Keywords

1 Introduction

Crystallization is widely used in various chemical industries such as pharmaceuticals and the food field. Crystallization is the unit operation with the nonequilibrium crystallization phenomenon of which driving force is supersaturation. A crystal is the solid form which the molecule and the ion arranged orderly, and crystallization is used not only as separation but as purification operation. In the case of solution-suspended crystallization, crystallization operation is also used for manufacturing crystalline particles. Thus, crystallization operation is the method to realize “separation and purification” and “crystalline particle production.” However, demand to crystalline qualities has been getting severe recently. The strategy of operation design to manufacture the crystalline particles with high quality is important.

The generation of supersaturation is essential to crystallization, because it is the driving force for nucleation and crystal growth. When crystalline particles are manufactured, particle size distribution is determined by the suspended crystallizer. In batch crystallization operation, as crystal growth proceeds, solution concentration changes. Accordingly, the subsequent nucleation and crystal growth processes are influenced by reduced supersaturation (Fig. 4.1). It is the characteristic of crystallization to have feedback structure in such processes. And the product quality of crystals is decided through these phenomena. Especially, when industrial productivity is taken into consideration, it is necessary to control the crystal size distribution. When the research target is extended to the field which deals with the nucleation and growth by the driving force of supersaturation, the application range of crystallization becomes wide. There are many contact points with crystallization operation in the field of solid-state material production of nanomaterial development. This chapter focuses on the solution crystallization operation in which the characteristics of crystalline particles are observed.

Fig. 4.1
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Relationships among crystallization phenomena

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2 Supersaturation in Crystallization Operation

In order to deposit crystals, the temperature must be lowered than the solubility curve, or the concentration must be higher than the solubility curve. If the clear solution (point P of Fig. 4.2) is cooled, this solution is saturated when solution states cross the solubility curve (point S). If the solution is cooled continuously, the solution reaches the supersaturation condition. If the solution temperature further decreases, nucleation occurs (point N) and the solution concentration begins to decrease because crystal growth begins. Since the supersaturation condition can be maintained whenever cooling operation continues, crystalline particles continue to grow. If the cooling operation stops, the solution concentration reaches the saturated concentration at this temperature (point E), and crystal growth stops. The driving force of crystallization is the supersaturation which is defined by Eq. (4.1) and is expressed as ln S and/or σ.

Fig. 4.2
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Solution concentration profile during cooling crystallization (phase diagram)

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$$ \frac{\Delta \mu }{kT}\cong \ln \left(\frac{C}{C^{*}}\right)= \ln S= \ln \left(1+\frac{\Delta C}{C^{*}}\right)= \ln \left(1+\sigma \right)\cong \sigma $$
(4.1)

The growth rate and the nucleation rate are required to decide a production rate and to estimate the number of crystals which is generated during operation, respectively. Therefore, it is important to estimate a degree of supersaturation. The growth phenomena are dominant if an operation point is in the region near the solubility curve. The nucleation becomes dominant if an operation point is more distant from the solubility curve. In cooling crystallization, the operation is carried out in a metastable zone [18] so that a nucleation may not become dominant [15].

Figure 4.3 is the time profile for the change in the solution concentration shown in Fig. 4.2. If an operating point exceeds a metastable zone, a nucleation occurs frequently. Therefore, the crystalline particles with undesired particle size distribution are obtained (Profile A). On the other hand, if a supersaturation peak is reduced, growth phenomenon becomes dominant and can control nucleation. For example, if sufficient quantity of seed crystals is introduced at the early stages of cooling, the consumption rate of solute becomes high and the peak of supersaturation decreases. Moreover, even if the cooling rate decreases at an early time, there is a possibility that the peak of supersaturation decreases (Profile B). In this way, it is important how the trajectory of supersaturation is designed in crystallization operation [21].

Fig. 4.3
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Solution concentration profile during cooling crystallization (changes in supersaturation)

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3 Quality of Crystalline Particles

Since pharmaceuticals are life-related substances, severe qualities of crystalline particles are required. In pharmaceutical production, the suspended-type crystallizer of batch process is often used. “Cooling crystallization” which deposits crystals by cooling, “anti-solvent addition method” which adds the solvent whose target pharmaceuticals do not dissolve, and “concentrating method” which removes the solvent by evaporation are used. Of course, there is also a crystallization method which combined these methods [16]. In addition to the high purity, the particle size distribution, polymorphism, and morphology which are required in industrial crystallization, bioavailability, solubility, and stability are important in pharmaceuticals production. Moreover, from the viewpoint of a pharmaceutical preparation process, the quality of compressibility, flowability, plasticity, and mixing nature are important. Such qualities are deeply concerned with particle size distribution and crystal morphology. It is necessary to carry out the operation in which various crystalline qualities are satisfied simultaneously. However, as shown in Fig. 4.1, there are few operational parameters, and most of those qualities are dependent on the supersaturation described earlier. That is, the generation method and generation rate of supersaturation are very important for the determination of crystalline qualities. And if the location and start period of nucleation and growth processes can be limited, it becomes easy to control the quality of crystalline particles.

