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Mechanisms of Crystal Agglomeration of Paracetamol in Acetone-Water Mixtures Eva M. A ° lander and A ° ke C. Rasmuson* Department of Chemical Engineering and Technology, Royal Institute of Technology, SE-100 44 Stockholm, Sweden
The mechanisms governing the influence of the solvent composition on the agglomeration in a crystallization process have been investigated. Narrowly sieved paracetamol crystals were suspended in supersaturated acetone-water solutions, and were allowed to grow at isothermal conditions, after which the agglomeration was recorded. In all experiments the same sieve size fraction was used as well as the same magma density. In each experiment the supersaturation was kept constant. Experiments were performed in different solvent compositions at different supersaturation, crystal growth rate, solution viscosity, and agitation rate. For a statistically sufficient number of particles from each experiment, the number of crystals in each product particle was determined by image analysis and multivariate data evaluation. From the resulting number distributions of crystals per product particle, parameters defining the “degree of agglomeration” were extracted. The experimental results clearly establish that there is an influence of the solvent composition on the degree of agglomeration, which cannot be explained by differences in crystal growth rate, or differences in solution viscosity. The degree of agglomeration is found to decrease with increasing solvent polarity. It is suggested that the mechanism by which the solvent influence relates to the crystal-solvent interaction and the physicochemical adhesion forces between crystals in the solution. Introduction Crystallization is extensively used for separation and purification of organic fine chemicals and pharmaceutical compounds. In the design of the process, the selection of the solvent is of key importance. The solvent very much determines the productivity and yield of the process. In addition, the selection of the solvent together with operating conditions can be used for particle design, e.g., control of crystal size and crystal shape. Quite often the product not only contains single crystals but also particles where a number of crystals have grown together into agglomerates. The degree of agglomeration and the properties of the agglomerates may vary significantly with solvent and process, and could be decisive for the particle size distribution and morphology of the final product. Agglomeration is hence of significant importance for the downstream processing, e.g., filtration, washing, and drying, as well as for product formulation and the end-use properties such as dissolution and bioavailability of pharmaceuticals. Agglomeration is in principle a three-step process: particles collide, adhere, and grow together. After collision, physicochemical and fluid mechanical forces compete and determine the lifetime of the aggregate and hence the time available for growing the crystalline bridges within the agglomerate. As discussed previously, in A° lander et al.,1 not only are the mechanisms of formation of agglomerates complex but so are also the properties and characterization. An agglomerate is a multi-particle body containing a number of crystals having a size distribution and a shape distribution, grown together to a varying level of crystalline bridging * To whom correspondence should be addressed. Tel.: 468-7908227. Fax: 46-8-105228. E-mail:
[email protected].
and porosity. Hence, in an agglomerated product there is a significant spread in the particle properties, and the properties may depend significantly on the processing conditions. Particularly important parameters influencing crystal agglomeration are particle concentration, supersaturation, particle size, and agitation rate. The collision rate and thereby the agglomeration rate increases with particle concentration, unless the formed agglomerates are weak and break down as a result of collisions. With increased supersaturation, the nucleation rate is higher, and hence influence on crystal size and concentration, and the growth rate is higher. Hounslow et al.2 and David et al.3 suggest agglomeration to be proportional to the crystal growth rate. Smaller particles agglomerate more easily than larger particles. Particles smaller than the Kolmogorov microscale collide because of viscous laminar shear stresses within the microscale eddies, whereas larger particles collide because of fluid turbulent velocity fluctuations. For particles larger than the Kolmogorov microscale, particle