under a variety of trade names.1,2 According to the patent literature (the principal patents are cited in refs 2 and 3), both asymmetric synthesis and racemate resolution strategies are used for the bulk production of 1. A wide variety of synthetic approaches to 1 have also been suggested in the scientific literature.4 The compound 2, namely, Scheme 1. Timolol 1 and Its Precursor 2

Received: December 3, 2013 Revised: February 3, 2014 Published: February 19, 2014 © 2014 American Chemical Society

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dx.doi.org/10.1021/cg4017905 | Cryst. Growth Des. 2014, 14, 1676−1683

Crystal Growth & Design

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According to the literature, the difference in melting temperatures for enantiopure 2 compared to the corresponding racemic samples amounts to 16−15 °C.8 This fact does not exclude the possibility of crystallization of this compound in the form of a racemic conglomerate. Crystallization of the chiral substance as a conglomerate offers many advantages for the isolation of its enantiopure form. Primarily, the effective racemate resolution in this case may be achieved through the use of the stereoselective crystallization. Even when direct resolution methods are unsuccessful, the “conglomerate-like” phase diagram suggests that an even slightly nonracemic sample can be substantially enantiomerically enriched by simple recrystallization, which is not always possible for a chiral substance with any other type of a phase diagram. As the phase diagrams for timolol maleate precursor 2 have never published in the previous literature, we decided to investigate its crystallization features in more detail. In this work, we have established that 2 represents a rare case of a conglomerate with partial solid solution. This was confirmed by our studies of the equilibrium solubility data, IR spectra analysis, construction of the binary phase diagram based on the thermochemical measurements, and single crystal X-ray analysis.

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Table 1. Crystallographic Data for Crystalline Compounds (S)-2 and limss-2 compound formula M (g/mol) temperature, K crystal class space group crystal size Z, Z′ ́ cell parameters V, Ǻ 3 F(000) ρcalc, g/cm3 μ, cm−1 θ, deg reflections measured independent reflections number of parameters/ restraints reflections [I > 2σ(I)] Flack parameter R1/wR2 [I > 2σ(I)] R1/wR2 (all reflections) goodness-of-fit on F2 ρmax/ρmin (e·Ǻ −3)

EXPERIMENTAL SECTION

Instrumentation. The IR spectra of the polycrystalline samples of rac- and scal-compounds in KBr pellets were recorded on a Bruker Tensor 27 spectrometer. Optical rotations were measured on a PerkinElmer model 341 polarimeter (concentration c is given as g/100 mL). HPLC analyses were performed on a Shimadzu LC-20AD system controller, using UV detector. The melting curves were measured on a Perkin-Elmer Diamond DSC differential scanning calorimeter in aluminum pans with the rate of heating of 10 °C·min−1; the mass of the samples amounted to approximately ∼1 mg and was controlled with a Sartorius CPA2P balance. Temperature scale and heat flux were calibrated against the data for indium and naphthalene. Substances. Racemic and enantiopure (S)-4-[4-(oxiran-2-ylmethoxy)-1,2,5-thiadiazol-3-yl]morpholines, rac-2 and (S)-2, were prepared from rac- and (R)-epichlorohydrin by analogy with published procedures.9,4c rac-2. Mp 100.5−101.5 °C [hexane/EtOAc (8:2)] (lit.:8 mp 97−99 °C). (S)-2. Mp 114−115 °C [hexane/EtOAc (8:2)], [α]D25 = +29.0 (c 1.0, CHCl3) {lit.:8 mp 113−114 °C, [α]D25 = +24.8 (c 1, CHCl3)}; 98% ee [chiral HPLC analysis; Chiralcel OJ (0.46 × 25 cm) column; eluent: hexane/2-propanol (7:3); flow rate: 1.0 mL/min; tR = 18.3 min (minor), tR = 22.2 min (major)]. X-ray Analysis. One of the crystals investigated in this work was prepared by slow evaporation at ambient temperature of the solution [hexane/EtOAc (8:2)] of enantiomerically enriched (S)-2 sample (ee 98%, see above). Another crystal was selected at random from a polycrystalline sample obtained by slow evaporation of the similar solution of rac-2. The X-ray diffraction data of the investigated crystals were collected on a Bruker AXS Smart Apex II CCD diffractometer in the ω- and φscan modes using graphite monochromated Mo Kα (λ 0.71073 Å) radiation at 296 K. The crystal data, data collection, and the refinement parameters are given in Table 1. Data were corrected for the absorption effect using SADABS program.10 The structures were solved by direct method and refined by the full matrix least-squares using SHELXTL11 and WinGX12 programs. All non-hydrogen atoms were refined anisotropically. The hydrogen atoms were inserted at calculated positions and refined as riding atoms. The absolute structure of the single nonracemic crystal was determined on the basis of the Flack parameter.13 Crystallography pointed to the same S configuration that the chemical data did; hereinafter, this crystal is denoted as (S)-2. Crystal grown from

