Keywords

1 Introduction

1.1 Crystallization of Organic Compounds

Crystallization is one of the important unit operations of separation and purification processes widely used in the production of pharmaceuticals, chemical products, foods, etc. Since the product substance is recovered as a solid-state, solid–liquid separation is possible by filtration, and the subsequent separation operation becomes easy. Also, since the molecules are regularly arranged in the crystal, the products with a high-purity can be obtained. The crystallization is generally considered to be a low energy consuming process in the unit operation.

Generally, the drugs contain an active pharmaceutical ingredient (API) as a solid (crystal), so crystallization is an important process. In particular, since the quality of the API crystal as the final product also affects the drug efficacy in the body, special care must be taken to control various crystal properties. For example, in the production process of API, the crystallizations are performed to separate the target substance from raw materials or by-products at each step of the synthesis route, which involves multiple steps. Care must be taken to improve yield and purity at each step. It is because desired crystal characteristics may not be obtained due to the influence of a small amount of raw material and by-products contained in crystals.

When the crystallization is performed in the manufacture of pharmaceuticals, it is necessary to control various crystal characteristics to produce the desired crystals with good reproducibility. There are various crystal characteristics to be controlled, such as particle size, particle size distribution, crystal polymorphism, purity, shape, and crystallinity. If control of such characteristics insufficient, the subsequent operability and quality may be significantly affected. Therefore, it is important to clarify the causal relationship between the crystallization conditions and the characteristics of the obtained crystals and to control the crystal characteristics based on the theory [1, 2].

1.2 Crystal Properties to Be Controlled

1.2.1 Crystal Size and Crystal Size Distribution

Crystal size and size distribution are one of the critical characteristics to be controlled in the crystallization process. In industrial crystallization, depending on the purpose, a large crystal may be desired, or a small crystal may be desired.

When importance is attached to solid–liquid separation in the filtration, uniform and large crystals without small crystals are desired because unwanted fine crystals can cause clogging of the filtration device. If it is difficult to obtain large crystals and there is a problem in the filterability due to generation of fine particles, preparation of agglomerates of the desired size by aggregation the micro crystals are attempted.

On the contrary, small crystals are often desired. When the size of the crystal is large, the gap between the crystals becomes wide, and the amount of the crystal that can be put in a specific container is reduced. When paying attention to the transportation of products, smaller crystals are advantageous because of their higher bulk density. Furthermore, in recent years, the number of poorly water-soluble pharmaceuticals has increased, and in order to improve the solubility, it is necessary to make fine crystals.

1.2.2 Polymorphs

In the crystal, the molecules are regularly arranged and bonded by appropriate intermolecular interactions. In the crystal, molecules at each point in the lattice have the same conformation. There may be one or more regular arrangements for a substance, and crystals with different structures are called crystal polymorphs.

Some compounds incorporate solvent molecules in the crystals, and such crystals are called solvates or pseudo polymorphs. Nowadays, solvates have also been considered as one of the polymorphs [3]. In the solvate crystal, not only the interaction between the solute molecules but also the interaction via the solvent molecule exists. So the solvent molecule should play an important role in crystal formation. Many hydrates are also found in the pharmaceutical products, and one-third of drugs registered in the European Pharmacopoeia is hydrate form.

Control of crystal polymorphism is crucial because different crystal structures have different solubility and stability in the same substance [4]. Particularly in drug substance, the dissolution properties of crystals may affect the pharmacokinetics of drugs, and a technique for reliably producing a particular crystal polymorph is required.

1.3 Crystallization Technics

Some oils are crystallized by melt crystallization, but many organic compounds are generally crystallized from the solution. There are various methods for crystallization from a solution. Cooling crystallization is the most common method. When the solution containing a given amount of solute is cooled via the outer jacket of the crystallization vessel or the cooling coil inserted inside, the solution becomes supersaturated. Thereafter, the crystal appears via nucleation and growth. The amount of crystals obtained can be estimated by the feed concentration and the solubility at the final cooling temperature. Therefore, the cooling crystallization is advantageous when crystallizing a substance having a high-temperature dependence of solubility.

