Characterization of Organic and Inorganic Chemicals Formed by

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Ind. Eng. Chem. Res. 2008, 47, 804-812

Characterization of Organic and Inorganic Chemicals Formed by Batch-Cooling Crystallization: Shape and Size Kumar Patchigolla*,† and Derek Wilkinson‡ Department of Chemical Engineering, Loughborough UniVersity, Loughborough, LE11 3TU, United Kingdom, and Department of Chemical Engineering, School of Engineering and Physical Sciences, Heriot-Watt UniVersity, Riccarton, Edinburgh EH14 4AS, United Kingdom

Batch-cooling crystallization is an important industrial unit operation often carried out from aqueous solutions. Measurement of crystal size and shape plays a major role in crystallizer control in order to improve product quality. Certain crystals grown from solution may exhibit polymorphism, which can significantly affect product properties such as bioavailability as well as impinging on downstream operations such as filtration and drying. L-Glutamate was considered as a model compound for this study because it crystallizes from aqueous solution into two polymorphic forms, R and β, which are rhombic and acicular respectively. In this study, cooling rate and initial solution concentration were chosen as manipulated variables to control polymorph formation. Rapid cooling from low solution concentration favors the formation of the R form, while slow cooling with high concentration favors the β form. Oxalic acid dihydrate and copper sulfate pentahydrate, which crystallize into monoclinic and triclinic systems, respectively, are also used in this study. Crystal morphology interacts with other product quality measurements, particularly crystal size. Currently, acquiring crystal size along with shape measurement is not readily achieved. Image analysis measures shape with size distribution but only for very small samples, and it is not currently practical for control in the process industries for small particle sizes using simple equipment. In this paper, size distributions obtained by ultrasonic attenuation spectroscopy (UAS), laser diffraction spectroscopy (LDS), focused-beam reflectance measurement (FBRM), and microscopic image analysis (MIA) are compared and the influence of crystal shape on size measurements is investigated. Data obtained from UAS are combined with information on shape factor (circularity) from imaging to obtain equivalent crystal-size distribution (CSD). Data obtained from LDS are converted with a shape factor (sphericity) from imaging to obtain CSD. In this paper, the influence of shape on size measurement is observed for these organic and inorganic chemicals. 1. Introduction Crystal shape and size are important parameters in the field of crystallization. Crystals can be characterized by particle mean diameter, size range, morphology, and shape. The physical properties of crystal products, such as shape of crystals and the crystal-size distribution (CSD), determine the quality of final product and affect operations such as filtration and drying. In order to get specified crystal shape and CSD with good reproducibility from batch to batch, the operating conditions, such as cooling mode and solution concentration, supersaturation, impurities, and additives, must be regulated. Many amino acids can have polymorphs with different mechanical, thermal, and physical properties such as compressibility, melting point, solubility, and crystal habit.1 These properties can have a great influence on the bioavailability, stability, and filtration of pharmaceutical materials.2,3 This is because the amino acid is present as zwitterions, which form strong hydrogen bonds in crystals, and molecules take various configurations through hydrogen bonding. Such polymorphic crystals give rise to various problems in industrial production. Thus, the control of polymorph formation is an important issue within industry. In the study of polymorphism, crystallization behavior and growth kinetics are influenced by surfactants,4 additives,4,5 supersaturation,6 and also choice of solvent.7 The * To whom correspondence should be addressed. E-mail: [email protected]. † Loughborough University. ‡ Heriot-Watt University.

Figure 1. Solubility data for L-glutamate crystals (R and β forms).

model compound used in this study was L-glutamate, which has two polymorphs, metastable R-form and stable β-form. Both belong to the same orthorhombic space group, but they have different lattice parameters. For example, the solubilities of the R- and β-forms of L-glutamate, shown in Figure 1,3,8 are different because of structural inequality. In the present study, trials producing R- and β-forms of L-glutamate were run and the controlling factors such as cooling rate and initial solution concentration were investigated. Oxalic acid dihydrate and copper sulfate pentahydrate crystallizations were studied at one concentration and one cooling rate because of their nonpolymorphic nature.

