Article pubs.acs.org/OPRD
Metastable Zone Widths, Conformational Multiplicity, and Seeding Terence L. Threlfall,* Russell W. De’Ath, and Simon J. Coles Chemistry, University of Southampton, Highfield, Southampton SO17 1BJ, United Kingdom ABSTRACT: The propensity for crystallisation of acetanilides and propionanilides was compared both by polythermal metastable zone width measurements and by isothermal induction time measurements. Although there were clear relationships between the metastable zone widths and the conformational multiplicity in some cases, they broke down for the chloroacylanilides. This failure could not be fully accounted for by the difference in the crystal structures of the chloro compounds. A surprising dependence of crystal size on seeding effectiveness could explain some of the crystallisation behaviour, particularly for the induction period measurements.
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INTRODUCTION It is well-known that compounds which possess many competing conformers crystallise reluctantly, for example, sugars.1 It is probably the reason also why peptides are so difficult to crystallise, compared with proteins for which the overall structure limits the conformational mobility. We encountered this phenomenon of reluctant crystallisation during the preparation and crystallisation of several hundred acylanilides for crystallographic comparison.2 It was observed that in general acetanilides, trifluoroacetanilides and trimethylacetanilides (pivalamides) crystallised much more readily than other anilides. It was further found that para substituted anilides crystallised more readily than ortho substituted anilides and these in turn crystallised more readily than meta substituted anilides. These observations were interpreted in terms of the conformational mobility and multiplicity. In that work the observations were empirical, and it was felt desirable to try to put them on a quantitative footing. Metastable zone width measurements seemed to offer such opportunity. Although metastable zone width measurements are extensively employed in industry,3 particularly during chemical development to establish optimum crystallisation conditions, their limitations have been more widely emphasised in academic papers than their uses. Their value in establishing nucleation and crystallisation parameters has been widely doubted. The earliest papers go back hundreds of years,4 but it was not until within the past half-century that intensive efforts were made,5−8 particularly by Nyvlt9,10 to relate metastable zone widths to nucleation parameters. Extensive criticism has been made7,11 of the deductions from such work, but this in no way affects the fact that metastable zone widths represent a measure of the tendency of solutions to crystallise. The attempt to relate metastable zone widths to nucleation parameters has recently been revived, particularly by the work of Kubota and collaborators.12 Again there has been criticism of the meaning of the measurements in terms of the extraction of nucleation rates.13 This work was undertaken in the expectation that the width of the metastable zone would be a direct measure of the conformational multiplicity of the compounds or at least of a combination of the conformational mobility and multiplicity. Derdour et al.14−16 have attacked the problem of crystallisation of compounds with alternative conformations from a different © 2013 American Chemical Society
angle, modelling the effect of the incorporation of the wrong conformer from solution on the rate of incorporation of the right conformer. In effect this is what was considered in a nonmathematical way in the previous study2 because the relatively free rotation of the bonds of the alkyl group made the conformation in solution less relevant.
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EXPERIMENTAL SECTION Jacketed vessels of capacities of about 15, 120, and 500 mL each were constructed in-house. The interiors were flat-bottomed and cylindrical of 25, 55, and 65 mm, respectively, designed so as to allow the temperature and turbidity probes to penetrate deeply into the solution without interfering with the magnetic stirrer bar even at minimum liquid content levels. The smallest vessel had a conical continuation above the cylindrical section to allow the entry of the probes. Stirrer bars of triangular cross section or of cruciform profile were used to maximise the lift at minimal stirring rates to ensure thorough mixing of the solution. A stirrer speed of 250 rpm was used for all the probemonitored measurements. The turbidity and temperature were monitored with an