Stability polymorphs

Dicko, C., Knight, D., Kenney, J., and Vollrath, F. (2005). Conformational polymorphism, stability and aggregation in spider dragline silks proteins. Int. J. Biol. Macromol. 36, 215-224. 

The results of the polymorph screening step in combination with bioavailability studies, provide the information required by the clinical research team to nominate the desired crystal form of the API for long term manufacture and formulation. This form will usually be the most stable polymorph, where a number of forms have been identified, or a salt form if bioavailability is low or when there are formulation concerns regarding polymorph stability. In some cases it may be necessary to select an amorphous form or metastable polymorph because of crystallization difficulties, time constraints or bioavailability requirement. The nomination of a hydrate or solvate is generally avoided because of their relative instability and compositional variability such constraints are less of a concern for the earlier synthetic intermediates. 

VELDE (B.), 1965a. Experimental determination of muscovite polymorph stabilities. Amer. Min. M), 436-49. 

Test results at 25°C and 90°C have been interpreted at Pennsylvania State University as follows. The higher the purity of the Zr02, the more likely it is to behave well as a pH sensor. Exceptions to this rule are titanium, which is beneficial for thermal shock resistance, and yttria, which is necessary for polymorphic stabilization. The optimum Y20, content was investigated by testing Zr02 tubes with Y203 contents of 4, 6, 8, 10, and 12 mol%. 

Teetsov, A. S. and McCrone, W. C. (1965). The microscopical study of polymorph stability diagrams. Mtcro.r. Cryst. Front, 15, 13-29. [279t, 280]... 

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. 

Table 3.18 The fi polymorphic stability of liquid oils containing hydrogenated palm olein...

It is also important to know that the stability ranking of true polymorphs (i.e., no solvates) is independent of the solvent used. ° For solvates, however, there is a dependency of stability on solvent composition and temperature. Therefore, if solvent effects are observed that seem to influence polymorph stability, they are of a kinetic nature, or the crystal form is not a true polymorph but a solvate. 

Figure 2 Calorimetry can be useful for examining relative polymorphic stability by comparing the solubility of the forms. Solubility can be derived from the heats of solution for a polymorphic form dispersed into a solvent divided by the enthalpy change offusion (A H). A correction can be made for the enthalpy of solvation using the amorphous form of the material. The graph shows the relative solubility of two polymorphs of a drug substance in development with GlaxoSmithKline...

These problems have not been elucidated until now, because the veiy different synthesized specimens were compared. It is obvious, that the stabilizer content must increase with the higher temperature polymorph stabiUzation. Also the same polymorph stabilization with various stabilizers needs generally their veiy different additions. 

A new hydraulic cement based on the alpha-belite polymorph, stabilized with alkalies and iron, has been patented by the Portland Cement Association (Fulvio Tang, 1996). The U.S. patent number is 5,509,962. 

Blanco, M., Valdes, D., Llorente, I. and Bayod, M. Application of NIR spectroscopy in polymorphic analysis Study of pseudo-polymorphs stability. J. Pharm. Sci. 94 1336-1342, 2005. 

L deMan, YL Xu, HS Chen, JM deMan. Polymorphic stability of hydrogenated palm oleins in dilutions with unhydrogenated liquid oils. J Am Oil Chem Soc 70 431-433, 1993. 

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