The Effect and Counter-Effect of Impurities on Crystallization of an

Dec 27, 2010 - ... Active Ingredient: Stereochemical Rationalization and Nanoscale Crystal Growth Visualization. Sendhil K. Poornachary†, Grace Lauâ...
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DOI: 10.1021/cg1012878

The Effect and Counter-Effect of Impurities on Crystallization of an Agrochemical Active Ingredient: Stereochemical Rationalization and Nanoscale Crystal Growth Visualization

2011, Vol. 11 492–500

Sendhil K. Poornachary,† Grace Lau,† Pui Shan Chow,† Reginald B. H. Tan,*,†,‡ and Neil George§ † 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, and § Process Studies Group, Syngenta, Jealott’s Hill International Research Centre, Bracknell, Berkshire RG42 6EY, United Kingdom

Received October 1, 2010; Revised Manuscript Received November 25, 2010

ABSTRACT: The molecular mechanisms underpinning the effects of impurities (reaction byproduct) on the crystallization of N-phosphonomethyl glycine (PMG), a common herbicide, are presented. The impurities, iminobismethylene phosphonic acid (IMPA) and amino methyl phosphonic acid (AMPA), were incorporated into PMG crystals by selectively adsorbing onto the (100) face, and subsequently, caused major reduction in the growth rate of this face of the crystal. In contrast, the impurity N-phosphonomethyl imino diacetic acid (PIDA), with a lower binding affinity to PMG crystals, did not affect the crystal habit significantly. These experimental results are rationalized based on stereospecific interaction of the impurities with the PMG crystal and binding energy calculations. Interestingly, when PIDA is present along with IMPA or AMPA in the crystallizing solution, it produced a beneficial effect by counteracting the habit-modifying effects of the other two impurities. In situ monitoring of crystal growth from pure and impure supersaturated aqueous solution using an atomic force microscope revealed that IMPA slowed down the propagation of steps on the (100) surface of PMG crystal and, in contrast, PIDA accelerated the propagation of steps on the crystal surface. On the basis of these observations, it is surmised that interaction of PIDA at the kink sites on the crystal surface reduced the step free energy and, in turn, led to resurrection of crystal growth from the inhibitory effect of IMPA.

1. Introduction In the manufacture of fine organic chemicals and pharmaceuticals via solution crystallization, impurities can directly affect the efficiency of active ingredient purification, solidliquid separation, yield, and throughput.1 Trace amounts of impurities present in the crystallizing medium can also indirectly impact formulation of the final dosage form; for instance, an impurity-mediated modification in the polymorph crystallized2,3 would, in turn, affect the stability and dissolution properties of the active ingredient. Likewise, incorporation of impurities into product crystals may lead to considerable strain/defect in the crystal lattice and affect the particle compaction.4 Although crystal growth is specific to the product molecules, certain byproduct produced during synthesis, which are molecular analogues of active molecules, are frequently found to have an effect on the crystallization behavior and the resulting crystal attributes. Such isomorphic impurities incorporate into the product crystals via formation of solid solution,5-8 often manifested by a modification in the crystal habit and/or polymorph with ramification on the product isolation stage including filtration, drying, and powder handling. Therefore, in an industrial system, efforts are sometimes directed toward designing an upstream process that can minimize the residual level of impurity by careful control of the reaction conditions and stoichiometry. At the crystallization stage, improvement of crystal habit may be *Corresponding author. Tel.: þ65 6796-3841. Fax: þ65 6873-4805. E-mail: [email protected]. pubs.acs.org/crystal

Published on Web 12/27/2010

achieved by tuning the operating variables, for example, by controlling the supersaturation/desupersaturation profiles so as to minimize the uptake of impurities during the crystal growth process. Undesirable crystal shapes may also be modified using certain additives which when added to a crystallizer will promote the required habit change.9 Previous studies7,10 have elucidated the phenomenon of molecular recognition at crystal interfaces via stereoselective habit modification in organic molecular crystals using tailormade additives. Essentially, tailor-made additives have many of the structural and chemical characteristics of the primary solute molecule but differ in some specific way. Hence, these additives undergo stereochemical adsorption on certain faces of crystals - with horizontal and downward bonds similar to the growth units in the crystal lattice but with weaker or repelling bonds upward11 - and thereafter inhibit growth perpendicular to that face, thus modifying relative growth rates and the crystal habit. However, recently we have shown that tailor-made additives can also accelerate the growth of molecular (γ-glycine) crystals.12 The effects of reaction byproduct on the crystallization of N-phosphonomethyl glycine (PMG) (Figure 1), an agrochemical active ingredient, were described previously1 without revealing the molecular chemistry of the compound. The original work identified which of the many impurities present in the crystallizing solution formed solid solution in the product crystals, and in the process, acted as habit modifiers. PMG crystallized from pure aqueous solution had a cubic and chunky crystal habit. The presence of impurities iminobismethylene r 2010 American Chemical Society