H.E.L. CrystalEyes system via the probes. The temperature control was via the circulating water from a ThermoHaake C35P water bath. This can nominally control the temperature to 0.01 °C and allow ramp rates from arbitrarily slow ones up to a practical limit of about 2 °C min−1 in external circulatory mode. For the MZW measurements a heating and cooling rate of 0.5 °C min−1 was used for the reasons discussed later. For faster heating and cooling rates, a 30-mL nonjacketed vessel, also constructed in-house of cylindrical cross section of 30 mm diameter with a conical section above to allow probe entry at an appropriate angle, was mounted in the water bath on an immersible magnetic stirrer (Thermo Electron Variomag Micro). There was always a temperature difference between the water bath temperature and the probe temperature. The probe temperature was assumed to be correct and is the one reported in the results. Every metastable zone width measurement was repeated at least five Special Issue: Polymorphism and Crystallization 2013 Received: December 3, 2012 Published: February 21, 2013 578
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and thus, faster rates are preferred. The limitation in this case is determined both because of the operational factors just stated and because faster rates tend to make the stochastic factors mentioned below more apparent, so that less reproducible results are obtained. In Table 1 are set out the factors which have been widely discussed in the literature as critical for metastable zone width measurements. In the second column are listed the effects of these factors in the current set of measurements; they are not statements that these factors might be of general importance. For example, it is widely recognised that impurities will hinder crystallisation.8,21 In these experiments two commercial samples of 4-chloroacetanilide were available from two suppliers plus one sample synthesised for this project. The latter was crystallised but not specially purified. There was no statistically significance difference in the MZWs of these samples. It was therefore concluded that ‘ordinary’ levels of purity were adequate and that it would be unnecessary to purify samples, for example by chromatographic processes, in order to achieve consistent results. It is generally believed that seeding
times, and in most cases 20 or more times. Samples of the acetanilides and propionanilides were made by the reaction of acetic anhydride or propionyl chloride with substituted anilines as previously described2 but on a larger scale. Commercial samples of 4-fluoroacetanilide and 4-chloroacetanilide were also used. Aqueous ethanol was used as the solvent for reasons discussed later. Both temperature of crystallisation and time to crystallisation at constant temperature (induction period) experiments7,11 were recorded. For the isothermal measurements, the solutions were cooled at 2 °C min−1 to a temperature-controlled ±0.01 °C and kept there until crystallisation. All the MZW measurements were obtained with external circulation, but the later isothermal measurements were obtained in internal mode to allow faster cooling with better control.
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RESULTS The metastable zone widths are shown in Table 2, together with the temperature ranges of the measurement. A typical automated run is shown for acetanilide in Figure 1, and a chart
Table 1. Factors of possible importance in MZW measurements and the results of preliminary manual MZW investigations to determine their importancea factor
significance for this study
rate of heating and cooling stirring rate vessel size (ref 22) overheating beyond dissolution time delay before heating/cooling seeding purity temperature range of experiments polymorphism unrecorded solution history concentration, solvent
Figure 1. Temperature and turbidity cycles of acetanilide in 25% aqueous ethanol. Output from H.E.L. CrystalEyes system.
of one of the isothermal experiments on propionanilide is shown in Figure 4. Table 3 lists the MZW limits obtained by extrapolation of the isothermal runs to infinite time. Table 4 shows the effect of varying the solution concentration and solvent composition for 4-methylacetanilide.
a
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lower rates increased MZW, so control was needed no effect seen no effect seen no effect seen no effect seen all experiments seeded, see text no effect seen of minor effect, see text not relevant occasionally significant; procedure was adopted to eliminate effect of minor effect, but difficult to disentangle from effect of temperature
See ref 26.