inertia and added mass effects become important. The collision rate is an order of magnitude higher for particles influenced by the Kolmogorov microscale eddies.4 In stirred tanks with turbulent conditions the flow pattern is complex and the shear field is far from uniform.5,6 As a rule, an increase in the agitation rate enhances collisions due to an increased fluid shear rate. However, higher fluid shear rates also mean larger disruptive fluid forces and shorter time-scale for growth of crystalline bridges. Hence, not all collisions lead to formation of agglomerates. As a consequence of the two opposing effects of fluid shear rate on agglomeration, there is a maximum in the agglomeration rate with increasing shear rate.7
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The solvent composition influences solution properties (such as density and viscosity), solute solubility, and solvent-crystal surface interaction, and the choice of the solvent is well known to influence crystal nucleation, growth, and morphology.8-10 Consequently, many of the parameters important in crystal agglomeration are influenced by solvent composition and in a rather complex way. Introductory studies on paracetamol1,11 have revealed that crystallization in acetone-toluene-water mixtures with a high concentration of acetone leads to a highly agglomerated product. On the other hand, when the crystallization is performed in acetone-toluene-water mixtures having a high concentration of water, and when crystallizing in pure ethylene glycol, 2-propanol, and acetic acid, the product contains a significant fraction of single crystals. These results could be correlated to the polarity as well as to the viscosity of the solvent. In other words, it was not possible to resolve whether the effect was related to the physicochemical conditions or to the fluid mechanical conditions (hydrodynamics). The present work aims to establish the mechanism by which the solvent influences the agglomeration, by a designed series of well-controlled, isothermal crystal growth/agglomeration experiments. Paracetamol is crystallized in different supersaturated acetone-water mixtures. The number concentration and the crystal size are controlled by seeding, and the supersaturation is kept constant and well-defined. The agglomeration behavior in different solvent compositions, at different levels of supersaturation, and with various agitation rates are evaluated. On the basis of the growth rate data of Granberg et al.12 even experiments in different solvent compositions but at equal overall crystal growth have been performed. Experimental Section Paracetamol of pharmaceutical grade (donated by Astra Zeneca, So¨derta¨lje, Sweden) and pro analysis acetone (>99.5%, Merck) were used. The water was distilled and filtered (0.2 µm) prior to use. Seeded, isothermal crystal growth/agglomeration experiments were carried out in a jacketed crystallizer (6 cm diameter, 6 cm high) with baffles and a three-blade propeller (2.5 cm diameter) placed 1.5 cm above the bottom. Acetone-water solutions (100:0, 85:15, 30:70, 0:100 wt %) saturated with paracetamol at different temperatures, were prepared, filtered through 0.45-µm membrane filters, and cooled to 16 °C. To the supersaturated solution (150 mL) was added 0.1 g of seeds of a narrow sieve size fraction (90-125 µm). The initial magma density was 0.67 g/L in all experiments. Seeds were allowed to grow and agglomerate for a certain time period, after which the crystalline product was filtered (Munktell, no. 3), washed with about 50 mL of water, and dried in an oven (45 °C). Solution concentrations were checked gravimetrically by evaporating samples to dryness. The supersaturation, S, defined as the ratio of the solute concentration to the solubility, was calculated using the solubility data of Granberg and Rasmuson.13 In all experiments the supersaturation decay was below 10%. Details of the experimental and fluid mechanical conditions are given in Tables 1 and 2, respectively. The dynamic viscosity of saturated paracetamol solutions at 20 °C was determined with a Ho¨ppler viscosimeter. The results are given in Table 2. By using the growth rate data of Granberg et al.,12 experiments
Table 1. Experimental Conditions acetone-water mixture (wt %) ln Sa 100:0 85:15 30:70 0:100
0.08 0.13 0.22 0.08 0.12 0.24 0.10 0.21 0.22 0.31
agitation rate (rpm)
crystallization time (min)
400 400, 500, 600, 750, 1000 400 400 400 400 400 400 400 400
4 8 4 4 4 4 4 4 4 4
a Supersaturation S is defined as the ratio of the solute concentration to the solubility concentration at 16 °C.