When the solubility does not change much with temperature, or when the solubility at low temperatures is high, the amount of solute recovered by cooling crystallization may be small. In such a case, a method other than cooling should be selected. For example, in order to generate supersaturation, the solvent composition is changed. The additional solvent is added to the solution to reduce solubility. We need to select such an appropriate solvent so that the solvent and the solution should be miscible. Usually, in the crystallization of hydrophilic compounds, water is used as a good solvent, and an organic solvent is used as an antisolvent. Conversely, water is used as an antisolvent for the crystallization of poorly water-soluble compounds.

What should be taken care of in the drowning out crystallization is that when the crystallization is performed from a condition where the concentration of the initial solution is excessively high, liquid–liquid phase separation often occurs without precipitation of crystals. Liquid–liquid phase separation is a phenomenon in which solute molecules exist in a liquid state with a super-high concentration, and in many cases, precipitation of crystals does not occur. It is because even if the concentration is very high, the solution contains a solvent with high affinity and is stable in the solution state. Moreover, since the viscosity is high due to the high concentration, nucleation is suppressed kinetically. On the other hand, there are some examples in which particle size control is attempted using liquid–liquid separation phenomena.

Drowning out crystallization is an effective method selected next to cooling crystallization, but the cost of the solvent used for that cannot be ignored. When repeatedly using a solvent, two or more solvents must be separated to pure solvents again by distillation or the like.

Evaporation of solvent is also used for crystallization of highly water-soluble compounds like sugars and amino acids. It is the simple method, but changes in various phenomena such as the thermal stability of the solute and the increase in viscosity due to concentration must be estimated in advance.

In any case, in crystallization from a solution, the solution should be supersaturated by a suitable method, and induce crystallization.

2 Production of Crystals with a Large and Narrow Size Distribution Using Internal Fines Dissolver [5]

2.1 Introduction

As mentioned above, industrial crystallization is expected to produce solids having not only a particular composition but also a desired crystal size distribution (CSD), because CSD often determines handling and many end-use properties. A product with unimodal and narrow size distribution and large mean size is often desired.

It is well known that CSD is dependent on the primary nucleation, growth kinetics, and also on secondary nucleation that is mainly caused by a collision between crystals and the impeller in the crystallizer.

We have proposed a novel crystallizer. The crystallizer, named as WWDJ-batch crystallizer, is equipped with a double-deck jacket and Wall Wetter™, which is a slurry sprinkler. The structure of the crystallizer is quite simple, as shown below. It is easy to wash and clean the inside of the vessel. This is a severe demand in the production of pharmaceuticals. The crystallizer allowed the batch production of large crystals with a narrow crystal size distribution (CSD) through the selective dissolution of fine crystals that progresses simultaneously with crystallization.

In this section, we describe the production of the large crystals of glycine with a narrow CSD using the WWDJ-batch crystallizer.

2.2 Apparatus

The WWDJ (Wall Wetter/Double-deck Jacket) batch crystallizer is illustrated in Fig. 5.1a. The crystallizer is a cylindrical glass vessel with a round bottom, covered with a double-deck jacket. The working volume of this crystallizer is 1.7 L. The crystallizer was equipped with a four-blade propeller. It was also equipped with a Wall Wetter [6] that is a slurry sprinkler, namely a device specially designed for sprinkling slurry or a solution on the wall of the crystallizer headspace.

Fig. 5.1
figure 1

Schematic diagrams of the WWDJ-crystallizer (a) and Wall-wetter™ (b)

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The Wall Wetter adopted in this study comprised two-channel bars with a J-shaped cross-section, as shown in Fig. 5.1b. The device was fixed to the agitation shaft at a given angle. The slurry was raised along the channel by centrifugal force and sprinkled on the upper wall, then fell down the wall. During the fall, it can be expected that crystals dissolve partially so that fine crystals disappear if the upper jacket temperature is higher than that of the lower jacket. The surviving large crystals are also expected to grow further, at the expense of fine crystals, after returning to the lower crystallization phase.

