Controlling Crystallization via Organic Solvent Nanofiltration: The

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Controlling Crystallization via Organic Solvent Nanofiltration: The Influence of Flux on Griseofulvin Crystallization James Campbell, Ludmila G. Peeva, and Andrew G. Livingston* Department of Chemical Engineering, Imperial College London, South Kensington Campus, London SW7 2AZ, United Kingdom ABSTRACT: Organic solvent nanofiltration (OSN) is suggested as a method for enhancing crystallization in the pharmaceutical industry. OSN crystallization has the potential to reduce energy and/or chemical inputs and allows for control of process conditions and crystal morphology. This work focuses on the crystallization of the pharmaceutical compound griseofulvin using OSN membranes to concentrate solutions via solvent removal. Griseofulvin solutions were concentrated in a pressure-driven dead-end nanofiltration cell, and crystals were allowed to spontaneously nucleate. The process was carried out using a range of different pressures to manipulate the solvent flux through the membrane. It was found that two distinct crystal types could be produced by altering the process solvent flux. At high flux, large crystals (≈1 mm) were produced, whereas, at low flux, small crystals (2−25 μm), which grew in clustered formations, were observed. The large crystals produced a previously unreported X-ray powder diffraction pattern, suggesting a slightly different morphology of griseofulvin than that resulting from traditional crystallization methods. The difference in crystallization morphologies could be attributed to the effect of preferential surface and bulk phase crystal nucleation and growth. The precise control of process conditions afforded by OSN crystallization might lead to rapid discovery of new morphologies of pharmaceutical compounds.

1. INTRODUCTION Crystallization is used throughout many different industries1−3 to obtain pure, solid product. Most common crystallization processes require a metastable or supersaturated state to be induced in the solution via antisolvent addition,4 cooling,4 or evaporative5 methods. Membrane separation offers an alternative crystallization method to the traditional crystallization routes.6,7 Membrane technology can allow for selective separation of compounds based on a difference in their ability to transport through the membrane.8 Originally developed for aqueous solutions, particularly desalination,9 the technology has now been extended for use in organic solvent solutions by development of organic solvent resistant membranes (e.g., organic solvent nanofiltration (OSN)).10−12 There are four main crystallization methodologies that incorporate the use of membrane technology. Membrane distillation, also known as evaporative membrane crystallization,13 was one of the first membrane crystallization processes to be developed.14 Membrane distillation uses microporous hydrophobic membranes to separate hot and cold aqueous streams. The membrane restricts the passage of liquid but allows vapor to pass from the hot stream to the cold stream.14,15 Membrane emulsification makes use of membranes to separate a solution and a second immiscible/antisolvent phase that flows tangentially to the membrane surface.16 The solution is forced through the membrane, and crystals or droplets are instantly formed on the membrane surface and are carried away by the flowing immiscible/antisolvent phase. Membrane templating uses membranes as structural support for growing crystals, rather than for separation of solvent and © 2014 American Chemical Society

solute. The membranes can then be removed to give particles of a given size and shape.13 The final membrane crystallization methodology is membrane-assisted crystallization reverse osmosis (mac-RO), a pressure-driven process that can be used to induce the transport of solvent from an area of high saturation to low saturation.17 Crystallization is achieved through concentrating a solute by allowing the solvent to pass through while retaining the desired product. The separations required to achieve crystallization can be comparable to evaporative methods; however, it can be achieved at a fraction of the capital and operational costs.18 Other advantages of mac-RO include the possibility of selectively removing impurities that could affect quality of crystalline product, and avoiding thermal degradation of the product associated with the high temperature required for distillation. The crystallization methodology most similar to the method employed in this work is mac-RO. Membrane crystallization has so far been applied to aqueous solutions including the crystallization of salt (sodium chloride),19,20 proteins,7,21,22 and sulfate wastes.23 The most extensive research into mac-RO has been carried out by Lakerveld et al. using the crystallization of ammonium sulfate and adipic acid in aqueous environments.24 The system used separate crystallizer and solution enrichment loops. The flow rates were designed to avoid concentration polarization and scaling on the membrane surface. Nevertheless, for solutes with Received: November 15, 2013 Revised: February 28, 2014 Published: March 14, 2014 2192

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Figure 1. Diagram demonstrating the concentration and crystallization of griseofulvin in a dead-end filtration cell.

