Article pubs.acs.org/crystal
Solubility Equilibria and Crystallographic Characterization of the L‑Threonine/L-allo-Threonine System, Part 1: Solubility Equilibria in the Threonine Diastereomeric System D. Binev,† N. Taratin,‡ E. Kotelnikova,‡ A. Seidel-Morgenstern,† and H. Lorenz*,† †
Max Planck Institute for Dynamics of Complex Technical Systems, Magdeburg D-39106, Germany Department of Crystallography, Saint Petersburg State University, Saint Petersburg 199034, Russia
‡
ABSTRACT: Solubility equilibria of threonine, allo-threonine, and their mixtures in water were measured in a temperature range between 10 and 80 °C. In comparison with allo-threonine, the threonine species exhibit higher solubility in water. The solubility phase diagram of the ternary system L-allo-threonine/Lthreonine/water shows maximum solubilities at L-threonine contents in the range of 56−66%, while the tie lines clearly indicate the presence of solid solutions. X-ray powder diffraction (XRPD) studies of various mixtures prove complete miscibility of L-allo-threonine and L-threonine molecules in the solid state, based on characteristic features of measured diffraction patterns and calculated lattice parameters. Applying the solubility data determined, fractional crystallization is suggested as an effective purification method of mixtures below or above the alyotropic composition.
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INTRODUCTION A considerable number of active pharmaceutical ingredients (API) are chiral substances, having at least one chiral center in the molecule, called enantiomers. Often the desired form is only one of the enantiomers, while the other can possess no, only weak, or different (usually not desired) pharmacological effects. When the API’s have two chiral centers in their molecules, a combination of four chiral molecules occurs, forming two pairs of enantiomers. The amino acids threonine (Thr) and allo-threonine (aThr) are stereoisomers of 2-amino3-hydroxybutanoic acid, a molecule that contains two chiral centers. The four different molecular configurations are shown in Figure 1. L-Thr/D-Thr and L-aThr/D-aThr form the two enantiomer pairs; L-Thr/L-aThr, L-Thr/D-aThr, D-Thr/L-aThr, and D-Thr/D-aThr are diastereoisomers to each other. As obvious from the interrelations in Figure 1, to evaluate the
crystallization (solubility) behavior in the threonine diastereomeric system, it is principally sufficient to study the two enantiomeric systems, one diastereomeric pair with species of the same sign of optical activity (e.g., L-Thr/L-aThr) and one diastereomeric pair with opposite sign of optical activity (e.g., LThr/D-aThr). L-Thr is one of the essential proteinogenic amino acids, and it is required for body growth, for uric acid metabolism, and in the immune system. It is an important component in the protein metabolism chain and contributes to the formation of enzymes and hormones.1 allo-Threonine on the other hand is a nonproteinogenic amino acid and therefore is unavailable from natural sources. The enzyme D-threonine aldolase isolated from Arthrobacter catalyzes the cleavage of D-Thr into glycine and acetaldehyde, where both D-Thr and D-aThr act as substrates with different kinetic parameters, since the aldolase reaction is reversible and almost equimolar amounts of both can be produced.2,3 D-aThr has been also found in several natural antibiotics.4,5 Enantiopure L-aThr is used as a starting material in the chemical synthesis of lysobactin, which displays strong antibiotic activity and is applied against methicillin-resistant Staphylococcus aureus (MRSA).6 The four amino acids can be obtained via fermentation7 and chemical synthesis.8 To avoid unwanted side effects from the impurities present in the resulting solutions, commonly crystallization is used for further purification purposes. However, the maximum extent of purification is thermodynami-
Figure 1. Molecular configurations of threonine molecules. Enantiomer pairs are indicated with blue lines and diastereoisomer pairs with red dashed lines. © XXXX American Chemical Society
Received: June 27, 2013 Revised: December 2, 2013
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also for the design of materials with predefined properties and a deeper understanding of the mechanisms behind miscibility of organic molecules in the solid state. This article is divided into two main sections. In the first section, measured solubility curves of DL-Thr, DL-aThr, L-Thr and L-aThr in water are reported and discussed. Further, results of systematic studies of the solid−liquid equilibria in the ternary L-aThr/L-Thr/water system are presented, and the ternary phase diagram is constructed. The second section addresses the XRPD-based characterization of the solid phase behavior in the system L-aThr/L-Thr/water, which allowed us to unambiguously determine and verify their solid state nature (pure compounds, mechanical mixture, intermediate compound, or solid solutions). Finally, based on the results obtained, a possible procedure for purifying mixtures of L-aThr and L-Thr is suggested.