2.3 Crystallization of Glycine Using WWDJ-Crystallizer

The cooling crystallization of glycine was carried out using WWDJ-crystallizer. First, the temperatures of the upper and lower jackets of the WWDJ-crystallizer were adjusted to 55.6 °C. An aqueous solution (1.7 L) of 250 mg/mL glycine was prepared at 70 °C and then quickly introduced into the crystallizer. After the solution temperature reached 55.6 °C, the solution was cooled at a constant cooling speed, 10 °C/h, where the final temperature of the solution and lower jacket were set at 25 °C and 10.3 °C, respectively. The upper jacket temperature was not changed during the crystallization. The temperature difference between the slurry falling down the upper wall and the slurry in the lower crystallization part, that is the driving force of the dissolution of fine crystals, was set at 7 °C.

Figure 5.2 shows a change in the temperature of the glycine solution during crystallization. Open symbols indicate for WWDJ-operation, and closed symbols indicate for conventional operation (control experiment). The crystallization temperature was controlled from 55.6 to 25 °C along with the same profile for these two crystallizers.

Fig. 5.2
figure 2

Changes in the temperature of the glycine solution for WWDJ operation (open symbols) and conventional operation (closed symbols)

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After the crystallization, we recovered the crystals obtained from both crystallizers and compared the crystal size distribution (CSD). Figure 5.3a shows the comparison of CSD. In the conventional crystallizer, a broad CSD with two peaks was observed. The smaller peak may be partially caused by the attrition of crystals with the propeller. On the other hand, in the WWDJ-crystallizer, the large crystals with a narrow CSD were obtained. Notably, small crystals less than 500 µm were well removed by the dissolution of fine particles. Figure 5.3b shows cumulative CSD. The 50% value of the cumulative CSD, L50, of glycine crystals obtained using WWDJ-crystallizer was 950 µm, compared with 460 µm in the conventional crystallizer not using the Wall Wetter. These results show that the WWDJ-crystallizer is useful for the production of large crystals with a narrow CSD.

Fig 5.3
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The comparison of crystal size distribution of glycine crystals obtained by WWDJ crystallizer and conventional crystallizer. a histogram, b cumulative distribution

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3 Control of Crystal Size Distribution Using a mL-Scale Continuous Crystallizer Equipped with a High-Speed Agitator [7]

3.1 Introduction

As described above, hardly water-soluble drugs are increasing [8, 9]. In such a case, smaller crystals have an advantage on dissolution property. Small particles are expected to increase the dissolution rate because of their large specific surface area. However, it is not easy to produce such fine particles. The birth of crystal is the result of the nucleation process. Therefore, the number of crystals obtained is determined by the frequency of nucleation events. In order to obtain a large number of small crystals, the nucleation event must be intensely accelerated. In addition, excessive growth must be suppressed after nucleation. For this purpose, it is necessary to prevent the crystals from staying in the crystallization vessel for a long time.

In this section, we propose a new crystallizer that overcomes these problems, namely “mL-scale continuous crystallizer.” The crystallizer is a small-size continuous crystallizer, and the particles after crystallization are quickly discharged from the crystallizer. In addition, a high-speed stirrer provides vigorous shearing to promote nucleation.

3.2 Apparatus

Figure 5.4 shows a schematic diagram of the mL-scale crystallizer. The crystallizer is composed of a stainless-steel vessel, a high-speed agitator (Ultra-turrax T25 homogenizer, IKA), and a syringe pump (IC3210, KD Scientific). The maximum rotation speed of homogenizer is 24,000 rpm. An agitation shaft is inserted from the top of the vessel and fixed by a screw lid and O-ring. The solute solution and the antisolvent are supplied from two inlet tubes by the syringe pump and intensely mixed with the agitator. The void volume of the crystallizer is 0.9 mL, respectively. The slurry is recovered from an outlet tube at the side of the vessel.

