Secondary Nucleation of Sodium Chlorate - ACS Publications

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Secondary Nucleation of Sodium Chlorate: The Role of Initial Breeding René R. E. Steendam, and Patrick J. Frawley Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.9b00317 • Publication Date (Web): 01 May 2019 Downloaded from http://pubs.acs.org on May 2, 2019

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Crystal Growth & Design

Secondary Nucleation of Sodium Chlorate: The Role of Initial Breeding

René R. E. Steendam*& Patrick J. Frawley

Synthesis and Solid State Pharmaceutical Centre (SSPC), Bernal Institute, University of Limerick, Castletroy, Limerick, Ireland.

* Corresponding author

ABSTRACT Secondary nucleation is the key mechanism behind the creation of new crystals in industrial crystallization processes. Sodium chlorate has widely been used throughout literature as a model compound to study secondary nucleation due to its ability to crystallize as a chiral solid which makes it feasible to determine whether new crystals have originated from solution or from a seed crystal. Despite its widespread use, a significant level of ambiguity regarding sodium chlorate still exists including inconsistent solubility data, non-transferrable results between batch- and continuous experiments and inconclusive theories about whether secondary nucleation of sodium chlorate is possible through fluid shear. In the present work, the inconsistencies around sodium chlorate are resolved using novel continuous shear-induced secondary nucleation experiments involving stationary seed crystals. First, accurate solubility data of sodium chlorate in water was determined using a laser method and compared with literature data. Secondly, the metastable zone width was determined to be surprisingly narrow and continuous shear-induced secondary nucleation experiments of sodium chlorate using stationary seed crystals were therefore unsuccessful as heterogeneous nucleation was favored over secondary nucleation. This explains why previous continuous secondary nucleation experiments failed. Finally it was found that mechanical impact readily created fines on the seed crystal surface and that the resulting fines acted as new particles through initial breeding. Based on microscopic analysis it was observed that a washing step was sufficient to remove fines from the seed crystal surface. Intriguingly, the resulting seed crystals without fines failed to induce secondary nucleation. Therefore, fluid shear was

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insufficient to disperse secondary nuclei of sodium chlorate. Overall the results presented herein reveal a better understanding of secondary nucleation as the impact of initial breeding is reported in detail for the first time. Initial breeding significantly contributes to secondary nucleation and controlling initial breeding is therefore essential to govern crystallization processes.

1. INTRODUCTION Crystallization is an essential unit operation in the chemical industry for the production and purification of fine chemicals, agrochemicals and pharmaceuticals.1 Industrial crystallization processes are typically initiated using seed crystals of the target product. Once added to a supersaturated solution, seed crystals grow, undergo breakage, agglomerate and induce the formation of new nuclei through secondary nucleation. The newly formed nuclei grow into crystals that in turn induce the formation of a new generation of nuclei, making secondary nucleation a highly efficient autocatalytic process. As a consequence, secondary nucleation significantly influences the crystallization process and final crystalline product specifications.2 Sodium chlorate (NaClO3) has been extensively used as a model system to investigate secondary nucleation mechanisms. Although achiral in solution, NaClO3 crystallizes in a noncentrosymmetric space group, making it chiral in the solid state.3,

4

Most of the physical-chemical

properties of the two chiral forms are the same and crystallization in the absence of seed crystals proceeds through primary nucleation, typically resulting in a racemic mixture of both chiral forms. On the other hand, chiral seed crystals induce secondary nucleation resulting in product crystals that have the same chiral form as the seed crystal. Hence, the chirality of NaClO3 product crystals can be used as a unique tool to establish whether nuclei have been formed through primary- or secondary nucleation. One of the suggested origins of secondary nuclei is the absorbed non-crystalline supersaturated solution layer on the surface of the seed crystal.5 Denk and Botsaris, and later Qian and Botsaris, showed that stagnant and agitated experiments involving NaClO3 at high levels of supersaturation led to the crystallization of both chiral forms, despite the presence of a chiral pure seed crystal.6, 7 The applied supersaturation was lower than the metastable limit (MSL) and the crystals could therefore not have been formed through primary nucleation. Instead, these results were explained by the Embryo