will reduce the MZW,19,20 and this seems a rational belief. However, it is thought that all the experiments described here must reflect nominally seeded situations. In the many re-entrant angles of the turbidity probe, small crystals were often found trapped. As the solution splashed up on the vessel sides, particularly as the crystallisation point was reached, it evaporated, and these tiny crystals were washed down by the next drop. It is difficult to believe that this latter situation can be avoided and therefore to know that a truly unseeded MZW experiment is possible. Clearly, the use of aqueous ethanol and higher temperatures exacerbates this effect, but it is difficult to believe other than it is present in all measurements. On the other hand, Nyvlt19 showed a clear and consistent difference between seeded and unseeded solutions, but the seeds he used were described as large. As discussed later, this may negate the comparison. The effect of vessel size has been the subject of a recent investigation.22 It was reported that 150 repetitions were required to establish the true MZW when using a 1-mL vessel, because of the stochastic nature of crystallisation. No problem of repeatability was apparent in a 1-L vessel. Intermediate sizes
DISCUSSION The Polythermal MZW Measurements. Many factors can affect the metastable zone width. Crystallisation is a kinetically controlled process. Solubility is a thermodynamic quantity, but because the attainment of equilibrium is so slow17,18 even this is subject to kinetic effects under normal operating conditions. Thus, the rate of heating, and more particularly of cooling, would be expected to be important as has been reported in innumerable papers.19,20 The results reported here, unsurprisingly, bear this out. Indeed it was the only variable which had a massive effect on the results and which therefore needed careful control. That was easily achievable with the heating and cooling programs of the water bath, provided that no overfast heating or cooling was attempted. The general approach in the literature would be to use the slowest cooling rate compatible with the need to complete the experiments within limited time scales. In the present case we are seeking to maximise the differences between conformational rotation times and crystallisation rates, 579
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The temperature range of the dissolution/crystallisation cycle can be varied by alteration of the concentration. In preliminary experiments this temperature variation was explored, and undoubtedly did make a small difference. It is well documented in the literature that lowering the temperature slightly widens the MZW, but in the present work increase, decrease, and no change were all observed. For example, 4-chloroacetanilide had an MZW of about 2.9 °C at 70 °C, but 3.9 °C at 50 °C. This difference may have been due to the change of concentration needed to produce the different temperature range as discussed below, but was more probably due to loss of ethanol at the higher temperature. The MZW measurements reported here were all below 50 °C and mostly below 40 °C. The change of solvent may be another variable affecting the MZWs. It cannot be disentangled completely from the concentration and temperature, but the values in Table 4 give an indication of the small variation of MZW values due to the solvent composition and solute concentration. Nyvlt20 has investigated the effect of concentration on MZWs and advanced theoretical reasons why this should be so. In the work presented here the range of concentrations was insufficient to alter the MZW values enough to affect the results. What Table 4 suggests is that the variation of the MZWs might be better described as more dependent on the temperature than on the concentration or solvent composition. No attempt was made to check the polymorphic consistency of products. Different polymorphs would be expected to show different solubilities and different metastable zone widths. However, the thermodynamic differences between polymorphs are rarely large, and consequently, the solubility differences are typically small. For the purposes of this study, which was to examine the differences between compounds, it does not matter which polymorph is obtained. If different polymorphs had appeared in different cycles, this might have resulted in erratic repetitions, which was not the case. Although there are MZW measurements from many substances in the literature, they are generally not directly comparable. This is because each substance has its own solubility. There is a fixed relationship between the solubility, concentration, and temperature, namely the solubility curve, unique to each substance. We wished to compare like with like insofar as this could be achieved. In the case of acetanilide and propionanilide, whilst both are more soluble in ethanol than in water, propionanilide is far less soluble in water but more soluble in ethanol than is acetanilide, and thus, it was possible to find a solvent mixture at which both substances were equisoluble at the same temperature. This made a direct comparison of the MZWs valid, at the expense of the undesirability of using mixed solvents. The results are shown in Table 2. Propionanilide has a far larger MZW than has acetanilide. It would perhaps have been desirable to equalise the solubilities at the dissolution temperature rather than the crystallisation temperature, but the difference is so large and the variation of MZW with temperature relatively so small that this possible error source can be neglected. This result is just that which was expected: the propionanilide with an alkyl group of lower symmetry crystallises less readily, or more slowly, than acetanilide. The graph of the data set for acetanilide is shown in Figure 1. The overall reproducibility can be noted, as well as the expected slight variations in each cycle, particularly of the turbidity curve, although at the scale shown, the consequent variation in crystallisation and dissolution point cannot be seen.
