Polymorphism, pharmaceutical industry

The pharmaceutical industry has taken great interest of late in the study of polymorphism and solvatomorphism in its materials, since a strong interest in the phenomena has developed now that regulatory authorities understand that the nature of the structure adopted by a given compound upon crystallization can exert a profound effect on its solid-state properties. For a given material, the heat capacity, conductivity, volume, density, viscosity, surface tension, diffusivity, crystal... 

The most widely used application of solid state NMR in the pharmaceutical industry is in the area of polymorphism, or pseudopolymorphism, and this will be the focus of this section. 

In a manner similar to that just described for differential thermal analysis, DSC can be used to obtain useful and characteristic thermal and melting point data for crystal polymorphs or solvate species. This information is of great importance to the pharmaceutical industry since many compounds can crystallize in more than one structural modification, and the FDA is vitally concerned with this possibility. Although the primary means of polymorph or solvate characterization s centered around x-ray diffraction methodology, in suitable situations thermal analysis can be used to advantage. 

Raman spectroscopy is emerging as a powerful analytical tool in the pharmaceutical industry, both in PAT and in qualitative and quantitative analyses of pharmaceuticals. Reviews of analyses of pharmaceuticals by Raman spectroscopy have been published.158 159 Applications include identification of raw materials, quantification of APIs in different formulations, polymorphic screening, and support of chemical development process scale-up. Recently published applications of Raman spectroscopy in high-throughput pharmaceutical analyses include determination of APIs in pharmaceutical liquids,160,161 suspensions,162 163 ointments,164 gel and patch formulations,165 and tablets and capsules.166-172... 

The prediction of crystal structures by ab initio quantum mechanical methods, and the identification of stable polymorphic forms and the conditions under which they will crystallize, is of great interest to the pharmaceutical industry. Some progress has been made towards this goal in recent years [17, 18] with a degree of success for small and conformationally simple pharmaceuticals. The methods are still a number of years away from routine use in the day to day research and development environment. 

Blagden, N., and Davey, R., Polymorphs take shape, Chem. in Brit., March 1999, p. 44. Owen, M., and Dewitt, S., Laboratory Automation in Chemical Development. In Process Chemistry in the Pharmaceutical Industry (K.G. Gadamasetti, ed.), Marcel Dekker, Inc., New York 1999, pp. 429-455 Conner, K., The drive to improve the bottom line. Today s Chemist at Work, November 1999, p. 29. Sullivan, M., Automation accelerates synthesis. Today s Chemist at Work, September 1999, p. 48. Studt, T., Raising the bar on combinatorial discovery, Drug Discovery Development, January/February 2000, p. 24. Harness, J.R., Automated sample handling supports synthesis and screening. Drug Discovery Development, January 1999, p. 69. 

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. 

The significance of polymorphism in the pharmaceutical industry lies in the fact that polymorphs can exhibit differential solubility, dissolution rate, chemical reactivity, melting point, chemical stability or bioavailability, among others. Such differences can have considerable impact on a drag s effectiveness. Usually, only one polymorph is stable at a given temperature, the others being metastable and evolving to the stable phase... 

Examples of terahertz spectroscopy as a PAT tool in the pharmaceutical industry include monitoring of polymorphism, tablet coatings, and crystallinity, even at the stage of product development to aid in process design. ... 

The importance of polymorphism in pharmaceuticals cannot be overemphasized. Some crystal structures contain molecules of water or solvents, known as hydrates or solvates, respectively, and they are also called as pseudopolymorphs. Identifying all relevant polymorphs and solvates at an early stage of development for new chemical entities has become a well-accepted concept in pharmaceutical industry. For poorly soluble compounds, understanding their polymorphic behavior is even more important since solubility, crystal shape, dissolution rate, and bioavailability may vary with the polymorphic form. Conversion of a drug substance to a more thermodynamically stable form in the formulation can signiLcantly increase the development cost or even result in product failure. 

R. Hilfiker, Polymorphism in the Pharmaceutical Industry, Wiley-VCH, Weinheim, 2006. [5a] H.G. Brittain, Polymorphism in Pharmaceutical Solids, second ed., Informa Healthcare... 

The topic of polymorphism is of tremendous and increasing academic and industrial importance in modern crystal chemistry and crystal engineering. The industrial interest stems from the pharmaceutical industry and has stimulated wide-ranging academic study. Legally, a molecule (termed an active pharmaceutical Ingredient, API) with particular biological activity in vivo can be patented as a new invention. Moreover, particular crystal forms of that molecule (polymorphs) can be separately patented as distinct inventions. If particular polymorphs are patented after the original API patent then upon the... 

Bernstein, J. Polymorphism and Patents from a Chemist s Point of View. In Hilfiker, R. (Ed.), Polymorphism In the Pharmaceutical Industry. Weinheim, Germany Wiley-VCH, 2006, Chapter 14. 

In the pharmaceutical industry, typically one will examine the previously defined API either as mixture of polymorphic forms or as a mixture of crystalline and amorphous phases (both having a simple linear intensity proportionality to concentration). Alternatively one may encounter a mixture of hydration or solvation states, in which cases the intensity would not necessarily be directly proportional to concentration. Figure 12.4 demonstrates the deviation from linearity resulting from differences in... 

Practical considerations may also arise. Supramolecular functionality introduced to control crystal architecture must be added without degrading the fundamental molecular properties of primary interest. Co-crystals offer an alternative approach for controlling crystal architecture without necessarily modifying the primary molecule of interest. In addition, we must recognize the role of the solvent from which the crystal grows. The occurrence of solvates and polymorphs, particularly relevant in the pharmaceutical industry, is still a relatively poorly understood aspect of crystal chemistry. The manner in which synthons are modified from normal geometries in non-crystalline organic structures is also yet to be explored fully. 

However, it is often very difficult to grow single crystals of suitable size for a successful diffraction experiment and the researcher has to resort to powder diffraction experiments on a polycrystalline sample. Powder patterns are fingerprints of the solid materials and are therefore used to identify polymorphs. In the pharmaceutical industry, and in associated laboratories, it is becoming common practice to accompany the routine quality control analyses on the production fine with the measurements of powder patterns. 

Because of these differences in efficacy and toxicity, polymorphisms in drug metabolizing enzymes are of considerable importance to the pharmaceutical industry. Because of the possibility of increased drug toxicity or decreased efficacy in a proportion of the population, the development of a new drug may be impacted negatively if its metabolism is mediated via a pathway that is known to be polymorphic. This possibility is now always taken into account in the planning of metabolic studies and clinical trials. 

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