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Crystallization Process and Related Phenomena


Crystallization is a separation operation in which crystals of blended components are obtained starting from a liquid mixture (solution or molten magma-solid). In some cases, it might generate components that are 100% pure. Crystallization creates thermodynamic conditions that compel molecules to catch up and regroup it into highly organized structures known as crystals. Sometimes, the operating conditions do not allow the production of 100% pure crystals owing to impurities that pass along the process. Molecules that have high affinity for the solute may also form part of the impurities.

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Crystallization is a crucial process in physical sciences. When multiple phases are in equilibrium, they are separated by an interface which is a thin surface layer whose properties are very different from those of the volume phase it separates. It is customary to replace this conceptually thin intermediate phase seat into large variations in terms of concentrations and pressures during the process of crystallization. The latter can take place without an interface thickness (Diao, Myerson, Hatton & Trout, 2011). The existence and properties of the interface are essential in understanding a number of crystallization phenomena such as boiling liquids, multiphase flow, split systems, emulsions and supersaturation.

Literature Review

The first step in the process of crystallization is referred to as nucleation. It is necessary in creating conditions within the mixture so that the molecules can give rise to the formation of crystals (Jie, Xu, Brush & Anantram, 2014). The crystallization process relies on both mass transfer mechanisms and amount of movement. In other words, the existence of a higher solute concentration in solution at the saturation concentration (solubility limit) speeds up the process of saturation. This state is naturally unstable and that is why nucleation is possible (Jacquier, Ferro, Cauwet, Chaussende & Monteil, 2003).

However, it is still possible for crystallization to occur through the processes of agitation or circulation of the liquid mixture which causes closer approach and collision between molecules. The latter also leads to momentum transfer. Once formed, the core crystals begin to grow. This is the crystal growth step. The speed of agitation or circulation of the crystallizer, the degree of supersaturation, temperature among other factors are the key operating parameters that influence the growth speed of crystals and final product characteristics (Piedade Cestari et al., 2014). For example, when the degree of supersaturation is very high, it leads into an unstable process. From the thermodynamic point of view, it can give rise to an extremely high nucleation rate. As a result, numerous nuclei are formed simultaneously and tiny crystals produce the final product (Lechuga-Ballesteros & Rodríguez-Hornedo, 1995).

Metal-Assisted and Microwave-Accelerated Evaporative Crystallization (MA-MAEC), is among the latest developments in the manufacture of drug compounds in form of crystals. Some of the key compounds used in this process include proteins, DNA and amino acids. The process heavily relies on the technology of engineered surfaces. For example, gylcine is among the compounds that can be rapidly crystallized. The compound has been used in a number of crystallization experiments to establish the functional nature of the MAEC technique. Functional surfaces that are hydrophilic in nature can readily form gylcine particles that are about 1 mm in size. This implies that the MAEC process is one of the best chemical techniques that can be used to grow large crystals. In addition, it has also been established that the formation of such crystals take a relatively short time ranging between 30 and 35 seconds (Grell, Pinard, Pettis & Aslan, 2012).

In regards to the α-form, 100 percent selectivity of the desired product is usually guaranteed. For surfaces that are moderately hydrophilic, it is possible to grow gylcine crystals at the immediate prevailing temperature. In addition, it is also crucial to mention that the size of the crystals can be enlarged by simply increasing the initial amount of the gylcine solution. In most past experiments, initial volumes were increased from 5 to 100 μL. It is interesting to learn that there is no need to increase crystallization time in order to obtain large crystals after original volumes have been increased. According to an experimental process carried out by Chen et al (2012), structural identification was observed on gylcine crystals prepared on surfaces that had already been engineered. Crystals obtained from the traditional evaporative method were indeed identical to those developed on engineered surfaces. Moreover, the findings coincided with two different experiments namely powder X-ray diffraction and Raman spectroscopy (Scopelliti et al., 2010).

There are quite a number of pharmaceutical solids that can crystallize well when taken through the process of morphology. In an empirical experiment by Doki, Yokota, Sasaki and Kubota. (2004), an ordinary pharmaceutical excipient was induced in a crystal habit modification process. In addition, molecular simulation was employed in analyzing molecular arrangements of the generated particles. From the findings, it was evident that host-additive interactions exist within the modified crystals. Moreover, the researchers deduced that improved compaction properties were evident in crystals subjected to modification. In other words, unmodified crystals lacked the compaction features. Active pharmaceutical ingredients can attain and sustain tabletting properties when morphology engineering process is carried out.