(S)-2 C9H13N3O3S 243.28 296(2) orthorhombic P212121 0.49 × 0.44 × 0.23 mm3 4, 1 a = 4.2026(1), b = 9.1884(1), c = 28.2702(4) Å 1091.66(3) 512 1.480 2.93 2.33 ≤ θ ≤ 28.99 10628 2749 [R(int) = 0.0292] 145/0

limss-2 C9H13N3O3S 243.28 296(2) triclinic P1 0.51 × 0.24 × 0.17 mm3 4, 4 a = 4.223(1), α = 90.056(5), b = 9.193(3), β = 90.057(6), c = 28.190(9) Å, γ = 90.049(6)° 1094.2(6) 512 1.477 2.92 2.22 ≤ θ ≤ 31.37 11234 8925 [R(int) = 0.0220] 617/3

2434

6936

0.0(1) 0.0459/0.1219 0.0525/0.1274

0.41(8) 0.0519/0.1233 0.0678/0.1334

1.050 0.588/−0.298

1.040 0.371/−0.410

racemic material is indicated in what follows as limss-2. The prefix “limss” means limit of the solid solution; the interpretation of this acronym will be clear from the discussion below. The positions of epoxy fragments of all four independed molecules in the limss-2 crystal were disordered over two positions with relative occupancies 0.77:0.23, 0.78:0.22, 0.76:0.24, and 0.80:0.20. All kinds of disordering were resolved using PART1 and PART2 parameters with separate FVAR parameters for each independent molecule. Data collection: images were indexed, integrated, and scaled using the APEX214 data reduction package. Other details of the refinement procedure are discussed below in the text. All figures were made using Mercury program.15 Molecular structures and conformations were analyzed by PLATON.16 Crystallographic data (excluding structure factors) for the structures of (S)-2 and limss-2 reported in this paper was deposited with the Cambridge Crystallographic Data Centre as supplementary publication numbers CCDC 973330 and 973329. Copies of the data can be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK, (fax: +44-(0)1223-336033 or e-mail: [email protected]. uk).

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RESULTS AND DISCUSSION Solubility Test. As it follows from general physical chemistry principles, the equilibrium solubility of the compounds, that form a solid phase, is determined by the activities of these compounds in the solid phase. At the same time, the activity of the pure compound constituting the individual phase within the solid mixture of complex composition is by definition equal to unity. Following these presumptions and provided that both enantiomers are present in the solid component, and at least one of them forms an individual phase, it is possible to show that the contents of enantiomers in the solution (in an achiral solvent) will meet the eutectic composition in the ternary equilibrium system for any 1677



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To allow for a more detailed visual comparison of the vibration spectra, we developed a new approach and proposed to use a graphical representation of the correlation between the two spectra, that is, visually display them in the coordinates AiR versus AiA. In the case of perfect coincidence (identity) of the spectra, the correlation trajectory degenerates into the first diagonal. Partial mismatch between the spectra in frequencies, intensity, baseline drift, the presence of impurities in the sample and/or matrix, or the like, results in a deviation from the diagonal trajectory and is described in a very characteristic way for each type of distinction. This test is extremely sensitive to such differences, but, nevertheless, for the “ideal” conglomerates correlation trajectory is inherently limited by the width of the area near the diagonal. The details of this approach have been described in our recent paper.17 The corresponding correlation trajectory for the two spectra of crystalline samples of 2 is shown in Figure 1a. In general, the image presented in Figure 1a is typical for well-correlated spectra. However, the trajectory is too “fuzzy” for a perfect conglomerate. The detailed analysis of correlation spikes shows that the main differences between the spectra are concentrated in the region of 400−950 cm−1. Typical examples are shown in Figure 2a−d. At the same, the differences between the spectra

initial enantiomeric composition of a solid sample (0 < eesolid < 1).17 In turn, the enantiomeric composition of the saturated solution and the composition of the equilibrium solid phase can be easily determined using “chiral” HPLC analysis. Following this procedure, we have found that the eutectic composition for epoxide 2 is equal to xeu = 0.506 ± 0.008 (here and hereinafter x = mole fraction of the predominant enantiomer) at room temperature (20 ± 1 °C) in cyclohexane. This means that under the experimental conditions, this substance most probably crystallizes in the form of a normal conglomerate. However, we will refrain from definitive conclusions about the phase behavior of 2 in the other temperature ranges. Interestingly, the experimental melting temperature difference of the crystalline racemic and enantiopure samples of 2, ΔTf = 15−16 °C appears to be too low for the case of enantiomers which are fully compatible in the liquid phase and completely incompatible in the solid phase (the property of the “ideal” normal conglomerate). Intrigued by these results, we set out to further investigate the crystallization behavior of 2 using another experimental approaches. IR Spectra Comparison. The comparison of the IR spectra of the pairs of racemic and highly enantiomerically enriched crystalline samples of a chiral compound in KBr pellets is a useful procedure for preliminary evaluation of the crystallization type. In this case, the similarity of the IR spectra is indicative of the similarity in the crystal structure of the racemic and enantiomerically enriched samples and suggests that the examined substance crystallizes as a conglomerate. In contrast, the IR spectra of the racemic compound is usually different from those of the respective enantiomers.6 The main difficulty associated with this approach consists of establishing of the reliable criteria of the similarities and differences of complex spectral curves. For this purpose, we have previously proposed to use the standard Pearson correlation coefficient r between two digital arrays (Ai, νi), where νi stands for the vibration frequency (usually expressed in wave numbers in increments of 1 cm−1), and Ai corresponds to the extinction at this wavenumber.18 Comparison of these spectra for compound 2 is shown in Figure 1. As seen from Figure 1b, there are some very minimal

