Crystallization of Paracetamol under Oscillatory Flow Mixing

Crystallization of Paracetamol under Oscillatory Flow Mixing Conditions Chew,†

Chun M. Radoljub I. James J. De Yoreo#

Ristic,*,†

Robert D.

Dennehy,‡

and

CRYSTAL GROWTH & DESIGN 2004 VOL. 4, NO. 5 1045-1052

Department of Chemical & Process Engineering, The University of Sheffield, Mappin Street, S1 3JD Sheffield, United Kingdom, GlaxoSmithKline, Strategic Technologies, Tonbridge, Kent TN11 9AN, United Kingdom, and Lawrence Livermore National Laboratory, 7000 East Avenue, Livermore, California 94550-9234 Received March 8, 2004;

Revised Manuscript Received June 17, 2004

ABSTRACT: There has been an increasing effort in designing pharmaceutical particles with controllable properties (quality) such as chemical purity, morphology, size distribution, surface characteristics, and microstrain content. In this paper, we explore the feasibility of oscillatory flow mixing (OFM) in improving the quality of pharmaceutical precipitates, using paracetamol (4-acetamidophenol) as a model system. In-situ atomic force microscopy (AFM) and optical microscopy were applied to observe the growth of {110} faces of single paracetamol crystals. These studies showed that (a) the bunching and macrostep formation occur at all values of supersaturation; and (b) the oscillation of solution with respect to the growing interface and its relative velocity are the critical parameters for the minimization of the interfacial instabilities, and in turn, for maintaining structural quality. These findings were tested in a conventional impeller driven batch crystallizer (IDBC) and in an oscillatory baffled batch crystallizer (OBBC), in which, apart from hydrodynamics, all external conditions such as initial supersaturation and crystallization temperature were kept constant. The physical properties (the quality) of the precipitates were characterized by low angle laser light scattering (LALLS), scanning electron microscopy (SEM), and X-ray powder diffraction (XRPD), respectively. The analysis of obtained results and their comparison for these two types of mixing shows clearly that particles precipitated in OBBC are of significantly higher quality than those produced in IDBC. A computational fluid dynamics (CFD) software package, Fluent 5, was used to model dynamical fluid patterns in both crystallizers. Introduction It is well-known that “elemental” growth steps (molecular layers of height of one or just a few crystal lattice units) spreading across any crystal face tend to lose their stability by coalescing into step bunches of dozens or hundreds of unit step heights. In other words, the growing interfaces are morphologically unstable with respect to step bunching.1 This instability is medium independent, so it is common to growth from vapor, melt, or solution. Once this instability has been initiated, it continues to evolve, leading to unsteady layer propagation accompanied by further step bunching consisting of a multitude of “domes” and “ridges” of different heights. Step bunching is generally identified as the major cause of nonuniform impurity trapping and consequent striation formation in the growing crystals.2,3 Bunched steps may, in turn, lose their stability and develop into macrosteps of thousands of unit cells height with a whipsaw-like shape. These steps and their propagation are the main reasons for trapping of vapor/ melt/solution inclusions and subsequent development of dislocations.4,5 The consequences of these instabilities are quite detrimental, in particular, to the properties such as compositional and structural uniformity (quality) of the crystallizing material. The understanding and control of step bunching are important in a wide range * To whom correspondence should be addressed. Tel: +44 (0)114 2227516. Fax: +44 (0)114 2227501. E-mail: [email protected]. † University of Sheffield. ‡ GlaxoSmithKline, Strategic Technologies. # Lawrence Livermore National Laboratory.