were not examined, but it may be assumed that the relation is a geometric rather than a linear one,23 so that the 120-mL vessel used for most of the experiments reported here, with a solution content of at least 90 mL for all experiments, would be free from the size problem. Indeed the hundreds of repeat observations on which this report is based would seem to bear this out. Stirring rate is clearly an issue in larger vessels, but within the vessel and stirring rate variations used here, no effect on the MZW could be discerned. Similarly the over-temperature to which the solution was heated and the time within which it was kept at that temperature had no effect.24,25 Solutions undoubtedly possess structure,26,27 and such structure can be altered or broken down by maintainenance for long periods at temperatures above the dissolution point. If sufficient change of these conditions occurred, then it would be expected that the MZW might vary. The small variations in temperature (2−6 °C) and in time (2−5 min) explored here were only to make sure that any drift or irreproducibility during the dissolution/ crystallisation cycles would not interfere with the measurements, and that incomplete dissolution would not interfere with subsequent recrystallisation. A related phenomenon is the influence of uncontrolled, unknown, or unrecorded solution history. So marked was this in some (but not all) of the present sets of results, that a policy of always ignoring the first cycle of heating and cooling was used. It is difficult to put a scientific explanation as to why a slurry which has been made by cooling a solution, which itself has been made by heating a slurry, should not behave rationally until subjected to the precise subsequent cycle, but this did appear sometimes to be the case. We encountered one extreme example of such erratic behaviour. A solution of 4-fluoroacetanilide which dissolved at 35 °C during the preliminary manual runs refused to crystallise during 3 days at 20 °C, despite repeated seeding. When it finally did crystallise, crystals larger than centimetre cubes appeared overnight. The subsequent MZW experiments as shown in Table 2 repeatedly produced an interval of only about 3 °C. Table 2. Metastable zone widths of acylanilides measured in aqueous ethanol at a heating and cooling rate of 0.5 °C min−1a cmpd acetanilide propionanilide 4-methylacetanilide 4-methylpropionanilide 3,4-dichloroacetanilide 3,5-dichloroacetanilide 3-fluoroacetanilide 4-fluoroacetanilide 3-fluoropropionanilide 4-fluoropropionanilide 2-chloroacetanilide 3-chloroacetanilide 4-chloroacetanilide 3-chloropropionanilide 4-chloropropionanilide 2-fluoroacetanilide
MZW/°C and rms
range/°C
± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±
37−41 37−48 39−44 28−35 28−37 34−41 29−32 47−50 27−33 27−41 30−34 28−29 32−41 22−27 23−29 22−30
4.02 12.23 5.28 6.66 8.55 7.38 3.07 2.99 5.95 3.60 4.36 1.24 8.88 5.37 6.12 8.07
0.20 0.25 0.60 0.22 0.24 0.13 0.35 0.75 0.66 0.40 0.60 0.39 0.48 0.49 0.41 0.67
a
The rms value is the root-mean-square calculated from all the measured MZW values with the exception of the initial cycle. 580
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Figure 2. Three hydrogen-bonded chains characteristic of the acylanilide crystal structures. (A) Screw axis symmetry symmetry. (B) Glide symmetry. (C) Ttranslational symmetry. Taken from the Ph.D. Thesis of L. Susanne Coles, University of Southampton, U.K., 2010.
was untenable, because some of the anomalies occurred between molecular comparisons with the same chain symmetries in the crystal. The MZWs of 2-fluoroacetanilide run later than those of the other fluoro compounds and also showed the ‘incorrect’ relationships to all the other fluoro compounds except to 4-fluoroacetanilide. Thus, it must be concluded that there are other, perhaps more complex forces at work determining the rate at which molecules can be incorporated at a surface. Because the screw arrangement is by far the most common, the original observations were mostly free from that complication. At this stage it was realised that an important contribution to the MZW had been overlooked, namely the steepness of the solubility curve. This can most easily be estimated thermochemically either from solution calorimetry28 or from the enthalpy of melting.29 If the MZWs are divided by the slope of the solubility, this should minimise this factor. The slope was calculated from the derived van’t Hoff equation, δ ln S = ΔH/T2, where S is the solubility, H the enthalpy of melting (derived from DSC data), and T the temperature of crystallisation. No difference in the order of MZW values was thereby found, for the differences in slope were typically less than a few tens of percentage, whilst some of the differences in MZW are 4-fold or more. So the conclusion remains that there are unknown factors contributing to the MZW. Isothermal Time to Crystallisation (Induction Period) Experiments. Several groups have used isothermal crystallisation methods7,11 as opposed to the polythermal MZW measurements discussed above. The solution is rapidly cooled to a fixed temperature somewhat above the spontaneous crystallisation temperature, and the elapsed time to the cloud point/first appearance of crystals is noted. The higher the fixed temperature, the longer the time needed for crystallisation. The most thoughtful discussion of this procedure is due to Janse and de Jonge.11 Their graph for potassium dichromate crystallisation is reproduced as Figure 3. This figure shows a saturated solution being cooled rapidly along the sloping line at
