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Demonstrating the Influence of Solvent Choice and Crystallization Conditions on Phenacetin Crystal Habit and Particle Size Distribution Denise M. Croker,*,† Dawn M. Kelly,‡ Danielle E. Horgan,‡ B. Kieran Hodnett,† Simon E. Lawrence,‡ Humphrey A. Moynihan,‡ and Åke C. Rasmuson† †

Synthesis & Solid State Pharmaceutical Centre (SSPC) and Materials and Surface Science Institute, Department of Chemical and Environmental Sciences, University of Limerick, Limerick, Ireland ‡ Synthesis & Solid State Pharmaceutical Centre (SSPC) and Analytical and Biological Chemistry Research Facility, Department of Chemistry, University College Cork, Cork, Ireland S Supporting Information *

ABSTRACT: Phenacetin was used as a model pharmaceutical compound to investigate the impact of solvent choice and crystallization conditions on the crystal habit and size distribution of the final crystallized product. The crystal habit of phenacetin was explored using crash-cooling crystallization (kinetically controlled) and slow evaporative crystallization (thermodynamically controlled) in a wide range of organic solvents. In general, a variety of needle-type shapes (needles, rods, or blades) were recovered from fast-cooling crystallizations, in contrast to hexagonal blocks obtained from slow evaporative crystallizations. The solubility of phenacetin was measured in five solvents from 10−70 °C to allow for the design of larger-scale crystallization experiments. Supersaturation and the nucleation temperature were independently controlled in isothermal desupersaturation experiments to investigate the impact of each on crystal habit and size. The crystal size (needle cross-sectional area) decreased with increasing supersaturation because of higher nucleation rates at higher supersaturation, and elongated needles were recovered. Increasing the nucleation temperature resulted in the production of larger crystals with decreased needle aspect ratios. Antisolvent phenacetin crystallizations were developed for three solvent/antisolvent systems using four different antisolvent addition rates to simultaneously probe the crystal habit and size of the final product. In general, increasing the antisolvent addition rate, associated with increased rate of generation of supersaturation, resulted in the production of shorter needle crystals.

1.0. INTRODUCTION Crystallization from solution is widely used for the isolation and purification of active pharmaceutical ingredients (APIs) in the final stages of manufacture.1 The operating conditions of the crystallization process determine the physical properties of the solid product, such as crystal purity, shape, and size distribution.2 These properties in turn affect the efficiency and duration of downstream operations such as filtering, drying, and drug product formulation, the batch-to-batch uniformity and product consistency, and indeed the drug efficacy itself. Controlled crystallization, where a defined product is produced in a reproducible manner, would result in improved crystal product quality, shorter process times, and reduction or elimination of compromised batches, ultimately achieving lower manufacturing costs and faster time to market. Crystallization control is achievable only by understanding the phenomena of crystal nucleation and growth. In relation to theory, the size distribution in a crystal product population is governed by the number of crystals sharing the crystallization mass. The number of crystals present is controlled by the nucleation rate.3 The nucleation rate depends primarily on supersaturation, temperature, fluid dynamics, and the chemical environment. The crystallization mass depends on the solution concentration and the solubility of the material to be crystallized under the crystallization conditions. The crystal shape of a given product is determined by the relative growth rates of the different faces.3a The specific growth rate of a face depends on the crystal structure, supersaturation, temperature, © XXXX American Chemical Society

and chemical environment. Thus, product crystal size and shape are impacted by kinetics. The general mechanisms controlling the product particle size distribution (PSD) and crystal shape are well-understood; however, they cannot be turned into quantitative terms for a specific case without corresponding experimental data. Nucleation and growth rates cannot be predicted, but it is known that these rates increase with increasing supersaturation and increasing temperature. The solvent plays an important role in the crystallization process, as the interaction between solute and solvent molecules (relative to solvent−solvent and/or solute−solute interactions) can have an impact on the nucleation and growth kinetics, including the metastable zone width, and hence on the product PSD and final crystal product shape4 as well as on other product characteristics such as the formation and properties of agglomerates.5 Solvent screening is commonly reported in the search for different polymorphs.6 Supersaturation has been demonstrated to have an impact on the habit of crystallized products.7 Boerrigter et al.7a presented three different morphologies of paracetamol at low, medium, and high supersaturation using Monte Carlo simulations. The morphology changes were due to variations in the growth rate as a function of supersaturation. The shape of potassium Special Issue: Polymorphism & Crystallisation 2015 Received: September 24, 2014