of modern technology fields, for example, fabrication of one-dimensional superlattice structures, creation of novel epitaxial architectures, e.g., quantum wires,6 growth of high quality laser doubling crystals,7 and preparation of high diffraction-quality protein crystals.8 On the other side, in industrial crystallization, there has been an increasing demand for high quality particle production, notably, in specialty chemicals and pharmaceuticals. Powder caking, control of purity, and lack of drug dosage controls in tableting are some of the direct consequences of interfacial instabilities. Growth conditions under which the interfacial instabilities are less likely to occur are not completely understood. Various reasons for the loss of step train stability, step bunching, and macrostep formation have been considered: (i) step-step interactions due to competition for growth units (atoms, ions, molecules) supply via surface diffusion,9,10 (ii) interactions due to overlapping of elastic fields of the steps,11 (iii) asymmetry for incorporation from top and lower terraces (Schwoebel effect),12 (iv) impurity effects,13,14 and (v) asymmetry due to solution flow.15,16 It should be noted that in all these studies, a fixed crystal face with respect to the moving fluid (vapor, solution, or melt) and constant driving force for crystallization have been assumed. It is then apparent that the overall contemplation and control of the interfacial stability of a small crystal (particle) growing in a batch crystallizer would become even more complicated. This is due to a spatialtemporal relative movement of a particle and fluid, relative change of its position with respect to the vicinal flow layers, and continuous decrease of supersaturation.

10.1021/cg049913l CCC: $27.50 © 2004 American Chemical Society Published on Web 08/12/2004

1046 Crystal Growth & Design, Vol. 4, No. 5, 2004

Chew et al.

Figure 2. (a, b) The effects of solution flow direction on interface instabilities. The dislocation source is indicated by the black arrow, and the direction of solution flow is indicated by the white arrow (after ref 1).

Figure 1. Interfacial morphology of the {110} face of paracetamol grown by (a) dislocation mechanism and (b) 2-D nucleation. (c) Step bunching occurring at low supersaturation. (d) Interface instabilities manifested at high supersaturation.

In this paper, we explore new strategies for reducing interfacial instabilities and thus improving the structural quality of pharmaceutical crystalline particles grown from a specially designed oscillatory baffled batch crystallizer (OBBC). The quality of these particles were compared to the quality of particles precipitated under the same conditions of temperature and initial supersaturation, but at different hydrodynamics, using “classical” impeller driven batch crystallizer (IDBC). The quality of particles was characterized by the size distribution measurements, surface characteristics, and microstrain of precipitated particles. Paracetamol has been used as a model system. Interfacial Instabilities of Paracetamol and Strategies for Their Minimization Instabilities of the {110} Faces of a Fixed Single Crystal. Different crystallographic interfaces may display different degrees of instability. Previous studies have shown that the {110} type interface is the least stable in paracetamol, and as such a major source of inclusions caused by the movement of macrosteps.17 Morphological instability of the {110} faces of paracetamol has been investigated in a wide range of supersaturations, from very low to very high (Figure 1). In all these experiments, the observed interface was fixed with respect to solution flow. At very low supersaturation (σ < 3%), because of virtually negligible growth rate, in-situ atomic force microscopy (AFM) was used.18 Figure 1a,b shows typical interfacial morphologies of the {110} face under these conditions. It grows either by a dislocation (spiral) mechanism or by twodimensional (2-D) nucleation. In both cases, the growth steps are elemental (monomolecular height) in the close vicinity of the growth step source, and it appears that there is no bunching because of the very small area that