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Coagulation Secondary Nucleation (ECSN) theory, which states that pre-nucleation clusters are attracted to a seed crystal through achiral van der Waals forces, resulting in the rapid agglomeration of clusters of both chiral forms into stable nuclei. A similar mechanism, which was coined as nuclei breeding more recently, was described using computer simulations.8 Once stable, secondary nuclei are dispersed from the seed crystal surface into the bulk solution through contact- and/or shear forces. In videotaped experiments involving NaClO3 it was observed that collisions of a seed crystal with an impeller resulted in contact nucleation, giving rise to thousands of crystals with the same chirality as the seed crystal.9, 10 In addition, contact nucleation of NaClO3 can proceed through microattrition from less significant sources of impact such as from sliding of crystals about the bottom of a flask.11 Secondary nuclei can alternatively be dispersed from the seed crystal surface through fluid shear.12-14 Experiments by Buhse et al., in which a supersaturated solution of NaClO3 was made to flow over a stationary chiral sodium bromate (NaBrO3) seed crystal, revealed that fluid shear alone was sufficient to induce secondary nucleation.15 In those experiments, the chirality of most of the NaClO3 product crystals was found to correlate to the chirality of the NaBrO3 seed crystals. After the formation and dispersion of secondary nuclei, the crystal surface becomes available to induce secondary nucleation again, provided that the solution remains sufficiently supersaturated. As a result, secondary nucleation is an excellent approach to make new crystals in continuous crystallization experiments as seed crystals would continuously convert a supersaturated feed solution into secondary nuclei.16 A proof of concept of the continuous generation of secondary nuclei has been reported for glycine and paracetamol, where secondary nuclei were formed through continuous contact nucleation.17 Alternatively, continuous shear-induced secondary nucleation through fluid shear should also be feasible. However, continuous flow experiments involving stationary NaClO3 seed crystals revealed that the chirality of the product crystals was stochastic and did not match the chirality of the seed crystals.7 The absence of a correlation in chirality between product- and seed crystals of NaClO3 in continuous flow experiments is surprising as batch experiments without contact nucleation involving stationary seed crystals of NaClO3 do result in chiral-specific crystallization.6, 7, 15



It remains unclear why continuous shear-induced secondary nucleation of NaClO3 is not feasible as opposed to batch experiments. Furthermore, the present work shows that literature solubility data of NaClO3 in water displays significant inconsistencies across multiple literature sources. Moreover, it is reported that like many other inorganic compounds, both NaClO3 and NaBrO3 are classified as inert seeds which means that the seed crystals grow only slowly and fail to proliferate.18 As outlined in the present introduction, this view is in contrast to studies that show that secondary nucleation of NaClO3 through fluid shear is feasible. Thus, an overall level of ambiguity regarding sodium chlorate still exists to date. Herein, the inconsistencies around NaClO3 are resolved using novel continuous shear-induced secondary nucleation experiments involving stationary seed crystals. The solubility and metastable zone width of NaClO3 was reviewed and accurately measured using a laser methodology. Seed crystals of NaClO3 and NaBrO3 were prepared and tested for initial breeding which is a mechanism through which fines that were present before the experiment are dislodged from the seed crystal to become nuclei. Finally, continuous shear-induced secondary nucleation experiments were carried out involving stationary seed crystals. The results presented herein provide a better understanding of NaClO3 and secondary nucleation mechanisms and show for the first time the significant impact of initial breeding.

2. EXPERIMENTAL SECTION

2.1. Materials The solutes NaClO3 (≥99%) and NaBrO3 (≥98%) were purchased from Merck and used as received. The purity of these solutes was determined by the supplier through a titration method. Ultrapure HPLC grade water was used as a solvent and was obtained through a PURELAB flex 3 purification instrument. Seed crystals of NaClO3 and NaBrO3 were prepared by evaporative recrystallization from water. A literature procedure was used to wash the seed crystals with deionized water to remove dust particles and fines.6, 15 Crystals of 3-4 mm in size were used in the continuous crystallization experiments (Figure 1) whereas larger seed crystals of about 10 mm in size were used in


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the sequential batch crystallization experiments (Figure 6). The chirality of the crystals was identified through optical rotation using polarized microscopy.

