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From Molecules to Crystals: The Solvent Plays an Active Role Throughout the Nucleation Pathway of Molecular Organic Crystals Carlos E. S. Bernardes, Manuel Matos Lopes, José Rosário Ascenso, and Manuel E. Minas da Piedade Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/cg500609g • Publication Date (Web): 15 Oct 2014 Downloaded from http://pubs.acs.org on October 21, 2014

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Crystal Growth & Design

From Molecules to Crystals: The Solvent Plays an Active Role Throughout the Nucleation Pathway of Molecular Organic Crystals Carlos E. S. Bernardes,†,‡,* Manuel L. S. Matos Lopes,†,§ José R. Ascenso,‡ Manuel E. Minas da Piedade.† †

Centro de Química e Bioquímica, Faculdade de Ciências, Universidade de Lisboa, 1749-016

Lisboa, Portugal. ‡

Centro de Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa, 1049-001

Lisboa, Portugal. §

Centro de Ciências Moleculares e Materiais, Faculdade de Ciências, Universidade de Lisboa,

1749-016 Lisboa, Portugal.

KEYWORDS: Nucleation, Crystallization, 1H-NMR, Dynamic Light Scattering, Colloidal Particles, 4’-hydroxyacetophenone

ACS Paragon Plus Environment

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ABSTRACT Crystallization is indisputably one of the oldest and most widely used purification methods. Despite this fact, our current understanding of the early stages of crystallization is still in its infancy. In this work dynamic light scattering and proton nuclear magnetic resonance were used to investigate the changes occurring in 4’-hydroxyacetophenone colloidal particles, as they form in a supersaturated aqueous solution and evolve towards anhydrous or hydrate materials during a cooling crystallization process. In the concentration range probed, the particles are initially composed by both solute and water. If the outcome of crystallization is an anhydrous phase, a complete loss of solvent from the particles is progressively observed up to the onset of crystal precipitation. These findings provide unique experimental evidence that the role of solvent in the formation of crystals can go well beyond influencing the self-assembly and clustering of solute molecules prior to nucleation.


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INTRODUCTION Crystallization from solution is, perhaps, the older and most widely used method for isolation and purification of crystalline materials.1,2 Despite this fact the early stages of crystallization are still poorly understood.3-7 Crystallization first requires the production of a supersaturated solution. Without the system entering this metastable state no crystallization occurs. Then, solute self-assembly and clustering is thought to lead to nucleation, a process by which embryos of the new crystalline phase are produced.3,8 These nuclei may subsequently grow into macroscopic crystals by incorporating further solute units into the crystal lattice. The nature, rate and mechanism of formation of the nuclei seem to dictate to a large extent the structural and physical properties of the crystallized substances.3,4,9 Understanding the early stages of crystallization from solution is thus of particular interest if a tight control over the crystal phase (polymorph or solvate), morphology, size and size distribution of a crystalline material obtained from solution is in view. The achievement of this goal would currently have a strong impact in areas such as the fine chemicals industry. Indeed, the lack of polymorphism control can, for instance, wreak havoc with the safe and effective use of an active pharmaceutical ingredient,10-12 as evidenced by the well-documented case of the AIDS drug Ritonavir.13 Considerable efforts have, therefore, been invested to gain better insight into the nucleation process,3,4,7,8,14,15 mainly within the framework of two schools of thought: (i) the classical nucleation theory, which considers that nucleation involves a transition state consisting of a molecular aggregate (critical nucleus) with a structure identical to the final crystal form; (ii) non-classical nucleation theories, such as the two-step nucleation theory,3,4,7 which assumes the formation of a solute rich domain where the solute molecules are clustered with a liquid-like structure (first step), followed by the development of an ordered crystal nucleus within this high concentration region (second step).


