Drug development polymorphism

R. Pfeiffer, Impact of Solid State factors on Drug Development, Polymorphs and Solvates of Drugs. Purdue University School of Pharmacy Short Course (1990). 

When the crystallography of compounds related by polymorphism is such that nuclei in the two structures are magnetically nonequivalent, it will follow that the resonances of these nuclei will not be equivalent. Since it is normally not difficult to assign organic functional groups to observed resonances, solid state NMR spectra can be used to deduce the nature of polymorphic variations, especially when the polymorphism is conformational in nature. Such information is extremely valuable at the early states of drug development when solved single crystal structures for each polymorph or solvate species may not yet be available. 

Thermal methods can be extremely useful during the course of preformulation studies, since carefully planned work can be used to indicate the existence of possible drug-excipient interactions in a prototype formulation [2]. During the course of this aspect of drug development, thermal methods can be used to evaluate compound purity, polymorphism, solvation, degradation, drug-excipient compatibility, and a wide variety of other desirable characteristics. Several recent reviews have been written on such investigations [2-6]. 

Ingelman-Sundberg, M. (2001) Implications of polymorphic cytochrome p450-dependent drug metabolism for drug development. Drug Metabolism and Disposition, 29 (4 Pt 2), 570-573. 

Polymorphisms of drug-metabolizing enzymes are of central importance during drug development. However, the seriousness of the consequences of such polymorphisms for the PK of a drug depends on a number of factors [10] (1) whether... 

Drugs that are metabolized by polymorphic enzymes are often actively screened out of the drug development process. However, such action may be unnecessary when the clinical relevance of the polymorphism in relation to the drug is assessed more carefully. It is also important to realize that there is wide variation in the abundance of enzymes even within the same genotype, as shown in Fig. 16.3. 

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