Crystallization of Stable and Metastable Phases of Phenylsuccinic Acid Veronica M. Profir and A° ke C. Rasmuson* Department of Chemical Engineering and Technology, Royal Institute of Technology, SE-100 44 Stockholm, Sweden
CRYSTAL GROWTH & DESIGN 2006 VOL. 6, NO. 5 1143-1153
ReceiVed March 11, 2005; ReVised Manuscript ReceiVed February 8, 2006
ABSTRACT: In the crystallization of a racemic mixture, formation of a conglomerate, i.e., a mechanical mixture of enantiomerically pure crystals, is the basic requirement for separation of enantiomers by preferential crystallization. Phenylsuccinic acid (PSA) is in the literature reported as a system forming a racemic compound, i.e., each crystal is an ordered mixture of the two enantiomers. In the present work, the properties of PSA were explored, with the underlying ambition of finding a conglomerate. Racemic PSA was crystallized by unseeded batch cooling crystallization in water, in acetic acid, and in 2-propanol (IPA). The corresponding data on solubility and the metastable limits were determined. Crystallization of racemic PSA in seven different solvents generated racemic PSA solvates with 2-propanol and with dioxane, respectively. The solubility of the (RS)-PSA‚IPA solvate was determined, and the transition temperature between the solvated and the ansolvate (RS)-PSA I was found to be 16.5 °C. In addition to the solution crystallization investigation, an extensive thermal analysis of the racemate and of pure (S)-PSA was performed. A metastable racemate was produced by melt crystallization but was never obtained in solution crystallization, although unusually high cooling rates combined with different levels of concentration and stirring conditions were used. Throughout this work, the solution concentration and the crystal modification type obtained upon nucleation were determined by in situ ATR-FTIR spectroscopy coupled with multivariate Partial Lease Squares (PLS) calibrations. The work suggests that for a system reported to be forming a racemic compound, there are at least three opportunities to find a conglomerate that should be explored: (i) a conglomerate that may be the stable modification at a different higher or lower temperature; (ii) a metastable conglomerate that may have a sufficient stability for a separation to be performed; (iii) a solvated conglomerate, either more or less stable than the ansolvate. Introduction Chiral compounds crystallize in their racemic form as one of three different types of crystal packing: (i) the racemic compound, in which both enantiomers alternate in a repetitive, well-ordered manner throughout the lattice, (ii) the racemic conglomerate, which is simply a mechanical mixture of pure crystals of each enantiomer, and (iii) the solid solution, in which the molecules of the two enantiomers are completely randomly mixed within the crystal lattice. It has been reported1 that most chiral compounds crystallize as racemic compounds (ca. 9095%), while the rest (5-10%) crystallize as racemic conglomerates. Racemic conglomerates are of significant interest, since they provide a basis for cheap and simple separation by preferential crystallization. Although discussed throughout the years in the literature,1-4 the preference that most compounds seem to have for crystallizing as racemic compounds and not as conglomerates is not well understood and certainly not predictable. An additional important aspect of crystallization of a racemic mixture is that most organic compounds and pharmaceuticals can crystallize in several crystal modifications such as polymorphs and solvates. We have previously studied the crystallization of mandelic acid from different solvents and from racemic and enantiomerically pure melts,5,6 with the goal of increasing the understanding of the interactions and phenomena that occur upon crystallization of racemic compounds. We found that a metastable mandelic acid racemate previously found only in quench cooled melts7-9 was formed also in supersaturated solutions. The formation and transformation of this racemate, which proved to be a metastable modification of the racemic compound,10 could be controlled and predicted by an appropriate choice of operating conditions. * To whom correspondence should be addressed. E-mail: rasmuson@ ket.kth.se.