10.1021/ie061381d CCC: $40.75 © 2008 American Chemical Society Published on Web 12/14/2007

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Figure 2. Particle-size distribution and shape of glass material.

Figure 4. Schematic diagram of crystallization setup and dimensioned drawing of standard retreat curve impeller with cylindrical baffle.

Figure 3. Particle-size distribution and shape of zinc dust material.

In the area of characterization, a number of papers dealing with particle shape and size using different techniques and applicability in different industries have been published.9-20 For example, consider two different samples, one is spherical and the other one is irregular, of materials that are of a range of different sizes. These could be measured as having similar particle-size distributions. The shapes and size distributions measured by laser diffraction of two such samples are shown in Figures 2 and 3. The particle-size data alone would not enable differentiation between them. A shape parameter would be a more appropriate discriminator between these two samples. In general, it is necessary to understand the particle shape and measured size and the interaction between these properties. According to a previous study,21 size distributions of needleshaped monosodium glutamate (MSG) can be obtained using image analysis, but most previous work has focused on inorganic and nonfragile particle shapes. In our case, crystal shape and size information was studied using ultrasonic attenuation spectroscopy (UAS), laser diffraction spectroscopy (LDS), and focused-beam reflectance measurement (FBRM) in addition to microscopic image analysis (MIA) for organic and inorganic crystals formed by batchcooling crystallization. Studies of all these techniques are based on off-line analysis. 2. Experimental Procedures 2.1. Crystallization Setup. Experiments were carried out in a 2 L jacketed glass vessel. The schematic diagram of the experimental rig is given in Figure 4 including the integrated temperature-control system. A perspex plate was placed on top of the 2 L, 150 mm diameter jacketed vessel, and silicone grease

Figure 5. L-Glutamate crystals before and after washing.

between the perspex plate and the chamber top made a seal in order to minimize evaporation and loss of solvent. The impeller (retreat curve) was used to reduce attrition and breakage and to obtain sufficient homogeneity and good heat transfer performance. A sketch of the retreat curve impeller dimensions is shown in Figure 4. The agitator was placed 20 mm from the bottom of the crystallizer. The diameter of the agitator is 97 mm, and one vertical cylinder baffle of 25 mm diameter was installed to avoid vortex formation and promote mixing. The agitation speed was kept at 100 rpm throughout the crystallization process. The experimental rig was connected to a thermostatically controlled water bath (Haake-F3) with a platinum resistance thermometer (Pt 100) to control the crystallization temperature. A PC running Labview controlled the heating and cooling rates within the chamber. The temperature of the crystallizer solution was recorded every 30 s. The solution temperature was adjusted automatically by the Labview control system to achieve a linear cooling rate. 2.2. Crystallization of Organic and Inorganic Chemicals. Cooling crystallization was performed using the setup shown in Figure 4. Initially, the solution was heated to above the saturation temperature and maintained at this temperature for 30 min in order to dissolve any nuclei formed during the handling of the solution. Later, the solution was cooled to below the saturation temperature through computer control at a preset

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Figure 6. Oxalic acid dihydrate and copper sulfate pentahydrate crystals before and after washing.

