It can be generated by various methods including indirect cooling, evaporation, adiabatic evaporative cooling, antisolvent addition and salting out, chemical reactions, and pH adjustment. Note that temperature changes may be detrimental for some systems, for example when dealing with protein-based drugs. Alternative methods most

frequently used to reduce solubility are pH adjustment to Inhibitors,research,lifescience,medical the isoelectric point, increasing ionic strength, addition of nonionic polymers, and addition of a miscible nonsolvent. 2.1.3. Complications Many factors can restrict productivity and purity. Of particular interest for the bottom-up approach are agglomeration, liquid inclusions, and inefficient mother liquor removal. Agglomeration — The particle

size can clearly be affected by agglomeration and fracture mechanisms. When growing crystals collide they may stick together and form new particles, that is, agglomerates form when the collisions are inelastic. The strength of the physical bonds thus formed Inhibitors,research,lifescience,medical determines their stability upon further collisions. For the bottom-up processing to be effective in AZD9291 limiting crystal size the probability of agglomeration needs to be low. Unfortunately, a large number of small particles are produced Inhibitors,research,lifescience,medical when operating in the unstable supersaturation region and collision frequency is high. To offset this concentration effect, it is necessary to limit the time for interaction and/or relieve SS quickly. Also, a surfactant may be effective in limiting the probability that the particles will stick to one another. Liquid Inclusion in Individual Crystals and Agglomerates — This Inhibitors,research,lifescience,medical is particularly undesired when liquid impurities are present. High growth rates can contribute to

increased amounts of liquid entrapped within a crystal. Also, liquid can get trapped between colliding particles during agglomeration and higher supersaturation levels increase the probability of that occurrence. Inhibitors,research,lifescience,medical Thus high supersaturation can have both beneficial and problematic outcomes. One can mitigate any associated problems by limiting the interaction time and/or relieve the supersaturation new condition rapidly. 2.1.4. Flow Patterns, Mixing, and Transport Phenomena Mixing at the nanometer scale occurs as reactants, which may include several liquid and solid phases, are subjected to high shear stresses and turbulence. The energy dissipation rate determines whether the macro-, meso-, or micromixing level is attained. The overall mixing process occurs within a flow field continuum which covers the wide range of length and time scales indicative of each of these mixing levels, each with distinct characteristics. For example, consider two miscible fluids. The large scale distribution by flow patterns that causes gross dispersion is considered macromixing. Next, the breakdown of large eddies into smaller ones via the “eddy cascade” is termed mesomixing.