Effects of Common Inorganic Salts on Glycine Polymorphic

Article pubs.acs.org/crystal

Effects of Common Inorganic Salts on Glycine Polymorphic Transformation: An Insight into Salt-Dependent Polymorphic Selectivity Guangjun Han,*,† Pui Shan Chow,† and Reginald B. H. Tan*,†,‡ †

Institute of Chemical and Engineering Sciences, A-STAR (Agency for Science, Technology and Research), 1, Pesek Road, Jurong Island, Singapore 627833 ‡ Department of Chemical and Biomolecular Engineering, National University of Singapore, 10 Kent Ridge Crescent, Singapore 119260 ABSTRACT: The effects of typical inorganic salts on solution-mediated polymorphic transformation from metastable α-glycine to stable γ-glycine were investigated, with the measurement of induction times of γ-glycine nucleation being the key objective. Interestingly, it was observed that all the inorganic salts examined in this study considerably shorten induction time, showing that they accelerate γ-glycine secondary nucleation to a great extent. Surprisingly, it was found that the divalent cation salts (Ca(NO3)2 and MgSO4) exert a peculiar effect in that they greatly promote γ-glycine secondary nucleation despite their significant inhibition to γglycine growth. Furthermore, it was revealed that the monovalent cation salts (NaCl, KNO3, and (NH4)2SO4) enhance γ-glycine nucleation far more than the divalent cation salts. These obtained results provide an insight into the general observation that the polymorphic selectivity of glycine from unseeded solution crystallization is salt-dependent. All the experimental observations were discussed and explained at the molecular level.

■

INTRODUCTION Crystal polymorphism1−3 is a general phenomenon in solution crystallization. It originates from different arrangements of the same molecules in the crystalline solid state, with each arrangement being one polymorph (one solid form). The importance of crystal polymorphs has well been recognized in chemical (especially pharmaceutical) manufacturing, because the physicochemical and biological properties of polymorphs can vary greatly. It is therefore crucial to control polymorph. However, there is a long way to go before robust polymorph control can be achieved given the poor fundamental understanding2−5 of solution crystallization. Such a challenge has been demonstrated well by the longstanding riddle2−4,6 of glycine polymorphic crystallization from solutions. Glycine (NH2CH2COOH) is an important classical polymorphic system, often used as a model2−4 for general mechanistic exploration of polymorphic selectivity. It has three polymorphs2−4 under usual conditions: α-glycine, βglycine, and γ-glycine. The least stable β-glycine is not sustainable7 in aqueous solution as it undergoes a nearly instantaneous transformation to α-glycine when in contact with water. The crystallization of metastable α-glycine and stable γglycine from aqueous glycine solutions was widely studied by numerous researchers2−4,6−32 over past decades. One of the reasons for such an intensive study is that α-glycine and γglycine exhibit interesting structural features (Figure 1) and © XXXX American Chemical Society

Figure 1. Different crystalline structures and distinct PXRD patterns of dimer-based α-glycine and monomer-based γ-glycine (CSD codes of gly29 and gly33 were used in PXRD simulation).

that their formation may be favored by a shift in solution chemistry. The centrosymmetric α-glycine is packed with cyclic glycine zwitterion dimers. In contrast, the asymmetric γ-glycine is packed with head-to-tail open glycine zwitterion chains. Given the big difference in crystalline structures of these two Received: August 7, 2016 Revised: September 26, 2016

A

DOI: 10.1021/acs.cgd.6b01177 Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design