In the present paper, we explore the crystallization of phenylsuccinic acid (PSA), which like mandelic acid is reported to belong to the group of compounds that form a racemic compound. The difference in thermodynamic stability, i.e., Gibbs free energy, between the racemic compound of PSA and its conglomerate is about the same as for the mandelic acid racemic compound and its conglomerate. Apart from the singlecrystal X-ray diffraction (XRD) characterization of the stable crystal modifications of the racemic and enantiomerically pure PSA,11,12 to the best of our knowledge no other studies of the crystallization of this compound have previously been reported in the literature. The goal of this paper is to characterize the stable solid phases, to study the solution and melt crystallization of racemic PSA, and to find and characterize metastable crystal modifications. The underlying ambition is to find a conglomerate that could be exploited in separation by preferential crystallization, either as a stable phase at a different temperature or as a metastable phase. Experimental Section Racemic PSA was crystallized in agitated tank cooling crystallizations in three solvent systems: water, acetic acid (HAc), and 2-propanol (IPA). The melting behavior of both racemic and enantiomerically pure PSA was extensively studied, and the thermodynamic properties were determined including the solubility of racemic PSA in water, HAc, and IPA. Further, recrystallization from methanol, acetonitrile, ethyl acetate, HAc, IPA, and dioxane was also conducted for racemic PSA as a solvent screening for metastable polymorphs, metastable conglomerates, and solvates. Chemicals. All solvents used were of HPLC grade except water, which was deionized and filtered by a 0.2 µm membrane filter, and HAc, which was glacial, Merck, 100%. (RS)- and (S)-PSA were 99% from Fluka. In previous work, the crystal structure of the commercial (RS)-PSA (denoted as (RS)-PSA-I)11 and of the enantiomer (S)-PSA12 were determined. Solubility and Crystallization. Initially, solvent screening was performed by allowing clear and filtered solutions (0.2 µm membrane
10.1021/cg050089q CCC: $33.50 © 2006 American Chemical Society Published on Web 04/05/2006
1144 Crystal Growth & Design, Vol. 6, No. 5, 2006
Profir and Rasmuson
Table 1. Details of Calibration Models Used in This Worka solvent
conc range (g/kg of solvent)
no. of solutions
no. of spectra
wavelength interval (cm-1)
derivative
no. of PC used
RMSEP (g/kg of solvent)
RMSEP (% rel error at the mean conc)
water HAc
5-45 114-371
9 8
305 276
IPA
10-498
9
548
1320-1127 1513-683 1879-650 1339-970 1879-650
yesa yesa no yesb no
4 3 3 5 4
0.82 1.70 2.48 2.8 5.1
3.28 0.70 1.02 1.11 1.99
a,b
The models constructed from derivatives of spectra were used for the measurement of the solution concentration of PSA.
filter) to evaporate quickly to dryness at room temperature. A 50 mL solution of (RS)-PSA in each respective solvent was prepared and was distributed into 10 vials. The solvent was then allowed to evaporate in a well-ventilated area. The solid-state IR spectra of the crystals formed were collected the next day. For IPA and dioxane, where IR spectra different from the (RS)-PSA I were observed, additional recrystallization experiments were performed. All cooling crystallization experiments were performed in a 100mL jacketed glass crystallizer equipped with pitched four bladed turbine type agitator and a probe for attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR) measurements. The influence of the operating conditions on the type of crystal modification obtained upon crystallization was studied by choosing different combinations of concentration level, cooling rate, and stirring conditions. Before the samples were introduced into the crystallizer, all solutions were screened through 0.2- or 0.5-µm membrane filters. The experimental set up and method, as well as the IR calibration procedure, have been described previously.5,6 Throughout all runs, IR spectra were continuously collected in situ. The solution concentration of PSA was estimated from each IR spectrum, by using one multivariate partial least squares (PLS) calibration model for each solvent system. Calibration models built from derivatives of spectra have the lowest root mean square error of prediction (RMSEP) and remove successfully all temperature-dependent nonlinearities and were therefore used for solution concentration determination. Calibration models built from raw spectra also were constructed when possible, and these models were used for extraction of spectral residuals for in situ crystal modification identification. Details about each calibration model including the number of principal components (PC) used in each model are given in Table 1. Savitsky-Golay smoothing and differentiation routines with a filter width of 15 points, a third-order polynomial function, and a first derivative (a) and a filter width of 17 points, a second-order polynomial function, and a first derivative (b), respectively (see Table 1). The solubility of the thermodynamically stable racemic compound, (RS)-PSA I, was determined both gravimetrically and by monitoring the solution concentration at equilibrium by ATR-FTIR. For IPA solutions, the solubility of the (RS)-PSA‚IPA solvate was also determined. Typically in gravimetric measurements, slurries of PSA and solvent are kept under continuous agitation and at constant temperature for at least 48 h. For HAc solutions after a long time, we observed spectra residuals that are completely different from the ones we measure in freshly prepared solutions used for calibration purposes and for cooling crystallizations. Further, the concentration starts to drift after 24 h at 15 °C and after 8 h at 45 °C. We suspect that a chemical reaction or decomposition, such as anhydride formation, occurs when PSA is kept in contact with HAc for long periods of time. Therefore, shorter equilibration times ranging from 2 to 6 h and simultaneous solution concentration determination by IR spectroscopy and gravimetry were used for solubility determination of (RS)-PSA in HAc. In IPA solutions, the solubility of (RS)-PSA I was determined by adding excess (RS)-PSA I to saturated solutions and monitoring the solution concentration change with time both by IR spectroscopy and gravimetry under isothermal and stirred conditions. The maximum constant solution concentration attained before the transformation to (RS)-PSA‚IPA was taken as the solubility of (RS)-PSA I. Typically, the transformation was completed after 24-72 h, and the constant solution concentration obtained then was taken as the solubility of the (RS)-PSA‚IPA solvate. Solid-state ATR-FTIR sampling of wet material and single-crystal XRD confirm the identity of (RS)-PSA‚IPA in these cases. Thermal Analysis. Reheating crystalline material obtained upon crystallization of a melt is a well-known method of screening for polymorphs and amorphous material.13 However, for reheated PSA, the interpretation is difficult since both the racemate and the pure enantiomer form anhydride upon melting. In addition, the anhydride
can easily be hydrolyzed back to PSA by uptake of moisture from the environment. In the present work, a melting point depression of (RS)PSA I was observed both by hot stage microscopy (HSM) and by differential scanning calorimetry (DSC) in reheated samples. It was established, however, that this did not signify the presence of a new polymorph but was found to be due to the presence of small amounts of PSA anhydride. Measurements of melting point, enthalpy of fusion, and enthalpies of transition were performed using a modulated differential scanning calorimeter (MDSC), model 2920, TA Instruments, New Castle, DE. The formation and thermal properties of metastable crystal modifications were sought by melting and reheating samples while recording all thermal events. The cell constant was calibrated with indium prior to each used heating rate. 50 mL/min of nitrogen gas was used for purging the instrument. The samples, which were typically 2-5 mg in aluminum hermetic pans, were heated according to both modulated and linear heating rates. After complete melting, all samples were cooled to room temperature at the highest cooling rate of the instrument (-15 °C/min) and then reheated again under identical conditions used for the initial heating. For the modulated heating rates, a modulation amplitude of (1 °C and a modulation period of 60 s was used, ensuring at least six modulation cycles through the melting events at linear heating rates of +5 °C/min and lower. All measurements were performed at least in triplicate. PSA is known to convert into an anhydride if kept for 10 min or more at temperatures above melting, with a weight loss of 9.3% at complete conversion. Further, the pure enantiomer is racemized if kept at temperatures of 150 °C and above.14 We therefore minimized the time at high temperature conditions and weighed all samples after each run, and only samples with weight losses less than 3% were used for evaluation. To discriminate between the influence of the anhydride on the melting behavior and any polymorphic transformations within this system, DSC runs were coupled with FTIR sampling of the crystalline material inside the DSC pans. The melting behavior of recrystallized racemic and enantiomerically pure PSA were also studied by HSM coupled with solid-state FTIR measurements. The HSM measurements were performed on a Mettler FP82 Hot Stage coupled with a Mettler FP 80 control unit, under an Olympus BH-2 optical microscope equipped with a Hitachi HV-C20 CCD camera. Small amounts of sample, typically 1-3 mg, were placed on object glass and heated at different rates. To minimize anhydride formation and avoid racemization, PSA was rapidly heated to its melting point and kept there for a maximum of 50 s. All samples were then removed from the HSM unit and quench-cooled to room temperature. The recrystallized material was then reheated in the HSM unit at +5 or +10 °C/min. The identity of the recrystallized material during reheating was checked by measuring the solid-state FTIR spectra of the crystals at various temperatures. Thermogravimetric analysis (TGA) was performed on a Perkin-Elmer TGA7 for all samples suspected to be solvates or hydrates. Samples of 3-8 mg were heated at +2, +5, and +20 °C/min while continuously flushing with a dry nitrogen gas flow rate of 20 mL/min. Solid-State Analysis. Solid-state FTIR spectra were collected with a Perkin-Elmer Spectrum One FTIR spectrometer, equipped with diffuse reflectance and horizontal attenuated total reflectance (HATR) accessories. Spectra of crystals without further preparation were collected as diffuse reflectance spectra and as HATR spectra. In addition, transmission spectra were collected after grinding and pressing disks of 1% sample concentration in dried KBr. No difference was observed between the diffuse reflectance and freshly sampled transmission spectra of (RS)-PSA I and (RS)-PSA II crystal modifications, respectively, which suggests that no major transformation occurred upon grinding and pressurizing. Spectra for wet solvate crystals were collected on a ZnSe HATR crystal in the range 4000-450 cm-1 with a spectral resolution of 4 cm-1 and a scan speed of 0.20 cm/s. All spectra are
Crystallization of Phenylsuccinic Acid
Crystal Growth & Design, Vol. 6, No. 5, 2006 1145
Figure 1. Rhombic dioxane solvate crystals in mother liquor.