Overall, most membrane crystallization processes concentrate the solution and then induce crystallization in a separate crystallization vessel. This is done to reduce fouling of the membrane surface, which would lead to reduced fluxes. This work studies the application of OSN crystallization, in situ at the membrane surface, utilizing the fact that polymer surfaces with rough topologies can increase the nucleation rate of crystals and even affect the orientation of the crystals, altering the crystal morphology.30,31 The pharmaceutical compound griseofulvin is used as a model compound. It is demonstrated that, through alteration of the OSN crystallization conditions, specifically, the solvent flux through the membrane, it is possible to produce griseofulvin crystals and manipulate their morphology. The crystallization methodology employed could be used to aid the discovery of novel crystal polymorphs.

high solubilities, the yield was low and concentration polarization effects did result in membrane scaling. Membrane crystallization has also been used to control the morphology of amino acids25,26 and paracetamol.27 By controlling the supersaturation state of the systems, the polymorphic structure of the crystalline material has been controlled. These studies performed by Di Profio et al. used the established technologies of membrane distillation27 and antisolvent membrane crystallization.25 Antisolvent membrane crystallization has the disadvantage of using a mixture of solvents that cannot be easily separated, while membrane distillation requires the application of heat and the use of a separate crystallizer vessel.20 To the best of our knowledge, research on crystallization using an organic solvent nanofiltration (OSN) system has not previously been published. The solubility and permeability of solutions filtered through OSN membranes differ greatly from that of aqueous solutions, indicating that significantly different phenomena could be observed. OSN crystallization could offer a number of advantages to/or in conjunction with traditional crystallization methods: 1. Energy saving − The electrical energy to drive pumps used for OSN requires less energy than the heat energy needed to evaporate solvent, as demonstrated by Kuhn et al.17 2. Product and/or solvent recovery − Similarly to aqueous membrane crystallization,28,29 the OSN crystallization can easily be incorporated with other crystallization processes (in organic solvents) to improve product and/ or solvent recovery from the mother liquor stream. 3. Wide range of solvents − OSN crystallization can easily be performed in high boiling point organic solvents, where evaporative methods would prove difficult. 4. Precise control over process conditions − Temperature, pressure, solvent mixture, and speed of saturation can all be controlled independently without the need for extra heat energy for solvent removal. This extra control, especially of solvent mixture and temperature, is of particular importance25−27 and might allow specific crystal morphologies to be obtained.

2. EXPERIMENTAL SECTION 2.1. Materials. Polypropylene nonwoven backing was supplied by Viledon, Germany. Polyimide (PI) polymer (Lenzing P84) was purchased from HP Polymer GmbH, Austria. Solvents used for membrane preparation and membrane testing [isopropanol, acetone, ethanol, DMF, dioxane, and polyethylene glycol (MW 400) (PEG400)] were obtained from VWR International. Griseofulvin was obtained from Sigma Aldrich. Polystyrene markers for solute rejection evaluation were purchased from Agilent Technologies, U.K. All the chemicals were used as received without any further purification. 2.2. Griseofulvin Solubility Testing. The solubility of griseofulvin was determined using a test tube reaction carousel (Radleys, U.K.) placed on a heating/stirring plate to regulate temperature and mixing. Test tubes were filled with 10 mL of ethanol or acetone, and then an excess of griseofulvin was added. The test tubes were left under continuous stirring at a fixed temperature of 25 °C overnight, in order to ensure that saturation conditions were reached. If all of the solute dissolved, extra was added to ensure that the solution had reached saturation. The concentrations of the saturated solutions were analyzed using a Shimadzu UV-1800 UV−vis spectrophotometer. Samples of solution were taken from the test tubes and analyzed after appropriate dilution. An indicative value for the nucleation concentration of griseofulvin in acetone was determined by leaving saturated griseofulvin solutions open to the atmosphere, until the appearance of small crystals could be observed. A sample was then taken from the solution and its concentration analyzed using UV−vis spectrophotometry. 2193