linear rate of cooling. In order to get a few grams of sample, the solution was kept at a constant temperature, which is below the saturation temperature for 90 min. Then the process was terminated, as crystal growth had consumed all the accumulated supersaturation. For L-glutamate, the cooling/heating rates used for these experiments were 6, 30, or 48 °C/h. These are the steps of the experimental protocol: • Step 1: heating at constant rate to above saturation temperature; • Step 2: temperature maintained for 30 min; • Step 3: cooling at constant rate to below saturation temperature; • Step 4: temperature maintained for 90 min; and • Step 5: crystallization terminated. This process was repeated for each of the cooling/heating rates, and the sizes and shapes of the crystals generated were recorded. Following the heating/cooling cycles, the concentration was changed to some other concentration. The experiments outlined above were then repeated for the new concentration. The initial concentrations used for these studies were 20, 30, or 40 g/L of solution. Thus, the effects of cooling/heating rate and initial solution concentration were studied on L-glutamate crystallization. For oxalic acid dihydrate and copper sulfate pentahydrate, the initial solution concentrations used were 150 and 400 g/L of solution, respectively, with a constant cooling/heating rate of 30 °C/h. The same experimental protocol was used with these materials. Crystallization was repeated at least 5-6 times to ensure good reproducibility and to collect a large number of samples for analysis of size and shape. 2.3. Washing of Product Crystals. The crystals were separated from the mother liquor on filter paper using a Buckner filter and dried for 30-45 min at 50 °C in an oven. The dried crystals appeared to agglomerate as shown in Figure 5 parts a and b and Figure 6 parts a and b. The crystals were washed with either methanol or ether in order to avoid agglomeration. Methanol was used for washing L-glutamate crystals, and ether was used for washing oxalic acid dihydrate and copper sulfate pentahydrate crystals, as these are very slightly soluble in methanol. Washing was repeated 4-5 times. With this method, individual crystals were obtained without agglomeration, as seen

Table 1. Steps in Crystallization of Organic and Inorganic Material at Different Concentrations L-glutamate

oxalic acid dihydrate

copper sulfate pentahydrate

steps

20 g/L

30 g/L

40 g/L

150 g/L

400 g/L

heated to (°C) hold time (m) cooled to (°C) hold time (m)

55 30 10 90

80 30 30 90

85 30 30 90

45 30 10 90

75 30 20 90

Table 2. Crystal Shape Formations by L-Glutamate at Different Cooling Rates and Concentrations Used initial solution concentration, g/L of solution cooling/heating rate, °C/h

20

30

40

6 30 48

R R R

β R R

β R + β (mostly β) R

in Figure 5 parts c and d and Figure 6 parts c and d. The dried product was used for analysis of shape and size distribution. 2.4. Characterization Techniques. The procedure for UAS (Malvern Ultrasizer) requires 2.8 L of sample suspension placed in the chamber of the Ultrasizer. Commercial sunflower oil was used as the dispersion medium. The solubilities of the organic and inorganic chemicals used are negligible in this oil. The internal stirrer was set at 300 rpm. The sample concentration used was 0.5% by volume to obtain the CSD. An external coil, through which water was passed from a Haake F3 water bath, controlled the temperature. The measurement temperature was maintained constant at 25 °C. The attenuation data against frequency was deconvoluted into particle volume-size distribution using proprietary software (Malvern Ultrasizer) based on the ECAH model.22,23 The software is applicable to particles in the size range 10 nm-1 mm at 0.1-50% by volume.24,25 Its applicability to crystallization processes was demonstrated previously.26 LDS technology (Malvern Mastersizer S long bench) requires a dilute suspension of sample consisting of a few milligrams of crystals. The sample was passed through the measuring cell using a peristaltic pump with a flow rate of 45 mL/min. The


Figure 9. Comparison of CSDs for β-glutamate (30 g/L of sol, 6 °C/h).

Figure 7. Crystal images from solution crystallization.

the midpoint (mean size) of an individual channel, and k is the total number of channels). This is analogous to volume distribution. MIA requires a small amount of homogeneous sample placed on a glass slide. An Optronics TEC 470 monochrome CCD camera mounted on a Nikon Optiphot XN with variable reflected light microscope was used to capture crystal images. This system captures images in a computer using a Scion CG-7 capture card. The images were processed with the commercially available Aequitas image analysis software. Details of image processing and data obtained from microscopy images are discussed in a previous paper.27 The crystal size distribution was reported for an average of 2000 particles from several glass slides each having around 7-15 crystals. The number-based distribution was converted to volume-based in order to compare with the other techniques. 3. Results and Discussion