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Figure 1. Molecular structures of N-phosphonomethyl glycine (PMG) and the impurities iminobismethylene phosphonic acid (IMPA), aminomethyl phosphonic acid (AMPA), and N-phosphonomethylimino diacetic acid (PIDA).

phosphonic acid (IMPA) and aminomethyl phosphonic acid (AMPA) in solution produced thin plate-like crystals, which formed an impermeable layer on the filter cloth during centrifugal filtration, and reduced the filtration rate significantly. In contrast, another reaction byproduct N-phosphonomethylimino diacetic acid (PIDA) in the crystallizing solution did not affect the PMG crystal habit significantly. Moreover, when PIDA was present along with IMPA or AMPA in the crystallizing solution, it produced a beneficial effect by counteracting the habit modifying effects of the latter impurities. The original study also found that the three impurities incorporated into the crystal lattice to varying degrees and formed solid solutions in the product crystals. The molecular mechanism of the impuritymediated habit modification in PMG crystals and the countereffect of PIDA, however, were not clearly understood. In this report, we explain these effects on PMG crystallization building on the stereoselectivity mechanism for impurity-crystal interactions. The mechanism by which PIDA counteracts the growth inhibitory effect of IMPA is rationalized based on the dynamics of step propagation on a pure and impurity-adsorbed crystal surface observed in situ using atomic force microscopy (AFM). 2. Experimental Section 2.1. Materials. Analytical grade PMG was purchased from Sigma-Aldrich (Riedel-de Ha€en) with 99.0þ% purity and used as received. AMPA, IMPA, and PIDA (used as the impurities) were purchased from Sigma-Aldrich with purities of 99.0%, 97.0þ%, and 95.0%, respectively. Impurity profiles of these compounds were not provided by the suppliers. Deionized, 0.22 μm filtered water was used in preparing PMG solutions. 2.2. Crystallization Experiments. PMG solution was prepared by dissolving 0.4 g of PMG in 20 g of water (0.178 M) at 50 °C. The solution was filtered through a 0.22 μm PTFE syringe filter and cooled to room temperature (∼20 °C) in a glass crystallization dish. Single crystals of PMG with distinguishable crystal faces (200-1000 μm size) were obtained from the supersaturated solution (S = ln(C/Cs) = 0.51; C = actual concentration of PMG in g/100 g of water and Cs = equilibrium concentration of PMG in g/100 g of water at 20 °C and at pH 2.0) approximately in a week’s time. 2.3. Microscopy. PMG crystals obtained from unstirred crystallization experiments were examined using an optical polarizing microscope (Olympus, BX51) connected to a CCD camera, and images were recorded using AnalySIS (Soft Imaging Systems) image capture software. 2.4. Face Indexing. The Miller indices of PMG crystal were assigned using a Rigaku single crystal X-ray diffraction system equipped with a Saturn-70 CCD detector. A PMG crystal (of dimensions 0.29 mm  0.16 mm  0.17 mm) was mounted on a glass fiber, and images of the crystal were captured along different