■

polymorphs, their characteristic powder X-ray diffraction (PXRD) patterns are greatly distinct (Figure 1). Previous studies2−4 have shown that the metastable α-glycine is readily formed from a pure aqueous glycine solution, while the thermodynamically stable γ-glycine usually has to be prepared with the assistance of acids, bases, and inorganic salts. The interpretation of the acid- and base-induced γ-glycine has been debated for a long time.2−4,8 The recent studies3,8 tend to draw the following conclusions: (1) In pure glycine solution, the glycine cyclic dimers do not exist predominantly, but they are significant enough to act as precursors of α-glycine, largely favoring the dimer-based α-glycine nucleation. (2) Introducing an acid or a base into a glycine solution causes solution pH to shift, thereby creating glycine ions. (3) These created glycine ions induce the formation of glycine head-to-tail chains which are viewed as the favorable precursors of γ-glycine, significantly promoting the nucleation of monomer-based γ-glycine. Another interesting general observation4,6,9,10 is that inorganic salts largely differ in determining the polymorphic selectivity of glycine from unseeded solution crystallization. It was found4,6 that various monovalent cation salts (e.g., NaCl and KNO3 which do not cause solution pH to shift) effectively induce γ-glycine, while typical divalent cation salts (e.g., MgSO4, Ca(NO3)2, and Mg(NO3)2) hardly induce γ-glycine. Little work has been done to analyze the mechanisms through which this salt-dependent polymorphic selectivity is governed. Among a few studies,9,10 NaCl was particularly chosen to examine its effect on glycine polymorphic crystallization. It was observed9 experimentally that NaCl promotes the nucleation of γ-glycine during solution-mediated transformation from αglycine to γ-glycine, which was attributed to a particular salt ion-glycine ordering in solution. However, such a particular ordering is questionable3 as no fundamental data indicate that this ordering is formed more readily than other orderings. Computationally, it was revealed10 that a double layer of Na+ and Cl− ions is established at the NH3+-rich (001) and COO−rich (001)̅ faces of a γ-glycine nucleus, decreasing the interfacial energy so as to favor γ-glycine nucleation. The formation of an ion double layer4 at a γ-glycine polar face is understandable. However, as suggested by an earlier analysis and experimental observation,4 such a double layer does not play a primary role in determining the polymorphic selectivity of glycine. Perhaps the greatest challenge to these interpretations9,10 is that none of them explain why divalent cation salts hardly induce γ-glycine. Another recent study6 presented an interesting observation. It was shown that divalent cation salts retard γ-glycine growth substantially more than α-glycine, thereby kinetically reinforcing the preferential formation of α-glycine on a relative basis. On the other hand, monovalent cation salts do not significantly change the relative growth rates of these two glycine polymorphs, but they do shift polymorphic selectivity from metastable α-glycine to stable γ-glycine. This suggests that beside growth kinetics of crystalline nuclei (crystals), other associated steps (e.g., solute aggregation and ordering) in a multistep nucleation process33−35 also play important parts in directing the route of polymorphic nucleation. Therefore, in this study, the effects of various inorganic salts on γ-glycine nucleation were systematically investigated using solutionmediated polymorphic transformation9,36−38 (SMPT), as part of the effort in resolving the riddle of the salt-dependent polymorphic selectivity of glycine from unseeded solution crystallization.

Article

EXPERIMENTAL SECTION

Materials. Both α- and γ-glycine crystals (99%) were from SigmaAldrich. These crystals and ultrapure water (Millipore, resistivity 18.2 MΩ·cm and filtered with pore size 0.22 μm) were used to prepare glycine solutions. Control experiments were performed with a higher grade of glycine (>99.7%, Sigma-Aldrich). Three monovalent cation salts (NaCl, KNO3, (NH4)2SO4) and two divalent cation salts (MgSO4, Ca(NO3)2·4H2O) were of analytical grade. Solubility Measurement. Solubilities of α- and γ-glycine in aqueous solutions in the presence of inorganic salts at 23 °C were measured in this study using an isothermal method.6 Preparation of Pure Fine α-Glycine Crystals. The α-glycine crystals for glycine polymorphic transformation were prepared by adding 150 mL of glycine aqueous solution (glycine c = 20 g/100 g H2O) at a controlled flow rate of 75 mL per minute to 200 mL of antisolvent MeOH (analytical grade), while the antisolvent was adequately agitated to keep the formed solution of suspension uniform for a better precipitation of glycine. The formed glycine crystals were harvested by vacuum filtration and then dried under ambient conditions, followed by polymorphic analysis using PXRD (Bruker D8 Advance Diffractometer). For consistency, these α-glycine crystals obtained from different batches were blended before they were used in polymorphic transformation experiments. The volume-mean size of these obtained α-glycine crystals, determined using a particle size analyzer (Malvern MS2000), was about 52 μm. Experiment for Solution-Mediated Polymorphic Transformation. For each experiment of SMPT, the first run was used to gauge the time scale, followed by a few more runs (typically three runs), with the average data reported. In each run, 115 mL of glycine solution at a concentration equal to the solubility of metastable αglycine at 23 °C was prepared. Through a syringe filter (0.22 μm), it was then transferred to a 250 mL jacketed beaker and kept at 23 °C using a Julabo circulator. The solution was agitated with a magnetic stirrer at 120 rpm After it was thermally equilibrated for 15 min at 23 °C, 10 g of the prepared α-glycine crystals (pre-equilibrated at 23 °C) was introduced into the solution, increasing the volume of the solution of suspension to about 125 mL. The glass jacketed beaker was sealed with parafilm to minimize solvent evaporation. A plastic syringe (pre-equilibrated at 23 °C) was used to regularly withdraw 3 mL of sample from the agitated bulk slurry. The slurry sample in the syringe was quickly separated into a liquid-rich top layer and solid-rich bottom layer for analysis so as to monitor glycine concentration in the liquid phase and polymorphic composition in the solid phase of the bulk slurry. The liquid-rich top layer was injected into a densitometer (Anton Paar DMA5000) through a syringe filter for a quick measurement of solution density which determines the glycine concentration.3,6 The leftover solid-rich layer in the syringe was immediately vacuum-filtered through a filter paper to harvest the solids which were thoroughly rinsed using a filtered pure (additive-free) α-glycine saturated solution. It took about 5 min from withdrawing a slurry sample to rinsing the wet solids. The rinsed glycine solids on the filter paper in the filter funnel were vacuumed for about 5 min to remove most of the free solution. The slightly wet glycine solids were dried under ambient conditions for 1 day. Polymorphs of the dried glycine solids (about 0.3 g) were analyzed using PXRD within subsequent 2 days. When the height of the major distinct characteristic peak of γ-glycine at 2θ = 25.3° (Figure 1) was about two times the height of the noise band, γ-glycine in the solid phase was deemed to be detectable, which indicated the onset of γ-glycine secondary nucleation in the slurry suspension and gave the corresponding induction time. An induction time of γ-glycine secondary nucleation was defined as a time lapse from the moment at which α-glycine crystals were introduced into a glycine solution to the moment at which γ-glycine in the solid phase of the glycine suspension became detectable. In addition, the height of this major characteristic peak was also used to approximate the γ-glycine content in the solid phase, based on a reasonable assumption that the γ-glycine content is proportional to the peak height. B