can be observed by AFM. By changing the locality of the observation at the same interface, step bunching can be found (Figure 1c), but to a lesser extent than that at higher supersaturations (Figure 1d). Therefore, particles grown at very low supersaturation should be of relatively high quality. However, because of their extremely low growth rates, the overall yield will be significantly less cost-effective and, as such, without commercial interest. The evidence that bunching occurs at all levels of supersaturation is compelling; it appears that it is unavoidable and is more pronounced at higher supersaturations. The question is how to reduce it to an optimal level by precipitating particles at a reasonably high supersaturation level with a cost-effective yield? To answer this question, we are inspired by wellestablished morphology behavior of a vicinal hillock around a dislocation source (indicated by the black arrow in Figure 2) subjected to a laminar flow.1 When a solution flows downward (white arrow), the lower slope hillock loses its stability and is covered with macrosteps (Figure 2a). After the change of the flow rate direction, the macrosteps on the lower slope of the hillock disappear and form on its upper slope (Figure 2b). As the distance from the center increases, the steps are seen to become gradually larger. In both cases, the steps of the hillock, facing the flow direction, experience stabilization (the macrostep becomes smaller), while the steps of the hillock coinciding with the solution direction suffer from destabilization. These results lead to the conclusion that the net effect of surface instabilities of a growing face will be lower, if the solution is forced to oscillate. Hence, the quality of a crystal whose faces are exposed to an oscillatory shear rate is expected to be higher than that grown at either stagnant solution or laminar flow. Instabilities of the {110} Faces of a Particle Grown in IDBC. In the real industrial systems such as IDBC, to increase yield precipitation always occurs at high initial supersaturation. Under such supersaturation, the morphology of the growing interfaces is markedly unstable. Figure 3 shows typical surface morphological instabilities of the {110} faces evolved at high supersaturation. The steps traveling from the edges toward the center of the interface become unstable and get bunched, lose their instability again, and become macrosteps with a whipsaw shape, and then trap inclusions of solvent. Apart from this, moving toward the center, the propa-

Crystallization of Paracetamol

Crystal Growth & Design, Vol. 4, No. 5, 2004 1047

Figure 3. Surface morphological instabilities manifested at high supersaturation.

Figure 5. Schematic diagram showing experimental setup of the OBBC.

Figure 4. Schematic diagram showing experimental setup of the IDBC.

gation of these macrosteps decelerates significantly due to the existence of a concentration gradient across the interface. Therefore, the design of a crystallizer, with such hydrodynamic characteristics, which would enable a considerable increase of the relative velocity of a solution with respect to a particle, is crucial. The findings described in the previous and this section suggest that for precipitation of high quality particles two factors may be critical: (1) oscillation of solution, and (2) relative velocity of solution/particle. The question is whether these conditions are achievable in a batch crystallizer, in which small crystals continuously change their positions, orientations, and velocity with respect to the mixed solution. To answer this question, parallel precipitation experiments were performed in two crystallizers that employ different mixing mechanisms: (i) IDBC, a conventional choice of mixing mechanism involving an axial, three bladed propeller and a set of four equally spaced rectangular baffle configuration. (ii) OBBC, an alternative mixing mechanism that generates intense eddy mixing by periodic oscillation of the process fluid in a baffled column (also known as the oscillatory flow mixing (OFM)).19 The quality of the precipitated paracetamol crystals obtained in IDBC and OBBC is measured, analyzed, and then compared by using different physical characterization methods. Experimental Section Impeller Driven Batch Crystallizer (IDBC). Figure 4 presents the schematic diagram of the IDBC used to provide reference results for comparison with the OBBC. It is in principle the same as those used in the industry, but with a smaller volume, so the mimicking of industrial batch crystallization is possible on a smaller scale. The system