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orientations. The acquired images were then processed using the RAXshape program in CrystalClear (Rigaku) software to assign the (hkl) faces. The single crystal data confirmed that the PMG crystals observed in this study have the same structure as the crystal structure obtained from the Cambridge Structural Database (CSD refcode: PHOGLY).17 2.5. Solubility Measurements. The solubility of pure PMG in water and in the presence of impurities (0.2 wt % (w/w water) of IMPA and PIDA, respectively) was measured at 30 °C using an Anton-Paar DMA5000 density meter. Initially, a calibration model was developed relating the solution density to PMG concentration in water þ PMG, water þ PMG þ 0.2 wt % IMPA, and water þ PMG þ 0.2 wt % PIDA mixtures, respectively. Also, a calibration model was obtained relating the solution density to PIDA concentration in water þ PIDA and water þ PIDA þ 0.2 wt % IMPA mixtures, respectively. Appropriate amounts of PMG (0.5-1.5 g) and 0.2 wt % of the impurity were dissolved in 100 g of water at 40 °C. The solution was injected into the density meter through a 0.2 μm Millipore nylon membrane filter and the solution density was measured at 25 °C. The calibration model included concentrations ranging from undersaturated to supersaturated conditions and was linear in this range. For supersaturated solutions, it was ensured that no crystallization had occurred from the solution during the density measurement. For solubility measurements, a slurry solution of PMG in water containing 0.2 wt % of IMPA (or PIDA) was stirred for 5 h at 30 °C in a jacketed glass crystallizer. A circulator water bath (Julabo FP 50 HL) was used for heating the solution. After equilibration, the solution was injected into the density meter through a 0.2 μm Millipore nylon membrane filter and the solution density was measured at 25 °C. The solution concentration (supersaturated) was determined from the measured solution density and the calibration model. The solution concentrations measured at 5 and 12 h time intervals remained constant suggesting thermodynamic equilibrium. Similarly, the solubility of pure PMG, PIDA, and PIDA þ 0.2 wt % of IMPA were determined from the solution density using the respective calibration models developed. The absolute mean deviation of the solubility data obtained by this method was less than 0.02 g/100 g of water. 2.6. In situ AFM. A Multimode Scanning Probe microscope (Nanoscope IV, Digital Instruments, Vecco Metrology Group, USA) with an E-type piezo-scanner, equipped with a quartz-body fluid cell (Digital Instruments) with an O-ring sealing, was used for imaging PMG crystal growth in situ in supersaturated aqueous solution. Images were acquired in contact mode using cantilevers equipped with integral silicon nitride tips of spring constant 0.06 N/m. The tip scan rate during image acquisition was maintained at 3.05 Hz with a scan size of 1 μm  1 μm. A minimum tip-sample contact force was applied (in order to minimize tip-induced surface etching) by adjusting the set point voltage for tip deflection to be less than 2.0 V. A Cole-Parmer KDS 200 syringe infusion pump was used to circulate supersaturated PMG solution (σ = ln(C/Cs) = 0.22, where C and Cs are the actual and saturation PMG concentrations at 23 °C, respectively) through the fluid cell at a constant rate of 0.1 mL/min. A PMG crystal was mounted with epoxy onto a magnetic stainless steel sample disk covered with mica. The crystal surface in contact with each of the solution media was scanned typically for 15-30 min. The solution temperature remained approximately constant at 23 °C indicating negligible local heating effect during the scan period.

3. Molecular Modeling 3.1. Crystal Habit Modeling. PMG crystal habit was simulated in vacuo via the Bravais-Friedel-DonnayHarker (BFDH) and the attachment energy methods13,14 respectively as implemented in Material Studio (Accelrys) modeling software.15 According to the BFDH theory, the relative growth rate of a crystal face is inversely proportional to the interplanar spacing (dhkl) of its corresponding lattice plane. Within the framework of the attachment energy model, it is assumed that the rate of growth of a face is

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proportional to the attachment energy (Eatt); Eatt is defined as the energy released on the addition of a growth slice onto the (hkl) surface of a crystal. The crystal habit is bound by the slow growing faces that have lower Eatt values, and correspondingly lower center-to-face distances in a Wulff Plot16 construction. The PMG crystal structure (CSD refcode: PHOGLY;17 only one polymorphic form has been reported for PMG in the CSD) consists of four molecules in the unit cell. The crystal structure comprises strong (NH2()NH 3 3 3 O(PO3H-) hydrogen bonds along the c axis and (COOH)OH 3 3 3 O(PO3H-) hydrogen bonds along the a axis. Initially, the various force field potentials with parameters as implemented in Materials Studio were screened for their ability to reproduce the experimental crystal structure of PMG in vacuo, as measured by the root-mean-square deviation18 (rmsd) of the minimized crystal structure from the experimental. The Ewald summation method was used to calculate nonbonded interactions between the PMG molecules (including the van der Waals and electrostatic contributions), and the energy minimization step was implemented using the conjugate gradient algorithm. The rmsd for the Dreiding19 potential, with partial atomic charges calculated using either the charge-equilibration20 (QEq) or Gasteiger21 method, and CVFF22 force field with self-assigned atomic charges, were all computed to be less than 0.2 A˚ (accuracy level set to 10-3 kcal/mol for the potential energy). However, because the Dreiding-QEq potential set reproduced the growth morphology of PMG crystal more accurately in comparison with the other force fields, it was selected for subsequent binding energy calculations. Here we note that in the absence of any experimental sublimation enthalpy value reported for PMG crystal, assessment of the appropriate force field potential could not be carried out based on comparison23 with the simulated lattice energies. 3.2. Binding Energy Calculations. The PMG crystal structure was cleaved parallel to the (100) plane with a depth of one unit cell (8.35 A˚) and constructed as a periodic superstructure of 4  4 unit cells comprising 64 molecules. A 25 A˚ thick vacuum slab was built in above the crystal slice. Likewise, for the (011) (dhkl = 6.12 A˚) and (001) (dhkl = 9.50 A˚) crystal surfaces, superstructures of 44 unit cells comprising 64 PMG molecules were constructed along with a 25 A˚ thick vacuum slab. In both cases, fractional positions of the symmetry-related PMG molecules within the cleaved surface layer were kept the same in all calculations. In order to assess the likelihood of impurity incorporation at the crystal surface, the differential binding energy (ΔEb) defined as the difference between the binding energies of a pure PMG (hkl) layer (Eb), and that of an impurity incorporated (hkl) layer (Eb0 ) - was computed using the atom-atom potential energy method. Eb and Eb0 were computed as the intermolecular interaction energies associated with the incorporation of a single PMG molecule and of an impurity molecule, respectively, at the center of the host crystal slice. The orientation of the docked PMG (or impurity) molecule was optimized by minimizing the energy of the layer with all the neighboring host molecules constrained as rigid bodies. The force field-charge set, summation method, and energy minimization algorithm were chosen to be similar to that used for crystal habit prediction as described in the previous section. The calculated values of binding energy were verified to be independent of the size of superstructures comprising PMG molecules.