Figure 2. The fragments of the correlation trajectory (left charts) and the corresponding fragments of the real IR spectra (right charts a−d) of the pair of racemic (red curves) and highly enantiomerically enriched (blue curves) crystalline samples of oxirane 2 in KBr pellets.

are insignificant in the region of stretching vibrations, including vibrations of C−H bonds (some of which are involved in nonclassical hydrogen bonds). Among them, the regions with the most noticeable differences are shown in Figure 2d. This comparison suggests that the supramolecular motifs in the rac-2 and scal-2 crystals are almost identical, and the differences are due to secondary effects (or defects) of the crystal packing. Further investigation of the phase behavior of a chiral epoxide 2 was performed by means of thermal analysis. Thermochemical Investigations. Differential scanning calorimetry (DSC) has served as a working method for the thermal measurements and for construction of a binary melting phase diagrams in this work. In many cases, a limited set of experimental data allows one to obtain a zero level approximation about the phase diagram of a chiral substance and, accordingly, about its type of crystallization, from the comparison of this data with the theoretical models. The minimum set in this case are the values of temperature and enthalpy of melting of enantiopure and

Figure 1. Correlation trajectory (a) for IR spectra (b) of the pair of racemic (red curve) and highly enantiomerically enriched (blue curve) crystalline samples of oxirane 2 in KBr pellets.

differences between the spectra of racemic (red curve) and enantiopure (blue curve) samples of 2; and the correlation coefficient r = 0.994 between the arrays AiR and AiA (here and hereinafter R and A indices stand for the racemic and enantiopure samples) is relatively high. 1678



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0.5 mol fraction should be observed. As reported above (“Solubility test” section), the same value, xeu = 0.506 ± 0.008, was obtained on the basis of an entirely different experimental approach. Thus, according to this criterion, epoxide 2 undergoes spontaneous resolution during crystallization and represents a normal racemic conglomerate, but simultaneously the thermochemical properties of the system do not match to those predicted by Schröder−Van Laar equation, that is, the system deviates from the ideal. This situation forces to us resort to the phase diagram liquidus line construction based on the precise empirical data for the samples of known enantiomeric composition spanning the interval 0 ≤ ee ≤ 1, but such systems are melted incongruently; their fusion curve shape in the posteutectic region (Figure 3, curves 2−6) makes it difficult to determine the exact experimental thermochemical characteristics. The trailing edge of the curves is significantly stretched on the temperature scale, which creates uncertainty in the correlation of the liquidus (the end of fusion point) with a singular point (peak, inflection, etc.) on the experimental curve. Analysis of the literature20,21 shows that there is certain arbitrariness in the methods of processing and interpretation of such experiments, and the observed effects, which hinder the processing of the experimental thermal images and obtaining the correct numerical data, are not always well understood and analyzed. Earlier, when faced with this problem, we suggested that the erosion of the trailing edge of the melting curve is caused by the unavoidable local inhomogeneities of the sample, which is represented by a mechanical mixture of the two (or more) solid phases.22 On the basis of this assumption, we have shown that this effect can be corrected by the extrapolation of the experimental melting curve in the posteutectic region by the equation:

racemic samples. The substitution of the thermochemical parameters of enantiopure sample melting in the known (simplified) Schröder−Van Laar equation19 ln x =

ΔHAf ⎛ 1 1⎞ ⎜⎜ f − f ⎟⎟ R ⎝ TA Tx ⎠

(1)

allows one to estimate the melting point of the hypothetical ideal conglomerate, Tfcong#. If this value is in satisfactory agreement with the experimental value of the melting point of the racemic sample, Tfcong# ≈ TfR, it is possible to conclude that the system has only one eutectic and to expect that the system crystallizes as a normal conglomerate. Figure 3 shows the DSC measured curves of the chiral epoxide 2 samples of different enantiomeric composition. The