cally limited by miscibility of the target compound and the impurity in the solid state, which can cover the entire composition range of the binary mixture or just a limited part (complete or finite solid solutions, respectively). For organic systems, miscibility in the solid state is not that frequent as known from inorganic metallic and mineral systems; literature references report an occurrence of such cases of about 15%.9 Besides miscibility in the solid state, two components can be also completely immiscible in the solid state, forming a simple eutectic (thus being a conglomerate in mixtures) or an intermediate compound in the related solubility phase diagram. The most common cases of such phase diagrams, representing solid−liquid equilibria of diastereomeric systems in a solvent, are presented in Figure 2.
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EXPERIMENTAL SECTION
Substances. DL-Threonine and L-threonine were obtained from Sigma-Aldrich with purity >98%. DL-allo-Threonine and L-allothreonine were purchased from TCI with purity >99%. The enantiomeric excess (ee) of the substances used was checked by HPLC and can be given as 0% ee for DL-Thr and DL-aThr and 100% ee for L-Thr and L-aThr. The water used was deionized. Measurement of Solubility Equilibria. Solubilities of DL-Thr, LThr, DL-aThr, L-aThr, and L-aThr/L-Thr mixtures of different compositions in water were studied in a temperature range between 10 and 80 °C using a polythermal method. Specific amounts of the substances were weighted and filled together with 1 g of distilled water and a magnetic stir bar in small vials. The vials were inserted in a Crystal16 multiple-reactor system (Avantium, The Netherlands). It consists of four independently thermostatted aluminum reactor blocks encased in a benchtop setup, which are electrically heated and cooled by a combination of Peltier elements and a cryostat. The turbidity was recorded per individual reactor to detect the disappearance of last crystals (“clear point”) in multiple heating runs. The corresponding temperatures represent the saturation temperatures of the respective sample. Heating rates of 3 K/h and a stirring rate of 400 min−1 were predefined using the apparatus software. The reproducibility of the solubility measurements was studied carrying out three experiments under same conditions. The standard deviation of the saturation temperature SDT = (∑Ni=1(Ti − T̅ )2/(N −1))1/2 was estimated to be 0.4 K, where {T1, T2, ..., TN} are the observed temperature values for each measurement and T̅ is the mean value of these observations. An isothermal method was used to determine the tie lines in the ternary phase diagram at 10 °C. Predefined mixtures with different compositions of L-Thr and L-aThr were inserted in vials, and subsequently 10 g of distilled water was added. The vials were heated well above the expected saturation temperature to completely dissolve the solids, and then tempered at 10 °C under stirring for 5 days to guarantee a saturated solution with an excess of crystals. Afterward, the phases were separated by filtration and both were analyzed for composition by HPLC (1200 series equipment, Agilent Technologies, Germany; column: Chirobiotic T, 5 μm, 250 mm × 4.6 mm, Astec, USA; eluent: 70/30 v/v, ethanol/water). For characterization of the solid state nature, the solid phases were analyzed via XRPD. The so measured solubilites were compared with solubilities from polythermal measurements. In the text, the solubilities are given in weight percent, which equals the mass of the substance multiplied by 100 and divided by the mass of the solution. Solid Phase Characterization via XRPD. Supplementary to the assays from solubility measurements, multiple extra samples for the XRPD study were prepared as follows: Defined quantities of L-Thr, LaThr, and mixtures of both were first completely dissolved in water. The solution was then placed in a Petri dish and kept at 50 °C in a drying oven until crystallization occurred and all solvent was evaporated. As a result the composition of the final product is
Figure 2. Main types of ternary phase diagrams occurring for diastereomeric systems of components A and B in a solvent: (a) simple eutectic between A and B; (b) an intermediate compound of A and B; (c) solid solutions of A and B with complete miscibility and a solubility minimum. Adapted from ref 10.