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For binding energy calculations involving a layer of water molecules on the PMG surface (only for pure PMG), the following procedure was employed. First, a water slab of dimension u  v corresponding to the lattice dimensions of the crystal surface was constructed using the Amorphous Cell tool box in Materials Studio. A Monte Carlo simulation using a modified Markov process24 was run to generate the initial configuration of water molecules in the slab. This simulation utilized an NVE (constant number of particles, volume, and enthalpy) ensemble, with bond conformational probabilities chosen to account for both intramolecular and intermolecular nonbonded interactions. Second, the energyminimized water layer was placed over the crystal surface (using the Layer Builder tool in Materials Studio), and a vacuum slab of 25 A˚ thickness was built in above the water layer. Finally, the orientation of water molecules on the crystal surface (with fractional coordinates of PMG molecules fixed) was optimized through an energy minimization step. The crystal layer energy was then calculated as the sum of intermolecular interactions between a PMG molecule placed at the center of host crystal slice and of water molecules above the layer. 4. Results and Discussion 4.1. PMG Crystal Habit and Impurity-Mediated Habit Modification. The pure solution-grown PMG crystal habit in Figure 2a (view along the a axis) exhibits the {100} front and back faces (of multiplicity 2), {011} side faces (of multiplicity 4), and {102} tapered edge faces (of multiplicity 2). The side view (along the b axis) of the crystals in Figure 2b exhibits the {011} and {102} faces. Although the {001} faces were indexed for the PMG crystal previously, it could not be assigned from the microscope images of the crystals. The crystal habit is nearly cubic with a lower aspect ratio along the a-axis. The predicted BFDH growth morphology (Figure 2c) of PMG crystal is prismatic, slightly elongated along the c direction, and bounded by the faces {100}, {011}, {110}, {111}, {002}, and {102}, in the order of morphological importance. The crystal habit simulated using the attachment energy model (Figure 2d, e, as viewed along the two different crystallographic orientations) is in good agreement with the experimental habit, with respect to both morphological importance of the faces as well as the c/a aspect ratio (viz. 3.0 (simulated) vs 3.3 ( 0.95 (experimental)). The minor {110} faces of the predicted habit, however, were absent in the solution grown crystal. PMG crystallized in the absence and presence of impurities from unseeded batch experiments are shown in Figure 3. As reported above, PMG crystal habit obtained from pure solution is nearly cubic and chunky, with the {100} and {011} faces primarily expressed (Figure 3a). In contrast, PMG crystals obtained from IMPA-doped solutions appear plate-like, clearly indicating habit modification normal to the {100} face (Figure 3b). Besides, the nearly hexagonal shape of these crystals may imply additional habit modification by the impurity along the c-axis (viz. {001} faces) - this particular observation is corroborated in the later section through binding energy calculations. In this context, we note that a PMG crystal obtained from pure solution at a very early stage of growth does exhibit a nearly hexagonal shape (for example, see the crystal labeled “1” in Figure 3a). PMG crystals obtained from AMPA-doped solutions were also plate-like exhibiting habit modification along the {100} faces (Figure 3c), however, to a lesser degree as compared to the

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Figure 2. PMG crystal habit: (a) and (b) microscope images of the experimental habit viewed along two different crystallographic orientations; (c) the BFDH model; (d, e) the attachment energy model as viewed along the a and b axis, respectively.