have been performed also at equal overall crystal growth rate in different solvent mixtures. For production of seeds, a saturated aqueous solution of paracetamol at 65 °C was filtered (Munktell, no. 3) and cooled to 40 °C (ln S ) 0.6) in a 1-L jacketed crystallizer with a three-blade propeller. The agitation rate was 450 rpm. Nucleation was initiated by means of an ultrasound tip immersed into the solution. With 20 s of ultrasound treatment (1 s on/1 s off, 36 W) the solution turned white due to vigorous nucleation. The crystals were allowed to grow for 5 min. Then the experiment was stopped and the crystalline product was isolated between two different sieves: 90 and 125 µm (DIN 4188 standard), where it was washed. The sieve fraction 90-125 µm was collected and dried in an oven (45 °C) before being used as seeds in the crystallization experiments. The seeds are shown in Figure 1. As can be seen, the seeds are mainly single crystals, but also some agglomerates are present. Product Characterization. The product particles were examined under a microscope to determine the degree of agglomeration. First, image analysis was used to measure image descriptors of about 300 particles from each crystallization experiment. The image descriptor data were then processed by principal component analysis (PCA) together with the corresponding data of a set of selected calibration particles, in such a way that the received loading-plot is determined by the calibration particles, and hence is equal for all samples. The score position of a sample particle then characterizes the particle in a fixed principal component frame. The number of crystals in each particle of the calibration set was counted manually in order to construct a correlation between the C/A-number (number of crystals per particle) and the principal component score position. This correlation was used to estimate the C/A-number of a sample particle from its principal component values. A C/A-number equal to unity means that the particle is a single crystal and higher C/A-numbers denote higher number of crystals grown together in the particle. The C/A-number distribution of a sample was obtained by counting the number of particles within defined ranges of C/A-number values (0-1, 1-2, 2-4, 4-8, and 8-16 crystals per particle). Details of descriptor selection, use of PCA, and the calibration model are presented elsewhere.1,14 Results Images of particles crystallized in different acetonewater mixtures at equal supersaturation are shown in Figure 2a-d. As can be seen, particles grown in pure acetone (2a) or acetone-water mixtures with low water
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Table 2. Fluid Mechanical Conditions with Different Solvent Compositions and Agitation Rates
a
acetone-water mixture (wt %)
dynamic viscositya (mNs/m2)
densitya (kg/m3)
agitation rate (rpm)
impeller Reb
Kolmogorov microscalec (µm)
100:0
0.52
820
400 500 600 750 1000
6570 8213 9856 12320 16426
76 64 56 47 38
97:3 93:7 85:15 70:30 30:70 0:100
0.70 1.01 1.83 2.77 2.03 0.97
850 880 910 950 970 1000
400
2072
180
400 400
1991 4296
186 104
Measurements of paracetamol saturated solutions at 20 °C. b Re ) ND2/ν. c λK ) (ν3/)0.25, ) NpN3D5/V.
Figure 1. Seeds (90-125 µm) added in crystallization experiments.
content (2b) are highly agglomerated. The fraction of single crystals and less agglomerated particles increases with increasing water content. There is essentially no agglomeration when crystallized in pure water (2d) and in the acetone-water mixture with 70 wt % of water (2c). The C/A-number distributions of particles crystallized in different acetone-water mixtures, at different supersaturation levels, are given in Figure 3a-d. The results of Figure 3 are in good agreement with the conclusions drawn from the images of Figure 2. In addition, the results of Figure 3 reveal that there is no significant influence of the supersaturation on the agglomeration. The only exception is for the acetonewater 85:15 wt % mixture. The overall crystal growth rates for the acetone-water system have been determined previously.12 On the basis of these growth rate measurements, the supersaturation in different solvent mixtures has been adjusted in order to obtain the same overall crystal growth rate. Figure 4 presents the C/Anumber distributions in different solvent mixtures at the same overall crystal growth rate (about 0.2 µm/s) as deduced from the data of Granberg et al.12 The figure clearly shows that the degree of agglomeration, at equal overall crystal growth rate, is significantly influenced by the solvent composition. C/A-number distributions for particles crystallized in pure acetone at different agitation rates (400, 500, and 600 rpm) are presented in Figure 5. For comparison the C/A-number distribution of the seeds is also shown. As can be seen, there is a gradual change toward a more agglomerated product with decreasing agitation rate. At high agitation an agglomeration only somewhat exceeding what is already present among the seeds can be observed. In Figure 6, the number fraction of the particles in a sample having C/A-number less than 2 is plotted versus the agitation rate. This fraction could be