A

DOI: 10.1021/op500308x Org. Process Res. Dev. XXXX, XXX, XXX−XXX

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Organic Process Research & Development

crystallographic information file (CIF) PYRAZB219b (Cambridge Structural Database) using Mercury 2.4. The solubility of phenacetin was determined in ethanol, acetonitrile, ethyl acetate, toluene, and water (at 10, 25, 40, 55, and 70 °C) using a gravimetric method. The solvent (30 mL) was placed in a glass tube equipped with a magnetic agitation bar and allowed to equilibrate in a water bath (Grant GR150 with a 38 L bath, equipped with a magnetic stirrer base plate) at the desired temperature for a minimum of 1 h. Solid phenacetin was added to the solvent until it remained in excess in the solution, and the solution was agitated at 400 rpm for 24 h. Agitation was stopped and the solid contents of the glass vial were allowed to settle. A sample of the clear supernatant was withdrawn from the vial using a syringe, and ∼1 mL was transferred to a preweighed sample tube (MV) using a 0.45 μm filter. The sample tube was sealed and weighed (MSOL) and then allowed to evaporate to dryness at room temperature. Once visibly dry, the sample tube was placed in a vacuum oven at 40 °C overnight to ensure complete dryness. The dry vial was sealed and weighed (MD). The solubility (in grams per gram of solvent) was calculated using eq 1:

dihydrogen phosphate particles in cooling crystallizations was shown to depend on supersaturation.7d Long narrow crystals were obtained at lower supersaturation and short broad crystals at higher supersaturation. A change in the habit of polar alanine crystals with increasing supersaturation was also demonstrated.7c Specific effects of temperature on crystal shape have not been reported. Antisolvent crystallizations are widely used in pharmaceutical manufacturing, often in conjunction with cooling, to provide optimum product yields. The use of an antisolvent offers additional scope for control of morphology and PSD through selection of the antisolvent, addition rate, agitation, and mixing. Antisolvent addition rates have been used to influence polymorphism and can be modulated by feedback control.8 The objectives of this work are to demonstrate the influence of different crystallization conditions on the final habit and size of a crystallized product using a model system. Phenacetin (Figure 1), an analgesic compound that is a structural analogue

solubility =

Figure 1. Chemical structure of phenacetin.

MD − MV MSOL − MD

(1)

2.2. Crystallization by Crash Cooling. The influence of the solvent on the crystal habit was explored using crashcooling and slow evaporative experiments. For the crashcooling experiments, 15 solvents were selected and divided into four groups on the basis of their boiling points (see Table 2). A saturation temperature was selected for each group, so as to be approximately 10 °C below the boiling point of the solvent, insofar as this was possible. The solvent (10 g) was placed in a 20 mL glass vial with a small magnetic stir bar and equilibrated at 5 °C below the saturation temperature. Solid phenacetin was added to the solvent until the point at which dissolution became sluggish. The total mass of phenacetin added to the solution was recorded (Table 2). The solution was heated to the saturation temperature and allowed to equilibrate for 30 min until the it became completely clear. The vial containing the clear solution was transferred to a second water bath held at 5 °C and allowed to nucleate. A slight variation of this method was used with diethyl ether and n-pentane because the added phenacetin did not fully dissolve even with extended equilibration time. In this case, the excess solid was allowed to settle in the vial, and the clear solution was decanted directly into a second vial at 5 °C. All of the solutions were filtered soon after nucleation. The recovered solids were dried in a vacuum oven at 55 °C overnight prior to analysis. 2.3. Crystallization by Evaporation. Slow evaporative crystallization was attempted in a smaller selection of the above solvents: ethanol, acetone, acetonitrile, methanol, 1-butanol, dichloromethane, and toluene. This method involved adding phenacetin to about 5 mL of the solvent in a Petri dish at room temperature until dissolution became sluggish. The solution was covered with Parafilm and allowed to stand in a fume hood overnight to ensure dissolution. A small number of holes were subsequently made in the Parafilm, and the solvent was allowed to evaporate for as long as necessary (the maximum evaporation time was 8 days, in toluene) until crystals could be observed. The crystals were removed from the remaining solution, allowed to air-dry, and analyzed using SEM.

of paracetemol, is used as a model compound for this study as it is widely available and inexpensive, has no known polymorphs, and is known to crystallize as needles from ethanol.9 Crystallization by crash cooling, evaporation, isothermal desupersaturation and antisolvent addition are investigated. This model study is intended to exemplify the use of common crystallization techniques, illustrate the impact of crystallization conditions on a crystallized product, rationalize crystallization behavior from first principles, and act as a source of information in current literature resources.