Figure 3. PMG crystallized from pure solution (a) and from impurity-doped solutions (1.0 wt % on PMG): (b) IMPA, (c) AMPA, and (d) PIDA.

effect of IMPA. As with IMPA, the crystal habit is somewhat hexagonal, possibly due to impurity adsorption and consequent growth inhibition along the {001} faces. Unlike the case with IMPA and AMPA, PMG crystals obtained from PIDA-doped solutions were chunkier (Figure 3d), implying insignificant growth inhibition along the (100) direction. However, some minor differences could be identified - while PMG crystals obtained from pure solutions exhibited two

additional {102} faces at the diagonal corners of the (100) face, those facets were not observed in the latter crystals. In the case of impurities inhibiting nucleation (during unseeded crystallization), the supersaturation at which crystals form would increase. As crystal growth morphology is a function of supersaturation,25 in turn, this may lead to habit modification of crystals obtained from unseeded experiments. However, for the PMG system, previous studies1 have shown

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Figure 4. Molecular models of PMG crystal (100) face: (a) a surface dominated by the -COOH group; (b) a surface dominated by the -PO3H- group. Color scale of atoms: C (gray), N (blue), O (red), P (purple), H (off-white). Hydrogen bonds are shown in cyan blue-dotted lines between the phosphonic acid and amino groups on each molecule.

that none of the impurities affected the supersaturation at which nucleation occurred. In addition, independent batch cooling experiments performed at constant supersaturation in this study (results not reported here) have shown that the impurities did not affect nucleation of PMG crystals. 4.2. PMG Crystal Surface Chemistry. The habit modification in PMG crystal revealed growth inhibition by the adsorbed impurities primarily along the a-axis. To understand this effect, initially, we investigated the (100) surface chemistry in detail. There are two alternative structures of the (100) cleavage plane: first, a surface dominated by carboxylic acid (-COOH) group (Figure 4a); and, second, a surface dominated by phosphonic acid (-PO3H-) group (Figure 4b). In the latter surface model, the negative charge of the PO3H- group is counter balanced by the proton of the -NH2þ group of the PMG molecule, and thus the overall surface charge is neutral. The more stable between these two structures was evaluated by calculating the intermolecular interaction energies within the (100) crystal layer (per molecule of PMG). The crystal layer energy of structure (a) was found to be -42.4 kcal/mol, and of structure (b) to be 18.1 kcal/mol. Strong hydrogen bonding interactions between the PMG molecules within the crystal layer apparently provided a greater stability for structure (a). In a solution environment, the crystalline face could however be stabilized by the solvent molecules in contact with the surface. In order to verify this effect, the (100) layer energies were recalculated with a layer of water molecules on the surface. The energies of crystal layer of structures (a) and (b) were calculated to be -75.2 and -6.4 kcal/mol, respectively, indicating that a greater degree of stabilization by the solvent molecules could be achieved in the case of (100) surface expressing the -COOH group. Therefore, it is postulated that the (100) surface of a PMG crystal grown in solution should most likely have the structure (a). 4.3. Affinity of Impurities onto PMG Crystal. The impurity molecules, IMPA, AMPA, and PIDA bear a structural similarity with PMG (cf. Figure 1), and hence could behave as “tailor-made” additives. By comparison of their molecular structures, the common functional group (-PO3H-) was assigned as the “binder” moiety on interaction with the PMG crystal surface. The distinct functional groups of the impurity molecules were viewed as the “perturber” moieties, which may affect regular attachment of solute molecules after incorporation into the PMG crystal lattice. On the basis of stereoselective interaction mechanism,7,10 an IMPA molecule was docked into the (100) crystal lattice with the binder moiety at the site of a PMG molecule (Figure 5a). Following

Figure 5. Molecular modeling of interaction of the impurities (a) IMPA, (b) AMPA, and (c) PIDA, respectively, with the (100) face of PMG crystal (edge-on-view along the b-axis). PMG molecules are represented in wireframe style and the impurity molecules as ball and stick.

this methodology, interactions of AMPA and PIDA were modeled respectively with the (100) face (Figure 5b, c). However, in the case of PIDA, vacancy sites were created in the host crystal lattice neighboring to the docking site, so as to avoid short atom contacts between the residual (-COOH) groups of PIDA and of the PMG molecule. Similarly, interaction of the impurity molecules with the (001) and (011) faces of PMG crystal were modeled. Intermolecular interactions between the impurities and PMG molecules occurring on the various faces of the crystal

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Table 1. Binding Energies (kcal/mol) of the Impurity Molecules on the Various Faces of PMG Crystala PMG (host) face (hkl)

Eb

(100) (011) (002)

-42.4 -18.0 -19.6

a

IMPA Eb

ΔEb

AMPA Eb

ΔEb

PIDA Eb

ΔEb

-65.2 -22.8 -47.3 -4.9 þ146.6 þ189.0 þ6.36 þ24.4 -11.2 þ6.8 -15.1 þ2.9 -41.4 -21.8 -21.3 -1.7 þ69.7 þ89.3

ΔEb = Eb,impurity - Eb,PMG.