seen as a measure of nonagglomerated crystals. A low value means a high degree of agglomeration, i.e., there are very few crystals that are not engaged in an agglomerate. For comparison the fraction value of C/A < 2 of the seedssthe dotted linesis shown. Furthermore, the number average particle size, determined by image analysis measuring the particle diameter of about 300 particles from each crystallization experiment, is given next to each data point. Obviously, there is a gradual decrease in degree of agglomeration, and hence of the average particle size, as the agitation rate increases. Above 600 rpm, there is still a certain degree of agglomeration beyond that present in the seeds, but the agglomeration degree and particle size seem rather independent of further increase in the agitation rate. Discussion In our earlier work1 on crystallization of paracetamol it was clearly found that the degree of agglomeration of the product particles, as well as the strength of the agglomerates, did depend significantly on the composition of the solvent. However, when the solvent is changed in the crystallization many of the parameters that influence agglomeration are changed. A different solubility curve leads to a different supersaturation profile, a different nucleation leads to a different particle concentration, a different physicochemical environment leads to different adhesion forces between crystals, a different growth rate leads to a different rate of bridging, and a different viscosity leads to a different fluid mechanical (hydrodynamic) environment. In the previous study, the experiments were performed at essentially the same initial supersaturation ratio, temperature, and agitation rate, but otherwise many of the important conditions differed. Hence, in the present experiments the conditions with respect to crystal size, magma density, supersaturation, and overall crystal growth rate are controlled in order to reveal the underlying mechanisms of the influence of the solvent on agglomeration. In particular, the ambition is to establish to what extent the physicochemical properties of the solvent have an influence beyond the influence of the crystallization kinetics and the influence of fluid mechanical conditions. Crystallization Kinetics. An increase in degree of agglomeration with increasing supersaturation (growth rate) has been reported previously.2,3 Hence, it is tempting to try to explain the influence of the solvent composition on the degree of agglomeration, as being related to differences in the crystal growth rate. Solvent molecules able to form hydrogen bonding to functional groups exposed at the surface may slow the growth rate.
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Figure 3. Influence of supersaturation on the product C/Anumber distribution at 400 rpm: (a) acetone, (b) acetone-water (85:15 wt %), (c) acetone-water (30:70 wt %), and (d) water.
Figure 2. Particles crystallized in (a) acetone, (b) acetone-water (85:15 wt %), (c) acetone-water (30:70 wt %), and (d) water. Same magnification (agitation rate 400 rpm, ln S ) 0.2).
This means that more time is needed for the formation of crystalline bridges that are strong enough to withstand the disruptive fluid mechanical forces. As a consequence, the probability of forming agglomerates becomes reduced. In addition, it is well-known that the solvent influences on the crystal shape (e.g., Lahav and
Figure 4. Influence of the solvent composition on the product C/A-number distribution at equal overall crystal growth rate (0.2 µm/s), agitation rate (400 rpm), and crystallization time (4 min).
Leiserowitz10), and the influence of the solvent-crystal interaction on the crystal growth rate of various faces is often used to explain this. Nikolakakis et al.15 found that the agglomeration of ibuprofen can be related to the shape of the primary crystals. However, in the present work the shape and size of the added seeds are the same in all experiments, and Figure 2 shows that over the course of an experiment the crystal shape does
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Figure 5. Influence of agitation rate on the product C/A-number distribution in pure acetone at equal supersaturation (ln S ) 0.1) and crystallization time (8 min).