consists of a jacketed borosilicate glass vessel of 95 mm internal diameter with nominal capacity of 900 mL. The water jacket is connected to an automated Haake thermostat circulator, which provides temperature control within an accuracy of ( 0.01 °C. Mixing of the solution during the crystallization experiments is provided by a 50-mm diameter three-bladed marine impeller, which is driven by an electronic controlled variable speed IKA overhead motor. Four baffles of 10 × 135 mm are attached to the lid. Two openings on the lid enable insertion of the temperature control probe and the sampling of crystal suspension for size distribution measurement. Oscillatory Baffled Batch Crystallizer (OBBC). Figure 5 shows the schematic diagram of the OBBC designed for studying the influence of oscillatory flow mixing on the characteristics of paracetamol precipitates. It consists of a vertical, cylindrical Perspex column of internal diameter 32 mm with a outer water jacket. The column is connected to a Lings dynamic system (LDS) electromagnetic oscillator, which provides oscillation of the column with an amplitude range of 1-4 mm, and a frequency range of 1-20 Hz. A baffle set consisting of 11 Perspex annular baffles with the thickness of 2 mm, interconnected by 3 Perspex rods, is inserted into the column and fixed by an outer frame during the crystallization experiments. A wide range of baffle spacing configuration has been used.20 To avoid large-scale flow channelling and to promote satisfactory vortex interaction, the baffle spacing of 1.5 times the column internal diameter is selected for the OBBC. The outer diameter of each annular baffle is 30 mm and orifice diameter 15 mm, which result in a restriction ratio of 0.25. Restriction ratio is defined as the ratio of the orifice cross-sectional area (flow area) and the total cross-sectional area of the baffles. The water jacket is connected to an automated Haake thermostat circulator, which can provide temperature control within an accuracy of ( 0.1 °C. The outer jacket is designed to ensure that the free surface within the inner column would be below the top of the water jacket at working volume up to 500 mL. In addition, to minimize the possibility of contamination during the experiment, a cover is designed to secure the top section of the oscillatory column. Material. The paracetamol powder used in the crystallization experiments is commercially available from Merck at the purity level of 99+%. The powder was used without further purification. Experimental Procedures. Paracetamol solution with desirable supersaturation was prepared using the procedure described in ref 21. The experiments were performed in the supersaturation range 10-50%. Supersaturations were expressed in terms of percentage supersaturation, (c/c* - 1) × 100%, where c and c* are the actual and equilibrium concen-


Chew et al.

Table 1. Summary of Operating Conditions and Their Corresponding Oscillatory Reynolds Number in an Ascending Order operating conditions

oscillatory Reynolds no., Reo

10 Hz-3 mm 5 Hz-7 mm 15 Hz-3 mm 10 Hz-5 mm

5660 6600 8480 9430

tration at the crystallization (working) temperature. The working temperature for the crystallization experiments was 20 °C. Once a solution of desired supersaturation was prepared, it was transferred to a crystallizer (IDBC or OBBC). The temperature of the crystallizer water jacket was temporarily increased to preheat the solution to 5 °C higher than that of the saturation temperature of the solution to dissolve any crystalline matter that may form during the transfer process, and to avoid the possibility of early nucleation at the cooler surface of the crystallizer. The preheating procedure would take 10-15 min, depending on the supersaturation level of the solution. After the preheating, the Haake thermostat circulator was set to cool the supersaturated paracetamol solution to the working temperature of 20 °C. The mixing mechanism of the crystallizer was switched on when a solution in the crystallizer reached the working temperature. For the IDBC, the impeller speeds used in this study were 800 and 600 rpm; for the OBBC, four combinations of oscillation frequency and amplitude were investigated. The four pairs of operating conditions can be characterized by the “oscillatory” Reynolds number, Reo, which is defined as:

Reo )

2π f0x0Fd µ

(1)

where d is the tube diameter (m), F is solution density (kg/ m3), µ is solution viscosity (kg/ms), f0 the oscillation frequency, and x0 is the oscillation amplitude. The oscillatory Reynolds number describes the mixing intensity applied to the crystallizer. The four pairs of OBBC operating conditions, and their corresponding Reo, are summarized in Table 1. The mixing mechanism was allowed to continue for a further 30 min after the onset of the first sign of any opacity caused by the nucleation and appearance of paracetamol crystals. After the precipitation period, the suspension was quickly poured into a clean conical flask, where 5-mL samples were pipetted off to have the size distribution analyzed. The remaining suspension was filtered through a Whatman 0.2 µm membrane filter and the precipitate was dried at 30 °C. Quality Assessment of Precipitates. The quality of precipitated crystals was characterized by the methods summarized in Table 2. Low Angle Laser Light Scattering (LALLS). The volume weighted median diameter, D50, of the paracetamol crystals precipitated in OBBC and IDBC was measured by Sympatec Helos LALLS instrument (Sympatec GmbH, Germany).22 It uses a standard helium-neon laser (632.8 nm wavelength) as the light source and has a measuring range of 0.1-875 µm. Scanning Electron Microscopy (SEM). The morphology and surface characteristics of the bulk crystallized samples were examined by a Camscan MK-2 scanning electron micro-