The same pattern is seen for 4-methylacetanilide and 4methylpropionanilide. Had the MZWs been recorded at the same temperature, then the differences admittedly would have been less certain. For 3,4-dichloroacetanilide and 3,5-dichloroacetanilide the expected smaller MZW value for the more symmetrical substitution was found. It was possible to compare the symmetry effects of both the alkyl group and the aromatic ring substitution for 3- and 4-fluoro-substituted acetanilides and propionanilides as shown in Table 2. These bear out the expected pattern in which the acetanilides show smaller MZW values than the propionanilides, and the para substitution yields smaller MZW values than meta substitution. However the differences are now much smaller, and indeed the values for 3and 4-fluoracetanilides are within the error limits. This suggests that there may be factors other than the conformational ones determining the MZW values. The values for the monochlorinated compounds no longer showed the pattern that had been encountered earlier. The values for 2-, 3-, and 4-chloroacetanilide were in the inverse order to that expected. The values for 3- and 4-chloropropionanilide were also inverted. Only the values for 3chloroacetanilide and 4-chloropropionanilide bore the expected relationship. All these values are very reliable, being derived from many repeats. It was initially thought that this all might be due to the differences in crystal structure encountered in the chlorinated compounds. Nearly all acylanilide structures are built up from hydrogen-bonded CO···H−N catemer chains. There are three chain symmetries encountered: the molecules in the chains may be related by translational, glide, or screw-axis symmetry (Figure 2). All the fluoro compounds possess the screw-axis symmetry, which is the commonest arrangement of the acylanilides, but the chloro compounds show all three symmetries. It is clear that the rate of incorporation into the growing crystal could be affected both by the preliminary conformational opportunities of the free molecules and by the final supraconformation of the crystal units. The effects of the latter may be difficult to disentangle. However, this explanation 581
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between this situation and that of solubility measurement. This is not the first instance where this hysteresis has been noted. Srisa-nga, Flood, and White35 and Wantha and Flood36 have reported the same observation in the cases of γ-D,L-methionine and α-glucose, respectively. Soehnel and Mullin7 observed hysteresis for two out of three compounds examined, but their explanation for the difference hardly addresses the phenomenon. Since they do not linearise their curves, it is in any case impossible to say whether potassium dichromate shows a small hysteresis or none. The concept of a ‘dead-zone’, a region near the solubility curve in which nucleation is not possible, was suggested long ago,5,37 but the reasons for its possible existence have never been examined in detail. We discuss the seeding aspects and a possible explanation later. Table 3. Metastable zone widths obtained from induction period measurements extrapolated to infinite time Figure 3. Plot of multiple isothermal runs on potassium dichromate, taken from Janse and de Jonge11 (with the permission of the Institute of Chemical Engineers).
the left of the figure to a temperature somewhat above the metastable limit. It is then maintained at this temperature, shown as one of the horizontal lines, until crystallisation takes place. The process is repeated at different temperatures, represented by the various horizontal lines. The dashed curve drawn through the crystallisation points, then, represents the dependence of crystallisation on the time factor. It has usually been assumed that the extrapolation of this crystallisation curve to infinite time would coincide with the thermodynamic solubility point. Since crystallisation (nucleation plus crystal growth) is not a process involving thermodynamic equilibrium, this seems unlikely. Mullin30 has commented that dissolution proceeds 5 times as fast as crystal growth (literature values up to 15 times can be found) which is clearly incompatible with a system in equilibrium. Therefore, the attainment of the solubility equilibrium must differ from the process of crystallisation itself. There has also been discussion of dissolution occurring in supersaturated solutions above the solubility point26,31 or the possibility of inducing crystallisation in slightly undersaturated solution.32 Since the mechanism of dissolution and crystallisation differ,33 even such a fundamental thermodynamic principle as that of microscopic reversibility does not apply to solubility, so it is a very curious equilibrium indeed. Mynukh34 has produced strong polemic arguments to show that in reversible solid−solid transitions there can be no equilibrium, but only conversion and reconversion points with a measurable temperature hysteresis between. So in some way solid-solution processes at the solubility point, which seem not to possess a measurable hysteresis, must differ from the solid− solid conversion process, which do. We sought a way of linearising the crystallisation curves of the type produced by Janse and de Jonge, and found that a simple exponential was often adequate. In applying this to induction period measurements for acylanilides, the infinity time always corresponded to a temperature below that of the solubility temperature. We then think that this is the true metastable zone width, free from kinetic interference and have reproduced the values obtained in Table 3. In the absence of seeds it is easily comprehended that that should be the case, but in the presence of seeds, as has been asserted earlier to be the inevitable case in MZW measurements it is certainly difficult to see the distinction
cmpd
measured MZW
‘true’ MZW
propionanilide 4-methylpropionanilide 4-fluoropropionanilide 2-chloroacetanilide