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Å), with a nickel filter, a fixed 10 mm mask, a 0.04 rad Soller slit, and divergence and antiscatter slits of 1/4° and 1/2°, respectively. The data were collected over the 5−50° angular range in 2θ in continuous scan mode using a step size of 0.05° and a step time of 2 s. XRPD patterns were compared to references in the literature34,35 to check for polymorphic changes in the crystal structure. Crystal size distributions were assessed via refractive light scattering using a Malvern Mastersizer. Pictures of the crystals were taken using an optical microscope and SEM. For the SEM images, the samples were sputtered with chromium under an argon atmosphere using an Emitech K575X peltier in order to render the samples conductive. The microscopic analyses were performed at 5 kV in a high-resolution LEO1525 Karl Zeiss SEM. 2.6. Modeling Concentration Polarization. Concentration polarization occurs because, even in a well-mixed system, there is a layer of stagnant liquid near the membrane surface. Solvent can pass through the membrane, but the concentration of the retained solutes increases in the boundary layer. The speed at which the solute diffuses back to the bulk depends on the concentration at the membrane surface and the diffusivity of the molecule. It has been shown previously that the concentration polarization in OSN systems can be greatly affected by the system flux.36 Equation 3 shows how the concentration at the membrane surface, CM [mol·m−3], can be estimated. The concentration at the membrane surface is dependent on CR (the bulk retentate concentration), CP (the concentration in the permeate solution [mol·m−3]), J (the flux through the membrane [L· m−2·h−1]), and k, the mass transfer coefficient in the system [m·s−1]. If the flux J is increased, but the mass transfer coefficient remains the same, the effect of concentration polarization is also increased. Equation 3 is derived by rearranging the simplified film theory equation,37 which describes the mass transfer in the region of liquid adjacent to the membrane surface. It was assumed that the concentration polarization establishes very quickly,38 which will allow for a quasi-steady-state approximation.

2.3. Membrane Preparation. Polyimide P84 membranes were produced via wet phase inversion. A range of cross-linked and noncross-linked membranes were prepared using dope solutions with ranging ratios of DMF and dioxane. These membranes ranged from high flux membranes with more open permeation pathways (high molecular weight cutoff, MWCO) to low flux membranes with narrower permeation pathways (low MWCO). Dope solutions were prepared by dissolving 24 wt % of polymer in DMF/1,4-dioxane solvent/co-solvent. The polymer was dissolved in the solvent/cosolvent mixture under continuous stirring in a sealed container to ensure that no moisture was absorbed by the dope solution. The dope solutions were cast onto a polypropylene nonwoven backing material using a casting knife (Elcometer 3700) set to a thickness of 250 μm. The polyimide was then precipitated from solution via immersion in water. The membranes were further placed in isopropanol (IPA) to remove water from the polymer matrix. Some of the membranes were cross-linked using hexamethylenediamine (HDA). The cross-linked membranes were submerged in solutions of HDA in IPA (30 g L−1) for 20 h. After cross-linking, the membranes were washed with IPA three times to remove excess cross-linking agent. More details of the fabrication of solvent resistant P84 nanofiltration membranes can be found in the work by See-Toh et al.32,33 2.4. Membrane Testing and Crystallization. To investigate OSN crystallization, different membranes were used at the same applied pressure of 15 bar. Griseofulvin solutions (100 mL) in acetone with concentrations of 20 g L−1 were concentrated in a dead-end filtration setup (see Figure 1) until the solvent flux had reduced to a negligible level. The solutions were continuously stirred using a magnetic stirrer bar and a Bibby Stuart SB161 magnetic stirrer plate, set at a speed setting of 2. Each membrane was tested twice to verify the reproducibility of the OSN crystallization process. The resulting permeate, retentate, and crystals were recovered and analyzed to calculate the crystal yield, and the membrane rejection. The solute concentrations in the permeate and retentate were determined using UV−vis spectrophotometric analysis. The rejection of each membrane was calculated using eq 1. Any crystals that formed were dried and weighed to assess the yield of griseofulvin

⎛ C ⎞ Rejection = R j = ⎜1 − P ⎟ ·100 = [%] CR ⎠ ⎝

C M = C R e J / k + C P(1 − e J / k )

If the solution flux is high enough, then the concentration at the membrane surface can even become sufficiently high to induce crystallization. This is illustrated in Figure 2. If the concentration at the membrane surface differs greatly from the bulk solution concentration, the nucleation and crystal growth may be altered, changing the types of crystals produced in the system.

