Pharmaceutical crystallization in Couette-Taylor crystallizer : A case study of polymorphism of amino acid L-glutamic acid

The influence of intensity Taylor vortex flow in Couette-Taylor crystallizer on the crystallization of polymorphic amino acid Lglutamic acid was investigated in cooling crystallization. Here, the L-glutamic acid was chosen as the model crystal product, where it has two kinds of polymorphism including the unstable phase α-form and stable phase β-form crystal. In cooling crystallization, the α-form crystal transformed to the β-form crystal corresponding to the phase transformation of αform to β-form crystal. The present study found that the selective polymorphism of α-form and βform crystal as well as the phase transformation significantly depended on the intensity of turbulent Taylor vortex flow in Couette-Taylor crystallizer. Here, the selective β-form nucleation and phase transformation were remarkably promoted as increasing the rotation speed of inner cylinder in Couette-Taylor crystallizer. By comparison with the conventional stirred tank (ST) crystallizer, the Couette-Taylor (CT) crystallizer was at least 2.0 times more effective as regards the selective βform polymorphism and phase transformation time. The advantage of CT crystallizer over the conventional ST crystallizer was explained in terms of the high shear stress and mass transfer of turbulent Taylor vortex flow in CT crystallizer. Here, the shear stress of Taylor vortex flow in CT crystallizer was at least 23.0 times higher than that of fluid motion in conventional ST crystallizer, whereas the mass transfer of Taylor vortex flow in CT crystallizer was at least 1.2 times higher than that of fluid motion in conventional ST crystallizer. As such, the high turbulent shear stress of Taylor vortex flow was expected to promote the β-form nucleation via the effective molecules alignment, whereas the high mass transfer of Taylor vortex flow facilitated the dissolution rate of α-form and growth rate of β-form crystal, resulting in an acceleration of phase transformation rate. SCIENCE & TECHNOLOGY DEVELOPMENT, Vol 19, No.K62016 Trang 12


INTRODUCTION
Crystallization is a significant separation, purification and particle technology used in various life science industries including pharmaceuticals, foods and fine chemicals, etc.
Crystallization is known as the crucial process in order to obtain high quality of solid products including purity, polymorphism, shape, size and size distribution, etc [1][2][3].
Even Since the conformation and packing of molecules in solution directly depended on the fluid hydrodynamic in crystallizer, the fluid hydrodynamic is certainly considered as the key factor to control the selective and phase transformation of polymorphism [7][8][9].For example, Sypek et al [7] reported that the stable phase of carbamazepine was selectively obtained in stirred crystallization, whereas the unstable phase was preferably crystallized in a stagnant crystallization.As regards the phase transformation, Davey et al [8] indicated that the completed phase transformation of 2,6dihydroxybenzoic acid from unstable to stable phase required at least 20 days in a stagnant crystallization, but it was significantly reduced to only 2−3 days in stirred crystallization.A similar phenomenon was observed in case of taltireline crystallization, where the agitation speed was attributed to promote the phase transformation of unstable phase to stable phase [9], etc.
Our patent Couette-Taylor crystallizer is known as the unique crystallizer which has an effective fluid hydrodynamic that is called the Taylor vortex flow.Couette-Taylor crystallizer has been widely applied in various crystallization processes including batch and continuous system for many organic and inorganic compounds.In addition, the flexibility of Couette-Taylor crystallizer is also demonstrated when it can be applied for varied crystallization techniques including the reaction, anti-solvent and cooling crystallization, etc [10][11][12][13][14][15][16].In the polymorphic organic and inorganic material crystallization, the Couette-Taylor crystallizer has been already applied in order to control the selection and phase transformation of polymorphic crystal.For instance, Nguyen et al [10][11][12][13][14][15] indicated that the phase transformation of guanosine 5-monophosphate from amorphous phase to crystalline hydrate phase was significantly facilitated over 5.0 times as using the Couette-Taylor crystallizer compared to that in the conventional stirred tank crystallizer.
Moreover, Lee et al [16] reported that the stable phase of sulfamerazine crystal was more favorably performed as using the Couette-Taylor crystallizer compared to that in the conventional stirred tank crystallizer, etc.Amino acids are valuable materials which have a wide application in various products including pharmaceutical, food, fine chemical, agricultural, cosmetic, etc. Almost amino acid crystal products have polymorphism such as Lglutamic acid, L-histidine, Glycine, L-lysine, etc.In our current work, the amino acid Lglutamic was chosen as a model crystal product to demonstrate the effectiveness of Couette-Taylor crystallizer in controlling polymorphism of amino acid.It is well known that L-glutamic acid crystal has two kinds of polymorphic crystal including the unstable phase α-form and stable phase β-form crystal, in which the unstable phase α-form transformed into the stable phase β-form crystal during crystallization.In case of L-glutamic acid crystallization, Kitamura et al [17] reported that the selective polymorphism of unstable phase αform was successfully obtained when the solution was agitated, whereas a polymorphic mixture of α-form and β-form crystal was crystallized in the stagnant solution.Florence et al [18] also indicated that the selective polymorphism of stable phase β-form crystal was performed as using the oscillatory baffled crystallizer, etc.
Although the crystallization of amino acid L-glutamic acid has been carried out, most of them were conducted in the conventional stirred tank crystallizer, where the phase transformation of unstable phase α-form to stable phase β-form required an extreme long crystallization time even beyond 40 hours.Meanwhile, the encrustation or blockage often occurs as using the other crystallizer such as oscillatory baffled and plug flow crystallizer, etc.Therefore, it is really necessary to develop the more effective crystallizer in order to control the polymorphism of amino acid L-glutamic acid in crystallization.
In contrast to previous studies, the Couette-Taylor crystallizer in our current work was developed to facilitate the polymorphic crystallization of L-glutamic acid, where the dependency of selective polymorph and phase transformation on the intensity Taylor vortex flow in Couette-Taylor crystallizer was deeply investigated.Moreover, according to , the crystallization research is not found in the South and East Asian countries including Vietnam, Indonesia, Philippine, Malaysia, etc, meaning that the crystallization research should be developed in the South and East Asian countries.
Here, the CT and ST crystallizer with 400 ml working volume were operated under the same crystallization conditions.During cooling crystallization, the temperature of both crystallizers was controlled via the circulating coolant from the chiller, while the rotation speed of inner cylinder in CT crystallizer and the agitation speed of impeller in ST crystallizer were controlled via the DC motor.
Amino acid L-glutamic acid material (≥98% purity) was purchased from Sigma Aldrich Company.The feed solution was prepared by dissolving the material into the distilled water at 70 0 C, and the concentration was always fixed at 45(g/L).The CT and ST crystallizer were initially filled with the feed solution, and then operated as the batch mode cooling crystallization with cooling rate of 0.5( 0 C/min).The products were periodically taken from the crystallizers and quickly filtered by using a vacuum pump.The crystal samples were then dried in a desiccator to analyze the shape, size, size distribution, polymorphism, etc.
Here, the shape and structure of crystal product were monitored and confirmed by Video microscope and XRD patterns (M18XHF-SRA, Japan), respectively, while the crystal fraction of β-form was detected by the FT-IR spectroscopy [21].During cooling crystallization, the solution temperature was continuously monitored by using the temperature indicator (Korea).Based on the mechanism of two-step nucleation that was reported by Myerson et al [22], the solute molecules were initially aggregated to form a disorder structure of cluster that had a random arrangement of molecules, but this disorder structure of cluster was then progressively restructured to form an order structure which became a specific polymorphic crystal.As such, the shear stress of fluid hydrodynamic might attribute to the restructure stage to determine the formation of polymorphic crystal, as shown in Figure 6

