Supersaturation reactive crystallization

The reactive crystallization has some peculiar characteristics like insoluble product, initiation of reaction by change in pH and conductivity. In this case the solution becomes saturated and eventually supersaturated with respect to reactant nucleation [30], The ultrasound assisted decomposition precursors includes dissolving metal organic precursors in organic solvents/water with the assistance of surfactants leads to monodisperse and reduced metal/metal oxide nanoparticles. 

Some of the reports are as follows. Mizukoshi et al. [31] reported ultrasound assisted reduction processes of Pt(IV) ions in the presence of anionic, cationic and non-ionic surfactant. They found that radicals formed from the reaction of the surfactants with primary radicals sonolysis of water and direct thermal decomposition of surfactants during collapsing of cavities contribute to reduction of metal ions. Fujimoto et al. [32] reported metal and alloy nanoparticles of Au, Pd and ft, and Mn02 prepared by reduction method in presence of surfactant and sonication environment. They found that surfactant shows stabilization of metal particles and has impact on narrow particle size distribution during sonication process. Abbas et al. [33] carried out the effects of different operational parameters in sodium chloride sonocrystallisation, namely temperature, ultrasonic power and concentration sodium. They found that the sonocrystallization is effective method for preparation of small NaCl crystals for pharmaceutical aerosol preparation. The crystal growth then occurs in supersaturated solution. Mersmann et al. (2001) [21] and Guo et al. [34] reported that the relative supersaturation in reactive crystallization is decisive for the crystal size and depends on the following factors. 

When supersaturation of a crystallizing compound is created by its formation by chemical reaction, the operation is characterized as reactive crystallization. The reaction may be between two complex organic compounds or can be neutralization by an acid or base to form a salt of a complex compound. These reactions can be very fast compared to both the mass transfer rates to the crystals, and the growth rate of the crystals, thereby leading to high local supersaturation and nucleation. These operations are also known as precipitations because of the rapid inherent kinetics. 

Several investigators have developed models for the effectiveness of collisions that lead to agglomeration including Nyvlt et al. (1985) and Sohnel and Garside (1992). This complex interaction of hydrodynamics and crystallization physical chemistry is difficult to predict or describe but can be critical to the successful operation and scale-up of a crystallization process. In particular, for reactive crystallization in which high supersaturation levels are inherently present, agglomeration is very likely to occur as the precipitate forms. Careful control may be necessary to avoid extensive agglomeration, as outlined in Section 5.4.3. below and in Examples 10-1 and 10-2 for reactive crystallization. 

The mixing texts referenced above contain extensive discussion of the importance of the location of feed streams. While these studies are primarily concerned with reagent feed for chemical reactions and the influence of local turbulence on reaction selectivity, the same issues are encountered in the addition of antisolvents and reagents for reactive crystallization because nucleation is a function of supersaturation, whether local or global. 

Although crystallization by antisolvent addition shares many characteristics with that caused by chemical reaction, the processes often differ in the rate of creation of supersaturation (e.g., a rapid reaction leading to a compound of very low solubihty). Reactive crystallization is also subject to other kinetic considerations which are sometimes less predictable than the known solubility effects caused by addition of an antisolvent. 

The complex issues regarding low solubi I ity and the nucleation characteristics of induction time and nucleation rate must be minimized by the maintenance of low supersaturation so that growth can predominate. Methods for promoting this balance will be indicated. Prior to that discussion, the issues encountered in the development of a reactive crystallization process will be briefly reviewed. 

Control of both local (point of addition) and global supersaturation is essential, as in all crystallizations, if a satisfactory balance between nucleation and growth is to be achieved. This is particularly relevant to reactive crystallization because of the creation of local high supersaturation of these low-solubility compounds that is unavoidable at the point of reaction. In addition to the mixing issues outlined above, the critical variables in minimizing supersaturation are as follows ... 

The requirement for increased amounts of seed for reactive crystallization compared with the cooling, evaporahon, and anti-solvent methods is discussed by Mullin (2001, p. 339). Amounts of seed up to 50% are indicated to be necessary in recycle systems to provide the seed area necessary. The requirement for this increased amount is the direct result of the rapid development of supersaturation by reaction and the need to have sufficient surface area for growth throughout the operation, especially at the start of reagent addihon. 

Reactive crystallization operations are subject to oiling out and/or agglomeration because of the inherently high local supersaturations encountered. As indicated in Section 10.3, the formation of a crystal may be preceded by oiling out as the first physical form that may or may not be observed (see also Chapter 5, Section 5.4). This oil may separate as a second phase because of the normally extremely low solubilities of the reaction products that result from the chemical reaction. This low solubility can cause a second liquid phase to form on a time scale that is shorter than the nucleation induction time. These issues are considered in Ostwald s Rule of Stages. 