Figure 8. Comparison of CSDs for R-glutamate (30 g/L of sol, 48 °C/h).

suspension was stirred to ensure good homogeneity. Sunflower oil was again used as the dispersant liquid. With LDS, the CSD that represents projected area-equivalent spherical diameters is calculated from the scattering pattern. The sample required for the FBRM (Mettler Toledo D600L) technique is around 300-350 mL. The sample was placed in a beaker provided with the instrument. The instrument was allowed to warm up for 30 min. The suspension was agitated using a pitched-blade stirrer set at 400 rpm. With this technique, a chord-length distribution (CLD) was obtained, unlike the CSD obtained from UAS and LDS. In this study, the crystal chordlength measurement is based on square-weighted chord-length k k distribution (Cs ) ∑i)1 niMi3/∑i)1 niMi2, where ni is the number of counts in an individual measurement channel, Mi is

3.1. Effects of Cooling Rate and Solution Concentration on Polymorphism. Nine experiments were carried out on L-glutamate solution crystallization to investigate the effects of cooling rate and solution concentration on crystal polymorphic form. Two experiments were performed using oxalic acid dihydrate and copper sulfate pentahydrate in which the effects of cooling rate and initial solution concentration were not investigated, as these compounds are nonpolymorphic in nature. The conditions used to perform crystallization were described in Section 2.2. With this procedure, L-glutamate crystallizes into one of two polymorphs shown in Figure 7 at different initial solution concentrations and cooling rates. Oxalic acid dihydrate and copper sulfate pentahydrate crystallize into one form each, which are also shown in Figure 7. For all the microscopic images, the parameters inside the bracket in the caption give information about the initial solution concentration and cooling rate used to generate that particular form. The critical steps involved in the crystallization of L-glutamate, oxalic acid dihydrate, and copper sulfate pentahydrate at different solution concentrations are summarized in Table 1 with initial and final set-point temperatures. Using the separation technique described in Section 2.3, a moderate amount of individual crystals was obtained without agglomeration. The photographs of crystals formed before and after the separation are given in Figures 5 and 6. The crystals of R- and β-glutamate, oxalic acid dihydrate, and copper sulfate pentahydrate were aggregated before the separation process, as seen from Figures 5a and 5b and Figures 6a and 6b, respectively. The R-crystals are rounded and the β-crystals are somewhat

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Table 3. Evolution of the CSD Using UAS for Different Chemical Systems

GM1 GD1 Prop1 GM2 GD2 Prop2 conc. residual GM GD conc. residual

R (20 g/L, 48 °C/h)

R (30 g/L, 48 °C/h)

R (40 g/L, 48 °C/h)

79.63 1.88 49.06 308.8 1.34 50.94 0.49 3.55

117.9 1.71 61.38 365.9 1.29 38.62 0.51 3.1

90.32 1.91 57.1 333.62 1.42 42.9 0.45 4.28

0.207 1.2 2.57 12.45

0.207 1.2 2.99 10.92

0.207 1.2 3.17 11.27

β (30 g/L, 6 °C/h)

oxalic acid dihydrate (150 g/L, 30 °C/h)

copper sulfate pentahydrate (400 g/L, 30 °C/h)/

Bimodal 62.51 1.87 93.14 482.3 1.2 6.86 0.37 2.24

128 1.2 32.98 172.5 1.55 67.02 0.46 2.98

139.1 1.52 76.65 412.7 1.25 23.35 0.47 1.93

Monomodal 63.72 1.99 0.29 4.11

108.3 1.74 0.1 15.06

184.2 1.53 0.18 13.17

Table 4. Size and Shape Properties for Different Organic and Inorganic Crystals R-glutamate at 48 °C/h measurement technique UAS LDS FBRM MIA

β-glutamate at 6 °C/h

oxalic acid dihydrate at 30 °C/h

copper sulfate pentahydrate at 30 °C/h

property

20 g/L of sol

30 g/L of sol

40 g/L of sol

30 g/L of sol

150 g/L of sol

400 g/L of sol

mean (µm) mean (µm) sq. wt. mean (µm) mean (µm) circularity sphericity aspect ratio