2.2. Laser Methodology to Determine Phase Diagram NaClO3 The metastable limit temperatures (cloud points) and saturation temperatures (clear points) of NaClO3 in water were determined using a methodology reported in literature.14 An accurately weighted amount of NaClO3 and water were dissolved and filtered using a 0.2 μm polyethersulfone membrane syringe filter. About 60 mL of the filtered solution was transferred to a 100 mL borosilicate flask, equipped with a Teflon-coated magnetic stirrer bar. In the unfiltered experiments, the solute and solvent were added directly to the borosilicate flask. The flask was tightly sealed with a screw cap and transferred to a transparent polycarbonate bath filled with deionized water. The temperature of the water was controlled using a Grant TX150 thermostat (stability ±0.005 °C and uniformity ±0.02 °C) and recorded using Labwise software. The difference between the set temperature and the solution temperature was within ±0.1 °C. The suspension was mixed using a MIXdrive magnetic stirring plate at a stirring rate of 300 rpm. The temperature was set to increase at a rate of 0.1 °C/min until all crystals dissolved. During the increase in temperature, the solids gradually dissolved as indicated by an increase in transmissivity of laser power which was emitted using an MRL-III-635L-30Mw red diode laser. The laser could detect particles of 20 nm and potentially smaller. The temperature at which maximum transmissivity was reached was taken as the saturation temperature. The solution was stirred for an hour at a temperature of 10 °C above the saturation temperature to ensure complete dissolution. Subsequently, the temperature of the water bath was set to decrease at a rate of 0.1 °C/min until crystallization occurred. The onset of crystallization was identified by a start of a decrease in transmissivity. The temperature at which the transmissivity started to decrease was taken as the cloud point temperature. Each concentration was measured three times and the resulting average metastable limit temperatures and saturation temperatures are reported.

2.3. Continuous Flow Experiments



Isothermal crystallization experiments involving NaClO3 in water were performed at a lab temperature of 20 °C. A Grant waterbath (type GR150; 38 L; stability ±0.005 °C and uniformity ±0.02 °C) was used to control the temperature of the solution of the continuous flow experiments. To ensure complete dissolution, each solution was stirred at 500 rpm using a Teflon coated magnetic stirrer for one hour on a hotplate set at a temperature of 50 °C. The resulting solution was filtered using a 0.2 μm syringe filter and transferred to a flask which was placed in a waterbath. In the experiments involving unfiltered solutions the flask was placed immediately in a waterbath without a filtration step. The temperature of the waterbath was set to 20 °C and the flask remained stagnant in the waterbath for one hour to create a supersaturated solution. The resulting supersaturation, denoted by supercooling ΔT, is expressed as the difference between the theoretical saturation temperature (T*) and the actual temperature (T) of the solution (i.e. 20 °C). For the tested supercoolings ΔT = 0 °C, 2.7 °C, 4.6 °C and 6.4 °C, the used concentrations were C = 949 mg/ml, 974 mg/ml, 992 mg/ml and 1009 mg/ml with corresponding clear point temperatures of T = 20 °C, 22.7 °C, 24.6 °C and 26.4 °C, respectively (Figure 2). The amount of solvent used in each experiment was 20 ml water. The saturated- or supersaturated solution was transferred through tubing (Figure 1) and was collected into petridishes over the course of 8 minutes. The solution was collected in a new petridish each minute, resulting in a total of 8 samples. A Lambda Preciflow peristaltic pump in combination with transparent silicon tubing (inside ø=3mm) was used to create a flow system. In the seeded experiments, a single crystal was placed at the end of the tubing. The seed crystal was secured in the tubing as the tube diameter was smaller than the seed crystal creating an interference fit. The applied flowrates were too small to remove the seed crystal from the tubing. After each experiment, the collection of solution stopped and 100 mL ultrapure HPLC grade water was transferred through the tubing to remove any residual NaBrO3 or NaClO3. The tubing was subsequently dried and used in the following experiment. The collected solution contained crystals of NaClO3 which were too small to be analyzed for optical rotation. Therefore, water was evaporated from the solution at a temperature of 20 °C over the course of 4 hours in order to grow the crystals to sufficiently large sizes for the analysis of the optical