4 Milli-segmented Flow Crystallizer

4.1 Anti-Solvent Crystallization

A grinding process is commonly used for producing fine crystalline particles. However, there are problems such as the difficulties in crystal size distribution and crystal shape control, improvement in energy efficiency, and treatment free of contamination. In the pharmaceutical industry, the denaturation behavior of materials by mechanical and thermal energy is also an important problem. The demands for manufacturing fine crystalline particles by solution crystallization are also growing for simplification of the pharmaceutical preparation process.

Anti-solvent crystallization (crystallization by mixing two solutions) is one of the techniques for producing crystalline particles. This crystallization process consists of three steps: (1) mixing of a feed solution and an anti-solvent, (2) nucleation from the mixed solution, and (3) crystal growth. In particular, supersaturation is achieved by mixing the feed solution and the anti-solvent, and then nucleation and crystal growth occur.

The generation method of the supersaturation of anti-solvent crystallization is illustrated on the phase diagram (Fig. 4.4). If solution B (point X) and solution A (anti-solvent, point Y) are mixed, the initial apparent concentration is point M. This solution is supersaturated, since crystallization occurs and the solution concentration reduces to give the saturated condition (point S). There is an operational merit that temperature operation is unnecessary, and it is possible to generate various supersaturation only by changing the mixing ratio.

Fig. 4.4
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Definition of supersaturation in anti-solvent crystallization

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If the number of crystal generation is controlled and crystal growth can be restricted, it can be expected that fine crystalline particles having monodispersed CSD (crystal size distribution) will be produced. In a stirred tank crystallizer, it takes a certain time period to mix a solution, since the crystallization field is large. Therefore, concentration distribution arises in the stirred tank. The existence of a concentration distribution has been clarified by a simulation [5]. Furthermore, it is difficult to control not only mixing but also nucleation because of the large crystallization field. Therefore, it is difficult for the stirred tank crystallizer to produce fine crystalline particles having monodispersed CSD.

A new crystallization method which produces fine crystals using a micro-reactor has been studied. The aim of this method is the restriction of crystal growth. For example, there are studies using a tubular crystallizer ([8]). The research of fine crystalline particle production using a micro-reactor has been reviewed by Zhao et al. [27]. The improvement in solution mixing behavior by using a segmented flow tubular reactor (SFTR) [6] has been studied. Solution volume is limited by segmented flow, which consists of the feed solution and anti-solvent joined at a mixer by immiscible fluid. The residence time of each segment in the tubular reactor is maintained constant if the flow rate of each fluid is controlled. However, in general, the crystallization using a micro-reactor also has a disadvantage in that the flow channel becomes clogged because of rapid crystal growth. On the other hand, in batch cooling crystallization, temperature profiles to produce crystals having a monodispersed CSD have been studied [14]. Takiyama et al. [20] reported that it is possible to make crystals with improved CSD by modulating the cooling program with heating operation (undersaturation operation) in the non-seeding operation.

If these approaches are applied and integrated with anti-solvent crystallization, it is expected that the CSD of fine crystals will be improved. For example, the nucleation zone can be introduced to a part of the segment flow in a milli-sized tube flow. There is a possibility of a further improvement in CSD by introducing temperature-modulated operation at the part of flow channel after nucleation. Furthermore, it is possible to prevent the flow channel clogging by introducing modulated operation. Thus, if each operating zone of a tubular crystallizer with milli-sized segmented flow has a crystallization function, it is expected to produce crystals which have a monodispersed CSD.

4.2 Nucleation Control

The nucleation control method was carried out for producing fine particles. The experiment was performed with the tubular-type crystallizer shown in Fig. 4.5. A taurine (solute) – water (solvent) – EtOH (anti-solvent) system was used. The feed solution and anti-solvent were a saturated taurine aqueous solution and pure ethanol, respectively. The tube flow crystallizer consisted of a Y-connector, T-connector, flexible connection tube, and metal tube ([10]). The metal tube was used for enhancement of nucleation by ultrasound irradiation. The Y-connector and T-connector were used as a mixer and a segmenter.

