Case studies crystal assessment

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. 

In many cases, simulation methods are used in a complementary manner to experimental studies, with the validity of the calculations assessed by comparing simulated properties (e.g., crystal structure and activation energies) with those determined experimentally. The major factor in determining the reliability of all the simulation methods is the accuracy of the description of the interaction between the ions. The majority of studies of ionically conducting systems have utilized parameterized potentials containing explicit expressions for the various interactions (short-range repulsion. Coulomb, etc.), although recent advances in available computer power have enabled the application of ab initio methods (see Chapter 7). 

The key issues in the study of drug polymorphism are the identification of different polymorphs (from a regulatory and patent viewpoint as much as from a formulation one), the determination of polymorph stability, and the assessment of processing conditions on polymorph generation. Whereas DSC is widely used as a means of routine screening for polymorphs, it is by no means universally effective as a means of identification. For example, several studies have indicated that DSC shows very similar traces for the various polymorphs of cimetidine (e.g., 15) hence, the generation of apparently identical peaks is not a guarantee of the absence of different crystal modifications. In other cases, however, the differentiation between polymorphs may be more obvious. 

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