(1)

where Rj is the observed rejection of the membrane and CP and CR are the concentrations [g·L−1] in the permeate and retentate, respectively. The pure solvent flux and solution flux for each membrane were recorded. The pure solvent flux was determined, using eq 2, by recording the time it took for 100 mL of pure acetone to pass through the membrane. The flux of the griseofulvin solution was recorded periodically throughout the filtration to determine the change in flux as the concentration increased in the retentate. The flux of the griseofulvin solution was also calculated from eq 2

Flux = J =

V = [L·m−2 ·h−1] At

(3)

(2)

where J is flux, V is the volume of solution that passes through the membrane [L], A is the membrane area [m2], and t is the time [h] taken for the volume, V, to pass through the membrane. The effect of concentration polarization on griseofulvin crystallization was determined using a single membrane at a range of different pressures, in order to alter the flux through the membrane. This work was also carried out in a dead-end filtration setup. Griseofulvin solutions (100 mL) with an initial concentration of 25 g L−1 in acetone were concentrated using OSN membranes at 6, 12, and 24 bar until the solvent flux was not measurable or 75 mL of the solution had passed through the membrane, which ever occurred first. The crystallization processes were carried out in a room with an average temperature of 20 ± 1 °C. 2.5. Crystal Analysis. X-ray powder diffraction (XRPD) was used to analyze the griseofulvin crystal structures. The X-ray powder diffraction patterns were acquired at room temperature on a PANalytical X’Pert Pro diffractometer using Cu Kα radiation (1.541

Figure 2. Schematic representation of the concentration polarization effect at different membrane fluxes. The purple line shows that the bulk concentration of both systems is the same. The blue curve represents the concentration profile of a low flux system, where the solute concentration at the membrane surface remains below the saturation concentration. The red curve represents the concentration profile of a high flux system; the effect of concentration polarization is large enough to increase the concentration of solutes at the membrane surface above the nucleation concentration. At this concentration, spontaneous crystallization of the solute from the solution can occur. 2194

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Table 1. Solubilities of Griseofulvin at 25 °C in Acetone and Ethanol compound

solvent

experimental solubility (g·L−1)/(mol·L−1)

literature values (g·L−1)

griseofulvin

acetone ethanol

35/∼0.100 5/∼0.014

4143 640

Table 2. Flux, Rejection, and Yield Data for OSN Crystallization of Griseofulvin at 15 bar membrane

DMF:dioxane ratio

cross-linked

A B C D

1:1 1:2 1:1 1:2

no no yes yes

average solution flux (L m−2 h−1) 131 77 29 8

± ± ± ±

15 3 3 1

rejection (%) 88 97 94 99

± ± ± ±

0 0 6 0

crystal yield (%) 8 36 38 43

± ± ± ±

0 10 6 10

The crystal yield for the lower flux OSN crystallization processes (using membranes B, C, and D) is an order of magnitude higher than the high flux OSN crystallization process (using membrane A). The low flux membranes typically had higher rejections, and this contributes to the difference in yields as griseofulvin material was lost to the permeated solvent in high flux membranes with only 88% rejection. It was observed that different crystals were produced by the low flux and high flux processes; images of these crystals can be found in Figure 3. Large crystals typically > 1 mm in size were produced during the high flux process, whereas, for the low flux processes, the crystals were much smaller.