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rotation. During evaporation, no primary nucleation occurred as test runs showed that the chirality of the product crystals was the same as chiral-pure starting material. Flow experiments were also carried out in combination with an approach based on a literature report, as shown in Figure 6a.15 In these experiments, the supersaturated solution was filtered through an 0.2 μm syringe filter and immediately passed over a chiral-pure seed crystal which was held stationary inside a tubing. The silicon tubing was flexible and it was therefore possible to insert a seed crystal with a larger diameter than the diameter of the tubing, creating an interference fit. As a result, the seed crystal remained in place despite the applied flow of solution. The water from the collected solution was slowly evaporated until the product crystals were sufficiently large to enable chiral identification.

Figure 1. Schematic overview of the experimental procedure to test initial breeding.

2.4. Microscopic Analysis of Optical Rotation and Seed Crystal Surface The chirality of NaClO3 and NaBrO3 can be described using the optical rotation, leading to the laevorotatory (l) and dextrorotary (d) or the (+) and (-) nomenclature.15, 19 The chiral configuration of the crystal structure is denoted by A and B and this description is used in the present work.7 An Olympus IX53 inverted microscope was used to determine the optical rotation of the crystals. Brightfield microscope settings were used and the light transmitted through the crystals was polarized using a polarization filter. After passing through the crystals, the polarized light was passed through another polarization filter (i.e. the analyzer) before reaching the camera or eyepiece of the



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microscope. By a clockwise rotation of the analyzer, A-NaClO3 and B-NaClO3 crystals become dark and bright, respectively. This situation is reversed for NaBrO3, where a clockwise rotation of the analyzer resulted in A-NaBrO3 and B-NaBrO3 crystals to become bright and dark, respectively. The optical rotation of each sample was identified and the solid phase enantiomeric excess (E) was determined through

𝑛𝐴 ― 𝑛𝐵

(3)

𝐸 = 𝑛𝐴 + 𝑛𝐵 × 100

where nA represents the number of A-NaClO3 crystals and nB represents the number of B-NaClO3. For example, an experiment involving an A-NaBrO3 seed crystal induced the crystallization of nA = 200 ANaClO3 crystals and nB =100 B-NaClO3. Therefore, the solid phase enantiomeric excess E = 33%. Some of the NaClO3 and NaBrO3 seed crystals were examined using scanning electron microscopy (SEM) to visualize the crystal surface. The crystals were placed on a SEM sample holder and coated with a thin layer of gold. The SEM images were taken using a JEOL CarryScope JCM-5700.

3. RESULTS The solubility and metastable limit of NaClO3 in water are described in the first section. The second part outlines the importance of seed crystal preparation and shows that a rigorous washing regime is required to avoid initial breeding. The final section describes continuous secondary nucleation and shows that the seeded chiral form could not be obtained through shear-induced crystallization experiments.

3.1. Solubility of NaClO3 in Water The solubility of NaClO3 in water has been reported in at least 28 literature sources to date. Miyamoto reviewed 22 publications and the corresponding data is shown in Figure 2.20 In addition, Figure 2 shows the solubility data obtained by Seidell21, Osaka22, Mullin23, Chen et al.,24 Mayer and


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Lacmann25, Ni et al.26 and Buhse et al.15 as well as our own solubility data. The solubility data by Ni et al. was taken from Seidell and reportedly verified and confirmed at a temperature T=40 °C with a solubility C*=1005.8 mg/mL. However, this data point is significantly different from the data from Seidell, who found a solubility of C*=1260 mg/mL at that temperature. A similar comparatively low solubility data point of C*=829 mg mL at T=23 °C was reported by Buhse et al. As all other solubility data is significantly higher, we assume that the two points reported by Ni et al. and Buhse et al. are incorrect. In most of the reported literature, the method used to determine the solubility has not been described but will most likely have been thermogravimetric analysis. Mayer and Lacmann used a temperature oscillating method and the resulting second-order equation is plotted in Figure 2.25 The lowest solubility data was obtained by Chen et al. where the solubility was measured through MachZehnder interferometry.24 In general, most solubility points are similar to our data except for the data obtained by Seidell and Mullin who found solubility data which is significantly higher than the majority of literature reports.