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A vapor-liquid-solid (VLS) mechanism can be used to grow crystals of SiC through the homoepitaxial process (Grell, Pinard, Pettis & Aslan, 2012). The latter requires a relatively low temperature. For instance, most experiments of this natured are undertaken below 1100 degrees centigrade. Al-Si droplet is a typical example of a compound that can be grown into crystals using the VLS mechanism. The conventional liquid-phase epitaxy (LPE) has quite a number of demerits compared to this method. For instance, LPE does not require any control of the thermal gradient. Hence, it is rather easy to master the process or mechanism. Nonetheless, the cooling process generates small crystals on the surface. While the process is highly efficient, it might not be the best approach for growing large crystals (Xiaojin, Chi, Wei, Chengdong & Dongliang, 2014). As a matter of fact, the latter is the main limitation of the procedure.

Some zones are left intact without any wetness during the process. Nevertheless, the dry zones are less than one percent of the entire sample. In regards to LPE configuration, both demerits are also evident (Hamilton, Weissbuch, Lahav, HiIlmyer & Ward, 2009).

The formation of crystals from liquid mixtures may also be executed through an optical resolution technique. This method employs both pulse heating and natural cooling crystallization. In this process, a separation agent must be used. In order to separate the different components, an additive which is tailor-made is used.

A mixture of asparagine (D,L-Asn) has been used for a long time as an additive agent.

One of the most profound amino acids in proteins is Alanine. The compound performs vital functions in the structures of most proteins (Radacsi, Stefanidis, Szabó-Révész & Ambrus, 2014). To begin with, food industries, pharmaceutical companies and chemical manufacturers highly demand the crystallized this molecule. Nonetheless, it takes quite a long time to generate crystals of this compound from the conventional evaporative method. worse still, this method does not guarantee useful crystals all the time. These limitations explain why other crystallization methods have been proposed, embraced and adopted. L-alanine crystals that are better and large enough in terms of size cam be obtained through a technique known as metal-assisted and microwave-accelerated evaporative crystallization (MA-MAEC). Since most industries prefer the production of large crystals, the MA-MAEC method is commonly used (Guijuan et al., 2007).

Different types of crystals tend to compete during the process of formation. Some of the factors that contribute towards this competition include sufficient reduction of surplus free energy, low surface energy of crystals and critical size effects. In addition, homogeneous nucleation process is used to grow β-glycine nanocrystals.

Nano-bio interface is a crucial section where chemical activities take place during crystallization. For example, the adsorption of proteins largely prefers this region due to its differentiation and cell adhesion properties. Protein adsorption is also influenced by nanoscale morphology. This knowledge is fundamental even though it still lacks in the discipline of science and technology.

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Numerous industrial processes apply evaporative crystallization in the formation of crystals. Solvent evaporation can be quickened through microwave irradiation. The latter is a crucial procedure in evaporative crystallization (Mojibola, Dongmo-Momo, Mohammed & Aslan, 2014). In other words, crystals are obtained at a faster rate when microwave irradiation is made as part and parcel of the experimental procedure. Indeed, drug formulation relies on this method owing to its efficiency. It ensures that the size of particles are minimized as desired. Modification of the size of the drug also facilitates rapid dissolution of the component (Lee, In Sung, Dette, Boerner & Myerson, 2005).

In order to comprehend both the chemical and physical properties of crystal structures, it is necessary to study them in-vivo and in-vitro. As much as several modern techniques of crystallization yield high quality and large samples, there are still inherent properties of crystals that can be studied apart from the merits. In any case, growing large crystals is not always desired in all production processes.

Polarized laser light process targets amino acids contained in proteins. Nanoscale cylindrical pores are also engineered surface s that can be used in this technique. The main advantage of such surfaces lies in the ability to control polymorphism. Alkane thiols can also be crystallized using the self-assembled monolayers (SAMs). Moreover, porous polymer surfaces have been studied in surface chemistry in terms of how they can contribute towards heterogeneous nucleation (Mirza et al., 2009).