Figure 3. Experimental XRPD patterns for the desolvated (RS)-PSA‚ IPA structure and the metastable (RS)-PSA II compared to the stable (RS)-PSA I and (S)-PSA I.
Figure 2. The solid-state IR spectra of the metastable (RS)-PSA II compared to the thermodynamically stable (a) (RS)-PSA I and (b) (S)PSA I. averages of eight scans. Air background is used. X-ray powder diffraction (XRPD) data were obtained with a Siemens D500 powder diffractometer. The radiation used is Cu KR (40 kV, 30 mA). Data were collected at room temperature from 2-45° with a 2θ step size of 0.02° and a step time of 1 s. Unfortunately, (RS)-PSA II formed very thin needlelike crystals, and despite several attempts we were not able to determine its crystal structure. Large single crystals of the IPA solvate were obtained by preparing solutions of low initial concentration (160-212 g/kg of IPA) that were cooled to 0 °C and seeded with crystals of either (RS)-PSA II or dried IPA solvate crystals. To prevent any large nucleation events, the stirring was immediately stopped when the seeds were added. A similar procedure was used for obtaining large single crystals of the dioxane solvate, this time cooling a filtered solution of initial concentration of 488 g/kg dioxane down to 15 °C and seeding with (RS)-PSA II crystals. Figure 1 shows the morphology of the dioxane solvate crystals obtained by this procedure.
Results and Discussion Melt Crystallization. Upon recrystallization of the sample from racemic melts of PSA, a metastable crystal modification
was always formed initially. Figure 2 shows the solid-state FTIR spectra of this metastable modification that is denoted (RS)PSA II. The spectra is compared to the corresponding modifications that are stable at room temperature conditions, denoted (RS)-PSA I and (S)-PSA I, respectively. The figure shows that the metastable racemic modification (RS)-PSA II has an IR spectrum that is significantly different from the spectrum of (RS)-PSA I and quite similar to the spectrum of (S)-PSA I. The (RS)-PSA II spectrum we obtained is consistent with the metastable (RS)-PSA II spectrum reported by Sollinger.15 Further, IR spectra of (RS)-PSA contaminated with the anhydride are different from the spectra shown in Figure 2, and hence such samples can easily be identified and excluded from evaluation. Figure 3 shows the XRPD pattern of (RS)-PSA II compared to those of (RS)-PSA I and of (S)-PSA I. Characteristic diffraction peaks of all PSA crystal modifications found in this work and their relative intensities are given in Table 2. The figure shows that (RS)-PSA I and (S)-PSA I share several common diffraction peaks, which is consistent with the structural similarities we have observed in the single-crystal XRD measurements.11,12 (RS)-PSA II shares a diffraction peak with (S)-PSA I (at 8.00°) and one diffraction peak very close to a characteristic (RS)-PSA I peak (at 15.68°), while its two major peaks are unique for this structure. This indicates that the crystal structure of (RS)-PSA II is different from the thermodynamically stable structures of the racemic compound and of the pure enantiomer, although it seems to have features similar to both structures. Samples contaminated with larger amounts of anhydride have also been identified here and excluded from evaluation. When reheated from room temperature, the metastable (RS)PSA II always transforms to the stable (RS)-PSA I. The transformation is visually seen in HSM, at a heating rate of +5
Table 2. The Six Largest Characteristic XRPD Diffraction Peaks for the Thermodynamically Stable (RS)-PSA I and (S)-PSA I, for the Metastable (RS)-PSA II and for the Desolvated (RS)-PSA‚IPA and (RS)-PSA‚dioxanea (RS)-PSA I
(S)-PSA I
2-θ (°)
intensity (% Imax)
2-θ (°)
intensity (% Imax)
11.25 15.6 17.65 19.75 22.75 23.4 25.1
16.3 86.4 70.3 99.5 43.3 100 55.9
8.00 17.55 19.55 22.55 24.38 28.55 39.85
8.62 100 46.5 44.1 46.4 19 23.1
a
(RS)-PSA II
(RS)-PSA‚IPA desolvate
(RS)-PSA‚dioxane desolvate
2-θ (°)
intensity (% Imax)
2-θ (°)
intensity (% Imax)
2-θ (°)
intensity (% Imax)
8.00 15.68 16.48 20.75 23.18 25.5
16.7 41 100 31 43.1 13.5
8.0 16.0 19.7 24.58 25.5 33.0
26.5 83.4 100 84.8 47.6 29.9
6.02 16.4 18.08 18.56 23.96 24.16
12.7 55.1 100 28.5 14.1 19
One additional characteristic peak each at low diffraction angles are included for (RS)-PSA I and (S)-PSA I.
