Particular polymorph

The obtainment of a particular polymorph, under given crystallization conditions, corresponds in most cases to the one which is thermodynamically more stable. In some cases, however, (when more than one minimum of free energy is available) the form which is obained is simply that one produced more rapidly (indicated as kinetically favored). 

The examples of this section summarise the recent application of the solvent-drop grinding approach to solid-state cocrystal preparation. The approach has been shown in certain instances to provide for either acceleration of CO crystallisation kinetics or selection of a particular polymorph via solid-state grinding. The approach is attractive, as it appears to incorporate some of the beneficial aspects of solvent participation while maintaining an essentially green, eco-friendly process. 

Magnesium sulfate may be effective in terminating refractory ventricular tachyarrhythmias, particularly polymorphic ventricular tachycardia. DigitaUs-induced arrhythmias are more likely in the presence of magnesium deficiency. Magnesium sulfate can be administered orally, intramuscularly, or, preferably, intravenously,... 

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... 

Cover Figure Raman spectra of two polymorphs of Cimetidine are shown on the cover Cimetidine is a pharmaceutical product that has six polymorphic forms and each form has a distinctive Raman spectrum as shown in Figure 4 25 of Chapter 4 (with permission of Ref 47). The particular polymorphic or crystalline form of a compound can be very important since the bio- availability and patent positions often depend upon the form Raman spectra can be used to easily identify the polymorphic form. 

Also, after determining the temporal distribution of crystallization peaks in a complete isothermal experiment, the melting thermogram of a particular polymorph can be determined. First, the sample is remelted completely, and held to erase its thermal memory. Then, the isothermal crystallization process is repeated, but only up to the time at which the polymorph of interest has completely solidified (exothermic peak fully formed). A heating scan is then performed immediately (Kawamura, 1980, 1981). 

A significant source of false-negative scores stems from DNA samples containing impurities that inhibit PCR amplification. Such samples are readily detected by noting the relative intensities of PCR products in an RAPD pattern other than the particular polymorphism being scored (Fig. 4, lane 9). If bands that are monomorphic throughout a population are weak or absent in an individual sample, it is likely that this sample contains some inhibitory contaminant. Further purification of the sample by any of a number of standard protocols normally corrects this problem. 

With the growing awareness among chemists of the phenomenon of polymorphism its actual occurrence in any particular system may not be as great a surprise as a generation or two ago. The predicted existence of any particular polymorphic structure for a single compound, the conditions and methods required to obtain it, and the properties it will exhibit are still problems that will challenge researchers for many years to come. ... 

A total of 163 clusters were obtained, where a cluster is a group of polymorphic crystal structures of the same compound. Of the 163 clusters, 147 contained two structures, 13 had three, and three had four structures. The authors note that these numbers are first evidence of the high frequency of polymorphism in organic crystals , although the number of clusters is a relatively small percentage of the entries in the database. The number of these clusters is probably more a measure of certain authors interest in the particular polymorphic system in question. A more realistic measure (although certainly not precise because of the caveats mentioned above) of the frequency of polymorphism in these compounds wouid be the fraction of compounds in the database known to be polymorphic, whether multiple structures have been done or not. 

As polymorphism has become an increasingly important factor in the commercial aspects of many solid materials, the number of patents relating to the discovery and use of particular polymorphic forms has increased. This is particularly important for pharmaceuticals, pigments and dyes, and explosive materials, which are discussed in Chapters 7-9. Some examples of the role of polymorphism in patent litigation are described in detail in Chapter 10. The patent literature is readily searchable using terms such as crystal form , polymorph etc., and since polymorphic behaviour often forms the basis of a patent (as opposed to many journal publications, where it may be peripheral to the main point of the paper) instances of polymorphism are relatively straightforward to locate. 

None of these rules is foolproof. However, they are useful guidelines, and the combination of relatively simple techniques can often be used to get a good estimate of the relative stability of polymorphs under a variety of conditions, information which is useful in understanding polymorphic systems, the properties of different polymorphs and the methods to be used to selectively obtain any particular polymorph (see Section 3.2). As noted above, much of that information can be included in the energy/temperature diagram, and the actual preparation of that diagram from experimentally determined quantities is described in Sections 4.2 and 4.3 following the description of the techniques used to obtain those physical data. 