Fig. 5.4
figure 4

Schematic diagrams of the mL-scale crystallizer. 1. Mixing vessel, 2. high speed agitator, 3. dispersing element, 4. plastic syringes, 5. syringe pump, 6. inlet tubes, 7. outlet tube, 8. glass vessel with an water jacket, and 9. enlarged illustration of the mixing vessel

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3.3 Crystallization of Glycine and Alanine Crystals

Amino acids, glycine, and alanine, were crystallized using the mL-crystallizer. The initial concentration of l-alanine and glycine were 166 mg/mL and 250 mg/mL, respectively. Methanol was used as an antisolvent. The solution and methanol were injected into the crystallizer by a syringe pump. The flow rate of a solution/methanol mixture was set to 1.6, 16, and 160 mL/min. These flow rates correspond to 33, 3.3, and 0.33 s of the average residence time τ, respectively.

Figure 5.5 presents SEM images of glycine crystals. The shorter the residence time, the smaller crystals were obtained. The size of crystals was measured from the SEM images. Figure 5.6 presents the size distribution of glycine crystals on the basis of the long axis length. The peak shifted to smaller size with a decrease of residence time. The recovery yield was higher at a short residence time rather than a long residence time as shown in Table 5.1. At the residence time of 0.33 and 3.3 s, the yield was 100%, but at τ = 33 s the yield was decreased to 93%. The fact that the crystal yield was 100% at short residence times indicated that the smaller size of crystals obtained at those residence times was not caused by insufficient nucleation and crystal growth due to the short residence time.

Fig. 5.5
figure 5

SEM images of the glycine crystals

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Fig. 5.6
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Size distribution of the glycine crystals on the basis of the long axis length

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Table 5.1 Yields of glycine and l-alanine crystals obtained at different residence time
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Figure 5.7 presents SEM images of the crystals of l-alanine obtained at various residence times. The crystals were needle-like and those were bundled. The typical shape of a l-alanine crystal is prismatic [10], which can be obtained by cooling crystallization. In the present poor solvent crystallization, needle-like crystals were obtained. However, since the XRD pattern for the needle-like crystals was the same as that of the prismatic crystals (data not shown), the difference of shape was not due to polymorphism. The crystals obtained at τ = 33 s were thick and easy to cleave. The crystals obtained at short residence time were thin.

Fig. 5.7
figure 7

SEM images of the alanine crystals

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In the present study, the homogenizer was used for agitation. There is some fear of breakage of crystals by high-speed mixing. Therefore, we checked the influence of agitation for the crystal size and shape. 0.84 g of l-alanine crystals of 65 µm in average size was suspended in 17 mL of saturated solution of l-alanine. The suspension was agitated by the homogenizer at 24,000 rpm for 10 min. After that, the crystals were recovered and observed by SEM. The shape and size of obtained crystals were almost the same as those of the original crystals. Therefore, we concluded that crystals with a size of less than at least 65 µm in average size were not broken by short (second time-scale) high-speed agitation.

Figure 5.8 shows size distributions on the basis of the long axis length. At τ = 0.33 and 3.3 s, the size of crystals was small and the distribution was narrow. A broad distribution was obtained at τ = 33 s. In a long mean residence time, some crystals may stay in the crystallizer for long time and the supplied supersaturation may be used for the growth of resident crystals, resulting in broad size distribution. The short residence time should be advantageous to produce small crystals with a narrow size distribution.