There, complete miscibility in the solid state is exemplarily shown on a phase diagram with solubility minimum (Figure 2c). Further possible cases are systems exhibiting a solubility maximum and also systems without any extremum in the solubility isotherms. Of course, partial miscibility can also occur for systems with a simple eutectic and for intermediate compound-forming systems. For separation purposes in such systems, thus, profound knowledge of the corresponding solid− liquid equilibria in combination with the particular solid phase behavior is therefore of crucial relevance. The enantiomer pairs L-Thr/D-Thr and L-aThr/D-aThr have been identified as conglomerate-forming systems, with a eutectic composition occurring at the racemic 1:1 composition of the enantiomers.11 For the L-Thr/L-aThr system, there is an indication of a possible formation of solid solutions, based on a single crystal X-ray diffraction study. For a crystal investigated, a statistical distribution of L-threonine molecules (45%) and Lallo-threonine molecules (55%) in the crystalline structure could be revealed.12 However, this was a single assay, and the ternary phase diagram of the system remained still unknown. This refers both to the binary melt phase diagram (which is not accessible due to thermal instability of the threonine species) and the solubility phase diagram of the diastereoisomers. A recently reported multistep approach for the separation of mixtures of L-Thr and L-aThr has shown that a simple recrystallization does not lead to demixing of the product. Moreover, a further derivatization stage was needed in order to complete the separation.13 The latter also could be considered as an indication of solid solutions within this system. Recently several articles were published concerning phase equilibria and related crystal structure features of chiral organic solid solutions.14−17 Such research is of relevance not only for successful crystallization-based separation and purification but B
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Figure 3. Solubility of the enantiomers and racemic mixtures of Thr and aThr as a function of temperature (this work and literature data19−23).
Table 1. Measured Saturation Temperatures in °C for L-aThr/L-Thr Mixtures at Different Total Solution Concentrations content of L-Thr in binary mixture (%)
a
solution concn (wt %)
100
75
70
65
60
55
50
25
0
7.41 9.09 10.71 13.04
16.3 32.9 44.8 59.7
a 1.7 18.6 35.3
a a 14 29.4
a a 6.7 8.3
a a 2.6 18.1
a a 12.1 27.5
a 1.5 29.4 41
28.7 43.8 55.3 b
47.4 60.7 71.4 b
Ice crystals formed in solution below 0 °C. bIncipient decomposition of the amino acids indicated by slight coloring of the solution.
increasing up to a difference of 0.7 wt % (or ∼5% relative) at about 60 °C. The solubilities of DL-aThr and L-aThr show slight exponential dependence on temperature. For both, just one solubility value at 10 °C was known from literature,23 which fits fairly well to the results measured in this work. Generally, the solubilities of DL-aThr and L-aThr are lower than the solubilities of the corresponding threonine species. For the ideal case, the solubility of the racemic solution equals the sum of the solubilities of the single enantiomers. In our case, with increase of temperature, the solubility ratios between the racemic mixture and the pure L-enantiomer change from ∼1.95 at 10 °C to ∼1.7 at 60 °C. The van’t Hoff plot (not shown here) gives almost perfect linearization, and the slopes for the four species are very similar. To study the influence of L-aThr on the L-Thr solubility in water, solubilities of predefined mixtures of both were measured. The corresponding experimental results are summarized in Table 1, represented as saturation temperatures of the pure substances and L-aThr/L-Thr mixtures of specified composition at various solution concentrations. As can be seen in Table 1, with increasing amount of L-aThr in the mixture, the saturation temperature rapidly decreases reaching a minimum at about 60−65% of L-Thr. The formation of ice in the solution was observed below 0 °C for samples with concentrations of 7.41 and 9.09 wt % (see Table 1), thus distorting the experiments with additional phase appearance. Solubilities for samples with a L-Thr content below 50% and a total concentration of 13.04 wt % (see Table 1) were not possible to accurately measure due to incipient decomposition of the amino acids indicated by slight coloring of the solution. In order to construct the saturation isotherms in the solubility phase diagram of the L-aThr/L-Thr/water system, the values from Table 1 were plotted on a temperature− composition diagram (not shown here). Extrapolation of the L-