DOI: 10.1021/acs.cgd.6b01177 Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design

Article

Table 1. Solubilities of α- and γ-Glycine in Various Salt Solutions at 23 °C additive concentration (molality, m)

salt additive

α-glycine solubility (g/100 g H2O)

γ-glycine solubility (g/100 g H2O)

solubility ratio (α:γ)

0 0.5 1.0 0.5 1.0 0.5 2.5 0.5 2.5 0.5 2.5

N/A MgSO4 MgSO4 Ca(NO3)2 Ca(NO3)2 KNO3 KNO3 NaCl NaCl (NH4)2SO4 (NH4)2SO4

24.02 28.51 31.26 32.20 39.05 25.88 29.86 25.07 27.45 26.64 28.56

22.63 26.97 29.58 30.51 37.55 24.31 28.17 23.51 25.79 25.09 26.98

1.06 1.06 1.06 1.06 1.04 1.06 1.06 1.07 1.06 1.06 1.06

It should be pointed out that it was important to rinse the glycine crystals harvested from an α-glycine slurry suspension in the presence of an additive salt. Through rinsing, the additive salt ions on the glycine crystal surfaces were removed so as to practically preserve the glycine polymorphs of the harvested glycine solids, because the nucleation of γ-glycine at α-glycine surface was slow in an additive-free environment. In fact, our screening experiments showed that stable γglycine hardly appeared from the rinsed and dried metastable α-glycine crystals over a period of even up to 3 weeks. So rinsing and drying of the harvested glycine solids essentially prevented γ-glycine from nucleation. As such, as long as the measured induction times of γglycine during SMPT were tremendously shorter than 3 weeks (which was the case in this study), they were highly determined by the γglycine secondary nucleation in α-glycine slurry suspensions. In addition, in the course of a polymorphic transformation, the slurry samples withdrawn before γ-glycine secondary nucleation were usually fewer than 6, accounting for merely 15% of the initial volume (125 mL) and having an insignificant impact on the induction time of γglycine secondary nucleation. Experiment for Growth Rate of a Single γ-Glycine Crystal. A similar experimental procedure6,12 was employed to measure growth rate of a single γ-glycine crystal. This procedure is briefly described here. A homogeneous glycine solution of a given concentration was prepared at an elevated temperature and then cooled to 23 °C. Through a syringe filter (0.22 μm), the cooled solution was filtered into a thermally pre-equilibrated (at 23 °C) glass crystallization cell where a single γ-glycine seed crystal was introduced for its growth at 23 °C. The images of the growing seed crystal were regularly captured using an optical polarizing microscope (Olympus, BX51, equipped with a CCD camera). The displacements along a given axis of the acquired images were measured using Analysis (image capture software), and they were plotted against time. The slope of the plotted straight line (R2 > 0.99) gave the corresponding growth rate along the axis. The average growth rate, computed with the results from at least three runs, was presented. The γ-glycine seed crystals with an identifiable c-axis used for measurement of growth rates were particularly prepared12 using a tailor-made-additive, DL-aspartic acid.