All parameters in eq 3 can be easily determined from experimental crystallization data except for k (the mass transfer coefficient). The mass transfer coefficient of the system was determined experimentally using the methodology suggested by Peeva et al.36

3. RESULTS AND DISCUSSION 3.1. Compound and Solvent Selection. The first consideration in selecting a system for application of OSN crystallization is to select a compound large enough to be retained by the membrane. The pharmaceutical compound griseofulvin has a molecular weight of 353 g mol−139 and thus can be readily retained by a number of nanofiltration membranes. The crystallization of griseofulvin has been studied in various papers. 40,41 The crystallization behavior of amorphous griseofulvin has also been studied in relation to surface-enhanced versus bulk crystallization rates,42 and it has been shown that the rate of surface crystallization far exceeds the bulk crystallization rate. Another important consideration for each system was the solubility of the compound in the chosen solvent. If the solubility of the compound is too high, the effect of osmotic pressure would inhibit solvent flux before crystallization could occur. It would be advantageous for the solubility not to be too low, as there is a restriction on the volume of solution in the dead-end cell, and at low concentration, only a small amount of crystals can be formed, complicating the analysis. The solubility of griseofulvin was tested in organic solvents, acetone and ethanol, in order to select a suitable system for OSN crystallization. The solubility results presented in Table 1 reveal that griseofulvin has a low solubility in ethanol, and this is in accordance with the value found in the literature.40 This low solubility would restrict OSN crystallization tests to low concentration ranges. The concentration of griseofulvin in acetone is an order of magnitude higher than that in ethanol; this is suitable to test OSN crystallization in a high concentration solution (yielding a reasonable amount of crystals), while being low enough to concentrate the solution above the saturation point using membranes, without an excessive increase in osmotic pressure. 3.2. OSN Crystallization Yields and Rejections. The polyimide OSN membranes, prepared by varying solvent/cosolvent ratios to alter the molecular weight cutoff, were used for the first set of griseofulvin crystallization experiments. All tests were conducted at 15 bar. The flux, rejection, and yield data for these membranes can be found in Table 2. The flux through the membranes differed greatly depending on the DMF/dioxane ratio and the addition of HDA cross-linking agent as expected.32,33

Figure 3. Optical microscope images of griseofulvin crystals formed by (A) membrane A, (B) membrane B, (C) membrane C, and (D) membrane D.

The large crystals produced by the high flux systems (membrane A) are much larger than the original griseofulvin crystals and the crystals from low flux systems, quite flat, and with clearly defined faces and edges. The griseofulvin crystals produced in the low flux systems (membranes B, C, and D) are smaller and clump together in clusters. The shape of these crystals is less clearly defined. Previous studies performed on the polyimide P84 nanofiltration membranes44 suggest that, the higher the membrane flux (lower dioxane content in the dope solution), the higher is the membrane roughness. In other words, membrane A has higher roughness than membrane B, which coincides with the formation of the larger crystals. Thus, the authors originally believed that the membrane topology may be a dominant factor for the formation of crystals in OSN 2195

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crystallization. However, as will be shown in the next section, it appeared that the transmembrane flux was far more important for the crystal structure than the membrane surface topography. 3.3. Effect of Solvent Flux on Crystal Structure. To evaluate the effect of the membrane surface on the structure of the griseofulvin crystals, a technique similar to that used by Diao et al. to test the effect of polymer surfaces on crystal nucleation30 was applied. Saturated solutions of griseofulvin, containing pieces of membrane A and pieces of membrane B, were left to evaporate until spontaneous nucleation occurred. Samples of the crystals were taken from the bulk solution and from the membrane surface. Figure 4 shows microscope images

Table 3. Applied Pressure and Acetone Flux through the Polyimide OSN Membrane B applied pressure (bar)

average process flux (L m−2 h−1)

24 12 6

91 43 17

Figure 5. SEM images of (A) crystals obtained at 24 bar, (B) crystals obtained at 12 bar, (C) crystals obtained at 6 bar, and (D) original griseofulvin crystals (Note: image A is obtained at 100× magnification, while images B, C, and D were obtained at 1800× magnification). Figure 4. Optical microscope images of griseofulvin crystals formed by evaporation (A) taken from the bulk solution (membrane A), (B) taken from the surface of membrane A, (C) taken from the bulk solution (membrane B), and (D) taken from the surface of membrane B.