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Both views are centered on the solute. There is ample evidence, however, that the nature of the solvent can influence the outcome of crystallization.5,14 Experiments have shown that solute self-association may occur for concentrations well below saturation14,16-20 and that the type of self-association dominant in a given solvent can determine the preferential nucleation of a specific polymorph.5,21-23 To our knowledge, however, in the case of small organic molecules, no significant results exist that shed light on the evolution of solute aggregates and the role of solvent along the pre-crystallization pathway.5,14 In this work the structural and compositional changes occurring in nanometric precursors of 4’-hydroxyacetophenone (HAP, Scheme 1) anhydrous and hydrate phases during cooling crystallization from water was investigated by dynamic light scattering (DLS) and proton nuclear magnetic resonance (1H-NMR). It is shown that the initial aggregates are not formed solely by solute molecules and that their rearrangement into the final crystal structure involves a progressive solvent loss as the temperature of the solution is reduced. This process, which, as mentioned above, is normally overlooked in the formulation of nucleation theories, dictates the formation of a solvate or anhydrous phase by cooling crystallization. The present findings give experimental support to the hypothesis that crystal precursors can be dynamic entities which change in structure and composition along the crystallization pathway.5

Scheme 1. 4’-Hydroxyacetophenone (HAP).


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EXPERIMENTAL SECTION General. Distilled and deionized water from a Millipore system (conductivity ≤0.1 µS) and D2O (Aldrich, 99.9 atom % D) were used in the preparation of all solutions. 4’-hydroxyacetophenone (HAP, 98% Aldrich) was purified by sublimation as described elsewhere.24 Dynamic Light Scattering (DLS). The light scattering experiments were performed using a reported in house designed and built apparatus.25 The light source was a Spectra Physics 127, 35 mW He-Ne laser, operated in single mode at 632.8 nm. The light reflected through mirrors reached the sample contained in a Hellma quartz cell with 10 mm optical path, placed in a Flash 200TM cuvette holder for laser spectroscopy. The temperature of the solution was controlled to better than ±0.02 K by a TC125 Quantum Northwest unit which also controlled the magnetic stirring inside the cuvette. Temperature measurements were performed with a precision of ±0.1 K using a PT100 probe connected to a Therm 2280-1 unit. This system had been previously calibrated against a reference Pt100 probe calibrated according to ITS-90. The collection optics captured the scattered light at an angle of 90o and conducted it through an optical fiber to an ALV/SO-SIPD detector. The intensity correlation functions were determined with a UNICOR photon correlator. The analysis of the measured autocorrelation functions, g1 (t ) , was performed using the tree cumulant expansion:26

1 1   g1 (t ) = A exp  − Γ t + µ 2t 2 + µ3t 3  2! 3!  

(1)

where A is a constant related with the amplitude of the correlation function,27 t is the correlation time, and Γ , µ2 and µ3 are the first second and the third cumulants. All the parameters in the


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previous equation are treated as adjustable, fitting log [ g1 (τ )] as a third order polynomial function. The first cumulant, is an average decay rate while the second and third cumulants are measures of the width and asymmetry of the particle size distribution. For monodispersed or closely monodispersed systems Γ can be related to a decay rate, inverse of the correlation time, which in turn can be related to the diffusion coefficient, D, and the scattering wave vector, q, as27

τ =  Dq 2 

−1

(2)

where

q=

4π no

λ

sin(θ / 2)

(3)

The refractive indices, no , at different temperatures needed for the determination of the wave vector were estimated from the values for water.28 In eq. 3, θ = 90o is the scattering detection angle and λ = 632.8 nm is laser wavelength. The hydrodynamic radii, Rh, were obtained through the Stokes-Einstein equation:

Do =

k BT 6πη Rh

(4)

where D0 is the diffusion coefficient at infinite dilution, kB is the Boltzmann constant, T is the temperature and η is the viscosity. Diluted solutions were used (HAP molar fraction, xHAP , in


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the range 0.004 < xHAP < 0.007), to ensure the applicability of eq. (4), and that their viscosities and refraction indexes were equal to that of pure water.28 In a typical experiment, known masses of HAP and water were placed in an Erlenmeyer flask and heated to complete solubilization under magnetic stirring (~330K). The weightings were performed with a precision of ±0.01 mg with a Mettler Toledo XS205 balance. The solution was transferred to a quartz cell maintained at 330 K, by using a pre-heated (at ~340K) syringe adapted to a membrane filter (Milipore SLFG013NL, 0.2 µm). This procedure allowed the removal of any dust or small particles from the solution, which could interfere with the DLS experiments. The solution was slowly cooled under magnetic stirring at ∼0.5 K·min-1 until the formation of the colloidal phase was observed. At this point stirring and cooling of the solution were stopped and the Rh variation analyzed during ∼30 minutes. After this analyses, the solution was subsequently cooled by few degrees and the Rh variation investigated during another 30 minutes. During each temperature step a cooling rate of ∼0.5 K·min-1 was applied with magnetic stirring. This procedure was repeated until precipitation of HAP occurred. 1

