Create Supersaturation

In our discussions of supersaturation and metastability, we have always focused on situations where supersaturation is created by temperature change (cooling). While this is a very common method to generate supersaturation and induce crystallization, it is not the only method available. 

There are four main methods to generate supersaturation that follow  

As we have discussed previously, the solubility of most materials declines with declining temperature so that cooling is often used to generate supersaturation. In many cases however, the solubility of a material remains high even at low temperatures or the solubility changes very little over the temperature range of interest. In these cases, other methods for the creation of supersaturation must be considered. 

After cooling, evaporation is the most commonly used method for creating supersaturation. This is especially true when the solvent is nonaqueous and has a relatively high vapor pressure. The principle of using evaporation to create supersaturation is quite simple. Solvent is being removed from the system, thereby increasing the system concentration. If this is done at a constant temperature, eventually the system will become saturated and then supersaturated. After some maximum supersaturation is reached, the system will begin to crystallize. 

There are a number of common methods used to evaporate solvents and crystallize materials based on the materials properties and solubility. One very common method for a material that has a solubility that decreases with decreasing temperature is to cool the system by evaporating solvent. Evaporation causes cooling in any system because of the energy of vaporization. If a system is put under a vacuum at a given temperature, the solvent will evaporate 

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Given these various methods of creating supersaturation, which is preferred ... 

At high enough wind speeds, bubbles of air are injected into the sea surfece. The gases in these bubbles dissolve imder some pressure. The extent of dissolution is dependent on the partial pressure of the gas in the air bubble and the gas s solubility. This can create supersaturated conditions to a degree that varies from gas to gas. 

In many cases in drug development, the solubility of some leads is extremely low. Fast dissolution rate of many drug delivery systems, for example, particle size reduction, may not be translated into good Gl absorption. The oral absorption of these molecules is usually limited by solubility (VWIImann et al., 2004). In the case of solubility limited absorption, creating supersaturation in the Gl Luids for this type of insoluble drugs is very critical as supersaturation may provide great improvement of oral absorption (Tanno et al., 2004 Shanker, 2005). The techniques to create the so-called supersaturation in the Gl Luids may include microemulsions, emulsions, liposomes, complexations, polymeric micelles, and conventional micelles, which can be found in some chapters in the book. 

Aerosol Solvent Extraction System (ASES) Here, the solution is sprayed through atomization nozzle into a chamber L lied with SCF. Expansion of solution occurs within the Lne droplets of solvent being sprayed, thus creating supersaturation and precipitation of solids as Lne particles. 

Methods that create supersaturation by increasing the solute concentration include ... 

The following is a qualitative discussion of several of the procedures that are used to create and maintain conditions under which crystallization can be carried out. These procedures create supersaturation by different methods and utilize seeding to varying degrees. The procedures are classified by the manner in which supersaturation is generated. 

Oihng out can be a critical factor in CrystaUization by any of the methods of creating supersaturation and becomes increasingly possible under several conditions, including... 

In a mixed solution without crystals present and at constant supersaturation, increased mixing intensity can reduce the induction time—the time elapsed after mixing to create supersaturation to the time crystals first appear. Induction time decreases up to a critical speed, after which it remains unchanged (Myerson 2001, p. 145). Additional discussion may be found in Chapter 4. 

Distillation is analogous to the cooling rate in creating supersaturation and may be controlled by similar methods to match the evaporation rate with the surface area available for growth. However, the wall and vapor disengagement effects on local concentration can cause excessive nucleation such that a predictable growth rate may not be achieved. Other factors that are difficult to control are as follows ... 

Equations (65) and (66) show that the process of creating supersaturation within the droplets is much slower than in homogeneous mixtures (i.e., at pressures above the critical mixture pressure). Increase of the solute concentration from Cco to 2cco is observed after 0.206tvap> which for t ap = 0.125 s... 

As we saw in our discussion of solubility, the mixing of solvents can result in a large change in the solubility of the solute in the solution. This can be used to design a solvent system with specific properties and can also be used as a method to create supersaturation. If we took, for example, a solution of terephthalic acid (TPA) in the solvent dimethylsulfoxide (DMSO) at 25 °C, the solubility of the TPA at this temperature is 16.5 wt%. A cooling-... 

This method of creating supersaturation is often called drowning out or adding a miscible nonsolvent. Normally you can find an appropriate solvent to add by looking for a material in which the solute is not soluble, that is miscible with the solute solvent system. This can be done experimentally or screening can be done using solubility calculations prior to experimental tests. This is a particularly valuable technique with organic materials. 

A crystallizer is an apparatus in which an environment can be created suitable for the formation and growth of crystalline materials. Paramount in the design of such equipment is the means that are chosen to create supersaturation at a temperature level that produces a desired or proper hydrate or composition of the product crystals. 

For substances whose solubility is weakly dependent on temperature (e.g., NaCl) or for those with an inverse dependence of the solubility on temperature (e.g., Na2S04), a method of choice to create supersaturation is evaporation of the solvent. In practice, evaporative crystallizers usually operate at constant temperature and reduced pressure. 

A phase, e g. a solution has to be supersaturated so that new crystals can arise or existing crystals can grow. Supersaturation can be achieved by cooling a solution or by evaporation of the solvent. This is called cooling and evaporative crystallization. For vacuiun crystallization flash evaporation is used to create supersaturation. In this case cooling and evaporation superimpose. 

When creating supersaturation levels sufficient to induce particle formation, precipitation of sparingly soluble salts and sol-gel processes are viewed differently. Precipitation normally involves mixing a cation solution with a precipitant solution. For example, consider preparation of an oxalate precursor to a CoO- and MnO-doped ZnO powder. In this process, the Zn, Mn, and Co are coprecipitated with controlled stoichiometry and the precipitate is calcined to the oxide. To form the oxalate, a state of supersaturation is created by mixing an aqueous solution of the metal nitrates or chlorides with an oxalate precipitant solution. The system is supersaturated with respect to the different metal oxalate phases and a crystalline coprecipitate forms. Depending on precipitation conditions (pH, concentrations, temperature, etc.), different metal complexes are present in solution. The form and concentration of these complexes determine the phase, morphology, and particle size distribution of the resulting precipitate. 

Antisolvents can be used in three ways (1) to create supersaturation in an isothermal process, (2) to decrease the solubility at the end of a cooling crystallization to increase yield, and (3) simply to modify, to decrease the solubility of moiety. 

The smaller the active crystal surface available, the slower the mass deposition rate d7w/df, and the larger the supersaturation remaining after each recirculation cycle. The point 0, in Figures 11.3 and 11.4 moves up, if crystal growth does not desupersaturate to Ac —> 0. As this residual supersaturation is added to the newly created supersaturation, it is certainly possible that the metastable zone width will be... 

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