Fig. 5.8
figure 8

Size distribution of the alanine crystals on the basis of the long axis length

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3.4 Control of Polymorph by Changing Mixing Ratio of Glycine Solution and Poor Solvent Methanol

The experimental results shown above were obtained by poor solvent crystallization where equal volume of the solution and methanol were mixed. The solubility changes with the composition of solvent and the supersaturation also change with those mixing ratios. Then, we investigated the effect of mixing ratio of the solution and poor solvent methanol on the crystallization of l-alanine. The mixing ratio of methanol was changed by using different size of plastic syringes to 50, 78, and 91%. The residence time was fixed to 3.3 s. Figure 5.9 presents the SEM images of l-alanine crystals. The size of crystals became small with an increase in the methanol composition. The supersaturation ratio was 3.1 at 50% methanol and 9.8 at 91% methanol. The high supersaturation resulted in micronization of crystals.

Fig. 5.9
figure 9

SEM images of the alanine crystals

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Three types of polymorphs have been reported for glycine. In cooling crystallization from the aqueous solution, metastable α-form and stable γ-form are obtained. On the other hand, it is known that needle-like β-form is precipitated from an aqueous alcohol solution. The β-form is the most unstable of the three polymorphs and is known to change to metastable α-form by solvent-mediated transformation in solution.

The polymorphs of the obtained crystals were identified by XRD. Figure 5.10 shows XRD profiles of glycine crystals obtained with different methanol compositions. The average residence time τ is 3.3 s. It can be seen that there is a difference in the XRD pattern between the methanol composition of 50% and the others. The α-form of glycine has characteristic peaks that are not found in other polymorphs at 2θ = 14.8°, 29.2°, 29.9°. In addition, the peaks peculiar to β-form appear at 17.9°, 33.8°, and 34.4°. From the results, it was found that α-form was obtained at 50% methanol, and β-form was obtained at 73 and 91% (Table 5.2).

Fig. 5.10
figure 10

XRD profiles of glycine crystals obtained with different methanol composition

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Table 5.2 Summary of polymorphs of the glycine crystals obtained at different methanol composition and residence time
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In general, obtaining metastable crystals is not as easy as obtaining stable crystals. It is necessary to suppress the nucleation of the stable form and recover the metastable form quickly before the transformation.

In the antisolvent crystallization of glycine, if the purpose is to obtain metastable β form selectively, the metastable crystals should be recovered quickly. Since the mL-scale crystallizer performs continuous crystallization with a residence time of seconds order, it is possible to recover successfully the desired polymorph before the transformation.

3.5 Comparison of Crystallizer Performance Between Conventional Crystallizers and the Present Continuous mL-Scale Crystallizer

In order to compare the performance of the mL-crystallizer with those of conventional crystallizers, the product crystals were compared. As conventional crystallizers, we chose a semi-batch crystallizer and a MSMPR type crystallizer having 64-times volume of the present mL-scale continuous crystallizer. Figure 5.11 presents SEM images of glycine crystals obtained by using three different crystallizers. In the semi-batch crystallization, large crystals were obtained. It was suggested that glycine supplied was consumed for the growth of crystals produced in the early stage of crystallization. In the continuous crystallization operated at the mean residence time of 11.5 min, small crystals were obtained, compared with those obtained by the semi-batch crystallization. Crystals obtained by using the continuous mL-crystallizer were much smaller and more homogeneous in size than the former two.

Fig. 5.11
figure 11

SEM images of glycine crystals obtained by using three different crystallizers

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4 Summary

In recent years, demand for development of continuous crystallizer especially in the fields of pharmaceutical crystallization. In order to obtain crystals with uniform physical properties, the tubular flow type is more advantageous than the stirred tank type which a residence time distribution. However, since the tubular type crystallizer is not sufficiently stirred, a very long apparatus must be manufactured. Therefore, the continuous oscillated baffled crystallizer (COBC), in which the tube is separated into multiple compartments, is attracting attention. This section introduced a device for obtaining large crystals and a small crystallizer for obtaining small crystals. In the future, more sophisticated crystallizers will be developed.