Figure 2. Solubility C* of NaClO3 expressed in mg per ml water and plotted as a function of temperature T.



The solubility C* of NaClO3 in water as determined herein is also shown in Figure 3 and shows a linear dependency to the temperature T. Such a linear temperature-concentration relationship was also found for NaBrO3 in water.16 The standard deviation in the solubility data increased with temperature T but remained smaller than 1 °C up to a temperature T of 55 °C. In addition to the solubility, knowledge of the metastable limit (MSL) at which point spontaneous nucleation occurs is also desirable for designing secondary nucleation experiments. In our work, we determined the MSL for both filtered and unfiltered solutions in magnetically stirred flasks. Figure 3 shows that the MSL for filtered solutions are very similar to the MSL of unfiltered solutions. The main difference between the two datasets is the standard deviation, which is wider for the filtered solutions. Particles in the unfiltered solutions may act as a template for heterogeneous nucleation and as such make primary nucleation a more deterministic process. On average across the investigated temperature range, the MZW was determined to be T=8.6 °C, which is narrow as is common for inorganic salts and small molecules.27

Figure 3. Averaged saturation temperatures T* (■) and metastable limits for filtered (▲) and unfiltered (●) aqueous NaClO3 solutions. Standard deviations are shown by horizontal bars. The line is a linear fit to the solubility data and the corresponding equation is shown in the graph.


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Thus, the solubility of NaClO3 in water shows variations across literature. The solubility data determined herein is similar to most reported literature data. The solubility and the MSL of NaClO3 in water were used as a framework for the continuous shear-induced secondary nucleation experiments.

3.2. Seed Crystal Preparation: Saturated Solutions Literature results from batch experiments show that NaClO3 single seed crystals induce chiralselective secondary nucleation of NaClO3.6, 7 Chiral-selective secondary nucleation of NaClO3 can also be realized with NaBrO3 seed crystals, as NaClO3 and NaBrO3 have isomorphous crystal structures.15 In the present work, both types of seed crystals were tested in secondary nucleation experiments, in which either a chiral pure NaClO3- or a chiral pure NaBrO3 seed crystal was used. Prior to the crystallization experiment, seed crystals are typically washed with a solvent to remove small crystalline fines from the seed crystal surface, as such particles would otherwise be transferred to the bulk solution through initial breeding. In previous studies6, 15, NaClO3- and NaBrO3 seed crystals were washed with water and the same approach was used herein. In the absence of initial breeding and supersaturation, the collected solution from the flow experiment must be free from crystals. After evaporation of the solvent (Figure 1), crystallization of NaClO3 should proceed through primary nucleation to give a racemic mixture of crystals where the solid phase enantiomeric excess E=0. In unseeded experiments tested herein, a flow of saturated solution of NaClO3 was continuously collected over time and the water from the resulting samples was evaporated until the crystals were sufficiently large for analysis. For the unseeded experiments, this resulted in a few large product crystals that were close to E=0 and randomly in favor of either the A- or B chiral form (Figure 4a). Deviations from a racemic mixture are typical, as a small odd number of crystals always lead to an enantiomeric excess (i.e. E≠0). The enantiomeric excess E was found to be randomly in favor of either A or B over time and no chiral selectivity was therefore observed in the absence of a seed crystal. Figure 4a also shows the solid phase enantiomeric excess E of NaClO3 product crystals collected over time after a flow of saturated solution of NaClO3 was subjected to a stationery NaBrO3 seed crystal. Interestingly, the chirality of the product crystals obtained after evaporation of water across



all samples was found to be, in majority, the same as the chirality of the seed crystal. These results were observed for both chiral forms of the NaBrO3 seed crystals. Over time, the correlation between the chirality of the product crystals and the seed crystal gradually disappeared.