were evaluated from the calculated values of differential binding energy (Table 1). Consequently, the following inferences were drawn: (a) interactions of both IMPA and AMPA with the (100) and (001) crystal faces respectively are more favored when compared to a PMG molecule as indicated by negative ΔEb values. Also, interactions of these two impurities with the (011) surface are unfavorable as indicated by positive ΔEb values; (b) interaction of PIDA is not favored on any of the PMG crystal faces, although the binding energy value for (011) face is relatively low; (c) interaction of IMPA with the PMG crystal is more favored as compared to AMPA as indicated by more negative ΔEb values. The basis of stereospecific interaction of the impurity molecules with the PMG crystal is explained in more detail. IMPA, having a residual phosphonic acid group (in contrast to a PMG molecule which has a carboxylic acid group) in its molecular structure, would undergo attractive electrostatic interaction with neighboring PMG molecules on the (100) and (001) crystal faces. AMPA, with a relatively smaller molecular structure and fewer functional groups as compared to PMG, would experience similar attractive interactions on the crystal surface, however, to a lesser degree as compared to IMPA. In contrast, PIDA, which has a residual carboxylic acid group and a branched molecular structure as compared to PMG, would undergo repulsive intermolecular interactions on the crystal surface. It is gratifying to note that the proposed mechanistic model for interaction of the impurities with the PMG crystal is in good agreement with the experimental habit modification. While IMPA, having the highest binding affinity to PMG crystal, produces the most dramatic effect on growth and results in thin {100} plates, AMPA, having a moderate binding affinity to the PMG crystal, results in a relatively thicker but still plate-like crystal habit. On the other hand, PIDA, with the least binding affinity to the PMG crystal, does not cause any significant effect on the crystal habit. Our calculated binding energy values (cf. Table 1) also correlated with the experimental segregation coefficient1 (ratio of concentration of impurities in the solid phase versus their concentration in the solution from which the crystals were isolated) values of the impurities in a semiquantitative manner. IMPA (impurity (1) in ref 1), with the most negative values of differential binding energy among the impurities, exhibited a rather high segregation coefficient at about 4. AMPA (impurity (2) in ref 1), with a negative differential binding energy value, exhibited a segregation coefficient of 1.5. PIDA (impurity (3) in ref 1) forms a solid solution in PMG crystals (values not reported) although its calculated binding energy is less than that of PMG. We explain this based on adsorption of PIDA at the kink sites on the (100) surface rather than lattice incorporation at the surface terrace during crystal growth (see discussion in Section 4.4.c). In a previous study,6 binding energy calculations were used

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as a measure of the equilibrium impurity segregation coefficient for solids (aromatic hydrocarbons) crystallized from mother liquor in the presence of impurities. While their approach involved optimizing the impurity molecule within the crystal lattice as well as on individual crystal surface lattice planes, we have performed calculations for host/ impurity interactions at the surface lattice planes only. 4.4. Counter-Effect of PIDA on PMG Crystal Habit Modification. Three possible explanations for the observed beneficial effect of PIDA in counteracting the habit-modifying effect of IMPA were considered. First, we examined the possibility that PIDA competes with IMPA (the primary impurity) to adsorb on the PMG crystal surface thereby restraining the growth inhibitory effect caused by IMPA. Second, we examined the possibility that PIDA forms a “molecular complex”26 with IMPA in solution, subsequently preventing it from adsorbing onto the PMG crystal surface (due to steric effect) and in doing so circumvent growth inhibition. Finally, it may be possible that PIDA adsorbs on the PMG crystal and alters the surface energy in such a way that growth is promoted notwithstanding the adsorption of IMPA. a. Competitive Adsorption on the Crystal Face. When more than one impurity is present in the growth medium, their interaction with the growing crystal will depend on the chemical affinity of the individual impurities to the crystal faces.27 In the case of a binary mixture of IMPA and PIDA present in the crystallizing solution, PIDA could adsorb preferentially at the growth sites (kinks, steps, or surface terrace) on the (100) face, and subsequently prevent IMPA to adsorb and affect the habit. However, analysis of PMG crystals grown from solutions doped with PIDA alone has a-vis impurity shown1 that its segregation coefficient;vis- incorporation into the crystal;is much lower as compared to IMPA. Besides, the segregation coefficient of IMPA in the crystals was not significantly affected by the presence of PIDA in the crystallizing solution.1 Our experimental observations show that the impact of PIDA on PMG crystal habit was negligible. The calculated binding energy for adsorption of PIDA on PMG crystal also suggested unfavorable interaction with the crystal lattice. On the basis of these evidences, we conclude that it is less likely for PIDA to compete with IMPA for adsorption on the (100) faces and produce the observed counter-effect on crystal habit. b. Complexation in the Solution Phase. The potential for PIDA forming a complex with IMPA in solution and thereafter producing a counter-effect on PMG crystal habit was explored. In order to verify this mechanism, we have used solution spectroscopy and solubility measurements to probe intermolecular interactions in the solution phase. Previously, IR28 and Raman spectroscopy29 have been used to study molecular self-association (of organic small molecules) in concentrated solutions. However, in this work, analysis of IR and Raman spectra of pure and mixture compounds in water indicated that there are no specific intermolecular interactions between IMPA and PIDA in solution (see Supporting Information). The possibility of complexation in solution phase was also investigated by measuring the equilibrium solubility of PMG and PIDA in pure aqueous solutions and in the presence of 0.2 wt % (w/w water) of IMPA (Table 2). At a given pH condition and in the presence of a known amount of IMPA, complexation between PIDA and IMPA in solution would increase the total solubility of PIDA from the saturated