Figure 3. Experimental DSC traces of the compound 2 samples with the enantiomeric composition corresponding: 1 (red), x = 0.5; 2 (magenta), x = 0.6; 3 (cyan), x = 0.68; 4 (green), x = 0.74; 5 (dark yellow), x = 0.83, 6 (black), x = 0.91; 7 (blue), x = 0.99.

first and seventh curves correspond to the congruently melting of nearly enantiopure and racemic samples. The nature of these curves allows determining the temperature and enthalpy of melting of rac-2 (100.8 °C and 38.6(9) kJ·mol−1) and (S)-2 (114.5 °C and 39.9(5) kJ·mol−1) unambiguously and precisely. The melting point of normal conglomerate calculated on this basis as the intersection for two Schröder−Van Laar curve legs was 93.9 °C, which is too low as compared with experimental 100.8 °C. Nevertheless, the melting curves for the samples of the intermediate composition (Figure 3, curves 2−6) shows that, despite the change in the composition of the solid phase, the same peak corresponding to the melting temperature of the racemic sample, TfR ∼ 100.8 °C, is reproduced with high accuracy. This means that in the actual phase diagram the only eutectic corresponding to the content of the enantiomers xeu =

2

Cp(T ) = (1 − x)

RT Af

(TAf − T )2

(2)

Here Cp(T) is the effective melting heat capacity as a function of temperature T; x is the sample composition in mole fractions; and TfA is the melting point of the pure component, dominant in the system relative to the eutectic. Leaving out technical details of the derivation of the equation, which are available in the original publication,22 the following discussion is aimed at providing some practical recommendations that are illustrated in Figure 4. In Figure 4a, the red curve is the posteutectic fragment of the melting curve of the sample, the composition of which lies in between the eutectic and enantiopure substance. This curve is

Figure 4. Simulation of the melting of hypothetical binary system (TfA = 100 °C, ΔHf = 30 kJ·mol−1, x = 0.75); solid red line - the melting curve taking into account the inhomogeneities; blue dashed line - the same curve inter- and extrapolated by eq 2. See text for details. 1679



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modeled by the Schröder−Van Laar equation, assuming the existence of local composition inhomogeneities in the sample due to the discrete nature of the sample. Such fluctuations in the composition are described by the Poisson distribution, but during the DSC measured curves modeling we have used the interpolation of a discrete distribution by a continuous Gaussian distribution. Up to the point of inflection (P), the notable differences between this model and the idealized melting contour (blue dotted line) calculated for a fully homogeneous sample are not observed.22,23 This region is well interpolated by the simple eq 2, which allows one to use this fragment to find the parameters of the interpolating function. Then this function can be used for extrapolation of the idealized melting curve to the region of fuzzy trailing edge (blue dashed line in Figure 4). If we assume that the enthalpy of melting is independent of the shape of the curve, then one should use the point Tf as the end of the melting temperature, for which the area under the extrapolated contour, P−Tf, is equal to the area under the contour of the experimentally observed melting peak, P−S (hatched areas marked in blue and red in Figure 4a). When analyzing the DSC measured curves of samples with a composition close to the eutectic, the posteutectic site can be further distorted by the imposition of the eutectic melting peak (see curves 2−4 in Figure 3). In this case, the parameters of the nonlinear eq 2 cannot be correctly determined. On the basis of a numerical simulation of such DSC measured curves in a wide range of parameters, we have found empirically that the abscissa of the point T*f, which lies at a height of ∼0.65 of maximum height of the experimental curve, h, could be used for the estimating the melting termination temperature for such samples. Red dashed line in Figure 4b illustrates the corresponding construction. By the above algorithms, we have evaluated the characteristic temperatures of the melting termination for the samples of intermediate composition. Then we have used these values for the construction of the experimental phase diagram of compound 2, which is shown in Figure 5a. As evidenced by this figure, the experimental liquidus points in the composition range 0.5 ≤ x ≤ 1 lie on a single smooth curve. This behavior is consistent with the hypothesis that the chiral epoxide 2 forms a normal conglomerate characterized by a single eutectic during crystallization, but this model still does not explain the

significant deviation from the behavior of the system predicted by Schröder−Van Laar equation. Lowering of the racemic conglomerate melting point with respect to the enantiopure sample predicted by this equation is due to the contribution of entropy of individual enantiomers mixing, ΔSlm to the melting process of the system. The value of R ln 2 = 5.76 J·mol−1·K−1 corresponds to idealized system. The formula for the estimation of this thermodynamic parameter from experimental data was proposed by Grant et al.24 −ΔSml =

ΔHAf TAf

−

ΔHAf TRf

−

ΔHAf − ΔHRf TAf − TRf

ln

TAf TRf

(3)