Solution-Mediated Polymorphic Transformation (SMPT). On the basis of the experimental procedure, experiments for glycine polymorphic transformations in solutions in the presence and in the absence of these five selected common inorganic salts were performed, respectively. The evolution of a typical glycine polymorphic transformation is illustrated in Figure 2.

Figure 2. Illustration of the evolution of a typical solution-mediated glycine transformation in the presence of 2.5 m NaCl, highlighting the onset and the corresponding induction time of γ-glycine secondary nucleation.

After α-glycine crystals were added to the α-glycine saturated clear solution at 23 °C, the glycine concentration in the liquid phase was practically unchanged, and the solid form in the solid phase remained as α-glycine before the secondary nucleation of the stable γ-glycine was initiated. On the basis of the onset of γglycine secondary nucleation, the corresponding induction time was calculated. With further development, γ-glycine increased while α-glycine decreased in the solid phase. Subsequently, αglycine disappeared and only γ-glycine existed in the solid phase even before the solution concentration reached γ-glycine solubility (Figure 2). Following the same procedure, the induction times (with a typical deviation of 25%) of γ-glycine nucleation in the presence of other salts were measured, and they are tabulated in Table 2. For further analysis, the enhancement factors of γglycine secondary nucleation are calculated (Table 2). A nucleation enhancement factor is defined as the ratio between induction time of γ-glycine nucleation in the absence of a salt additive and that in the presence of a salt additive. It should be pointed out that γ-glycine did not crystallize from an unseeded pure (additive-free) glycine solution having a

■

RESULTS AND DISCUSSION Glycine Solubilities. The solubilities of α-glycine and γglycine in aqueous solutions in the presence of salt additives at 23 °C were measured in this study. These solubilities, together with those6 reported previously, are tabulated in Table 1. It should be highlighted that all the five salts exert a salting-in effect on glycine solubilities and that divalent cation salts have a greater salting-in effect than monovalent cation salts. Similar salting-in effects were observed before,6 and they were explained6 on the basis of different ion−dipole and dipole− dipole interactions. Another interesting observation is that the ratios of α-glycine solubility to γ-glycine solubility in given salt solutions are close to 1.06, which was also discussed before.6 C

DOI: 10.1021/acs.cgd.6b01177 Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design

Article

Table 2. Induction Times and Enhancement Factors of γGlycine Secondary Nucleation during SMPT salt additive

induction time (min)

γ-glycine enhancement factor

pure water 1.0 m MgSO4 1.0 m Ca(NO3)2 0.5 m MgSO4 0.5 m Ca(NO3)2 0.5 m KNO3 0.5 m NaCl 2.5 m KNO3 0.5 m (NH4)2SO4 2.5 m (NH4)2SO4 2.5 m NaCl

15640 480 375 270 260 191 113 51 50 45 43

1 33 42 58 60 82 138 307 313 348 368

tion. Such a huge decrease in induction time is far beyond the experimental uncertainty. Since a shorter induction time means a higher nucleation rate of γ-glycine, all these salt additives promote γ-glycine nucleation to a great extent. In addition, these induction times indicate that monovalent cation salts are generally more effective than divalent cation salts in accelerating γ-glycine nucleation during glycine transformation. Mechanisms for the Salt-Enhanced γ-Glycine Secondary Nucleation. It is reasonable to suggest that the observed salt-enhanced γ-glycine secondary nucleation may be attributed to the salt-altered γ-glycine growth kinetics. In order to elucidate the role of growth kinetics, the growth rates of γglycine seed crystals from solutions saturated with α-glycine at 23 °C at selected concentrations of the salt additives were measured. It was found that, in various α-glycine saturated solutions which correspond to practically the same supersaturation σ = 1.06 (Table 1) with respect to γ-glycine at 23 °C, all these salts hardly affect the growth along the slow growing γ-glycine c-axis, but they affect the growth along the γ-glycine b-axis (width) differently, as illustrated in Figures 3 and 4. The divalent cation salts (e.g., MgSO4) retard γ-glycine b-axis growth (Figure 3), while the monovalent cation salts (e.g., KNO3) promote γglycine b-axis growth (Figure 4). These observed promoting and retarding effects are consistent with those observed in our earlier study.6 Such growth kinetics largely explains why the γglycine crystals obtained in the presence of salts is not elongated along its c-axis but bipyramid-like instead.6,9 Given the very slow growth along the γ-glycine c-axis, the growth rate along the b-axis primarily determines the overall growth rate of a γ-glycine crystal. From the measured growth data (Figure 5) and the nucleation induction times (Table 2), it is surprising to note that divalent cation salts, MgSO4 and Ca(NO3)2, enhance γ-glycine nucleation considerably despite their significant inhibition to γ-glycine growth. This is contrary to the usual expectation and difficult to be interpreted using classical nucleation theory (CNT)5,33−35 according to which slow crystal growth supposedly leads to slow nucleation. In