By making use of Volmer s equations some attempts have been made by Becker and Doring (1935), Stranski and Totomanov (1933), and Davey (1993) to explain the Rule in kinetic terms. In doing this, it becomes apparent that the situation is by no means as clear cut as Ostwald might have us believe. Figure 2.11 shows the three possible simultaneous solutions of the nucleation equations which indicate that by careful control of the occurrence domain there may be conditions in which the nucleation rates of two polymorphic forms are equal, and hence their appearance probabilities are nearly equal. Under such conditions we might expect the polymorphs to crystallize concomitantly (see Section 3.3). In other cases, there is a clearer distinction between kinetic and thermodynamic crystallization conditions, and that distinction may be utilized to selectively obtain or prevent the crystallization of a particular polymorph. 

The important point is that the determination of the crystallization conditions for various polymorphic forms need not be a completely random process. The combination of keen thoughtful observation with consideration of all the available crystal structures and thermodynamic information can provide extremely useful guidelines, if not for success, then at the very least for further experiments. Crystallization is almost never a sure-fire procedure, especially when one is trying to selectively produce a particular polymorph, and one that has proven consistently or suddenly elusive. 

It is important to make the distinction between the determination of polymorphic identity and polymorphic purity. The former is essentially a qualitative determination, asking the question, Ts a particular polymorph present in a given sample The latter is a question of quantitative analysis, and it is generally (though not always) assumed that the sample is chemically pure, so the analytical problem to be addressed is the determination of the relative amounts of different polymorphs in the sample. Recalling that different polymorphs are for all intents and purposes different solids, the determination of polymorphic purity is then no different in principle from quantitative determination of the composition of a mixture of solids. Such quantitative determinations comprise one of the traditional activities of analytical chemistry, especially when the materials are different chemical entities. In those cases, a variety of different analytical methods may be employed. In the case of polymorphic mixtures, or the determination of polymorphic purity, the choice of analytical method is considerably more restricted, and X-ray diffraction is one of the most definitive techniques (see e.g. Stowell 2001). 

The kinetics of thermal decomposition of three of the modifications were studied by thermogravimetry, IR spectroscopy and optical and electron microscopy (Nedelko et al. 2000), with the conclusion that the rate increases in the series a > y > s. However, it was found that the results for a particular polymorph also depend upon the morphological features of the crystals as well as their size distribution and mean size. 

Membrane lipids are invariably polymorphic that is, they can exist in a variety of kinds of organized structures, especially when hydrated. The particular polymorphic form that predominates depends not only on the stmcture of the lipid molecule itself and on its degree of hydration, but also on such variables as temperature, pressure, ionic strength and pH (see References 11 and 12 and article Lipids, Phase Transitions of). However, under physiologically relevant conditions, most (but not all) membrane lipids exist in the lamellar or bilayer phase, usually in the lamellar liquid-crystalline phase but sometimes in the lamellar gel phase. It is not surprising, therefore, that the lamellar gel-to-liquid-crystalline or chain-melting phase transition has been the most intensively studied lipid phase transition... 

In humans, genetic studies have shown that particular polymorphisms of the Ds and D4 DA receptors are associated with depressed phenotypes. In studies of CSE concentrations of ho-movanillic acid (HVA), which is a metabolite of DA, lower levels than controls have been reported in some depressed patients. Conversely, depressed individuals with psychotic symptoms have been reported to have increased CSE levels of HVA and DA compared with controls (33). 

The concentration threshold above which crystallization is observed at times shorter than the processing time or desired product shelf-life or GI transit time, is determined by the kinetic stability of supersaturated states and is regulated by the nucleation mechanisms and kinetics. Nucleation phenomena are equally important in the control of micrometric properties and in the selective crystallization of a particular polymorph. 

Systematic names are based on the number of atoms in the molecule, indicated by a multiplicative prefix from Table IV. The prefix mono is only used when the element does not normally occur in a monoatomic state. If the number is large and unknown, as in long chains or large rings, the prefix poly may be used. Where necessary, appropriate prefixes (Table V) may be used to indicate structure. When it is desired to specify a particular polymorph of an element with a defined structure (such as the a-, (3- or y-forms of Sg) the method of Section IR-3.4.4 should be used (see Examples 13-15 in Section IR-3.4.4). 

The attraction force between two neighboring molecules of a solute is determined by the interactions existing in the crystal structure. Consequently, the internal energy (U) of a particular polymorph is equal to the sum of the individual energies of interaction between each pair of neighboring molecules as these are dictated by the details of the crystal structure. At constant pressure (P), the enthalpy (//) of a polymorph is defined as ... 

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