Fig. 4.5
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Schematic diagram of the experimental apparatus

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4.3 Production of Fine Crystals

The experimental conditions and obtained crystal qualities are shown in Table 4.1. An SEM image for the samples of Run X and Run D is shown in Fig. 4.6.

Table 4.1 Experimental conditions and crystal quality
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Fig. 4.6
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SEM photomicrographs for samples of Run X and Run D

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Based on Table 4.1, the effect of nucleation is not observed only under the cooling operation condition. On the other hand, ultrasound irradiation is effective in inducing nucleation. In addition, it was observed that the nucleation was enhanced by integrating ultrasound irradiation and temperature modulation. For Run D and Run X, each number-based CSD is shown in Fig. 4.7.

Fig. 4.7
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CSDs for samples of Run X and Run D

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While the CSD became wide and the mean size of crystals also became larger in the early stage in the case of Run X, which was carried out as a batch crystallization, fine crystalline particles which have monodispersed and comparatively narrow CSD were obtained in Run D. From these results, it became clear that the integration method of ultrasound irradiation and temperature modulation in milli-sized segmented flow is capable of controlling nucleation, and fine particles with monodispersed CSD were produced.

Based on these results, an operation strategy could be proposed. This strategy is the adjustment of slurry concentration by controlling the anti-solvent composition and flow rate of each fluid. It was confirmed that the integration of ultrasound irradiation and temperature modulation in a milli-sized segmented flow is effective in producing organic fine crystalline particles having monodispersed and narrow CSD.

5 Templated Crystallization

5.1 Nucleation at the Interface

Fine monomodal crystalline particles are required in many fields such as pharmaceuticals and fine chemicals. The production of crystals with well-controlled size distribution facilitates improvement of dissolution rate. The inhaled drug delivery systems require particle size between 1 and 6 μm for maximum efficiency [23]. Control of nucleation is essential technology to produce fine monomodal crystalline particles. The effects of operations for nucleation control were investigated in many studies. The templated crystallization is a method which can constrain nucleation field. Templated crystallization by using organic molecular assembly that can control molecular arrangement and constrain crystallization field has been also investigated in various studies. Since templated crystallization can control molecular arrangement directly, this method is investigated to control polymorphism [11, 1, 17, 13]. This method is used to investigate for mimicking biomineralization processes [12, 2, 3]. One of key features of templated crystallization is preferential appearance of crystals at template interface by interaction of template molecules and objective molecules. This characteristic nature at the template interface has advantageous field for crystallization.

In this section, the effect of template at the air/solution interface on the nucleation phenomena was introduced. If the timing of nucleation can be controlled by using template effects, monomodal crystalline particles can also be produced. Moreover, if crystalline particles after nucleation can be collected immediately, fine monomodal crystalline particles can be produced.

5.2 Templated Crystallization

There are some studies of templated crystallization that used glycine and L-leucine [24, 25, 4]. It was understood that L-leucine molecules were arranged in air/solution interface and glycine crystals grow at the interface. Then air bubble was inserted into the solution (this time was θ Air-in), and glycine crystals were observed at the air bubble/solution interface by using optical microscope ([26]).

Figure 4.8 shows the crystal growth at the template interface (θ Air-in = 458 s) in bubble insert experiment. The crystals at the interface had the same pyramid-like morphology and the same size, and these crystals are deposited selectively on the air/solution interface. These crystals were similarly grown and uniformed.

Fig. 4.8
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Glycine crystals grown at the air bubble/solution interface (θ Air-in = 458 s)

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Figure 4.9 shows crystal growth curves (crystal a and b in Fig. 4.8). The key of inverted triangle showed the timing when the bubble was inserted and the template interface was created. According to these growth curves, timings of nucleation were estimated. When growth curves were extrapolated L = 0, the value of θ was the nucleation time, θ Nuc. The θ Nuc values of crystal a and crystal b were identical 458 s. This result indicated that crystal nucleation was induced immediately after insert of the bubble into the supersaturated solution.

Fig. 4.9
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Glycine crystal growth curves of crystal a and crystal b (θ Air-in = 458 s)

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This experiment was carried out under the conditions of several air bubble insert times (θ Air-in). Figure 4.10 shows the relationships between θ Air-in and θ Nuc. All plots were located on a diagonal line. These experimental results indicated that the timings of air bubble insert θ Air-in and the timings of nucleation θ Nuc were very close, even if the air bubbles were inserted at any timing. The repeatability of nucleation phenomena often becomes a problem. However, this result indicated that crystal nucleation was able to be induced immediately after insert of the bubble into the supersaturated solution. Consequently, formation of air/solution interface into the supersaturated solution acted as the nucleation trigger.