H Nuclear Magnetic Resonance (NMR). The 1H-NMR measurements were carried out on a

Bruker Avance III 500 MHz spectrometer equipped with a 3 mm BBO probe. All NMR experiments were performed for a mixture of 54.6 mg of HAP and 1.023 g of a 1:1 (v/v) H2O/D2O. This solution was prepared in a small beaker, and heated under magnetic stirring until complete solubilization was observed. Approximately ~0.3 mL of the solution was transferred to a 3 mm diameter NMR tube. The weightings were performed in an Ohaus GA110 balance, with a precision of ±0.1 mg. T2 relaxation times of water protons at various temperatures were measured by the CarrPurcell-Meiboom-Gill (cpmg) pulse sequence using a fixed echo time of 400 µs. The cpmg


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pulse sequence produces a pseudo array of 12 spin echoes from which the T2 value could be extracted using the relaxation module of Bruker software. The experiments were performed by heating initially the mixture to 343 K inside the apparatus, applying a rotation to the NMR tube. The solution was then left to equilibrate for ~ 30 minutes. After temperature stabilization, the rotation of the tube was stopped and experiments to determine T2 performed. The solution was subsequently cooled a few degrees at 1 K·min-1, applying rotation to the tube, and then left to equilibrate for another ~30 minutes before new evaluation of T2. Each T2 determination took approximately one hour and only one experiment was performed at each temperature. The procedure above was repeated until a final temperature of 298 K was achieved. NOESY spectra were acquired with a mixing time of 500 ms, which is long enough to observe a good signal to noise ratio. These spectra were acquired as a 2k × 256 data array with 32 scans per increment. After zero filling the spectra were processed with a shifted square sinbell in both t1 and t2 domains. Difference spectra were obtained by subtraction of a control spectrum obtained with no irradiation and a spectrum obtained with saturation of the water peak region at 4.8 ppm.29 All these experiments were performed using a solution pre-heated at 343 K for ~10 minutes inside the NMR apparatus and subsequently cooled at approximately 1 K·min-1, to the final temperature of 326 K.

RESULTS AND DISCUSSION In a recent work it was found that on cooling HAP aqueous solutions with concentrations cHAP > 29 g·kg-1, crystallization was preceded by the formation of a colloidal phase, Figure 1.30


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339

Solution 324

T /K

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


309

294

279 29

e Zon l e st ab Colloidal Phase Meta

Solution + Form I

Solution + Hydrate 39

49

59

-1

cHAP / g.kg

Figure 1. Detail of the phase diagram of the HAP + H2O system reported in reference 30. The concentration of 4'-hydroxyacetophenone, cHAP, refers to grams of anhydrous solute per 1 kg of water. The diagram shows the approximate regions where the different phases/mixtures are observed during a cooling crystallization procedure at constant concentration. For cHAP < 37 g·kg-1 a hydrate precipitates initially from solution while, for cHAP > 37 g·kg-1, the anhydrous polymorph dubbed form I is prepared (vertical dash line). In both cases crystallization is preceded by the formation of a colloidal phase.

Furthermore, by controlling the initial solution concentration, hydrates (cHAP < 37 g·kg-1) or an anhydrous polymorph dubbed form I (cHAP > 37 g·kg-1) could be selectively and reproducibly prepared.24,30 These findings suggested that the investigation of the nature and evolution of this colloidal phase along the crystallization pathway could provide a unique opportunity to probe the nucleation process of an organic compound (please see supporting information for more details about the colloidal phases of HAP).