2.0. EXPERIMENTAL SECTION All chemicals purchased were reagent grade (Sigma-Aldrich) and were used without further purification. Distilled water was used in all of the experiments. Optical microscopy was carried out using a Nikon Eclipse 50i POL polarizing microscope equipped with a Nikon DS-Fi1 CCD camera. Scanning electron microscopy (SEM) was conducted using a JEOL Carryscope 5700 scanning electron microscope; samples were sputtercoated with gold prior to SEM analysis. Powder X-ray diffraction (XRD) measurements were completed using a Panalytical X’Pert MPD PRO powder X-ray diffractometer. Samples were lightly ground and pressed on a zero-background plate prior to analysis. Particle sizing was carried out on a Horiba particle size distribution analyzer, model LA-920. Solids (∼1 g) were suspended in water containing sodium dodecyl sulfate (SDS) surfactant and analysed at circulation speed 3 without sonication. Sonication was avoided, as it is known to damage needle-shaped crystals. Sizing was carried out in duplicate, and the results are presented on a volume-weighted basis. In this work, supersaturation is defined as the concentration of phenacetin in solution divided by the solubility of phenacetin in that solvent at that temperature. 2.1. Crystal Habit Determination and Solubility Measurement. The Bravais−Friedel−Donnay−Harker (BFDH) morphology of phenacetin was generated from B


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Figure 2. BDFH morphology calculated for phenacetin (generated from PYRAZB219b).

and dried overnight in a vacuum oven at 50 °C. The crystal habit of the dry solids was analyzed using SEM, and the particle size distribution was measured using laser diffraction. 2.5. Crystallization by Antisolvent Addition. Antisolvent crystallizations were carried out using three solvent systems: ethanol/water, ethyl acetate/hexane, and toluene/ hexane. The three systems can be considered as polar (ethanol/ water), nonpolar (toluene/hexane) and of intermediate polarity (ethyl acetate/hexane), allowing the effect of solvent polarity on the phenacetin crystal morphology in antisolvent crystallization to be assessed. Hexane was used here as a model nonpolar solvent; it is acknowledged that hexane is not a desirable solvent to work with on a large scale for safety and environmental considerations. Investigation of different antisolvent addition rates allowed the effect of the rate of supersaturation generation by antisolvent addition to be examined. The experiments were conducted using a 1 L HEL Autolab jacketed, unbaffled glass reaction vessel with an inner diameter of 13 cm containing Huber P20 silicone thermofluid in the jacket, controlled by a Huber Unistat 815 thermoregulator. Agitation was via a four-pitched-blade impeller agitator with a diameter of 7 cm and a vertical clearance of 2 cm from the bottom of the vessel. The agitator speed was held at 150 rpm with an overhead motor, giving a tip speed of 0.6 m/s. The temperature of the contents of the vessel was measured by a PTFE PT100 thermocouple. Antisolvent was added using a ProMinent gamma/L pump. The point of addition was above the surface of the fluids at a position 3.5 cm from the shaft of the stirrer and 3.0 cm from the vessel wall. Heating and cooling, agitation, and addition of antisolvent were programmed using HEL WinISO software, version 2.3.40. Phenacetin was added to 500 mL of solvent held at 40 °C and agitated at 150 rpm to give a saturated solution in each solvent. The solutions were heated to 50 °C, held for 30 min, then cooled to 40 °C at a constant rate of 0.5 °C min−1, and held for 30 min. Antisolvent was added at a constant rate (1, 2, 4, 5, or 8 g min−1) at 40 °C until an volume of antisolvent equal to the solvent volume was obtained. When crystallization was complete, the slurry was filtered and the recovered solids were washed with 50 mL of the 1:1 solvent/antisolvent mixture and dried overnight at room temperature under vacuum.

2.4. Crystallization by Isothermal Desupersaturation. Two types of isothermal desupersaturation experiments were performed: isothermal desupersaturation at constant supersaturation and, independently, constant nucleation temperature. Isothermal desupersaturation crystallizations were conducted in a 250 mL jacketed glass reaction vessel (flatbottomed, diameter 10 cm, with a 4.5 cm diameter fourpitched-blade impeller agitator, 250 rpm tip speed = 0.5 m/s, clearance = 1−1.5 cm from the bottom of the vessel) with temperature control provided by a PT100 probe and a Lauda E300 thermostat and were recorded using Wintherm Plus software. Solution concentration was monitored in situ with an infrared reaction probe (Mettler Toledo iC10 React IR). Phenacetin exhibits a number of distinct absorption peaks relative to an ethanol standard spectrum (see the Supporting Information), making this technique very suitable for monitoring the concentration of dissolved phenacetin. In particular, the peak at 1700 cm−1 was used to identify phenacetin in solution as described previously.10 The peak area at this position was used qualitatively as an indicator of phenacetin solution concentration. Peak area to two-point baseline was tracked using Mettler Toledo ICIR 3.0 software. Over a 60 s measurement window, 256 coaveraged scans were collected in the 2000−650 cm−1 region with a resolution of 8 cm−1. Isothermal Desupersaturation at Constant Nucleation Temperature. Three solutions of phenacetin in ethanol were prepared as per Table 3 and heated to 5 °C above their saturation temperature for 30 min. The solutions were cooled at 1 °C min−1 to 30 °C and held at this temperature until nucleation occurred. The objective was to nucleate the three solutions isothermally at three different supersaturation levels. Isothermal Desupersaturation at Constant Supersaturation. Three additional solutions of phenacetin in ethanol were prepared at different concentrations (see Table 4). The solutions were cooled to a temperature corresponding to a supersaturation of 1.5 and allowed to nucleate. The objective here was to bring about nucleation at equal supersaturation but different nucleation temperatures. The aim in both sets of experiments was to have nucleation take place isothermally (at constant temperature) so as to remove the impact of changing temperature from the observed results. The solutions were allowed to desupersaturate to the point at which the solution concentration, as indicated by the iC10 IR probe, reached a plateau. The solids were isolated using a 0.45 μm filter, washed with ∼30 mL of pure ethanol,