However, the authors have participated in development and scale-up of some successfiil reactive crystallization processes, and the examples to follow (Examples 10-1 and 10-2) are included to illustrate the concepts and application of the principles discussed above in these processes. These developments were based on the three essential concepts of seeding, control of supersaturation and promotion of growth, as described above. The key variables are, therefore,... 

As with any crystallization process, reactive crystallization will, in general, produce fine particles unless the entire operation is run within the metastable region. This condition can be realized by provision of heavy seeding and by slow addition to control supersaturation at a low level. Adequate mixing is necessai-y, but shear damage must be avoided by selection of the correct impeller speed and type. 

In the reactive crystallization of an API, methane sulfonic acid (MSA) is reacted with the free base of the previous intermediate. Due to the highly compressible nature of the resulting crystals on filtration, caused by fines from the crystallization, it is desirable to minimize the level of secondary nucleation by reducing the degree of supersaturation and allowing a slower release of supersaturation during the reactive crystallization. 

In-line methods are applicable to reactive crystallization with systems with a relatively fast reaction rate and a short nucleation induction time. There are two in-line devices that have potential for these applications impinging jets and vortex mixers. The reader is referred to Chapter 9 for a discussion of impinging jets as applied to antisoivent crystallization. The application to reactive crystallization is similar—creation of high supersaturation in a... 

Classification of batch crystallizers and batch crystallization operations according to the means by which supersaturation is created is still a widely accepted method. Therefore, the discussion of such operations may include cooling crystallization, evaporative crystallization, vacuum crystallization, antisolvent crystallization, reaction (reactive) crystallization, etc. The vacuum crystallization operation can be considered as a combination of the evaporative and cooling crystallization and thus will not be discussed separately. Reaction crystallization (precipitation) is discussed in detail in Chapter 6. 

Sometimes a drowning-out medium is added to a solution. It reduces the solubility of the solute and hence leads to supersaturation. This is called drowning-out crystallization. The solubility of many aqueous solutions of inorganic salts can be reduced by the addition of organic solvents (e.g., acetone, methanol). In reactive crystallization two or more reactants form a product which is less soluble and therefore crystallizes. For example, reactions between an acid and a base lead to the precipitation of a solid salt. This is called precipitation crystallization. However, it should be mentioned that this term is neither clearly defined nor uniformly used. 

Resolution Crystal growth in this reactive crystallization can be controlled by limiting supersaturation by slow reagent addition, high level seeding, and low-shear, high-circulation mixing. 

Initially, Marco was at a bit of a loss because his group had always had difficulty with reactive crystallizations and had not developed a snccessful strategy for overcoming the basic issues inherent to this type of crystallization (also termed precipitation). Since these operations are almost always carried out at high supersaturation, they are nucleation based and therefore tend to produce small crystals, typically 5 to 10 p.m in size, with many in the 1 p,m range. Both occlusion of impurities and unacceptable physical attributes can result. Marco assigned Carol, a new engineer, to work with Joe, a veteran of many crystallization developments, who remained hopeful that this dilemma of precipitation could be solved. 

The fact that the initial setting process for magnesium oxychloride cements takes place without observable formation of either the 5 1 8 or the 3 1 8 phase is important. It indicates that formation of an amorphous gel structure occurs as the first step, and that crystallization is a secondary event which takes place from what is effectively a supersaturated solution (Urwongse Sorrell, 1980a). This implies that crystallization is likely to be extremely dependent upon the precise conditions of cementition, including temperature, MgO reactivity, heat build-up during reaction and purity of the components in the original cement mixture. 

The influence of plastic deformation on the reaction kinetics is twofold. 1) Plastic deformation occurs mainly through the formation and motion of dislocations. Since dislocations provide one dimensional paths (pipes) of enhanced mobility, they may alter the transport coefficients of the structure elements, with respect to both magnitude and direction. 2) They may thereby decisively affect the nucleation rate of supersaturated components and thus determine the sites of precipitation. However, there is a further influence which plastic deformations have on the kinetics of reactions. If moving dislocations intersect each other, they release point defects into the bulk crystal. The resulting increase in point defect concentration changes the atomic mobility of the components. Let us remember that supersaturated point defects may be annihilated by the climb of edge dislocations (see Section 3.4). By and large, one expects that plasticity will noticeably affect the reactivity of solids. 

Both the evolution of the atomic fractions in the solution and of the chemical shift of all species (Fig. 9(b)-(e)) allow four steps in the formation of A1P04—CJ2 induction, dissolution, nucleation and crystal growth. During the induction period, a constant amount of A1 atoms in the solution is observed during the set up of the pH synthesis. The dissolution step, which is quasi simultaneous with the induction period, is characterized by an increase of the amount of A1 species in the solution (Fig. 9(b)-(c)). During this period, the different NMR results show the development of the right solution composition for the formation of soluble reactive species, the development of supersaturation conditions (with an increase of the soluble species concentration) and the formation of the solution species involved in the crystallization. 

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