determined by the composition of the initial solution. The high evaporation rate caused almost instantaneous crystallization, avoiding “continuous fractionation” of the solid and thus inherent inhomogeneity of the crystal composition. The so cocrystallized samples were ground in a mortar and prepared on background-free sample holders. Ultrapure germanium powder (∼10 wt %) was used as internal standard to avoid the zero shift in XRPD measurements for unit cell parameter calculations. High-resolution XRPD patterns were measured with an X’Pert Pro diffractometer (PANanalytical GmbH, Germany) using Cu Kα radiation and an X’Celerator detector. The patterns were recorded in a 2Θ range of 3−40°, a step size of 0.004°, and a counting time of 300 s per step. Some additional measurements were performed on a Stoe Stadi P diffractometer in an extended 2Θ range of 3−50° (linear PSD detector, transmission mode, step size 0.01° at 30 s per step). Initial positions of 2Θ and intensities were accurately determined by means of the profile fitting in the X’Pert High Score Plus software. After this, positions of 2Θ were adjusted according to the constant systematic correction. All XRPD patterns were indexed using the calculated powder pattern from the crystal structure of L-threonine18 as a starting point. For the calculation of unit cell parameters, the comprehensive set of hkl reflexes within the range of 2Θ 10−50° was used.
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RESULTS AND DISCUSSION Solubility Equilibria. The solubilities of the pure enantiomers and racemic mixtures of Thr and aThr in water are presented in Figure 3. The trend lines for each substance consider all experimental points and additional data from literature. For all species, a positive slope of the solubility curves is observed, that is, the solubility increases with temperature. The results presented for DL-Thr fit almost perfectly to literature data, and a linear dependence of solubility on temperature can be derived. The latter also holds for L-Thr; the measured and reference data slightly deviate starting at about 30 °C and C
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In Figure 5 the solubility equilibria of L-aThr and L-Thr in water are represented on a triangular diagram as commonly used for ternary systems with one component being a classical solvent and introduced before in Figure 2. Additionally, tie lines exemplarily measured for the 10 °C isotherm are incorporated. They specify the composition of coexisting solid and liquid phases in equilibrium and clearly indicate the formation of solid solutions in the L-aThr/L-Thr system. The gradual and steady shift of the solid phase composition concertedly with the liquid phase composition suggests the occurrence of complete miscibility of the diastereoisomers in the solid state, with a solubility maximum in the phase diagram. To verify the results and to exactly determine possible miscibility limits of solid solutions in the system, X-ray powder diffraction studies of the solid phase behavior will be discussed in the following. Characterization of the Solid Phase Behavior via XRPD. The study was conducted using samples of pure L-aThr and L-Thr, as well as 18 samples of coprecipitated mixtures of the pure diastereomers in different ratios. Indices for all the XRPD patterns were obtained in the orthorhombic space group P212121 and are in good agreement with the literature.12,18,25 Exemplary XRPD patterns, obtained for the pure diastereomers and three intermediate compositions (25%, 50%, and 75% of L-Thr) are shown in Figure 6. Indexing results are given on the example of the L-aThr pattern. Figure 6 also contains a diffractogram of an equimolar mechanical mixture of L-aThr and L-Thr. The powder patterns of pure diastereomers have similar configurations, that is, contain identical sets of peaks having similar relative intensities. Accordingly, the diffractogram of the mechanical mixture contains two sets of peaks, each set corresponding to an individual diastereomer. At first glance, the XRPD patterns of the pure diastereomers and their
Figure 4. Quasi-binary solubility phase diagram of the system L-aThr/ L-Thr/water with solubility isotherms between 10 and 40 °C (isotherm lines are guides to the eyes.).