concentration equal to α-glycine solubility at 23 °C, even if the solution was agitated for up to 86 400 min (i.e., 60 days), showing that there is a huge barrier for primary nucleation of γglycine. When α-glycine crystals (10 g per 115 mL of clear solution) were present in an additive-free glycine solution of the same concentration, the time required for γ-glycine to crystallize was significantly shortened to 15 640 min (about 11 days). According to the idea that the surface of one polymorph (here α-glycine) acts as a template37−40 for the nucleation of another polymorph (here γ-glycine), the appearance of γglycine was initiated primarily at the α-glycine surface via secondary nucleation. In other words, α-glycine surface provides favorable active sites to ease the barrier to γ-glycine nucleation. Perusal of the data (Table 2) reveals that transformation from α-glycine to γ-glycine in pure (additive-free) solution is very slow, as indicated by a long induction time (15 640 min) of γ-glycine secondary nucleation. This explains why metastable α-glycine is practically stable under usual conditions. Furthermore, it is surprising to note that all the salts examined in this study considerably shorten the induction times of γglycine secondary nucleation during polymorphic transforma-

Figure 3. (a−d) Illustration of the inhibiting effect of MgSO4 on γ-glycine b-axis (width) growth at γ-glycine supersaturation σ = 1.06 at 23 °C. D

DOI: 10.1021/acs.cgd.6b01177 Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design

Article

Figure 4. (a−d) Illustration of the promoting effect of KNO3 on γ-glycine b-axis (width) growth at γ-glycine supersaturation σ = 1.06 at 23 °C.

(acting as a template for γ-glycine nucleation), hence retarding rather than enhancing γ-glycine secondary nucleation. As such, adsorption of salt ions onto α-glycine surface is not likely to accelerate γ-glycine nucleation. It is therefore interesting to further explore why common inorganic salts generally accelerate γ-glycine nucleation even if they may inhibit γglycine growth. According to the two-step (nonclassical) nucleation theory,33−35 before the structured nuclei are formed, solute molecules undergo aggregation (clustering) and ordering in solution. Perhaps the addition of a salt to aqueous glycine solution profoundly impacts such solute aggregation and ordering. Taking NaCl as an example, it is dissociated into Cl− and Na+ in aqueous glycine solution. Either Cl− or Na+ interacts with a polar glycine zwitterion. Such an ion−glycine interaction is expected to be stronger than the dipole−dipole interaction (either water−glycine or glycine−glycine interaction), forming Cl−···NH3+CH2COO− and NH3+CH2COO−··· Na+ complexes. These charged complexes can attract another few glycine zwitterions to form a long ordered head-to-tail aggregate (or cluster), e.g., Cl − ···NH 3 + CH 2 COO − ··· NH3+CH2COO−···NH3+CH2COO− and NH3+CH2COO−··· NH3+CH2COO−···NH3+CH2COO−···Na+, compared with the chain formation by glycine−glycine interaction (e.g., NH3+CH2COO−···NH3+CH2COO−). These induced head-totail glycine chains are structurally similar to γ-glycine packing, which can serve as nucleation precursors of γ-glycine. By doing so, γ-glycine nucleation is enhanced. A similar mechanism41 was postulated to interpret an observation that inorganic salts generally promote the nucleation of DL-alanine crystal which is structurally akin to γ-glycine. The key idea postulated here is that the salt ion-assisted head-to-tail ordering of glycine molecules is the reason for the observed salt-enhanced γ-glycine nucleation. The observation that the divalent cation salts enhance γ-glycine nucleation less tremendously than the monovalent cation salts may also be understandable. One reason for this is that the stronger ion− dipole interaction42 between divalent cation and glycine zwitterion exhibits a greater difficulty in removing the salt

Figure 5. γ-Glycine b-axis (width) growth rates at γ-glycine supersaturation σ = 1.06 (corresponding to α-glycine saturated solution) at 23 °C, showing that monovalent cation salts considerably promote while divalent cation salts significantly retard γ-glycine b-axis growth. The error bar = 20%.