Particle size distributions for the griseofulvin crystals formed at different fluxes can be found in Figure 6. The crystals formed

of griseofulvin crystals obtained via this technique. The images show that the crystal size and shape for both the bulk solution and membrane surface (membranes A and B) are the same, and different from those formed via OSN crystallization by membrane A. Also, the crystals formed by evaporation have the shape of the small crystals formed by the lower flux systems. This is also confirmed with XRPD analysis (see Figure 7). As such, it can be seen that the presence of the membrane surface alone is not sufficient to induce formation of the large crystal type produced via OSN crystallization using membrane A. To further elucidate the effect of solvent flux on crystal structure, an un-cross-linked P84 membrane (membrane B) was used at 24, 12, and 6 bar to crystallize griseofulvin solutions. The higher the applied system pressure, the higher the solvent flux through the membrane is, while by using the same membrane at different pressures/fluxes, the effect of the membrane surface on the crystal structure will be eliminated. The applied pressures and associated average process fluxes can be found in Table 3. Figure 5 shows SEM images of the crystals formed at high flux (24 bar) and low flux (6 and 12 bar) and the original griseofulvin crystals. Here, the shapes of the crystals can be clearly seen. The original crystals (D), as well as the crystals formed at lower flux (B and C), are mostly octahedral in shape. The crystals formed at high flux (A) have large flat surfaces, in a multitude of shapes.

Figure 6. Particle size distribution of griseofulvin crystals formed via OSN crystallization at 6 bar (blue, dotted line), 12 bar (red, solid line), and 24 bar (black, dashed line).

at the two lower pressures have similar crystal size distributions, whereas the crystals formed at the highest flux have a clearly distinct crystal size distribution of larger crystals. Interestingly, the crystals formed at 24 bar are on average over 16 times bigger than the other crystals, which have very similar median crystal sizes (∼422 mm vs ∼25 mm).The second smaller peak observed in the 6 and 12 bar samples (Figure 6) could be either an artifact from crystal agglomeration, a result of a secondary 2196

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therefore, the lowest mass transfer coefficient, 8.3 × 10−5 m·s−1, was used to calculate the concentration of griseofulvin at the membrane surface. The flux of the griseofulvin solutions was measured for each applied pressure. As could be expected in a batch filtration, flux decline was observed as the concentration of griseofulvin in the solutions increased. The higher the applied pressure, the larger the decline in flux. The flux decline over time can be seen in Figure 8. The measured flux is compared to a calculated flux,

nucleation in the bulk phase, or an evidence of surface crystallization at a smaller scale for the low flux systems. Figure 7 shows the XRPD patterns for the crystals produced under different flux conditions. The XRPD pattern of the

Figure 7. XRPD data for griseofulvin crystals formed via OSN crystallization at 24 bar (a), 12 bar (b), and 6 bar (c); griseofulvin crystals formed via evaporation found in the bulk solution (d) and at the membrane surface (e); and the originally supplied griseofulvin crystals (f). Figure 8. Experimental flux profiles of griseofulvin concentration and crystallization process over time compared to the predicted flux profiles of the membranes calculated taking into account only the osmotic pressure effect (note that the osmotic pressure was calculated assuming ideal solution and without considering concentration changes due to crystallization).

original crystals is very similar to those found in the literature,34,35 with its largest peaks coming at 2θ angles of 10.8, 13.2, 14.6, and 16.5°. The crystals produced at low flux (6 and 12 bar) also follow this pattern, with the largest peaks for these crystals coming at 16.5°. Only the crystal pattern for the crystals produced at 24 bar deviates from this fixed pattern. The peak at 13.2° is very small, and the peak at 16.5° (previously, the largest peak for all XRPD patterns from the other crystals) has been greatly reduced in size. Correspondingly, the peak at 10.8 has grown to become the largest peak, whereas the second largest peak on the XRPD pattern comes at 21.7°. The XRPD pattern for the crystals produced at 24 bar represents a previously unreported pattern for griseofulvin crystals. Though there are no examples of polymorphism of griseofulvin in the literature, the XRPD results suggest that the crystal structure of this compound can be changed by varying the process conditions. 3.4. Effect of Concentration Polarization. We have demonstrated that the solvent flux through a membrane influences both the structure and the size of griseofulvin crystals formed via OSN crystallization. We speculate that this occurs due to the effect of concentration polarization in the OSN crystallization processes. In high flux systems, the concentration of solute at the membrane surface can become much higher than that in the bulk solution, leading to supersaturation and crystallization only in the boundary layer by the membrane surface. The effect of concentration polarization was modeled using eq 3. The magnetic stirrer used had speed settings between 0 and 9 (corresponding to a stirring speed range of 0−1500 rpm, according to the manufacturer). The mass transfer coefficient for the system was calculated to range from 8.3 × 10−5 to 3.3 × 10−4 m·s−1 for speed settings 2−5. Below speed setting 2, the stirrer bar did not spin, whereas, above speed setting 5, the stirring was erratic and irregular. For the crystallization experiments, the magnetic stirrer was set at speed setting 2;