Characteristic of Taylor vortex flow in
Meanwhile, the Sherwood number corresponding to the mass transfer at the solidliquid interface in CT crystallizer was expressed by Nguyen et al [10][11][12][13][14][15]   As such, the shear stress and mass transfer of Taylor vortex flow in CT crystallizer could be estimated via the (1) and ( 2).As shown in Figure 7, the shear stress and mass transfer of Taylor vortex flow in CT crystallizer obviously increased as increasing the intensity fluid hydrodynamic, meaning that the higher intensity Taylor vortex flow provided the higher shear stress, so the β-form nucleation was promoted, leading to enhancement of the crystal fraction of β-form in the solid product (Figure 3-5).Plus, the higher intensity of Taylor vortex flow also provided the higher mass transfer rate, so the dissolution rate of α-form and growth rate of βform crystal would be more facilitated, implying that the phase transformation of α-form to βform crystal was more accelerated as increasing the intensity fluid hydrodynamic, which resulted in an increase of the crystal fraction of β-form in the solid product, as depicted in Figure 3-5.As shown in Figure 8(a), it was revealed that the shear stress of fluid hydrodynamic in both CT and ST crystallizers increased as increasing the agitation speed of inner cylinder and impeller.However, there was a significant difference in terms of the shear stress between the CT and conventional ST crystallizer according with the agitation speed.Here, the shear stress of Taylor vortex flow in CT crystallizer was at least 23.0 times higher than that of fluid hydrodynamic in conventional ST crystallizer in a whole range of agitation speed.This result implied that the β-form nucleation was much more facilitated as using CT crystallizer compared to the conventional ST crystallizer.Thus, the phase transformation of α-form to βform crystal were much more facilitated as using the CT crystallizer than that in the conventional ST crystallizer.The above result matched well with the previous result reported by Khuu et al [24], where the induction time of β-form and reconstruction time of phase transformation were significantly reduced at least 2.0 times as using the CT crystallizer compared to the conventional ST crystallizer.