Thr composition at a constant temperature from the concentration isopleths then gives the necessary data points for the isotherms. The error of the extrapolation was estimated to be ∼2%. The results are shown in Figure 4 in a quasi-binary solubility phase diagram (so-called Lippmann diagram24). As can be seen, the solubility in the diastereomeric system increases from both pure component sides with rising level of the other component, reaching maximum values at L-Thr contents between ∼56% and 66%. Consequently, the phase diagram is not symmetric, unlike that for enantiomer pairs11 (e.g., L-Thr and D-Thr).19 This was expected, because diastereomers, in contrast to enantiomers, possess different chemical and physical properties, as obvious from the solubilities of pure L-Thr and L-aThr, shown in Figure 3.
Figure 5. Ternary solubility phase diagram of the system L-aThr/L-Thr/water with tie lines for the 10 °C solubility isotherm (axes in weight fractions). Isotherms at 10 (highest), 20, 30 and 40 °C (lowest) are shown, respectively. D
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Figure 6. XRPD patterns of L-Thr, L-aThr, and different cocrystallized mixtures of intermediate composition. MM*, mechanical 50:50 mixture of LThr and L-aThr.
pairs 200110 and 310020, in the spectra of the intermediate compositions, the same peaks are partially overlapped, and in the case of compositions close to equimolar ratio of L-Thr and L-aThr, peaks merge completely. Figure 8 shows the dependence of the orthorhombic cell parameters a, b, c (Å) and its volume V (Å3) on the sample composition. In the composition range 0−35% of L-Thr, parameter a gradually decreases, while parameter b increases; it was also observed that the variation of parameter a was comparable to that of parameter b: Δa ≈ 0.08 and Δb ≈ 0.09 Å. In the composition range 35−100% of L-Thr, parameter a changes insignificantly (up to 0.02 Å). However, variation of parameter b in the same compositional range is more complex. In the composition range 35−65% of L-Thr, parameter b does not alter noticeably (up to 0.01 Å), while in the compositional range of 65−100%, it diminishes considerably (Δb ≈ 0.13 Å). Parameter c is the least sensitive to the compositional change in the crystal, and its value is slightly lowering in the whole compositional region ranging from L-aThr to L-Thr (Δc ≈ 0.03 Å). The cell volume V does not vary substantially in the composition range 0−65% of L-Thr (no more than 1.5 Å3) and decreases in the range of 65−100% of L-Thr (ΔV ≈ 10 Å3). The presented dependence of the unit cell parameters on the composition in the L-aThr/L-Thr system clearly verifies the formation of continuous solid solutions, caused by the incorporation of the “foreign” molecules into the “host” diastereomer structure. Additional evidence of solid solution formation is that the XRPD patterns of the mechanical and coprecipitated equimolar diastereomer mixtures in Figure 6 (MM* and 50% L-Thr, respectively) are clearly different. While the powder pattern of the mechanical mixture consistently shows two separate solid phases, for the coprecipitated sample, only one phase is observed. Further, as obvious from Figure 8, our results are in a good agreement with data obtained by X-ray structural analysis for single crystals of L-Thr,18 L-aThr,25 and a mixed crystal containing 45% L-Thr.12 A characteristic feature of L-aThr/L-Thr solid solutions is that in the compositional range close to equimolar ratio (35−65%
coprecipitated mixtures in the L-aThr/L-Thr system seem to be almost identical. In fact, this only applies to the pure components L-aThr and L-Thr. For the cocrystallized samples of intermediate compositions, the diffraction peaks tend to be broader and not that sharp as measured for pure components. A more thorough investigation of the XRPD patterns reveals dissimilarities between those of the pure diastereomers and intermediate compositions, particularly in the 2Θ ranges of 12.9−13.3° and 22.6−23.2°. These characteristic sections are shown in detail in Figure 7. While X-ray patterns of the diastereomers contain two sharply resolved peaks in each of the
Figure 7. Characteristic “fingerprint” sections of the XRPD patterns of pure L-Thr, L-aThr, and several mixtures of them. The sample with 95% L-Thr was measured in transmission mode; all other shown samples were measured in reflection mode. E
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Similar peculiarities of diffraction patterns and analogous pairs of peaks (h00hk0 and hk00k0) were observed during the investigation of solid solutions of n-alkanes in broad compositional and temperature ranges.26 It was explained as a transformation from an orthorhombic crystalline phase into a hexagonal rotator-crystal phase due to compositional or thermal deformations of the crystal structure. However, the authors believe that a simple geometrical “hexagonal ratio” between parameters a and b observed for some compositions in the L-aThr/L-Thr system cannot prove the presence of an individual phase with essentially different (hexagonal) crystalline structure. The shown dependence of solubility on sample composition (Figures 4 and 5) also confirms the above suggestion, as do the results of thermal X-ray diffraction analysis and single crystal X-ray analysis of mixed crystals of LThr and L-aThr, which will be discussed in a separate article that forms part 2 of this study. Suggestion of a Possible Purification. In a system of two diastereomers that show complete miscibility in the solid state with a solubility maximum in the phase diagram (as found for LaThr and L-Thr, Figures 4 and 5), from compositions left and right of the solubility maximum the corresponding diastereomers can be gained by fractional crystallization. Thus, both purified L-aThr and L-Thr are accessible from mixtures exploiting the knowledge of the phase diagram. Based on the tie lines specified in the ternary solubility phase diagram in Figure 9, a hypothetical purification experiment of an arbitrary 85/15 L-Thr/L-aThr mixture will exemplarily be discussed here.