which was found based on the effect of the applied pressure across the membrane and the increasing osmotic pressure at the membrane surface due to the effect of concentration polarization. The calculated flux was found using eq 4 J = B(ΔP − C R e J / k R jRT )

(4)

where B is the permeability coefficient of the membrane in acetone, found by measuring the flux of pure solvent through the membrane [3.18 × 10−11 L·m−2·h−1·bar−1]. ΔP is the applied pressure on the membrane [Pa], C R is the concentration of the retentate [mol·L−1], Rj is the rejection of the solute, R is the universal gas constant [J·mol−1·K−1], and T is temperature [K]. Equation 4 can be solved using iteration. During the crystallization experiments, the permeate concentration was periodically measured and the permeate volume was recorded. Using this data and a griseofulvin mass balance, the retentate concentrations were estimated. The measured fluxes and estimated retentate concentrations were then used, along with the calculated mass transfer coefficient, to calculate the concentration of griseofulvin at the membrane surface by substituting the experimental values into eq 3. Figure 9 shows the change in concentration in the bulk retentate solution (CR) and at the membrane surface over time. The saturation and nucleation concentrations of griseofulvin in acetone were determined experimentally (see the Experimental Section). Note that the concentrations were calculated without considering concentration changes due to crystallization, and the values above nucleation concentration are only hypothetical and for illustrative purposes. Figure 9 suggests that the calculated griseofulvin concentration at the membrane surface 2197

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on the membrane surface, forming a cake). Concentration polarization (often referred to as the concentration polarization modulus = exp(J/k)46) plays an important role in this process. At high values of concentration polarization, crystal formation occurs more through surface crystallization. For example, crystal formation in an unstirred batch filtration device mainly occurs through surface crystallization. Low values of concentration polarization (e.g., intensive mixing or high cross-flow rate) are a favorable condition for bulk crystallization. In many cases, these two phenomena coexist.46 Lee et al.45,46 also observed a distinctive difference between the crystals formed under different concentration polarization moduli. With an unstirred batch cell and cross-flow module under low flow velocity, they observed clumps of needle-shaped CaSO4 crystals grown in a radial direction, which represents the typical surface crystallization. At high cross-flow velocity, the membrane surface was covered with the deposited crystal particles (cake layer) and no crystals of the radial growth type were observed. Other studies also advocate formation of a different crystal polymorph as a result of homogeneous or heterogeneous crystallization in membrane processes.47 Our calculations and the experimental data suggest that, for the high flux experiment (24 bar), surface crystallization was the preferential mechanism of crystal formation, whereas, for the lower flux experiments (6 and 12 bar), probably both mechanisms coexisted, but the preferential crystallization pathway was the bulk crystallization. The size distribution of the crystals (Figure 6) also confirms this hypothesis. Whereas, at 6 and 12 bar, two different sized crystals are observed, the smaller ones being a much larger fraction, at 24 bar only the larger crystals were formed. As expected from the calculations, more large sized crystals were formed during the 12 bar experiment (bigger contribution of the surface crystallization) than in the 6 bar experimental run (Figure 6). The flux variation in our system is also in agreement with the data reported in the literature. During the nanofiltration of CaSO4 solution in an unstirred batch nanofiltration cell, Lee et al.45,46 observed rapid and continuous flux decline, even though the supersaturation degree and the turbidity of the bulk phase were quite low throughout the nanofiltration, suggesting that no significant bulk crystallization occurred in the bulk phase, but fast crystallization occurred at the membrane surface, rapidly blocking it. Because of the combined effects of concentration polarization and crystallization, it is difficult to estimate the actual concentration at the membrane surface. For illustration only, we calculated the expected flux decline due to the osmotic pressure buildup at the membrane surface (see eq 4), neglecting the concentration change due to crystallization. As can be seen in Figure 8, the actual flux decline is much more severe than the decline expected solely from the increase in osmotic pressure. The effect is clearly more pronounced at the 24 bar experiment, again suggesting occurrence of a rapid surface crystallization. We admit that crystallization is a very complex process with many factors affecting it. Complete understanding of the observed phenomenon is beyond the scope of this paper. Our aim was to draw the attention of the crystallization scientific community to this very interesting and largely unexplored methodology that may lead to rapid discoveries in the area of crystal formation and morphology.