1146 Crystal Growth & Design, Vol. 6, No. 5, 2006
Profir and Rasmuson
Figure 4. (RS)-PSA II heated at a rate of +5 °C/min in HSM. FTIR sampling at 30, 50, 78, 87, 95, 107, and 120 °C reveals that the dark front spreading through the sample is a solid-solid transformation from (RS)-PSA II to (RS)-PSA I, which in this run starts at 87 °C and is completed at 107 °C.
Figure 5. Typical MDSC traces for (RS)-PSA reheated at +1 °C/min at low winter time humidity (a) and high summer time humidity (b). Peak maximum temperatures are shown. Crystal modifications identified by FTIR. Table 3. Thermodynamic Data of PSAa crystal modification
melting point (°C)
(RS)-PSAI (S)-PSAI
( 0.7 173.68b ( 0.8 166.9a
∆Hf (kJ/mol)
∆Cp [J/(mol, K)]
∆G° (kJ/mol)
( 0.53 41.84b ( 0.54
100.8b
-1.90
37.37a
88.9b
a Melting points are defined as the onset melting temperature. The heat capacity difference between solid and molten state and the Gibb’s free energy of formation of thermodynamically stable PSA are valid at the melting point. All data are measured by a MDSC method at a heating rate of +1 °C/mina or +2 °C/min. b Errors are given as standard deviations of six and three measurements for (RS)-PSA I and (S)-PSA I, respectively.
or +10 °C/min, as a darkening of the crystals that occurs at an average (six runs) temperature of 95 °C (see Figure 4). Upon reheating melted and recrystallized (RS)-PSA, platelike crystals can be observed to grow at the expense of the needlelike (RS)-PSA II polycrystalline material. Although these plates melt in the temperature range of 153-158 °C, which is considerably lower than the melting point of (RS)-PSA I both single crystal and powder XRD reveal that they are (RS)-PSA I. As discussed in previous and following sections, presence of PSA anhydride leads to a melting point depression of (RS)-PSA I. Thermal Analysis. Figure 5 shows a typical run, in which the crystalline material inside the pan is sampled by FTIR prior to and after the exothermic event observed upon reheating melted and recrystallized (RS)-PSA. Although the metastable (RS)-PSA II is transformed into (RS)-PSA I during the exothermic event at 46 °C (as shown by the FTIR spectra), the melting point measured after this transformation is 154.2 °C, i.e., clearly below the melting point of (RS)-PSA I. FTIR spectra suggest that the material is (RS)-PSA I, which is supported by the findings described in the paragraph above. However, the FTIR spectra also reveal the presence of small amounts of PSA anhydride. By uptake of moisture from the environment, the anhydride can easily be hydrolyzed back to PSA, and hence when the same experiment is performed in the presence of a higher relative humidity (in mid July as compared to mid December), the measured melting point after the exothermic transformation is the melting point of (RS)-PSA I (see Figure 5b). Hence, we conclude that the melting point of (RS)-PSA II reported by Kuhnert-Brandsta¨tter & Sollinger16 and by Sollinger15 to be in the range 153-155 °C is therefore probably incorrect
and is actually the melting point of (RS)-PSA I in the presence of PSA anhydride. In this work, no melting point could be determined for (RS)-PSA II. All reheated (RS)-PSA samples exhibit an exothermic solidsolid transformation (see in Figure 5) that corresponds to a monotropic relation between the polymorphs, according to Burger’s heat of transition rule.17 This event of 5 kJ/mol with a peak maximum of 47-115 °C depending on the heating rate is well correlated to the solid-solid transformation observed and measured by HSM (shown in Figure 4) and also to the monotropic solid-solid transformation at 65 °C of (RS)-PSA II into (RS)-PSA I reported by Sollinger.15 A summary of the determined thermal data for the PSA crystal modifications that are thermodynamically stable at room temperature is given in Table 3. The melting points, enthalpies of fusion, and heat capacity differences