205.5 315.8 100.4 437.6 0.584 0.714 1.15

189.2 300.2 111.2 355.6 0.555 0.655 1.3

242.9 326.6 97.9 399.3 0.558 0.632 1.35

66.3 169.9 140.7 313.4 0.144 0.277 8.96

183.6 354.4 142.2 489.1 0.4 0.535 3.11

163.8 327.9 86.3 384.7 0.501 0.705 1.404

broken, as observed in Figure 5 parts c and d, probably due to collisions. Oxalic acid dihydrate crystals show slight changes in their regularity and some breakage at the edges due to processing, as seen in Figure 6c. Figure 6d shows that a few copper sulfate pentahydrate crystals are broken at the edges but most of them have regular shape. The generation of different polymorphic crystals (R- or β-glutamate) under different conditions by solution crystallization is summarized in Table 2. Some specific differences between R- and β-glutamate generation can clearly be observed in the solubility curves of L-glutamate polymorphs at different temperatures, as shown in Figure 1. According to the experimental results, the β- glutamate polymorph predominates at slow cooling rate with high solution concentration, whereas the combination of rapid cooling rate with low concentration favors R-glutamate. Both R- and β-glutamate were observed with a cooling rate of 30 °C/h with 40 g/L of initial solution concentration, but most of the crystals observed were β-form. This may be due to the partial transition from R- to β-form, which researchers have observed in studies on transition of L-glutamate.7,28-31 The R-glutamate was always generated in well-formed rhombs, while β-glutamate tended to crystallize as clusters of fragile needles. With these experimental results, a matrix was generated of shapes for different cooling rates and concentrations (Table 2). Elements above the diagonal of the matrix were observed as β-form, and all the other elements were observed as R-glutamate. The effect of cooling rate and solution concentration for oxalic acid dihydrate and copper sulfate pentahydrate crystallization was not studied because of the nonpolymorphic nature of the compounds, but the shapes of copper sulfate pentahydrate and oxalic acid dihydrate crystals were seen to be similar to R- and β-glutamate crystals, respectively. 3.2. Size Characterization of Organic and Inorganic Crystals. Three samples of R-glutamate were obtained at different concentrations with constant cooling rate (48 °C/h)

and one sample of β-glutamate was obtained (30 g/L of sol, 6 °C/h) for analysis of their size distributions. One sample each of oxalic acid dihydrate (150 g/L of sol, 30 °C/h) and copper sulfate pentahydrate (400 g/L of sol, 30 °C/h) were also used for size characterization. Figures 8 and 9 compare the CSDs of R-glutamate and β-glutamate crystals, respectively, measured using different techniques. The comparisons are shown as plots of cumulative volume fraction against crystal size. For all the measured crystals, UAS predicted bimodal crystal-size distributions, unlike the monomodal distributions found using LDS, FBRM, and MIA. This can be interpreted in terms of the measurement principles of the technique; crystal size by UAS is sensitive to the volume of the crystal. UAS assumes the crystal is spherical. In the case of an irregular crystal, the diameter is based on a sphere, which has the same volume as that of an irregular crystal. Table 3 presents the full record of the bimodal analysis of UAS by Ultrasizer software and results obtained when the UAS analysis was constrained to be monomodal. In that table, GM, GD, and Prop refer to the geometric means, geometric deviations, and proportions of modes 1 and 2; monomodal parameters are included in the same table. The residual gives an indication of the quality of fit between the measured spectrum and the theoretical spectrum associated with the estimated size distribution. A maximum residual value of 5% is usually recommended for a good analysis. Therefore, bimodal distributions were selected because of the low residual values obtained by bimodal analyses. For MIA, the mean size was reported from measurement of around 2000 crystals. Manual analysis of these crystals, with typically 200 images, took 7-8 h with the microscopy used in the present study. Recently, researchers32,33 reported using image analysis of 500-1000 particles to obtain statistically reliable results. Differently from the other techniques used, FBRM provides chord-length distribution in place of crystal-size distribution. For MIA, the 2D projected areas are measured for individual


Figure 10. Dimensions of length against width for R-glutamate (20 g/L of sol, 48 °C/h).