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concentration value. In turn, the equilibrium constant for the association between the molecular species can be calculated from the increase in the total solubility of PIDA. However, the measured aqueous solubility of PIDA in the presence of IMPA actually decreased from 0.85 g/100 g to 0.71 g/100 g, suggesting that the molecular species do not form a complex in solution (in this case, the difference in solubility could be caused by a small difference in the pH). On the other hand, the solubility of PMG in the presence of 0.2 wt % of IMPA or PIDA did not change significantly from pure solution solubility. Hence, it is concluded that complex formation between these molecular species in solution may not be favorable. Table 2. Solubility of Pure and Impure (0.2 wt % impurity, w/w water) Aqueous Solutions at 30 °C compound

solubility (g/100 g)

PMG PIDA PMGþIMPA PMGþPIDA PIDAþIMPA

1.28 0.85 1.21 1.28 0.71

c. Alteration of Crystal Growth Mechanism. In the third possible mechanism, we hypothesize that simultaneous adsorption of the two impurities (IMPA and PIDA) on PMG crystal could bring in surface energy changes and thereby promote crystal growth. In order to provide evidence supporting this mechanism, we used AFM to monitor PMG crystal growth in situ (at the nanoscale) from supersaturated aqueous solutions in the absence and presence of these impurities. Figure 6a shows an image of the (100) surface of PMG crystal scanned during growth from supersaturated pure aqueous soltuion. The horizontal steps on the (100) face

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form as part of the growth spirals and provide evidence for crystal growth via the screw dislocation mechanism, which operates at low supersaturation conditions.27 The molecular steps on the crystal surface, whose lateral resolution is in the order of 10 nm, propagated in the direction perpendicular to the vertical (slow) scan axis. However, the displacement rates of these steps could not be determined by tracking the absolute position of particular step fronts in the sequential scan images. Hence, the kinetics of step progation could not be precisely measured. On introducing supersaturated PMG solution containing 1 wt % of IMPA on the (100) crystal surface, step motion was completely inhibited, resulting in a “dead” supersaturation zone for crystal growth.12,30 The interspacing between elementary steps on the surface significantly widened by at least an order of magnitude due to decreased step velocity (Figure 6b). At the same time, successive elementary steps on the surface coalesced to form step bunches, causing an increase in vertical step heights (2.0 ( 0.2 nm). In comparison, step heights measured during growth from pure PMG solution were on the order of 0.8 ( 0.1 nm, which correspond to the unit cell dimension along the a axis (8.682 A˚).17 These observations clearly show that IMPA adsorbs on the crystal surface (either at the surface terrace, step, or kink site) and consequently stops step propagation. When a supersaturated solution containing a mixture of 1 wt % of IMPA and 1 wt % of PIDA respectively was introduced on the crystal surface, densely spaced steps reappeared (Figure 6c). With time, several kink sites were formed on the step ledge, which grew perpendicular to the direction of step motion. As observed from successive scan images, the steps developed a roughened interface and propagated at an accelerated rate.

Figure 6. AFM scan images of the same area (1 μm  1 μm) on the (100) face of PMG crystal as grown from supersaturated aqueous solution: (a) pure solution; (b) 1.0 wt % (w/w of PMG) of IMPA added to the solution; (c) a mixture of 1.0 wt % of IMPA and 1.0 wt % of PIDA added to the solution; (d) sectional analysis (of image (b)) showing the step heights. The block arrow symbol represents the direction of step propogation and the scale bar represents vertical scan resolution.

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Figure 7. AFM scan images (1 μm  1 μm) of the (100) face of PMG crystal as grown from supersaturated aqueous solution containing 1.0 wt % (w/w/of PMG) PIDA. The block arrow symbol represents the direction of step propogation and the scale bar represents vertical scan resolution.

Scheme 1. Illustration of Adsorption of PMG and Impurity Molecules on the (100) Face of PMG Crystala

a IMPA adsorbs at a lattice site on the step ledge or surface terrace; PIDA adsorbs at a kink site on the step.