Figure 6. Volume-weighted median diameter, D50, of particles precipitated in IDBC and OBBC at different initial levels of supersaturation. Each point represents the average value of several sets of experiments under similar operating conditions. scope. Prior to SEM observations, the samples were goldcoated in a sputter coater unit (Emscope SC-500). X-ray Powder Diffraction (XRPD). The X-ray powder diffraction (XRPD) of precipitated samples was measured by a Bruker D8 Advance X-ray diffractometer (Bruker AXS, UK) using characteristic Cu-KR radiation. To assess an average crystalline size and microstrain in the particles, these data were subjected to the line broadening profile analysis. For this purpose, a simultaneous crystalline size-strain analysis was performed by the Rietquan program.23 The program uses the single line integral breadth method,24,25 in which the convolution pattern fitting is carried out with Voigt function. An important parameter in this profile function, which enables the estimation of crystallite size and microstrain is the integral breadth, or the half width at half maximum (HWHM) of the diffraction peaks. The crystallite size and microstrain can be estimated from the individual Lorentzian and Gaussian contribution to the total integral breath, respectively. The “extraction” procedure of these two contributions can be found elsewhere.26,27

Results and Discussions Final Size Distribution. Figure 6 shows the volumeweighted median diameter of particles, D50, as a function of initial supersaturation for paracetamol crystals precipitated in IDBC and OBBC. A family of two lines, with nonzero slopes, corresponds to IDBC, while a family of four horizontal lines corresponds to OBBC. For IDBC, the upper line is obtained for the impeller speed of 600 rpm and the lower line is for 800 rpm. For OBBC, each horizontal line refers to a particular value of oscillatory Reynolds number, Reo, defined by eq 1. Several important findings can be drawn from Figure 6:

Table 2. Physical Methods Used to Assess the Quality of Precipitated Crystals final size distribution crystal morphology and surface characteristics crystalline imperfections

physical characterization method

expression of quality

low angle laser light scattering (LALLS) scanning electron microscopy (SEM)

volume weighted median diameter, D50 direct visualization of crystal morphology and evidence for interfacial instability crystalline microstrain

X-ray powder diffraction (XRPD) line broadening profile analysis by Rietveld refinement


(a) The increase of agitation intensity in both IDBC and OBBC results in the formation of smaller particles. The agitation intensity is related to operating parameters such as oscillation frequency, amplitude, and impeller speed. (b) Considerably smaller particles were precipitated in OBBC than in IDBC. (c) The size distributions of particles crystallized in OBBC were almost independent of the initial supersaturation. Although not completed yet, the above results are already suggestive that the OBBC is an alternative and innovative crystallization system whose mode of mixing can substantially influence some physical properties of precipitated particles. The capability of the OBBC to produce particles of the properties indicated in a-c is rather intriguing. All findings can be associated to a higher dynamical nucleation rate induced by the oscillatory mixing. Dynamic nucleation is defined as any nucleation event that occurs as the result of relative motion between different parts of the crystallization system, which includes the liquid and any solid in contact with it.28 The dynamic stimulus is likely to manifest in the form of shear rate (∼ relative rate of a fluid layer with respect to the rates of its neighboring layers). Early molecular dynamics simulation studies have demonstrated the effects of shear-induced ordering, where fluid molecules show signs of ordering (in terms of alignment angle and end-to-end distance), and phase transition when shear rate is applied on the systems.29-31 This alignment will serve as a template for nucleation. It is thus speculated that the OBBC may generate a higher shear rate than that of the IDBC, and subsequently brings upon a more active role in dynamical nucleation. Surface Characteristics. Figure 7 shows typical SEM images of paracetamol crystals precipitated in IDBC. A significant proportion of the crystals have cavities near the central region of their faces. At the later stage of growth, these cavities are occluded causing inclusion formation. This decreases chemical purity of the drug and may result in caking during their storage. Using our previous experience on the fixed single-crystal face, we argue that a frequent macrostep and cavity formation at the interfaces of growing particles are caused by low solution/solid shear rates as well as by the lack of alternative change of their flow directions. Figure 8 shows the SEM images of paracetamol crystals precipitated in OBBC. Compared to those precipitated in the IDBC, it is apparent that these crystals have smoother surfaces, and significantly less evidence of particles with cavities. These features are typical for all particles crystallized in OBBC. Using the same philosophy established for the fixed single crystal, we conclude that, on average, the interfaces of the precipitated particles had been subjected to much higher alternating shear rates and exposed to them for a considerably longer time. At this stage, we believe that OBBC is able to produce almost equal amounts of clock/anticlockwise vortices providing a hydrodynamic environment, in which interface instabilities are markedly reduced. Microstrain Assessment by Rietveld Refinement. Figure 9a,b shows the microstrain values of different paracetamol samples obtained from OBBC and