Substitution of the experimental data in the formula 3 gives a value of ΔSlm = 3.7 J·mol−1·K−1. This value should be regarded only as estimates, because during the derivation of eq 3 any difference in the melting enthalpy of the racemate and conglomerate was attributed to contribution of the specific heat increment, associated with the transition from a solid phase material to a liquid melt, which is obviously not always a valid assumption. Nevertheless, the calculation indicates the probable presence of an entropy defect in the process of melting of the studied racemic system in relation to the ideal racemic conglomerate. Since there are no reasons to expect the entropy anomaly for mixing of liquid enantiomers under investigation, it means that the entropy of the real crystals of the substance 2 racemic conglomerate is higher than the entropy of the mechanical mixture of the enantiopure crystals. We believe that the most obvious and simple process leading to an increase in the entropy of two solid enantiomers mixture lies in the formation by such a system of (limited) solid solution. This model describes the experimentally observed phase diagram (Figure 5a) and the deviation of the experimental points from the liquidus curve predicted by Schröder−Van Laar equation. Binary systems of enantiomers rarely form solid solutions; according some general estimates (these assessments, however, are not always applicable to the particular sampling) share of such systems is about 1%.6 Examples of chiral substances that undergo spontaneous resolution (in the other words, which are conglomerates), and at the same time having a zone of solid solution on the phase diagram, are even more scarce. We are aware of only three such cases: two belong to the derivatives of mandelic acid,25,26 and the third deals with the chiral sulfoxide, synthetic precursor of API modafinil.27 Therefore, we felt it worthwhile to further investigate this case. The boundary of the zone of mutual solubility of the solid components in this case can be found from the dependence of the eutectic enthalpy (ΔHfeu) on the composition of binary system x, that is, by constructing of a well-known Tammann diagram.28 For homogeneous systems, this dependence must be linear, and its extrapolation to zero eutectic peak area gives the value of maximum solubility of one component in the other in the solid phase. For the system under study, this dependence is shown in Figure 5b. From this figure, it is clear that the regression line crosses the x-axis for x < 1, which confirms the existence of a solid solution within the crystalline phase of chiral 2. The construction of the confidence interval (Figure 5b, area hatched in red) for the linear regression29 through the experimental points of Tammann diagram allows us to estimate the saturation concentration of the proposed solid solution. The range of possible values is defined by the intersection of

Figure 5. (a) The experimental binary melting phase diagram for epoxide 2. Red solid lines - liquidus, blue solid lines - solidus, blue dashed lines - hypothetical solvus. (b) Tammann diagram for binary mixtures of compound 2 enantiomers. Blue circles - experimental values of the eutectic melting enthalpy peak area (y-axis) against the enantiomeric composition of the sample (x-axis). Red shaded area hyperbolic confidence band (confidence level 0.95) for the linear regression trace (solid blue line). 1680



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If one follows the direction of “closest donor−closest acceptor next”, then the figure shows that the sequence of hydrogen bonds in conjunction with the shortest sequence of covalent bonds that unite donor and acceptor fragments within single molecule (Figure 7b) forms a right-handed P-helix. In enantiomorphic crystals formed by R-enantiomers, the same helical sequence has an opposite M configuration. In the crystal lattice, the adjacent 1D columns, linked by translation along the 0a axis, form the bilayer (Figure 8).

the confidence bands with the abscissa axis and corresponds to x ≈ 0.79/0.92. It was demonstrated by Coquerel et al.27 that valuable information related to the boundaries of the mutual solubility of the enantiomers can be obtained by studying the crystal structure of the chiral substance. We also make an attempt in this direction. Single Crystal X-ray Investigations. Enantiopure 4-[4(oxiran-2-ylmethoxy)-1,2,5-thiadiazol-3-yl]morpholine 2, characterized by a positive value of the specific rotation {[α]D25 = +29.0 (c 1.0, CHCl3)}, crystallizes in Sohncke space group P212121 with the only symmetry independent S-molecule in the orthorhombic unit cell [a = 4.2026(1), b = 9.1884(1), c = 28.2702(4) Å]. Flack parameter for this crystal was 0.0, so the thus determined absolute configuration of 2 coincides with those attributed on the basis of chemical arguments. The (S)-2 molecules in crystals have no unusual structural parameters. The molecular structure and the numbering adopted for the compound are shown in Figure 6.

Figure 8. A fragment of (S)-2 crystal packing; (a) view along the 0b axis, (b) view along the 0a axis. A general color denotes the molecules combined in an infinite 1D column through a helical sequence of nonclassical hydrogen bonds.

Furthermore, these structures are combined into the 3D crystal packing due to dispersion interactions of thiadiazole and morpholine fragments located on the periphery of the bilayer (Figure 9). This packing pattern is rather dense; the packing index is 70.9%.

Figure 6. The molecular structure of (S)-4-[4-(oxiran-2-ylmethoxy)1,2,5-thiadiazol-3-yl]morpholine, (S)-2 in the crystalline state and the numbering adopted for its atoms.