3.0. RESULTS AND DISCUSSION 3.1. Crystal Habit Determination and Solubility Measurement. The BDFH simulations yielded a hexagonal C


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Table 1. Solubilities of phenacetin in ethanol, water, ethyl acetate, acetonitrile, and toluene at 10−70 °C and the calculated van’t Hoff enthalpies of solution in these solvents T (°C)

ethanol

10 25 40 55 70

4.1 × 10−2 7.2 × 10−2 1.34 × 10−1 2.58 × 10−1 5.78 × 10−1

−

33.6

water

ethyl acetate

Solubility (g/g of solvent) 9 × 10−4 1.5 × 10−2 −3 1.1 × 10 2.4 × 10−2 −3 2 × 10 4.5 × 10−2 3 × 10−3 9.2 × 10−2 6 × 10−3 2.2 × 10−1 van’t Hoff Enthalpy of Solution (kJ mol 30.6 34.5

acetonitrile 2.6 4.8 9.8 2.0 4.6 −1

× × × × ×

10−2 10−2 10−2 10−1 10−1

toluene 3.0 3.0 6.0 1.4 3.4

× × × × ×

10−3 10−3 10−3 10−2 10−2

) 37.3

41

Figure 3. (a) Experimentally determined solubilities of phenacetin in the listed solvents at 10−70 °C (283−343 K) and (b) the corresponding van’t Hoff plots for these data.

crystal morphology for phenacetin (Figure 2). The BDFH shape is calculated on the assumption that the growth rate of a particular face is inversely proportional to the corresponding lattice spacing. Accordingly, the shape predicted can be regarded as a simplified representation of the thermodynamic shape in the absence of any interaction with the surroundings. The solubility of phenacetin in each solvent as a function of temperature is presented in Table 1 and Figure 3. A clear solubility hierarchy is evident, with the solubility increasing in the order water < toluene < ethyl acetate < acetonitrile < ethanol; the solubility increased with increasing temperature in all of the solvents. A van’t Hoff plot was constructed using the solubility data in each solvent, allowing the van’t Hoff enthalpy of solution to be calculated from the slope of the linear plot. 3.2. Crystallization by Crash Cooling. There was a large variation in the amount of phenacetin that dissolved in each solvent used for the crash-cooling experiments (Figure 4 and Table 2). The greatest amount of phenacetin dissolved in ethanol at 70 °C, and the solvent hierarchy observed for the solubility measurements in Table 1 and Figure 2 was maintained for those five solvents (ethanol > acetonitrile > ethyl acetate > toluene > water). Interestingly, a greater amount of phenacetin dissolved in the solvents grouped at 70 °C than those grouped at 90 °C, demonstrating that solvent interactions contribute more to the solubility than the temperature does. After crash cooling, solids were recovered from 14 of the 15 solvents; no solids were recovered from n-pentane. In each case, pure monoclinic phenacetin was the only solid product phase; no solvates or polymorphs were formed (as confirmed by XRD analysis; see the Supporting Information). The habit of the product crystals was investigated with SEM (Figure 5). Different observation scales were necessary to most adequately

Figure 4. Mass of phenacetin dissolved in each solvent as a function of saturation temperature. The label for MTBE is omitted as it closely overlaps with methanol.

capture the particle habit in these samples because of wide fluctuations in the size of the recovered particles. In general, the particles had a tendency toward needle-type habit, with a variety of different manifestations observed: genuine needles (i.e., elongated particles with a high aspect ratio (length/ width)) were recovered from ethanol and 1-propanol; rods (more cylindrical needles with reduced aspect ratio) were recovered from acetone and methanol; blades (flattened needles) of varying aspect ratio were recovered from toluene, 1,4-dioxane, methyl tert-butyl ether (MTBE), and acetonitrile; and mixtures of rods, needles, and/or blades were recovered from butanol, 2-propanol, and diethyl ether. Very thin, brittle D