In order to gain further insights into the mechanism by which this process is activated, we investigated the step dynamics on the (100) surface during PMG crystal growth from a supersaturated solution containing 1 wt % of PIDA. Initially (t = 2 min), the (100) steps propagated in the direction perpendicular to the vertical scan axis (Figure 7a). With time several kink sites developed on the step ledges leading to “step roughening” (Figure 7b). This growth behavior contrasts with that from pure solution wherein nearly straight (100) step ledges developed (cf. Figure 6a). These steps appeared to propagate at an accelerated rate as compared to that observed in the presence of IMPA, although precise values of these displacement rates could not measured. On the basis of the above observations, we now postulate a possible mechanism by which PIDA counteracts the growth inhibitory effect of IMPA. Scheme 1 shows a schematic illustration of adsorption of the impurities (IMPA and PIDA) on the (100) face of a PMG crystal. As IMPA undergoes stereospecific interaction with the crystal face, it adsorbs firmly at a lattice site on the surface terrace and becomes “immobile”.26 In this case, the free energy change associated with the adsorption of IMPA on the crystal surface would be lower - corresponding to a negative binding energy value - than the energy required for migration of the adsorbed impurity molecule.26 Consequently, an advancing step front would be impeded by the impurity

molecules adsorbed on the surface terrace resulting in reduced step velocity (Cabrera-Vermilyea model).31At sufficiently large surface coverage, step motion stops completely and growth ceases. On the other hand, PIDA has a low binding affinity on the (100) surface terrace, corresponding to a positive binding energy value for this face. PIDA could instead adsorb preferentially at a kink site in the step where it is not constrained by stereospecific interactions. This reasoning can be supported qualitatively by the fact that binding energy for incorporation of PIDA on the {011} face (which is equivalent to adsorption at a kink site on the (100) face) is relatively low (albeit a positive value) compared to its adsorption at any other sites on the PMG crystal. PIDA could therefore behave as a “mobile”27 impurity and act as stoppers for the displacement of the step. At the molecular level, the side chain moiety (COOH) of PIDA would impose steric hindrance to the incorporation of solute molecules at the adjacent kink site in the step (cf. Scheme 1). Thus, PIDA would impede growth along the direction of step motion as well as in the direction of the kink propagation. These arguments are supported by AFM observations, which reveal development of a roughened interface at the (100) step along with an increase in the interstep distance (although not to the extent as in the case of IMPA) during growth from PIDA doped solution. Besides, in the presence of a mixture of IMPA and PIDA, several kink sites (along the b and c directions) develop on the (100) step. In both cases, however, the step heights did not increase (0.7 ( 0.1 nm) implying that PIDA inhibits only the development of the step ledge where it adsorbs and not the preceding steps. Moreover, unlike the effect of IMPA, propagation of steps on the (100) surface was not strongly impeded by the presence of PIDA. From pure solution, PMG crystal growth proceeds through propagation of densely spaced straight (kink-free) step ledges on the (100) surface (cf. Figure 6a). This could imply that step motion along the surface is rate-limited by the attachment of PMG molecules at the step ledge. On the other hand, interaction of PIDA at the step leads to generation of several kink sites and, in turn, promotes growth via a step roughening27 mechanism. With an increase in the density of kinks and steps, growth of steps on the (100) surface could proceed at an accelerated rate and consequently overcome the inhibitory effect of IMPA adsorbed on the surface terrace. 5. Conclusions In this paper, we have explained the habit-modifying effect of reaction byproducts (IMPA, AMPA, and PIDA) on PMG

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crystals on the basis of stereoselective adsorption of the impurities on the (100) face and subsequent growth inhibition normal to that face. Binding energy values calculated for impurity-crystal interactions were in good agreement with the experimental segregation coefficients of the respective impurities and also corroborated the degree of crystal habit modification. The counter-effect of PIDA on the habit-modifying effect of IMPA was rationalized based on the changes in crystal growth mechanism observed at the nanoscale. While IMPA caused growth cessation of the molecular steps on the (100) surface, the presence of PIDA in the growth medium generated a higher density of kink sites and molecular steps that propagated at an accelerated rate. It is concluded that a reduced step free energy due to kink formation can promote crystal growth and, in turn, counteract the growth-inhibitory effect of IMPA. Acknowledgment. We thank Dr. Will Wood (Syngenta) for the initial studies on PMG, Professors Brian Cox and Simon Black (AstraZeneca) and Roger Davey (University of Manchester) and Dr. Keith Carpenter (ICES) for helpful discussions. We thank Mr. Kwek Jin Wang (ICES) for helping with the AFM experiments. We gratefully acknowledge Syngenta for providing approval to publish this work. Supporting Information Available: Spectroscopic (IR and Raman) analysis of the solutions of pure compounds (PMG, IMPA, and PIDA) and 1:1 mixture (PMG þ IMPA, PMG þ PIDA, and IMPA þ PIDA, respectively) in water. This material is available free of charge via the Internet at http://pubs.acs.org.

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