12.23 6.66 3.60 4.36
8.38 1.73 2.14 3.36
Table 4. Dependence of metastable zone widths of 4methylacetanilide on solute concentration and solvent compositiona 4methylacetanilide (%)
aqueous ethanol (%)
crystallisation/ dissolutionοC
0.68 0.73 0.68 0.65 0.62 0.91
23.7 19.1 23.1 25.9 28.6 28.6
39/44 50/54 44/39 33/39 28/35 40/45
MZW/οC 5.28 4.20 5.94 6.16 6.65 5.16
± ± ± ± ± ±
0.60 0.17 0.48 0.54 0.36 0.31
The first entry is that from Table 2. The subsequent solutions were one of 0.88 g of 4-methylacetanilide in 20 mL ethanol plus 100 mL water which was diluted with 10, 5, and 5 mL of ethanol for the third, fourth, and fifth row, respectively. Finally 0.4 g of 4-methylacetanilide was added to give the entries for the sixth row. a
During the course of this work we generated crystallisation curves such as that shown in Figure 4, which is the clearest example out of several similar ones of what is about to be discussed, and which contains the most comprehensive set of data. At the point labelled ‘cloud point’ the system recorded the first deviation from the baseline. With a good light behind the crystallising vessel, it was also possible to see by eye that there was then a faint turbidity in the solutiona. The crystals at this point must be large enough to scatter/obscure light, and it can be calculated that they each must contain around 1011 molecules and be numerous enough to obscure 1% of the light. This would mean about 106 crystalsb. The usual descriptor of such curves is either second order, corresponding to an increase in crystal area, third order, corresponding to increased mass in the form of new crystals, or to something inbetween, representing a mixture of both processes. The curve in the present instance cannot be fitted by less than a fifth- or sixth-order curve. However, if the point marked ‘secondary nucleation’ at ∼870 min is considered as a break point, then a low-order curve (second or third order, because the limited range of the turbidity values is insufficient to distinguish) can 582
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be fitted up to 870 min. A different second- or third-order curve (the number of time points in this case is insufficient to provide a distinction) can be fitted to the curve after 870 min. The most rational explanation is that the small particles are incapable of acting as seeds until they have grown sufficiently large to do so at ∼870 min. This size would be about 0.1 μm. This phenomenon has been observed previously;37−39 the time to the significant nucleation point has been called the ‘latent period’ by Mullin,26 although no suggestions have been made as to the processes which may be bringing it about. The phenomenon of ‘initial breeding’ seems also to be of the same origin.40
describe the crystal size but sets an upper limit on that size, which is in the region of that suggested above for the cloud point of propionanilide. The fact that this phenomenon of critical seed size has been observed by so many groups in relation to so many substances makes it unlikely to be erroneous, but it is not easy to see why a surface of a crystal containing a million or more ions or molecules should be incapable of growing in a supersaturated solution. However, it does provide a possible explanation of three of the observations made during the course of this work. First, the presence of seeds in the polythermal MZW measurements fails to bring about crystallisation. Second, there is a dead-zone even in the presence of seeds between the thermodynamic solubility point and the isothermal experiments extrapolated to infinity. Third, there is the long period of 10 h between the first seeds and the massive nucleation point in the experiment just described. These results obviously have a bearing on practical aspects of seeding. An alternative explanation, and again one that is difficult to understand in terms of the detailed mechanics is based on the concept that macroscopically rough surfaces grow slowly.31 The time between the cloud point and the increased crystallisation point may then be regarded as the period of surface healing. Dudognon et al.48 have shown that, in the case of ibuprofen melts, the nucleation and crystal growth take place at different temperatures, so that the initially formed nuclei cannot grow at the temperature of nucleation but only at ∼90 °C above that temperature. This is clearly incompatible with the classical view of nucleation, as noted by the authors, but is understandable in terms of Vekilov’s two-stage mechanism.49 In this the nucleation is regarded as a densification process and crystallisation as a reordering process followed by crystal growth. This would suggest that the initial nuclei or observed ‘crystals’ may be amorphous or semiamorphous in nature and incapable of growth until a certain degree of crystallinity has been achieved. There is precedent in the literature for the concept of crystalline growth on an amorphous core.50 It is evident that this could take time and be influenced by temperature and by the concentration of the solution in which the particles are immersed. Further discussion about seed characteristics can be found in the literature.51,52 It is not relevant to the anomalous crystallisation behaviour discussed here, but could be important for seeding in practical situations as could the immediately preceding discussion. For it suggests that it may be counter-productive to grind seeds too finely, and that attention should be paid to the size distribution as well as to the mass of seeds and their history. The best procedure may well be to grind seeds in a slurry,51 but only roughly, and then allow a period of regeneration before addition.52 There is clearly much about seeds and seeding that is yet to be learned.