Figure 7. SEM images showing typical surface characteristics of paracetamol crystals precipitated in IDBC.

IDBC, for supersaturation of 40 and 50%, under different operating conditions. Each sample is arbitrarily assigned to a number, as shown on the x-axis. The obtained results show that for the explored range of supersaturation, the average value of microstrain induced in particles crystallized in OBBC is by a few orders of magnitude smaller than that in particles precipitated in IDBC. These remarkably low microstrain values signify less formation of inclusions in the particles precipitated from OBBC. This is consistent with the deductions drawn in the previous section, in which the interface stabilization effects were linked to close interaction between interfaces of growing particles and vortices of different signs continuously produced by the OBBC. This compelling visual evidence offered by the SEM images (Figures 7 and 8) and supported by the findings of the microstrain from the Rietveld refinement (Figure 9a,b) reaffirm that the precipitates produced from the OBBC are of higher quality than those from the IDBC. Computational Fluid Dynamics Model. To validate some speculations used in the previous three sections, we performed computational fluid dynamics (CFD) modeling to evaluate the spatial shear rate distributions in both mixing devices.32 The data are given in Table 3.


Chew et al.

Figure 9. Tabulation of microstrain results for supersaturation levels of (a) 40.5% and (b) 51.4%. Horizontal lines represent the mean values of microstrain for the particular mixing mechanism at the respective supersaturation.

Figure 8. SEM images showing typical surface characteristics of paracetamol crystals precipitated in OBBC.

The marked difference in the volume-averaged shear rate between two types of crystallizers is evident. It appears that dynamical nucleation, induced by oscillatory mixing, is the major contributor to a higher nucleation rate in the OBBC compared to that in the IDBC. On the other side, one may argue that the increased shear rate will also lead to increased secondary nucleation rate. If this assumption was correct, the integral strain in the OBBC precipitated particles would be either similar or appreciably higher than that obtained from IDBC precipitated particles. However, the microstrain assessment of the OBBC particles shows the opposite results. Therefore, dynamical nucleation process is likely to dominate in OBBC. An additional consequence of the increased nucleation rate was manifested through the particles of smaller sizes observed in the OBBC precipitates (Figure 6). A clear existence of the particle size-supersaturation dependence in the IDBC can be explained by a relatively low dynamical nucleation, compared to that in the OBBC. The markedly lower shear rate in the IDBC suggests a negligible contribution of dynamical nucleation to the overall crystallization rate in this system. For the same material crystallizing at constant temperature, nucleation rate (expressed as the number of nuclei produced per unit time per unit volume) increases rapidly with supersaturation.33 On the contrary, a lower

Table 3. Summary of Volume-Averaged Shear Rate in Two Mixing Mechanisms at Different Operating Conditions type of crystallizer and operating conditions

volume-averaged shear rate (s-1)