addition, in the presence of monovalent cation salts, shorter induction times (Table 2) hence greater enhancements of γglycine nucleation generally do not correspond to faster growth rates of γ-glycine (Figure 5). All these experimental observations point toward a conclusion that the salt-altered γglycine growth kinetics does not primarily explain the saltenhanced γ-glycine nucleation during glycine polymorphic transformation. It is known that a significant shift of solution pH promotes γglycine nucleation.3,4 However, it is not the case here, as NaCl and KNO3 do not cause the solution pH to change. In fact, a small pH change (e.g., from 6.20 in pure glycine solution to 5.84 in a glycine solution in the presence of 1 m MgSO4) caused by a salt does not affect nucleation. As our experiment showed, even at glycine solution pH = 5.84 (in the presence of 0.000125 m H2SO4), acceleration of γ-glycine nucleation during transformation was not observed. From the point of view of active nucleation sites, the salt ions can be strongly adsorbed on the polar surface13 of α-glycine crystal, blocking the nucleation active sites at α-glycine surface E

DOI: 10.1021/acs.cgd.6b01177 Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design

Article

these inorganic salts except 1 m Ca(NO3)2 and 1 m MgSO4 which had been reported4 to yield α-glycine preferentially. The results (Figure 6) of glycine primary nucleation show that, even when the salt-assisted enhancement factors are significant, ranging from 33 to up to 82, only α-glycine nucleates via primary (unseeded) nucleation. This is perhaps a good reflection that primary nucleation rate of α-glycine is dominant over that of γ-glycine in unseeded pure (additivefree) glycine solution. Consequently, even a profound saltaided enhancement of γ-glycine nucleation is not enough for γglycine to surpass α-glycine. In the presence of 0.5 m NaCl, the enhancement factor is increased to 138 and γ-glycine competitively nucleates. Surprisingly, the glycine crystals obtained in the presence of 0.5 m NaCl were either pure αglycine or pure γ-glycine, not a mixture of both polymorphs. With the enhancement factor further increased to a level above 300 in the presence of concentrated monovalent cation salts, only γ-glycine appeared. These results strongly indicate that there is a clear connection between the salt-associated enhancements of γ-glycine primary nucleation and the saltdependent polymorphic selectivity. It should be noted that, in the unseeded solution crystallization of γ-glycine performed in this study, it typically took about only 10 min for the initially formed visible glycine crystals to develop into a sufficient mass (about 0.5 g for PXRD). This is far shorter than induction times of secondary nucleation (Table 2). It therefore reaffirms that the appearance of γ-glycine was an outcome of γ-glycine primary nucleation rather than transformation from α-glycine to γ-glycine.

ions adsorbed to glycine aggregates/clusters for sustainable nucleation, weakening the enhancement of γ-glycine nucleation. Therefore, there is a trade-off between salt ion−glycine interaction and removal of the attached salt ions from glycine clusters. Different from a divalent cation, a divalent anion SO4−2 does not have a strong interaction with glycine zwitterion, despite the same magnitude of ion charges. As explained earlier,6 this is because a divalent anion SO42− is hydrated more heavily than a divalent cation (e.g., Ca2+ and Mg2+).43,44 Consequently, the SO4−2−glycine interaction is significantly mitigated by these surrounding water molecules, leading to the fact that (NH4)2SO4, similar to other monovalent cation salts, enhances γ-glycine nucleation to a great extent. An Insight into Salt-Dependent Polymorphic Selectivity. Previous studies4,6 revealed that divalent cation salts hardly induce γ-glycine, while monovalent cation salts readily induce γ-glycine in unseeded crystallization at usual supersaturation levels. The new result and analysis given in this study provide an insight into the unresolved riddle of the observed salt-dependent glycine polymorphic selectivity. On the same fundamental basis of salt-assisted head-to-tail glycine ordering in seeded crystallization, it can be inferred that the structurally favorable glycine head-to-tail chains ease the barriers to γ-glycine primary nucleation in unseeded crystallization. It is therefore suggested that typical inorganic salts generally induce the favorable head-to-tail ordering of glycine molecules, thereby enhancing γ-glycine primary nucleation during unseeded crystallization, with monovalent cation salts being far more effective than divalent cation salts. It is difficult to measure the salt-assisted enhancement factors of γ-glycine unseeded primary nucleation as γ-glycine may not nucleate. However, it may be reasonable to assume that, on a relative basis, the salt-assisted enhancement factors of γ-glycine unseeded primary nucleation are similar to those (Table 2) of γ-glycine secondary nucleation during polymorphic transformation. On the basis of this assumption, it is interesting to establish a relationship (Figure 6) between glycine polymorphic selectivity and the inferred salt-associated enhancement factors of γ-glycine unseeded primary nucleation. Polymorphic selectivity of glycine from unseeded solution crystallization was screened using a similar cooling method4 in the presence of

