198 Topics in Current Chemistry Editorial Board: A. de Meijere KN ...

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188 M.R. Caira The use of white-light microscopy to identify differently coloured polymorphs was mentioned above. Colour polymorphism may be quantified using UV/vis electronic spectroscopy (diffuse reflectance, fluorescence methods). Colour differences for polymorphs of the same compound may originate from differences in charge transfer interactions or different molecular conformations in the crystals. Pseudopolymorphs may also be distinguished using fluorescence spectroscopy since they may display characteristic absorption maxima as well as fluorescence intensities. Systems which exhibit colour polymorphism have been reviewed [27]. Implicit in the examples cited above to illustrate applications of various analytical methods for studying polymorphism is the definitive role of single crystal X-ray diffraction in providing unequivocal evidence for the very existence of these forms. Different polymorphs of a given compound have, by definition, non-equivalent crystal structures and the method of choice for detecting such non-equivalence is single crystal X-ray analysis. In many instances, the differences between polymorphs are so subtle that they can be distinguished only by this method [79]. This technique goes well beyond merely detecting different forms, providing in addition a wealth of structural information for each species at a level of detail and precision currently unsurpassed by other analytical techniques. Furthermore, as illustrated by several of the examples above, detailed knowledge of the molecular parameters and crystal packing features obtained by this method provides a very reassuring basis for the interpretation of results gleaned from other analytical techniques. For these reasons, much effort is expended by researchers in growing single crystals of polymorphs and pseudopolymorphs with adequate quality for complete X-ray structural elucidation. For routine crystallographic studies of polymorphs or pseudopolymorphs containing small and medium-sized molecules, the methodology of crystal structure determination is well established and the reader is referred to standard monographs on the subject [122, 123]. However, a few points on current routine methodology are worth emphasising in order to place some of the newer developments (to be discussed later) in perspective. Existing standard methods employ single crystals usually no smaller than 0.1–0.5 mm, automated X-ray intensity data-collection (typically with a four-circle diffractometer) and standard crystallographic software packages for data-processing, structure solution and refinement. Room-temperature datacollection is common, despite the gain in structural definition possible with cryostatic devices for cooling the crystal. Low-temperature analyses are sometimes carried out on pseudopolymorphs in which the included solvent molecules tend to have excessive thermal motion or are disordered at room-temperature. The advent of fast detectors (organic scintillators, image-plates, multiwire area detectors) and more powerful structure determination packages has greatly increased the speed with which crystal structures can be solved and refined [124]. In the absence of single crystals of suspected polymorphic forms, X-ray powder diffraction (XDP) serves as the primary test for non-equivalence of crystal structures, the XDP pattern of such a species being unique [25]. However, since
Crystalline Polymorphism of Organic Compounds 189 sample preparation involves grinding in a mortar to an average particle size £ 100 mm to minimise preferred orientation effects, the possibility of a pressure-induced phase transformation during sample preparation must be considered. The XRD pattern of an unground sample of the material may be checked as a precautionary measure. Patterns are generally recorded on samples with mass range 200–500 mg using automatic diffractometers with strip chart output. The method is generally non-destructive, allowing recovery of the sample. Film methods (e.g. the Debye-Scherrer technique) require a few mg of material only and are still frequently used when only small amounts of polymorphic forms can be isolated. According to the guidelines specified in the US Pharmacopeia [125], agreement between a sample and a reference standard should be within the calibrated precision of the diffractometer for diffraction angle (typically a reproducibility of ± 0.10–0.20° in 2q) with permissible relative intensity variations of up to 20%. A recent analytical study stresses the growing need, prompted partly by legislatory requirements, to differentiate polymorphs and to quantify polymorphic mixtures in pharmaceutical production [126]. The compounds benzil and benzoic acid were chosen as a model system for the development of an XRD protocol which could be extended to the quantification of mixtures of drug polymorphs. The study involved the evaluation of sample thickness, the determination of preferred orientation effects, optimum milling conditions and the construction of diffraction intensity-composition calibration curves for mixtures of benzil and benzoic acid. Since the composition of such mixtures can be accurately determined by an independent method, namely HPLC, validation of the quantification of mixtures by the XRD protocol was possible. It was concluded that the protocol is accurate for the model system to within a few percent. It is desirable that the general validity of the approach suggested be tested on a range of real polymorphic systems. The information contained in an XRD pattern of a powdered material is a significantly condensed version of that obtained by single crystal X-ray analysis and it is a routine matter to reconstruct the XRD pattern of a polymorph by computation, using as input the space group data, refined atomic coordinates, atomic thermal parameters and unit cell data which have been obtained from a single crystal X-ray study of that species. Some years ago, it was recommended [127] that computation of the XRD pattern of a new polymorph should always be carried out if single crystal data become available. The computed pattern, being free of experimental aberrations, serves as the best reference pattern for the polymorph in question. We have followed this practice and can strongly endorse its usefulness, not only for the purpose of identifying the polymorphic form present in a newly crystallized sample, but also for assessing the polymorphic purity of such a sample. Figure 11 shows the experimental XRD pattern of a polymorph of the non-steroidal anti-inflammatory drug tenoxicam and, for comparison, the computed pattern based on the single crystal X-ray data [106]. The level of agreement in peak positions attests to the polymorphic purity of the sample (no extraneous peaks being evident in the experimental pattern) while the discrepancies in corresponding peak intensities indicate some degree of preferred orientation in the sample. Finally, since the sample was a powder derived
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198 Topics in Current Chemistry Edi
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Design of Organic Solids Volume Edi
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Volume Editors Prof. Dr. Edwin Webe
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VIII preface tion at an amazing lev
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Contents of Volume 196 Carbon Rich
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2 J.P. Glusker 5 Interactions of Pl
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4 J.P. Glusker Perturbations to the
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6 J.P. Glusker 2.1 Sources of Cryst
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10 J.P. Glusker The forces here hav
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12 J.P. Glusker lographic structure
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14 J.P. Glusker a c Fig. 6 a - c. D
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16 J.P. Glusker hydrogen bond H◊
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18 J.P. Glusker Fig. 9. Citric acid
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20 J.P. Glusker peptide plane and a
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22 J.P. Glusker 4.5 F◊◊◊H Int
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26 J.P. Glusker Fig. 17. The packin
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28 J.P. Glusker bind to a metal ion
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30 J.P. Glusker As for carboxylate
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32 J.P. Glusker Fig. 24. The magnes
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36 J.P. Glusker b a Fig. 28 a, b. A
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42 J.P. Glusker Fig. 34. Glycine cr
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44 J.P. Glusker bonding capabilitie
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48 J.P. Glusker d Fig. 37 d. The ch
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50 J.P. Glusker Fig. 39. Hydrogen-b
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52 J.P. Glusker 72, 104], but other
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54 J.P. Glusker 23. Cody V, Murray-
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56 J.P. Glusker: Directional Aspect
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58 A. Nangia · G.R. Desiraju 7 Sup
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68 A. Nangia · G.R. Desiraju Fig.
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70 A. Nangia · G.R. Desiraju -NH 2
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132 Y. Aoyama 4 Catalysis . . . . .
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134 Y. Aoyama 2.2 Symmetry-Controll
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