Classical hydrogen bond donors are absent in the molecule of epoxide 2. The main directed interactions that form the primary supramolecular motif in 2 crystals are nonclassical hydrogen bonds C(8)−H(81)···O(1′). The parameters of the interaction are as follows: d[C(8)···O(1)] 3.448(3) Å, d[H(81)···O(1′)] 2.57 Å, angle ∠[C(8)−H(81)···O(1′)] 151(1)°, symmetry operation (1 − x, 1/2 + y, 1/2 − z). The infinite one-dimensional (1D) column formed with the participation of these bonds is shown in Figure 7a.

Figure 9. A fragment of the molecular packing in the crystals of (S)-2. Two adjacent bilayers combined by the contacts of peripheral heterocyclic fragments.

Next, we have studied the single crystal limss-2 (as it was mentioned above, prefix “limss” means limit of the solid solution), randomly selected from a racemic polycrystalline sample of compound 2. It was originally solved in the same space group P212121 with similar unit cell parameters. At the same time, the volume of the unit cell was slightly but statistically reliably larger than those of the (S)-2 crystal [1094.2(6) against 1091.66(3) Å3]. To some extent, this fact may indicate a decrease in the packing density of the molecules in the crystal and be a sign of possible molecular disorder. Another difference between the studied crystals of S-2 and limss-2 samples was that for a crystal randomly selected from the racemate, the symmetry independent molecule in the unit

Figure 7. (a) The primary supramolecular motif in (S)-2 crystals; nonclassical CH···O hydrogen bonds are denoted by gray dashed lines; view along the 0b axis. (b) The same fragment, where, for clarity, only retain the hydrogen CH···O bonds and the covalent bonds, which form the shortest path between the donor (H81) and acceptor (O1) fragments of each molecule. 1681



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cell had the R-configuration, but the value of Flack parameter for limss-2 crystal was 0.52(19). This leads us, first, to ignore the absolute configuration of the molecules in the crystal and, second, to doubt the crystal’s high enantiomeric purity. The analysis of thermal anisotropic parameters reveals that the position of the epoxy fragment of the molecule can be disordered in the crystal. In addition to the large thermal ellipsoids of the atoms in the epoxy moieties, the presence of sufficiently strong residual peaks on the electron density difference curve also cast doubt on the correctness of the structure refinement of limss-2. Location of these peaks also corresponded to disorder of the epoxy cycle in two positions and, therefore, possible changes in the configuration of a chiral center (i.e., the presence of different enantiomers within the same site). All these facts demand the introduction of certain amendments to the terms of refining the structure. In principle, a further refinement could be carried out in various ways. We could use a parameter that takes into account the epitaxial nature of the crystal and continue the structure refinement using the existent orthorhombic crystal system. However, the model of epitaxy (regardless of the crystal system used) suggests the presence of individual phases of both enantiomers in the sample. Actually, one can consider the crystalline domains of pure enantiomers having a size of about tens of micrometers, but not the dimensions of several unit cells. We believe that within the framework of thermodynamic model the existence of independent enantiopure phases in a racemic sample comes into conflict with the above results of DSC analysis. On the contrary, solid solution model, in general, does not suggest the regularity in the arrangement of enantiomers in all crystallographic sites. Therefore, we have not found it possible to use molecules disorder refinement in the P212121 group, which implies the presence of a single independent molecule. This in turn would lead to a priori attribution of the same type of disorder to all the sites of the cell. In contrast, in the asymmetric group P1 refinement with all independent molecules (sites) does not impose such restrictions. So we chose to reduce the symmetry of the crystal with a simultaneous increase in the number (actually, up to four) of independent (disordered) molecules. With this approach, the missing elements of symmetry in the crystal would undoubtedly be revealed in the process of refinement. In turn, this would allow returning to the higher crystal system appropriate to these “newly found” symmetry elements. To not make unnecessary restrictions, we thought of varying the degrees of disorder for each of the symmetry independent molecules, although all independent molecules would have the same disordering fragment. To do this, in the process of refining the structure, individual occupancy parameters (statistical occupancy factors, s.o.f.) have been attributed to each molecule. As a result of the limss-2 crystal structure refinement in this approximation, we have obtained very good statistical characteristics and satisfactory values of residual electron density peaks (Table 1). Having obtained this result, we have not considered it necessary to return to a more symmetric group. It was established that the positions of epoxy fragments of all independent molecules in the crystal of limss-2 are disordered over two positions with s.o.f. 0.77:0.23, 0.78:0.22, 0.76:0.24, and 0.80:0.20. Analyzing these values, we would like to emphasize that, first, in spite of the initial parameters PART being independent for each molecule, they all fall into very narrow limits. Consequently, none of the crystallographic sites

has any advantages during the substitution of an enantiomer for its antipode. Second, the quantitative characteristics of the disorder, 0.78(0.02):0.22(0.02), are very close to the range of mutual solubility of one enantiomer in the other in the solid phase, which were determined as described above (Figure 5) through a completely independent approach. All the disordered molecules retain their conformation as a whole, and the configuration of the epoxy fragments belonging to the molecules with the greatest (and, consequently, the least) occupancy is the same for all four independent sites. Being similar to the details with the scal-2 packing (see Figure 8 for comparison), the crystal packing in the limss-2 crystal is additionally characterized by alternating along the 0c direction of individual layers comprising different independent molecules of the compound 2 (Figure 10). Although the calculated crystal

