Pharmaceutical applications polymorphism

F. Laplant and A. De Paepe, Raman spectroscopy for identifying polymorphs, in Pharmaceutical Applications of Raman Spectroscopy, S. Sasic (Ed), Technology for the Pharmaceutical Industry Series, John WUey Sons, Ltd, Hoboken, 2008. 

In pharmaceutical applications the choice of polymorphic modification for formulation depends very much on the robustness of the crystallization process as well as the properties and characteristics of the preferred modification. Hence, considerable effort is expended in gaining control over the polymorphic form obtained under various conditions. As noted above, up to four polymorphic modifications and three monohydrates have been reported for cimetidine (SmithKline Beecham s Tagamet ) (Bavin et flZ.1979 Prodic-Kojic et al. 1979 Shibata etal. 1983 Hegedus and Gorog 1985). In experiments to selectively crystallize the A form in preference to the more stable B congener it was found that with isopropanol as a solvent, A crystallizes exclusively at high supersaturation, in the presence or absence of seeds (Sudo et al. 1991). 

Polymorphism is the ability of a chemical species to crystallize in more than one distinct crystal habit. The pharmaceutical applications of polymorphism have been reviewed by several authors. The differences in dissolution rate and solubility that polymorphs can produce may have a dramatic impact on bioavailability when dissolution is the rate-limiting step in the absorption process. 

In contrast to solution-phase or direct polarization solid-state NMR experiments, CP-MAS is not a truly quantitative technique. As a result of the cross-polarization step, the integral intensities of peaks in CP-MAS spectra do not directly reflect the stoichiometry of nuclei in the molecule. CP-MAS signals originate from protons, and its transfer efficiency varies from carbon to carbon, based on proximity of protons and local mobility of the molecule. In most pharmaceutical applications, only relative concentrations of mixtures of two or more polymorphs need to be determined even in complex dosage forms. The absolute concentration of the drug in formulation is usually known or can be determined by other techniques. 

HalebUan J, McCrone W. Pharmaceutical applications of polymorphism. J Pharm Sci 1969 58 911-929. 

The greatest advantage of the NMR method lies in the assignment of a minor polymorphic form in the dominant environment of the other form, and, additionally, the analysis is carried out in a non-destructive manner. The majority of pharmaceutical applications of solid state NMR reviewed in 1991 by Brittain et al. [27] and later by Bugay [28] were the... 

BeUantone RA, Patel P, Sandhu H, Choi D, Singhal D, Chokshi H, Malick AW, Shah NH (2012) A method to predict the equilibrium solubility of dmgs in solid polymers near room temperature using thermal analysis. J Pharm Sd 101 4549-4558 Burger A, Ramberger R (1979) On the polymorphism of pharmaceutical and other molecular crystals I. Theory of thermodynamic rules. Mikrochimica Acta 11 259-281 Chiou WL, Riegelman S (1971) Pharmaceutical applications of solid dispersion systems. J Pharm Sd 60 1281-1302... 

A Burger, R Ramberger. On the polymorphism of pharmaceuticals and other molecular crystals. II. Applicability of thermodynamic rules. Mikrochim Acta (Wein) 2 273-316, 1979. 

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