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

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182 M.R. Caira Measurement of the interfacial angles of a crystal section both microscopically and using an optical goniometer yielded values of 120 ± 1°. Thus, a new polymorph belonging to either of the trigonal or hexagonal systems was unequivocally identified. This was confirmed by subsequent X-ray photography which revealed a trigonal space group [102]. Owing to its vast depth of field, scanning electron microscopy (SEM) is widely used for observing the texture, morphology and surface features of both powders and large single crystals of polymorphs. The high vacuum used for sample observation precludes study of pseudopolymorphs containing volatile solvents but SEM micrographs of polymorphs are useful for purposes of identification provided that crystallization conditions and SEM sampling methods are carefully controlled. Crystal density is an important technological parameter since it affects the flow properties of bulk solids. Due to the different bulk densities of polymorphs and their abilities to retain solvent, different isolation strategies are required in industry [24]. Furthermore, if mixtures of different solid phases are present in a sample (e.g. in a powdered pharmaceutical formulation), differences in component densities may lead to a heterogeneous product during processing due to phase segregation. Distinguishing polymorphs of the same compound by density measurement (determined by flotation or gas displacement pycnometry) is difficult because, as shown in Fig. 6b, differences in the densities of such species seldom exceed 5% and the experimental error of routine measurements is typically 2%. However, the latter can be reduced if special precautions are taken during flotation measurements, especially with regard to eliminating occluded air. Under these conditions, anomalously high or low measured densities may be useful indicators of the presence of pseudopolymorphs. Thus, e.g., a measured density of 1.30(1) g cm –3 for a crystal of doxylamine succinate obtained from ethyl acetate was sufficiently different from that of polymorphic Form I (Ç =1.21(1) g cm –3 ) to indicate the presence of a pseudopolymorph. Subsequent X-ray analysis showed the crystal to have the unexpected composition (doxylamine succinate) 2 ◊ (succinic acid) [103]. Among the thermal methods of analysis, thermogravimetric analysis (TGA), differential thermal analysis (DTA) and differential scanning calorimetry (DSC) have been used extensively to quantify thermal events accompanying controlled heating of polymorphs and pseudopolymorphs [18, 23]. Figure 7 shows combined TGA and DSC traces for two pseudopolymorphs of nitrofurantoin [61], containing respectively N,N-dimethylformamide (DMF) and dimethylsulphoxide (DMSO). In TGA, the sample (~ 5–10 mg) is heated at a predetermined rate and the weight is recorded as a function of temperature. This technique cannot distinguish polymorphs of a given organic compound, but for pseudopolymorphs which lose their included solvents prior to melting or decomposition of the parent (“host”) compound, the percentage weight loss may be accurately measured and used to calculate the stoichiometry of the pseudopolymorph. Data recorded from the TGA traces shown in Fig. 7 indicated a nitrofurantoin : DMF stoichiometric ratio of 1 : 1 and a nitrofurantoin : DMSO ratio of 2 : 1. A TGA trace may reflect simple one-step weight loss of included solvent or more complex
Crystalline Polymorphism of Organic Compounds 183 Heat Flow / mW Heat Flow / mW a b Temperature / °C Temperature / °C Fig. 7 a, b. Combined TGA-DSC traces for pseudopolymorphs of nitrofurantoin containing: a DMF; b DMSO (Reprnted with permission from [61], copyright 1996, Gordon and Breach Publishers) multi-step weight losses. Coupled with TGA, evolved gas analysis (EGA) using IR or mass spectrometry is an important means of identifying gaseous products [18] and may be used to quantify both the pyrolysis products from thermal degradation of polymorphs as well as solvents released from desolvation of pseudopolymorphs. Another important application of the TGA method is the determination of the activation energy for desolvation of a pseudopolymorph from traces recorded at varying heating rates [104]. Its application to pseudopolymorphs of succinylsulfathiazole [105] and tenoxicam [106], and to inclusion compounds of synthetic hosts [50] have recently been described. In DTA, the sample temperature (T s) is compared with that of a reference compound (T r) as a function of increasing temperature. The resulting plot of DT (=T s–T r) vs T may display endothermic peaks corresponding to desolvation (for pseudopolymorphs) or fusion (for polymorphs) and exothermic peaks representing recrystallization or decomposition processes. In the related DSC technique, the difference in energy inputs into a compound and a reference substance is plotted against T during a controlled temperature programme. In Weight / % Weight / %
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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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8 J.P. Glusker other induced, will
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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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34 J.P. Glusker structures of magne
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36 J.P. Glusker b a Fig. 28 a, b. A
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40 J.P. Glusker 7.1 Descriptions of
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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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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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