Figure 13. Dimensions of length against width for β-glutamate (30 g/L of sol, 6 °C/h).

crystals. As crystals lie in their most stable state, the images give maximum areas. The number-based CSD was converted to volume-based CSD. For LDS, the scattering patterns are due to 2D projections of crystals perpendicular to the beam. The LDS measurement is taken from a group of crystals, which are at different orientations and cumulatively averaged. In UAS, the attenuation spectrum is measured in 3D space due to interactions between sound waves and crystals. The CSD given by UAS is the equivalent 3D volume diameter instead of the 2D equivalent area diameter of MIA (largest projected area) and LDS (average projected area). The results from UAS and LDS measurements are given for volume-based CSD. Similar to MIA and LDS, the CLD measured by FBRM is obtained from the 2D projected areas of individual crystals, which depend on crystal orientation. The results from FBRM measurements are for the square-weighted number distribution to convert to volume basis. The volume mean size results reported for UAS measurements in Table 4 are the D50 by volume of the bimodal distributions obtained by the UAS deconvolution. The measured mean sizes of the different crystals of R- and β-glutamate, oxalic acid dihydrate, and copper sulfate pentahydrate samples measured using UAS, LDS, MIA, and FBRM are summarized in Table 4. The mean values measured by all these techniques do not follow any particular trend with concentration at a cooling rate of 48 °C/h for R-glutamate crystals. Table 4 shows that the mean sizes obtained by MIA are much larger than those obtained by UAS and LDS. Also, the mean size found by UAS is smaller than the mean size found by LDS for R-glutamate. Similar phenomena were observed for the other crystal shapes studied. The mean of square-weighted CLD by FBRM is less than that by MIA or LDS but larger

than that by UAS for all measured crystals apart from β-glutamate. Thus, it is not true that the mean of the CLD is always smaller than the CSD mean, but it depends on the measurement technique and on the crystal shape. The following relationship is defined for the measured organic and inorganic crystals:

{

UASmean > CLDmean MIAmean > LDSmean > or CLDmean > UASmean

}

(1)

For all the techniques used, a discrepancy of measured mean sizes is evident for the distributions of nonspherical crystals. This is probably due to the interaction of shape effect with the measurement principles. However, a close match of measured mean size was observed for spherical beads in our previous study27 using all these techniques. For the initial solution concentrations and cooling rates used, size distributions are observed to cover a broad size range from 20 to 1000 µm, as shown in Figures 8 and 9. This could be due to either secondary nucleation or orientation of the crystals. Without seeding, crystallization can produce broad size distributions. Seeded crystallization is recommended to produce narrow size distributions.34 Laser diffraction spectroscopy gives a broader apparent distribution because measurements are made at random orientations. Ultrasonic attenuation spectroscopy gives bimodal distribution with little effect of orientation because the measurement is based on 3D equivalent spherical volume. 3.3. Shape Characterization by MIA. The shapes of the crystals were measured using MIA technique. Simple shape descriptors that can be used for quantitative evaluation of shape

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Figure 14. Dimensions of length against width for oxalic acid dihydrate (150 g/L sol, 30 °C/h).