■

CONCLUSION Our experimental results reveal that all the inorganic salts examined in this study substantially shorten induction time during polymorphic transformation, thereby greatly enhancing γ-glycine secondary nucleation. Furthermore, the monovalent cation salts enhance γ-glycine secondary nucleation far more than the divalent cation salts. A more surprising observation is that divalent cation salts accelerate γ-glycine nucleation to a great extent, but they significantly retard γ-glycine growth, a phenomenon difficult to interpret by classical nucleation theory. This salt-assisted promotion of γ-glycine secondary nucleation is primarily attributed to salt-assisted head-to-tail ordering of glycine molecules. Such ordered glycine chains, structurally similar to the crystalline packing of γ-glycine, ease the barrier to γ-glycine secondary nucleation. The greater difficulty in removing divalent cations strongly adsorbed onto the aggregated glycine clusters explains why divalent cation salts are less effective than monovalent cation salts in enhancing γglycine secondary nucleation. The suggested idea of salt-assisted head-to-tail ordering of glycine molecules in the liquid phase is extended from secondary nucleation to primary nucleation. Our analysis and experimental data point toward a conclusion that monovalent cation salts potentially enhance γ-glycine primary nucleation to a greater extent than those divalent cation salts. This may largely explain the general observation that monovalent cation salts are more effective in inducing γ-glycine than divalent cation salts, shedding light on the phenomenon of saltdependent polymorphic selectivity of glycine from unseeded solution crystallization.

Figure 6. Relationship between glycine polymorphic selectivity and the inferred enhancement factors of γ-glycine primary nucleation from unseeded crystallization, suggesting that the salt-aided head-to-tail ordering enhances γ-glycine nucleation and plays a primary role in determining the outcome of glycine polymorphic crystallization. F

DOI: 10.1021/acs.cgd.6b01177 Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design

■

Article

(26) Poornachary, S. K.; Chow, P. S.; Tan, R. B. H. Cryst. Growth Des. 2008, 8, 179−185. (27) He, G.; Bhamidi, V.; Wilson, S. R.; Tan, R. B. H.; Kenis, P. J. A.; Zukoski, C. F. Cryst. Growth Des. 2006, 6, 1746−1749. (28) Weissbuch, I.; Leisorowitz, L.; Lahav, M. Adv. Mater. 1994, 6, 952−956. (29) Yani, Y.; Chow, P. S.; Tan, R. B. H. Cryst. Growth Des. 2012, 12, 4771−4778. (30) Chen, J.; Trout, B. L. J. J. Phys. Chem. B 2010, 114, 13764− 13772. (31) Cheong, D. W.; Boon, Y. D. Cryst. Growth Des. 2010, 10, 5146− 5158. (32) Friant-Michel, P.; Ruiz-Lopez, M. F. ChemPhysChem 2010, 11, 3499−3504. (33) Erdemir, D.; Lee, A. Y.; Myerson, A. S. Acc. Chem. Res. 2009, 42, 621−629. (34) Vekilov, P. G. Cryst. Growth Des. 2010, 10, 5007−5019. (35) Gebauer, D.; Cölfen, H. Nano Today 2011, 6, 564−584. (36) Ono, Y.; Kramer, H. J.M.; Ter Horst, J. H.; Jansens, P. J. Cryst. Growth Des. 2004, 4, 1161−1167. (37) Croker, D.; Hodnett, B. K. Cryst. Growth Des. 2010, 10, 2806− 2816. (38) Liang, S.; Duan, X.; Zhang, X.; Qian, G.; Zhou, X. Cryst. Growth Des. 2015, 15, 3602−3608. (39) Yu, L. J. Am. Chem. Soc. 2003, 125, 6380−6381. (40) Yu, L. CrystEngComm 2007, 9, 847−851. (41) Han, G.; Chow, P. S.; Tan, R. B. H. Cryst. Growth Des. 2014, 14, 1406−1411. (42) Fedotova, M. V.; Kruchinin, S. E. Biophys. Chem. 2014, 190− 191, 25−31. (43) Wang, X. B.; Yang, X.; Nicholas, J. B.; Wang, L. S. Science 2001, 294, 1322−1325. (44) Jiao, D.; King, C.; Grossfield, A.; Darden, T. A.; Ren, P. J. Phys. Chem. B 2006, 110, 18553−18559.

