Solvent design for crystallization

Solvent design for crystallization of pharmaceutical products 4.2.6 Viscosity of the Solvent... 

NRTL-SAC has been demonstrated through the case study on Cimetidine as a valuable aid to solubility data assessment and targeted solvent selection for crystallization process design. The average model error is typically 0.5 Ln (x) [1] and is sufficient as a solvent screening tool. Methods that can deliver greater accuracy would increase the value and utility of these techniques. It is impressive in the case of Cimetidine that the NRTL-SAC correlation is capable of reasonable accuracy and predictive capability on the basis of just 2 fitted parameters. Further work to extend the solvent database and optimize the descriptive parameters will be beneficial, and are planned by the developers. 

A new class of solvents called ionic liquids has been developed to meet this need. A typical ionic liquid has a relatively small anion, such as BF4, and a relatively large, organic cation, such as l-butyl-3-methylimidazolium (16). Because the cation has a large nonpolar region and is often asymmetrical, the compound does not crystallize easily and so is liquid at room temperature. However, the attractions between the ions reduces the vapor pressure to about the same as that of an ionic solid, thereby reducing air pollution. Because different cations and anions can be used, solvents can be designed for specific uses. For example, one formulation can dissolve the rubber in old tires so that it can be recycled. Other solvents can be used to extract radioactive waste from groundwater. 

Karunanithi, A., Achenie, L. E. K. Gani, R. (2006), A computer aided molecular design framework for crystallization solvent design, Chemical Engineering Science, 61, 1243-1256. 

The non-random two-liquid segment activity coefficient model is a recent development of Chen and Song at Aspen Technology, Inc., [1], It is derived from the polymer NRTL model of Chen [26], which in turn is developed from the original NRTL model of Renon and Prausznitz [27]. The NRTL-SAC model is proposed in support of pharmaceutical and fine chemicals process and product design, for the qualitative tasks of solvent selection and the first approximation of phase equilibrium behavior in vapour liquid and liquid systems, where dissolved or solid phase pharmaceutical solutes are present. The application of NRTL-SAC is demonstrated here with a case study on the active pharmaceutical intermediate Cimetidine, and the design of a suitable crystallization process. 

Karunanithi, A.T., Achenie, L.E.K., Gani, R., 2005, A Computer Aided Molecular Design Framework for Crystallization Solvent Design, Chemical Engineering Science, In Press. 

In some mixture design problems (such as formulations), it may not be necessary to consider processing issues and hence we would not have the process model constraints. In this case the problem becomes a simple mixing problem, which would already have been addressed by the miscibility criteria in sub-problem 4M. Hence, for these problems, we will not need sub-problem 5M. Also in some cases we might have to identify a mixture whose constituents perform different functions such as solvents and anti solvents for crystallization. In such cases we would have to formulate and solve more than one single compound design problems to identify the constituents and then solve the final two sub-problems to identify the optimal mixture. In certain cases we may not have process model constraints, however, we may still have to solve an optimization problem with other constraints, in sub-problem 4 and sub-problem 5m respectively. 

This chapter provides a framework for the design of crystallization solvents for pharmaceutical products. The design part involves application of a... 

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