compared with R-glutamate crystals in Figures 10-12 and copper sulfate pentahydrate in Figure 15. This is believed to be due to breakage of β-glutamate crystals and oxalic acid dihydrate crystals. Other shape factors, sphericity and circularity, are also given in Table 4. The values of each of these shape factors for the R-glutamate crystals were found to vary slightly with initial solution concentration used. The small variation of shape factors indicates a largely uniform shape in the population. The small differences may be due to surface irregularities along with errors during image processing. The image-processing errors are likely to arise from debris removal, the process of deleting objects in the microscopic image, which clearly mismatch with size and/ or shape criteria. 3.4. Interaction of Measured Size with Shape. Another issue for this study was the interaction of measured crystal size with shape. The shape factors and size information obtained by MIA were compared with size data from UAS and LDS. For R-glutamate (30 g/L, 48 °C/h) crystals, the calculated ratios of UASmean /MIAmean and LDSmean/MIAmean were 0.53 and 0.84, respectively. Values of 0.21 and 0.54 were found for UASmean/ MIAmean and LDSmean/MIAmean, respectively, for β-glutamate (30 g/L, 6 °C/h) crystals. The ratio (UASmean/MIAmean) is roughly equal to the circularity, 0.55 for R-glutamate (30 g/L, 48 °C/h) and 0.14 for β-glutamate (30 g/L, 6 °C/h) crystals. The ratio (LDSmean/MIAmean) is also roughly equal to the square root of sphericity, 0.81 for R-glutamate (30 g/L, 48 °C/h) and 0.53 for β-glutamate (30 g/L, 6 °C/h). Similar phenomena were observed for the other materials: oxalic acid dihydrate, copper sulfate pentahydrate, and R-glutamate at other concentrations. These relationships can be summarized by

UASconverted mean ) C‚MIAmean ) (C/xS)LDSmean

Figure 15. Dimensions of length against width for copper sulfate pentahydrate (400 g/L of sol, 30 °C/h).

such as circularity, sphericity, and aspect ratio were used to characterize each sample for all the measured crystals. Definitions of these shape factors were presented in another paper.27 The ranges of these shape factors are from 0 to 1 except for the aspect ratio, which is from 1 to ∞. The maximal Feret diameter was obtained from the image-analysis software used, and the size descriptor width W was estimated using equations defined in the earlier paper27 for each crystal. The mean shape factors of L-glutamate crystals formed at different concentrations and cooling rates are summarized in Table 4 along with those of oxalic acid dihydrate and copper sulfate pentahydrate crystals at one concentration and cooling rate. The scatter graphs in Figures 10-13 show the distribution of width W and length L for R- and β-crystals of glutamate, and Figures 14 and 15 show the distributions for oxalic acid dihydrate and copper sulfate pentahydrate, respectively. The mean aspect ratio (L/W) for all these crystal systems are summarized in Table 4. It can be seen from these scatter graphs that small variation in aspect ratio is found for the R-crystals at all concentrations and cooling rates. Aspect ratios of needleshaped crystals in Figures 13 and 14 are scattered widely

(2)

LDSconverted mean ) xS‚MIAmean ) (xS/C)UASmean (3) MIAconverted mean ) (1/C)UASmean ) (1/xS)LDSmean (4) where C ) circularity and S ) sphericity. These similarities can be accounted for in terms of the different measurement principles; crystal size by UAS is based on a sphere, which has the same volume as that of the irregular crystal, while the crystal size by MIA is based on a circle, which has the same area as the projected area of the crystal. The ratio of these two crystal sizes is represented by the circularity. The LDS crystal size is dependent on crystal cross-sectional area normal to the light beam, so the measured mean size distribution is due to the mean cross-sectional area of the crystals. Hence, the ratio between LDS and MIA crystal size is given by the square root of sphericity and the ratio between image area diameter and equivalent circular perimeter diameter.27 The same relationships have been observed in a previous study for glass and silica flakes35 and for commercially available monosodium glutamate, oxalic acid dihydrate, and sucrose along with crystallized L-glutamic acid, which were sieved into narrow size ranges for measurements.27

Table 5. Percentage Mean Errors in Conversions between Measurement Techniques for Different Crystals based on MIAmean

based on UASmean

based on LDSmean

compound

UASerror (%)

LDSerror (%)

LDSerror (%)

MIAerror (%)

UASerror (%)

MIAerror (%)