AUTHOR INFORMATION

Corresponding Authors

*Tel: +65 6796-3879. Fax: +65 6316-6183. E-mail: han_ [email protected] (G.H.). *E-mail: [email protected] (R.B.H.T.). Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS This work was financially supported by the Agency for Science, Technology and Research (A*STAR), Singapore. We thank Mervin Law Yi Ting and Wesmond Chua Kang Wei for their assistance with the experiments.

■

REFERENCES

(1) Bernstein, J. Polymorphism in Molecular Crystals; Oxford University Press: Oxford, U.K., 2002. (2) Huang, J.; Stringfellow, T. C.; Yu, L. J. J. Am. Chem. Soc. 2008, 130, 13973−13980. (3) Han, G.; Thirunahari, S.; Chow, P. S.; Tan, R. B. H. CrystEngComm 2013, 15, 1218−1224. (4) Towler, C. S.; Davey, R. J.; Lancaster, R. W.; Price, C. J. J. J. Am. Chem. Soc. 2004, 126, 13347−13353. (5) Davey, R. J.; Sven, L. M.; Schroeder, S. L. M.; ter Horst, J. H. Angew. Chem., Int. Ed. 2013, 52, 2166−2179. (6) Han, G.; Chow, P. S.; Tan, R. B. H. CrystEngComm 2016, 18, 462−470. (7) Dang, L.; Yang, H.; Black, S. N.; Wei, H. Org. Process Res. Dev. 2009, 13, 1301−1306. (8) Han, G.; Chow, P. S.; Tan, R. B. H. Cryst. Growth Des. 2012, 12, 2213−2220. (9) Yang, X.; Lu, J.; Wang, X. J.; Ching, C. B. J. Cryst. Growth 2008, 310, 604−611. (10) Duff, N.; Dahal, Y. R.; Schmit, J. D.; Peters, B. J. J. Chem. Phys. 2014, 140, 014501. (11) (,) Kim, J. W.; Koo, K. K. Cryst. Growth Des. 2012, 12, 4927− 4934. (12) Han, G.; Poornachary, K. S.; Chow, P. S.; Tan, R. B. H. Cryst. Growth Des. 2010, 10, 4883−4889. (13) Li, L.; Rodriguez-Hornedo, N. J. J. Cryst. Growth 1992, 121, 33− 38. (14) Kim, J. W.; Shim, H. M.; Lee, J. E.; Koo, K. K. Cryst. Growth Des. 2012, 12, 4739−4744. (15) Xu, M.; Harris, K. D. M. J. Phys. Chem. B 2007, 111, 8705− 8707. (16) Hughes, C. E.; Harris, K. D. M. Chem. Commun. 2010, 46, 4982−4984. (17) Hamad, S.; Hughes, C. E.; Catlow, C. R. A.; Harris, K. D. M. J. Phys. Chem. B 2008, 112, 7280−7288. (18) Hamad, S.; Catlow, C. R. A. CrystEngComm 2011, 13, 4391− 4399. (19) Dowling, R.; Davey, R. J.; Curtis, R.; Han, G.; Poornachary, S. K.; Chow, P. S.; Tan, R. B. H. Chem. Commun. 2010, 46, 5924−5926. (20) Carter, P. W.; Hillier, A. C.; Ward, M. D. J. Am. Chem. Soc. 1994, 116, 944−953. (21) Gidalevitz, D.; Feidenhans’l, R.; Matlis, S.; Smilgies, D. M.; Christensen, M. J.; Leiserowitz, L. Angew. Chem., Int. Ed. Engl. 1997, 36, 955−959. (22) Aber, J. E.; Arnold, S.; Garetz, B. A.; Myerson, A. S. Phys. Rev. Lett. 2005, 94, 145503. (23) Di Profio, G.; Tucci, S.; Curcio, E.; Drioli, E. Cryst. Growth Des. 2007, 7, 526−530. (24) Chew, J. W.; Black, S. N.; Chow, P. S.; Tan, R. B. H.; Carpenter, K. J. CrystEngComm 2007, 9, 128−130. (25) Di Profio, G.; Reijonen, M. T.; Guagliardi, R. A.; Curcio, E.; Drioli, E.; Caliandro, R. Phys. Chem. Chem. Phys. 2013, 15, 9271− 9280. G

DOI: 10.1021/acs.cgd.6b01177 Cryst. Growth Des. XXXX, XXX, XXX−XXX