From the outset, the desire to adopt new delivery methods for drugs has been prevalent for a long time. In fact, pharmaceutical companies greatly prefer more efficient, fast and high quality methods of manufacturing drug samples. The ability to determine purity and size of crystals is instrumental when discussing the aspect of crystallization (Lechuga-Ballesteros & Rodrı́guez-Hornedo, 1993). For instance, a crystallization process that generates impure samples may be less useful in the end. Moreover, the size of the crystals formed determines their eventual suitability among consumers. During the process of manufacturing drugs, there are a number of ingredients that should not be interfered with at all. Better still, the stability of a finished product is supposed to remain as initially desired. Hence, the choice of crystallization method selected should adhere with the above considerations as much as possible.

Doki, Yokota, Sasaki and Kubota (2004) lament that most modern crystallization methods may fail to meet these standards even though they are used in large scale. A case in point is the milling process that takes place as a post-crystallization technique. It is also prudent to underscore the fact that supersaturation of liquid mixtures determines the overall nature of crystals formed (Alabanza, Pozharski & Aslan, 2012). When mixtures are saturated beyond a certain limit, the growth of crystals may be hampered significantly. In most instances, nucleation takes place when liquid mixtures are exposed to extreme supersaturation. The latter affects sub-processes such as spray drying, high-pressure homogenization, solvent shifting, impinging jet crystallization, and supercritical fluid crystallization (Mohammed, Syed, Bhatt, Hoffman & Aslan, 2012).

The above methods often generate fine crystals. Nevertheless, liquid mixtures exposed to extreme saturation tend to form solids that are not crystalline at all. In some cases, undesired forms of crystals may be generated when supersaturation takes place. It is only the polymorph forms that are desired during the process of crystallization (Anginelle & Kadir, 2011).

Research studies also indicate that organic compounds usually undergo crystallization kinetics. However, liquid mixtures may fail to go through full crystallization kinetics when additives are present. As a result, it is possible to interfere with the growth process of crystals when additives are not eliminated from solutions (Alabanzab, Mohammeda & Aslana, 2012). This also explains why some crystallization processes yield low quality crystals coupled with impurities. When the concentration of additives is low in solutions, the considerable effects may not be seen. However, there are some additives that can influence the formation of crystals even if their concentrations are very low. Examples include colloidal materials and surfactants.


In summary, research studies concur that crystallization process has been transforming systematically in order to meet the demand for crystalline compounds such as drugs. Needless to say, pharmaceutical companies have immensely benefitted from this chemical process. Crystallization generates pure samples of biological and organic molecules that may be instrumental in manufacturing solid drugs. From the above literature review, it can be confirmed that additives serve important functions in the process of crystallization bearing in mind that they facilitate the production of molecules of various sizes and structures.

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Alabanza, A.M., Pozharski, E. & Aslan, K. (2012). Rapid Crystallization of l-Alanine on Engineered Surfaces by Use of Metal-Assisted and Microwave-Accelerated Evaporative Crystallization. Cryst. Growth Des., 12 (1), 346–353.

Alabanzab, M.A., Mohammeda, M. & Aslana, K. (2012). Crystallization of L-alanine in the presence of additives on a circular PMMA platform designed for metal- assisted and microwave-accelerated evaporative crystallization. CrystEngComm. 14(24), 8424–8431.

Anginelle, M.A., & Kadir, A. (2011). Metal-Assisted and Microwave-Accelerated Evaporative Crystallization: Application to l-Alanine. Crystal Growth & Design, 11(10), 4300-4304.

Chen, W., Yu, D., Ruan, H., Li, D., Hu, Y., Chen, Y., &… Lloyd, I. K. (2012). Microwave- Assisted Rapid Synthesis of ZnO Hexagonal Quasi-Hourglasses. Journal Of The American Ceramic Society, 95(7), 2322-2329.

Diao, Y., Myerson, A.S., Hatton, S. & Trout, L.B. (2011). Surface Design for Controlled Crystallization: The Role of Surface Chemistry and Nanoscale Pores in Heterogeneous Nucleation. Langmuir, 27 (9), 5324–5334.

Doki, N., Yokota, M., Sasaki, S., & Kubota, S. (2004). Simultaneous Crystallization of d- and l-Asparagines in the Presence of a Tailor-Made Additive by Natural Cooling Combined with Pulse Heating. Crystal Growth & Design, 4(6), 1359-1363.

