Polymorphism, pharmaceutical industry solid-state characterization

Commonly used Raman scattering and collection geometries. Reproduced from Vibrational Spectroscopic Methods in Pharmaceutical Solid-state Characterization, J. M. Chalmers and G. Dent, pp. 95-138 in Polymorphism in the Pharmaceutical Industry, ed. R. Hilfiker, Wiley-VCH Verlag GmbH Co. KGaA, Weinheim (2006). 

Within various pharmaceutical laboratories (industrial and academic), the mul-tinuclear technique of solid state NMR has primarily been applied to the study of polymorphism at the qualitative and quantitative levels. Although the technique ideally lends itself to the structure determination of drug compounds in the solid state, it is anticipated that in the future, solid state NMR will become routinely used for method development and problem solving activities in the analytical/materials science/physical pharmacy area of the pharmaceutical sciences. During the past few years, an increasing number of publications have emerged in which solid state NMR has become an invaluable technique. With the continuing development of solid state NMR pulse sequences and hardware improvements (increased sensitivity), solid state NMR will provide a wealth of information for the physical characterization of pharmaceutical solids. 

Polymorphism can influence every aspect of the solid state properties of a drug. Many of the examples given in preceding chapters on the preparation of different crystal modifications, on analytical methods to determine the existence of polymorphs and to characterize them and to study structure/property relations, were taken from the pharmaceutical industry, in part because there is a vast and growing body of literature to provide examples. One of the important aspects of polymorphism in pharmaceuticals is the possibility of interconversion among polymorphic forms, whether by design or happenstance. This topic has also been recently reviewed (Byrn et al. 1999, especially Chapter 13) and will not be covered here. Rather, in this section, we will present some additional examples of the variation of properties relevant to the use, efficacy, stability, etc. of pharmaceutically important compounds that have been shown to vary among different crystal modifications. 

The development of a pharmaceutical product can be a long, arduous and expensive process. For those that are marketed in solid dosage forms that process deals with many matters of solid state chemistry, among them the detection, characterization, and preparation of various modifications. We have attempted here to touch on many of those issues, and as noted at the beginning of the chapter, examples of these various aspects of polymorphism and their manifestations in the pharmaceutical industry may be found throughout this book. 

As stated in Section 5.1, all solid-state properties of different polymorphs will be different. Which of these parameters is of special importance for a particular type of industry and a particular application can vary. While color is probably the most important parameter of a pigment, taste and feel are decisive for foods, density for explosives, solubility, processability and stability in the pharmaceutical industry, and so on. In any case, it is imperative for aH industries that all possible forms are known and characterized, since the unexpected appearance of a new form may have very serious consequences. An example for that is the well-known Norvir Case [30], where the thermodynamically stable form was found only long after the product was on the market. Subsequently, the original metastable form could not be produced anymore and a new formulation for the product had to be developed [31] causing very high costs. 

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