presented in Table 3 can be utilized for calculation of the thermodynamic stability of a crystal structure, expressed as Gibb’s free energy of formation. This was previously described in detail in the literature,1,2,6,18 and the calculations will not be described in detail in this paper. The calculated Gibb’s free energy of formation of the PSA racemic compound from its hypothetical racemic conglomerate, ∆G0, is given in Table 3. A negative value denotes a higher thermodynamic stability of the racemic compound than of the conglomerate at the melting point.1,2,18 In the absence of single-crystal XRD data that unambiguously characterizes the type of racemate obtained for a compound, these types of calculations are useful as identification criteria when determining the nature of a racemate.1,19 The value estimated for (RS)-PSA I shown in Table 3
Crystallization of Phenylsuccinic Acid
Figure 6. Free energy versus temperature diagram for PSA. Solid lines represent the free energies of (a) (RS)-PSA I, and (c) the racemic molten state. Dashed lines represent (b) the lowest limit for the monotropic (RS)-PSA II, (d) the conglomerate of (R)- and (S)-PSA I, and (e) the supercooled (RS)-PSA melt. A transition point is marked by an arrow.
suggests that the racemic compound is slightly more stable than a conglomerate of (R)- and (S)-PSA I. Similar calculations can be performed for different crystal modifications leading to the construction of a free energy versus temperature diagram that can be used to predict and explain the behavior of polymorphs20,21 and the relative stability of a conglomerate to a racemic compound.21 The free energy difference at the melting point can be extrapolated to lower temperature,18,20 by assuming a constant heat capacity difference between the (supercooled) melt and the solid-phase implying a linear variation of the free energy with temperature.20 To construct a true free energy diagram, accurate thermodynamic data are required. In previous sections, the difficulty of determining the melting point of (RS)-PSA II was extensively discussed. This implies that such a diagram cannot accurately be constructed for PSA. Figure 6 illustrates, however, a schematic diagram of PSA with calculations based on the data reported in Table 3. Data for (RS)-PSA II were arbitrarily chosen as 155 °C for the melting point and a slightly lower enthalpy of fusion than the enthalpy of fusion of the stable (RS)-PSA I (35 kJ/mol). Both values are in accordance with Burger’s rules for a monotropic relation between the two modifications. Higher enthalpy of fusion and/or lower melting point would indicate an enantiotropic relation between the two PSA racemates. Lower
Crystal Growth & Design, Vol. 6, No. 5, 2006 1147
enthalpy of fusion and/or higher melting point increases the monotropic relation even more. Therefore, the data included for (RS)-PSA II illustrates actually the lowest limit of monotropy between the two racemates. It also serves as comparison for the behavior of a hypothetical conglomerate of (R)- and (S)PSA I. The heat capacity difference measured for (RS)-PSA I was used for both (RS)-PSA I and (RS)-PSA II and for the conglomerate of (S)- and (R)-PSA I. The figure shows that a conglomerate formed from (R)- and (S)-PSA I should have a melting point of 148 °C and a free energy of formation that is 1.66 kJ/mol higher than that of (RS)PSA I at this melting point. Although this value is low enough to be overcome by crystallization kinetics enabling the existence of this conglomerate as a metastable phase, upon recrystallization from racemic melts we only observed the metastable (RS)PSA II, which most likely is not the conglomerate of (R)- and (S)-PSA I. However, the calculations suggest that the free energy of the conglomerate may decrease strongly with decreasing temperature, and the conglomerate may even become stable at reasonable processing temperatures (