Figure 4. a) The solid phase enantiomeric excess E of NaClO3 product crystals as a function of time for an unseeded experiment (▲) as well as experiments involving a damaged A-NaBrO3 (●) and BNaBrO3 (■) single seed crystal. A flow of saturated solution of ΔT = 0 °C was used and the product crystals from the seeded experiments therefore originated from initial breeding. The lines are linear fits to the data. b) SEM image of the surface of a damaged NaBrO3 seed crystal.

The decrease in solid phase enantiomeric excess E over time due to the presence of a NaBrO3 seed crystal points to initial breeding, as fines could dislodge and transfer from the seed crystal to the bulk solution as a result of the continuously applied flow of saturated solution. Fines were indeed observed on the surface of the NaBrO3 seed crystals by SEM microscopy, even though the seed crystals were thoroughly washed before use (Figure 4b). Crystals of both NaBrO3 and NaClO3 are highly brittle and friction or impact from another solid object would easily cause the formation of fines. The fines were probably formed in our experiments after the washing step due to crystal breakage during the seed crystal preparation procedure, as the seed crystals were placed on a glass slide for microscopic analysis and were moved using a pair of tweezers.


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Prior to each experiment, the seed crystals were washed again with water to remove any fines that were formed during the seed crystal preparation procedure. The surface of the resulting crystals appeared to be free from fines, as indicated by SEM microscopy (Figure 5b). These freshly washed NaBrO3 seed crystals, as well as NaClO3 seed crystals, were carefully subjected to a flow of saturated solution of NaClO3 and the solution was collected over time. Water from the samples was evaporated which resulted in the formation of a small number of large NaClO3 crystals with a solid phase enantiomeric excess E that was randomly in favor of either the A- or B chiral form (Figure 5a). Therefore, no correlation in chirality existed between the seed crystal and the product crystals, showing that initial breeding did not take place with the freshly washed seed crystals.

Figure 5. The solid phase enantiomeric excess E of NaClO3 product crystals as a function of time for experiments involving a freshly washed A-NaBrO3 (●), B-NaBrO3 (■), A-NaClO3 (▲) or B-NaClO3 (▼) single seed crystal. A flow of saturated solution of ΔT = 0 °C was used. b) SEM image of the surface of a freshly washed NaBrO3 seed crystal.

3.3. Supersaturated Seeded Experiments Having established the phase diagram of NaClO3 in water (paragraph 3.1) as well as a procedure to prepare the seed crystals (paragraph 3.2), the stage was set to test whether continuous secondary nucleation of NaClO3 using a stationary enantiopure seed crystal is feasible. The continuous flow setup in Figure 1 was tested in combination with a flow of supersaturated solution of ΔT=2.7 °C and in the absence of a seed crystal. The resulting solution contained many small crystals after passing through



the tubing whereas the same solution that was not subjected to flow conditions remained clear. The flow setup therefore induces heterogeneous nucleation and as such could not be used to study secondary nucleation through seeding. Therefore, heterogeneous nucleation may explain why a previous study involving seeded continuous crystallization attempts with NaClO3 did not lead to secondary nucleation.7 To avoid heterogeneous nucleation, an approach similar to the one used by Buhse et al.15 was employed where a filtered supersaturated solution of NaClO3 was made to flow over a seed crystal (Figure 6a). In the present work, the seed crystal was fixed partially inside a stationary piece of tubing as to avoid the creation of fines and initial breeding. It was found that the setup in Figure 6a was suitable to study secondary nucleation of NaClO3 as heterogeneous nucleation was only observed at a supersaturation of ΔT=6.5 °C and higher.

Figure 6. a) Schematic depiction of the flow setup, in which a filtered supersaturated solution of NaClO3 was passed over a stationary seed crystal that was fixed inside a piece of tubing. b) The solid phase enantiomeric excess E of NaClO3 product crystals obtained from the setup in Figure 6a in combination with supersaturation ΔT=4.6 °C and a single seed crystal of A-NaBrO3 (●), B-NaBrO3 (■), A-NaClO3 (▲) or B-NaClO3 (▼). Four consecutive experiments were carried out for each chiral pure seed crystal.