Fig. 4.10
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The relationships between the template interface formation timing θ Air-in and the nucleation timing θ Nuc

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5.3 Nucleation Trigger

In order to produce fine monomodal crystalline particles, the experiment was carried out to collect crystals just after nucleation by using nucleation trigger. The experimental apparatus is shown in Fig. 4.11. This apparatus produced segmented flow of air bubbles and solution by pumping water and solution. The production timing of the air bubble in segmented flow was able to act as the nucleation trigger. So, fine monomodal crystalline particles were able to be produced by collecting immediately after using the nucleation trigger. Based on this operation strategy, the experiment was carried out ([26]).

Fig. 4.11
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Experimental apparatus for application of microcrystal generation by using the nucleation trigger

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Under the certain condition, the fine crystalline particles (number-based mean size L N = 0.62 μm, coefficient of variation CV N = 56 %) were obtained (Fig. 4.12). The glycine crystals had well-defined crystal face and pyramid-like morphology. It means that these fine crystals were generated on the air/solution interface. In these ways, by collecting crystalline particles immediately after nucleation was induced by nucleation trigger, submicron-order particles were obtained. Moreover, this operation method by using the nucleation trigger has the potential to produce fine crystalline particles with desirable size.

Fig. 4.12
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Obtained glycine microcrystals by using the nucleation trigger

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6 Liquid-Liquid Interface in Emulsion

6.1 Liquid-Liquid Interface

An anti-solvent crystallization method is the operation which adds the anti-solvent for reducing the solubility of the object solute and can be operated at ambient temperatures. This crystallization operation is used for the production of many pharmaceuticals. However, there are problems such as the difficulty of control of crystal morphology and size and generation of agglomerated crystals [19, 7]. In the previous report of the anti-solvent crystallization method, it becomes clear that a supersaturation ratio influences crystal size and morphology [19]. However, if local fluctuation of the supersaturation exists at the time of anti-solvent addition, various crystal sizes and morphologies would be deposited during desupersaturation.

In original anti-solvent crystallization, the supersaturation is generated by mixing a good solvent and an anti-solvent. And the contact area of these solvents is not controlled. It is considered that high local fluctuation of the supersaturation is produced in the case that the contact interface area between a good solvent and an anti-solvent is insufficient or in the case of slow solvent diffusion rate. Therefore, the following method can be proposed. First, rich contact surface area is built up in a solution, and then the crystallization is carried out at this limited interface. Specifically, a rich contact interface is generated by preparing an emulsion with an immiscible good solvent and anti-solvent. Next, a solvent diffusion rate is adjusted by adding the coupled solvent which can mingle with each solution. If the solvent diffusion rate in the liquid-liquid interface of an emulsion is controllable, it is possible to reduce high local fluctuation of the supersaturation.

There is a spherical crystallization method as an example of crystallization using an emulsion interface [9]. A spherical crystallization method generates the emulsion drop of uniform size, and supersaturation is supplied by temperature operation or anti-solvent addition. The crystallization occurred in an emulsion drop and the spherical agglomeration crystals of uniform size are obtained. There is a research of particle size distribution control of agglomeration crystals; however, there are very few discussions with the objective of crystallization engineering such as relationships between supersaturation and crystallization. In this session, the establishment of operating conditions of crystallization to produce fine crystals with desired size and shape in an anti-solvent crystallization with emulsion is introduced.

6.2 Production of Particles by Using Liquid-Liquid Interface

6.2.1 Observation of Crystallization at Liquid-Liquid Interface

The taurine-saturated aqueous ethanol solution (Liquid A), the taurine-saturated hexane solution (Liquid B), and the taurine-saturated aqueous ethanol solution (Liquid C) of arbitrary concentration were prepared. A crystallization target is taurine. Quaternary system of taurine (crystalline material), water (original solvent), hexane (anti-solvent), and ethanol (coupled solvent) was considered.

A single small droplet of Liquid A was prepared in Liquid B by using microsyringe between two glass plates. Liquid-liquid interface was observed by using an optical microscope. After predetermined period, Liquid C (coupled solvent) was added. The crystallization phenomenon near the place of liquid-liquid interface was observed ([22]).