Figure 10. Detail of molecular packing in the limss-2 crystals. View along the crystallographic 0a axis. Four independent molecules are indicated by different colors; epoxy fragments are shown for the most populated sites.

density decreased only slightly, calculations show that the packing index (when disordered part is excluded) tends to decrease and is equal to 70.6%.

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CONCLUSIONS The synthetic precursor of the valuable chiral drug substance timolol 2 represents a rare case of a compound that crystallizes as a stable conglomerate while forming partial solid solution. Racemic composition of the single eutectic of 2 was evaluated on the grounds of original equilibrium solubility test. The detailed analysis of the IR spectra reveals some deviations from the ideal normal conglomerate behavior. DSC data for congruently melting racemic and enantiopure samples of 2, alongside the well-known Schröder−Van Laar equation, show a deviation of the studied system from the ideal case. The special procedure was developed for quantitative analysis of complex DSC measured curves for incongruently melting samples of intermediate enantiomeric composition. This approach allows establishing the binary phase diagram with single racemic eutectic, which is complicated by the presence of mutual solubility zones for enantiomers in the solid state. Two single crystals of compound 2 were investigated by Xray analysis. One of them was prepared from single enantiomeric feed material, whereas the second one (limss-2) 1682



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(10) Sheldrick, G. M. SADABS, Program for Empirical X-ray Absorption Correction; Bruker-Nonius: Delft, 2004. (11) Sheldrick, G. M. SHELXTL, Structure Determination Software Suite, v.6.1; Bruker AXS, Madison: Wisconsin, USA, 2000. (12) Farrugia, L. J. J. Appl. Crystalogr. 1999, 32, 837−838. (13) (a) Flack, H. D. Acta Crystallogr. 1983, A39, 876−881. (b) Flack, H. D.; Bernardinelli, G. J. Appl. Crystallogr. 2000, 33, 1143− 1148. (c) Parsons, S.; Flack, H. D.; Wagner, T. Acta Crystallogr., Sect. B: Struct. Sci. 2013, 69, 249−259. (14) APEX2 (Version 2.1), SAINTPlus. Data Reduction and Correction Program (Version 7.31A), Bruker Advanced X-ray Solutions; BrukerAXS Inc.: Madison, WI, 2006. (15) Macrae, C. F.; Edgington, P. R.; McCabe, P.; Pidcock, E.; Shields, G. P.; Taylor, R.; Towler, M.; van de Streek, J. J. Appl. Crystallogr. 2006, 39, 453−457. (16) Spek, A. L. J. Appl. Crystallogr. 2003, 36, 7−13. (17) Bredikhin, A. A.; Zakharychev, D. V.; Fayzullin, R. R.; Antonovich, O. A.; Pashagin, A. V.; Bredikhina, Z. A. Tetrahedron: Asymmetry 2013, 24, 807−816. (18) Bredikhin, A. A.; Bredikhina, Z. A.; Akhatova, F. S.; Zakharychev, D. V.; Polyakova, E. V. Tetrahedron: Asymmetry 2009, 20, 2130−2136. (19) Prigogine, I.; Defay, R. Chemical Thermodynamics; Longmans Green and Co: London, 1954. (20) (a) Haines, P. J.; Reading, M.; Wilburn, F. W. In Handbook of Thermal Analysis and Calorimetry; Brown, M. E., Ed.; Elsevier Science B.V.: Amsterdam, The Netherlands, 1998; Vol. 1, Chapter 5, pp 279− 361; (b) Höhne, G.; Hemminger, W.; Flammersheim, H.-J. Differential Scanning Calorimetry; Springer-Verlag: Berlin, 2003. (c) Brown, M. E. Introduction to Thermal Analysis: Techniques and Applications; Kluwer Academic Publishers: New York, 2004. (21) Boettinger, W. J.; Kattner, U. R.; Moon, K.-W.; Perepezko, J. H. DTA and Heat-flux DSC Measurements of Alloy Melting and Freezing; Spec. Publ. 960−15, National Institute of Standards and Technology: Gaithersburg, MD, 2006. (22) Zakharychev, D. V.; Bredikhin, A. A. Rus. Chem. Bull. Int. Ed. 2007, 56, 1337−1342. (23) Bader, R. G.; Schawe, J. E. K.; Höhne, G. W. H. Thermochim. Acta 1993, 229, 85−96. (24) Li, Z. J.; Zell, M. T.; Munson, E. J.; Grant, D. J. W. J. Pharm. Sci. 1999, 88, 337−346. (25) Wermester, N.; Aubin, E.; Pauchet, M.; Coste, S.; Coquerel, G. Tetrahedron: Asymmetry 2007, 18, 821−831. (26) Taratin, N. V.; Lorenz, H.; Kotelnikova, E. N.; Glikin, A. E.; Galland, A.; Dupray, V.; Coquerel, G.; Seidel-Morgenstern, A. Cryst. Growth Des. 2012, 12, 5882−5888. (27) Renou, L.; Morelli, T.; Coste, S.; Petit, M. N.; Berton, B.; Malandain, J. J.; Coquerel, G. Cryst. Growth Des. 2007, 7, 1599−1607. (28) (a) Tammann, G. Z. Anorg. Chem 1903, 37, 303−313. (b) Tammann, G. Lehrbuch der heterogenen gleichgewichte; Friedr, Vieweg & Sohn: Braunschweig, 1924. (29) Kenney, J. F.; Keeping, E. S. In Mathematics of Statistics, Pt. 1, 3rd ed.; Van Nostrand: Princeton, NJ, 1962; Chapter 15, pp 252−285.