3.3.1. NaClO3 Seed Crystals


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Experiments by Denk and Botsaris, and later by Qian and Botsaris, showed that shear-induced secondary nucleation of NaClO3 in the presence of a stationary NaClO3 seed crystal is feasible in both stirred and stagnant batch solutions.6, 7 In their experiments, a correlation was observed between the chirality of the seed crystal and the product crystals at a supercooling range with an average supercooling of about ΔT=4 °C. To test if secondary nucleation is possible using just a flow, we passed a supersaturated solution of NaClO3 of supercooling ΔT=4.6 °C over a chiral-pure stationary NaClO3 seed crystal using the setup in Figure 6a. This procedure was carried out four times in a row. Figure 6b shows that the chirality of the resulting small number of NaClO3 product crystals was stochastic as it does not correlate with the chirality of the NaClO3 seed crystals across all samples. The same stochastic outcome was obtained for experiments involving supercoolings ΔT=2.7 °C and ΔT=6.4 °C. These results therefore show that continuous chiral-selective secondary nucleation of NaClO3 by flow in combination with a stationary seed crystal of NaClO3 is not possible.

3.3.2. NaBrO3 Seed Crystals To investigate whether secondary nucleation of NaClO3 is feasible using a stationary NaBrO3 seed crystal, we attempted to reproduce the experiments by Buhse et al.15 In their work, Buhse et al. prepared a saturated solution at 23 °C of C=829 mg/mL of NaClO3 in water which was subsequently brought to a temperature of 19 °C to create a supersaturated solution of ΔT=4 °C. However, according to our solubility data, a temperature of 19 °C leads to a saturated solution of 935 mg/mL, which is significantly higher than the concentration used by Buhse et al. As a result, the concentration and temperature combination employed by Buhse et al. would create an undersaturated solution according to our solubility data. To test the secondary nucleation approach by Buhse et al., a supersaturated solution of ΔT=4.6 °C was created using the solubility data obtained in the present work. The supersaturated solution was passed over a stationary NaBrO3 seed crystal using the approach in Figure 6a. This approach was adapted from the work of Buhse et al. who used a pair of tweezers to keep the NaBrO3 seed crystal stationary whereas in the present work the seed crystal was fixed partially inside a piece of stationary tube. In our work, the chirality of the resulting small number of NaClO3 product crystals did not



correlate with the chirality of the NaBrO3 seed crystal across all samples but instead was found to be stochastic (Figure 6b). As with the experiments involving NaClO3 seed crystals, similar flow experiments involving supercoolings ΔT=2.7 °C and ΔT=6.4 °C also resulted in a stochastic product outcome. Thus continuous chiral-selective secondary nucleation of NaClO3 by flow in combination with a stationary NaBrO3 seed crystal is not possible without initial breeding.

4. DISCUSSION To date, two conflicting views regarding the dispersion of secondary nuclei are reported. Some authors have discussed that secondary nuclei can be dispersed through fluid flow alone whereas others have found that secondary nucleation can only occur through impact.18 The significant differences in compounds, solvents and experimental conditions across literature makes an exact comparison between the results virtually impossible. In the case of NaClO3 it has been widely reported and recognized that impact can disperse secondary nuclei. On the other hand, shear-induced secondary nucleation of NaClO3 is less well established and was first proposed by Denk and Botsaris who found a correlation between the chirality of the stationary seed crystal and the product crystals.7 Later, similar experiments were carried out by Qian and Botsaris who again found a correlation between the chirality of the stationary seed crystal and the product crystals, depending on the applied supersaturation.6 In these experiments, both stagnant and stirred batch crystallization experiments were used in combination with a stationary seed crystal. It is unclear why the experiments reported in literature by Denk and Botsaris as well as by Qian and Botsaris led to a correlation between the chirality of the seed crystal and the product crystals whereas in the present work no such correlation could be established. Although some experimental information has been reported in literature, the important information such as solubility data and details regarding the washing step of the seed crystals is missing. Moreover, in literature the seed crystal was mounted in a stainless steel rod with a split end and the experiments were conducted in 2L jacketed vessels. Overall, the significant differences in experimental approach and absence of experimental details makes it very difficult to compare the present results with the previously reported findings. However, it should be noted that in stirred crystallization experiments the presence of agitation may