Grell, T. J., Pinard, M. A., Pettis, D., & Aslan, K. (2012). Rapid crystallization of glycine using metal-assisted and microwave-accelerated evaporative crystallization: the effect of engineered surfaces and sample volume. Nano Biomedicine & Engineering, 4(3), 125-131.

Guijuan, L., Yuyuan, S., Xiang, Y., Fanjing, M., Kunyan, W., & Xiaoduo, X. (2007). The Effect of Microwave Irradiation on the Crystallization Behavior of PET/PEN Blends. Journal of Macromolecular Science: Physics, 46(6), 1139-1149.

Hamilton, B. D., Weissbuch, I., Lahav, M., HiIlmyer, M. A., & Ward, M. D. (2009). Manipulating Crystal Orientation in Nanoscale Cylindrical Pores by Stereochemical Inhibition. Journal Of The American Chemical Society, 131(7), 2588-2596.

Jacquier, C., Ferro, G., Cauwet, F., Chaussende, D. & Monteil ,Y. (2003). SiC Homoepitaxial Growth at Low Temperature by Vapor-Liquid-Solid Mechanism in Al-Si Melt. Crystal Growth & Design, 3(3), 285-287.

Jie, L., Xu, X., Brush, L., & Anantram, M. P. (2014). A multi-scale analysis of the crystallization of amorphous germanium telluride using ab initio simulations and classical crystallization theory. Journal Of Applied Physics, 115(2), 1-7.

Lechuga-Ballesteros, D. & Rodrı́guez-Hornedo, N. (1993). The relation between adsorption of additives and crystal growth rate of L-Alanine. Journal of Colloid and Interface Science, 157(1), 147–153.

Lechuga-Ballesteros, D. & Rodríguez-Hornedo, N. (1995). Effects of molecular structure and growth kinetics on the morphology of l-alanine crystals. International Journal of Pharmaceutics, 115 (2), 151–160.

Lee, A. Y., In Sung, L., Dette, S. S., Boerner, J., & Myerson, A. S. (2005). Crystallization on Confined Engineered Surfaces: A Method to Control Crystal Size and Generate Different Polymorphs. Journal of The American Chemical Society, 127(43), 14982-14983.

Mirza, M., Miroshnyk, I., i Heinämäki, J., Antikainen, O., Rantanen, J., Vuorela, P… &Yliruusi, J. (2009). Crystal Morphology Engineering of Pharmaceutical Solids: Tabletting Performance Enhancement. AAPS PharmSciTech, 10(1): 113–119.

Mohammed, M., Syed, M. F., Bhatt, M. J., Hoffman, E. J., & Aslan, K. (2012). Rapid and Selective Crystallization of Acetaminophen using Metal-Assisted and Microwave- Accelerated Evaporative Crystallization. Nano Biomedicine & Engineering, 4(1), 35-40.

Mojibola, A., Dongmo-Momo, G., Mohammed, M. & Aslan, K. (2014). Crystal Engineering of l-Alanine with l-Leucine Additive using Metal-Assisted and Microwave Accelerated Evaporative Crystallization. Cryst. Growth Des., 14 (5), 2494–2501.

Piedade Cestari, S., Mendes, L. C., Altstädt, V., Biasotto Mano, E., França da Silva, D., & Keller, J. (2014). Crystallization Kinetics of Recycled High Density Polyethylene and Coffee Dregs Composites. Polymers & Polymer Composites, 22(6), 541-549.

Radacsi, N., Stefanidis, G. D., Szabó-Révész, P., & Ambrus, R. (2014). Analysis of niflumic acid prepared by rapid microwave-assisted evaporation. Journal of Pharmaceutical & Biomedical Analysis, 9816-21.

Scopelliti, P. E., Borgonovo, A., Indrieri, M., Giorgetti, L., Bongiorno, G., Carbone, R… & Milani, P. (2010). The Effect of Surface Nanometre-Scale Morphology on Protein Adsorption. Plos ONE, 5(7), 1-9.

Xiaojin, Z., Chi, M., Wei, B., Chengdong, X., & Dongliang, C. (2014). Miscibility and Isothermal Crystallization Behavior of Poly-(L-lactideco- glycolide)/ Poly(ρ- dioxanone) Blends. Polymers & Polymer Composites, 22(8), 705-711.

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