CONCLUSION
The present study found that the intensity has two kinds of polymorphism including the unstable phase α-form and stable phase β-form crystal.In cooling crystallization, the α-form crystal transformed to the β-form crystal corresponding to the phase transformation of αform to β-form crystal.The present study found that the selective polymorphism of α-form and βform crystal as well as the phase transformation significantly depended on the intensity of turbulent Taylor vortex flow in Couette-Taylor crystallizer.Here, the selective β-form nucleation and phase transformation were remarkably promoted as increasing the rotation speed of inner cylinder in Couette-Taylor crystallizer.By comparison with the conventional stirred tank (ST) crystallizer, the Couette-Taylor (CT) crystallizer was at least 2.0 times more effective as regards the selective βform polymorphism and phase transformation time.The advantage of CT crystallizer over the conventional ST crystallizer was explained in terms of the high shear stress and mass transfer of turbulent Taylor vortex flow in CT crystallizer.Here, the shear stress of Taylor vortex flow in CT crystallizer was at least 23.0 times higher than that of fluid motion in conventional ST crystallizer, whereas the mass transfer of Taylor vortex flow in CT crystallizer was at least 1.2 times higher than that of fluid motion in conventional ST crystallizer.As such, the high turbulent shear stress of Taylor vortex flow was expected to promote the β-form nucleation via the effective molecules alignment, whereas the high mass transfer of Taylor vortex flow facilitated the dissolution rate of α-form and growth rate of β-form crystal, resulting in an acceleration of phase transformation rate.
crystallizer should be clearly understood before investigating the crystallization.In Couette-Taylor crystallizer, when the inner cylinder is rotated, the centrifugal force of inner cylinder make the fluid element move from the surface of inner cylinder to the surface of outer cylinder[10][11][12][13][14][15].At a certain rotating speed, when the centrifugal force is larger than the viscous force, the fluid hydrodynamic in the gap cylinders between the inner and outer cylinder becomes instability.The ratio of centrifugal force to viscous force is expressed via the dimensionless Taylor number (Ta), and based on the Taylor number the fluid hydrodynamic regime of Couette-Taylor crystallizer can be the laminar Couette flow, laminar Taylor vortex flow, singly wavy vortex flow, doubly wavy vortex flow, weakly turbulent wavy vortex flow and turbulent vortex flow.As such, the Taylor vortex flow in Couette-Taylor crystallizer appears when the Taylor number (Ta) is beyond the critical value that denoted the critical Taylor number (Ta c ).It is well known that the Taylor vortex flow is the strong periodic circular fluid motion which has the high mass/heat transfer and homogeneous mixing condition.Since the one pair of Taylor vortex flow is assumed as a micro-stirred tank crystallizer, the Couette-Taylor crystallizer can be considered as a series of connected micro-stirred tank crystallizer, as shown in Figure 1.Thus, it is expected that the Couette-Taylor crystallizer will be more effective than the stirred tank crystallizer as regards the amino acid L-glutamic acid crystallization.In present study, the fluid hydrodynamic in Couette-Taylor crystallizer was designed as the Taylor vortex flow in a whole range of operating conditions, implying that the crystallization of amino acid L-glutamic acid in Couette-Taylor crystallizer is always conducted under the Taylor vortex flow, as displayed in Figure 1.

Figure 4 .
Figure 4. Typical solid product as regards to the effect of intensity Taylor vortex flow and crystallization time: (a) Ta = 1034 and (b) Ta = 10335

Figure 5 .
Figure 5.Effect of crystallization time (a) and intensity Taylor vortex flow (b) on the crystal fraction of β-form in CT crystallizer Figure 6(b).

Figure 6 .
Figure 6.Schematic influence of fluid shear (a) and mass transfer (b) on the selective polymorphism and phase transformation of L-glutamic acid For deep understanding, the shear stress and mass transfer of Taylor vortex flow in CT crystallizer were clarified.Here, the shear stress () of turbulent Taylor vortex flow in CT crystallizer was estimated by Nguyen et al [10-15] as as , d p indicates the diameter of the solid particles, while D f and k are the diffusion coefficient and mass transfer coefficient, respectively.

Figure 7 .
Figure 7. Influence of intensity fluid hydrodynamic on the shear stress and mass transfer in CT crystallizer 3.3.Comparison of Couette-Taylor (CT) and Stirred tank (ST) crystallizer In order to evaluate the value of CT crystallizer with respect to the polymorphic Lglutamic acid in cooling crystallization, the comparison between the Couette-Taylor (CT) and conventional standard stirred tank (ST) crystallizer was investigated.Since the shear stress and mass transfer of fluid hydrodynamic in crystallizer played key roles to determine the efficiency of L-glutamic acid crystallization, the shear stress and mass transfer of fluid hydrodynamic in both crystallizers should be estimated and compared.

Figure 8 .
Figure 8.Comparison the shear stress and mass transfer of fluid hydrodynamic in CT and ST crystallizers As shown in Figure 8(b), although the mass transfer of fluid hydrodynamic in both crystallizers increased as increasing agitation speed, the mass transfer of Taylor vortex flow in CT crystallizer was also at least 1.2 times higher than that of fluid hydrodynamic in conventional ST crystallizer in a wide range of agitation speed, meaning that the dissolution rate of αform and growth rate of β-form crystal were much more accelerated under the Taylor vortex flow in CT crystallizer compared to that under the fluid motion in conventional ST crystallizer.