Figure 9. Calculated griseofulvin concentration in the bulk retentate solution (CR, calculated from the mass balance) and at the membrane surface (CM, calculated from eq 3) throughout the concentration and crystallization of griseofulvin process, over time (note that the concentrations were calculated without considering concentration changes due to crystallization, and the values above nucleation concentration are only hypothetical and for illustrative purposes).

is above the nucleation concentration of griseofulvin at the start of the filtration at a pressure of 24 bar. This means that crystallization can occur instantly at the membrane surface, before the bulk solution concentration is high enough to sustain crystal growth. This difference between the concentrations at the membrane surface and the bulk solution, along with the influence of the polymer surface on nucleation, could have led to the difference in structure of the griseofulvin crystals produced at high flux. The unusual surface concentration profile of the high flux crystallization process is due to the rapid rate of flux decline at the beginning and the end of the process, probably caused by the rapid nucleation and growth of crystals blocking solvent flux through the membrane. The solution concentration calculated at the membrane surface for the 24 bar experiment would suggest rapid and spontaneous crystal nucleation and growth. This would usually lead to a formation of small crystals; however, the large crystals observed with the high flux system could be attributed to a combined effect of the concentration polarization and the membrane surface on the crystallization kinetics. To eliminate the effect of crystallization time (duration of the OSN crystallization), we repeated the experiment at 12 bar starting from a concentration of 33 g L−1 (close to the saturation concentration) and ran the filtration for 45 min (the same duration as the 24 bar experiment). Using this initial concentration at 12 bar, the solution would become saturated soon after the beginning of the filtration. The crystals formed during this experiment were identical to the crystals formed over the longer time periods. This confirms our conclusion that the concentration polarization, and not the crystallization time, is predominantly responsible for the unusual crystal morphology. Our results are in agreement with the crystal formation mechanisms in membrane processes proposed in the literature. According to Lee at al.,45 two pathways for crystallization in membrane processes have been identified: surface (heterogeneous) crystallization (occurring via lateral growth of the crystals on the membrane) and bulk (homogeneous) crystallization (crystals formed in the bulk solution sediment 2198

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4. CONCLUSIONS This work demonstrated successful concentration and crystallization of the pharmaceutical compound griseofulvin from acetone solutions via OSN. High griseofulvin rejections obtained indicate that OSN membranes could be used for product recovery from mother liquor streams exiting traditional crystallization processes. Membrane fouling limits the application of OSN crystallization in a single vessel as an alternative for the production of crystalline pharmaceutical compounds; however, it is a valuable tool for rapid discoveries in the areas of crystal formation and morphology. By controlling the level of concentration polarization in an OSN crystallization system, thus differentiating the concentration of product in the bulk and at the membrane surface, the structure of the crystals produced can be altered. Large crystals with a new XRPD pattern were formed by OSN crystallization processes with high fluxes. By fine-tuning crystallization conditions via flux, rejection, and mass-transfer, the nucleation mechanism can be altered toward the production of different crystal morphologies. The specific interactions between the solute molecules and the membrane surface could also lead to the formation and discovery of novel crystal polymorphs.

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AUTHOR INFORMATION

Corresponding Author

*Tel: +44 (0)20 7594 5582. E-mail: [email protected]. uk. Author Contributions

The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors would like to acknowledge financial support provided by the EPSRC, UK - DTA awards EP/P504953/1; EP/P505550/1; Platform Grant award EP/J014974/1 and the financial support from the Pharmacat Consortium.

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