Figure 4.13 shows the observation of crystallization near the interface. Figure 4.13a shows the liquid-liquid interface of Liquid A and Liquid B. After addition of coupled solvent Liquid C, crystallization was stated at the place of liquid-liquid interface (Fig. 4.13b). The supersaturation was generated by adding the coupled solvent which can be mixed with Liquid A and Liquid B. So it can be confirmed that the liquid-liquid interface should act as the limited crystallization field. In the case of original conventional anti-solvent crystallization, the supersaturation was generated by the direct mixture to a good solvent and an anti-solvent. However, by using this method, the direct mixture is avoided and it is expected that the solvent diffusion rate can be adjusted by the coupled solvent conditions. Furthermore, the influence of local supersaturation fluctuation can be reduced by increasing the liquid-liquid surface area with emulsification.

Fig. 4.13
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Photomicrographs of crystallization phenomena near the liquid-liquid interface

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6.2.2 Production of Particles by Using Liquid-Liquid Interface in Emulsion

The capacity of the crystallizer equipped with a jacket and homogenizer was 100 mL. A predetermined amount of Liquid A and Liquid B was physically emulsified at 14,500 rpm by the mechanical shearing force by homogenizer, and the crystallization field was prepared. The obtained crystal morphologies, mass-based mean crystal size of major length (L M), and coefficient of variation (CV) changed depending on the operating conditions. In order to consider the relationships between crystal morphology and an operating condition in detail, categorization of crystal morphology was attempted by the supersaturation. In order to calculate a supersaturation ratio, the quaternary phase diagram was determined (Fig. 4.14). This phase diagram is indicated by the triangular pyramid coordinate. The curve on the x-y plane shows the liquid-liquid equilibrium. The curve on the y-z plane indicates the liquid/solid equilibrium.

Fig. 4.14
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Quaternary phase diagram of taurine, water, hexane, and ethanol

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The degree of supersaturation ΔC and supersaturation ratio ln S was calculated by applying the lever rule to this quaternary phase diagram. The relationship between supersaturation and crystal morphology was shown in Figs. 4.15 and 4.16.

Fig. 4.15
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Relationships between crystal shapes and operating conditions in anti-solvent crystallization with emulsion

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Fig. 4.16
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Relationships between crystal shapes and supersaturation ratio in anti-solvent

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In Fig. 4.15, the horizontal axis means equilibrium concentration, the vertical axis means a degree of supersaturation, and the slope of straight line means the supersaturation S-1. As a result, it became clear that a taurine crystal becomes rodlike under the low supersaturation condition and becomes needlelike under the high supersaturation condition. When the result of the proposed crystallization method is compared with that of the conventional anti-solvent crystallization method, it is characteristic that the region where different kinds of crystal morphologies coexist is narrow. In the conventional anti-solvent crystallization, diffusion of the solute occurs only from the local point where the anti-solvent was added. Therefore, the difference in the solute concentration between an anti-solvent and a good solvent is large in an addition position. On the other hand, the difference of solute concentrations becomes small in the area distant from the anti-solvent addition position. Thus, the supersaturation distribution arises depending on the location in a solution. Since there is high local supersaturation fluctuation in an anti-solvent addition position, it is easy to generate a needlelike crystal. More than two kinds of crystal morphologies deposit easily because supersaturation distribution arises in a solution. In the case of emulsion conditions, supersaturation is not generated directly by addition of an anti-solvent, but supersaturation generates on a rich liquid-liquid interface after solvent diffusion. Therefore, local fluctuation of the supersaturation is not produced, but supersaturation is homogeneous in a solution. And the crystallization region of a needlelike crystal was limited, and there were few cases that more than two kinds of crystal morphologies were intermingled in the case of emulsion. The liquid-liquid interface area is used effectively for uniformed crystallization by dispersion of local supersaturation.

In the crystallization of an emulsion application, the relationships between supersaturation ratio and crystal morphology were correlated by estimating the quaternary phase diagram and analyzing supersaturation in equilibrium theory. Moreover, high local supersaturation fluctuation has been reduced by using a liquid-liquid interface as a crystallization field. Therefore, the method using the limited crystallization field such as liquid-liquid interface is useful for controlling the crystal size distribution and morphology in an anti-solvent crystallization.

7 Conclusions

The driving force of both nucleation and growth phenomena is supersaturation, so these phenomena occur in the same location at the same time. This is the reason why control of the quality of crystalline particles is not easy. Therefore, the operation design has been investigated to separate the location of nucleation and growth and the start period of these phenomena. If both phenomena can be limited separately, the quality of crystalline particles can be improved. The research topics are introduced to control the quality by designing both nucleation and growth phenomena in the limited crystallization field. The examples of the limited crystallization field are the air/solution interface of the segmented flow and the liquid-liquid interface of the emulsion. From the experimental results, the crystallization method using the limited crystallization field is useful for controlling the crystal size distribution and morphology. The advanced study on the limited crystallization field will further improve the quality of crystalline particles.