IDBC, 600 rpm IDBC, 800 rpm OBBC, 10 Hz-3 mm OBBC, 10 Hz-5 mm

18 20 108 179

nucleation rate is expected at lower supersaturation. Under these circumstances, the particles are more likely to achieve larger sizes than those nucleated at initially higher supersaturation. Variations in the shear rates of both mixing mechanisms were quantified in terms of its spatial and temporal distributions. For the modeled operating conditions, our analysis of the spatial shear rate distribution showed that periodic vortex shedding ensures alternating of high and low shear regions in the OBBC, thus providing an efficient chaotic mixing within the agitated vessel (Figure 10). On the other hand, the spatial shear rate distribution in the IDBC consists of predominantly localized shear regions (Figure 11), in which the volume-averaged shear rate is of one order magnitude smaller than that of the OBBC (Table 3). Apart from this, the modeling shows that in the case of OBBC, particles spend most of their residence time in the high shear regions, while particles in IDBC reside mainly in the regions of considerably lower shear rates (Figure 12).



Figure 10. (a, b) Flow field superimposed on shear (strain) rate contour, for 10 Hz-5 mm, during different phases of oscillation. Bulk flow is from right to left, with a phase shift with respect to the boundary conditions.

Figure 11. x-z plane at the midway the impeller rod in IDBC, showing superimposed tangential velocity field on shear rate contour. The high shear region is localized mainly at the central part of the crystallizer.

Our simulations have also revealed the coexistence of dominant vortices of opposite signs (clockwise/anticlockwise) during the flow cycle in OBBC (Figure 13). The markedly higher volume-averaged shear rate, longer particle residence time in the high shear region, and the coexistence of strong circulation vortices of

Figure 12. Comparison of the cumulative temporal shear rate distribution of IDBC and OBBC under different operating conditions. (O: IDBC, 800 rpm; ∆: OBBC, 10 Hz-5 mm).

opposite signs, contribute to the quality improvement. Higher volume-averaged shear rate and longer particle residence time in the high shear region ensure higher relative velocity of the solution layer adjacent to the growing crystal interface, and hence, better mass trans-


Chew et al.

Acknowledgment. This work is financially supported by EPSRC and GSK through Grants GR/M96858 and RF103869. The authors gratefully acknowledge the support of the director and staff of the Lawrence Livermore National Laboratory (CA) through the provision of the AFM facilities. C.M.C. and R.I.R. are particularly thankful to Prof. M. R. Mackley at the University of Cambridge (UK) for providing the LDS oscillator. References

Figure 13. Typical velocity vector maps at the cross-section of the interbaffle region during different stages of OFM oscillation, at 10 Hz-5 mm operating conditions. Dominant vortices pairs and their direction are indicated by circular arrows.

fer. The coexistence of strong circulation vortices, acting in opposite directions, further promote the stabilization of crystal interfaces when the solution layers in intimate contact with crystal interfaces are forced to oscillate as the crystals travel from one vortices to another. Conclusions It is shown that the interface instabilities can be reduced to a remarkable level by oscillatory mixing. This was tested by precipitating paracetamol crystals from batch crystallizers employing two different mixing mechanisms, OBBC and IDBC. Investigations were conducted to explore quality improvement of the crystals in terms of particle size, surface characteristics, and crystalline microstrain. Our results showed that particles precipitated from OBBC exhibit higher quality than those from IDBC. The improvements in different aspects are summarized below: (i) Smaller volume weighted median diameter, D50, were observed for particles precipitated from OBBC. (ii) Smoother surface characteristics and lesser evidence of interface instabilities were observed for particles precipitated from OBBC, while cavities were observed in most particles from IDBC. (iii) Significant reduction of the microstrain level occurred in the particles crystallized from OBBC.

