Characterization of polymorphs

Some chiral compounds exhibit a different crystal structure for each pure enantiomer and their mixture the difference can be used to distinguish them. Again, the use of cascading libraries allows pure compounds to be distinguished from compounds contaminated with relatively small amounts of the other chiral forms. 

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Infrared spectroscopy has been widely used for the qualitative and quantitative characterization of polymorphic and pseudopolymorphic compounds of pharmaceutical interest. Since solid state IR can be used to probe the nature of (pseudo)polymorphism on the molecular level, this method is particularly useful in instances where full crystallographic characterization of (pseudo)poly-morphism was not found to be possible. Recently, a significant number of publications have appeared that discuss where a multidisciplinary, spectroscopic... 

H.G. Brittain, Methods for the characterization of polymorphs and solvates. In H.G. Brittain (Ed.), Polymorphism in Pharmaceutical Solids, Marcel Dekker, New York, 1999, pp. 227-278 Chapter 6. 

Brittain H. Methods for the characterization of polymorphs and Solvates in Pol5unorphism in Pharmaceutical Solids. In Brittain H, ed. 1st ed. New York Marcel Dekker Inc., 1999 227-278. 

Chauvet, A., Masse, J., Ribet, J.-P, Bigg, D., Autin, J.-M., Maurel, J.-L., Patoiseau, J.-F., and Jaud, J. (1992). Characterization of polymorphs and solvates of 3-aminortr( uoromethylphenyl)-6-methyl-1H-pyridazin-4-onevJ. Pharm. Sci., 81 836-841. 

Giron, D. (1995). Thermal analysis and calorimetric methods in the characterization of polymorphs and solvates, Thermochim. Acta, 248 1-59. 

Lindenbaum, S. and McGraw, S.E. (1985). The identi cation and characterization of polymorphism in drugs by solution calorimetryPharm. Manufact, 2 27-30. 

Roston DA, Walters MC, Rhinebarger RR, Ferro LJ. 1993. Characterization of polymorphs of a new anti-inflammatory drug. J. Pharm. Biomed. Anal. 11 293-300. 

Infrared Characterization of polymorphs based on functional groups characterization of hydrates and solvates... 

Polymorphism is an ability of the drug substance to form crystals with different molecular arrangements giving distinct crystal species with different physical properties such as solubility, hygroscopicity, compressibility, and others. This phenomenon is well known within pharmaceutical companies. The reader can find additional information in references 47 and 48. The determination of possible polymorphic transition and existence of thermodynamically unstable forms during preformulation stage of drug development is important. Typical methods used for solid-state characterization of polymorphism are DSC,... 

X-ray crystallographic methods, which reflect differences in crystal structure, in most cases can be definitive in the identification and characterization of polymorphs, and whenever possible should be included in the analytical methods utilized to define a polymorphic system. 

In spite of many of the potential experimental pitfalls and difficulties (which should be viewed here as caveats rather than as deterrents), IR spectroscopy is still one of the simplest and most widely and routinely employed analytical tools in the study and characterization of polymorphs. Some other modifications, developments and hyphenated techniques are worthy of note here, since they often considerably enhance the potential of the technique while reducing the drawbacks. Perhaps the most obvious of these is the combination of microscopy with FTIR spectroscopy for visual examination and spectral characterization of small areas in heterogeneous samples or identity and analysis of the spatial distribution of components of mixtures (e.g. pharmaceutical formulations) (Messerschmidt and Harthcock 1988). 

In the characterization of polymorphs, SSNMR can provide important crystallographic information, even in the absence of single crystal samples for full structure determination. Since the technique is a probe of crystal environment, differences among polymorphs in the number of molecules in the asymmetric unit are expected to be manifested in the solid state spectra. Multiple molecules in the unit cell in principle lead to splittings for individual atomic peaks, since chemically equivalent atoms in crystallographically inequivalent molecules can have different surroundings... 

As noted above, the characterization of polymorphs by SSNMR is by no means limited to spectra. For instance, Bauer et al. (1998), showed that CPMAS could easily distinguish between the two polymorphs of Irbesartan 4-1 and could be used to study the difference of the tautomeric behaviour in the tetrazole ring of the two polymorphic forms. Variable temperature spectra indicate that the ring in Form B is involved in an exchange process that does not occur in Form A (Fig. 4.37). 

Since IR spectroscopy is a standard, and perhaps currently the most widely used tool in the search for and characterization of polymorphs, there are likely to be thousands of references to the use of the technique in connection with polymorphs. The vast majority of these deal with the determination of the IR fingerprint of a polymorphic modification. In this section, we wish to note a few cases in which the IR and Raman techniques were employed to obtain chemical information somewhat beyond the mere identification of a particular crystal modification. For instance, Mathieu (1973) showed for a number of chiral compounds that it is possible to distinguish between a dl racemate and a conglomerate of d and / crystals by use of IR and/or Raman spectroscopy, even when it may not be possible to make such a distinction by physical or visual means. 

Bock, M., Depke, G., Egner, U., Muller-Fahrnow, A. and Winter, G. (1994). Detection and characterization of polymorphic modifications of the anxiolytic drug Abecarnil. Tetrahedron, 50, 13125-34. [160]... 

Brittain, H. G. (1999c). Application of the phase rule to the characterization of polymorphic systems. In Drugs in the pharmaceutical sciences (ed. J. Sarbrick), Vol. 95 Polymorphism in pharmaceutical solids (ed. H. G. Brittain), pp. 35-72. Marcel Dekker, New York. [30]... 

Harper, J. K. and Grant, D. M. (2000). Solid state C-13 chemical shift tensors in terpenes. 3. Structural characterization of polymorphous verbenol. J. Am. Chem. Soc., 122, 3708-14. 

The thermal analysis methods reported for the characterization of ezeti-mibe were conducted using thermogravimetric analysis (TGA), differential thermal analysis (DTA), and differential scanning calorimetry (DSC). As detailed in Table 3.2, the TGA and DSC characterization of polymorphs of ezefimibe was reported in a patent publication. 

Of all the methods available for the physical characterization of solid materials, it is generally agreed that crystallography, microscopy, thermal analysis, solubility studies, vibrational spectroscopy, and nuclear magnetic resonance are the most useful for characterization of polymorphs and solvates. However, it cannot be overemphasized that the defining criterion for the existence of polymorphic types must always be a non-equivalence of crystal structures. For compounds of pharmaceutical interest, this ordinarily implies that a non-equivalent X-ray powder diffraction pattern is observed for each suspected polymorphic variation. All other methodologies must be considered as sources of supporting and ancillary information, but cannot be taken as definitive proof for the existence of polymorphism by themselves. 

An extremely important tool for the characterization of polymorphs and solvates is that of microscopy, since the observable habits of differing crystal structures must necessarily be different and therefore useful for the characterization of such systems. Clearly, visual observation of materials suspected of being... 

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