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much larger in size. The larger size is attributed to much slower generation of supersaturation in these experiments, resulting in smaller nucleation events. It is proposed that thermodynamically controlled growth prevails in the evaporative crystallizations, whereas kinetically controlled growth governs the fastcooling crystallizations. 3.4. Crystallization by Isothermal Desupersaturation. 3.4.1. Isothermal Desupersaturation at Constant Nucleation Temperature. In the experiments performed at different initial supersaturations but the same nucleation temperature (Table 3), the least-supersaturated experiment (T34) nucleated 41 min after the 30 °C set point was reached, and nucleation was accompanied by a gradual reduction in the concentration of phenacetin in solution. Figure 7a presents the measured peak area of the phenacetin peak at 1700 cm−1 from the time the 30 °C set point was reached. The normalized peak area (all peak area values were divided by the first measurement at 30 °C) is presented so as to minimize fluctuations between individual experiments. The resulting crystals had a thick rodlike habit, were of millimeter magnitude in their longest dimension (Figure 8), and returned a D90 of 918 μm from particle size analysis (Table 3). At higher initial supersaturation (T38), the desupersaturation was more rapid, and the concentration plateaued within about 15 min (Figure 7a). The resulting crystals were rods with reduced cross-sectional width, resulting in an increased aspect ratio (Figure 8 and Table 3). At the highest initial supersaturation (T42), nucleation occurred before the set point was reached (TNUC = 33 °C), after which a sharp decrease in supersaturation was observed. Subsequent fluctuations in the phenacetin peak area were observed before a plateau was reached, consistent with fluctuations in the temperature. A further reduction in cross-sectional width was observed, which resulted in the recovery of thin needles in this sample. Across all three samples, a decrease in cross-sectional width was apparent with increasing supersaturation. The recoverable crystal yield was calculated for each experiment by subtracting the solubility of phenacetin (MP,eq) from the mass of phenacetin charged to the experiment (MP), as shown in eq 2:

Table 2. Solvent names, boiling points, and types for the solvent screening experiments

solvent

boiling point

solvent type

mass of phenacetin dissolved at the saturation temperature (g/g of solvent)

Boiling Point > 90 °C; Saturation Temperature = 90 °C 1,4-dioxane 101 nonpolar/slightly polar 0.077 1-propanol 97 polar, protic 0.131 1-butanol 97 polar, protic 0.120 toluene 110 nonpolar 0.0027 70 °C < Boiling Point < 90 °C; Saturation Temperature = 70 °C ethyl acetate 77 slightly polar, aprotic 0.142 ethanol 78 polar, protic 0.343 2-propanol 83 polar, protic 0.187 butanone 80 polar, aprotic 0.262 acetonitrile 82 polar, aprotic 0.247 50 °C < Boiling Point < 70 °C; Saturation Temperature = 50 °C acetone 56 polar, aprotic 0.178 methanol 65 polar, protic 0.015 MTBE 55 nonpolar 0.013 30 °C < Boiling Point < 50 °C; Saturation Temperature = 30 °C dichloromethane 40 slightly polar, aprotic 0.055 diethyl ether 35 nonpolar 0.026* n-pentane 36 nonpolar 0.009*

*Solids did not fully dissolve, even with extended equilibration time. Excess solids were allowed to settle and clear solution was decanted directly into a second vial at 5 °C.

plates were isolated from butanone and ethyl acetate, and dichloromethane yielded tabular plates. In general, none of the recovered crystals displayed a habit similar to the calculated BDFH morphology. Besides the approximate nature of the BDFH simulation to capture the thermodynamic habit in the absence of external interactions, there are two major aspects of the fast-cooling experiments that can influence the habit. First, the crystals were grown at high nucleation and growth rates as the supersaturation across all experiments was very high (because of the instantaneous temperature change). The crystal habit is determined by the relative growth rates of the different faces. The face growth rate is strongly dependent on the supersaturation; different faces may have different dependences and grow by different mechanisms, and in fact the growth mechanism can change depending on the supersaturation. Second, the solvent can influence the thermodynamics of the face, i.e., its interfacial energy, as well as the dependence of its growth rate on the supersaturation. 3.3. Crystallization by Evaporation. In the majority of solvents, the slow-evaporation experiments resulted in a residue on the walls of the Petri dish and crystals did not form. In ethanol, acetone, and toluene, crystals were obtained and are presented in Figure 6. Tabular crystals were recovered from acetone and ethanol and long blades from toluene. The crystals produced in acetone and ethanol show significantly different morphology from the crystals recovered from the fast-cooling crystallization in the same solvent. The morphology of the crystals from the slow-evaporation experiments was actually quite similar to the calculated BFDH morphology, which is to be expected as crystals produced at low growth rates are expected to more closely capture the thermodynamic habit. The crystals returned from toluene were relatively similar in habit to those obtained from the fast-cooling crystallization but

recoverable crystal yield = MP − MP,eq

(2)