was picked out from racemic polycrystalline sample. The structure of the enantiopure crystal was solved and refined in the Sohncke space group P212121 with the only symmetry independent molecule in the orthorhombic unit cell. To obtain satisfactory statistics, the structure of the limss-2 crystal was solved and refined in the P1 space group with four symmetry independent molecules in the triclinic unit cell. It was established that the positions of epoxy-fragments of the independent molecules in this crystal were disordered over two positions with almost equal relative occupancies of opposite enantiomers for all the molecules. The quantitative characteristics of the disorder, the statistical occupancy factors 0.78(0.02):0.22(0.02), are very close to the range of mutual solubility of one enantiomer in the other in the solid phase, found by a completely independent method of the Tammann diagram. The detailed understanding of crystallization behavior of chiral compounds is of high importance for optimization of the methods of chiral drug production and purification. In this work, we also developed some new procedures that help reveal the unusual crystallization properties that otherwise can easily remain unnoticed in binary and/or ternary enantiomeric systems.

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ASSOCIATED CONTENT

S Supporting Information *

Crystallographic information files. This information is available free of charge via the Internet at http://pubs.acs.org/.

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AUTHOR INFORMATION

Corresponding Author

*Phone/fax: +7 843 2319167/+7 843 2731872. E-mail: baa@ iopc.ru. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors thank the Russian Fund of Basic Research for financial support (Grant No. 13-03-00174). We also wish to thank Dr. R.M. Eliseenkova for valuable technical assistance.

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REFERENCES

(1) Mazzo, D. J.; Loper, A. E. Anal. Profiles Drug Subs. 1987, 16, 641−692. (2) The Merck Index, 14th ed.; O’Neil, M. J., Ed.; Merck and Co., Inc.: Whitehouse Station, NJ, 2006; p 9444. (3) Vardanyan, R. S.; Hruby, V. J. Synthesis of Essential Drugs; Elsevier: Amsterdam, 2006; pp 166−177. (4) (a) Weinstock, L. M.; Mulvey, D. M.; Tull, R. J. Org. Chem. 1976, 41, 3121−3124. (b) Bredikhina, Z. A.; Pashagin, A. V.; Savel’ev, D. V.; Bredikhin, A. A. Rus. Chem. Bull. Int. Ed. 2001, 50, 436−439. (c) Tosi, G.; Zironi, F.; Caselli, E.; Forni, A.; Prati, F. Synthesis 2004, 1625− 1628. (d) Narina, V. N.; Sudalai, A. Tetrahedron 2007, 63, 3026−3030. (5) Bredikhin, A. A.; Bredikhina, Z. A.; Zakharychev, D. V. Mendeleev Commun. 2012, 22, 171−180. (6) (a) Jacques, J.; Collet, A.; Wilen, S. H. Enantiomers, Racemates and Resolutions; Krieger Publishing Company: Malabar, FL, 1994. (b) Eliel, E. L.; Wilen, S. H.; Doyle, M. P. Basic Organic Stereochemistry; Wiley-Interscience: New York, 2001. (7) Bredikhin, A. A.; Bredikhina, Z. A.; Zakharychev, D. V.; Gubaidullin, A. T.; Fayzullin, R. R. CrystEngComm 2012, 14, 648−655. (8) McClure, D. E.; Engelhardt, E. L.; Mensler, K.; King, S.; Saari, W. S.; Huff, J. R.; Baldwin, J. J. J. Org. Chem. 1979, 44, 1826−1831. (9) Peuschel, K. E. WO Pat. 93/20814, 1993. 1683


Crystallization Features of the Chiral Drug Timolol Precursor: The

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