Figure 9. L -Thr purification steps using multiple fractional crystallization. The dashed lines represent water addition (axes in weight fractions; the upper 15% section of the diagram is enlarged and isotherms at 10, 20, 30, and 40 °C are shown, from top to bottom, for clarity purposes).
Figure 8. Dependence of the orthorhombic cell parameters of the samples on their compositions in the L-aThr/L-Thr system. Black circles represent data obtained by the authors, while red circles stand for the data, given in literature12,18,25 for compositions 0%, 45%, and 100% of L-Thr, respectively. Error bars for unit cell parameters are indicated.
A mixture of 85% L-Thr and 15% L-aThr (point 1) is completely dissolved in water at 30 °C to provide after a crystallization at 10 °C a liquid phase with a composition of 82% L-Thr and 18% L-aThr (point 2) and a solid phase (a solid solution) of 93% L-Thr and 7% L-aThr (point 3). After solid/ liquid separation and a further dissolution and crystallization step, a liquid phase containing 93% L-Thr and 7% L-aThr (point 4) and a solid phase containing 97% L-Thr and 3% L-aThr (point 5) result. A third step (not shown in Figure 9) allows achieving a purity of >99%. The feasibility of such a fractional
of L-Thr) the orthorhombic cell parameters a and b become almost “insensitive” to the incorporation of molecules of one diastereomer into the crystalline structure of the other. On the XRPD patterns of such compositions, the peaks in pairs 200 110 and 310020 merge completely (see Figure 7), and the ratio between orthorhombic parameters a and b is almost equal to a/b = √3. This means that the parameters for the said compositions can be calculated not only in the orthorhombic but also in the hexagonal unit cell. F
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(7) Leuchtenberger, W.; Huthmacher, K.; Drauz, K. Appl. Microbiol. Biotechnol. 2005, 69, 1−8. (8) Coppola, G. M., Schuster, H. F. Asymmetric Syntheses, Construction of Chiral Molecules Using Amino Acids; John Wiley & Sons: New York, 1987. (9) Matsuoka, M. in Advances in Industrial Crystallization; Garside, J., Davey, R. J., Jones, A. G., Eds.; Butterworth-Heinemann: Oxford, 1991. (10) Sistla Venkata, S.; von Langermann, J.; Lorenz, H.; SeidelMorgenstern, A. Cryst. Growth Des. 2011, 11 (9), 3761−3768. (11) Jacques, J., Collet, A., Wilen, S. H. Enantiomers, Racemates, and Resolutions; Krieger: Malabar, 1994. (12) Swaminathan, P.; Srinivasan, R. J. Cryst. Mol. Struct. 1975, 5, 101−111. (13) Yajima, T.; Ichimura, S.; Horii, S.; Shiraiwa, T. Biosci., Biotechnol., Biochem. 2010, 74, 2106−2109. (14) Wermester, N.; Aubin, E.; Pauchet, M.; Coste, S.; Coquerel, G. Tetrahedron: Asymmetry 2007, 18, 821−831. (15) Renou, L.; Morelli, T.; Coste, S.; Petit, M.; Berton, B.; Malandain, J.; Coquerel, G. Cryst. Growth Des. 2007, 7, 1599−1607. (16) Bredikhin, A. A.; Bredikhina, Z. A.; Zakharychev, D. V.; Gubaidullin, A. T.; Fayzullin, R. R. CrystEngComm 2012, 14, 648−655. (17) 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. (18) Janczak, J.; Zobel, D.; Luger, P. Acta Crystallogr. 