Particle size analysis returned a decrease in absolute product crystal size with increasing supersaturation, a result of the spherical approximation that accompanies laser diffraction sizing measurements. Relating this back to the actual anisotropic rods/needles in Figure 8, the “decreased particle size” reflects a decrease in average cross-sectional area. Again, the length of the individual crystals was roughly invariant across the three conditions; it was the width of the crystals that was affected. The span, calculated as shown in eq 3, is a measure of the width/broadness of the PSD. An increase in span was observed with increasing supersaturation, indicating greater variance in the size (most likely cross-sectional area) of particles formed at higher supersaturation.

span =

D90 − D10 D50

(3)

A measure of the supersaturation level in each experiment was approximated by using the final peak area as a measure of phenacetin solubility (eq 4): supersaturation ratio = S = E

peak area final peak area

(4)


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Figure 5. SEM images of solids recovered from the fast-cooling experiments. When comparing the images, the reader should note the individual scale bars, which are necessary because of the wide range of sizes observed across the different experiments.

each experiment. As designed, the supersaturation level in T42 was the highest, followed by T38 and T34, with all of the experiments plateauing at one saturated level after crystallization. The size of the crystals produced in an isothermal desupersaturation experiment is a combined result of the

It is acknowledged that the systems are not at true equilibrium at the end of the crystallization, so this measurement is approximate, but it should be sufficiently accurate for this discussion. This relationship holds true only for measurements taken at constant temperature, as was the intention for these experiments. Figure 7b illustrates the supersaturation level in F


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Figure 6. SEM images of crystals recovered from slow evaporation in acetone, ethanol, and toluene.

Table 3. Desupersaturation experiments at constant nucleation temperature (Tnucl = 30 °C): phenacetin solution concentration (C), saturation temperature (TSAT), supersaturation (S), induction time (tIND), crystal yield, and PSD analysis of solids recovered from the experiment PSD analysisb ID

C (g/g)a

TSAT (°C)

S at 30 °C

tIND (min)

yield (g)

D10 (μm)

D50 (μm)

D90 (μm)

span

T34 T38 T42

0.10 0.12 0.15

34 38 42

1.18 1.41 1.65

41 0 −

2.4 5.3 8.7

233 164 109

517 438 343

918 862 799

1.32 1.59 2.01

a In g/g of EtOH, using 150 g of EtOH as a basis. bThe terms D10, D50, and D90 indicate that 10%, 50%, and 90%, respectively, of the crystal population have a size smaller than the value specified. The span is defined in eq 3.

Figure 7. (a) Normalized phenacetin peak area and (b) relative phenacetin supersaturation measured during isothermal desupersaturation crystallization at constant nucleation temperature (30 °C).

Figure 8. Scanning electron micrographs of the solids recovered from crystallization experiments of phenacetin in ethanol at TNUC = 30 °C. Scale bars = 500 μm.

nucleation and growth rates during the experiment.3a As the supersaturation increases, the nucleation rate increases according to classical nucleation theory. The production of a

greater number of nuclei provides a large surface area for crystal growth, by which the desupersaturation becomes faster. Conversely, when the nucleation rate is low, fewer nuclei are G


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Table 4. Desupersaturation experiments at constant supersaturation: phenacetin solution composition (C), crystallization temperatures (saturation temperature, TSAT; nucleation temperature, TNUC), supersaturation (S), crystal yield, and PSD analysis for the product crystals PSD analysis

a

ID

C (g/g)

T26 T40 T64

0.07 0.13 0.39

a

TSAT (°C)

TNUC (°C)

S at TNUC

yield (g)

D10 (μm)

D50 (μm)

D90 (μm)

span

26 40 64

15 30 55

1.5 1.5 1.5

3 4.6 13.4

59 67 120

197 215 388

542 620 813

2.45 2.57 1.79

In g/g of EtOH, on a scale of 100 g of EtOH.

produced, and these nuclei will grow to a large size unless they are removed from the solution. As indicated in Figure 8, the results are in good agreement with this theory, suggesting that a larger number of crystals were produced in experiment T42, which had the largest supersaturation. This figure also illustrates that at constant temperature it is the nucleation rate, and not the amount of material to be crystallized, that defines the overall product size: T42 generated the largest mass of crystallized product but the smallest product crystal size (Table 3). 3.4.2. Isothermal Desupersaturation at Constant Supersaturation. The influence of the nucleation temperature at a constant initial supersaturation ratio of 1.5 was also explored (Table 4). At the lowest temperature (T26), desupersaturation was gradual and the solution concentration reached a steady plateau, as shown in Figure 9. The resulting crystals appeared as a mixture of rods and needles (Figure 10), and PSD analysis indicated a broad size distribution (Table 4).