Figure 6. Influence of agitation rate on fraction of nonagglomerated particles in pure acetone at ln S ) 0.1. Average size of product particles is given in the graph. Dotted line (- - -) represents seeds.
not change significantly. The results of Figure 2 clearly show an increase in agglomeration with increasing concentration of acetone in the solvent. As can be seen in Figure 3a-d, this change in agglomeration degree cannot be explained by a change in the supersaturation level. Only for the 85:15 wt % acetone-water mixture (Figure 3b) an influence of the supersaturation can be distinguished, and in this case there is a quite dramatic increase in the overall growth rate from about 0.45 µm/s at ln S ) 0.12 to 1.7 µm/s at ln S ) 0.24 (data taken from Granberg et al.12). However, as shown in Figure 4, at equal overall crystal growth rate the agglomeration clearly increases with increasing content of acetone. Hence, within the investigated range of growth rates, there is certainly a significant influence of the solvent that is beyond the role of the overall crystal growth rate. An appropriate remark would be that the influence of the growth rate on agglomeration should concern the face growth rate, rather than the overall growth rate. At equal overall crystal growth rate we may still have differences in the face growth rate of certain faces. However, in the range of the present study the agglomeration in a certain solvent is not strongly influenced by the supersaturation and accordingly not by the crystal growth rate, and hence the overall conclusion should be justified, namely that there is a significant influence of the solvent composition on agglomeration that cannot be explained by growth rate effects. Fluid Mechanical Conditions. In Figure 6, there is a gradual decrease in the degree of agglomeration as the agitation rate increases from 400 to 600 rpm. The fluid mechanical shear forces breaking the aggregates become increasingly competitive to the physicochemical adhesion forces, and this leads to reduced agglomeration. Above 600 rpm, the fluid mechanical forces dominate and the agglomeration of the seeds is weak. This
Figure 7. Influence of solvent composition (on solute free basis) on the dynamic viscosity (20 °C) of pure acetone-water mixtures (Baldauf and Knapp16) and of the corresponding mixtures saturated by paracetamol (PA).
Figure 8. Ratio of the viscosity of the saturated paracetamol solution to the viscosity of the pure acetone-water mixture versus solubility of paracetamol (20 °C) (solubility data from Granberg and Rasmuson13).
means that at 400 rpm we operate in a range where the adhesion forces compete with the fluid mechanical forces, and that the change in degree of agglomeration may reflect changes in adhesion forces with solvent composition. The conditions at 400 rpm are not fully turbulent. However, in a first rough analysis we use the classical equation of the Kolmogorov microscale to estimate the size of the smallest eddies. As shown in Table 2, the seed crystals are essentially equal to this Kolmogorov microscale in pure water and in pure acetone at 400 rpm. In the acetone-water mixtures the Kolmogorov microscale may be about twice the size of the seeds. Hence, the particles in the experiments are in a size range where they can be exposed to the laminar shear forces that depend on the viscosity. Increased viscosity leads to increased shear stresses and decreased shear rate (collision rate). Consequently, the degree of agglomeration is expected to decrease with increasing solution viscosity. The solvent composition influences the solution viscosity. In Figure 7, the dynamic viscosity of saturated paracetamol solutions at 20 °C, determined in the present work, is shown and compared to literature data on pure acetone-water mixtures as given by Baldauf and Knapp.16 The viscosity is significantly influenced by the solvent composition and it is higher for the saturated solution than for the corresponding pure mixture of the solvents. Figure 8 shows that the viscosity of the saturated paracetamol solution in relation to the viscosity of the pure acetone-water mixture (on the y-axis) is proportional to the paracetamol solubility in the corresponding solvent mixture. In other words, the viscosity of the saturated paracetamol solution reflects that there is a very dramatic change in the solubility13 when the solvent composition changes from pure water, over different binary mixtures, to pure acetone.
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Figure 9. Correlation of degree of agglomeration at 400 rpm and 4-min crystallization time to solution viscosity. Overall crystal growth rate < 0.4 µm/s.
Figure 10. Correlation of degree of agglomeration at 400 rpm and 4-min crystallization time to solvent polarity (polarity data from Novaki and El Seoud17).