1997, C53, 1901−1904. (19) Sapoundjiev, D.; Lorenz, H.; Seidel-Morgenstern, A. J. Chem. Eng. Data 2006, 51, 1562−1566. (20) Shiraiwa, T.; Yamauchi, M.; Yamamoto, Y.; Kurokawa, H. Bull. Chem. Soc. Jpn. 1990, 63, 3296−3299. (21) Profir, V. M.; Matsuoka, M. Colloids Surf., A 2000, 164, 315− 324. (22) Funakoshi, K.; Matsuoka, M. Cryst. Growth Des. 2008, 8, 1754− 1759. (23) Miyazaki, H.; Morita, H.; Shiraiwa, T.; Kurokawa, H. Bull. Chem. Soc. Jpn. 1994, 67, 1899−1903. (24) Prieto, M. Rev. Mineral. Geochem. 2009, 70, 47−85. (25) Swaminathan, P.; Srinivasan, R. Acta Crystallogr. 1975, B31, 217−221. (26) Chazhengina, S. Yu.; Kotelnikova, E. N.; Filipova, I. V.; Filatov, S. K. J. Cryst. Mol. Struct. 2003, 647, 243−257. (27) Binev, D., Wloch, S., Lorenz, H., Seidel-Morgenstern, A. Proceedings of the HANBAT International Workshop on Industrial and Pharmaceutical Crystallization - HIW2012, Kim, K.-J., Ed.; Hanbat National University in cooperation with Korea Drug Research Association: Daejeon, South Korea, 2012; pp 127−135. (28) Temmel, E.; Wloch, S.; Müller, U.; Grawe, D.; Eilers, R.; Lorenz, H.; Seidel-Morgenstern, A. Chem. Eng. Sci. 2013, 104, 662− 673.
crystallization process has been already demonstrated on a similar type of system27 and can favorably be performed in a semiautomatic manner.28
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CONCLUSIONS A fundamental study of solubility equilibria of threonine, allothreonine, and their mixtures in water was performed using polythermal and isothermal methods. The resulting solubility phase diagram of the ternary system L-aThr/L-Thr/water indicates complete miscibility in the solid state in the temperature range of 10−40 °C, based on the shape of the solubility isotherms and particularly on the course of the corresponding tie lines. The diastereomeric system shows maximum solubilities at L-Thr contents between 56% and 66%. The formation of continuous solid solutions, that is, full miscibility of L-aThr and L-Thr molecules in the solid state, could be clearly verified by X-ray powder diffraction studies. This conclusion is based on both characteristic features of measured powder patterns and unit cell parameters calculated for samples with various compositions. The discontinuous change of the lattice parameters with composition in the system correlates with the maximum in the saturation isotherms in the solubility phase diagram (almost constant parameters a and b in this range and alteration of unit cell volume at ∼65% L-Thr), which thus can be interpreted (in analogy to the azeotropic composition for liquid/gas equilibria) as alyotropic composition.24 Part 2 of this ongoing investigation will focus on deeper understanding of the solid state behavior in the L-aThr/L-Thr system. In this context, it addresses the following issues: (1) study of thermal deformations of the crystal structure of L-Thr, L-aThr and selected mixed crystals by temperature-resolved XRPD and (2) discussion of some special features of the crystal structure of L-Thr/L-aThr mixed crystals based on single crystal XRD analyses to provide new insights in the mechanisms behind.
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work is dedicated to the memory of the late Professor Arkady E. Glikin. Nikolay Taratin acknowledges support by RFBR Grants 13-05-12053 and 12-05-00876.
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REFERENCES
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dx.doi.org/10.1021/cg400968t | Cryst. Growth Des. XXXX, XXX, XXX−XXX