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Four HAP solutions in water with concentrations in the range 32 to 55 g·kg-1 were investigated by DLS. On general, the colloidal phase formed from these solutions exhibit a high concentration of particles. This fact, suggest that multiple scattering effects can occur during the DLS studies, leading to apparent hydrodynamic radius smaller than the actual Rh (see discussion below). Nevertheless, the experiments led to approximate single exponential decay correlation functions and, as a consequence, to values of polydispersity index characteristic of monodisperse systems. This suggests that, at a specific concentration and temperature, the HAP colloidal particles were all of similar size. Figure 3a shows the variation of the hydrodynamic radius, Rh, of the colloidal particles with temperature, for initial cHAP values leading to the formation of anhydrous form I HAP. The results obtained for cHAP = 50.5 g·kg-1, were found from two sets of independent runs, showing a good reproducibility of the procedure. For the remaining concentrations, Rh was obtained from a single cooling run. The plotted Rh data correspond to the averages of the particle radii obtained over a period of ∼15 min, after temperature stabilization had been attained and an approximately constant size of the aggregates was observed. The errors given in the picture correspond to the standard error of the average value of Rh analyzed during ~15 minutes. It can be concluded from Figure 3a that: (i) independently of the concentration, a tendency for a hydrodynamic radius decrease is observed as the temperature decreases; (ii) lower initial solution concentrations lead to the formation of particles with higher Rho values (i.e. the hydrodynamic radius observed immediately after detection of aggregates); (iii) as previously observed,30 independently of the initial concentration, crystallization always occurs at approximately the same temperature (~314 K); and (iv) whatever the starting concentration, on cooling, all particles tend to nearly the same Rh value (~115 nm) prior crystallization.


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(a)

(b) 280

830

1

g k . g 7 . 2 4 =

1

g k . g 5 . 0 5 =

684

P

A cH

P

A cH

Rh /nm

190

o

Rh / nm

235

317

321

392

1

100 313

538

246

P

145

g k . g 2 . 5 5 =

A cH

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


325

329

100 30

T/K

40

50

60

-1

cHAP /gkg

Figure 2. Hydrodynamic radius (Rh) of the 4’-hydroxyacetophenone colloidal particles determined by dynamic light scattering. (a) Variation of Rh on cooling HAP solutions that lead to the crystallization of anhydrous form I HAP: cHAP = 55.2 g·kg-1 (solid line), cHAP = 50.5 g·kg-1 (dash line) and  cHAP = 42.7 g·kg-1 (dotted line); (b) Hydrodynamic radii ( Rho ) observed immediately after the detection of the colloidal suspension, for concentrations leading to hydrate (cHAP = 32.8 g·kg-1) and anhydrous (cHAP = 55.2 g·kg-1, cHAP = 50.5 g·kg-1, and cHAP = 42.7 g·kg1

) phases.

As pointed out, most likely, the amount of particles formed during the investigated nucleation process was excessively high for the DLS studies. Under these conditions, the results can be affected by the occurrence of multiple scattering leading, necessarily, to smaller hydrodynamic radii than real. However, because the intensity profiles of the scattered light was approximately the same for all experiments and the determined aggregate sizes is rather similar in all cases, also the concentration of particles should be similar in all solutions. As a result, under these circumstances, the profile of the size variations in Figure 2a should be accurate,


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although in reality shifted to higher Rh values. Thus, the conclusions highlighted above, remain essentially the same, even if effects of multiple scattering occurred during the experiments. For HAP concentrations leading to hydrate formation, the temperature gap between the detection of colloidal particles and crystals separation from the mother liquor is very narrow (∼3 K).30 This precluded the study of particle size variation with temperature within this domain of the phase diagram. Therefore, for cHAP = 32.8 g·kg-1 only Rho could be determined. The obtained value is compared in Figure 3b with the corresponding data from the experiments at cHAP = 55.2 g·kg-1, cHAP = 50.5 g·kg-1, and cHAP = 42.7 g·kg-1, which led to anhydrous HAP (see Figure 3a). The comparison shows that the initial aggregates preceding the formation of the hydrate are ∼4 times larger than those leading to the formation of the anhydrous phase. The structural modifications accompanying the size variation of the colloidal particles with temperature prior the formation of anhydrous form I HAP (Figure 1) were investigated by 1

H-NMR. These studies were performed for a 53.4 g·kg−1 HAP solution in 1:1 (v/v) H2O/D2O.