Desupersaturation was faster in the experiment at a higher nucleation temperature (T40), and the solution concentration also reached a steady plateau (Figure 9). The crystals recovered from the experiment were very similar in appearance to those obtained from experiment T26 (Figure 10) and had a thicker rodlike habit. This was supported by PSD analysis, which indicated a larger D90 for these product crystals than for those obtained from experiment T26. At the highest nucleation temperature (T64), nucleation occurred slightly before the nucleation temperature was reached (56.5 °C), and subsequent temperature fluctuation was reflected in the solution phenacetin concentration before a plateau was reached (Figure 9). The decrease in concentration upon nucleation was very sharp, indicating a high nucleation rate. The crystals recovered from the experiment were much thicker than those seen previously and had a thick rodlike character (Figure 10). These crystals gave the largest particle size dimensions in the PSD analysis (Table 4). It was not possible to plot supersaturation for this series of experiments because the effect of temperature on the infrared spectra made comparing data sets difficult. At constant supersaturation, the nucleation and growth rates are expected to increase with increasing temperature, which explains the steeper desupersaturation observed at higher temperatures. In this case, the product crystal cross-sectional area also appears to increase with increasing temperature (Table 4). A possible explanation is that the effect of the increased nucleation rate is superseded by the increase in the growth rate. However, a more probable explanation is that as the nucleation temperature increases at constant supersaturation, the mass of product to be crystallized also increases: 3 g of product was expected for T26, and this increased to 13 g of product for T64. This is due to the increasing slope of the solubility curve at higher temperatures, which results in the requirement of much larger solution concentrations at higher temperatures to achieve the same supersaturation ratio as at

Figure 9. Normalized phenacetin concentration profiles observed by in situ IR spectroscopy during crystallization at a constant initial supersaturation ratio of S = 1.5.

Figure 10. Scanning electron micrographs of the solids recovered from crystallization experiments at an initial supersaturation ratio of S = 1.5. H


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Crystallization of phenacetin from ethanol/water resulted in needle-habit crystal products; the essentially needlelike habit was retained when water was used as the antisolvent, but with less uniformity and an increase in irregular polycrystalline particles. The fastest antisolvent addition rate (8 g min−1) gave the smallest, most acicular crystals, consistent with the most rapid generation of supersaturation. A steady decrease in the D50 value with increasing antisolvent addition rate was observed (Table 5, entries 1−4). Figure 12 shows examples of phenacetin crystals obtained from the ethyl acetate/hexane system. Phenacetin crystals

lower temperatures. In the previous series of isothermal desupersaturation crystallizations (constant nucleation temperature), the increase in nucleation rate as a result of increasing supersaturation resulted in much narrower product crystals in spite of a larger mass crystallized. In this series, the likely increase in nucleation at increased temperatures is masked by the increased growth rate at higher temperatures or the increased mass to be crystallized. 3.5. Crystallization by Antisolvent Addition. In each system (ethanol/water, ethyl acetate/hexane, and toluene/ hexane), the solvent and antisolvent are miscible and show considerable differences in solubility on basis of the data in Table 1 and Figure 2 (using data for pentane to approximate those for hexane). Antisolvent experiments employing a feed rate of 1 g min−1 were unsuccessful. Examples of phenacetin crystals obtained from the ethanol/water system are shown in Figure 11, and the crystal size data are given in Table 5.

Figure 12. Phenacetin crystallized from ethyl acetate solution by the addition of hexane antisolvent at antisolvent addition rates of 2, 4, 5, and 8 g min−1. Images are intended to represent particle habit only and are not indicative of particle size.

grown by fast cooling directly from ethyl acetate were obtained as irregular prisms and needles (Figure 5). However, the crystals obtained from ethyl acetate solution by the addition of hexane antisolvent were found to be well-formed prisms, especially at the lower antisolvent addition rates of 2 and 4 g min−1. Increasing the addition rate to 5 or 8 g min−1 resulted in smaller, less well formed particles. The crystal size data given in entries 5, 6, and 8 of Table 5 show that crystals obtained from the ethyl acetate/hexane system where generally larger than those obtained from ethanol/water. As with the ethanol/water system, increasing the antisolvent addition rate resulted in smaller D50s. The results for the toluene/hexane systems are shown in Figure 13 and entries 9−12 of Table 5. Crystallization of phenacetin by cooling from toluene gave elongated prisms. This morphology was also found in the toluene/hexane antisolvent crystallization, but with a lesser degree of elongation. An increase in D50 was observed for antisolvent addition at rates of 2, 4, and 5 g min−1 but not at 8 g min−1. Interestingly the crystals became less elongated at higher addition rates. The observed morphologies were generally prismatic, although more acicular crystals were also observed. While some acicular crystals were observed at higher antisolvent addition rates for the toluene/hexane system, few smaller particles were observed. Acicular crystals were not observed with the ethyl acetate/toluene system, although a

Figure 11. Phenacetin crystallized from ethanol solution by the addition of water antisolvent at antisolvent addition rates of 2, 4, 5, and 8 g min−1. The images are intended to represent particle habit only and are not indicative of particle size.