Figure 9 presents the fraction of nonagglomerated particles (C/A < 2) versus the saturated solution viscosity of the experiments. All experiments shown were performed at equal agitation rate, 400 rpm, and in all cases the duration was 4 min. For each solvent composition (i.e., solution viscosity) there are two experiments corresponding to two different supersaturation levels. In all experiments shown the overall crystal growth rate is lower than 0.4 µm/s where it has been shown that the influence of the growth rate on the agglomeration is negligible. Obviously, there is no clear correlation between the degree of agglomeration and the solution viscosity, and hence the influence of the solvent composition cannot be explained in terms of fluid mechanics. As shown in Figures 7 and 8, the solution viscosity depends on the dissolved amount of paracetamol. If we take into consideration that the solution actually is supersaturated in the agglomeration experiments, not just saturated as in the viscosity measurements, the actual viscosity is about 10-20% higher in the agglomeration experiments. However, this will not alter the overall conclusions drawn from Figure 9. Physicochemical Conditions. In the previous introductory work1 it was observed that the degree of agglomeration is strongly correlated to the Reichardt solvent polarity (ET), where the ET value was interpreted as a measure of the hydrogen bonding ability of the solvent. Figure 10 presents the corresponding results of the present study, in which the crystal size and the magma density are controlled. The experimental conditions are the same as those in Figure 9. Figure 10 clearly reveals a nice correlation between the degree of agglomeration and the polarity of the solvent. This correlation can now be considered together with other results of this work: (i) the degree of agglomeration increases with the acetone content of the acetone-water mixture at equal overall crystal growth rate (Figure 4),
(ii) the agglomeration results cannot be explained by differences in the crystal growth rate (Figure 3a-d), (iii) the agglomeration results do not clearly correlate to differences in the viscosity (Figure 9), and (iv) below 600 rpm the degree of agglomeration decreases with increasing agitation rate (Figures 5 and 6). These results together strongly suggest that the crystal agglomeration behavior relates to the influence of the solvent composition on the physicochemical adhesion forces between the crystals. The degree of agglomeration is reduced as the solvent-crystal surface interaction becomes stronger. In water, the hydration of crystalline hydrophilic surfaces (e.g., silica and mica) is known to cause repulsive forces between the surfaces.19 These repulsive hydration forces are believed to arise whenever water molecules strongly interact with the surfaces containing hydrophilic or H-bonding groups that modify the H-bonding network of water molecules adjacent to them. The strength of the repulsive force depends on the energy needed to disrupt this H-bonding network and to dehydrate two approaching surfaces.19 The observed decrease in degree of agglomeration with increasing water content established in our work could probably be related to a similar situation where strong crystalsolvent interactions reduce the adhesion between crystals. The water molecule can act both as H-bond acceptor and donor, while acetone only can act as H-bond acceptor. The crystal surfaces of paracetamol are characterized18 by the fact that the paracetamol molecule has a hydroxyl group and an amide group, both being hydrogen-bond donating as well as hydrogen-bond accepting. Hence, several of the faces of the crystal can interact more strongly with water than with acetone. Conclusions Well-defined agglomeration experiments have been performed on paracetamol in acetone-water solutions. The results show that the agglomeration increases with increasing acetone concentration in the solution. The experimental results clearly show that there is a significant influence of the solvent composition on the agglomeration, even when the same magma density of equal seed crystals is used, and when agglomeration takes place at constant and equal supersaturation, or at constant and equal overall crystal growth rate. It is shown that this result cannot be explained by changes in the solution viscosity (fluid mechanics). There is a very clear correlation between the degree of agglomeration and the polarity of the solvent mixture, as described by the Reichardt polarity parameter ET. Water molecules, possessing both H-bond accepting and donating ability, can interact strongly with H-bonding groups at the crystal surfaces and hence reduce crystals from adhering to one another. The acetone molecule can only act as H-bond acceptor. The weaker solvent-crystal interaction of acetone allows for crystal-crystal adhesion and growth of crystalline bridging between the crystals. Literature Cited (1) A° lander, E. M.; Uusi-Penttila¨, M. S.; Rasmuson, A° . C. Agglomeration of Paracetamol during Crystallization in Pure and Mixed Solvents. Ind. Eng. Chem. Res. 2004, 43, 629. (2) Hounslow, M. J.; Mumtaz, H. S.; Collier, A. P.; Barrick, J. P.; Bramley, A. S. A Micro-Mechanical Model for the Rate of Aggregation during Precipitation from Solution. Chem. Eng. Sci. 2001, 56 (7), 2543.