R (20 g/L, 48 °C/h) R (30 g/L, 48 °C/h) R (40 g/L, 48 °C/h) β (30 g/L, 6 °C/h) oxalic acid dihydrate (150 g/L, 30 °C/h) copper sulfate pentahydrate (400 g/L, 30 °C/h)

-24.4 -4.3 8.3 31.9 -6.6 -17.6

-17.1 4.3 2.8 2.9 -0.9 1.5

5.8 8.1 -5.9 -32.3 5.3 16.3

19.6 4.1 -9.0 -36.7 6.2 15.0

-6.2 -8.8 5.6 29.8 -5.6 -19.5

14.6 -4.4 -2.9 -3.1 0.9 -1.6


The errors in converting between means obtained by different techniques can be calculated by applying eqs 2-4 and 5.

eration of colleagues on the project “Chemicals Behaving Badly II” is also gratefully acknowledged.

Techniqueerror(%) ) [(Techniquemean Techniqueconverted mean) × 100]/Techniquemean (5)

Nomenclature

where Technique is one of UAS, LDS, or MIA. The conversion errors are shown in Table 5 for all crystals measured using UAS, LDS, and MIA. From the values summarized in Table 5, a good agreement of conversions is seen for most of the crystals measured, though β-glutamate (30 g/L, 6 °C/h) and copper sulfate pentahydrate (400 g/L, 30 °C/ h) showed significant conversion errors. The discrepancy for β-glutamate (30 g/L, 6 °C/h) crystals is believed to be mainly due to the length of these thin needle crystals exceeding 1000 µm, the maximum size measurable by the UAS technique. The significant conversion errors for copper sulfate pentahydrate (400 g/L, 30 °C/h) are mainly due to the presence of air bubbles in the suspension. These were caused by the aggressive mixing required to suspend these high-density crystals (specific gravity of 2.284) in sunflower oil. The discrepancy for R-glutamate (20 g/L, 48 °C/h) crystals is mainly due to the MIA, in which large crystals dominate the distribution compared to fine crystals. The small conversion errors for other measured crystals are likely to be due to experimental and image-processing errors mainly caused by surface roughness, noise, crystal breakage, and aggregation. The residual errors generated by deconvolution of attenuation spectra into CSD using Ultrasizer were also included. The error in converting number distribution by MIA to volume distribution was considered to be significant. When converting a number distribution to a volume distribution, large crystals dominate the result. For example, if the mean size of a number distribution by MIA is subject to an error of (2%, after conversion the error will increase to (6% error because the volume mean is a cubic function of diameter. 4. Conclusions In this research, the parameters controlling formation of polymorphic L-glutamate crystals (R as rhombs and β as needles) and nonpolymorphic crystals oxalic acid dihydrate and copper sulfate pentahydrate were discussed. The crucial effects of cooling rate and solution concentration were observed on L-glutamate crystallization. The β-polymorph of L-glutamate predominates at slow cooling rate with high solution concentration; a combination of rapid cooling rate with low concentration favors the R-form. These controlling factors for the formation of L-glutamate crystals can be used to optimize the polymorph crystallization process with the aid of dynamic simulations using a kinetic model. The size and shape of these forms were studied using ultrasonic attenuation spectroscopy, laser diffraction spectroscopy, focused-beam reflectance measurement, and microscopic image analysis. Comparing these analysis techniques, the following conclusions were obtained. The mean sizes obtained from these techniques follow a trend for all measured organic and inorganic crystals. Crystal shape strongly affects the mean size measured by different techniques for all the crystals measured here. Conversions among mean sizes by these techniques excluding FBRM are possible and can be done using the crystal shape factors circularity and sphericity. Acknowledgment The financial support of EPSRC (Grant GR/R93353/01) and Heriot-Watt University is gratefully acknowledged. The coop-

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ReceiVed for reView October 27, 2006 ReVised manuscript receiVed October 3, 2007 Accepted October 17, 2007 IE061381D

Characterization of Organic and Inorganic Chemicals Formed by

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