The use of a H2O/D2O mixture was necessary because the 1H-NMR experiments required the presence of a deuterated solvent to lock the magnetic field. Since the crystallization of HAP and the corresponding phase diagram had been studied in pure water,30 the effect of replacing H2O by H2O/D2O was tested prior to the 1H-NMR experiments. These tests indicated that the use of the 1:1 (v/v) H2O/D2O mixture was essentially equivalent to the use of pure water.30 Indeed for cHAP = 53.4 g·kg−1 in 1:1 (v/v) H2O/D2O, saturation and the onset of colloidal phase separation were found to occur at ~331 K and ~327 K, respectively, as previously observed in H2O.30 The 1HNMR spectra obtained before (337 K) and after (326 K) the formation of colloidal particles are illustrated in Figure 4a. Because the intensity ratio between the HAP and H2O peaks is approximately 1:100, the region corresponding to the water protons was removed from all


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(b)

(a) 326K 337K

8.1

8.0

7.9

7.5

8.5

7.7

7.1 7.0 6.9

6.7

6.9

2.2

2.8

2.4

2.0

Chemical Shift / ppm

(c)

(d)

8.5

7.8

7.1

6.4

2.8

2.4

2.0

Chemical Shift / ppm Figure 3. Results of the 1H-NMR experiments for a 53.4 g·kg-1 HAP solution in 1:1 (v/v) H2O/D2O. (a) 1H-NMR spectra recorded before (337 K) and after (326 K) the formation of the colloidal particles. (b) and (c) Different regions of the NOESY spectra recorded at 326 K. (d) Difference between the 1H-NMR spectra recorded at 326 K before and after irradiation at 4.8 ppm;29 the region corresponding to the water peak (4.8 ppm) was removed from all spectra (see text).


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spectra. The spectrum at 337 K essentially consists of three main peaks: 8.0 ppm and 7.1 ppm, which can be assigned to the two types of aromatic protons, and 2.8 ppm corresponding to the methyl group protons. The peak splittings are, however, much more complex than the doublet and singlet patterns expected for aromatic and methyl protons in non-associated HAP, respectively.24 This is an indication that some degree of HAP aggregation already exists in solution before saturation. Such conclusion is consistent with recent findings that supramolecular structures are present in a large variety of solute/solvent mixtures well below saturation.14,16-20 It should also be pointed out that no evidence of aggregate formation under the same pre-saturation conditions was detected by DLS. When the system was cooled to 326 K a small upfield shift (∼0.1 ppm) of the peaks at 8.0 ppm, 7.1 ppm, and 2.8 ppm was observed, which is due to the temperature variation. The signals also became less complex, showing the doublet and singlet patterns expected for aromatic and methyl protons in “free” HAP. This suggests that the bulk solution essentially contains nonassociated HAP molecules, probably due to the decrease in solute concentration accompanying the colloidal phase formation. A further important aspect is the appearance of a new set of small peaks at 2.2, 6.7 and 7.5 ppm (indicated by arrows in Figure 4a), which can be assigned to HAP molecules incorporated into the dense liquid-like colloidal particles. In order to investigate the dynamic equilibrium between the different species forming the colloidal system a NOESY experiment with a long mixing time (500 ms) was carried out. The corresponding spectra (Figure 4b-c) show negative cross peaks between the protons of HAP in solution and in the colloidal particles (off-diagonal orange regions), thus indicating a slow exchange of HAP molecules between the two phases. NOE cross peaks are also observed for protons of HAP molecules in solution (positive peaks; light blue off-diagonal regions), but not


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for molecules in the colloidal particles. When irradiation at 4.8 ppm (water peak region) was performed (Figure 4d), NOE and saturation transfer to the protons of HAP included in the colloidal particles occurred.29 This effect is usually noted when water is confined to small channels or cavities inside particles.31 Thus, in the present case, the pattern in Figure 4d can, at least in part, be the result of magnetization transfer from H2O to HAP molecules at the channel/cavity interface. The presence of water in channels or cavities inside the particles was also inferred from an investigation of the temperature dependence of H2O relaxation times, T2. This method has been used to study hydration water in colloidal dispersions,32 hydrogel polymers33 and proteins.34 As expected,35 the T2 of water in H2O/D2O steadily decreases with temperature (Figure 4). In contrast, the results obtained for a 53.4 g·kg−1 HAP solution in H2O/D2O (Figure 4) show that: (i) the water relaxation times in the HAP solution are at least one order of magnitude smaller than in “pure” H2O/D2O; (ii) the T2 values smoothly increase when the temperature decreases to ~314 K (onset of crystallization shown in Figure 2a); and (iii) below ~314 K, T2 decreases as previously observed for the H2O/D2O mixture. These variations can be rationalized based on the equation:36

x 1 x = p + B T2 T2, P T2, B

(5)

where xP and xB, and T2,P and T2,B are the mole fractions and the relaxation times of H2O in the