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lead to Viedma ripening which could cloud the results and conclusions.28 Agitation-free experiments are therefore more suitable to study shear-induced secondary nucleation. The third and final literature report on shear-induced secondary nucleation of NaClO3 was by Buhse et al., who used a stationary NaBrO3 seed crystal in a setup similar to Figure 6a.15 However, in their work the seed crystal was held stationary using a pair of tweezers. In our work we found that any small impact from a solid object, including the use of a pair of tweezers, readily creates small fines on the surface of the seed crystal. Therefore, initial breeding of NaClO3 and NaBrO3 readily occurs and may explain the reported correlation in chirality by Buhse et al. The reported differences in solid phase enantiomeric excess E between experiments may be explained by differences in the amount of crystal attrition and initial breeding. Overall our results show that the dispersion of secondary nuclei of NaClO3 through fluid shear alone was not feasible under the tested conditions. Instead, secondary nucleation using a flow was only possible through initial breeding. Initial breeding readily occurred and could easily be mistaken for nuclei breeding. Failure of NaClO3 and NaBrO3 to bring about secondary nucleation through fluid shear has been recognized before, as both compounds are considered to be inert seeds like many other inorganic compounds.18 For instance, in stirred crystallization experiments secondary nucleation of NaClO3 failed to occur in the presence of small seed crystals but only occurred for large seed crystals.25 This is because contact nucleation more readily occurs for larger crystals.29 Shear-induced nucleation on the other hand should also occur for small crystals but this was not observed. Therefore, the results in literature and the results presented herein show that the dispersion of secondary nuclei of NaClO3 requires contact interactions as fluid shear alone is insufficient. It is important to take great care in seed crystal preparation as initial breeding readily occurs and could cloud the experimental results. An inspection of the seed crystal surface is a straightforward approach to provide an indication of whether fines are present. In addition, continuous- or sequential batch experiments may be used to test the feasibility of whether fluid shear is capable of dispersing secondary nuclei as such an approach would firstly lead to any potential initial breeding which would then be followed up by nuclei breeding.



5. CONCLUSIONS The solubility of NaClO3 in water is reviewed and the measured solubility data corresponds to most of the reported literature data. Due to the narrow metastable zone width it was not possible to employ a continuous flow setup as such conditions favor heterogeneous nucleation over secondary nucleation. Seed crystals of NaClO3 and NaBrO3 were found to be highly susceptible to undergo attrition and fines on the seed crystal surface were easily created. Sufficiently washed seed crystals of NaClO3 and NaBrO3 failed to induce secondary nucleation through fluid shear. Importantly, chiral-selective secondary nucleation of NaClO3 through fluid shear was only possible through initial breeding. The results presented herein reveal a better understanding of secondary nucleation as the role of initial breeding is significant and influences the development of secondary nucleation mechanisms.

AUTHOR INFORMATION Corresponding Author *E-mail: [email protected]

ORCID René R. E. Steendam: 0000-0002-3363-4160 Patrick J. Frawley: 0000-0001-7066-0942

Funding This research has been conducted as part of the Synthesis and Solid State Pharmaceutical Centre (SSPC) and funded by Science Foundation Ireland (SFI) under Grant 12/RC/2275.


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Notes The authors declare no competing financial interest.

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For Table of Contents Use Only

Secondary Nucleation of Sodium Chlorate: The Role of Initial Breeding

René R. E. Steendam*& Patrick J. Frawley

Solubility and metastable limits for sodium chlorate in water are reported and compared to literature data. Flow-induced secondary nucleation of sodium chlorate was only feasible through initial breeding.


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Secondary Nucleation of Sodium Chlorate - ACS Publications

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