Figure 4. Isothermal measurement on propionanilide. The long run shows the cloud point at about 230 min, followed by massive crystallisation at about 850 min. The excursions below 100 minutes are due two earlier, shorter isothermal runs of the same set.
In the literature are papers from several groups describing how seeds need to be of a certain size before they can be effective. Ting and McCabe37 noted the effect of the seeding crystal size of magnesium sulfate on the metastable zone width. Cayey and Estrin41 state that the critical size of magnesium sulfate is 0.2 mm, below which the crystals are ineffective. Bauer, Rousseau, and McCabe42 investigated the dependence of seeding on crystal size for magnesium sulfate and potassium sulfate. Kubota and Fujiwara43 report that seeds of alum are ineffective for seeding below 0.5 mm and referenced earlier reports of this phenomenon. Herden44 showed that, for solutions of potassium chloride, sodium chlorate, and ammonium sulfate, crystals of ∼0.7 mm diameter were more effective in reducing MZWs than those of ∼0.2 mm diameter. This followed from Mayer’s experiments in which he showed that larger crystals of sodium chlorate formed more effective seeds than smaller ones.45 Kondepudi’s group46 found that sodium bromate crystals need to be 0.9 mm in order to bring about secondary nucleation of sodium chlorate solution. The explanations that have been put forth by Kubota and earlier authors are that only huge seeds hitting the impeller blades will shatter and produce secondary nuclei. This does not explain why the original crystals are inert. Furthermore, this explanation cannot account for the results of Kondepudi’s experiment, in which a supersaturated solution of sodium chlorate (which is achiral) is allowed to drip slowly over a single sodium bromate crystal (which is chiral), and the quantity of chiral sodium chlorate crystals generated is measured. Ostwald reported that the minimum seed load which was effective in the case of thymol melts was 1011 g.47 This in itself does not
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CONCLUSIONS
(1) Although there is some tendency for the compounds with more conformational opportunities to have wider metastable zone widths, this is not always so. There must be further factors determining the crystallisation or nucleation rate. (2) Extrapolation of isothermal runs to infinite time does not result in a temperature of crystallisation which coincides with the solubility temperature. There is always a hysteresis, the value of which is proposed to represent the true MZW.
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Organic Process Research & Development
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(3) Some of the crystallisation behaviour observed could be explained by a minimum size for seeding as has been reported in the literature or by macroscopic surface roughness. However, it is difficult to formulate any rational explanation for either phenomenon.
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The authors declare no competing financial interest.
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ADDITIONAL NOTES As noted, many of the preliminary observations were made by eye. The eye and the turbidimeter appear to be of similar sensitivity in respect of cloud point determination, but it is often possible to detect a change of translucency or even a shimmering effect of the solution immediately prior to crystallisation. b Even if these figures are enormously wrong, it makes no difference, as it is only the ratio of the numbers at the cloud point and the secondary nucleation point which is of interest. a
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dx.doi.org/10.1021/op3003486 | Org. Process Res. Dev. 2013, 17, 578−584
