Supersaturation creation methods

Condensation method for generating a foam involves creation of gas bubbles in the solution by decreasing external pressure or by increasing temperature (up to achieving a supersaturation of the solution) or as a result of a chemical reaction. 

Since the inherent growth rate of many organic compounds is relatively slow, addition times may be long in order to achieve supersaturation control within the metastable zone. Higher addition rates can result in nucleation and the creation of a bimodal distribution. Experimentation to determine acceptable addition rates can be evaluated by focused beam reflectance measurement (FBRM) and other in-sim, online methods (Chapter 2) or microscopic observation of the crystal slurry which could reveal the presence of fines. These issues are highhghted in the examples below. 

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... 

Apart from the seed zone method, a conventional seeding technique can also be used for preparing microcrystals for inhalation. This method involves the creation of seeds by suspending protein particles in a suitable buffer solution and centrifuging this suspension at about 10,000rpm for about lOmin. The supernatant can then be stored at 4°C, to be used as a seed solution. Protein particles can then be dissolved in another buffer solution but at a much lower pH to facilitate the dissolution of the protein. The amount of protein is then slowly increased to achieve supersaturation. The solution is then filtered and the initially prepared seed solution is added to the filtrate. The mixture is sealed and incubated at 37°C. The only issue with this conventional seeding method is that crystals above 5 pm could be formed, which are not suitable for pulmonary delivery (see Note 2). 

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. 

A common method for producing a precipitate is to mix two reactant solutions together as quickly as possible, but the analysis of this apparently simple operation can be exceedingly complex. Precipitation processes, almost by definition, involve the creation of highly supersaturated systems and the main practical difficulty is to maintain reasonably uniform conditions throughout the reaction vessel. The choice of the method of mixing the reactants is therefore very important and the aim should be to avoid any accidental development of zones of excessive supersaturation. The sequence of reactant mixing can... 

Depending on the method of creation of supersaturation, it is common to distinguish four different kinds of ciystalhzation from solution ... 

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