Pharmaceuticals, crystal polymorphism

Price, S. L The computational predirtion of pharmaceutical crystal strurtures and polymorphism. Adv. Drug Deliv. Rev. 2004, 56, 301-319. 

Various drugs are known to exist in different polymorphic forms (e.g., cortisone and prednisolone). The rate of conversion from a metastable into the stable form is an important criteria to be considered with respect to the shelf life of a pharmaceutical product. Polymorphic changes have also been observed during the manufacture of steroid suspensions. When steroid powders are subjected to dry heat sterilization, subsequent rehydration of anhydrous steroid in the presence of an aqueous vehicle results in the formation of large, needle-like crystals. A similar effect may be... 

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. 

Keywords Solid-state grinding Cocrystal formation Crystal engineering Pharmaceutical materials Polymorphism... 

Morisette SL, Almarsson O, Peterson ML, Remenar JF, Read MJ, Lemmo AV, Ellis S, Cima MJ, Gamer CR. 2004. High-throughput crystallization polymorphs, salts, co-crystals and solvates of pharmaceutical solids. Adv. Dmg Deliv. Rev. 56 275-300. 

The nature of the TAG molecule is such that it can often take multiple forms in a crystal lattice. That is, the same molecule can crystallize into different crystalline forms dependent on processing conditions. The phenomenon is called polymorphism. Although there are numerous molecules that exhibit polymorphism in nature (many in the pharmaceutical field), polymorphism is somewhat unique to lipids in the food industry (although some sugar alcohols also form polymorphs). 

High-throughput crystallization polymorphs, salts, co-crystals 75. and solvates of pharmaceutical solids. Adv. Drug Del. Rev. 

Borka, L. Haleblian, J.K. Crystal polymorphism of pharmaceuticals. Acta Pharm. Jugosl. 1990, 40, 71-94. 

The importance of polymorphism within crystal engineering is substantial and in the area of pharmaceutical crystals has proven to be of great importance financially (Chapter 3.3). Studies using pressure as a variable have been applied recently to the studies of pharmaceutical or related compounds to explore more widely potential polymorphism in such compounds. The examples of glycine and paracetamol are discussed below. 

Although titanium dioxide can be obtained naturally as one of three crystal polymorphs (anatase, rutile, or brookite), pharmaceutically acceptable material is produced synth cally. 

Sometimes the difference between success and failure of a pharmaceutical development projea will depend on obtaining an appropriate crystalline form of a compound. Properties such as mixability of the substance with other ingredients of a capsule, the rate of dissolution, or the stability will depend on the polymorph. Similarly, materials researchers may want to control the polymorph that is being produced. Understanding why and how compounds crystallize the way they do is an area of research to which computations can contribute. In Chapter 7, Drs. Paul Verwer and Frank J. J. Leusen discuss methods for predicting crystal polymorphs by computer simulation. 

The identification, structural and thermal characterization of new polymorphs is an important topic in solid-state chemistry and requires a battery of techniques that includes X-ray diffraction and spectroscopic methods, in addition to thermal analysis methods and dissolution techniques to determine solubility trends. Such studies are described by Caira in Chapter 16, as well as more recent theoretical techniques aimed at the prediction of the crystal structures of new polymorphs. Crystal polymorphism is particularly important in pharmaceutical products, so there is an emphasis on this area. Systems displaying solvatomorphism (the ability of a substance to exist in two or more crystalline phases arising from differences in their solvation states) molecular inclusion and isostructurality (the inverse of polymorphism) are also given due attention in this chapter. 

No doubt, polymorph screening of co-crystals will continue to attract more attention as these materials continue to gain momentum as another solid form choice in the development of new pharmaceuticals. As with salts, co-crystal polymorphs offer additional options to alter properties, increase patent protection, and improve marketed formulations. 

In Structural analysis of active pharmaceutical ingredients, crystal polymorphism is an important subject of study. Crystal structures are determined by X-ray diffraction studies. Once the correlation between crystal polymorphs and their infrared spectra has been established, it can then become a relatively easy task to distinguish polymorphs by measuring their microphotographs and corresponding microscopic infrared spectra, as infrared microspectrometric measurements can be conveniently performed within a much shorter time than X-diffraction analysis. 

---