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(3) David, R.; Marchal, P.; Klein, J. P. Crystallization and Precipitation Engineering - IV. Kinetic Model of Adipic Acid Crystallization. Chem. Eng. Sci. 1991, 46 (4), 1129. (4) Kruis, F. E.; Kusters, K. A. The Collision Rate of Particles in Turbulent Flow. Chem. Eng. Commun. 1997, 158, 201. (5) Pettersson, M.; Rasmuson, A° . C. Hydrodynamics of Suspensions Agitated by a Pitched Blade Turbine. AIChE J. 1998, 44, 513. (6) Yu, Z.; Rasmuson, A° . C. Trailing Vortices, Reynold Stresses and Anisotropy in the Stirred Tank Agitated by a Pitched Blade Turbine. Chem. Eng. Sci. 2004, submitted for publication. (7) Mumtaz, H. S.; Hounslow, M. J. Aggregation during Precipitation from Solution: An Experimental Investigation using Poiseuille Flow. Chem. Eng. Sci. 2000, 55, 5671. (8) Davey, R. J. Solvent Effects in Crystallisation Processes. Curr. Top. Mater. Sci. 1982, 8, 431. (9) Klug, D. L. The Influence of Impurities and Solvents on Crystallization. In Handbook of Industrial Crystallization; Meyerson, A. S., Ed.; Butterworth-Heinemann: Boston, MA, 1993; p 65. (10) Lahav, M.; Leiserowitz, L. The Effect of Solvent on Crystal Growth and Morphology. Chem. Eng. Sci. 2001, 56 (7), 2245. (11) Uusi-Penttila¨, M. S.; Rasmuson, A° . C. Experimental Study for Agglomeration Behaviour of Paracetamol in Acetone-TolueneWater Systems. Chem. Eng. Res. Des. 2003, 81 (A4), 489. (12) Granberg, R. A.; Bloch, D. G.; Rasmuson, A° . C. Crystallisation of Paracetamol in Acetone-Water Mixtures. J. Cryst. Growth 1999, 198/199, 1287.
(13) Granberg, R. A.; Rasmuson, A. C. Solubility of Paracetamol in Binary and Ternary Mixtures of Water+Acetone+Toluene. J. Chem. Eng. Data 2000, 45, 478. (14) A° lander, E. M.; Uusi-Penttila¨, M. S.; Rasmuson, A° . C. Characterization of Paracetamol Agglomerates by Image Analysis and Strength Measurement. Powder Technol. 2003, 130, 298. (15) Nikolakakis, I.; Kachrimanis, K.; Malamataris, S. Relations between Crystallisation Conditions and Micromeritic Properties of Ibuprofen. Int. J. Pharm. 2000, 201, 79. (16) Baldauf, W.; Knapp, H. Experimental Determination of Diffusion Coefficients, Viscosities, Densities and Refractive Indexes of 11 Binary Liquid Systems. Ber. Bunsen-Ges. Phys. Chem. 1983, 87, 304. (17) Novaki, L. P.; El Seoud, O. A. Solvatochromism in Binary Solvent Mixtures: Effects of the Molecular Structure of the Probe. Ber. Bunsen-Ges. Phys. Chem. 1997, 101, 1(6), 902. (18) Green, D. A.; Meenan, P. Acetaminophen Crystal Habit: Solvent Effects. In Crystal Growth of Organic Materials; Myerson, A. S., Green, D. A., Meenan, P.; Conference Proceedings Series, American Chemical Society: Washington DC, 1996; p 78. (19) Israelachvili, J. N. Intermolecular and Surface Forces, 2nd ed.; Academic Press: London, 1992.
Received for review November 8, 2004 Revised manuscript received April 14, 2005 Accepted April 25, 2005 IE0489204