Table 5. D50 values for equivalent diameters of batches of phenacetin crystals obtained by antisolvent crystallization at different antisolvent addition rates entry

solvent/antisolvent

antisolvent addition rate (g min−1)

D50 (μm)

1 2 3 4 5 6 7 8 9 10 11 12

EtOH/H2O EtOH/H2O EtOH/H2O EtOH/H2O EtOAc/hexane EtOAc/hexane EtOAc/hexane EtOAc/hexane toluene/hexane toluene/hexane toluene/hexane toluene/hexane

2 4 5 8 2 4 5 8 2 4 5 8

514 381 335 288 640 576 nda 442 310 343 466 380

a

nd = not determined.

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with the BFDH-predicted morphology. The solvent impacts the crystal habit by interacting with solute molecules and promoting/hindering growth at different crystal faces, whereas the crystallization conditions impact the habit by controlling nucleation and growth events for the crystal population. Isothermal slurry equilibrations in ethanol, acetonitrile, ethyl acetate, toluene, and water as a function of temperature generated precise solubility measurements in each solvent via gravimetric analysis. This allowed for the determination of supersaturation in subsequent cooling experiments. As supersaturation increases at constant temperature, the cross-sectional area of phenacetin crystals decreases and the average length remains approximately the same, with the end result that particle size analysis records decreasing particle dimensions. As the nucleation temperature increases at constant supersaturation, the cross-sectional area of the crystals increases (particularly above 30 °C) with the length remaining approximately the same, which is reflected by increasing particle dimensions from particle size analysis. This demonstrates that the growth direction of phenacetin crystals is highly influenced by supersaturation and nucleation temperature. Growth in the direction perpendicular to the needle direction is activated at high temperatures and low supersaturation but decreases with increasing supersaturation or decreasing nucleation temperature. For the antisolvent crystallizations, shorter crystals were observed at higher addition rates because of the increased rate at which supersaturation was achieved. The nature of the crystals obtained was solvent-dependent, with aprotic solvents forming larger crystals and polar solvents leading to smaller crystals with less well defined habits. The knowledge gained in this study could be used to design a crystallization process that will deliver a desired particle habit and size distribution for phenacetin. Understanding the impact of the crystallization conditions on the crystal size and habit is the first step in gaining control of the crystallization process.

Figure 13. Phenacetin crystallized from toluene solution by the addition of hexane antisolvent at antisolvent addition rates of 2, 4, 5, and 8 g min−1. Images are intended to represent particle habit only and are not indicative of particle size.

significant number of small particles were observed at higher addition rates. In general, increasing the antisolvent addition rate, which can be associated with increased rate of generation of supersaturation, gave smaller crystals. The ethyl acetate/hexane system at lower antisolvent addition rates of 2 and 4 g min−1 gave large, well-formed prisms (D50 ≈ 600 μm) which would be expected to be optimal for rapid filtration and effective washing and drying. The toluene/hexane system may provide better access to smaller crystals with a narrower distribution. For phenacetin at least, the use of antisolvents to generate supersaturation can direct crystal morphologies and size distributions in a given crystal batch. It is acknowledged that the robustness of this approach at larger scales would require additional consideration. Antisolvent crystallizations of phenacetin were developed from the three solvent/antisolvent systems ethanol/water, ethyl acetate/hexane, and toluene/ hexane. The aprotic systems (ethyl acetate/hexane and toluene/hexane) gave better-formed, generally prismatic crystals, while the protic ethanol/water system gave needles and less well formed polycrystalline particles. Better-faceted crystals were therefore obtained from the aprotic systems of intermediate and low polarity rather than the protic polar ethanol/water system. This may reflect the impact of solvent on crystal growth in various crystallographic directions, with the polar protic system having a strong effect on faces presenting amide hydrogen bonds (Figure 2) and variable effects at other faces, whereas the moderately polar aprotic systems interact more equally in all growth directions.

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ASSOCIATED CONTENT

S Supporting Information *

PXRD patterns of solids recovered from crash cooling, sample infrared spectra from ethanol and a solution of phenacetin in ethanol, and particle size distributions for solids recovered from isothermal desupersaturation experiments. This material is available free of charge via the Internet at http://pubs.acs.org.

■

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest.

■ ■

ACKNOWLEDGMENTS The authors collectively acknowledge funding by Science Foundation Ireland under Grant 07/SRC/B1158.

4.0. CONCLUSIONS Phenacetin crystal habit and size are influenced by both the crystallization conditions and the crystallization solvent. Fast growth in a variety of solvents, as demonstrated in the crashcooling experiments, resulted in the crystallization of a variety of different needle-type habits: rods, blades, and true needles. Slow growth, as demonstrated with the evaporative crystallizations, yielded a hexagonal crystal habit more in accordance

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