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T2 /s

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Colloidal particles Formation

4.0 0.31 0.28 0.25 295

Crystal Formation

305

315 325 T/K

335

345

Figure 4. Water protons relaxation times, T2, as a function of temperature, obtained by 1HNMR. The results refer to a pure 1:1 (v/v) H2O/D2O mixture (red circles) and to a 53.4 g·kg-1 HAP solution in H2O/D2O (blue square dots).

particles (P) and in the bulk solution (B), respectively. Since the outcome of cooling crystallization of HAP from a cHAP = 53.4 g·kg−1 solution is the anhydrous form I, then the increase in T2 observed in the decreasing temperature range 343-317 K must be related to a progressive decrease of water content inside the colloidal particles (decrease of xP). Below the onset of form I crystallization (T ∼ 314 K) 1/T2 ∼ 1/T2,B and the expected decrease of T2 with temperature is observed. It can therefore be concluded that the Rh decrease on cooling noted in Figure 2a is linked to a progressive loss of water from the particles.


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CONCLUSION In summary, the DLS and 1H-NMR results indicate that: (i) the colloidal particles mediating the crystallization of HAP from water are dynamic entities that exchange both HAP and H2O with the solution; (ii) inside the particles water is confined to small channels or cavities; (iii) the increase of Rho with the decrease of the initial cHAP value (Figure 3) must be related with a larger H2O/HAP molar ratio inside the particles. Indeed, solutions with lower HAP concentration have fewer solute molecules available to form colloidal particles. Because immediately before crystallization of form I HAP the particles show essentially the same size, regardless of the initial cHAP value, their increase in Rho must result from an increase of the initial H2O/HAP ratio. Overall, this work suggests that, at least in the region of the T-cHAP phase diagram probed, the nucleation of anhydrous or hydrate HAP forms follows a non-classical mechanism (Figure 6). Solute aggregates are already present in solution at temperatures below saturation. On entering the metastable zone HAP colloidal particles are formed which contain bound solvent and continuously exchange H2O and HAP with the bulk solution. The fact that the particle size at a given temperature remains stable for several hours, suggests an equilibrium exchange. The H2O/HAP ratio in the particles progressively decreases on cooling, until a stable packing is attained and crystals are formed. Full loss of solvent from the particles occurs in the domain of anhydrous HAP. The loss is incomplete when a hydrate is formed. Hopefully other examples will be found, which allow further exploration of the nature and dynamics of clusters mediating the crystallization of small organic molecules, so that nucleation processes can be better understood and controlled.


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Figure 5. Scheme of the two alternative pathways for the crystallization of anhydrous (bottom) and hydrate (top) forms of 4’-hydroxyacetophenone. Open circles represent water molecules (solvent) and closed circles refer to HAP (solute). In the anhydrous pathway, complete removal of the solvent occurs prior to crystal formation.

AUTHOR INFORMATION Corresponding Author *(C.E.S.B). Tel: +351-21-75000208. Fax: +351-21-7500088 E-mail: [email protected]

ACKNOWLEDGMENT This work was supported by Fundação para a Ciência e a Tecnologia (FCT), Portugal (PEstOE/QUI/UI0612/2013). A post-doctoral grant from FCT (SFRH/BPD/43346/2008) is also gratefully acknowledged by C. Bernardes.


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SUPPORTING INFORMATION The supplementary information associated with this article is available free of charge via the Internet at http://pubs.acs.org/.

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For Table of Contents Use Only

From Molecules to Crystals: The Solvent Plays an Active Role Throughout the Nucleation Pathway of Molecular Organic Crystals

Carlos E. S. Bernardes, Manuel L. S. Matos Lopes, José R. Ascenso, Manuel E. Minas da Piedade.

Table of Contents Graphic

Synopsis. The study of colloidal suspensions of 4’-hydroxyacetophenone in water evidenced the role of solvent in the early steps of hydrate or anhydrous crystalline phases formation.


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From Molecules to Crystals - American Chemical Society

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