(1) Chernov, A. A. Contemp. Phys. 1989, 30, 251-276. (2) Rosenberger, F. Fundamentals of Crystal Growth, Vol. 1: Macroscopic Equilibrium and Transport Concepts; Springer: Berlin, 1979; p 450. (3) Chernov, A. A. Modern Crystallography, Vol. III: Growth of Crystals; Springer: Berlin, 1984; p 246. (4) Ristic, R. I.; Sherwood, J. N.; Shripathi, T. J. Cryst. Growth 1998, 179, 194. (5) Halfpenny, P. J.; Oneil, L.; Sherwood, J. N.; Simpsons, G. S.; Yokotani, A.; Miyamoto, A.; Sasaki, T.; Nakai, S. J. Cryst. Growth 1991, 113, 722-725. (6) Bauer, E. G.; Dodson, B. W.; Ehrlich D. J. et al. J. Mater. Res. 1990, 5, 852-894. (7) Booth, N. A.; Chernov, A. A.; Vekilov, P. G. J. Cryst. Growth. 2002, 237-239, 1818-1824. (8) Vekilov, P. G.; Lin, H.; Rosenberger, F. Phys. Rev. E. 1997, 55, 3202. (9) Sato, M.; Uwaha, M. Phys. Rev. B. 1995, 51, 11172. (10) Uwaha, M.; Saito, Y.; Sato, M. J. Cryst. Growth 1995, 146, 164. (11) Bakes, G. S.; Zangwill, A. Phys. Rev. B. 1990, 41, 5500. (12) Schwoebel, R. L.; Shipsey, E. J. J. Appl. Phys. 1966, 37, 3682. (13) v.d. Eerden, J. P.; Muller-Krumbhaar, H. Phys. Rev. Lett. 1986, 57, 2431-2433. (14) Potapenko, S. Y. J. Cryst. Growth 1995, 147, 223. (15) Coriell, S. R.; Murray, B. T.; Chernov, A. A.; McFadden, G. B. J. Cryst. Growth 1996, 169, 773. (16) Chernov, A. A. J. Cryst. Growth 1992, 118, 333. (17) Ristic, R. I.; Finnie, S.; Sheen, D. B.; Sherwood, J. N. J. Phys. Chem. B 2001, 105, 9057-9066. (18) Chew, C. M.; Ristic, R. I.; de Yoreo, J. J., manuscript in preparation. (19) Mackley, M. R.; Smith, K. B.; Wise, N. P. Chem. Eng. Res. Des. 1993, 71, 649-656. (20) Brunold, C. R.; Hunns, J. C. B.; Mackley, M. R.; Thompson, J. W. Chem. Eng. Sci. 1989, 44, 1227-1244. (21) Finnie, S. D.; Ristic, R. I.; Sherwood, J. N.; Zikic, A. M. J. Cryst. Growth 1999, 207, 308-318. (22) Sympatec, Sympatec User’s Manual, Sympatec GmbH, Germany, 1988. (23) Lutterotti, L.; Scardi, P. J. Appl. Crystallogr. 1990, 23, 246252. (24) De Keijser, Th. H.; Langford, J. I.; Mittemeijer, E. J.; Vogels, A. B. P. J. Appl. Crystallogr. 1982, 15, 308-314. (25) De Keijser, Th. H.; Mittemeijer, E. J.; Rozendaal, H. C. F. J. Appl. Crystallogr. 1983, 16, 309-316. (26) Young, R. A. The Rietveld Method; Oxford University Press: Oxford, U.K., 1993. (27) Rietveld, H. M. J. Appl. Crystallogr. 1969, 2, 65-71 (28) Chalmers, B. In Liquids: Structure, Properties, Solid Interactions; Hughel, T. J. Eds.; Elsevier Publishing Company: New York, 1963; pp 308-325. (29) Morriss, G. P.; Daivis, P. J.; Evans, D. J. J. Chem. Phys. 1991, 94, 7420-7433. (30) Erpenbeck, J. J. Phys. Rev. Lett. 1984, 52, 1333-1335. (31) Van der Eerden J. P., Utrecht University, The Netherlands, private communication. (32) Chew, C. M.; Ristic, R. I.; Reynolds, G. K.; Ooi, R. C. Chem. Eng. Sci. 2004, 59, 1557-1568. (33) Mullin, J. W. Crystallisation, 3rd ed.; Butterworth-Heinemann: U.K., 1993; pp 172-200.

CG049913L

Crystallization of Paracetamol under Oscillatory Flow Mixing

Recommend Documents